CN112236429A - 用作ii型irak抑制剂的杂芳基化合物及其用途 - Google Patents
用作ii型irak抑制剂的杂芳基化合物及其用途 Download PDFInfo
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- CN112236429A CN112236429A CN201980024556.5A CN201980024556A CN112236429A CN 112236429 A CN112236429 A CN 112236429A CN 201980024556 A CN201980024556 A CN 201980024556A CN 112236429 A CN112236429 A CN 112236429A
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Classifications
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
本发明涉及作为IRAK抑制剂的通式I所示的化合物及药学上可接受的组合物。
Description
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(包括炎症性疾病、自身免疫性疾病和癌症)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)是丝氨酸/苏氨酸激酶,在TNF-R、IL-1β-R、IL-18R以及Toll样受体下游转导信号。IRAK继而介导JNK/p38和NFκB激活,导致促炎性细胞因子的产生。在四个家族成员中,只有IRAK1和4具有激酶活性,其中在同一个路径中IRAK4位于IRAK1的上游起作用。在骨髓细胞中,IRAK1是LPS诱导的IL-8和INF-γ释放、STAT3激活、IL10释放和β2-整联蛋白介导的细胞扩散所必需的。在pDC中,IRAK介导TLR7和9诱导的INF-α释放。在T细胞中,IRAK介导IL-2的产生和增殖,以及IL-18诱导的Th1细胞的增殖和INF-γ的产生。IRAK在内皮、上皮、巨噬细胞、单核细胞、肥大细胞、粒细胞、树突细胞、B细胞、T细胞和NK细胞中的表达特别高。缺乏IRAK1或IRAK4的小鼠响应TLR7/9激活而导致INF-α的产生受损,无法响应IL-18或IL-1来激活NFκB,Th1和NK细胞中INF-γ的产生急剧下降。它们在LPS诱导的心脏衰竭、CIA、卡拉胶、肺部炎症和纤维化以及MOG诱导的EAE的模型中也受到保护。在用LPS治疗RA患者的滑膜细胞后,IRAK1磷酸化得到增强。IRAK1中的SNP与SLE相关联。
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,其中A’、L、X、Y、Z、R1和R2如下文所定义和实施例所描述那样。
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,尤其是人,的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、缺血性病症和癌症。
根据另一方面,本发明提供对IRAK-4和/或IRAK-1具有选择性且具有II型结合模式(mode of binding)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具有选择性且具有II型结合模式的通式(I)的化合物。
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)0–2N小时·、–(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、–N小时·、–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、–N小时·、–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:
A’ 是C=O、C(R)2或NR;
L 是二价基团,选自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;
X 是CR或N;
Y 是NR或S;
Z 是CR或N;
R1 是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;
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;
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。
在某些实施例中,A’是C=O。在某些实施例中,A’是C(R)2。在某些实施例中,A’是NR。
在某些实施例中,A’是C=O、CH2、CHOH或者NH。
在某些实施例中,A’是C=O。在某些实施例中,A’是CH2。在某些实施例中,A’是CHOH。在某些实施例中,A’是NH。
在某些实施例中,L是二价的任选经取代的C3–10芳基。在某些实施例中,L是二价的任选经取代的3-8元饱和或部分不饱和碳环。在某些实施例中,L是二价的任选经取代的3-7元杂环,所述杂环具有1-4个独立地选自氮、氧或硫的杂原子。在某些实施例中,L是二价的任选经取代的5-6元单环杂芳环,所述杂芳环具有1-4个独立地选自氮、氧或硫的杂原子。
在某些实施例中,L是二价基团,所述二价基团选自苯基,萘基,环丙基,环丁基,环戊基,环己基,环己烯基,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(acridinyl),吖辛因基(azocinyl),苯并咪唑基,苯并呋喃基,苯并噻吩基,苯并硫代呋喃基,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(indolenyl),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(isoindolenyl),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(phenoxathiinyl),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(thienothiazolyl),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,以及呫吨基;上述每个基团任选经取代。
在某些实施例中,L是二价基团,所述二价基团选自苯基,环戊基,环己基,环己烯基,环庚烷,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(indolenyl),异噁唑基,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,嘌呤基,吡喃基,吡嗪基,吡唑烷基,吡唑啉基,吡唑基,哒嗪基,吡啶基(pyridinyl),吡啶基(pyridyl),嘧啶基,吡咯烷基,吡咯啉基,2H-吡咯基,吡咯基,四氢呋喃基,噻唑基,噻吩基,硫代苯基,氧杂环丁烷基,以及氮杂环丁烷基;上述每个基团任选经取代。
在某些实施例中,L是二价基团,所述二价基团选自苯基,环己基以及环己烯基,上述每个基团任选经取代。
在某些实施例中,L是二价基团,所述二价基团选自:
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,Y是NR。在某些实施例中,Y是NMe。在某些实施例中,Y是S。
在某些实施例中,Z是CR。在某些实施例中,Z是CH。在某些实施例中,Z是N。
在某些实施例中,Z是N,Y是NR,并且X是CR。
在某些实施例中,Z是N,Y是NR,并且X是N。
在某些实施例中,Z是N,Y是S,并且X是CR。
在某些实施例中,Z是CR,Y是NR,并且X是N。
在某些实施例中,R1是C3–10芳基。
在某些实施例中,R1是
在某些实施例中,R2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,R2是C1–6脂族基团。
在某些实施例中,R2是C3–10芳基。
在某些实施例中,R2是3-8元饱和或部分不饱和碳环。
在某些实施例中,R2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。
在某些实施例中,R2是具有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。
在某些实施例中,R2是C1–6脂族基团或者具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环。
在某些实施例中,R2是甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、直链或支链戊基、直链或支链己基,或者R2是具有1-4个独立地选自氮、氧或硫的杂原子的4元杂环。
在某些实施例中,R2是-CF3,
在某些实施例中,A’、L、X、Y、Z、R、R1和R2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L、X、Y、R1和R2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L、X、R1和R2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L、X、Y、R1和R2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L、X、R1和R2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L、X、Y、Z、R1和R2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L、X、Y、R1和R2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-g所示的化合物,
或其药学上可接受的盐,其中L、X、Y、R1和R2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-h所示的化合物,
或其药学上可接受的盐,其中L、X、R1和R2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-j所示的化合物,
或其药学上可接受的盐,其中L、X、Z、R1和R2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。
在某些实施例中,本发明化合物的微粒体稳定性和渗透性增加。
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-c小时onic)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。
因此,特别优选的是:
(1)通式I所示的化合物,
或药学上可接受的盐,式中:
A’ 是C=O、C(R)2或NR;
L 是二价基团,选自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;
X 是CR或N;
Y 是NR或S;
Z 是CR或N;
R1 是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;
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;
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。
(2)用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)的章节中所述的化合物,其中A’是C=O、CH2、CHOH或NH。
(3)用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)和/或(2)的章节中所述的化合物,其中L是二价基团,所述二价基团选自苯基,环戊基,环己基,环己烯基,环庚烷,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,异噁唑基,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,嘌呤基,吡喃基,吡嗪基,吡唑烷基,吡唑啉基,吡唑基,哒嗪基,吡啶基(pyridinyl),吡啶基(pyridyl),嘧啶基,吡咯烷基,吡咯啉基,2H-吡咯基,吡咯基,四氢呋喃基,噻唑基,噻吩基,硫代苯基,氧杂环丁烷基,以及氮杂环丁烷基;上述每个基团任选经取代。
(5)用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)至(4)的章节中的一或多者中所述的化合物,其中R1是C3-10芳基。
(7)用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)至(6)的章节中的一或多者中所述的化合物,其中R2是C1-6脂族基团或者是具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环。
(8)用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)至(7)的章节中的一或多者中所述的化合物,其中R2是甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、直链或支链戊基、直链或支链己基,或者R2是具有1-4个独立地选自氮、氧或硫的杂原子的4元杂环。
(10)用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)至(9)的章节中的一或多者中所述的化合物,尤其优选编号为(1)的章节中所述的化合物,其中所述化合物是通式I-a所示的化合物,
和/或其药学上可接受的盐。
(11)用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)至(10)的章节中的一或多者中所述的化合物,尤其优选编号为(1)的章节中所述的化合物,其中所述化合物是通式I-c所示的化合物,
和/或其药学上可接受的盐。
(12)用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)至(10)的章节中的一或多者中所述的化合物,尤其优选编号为(1)的章节中所述的化合物,其中所述化合物是通式I-e所示的化合物,
和/或其药学上可接受的盐。
(13)用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)至(10)的章节中的一或多者中所述的化合物,尤其优选编号为(1)的章节中所述的化合物,
其中所述化合物是通式I-h所示的化合物,
和/或其药学上可接受的盐。
(14)用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)至(10)的章节中的一或多者中所述的化合物,尤其优选编号为(1)的章节中所述的化合物,所述化合物选自表1所列的化合物。
(15)药物组合物,所述药物组合物包含用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)至(14)的章节中的一或多者中所述的化合物,尤其优选编号为(1)的章节中所述的化合物,以及药学上可接受的佐剂、运载体和/或赋形剂。
(16)一种用于抑制在病人或生物样品中的IRAK和/或其突变体的活性的方法,包括向所述病人施加包含用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)至(14)的章节中的一或多者中所述的化合物,尤其优选编号为(1)的章节中所述的化合物,和/或其生理学上可接受的盐,或者使所述生物样品与包含用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)至(14)的章节中的一或多者中所述的化合物,尤其优选编号为(1)的章节中所述的化合物,和/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:向所述病人给予包含用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)至(14)的章节中的一或多者中所述的化合物,尤其优选编号为(1)的章节中所述的化合物,和/或其生理学上可接受的盐。
(18)一种此处描述的方法,优选如上述和/或下述编号章节中所述、且更优选如编号为(16)和/或(17)的章节所述的方法,尤其优选编号为(17)的章节中所述的方法,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、子宫异位症、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、帕金森病以及癌症。
(19)一种治疗此处描述的病人的癌症的方法,优选如上述和/或下述编号章节中所述、且更优选是一种治疗病人的癌症的方法,所述方法包括如下步骤:向病人给予用于如本文中所述、优选如上述和/或下述编号章节中所述、且更优选如编号为(1)至(14)的章节中的一或多者中所述的化合物,尤其优选编号为(1)的章节中所述的化合物,和/或其生理学上可接受的盐。
(20)一种此处描述的方法,优选如上述和/或下述编号章节中所述、且更优选如编号为(16)、(17)、(18)和/或(19)的章节所述的方法,尤其优选编号为(18)的章节中所述的方法,其中所述疾病选自类风湿性关节炎、系统性红斑狼疮、狼疮肾炎和多发性硬化症。
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。
如本文中针对数字、图、范围和/或量所述使用地,术语“约(about)”优选意图意指“大约(circa)”和/或“大致(approximately)”。那些术语的含义在本领域中熟知,且优选包括加/减15%、且尤其是加/减10%的各个数字、图、范围和/或量的差异、偏差和/或变化。
在任何情况中,如本文中相对于数字、图、范围和/或量所述使用地,术语“约(about)”优选意图意指“大约(circa)”和/或“大致(approximately)”。那些术语的含义在本领域中熟知,且优选包括至少加/减5%或者加/减5%的各个数字、图、范围和/或量的差异、偏差和/或变化。
如本文中所述地使用的术语“病症(disorder(s))”和“疾病(disease(s))”在本领域中熟知且被理解。在本发明的上下文中,如果在本文中使用这些术语的上下文没有强力暗示,否则这些术语优选用作同义词且由此优选可互换。
在包括(但不限于)治疗疗法、给药计划和临床试验设计的医学背景(medicalcontext)中,为了患者、医学工作人员和/或医生的方便和/或易用、以及结果的可靠性和/或可重现性等,术语“周/一周(week/a week)”、“月/一个月(month/a month)”和/或“年/一年(year/a year)”可在与公历(gregorian calendar)的定义有轻微偏差的情况下使用。例如,在所述医学背景中,一个月通常指28天,且一年通常指48周。
因此,在本发明的上下文中,术语“周(week)”或“一周(a week)”优选指约5天、约6天或约7天、更优选约7天的时间周期。
在医学背景中,术语“月(month)”或“一个月(a month)”优选指约28天、约29天、约30天或约31天、更优选约28天、约30天或约31天的时间周期。
在医学背景中,术语“年(year)”或“一年(a year)”优选指约12个月的时间周期或约48周、约50周或约52周、更优选12个月、或约48周或约52周的时间周期。
根据本发明尤其优选的是如本文中所述的主题,其中两个或多于两个优选的、更优选的和/或尤其优选的实施方案、方面和/或主题的特性被组合为一个实施方案、方面和/或主题。优选地,根据本发明,优选的主题或实施方案可与其它优选的主题或实施方案组合;更优选的主题或实施方案可与其它不太优选的或甚至更优选的主题或实施方案组合;尤其优选的主题或实施方案可与其它正好优选或正好甚至更优选的主题或实施方案组合等。
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。
在Bruker Avance III 400NMR光谱仪或者Bruker DPX-300MHz上记录全部NMR实验结果,该Bruker Avance III 400NMR光谱仪配置了Bruker PABBO BB-1H/D Z GRD探针,在400MHz处进行质子NMR。大部分氘化溶剂通常含有0.03%至0.05%v/v四甲基硅烷,其用作参考信号(1H和13C均设置为δ0.00)。在氘化溶剂不含四烷基硅烷的情况下,根据公布的指南(J.Org.Chem.,Vol.62,No.21,1997),将残留的非氘化溶剂峰用作参考信号。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),qt(五重峰)或brs(宽单峰)。
以下缩写是指下文中所使用的缩写:
Ac(乙酰基);ACN(乙腈);atm(大气压);DIEA(二异丙基乙胺);℃(摄氏度);DMF(二甲基甲酰胺);DMSO(二甲基亚砜);dppf(1,1'-双(二苯基膦)二茂铁);eq(当量);EtOAc(乙酸乙酯);g(克);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);LC(液相色谱法);LDA(二异丙基氨基锂);MeOH(甲醇);min(分钟);mL(毫升);mmol(毫摩尔);MS(质谱法);NMR(核磁共振);O/N(过夜);PE(石油醚);RT(室温);TBDMS(叔丁基二甲基甲硅烷基);TEA(三乙胺);TFA(三氟乙酸);THF(四氢呋喃);TMS(三甲基硅烷基)。
在配备有SQ检测器(ESI)的Waters AquityH进行UPLC/MS分析,或者在Agilent1200系列质谱仪上或SHIMADZU LC-MS仪器进行LC-MS分析,其中该Agilent 1200系列配备有四极检测器,该SHIMADZU LC-MS仪器由UFLC 20-AD系统和LCMS 2020MS检测器组成。
纯度由Waters AquityH测量,该Waters AquityH装载XBridge C8柱,3.5μm,4.6x50mm),以水/ACN+0.1%TFA为洗脱液,8分钟内梯度:0至100%(记录为‘UPLC’),除非另有指明。
使用Biotage Initiator Microwave Synthesizer按照本领域已知的标准协议进行微波反应。
本发明的化合物可以利用若干合成方法由容易得到的起始物而制备,使用液相和固相化学方案或者混合溶液和固相方案。在下面的实施例中描述了合成路径的例子。除非另有说明,可以通过将作为外消旋混合物所获得的本发明的化合物分离,以提供富含对映异构体的混合物或者纯对映异构体。
除非另有说明,以下实验说明中所使用的市售起始物是从Sigma-Aldrich或Fisher公司购得。
中间体1:3-(4-氨基苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺
把4-(四甲基-1,3,2-二氧硼戊环-2-基)苯胺(300mg,1.37mmol,1.0eq)、3-溴-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺(310mg,1.36mmol,1.0eq)、Pd(dppf)Cl2(100mg,0.14mmol,0.10eq)在二噁烷(12mL)中的混合物和碳酸氢钠(110mg,1.31mmol,1.0eq)在水(4mL)中的溶液放置在密封试管中,用氮气吹扫,然后在100℃加热2小时。得到的溶液减压浓缩,用水(50mL)稀释,并且用乙酸乙酯(3x20mL)萃取。有机层合并,用无水硫酸钠干燥,过滤,浓缩,获得标题化合物(300mg,82%),为黄色固体。LC/MS:241.0[M+H]。
中间体2:3-(4-氨基-2-氟-苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺
把3-溴-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺(231mg;1.01mol,1.2eq)、3-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊环-2-基)-苯基胺(200mg;0.84mmol,1eq)、Pd(dppf)Cl2.DCM(138mg;0.17mmol;0.2eq)和碳酸铯(605mg;1.8mmol;2.2eq)在1,4-二噁烷(4mL)和水(1mL)中的混合物在100℃和氮气气氛下搅拌过夜。反应混合物经硅藻土过滤。滤液用乙酸乙酯(50mL)稀释,1M NaOH(2x30mL)和盐水(2x30mL)洗涤。有机层用硫酸钠干燥,过滤,浓缩。经快速硅胶色谱法纯化(DCM:甲醇,梯度:99:1至80:20),获得标题化合物(95mg,44%),为褐色固体。LC/MS:259.1[M+H]。
中间体3:3-(4-氨基-3-氟-苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺
采用2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊环-2-基)-苯基胺(200mg;0.84mmol)为起始材料,依据中间体2描述的程序制备标题化合物,为白色固体(90mg,41%)。
中间体4:3-(4-氨基-3-氯-苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺
采用4-氨基-3-氯苯基硼酸频哪醇酯(200mg;0.79mmol)为起始材料,依据中间体2描述的程序制备标题化合物,为白色固体(111mg,51%)。1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.88(s,1H),8.33(t,J=8.4Hz,1H),8.26(s,1H),7.48-7.34(m,6H),6.42(s,1H),5.76(s,1H),3.95(s,3H),2.40(s,3H),1.29(s,9H)。UPLC:(254nm)100%纯度;停留时间:1.66min。UPLC/MS:275.2[M+H]。
中间体5:5-(4-氨基-2-氟-苯基)-噻吩并[2,3-d]嘧啶-4-基胺
采用5-溴-噻吩并[2,3-d]嘧啶-4-基胺(233mg;1.0mmol)和4-氨基-2-氟苯基硼酸频哪醇酯(200mg;0.84mmol)为起始材料,依据中间体2描述的程序制备标题化合物,为黄色油(126mg,57%)。
中间体6:5-(4-氨基-3-氟-苯基)-噻吩并[2,3-d]嘧啶-4-基胺
采用4-氨基-3-氟苯基硼酸频哪醇酯(200mg;0.84mmol)和5-溴-噻吩并[2,3-d]嘧啶-4-基胺(233mg;1.0mmol)为起始材料,依据中间体2描述的程序制备标题化合物,为白色固体(132mg,60%)。
中间体7:3-(4-氨基-2-氯-苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺
采用3-溴-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺(216mg;1.0mmol)和3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯胺(200mg;0.79mmol)为起始材料,依据中间体2描述的程序制备标题化合物,为白色固体(169mg,78%)。
中间体8:3-{3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-基}-1-[2-氟-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]脲
把4-硝基苯基氯甲酸酯(440mg,2.07mmol,1.0eq)、二氯甲烷(5mL)、吡啶(235mg,2.91mmol,1.4eq)和3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-胺(参照Molecules,2014,Volume19,Issue 2,2004-2028描述的方法制备,520mg,1.92mmol,0.93eq)在DCM(5mL)中的溶液保持在氮气气氛下并且在5℃搅拌2小时,然后加入2-氟-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯胺(470mg,1.88mmol,0.9eq)和DIEA(520mg,3.94mmol,1.9eq)。得到的反应混合物在室温搅拌3小时。减压除去溶剂,粗产物经快速硅胶色谱法纯化(乙酸乙酯:石油醚;1:1),获得标题化合物,为黄色固体(300mg,19%)。
中间体9:5-(4-氨基-2-氯-苯基)-噻吩并[2,3-d]嘧啶-4-基胺
采用5-溴-噻吩并[2,3-d]嘧啶-4-基胺(218mg;0.95mmol;1.2eq)和3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯胺(200mg;0.79mmol;1.0eq)为起始材料,依据中间体2描述的程序制备标题化合物,为白色无定形固体(71mg,32%)。
中间体10:5-(4-氨基-2-氯-苯基)-噻吩并[2,3-d]嘧啶-4-基胺
采用5-溴-噻吩并[2,3-d]嘧啶-4-基胺(218mg;0.95mmol;1.20eq.)和3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯胺(200mg;0.79mmol;1.0eq)为起始材料,依据中间体2描述的程序制备标题化合物,为黄色油(71mg,32%)。
中间体11:1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-[4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊环-2-基)-苯基]-脲
保持在0℃和氮气气氛下,把(4-异氰酸根苯基)硼酸频哪醇酯(200mg;0.82mmol;1.0eq)在DCM(1mL)中的溶液缓慢地加入5-叔丁基-2-对甲苯基-2H-吡唑-3-基胺(187mg;0.82mmol;1.0eq)在DCM(17mL)中的溶液中。让反应混合物的温度升至室温,搅拌16小时。减压除去溶剂,粗产物经制备型HPLC色谱法纯化(柱:C18 X-Bridge 30x250mm,10um,梯度:30-95%CAN,含有0.1%氢氧化铵),获得标题化合物,为白色固体(172mg,45%)。
中间体12:3-碘-1-甲基-1H-吡唑并[4,3-c]吡啶-4-胺
步骤1:N-[(2,4-二甲氧基苯基)甲基]-3-碘-1H-吡唑并[4,3-c]吡啶-4-胺
把4-氯-3-碘-1H-吡唑并[4,3-c]吡啶(1.10g,3.74mmol,1.00eq)和(2,4-二甲氧基苯基)甲胺(1.97g,11.2mmol,3.0eq)在DMSO(20mL)中的溶液在氮气气氛和120℃搅拌过夜。反应混合物用水(30mL)稀释,并用DCM(2x30mL)萃取。有机层合并,用盐水洗涤,无水硫酸钠干燥,过滤,浓缩。经快速硅胶色谱法纯化(DCM:甲醇,梯度:100:1至10:1),获得标题化合物,为褐色固体(1.3g,67%)。LC/MS:410.9[M+H]。
步骤2:3-碘-1H-吡唑并[4,3-c]吡啶-4-胺
把-[(2,4-二甲氧基苯基)甲基]-3-碘-1H-吡唑并[4,3-c]吡啶-4-胺(1.3g,2.54mmol,1.0eq)在TFA(10mL)中的溶液在50℃加热3小时。减压除去TFA,得到的油用乙酸乙酯(50mL)萃取。用碳酸氢钠(30mL)洗涤,无水硫酸钠干燥,过滤,浓缩,获得标题化合物,为褐色固体(450mg,58%)。LC/MS:260.8[M+H]。
步骤3:3-碘-1-甲基-1H-吡唑并[4,3-c]吡啶-4-胺
把3-碘-1H-吡唑并[4,3-c]吡啶-4-胺(100mg,0.33mmol,1.0eq)、氢化钠(19mg,0.79mmol,1.20equiv)和MeI(56mg,0.39mmol,1.2eq)的混合物在DMF(3mL)中室温搅拌2小时。然后加入5mL饱和NH4Cl溶液淬灭反应,用DCM(2x10mL)萃取。有机层合并,用盐水(2x10mL)洗涤,无水硫酸钠干燥,过滤,浓缩。经快速硅胶色谱法纯化(乙酸乙酯:石油醚,梯度:1:10至1:1),获得标题化合物,为褐色固体(60mg,62%)。LC/MS(柱:Kinetex EVO C18100A,3.0x50mm,2.6um;水/5mM NH4HCO3/乙腈,10至95%,254nm):93%纯度;274.7[M+H]。
中间体13:3-{3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-基}-1-[4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]脲
采用3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-胺(520mg,1.92mmol,1.00eq)和4-(四甲基-1,3,2-二氧硼戊环-2-基)苯胺(440mg,1.91mmol,0.99eq)为起始材料,依据中间体8描述的程序制备标题化合物,为黄色固体(600mg,59%)。LC/MS(柱:Shim-pack XR-ODS,3.0x50mm,2.2um;水/ACN,含有0.05%TFA,2.2分钟内梯度:5至100%,保持1.0min;254nm):86.0%纯度;503.2[M+H]。
中间体14:N-{3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-基}-2-[4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]乙酰胺
把HATU(228mg,0.57mmol,1.05eq)在DMF(2mL)中的溶液滴加入2-[4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]乙酸(150mg,0.54mmol,1.0eq)、3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-胺(180mg,0.63mmol,1.16eq)和DIEA(222mg,1.63mmol,3.0eq)在DMF(3mL)中的溶液中。然后使反应混合物在15℃搅拌16小时,减压浓缩。经制备型硅胶TLC法纯化(石油醚:乙酸乙酯,5:1),获得标题化合物,为黄色油(65mg,16%)。LC/MS:502.4[M+H]。
中间体15:N-{3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-基}-2-[2-氟-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]乙酰胺
步骤1:2-(4-溴-2-氟苯基)-N-{3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-
基}乙酰胺
采用4-溴-2-氟苯甲酸(500mg,2.17mmol,1.0eq)和3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-胺(611mg,2.26mmol,1.0eq)为起始材料,依据中间体14描述的程序制备标题化合物,为黄色固体(1.38g,100%)。LC/MS(柱:Kinetex EVO C18 100A,3.0x50mm,2.6um;水/5mM NH4HCO3/乙腈,10至95%,254nm):76.0%纯度;472.2[M+H]。
步骤2:N-{3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-基}-2-[2-氟-4-(四甲
基-1,3,2-二氧硼戊环-2-基)苯基]乙酰胺
把2-(4-溴-2-氟苯基)-N-[3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-基]乙酰胺(200mg,0.32mmol,1.0eq)、4,4,5,5-四甲基-2-(四甲基-1,3,2-二氧硼戊环-2-基)-1,3,2-二氧硼戊环(133mg,0.50mmol,1.55eq)、Pd(dppf)Cl2.CH2Cl2(33mg,0.04mmol,0.12eq)和乙酸钾(66mg,0.64mmol,2.0eq)在二噁烷(5mL)中的混合物放置在密封试管中,用氮气吹扫,然后在100℃加热3.5小时。减压除去溶剂,残留物用DCM稀释,盐水洗涤,并用无水硫酸钠干燥,过滤,浓缩,获得标题化合物(300mg,82%),为黑色油(300mg,100%)。LC/MS):520.3[M+H]。
中间体16:2-[5-({[2-氯-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]氨基甲酰基}氨基)-1-(4-甲基苯基)-1H-吡唑-3-基]-2-甲基乙酸丙酯
采用2-[5-氨基-1-(4-甲基苯基)-1H-吡唑-3-基]-2-甲基乙酸丙酯(参照Journalof Medicinal Chemistry,46(22),4676-4686;2003描述的方法制备;290mg,0.96mmol,0.93eq)和2-氯-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯胺(250mg,0.94mmol,0.90eq)为起始材料,依据中间体8描述的程序制备标题化合物,为黄色固体(300mg,51%)。LC/MS:567.2[M+H]。
中间体17:3-(3-甲基氧杂环丁-3-基)-1-(4-甲基苯基)-1H-吡唑-5-胺
步骤1:3-(3-甲基氧杂环丁-3-基)-3-氧代丙腈
保持在氮气气氛下,把叔丁醇钾(9g,78.60mmol,2.00eq)在THF(30mL)中的溶液滴加入3-甲基氧杂环丁烷-3-羧酸苄酯(9g,39.28mmol,1.0eq)和乙腈(2.1mL,39.95mmol,1.02equiv)在THF(100mL)中的溶液中。反应混合物在25℃搅拌16小时。然后减压浓缩,经快速硅胶色谱法纯化(乙酸乙酯:石油醚,梯度:1:4至1:2),获得标题化合物,为黄色油(4.0g,66%)。
步骤2:3-(3-甲基氧杂环丁-3-基)-1-(4-甲基苯基)-1H-吡唑-5-胺
把3-(3-甲基氧杂环丁-3-基)-3-氧代丙腈(7.8g,50.4mmol,1.0eq)、(4-甲基苯基)肼盐酸盐(8.17g,50.5mmol,1.0eq)和乙酸(310mg,5.06mmol,0.1eq)在乙醇(150mL)中的溶液在50℃搅拌16小时。减压除去溶剂,经快速硅胶色谱法纯化(乙酸乙酯:石油醚,梯度:1:4至1:2),再经C18硅胶柱纯化(甲醇:水,梯度:1:4至1:3),获得标题化合物,为黄色固体(1g,9%)。1H NMR(300MHz,DMSO-d6)δ7.45(d,J=8.4Hz,2H),7.26(d,J=8.1Hz,2H),5.46(s,1H),5.27(s,2H),4.78(d,J=5.2Hz,2H),4.40(d,J=5.2Hz,2H),2.34(s,3H),1.59(s,3H)。LC/MS(柱:Kinetex EVO C18 100A,3.0x50mm,2.6um;水/5mM NH4HCO3/乙腈,10至95%,254nm):97%纯度;244.2[M+H];熔点:136-140℃。
中间体18:1-[2-氯-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]-3-[3-(3-甲基氧杂环丁-3-基)-1-(4-甲基苯基)-1H-吡唑-5-基]脲
采用3-(3-甲基氧杂环丁-3-基)-1-(4-甲基苯基)-1H-吡唑-5-胺(101mg,0.40mmol,1.0eq)和2-氯-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯胺(114mg,0.40mmol,1.01eq)为起始材料,依据中间体8描述的程序制备标题化合物,为黄色固体(140mg,54%)。LC/MS(柱:Phenomenex Kinetext 3.0x50mm,2.7um;水/ACN,含有0.05%TFA;1.1分钟内梯度:5%至100%,保持0.5min;254nm):80%纯度;523.3[M+H]。
中间体19:N-[3-叔丁基-1-(4-甲基苯基)-1H-吡唑-5-基]-2-羟基-2-[4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]乙酰胺
步骤1:N-[3-叔丁基-1-(4-甲基苯基)-1H-吡唑-5-基]-2-[4-(四甲基-1,3,2-二
氧硼戊环-2-基)苯基]-2-[(三甲基甲硅烷基)氧基]乙酰胺
保持在氮气气氛下,把三甲基氯硅烷(188mg,1.64mmol,2.0eq)加入2-(4-溴苯基)-2-羟基乙酸(200mg,0.82mmol,1.00eq)、4-二甲基氨基吡啶(10.6mg,0.08mmol,0.10eq)和吡啶(137mg,1.65mmol,2.00eq)在DCM(2mL)中的溶液中。反应混合物在室温搅拌4小时。然后冷却至0℃。先后滴加入DMF(0.2mL)和草酰氯(115mg,0.86mmol,1.05eq),反应混合物在0℃搅拌1小时。让温度升至室温,再加入3-叔丁基-1-(4-甲基苯基)-1H-吡唑-5-胺(218mg,0.86mmol,1.04eq)在吡啶(0.2mL)中的溶液,在15℃额外搅拌2小时。用水稀释后,混合物用DCM(3x5mL)萃取。有机层合并,用饱和NaHCO3溶液和盐水洗涤,无水硫酸钠干燥,过滤,浓缩。经制备型硅胶TLC法纯化(石油醚:乙酸乙酯,5:1),获得标题化合物,为黄色固体(95mg,24%)。
步骤2:N-[3-叔丁基-1-(4-甲基苯基)-1H-吡唑-5-基]-2-羟基-2-[4-(四甲基-1,
3,2-二氧硼戊环-2-基)苯基]乙酰胺
采用2-(4-溴苯基)-N-[3-叔丁基-1-(4-甲基苯基)-1H-吡唑-5-基]-2-羟基乙酰胺(85mg,0.17mmol,1.0eq)为起始材料,依据中间体15步骤2描述的程序制备标题化合物,为黄色固体(80mg,58%)。LC/MS:490.4[M+H]。
中间体20:2-(5-氨基-1-对甲苯基-1H-吡唑-3-基)-2-甲基-丙腈
采用2,2-二甲基-3-氧代戊二醛为起始材料,依据中间体17步骤2描述的程序制备标题化合物。LC/MS:241.1[M+H]。
中间体21:2-氯-3-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊环-2-基)-苯基胺
采用4-溴-2-氯-3-氟-苯基胺(100mg;0.45mmol)为起始材料,依据中间体15步骤2描述的程序制备标题化合物,为褐色固体(100mg,83%)。UPLC/MS:272.3[M+H]。
中间体22:5-(4-氨基-3-氯-2-氟-苯基)-噻吩并[2,3-d]嘧啶-4-基胺
采用5-溴-噻吩并[2,3-d]嘧啶-4-基胺(102mg;0.44mmol;1.2eq)和2-氯-3-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊环-2-基)-苯基胺(100mg;0.37mmol;1eq)为起始材料,依据中间体2描述的程序制备标题化合物,为黄色固体(31mg,29%)。
中间体23:1-(4-甲基苯基)-3-(1,1,1-三氟-2-甲基丙烷-2-基)-1H-吡唑-5-胺
把5,5,5-三氟-4,4-二甲基-3-氧代戊腈(4g,19mmol,1.0eq)和(4-甲基苯基)肼盐酸盐(3.3g,19.8mmol,1.04eq)在乙醇(50mL)中的溶液在80℃加热16小时。减压除去有机溶剂,经快速C18-硅胶色谱法纯化(水:甲醇;1:1),获得标题化合物,为黄色固体(2g,35%)。1H NMR(400MHz,DMSO-d6)d 7.43(d,J=8.3Hz,2H),7.28(d,J=8.1Hz,2H),5.50(s,1H),5.29(s,2H),2.34(s,3H),1.4(s,6H)。LC/MS:284.1[M+H]。熔点:90℃。
中间体24:5-(4-氨基环己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步骤1:N-(4-{4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}环己-3-烯-1-基)氨
基甲酸叔丁酯
采用N-[4-(四甲基-1,3,2-二氧硼戊环-2-基)环己-3-烯-1-基]氨基甲酸叔丁酯(501mg,1.47mmol,1.20eq)和5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(372mg,1.22mmol,1.00eq)为起始材料,依据中间体2描述的程序制备标题化合物,为褐色固体(200mg,43%)。LC/MS(柱:Ascentis Express C18,3.0*x50mm,0.7um;水/ACN,含有0.05%TFA,1.2分钟内梯度:5至100%,保持0.5min;254nm):90%纯度;344.0[M+H]。
步骤2:5-(4-氨基环己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
把N-(4-[4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基]环己-3-烯-1-基)氨基甲酸叔丁酯(200mg,0.52mmol,1.0equiv,90%)和三氟乙酸(1mL)在DCM(5mL)中的溶液在25℃搅拌3小时。加入NH4OH调pH至8,混合物用DCM(20mL)稀释。有机层合并,用盐水(2x20mL)洗涤,无水硫酸钠干燥,过滤,浓缩,获得标题化合物,为褐色固体(130mg,92%)。LC/MS(柱:Ascentis Express C18,3.0x50mm,2.7um;水/ACN,含有0.05%TFA,1.2分钟内梯度:5至100%,保持0.5min;254nm):90%纯度;244.0[M+H]。
中间体25:3-[3-叔丁基-1-(4-甲基苯基)-1H-吡唑-5-基]-1-[2-氟-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]脲
保持在0℃和氮气气氛下,把3-叔丁基-1-(4-甲基苯基)-1H-吡唑-5-胺(300mg,1.18mmol,1.0eq)和DIEA(641mg,4.7mmol,4.0eq)在DCM(1mL)中的溶液滴加入三光气(69mg,0.22mmol,0.6eq)在DCM(5mL)中的溶液中。反应混合物在0℃搅拌20分钟,把该混合物加入2-氟-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯胺(323mg,1.3mmol,1.1eq)在DCM(3mL)中的溶液中。得到的反应混合物在室温搅拌3小时,用饱和NH4Cl溶液(2x10mL)和盐水(1x10mL)洗涤,无水硫酸钠干燥,过滤,浓缩。经快速硅胶色谱法纯化(DCM:甲醇;3:1),获得标题化合物,为褐色固体(180mg,20%)。LC/MS:493.0[M+H]。
实施例1:1-(4-{4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基}苯基)-3-{3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-基}脲(15)
保持在5℃,把3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-胺(参照Molecules,2014,Volume19,Issue 2,2004-2028描述的方法制备,257mg,1.00mmol,1.0eq)在DCM(2mL)中的溶液滴加入4-硝基苯基氯甲酸酯(220mg,1.09mmol,1.1eq)和吡啶(120mg,1.52mmol,1.6eq)在DCM(20mL)中的溶液中。然后加入3-(4-氨基苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺(中间体1,240mg,1.00mmol,1.0eq)和DIEA(260mg,2.01mmol,2.0eq),得到的反应混合物在25℃搅拌16小时。真空浓缩,经制备型HPLC纯化(柱:Gemini-NXC18AXAI,21.2x150mm,5um;水,含有10mM NH4HCO3和ACN,梯度:40%至63%,10min),获得标题化合物,为黄色固体(6mg,19%)。1H NMR(400MHz,DMSO-d6):9.24(s,1),8.48(s,1),8.25(s,1),7.59(m,4),7.43(m,4),6.40(s,1),3.94(s,3),2.98(t,1,J=6.8Hz),1.28(s,9),1.25(d,6,J=7.2Hz);LC/MS(柱:Shim-pack XR-ODS,3.0x50mm,2.2um;水/ACN,含有0.05%TFA,3.6分钟内梯度:5至100%,保持1.0min;254nm):(纯度)97.9%;524.3[M+H]。
实施例2:1-[4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)-3-氟-苯基]-3-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-脲(2)
采用5-叔丁基-2-对甲苯基-2H-吡唑-3-基胺(67mg;0.29mmol;1.5eq)和3-(4-氨基-2-氟-苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺(中间体2,50mg;0.19mmol;1.0eq)为起始材料,依据实施例1描述的类似程序制备标题化合物,为白色固体(15mg,15%)。1HNMR(400MHz,DMSO-d6)δ9.12(s,1H),8.88(s,1H),8.33(t,J=8.4Hz,1H),8.26(s,1H),7.48-7.34(m,6H),6.42(s,1H),5.76(s,1H),3.95(s,3H),2.40(s,3H),1.29(s,9H)。UPLC:(254nm)100%纯度;停留时间:3.5min。UPLC/MS:514.5[M+H]。
实施例3:1-[4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)-3-氟-苯基]-3-[5-叔丁基-2-(4-异丙基-苯基)-2H-吡唑-3-基]-脲(11)
采用3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-胺(86mg,0.32mmol,1.0eq)为起始材料,依据实施例1描述的类似程序制备标题化合物,为白色固体(20mg,12%)。1HNMR(300MHz,DMSO-d6)δ9.42(s,1H),8.54(s,1H),8.24(s,1H),7.66-7.60(m,1H),7.46-7.39(m,5H),7.25-7.21(m,1H),6.39(s,1H),3.94(s,3H),3.00-2.95(m,1H),1.28(s,9H),1.26-1.24(d,J=6.9Hz,6H);LC/MS(柱:Kinetex EVO C18 100A,3.0x50mm,2.6um,水,含有5mM NH4HCO3/ACN,2.0分钟内梯度:10%至95%,保持0.5min;254nm):99.6%纯度;542.3[M+H]。熔点:160.0至162.0℃。
实施例4:1-[4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)-2-氟-苯基]-3-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-脲(6)
采用5-叔丁基-2-对甲苯基-2H-吡唑-3-基胺(44mg;0.19mmol;1.0eq)和3-(4-氨基-3-氟-苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺(中间体3,50mg;0.19mmol;1.0eq)为起始材料,依据实施例1描述的类似程序制备标题化合物,为白色固体(15mg,15%)。1HNMR(400MHz,DMSO-d6)δ9.12(s,1H),8.88(s,1H),8.33(t,J=8.6Hz,1H),8.26(s,1H),7.50-7.31(m,6H),6.42(s,1H),3.95(s,3H),2.40(s,3H),1.29(s,8H)。UPLC:(254nm)100%纯度;停留时间:3.5min。UPLC/MS:514.5[M+H]。
实施例5:1-[4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)-2-氯-苯基]-3-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-脲(4)
采用5-叔丁基-2-对甲苯基-2H-吡唑-3-基胺(658mg;2.87mmol;1.0eq)和3-(4-氨基-3-氯-苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺(中间体4,789mg;2.87mmol;1.0eq)为起始材料,依据实施例1描述的类似程序制备标题化合物,为白色固体(41mg,3%)。1H NMR(400MHz,DMSO-d6)d 9.21(s,1H),8.77(s,1H),8.30(d,J=8.6Hz,1H),8.26(s,1H),7.68(d,J=2.1Hz,1H),7.58(dd,J=8.6,2.1Hz,1H),7.45-7.33(m,4H),6.41(s,1H),3.95(s,3H),2.39(s,3H),1.29(s,9H)。UPLC:(254nm)100%纯度;停留时间:3.65min。UPLC/MS:530.5[M+H]。
实施例6:1-[4-(4-氨基-噻吩并[2,3-d]嘧啶-5-基)-3-氟-苯基]-3-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-脲(12)
采用5-叔丁基-2-对甲苯基-2H-吡唑-3-基胺(73mg;0.32mmol)和3-(4-氨基-2-氟-苯基)-异噻唑并[5,4-d]嘧啶-4-基胺(中间体5,83mg;0.32mmol)为起始材料,依据实施例1描述的类似程序制备标题化合物,为白色固体(34mg,20%)。1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.50(s,1H),8.34(s,1H),7.61(dd,J=12.4,2.1Hz,1H),7.52(s,1H),7.45-7.33(m,5H),7.23(dd,J=8.4,2.1Hz,1H),6.39(s,1H),2.39(s,3H),1.29(s,8H)。UPLC:(254nm)100%纯度;停留时间:3.81min。UPLC/MS:516[M+H]。
实施例7:1-[4-(4-氨基-噻吩并[2,3-d]嘧啶-5-基)-2-氟-苯基]-3-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-脲(9)
采用5-叔丁基-2-对甲苯基-2H-吡唑-3-基胺(116mg;0.51mmol)和5-(4-氨基-3-氟-苯基)-噻吩并[2,3-d]嘧啶-4-基胺(中间体6,132mg;0.51mmol)为起始材料,依据实施例1描述的类似程序制备标题化合物,为黄色固体(27mg,10%)。1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.88(s,1H),8.35(s,1H),8.29(t,J=8.5Hz,1H),7.49(s,1H),7.44-7.34(m,5H),7.29-7.19(m,1H),6.41(s,1H),2.40(s,3H),1.29(s,10H)。UPLC:(254nm)100%纯度;停留时间:3.7min。UPLC/MS:516[M+H]。
实施例8:1-[4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)-3-氯-苯基]-3-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-脲(8)
采用5-叔丁基-2-对甲苯基-2H-吡唑-3-基胺(42mg;0.18mmol)和3-(4-氨基-2-氯-苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺(中间体7,50mg,0.18mmol)为起始材料,依据实施例1描述的类似程序制备标题化合物,为白色固体(8mg,8%)。1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.48(s,1H),8.24(s,1H),7.86(d,J=1.9Hz,1H),7.49-7.24(m,5H),6.39(s,1H),3.94(s,3H),2.39(s,3H),1.30(s,9H)。UPLC:(254nm)96%纯度;停留时间:3.63min。UPLC/MS:530.3[M+H]。
实施例9:1-(4-{4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基}-2-氟苯基)-3-{3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-基}脲(10)
把3-[3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-基]-1-[2-氟-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]脲(中间体8,160mg,0.29mmol,1.0eq)、3-碘-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺(101mg,0.35mmol,1.2eq)、Pd(dppf)Cl2.CH2Cl2(25mg,0.03mmol,0.10eq)和乙酸钾(90.4mg,0.90mmol,3.1eq)在二噁烷(15mL)和水(1.5mL)中的混合物放置于密封试管中,用氮气吹扫,在80℃通过微波加热1小时。减压除去溶剂,残留物经快速硅胶色谱法纯化(DCM:甲醇,20:1),获得标题化合物,为白色固体(30mg,19%)。熔点:166-168℃。1H NMR(400MHz,DMSO-d6)δ9.13-9.12(m,1H),8.94(s,1H),8.34-8.30(m,1H),8.24(s,1H),7.45-7.41(m,6H),6.40(s,1H),3.92(s,3H),2.99-2.95(m,1H),1.26-1.23(m,15H)。LC/MS(柱:XBridge C18,4.6x50mm,3.5um;水,含有5mM NH4HCO3/ACN;1.2分钟内梯度:10%至95%,保持1.0min;254nm):99%(纯度);542.2[M+H]。
实施例10:1-[4-(4-氨基-噻吩并[2,3-d]嘧啶-5-基)-3-氯-苯基]-3-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-脲(14)
采用5-叔丁基-2-对甲苯基-2H-吡唑-3-基胺(58mg;0.26mmol;1.0eq)和5-(4-氨基-2-氯-苯基)-噻吩并[2,3-d]嘧啶-4-基胺(中间体9,71mg;0.26mmol;1.0eq)为起始材料,依据实施例1描述的类似程序制备标题化合物,为黄色泡沫(12mg,12%)。1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.50(s,1H),8.34(s,1H),7.87(d,J=2.0Hz,1H),7.48(s,1H),7.44-7.32(m,6H),6.39(s,1H),2.39(s,3H),1.29(s,9H)。UPLC:(254nm)100%纯度;停留时间:3.97min。LC/MS:533.2[M+H]。
实施例11:1-[4-(4-氨基-噻吩并[2,3-d]嘧啶-5-基)-2-氯-苯基]-3-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-脲(20)
采用5-叔丁基-2-对甲苯基-2H-吡唑-3-基胺(76mg;0.33mmol;1.0eq)和5-(4-氨基-3-氯-苯基)-噻吩并[2,3-d]嘧啶-4-基胺(中间体10,91mg;0.33mmol;1.0eq)为起始材料,依据实施例1描述的类似程序制备标题化合物,为黄色泡沫(10mg,5%)。1H NMR(400MHz,DMSO-d6)d 9.20(s,1H),8.78(s,1H),8.35(s,1H),8.26(d,J=8.5Hz,1H),7.58(d,J=2.1Hz,1H),7.52(s,1H),7.44–7.34(m,5H),6.40(s,1H),2.39(s,3H),1.29(s,8H)。UPLC:(254nm)99%纯度;停留时间:3.93min。LC/MS:533.2[M+H]。
实施例12:1-[4-(4-氨基-噻吩并[2,3-d]嘧啶-5-基)-苯基]-3-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-脲(13)
把5-溴-噻吩并[2,3-d]嘧啶-4-基胺(100mg;0.43mmol;1.2eq)、1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-[4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊环-2-基)-苯基]-脲(172mg;0.36mmol;1.0eq)、Pd(dppf)Cl2.DCM(59mg;0.73mmol;0.2eq)和碳酸铯(260mg;0.8mmol;2.2eq)在1,4-二噁烷(3.5mL)和水(1mL)中的混合物在100℃和氮气气氛下搅拌过夜。反应混合物通过硅藻土垫过滤。滤液用乙酸乙酯(50mL)稀释,1M NaOH(2x30mL)和盐水(2x30mL)洗涤。有机层合并,用硫酸钠干燥,过滤,浓缩。经制备型HPLC纯化(柱:C18 X-Bridge 30x250mm,10um,梯度:30-95ACN,含有0.1%氢氧化铵),获得标题化合物,为白色粉末(41mg,23%)。1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.44(s,1H),8.34(s,1H),7.57(d,J=8.6Hz,2H),7.48–7.28(m,7H),6.38(s,1H),2.39(s,3H),1.29(s,9H)。UPLC:(254nm)100%纯度;停留时间:3.63min。LC/MS:598.3[M+H]。
实施例13:1-[4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)-3-氟-苯基]-3-(2-对甲苯基-5-三氟甲基-2H-吡唑-3-基)-脲(26)
采用2-对甲苯基-5-三氟甲基-2H-吡唑-3-基胺(56mg;0.23mmol;1.0eq)和3-(4-氨基-2-氟-苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺(中间体2,60mg;0.23mmol;1.0eq)为起始材料,依据实施例1描述的类似程序制备标题化合物,为白色粉末(7mg,6%)。1HNMR(400MHz,DMSO-d6)δ9.24(s,1H),9.20(s,1H),8.31(t,J=8.6Hz,1H),8.26(s,1H),7.57-7.39(m,6H),6.91(s,1H),3.95(s,3H),2.44(s,3H)。UPLC:(254nm)100%纯度;停留时间:3.72min。LC/MS:525.2[M+H]。
实施例14:1-[4-(4-氨基-1-甲基-1H-吡唑并[4,3-c]吡啶-3-基)-苯基]-3-[5-叔丁基-2-(4-异丙基-苯基)-2H-吡唑-3-基]-脲(16)
采用3-[3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-基]-1-[4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]脲(中间体13,200mg,0.38mmol,1.0eq)和3-碘-1-甲基-1H-吡唑并[4,3-c]吡啶-4-胺(中间体12,130mg,0.45mmol,1.2eq)为起始材料,依据实施例9描述的类似程序制备标题化合物,为白色固体(20mg,10%)。1H NMR(400MHz,DMSO-d6):δ9.22(s,1H),8.48(s,1H),7.74-7.73(d,J=6Hz,1H),7.59-7.51(m,4H),7.44-7.38(m,4H),6.83-6.82(d,J=6Hz,1H),6.38(s,1H),5.74(s,2H),3.94(s,3H),2.98-2.95(m,1H),1.27(s,9H),1.25-1.23(d,J=6.8Hz,6H);LC/MS(柱:Kinetex 2.6u XB-C18 100A,3.0x50mm,2.6um;水/ACN,含有0.05%TFA,1.2分钟内梯度:5%至95%,保持0.55min;254nm):99%纯度;523[M+H]。熔点:152-154℃。
实施例15:2-[4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)-苯基]-N-[5-叔丁基-2-(4-异丙基-苯基)-2H-吡唑-3-基]-乙酰胺(21)
采用N-[3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-基]-2-[4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]乙酰胺(中间体14,65mg,0.09mmol,1.0eq)和3-碘-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺(30mg,0.10mmol,1.1eq)为起始材料,依据实施例9描述的类似程序制备标题化合物,为白色固体(15mg,32%)。1H NMR(300MHz,CDCl3)δ8.43(s,1H),7.68(d,J=8.0Hz,2H),7.44-7.34(m,3H),7.24-7.17(m,2H),7.09(m,2H),6.64(s,1H),5.40(s,2H),4.12(s,3H),3.78(s,2H),2.80(m,1H),1.33(s,9H),1.11(d,J=6.9Hz,6H)。LC/MS(柱:Kinetex EVO C18 100A,3.0x50mm,2.6um;水,含有5mM NH4HCO3/ACN,2.0分钟内梯度:10%至95%,保持0.5min;254nm):100%纯度;523.3[M+H]。熔点:218-219℃。
实施例16:2-[4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)-2-氟-苯基]-N-[5-叔丁基-2-(4-异丙基-苯基)-2H-吡唑-3-基]-乙酰胺(19)
采用N-[3-叔丁基-1-[4-(丙烷-2-基)苯基]-1H-吡唑-5-基]-2-[2-氟-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]乙酰胺(300mg,0.32mmol,1.0eq)和3-碘-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺(150mg,0.38mmol,1.2eq)为起始材料,依据实施例9描述的类似程序制备标题化合物,为白色固体(30mg,17%)。1H NMR(400MHz,CDCl3)δ8.41(s,1H),7.54-7.43(m,4H),7.29(m,2H),7.24(m,2H),6.63(s,1H),5.81(s,2H),4.12(s,3H),3.77(s,2H),2.89(m,1H),1.33(s,9H),1.19(d,J=6.9Hz,6H)。LC/MS(柱:Kinetex EVO C18 100A,3.0x50mm,2.6um;水/5mM NH4HCO3/乙腈,10至95%,254nm):100%纯度;541.3[M+H]。
实施例17:1-(4-{4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基}-2-氯苯基)-3-[3-(1-羟基-2-甲基丙烷-2-基)-1-(4-甲基苯基)-1H-吡唑-5-基]脲(22)
步骤1:2-(5-{3-[4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)-2-氯-苯
基]-脲基}-1-对甲苯基-1H-吡唑-3-基)-2-甲基-乙酸丙酯
采用2-[5-([[2-氯-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]氨基甲酰基]氨基)-1-(4-甲基苯基)-1H-吡唑-3-基]-2-甲基乙酸丙酯(中间体16,200mg,0.35mmol,1.00eq)和3-碘-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺(100mg,0.36mmol,1.03eq)为起始材料,依据实施例9描述的类似程序制备标题化合物,为乳白色固体(15mg,7%)。1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.79(s,1H),8.29-8.27(d,1H),8.24(s,1H),7.66-7.65(d,1H),7.57-7.54(dd,1H),7.41-7.39(d,2H),7.36-7.34(d,2H),6.43(s,1H),4.09(s,2H),3.92(s,3H),2.37(s,3H),2.01(s,3H),1.27(s,6H)。LC/MS(柱:Kinetex EVO C18100A,3.0x50mm,2.6um;水,含有5mM NH4HCO3/ACN,2.0分钟内梯度:10%至95%,保持0.5min;254nm):96%纯度;588.2[M+H]。熔点:126-128℃。
步骤2:1-(4-{4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基}-2-氯苯基)-3-[3-
(1-羟基-2-甲基丙烷-2-基)-1-(4-甲基苯基)-1H-吡唑-5-基]脲
把2-(5-[[(4-[4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基]-2-氯苯基)氨基甲酰基]氨基]-1-(4-甲基苯基)-1H-吡唑-3-基)-2-甲基乙酸丙酯(100mg,0.15mmol,1.00eq)和碳酸钾(33mg,0.23mmol,1.5eq)在甲醇(5mL)中的溶液在室温搅拌2小时。减压除去溶剂。经制备型HPLC纯化(柱:Gemini-NX C18 AXAI Packed,21.2x150mm,5um,水,含有0.05%NH4OH/ACN,8分钟内梯度:33%至46%),获得标题化合物,为白色固体(10mg,12%)。1H NMR(300MHz,DMSO-d6)δ9.22(s,1H),8.78(s,1H),8.30(d,J=8.6Hz,1H),8.26(s,1H),7.67(d,J=2.0Hz,1H),7.57(dd,J=8.6,2.1Hz,1H),7.45-7.33(m,4H),6.91(s,1H),6.39(s,1H),4.62(t,J=5.5Hz,1H),3.94(s,3H),3.44(d,J=5.1Hz,2H),2.38(s,3H),1.22(s,6H)。LC/MS(柱:Kinetex EVO C18 100A,3.0x50mm,2.6um;水,含有5mM NH4HCO3/ACN,2.0分钟内梯度:10%至95%,保持0.5min;254nm):98%(纯度);546.3[M+H],熔点:192-194℃。
实施例18:1-(4-{4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基}-2-氯苯基)-3-[3-(3-甲基氧杂环丁-3-基)-1-(4-甲基苯基)-1H-吡唑-5-基]脲(24)
采用1-[2-氯-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]-3-[3-(3-甲基氧杂环丁-3-基)-1-(4-甲基苯基)-1H-吡唑-5-基]脲(中间体18,120mg,0.18mmol,1.0eq)和3-碘-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺(中间体17,68mg,0.22mmol,1.2eq)为起始材料,依据实施例9描述的类似程序制备标题化合物,为白色固体(10mg,10%)。1H NMR(300MHz,DMSO-d6)δ9.32(s,1H),8.83(s,1H),8.30(d,J=8.6Hz,1H),8.26(s,1H),7.68(d,J=2.0Hz,1H),7.58(dd,J=8.5,2.0Hz,1H),7.41(d,4H),6.93(s,1H),6.54(s,1H),4.85(d,J=5.3Hz,2H),4.47(d,J=5.4Hz,2H),3.94(s,3H),2.40(s,3H),1.67(s,3H)。LC/MS(柱:Shim-packXR-ODS,3.0x50mm,2.2um;水/ACN,含有0.05%TFA,2.2分钟内梯度:5至100%,保持1.0min;254nm):95%纯度;544.2[M+H]。熔点:170-172℃。
实施例19:2-[4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)-苯基]-N-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-2-羟基-乙酰胺(17)
采用N-[3-叔丁基-1-(4-甲基苯基)-1H-吡唑-5-基]-2-羟基-2-[4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]乙酰胺(中间体19,40mg,0.07mmol,1.0eq)和3-碘-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺(22mg,0.07mmol,1.10eq)为起始材料,依据实施例9描述的类似程序制备标题化合物,为白色固体(21mg,62%)。1H NMR(300MHz,DMSO-d6)δ9.87(s,1H),8.28(s,1H),7.65(d,J=8.2Hz,2H),7.55(d,J=8.1Hz,2H),7.34-7.24(m,2H),7.19(d,J=8.3Hz,2H),6.66-6.57(m,1H),6.30(s,1H),5.18-5.12(m,1H),3.97(s,3H),2.30(s,3H),1.26(s,9H)。LC/MS(柱:Shim-pack XR-ODS,3.0x50mm,2.2um;水/ACN,含有0.05%TFA,2.2分钟内梯度:5%至100%,保持1.0min;254nm):99%纯度;511.3[M+H]。熔点:260-262℃。
实施例20:2-[4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)-苯基]-N-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-2-氧代-乙酰胺(7)
把2-(4-[4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基]苯基)-N-[3-叔丁基-1-(4-甲基苯基)-1H-吡唑-5-基]-2-羟基乙酰胺(50mg,0.09mmol,1.0eq)和IBX(52mg,0.18mmol,2.0eq)在DMSO(1mL)中的溶液在20℃搅拌4小时。经制备型HPLC纯化(柱:Gemini-NX C18AXAI Packed,21.2x150mm,5um,水,含有0.05%NH4OH/ACN,8分钟内梯度:50%至62%),获得标题化合物,为黄色固体(20mg,44%)。1H NMR(300MHz,DMSO-d6)δ10.99(s,1H),8.30(s,1H),8.00(d,J=8.4Hz,2H),7.84(d,J=8.4Hz,2H),7.40(d,J=8.4Hz,2H),7.32(d,J=8.3Hz,2H),7.05(s,2H),6.53(s,1H),3.99(s,3H),2.37(s,3H),1.32(s,9H)。LC/MS(柱:Phenomenex Gemini-NX C18 3.0x50mm,3.0um;水,含有6.5mM NH4HCO3/ACN,2.2分钟内梯度:5%至95%,保持1.0min;254nm):99%纯度;509.1[M+H]。
实施例21:1-(4-{4-氨基噻吩并[2,3-d]嘧啶-5-基}-2-氯苯基)-3-[3-(1-羟基-2-甲基丙烷-2-基)-1-(4-甲基苯基)-1H-吡唑-5-基]脲(27)
步骤1:2-(5-{3-[4-(4-氨基-噻吩并[2,3-d]嘧啶-5-基)-2-氯-苯基]-脲基}-1-
对甲苯基-1H-吡唑-3-基)-2-甲基-乙酸丙酯
采用2-(5-氨基-1-对甲苯基-1H-吡唑-3-基)-2-甲基-丙酯(参照Journal ofMedicinal Chemistry,46(22),4676-4686;2003描述的方法制备;208mg;0.72mmol;1.0eq)和5-(4-氨基-3-氯-苯基)-噻吩并[2,3-d]嘧啶-4-基胺(中间体10;200mg;0.72mmol;1.0eq)为起始材料,依据实施例1描述的类似程序制备标题化合物,为白色固体(40mg,9%)。1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.78(s,1H),8.35(s,1H),8.25(d,J=8.6Hz,1H),7.63–7.27(m,7H),6.45(s,1H),4.12(s,2H),2.39(s,3H),2.04(s,3H),1.29(s,6H)。UPLC/MS 590.3[M+H]。
步骤2:1-(4-{4-氨基噻吩并[2,3-d]嘧啶-5-基}-2-氯苯基)-3-[3-(1-羟基-2-甲 基丙烷-2-基)-1-(4-甲基苯基)-1H-吡唑-5-基]脲
把2-(5-{3-[4-(4-氨基-噻吩并[2,3-d]嘧啶-5-基)-2-氯-苯基]-脲基}-1-对甲苯基-1H-吡唑-3-基)-2-甲基-丙酯(40mg;0.07mmol;1.0eq)和K2CO3(28mg,0.20mmol;3eq)在甲醇(2mL)中的溶液在室温搅拌1小时。接着,反应混合物用饱和碳酸氢钠溶液(2mL)稀释,乙酸乙酯(3x3mL)萃取。有机层合并,用盐水洗涤,无水硫酸钠干燥,过滤,浓缩。经快速硅胶色谱法纯化(石油醚:乙酸乙酯;梯度:100:0至0:100),获得标题化合物,为白色固体(27mg,73%)。1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.77(s,1H),8.35(s,1H),8.26(d,J=8.5Hz,1H),7.57(d,J=2.1Hz,1H),7.52(s,1H),7.47-7.33(m,4H),6.39(s,1H),4.59(t,J=5.6Hz,1H),3.45(d,J=5.5Hz,2H),2.39(s,3H),1.23(s,6H)。UPLC:(254nm)100%纯度;停留时间:3.13min。LC/MS:551.0[M+H]。
实施例22:1-[4-(4-氨基-噻吩并[2,3-d]嘧啶-5-基)-2-氯-苯基]-3-[5-(氰基-二甲基-甲基)-2-对甲苯基-2H-吡唑-3-基]-脲(25)
采用2-(5-氨基-1-对甲苯基-1H-吡唑-3-基)-2-甲基-丙腈(中间体21;43mg;0.18mmol;1.0eq)和5-(4-氨基-3-氯-苯基)-噻吩并[2,3-d]嘧啶-4-基胺(中间体10;50mg;0.18mmol;1.0eq)为起始材料,依据实施例1描述的类似程序制备标题化合物,为白色固体(18mg,19%)。1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.86(s,1H),8.35(s,1H),8.26(d,J=8.5Hz,1H),7.58(d,J=2.1Hz,1H),7.53(s,1H),7.48-7.38(m,5H),6.62(s,1H),5.76(s,1H),2.42(s,3H),1.71(s,6H)。UPLC:(254nm)99%纯度;停留时间:3.69min。UPLC/MS:543.0[M+H]。
实施例23:1-[4-(4-氨基-噻吩并[2,3-d]嘧啶-5-基)-2-氯-3-氟-苯基]-3-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-脲(23)
采用5-叔丁基-2-对甲苯基-2H-吡唑-3-基胺(24mg;0.11mmol;1.0eq)和5-(4-氨基-3-氯-2-氟-苯基)-噻吩并[2,3-d]嘧啶-4-基胺(中间体23;31mg;0.11mmol;1.0eq)为起始材料,依据实施例1描述的类似程序制备标题化合物,为白色固体(3mg,5%)。1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.90(s,1H),8.35(s,1H),8.13(d,J=8.2Hz,1H),7.59(s,1H),7.48-7.28(m,4H),6.41(s,1H),2.40(s,3H),1.29(s,9H)。UPLC:(254nm)100%纯度;停留时间:4.02min。UPLC/MS:550.0[M+H]。
实施例24:1-[4-(4-氨基-噻吩并[2,3-d]嘧啶-5-基)-2-氯-苯基]-3-[2-对甲苯基-5-(2,2,2三氟-1,1-二甲基-乙基)-2H-吡唑-3-基]-脲(18)
采用2-对甲苯基-5-(2,2,2三氟-1,1-二甲基-乙基)-2H-吡唑-3-基胺(51mg;0.18mmol;1.0eq)和5-(4-氨基-3-氯-苯基)-噻吩并[2,3-d]嘧啶-4-基胺(中间体10;50mg;0.18mmol;1.0eq)为起始材料,依据实施例1描述的类似程序制备标题化合物,为白色固体(14mg,13%)。1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.83(s,1H),8.35(s,1H),8.26(d,J=8.6Hz,1H),7.58(d,J=2.1Hz,1H),7.53(s,1H),7.46(d,J=8.1Hz,2H),7.42-7.37(m,3H),6.59(s,1H),2.41(s,3H),1.53(s,6H)。UPLC:(254nm)100%纯度;停留时间:4.28min。LC/MS:586.0[M+H]。
实施例25:1-[4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-环己-3-烯基]-3-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-脲(1)
保持在0℃和氮气气氛下,把3-叔丁基-1-(4-甲基苯基)-1H-吡唑-5-胺(94mg,0.37mmol,1.0eq)和DIEA(201mg,1.48mmol,4.0eq)在DCM(2mL)中的溶液滴加入三光气(69mg,0.22mmol,0.6eq)在DCM(2mL)中的溶液中。反应混合物在0℃搅拌2小时,然后加入5-(4-氨基环己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(中间体24;100mg,0.37mmol,1.0eq)在DMF(2mL)中的溶液。得到的反应混合物在室温搅拌4小时,用DCM(10mL)稀释。然后用饱和NH4Cl溶液(2x10mL)和盐水(1x10mL)洗涤,无水硫酸钠干燥,过滤,浓缩。经制备型HPLC纯化(柱:XBridge BEH130 Prep C18 OBD柱,19x150mm,5um;水,含有0.05%NH4OH/ACN,36%ACN保持17min),获得标题化合物,为白色固体(16mg,8%)。1H NMR(300MHz,DMSO-d6)δ8.09-8.04(m,2H),7.36-7.29(m,4H),7.18(s,1H),6.68-6.65(m,1H),6.29-6.25(m,3H),5.62(s,1H),3.85-3.81(m,1H),3.66(s,3H),2.49-2.43(m,3H),2.36(s,3H),2.08-2.01(m,1H),1.91-1.88(m,1H),1.68-1.62(m,1H),1.25(s,9H)。LC/MS(柱:AscentisExpress C18,3.0x50mm,2.7um;水/ACN,含有0.05%TFA,1.2分钟内梯度:5%至100%,保持0.5min;254nm):96%纯度;499.3[M+H]。熔点:145-147℃。
实施例26:1-[4-(4-氨基-1-甲基-1H-吡唑并[4,3-c]吡啶-3-基)-2-氟-苯基]-3-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-脲(3)
采用3-[3-叔丁基-1-(4-甲基苯基)-1H-吡唑-5-基]-1-[2-氟-4-(四甲基-1,3,2-二氧硼戊环-2-基)苯基]脲(中间体25,150mg,0.27mmol,1.0eq)和3-碘-1-甲基-1H-吡唑并[4,3-c]吡啶-4-胺(中间体12,894mg,3.1mmol,11.3eq)为起始材料,依据实施例9描述的类似程序制备标题化合物,为白色固体(10mg,7%)。1H NMR(300MHz,DMSO-d6)δ9.09(s,1H),8.86(s,1H),8.27(t,J=8.4Hz,1H),7.73(d,J=6.1Hz,1H),7.49-7.27(m,6H),6.82(d,J=6.0Hz,1H),6.38(s,1H),5.79(s,2H),3.93(s,3H),2.36(s,3H),2.04(s,1H),1.25(s,10H)。LC/MS(柱:Poroshell HPH-C18,3.0x50mm,2.7um;水,含有5mM NH4HCO3/ACN,2.2分钟内梯度:10%至95%,保持1.0min;254nm):100%纯度;513.0[M+H]。
实施例27:3-[3-叔丁基-1-(4-甲基苯基)-1H-吡唑-5-基]-1-[(1s,4s)-4-{4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}环己基]脲(5)
在钯/炭(20mg)存在下,把1-(4-[4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基]环己-3-烯-1-基)-3-[3-叔丁基-1-(4-甲基苯基)-1H-吡唑-5-基]脲(60mg,0.11mmol,1.0eq)在甲醇(5mL)中的溶液进行氢化反应(1atm)48小时。反应混合物经硅藻土垫过滤,减压浓缩。经制备型HPLC纯化(柱:X-Bridge Prep C18 OBD柱,19x150mm,5um,水,含有10mMNH4HCO3+0.1%NH4OH/ACN,20分钟内梯度:38.0%至40.0%),获得标题化合物,为白色固体(9.9mg,17%)。1H NMR(300MHz,DMSO-d6):δ8.05-8.03(m,2H),7.36-7.30(m,4H),6.83(s,1H),6.74-6.71(m,1H),6.43(s,2H),6.29(s,1H),3.86(m,1H),3.58(s,3H),2.97(s,1H),2.32(s,3H),2.01-1.56(m,6H),1.40(m,2H),1.21(s,9H)。LC/MS(柱:Shim-pack XR-ODS,3.0x50mm,2.2um;水/ACN,含有0.05%TFA,2.0分钟内梯度:5%至100%,保持0.7min;254nm):95%纯度;501.3[M+H]。熔点:228-230℃。
实施例28:1-(4-{4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基}-2-氯苯基)-3-[3-叔丁基-1-(4-氰基苯基)-1H-吡唑-5-基]脲(28)
采用4-[5-氨基-3-(1,1-二甲基乙基)-1H-吡唑-1-yl]苄腈为起始材料,依据实施例1描述的类似程序制备标题化合物,为米色固体。1H NMR(400MH,DMSO-d6)δ1.30(s,9H),3.99(s,3H),5.76(s,1H),7.55(d,J=8.6Hz,1H),7.69(d,J=1.6Hz,1H),7.77(d,J=7.2Hz,2H),7.98(d,J=7.2Hz,2H),8.20(d,J=8.5Hz,1H),8.39(s,1H),8.80(s,1H),9.43(s,1H)。HPLC(Atlantis dC18,254x4.6mm,5um,15分钟内梯度:TFA 0.1%,在水/ACN中的溶液,10%至100%,254nm)98.0%纯度;停留时间:12.7min。LC/MS(ESI-):539.0[M-H]。
实施例29:1-[4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)-2-氯-苯基]-3-[5-叔丁基-2-(3-氟-4-甲基-苯基)-2H-吡唑-3-基]-脲(29)
采用5-叔丁基-2-(3-氟-4-甲基-苯基)-2H-吡唑-3-基胺为起始材料,依据实施例1描述的类似程序制备标题化合物,为米色固体。1H NMR(400MH,DMSO-d6)δ1.28(s,9H),2.29(s,3H),3.98(s,3H),4.5(brs,2H),6.41(s,1H),7.30(d,J=8.1Hz,1H),7.37(d,J=11.8Hz,1H),7.45(t,J=8.3Hz,1H),7.57(d,J=8.6Hz,1H),7.69(d,J=1.4Hz,1H),8.29(d,J=8.6Hz,1H),8.80(s,1H),9.28(s,1H)。HPLC:(Atlantis dC18,254x4.6mm,5um,15分钟内梯度:TFA 0.1%,在水/ACN中的溶液,10%至100%,254nm)97.3%纯度;停留时间:13.3min。LC/MS(ESI-):546.0[M-H]。
实施例30:酶学试验和细胞分析试验
IRAK4酶学试验
IRAK4是人纯化重组酶(His-TEV-IRAK1(1-460)。在本试验中1,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CisBioInternational公司)。在384孔板中基于发光分析(Promega的ADP-GloTM激酶分析)测量IRAK-4抑制。将纯化的人重组IRAK4(0.3μg/ml)以及在DMSO中连续稀释的化合物(浓度范围在10μM至0.5nM之间)或对照物(1%DMSO)在室温下在分析缓冲液中培育15分钟,所述分析缓冲液含有50mM Hepes pH 7.0、脂肪酸-游离BSA 0.1%、二硫苏糖醇(DTT)2mM、MgCl210mM、EGTA 0.5mM、Triton X-100 0.01%、MnCl2 5mM。随后添加ATP(2μM)和肽底物STK1-生物素肽(300nM)引发激酶反应。在室温培育2小时之后,使反应停止,根据供货商指示添加ADP-GloTM试剂耗尽未使用的ATP。在室温培育40分钟之后,再根据供货商指示将激酶检测试剂添加至分析培养板。在室温培育20分钟之后,用读板亮度计(PerkinElmer Envision或等效读取器)测量发光信号。
IRAK1酶学试验
IRAK1是人纯化重组酶(His-TEV-IRAK1(194-712))。在本试验中,IRAK1水解ATP并且自磷酸化。在384孔板中基于发光分析(Promega的ADP-GloTM激酶分析)测量IRAK-1抑制。将纯化的人重组IRAK1(0.3μg/ml)以及在DMSO中连续稀释的化合物(浓度范围在10μM至0.5nM之间)或对照物(1%DMSO)在室温下在分析缓冲液中培育15分钟,所述分析缓冲液含有50mM Hepes pH 7.0、脂肪酸-游离BSA 0.1%、二硫苏糖醇(DTT)2mM、MgCl210mM、EGTA0.5mM、Triton X-100 0.01%。随后添加浓度1μM ATP引发激酶反应。在室温培育2小时之后,使反应停止,根据供货商指示添加ADP-GloTM试剂耗尽未使用的ATP。在室温培育40分钟之后,再根据供货商指示将激酶检测试剂添加至分析培养板。在室温培育20分钟之后,用亮度计(PerkinElmer Envision或等效读取器)测量发光信号。
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。从健康志愿者获得的新鲜制成或冷冻的血沉棕黄层(富含白细胞和血小板的全血)制备人PBMC,平铺在试验培养基(RPMI+2%P/S/L-glu+10%HI-FBS)上并用溶解在DMSO/培养基中的化合物(浓度范围从25μM到.4nM)或对照物(0.25%DMSO)在37℃在试验培养基中预处理30分钟。在用IRAK1和IRAK4抑制剂预处理后,在37℃下与TLR7特异性配体(2μM)孵育过夜(16-18小时),以刺激PBMC。温育后,将上清液转移至384孔板PE AlphaPlate-384,并使用Perkin Elmer IL-6Alpha LISA试剂盒(AL223C)定量分析IL-6。使用的读板器读板。
结果列于下表中。
*IC50>5μM
**IC50:1μM–5μM
***IC50:100nM-1.0μM
****IC50<100nM
NT未测试
实施例31: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:
A’是C=O、C(R)2或NR;
L是二价基团,选自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;
X是CR或N;
Y是NR或S;
Z是CR或N;
R1是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;
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;
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。
2.如权利要求1所述的化合物,其中A’是C=O、CH2、CHOH或NH。
3.如任一项前述权利要求所述的化合物,其中L是二价基团,所述二价基团选自苯基,环戊基,环己基,环己烯基,环庚烷,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,异噁唑基,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,嘌呤基,吡喃基,吡嗪基,吡唑烷基,吡唑啉基,吡唑基,哒嗪基,吡啶基(pyridinyl),吡啶基(pyridyl),嘧啶基,吡咯烷基,吡咯啉基,2H-吡咯基,吡咯基,四氢呋喃基,噻唑基,噻吩基,硫代苯基,氧杂环丁烷基,以及氮杂环丁烷基;上述每个基团任选经取代。
5.如任一项前述权利要求所述的化合物,其中R1是C3–10芳基。
7.如任一项前述权利要求所述的化合物,其中R2是C1–6脂族基团或者是具有1-4个独立地选自氮、氧或硫的杂原子的3-7元杂环。
8.如任一项前述权利要求所述的化合物,其中R2是甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、直链或支链戊基、直链或支链己基,或者R2是具有1-4个独立地选自氮、氧或硫的杂原子的4元杂环。
14.如权利要求1所述的化合物,选自表1所列的化合物。
15.一种药物组合物,所述药物组合物包含如权利要求1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D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、子宫异位症、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、帕金森病以及癌症。
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所述的化合物或其生理学上可接受的盐。
20.如权利要求18所述的方法,其中所述疾病选自类风湿性关节炎、系统性红斑狼疮、狼疮肾炎和多发性硬化症。
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US20230210853A1 (en) * | 2020-05-08 | 2023-07-06 | Halia Therapeutics, Inc. | Targeted nek7 inhibition for modulation of the nlrp3 inflammasome |
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