CN115843272A - Nek7激酶的抑制剂 - Google Patents
Nek7激酶的抑制剂 Download PDFInfo
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- CN115843272A CN115843272A CN202180048858.3A CN202180048858A CN115843272A CN 115843272 A CN115843272 A CN 115843272A CN 202180048858 A CN202180048858 A CN 202180048858A CN 115843272 A CN115843272 A CN 115843272A
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Abstract
Description
背景
技术领域
本公开内容的实施方案通常涉及化合物及其制备方法和作为例如用于治疗炎症的治疗剂或预防剂的用途。
相关技术的描述
炎性体是多蛋白复合物,其活化在先天性免疫及炎症中起核心作用。迄今为止,已描述四种炎性体:NLRP1、NLRC4、NLRP3和AIM2。NLRP3炎性体由NLRP3、ASC和半胱天冬酶-I构成。其活化引起半胱天冬酶-I的活化,这促进了IL-1β和IL-18的分泌,IL-1β和IL-18是介导若干自身免疫性疾病、心肌梗塞、代谢综合征、炎性肠病和巨噬细胞活化综合症的动物疾病模型中的炎症的细胞因子。
NEK7是NIMA相关激酶(NEK)的家族成员,其充当调节其寡聚化及活化的NLRP3结合蛋白。NEK7是有丝分裂进入、细胞周期进程、细胞分裂及有丝分裂进程所必需的丝氨酸/苏氨酸激酶。它在多种组织中表达,例如大脑、心脏、肺、肝和脾。NEK7的过表达诱导异常细胞的产生,所述异常细胞与肿瘤(例如视网膜母细胞瘤、胆囊癌和头颈癌)紧密相关。
大量抑制剂已广泛用于干扰涉及IL-1β或IL-18的效应物信号传导路径而不消除炎症反应。阻断NLRP3-NEK7相互作用的NLRP3炎性体活化的抑制剂可以在若干人类疾病(例如2型糖尿病(T2D)、动脉粥样硬化、痛风和神经退行性疾病)中具有治疗或预防活性。然而,NLRP3-NEK7的确切机制尚未充分理解。
因此,需要开发将直接靶向NEK7的抑制剂,以影响若干病理性疾病(例如痛风、动脉粥样硬化、2型糖尿病、代谢综合征、黄斑变性、阿尔茨海默病、多发性硬化症和炎性肠病)中由NLRP3炎性体调节的炎性反应。本公开内容的实施方案满足此需求且提供其它相关优势。
发明内容
简而言之,本公开内容的实施方案提供能够抑制NEK7和/或调节NLRP3炎性体的活性的化合物,包括其药物可接受的盐、立体异构体和前药。
在一个方面,本发明提供结构(I)的化合物:
其药物可接受的盐、立体异构体或前药,其中A、X、Y、R1、R2、R3、R4和R5各自如以下定义。
在另一方面,还提供包含所公开的化合物的药物组合物及其用于治疗炎症的使用方法。
具体实施方式
在以下描述中,阐述某些具体细节以提供对本公开内容的各种实施方案的透彻理解。然而,本领域技术人员应理解,可以在没有这些细节的情况下实践本公开内容。
除非上下文另外要求,否则在整个说明书和权利要求书中,词语“包含(comprise)”及其变体(例如“包含(comprises)”和“包含(comprising)”)被解释为开放式的、包括的含义,即,解释为“包括,但不限于”。
在本说明书中,任何浓度范围、百分比范围、比率范围或整数范围均应理解为包括在所述范围内的任何整数的值,以及在适当时包括其分数(例如整数的十分之一和百分之一),除非另外说明。如本文所用,术语“约”和“大约”意指所示范围、值或结构的±20%、±10%、±5%或±1%,除非另外说明。应理解,如本文使用的术语“一个/一种(a)”和“一个/一种(an)”是指所枚举组分中的“一个/一种或者多个/多种”。可选方案(例如,“或”)的使用应理解为意指可选方案中的一者或两者或其任意组合。
在整个说明书中提及的“一个实施方案”或者“实施方案”意指关于实施方案所描述的具体特征、结构或特性被包括在本发明的至少一个实施方案中。因此,在整个本说明书的多处出现的短语“在一个实施方案中”或“在实施方案中”不必全部是指同一实施方案。此外,具体特征、结构或特性可以以任何适合的方式组合在一个或多个实施方案中。
除非另外定义,否则本文使用的所有技术术语和科学术语具有与本公开内容所属领域的普通技术人员通常理解相同的含义。如本说明书和权利要求书中使用,单数形式“一(a)”、“一(an)”和“所述(the)”包括多个指示物,除非上下文另外明确规定。
“氨基”是指-NH2基团。
“羧基”(carboxy/carboxyl)是指CO2H基团。
“氰基”是指-CN基团。
“羟基”(hydroxy/hydroxyl)是指-OH基团。
“硝基”是指-NO2基团。
“氧代”是指=O取代基。
“硫醇”是指-SH取代基。
“硫代”是指=S取代基。
“烷基”是指仅由碳原子和氢原子构成的饱和的直链或支链烃链基团,其具有一至十二个碳原子(C1-C12烷基)、一至八个碳原子(C1-C8烷基)或一至六个碳原子(C1-C6烷基)或这些范围内的任何值(例如C4-C6烷基等),并且其通过单键连接至分子的其余部分,例如甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基、1,1-二甲基乙基(叔丁基)、3-甲基己基、2-甲基己基等。所提及的碳的数量涉及主链碳和支链碳,但不包括属于任何取代基的碳原子。除非说明书中另外具体说明,否则烷基基团任选地被取代。
“烯基”是指仅由碳原子和氢原子组成的不饱和的直链或支链的烃链基团,其含有一个或多个碳-碳双键,具有二至十二个碳原子(C2-C12烯基)、二至八个碳原子(C2-C8烯基)或二至六个碳原子(C2-C6烯基)或这些范围内的任何值,并且其通过单键连接至分子的其余部分,例如乙烯基、丙-1-烯基、丁-1-烯基、戊-1-烯基、戊-1,4-二烯基等。所提及的碳的数量涉及主链碳和支链碳,但不包括属于任何取代基的碳原子。除非本说明书中另外具体说明,否则烯基基团任选地被取代。
术语“炔基”是指不饱和的直链或支链烃基,其具有2至12个碳原子(C2-C12炔基)、2至9个碳原子(C2-C9炔基)或2至6个碳原子(C2-C6炔基)或这些范围内的任何值,并且具有至少一个碳-碳叁键。炔基基团的实例可以选自乙炔基、炔丙基、丁-1-炔基、丁-2-炔基等。所提及的碳的数量涉及主链碳和支链碳,但不包括属于任何取代基的碳原子。除非本说明书中另外具体说明,否则炔基基团任选地被取代。
“烷氧基”是指式-ORa的基团,其中Ra是如以上所定义的烷基,其含有一至十二个碳原子(C1-C12烷氧基)、一至八个碳原子(C1-C8烷氧基)或一至六个碳原子(C1-C6烷氧基)或这些范围内的任何值。除非说明书中另外具体说明,否则烷氧基基团任选地被取代。
“胺基”是指式-NRaRb的基团,其中Ra和Rb各自独立地是H或如以上所定义的C1-C6烷基。当Ra和Rb均是H时,“胺基(aminyl)”基团与如以上所定义的“胺基(amino)”相同。除非另外说明,胺基基团的C1-C6烷基部分任选地被取代。
“胺基烷基环烃基”是指式–RaRbNRcRd的基团,其中Ra为如本文所定义的环烃基,Rb为C1-C6烷基,Rc是H或C1-C6烷基,并且Rd为如以上所定义的C1-C6烷基。除非另外说明,否则胺基烷基环烃基基团的环烃基和每个C1-C6烷基部分任选地被取代。
“芳香族环”是指具有共振键的环的环状平面分子或分子的部分(即,基团),其相对于具有相同原子组的其它连接布置表现出增加的稳定性。通常,芳香族环含有一组共价键合的共面原子,并且包含许多π-电子(例如,交替的双键和单键),所述π-电子是偶数但不是4的倍数(即,4n+2个π-电子,其中n=0、1、2、3等)。芳香族环包括但不限于苯基、萘基、咪唑基、吡咯基、吡啶基、嘧啶基、吡嗪基、吡啶基、哒嗪基、嘧啶基。除非在说明书中另外具体说明,否则“芳香族环”包括任选取代的所有基团。
“芳基”是指包含6至18个碳原子(例如6至10个碳原子(C6-C10芳基))和至少一个碳环芳香族环的碳环系统。出于本发明的实施方案的目的,芳基为单环、双环、三环或四环的环系统,其可包括稠合或桥接的环系统。芳基包括但不限于衍生自以下的芳基:醋蒽烯、苊烯、醋菲烯、蒽、薁、苯、荧蒽、芴、不对称引达省、对称引达省、茚满、茚、萘、非那烯、菲、七曜烯、芘和苯并菲。除非说明书中另外具体说明,否则芳基基团任选地被取代。
“氰基烷基”是指包含至少一个氰基取代基的烷基。-CN取代基可以在伯、仲或叔碳上。除非说明书中另外具体说明,否则氰基烷基基团任选地被取代。
“碳环(carbocyclic/carbocycle)”是指环系统,其中环原子中的每一个为碳。
“环烃基”是指仅由碳原子和氢原子组成的非芳香族单环或多环碳环基团,其可包括稠合或桥接的环系统,具有三至十五个环碳原子(C3-C15环烃基)、三至十个环碳原子(C3-C10环烃基)或三至八个环碳原子(C3-C8环烃基)或这些范围内的任何值,例如三至四个碳原子(C3-C4环烃基),并且其是饱和或部分不饱和的并且通过单键连接至分子的其余部分。单环基团包括例如环丙基、环丁基、环戊基、环己基、环庚基和环辛基。多环基团包括例如金刚烷基、降冰片基、十氢萘基、7,7-二甲基-二环[2.2.1]庚基等。除非说明书中另外具体说明,否则环烃基基团任选地被取代。
“烷基环烃基”是指式–RaRb的基团,其中Ra是环烃基且Rb是如以上所定义的烷基。除非说明书中另外具体说明,否则烷基环烃基基团任选地被取代。
“稠合”是指本文描述的稠合至另一环结构的任何环结构。
“卤素”是指溴、氯、氟或碘。
“卤代烷基”是指被一个或多个如以上所定义的卤素基团取代的如以上所定义的烷基,例如三氟甲基、二氟甲基、三氯甲基、2,2,2-三氟乙基、1,2-二氟乙基、3-溴-2-氟丙基、1,2-二溴乙基等。除非说明书中另外具体说明,否则卤代烷基基团任选地被取代。
“卤代环烃基”是指被一个或多个如以上所定义的卤素基团取代的如以上所定义的环烃基,例如三氟甲基、二氟甲基、三氯甲基、2,2,2-三氟乙基、1,2-二氟乙基、3-溴-2-氟丙基、1,2-二溴乙基等。除非说明书中另外具体说明,否则卤代环烃基基团任选地被取代。
“卤代烷基环烃基”是指式–RaRb的基团,其中Ra是环烃基且Rb是如以上所定义的卤代烷基。除非说明书中另外具体说明,否则卤代烷基环烃基基团任选地被取代。
“羟基烷基”是指被一个或多个羟基取代的如以上所定义的烷基。羟基烷基通过烷基碳原子连接在主链处。除非说明书中另外具体说明,否则羟基烷基基团任选地被取代。
“杂环基”是指3-18元,例如3-10元或3-8元非芳香族环基团,其具有一至十个环碳原子(例如,二至十个)和选自氮、氧和硫的一至六个环杂原子。除非本说明书中另外具体说明,否则杂环基是部分或完全饱和的并且是单环、双环、三环或四环的环系统,其可包括稠合、螺环和/或桥接的环系统。杂环基中的氮、碳和硫原子任选地被氧化,并且氮原子任选地被季铵化。此类杂环基的实例包括但不限于二氧戊环基、噻吩基[1,3]二噻烷基、十氢异喹啉基、呋喃酮基、咪唑啉基、咪唑烷基、异噻唑烷基、异噁唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、六氢-1H-吡咯嗪、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、噁唑烷基、环氧乙烷基、哌啶基、哌嗪基、4-哌啶酮基、氮杂环丁烷基、吡咯烷基、吡唑烷基、奎宁环基、噻唑烷基、四氢呋喃基、三噻烷基、四氢吡喃基、硫代吗啉基、硫杂吗啉基、1-氧代-硫代吗啉基和1,1-二氧代-硫代吗啉基。除非说明书中另外具体说明,否则杂环基基团任选地被取代。
“卤代杂环基烷基”是指式-RaRb的基团,其中Ra是烷基且Rb是如本文所定义的卤代杂环基。除非说明书中另外具体说明,否则卤代杂环基烷基基团任选地被取代。
“杂环基烷基”是指式-RaRb的基团,其中Ra是烷基且Rb是如本文所定义的杂环基。除非说明书中另外具体说明,否则杂环基烷基基团任选地被取代。
“杂芳基”是指5-18元,例如5-6元环系统基团,其包含一至十三个环碳原子、一至六个选自氮、氧和硫的环杂原子以及至少一个芳香族环。杂芳基可以是单环、双环、三环或四环系统,其可以包括稠合或桥接的环系统;并且杂芳基中的氮、碳或硫原子可以任选地被氧化;氮原子可以任选地被季铵化。实例包括但不限于氮杂卓基、吖啶基、苯并咪唑基、苯并噻唑基、苯并吲哚基、苯并二氧杂环戊烯基、苯并呋喃基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、苯并[b][1,4]二氧杂卓基、1,4-苯并二噁烷基、苯并萘并呋喃基、苯并噁唑基、苯并二氧杂环戊烯基、苯并二氧杂环己烯基、苯并哌喃基、苯并哌喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基(benzothienyl/benzothiophenyl)、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、咔唑基、噌啉基、二苯并呋喃基、二苯并噻吩基、呋喃基、异噻唑基、咪唑基、吲唑基、吲哚基、吲唑基、异吲哚基、吲哚啉基、异吲哚啉基、异喹啉基、吲哚嗪基、异噁唑基、萘啶基、噁二唑基、2-氧代氮杂卓基、噁唑基、1-氧化吡啶基、1-氧化嘧啶基、1-氧化哒嗪基、1-苯基-1H-吡咯基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、蝶啶基、嘌呤基、吡咯基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、喹唑啉基、喹喔啉基、喹啉基、异喹啉基、四氢喹啉基、噻唑基、噻二唑基、三唑基、四唑基、三嗪基和噻吩基(即,硫杂环戊二烯基)。除非本说明书中另外具体说明,否则杂芳基基团任选地被取代。
噁唑基、异噁唑基、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、1,2,3-三唑基、1,2,4-三唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基和1,3,4-噻二唑基分别是指以下结构:
其中噁唑基、异噁唑基、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、1,2,3-三唑基、1,2,4-三唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基和1,3,4-噻二唑基通过噁唑基、异噁唑基、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、1,2,3-三唑基、1,2,4-三唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基和1,3,4-噻二唑基的环中的碳原子中的一个的共价键连接至分子的其余部分。
如本文使用的术语“取代的”意指其中至少一个氢原子(例如,1、2、3个或所有氢原子)被与非氢取代基的键替代的上述基团(例如,烷基、烯基、亚烷基、烷基羰基、烷氧基、烷氧基烷基、胺基烷基、芳基、氰基烷基、环烃基、卤代烷基、杂环基、杂环烯基、杂环基烷基、杂芳基、杂芳基烷基和/或羟基烷基)中的任一个。非氢取代基的实例包括但不限于:氨基、羧基、氰基、羟基、卤素、硝基、氧代、硫醇、硫代、烷基、烯基、烷基羰基、烷氧基、芳基、氰基烷基、环烃基、卤代烷基、杂环基、杂环基烷基、杂芳基、杂芳基烷基和/或羟基烷基取代基,其还可以各自任选地被一个或多个上述取代基取代。
在一些具体实施方案中,任选的取代基独立地选自卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、C3-C8卤代环烃基、C6-C10芳基、5或6元杂芳基、C1-C6烷氧基和3-8元杂环基。
术语“有效量”或“治疗有效量”是指足以实现预期应用的本文所述的化合物的量,所述预期应用包括但不限于如下定义的疾病治疗。治疗有效量可以根据预期的治疗应用(体内),或所治疗的个体和疾病病况,例如个体的体重和年龄、疾病病况的严重程度、施用方式等而变化,这可以是本领域普通技术人员容易确定的。该术语还适用于在靶细胞中诱导特定反应的剂量,例如血小板粘附和/或细胞迁移的减少。具体剂量将根据所选择的具体化合物、所遵循的给药方案、是否与其它化合物联合施用、施用的时间安排、所施用的组织以及其所携带的物理递送系统而变化。
如本文使用,“治疗(treatment)”或“治疗(treatment)”是指用于获得关于疾病、病症或医学病况的有益或期望的结果(包括但不限于治疗效果和/或预防效果)的方法。治疗益处意指根治或改善所治疗的潜在病症。此外,通过根治或改善与潜在病症相关的一种或多种生理症状来实现治疗益处,从而观测到个体的改善,尽管该个体仍可能罹患潜在病症。预防作用包括延迟或消除疾病或病况的出现,延迟或消除疾病或病况的症状发作,减缓、阻止或逆转疾病或病况的进展,或其任意组合。在某些实施方案中,对于预防益处,向处于有风险患有特定疾病的个体、或报导疾病的一种或多种生理症状的个体施用组合物,即使可能尚未诊断出此疾病。
如本文使用,术语“共施用”、“组合施用”和其语法等同物涵盖向包括人的动物施用两种或更多种药剂,使得两种药剂和/或其代谢物同时存在于个体中。共施用包括以单独组合物同时施用、以单独组合物在不同时间施用、或以两种药剂均存在于其中的组合物施用。
“药物可接受的盐”包括酸加成盐和碱加成盐两者。
“药物可接受的酸加成盐”是指保留游离碱的生物学有效性、在生物学上可耐受或以其它方式在生物学上适用于向个体施用的那些盐。通常,参见S.M.Berge等人,"Pharmaceutical Salts",J.Pharm.Sci.,1977,66:1-19,以及Handbook ofPharmaceutical Salts,Properties,Selection,and Use,Stahl and Wermuth,编辑,Wiley-VCH and VHCA,Zurich,2002。优选的药物可接受的酸加成盐是药理学上有效且适用于与患者组织接触而无异常毒性、刺激或过敏反应的那些盐。药物可接受的酸加成盐由以下形成:无机酸,例如但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸等;以及有机酸,例如但不限于乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬胺酸、苯磺酸、苯甲酸、4-乙酰胺基苯甲酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己氨磺酸、十二烷硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡糖庚酸、葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖酸、月桂酸、马来酸、苹果酸、丙二酸、杏仁酸、甲磺酸、粘酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟碱酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一碳烯酸等
“药物可接受的碱加成盐”是指保留游离碱的生物学有效性、在生物学上可耐受或以其它方式在生物学上适用于向个体施用的那些盐。通常,参见S.M.Berge等人,"Pharmaceutical Salts",J.Pharm.Sci.,1977,66:1-19,and Handbook ofPharmaceutical Salts,Properties,Selection,and Use,Stahl and Wermuth,编辑,Wiley-VCH and VHCA,Zurich,2002。优选的药物可接受的碱加成盐是药理学上有效且适用于与患者组织接触而无异常毒性、刺激或过敏反应的那些盐。药物可接受的碱加成盐由将无机碱或有机碱添加至游离酸中来制备。来自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐是铵盐、钠盐、钾盐、钙盐和镁盐。来自有机碱的盐包括但不限于以下物质的盐:伯胺、仲胺、叔胺、取代胺,包括天然存在的取代胺、环胺和碱离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-乙基氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明(hydrabamine)、胆碱、甜菜碱、苯乙苄胺、苄星青霉素、乙二胺、葡萄糖胺、甲葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
在一些实施方案中,药物可接受的盐包括季铵盐,例如季胺烷基卤盐(例如,溴甲烷)。
术语“拮抗剂”与“抑制剂”可互换使用,并且他们是指具有抑制目标蛋白的生物功能的能力的化合物,无论是通过抑制蛋白质(例如NLRP3炎性体或NEK7)的活性或表达还是通过抑制NLRP3炎性体与NEK7的缔合。因此,术语“拮抗剂”和“抑制剂”在目标蛋白的生物学作用的情形下定义。尽管本文中的优选拮抗剂尤其与目标相互作用(例如,结合),但通过与目标蛋白作为其中成员的信号转导途径中的其它成员相互作用来抑制目标蛋白生物活性的化合物也尤其包括在该定义内。拮抗剂所抑制的优选生物活性与肿瘤的发展、生长或扩散相关。
如本文使用,术语“激动剂”是指具有引发或增强目标蛋白的生物功能的能力的化合物,无论是否通过抑制目标蛋白的活性或表达。因此,术语“激动剂”在目标多肽的生物学作用的情形下被定义。尽管本文中的优选激动剂尤其与目标相互作用(例如,结合),但通过与目标多肽作为其中成员的信号转导途径的其它成员相互作用来引发或增强目标多肽的生物活性的化合物也尤其包括于该定义内。
“信号转导”是刺激或抑制性信号传递至细胞中和细胞内以引发胞内反应的过程。
术语“选择性抑制”或“选择性地抑制”是指生物活性剂通过与目标的直接或间接相互作用,使该药剂与脱靶信号传导活性相比优先地降低目标信号传导活性的能力。
“个体”是指动物,例如哺乳动物,例如人。本文描述的方法可用于人治疗和兽医应用。在一些实施方案中,个体是哺乳动物,并且在一些实施方案中,个体是人。
“哺乳动物”包括人和牲畜动物以及非牲畜动物,所述牲畜动物例如实验室动物和家庭宠物(例如,猫、狗、猪、牛、羊、山羊、马、兔),所述非牲畜动物例如野生动物等。
“前药”意在表示可以在生理条件下或通过溶剂分解转化为本文所述的生物活性化合物的化合物(例如,结构(I)的化合物)。因此,术语“前药”是指药物可接受的生物活性化合物的前体。在一些方面,前药在施用于对象时是惰性的,但在体内转化为活性化合物,例如通过水解。前药化合物经常提供溶解性、组织相容性或在哺乳动物有机体中延迟释放的优点(参见,例如,Bundgard,H.,Design of Prodrugs(1985),第7-9页,第21-24页(Elsevier,Amsterdam)。在Higuchi,T.,等人,“Pro-drugs as Novel Delivery Systems,”A.C.S.Symposium Series,第14卷,以及在Bioreversible Carriers in Drug Design,编辑,Edward B.Roche,American Pharmaceutical Association and Pergamon Press,1987中提供了前药的讨论,两者通过引用全部并入本文。术语“前药”还意指包括任何共价键合的载体,所述载体在此类前药施用于哺乳动物个体时在体内释放活性化合物。如本文描述的活性化合物的前药通常通过修饰活性化合物中存在的官能团来制备,其方式为使得修饰在常规操作中或在体内裂解为母体活性化合物。前药包括其中羟基、氨基或硫醇基团与任何基团连接的化合物,当将活性化合物的前药施用于哺乳动物个体时分别裂解形成游离羟基、游离氨基或游离硫基基团。前药的实例包括但不限于活性化合物中的羟基官能团的乙酸、甲酸和苯甲酸衍生物,或胺官能团的乙酰胺、甲酰胺和苯甲酰胺衍生物等。
术语“体内”是指发生于个体体内的事件。
本文中公开的实施方案也意指涵盖所有药物可接受的结构(I)的化合物。
某些实施方案还意指包括所公开的化合物的体内代谢产物。此类产物可以产生于例如所施用化合物的氧化、还原、水解、酰胺化、酯化等,主要是由于酶促过程。因此,实施方案包括由通过包括向哺乳动物施用本公开内容的化合物持续足以产生其代谢产物的时间段的方法所产生的化合物。通常通过向动物(例如大鼠、小鼠、豚鼠、猴)或向人施用可检测剂量的本公开内容的放射性标记化合物,使得存在足够的代谢时间,并且从尿、血液或其它生物样品中分离其转化产物来鉴定此类产物。
“稳定化合物”和“稳定结构”意指表示足够稳定以从反应混合物中分离至有用纯度并且配制成有效的治疗剂的化合物。
通常,结晶产生本文公开的化合物的溶剂化物。如本文使用,术语“溶剂化物”是指包含一种或多种本公开内容的化合物分子与一种或多种溶剂分子的聚集体。在一些实施方案中,溶剂为水,在此情况下,溶剂合物为水合物。替代地,在其它实施方案中,溶剂为有机溶剂。因此,本公开内容的化合物可以存在为水合物,包括一水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等,以及相应的溶剂化形式。本公开内容的化合物可以是真溶剂化物,而在其它情况下,本公开内容的化合物仅保留外来的水或为水加一些外来溶剂的混合物。
“任选的”或“任选地”意指随后描述的情况事件可以发生或可以不发生,并且意指描述包括其中所述事件或情况发生的例子以及不发生的例子。例如,“任选取代的芳基”意指芳基基团可以被取代或可以不被取代,并且所述描述包括取代的芳基基团和没有取代基的芳基基团。
“药物组合物”是指本公开内容的化合物与通常在本领域接受用于向哺乳动物(例如人)递送本公开内容的化合物的介质的制剂。此类介质包括所有药物可接受的载体、用于其的稀释剂或赋形剂。
“药物可接受的载体、稀释剂或赋形剂”包括但不限于任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等张剂、溶剂或乳化剂。
“立体异构体”是指由相同键键合相同的原子所组成但具有不同三维结构的化合物,所述不同三维结构是不可互换的。本公开内容预期各种立体异构体及其混合物并且包括“对映体”,所述对映体是指分子为彼此不可重叠的镜像的两种立体异构体。
本公开内容的化合物(即,结构(I)的化合物)或其药物可接受的盐可含有一个或多个几何不对称中心,并且因此可产生立体异构体,例如对映异构体、非对映异构体和其它立体异构形式,其在绝对立体化学方面被定义为胺基酸的(R)-或(S)-,或(D)-或(L)-。实施方案因此包括所有此类可能的异构体,以及其外消旋和光学纯形式。任选的活性(+)和(-)、(R)-和(S)-或(D)-和(L)-异构体可以使用手性合成子或手性试剂进行制备,或者使用常规技术例如色谱法和分级结晶进行拆分。用于制备/分离单独对映体的常规技术包括由适合的光学纯前体的手性合成或使用例如手性高压液相色谱(HPLC)对外消旋体(或者盐或衍生物的外消旋体)进行拆分。当本文所述的化合物含有烯烃双键或其他几何非对称中心时,除非另外指明,这意指化合物包括E和Z几何异构体。同样地,也旨在包括所有互变异构形式。
本公开内容的实施方案包括本发明的化合物的旋转异构体的所有方式和构形上受限的状态。还包括阻转异构体,其是由于围绕单键的位阻旋转而产生的立体异构体,其中由立体应变或其它促成因素所致的能量差异产生足够高以允许个别构象异构体分离的旋转障碍。作为实例,本公开内容的某些化合物可以以阻转异构体的混合物形式存在,或者经纯化或富集以存在一种阻转异构体。
在一些实施方案中,结构(I)的化合物是对映异构体或非对映异构体的混合物。在其它实施方案中,结构(I)的化合物实质上是一种对映异构体或非对映异构体。
“互变异构体”是指从分子的一个原子至同一分子的另一原子的质子迁移。实施方案因此包括所公开的化合物的互变异构体。
本文使用的化学命名方案和结构图是I.U.P.A.C.命名法系统的修改形式,其使用ACD/命名9.07版软件程序和/或ChemDraw Profesional 17.0.0.206版软件命名程序(CambridgeSoft)。对于本文使用的复杂化学名称,取代基通常在其所连接的基团之前命名。例如,环丙基乙基包含具有环丙基取代基的乙基主链。除非下文描述,在本文的化学结构图中标识所有键,但假定一些碳原子上的所有键键合至足够的氢原子以完成价数。
化合物
本公开内容提供能够抑制NEK7和/或调节NLRP3炎性体的活性的化合物,包括其药物可接受的盐、立体异构体和前药。
本公开内容的实施方案提供具有以下结构(I)的化合物:
或其药物可接受的盐、立体异构体或前药,其中:
A是各自任选地被一个或多个R6取代的C6-C10芳基、C3-C10环烃基、3-10元杂环基或5-6元单环杂芳基;
Y是CHOH或NH;
R1是H或C1-C6烷基;
R2是各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基;
R3是H,各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基和C1-C6烷氧基;
R4是选自以下的杂芳基:各自任选地被一个或多个取代基取代的噁唑基、异噁唑基、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、1,2,3-三唑基、1,2,4-三唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基和1,3,4-噻二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基,或其组合;
R5是H,各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、C6-C10芳基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基和C1-C6烷氧基;以及
R6在每次出现时独立地是卤素、C1-C6烷基、氰基、C1-C6羟基烷基、C1-C6烷氧基或C1-C6卤代烷基。
在结构(I)的一些实施方案中:
A是各自任选地被一个或多个R6取代的C6-C10芳基、C3-C10环烃基、3-10元杂环基或5-6元单环杂芳基;
Y是CHOH或NH;
R1是H或C1-C6烷基;
R2是各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基;
R3是H,各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基和C1-C6烷氧基;
R4是选自以下的杂芳基:各自任选地被一个或多个取代基取代的噁唑基、异噁唑基、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、1,2,3-三唑基、1,2,4-三唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基和1,3,4-噻二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基和C3-C8卤代环烃基;
R5是H,各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、C6-C10芳基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基和C1-C6烷氧基;以及
R6在每次出现时独立地是卤素、C1-C6烷基或C1-C6卤代烷基。
一些更具体的实施方案提供具有以下结构(I)的化合物:
或其药物可接受的盐、立体异构体或前药,其中:
A是各自任选地被一个或多个R6取代的C6-C10芳基、C3-C10环烃基、3-10元杂环基或5-6元单环杂芳基;
X是CH或N;
Y是CHOH或NH;
R1是H或C1-C6烷基;
R2是各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基;
R3是H,各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基和C1-C6烷氧基;
R4是选自以下的杂芳基:各自任选地被一个或多个取代基取代的噁唑基、异噁唑基、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、1,2,3-三唑基、1,2,4-三唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基和1,3,4-噻二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基;
R5是H,各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、C6-C10芳基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基和C1-C6烷氧基;以及
R6在每次出现时独立地是卤素、C1-C6烷基、C1-C6烷氧基、氰基、C1-C6羟基烷基或C1-C6卤代烷基。
在某一实施方案中,R1是H。在其它实施方案中,R1是C1-C6烷基,例如甲基。
在一个实施方案中,提供结构(I)的化合物,其中R2是各自任选地被一个或多个取代基取代的支链C4-C6烷基、C3-C4环烃基、C3-C8杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基。
在另一实施方案中,提供结构(I)的化合物,其中R2是各自任选地被一个或多个取代基取代的支链C4-C6烷基、C3-C4环烃基或C3-C8杂环基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基。
在具体实施方案中,R2是各自任选地被一个或多个取代基取代的环丙基或氧杂环丁烷基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基。在一些实施方案中,R2是环丙基。在其它实施方案中,R2是氧杂环丁烷基。在一些实施方案中,R2是未取代的环丙基或氧杂环丁烷基。
在具体实施方案中,R2是各自任选地被一个或多个取代基取代的环丙基、环丁基、吡咯烷基、哌啶基或氧杂环丁烷基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基。在一些实施方案中,R2是环丙基。在其它实施方案中,R2是氧杂环丁烷基。在一些实施方案中,R2是未取代的环丙基或氧杂环丁烷基。在一些实施方案中,R2是N-甲基取代的吡咯烷基。在某些具体实施方案中,R2是未取代的环丁基。
在不同实施方案中,R2是任选地被一个或多个取代基取代的支链C4-C6烷基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基。例如,在一些实施方案中,R2是任选地被羟基取代的2-甲基丙基。
在一些更具体的实施方案中,R2具有以下结构中的一个:
在一些具体实施方案中,R2具有以下结构中的一个:
在其它实施方案中,R3是H。在其它实施方案中,R3是C1-C6烷基,例如甲基。
在前述实施方案中的任一个中,R4是各自任选地被一个或多个取代基取代的噁唑基、异噁唑基、1,2,3-噁二唑基或1,3,4-噁二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。例如,在某些实施方案中,R4是任选地被一个或多个取代基取代的异噁唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基和C3-C8卤代环烃基。在其它具体实施方案中,R4被C1-C6烷基、C1-C6卤代烷基、C3-C8环烃基或C3-C8卤代环烃基取代。
在某些实施方案中,R4是各自任选地被一个或多个取代基取代的噁唑基、异噁唑基、1,2,3-噁二唑基、噻唑基、异噻唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,4-三唑基或1,3,4-噁二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
在某些实施方案中,R4是任选地被一个或多个取代基取代的异噁唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
在某些实施方案中,R4是任选地被一个或多个取代基取代的三唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
在某些实施方案中,R4是任选地被一个或多个取代基取代的异噻唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
在某些实施方案中,R4是任选地被一个或多个取代基取代的1,2,4-噻二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
在某些实施方案中,R4是任选地被一个或多个取代基取代的1,3,4-噻二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
在某些实施方案中,R4是任选地被一个或多个取代基取代的1,2,4-三唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
在某些实施方案中,R4是任选地被一个或多个取代基取代的1,3,4-噁二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、3-8元杂环基和C3-C8卤代环烃基或其组合。
在某些实施方案中,R4被C1-C6烷基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合取代。
在各种实施方案中,R4具有以下结构中的一种:
在其它各种实施方案中,R4具有以下结构中的一种:
在其它各种实施方案中,R4具有以下结构中的一种:
在某些具体实施方案中,R2是各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基;以及
R4具有以下结构中的一种:
在某些具体实施方案中,R2是各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基;以及
R4具有以下结构中的一种:
在更具体的实施方案中,R2是被羟基或C1-C6烷氧基取代的C1-C6烷基。在一些实施方案中,R2具有以下结构中的一种:
在其它实施方案中,R5是H。在其它实施方案中,R5是C1-C6烷基,例如甲基。
在某些实施方案中,Y是C(H)(OH)。在其它实施方案中,Y是NH。
在各种实施方案中,A是各自任选地被一个或多个R6取代的C6-C10芳基、C3-C10环烃基、或5-6元单环杂芳基。应理解,A是二价基团。
在某些实施方案中,A是二价任选取代的C6-10芳基。在某些实施方案中,A是二价任选取代的3-8元饱和或部分不饱和碳环。在某些实施方案中,A是二价任选取代的具有1-4个独立地选自氮、氧或硫的杂原子的3-10元杂环。在某些实施方案中,A是二价任选取代的具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳基环。
在某些实施方案中,A是各自任选地被取代的选自苯基、吡啶基、环己基和环己烯基的二价基团。在其它实施方案中,A是苯基。在不同实施方案中,A是饱和或不饱和的环己烃基。在更多实施方案中,A是吡啶基。
在某些实施方案中,A是任选地被取代的嘧啶基。
在任一前述实施方案中,A是未取代的。在不同的前述实施方案中,A被一个或多个R6取代。例如,在一些实施方案中,R6是卤素。在一些实施方案中,R6是氯或氟。在其它实施方案中,R6是氟。
在一些实施方案中,R6是C1-C6羟基烷基。在一些实施方案中,C1-C6羟基烷基是-CH2CH2OH。在其它实施方案中,R6是氰基。在一些实施方案中,R6是C1-C6烷氧基。在更具体的实施方案中,C1-C6烷氧基是甲氧基。
在某些实施方案中,A是选自以下的二价基团:各自任选地被取代的苯基、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]二环辛基、[4.3.0]二环壬基、[4.4.0]二环癸基、[2.2.2]二环辛基、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、苯并硫杂噻吩基、苯并噻吩基、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、二噻嗪基、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、假吲哚基、吲哚啉基、吲哚嗪基、吲哚基、3-吲哚基、异吲哚啉基、异假吲哚基、异苯并呋喃基、异色满基、异吲唑基、异吲哚啉基、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、吩噁噻基、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、2-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、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、噻吩基、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、氮杂环丁烷基和呫吨基。
在具体实施方案中,A具有以下结构中的一种:
在一些具体实施方案中,A具有以下结构中的一种:
在一些具体实施方案中,A具有以下结构中的一种:
在某些实施方案中,化合物具有以下结构(IA):
或其药物可接受的盐、立体异构体或前药,其中:
R2a是各自任选地被一个或多个取代基取代的C1-C6烷基或C3-C8环烃基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基;
R4a是任选地被一个或多个选自取代基取代的异噁唑基,所述取代基选自:C1-C6卤代烷基、C3-C8环烃基或C3-C8卤代烷基环烃基。
在更具体的实施方案中,R2a是被羟基取代的支链C1-C6烷基。在一些实施方案中,R2a是C3-C8环烃基。在更具体的实施方案中,R2a具有以下结构中的一种:
在某些实施方案中,R4a是被C3-C8卤代烷基环烃基取代的异噁唑基。在一些实施方案中,R4a是C3-C8氟烷基环烃基。在更具体的实施方案中,R4a是氟烷基环丙基或氟烷基环丁基。在更具体的实施方案中,R4a具有以下结构中的一种:
在一些实施方案中,X是CH。在一些更具体的实施方案中,化合物具有以下结构(IB):
或其药物可接受的盐、立体异构体或前药,其中:
A是各自任选地被一个或多个R6取代的C6-C10芳基、C3-C10环烃基、3-10元杂环基或5-6元单环杂芳基;
X是CH或N;
Y是CHOH或NH;
R1是H或C1-C6烷基;
R2是各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基;
R3是H,各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基和C1-C6烷氧基;
R4是选自以下的杂芳基:各自任选地被一个或多个取代基取代的噁唑基、异噁唑基、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、1,2,3-三唑基、1,2,4-三唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基和1,3,4-噻二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基;
R5是H,各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、C6-C10芳基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基和C1-C6烷氧基;以及
R6在每次出现时独立地是卤素、C1-C6烷基、C1-C6烷氧基、氰基、C1-C6羟基烷基或C1-C6卤代烷基。
在某些实施方案中,结构(I)的化合物是NLRP3炎性体的调节剂。
在具体实施方案中,结构(I)的化合物是患者或生物样品中的NEK7的抑制剂。
在各种不同实施方案中,化合物具有下表1中阐述的结构中的一种,或其药物可接受的盐、立体异构体或前药。表1中的化合物如实施例或本领域已知的方法中所述制备并通过质谱和/或1H NMR分析。
表1.结构(I)的代表性化合物
应理解,在本描述中,所述式的取代基和/或变量的组合只有在此类作用产生稳定化合物时才是允许的。
在另外的实施方案中,以游离碱或酸形式存在的本公开内容的各种化合物可以通过本领域技术人员已知的方法用适当的无机或有机的碱或酸处理而转化成其药物可接受的盐。本公开内容的化合物的盐可以通过标准技术转化成它们的游离碱或酸形式。
下文提供了用于生产本文所述的化合物的方法。通常,可以从诸如SigmaAldrich、Lancaster Synthesis,Inc.、Maybridge、Matrix Scientific、TCI和FluorochemUSA等的来源获得起始组分,或根据本领域技术人员已知的来源合成起始组分(参见,例如,Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,第5版,(Wiley,December 2000))或者如本文所述制备起始组分。
以下一般反应方案例示出本发明的结构(I)的化合物的实例:
或其药物可接受的盐、立体异构体或前药,其中A、X、Y、R1、R2、R3、R4和R5各自如以下定义。
一般反应方案1
以下一般反应方案(其中X1和X2独立地为卤素,并且X、R1、R2、R3和A具有本文所述的含义)例示出了制备胺中间体D的方法的实施例:
如一般反应方案1所示,嘧啶/吡啶吡咯(即,中间体A)用环烃基硼酸酯或适当的亲电体在碱的存在下烷基化得到中间体B。该前体用氢氧化铵处理以形成吡咯并嘧啶/吡啶-4-胺衍生物中间体C。然后可以使所得中间体C经受钯催化的芳基化以形成中间体D。
一般反应方案2
以下一般反应方案例示出制备氨基甲酸酯中间体E的方法的实施例:
如一般反应方案2所示,中间体E可以在碱的存在下通过氯甲酸苯酯和所示杂芳基胺(R4的胺取代的类似物)的反应来制备。一般反应方案2描述了其中R5是H的化合物的制备;然而,其中R5不是H的化合物可以通过类似方法通过在制备中间体E之后滴注R5来制备,或通过使用适当取代的杂芳基胺来制备。一般反应方案3
以下一般反应方案例示出制备结构(I)的化合物的方法的实施例:
在THF中用碱(例如,三甲胺、DIPEA、DMAP等)处理中间体D和中间体E以得到结构(I)的化合物。
一般反应方案4
以下一般反应方案例示出制备结构(I)的化合物的方法的实施例:
使中间体D与所示的氯甲酸苯酯在适当条件下反应以得到中间体E。然后在THF中使用适合的碱(例如,三甲胺、DIPEA、DMAP等)使中间体E与胺偶联以得到结构(I)的化合物。
可在任何步骤处修改以上反应方案中的任一个以添加和/或修饰取代基,取代基可以在所需化合物的整个合成的任何阶段期间适当地添加或修改。
本领域技术人员还应理解,在制备本文所述的化合物的方法中,中间体化合物的官能团可能需要由合适的保护基保护。此类官能团包括但不限于羟基、氨基、巯基和羧酸。羟基的合适保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如,叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。氨基、脒基和胍基的适合的保护基团包括叔丁氧基羰基、苄氧基羰基等。巯基的适合的保护基团包括-C(O)-R"(其中R"是烷基、芳基或芳基烷基)、对甲氧基苄基、三苯甲基等。羧酸的适合的保护基团包括烷基酯、芳基酯或芳基烷基酯。保护基团任选地根据本领域技术人员已知的和如本文所述的标准技术添加或去除。在Green,T.W.和P.G.M.Wutz,Protective Groups inOrganic Synthesis(1999),第3版,Wiley中详细描述了保护基团的用途。正如本领域技术人员将理解,保护基团也可以是聚合物树脂,例如Wang树脂、Rink树脂或2-氯三苯甲基-氯化物树脂。
本领域技术人员还将理解,尽管本公开内容的化合物的此类受保护的衍生物可以不具有药理活性,同样地,可以将它们施用于哺乳动物并且此后在体内代谢以形成具有药理活性的本公开内容的化合物。因此可以将此类衍生物描述为“前药”。本公开内容的化合物的前药包括在本公开内容的实施方案的范围内。
药物组合物
其它实施方案涉及药物组合物。药物组合物包含前述化合物中的任一种(或多种)以及药物可接受的载体。在一些实施方案中,药物组合物被配制用于口服施用。在其它实施方案中,药物组合物被配制用于注射。在更多的实施方案中,药物组合物包含本文公开的化合物和另外的治疗剂(例如,抗癌剂)。此类治疗剂的非限制性实例在下文描述。
合适的施用途径包括但不限于口服、静脉内、直肠、气溶胶、肠胃外、眼、,肺、经粘膜、透皮、阴道、耳、鼻和局部施用。另外,仅作为实例,肠胃外递送包括肌内、皮下、静脉内、髓内注射、以及鞘内、直接心室内、腹膜内、淋巴内和鼻内注射。
在某些实施方案中,本文所述的化合物以局部而非全身方式施用,例如,通过将化合物直接注射到器官中,通常以贮库制剂或持续释放制剂的形式施用。在具体的实施方案中,长效制剂通过植入(例如皮下或肌内)或通过肌内注射施用。此外,在其它实施方案中,化合物在靶向药物递送系统中递送,例如在用器官特异性抗体包被的脂质体中。在此类实施方案中,脂质体靶向器官并被器官选择性地吸收。在其它实施方案中,如本文所述的化合物以快速释放制剂的形式、延长释放制剂的形式或中间释放制剂的形式提供。在其它实施方案中,局部施用本文所述的化合物。
在根据本发明的实施方案的治疗方法中,将有效量的至少一种结构(I)的化合物施用于患有或被诊断为患有这样的疾病、病症或医学病况的个体。有效量或剂量可通过诸如建模、剂量递增研究或临床试验的方法来确定,例如施用或药物递送的模式或途径,药剂的药代动力学,疾病、病症或病况的严重性和进程,个体先前或正在进行的疗法,个体的健康状态和对药物的反应以及治疗医师的判断。
根据本公开内容的化合物在宽的剂量范围内是有效的。例如,在成人的治疗中,10至5000mg/天、100至5000mg/天、1000至4000mg/天和1000至3000mg/天的剂量是用于一些实施方案中的剂量的实例。精确的剂量取决于施用途径、施用的化合物形式、待治疗的对象、待治疗的对象的体重、主治医师的喜好和经验。
在一些实施方案中,本公开内容的化合物以单剂量施用。通常,这种施用将通过注射,例如静脉内注射,以便快速引入药剂。然而,视情况使用其它途径。单次剂量的本公开内容的化合物也可用于治疗急性病况。
在一些实施方案中,本公开内容的化合物以多剂量施用。在一些实施方案中,每天给药为约一次、两次、三次、四次、五次、六次或大于六次。在其它实施方案中,给药为约每月一次、每两周一次、每周一次或每隔一天一次。在另一个实施方案中,本公开内容的化合物和另一种药剂(例如,抗癌剂)一起施用约每天一次至约每天6次。在另一个实施方案中,施用本公开内容的化合物和药剂持续少于约7天。在另一个实施方案中,施用持续大于约6天、10天、14天、28天、两个月、六个月或一年。在一些情况下,必要时,实现和维持持续给药。
本公开内容的化合物的施用可以按需要持续尽可能长的时间。在一些实施方案中,本公开内容的化合物施用超过1天、2天、3天、4天、5天、6天、7天、14天或28天。在一些实施方案中,本公开内容的化合物施用少于28天、14天、7天、6天、5天、4天、3天、2天或1天。在一些实施方案中,本公开内容的化合物在持续进行的基础上长期施用,例如用于治疗慢性效应。
在一些实施方案中,本公开内容的化合物以单独的剂型施用。本领域已知的是,由于化合物药代动力学的个体间差异,给药方案的个体化对于最佳治疗是必需的。
在一些实施方案中,本文所述的化合物被配制成药物组合物。在具体实施方案中,药物组合物以常规方式使用一种或多种生理学上可接受的载体配制,所述载体包含赋形剂和助剂,其有助于将所公开的化合物加工成可药用的制剂。适当的制剂取决于所选的施用途径。任何药物可接受的技术、载体和赋形剂适用于配制本文所述的药物组合物:Remington:The Science and Practice of Pharmacy,Nineteenth Ed(Easton,Pa.:MackPublishing Company,1995);Hoover,John E.,Remington’s Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pennsylvania 1975;Liberman,H.A.and Lachman,L.编著,Pharmaceutical Dosage Forms,Marcel Decker,New York,N.Y.,1980;以及Pharmaceutical Dosage Forms and Drug Delivery Systems,第七版,(LippincottWilliams&Wilkins1999)。
本文提供了包含一种或多种结构(I)的化合物和药物可接受的载体的药物组合物。
本文提供了药物组合物,其包含一种或多种选自结构(I)的化合物和药物可接受的稀释剂、赋形剂和载体的化合物。在某些实施方案中,所述化合物作为药物组合物施用,其中选自结构(I)的化合物的一种或多种化合物与其它活性成分混合,如在组合疗法中。本文涵盖下文组合疗法部分中所阐述的活性物质的所有组合以及本公开内容通篇所阐述的活性物质的所有组合。在具体实施方案中,药物组合物包括一种或多种结构(I)的化合物。
在某个实施方案中,结构(I)的化合物的药物组合物是NLRP3炎性体的调节剂。
在具体实施方案中,结构(I)的化合物的药物组合物在施用于患者或生物样品时抑制NEK7。
如本文所用的药物组合物是指选自结构(I)的化合物的一种或多种化合物与其它化学组分的混合物,所述其它化学组分例如载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂和/或赋形剂。在某些实施方案中,药物组合物促进化合物对生物体的施用。在一些实施方案中,治疗有效量的选自本文提供的结构(I)的化合物的一种或多种化合物在药物组合物中施用于患有待治疗的疾病、病症或医学病况的哺乳动物。在具体的实施方案中,哺乳动物是人。在某些实施方案中,治疗有效量根据疾病的严重程度、个体的年龄和相对健康状况、所用化合物的功效和其它因素而变化。本文所述的化合物单独或与一种或多种治疗剂组合用作混合物的组分。
在一个实施方案中,将选自结构(I)的化合物的一种或多种化合物配制成水溶液。在具体实施方案中,仅作为实例,水溶液选自生理相容性缓冲液,例如汉克氏溶液、林格氏溶液或生理盐水缓冲液。在其它实施方案中,选自结构(I)的化合物的一种或多种化合物被配制用于经粘膜施用。在具体实施方案中,经粘膜制剂包括适于待渗透屏障的渗透剂。在其它实施方案中,其中本文所述的化合物被配制用于其它肠胃外注射,合适的制剂包括水性或非水性溶液。在具体实施方案中,这种溶液包括生理上相容的缓冲液和/或赋形剂。
在另一个实施方案中,本文所述的化合物被配制用于口服施用。本文所述的化合物通过将活性化合物与例如药物可接受的载体或赋形剂组合来配制。在各种实施方案中,本文所述的化合物被配制成口服剂型,所述口服剂型包括(仅作为实例)片剂、粉末、丸剂、糖衣丸、胶囊、液体、凝胶、糖浆、酏剂、浆液、悬浮液等。
在某些实施方案中,用于口服使用的药物制剂通过以下方式获得:将一种或多种固体赋形剂与一种或多种本文所述的化合物混合,任选地研磨所得混合物,并且在添加合适的助剂(如果需要的话)之后加工颗粒混合物以获得片剂或糖衣丸芯。合适的赋形剂特别是填充剂,例如糖,包括乳糖、蔗糖、甘露糖醇或山梨糖醇;纤维素制剂,例如:玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、黄蓍胶、甲基纤维素、微晶纤维素、羟丙基甲基纤维素、羧甲基纤维素钠;或其它物质,例如:聚乙烯吡咯烷酮(PVP或聚维酮)或磷酸钙。在具体的实施方案中,任选地加入崩解剂。仅作为实例,崩解剂包括交联的交联羧甲基纤维素钠、聚乙烯吡咯烷酮、琼脂或藻酸或其盐如藻酸钠。
在一个实施方案中,剂型,例如糖衣丸芯和片剂,提供有一种或多种合适的包衣。在具体实施方案中,浓缩的糖溶液用于包覆剂型。糖溶液任选地包含另外的组分,例如仅作为实例,阿拉伯树胶、滑石、聚乙烯吡咯烷酮、卡波姆凝胶、聚乙二醇和/或二氧化钛、漆溶液和合适的有机溶剂或溶剂混合物。为了识别的目的,染料和/或颜料也任选地添加到包衣中。另外,染料和/或颜料任选地用于表征活性化合物剂量的不同组合。
在某些实施方案中,将治疗有效量的至少一种本文所述的化合物配制成其它口服剂型。口服剂型包括由明胶制成的推入配合(push-fit)胶囊,以及由明胶和增塑剂(例如甘油或山梨糖醇)制成的软密封胶囊。在具体的实施方案中,推入配合胶囊含有与一种或多种填充剂混合的活性成分。填充剂包括(仅作为实例)乳糖、粘合剂(例如淀粉)和/或润滑剂(例如滑石或硬脂酸镁)以及任选的稳定剂。在其它实施方案中,软胶囊含有一种或多种溶解或悬浮在合适液体中的活性化合物。合适的液体包括,仅作为实例,一种或多种脂肪油、液体石蜡或液体聚乙二醇。此外,任选地加入稳定剂。
在其它实施方案中,本文所述的化合物被配制用于肠胃外注射,包括适于快速浓注或连续输注的制剂。在具体的实施方案中,用于注射的制剂以单位剂型(例如,在安瓿中)或在多剂量容器中提供。任选地将防腐剂添加至注射制剂中。在其它实施方案中,药物组合物被配制成适于肠胃外注射的形式,作为在油性或水性媒介物中的无菌悬浮液、溶液或乳液。肠胃外注射制剂任选地含有配制剂,例如悬浮剂、稳定剂和/或分散剂。在具体的实施方案中,用于肠胃外施用的药物制剂包括水溶性形式的活性化合物的水溶液。在另外的实施方案中,将选自结构(I)的化合物的一种或多种化合物的悬浮液制备为适当的油性注射悬浮液。用于本文所述的药物组合物中的合适的亲脂性溶剂或媒介物包括(仅作为实例)脂肪油(例如芝麻油)或合成脂肪酸酯(例如油酸乙酯或甘油三酯)或脂质体。在某些具体的实施方案中,水性注射悬浮液含有增加悬浮液粘度的物质,例如羧甲基纤维素钠、山梨糖醇或葡聚糖。任选地,悬浮液含有合适的稳定剂或增加化合物的溶解度的试剂,以允许制备高度浓缩的溶液。或者,在其它实施方案中,活性成分为粉末形式,用于在使用前与合适的媒介物(例如无菌无热原水)构成。
药物组合物包括至少一种药物可接受的载体、稀释剂或赋形剂,以及选自本文所述的结构(I)的化合物的一种或多种化合物作为活性成分。活性成分为游离酸或游离碱形式或药物可接受的盐形式。此外,本文所述的方法和药物组合物包括使用具有相同类型活性的这些化合物的N-氧化物、结晶形式(也称为多晶型物)以及活性代谢物。本文所述的化合物的所有互变异构体都包括在本文呈现的化合物的范围内。此外,本文所述的化合物包括非溶剂化的形式以及与药物可接受的溶剂如水、乙醇等的溶剂化形式。本文呈现的化合物的溶剂化形式也被认为是本文公开的。此外,药物组合物任选地包括其它药物或药剂,载体,佐剂,例如防腐剂,稳定剂、润湿剂或乳化剂,溶解促进剂,用于调节渗透压的盐,缓冲剂和/或其它有治疗价值的物质。
用于制备包含本文所述的化合物的组合物的方法包括将化合物与一种或多种惰性的药物可接受的赋形剂或载体一起配制以形成固体、半固体或液体。固体组合物包括但不限于粉末、片剂、可分散颗粒、胶囊、扁囊剂和栓剂。液体组合物包括化合物溶解于其中的溶液,包含化合物的乳液,或包含脂质体、胶束或包含本文公开的化合物的纳米颗粒的溶液。半固体组合物包括但不限于凝胶、悬浮液和乳膏。本文所述的药物组合物的形式包括液体溶液或悬浮液,适于在使用前在液体中溶解或悬浮的固体形式,或作为乳液。这些组合物还任选地含有少量无毒的辅助物质,例如湿润剂或乳化剂、pH缓冲剂等。
在一些实施方案中,包含选自结构(I)的化合物的一种或多种化合物的药物组合物示例性地采取液体的形式,其中药剂存在于溶液、混悬剂或两者中。通常,当组合物作为悬浮液施用时,药剂的第一部分存在于溶液中,并且药剂的第二部分以悬浮在液体基质中的颗粒形式存在。在一些实施方案中,液体组合物包括凝胶制剂。在其它实施方案中,液体组合物是水性的。
在某些实施方案中,水性悬浮液含有一种或多种聚合物作为悬浮剂。聚合物包括水溶性聚合物,例如纤维素聚合物,例如羟丙基甲基纤维素;以及水不溶的聚合物,例如交联的含羧基的聚合物。本文所述的某些药物组合物包含粘膜粘附聚合物,其选自例如羧甲基纤维素、卡波姆(丙烯酸聚合物)、聚(甲基丙烯酸甲酯)、聚丙烯酰胺、聚卡波非、丙烯酸/丙烯酸丁酯共聚物、海藻酸钠和葡聚糖。
药物组合物还任选地包括增溶剂以有助于选自结构(I)的化合物的一种或多种化合物的溶解度。术语“增溶剂”通常包括导致形成药剂的胶束溶液或真实溶液的药剂。某些可接受的非离子表面活性剂,例如聚山梨醇酯80可用作增溶剂,也可用作眼科可接受的乙二醇、聚乙二醇,例如聚乙二醇400和乙二醇醚。
此外,药物组合物任选地包括一种或多种pH调节剂或缓冲剂,包括酸,例如乙酸、硼酸、柠檬酸、乳酸、磷酸和盐酸;碱,例如氢氧化钠、磷酸钠、硼酸钠、柠檬酸钠、乙酸钠、乳酸钠和三羟甲基氨基甲烷;以及缓冲剂,例如柠檬酸盐/葡聚糖、碳酸氢钠和氯化铵。这种酸、碱和缓冲剂以将组合物的pH维持在可接受的范围内所需的量被包含。
任选地,组合物还以使得组合物的渗透压达到可接受的范围的量包括一种或多种盐。这种盐包括具有钠、钾或铵阳离子和氯化物、柠檬酸盐、抗坏血酸盐、硼酸盐、磷酸盐、碳酸氢盐、硫酸盐、硫代硫酸盐或亚硫酸氢盐阴离子的盐;合适的盐包括氯化钠、氯化钾、硫代硫酸钠、亚硫酸氢钠和硫酸铵。
其它药物组合物任选地包括一种或多种防腐剂以抑制微生物活性。合适的防腐剂包括含汞的物质,例如硝酸苯汞和硫柳汞;稳定的二氧化氯;以及季铵化合物,例如苯扎氯铵、十六烷基三甲基溴化铵和十六烷基吡啶鎓氯化物。
组合物可以包含一种或多种表面活性剂以增强物理稳定性或用于其它目的。合适的非离子表面活性剂包括聚氧乙烯脂肪酸甘油酯和植物油,例如聚氧乙烯(60)氢化蓖麻油;以及聚氧乙烯烷基醚和烷基苯基醚,例如辛苯聚醇10、辛苯聚醇40。
组合物可以包含一种或多种抗氧化剂,以在需要时增强化学稳定性。合适的抗氧化剂包括,仅作为实例,抗坏血酸和焦亚硫酸钠。
在某些实施方案中,水性悬浮液组合物被包封在单剂量不可再封闭容器中。或者,使用多剂量可再封闭容器,在这种情况下,通常在组合物中包含防腐剂。
在替代实施方案中,使用用于疏水性药物化合物的其它递送系统。脂质体和乳液是可用于本文的递送媒介物或载体的实例。在某些实施方案中,还使用有机溶剂,例如N-甲基吡咯烷酮。在另外的实施方案中,使用持续释放系统,例如含有治疗剂的固体疏水性聚合物的半渗透性基质,递送本文所述的化合物。各种持续释放材料在本文中是有用的。在一些实施方案中,持续释放胶囊将化合物释放数周直至超过100天。根据治疗剂的化学性质和生物稳定性,采用另外的蛋白质稳定策略。
在某些实施方案中,本文所述的制剂包含一种或多种抗氧化剂、金属螯合剂、含硫醇的化合物和/或其它一般稳定剂。这种稳定剂的实例包括但不限于:(a)约0.5%至约2%w/v甘油,(b)约0.1%至约1%w/v甲硫氨酸,(c)约0.1%至约2%w/v单硫代甘油,(d)约1mM至约10mM EDTA,(e)约0.01%至约2%w/v抗坏血酸,(f)0.003%至约0.02%w/v聚山梨醇酯80,(g)0.001%至约0.05%w/v聚山梨醇酯20,(h)精氨酸,(i)肝素,(j)硫酸葡聚糖,(k)环糊精,(l)戊聚糖多硫酸酯和其它类肝素,(m)二价阳离子,例如镁和锌;或(n)它们的组合。
在一些实施方案中,提供在本公开内容的药物组合物中的选自结构(I)的化合物的一种或多种化合物的浓度大于90%、80%、70%、60%、50%、40%、30%、20%、19.75%、19.50%、19.25%19%、18.75%、18.50%、18.25%18%、17.75%、17.50%、17.25%17%、16.75%、16.50%、16.25%16%、15.75%、15.50%、15.25%15%、14.75%、14.50%、14.25%14%、13.75%、13.50%、13.25%13%、12.75%、12.50%、12.25%12%、11.75%、11.50%、11.25%11%、10.75%、10.50%、10.25%10%、9.75%、9.50%、9.25%9%、8.75%、8.50%、8.25%8%、7.75%、7.50%、7.25%7%、6.75%、6.50%、6.25%6%、5.75%、5.50%、5.25%5%、4.75%、4.50%、4.25%、4%、3.75%、3.50%、3.25%、3%、2.75%、2.50%、2.25%、2%、1.75%、1.50%、125%、1%、0.5%、0.4%、0.3%、0.2%、0.1%、0.09%、0.08%、0.07%、0.06%、0.05%、0.04%、0.03%、0.02%、0.01%、0.009%、0.008%、0.007%、0.006%、0.005%、0.004%、0.003%、0.002%、0.001%、0.0009%、0.0008%、0.0007%、0.0006%、0.0005%、0.0004%、0.0003%、0.0002%、或0.0001%w/w、w/v或v/v。
在一些实施方案中,提供在本公开内容的药物组合物中的选自结构(I)的化合物的一种或多种化合物的浓度为约0.0001%至约50%、约0.001%至约40%、约0.01%至约30%、约0.02%至约29%、约0.03%至约28%、约0.04%至约27%、约0.05%至约26%、约0.06%至约25%、约0.07%至约24%、约0.08%至约23%、约0.09%至约22%、约0.1%至约21%、约0.2%至约20%、约0.3%至约19%、约0.4%至约18%、约0.5%至约17%、约0.6%至约16%、约0.7%至约15%、约0.8%至约14%、约0.9%至约12%、约1%至约10%w/w、w/v或v/v。
在一些实施方案中,提供在本公开内容的药物组合物中的选自结构(I)的化合物的一种或多种化合物的量等于或低于10g、9.5g、9.0g、8.5g、8.0g、7.5g、7.0g、6.5g、6.0g、5.5g、5.0g、4.5g、4.0g、3.5g、3.0g、2.5g、2.0g、1.5g、1.0g、0.95g、0.9g、0.85g、0.8g、0.75g、0.7g、0.65g、0.6g、0.55g、0.5g、0.45g、0.4g、0.35g、0.3g、0.25g、0.2g、0.15g、0.1g、0.09g、0.08g、0.07g、0.06g、0.05g、0.04g、0.03g、0.02g、0.01g、0.009g、0.008g、0.007g、0.006g、0.005g、0.004g、0.003g、0.002g、0.001g、0.0009g、0.0008g、0.0007g、0.0006g、0.0005g、0.0004g、0.0003g、0.0002g、或0.0001g。
在一些实施方案中,在本公开内容的药物组合物中提供的选自结构(I)的化合物的一种或多种化合物的量为0.0001-10g、0.0005-9g、0.001-8g、0.005-7g、0.01-6g、0.05-5g、0.1-4g、0.5-4g或1-3g。
用于包装本文所述的药物组合物的包装材料包括在例如第5,323,907号、第5,052,558号和第5,033,252号美国专利中所发现的那些。药物包装材料的实例包括(但不限于)泡罩包装、瓶、管、吸入器、泵、袋、小瓶、容器、注射器、瓶子和适用于所选制剂和预期施用和治疗模式的任何包装材料。例如,容器包括一种或多种本文所述的化合物,任选地以组合物的形式或与本文公开的另一种药剂组合。容器任选地具有无菌进入口(例如容器是静脉溶液袋或具有可被皮下注射针刺穿的塞子的小瓶)。这样的试剂盒任选地包含具有鉴定描述或标签或与其在本文所述的方法中的使用有关的说明书的化合物。
例如,试剂盒通常包括一个或多个另外的容器,每个容器具有一种或多种从商业和用户观点来看使用本文所述的化合物所期望的各种材料(例如试剂,任选地呈浓缩形式,和/或装置)。此类材料的非限制性实例包括但不限于缓冲剂、稀释剂、过滤器、针、注射器;列出内容物和/或使用说明的载体、包装、容器、小瓶和/或管标签,以及具有使用说明的包装说明书。通常还将包括一组指令。标签可选地位于容器上或与容器相关联。例如,当形成标签的字母、数字或其它字符被附着、模制或蚀刻到容器本身时,标签位于容器上,当标签存在于也保持容器的容器或载体内时,标签与容器相关联,例如作为包装说明书。此外,标签用于指示内容物将用于特定的治疗应用。此外,标签指示内容物的使用说明,例如在本文所述的方法中。在某些实施方案中,药物组合物存在于包含一种或多种含有本文提供的化合物的单位剂型的包装或分配器装置中。包装例如包含金属或塑料箔,例如泡罩包装。或者,包装或分配器装置附有施用说明书。或者,包装或分配器还附有与容器相关的由管理药物的制造、使用或销售的政府机构规定的通知,该通知反映了该机构批准用于人或兽医施用的药物形式。这种通知,例如,是美国食品和药品管理局批准的处方药物的标签,或批准的产品说明书。在一些实施方案中,制备含有配制在相容的药物载体中的本文提供的化合物的组合物,将其置于适当的容器中,并标记用于治疗指定的病况。
方法
本公开内容的实施方案通过抑制宿主物种中的NEK7可用作NLRP3炎性体的调节剂。因此,结构(I)的化合物还可用于治疗由效应物信号传导分子如IL-β和IL-18介导的病况。
宿主或患者可以属于任何哺乳动物物种,例如灵长类物种,特别是人;啮齿类,包括小鼠、大鼠和仓鼠;兔子;马、牛、狗、猫等。动物模型对于实验研究是令人感兴趣的,提供了治疗人类疾病的模型。
在一个实施方案中,本公开内容可用作NLRP3炎性体活化机制的抑制剂。因此,结构(I)的化合物也可用于治疗由宿主物种中的活化引起的病况。
在另一个实施方案中,结构(I)的化合物可用作NLRP3(蛋白质)-NEK7(蛋白质)相互作用的抑制剂。因此,所述化合物还可用于治疗由宿主物种中的NLRP3-NEK7的缔合引起的病况。
在某些实施方案中,结构(I)的化合物可用于治疗由选自IL-β、IL-18和半胱天冬酶-1的效应物介导的人病况。
本公开内容的实施方案还涉及根据结构(I)的化合物和/或其生理学上可接受的盐用于预防性或治疗性治疗和/或监测由NLRP3炎症体活性引起、介导和/或调节的疾病的用途。此外,本发明的实施方案涉及根据结构(I)的化合物和/或其生理学上可接受的盐用于制备用于预防性或治疗性治疗和/或监测由NLRP3炎症体活性引起、介导和/或调节的疾病的药物的用途。在某些实施方案中,本发明提供了根据结构I的化合物或其生理学上可接受的盐用于制备用于预防性或治疗性治疗NLRP3介导的病症的药物的用途。
在另一个实施方案中,本公开内容涉及通过向有需要的患者施用治疗有效量的结构(I)的化合物来治疗由NLRP3炎性体介导的炎性疾病或病况的方法。
在某些实施方案中,可用结构(I)的化合物治疗的疾病包括II型糖尿病、动脉粥样硬化、阿尔茨海默病、衰老、脂肪肝、代谢综合征、哮喘、银屑病、肥胖、由感染引起的急性和慢性组织损伤、痛风、关节炎、肠炎、肝炎、腹膜炎、硅肺病、UV诱导的皮肤晒伤、接触性超敏反应、败血症、癌症、神经变性疾病、多发性硬化症和穆-韦二氏综合征(Muckle-Wellssyndrome)。
在某些其它实施方案中,结构(I)的化合物用于治疗病症或疾病的方法中,所述病症或疾病选自自身免疫性疾病、炎性病症、心血管疾病、神经变性病症、细菌和病毒感染、过敏症、哮喘、胰腺炎、多器官衰竭、肾病、血小板聚集、移植、精子活力、红血球缺乏症、移植排斥、肺损伤、呼吸道疾病、缺血性病况和癌症。在一些更具体的实施方案中,结构(I)的化合物用于治疗骨髓增生异常综合征(MDS)的方法中。
在一些实施方案中,可用结构(I)的化合物治疗的与NEK7相关的病症选自类风湿性关节炎、银屑病关节炎、骨关节炎、系统性红斑狼疮、狼疮肾炎、强直性脊柱炎、骨质疏松症、系统性硬化症、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、隐热蛋白相关周期性综合征、施尼茨勒综合征、系统性幼年特发性关节炎、成年发病型斯蒂尔氏病、痛风、假性痛风、SAPHO综合征、卡斯尔曼病、败血症、中风、动脉粥样硬化、乳糜泻、DIRA(IL-1受体拮抗剂缺乏)、阿尔茨海默病、帕金森病和癌症。
本文还包括治疗方法,其中至少一种结构(I)的化合物与抗炎剂或治疗剂组合施用。抗炎剂包括但不限于NSAID,非特异性和COX-2特异性的环加氧酶抑制剂、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。NSAID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。
NSAID的实例还包括COX-2特异性抑制剂,例如塞来昔布、伐地昔布、罗美昔布和/或依托昔布。
在一些实施方案中,抗炎剂是水杨酸盐。水杨酸盐包括但不限于乙酰水杨酸或阿司匹林、水杨酸钠、以及胆碱和水杨酸镁。
抗炎剂也可以是皮质类固醇。例如,皮质类固醇可以是可的松、地塞米松、甲基强的松龙、强的松龙、强的松龙磷酸钠或强的松。
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。
本公开内容还包括其中抗炎剂是代谢抑制剂的实施方案,例如二氢叶酸还原酶抑制剂,例如甲氨蝶呤或二氢乳清酸脱氢酶抑制剂,例如来氟米特。
治疗剂还可以包括用于疼痛和炎症的药剂,例如组胺和组胺拮抗剂、缓激肽和缓激肽拮抗剂、5-羟基色胺(血清素)、通过膜磷脂的选择性水解的产物的生物转化产生的脂质物质、类花生酸、前列腺素、血栓烷、白细胞三烯、阿司匹林、非甾体抗炎剂、止痛解热剂、抑制前列腺素和血栓烷合成的药剂、诱导型环加氧酶的选择性抑制剂、诱导型环加氧酶-2的选择性抑制剂、内分泌物、旁分泌激素、生长抑素、胃泌素、介导参与体液和细胞免疫反应的相互作用的细胞因子、脂质衍生的内分泌物、类花生酸、β-肾上腺素能激动剂、异丙托铵、糖皮质激素、甲基黄嘌呤、钠通道阻断剂、阿片受体激动剂、钙通道阻断剂、膜稳定剂和白细胞三烯抑制剂。
本公开内容的其它实施方案涉及其中至少一种抗炎化合物是抗单克隆抗体(例如,依库珠单抗或派克珠单抗)、TNF拮抗剂(例如,依那西普或英夫利昔单抗,其是抗TNFα单克隆抗体)的组合。
与结构(I)的化合物组合使用的治疗剂还可以包括抑制NLRP3炎症体的活化的小分子化合物,例如MCC950、莱菔硫烷、异甘草素、β-羟基丁酸酯、氟芬那酸、甲芬那酸、3,4-亚甲二氧基-β-硝基苯乙烯(MNS)和小白菊内酯。
本公开内容的其它实施方案还涉及其中至少一种活性剂是免疫抑制化合物的组合,所述免疫抑制化合物例如选自甲氨蝶呤、来氟米特、环孢菌素、他克莫司、硫唑嘌呤和霉酚酸酯的免疫抑制化合物。
所公开的结构(I)的化合物可以与其它已知的治疗剂(包括抗癌剂)组合施用。如本文使用,术语“抗癌剂”涉及为治疗癌症而向患有癌症的患者施用的任何药剂。
在一些实施方案中,抗癌剂属于以下类别:
烷基化剂:例如六甲嘧胺、苯达莫司汀、白消安、卡莫司汀、苯丁酸氮芥、氮芥、环磷酰胺、达卡巴嗪、异环磷酰胺、英丙舒凡、托西酸酯、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、曲奥舒凡、二氯甲基二乙胺、卡波醌;阿帕齐醌、福莫司汀、谷磷酰胺、异环磷酰胺、哌泊溴烷、曲磷胺、乌拉莫司汀、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、沙铂;
DNA改变剂:例如氨柔比星、比生群、地西他滨、米托蒽醌、丙卡巴肼、曲贝替定、氯法拉滨;安吖啶、布洛林星、匹蒽醌(pixantrone)、拉莫斯汀1,3;
拓朴异构酶抑制剂:例如依托泊苷、伊立替康、雷佐生、索布佐生、替尼泊苷、拓朴替康;氨萘非特、贝洛替康、依利醋铵、伏利拉辛;
微管调节剂:例如卡巴他赛、多西他赛、艾瑞布林、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;福布瑞林、替司他赛;
抗代谢物: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、巯基嘌呤、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、放线菌素D、多柔比星、表柔比星、伊达比星、左旋咪唑、米替福新、丝裂霉素C、罗米地辛、链脲霉素、戊柔比星、净司他丁、佐柔比星、道诺霉素、普卡霉素;阿柔比星、培洛霉素、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、卡鲁睾酮、氯烯雌醚、地加瑞克、地塞米松、雌二醇、氟可龙、氟甲睾酮、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、萘法瑞林、诺龙、尼鲁米特、奥曲肽、泼尼松龙、雷洛昔芬、他莫昔芬、促甲状腺素α、托瑞米芬、曲洛司坦、曲普瑞林、己烯雌酚;阿考比芬、达那唑、地洛瑞林、环硫雄醇、奥特罗那、恩杂鲁胺1,3;
芳香酶抑制剂:例如氨鲁米特、阿那曲唑、依西美坦、法屈唑、来曲唑、睾内酯;福美司坦;
小分子激酶抑制剂:例如克唑替尼、达沙替尼、埃罗替尼、伊马替尼、拉帕替尼、尼洛替尼、帕唑帕尼、瑞格非尼、鲁索替尼、索拉非尼、舒尼替尼、凡德他尼、维莫非尼、伯舒替尼、吉非替尼、阿昔替尼;阿法替尼、阿立塞替(alisertib)、达拉非尼、达可替尼、戴那昔布(dinaciclib)、多韦替尼、恩扎妥林(enzastaurin)、尼达尼布、乐伐替尼、立尼法尼(linifanib)、林斯替尼(linsitinib)、马赛替尼、米哚妥林、莫替沙尼、奈拉替尼(neratinib)、奥兰替尼(orantinib)、哌立福新、帕纳替尼、拉多替尼(radotinib)、利戈舍替布、替法米布(tipifamib)、替瓦替尼(tivantinib)、替沃扎尼(tivozanib)、曲美替尼(trametinib)、曲美替尼、派吗替布(pimasertib)、布立尼布丙胺酸酯、西地尼布。
在一些实施方案中,与本文所述的化合物联合施用的药物包括通过吸入有效递送的任何合适的药物,例如镇痛剂,例如可待因、二氢吗啡、麦角胺、芬太尼或吗啡;心绞痛制剂,例如地尔硫卓;抗过敏药,例如色甘酸盐、酮替芬或奈多罗米;抗感染药,例如头孢菌素、青霉素、链霉素、磺酰胺、四环素或戊烷脒;抗组胺剂,例如美沙吡林;抗炎药,例如倍氯米松、氟尼缩松、布地奈德、替泼尼旦、曲安奈德或氟替卡松;镇咳药,例如诺思卡品;支气管扩张剂,例如麻黄碱、肾上腺素、非诺特罗、福莫特罗、异丙肾上腺素、奥西那林、苯肾上腺素、苯丙醇胺、吡布特罗、茶丙特罗、利米特罗、沙丁胺醇、沙美特罗、特布他林、异他林、妥洛特罗、奥西那林或(-)-4-氨基-3,5-二氯-α-[[[6-[2-(2-吡啶基)乙氧基]己基]-氨基]甲基]苯甲醇;利尿剂,例如阿米洛利;抗胆碱能药,例如异丙托铵、阿托品或氧托品;激素,例如可的松,氢化可的松或泼尼松龙;黄嘌呤,例如,氨茶碱、胆茶碱、赖氨酸茶碱或茶碱;以及治疗性蛋白质和肽,例如胰岛素或胰高血糖素。本领域技术人员将清楚,在适当的情况下,药物以盐的形式(例如,作为碱金属或胺盐或作为酸加成盐)或作为酯(例如,低级烷基酯)或作为溶剂化物(例如,水合物)使用,以优化药物的活性和/或稳定性。
本文公开的药剂或其它合适的药剂根据所治疗的病况施用。因此,在一些实施方案中,本公开内容的一种或多种化合物将与如上所述的其它药剂共同施用。当用于组合疗法时,本文所述的化合物与第二药剂同时或分开施用。这种联合施用可以包括在同一剂型中同时施用两种药剂,在分开的剂型中同时施用和分开施用。换而言之,本文所述的化合物和任何上述药剂可一起配制在相同剂型中并同时施用。或者,本公开内容的化合物和任何上述药剂可同时施用,其中两种药剂存在于单独的制剂中。在另一个替代方案中,本公开内容的化合物可以仅在上文描述的任何药剂之后施用,或反之亦然。在单独施用方案的一些实施方案中,本公开内容的化合物和上文所述的任何药剂以相隔几分钟、或相隔几小时、或相隔几天施用。
在一些实施方案中,结构(I)的化合物作为单一疗法施用。
为了鉴定信号转导或机制途径以及为了检测各种信号转导途径之间的相互作用,各科学家已经开发了合适的模型或模型系统,例如细胞培养模型和转基因动物的模型。为了确定信号转导级联中的某些阶段,可以利用相互作用的化合物来调节信号。本公开内容的实施方案的化合物还可以用作在动物和/或细胞培养模型中或在本申请中提及的临床疾病中测试NEK7依赖性信号转导途径的试剂。
本发明的实施方案的实施方案的方法可以在体外或体内进行。特定细胞对用结构(I)的化合物治疗的敏感性可以通过体外测试(无论是在研究过程中还是在临床应用中)特别确定。通常,将细胞培养物与各种浓度的化合物组合一段时间,所述时间段足以使活性剂抑制NEK7活性,通常为约1小时至1周。可以使用来自活检样品或细胞系的培养细胞进行体外处理。
在一些实施方案中,结构(I)的化合物抑制NEK7的IC50通过抑制50% NEK激酶活性所需的化合物浓度来确定。结构(I)的化合物显示IC50的效力值小于约5mM,优选小于约1mM,甚至更优选小于约0.100mM,如在实施例中进一步详细描述。
以下提供的实施例和制剂进一步说明和例示本公开内容的化合物以及制备和测试此类化合物的方法。应理解,本公开内容的范围不以任何方式受以下实施例和制剂的范围限制。在以下实施例中,并且在整个说明书和权利要求书中,除非另外说明,具有单个立构中心的分子作为外消旋混合物存在。除非另外说明,否则具有两个或更多个立构中心的那些分子作为非对映异构体的外消旋混合物存在。单一对映异构体/非对映异构体可以通过本领域技术人员已知的方法获得。
实施例
出于示例性目的提供以下实施例。
一般程序
在配备有BBFO探针的Bruker NEO光谱仪上在400MHz下记录所有质子NMR实验。氘化溶剂含有小于0.05%v/v四甲基硅烷,其用作参考信号(设定在0.00ppm)。当氘化溶剂不含四甲基硅烷时,按照公开的指导原则(J.Org.Chem.1997,62(21),7512-7515)将残余未氘化溶剂峰用作参考信号。化学位移以百万分率(ppm,δ单位)表示。偶合常数以赫兹(Hz)为单位。拆分图案描绘了明显的多峰性且指定为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)。
在具有G6125 MS探测器的Agilent Technologies UHPLC 1290 Infinity II上进行LC/MS分析。
使用标准方案通过Anton Paar GmbH用Monowave 300进行微波反应。
NEK7酶分测定
酪蛋白底物(来自牛乳,α、β和κ酪蛋白的水解和部分去磷酸化混合物,获自SigmaAldrich,目录号#C4765,在蒸馏水中稀释至最终浓度1mg/mL)和全长重组人NEK7(使用N-末端GST标签由Sf9昆虫细胞中的杆状病毒表达,获自SignalChem,目录号#N09-10 G,0.1μg/μL)在测定缓冲液(20mM Hepes pH 7.5,10mM MgCl2,1mM EGTA,0.02% Brij35,0.02mg/mlBSA,0.1mM Na3VO4,2mM DTT,1%DMSO)中混合。通过声学技术(Echo550;纳升范围)将感兴趣的化合物(在DMSO中连续3倍稀释,为10μM至0.5nM)或媒介物(1%DMSO)分配至激酶反应混合物中。在室温下孵育20分钟后,通过添加[33P]-ATP(比活性10μCi/μl)引发激酶反应,并且将混合物在室温下孵育2小时。然后,通过将反应混合物点样于磷酸纤维素P81纸上来停止反应。在洗涤后,量测P81纸的放射性,并且激酶活性数据表示为与媒介物反应相比测试样品中的剩余激酶活性百分比。使用Prism(GraphPad Software)获得IC50值和曲线拟合。
IL-1β释放测定
将约150万个THP-1细胞接种于6孔TC板的各个孔中,并且与40nM PMA一起在RPMI(10% FBS,1% Penstrep)中孵育24小时。然后去除培养基并且将细胞在RPMI(10% FBS,1% Penstrep)中静置24小时,此后去除培养基并且将细胞用RPMI(5% FBS)中的各种浓度的感兴趣的化合物(通常在RPMI+5%FBS中连续3倍稀释,浓度范围为1μM至0.5nM)预处理2小时。再次去除培养基,用250ng/mL LPS和感兴趣的化合物(浓度如上)在RMPI(5% FBS)中孵育细胞2小时。最后一次去除培养基,将细胞与20μM尼日利亚菌素和感兴趣的化合物(浓度如上)在Opti-MEM中孵育30分钟。然后收集细胞培养基并且使用JESS仪器(ProteinSimple)和标准方案测定裂解的IL-1β的量。裂解Il-1β抗体获自Cell Signaling(目录号#83186S),并且在抗体稀释剂2中以1:20稀释度使用。Protein Simple 1x抗兔HRP二级抗体与Protein Simple鲁米诺和过氧化物一起用于化学发光检测。初级抗体孵育时间从30分钟增加至60分钟。
缩写:
℃(摄氏度);1H NMR(质子核磁共振);CAN(乙腈);Boc(叔丁氧羰基);DCM(二氯甲烷);DIPEA(N,N-二异丙基乙胺);DMAP(4-二甲胺基吡啶);DMF(N,N-二甲基甲酰胺);DMSO-d6(氘化二甲亚砜);eq(当量);EtOAc(乙酸乙酯);g(公克);h(小时);HPLC(高效液相层析);LCMS(液相层析质谱);MeOH(甲醇);mg(毫克);min(分钟);mL(毫升);mmol(毫莫耳);n-BuOH(1-丁醇);Pd(PPh3)4(钯-四(三苯基膦));PdCl2(dppf)([1,1'-双(二苯基膦基)二茂铁]二氯化钯(II));TBAF(四正丁基氟化铵);TBDMS(叔丁基二甲基硅基);TFA(三氟乙酸);THF(四氢呋喃);TLC(薄层色谱法)。
合成中间体的制备
中间体A
4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶
在0℃下将N-碘琥珀酰亚胺(1.465g,6.51mmol)添加至4-氯-7H-吡咯并[2,3-d]嘧啶(1.000g,6.51mmol)在DMF(10mL)中的搅拌溶液中并且将所得混合物在25℃下搅拌12小时。在反应完成(如通过TLC指示)后,将反应混合物倒入冰冷水(100mL)中并在25℃下搅拌15分钟。将所得固体过滤,用水(2×25mL)洗涤,并且干燥,以得到呈灰白色固体的标题化合物(1.7g,93%产率)。1H NMR(400MHz,DMSO-d6)δ=12.96(bs,1H),8.60(s,1H),7.95(d,J=2.40Hz,1H);LCMS:279.9[M+H]。
中间体B1
4-氯-7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶
将乙酸铜(II)(0.650g,3.58mmol)、2,2'-联吡啶(0.559g,3.58mmol)和碳酸氢钠(0.601g,7.16mmol)添加至4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(A1,1.000g,3.58mmol)和环丙基硼酸(0.615g,7.16mmol)在二氯乙烷(10mL)中的溶液中,并且将所得混合物在70℃在氧气氛下搅拌12小时。在反应完成后(如TLC所示),通过硅藻土垫过滤反应混合物,然后用DCM(2×20mL)清洗。将合并的滤液用水(20mL)和盐水(25mL)洗涤,经Na2SO4干燥,过滤,并在减压下浓缩,以得到粗材料,将其通过快速色谱法(硅胶230-400目,用石油醚中的15%EtOAc洗脱)纯化,得到呈灰白色固体的标题化合物(0.7g,61%产率)。1H NMR(400MHz,DMSO-d6)δ=8.67(s,1H),7.96(s,1H),3.63-3.69(m,1H),1.06-1.10(m,4H)。LCMS:319.9[M+H]。
中间体B2
4-氯-5-碘-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶
将K2CO3(0.40g,2.86mmol)和3-碘氧杂环丁烷(0.32g,1.71mmol)添加至4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(A,0.40g,1.43mmol)在DMF(5mL)中的溶液中,并且将所得混合物在密封管中在90℃搅拌16小时。在反应完成(如通过TLC指示)后,将反应混合物倒入碎冰(50g)中并且搅拌15分钟。将所得固体过滤,用水(2×5mL)洗涤,并且干燥,以得到呈灰白色固体的标题化合物(0.2g,42%产率)。LCMS:335.7[M+H]。
中间体B3
1-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)-2-甲基丙烷-2-醇
将NaH2PO4(0.105g,0.877mmol)添加至4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(A1,0.250g,0.895mmol)、2,2-二甲基环氧乙烷(0.157ml,1.762mmol)和K2CO3(0.121g,0.877mmol)在ACN(3mL)和水(1mL)中的混合物中。将所得混合物在密封管中在150℃下进行微波照射1小时。在反应完成(如TLC所示)后,将反应混合物在减压下浓缩,并且将所得粗材料通过快速色谱法(硅胶230-400目,用在石油醚中的18% EtOAc洗脱)纯化,得到呈淡棕色固体的标题化合物(0.1g,17%产率)。LCMS:351.9[M+H]。
中间体B4
4-氯-5-碘-7-(吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶
将三乙胺(0.905g,8.95mmol)和乙酸铜(II)(0.975g,5.37mmol)添加至4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(A,1.000g,3.58mmol)和3-吡啶基硼酸(0.880g,7.16mmol)在DCM(25mL)中的溶液中,并且将所得混合物在40℃在氧气氛下搅拌40小时。在反应完成后(如LCMS所示),通过硅藻土垫过滤反应混合物,然后用DCM(2×50mL)清洗。将合并的滤液用水(10mL)和盐水(10mL)洗涤,经Na2SO4干燥,过滤,并且在减压下浓缩,以得到粗材料。将其与在石油醚中的30%二乙醚在25℃搅拌30分钟,过滤,并且干燥,以得到呈棕色固体的标题化合物(0.4g,29%产率)。1H NMR(400MHz,DMSO-d6)δ=9.05(bs,1H),8.73(s,1H),8.67(bs,1H),8.48(s,1H),8.26-8.28(m,1H),7.64-7.67(m,1H)。LCMS:356.8[M+H]。
中间体B5
4-氯-5-碘-7-(吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶
通过按照对于B4所述的类似程序,从4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(A,0.50g,1.789mmol)和4-吡啶基硼酸(0.44g,3.580mmol)开始获得标题化合物,并且作为棕色固体获得(0.21g,29%产率)。LCMS:356.9[M+H]。
中间体B6
4-氯-5-碘-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶
如第WO 2017/220477号PCT公开中报道制备标题化合物。
中间体B7
7-(3-(苄氧基)环丁基)-4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶
将Cs2CO3(0.583g,1.789mmol)和甲磺酸3-(苄氧基)环丁酯(如第WO 2019/092170号PCT公开中报道制备,0.459g,1.789mmol)添加至4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(A,0.250g,0.895mmol)在DMF(5mL)中的溶液中,并且将所得混合物在90℃搅拌12小时。在反应完成后(如TLC所示),将反应混合物倒入冰水(50mL)中并用乙酸乙酯(2×30mL)萃取。将合并的有机萃取物用Na2SO4干燥,过滤,并在减压下浓缩,得到粗材料,将其通过快速色谱法(硅胶230-400目,用石油醚中的30%EtOAc洗脱)纯化,得到呈无色胶状物的标题化合物(0.14g,31%产率)。LCMS:440.0[M+H]。
中间体B8
2-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇
将K2CO3(0.742g,5.37mmol)和2-溴乙烷-1-醇(0.537g,4.29mmol)添加至4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(A,1.000g,3.58mmol)在DMF(6mL)中的溶液中,并且将所得悬浮液在80℃搅拌2小时。在反应完成后(如TLC所示),将反应混合物倒入碎冰(25g)中。将所得固体过滤,用水(20mL)洗涤,并且干燥,以得到呈黄色固体的标题化合物(0.84g,64%产率)。LCMS:323.9[M+H]。
中间体B9
4-氯-1-环丙基-3-碘-1H-吡咯并[3,2-c]吡啶
步骤1:4-氯-1-环丙基-1H-吡咯并[3,2-c]吡啶的合成
将三乙胺(0.332g,3.280mmol)、乙酸铜(II)(0.298g,1.638mmol)和分子筛(粉末状,0.050g)添加至4-氯-1H-吡咯并[3,2-c]吡啶(0.250g,1.638mmol)和环丙基硼酸(0.279g,3.280mmol)在DMF(10mL)中的溶液中,并且将所得悬浮液在密封管中在60℃下搅拌12小时。在反应完成后(如TLC所示),通过硅藻土垫过滤反应混合物,然后用EtOAc清洗。将合并的滤液在减压下浓缩,得到粗材料,将其通过Isolera(硅胶230-400目,用石油醚中的20% EtOAc洗脱)纯化,得到呈黄色固体的标题化合物(0.19g,59%产率)。1H NMR(400MHz,DMSO-d6)δ=8.04(d,J=5.6Hz,1H),7.56-7.60(m,2H),6.52-6.53(m,1H),3.55-3.58(m,1H),1.00-1.13(m,4H)。LCMS:193.1[M+H]。
步骤2:4-氯-1-环丙基-3-碘-1H-吡咯并[3,2-c]吡啶的合成
将N-碘琥珀酰亚胺(0.350g,1.557mmol)添加至4-氯-1-环丙基-1H-吡咯并[3,2-c]吡啶(0.200g,1.038mmol)在DMF(5mL)中的溶液中,并且将所得混合物在80℃下搅拌1小时。在反应完成后(如LCMS所示),将反应混合物倒入碎冰(25g)中并用EtOAc(2×25mL)萃取。将合并的有机萃取物用盐水洗涤,经Na2SO4干燥,过滤,并在减压下浓缩,得到标题产物(0.2g),其在未经进一步纯化的情况下使用。LCMS:319.0[M+H]。
中间体C1
7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺
将4-氯-7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶(B1,1.00g,2.191mmol)和氢氧化铵(25%在水中,5mL)的混合物在150℃下进行微波照射1小时。在反应完成后(如TLC所示),将反应混合物在减压下浓缩,得到呈灰白色固体的标题化合物(0.75g,80%产率)。1H NMR(400MHz,DMSO-d6)δ=8.12(s,1H),7.39(s,1H),6.57(bs,2H),3.48-3.54(m,1H),0.97-1.01(m,4H)。LCMS:301.0[M+H]。
中间体C2
5-碘-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
将标题化合物经由关于C1所述的类似程序,从4-氯-5-碘-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶(B2,0.5g,1.49mmol)和氢氧化铵水溶液(25%在水中,2.5mL)开始来制备,并且作为淡棕色固体获得(0.27g,58%产率)。LCMS:316.8[M+H]。
中间体C3
1-(4-氨基-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)-2-甲基丙烷-2-醇
按照关于C1所述的类似程序,从1-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)-2-甲基丙烷-2-醇(B3,0.1g,0.284mmol)和氢氧化铵(25%在水中,0.5mL)开始,获得呈灰白色固体的标题化合物(0.08g,85%产率)。1H NMR(400MHz,DMSO-d6)δ=8.12(s,1H),7.38(s,1H),4.81(s,1H),4.04(s,2H),1.03(s,6H)。LCMS:333.0[M+H]。
中间体C4
5-碘-7-(吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
将氢氧化铵(25%在水中,1mL)添加至4-氯-5-碘-7-(吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶(B4,0.30g,0.841mmol)在二噁烷(10mL)中的溶液中,并且将所得混合物在150℃下进行微波照射2小时。在反应完成后(如LCMS所示),将反应混合物减压浓缩,得到粗材料,将其用甲基叔丁基醚洗涤并干燥,得到呈灰白色固体的标题化合物(0.21g,63%产率)。LCMS:337.8[M+H]。
中间体C5
5-碘-7-(吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
按照关于C4所述的类似程序,从4-氯-5-碘-7-(吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶(B5,0.21g,0.589mmol)和氢氧化铵(25%在水中,1mL)开始,获得标题化合物,并且作为灰白色固体获得(0.16g,69%产率)。LCMS:337.9[M+H]。
中间体C6
5-碘-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
如第WO 2017/220477号PCT公开中报道制备标题化合物。
中间体C7
7-(3-(苄氧基)环丁基)-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于C4所述的类似程序,从7-(3-(苄氧基)环丁基)-4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(B7,0.140g,0.318mmol)和氢氧化铵(25%在水中,1.4mL)开始获得标题化合物,并且作为灰白色固体获得(0.06g,45%产率)。LCMS:421.1[M+H]。
中间体C8
5-碘-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-4-胺
如第WO 2014/184069A1号PCT公开中报道制备标题化合物。
中间体C9
2-(4-氨基-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇
通过按照关于C4所述的类似程序,从2-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇(B8,0.84g,2.61mmol)和氢氧化铵(25%在水中,8mL)开始获得标题化合物,并且作为灰白色固体获得(0.94g,69%产率)。LCMS:305.0[M+H]。
中间体C10
7-环丁基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺
如第WO 2016/075224号PCT公开中报道制备标题化合物。
中间体C11
5-碘-7-(1-甲基吡咯烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
如第WO 2016/075224号PCT公开中报道制备标题化合物。
中间体D1
5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
将7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.160g,0.533mmol)、2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.190g,0.800mmol)和K2CO3(0.221g,1.599mmol)在1,4-二噁烷(1mL)和水(0.3mL)中的混合物用N2吹扫10分钟。然后添加Pd(PPh3)4(0.062g,0.053mmol),并且将反应混合物在100℃下搅拌12小时。在反应完成后(如TLC所示),通过硅藻土垫过滤混合物,然后用EtOAc(2x 10mL)清洗。将合并的滤液在减压下浓缩,得到粗材料,将其通过快速色谱法(硅胶230-400目,用DCM中的3%MeOH洗脱)纯化,得到呈黄色固体的标题化合物(0.110g,73%产率)。1H NMR(400MHz,DMSO-d6)δ=8.14(s,1H),7.13(s,1H),7.05-7.09(m,1H),6.95-6.98(m,1H),6.82-6.86(m,1H),6.10(bs,2H),5.22(bs,2H),3.52-3.58(m,1H),1.00-1.04(m,4H)。LCMS:284.1[M+H]。
中间体D2
5-(4-氨基苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步骤1:5-(4-硝基苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
将标题化合物经由关于D1所述的类似程序,从4-氯-5-碘-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶(C2,0.252g,0.797mmol)和(4-硝基苯基)硼酸(0.200g,1.198mmol)开始来制备,并且作为淡棕色固体获得(0.143g,58%产率)。LCMS:312.1[M+H]。
步骤2:5-(4-氨基苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
将铁粉(0.251g,4.5mmol)和氯化铵(0.240g,4.5mmol)添加至5-(4-硝基苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(0.14g,0.45mmol)在乙醇(5mL)和水(2mL)中的溶液中,并且将所得混合物在80℃搅拌3小时。在反应完成后(如TLC所示),通过硅藻土垫过滤混合物,然后用EtOAc(2x 5mL)清洗。将合并的滤液在减压下浓缩,得到残余物,将其溶解在EtOAc(25mL)中,用盐水(5mL)洗涤,经Na2SO4干燥,过滤,并且在减压下浓缩,得到呈棕色固体的标题化合物(0.12g,定量产率),其在未经进一步纯化的情况下使用。LCMS:281.9[M+H]。
中间体D3
1-(4-氨基-5-(4-氨基-3-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)-2-甲基丙烷-2-醇
通过关于D1所述类似的方法,从1-(4-氨基-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)-2-甲基丙烷-2-醇(C3,0.100g,0.301mmol)和2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.086g,0.361mmol)开始制备标题化合物,并且作为淡黄色胶状物获得(0.05g,53%产率)。LCMS:316.1[M+H]。
中间体D4
5-(4-氨基苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
步骤1:7-环丙基-5-(4-硝基苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
通过按照关于D1所述的类似程序,从7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.18g,0.60mmol)和(4-硝基苯基)硼酸(0.12g,0.72mmol)开始获得标题化合物,并且作为浅棕色固体获得(0.10g,56%产率)。1H NMR(400MHz,DMSO-d6)δ=8.28-8.32(m,2H),8.21(s,1H),7.77(s,1H),7.70-7.73(m,2H),7.55(s,1H),5.69(bs,2H),3.61-3.64(m,1H),1.04-1.09(m,4H)。LCMS:296.1[M+H]。
步骤2:5-(4-氨基苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
按照关于D2的步骤2所述的类似方法,从7-环丙基-5-(4-硝基苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(0.10g,0.33mmol)和Fe/NH4Cl开始来获得标题化合物,并且作为棕色胶状物获得(0.08g,90%产率),其在未经进一步纯化的情况下使用。1H NMR(400MHz,DMSO-d6)δ=8.13(s,1H),7.04-7.11(m,2H),7.04(s,1H),6.63-6.67(m,2H),6.05(bs,2H),5.27(bs,2H),3.51-3.57(m,1H),0.99-1.04(m,4H)。LCMS:266.0[M+H]。
中间体D5
5-(4-氨基-2-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D1所述的类似程序,从7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.21g,0.69mmol)和3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.20g,0.83mmol)开始获得标题化合物,并且作为淡黄色胶状物获得(0.15g,76%产率)。LCMS:284.1[M+H]。
中间体D6
5-(6-氨基吡啶-3-基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
步骤1:7-环丙基-5-(6-硝基吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
通过按照关于D1描述的类似程序,从7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.28g,0.94mmol)和2-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶(0.28g,1.13mmol)开始来获得标题化合物,并且作为浅棕色固体获得(0.16g,57%产率)。1H NMR(400MHz,DMSO-d6)δ=8.73(d,J=2.0Hz,1H),8.39(d,J=8.8Hz,1H),8.23(s,1H),8.17-8.20(m,1H),7.67(s,1H),6.49(bs,2H),3.61-3.67(m,1H),1.06-1.09(m,4H)。LCMS:297.1[M+H]。
步骤2:5-(6-氨基吡啶-3-基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
通过按照关于D2的步骤2所述的类似程序,从7-环丙基-5-(6-硝基吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(0.16g,0.54mmol)和Fe/NH4Cl开始来获得标题化合物,并且作为淡棕色固体获得(0.1g,70%产率),其在未经进一步纯化的情况下使用。LCMS:267.0[M+H]。
中间体D7
5-(4-氨基环己-1-烯-1-基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
步骤1:(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)环己-3-烯-1-基)氨基甲酸叔丁酯的合成
将K2CO3(0.318g,2.299mmol)添加至7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(Cl,0.230g,0.766mmol)和(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)环己-3-烯-1-基)氨基甲酸叔丁酯(0.372g,1.150mmol)在二噁烷(1mL)和水(0.3mL)中的溶液中。将溶液用N2吹扫10分钟,然后添加Pd(PPh3)4(0.044g,0.038mmol),并且将所得混合物在100℃下进行微波照射1小时。在反应完成后(如TLC所示),通过硅藻土垫过滤混合物,然后用EtOAc(2x 10mL)清洗。将合并的滤液在减压下浓缩,得到粗材料,将其通过制备型HPLC(基于质量,用乙酸铵在水和ACN中的梯度洗脱)纯化,得到呈淡黄色胶状物的标题产物(0.18g,62%产率)。LCMS:370.2[M+H]。
步骤2:5-(4-氨基环己-1-烯-1-基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
在0℃下,将TFA(0.012g,0.108mmol)添加至(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)环己-3-烯-1-基)氨基甲酸叔丁酯(0.040g,0.108mmol)在DCM(2mL)中的溶液中,并且将所得溶液在室温下搅拌12小时。在反应完成后(如TLC所示),将反应混合物在减压下浓缩,得到呈棕色胶状物的标题产物(0.029g),其在未经进一步纯化的情况下使用。LCMS:270.1[M+H]。
中间体D8
5-(4-氨基-3-氟苯基)-7-(吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
将5-碘-7-(吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(C4,0.160g,0.475mmol)、2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.169g,0.712mmol)和K2CO3(0.131g,0.949mmol)在二噁烷(5mL)、水(2mL)和乙醇(3mL)中的混合物用N2吹扫10分钟。添加PdCl2(dppf)(0.017g,0.024mmol),并且将所得混合物在100℃下进行微波照射1小时。在反应完成后(如LCMS所示),通过硅藻土垫过滤反应混合物,然后用EtOAc(5mL)清洗。将合并的滤液在减压下浓缩,得到残余物,将其溶于EtOAc(50mL),用水(5mL)和盐水(5mL)洗涤,经Na2SO4干燥,过滤并且在减压下浓缩。通过GRACE(硅胶230-400目,用DCM中的4%MeOH洗脱)纯化所得粗材料,得到呈棕色固体的标题化合物(0.2g,70%产率)。LCMS:321.0[M+H]。
中间体D9
5-(4-氨基-3-氟苯基)-7-(吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
按照关于D8所述的类似程序,从5-碘-7-(吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(C5,0.160g,0.475mmol)和2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.169g,0.712mmol)开始来获得标题化合物,并且作为淡黄色胶状物获得(0.08g,51%产率)。LCMS:321.0[M+H]。
中间体D10
5-(4-氨基-3-氟苯基)-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D8所述的类似程序,从5-碘-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(C6,0.180g,0.504mmol)和2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.131g,0.554mmol)开始来获得标题化合物,并且作为棕色胶状物获得(0.15g,80%产率)。LCMS:341.1[M+H]。
中间体D11
5-(4-氨基-3-甲基苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D8所述的类似程序,从7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.250g,0.833mmol)和2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.214g,0.916mmol)开始来获得标题化合物,并且作为棕色胶状物获得(0.13g,56%产率)。LCMS:280.1[M+H]。
中间体D12
5-(4-氨基-3-氟苯基)-7-(3-(苄氧基)环丁基)-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D8所述的类似程序,从7-(3-(苄氧基)环丁基)-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C7,0.060g,0.143mmol)和2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.037g,0.157mmol)开始来获得标题化合物,并且作为棕色固体获得(0.03g,53%产率)。LCMS:404.2[M+H]。
中间体D13
步骤1:7-环丙基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
将乙酸钾(0.245g,2.499mmol)添加至7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.250g,0.833mmol)和双(频哪醇根合)二硼(0.317g,1.250mmol)在DMSO(5mL)中的溶液中,并且将所得混合物用N2吹扫10分钟。然后添加PdCl2(dppf)(0.030g,0.042mmol),并且将反应混合物在85℃下搅拌2小时。在反应完成后,通过硅藻土垫过滤反应混合物,然后用DCM(2×20mL)清洗。将合并的滤液在减压下浓缩,得到呈黑色残余物的标题化合物,其在未经进一步纯化的情况下使用。LCMS:300.9[M+H]。
步骤2:5-(5-氨基-4-甲基吡啶-2-基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
通过按照关于D8描述的类似程序,从6-溴-4-甲基吡啶-3-胺(0.142g,0.759mmol)和7-环丙基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(0.251g,0.835mmol)开始来获得标题化合物,并且作为棕色胶状物获得(0.05g,13%产率)。LCMS:281.0[M+H]。
中间体D14
5-(5-氨基吡啶-2-基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D8所述的类似程序,从6-溴-4-甲基吡啶-3-胺(0.130g,0.751mmol)和7-环丙基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(中间体D13的步骤1,0.248g,0.827mmol)开始来获得标题化合物,并且作为棕色胶状物获得(0.03g,4.5%产率)。LCMS:267.0[M+H]。
中间体D15
5-(4-氨基-3,5-二氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D8所述的类似程序,从7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.500g,0.751mmol)和2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.425g,1.666mmol)开始来获得标题化合物,并且作为浅黄色固体获得(0.10g,19%产率)。LCMS:302.1[M+H]。
中间体D16
5-(4-氨基-2,5-二氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D8所述的类似程序,从7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.125g,0.417mmol)和2,5-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(如第WO 2017/172093号PCT公开报道制备,0.106g,4.17mmol)开始来获得标题化合物,并且作为浅黄色固体获得(0.05g,40%产率)。LCMS:302.1[M+H]。
中间体D17
5-(4-氨基-2,6-二氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D8所述的类似程序,从7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.055g,0.183mmol)和3,5-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(如第WO 2017/172093号PCT公开报道制备,0.056g,0.220mmol)开始来获得标题化合物,并且作为淡棕色胶状物获得(0.046g),其在未经进一步纯化的情况下使用。LCMS:301.9[M+H]。
中间体D18
1-(4-氨基-5-(6-氨基吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-7-基)-2-甲基丙烷-2-醇
通过按照关于D8描述的类似程序,从1-(4-氨基-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)-2-甲基丙烷-2-醇(C3,0.280g,0.733mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-胺(0.161g,0.733mmol)开始来获得标题化合物,并且作为黄色胶状物获得(0.12g,50%产率)。LCMS:299.1[M+H]。
中间体D19
5-(2-氨基嘧啶-5-基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D8所述的类似程序,从7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.25g,0.833mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)嘧啶-2-胺(0.184g,0.833mmol)开始来获得标题化合物,并且作为无色胶状物获得(0.08g,34%产率)。LCMS:268.2[M+H]。
中间体D20
(2-氨基-5-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)甲醇
通过按照关于D8所述的类似程序,从7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.200g,0.666mmol)和(2-氨基-5-(4,4,5,5-四甲基-1,3-二氧戊环-2-基)苯基)甲醇(如第WO 2011/130628号PCT公开报道制备,0.184g,0.733mmol)开始来获得标题化合物,并且作为浅黄色胶状物获得(0.025g,13%产率)。LCMS:296.0[M+H]。
中间体D21
2-氨基-5-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苄腈
通过按照关于D8所述的类似程序,从7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.250g,0.833mmol)和2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄腈(0.203g,0.833mmol)开始来获得标题化合物,并且作为黄色胶状物获得(0.13g,34%产率)。LCMS:291.2[M+H]。
中间体D22
5-(4-氨基-3-氟苯基)-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D8所述的类似程序,从5-碘-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-4-胺(C8,0.200g,0.629mmol)和2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.149g,0.629mmol)开始来获得标题化合物,并且作为淡棕色固体获得(0.12g,42%产率)。LCMS:302.2[M+H]。
中间体D23
2-(4-氨基-5-(4-氨基-3-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇
通过按照关于D8所述的类似程序,从2-(4-氨基-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇(C9,0.50g,1.644mmol)和2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.39g,1.644mmol)开始来获得标题化合物,并且作为棕色固体获得(0.3g,63%产率)。LCMS:288.1[M+H]。
中间体D24
5-(4-氨基-3-氟苯基)-7-环丁基-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D8所述的类似程序,从7-环丁基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C10,0.410g,1.305mmol)和2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.309g,1.305mmol)开始来获得标题化合物,并且作为棕色固体获得(0.18g,37%产率)。1H NMR(400MHz,DMSO-d6)δ=8.13(s,1H),7.51(s,1H),7.09-7.13(m,1H),6.98-7.01(m,1H),6.84-6.88(m,1H),6.21(bs,2H),5.14-5.26(m,3H),2.67-2.68(m,2H),2.38-2.39(m,2H),1.85-1.86(m,2H)。LCMS:298.0[M+H]。
中间体D25
5-(4-氨基-3-氯苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D8所述的类似程序,从7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.250g,0.833mmol)和2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.211g,0.833mmol)开始来获得标题化合物,并且作为黄色固体获得(0.03g,12%产率)。LCMS:300.1[M+H]。
中间体D26
5-(4-氨基-3-甲氧基苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D8所述的类似程序,从7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(C1,0.250g,0.833mmol)和2-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.208g,0.833mmol)开始来获得标题化合物,并且作为淡黄色胶状物获得(0.04g,16%产率)。LCMS:296.1[M+H]。
中间体D27
5-(4-氨基-3-氟苯基)-7-(1-甲基吡咯烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
通过按照关于D8所述的类似程序,从5-碘-7-(1-甲基吡咯烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(C11,0.155g,0.452mmol)和2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.107g,0.452mmol)开始来获得标题化合物,并且作为棕色固体获得(0.084g,27%产率)。LCMS:327.2[M+H]。
中间体E1-E25
用于合成氨基甲酸酯中间体E的一般程序:
在0℃下将吡啶(1.2当量)和氯甲酸苯酯(1.5当量)添加至胺(1.0当量)在THF(10体积)中的溶液中。使得反应混合物升温至25℃并且搅拌12小时。在反应完成后(如TLC所示),将混合物用EtOAc(10mL)稀释并用盐水(5mL)洗涤。将有机层经Na2SO4干燥,过滤,并且在减压下浓缩,得到粗材料,将其通过快速色谱法(硅胶230-400目,用石油中的10%至20%EtOAc)纯化,得到所需的氨基甲酸酯。
使用上述一般程序制备以下氨基甲酸酯:
用于合成氨基甲酸酯中间体E的所有胺均可商购,除了以下之外:
如Synthesis 2013,45,171–173中报道合成3-(1-(三氟甲基)环丙基)异噁唑-5-胺(E6的前体)和5-(1-(三氟甲基)环丙基)异噁唑-3-胺(E7的前体)。
分别由3,3,3-三氟-2,2-二甲基丙酸甲酯和2-氟-2-甲基丙酸甲酯合成3-(1,1,1-三氟-2-甲基丙-2-基)异噁唑-5-胺(E8的前体)和3-(2-氟丙-2-基)异噁唑-5-胺(E9的前体),随后进行Synthesis 2013,45,171–173中报道的程序。
如第WO 2010/036630号PCT公开中报道合成3-(1-((叔丁基二甲基甲硅烷基)氧基)-2-甲基丙烷-2-基)异噁唑-5-胺(E16的前体)。
如J.Med.Chem.2012,55(3),1082-1105中报道合成2-(5-氨基异噁唑-3-基)-2-甲基丙腈(E22的前体)和3-(1-(三氟甲基)环丁基)异噁唑-5-胺(E24的前体)。
如第WO 2013/104561号PCT公开中报道合成3-(((叔丁基二苯基甲硅烷基)氧基)甲基)异噁唑-5-胺(E23的前体)。
如第WO 2011/022473号PCT公开合成5-(1-(三氟甲基)环丁基)异噁唑-3-胺(E25的前体)。
3-(3-甲基氧杂环丁烷-3-基)异噁唑-5-胺(E14的前体)的合成:
将NH2OH·H2SO4(0.520g,3.16mmol)添加至3-(3-甲基氧杂环丁烷-3-基)-3-氧代丙腈(如第WO 2019/192962号PCT公开中报道制备,0.400g,2.87mmol)和氢氧化钠(0.126g,3.16mmol)在EtOH(10mL)和水(10mL)中的溶液。使用NaOH水溶液(1M)将所得混合物的pH调节至7.5,并且将反应混合物在80℃下搅拌15小时。反应完成后(如TLC所示),将反应混合物在减压下浓缩,得到残余物,将其溶于EtOAc(25mL),用水(10mL)洗涤,经Na2SO4干燥,过滤,并在减压下浓缩。通过快速色谱(硅胶230-400目,用石油醚中的30% EtOAc洗脱)纯化所得粗材料,得到呈浅棕色固体的标题产物(0.09g,20%产率)。1H NMR(400MHz,CDCl3)δ=5.21(s,1H),4.90-4.93(m,2H),4.56-4.59(m,2H),1.70(s,3H)。LCMS:155.1[M+H]。
3-(1-甲基环丁基)异噁唑-5-胺(E21的前体)的合成:
将NH2OH·H2SO4(0.699g,4.25mmol)添加至3-(1-甲基环丁基)-3-氧代丙腈(如第WO 2017/060874号PCT公开中报道制备,0.500g,3.86mmol)和氢氧化钠(0.170g,4.25mmol)在EtOH(10mL)和水(10mL)中的溶液中。使用NaOH水溶液(1M)将所得混合物的pH调节至7.5,并且将反应混合物在80℃下搅拌15小时。在反应完成后(如TLC所示),将反应混合物在减压下浓缩,得到残余物,将其置于DCM(25mL)中,用水(10mL)洗涤,经Na2SO4干燥,过滤,并在减压下浓缩。通过快速色谱法(硅胶230-400目,用石油醚中的40% EtOAc洗脱)纯化所得粗材料,得到呈灰白色固体的标题产物(0.110g,19%产率)。1H NMR(400MHz,CDCl3)δ=5.04(s,1H),2.43-2.49(m,2H),1.96-2.02(m,4H),1.50(s,3H)。LCMS:153.2[M+H]。
实施例的制备
用于合成实施例1至实施例62的一般脲形成程序
方法A-将三乙胺(2.0当量)添加至胺中间体D(1.0单量)和氨基甲酸酯中间体E(1.0当量)在THF(10体积)中的混合物中,并且将所得混合物在密封管中在60℃下搅拌12小时。在反应完成后(如LCMS所示),将反应混合物减压浓缩,得到粗材料,将其通过反相制备型HPLC纯化,得到所需产物。
方法B-将DMAP(0.05当量)和DIPEA(1.5当量)添加至胺中间体D(1.0当量)和氨基甲酸酯中间体E(1.0当量)在THF(10体积)中的溶液中,并且将所得混合物在密封管中在60℃下搅拌12小时。在反应完成后(如LCMS所示),将反应混合物在减压下浓缩,得到粗材料,将其通过反相制备型HPLC纯化,以得到所需产物。
使用上述一般方法制备以下化合物。
实施例1
1-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-3-(3-(叔丁基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(D2,0.178g,0.63mmol)和(3-(叔丁基)异噁唑-5-基)氨基甲酸苯酯(E1,0.16g,0.30mmol)开始来制备标题化合物,并且作为灰白色固体获得(0.026g,9%产率)。1H NMR(400MHz,DMSO-d6)δ=10.48(bs,1H),9.34(bs,1H),8.15(s,1H),7.70(s,1H),7.61(d,J=8.8Hz,2H),7.45(d,J=8.8Hz,2H),6.08(bs,2H),6.07(s,1H),5.86-5.90(m,1H),4.97-5.05(m,4H),1.27(s,9H)。LCMS:448.2[M+H]。
实施例2
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(叔丁基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(D2,0.178g,0.63mmol)和(3-(叔丁基)异噁唑-5-基)氨基甲酸苯酯(E1,0.16g,0.30mmol)开始来制备标题化合物,并且作为灰白色固体获得(0.026g,9%产率)。1H NMR(400MHz,DMSO-d6)δ=10.48(bs,1H),9.34(bs,1H),8.15(s,1H),7.70(s,1H),7.61(d,J=8.8Hz,2H),7.45(d,J=8.8Hz,2H),6.08(bs,2H),6.07(s,1H),5.86-5.90(m,1H),4.97-5.05(m,4H),1.27(s,9H)。LCMS:448.2[M+H]。
实施例3
1-(5-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)吡啶-2-基)-3-(3-(叔丁基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(6-氨基吡啶-3-基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D6,0.100g,0.376mmol)和(3-(叔丁基)异噁唑-5-基)氨基甲酸苯酯(E1,0.098g,0.386mmol)开始来制备标题化合物,并且作为灰白色固体获得(9.6mg,6%产率)。1H NMR(400MHz,CD3OD)δ=8.46-8.47(m,1H),8.22(s,1H),7.89-7.92(m,2H),7.35-7.38(m,1H),7.28(s,1H),6.23(s,1H),3.50-3.57(m,1H),1.27(s,9H),1.07-1.16(m,4H);LCMS:433.2[M+H]。
实施例4
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(5-(叔丁基)异噁唑-3-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.100g,0.35mmol)和(5-(叔丁基)异噁唑-3-基)氨基甲酸苯酯(E2,0.091g,0.35mmol)开始来制备标题化合物,并且作为灰白色固体获得(0.021m g,13%产率)。1H NMR(400MHz,DMSO-d6)δ=9.86(bs,1H),8.87(bs,1H),8.17-8.21(m,2H),7.24-7.35(m,3H),6.51(s,1H),6.17(bs,2H),3.56-3.60(m,1H),1.31(s,9H),1.02-1.07(m,4H)。LCMS:450.2[M+H]。
实施例5
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.080g,0.282mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.088g,0.282mmol)开始来制备标题化合物,并且作为白色固体获得(0.031mg,22%产率)。1H NMR(400MHz,DMSO-d6)δ=10.59(bs,1H),8.84(bs,1H),8.11-8.17(m,2H),7.26-7.37(m,3H),6.20(s,1H),6.16(bs,2H),3.55-3.61(m,1H),1.45-1.49(m,2H),1.38-1.43(m,2H),1.03-1.08(m,4H)。LCMS:502.1[M+H]。
实施例6
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.060g,0.180mmol)和(5-环丙基异噁唑-3-基)氨基甲酸苯酯(E5,0.044g,0.282mmol)开始来制备标题化合物,并且作为灰白色固体获得(8.4mg,9%产率)。1H NMR(400MHz,CD3OD)δ=8.20-8.22(m,2H),7.28-7.33(m,2H),7.22(s,1H),6.35(s,1H),3.49-3.55(m,1H),2.08-2.12(m,1H),1.08-1.16(m,6H),0.97-0.99(m,2H)。LCMS:434.2[M+H]。
实施例7
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-甲基异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.100g,0.35mmol)和(3-甲基异噁唑-5-基)氨基甲酸苯酯(E3,0.077g,0.35mmol)开始来制备标题化合物,并且作为灰白色固体获得(0.024m g,17%产率)。1H NMR(400MHz,DMSO-d6)δ=10.35(bs,1H),8.84(bs,1H),8.10-8.18(m,2H),7.25-7.36(m,3H),6.13(bs,2H),5.99(s,1H),3.55-3.61(m,1H),2.18(s,3H),1.00-1.08(m,4H)。LCMS:408.1[M+H]。
实施例8
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(5-甲基异噁唑-3-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.127g,0.44mmol)和(5-甲基异噁唑-3-基)氨基甲酸苯酯(E4,0.097g,0.44mmol)开始来制备标题化合物,并且作为白色固体获得(0.033m g,18%产率)。1HNMR(400MHz,DMSO-d6)δ=9.88(bs,1H),8.96(bs,1H),8.15-8.19(m,2H),7.24-7.35(m,3H),6.54(s,1H),6.15(bs,2H),3.55-3.61(m,1H),2.38(s,3H),1.00-1.07(m,4H)。LCMS:408.2[M+H]。
实施例9
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(2-氟丙-2-基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.076g,0.26mmol)和(3-(2-氟丙-2-基)异噁唑-5-基)氨基甲酸苯酯(E9,0.070g,0.26mmol)开始来制备标题化合物,并且作为白色固体获得(0.018g,14%产率)。1H NMR(400MHz,DMSO-d6)δ=8.99(bs,1H),8.17(s,1H),8.09-8.14(m,1H),7.25-7.36(m,3H),6.18(s,1H),6.09(bs,2H),3.57-3.61(m,1H),1.71(s,3H),1.66(s,3H),1.02-1.05(m,4H)。LCMS:454.2[M+H]。
实施例10
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(5-(1-(三氟甲基)环丙基)异噁唑-3-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.10g,0.35mmol)和(5-(1-(三氟甲基)环丙基)异噁唑-3-基)氨基甲酸苯酯(E7,0.11g,0.35mmol)开始来制备标题化合物,并且作为灰白色固体获得(0.010g,6%产率)。1H NMR(400MHz,DMSO-d6)δ=9.99(bs,1H),8.86(bs,1H),8.14-8.18(m,2H),7.24-7.36(m,3H),6.90(s,1H),6.15(bs,2H),3.56-3.61(m,1H),1.48-1.57(m,4H),1.02-1.07(m,4H)。LCMS:502.2[M+H]。
实施例11
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-2-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D5,0.070g,0.24mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.082g,0.24mmol)开始来制备标题化合物,并且作为灰白色固体获得(0.011g,9%产率)。1H NMR(400MHz,DMSO-d6)δ=10.56(bs,1H),9.29(bs,1H),8.16(s,1H),7.58-7.62(m,1H),7.27-7.36(m,2H),7.22(s,1H),6.20(s,1H),6.00(bs,2H),3.55-3.60(m,1H),1.38-1.48(m,4H),1.02-1.06(m,4H)。LCMS:502.2[M+H]。
实施例12
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1,1,1-三氟-2-甲基丙烷-2-基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-2-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.050g,0.176mmol)和(3-(1,1,1-三氟-2-甲基丙-2-基)异噁唑-5-基)氨基甲酸苯酯(E8,0.055g,0.176mmol)开始来制备标题化合物,并且作为灰白色固体获得(9.9mg,11%产率)。1H NMR(400MHz,DMSO-d6)δ=10.59(bs,1H),8.83(bs,1H),8.18(s,1H),8.12-8.17(m,1H),7.25-7.36(m,3H),6.22(s,1H),6.17(bs,2H),3.55-3.61(m,1H),1.52(s,6H),1.02-1.07(m,4H)。LCMS:504.2[M+H]。
实施例13
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-3-(3-(叔丁基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D4,0.080g,0.30mmol)和(3-(叔丁基)异噁唑-5-基)氨基甲酸苯酯(E1,0.078g,0.30mmol)开始来制备标题化合物,并且作为灰白色固体获得(0.036g,28%产率)。1HNMR(400MHz,DMSO-d6)δ=10.13(bs,1H),8.93(bs,1H),8.16(s,1H),7.56(d,J=8.4Hz,2H),7.40(d,J=8.8Hz,2H),7.22(s,1H),6.08(s,1H),6.00(bs,2H),3.56-3.59(m,1H),1.27(s,9H),1.05-1.07(m,4H)。LCMS:430.2[M-H]。
实施例14
1-(4-(4-氨基-7-(2-羟基-2-甲基丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从1-(4-氨基-5-(4-氨基-3-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)-2-甲基丙烷-2-醇(D3,0.086g,0.273mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.085g,0.273mmol)开始来制备标题化合物,并且作为浅棕色固体获得(0.011g,8%产率)。1H NMR(400MHz,DMSO-d6)δ=10.92(bs,1H),9.06(bs,1H),8.11-8.15(m,2H),7.26-7.35(m,3H),6.18(s,1H),6.14(bs,2H),4.86(bs,1H),4.11(bs,2H),1.37-1.46(m,4H),1.06-1.08(m,6H)。LCMS:534.1[M+H]。
实施例15
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)环己-3-烯-1-基)-3-(3-(叔丁基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基环己-1-烯-1-基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D7,0.120g,0.446mmol)和(3-(叔丁基)异噁唑-5-基)氨基甲酸苯酯(E1,0.116g,0.446mmol)开始来制备标题化合物,并且作为灰白色固体获得(0.013g,7%产率)。1HNMR(400MHz,DMSO-d6)δ=9.83(bs,1H),8.39(bs,1H),7.47(s,1H),6.54(d,J=7.6Hz,1H),5.93(s,1H),5.67(bs,1H),3.88-3.90(m,2H),3.61-3.67(m,2H),2.08-2.14(m,1H),1.92-1.95(m,1H),1.69-1.73(m,1H),1.24(s,9H),1.05-1.08(m,4H)。LCMS:436.2[M+H]。
实施例16
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)环己基)-3-(3-(叔丁基)异噁唑-5-基)脲
将氧化铂(0.016g,0.069mmol)添加至1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)环己-3-烯-1-基)-3-(3-(叔丁基)异噁唑-5-基)脲(实施例15,0.100g,0.230mmol)在EtOAc(5mL)中的溶液中,并且将所得悬浮液在室温在H2气氛下搅拌12小时。在反应完成后(如LCMS所示),通过硅藻土垫过滤反应混合物,然后用EtOAc(2x5mL)清洗。将合并的滤液在减压下浓缩,得到粗材料,将其通过制备型HPLC(基于质量,用乙酸铵在水和ACN中的梯度洗脱)纯化,得到呈灰白色固体的标题产物(2.0mg,2%产率)。1H NMR(400MHz,CD3OD)δ=8.12(s,1H),6.92(s,1H),6.02(s,1H),3.50-3.51(m,1H),2.87-2.90(m,1H),2.13-2.18(m,6H),1.51-1.57(m,3H),1.33(s,9H),0.90-1.20(m,4H)。LCMS:436.2[M-H]。
实施例17
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-甲基环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.050g,0.176mmol)和(3-(1-甲基环丙基)异噁唑-5-基)氨基甲酸苯酯(E10,0.046g,0.176mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.013g,16%产率)。1H NMR(400MHz,DMSO-d6)δ=10.40(bs,1H),8.84(bs,1H),8.11-8.17(m,2H),7.24-7.36(m,3H),6.16(bs,2H),5.84(s,1H),3.55-3.61(m,1H),1.38(s,3H),1.02-1.07(m,4H),0.94-0.96(m,2H),0.83-0.84(m,2H)。LCMS:448.2[M+H]。
实施例18
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(4-(叔丁基)噻唑-2-基)脲
根据用于脲形成的一般程序(方法A),从(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)氨基甲酸苯酯(E11,0.040g,0.099mmol)和4-(叔丁基)噻唑-2-胺(0.015g,0.099mmol)开始来获得标题化合物,并且作为灰白色固体获得(7.0m g,15%产率)。1H NMR(400MHz,DMSO-d6)δ=10.99(bs,1H),9.29(bs,1H),8.46(s,1H),8.26-8.30(m,1H),7.67(s,1H),7.38-7.41(m,1H),7.27-7.30(m,1H),6.70(s,1H),3.71(bs,1H),1.27(s,9H),1.10-1.10(m,4H)。LCMS:466.0[M+H]。
实施例19
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(5-(叔丁基)-1,3,4-噻二唑-2-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.050g,0.176mmol)和(5-(叔丁基)-1,3,4-噻二唑-2-基)氨基甲酸苯酯(E12,0.049g,0.176mmol)开始来获得标题化合物,并且作为灰白色固体获得(2.0m g,2%产率)。1H NMR(400MHz,CD3OD)δ=8.19-8.23(m,2H),7.30-7.35(m,2H),7.23(s,1H),3.50-3.54(m,1H),1.49(s,9H),1.08-1.17(m,4H)。LCMS:466.9[M+H]。
实施例20
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(叔丁基)异噻唑-5-基)脲
根据用于脲形成的一般程序(方法A),从(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)氨基甲酸苯酯(E11,0.040g,0.099mmol)和4-(叔丁基)噻唑-2-胺(0.015g,0.099mmol)开始来获得标题化合物,并且作为灰白色固体获得(2.0m g,4%产率)。1H NMR(400MHz,CD3OD)δ=8.21(s,1H),8.11-8.17(m,1H),7.30-7.34(m,2H),7.23(s,1H),6.78(s,1H),3.50-3.54(m,1H),1.35(s,9H),1.08-1.30(m,4H)。LCMS:466.0[M+H]。
实施例21
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(叔丁基)-1,2,4-噻二唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.050g,0.176mmol)和(3-(叔丁基)-1,2,4-噻二唑-5-基)氨基甲酸苯酯(E13,0.049g,0.176mmol)开始来获得标题化合物,并且作为灰白色固体获得(8.0mg,10%产率)。1H NMR(400MHz,DMSO-d6)δ=11.54(bs,1H),9.00(bs,1H),8.09-8.18(m,2H),7.28-7.39(m,3H),6.19(bs,2H),3.57-3.61(m,1H),1.34(s,9H),1.03-1.05(m,4H)。LCMS:467.0[M+H]。
实施例22
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(1-(叔丁基)-1H-1,2,4-三唑-3-基)脲
根据用于脲形成的一般程序(方法A),从(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)氨基甲酸苯酯(E11,0.040g,0.099mmol)和1-(叔丁基)-1H-1,2,4-三唑-3-胺(0.014g,0.099mmol)开始来获得标题化合物,并且作为灰白色固体获得(3.0mg,6%产率)。1H NMR(400MHz,DMSO-d6)δ=10.70(bs,1H),10.16(bs,1H),8.54(s,1H),8.31-8.35(m,1H),8.16(s,1H),7.25-7.37(m,3H),6.17(bs,2H),3.56-3.59(m,1H),1.57(s,9H),1.02-1.05(m,4H)。LCMS:450.0[M+H]。
实施例23
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(5-(叔丁基)-1,3,4-噁二唑-2-基)脲
根据用于脲形成的一般程序(方法A),从(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)氨基甲酸苯酯(E11,0.040g,0.099mmol)和5-(叔丁基)-1,3,4-噁二唑-2-胺(0.014g,0.099mmol)开始来获得标题化合物,并且作为灰白色固体获得(2.0mg,4%产率)。1H NMR(400MHz,CD3OD)δ=8.35(s,1H),8.26-8.30(m,1H),7.48(s,1H),7.31-7.40(m,2H),3.69-3.71(m,1H),1.45(s,9H),1.17-1.22(m,4H)。LCMS:451.0[M+H]。
实施例24
1-(4-(4-氨基-7-(吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-(吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(D8,0.100g,0.312mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.107g,0.343mmol)开始来获得标题化合物,并且作为白色固体获得(0.023g,14%产率)。1H NMR(400MHz,DMSO-d6)δ=10.69(bs,1H),9.13(bs,1H),8.97(bs,1H),8.62(d,J=4.8Hz,1H),8.31-8.36(m,2H),8.20-8.24(m,1H),7.95(s,1H),7.62-7.65(m,1H),7.38-7.50(m,2H),6.76(bs,2H),6.21(s,1H),1.39-1.47(m,4H)。LCMS:538.8[M+H]。
实施例25
1-(4-(4-氨基-7-(吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-(吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(D9,0.080g,0.250mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.086g,0.275mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.046g,33%产率)。1H NMR(400MHz,DMSO-d6)δ=10.68(bs,1H),9.00(bs,1H),8.89(d,J=6.4Hz,2H),8.58(d,J=6.4Hz,2H),8.43(s,1H),8.21-8.27(m,2H),7.49-7.52(m,1H),7.39-7.42(m,1H),6.90(bs,2H),6.22(s,1H),1.39-1.49(m,4H)。LCMS:538.9[M+H]。
实施例26
1-(4-(4-氨基-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(D10,0.020g,0.059mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.018g,0.059mmol)开始来获得标题化合物,并且作为白色固体获得(2.4mg,7%产率)。1H NMR(400MHz,DMSO-d6)δ=10.68(bs,1H),8.96(bs,1H),8.32(s,1H),8.16-8.20(m,1H),7.55(s,1H),7.38-7.41(m,1H),7.29-7.31(m,1H),6.98(bs,2H),6.21(s,1H),4.85-4.91(m,1H),3.59-3.62(m,4H),2.85(s,3H),2.21-2.34(m,4H),1.38-1.49(m,4H)。LCMS:559.2[M+H]。
实施例27
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(3-甲基氧杂环丁烷-3-基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.050g,0.176mmol)和(3-(3-甲基氧杂环丁烷-3-基)异噁唑-5-基)氨基甲酸苯酯(E14,0.048g,0.176mmol)开始来获得标题化合物,并且作为白色固体获得(3.4m g,4%产率)。1H NMR(400MHz,DMSO-d6)δ=10.56(s,1H),8.94(bs,1H),8.42(s,1H),8.19(t,J=8.4Hz,1H),7.57(bs,3H),7.38(d,J=10.8Hz,1H),7.28(d,J=8.4Hz,1H),6.22(s,1H),4.77(d,J=5.6Hz,2H),4.52(d,J=5.6Hz,2H),3.68-3.69(m,1H),1.63(s,3H),1.09-1.10(m,4H)。LCMS:464.1[M+H]。
实施例28
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(三氟甲基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.050g,0.176mmol)和(3-(三氟甲基)异噁唑-5-基)氨基甲酸苯酯(E15,0.048g,0.176mmol)开始来获得标题化合物,并且作为白色固体获得(2.9m g,4%产率)。1H NMR(400MHz,DMSO-d6)δ=11.03(bs,1H),8.97(bs,1H),8.19(s,1H),8.10(t,J=8.4Hz,1H),7.27-7.38(m,3H),6.54(s,1H),6.30(bs,2H),3.56-3.60(m,1H),1.03-1.05(m,4H)。LCMS:461.9[M+H]。
实施例29
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-羟基-2-甲基丙烷-2-基)异噁唑-5-基)脲
步骤1:1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-((叔丁基二甲基甲硅烷基)氧基)-2-甲基丙烷-2-基)异噁唑-5-基)脲的合成
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.131g,0.461mmol)和(3-(1-((叔丁基二甲基甲硅烷基)氧基)-2-甲基丙-2-基)异噁唑-5-基)氨基甲酸苯酯(E16,0.180g,0.461mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.013g,5%产率)。LCMS:580.0[M+H]。
步骤2:1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-羟基-2-甲基丙烷-2-基)异噁唑-5-基)脲的合成
在0℃下将TBAF(1M在THF中,0.067ml)添加至1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-((叔丁基二甲基甲硅烷基)氧基)-2-甲基丙-2-基)异噁唑-5-基)脲(0.013g,0.022mmol)在THF(2ml)的溶液中,并且将所得溶液在25℃下搅拌4小时。在反应完成后(如TLC所示),将反应混合物在减压下浓缩,得到粗材料,将其通过制备型HPLC纯化,得到呈白色固体的标题化合物(TFA盐,2.2mg,21%产率)。1H NMR(400MHz,CD3OD)δ=8.36(s,1H),8.23(t,J=8.4Hz,1H),7.49(s,1H),7.30-7.38(m,2H),6.20(s,1H),3.69-3.72(m,1H),3.61(s,2H),1.32(s,6H),1.18-1.24(m,4H)。LCMS:466.2[M+H]。
实施例30
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(叔丁基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.055g,0.194mmol)和(3-(仲丁基)异噁唑-5-基)氨基甲酸苯酯(E17,0.051g,0.194mmol)开始来获得标题化合物,并且作为白色固体获得(0.012g,14%产率)。1H NMR(400MHz,DMSO-d6)δ=10.39(bs,1H),8.84(bs,1H),8.12-8.14(m,2H),7.25-7.36(m,3H),6.16(bs,2H),6.02(s,1H),3.56-3.59(m,1H),2.68-2.73(m,1H),1.56-1.60(m,2H),1.18-1.20(m,3H),1.01-1.10(m,4H),0.81-0.89(m,3H)。LCMS:450.0[M+H]。
实施例31
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(戊烷-3-基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.050g,0.176mmol)和(3-(戊-3-基)异噁唑-5-基)氨基甲酸苯酯(E18,0.048g,0.176mmol)开始来获得标题化合物,并且作为白色固体获得(0.016g,19%产率)。1H NMR(400MHz,DMSO-d6)δ=10.65(bs,1H),9.06(bs,1H),8.37(s,1H),8.18(t,J=8.4Hz,1H),7.51(s,1H),7.35-7.38(m,1H),7.26-7.28(m,3H),5.98(s,1H),3.65-3.68(m,1H),1.49-1.68(m,4H),1.07-1.09(m,4H),0.79-0.82(m,6H)。LCMS:464.0[M+H]。
实施例32
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-异丙基异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.056g,0.198mmol)和(3-异丙基异噁唑-5-基)氨基甲酸苯酯(E19,0.049g,0.198mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.018g,21%产率)。1H NMR(400MHz,DMSO-d6)δ=10.34(bs,1H),8.81(bs,1H),8.12-8.16(m,2H),7.25-7.36(m,3H),6.15(bs,2H),6.04(s,1H),3.55-3.59(m,1H),2.89-2.96(m,1H),1.21-1.25(m,6H),1.07-1.09(m,4H)。LCMS:436.0[M+H]。
实施例33
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-乙基异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.061g,0.215mmol)和(3-乙基异噁唑-5-基)氨基甲酸苯酯(E20,0.050g,0.215mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.020g,22%产率)。1H NMR(400MHz,DMSO-d6)δ=10.31(bs,1H),8.81(bs,1H),8.12-8.17(m,2H),7.25-7.36(m,3H),6.15(bs,2H),6.03(s,1H),3.55-3.60(m,1H),2.54-2.60(m,2H),1.05-1.21(m,3H),1.03-1.04(m,4H)。LCMS:422.0[M+H]。
实施例34
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-甲基环丁基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.075g,0.265mmol)和(3-(1-甲基环丁基)异噁唑-5-基)氨基甲酸苯酯(E21,0.072g,0.265mmol)开始来获得标题化合物,并且作为白色固体获得(6.8mg,5%产率)。1H NMR(400MHz,DMSO-d6)δ=10.42(bs,1H),8.90(bs,1H),8.42(s,1H),8.18-8.22(m,1H),7.58(s,1H),7.37-7.40(m,1H),7.27-7.29(m,1H),6.06(s,1H),3.67-3.71(m,1H),2.34-2.38(m,2H),1.85-2.08(m,4H),1.42(s,3H),1.07-1.11(m,4H)。LCMS:462.2[M+H]。
实施例35
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(2-氰基丙烷-2-基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.070g,0.247mmol)和(3-(2-氰基丙烷-2-基)异噁唑-5-基)氨基甲酸苯酯(E22,0.067g,0.247mmol)开始来获得标题化合物,并且作为白色固体获得(4.1m g,3%产率)。1H NMR(400MHz,CD3OD)δ=8.33(s,1H),8.20-8.24(m,1H),7.43(s,1H),7.31-7.38(m,2H),6.33(s,1H),3.50-3.66(m,1H),1.77(s,6H),1.15-1.21(m,4H)。LCMS:461.1[M+H]。
实施例36
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(羟基甲基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.250g,0.882mmol)和(3-(((叔丁基二甲基甲硅烷基)氧基)甲基)异噁唑-5-基)氨基甲酸苯酯(E23,0.308g,0.882mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.029g,8%产率)。1H NMR(400MHz,DMSO-d6)δ=10.43(bs,1H),8.92(bs,1H),8.40(s,1H),8.18-8.22(m,1H),7.56(s,1H),7.37-7.40(m,1H),7.27-7.29(m,1H),6.12(s,1H),4.43(s,2H),3.66-3.71(m,1H),1.08-1.11(m,4H)。LCMS:422.0[M-H]。
注释:当用10mM乙酸铵在水和ACN中的梯度洗脱时,在纯化期间观察到TBDMS基团的裂解。
实施例37
1-(5-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)吡啶-2-基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(6-氨基吡啶-3-基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D6,0.300g,1.127mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.352g,1.127mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.018g,3%产率)。1H NMR(400MHz,DMSO-d6)δ=11.77(bs,1H),9.85(bs,1H),8.39-8.40(m,1H),8.18(s,1H),7.86-7.88(m,1H),7.62(d,J=8.4Hz,1H),7.34(s,1H),6.26(s,1H),6.23(bs,2H),3.58-3.61(m,1H),1.40-1.49(m,4H),1.03-1.06(m,4H)。LCMS:485.0[M+H]。
实施例38
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲基苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-甲基苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D11,0.270g,0.967mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.302g,0.967mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.080g,16%产率)。1H NMR(400MHz,DMSO-d6)δ=10.63(bs,1H),8.29(bs,1H),8.16(s,1H),7.87(d,J=8.4Hz,1H),7.22-7.32(m,3H),6.17(s,1H),6.08(bs,2H),3.55-3.60(m,1H),2.29(s,3H),1.37-1.48(m,4H),1.00-1.05(m,4H)。LCMS:498.1[M+H]。
实施例39
1-(4-(4-氨基-7-(3-羟基环丁基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
步骤1:1-(4-(4-氨基-7-(3-(苄氧基)环丁基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲的合成
根据用于脲形成的一般程序(方法B),从5-(4-氨基-3-氟苯基)-7-(3-(苄氧基)环丁基)-7H-吡咯并[2,3-d]嘧啶-4-胺(D12,0.033g,0.082mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.028g,0.090mmol)开始来获得标题化合物,并且作为色胶状物获得(0.038g,29%产率)。LCMS:622.3[M+H]。
步骤2:1-(4-(4-氨基-7-(3-羟基环丁基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲的合成
在-60℃下将三氯化硼(1M在DCM中,0.901mL,0.901mmol)滴加至1-(4-(4-氨基-7-(3-(苄氧基)环丁基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲(0.070g,0.113mmol)在DCM(5mL)中的溶液中,并且将所得混合物在0℃下搅拌3小时。在反应完成后(如通过TLC和LCMS所示),将反应混合物冷却至-70℃,用NH4OH(25%在水中)中和,并用DCM(2×10mL)萃取。将合并的有机萃取物经Na2SO4干燥,过滤,并在减压下浓缩,得到粗材料,将其通过制备型HPLC(用1% TFA在水和ACN中的梯度洗脱)纯化,得到呈白色固体的标题产物(0.012g,20%产率)。1H NMR(400MHz,CD3OD)δ=8.33(s,1H),8.22-8.26(m,1H),7.77(s,1H),7.34-7.42(m,2H),6.33(s,1H),5.58-5.62(m,1H),4.64-4.66(m,1H),2.85-2.92(m,2H),2.58-2.64(m,2H),1.39-1.49(m,4H)。LCMS:531.8[M+H]。
实施例40
1-(6-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-4-甲基吡啶-3-基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(5-氨基-4-甲基吡啶-2-基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D13,0.050g,0.102mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.032g,0.102mmol)开始来获得标题化合物,并且作为灰白色固体获得(8mg,16%产率)。1H NMR(400MHz,DMSO-d6)δ=9.81(bs,1H),8.76(s,1H),8.51(bs,1H),8.08(s,1H),7.93-7.94(m,2H),7.12(bs,2H),6.17(s,1H),3.53-3.56(m,1H),2.30(s,3H),1.37-1.46(m,4H),1.05-1.08(m,4H)。LCMS:499.2[M+H]。
实施例41
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,6-二氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法B),从5-(4-氨基-3,5-二氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D15,0.080g,0.266mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.083g,0.266mmol)开始来获得标题化合物,并且作为灰白色固体获得(8mg,5.6%产率)。1H NMR(400MHz,DMSO-d6)δ=10.78(bs,1H),8.71(bs,1H),8.42(bs,1H),7.67(s,1H),7.56(bs,2H),7.23-7.29(m,2H),6.14(s,1H),3.67-3.76(m,1H),1.37-1.47(m,4H),1.09-1.12(m,4H)。LCMS:519.7[M+H]。
实施例42
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,5-二氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法B),从5-(4-氨基-2,5-二氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D16,0.100g,0.332mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.104g,0.332mmol)开始来获得标题化合物,并且作为灰白色固体获得(8mg,5%产率)。1H NMR(400MHz,DMSO-d6)δ=10.63(bs,1H),9.01(bs,1H),8.16(s,1H),8.04-8.09(m,1H),7.28-7.34(m,2H),6.21(s,1H),6.16(bs,2H),3.55-3.61(m,1H),1.36-1.49(m,4H),1.00-1.04(m,4H)。LCMS:520.1[M+H]。
实施例43
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-3,5-二氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法B),从5-(4-氨基-2,6-二氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D17,0.0724g,0.240mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.075g,0.240mmol)开始来获得标题化合物,并且作为灰白色固体获得(3mg,2%产率)。1H NMR(400MHz,DMSO-d6)δ=8.14(s,1H),7.39-7.42(m,2H),7.24(s,1H),6.15(s,1H),6.02(bs,2H),3.58-3.59(m,1H),1.36-1.44(m,4H),1.03-1.05(m,4H)。LCMS:520.2[M+H]。
实施例44
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-3,5-二氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
步骤1:1-(5-溴-3-氟吡啶-2-基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲的合成
根据用于脲形成的一般程序(方法B),从5-溴-3-氟吡啶-2-胺(0.040g,0.209mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.065g,0.209mmol)开始来获得标题化合物,并且作为浅黄色固体获得(0.020g,23%产率)。LCMS:410.9[M+H]。
步骤2:1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-3,5-二氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲的合成
根据用于中间体D8的类似程序,从1-(5-溴-3-氟吡啶-2-基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲(0.020g,0.049mmol)和(叔丁氧基羰基)(7-环丙基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基甲酸叔丁酯(如第WO2018/015879号PCT公开中报道制备,0.024g,0.049mmol)开始来获得标题化合物,并且作为灰白色固体获得(2mg,7%产率)。1H NMR(400MHz,CD3OD)δ=8.32-8.33(m,2H),7.81-7.84(m,1H),7.50(s,1H),6.42(s,1H),3.60-3.68(m,1H),1.41-1.50(m,4H),1.13-1.23(m,4H)。LCMS:503.1[M+H]。注释:在反应期间观察到Boc基团的裂解。
实施例45
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丁基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.080g,0.282mmol)和(3-(1-(三氟甲基)环丁基)异噁唑-5-基)氨基甲酸苯酯(E24,0.092g,0.282mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.035g,22%产率)。1H NMR(400MHz,DMSO-d6)δ=10.66(bs,1H),8.90(bs,1H),8.21(s,1H),8.12-8.16(m,1H),7.26-7.36(m,3H),6.41(bs,2H),6.14(s,1H),3.54-3.56(m,1H),2.57-2.68(m,4H),2.03-2.05(m,2H),1.04-1.06(m,4H)。LCMS:515.9[M+H]。
实施例46
1-(5-(4-氨基-7-(2-羟基-2-甲基丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)吡啶-2-基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法B),从1-(4-氨基-5-(6-氨基吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-7-基)-2-甲基丙-2-醇(D18,0.100g,0.335mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.105g,0.335mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.010g,6%产率)。1H NMR(400MHz,DMSO-d6)δ=11.74(bs,1H),9.91(bs,1H),8.41-8.43(m,2H),7.89-7.92(m,1H),7.80(bs,2H),7.68-7.71(m,1H),7.59(s,1H),6.26(s,1H),4.20(s,2H),1.38-1.50(m,4H),1.11-1.12(m,6H)。LCMS:516.9[M+H]。
实施例47
1-(4-(4-氨基-7-(2-羟基-2-甲基丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(5-(1-(三氟甲基)环丙基)异噁唑-3-基)脲
根据用于脲形成的一般程序(方法B),从1-(4-氨基-5-(4-氨基-3-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)-2-甲基丙-2-醇(D3,0.120g,0.381mmol)和(5-(1-(三氟甲基)环丙基)异噁唑-3-基)氨基甲酸苯酯(E7,0.119g,0.381mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.028g,13%产率)。1H NMR(400MHz,DMSO-d6)δ=10.04(bs,1H),8.94(bs,1H),8.41(s,1H),8.23-8.27(m,1H),7.55(s,1H),7.36-7.40(m,1H),7.27-7.30(m,1H),6.91(s,1H),4.18(s,2H),1.51-1.58(m,4H),1.07-1.11(m,6H)。LCMS:534.2[M+H]。
实施例48
1-(5-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)嘧啶-2-基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法B),从5-(2-氨基嘧啶-5-基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D19,0.080g,0.299mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.093g,0.299mmol)开始来获得标题化合物,并且作为灰白色固体获得(4mg,3%产率)。1H NMR(400MHz,DMSO-d6)δ=10.76(bs,1H),9.04(bs,1H),8.65(bs,1H),8.34(bs,2H),7.61(s,1H),6.66(bs,2H),6.10(s,1H),3.66-3.71(m,1H),1.37-1.45(m,4H),1.11-1.11(m,4H)。LCMS:485.9[M+H]。
实施例49
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-(羟基甲基)苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法A),从(2-氨基-5-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)甲醇(D20,0.020g,0.068mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.021g,0.068mmol)开始来获得标题化合物,并且作为灰白色固体获得(3mg,8%产率)。1H NMR(400MHz,DMSO-d6)δ=10.96(bs,1H),8.56(bs,1H),8.17(s,1H),7.91-7.93(m,1H),7.34-7.42(m,2H),7.21(s,1H),6.04-6.17(m,3H),5.49(bs,1H),4.57(bs,2H),3.56-3.61(m,1H),1.37-1.47(m,4H),1.00-1.06(m,4H)。LCMS:514.1[M+H]。
实施例50
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氰基苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法B),从2-氨基-5-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苄腈(D21,0.130g,0.287mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.089g,0.287mmol)开始来获得标题化合物,并且作为灰白色固体获得(5mg,3%产率)。1H NMR(400MHz,DMSO-d6)δ=8.62(s,1H),7.43-7.52(m,3H),6.86(s,1H),6.05(s,1H),3.67-3.70(m,1H),1.38-1.46(m,4H),1.08-1.10(m,4H)。LCMS:509.2[M+H]。
实施例51
1-(4-(4-氨基-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法B),从5-(4-氨基-3-氟苯基)-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-4-胺(D22,0.075g,0.249mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.078g,0.249mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.037g,28%产率)。1H NMR(400MHz,DMSO-d6)δ=10.63(bs,1H),8.88(bs,1H),8.13-8.18(m,2H),7.42(s,1H),7.26-7.36(m,2H),6.35(bs,2H),6.20(s,1H),4.34(t,J=5.6Hz,2H),3.72(t,J=5.2Hz,2H),3.26(s,3H),1.38-1.49(m,4H)。LCMS:520.2[M+H]。
实施例52
1-(4-(4-氨基-7-(2-羟基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法B),从2-(4-氨基-5-(4-氨基-3-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)乙-1-醇(D23,0.080g,0.278mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.087g,0.278mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.011g,7%产率)。1H NMR(400MHz,DMSO-d6)δ=10.53(bs,1H),8.78(bs,1H),8.05-8.09(m,2H),7.32(s,1H),7.19-7.28(m,2H),6.18(bs,2H),6.13(s,1H),4.90(t,J=5.2Hz,1H),4.14(t,J=6.0Hz,2H),3.66-3.69(m,2H),1.31-1.41(m,4H)。LCMS:506.2[M+H]。
实施例53
1-(4-(4-氨基-7-环丁基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法B),从5-(4-氨基-3-氟苯基)-7-环丁基-7H-吡咯并[2,3-d]嘧啶-4-胺(D24,0.150g,0.504mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.158g,0.504mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.111g,38%产率)。1H NMR(400MHz,DMSO-d6)δ=10.67(bs,1H),8.96(bs,1H),8.38(s,1H),8.18-8.22(m,1H),7.93(s,1H),7.43(bs,2H),7.41(d,J=1.6Hz,1H),7.32(d,J=8.4Hz,1H),6.21(s,1H),5.23-5.27(m,1H),2.51-2.68(m,4H),1.84-1.89(m,2H),1.38-1.49(m,4H)。LCMS:516.1[M+H]。
实施例54
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氯苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法B),从5-(4-氨基-3-氯苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D25,0.050g,0.167mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.052g,0.167mmol)开始来获得标题化合物,并且作为灰白色固体获得(6mg,7%产率)。1H NMR(400MHz,DMSO-d6)δ=11.04(bs,1H),8.67(bs,1H),8.40(s,1H),8.23-8.25(m,1H),7.58-7.60(m,2H),7.42-7.44(m,1H),6.21(s,1H),3.67-3.73(m,1H),1.46-2.33(m,2H),1.37-1.38(m,2H),1.11-1.13(m,4H)。LCMS:518.2[M+H]。
实施例55
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲氧基苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法B),从5-(4-氨基-3-甲氧基苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D26,0.020g,0.068mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.021g,0.068mmol)开始来获得标题化合物,并且作为灰白色固体获得(7mg,19%产率)。1H NMR(400MHz,DMSO-d6)δ=10.96(bs,1H),8.65(bs,1H),8.23(s,1H),8.17(d,J=8.4Hz,1H),7.30(s,1H),7.12-7.17(m,1H),7.01-7.04(m,1H),6.47(bs,2H),6.19(s,1H),3.94(s,3H),3.60-3.62(m,1H),1.45-1.48(m,2H),1.36-1.38(m,2H),1.04-1.07(m,4H)。LCMS:513.9[M+H]。
实施例56
1-(4-(4-氨基-7-(1-甲基吡咯烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法B),从5-(4-氨基-3-氟苯基)-7-(1-甲基吡咯烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(D27,0.040g,0.123mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.036g,0.115mmol)开始来获得标题化合物,并且作为白色固体获得(0.015m g,24%产率)。1H NMR(400MHz,DMSO-d6)δ=10.82(bs,1H),9.07(bs,1H),8.39(s,1H),8.19-8.23(m,1H),7.84(s,1H),7.14-7.40(m,2H),6.21(s,1H),5.55-5.66(m,1H),3.90-4.09(m,2H),2.95(bs,4H),2.08(s,3H),1.38-1.49(m,4H)。LCMS:545.3[M+H]。
实施例57
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(5-(1-(三氟甲基)环丁基)异噁唑-3-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3-氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D1,0.160g,0.565mmol)和(5-(1-(三氟甲基)环丁基)异噁唑-3-基)氨基甲酸苯酯(E25,0.184g,0.565mmol)开始来获得标题化合物,并且作为白色固体获得(0.081mg,28%产率)。1H NMR(400MHz,DMSO-d6)δ=10.02(bs,1H),8.87(bs,1H),8.15-8.20(m,2H),7.25-7.36(m,3H),6.96(s,1H),6.16(bs,2H),3.55-3.61(m,1H),2.59-2.68(m,4H),2.03-2.11(m,2H),1.02-1.11(m,4H)。LCMS:516.2[M+H]。
实施例58
1-(4-(4-氨基-7-环丁基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(5-(1-(三氟甲基)环丙基)异噁唑-3-基)脲
根据用于脲形成的一般程序(方法B),从5-(4-氨基-3-氟苯基)-7-环丁基-7H-吡咯并[2,3-d]嘧啶-4-胺(D24,0.204g,0.686mmol)和(5-(1-(三氟甲基)环丙基)异噁唑-3-基)氨基甲酸苯酯(E7,0.214g,0.686mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.096g,27%产率)。1H NMR(400MHz,DMSO-d6)δ=10.01(bs,1H),8.87(bs,1H),8.14-8.20(m,2H),7.66(s,1H),7.28-7.39(m,2H),6.91(s,1H),6.18(bs,2H),5.18-5.23(m,1H),2.39-2.41(m,4H),1.81-1.90(m,2H),1.54-1.55(m,4H)。LCMS:516.2[M+H]。
实施例59
1-(6-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)吡啶-3-基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
根据用于脲形成的一般程序(方法B),从5-(5-氨基吡啶-2-基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D14,0.030g,0.045mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.014g,0.045mmol)开始来获得标题化合物,并且作为灰白色固体获得(5mg,23%产率)。1H NMR(400MHz,DMSO-d6)δ=10.67(bs,1H),9.68(bs,1H),9.12(s,1H),8.59-8.60(m,1H),8.09(s,1H),7.92-8.00(m,2H),7.17(bs,2H),6.20(s,1H),3.58-3.63(m,1H),1.36-1.48(m,4H),1.06-1.10(m,4H)。LCMS:485.2[M+H]。
实施例60
1-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,6-二氟苯基)-3-(5-(1-(三氟甲基)环丙基)异噁唑-3-基)脲
根据用于脲形成的一般程序(方法A),从5-(4-氨基-3,5-二氟苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(D15,0.150g,0.498mmol)和(5-(1-(三氟甲基)环丙基)异噁唑-3-基)氨基甲酸苯酯(E7,0.155g,0.498mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.015g,6%产率)。1H NMR(400MHz,DMSO-d6)δ=11.47(bs,1H),10.17(bs,1H),8.18(s,1H),7.42(s,1H),7.18-7.22(m,2H),6.82(s,1H),6.27(bs,2H),3.51-3.55(m,1H),1.46-1.51(m,4H),1.04-1.05(m,4H)。LCMS:520.2[M+H]。
实施例61
1-(4-(4-氨基-7-(2-羟基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-3-(5-(1-(三氟甲基)环丙基)异噁唑-3-基)脲
根据用于脲形成的一般程序(方法B),从2-(4-氨基-5-(4-氨基-3-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)乙-1-醇(D23,0.100g,0.348mmol)和(5-(1-(三氟甲基)环丙基)异噁唑-3-基)氨基甲酸苯酯(E7,0.109g,0.348mmol)开始来获得标题化合物,并且作为白色固体获得(0.035mg,20%产率)。1H NMR(400MHz,CD3OD)δ=8.35(s,1H),8.23-8.27(m,1H),7.58(s,1H),7.32-7.39(m,2H),6.81(s,1H),4.47(t,J=10.8Hz,2H),3.95-3.98(m,2H),1.49-1.59(m,4H)。LCMS:506.2[M+H]。
实施例62
1-(4-(4-氨基-1-环丙基-1H-吡咯并[3,2-c]吡啶-3-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲
步骤1:1-环丙基-N-(2,4-二甲氧基苄基)-3-碘-1H-吡咯并[3,2-c]吡啶-4-胺的合成
将4-氯-1-环丙基-3-碘-1H-吡咯并[3,2-c]吡啶(B9,0.300g,0.942mmol)和(2,5-二甲氧基苯基)甲胺(0.429mL,2.83mmol)在n-BuOH(10mL)中的混合物在110℃搅拌12小时。在反应完成后(如LCMS所示),将反应混合物在减压下浓缩,得到粗材料,将其通过Isolera(硅胶230-400目,用在石油醚中的30% EtOAc洗脱)纯化。得到呈黄色胶状物的标题产物(0.10g,19%产率)。LCMS:450.0[M+H]。
步骤2:3-(4-氨基-3-氟苯基)-1-环丙基-N-(2,4-二甲氧基苄基)-1H-吡咯并[3,2-c]吡啶-4-胺的合成
根据用于中间体D8所述的类似程序,从1-环丙基-N-(2,4-二甲氧基苄基)-3-碘-1H-吡咯并[3,2-c]吡啶-4-胺(0.190g,0.423mmol)和2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.100g,0.423mmol)来获得标题化合物,并且作为棕色胶状物获得(0.080g,41%产率)。LCMS:433.2[M+H]。
步骤3:1-(4-(1-环丙基-4-((2,4-二甲氧基苄基)氨基)-1H-吡咯并[3,2-c]吡啶-3-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲的合成
根据用于脲形成的一般程序(方法B),从3-(4-氨基-3-氟苯基)-1-环丙基-N-(2,4-二甲氧基苄基)-1H-吡咯并[3,2-c]吡啶-4-胺(0.080g,0.185mmol)和(3-(1-(三氟甲基)环丙基)异噁唑-5-基)氨基甲酸苯酯(E6,0.058g,0.185mmol)开始来获得标题化合物,并且作为灰白色固体获得(0.027g,17%产率)。LCMS:651.3[M+H]。
步骤4:1-(4-(4-氨基-1-环丙基-1H-吡咯并[3,2-c]吡啶-3-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲的合成
在0℃下将三乙基硅烷(4.8mg,0.041mmol)和TFA(4.7mg,0.041mmol)添加至1-(4-(1-环丙基-4-((2,4-二甲氧基苄基)氨基)-1H-吡咯并[3,2-c]吡啶-3-基)-2-氟苯基)-3-(3-(1-(三氟甲基)环丙基)异噁唑-5-基)脲(0.027g,0.041mmol)在DCM(2mL)中的溶液中,并且将所得混合物在25℃下搅拌12小时。在反应完成后(如LCMS所示),将反应混合物在减压下浓缩,得到粗材料,将其通过制备型HPLC(用0.1% TFA在水中的梯度洗脱)纯化,得到呈灰白色固体的标题产物(5mg,24%产率)。1H NMR(400MHz,CD3OD)δ=8.21-8.25(m,1H),7.64-7.66(m,1H),7.51(s,1H),7.30-7.38(m,3H),6.33(s,1H),3.59-3.62(m,1H),1.39-1.49(m,4H),1.13-1.26(m,4H)。LCMS:501.2[M+H]。
生物实施例1
化合物的生化测定
根据上述程序测试代表性化合物对NEK7和IL-1β释放的抑制活性。结果在下表中给出。
表2.代表性化合物的活性
对于表2中的NEK7 IC50活性:
* IC50大于1500nM
** IC50为501–1500nM
*** IC50为301–500nM
**** IC50为151–300nM
***** IC50小于150nM
对于表2中的IL-1βIC50活性:
+ IC50大于1000nM
++ IC50为301–500nM
+++ IC50为151–300nM
++++ IC50小于150nM
- 表示未测定到值
可以将以上描述的各种实施方案进行组合以提供其它实施方案。在本书明书中参考和/或在申请数据表中列出的所有美国专利、美国专利申请公开、美国专利公开、外国专利、外国专利申请和非专利公开包括但不限于2020年5月8日提交的第63/022,159号美国临时专利申请和2021年4月5日提交的第63/170,761号美国临时专利申请通过引用整体并入本文。若必要,可以修改实施方案的方面以采用各种专利、申请和公开的构思,从而提供其它实施方案。
可以根据以上详细描述对实施方案作出这些和其它改变。通常,在所附权利要求书中,使用的术语不应被解释为将权利要求限制于本说明书和权利要求书中公开的具体实施方案,而是应解释为包括所有可能的实施方案连同此类权利要求所规定的等效物的所有范围。因此,权利要求不受本公开内容限制。
Claims (52)
1.化合物,具有以下结构(I):
或其药物可接受的盐、立体异构体或前药,其中:
A是各自任选地被一个或多个R6取代的C6-C10芳基、C3-C10环烃基、3-10元杂环基或5-6元单环杂芳基;
X是CH或N;
Y是CHOH或NH;
R1是H或C1-C6烷基;
R2是各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基;
R3是H,各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基和C1-C6烷氧基;
R4是选自以下的杂芳基:各自任选地被一个或多个取代基取代的噁唑基、异噁唑基、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、1,2,3-三唑基、1,2,4-三唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基和1,3,4-噻二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基;
R5是H,各自任选地被一个或多个取代基取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烃基、3-8元杂环基、C6-C10芳基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基和C1-C6烷氧基;以及
R6在每次出现时独立地是卤素、C1-C6烷基、C1-C6烷氧基、氰基、C1-C6羟基烷基或C1-C6卤代烷基。
2.如权利要求1所述的化合物,其中R1是H。
3.如权利要求1或2所述的化合物,其中R2是各自任选地被一个或多个取代基取代的支链C4-C6烷基、C3-C4环烃基、C3-C8杂环基、或者5或6元杂芳基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基。
4.如权利要求1至3中任一项所述的化合物,其中R2是各自任选地被一个或多个取代基取代的支链C4-C6烷基、C3-C4环烃基或C3-C8杂环基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基。
5.如权利要求1至4中任一项所述的化合物,其中R2是各自任选地被一个或多个取代基取代的环丙基、环丁基、吡咯烷基、哌啶基或氧杂环丁烷基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基。
6.如权利要求5所述的化合物,其中R2是未取代的。
7.如权利要求1至4中任一项所述的化合物,其中R2是任选地被一个或多个取代基取代的支链C4-C6烷基,所述取代基选自:卤素、羟基、氰基、胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基和3-8元杂环基。
8.如权利要求7所述的化合物,其中R2是任选地被羟基取代的2-甲基丙基。
10.如权利要求1至9中任一项所述的化合物,其中R3是H。
11.如权利要求1至10中任一项所述的化合物,其中R4是各自任选地被一个或多个取代基取代的噁唑基、异噁唑基、1,2,3-噁二唑基、噻唑基、异噻唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,4-三唑基或1,3,4-噁二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
12.如权利要求11所述的化合物,其中R4是任选地被一个或多个取代基取代的异噁唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
13.如权利要求11所述的化合物,其中R4是任选地被一个或多个取代基取代的噻唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
14.如权利要求11所述的化合物,其中R4是任选地被一个或多个取代基取代的异噻唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
15.如权利要求11所述的化合物,其中R4是任选地被一个或多个取代基取代的1,2,4-噻二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
16.如权利要求11所述的化合物,其中R4是任选地被一个或多个取代基取代的1,3,4-噻二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
17.如权利要求11所述的化合物,其中R4是任选地被一个或多个取代基取代的1,2,4-三唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
18.如权利要求11所述的化合物,其中R4是任选地被一个或多个取代基取代的1,3,4-噁二唑基,所述取代基选自:卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基和C3-C8卤代环烃基及其组合。
19.如权利要求1至18中任一项所述的化合物,其中R4被C1-C6烷基、C1-C6卤代烷基、C3-C8环烃基、氰基、胺基、C1-C6羟基烷基、C1-C6氰基烷基、3-8元杂环基、C3-C8卤代烷基环烃基、C3-C8胺基烷基环烃基、C3-C8烷基环烃基、3-8元杂环基烷基、3-8元烷基杂环基环烃基、3-8元卤代杂环基烷基或C3-C8卤代环烃基或其组合取代。
22.如权利要求21所述的化合物,其中R2是被羟基或C1-C6烷氧基取代的C1-C6烷基。
24.如权利要求1至23中任一项所述的化合物,其中R5是H。
25.如权利要求1至24中任一项所述的化合物,其中Y是NH。
26.如权利要求1至24中任一项所述的化合物,其中Y是CHOH。
27.如权利要求1至26中任一项所述的化合物,其中A是各自任选地被一个或多个R6取代的C6-C10芳基、C3-C10环烃基或5-6元单环杂芳基。
28.如权利要求27所述的化合物,其中A是苯基。
29.如权利要求27所述的化合物,其中A是饱和或不饱和的环己烃基。
30.如权利要求27所述的化合物,其中A是吡啶基。
31.如权利要求27所述的化合物,其中A是嘧啶基。
32.如权利要求1至31中任一项所述的化合物,其中A是未取代的。
33.如权利要求1至31中任一项所述的化合物,其中A被一个或多个R6取代。
34.如权利要求33所述的化合物,其中R6是卤素。
35.如权利要求34所述的化合物,其中卤素是氯或氟。
36.如权利要求33所述的化合物,其中R6是C1-C6羟基烷基。
37.如权利要求36所述的化合物,其中C1-C6羟基烷基是-CH2CH2OH。
38.如权利要求33所述的化合物,其中R6是氰基。
39.如权利要求33所述的化合物,其中R6是C1-C6烷氧基。
40.如权利要求39所述的化合物,其中C1-C6烷氧基是甲氧基。
45.如权利要求1至41中任一项所述的化合物,其中X是CH。
46.如权利要求1所述的化合物,其中所述化合物具有表1中列出的结构中的一种,或其药物可接受的盐、立体异构体或前药。
47.如权利要求1至46中任一项所述的化合物,其中所述化合物是NLRP3炎性体的调节剂。
48.如权利要求1至47中任一项所述的化合物,其中所述化合物是NEK7的抑制剂。
49.药物组合物,包含权利要求1至48中任一项所述的化合物和药物可接受的载体、稀释剂或赋形剂。
50.治疗NLRP3介导的病症的方法,包括向有需要的个体施用治疗有效量的权利要求1至48中任一项所述的化合物或权利要求49所述的药物组合物。
51.如权利要求50所述的方法,其中所述病症选自自身免疫性疾病、炎性病症、心血管疾病、神经退行性病症、细菌和病毒感染、过敏症、哮喘、胰腺炎、多器官衰竭、肾病、血小板聚集、癌症、移植、精子活力、红血球缺乏症、移植排斥、肺损伤、呼吸道疾病和缺血性病况。
52.如权利要求50或51所述的方法,其中所述病症选自II型糖尿病、动脉粥样硬化、阿尔茨海默病、衰老、脂肪肝、代谢综合征、哮喘、银屑病、肥胖、由感染引起的急性和慢性组织损伤、痛风、关节炎、黄斑变性、肠炎、肝炎、腹膜炎、硅肺病、UV诱导的皮肤晒伤、接触性超敏反应、败血症、癌症、神经退行性疾病、多发性硬化症和穆-韦二氏综合征。
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CN114751874A (zh) * | 2022-05-30 | 2022-07-15 | 江南大学 | 作为TRPV4-KCa2.3促耦联剂的1-苄基-4-乙基哌嗪衍生物及其应用 |
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