CN114230523A - 作为ROR-γ的调节剂的苯并咪唑衍生物 - Google Patents
作为ROR-γ的调节剂的苯并咪唑衍生物 Download PDFInfo
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- CN114230523A CN114230523A CN202111366970.XA CN202111366970A CN114230523A CN 114230523 A CN114230523 A CN 114230523A CN 202111366970 A CN202111366970 A CN 202111366970A CN 114230523 A CN114230523 A CN 114230523A
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- benzo
- ethylsulfonyl
- imidazole
- benzyl
- carboxamide
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Abstract
Description
本申请为2017年1月27日提交的申请号为201780009016.0的名称为“作为ROR-γ的调节剂的苯并咪唑衍生物”的申请的分案申请。
技术领域
本公开涉及新型的视黄酸受体相关的孤儿受体γ(“RORγ”或“ROR-γ”)调节剂,其制备方法,含有这些调节剂的药物组合物,以及它们在治疗由RORγ介导的炎性疾病、代谢性疾病、自身免疫疾病和其他疾病中的用途。
背景技术
视黄酸受体相关的孤儿受体(ROR)是类固醇激素核受体超家族中转录因子的亚家族(Jetten&Joo(2006)Adv.Dev.Biol.2006年,第16卷,第313-355页)。ROR家族由ROR alpha(RORα)、ROR beta(RORβ)和ROR gamma(RORγ)组成,各自由单独的基因编码(在人类中:分别为RORA、RORB和RORC;在小鼠中:分别为rora、rorb和rorc)。ROR包含大多数核受体共有的四个主要结构域:N-末端结构域、由两个锌指基序组成的高度保守的DNA结合结构域(DBD)、铰链结构域和配体结合结构域(LBD)。每个ROR基因产生几种同种型,仅在其N末端结构域有所不同。RORγ具有两种同种型:RORγ1和RORγ2(也称为RORγt)。RORγ是指RORγ1和/或RORγt。RORγ1在包括胸腺、肌肉、肾脏和肝脏的多种组织中表达,但RORγt仅在免疫系统的细胞中表达,在胸腺生成和几种次级淋巴组织的发育中起关键作用,并且是Th17细胞分化的关键调节剂(Jetten,2009年,Nucl.Recept.Signal.,7:e003,doi:10.1621/nrs.07003,电子版2009年4月3日)。
Th17细胞是辅助T细胞的亚群,其优先产生促炎性细胞因子IL-17A、IL-17F、IL-21和IL-22。Th17细胞及其效应分子(诸如IL-17、IL-21、IL-22、GM-CSF和CCL20)与几种自身免疫疾病和炎性疾病(诸如类风湿性关节炎、系统性红斑狼疮、多发性硬化症、银屑病、炎症性肠病、过敏和哮喘)的发病机制有关(Maddur等人,2012年,Am.J.Pathol.,第181卷,第8-18页)。最近的研究结果支持IL17和Th17细胞在痤疮发病机制中的作用(Thiboutot等人,2014年,J.Invest.Dermatol.,第134卷,第2期,第307-310页,doi:10.1038/jid.2013.400;Agak等人,2014年,J.Invest.Dermatol.,第134卷,第2期,第366-73页,doi:10.1038/iid.2013.334,电子版2013年8月7日)。Th17细胞也是与子宫内膜异位症相关的炎症的有效诱导物,子宫内膜异位症是一种慢性炎性疾病(Hirata等人,2010年,Endocrinol.,第151卷:第5468-5476页;Hirata等人,Fertil Steril.,2011年7月;第96卷第1期,第113-117页,doi:10.1016/j.fertnstert.2011.04.060,电子版2011年5月20日)。此外,Th17细胞在实验性自身免疫性脑脊髓炎(EAE)、胶原诱导性关节炎(CIA)和佐剂诱导性关节炎(AIA)的小鼠自身免疫性模型中具有关键作用(Bedoya等人,2013年,Clin.Dev.Immunol.,2013:986789。电子版2013年12月26日)。Th17细胞在炎症和自身免疫疾病过程中被激活,并负责募集其他炎症细胞类型,特别是嗜中性粒细胞,以介导靶组织中的病变(Miossec&Kolls,2012年,Nature Rev.,第11卷:第763-776页;Korn等人,2009年,Annu.Rev.Immunol.,第27卷:第485-517页)。异常Th17细胞功能涉及多种自身免疫疾病,包括多发性硬化症和类风湿性关节炎。自身免疫疾病被认为是由效应T细胞和调节性T细胞之间的平衡被破坏引起的(Soit等人,2012年,ACS Chem.Biol.,第7卷,第1515-1519页,电子版2012年7月9日)。RORγt对Th17细胞分化的重要性和Th17细胞的致病作用通过RORγt缺陷型小鼠具有极少的Th17细胞并且EAE严重性降低的事实得以证明(Ivanov等人,2006年,Cell,第126卷:第1121至1133页)。
最近,已发现产生IL-17的中性粒细胞促进炎症,导致角膜和其他组织中的微生物清除和IL-17相关组织损伤(Taylor等人,2014年,J.Immunol,第192卷:第3319-3327页;Taylor等人,2014年,Nat.Immunol.,第15卷:第143-151页),支持在治疗角膜溃疡和与表达IL-17的中性粒细胞相关的其他疾病和障碍中抑制RORγ活性的化合物的作用。
昼夜节律是由内源性昼夜节律钟调节的行为和生理变化的昼夜周期。许多研究已经建立了核受体(包括RORγ)功能和表达、昼夜节律调节电路和各种生理过程的调节之间的联系(Jetten(2009)op.cit.)。
阻塞性睡眠呼吸暂停综合征(OSAS)是由T淋巴细胞调节的慢性炎性疾病。OSAS患者的外周Th17细胞频率、IL-17和RORγt水平显着增加(Ye等人,2012年,MediatorsInflamm.,815308,doi:10.1155/2012/815308,电子版2012年12月31日)。
许多研究已提供了ROR在癌症中的作用的证据。缺乏RORγ表达的小鼠表现出高的胸腺淋巴瘤发病率,其经常转移到肝脏和脾脏。肿瘤微环境中Th17相关基因(包括RORγ)的高表达和Th17细胞的高水平已被证明与各种癌症(包括肺癌、胃癌、乳腺癌和结肠癌)的不良预后相关(Tosolini等人,2011年,Cancer Res.,第71卷:第1263-1271页,doi:10.1158/0008-5472.CAN-10-2907,电子版2011年2月8日;Su等人,2014年,Immunol.Res.,第58卷:第118-124页,doi:10.1007/s12026-013-8483-y,电子版2014年1月9日;Carmi等人,2011年,J.Immunol.,第186卷:第3462-3471页,doi:10.4049/jimmunol.1002901,电子版2011年2月7日;Chen等人,2013年,Histopathology,第63卷:第225-233页,doi:10.1111/his.12156,电子版2013年6月6日)。最近的证据还表明RORγ在转移性去势抗性前列腺癌肿瘤中过表达和扩增,并且RORγ拮抗剂抑制肿瘤在表达多种雄激素受体的前列腺癌异种移植模型中的生长。参见例如,Nature Medicine,2016年3月28日,提前在线出版,doi:10.1038/nm.4070。
RORγ还被确认为在脂质/葡萄糖稳态中具有调节作用,并且已涉及代谢综合征、肥胖症(Meissburger等人,2011年,EMBO Mol.Med.,第3卷,第637-651页)、肝脂肪变性、胰岛素抗性和糖尿病。
对RORγ在炎性、代谢性、昼夜节律效应、癌症和自身免疫疾病和障碍的发病机制中的作用的进一步支持可见于以下参考文献:Chang等人,2012年,J.Exp.Pharmacol.,第4卷:第141-148页;Jetten等人,2013年,Frontiers Endocrinol.,第4卷:第1-8页;Huh&Littman,2012年,Eur.J.Immunol.,第42卷:第2232-2237页;Martinez等人,2008年,Ann.N.Y.Acad.Sci.,第1143卷:第188-211页;Pantelyushin等人,2012年,J.Clin.Invest.,第122卷:第2252-2256页;Jetten&Ueda,2002年,Cell Death Differen.,第9卷:第1167-1171页;Soit等人,2010年,Curr.Opin.Lipidol.,第21卷:第204-211页。
鉴于RORγ在疾病发病机制中的作用,抑制RORγ活性和Th17细胞分化和活性,包括IL17产生,具有显着的治疗有益效果。在WO 2014/179564和WO 2015/116904中描述了抑制RORγ活性并因此在治疗例如炎性疾病、自身免疫疾病、代谢性疾病、昼夜节律效应、癌症和由RORγ介导的其他疾病中有用的化合物。然而,一直需要开发调节RORγ并且可用于治疗疾病的新的和改进的药物。
发明内容
现已发现,本文所述的化合物及其可药用组合物是RORγ的有效调节剂(参见例如,表3)。这种化合物包括式I的化合物:
或其可药用盐,其中Cy1、Cy2、L2、R1、R7、R8和X各自如本文所定义和描述。
所提供的化合物可以单独使用(即,作为单一疗法)或与有效治疗本文所述任何适应症的一种或多种其他治疗剂组合使用。
附图说明
图1描绘了(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-130.1)盐酸盐的粉末X-射线衍射图。
图2描绘了(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-130.1)游离碱的粉末X-射线衍射图。
图3描绘了(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-11.1)形式I的粉末X-射线衍射图。
图4描绘了(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-11.1)形式II的粉末X-射线衍射图。
图5描绘了(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-11.1)形式III的粉末X-射线衍射图。
图6描绘了(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-131.1)盐酸盐的粉末X-射线衍射图。
图7描绘了(R)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-132.1)游离碱的粉末X-射线衍射图。
具体实施方式
1.化合物概述
在某些实施方案中,本公开提供了式I的化合物:
或其可药用盐,其中:
X为-C(O)NH-或-NHC(O)-;
R1为(C1-C4)烷基-C(=O)ORc、卤代(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、-NRdRe、单环杂环基或单环环烷基,其中所述(C1-C4)烷基任选地被-ORc取代,所述单环杂环基任选地被(C1-C4)烷基或=O取代,并且所述单环环烷基任选地被-C(=O)ORc、-CN或一种或多种卤素取代;
L2为CH2、CHMe或环丙基;
Cy1为芳基、杂芳基、杂环基或环烷基,其中的每一种任选地被独立地选自R5的1至3个基团取代;
Cy2为芳基、杂芳基或杂环基,其中的每一种任选地被独立地选自R6的1至3个基团取代;
R5和R6各自独立地选自卤素、-CN、-ORc、-NRdRe、-S(O)kRb、-NRcS(O)2Rc、-S(O)2NRdRe、-C(=O)ORc、-OC(=O)ORc、-OC(=O)Rc、-OC(=S)ORc、-C(=S)ORc、-OC(=S)Rc、-C(=O)NRdRe、-NRcC(=O)Rc、-C(=S)NRdRe、-NRcC(=S)Rc、-NRcC(=O)ORc、-OC(=O)NRdRe、-NRc(C=S)ORc、-OC(=S)NRdRe、-NRcC(=O)NRdRe、-NRc(C=S)NRdRe、-C(=S)Rc、-C(=O)Rc、氧代基、(C1-C6)烷基、环烷基、-(CH2)1-4-环烷基、杂环基、-(CH2)1-4-杂环基、芳基、-NHC(=O)-杂环基、-NHC(=O)-环烷基、-(CH2)1-4-芳基、杂芳基和-(CH2)1-4-杂芳基,其中存在于R5和R6的所述(C1-C6)烷基、环烷基、-(CH2)1-4-环烷基、杂环基、-(CH2)1-4-杂环基、芳基、-(CH2)1-4-芳基、杂芳基和-(CH2)1-4-杂芳基取代基的每一种中的烷基、环烷基、杂环基、芳基或杂芳基部分进一步任选地被一种或多种卤素、ORc、-NO2、-CN、-NRcC(=O)Rc、-NRdRe、-S(O)kRb、-C(=O)ORc、-C(=O)NRdRe、-C(=O)Rc、(C1-C3)烷基、卤代(C1-C3)烷基、(C1-C3)烷氧基(C1-C3)烷基、(C1-C3)烷氧基或卤代(C1-C3)烷氧基取代;
R7和R8各自独立地为氢、ORc、-C(=O)ORc、单环杂环基、卤代苯基或(C1-C3)烷基,其中(C1-C3)烷基任选地被ORc、-NRdRe、-O(C1-C3)烷基-C(=O)ORc、-C(=O)ORc、-C(=O)NRdRe或卤代苯基取代;
k为0、1或2;
每个Rb独立地选自氢以及任选地被OH、-O(C1-C3)烷基、-C(O)O(C1-C3)烷基、-C(O)NH2、-C(O)NH(C1-C3)烷基或-C(O)N((C1-C3)烷基)2取代的(C1-C3)烷基;
每个Rc独立地选自氢以及任选地被一种或多种卤素取代的(C1-C3)烷基;并且
每个Rd和Re独立地选自氢和(C1-C3)烷基。
2.化合物和定义
本文所用的术语“卤代”和“卤素”是指选自氟(氟代,-F)、氯(氯代,-Cl)、溴(溴代,-Br)和碘(碘代,-I)的原子。
单独使用或作为较大部分(诸如例如,“卤代烷基”)的一部分使用的术语“烷基”是指除非另外指明,否则具有1-10个碳原子并且包括例如,甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、正己基、正庚基、正辛基、正壬基、正癸基等的饱和的单价直链或支链烃基团。“单价”是指在一个点上与分子的其余部分连接。
术语“卤代烷基”或“卤代环烷基”包括单卤代、多卤代和全卤代烷基基团,其中卤素独立地选自氟、氯和溴。
除非另外指明,否则术语“环烷基”是指具有3至10个碳环原子的环状烃。单环环烷基基团包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环庚烯基和环辛基。应当理解,当指定时,环烷基或脂环族基团上的任选取代基可存在于任何可取代的位置上,并且包括例如环烷基或脂环族基团连接的位置。
单独使用或作为较大部分如在“芳烷基”、“芳烷氧基”或“芳氧基烷基”中的一部分使用的术语“芳基”是指除非另有说明,总共具有6元环至10元环的芳族碳环体系。术语“芳基”可与术语“芳环”、“芳基基团”、“芳基部分”或“芳基自由基”互换使用。在某些实施方案中,“芳基”是指芳环体系,其包括但不限于苯基(缩写为“Ph”)、萘基等。应当理解,当指定时,芳基基团上的任选取代基可存在于任何可取代的位置上,并且包括例如芳基连接的位置。
单独使用或作为较大部分如在“杂芳基烷基”、“杂芳基烷氧基”或“杂芳基氨基烷基”中的一部分使用的术语“杂芳基”是指含有1-4个选自N、O和S的杂原子的5元至12元芳族自由基。术语“杂芳基”可与术语“杂芳基环”,“杂芳基基团”或“杂芳族”互换使用。杂芳基基团可以是单环或双环。单环杂芳基包括,例如,噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、恶唑基、异恶唑基、恶二唑基、噻唑基、异噻唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基。
双环杂芳基包括其中单环杂芳基环与一个或多个芳基或杂芳基环稠合的基团。非限制性示例包括吲哚基、苯并恶唑基、苯并氧代二唑基、吲唑基、苯并咪唑基、苯并噻唑基、喹啉基、喹唑啉基、喹恶啉基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并吡啶基、噻吩并吡啶基、噻吩并嘧啶基、吲嗪基、嘌呤基、萘啶基和蝶啶基。应当理解,当指定时,杂芳基基团上的任选取代基可存在于任何可取代的位置上,并且包括例如杂芳基连接的位置。
术语“杂环基”是指含有1至4个独立地选自N、O和S的杂原子的4元至12元饱和或部分不饱和的杂环。术语“杂环”、“杂环基”、“杂环基环”、“杂环基团”、“杂环部分”和“杂环自由基”在本文中可互换使用。杂环基环可以在任何杂原子或碳原子上与其侧基连接,从而产生稳定的结构。杂环基可以是单环或双环。单环饱和或部分不饱和杂环自由基的示例包括但不限于四氢呋喃基、四氢噻吩基、四氢吡喃基、吡咯烷基、吡咯烷酮基、哌啶基、恶唑烷基、哌嗪基、二恶烷基、二氧戊环基、吗啉基、二氢呋喃基、二氢吡喃基、二氢吡啶基、四氢吡啶基、二氢嘧啶基和四氢嘧啶基。双环杂环基基团包括,例如,与另一个不饱和杂环自由基、环烷基或者芳族或杂芳基环稠合的不饱和杂环自由基,诸如例如,苯并间二氧杂环戊基、二氢苯并二氧杂环己基、6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑基、5,6,7,8-四氢咪唑并[1,2-a]吡啶基、1,2-二氢喹啉基、二氢苯并呋喃基、四氢萘啶、吲哚啉酮、二氢吡咯并三唑、喹啉酮、二氧杂螺环癸烷。应当理解,当指定时,杂环基基团上的任选取代基可存在于任何可取代的位置上,并且包括例如杂环基连接的位置。
如本文所用,术语“受治疗者”和“患者”可互换使用,并且是指需要治疗的哺乳动物,例如,伴侣动物(例如,狗、猫等)、农场动物(例如,牛、猪、马、绵羊、山羊等)和实验室动物(例如,大鼠、小鼠、豚鼠等)。通常,受治疗者是需要治疗的人。
某些公开的化合物可以各种立体异构形式存在。立体异构体是仅在空间排列上不同的化合物。对映体是立体异构体对,其镜像不可重叠,最常见的原因是因为它们含有非对称取代的碳原子作为手性中心。“对映体”是指互为彼此的镜像并且不可重叠的一对分子中的一者。非对映体是含有两个或更多个非对称取代的碳原子的立体异构体。结构式中的符号“*”表示手性碳中心的存在。“R”和“S”表示取代基围绕一个或多个手性碳原子的构型。因此,“R*”和“S*”表示取代基围绕一个或多个手性碳原子的相对构型。
如本文所用,所列出的基团的开头或结尾的连字符(“-“)表示所列出的基团与定义的基团连接的点。例如,-SO2-(C1-C3)烷基-(C2-C6)环烷基是指该基团通过磺酰基连接。
“外消旋物”或“外消旋混合物”是指等摩尔量的两种对映体的化合物,其中这类混合物没有表现出光学活性,即,它们不旋转偏振光的平面。
“几何异构体”是指取代基原子相对于碳-碳双键、环烷基环或桥连双环体系的取向不同的异构体。碳-碳双键各侧的原子(除H外)可处于E(取代基在碳-碳双键的相对侧)或Z(取代基在同一侧取向)构型。“R”、“S”、“S*”、“R*”、“E”、“Z”、“顺式”和“反式”表示相对于核心分子的构型。当所公开的化合物按结构命名或描绘而没有指示出具体的几何异构体形式时,应当理解该名称或结构涵盖一种不含其他几何异构体的几何异构体、几何异构体的混合物或所有几何异构体的混合物。
本文的化合物可通过对映体特异性合成制备成单独的对映体,或者从富含对映体的混合物中拆分。常规拆分技术包括使用光学活性酸形成对映体对的每种异构体的游离碱的盐(随后分级结晶并再生游离碱),使用光学活性胺形成对映体对的每种对映体的酸形式的盐(随后分级结晶并再生游离酸),使用光学纯的酸、胺或醇形成对映体对的每种对映体的酯或酰胺(随后进行色谱分离并除去手性助剂),或者使用各种熟知的色谱方法拆分原料或最终产物的对映体混合物。
当按结构命名或描绘所公开化合物的立体化学时,所命名或描绘的立体异构体相对于所有其他立体异构体为至少60%、70%、80%、90%、99%或99.9%重量纯。相对于所有其他立体异构体的重量纯百分比是一种立体异构体的重量与其他立体异构体的重量的比率。当按结构命名或描绘单个对映体时,所描绘或命名的对映体为至少60%、70%、80%、90%、99%或99.9%重量光学纯。重量光学纯度百分比是对映体重量与对映体重量加上其光学异构体重量的比率。
当按结构命名或描绘所公开化合物的立体化学,并且所命名或描绘的结构涵盖多于一种立体异构体(例如,如在非对映体对中)时,应当理解,所涵盖的立体异构体之一或所涵盖的立体异构体的任何混合物包括在内。还应当理解,所命名或描绘的立体异构体相对于所有其他立体异构体的立体异构纯度为至少60%、70%、80%、90%、99%或99.9%重量纯。在这种情况下,立体异构纯度通过将名称或结构所涵盖的立体异构体混合物的总重量除以所有立体异构体混合物的总重量来确定。
当所公开的化合物按结构命名或描绘而没有指示出立体化学,并且该化合物具有一个手性中心时,应当理解,该名称或结构涵盖化合物的不含对应光学异构体的一种对映体、化合物的外消旋混合物,或者相对于其对应光学异构体富含一种对映体的混合物。
当所公开的化合物按结构命名或描绘而没有指示出立体化学,并且例如该化合物具有多于一个手性中心(例如,至少两个手性中心)时,应当理解,该名称或结构涵盖不含其他立体异构体的一种立体异构体、立体异构体混合物,或者其中相对于其他立体异构体富集一种或多种立体异构体的立体异构体混合物。例如,该名称或结构可涵盖不含其他非对映体的一种立体异构体、立体异构体混合物,或者其中相对于其他非对映体富集一种或多种非对映体的立体异构体混合物。
本文的化合物可以可药用盐形式存在。对于在医学中使用而言,本发明的化合物的盐类是指无毒的“可药用盐”。可药用盐形式包括可药用的酸性/阴离子或碱性/阳离子盐。
可药用的碱性/阳离子盐包括钠、钾、钙、镁、二乙醇胺、n-甲基-D-葡糖胺、L-赖氨酸、L-精氨酸、铵、乙醇胺、哌嗪和三乙醇胺盐。
可药用的酸性/阴离子盐包括,例如,乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、碳酸盐、柠檬酸盐、二盐酸盐、葡糖酸盐、谷氨酸盐、对羟乙酰氨基苯胂酸盐、己基间苯二酚盐、氢溴酸盐、盐酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、硝酸盐、水杨酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐和甲苯磺酸盐。
3.示例性化合物的描述
在第一实施方案中,本公开提供了式I的化合物:
或其可药用盐,其中变量如上所述。
在第二实施方案中,式I中的Cy2是杂芳基或杂环基,其中的每一种任选地被独立地选自R6的1至3个基团取代,其中剩余的变量如上文针对式I所述。
在第三实施方案中,式I中的Cy2是双环杂环基或双环杂芳基,其中的每一种任选地被独立地选自R6的1至3个基团取代,其中剩余的变量如上文针对式I和第二实施方案所述。
在第四实施方案中,式I中的Cy2选自:
其中的每一种任选地被独立地选自R6的1至3个基团取代,其中剩余的变量如上文针对式I和第二或第三实施方案所述。
在第五实施方案中,式I中的Cy2选自:
其中的每一种任选地被独立地选自R6的1至3个基团取代,其中剩余的变量如上文针对式I和第二、第三或第四实施方案所述。
在第六实施方案中,式I中的Cy2
任选地被独立地选自R6的1至3个基团取代,其中剩余的变量如上文针对式I和第二、第三、第四或第五实施方案所述。
在第七实施方案中,式I中的Cy2是任选地被独立地选自R6的1至3个基团取代的单环杂芳基,其中剩余的变量如上文针对式I和第二实施方案所述。
在第八实施方案中,式I中的Cy2是吡啶基或嘧啶基,其中的每一种任选地被独立地选自R6的1至3个基团取代,其中剩余的变量如上文针对式I和第二或第七实施方案所述。
在第九实施方案中,式I中的Cy2是苯基,其任选地被独立地选自R6的1至3个基团取代,其中剩余的变量如上文针对式I所述。
在第十实施方案中,式I中的L2是CH2或CHMe,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八或第九实施方案所述。
在第十一实施方案中,式I的化合物具有式II:
或其可药用盐,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九或第十实施方案所述。
在第十二实施方案中,式I的化合物具有式III:
或其可药用盐,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十或第十一实施方案所述。
在第十三实施方案中,式I的化合物具有式IV:
或其可药用盐,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一或第十二实施方案所述。
在第十四实施方案中,式I的化合物具有式V:
或其可药用盐,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二或第十三实施方案所述。
在第十五实施方案中,式I至V中的Cy1选自芳基、单环杂芳基和单环杂环基,其中的每一种任选地被独立地选自R5的1至3个基团取代,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三或第十四实施方案所述。
在第十六实施方案中,式I至V中的Cy1选自苯基、吡啶基和哌啶基,其中的每一种任选地被独立地选自R5的1至3个基团取代,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四或第十五实施方案所述。
在第十七实施方案中,式I至V中的Cy1为任选地被独立地选自R5的1至3个基团取代的苯基或吡啶基,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五或第十六实施方案所述。
在第十八实施方案中,式I至V中的R7为氢、ORc或任选地被ORc或NRdRe取代的(C1-C3)烷基;并且R8当存在时为氢,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六或第十七实施方案所述。
在第十九实施方案中,式I至V中的R7为氢或任选地被ORc取代的(C1-C3)烷基;并且R8当存在时为氢,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七或第十八实施方案所述。
在第二十实施方案中,式I至V中的R7为氢或(C1-C3)烷基-OH;并且R8当存在时为氢,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八或第十九实施方案所述。
在第二十一实施方案中,式I至V中的R1选自(C1-C4)烷基、卤代(C1-C4)烷基、环丁基、四氢呋喃基、(C1-C4)烷氧基、-N((C1-C3)烷基)2、-(C1-C3)烷基-O-(C1-C2)烷基、-C(O)O(C1-C2)烷基和环丙基,其中所述环丁基和环丙基各自任选地被C(=O)OMe、-CN或1至3个卤素取代,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九或第二十实施方案所述。
在第二十二实施方案中,式I至V中的R1选自(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、环丁基和环丙基,其中所述环丁基和环丙基各自任选地被1至3个卤素取代,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十或第二十一实施方案所述。
在第二十三实施方案中,式I至V中的R1为卤代(C1-C4)烷基、环丁基或环丙基,其中所述环丁基和环丙基任选地被1至3个卤素取代,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十、第二十一或第二十二实施方案所述。
在第二十四实施方案中,式I至V中的R1为CF3、CHF2、环丁基或环丙基,其中所述环丁基和环丙基任选地被1至2个氟取代,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十、第二十一、第二十二或第二十三实施方案所述。
在第二十五实施方案中,式I至V中的R1为-C(=O)ORc、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、-NRdRe、单环杂环基或单环环烷基,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三或第二十四实施方案所述。
在第二十六实施方案中,式I至V中的R1为环丁基、四氢呋喃基、(C1-C4)烷氧基、-N((C1-C3)烷基)2、-C(O)O(C1-C2)烷基或环丙基,其中所述环丁基和环丙基各自任选地被C(=O)OMe、-CN或1至3个卤素取代,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三、第二十四或第二十五实施方案所述。
在第二十七实施方案中,式I至V中的R1选自(C1-C4)烷氧基、环丁基和环丙基,其中所述环丁基和环丙基各自任选地被1至3个卤素取代,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三、第二十四、第二十五或第二十六实施方案所述。
在第二十八实施方案中,式I至V中的R5选自卤素、-CN、-ORc、-NRdRe、-NRcS(O)2Rc、-S(O)2NRdRe、-C(=O)ORc、-C(=O)NRdRe、-NRcC(=O)Rc、-NRcC(=O)ORc、-OC(=S)NRdRe、-C(=O)Rc、-SO2Rb和(C1-C4)烷基任选被1至3个卤素取代,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三、第二十四、第二十五、第二十六或第二十七实施方案所述。
在第二十九实施方案中,式I至V中的R5选自-CN、-S(O)2NRdRe和-SO2Rb,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三、第二十四、第二十五、第二十六、第二十七或第二十八实施方案所述。
在第三十实施方案中,式I至V中的R5选自-S(O)2NRdRe和-SO2Rb,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三、第二十四、第二十五、第二十六、第二十七、第二十八或第二十九实施方案所述。
在第三十一实施方案中,式I至V中的R5为-SO2(C1-C3)烷基、-SO2NH2、-SO2NH(C1-C3)烷基、-SO2(C1-C3)烷基-OH、-SO2(C1-C3)烷基-C(O)O(C1-C3)烷基、-SO2(C1-C3)烷基-C(O)NH(C1-C3)烷基、-SO2(C1-C3)烷基-O(C1-C3)烷基和-SO2(C1-C3)烷基-C(O)NH2,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三、第二十四、第二十五、第二十六、第二十七、第二十八、第二十九或第三十实施方案所述。
在第三十二实施方案中,式I至V中的R5为-SO2(C1-C3)烷基或-SO2NH(C1-C3)烷基,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三、第二十四、第二十五、第二十六、第二十七、第二十八、第二十九、第三十或第三十一实施方案所述。
在第三十三实施方案中,式I至V中的R6选自卤素、-CN、-ORc、-NRdRe、-NRcS(O)2Rc、-S(O)2NRdRe、-C(=O)ORc、-OC(=O)ORc、-OC(=O)Rc、-C(=O)NRdRe、-NRcC(=O)Rc、-C(=S)NRdRe、-NRcC(=S)Rc、-NRcC(=O)ORc、-OC(=O)NRdRe、-NRc(C=S)ORc、-OC(=S)NRdRe、-NRcC(=O)NRdRe、-NRc(C=S)NRdRe、-C(=S)Rc、-C(=O)Rc、-SO2Rb和任选地被1至3个卤素取代的(C1-C4)烷基,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三、第二十四、第二十五、第二十六、第二十七、第二十八、第二十九、第三十、第三十一或第二十二实施方案所述。
在第三十四实施方案中,式I至V中的R6选自卤素、-CN、-ORc、(C1-C4)烷基和任选地被1至3个卤素取代的(C1-C4)烷基,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三、第二十四、第二十五、第二十六、第二十七、第二十八、第二十九、第三十、第三十一、第二十二或第二十三实施方案所述。
在第三十五实施方案中,式I至V中的R6选自卤素、-CN、-ORc和(C1-C3)烷基;并且Rc为(C1-C3)烷基,其中剩余的变量如上文针对式I和第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三、第二十四、第二十五、第二十六、第二十七、第二十八、第二十九、第三十、第三十一、第二十二、第二十三或第二十四实施方案所述。
在第三十六实施方案中,式I的化合物具有式VI:
或其可药用盐,其中A是N或CH;R1为(C1-C4)烷基、卤代(C1-C4)烷基或任选地被1至3个卤素取代的环烷基;L2为CH2或CHMe;Cy2为双环杂环基或双环杂芳基,其中的每一种任选地被独立地选自卤素、(C1-C4)烷基和(C1-C4)烷氧基的1至3个基团取代,其中所述(C1-C4)烷基和(C1-C4)烷氧基任选地被1至3个卤素取代;R7为氢或-CH2OH;并且R9为-NH(C1-C4)烷基、(C1-C4)烷基或被OH取代的(C1-C4)烷基。
在第三十七实施方案中,式I的化合物具有式VII:
或其可药用盐,其中剩余的变量如上文针对式I和第三十六实施方案所述。
在第三十八实施方案中,式I的化合物具有VIII:
或其可药用盐,其中Z为具有选自氧或氮的一个或多个杂原子的5元或6元杂环基环;并且其中Z任选地被(C1-C4)烷基或1至3个卤素取代,并且其中剩余的变量如上文针对式I和第三十六或第三十七实施方案所述。
在第三十九实施方案中,式I的化合物具有式IX或X:
或其可药用盐,其中R10和R11各自独立地为氢、(C1-C3)烷基或卤素,其中剩余的变量如上文针对式I和第三十六、第三十七或第三十八实施方案所述。
在第四十实施方案中,式I的化合物具有式XI:
或其可药用盐,其中R10和R11各自独立地为氢或卤素,其中剩余的变量如上文针对式I和第三十六、第三十七、第三十八或第三十九实施方案所述。
在第四十一实施方案中,式IX至XI中的R10和R11各自为卤素,其中剩余的变量如上文针对式I和第三十六、第三十七、第三十八、第三十九或第四十实施方案所述。
在第四十二实施方案中,式IX至XI中的R10和R11各自为氟,其中剩余的变量如上文针对式I和第三十六、第三十七、第三十八、第三十九、第四十或第四十一实施方案所述。
在第四十三实施方案中,式VI至XI中的R1为卤代(C1-C4)烷基、环丙基或环丁基,其中所述环丙基和环丁基各自任选地被1至3个卤素取代,其中剩余的变量如上文针对式I和第三十六、第三十七、第三十八、第三十九、第四十、第四十一或第四十二实施方案所述。
在第四十四实施方案中,式VI至XI中的R1为CF3、CHF2或环丁基,其中剩余的变量如上文针对式I和第三十六、第三十七、第三十八、第三十九、第四十、第四十一、第四十二或第四十三实施方案所述。
在第四十五实施方案中,式VI至XI中的R9为(C1-C3)烷基,其中剩余的变量如上文针对式I和第三十六、第三十七、第三十八、第三十九、第四十、第四十一、第四十二、第四十三或第四十四实施方案所述。
在第四十六实施方案中,式VI至XI中的L2为CH2,其中剩余的变量如上文针对式I和第三十六、第三十七、第三十八、第三十九、第四十、第四十一、第四十二、第四十三、第四十四或第四十五实施方案所述。
在第四十六实施方案中,式VI至XI中的R7为-CH2OH;并且A为N,其中剩余的变量如上文针对式I和第三十六、第三十七、第三十八、第三十九、第四十、第四十一、第四十二、第四十三、第四十四、第四十五或第四十六实施方案所述。
在第四十七实施方案中,式I的化合物具有式XII:
或其可药用盐,其中:
A为N或CH;
R1为(C1-C4)烷基、卤代(C1-C4)烷基、任选地被1至3个卤素取代的环丁基或任选地被1至3个卤素取代的环丙基;
L2为CH2或CHMe;
每个R6独立地选自卤素、-CN、-ORc、(C1-C4)烷基和被卤素取代的(C1-C4)烷基;
m为1或2;
R7为氢或-CH2OH;并且
R9为-NH(C1-C4)烷基、(C1-C4)烷基或被OH取代的(C1-C4)烷基。
在第四十八实施方案中,式I的化合物选自表1中的任何一种化合物或其可药用盐。
表1
a该化合物由(R)-四氢呋喃-2-羧酸制备,但未确定产物中立构中心的完整性。b该化合物由(S)-四氢呋喃-2-羧酸制备,但未确定产物中立构中心的完整性。c在手性柱上通过色谱法分离异构体。未确定异构体的立体化学构型。
还提供了(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-130.1)的结晶盐酸盐形式。参见下面的实施例3。
在一个方面,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶盐酸盐的特征在于选自11.20°、12.60°、17.86°、19.04°、21.12°和21.71°的2θ角处的至少三个X射线粉末衍射峰。另选地,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶盐酸盐的特征在于选自11.20°、12.60°、17.86°、19.04°、21.12°和21.71°的2θ角处的至少四个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶盐酸盐的特征在于选自11.20°、12.60°、17.86°、19.04°、21.12°和21.71°的2θ角处的至少五个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶盐酸盐的特征在于选自11.20°、12.60°、17.86°、19.04°、21.12°和21.71°的2θ角处的X射线粉末衍射峰。在另一个实施方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶盐酸盐的特征在于选自表2的2θ角处的X-射线粉末衍射峰。在另一个实施方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶盐酸盐的特征在于与图1基本上类似的X射线粉末衍射图谱。
表2
在一个方面,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶盐酸盐的特征在于选自11.20°、12.60°、17.86°、19.04°、21.19°和21.71°的2θ角处的至少三个X射线粉末衍射峰。另选地,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶盐酸盐的特征在于选自11.20°、12.60°、17.86°、19.04°、21.19°和21.71°的2θ角处的至少四个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶盐酸盐的特征在于选自11.20°、12.60°、17.86°、19.04°、21.19°和21.71°的2θ角处的至少五个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(-1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶盐酸盐的特征在于选自11.20°、12.60°、17.86°、19.04°、21.19°和21.71°的2θ角处的X射线粉末衍射峰。在另一个实施方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶盐酸盐的特征在于选自表2-1的2θ角处的X-射线粉末衍射峰。
表2-1
在一个方面,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶盐酸盐为至少50%重量纯、至少75%重量纯、至少80%重量纯、至少90%重量纯、至少95%重量纯或至少98%重量纯。
还提供了(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-130.1)的游离碱的结晶形式。参见下面的实施例3。
在一个方面,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的游离碱的结晶形式的特征在于选自17.25°、18.89°、19.33°、20.49°、21.97°和23.73°的2θ角处的至少三个X射线粉末衍射峰。另选地,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的游离碱的结晶形式的特征在于选自17.25°、18.89°、19.33°、20.49°、21.97°和23.73°的2θ角处的至少四个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的游离碱的结晶形式的特征在于选自17.25°、18.89°、19.33°、20.49°、21.97°和23.73°的2θ角处的至少五个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的游离碱的结晶形式的特征在于17.25°、18.89°、19.33°、20.49°、21.97°和23.73°的2θ角处的X射线粉末衍射峰。在另一个实施方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的游离碱的结晶形式的特征在于选自表2a的2θ角处的X-射线粉末衍射峰。在另一个实施方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的游离碱的结晶形式的特征在于与图2基本上类似的X-射线粉末衍射图谱。
表2a
在一个方面,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的游离碱的结晶形式为至少50%重量纯、至少75%重量纯、至少80%重量纯、至少90%重量纯、至少95%重量纯或至少98%重量纯。
还提供了(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-11.1)的结晶形式I。参见下面的实施例2。
在一个方面,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式I的特征在于选自15.52°、17.30°、19.39°、21.68°、23.32°和23.82°的2θ角处的至少三个X射线粉末衍射峰。另选地,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式I的特征在于选自15.52°、17.30°、19.39°、21.68°、23.32°和23.82°的2θ角处的至少四个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式I的特征在于选自15.52°、17.30°、19.39°、21.68°、23.32°和23.82°的2θ角处的至少五个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式I的特征在于15.52°、17.30°、19.39°、21.68°、23.32°和23.82°的2θ角处的X射线粉末衍射峰。在另一个实施方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式I的特征在于选自表2b的2θ角处的X射线粉末衍射峰。在另一个实施方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式I的特征在于与图3基本上类似的X-射线粉末衍射图谱。
表2b
在一个方面,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式I为至少50%重量纯、至少75%重量纯、至少80%重量纯、至少90%重量纯、至少95%重量纯或至少98%重量纯。
还提供了(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-11.1)的结晶形式II。参见下面的实施例2。
在一个方面,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式II的特征在于选自13.18°、14.46°、16.47°、17.97°、19.80°和26.52°的2θ角处的至少三个X射线粉末衍射峰。另选地,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式II的特征在于选自13.18°、14.46°、16.47°、17.97°、19.80°和26.52°的2θ角处的至少四个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式II的特征在于选自13.18°、14.46°、16.47°、17.97°、19.80°和26.52°的2θ角处的至少五个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式II的特征在于13.18°、14.46°、16.47°、17.97°、19.80°和26.52°的2θ角处的X射线粉末衍射峰。在另一个实施方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式II的特征在于选自表2c的2θ角处的X射线粉末衍射峰。在另一个实施方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式II的特征在于与图4基本上类似的X-射线粉末衍射图谱。
表2c
在一个方面,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式II为至少50%重量纯、至少75%重量纯、至少80%重量纯、至少90%重量纯、至少95%重量纯或至少98%重量纯。
还提供了(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-11.1)的结晶形式III。参见下面的实施例2。
在一个方面,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式III的特征在于选自6.62°、14.48°、16.53°、17.96°、19.89°和26.53°的2θ角处的至少三个X射线粉末衍射峰。另选地,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式III的特征在于选自6.62°、14.48°、16.53°、17.96°、19.89°和26.53°的2θ角处的至少四个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式III的特征在于选自6.62°、14.48°、16.53°、17.96°、19.89°和26.53°的2θ角处的至少五个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式III的特征在于6.62°、14.48°、16.53°、17.96°、19.89°和26.53°的2θ角处的X射线粉末衍射峰。在另一个实施方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式III的特征在于选自表2d的2θ角处的X射线粉末衍射峰。在另一个实施方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式III的特征在于与图5基本上类似的X-射线粉末衍射图谱。
表2d
在一个方面,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式III为至少50%重量纯、至少75%重量纯、至少80%重量纯、至少90%重量纯、至少95%重量纯或至少98%重量纯。
还提供了(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-131.1)的盐酸盐的结晶形式。参见下面的实施例4。
在一个方面,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的盐酸盐的结晶形式的特征在于选自7.67°、12.60°、13.35°、15.39°、18.86°和25.38°的2θ角处的至少三个X射线粉末衍射峰。另选地,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的盐酸盐的结晶形式的特征在于选自7.67°、12.60°、13.35°、15.39°、18.86°和25.38°的2θ角处的至少四个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的盐酸盐的结晶形式的特征在于选自7.67°、12.60°、13.35°、15.39°、18.86°和25.38°的2θ角处的至少五个X射线粉末衍射峰。在另一替代方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的盐酸盐的结晶形式的特征在于7.67°、12.60°、13.35°、15.39°、18.86°和25.38°的2θ角处的X射线粉末衍射峰。在另一个实施方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的盐酸盐的结晶形式的特征在于选自表2e的2θ角处的X-射线粉末衍射峰。在另一个实施方案中,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的盐酸盐的结晶形式的特征在于与图6基本上类似的X-射线粉末衍射图谱。
表2e
在一个方面,(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的盐酸盐的结晶形式为至少50%重量纯、至少75%重量纯、至少80%重量纯、至少90%重量纯、至少95%重量纯或至少98%重量纯。
还提供了(R)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-132.1)的结晶形式。参见下面的实施例5。
在一个方面,(R)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式的特征在于选自12.23°、14.00°、15.78°、16.41°、17.77°和19.70°的2θ角处的至少三个X射线粉末衍射峰。另选地,(R)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式的特征在于选自12.23°、14.00°、15.78°、16.41°、17.77°和19.70°的2θ角处的至少四个X射线粉末衍射峰。在另一替代方案中,(R)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式的特征在于选自12.23°、14.00°、15.78°、16.41°、17.77°和19.70°的2θ角处的至少五个X射线粉末衍射峰。在另一替代方案中,(R)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式的特征在于12.23°、14.00°、15.78°、16.41°、17.77°和19.70°的2θ角处的X射线粉末衍射峰。在另一个实施方案中,(R)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式的特征在于选自表2f的2θ角处的X-射线粉末衍射峰。在另一个实施方案中,(R)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式的特征在于与图7基本上类似的X-射线粉末衍射图谱。
表2f
在一个方面,(R)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺的结晶形式为至少50%重量纯、至少75%重量纯、至少80%重量纯、至少90%重量纯、至少95%重量纯或至少98%重量纯。
除非另外指明,否则本文定义的结晶形式的XRPD图谱/分配不应被解释为绝对的并且可变化±0.2度。
化合物的具体示例在范例中提供。本文包括这些化合物的可药用盐以及中性形式。
在某些实施方案中,本公开提供了治疗患有由RORγ介导的障碍的患者(例如,人)的方法,该方法包括向患者施用有效量的具有本文所述的任何化合物或其可药用盐或组合物的化合物的步骤。
4.用途、配制和施用
可药用组合物
根据另一个实施方案,本公开提供了使用包含式I的化合物及其可药用载体、佐剂或媒介物的组合物治疗患有由RORγ介导的障碍的受治疗者(例如,人)的方法。
术语“可药用载体”是指不破坏与其一起配制的化合物的药理活性的无毒载体、佐剂或媒介物。可用于本公开的组合物中的可药用载体、佐剂或媒介物包括但不限于适用于药物应用的有机或无机载体、赋形剂或稀释剂。
本文所述的组合物可以口服、肠胃外、通过雾化吸入、局部、直肠、鼻腔、口腔、阴道或通过植入型药盒施用。本文所用的术语“肠胃外”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。本文包括液体剂型、可注射制剂、固体分散体剂型和用于局部或透皮施用化合物的剂型。
可与载体材料组合以产生单一剂型的组合物的所提供化合物的量将根据待治疗的患者和具体给药方式而不同。
还应当理解,任何特定患者的具体剂量和治疗方案将取决于多种因素,包括年龄、体重、一般健康状况、性别、饮食、给药时间、排泄率、药物组合、治疗医师的判断,以及所治疗的特定疾病的严重程度。组合物中提供的化合物的量也将取决于组合物中的特定化合物。
化合物和可药用组合物的用途
本文所述的化合物和组合物通常可用于调节RORγ。因此,在一些实施方案中,本公开提供了治疗由RORγ介导的炎性、代谢性和自身免疫性疾病或障碍的方法,包括施用所提供的化合物或组合物。更具体地讲,本文所述的化合物和组合物充当RORγ的反向激动剂或拮抗剂。
如本文所用,术语“治疗”(“treatment”、“treat”和“treating”)是指如本文所述的逆转、缓解、延缓疾病或障碍或其一种或多种症状的发作或抑制其进展。在一些实施方案中,可在一种或多种症状已经发展之后施用治疗,即治疗目的性治疗。在其他实施方案中,可在没有症状的情况下施用治疗。例如,可在症状发作之前(例如,根据症状病史和/或根据遗传或其他易感因素)对易感个体施用治疗,即预防性治疗。症状消退后也可继续治疗,例如预防或延缓其复发。
RORγ的调节(或调节RORγ)意指从施用一种或多种本文所述的化合物后发生RORγ活性的变化或改变。调节可以是RORγ的活性或功能的大小的上调(增加)或下调(减少)。示例性活性和功能包括例如,结合特征、酶活性、细胞受体活化、转录活性和信号转导。在一个方面,本文所述的化合物抑制RORγ。在其他方面,本文所述的化合物充当RORγ的激动剂、拮抗剂或反向激动剂。
在另一方面,本文所述的化合物和组合物可用于减少受治疗者中IL-17的量。因此,在一些实施方案中,本文提供了减少受治疗者中IL-17的量的方法,包括施用有效量的所提供的化合物或组合物。在这样的方法中也可使用WO 2014/179564、WO 2015/116904、WO2016/061160、PCT/US2016/045318、PCT/US2016/062422和美国专利公布号US 2016-0122318和US 2016-0122345中公开的RORγ调节剂。
在另一方面,本文所述的化合物和组合物可用于抑制受治疗者中IL-17的合成。因此,在一些实施方案中,本文提供了抑制受治疗者中IL-17合成的方法,包括施用有效量的所提供的化合物或组合物。在这样的方法中也可使用WO 2014/179564、WO 2015/116904、WO2016/061160、PCT/US2016/045318、PCT/US2016/062422和美国专利公布号US 2016-0122318和US 2016-0122345中公开的RORγ调节剂。
可根据本文方法治疗的疾病和病症包括但不限于由RORγ介导的炎性、代谢性和自身免疫性疾病或障碍。这些疾病和病症包括,例如,哮喘、慢性阻塞性肺病(COPD)、支气管炎、过敏性鼻炎、特应性皮炎、接触性皮炎、痤疮、荨麻疹、麻疹、血管性水肿、囊性纤维化、同种异体移植排斥、多发性硬化症、Balo同心圆硬化、巴娄病、同心性脑中叶硬化、同心性轴周性脑炎、硬皮病、局限性硬皮病、CREST综合征、关节炎、类风湿性关节炎、幼年型类风湿性关节炎、反应性关节炎、莱特尔氏综合征、骨关节炎、强直性脊柱炎、系统性红斑狼疮(SLE)、桥本氏病、胰腺炎、自身免疫性糖尿病、I型糖尿病、自身免疫性眼部疾病、溃疡性结肠炎、克罗恩氏病、局限性肠炎、炎症性肠病(IBD)、炎症性肠综合征(IBS)、干燥综合征、视神经炎、肥胖症、肝脂肪变性、脂肪组织相关炎症、胰岛素抗性、II型糖尿病、视神经脊髓炎、重症肌无力、年龄相关性黄斑变性、干眼症、葡萄膜炎、格林-巴利综合征、银屑病、斑块状银屑病、滴状银屑病、反转型银屑病、脓疱性银屑病、红皮病型银屑病、银屑病表皮增生、表皮增生、银屑病性关节炎(PsA)、类固醇抵抗型哮喘、格雷夫斯病、巩膜炎、子宫内膜异位症、阻塞性睡眠呼吸暂停综合征(OSAS)、贝赛特氏症、皮肌炎、多肌炎、移植物抗宿主病、慢性移植物抗宿主病、急性移植物抗宿主病、原发性胆汁性肝硬化、肝纤维化、非酒精性脂肪性肝病(NAFLD)、结节病、原发性硬化性胆管炎、自身免疫性甲状腺疾病、I型自身免疫性多内分泌腺病综合征、II型自身免疫性多内分泌腺病综合征、乳糜泻、口炎性腹泻、神经脊髓炎、幼年特发性关节炎、系统性硬化症、心肌梗塞、肺动脉高压、骨关节炎、皮肤利什曼病、鼻息肉病和癌症,癌症包括但不限于肺癌、胃癌、乳腺癌和结肠癌。在一个方面,根据本文的方法可治疗的癌症的示例性形式还包括前列腺癌,例如(转移性去势抗性前列腺癌肿瘤)。在另一方面,根据本文方法可治疗的癌症的示例性形式包括,例如,恶性肿瘤、血管生成性青光眼、婴儿血管瘤、多发性骨髓瘤、急性成髓细胞白血病、慢性肉瘤、慢性髓细胞性白血病、转移性黑素瘤、卡波西氏肉瘤、血管增生、恶病质、结肠直肠癌(例如,家族性结直肠癌、遗传性非息肉病性结直肠癌和胃肠道间质瘤)、肺癌(例如,非小细胞肺癌、小细胞肺癌和恶性间皮瘤)、间皮瘤、胰腺癌(例如,胰管癌)、胃癌(例如,乳头状腺癌、粘液腺癌和腺鳞癌)、乳腺癌(例如,浸润性导管癌、原位导管癌、炎性乳腺癌和转移性乳腺癌)、卵巢癌(例如,卵巢上皮癌、性腺外生殖细胞肿瘤、卵巢生殖细胞肿瘤和卵巢低恶性潜能肿瘤)、激素依赖性前列腺癌、非激素依赖性前列腺癌、肝癌(例如,原发性肝癌和肝外胆管癌)、甲状腺癌(例如,甲状腺髓样癌)、肾癌(例如,肾细胞癌、肾和尿管中的移行细胞癌)、子宫癌、子宫内膜癌、脑肿瘤(例如,松果体星形细胞瘤、毛细胞性星形细胞瘤、弥漫性星形细胞瘤和间变性星形细胞瘤)、黑素瘤、肉瘤、膀胱癌、血液癌、垂体腺瘤、胶质瘤、听神经瘤、视网膜母细胞瘤、头颈癌、头颈部鳞状细胞癌、咽癌、喉癌、舌癌、胸腺瘤、食道癌、十二指肠癌、结直肠癌、直肠癌、肝癌、胰腺内分泌肿瘤、胆管癌、胆囊癌、阴茎癌、尿管癌、睾丸肿瘤、外阴癌、宫颈癌、子宫内膜癌、子宫肉瘤、阴道癌、皮肤癌、真菌性真菌病、基底细胞瘤、软组织肉瘤、恶性淋巴瘤、霍奇金病、骨髓增生异常综合征、急性淋巴细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、恶性骨髓瘤、成人T细胞白血病、慢性骨髓增生性疾病、胰腺内分泌肿瘤、纤维性组织细胞瘤、平滑肌肉瘤、横纹肌肉瘤、原发灶不明转移癌、癌症驱动的骨髓细胞生成、肿瘤生长和转移。
由IL-17表达介导并且使用本文所述的化合物可治疗的疾病和障碍还包括例如肺气肿、肺纤维化、特发性肺纤维化、腹膜后纤维化、巨细胞动脉炎、巨细胞性心肌炎、动脉硬化、肝炎、慢性活动性肝炎、酒精性肝炎、酒精性肝纤维化、酒精性肝硬化、病毒性肝炎、乙型肝炎病毒性肝脏障碍、自身免疫性肝炎、软骨炎症、骨退化、幼年型关节炎、少关节性幼年型类风湿性关节炎、多关节性幼年型类风湿性关节炎、全身发作性幼年型类风湿性关节炎、脊柱关节炎、幼年型强直性脊柱炎、幼年型肠病性关节炎、幼年型反应性关节炎、幼年型莱特尔氏综合征(juvenile Reiter′s syndrome)、血清阴性肌腔端病和关节病(SEA)综合征、幼年型皮肌炎、幼年型银屑病性关节炎、幼年型硬皮病、幼年系统性红斑狼疮、幼年型血管炎、少关节性类风湿性关节炎、多关节性类风湿性关节炎、全身发作性类风湿关节炎、肠病性关节炎、血管炎、白细胞破碎性血管炎、肌炎、幼年型肌炎、多肌炎、自身免疫性肌炎、骨关节炎、结节性多动脉炎、动脉炎、多发性大动脉炎、颞动脉炎、巨细胞动脉炎睾丸自身免疫病、风湿性多肌痛、风湿性热、硬化症、原发性胆道硬化症、原发性胆汁性肝硬化、硬化性胆管炎、原发性硬化性胆管炎、肌腱端炎、肌腱端病、皮炎、疱疹样皮炎、孕酮性皮炎、特应性湿疹、接触性湿疹、湿疹、动脉粥样硬化、斯提耳氏病、爱迪生氏病、雷诺氏现象、红皮病型银屑病、非感染性葡萄膜炎、周边葡萄膜炎、梗死后综合征(Dressier’s syndrome)、嗜酸细胞性食管炎、嗜酸细胞性筋膜炎、结节性红斑、实验性变应性脑脊髓炎、伊文氏综合征、纤维化肺泡炎、伏格特-小柳-原田综合征、黏膜利什曼病、川崎氏疾病或综合征、桥本脑病、桥本氏甲状腺炎、血小板减少性紫癜、免疫性血小板减少性紫癜(也称为免疫性血小板减少症、特发性免疫血小板减少症、特发性血小板减少性血栓性紫癜、原发性免疫血小板减少症、特发性血小板减少性紫癜(ITP)、原发性免疫性血小板减少性紫癜或自身免疫性血小板减少性紫癜)、无丙种球蛋白血症、肾炎、间质性肾炎、肾病、慢性肾病、肾衰竭、急性肾衰竭、终末期肾病、急性肾损伤、顺铂诱导的急性肾衰竭、脓毒症诱导的急性肾衰竭、抗肾小球基底膜(GBM)肾炎、抗肾小管基底膜(TBM)肾炎、抗磷脂综合征(APS)、肾脏炎症、肾毒性肾炎、肾小球性肾炎、急性肾小球肾炎、抗中性粒细胞胞质自身抗体(ANCA)相关血管炎、显微镜下多血管炎、肉芽肿性多血管炎(GPA)、韦格纳氏肉芽肿病、肌萎缩性脊髓侧索硬化症、狼疮肾炎、过敏性湿疹、移植排斥、非放射脊柱关节病、眼科障碍、器官移植排斥、纤维化肺、肾功能不全、糖尿病并发症、糖尿病性肾病、糖尿病视网膜病变、糖尿病性视网膜炎、糖尿病性微血管病变、胰岛炎、肺结核、侵入性葡萄球菌感染、侵入性金黄色葡萄球菌感染、白内障手术后炎症、过敏性结膜炎、脱发、斑秃、慢性荨麻疹、过敏性哮喘、嗜中性粒细胞性哮喘、牙周疾病、牙周炎、齿龈炎、齿龈疾病、心肌病、舒张心肌病、心肌梗塞、心肌炎、慢性心力衰竭、先天性心脏传导阻滞、柯萨奇病毒性心肌炎、心肌梗死后综合征、心包切开术后综合征、心内膜炎、亚急性细菌性心内膜炎(SBE)、血管狭窄、再狭窄、再灌注障碍、自身免疫性胰腺炎、急性胰腺炎、慢性胰腺炎、哮喘、支气管哮喘、急性呼吸窘迫综合征、成人呼吸窘迫综合征、炎性骨疾病、炎性肺疾病、脑缺血发作、短暂性脑缺血发作、全身性炎症反应综合征、青光眼、眼眶蜂窝织炎、突发性眼眶炎症、术后炎症、创伤后炎症、过敏性炎症、肠道炎症、粘膜炎症、前列腺炎症、前列腺炎、慢性骨盆疼痛综合症、睾丸炎症、慢性睾丸炎、睾丸炎、睾丸炎介导的不孕、肝功能紊乱症、肝损伤、肝脏毒性、肺炎、脑膜炎、膀胱炎、间质性膀胱炎、咽喉炎、胃黏膜损伤、慢性肺炎、肺梗塞、硅肺病、类肉状瘤病、肺结节病、自身免疫性血管性水肿、自身免疫性家族性自主神经异常、自身免疫性肝炎、自身免疫性高脂血症、自身免疫性免疫缺陷、自身免疫性内耳疾病(AIED)、自身免疫性心肌炎、自身免疫性卵巢炎、自身免疫性再生障碍性贫血、自身免疫性贫血、自身免疫性溶血性贫血、溶血性贫血、自身免疫性视网膜病、自身免疫性血小板减少性紫癜(ATP)、自身免疫性甲状腺疾病、自身免疫性荨麻疹、肺出血肾炎综合征、鼻窦炎、慢性肥厚性鼻炎、慢性炎性脱髓鞘多发性神经病、混合性结缔组织病、未分化结缔组织病(UCTD)、认知障碍、阿尔茨海默氏病中的认知障碍、帕金森氏病、脊髓性肌萎缩、脊髓性小脑萎缩、进行性核上性麻痹、菲希尔综合征(Fisher syndrome)、盘状狼疮(dicoidlupus)、中枢神经系统狼疮、视神经脊髓炎(NMO;也称为德维克氏病或德维克氏综合征)、脑脊髓炎、急性播散性脑脊髓炎(ADEM)、横贯性脊髓炎、急性坏死性出血性白质脑炎、多系统萎缩、亨廷顿病、脑血管性痴呆、弥漫性路易体病、淀粉样变性、脑血管障碍、脑梗塞、短暂性脑缺血发作、颅内出血、脊髓血管疾病、脊髓梗死、兰伯特-伊顿综合征、肌营养不良症、代谢性肌病、炎性肌病、南美锥虫病、慢性炎性脱髓鞘性多发性神经病(CIDP)、慢性复发性多灶性骨髓炎(CRMO)、变应性肉芽肿性血管炎、科干综合征、冷凝集素病、原发性混合型冷球蛋白血症、脱髓鞘性神经病、包涵体肌炎、脑炎、类天疱疮、大疱性类天疱疮、天疱疮、寻常天疱疮、落叶型天疱疮、瘢痕性类天疱疮、眼瘢痕性类天疱疮、良性粘膜类天疱疮、卡斯特雷曼氏症(也称为巨大淋巴结增生或血管滤泡性淋巴结增生、淋巴样错构瘤和血管滤泡性淋巴结增生)、深红斑狼疮、慢性甲状腺炎、自身免疫性胃炎、脓毒症、烧伤、轴索和神经元神经病、疼痛、神经病、周围神经病、慢性疼痛、视神经炎、视神经病变、外伤性视神经病变、缺血性脑损伤、深静脉血栓形成、嗜中性粒细胞减少症、自身免疫性嗜中性粒细胞减少症、血小板减少症、异常免疫应答、放射性皮炎、骨质疏松症、寄生虫感染、支睾吸虫病、隐孢子虫感染、肺炎链球菌携带、慢性肺炎球菌携带、与致病性淋巴细胞的活性相关或由其引起的免疫障碍、过敏性紫癜、妊娠疱疹、低丙球蛋白血症、IgA肾病、IgG4相关性硬化疾病、免疫调节脂蛋白、兰伯特-伊顿综合征、扁平苔癣、硬化性苔藓、木样结膜炎、线性IgA病(LAD)、慢性莱姆病、梅尼埃病、显微镜下多血管炎、混合性结缔组织病(MCTD)、蚕蚀性角膜溃疡、哈二氏病、发作性嗜睡症、复发性风湿病、与链球菌相关的儿童自身免疫性神经精神障碍(PANDAS)、副肿瘤性小脑变性、阵发性睡眠性血红蛋白尿症(PNH)、罗二氏综合征、牧师特纳综合征(Parsonnage-Turner syndrome)、睫状体扁平部炎、周围性脑脊髓炎、恶性贫血、POEMS综合征、I型自身免疫性多腺体综合征、II型自身免疫性多腺体综合征、III型自身免疫性多腺体综合征、坏疽性脓皮病、纯红细胞再生障碍、反射性交感神经营养不良、复发性多软骨炎、不宁腿综合征、施密特氏综合征、精子自身免疫病、僵人综合征、苏萨克氏症候群(Susac′ssyndrome)、交感性眼炎、痛性眼肌麻痹综合征、水疱性皮肤病以及白癜风。
还包括受个体的昼夜节律调节影响的疾病或障碍,包括例如重度抑郁症、季节性情绪障碍、创伤后应激障碍(PTSD)、双相情感障碍、自闭症、癫痫、阿尔茨海默病和其他与睡眠和/或昼夜节律改变相关的中枢神经系统(CNS)障碍。
还包括由IL-17表达介导的疾病和障碍,所述IL-17表达包括在嗜中性粒细胞中由STAT3介导的IL-17表达,并且所述疾病和障碍包括例如角膜真菌感染;角膜真菌感染的风险;角膜溃疡;由真菌角膜炎引起的角膜溃疡;由真菌感染引起的角膜溃疡;角膜真菌感染和相关炎症;角膜炎;真菌角膜炎;角膜炎症;角膜疾病;眼部疾病;真菌介导的角膜感染、角膜溃疡、角膜炎症、或眼部溃疡、眼部炎症或眼部感染;细菌介导的角膜感染、角膜溃疡、角膜炎症、或眼部溃疡、眼部炎症或眼部感染;微生物疾病;细菌感染;真菌感染;曲霉菌性角膜炎;镰胞菌角膜炎;皮肤T细胞淋巴瘤;肺部炎症;急性肾缺血再灌注损伤;炭疽病,包括皮肤炭疽病、吸入性炭疽病、胃肠炭疽病和注射炭疽病;曲霉菌病,包括肺曲霉菌病、慢性肺曲霉菌病(CPA)、慢性曲霉菌病、慢性空洞性肺曲霉菌病(CCPA)、变应性支气管肺曲霉菌病(ABPA)、变应性曲霉菌性鼻窦炎、曲霉肿、侵袭性曲霉病、慢性坏死性曲霉菌病和皮肤曲霉病;以及组织胞浆菌病,包括全身性组织胞浆菌病。在具体实施方案中,介导上述疾病或障碍的真菌或真菌感染包括以下项中的一个或多个:曲霉菌(Aspergillus)、镰胞菌(Fusarium)、链格孢菌(Alternaria)、念珠菌(Candida)、弯孢菌(Curvularia)或组织胞浆菌(Histoplasma)。
本文所述的化合物还可用于治疗或降低胎儿患异常皮质发育或精神障碍如自闭症谱系障碍(ASD)、精神分裂症和/或抑郁症的风险。本文所述的化合物还可用于治疗具有与感染(诸如病毒或细菌感染)相关或与在怀孕期间暴露于炎性或环境毒素相关的高炎症状态的妊娠女性。在具体实施方案中,用本文所公开的化合物治疗在妊娠女性子宫内的胎儿以降低胎儿患上精神障碍的风险、减少妊娠女性的炎症、降低胎儿皮质发育异常的风险,并且/或者减轻妊娠女性后代的精神疾病障碍。
在一个实施方案中,用式I的化合物和可药用载体、佐剂或媒介物来治疗人类患者,其中所述化合物以治疗或改善上述疾病和病症中的一种或多种疾病和病症的量存在。在一个替代实施方案中,用式I的化合物治疗或改善的疾病和病症包括患者的例如哮喘、特应性皮炎、痤疮、克罗恩氏病、局限性肠炎、溃疡性结肠炎、干燥综合征、葡萄膜炎、贝赛特氏症、皮肌炎、多发性硬化症、强直性脊柱炎、系统性红斑狼疮(SLE)、硬皮病、银屑病、银屑病性关节炎(PsA)、类固醇抵抗型哮喘和类风湿性关节炎。在一个替代实施方案中,用式I的化合物治疗或改善的疾病和病症包括例如特应性皮炎、痤疮、皮肌炎、硬皮病、银屑病、银屑病性关节炎(PsA)和类风湿性关节炎。
本公开还涉及用于治疗或改善本文所述的疾病或障碍的联合疗法。在一些实施方案中,该联合疗法包括将至少一种由结构式I表示的化合物与一种或多种药剂联合施用来治疗或改善由RORγ介导的炎性、代谢性和自身免疫性疾病或障碍。在一些实施方案中,该联合疗法包括将至少一种由结构式I表示的化合物与一种或多种药剂联合施用来治疗疾病,所述疾病包括哮喘、慢性阻塞性肺病(COPD)、支气管炎、过敏性鼻炎、特应性皮炎、接触性皮炎、痤疮、囊性纤维化、同种异体移植排斥、多发性硬化症、硬皮病、关节炎、类风湿性关节炎、幼年型类风湿性关节炎、骨关节炎、强直性脊柱炎、系统性红斑狼疮(SLE)、桥本氏病、胰腺炎、自身免疫性糖尿病、I型糖尿病、自身免疫性眼病、溃疡性结肠炎、克罗恩氏病、局限性肠炎、炎症性肠病(IBD)、炎症性肠综合征(IBS)、干燥综合征、视神经炎、肥胖症、肝脂肪变性、脂肪组织相关炎症、胰岛素抗性、II型糖尿病、视神经脊髓炎、重症肌无力、年龄相关性黄斑变性、干眼症、葡萄膜炎、格林-巴利综合征、银屑病、银屑病性关节炎(PsA)、类固醇抵抗型哮喘、格雷夫斯病、巩膜炎、重度抑郁症、季节性情绪障碍、PTSD、双相情感障碍、自闭症、癫痫、阿尔茨海默症、与睡眠和/或昼夜节律改变相关的CNS障碍、子宫内膜异位症、阻塞性睡眠呼吸暂停综合征(OSAS)、贝赛特氏症、皮肌炎、多肌炎、移植物抗宿主病、原发性胆汁性肝硬化、肝纤维化、非酒精性脂肪性肝病(NAFLD)、结节病、原发性硬化性胆管炎、自身免疫性甲状腺疾病、I型自身免疫性多内分泌腺病综合征、II型自身免疫性多内分泌腺病综合征、乳糜泻、神经脊髓炎、幼年特发性关节炎、系统性硬化症、心肌梗塞、肺动脉高压、骨关节炎、皮肤利什曼病、鼻窦息肉病,以及癌症,包括但不限于肺癌、胃癌、乳腺癌和结肠癌。
本文的化合物也可单独或与免疫疗法联合来治疗本文所公开的疾病或障碍。
联合疗法包括例如共同施用本文所述的化合物和一种或多种其他药剂,顺序施用本文所述的化合物和一种或多种其他药剂,施用含有本文所述的化合物的组合物和一种或多种其他药剂,或者同时施用含有本文所述的化合物的单独组合物和一种或多种其他药剂。
本公开进一步提供了用于治疗患有上述障碍或疾病中的一者的受治疗者如人的方法。
在一个方面,还可以在本文公开的方法中使用在WO 2014/179564、WO 2015/116904、WO 2016/061160、PCT/US2016/045318、PCT/US2016/062422和美国专利公布号US2016-0122318和US 2016-0122345中公开的RORγ调节剂来治疗或改善受治疗者的本文所述的疾病和/或障碍和/或病症中的一种或多种。在一个实施方案中,用在WO 2014/179564、WO 2015/116904、WO 2016/061160、PCT/US2016/045318、PCT/US2016/062422和美国专利公布US 2016-0122318或US 2016-0122345中公开的一种或多种RORγ调节剂和可药用载体、佐剂或媒介物来治疗受治疗者,其中所述RORγ调节剂以治疗或改善选自以下项的疾病或障碍的量存在:角膜真菌感染;角膜真菌感染的风险;角膜溃疡;由真菌角膜炎引起的角膜溃疡;由真菌感染引起的角膜溃疡;角膜真菌感染和相关炎症;角膜炎;真菌角膜炎;角膜炎症;角膜疾病;眼部疾病;真菌介导的角膜感染、角膜溃疡、角膜炎症、或眼部溃疡、眼部炎症或眼部感染;细菌介导的角膜感染、角膜溃疡、角膜炎症、或眼部溃疡、眼部炎症或眼部感染;微生物疾病;细菌感染;真菌感染;曲霉菌性角膜炎;镰胞菌角膜炎;皮肤T细胞淋巴瘤;肺部炎症;急性肾缺血再灌注损伤;炭疽病,包括皮肤炭疽病、吸入性炭疽病、胃肠炭疽病和注射炭疽病;曲霉菌病,包括肺曲霉菌病、慢性肺曲霉菌病(CPA)、慢性曲霉菌病、慢性空洞性肺曲霉菌病(CCPA)、变应性支气管肺曲霉菌病(ABPA)、变应性曲霉菌性鼻窦炎、曲霉肿、侵袭性曲霉病、慢性坏死性曲霉菌病和皮肤曲霉病;组织胞浆菌病,包括全身性组织胞浆菌病;以及前列腺癌。在一些实施方案中,将在WO 2014/179564、WO 2015/116904、WO 2016/061160、PCT/US2016/045318、PCT/US2016/062422和美国专利公布US 2016-0122318和US2016-0122345中公开的一种或多种RORγ调节剂与一种或多种附加的药剂联合施用来治疗疾病或障碍。
本公开进一步涉及所提供的化合物用于生产治疗和/或预防和/或改善本文提到的疾病和障碍所用的药物组合物的用途。
本文所述的化合物或组合物可以使用有效治疗或减轻本文所述的疾病和病症中的一种或多种的严重程度的任何量和任何给药途径施用。所需的确切量将因受治疗者而不同,具体取决于受治疗者的物种、年龄和一般状况、感染的严重程度、具体药剂、具体药剂的给药方式等。所提供的化合物优选配制成单位剂型以便于给药和剂量的均匀性。如本文所用的表述“单位剂型”是指适合于待治疗患者的物理上分立的药剂单位。然而应当理解,本公开的化合物和组合物的每日总用量将由主治医师在合理的医学判断范围内决定。任何特定患者或生物体的具体有效剂量水平将取决于多种因素,包括所治疗的障碍和障碍的严重程度;所采用的具体化合物的活性;所采用的具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;所采用的具体化合物的给药时间、给药途径和排泄率;治疗的持续时间;与所采用的具体化合物联合或一致使用的药物,以及医学领域中熟知的类似因素。
本公开的可药用组合物可以口服、直肠、肠胃外、脑池内、阴道内、腹膜内、局部(如用粉末、霜剂、膏剂或滴剂)、口腔、作为口腔或鼻腔喷剂等等方式施用于人和其他动物,具体取决于所治疗的感染的严重程度。在某些实施方案中,所提供的化合物可以每天以约0.01mg/kg受治疗者体重/天至约50mg/kg受治疗者体重/天,优选约1mg/kg受治疗者体重/天至约25mg/kg受治疗者体重/天的剂量水平口服或肠胃外施用一次或多次,以获得所需疗效。
在其他实施方案中,所提供的化合物局部地施用。
可以与载体材料组合以产生单一剂型的所提供化合物和附加治疗剂(在包含如上所述的附加治疗剂的那些组合物中)两者的量将根据所治疗的宿主和具体给药方式而不同。
在那些包含附加治疗剂的组合物中,该附加治疗剂和所提供的化合物可以协同作用。因此,此类组合物中的附加治疗剂的量将小于仅利用该治疗剂的单一疗法中所需的量。
存在于本公开的组合物中的附加治疗剂的量将不超过通常在包含该治疗剂作为唯一活性剂的组合物中所施用的量。
范例
如下文实施例中所述,在某些示例性实施方案中,根据以下一般过程来制备化合物。应当理解,如本文所述,虽然一般方法描述了本文某些化合物的合成,但是以下一般方法和本领域的普通技术人员已知的其他方法可以应用于所有化合物和这些化合物中的每一者的亚型和种类。
对合成的一般描述
本文所述的化合物可以根据以下反应方案和示例或其修改形式,使用易得的起始物质、试剂和常规合成过程而轻易地制备。许多反应也可以在微波(MW)条件下或使用常规加热或利用其他技术诸如固相试剂/清除剂或流动化学来进行。在这些反应中,还可以利用本身为本领域的普通技术人员已知但是没有更详细提及的变型。此外,根据以下反应方案和示例,制备本文所述化合物的其他方法对于本领域的普通技术人员而言将是显而易见的。在合成中间体和最终产物含有可能干扰所需反应的潜在反应性官能团如氨基、羟基、硫醇基和羧酸基团的情况下,采用中间体的受保护形式可能是有利的。用于保护基团的选择、引入和后续去除的方法是本领域的技术人员熟知的。在下面的讨论中,除非另外指明,否则变量具有上述含义。在下文列出了在这些实验细节中使用的缩写,并且其他缩写应为合成领域的技术人员已知的。此外,可以参考以下参考文献来获知合适的合成方法:如在March,Advanced Organic Chemistry,第3版,John Wiley&Sons,1985年;Greene和Wuts,Protective Groups in Organic Synthesis,第2版,John Wiley&Sons,1991年;以及Richard Larock,Comprehensive Organic Transformations,第4版,VCH publishersInc.,1989年中所描述的。
通常,反应方案中的试剂以等摩尔量使用;然而,在某些情况下可能期望使用过量的一种试剂来驱动反应完成。当过量试剂可通过蒸发或萃取容易地去除时尤其如此。用于中和反应混合物中的HCl的碱通常略微过量(1.05至5当量)使用。
在提供NMR数据的情况下,光谱在Varian 400(400MHz)或300(300MHz)上获得,并被报告为从四甲基硅烷下移的ppm,其中质子数、多重性和偶合常数与氘代溶剂一起表示在括号内。
本发明通过以下示例说明,其中可以采用以下缩写。
式I的化合物的制备
根据下文概述的一般过程制备式I的化合物。
在第一种方法中,使用肽键形成试剂如EDC以及HOBt、PyBOP或HATU,由式100的苯并咪唑羧酸和式105的胺制备式I的化合物,其中X=CONH。或者,使用式100的酸性氯化物。
在第二种方法中,使用肽键形成试剂如EDC以及HOBt、PyBOP或HATU,由式110的氨基苯并咪唑和式115的羧酸制备式I的化合物,其中X=NHCO。或者,使用式115的酸性氯化物。
在第三种方法中,通过加热式125的二胺以及式120的羧酸来制备式I的化合物。式125的羧酸可购买或通过文献方法制备。
在第三种方法的替代方案中,由式125的二胺分两步制备式I的化合物。在第一步中,使用肽键形成试剂如EDC、HOBt或HATU使式120的羧酸与式125的二胺反应,得到式130的单酰胺。或者,使用式120的酸性氯化物。在第二步中,将式130的单酰胺与酸如HOAc或TFA一起加热,得到式I的化合物。
在第四种方法中,使式125的二胺与式135的α,α-二氯酯反应,得到式I的化合物,其中R1是-C(=O)ORc。
在第五种方法中,使式125的二胺与式140的二氯亚胺盐反应,得到式I的化合物,其中R1是NRdRe。
在第六种方法中,在有机或无机碱的存在下,通过使式145的苯并咪唑与式150的化合物反应来制备式I的化合物,其中R100是离去基团,如碘离子、溴离子、氯离子、甲磺酸根、甲苯磺酸根或三氟甲磺酸根。
在第七种方法中,式I的化合物由另一种式I的化合物制备。此方法的非限制性示例包括:(I)用BBr3或Me3SiI处理其中R5或R6是OMe的式I的化合物,得到式I的化合物,其中R5或R6是OH;(2)使其中Cy1或Cy2是带有游离NH的氮杂环丁烷基、吡咯烷基或哌啶基的式I的化合物与烷基化剂如(C1-C6)烷基卤化物或卤代(C1-C6)烷基三氟甲磺酸盐反应,得到式I的化合物,其中R5或R6是附接到氮杂环丁烷、吡咯烷或哌啶环的N上的(C1-C6)烷基或卤代(C1-C6)烷基;(3)使其中Cy1或Cy2是带有游离NH的氮杂环丁烷基、吡咯烷基或哌啶基的式I的化合物与杂芳基卤化物如任选取代的2-氯吡啶、2-氯嘧啶或4-氯嘧啶反应,以得到式I的化合物,其中R5或R6是附接到氮杂环丁烷、吡咯烷或哌啶环的N上的杂芳基,如任选取代的吡啶基或嘧啶基;(4)用过酸如m-CPBA将其中Cy1或Cy2是吡啶环的式I的化合物氧化成式I的相应吡啶氮氧化物;(5)用氢化物还原剂如NaBH4、NaBH4/CaCl2或LiBH4将其中R5、R6、R7或R8是-C(=O)ORc或被-C(=O)ORc取代的(C1-C2)烷基的式I的化合物还原,得到式I的化合物,其中R5、R6、R7或R8是被OH取代的(C1-C3)烷基;(6)用碱金属氢氧化物将其中R5、R6、R7或R8是-C(=O)ORc或被(C1-C3)烷基取代的-C(=O)ORc并且Rc是(C1-C3)烷基的式I的化合物水解,得到式I的化合物,其中R5、R6、R7或R8是-C(=O)OH或被(C1-C3)烷基取代的-C(=O)OH;(7)在肽偶联条件下,使其中R5、R6、R7或R8是-C(=O)OH或(C1-C3)烷基取代的-C(=O)OH的式I的化合物与胺RdReNH反应,得到式I的化合物,其中R5、R6、R7或R8是-C(=O)NRdRe或(C1-C3)烷基取代的-C(=O)NRdRe;(8)用过酸如m-CPBA将其中Cy1和/或Cy2被为-SRb的R5或R6取代的式I的化合物氧化,得到式I的化合物,其中R5和/或R6是-S(O)kRb,其中k是1或2。
在第八种方法中,分四步制备式100的苯并咪唑羧酸,其为式I的化合物的前体。在有机碱如i-Pr2NEt的存在下,使式155的胺与其中R110是F或Cl的式160的卤代硝基酯反应,得到式165的硝基苯胺。例如在NH4Cl存在下使用锌粉、在C上的Pd存在下使用HOAc、SnCl2或的H2中的铁粉将式165的硝基还原,得到式170的二氨基酯。使用第三种方法中描述的过程将二氨基酯170转化为苯并咪唑酯175。最后,使用碱金属氢氧化物水解175中的酯,得到100。
在第九种方法中,分四步制备式110的氨基苯并咪唑,其为式I的化合物的前体。使胺155与其中R110是F或Cl的硝基苯180反应,得到硝基苯胺185。使用例如SnCl2还原185,得到二胺190。使用第三种方法中描述的过程将二胺190转化为溴苯并咪唑195。使用例如NaN3、CuI将溴苯并咪唑195转化为氨基苯并咪唑110。
在第十种方法中,分三步制备式125的二胺,其为式I的化合物的前体。在由例如HATU、HBTU或EDC介导的肽偶联条件下,使式200的苯甲酸与式105的胺反应,得到式205的酰胺。205与式155的胺反应得到式210的硝基苯胺,使用例如SnCl2还原该硝基苯胺,得到二胺125。
在第十一种方法中,分三步制备式145的苯并咪唑,其为式I的化合物的前体。如第三种方法中所述使二氨基酯215与式120的羧酸反应,得到式220的苯并咪唑酯。用碱金属氢氧化物处理酯220,得到式225的酸,在由例如HATU、HBTU或EDC介导的肽偶联条件下,使该酸与式105的胺反应,得到式145的酰胺。
示例性LC-MS方法包括:
方法1
梯度程序:
质谱仪参数
方法2
10-80AB_2MIN
方法3
5-95 AB_1.5MIN
式I的化合物的前体的制备例
羧酸AC1-AC6是购买的:
制备例1
2-(1-(甲基磺酰基)哌啶-4-基)乙酸(AC7)
步骤1
向4-(2-甲氧基-2-氧乙基)哌啶-1-羧酸叔丁酯(100mg,0.39mmol)在无水CH2Cl2(3mL)中的混合物中滴加HCl/二氧杂环己烷(1mL,4N)。将混合物在10℃搅拌2小时。TLC显示起始物质被消耗。将混合物减压浓缩,得到呈白色固体的粗制2-(哌啶-4-基)乙酸甲酯盐酸盐(75mg,99%),其直接用于下一步骤,无需进一步纯化。
步骤2
向粗制2-(哌啶-4-基)乙酸甲酯盐酸盐(34mg,0.18mmol)在无水CH2Cl2(2mL)中的混合物中加入Et3N(88mg,0.88mmol)。将混合物在0℃在N2下搅拌10分钟。加入MsCl(30mg,0.26mmol)。将混合物在0℃搅拌2小时。TLC(石油醚/EtOAc=1/2)显示新点被观察到。将混合物用H2O(10mL)淬灭并用CH2Cl2(3×10mL)萃取。将合并的有机层用H2O(10mL)和盐水(10mL)洗涤,用无水Na2SO4干燥,过滤并减压浓缩,得到呈白色固体的粗制2-(1-(甲基磺酰基)哌啶-4-基)乙酸甲酯(41mg,99%),其直接用于下一步骤,无需进一步纯化。1H NMR(CDCl3400MHz):δ3.80(d,J=12.4Hz,2H),3.69(s,3H),2.78(s,3H),2.71-2.65(m,2H),2.30(d,J=7.2Hz,2H),1.92-1.90(m,1H),1.85(d,J=14.0Hz,2H),1.42-1.33(m,2H)
步骤3
向粗制2-(1-(甲基磺酰基)哌啶-4-基)乙酸甲酯(20mg,0.085mmol)在MeOH/H2O/CH2Cl2(2mL,v/v/v=1/1/1)中的混合物中加入LiOH·H2O(18mg,0.43mmol)。将混合物在室温下搅拌4小时。TLC(石油醚/EtOAc=1/5)显示起始物质被消耗。将混合物减压浓缩。将残余物用2NHCl溶液(5mL)中和,并用CH2Cl2(3×5mL)萃取。将合并的有机层用H2O(5mL)和盐水(5mL)洗涤,用无水Na2SO4干燥,过滤并减压浓缩,得到呈白色固体的粗制2-(1-(甲基磺酰基)哌啶-4-基)乙酸(15mg,80%),其直接用于下一步骤,无需进一步纯化。1H NMR(CDCl3400MHz):δ3.81(d,J=12.0Hz,2H),3.78(s,3H),2.72-2.66(m,2H),2.34(d,J=6.4Hz,2H),1.98-1.85(m,3H),1.42-1.30(m,2H)。
制备例2
2-(4-(2-乙氧基-2-氧乙基)苯基)乙酸(AC8)
和
2,2′-(1,4-亚苯基)二乙酸(AC9)
向2,2′-(1,4-亚苯基)二乙酸二乙酯(950mg,3.8mmol)在3∶1∶1EtOH/THF/H2O(50mL)中的经搅拌溶液中加入LiOH.H2O(200mg,4.7mmol)。将混合物搅拌过夜并浓缩。将残余物水溶液用水(10mL)稀释,用乙醚(60mL)洗涤并用浓HCl酸化。将酸性溶液用乙醚(2×50mL)萃取。将这些乙醚萃取液合并,用盐水(10mL)洗涤,用Na2SO4干燥并浓缩,得到白色固体。1H NMR指示所需单酯(AC8,R=Et)与二酸(AC9,R=H)的约2∶1混合物,其无需进一步纯化即可使用。
制备例3
2-(4-(乙硫基)苯基)-2-乙醛酸(AC10)
按照与针对AC8所述的过程类似的过程,由2-(4-(乙硫基)苯基)-2-乙醛酸乙酯(Matrix Scientific)制备标题化合物。
以下胺类是购买的。
制备例4
(4-(丙基磺酰基)苯基)甲酰胺(AM3)
步骤1
向4-氟苄腈(1.1g,9mmol)在无水DMF(20mL)中的混合物中加入丙烷-1-硫醇钠(1g,10mmol)。将混合物在0℃搅拌2小时。将混合物用水(20mL)稀释,并用EtOAc(3×20mL)萃取。将合并的有机层用水(3×20mL)洗涤,用无水Na2SO4干燥,过滤并减压浓缩,得到呈无色油状物的粗制4-(丙硫基)苄腈(1.6g,100%),其直接用于下一步骤,无需进一步纯化。1HNMR(CDCl3400MHz):δ7.51(d,J=4.8Hz,2H),7.28(d,J=4.8Hz,2H),2.95(t,J=7.6Hz,2H),1.76-1.69(m,2H),1.06(t,J=4.0Hz,3H)。
步骤2
向粗制4-(丙硫基)苄腈(1g,5.6mmol)在MeOH(10mL)和H2O(2mL)中的混合物中加入过硫酸氢钾(6.9g,11.2mmol)。将混合物在16℃搅拌2小时。TLC(石油醚/EtOAc=1/1)显示反应完全。将混合物直接冻干。然后将混合物溶解在CH2Cl2(30mL)中并过滤。将滤液减压浓缩,得到呈白色固体的粗制4-(丙基磺酰基)苄腈(500mg,42%),其直接用于下一步骤,无需进一步纯化。1H NMR(CDCl3400MHz):δ8.04(d,J=6.8Hz,2H),7.88(d,J=5.2Hz,2H),3.11(t,J=5.4Hz,2H),1.78-1.72(m,2H),1.02(t,J=12Hz,3H)。
步骤3
在0℃、N2下,向粗制4-(丙基磺酰基)苄腈(100mg,0.48mmol)在无水THF(5mL)中的混合物中加入LiAlH4(0.95mL,0.95mmol,1M的THF溶液)。将混合物在室温下搅拌2小时。TLC(EtOAc)显示反应完全。将混合物用水(0.04mL)和NaOH水溶液(0.04mL,10%)在0℃淬灭。将混合物过滤,并将滤液减压浓缩。将残余物通过制备型TLC(EtOAc)纯化,得到呈黄色油状物的(4-(丙基磺酰基)苯基)甲酰胺(25mg,24%)。
制备例5
(5-(甲磺酰基)吡啶-2-基)甲酰胺(AM4)
按照与针对AM5所述的过程类似的过程来制备此化合物。
制备例6
(5-(乙磺酰基)吡啶-2-基)甲酰胺(AM5)
步骤1
向配备有搅拌棒的火焰干燥烧瓶中加入((5-溴吡啶-2-基)甲基)氨基甲酸叔丁酯(2.92g,10.2mmol)、乙烷亚磺酸钠盐(2.36g,20.3mmol)、L-脯氨酸(234mg,2.03mmol),碘化亚铜(I)(194mg,1.02mmol)和氢氧化钠(81.3mg,2.03mmol)。将烧瓶用N2吹扫,然后加入DMSO(35mL)。将反应混合物加热至110℃并搅拌15小时。然后将烧瓶冷却至室温,将混合物在EtOAc(150mL)和饱和NH4Cl水溶液(150mL)之间分配。将有机相分离,用盐水(50mL)洗涤,用无水MgSO4干燥,过滤并减压浓缩。将残余物通过硅胶色谱法纯化(用35%EtOAc的己烷溶液洗脱,梯度至60%),得到1.81g((5-溴吡啶-2-基)甲基)氨基甲酸叔丁酯(59%)。在1分钟的色谱中,LC-MS tR=0.74分钟,MS(ESI)m/z 301.4[M+H]+。1H NMR(CDCl3,400MHz):δ9.02(dd,J=0.8Hz,2.0Hz,1H),8.15(dd,J=2.4Hz,8.4Hz,1H),7.49(dd,J=0.8Hz,8.4Hz,1H),5.49(宽峰s,1H),4.55(d,J=7.0Hz,2H),3.15(q,J=7.2Hz,2H),1.47(s,9H),1.31(t,J=7.2Hz,3H)。
步骤2
在0℃下,在5分钟内向((5-溴吡啶-2-基)甲基)氨基甲酸叔丁酯(1.81g,6.03mmol)在MeOH(40mL)中的溶液中滴加乙酰氯(4.30mL,60.3mmol)。将溶液升温至室温并搅拌3小时。将混合物减压浓缩,得到1.64g(5-(乙基磺酰基)吡啶-2-基)甲胺二盐酸盐(约100%)。在1分钟的色谱中,LC-MS tR=0.25分钟,MS(ESI)m/z 201.2[M+H]+。1H NMR(CD3OD,400MHz):δ9.09(d,J=1.2Hz,1H),8.35(dd,J=2.4Hz,8.4Hz,1H),7.49(d,J=8.4Hz,1H),4.45(s,2H),3.31(q,J=7.2Hz,2H),1.26(t,J=7.2Hz,3H)。
制备例7
(R)-2-氨基-2-(4-(甲基磺酰基)苯基)乙醇(AM7.1)
使用与针对AM8.1所述的那些过程类似的过程,用MeI代替步骤1中的EtBr,来制备此化合物。
制备例8
(S)-2-氨基-2-(4-(甲基磺酰基)苯基)乙醇(AM7.2)
按照与针对AM8.1所述的那些过程类似的过程,使用碘甲烷代替步骤1中的EtBr和步骤4的(S)-2-甲基丙烷-2-亚磺酰胺,来制备此化合物。
制备例9
(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(AM8.1)
步骤1:(4-溴苯基)(乙基)硫烷
将4-溴苯硫酚(50g,0.26mol)、溴乙烷(58g,0.53mol)和三乙胺(78g,0.78mol)在乙腈(1L)中的混合物在回流下搅拌17小时。将该混合物冷却至室温并过滤。将滤液真空浓缩。将残余物通过硅胶色谱法纯化(用石油醚洗脱),得到呈油状物的(4-溴苯基)(乙基)硫烷(55g,96%)。1H NMR(CDCl3,400MHz):δ7.40-7.42(dd,J=6.4,2.0Hz,2H),7.18-7.20(dd,J=6.4,2.0Hz,2H),2.91-2.96(q,J=7.2Hz,2H),1.30-1.33(t,J=7.2Hz,3H)。
步骤2:2-((叔丁基二甲基甲硅烷基)氧基)乙醇
在室温下向乙烷-1,2-二醇(110g,1.77mol)在无水CH2Cl2(1.1L)中的溶液中加入三乙胺(215.2g,296mL,2.13mol)。将该混合物冷却至0℃,然后在1小时内滴加溶解在CH2Cl2(300mL)中的叔丁基二甲基氯硅烷(267.1g,1.77mol)。将混合物在室温下搅拌过夜。将反应混合物用饱和NH4Cl水溶液(400mL)淬灭并分离。将水相用MTBE(2×400mL)萃取。将合并的有机层真空浓缩,并将残余物重新溶解在MTBE(400mL)中。将MTBE层用水(2×500mL)和盐水(500mL)洗涤,用无水Na2SO4干燥,过滤并真空浓缩,得到略呈油状物的2-((叔丁基二甲基甲硅烷基)氧基)乙醇(280g,90%),其直接用于下一步骤,无需进一步纯化。1H NMR(CDCl3,400MHz):δ3.64-3.66(m,2H),3.57-3.60(m,2H),0.85(s,9H),0.02(s,6H)。
步骤3:2-((叔丁基二甲基甲硅烷基)氧基)乙醛
向冷却至-30℃的CH2Cl2(1.8L)溶液中滴加草酰氯(79.2g,52.8mL,624mmol)。将该混合物冷却至-78℃,然后滴加DMSO(62.5g,88.5mL,1.25mmol)。加入后,将该混合物在-78℃下搅拌30分钟。在-78℃下缓慢加入溶解在CH2Cl2(200mL)中的2-((叔丁基二甲基甲硅烷基)氧基)乙醇(100g,567mmol)的溶液。将反应混合物在-78℃下搅拌1小时。在-78℃下滴加三乙胺(287g,395mL,2.84mmol)。将混合物在-78℃下搅拌30分钟,然后在室温下搅拌过夜。将反应混合物用水(1L)、1N HCl(2×1L)、饱和NaHCO3水溶液(1L)和盐水(1L)洗涤。将有机层用无水Na2SO4干燥,过滤并真空浓缩,得到呈棕色油状物的2-((叔丁基二甲基甲硅烷基)氧基)乙醛(98.5g,99.8%),其直接用于下一步骤,无需进一步纯化。1H NMR(CDCl3,400MHz):δ9.70(s,1H),4.22(s,2H),0.93(s,9H),0.11(s,6H)。
步骤4:(R.E)-N-(2-((叔丁基二甲基甲硅烷基)氧基)亚乙基)-2-甲基丙烷-2-亚
磺酰胺
将2-((叔丁基二甲基甲硅烷基)氧基)乙醛(93.5g,0.54mol)、(R)-2-甲基丙烷-2-亚磺酰胺(78.8g,0.65mol)和硫酸铜(II)(215g,1.35mol)在无水CH2Cl2(1.5L)中的混合物在室温下搅拌16小时。将混合物用H2O(800mL)淬灭并分离。将水相用CH2Cl2(2×1L)萃取。将合并的有机层用水(1L)和盐水(1L)洗涤,用无水Na2SO4干燥,过滤并真空浓缩。将残余物通过硅胶色谱法纯化(用石油醚∶EtOAc=8∶1洗脱),得到呈黄色油状物的(R,E)-N-(2-((叔丁基二甲基甲硅烷基)氧基)亚乙基)-2-甲基丙烷-2-亚磺酰胺(38.5g,26%)。1H NMR(CDCl3,400MHz):δ7.96-7.97(t,J=3.2Hz,1H),4.44-4.45(d,J=2.8Hz,2H),1.11(s,9H),0.00(s,6H)。
步骤5:(R)-N-((R)-2-((叔丁基二甲基甲硅烷基)氧基)-1-(4-(乙硫基)苯基)乙
基)-2-甲基丙烷-2-亚磺酰胺
在-78℃下向(4-溴苯基)(乙基)硫烷(28.9g,133.1mmol)在无水THF(500mL)中的溶液中滴加正丁基锂(73mL,181.5mmol,2.5M的己烷溶液)。将混合物在-78℃下搅拌30分钟。在-78℃下将(R,E)-N-(2-((叔丁基二甲基甲硅烷基)氧基)亚乙基)-2-甲基丙烷-2-亚磺酰胺(33.5g,121mmol)在无水THF(100mL)中的溶液加入该混合物中。将混合物在-78℃下搅拌2小时,然后将混合物升温至室温并搅拌2小时。将混合物用饱和NH4Cl水溶液(200mL)淬灭并用EtOAc(3×300mL)萃取。将合并的有机层用水(200mL)和盐水(200mL)洗涤,用无水Na2SO4干燥,过滤并真空浓缩。将残余物通过硅胶色谱法纯化三次(用石油醚∶EtOAc=15∶1洗脱),得到呈黄色油状物的(R)-N-((R)-2-((叔丁基二甲基甲硅烷基)氧基)-1-(4-(乙硫基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(22g,44%)。1H NMR(CDCl3,400MHz):δ7.21-7.24(d,J=1.2Hz,2H),7.18-7.21(d,J=8.4Hz,2H),4.42-4.45(dd,J=8.8,2.4Hz,1H),4.21(brs,1H),3.69-3.73(dd,J=10.4,4.4Hz,1H),3.51-3.56(t,J=9.6Hz,1H),2.87-2.92(q,J=7.6Hz,2H),1.25-1.29(t,J=7.2Hz,3H),1.18(s,9H),0.88(s,9H),0.02(s,6H)。LC-MS方法3 tR=1.010分钟MS(ESI)m/z 437.9[M+Na]+。在12分钟的色谱(AD-H_5_5_40_2.3 5ML)中,异构体SFC tR=3.607和4.014分钟,ee=90.85%。
步骤6:(R)-2-氨基-2-(4-(乙硫基)苯基)乙醇
在0℃下,向(R)-N-((R)-2-((叔丁基二甲基甲硅烷基)氧基)-1-(4-(乙硫基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(22g,52.9mmol)在CH2Cl2(250mL)中的溶液中加入HCl(26.5mL,4N的二氧杂环己烷溶液)。将混合物在室温下搅拌2小时。LC-MS显示没有起始物质残留。将混合物减压浓缩,得到呈棕色固体的粗制(R)-2-氨基-2-(4-(乙硫基)苯基)乙醇盐酸盐(12.3g,100%),其直接用于下一步骤,无需进一步纯化。在0-30AB_2分钟的色谱(Xtimate 3um,C18,2.1*30mm)中,LC-MS tR=1.226分钟,MS(ESI)m/z 180.9[M-OH]+。
步骤7:(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇
在0℃下,向(R)-2-氨基-2-(4-(乙硫基)苯基)乙醇(15.2g,65.0mmol)在甲醇(200mL)中的混合物中滴加过硫酸氢钾试剂(80.0g,130.0mmol)在水(200mL)中的溶液。将混合物在室温下搅拌1.5小时;LC-MS显示没有起始物质残留。将混合物过滤,并减压去除甲醇。将水相用EtOAc(2×80mL)萃取,然后在0℃下用固体碳酸钠将水层分批碱化至pH=8-9,然后将此溶液冻干(含有Na2CO3)。将该固体溶于CH2Cl2∶MeOH(3∶1,600mL)中并搅拌30分钟,过滤,然后减压浓缩。将残余物通过硅胶色谱法纯化(用CH2Cl2∶MeOH=1∶0至4∶1洗脱),得到呈白色固体的(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(11.5g,77%)。在0-30CD_POS色谱(Xtimate ODS 2.1*30mm,3um)中,LC-MS tR=0.738分钟,MS(ESI)m/z 230.1[M+H]+。在30分钟的色谱(CD-PH_10-80_B_08ML)中,异构体SFC tR=6.99分钟,ee=97.42%。1H NMR(D2O,400MHz):δ7.82-7.84(d,J=8.0Hz,2H),7.54-7.56(d,J=8.4Hz,2H),4.33-4.35(t,J=6.4Hz,1H),3.72-3.78(m,2H),3.19-3.25(q,J=7.6Hz,2H),1.03-1.07(t,J=7.6Hz,3H)。
制备例10
AM8.1的替代制备例:
步骤1:4-(乙基磺酰基)苯甲醛
向4-氟苯甲醛(24.6g,198mmol)在二甲基亚砜(60mL)中的溶液中加入乙基亚磺酸钠(46g,396mmol)。将所得混合物在125℃下搅拌20小时。冷却至室温后,将反应混合物用350mL的H2O磨碎。将产物过滤,用两份各10mL的EtOH洗涤并真空干燥,得到呈浅黄色固体的4-(乙基磺酰基)苯甲醛(31.2g,收率80%)。在2分钟的色谱中,LC-MS tR=1.19分钟,MS(ESI)m/z 199.1[M+H]+。1H NMR(CDCl3)δ10.14(s,1H),8.09(s,4H),3.16(q,J=7.2Hz,2H),1.30(t,J=7.2Hz,3H)。
步骤2:2-(4-(乙基磺酰基)苯基)环氧乙烷
在室温下向4-(乙基磺酰基)苯甲醛(10g,50.5mmol)在DMF(85mL)中的溶液中加入三甲基碘化锍(11.9g,58.1mmol),随后加入氢氧化钾粉末(5.66g,101mmol)。将反应混合物在室温下搅拌20分钟,然后用H2O(50mL)淬灭。将混合物用1N HCl溶液(55mL)小心地中和,并用EtOAc(3×100mL)萃取。将合并的有机相用盐水洗涤,用无水Na2SO4干燥,并穿过硅胶垫(用EtOAc洗脱)。将该有机相减压浓缩,得到呈黄色油状物的粗制2-(4-(乙基磺酰基)苯基)环氧乙烷,其直接用于下一步骤,无需进一步纯化。在2分钟的色谱中,LC-MS tR=1.13分钟,MS(ESI)m/z 213.2[M+H]+。
步骤3:2-氨基-2-(4-(乙基磺酰基)苯基)乙-1-醇
在0℃下,向粗制2-(4-(乙基磺酰基)苯基)环氧乙烷(50.5mmol)在CH3CN(200mL)中的溶液中缓慢加入浓硫酸(5.4mL,101mmol)。将混合物在室温下搅拌1.5小时。LC-MS显示起始物质被消耗。将H2O(15mL)加入反应混合物中。在室温下继续搅拌8小时,然后在45℃下搅拌10小时。冷却至室温后,通过加入1N NaOH溶液(90mL)将反应混合物的pH调节至3-4。将混合物用EtOAc(100mL)萃取。然后将有机相用H2O(2×30mL)萃取。然后将合并的水层用1NNaOH溶液(110mL)碱化至pH=9,并用1-丁醇(5×60mL)萃取。将合并的有机层(由1-丁醇萃取物组成)用无水Na2SO4干燥,过滤并减压浓缩。将该有机层在高真空下干燥,得到呈灰白色固体的粗制2-氨基-2-(4-(乙基磺酰基)苯基)乙-1-醇(4g,在3个步骤中的收率为35%)。中间体4-(4-(乙基磺酰基)苯基)-2-甲基-4,5-二氢恶唑:在2分钟的色谱中,LC-MS tR=0.77、0.81分钟,MS(ESI)m/z 254.26[M+H]+。2-氨基-2-(4-(乙基磺酰基)苯基)乙-1-醇:在2分钟的色谱中,LC-MS tR=0.61分钟,MS(ESI)m/z 230.21[M+H]+。1H NMR(CD3OD):δ7.88(d,J=8.4Hz,2H),7.64(d,J=8.4Hz,2H),4.16-4.12(m,1H),3.76-3.72(m,1H),3.66-3.61(m,1H),3.17(q,J=7.2Hz,2H),1.19(t,J=1.2Hz,3H)。
步骤4:2-氨基-2-(4-(乙基磺酰基)苯基)乙-1-醇单扁桃酸盐
在50℃下,向2-氨基-2-(4-(乙基磺酰基)苯基)乙-1-醇(238mg,1.0mmol)在MeOH(3mL)中的溶液中加入(R)-扁桃酸(76mg,0.5mmol)在MeOH(1mL)中的溶液。将所得溶液缓慢冷却至环境温度。搅拌1天后,将所得结晶通过真空过滤收集并在高真空下干燥,得到呈白色晶体的单扁桃酸盐107mg(收率28%),92.5%ee。1H NMR(CD3OD):δ7.97(d,J=8.0Hz,2H),7.71(d,J=8.4Hz,2H),7.46(d,J=8.0Hz,2H),7.46(d,J=8.0Hz,2H),7.31-7.27(m,2H),7.25-7.22(m,1H),4.42-4.42(m,1H),3.92-3.89(m,1H),3.81-3.77(m,1H),3.21(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H)。
制备例11
(S)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(AM8.2)
按照与针对AM8.1所述的那些过程类似的过程,在步骤4中使用(S)-2-甲基丙烷-2-亚磺酰胺,来制备此化合物。
制备例12
(R)-2-氨基-2-(4-(乙基磺酰基)-2-氟苯基)乙-1-醇(AM9.1)
按照与针对AM8.1所述的那些过程类似的过程,在步骤5中使用(4-溴-3-氟苯基)(乙基)硫烷,来制备此化合物。
制备例13
(R)-2-氨基-2-(5-(甲基磺酰基)吡啶-2-基)乙醇(AM10.1)
使用与针对AM11.1所述的那些过程类似的过程,在步骤1中使用NaSMe,来制备此化合物。
制备例14
(S)-2-氨基-2-(5-(甲基磺酰基)吡啶-2-基)乙醇(AM10.2)
按照与针对AM11.1所述的那些过程类似的过程,在步骤1中使用NaSMe并在步骤2中使用(S,E)-N-(2-((叔丁基二甲基甲硅烷基)氧基)亚乙基)-2-甲基丙烷-2-亚磺酰胺,来制备此化合物。
制备例15
(R)-2-氨基-2-(5-(乙基磺酰基)吡啶-2-基)乙醇(AM11.1)
步骤1:2-溴-5-(乙硫基)吡啶
向2-溴-5-氟吡啶(6.28g,35.66mmol)在无水DMF(60mL)中的混合物中加入乙硫醇钠(3g,35.66mmol)。将混合物在100℃下搅拌3小时。TLC(石油醚/EtOAc=10/1)显示起始物质未被完全消耗。将另外的乙硫醇钠(0.9g,9.56mmol)加入混合物中。将混合物在100℃下搅拌12小时。将混合物用H2O(150mL)淬灭并用EtOAc(3×150mL)萃取。将合并的有机层用盐水(400mL)洗涤,用无水Na2SO4干燥,过滤并减压浓缩。将残余物通过硅胶色谱法纯化(用石油醚/EtOAc=80/1洗脱),得到呈无色油状物的2-溴-5-(乙硫基)吡啶(7.0g,90%)。LC-MS方法3 tR=0.717分钟,MS(ESI)m/z 217.6[M+H]+。
步骤2:(R)-N-((R)-2-((叔丁基二甲基甲硅烷基)氧基)-1-(5-(乙硫基)吡啶-2-
基)乙基)-2-甲基丙烷-2-亚磺酰胺
在-78℃下,向甲苯溶液(60mL)中滴加n-BuLi(10.6mL,26.48mmol,2.5M的己烷溶液);内部温度不超过-50℃。然后在-78℃下,将2-溴-5-(乙硫基)吡啶(3.85g,17.65mmol)在甲苯(10mL)中的溶液中加入反应混合物中;内部温度不超过-65℃。将混合物在-78℃下搅拌1小时。在-78℃下,将(R,E)-N-(2-((叔丁基二甲基甲硅烷基)氧基)亚乙基)-2-甲基丙烷-2-亚磺酰胺(4.90g,17.65mmol)在甲苯(10mL)中的溶液加入反应混合物中;内部温度不超过-60℃。将混合物在-78℃下再搅拌2小时。将混合物在-78℃下用盐水(150mL)淬灭并用EtOAc(3×150mL)萃取。将合并的有机层用盐水(400mL)洗涤,用无水Na2SO4干燥,过滤并减压浓缩。将残余物通过硅胶色谱法纯化(用石油醚/EtOAc=10/1至3/1洗脱),得到呈淡黄色油状物的(R)-N-((R)-2-((叔丁基二甲基甲硅烷基)氧基)-1-(5-(乙硫基)吡啶-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺(3.0g,41%)。LC-MS方法3 tR=1.014分钟,MS(ESI)m/z417.2[M+H]+。
步骤3:(R)-2-氨基-2-(5-(乙硫基)吡啶-2-基)乙醇
采用与制备例9的步骤6中的过程类似的过程。
步骤4:(R)-2-氨基-2-(5-(乙基磺酰基)吡啶-2-基)乙醇
采用与制备例9的步骤7中的过程类似的过程。
1H NMR(CD3OD,400MHz):δ9.08(s,1H),8.35(dd,J=2.0,8.4Hz,1H),7.79(d,J=8.4Hz,1H),4.70(t,J=5.6Hz,1H),4.03(dd,J=4.8,12.0Hz,1H),3.91(dd,J=4.8,11.6Hz,1H),3.29(q,J=7.2Hz,2H),1.25(t,J=7.2Hz,3H)。
制备例16
(S)-2-氨基-2-(5-(乙基磺酰基)吡啶-2-基)乙醇(AM11.2)
使用与针对AMl1.1所述的那些过程类似的过程,在步骤2中使用(S,E)-N-(2-((叔丁基二甲基甲硅烷基)氧基)亚乙基)-2-甲基丙烷-2-亚磺酰胺,来制备此化合物。
制备例17
2-((4-(氨基甲基)哌啶-1-基)磺酰基)乙酸甲酯(AM13)
步骤1
向(哌啶-4-基甲基)氨基甲酸叔丁酯(100mg,0.469mmol)在CH2Cl2(2mL)中的混合物中加入2-(氯磺酰基)乙酸甲酯(89mg,0.516mmol)和Et3N(95mg,0.938mmol)。将混合物在室温下搅拌16小时。TLC(石油醚/EtOAc=1/1)显示新点被观察到,并且TLC(CH2Cl2/MeOH=10/1)显示起始物质被完全消耗。将混合物用H2O(20mL)淬灭并用CH2Cl2(3×20mL)萃取。将合并的有机层用无水Na2SO4干燥,过滤并减压浓缩。将残余物通过制备型TLC用石油醚/EtOAc=1/1纯化,得到呈白色固体的2-((4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-基)磺酰基)乙酸甲酯(100mg,61%)。1H NMR(CDCl3400MHz):δ4.70-4.59(m,1H),3.93(s,2H),3.85(d,J=12.4Hz,2H),3.80(s,3H),3.04(t,J=6.0Hz,2H),2.86(dt,J=2.0,12.0Hz,2H),1.78(d,J=10.4Hz,2H),1.70-1.53(m,1H),1.44(s,9H),1.38-1.24(m,2H)。
步骤2
将2-((4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-基)磺酰基)乙酸甲酯(60mg,0.33mmol)的二氧杂环己烷(1mL)溶液中加入HCl/二氧杂环己烷(3mL,4M),然后在室温下搅拌2小时。TLC(石油醚/EtOAc=1/1)显示反应完全。将混合物减压浓缩,得到呈黄色油状物的粗制2-((4-(氨基甲基)哌啶-1-基)磺酰基)乙酸甲酯盐酸盐(36mg,73%),其直接用于下一步骤,无需进一步纯化。
制备例18
(R)-1-(4-(乙基磺酰基)苯基)-2-甲氧基乙-1-胺(AM16)
步骤1
使用冰水浴在N2下在20分钟内通过滴液漏斗向NaH(87g,2179.08mmol,60%的矿物油溶液)的无水THF(600mL)溶液中滴加(E)-丁-2-烯-1,4-二醇(80g,907.95mmol)的无水THF(200mL)溶液。将反应混合物在0-5℃下搅拌1小时。然后在30分钟内滴加CH3I(758g,5340.28mmol)。将所得混合物在16-19℃下搅拌16小时。TLC(石油醚∶EtOAc=5∶1)显示起始物质被消耗。用冰水浴冷却反应,用水(100mL)淬灭,用EtOAc(1.5L)稀释。将混合物用盐水(3×500mL)洗涤,用无水Na2SO4干燥,过滤并将滤液减压浓缩,得到呈无色油状物的(E)-1,4-二甲氧基丁-2-烯(94.9g粗品,90%纯度,90%),其直接用于下一步骤,无需进一步纯化。1HNMR(CDCl3,400MHz):δ5.71(t,J=3.6Hz,2H),4.00(d,J=4.4Hz,4H),3.33(s,6H)。
步骤2
在-78℃下,用臭氧鼓泡(E)-1,4-二甲氧基丁-2-烯(86.9g,748.28mmol)在无水CH2Cl2(1L)和无水MeOH(0.5L)中的溶液。将反应混合物在-78℃下搅拌1小时后,反应混合物变蓝。通过将氩气通过反应混合物鼓泡来去除过量的臭氧。TLC(石油醚∶EtOAc=5∶1)显示起始物质被消耗。将2-甲氧基乙醛(在CH2Cl2和MeOH中的粗品,100%)直接用于下一步骤,无需进一步纯化。
步骤3
在N2下向上述2-甲氧基乙醛(在CH2Cl2和MeOH中的粗品,748.28mmol)的溶液中加入(R)-2-甲基丙烷-2-亚磺酰胺(109g,897.93mmol)的无水CH2Cl2(500mL)溶液和CuSO4(179g,1127.42mmol)的无水CH2Cl2(1.5L)溶液。将反应混合物在18℃-20℃下搅拌20小时。TLC(石油醚∶EtOAc=5∶1)显示反应完全。过滤反应混合物,用CH2Cl2(3×1.5L)洗涤滤饼。将合并的有机层减压浓缩,通过硅胶柱色谱纯化(用石油醚∶EtOAc=20∶1至3∶1洗脱),得到呈棕色油状物的(R,E)-N-(2-甲氧基亚乙基)-2-甲基丙烷-2-亚磺酰胺(47g,92%纯度,35%)。1H NMR(CDCl3400MHz):δ8.08(t,J=2.8Hz,1H),4.32(t,J=3.6Hz,2H),3.45(s,3H),1.20(s,9H)。
步骤4
在-78℃和N2下,在30分钟内通过滴液漏斗向(4-溴苯基)(乙基)硫烷(51.2g,235.8mmol)的无水THF(1L)溶液中滴加n-BuLi(128.6mL,321.55mmol,2.5M的己烷溶液)。添加后,将反应混合物在-78℃下搅拌30分钟。然后在30分钟内通过滴液漏斗滴加(R,E)-N-(2-甲氧基亚乙基)-2-甲基丙烷-2-亚磺酰胺(38g,214.37mmol)的无水THF(300mL)溶液。将反应混合物在-78℃下搅拌1小时。TLC(石油醚∶EtOAc=2∶1)显示起始物质被消耗。用饱和NH4Cl水溶液(100mL)淬灭混合物。向混合物中加入EtOAc(1.2L),用盐水(3×500mL)洗涤,用无水Na2SO4干燥,过滤并减压浓缩,通过硅胶柱色谱纯化(用石油醚∶EtOAc=10∶1-2∶3洗脱),得到(R)-N-((R)-1-(4-(乙硫基)苯基)-2-甲氧基乙基)-2-甲基丙烷-2-亚磺酰胺(9g,93%纯度)以及外消旋(R)-N-((R)-1-(4-(乙硫基)苯基)-2-甲氧基乙基)-2-甲基丙烷-2-亚磺酰胺与(R)-N-((S)-1-(4-(乙硫基)苯基)-2-甲氧基乙基)-2-甲基丙烷-2-亚磺酰胺的混合物(35g)。通过制备型HPLC(中性)进一步纯化外消旋,得到呈无色油状物的(R)-N-((R)-1-(4-(乙硫基)苯基)-2-甲氧基乙基)-2-甲基丙烷-2-亚磺酰胺(18g,99%纯度,40%)和(R)-N-((S)-1-(4-(乙硫基)苯基)-2-甲氧基乙基)-2-甲基丙烷-2-亚磺酰胺(7.0g,99%纯度,10%)。LC-MS方法2 tR=1.306min,MS(ESI)m/z 316.2[M+H]+。
中性制备型HPLC方法
流动相A:含有10mM NH4HCO3的水溶液
流动相B:CH3CN
流速:150mL/min
检测:UV 220nm/254nm
色谱柱:Phenomenex luna C18 250*77mm*10um
柱温:30℃
步骤5
在N2下,在10分钟内通过滴液漏斗向(R)-N-((R)-1-(4-(乙硫基)苯基)-2-甲氧基乙基)-2-甲基丙烷-2-亚磺酰胺(18.0g,57.05mmol)的无水CH2Cl2溶液(400mL)中滴加HCl/二氧杂环己烷(28.5mL,114.10mmol,4.0M的1,4-二氧杂环己烷溶液)。然后将反应物在室温下搅拌16小时。TLC(石油醚∶EtOAc=1∶3)显示起始物质被消耗。将溶剂减压去除,得到呈棕色固体的粗制(R)-1-(4-(乙硫基)苯基)-2-甲氧基乙胺盐酸盐(20g粗品,89.48%纯度,100%),其直接用于下一步骤,无需进一步纯化。LC-MS:tR=1.225min,0-60AB_2.0min色谱(A:Xtimate ODS 2.1*30mm,B:XBrige Shield RP18 2.1*50mm),MS(ESI)m/z 195.2[M-NH3]+。
步骤6
在0-5℃下,用冰水浴在30分钟内通过滴液漏斗向(R)-1-(4-(乙硫基)苯基)-2-甲氧基乙胺(20g粗品,57.05mmol)的MeOH(300mL)溶液中滴加过硫酸氢钾(63g,102.69mmol)的H2O(500mL)溶液。然后将反应混合物在室温下搅拌2小时。LC-MS显示起始物质被消耗。将混合物用冰水浴冷却至0℃-5℃并保持10分钟,用饱和Na2SO3溶液(300mL)淬灭,用10重量%NaOH溶液碱化至pH=12-14,用EtOAc(3×1L)萃取。将合并的有机层用盐水(3×1.2L)洗涤,用无水Na2SO4干燥,过滤并减压浓缩。将残余物通过硅胶柱色谱法纯化(用CH2Cl2∶MeOH=50∶1至10∶1洗脱),得到呈棕色油状物的(R)-1-(4-(乙基磺酰基)苯基)-2-甲氧基乙胺(12.5g,97%纯度,90%)。LC-MS:tR=1.428min,0-60CD_POS_3.0min色谱(A:Xtimate ODS2.1*30mm,B:XBrige Shield RP18 2.1*50mm),MS(ESI)m/z 244.1[M+H]+。
制备例19
(R)-1-(5-(乙基磺酰基)吡啶-2-基)-2-甲氧基乙-1-胺(AM17)
使用与针对AM17所述类似的过程制备该化合物。
制备例20
4-(氨基甲基)-N-甲基哌啶-1-磺酰胺(AM18)
步骤1
向(哌啶-4-基甲基)氨基甲酸叔丁酯(30mg,0.141mmol)在CH2Cl2(1mL)中的混合物中加入甲基磺酰胺基氯(21mg,0.155mmol)和Et3N(43mg,0.423mmol)。将混合物在室温和N2下搅拌16小时。TLC(石油醚/EtOAc=1/2)显示观察到新的主要点。将混合物用CH2Cl2(20mL)稀释,并用盐水(20mL)洗涤。将有机层用无水Na2SO4干燥,过滤并减压浓缩。将残余物通过制备型TLC用石油醚/EtOAc=1/2纯化,得到呈黄色油状物的((1-(N-甲基磺酰胺基)哌啶-4-基)甲基)氨基甲酸叔丁酯(35mg,81%)。1H NMR(CDCl3 400MHz):S 4.66-4.55(m,1H),4.00-3.92(m,1H),3.96(d,J=4.8Hz,2H),3.03(t,J=6.4Hz,2H),2.80-2.69(m,5H),1.76(d,J=13.2Hz,2H),1.62-1.55(m,1H),1.43(s,9H),1.33-1.20(m,2H)。
步骤2
向((1-(N-甲基磺酰胺基)哌啶-4-基)甲基)氨基甲酸叔丁酯(35mg,0.114mmol)的二氧杂环己烷(1mL)溶液中加入HCl/二氧杂环己烷(3mL,4M)。将混合物在室温下搅拌2小时。TLC(石油醚/EtOAc=1/2)显示起始物质被完全消耗。将混合物减压浓缩,得到呈浅黄色油状物的粗制4-(氨基甲基)-N-甲基哌啶-1-磺酰胺盐酸盐(28mg,100%),其直接用于下一步骤,无需进一步纯化。
制备例21
2-((4-(氨基甲基)哌啶-1-基)磺酰基)-N-甲基乙酰胺(AM19)
步骤1
向(哌啶-4-基甲基)氨基甲酸叔丁酯(100mg,0.469mmol)在CH2Cl2(2mL)中的混合物中加入2-(氯磺酰基)乙酸甲酯(89mg,0.516mmol)和Et3N(95mg,0.938mmol)。将混合物在室温下搅拌16小时。TLC(石油醚/EtOAc=1/1)显示观察到所需的点,并且TLC(CH2Cl2/MeOH=10/1)显示起始物质被完全消耗。将混合物用H2O(20mL)淬灭,并用CH2Cl2(3×20mL)萃取。将合并的有机层用无水Na2SO4干燥,过滤并减压浓缩。将残余物通过制备型TLC用石油醚/EtOAc=1/1纯化,得到呈白色固体的2-((4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-基)磺酰基)乙酸甲酯(100mg,61%)。1H NMR(CDCl3400MHz):δ4.70-4.59(m,1H),3.93(s,2H),3.85(d,J=12.4Hz,2H),3.80(s,3H),3.04(t,J=6.0Hz,2H),2.86(dt,J=2.0,12.0Hz,2H),1.78(d,J=10.4Hz,2H),1.70-1.53(m,1H),1.44(s,9H),1.38-1.24(m,2H)。
步骤2
向2-((4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-基)磺酰基)乙酸甲酯(100mg,0.286mmol)在MeOH(5mL)中的混合物中加入LiOH·H2O(120mg,2.86mmol)和H2O(1mL)。将混合物在室温下搅拌5小时。TLC(EtOAc)显示反应完全。将混合物减压浓缩。将残余物用H2O(10mL)稀释,并用1N HCl溶液调节至pH=4-5。用EtOAc(3×15mL)萃取水层。将合并的有机层用无水Na2SO4干燥,过滤并减压浓缩,得到呈浅黄色固体的粗制2-((4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-基)磺酰基)乙酸(96mg,100%),其直接用于下一步骤,无需进一步纯化。
步骤3
向粗制2-((4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-基)磺酰基)乙酸(96mg,0.286mmol)在DMF(5mL)中的混合物中加入MeNH2HCl(38mg,0.572mmol)、HATU(217mg,0.572mmol)和Et3N(58mg,0.572mmol)。将混合物在室温和N2下搅拌16小时。TLC(EtOAc)显示观察到新点。将混合物用EtOAc(30mL)稀释,并用盐水(3×30mL)洗涤。将有机层用无水Na2SO4干燥,过滤并减压浓缩。将残余物通过制备型TLC用EtOAc纯化,得到呈淡黄色固体的((1-((2-(甲基氨基)-2-氧乙基)磺酰基)哌啶-4-基)甲基)氨基甲酸叔丁酯(65mg,65%)。1H NMR(CDCl3400MHz):δ6.47-6.39(m,1H),4.60-4.50(m,1H),3.80-3.70(m,4H),3.03-2.94(m,2H),2.82-2.70(m,5H),1.75-1.68(m,2H),1.61-1.57(m,1H),1.37(s,9H),1.30-1.16(m,2H)。
步骤4
向((1-((2-(甲基氨基)-2-氧乙基)磺酰基)哌啶-4-基)甲基)氨基甲酸叔丁酯(35mg,0.1mmol)在二氧杂环己烷(0.5mL)中的混合物中加入HCl/二氧杂环己烷(2mL,4M)。将混合物在室温下搅拌2小时。TLC(EtOAc)显示反应完全。将混合物减压浓缩,得到呈黄色油状物的粗制2-((4-(氨基甲基)哌啶-1-基)磺酰基)-N-甲基乙酰胺盐酸盐(28mg,100%),其直接用于下一步骤,无需进一步纯化。
制备例22
2-氨基-2-(1-(甲磺酰基)哌啶-4-基)乙酸甲酯(AM21)
步骤1
在0℃和N2下,向2-((叔丁氧基羰基)氨基)-2-(哌啶-4-基)乙酸甲酯(0.3g,1.1mmol)的无水CH2Cl2(6mL)溶液中加入Et3N(0.33g,3.3mmol)。然后在0℃和N2下滴加MsCl(0.13mL,1.7mmol)。然后将混合物在0℃下搅拌1.5小时。TLC(CH2Cl2/MeOH=15/1)显示反应完全。在0℃下向混合物中加入冰水(10mL)。用CH2Cl2(3×10mL)萃取混合物。将合并的有机层用无水Na2SO4干燥,过滤并减压浓缩,得到呈白色固体的粗制2-((叔丁氧基羰基)氨基)-2-(1-(甲基磺酰基)哌啶-4-基)乙酸甲酯(360mg,93%),其直接用于下一步骤,无需进一步纯化。
步骤2
采用与步骤2中用来制备AM26的过程类似的过程。
制备例23
2-((4-(氨基甲基)哌啶-1-基)磺酰基)乙酰胺(AM22)
按照与用于AM19的那些类似的过程,在步骤3中用NH4Cl代替MeNH2.HCl,制备标题化合物。
制备例24
(S)-3-氨基-3-(4-(乙基磺酰基)苯基)丙酸甲酯(AM25)
步骤1
向(S)-3-(4-溴苯基)-3-((叔丁氧基羰基)氨基)丙酸(AstaTech,990mg,2.88mmol)在MeOH(5mL)和乙醚(5mL)中的搅拌溶液中加入2M Me3SiCHN2的己烷溶液(以每2分钟间隔1mL等分试样添加5mL,10mmol),直至获得持久的黄色溶液。将溶液搅拌15分钟,并滴加冰HOAc,直至黄色淬灭并且气体逸出停止。将溶液浓缩,并将残余物通过12g二氧化硅柱上的色谱法纯化,用0-50%EtOAc的己烷溶液梯度洗脱,得到呈蜡状固体的(S)-3-(4-溴苯基)-3-((叔丁氧基羰基)氨基)丙酸甲酯(890mg,86%)。LC-MS 1.5分钟方法tR=0.97min,m/z=360、358、304、302。
步骤2
在烧瓶中装入(S)-3-(4-溴苯基)-3-((叔丁氧基羰基)氨基)丙酸甲酯(890mg,2.5mmol)、NaSO2Et(1.16g,10.0mmol)、CuI(95mg,0.5mmol)和L-脯氨酸钠盐(137mg,1.0mmol)。将烧瓶用隔膜封盖,并用干燥N2吹扫10分钟。通过注射器引入干燥DMSO(6mL),并将混合物在100℃下加热1天。将混合物冷却,用EtOAc(100mL)稀释,用水(3×10mL)和盐水(10mL)洗涤,并用Na2SO4干燥。去除溶剂,得到油状物(909mg)。在12g硅胶柱上进行色谱法,用0-80%EtOAc的己烷溶液梯度洗脱,得到(S)-3-((叔丁氧基羰基)氨基)-3-(4-(乙基磺酰基)苯基)丙酸甲酯(494mg,53%)。LC-MS 1.5分钟方法tR=0.80min,m/z=316。还回收未反应的起始物质(147mg,16%)。
步骤3
采用与步骤2中用来制备AM26的过程类似的过程。
制备例25
2-氨基-2-(1-(甲磺酰基)哌啶-4-基)乙-1-醇(AM26)
步骤1
在0℃和N2下,向CaCl2(158mg,1.42mmol)的THF/EtOH(1mL,VTHF/VEtOH=1/1)溶液中加入NaBH4(108mg,2.84mmol)。将混合物在0℃和N2下搅拌1小时。然后在0℃下,将粗制2-((叔丁氧基羰基)氨基)-2-(1-(甲基磺酰基)哌啶-4-基)乙酸甲酯(50mg,0.14mmol)的THF/EtOH(1mL,VTHF/VEtOH=1/1)溶液加入到反应混合物中。使混合物升温至室温,并在室温和N2下搅拌过夜。在0℃下,用水(10mL)缓慢淬灭混合物。将混合物直接冻干,然后加入EtOAc(30mL)。将混合物在25℃下搅拌1小时并过滤。用EtOAc(2×10mL)洗涤滤饼。将合并的有机层减压浓缩,得到呈白色固体的粗制(2-羟基-1-(1-(甲基磺酰基)哌啶-4-基)乙基)氨基甲酸叔丁酯(45mg,98%),其直接用于下一步骤,无需进一步纯化。1H NMR(CDCl3400MHz):δ4.92(d,J=9.2Hz,1H),3.90-3.75(m,2H),3.73-3.60(m,2H),3.55-3.40(m,1H),2.83(brs,1H),2.77(s,3H),2.68-2.55(m,2H),1.95-1.76(m,2H),1.75-1.66(m,1H),1.42(s,9H),1.42-1.30(m,2H)。
步骤2
在室温下,向粗制(2-羟基-1-(1-(甲基磺酰基)哌啶-4-基)乙基)氨基甲酸叔丁酯(45mg,0.14mmol)的无水CH2Cl2(2mL)溶液中加入HCl/二氧杂环己烷(2mL,4M)。将混合物搅拌1小时。减压去除溶剂,然后加入水(5mL)。用MTBE(3×5mL)萃取混合物。将水层直接冻干,得到呈无色油状物的粗制2-氨基-2-(1-(甲基磺酰基)哌啶-4-基)乙醇盐酸盐(36mg,100%),其直接用于下一步骤,无需进一步纯化。1H NMR(CD3OD 400MHz):δ3.90-3.80(m,2H),3.75-3.70(m,2H),3.20-3.05(m,1H),2.86(s,3H),2.85-2.70(m,2H),1.95-1.80(m,3H),1.60-1.40(m,2H)。
制备例26
2-((4-(氨基甲基)苯基)磺酰基)乙酸甲酯(AM27)
向2-((4-氰基苯基)磺酰基)乙酸甲酯(10mg,0.042mmol)的无水THF(1mL)溶液中加入雷尼镍(20mg)。在室温和H2(30psi)下将混合物搅拌2小时。TLC(石油醚/EtOAc=3/1)显示反应完全。向混合物中加入CH2Cl2(10mL)并过滤。将滤液用无水Na2SO4干燥,过滤并减压浓缩,得到呈浅黄色油状物的粗制2-((4-(氨基甲基)苯基)磺酰基)乙酸甲酯(10mg,100%),其直接用于下一步骤,无需进一步纯化。LC-MS tR=1.702min,0-30CD_3.0min色谱(Xtimate ODS2.1×30mm,3um),MS(ESI)m/z 244.0[M+H]+
制备例27
(R)-2-(2-氨基-2-(4-(乙基磺酰基)苯基)乙氧基)乙酸乙酯(AM28)
步骤1
在0℃和N2下,向(R)-N-((R)-1-(4-(乙硫基)苯基)-2-羟乙基)-2-甲基丙烷-2-亚磺酰胺(500mg,1.65mmol)和2-溴乙酸乙酯(551mg,3.30mmol)的无水THF(10mL)溶液中加入NaH(200mg,4.95mmol,60%矿物油溶液)。添加后,将混合物在70℃下搅拌4小时。LC-MS显示起始物质完全消耗,产物:副产物(2-((R)-2-((R)-1,1-二甲基乙基亚磺酰氨基)-2-(4-(乙硫基)苯基)乙氧基)乙酸)的比例为3∶5。向混合物中加入饱和NH4Cl溶液(6mL),并用EtOAc(3×10mL)萃取。将合并的有机层用水(20mL)洗涤,用无水Na2SO4干燥,过滤并减压浓缩。将残余物通过硅胶柱色谱法纯化,用石油醚/EtOAc=1/1洗脱,得到呈浅棕色油状物的2-((R)-2-((R)-1,1-二甲基乙基亚磺酰氨基)-2-(4-(乙硫基)苯基)乙氧基)乙酸乙酯(150mg,23.5%)。LC-MS方法3 tR=0.780min,MS(ESI)m/z 387.9[M+H]+
步骤2
向2-((R)-2-((R)-1,1-二甲基乙基亚磺酰氨基)-2-(4-(乙硫基)苯基)乙氧基)乙酸乙酯(150mg,0.088mmol)的无水CH2Cl2(1mL)溶液中加入HCl/二氧杂环己烷(1mL,4M)。将混合物在14℃下搅拌2小时。TLC(石油醚/EtOAc=1/1)显示反应完全。将混合物减压浓缩,得到呈棕色油状物的粗制(R)-乙基2-(2-氨基-2-(4-(乙硫基)苯基)乙氧基)乙酸盐酸盐(150mg,>100%),其直接用于下一步骤,无需进一步纯化。
步骤3
向(R)-乙基2-(2-氨基-2-(4-(乙硫基)苯基)乙氧基)乙酸盐酸盐(粗制品150mg,0.088mmol)的H2O/MeOH(4mL/2mL)溶液中加入过硫酸氢钾(475mg,0.773mmol)。将混合物在13℃下搅拌2小时。LC-MS显示大多数是期望的MS。向混合物中加入H2O(15mL)和Na2SO3(95mg,0.773mmol),然后直接冷冻干燥,得到呈白色固体的粗制(R)-乙基2-(2-氨基-2-(4-(乙基磺酰基)苯基)乙氧基)乙酸酯(670mg,>100%,含有大量盐),其直接用于下一步骤,无需进一步纯化。LC-MS方法3 tR=0.471min,MS(ESI)m/z 315.9[M+H]+
制备例28
4-苄基1-(叔丁基)-5-(氨基甲基)-1,4-二氮杂环庚烷-1,4-二羧酸酯(AM29)
制备例29
2-(氨基甲基)-5-(乙基磺酰基)苯酚(AM30)
二胺制剂
制备例30
4-溴-N1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)苯-1,2-二胺
步骤1
将(2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲胺(265mg,1.4mmol)、4-溴-1-氟-2-硝基苯(0.17mL,1.4mmol)和i-Pr2NEt(0.53mL,2.9mmol)的EtOH(7mL)溶液在室温下搅拌2小时,然后在50℃下搅拌17小时。浓缩该混合物。将残余物溶于EtOAc(90mL)中,用5%HCl水溶液(10mL)和盐水(10mL)洗涤,用Na2SO4干燥。去除溶剂,得到呈黄色固体的粗制4-溴-N-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-硝基苯胺(820mg)。
步骤2
将经搅拌的粗制4-溴-N-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-硝基苯胺(820mg,≤1.4mmol)和SnCl2(1.08g,5.7mmol)在无水DMF(10mL)中的混合物在80℃下加热2小时。加入另外的SnCl2(1.08g,5.7mmol)并继续加热0.5小时。冷却后,加入饱和NaHCO3水溶液(10mL),然后加入硅藻土。将混合物搅拌15分钟,并通过另外的硅藻土过滤,再用EtOAc洗涤。用盐水洗涤滤液,用Na2SO4干燥并旋转蒸发,得到棕色油状物。在12g硅胶柱上进行色谱法,用0-100%EtOAc的己烷溶液梯度洗脱,得到4-溴-N1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)苯-1,2-二胺(305mg,两步60%)。LC-MS方法1 tR=1.89min,m/z=359,357。
制备例31
3-氨基-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲
酯
步骤1
向经搅拌的(2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲胺(PharmaBlock,2.98g,15.9mmol)和4-氟-3-硝基苯甲酸甲酯(CombiBlocks,3.33g,16.7mmol)的MeOH(80mL)溶液中加入i-Pr2NEt(6mL,33.5mmol)。将混合物在室温下搅拌2天。形成粘稠的黄色沉淀。浓缩混合物,将残余物溶于5%HCl水溶液(50mL)和EtOAc(100mL)中。分离水层,并用EtOAc(100mL)萃取。用盐水(20mL)洗涤合并的EtOAc层,用Na2SO4干燥并浓缩,得到呈黄色固体的粗制4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)-3-硝基苯甲酸甲酯(6.07g,104%)。LC-MS 2.5min方法tR=1.88min,m/z=367。
步骤2
在存在10%碳载钯(250mg)的情况下,将4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)-3-硝基苯甲酸甲酯(5.88g,16.1mmol)的2∶1EtOAc/EtOH(150mL)溶液在H2(1atm,气球)下搅拌4小时。将混合物通过硅藻土过滤,用EtOAc洗涤。浓缩滤液,得到固体(6.69g)。在80g硅胶柱上进行色谱法,用0-60%EtOAc的己烷溶液梯度洗脱,得到呈灰白色固体的3-氨基-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲酯(4.75g,87%)。LC-MS 2.5min方法tR=1.56min,m/z=337。
另选步骤2
向4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)-3-硝基苯甲酸甲酯(7.2g,19.7mmol)的H2O/MeOH/THF(120mL,V/V/V=1∶1∶1)溶液中加入Zn(12.8g,197mmol)和NH4Cl(10.4g,197mmol)。将混合物在22℃下搅拌45分钟。TLC(石油醚/EtOAc=5/1)显示反应完全。向混合物中加入CH2Cl2(100mL)并过滤。将滤液用无水Na2SO4干燥,过滤并减压浓缩,得到呈黄色固体的3-氨基-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲酯(6.6g,99%),其直接用于下一步骤,无需进一步纯化。LC-MS方法3tR=0.708min,MS(ESI)m/z 336.9[M+H]+。
按照类似过程,在步骤1中使用适当的胺Cy2-L2-NH2代替(2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲胺,制备下列二胺。
制备例32
3-氨基-N-(4-(乙基磺酰基)苄基)-4-((2-氟-3-甲氧基苄基)氨基)苯甲酰胺
步骤1
向经搅拌的4-氟-3-硝基苯甲酸(0.47g,2.5mmol)、AM2(0.47g,2.4mmol)和i-Pr2NEt(1.4mL,7.8mmol)的CH2Cl2(20mL)溶液中加入固体HATU(1.5g,3.9mmol)。将混合物在室温下搅拌2小时并浓缩。将残余物溶于EtOAc(90mL)中,用5%HCl水溶液(2×10mL)、饱和NaHCO3水溶液(10mL)和盐水(10mL)洗涤,并用Na2SO4干燥。去除溶剂,得到黄色泡沫(1.72g)。在40g硅胶柱上进行色谱法,用20%-100%EtOAc的己烷溶液梯度洗脱,得到呈粘性固体的N-(4-(乙基磺酰基)苄基)-4-氟-3-硝基苯甲酰胺(1.08g,%)。LC-MS方法1tR=1.44min,m/z=367。
步骤2
将N-(4-(乙基磺酰基)苄基)-4-氟-3-硝基苯甲酰胺(99mg,0.27mmol)、2-氟-3-甲氧基苄胺(52mg,0.34mmol)、i-Pr2NEt(0.15mL,0.82mmol)和i-PrOH(1mL)的混合物在60℃油浴中加热16小时。用EtOAc(90mL)稀释混合物,用5%HCl水溶液(10mL)和1∶1饱和NaHCO3水溶液/盐水(10mL)洗涤,并用Na2SO4干燥。浓缩得到呈黄色油状物的粗制N-(4-(乙基磺酰基)苄基)-4-((2-氟-3-甲氧基苄基)氨基)-3-硝基苯甲酰胺(130mg)。LC-MS方法1 tR=1.67min,m/z=502。
步骤3
在存在10%碳载钯(催化量)的情况下,将N-(4-(乙基磺酰基)苄基)-4-((2-氟-3-甲氧基苄基)氨基)-3-硝基苯甲酰胺(26mg,52mol)的EtOAc(10mL)溶液在H2(1atm气球)下搅拌45min。将溶液过滤并浓缩,得到呈黄色油状物的粗制3-氨基-N-(4-(乙基磺酰基)苄基)-4-((2-氟-3-甲氧基苄基)氨基)苯甲酰胺(16mg)。LC-MS方法1 tR=1.36min,m/z=472。
按照类似过程,在步骤2中使用适当的胺Cy2-L2-NH2代替2-氟-3-甲氧基苄胺,制备下列化合物。
苯并咪唑制剂
制备例33
1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并
[d]咪唑-5-胺
步骤1
将4-溴-N1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)苯-1,2-二胺(305mg,0.85mmol)的TFA(5mL)溶液在70℃下加热2小时并浓缩。将残余物溶于EtOAc(90mL)中,用饱和NaHCO3水溶液(10mL)和盐水(10mL)洗涤,用Na2SO4干燥并浓缩,得到油状物(283mg)。在12g硅胶柱上进行色谱法,用0-100%EtOAc的己烷溶液梯度洗脱,得到呈油状物的5-溴-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基-1)-1H-苯并[d]咪唑(138mg,37%)。LC-MS方法1 tR=2.03min,m/z=437,435。
步骤2
在烧瓶中装入5-溴-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑(40mg,0.09mmol)、CuI(22mg,0.12mmol)、Na2CO3(15mg,0.14mmol)、NaN3(15mg,0.23mmol)和DMEDA(17.5μL,0.16mmol)。用隔膜密封烧瓶,并用N2吹扫5分钟。使用注射器注入干燥DMSO(1mL),并将混合物在110℃下加热1.5小时。冷却后,将混合物用EtOAc(80mL)稀释,用水(10mL)和盐水(10mL)洗涤,并用Na2SO4干燥。去除溶剂,得到油状物(37mg),将其在12g硅胶柱上通过色谱法纯化,用0-100%EtOAc的己烷溶液梯度洗脱,得到呈油状物的1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-胺(27mg,79%)。LC-MS方法1 tR=1.48min,m/z=372。
制备例34
1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并
[d]咪唑-5-羧酸
步骤1
将经搅拌的3-氨基-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲酯(290mg,0.86mmol)的CF3CO2H(5mL)溶液在70℃下保持2小时。浓缩该混合物。将残余物溶于CH2Cl2(70mL)中,用9∶1盐水/饱和NaHCO3水溶液(10mL)洗涤,并用Na2SO4干燥。去除溶剂,得到油状物(368mg)。在12g硅胶柱上进行色谱法,用0-100%EtOAc的己烷溶液梯度洗脱,得到呈无色油状物的1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-羧酸甲酯(292mg,82%)。LC-MS方法1 tR=1.81min,m/z=415。
步骤2
向经搅拌的1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-羧酸甲酯(292mg,0.70mmol)的2∶1∶1MeOH/THF/H2O(8mL)溶液中加入LiOH.H2O(93mg,2.2mmol)。搅拌过夜后,浓缩该混合物。将残余物在EtOAc(90mL)和5%HCl水溶液(10mL)之间分配。将有机层用Na2SO4干燥并浓缩,得到呈固体的粗制1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-羧酸(306mg,108%),其无需进一步纯化即可使用。LC-MS方法1 t R=1.63min,m/z=401。
通过类似的过程制备以下苯并咪唑羧酸。
通过与上述类似的过程,在步骤1中使用MeCF2CO2H并加热至80℃,制备以下苯并咪唑羧酸。
制备例35
2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-1H-苯并[d]咪
唑-5-羧酸
步骤1
将3-氨基-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲酯(6.6g,19.6mmol)、环丁烷羧酸(3.94g,39.3mmol)、Et3N(6.0g,58.9mmol)和HATU(8.2mg,21.6mmol)在无水CH2Cl2(150mL)中的混合物在22℃和N2下搅拌2小时。LC-MS显示反应完全。向混合物中加入CH2Cl2(100mL),并用水(200mL×3)洗涤,用无水Na2S04干燥,过滤并减压浓缩。将残余物通过硅胶柱色谱法纯化,用石油醚/EtOAc=10∶1-5∶1洗脱,得到呈浅黄色固体的3-(环丁烷甲酰胺基)-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲酯(8.2g,99%)。LC-MS方法3 tR=0.789min,MS(ESI)m/z 419.0[M+H]+。
步骤2
将3-(环丁烷甲酰胺基)-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲酯(8.2g,19.6mmol)的TFA(80mL)溶液在70℃和N2下搅拌8小时。LC-MS显示反应完全。将混合物减压浓缩。向混合物中加入水(20mL)。用饱和NaHCO3溶液将水层调节至pH=6-7,并用CH2Cl2(3×50mL)萃取。将合并的有机层用盐水(100mL)洗涤,用无水Na2SO4干燥,过滤并减压浓缩。将残余物通过硅胶柱色谱法纯化,用石油醚/EtOAc=10∶1-5∶1洗脱,得到呈浅黄色油状物的2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-1H-苯并[d]咪唑-5-羧酸甲酯(6.7g,85%)。LC-MS方法3 tR=0.701min,MS(ESI)m/z401.1[M+H]+1H NMR(CDCl3400MHz):δ8.53(s,1H),7.97(d,J=8.4Hz,1H),7.24(d,J=8.4Hz,1H),7.01(d,J=8.0Hz,1H),6.95(t,J=8.0Hz,1H),6.45(d,J=8.0Hz,1H),5.32(s,2H),3.95(s,3H),3.79-3.66(m,1H),2.67-2.58(m,2H),2.46-2.32(m,2H),2.19-1.99(m,2H)。
步骤3
向2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-1H-苯并[d]咪唑-5-羧酸甲酯(8.0g,20mmol)的H2O/MeOH(100mL,V/V=1∶5)溶液中加入LiOH·H2O(4.2g,100mmol)。将混合物在22℃下搅拌16小时,并在40℃下搅拌3小时。LC-MS显示反应完全。将混合物减压浓缩。向残余物中加入H2O(50mL),并用1N HCl溶液调节至pH=3-4,得到沉淀。过滤后,将滤饼溶于MeOH(500mL)中,用无水Na2SO4干燥,过滤并减压浓缩,得到呈黄色固体的粗制2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-1H-苯并[d]咪唑-5-羧酸(7.68g,99%),其直接用于下一步骤,无需进一步纯化。LC-MS方法3 tR=0.653min,MS(ESI)m/z 387.0[M+H]+。
制备例36
1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-1H-苯并
[d]咪唑-5-羧酸
步骤1
在0℃下,向3-氨基-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲酯(16g,47.62mmol)、2,2-二氟乙酸(9.1g,95.24mmol)、HOBt(12.9g,95.24mmol)和EDCI(18.4g,95.24mmol)在无水CH2Cl2(360mL)中的混合物中加入Et3N(24g,0.24mol)。将混合物在12-21℃和N2下搅拌16小时。LC-MS显示仍有10%的起始物质残留。向混合物中加入水(600mL),出现大量沉淀。过滤后,用石油醚(3×50mL)洗涤滤饼,然后用CH2Cl2/MeOH(8∶1,400mL)溶解,用无水Na2SO4干燥,过滤并减压浓缩,得到呈白色固体的粗制3-(2,2-二氟乙酰氨基)-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲酯(14.4g,73%),其直接用于下一步骤,无需进一步纯化。LC-MS方法3 tR=0.888min,MS(ESI)m/z 414.9[M+H]+。
步骤2
将3-(2,2-二氟乙酰氨基)-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲酯(15g,36.23mmol)在TFA(50mL)中的混合物在70℃下搅拌3小时。TLC显示反应完全。将混合物减压浓缩。向残余物中加入饱和NaHCO3溶液,调节至pH=7-8,并用EtOAc(2×100mL)萃取。将合并的有机层用无水Na2SO4干燥,过滤并减压浓缩。将残余物通过硅胶柱色谱法纯化,用石油醚/EtOAc=7/3洗脱,得到呈白色固体的1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-1H-苯并[d]咪唑-5-羧酸甲酯(9.3g,65%)。LC-MS方法3 tR=0.787min,MS(ESI)m/z 396.9[M+H]+。
步骤3
向1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-1H-苯并[d]咪唑-5-羧酸甲酯(15g,37.78mmol)在MeOH/H2O(3/1,180mL)中的混合物中加入LiOH·H2O(7.9g,0.19mol)。将混合物在15-19℃下搅拌16小时,并在50℃下搅拌3小时。LC-MS显示反应完全。将混合物减压浓缩,去除THF。用2NHCl溶液将残余物调节至pH=4-5。用EtOAc(3×100mL)萃取水层。将合并的有机层用无水Na2SO4干燥,过滤并减压浓缩,得到呈白色固体的粗制1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-1H-苯并[d]咪唑-5-羧酸(14.5g,100%),其直接用于下一步骤,无需进一步纯化。LC-MS方法3tR=0.717min,MS(ESI)m/z 382.9[M+H]+。
制备例37
2-环丙基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-1H-苯并[d]咪
唑-5-羧酸
步骤1
将经搅拌的3-氨基-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲酯(252mg,0.75mmol)和吡啶(0.13mL,1.5mmol)的CH2Cl2(10mL)溶液冷却至-70℃,并加入环丙烷碳酰氯(65μL,0.71mmol)。使干冰浴耗尽。2.5小时后,混合物达到室温,并加入水(5mL)。浓缩该混合物。将含水残余物用EtOAc(90mL)稀释,用水(5mL)、饱和NaHCO3水溶液(10mL)和盐水(10mL)洗涤,并用Na2SO4干燥。去除溶剂,得到呈油状物的粗制3-(环丙烷甲酰胺基)-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲酯(307mg),其无需进一步纯化即可使用。
步骤2
将粗制3-(环丙烷甲酰胺基)-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲酯(307mg)溶于HOAc(2mL)中,并在100℃下加热2小时。浓缩该混合物。将残余物溶于CH2Cl2(3mL)中,并施加到已经用饱和NaHCO3水溶液(5mL)预润湿的10mLChemElut柱上。将柱用EtOAc(80mL)洗脱。浓缩洗脱液,得到棕色油状物(261mg)。在12g硅胶柱上进行色谱法,用0-100%EtOAc的己烷溶液梯度洗脱,得到呈油状物的2-环丙基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-1H-苯并[d]咪唑-5-羧酸甲酯(63mg,两步22%)。LC-MS方法1 tR=1.29min,m/z=387。
步骤3
将2-环丙基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-1H-苯并[d]咪唑-5-羧酸甲酯(63mg,0.16)和将LiOH.H2O(75mg,1.8mmol)的2∶1∶1MeOH/THF/H2O(2mL)溶液在室温下搅拌过夜,浓缩去除有机溶剂。将含水残余物用5%HCl水溶液(10mL)酸化,并用EtOAc(80mL)萃取。分离有机层,用盐水(10mL)洗涤,用Na2SO4干燥并浓缩,得到标题化合物(70mg,定量)。LC-MS方法1 tR=1.11min,m/z=373。
按照与制备例35、36和37所述类似的过程,在步骤1中使用酸R1CO2H或酰氯R1COCl,制备以下苯并咪唑羧酸。
制备例38
1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-甲氧基-1H-苯并[d]咪
唑-5-羧酸
步骤1
向经搅拌的、冰冷的3-氨基-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)苯甲酸甲酯(66mg,0.2mmol)的2∶1THF/CH2Cl2(6mL)溶液中加入Et3N(4当量),然后滴加三光气(0.5当量)的CH2Cl2(3mL)溶液。15分钟后,移去冷却浴,将混合物在室温下搅拌3小时。水性后处理(Aqueous work up)得到1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-羧酸甲酯(66mg,93%)。LC-MS方法1 tR=1.42min,m/z=363。
步骤2
将1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-羧酸甲酯(66mg,0.18mmol)的POCl3(4mL)溶液在120℃下加热2.5小时。冷却混合物并将其倒入碎冰中。待冰融化后,用EtOAc(3×)萃取该含水混合物。用水和盐水洗涤所合并的有机层,并用Na2SO4干燥。去除溶剂,得到粗制2-氯-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-1H-苯并[d]咪唑-5-羧酸甲酯(21mg),其无需进一步纯化即可使用。LC-MS方法1 t R=1.73min,m/z=381。
步骤3
将2-氯-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-1H-苯并[d]咪唑-5-羧酸甲酯(21mg,0.055mmol)、25重量%NaOMe的MeOH溶液(0.5mL)和MeOH(3mL)的混合物在室温下搅拌过夜。加入饱和NH4Cl水溶液,浓缩混合物以去除MeOH。用EtOAc稀释含水残余物,用1%HCl水溶液、水和盐水洗涤,用Na2SO4干燥并浓缩。通过在4g硅胶柱上的色谱法纯化残余物,用10%-50%EtOAc的己烷溶液梯度洗脱,得到1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-甲氧基-1H-苯并[d]咪唑-5-羧酸甲酯(7.5mg)。LC-MS方法1tR=1.69min,m/z=377。
步骤4
使用与制备例37步骤3所述类似的过程,将1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-甲氧基-1H-苯并[d]咪唑-5-羧酸甲酯(7.5mg)与LiOH反应,得到标题化合物。LC-MS方法1 tR=1.36min,m/z=363。
制备例39
N-(4-(乙基磺酰基)苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
步骤1
将3,4-二氨基苯甲酸甲酯(2.93g,17.6mmol)和TFA(10mL)的混合物回流加热2.5小时并浓缩。将残余物在EtOAc(175mL)和饱和NaHCO3(40mL)之间分配。分离有机层,用饱和NaHCO3水溶液(20mL)和盐水(20mL)洗涤,并用Na2SO4干燥。去除溶剂,得到深色固体(4.38g)。在40g硅胶柱上进行色谱法,用0-100%EtOAc的己烷溶液梯度洗脱,得到2-(三氟甲基)-1H-苯并[d]咪唑-5-羧酸甲酯(3.06g,71%)。LC-MS方法1 tR=1.38min,m/z=245。
步骤2
将经搅拌的2-(三氟甲基)-1H-苯并[d]咪唑-5-羧酸甲酯(278mg,1.1mmol)、LiOH.H2O(198mg,4.7mmol)的3∶1MeOH/H2O(8mL)溶液在40℃下加热2天并浓缩。将残余物溶于5%HCl水溶液(5mL)和MeCN(5mL)中并再次浓缩,得到粗制2-(三氟甲基)-1H-苯并[d]咪唑-5-羧酸。
步骤3
将来自步骤2的粗制2-(三氟甲基)-1H-苯并[d]咪唑-5-羧酸的一半(≤0.55mmol)、AM2(150mg,0.75mmol)和i-Pr2NEt(0.36mL,2.0mmol)在5∶1CH2Cl2ZDMF(6mL)中搅拌,并加入固体HATU(285mg,0.75mmol)。搅拌2小时后,用EtOAc(90mL)稀释混合物,用5%HCl水溶液(10mL)、饱和NaHCO3水溶液(10mL)和盐水(10mL)洗涤,并用Na2SO4干燥。去除溶剂,得到油状物(348mg)。在12g硅胶柱上进行色谱法,用0-100%EtOAc的己烷溶液梯度洗脱,得到呈油状物的N-(4-(乙基磺酰基)苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(127mg,62%)。LC-MS方法1 tR=1.35min,m/z=412。
制备例40
3-(4-(乙硫基)苯基)氧杂环丁-3-胺
步骤1
将经搅拌的(4-溴苯基)(乙基)硫烷(1.05g,4.8mmol)的无水THF(20mL)溶液冷却至-70℃,并在5min内滴加2.2M n-BuLI的环己烷(2.8mL,6.1mmol)溶液。将该混合物在-70℃下搅拌1小时。在2min内滴加2-甲基-N-(氧杂环丁-3-亚基)丙烷-2-亚磺酰胺(936mg,5.3mmol)的无水THF(2mL)溶液。将该混合物在-70℃下搅拌0.5小时,从冷却浴中移出,并用饱和NH4Cl(20mL)和水(10mL)淬灭。用EtOAc(2×40mL)萃取混合物。用盐水(10mL)洗涤所合并的有机层,用Na2SO4干燥并浓缩,得到黄色油状物(1.66g)。在12g硅胶柱上进行色谱法,用10%-100%EtOAc的己烷溶液梯度洗脱,得到呈油状物的N-(3-(4-(乙硫基)苯基)氧杂环丁-3-基)-2-甲基丙烷-2-亚磺酰胺(1.07g,71%)。LC-MS方法1 tR=1.33min,m/z=314。
步骤2
向经搅拌的、冰冷的N-(3-(4-(乙硫基)苯基)氧杂环丁-3-基)-2-甲基丙烷-2-亚磺酰胺(1.07g,3.4mmol)的MeOH(5mL)溶液中加入4M HCl的二氧杂环己烷(1.3mL,5.1mmol)溶液。将混合物搅拌2分钟并浓缩,得到标题化合物的HCl盐形式。LC-MS方法1 tR=0.65min,m/z=193[M-NH2]+
式I化合物的制备
实施例1
N-(1-((2,2-二氟-3a,7a-二氢苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟
甲基)-1H-苯并[d]咪唑-5-基)-2-(4-(乙基磺酰基)苯基)乙酰胺(I-1)
向经搅拌的1-((2,2-二氟-3a,7a-二氢苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-胺(13.5mg,36μmol)、ACl(13mg,58μmol)和i-Pr2NEt(26μL,0.14mmol)的CH2Cl2(2mL)溶液中加入固体HATU(40mg,0.11mmol)。将混合物在室温下搅拌0.5小时并浓缩。通过制备型HPLC纯化残余物,得到N-(1-((2,2-二氟-3a,7a-二氢苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-基)-2-(4-(乙基磺酰基)苯基)乙酰胺(16mg,%)。1H NMR(d4-MeOH)δ1.20(t,3H),3.18(q,2H),3.84(s,2H),5.72(s,2H),6.77(d,1H),7.04-7.18(m,2H),7.47(d,1H),7.59(d,1H),7.62(d,2H),7.86(d,2H),8.19(s,1H)。LC-MS方法1 tR=1.80min,m/z=582。
按照类似的过程,使用选自AC1至AC9的适当的酸p-R6-C6H4CH2CO2H,制备以下化合物:
通过类似的过程制备化合物I-10:
实施例2
(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰
基)苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-11.1)
向经搅拌的粗制1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-羧酸(17mg,42μmol)、(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙-1-醇(AM8.1,12.7mg,64μmol)和i-Pr2NEt(30uL,0.17mmol)的CH2Cl2(2mL)溶液中加入固体HATU(25mg,65μmol)。将混合物搅拌过夜并浓缩。通过制备型HPLC纯化残余物,得到呈油状物的(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰基))苯基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(22mg,84%)。1H NMR(d4-MeOH)δ1.24(t,3H),3.23(q,2H),3.99(d,2H),5.38(t,1H),5.86(s,2H),6.88(d,1H),7.13-7.22(m,2H),7.70(d,1H),7.77(d,2H),7.95(d,2H),8.03(d,1H),8.48(s,1H)。LC-MS2.5min方法tR=1.47min,m/z=612。
用n-Pr2O(4mL)稀释I-11.1(100mg)的CH2Cl2(2mL)溶液。加入另外的CH2Cl2(0.5mL)以溶解沉淀,并加入I-130.1的晶种。使混合物在封闭的小瓶中静置36天,过滤并真空干燥,得到I-11.1(64mg),熔点为134℃-136℃。该物质具有图3所示的X射线粉末衍射图案。
用CCl4(8mL)稀释I-11.1(150mg)的i-PrOAc(2mL)溶液。使混合物静置过夜并过滤。将收集的白色固体真空干燥,得到I-11.1(106mg),其在97℃-102℃下软化并在135℃-137℃下熔化。该物质具有图4所示的X射线粉末衍射图案。
用苯(2mL)稀释I-11.1(100mg)的t-BuOAc(2mL)溶液。用如上所述制备的固体接种溶液,并静置过夜。收集白色固体并真空干燥,得到I-11.1(77mg),其在97℃下软化并在约105℃下熔化。该物质具有图5所示的X射线粉末衍射图案。
通过类似的过程,使用AM8.2制备化合物I-11.2,即I-11.1的对映体。
按照与针对I-11.1所述类似的过程,使用适当的苯并咪唑羧酸代替1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-羧酸,制备下列化合物。
按照类似的过程,使用胺AM7.1和AM7.2制备下列化合物。
按照类似的过程制备以下化合物。
a由对应的手性四氢呋喃-2-羧酸制备。最终产品的手性中心的立体化学完整性未得到证实。b在手性柱上通过色谱法分离对映体。
按照类似的过程制备以下化合物。
按照类似的过程制备以下化合物。
按照类似的过程制备以下化合物。
a在手性柱上通过色谱法分离异构体。未建立异构体的立体化学构型。按照类似的过程制备以下化合物。
实施例3
(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰
基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-130.1)
和
(S)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰
基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-130.2)
向1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-羧酸(5.4g,13.5mmol)和(R)-2-氨基-2-(5-(乙基磺酰基)吡啶-2-基)乙醇盐酸盐(5.4g,20.2mmol)的无水DCM(120mL)溶液中加入Et3N(8.2g,81.0mmol)。然后将混合物溶液冷却至0℃并分批加入HATU(6.7g,17.6mmol)。将混合物在25℃和N2下搅拌4小时。LC-MS显示反应完全。将混合物与另外3.6g批料合并,用DCM(100mL)稀释,用水(2×100mL)和盐水(200mL)洗涤。将有机层在用水Na2SO4干燥,过滤并减压浓缩。将残余物通过硅胶柱色谱法纯化,用石油醚/EtOAc=1/4洗脱,得到外消旋化合物(12.4g,90%)。通过SFC分离(AD)、碱性制备型HPLC分离来分离该外消旋化合物,然后冷冻干燥分离外消旋化合物,得到呈白色固体的(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-301.1,6.73g,49%,EE=99.54%)和(S)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-130.2,1.17g,9%,EE=98.84%)。
在SFC分离之前:异构体SFC tR=4.83和5.37min,10min色谱(色谱柱:AD-H;方法名称:AD_3_IPA_DEA_5_40_25ML,ee=66%)
SFC分离条件:
仪器:Thar 80
色谱柱:AD 250mm*30mm,10um
流动相:A:超临界CO2,B:IPA(0.05%NH3H2O),A∶B=70∶30,200mL/min
柱温:38℃
喷嘴压力:100Bar
喷嘴温度:60℃
蒸发器温度:20℃
修剪器温度:25℃
波长:220nm
化合物编号I-130.1(6.73g,48.8%,EE=99.54%),呈白色固体LC-MS方法3 tR=0.729min,MS(ESI)m/z 613.0[M+H]+。1H NMR(CDCl3400MHz):δ9.05(s,1H),8.43(s,1H),8.22(dd,J=2.0,8.4Hz,1H),7.96(d,J=8.8Hz,1H),7.86(d,J=6.8Hz,1H),7.73(d,J=8.0Hz,1H),7.42(d,J=8.8Hz,1H),7.10-6.92(m,2H),6.59(d,J=8.0Hz,1H),5.62(s,2H),5.52-5.40(m,1H),4.35-4.15(m,1H),4.08-3.90(m,1H),3.51-3.44(m,1H),3.18(q,J=7.6Hz,2H),1.35(t,J=7.6Hz,3H)。异构体SFC tR=5.395min,10min色谱(色谱柱:AD-3;方法名称:
AD_3_IPA_DEA_5_40_25mL_10min.met,ee=99.54%)
碱性制备型HPLC方法:
流动相A:含有0.05%NH3H2O的水溶液
流动相B:MeCN
流速:120mL/min
检测:UV 220nm
色谱柱:Phenomenex Gemini150*25mm*10um
柱温:40℃
化合物编号I-130.2(1.17g,8.5%,EE=98.84%),呈白色固体LC-MS方法3 tR=0.728min,MS(ESI)m/z 613.0[M+H]+。1H NMR(CDCl3400MHz):δ9.05(s,1H),8.43(s,1H),8.21(dd,J=2.4,8.0Hz,1H),7.96(d,J=8.4Hz,1H),7.87(d,J=7.2Hz,1H),7.73(d,J=8.0Hz,1H),7.42(d,J=8.8Hz,1H),7.07-6.97(m,2H),6.59(d,J=8.0Hz,1H),5.62(s,2H),5.51-5.43(m,1H),4.27-4.20(m,1H),4.10-4.04(m,1H),3.55-3.46(m,1H),3.18(q,J=7.6Hz,2H),1.34(t,J=7.6Hz,3H)。异构体SFC tR=4.840min,10min色谱(色谱柱:AD-3;方法名称:
AD_3_IPA_DEA_5_40_25mL_10min.met,ee=98.84%)
碱性制备型HPLC方法:
流动相A:含有0.05%NH3H2O的水溶液
流动相B:MeCN
流速:120mL/min
检测:UV 220nm
色谱柱:Gemini 150×255u
柱温:40℃
用5%HCl水溶液(约20mL)稀释化合物编号I-130.1(0.5g)的MeCN(5mL)溶液,直至溶液变为乳状并立即在干冰/丙酮浴中冷冻。将所得的固体冻干,得到呈褐色固体的I-130.1盐酸盐。1H NMR(CD3OD 400MHz):δ9.20(s,1H),8.79(d,1H),8.48(s,1H),8.24(d,1H),8.03(d,1H),7.67(d,1H),7.10-7.21(m,2H),6.89(d,1H),5.82(s,2H),5.43(m,1H),4.15(m,2H),3.40(q,2H),1.27(t,3H)。
通过将醚蒸气扩散到冻干I-130.1盐酸盐(3mg-5mg)的MeCN(0.25mL)溶液中,获得晶种。
用Et2O(12mL)稀释冻干I-130.1盐酸盐(1.80g)的MeCN(36mL)溶液,并加入晶种。静置过夜后,过滤收集固体,并在高度真空下干燥,得到呈白色固体的I-130.1盐酸盐(1.39g),熔点为139℃-142℃。该物质具有图1所示的X射线粉末衍射图案。
使用Bruker D8Advance X射线衍射仪进行XRPD分析,所述衍射仪使用Cu辐射源在40kV、40mA下通过具有0.60mm/2.5°的发散狭缝的Ni过滤器操作。
用己烷(7mL)稀释I-130.1游离碱(0.30g)的EtOAc(3mL)溶液,并使其在松散覆盖的状态下静置5天。过滤得到固体(224mg),熔点为149℃-152℃。该物质具有图2所示的X射线粉末衍射图案。
实施例4
(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-N- (1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-131.1)
和
(S)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-N-
(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-131.2)
在0℃下,向1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-1H-苯并[d]咪唑-5-羧酸(8.5g,22.25mmol)和Et3N(6.7g,66.75mmol)的CH2Cl2(350mL)溶液中加入(R)-2-氨基-2-(5-(乙基磺酰基)吡啶-2-基)乙醇盐酸盐(7.7g,28.83mmol)。然后将混合物在0℃下搅拌5分钟。分批加入HATU(10.1g,26.7mmol)。将混合物在0℃-16℃下搅拌3小时。LC-MS显示反应完全。将混合物与另外13.2g批料合并,用水(3×300mL)和盐水(300mL)洗涤,用无水Na2SO4干燥,过滤并减压浓缩。将残余物通过硅胶柱色谱法纯化,用石油醚/EtOAc=1/4-0/1洗脱,通过SFC(AD)、制备型HPLC分离进行分离,并干燥冷冻,得到呈白色固体的(R)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-131.1,7.96g,28%,中性制备型HPLC分离)和(S)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二氟甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-131.2,1.71g,6%,碱性制备型HPLC分离)。
在SFC分离之前:异构体SFC tR=0.556和0.760min,3min色谱(色谱柱:AD-H;方法名称:AD-H_3UM_4_40_4ML_3MIN.M,ee=68%)
SFC分离条件:
仪器:Thar 80
色谱柱:AD 250mm*30mm,10um
流动相:A:超临界CO2,B:IPA(0.05%NH3H2O),A∶B=60∶40,200mL/min
柱温:38℃
喷嘴压力:100Bar
喷嘴温度:60℃
蒸发器温度:20℃
修剪器温度:25℃
波长:220nm
化合物编号I-131.1(7.96g,25%),呈白色固体LC-MS方法3 tR=0.713min,MS(ESI)m/z 595.1[M+H]+。1H NMR(CDCl3400MHz):δ9.04(d,J=2.0Hz,1H),8.37(s,1H),8.21(dd,J=2.4,8.0Hz,1H),7.90(d,J=8.8Hz,1H),7.84(d,J=6.8Hz,1H),7.72(d,J=8.4Hz,1H),7.38(d,J=8.4Hz,1H),7.02(t,J=52.4Hz,1H),7.04-6.96(m,2H),6.64(d,J=8.0Hz,1H),5.66(s,2H),5.49-5.46(m,1H),4.23(dd,J=4.0,11.2Hz,1H),4.23(dd,J=4.0,11.6Hz,1H),3.17(q,J=7.6Hz,2H),1.34(t,J=7.6Hz,3H)。异构体SFC tR=0.814min,3min色谱(色谱柱:AD-H;方法名称:AD-H_3UM_4_40_4ML_3MIN.M,ee=99.47%)
中性制备型HPLC方法:
流动相A:含有10mM NH4HCO3的水溶液
流动相B:MeCN
流速:120mL/min
检测:UV 220nm
色谱柱:Phenomenex luna C18 250*50mm*10um
柱温:40℃
化合物编号I-131.2(1.71g,5%),呈白色固体LC-MS方法3 tR=0.719min,MS(ESI)m/z 595.0[M+H]+。1H NMR(CDCl3400MHz):δ9.04(s,1H),8.36(s,1H),8.18(d,J=8.4Hz,1H),7.89(d,J=8.4Hz,1H),7.87-7.84(m,1H),7.71(d,J=8.0Hz,1H),7.38(d,J=8.4Hz,1H),7.01(t,J=52.4Hz,1H),7.03-6.95(m,2H),6.64(d,J=8.0Hz,1H),5.65(s,2H),5.49-5.45(m,1H),4.25-4.21(m,1H),4.06-4.03(m,1H),3.16(q,J=7.6Hz,2H),1.33(t,J=7.6Hz,3H)。异构体SFC tR=0.577min,3min色谱(色谱柱:AD-H;方法名称:AD-H_3UM_4_40_4ML_3MIN.M,ee=95.60%)
碱性制备型HPLC方法:
流动相A:含有0.05%NH3H2O的水溶液
流动相B:MeCN
流速:110mL/min
检测:UV 220nm
色谱柱:Phenomenex Synergi Max-RP 250*50mm*10um
柱温:40℃
用Et2O(12mL)稀释冻干I-130.1.盐酸盐(2.03g)的MeCN(36mL)溶液,并加入I-130.1盐酸盐的晶种。静置过周末后,将混合物置于冰箱中2周。过滤收集白色固体,并在高度真空下干燥,得到I-131.1盐酸盐(1.30g),熔点为129℃-134℃。该物质具有图6所示的X射线粉末衍射图案。
实施例5
(R)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5- (乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-132.1)
和
(S)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-
(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-132.2)
在0℃和N2下,向2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-1H-苯并[d]咪唑-5-羧酸(3.6g,9.32mmol)的无水CH2Cl2(150mL)溶液中分批加入(R)-2-氨基-2-(5-(乙基磺酰基)吡啶-2-基)乙醇盐酸盐(3.2g,12.0mmol)、Et3N(2.83g,28mmol)和HATU(4.6g,12.12mmol)。将混合物在22℃下搅拌1小时。LC-MS显示反应完全。向混合物(与另外的5.5g批料一起)中加入水(300mL),并用CH2Cl2(3×300mL)洗涤。将合并的有机层用盐水(500mL)洗涤,用无水Na2SO4干燥,过滤并减压浓缩。将残余物通过硅胶柱色谱法纯化,用CH2Cl2∶MeOH=50∶1-25∶1洗脱,得到呈黄色固体的2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(11.72g),其通过SFC分离(纤维素-2)得到(R)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-132.1,6.2g+2.4g)和(S)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-132.2,1.6g)。
将I-132.1(6.2g)通过碱性制备型HPLC分离进行纯化,并干燥冷冻,得到呈白色固体的(R)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-132.1,4.88g,35%)。
将I-132.2(1.6g)通过碱性制备型HPLC分离进行纯化,并干燥冷冻,得到呈白色固体的(S)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-132.2,784mg,6%)。
将I-132.1(2.4g)通过HCl制备型HPLC分离进行纯化,并干燥冷冻,得到呈白色固体的(R)-2-环丁基-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(5-(乙基磺酰基)吡啶-2-基)-2-羟乙基)-1H-苯并[d]咪唑-5-甲酰胺(I-132.1,1.29g,9%)。
在SFC分离之前:异构体SFC tR=7.525和10.107min,12min色谱(色谱柱:CELLULOSE-2;方法名称:CELLULOSE-2_ETOH(DEA)_40_2_12mn.met,ee=67.57%)。
SFC分离条件:
仪器:Berger MultiGramTM SFC,Mettler Toledo Co,Ltd
色谱柱:C2 250mm*50mm,10um
流动相:A:超临界CO2,B:EtOH(0.05%NH4OH),A∶B=60∶40,200mL/min
柱温:40℃
喷嘴压力:100Bar
喷嘴温度:60℃
蒸发器温度:20℃
修剪器温度:25℃
波长:220nm
化合物编号I-132.1(4.88g,游离碱),呈白色固体LC-MS方法3 tR=0.649min,MS(ESI)m/z 599.1[M+H]+1H NMR(CDCl3400MHz):δ9.01(s,1H),8.34(s,1H),8.07-7.97(m,2H),7.84(d,J=12.4Hz,1H),7.67(d,J=8.0Hz,1H),7.29(s,1H),7.03(d,J=7.6Hz,1H),6.97(t,J=8.0Hz,1H),6.46(d,J=8.0Hz,1H),5.52-5.35(m,1H),5.35(s,2H),4.60-4.36(m,1H),4.31-4.25(m,1H),4.11-4.05(m,1H),3.76-3.68(m,1H),3.16(q,J=7.6Hz,2H),2.61-2.50(m,2H),2.48-2.31(m,2H),2.19-2.08(m,1H),2.07-1.98(m,1H),1.33(t,J=7.2Hz,3H)。异构体SFC tR=10.480min,14min色谱(色谱柱:CELLULOSE-2;方法名称:CELLULOSE-2_ETOH(DEA)_40_2,5M-14min.met,ee=99.66%)。
碱性制备型HPLC方法
流动相A:水(0.05%氢氧化铵v/v)-ACN
流动相B:CH3CN
流速:150mL/min
检测:UV 220nm/254nm
色谱柱:Phenomenex Synergi Max-RP 250*50mm*10um
柱温:30℃
用己烷(3mL)稀释I-132.1游离碱(0.25g)的EtOAc(3mL)溶液,并使其在松散覆盖的状态下静置。过滤并真空干燥,得到呈固体的I-132.1(177mg),熔点为96℃-110℃。该物质具有图7所示的X射线粉末衍射图案。
化合物编号I-132.2(0.784g,游离碱),呈白色固体LC-MS方法3 tR=0.653min,MS(ESI)m/z 599.2[M+H]+1H NMR(CDCl3400MHz):δ8.91(s,1H),8.37(s,1H),8.16(d,J=7.6Hz,1H),7.87-7.78(m,2H),7.57(d,J=8.0Hz,1H),7.23(d,J=8.4Hz,1H),6.98(d,J=7.6Hz,1H),6.92(t,J=8.0Hz,1H),6.42(d,J=8.0Hz,1H),5.52-5.41(m,1H),5.35-5.20(m,2H),5.15-4.93(m,1H),5.34(dd,J=3.6,11.6Hz,1H),4.10-4.02(m,1H),3.71-3.62(m,1H),3.08(q,J=7.6Hz,2H),2.61-2.52(m,2H),2.49-2.21(m,2H),2.15-1.91(m,2H),1.26(t,J=7.6Hz,3H)。异构体SFC tR=7.466min,13min色谱(色谱柱:CELLULOSE-2;方法名称:CELLULOSE-2_ETOH(DEA)_40_2,5M-13min.met,ee=95.17%)。
碱性制备型HPLC方法
流动相A:水(0.05%氢氧化铵v/v)-ACN
流动相B:CH3CN
流速:25mL/min
检测:UV 220nm/254nm
色谱柱:Phenomenex Gemini 150*25mm*10um
柱温:30℃
化合物编号I-132.1(1.29g,盐酸盐),呈白色固体LC-MS方法3tR=0.663min,MS(ESI)m/z 599.1[M+H]+1H NMR(CD3OD 400MHz):δ9.05(s,1H),8.43-8.36(m,1H),8.35-8.22(m,1H),8.16(d,J=7.2Hz,1H),7.88(d,J=8.8Hz,1H),7.83-7.22(m,1H),7.27-7.21(m,2H),7.17(d,J=7.2Hz,1H),5.88(s,2H),5.43(t,J=6.0Hz,1H),4.39-4.31(m,1H),4.12-4.03(m,2H),3.29-3.27(m,2H),2.66-2.51(m,4H),2.36-2.26(m,1H),2.17-2.06(m,1H),1.28(t,J=7.2Hz,3H)。异构体SFC tR=9.673min,13min色谱(色谱柱:CELLULOSE-2;方法名称:CELLULOSE-2_ETOH(DEA)_40_2,5M-13min.met,ee=99.77%)。
HCl制备型HPLC方法
流动相A:水(0.05%HCl)-ACN
流动相B:CH3CN
流速:120mL/min
检测:UV 220nm/254nm
色谱柱:Phenomenex Synergi Max-RP 250*50mm*10um
柱温:30℃
使用与实施例3、4和5类似的过程制备以下化合物。
实施例6
N-(4-(乙基磺酰基)苄基)-1-(2-氟-3-甲氧基苄基)-2-(三氟甲基)-1H-苯并[d]
咪唑-5-甲酰胺(I-136)
将3-氨基-N-(4-(乙基磺酰基)苄基)-4-((2-氟-3-甲氧基苄基)氨基)苯甲酰胺(16.5mg,mol)的TFA(2mL)溶液在70℃下搅拌3小时。浓缩后,通过制备型HPLC纯化残余物,得到呈油状物的标题化合物(6mg,31%)。1H NMR(d4-MeOH)δ1.20(s,3H),3.19(q,2H),3.87(s,3H),4.71(s,2H),5.75(s,2H),6.34-6.42(m,1H),6.96-7.10(m,2H),7.58-7.64(m,3H),7.88(d,2H),7.97(d,1H),8.38(s,1H)。LC-MS方法1 tR=1.63min,m/z=550。
使用类似的过程制备以下化合物
a用Boc2O处理粗产物,以再次引入Boc基团。
通过类似的过程制备以下化合物。
实施例7
1-(苯并[c][1,2,5]恶二唑-4-基甲基)-N-(4-(乙基磺酰基)苄基)-2-(三氟甲
基)-1H-苯并[d]咪唑-5-甲酰胺(I-151)
将N-(4-(乙基磺酰基)苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(37mg,90μmol)、苯并[c][1,2,5]恶二唑-4-基甲基甲磺酸酯(31mg,135μmol)、粉末状NaHCO3(23mg,0.27mmol)和无水DMF(2mL)的搅拌混合物在60℃下加热3小时。用EtOAc(90mL)稀释该混合物,用水(10mL)和盐水(10mL)洗涤,并用Na2SO4干燥。去除溶剂,得到油状物(111mg),将其通过制备型HPLC纯化,得到呈与所示区域异构体的1∶1混合物形式的标题化合物。LC-MS方法1tR=1.56min,m/z=545。
通过类似的过程制备以下化合物,同样为区域异构体的混合物形式。
实施例8
2-环丙基-N-(4-(乙基磺酰基)苄基)-1-(3-羟基-5-(三氟甲氧基)苄基)-1H-苯并
[d]咪唑-5-甲酰胺(I-153)
向经搅拌的、冰冷的2-环丙基-N-(4-(乙基磺酰基)苄基)-1-(3-甲氧基-5-(三氟甲氧基)苄基)-1H-苯并[d]咪唑-5-甲酰胺(28mg,48mol)的CH2Cl2(2mL)溶液中加入1M BBr3的CH2Cl2溶液(0.25mL,0.25mmol)。使混合物达到室温,搅拌过夜,并用MeOH(5mL)处理。浓缩该混合物,将残余物通过制备型HPLC纯化,得到TFA盐形式的2-环丙基-N-(4-(乙基磺酰基)苄基)-1-(3-羟基-5-(三氟甲氧基)苄基)-1H-苯并[d]咪唑-5-甲酰胺(11mg,40%)。1H NMR(CD3OD,400MHz)δ8.15(s,1H),8.05(d,1H),7.82(d,2H),7.72(d,1H),7.57(d,2H),6.57-6.65(m,2H),6.54(s,1H),5.72(s,2H),4.66(s,2H),3.10(q,2H),2.37-2.47(m,1H),1.25-1.45(m,4H),1.13(t,3H)。LC-MS方法1 tR=1.26min,m/z=574。
使用类似的过程由化合物编号I-119制备以下化合物:
实施例9
N-(4-(乙基磺酰基)苄基)-1-((1-(2,2,2-三氟乙基)哌啶-4-基)甲基)-2-(三氟
甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-155)
步骤1
将4-((5-((4-(乙基磺酰基)苄基)氨基甲酰基)-2-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)哌啶-1-羧酸叔丁酯(42mg,69μmol)的4∶1CH2Cl2/TFA(5mL)溶液在室温下搅拌2小时并浓缩,得到TFA盐形式的粗制N-(4-(乙基磺酰基)苄基)-1-(哌啶-4-基甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(53mg,定量)。LC-MS方法1 tR=0.74min,m/z=509。
步骤2
向经搅拌的N-(4-(乙基磺酰基)苄基)-1-(哌啶-4-基甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺TFA盐(18mg,29μmol)和i-Pr2NEt(21μL,0.12mmol)的MeCN(1mL)溶液中加入2,2,2-三氟乙基三氟甲磺酸酯(5μL,35μmol)。将混合物在室温下搅拌过夜,并通过制备型HPLC纯化,得到TFA盐形式的标题化合物(8mg,39%)。1H NMR(CD3OD,400MHz)δ8.38(s,1H),8.03(d,1H),7.82-7.95(m,3H),7.62(d,2H),4.71(s,2H),4.40(d,2H),3.68(q,2H),3.36(m,2H),3.19(q,2H),2.78(t,2H),2.15-2.30(m,1H),1.60-1.78(m,2H),1.18(t,3H)。LC-MS方法1 tR=1.26min,m/z=591。
使用类似的过程制备以下化合物。
实施例10
N-(4-(乙基磺酰基)苄基)-1-((1-(5-氟嘧啶-2-基)哌啶-4-基)甲基)-2-(三氟甲
基)-1H-苯并[d]咪唑-5-甲酰胺(I-158)
将N-(4-(乙基磺酰基)苄基)-1-(哌啶-4-基甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺TFA盐(18mg,29μmol)、2-氯-5-氟嘧啶(11.5mg,86μmol)和i-Pr2NEt(21μL,0.12mmol)的MeCN(1mL)溶液在100℃的微波中加热3小时。通过制备型HPLC得到TFA盐形式的标题化合物(5mg,23%)。1H NMR(CD3OD,400MHz)δ8.40(s,1H),8.28(s,2H),8.08(d,1H),7.86-7.98(m,3H),7.68(d,2H),4.77(s,2H),4.41(d,2H),3.15-3.40(m,4H),2.78-2.90(m,2H),2.28-2.42(m,1H),1.58-1.68(m,2H),1.35-1.50(m,2H),1.25(t,3H)。LC-MS方法1 tR=1.54min,m/z=605。
使用类似的过程制备以下化合物。
实施例11
2-((1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-
苯并[d]咪唑-5-甲酰氨基)甲基)-5-(乙基磺酰基)吡啶1-氧化物(I-161)
向经搅拌的1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-((5-(乙基磺酰基)吡啶-2-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(28mg,49μmol)的CH2Cl2(2mL)溶液中加入m-CPBA(16mg,65μmol,假定70%纯度)。将该混合物在室温下搅拌过夜,浓缩,并通过制备型HPLC纯化残余物,得到标题化合物(5.6mg,19%)。1H NMR(CD3OD,400MHz)δ8.78(s,1H),8.46(s,1H),8.03(d,1H),7.93(d,1H),7.75(d,1H),7.68(d,1H),7.08-7.21(m,2H),6.86(d,1H),5.83(s,2H),4.83(s,2H),3.35(q,2H),1.25(t,3H)。LC-MS方法1tR=1.43min,m/z=599。还回收起始物质(14mg,50%)。
实施例12
1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(二甲基氨基)-N-(4-
(乙基磺酰基)苄基)-1H-苯并[d]咪唑-5-甲酰胺(I-162)
将3-氨基-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)-N-(4-(乙基磺酰基)苄基)苯甲酰胺(52mg,0.1mmol)、光气氯化亚胺(34mg,0.21mmol)、i-Pr2NEt(0.3mL,1.7mmol)和1,2-二氯乙烷(1mL)的混合物在室温下搅拌4小时。将该混合物用EtOAc(90mL)稀释,用水(10mL)、饱和NaHCO3水溶液(5mL)和盐水(5mL)洗涤,并用Na2SO4干燥。去除溶剂,得到油状物(50mg)。通过制备型HPLC得到呈油状物的标题化合物(5mg,7%)。1H NMR(CD3OD,400MHz)δ7.99(s,1H),7.82-7.88(m,3H),7.62(d,2H),7.47(d,1H),7.15-7.27(m,2H),7.08(d,1H),5.72(s,2H),4.68(d,2H),3.30(s,6H),3.18(q,2H),1.20(t,3H)。LC-MS方法1 tR=1.30min,m/z=557。
实施例13
1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-((1-((2-羟乙基)磺酰
基)哌啶-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-163)
向2-((4-((1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺基)甲基)哌啶-1-基)磺酰基)乙酸甲酯(化合物编号I-74,25mg,0.0396mmol)在MeOH(1mL)中的混合物中加入NaBH4(8mg,0.1978mmol)。将混合物在室温和N2下搅拌2小时。LC-MS显示观察到63%的产物。用饱和NH4Cl水溶液(15mL)淬灭混合物,然后用EtOAc(3×15mL)萃取。将合并的有机层用无水Na2SO4干燥,过滤并减压浓缩。通过采用CH2Cl2/丙酮=2/1的制备型TLC和碱性制备型HPLC分离纯化残余物,然后直接冷冻干燥,得到呈白色固体的1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-((1-((2-羟乙基)磺酰基)哌啶-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-163,9.90mg,41%)。LC-MS方法3 tR=0.731min,MS(ESI)m/z 605.0[M+H]+。1H NMR(CDCl3400MHz):δ8.26(s,1H),7.90(d,J=8.8Hz,1H),7.39(d,J=8.8Hz,1H),7.06-6.96(m,2H),6.57(d,J=8.0Hz,1H),6.45-6.38(m,1H),5.59(s,2H),4.11-4.04(m,2H),3.83(d,J=12.4Hz,2H),3.41(t,J=5.6Hz,2H),3.13(t,J=5.6Hz,2H),2.90-2.75(m,3H),1.93-1.81(m,3H),1.45-1.32(m,2H)。
碱性制备型HPLC方法:
流动相A:含有0.05%氨的水溶液
流动相B:MeCN
流速:25mL/min
检测:UV 220nm
色谱柱:Gemini 150*255u
柱温:40℃
实施例14
(S)-3-(1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-
1H-苯并[d]咪唑-5-甲酰氨基)-3-(4-(乙基磺酰基)苯基)丙酸(I-165)
步骤1
按照与实施例2所述类似的条件制备(S)-3-(1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰氨基)-3-(4-(乙基磺酰基)苯基)丙酸甲酯。
步骤2
在与制备例21步骤2所述类似的条件下,完成甲酯的水解,得到I-165。1H NMR(CDCl3400MHz):δ8.49(s,1H),8.24(s,1H),7.78(d,J=8.4Hz,1H),7.57(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),7.23(d,J=8.8Hz,1H),6.90-6.80(m,2H),6.45(d,J=7.6Hz,1H),5.55-5.41(m,3H),4.85-4.70(m,2H),2.95-2.75(m,3H),1.00(t,J=7.2Hz,3H)。
按照类似的过程制备下面所示的化合物。
实施例15
(S)-1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(1-(4-(乙基磺酰
基)苯基)-3-(甲基氨基)-3-氧代丙基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-167)
按照与实施例2类似的过程,由I-165制备标题化合物。1H NMR(CDCl3400MHz):δ9.24(d,J=7.2Hz,1H),8.53(s,1H),7.98(d,J=8.4Hz,1H),7.85(d,J=8.4Hz,2H),7.56(d,J=8.4Hz,2H),7.40(d,J=8.4Hz,1H),7.06-6.98(m,2H),6.58(d,J=8.0Hz,1H),5.62(s,2H),5.57-5.51(m,2H),3.09(q,J=7.6Hz,2H),2.92(dd,J=4.8,14.4Hz,1H),2.73(d,J=4.4Hz,3H),2.63(dd,J=4.4,14.8Hz,1H),1.28(t,J=7.6Hz,3H)。
通过类似的过程制备以下化合物。
实施例16
N-(1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯
并[d]咪唑-5-基)-2-(4-(乙基磺酰基)苯基)-2-羟乙酰胺(I-170)
步骤1
遵循与实施例1类似的过程。LC-MS方法1 tR=2.03min,m/z=564(M+H)。
步骤2
用过硫酸氢钾(3当量)处理0.05M硫醚的1∶1MeCN/H2O溶液,并在室温下搅拌过夜。浓缩该混合物。用EtOAc(2×)萃取含水残余物。用盐水洗涤所合并的EtOAc层,用Na2SO4干燥并浓缩,得到粗制砜。LC-MS方法1tR=1.79min,m/z=596(M+H)。
步骤3
按照与实施例13类似的过程,得到I-170。1H NMR(CD3OD,400MHz)δ8.20(s,1H),7.92(d,2H),7.85(d,2H),7.63(d,1H),7.50(d,1H),7.07-7.18(m,2H),6.80(d,1H),5.76(s,2H),5.32(s,1H),3.20(q,2H),1.30(t,3H)。在手性柱上通过色谱法分离对映异构体(I-170.1和I-170.2)。
实施例17
1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-((4-甲基-1-(甲基磺
酰基)-1,4-二氮杂环庚烷-5-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-171)
实施例18
1-((2,3-二氢苯并呋喃-4-基)甲基)-N-(4-(乙基磺酰基)苄基)-2-(三氟甲基)-
1H-苯并[d]咪唑-5-甲酰胺(I-172)
在室温下,在存在Pd(OH)2(催化量)的情况下,将I-95(8mg)的4∶2∶1EtOH/H2O/HOAc(3.5mL)溶液在H2(1atm,气球)下搅拌过夜。通过制备型HPLC得到标题化合物(1.1mg)。1HNMR(CD3OD,400MHz)δ8.40(s,1H),7.94(d,1H),7.87(d,2H),7.64(d,2H),7.50(d,1H),6.99(t,1H),7.68(d,2H),6.19(d,1H),5.66(s,2H),4.73(d,2H),4.55(t,2H),3.19(q,2H),3.05(t,2H),1.20(t,3H)。
实施例19
1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-5-((4-(乙基磺酰基)苄
基)氨基甲酰基)-1H-苯并[d]咪唑-2-羧酸甲酯(I-173)
步骤1
在18℃下,向3-氨基-4-(((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)氨基)-N-(4-(乙基磺酰基)苄基)苯甲酰胺(47mg,0.093mmol)、DIPEA(72mg,0.56mmol)和DMAP(5.7mg,0.047mmol)在DCE(4mL)中的混合物中加入2,2-二氯-2-甲氧基乙酸甲酯(48mg,0.28mmol)。在18℃下搅拌0.5小时、在40℃下搅拌1小时并在60℃下搅拌0.5小时后,LC-MS显示大部分是产物。用H2O(25mL)和DCM(30mL)稀释该混合物。分配后,将有机层用Na2SO4干燥,过滤,减压浓缩,通过中性制备型HPLC分离纯化并冷冻干燥,得到呈白色固体的标题化合物(11.60mg,23%)。
LC-MS方法3 tR=0.725min,MS(ESI)m/z 572.0[M+H]+。1H NMR(CDCl3400MHz):δ8.08(d,J=2.0Hz,1H),7.87(d,J=8.0Hz,3H),7.55(d,J=8.0Hz,2H),7.32(d,J=8.4Hz,1H),7.00-6.98(m,2H),6.92-6.91(m,1H),6.70-6.69(m,1H),5.58(s,2H),4.77(d,J=6.0Hz,2H),4.15(s,3H),3.11(q,J=7.6Hz,2H),1.28(t,J=7.6Hz,3H)。
中性制备型HPLC方法:
流动相A:含有10mM NH4HCO3的水溶液
流动相B:CH3CN
流速:22mL/min
检测:UV 220nm/254nm
色谱柱:Phenomenex Synergi C18 150*25*10um
柱温:30℃
实施例20
1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(2-(4-(乙基磺酰基)
苯基)-1,3-二羟基丙-2-基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(I-174)
步骤1
向经搅拌的1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-羧酸(137mg,0.34mmol)、3-(4-(乙硫基)苯基)氧杂环丁烷-3-胺盐酸盐(126mg,0.51mmol)和i-Pr2NEt(0.25mL,1.4mmol)的CH2Cl2(5mL)溶液中加入固体HATU(0.26g,0.69mmol)。将混合物搅拌1小时,用EtOAc(90mL)稀释,用5%HCl水溶液(10mL)、饱和NaHCO3水溶液(10mL)和盐水(10mL)洗涤,并用Na2SO4干燥。去除溶剂,得到油状物(570mg)。在12g硅胶柱上进行色谱法,用0-100%EtOAc的己烷溶液梯度洗脱,得到油状物(142mg)。通过制备型HPLC(MeCN的水溶液梯度,0.1%TFA)纯化23mg该油状物部分,得到呈固体的粗制1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)-N-(2-(4-(乙硫基)苯基)-1,3-二羟基丙-2-基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(16mg)。LC-MS方法1tR=1.26min,m/z=610。
步骤2
向经搅拌的、冰冷的粗制1-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)甲基)N-(2-(4-(乙硫基)苯基)-1,3-二羟基丙-2-基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺(16mg,26μmol)的CH2Cl2(2mL)溶液中加入m-CPBA(≤77%纯,12mg,≤53μmol)。将混合物在冰浴中搅拌1小时,并加入第二份m-CPBA(≤77%,16mg,≤70μmol)。将混合物在室温下搅拌2小时,用CH2Cl2(40mL)稀释,用1M NaOH水溶液(5mL)洗涤,用Na2SO4干燥并浓缩,得到油状物(19mg)。通过制备型HPLC得到呈油状物的标题化合物(10mg,59%)。LC-MS方法1tR=1.11min,m/z=642。1H NMR(CD3OD,400MHz):δ8.43(s,1H),8.02-8.08(m,3H),7.63(d,2H),7.63(d,1H),7.10-7.20(m,2H),6.87(d,1H),5.81(s,2H),5.0(d,1H),4.91(d,1H),4.15(d,1H),4.04(d,1H),3.21(q,2H),1.16(t,3H)。
LC-MS数据
所选化合物的1H NMR数据
生物学测定
放射性配体RORγ结合测定(测定1)
在无细胞竞争性测定中,使用可商购获得的放射性配体(RL)、25-羟基[26,27-3H]-胆固醇(珀金埃尔默公司(PerkinElmer),产品目录号NET674250UC),针对表达为6xHis-谷胱甘肽-S-转移酶(GST)融合体的重组RORγ配体结合域(LBD)蛋白上的配体结合位点,测试本文所述的化合物结合RORγ的能力。该测定在96孔SPA板(珀金埃尔默公司(PerkinElmer),产品目录号1450-401)中的50mM HEPES缓冲液(pH 7.4)中进行,该缓冲液含有150mM NaCl、5mM MgCl2、10%(v/v)甘油、2mM CHAPS、0.5mMβ-辛基吡喃葡萄糖苷和5mMDTT。将测试的化合物溶于DMSO中,并且在相同溶剂中制备化合物的半对数(3.162x)连续稀释液。将两微升DMSO溶液与28μL的8.6nM 25-羟基[26,27-3H]-胆固醇和50μL的24nM RORγLBD混合。将板在700rpm下摇动20min,并在室温下温育10min,然后加入40μL聚赖氨酸YSiSPA微珠(珀金埃尔默公司(PerkinElmer),产品目录号RPNQ0010),以实现每孔50μg微珠。将板在定轨振荡器上温育20min,然后在室温下在不搅拌的情况下保持10min。将氚β辐射的SPA信号记录在PerkinElmer Microbeta读板器上。基于用DMSO对照获得的高信号计算抑制百分比值,并且用10μM标准RORγ反向激动剂T0901317(西格玛奥德里奇公司(SigmaAldrich),产品目录号T2320)获得低信号。将抑制百分比对浓度数据拟合到四参数模型中,并且通过拟合计算IC50值,作为对应于剂量-响应曲线上的拐点的浓度。使用下面的等式计算抑制常数(Ki),其中[RL]为测定中的浓度,并且KD为25-羟基[26,27-3H]-胆固醇的解离常数:
Jurkat细胞中的RORγ 5xRORE测定(测定2)
在基于细胞的转录活性测定中测试本文所述化合物的RORγ反向激动剂活性。将分泌的荧光素酶用作Jurkat细胞(ATCC,产品目录号TIB-152)中全长RORγt的转录活性的报告因子。通过使用KpnI和HindIII限制性位点,将5个ROR应答组件(RORE)AAAGTAGGTCA(SEQ ID NO:1)的重复序列插入可商购获得的无启动子质粒pNL1.3[secNluc](普洛麦格公司(Promega),产品目录号N1021)中,构建报告基因质粒。购买RORγt的表达质粒(Geneocopoeia公司,产品目录号EX-T6988-M02)。使用LTX和PlusTM试剂(生命科技公司(Life Technologies),产品目录号15338-100),在培养基中用11μg的EX-T6988-MO2和26μg的报告基因质粒转染Jurkat细胞(3千万个细胞)。在37℃/5%CO2下温育5-6小时后,收集细胞,再悬浮在含有10%(v/v)脱脂FBS的无酚红培养基(Hyclone公司,产品目录号SH30855.03)中,并分配到96孔透明底部组织培养板(CoStar公司,产品目录号3603)中,每孔80,000个细胞。将测试的化合物加入到相同培养基内的细胞中(DMSO的最终浓度为0.1%(v/v)),并将板在37℃/5%CO2下温育16-18小时。用测定试剂(Promega公司,产品目录号N1130)测定经调整的上清液中的荧光素酶活性。基于完全抑制和未抑制(DMSO)对照计算抑制百分比值,并且使用四参数非线性拟合模型将值相对于测试化合物的浓度回归分析,以得到IC50值。
测定1和2的结果示于下面的表3中。
表3
nt=未测试;+表示>1000nM;++表示100nM-1000nM;+++表示<100nM。
虽然我们已经描述了许多实施方案,但显然可以改变我们的基本示例以提供利用本发明化合物和方法的其他实施方案。因此,应当理解,本发明的范围由所附权利要求限定,而不是由通过示例表示的特定实施方案限定。
本申请通篇引用的所有参考文献的内容(包括参考文献、公布的专利、公布的专利申请和共同未决的专利申请)据此全文以引用方式明确地并入本文。除非另外定义,否则本文使用的所有技术和科学术语均符合本领域的普通技术人员公知的含义。
Claims (8)
1.一种式II的化合物:
或其可药用盐,其中:
R1选自(C1-C4)烷基、卤代(C1-C4)烷基和环丙基;
L2为CH2、CHMe或环丙基,
其中Cy1为苯基或吡啶基,其中的每一种被-SO2Rb取代;
Cy2为芳基、单环杂芳基或单环杂环基,其中的每一种任选地被独立地选自R6的1至3个基团取代;
每个R6独立地选自卤素、-CN、-ORc、(C1-C4)烷基、任选地被1至3个卤素取代的(C1-C4)烷基、-C(=O)ORc和进一步任选地被一种或多种卤素取代的杂芳基;
R7和R8为氢;
Rb为任选地被OH取代的(C1-C3)烷基;
每个Rc独立地选自氢以及任选地被一种或多种卤素取代的(C1-C3)烷基。
5.根据权利要求1所述的化合物,其中所述化合物选自以下的化合物或为其可药用盐:
1-(3,5-二甲氧基苄基)-N-(4-(乙基磺酰基)苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
1-(3-氰基-4-甲氧基苄基)-N-(4-(乙基磺酰基)苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
N-(4-(乙基磺酰基)苄基)-1-(4-(三氟甲氧基)苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
1-(4-氰基苄基)-N-(4-(乙基磺酰基)苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
N-(4-(乙基磺酰基)苄基)-1-(3-甲氧基苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
N-(4-(乙基磺酰基)苄基)-1-((2-甲氧基吡啶-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
1-(3-氰基苄基)-N-(4-(乙基磺酰基)苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
1-(1-(3-氰基苯基)环丙基)-N-(4-(乙基磺酰基)苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
(S)-1-(1-(3-氰基苯基)乙基)-N-(4-(乙基磺酰基)苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
(R)-1-(1-(3-氰基苯基)乙基)-N-(4-(乙基磺酰基)苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
1-(5-氰基-2-氟代苄基)-N-(4-(乙基磺酰基)苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
3-((5-((4-(乙基磺酰基)苄基)氨基甲酰基)-2-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)苯甲酸甲酯
2-环丙基-1-(3,5-二甲氧基苄基)-N-(4-(乙基磺酰基)苄基)-1H-苯并[d]咪唑-5-甲酰胺
2-环丙基-N-(4-(乙基磺酰基)苄基)-1-(4-(三氟甲氧基)苄基)-1H-苯并[d]咪唑-5-甲酰胺
2-环丙基-N-(4-(乙基磺酰基)苄基)-1-(2-(三氟甲氧基)苄基)-1H-苯并[d]咪唑-5-甲酰胺
(R)-3-((2-环丙基-5-((4-(乙基磺酰基)苄基)氨基甲酰基)-1H-苯并[d]咪唑-1-基)甲基)吡咯烷-1-羧酸叔丁酯
(R)-2-((2-环丙基-5-((4-(乙基磺酰基)苄基)氨基甲酰基)-1H-苯并[d]咪唑-1-基)甲基)吡咯烷-1-羧酸叔丁酯
2-环丙基-N-(4-(乙基磺酰基)苄基)-1-(3-(三氟甲氧基)苄基)-1H-苯并[d]咪唑-5-甲酰胺
2-环丙基-N-(4-(乙基磺酰基)苄基)-1-(2-甲氧基-3-(三氟甲基)苄基)-1H-苯并[d]咪唑-5-甲酰胺
2-环丙基-N-(4-(乙基磺酰基)苄基)-1-((1-(2,2,2-三氟乙基)-1H-吡唑-4-基)甲基)-1H-苯并[d]咪唑-5-甲酰胺
1-(3-氰基苄基)-2-环丙基-N-(4-(乙基磺酰基)苄基)-1H-苯并[d]咪唑-5-甲酰胺
2-环丙基-1-(3-(二氟甲氧基)苄基)-N-(4-(乙基磺酰基)苄基)-1H-苯并[d]咪唑-5-甲酰胺
2-环丙基-N-(4-(乙基磺酰基)苄基)-1-((1-(2,2,2-三氟乙基)-1H-吡唑-3-基)甲基)-1H-苯并[d]咪唑-5-甲酰胺
2-环丙基-N-(4-(乙基磺酰基)苄基)-1-(3-甲氧基-5-(三氟甲氧基)苄基)-1H-苯并[d]咪唑-5-甲酰胺
2-环丙基-N-(4-(乙基磺酰基)苄基)-1-((6-氧代-1-(2,2,2-三氟乙基)-1,6-二氢吡啶-3-基)甲基)-1H-苯并[d]咪唑-5-甲酰胺
2-环丙基-1-(2,3-二甲氧基苄基)-N-(4-(乙基磺酰基)苄基)-1H-苯并[d]咪唑-5-甲酰胺
1-(3,5-二甲氧基苄基)-N-(4-((2-羟乙基)磺酰基)苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
1-(3,5-二甲氧基苄基)-N-((5-(乙基磺酰基)吡啶-2-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
N-(4-(乙基磺酰基)苄基)-1-(2-氟-3-甲氧基苄基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
N-(4-(乙基磺酰基)苄基)-1-((4-甲基-6-(三氟甲基)嘧啶-2-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
N-(4-(乙基磺酰基)苄基)-1-((6-氧代-1-(2,2,2-三氟乙基)-1,6-二氢吡啶-2-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
4-((5-((4-(乙基磺酰基)苄基)氨基甲酰基)-2-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)哌啶-1-羧酸叔丁酯
N-(4-(乙基磺酰基)苄基)-1-((1-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
1-苄基-N-(4-(乙基磺酰基)苄基)-2-甲基-1H-苯并[d]咪唑-5-甲酰胺
2-环丙基-N-(4-(乙基磺酰基)苄基)-1-(3-羟基-5-(三氟甲氧基)苄基)-1H-苯并[d]咪唑-5-甲酰胺
2-环丙基-1-(2,3-二羟基苄基)-N-(4-(乙基磺酰基)苄基)-1H-苯并[d]咪唑-5-甲酰胺
N-(4-(乙基磺酰基)苄基)-1-((1-(2,2,2-三氟乙基)哌啶-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
(S)-2-环丙基-N-(4-(乙基磺酰基)苄基)-1-((1-(2,2,2-三氟乙基)吡咯烷-3-基)甲基)-1H-苯并[d]咪唑-5-甲酰胺
(R)-2-环丙基-N-(4-(乙基磺酰基)苄基)-1-((1-(2,2,2-三氟乙基)吡咯烷-2-基)甲基)-1H-苯并[d]咪唑-5-甲酰胺
N-(4-(乙基磺酰基)苄基)-1-((1-(5-氟嘧啶-2-基)哌啶-4-基)甲基)-2-(三氟甲基)-1H-苯并[d]咪唑-5-甲酰胺
(R)-2-环丙基-N-(4-(乙基磺酰基)苄基)-1-((1-(5-氟嘧啶-2-基)吡咯烷-3-基)甲基)-1H-苯并[d]咪唑-5-甲酰胺
(R)-2-环丙基-N-(4-(乙基磺酰基)苄基)-1-((1-(5-氟嘧啶-2-基)吡咯烷-2-基)甲基)-1H-苯并[d]咪唑-5-甲酰胺。
6.一种药物组合物,包含根据权利要求1至5中任一项所述的化合物或其可药用盐;以及可药用载体。
7.根据权利要求1至5中任一项所述的化合物、或其可药用盐、或根据权利要求6所述的药物组合物在制备用于治疗受治疗者中由ROR-γ介导的一种或多种疾病或障碍的制剂中的用途。
8.根据权利要求7所述的用途,其中所述疾病或障碍选自哮喘、慢性阻塞性肺病(COPD)、支气管炎、过敏性鼻炎、特应性皮炎、接触性皮炎、痤疮、囊性纤维化、同种异体移植排斥、多发性硬化症、硬皮病、关节炎、类风湿性关节炎、幼年型类风湿性关节炎、强直性脊柱炎、系统性红斑狼疮(SLE)、桥本氏病、胰腺炎、自身免疫性糖尿病、I型糖尿病、自身免疫性眼病、溃疡性结肠炎、克罗恩氏病、局限性肠炎、炎症性肠病(IBD)、炎症性肠综合征(IBS)、干燥综合征、视神经炎、肥胖症、肝脂肪变性、脂肪组织相关炎症、胰岛素抗性、II型糖尿病、视神经脊髓炎、重症肌无力、年龄相关性黄斑变性、干眼症、葡萄膜炎、格林-巴利综合征、银屑病、银屑病性关节炎(PsA)、类固醇抵抗型哮喘、格雷夫斯病、巩膜炎、重度抑郁症、季节性情绪障碍、PTSD、双相情感障碍、自闭症、癫痫、阿尔茨海默症、与睡眠和/或昼夜节律改变相关的CNS障碍、子宫内膜异位症、阻塞性睡眠呼吸暂停综合征(OSAS)、贝赛特氏症、皮肌炎、多肌炎、移植物抗宿主病、原发性胆汁性肝硬化、肝纤维化、非酒精性脂肪性肝病(NAFLD)、结节病、原发性硬化性胆管炎、自身免疫性甲状腺疾病、I型自身免疫性多内分泌腺病综合征、II型自身免疫性多内分泌腺病综合征、乳糜泻、神经脊髓炎、幼年特发性关节炎、系统性硬化症、心肌梗塞、肺动脉高压、骨关节炎、皮肤利什曼病、鼻窦息肉病和癌症。
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- 2017-01-27 UY UY0001037098A patent/UY37098A/es not_active Application Discontinuation
- 2017-01-27 RU RU2021133444A patent/RU2021133444A/ru unknown
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- 2017-01-27 JP JP2018539070A patent/JP6948333B2/ja active Active
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- 2017-01-27 MA MA055328A patent/MA55328A/fr unknown
- 2017-01-27 BR BR112018015273A patent/BR112018015273A2/pt not_active Application Discontinuation
- 2017-01-27 AU AU2017212577A patent/AU2017212577B2/en active Active
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CN109071509B (zh) | 2021-11-30 |
TW201734001A (zh) | 2017-10-01 |
US20190352286A1 (en) | 2019-11-21 |
RU2021133444A (ru) | 2021-11-29 |
AU2017212577A1 (en) | 2018-08-02 |
CN109071509A (zh) | 2018-12-21 |
AU2017212577B2 (en) | 2021-05-13 |
JP6948333B2 (ja) | 2021-10-13 |
EP3408268A1 (en) | 2018-12-05 |
TWI757266B (zh) | 2022-03-11 |
MA55328A (fr) | 2022-01-19 |
UY37098A (es) | 2017-08-31 |
US20210094940A1 (en) | 2021-04-01 |
BR112018015273A2 (pt) | 2018-12-18 |
RU2018127360A3 (zh) | 2020-04-06 |
WO2017132432A1 (en) | 2017-08-03 |
RU2760366C2 (ru) | 2021-11-24 |
JP2019503385A (ja) | 2019-02-07 |
SA518392101B1 (ar) | 2022-03-16 |
EP3408268B1 (en) | 2021-08-04 |
MA45646A (fr) | 2021-03-24 |
KR20180100697A (ko) | 2018-09-11 |
JP2021193131A (ja) | 2021-12-23 |
EP3408268B8 (en) | 2023-12-06 |
CA3011838A1 (en) | 2017-08-03 |
EP3939974A1 (en) | 2022-01-19 |
RU2018127360A (ru) | 2020-03-02 |
TW202220968A (zh) | 2022-06-01 |
US10829481B2 (en) | 2020-11-10 |
WO2017132432A8 (en) | 2017-08-31 |
MX2018009257A (es) | 2018-11-09 |
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