CN107108555B - 三环阻转异构体化合物 - Google Patents
三环阻转异构体化合物 Download PDFInfo
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- CN107108555B CN107108555B CN201580070254.3A CN201580070254A CN107108555B CN 107108555 B CN107108555 B CN 107108555B CN 201580070254 A CN201580070254 A CN 201580070254A CN 107108555 B CN107108555 B CN 107108555B
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- carbazole
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- carboxamide
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Abstract
Description
相关申请的交叉引用
本申请要求对于2014年10月24日提交的美国序列号62/068,244的权益,将其全部并入本申请。
技术领域
本发明大体涉及可用作激酶调节剂(包括调节Bruton酪氨酸激酶(Btk)和其它Tec家族激酶诸如Itk)的三环化合物。本申请提供了三环化合物、包含所述化合物的组合物和它们的使用方法。本发明还涉及含有可用于治疗与激酶调节相关的病症的至少一种本发明化合物的药物组合物以及在哺乳动物中抑制激酶(包括Btk和其它Tec家族激酶诸如Itk)的活性的方法。
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。Btk是酪氨酸激酶的Tec家族的成员,并且是早期B细胞发育以及成熟B细胞活化、信号传导和存活的调节剂。
经B细胞受体(BCR)的B细胞信号传导可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介导的信号传导能造成失调的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相关的血内γ球蛋白缺乏症(X-linkedagammaglobulinaemia,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。
已经在缺乏Btk的小鼠模型中建立了有关Btk在变应性病症和/或自身免疫性疾病和/或炎性疾病中的作用的证据。例如,已经在系统性红斑狼疮(SLE)的标准鼠类临床前模型中显示出Btk缺乏导致疾病进展的显著改善。此外,Btk缺陷小鼠还可抵抗形成胶原诱发性关节炎并可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药物诸如代表治疗许多自身免疫疾病和/或炎性疾病的重要途径。由于Btk在B细胞活化中的作用,Btk的抑制剂可用作B细胞介导的致病性活动(诸如产生自身抗体)的抑制剂。
Btk也在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和其它炎性细胞因子的释放)有关,并且人体内Btk缺陷与由活化的单核细胞产生TNF-α大大减少有关。
由此,Btk活性的抑制可用于治疗变应性病症和/或自身免疫性和/或炎性疾病,这些疾病包括但不限于:SLE、类风湿性关节炎、多发性血管炎、特发性血小板减少性紫癜(ITP)、重症肌无力、变应性鼻炎、多发性硬化(MS)、移植排斥、I型糖尿病、膜性肾炎、炎性肠病、自身免疫性溶血性贫血、自身免疫性甲状腺炎、冷凝集素和温凝集素疾病、埃文斯综合征(Evan’s syndrome)、溶血性尿毒症综合征/血栓性血小板减少性紫癜(HUS/TTP)、结节病、斯耶格伦综合征(Sjogren’s syndrome)、外周神经病(例如格林-巴利综合征(Guillain-Barre syndrome))、寻常型天疱疮和哮喘。
此外,已报道Btk在某些B细胞癌症中对控制B细胞存活起作用。例如,已显示Btk对于BCR-Abl阳性B细胞急性淋巴细胞白血病细胞的存活是重要的。因此,Btk活性的抑制可用于治疗B细胞淋巴瘤和白血病。
通过与酶反应以形成共价键来抑制酶的化合物相比于不形成此类共价键的化合物可提供优势。(参见例如Liu,Q.et al.,Chem.Biol.,20:146(2013);Barf,T.et al.,J.Med.Chem.,55:6243(2012);Kalgutkar,A.et al.,Expert Opin.Drug Discov.,7:561(2012);and Garuti,L.et al.,Curr.Med.Chem.,18:2981(2011);以及其中引用的参考文献)。不形成共价键的化合物可从酶中解离出来,使酶从由其结合产生的抑制中释放。此类可逆抑制可能需要相对高且连续浓度的抑制性化合物以通过抑制剂驱使结合平衡达到足够的酶占据以实现有效的酶抑制。较高的化合物浓度可能需要向需要此类抑制的哺乳动物施用较高剂量的化合物,并且在较高浓度下,抑制剂可能由于抑制其它非靶向酶而具有不期望的作用。此类脱靶抑制可能包括毒性。另外,可能需要更频繁的给药,因为抑制性化合物在从靶标酶解离后可通过代谢和/或消除从身体中除去,降低可用于实现靶标酶抑制的浓度。
相反,与其靶标酶形成共价键的抑制剂不可逆地抑制酶。不可逆抑制将由抑制剂的缓慢或可忽略的解离产生,因为此类解离将需要破坏共价键。如果此类共价抑制剂对其靶标酶的亲和力相对于其它脱靶酶的亲和力足够大,则显著较低浓度的抑制剂可导致相对于可逆性抑制所需的浓度的有用抑制。较低的浓度可降低不期望的脱靶抑制和潜在毒性的可能性。此外,由于共价抑制剂可基本上不可逆地与靶标酶结合,所以随着通过代谢和/或消除将非结合的抑制剂从身体中除去,即使还保持有用的酶抑制,抑制剂的游离(非结合)浓度可变得非常低。这可减少不期望作用的可能性。另外,由于可不可逆地抑制酶,因此可能需要较少频率的给药以实现有用的抑制作用。
某些反应性官能团可连接至对靶标酶具有良好亲和力的化合物,这将允许与靶标酶中的官能团形成共价键。例如,连接至吸电子基团(诸如酮、酰胺、砜、磺酰胺)或吸电子杂环(诸如吡啶基)的亲电基团(诸如乙烯基或乙炔基)可与存在于靶标酶中的亲核基团(诸如半胱氨酸残基的硫醇或硫醇酯基团)反应,以形成共价键。此类反应在正常的生理条件下基本上是不可逆的。为了实现此类反应,抑制剂化合物必须与靶标酶结合,并且所连接的亲电子基团以正确的空间取向存在,以允许与进攻亲核试剂有良好的相互作用。如果取向不正确,则共价键可能不容易形成,并且可能无法实现期望的不可逆抑制。在这种情况下,所述化合物将表现为可逆性抑制剂,并且不可实现不可逆抑制的益处。此外,如果结合的抑制剂上亲电试剂的取向不适于与靶标酶的亲核基团反应,则抑制剂将能够从靶标酶解离,导致较高的抑制剂浓度及反应性亲电子基团可与其它非靶标亲核试剂反应并引起不期望作用(诸如毒性)的更大可能性。
美国专利8,084,620和8,685,969公开了三环甲酰胺化合物,其可用作激酶抑制剂,包括Btk和其它Tec家族激酶的调节。
鉴于预期受益于涉及对蛋白激酶进行调节的治疗的多种病症,非常明显的是,能够调节蛋白激酶诸如Btk的新化合物和使用这些化合物的方法应当向众多患者提供实质上的治疗益处。
仍然需要用作Btk抑制剂的化合物。此外,仍然需要用作Btk抑制剂的化合物,其可在较低剂量施用或在较低浓度是有效的。另外,仍然需要具有组合作为Btk抑制剂的改善效力和Ramos FLIPR测定中改善效力的化合物。
申请人已经发现具有作为Btk抑制剂有效化合物。本申请提供可用作药物的这些化合物,其具有对于它们的成药性重要的期望稳定性、生物利用度、治疗指数和毒性值。
发明内容
本发明提供用作Btk抑制剂并且用于治疗增殖性疾病、变应性疾病、自身免疫性疾病和炎性疾病的三环化合物,包括它们的前药。
本发明还提供药物组合物,所述药物组合物包含至少一种式(I)化合物和药学上可接受的载体。
本发明还提供抑制Btk活性的方法,所述方法包括向有此需要的哺乳动物施用至少一种式(I)化合物。
本发明还提供治疗变应性病症和/或自身免疫性疾病和炎性疾病的方法,所述方法包括向有此需要的哺乳动物施用至少一种式(I)化合物。
本发明还提供治疗增殖性疾病诸如癌症的方法,所述方法包括向有此需要的哺乳动物施用至少一种式(I)化合物。
本发明还提供治疗与Btk活性相关的疾病并病症的方法,所述方法包括向有此需要的哺乳动物施用至少一种式(I)化合物。
本发明还提供用于制备式(I)化合物的方法和中间体。
本发明还提供式(I)化合物,其用于疗法中。
本发明还提供式(I)化合物在制备用于治疗或预防Btk相关病症的药物中的用途,所述Btk相关病症诸如增殖性疾病、变应性疾病、自身免疫性疾病和炎性疾病。
本发明还提供式(I)化合物或在制备用于治疗癌症的药物中的用途。
式(I)化合物和包含式(I)化合物的组合物可用于治疗、预防或治愈各种Btk相关病症。包含这些化合物的药物组合物可用于治疗、预防或减慢各种治疗领域中疾病或病症的进展,所述Btk相关病症诸如增殖性疾病、变应性疾病、自身免疫性疾病和炎性疾病。
随着公开内容的继续,本发明的这些和其它特征将以扩展形式详述。
附图简述
通过参考下文所述附图举例说明本发明。
图1示出实施例5(左)、实施例12(中)和实施例8(右)的绝对立体化学。
具体实施方式
本发明的第一方面提供式(I)化合物或其盐,
其中:
两条虚线表示两个单键或两个双键;且R1b如果所述两条虚线为两个单键则仅存在;
X为:
(i)当两条虚线表示两个单键时,CR2aR2b or NR2b;或
(ii)当两条虚线表示两个双键时,CR2a或N;
Q为:
R1a为H、-CN、-CF3、-CH3、-CR6aR6bOH、-CH2CH2OH、-CH(OH)CH2OH、-CH2CH2F、-NHR7或-C(O)NR8aR8b;
R1b,当存在时,为H或-CH3,条件是如果R1a为H,则R1b也为H;
R2a为H、F或Cl,条件是如果R1a不为H,则R2a为H;
R2b,当存在时,与R2a相同;
R3为F、Cl、-CN或-CH3;
R4为H、F、Cl、-OCH3或-OCF3;
R5为-CN或-C(O)CH=CH2;
R6a和R6b独立地为H或-CH3;
R7为C1-4烷基;且
R8a和R8b独立地为H或-CH3.
本发明的第二方面提供式(II)化合物或其盐,
其中:
两条虚线表示两个单键或两个双键;且如果所述两条虚线为两个单键则仅存在R1b和R2b;
Q为:
R1a为H、-CN、-CF3、-CH3、-CR6aR6bOH、-CH(OH)CH2OH、-NHR7或-C(O)NR8aR8b;
R1b,当存在时,为H或-CH3,条件是如果R1a为H,则R1b也为H;
R2a为H或F,条件是如果R1a不为H,则R2a为H;
R2b,当存在时,与R2a相同;
R3为F、Cl、-CN或-CH3;
R4为H、F、Cl、-OCH3或-OCF3;
R5为-C(O)CH=CH2;
R6a和R6b独立地为H或-CH3;
R7为C1-4烷基;且
R8a和R8b独立地为H或-CH3。
一个实施方案提供式(I)化合物或其盐,其中所述两条虚线表示两个双键且X为CR2a。该实施方案的化合物具有式(Ia)的结构:
其中Q、R1a、R2a和R3如第一方面或第二方面中所定义。
一个实施方案提供式(I)化合物或其盐,其中所述两条虚线表示两个单键且X为CR2aR2b。该实施方案的化合物具有式(Ib)的结构:
其中Q、R1a、R1b、R2a、R2b和R3如第一方面或第二方面中所定义。
一个实施方案提供式(I)化合物或其盐,其中所述两条虚线表示两个双键且X为N。该实施方案的化合物具有式(Ic)的结构:
其中Q、R1a和R3如第一方面中所定义。
一个实施方案提供式(I)化合物或其盐,其中所述两条虚线表示两个单键且X为NR2a。该实施方案的化合物具有式(Id)的结构:
其中Q、R1a、R1b、R2a和R3如第一方面中所定义。
由式(Ib)表示的四氢咔唑化合物和由式(Id)表示的化合物,其中R1a不为H,在连接至R1a的碳原子上也具有手性中心,并因此可在该手性中心处以S-和R-异构体存在。这些异构体是可分离和稳定的。一个实施方案提供具有作为S-异构体的连接至R1a的碳手性中心的式(Ib)化合物。一个实施方案提供此类具有作为R-异构体的连接至R1a的碳手性中心的式(Ib)化合物。另一实施方案提供具有作为S-异构体的连接至R1a的碳手性中心的式(Id)化合物。另一实施方案提供此类具有作为R-异构体的连接至R1a的碳手性中心的式(Id)化合物。
阻转异构体是由单键轴的受阻旋转产生的立体异构体,其中旋转壁垒足够高,以允许单个旋转异构体的分离。(LaPlante et al.,J.Med.Chem.,54:7005(2011))。式(I)化合物,其中R3不为氢,且Q为取代有除氢以外的R4的苯基、经取代的1,2,3,4-四氢异喹啉-5-基、经取代的3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基、2,3,4,5-四氢[b][1,4]氧氮杂-9-基或经取代的异二氢吲哚-4-基,在三环四氢咔唑/咔唑与基团Q组之间的键处具有手性轴(stereogenic axis)。由于在通过该键上连接的环上的取代的不对称性质,并且由于由空间位阻引起的该键的受限旋转,此类式(I)化合物可形成旋转异构体。如果旋转能垒足够高,则围绕该键的受阻旋转以足够慢的速率发生,以允许分离作为不同化合物的分开的阻转异构体。因此,这些式(I)化合物可形成两种旋转异构体,所述旋转异构体在某些情况下,诸如在手性固定相上的色谱,可分离成单独阻转异构体。此类式(I)化合物可作为两种阻转异构体的混合物或作为单一阻转异构体提供。发现此类式(I)化合物在环境和生理温度在溶液中是可分离和稳定的。阻转异构体的绝对空间结构可通过单晶x射线晶体学来确定。这些式(I)化合物可作为单独阻转异构体或作为包含任意比例的式(I)的两种阻转异构体的混合物提供。
一个实施方案提供式(I)化合物或其盐,其中仅提供一种阻转异构体,或者其中仅提供一种与少量其它阻转异构体混合的阻转异构体。如果未归属绝对构型,则在特定条件下在手性固定相上进行色谱期间,所提供的阻转异构体可通过相对于另一阻转异构体的洗脱顺序来定义。
式(I)化合物为阻转异构体,其中可提供基本上不含其互补阻转异构体的每种式(I)的阻转异构体化合物。本申请使用的“基本上不含”是指提供具有至少95%阻转异构体纯度,优选至少99%阻转异构体纯度,更优选至少99.5%阻转异构体纯度的式(I)化合物。
一个实施方案提供式(I)、式(Ia)或式(Ib)化合物或其盐,其中R1a为H、-CF3或-C(CH3)2OH;R1b为H;R2a为H或F,条件是如果R1a不为H,则R2a为H;R2b,当存在时,与R2a相同;R3为F;且R4为H;R5为-C(O)CH=CH2;且Q在第一方面中定义。
一个实施方案提供式(I)、式(Ia)、式(Ib)化合物或其盐,其中R1a为H、-CN、-CF3、-CR6aR6bOH或-NHR7;R2a为H;R3为F或Cl;R4为H、F、Cl或-OCH3;R5为-C(O)CH=CH2;R6a为H或-CH3;R6b为H或-CH3;R7为C2-3烷基;且Q在第一方面中定义。
一个实施方案提供式(I)、式(Ia)或式(Ib)化合物或其盐,其中Q为:
且R1a、R1b、R2a、R2b、R3、R4和R5在第二方面中定义。该实施方案包括化合物,其中R1a为H或-CF3和R3为F。该实施方案还包括式(Ia)化合物,其中R1a为H或-CF3;R2a为H;R3为F;且R4为H。
一个实施方案提供式(I)、式(Ia)或式(Ib)化合物或其盐,其中Q为且R1a、R1b、R2a、R2b、R3、R4和R5在第二方面中定义。该实施方案包括化合物,其中R1a为H或-CF3和R3为F。该实施方案还包括式(Ia)化合物,其中R1a为H或-CF3;R2a为H;R3为F;且R4为H。
一个实施方案提供式(Ib)化合物或其盐,其中Q为R1a为H、-CH3、-CF3、-CR6aR6bOH或-C(O)NR8aR8b;R1b为H;R2a为H或F,条件是如果R1a不为H,则R2a为H;R2b为H或F,条件是如果R2a和R2b相同;R3为F或Cl;R4为H、F、Cl或-OCH3;且R8a和R8b各自为CH3。
一个实施方案提供式(I)、式(Ia)或式(Ib)化合物或其盐,其中Q为R1a为H、-CF3或-C(CH3)2OH;且R1b、R2a、R2b、R3、R4和R5在第二方面中定义。该实施方案还包括化合物,其中R3为F和R4为H。
一个实施方案提供式(I)、式(Ic)或式(Id)化合物或其盐,其中Q为R1a为H、-CF3或-C(CH3)2OH;且R1b、R2b、R3、R4和R5如第一方面中所定义。该实施方案包括化合物,其中R3为F或Cl;且R4为H。还包括化合物,其中R2b为H。
一个实施方案提供式(I)、式(Ia)、式(Ib)、式(Ic)或式(Id)化合物或其盐,其中R3为F、Cl或-CN;且R1a、R1b、R2a、R2b、R4、R5和Q如第一方面中所定义。该实施方案包括化合物,其中R3为F或-CN。该实施方案还包括化合物,其中R3为-CN。
一个实施方案提供式(I)、式(Ia)、式(Ib)、式(Ic)或式(Id)化合物或其盐,其中R3为F或Cl;且R1a、R1b、R2a、R2b、R4、R5和Q如第一方面中所定义。该实施方案包括化合物,其中R3为F。该实施方案还包括化合物,其中R3为Cl。
一个实施方案提供式(I)、式(Ia)、式(Ib)、式(Ic)或式(Id)化合物或其盐,其中R3为Cl、-CN或-CH3;且R1a、R1b、R2a、R2b、R4、R5和Q如第一方面中所定义。该实施方案包括化合物,其中R3为-CN或-CH3。该实施方案还包括化合物,其中R3为-CH3。
一个实施方案提供式(I)、式(Ia)、式(Ib)、式(Ic)或式(Id)化合物或其盐,其中R5为-C(O)CH=CH2;且R1a、R1b、R2a、R2b、R3、R4和Q如第一方面中所定义。该实施方案包括化合物,其中R3为F或-Cl。还包括化合物,其中X为CR2aR2b或CR2a。
一个实施方案提供式(I)、式(Ia)、式(Ib)、式(Ic)或式(Id)化合物或其盐,其中R5为-CN;且R1a、R1b、R2a、R2b、R3、R4、R5和Q如第一方面中所定义。该实施方案包括化合物,其中R3为F或-Cl。还包括化合物,其中X为CR2aR2b或CR2a。
一个实施方案提供式(I)、式(Ia)、式(Ib)、式(Ic)或式(Id)化合物或其盐,其中R1a为-CN、-CF3、-CH3、-CR6aR6bOH、-CH2CH2OH、-CH(OH)CH2OH、-CH2CH2F、-NHR7或-C(O)NR8aR8b;且R1b、R2a、R2b、R3、R4、R5、R6a、R6b、R7、R8a、R8b和Q如第一方面中所定义。该实施方案包括化合物,其中R1a为-CN、-CF3或-CH3。该实施方案还包括化合物,其中R1a为-C(CH3)2OH、-CH2CH2OH、-CH(OH)CH2OH、-CH2CH2F或-C(O)N(CH3)2。
一个实施方案提供式(I)化合物或其盐,其中所述化合物为(RS)-5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3,3,6-三氟-2,3,4,9-四氢-1H-咔唑-8-甲酰胺(1);(RS)-4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-9H-咔唑-1-甲酰胺(2);(RS)-4-(4-丙烯酰基-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺(3);(RS)-4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺(4);4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-9H-咔唑-1-甲酰胺,单一对映异构体(5);5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3,3,6-三氟-2,3,4,9-四氢-1H-咔唑-8-甲酰胺,单一对映异构体(6);4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺,单一对映异构体(7);4-(4-丙烯酰基-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺,单一对映异构体(8);5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(S)-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺,单一非对映异构体(9);5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺,单一纯手性非对映异构体(10和11);4-(5-丙烯酰基-2,3,4,5-四氢苯并[b][1,4]氧氮杂-9-基)-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺,单一对映异构阻转异构体(12);(RS)-4-(4-丙烯酰基-3,4-二氢-2H-苯并[b][1,4]噻嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺(13);4-(4-丙烯酰基-3,4-二氢-2H-苯并[b][1,4]噻嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺,单一对映异构体(14);4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氯-9H-咔唑-1-甲酰胺(24);4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-7-(2-羟基乙基)-9H-咔唑-1-甲酰胺,外消旋体(25);4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-7-(2-氟乙基)-9H-咔唑-1-甲酰胺,外消旋体(26);4-(2-氰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-7-(2-羟基乙基)-9H-咔唑-1-甲酰胺,外消旋体(27);4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-N7,N7-二甲基-9H-咔唑-1,7-二甲酰胺,外消旋体(28);4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氯-3-氟-9H-咔唑-1-甲酰胺,外消旋体(29);4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-9H-咔唑-1-甲酰胺,外消旋体(30);9-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-8-氟-5H-吡啶并[4,3-b]吲哚-6-甲酰胺,外消旋体(31);5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氯-2,3,4,9-四氢-1H-咔唑-8-甲酰胺,外消旋体(32);或9-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-8-氯-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚-6-甲酰胺,外消旋体(33)。
本发明可在不背离本发明的精神或基本特性下以其它特定形式实施。本发明涵盖本申请所述的本发明的方面和/或实施方案的所有组合。应当理解,本发明的任何和所有实施方案可连同任何其它实施方案一起来描述其它实施方案。还应当理解,实施方案的各个别要素意欲与任何实施方案的任何和所有其它要素组合以描述其它实施方案。
定义
本发明的特征和优势可由本领域普通技术人员在阅读以下详细描述后更容易理解。应当理解,出于清楚原因,上文和下文在各个实施方案的情况下描述的本发明的某些特征也可组合形成单一实施方案。反之,出于简要原因,在单一实施方案的情况下描述的本发明的各种特征也可组合形成其亚组合。本申请确定为示例性或优选的实施方案意欲具说明性而非具限制性。
除非本申请另外特定说明,否则以单数形式提及也可包括复数。例如,“一(a)”和“一(an)”可指一个/种或者一个/种或多个/种。
本申请使用的短语“化合物”是指至少一种化合物。例如,式(I)化合物包括一种式(I)化合物和两种或更多种式(I)化合物。
除非另外指示,否则任何具有不饱和化合价的杂原子被认为具有足以满足这种化合价的氢原子。
本申请所阐述的定义优先于以引用方式并入本申请中的任何专利、专利申请和/或专利申请公开中所阐述的定义。
用于描述本发明的各种术语的定义列于下文中。当术语在整篇说明书(除非其在特定情况下另外限制)中个别地或作为较大基团的部分使用时,这些定义均适用于这种术语。
在整篇说明书中,基团及其取代基可由本领域技术人员选择以提供稳定的部分和化合物。
本申请使用的术语“烷基”是指含有例如1至12个碳原子、1至6个碳原子和1至4个碳原子的支链和直链饱和脂族烃基。烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(例如,正丙基和异丙基)、丁基(例如,正丁基、异丁基、仲丁基和叔丁基)和戊基(例如,正戊基、异戊基、新戊基)、正己基、2-甲基戊基、2-乙基丁基、3-甲基戊基和4-甲基戊基。当数字出现在符号“C”之后的下标中时,下标更特定地定义为具体基团可含有的碳原子数。例如,“C1-4烷基”表示具有1至4个碳原子的直链和支链烷基。
术语“羟基烷基”包括取代有一个或多个羟基的支链和直链饱和烷基。例如,“羟基烷基”包括-CH2OH、-CH2CH2OH和C1-4羟基烷基。
短语“药学上可接受的”在本申请中用于指在正确医学判断范畴内适用于与人类和动物组织接触而无过度毒性、刺激性、变应性响应或其它问题或并发症且与合理效益/风险比率相称的那些化合物、物质、组合物和/或剂型。
式(I)化合物可以无定形固体或结晶固体形式提供。可采用冻干法以无定形固体形式提供式(I)化合物。
某些式(I)化合物可以游离形式(未离子化)或可形成也在本发明范围内的盐。除非另有指明,否则提到本发明化合物应被理解为包括提到游离形式及其盐。术语“盐”表示与无机和/或有机酸形成的酸性盐。药学上可接受的(即无毒的生理学上可接受的)盐是优选的,诸如,例如,其中阳离子并不明显有助于所述盐的毒性或生物活性的盐。然而,其它盐可用于例如在制备过程中可使用的分离或纯化步骤,且因此涵盖在本发明的范围内。式(I)化合物的盐可通过以下方式形成:例如,式(I)化合物与一定量(诸如等量)的酸,在介质(诸如盐在其中析出的介质)中或在含水介质中反应,然后进行冻干。
示例性的酸加成盐包括乙酸盐(诸如与乙酸或三卤代乙酸(例如三氟乙酸)形成的盐)、己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、枸橼酸盐、樟脑酸盐、樟脑磺酸盐、环戊丙酸盐、二葡糖酸盐(digluconate)、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐(glucoheptanoate)、甘油磷酸盐(glycerophosphate)、半硫酸盐、庚酸盐、己酸盐、盐酸盐(与盐酸形成)、氢溴酸盐(与氢溴酸形成)、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐(与马来酸形成)、甲磺酸盐(与甲磺酸形成)、萘-2-磺酸盐、烟酸盐(nicotinate)、硝酸盐、草酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐(诸如与硫酸形成的那些盐)、磺酸盐(诸如本申请提及的那些磺酸盐)、酒石酸盐、硫氰酸盐、甲苯磺酸盐(诸如甲苯磺酸盐)、十一烷酸盐等。
还应当理解,式(I)化合物的溶剂化物(例如,水合物)也在本发明的范围内。术语“溶剂化物”意指式(I)化合物与一个或多个溶剂分子(无论是有机的还是无机的)的物理缔合物。该物理缔合物包括氢键。在一些情况中,该溶剂化物能够分离,例如当一个或多个溶剂分子掺入至结晶固体的晶格中时。“溶剂化物”涵盖溶液相溶剂化物和可分离的溶剂化物。示例性溶剂化物包括水合物、乙醇合物、甲醇合物、异丙醇合物、乙腈溶剂化物和乙酸乙酯溶剂化物。溶剂化的方法是本领域已知的。
各种前药形式式本领域公知的且描述于以下文献中:
a)Wermuth,C.G.et al.,The Practice of Medicinal Chemistry,Chapter 31,Academic Press(1996);
b)Bundgaard,H.ed.,Design of Prodrugs,Elsevier(1985);
c)Bundgaard,H.,Chapter 5,“Design and Application of Prodrugs”,ATextbook of Drug Design and Development,pp.113-191,Krogsgaard-Larsen,P.etal.,eds.,Harwood Academic Publishers(1991);和
d)Testa,B.et al.,Hydrolysis in Drug and Prodrug Metabolism,Wiley-VCH(2003)。
此外,式(I)化合物在制备之后可被分离和纯化,以获得含有等于或大于99重量%的量的式(I)化合物(“基本上纯”)的组合物,然后如本申请所述使用或配制。所述“基本上纯”的式(I)化合物在本申请中也涵盖作为本发明的部分。
“稳定的化合物”和“稳定的结构”是指足够坚固以能经受从反应混合物中分离至有用纯度并配制成有效治疗药物的化合物。本发明意欲包含稳定的化合物。
“治疗有效量”意欲包括单独本发明化合物的量,或要求保护的化合物组合的量,或与有效用作Btk抑制剂或有效治疗或预防自身免疫和/或炎性和/或增殖性疾病状态(诸如多发性硬化和类风湿性关节炎)的其它活性成分组合的本发明化合物的量。
本申请使用的“治疗(treating)”或“处置(treatment)”涵盖治疗哺乳动物(具体为人类)的疾病状态,且包括:(a)预防哺乳动物出现疾病状态,具体为在所述哺乳动物易患所述疾病状态但尚未诊断为患有所述疾病状态时;(b)抑制所述疾病状态,即阻止其发展;和/或(c)减轻所述疾病状态,即引起所述疾病状态消退。
本发明化合物意欲包括本发明化合物中存在的原子的所有同位素。同位素包括原子序数相同但质量数不同的那些原子。作为一般实例且非限制,氢的同位素包括氘(D)和氚(T)。碳的同位素包括13C和14C。通常,同位素标记的本发明化合物可如下制备:通过本领域技术人员已知的常规技术或通过类似于本申请所述方法的方法,使用适当的同位素标记试剂替代以其它方式使用的未经标记的试剂。例如,甲基(-CH3)还包括氘代甲基诸如-CD3。
式(I)化合物可通过任何适用于待治疗的病症的方式施用,所述方式可取决于对部位特异性治疗的需要或待递送的式(I)化合物的量。
本发明还涵盖一类药物组合物,其包含至少一种式(I)化合物和一种或多种无毒的药学上可接受的载体和/或稀释剂和/或佐剂(本申请统称为“载体”物质)和其它活性成分(必要时)。式(I)化合物可通过任何合适途径,优选以适于所述途径的药物组合物形式且以有效用于预期治疗的剂量施用。本发明的化合物和组合物可以含有常规药学上可接受的载体、佐剂和媒介物的剂量单位制剂形式,例如口服、经粘膜或肠胃外(包括血管内、静脉内、腹膜内、皮下、肌内和胸骨内)施用。例如,药物载体可含有甘露糖醇或乳糖和微晶纤维素的混合物。混合物可含有其它组分,诸如润滑剂,例如硬脂酸镁;和崩解剂,诸如交聚维酮(crospovidone)。载体混合物可填充至明胶胶囊中或压制成片剂。药物组合物可以例如口服剂型或输注剂形式施用。
对于口服施用,药物组合物可呈例如片剂、胶囊剂、液体胶囊剂、混悬剂或液体形式。药物组合物优选以含有特定量的活性成分的剂量单位形式制备。例如,药物组合物可以包含约0.1mg至1000mg,优选约0.25mg至250mg,且更优选约0.5mg至100mg范围内的量的活性成分的片剂或胶囊剂形式提供。虽然适用于人类或其它哺乳动物的日剂量可取决于患者的病症和其它因素而广泛变化,但可使用常规方法确定。
本申请涵盖的任何药物组合物可例如经由任何可接受且合适的口服制剂来口服递送。示例性口服制剂包括,但不限于,例如片剂、糖衣锭(troches)、口含锭(lozenges)、水性和油性混悬剂、可分散性散剂或颗粒剂、乳剂、硬胶囊剂和软胶囊剂、液体胶囊剂、糖浆剂和酏剂。意欲口服施用的药物组合物可根据本领域中已知用于制造意欲口服施用的药物组合物的任何方法来制备。为提供药学上适口的制剂,本发明药物组合物可含有至少一种选自以下的试剂:增甜剂、矫味剂、着色剂、缓和剂、抗氧化剂和防腐剂。
片剂可例如通过以下方式制备:使至少一种式(I)化合物与至少一种适用于制备片剂的无毒的药学上可接受的赋形剂混合。示例性赋形剂包括,但不限于,例如,惰性稀释剂,诸如碳酸钙、碳酸钠、乳糖、磷酸钙和磷酸钠;成粒剂和崩解剂,诸如微晶纤维素、交联羧甲纤维素钠、玉米淀粉和海藻酸;粘合剂,诸如淀粉、明胶、聚乙烯-吡咯烷酮和阿拉伯胶(acacia);和润滑剂,诸如硬脂酸镁、硬脂酸和滑石。此外,片剂可无包衣,或通过已知技术包覆包衣以掩蔽味道令人不悦的药物的不良味道,或延迟活性成分在胃肠道中的崩解和吸收,从而使活性成分的作用持续较长时段。示例性水溶性味道掩蔽物质包括,但不限于,羟基丙基甲基纤维素和羟基丙基纤维素。示例性时间延迟物质包括,但不限于,乙基纤维素和乙酸丁酸纤维素。
硬明胶胶囊剂可通过以下方式制备:例如,混合至少一种式(I)化合物与至少一种惰性固体稀释剂,诸如碳酸钙;磷酸钙;和高岭土。
软明胶胶囊剂可通过以下方式制备:例如,混合至少一种式(I)化合物与至少一种水溶性载体,诸如聚乙二醇;和至少一种油介质,诸如花生油、液体石蜡和橄榄油。
水性混悬剂可通过以下方式制备:例如,混合至少一种式(I)化合物与至少一种适用于制备水性混悬剂的赋形剂。适用于制备水性混悬剂的示例性赋形剂包括,但不限于,例如助悬剂,诸如羧甲基纤维素钠、甲基纤维素、羟基丙基甲基纤维素、海藻酸钠、海藻酸、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯胶;分散剂或湿润剂,诸如天然存在的磷脂,例如卵磷脂;环氧烷与脂肪酸的缩合产物,诸如聚氧乙烯硬脂酸酯;环氧乙烷与长链脂族醇的缩合产物,诸如十七亚乙基-氧基鲸蜡醇;环氧乙烷与源自脂肪酸和己糖醇的偏酯的缩合产物,诸如聚氧乙烯山梨糖醇单油酸酯;和环氧乙烷与源自脂肪酸和己糖醇酐的偏酯的缩合产物,诸如聚乙烯脱水山梨糖醇单油酸酯。水性混悬剂还可含有至少一种防腐剂,诸如对羟基苯甲酸乙酯和对羟基苯甲酸正丙酯;至少一种着色剂;至少一种矫味剂;和/或至少一种增甜剂,其包括,但不限于,例如蔗糖、糖精和阿斯巴甜。
油性混悬剂可通过以下方式制备:例如,将至少一种式(I)化合物悬浮于植物油(诸如花生油;橄榄油;芝麻油;和椰子油);或矿物油(诸如液体石蜡)中。油性混悬剂还可含有至少一种增稠剂,诸如蜂蜡;硬石蜡;和鲸蜡醇。为提供适口的油性混悬剂,可将至少一种上文已描述的增甜剂和/或至少一种矫味剂添加至油性混悬剂中。油性混悬剂可进一步含有至少一种防腐剂,其包括,但不限于,例如抗氧化剂,诸如丁基化羟基茴香醚和α-生育酚。
可分散性粉剂和颗粒剂可通过以下方式制备:例如,混合至少一种式(I)化合物与至少一种分散剂和/或湿润剂;至少一种助悬剂;和/或至少一种防腐剂。合适的分散剂、湿润剂和助悬剂如上文已描述。示例性防腐剂包括,但不限于,例如抗氧化剂,例如抗坏血酸。此外,可分散性粉剂和颗粒剂还可含有至少一种赋形剂,其包括,但不限于,例如增甜剂;矫味剂;和着色剂。
至少一种式(I)化合物的乳剂可例如制备成水包油型乳剂。包含式(I)化合物的乳剂的油相可由已知成分以已知方式构成。油相可由(但不限于)例如植物油(诸如橄榄油和花生油);矿物油(诸如液体石蜡);和其混合物提供。虽然所述相可仅包含乳化剂,但其可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。合适的乳化剂包括,但不限于,例如天然存在的磷脂,例如大豆卵磷脂;源自脂肪酸和己糖醇酐的酯或偏酯,诸如脱水山梨糖醇单油酸酯;和偏酯与环氧乙烷的缩合产物,诸如聚氧乙烯脱水山梨糖醇单油酸酯。优选地,亲水性乳化剂连同用作稳定剂的亲脂性乳化剂一起包括在内。还优选包括油和脂肪两者。具有或不具有稳定剂的乳化剂一起组成所谓乳化蜡,且所述蜡与油和脂肪一起组成所谓乳化软膏基质,所述乳化软膏基质形成乳膏剂制剂的油性分散相。乳剂还可含有增甜剂、矫味剂、防腐剂和/或抗氧化剂。适用于本发明制剂中的乳化剂和乳剂稳定剂包括吐温(Tween)60、斯潘(Span)80、鲸蜡硬脂醇(cetostearyl alcohol)、肉豆蔻醇、单硬脂酸甘油酯、月桂基硫酸钠、单独或与蜡一起的二硬脂酸甘油酯,或本领域公知的其它物质。
式(I)化合物还可例如经由任何药学上可接受且合适的可注射形式静脉内、皮下和/或肌内递送。示例性可注射形式包括,但不限于,例如包含可接受的媒介物和溶剂(诸如水、林格溶液(Ringer's solution)和等张氯化钠溶液)的无菌水溶液;无菌水包油型微乳剂;和水性或油性混悬剂。
用于肠胃外施用的制剂可为水性或非水性等张无菌注射溶液剂或混悬剂的形式。这些溶液剂和混悬剂可使用所提及的用于口服施用的制剂的一种或多种载体或稀释剂或通过使用其它合适的分散剂或湿润剂和助悬剂由无菌粉末或颗粒制备。所述化合物可溶于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苄醇、氯化钠、黄蓍胶和/或各种缓冲液中。其它佐剂和施用方式是药物领域中公知的。活性成分还可以作为含合适载体(包括盐水、右旋糖或水)或含环糊精(即)、共溶剂溶解(即丙二醇)或胶束溶解(即吐温80)的组合物形式通过注射施用。
无菌可注射制剂还可为在无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液剂或混悬剂,例如在1,3-丁二醇中的溶液剂。可使用的可接受的媒介物和溶剂为水、林格溶液和等张氯化钠溶液。此外,无菌不挥发性油惯常用作溶剂或悬浮介质。出于此目的,可使用任何温和的不挥发性油,包括合成性单酸甘油酯或二酸甘油酯。此外,在可注射剂制备中可使用脂肪酸,诸如油酸。
无菌可注射水包油型微乳剂可通过以下方式制备:例如,1)至少一种式(I)化合物溶解于油相(诸如大豆油与卵磷脂的混合物)中;2)组合含有式(I)的油相与水和甘油混合物;和3)加工所述组合,形成微乳剂。
无菌水性或油性混悬剂可根据本领域早已已知的方法来制备。例如,无菌水溶液剂或混悬剂可用无毒肠胃外可接受的稀释剂或溶剂来制备,诸如1,3-丁二醇;且无菌油性混悬剂可用无菌无毒可接受的溶剂或悬浮介质来制备,诸如无菌不挥发性油,例如合成性单酸甘油酯或二酸甘油酯;和脂肪酸,诸如油酸。
可用于本发明药物组合物中的药学上可接受的载体、辅料和媒介物包括,但不限于,离子交换剂、氧化铝、硬脂酸铝、卵磷脂;自乳化药物递送系统(SEDDS),诸如d-α-生育酚聚乙二醇1000琥珀酸酯;用于药物剂型中的表面活性剂,诸如吐温、聚乙氧基蓖麻油,诸如表面活性剂(BASF),或其它类似聚合递送基质;血清蛋白,诸如人血清白蛋白;缓冲物质,诸如磷酸盐;甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物;水、盐或电解质,诸如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐;胶态二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。环糊精(诸如α-环糊精、β-环糊精和γ-环糊精)或经化学修饰的衍生物(诸如羟基烷基环糊精,包括2-羟基丙基-环糊精和3-羟基丙基-环糊精)或其它溶解的衍生物也可有利地用于增强本申请所述式的化合物的递送。
本发明的药物活性化合物可根据常规药学方法加工以产生用于向患者(包括人类和其它哺乳动物)施用的医药药剂。药物组合物可经受常规药学操作(诸如杀菌)和/或可含有常规佐剂,诸如防腐剂、稳定剂、湿润剂、乳化剂、缓冲剂等。片剂和丸剂可另外用肠溶包衣制备。所述组合物还可包含佐剂,诸如湿润剂、增甜剂、矫味剂和芳香剂。
所施用的化合物的量和以本发明的化合物和/或组合物治疗疾病病症的施用方案取决于多种因素,包括受试者的年龄、体重、性别、身体状况(medical condition)、疾病的类型、疾病的严重度、施用的途径和频率以及所采用的具体化合物。因此,施用方案可广泛变化,但可使用标准方法来常规地确定。适当的日剂量为约0.001至100mg/kg体重,优选约0.0025mg至约50mg/kg体重且最优选约0.005mg至10mg/kg体重。日剂量可以每日一至四个剂量施用。其它给药时间表包括每周一个剂量或每两周周期一个剂量。
为达治疗目的,通常将本发明的活性化合物与适用于所示施用途径的一种或多种佐剂组合。若口服施用,则可将化合物与乳糖、蔗糖、淀粉粉末、烷酸的纤维素酯、纤维素烷基酯、滑石、硬脂酸、硬脂酸镁、氧化镁、磷酸和硫酸的钠盐和钙盐、明胶、阿拉伯胶、海藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇混合,然后制成片剂或胶囊剂以方便施用。所述胶囊剂或片剂可含有控制释放制剂,如可以活性化合物在羟基丙基甲基纤维素中的分散液的形式提供。
本发明的药物组合物包含式(I)化合物和任选的其它选自任何药学上可接受的载体、佐剂和媒介物的试剂。本发明的替代组合物包含本申请所述的式(I)化合物或其前药和药学上可接受的载体、佐剂或媒介物。
实用性
本发明化合物调节激酶活性,包括调节Btk。其它类型的激酶活性可通过本发明化合物来调节,所述化合物包括,但不限于,Tec家族的激酶,诸如BMX、Btk、ITK、TXK和Tec,及其突变体。
因此,式(I)化合物在以下方面具有实用性:治疗与调节激酶活性相关的病症,以及具体是对Btk活性的选择性抑制。所述病症包括与B细胞介导的疾病,其中细胞因子水平作为胞内信号传导的结果进行调节。
本申请使用的术语“治疗(treating)”或“处置(treatment)”包括响应和预防措施中的一种或两种,例如,用于抑制或者延缓疾病或病症发作,实现症状或病症的完全或部分减轻,和/或缓解、改善、减少或治愈疾病或病症和/或其症状的措施。
鉴于它们作为Btk的选择性抑制剂的活性,式(I)化合物可用于治疗与细胞因子相关的疾病,其包括,但不限于,炎性疾病,诸如克罗恩病和溃疡性结肠炎、哮喘、移植物抗宿主病、慢性阻塞性肺病;自身免疫性疾病,诸如格雷夫斯病、类风湿性关节炎、系统性红斑狼疮、牛皮癣;破坏性骨疾病,诸如骨重吸收疾病、骨关节炎、骨质疏松症、多发性骨髓瘤相关骨疾病;增殖性疾病,诸如急性骨髓性白血病、慢性髓细胞性白血病;血管生成病症,诸如包括实体瘤、眼部新血管形成和婴儿血管瘤的血管生成病症;感染性疾病,诸如败血病、感染性休克和志贺菌病;神经变性疾病,诸如阿尔茨海默病、帕金森病、由创伤性损伤引起的脑缺血或神经变性疾病;肿瘤疾病和病毒疾病,分别诸如转移性黑素瘤、卡波西肉瘤、多发性骨髓瘤,和HIV感染及CMV视网膜炎、AIDS。
更具体地,本发明化合物可治疗的具体病症或疾病包括,但不限于,胰腺炎(急性或慢性)、哮喘、变态反应、成人呼吸窘迫综合征、慢性阻塞性肺病、肾小球肾炎、类风湿性关节炎、系统性红斑狼疮、硬皮病、斯耶格伦综合征、慢性甲状腺炎、格雷夫斯病、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性中性粒细胞减少症、血小板减少症、特应性皮炎、慢性活动性肝炎、重症肌无力、多发性硬化、炎性肠病、溃疡性结肠炎、克罗恩病、牛皮癣、移植物抗宿主病、内毒素诱发的炎性反应、肺结核、动脉粥样硬化、肌肉变性、恶病质、牛皮癣关节炎、莱特尔综合征(Reiter’s syndrome)、痛风、外伤性关节炎、风疹性关节炎、急性滑膜炎、胰腺β细胞疾病;以大量中性粒细胞浸润为特征的疾病;类风湿性脊椎炎、痛风性关节炎和其它关节炎病症、川崎病、慢性炎性脱髓鞘性多发性神经病(CIDP)、皮肌炎、葡萄膜炎、抗因子VIII病、强直性脊柱炎、重症肌无力,古德帕斯彻病、抗磷脂综合征、ANCA相关性血管炎、皮肌炎/多肌炎、脑型疟、慢性肺部炎性疾病、矽肺、肺结节病、骨重吸收疾病、同种异体移植物排斥、由感染引起的发热和肌痛、继发于感染的恶病质、髓细胞瘤形成(myeloid formation)、瘢痕组织形成、溃疡性结肠炎、发热、流行性感冒、骨质疏松症、骨关节炎、急性骨髓性白血病、慢性骨髓性白血病、转移性黑素瘤、卡波西肉瘤、多发性骨髓瘤、败血病、感染性休克和志贺菌病;阿尔茨海默病、帕金森病、由创伤性损伤引起的脑缺血或神经变性疾病;血管生成病症,包括实体瘤、眼部新血管形成和婴儿血管瘤;病毒疾病,包括急性肝炎感染(包括甲型肝炎、乙型肝炎和丙型肝炎)、HIV感染和CMV视网膜炎、AIDS、ARC或恶性肿瘤和疱疹;中风、心肌缺血、中风心脏病发作中的缺血、器官机能减退、血管增生、心脏和肾脏再灌注损伤、血栓形成、心脏肥大、凝血酶诱发的血小板聚集、内毒素血症和/或中毒性休克综合征、与前列腺素内过氧化酶合酶-2相关的病症和寻常型天疱疮。
优选的治疗方法是治疗选自以下病症的方法:克罗恩病和溃疡性结肠炎、同种异体移植物排斥、类风湿性关节炎、牛皮癣、强直性脊椎炎、牛皮癣关节炎、寻常型天疱疮和多发性硬化。可选地,优选的治疗方法是治疗选自以下病症的方法:缺血再灌注损伤,包括由中风引起的脑缺血再灌注损伤和由心肌梗塞引起的心脏缺血再灌注损伤。另一种优选的治疗方法是其中病症为多发性骨髓瘤的治疗方法。
此外,本发明的Btk抑制剂抑制可诱导促炎性蛋白的表达,所述可诱导促炎蛋白诸如前列腺素内过氧化物合酶-2(PGHS-2),其也称为环氧合酶-2(COX-2)。因此,其它与Btk相关的病症包括水肿、痛觉缺失(analgesia)、发热和疼痛,诸如神经肌肉疼痛、头痛、由癌症引起的疼痛、牙痛和关节炎疼痛。本发明化合物还可用于治疗兽医学病毒感染,诸如慢病毒属感染,其包括,但不限于马传染性贫血症病毒;或逆转录病毒感染,其包括猫免疫缺陷病毒、牛免疫缺陷病毒和犬免疫缺陷病毒。
当术语“Btk相关病症”或“Btk相关疾病或障碍”在本申请中使用时,每种术语意欲涵盖上文以重复详尽定义的所有病症以及受Btk激酶活性影响的任何其它病症。
“治疗有效量”意欲包括当单独施用或组合施用时可有效抑制Btk的本发明化合物的量。
一个实施方案提供治疗所述Bkt相关病症的方法,包括向由此需要的受试者施用治疗有效量的至少一种式(I)化合物。可施用用于治疗所述病症的治疗有效量。该实施方案的方法可用于治疗Btk相关病症,诸如变应性病症和/或自身免疫性和/或炎性疾病的治疗,所述病症和/或疾病包括,但不限于,SLE、类风湿性关节炎、多发性血管炎、特发性血小板减少性紫癜(ITP)、重症肌无力、过敏性鼻炎、多发性硬化症(MS)、移植排斥、I型糖尿病、膜性肾炎、炎性肠病、自身免疫性溶血性贫血、自身免疫性甲状腺炎、冷温凝集素疾病、埃文斯综合征、溶血性尿毒性综合征/血栓性血小板减少性紫癜(HUS/TTP)、结节病、斯耶格伦综合征、周围神经病(例如,格林巴利综合症)、寻常型天疱疮和哮喘。
治疗Btk激酶相关病症的方法可包括单独施用至少一种式(I)化合物或与每种其它和/或其它用于治疗所述病症的合适的治疗药物组合施用。可施用治疗有效量的至少一种式(I)化合物或其它用于治疗所述病症的合适的治疗药物。因此,“治疗有效量”还意欲包括可有效治疗Btk激酶相关疾病的要求保护的化合物的组合的量。化合物的组合优选为协同性组合。协同作用(Synergy),例如由Chou et al.,Adv.Enzyme Regul.,22:27-55(1984)所描述,组合施用时化合物的效应(在本案中,Btk的抑制作用)大于作为单一药物单独施用化合物的累加效应时存在。一般而言,协同性效应在化合物的亚最佳浓度最清楚地被证明。协同作用可呈现较低的细胞毒性,增加的抗Btk效果,或与单个组分相比组合的一些其它有益效果。
所述其它治疗药物的实例包括皮质类甾醇、咯利普兰、钙感光蛋白(calphostin)、细胞因子抑制性抗炎药(CSAID)、美国专利4,200,750公开的4-取代的咪唑并[1,2-a]喹喔啉;白介素-10、糖皮质激素、水杨酸酯、一氧化氮和其它免疫抑制剂;核转位抑制剂,诸如脱氧精胍菌素(DSG);非甾类抗炎药(NSAID),诸如布洛芬、塞来考昔和罗非考昔;甾类,诸如泼尼松或地塞米松;抗病毒剂,诸如阿巴卡韦;抗增殖剂,诸如甲氨喋呤、来氟米特、FK506(他克莫司,);细胞毒性药物,诸如硫唑嘌呤和环磷酰胺;TNF-α抑制剂,诸如替尼达普、抗TNF抗体或可溶性TNF受体;和雷帕霉素(西罗莫司或)或它们的衍生物。
上述其它治疗药物,当与本发明化合物联用时,可例如以Physicians'DeskReference(PDR)中标示的那些量或本领域技术人员所确定的其它量使用。在本发明的方法中,所述其它治疗药物可在施用本发明化合物之前、同时或之后施用。如上文所述,本发明还提供能够治疗Btk激酶相关病症(包括IL-1、IL-6、IL-8、IFNγ和TNF-α介导的疾病)的药物组合物。
本发明组合物可含有上述其它治疗药物,并且可例如如下配制:按照例如药物制剂领域公知的技术,使用常规的固态或液态媒介物或稀释剂以及适于所期望施用模式的药物添加剂(例如赋形剂、粘合剂、防腐剂、稳定剂、香料等)。
另一实施方案提供式(I)化合物,其用于疗法中。在本实施方案中,用于疗法可包括施用治疗有效量的式(I)化合物。
另一实施方案提供式(I)化合物,其用于疗法中。在本实施方案中,用于疗法可包括施用治疗有效量的式(I)化合物。
本发明还提供式(I)化合物在制备用于治疗或预防变应性病症和/或自身免疫性疾病和/或炎性疾病的药物中的用途。在本实施方案中,制备药物的用途可包括施用治疗有效量的式(I)化合物用于治疗或预防变应性病症和/或炎性疾病的药物中的用途。
本发明还提供式(I)化合物用于治疗癌症的药物中的用途。本发明可包括制备用于治疗或预防变应性病症和/或自身免疫性疾病和/或炎性疾病的药物中的用途,其包括施用治疗有效量的式(I)化合物。
本发明还包括组合物,所述组合物包含一种或多种式(I)化合物和药学上可接受的载体。
本发明还包括组合物,所述组合物包含一种或多种式(I)化合物和药学上可接受的载体。
“药学上可接受的载体”是指本领域通常接受的用于将生物活性药物递送至动物特别是哺乳动物的介质。药学上可接受的载体根据本领域普通技术人员知识范围内公知的多种因素来配制。这些因素包括但不限于所配制的活性药物的类型和性质;待施用含试剂组合物的受试者;组合物的预期施用途径;和所靶向的治疗适应症。药学上可接受的载体包括水性和非水性液体介质以及各种固体和半固体剂型。除活性药物之外,所述载体还可包括多种不同的成分和添加剂,这样的其它成分出于本领域普通技术人员公知的各种原因(例如使活性药物、粘合剂等稳定)而包含于制剂中。有关合适的药学上可接受的载体和选择它们时所涉及的因素的描述可很容易找到,参考如Remington’s PharmaceuticalSciences,第17版(1985),通过引用的方式将其全文并入本申请。
式(I)化合物可以适于待治疗病症的任何方式施用,这可取决于对位点特异性治疗或待递送药物的量的需要。尽管其它递送模式也包括在本发明中,局部施用通常优选用于皮肤相关疾病,而全身治疗优选用于癌症病症或癌前病症(pre-cancerous condition)。例如,所述化合物可口服递送,诸如以片剂、胶囊、颗粒、粉末或液态制剂(包括糖浆剂)的形式;局部递送,诸如以溶液、混悬液、凝胶或软膏的形式;舌下递送;口腔递送;肠胃外递送,诸如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如以无菌注射水或非水溶液或混悬液);经鼻递送,诸如通过吸入喷雾;局部递送,诸如以乳液或软膏的形式;经直肠递送,诸如以栓剂的形式;或通过脂质体递送。可施用含有无毒的药学上可接受的媒介物或稀释剂的剂量单位制剂。所述化合物可按适于立即释放或延长释放的形式施用。立即释放或延长释放可通过以下方法实现:使用合适的药物组合物,或特别是在延长释放的情况下,使用诸如皮下植入物或渗透泵那样的装置。
用于局部施用的示例性组合物包括局部载体诸如Plastibase(与聚乙烯一起胶凝的矿物油)。
用于口服施用的示例性组合物包括混悬剂,其可含有例如用于赋予体积(bulk)的微晶纤维素、作为助悬剂的海藻酸或海藻酸钠、作为增稠剂的甲基纤维素以及诸如本领域已知的增甜剂或矫味剂;立即释放的片剂,其可含有例如微晶纤维素、磷酸二钙、淀粉、硬脂酸镁和/或乳糖和/或如本领域已知的其它赋形剂、粘合剂、膨胀剂、崩解剂、稀释剂和润滑剂。本发明化合物还可通过舌下施用和/或口腔施用例如以模制的、压制的或冷冻干燥的片剂的形式经口递送。示例性组合物可包括快速溶解的稀释剂,诸如甘露醇、乳糖、蔗糖和/或环糊精。所述制剂还可包括高分子量赋形剂诸如纤维素或聚乙二醇(PEG);辅助粘膜粘附的赋形剂诸如羟基丙基纤维素(HPC)、羟基丙基甲基纤维素(HPMC)、羧甲基纤维素钠(SCMC)和/或马来酸酐共聚物(例如Gantrez);以及用于控制释放的物质诸如聚丙烯酸(酯)共聚物(例如Carbopol 934)。还可加入润滑剂、助流剂、香料、着色剂和稳定剂以便于加工和使用。
用于鼻气雾剂或用于吸入施用的示例性组合物包括溶液,其可含有例如苄醇或其它合适的防腐剂、提高吸收和/或生物利用度的吸收促进剂,和/或诸如本领域已知的其它增溶剂或分散剂。
用于肠胃外施用的示例性组合物包括注射用溶液或混悬剂,其可含有例如合适的无毒的肠胃外可接受的稀释剂或溶剂(诸如甘露醇、1,3-丁二醇、水、林格溶液、等张氯化钠溶液)或其它合适的分散剂或湿润剂及助悬剂(包括合成的甘油一酯或甘油二酯及脂肪酸(包括油酸))。
直肠施用的示例性组合物包括栓剂,其可含有例如合适的非刺激性的赋形剂,诸如可可酯、合成的甘油酯或聚乙二醇,所述栓剂在常温是固态的,但在直肠腔道中液化和/或溶解以释放药物。
本发明化合物的治疗有效量可由本领域普通技术人员确定,并且包括用于哺乳动物的示例性剂量即每日每千克体重约0.05-1000mg、1-1000mg、1-50mg、5-250mg、250-1000mg活性化合物,其可按单一剂量形式施用或按各个分开剂量(诸如每天1至4次)形式施用。应当理解,就任何特定受试者而言的具体剂量水平和施用频率可发生变化且将取决于多种因素,这些因素包括所使用的具体化合物的活性;所述化合物的代谢稳定性和作用持续时间;受试者的物种、年龄、体重、一般健康情况、性别和饮食;施用模式和施用时间;排泄速率;药物组合和具体病症的严重程度。优选的治疗受试者包括动物,最优选为哺乳动物物种,诸如人类和家畜(诸如狗、猫、马等)。因此,当术语“患者”在本申请使用时,该术语意欲包括受Btk酶水平介导所影响的所有受试者,最优选为哺乳动物物种。
下文“实施例”节中详述的式(I)化合物的实施例,已在一种或多种下文所述的测定法中的测试。
在一个实施方案中,如通过人重组Btk酶测定所测量,式(I)化合物抑制Btk酶,IC50值为0.4nM或更小,例如0.001至0.4nM。该实施方案包括抑制Btk酶的式(I)化合物,IC50值为0.3nM和更小,例如0.001至0.3nM。该实施方案的其它化合物抑制Btk酶,IC50值为0.25nM或更小,例如0.001至0.25nM。
在一个实施方案中,式(I)化合物具有抑制用抗-人IgM刺激的Ramos RA1B细胞中的细胞内钙通量的有用效力,IC50值为25nM或更小,例如0.1至25nM。该实施方案包括式(I)化合物,其具有抑制用抗人IgM刺激的Ramos RA1B细胞中的细胞内钙通量的效力,IC50值为20nM或更小,例如为0.1至20nM;并且IC50值为15nM或更小,例如0.1至15nM。
在一个实施方案中,式(I)化合物抑制Btk酶,如通过人重组Btk酶测定法所测量,IC50值为0.4nM或更小,例如0.001至0.4nM,并且抑制用抗-人IgM刺激的Ramos RA1B细胞中的细胞内钙通量,IC50值为25nM或更小,例如0.1至25nM。
在一个实施方案中,式(I)化合物抑制Btk酶,如通过人重组Btk酶测定法所测量,IC50值为0.4nM或更小,例如0.001至0.4nM,并且抑制用抗-人IgM刺激的Ramos RA1B细胞中的细胞内钙通量,IC50值为20nM或更小,例如0.1至20nM。
制备方法
本发明化合物可以有机合成领域技术人员已知的多种方式制备。本发明化合物可使用下文描述的方法以及合成有机化学领域已知的合成方法,或通过本领域技术人员所理解的它们的变化形式合成。优选的方法包括但不限于下述那些。反应在适用于所采用的试剂和材料且适用于所进行的转化的溶剂或溶剂混合物中进行。有机合成领域技术人员应当理解,分子上存在的官能团应与所提出的转化一致。为了获得期望的本发明化合物,有时需要作出判断以修正合成步骤的顺序,或者相对于另一种方法而选择一种特定的方法。
有机合成领域的技术人员应当认识到,一些存在于中间体化合物或式(I)化合物中的官能团可能不稳定或以其它方式不适于一些用于制备它们或将它们转化成其它中间体或式(I)化合物的反应条件。在这些情况下,可通过转化成替代官能团来保护所述官能团,所述替代官能团对所要采用的反应条件是稳定的或更适于所要采用的反应条件。然后,这些经保护的官能团可在合成的后期转化回原来的官能团。实例是将羧酸保护成羧酸酯,将伯胺或仲胺保护成叔丁基氧基羰基(Boc)衍生物或苄基氧基羰基(Cbz)衍生物,或将咔唑或四氢咔唑氮保护成2-三甲基甲硅烷基乙氧基甲基(SEM)衍生物。保护基团的使用是文献中公知的;对于受过培训的从业者而言,描述许多替代物的权威性著作是Wuts,P.et al.,Greene's Protective Groups in Organic Synthesis,Fourth Edition,Wiley-Interscience(2006)。
表示某些式(I)化合物的化合物3可使用方案1中所示的方法制备。
方案1
经取代的咔唑甲酰胺或四氢咔唑甲酰胺1,其中Y为适当的基团诸如Br、Cl或三氟甲磺酰基氧基,与硼酸或硼酸酯2(其中R为例如H、烷基或一起形成任选取代的1,3,2-二氧杂硼杂环戊烷或1,3,2-二氧杂硼杂环己烷),其中Ar表示式(I)的基团Q之一,以提供化合物3。该反应可如下进行:通过使用合适的碱(诸如碳酸钾、碳酸铯或磷酸三钾),以及合适的催化剂(诸如四(三苯基膦)钯、1,1'-双(二苯基膦基)二茂铁氯化钯(II)或1,1'-双(二叔丁基膦基)二茂铁氯化钯(II)),于合适的溶剂(诸如1,4-二噁烷、N,N-二甲基甲酰胺或四氢呋喃)中,所述溶剂任选地含有一种或多种合适的助溶剂(诸如水或乙醇)。此类偶联反应通常称为Suzuki-Miyaura偶联反应,并且在化学文献中已知(参见例如Heravi,M.et al.,Tetrahedron,68:9145(2012)及其中引用的参考文献)。
可选择地,使用化学文献中已知的方法(参见,例如Ishiyama,T.et al.,Tetrahedron,57:9813(2001)及其中引用的参考文献),可将经取代的咔唑甲酰胺或四氢咔唑甲酰胺1转化成相应的硼酸或硼酸酯4(其中R为例如H、烷基或一起形成任选取代的1,3,2-二氧杂硼杂环戊烷或1,3,2-二氧杂硼杂环己烷)。此类方法的实例为1与试剂(诸如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))在碱(诸如乙酸钾)和合适的催化剂(诸如1,1'-双(二苯基膦基)二茂铁氯化钯(II))存在下于合适的溶剂中的反应。可选择地,化合物1(其中Y为Br)与有机金属试剂(诸如丁基锂或异丙基氯化镁)反应,随后用硼酸酯(诸如硼酸三甲酯或硼酸三异丙酯)处理,随后水解所得硼酸酯,可得到硼酸4(R=H)。使用如上所述的Suzuki-Miyaura偶联反应,化合物4与合适的化合物5反应,其中Ar表示式(I)的基团Q之一,Y为适当的基团,诸如Br、Cl或三氟甲磺酰基氧基,也可得到化合物3。
化合物2可使用与由化合物1制备化合物4所述相同的方法由化合物5制备。
方案2
如方案2所示,空间位阻可引起围绕标记为a的键的受限旋转,并且化合物3a展现出手性,称为阻转异构体,并且可以两种对映异构体3b和3c存在。(在方案2中,为了说明的目的,Q表示为四氢异喹啉-5-基)。在某些条件下,诸如手性固定相上的色谱,可在色谱图中观察到对映异构的阻转异构体作为两个单独的峰。可将此类化合物作为对映异构体的混合物分离,或者可使用本领域已知的方法分离对映异构体,诸如固定相上的制备型色谱。在适当的储存和处理条件下,分离的对映体可为可分离且稳定的。
在某些情况下,化合物3为四氢咔唑甲酰胺(其中虚线表示单键),且R1a和R1b彼此不同。一个实例为3d,如方案3所示,其中R1a不为氢。(该实例仅为说明性的而非限制性的)。在这种情况下,存在两个手性中心:R1a的连接点和如上所述的标记为a的键。因此,四种非对映异构体是可能的(3e、3f、3g和3h)。因此,化合物3d可作为所有四种非对映异构体的混合物,或作为单一非对映异构体,或作为两种或更多种非对映异构体的混合物存在。非对映异构体对(3e、3f、3g和3h)的外消旋混合物是可能的。如上所述,非对映异构体可使用文献中已知的方法分离,诸如手性固定相上的色谱。
方案3
在某些情况下,化合物3可由手性四氢咔唑甲酰胺1或4的单一对映异构体制备。在这些情况下,两种非对映异构体的混合物可由得到化合物3的Suzuki-Miyaura反应产生。实例为3i和3j,如方案3所示,其中R1、R3和R4均不为氢。(这些实例仅为说明性的而非限制性的)。由适当化合物1或4的一种对映异构体形成的化合物3i将是非对映异构体3e和3f的混合物,而由适当化合物1或4的另一种对映异构体形成的化合物3j将是非对映异构体3g和3h的混合物。如上所述,可使用文献中已知的方法分离这些非对映异构体,诸如色谱或选择性结晶。
在某些情况下,其中1或4为手性四氢咔唑甲酰胺,在Suzuki-Miyaura偶联反应中可发生手性诱导,以得到化合物3。在这些情况下,可获得不是等摩尔混合物的非对映异构体的混合物;也就是说,化合物3可为非对映异构体的混合物,其中一种或多种具有键a(具有一种绝对构型)的非对映异构体比一种或多种具有键a(具有相反绝对构型)的非对映异构体以更大的程度存在。
某些由7表示的式(I)化合物可使用方案4中所示的方法制备。
方案4
这些方法涉及使携带仲胺的化合物6(即,其中XH表示式(I)的基团Q,其中R5被H替代)与适当的试剂R5-Z反应,其中Z表示离去基团诸如Cl或OH,以得到化合物7,其中XR5表示由此类反应得到的式(I)的基团Q之一。此类胺的反应是文献中已知的。此类反应的一个实例为化合物6的胺与羧酸酰氯或羧酸酐的酰化,通常在合适的溶剂(诸如四氢呋喃、乙酸乙酯、乙腈或二氯甲烷)中,通常在碱(诸如三乙胺、二异丙基乙基胺、吡啶)或无机碱(诸如氢氧化钠或碳酸钾)的水溶液存在下进行。可替换地,可使用溶剂(诸如吡啶),在这种情况下溶剂也可用作碱。
方案4中所示的反应的另一实例是使用文献中已知的许多酰胺偶联剂,使化合物6的胺与羧酸进行酰化,例如,(苯并三唑-1-基氧基)三(二甲基氨基)鏻鎓六氟磷酸盐(也称为BOP或Castro试剂)、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(也称为HATU),或N,N′-二环己基碳二亚胺或1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(也称为EDC)与试剂诸如1-羟基苯并三唑(也称为HOBT)或1-羟基-7-氮杂苯并三唑(也称为HOAT)的组合。此类反应通常在合适的溶剂(诸如乙酸乙酯、二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺或N-甲基吡咯烷-2-酮)中,在合适的碱(诸如三乙胺或二异丙基乙基胺)存在下进行。
方案4的某些化合物6,其中XH表示其中R5被H替代的式(I)的基团Q,可如方案5所示制备。
方案5
化合物1与硼酸或硼酸酯8(其中XP类似于方案4中的XH)的反应;P可为H或合适的胺保护基,例如叔丁基氧基羰基(Boc)或苄基氧基羰基(Cbz),其在文献中被称为胺的保护基团),使用如上所述的Suzuki-Miyaura偶联物(方案1),如果必要,可在除去保护基团P后得到相应的化合物6。如果化合物8中的P表示H,则可直接获得化合物6。
通过类似于方案1中所示的方法,方法5中还示出了制备方案4的化合物6的替代方法,其中XH表示其中R5被H替代的式(I)的基团Q。方案1的硼酸或硼酸酯4(其中R为例如H、烷基或一起形成任选取代的1,3,2-二氧杂硼杂环戊烷或1,3,2-二氧杂硼杂环己烷)与化合物9反应,其中Y为适当的离去基团诸如Br、Cl或三氟磺酰基氧基,使用如上所述的Suzuki-Miyaura偶联,也可得到化合物6。如上所述,P可为H,或P可为合适的保护基团,在这种情况下脱保护可得到化合物6。
此外,化合物8可使用针对由化合物1制备化合物4所述的方法(方案1)相同的方法由化合物9制备。
用于制备式(I)化合物的化合物1(参见方案1)可使用方案6中所示的操作制备。
方案6
可使用文献中已知的方法将经取代的2-氨基苯甲酸10(文献中已知的或使用文献中已知的方法制备)转化成相应的2-肼基苯甲酸11,其为盐酸盐,例如通过用亚硝酸钠/盐酸水溶液处理,随后用氯化锡(II)还原,转化成相应的重氮盐。11与合适的环己酮12于合适的溶剂中与合适的催化剂(例如乙醇与盐酸、甲苯与对甲苯磺酸或三氟乙酸或乙酸)反应(在这种情况下,溶剂也可作为催化剂),可得到相应的经取代的四氢咔唑13。该反应通常称为Fischer吲哚合成,并且是化学文献中已知的(例如,参见Kamata,J.et al.,Chem.Pharm.Bull.,52:1071(2004))。可选择地,可在两个连续的步骤中进行Fischer吲哚合成:11可在合适的条件下(诸如在合适的溶剂(诸如乙醇或甲苯)中,任选用合适的催化剂(诸如对甲苯磺酸))与12反应形成中间体腙,其可被分离,然后在合适的条件(例如乙醇与盐酸、乙酸与氯化锌或三氟乙酸与甲苯)下进一步反应,得到化合物13。
可使用化学文献中已知的方法将化合物13的羧酸转化成化合物14的相应的羧酰胺(其为方案1中所示的化合物1的实例),例如通过以下方法将化合物13转化成相应的酰氯:用草酰氯或亚硫酰氯处理相应的酸,随后用氨处理;或在偶联剂诸如碳二亚胺或EDC与HOAT的混合物存在下用氨或氯化铵处理化合物13。在其中R1b和R2b均为H的化合物14的情况下,可使用化学文献中已知的方法将化合物14转化成相应的咔唑16(其为方案1所示的化合物1的另一实例),例如,在合适的溶剂中用氧化剂(诸如DDQ)处理化合物14。
可选择地,可颠倒酰胺形成和氧化步骤的顺序以将化合物13(其中R1b和R2b均为H)转化成化合物16。因此,可使用上述方法或类似操作将化合物13(其中R1b和R2b均为H)氧化,得到相应的化合物15。然后,可再次使用上述方法或类似操作将化合物15的羧酸转化成伯酰胺,得到相应的化合物16。
化合物13和14(其中R1a和R1b彼此不同)含有手性中心,因此作为两种对映异构体存在。如方案6所示的化合物13和14的制备可得到外消旋产物,其可用于制备如方案1所示的式(I)化合物。可选择地,化合物13和14可使用公知的方法诸如手性固定相上的色谱解析成分离的对映异构体。
有机合成领域的技术人员将认识到,,一些取代基R1a可能与如方案1、4、5和6所示用于制备式(I)化合物或中间体化合物的反应条件不相容。在这些情况下,在某些合成步骤中不同的取代基可代替R1a,并且在合成的适当阶段使用化学文献中已知的方法将其转化为R1a。可选择地,在某些情况下,合适的保护基团可用于在某些合成步骤中保护R1a,并在合成的适当阶段除去。此类情况对于本领域技术人员是显而易见的。此类合成转化的一些实例示于方案7。
方案1所示的携带某些取代基R1a和R1b的化合物1可由前体化合物17制备。化合物17可使用方案6中所示的方法制备,但是在方案6中用3-氧代环己烷甲酸乙酯代替化合物12。(化合物17的一些实例述于文献中,例如美国专利8,084,620中的中间体47-2和48-1及实施例73-1)。化合物17的羧酸酯向R1a和R1b的一些转化示于方案7;这些中的一些以及其它也在美国专利8,084,620的实施例中说明。方案7中的化合物18、20和22为方案1中所示的化合物1的实例。
方案7
通过用合适的还原剂(诸如氢化铝锂)在合适的溶剂(诸如四氢呋喃)中处理,可将化合物17的酯部分还原成化合物18的相应的伯甲醇(primary carbinol)(Ra和Rb均为H)。可选择地,通过在合适的溶剂(诸如四氢呋喃)中,用合适的试剂(诸如甲基氯化镁或甲基锂)处理,可将化合物17的酯部分转化成化合物18的相应的叔甲醇(Ra和Rb均为甲基)。
化合物17的酯部分可水解成化合物19的相应羧酸,例如,通过在合适的共溶剂(诸如甲醇、乙醇或四氢呋喃)中用氢氧化锂或氢氧化钠水溶液处理。化合物19的羧酸部分可转化成化合物18的仲甲醇部分(Ra和Rb中的一个为H,另一个为甲基),例如,通过转化为N,O-二甲基羟肟酸酯(通常称为Weinreb酰胺),随后用试剂(诸如甲基氯化镁或甲基锂)处理,随后用合适的还原剂(诸如硼氢化钠)还原如此形成的酮。可选择地,化合物19的羧酸部分可使用各种方法中的任一种转化为化合物20的酰胺,诸如转化成酰氯,然后用氨或伯胺或仲胺处理,或通过在合适的偶联试剂(诸如HATU、BOP或EDC与HOBT或HOAT的组合)存在下用氨或氯化铵或伯胺或仲胺处理。
在化合物17的虚线表示单键的情况下,可通过在合适的溶剂(诸如四氢呋喃)中用碱(诸如双(三甲基甲硅烷基)氨基锂或二异丙基氨基锂)处理化合物17,并用烷基化剂(诸如碘甲烷)处理所得阴离子,将携带酯部分的碳原子烷基化,得到化合物21,其中R'为甲基。然后通过与如上所述用于制备化合物18相同的方法,可将化合物21的酯部分转化成化合物22的甲醇(carbinol)部分(其中Ra和Rb均为H、甲基或一个为H,且另一个为甲基)。
用于制备式(I)化合物的方案1的某些化合物1也可使用方案8中所示的操作制备。
方案8
可用适当的卤化试剂处理如方法6所示由适当的2-肼基苯甲酸制备的化合物23(参见,例如,美国专利8,084,620,中间体48-1),得到化合物24,其中R3为卤素原子。例如,用氯化试剂诸如N-氯代琥珀酰亚胺处理化合物23可得到其中R3为Cl的化合物24,而用氟化试剂诸如1-(氯甲基)-4-氟-1,4-二氮杂二环[2.2.2]辛烷-双(四氟硼酸)盐处理化合物23可得到其中R3为F的化合物24。可使用文献中已知的方法来实现化合物24转化成相应的化合物25(其为方案1的化合物1的实例),其中一些述于方案7的讨论中。
如方案9所示,化合物26可转化成化合物27,化合物27为方案1的化合物5的实例。类似地,化合物28可转化成化合物29,化合物29为方案1的化合物2的实例。
方案9
在方案11中,Y表示适合的基团,诸如Br、Cl或三氟甲磺酰基氧基;(RO)2B表示硼酸或硼酸酯;并且XH表示式(I)的基团Q,其中R5被H替代。化合物26转化成化合物27,化合物28转化成化合物29可使用与针对方案4中化合物6转化成化合物7的类似转化所述相同的方法来实现。此外,化合物26转化成化合物28以及化合物27转化成化合物29可使用与针对方案1中化合物1转化成化合物4的转化所述的方法来实现。
在一些情况下,当中间体化合物转化成另一种中间体化合物或式(I)化合物需要多于一个合成反应时,可改变各步骤的顺序。有机合成领域的技术人员应当认识到这些情况。一个实例示于方案9。化合物26转化成化合物29可通过以下方式进行:(1)将化合物26的胺转化成化合物27的经取代的胺,随后(2)将化合物27的基团Y转化成化合物29的硼酸或硼酸酯。可选择地,化合物26向化合物29的相同转化可通过以下方式进行:(1)将化合物26的基团Y转化成化合物28的硼酸或硼酸酯,随后(2)将化合物28的胺转化为化合物29的经取代的胺。另一实例示于方案6。化合物13转化成化合物16可通过以下方式进行:(1)将化合物13的羧酸转化成化合物14的羧酰胺,随后(2)将化合物14氧化成咔唑16。可选择地,化合物13向化合物16的相同转化可通过以下方式进行:(1)将化合物13氧化成咔唑15,随后(2)将化合物15的羧酸转化成化合物16的羧酰胺。
实施例
本发明化合物和用于制备本发明化合物的中间体可使用以下实施例和相关存在中所示的存在制备。这些实施例中使用的方法和条件以及这些实施例中制备的实际化合物并非意在限制,而是意在说明可如何制备本发明化合物。这些实施例中使用的起始物质和试剂,当不是通过本申请所述的方法制备时,通常是可商购的,或化学文献中报道的,或者可通过使用化学文献中描述的方法制备。本发明在以下实施例中进一步限定。应当理解,实施例仅以说明的方式给出。从上述讨论和实例中,本领域技术人员可确定本发明的基本特征,并且在不脱离本发明的精神和范围的情况下,可进行各种改变和修正,以使本发明适应各种用途和条件。结果是,本发明不受下文阐述的说明性示例的限制,而是由所附权利要求限定。
在给定实施例中,短语“干燥和浓缩”通常是指使用无水硫酸钠或硫酸镁从有机溶剂中的溶液中除去大部分残留水,随后过滤并从滤液中除去溶剂(通常在减压下且在适于待制备的物质的稳定性的温度)。柱色谱通常如下进行:使用快速色谱法(Still,W.et al.,J.Org.Chem.,43:2923(1978))或使用Isco中压色谱仪用预先填充的硅胶管柱(TeledyneCorporation),用指示的溶剂或溶剂混合物洗脱。制备型高压液相色谱(HPLC)如下进行:以适于柱尺寸和分离的洗脱速度,使用具有适于待分离物质的量的尺寸的反相柱(WatersSunFire C18,Waters XBridge C18,Axia C18,YMC S5ODS等),通常用增加浓度的甲醇或乙腈/水的梯度洗脱,其还含有0.05%或0.1%三氟乙酸或10mM乙酸铵。使用超临界流体色谱(SFC),一种含有超临界或亚临界流体CO2和极性有机改性剂(诸如醇)的流动相的正相HPLC的形式,分离手性化合物。(White,C.et al.,J.Chromatography A,1074:175(2005))。使用针对个别情况描述的条件进行对映异构体或非对映异构体的手性SFC分离。通过使用电喷雾离子化的液相色谱-质谱获得质谱数据。
使用Cu Kα辐射在Bruker-AXS APEX2CCD系统上收集单晶x射线衍射数据。使用APEX2软件包/程序套件进行所测量的强度数据的索引和处理(参见APEX2用户手册,v1.27;Bruker AXS,Inc.,WI 53711USA)。当指示时,在数据收集期间,将晶体在Oxford冷冻系统低温冷却器的冷流中冷却(Cosier,J.et al.,J.Appl.Cryst.,19:105(1986))。通过直接方法解析结构,并使用晶体学包SHELXTL(参见APEX2用户手册,v1.27;Bruker AXS,Inc.,WI 53711USA)在观察到的反射的基础上进行精修。通过全矩阵最小二乘法对得到的原子参数(坐标和温度因子)进行精修。精修中最小化的函数为Σw(|Fo|-|Fc|)2。R定义为Σ||Fo|-|Fc||/Σ|Fo|而Rw=[Σw(|Fo|-|Fc|)2/Σw|Fo|2]1/2,其中w为基于观察到的强度的误差的适当的加权函数。在各个精修阶段检查了差异图(Differencemap)。将氢引入具有各向同性温度因子的理想位置,但氢参数没有变化。根据Stout etal.,X-Ray Structure Determination:A Practical Guide,MacMillan(1968)中所述的操作获得单位晶胞参数。
化学名称使用ChemBioDraw Ultra 12.0版(CambridgeSoft)来确定。
缩写
Ac 乙酰基
ACN 乙腈
AcOH 乙酸
aq. 含水的
anhyd. 无水的
Boc 叔丁基氧基羰基
BOP 苯并三唑-1-基氧基)三(二甲基氨基)鏻鎓六氟磷酸盐
Cbz 苄基氧基羰基
Conc. 浓度
DCM 二氯甲烷
DDQ 2,3-二氯-5,6-二氰基-1,4-苯醌
DIEA 二异丙基乙基胺
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
dppf 1,1′-双(二苯基膦基)二茂铁
EDC 1-[3-(二甲基氨基)丙基]-3-乙基-碳二亚胺盐酸盐
eq.或Eq.或equiv. 当量
EtOAc 乙酸乙酯
h或hr 小时
HATU O-(7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐
HOAT 1-羟基-7-氮杂苯并三唑
HOBT 1-羟基苯并三唑
LC 液相色谱
LCMS或LC/MS 液相色谱质谱
Me 甲基
MeOH 甲醇
MHz 兆赫
min. 分钟
M+ (M+H)+
M+1 (M+H)+
MS 质谱
m/z 质荷比
N 当量浓度
NMP N-甲基吡咯烷酮
NMR 核磁共振
ppm 百万分之一
Ret Time或Rt 保留时间
sat.或sat'd. 饱和的
sec 秒
TFA 三氟乙酸
THF 四氢呋喃
中间体1
(RS)-5-溴-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺
中间体1A:4-溴-2,5-二氟苯甲酸
将于干冰-丙酮浴中冷却的1,4-二溴-2,5-二氟苯(640mg,2.35mmol)在无水乙醚(10mL)中的溶液用2.5M正丁基锂/己烷(1.04mL,2.59mmol)逐滴处理。将溶液在-78℃搅拌30分钟,然后用一片干冰处理。5分钟后移除冷却浴并将混合物再搅拌30分钟,同时温热至室温。用EtOAc和水洗涤该混合物。分出有机相并用饱和NaHCO3水溶液洗涤两次。用1M HCl水溶液酸化合并的有机相,用DCM萃取两次,将合并的有机相干燥并浓缩,得到4-溴-2,5-二氟苯甲酸,其为白色固体(297mg,53%产率)。
中间体1B:4-溴-5-氟-2-肼基苯甲酸盐酸盐
将4-溴-2,5-二氟苯甲酸(2.50g,10.6mmol)和肼(3.81mL,121mmol)在N-甲基-2-吡咯烷酮(2mL)中的混合物在95℃加热4小时。将冷却的混合物倾入在NaCl-冰浴中冷却的剧烈搅拌的6M HCl水溶液(400mL)中。通过过滤收集所得析出物,用6M HCl水溶液(200mL)洗涤并在真空下干燥,得到4-溴-5-氟-2-肼基苯甲酸盐酸盐,其为黄色固体(1.88g,71%纯度,44%产率),未经进一步纯化即使用。
中间体1B的替代合成:
将在NaCl-冰浴上搅拌的2-氨基-4-溴-5-氟苯甲酸(10.0g,42.7mmol)在37%HCl水溶液(42.7mL)和水(14.3mL)的混合物中的混悬液用亚硝酸钠(3.24g,47.0mmol)在水(15.7mL)中的溶液逐滴处理。当添加完成时,将混合物再搅拌30分钟。逐滴添加氯化亚锡(II)二水合物(28.9g,128mmol)在37%HCl水溶液(27.5mL)中的溶液。移除冷却浴并将混合物在室温搅拌45分钟。过滤浓混悬液,用水彻底洗涤所收集的析出物并减压干燥过夜。伴随超声处理用MeOH研磨固体,通过过滤收集沉淀,用MeOH洗涤并干燥。将滤液浓缩,并用DCM研磨残余物。通过过滤收集所得固体并干燥,将两种固体合并,得到4-溴-5-氟-2-肼基苯甲酸盐酸盐(5.37g,44%产率),其为白色固体。质谱m/z 249,251(M+H)+。
中间体1C:5-溴-6-氟-2-(三氟甲基)-23,4,9-四氢-1H-咔唑-8-甲酸
将4-溴-5-氟-2-肼基苯甲酸盐酸盐(5.00g,17.5mmol)和(RS)-3-三氟甲基环己酮(4.07g,24.5mmol)在乙酸(8.0mL)中的混合物在78℃搅拌18小时。将混合物冷却至室温并浓缩。将残余物混悬于EtOAc,通过过滤收集析出物并干燥。浓缩滤液并将残余物混悬于DCM。通过过滤收集析出物并干燥,将两种析出物合并,得到5-溴-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酸,其为浅橙色固体(4.10g,55%产率)。质谱m/z 380,382(M+H)+。
中间体1:
将5-溴-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酸(2.00g,5.26mmol)、NH4Cl(2.81g,52.6mmol)和HATU(2.20g,5.79mmol)在DMF(25mL)中的溶液用三乙胺(3.67mL,26.3mmol)处理并将混合物在室温搅拌90分钟。添加冰水(30mL)并将混合物搅拌30分钟。通过过滤收集析出物并用水(60mL)洗涤。将所收集的固体两次混悬于甲苯(30mL)并真空浓缩,然后干燥。残余物经受用10%MeOH/EtOAc-己烷(0-100%的梯度)洗脱的硅胶柱色谱,得到5-溴-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺,其为浅黄色固体(1.55g,74%产率)。质谱m/z 379,381(M+H)+。1H NMR(400MHz,MeOH-d4)δ7.46(d,J=9.9Hz,1H),3.46(dd,J=16.1,4.4Hz,1H),3.11(dd,J=16.4,5.3Hz,1H),3.06-2.93(m,1H),2.92-2.80(m,1H),2.79-2.59(m,1H),2.37-2.23(m,1H),1.86-1.65(m,1H)。
中间体2
5-溴-3,3,6-三氟-2,3,4,9-四氢-1H-咔唑-8-甲酰胺
遵循用于将中间体1B转化成中间体1的操作,将4,4-二氟环己酮转化成5-溴-3,3,6-三氟-2,3,4,9-四氢-1H-咔唑-8-甲酰胺。质谱m/z 347,349(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.12(br.s.,1H),7.64(d,J=10.1Hz,1H),7.57(br.s.,1H),3.54(t,J=14.4Hz,2H),2.97(t,J=6.6Hz,2H),2.31(tt,J=13.9,6.7Hz,2H)。
中间体3
4-溴-3-氟-9H-咔唑-1-甲酰胺
中间体3A:5-溴-6-氟-2,3,4,9-四氢-1H-咔唑-8-甲酸
将4-溴-5-氟-2-肼基苯甲酸盐酸盐[中间体1B](12.0g,42.0mmol)和环己酮(12.4g,126mmol)在乙酸(90mL)中的混合物在搅拌90℃过夜。将混合物冷却至室温并通过过滤收集析出物,用水洗涤并干燥,得到5-溴-6-氟-2,3,4,9-四氢-1H-咔唑-8-甲酸(5.02g,16.1mmol,38%产率),其为浅黄色固体。质谱m/z 312,314(M+H)+。
中间体3B:4-溴-3-氟-9H-咔唑-1-甲酸
将5-溴-6-氟-2,3,4,9-四氢-1H-咔唑-8-甲酸(5.00g,16.0mmol)和DDQ(8.00g,35.2mmol)在THF(60mL)中的混合物在60℃搅拌3小时。将混合物冷却至室温,用EtOAc稀释,依序用饱和NaHCO3水溶液、水和1M HCl水溶液洗涤,干燥并浓缩,得到粗制的4-溴-3-氟-9H-咔唑-1-甲酸(5.30g,86%纯度,80%纯度),其未经进一步纯化即使用。
中间体3:
将4-溴-3-氟-9H-咔唑-1-甲酸(4.70g,15.3mmol)、HOBT(2.34g,15.3mmol)和EDC(2.92g,15.3mmol)在THF(70mL)中的混合物在室温搅拌30分钟。添加氢氧化铵水溶液(0.891mL,22.9mmol)并将混合物在室温搅拌过夜。浓缩该混合物并将残余物溶于EtOAc,用水洗涤两次,然后用饱和NaHCO3水溶液洗涤,干燥并浓缩。用DCM研磨残余物,得到4-溴-3-氟-9H-咔唑-1-甲酰胺,其为浅棕色固体(3.40g,73%产率)。质谱m/z 307,309(M+H)+,290,292(M+H-NH3)+。1H NMR(400MHz,MeOH-d4)δ8.73(dd,J=8.1,0.9Hz,1H),7.83(d,J=9.9Hz,1H),7.69-7.63(m,1H),7.54(ddd,J=8.2,7.1,1.2Hz,1H),7.29(ddd,J=8.1,7.1,1.0Hz,1H)。
中间体4
4-溴-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺
遵循用于将中间体3A转化成中间体3的操作,将5-溴-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酸[中间体1C]转化成4-溴-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺。质谱m/z 416,418(M+H+CH3CN)+。1H NMR(400MHz,MeOH-d4)δ8.83(d,J=8.6Hz,1H),8.00(d,J=0.7Hz,1H),7.89(d,J=9.8Hz,1H),7.52(dd,J=8.4,1.1Hz,1H)。
中间体5
(RS)-5-溴-6-氟-2-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺
中间体5A:(RS)-5-溴-2-(乙氧基羰基)-6-氟-2,3,4,9-四氢-1H-咔唑-8-甲酸
将4-溴-5-氟-2-肼基苯甲酸盐酸盐[中间体1B](5.37g,18.8mmol)、(RS)-3-氧代环己烷甲酸乙酯(3.52g,20.7mmol)和乙酸(3.23mL,56.4mmol)在甲苯(90mL)中的混合物在110℃加热20小时。减压除去溶剂,并用甲苯(43mL)和TFA(11mL)稀释残余物。将混合物在90-94℃搅拌过夜。用EtOAc稀释经冷却的混合物,超声处理,并通过过滤收集析出物。浓缩滤液并伴随超声将残余物混悬于EtOAc,得到另一份析出物,同样通过过滤收集并用EtOAc洗涤。用MeOH研磨合并的固体两次,得到固体。浓缩合并的滤液并用MeOH研磨残余物,得到另外的固体。合并固体,得到(RS)-5-溴-2-乙氧基羰基-6-氟-2,3,4,9-四氢-1H-咔唑-8-甲酸,其为淡黄色固体(3.38g)。质谱m/z 384,386(M+H)+。
中间体5B:(RS)-5-溴-8-氨甲酰基-6-氟-2,3,4,9-四氢-1H-咔唑-2-甲酸乙酯
将(RS)-5-溴-2-(乙氧基羰基)-6-氟-2,3,4,9-四氢-1H-咔唑-8-甲酸(0.513g,1.34mmol)、EDC(0.384g,2.00mmol)和HOBT(0.307g,2.00mmol)在THF(10mL)和DCM(1.7mL)中的混合物在室温搅拌20分钟。添加NH4OH水溶液(28%,0.078mL,2.00mmol),并将混合物在室温搅拌60分钟。将混合物用EtOAc稀释并先后用饱和NaHCO3水溶液和盐水洗涤。用EtOAc萃取水层,将合并的有机层干燥并浓缩。伴随超声在MeOH中研磨残余物,得到(RS)-5-溴-8-氨甲酰基-6-氟-2,3,4,9-四氢-1H-咔唑-2-甲酸乙酯,其为黄色固体(0.432g,84%产率)。质谱m/z 383,385(M+H)+。
中间体5:
在-78℃,历时30分钟,将(RS)-5-溴-8-氨甲酰基-6-氟-2,3,4,9-四氢-1H-咔唑-2-甲酸乙酯(10.0g,26.1mmol)在THF(200mL)中的溶液用1.6M甲基锂/醚(49mL,78mmol)逐滴处理。将混合物在-78℃搅拌45分钟,然后历时25分钟用另外的甲基锂溶液处理(33mL)。将混合物在-78℃再搅拌90分钟,然后用饱和NH4Cl水溶液处理并温热至室温。用EtOAc稀释该混合物并依序用水和盐水洗涤。用EtOAc萃取水层。将合并的有机层干燥并浓缩。将残余物溶于EtOAc(约100mL)并经顶置硅胶垫的垫过滤。进一步用EtOAc(约1000mL)洗涤和硅。浓缩合并的滤液,得到(RS)-5-溴-6-氟-2-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺,其为淡黄色固体(9.24g,96%产率)。质谱m/z 369,371(M+H)+。
中间体6和7
(R)-5-溴-6-氟-2-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺(I-6),和
(S)-5-溴-6-氟-2-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺(I-7)
通过手性超临界流体色谱(柱:OD-H(3×25cm,5μm);流动相:CO2-MeOH(70:30),150mL/min,40℃)分离(RS)-5-溴-6-氟-2-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺[中间体5]的样品。从柱中洗脱的第一个峰提供(R)-5-溴-6-氟-2-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺[中间体6]。从柱中洗脱的第二个峰提供(S)-5-溴-6-氟-2-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺[中间体7]。两种对映异构体的质谱和1H NMR谱相同。质谱m/z 369,371(M+H)+。1H NMR(500MHz,DMSO-d6)δ10.96(s,1H),8.07(br.s.,1H),7.55(d,J=10.3Hz,1H),7.50(br.s.,1H),4.24(s,1H),3.26(dd,J=15.8,4.4Hz,1H),2.93(dd,J=17.1,4.6Hz,1H),2.72(t,J=11.7Hz,1H),2.48-2.40(m,1H),2.12(d,J=9.2Hz,1H),1.70-1.62(m,1H),and 1.32(qd,J=12.4,5.3Hz,1H)。
替代的超临界流体色谱分离:
通过手性超临界流体色谱(柱:AD-H(3×25cm,5μm);流动相:CO2-MeOH(55:45),150mL/min,40℃)分离(RS)-5-溴-6-氟-2-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺[中间体5]的样品。从柱中洗脱的第一个峰提供(S)-5-溴-6-氟-2-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺[中间体7]。从柱中洗脱的第二个峰提供(R)-5-溴-6-氟-2-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺[中间体6]。
中间体8
6-氟-2-(S)-(2-羟基丙-2-基)-5-(RS)-(1,2,3,4-四氢异喹啉-5-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺(非对映异构体的混合物)
中间体8A:5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯
使5-溴-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯(0.500g,1.60mmol)和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)(0.488g,1.92mmol)在DMF(8mL)中的混合物经受3次的抽真空-用氮气填充的循环。添加乙酸钾(0.472g,4.80mmol)和PdCl2(dppf)DCM络合物(0.117g,0.160mmol),并使混合物再经受2次抽真空-用氮气填充的循环,并在90℃在氮气气氛下加热过夜。将混合物冷却至室温,用EtOAc稀释,依序用水、10%LiCl水溶液和饱和盐水洗涤,干燥并浓缩。残余物经受用EtOAc-己烷洗脱的硅胶柱色谱,得到5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯,其为白色固体(0.514g,89%产率)。质谱m/z 360(M+H)+。
中间体8B:5-(RS)-(8-氨甲酰基-6-氟-2-(S)-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-5-基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯(非对映异构体的混合物)
将(S)-5-溴-6-氟-2-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺[中间体7](0.155g,0.420mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯(0.181g,0.504mmol)、2M K3PO4水溶液(0.630mL,1.26mmol)和THF(3mL)的混合物经受3次抽真空-用氮气填充的循环。将混合物用1,1′-双(二叔丁基膦基)二茂铁二氯化钯(0.014g,0.021mmol)处理并使混合物再经受2次抽真空-用氮气填充的循环。将混合物在室温搅拌过夜,然后用EtOAc稀释,依序用水和饱和盐水洗涤,干燥并浓缩。残余物经受用EtOAc-己烷(50-70%的梯度)洗脱的硅胶柱色谱,得到5-(RS)-(8-氨甲酰基-6-氟-2-(S)-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-5-基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯,即非对映异构体的混合物,其为灰白色固体(0.178g,81%产率)。质谱m/z 522(M+H)+。
中间体8:
将5-(RS)-(8-氨甲酰基-6-氟-2-(S)-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-5-基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯(非对映异构体的混合物)(0.178g,0.341mmol)和TFA(5mL)的混合物在室温搅拌30分钟。浓缩该混合物并用EtOAc稀释残余物,依序用1.5MK2HPO4水溶液和饱和盐水洗涤,干燥并浓缩,得到6-氟-2-(S)-(2-羟基丙-2-基)-5-(RS)-(1,2,3,4-四氢异喹啉-5-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺,即非对映异构体的混合物,其未经进一步纯化即使用。质谱m/z 422(M+H)+。
中间体9和10
6-氟-2-(S)-(2-羟基丙-2-基)-5-(1,2,3,4-四氢异喹啉-5-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺(单一非对映异构体)
粗制的6-氟-2-(S)-(2-羟基丙-2-基)-5-(RS)-(1,2,3,4-四氢异喹啉-5-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺(非对映异构体的混合物)[中间体8]经受制备型反相HPLC。用饱和NaHCO3水溶液中和后,从柱中洗脱出的第一个峰提供一种6-氟-2-(S)-(2-羟基丙-2-基)-5-(1,2,3,4-四氢异喹啉-5-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺的一种非对映异构体[中间体9](0.036g,25%产率),掺杂有1-2%第二个峰的非对映异构体。用饱和NaHCO3水溶液中和后,从柱中洗脱出的第二个峰提供6-氟-2-(S)-(2-羟基丙-2-基)-5-(1,2,3,4-四氢异喹啉-5-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺的另一种非对映异构体[中间体10](0.031g,20%产率),掺杂有8%第一个峰的非对映异构体。两种非对映异构体的质谱与中间体8的相同。HPLC保留时间(柱:SpeedROD 4.6×50mm;溶剂:含有0.1%TFA的MeOH-水,4.0mL/min;梯度:10-90%,历时4分钟):中间体9-1.88分钟;中间体10-2.02分钟。没有归属阻转异构键的绝对构型。
中间体11
(RS)-3-氟-4-(1,2,3,4-四氢异喹啉-5-基)-9H-咔唑-1-甲酰胺
遵循用于制备中间体8的操作,将4-溴-3-氟-9H-咔唑-1-甲酰胺[中间体3]转化成(RS)-3-氟-4-(1,2,3,4-四氢异喹啉-5-基)-9H-咔唑-1-甲酰胺。质谱m/z360(M+H)+。1H NMR(400MHz,MeOH-d4)δ7.85(d,J=10.4Hz,1H),7.60(d,J=8.2Hz,1H),7.53-7.46(m,1H),7.45-7.41(m,1H),7.40-7.36(m,1H),7.36-7.30(m,1H),6.93-6.86(m,1H),6.85-6.78(m,1H),4.50-4.27(m,2H),3.30-3.07(m,2H),2.85-2.68(m,1H),2.62-2.43(m,1H)。
中间体12
(RS)-3,3,6-三氟-5-(1,2,3,4-四氢异喹啉-5-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺
遵循用于制备中间体8的操作,将5-溴-3,3,6-三氟-2,3,4,9-四氢-1H-咔唑-8-甲酰胺[中间体2]转化成(RS)-3,3,6-三氟-5-(1,2,3,4-四氢异喹啉-5-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺。质谱m/z 400(M+H)+。1H NMR(400MHz,CDCl3)δ10.10(br.s.,1H),7.34-7.29(m,1H),7.27-7.23(m,1H),7.20(d,J=9.8Hz,1H),7.15(dd,J=7.4,1.3Hz,1H),4.81-4.55(m,2H),3.75-3.59(m,1H),3.47(ddd,J=12.8,7.9,4.6Hz,1H),3.01(t,J=6.6Hz,2H),2.68-2.17(m,6H)。
中间体13
(RS)-3-氟-4-(1,2,3,4-四氢异喹啉-5-基)-7-(三氟甲基)-9H-咔唑-1-甲酰胺TFA盐
遵循用于制备中间体8的操作,将4-溴-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺[中间体4]转化成(RS)-3-氟-4-(1,2,3,4-四氢异喹啉-5-基)-7-(三氟甲基)-9H-咔唑-1-甲酰胺TFA盐。质谱m/z 428(M+H)+,469(M+H+CH3CN)+。
中间体14
6-氟-5-(1,2,3,4-四氢异喹啉-5-基)-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺TFA盐(非对映异构体的混合物)
遵循用于制备中间体8的操作,将(RS)-5-溴-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺[中间体1]转化成(RS)-3-氟-4-(1,2,3,4-四氢异喹啉-5-基)-7-(三氟甲基)-9H-咔唑-1-甲酰胺TFA盐,其为非对映异构体的混合物。质谱m/z 432(M+H)+,473(M+H+CH3CN)+。
中间体15
(RS)-4-(3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺
中间体15A:8-溴-2H-苯并[b][1,4]噁嗪-4(3H)-甲酸叔丁酯
将8-溴-3,4-二氢-2H-苯并[b][1,4]噁嗪[根据PCT公开号WO 2012/149236的实施例10中所述的操作制备](1.20g,5.61mmol)、一缩二碳酸二叔丁酯(1.43mL,6.17mmol)和三乙胺(2.34mL,16.8mmol)在THF(20mL)中的溶液在室温搅拌5小时。未观察到反应,故将混合物浓缩。将残余物溶于1,4-二噁烷(25mL),用K2CO3(0.775g,5.61mmol)和另外的一缩二碳酸二叔丁酯(1.43mL,6.17mmol)处理,并将混合物在90℃加热3天。过滤该混合物并浓缩滤液。通过用EtOAc-己烷(0-50%的梯度)洗脱的硅胶柱色谱纯化残余物,得到8-溴-2H-苯并[b][1,4]噁嗪-4(3H)-甲酸叔丁酯,其为浅棕色油状物(1.37g,78%产率)。1H NMR(400MHz,CDCl3)δ7.75(d,J=7.5Hz,1H),7.27(dd,J=8.0,1.5Hz,1H),6.78(t,J=8.2Hz,1H),4.38(dd,J=5.1,4.2Hz,2H),3.92-3.87(m,2H),1.56(s,9H)。
中间体15:
遵循用于制备中间体8的操作,但在步骤B中用4-溴-3-氟-9H-咔唑-1-甲酰胺[中间体3]替代(S)-5-溴-6-氟-2-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺[中间体7],将8-溴-2H-苯并[b][1,4]噁嗪-4(3H)-甲酸叔丁酯转化成(RS)-4-(3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺。质谱m/z362(M+H)+。1H NMR(400MHz,MeOH-d4)δ7.76(d,J=10.4Hz,1H),7.56(d,J=8.2Hz,1H),7.35(ddd,J=8.2,7.1,1.2Hz,1H),7.24-7.18(m,1H),6.98-6.89(m,2H),6.87-6.81(m,1H),6.67(dd,J=7.3,1.6Hz,1H),4.16-3.96(m,2H),3.43-3.34(m,2H)。
中间体16
遵循用于制备中间体8的操作,但用9-溴-3,4-二氢苯并[b][1,4]氧氮杂-5(2H)-甲酸叔丁酯[根据PCT公开号WO 2012/170752的中间体D53所述的操作制备]替代5-溴-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯,将4-溴-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺[中间体4]转化成(RS)-3-氟-4-(2,3,4,5-四氢苯并[b][1,4]氧氮杂-9-基)-7-(三氟甲基)-9H-咔唑-1-甲酰胺as the TFA盐。质谱m/z 444(M+H)+。
中间体17
3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-9H-咔唑-1-甲酰胺
遵循用于制备中间体15的操作,将4-溴-3-氟-9H-咔唑-1-甲酰胺[中间体3]转化成3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-9H-咔唑-1-甲酰胺,其为黄色玻璃状固体,产率12%。质谱m/z 355(M+H)+。1H NMR(400MHz,CDCl3)δ8.56(d,J=8.1Hz,1H),7.58-7.48(m,2H),7.37-7.20(m,2H),1.56(s,12H)。
中间体18
(RS)-4-(3,4-二氢-2H-苯并[b][1,4]噻嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺TFA盐
中间体18A:8-溴-2H-苯并[b][1,4]噻嗪-4(3H)-甲酸叔丁酯
遵循用于制备中间体15A的操作,将8-溴-3,4-二氢-2H-苯并[b][1,4]噻嗪[根据PCT公开号WO 2012/149236的实施例331中所述的操作制备]转化成8-溴-2H-苯并[b][1,4]噻嗪-4(3H)-甲酸叔丁酯,其为棕色油状物,产率65%。质谱m/z 274,276(M+H-C4H8)+。
中间体18:
将3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-9H-咔唑-1-甲酰胺[中间体17](38mg,0.107mmol)、8-溴-2H-苯并[b][1,4]噻嗪-4(3H)-甲酸叔丁酯(37.2mg,0.113mmol)、K3PO4(45.5mg,0.215mmol)和1,1′-双(二叔丁基膦基)二茂铁二氯化钯(3.5mg,5.36μmol)在THF(1.5mL)和水(0.2mL)中的混合物用氮气清洗并在60℃搅拌过夜。将混合物冷却至室温,经过滤并浓缩。将残余物溶于DCM(2mL),用TFA处理并将混合物在室温搅拌30分钟。浓缩该混合物并使残余物经受制备型反相HPLC(YMC C18柱,5μm,30×250mm,用含0.1%TFA的乙腈-水洗脱,10-100%的梯度),得到(RS)-4-(3,4-二氢-2H-苯并[b][1,4]噻嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺TFA盐(23.6mg,58%产率),其为棕色固体。质谱m/z 378(M+H)+。1H NMR(400MHz,MeOH-d4)δ7.78(d,J=10.3Hz,1H),7.57(d,J=8.3Hz,1H),7.36(ddd,J=8.3,7.0,1.3Hz,1H),7.18(t,J=7.8Hz,1H),7.01-6.94(m,2H),6.94-6.88(m,1H),6.84(d,J=7.5Hz,1H),3.70-3.57(m,2H),3.07-2.88(m,2H)。
实施例1
(RS)-5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3,3,6-三氟-2,3,4,9-四氢-1H-咔唑-8-甲酰胺
将3,3,6-三氟-5-(1,2,3,4-四氢异喹啉-5-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺[中间体12](47mg,0.118mmol)和DIEA(62μL,0.353mmol)在3:1DCM-THF(0.5mL)中的混合物在0℃用丙烯酰氯(11μl,0.129mmol)处理。搅拌10分钟后,将混合物用DCM稀释,用水洗涤,干燥并浓缩。用EtOAc研磨残余物,得到(RS)-5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3,3,6-三氟-2,3,4,9-四氢-1H-咔唑-8-甲酰胺,其为白色固体(47mg,84%产率)。质谱m/z454(M+H)+。1H NMR(500MHz,DMSO-d6)δ11.20(s,1H),8.14(br.s.,1H),7.62(d,J=10.7Hz,1H),7.55(br.s.,1H),7.42-7.26(m,2H),7.19-7.11(m,1H),7.00-6.70(m,1H),6.14(d,J=16.6Hz,1H),5.88-5.62(m,1H),4.95-4.66(m,2H),3.80-3.48(m,2H),2.94(t,J=5.5Hz,2H),2.48-2.08(m,6H)。
通过实施例1所述的通用操作或类似操作,使用指定的原料制备表1中的实施例。
表1
实施例5
4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-9H-咔唑-1-甲酰胺(单一对映异构的阻转异构体)
通过手性超临界流体色谱(柱:AS-H(3×25cm,5μm);流动相:CO2-MeOH(70:30),150mL/min,100巴,35℃;样品制备:3mg/mL于MeOH中;注射:1.5mL)分离(RS)-4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-9H-咔唑-1-甲酰胺[实施例2]的样品(13mg)。从柱中洗脱的第一个峰提供4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-9H-咔唑-1-甲酰胺的一种对映异构的阻转异构体[实施例5](5.2mg)。质谱m/z 414(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),8.25(br.s.,1H),7.99(d,J=10.6Hz,1H),7.74(d,J=8.2Hz,1H),7.66(br.s.,1H),7.53-7.39(m,2H),7.38-7.17(m,2H),7.08-6.54(m,3H),6.28-6.01(m,1H),5.83-5.54(m,1H),5.12-4.69(m,2H),3.89-3.41(m,2H),2.71-2.28(m,2H,埋在残留DMSO峰下)。尚未归属实施例5的绝对构型。
实施例6
5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3,3,6-三氟-2,3,4,9-四氢-1H-咔唑-8-甲酰胺(单一对映异构的阻转异构体)
通过手性超临界流体色谱(柱:AS-H(3×25cm,5μm);流动相:CO2-MeOH(65-35),150mL/min,100巴,35℃;样品制备:7mg/mL于MeOH-DMF(9:1)中;注射:1.75mL)分离(RS)-5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3,3,6-三氟-2,3,4,9-四氢-1H-咔唑-8-甲酰胺[实施例1]的样品(42mg)。从柱中洗脱的第一个峰提供5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3,3,6-三氟-2,3,4,9-四氢-1H-咔唑-8-甲酰胺的一种对映异构的阻转异构体[实施例6](5mg)。质谱m/z 454(M+H)+。1H NMR(400MHz,MeOH-d4)δ7.50(d,J=10.6Hz,1H),7.41-7.31(m,2H),7.19(d,J=3.3Hz,1H),6.97-6.70(m,1H),6.25(dd,J=16.7,1.8Hz,1H),5.84-5.70(m,1H),4.98-4.86(m,2H),3.93-3.78(m,1H),3.78-3.53(m,1H),3.09-2.93(m,2H),2.73-2.34(m,3H),2.30-2.07(m,3H)。尚未归属实施例6的绝对构型。
实施例7
4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺(单一对映异构的阻转异构体)
通过手性超临界流体色谱(柱:IC(3×25cm,5μm);流动相:CO2-MeOH(60:40)at140mL/min,100巴,30℃;样品制备:2.5mg/mL于MeOH中;注射:1.7mL)分离(RS)-4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺[实施例4]的样品(20mg)。从柱中洗脱的第二个峰提供的一种对映异构的阻转异构体4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺[实施例7](5.8mg)。质谱m/z 482(M+H)+。1H NMR(400MHz,MeOH-d4)δ8.02-7.90(m,2H),7.56-7.45(m,2H),7.37-7.28(m,1H),7.19-7.08(m,1H),6.96-6.85(m,1H),6.71(dd,J=16.7,10.7Hz,1H),6.24(t,J=15.7Hz,1H),5.88-5.63(m,1H),5.06-4.92(m,2H),3.80(td,J=12.4,5.6Hz,1H),3.72-3.55(m,1H),2.74-2.57(m,1H),2.56-2.35(m,1H)。尚未归属实施例7的绝对构型。
实施例8
4-(4-丙烯酰基-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺(单一对映异构的阻转异构体)
通过手性超临界流体色谱(柱:IC 3×25cm;5μM;流动相:CO2-MeOH(55:45),140mL/min,30℃;样品制备:溶于1:1MeOH-DCM;注射:2.0mL)分离(RS)-4-(4-丙烯酰基-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺[实施例3]的样品(76mg)。从柱中洗脱的第一个峰提供4-(4-丙烯酰基-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺的一种对映异构的阻转异构体[实施例8](31.1mg)。质谱m/z 416(M+H)+。1H NMR(400MHz,MeOH-d4)δ7.80(d,J=10.5Hz,1H),7.59(m,2H),7.37(ddd,J=8.2,7.1,1.2Hz,1H),7.27(dd,J=7.6,1.6Hz,1H),7.20-7.14(m,1H),7.11(d,J=7.9Hz,1H),7.02-6.91(m,2H),6.47(dd,J=16.8,1.8Hz,1H),5.97-5.89(m,1H),4.28-4.07(m,4H)。尚未归属实施例8的绝对构型。
实施例9
5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(S)-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺(单一非对映异构体)
将6-氟-2-(S)-(2-羟基丙-2-基)-5-(1,2,3,4-四氢异喹啉-5-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺的单一非对映异构体[中间体9](0.036g,0.085mmol)和DIEA(0.060mL,0.342mmol)在THF(2mL)中的混合物在室温用丙烯酰氯(6.9μL,0.085mmol)处理。将混合物搅拌30分钟,用EtOAc稀释,依序用水和饱和盐水洗涤,干燥并浓缩。通过用EtOAc-己烷(50-75%的梯度)洗脱的硅胶柱色谱纯化残余物。通过手性超临界流体色谱(柱:AS-H(3×25cm,5μm);流动相:CO2-MeOH(65:35),150mL/min,35℃)进一步纯化所得物质。从柱中洗脱的第二个峰提供5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(S)-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺的单一非对映异构体,其为白色固体(0.030g,73%产率)。质谱m/z 476(M+H)+。未确定阻转异构键的绝对构型。
实施例10和11
5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺,单一纯手性非对映异构体
遵循用于制备实施例1的操作,将6-氟-5-(1,2,3,4-四氢异喹啉-5-基)-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺TFA盐(非对映异构体的混合物)[中间体14]转化成5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺,其为四种非对映异构体的混合物,产率49%。质谱m/z 486(M+H)+。
通过手性超临界流体色谱(柱:Chiral IC(3×25cm,5μm);流动相:CO2-MeOH(70:30)at 85mL/min;样品制备:10.7mg/mL于MeOH中;注射:1.0mL)分离该物质的样品(107mg)。从柱中洗脱的第三个峰提供5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺的一种纯手性非对映异构体[实施例10](14.5mg)。1H NMR(400MHz,MeOH-d4)δ7.49(d,J=10.4Hz,1H),7.38-7.28(m,2H),7.24-7.13(m,1H),6.99-6.68(m,1H),6.26(dd,J=16.8,1.8Hz,1H),5.87-5.71(m,1H),4.93-4.87(m,2H),3.77(quin,J=6.2Hz,2H),3.08(dd,J=16.4,4.6Hz,1H),2.83(dd,J=16.3,11.4Hz,1H),2.67-2.40(m,3H),2.08-1.86(m,3H),1.66-1.43(m,1H)。
从柱中洗脱的第四个峰提供5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺的另一种纯手性非对映异构体[实施例11](21.2mg),其掺杂有约2%作为第三个峰洗脱的纯手性非对映异构体[实施例10]。1HNMR(400MHz,MeOH-d4)δ7.48(d,J=10.5Hz,1H),7.36-7.27(m,2H),7.19-7.11(m,1H),6.98-6.70(m,1H),6.26(d,J=16.8Hz,1H),5.86-5.68(m,1H),4.99-4.75(m,2H),3.96-3.56(m,2H),3.09(dd,J=16.5,5.3Hz,1H),2.90-2.75(m,1H),2.74-2.33(m,3H),2.24-2.07(m,1H),1.95(dd,J=15.2,2.9Hz,1H),1.82(d,J=16.0Hz,1H),1.49(qd,J=12.2,5.2Hz,1H)。
两种纯手性非对映异构体的质谱与混合物的相同:m/z 486(M+H)+。尚未归属实施例10和11的绝对构型。
实施例12
遵循用于制备实施例1的操作,(RS)-3-氟-4-(2,3,4,5-四氢苯并[b][1,4]氧氮杂-9-基)-7-(三氟甲基)-9H-咔唑-1-甲酰胺TFA盐[中间体16]转化成(RS)-4-(5-丙烯酰基-2,3,4,5-四氢苯并[b][1,4]氧氮杂-9-基)-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺,产率77%。质谱m/z 498(M+H)+。
通过手性超临界流体色谱(柱:OJ-H(3×25cm,5μm);流动相:CO2-MeOH(80:20),85mL/min;样品制备:15.75mg/mL于MeOH中;注射:2.0mL)纯化该物质的样品(63mg)。从柱中洗脱的第二个峰提供4-(5-丙烯酰基-2,3,4,5-四氢苯并[b][1,4]氧氮杂-9-基)-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺的单一对映异构的阻转异构体(21.3mg)。质谱m/z 498(M+H)+。1H NMR(400MHz,MeOH-d4)δ8.05-7.83(m,2H),7.55-7.32(m,3H),7.28-6.97(m,2H),6.36(m,2H),5.77(br.s.,1H),4.90(br.s.,1H),4.28-3.74(m,2H),3.05(br.s.,1H),2.28-2.04(m,1H),1.85(br.s.,1H)。未确定阻转异构键的绝对构型。
使用所示的起始物质和操作,通过上述操作制备的其它实施例示于表2。
表2
(a)遵循用于实施例1制备的操作或类似操作制备。
(b)通过外消旋混合物的超临界流体色谱制备。尚未归属绝对构型。
比较实施例15
4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-9H-咔唑-1-甲酰胺(单一对映异构的阻转异构体)
在通过分离实施例2以分离出实施例5的过程中,由从柱中洗脱的第二个峰分离出4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-9H-咔唑-1-甲酰胺的另一种对映异构的阻转异构体,并提供比较实施例12(6.1mg)。该物质具有与实施例5相同的质谱和NMR谱。尚未确定比较实施例12的绝对构型。
比较实施例16
5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3,3,6-三氟-2,3,4,9-四氢-1H-咔唑-8-甲酰胺(单一对映异构的阻转异构体)
在通过分离实施例1以分离出实施例6的过程中,由从柱中洗脱的第二个峰分离出5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3,3,6-三氟-2,3,4,9-四氢-1H-咔唑-8-甲酰胺的另一种对映异构的阻转异构体,并提供比较实施例13(5mg)。该物质具有与实施例6相同的质谱和NMR谱。尚未确定比较实施例13的绝对构型。
比较实施例17
4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺(单一对映异构的阻转异构体)
在通过分离实施例4以分离出实施例7的过程中,由从柱中洗脱的第二个峰分离出4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺的另一种对映异构的阻转异构体,并提供比较实施例14(5.9mg)。该物质具有与实施例7相同的质谱和NMR谱。尚未确定比较实施例14的绝对构型。
比较实施例18
4-(4-丙烯酰基-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺(单一对映异构的阻转异构体)
在通过分离实施例3以分离出实施例8的过程中,由从柱中洗脱的第二个峰分离出4-(4-丙烯酰基-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺的另一种对映异构的阻转异构体,并提供比较实施例15(32.1mg)。该物质具有与实施例8相同的质谱和NMR谱。尚未确定比较实施例15的绝对构型。
比较实施例19
5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(S)-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺(单一非对映异构体)
遵循用于由中间体10制备实施例9的操作,将6-氟-2-(S)-(2-羟基丙-2-基)-5-(1,2,3,4-四氢异喹啉-5-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺的另一中非对映异构体[中间体11]转化成5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(S)-(2-羟基丙-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺的单一非对映异构体,其为白色固体,产率76%。质谱m/z 476(M+H)+。未确定阻转异构键的绝对构型。
比较实施例20和21
5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺,单一纯手性非对映异构体
在通过手性超临界流体色谱分离实施例10和11的过程中,分离出5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺的两种另外的纯手性非对映异构体。从柱中洗脱的第一个峰提供5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺的一种纯手性非对映异构体[比较实施例20](15.0mg)。该物质具有与实施例10相同的NMR谱,且因此实施例10和比较实施例20为对映异构体。
从柱中洗脱的第二个峰提供5-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-6-氟-2-(三氟甲基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺的另一种纯手性非对映异构体[比较实施例21](21.2mg),其掺杂有约2%作为第一个峰洗脱的纯手性非对映异构体[比较实施例20]。该物质具有与实施例11相同的NMR谱,且因此实施例11和比较实施例21为对映异构体。
两种纯手性非对映异构体的质谱与混合物的相同:m/z 486(M+H)+。尚未确定比较实施例10和21的绝对构型。
比较实施例22
在通过手性超临界流体色谱分离实施例12的过程中,由从柱中洗脱的第一个峰分离出4-(5-丙烯酰基-2,3,4,5-四氢苯并[b][1,4]氧氮杂-9-基)-3-氟-7-(三氟甲基)-9H-咔唑-1-甲酰胺的另一种对映异构的阻转异构体,并提供比较实施例22(20.5mg)。该物质具有与实施例12相同的质谱和NMR谱。尚未确定比较实施例22的绝对构型。
比较实施例23
4-(4-丙烯酰基-3,4-二氢-2H-苯并[b][1,4]噻嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺(单一对映异构的阻转异构体)
在通过手性超临界流体色谱分离实施例14的过程中,由从柱中洗脱的第二个峰分离出4-(4-丙烯酰基-3,4-二氢-2H-苯并[b][1,4]噻嗪-8-基)-3-氟-9H-咔唑-1-甲酰胺的另一种对映异构的阻转异构体,并提供比较实施例23。该物质具有与实施例14相同的质谱和NMR谱。尚未确定比较实施例23的绝对构型。
实施例24
4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氯-9H-咔唑-1-甲酰胺,阻转异构体1
中间体24A:4-溴-3-氯-9H-咔唑-1-甲酸
向5-溴-6-氯-2,3,4,9-四氢-1H-咔唑-8-甲酸(793mg,2.413mmol)在THF(30mL)中的溶液中添加DDQ(1096mg,4.83mmol),将混合物在60℃搅拌18小时。浓缩该混合物。粗产物经受ISCO快速色谱(硅胶/DCM:MeOH:HOAc93.5:5:1.5)。得到4-溴-3-氯-9H-咔唑-1-甲酸(350mg,1.024mmol,42.5%产率),其为棕色固体。LCMS:1.19分钟,M+H 324。
中间体24B:4-溴-3-氯-9H-咔唑-1-甲酰胺
将4-溴-3-氯-9H-咔唑-1-甲酸(350mg,1.078mmol)、氯化铵(288mg,5.39mmol)、BOP(525mg,1.186mmol)和TEA(1.503mL,10.78mmol)在DMF(5.0mL)中的混合物在室温搅拌60分钟。用EtOAc(15mL)稀释该混合物并用1.0M HCl水溶液(2x15mL)洗涤。将乙酸乙酯层以硫酸钠干燥并浓缩。粗产量:4-溴-3-氯-9H-咔唑-1-甲酰胺(203mg,0.596mmol,55.3%产率),其为棕色固体。1H NMR(400MHz,甲醇-d4)δ8.77(d,J=8.2Hz,1H),8.08(s,1H),7.71-7.62(m,1H),7.60-7.49(m,1H),7.30(ddd,J=8.2,7.2,1.0Hz,1H)。
中间体24C:5-(1-氨甲酰基-3-氯-9H-咔唑-4-基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯
将4-溴-3-氯-9H-咔唑-1-甲酰胺(80mg,0.247mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯(89mg,0.247mmol)、1,1′-双(二叔丁基膦基)二茂铁二氯化钯(8.06mg,0.012mmol)和2.0M磷酸钾水溶液(0.618mL,1.236mmol)在二噁烷(4.0mL)中的混合物在60℃在密封小瓶中在氮气下搅拌18小时。用EtOAc(15mL)稀释该混合物并用饱和碳酸氢钠水溶液(2×15mL)和1.0M HCl水溶液(15mL)洗涤。将乙酸乙酯层以硫酸钠干燥并浓缩。粗产物经受ISCO快速色谱(硅胶/DCM-EtOAc100:0至0:100梯度)。得到5-(1-氨甲酰基-3-氯-9H-咔唑-4-基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯(90mg,0.180mmol,72.7%产率),其为白色泡沫状物。LCMS:1.21分钟,2M+H 324。
实施例24:
向5-(1-氨甲酰基-3-氯-9H-咔唑-4-基)-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯(70mg,0.147mmol)在DCM(1.0mL)中的溶液中添加TFA(1.0mL),将混合物在室温搅拌30分钟。将混合物浓缩,得到粗制的3-氯-4-(1,2,3,4-四氢异喹啉-5-基)-9H-咔唑-1-甲酰胺,TFA盐.
在0℃,向3-氯-4-(1,2,3,4-四氢异喹啉-5-基)-9H-咔唑-1-甲酰胺,TFA盐和TEA(0.102mL,0.735mmol)在DCM(1.0mL)中的溶液中添加丙烯酰氯(0.013mL,0.162mmol)在DCM(0.5mL)中的溶液,将混合物在室温搅拌30分钟。粗产物经受ISCO快速色谱(硅胶/己烷-EtOAc 100:0至0:100梯度),得到4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氯-9H-咔唑-1-甲酰胺(43.52mg,0.096mmol,65.4%产率)。LCMS:0.88分钟,M+H 430。
通过手性超临界流体色谱(Chiral IC(3×25cm,5μm);流动相:CO2-MeOH60-40,850mL/min;样品制备:85mg在5mL MeOH中)分离4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氯-9H-咔唑-1-甲酰胺(33mg)。从柱中洗脱的第一个峰提供4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氯-9H-咔唑-1-甲酰胺的一种对映异构体,其为白色粉末(11.99mg)。1H NMR(400MHz,甲醇-d4)δ8.11(s,1H),7.59(d,J=8.2 Hz,1H),7.52-7.41(m,2H),7.39-7.28(m,1H),7.26-7.13(m,1H),6.89-6.79(m,1H),6.74-6.50(m,2H),6.32-6.10(m,1H),5.88-5.62(m,1H),4.95(d,J=13.7 Hz,2H),3.83-3.54(m,2H),2.66-2.49(m,1H),2.37(m,1H)。LCMS:0.88分钟,M+H 430。从柱中洗脱的第二个峰提供4-(2-丙烯酰基-1,2,3,4-四氢异喹啉-5-基)-3-氯-9H-咔唑-1-甲酰胺的另一种对映异构体,其为白色粉末(10.78mg)。1H NMR(400MHz,甲醇-d4)δ8.11(s,1H),7.59(d,J=8.2 Hz,1H),7.52-7.41(m,2H),7.38-7.29(m,1H),7.24-7.16(m,1H),6.90-6.79(m,1H),6.73-6.52(m,2H),6.32-6.13(m,1H),5.86-5.64(m,1H),4.97(m,2H),3.82-3.55(m,2H),2.58(m,1H),2.44-2.27(m,1H)。LCMS:0.88分钟,M+H 430.
使用适当的起始物质,通过上述实施例所述的通用操作或本领域已知的类似操作制备表1中的实施例。
表1
生物学测定
本发明化合物的药理学性质可通过许多生物测定来证实。已用本发明化合物进行以下示例性生物测定。
人重组Btk酶测定
向V形底384孔板中加入测试化合物、人重组Btk(1nM,Invitrogen Corporation)、荧光素肽(fluoresceinated peptide)(1.5μM)、ATP(20μM)和测定缓冲液(20mM HEPES pH7.4,10mM MgCl2,0.015%Brij 35表面活性剂和4mM DTT在1.6%DMSO中的溶液),终体积为30μL。在室温温育60分钟后,通过向每个样品中加入45μL 35mM EDTA终止反应。通过荧光底物和磷酸化产物的电泳分离在Caliper3000(Caliper,Hopkinton,MA)上分析反应混合物。如下计算抑制数据:将无酶对照反应混合物(100%抑制)与无抑制剂对照(0%抑制)相比。作出剂量响应曲线以确定抑制50%激酶活性所需的浓度(IC50)。化合物以10mM溶于DMSO中并以11个浓度进行评价。
Ramos FLIPR测定
将在含0.1%BSA(Sigma A8577)的RPMI minus酚红(Invitrogen11835-030)和50mM HEPES(Invitrogen 15630-130)中密度为2×106个细胞/mL的Ramos RA1B细胞(ATCCCRL-1596)加至一半体积的钙上样缓冲液(用于丙磺舒敏感性测定的BD大试剂盒(bulkkit),#640177)中并在室温在黑暗中温育1小时。将负载染料的细胞Dye-loaded cellswere pelleted(Beckmann GS-CKR,1200rpm,室温,5分钟)并在室温重新混悬在具有50mMHEPES和10%FBS的RPMI minus酚红中至密度为1×106个细胞/mL。将150μL等分试样(150,000个细胞/孔)加至96孔聚-D-赖氨酸包覆的测定板(BD 35 4640)中并短暂离心(BeckmannGS-CKR 800rpm,5分钟,无制动)。接着,将50μL化合物在0.4%DMSO/RPMI minus酚红+50mMHEPES+10%FBS中的稀释液加至孔中并将板在室温在黑暗中温育1小时。在测量钙水平之前将测定板如上所述短暂离心。使用FLIPR1(Molecular Devices),通过加入山羊抗-人IgM(Invitrogen AHI0601)至2.5μg/mL来刺激细胞。历时180秒测量细胞内钙浓度的变化并确定相对于仅存在刺激时观察到的峰值钙水平的抑制百分数。Ramos测定法测量化合物通过细胞膜移入细胞内部的能力。较低的IC50值表明进入细胞内部的能力更大。
表3示出在人重组Btk酶测定和Ramos FLIPR测定中获自实施例1、3和5-14的评价的Btk IC50值和Ramos IC50值。
表3
表4示出人重组Btk酶测定和Ramos FLIPR测定中实施例5-12和14以及比较实施例15至23的Btk IC50值和Ramos IC50值。
表4
a重组人Btk酶测定中的IC50(nM)
bRamos FLIPR测定中的IC50(nM)
c比较实施例的重组人Btk酶测定中与相应实施例中IC50值的比率。
d比较实施例的Ramos FLIPR测定中与相应实施例中IC50值的比率。
已将实施例5至12和14所例举的式(I)化合物与其立体异构体(比较实施例15至23)进行比较,且已发现具有改善的Btk效力。增加的效力由较小的Btk IC50值表示。如表4所示,在报道的Btk测定中,实施例5至12和14的Btk IC50值小于0.4 nM。相比之下,比较实施例15至23的Btk IC50值在1.5至28 nM的范围内。表4中还报道了实施例5至12和14的Btk IC50值与其相应的立体异构体的Btk IC50值的比较。Btk比率被报道为相应的立体异构体(比较实施例15至23)的Btk IC50活性值与式(I)的实施例的Btk IC50值的比。与其立体异构体相比,较高的Btk IC50比率表明实施例化合物的效力改善。与它们的立体异构体相比,实施例5至12和14所例举的式(I)化合物显示出效力改善至少19倍或更大。
已将实施例5至12和14所例举的式(I)化合物与其立体异构体(比较实施例15-23)进行比较,且已发现在Ramos FLIPR测定中具有改善的效力。增加的效力由较小的RamosIC50值表示。如表4所示,在报道的Ramos测定中,实施例5至12和14的Ramos IC50值为23nM或更低。相比之下,比较实施例15-23的Ramos IC5050值为65nM或更大。表4中还报道了实施例5至12和14的Ramos IC50值与其相应立体异构体的Ramos IC50值的比较。Ramos比率被报道为对应的立体异构体(比较实施例15-23)的Ramos IC50活性值与式(I)的实施例的Ramos IC50值的比。与其立体异构体相比,较高的Ramos IC50比率表明实施例化合物的效力改善。与其立体异构体相比,实施例5至12和14所例举的式(I)化合物显示出Ramos效力改善至少9.4倍或更大。
已将实施例5至12和14所例举的式(I)化合物与其立体异构体(比较实施例15-23)进行比较,且已发现是有利的。与其立体异构体相比,式(I)化合物具有令人惊讶的优点:增加的Btk效力和增加的Ramos活性的组合。与其立体异构体相比,实施例5至12和14显示出以下组合:Btk效力改善至少19倍或更大,且Ramos效力改善至少9.4倍或更大。
这些结果表明分子的绝对三维排列对于式(I)化合物的效力是重要的。
人重组Btk解离透析测定
将测试化合物与人重组Btk(100nM)温育1.5小时,浓度为Btk抑制的IC50的25倍或200nM(取较大者)。在测定缓冲液(20mM HEPES pH 7.5,10mM MgCl2,2mM二硫苏糖醇,50μg/mL胎牛血清和0.015%Brij 35)中进行温育。然后将反应混合物每次对1L测定缓冲液透析两次,每次6小时。然后将透析的反应混合物(0.5μL)稀释至ATP(2mM)和底物肽(5μM Src-tide,AnaSpec)的溶液(100μL),使得最终的Btk浓度为1nM(连同仍然结合的任何抑制剂)。在基质聚丙烯384孔板中进行测定。通过电泳分离底物和磷酸化产物(压力-1.2psi,下游电压-500V,上游电压-2300V),在Caliper上监测反应进程曲线。在线性相上测量反应速度,并在2小时通过比较磷酸化肽产物相对于不含实施例抑制剂的经DMSO处理的Btk对照反应的分数来评估Btk活性的百分比回收率。没有Btk的对照反应也用于测量背景信号。可逆性抑制剂将显示Btk活性的几乎完全恢复,而不可逆抑制剂将显示出很少或没有Btk活性的恢复。
Claims (12)
1.式(I)化合物或其盐
其中:
两条虚线表示两个单键或两个双键;且仅当所述两条虚线为两个单键时存在R1b;
X为:
(i)当两条虚线表示两个单键时,CR2aR2b或NR2b;或
(ii)当两条虚线表示两个双键时,CR2a或N;
Q为:
R1a为H、-CN、-CF3、-CH3、-CR6aR6bOH、-CH2CH2OH、-CH(OH)CH2OH、-CH2CH2F、-NHR7或-C(O)NR8aR8b;
R1b,当存在时,为H或-CH3,条件是如果R1a为H,则R1b也为H;
R2a为H、F或Cl,条件是如果R1a不为H,则R2a为H;
R2b,当存在时,与R2a相同;
R3为F或Cl;
R4为H、F、Cl、-OCH3或-OCF3;
R5为-CN或-C(O)CH=CH2;
R6a和R6b独立地为H或-CH3;
R7为C1-4烷基;且
R8a和R8b独立地为H或-CH3。
2.权利要求1的化合物或其盐,其中:
X为:
(i)当两条虚线表示两个单键时,CR2aR2b;或
(ii)当两条虚线表示两个双键时,CR2a。
3.权利要求1的化合物或其盐,其中:
X为:
(i)当两条虚线表示两个单键时,NR2b;或
(ii)当两条虚线表示两个双键时,N。
4.权利要求1的化合物或其盐,其中:
R1a为H、-CF3或-C(CH3)2OH;
R1b为H;
R2a为H或F,条件是如果R1a不为H,则R2a为H;
R2b,当存在时,与R2a相同;
R3为F;且
R4为H。
10.权利要求4的化合物或其盐,其中:
R3为F;
R4为H;且
R5为-C(O)CH=CH2。
11.一种药物组合物,其包含权利要求1-10中任一项的化合物和药学上可接受的载体。
12.权利要求1-10中任一项的化合物在制备用于治疗自身免疫性疾病或慢性炎性疾病的药物中的用途。
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