CN107108561A - 用作irak抑制剂的杂芳基化合物及其用途 - Google Patents
用作irak抑制剂的杂芳基化合物及其用途 Download PDFInfo
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- CN107108561A CN107108561A CN201580073060.9A CN201580073060A CN107108561A CN 107108561 A CN107108561 A CN 107108561A CN 201580073060 A CN201580073060 A CN 201580073060A CN 107108561 A CN107108561 A CN 107108561A
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- Prior art keywords
- bases
- compound
- pyrazoles
- methyl isophthalic
- pyrimidine
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Abstract
本发明涉及通式I所示的化合物及其药学上可接受的盐,它们可用作IRAK抑制剂。
Description
相关申请
本专利申请要求于2014年11月20日提交的的美国临时专利申请第62/082,231号的优先权。上述专利申请的全部内容纳入作为参考。
技术领域
本发明提供作为IRAK抑制剂的通式(I)所示的化合物、以及它们在治疗癌症和与IRAK过度表达有关的其他疾病(例如类风湿关节炎、系统性红斑狼疮或狼疮性肾炎)中的用途。
发明背景
激酶催化蛋白质、脂类、糖类、核苷类和其他细胞代谢产物的磷酸化,并且在真核细胞生理学的所有方面发挥关键作用。特别是,蛋白激酶和脂类激酶参与响应于细胞外介质或刺激(例如生长因子、细胞因子或趋化因子)来控制细胞的活化、生长、分化和生存的信号转导事件。一般而言,蛋白激酶被分类成两组,优先地磷酸化酪氨酸残基的组以及优先地磷酸化丝氨酸和/或苏氨酸残基的组。
激酶是抗炎药开发的重要治疗靶点(Cohen,2009年.Current Opinion inCellBiology21,1-8),例如涉及适应性免疫应答和天然免疫应答的和谐结合的激酶。令人特别感兴趣的激酶靶点是IRAK家族的成员。
白细胞介素-1受体相关激酶(IRAK)关键地涉及对控制炎症的细胞内信号转导网络的调节(Ringwood和Li,2008年.Cytokine42,1-7)。IRAK在许多细胞类型中得到表达并且可以介导来自各种细胞受体(包括toll样受体(TLR))的信号。IRAK4被认为是在白细胞介素-1(IL-1)受体和除TLR3外的所有toll样受体(TLR)的下游被活化的最初蛋白激酶,并且通过IRAKI的快速活化和IRAK2的较慢活化而在先天免疫系统中启动信号转导。IRAKI是首先通过对与IL-1I型受体共同免疫沉淀的IL-1依赖性激酶活性的生物化学纯化而确认(Cao等人,1996年.Science271(5252):1128-31)。IRAK2是通过在人表达序列标签(EST)数据库搜索与IRAKI同源的序列而得到确认(Muzio等人,1997年.Science278(5343):1612-5)。IRAK3(也称为IRAKM)是使用对具有通过筛选人植物凝集素活化外周血白细胞(PBL)CDNA库而发现与IRAKI显着同源性的多肽进行编码的小鼠EST序列而得到确认(Wesche等人,1999.J.Biol.Chem.274(27):19403-10)。IRAK4是利用IRAK样序列的数据库搜索和通用cDNA库的PCR而确认(Li等人,2002年.Proc.Natl.Acad.Sc1.USA99(8):5567-5572)。
表达IRAK4的催化无活性突变体而不是野生型激酶的小鼠对由若干TLR激动剂所引发腐败性休克完全耐受,并且它们在对IL-1的响应中受损害。由于遗传缺陷而缺乏IRAK4活性的儿童易发生由脓生成菌所引起的复发感染。IRAK-依赖性TLR和IL-1R似乎对于针对一些脓生成菌的儿童免疫力是至关重要的,但在针对成年人大部分感染的保护性免疫中却发挥多余的作用。因此,IRAK4抑制剂可用于治疗成年人的慢性炎症性疾病,并且不使他们对细菌和病毒感染太敏感(Cohen,2009年.CurrentOpinion in CellBiology21,1-8)。先已开发强效IRAK4抑制剂(Buckley等人,2008年.Bioorg MedChem Lett.18(12):3656-60)。IRAKI对于IRF7的TLR7介导和TLR9介导活化和干扰素-a(IFN-α)的生成是必不可少的,这表明IRAKI抑制剂可用于系统性红斑狼疮(SLE)的治疗。IRAK2在IRAK4的下游被活化并且在促炎性细胞因子生成中发挥作用。因此,IRAK2抑制剂可用于炎症性疾病。
发明内容
根据本发明的一个方面,提供通式(I)的化合物,
及其药学上可接受的衍生物、溶剂化物、盐、水合物和立体异构体。
根据本发明的另一方面,提供适用于治疗和/或预防与IRAK有关的疾病的通式(I)的化合物。根据本发明的另一方面,提供能够调节(特别是抑制)IRAK在哺乳动物(特别是人)疾病状态中的活性或功能的化合物。
根据本发明的另一方面,提供用于治疗和/或预防疾病的方法,该疾病是选自自身免疫、炎性疾病、心血管疾病、神经退行性疾病、细菌和病毒感染、过敏反应、哮喘、胰腺炎、多器官功能衰竭、肾脏病、血小板聚集、癌症、移植、精子活力、红细胞缺乏、移植物排斥、肺损伤、呼吸疾病和缺血性病症。
根据另一方面,本发明提供对IRAK-4和/或IRAK-1具有选择性的通式(I)的化合物。
根据另一方面,本发明提供对IRAK-4和IRAK-1具有选择性的通式(I)的化合物。
根据本发明的另一方面,提供一种包含至少一种通式(I)的化合物,优选地连同免疫调节剂的试剂盒或套组(set)。
优选地,该试剂盒由以下单独的包装所组成:
(a)有效量的通式(I)的化合物和/或其药学上有用的衍生物、溶剂化物、盐、水合物和立体异构体,包括其所有比例的混合物;以及
(b)有效量的另一种药物活性成分。
根据本发明的另一方面,提供一种用于合成通式(I)所示的化合物的方法。
某些实施例的详细描述
1.本发明化合物的一般定义
在某些方面,本发明提供IRAK抑制剂。在一些实施方案中,这样的化合物包括以本文描述的通式表示的那些或其药学上可接受的盐,其中定义和描述了各变量。
2.化合物和定义
本发明的化合物包括上文所概述的化合物,且按本文所揭示的类别、子类和种类进一步加以说明。除非另外指示,否则如本文所用的以下定义应适用。就本发明来说,化学元素是根据元素周期表(the Periodic Table of the Elements)(化学文摘社版本(CASversion),化学与物理手册(Handbook of Chemistry和Physics),第75版)来识别。另外,有机化学的一般原理描述于“有机化学(Organic Chemistry)”(托马斯·索瑞尔(ThomasSorrell),大学自然科学图书公司(University Science Books),索萨利托(Sausalito):1999)和“马奇高等有机化学(March′s Advanced Organic Chemistry)”(第5版,编辑:史密斯(SmitH,M.B.)和马奇(MarcH,J.),约翰威立父子出版公司(John Wiley&Sons),纽约(NewYork):2001)中,这些书籍的全部内容都以引用的方式并入本文中。
本文所用的术语“脂族”或“脂族基团”是指完全饱和或含有一个或一个以上不饱和单元的经取代或未经取代的直链(即无支链)或支链烃链,或完全饱和或含有一个或一个以上不饱和单元但不为芳香族的单环烃或双环烃,其具有单个连接点与分子的其余部分相连接。除非另外说明,否则脂肪族基含有1-6个脂肪族碳原子。在一些实施例中,脂肪族基含有1-5个脂肪族碳原子。在一些实施例中,脂肪族基含有1-4个脂肪族碳原子。在一些实施例中,脂肪族基含有1-3个脂肪族碳原子,并且在一些实施例中,脂肪族基含有1-2个脂肪族碳原子。在一些实施例中,“环脂肪族基”(或“碳环”或“环烷基”)是指完全饱和或含有一个或一个以上不饱和单元但非芳香族的单环C3-C6烃,其具有单个连接点与分子的其余部分相连接。示例性脂族基团是直链或支链的取代的或未取代的C1-C8烷基、C2-C8烯基、C2-C8炔基及其杂化物,例如(环烷基)烷基、(环烯基)烷基或(环烷基)烯基。
术语“低级烷基”是指C1-4直链或支链烷基。示例性低级烷基是甲基、乙基、丙基、异丙基、丁基、异丁基和叔丁基。
术语“低级卤代烷基”指的是含有一个或多个卤素原子的C1-4直链或支链烷基。
术语“杂原子”是指一个或一个以上氧、硫、氮、或磷(包括氮、硫、或磷的任何氧化形式;任何碱性氮的季铵化形式;杂环的可取代氮,例如N(如在3,4-二氢-2H-吡咯基)、NH(如在吡咯烷基中)或NR+(如在N-取代的吡咯烷基中))。
本文所用的术语“不饱和”是指具有一个或更多个不饱和单元的部分。
本文所用的术语“二价C1-8(或C1-6)饱和或不饱和的直链或支链烃链”是指二价亚烷基、亚烯基、亚炔基链,它们是此处定义的直链或支链。
术语“亚烷基”是指二价烷基。“亚烷基链”是聚亚甲基,即-(CH2)n-,其中n为正整数,优选为1到6、1到4、1到3、1到2或者2到3。经取代的亚烷基链是一个或一个以上亚甲基氢原子经取代基置换的聚亚甲基。合适的取代基包括下文关于经取代的脂肪族基所描述的取代基。
术语“亚烯基”是指二价烯基。取代的亚烯基链是含有至少一个双键的聚亚甲基,其中一个或多个氢原子被取代基置换。合适的取代基包括下文描述有关取代的脂族基团的那些。
术语“卤素”指F、Cl、Br或I。
单独使用或作为较大部分如“芳烷基”、“芳羟基”或“芳氧基烷基”的一部分使用的术语“芳基”指单环和双环系统,所述系统共具有5至14个环成员,其中系统中至少一个环是芳族,并且其中系统中各环含有3至7个环成员。术语“芳基”与术语“芳基环”互换使用。在本发明的某些实施方案中,“芳基”是指芳香环系统。示例性芳基是苯基、联苯基、萘基、蒽基等,其任选地包括一个或多个取代基。。如本文中所用,术语“芳基”的范围内也包括芳环与一个或一个以上非芳环稠合而成的基团,例如茚满基、邻苯二甲酰亚胺基、萘二甲酰亚胺基(naphthimidyl)、菲啶基或四氢萘基等。
单独使用或作为例如“杂芳烷基”或“杂芳羟基”等较大部分的一部分使用的术语“杂芳基”和“杂芳-”是指如下基团,其具有5到10个环原子,优选5、6或9个环原子;环系(cyclic array)中共享6、10或14个π电子;并且除碳原子外,还具有1到5个杂原子。术语“杂原子”是指氮、氧或硫,并包括氮或硫的任何氧化形式和碱性氮的任何季铵化形式。杂芳基包括(但不限于)噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、噻唑基、异噻唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吲哚嗪基、嘌呤基、萘啶基和蝶啶基。如本文所用的术语“杂芳基”和“杂芳-”也包括杂芳环与一个或一个以上芳环、环脂肪族环或杂环稠合而成的基团,其中连接基团或连接点在杂芳环上。非限制性实例包括吲哚基、异吲哚基、苯并噻吩基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯并噻唑基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、喹喔啉基、4H-喹嗪基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基、四氢喹啉基、四氢异喹啉基和吡啶并[2,3-b]-1,4-噁嗪-3(4H)-酮。杂芳基可为单环或双环的。术语“杂芳基”与术语“杂芳环”或“杂芳香族基”可互换使用,任一术语都包括任选经取代的环。术语“杂芳烷基”是指经杂芳基取代的烷基,其中烷基和杂芳基部分独立地任选经取代。
本文所用的术语“杂环”、“杂环基”、“杂环基团”和“杂环状环”可互换使用,并且是指饱和或部分不饱和并且除碳原子外还具有一个或一个以上、优选1到4个如上文所定义的杂原子的稳定的5到7元单环或7-10元双环杂环部分。当关于杂环的环原子而使用时,术语“氮”包括经取代的氮。举例来说,在具有0-3个选自氧、硫或氮的杂原子的饱和或部分不饱和环中,氮可能是N(如3,4-二氢-2H-吡咯基中)、NH(如吡咯烷基中)或+NR(如N-取代的吡咯烷基中)。
杂环可在任何杂原子或碳原子上连接到其侧基,从而形成稳定结构,并且任何环原子都可以任选经取代。这些饱和或部分不饱和杂环基的实例包括(但不限于)四氢呋喃基、四氢噻吩基、吡咯烷基、哌啶基、吡咯啉基、四氢喹啉基、四氢异喹啉基、十氢喹啉基、噁唑烷基、哌嗪基、二噁烷基、二氧戊环基、二氮杂卓基、氧氮杂卓基、硫氮杂卓基、吗啉基和奎宁环基。术语“杂环”、“杂环基”和“杂环部分”在本文中可互换使用,并且也包括杂环与一个或一个以上芳环、杂芳环或环脂肪族环稠合而成的基团,例如吲哚啉基、3H-吲哚基、色满基、菲啶基或四氢喹啉基,其中连接基团或连接点在杂环上。杂环基可为单环或双环的。术语“杂环基烷基”是指经杂环基取代的烷基,其中烷基和杂环基部分独立地任选经取代。
如本文所用的术语“部分不饱和”是指包括至少一个双键或三键的环部分。术语“部分不饱和”打算涵盖具有多个不饱和位点的环,但不打算包括如本文中所定义的芳基或杂芳基部分。
如本文所述,本发明的某些化合物可含有“任选经取代”的部分。一般来说,术语“经取代”之前无论是否存在术语“任选”,都意指指定部分的一个或一个以上氢经合适的取代基置换。“取代的”适用于结构上明确的或暗示的一个或多个氢原子(例如,至少指以及至少指 除非另外指示,否则“任选经取代”的基团可能在此基团的各可取代位置上都具有合适的取代基,并且当任何给定结构中的一个以上位置可经一个以上选自规定基团的取代基取代时,每个位置上的取代基可能相同或不同。本发明所预想的取代基组合优选是会形成稳定或化学上可行的化合物的取代基组合。如本文所用的术语“稳定”是指化合物在经受允许其制造、检测和在某些实施例中允许其回收、纯化以及用于达成一个或一个以上本文中所揭示的目的的条件时实质上不发生改变。
“任选经取代”的基团的可取代碳原子上的合适单价取代基独立地为氘;卤素;–(CH2)0–4R°;–(CH2)0–4OR°;-O(CH2)0-4R°,–O–(CH2)0–4C(O)OR°;–(CH2)0–4CH(OR°)2;–(CH2)0– 4SR°;–(CH2)0–4PH,其可经R°取代;–(CH2)0–4O(CH2)0–1PH,其可经R°取代;–CH=CHPH,其可经R°取代;–(CH2)0–4O(CH2)0–1-吡啶基,其可经R°取代;–NO2;–CN;–N3;-(CH2)0–4N(R°)2;–(CH2)0–4N(R°)C(O)R°;–N(R°)C(S)R°;–(CH2)0–4N(R°)C(O)NR°2;-N(R°)C(S)NR°2;–(CH2)0–4N(R°)C(O)OR°;–N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;–(CH2)0–4C(O)R°;–C(S)R°;–(CH2)0–4C(O)OR°;–(CH2)0–4C(O)SR°;-(CH2)0–4C(O)OSiR°3;–(CH2)0–4OC(O)R°;–OC(O)(CH2)0–4SR°,SC(S)SR°;–(CH2)0–4SC(O)R°;–(CH2)0–4C(O)NR°2;–C(S)NR°2;–C(S)SR°;–SC(S)SR°,-(CH2)0–4OC(O)NR°2;-C(O)N(OR°)R°;–C(O)C(O)R°;–C(O)CH2C(O)R°;–C(NOR°)R°;-(CH2)0–4SSR°;–(CH2)0–4S(O)2R°;–(CH2)0–4S(O)2OR°;–(CH2)0–4OS(O)2R°;–S(O)2NR°2;-(CH2)0–4S(O)R°;-N(R°)S(O)2NR°2;–N(R°)S(O)2R°;–N(OR°)R°;–C(NH)NR°2;–P(O)2R°;-P(O)R°2;-OP(O)R°2;–OP(O)(OR°)2;SiR°3;–(C1–4直链或支链亚烷基)O–N(R°)2;或(C1–4直链或支链亚烷基)C(O)O–N(R°)2,其中各R°可如下文所定义经取代并且独立地为氢、C1-6脂肪族基、-CH2Ph、-O(CH2)0-1Ph、-CH2-(5-6元杂芳基环)、或具有0-4个独立地选自氮、氧或硫的杂原子的5-6元饱和环、部分不饱和环或芳环,或不管以上定义,两个独立存在的R°连同插入其间的原子一起形成具有0-4个独立地选自氮、氧或硫的杂原子的3-12元饱和、部分不饱和或芳基单环或多环,此环可如下文所定义经取代。
R°(或由两个独立存在的R°连同插入其间的原子一起形成的环)上的合适单价取代基独立地为氘、卤素、–(CH2)0–2R●、–(卤代R●)、–(CH2)0–2OH、–(CH2)0–2OR●、–(CH2)0–2CH(OR●)2、-O(卤代R●)、–CN、–N3、–(CH2)0–2C(O)R●、–(CH2)0–2C(O)OH、–(CH2)0–2C(O)OR●、–(CH2)0–2SR●、–(CH2)0–2SH、–(CH2)0–2NH2、–(CH2)0–2NHR●、–(CH2)0–2NR● 2、–NO2、–SiR● 3、–OSiR● 3、-C(O)SR●、–(C1–4直链或支链亚烷基)C(O)OR●、或–SSR●,其中各R●未经取代或在前面有“卤代”的情况下仅经一个或一个以上卤素取代,并且独立地选自C1-4脂肪族基、–CH2Ph、–O(CH2)0–1Ph、或具有0-4个独立地选自氮、氧或硫的杂原子的5-6元饱和环、部分不饱和环或芳环。R°的饱和碳原子上的合适二价取代基包括=O和=S。
“任选经取代”的基团的饱和碳原子上的合适二价取代基包括以下:=O、=S、=NNR* 2、=NNHC(O)R*、=NNHC(O)OR*、=NNHS(O)2R*、=NR*、=NOR*、–O(C(R* 2))2–3O–、或–S(C(R* 2))2–3S–,其中各独立存在的R*是选自氢、可如下文所定义经取代的C1-6脂肪族基或具有0-4个独立地选自氮、氧或硫的杂原子的未经取代的5-6元饱和环、部分不饱和环或芳环。与“任选经取代”的基团的邻位可取代碳结合的合适二价取代基包括:–O(CR* 2)2–3O–,其中各独立存在的R*是选自氢、可如下文所定义经取代的C1-6脂肪族基或具有0-4个独立地选自氮、氧或硫的杂原子的未经取代的5-6元饱和环、部分不饱和环或芳环。
R*的脂肪族基上的合适取代基包括卤素、–R●、-(卤代R●)、-OH、–OR●、–O(卤代R●)、–CN、–C(O)OH、–C(O)OR●、–NH2、–NHR●、–NR● 2、或–NO2,其中各R●未经取代或在前面有“卤代”的情况下仅经一个或一个以上卤素取代,并且独立地为C1-4脂肪族基、–CH2PH,–O(CH2)0– 1Ph或具有0-4个独立地选自氮、氧或硫的杂原子的5-6元饱和环、部分不饱和环或芳环。
“任选经取代”的基团的可取代氮上的合适取代基包括 或其中各独立地为氢、可如下文所定义经取代的C1-6脂肪族基、未经取代的-OPh或具有0-4个独立地选自氮、氧或硫的杂原子的未经取代的5-6元饱和环、部分不饱和环或芳环,或不管以上定义,两个独立存在的连同插入其间的原子一起形成具有0-4个独立地选自氮、氧或硫的杂原子的未经取代的3-12元饱和、部分不饱和或芳基单环或双环。
的脂肪族基上的合适取代基独立地为卤素、–R●、-(卤代R●)、–OH、–OR●、–O(卤代R●)、–CN、–C(O)OH、–C(O)OR●、–NH2、–NHR●、–NR● 2、或-NO2,其中各R●未经取代或在前面有“卤代”的情况下仅经一个或一个以上卤素取代,并且独立地为C1-4脂肪族基、–CH2Ph、–O(CH2)0– 1PH,或具有0-4个独立地选自氮、氧或硫的杂原子的5-6元饱和环、部分不饱和环或芳环。
在某些实施方案中,术语“任选经取代的”,“任选经取代的烷基”,“任选经取代的烯基”,“任选经取代的炔基”,“任选经取代的碳环”,“任选经取代的芳基”,“任选经取代的杂芳基”,“任选经取代的杂环”,以及本文中所使用的任何其它任选经取代的基团,是指未被取代的基团或者被取代的基团,其中由典型的取代基独立地置换该基团上一个、两个、三个或更多个氢原子,所述典型的取代基不限于:
-F、-Cl、-Br、-I、氘,
-OH、保护的羟基、烷氧基、氧代、硫代氧代,
-NO2、-CN、CF3、N3,
-NH2、保护的氨基、-NH烷基、-NH烯基、-NH链炔基、-NH环烷基、-NH-芳基、-NH-杂芳基、-NH-杂环基、-二烷基氨基、-二芳基氨基、-二杂芳基氨基,
-O-烷基、-O-烯基、-O-炔基、-O-环烷基、-O-芳基、-O-杂芳基、-O-杂环基,
-C(O)-烷基、-C(O)-烯基、-C(O)-炔基、-C(O)-碳环基、-C(O)-芳基、-C(O)-杂芳基、-C(O)-杂环基,
-CONH2、-CONH-烷基、-CONH-烯基、-CONH-炔基、-CONH-碳环基、-CONH-芳基、-CONH-杂芳基、-CONH-杂环基,
-OCO2-烷基、-OCO2-烯基、-OCO2-炔基、-OCO2-碳环基、-OCO2-芳基、-OCO2-杂芳基、-OCO2-杂环基、-OCONH2、-OCONH-烷基、-OCONH-烯基、-OCONH-炔基、-OCONH-碳环基、-OCONH-芳基、-OCONH-杂芳基、-OCONH-杂环基,
-NHC(O)-烷基、-NHC(O)-烯基、-NHC(O)-炔基、-NHC(O)-碳环基、-NHC(O)-芳基、-NHC(O)-杂芳基、-NHC(O)-杂环基、-NHCO2-烷基、-NHCO2-烯基、-NHCO2-炔基、-NHCO2-碳环基、-NHCO2-芳基、-NHCO2-杂芳基、-NHCO2-杂环基、-NHC(O)NH2、-NHC(O)NH-烷基、-NHC(O)NH-烯基、-NHC(O)NH-烯基、-NHC(O)NH-碳环基、-NHC(O)NH-芳基、-NHC(O)NH-杂芳基、-NHC(O)NH-杂环基、NHC(S)NH2、-NHC(S)NH-烷基、-NHC(S)NH-烯基、-NHC(S)NH-炔基、-NHC(S)NH-碳环基、-NHC(S)NH-芳基、-NHC(S)NH-杂芳基、-NHC(S)NH-杂环基、-NHC(NH)NH2、-NHC(NH)NH-烷基、-NHC(NH)NH--烯基、-NHC(NH)NH-烯基、-NHC(NH)NH-碳环基、-NHC(NH)NH-芳基、-NHC(NH)NH-杂芳基、-NHC(NH)NH-杂环基、-NHC(NH)-烷基、-NHC(NH)-烯基、-NHC(NH)-烯基、-NHC(NH)-碳环基、-NHC(NH)-芳基、-NHC(NH)-杂芳基、-NHC(NH)-杂环基,
-C(NH)NH-烷基、-C(NH)NH-烯基、-C(NH)NH-炔基、-C(NH)NH-碳环基、-C(NH)NH-芳基、-C(NH)NH-杂芳基、-C(NH)NH-杂环基,
-S(O)-烷基、-S(O)-烯基、-S(O)-炔基、-S(O)-碳环基、-S(O)-芳基、-S(O)-杂芳基、-S(O)-杂环基-SO2NH2、-SO2NH-烷基、-SO2NH-烯基、-SO2NH-炔基、-SO2NH-碳环基、-SO2NH-芳基、-SO2NH-杂芳基、-SO2NH-杂环基,
-NHSO2-烷基、-NHSO2-烯基、-NHSO2-炔基、-NHSO2-碳环基、-NHSO2-芳基、-NHSO2-杂芳基、-NHSO2-杂环基,
-CH2NH2、-CH2SO2CH3,
-一-、二-、或三-烷基甲硅烷基,
-烷基、-烯基、-炔基、-芳基、-芳基烷基、-杂芳基、-杂芳基烷基、-杂环烷基、-环烷基、-碳环基、-杂环基、聚烷氧基烷基、聚烷氧基、-甲氧基甲氧基、-甲氧基乙氧基、-SH、-S-烷基、-S-烯基、-S-炔基、-S-碳环基、-S-芳基、-S-杂芳基、-S-杂环基、或者甲基硫代甲基。
本文所用的术语“药学上可接受的盐”用以指在可靠医学判断的范围内,适于与人类和低等动物的组织接触使用而没有过多毒性、刺激、过敏反应或其它问题或并发症,并且与合理的效益/风险比相称的那些盐。药学上可接受的盐是公知的现有技术。例如,SMBerge等人在J.Pharmaceutical ScienceS,第1977年,66,1-19,详细描述了药学上可接受的盐,纳入其内容作为参考。本发明的化合物的药学上可接受的盐包括从适合的无机酸和碱以及有机酸和碱衍生而来的那些盐。药学上可接受的无毒性酸加成盐的实例是氨基与无机酸如盐酸,氢溴酸,磷酸,硫酸和高氯酸,或者与有机酸如乙酸,草酸,马来酸、酒石酸,柠檬酸,琥珀酸或丙二酸形成的盐,或者通过使用诸如离子交换等本领域的其他方法形成的盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。
从适当的碱衍生的盐包括碱金属、碱土金属、铵和N+(C1–4烷基)4盐。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁等。其它药学可接受的盐包括使用诸如卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、低级烷基磺酸盐和芳基磺酸盐形成的合适的无毒的铵盐,季铵盐和胺阳离子。
除非另有说明,本文所描述的结构也意味着包括结构的所有异构形式(例如,对映体、非对映体和几何(或构象)异构体);例如,每一不对称中心的R和S构型、Z和E双键异构体、以及Z和E构象异构体。因此,本发明化合物的混合物的单个立体化学异构体以及对映体、非对映体、互变异构体和几何(或构象)异构体的混合物在本发明的范围之内。除非另有说明,本发明的化合物的所有互变异构形式都在本发明的范围之内。
另外,除非另有说明,本文所述的结构包括这样的化合物:其区别仅在于存在一个或多个同位素富集的原子。例如,具有本发明结构的化合物包括由氘或氚替换氢、或由一个13C-或14C-富集碳置换碳,这些化合物都本发明的范围之内。在一些实施方案中,基团包含一个或多个氘原子。
具有通式I的化合物还应包括其同位素标记形式。具有通式I的化合物的同位素标记形式与所述化合物的区别仅在于所述化合物的一个或多个原子被原子量或质量数与通常是天然存在的原子的原子量或质量数不同的一个或多个原子取代。市场上容易买到且可通过已知方法被结合到具有通式I的化合物中的同位素的例子包括氢、碳、氮、氧、磷、氟和氯,例如分别为2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36CI。含有一或多个上述同位素和/或其他原子的同位素的通式I化合物、其前药或它们中任一个的药学上可接受的盐都应理解为本发明的一部分。可以多种有利的方式使用同位素标记的通式I化合物。例如,结合了诸如3H或14C的放射性同位素的同位素标记的通式1化合物可用于药物和/或底物组织分布试验。由于其制备简单及可检测性良好而尤其优选这两种放射性同位素,即氚(3H)和碳-14(14C)。由于诸如氘(2H)的较重的同位素具有较高的代谢稳定性,将这种同位素标记化合物结合到通式I化合物中在治疗上是有好处的。较高的代谢稳定性直接导致体内半衰期延长或剂量减少,这在多数情况下代表了本发明的优选实施例。通常可通过进行本文本的实施例部分和制备部分中的合成方案和相关描述中公开的步骤来制备同位素标记的通式I化合物,用容易得到的同位素标记反应物代替非同位素标记反应物。
为了通过一级动力学同位素效应控制化合物的氧化代谢,可将氘(2H)结合到所述化合物中。一级动力学同位素效应是由于同位素核的替换而导致化学反应速率发生变化,这是由于所述同位素替换之后形成共价键所需的基态能量的变化而引起的。较重的同位素的替换通常导致化学键的基态能量降低,从而引起速率限制的键断裂反应的速率降低。如果键断裂发生在沿着多产物反应的坐标的鞍点区中或其附近,产物分布比率可被显着改变。解释如下:如果氘被键合到碳原子的非可替换位置上,通常速率差异km/kd=2-7。如果该速率差异被成功地应用于易于氧化的通式I化合物,则该化合物在体内的性质可被显着地改变,从而改善药物动力学特性。
在发现和开发治疗剂时,本领域技术人员尝试在保持有利的体外特性的同时优化药物动力学参数。可以合理地认为,许多药物动力学性质差的化合物易于被氧化代谢。现有的体外肝微粒体试验提供了关于这种类型的氧化代谢过程的有价值的信息,这些信息使得可以合理地设计具有通式I的含氘化合物,使其由于抗氧化代谢而提高稳定性。因此,通式I化合物的药物动力学性质显着地改善了,这种改善可用体内半衰期(t/2)的延长、疗效最好的浓度(Cmax)、剂量响应曲线下的面积(AUC)以及F来定量地表示,也可用降低的清除率、剂量和材料成本来定量地表示。
以下阐述用于说明上述内容:把通式I化合物制备成一系列类似物,其中所述通式I化合物具有多个氧化代谢可能攻击的位点,例如苯甲基氢原子和与氮原子键合的氢原子,在所述类似物中各种组合的氢原子被氘原子取代,因此所述氢原子中的一部分、大多数或全部被氘原子取代。半衰期的确定使得可以有利地及准确地确定对氧化代谢的抵抗能力提高的程度。通过这种方式确定了,由于这种类型的氘-氢替换,母化合物的半衰期可被提高高达100%。
通式I化合物中的氘-氢替换也可被用来有利地改变起始化合物的代谢物谱,以减少或消除不良有毒代谢物。例如,如果通过氧化性碳-氢(C-H)键断裂产生了有毒代谢物,可以合理地认为,含氘类似物将会显着地减少或消除不良代谢物的产生,即使该具体的氧化反应并不是速率决定步骤。更多现有技术中关于氘-氢替换的信息可参见例如Hanzlik等,J.Org.Chem.55,3992-3997,1990,Reider等,J.Org.Chem.52,3326-3334,1987,FosteR,Adv.Drug Res.14,1-40,1985,Gillette等,Biochemistry 33(10)2927-2937,1994,和Jarman等Carcinogenesis 16(4),683-688,1993。
本文所使用的术语“调节剂”被定义为以可测量的亲和力结合和/或抑制靶的化合物。在某些实施方案中,调节剂的IC50和/或结合常数约小于50μM,约小于1μM,约小于500nM,约小于100nM,或者约小于10nM。
本文所使用的术语“可测量的亲和力”和“可测量地抑制”是指在含有本发明化合物或其组合物和IRAK的样本与包含IRAK但不含有本发明化合物或其组合物的等效样品之间的IRAK活性发生可测量的变化。
本发明预想的取代基和变量的组合仅为形成稳定化合物的那些。本文所用的术语“稳定”是指具有的稳定性足以允许制造,并且能保持化合物的完整性足够长的时间以用于本文详述的各种目的(例如,向受试者治疗性或预防性给药)。
本文的变量的任何定义中化学基团列表的记载包括该变量作为任何单个基团或列出基团的组合的定义。本文的变量的实施方案的记载包括该实施方案作为任何单个实施方案或与任何其他实施方案结合。
3.实施例化合物的描述
本发明的一方面提供通式I所示的化合物,
或药学上可接受的盐,式中:
X是CR或者N;
A是O、S、SO2、SO、-NRC(O)、-NRSO2、或者N(R);或者A不存在;
R3是-R、卤素、-卤代烷基、-OR、-SR、-CN、-NO2、-SO2R、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)N(R)2、-NRSO2R、或者-N(R)2;或者
当A是-NRC(O)、-NRSO2或者N(R)时;那么R和R3与与它们各自所连接的原子一起形成具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环,或者具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;上述每个基团任选经取代;
X’是CR或者N;
环Z是具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环,或者具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;上述每个基团任选经取代;
R1是-R、卤素、-卤代烷基、-OR、-SR、-CN、-NO2、-SO2R、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)N(R)2、-NRSO2R、或者-N(R)2;
Ra不存在或者是-R、卤素、-卤代烷基、-OR、-SR、-CN、-NO2、-SO2R、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)N(R)2、-NRSO2R、或者-N(R)2;
环Y是任选可取代的具有2-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;
R2是-R、卤素、-卤代烷基、-OR、-SR、-CN、-NO2、-SO2R、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)N(R)2、-NRSO2R、或者-N(R)2;
Rb不存在或者是-R、卤素、-卤代烷基、-OR、-SR、-CN、-NO2、-SO2R、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)N(R)2、-NRSO2R、或者-N(R)2;
每个R独立地是氢,C1–6脂族基团,C3-10芳基,3-8元饱和或部分不饱和碳环,具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环,或者具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;上述每个基团任选经取代;或者
在同一个原子上的两个R基团与它们所连接的原子一起形成C3-10芳基,3-8元饱和或部分不饱和碳环,具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环,或者具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;上述每个基团任选经取代;
其中当X是N且A不存在时,那么R3不是H。
在某些实施例中,X是CR。在某些实施例中,X是CH。在某些实施例中,X是N。
在某些实施例中,A是O或者N(R)。在某些实施例中,A是O。在某些实施例中,A是N(R)。在另一实施例中,A是NH或者N-Me。
在某些实施例中,A不存在。
在某些实施例中,当R3是烷基或者取代的烷基时,A不存在。
在某些实施例中,A是N(R),由R和R3形成的环是具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环,或者具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;上述每个基团任选经取代。
在某些实施例中,R3是-R、-卤代烷基、-C(O)R,-CO2R、或者-C(O)N(R)2。
在某些实施例中,R3是-H。
在某些实施例中,R3是C1–6脂族基团,C3–10芳基,3-8元饱和或部分不饱和碳环,具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环,或者具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;上述每个基团任选经取代。
在某些实施例中,R3是甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、直链或支链的戊基、或直链或支链的己基,上述每个基团任选经取代。
在某些实施例中,R3是苯基,萘基,环丙基,环丁基,环戊基,环己基,环庚基,金刚烷基,环辛基,[3.3.0]双环辛烷基,[4.3.0]双环壬烷基,[4.4.0]双环癸烷基,[2.2.2]双环辛烷基,芴基,茚满基,四氢萘基,吖啶基,吖辛因基,苯并咪唑基,苯并呋喃基,苯并噻吩基,苯并苯硫基,苯并噁唑基,苯并噻唑基,苯并三唑基,苯并四唑基,苯并异噁唑基,苯并异噻唑基,苯并咪唑啉基,咔唑基,NH-咔唑基,咔啉基,色满基,色烯基,噌啉基,十氢喹啉基,2H,6H-1,5,2-二噻嗪基,二氢呋喃并[2,3-b]四氢呋喃基,呋喃基,呋咱基,咪唑烷基,咪唑啉基,咪唑基,1H-吲唑基,吲哚烯基,二氢吲哚基,中氮茚基,吲哚基,3H-吲哚基,异二氢吲哚,异吲哚烯基,异苯并呋喃基,异色满基,异吲唑基,异二氢吲哚,异吲哚基,异喹啉基,异噻唑基,异噁唑基,吗啉基,萘啶基,八氢异喹啉基,噁二唑基,1,2,3-噁二唑基,1,2,4-噁二唑基;1,2,5-噁二唑基,1,3,4-噁二唑基,噁唑烷基,噁唑基,噁唑烷基,嘧啶基,菲啶基,菲咯啉基,吩嗪基,吩噻嗪基,苯并氧硫杂环己二烯基,吩噁嗪基,酞嗪基,哌嗪基,哌啶基,蝶啶基,嘌呤基,吡喃基,吡嗪基,吡唑烷基,吡唑啉基,吡唑基,哒嗪基,吡啶并噁唑,吡啶并咪唑,吡啶并噻唑,吡啶基,吡啶基,嘧啶基,吡咯烷基,吡咯啉基,2H-吡咯基,吡咯基,喹唑啉基,喹啉基,4H-喹嗪基,喹喔啉基,奎宁环基,四氢呋喃基,四氢异喹啉基,四氢喹啉基,6H-1,2,5-噻二嗪基,1,2,3-噻二唑基,1,2,4-噻二唑基,1,2,5-噻二唑基,1,3,4-噻二唑基,噻蒽基,噻唑基,噻吩基,噻吩并噻唑基,噻吩并噁唑基,噻吩并咪唑基,硫代苯基,三嗪基,1,2,3-三唑基,1,2,4-三唑基,1,2,5-三唑基,1,3,4-三唑基,氧杂环丁烷基,氮杂环丁烷基,或呫吨基,上述每个基团任选经取代。
在某些实施例中,R3是环丙基、环丁基、环戊基、环己基、四氢呋喃、哌啶、哌啶酮、螺庚烷或二环己烷;上述每个基团任选经取代。
在某些实施例中,-A-R3是–H、–CH3、-CF3、
在某些实施例中,X’是CR。在某些实施例中,X’是CH。在某些实施例中,X’是N。
在某些实施例中,环Z是具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环,或者具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;上述每个基团任选经取代。
在某些实施例中,环Z是其中X是O、S或者NR1;Y是C或者N;且T是C或者N。
在某些实施例中,环Z是四氢呋喃基,呋喃基,呋咱基,咪唑烷基,咪唑啉基,咪唑基,1H-吲唑基,异噻唑基,异噁唑基,吗啉基,噁二唑基,1,2,3-噁二唑基,1,2,4-噁二唑基;1,2,5-噁二唑基,1,3,4噁二唑基,噁唑烷基,噁唑基,噁唑烷基,嘧啶基,哌嗪基,哌啶基,吡喃基,吡嗪基,吡唑烷基,吡唑啉基,吡唑基,哒嗪基,吡啶基,吡啶基,嘧啶基,吡咯烷基,吡咯啉基,2H-吡咯基,吡咯基,噻唑基,噻吩基,三嗪基,噻二唑,1,2,3-三唑基,1,2,4-三唑基,1,2,5-三唑基或1,3,4三唑基;上述每个基团任选经取代。
在某些实施例中,环Z是吡唑环。
在某些实施例中,R1是-R、卤素、-卤代烷基、-OR、-SR、-CN、-NO2、-SO2R、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)N(R)2、-NRSO2R、或者-N(R)2。
在某些实施例中,R1是–R。
在某些实施例中,环Z是
在某些实施例中,Ra不存在。
在某些实施例中,Ra是OR、CF3、Hal、或者NO2。
在某些实施例中,环Y是任选可取代的具有2-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环。
在某些实施例中,环Y是四氢呋喃,呋喃基,呋咱基,咪唑烷基,咪唑啉基,咪唑基,1H-吲唑基,异噻唑基,异噁唑基,吗啉基,噁二唑基,1,2,3-噁二唑基,1,2,4-噁二唑基。1,2,5-噁二唑基,1,3,4-噁二唑基,噁唑烷基,噁唑基,噁唑烷基,嘧啶基,哌嗪基,哌啶基,吡喃基,吡嗪基,吡唑烷基,吡唑啉基,吡唑基,哒嗪基,吡啶基,吡啶基,嘧啶基,吡咯烷基,吡咯啉基,2H-吡咯基,吡咯基,噻唑基,噻吩基,三嗪基,噻二唑,1,2,3-三唑基,1,2,4-三唑基,1,2,5-三唑基或1,3,4三唑基;上述每个基团任选经取代。
在某些实施例中,环Y是任选经取代的吡啶基、吡唑或噻二唑。
在某些实施例中,环Y是任选经取代的吡唑。
在某些实施例中,环Y任选经取代的噻二唑。
在某些实施例中,环Y是任选经取代的吡啶基。
在某些实施例中,R2是-R、-OR、-SR、-SO2R、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)N(R)2、-NRSO2R、或者-N(R)2。
在某些实施例中,R2是-R、-C(O)R、-CO2R、-C(O)N(R)2、或者-N(R)2。
在某些实施例中,Rb不存在。在某些实施例中,Rb是任选经取代的C1–6脂族基团、C(O)NR2、或者COR。
在某些实施例中,环Y是
在某些实施例中,环Z、环Y、R1、R2、R3、Ra、Rb、A、X和X’各自的定义如上所述,且按实施例、类别、子类和本文单独或结合进一步加以描述。
在某些实施例中,本发明提供通式I-a所示的化合物,
或其药学上可接受的盐,其中环Y、R2、R3、Ra、Rb、A、X和X’各自的定义如上所述,且按实施例、类别、子类和本文单独或结合进一步加以描述。
在某些实施例中,本发明提供通式I-b所示的化合物,
或其药学上可接受的盐,其中环Y、R2、R3、Ra、Rb、A和X’各自的定义如上所述,且按实施例、类别、子类和本文单独或结合进一步加以描述。
在某些实施例中,本发明提供通式I-c所示的化合物,
或其药学上可接受的盐,其中环Y、R2、R3、Ra、Rb、A和X’各自的定义如上所述,且按实施例、类别、子类和本文单独或结合进一步加以描述。
在某些实施例中,本发明提供通式I-d所示的化合物,
或其药学上可接受的盐,其中R2、R3、A和X’各自的定义如上所述,且按实施例、类别、子类和本文单独或结合进一步加以描述。
在某些实施例中,本发明提供通式I-e所示的化合物,
或其药学上可接受的盐,其中R2、R3、A和X’各自的定义如上所述,且按实施例、类别、子类和本文单独或结合进一步加以描述。
在某些实施例中,本发明提供通式I-f所示的化合物,
或其药学上可接受的盐,其中R2、R3、A和X’各自的定义如上所述,且按实施例、类别、子类和本文单独或结合进一步加以描述。
在某些实施例中,本发明提供表1中给出的化合物:
表1
在一些实施例中,本发明提供选自上文描述的化合物或其药学上可接受的盐。
各种结构示式可以显示杂原子,没有与其连接的基团、根、电荷或反离子。本领域普通技术人员会明白这样的示式意指杂原子与氢连接(例如,应理解为)。
在某些实施例中,按照以下实施例列出的流程合成本发明的化合物。
4.用途、制剂和给药
药学上可接受的组合物
根据另一个实施方案中,本发明提供包含本发明的化合物或其药学上可接受的衍生物和药学上可接受的载体、佐剂或媒介物的组合物。在本发明的组合物中化合物的量要能在生物样品或病人中有效地可测量抑制IRAK或其变体。在某些实施例中,在本发明的组合物中化合物的量要能在生物样品或病人中有效地可测量抑制IRAK或其变体。在某些实施例中,本发明的组合物被配制用于施用至有需要该组合物的病人。
本文所用的术语“病人”或“受试者”指动物,优选哺乳动物,最佳是人。
术语“药学上可接受的载体、佐剂或媒介物”指的是无毒的载体、佐剂、或媒介物,它们不会破坏与其一起配制的化合物的药理学活性。用在本发明的组合物中的药学上可接受的载体、佐剂或媒介物包括,但不限于,离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙基烯乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段共聚物、聚乙基烯乙二醇和羊毛脂。
“药学上可接受的衍生物”是指任何无毒性的盐、酯、酯的盐或本发明的化合物的其它衍生物,它们被施加于接受者后能够直接或间接地提供本发明的化合物或具有抑制活性的代谢物或残余物。
本发明的组合物通过口服、肠胃外、吸入喷雾、局部、直肠、经鼻、口腔、阴道或植入容器给予。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。优选的是,组合物是经口服、腹膜内或静脉内给予。本发明的组合物的无菌可注射形式包括水性或油性悬浮液。这些悬浮液按照在本领域中已知的技术使用适合的分散或润湿剂和悬浮剂配制。无菌可注射制剂也可以是用无毒的肠胃外可接受的稀释剂或溶剂(例如在1,3-丁二醇中的溶液)制成的无菌可注射溶液或悬浮液。所使用的可接受的媒介物和溶剂包括水、林格氏溶液和等渗氯化钠溶液。此外,无菌不挥发性油通常用作溶剂或悬浮介质。
为此,任何可用的温和的固定油包括合成的单-或二-甘油酯。诸如油酸及其甘油酯衍生物的脂肪酸可用于制备注射剂,如同天然的药学上可接受的油,例如橄榄油或蓖麻油,尤其是它们的聚氧乙基化油。这些油溶液或悬浮液还含有长链醇稀释剂或分散剂,例如羧甲基纤维素或类似的分散剂,它们常用于制备药学上可接受的剂型制剂中,包括乳剂和混悬剂。其它常用的表面活性剂,如吐温(Tweens)、司盘(Spans)和其它乳化剂或生物利用度增强剂,它们常用于制备药学上可接受的固体、液体,或者其它剂型也可以用于配制的目的。
本发明的药学上可接受的组合物以任何口服可接受的剂型口服给药。示例性口服剂型是胶囊、片剂、水性混悬剂或溶液。对于口服用片剂,常用的载体包括乳糖和玉米淀粉。通常也会加入润滑剂如硬脂酸镁。对于以胶囊形式的口服给药,有用的稀释剂包括乳糖和干玉米淀粉。当需要口服水悬浮液时,活性成分与乳化剂和悬浮剂结合。如果需要的话,任选地可加入某些甜味剂、调味剂或着色剂。
或者,本发明的药学上可接受的组合物以直肠给药的栓剂形式给药。这些通过将药剂与合适的无刺激性赋形剂混合来制成,其中所述赋形剂在室温下为固体,但在直肠温度下为液体,因此将在直肠中熔融并释放出药物。这样的材料包括可可脂、蜂蜡和丙二醇。
本发明的药学上可接受的组合物也可以局部给药,尤其当治疗目标包括局部施用容易到达的部位和器官,包括眼、皮肤或下肠道疾病。根据各个部位或器官容易制备适合的局部制剂。
可以以直肠栓剂制剂(参见上文)或合适的灌肠剂来实现下肠道的局部施用。也可使用局部透皮贴剂。
对于局部施用,在合适的软膏中配制药学上可接受的组合物,所述软膏含有悬浮或溶解于一种或多种载体中的活性成分。局部施用本发明化合物的示例性载体包括矿物油、液体凡士林、白凡士林、丙基烯二醇、聚氧乙基烯、聚氧丙基烯化合物、乳化蜡和水。可替代地,在合适的洗液或乳膏中配制药学上可接受的组合物,所述洗液或乳膏含有悬浮或溶解于一种或多种载体中的活性成分。合适的载体包括,但不限于,矿物油、脱水山梨醇单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、CETE芳基醇、2-辛基十二烷醇、苯甲醇和水。
本发明的药学上可接受的组合物任选地通过鼻气雾剂或吸入给药。这种组合物根据药物制剂领域中公知的技术制备,可制成在盐水中的溶液,采用苯甲醇或其他合适的防腐剂、吸收促进剂以提高生物利用度,也可采用碳氟化合物和/或其它常规增溶剂或分散剂。
最优选地,本发明的药学上可接受的组合物配制用于口服给药。这类制剂可与或不与食物施用。在一些实施方案中,本发明的药学上可接受的组合物不与食物一起施用。在其他实施方案中,本发明的药学上可接受的组合物与食物施用。
本发明的化合物任选地与载体材料组合以产生单一剂型的组合物,所述化合物的量将取决于所治疗的宿主、具体的给药模式。优选地,提供的组合物应配制成0.01-100mg/kg体重/化合物之间的剂量,可以每天给予病人接受这些组合物。
还应当理解,对于任何特定病人的具体剂量和治疗方案将取决于多种因素,包括采用的特定化合物的活性、年龄、体重、一般健康状况、性别、饮食状况、给药时间、排泄速率、药物组合、以及治疗医师的判断和具体疾病的严重程度。在组合物中本发明化合物的量还将取决于组合物中的特定化合物。
化合物和药学上可接受的组合物的用途
本发明还涉及一种用于治疗患有IRAK相关疾病的对象的方法,包括给所述对象施用有效量的通式(I)及相关式的化合物。
本发明优选地涉及一种方法,其中IRAK相关疾病是自体免疫疾病或者与过度活跃的免疫反应或癌症相关的疾病。此外,本发明还涉及一种治疗患有免疫调节异常的对象的方法,包括以有效治疗所述免疫调节异常的量给所述对象施用通式(I)及相关式的化合物。
本发明优选地涉及一种方法,其中免疫调节异常是一种选自下组的自身免疫性或慢性炎症性疾病:变态反应性疾病、肌萎缩性侧索硬化(ALS)、全身性红斑狼疮、慢性类风湿性关节炎、I型糖尿病、炎症性肠病、胆汁性肝硬化、葡萄膜炎、多发性硬化症、克罗恩氏病、溃疡性结肠炎、大疱性类天疱疮、结节病、银屑病、自身免疫性肌炎、韦格纳肉芽肿、鱼鳞癣、Graves眼病和哮喘。
本发明还涉及一种方法,其中免疫调节异常是骨髓或器官移植排斥或者移植物抗宿主病。
本发明还涉及一种方法,其中免疫调节异常是选自:器官或组织的移植、由移植引起的移植物抗宿主病、自身免疫性综合征(包括类风湿性关节炎)、全身性红斑狼疮、桥本氏甲状腺炎、多发性硬化症、系统性硬化病、重症肌无力、I型糖尿病、葡萄膜炎、后葡萄膜炎、变态反应性脑脊髓炎、肾小球性肾炎、感染后自身免疫性疾病(包括风湿热和感染后肾小球性肾炎)、炎症性和过度增生性皮肤病、银屑病、特应性皮炎、接触性皮炎、湿疹性皮炎、脂溢性皮炎、扁平苔癣、天疱疮、大疱性类天疱疮、大疱性表皮松解、荨麻疹、血管性水肿、血管炎、红斑、皮肤嗜酸性粒细胞增多症、红斑狼疮、痤疮、斑秃、角膜结膜炎、春季结膜炎、与白塞氏病相关的葡萄膜炎、角膜炎、疱疹性角膜炎、圆锥形角膜、角膜上皮营养不良、角膜白斑、眼天疱疮、角膜侵蚀性溃疡、巩膜炎、Graves’眼病、沃格特-小柳-原田三氏综合征、结节病、花粉过敏、可逆阻塞性气道疾病、支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、灰尘哮喘、慢性或顽固性哮喘、迟发性哮喘和气道高反应性、支气管炎、胃溃疡、由缺血性疾病和血栓形成引起的血管损伤、缺血性肠病、炎性肠病、坏死性小肠结肠炎、与热灼伤有关的肠损伤、腹腔病、直肠炎、嗜酸细胞性胃肠炎、肥大细胞增多症、克罗恩氏病、溃疡性结肠炎、偏头痛、鼻炎、湿疹、间质性肾炎、古德帕斯丘综合征、溶血性尿毒综合征、糖尿病性肾病、多发性肌炎、格林-巴利二氏综合征、美尼尔氏病、多神经炎、多发性神经炎、单神经炎、神经根病、甲状腺功能亢进、巴塞多氏病、单纯性红细胞再生不良、再生障碍性贫血、再生不良性贫血、原发性血小板减少性紫癜、自身免疫性溶血性贫血、粒性白细胞缺乏症、恶性贫血、巨幼红细胞性贫血、红细胞发生不能、骨质疏松、结节病、纤维化肺、特发性间质性肺炎、皮肤肌炎、寻常型白癜风、寻常性鱼鳞病、光变应性敏感、皮肤T细胞淋巴瘤、慢性淋巴细胞白血病、动脉硬化、动脉粥样硬化、主动脉炎综合征、多发性结节性动脉炎、心肌病、硬皮病、韦格纳坏死性肉芽肿、斯耶格伦综合征、肥胖病、嗜酸性筋膜炎、牙龈损伤、牙周组织、牙槽骨、牙骨质龋、肾小球性肾炎、通过防止头发脱落或者通过毛发发芽和/或促进生发和毛发生长治疗男性型秃发或老年脱发、肌肉萎缩症、脓皮病和赛杂瑞综合征、阿狄森氏病、保存时发生的器官的局部缺血再灌注损伤、移植或缺血性疾病、内毒素休克、假膜性结肠炎、由药物或辐射引起的结肠炎、缺血性急性肾功能不全、慢性肾功能不全、由肺氧或药物引起的毒素病、肺癌、肺气肿、白内障、铁质沉着、色素性视网膜炎、老年性黄斑变性、玻璃体结疤、角膜碱烧伤、皮炎多形性红斑、线状IgA大疱性皮肤病和水泥皮炎(cement dermatitis)、齿银炎、牙周炎、败血症、胰腺炎、由环境污染引起的疾病、老化、致癌作用、癌的转移和低气压病、由组胺或白细胞三烯-C4释放引起的疾病、白塞氏病、自身免疫性肝炎、原发性胆汁性肝硬化、硬化性胆管炎、部分肝切除、急性肝坏死、由毒素引起的坏死、病毒性肝炎、休克、或缺氧症、B病毒性肝炎、非A/非B型肝炎、肝硬化、酒精性肝硬化、肝功能衰竭、暴发性肝功能衰竭、迟发性肝功能衰竭、慢加急性(acute-on-chronic)肝衰竭、化疗效果增强、巨细胞病毒感染、HCMV感染、艾滋病、癌症、老年性痴呆、帕金森病、外伤、和慢性细菌感染。
在某些实施例中,与IRAK相关的疾病是选自:类风湿性关节炎、银屑病关节炎、骨关节炎、全身性红斑狼疮、狼疮性肾炎、强直性脊柱炎、骨质疏松、系统性硬化病、多发性硬化症、银屑病、I型糖尿病、II型糖尿病、炎性肠病(克罗恩病和溃疡性结肠炎)、高免疫球蛋白血症和周期性发热综合征、Cryopyrin-相关周期性综合征、施尼茨勒综合征、全身型幼年特发性关节炎、成人发病性斯提耳氏病、痛风、假性痛风、SAPHO综合征、卡斯尔曼氏病、败血症、中风、动脉粥样硬化、腹腔病、DIRA(IL-1受体拮抗剂缺乏)、阿尔茨海默氏病、帕金森病、癌症。
在某些实施例中,所述癌症选自癌,淋巴瘤,胚细胞瘤(包括成神经管细胞瘤和成视网膜细胞瘤),肉瘤(包括脂肪肉瘤和滑膜细胞肉瘤),神经内分泌肿瘤(包括类癌瘤,胃泌素瘤和胰岛细胞癌),间皮瘤,神经鞘瘤(包括听神经瘤),脑膜瘤,腺癌,黑素瘤和白血病或淋巴恶性肿瘤。这样的癌症的更具体实例包括鳞状细胞癌(例如,上皮鳞状细胞癌),肺癌(包括小细胞肺癌,SCLC),非小细胞肺癌(NSCLC),肺腺癌和鳞状细胞癌肺癌,腹膜癌,肝细胞癌,胃腺癌或胃癌(包括胃肠癌),胰腺癌,成胶质细胞瘤,子宫颈癌,卵巢癌,肝癌,膀胱癌,肝癌,乳腺癌(包括转移性乳腺癌),结肠癌,癌症,结肠直肠癌,子宫内膜或子宫癌,唾液腺癌,肾或肾癌,前列腺癌,外阴癌,甲状腺癌,肝癌,肛门癌,阴茎癌,睾丸癌,食管癌,胆道肿瘤,以及头颈癌。
在某些实施例中,癌症是脑癌,肺癌,结肠癌,表皮样癌,鳞状细胞癌,膀胱癌,胃腺癌,胰腺癌,乳腺癌,头癌,颈癌,肾脏癌,肾癌,肝癌,卵巢癌,前列腺癌,结肠直肠癌,子宫癌,直肠癌,食管癌,睾丸癌,妇科癌,甲状腺癌癌,黑素瘤,血液恶性肿瘤(例如急性骨髓性白血病,多发性骨髓瘤,慢性骨髓性白血病,骨髓细胞白血病),神经胶质瘤,卡波西氏肉瘤或任何其他类型的实体瘤或液体肿瘤。在一些实施例中,癌症是转移性癌症。在一些实施例中,癌症是结肠直肠癌。在一些实施方案中,癌症是结肠癌。
在各个实施例中,通式(I)及相关式的化合物的针对IRAK结合的IC50小于大约5μΜ、优选小于大约IμΜ、更优选小于大约0.100μM。
本发明的方法可以在体外或体内进行。可在研究和临床应用的过程中用体外试验测定对用本发明化合物治疗具体细胞的敏感性。通常混合培育细胞培养物与各种浓度的本发明化合物足够时间,其时间使活性药物得以抑制IRAK的活性,培养时间常介于1小时与1周之间。可用活检样品或细胞系的培养细胞进行体外处理。
宿主或病人可属于哺乳动物,如灵长类动物,具体是人;啮齿动物,包括小鼠、大鼠和仓鼠;兔、马、牛、狗、猫等。供实验研究的感兴趣动物模型可提供治疗人类疾病的模型。
为了鉴定信号转导通路和检测各种信号转导通路之间的相互作用,许多科学家开发了适当的模型或模型系统,例如细胞培养模型和转基因动物模型。为了检测信号转导级联反应所处的某些阶段,可采用相互作用的化合物来调节信号。可将本发明化合物用作试剂来检测动物模型和/或细胞培养模型或本申请书中所提及临床疾病中的IRAK依赖性信号转导通路状况。
此外,本说明书以下涉及通式(1)化合物及其衍生物在制备预防、或治疗和/或控制疾病进程的药物上的用途的教导是有效的和适用的,如果看起来合理,可不限于本发明化合物抑制IRAK活性的用途。
本发明还涉及通式I所示的化合物和/或其生理学上可接受的盐在预防性或治疗性治疗和/或监测由IRAK活性引致、介导和/或蔓延的疾病中的用途。此外,本发明涉及通式I所示的化合物和/或其生理学上可接受的盐在制备用于预防性或治疗性治疗和/或监测由IRAK活性引致、介导和/或蔓延的疾病的药物中的用途。在某些实施例中,本发明提供了通式I所示的化合物和/或其生理学上可接受的盐在制备用于预防性或治疗性治疗由IRAK介导的疾病的药物中的用途。
通式I所示的化合物和/或其生理上可接受的盐可以用作制备其他药物活性成分的中间体。药物优选地以非化学方法制备,例如通过将活性成分与至少一种固体、液体和/或半液体载体或赋形剂结合,任选地在合适的剂型中掺合一或多种其他活性物质。
本发明通式I所示的化合物可在发病前或后给予一次或多次作为治疗。本发明的上述化合物和医学产品特别用于治疗性治疗。治疗相关作用指某程度上解除一种或多种疾病症状,或部分或完全地将与疾病或病理相关的或导致疾病或病理改变的一种或多种生理或生化参数逆转成正常状态。假如化合物以不同的时间间隔给予,监测可被认为是一种治疗,以增强应答和完全根除疾病病原体和/或症状。可以施加同一种或不同种化合物。也可以使用药物来减低发展疾病或者甚至预先防止与IRAK活性相关的病症出现,或者治疗出现的或持续有的病症。
在本发明的意义中,如果受试者拥有上述生理或病理状况的前置条件,例如家族性倾向、基因缺陷、或者曾经有过病史,给予预防性治疗是可取的。
本发明也涉及含有至少一种本发明化合物和/或其药学上可用的衍生物、盐、溶剂化物和立体异构体,包括它们的各种比例混合物的药物。在某些实施例中,本发明还涉及包含至少一种本发明化合物和/或其生理学上可接受的盐的药物。
本发明意义的“药物”是药物领域的任何药剂,包括一或多种通式I化合物或其制剂(例如药物组合物或药物制剂),可用于预防、治疗、跟进或治疗后调养患有与IRAK活性相关的疾病的病人,所述病人至少暂时地显示整体病况或病人机体个别部分的病理改变。
在各个实施例中,活性成分可以单独给予或者与其他治疗一起联用。在药物组合物中使用根据本发明的一或多化合物可取得增效作用,即通式I化合物与作为活性成分的至少一种其他药剂联用,该其他药剂可以是通式I的另一种化合物或者具有不同结构骨架的化合物。该些活性成分可以同时或依次使用。
本文包括治疗方法,其中本文提供的至少一种化学个体与抗炎剂联用。抗炎剂包括但不限于非甾体抗炎药、非特异性和对COX-2具有特异性的环氧合酶酶抑制剂、金化合物、皮质类固醇、甲氨蝶呤、肿瘤坏死因子(TNF)拮抗剂、免疫抑制剂和甲氨蝶呤。
非甾体抗炎药的实例包括但不限于,布洛芬、氟比洛芬、萘普生和萘普生钠、双氯芬酸、双氯芬酸钠和米索前列醇的组合、舒林酸、奥沙普秦、二氟尼柳、吡罗昔康、吲哚美辛、依托度酸、非诺洛芬钙、酮洛芬、萘丁美酮钠、柳氮磺吡啶、托美丁钠和羟氯喹。非甾体抗炎药的实例还包括对COX-2具有特异性的抑制剂,如塞来考昔、伐地考昔、芦米考昔DND/或艾托考昔。
在一些实施方案中,所述抗炎剂是水杨酸盐。水杨酸盐包括由不限于,乙酰基水杨酸或阿斯匹林、水杨酸钠、胆碱以及水杨酸镁。
抗炎剂还可以是皮质类固醇。例如,皮质类固醇可以是可的松、地塞米松、甲泼尼龙、泼尼松龙、强的松龙磷酸钠、或泼尼松。
在另外的实施方案中,抗炎剂是金化合物,例如硫代苹果酸金钠或金诺芬。
本发明还包括这样的实施方案,其中抗炎剂是代谢抑制剂,例如二氢叶酸还原酶抑制剂(诸如甲氨蝶呤)或二氢乳清酸脱氢酶抑制剂(诸如来氟米特)。
本发明的其它实施方案涉及一些组合,其中至少一种抗炎化合物是抗单克隆抗体(如依库珠单抗或培克珠单抗)、TNF拮抗剂(如依那西普或英夫利昔单抗),TNF拮抗剂是一种抗肿瘤坏死因子α单克隆抗体。
本发明的其它实施方案涉及一些组合,其中至少一种活性成分是免疫抑制剂化合物,选自氨甲喋呤、来氟米特、环孢菌素、他克莫司、硫唑嘌呤和麦考酚酸莫酯。
本申请公开的通式I所示的化合物可与包括抗癌药物在内的已知的治疗剂联用。此处所用的术语“抗癌药物”涉及给予癌症患者用于治疗癌症的任何药物。
以上定义的抗癌治疗可作为单一疗法应用,或者除了本文公开的此处公开的通式I所示的化合物之外可包括常规手术或放射疗法或药物治疗。这种药物治疗例如化疗或靶向治疗,可包括一种或多种,但是优选地为一种以下抗肿瘤药物:
烷化剂:例如六甲密胺、苯达莫司汀、白消安、卡莫司汀、苯丁酸氮芥、氮芥、环磷酰胺、氮烯唑胺、异环磷酰胺、甲磺丙胺、洛莫司汀、美法仑、二溴甘露醇、二溴卫矛醇、尼莫司汀、雷莫司汀、替莫唑胺、噻替派、苏消安、二氯甲基二乙胺、卡波醌、阿帕齐醌、福莫司汀、葡磷酰胺、帕利伐米、呱血生、曲磷胺、尿啼陡氮芥、TH-3024、VAL-0834;
铂化合物:例如卡铂、顺铂、依铂、米铂水合物、奥沙利铂、洛铂、奈达铂、吡铂、沙铂;洛铂、奈达铂、吡铂、赛特铂;
DNA改性剂:例如氨柔比星、蒽双咪腙、地西他滨、米托蒽醌、甲基苄肼、曲贝替定、氯法拉滨;安吖啶、溴他里辛、匹杉琼、laromustine1,3;
拓扑异构酶抑制剂:例如依托泊苷、伊立替康、雷佐生、索布佐生、替尼泊苷、托泊替康;氨萘非特、贝洛替、依利醋铵、伏利拉辛(voreloxin);
微管改性剂:例如卡巴他赛、多西他赛、艾日布尔、伊沙匹隆、紫杉醇、长春碱、长春新碱、长春瑞滨、长春地辛、长春氟宁;康普瑞汀A4前体药物(fosbretabulin)、替司他赛;
抗代谢药物:例如天冬酰胺酶3、阿扎胞苷、左亚叶酸钙、卡培他滨、克拉屈滨、阿糖胞苷、依诺他滨、氟尿苷、氟达拉滨、氟尿嘧啶、吉西他滨、巯嘌呤、甲氨蝶呤、奈拉滨、培美曲塞、普拉曲沙、硫唑嘌呤、硫鸟嘌呤、卡莫氟;脱氧氟尿苷、艾西拉滨、雷替曲塞、沙帕他滨、替加氟2,3、三甲曲沙;
抗癌抗生素:例如博来霉素,更生霉素、阿霉素、表阿霉素、伊达比星、左旋咪唑、米替福新、丝裂霉素C、罗米地辛、链佐星、戊柔比星、净司他丁、佐柔比星、柔红霉素、普卡霉素;阿柔比星、派来霉素、吡柔比星;
激素/拮抗剂:例如阿巴瑞克、阿比特龙、比卡鲁胺、布舍瑞林、卡普睾酮、氯烯雌醚、地加瑞克、地塞米松、雌二醇、氟可龙、甲睾酮、氟他胺、氟维司群、戈舍瑞林、组氨瑞林、亮丙瑞林、甲地孕酮、米托坦、那法瑞林、诺龙、尼鲁米特、奥曲肽、泼尼松龙、雷洛昔芬、他莫昔芬、促甲状腺激素阿尔法、托瑞米芬、曲洛司坦、曲普瑞林、二乙基己烯雌酚;阿考比芬、达那唑、洛瑞林、环硫雄醇、orteronel、恩杂鲁胺1,3;
芳香酶抑制剂:例如氨基格鲁米特、阿那曲唑、依西美坦、法倔、来曲唑、睾内酯、福美坦;
小分子激酶抑制剂:例如克唑替尼、达沙替尼、厄洛替尼、伊马替尼、拉帕替尼、尼洛替尼、帕唑帕尼、瑞格非尼、鲁索利替尼、索拉非尼、舒尼替尼、凡德他尼、维罗非尼、博舒替尼、吉非替尼、阿西替尼、阿法替尼、alisertib、达拉菲尼、达可替尼、dinaciclib、多韦替尼、恩扎妥林、尼达尼布、乐伐替尼、利尼伐尼、linsitinib、马赛替尼、米哚妥林、莫特塞尼、来那替尼(neratinib)、orantinib、呱立福辛、普纳替尼、拉多替尼、rigosertib、替批法尼、tivantinib、tivozanib、曲美替尼、pimasertib、丙氨酸布立尼布、西地尼布、阿帕替尼、卡波替尼S-苹果酸盐1,3、依鲁替尼1,3、埃克替尼4,buparlisib2,西帕替尼4,cobimetinib1,3,艾德利布1,3,fedratinib1,XL-6474
光敏剂:例如甲氧沙林3、吓吩姆钠、他拉泊芬、替莫泊芬;
抗体:例如阿仑单抗、贝西索单抗、贝伦妥单抗-维多汀、西妥昔单抗、迪诺塞麦、易普利单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、群司珠单抗、贝伐单抗2,3、卡妥索单抗、elotuzumab、依帕珠单抗、farletuzumab、mogamulizumab、necitumumab、尼妥珠单抗、奥奴珠单抗、ocaratuzumab、奥戈伏单抗、雷莫芦单抗、利妥木单抗、司妥昔单抗、托珠单抗、扎鲁木单抗、扎木单抗、马妥珠单抗、达妥珠单抗1,2,3、onartuzumab1,3、雷妥莫单抗1、tabalumab1,3,EMD-5257974,纳武单抗(nivolumab1,3);
细胞因子:例如阿地白介素、干扰素α2、干扰素α2a3、干扰素α2b2,3、西莫白介素、他索纳明、替西白介素、奥普瑞白介素1,3、重组白介素β-1a4;
药物轭合物:例如地尼白介素-毒素连接物、替伊莫单抗、碘苄胍1123、松龙苯芥、曲妥珠单抗-emtansine、雌莫司汀、吉妥珠单抗、奥唑米星、阿柏西普、cintredekinbesudotox、依多曲肽、奥英妥珠单抗、那莫单抗、莫奥珠单抗、锝(99mTc)阿西莫单抗、vintafolide1,3;
疫苗:例如前列腺癌疫苗(sipuleucel3)、维特斯朋3、emepepimut-S3、结肠癌疫苗(oncoVAX4)、rindopepimut3、troVax4、MGN-16014、MGN-17034;以及
其它药物:阿利维甲酸、贝沙罗汀、硼替佐米、依维莫司、伊班膦酸、咪喹莫特、来那度胺、蘑菇多糖、甲酪氨酸、米伐木肽、帕米磷酸、培加帕酶、喷司他丁、sipuleucel3、西佐糖、他米巴洛汀、替西莫司、沙利度胺、维A酸、维莫德吉、唑来膦酸、沙利度胺、伏立诺他、塞来考昔、西仑吉肽、恩替诺特、依他硝唑、ganetespib、idronoxil、iniparib、ixazomib、氯尼达明、尼莫唑、帕比司他、培瑞维A酸、plitidepsin、泊马度胺、procodazol、ridaforolimus、他喹莫德、telotristat、胸腺法新、替拉扎明、托多司他、trabedersen、乌苯美司、伐司朴达多、今又生(gendicine4)、溶链菌4、reolysin4、盐酸瑞他霉素1,3、trebananib2,3、维鲁利秦4、卡非佐米1,3,血管内皮抑制素4,immucothel4,贝利司他3,MGN-17034。
(1Prop.INN(建议采用的国际非专有名称);2Rec.INN(推荐采用的国际非专有名称);3USAN(美国采用的名称);4no INN(没有名称))。
本发明的另一方面提供药盒,其由分开包装的有效量的本发明化合物和/或其药学上可接受的盐、衍生物、溶剂化物和立体异构体,包括它们的各种比例混合物,以及任选地有效量的其他活性成分所组成。该药盒包含合适的容器,例如,盒子、各种瓶子、袋子或安瓿。例如,该药盒可包含分置的安瓿,每个安瓿装有溶解形式或冻干形式的有效量本发明化合物和/或其药学上可接受的盐、衍生物、溶剂化物和立体异构体,包括它们的各种比例混合物,和有效量的其他活性化合物。
本文所用的术语“治疗”指逆转、减缓、延迟此处描述的疾病或病症或者一或多种症状的出现或抑制此处描述的疾病或病症或者一或多种症状的发展。在一些实施方案中,在一或多种症状已经出现后给予治疗。在其他实施方案中,治疗是在没有症状的情况下给予。例如,在易感个体的症状发作之前给予治疗(例如,基于症状历史和/或遗传或其它感受因素)。在症状消失后可继续治疗,例如防止或延迟其复发。
根据本发明的方法采用任何能有效地治疗或减轻上述病症的严重程度的给药量和给药途径给予化合物和组合物。所需要的确切量视乎不同受试者会有所不同,取决于人种、年龄和受试者的一般状况、感染的严重程度、特定药物、给药方式等。本发明的化合物优选配制成剂量单元形式,易于给药和保持剂量均一。如本文中所使用的术语“单位剂型”指在物理上分开的单位,适于给待治疗的病人单一剂量使用。然而,可以理解的是,本发明的化合物与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。任一具体病人或生物的特定剂量水平取决于多种因素,包括,需要治疗的具体病情及其严重程度、所选用具体化合物的活性、所使用的具体组合物、年龄、体重、健康状况、性别、饮食状态、给药时间和途径、具体化合物的排泄率、治疗的持续时间、与所述用具体化合物联用或共享的药物等等本领域内公知的因素。
本发明的药学上可接受的组合物可经口服、直肠、胃肠外、脑池内、阴道内、腹膜内、局部(如通过粉剂、软膏、或滴剂)、颊内、口用或鼻用喷雾剂等等途径施用于人和其他动物,这取决于感染的严重程度。在某些实施例中,本发明的化合物以剂量水平约0.01mg/kg受试者体重至100mg/kg受试者体重,优选约1mg/kg受试者体重至50mg/kg受试者体重经口服或肠胃外给药,每天一次或更多次,以获得所需的治疗效果。
在某些实施例中,治疗有效量的通式(I)及相关式的化合物以及其他活性成分取决于一些因素,包括例如动物的年龄和体重,需要治疗的准确疾病状态、及其严重程度、制剂的性质和给药的方法,并且最终由治疗医生或兽医决定。然而,化合物的有效量通常在0.1至100mg/kg接受者(哺乳动物)体重/天的范围内,特别是通常在I至10mg/kg体重/天的范围内。因此,体重70kg的成年哺乳动物每天的实际剂量通常在70和700mg之间,其中此量可以采用单独剂量/天、或者通常以一系列部分剂量(例如,2、3、4、5或6次)/天的形式给药,因此总的日剂量是相同的。可以作为化合物本身有效量的分数,来确定其生理功能衍生物的盐或溶剂化物的有效量。
在某些实施例中,药物制剂可以以单位剂量的形式给药,包括每单位剂量的预定量的活性成分。基于被治疗的疾病状况、给药方法及患者的年龄、体重和条件,这种单位剂量可以包含例如0.5mg至lg、优选Img至700mg、特别优选5mg至100mg的本发明化合物;或者药物制剂可以以剂量单位的形式给药,所述剂量单位包含每单位剂量预定量的活性成分。优选的剂量单位剂型是包含每日剂量或者部分剂量(如上所述),或者其相应分数的活性成分的剂型。此外,此类型的药物制剂可以利用药学领域所一般所知的方法制备。
适合口服给药的液体剂型包括,但不限于,药学上可接受的乳剂、微乳液、溶液、悬浮液、糖浆和酏剂。除了活性化合物外,液体剂型任选地含有本领域中常用的惰性稀释剂(例如水或其他溶剂),增溶剂和乳化剂(例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙基烯二醇、1,3-丁基烯二醇、二甲基甲酰胺、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇、脱水山梨醇的脂肪酸酯、以及它们的混合物。除了惰性稀释剂,口服组合物还可以包括助剂如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和芳香剂。
注射制剂,例如无菌可注射的水性或油性悬浮液,是按照已知技术使用适合的分散剂或润湿剂和悬浮剂来配制。无菌可注射制剂也可以是用无毒性的肠胃外可接受的稀释剂或溶剂(例如在1,3-丁二醇中的溶液)配制成无菌注射溶液、悬浮液或乳液。可采用的可接受的载体和溶剂中有水、林格氏溶液、U.S.P和等渗氯化钠溶液。此外,通常使用无菌的不挥发性作为油溶剂或悬浮介质。为此,可以使用任何温和的固定油,包括合成的单甘油酯或二甘油酯。此外,制备注射剂可使用脂肪酸例如油酸。
在使用之前,通过细菌截留过滤器进行灭菌,或以灭菌固体组合物的形式掺入灭菌剂,所述组合物可溶解或分散在灭菌水或其它灭菌可注射介质中,以将注射用制剂灭菌。
为了延长本发明化合物的作用,一般会减慢化合物经皮下或肌肉注射的吸收。这可通过使用水溶性差的结晶或非晶态物质的液体悬浮液来实现。化合物的吸收速率取决于它的溶解速率,而溶解速率又取决于晶体大小和结晶形式而变化的。或者,通过将化合物溶解或悬浮在油类载体中,延迟肠胃外给药的化合物的吸收。在可生物降解的聚合物(聚交酯-聚乙醇酸交酯)中形成化合物的微胶囊基质,制备注射剂的储库形式。根据化合物与聚合物的比例和所用特定聚合物的性质,可以控制化合物的释放速率。其它可生物降解的聚合物的实例包括聚(原酸酯)和聚(酸酐)。将化合物包埋在与机体组织兼容的脂质体或微乳液中,也可制备贮库式可注射制剂。
用于直肠或阴道给药的组合物优选地是栓剂,所述栓剂可通过将本发明的化合物与合适的无刺激性赋形剂或载体如可可脂、聚乙二醇或栓剂用蜡混合来制备,其中所述赋形剂在室温下为固体,但在体温下为液体,因此将在直肠或阴道腔中熔融并释放出活性化合物。
用于口服的固体剂型包括胶囊、片剂、丸剂、粉末和粒剂。在所述固体剂型中,活性化合物与至少一种惰性的药用可接受赋形剂或载体混合,所述药用可接受赋形剂或载体包括柠檬酸钠或磷酸二钙和/或a)填料或补充剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖和硅酸,b)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯树胶,c)致湿剂,例如甘油,d)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、特定的硅酸盐和碳酸钠,e)溶液阻滞剂,例如石蜡,f)吸收促进剂,例如季铵化合物,g)湿润剂,例如十六烷醇和甘油单硬脂酸酯,h)吸收剂,例如高岭土和膨润土,以及i)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基磺酸钠及其混合物。在胶囊、片剂或丸剂的情况下,剂型中还可含有缓冲剂。
相似类型的固体组合物还可以作为填料用于软或硬填充的明胶胶囊,所述胶囊使用例如乳糖或奶糖,以及大分子量的聚乙二醇等作为赋形剂。片剂、糖衣丸、胶囊、丸剂和粒剂的固体剂型可以采用包衣和外壳制备,例如肠溶衣和药物配制领域公知的其它包衣。它们任选地含有不透明剂,并且成为组合物,任选地以滞后的方式,仅仅(或优选)在肠道的特定部位释放活性成分。可使用的包埋组合物的例子包括聚合物和蜡。相似类型的固体组合物还可以作为填料用于软或硬填充的明胶胶囊,所述胶囊使用例如乳糖或奶糖,以及大分子量的聚乙二醇等作为赋形剂。
活性化合物也可与一种或多种赋形剂,例如上文描述的赋形剂,一起配制为微胶囊形式。片剂、糖衣丸、胶囊、丸剂和粒剂的固体剂型可以采用包衣和外壳制备,例如肠溶衣、控释包衣和药物配制领域公知的其它包衣。在所述固体剂型中,活性化合物与至少一种惰性稀释剂混合,所述稀释剂例如是蔗糖、乳糖或淀粉。正常实践中,这样的剂型也包括除惰性稀释剂之外的压片润滑剂和其它压片助剂,例如硬脂酸镁和微晶纤维素。在胶囊、片剂或丸剂的情况下,剂型中还可含有缓冲剂。它们任选地含有不透明剂,并且成为组合物,任选地以滞后的方式,仅仅(或优选)在肠道的特定部位释放活性成分。可使用的包埋组合物的例子包括聚合物和蜡。
用于局部或经皮给药的本发明化合物的剂型包括软膏剂、糊剂、霜剂、洗剂、凝胶、粉剂、溶液、喷雾剂、吸入剂或贴剂。活性化合物在灭菌条件下与药用可接受载体以及任何需要的防腐剂、缓冲剂或推进剂混合。眼用的制剂、滴耳剂和滴眼剂也在本发明考虑的范围内。另外,本发明涵盖使用经皮贴片,其额外优点是能够可控地向机体递送化合物。在适当的介质中溶解或分散化合物,可制成这种剂型。也可使用吸收增强剂,用于增加化合物通过皮肤的通量。提供速率控制膜或将化合物分散在聚合物基质或凝胶中,可以控制所述速率。
根据一个实施方案,本发明涉及一种在生物样品中抑制IRAK活性的方法,所述方法包括使所述生物样品与本发明的化合物或包含本发明化合物的组合物接触的步骤。
根据另一个实施方案,本发明涉及一种在生物样品中正向地抑制IRAK或其突变体的活性的方法,所述方法包括使所述生物样品与本发明的化合物或包含本发明化合物的组合物接触的步骤。
体外使用本发明的化合物作为理解IRAK生物作用的独特工具,所述生物作用包括评价许多因子,这些因子被认为影响IRAK生产以及IRAK的相互作用,以及被IRAK生产以及IRAK的相互作用所影响的许多因子。本发明的化合物也可用在研发与IRAK相互作用的其他化合物,这是因为本发明的化合物提供了进行这种研发的重要的结构-活性关系(SAR)信息。本发明的化合物与IRAK结合,其用作试剂可检测活细胞上、固定细胞上、生物流体内、组织匀浆内、纯的天然材料内的IRAK,等等。例如,通过标记所述化合物,人们就能够鉴定到表达IRAK的细胞。另外,由于本发明的化合物具有能够与IRAK结合的能力,它们可用在原位染色、FACS(荧光活化细胞分拣)、十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)、ELISA(酶联免疫吸附试验)、酶纯化中,或者用于纯化在透化细胞内表达IRAK的细胞。本发明的化合物也可用作各种医学研究和诊断用途的商业研究试剂。这样的用途包括但不限于:在各种功能性试验中用作定量候选IRAK抑制剂的活性的校准标准;在随机化合物筛选中用作阻断剂,即在寻找新的IRAK配体家族时,可使用化合物来阻断本发明要求保护的IRAK化合物的恢复;与IRAK酶在共结晶中使用,即本发明的化合物允许化合物与IRAK结合形成晶体,从而通过X射线晶体照相术来确定酶/化合物的结构;用于其他研究和诊断应用,其中IRAK较佳地被启动,或这样的启动相对于已知量的IRAK抑制剂能方便地进行校准;用在分析试验中作为探针来确定细胞内IRAK的表达;以及用于研发分析试验中检测IRAK结合配体所在的位点的化合物。
可施加本发明的化合物或者将本发明的化合物与物理手段结合来诊断治疗效果。含有所述化合物的药物组合物以及所述化合物用于治疗IRAK介导的病症是有前景的一种新方法,可应用在各种不同的治疗中,能直接和实时改善人或动物的健康状况。本发明的口服生物利用度和新的活性化学物质更加方便了病人和医生的顺从性。
通式(I)化合物及其盐、异构体、互变异构体、对映体形式、非对映体、外消旋体、衍生物、前药和/或代谢物的特征是高特异性和稳定性、低制造成本和方便处理。这些特征构成能重复再现作用的基础,其中包括没有交叉反应,并且可靠安全地与靶结构相互作用。
本文所用的术语“生物样品”包括,但不限于,细胞培养物或其提取物、从哺乳动物或其提取物获得的活组织检查材料、以及血液、唾液、尿液、粪便、精液、泪液或者其他体液或其提取物。
调节生物样品中的IRAK或其突变体的活性可用于各种本领域技术人员已知的各种目的。这类目的的实例包括,但不限于,输血、器官移植、生物试样储存和生物试验。
具体实施方式
如在下面的实施例所描述那样,在某些示例性实施方案中按照以下一般程序制备化合物。应当理解,尽管一般方法描述了本发明某些化合物的合成,但下面的一般方法以及本领域普通技术人员所公知的其他方法的也适用于合成本文描述的所有化合物及每个化合物的子类和种类。
以下方法、流程和实施例的下列描述中使用的符号和惯例与现代科学文献(例如美国化学协会或生物化学杂志)中使用的那些一致。
除非另外指明,所有温度以℃(摄氏度)表示。
除非另外指出,全部反应在室温下进行。本发明的全部化合物由发明人设计的方法合成。
在Bruker Avance III 400MHz或Bruker DPX-300MHz光谱仪上记录1H-NMR谱。化学位移以在每百万份(ppm,δ单位)表示。偶合常数以赫兹为单位(Hz)。分裂模式描述明显的多重性,表示如下:s(单峰),d(双峰),t(三重峰),q(四重峰),m(多重峰),br(宽)。
从Agilent technologies的Agilent 1200系列质谱仪上获得质谱数据,使用大气化学电离(APCI)或电喷雾离子化(ESI)。柱:XBridge C8,3.5μm,4.6x 50mm;溶剂A:水+0.1%TFA;溶剂B:ACN;流量:2毫升/分钟;梯度:0分:5%B,8分钟:100%B,8.1分钟:100%B,8.5分:5%B,10分钟,5%B或LC/MS水s ZMD(ESI)。
从Agilent technologies的Agilent 1100系列高效液相色谱仪上获得HPLC数据,使用柱(XBridge C8,3.5μm,4.6x 50mm)和两个流动相(流动相A:水+0.1%TFA;流动相B:ACN+0.1%TFA)。流量:2毫升/分钟。梯度方法是:0分:5%B,8分钟:100%B,8.1分钟:100%B,8.5分:5%B,10分钟,5%B,除非另有指明。
使用Biotage Initiator Microwave Synthesizer或者单模式微波反应器EmrysTMOptimiser按照本领域已知的标准协议进行微波反应。
以下实施例使用的化合物编号对应于上文的化合物编号。
以下缩写是指下文中所使用的缩写:
Ac(乙酰基)、BINAP(2,2’-双(二苯基膦)-1,1’-联萘)、dba(二苄叉丙酮)、Bu(丁基)、tBu(叔丁基)、DCE(二氯乙烷)、DCM(二氯甲烷)、δ(化学位移)、DIEA(二异丙基乙胺)、DMA(二甲基乙酰胺)、DMSO(二甲基亚砜)、DMF(N,N-二甲基甲酰胺)、Dppf(1,1'-双(二苯基膦)二茂铁)、乙酸乙酯(乙酸乙酯)、EtOH(乙醇)、eq(当量)、g(克)、cHex(环己烷)、HATU(六氟磷酸N-[(二甲基氨基)(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基氧基)亚甲基]-N-甲基甲铵)、HPLC(高效液相色谱法)、h(小时)、LDA(二异丙基胺锂)、LiHMDS(双(三甲基硅烷基)氨基锂)、MHz(兆赫)、甲醇(甲醇)、min(分钟)、mL(毫升)、mmol(毫摩尔)、mM(毫摩尔/升)、mp(熔点)、MS(质谱法)、MW(微波)、NMR(核磁共振)、O/N(过夜)、PBS(磷酸盐缓冲生理盐水)、RT(室温)、TEA(三乙胺)、TFA(三氟乙酸)、THF(四氢呋喃)、TLC(薄层层析法)。
一般而言,根据本发明的通式(I)及相关式的化合物可以从容易获得的起始物质制备。如果这种起始物质无法从市场上买到,则可利用标准合成技术制备。一般而言,用于通式(I)及相关式的任何单个化合物的合成路径将取决于各分子的具体取代基,此类因子正如本领域普通技术人员所理解的。可采用下文实施例中所描述的以下一般方法和步骤来制备通式(I)及相关式的化合物。下面合成路线中所描述的反应条件(例如温度、溶剂、或共试剂)只是作为例子给出而并不是限制性的。应当理解的是,在给出典型的或优选的实验条件(即反应温度、时间、试剂的摩尔数、溶剂等)的情况下,除非另有说明也可以采用其他实验条件。最佳反应条件可视所使用的具体反应剂或溶剂而变化,但这种条件可以由本领域技术人员利用常规的优化步骤来确定。对于所有的保护和脱保护方法,参见PhilipJ.Kocienski的“保护基(Protecting Groups),Georg Thieme Verlag Stuttgart,纽约(1994年)、以及Theodora W.Greene和Peter G.M.Wuts in“有机合成中的保护基(Protective Groups in Organic Synthesis),Wiley Interscience,第三版(1999年)。
流程1:苯基-吡啶的合成路途的例子
流程2:吡啶基-吡啶的合成路途的例子
流程3:吡唑基-嘧啶(其中A是O或者NR)的合成路途的例子
流程4:噻二唑基-嘧啶(其中A是O或者NR)的合成路途的例子
中间体1:4-{4-[6-(3-氨基苯基)吡啶-3-基]-1H-吡唑-1-基}哌啶-1-羧酸叔丁酯
5-溴-2-碘吡啶(500mg;1.76mmol;1.00eq.)、3-氨基苯基硼酸(241mg;1.76mmol;1.00eq.)、碳酸钾(974mg;7.04mmol;4.00eq.)和Pd(PPh3)4(102mg;0.09mmol;0.05eq.)在二噁烷(7.50mL)和水(3.75mL)中的混合物装在密封小瓶中,在100℃加热过夜。反应混合物用乙酸乙酯稀释,水洗涤。有机层用乙酸乙酯反萃取,有机层合并,经MgSO4干燥,过滤,浓缩,获得3-(5-溴吡啶-2-基)苯胺(438mg,100%)。将3-(5-溴吡啶-2-基)苯胺(435mg;1.75mmol;1.00eq.)、4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-吡唑-1-基]-哌啶-1-羧酸叔丁酯(659mg;1.75mmol;1.00eq.)、碳酸钾(965mg;6.98mmol;4.00eq.)和Pd(PPh3)4(101mg;0.09mmol;0.05eq.)在密封小瓶中悬于二噁烷(6.5mL)和水(3.4mL)中。反应混合物在120℃微波加热30分钟,然后用乙酸乙酯稀释,水洗涤。有机层用乙酸乙酯反萃取。有机层合并,经MgSO4干燥,过滤,浓缩。通过硅胶快速色谱法纯化(乙酸乙酯:DCM,梯度从50%至100%),获得标题化合物,为米色固体(390mg;37%)。1H NMR(300MHz,DMSO-d6):8.87(dd,J=2.0Hz,0.6Hz,1H),8.42(s,1H),8.02-7.98(m,2H),7.79(dd,J=8.4Hz,0.6Hz,1H),7.34(t,J=2.0Hz,1H),7.19(dt,J=7.8Hz,1.5Hz,1H),7.11(t,J=7.8Hz,1H),6.62-6.58(m,1H),5.18(s,2H),4.43-4.34(m,1H),4.07-3.99(m,2H),2.93(m,2H),2.07-2.03(m,2H),1.88-1.74(m,2H),1.43(s,9H)。
中间体2:4-{4-[6-(3-碘苯基)吡啶-3-基]-1H-吡唑-1-基}哌啶-1-羧酸叔丁酯
将亚硝酸异戊酯(稳定的,375μl;2.79mmol;3.00eq.)加入至4-4-[6-(3-氨基苯基)吡啶-3-基]-1H-吡唑-1-基哌啶-1-羧酸叔丁酯(390mg;0.93mmol;1.00eq.)、碘化亚铜(212mg;1.12mmol;1.20eq.)和二碘甲烷(377μl;4.65mmol;5.00eq.)在干THF(15.6mL)中的溶液中,反应混合物回流1小时。反应混合物再经由硅藻土垫过滤,滤液浓缩至干。通过硅胶快速色谱法纯化(乙酸乙酯:庚烷,梯度:由20%至100%乙酸乙酯),获得标题化合物(215mg;43.6%)。1H NMR(300MHz,DMSO-d6):8.94(dd,J=2.0Hz,0.7Hz,1H),8.47-8.45(m,2H),8.13-7.95(m,4H),7.79-7.76(m,2H),7.29(t,J=7.8Hz,1H),4.45-4.35(m,1H),4.08-4.00(m,2H),2.94(m,2H),2.04-2.03(m,2H),1.88-1.74(m,2H),1.43(s,9H)。LC/MS:531.5(M+1)。
中间体3:4-[4-(6-氨基-吡啶-3-基)-吡唑-1-基]-哌啶-1-羧酸叔丁酯
将在密封小瓶中的5-碘-吡啶-2-基胺(1.10g;5.00mmol;1.0eq.)、4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-吡唑-1-基]-哌啶-1-羧酸叔丁酯(2.07g;5.50mmol;1.10eq.)、Pd(PPh3)4(289mg;0.25mmol;0.05eq.)和碳酸钾(2.07g;15.00mmol;3.00eq.)在二噁烷(38mL)中的混合物在100℃加热过夜。反应混合物用乙酸乙酯稀释,水洗涤。有机层用乙酸乙酯反萃取,有机层合并,经MgSO4干燥,过滤,浓缩。将获得的固体悬于乙酸乙酯中过滤,真空干燥,获得标题化合物,为米色固体(1g,70%)。HPLC:(254nm)95%;Rt(min)2.60;LC/MS:344.3(M+1)。
中间体4:4-[4-(6-碘-吡啶-3-基)-吡唑-1-基]-哌啶-1-羧酸叔丁酯
采用4-[4-(6-氨基-吡啶-3-基)-吡唑-1-基]-哌啶-1-羧酸叔丁酯(1.21g;3.52mmol;1.00éq.)为起始材料,依据中间体2的方法制备标题化合物,为褐色胶状物(390mg;0.86mmol)。HPLC:(254nm)68%;Rt(min)4.44.LC/MS:455.4(M+1)。
中间体5:4-[4-(6'-氯-[2,2']二吡啶基-5-基)-吡唑-1-基]-哌啶-1-羧酸叔丁酯
采用4-[4-(6-碘-吡啶-3-基)-吡唑-1-基]-哌啶-1-羧酸叔丁酯(150mg;0.33mmol;1.00eq.)和2-氯-6-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-吡啶(87mg;0.36mmol;1.10eq.)为起始材料,依据以下实施例1步骤1的方法制备标题化合物,为褐色胶状物(180mg,定量)。LC/MS:440.4(M+1)。
中间体6:3-[(5-溴-2-氯-嘧啶-4-基氨基)-甲基]-哌啶-1-羧酸叔丁酯
保持在0℃,将5-溴-2,4-二氯-嘧啶(2.12g;9.33mmol;2.00eq.)加入至NaH(134mg;5.6mmol;1.20eq.)在THF(16mL)中的悬液中。反应混合物搅拌5分钟,然后向混合物加入3-氨基甲基-哌啶-1-羧酸叔丁酯(1.0g;4.67mmol;1.00eq.)。在0℃下搅拌过夜,用甲醇稀释,经硅藻土过滤,浓缩。通过硅胶快速色谱法纯化(乙酸乙酯:己烷,梯度:由0至100%,然后换成甲醇:DCM,梯度:由0至20%),在第二次洗脱馏分中获得标题化合物,为白色粉末(587mg,31%)。1H NMR(400MHz,氯仿-d)δ8.22(s,1H),4.84(brs,1H),4.37-4.12(m,2H),3.25-3.09(m,2H),3.03(m,1H),2.99-2.86(m,1H),1.90(m,2H),1.81(m,1H),1.67(m,1H),1.46(s,9H),1.32(m,1H)。LC/MS:405.0(M+1)。
中间体7:3-{[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基氨基]-甲基}-哌啶-1-羧酸叔丁酯
3-[(5-溴-2-氯-嘧啶-4-基氨基)-甲基]-哌啶-1-羧酸叔丁酯(252mg;0.62mmol;1.00eq.)、1-甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(194mg;0.93mmol;1.50eq.)、K3PO4(264mg;1.24mmol;2.00eq.)和Pd(dppf)Cl2(23mg;0.03mmol;0.05eq.)在水(0.2mL)和2-甲基四氢呋喃(5.6mL)中的混合物脱氩气,并在密封试管中加热至100℃,保持2小时。然后经硅藻土垫过滤,减压浓缩。通过硅胶快速色谱法纯化(乙酸乙酯:己烷,梯度:由0至100%),获得标题化合物,为白色固体(97mg,38%)。LC/MS:407.7(M+1)。
中间体8:[1-(5-溴-2-氯-嘧啶-4-基)-哌啶-3-基甲基]-氨基甲酸叔丁酯
采用5-溴-2,4-二氯-嘧啶(3.3mL;23.33mmol;2.00eq.)和哌啶-3-基甲基-氨基甲酸叔丁酯(2.5g;11.7mmol;1.00eq.)为起始材料,依据中间体6的方法制备标题化合物,为黄色固体1H NMR(400MHz,氯仿-d)δ8.24(s,1H),4.81(s,1H),4.27(t,J=13.7Hz,2H),3.16(m,2H),3.10–3.02(m,1H),3.02–2.85(m,1H),1.98–1.86(m,2H),1.81(m,1H),1.74–1.61(m,1H),1.48(s,9H),1.42–1.23(m,1H)。LC/MS:405.1(M+1)。
中间体9:{1-[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基]-哌啶-3-基甲基}-氨基甲酸叔丁酯
[1-(5-溴-2-氯-嘧啶-4-基)-哌啶-3-基甲基]-氨基甲酸叔丁酯(750mg;1.85mmol;1.00eq.)、1-甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(462mg;2.22mmol;1.20eq.)、磷酸钾(785mg;3.70mmol;2.00eq.)和Pd(dppf)Cl2.DCM(135mg;0.18mmol;0.10eq.)在水(0.60mL)和2-甲基四氢呋喃(5.6mL)中的混合物脱氩气,并在密封试管中加热至100℃,保持2小时。然后经硅藻土垫过滤,减压浓缩。通过硅胶快速色谱法纯化(乙酸乙酯:己烷,梯度:由0至100%),获得标题化合物,为黄色泡沫(640mg,85%)。1H NMR(400MHz,氯仿-d)δ7.94(s,1H),7.55(s,1H),7.49(s,1H),4.85(t,J=6.4Hz,1H),3.96(s,3H),3.87–3.73(m,1H),3.73–3.58(m,1H),3.04(dt,J=12.8,5.8Hz,1H),2.87(m,3H),1.86–1.68(m,2H),1.68–1.54(m,1H),1.43(brs,11H);LC/MS:407.2(M+1)。
中间体10:4-[(5-溴-2-氯-嘧啶-4-基氨基)-甲基]-哌啶-1-羧酸叔丁酯
采用5-溴-2,4-二氯-嘧啶(1.33mL;9.33mmol;2.00eq.)和4-氨基甲基-哌啶-1-羧酸叔丁酯(1g;4.67mmol;1.00eq.)为起始材料,依据中间体6的方法制备标题化合物,为白色固体(1.6g,83%)。LC/MS:405(M+1)。
中间体11:4-{[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基氨基]-甲基}-哌啶-1-羧酸叔丁酯
采用3-[(5-溴-2-氯-嘧啶-4-基氨基)-甲基]-哌啶-1-羧酸叔丁酯(300mg;0.74mmol;1.00eq.)和1-甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(参照WO 2014008992描述的方法制备;231mg;1.11mmol;1.50eq)为起始材料,依据中间体9的方法制备标题化合物(125mg,42%)。LS/MS:407.2(M+1)。
中间体12:5-溴-2-氯-4-(四氢-吡喃-2-基甲氧基)-嘧啶
保持在0℃,将5-溴-2,4-二氯-嘧啶(4.16mL;29.3mmol;2.00eq.)加入至NaH(702mg;17.6mmol;1.20eq.)在THF(37mL)中的悬液中。反应混合物搅拌5分钟,然后向混合物加入(四氢-吡喃-2-基)-甲醇(1.7mL;14.6mmol;1.00eq.)。在0℃下搅拌过夜,用甲醇稀释,经硅藻土过滤,浓缩。通过硅胶快速色谱法纯化((乙酸乙酯:己烷,0至50%),获得标题化合物,为白色固体(1.61g,34%)。LC/MS:307.0(M+H)。
中间体13:5-(1-甲基-1H-吡唑-3-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-4-(四氢-吡喃-2-基甲氧基)-嘧啶
5-溴-2-氯-4-(四氢-吡喃-2-基甲氧基)-嘧啶(400mg;1.30mmol;1.00eq.)、1-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(406mg;1.95mmol;1.50eq.)、K3PO4(552mg;2.60mmol;2.00eq.)和Pd(dppf)Cl2*DCM(95mg;0.13mmol;0.10eq.)在水(0.30mL)和2-甲基四氢呋喃(3.00mL;29.95mmol;23.03eq.)中的溶液鼓泡15分钟,脱氩气,然后加热至100℃,保持30min。冷却至室温,经硅藻土垫过滤。硅藻土垫用乙酸乙酯洗涤,减压浓缩滤液。通过硅胶快速色谱法纯化(乙酸乙酯:己烷,梯度:由0至100%,再换成甲醇/DCM,梯度:由10至20%),获得标题化合物,为浅黄色固体(272mg,64.4%)。LC/MS:309.9(M+1)。
中间体14:5-溴-2-氯-4-(3-甲基-氧杂环丁烷-3-基甲氧基)-嘧啶
在0℃和氮气气氛下,15分钟内将(3-甲基-氧杂环丁烷-3-基)-甲醇(2g;19.6mmol;1.00eq.)滴加入氢化钠(60%矿物油溶液,0.98g;24.48mmol;1.25eq.)和5-溴-2,4-二氯-嘧啶(8.92g;39.2mmol;2.00eq.)在THF(50mL)中的悬液中。减压移除溶剂,粗残留物经硅胶柱快速色谱法(乙酸乙酯:己烷,梯度:由0至100%,再换成甲醇:DCM梯度:由10至20%)纯化,获得标题化合物,为白色固体(375mg,6.5%)。1H NMR(400MHz,氯仿-d)δ8.47(s,1H),4.63(d,J=6.1Hz,2H),4.55(s,2H),4.47(d,J=6.1Hz,2H),1.46(s,3H)。
中间体15:
采用5-溴-2-氯-4-(3-甲基-氧杂环丁烷-3-基甲氧基)-嘧啶(375mg;1.28mmol;1.00eq.)、1-甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(399mg;1.92mmol;1.50eq.)为起始材料,依据中间体13的方法制备标题化合物,为黄褐色固体(165.1mg,44%)。LC/MS:407.72(M+1)。
中间体16:3-{[2-氯-5-(1-甲基-1H-吡唑-3-基)-嘧啶-4-基氨基]-甲基}-哌啶-1-羧酸叔丁酯
采用3-[(5-溴-2-氯-嘧啶-4-基氨基)-甲基]-哌啶-1-羧酸叔丁酯(400mg;0.99mmol;1.00eq.)和1-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(308mg;1.48mmol;1.50eq.)为起始材料,依据中间体9的方法制备标题化合物,为褐色固体(680mg,定量)。LC/MS:407.2(M+1)。
中间体17:5-溴-2-氯-4-(氧杂环丁烷-3-基甲氧基)-嘧啶
采用5-溴-2,4-二氯-嘧啶(1.62mL;11.35mmol;2.00eq.)和氧杂环丁烷-3-基-甲醇(500mg;5.68mmol;1.00eq.)为起始材料,依据中间体14的方法制备标题化合物,为黄色油(500mg,31.5%)。1H NMR(400MHz,氯仿-d)δ8.42(d,J=1.1Hz,1H),4.84(ddd,J=7.7,6.3,1.1Hz,2H),4.67(dd,J=6.7,1.1Hz,2H),4.62–4.42(m,2H),3.48(qt,J=5.8Hz,1H)。
中间体18:2-氯-5-(1-甲基-1H-吡唑-4-基)-4-(氧杂环丁烷-3-基甲氧基)-嘧啶
采用5-溴-2-氯-4-(氧杂环丁烷-3-基甲氧基)-嘧啶(500mg;1.79mmol;1.00eq.)和1-甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(558mg;2.68mmol;1.50eq.)为起始材料,依据中间体9的方法制备标题化合物,为白色固体(109mg,22%)。LC/MS:281.1(M+1)。
中间体19:4-{[2-氯-5-(1-甲基-1H-吡唑-3-基)-嘧啶-4-基氨基]-甲基}-哌啶-1-羧酸叔丁酯
采用4-[(5-溴-2-氯-嘧啶-4-基氨基)-甲基]-哌啶-1-羧酸叔丁酯(800mg;1.97mmol;1.00eq.)、1-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(615mg;2.96mmol;1.50eq.)为起始材料,依据中间体9的方法制备标题化合物,为褐色固体(541mg,67%)。LC/MS:407.2(M+1)。
中间体20:[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基]-(四氢-吡喃-4-基甲基)-胺
采用(5-溴-2-氯-嘧啶-4-基)-(四氢-吡喃-4-基甲基)-胺(335mg;1.09mmol;1.00eq.)和1-甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(341mg;1.64mmol;1.50eq.)为起始材料,依据中间体7的方法制备标题化合物,为褐色油(206mg,49%)。LC/MS:308.2(M+1)。
中间体21:(5-溴-2-氯-嘧啶-4-基)-(1-甲磺酰基-哌啶-4-基)-胺
5-溴-2,4-二氯-嘧啶(1.72mL;13.46mmol;1.20eq.)、1-甲磺酰基-哌啶-4-基胺(2.0g;11.22mmol;1.00eq.)和DIPEA(3.0mL;17.22mmol;1.54eq.)在THF(34.00mL)中的混合物在室温和氮气气氛下搅拌90分钟。减压除去溶剂,粗产物经硅胶快速色谱法(乙酸乙酯:己烷,梯度:由60%to 100%)纯化,获得标题化合物,为白色固体(318mg,8%)。LC/MS:369.0(M+1)。
中间体22:[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基]-(1-甲磺酰基-哌啶-4-基)-胺
采用(5-溴-2-氯-嘧啶-4-基)-(1-甲磺酰基-哌啶-4-基)-胺(2165mg;5.86mmol;1.00eq.)和1-甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(1828mg;8.78mmol;1.50eq.)为起始材料,依据中间体7的方法制备标题化合物,为米色固体(870mg,32%)。LC/MS:371.1(M+1)。
中间体23:2-氯-4-异丙基氨基-嘧啶-5-羧酸乙酯
2,4-二氯-嘧啶-5-羧酸乙酯(8.00g;34.4mmol;1.00eq.)、乙基-二异丙基胺(12.10mL;68.77mmol;2.00eq.)和异丙基胺(2.09g;35.1mmol;1.02eq.)在DCM(80mL)中的溶液室温搅拌3小时。反应混合物用水洗涤,有机层经硫酸钠干燥,过滤,浓缩。通过硅胶快速色谱法纯化获得标题化合物,为无色液体(7.6g;30.28mmol;88.1%)。1H NMR(400MHz,DMSO)8.61(s,1H),8.24(d,J=7.6Hz,1H),4.32-4.27(m,2H),4.25-4.22(m,1H),1.30(t,J=7.0Hz,3H),1.21(d,J=6.5Hz,6H);HPLC:(254nm)96%;Rt 4.69min;LC/MS:244(M+1)。
中间体24:4-异丙基氨基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-羧酸乙酯
将Pd(dppf)2Cl2.CH2Cl2加入至脱气后的2-氯-4-异丙基氨基-嘧啶-5-羧酸乙酯(7.0g;28.0mmol;1.00eq.)、碳酸钾(7.98g;56.00mmol;2.00eq.)和1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(11g;30.80mmol;1.10eq.)在二噁烷-1,4(140mL)和水(35mL)中的溶液中。反应混合物在100℃搅拌过夜。再经硅藻土垫过滤,减压浓缩。残留物用水(50mL)稀释,乙酸乙酯(2 x 50mL)萃取。有机层合并,无水Na2SO4干燥,过滤,浓缩。通过硅胶快速色谱法纯化(乙酸乙酯:PE,50:50),获得标题化合物,为白色固体(3.5g,29%)。HPLC:(254nm)90%;Rt 3.88min;LC/MS:366.3(M+1)。
中间体25:4-异丙基氨基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-羧酸酰肼
边搅拌边将肼一水合物(0.17mL;3.47mmol;5.00eq.)加入至4-异丙基氨基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-羧酸乙酯(300mg;0.69mmol;1.00eq.)在乙醇(6.00mL)中的溶液中。反应混合物在90℃回流过夜。然后冷却至室温,减压浓缩(一半体积)。滤出沉淀物,用冷冻乙醇洗涤,获得标题化合物,为白色固体(180mg,73%)。1H NMR(400MHz,DMSO):9.94(s,1H),8.66(s,1H),8.60(d,J=7.4Hz,1H),8.48(s,1H),8.21(s,1H),8.17(d,J=7.9Hz,1H),7.88(s,1H),7.70(d,J=7.8Hz,1H),7.48(t,J=7.8Hz,1H),4.52(brs,2H),4.47-4.39(m,1H),3.88(s,3H),1.28(d,J=6.52Hz,6H)。HPLC:(254nm)94%;Rt 2.9min;LC/MS:352.3(M+1)。
中间体26:5-{4-异丙基氨基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-基}-[1,3,4]噻二唑-2-羧酸乙酯
步骤1:(N'-{4-异丙基氨基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-羰
基}-肼基)-氧代-乙酸乙酯
保持在0℃,将氯-氧代-乙酸乙酯(0.32mL;2.82mmol;1.05eq.)滴加入4-异丙基氨基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-羧酸酰肼(0.95g;2.68mmol;1.0eq.)和TEA(1.05mL;8.05mmol;3.00eq.)在DCM(28.50mL)中的溶液中。反应混合物升至室温,搅拌30分钟。加入饱和NaHCO3溶液淬灭反应物,再用DCM萃取。有机层合并,经Na2SO4干燥,过滤,浓缩。通过硅胶快速色谱法纯化(DCM:甲醇),获得标题化合物,为黄色固体(1g,70%)。HPLC:(254nm)92%;Rt 3.36min;LC/MS:452.2(M+1)。
步骤2:5-{4-异丙基氨基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-基}-[1,
3,4]噻二唑-2-羧酸乙酯
将(N'-{4-异丙基氨基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-羰基}-肼基)-氧代-乙酸乙酯(0.78g;1.62mmol;1.00eq.)和2,4-二-(4-甲氧基-苯基)-[1,3,2,4]二硫杂二磷杂环丁烷(dithiadiphosphetane)2,4-二硫化物(1.49g;3.57mmol;2.20eq.)在THF(39mL)中的溶液回流加热3小时。反应混合物用乙酸乙酯稀释,10%NaHCO3溶液洗二次。有机层经Na2SO4干燥,过滤,浓缩。通过硅胶快速色谱法纯化(DCM:甲醇),获得标题化合物,为黄色固体(1g,82%)。1H NMR(400MHz,DMSO-d6)δ:8.99(s,1H),8.85(d,J=7.24Hz,1H),8.55(s,1H),8.31-8.21(m,2H),7.90(s,1H),7.75(d,J=7.40Hz,1H),7.52(t,J=8.08Hz,1H),5.75(s,2H),4.65-4.60(m,1H),4.49-4.44(m,2H),3.89(s,3H),3.80-3.60(m,1H),1.39-1.35(m,9H)。HPLC:(254nm)99%;Rt 4.33min;LC/MS:450.2(M+H)。
中间体27:4-(1-叔丁氧基羰基-哌啶-3-基氨基)-2-氯-嘧啶-5-羧酸乙酯
采用2,4-二氯-嘧啶-5-羧酸乙酯(5.0g;21.49mmol;1.00eq.)和3-氨基-哌啶-1-羧酸叔丁酯(4.43g;21.92mmol;1.02eq.)为起始材料,依据中间体23的方法制备标题化合物,为黄色胶状物(8.50g;17.14mmol;79.7%)。HPLC:(254nm)72%;Rt 5.27min;LC/MS:385(M+1)。
中间体28:3-{5-肼基羰基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-哌啶-1-羧酸叔丁酯
步骤1:4-(1-叔丁氧基羰基-哌啶-3-基氨基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯
基]-嘧啶-5-羧酸乙酯
采用4-(1-叔丁氧基羰基-哌啶-3-基氨基)-2-氯-嘧啶-5-羧酸乙酯(8.0g;16.01mmol;1.00eq.)和1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(6.29g;17.61mmol;1.10eq.)为起始材料,依据中间体24的方法制备标题化合物,为胶状物(5.0g,59%)。HPLC:(254nm)93%;Rt 4.51min;LC/MS:507.2(M+1)。
步骤2:3-{5-肼基羰基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-
哌啶-1-羧酸叔丁酯
采用4-(1-叔丁氧基羰基-哌啶-3-基氨基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-羧酸乙酯(3.0g;5.68mmol;1.00eq.)为起始材料,依据中间体25的方法制备标题化合物,为乳白色固体(2g,69%)。HPLC:(254nm)89%;Rt 3.53min;LC/MS:493.2(M+H)。
中间体29:3-{5-(5-乙氧基羰基-[1,3,4]噻二唑-2-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-哌啶-1-羧酸叔丁酯
步骤1:3-{5-(N'-乙氧基草酰基-肼基羰基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯
基]-嘧啶-4-基氨基}-哌啶-1-羧酸叔丁酯
采用3-{5-肼基羰基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-哌啶-1-羧酸叔丁酯(500mg;0.98mmol;1.00eq.)在DCM(10mL)中的溶液和氯-氧代-乙酸乙酯(0.12mL;1.03mmol;1.05eq.)为起始材料,依据中间体26步骤1的方法制备标题化合物,为黄色固体(420mg,66%)。HLPC:(254nm)89%;Rt 3.94min;LC/MS:593.3(M+H)。
步骤2:3-{5-(5-乙氧基羰基-[1,3,4]噻二唑-2-基)-2-[3-(1-甲基-1H-吡唑-4-
基)-苯基]-嘧啶-4-基氨基}-哌啶-1-羧酸叔丁酯
采用3-{5-(N'-乙氧基草酰基-肼基羰基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-哌啶-1-羧酸叔丁酯(300mg;0.47mmol;1.00eq.)为起始材料,依据中间体26步骤2的方法制备标题化合物,为黄色固体(150mg,52%)。HPLC:(254nm)88%;Rt5.05min;LC/MS:591.2(M+H)。
中间体30:4-[(1-叔丁氧基羰基-氮杂环丁烷-3-基甲基)-氨基]-2-氯-嘧啶-5-羧酸乙酯
采用2,4-二氯-嘧啶-5-羧酸乙酯(2.50g;10.74mmol;1.00eq.)和3-氨基甲基-氮杂环丁烷-1-羧酸叔丁酯(2.06g;10.96mmol;1.02eq.)为起始材料,依据中间体23的方法制备标题化合物,为无色胶状物(2.0g,54%)。HPLC:(254nm)98%;Rt 6.35min;LC/MS:369.0(M+H)。
中间体31:3-({5-肼基羰基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-甲基)-氮杂环丁烷-1-羧酸叔丁酯
步骤1:4-[(1-叔丁氧基羰基-氮杂环丁烷-3-基甲基)-氨基]-2-[3-(1-甲基-1H-
吡唑-4-基)-苯基]-嘧啶-5-羧酸乙酯
采用4-[(1-叔丁氧基羰基-氮杂环丁烷-3-基甲基)-氨基]-2-氯-嘧啶-5-羧酸乙酯(2.20g;5.81mmol;1.00eq.)和1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(2.28g;6.40mmol;1.10eq.)为起始材料,依据中间体24的方法制备标题化合物,为白色固体(2.0g,54%)。1H NMR(400MHz,DMSO-d6)δ:8.86(s,1H),8.51-8.47(m,1H),8.21-8.19(m,2H),7.89(d,J=0.44Hz,1H),7.75-7.72(m,1H),7.49(t,J=7.76Hz,1H),4.36-4.30(m,2H),3.88(s,6H),3.74-3.80(m,2H),3.20-3.00(m,1H),1.35-1.31(m,12H)。HPLC(XBridge C8(50x4.6mm,3.5μm):(254nm)96%;Rt 4.0min;LC/MS:493.2(M+H)。
步骤2:3-({5-肼基羰基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-
甲基)-氮杂环丁烷-1-羧酸叔丁酯
采用苯基-嘧啶-5-羧酸乙酯(1.10g;2.14mmol;1.00eq.)为起始材料,依据中间体25的方法制备标题化合物,为乳白色固体(900mg,82%)。HPLC(254nm)90%;Rt 3.43min;LC/MS:479.2(M+H)。
中间体32:5-{4-[(1-叔丁氧基羰基-氮杂环丁烷-3-基甲基)-氨基]-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-基}-[1,3,4]噻二唑-2-羧酸甲酯
步骤1:3-({5-(N'-甲氧基草酰基-肼基羰基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯
基]-嘧啶-4-基氨基}-甲基)-氮杂环丁烷-1-羧酸叔丁酯
采用3-({5-肼基羰基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-甲基)-氮杂环丁烷-1-羧酸叔丁酯(400mg;0.78mmol;1.00eq.)和氯-氧代-乙酸甲酯(0.08mL;0.82mmol;1.05eq.)为起始材料,依据中间体26步骤1的方法制备标题化合物,为黄色固体(300mg,66%)HPLC:(254nm)94%;Rt 3.55min;LC/MS:565.3(M+H)。
步骤2:5-{4-[(1-叔丁氧基羰基-氮杂环丁烷-3-基甲基)-氨基]-2-[3-(1-甲基-
1H-吡唑-4-基)-苯基]-嘧啶-5-基}-[1,3,4]噻二唑-2-羧酸甲酯
采用3-({5-(N'-甲氧基草酰基-肼基羰基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-甲基)-氮杂环丁烷-1-羧酸叔丁酯(300mg;0.51mmol;1.00eq.)为起始材料,依据中间体26步骤2的方法制备标题化合物,为黄色固体(150mg;52%)。HPLC:(254nm)92%;Rt 4.44min;LC/MS:563.3(M+H)。
中间体33:[5-(6-氯-4-异丙基氨基-吡啶-3-基)-[1,3,4]噻二唑-2-基]-((R)-3-羟基-吡咯烷-1-基)-甲酮
步骤1:6-氯-4-异丙基氨基-烟酸酰肼
将水合肼一水合物(8.07mL;164mmol)和6-氯-4-异丙基氨基-烟酸乙酯(7.0g;27.4mmol)在乙醇(50mL)中的溶液在80℃回流加热3小时。反应混合物减压浓缩,粗产物在二乙醚中研磨,获得所希望的产物,为白色固体(6g,79%)。LC/MS:229.00(M+1)。
步骤2:[N'-(6-氯-4-异丙基氨基-吡啶-3-羰基)-肼基]-氧代-乙酸甲酯
采用6-氯-4-异丙基氨基-烟酸酰肼(5.5g;21.6mmol)为起始材料,依据中间体26步骤1的方法制备标题化合物,为白色固体(4g,50%)。1H NMR(400MHz,DMSO-d6):d 10.44(s,1H),8.56(s,1H),8.40(s,1H),6.70(s,1H),3.82(s,3H),3.48-0.00(m,1H),1.16-1.09(m,6H)。
步骤3:5-(6-氯-4-异丙基氨基-吡啶-3-基)-[1,3,4]噻二唑-2-羧酸甲酯
采用[N'-(6-氯-4-异丙基氨基-吡啶-3-羰基)-肼基]-氧代-乙酸甲酯(4.0g;10.8mmol)为起始材料,依据中间体26步骤2的方法制备标题化合物,为乳白色固体(3g,67%)。LC/MS:313.0(M+1)。
步骤4:[5-(6-氯-4-异丙基氨基-吡啶-3-基)-[1,3,4]噻二唑-2-基]-((R)-3-羟
基-吡咯烷-1-基)-甲酮
5-(6-氯-4-异丙基氨基-吡啶-3-基)-[1,3,4]噻二唑-2-羧酸甲酯(2.5g;7.2mmol)和(R)-吡咯烷-3-醇(3.84g;43.16mmol)在甲醇(25mL)中的溶液在80℃微波加热1小时。减压除去溶剂,粗产物经硅胶快速色谱法(石油醇,乙酸乙酯)纯化,获得标题化合物,为浅黄色固体(1g,41%)。1H NMR(400MHz,DMSO-d6)δ8.76(d,1H),8.55(s,1H),6.95(s,1H),5.08(d,1H),4.39(d,1H),4.19-3.93(m,3H),3.68-3.53(m,2H),1.99(m,2H),1.27(d,6H)。
中间体33:2-[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基氨基]-乙酰胺
2-(5-溴-2-氯-嘧啶-4-基氨基)-乙酰胺(Aurora Building Blocks;200mg;0.75mmol;1.00eq.)、1-甲基-4-(4,4,5,5-四甲基-[1,3]二氧杂环戊烷-2-基)-1H-吡唑(166mg;0.79mmol;1.05eq.)、四(三苯基膦)钯(4.35mg;0.002mmol;0.01eq.)、碳酸钾(125mg;0.90mmol;1.20eq.)在二噁烷(6mL)和水(0.6mL)中的混合物在密封小瓶中在90℃搅拌过夜。反应混合物再在减压下浓缩,经KPNH快速色谱法纯化(乙酸乙酯:甲醇梯度:由0:100至30:70),获得标题化合物,为白色固体(183mg,87%)。LC/MS:267.1(M+H)。
中间体34:[2-氯-5-(1-甲基-1H-吡唑-3-基)-嘧啶-4-基]-环丁基-胺
(5-溴-2-氯-嘧啶-4-基)-环丁基-胺(Aurora Building Blocks,200mg;0.76mmol;1.00eq.)、1-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(166mg;0.80mmol;1.05eq.)、双(三苯基膦)二氯化钯(II)(2.81mg;0.002mmol;0.01eq.)和碳酸钾(126mg;0.91mmol;1.20eq.)在二噁烷(6mL)和水(0.60mL)中的混合物在密封小瓶中在90℃搅拌过夜。反应混合物再在减压下浓缩,经硅胶快速色谱法纯化(乙酸乙酯:己烷,梯度:由10至50%),获得标题化合物,为白色固体(63mg,30%)。LC/MS:264.6(M+H)。
中间体35:6-(5-溴-2-氯-嘧啶-4-基氨基)-2-氮杂-螺[3.3]庚烷-2-羧酸叔丁酯
5-溴-2,4-二氯-嘧啶(650mg;2.85mmol;1.00eq.)、6-氨基-2-氮杂-螺[3.3]庚烷-2-羧酸叔丁酯(727mg;3.42mmol;1.20eq.)、乙基-二异丙基-胺(1.49mL;8.56mmol;3.00eq.)在NMP(5.0mL)中的混合物在密封小瓶中在50℃搅拌过夜。反应混合物再在减压下浓缩,经硅胶快速色谱法纯化(乙酸乙酯:己烷,梯度:由0至40%),获得标题化合物,为白色固体(1.2g,100%)。LC/MS:403(M+H)403。
中间体36:6-[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基氨基]-2-氮杂-螺[3.3]庚烷-2-羧酸叔丁酯
6-(5-溴-2-氯-嘧啶-4-基氨基)-2-氮杂-螺[3.3]庚烷-2-羧酸叔丁酯(200mg;0.50mmol;1.00eq.)、1-甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(155mg;0.74mmol;1.50eq.)、双(三苯基膦)二氯化钯(II)(1.83mg;0.002mmol;0.01eq.)和碳酸钾(82mg;0.59mmol;1.20eq.)在二噁烷(5mL)和水(0.5mL)中的混合物在密封小瓶中在100℃搅拌过夜。反应混合物再在减压下浓缩,经硅胶快速色谱法纯化(乙酸乙酯:己烷,梯度:由20至100%),获得标题化合物,为黄色固体(201mg,95%)。LC/MS:405.2(M+H)。
中间体37:4-[(5-溴-2-氯-嘧啶-4-基氨基)-甲基]-哌啶-1-羧酸叔丁酯
4-氨基甲基-哌啶-1-羧酸叔丁酯(3.39g;15.80mmol;1.20eq.)和5-溴-2,4-二氯-嘧啶(3.00g;13.17mmol;1.00eq.)溶解在THF(30mL)和DIPEA(6.9mL)中。混合物在50℃和氮气气氛下搅拌2小时。反应混合物用水(150mL)和乙酸乙酯(75mL)稀释。分离两层,水层用乙酸乙酯(3x 50mL)萃取。有机层合并,用水和盐水洗涤,Na2SO4干燥,过滤,浓缩,获得无色油。通过硅胶快速色谱法纯化(乙酸乙酯:己烷,梯度:由10至30%),获得标题化合物,为白色固体(4.0g,75%)。1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),7.75(t,1H),3.92(d,2H),3.27(t,2H),2.79–2.59(bs,2H),1.81(m,1H),1.60(dd,2H),1.40(s,9H),1.02(qd,2H)。LC/MS:349((M-tBu)+H)。
中间体38:N-[(1S,2S,3S)-3-氨基-2-羟基环己基]-N-甲基氨基甲酸叔丁酯(相对立体化学-外消旋体)
步骤1:N-[(1S,2R,3S)-2-羟基-3-(甲基氨基)环己基]氨基甲酸苄酯(相对立体化
学-外消旋体)
N-[(1S,2S,6R)-7-氧杂双环[4.1.0]庚烷-2-基]氨基甲酸苄酯(具有相对立体化学式,外消旋体,参照Org.Lett.,2003,p.4955-49557描述的方法制备,730mg,2.66mmol,1.00eq.)和甲胺(850mg,26.82mmol,10.1eq.,)在甲醇(10mL)中的溶液在密封试管中在45℃加热16小时。得到的混合物在真空下浓缩,经硅胶快速色谱法(甲醇/DCM,1:10)纯化,获得标题化合物,为浅黄色油(800mg,97%)。
步骤2:苄基N-[(1S,2S,3S)-3-{[(叔丁氧基)羰基](甲基)氨基}-2-羟基环己基]
氨基甲酸酯(相对立体化学-外消旋体)
N-[(1S,2R,3S)-2-羟基-3-(甲基氨基)环己基]氨基甲酸苄酯(外消旋体,800mg,2.59mmol,1.00eq..)、TEA(535mg,5.18mmol,2.00eq.,)、Boc2O(864mg,3.88mmol,1.50eq.)在DCM(40mL)中的溶液在25℃加热2小时。得到的混合物在真空下浓缩,经硅胶快速色谱法(甲醇/DCM,1:15)纯化,获得标题化合物,为浅黄色固体(1g,92%)。
步骤3:N-[(1S,2S,3S)-3-氨基-2-羟基环己基]-N-甲基氨基甲酸叔丁酯(相对立
体化学-外消旋体)
在氮气气氛下将Pd/C(253mg,0.24mmol,0.10eq..)加入至N-[(1S,2S,3S)-3-[[(叔丁氧基)羰基](甲基)氨基]-2-羟基环己基]氨基甲酸苄酯(1g,2.38mmol,1.00eq..)在甲醇(4mL)中的溶液中。混合物在氢气球内在室温下进行加氢反应16小时。滤出固体,得到的混合物在真空下浓缩,获得标题化合物,为浅黄色固体(630mg,98%)。
中间体39:N-[(1S,2S,3S)-3-[(5-溴-2-氯嘧啶-4-基)氨基]-2-羟基环己基]-N-甲基氨基甲酸叔丁酯(相对立体化学-外消旋体)。
N-[(1S,2S,3S)-3-氨基-2-羟基环己基]-N-甲基氨基甲酸叔丁酯(630mg,2.32mmol,1.00eq.)、5-溴-2,4-二氯嘧啶(652mg,2.80mmol,1.21eq.)和DIEA(612mg,4.64mmol,2.00eq.)在THF(10mL)中的溶液在室温加热2小时。得到的混合物在真空下浓缩,经硅胶快速色谱法(乙酸乙酯/石油醚,1:2)纯化,获得标题化合物,为黄色固体(630mg,56%)。LC/MS(柱:Shim-pack XR-ODS,3.0*50mm,2.2um;流动相A:水/0.05%TFA,流动相B:ACN/0..05%TFA;流速:1.0mL/min;2.2分钟梯度:5%B至100%B,保持1.0min;254nm):(纯度)90%;[M+H]+计算结果:435.1;实验结果:435.1。
中间体40:N-[(1S,2S,3S)-3-{[2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基]氨基}-2-羟基环己基]-N-甲基氨基甲酸叔丁酯(相对立体化学-外消旋体)。
N-[(1S,2S,3S)-3-[(5-溴-2-氯嘧啶-4-基)氨基]-2-羟基环己基]-N-甲基氨基甲酸叔丁酯(630mg,1.30mmol,1.00eq.,90%)、1-甲基-4-(四甲基-1,3,2-二氧杂硼戊烷-2-基)-1H-吡唑(415mg,1.95mmol,1.50eq.,98%)、Pd(dppf)Cl2.CH2Cl2(108mg,0.13mmol,0.10eq.,98%)和K3PO4(566mg,2.61mmol,2.01eq.)在二噁烷(10mL)和水(2mL)中的混合物脱氮气,并在密封试管内在100℃加热2小时。得到的混合物在真空下浓缩,经硅胶快速色谱法(乙酸乙酯/石油醚,1:12)纯化,获得标题化合物,为黄色固体(420mg,66%)。
中间体41:N-[1-(5-溴-2-氯嘧啶-4-基)-5,5-二氟哌啶-3-基]氨基甲酸叔丁酯
采用N-(5,5-二氟哌啶-3-基)氨基甲酸叔丁酯(500mg,2.01mmol,0.93eq.)为起始材料,依据中间体39的方法制备标题化合物,为白色固体(460mg,37%)。
中间体42:N-{1-[2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基]-5,5-二氟哌啶-3-基}氨基甲酸叔丁酯
采用N-[1-(5-溴-2-氯嘧啶-4-基)-5,5-二氟哌啶-3-基]氨基甲酸叔丁酯(460mg,0.81mmol,1.00eq.)为起始材料,依据中间体40的方法制备标题化合物,为白色固体(220mg,57%)。LC/MS(柱:Shim-pack XR-ODS,3.0*50mm,2.2um;流动相A:水/0.05%TFA,流动相B:ACN/0..05%TFA;流速:1.0mL/min;2.2分钟梯度:5%B至100%B,保持1.0min;254nm):(纯度)90%;[M+H]+计算结果:428.2;实验结果:428.2。
中间体43:(1S,2S,6S)-2-氨基-6-氟环己烷-1-醇(相对立体化学,外消旋体)
步骤1:N-[(1S,2S,6R)-7-氧杂双环[4.1.0]庚烷-2-基]氨基甲酸苄酯(相对立体
化学,外消旋体)
N-(环己-2-烯-1-基)氨基甲酸苄酯(400mg,1.56mmol,1.00eq.,90%)、碳酸氢钠(267mg,3.11mmol,2.00eq.,98%)和m-CPBA(549mg,3.12mmol,2.00eq.,98%)在DCM(25mL)中的溶液在20℃加热3小时。加入15mL Na2SO3淬灭反应,反应物用30mL水稀释。然后用DCM(3x15mL)萃取。有机层合并,真空浓缩,经硅胶快速色谱法(乙酸乙酯/石油醚,1:5)纯化,获得标题化合物,为褐色固体。
步骤2:N-[(1S,2S,3S)-3-氟-2-羟基环己基]氨基甲酸酯氨基甲酸苄酯(相对立体
化学,外消旋体)
在0℃和氮气气氛下,将HF-吡啶(0.5mL,3.88mmol,1.52eq.,70%纯度)滴加入DCM(10mL)中。然后再滴加入N-[7-氧杂双环[4.1.0]庚烷-2-基]氨基甲酸苄酯(700mg,2.55mmol,1.00eq.)在二氯甲烷(3mL)中的溶液,得到的混合物在0℃搅拌2小时。用饱和碳酸氢钠(水溶液)调溶液的pH值至7。用20mL水稀释后,得到的混合物用DCM(3x15mL)萃取。有机层合并,用盐水(20mL)洗涤,无水Na2SO4干燥,过滤,浓缩。通过硅胶快速色谱法纯化(乙酸乙酯/石油醚,1:15至1:4),获得标题化合物,为浅黄色固体(700mg,93%产率)。
步骤3:(1S,2S,6S)-2-氨基-6-氟环己烷-1-醇(相对立体化学,外消旋体)
采用N-[(1S,2S,3S)-3-氟-2-羟基环己基]氨基甲酸苄酯(外消旋体,相对构型,700mg,2.36mmol)为起始材料,依据实施例38步骤3的方法制备标题化合物,为白色固体(300mg,86%)。
中间体44:(1S,2S,6S)-2-[(5-溴-2-氯嘧啶-4-基)氨基]-6-氟环己烷-1-醇(相对立体化学,外消旋体)
采用(1S,2S,6S)-2-氨基-6-氟环己烷-1-醇(中间体43,300mg,2.03mmol,1.00eq.)为起始材料,依据实施例39的方法制备标题化合物,为黄色固体(500mg,68%)。LC/MS(柱:Shim-pack XR-ODS,3.0*50mm,2.2um;流动相A:水/0.05%TFA,流动相B:ACN/0..05%TFA;流速:1.0mL/min;2.2分钟梯度:5%B至100%B,保持1.0min;254nm):(纯度)90%;[M+H]+计算结果:324.0;实验结果:324.0。
中间体45:(1S,2S,6S)-2-[[2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基]氨基]-6-氟环己烷-1-醇(相对立体化学,外消旋体)
采用(1S,2S,6S)-2-[(5-溴-2-氯嘧啶-4-基)氨基]-6-氟环己烷-1-醇(中间体44,外消旋体,440mg,1.22mmol,1.00eq.)为起始材料,依据实施例40的方法制备标题化合物,为黄色固体(360mg,82%)。LC/MS(柱:Shim-pack XR-ODS,3.0*50mm,2.2um;流动相A:水/0.05%TFA,流动相B:ACN/0..05%TFA;流速:1.0mL/min;2.2分钟梯度:5%B至100%B,保持1.0min;254nm):[M+H]+计算结果:326.0;实验结果:326.0。
中间体46:(1S,6R)-6-氨基-2,2-二氟环己-1-醇
步骤1:2,2-二氟-6-{[(1R)-1-苯基乙基]氨基}环己-1-醇
将(1R)-1-苯基乙-1-胺(2.375g,18.62mmol,1.30eq.,95%)在DCM(12mL)中的溶液冷却至0℃,并在氮气气氛下用三甲基铝(11mL,1.20eq.,2M在甲苯中的溶液)处理。搅拌1小时,然后加入(1R,6R)-2,2-二氟-7-氧杂双环[4.1.0]庚烷(外消旋体,相对立体化学,2.260g,14.32mmol,1.00eq.)在DCM(50mL)中的溶液。得到的溶液在室温搅拌2天。加入NH4Cl溶液淬灭反应物。水层再用二氯甲烷萃取,有机层合并,经盐水洗涤,无水Na2SO4干燥,过滤,真空浓缩。通过硅胶快速色谱法纯化(MTBE/石油醚,1:10),获得标题化合物(第一洗脱异构体),为白色固体(1.36g,33%)。
步骤2:(1S,6R)-6-氨基-2,2-二氟环己-1-醇
(1S,6R)-2,2-二氟-6-[[(1R)-1-苯基乙基]氨基]环己-1-醇(1.360g,4.79mmol,1.00eq.)在甲醇(30mL)中的溶液脱氮气,然后加入钯/炭(1.701g,9.59mmol,2.00eq.,60%)。将反应混合物置于氢气(1atm.)气氛下,室温搅拌过夜。混合物经硅藻土垫过滤,浓缩,获得标题化合物,为白色固体(765mg,95%)。1H NMR(300MHz,甲醇-d4,ppm)3.40-3.30(m,1H),2.73(m,1H),2.05(m,1H),1.90-1.39(m,4H),1.34-1.17(m,1H)。
中间体47:(1S,6R)-6-[(5-溴-2-氯嘧啶-4-基)氨基]-2,2-二氟环己-1-醇
采用(1S,6R)-6-氨基-2,2-二氟环己-1-醇(200mg,1.19mmol,1.00eq.)为起始材料,依据中间体39的方法制备标题化合物,为黄色固体(451mg,87%)。
中间体48:(1S,6R)-6-{[2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基]氨基}-2,2-二氟环己-1-醇
采用(1S,6R)-6-[(5-溴-2-氯嘧啶-4-基)氨基]-2,2-二氟环己-1-醇(451mg,1.04mmol,1.00eq.)为起始材料,依据中间体40的方法制备标题化合物,为黄色固体(208mg,58%)。
中间体49:(3aS,4S,8aR)-2,2-二甲基-八氢环庚[d][1,3]间二氧杂环戊烯-4-胺盐酸盐(外消旋体-相对立体化学)。
步骤1:2,2,2-三氯-N-[(1S,2S,3R)-2,3-二羟基环庚基]乙酰胺(外消旋体–相对
立体化学)
2,2,2-三氯-N-[(1S,2S,3R)-2,3-二羟基环庚基]乙酰胺(外消旋体-相对立体化学,参照JOC,2002,p 7946-7956描述的方法制备,10mg,0.03mmol,1.00eq.)、2,2-二甲氧基丙烷(7mg,0.06mmol,2.06eq.)和TsOH(0.5mg,0.09eq.)在丙酮(1mL)中的溶液在室温搅拌16小时。反应混合物减压浓缩,残留物重溶解在DCM中。有机层用饱和NaHCO3溶液和盐水洗涤,无水硫酸镁干燥,过滤,浓缩,获得标题化合物,可直接用在下一步骤中。
步骤2:(3aS,4S,8aR)-2,2-二甲基-八氢环庚[d][1,3]间二氧杂环戊烯-4-胺盐酸
盐(外消旋体-相对立体化学)。
保持在0℃,将NaBH4(71mg,1.78mmol,5.04eq.)分批加入N-[(3aS,4S,8aR)-2,2-二甲基-八氢环庚[d][1,3]间二氧杂环戊烯-4-基]-2,2,2-三氯乙酰胺(外消旋体,130mg,0.35mmol,1.00eq.)在乙醇(10mL)中的溶液中。得到的溶液在40℃搅拌16小时。加入盐酸溶液(1M)淬灭反应物,混合物最后在减压下浓缩,获得标题化合物,为白色固体(140mg)。中间体50:N-[(3aS,4S,8aR)-2,2-二甲基-八氢环庚[d][1,3]间二氧杂环戊烯-4-基]-5-溴-2-氯嘧啶-4-胺(外消旋体–相对立体化学)
采用(3aS,4S,8aR)-2,2-二甲基-八氢环庚[d][1,3]间二氧杂环戊烯-4-胺盐酸盐(外消旋体,185mg,0.90mmol,0.79eq.)为起始材料,依据中间体39的方法制备标题化合物,为乳白色固体(210mg,44%)。1H NMR(300MHz,氯仿-d)8.11(s,1H),6.01(d,J=8.2Hz,1H),4.49(t,J=7.3Hz,1H),4.34(d,J=8.3Hz,1H),4.23(t,J=9.1Hz,1H),2.22-1.90(m,2H),1.73(dd,J=11.4,5.8Hz,3H),1.54(s,6H),1.37(s,3H)。
中间体51:N-[(3aS,4S,8aR)-2,2-二甲基-八氢环庚[d][1,3]间二氧杂环戊烯-4-基]-2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-胺(外消旋体–相对立体化学)
采用N-[(3aS,4S,8aR)-2,2-二甲基-八氢环庚[d][1,3]间二氧杂环戊烯-4-基]-5-溴-2-氯嘧啶-4-胺(外消旋体,240mg,0.57mmol,1.00eq.)为起始材料,依据中间体40的方法制备标题化合物,为黄色油(185mg,77%)。LC/MS(柱:Shim-pack XR-ODS,3.0*50mm,2.2um;流动相A:水/0.05%TFA,流动相B:ACN/0..05%TFA;流速:1.0mL/min;2.2分钟梯度:5%B至100%B,保持1.0min;254nm):(纯度)87.3%;[M+H]+计算结果:378.2;实验结果:378.2。
中间体52:(1S,2S,3S)-3-氨基-2-(甲氧基甲氧基)环己基乙酸酯(外消旋体-相对立体化学)
步骤1:(1S,2S,3S)-3-{[(苄基氧基)羰基]氨基}-2-羟基环己基乙酸酯(外消旋
体-相对立体化学)
N-[(1S,2S,6R)-7-氧杂双环[4.1.0]庚烷-2-基]氨基甲酸苄酯(参照Org.Lett.,2003,p4955-4957描述的方法制备,350mg,1.27mmol,1.00eq.)、乙酸钠(214mg,2.56mmol,2.01eq.)和乙酸(5mL)的混合物在100℃搅拌30分钟。将反应混合物冷却至室温,用60mL水稀释。加入碳酸氢钠溶液调pH至7。得到的溶液用DCM(3x)稀释。有机层合并,用盐水洗涤,硫酸钠干燥,过滤,真空浓缩,获得标题化合物,为乳白色固体(300mg,69%)。LC/MS(柱:Shim-pack XR-ODS,3.0*50mm,2.2um;流动相A:水/0.05%TFA,流动相B:ACN/0..05%TFA;流速:1.0mL/min;2.2分钟梯度:5%B至100%B,保持1.0min;254nm):[M+Na]+23计算结果:330.0;实验结果:330.0。
步骤2:(1S,2S,3S)-3-{[(苄基氧基)羰基]氨基}-2-(甲氧基甲氧基)环己基乙酸
酯(外消旋体-相对立体化学)
(1S,2S,3S)-3-[[(苄基氧基)羰基]氨基]-2-羟基环己基乙酸酯(250mg,0.73mmol,1.00eq.)、DIEA(194mg,1.47mmol,2.01eq.)和氯(甲氧基)甲烷(91mg,1.11mmol,1.51eq.)在DMF(15mL)中的溶液在70℃和氮气气氛下搅拌3小时。加入饱和NaHCO3溶液淬灭反应物,再用DCM(3x)萃取。有机层合并,用盐水洗涤,硫酸镁干燥,过滤,浓缩。通过硅胶快速色谱法纯化(乙酸乙酯/石油醚,1:6),获得标题化合物,为黄色固体(270mg,94%)。LC/MS:[M+H]+计算结果:352.1;实验结果:352.1。
步骤3:(1S,2S,3S)-3-氨基-2-(甲氧基甲氧基)环己基乙酸酯(外消旋体-相对立
体化学)
采用(1S,2S,3S)-3-[[(苄基氧基)羰基]氨基]-2-(甲氧基甲氧基)环己基乙酸酯(250mg,0.64mmol,1.00eq.)为起始材料,依据中间体43步骤2的方法制备标题化合物,为无色油(150mg,97%)。LC/MS:[M+H]+计算结果:218.2;实验结果:218.2。
中间体53:(1S,2S,3S)-3-[(5-溴-2-氯嘧啶-4-基)氨基]-2-(甲氧基甲氧基)环己基乙酸酯(相对立体化学,外消旋体)
采用(1S,2S,3S)-3-氨基-2-(甲氧基甲氧基)环己基乙酸酯(中间体52,外消旋体,370mg,1.53mmol,1.00eq.)为起始材料,依据中间体39的方法制备标题化合物,为黄色固体(560mg,80%)。MS:m/z=408.1[M+H]+。
中间体54:(1S,2S,3S)-3-[[2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基]氨基]-2-(甲氧基甲氧基)环己基乙酸酯((相对立体化学,外消旋体)
采用(1S,2S,3S)-3-[(5-溴-2-氯嘧啶-4-基)氨基]-2-(甲氧基甲氧基)环己基乙酸酯(中间体53,外消旋体,560mg,1.23mmol,1.00eq.)为起始材料,依据实施例40的方法制备标题化合物,为黄色固体(330mg,59%)。
中间体55:5-溴-2-氯-N-(环庚-2-烯-1-基)嘧啶-4-胺
采用环庚-2-烯-1-胺(650mg,2.92mmol,1.02eq.)为起始材料,依据中间体39的方法制备标题化合物,为黄色油(460mg,48%)。LC/MS:[M+H]+计算结果:302.0;实验结果:302.0。
中间体56:2-氯-N-(环庚-2-烯-1-基)-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-胺
采用5-溴-2-氯-N-(环庚-2-烯-1-基)嘧啶-4-胺(中间体55,450mg,1.34mmol,1.00eq.)为起始材料,依据中间体40的方法制备标题化合物,为黄色油(100mg,22%)。LC/MS:[M+H]+计算结果:304.1;实验结果:304.0。
实施例1:2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-5-(1-哌啶-4-基-1H-吡唑-4-基)-吡啶盐酸盐
步骤1:4-(4-{6-[3-(1-甲基-1H-吡唑-4-基)苯基]吡啶-3-基}-1H-吡唑-1-基)哌
啶-1-羧酸叔丁酯
4-4-[6-(3-碘苯基)吡啶-3-基]-1H-吡唑-1-基哌啶-1-羧酸叔丁酯(215mg;0.41mmol;1.00eq.)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊烷-2-基)-1H-吡唑(84mg;0.41mmol;1.00eq.)、Pd(PPh3)4(23mg;0.02mmol;0.05eq.)和碳酸钾(168mg;1.22mmol;3.0eq.)在二噁烷(3.2mL)和水(1.61mL)中的混合物装在密封试管内在120℃微波加热30分钟。反应混合物用乙酸乙酯稀释,水洗涤。有机层用乙酸乙酯反萃取,有机层合并,用MgSO4干燥,过滤,浓缩。通过硅胶快速色谱法纯化(乙酸乙酯:庚烷,梯度:由50至100%),获得标题化合物,为黄色胶状物(110mg;56%)。1H NMR(300MHz,DMSO-d6)8.94(dd,J=2.0Hz,1.0Hz,1H),8.46(s,1H),8.26-8.05(m,2H),8.07-8.05(m,3H),7.96(d,J=1.0Hz,1H),7.93(ddd,J=7.9Hz,2.0Hz,1.0Hz,1H),7.61(ddd,J=7.9Hz,2.0Hz,1.0Hz,1H),7.46(t,J=7.9Hz,1H),4.46-4.35(m,1H),4.09(m,2H),3.89(s,3H),2.94(m,2H),2.09-2.04(m,2H),1.89-1.75(m,2H),1.43(s,9H)。LC/MS:485.6(M+1)。
步骤2:2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-5-(1-哌啶-4-基-1H-吡唑-4-基)-
吡啶盐酸盐
4-(4-6-[3-(1-甲基-1H-吡唑-4-基)苯基]吡啶-3-基-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(110mg;0.23mmol;1.00eq.)和盐酸(0.85mL 4N在二噁烷中的溶液;3.40mmol;15eq.)在DCM(1.1mL)和甲醇(1.10mL)中的溶液在室温下搅拌1小时。滤出反应混合物,用DCM洗涤得到的固体。通过自动式制备型LC/MS纯化,获得标题化合物,为黄色粉末(65mg;67%)。1H NMR(300MHz,DMSO-d6)9.35-9.26(m,1H),9.13-9.06(m,1H),9.05(d,J=2.0Hz,1H),8.63(s,1H),8.45(d,J=9.1Hz,1H),8.36(t,J=2.0Hz,1H),8.32-8.29(m,2H),8.26(s,1H),8.03(d,J=1.0Hz,1H),7.96-7.92(m,1H),7.73(dt,J=7.8Hz,1.0Hz,1H),7.55(t,J=7.8Hz,1H),4.61-4.51(m,1H),3.90(s,3H),3.42-3.38(m,2H),3.16-3.06(m,2H),2.29-2.14(m,4H);HPLC:(254nm)100%;Rt(min)2.02。LC/MS:385.5(M+1)。
实施例2:6'-(1-甲基-1H-吡唑-4-基)-5-(1-哌啶-4-基-1H-吡唑-4-基)-[2,2']二吡啶基
步骤1:4-{4-[6'-(1-甲基-1H-吡唑-4-基)-[2,2']二吡啶基-5-基]-吡唑-1-基}-
哌啶-1-羧酸叔丁酯
4-[4-(6'-氯-[2,2']二吡啶基-5-基)-吡唑-1-基]-哌啶-1-羧酸叔丁酯(130mg;0.30mmol;1.0eq.)、Pd(PPh3)2Cl2(21mg;0.03mmol;0.10eq.)、PPh3(15.5mg;0.06mmol;0.20eq.)、氟化铯(134.7mg;0.89mmol;3.00eq.)和1-甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(92mg;0.44mmol;1.50eq.)在1,2-二甲氧基-乙烷(2.2mL)中的混合物在密封小瓶中在100℃加热过夜。混合物经硅藻土垫过滤。水相用DCM萃取,有机层合并,用水洗涤,MgSO4干燥,过滤,浓缩。通过硅胶快速色谱法纯化(乙酸乙酯:庚烷,80:20),获得标题化合物(104mg,72%)。LC/MS:486.3(M+1)。
步骤2:6'-(1-甲基-1H-吡唑-4-基)-5-(1-哌啶-4-基-1H-吡唑-4-基)-[2,2']二
吡啶基
采用4-{4-[6'-(1-甲基-1H-吡唑-4-基)-[2,2']二吡啶基-5-基]-吡唑-1-基}-哌啶-1-羧酸叔丁酯(100mg;0.21mmol;1.00eq.)为起始材料,依据实施例1步骤2的方法制备标题化合物,为米色固体(10mg,13%)。1H NMR(300MHz,DMSO-d6)8.97(d,J=1.7Hz,1H),8.52(d,J=8.0Hz,1H),8.46-8.43(m,2H),8.32(bs,1H),8.17-8.10(m,4H),7.89(t,J=8.0Hz,1H),7.67(dd,J=8.0Hz,1.0Hz,1H),4.41-4.28(m,1H),3.92(s,3H),3.23-3.19(m,2H),2.86-2.73(m,2H),2.13-1.89(m,4H)。HPLC:(254nm)98%;Rt(min)1.61。LC/MS:386.4(M+1)。
实施例3:3-({5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-甲基)-哌啶-1-羧酸叔丁酯
3-{[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基氨基]-甲基}-哌啶-1-羧酸叔丁酯(94mg;0.23mmol;1.00eq.)、Pd(PPh3)Cl2(3.2mg;0.01mmol;0.02eq.)、碳酸钾(0.15mL 2M水溶液)、1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(参照WO 2014008992描述的方法制备;79mg;0.28mmol;1.20eq.)在脱气后的二噁烷(1.1mL)中的混合物在密封小瓶中在150℃微波加热20分钟。再经硅藻土垫过滤,减压浓缩。通过硅胶快速色谱法纯化(乙酸乙酯:己烷s,梯度:由0至100%,再换成甲醇:DCM,梯度:由0至20%),获得标题化合物,为黄色泡沫(48mg,34%)。1H NMR(400MHz,氯仿-d)δ8.53(s,1H),8.33(s,1H),8.27(d,J=7.8Hz,1H),7.86(s,1H),7.75(s,1H),7.71(s,1H),7.64–7.53(app m,2H),7.47(d,J=7.6Hz,1H),4.56(s,1H),4.00(s,3H),3.97(s,3H),3.86(d,J=12.3Hz,1H),3.04(t,J=6.5Hz,2H),2.94–2.80(t,1H),2.72(t,J=11.5Hz,1H),1.95–1.76(app m,3H),1.71(d,J=12.9Hz,1H),1.64–1.50(m,1H),1.44(s,9H),1.23(td,J=13.9,13.4,8.0Hz,1H);HPLC:(254nm)95.8%;RT(min)3.629;LC/MS:429.4(M+1)。
实施例4:{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-哌啶-3-基甲基-胺盐酸盐
3-({5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-甲基)-哌啶-1-羧酸叔丁酯(34mg;0.06mmol;1.0eq.)和氯化氢(1.0mL 2M在乙醚中的溶液;0.2mmol;3.3eq.)在甲醇(3.00mL)中的溶液在室温搅拌30分钟。反应混合物与5x10mL乙醚共蒸发,减压干燥,获得标题化合物,为白色固体(26mg,81%)。1H NMR(400MHz,甲醇-d4)δ8.61(s,1H),8.56(s,1H),8.50(s,1H),8.23(s,1H),8.21(s,1H),8.09(s,1H),8.01(d,J=7.7Hz,1H),7.85(s,1H),7.74(t,J=7.7Hz,1H),4.74(m,1H),4.28(brs,1H),4.15(s,3H),4.05(s,3H),3.21(d,J=10.5Hz,2H),3.07–2.83(m,2H),2.19(brs,1H),2.05(d,J=12.6Hz,1H),1.84(d,J=13.2Hz,1H),1.68(m,1H),1.50(m,1H)。HPLC:(254nm)100%;RT(min)2.29。LC/MS:429.2(M+1)。
实施例5:(1-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-哌啶-3-基甲基)-氨基甲酸叔丁酯
{1-[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基]-哌啶-3-基甲基}-氨基甲酸叔丁酯(285mg;0.70mmol;1.00eq.)、Pd(PPh3)Cl2(98mg;0.14mmol;0.20eq.)、1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(参照WO 2014008992描述的方法制备;238mg,0.84mmol,1.2eq.)和碳酸钾(0.2mL of a 2M solution in水)在脱气后的二噁烷(3.3mL)中的混合物在密封小瓶中在150℃加热80分钟。再经硅藻土垫过滤,减压浓缩。通过硅胶快速色谱法纯化(乙酸乙酯:己烷,梯度:由0:100%,再换成甲醇:DCM梯度:由0至20%),接着经制备型HPLC进行第二次纯化,获得标题化合物,为白色固体。1H NMR(400MHz,氯仿-d)δ8.54(s,1H),8.35(s,1H),8.29(d,J=7.8Hz,1H),7.88(s,1H),7.77(s,1H),7.72(d,J=3.3Hz,1H),7.62(s,1H),7.57(d,J=2.5Hz,1H),7.49(d,J=7.5Hz,1H),4.56(brs,1H),4.02(s,3H),3.99(s,3H),3.94(d,J=3.0Hz,2H),3.06(t,J=6.5Hz,2H),2.94–2.85(t,2H),2.74(t,J=11.7Hz,1H),2.35(t,J=7.3Hz,1H),1.87(d,J=11.5Hz,2H),1.46(s,9H),1.00(t,J=7.6Hz,1H)。HPLC:(254nm)97.9%;RT(min)3.48;LC/MS:529.3(M+1)。
实施例6:C-(1-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-哌啶-3-基)-甲基胺盐酸盐
采用(1-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-哌啶-3-基甲基)-氨基甲酸叔丁酯(78mg;0.15mmol;1.00eq.)为起始材料,依据实施例4的方法制备标题化合物,为黄色粉末(30mg,30%)。1H NMR(400MHz,甲醇-d4)δ8.38(s,1H),8.21(s,1H),8.17(s,1H),8.10(d,J=7.9Hz,1H),8.05(s,1H),8.00(s,1H),7.95(d,J=7.8Hz,1H),7.76(s,1H),7.68(t,J=7.8Hz,1H),4.73(brs,1H),4.25(brs,1H),4.15(s,3H),4.05(s,3H),3.23(m,2H),3.08–2.84(m,2H),2.21(m,1H),2.05(brs,1H),1.84(brs,1H),1.68(brs,1H),1.51(brs,1H),1.32(m,1H)。HPLC:(254nm)94.6%;RT(min)2.231;LC/MS:429.3(M+1)。HPLC:(254nm)94.6%;RT(min)2.23;LC/MS:429.3(M+1)。
实施例7:{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-哌啶-4-基甲基-胺
步骤1:4-({5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧
啶-4-基氨基}-甲基)-哌啶-1-羧酸叔丁酯
采用4-{[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基氨基]-甲基}-哌啶-1-羧酸叔丁酯(125mg;0.31mmol;1.00eq.)和1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(105mg;0.37mmol;1.20eq.)为起始材料,依据实施例3的方法制备标题化合物,为黄色泡沫(87mg,48%)。LC/MS:529.4(M+1)。
步骤2:{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-
4-基}-哌啶-4-基甲基-胺盐酸盐
4-({5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-甲基)-哌啶-1-羧酸叔丁酯(84mg;0.16mmol;1.00eq.)和氯化氢(3.0m 2M在乙醚中的溶液;0.16mmol;1.00eq.)在甲醇(3.00mL)中的溶液在室温下搅拌30分钟。反应混合物与5x 10mL乙醚共蒸发,减压干燥,获得标题化合物,为黄色油(68mg,定量)。1H NMR(400MHz,甲醇-d4)δ8.48(s,1H),8.40(s,1H),8.26(s,1H),8.17(s,1H),8.13(d,J=7.9Hz,1H),8.04(s,1H),7.95(d,J=7.8Hz,1H),7.78(s,1H),7.68(d,J=7.8Hz,1H),4.77–4.54(m,1H),4.06(s,3H),4.01(s,3H),3.21(t,J=12.6Hz,2H),2.91(d,J=6.9Hz,2H),2.19–2.00(m,1H),2.00–1.84(m,2H),1.57–1.37(m,2H);HPLC:(254nm)98.3%;RT(min)2.21;LC/MS:429.3(M+1)。
实施例8:5-(1-甲基-1H-吡唑-3-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-4-(四氢-吡喃-2-基甲氧基)-嘧啶
采用2-氯-5-(1-甲基-1H-吡唑-3-基)-4-(四氢-吡喃-2-基甲氧基)-嘧啶(209mg;0.68mmol;1.00eq.)和1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(参照WO 2014008992描述的方法制备;231mg;0.81mmol;1.20eq.)为起始材料,依据实施例3的方法制备标题化合物,为米色粉末(38mg,12%)。1H NMR(400MHz,氯仿-d)δ9.23(s,1H),8.58(d,J=1.9Hz,1H),8.33(dt,J=7.7,1.4Hz,1H),7.88(s,1H),7.75(s,1H),7.59(dt,J=7.7,1.5Hz,1H),7.49(t,J=7.8Hz,1H),7.45(s,1H),6.94(d,J=2.2Hz,1H),4.64(d,J=5.2Hz,2H),4.00(s,3H),3.99(s,3H),3.88(m,1H),3.61–3.47(m,2H),1.87–1.76(m,2H),1.64–1.52(m,4H);UPLC:(254nm)93%;RT(min)3.9;LC/MS:431.2(M+1)。
实施例9:4-(3-甲基-氧杂环丁烷-3-基甲氧基)-5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶
采用2-氯-4-(3-甲基-氧杂环丁烷-3-基甲氧基)-5-(1-甲基-1H-吡唑-4-基)-嘧啶(151mg;0.51mmol;1.00eq.),和1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(参照WO 2014008992描述的方法制备;175mg;0.62mmol;1.20eq.)为起始材料,依据实施例3的方法制备标题化合物,为白色固体(165mg,44%)。1H NMR(400MHz,甲醇-d4)δ8.87(s,1H),8.55(d,J=1.9Hz,1H),8.31(s,1H),8.25(d,J=7.8Hz,1H),8.09(s,1H),8.03(s,1H),7.90(s,1H),7.67(d,J=7.7Hz,1H),7.48(t,J=7.7Hz,1H),4.83(d,J=6.1Hz,2H),4.70(s,2H),4.59(d,J=6.0Hz,2H),3.96(s,3H),3.95(s,3H),1.51(s,3H);UPLC:(254nm)100%;RT(min)3.27;LC/MS:417.2(M+1)。
实施例10:{5-(1-甲基-1H-吡唑-3-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-哌啶-3-基甲基-胺
步骤1:3-({5-(1-甲基-1H-吡唑-3-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧
啶-4-基氨基}-甲基)-哌啶-1-羧酸叔丁酯
采用3-{[2-氯-5-(1-甲基-1H-吡唑-3-基)-嘧啶-4-基氨基]-甲基}-哌啶-1-羧酸叔丁酯(261mg;0.64mmol;1.00eq.)和1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(219mg;0.77mmol;1.20eq.)为起始材料,依据实施例3的方法制备标题化合物,为米色固体(19mg,55%)。LC/MS:529.4(M+1)。
步骤2:{5-(1-甲基-1H-吡唑-3-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-
4-基}-哌啶-3-基甲基-胺盐酸盐
采用3-({5-(1-甲基-1H-吡唑-3-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-甲基)-哌啶-1-羧酸叔丁酯(15mg;0.03mmol;1.00eq.)为起始材料,依据实施例3的方法制备标题化合物,为白色固体(10mg,80%)。1H NMR(400MHz,甲醇-d4)δ8.71(s,1H),8.47–8.40(m,1H),8.18(s,1H),8.13(d,J=7.7Hz,1H),8.01(s,1H),7.95(d,J=7.8Hz,1H),7.87–7.81(m,1H),7.69(t,J=7.8Hz,1H),7.08–6.99(m,1H),4.08(s,3H),4.05(s,3H),3.61–3.48(d,2H),2.96(q,J=13.5,12.4Hz,2H),2.42(brs,2H),2.08(dd,J=25.8,14.3Hz,2H),1.84(t,J=13.1Hz,2H),1.64–1.42(m,2H),1.20(s,1H);HPLC:(254nm)100%;RT(min)2.462。LC/MS:计算结果:429.2(M+1)。
实施例11:5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-4-(氧杂环丁烷-3-基甲氧基)-嘧啶
采用2-氯-5-(1-甲基-1H-吡唑-4-基)-4-(氧杂环丁烷-3-基甲氧基)-嘧啶(55mg;0.20mmol;1.00eq.)和1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(67mg;0.24mmol;1.20eq.)为起始材料,依据实施例3的方法制备标题化合物,为白色固体(13mg,16%)。1H NMR(400MHz,氯仿-d)δ8.83(s,1H),8.56(d,J=1.8Hz,1H),8.30(d,J=7.8Hz,1H),8.07(s,1H),7.98(s,1H),7.88(s,1H),7.75(s,1H),7.60(d,J=7.7Hz,1H),7.50(t,J=7.7Hz,1H),5.06–4.96(m,2H),4.88(d,J=5.6Hz,2H),4.75(t,J=6.0Hz,2H),3.99(s,6H),3.59(qt,J=5.5Hz,1H);UPLC(H2O TFA 0.1%-ACN TFA 0.1%;梯度8分钟TFA):(254nm)80%;RT(min)2.97;LC/MS:403.2(M+1)。
实施例12:{5-(1-甲基-1H-吡唑-3-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-哌啶-4-基甲基-胺
步骤1:4-({5-(1-甲基-1H-吡唑-3-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧
啶-4-基氨基}-甲基)-哌啶-1-羧酸叔丁酯
采用4-{[2-氯-5-(1-甲基-1H-吡唑-3-基)-嘧啶-4-基氨基]-甲基}-哌啶-1-羧酸叔丁酯(541mg;1.33mmol;1.00eq.)和1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(453mg;1.60mmol;1.20eq.)为起始材料,依据实施例3的方法制备标题化合物,为米色固体(53mg mg,7%)。LC/MS:529.3(M+1)。
步骤2:{5-(1-甲基-1H-吡唑-3-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-
4-基}-哌啶-4-基甲基-胺
采用4-({5-(1-甲基-1H-吡唑-3-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-甲基)-哌啶-1-羧酸叔丁酯(52mg;0.10mmol;1.00eq)为起始材料,依据实施例4的方法制备标题化合物,为米色固体(40mg,94%)。1H NMR(400MHz,甲醇-d4)δ8.69(d,J=0.9Hz,1H),8.41(d,J=2.2Hz,1H),8.16(s,1H),8.11(d,J=8.3Hz,1H),8.00(s,1H),7.95(d,J=7.8Hz,1H),7.85(d,J=2.4Hz,1H),7.68(t,J=7.8Hz,1H),7.04(d,J=2.4Hz,1H),4.08(s,3H),4.00(d,J=3.2Hz,3H),3.52–3.44(m,2H),3.12–3.00(m,2H),2.35–2.21(m,1H),2.14(d,J=14.4Hz,2H),1.75–1.54(m,2H),1.20(t,J=7.0Hz,2H);UPLC:(254nm)100%;RT(min)1.9;LC/MS:429.3(M+1)。
实施例13:{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-(四氢-吡喃-4-基甲基)-胺
采用[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基]-(四氢-吡喃-4-基甲基)-胺(206mg;0.67mmol;1.00eq.)和1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(228mg;0.80mmol;1.20eq.)为起始材料,依据实施例3的方法制备标题化合物,为米色固体(93mg,32%)。1H NMR(400MHz,氯仿-d)δ8.54–8.49(m,1H),8.25(m,2H),7.88(s,1H),7.75(s,1H),7.68(s,1H),7.63–7.59(m,1H),7.49(t,J=7.7Hz,1H),5.39(t,J=6.1Hz,1H),5.12(brs,2H),4.03(s,3H),3.99(s,3H),3.58(t,J=6.4Hz,2H),3.42(t,J=11.8Hz,2H),2.00(m,1H),1.77–1.65(m,2H),1.46(m,2H);UPLC(H2O TFA 0.1%-ACNTFA 0.1%;梯度8分钟TFA):(254nm)100%;RT(min)2.39;LC/MS:430.2(M+1)。
实施例14:(1-甲磺酰基-哌啶-4-基)-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-胺
采用[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基]-(1-甲磺酰基-哌啶-4-基)-胺(870mg;2.35mmol;1.00eq)和1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(780mg;2.82mmol;1.20eq.)为起始材料,依据实施例3的方法制备标题化合物,为白色固体(600mg,52%)。1H NMR(400MHz,氯仿-d)δ8.51(brs,1H),8.26(d,J=1.2Hz,1H),8.21(dd,J=7.8,1.5Hz,1H),7.88(s,1H),7.74(s,1H),7.67(s,1H),7.60(dd,J=7.8,1.6Hz,1H),7.56(s,1H),7.49(t,J=7.7Hz,1H),5.09(d,J=7.2Hz,1H),4.36(m,1H),4.04(s,3H),4.00(s,3H),3.88(d,J=11.9,2H),3.06–2.91(m,2H),2.87(s,3H),2.29(m,2H),1.67(m,2H);UPLC(H2O TFA 0.1%-ACN TFA 0.1%;梯度8分钟TFA):(254nm)100%;RT(min)2.17;LC/MS:493.2(M+1)。
实施例15:异丙基-[2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-5-(5-甲基-[1,3,4]噻二唑-2-基)-嘧啶-4-基]-胺
步骤1:4-异丙基氨基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-羧酸N'-乙
酰基-肼
保持在0℃,将乙酰氯(0.04mL;0.53mmol;1.05eq.)滴加入4-异丙基氨基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-羧酸酰肼(180mg;0.50mmol;1.00eq.)和TEA(0.2mL,1.51mmol;3.00eq.)在DCM(4.5mL)中的溶液中。反应混合物升至室温,搅拌30分钟。然后加入饱和NaHCO3溶液淬灭反应,混合物用DCM萃取。有机层用Na2SO4干燥,过滤,浓缩。通过硅胶快速色谱法纯化(DCM:甲醇),获得标题化合物,为黄色胶状物(160mg,74%)。1H NMR(400MHz,DMSO-d6)δ:10.44(s,1H),9.88(s,1H),8.79(s,1H),8.50-8.49(m,2H),8.22(s,1H),8.19(d,J=7.9Hz,1H),7.89(s,1H),7.72(d,J=8.2Hz,1H),7.49(t,J=7.8Hz,1H),4.50-4.42(m,1H),3.88(s,3H),1.93(s,3H),1.28(d,J=6.52Hz,6H)。HPLC(254nm)90%;Rt2.88min;LC/MS:394.2(M+H)。
步骤2:异丙基-[2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-5-(5-甲基-[1,3,4]噻二
唑-2-基)-嘧啶-4-基]-胺
2,4-二-(4-甲氧基-苯基)-[1,3,2,4]二硫杂二磷杂环丁烷2,4-二硫化物(311mg;0.75mmol;2.00eq.)和4-异丙基氨基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-羧酸N'-乙酰基-肼(160mg;0.37mmol;1.00eq.)在THF(8.0mL)中的溶液回流加热2小时。反应混合物用乙酸乙酯稀释,10%NaHCO3溶液洗涤。分离出有机层,经Na2SO4干燥,过滤,浓缩。通过硅胶柱快速色谱法纯化(DCM:甲醇),获得标题化合物,为黄色固体(80mg,52%)。1H NMR(400MHz,DMSO-d6)δ:8.85(d,J=7.2Hz,1H),8.80(s,1H),8.53(s,1H),8.23(s,1H),8.20(s,1H),7.89(s,1H),7.72(d,J=7.7Hz,1H),7.51(t,J=7.8Hz,1H),4.62-4.57(m,1H),3.89(s,3H),2.80(s,3H),1.37(d,J=6.48Hz,6H)。HPLC:(254nm)94%;Rt 3.58min。LC/MS:392.3(M+H)。
实施例16:((R)-3-羟基-吡咯烷-1-基)-(5-{4-异丙基氨基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-基}-[1,3,4]噻二唑-2-基)-甲酮
在0℃下将二(三甲基铝)-1,4-二氮杂二环(2.2.2)辛烷加合物(78mg;0.30mmol;1.00eq.)和(R)-吡咯烷-3-醇(32mg;0.36mmol;1.20eq.)依次加入至5-{4-异丙基氨基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-基}-[1,3,4]噻二唑-2-羧酸乙酯(150mg;0.30mmol;1.00eq.)在THF(3.00mL)中的溶液中。反应混合物在密封试管中回流加热8小时。冷却至室温,用乙酸乙酯稀释,1.5N HCl溶液洗涤。分离出有机层,用Na2SO4干燥,过滤,浓缩。通过硅胶快速色谱法(DCM/甲醇)纯化,获得标题化合物,为黄色固体(80mg,51%)。1HNMR(400MHz,DMSO-d6)δ:8.96(s,1H),8.88(d,J=7.20Hz,1H),8.55(t,J=1.52Hz,1H),8.23(t,J=7.04Hz,2H),7.90(d,J=0.56Hz,1H),7.74(d,J=7.84Hz,1H),7.52(t,J=7.72Hz,1H),5.10(d,J=3.48Hz,1H),4.66-4.61(m,1H),4.38(d,J=24.84Hz,1H),4.21(d,J=8.92Hz,2H),3.89(s,3H),3.72-3.51(m,2H),2.05-1.86(m,2H),1.40-1.22(m,6H)。HPLC:(254nm)95%;Rt 3.53min。LC/MS:491.2(M+H)。
实施例17:[2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-5-(5-甲基-[1,3,4]噻二唑-2-基)-嘧啶-4-基]-哌啶-3-基-胺盐酸盐
步骤1:3-{5-(N'-乙酰基-肼基羰基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧
啶-4-基氨基}-哌啶-1-羧酸叔丁酯
采用3-{5-肼基羰基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-哌啶-1-羧酸叔丁酯(600mg;1.18mmol;1.00eq.)为起始材料,依据实施例15步骤1的方法制备标题化合物,为黄色固体(500mg,70%)。HPLC(柱:XBridge C8,3.5μm,4.6x 50mm):(254nm)81%;Rt 3.5min;LC/MS:535.2(M+H)。
步骤2:3-[2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-5-(5-甲基-[1,3,4]噻二唑-2-
基)-嘧啶-4-基氨基]-哌啶-1-羧酸叔丁酯
采用3-{5-(N'-乙酰基-肼基羰基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-哌啶-1-羧酸叔丁酯(500mg;0.83mmol;1.00eq.)为起始材料,依据实施例15步骤2的方法制备标题化合物,为黄色固体(350mg;71.2%)。HPLC:(254nm)74%;Rt 4.21min;LC/MS:533.3(M+H)。
步骤3:[2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-5-(5-甲基-[1,3,4]噻二唑-2-
基)-嘧啶-4-基]-哌啶-3-基-胺盐酸盐
3-[2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-5-(5-甲基-[1,3,4]噻二唑-2-基)-嘧啶-4-基氨基]-哌啶-1-羧酸叔丁酯(100mg;0.14mmol;1.00eq.)和氯化氢(1mL 4M在二噁烷中的溶液)在二噁烷(0.5mL)中的溶液在室温搅拌4小时。反应混合物减压浓缩,滤出沉淀物,用二乙醚(20mL)洗涤,干燥,获得标题化合物,为白色固体(20mg,29%)。1H NMR(400MHz,DMSO-d6)δ:9.06(d,J=7.12Hz,1H),8.83(s,1H),8.54(t,J=1.56Hz,1H),8.26(d,J=7.92Hz,1H),8.22(s,1H),7.91(s,1H),7.74-7.72(m,1H),7.51(t,J=7.72Hz,1H),4.60-4.50(m,1H),3.89(s,3H),2.99-2.93(m,1H),2.90-2.82(m,1H),2.81-2.80(m,4H),2.30-2.00(m,1H),1.82-1.73(m,3H)。HPLC:(254nm)91%;Rt 2.6min。LC/MS:433.3(M+H)。
实施例18:5-[2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-4-(哌啶-3-基氨基)-嘧啶-5-基]-[1,3,4]噻二唑-2-羧酸甲酯盐酸盐
3-{5-(5-甲氧基羰基-[1,3,4]噻二唑-2-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-哌啶-1-羧酸叔丁酯(100mg;0.17mmol;1.00eq.)和氯化氢(2mL 4M在二噁烷中的溶液)在二噁烷(5mL)中的溶液在室温搅拌4小时。反应混合物减压浓缩,通过制备型HPLC纯化,获得标题化合物,为黄色固体(45mg,51%)。1H NMR(400MHz,DMSO-d6)δ:9.08(s,1H),8.91(d,J=7.20Hz,1H),8.7-8.8(brs,2H),8.57(s,1H),8.31(d,J=7.88Hz,1H),8.24(s,1H),7.94(s,1H),7.77(d,J=7.96Hz,1H),7.54(t,J=7.72Hz,1H),4.71(s,1H),4.01(s,3H),3.90(s,3H),3.32-3.29(m,1H),3.18-3.16(m,1H),2.98-2.95(m,1H),2.17-2.15(m,1H),2.01-1.98(m,1H),1.89-1.84(m,2H)。HPLC:(254nm)98%;Rt 3.01min;LC/MS:477.2(M+H)。
实施例19:5-{4-[(氮杂环丁烷-3-基甲基)-氨基]-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-基}-[1,3,4]噻二唑-2-羧酸甲酯三氟乙酸酯
保持在0℃,将三氟乙酸(1.00mL)加入至5-{4-[(1-叔丁氧基羰基-氮杂环丁烷-3-基甲基)-氨基]-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-基}-[1,3,4]噻二唑-2-羧酸甲酯(100mg;0.17mmol;1.00eq.)在DCM(5mL)中的溶液中。反应混合物升至室温,搅拌2小时。减压浓缩,通过制备型HPLC纯化,获得标题化合物,为黄色固体(20mg;20%)。1H NMR(400MHz,DMSO-d6)δ9.09(t,J=5.84Hz,1H),9.03(s,1H),8.54(s,2H),8.43(s,1H),8.27(d,J=8.00Hz,1H),8.23(s,1H),7.93(s,1H),7.76(d,J=8.12Hz,1H),7.53(t,J=7.76Hz,1H),4.03-3.94(m,9H),3.90(s,3H),3.36-3.29(m,1H)。HPLC:(254nm)93%;Rt 2.76min。LC/MS:463.3(M+H)。
实施例20:((R)-3-羟基-吡咯烷-1-基)-{5-[2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-4-(哌啶-3-基氨基)-嘧啶-5-基]-[1,3,4]噻二唑-2-基}-甲酮盐酸盐
步骤1:3-{5-[5-((R)-3-羟基-吡咯烷-1-羰基)-[1,3,4]噻二唑-2-基]-2-[3-(1-
甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-哌啶-1-羧酸叔丁酯
采用3-{5-(5-乙氧基羰基-[1,3,4]噻二唑-2-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-哌啶-1-羧酸叔丁酯(150mg;0.24mmol;1.00eq.)和(R)-吡咯烷-3-醇(32.22mg;0.36mmol;1.50eq.)为起始材料,依据实施例16步骤1的方法制备标题化合物,为黄色固体(100mg,63%)。HPLC:(254nm)94%;Rt 4.07min;LC/MS:632.2(M+H)。
步骤2:((R)-3-羟基-吡咯烷-1-基)-{5-[2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-
4-(哌啶-3-基氨基)-嘧啶-5-基]-[1,3,4]噻二唑-2-基}-甲酮盐酸盐
采用3-{5-[5-((R)-3-羟基-吡咯烷-1-羰基)-[1,3,4]噻二唑-2-基]-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-哌啶-1-羧酸叔丁酯(100mg;0.15mmol;1.00eq.)为起始材料,依据实施例18步骤1的方法制备标题化合物,为黄色固体(20mg,23%)。1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.96(d,J=7.24Hz,1H),8.75(s,2H),8.56(s,1H),8.31(d,J=7.84Hz,1H),8.24(s,1H),7.94(s,1H),7.76(d,J=8.12Hz,1H),7.54(t,J=7.80Hz,1H),4.72(s,1H),4.42-4.36(m,1H),4.22-4.17(m,1H),4.01-3.99(m,2H),3.90(s,3H),3.61-3.60(m,2H),3.32-3.29(m,1H),3.19-3.17(m,1H),2.97(s,1H),2.17-2.16(m,1H),1.98-1.96(m,2H),1.88-1.84(m,2H)。HPLC(XBridge C8(50X4.6)mm,3.5μm;A:10mM NH4HCO3水溶液,B:ACN;):(254nm)98%;Rt 4.55min。LC/MS:532.1(M+H)。
实施例21:((R)-3-羟基-吡咯烷-1-基)-(5-{4-异丙基氨基-6-[3-(1-甲基-1H-吡唑-4-基)-苯基]-吡啶-3-基}-[1,3,4]噻二唑-2-基)-甲酮
1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(250mg;0.88mmol;1.00eq.)、[5-(6-氯-4-异丙基氨基-吡啶-3-基)-[1,3,4]噻二唑-2-基]-((R)-3-羟基-吡咯烷-1-基)-甲酮(324mg;0.88mmol;1.00eq.)、K2CO3(365mg;2.64mmol;3.00eq.)和反式-二氯二(三环己基膦)钯(II)(6.49mg;0.01mmol;0.01eq.)在二噁烷(4mL)和水(0.4mL)中的混合物脱气,在100℃加热0.5小时。完成后,反应物过滤,有机层浓缩,经硅胶快速色谱法纯化,洗脱梯度:10-100%乙酸乙酯在己烷中的溶液,获得标题化合物,为米色固体(115mg,27%)。1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.67(d,1H),8.28–8.21(m,2H),7.99–7.92(m,2H),7.65(d,1H),7.48(t,1H),7.36(s,1H),3.94–3.87(m,3H),5.75(s,1H),5.07(d,1H),4.39(d,1H),4.24(m,2H),4.09–3.97(m,2H),3.73–3.50(m,2H),1.34(d,6H)。HPLC:(254nm)96.6%;Rt(min)3.09。LC/MS:490.2。
实施例22:((R)-3-羟基-吡咯烷-1-基)-{5-[4-异丙基氨基-6'-(1-甲基-1H-吡唑-4-基)-[2,2']二吡啶基-5-基]-[1,3,4]噻二唑-2-基}-甲酮
步骤1:[5-(6'-氯-4-异丙基氨基-[2,2']二吡啶基-5-基)-[1,3,4]噻二唑-2-
基]-((R)-3-羟基-吡咯烷-1-基)-甲酮
2-氯-6-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-吡啶(332.71mg;1.39mmol;1.00eq.)、[5-(6-氯-4-异丙基氨基-吡啶-3-基)-[1,3,4]噻二唑-2-基]-((R)-3-羟基-吡咯烷-1-基)-甲酮(511.00mg;1.39mmol;1.00eq.)、K2CO3溶液(575.94mg;4.17mmol;3.00eq.)和反式-二氯二(三环己基膦)钯(II)(10.25mg;0.01mmol;0.01eq.)在水(0.4mL)和二噁烷(4mL)中的混合物脱气数分钟,在100℃加热0.5小时。完成后,反应物过滤,有机层浓缩,经硅胶快速色谱法纯化,洗脱梯度:10-100%乙酸乙酯在己烷中的溶液,获得标题化合物,为米色固体(175mg;15.8%)。
步骤2:((R)-3-羟基-吡咯烷-1-基)-{5-[4-异丙基氨基-6'-(1-甲基-1H-吡唑-4-
基)-[2,2']二吡啶基-5-基]-[1,3,4]噻二唑-2-基}-甲酮
[5-(6'-氯-4-异丙基氨基-[2,2']二吡啶基-5-基)-[1,3,4]噻二唑-2-基]-((R)-3-羟基-吡咯烷-1-基)-甲酮(85mg;0.11mmol;1.00eq.)溶解在DMF(4.00mL;51.44mmol;481.41eq.)中。然后一次性加入1-甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(33.35mg;0.16mmol;1.50eq.),再加入NaHCO3(10.77mg;0.13mmol;1.20eq.)在水(0.40mL;22.20mmol;207.74eq.)中的溶液。反应物脱氮气,加入双(三苯基膦)二氯化钯(II)(0.38mg;0.00mmol;0.01eq.)。反应混合物在80℃搅拌过夜。反应混合物冷却至室温,用200mL水稀释,乙酸乙酯(3x80mL)萃取。有机相合并,用水(2x75mL)和盐水(1x75mL)洗涤;用Na2SO4干燥,过滤,浓缩至金色油,经制备型HPLC纯化,获得标题化合物,为蓬松的黄色固体(32.1mg,61.2%)。1H NMR(400MHz,DMSO-d6)δ12.73(s,1H),8.84(s,2H),8.42(s,3H),8.26–8.19(m,3H),8.16(d,4H),8.00(s,3H),7.98–7.90(m,3H),7.75(d,3H),5.09(s,3H),4.43(s,2H),4.38(s,2H),4.22(d,6H),4.06(t,5H),3.99–3.92(m,9H),3.75–3.51(m,6H),1.99(dd,5H),1.47–1.36(m,17H)。HPLC:(254nm)100%;Rt(min)2.25.LC/MS:491.4。
实施例23:2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-5-[1-(四氢-吡喃-4-基)-1H-吡唑-4-基]-4-三氟甲基-吡啶
步骤1:5-氯-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-4-三氟甲基-吡啶
2-溴-5-氯-4-三氟甲基-吡啶(0.23mL;1.92mmol;1.00eq.)、1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(573mg;2.02mmol;1.05eq.)、四(三苯基膦)钯(11mg;0.01mmol;0.01eq.)和碳酸钾(0.32g;2.30mmol;1.20eq.)在二噁烷(10.00mL)和水(1mL)中的混合物在密封试管中在90℃搅拌过夜。减压浓缩,经硅胶快速色谱法(乙酸乙酯:己烷,梯度:由10至50%)纯化,获得标题化合物,为黄色固体(285mg,42%);LC/MS:338.1(M+1)。
步骤2:2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-5-[1-(四氢-吡喃-4-基)-1H-吡唑-
4-基]-4-三氟甲基-吡啶
5-氯-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-4-三氟甲基-吡啶(40mg;0.12mmol;1.00eq.)、1-(四氢-吡喃-4-基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(35mg;0.12mmol;1.05eq.)、四(三苯基膦)钯(0.68mg;0.0006mmol;0.01eq.)和碳酸钾(0.02g;0.14mmol;1.20eq.)在二噁烷(1mL)和水(0.1mL)中的混合物在密封小瓶中在150℃搅拌过夜。减压浓缩,先经硅胶快速色谱法(己烷:乙酸乙酯,梯度:由80:20至100:0,再换成乙酸乙酯:甲醇,100至80%),再经制备型HPLC纯化,获得标题化合物,为白色固体(35mg,62%)。1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.32(d,J=15.7Hz,3H),8.20(s,1H),8.06–7.99(m,2H),7.79(s,1H),7.70(d,J=7.5Hz,1H),7.53(t,J=7.8Hz,1H),4.53(td,J=10.2,5.1Hz,1H),4.00(dt,J=13.6,2.7Hz,2H),3.91(d,J=1.4Hz,3H),3.50(td,J=11.2,3.8Hz,2H),2.04(dtd,J=12.0,6.7,5.2,2.2Hz,4H)。HPLC:99.8%(254nm);Rt(min)4.45;LC/MS:454.2(M+1)。
实施例24:4-甲基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-5-[1-(四氢-吡喃-4-基)-1H-吡唑-4-基]-吡啶
步骤1:2-氯-4-甲基-5-[1-(四氢-吡喃-4-基)-1H-吡唑-4-基]-吡啶
5-溴-2-氯-4-甲基-吡啶(200mg;0.97mmol;1.00eq.)、1-(四氢-吡喃-4-基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-1H-吡唑(283mg;1.02mmol;1.05eq.)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)与二氯甲烷的络合物(1:1)(158mg;0.19mmol;0.20eq.)、碳酸铯(947mg;2.91mmol;3.00eq.)在二噁烷(5.00mL)和水(0.50mL)中的混合物在密封试管中在90℃搅拌过夜。减压浓缩,经硅胶快速色谱法(己烷:乙酸乙酯,梯度:由80至20%)纯化,获得标题化合物,为黄色固体(170mg,63%)。LC/MS:278.1(M+1)。
步骤2:4-甲基-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-5-[1-(四氢-吡喃-4-基)-
1H-吡唑-4-基]-吡啶
2-氯-4-甲基-5-[1-(四氢-吡喃-4-基)-1H-吡唑-4-基]-吡啶(50mg;0.18mmol;1.00eq.)、1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(54mg;0.19mmol;1.05eq.)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)与二氯甲烷的络合物(1:1)(0.74mg;0.0006mmol;0.01eq.)、碳酸铯(90mg;0.27mmol;1.50eq.)在二噁烷(2mL)和水(0.20mL)中的混合物在密封小瓶中在120℃搅拌过夜。减压浓缩,经KPNH快速色谱法(己烷:乙酸乙酯,梯度:由70至20%)纯化,获得标题化合物,为白色固体(15mg,21%)。1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.30–8.21(m,4H),7.99–7.86(m,5H),7.61(d,J=7.4Hz,2H),7.47(t,J=7.7Hz,1H),4.49(p,J=8.4,7.6Hz,1H),4.04–3.97(m,3H),3.90(d,J=1.3Hz,3H),3.55–3.46(m,3H),2.04(td,J=10.6,9.2,3.7Hz,5H)。;HPLC:91%(254nm);LC/MS:400.2(M+1)。
实施例25和26:2-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-乙酰胺甲酸酯和{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-乙酸甲酯
2-[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基氨基]-乙酰胺(50mg;0.19mmol;1.00eq.)、1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(80mg;0.28mmol;1.50eq.)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II).CH2Cl2(15mg;0.02mmol;0.10eq.)和碳酸铯(91.6mg;0.28mmol;1.50eq.)在二噁烷(2mL)和水(0.20mL)中的混合物在120℃搅拌过夜。反应混合物减压浓缩,经KPNH快速色谱法(乙酸乙酯:甲醇梯度:由0至100%)纯化,获得标题化合物的混合物。通过制备型HPLC分离开这两个化合物:
第一洗脱馏分(实施例25,2-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-乙酰胺甲酸酯):白色固体(9mg,11%):1H NMR(400MHz,DMSO-d6)δ8.55(d,J=1.9Hz,1H),8.42(s,0H),8.28(s,1H),8.23–8.15(m,2H),8.11(s,1H),7.94(s,1H),7.81(s,1H),7.66(d,J=7.8Hz,1H),7.53(s,1H),7.45(t,J=7.7Hz,1H),7.12(s,1H),6.93(t,J=5.4Hz,1H),6.63(s,1H),4.03–3.88(m,8H);HPLC:98.8%(254nm);LC/MS:389.2(M+H)。
第二洗脱馏分(实施例26,5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-乙酸甲酯):白色固体(12mg,14.7%):1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.30(s,1H),8.20–8.14(m,2H),8.07(s,1H),7.91(s,1H),7.78(s,1H),7.66(d,J=8.0Hz,1H),7.45(t,J=7.7Hz,1H),7.08(t,J=5.5Hz,1H),6.52(s,0H),4.08(s,2H),3.92(d,J=15.5Hz,4H)。HPLC:98.6%(254nm);LC/MS:390.2(M+1)。
实施例27:环丁基-{5-(1-甲基-1H-吡唑-3-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-胺
[2-氯-5-(1-甲基-1H-吡唑-3-基)-嘧啶-4-基]-环丁基-胺(60mg;0.23mmol;1.00eq.)、1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(97mg;0.34mmol;1.50eq.)、、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II).CH2Cl2(18mg;0.02mmol;0.10eq.)和碳酸铯(111mg;0.34mmol;1.50eq.)在二噁烷(2.00mL)和水(0.20mL)中的混合物在密封小瓶中在120℃搅拌过夜。反应混合物减压浓缩,经KPNH快速色谱法(乙酸乙酯:己烷,梯度:由40至70%)纯化,获得标题化合物,为白色固体(17mg,17%)。1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.78(s,1H),8.53(t,J=1.8Hz,1H),8.27–8.12(m,2H),7.98–7.87(m,2H),7.74(dt,J=7.7,1.4Hz,1H),7.54(t,J=7.7Hz,1H),7.04(d,J=2.4Hz,1H),4.81(H,J=8.0Hz,1H),3.96(d,J=34.9Hz,6H),2.18–2.05(m,2H),1.96–1.81(m,2H);HPLC:98.0%(254nm);LC/MS:386.2(M+H)。
实施例28:2-氨基甲基-2-(2-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-乙基)-丙烷-1,3-二醇
步骤1:6-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧
啶-4-基氨基}-2-氮杂-螺[3.3]庚烷-2-羧酸叔丁酯
6-[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基氨基]-2-氮杂-螺[3.3]庚烷-2-羧酸叔丁酯(190mg;0.47mmol;1.00eq.)、1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(160mg;0.56mmol;1.20eq.)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II).CH2Cl2(38mg;0.05mmol;0.10eq.)、碳酸铯(229mg;0.70mmol;1.50eq.)在二噁烷(3.00mL)和水(0.30mL)中的混合物在密封试管中在120℃搅拌过夜。反应混合物减压浓缩,经硅胶快速色谱法(甲醇:乙酸乙酯,梯度:由0:100至20:80)纯化,获得标题化合物,为黄色固体(156mg,63%)。LC/MS:527.3(M+H)。
步骤2:2-氨基甲基-2-(2-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-
4-基)-苯基]-嘧啶-4-基氨基}-乙基)-丙烷-1,3-二醇
将氯化氢(0.71mL 2M在乙醚中的溶液;1.42mmol;5.00eq.)加入至6-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-2-氮杂-螺[3.3]庚烷-2-羧酸叔丁酯(150mg;0.28mmol;1.00eq.)在甲醇(3.00mL)中的溶液。反应混合物在室温搅拌过夜。
反应混合物的LC/MS分析结果显示,反应完全,但主要的产物是开环副产物。反应混合物减压浓缩,经制备型HPLC纯化,获得标题化合物,为白色固体(13mg,10%)。1H NMR(400MHz,DMSO-d6)δ8.53(d,J=1.9Hz,1H),8.25–8.15(m,3H),8.06(s,1H),7.90(s,1H),7.76(s,1H),7.66(d,J=7.7Hz,1H),7.47(t,J=7.6Hz,1H),6.77(d,J=6.3Hz,1H),4.73(m,1H),3.99–3.86(m,7H),2.67(s,2H),2.35–2.27(m,2H),2.05–1.96(m,2H)。;HPLC:97.0%(254nm);LC/MS:463.3(M+H)。
按照类似的路途和方案制备下列化合物:
实施例86:1-甲基-8-(4-{2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-4-[(哌啶-4-基甲基)-氨基]-嘧啶-5-基}-吡唑-1-基)-1-氮杂-螺[4.5]癸-2-酮盐酸盐
步骤1:4-({2-氯-5-[1-(1-甲基-2-氧代-1-氮杂-螺[4.5]癸-8-基)-1H-吡唑-4-
基]-嘧啶-4-基氨基}-甲基)-哌啶-1-羧酸叔丁酯
8-(4-溴-吡唑-1-基)-1-甲基-1-氮杂-螺[4.5]癸-2-酮(410mg;1.31mmol;1.00eq.)、4,4,5,5,4',4',5',5'-八甲基-[2,2']二[[1,3,2]二氧杂环戊硼](366mg;1.44mmol;1.10eq.)、乙酸钾(193mg;1.97mmol;1.50eq.)和PdCl2(PPh3)2(9mg;0.01mmol;0.01eq.)在二噁烷(7.50mL)中的混合物在100℃和氮气气氛下搅拌22小时。
反应混合物冷却至室温,用初始加入量的0.5倍试剂(除了溴化物外)处理,100℃搅拌29小时。冷却至室温,加入4-[(5-溴-2-氯-嘧啶-4-基氨基)-甲基]-哌啶-1-羧酸叔丁酯(586mg;1.44mmol;1.10eq.)在二噁烷(2mL)中的溶液以及K2CO3(544mg;3.94mmol;3.00eq.)在水(2.50mL)中的溶液。让氮气鼓泡5分钟,逸出溶液,加入PdCl2(PPh3)2(9mg;0.01mmol;0.01eq.),混合物在90℃搅拌过夜。冷却至室温,用乙酸乙酯(10mL)和水(2mL)稀释。移除水层,有机层过滤,浓缩。通过硅胶快速色谱法纯化(乙酸乙酯:己烷,梯度:由20至70%,再换成甲醇:DCM,10:90),获得标题化合物,为金色泡沫(390mg,32%)。LC/MS:559(M+H)。
步骤2:甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-甲基)-哌啶-1-羧酸叔丁酯
4-({2-氯-5-[1-(1-甲基-2-氧代-1-氮杂-螺[4.5]癸-8-基)-1H-吡唑-4-基]-嘧啶-4-基氨基}-甲基)-哌啶-1-羧酸叔丁酯(390mg;0.42mmol;1.00eq.)、1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(179mg;0.63mmol;1.50eq.)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II).CH2Cl2(34mg;0.04mmol;0.10eq.)和碳酸铯(629μl;1.26mmol;3.00eq.)在二噁烷(6.0mL)中的混合物在100℃和氮气气氛下搅拌过夜。反应混合物冷却至室温,用乙酸乙酯(10mL)和水(3mL)稀释。分离出有机层,经硅藻土过滤,减压浓缩。通过快速色谱法(乙酸乙酯,100%,再换成甲醇:DCM,梯度:由0至10%)过滤,获得标题化合物,为金色油(229mg,80%)。1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.23(s,1H),8.18(d,2H),8.12(s,1H),7.86(s,1H),7.78(s,1H),7.65(d,1H),7.47(t,1H),6.76(t,1H),4.27(m,1H),4.02–3.91(m,2H),3.90(s,3H),3.47(t,2H),2.71(m,1H),2.68(s,3H),2.28(t,2H),2.14(d,2H),2.10–1.86(m,6H),1.73(d,2H),1.55(d,2H),1.39(s,9H),1.13(qd,2H)。LC/MS:680(M+1)。
步骤3:1-甲基-8-(4-{2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-4-[(哌啶-4-基甲
基)-氨基]-嘧啶-5-基}-吡唑-1-基)-1-氮杂-螺[4.5]癸-2-酮盐酸盐
将氯化氢(0.71mL 2M在乙醚中的溶液;1.42mmol;5.00eq.)加入至4-({5-[1-(1-甲基-2-氧代-1-氮杂-螺[4.5]癸-8-基)-1H-吡唑-4-基]-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-甲基)-哌啶-1-羧酸叔丁酯(225mg;0.33mmol;1.00eq.)在甲醇(3mL)中的溶液。反应混合物在室温搅拌2小时。用乙醚稀释,过滤。高真空干燥固体,获得标题化合物,为白色固体(180mg,79%)。1H NMR(400MHz,DMSO-d6)δ8.93(brs,2H),8.68(s,1H),8.64(m,1H),8.37(s,1H),8.33(s,1H),8.23(s,1H),8.17(d,1H),8.06(s,1H),7.91(d,2H),7.65(t,1H),4.32(m,1H),3.64(t,2H),3.28(d,2H),2.93–2.77(m,2H),2.68(s,3H),2.28(t,2H),2.20–1.91(m,9H),1.91–1.80(d,2H),1.57(m,4H)。LC/MS:580(M+1)。
实施例87:1-甲基-8-(4-{4-[(1-甲基-哌啶-4-基甲基)-氨基]-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-5-基}-吡唑-1-基)-1-氮杂-螺[4.5]癸-2-酮
将碘甲烷(用银使其稳定,5μl;79.81μmol;1.10eq.)滴加入1-甲基-8-(4-{2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-4-[(哌啶-4-基甲基)-氨基]-嘧啶-5-基}-吡唑-1-基)-1-氮杂-螺[4.5]癸-2-酮盐酸盐(3)(50mg;0.07mmol;1.00eq.)和TEA(40μl;0.29mmol;4.00eq.)在N,N-二甲基甲酰胺(3.0mL)中的溶液中。澄清溶液在室温搅拌过夜,减压浓缩,经制备型HPLC纯化(C-18(10um),30x150mm,0.1%NH4OH修饰的流动相(A=水,B=ACN),方法:25分钟内25至75%ACN,流速:60mL/min),获得标题化合物,为白色固体(8mg,17%)。1HNMR(500MHz,DMSO-d6)δ8.49(t,1H),8.21(s,1H),8.16(d,2H),8.10(s,1H),7.84(s,1H),7.76(s,1H),7.66–7.61(m,1H),7.46(t,1H),6.73(t,1H),4.31–4.19(m,1H),3.88(s,3H),3.44(t,2H),2.75(d,2H),2.66(s,3H),2.26(t,2H),2.11(s,5H),2.05–1.88(m,6H),1.85–1.72(m,3H),1.68(d,2H),1.52(d,2H),1.27(m,2H);LC/MS:594(M+1)。
按照类似的路途和方案制备下列化合物:
实施例133和134:(1R,2S,3R)-3-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环己烷-1,2-二醇和(1S,2R,6R)-2-氨基-6-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氧基}-环己醇(外消旋体-相对构型)
(1S,2R,3S)和(1R,2S,3R)-3-[2-氯-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基氨基]-环己烷-1,2-二醇(390mg;1.20mmol;1.00eq.)的外消旋体混合物、1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼戊烷-2-基)-苯基]-1H-吡唑(411mg;1.45mmol;1.20eq.)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II).CH2Cl2(98mg;0.12mmol;0.10eq.)和碳酸铯(589mg;1.81mmol;1.50eq.)在二噁烷(4mL)和水(0.40mL)中的悬液在密封试管中在120℃搅拌过夜。反应混合物冷却至室温,经硅藻土垫过滤,浓缩,经制备型HPLC(23-25%CH3CN在0.1%NH4OH水溶液中的溶液)纯化,获得标题化合物(175mg,36%),是(1S,2R,3R)和(1R,2S,3R)-3-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环己烷-1,2-二醇(175.00mg;0.39mmol)的外消旋体混合物,为白色固体。1H NMR(400MHz,DMSO-d6)d8.53(s,1H),8.23–8.15(m,3H),8.07(s,1H),7.86(s,1H),7.78(s,1H),7.66(d,J=7.7Hz,1H),7.48(t,J=8.5Hz,1H),6.06(d,J=6.8Hz,1H),4.59(d,J=6.4Hz,1H),4.52–4.48(m,1H),4.40(m,1H),3.93(s,3H),3.90(s,3H),3.63–3.56(m,1H),2.21–2.11(m,1H),1.77(m,2H),1.48–1.26(m,3H)。LC/MS446.2(M+H)。
第二馏分含有(1S,2R,3R)和(1S,2R,6R)-2-氨基-6-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氧基}-环己醇(O-烷基化副产物)的外消旋体混合物,分离得到白色固体(24mg)。1H NMR(400MHz,DMSO-d6)8.49(s,1H),8.25(s,1H),8.20–8.14(m,2H),8.07(s,1H),7.87(s,1H),7.80(s,1H),7.65(d,J=7.7Hz,1H),7.50–7.44(m,1H),6.69(s,1H),5.07–4.84(m,2H),4.40(s,1H),3.95(s,3H),3.88(s,3H),3.74(m,2H),1.64(m,4H),1.52(s,1H),1.31(s,1H)。LC/MS:446.3(M+H)。
按照类似的路途和方案制备下列化合物:
实施例195和196:顺式和反式N-(3-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环丁基甲基)-甲磺酰胺
将甲磺酰氯(0.07ml;0.93mmol;1.20eq.)加入至(3-氨基甲基-环丁基)-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-胺盐酸盐(350mg;0.78mmol;1.00eq.)和TEA(0.22mL;1.55mmol;2.00eq.)在DMF(3mL)中的溶液中。反应混合物室温搅拌过夜。减压浓缩,经制备型HPLC(25-28%CH3CN在0.1%NH4OH水溶液中的溶液)纯化,获得标题化合物,为顺式和反式异构体:
第一洗脱异构体:黄色固体(17mg)。1H NMR(400MHz,DMSO-d6)d 8.50(d,J=1.9Hz,1H),8.25–8.16(m,3H),8.07(s,1H),7.90(s,1H),7.76(s,1H),7.67(d,J=7.7Hz,1H),7.47(t,J=7.7Hz,1H),7.17–7.06(m,1H),6.66(d,J=6.5Hz,1H),4.77(m,1H),3.93(s,3H),3.91(s,3H),3.17(t,J=6.7Hz,2H),2.95(s,3H),2.29(m,5H)。LC/MS:493.3(M+H)。
第一洗脱异构体:白色固体(17mg)。1H NMR(400MHz,DMSO-d6)δ8.49(d,J=1.9Hz,1H),8.25–8.16(m,3H),8.05(s,1H),7.89(s,1H),7.75(s,1H),7.66(d,J=7.7Hz,1H),7.48(t,J=7.7Hz,1H),6.98(brs,1H),6.63(d,J=6.9Hz,1H),4.61(m,1H),3.93(s,3H),3.90(s,3H),3.02(d,J=6.9Hz,2H),2.89(s,3H),2.31–2.14(m,1H),1.90–1.79(m,2H)。LC/MS:493.3(M+H)。
按照类似的路途和方案制备下列化合物:
实施例206和207:N-[(顺式)-2-({5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-甲基)-环戊基]-乙酰胺和N-[(反式)-2-({5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-甲基)-环戊基]-乙酰胺
将乙酰氯(0.01ml;0.13mmol;1.20eq.)加入至(2-氨基-环戊基甲基)-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-胺盐酸盐(50mg;0.11mmol;1.00eq.)和TEA(0.03ml;0.22mmol;2.00eq.)在DMF(2mL)中的溶液中。反应混合物室温搅拌过夜。减压浓缩,经制备型HPLC(25-28%CH3CN在0.1%NH4OH水溶液中的溶液)纯化,获得标题化合物,为顺式和反式异构体:
第一洗脱异构体:黄色固体(15mg)。1H NMR(400MHz,DMSO-d6)d 8.50(s,1H),8.20(m,3H),8.08(s,1H),7.90(m,2H),7.76(s,1H),7.65(m,1H),7.46(t,J=7.7Hz,1H),6.73(t,J=5.6Hz,1H),3.92(s,3H),3.87(s,3H),3.86(m,1H),3.69(m,1H),3.43(m,1H),2.11(mz,1H),1.89(m,4H),1.85(s,3H),1.62(m 2H),1.44(m,2H)。LC/MS:471.2(M+H)。
第二洗脱异构体:黄色固体(11mg)。1H NMR(400MHz,DMSO-d6)d 8.51(s,1H),8.20(m,3H),8.11(s,1H),7.89(s,1H),7.81(m,2H),7.66(d,J=7.6Hz,1H),7.46(t,J=7.7Hz,1H),6.75(m,1H),4.22(m,1H),3.92(s,3H),3.90(s,3H),3.86(m,1H),3.11(m,1H),2.27(m,1H),1.87(s,3H),1.81–1.71(m,3H),1.60–1.49(m,2H),1.41(m,1H)。LC/MS:471.2(M+H)。
实施例208:(1S,2R,3S)-3-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环己烷-1,2-二醇
步骤1:((3aR,4S,7aS)-2,2-二甲基-六氢-苯并[1,3]间二氧杂环戊烯-4-基)-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-胺
采用2-[(3aR,4S,7aS)-2,2-二甲基六氢-1,3-苯并间二氧杂环戊烯-4-基]-1H-异吲哚-1,3(2H)-二酮(参照WO 2010017051描述的方法制备)为起始材料,依据实施例28的方法制备标题化合物。LC/MS:486.3(M+H)。
步骤2:(1S,2R,3S)-3-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环己烷-1,2-二醇
将氯化氢(1.24ml;2.47mmol;5.00eq.)(2.0M在乙醚中的溶液)加入至((3aR,4S,7aS)-2,2-二甲基-六氢-苯并[1,3]间二氧杂环戊烯-4-基)-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-胺(240mg;0.49mmol;1.00eq.)在甲醇(3.0mL)中的溶液。反应混合物在室温搅拌过夜。减压浓缩,经制备型HPLC(20-24%CH3CN在0.1%NH4OH水溶液中的溶液)纯化,获得标题化合物,为白色固体(180mg;82%)。1H NMR(400MHz,DMSO-d6)d 8.53(s,1H),8.24–8.14(m,3H),8.07(s,1H),7.86(s,1H),7.78(s,1H),7.66(d,J=7.7Hz,1H),7.48(t,J=7.8Hz,1H),6.06(d,J=6.9Hz,1H),4.73–4.35(m,3H),3.92(m,7H),3.59(d,J=9.7Hz,1H),2.20–2.11(m,1H),1.77(m,2H),1.37(m,3H)。LC/MS:446.2(M+H)。
按照类似的路途和方案制备下列化合物:
实施例211和212:顺式和反式N-(3-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环丁基甲基)-乙酰胺
采用(3-氨基甲基-环丁基)-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-胺盐酸盐(两种异构体的混合物)为起始材料,依据实施例208和209的方法制备标题化合物。
第一洗脱异构体:白色固体(47mg)。1H NMR(400MHz,DMSO-d6)d 8.50(s,1H),8.24–8.15(m,3H),8.06(s,1H),7.90(m,1H),7.85(s,1H),7.75(s,1H),7.67(d,J=7.7Hz,1H),7.47(td,J=7.8,2.0Hz,1H),6.64(d,J=6.6Hz,1H),4.79(m,1H),3.93(s,3H),3.90(s,3H),3.28(t,J=7.3Hz,2H),2.33–2.14(m,5H),1.85(s,3H)。LC/MS:457.3(M+H)。
第二洗脱异构体:白色固体(25mg)。1H NMR(400MHz,DMSO-d6)d 8.50(s,1H),8.18-8.22(m,3H),8.05(2,1H),7.89(s,1H),7.80(m,1H),7.75(s,1H),7.66(d,J=4Hz,1H,7.48(t,J=8Hz,1H),6.60(d,J=8Hz,1H),4.55(m,1H),3.93(s,3H),3.90(s,3H),3.13(m,2H),2.45(m,2H),2.17(m,1H),1.85(m,1H),1.77(s,3H)。LC/MS:457.3(M+H)。
按照类似的路途和方案制备下列化合物:
实施例281:(1R,2S,6S)-2-甲基氨基-6-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环己醇(外消旋体–相对构型)
步骤1:N-[(1S,2S,3S)-2-羟基-3-{[5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-
1H-吡唑-4-基)苯基]嘧啶-4-基]氨基}环己基]-N-甲基氨基甲酸叔丁酯(外消旋体相对构
型)
N-[(1S,2S,3S)-3-[[2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基]氨基]-2-羟基环己基]-N-甲基氨基甲酸叔丁酯(中间体40,外消旋体,相对构型,420mg,0.87mmol,1.00equiv,90%)、1-甲基-4-[3-(四甲基-1,3,2-二氧杂硼戊烷-2-基)苯基]-1H-吡唑(440mg,1.30mmol,1.50equiv,84%)、Pd(PPh3)2Cl2(62mg,0.09mmol,0.10equiv,98%)和碳酸钾(245mg,1.74mmol,2.01equiv,98%)在二噁烷(10mL)和水(1mL)中的混合物脱氮气,并在150℃微波加热30分钟。得到的混合物真空浓缩,经硅胶快速色谱法(甲醇/DCM,1:5)纯化,获得标题化合物,为黄色固体(390mg,73%)。LC/MS(柱:Shim-pack XR-ODS,3.0*50mm,2.2um;流动相A:水/0.05%TFA,流动相B:ACN/0.05%TFA;流速:1.0mL/min;3.6分钟梯度:5%B至100%B,保持1.0min;254nm):(纯度)90%;[M+H]+计算结果:559.3;实验结果:559.3。
步骤2:(1R,2S,6S)-2-{[5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-
基)苯基]嘧啶-4-基]氨基}-6-(甲基氨基)环己-1-醇(外消旋体相对构型)
N-[(1S,2S,3S)-2-羟基-3-[[5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)苯基]嘧啶-4-基]氨基]环己基]-N-甲基氨基甲酸叔丁酯(50mg,0.08mmol,1.00equiv,90%)和浓盐酸(0.5mL,6.01mmol,74eq.,36.5%)在甲醇(2mL)中的溶液在25℃搅拌2小时。用碳酸氢钠调溶液的pH值至7,得到的混合物在真空下浓缩。残留物溶解在10mLDCM中,滤出固体,得到的混合物真空浓缩。粗产物(25mg)经HPLC纯化后,获得标题化合物,为黄色固体(5mg,15%)。熔点:88-92℃。LC/MS(柱:Shim-pack XR-ODS,2.0*50mm,1.6um;流动相A:水/0.05%TFA,流动相B:ACN/0.05%TFA;流速:0.7mL/min;2.0分钟梯度:5%B至100%B,保持0.5min;220nm):(纯度)98%;[M+H]+计算结果:459.3;实验结果:459.3。1HNMR(300MHz,DMSO-d6,ppm)δ8.52(t,J=1.7Hz,1H),8.24-8.12(m,3H),8.06(s,1H),7.89(s,1H),7.75(s,1H),7.71-7.60(m,1H),7.47(t,J=7.7Hz,1H),5.84(d,J=7.7Hz,1H),5.07(d,J=4.4Hz,1H),4.55(s,1H),3.93(s,3H),3.89(s,3H),3.75(q,J=3.9Hz,1H),2.60(d,J=3.8Hz,1H),2.33(s,3H),1.69(m,5H),1.41(m,2H)。
实施例283和284:(R)-5,5-二氟-1-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-哌啶-3-基胺和(S)-5,5-二氟-1-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基}-哌啶-3-基胺
步骤1:N-{5,5-二氟-1-[5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-
基)苯基]嘧啶-4-基]哌啶-3-基}氨基甲酸叔丁酯
采用N-[1-[2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基]-5,5-二氟哌啶-3-基]氨基甲酸叔丁酯(中间体42,220mg,0.46mmol,1.00eq.)为起始材料,依据实施例281步骤1的方法制备标题化合物,为白色固体(135mg,44%)。LC/MS(柱:Shim-pack XR-ODS,2.0*50mm,1.6um;流动相A:水/0.05%TFA,流动相B:ACN/0.05%TFA;流速:0.7mL/min;2.1分钟梯度:5%B至100%B,保持0.5min;220nm):(纯度)83.7%;[M+H]+计算结果:551.4;实验结果:551.4。
步骤2:(3R)和(3S)-5,5-二氟-1-[5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-
吡唑-4-基)苯基]嘧啶-4-基]哌啶-3-胺
保持在0℃,将三氟乙酸(1mL,13.46mmol,70.85equiv)滴加入N-[5,5-二氟-1-[5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)苯基]嘧啶-4-基]哌啶-3-基]氨基甲酸叔丁酯(125mg,0.19mmol,1.00eq.)在二氯甲烷(4mL)中的溶液中。得到的溶液在25℃搅拌2小时。真空浓缩,经制备型HPLC(XBridge C18)纯化,获得标题化合物,为外消旋体混合物(30mg)。再通过手性制备型HPLC(Lux 5u Cellulose-4,AXIA Packed,100.0%甲醇,0.1%DEA)分离开这两种异构体。
第一洗脱异构体:白色固体(14.4mg,16%)。熔点:70-73℃.LC/MS(柱:Shim-packXR-ODS,2.0*50mm,1.6um;流动相A:水/0.05%TFA,流动相B:ACN/0.05%TFA;流速:0.7mL/min;2.1分钟梯度:5%B至100%B,保持0.5min;220nm):(纯度)97.5%;[M+H]+计算结果:451.3;实验结果:451.3。1H NMR(400MHz,DMSO,ppm):8.49(m,2H),8.21-8.18(m,2H),8.03(s,1H),7.90(s,1H),7.73(s,1H),7.68-7.66(m,1H),7.49-7.45(m,1H),4.10-4.08(m,1H),3.94-3.85(m,7H),3.35(s,1H),3.30-3.17(m,1H),2.69-2.63(m,1H),2.49-2.47(m,1H),2.31(m,1H),1.83-1.72(m,1H)。
第二洗脱异构体:白色固体(15mg,17%)。LC/MS(柱:Shim-pack XR-ODS,2.0*50mm,1.6um;流动相A:水/0.05%TFA,流动相B:ACN/0.05%TFA;流速:0.7mL/min;2.1分钟梯度:5%B至100%B,保持.5min;220nm):(纯度)97.8%;[M+H]+计算结果:451.3;实验结果:451.3。
实施例285和286:(1S,2S,6S)-2-氟-6-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环己醇和(1R,2R,6R)-2-氟-6-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环己醇
采用(1S,2S,6S)-2-[[2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基]氨基]-6-氟环己烷-1-醇(中间体45,相对立体化学,外消旋体,360mg,0.99mmol,1.00eq.)为起始材料,依据实施例287的方法,制备标题化合物的外消旋体混合物。通过制备型HPLC[SHIMADZU:柱:XBridge BEH130Prep C18OBD柱,19x 150mm,5μm,13nm;流动相:水(10mmol/L NH4HCO3)和乙醇(12分钟内梯度:55%至67%);检测器:UV 254nm]纯化所述混合物,得到标题化合物,为白色固体(200mg,43%)。熔点:176-180℃。HPLC(UV 254nm):94.57%纯度。MS:m/z=448.2[M+H]+;1H NMR(300MHz,DMSO-d6,ppm):δ8.51(s,1H),8.26(s,1H),8.17-8.14(m,2H),8.07(s,1H),7.86(s,1H),7.77(s,1H),7.67-7.65(m,1H),7.50-7.44(m,1H),5.91(d,J=7.8Hz,1H),5.55(d,J=4.8Hz,1H),4.87-4.65(m,1H),4.52-4.42(m,1H),4.07-4.02(m,1H),3.93(s,3H),3.88(s,3H),1.85-1.55(m,6H)。
通过手性制备型HPLC[柱:Repaired Chiral ADH,21.2x 250mm,5μm;流动相:己烷和乙醇(保持30%乙醇25min);检测器:UV 254/220nm]解析该外消旋体混合物。
第一洗脱异构体:(1S,2S,6S)-2-氟-6-[[5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)苯基]嘧啶-4-基]氨基]环己-1-醇(假定立体化学):白色固体(40mg)。熔点:144-148℃。HPLC(UV 254nm):98.26%纯度。手性纯度:e.e.%>99.99%。
第二洗脱异构体:(1R,2R,6R)-2-氟-6-[[5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)苯基]嘧啶-4-基]氨基]环己-1-醇(假定立体化学):白色固体,40mg(9%)。熔点:200-202℃。HPLC(UV 254nm):99.25%纯度。手性纯度:e.e.%>99.99%。
实施例287:(1S,6R)-2,2-二氟-6-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环己醇
(1S,6R)-6-[[2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基]氨基]-2,2-二氟环己-1-醇(中间体46,50mg,0.12mmol,1.00eq.)、1-甲基-4-[3-(四甲基-1,3,2-二氧杂硼戊烷-2-基)苯基]-1H-吡唑(53mg,0.18mmol,1.45eq.)、Pd(PCy3)2Cl2(11mg,0.01mmol,0.12eq.)和K3PO4(62mg,0.28mmol,2.27eq)在二噁烷(2mL)和水(0.5mL)中的混合物在密封试管中在100℃和氮气气氛下加热3小时。得到的混合物真空浓缩。残留物用DCM稀释。分离出水相,用DCM萃取二次。有机相合并,用盐水洗涤,硫酸镁干燥,过滤,浓缩。经制备型HPLC(XBridgeBEH130Prep C18OBD柱)纯化,获得标题化合物,为白色固体(35mg,61%)。LC/MS(柱:Shim-pack XR-ODS,2.0*50mm,1.6um;流动相A:水/0.05%TFA,流动相B:ACN/0.05%TFA;流速:0.7mL/min;2.1分钟梯度:5%B至100%B,保持0.5min;220nm):(纯度)99.9%;[M+H]+计算结果:466.3;实验结果:466.3。1H NMR(300MHz,DMSO-d6,ppm)8.48(s,1H),8.23(s,1H),8.17(s,1H),8.13(d,J=8.1Hz,1H),8.05(s,1H),7.84(s,1H),7.78(s,1H),7.65(d,J=7.5Hz,1H),7.48(t,J=7.7Hz,1H),6.36(d,J=7.6Hz,1H),5.62(d,J=6.4Hz,1H),4.31(m,1H),3.92(s,3H),3.89(s,3H),2.13(m,2H),1.75(m,2H),1.53(m,2H)。
实施例288和289:(1R,2S,3S)-3-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环庚烷-1,2-二醇和(1S,2R,3R)-3-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环庚烷-1,2-二醇
步骤1:N-[(3aS,4S,8aR)-2,2-二甲基-八氢环庚[d][1,3]间二氧杂环戊烯-4-
基]-2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-胺(外消旋体–相对立体化学)
采用N-[(3aS,4S,8aR)-2,2-二甲基-八氢环庚[d][1,3]间二氧杂环戊烯-4-基]-2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-胺(中间体51,180mg,0.43mmol,1.00eq.)为起始材料,依据实施例287的方法,制备标题化合物,为黄色油(220mg,92%)。LC/MS(柱:Shim-pack XR-ODS,2.0*50mm,1.6um;流动相A:水/0.05%TFA,流动相B:ACN/0.05%TFA;流速:0.7mL/min;2.1分钟梯度:5%B至100%B,保持0.5min;220nm):(纯度)90.0%;[M+H]+计算结果:500.3;实验结果:500.0。
步骤2:(1R,2S,3S)-3-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-
基)-苯基]-嘧啶-4-基氨基}-环庚烷-1,2-二醇和(1S,2R,3R)-3-{5-(1-甲基-1H-吡唑-4-
基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环庚烷-1,2-二醇
保持在0℃,将浓盐酸(0.75mL,24.68mmol,62eq.)在甲醇(1mL)中的溶液滴加入N-[(3aS,4S,8aR)-2,2-二甲基-八氢环庚[d][1,3]间二氧杂环戊烯-4-基]-5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)苯基]嘧啶-4-胺(220mg,0.40mmol,1.00eq.)在甲醇(2mL)中的溶液中。得到的溶液在室温搅拌16小时。加入氨水调溶液的pH值至8。反应混合物真空浓缩,经快速色谱法(H2O:甲醇,1:1)纯化,获得标题化合物,为外消旋体的混合物(130mg)。通过手性制备型HPLC(Chiralpak IC,甲醇)分离开这两种异构体。
第一洗脱异构体:50mg(31%)。熔点:176-178℃。LC/MS(柱:Shim-pack XR-ODS,2.0*50mm,1.6um;流动相A:水/0.05%TFA,流动相B:ACN/0.05%TFA;流速:0.7mL/min;2.1分钟梯度:5%B至100%B,保持0.5min;220nm):(纯度)99.1%;[M+H]+计算结果:460.2;实验结果:460.0。1H NMR(300MHz,氯仿-d)8.50(s,1H),8.20(d,J=8.0Hz,2H),7.86(s,1H),7.75(s,1H),7.68(s,1H),7.56(d,J=10.6Hz,2H),7.45(t,J=7.7Hz,1H),6.00(d,J=7.4Hz,1H),4.62-4.42(m,1H),4.12(d,J=2.8Hz,1H),4.10-4.01(m,1H),3.97(d,J=8.0Hz,5H),2.21-2.01(m,1H),1.93(q,J=9.8,9.1Hz,1H),1.86-1.76(m,3H),1.69(d,J=6.3Hz,3H),1.63-1.45(m,2H)。
第二洗脱异构体:59mg(31%)。熔点:176-178℃。LC/MS(柱:Shim-pack XR-ODS,2.0*50mm,1.6um;流动相A:水/0.05%TFA,流动相B:ACN/0.05%TFA;流速:0.7mL/min;2.1分钟梯度:5%B至100%B,保持0.5min;220nm):(纯度)98.6%;[M+H]+计算结果:460.2;实验结果:460.0。
实施例290:(1S,2R,6S)-2-氟-6-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环己醇(外消旋体–相对构型)
步骤1:(1S,2S,3S)-2-(甲氧基甲氧基)-3-[[5-(1-甲基-1H-吡唑-4-基)-2-[3-
(1-甲基-1H-吡唑-4-基)苯基]嘧啶-4-基]氨基]环己基乙酸酯(外消旋体–相对立体化学)
采用(1S,2S,3S)-3-[[2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基]氨基]-2-(甲氧基甲氧基)环己基乙酸酯(中间体54,外消旋体,330mg,0.72mmol,1.00eq.)为起始材料,依据实施例287的方法,制备标题化合物,为黄色固体(480mg,100%)。MS:m/z=532.5[M+H]+。
步骤2:(1S,2S,3S)-2-(甲氧基甲氧基)-3-[[5-(1-甲基-1H-吡唑-4-基)-2-[3-
(1-甲基-1H-吡唑-4-基)苯基]嘧啶-4-基]氨基]环己-1-醇(外消旋体–相对立体化学)
(1S,2S,3S)-2-(甲氧基甲氧基)-3-[[5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)苯基]嘧啶-4-基]氨基]环己基乙酸酯(外消旋体,480mg,0.81mmol,1.00eq.)和氢氧化钠(100mg,2.45mmol,3.02eq.)在THF(10mL)和水(2mL)中的溶液在25℃搅拌2小时。然后减压浓缩,用水(20mL)稀释。得到的混合物用DCM(3x10mL)萃取。有机层合并,用盐水洗涤,无水Na2SO4干燥,过滤,真空浓缩。通过硅胶快速色谱法纯化(甲醇/DCM,1:100至1:25),获得标题化合物,为褐色固体(340mg,77%)。MS:m/z=490.4[M+H]+。
步骤3:N-[(1S,2S,3R)-3-氟-2-(甲氧基甲氧基)环己基]-5-(1-甲基-1H-吡唑-4-
基)-2-[3-(1-甲基-1H-吡唑-4-基)苯基]嘧啶-4-胺(外消旋体–相对立体化学)
保持在0℃和氮气气氛,将(1S,2S,3S)-2-(甲氧基甲氧基)-3-[[5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)苯基]嘧啶-4-基]氨基]环己-1-醇(外消旋体,340mg,0.56mmol,1.00eq.,80%纯度)在二氯甲烷(1mL)中的溶液滴加入XtalFluor-E(195mg,0.83mmol,1.50equiv,98%纯度)在DCM(10mL)中的溶液。然后在0℃向得到的混合物滴加入TEA.3HF(147mg,0.89mmol,1.61equiv,98%纯度)。反应混合物升至室温,搅拌1小时。然后加入20mL水淬灭反应,用DCM(3x10mL)萃取。有机层用盐水(1mL)洗涤,无水硫酸钠干燥,过滤,浓缩。通过硅胶快速色谱法纯化(甲醇/DCM,1:100至1:20),获得标题化合物,为黄色固体(144mg,47%)。MS:m/z=492.4[M+H]+。
步骤4:(1S,2R,6S)-2-氟-6-[[5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡
唑-4-基)苯基]嘧啶-4-基]氨基]环己-1-醇(外消旋体–相对立体化学)
将氯化氢(g)在二噁烷(2mL)中的溶液加入至N-[(1S,2S,3R)-3-氟-2-(甲氧基甲氧基)环己基]-5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)苯基]嘧啶-4-胺(外消旋体,139mg,0.28mmol,1.00eq.)在二噁烷(2mL)中的溶液。反应混合物在25℃搅拌2小时。用饱和碳酸氢钠水溶液调溶液的pH值至7,得到的混合物真空浓缩。用10mL DCM稀释残留物。滤出固体。滤液真空浓缩,粗产物(100mg)经制备型HPLC[SHIMADZU:柱:XBridgeBEH130Prep C18OBD柱,19x 150mm,5μm,13nm;流动相:水s(10mmol/L NH4HCO3)和ACN(10分钟梯度:35%至41%);检测器:UV 254nm]纯化,获得标题化合物,为白色固体(73mg,56%)。熔点:116-120℃。HPLC(UV 254nm):97.85%纯度。MS:m/z=448.3[M+H]+。1H NMR(300MHz,DMSO-d6,ppm):δ8.51(s,1H),8.26(s,1H),8.17-8.14(m,2H),8.07(s,1H),7.86(s,1H),7.77(s,1H),7.69-7.63(m,1H),7.50-7.43(m,1H),5.90(d,J=7.7Hz,1H),5.54(d,J=4.8Hz,1H),4.87-4.67(m,1H),4.52-4.42(m,1H),4.06-4.02(m,1H),3.93(s,3H),3.88(s,3H),1.82-1.56(m,6H)。
实施例291:(1R,2S,7S)-2-甲基氨基-7-{5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)-苯基]-嘧啶-4-基氨基}-环庚醇(外消旋体–相对构型)
步骤1:N-(环庚-2-烯-1-基)-5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡
唑-4-基)苯基]嘧啶-4-胺
采用2-氯-N-(环庚-2-烯-1-基)-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-胺(中间体56,12mg,0.04mmol,1.00eq.)为起始材料,依据实施例287的方法,制备标题化合物,为黄色油(10mg,59%)。LC/MS:[M+H]+计算结果:426.2;实验结果:426.0。
步骤2:5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)苯基]-N-[(1S,
7R)-8-氧杂双环[5.1.0]辛-2-基]嘧啶-4-胺(外消旋体-相对立体化学)
保持在0℃和氮气气氛,将mCPBA(156mg,0.86mmol,3.12eq.)分批加入N-(环庚-2-烯-1-基)-5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)苯基]嘧啶-4-胺(130mg,0.27mmol,1.00eq.)在DCM(8mL)中的溶液中。加入碳酸氢钠(78mg,0.88mmol,3.21eq.),得到的混合物在20℃搅拌6小时。混合物用DCM稀释,并用碳酸钠溶液和盐水洗涤。有机层用无水硫酸钠干燥,过滤,浓缩。通过硅胶快速色谱法纯化(DCM:甲醇,20:1),获得标题化合物,为黄色油(70mg,46%)。LC/MS:[M+H]+计算结果:442.2;实验结果:442.0。
步骤3:(1R,2S,7S)-2-[[5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-
基)苯基]嘧啶-4-基]氨基]-7-(甲基氨基)环庚烷-1-醇(外消旋体-相对立体化学)
将CH3NH2(310mg,9.98mmol)在甲醇(5mL)中的溶液加入5-(1-甲基-1H-吡唑-4-基)-2-[3-(1-甲基-1H-吡唑-4-基)苯基]-N-[(1S,2S,7R)-8-氧杂双环[5.1.0]辛-2-基]嘧啶-4-胺(外消旋体,65mg,0.13mmol,1.00equiv,85%纯度)。得到的反应混合物在80℃搅拌36小时。然后真空浓缩,粗产物(50mg)经制备型HPLC[SHIMADZU:柱:XBridge BEH130 PrepC18 OBD柱,19x 150mm,5μm,13nm;流动相:水(10mmol/L NH4HCO3)和ACN(8分钟梯度:27%至34%);检测器:UV 254nm]纯化,获得标题化合物(10mg,16%产率),为乳白色固体。熔点:120-122℃。HPLC(UV 254nm):96.53%纯度。MS:m/z=473.2[M+H]+;1H NMR(400MHz,氯仿-d,ppm):δ8.46(s,1H),8.21-8.17(m,2H),7.85(s,1H),7.73(s,1H),7.66(s,1H),7.61(s,1H),7.58-7.53(m,1H),7.48-7.42(m,1H),5.93(d,J=6.8Hz,1H),4.53(brs.,1H),4.13-4.09(m,1H),3.94(s,3H),3.00-2.92(m,1H),2.63(s,3H),2.01-1.92(m,2H),1.85-1.74(m,5H),1.51-1.40(m,1H)。
实施例292:酶学试验
IRAK1酶学试验
IRAK1是人纯化重组酶(His-TEV-IRAK1(194-712)。在该试验中,IRAK-1水解ATP,并且自磷酸化。IRAK-1抑制的测量是在涂布有链霉亲和素的384孔FlashPlate板(PerkinElmer#SMP410A)中进行。
将His-TEV-IRAK-1(15ng/孔)、ATP(1μM,[33P]ATP 0.25μCi/孔)和溶解于DMSO的化合物(浓度范围为20μM至1nM)或对照物(2%DMSO)在试验缓冲液(包含:Hepes pH7.050mM、无脂肪酸BSA 0.1%、二硫苏糖醇DTT 2mM、MgCl2 10mM、EGTA 0.5mM、Triton-X-1000.01%)中于30℃下保温培养3小时。通过添加EDTA而中止激酶反应。丢弃上清液,将培养板用150mM NaCl清洗三次,然后在Microbeta Trilux读数器中测量放射性。
IRAK4酶学试验
IRAK4是人纯化重组酶(His-TEV-IRAK1(194-712)。IRAK4水解ATP,并且自磷酸化和磷酸化丝氨酸/苏氨酸类的肽底物(STK:61ST1BLC,购自总部位于Bagnols/Cèze法国的CisBio International公司)。
IRAK-4抑制的测量是在涂布有链霉亲和素的384孔FlashPlate板(PerkinElmer#SMP410A)中进行。将His-TEV-IRAK4(20ng/孔)、ATP(2μM,[33P]ATP 0.25μCi/孔)、STK1-生物素肽(300nM)和溶解于DMSO的化合物(浓度范围为20μM至1nM)或对照物(2%DMSO)在试验缓冲液(包含:Hepes pH7.0 50mM、无脂肪酸BSA 0.1%、二硫苏糖醇DTT 2mM、MgCl2 10mM、EGTA 0.5mM、Tween-20 0.01%、MnCl2 5mM)中于30℃下保温培养3小时。
通过添加EDTA而中止激酶反应。丢弃上清液,将培养板用150mM NaCl清洗三次,然后在Microbeta Trilux读数器中测量放射性。
TLR7诱导人PBMC中的IL-6
作为功能性试验之一的人PBMC试验被用来监测IRAK1和IRAK4小分子抑制剂对TLR7诱导人单核细胞(PBMC的)中分泌IL-6的活性。从健康志愿者(富含白细胞和血小板的全血)的白细胞层(新鲜或冷冻)制备人PBMC,铺在测定培养基(RPMI+2%P/S/L-glu+10%HI-FBS)中,在37℃下用溶解在DMSO/培养基中的化合物(浓度的范围为25μM至0.4nM)或对照(0.25%DMSO)预处理在测定培养基中的人PBMC 30分钟。然后用IRAK1和IRAK4抑制剂预处理,在37℃下用TLR7特异性配体(2μM)刺激PBMC,过夜(16-18小时)。温育后,把上清液转移至384孔PE AlphaPlate-384板(6005350),使用Perkin Elmer IL-6 Alpha LISA试剂盒(AL223C)定量IL-6。在Alpha的板读数器中读取上述板。
将结果总结于下面的表中:
实施例293.药物制剂
(A)注射液瓶:将100g本发明化合物作为活性成分与5g磷酸二氢钠在3L再蒸馏水中的溶液用2N盐酸调它的pH至6.5,无菌过滤,转移到注射瓶中,无菌条件下冻干,并在无菌条件下密封。每个注射液瓶含有5mg活性成分。
(B)栓剂:将20g本发明化合物作为活性成分与100g大豆卵磷脂和1400g可可油混合,倒入模中,冷却。每片栓剂含20mg活性成分。
(C)溶液制剂:由1g作为活性成分的本发明化合物、9.38g NaH2PO4·2H2O、28.48gNa2HPO4·12H2O和0.1g苯扎氯铵在940mL再蒸馏水中制成一种溶液。将该溶液的pH调至6.8,再将该溶液配至1L,放射灭菌。该溶液以眼药水形式使用。
(D)软膏:在无菌条件下将500mg本发明化合物作为活性成分与99.5g凡士林混合。
(E)片剂:将1kg本发明化合物作为活性成分、4kg乳糖、1.2kg马铃薯粉、0.2kg滑石和0.1kg硬脂酸镁按照常规方法压成片剂,以致于每片含10mg活性成分。
(F)包衣片剂:类似实施例E压成片剂,然后按照常规方法用蔗糖包衣、马铃薯粉、滑石、黄芪胶和染料来包衣片剂。
(G)胶囊剂:将2kg本发明化合物作为活性成分按照常规方法导入硬胶囊中,以致于每个胶囊含20mg活性成分。
(H)安瓿剂:将1kg本发明化合物作为活性成分在60L再蒸馏水中的溶液无菌过滤,转移到安瓿中,无菌条件下冻干,并在无菌条件下密封。每个安瓿含有10mg活性成分。
(I)吸入喷雾剂:将14g本发明化合物作为活性成分溶解在10L等渗氯化钠溶液中,将该溶液转移至商业可买到的带泵机构的喷雾容器中。可将溶液喷入嘴或鼻内。一次喷射(约0.1ml)相当于一剂约0.14mg。
尽管此处描述了本发明的许多实施例,但显然采用本发明的化合物和方法可以改变基本实施例,从而提供其他实施例。因此,应当理解,本发明的范围由所附的权利要求书而非以示例方式提供的具体实施例限定。
Claims (20)
1.通式I所示的化合物,
或药学上可接受的盐,式中:
X是CR或者N;
A是O、S、SO2、SO、-NRC(O)、-NRSO2、或者N(R);或者A不存在;
R3是-R、卤素、-卤代烷基、-OR、-SR、-CN、-NO2、-SO2R、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)N(R)2、-NRSO2R、或者-N(R)2;或者
当A是-NRC(O)、-NRSO2或者N(R)时;那么R和R3与与它们各自所连接的原子一起形成具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环,或者具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;上述每个基团任选经取代;
X’是CR或者N;
环Z是具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环,或者具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;上述每个基团任选经取代;
R1是-R、卤素、-卤代烷基、-OR、-SR、-CN、-NO2、-SO2R、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)N(R)2、-NRSO2R、或者-N(R)2;
Ra不存在或者是-R、卤素、-卤代烷基、-OR、-SR、-CN、-NO2、-SO2R、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)N(R)2、-NRSO2R、或者-N(R)2;
环Y是任选可取代的具有2-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;
R2是-R、卤素、-卤代烷基、-OR、-SR、-CN、-NO2、-SO2R、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)N(R)2、-NRSO2R、或者-N(R)2;
Rb不存在或者是-R、卤素、-卤代烷基、-OR、-SR、-CN、-NO2、-SO2R、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)N(R)2、-NRSO2R、或者-N(R)2;
每个R独立地是氢,C1–6脂族基团,C3-10芳基,3-8元饱和或部分不饱和碳环,具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环,或者具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;上述每个基团任选经取代;或者
在同一个原子上的两个R基团与它们所连接的原子一起形成C3-10芳基,3-8元饱和或部分不饱和碳环,具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环,或者具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;上述每个基团任选经取代;
其中当X是N且A不存在时,那么R3不是H。
2.如权利要求1所述的化合物,其中X是CH。
3.如权利要求1所述的化合物,其中X是N。
4.如上述权利要求中任一项所述的化合物,其中A是O或者N(R),或者A不存在。
5.如上述权利要求中任一项所述的化合物,其中R3是-R、-卤代烷基、-C(O)R、-CO2R、或者-C(O)N(R)2。
6.如上述权利要求中任一项所述的化合物,其中R3是C1–6脂族基团,C3–10芳基,3-8元饱和或部分不饱和碳环,具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环,或者具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环;上述每个基团任选经取代。
7.如上述权利要求中任一项所述的化合物,其中A-R3是-H、-CH3、-CF3、
8.如上述权利要求中任一项所述的化合物,其中环Z是:
式中X是O、S或者NR1;Y是C或者N;和T是C或者N。
9.如上述权利要求中任一项所述的化合物,其中环Z是
10.如上述权利要求中任一项所述的化合物,其中环Y是任选可取代的吡唑、噻二唑或吡啶基。
11.如上述权利要求中任一项所述的化合物,其中环Y是
12.如权利要求1所述的化合物,具有以下结构式I-b,
或其药学上可接受的盐。
13.如权利要求1所述的化合物,具有以下结构式I-c,
或其药学上可接受的盐。
14.如权利要求1所述的化合物,选自表1中列出的那些。
15.一种药物组合物,所述药物组合物包含如权利要求1-14中任一项所述的化合物以及药学上可接受的佐剂、载体或媒介质。
16.一种用于抑制在病人或生物样品中的IRAK或其突变体的活性的方法,所述方法包括如下步骤:向所述病人施加如权利要求1-14中任一项所述的化合物或其生理学上可接受的盐,或者使所述生物样品与如权利要求1-14中任一项所述的化合物或其生理学上可接受的盐接触。
17.一种治疗有需要的病人中由IRAK介导的疾病的方法,包括如下步骤:向所述病人给予如权利要求1-14中任一项所述的化合物。
18.如权利要求17所述的方法,其中所述疾病选自类风湿性关节炎、银屑病关节炎、骨关节炎、全身性红斑狼疮、狼疮性肾炎、强直性脊柱炎、骨质疏松、系统性硬化病、多发性硬化症、银屑病、I型糖尿病、II型糖尿病、炎性肠病(克罗恩病和溃疡性结肠炎)、高免疫球蛋白血症和周期性发热综合征、Cryopyrin-相关周期性综合征、施尼茨勒综合征、全身型幼年特发性关节炎、成人发病性斯提耳氏病、痛风、假性痛风、SAPHO综合征、卡斯尔曼氏病、败血症、中风、动脉粥样硬化、腹腔病、DIRA(IL-1受体拮抗剂缺乏)、阿尔茨海默氏病、帕金森病、癌症。
19.一种治疗病人的癌症的方法,包括如下步骤:向所述病人给予如权利要求1-14中任一项所述的化合物或其生理学上可接受的盐。
20.一种制备如权利要求1所述的通式I所示的化合物的方法,包括以下步骤:
将通式(A)化合物,
与反应;
式中,X、Y、A、R、Ra、Rb、R2和R3具有权利要求1指明的含义;得到通式(B)化合物:
以及将通式(B)化合物与反应;
式中,Z和R1具有权利要求1指明的含义;
得到如权利要求1所述的通式I所示的化合物。
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CN116514769B (zh) * | 2022-01-21 | 2024-02-27 | 中国药科大学 | 4-羟基嘧啶-5-甲酰腙衍生物、制备方法、药物组合物和应用 |
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