CN114174304B - 可用作irak4抑制剂的噻吩并吡啶基化合物和噻唑并吡啶基化合物 - Google Patents
可用作irak4抑制剂的噻吩并吡啶基化合物和噻唑并吡啶基化合物 Download PDFInfo
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- CN114174304B CN114174304B CN202080052689.6A CN202080052689A CN114174304B CN 114174304 B CN114174304 B CN 114174304B CN 202080052689 A CN202080052689 A CN 202080052689A CN 114174304 B CN114174304 B CN 114174304B
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- pyridine
- carboxamide
- thieno
- isopropylamino
- hydroxy
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Abstract
公开了式(I)的化合物或其盐或前药,其中:X是CR4或N;并且R1、R2、R3、R4和n在本文中定义。还公开了使用此类化合物作为IRAK4调节剂的方法,以及包含此类化合物的药物组合物。这些化合物可用于治疗、预防或减慢炎性疾病或自身免疫性疾病,或用于治疗癌症。
Description
相关申请的交叉引用
本申请要求2019年7月23日提交的美国临时申请序列号62/877,334的权益,将所述临时申请以其整体并入本文。
说明书
本发明总体上涉及可用作激酶抑制剂(包括IRAK-4的调节)的噻吩并吡啶基化合物和噻唑并吡啶基化合物。本文提供了噻吩并吡啶基化合物和噻唑并吡啶基化合物、包含此类化合物的组合物、和它们的使用方法。本发明进一步涉及含有至少一种根据本发明的化合物的药物组合物,所述药物组合物可用于治疗与激酶调节相关的病症,和抑制激酶(包括哺乳动物中的IRAK-4)的活性的方法。
Toll/IL-1受体家族成员是炎症和宿主抗性的重要调节因子。Toll样受体(TLR)家族识别源自包括细菌、真菌、寄生虫和病毒的传染性生物体的分子模式(综述于Kawai,T.等人,Nature Immunol.,11:373-384(2010)中)。与受体结合的配体诱导衔接子分子的二聚化和募集到被称为Toll/IL-1受体(TIR)的受体的结构域中的保守细胞质基序。除TLR3外,所有TLR都募集衔接子分子MyD88。IL-1受体家族还含有细胞质TIR基序并且在配体结合时募集MyD88(综述于Sims,J.E.等人,Nature Rev.Immunol.,10:89-102(2010)中)。
丝氨酸/苏氨酸激酶的IRAK家族的成员经由与MyD88相互作用而被募集到受体中。所述家族由四个成员组成。有几条证据线表明,IRAK4在经由MyD88依赖性TLR和IL-1R家族成员的启动信号传导中起着关键且非冗余的作用。结构数据证实,IRAK4直接与MyD88相互作用并且随后将IRAK1或IRAK2募集至受体复合物以促进下游信号传导(Lin,S.等人,Nature,465:885-890(2010))。IRAK4直接磷酸化IRAK1以促进向E3泛素连接酶TRAF6的下游信号传导,导致丝氨酸/苏氨酸激酶TAK1的激活以及随后NFκB途径和MAPK级联的激活(Flannery,S.等人,Biochem.Pharmacol.,80:1981-1991(2010))。鉴定了缺乏IRAK4表达的人类患者子集(Picard,C.等人,Science,299:2076-2079(2003))。来自这些患者的细胞不能对所有TLR激动剂做出反应,除了TLR3以及IL-1家族的成员(包括IL-1β和IL-18)(Ku,C.等人,J.Exp.Med.,204:2407-2422(2007))。小鼠中IRAK4的缺失导致IL-1、IL-18和所有TLR(除TLR3外)依赖性反应的严重阻断(Suzuki,N.等人,Nature,416:750-754(2002))。相比之下,IRAK1(Thomas,J.A.等人,J.Immunol.,163:978-984(1999);Swantek,J.L.等人,J.Immunol.,164:4301-4306(2000))或IRAK2(Wan,Y.等人,J.Biol.Chem.,284:10367-10375(2009))的缺失导致信号传导的部分丧失。此外,IRAK4是IRAK家族中唯一的已经显示其激酶活性是启动信号传导所需的成员。将小鼠基因组中的野生型IRAK4用激酶失活突变体(KDKI)替换损害了经由所有的MyD88依赖性受体(包括IL-1、IL-18和除TLR3之外的所有TLR)的信号传导(Koziczak-Holbro,M.等人,J.Biol.Chem.,282:13552-13560(2007);Kawagoe,T.等人,J.Exp.Med.,204:1013-1024(2007);和Fraczek,J.等人,J.Biol.Chem.,283:31697-31705(2008))。
与野生型动物相比,IRAK4 KDKI小鼠在多发性硬化症(Staschke,K.A.等人,J.Immunol.,183:568-577(2009))、类风湿性关节炎(Koziczak-Holbro,M.等人,ArthritisRheum.,60:1661-1671(2009))、动脉粥样硬化(Kim,T.W.等人,J.Immunol.,186:2871-2880(2011)和Rekhter,M.等人,Biochem.Biophys.Res.Comm.,367:642-648(2008))、和心肌梗塞(Maekawa,Y.等人,Circulation,120:1401-1414(2009))的小鼠模型中显示出大大降低的疾病严重程度。如所述,IRAK4抑制剂将阻断所有MyD88依赖性信号传导。已显示MyD88依赖性TLR有助于多发性硬化症、类风湿性关节炎、心血管疾病、代谢综合征、败血症、系统性红斑狼疮、炎性肠病(包括克罗恩病和溃疡性结肠炎)、自身免疫性葡萄膜炎、哮喘、过敏、I型糖尿病和同种异体移植排斥的发病机理(Keogh,B.等人,Trends Pharmacol.Sci.,32:435-442(2011);Mann,D.L.,Circ.Res.,108:1133-1145(2011);Horton,C.G.等人,Mediators Inflamm.,Article ID 498980(2010),doi:10.1155/2010/498980;Goldstein,D.R.等人,J.Heart Lung Transplant.,24:1721-1729(2005);和Cario,E.,Inflamm.BowelDis.,16:1583-1597(2010))。已鉴定出弥漫性大B细胞淋巴瘤中的致癌活性MyD88突变,这些突变对IRAK4抑制是敏感的(Ngo,V.N.等人,Nature,470:115-121(2011))。全基因组测序还鉴定出与慢性淋巴性白血病相关的MyD88突变,表明IRAK4抑制剂还具有治疗白血病的效用(Puente,X.S.等人,Nature,475:101-105(2011))。
除了阻断TLR信号传导外,IRAK4抑制剂还将阻断通过IL-1家族成员的信号传导。IL-1的中和已显示对包括以下的多种疾病有效:痛风;痛风性关节炎;2型糖尿病;自身炎性疾病,包括Cryopyrin相关的周期性综合征(CAPS)、TNF受体相关的周期性综合征(TRAPS)、家族性地中海热(FMF)、成人发作的斯蒂尔病;全身性发作的幼年特发性关节炎;中风;移植物抗宿主病(GVHD);冒烟型多发性骨髓瘤;复发性心包炎;骨关节炎;肺气肿(Dinarello,C.A.,Eur.J.Immunol.,41:1203-1217(2011)和Couillin,I.等人,J.Immunol.,183:8195-8202(2009))。在阿尔茨海默病的小鼠模型中,IL-1受体的阻断会改进认知缺陷,减弱蛋白病理学,并且减少淀粉样蛋白β的寡聚形式(Kitazawa,M.等人,J.Immunol.,187:6539-6549(2011))。还已显示出,IL-1是导致适应性免疫的关键环节,驱动TH17效应T细胞亚群的分化(Chung,Y.等人,Immunity,30:576-587(2009))。因此,预测IRAK4抑制剂在TH17相关的疾病中具有功效,这些疾病包括多发性硬化症、银屑病、炎性肠病、自身免疫性葡萄膜炎和类风湿性关节炎(Wilke,C.M.等人,Trends Immunol.,32:603-661(2011))。
鉴于可能通过涉及调节蛋白激酶的治疗而受益的病症,立即清楚的是,能够调节蛋白激酶(诸如IRAK-4)的新化合物以及使用这些化合物的方法可以为多种多样患者提供实质性治疗益处。
发明内容
本发明涉及一类新的噻吩并吡啶基化合物和噻唑并吡啶基化合物,它们被发现是蛋白质激酶(包括IRAK-4)的有效抑制剂。提供的这些化合物可用作具有对其成药性重要的所希望的稳定性、生物利用度、治疗指数和毒性值的药物。
本发明提供了可用作IRAK-4的抑制剂并且可用于治疗增殖性疾病、过敏性疾病、自身免疫性疾病和炎性疾病的式(I)的化合物,或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药。
本发明还提供了药物组合物,所述药物组合物包含药学上可接受的载体以及至少一种本发明的化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药。
本发明还提供了一种用于抑制IRAK-4的方法,包括向需要此类治疗的宿主施用治疗有效量的本发明的化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药中的至少一种。
本发明还提供了一种用于治疗增殖性、代谢性、过敏性、自身免疫性和炎性疾病的方法,包括向需要此类治疗的宿主施用治疗有效量的本发明的化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药中的至少一种。
一个实施方案提供了一种用于治疗炎性疾病和自身免疫性疾病的方法,其中,甚至更优选的是治疗炎性疾病。具体的炎性疾病和自身免疫性疾病包括但不限于,克罗恩病、溃疡性结肠炎、哮喘、移植物抗宿主病、同种异体移植排斥、慢性阻塞性肺疾病、格雷夫斯病、类风湿性关节炎、系统性红斑狼疮、狼疮性肾炎、皮肤狼疮、银屑病、cryopyrin相关的周期性综合征(CAPS)、TNF受体相关的周期性综合征(TRAPS)、家族性地中海热(FMF)、成人发作的斯蒂尔病、全身性发作的幼年特发性关节炎、多发性硬化症、神经性疼痛、痛风和痛风性关节炎。
一个实施方案提供了一种用于治疗痛风和痛风性关节炎的方法。
一个可替代的优选实施方案是一种用于治疗代谢性疾病(包括2型糖尿病和动脉粥样硬化)的方法。
一个实施方案提供了一种用于治疗癌症的方法,所述方法包括向需要此类治疗的宿主施用治疗有效量的本发明的化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药中的至少一种。
本发明还提供了本发明的化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,用于疗法。
本发明还提供了本发明的化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药用于制造用于治疗癌症的药剂的用途。
本发明还提供了在试剂盒中的式(I)的化合物或药物组合物以及使用所述化合物或组合物的说明书。
本发明还提供了制备本发明的化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药的方法和中间体。
本发明的这些和其他特征将随本公开文本的展开以扩展的形式阐述。
具体实施方式
本发明的第一方面提供了至少一种式(I)的化合物:
或其盐或前药,其中:
X是CR4或N;
R1是:
(i)-C(O)NHR1a或-C(O)NH(CH2)1-3R1b;或
(ii)吡唑基、咪唑基、异噁唑基或三唑基,各自被0或1个R1c取代;
R1a是:
(i)氢或被1至4个独立地选自以下的取代基取代的C3-6烷基:F、-CN、-OH、C1-2烷氧基、C1-2氟烷氧基、-NRyRy、-NRxC(O)(C1-3烷基)、-C(O)NRyRy、-S(O)2(C1-3烷基)和-NRxS(O)2(C1-3烷基);或
(ii)选自以下的环状基团:C3-6环烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吡咯基、吡唑基、吡啶基、咪唑基和三唑基,其中所述环状基团被零或一个选自以下的取代基取代:-OH、-C(O)(C1-3烷基)、-C(O)(C1-3氟烷基)、-C(O)O(C1-3烷基)、-NRaRa、-NRaC(O)(C1-3烷基)、-NRaC(O)O(C1-3烷基)、-S(O)2(C1-3烷基)、-S(O)2(C1-3氟烷基)、-C(O)(C3-6环烷基)、-C(O)(吗啉基)、-CH2(吡啶基)、-S(O)2(吡啶基)、吗啉基和三唑基;
R1b是C3-6环烷基、氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、二氧化硫代吗啉基、吡咯基、吡唑基、咪唑基、三唑基或吡啶基,各自被0至3个独立地选自以下的取代基取代:F、-OH、-CH3、-CF3和-CH2OH;
R1c是F、Cl、-OH、-CN或被0至4个独立地选自以下的取代基取代的C1-6烷基:F、-CN、-OH、C1-2烷氧基、C3-6环烷基、-NRyRy、-NRxC(O)(C1-3烷基)、-C(O)NRyRy、-S(O)2(C1-3烷基)和-NRxS(O)2(C1-3烷基);
R2是:
(i)被0至4个独立地选自以下的取代基取代的C1-6烷基:F、Cl、-OH和-CN;或
(ii)选自以下的环状基团:C3-6环烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基和吡唑基,其中所述环状基团被0至3个独立地选自以下的取代基取代:F、-OH、-CN、C1-2烷基、C1-2氟烷基和C1-2羟烷基;
R3是R3a或-NHR3a;
R3a是吡唑基、噻唑基、苯基、吡啶基、吡啶酮基、哒嗪基、吡咯并[2,3-b]吡啶基或咪唑并[1,2-a]吡啶基,各自被0至1个选自以下的取代基取代:F、Cl、-CN、C1-2烷基、C1-2氟烷基、C1-2羟烷基、C1-2烷氧基、-NRxRx、-S(O)2(C1-3烷基)和吡唑基;
每个R4独立地是氢、F、Cl、-CH3或-CF3;
每个Rx独立地是氢或-CH3;并且
每个Ry独立地是氢或C1-4烷基。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中X是CR4。此实施方案的化合物具有式(Ia)的结构:
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中X是N。此实施方案的化合物具有式(Ib)的结构:
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中
R1是:
(i)-C(O)NHR1a或-C(O)NH(CH2)1-3R1b;或
(ii)吡唑基、咪唑基、异噁唑基或三唑基,各自被0或1个R1c取代;
R1a是:
(i)氢或被1至4个独立地选自以下的取代基取代的C3-5烷基:F、-CN、-OH、C1-2烷氧基、C1-2氟烷氧基、-NRaRa、-C(O)NRaRa、-S(O)2(C1-2烷基)和-NRaS(O)2(C1-2烷基);或
(ii)选自以下的环状基团:C3-6环烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、哌啶基和吡啶基,各自被零或一个选自以下的取代基取代:-OH、-C(O)(C1-2烷基)、-C(O)O(C1-3烷基)、-NRaRa、-NRaC(O)(C1-2烷基)、-NRaC(O)O(C1-2烷基)、-S(O)2(C1-2烷基)、-S(O)2(C1-3氟烷基)、-C(O)(C3-6环烷基)、-C(O)(吗啉基)、-CH2(吡啶基)、-S(O)2(吡啶基)、吗啉基和三唑基;
R1b是C3-6环烷基、吡咯烷基、哌啶基、二氧化硫代吗啉基、三唑基或吡啶基,各自被0至3个独立地选自以下的取代基取代:F、-OH、-CH3和-CH2OH;
R1c是F、Cl、-OH、-CN或被0至4个独立地选自以下的取代基取代的C1-6烷基:F、-CN、-OH、C1-2烷氧基、C3-6环烷基、-NRyRy、-NRxC(O)(C1-2烷基)和-C(O)NRyRy;
R2是:
(i)被0至2个独立地选自以下的取代基取代的C1-4烷基:F、-OH和-CN;或
(ii)选自以下的环状基团:C3-6环烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基和吡唑基,其中所述环状基团被0至2个独立地选自以下的取代基取代:F、-OH、-CN、C1-2烷基、C1-2氟烷基和C1-2羟烷基;并且
R3a是吡唑基、噻唑基、苯基、吡啶基、吡啶酮基、哒嗪基、吡咯并[2,3-b]吡啶基或咪唑并[1,2-a]吡啶基,各自被0至1个选自以下的取代基取代:F、Cl、-CN、C1-2烷基、-CF3、C1-2羟烷基、C1-2烷氧基、-NH2、-S(O)2(C1-2烷基)和吡唑基。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中:
R1是:
(i)-C(O)NHR1a或-C(O)NH(CH2)1-3R1b;或
(ii)被-CH2CH2CH(CH3)2、-CH2CH2CH2OH、-CH2CH2C(CH3)2OH或-CH2(环丙基)取代的三唑基;
R1a是:
(i)-CH2CH2CN、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2CH(CH3)OH、-CH2CH2S(O)2CH3、-CH2CH2NHS(O)2CH3、-CH2CHFC(CH3)2OH或-CH2CH2CH2NHS(O)2CH3;或
(ii)环丁基、环己基或哌啶基,各自被-OH、-NH2、-C(O)CH3、-OC(O)CH3、-NHC(O)CH3或-NHC(O)OCH3取代;
R1b是环丙基、环丁基、吡咯烷基、哌啶基、二氧化硫代吗啉基、三唑基或吡啶基,各自被0至3个独立地选自以下的取代基取代:F、-OH和-CH2OH;
R2是-CH2CH3、-CH(CH3)2、-CH(CH3)CH2OH、环丙基、环戊基、氧杂环丁烷基四氢吡喃基或二氟乙基吡唑基;并且
R3a是吡唑基、噻唑基、苯基、吡啶基、吡啶酮基、哒嗪基、吡咯并[2,3-b]吡啶基或咪唑并[1,2-a]吡啶基,各自被0至1个选自以下的取代基取代:F、-CN、-CH3、-OCH3、-NH2、-S(O)2CH3和吡唑基。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R1是:(i)-C(O)NHR1a或-C(O)NH(CH2)1-3R1b;或(ii)被-CH2CH2CH(CH3)2、-CH2CH2CH2OH、-CH2CH2C(CH3)2OH或-CH2(环丙基)取代的三唑基.
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R1是-C(O)NHR1a或-C(O)NH(CH2)1-3R1b。此实施方案中包括其中R1是-C(O)NHR1a的化合物。此实施方案中还包括其中R1是-C(O)NH(CH2)1-3R1b的化合物。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R1是吡唑基、咪唑基、异噁唑基或三唑基,各自被0或1个R1c取代。此实施方案中包括这样的化合物,其中R1是被-CH2CH2CH(CH3)2、-CH2CH2CH2OH、-CH2CH2C(CH3)2OH或-CH2(环丙基)取代的三唑基。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R1a是:(i)氢或被1至4个独立地选自以下的取代基取代的C3-5烷基:F、-CN、-OH、C1-2烷氧基、C1-2氟烷氧基、-NRaRa、-C(O)NRaRa、-S(O)2(C1-2烷基)和-NRaS(O)2(C1-2烷基);或(ii)选自以下的环状基团:C3-6环烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、哌啶基和吡啶基,各自被零或一个选自以下的取代基取代:-OH、-C(O)(C1-2烷基)、-C(O)O(C1-3烷基)、-NRaRa、-NRaC(O)(C1-2烷基)、-NRaC(O)O(C1-2烷基)、-S(O)2(C1-2烷基)、-S(O)2(C1-3氟烷基)、-C(O)(C3-6环烷基)、-C(O)(吗啉基)、-CH2(吡啶基)、-S(O)2(吡啶基)、吗啉基和三唑基。此实施方案中包括这样的化合物,其中R1a是(i)-CH2CH2CN、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2CH(CH3)OH、-CH2CH2S(O)2CH3、-CH2CH2NHS(O)2CH3、-CH2CHFC(CH3)2OH或-CH2CH2CH2NHS(O)2CH3;或(ii)环丁基、环己基或哌啶基,各自被-OH、-NH2、-C(O)CH3、-OC(O)CH3、-NHC(O)CH3或-NHC(O)OCH3取代;
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R1a是氢或被1至4个独立地选自以下的取代基取代的C3-6烷基:F、-CN、-OH、C1-2烷氧基、C1-2氟烷氧基、-NRyRy、-NRxC(O)(C1-3烷基)、-C(O)NRyRy、-S(O)2(C1-3烷基)和-NRxS(O)2(C1-3烷基)。此实施方案中包括这样的化合物,其中R1a是氢或被1至4个独立地选自以下的取代基取代的C3-5烷基:F、-CN、-OH、C1-2烷氧基、C1-2氟烷氧基、-NRaRa、-C(O)NRaRa、-S(O)2(C1-2烷基)和-NRaS(O)2(C1-2烷基)。此实施方案中包括这样的化合物,其中R1a是-CH2CH2CN、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2CH(CH3)OH、-CH2CH2S(O)2CH3、-CH2CH2NHS(O)2CH3、-CH2CHFC(CH3)2OH或-CH2CH2CH2NHS(O)2CH3。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R1a是被1至4个独立地选自以下的取代基取代的C3-6烷基:F、-CN、-OH、C1-2烷氧基、C1-2氟烷氧基、-NRyRy、-NRxC(O)(C1-3烷基)、-C(O)NRyRy、-S(O)2(C1-3烷基)和-NRxS(O)2(C1-3烷基)。此实施方案中包括这样的化合物,其中R1a是被1至4个独立地选自以下的取代基取代的C3-5烷基:F、-CN、-OH、C1-2烷氧基、C1-2氟烷氧基、-NRaRa、-C(O)NRaRa、-S(O)2(C1-2烷基)和-NRaS(O)2(C1-2烷基)。此实施方案中包括这样的化合物,其中R1a是-CH2CH2CN、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2CH(CH3)OH、-CH2CH2S(O)2CH3、-CH2CH2NHS(O)2CH3、-CH2CHFC(CH3)2OH或-CH2CH2CH2NHS(O)2CH3。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R1a是氢。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R1a是选自以下的环状基团:C3-6环烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吡咯基、吡唑基,吡啶基、咪唑基和三唑基,其中所述环状基团被零或一个选自以下的取代基取代:-OH、-C(O)(C1-3烷基)、-C(O)(C1-3氟烷基)、-C(O)O(C1-3烷基)、-NRaRa、-NRaC(O)(C1-3烷基)、-NRaC(O)O(C1-3烷基)、-S(O)2(C1-3烷基)、-S(O)2(C1-3氟烷基)、-C(O)(C3-6环烷基)、-C(O)(吗啉基)、-CH2(吡啶基)、-S(O)2(吡啶基)、吗啉基和三唑基。此实施方案中包括这样的化合物,其中R1a是选自以下的环状基团:C3-6环烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、哌啶基和吡啶基,各自被零或一个选自以下的取代基取代:-OH、-C(O)(C1-2烷基)、-C(O)O(C1-3烷基)、-NRaRa、-NRaC(O)(C1-2烷基)、-NRaC(O)O(C1-2烷基)、-S(O)2(C1-2烷基)、-S(O)2(C1-3氟烷基)、-C(O)(C3-6环烷基)、-C(O)(吗啉基)、-CH2(吡啶基)、-S(O)2(吡啶基)、吗啉基和三唑基。此实施方案中还包括这样的化合物,其中R1a是环丁基、环己基或哌啶基,各自被-OH、-NH2、-C(O)CH3、-OC(O)CH3、-NHC(O)CH3或-NHC(O)OCH3取代。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R1b是C3-6环烷基、吡咯烷基、哌啶基、二氧化硫代吗啉基、三唑基或吡啶基,各自被0至3个独立地选自以下的取代基取代:F、-OH、-CH3和-CH2OH。此实施方案中包括这样的化合物,其中R1b是环丙基、环丁基、吡咯烷基、哌啶基、二氧化硫代吗啉基、三唑基或吡啶基,各自被0至3个独立地选自以下的取代基取代:F、-OH和-CH2OH。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R1c是F、Cl、-OH、-CN或被0至4个独立地选自以下的取代基取代的C1-6烷基:F、-CN、-OH、C1-2烷氧基、C3-6环烷基、-NRyRy、-NRxC(O)(C1-2烷基)和-C(O)NRyRy。此实施方案中包括这样的化合物,其中R1c是F、Cl、-OH、-CN、-CH3、-CH2CH3、-CHF2、-CF3或-NH2。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R2是:(i)被0至2个独立地选自以下的取代基取代的C1-4烷基:F、-OH和-CN;或(ii)选自以下的环状基团:C3-6环烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基和吡唑基,其中所述环状基团被0至2个独立地选自以下的取代基取代:F、-OH、-CN、C1-2烷基、C1-2氟烷基和C1-2羟烷基。此实施方案中包括这样的化合物,其中R2是-CH2CH3、-CH(CH3)2、-CH(CH3)CH2OH、环丙基、环戊基、氧杂环丁烷基四氢吡喃基或二氟乙基吡唑基。此外,此实施方案中包括这样的化合物,其中R2是-CH(CH3)2。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R2是被0至2个独立地选自以下的取代基取代的C1-4烷基:F、-OH和-CN。此实施方案中包括这样的化合物,其中R2是-CH2CH3、-CH(CH3)2或-CH(CH3)CH2OH。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R2是选自以下的环状基团:C3-6环烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基和吡唑基,其中所述环状基团被0至2个独立地选自以下的取代基取代:F、-OH、-CN、C1-2烷基、C1-2氟烷基和C1-2羟烷基。此实施方案中包括这样的化合物,其中R2是环丙基、环戊基、氧杂环丁烷基四氢吡喃基或二氟乙基吡唑基。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R3是R3a。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R3是-NHR3a。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中R3a是吡唑基、噻唑基、苯基、吡啶基、吡啶酮基、哒嗪基、吡咯并[2,3-b]吡啶基或咪唑并[1,2-a]吡啶基,各自被0至1个选自以下的取代基取代:F、Cl、-CN、C1-2烷基、C1-2氟烷基、C1-2羟烷基、C1-2烷氧基、-NRxRx、-S(O)2(C1-3烷基)和吡唑基。此实施方案中包括这样的化合物,其中R3a是吡唑基、噻唑基、苯基、吡啶基、吡啶酮基、哒嗪基、吡咯并[2,3-b]吡啶基或咪唑并[1,2-a]吡啶基,各自被0至1个选自以下的取代基取代:F、Cl、-CN、C1-2烷基、-CF3、C1-2羟烷基、C1-2烷氧基、-NH2、-S(O)2(C1-2烷基)和吡唑基。此实施方案中还包括这样的化合物,其中R3a是吡唑基、噻唑基、苯基、吡啶基、吡啶酮基、哒嗪基、吡咯并[2,3-b]吡啶基或咪唑并[1,2-a]吡啶基,各自被0至1个选自以下的取代基取代:F、-CN、-CH3、-OCH3、-NH2、-S(O)2CH3和吡唑基。
在一个实施方案中,提供了一种式(I)的化合物或其盐或前药,其中每个R4独立地是氢、F、Cl或-CH3。此实施方案中包括这样的化合物,其中每个R4独立地是氢或-CH3。此实施方案中还包括这样的化合物,其中每个R4是氢。
一个实施方案提供了一种式(I)的化合物或其盐,其中所述化合物选自:(R)-7-(环丙基氨基)-N-(2-氟-3-羟基-3-甲基丁基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(1);(R)-N-(2-氟-3-羟基-3-甲基丁基)-7-(异丙基氨基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(2);(R)-7-(环戊基氨基)-N-(2-氟-3-羟基-3-甲基丁基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(3);(R)-N-(2-氟-3-羟基-3-甲基丁基)-2-苯基-7-((四氢-2H-吡喃-4-基)氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(4);(R)-7-(乙基氨基)-N-(2-氟-3-羟基-3-甲基丁基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(5);N-((R)-2-氟-3-羟基-3-甲基丁基)-7-(((R)-1-羟基丙-2-基)氨基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(6);(R)-N-(3-羟基-3-甲基丁基)-7-((1-羟基丙-2-基)氨基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(7);(R)-7-((1-羟基丙-2-基)氨基)-N-(3-吗啉代丙基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(8);(R)-N-(2-氰基乙基)-7-((1-羟基丙-2-基)氨基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(9);(R)-7-((1-羟基丙-2-基)氨基)-N-(2-(甲基磺酰基)乙基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(10);(R)-N-(2-氟-3-羟基-3-甲基丁基)-7-(异丙基氨基)-2-(吡啶-3-基)噻唑并[5,4-b]吡啶-6-甲酰胺(11);N-(3-羟基-3-甲基丁基)-2-(吡啶-3-基)-7-((四氢-2H-吡喃-4-基)氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(12);N-(2-(4-羟基哌啶-1-基)乙基)-2-(吡啶-3-基)-7-((四氢-2H-吡喃-4-基)氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(13);(R)-N-(2-氟-3-羟基-3-甲基丁基)-2-(吡啶-3-基)-7-((四氢-2H-吡喃-4-基)氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(14);(R)-2-((4-(1H-吡唑-1-基)苯基)氨基)-N-(2-氟-3-羟基-3-甲基丁基)-7-(异丙基氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(15);(R)-N-(2-氟-3-羟基-3-甲基丁基)-7-(异丙基氨基)-2-(吡啶-3-基氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(16);(R)-N-(2-氟-3-羟基-3-甲基丁基)-7-(异丙基氨基)-2-((4-(甲基磺酰基)苯基)氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(17);7-(异丙基氨基)-2-(吡啶-3-基)-N-(3,3,3-三氟丙基)噻唑并[5,4-b]吡啶-6-甲酰胺(18);N-(2-环丙基乙基)-7-(异丙基氨基)-2-(吡啶-3-基)噻唑并[5,4-b]吡啶-6-甲酰胺(19);(1r,4r)-4-(7-(异丙基氨基)-2-(吡啶-3-基)噻唑并[5,4-b]吡啶-6-甲酰胺基)环己基乙酸酯(20);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(1H-吡唑-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺(21);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(吡啶-3-基)噻吩并[2,3-b]吡啶-5-甲酰胺(22);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(吡啶-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺(23);(R)-2-(3-氰基苯基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(24);(R)-2-(6-氰基吡啶-3-基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(25);(R)-N-(2-氟-3-羟基-3-甲基丁基)-2-(咪唑并[1,2-a]吡啶-6-基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(26);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(27);(R)-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(28);N-异戊基-4-(异丙基氨基)-2-(吡啶-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺(29);N-异戊基-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(30);N-异戊基-4-(异丙基氨基)-2-(吡啶-3-基)噻吩并[2,3-b]吡啶-5-甲酰胺(31);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(哒嗪-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺(32);N-异戊基-4-(异丙基氨基)-2-(哒嗪-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺(33);4-(异丙基氨基)-N-(2-甲氧基乙基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(34);4-(异丙基氨基)-N-((3-甲基异噁唑基-5-基)甲基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(35);N-((1r,4r)-4-羟基环己基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(36);N-(2-(1-(羟基甲基)环丙基)乙基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(37);N-((1r,4r)-4-氨基环己基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(38);N-(1-环丙基-3-羟基丙基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(39);(R)-N-(4-羟基丁-2-基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(40);4-(异丙基氨基)-N-(噁唑基-4-基甲基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(41);N-((1H-1,2,4-三唑-5-基)甲基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(42);N-(2-乙氧基乙基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(43);N-(3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(44);N-((1r,4r)-4-乙酰胺基环己基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(45);N-(3-羟基-2,2-二甲基丙基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(46);N-((3-(羟基甲基)氧杂环丁烷-3-基)甲基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(47);(R)-4-((1-(2,2-二氟乙基)-1H-吡唑-4-基)氨基)-N-(4-羟基丁-2-基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(48);4-((1-(2,2-二氟乙基)-1H-吡唑-4-基)氨基)-N-((1s,4s)-4-羟基环己基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(49);((1r,4r)-4-(4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺基)环己基)氨基甲酸甲酯(50);4-((1-(2,2-二氟乙基)-1H-吡唑-4-基)氨基)-N-(2-甲氧基乙基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(51);(R)-4-((1-(2,2-二氟乙基)-1H-吡唑-4-基)氨基)-N-(2-氟-3-羟基-3-甲基丁基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(52);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(氧杂环丁烷-3-基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(53);N-((1s,4s)-4-羟基环己基)-4-(氧杂环丁烷-3-基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(54);N-((1H-1,2,4-三唑-5-基)甲基)-4-(氧杂环丁烷-3-基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(55);(R)-2-(2-氨基噻唑-5-基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(56);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(2-甲基噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(57);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(2-甲氧基噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(58);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(6-氧代-1,6-二氢吡啶-3-基)噻吩并[2,3-b]吡啶-5-甲酰胺(59);N-(3-羟基丁基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(60);N-(3-羟基环丁基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(61);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(噻唑-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺(62);N-(2-(3,3-二氟-1-羟基环丁基)乙基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(63);(R)-2-(6-氰基吡啶-3-基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(64);(R)-2-(5-氰基吡啶-3-基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(65);N-(1-乙酰基哌啶-4-基)-4-(异丙基氨基)-2-(6-氧代-1,6-二氢吡啶-3-基)噻吩并[2,3-b]吡啶-5-甲酰胺(66);4-(异丙基氨基)-N-(3-(甲基磺酰胺基)丙基)-2-(6-氧代-1,6-二氢吡啶-3-基)噻吩并[2,3-b]吡啶-5-甲酰胺(67);N-(2-(1,1-二氧化硫代吗啉代)乙基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(68);N-((1,1-二氧化四氢噻吩-3-基)甲基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(69);4-(异丙基氨基)-2-(6-氧代-1,6-二氢吡啶-3-基)-N-(2-(吡咯烷-3-基)乙基)噻吩并[2,3-b]吡啶-5-甲酰胺(70);4-(异丙基氨基)-2-(6-氧代-1,6-二氢吡啶-3-基)-N-(2-(吡啶-4-基)乙基)噻吩并[2,3-b]吡啶-5-甲酰胺(71);4-(异丙基氨基)-2-(6-氧代-1,6-二氢吡啶-3-基)-N-(2-(吡啶-3-基)乙基)噻吩并[2,3-b]吡啶-5-甲酰胺(72);N-(2-(1,1-二氧化硫代吗啉代)乙基)-4-(异丙基氨基)-2-(6-氧代-1,6-二氢吡啶-3-基)噻吩并[2,3-b]吡啶-5-甲酰胺(73);4-(1-(4-(异丙基氨基)-2-(吡啶-3-基)噻吩并[2,3-b]吡啶-5-基)-1H-1,2,3-三唑-4-基)-2-甲基丁-2-醇(74);4-(1-(4-(异丙基氨基)-2-(吡啶-4-基)噻吩并[2,3-b]吡啶-5-基)-1H-1,2,3-三唑-4-基)-2-甲基丁-2-醇(75);5-(4-异戊基-1H-1,2,3-三唑-1-基)-N-异丙基-2-(吡啶-4-基)噻吩并[2,3-b]吡啶-4-胺(76);5-(5-异戊基-1H-1,2,4-三唑-3-基)-N-异丙基-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-4-胺(77);5-(1-(环丙基甲基)-1H-1,2,3-三唑-4-基)-N-异丙基-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-4-胺(78);3-(4-(4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-基)-1H-1,2,3-三唑-1-基)丙-1-醇(79);和5-(5-(1-(3-羟基丙基)-1H-1,2,3-三唑-4-基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-2-基)吡啶-2(1H)-酮(80)。
一个实施方案提供了具有≤0.6μM的IRAK4 IC50值的式(I)化合物。
一个实施方案提供了具有≤0.1μM的IRAK4 IC50值的式(I)化合物。
一个实施方案提供了具有≤0.05μM的IRAK4 IC50值的式(I)化合物。
一个实施方案提供了具有≤0.025μM的IRAK4 IC50值的式(I)化合物。
一个实施方案提供了具有≤0.015μM的IRAK4 IC50值的式(I)化合物。
一个实施方案提供了具有≤0.01μM的IRAK4 IC50值的式(I)化合物。
定义
在阅读以下具体实施方式时,本领域普通技术人员可以更容易地理解本发明的特征和优点。应理解,出于清楚的原因,在分开的实施方案的上下文中所述的本发明的某些特征也可以组合以形成单个实施方案。相反,出于简洁性原因而在单个实施方案的上下文中描述的本发明的各种特征还可以组合以形成其子组合。在本文中标识为示例性或优选的实施方案旨在是说明性的而非限制性的。
除非本文另有明确说明,否则以单数形式做出的提及还可以包括复数形式。例如,“一个/一种(a)”和“一个/一种(an)”可以指代一个/一种或者一个/一种或多个/多种。
如本文所用,相“化合物”是指至少一种化合物。例如,一种式(I)的化合物包括一种式(I)的化合物和两种或更多种式(I)的化合物。
除非另有说明,否则具有未满足的化合价的任何杂原子被假定为具有足以满足这些化合价的氢原子。
本文所阐述的定义优先于在通过引用并入本文的任何专利、专利申请和/或专利申请公开物中所阐述的定义。
下文列出了用于描述本发明的各种术语的定义。这些定义适用于如它们在整个说明书中单独地或作为更大基团的一部分使用的术语(除非它们在特定情况下另有限制)。
在整个说明书中,本领域技术人员可以选择基团及其取代基以提供稳定的部分和化合物。
根据本领域中使用的惯例,在本文的结构式中使用
来描绘作为部分或取代基与核或骨架结构附接的点的键。
如本文所用的术语“卤”和“卤素”是指F、Cl、Br和I。
术语“氰基”是指基团-CN。
术语“氨基”是指基团-NH2。
术语“氧代基”是指基团=O。
如本文所用,术语“烷基”是指含有例如从1至12个碳原子、从1至6个碳原子和从1至4个碳原子的支链和直链饱和脂族烃基团二者。烷基的例子包括但不限于甲基(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,下标更具体地定义了特定基团可能含有的碳原子的数目。例如,“C1-6烷基”表示具有一至六个碳原子的直链和支链烷基。
如本文所用的术语“氟烷基”旨在包括被一个或多个氟原子取代的支链和直链饱和脂族烃基团二者。例如,“C1-4氟烷基”旨在包括被一个或多个氟原子取代的C1、C2、C3和C4烷基。氟烷基的代表性例子包括但不限于-CF3和-CH2CF3。
术语“羟烷基”包括被一个或多个羟基取代的支链和直链饱和烷基二者。例如,“羟烷基”包括-CH2OH、-CH2CH2OH和C1-4羟烷基。
如本文所用,术语“环烷基”是指通过从饱和环碳原子上除去一个氢原子而由非芳族单环或多环烃分子衍生的基团。环烷基的代表性例子包括但不限于环丙基、环戊基和环己基。当数字出现在符号“C”之后的下标中时,下标更具体地定义了特定环烷基可能含有的碳原子的数目。例如,“C3-6环烷基”表示具有三至六个碳原子的环烷基。
如本文所用,术语“烷氧基”是指通过氧原子与母体分子部分附接的烷基,例如甲氧基(-OCH3)。例如,“C1-3烷氧基”表示具有一至三个碳原子的烷氧基。
术语“氟烷氧基”和“-O(氟烷基)”表示通过氧键联(-O-)附接的如上文定义的氟烷基。例如,“C1-4氟烷氧基”旨在包括C1、C2、C3和C4氟烷氧基。
短语“药学上可接受的”在本文中用于指在合理的医学判断的范围内,适用于与人类和动物的组织接触而没有过度的毒性、刺激、过敏反应或其他问题或并发症,与合理的效益/风险比相称的那些化合物、材料、组合物和/或剂型。
式(I)的化合物可以作为无定形固体或结晶固体来提供。可以使用冻干来提供呈无定形固体的式(I)的化合物。
还应当理解,式(I)的化合物的溶剂化物(例如,水合物)也在本发明的范围内。术语“溶剂化物”意指式(I)的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。此物理缔合包括氢键。在某些情况下,溶剂化物将是能够分离的,例如当一个或多个溶剂分子被掺在结晶固体的晶格中时。“溶剂化物”包括溶液相和可分离溶剂化物二者。示例性的溶剂化物包括水合物、乙醇化物、甲醇化物、异丙醇化物、乙腈溶剂化物和乙酸乙酯溶剂化物。溶剂化方法在本领域中是已知的。
各种形式的前药是本领域熟知的,并且描述于:
a)The Practice of Medicinal Chemistry,Camille G.Wermuth等人,第31章,(Academic Press,1996);
b)Design of Prodrugs,由H.Bundgaard编辑,(Elsevier,1985);
c)A Textbook of Drug Design and Development,P.Krogsgaard–Larson和H.Bundgaard,编辑第5章,第113-191页(Harwood Academic Publishers,1991);以及
d)Hydrolysis in Drug and Prodrug Metabolism,Bernard Testa和JoachimM.Mayer,(Wiley-VCH,2003)。
e)Rautio,J.等人,Nature Review Drug Discovery,17,559-587(2018)。
此外,可以在式(I)的化合物制备之后将其分离并且纯化以获得含有按重量计等于或大于99%的量的式(I)的化合物(“基本上纯的”)的组合物,然后如本文所述使用或配制所述组合物。此类“基本上纯的”式(I)的化合物在本文中也被考虑作为本发明的一部分。
“稳定的化合物”和“稳定的结构”意在指示化合物足够稳健以经受住从反应混合物中分离至有用程度的纯度并且配制成有效的治疗剂。本发明旨在实施稳定的化合物。
“治疗有效量”旨在包括单独的本发明的化合物的量,或所要求保护的多种化合物的组合的量,或与其他活性成分组合的本发明的化合物的量,这些活性成分有效充当IRAK4的抑制剂;或有效治疗或预防自身免疫和/或炎性疾病状态,诸如多发性硬化症和类风湿性关节炎;或有效治疗癌症。
如本文所用,“治疗(treating或treatment)”涵盖哺乳动物(特别是人)的疾病状态的治疗,并且包括:(a)防止所述疾病状态在哺乳动物中发生,特别是当这种哺乳动物易患所述疾病状态,但尚未被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)缓解所述疾病状态,即引起所述疾病状态的消退。
本发明的化合物旨在包括本发明的化合物中存在的原子的所有同位素。同位素包括原子数相同但质量数不同的那些原子。通过通用例子的方式并且在非限制情况下,氢的同位素包括氘(D)和氚(T)。碳的同位素包括13C和14C。本发明的同位素标记的化合物通常可以通过本领域技术人员已知的常规技术或通过与本文所述那些类似的方法,使用适当的同位素标记的试剂代替原本采用的未经标记的试剂来制备。例如,甲基(-CH3)还包括氘代甲基,诸如-CD3。
效用
本发明的化合物调节激酶活性,包括IRAK-4的调节。可以通过本发明的化合物调节激酶活性的其他类型包括但不限于Pelle/IRAK家族及其突变体。
因此,式(I)的化合物具有治疗与激酶活性的调节并且特别是IRAK-4活性的选择性抑制或IRAK和其他Pelle家族激酶的抑制相关的病症的效用。此类病症包括TLR/IL-1家族受体相关的疾病,其中细胞因子水平因细胞内信号传导而被调节。此外,式(I)的化合物具有对于IRAK-4活性有利的选择性,优选选择性高从至少20倍至超过1,000倍。
如本文所用,术语“治疗”(“treating”或“treatment”)涵盖对哺乳动物、特别是人类中的疾病状态的治疗,并且包括:(a)预防或延迟哺乳动物中疾病状态的发生,特别是当这个哺乳动物易患所述疾病状态但尚未被诊断为患有所述疾病状态时;(b)抑制疾病状态,即,阻止其发展;和/或(c)实现症状或疾病状态的完全或部分减少和/或缓解、改善、减轻或治愈疾病或障碍和/或其症状。
鉴于它们作为选择性抑制剂IRAK-4的活性,式(I)的化合物可用于治疗TLR/IL-1家族受体相关的疾病,分别包括但不限于炎性疾病,诸如克罗恩病、溃疡性结肠炎、哮喘、移植物抗宿主病、同种异体移植排斥、慢性阻塞性肺疾病;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、银屑病;自身炎性疾病,包括CAPS、TRAPS、FMF、成人发作的斯蒂尔病、全身性发作的幼年特发性关节炎、痛风、痛风性关节炎;代谢性疾病,包括2型糖尿病、动脉粥样硬化、心肌梗塞;破坏性骨病,诸如骨吸收疾病、骨关节炎、骨质疏松症、多发性骨髓瘤相关骨病;增生性障碍,诸如急性骨髓性白血病、慢性骨髓性白血病;血管生成障碍,诸如血管生成障碍,包括实体瘤、眼部新生血管性疾病和婴儿血管瘤;感染性疾病,诸如败血症、感染性休克和志贺氏菌病;神经退行性疾病,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退行性疾病;肿瘤和病毒性疾病,诸如转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤;以及HIV感染和CMV视网膜炎、AIDS。
更特定地,可用本发明的化合物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、过敏症、成人呼吸窘迫综合征、慢性阻塞性肺疾病、肾小球肾炎、类风湿性关节炎、系统性红斑狼疮、硬皮病、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、血小板减少、特应性皮炎、慢性活动性肝炎、重症肌无力、多发性硬化症、炎性肠病、溃疡性结肠炎、克罗恩病、银屑病、移植物抗宿主病、内毒素诱导的炎症反应、结核、动脉粥样硬化、肌肉变性、恶病质、银屑病关节炎、莱特尔综合征、痛风、创伤性关节炎、风疹性关节炎、急性滑膜炎、胰腺β-细胞疾病;特征为大量嗜中性粒细胞浸润的疾病;类风湿性脊柱炎、痛风性关节炎和其他关节炎性病症、脑型疟疾、慢性肺部炎性疾病、矽肺病、肺结节病、骨吸收疾病、同种异体移植排斥、由于感染所致的发热和肌痛、继发于感染的恶病质、瘢痕疙瘩形成、瘢痕组织形成、溃疡性结肠炎、热症、流感、骨质疏松症、骨关节炎、急性髓性白血病、慢性髓性白血病、转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤、败血症、脓毒性休克和细菌性痢疾;阿尔茨海默病、帕金森病、脑缺血或由创伤性损伤引起的神经变性疾病;血管生成性障碍,包括实体瘤、眼部新生血管和婴幼儿血管瘤;病毒性疾病,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或恶性病和疱疹;中风、心肌缺血、中风心脏病发作中的缺血、器官缺氧、血管增生、心脏和肾脏再灌注损伤、血栓形成、心脏肥大、凝血酶诱导的血小板聚集、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。优选的治疗方法是其中病症选自克罗恩病、溃疡性结肠炎、同种异体移植物排斥、类风湿性关节炎、银屑病、强直性脊柱炎、银屑病关节炎和寻常型天疱疮的那些方法。可替代地,优选的治疗方法是其中病症选自缺血再灌注损伤的那些方法,所述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肌缺血再灌注损伤。另一种优选的治疗方法是所述病症为多发性骨髓瘤的治疗方法。
在一个实施方案中,式(I)的化合物可用于治疗癌症,包括瓦尔登斯特伦巨球蛋白血症(Waldenstrom’s Macroglobulinemia,WM)、弥漫性大B细胞淋巴瘤(DLBCL)、慢性淋巴细胞白血病(CLL)、皮肤弥漫性大B细胞淋巴瘤、和原发性CNS淋巴瘤。
此外,本发明的激酶抑制剂会抑制诱导型促炎蛋白的表达,诸如前列腺素内过氧化物合酶-2(PGHS-2),也称为环氧合酶-2(COX-2)、IL-1、IL-6、IL-18、趋化因子。因此,另外的IRAK-4相关的病症包括水肿、镇痛、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)。本发明的化合物还可以用于治疗兽医病毒感染,诸如慢病毒感染,包括但不限于马传染性贫血病毒;或逆转录病毒感染,包括猫免疫缺陷病毒、牛免疫缺陷病毒和犬免疫缺陷病毒。
当在本文中使用术语“IRAK-4相关的病症”或“IRAK-4相关的疾病或障碍”时,每个术语旨在涵盖上文鉴定的所有病症,如同重复长度、以及受IRAK-4激酶活性影响的任何其他病症。
因此,本发明提供了用于治疗此类病症的方法,包括向对其有需要的受试者施用治疗有效量的至少一种式(I)的化合物或其盐。“治疗有效量”旨在包括当单独或组合施用时有效抑制IRAK-4和/或治疗疾病的本发明化合物的量。
治疗IRAK-4激酶相关病症的方法可以包括单独或与彼此和/或可用于治疗此类病症的其他合适治疗剂组合地施用式(I)的化合物。因此,“治疗有效量”还旨在包括有效抑制IRAK-4和/或治疗与IRAK-4相关的疾病的所要求保护的化合物的组合的量。
此类其他治疗剂的例子包括皮质类固醇、咯利普兰、卡弗他丁、细胞因子抑制性抗炎药(CSAID)、白细胞介素-10、糖皮质激素、水杨酸盐、一氧化氮和其他免疫抑制剂;核转位抑制剂,诸如脱氧精胍菌素(DSG);非甾体抗炎药(NSAID),诸如布洛芬、塞来昔布和罗非昔布;类固醇,诸如泼尼松或地塞米松;抗病毒剂,诸如阿巴卡韦;抗增殖剂,诸如甲氨蝶呤、来氟米特、FK506(他克莫司,);抗疟药,诸如羟基氯喹;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,以及雷帕霉素(西罗莫司或/>)或其衍生物。
当与本发明的化合物组合使用时,以上其他治疗剂可以例如以Physicians’DeskReference(PDR)中指示的或者如本领域普通技术人员以其他方式确定的那些量来使用。在本发明的方法中,一种或多种此类其他治疗剂可以在施用本发明的化合物之前、同时或之后施用。本发明还提供了能够治疗IRAK-4激酶相关病症的药物组合物,这些病症包括如上所描述的TLR和IL-1家族受体介导的疾病。
本发明的组合物可以含有如上所描述的其他治疗剂,并且可以例如通过使用常规的固体或液体媒介物或稀释剂以及适合于所希望的施用方式的类型的药物添加剂(例如,赋形剂、粘合剂、防腐剂、稳定剂、调味剂等)根据药物配制领域熟知的那些的技术来配制。
因此,本发明进一步包括包含一种或多种式(I)的化合物和药学上可接受的载体的组合物。
“药学上可接受的载体”是指本领域通常接受用于将生物活性剂递送至动物、特别是哺乳动物的介质。药学上可接受的载体是根据本领域普通技术人员认知范围内的许多因素来配制。这些因素包括但不限于所配制的活性剂的类型和性质;待被施用含有药剂的组合物的受试者;组合物的预期施用途径;以及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二者,以及多种固体和半固体剂型。此类载体还可包括除活性剂之外的许多不同的成分和添加剂,此类另外的成分出于本领域普通技术人员熟知的多种原因(例如,活性剂、粘合剂等的稳定化)被包括在配制品中。合适的药学上可接受的载体及其选择中涉及的因素的描述在多种可容易获得的来源(例如像Remington's PharmaceuticalSciences,第17版(1985))中找到,将其通过引用以其整体并入本文。
根据式(I)的化合物可以通过适用于待治疗病症的任何手段施用,这可取决于位点特异性治疗或待递送的式(I)的化合物的量的需要。
本发明中还包括一类药物组合物,其包含式(I)的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(在本文中统称为“载体”材料)以及(如果希望)其他活性成分。式(I)的化合物可以通过任何合适的途径、优选以适于此类途径的药物组合物的形式,并且以对于预期治疗有效的剂量施用。本发明的化合物和组合物可以例如在含有常规药学上可接受的载体、佐剂和媒介物的剂量单位配制品中口服、粘膜、或亲本地(包括血管内、静脉内、腹膜内、皮下、肌内、和胸骨内)施用。例如,所述药物载体可以含有甘露糖醇或乳糖和微晶纤维素的混合物。所述混合物可以含有另外的组分,诸如润滑剂(例如,硬脂酸镁)和崩解剂(诸如交聚维酮)。载体混合物可以填充到明胶胶囊剂中或压缩成片剂。例如,药物组合物可以作为口服剂型或输注剂施用。
对于口服施用,药物组合物可以是例如片剂、胶囊剂、液体胶囊剂、混悬剂或液体的形式。所述药物组合物优选地以含有特定量活性成分的剂量单位的形式制造。例如,所述药物组合物可以以片剂或胶囊剂提供,所述片剂或胶囊剂包含在从约0.1至1000mg、优选从约0.25至250mg、更优选从约0.5至100mg范围内的量的活性成分。根据患者的状况和其他因素,对于人或其他哺乳动物的合适的日剂量可能有很大差异,但是可以使用常规方法确定。
本文中考虑的任何药物组合物可以例如经由任何可接受且合适的口服制剂口服递送。示例性的口服制剂包括但不限于例如片剂、锭剂、糖锭剂、水性和油性混悬剂、可分散散剂或颗粒剂、乳剂、硬和软胶囊剂、液体胶囊剂、糖浆和酏剂。旨在用于口服施用的药物组合物可以根据本领域已知的用于制造旨在用于口服施用的药物组合物的任何方法制备。为了提供药学上可口的制剂,根据本发明的药物组合物可含有至少一种选自甜味剂、调味剂、着色剂、缓和剂、抗氧化剂、和防腐剂的试剂。
片剂可以例如通过将至少一种式(I)的化合物与适合于制造片剂的至少一种无毒的药学上可接受的赋形剂混合来制备。示例性的赋形剂包括但不限于例如惰性稀释剂,例如像碳酸钙、碳酸钠、乳糖、磷酸钙和磷酸钠;制粒剂和崩解剂,例如像微晶纤维素、交联羧甲基纤维素钠、玉米淀粉和海藻酸;粘合剂,例如像淀粉、明胶、聚乙烯吡咯烷酮和阿拉伯胶;以及润滑剂,例如像硬脂酸镁、硬脂酸和滑石。另外,片剂可以是未包衣的,或通过已知技术包衣,以掩蔽尝起来令人不快的药物的不良味道,或延迟胃肠道中活性成分的崩解和吸收,从而维持活性成分的作用持续更长时间。示例性的水溶性味道掩蔽材料包括但不限于羟丙基甲基纤维素和羟丙基纤维素。示例性的延时材料包括但不限于乙基纤维素和乙酸丁酸纤维素。
硬明胶胶囊剂可以例如通过将至少一种式(I)的化合物与至少一种惰性固体稀释剂(例如像碳酸钙、磷酸钙和高岭土)混合来制备。
软明胶胶囊剂可以例如通过将至少一种式(I)的化合物与至少一种水溶性载体(例如像聚乙二醇);和至少一种油介质(例如像花生油、液体石蜡和橄榄油)混合来制备。
水性混悬剂可以例如通过将至少一种式(I)的化合物与至少一种适用于制造水性混悬剂的赋形剂混合来制备。适合于生产水性混悬剂的示例性赋形剂包括但不限于例如悬浮剂,例如像羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、海藻酸、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶;分散剂或润湿剂,例如像天然存在的磷脂,例如卵磷脂;环氧烷与脂肪酸的缩合产物,例如像聚氧乙烯硬脂酸酯;环氧乙烷与长链脂族醇的缩合产物,例如像十七烷乙烯-氧基鲸蜡醇;环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物,例如像聚氧乙烯山梨糖醇单油酸酯;以及环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物,例如像聚乙烯脱水山梨糖醇单油酸酯。水性混悬剂还可以含有至少一种防腐剂,例如像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;至少一种调味剂;和/或至少一种甜味剂,包括但不限于例如蔗糖、糖精和阿斯巴甜。
油性混悬剂可以例如通过将至少一种式(I)的化合物悬浮在植物油(例如像花生油;橄榄油;芝麻油;和椰子油)或矿物油(例如,液体石蜡)中来制备。油性混悬剂还可以含有至少一种增稠剂,例如像蜂蜡、硬石蜡和十六醇。为了提供可口的油性混悬剂,可以将以上已经描述的至少一种甜味剂和/或至少一种调味剂添加到油性混悬剂中。油性混悬剂可以进一步含有至少一种防腐剂,包括但不限于例如抗氧化剂,例如像丁基化羟基茴香醚和α-生育酚。
可分散粉剂和颗粒剂可以例如通过将至少一种式(I)的化合物与至少一种分散剂和/或润湿剂;至少一种悬浮剂;和/或至少一种防腐剂混合来制备。合适的分散剂、润湿剂和悬浮剂已如上文所述。示例性的防腐剂包括但不限于例如抗氧化剂,例如抗坏血酸。此外,可分散散剂和颗粒剂还可以含有至少一种赋形剂,包括但不限于例如甜味剂、调味剂和着色剂。
其至少一种其式(I)的化合物的乳剂可以例如制备为水包油乳剂。包含式(I)的化合物的乳剂的油相可以以已知方式由已知成分构成。油相可以通过但不限于例如植物油(例如像橄榄油和花生油)、矿物油(例如像液体石蜡)及其混合物来提供。虽然所述相可以仅包含乳化剂,但是它可以包含至少一种乳化剂与脂肪或油或与脂肪和油二者的混合物。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;衍生自脂肪酸和己糖醇酐的酯或偏酯,例如像脱水山梨糖醇单油酸酯;以及偏酯与环氧乙烷的缩合产物,例如像聚氧乙烯脱水山梨糖醇单油酸酯。优选地,亲水性乳化剂与亲脂性乳化剂一起被包含,所述亲脂性乳化剂充当稳定剂。还优选的是包含油和脂肪二者。一种或多种乳化剂与或不与一种或多种稳定剂一起构成所谓的乳化蜡,并且蜡与油和脂肪一起构成所谓的乳化软膏基质,其形成乳膏配制品的油性分散相。乳剂还可以含有甜味剂、调味剂、防腐剂和/或抗氧化剂。适用于本发明配制品的乳化剂和乳液稳定剂包括Tween 60、Span 80、鲸蜡硬脂醇、肉豆蔻醇、单硬脂酸甘油酯、十二烷基硫酸钠、单独或与蜡一起的二硬脂酸甘油酯或本领域熟知的其他材料。
例如,式(I)的化合物还可以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。示例性的可注射形式包括但不限于例如无菌水溶液,其包含可接受的媒介物和溶剂,例如像水、林格氏溶液和等渗氯化钠溶液;无菌水包油微乳剂;以及水性或油性混悬剂。
用于肠胃外施用的配制品可以呈水性或非水性等渗无菌注射溶液或混悬剂的形式。这些溶液和混悬剂可以使用提及用于在供口服施用的配制品中使用的一种或多种载体或稀释剂或者通过使用其他合适的分散剂或润湿剂和悬浮剂由无菌散剂或颗粒剂制备。可以将化合物溶解在水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苯甲醇、氯化钠、黄芪胶和/或各种缓冲液中。其他佐剂和施用方式是制药领域中熟知且熟知的。活性成分也可以通过作为与合适的载体(包括盐水、右旋糖或水)或与环糊精(即Captisol)、共溶剂增溶(即丙二醇)或胶束增溶(即Tween 80)的组合物注射来施用。
无菌可注射制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬剂,例如作为在1,3-丁二醇中的溶液。可以采用的可接受的媒介物和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外,常规地将无菌的非挥发性油用作溶剂或悬浮介质。为此目的,可以采用任何温和的非挥发性油,包括合成的单甘油酯或二甘油酯。此外,脂肪酸(诸如油酸)可用于制备注射剂。
无菌可注射水包油微乳液可以例如通过以下方式来制备:1)将至少一种式(I)的化合物溶于油相(例如像大豆油和卵磷脂的混合物)中;2)将含式(I)的油相与水和甘油混合物组合;并且3)加工所述组合以形成微乳液。
可以根据本领域已知的方法制备无菌水性或油性混悬剂。例如,可以用无毒的肠胃外可接受的稀释剂或溶剂(例如像1,3-丁二醇)制备无菌水溶液或混悬剂;并且可以用无菌无毒可接受溶剂或悬浮介质(例如像无菌非挥发性油,例如合成的甘油单酯或甘油二酯;和脂肪酸,例如像油酸)制备无菌油性混悬剂。
可用于本发明药物组合物的药学上可接受的载体、佐剂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,用于药物剂型的表面活性剂诸如Tween类,聚乙氧基化蓖麻油诸如CREMOPHOR表面活性剂(BASF),或其他类似的聚合物递送基质,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),胶体二氧化硅,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。诸如α-、β-和γ-环糊精等环糊精或诸如羟烷基环糊精(包括2-和3-羟丙基-环糊精)等化学改性的衍生物或其他溶解的衍生物也可以有利地用于增强本文描述的式的化合物的递送。
可以根据常规药学方法加工本发明的药物活性化合物,以生产用于施用至患者(包括人类和其他哺乳动物)的医学药剂。所述药物组合物可以经受诸如灭菌的常规制药操作和/或可以含有常规佐剂,诸如防腐剂、稳定剂、润湿剂、乳化剂、缓冲液等。此类组合物还可以包含佐剂,诸如润湿剂、甜味剂、调味剂和芳香剂。
所施用的化合物的量和用于用本发明的化合物和/或组合物治疗病状的剂量方案取决于多种因素,包括受试者的年龄、重量、性别、医学状况、疾病类型、疾病的严重程度、施用途径和频率、以及所使用的具体化合物。因此,剂量方案可以广泛变化,但是可以使用标准方法常规确定。约0.001至100mg/kg体重、优选约0.0025与约50mg/kg体重之间、并且最优选约0.005至10mg/kg体重之间的日剂量可能是适当的。日剂量可以以一至四剂/天施用。其他给药方案包括一剂/周和一剂/两天周期。
出于治疗目的,本发明的活性化合物通常与一种或多种适合于所指示的施用途径的佐剂组合。如果口服施用,可以将化合物与乳糖、蔗糖、淀粉、烷酸的纤维素酯、纤维素烷基酯、滑石粉、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,并且然后压片或胶囊化以方便施用。此类胶囊剂或片剂可以含有控释配制品,其可以在活性化合物在羟丙基甲基纤维素中的分散体中提供。
本发明的药物组合物包含至少一种式(I)的化合物和任选地选自任何药学上可接受的载体、佐剂和媒介物的另外药剂。本发明的替代组合物包含本文所述的式(I)的化合物或其前药以及药学上可接受的载体、佐剂或媒介物。
本发明还涵盖制品。如本文所用,制品旨在包括但不限于试剂盒和包装。本发明的制品包含:(a)第一容器;(b)位于第一容器内的药物组合物,其中所述组合物包含:第一治疗剂,其包含本发明的化合物或其药学上可接受的盐形式;以及(c)包装插页,其说明所述药物组合物可以用于治疗心血管障碍、利尿和/或尿钠排泄。在另一个实施方案中,所述包装插页说明所述药物组合物可以与用于治疗心血管障碍、利尿和/或尿钠排泄的第二治疗剂组合(如先前所定义)使用。所述制品可以进一步包含:(d)第二容器,其中组分(a)和(b)位于第二容器内,并且组分(c)位于第二容器内或外。位于第一容器和第二容器内意味着相应的容器将物品保持在其边界内。
第一容器是用于保持药物组合物的接收容器。此容器可以用于制造、储存、运输和/或单独/批量销售。第一容器旨在涵盖瓶、罐、小瓶、烧瓶、注射器、管(例如,用于乳膏制剂)或用于制造、保持、储存或分配药物产品的任何其他容器。
第二容器是用于保持第一容器和任选地包装插页的容器。第二容器的例子包括但不限于盒(例如,纸板或塑料)、板条箱、纸箱、袋(例如,纸或塑料袋)、小袋和大袋。所述包装插页可以经由胶带、胶水、订书钉或另一种附接方法物理地附接到第一容器的外侧,或者它可以静置在第二容器的内侧而无需与第一容器附接的任何物理装置。可替代地,所述包装插页位于第二容器的外侧。当位于第二容器的外侧时,优选的是,所述包装插页经由胶带、胶水、订书钉或另一种附接方法物理地附接。可替代地,它可以与第二容器的外侧相邻或接触,而不是物理地附接。
所述包装插页是标签、签条、标记或其他书面表格,其列举了与位于第一容器内的药物组合物相关的信息。所列举的信息将通常由管理其中销售制品的地区的管理机构(例如,美国食品和药物管理局)来确定。优选地,所述包装插页具体列举了已被批准药物组合物所针对的适应症。所述包装插页可以由人可以阅读其中或其上所含信息的任何材料制成。优选地,所述包装插页是可印刷材料(例如,纸、塑料、纸板、箔、粘合剂背衬的纸或塑料),在其上已形成(例如,印刷或施加)所需的信息。
制备方法
本发明的化合物可以通过有机合成领域的技术人员熟知的多种方式制备。本发明的化合物可以使用以下所述的方法,连同有机化学领域中已知的合成方法、或如本领域技术人员所理解的其变化来合成。优选的方法包括但不限于以下所述的那些。
本章节所述的反应和技术在适合于所用试剂和材料的溶剂中进行,并且适用于所进行的转化。此外,在以下所述的合成方法的描述中,应理解,所有提出的反应条件(包括溶剂的选择、反应气氛、反应温度、实验的持续时间和后处理程序)被选择为对于该反应为标准的条件,本领域技术人员应该容易认识到这一点。有机合成领域的技术人员应理解,分子的各部分上存在的官能团必须与所提出的试剂和反应相容。对于与反应条件相容的取代基的此类限制将对于本领域技术人员而言是容易清楚的,并且于是必须使用替代方法。有时,这将需要判断以修改合成步骤的顺序或选择一种而不是另一种特定的过程方案,以便获得所希望的本发明化合物。还将认识到,在此领域的任何合成途径的规划中的另一个主要考虑因素是明智地选择用于保护本发明中所述化合物中存在的反应性官能团的保护基团。向训练有素的从业者描述许多可替代方案的权威性报道是Greene等人(Protective Groupsin Organic Synthesis,第三版,Wiley and Sons(1999))。
式I的化合物也可以如方案1中所概述的制备。可以将溴噻唑1A与2-(乙氧基亚甲基)丙二酸二乙酯在酸性溶剂(诸如TFA)中在升高的温度下反应以得到1B。在升高的温度下与POCl3反应后,可以促进环化和转化为氯化物1C。可以使溴中间体1C与多种交叉偶联剂(诸如芳基硼酸)在过渡金属催化剂的存在下反应以得到通用结构1D的中间体。可以使酯1D经受皂化条件(NaOH/溶剂/水)以得到酸1E,可以使其在标准酰胺键形成条件下与多种胺反应以得到化合物,诸如1F。可以进一步使中间体1F与多种胺反应以得到通用结构I的化合物。
方案1
式I的另外的化合物也可以如方案2中所概述的制备。可以使中间体2A与多种胺反应以得到2B,可以使其与多种芳基交叉偶联试剂进一步反应(如前所述)以得到中间体,诸如2C。可以将2C的酯官能团在标准皂化条件(NaOH/溶剂/水)下转化为羧酸以得到酸中间体2D。如前所述,可以使2D型的中间体与多种胺在标准酰胺键形成条件下反应以得到通式I的化合物。
方案2
式I的另外的化合物也可以如方案3中所概述的制备。可以将中间体3A经由酯水解转化为羧酸3B,并且然后与多种或交叉偶联试剂(诸如芳基硼酸)反应以得到3C。然后可以将3C在升高的温度下在溶剂中与(二乙酰氧基碘)苯和亲电子碘源(诸如NIS)反应后,转化为相应的碘化物3D。可以在CuI和抗坏血酸钠和二氨基配体的存在下与适当取代的炔烃和叠氮化钠的混合物反应(通常称为点击化学)后,将碘化物中间体3D转化为通式I的化合物。
方案3
实施例
本发明的化合物和用于制备本发明化合物的中间体可以使用以下实施例中示出的程序和相关程序来制备。这些实施例中使用的方法和条件以及在这些实施例中制备的实际化合物并不意在是限制性的,而是意在证明如何可以制备本发明的化合物。当不通过本文所述的方法程序时,这些实施例中使用的起始材料和试剂通常是可商购的,或者报道在化学文献中,或者可以通过使用化学文献中描述的程序制备。在以下实施方案中进一步定义了本发明。应当理解,实施例仅以说明的方式给出。从以上讨论和实施方案看出,本领域技术人员可以确定本发明的本质特征,并且在不背离其精神和范围的情况下,可以进行各种改变和修改以使本发明适应各种用途和条件。因此,本发明不受下文所述的说明性实施例的限制,而是由所附权利要求限定。
在给出的实施例中,短语“干燥并且浓缩”通常是指将在有机溶剂中的溶液经硫酸钠或硫酸镁干燥,接着过滤并且从滤液中除去溶剂(通常在减压下并且在适用于所制备的材料的稳定性的温度下)。
使用Isco中压色谱装置(Teledyne Corporation)用预填充的硅胶管柱进行柱色谱,用所指示的溶剂或溶剂混合物洗脱。使用反相柱(Waters Sunfire C18,Waters XbridgeC18,Axia C18,YMC S5ODS等)进行制备型高效液相色谱(HPLC),所述反相柱的尺寸适用于分离的材料的量,通常用在水中渐增浓度的甲醇或乙腈(还含有0.05%或0.1%三氟乙酸或10mM乙酸铵)梯度以适合于柱尺寸和待实现的分离的洗脱速度进行洗脱。使用ChemDraw Ultra,版本9.0.5(CambridgeSoft)确定化学名称。使用了以下缩写:
aq. 水溶液
盐水 饱和氯化钠水溶液
BOP 苯并三唑-1-基氧基三-(二甲基氨基)-鏻六氟磷酸盐
DCM 二氯甲烷
DIPEA 二异丙基乙胺
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
EtOAc 乙酸乙酯
EtOH 乙醇
g 克
h 小时
HPLC 高效液相色谱法
LCMS 液相色谱-质谱法
MeCN 乙腈
MeOH 甲醇
NH4OAc 乙酸铵
NIS N-碘琥珀酰亚胺
Pd(OAc)2 乙酸钯
pet ether 石油醚
t-BuOH 叔丁醇
TEA 三乙醇胺
TFA 三氟乙酸
THF 四氢呋喃
HPLC条件:
方法A:Waters Acquity UPLC BEH C18,2.1x 50mm,1.7μm颗粒;流动相A:5:95乙腈:水(具有10mM乙酸铵);流动相B:95:5乙腈:水(具有10mM乙酸铵);温度:50℃;梯度:经3分钟0-100%B,然后在100%B下保持0.75分钟;流速:1.0mL/min;检测:在220nm下的UV。
方法B:Waters Acquity UPLC BEH C18,2.1x 50mm,1.7μm颗粒;流动相A:5:95乙腈:水(具有0.1%三氟乙酸);流动相B:95:5乙腈:水(具有0.1%三氟乙酸);温度:50℃;梯度:经3分钟0-100%B,然后在100%B下保持0.75分钟;流速:1.0mL/min;检测:在220nm下的UV。
方法C:Xbridge Ph 3.5μm 4.6X 150mm;梯度时间:12min,保持3分钟;流速=2ml/min;溶剂A=5%MeCN-95%水-0.05%TFA;溶剂B=95%MeCN-5%水-0.05%TFA;起始%B=10;最终%B=100。
实施例1
(R)-7-(环丙基氨基)-N-(2-氟-3-羟基-3-甲基丁基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺
中间体1A:2-(((2-溴噻唑-5-基)氨基)亚甲基)丙二酸二甲酯
将TFA(24mL)添加到(2-溴噻唑-5-基)氨基甲酸叔丁酯(1.52g,5.4mmol)和甲氧基亚甲基丙二酸二甲酯(1.42g,8.2mmol)的组合中。将澄清的黄色反应溶液在室温下搅拌1h。在真空下去除TFA,然后与己烷/醚共蒸发两次以得到奶油色固体。在硅胶上的快速色谱法(Teledyne-Isco RediSep Rf 40g柱),分别用200mL的98:2、95:5,400mL的90:10,400mL的80:20,400mL的75:25,和200mL的60:40己烷:EtOAc洗脱得到1.44g的黄色固体。将固体在40mL的90:10己烷:醚中简单地超声并且研磨,并且将固体通过过滤收集并且用90:10己烷:醚冲洗。干燥后,获得呈淡黄色固体的2-(((2-溴噻唑-5-基)氨基)亚甲基)丙二酸二甲酯(1.24g,71%产率)。1H NMR(400MHz,氯仿-d)δ10.96(d,J=11.9Hz,1H),8.05(d,J=12.8Hz,1H),7.29(s,1H),3.87(s,3H),3.80-3.77(m,3H);LC/MS:m/z 290.94(M-OMe)。
中间体1B:2-溴-7-氯噻唑并[5,4-b]吡啶-6-甲酸甲酯
将2-(((2-溴噻唑-5-基)氨基)亚甲基)丙二酸二甲酯(1.241g,3.87mmol)在三氯氧磷中的溶液与具有2个Friedrich冷凝器的CaCl2干燥管在110℃下加热16h。在真空下彻底去除POCl3。添加冰冷的DCM和冰冷的饱和NaHCO3水溶液。分离各层并且将水层用DCM萃取。将合并的DCM层用冰冷的饱和NaHCO3水溶液洗涤,然后用盐水洗涤并且经Na2SO4干燥,并且浓缩为橙色固体。经由柱色谱法(98:2CH2Cl2:EtOAc)纯化得到2-溴-7-氯噻唑并[5,4-b]吡啶-6-甲酸甲酯(631mg,53%产率)。1H NMR(400MHz,氯仿-d)δ9.02(s,1H),4.03(s,3H);LCMS:m/z 304.0(来自Cl/Br模式的一个峰)。
中间体1C:7-氯-2-苯基噻唑并[5,4-b]吡啶-6-甲酸甲酯
将2-溴-7-氯噻唑并[5,4-b]吡啶-6-甲酸甲酯(0.200g,0.65mmol)和苯基硼酸(0.198g,1.63mmol)在二噁烷(4.89mL)和磷酸钾盐(2.0M)(1.24mL,2.47mmol)中的溶液用N2气脱气几分钟。仍脱气的同时,添加Pd(OAc)2(15mg,0.065mmol)和2-(二环己基膦基)-2',4',6'-三异丙基联苯基(X-Phos)(62mg,0.130mmol)。将反应混合物在55℃下搅拌5h。添加另外的2-(二环己基膦基)-2',4',6'-三异丙基联苯基(X-Phos)(62mg,0.130mmol)和Pd(OAc)2(15mg,0.065mmol)。将反应混合物脱气几分钟,重新密封并且在55℃下继续搅拌16h。将反应混合物冷却至室温,添加EtOAc和水,并且分离各层。将EtOAc层用水和盐水洗涤,然后经Na2SO4干燥。将有机层浓缩并且将固体悬浮在己烷中,超声1分钟,通过过滤收集,用己烷重新并且在真空下干燥以得到0.192g的棕褐色固体。将产物经由柱色谱法(95:5己烷:EtOAc)纯化以得到呈浅棕褐色固体的7-氯-2-苯基噻唑并[5,4-b]吡啶-6-甲酸甲酯(94.7mg,48%产率)。LCMS m/z 305.0(M+H)。
中间体1D:7-氯-2-苯基噻唑并[5,4-b]吡啶-6-甲酸
将7-氯-2-苯基噻唑并[5,4-b]吡啶-6-甲酸甲酯(94.5mg,0.31mmol)在THF(1.24mL)、甲醇(1.24mL)和NaOH(1.0M)(1.24mL,1.24mmol)中的悬浮液在室温下搅拌几分钟。底物不溶解。添加另外的甲醇(大约5mL),最终溶解底物。继续搅拌1h。1h后的HPLC指示反应完成。在真空下去除甲醇和THF。将烧瓶浸入碎冰中,并且添加1N HCl。将沉淀物通过过滤收集,用水冲洗,并且在真空下干燥以得到76.5mg的淡棕褐色固体。干燥后,将固体用己烷洗涤并且在真空下干燥以得到呈淡棕褐色固体的7-氯-2-苯基噻唑并[5,4-b]吡啶-6-甲酸(76.5mg,85%产率)。1H NMR(400MHz,DMSO-d6)δ13.97(br.s.,1H),8.96(s,1H),8.33-7.99(m,2H),7.81-7.38(m,3H)。LCMS m/z 291.0(M+H)。
中间体1E:(R)-7-氯-N-(2-氟-3-羟基-3-甲基丁基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺
向7-氯-2-苯基噻唑并[5,4-b]吡啶-6-甲酸(50mg,0.0.172mmol)、BOP(23mg,0.0.19mmol)和(R)-4-氨基-3-氟-2-甲基丁-2-醇(23mg,0.0.189mmol)在DMF(0.5mL)中的溶液中添加DIPEA(64μL,0.36mmol)。将混合物在室温下搅拌1h。添加水并且将沉淀的固体过滤并且用水洗涤,并且然后干燥以得到(R)-7-氯-N-(2-氟-3-羟基-3-甲基丁基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(52mg,77%产率)。
实施例1:
向(R)-7-氯-N-(2-氟-3-羟基-3-甲基丁基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(10mg,0.025mmol)、BOP(3.6mg,0.028mmol)和环丙胺(1.6mg,0.028mmol)在DMF(0.5mL)中的溶液中添加DIPEA(9.5μL,0.053mmol)。将混合物在80℃下加热过夜并且然后冷却至室温。将产物经由制备型HPLC纯化以得到(R)-7-(环丙基氨基)-N-(2-氟-3-羟基-3-甲基丁基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(7.3mg,68%产率)。1H NMR(500MHz,DMSO-d6)δ9.17(br s,1H),8.58(m,1H),8.29(s,2H),7.83(m,2H),7.34(m,3H),4.67(m,1H),4.14(m,1H),3.73-3.52(m,2H),0.94(m,6H),0.70(m,2H),0.38(m,2H)。LCMS m/z 415.2(M+H),HPLC,室温,1.83min,条件A。
使用适当的起始材料,使用实施例1概述的通用方法制备表1中的实施例。
表1
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实施例21
(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(1H-吡唑-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺
中间体21A:2-溴-4-氯噻吩并[2,3-b]吡啶-5-甲酸乙酯
将溴(0.646mL,12.54mmol)添加到4-羟基噻吩并[2,3-b]吡啶-5-甲酸乙酯(1.4g,6.27mmol)在乙酸(30mL)中的溶液中,将混合物在80℃下加热1h,冷却至室温,并且然后添加冰水。将所得的黄色沉淀物过滤并且干燥。将此固体吸收在POCl3(10mL,107mmol)中,添加N,N-二甲基苯胺(1g,8.25mmol),并且将混合物在100℃下加热1h。将混合物浓缩。将残余物在水与DCM之间分配,并且将有机相分离并且干燥(MgSO4)并且浓缩。使粗产物经受ISCO快速色谱法(硅胶/己烷-EtOAc 100:0至0:100梯度)以得到呈浅黄色固体的2-溴-4-氯噻吩并[2,3-b]吡啶-5-甲酸乙酯(1.4g,70%产率)。LCMS 321.9(M+H)。
中间体21B:2-溴-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酸乙酯
将2-溴-4-氯噻吩并[2,3-b]吡啶-5-甲酸乙酯(160mg,0.5mmol)、丙-2-胺(148mg,2.5mmol)和TEA(348μL,2.5mmol)在乙腈(3mL)中的混合物在90℃下在密封小瓶中搅拌1h并且浓缩。将残余物吸收在二氯甲烷中并且用饱和碳酸氢钠水溶液洗涤。将有机相干燥(MgSO4)并且浓缩以得到2-溴-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酸乙酯(160mg,93%产率)。LCMS m/z 345.0(M+2);1H NMR(400MHz,氯仿-d)δ9.97(br s,1H),8.93(s,1H),7.55(s,1H),4.40(q,J=7.1Hz,2H),4.35-4.24(m,1H),1.47(d,J=6.3Hz,6H),1.42(t,J=7.1Hz,3H)。
实施例21:
将双(三苯基膦)氯化钯(6.13mg,8.74μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-甲酸叔丁酯(30.9mg,0.105mmol)、2-溴-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酸乙酯(30mg,0.087mmol)和碳酸钠(27.8mg,0.262mmol)在THF(1mL)和水(0.15mL)中的混合物在90℃下在密封小瓶中搅拌1.5h。将反应混合物用二氯甲烷稀释并且用饱和碳酸氢钠水溶液洗涤。将有机相干燥(MgSO4)并且浓缩以得到粗产物。使粗产物经受制备型HPLC(ODS柱/水-MeOH-TFA 90:10:0.1至10:90:0.1梯度)以得到呈白色固体的2-(1-(叔丁氧基羰基)-1H-吡唑-4-基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酸乙酯(24mg,64%产率)。将白色固体吸收在二噁烷(1mL)中,添加1N NaOH(0.5mL,0.5mmol),并且将混合物在100℃下搅拌3h。将混合物用添加浓HCl进行酸化并且然后浓缩。将残余物用MeOH萃取并且将萃取物浓缩。将残余物在室温下与BOP(38.7mg,0.087mmol)、(R)-4-氨基-3-氟-2-甲基丁-2-醇(10.6mg,0.087mmol)和TEA(0.061mL,0.44mmol)一起搅拌30min。将反应混合物用EtOAc稀释,用饱和碳酸氢钠洗涤,干燥(MgSO4)并且浓缩。使粗产物经受制备型HPLC(ODS柱/水-MeOH-TFA 90:10:0.1至10:90:0.1梯度)以得到呈白色固体的(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(1H-吡唑-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺,TFA(9mg,19.82%产率)。1H NMR(400MHz,MeOH-d4)δ8.51(s,1H),8.10(s,2H),7.80(s,1H),4.58(spt,J=6.24Hz,1H),4.29-4.51(m,1H),3.83-4.01(m,1H),3.50(ddd,J=9.41,14.61,15.96Hz,1H),1.45(d,J=6.24Hz,6H),1.29(d,J=1.59Hz,6H);19F NMR(376MHz,MeOH-d4)δ-77.11(s,3F),-195.26(s,1F);LCMS m/z 406.1(M+H);HPLC,室温,4.52min,条件C。
使用适当的起始材料,使用实施例21概述的通用方法制备表2中的实施例。
表2
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实施例74
4-(1-(4-(异丙基氨基)-2-(吡啶-3-基)噻吩并[2,3-b]吡啶-5-基)-1H-1,2,3-三唑-4-基)-2-甲基丁-2-醇
中间体74A:2-溴-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酸
将2-溴-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酸乙酯(400mg,1.16mmol)溶解于THF(6mL)和MeOH(1.5mL)中。向此溶液中添加LiOH(2.33mL,4.7mmol)并且将混合物在室温下搅拌过夜。将溶液用0.5N HCl酸化并且将所得的固体收集,用水洗涤并且在真空下干燥以得到呈白色固体的2-溴-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酸(320mg,87%产率)。LCMS 317.0(M+2)。
中间体74B:5-碘-N-异丙基-2-(吡啶-3-基)噻吩并[2,3-b]吡啶-4-胺
将2-溴-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酸(154mg,0.49mmol)、吡啶-3-硼酸(69.1mg,0.56mmol)、磷酸钾(2M)(0.244mL,0.49mmol)在DMF(4mL)中的混合物用N2吹扫5min。接下来,添加1,1'-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷复合物(40mg,0.049mmol)并且将所得的混合物在90℃下搅拌20h。将混合物冷却至室温并且将产物经由制备型HPLC直接纯化。产物级分含有脱溴产物并且不经进一步纯化使用。
中间体74B:5-碘-N-异丙基-2-(吡啶-3-基)噻吩并[2,3-b]吡啶-4-胺
将4-(异丙基氨基)-2-(吡啶-3-基)噻吩并[2,3-b]吡啶-5-甲酸(80mg,0.26mmol)和二乙酸碘苯(45mg,0.14mmol)在MeCN(3mL)和水(1mL)中的溶液在60℃下搅拌10min。接下来,添加1-碘吡咯烷-2,5-二酮(66.1mg,0.294mmol)。将反应混合物在60℃下加热4h,冷却至室温,并且在真空下去除溶剂。将产物经由制备型HPLC直接纯化以得到5-碘-N-异丙基-2-(吡啶-3-基)噻吩并[2,3-b]吡啶-4-胺(21mg,21%产率)。LCMS m/z 396.0(M+H)。
实施例74:
将(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(1.94mg,0.014mmol)、叠氮化钠(5.9mg,0.09mmol)、抗坏血酸钠(1.80mg,9.1μmol)、碘化铜(I)(1.74mg,9.11μmol)、5-碘-N-异丙基-2-(吡啶-3-基)噻吩并[2,3-b]吡啶-4-胺(18mg,0.046mmol)和2-甲基己-5-炔-2-醇(5.11mg,0.046mmol)的混合物在DMSO(1.5mL)和水(0.3mL)中在室温下在搅拌的情况下混合。将反应小瓶密封。将反应混合物在室温下搅拌20小时。添加另一组试剂并且在室温下继续反应另外的24h。将产物经由制备型HPLC直接分离。LCMS m/z 422.9(M+H);HPLC,室温,1.59min,条件A。
使用适当的起始材料,使用实施例74概述的通用方法制备表3中的实施例。
表3
生物学测定
本发明化合物的药理学特性可以通过许多生物学测定证实。已经用本发明的化合物进行以下例示的生物学测定。
IRAK4抑制测定
所述测定在U形底384孔板中进行。最终的测定体积为通过以下制备的30μL:添加15μL酶和底物(荧光肽和ATP)以及在测定缓冲液中的测试化合物(20mM HEPES pH 7.2,10mM MgCl2,0.015%Brij 35和4mM DTT)。通过IRAK4与底物和测试化合物组合引发反应。将反应混合物在室温下孵育60min,并且通过向每个样品中添加45μL的35mM EDTA而终止。在Caliper3000(Caliper,马萨诸塞州霍普金顿)上通过电泳分离荧光底物和磷酸化产物来分析反应混合物。通过与100%抑制的无酶对照反应和0%抑制的仅媒介物反应进行比较来计算抑制数据。测定中试剂的最终浓度为:ATP,500μM;FL-IPTSPITTTYFFFKKK肽1.5μM;IRAK4,0.6nM;以及DMSO,1.6%。
IRAK4全血测定
将含有抗凝剂ACD-A的人全血铺板在384孔板中(25μL/孔),并在5%CO2培养箱中与化合物一起在37℃下孵育60分钟。在5%CO2培养箱中,将血液用TLR2激动剂即在25μLRPMI(Gibco)中终浓度为10μg/mL的脂磷壁酸(Invivogen,加利福尼亚州圣地亚哥)刺激5小时。在孵育结束时,将板以2300rpm离心5分钟。收获上清液并且通过流式细胞术珠测定(BDBiosciences,加利福尼亚州圣何塞)分析IL-6水平。
PBMC TLR2诱导的IL-6测定。
通过Ficoll梯度离心从含有抗凝剂EDTA(2.5mM)的人血中分离外周血单核细胞(PBMC)。在5%CO2培养箱中,将PBMC(250000个细胞/孔)与化合物一起在测定培养基(具有10%热灭活FCS的RPMI)中在37℃下培养30分钟。用化合物预处理后,将细胞用TLR2激动剂10μg/ml脂磷壁酸(Invivogen,加利福尼亚州圣地亚哥)刺激5小时。在培养结束时,将板以1800rpm离心10分钟以沉淀细胞。收获上清液并且通过ELISA(BD Biosciences,加利福尼亚州圣何塞)分析IL-6水平。
下表列出了在IRAK4抑制测定、IRAK4全血测定中测量的本发明以下实施例的IRAK4 IC50值和全血EC50值。
表4IRAK4抑制数据
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序列表
<110> 百时美施贵宝公司
<120> 用作IRAK4抑制剂的噻吩并吡啶基化合物和噻唑并吡啶基化合物
<130> 13301-WO-PCT
<150> US62/877,334
<151> 2019-07-23
<160> 1
<170> PatentIn 3.5版
<210> 1
<211> 16
<212> PRT
<213> 智人
<220>
<221> 尚未归类的特征
<223> 附接至氨基酸1的荧光标签
<400> 1
Ile Pro Thr Ser Pro Ile Thr Thr Thr Tyr Phe Phe Phe Lys Lys Lys
1 5 10 15
Claims (8)
1.一种式(I)的化合物
或其盐,其中:
X是CR4或N;
R1是:
(i)-C(O)NHR1a或-C(O)NH(CH2)1-3R1b;或
(ii)吡唑基、咪唑基、异噁唑基或三唑基,各自被0或1个R1c取代;
R1a是:
(i)氢或被1至4个独立地选自以下的取代基取代的C3-6烷基:F、-CN、-OH、C1-2烷氧基、C1-2氟烷氧基、-NRyRy、-NRxC(O)(C1-3烷基)、-C(O)NRyRy、-S(O)2(C1-3烷基)和-NRxS(O)2(C1-3烷基);或
(ii)选自以下的环状基团:C3-6环烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吡咯基、吡唑基、吡啶基、咪唑基和三唑基,其中所述环状基团被零或一个选自以下的取代基取代:-OH、-C(O)(C1-3烷基)、-C(O)(C1-3氟烷基)、-C(O)O(C1-3烷基)、-NRaRa、-NRaC(O)(C1-3烷基)、-NRaC(O)O(C1-3烷基)、-S(O)2(C1-3烷基)、-S(O)2(C1-3氟烷基)、-C(O)(C3-6环烷基)、-C(O)(吗啉基)、-CH2(吡啶基)、-S(O)2(吡啶基)、吗啉基和三唑基;
R1b是C3-6环烷基、氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、二氧化硫代吗啉基、吡咯基、吡唑基、咪唑基、三唑基或吡啶基,各自被0至3个独立地选自以下的取代基取代:F、-OH、-CH3、-CF3和-CH2OH;
R1c是F、Cl、-OH、-CN或被0至4个独立地选自以下的取代基取代的C1-6烷基:F、-CN、-OH、C1-2烷氧基、C3-6环烷基、-NRyRy、-NRxC(O)(C1-3烷基)、-C(O)NRyRy、-S(O)2(C1-3烷基)和-NRxS(O)2(C1-3烷基);
R2是:
(i)被0至4个独立地选自以下的取代基取代的C1-6烷基:F、Cl、-OH和-CN;或
(ii)选自以下的环状基团:C3-6环烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基和吡唑基,其中所述环状基团被0至3个独立地选自以下的取代基取代:F、-OH、-CN、C1-2烷基、C1-2氟烷基和C1-2羟烷基;
R3是R3a或-NHR3a;
R3a是吡唑基、噻唑基、苯基、吡啶基、吡啶酮基、哒嗪基、吡咯并[2,3-b]吡啶基或咪唑并[1,2-a]吡啶基,各自被0至1个选自以下的取代基取代:F、Cl、-CN、C1-2烷基、C1-2氟烷基、C1-2羟烷基、C1-2烷氧基、-NRxRx、-S(O)2(C1-3烷基)和吡唑基;
每个R4独立地是氢、F、Cl、-CH3或-CF3;
每个Rx独立地是氢或-CH3;并且
每个Ry独立地是氢或C1-4烷基。
2.根据权利要求1所述的化合物或其盐,其中:
R1a是:
(i)氢或被1至4个独立地选自以下的取代基取代的C3-5烷基:F、-CN、-OH、C1-2烷氧基、C1-2氟烷氧基、-NRaRa、-C(O)NRaRa、-S(O)2(C1-2烷基)和-NRaS(O)2(C1-2烷基);或
(ii)选自以下的环状基团:C3-6环烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、哌啶基和吡啶基,各自被零或一个选自以下的取代基取代:-OH、-C(O)(C1-2烷基)、-C(O)O(C1-3烷基)、-NRaRa、-NRaC(O)(C1-2烷基)、-NRaC(O)O(C1-2烷基)、-S(O)2(C1-2烷基)、-S(O)2(C1-3氟烷基)、-C(O)(C3-6环烷基)、-C(O)(吗啉基)、-CH2(吡啶基)、-S(O)2(吡啶基)、吗啉基和三唑基;
R1b是C3-6环烷基、吡咯烷基、哌啶基、二氧化硫代吗啉基、三唑基或吡啶基,各自被0至3个独立地选自以下的取代基取代:F、-OH、-CH3和-CH2OH;
R1c是F、Cl、-OH、-CN或被0至4个独立地选自以下的取代基取代的C1-6烷基:F、-CN、-OH、C1-2烷氧基、C3-6环烷基、-NRyRy、-NRxC(O)(C1-2烷基)和-C(O)NRyRy;
R2是:
(i)被0至2个独立地选自以下的取代基取代的C1-4烷基:F、-OH和-CN;或
(ii)选自以下的环状基团:C3-6环烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基和吡唑基,其中所述环状基团被0至2个独立地选自以下的取代基取代:F、-OH、-CN、C1-2烷基、C1-2氟烷基和C1-2羟烷基;并且
R3a是吡唑基、噻唑基、苯基、吡啶基、吡啶酮基、哒嗪基、吡咯并[2,3-b]吡啶基或咪唑并[1,2-a]吡啶基,各自被0至1个选自以下的取代基取代:F、Cl、-CN、C1-2烷基、-CF3、C1-2羟烷基、C1-2烷氧基、-NH2、-S(O)2(C1-2烷基)和吡唑基。
3.根据权利要求1所述的化合物或其盐,其中:
R1是:
(i)-C(O)NHR1a或-C(O)NH(CH2)1-3R1b;或
(ii)被-CH2CH2CH(CH3)2、-CH2CH2CH2OH、-CH2CH2C(CH3)2OH或-CH2(环丙基)取代的三唑基;
R1a是:
(i)-CH2CH2CN、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2CH(CH3)OH、-CH2CH2S(O)2CH3、-CH2CH2NHS(O)2CH3、-CH2CHFC(CH3)2OH或-CH2CH2CH2NHS(O)2CH3;或
(ii)环丁基、环己基或哌啶基,各自被-OH、-NH2、-C(O)CH3、-OC(O)CH3、-NHC(O)CH3或-NHC(O)OCH3取代;
R1b是环丙基、环丁基、吡咯烷基、哌啶基、二氧化硫代吗啉基、三唑基或吡啶基,各自被0至3个独立地选自以下的取代基取代:F、-OH和-CH2OH;
R2是-CH2CH3、-CH(CH3)2、-CH(CH3)CH2OH、环丙基、环戊基、氧杂环丁烷基四氢吡喃基或二氟乙基吡唑基;并且
R3a是吡唑基、噻唑基、苯基、吡啶基、吡啶酮基、哒嗪基、吡咯并[2,3-b]吡啶基或咪唑并[1,2-a]吡啶基,各自被0至1个选自以下的取代基取代:F、-CN、-CH3、-OCH3、-NH2、-S(O)2CH3和吡唑基。
4.根据权利要求1所述的化合物或其盐,其中所述化合物具有式(Ia)的结构:
5.根据权利要求1所述的化合物或其盐,其中所述化合物具有式(Ib)的结构:
6.根据权利要求1所述的化合物或其盐,其中所述化合物选自:(R)-7-(环丙基氨基)-N-(2-氟-3-羟基-3-甲基丁基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(1);(R)-N-(2-氟-3-羟基-3-甲基丁基)-7-(异丙基氨基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(2);(R)-7-(环戊基氨基)-N-(2-氟-3-羟基-3-甲基丁基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(3);(R)-N-(2-氟-3-羟基-3-甲基丁基)-2-苯基-7-((四氢-2H-吡喃-4-基)氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(4);(R)-7-(乙基氨基)-N-(2-氟-3-羟基-3-甲基丁基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(5);N-((R)-2-氟-3-羟基-3-甲基丁基)-7-(((R)-1-羟基丙-2-基)氨基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(6);(R)-N-(3-羟基-3-甲基丁基)-7-((1-羟基丙-2-基)氨基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(7);(R)-7-((1-羟基丙-2-基)氨基)-N-(3-吗啉代丙基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(8);(R)-N-(2-氰基乙基)-7-((1-羟基丙-2-基)氨基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(9);(R)-7-((1-羟基丙-2-基)氨基)-N-(2-(甲基磺酰基)乙基)-2-苯基噻唑并[5,4-b]吡啶-6-甲酰胺(10);(R)-N-(2-氟-3-羟基-3-甲基丁基)-7-(异丙基氨基)-2-(吡啶-3-基)噻唑并[5,4-b]吡啶-6-甲酰胺(11);N-(3-羟基-3-甲基丁基)-2-(吡啶-3-基)-7-((四氢-2H-吡喃-4-基)氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(12);N-(2-(4-羟基哌啶-1-基)乙基)-2-(吡啶-3-基)-7-((四氢-2H-吡喃-4-基)氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(13);(R)-N-(2-氟-3-羟基-3-甲基丁基)-2-(吡啶-3-基)-7-((四氢-2H-吡喃-4-基)氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(14);(R)-2-((4-(1H-吡唑-1-基)苯基)氨基)-N-(2-氟-3-羟基-3-甲基丁基)-7-(异丙基氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(15);(R)-N-(2-氟-3-羟基-3-甲基丁基)-7-(异丙基氨基)-2-(吡啶-3-基氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(16);(R)-N-(2-氟-3-羟基-3-甲基丁基)-7-(异丙基氨基)-2-((4-(甲基磺酰基)苯基)氨基)噻唑并[5,4-b]吡啶-6-甲酰胺(17);7-(异丙基氨基)-2-(吡啶-3-基)-N-(3,3,3-三氟丙基)噻唑并[5,4-b]吡啶-6-甲酰胺(18);N-(2-环丙基乙基)-7-(异丙基氨基)-2-(吡啶-3-基)噻唑并[5,4-b]吡啶-6-甲酰胺(19);(1r,4r)-4-(7-(异丙基氨基)-2-(吡啶-3-基)噻唑并[5,4-b]吡啶-6-甲酰胺基)环己基乙酸酯(20);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(1H-吡唑-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺(21);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(吡啶-3-基)噻吩并[2,3-b]吡啶-5-甲酰胺(22);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(吡啶-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺(23);(R)-2-(3-氰基苯基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(24);(R)-2-(6-氰基吡啶-3-基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(25);(R)-N-(2-氟-3-羟基-3-甲基丁基)-2-(咪唑并[1,2-a]吡啶-6-基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(26);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(27);(R)-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(28);N-异戊基-4-(异丙基氨基)-2-(吡啶-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺(29);N-异戊基-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(30);N-异戊基-4-(异丙基氨基)-2-(吡啶-3-基)噻吩并[2,3-b]吡啶-5-甲酰胺(31);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(哒嗪-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺(32);N-异戊基-4-(异丙基氨基)-2-(哒嗪-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺(33);4-(异丙基氨基)-N-(2-甲氧基乙基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(34);4-(异丙基氨基)-N-((3-甲基异噁唑基-5-基)甲基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(35);N-((1r,4r)-4-羟基环己基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(36);N-(2-(1-(羟基甲基)环丙基)乙基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(37);N-((1r,4r)-4-氨基环己基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(38);N-(1-环丙基-3-羟基丙基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(39);(R)-N-(4-羟基丁-2-基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(40);4-(异丙基氨基)-N-(噁唑基-4-基甲基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(41);N-((1H-1,2,4-三唑-5-基)甲基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(42);N-(2-乙氧基乙基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(43);N-(3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(44);N-((1r,4r)-4-乙酰胺基环己基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(45);N-(3-羟基-2,2-二甲基丙基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(46);N-((3-(羟基甲基)氧杂环丁烷-3-基)甲基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(47);(R)-4-((1-(2,2-二氟乙基)-1H-吡唑-4-基)氨基)-N-(4-羟基丁-2-基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(48);4-((1-(2,2-二氟乙基)-1H-吡唑-4-基)氨基)-N-((1s,4s)-4-羟基环己基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(49);((1r,4r)-4-(4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺基)环己基)氨基甲酸甲酯(50);4-((1-(2,2-二氟乙基)-1H-吡唑-4-基)氨基)-N-(2-甲氧基乙基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(51);(R)-4-((1-(2,2-二氟乙基)-1H-吡唑-4-基)氨基)-N-(2-氟-3-羟基-3-甲基丁基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(52);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(氧杂环丁烷-3-基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(53);N-((1s,4s)-4-羟基环己基)-4-(氧杂环丁烷-3-基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(54);N-((1H-1,2,4-三唑-5-基)甲基)-4-(氧杂环丁烷-3-基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(55);(R)-2-(2-氨基噻唑-5-基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(56);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(2-甲基噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(57);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(2-甲氧基噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(58);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(6-氧代-1,6-二氢吡啶-3-基)噻吩并[2,3-b]吡啶-5-甲酰胺(59);N-(3-羟基丁基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(60);N-(3-羟基环丁基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(61);(R)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)-2-(噻唑-4-基)噻吩并[2,3-b]吡啶-5-甲酰胺(62);N-(2-(3,3-二氟-1-羟基环丁基)乙基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(63);(R)-2-(6-氰基吡啶-3-基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(64);(R)-2-(5-氰基吡啶-3-基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-5-甲酰胺(65);N-(1-乙酰基哌啶-4-基)-4-(异丙基氨基)-2-(6-氧代-1,6-二氢吡啶-3-基)噻吩并[2,3-b]吡啶-5-甲酰胺(66);4-(异丙基氨基)-N-(3-(甲基磺酰胺基)丙基)-2-(6-氧代-1,6-二氢吡啶-3-基)噻吩并[2,3-b]吡啶-5-甲酰胺(67);N-(2-(1,1-二氧化硫代吗啉代)乙基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(68);N-((1,1-二氧化四氢噻吩-3-基)甲基)-4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-甲酰胺(69);4-(异丙基氨基)-2-(6-氧代-1,6-二氢吡啶-3-基)-N-(2-(吡咯烷-3-基)乙基)噻吩并[2,3-b]吡啶-5-甲酰胺(70);4-(异丙基氨基)-2-(6-氧代-1,6-二氢吡啶-3-基)-N-(2-(吡啶-4-基)乙基)噻吩并[2,3-b]吡啶-5-甲酰胺(71);4-(异丙基氨基)-2-(6-氧代-1,6-二氢吡啶-3-基)-N-(2-(吡啶-3-基)乙基)噻吩并[2,3-b]吡啶-5-甲酰胺(72);N-(2-(1,1-二氧化硫代吗啉代)乙基)-4-(异丙基氨基)-2-(6-氧代-1,6-二氢吡啶-3-基)噻吩并[2,3-b]吡啶-5-甲酰胺(73);4-(1-(4-(异丙基氨基)-2-(吡啶-3-基)噻吩并[2,3-b]吡啶-5-基)-1H-1,2,3-三唑-4-基)-2-甲基丁-2-醇(74);4-(1-(4-(异丙基氨基)-2-(吡啶-4-基)噻吩并[2,3-b]吡啶-5-基)-1H-1,2,3-三唑-4-基)-2-甲基丁-2-醇(75);5-(4-异戊基-1H-1,2,3-三唑-1-基)-N-异丙基-2-(吡啶-4-基)噻吩并[2,3-b]吡啶-4-胺(76);5-(5-异戊基-1H-1,2,4-三唑-3-基)-N-异丙基-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-4-胺(77);5-(1-(环丙基甲基)-1H-1,2,3-三唑-4-基)-N-异丙基-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-4-胺(78);3-(4-(4-(异丙基氨基)-2-(噻唑-5-基)噻吩并[2,3-b]吡啶-5-基)-1H-1,2,3-三唑-1-基)丙-1-醇(79);和5-(5-(1-(3-羟基丙基)-1H-1,2,3-三唑-4-基)-4-(异丙基氨基)噻吩并[2,3-b]吡啶-2-基)吡啶-2(1H)-酮(80)。
7.一种药物组合物,所述药物组合物包含一种或多种根据权利要求1-6中任一项所述的化合物或其盐,和药学上可接受的载体或稀释剂。
8.根据权利要求1-6中任一项所述的化合物或其盐在制备用于治疗选自克罗恩病、溃疡性结肠炎、哮喘、移植物抗宿主病、同种异体移植排斥、慢性阻塞性肺疾病、格雷夫斯病、类风湿性关节炎、系统性红斑狼疮、狼疮性肾炎、皮肤狼疮、银屑病、cryopyrin相关的周期性综合征、TNF受体相关的周期性综合征、家族性地中海热、成人发作的斯蒂尔病、全身性发作的幼年特发性关节炎、多发性硬化症、神经性疼痛、痛风和痛风性关节炎的疾病的药物中的用途。
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JP2022541819A (ja) | 2022-09-27 |
KR20220041124A (ko) | 2022-03-31 |
CN114174304A (zh) | 2022-03-11 |
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