CN110099899B - 用作irak抑制剂的噁唑衍生物及其制备方法 - Google Patents
用作irak抑制剂的噁唑衍生物及其制备方法 Download PDFInfo
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- CN110099899B CN110099899B CN201780080581.6A CN201780080581A CN110099899B CN 110099899 B CN110099899 B CN 110099899B CN 201780080581 A CN201780080581 A CN 201780080581A CN 110099899 B CN110099899 B CN 110099899B
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- Prior art keywords
- pyrazol
- oxazole
- compound
- carboxamide
- substituted
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Abstract
所公开的实施方案涉及是式1噁唑化合物的白介素受体相关激酶(IRAK)抑制剂和包含此类抑制剂的组合物。还公开了制备和使用该化合物和组合物的方法。所公开的化合物和/或组合物可用于治疗或预防IRAK相关疾病或病症。
Description
相关申请的交叉援引
本申请要求提交日更早的于2016年10月26日提交的美国临时专利申请第62/413,217号的优先权,通过引用将该申请全文纳入本文。
技术领域
本发明涉及白介素受体相关激酶(IRAK)抑制剂,例如噁唑化合物,以及制备和使用这些化合物来治疗与IRAK相关的疾病和病症的方法的实施方式。
背景技术
白介素-1受体相关激酶(IRAK)是信号传导过程,如Toll样受体(TLR)和白介素-1受体(IL-1R)信号传导过程的重要介质。IRAK涉及调节控制炎症、细胞凋亡和细胞分化的信号传导网络。已经在人类基因组中鉴定出四种IRAK基因(IRAK1,IRAK2,IRAK3和IRAK4),并且研究揭示了不同的、非冗余的生物学作用。已显示IRAK1和IRAK4表现出激酶活性。
发明内容
某些公开的实施方式涉及式I的化合物
或其盐。本领域普通技术人员将理解,式1中的化合物也可以是其溶剂化物、水合物和/或前药。参考式1,R1和R2中的至少一个是芳族的,并且剩余的R1或R2是H、烷基、卤代烷基、硝基、氰基、酰胺、氨基、羟基、羧基、羧基酯或酰基。对于具体的实施方式,R1和R2中的一个是含氮杂芳基,例如6元含氮杂芳基,特别是吡啶基、嘧啶基或吡嗪基,例如嘧啶-2-基,嘧啶-4-基,吡嗪-2-基,6-(二氟甲基)吡啶-2-基,3-氟-6-(三氟甲基)吡啶-2-基,3,6-二氟吡啶-2-基或3,5-二氟吡啶-2-基,R1和R2中的另一个是H或C1-6烷基。R3是H、脂族、杂脂族、杂环基、酰胺、芳族或芳脂族。在具体的实施方式中,R3是H,烷基,环烷基,杂脂族或杂环脂族,甚至更具体地,R3是C1-6烷基,四氢吡喃,未取代的杂脂族,被卤素取代的杂脂族,未取代的环丁基,被烷氧基取代的环丁基,未取代的环己基,或被-OH、烷氧基或杂环脂族取代的环己基。公开的化合物的示例性物质包括:R3选自甲基,4-乙氧基环己基,4-吗啉基环丁基,3-乙氧基环丁基,4-羟基环己基,3-羟基环丁基,4-(4-甲基哌嗪-1-基)环己基,3-吗啉基环己基或(2,6-二甲基吗啉基)环己基的化合物。R4是H、脂族、杂脂族,或R1和R2中的一个与R4以及与它们所连接的原子一起形成杂环。在具体的实施方式中,R4是H或C1-6烷基,通常是H。R5是H或脂族,更通常是H、C1-6烷基或C1-6卤代烷基。环A通常是杂芳基,更通常环A是含氮杂芳基,例如吡唑基。环A可以是未取代的。或者,环A可以被1-4个取代基取代,例如至少一个取代基选自:脂族,卤素,烷基磷酸酯或烷基膦酸酯。
因此,某些公开的实施方式涉及具有式1的化合物,其中R1和R2中的一个选自吡啶基,嘧啶基或吡嗪基,R1和R2中的另一个是H;R3为C1-6烷基,四氢吡喃,未取代的杂脂族,被卤素取代的杂脂族基,未取代的环丁基,被-OH、烷氧基或杂环脂族取代的环丁基,未取代的环己基,或被-OH、烷氧基或杂环脂族取代的环己基;R4是H;R5是H;环A是吡唑基。
本发明还公开了式2的化合物:
其中,取代基如式1的定义。
本发明还公开了式3的化合物:
其中R1-R5如式1和2的定义。式3中的每个R6独立地是H,脂族,环脂族,杂脂族,卤素,芳基,-O-脂族,芳脂族,杂环基,磺酰基,硝基,-OH,卤代烷基,羧基酯,氰基,酰基,氨基,烷基磷酸酯或烷基膦酸酯。更典型地,式3中的每个R6独立地为H,卤素,环脂族,或烷基磷酸酯或烷基膦酸酯或其盐。
本发明还公开了式4的化合物:
其中R1-R5如式1-3的定义。R7、R8和R9各自独立地是H,脂族,环脂族,杂脂族,卤素,芳基,-O-脂族,芳脂族,杂环基,磺酰基,硝基,-OH,卤代烷基,羧基酯,氰基,酰基,氨基,烷基磷酸酯或烷基膦酸酯。R7通常为H,烷基,羧基酯,酰基,烷基磷酸酯,烷基膦酸酯,杂环烷基或芳烷基,例如H、-CH2OP(O)(OH)2或其盐。具体实施方式中R8和R9独立地选自:H,卤素,烷基或卤代烷基,甚至更具体的实施方式中R8和R9是H,或者R8和R9中的一个为H而另一个为F。
参考式1的化合物,R1和R2中的一个是杂芳基,剩余的R1或R2是H,烷基,卤代烷基,硝基,氰基,酰胺基,氨基,羟基,羧基,羧基酯或酰基。R3是Ra,Rb,被1、2或3个Rb取代的Ra,被Rb和Rc取代的Ra,被Rc -取代的Ra,–(CRaRa)n-Ra,-(CH2)n-Ra,-(CRaRa)n-Rb,
-(CH2)n-Rb,-[(CH2)m-O-]n-Ra,-[(CH2)m-O-]n-[被1、2或3个Rb取代的Ra],或
-(CH2)m-O-(CH2)m-O-Ra,其中m和n各自独立地是1、2或3。R4是Ra,
-(CRaRa)m-O-Ra,-(CH2)m-O-Ra,-(CRaRa)m-O-(CRaRa)m-O-Ra,-[(CH2)m-O-]n-Ra或
-(CH2)m-O-(CH2)m-O-Ra,其中m和n各自独立地是1、2或3。R5是Ra或Rb。对于每次出现,Ra独立地是H,D,C1-6烷基,C1-6卤代烷基,C3-6环烷基,C3-6杂脂环基, 其中Y和Z独立地是–CH2、-CHRb、O或NRd。对于每次出现,Rc独立地是C1-6烷基,C3-6杂脂环基,被1、2或3个Re取代的C1-6烷基,
被1、2或3个Re取代的C3-6环烷基,或被1、2或3个Re取代的C3-6杂脂环基。对于每次出现,Rd独立地是–C(O)Ra,任选地被1、2或3个Re取代的C1-6烷基,或者两个Rd基团与它们所连接的氮一起形成任选地被C1-6烷基取代并且任选地含有一或两个–O–或–N(Rg)的C3-6杂脂环基部分(其中Rg是R70)。对于每次出现,Re独立地是C1-6烷基或-ORa。
根据本发明的示例性化合物可选自:N-(1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-((1r,4r)-4-吗啉基环己基)-3-(嘧啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-((1r,4r)-4-乙氧基环己基)-3-(嘧啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(3-(6-(二氟甲基)吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(3-(6-(二氟甲基)吡啶-2-基)-1-((1R,4r)-4-((2R,6S)-2,6-二甲基吗啉基)环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-((1r,4r)-4-乙氧基环己基)-3-(嘧啶-4-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(3-(3-氟-6-(三氟甲基)吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;(4-(4-((3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基磷酸钠;N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(3-(3,6-二氟吡啶-2-基)-1-((1s,3s)-3-乙氧基环丁基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-羟基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;磷酸二氢(4-(4-((3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基酯;N-(3-(3,5-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(5-(3,6-二氟吡啶-2-基)-1-((1r,4R)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;2-(1H-吡唑-4-基)-N-(3-(吡啶-2-基)-1-(2-(2,2,2-三氟乙氧基)乙基)-1H-吡唑-4-基)噁唑-4-甲酰胺;((4-(4-((1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基)磷酸二叔丁酯;磷酸二氢(4-(4-((1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基酯;(4-(4-((1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基磷酸钠;2-(1-(环丙基甲基)-1H-吡唑-4-基)-N-(1-甲基-3-(吡啶-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺;2-(1H-吡唑-4-基)-N-(3-(吡啶-2-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-(2-乙氧基乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-((1s,3s)-3-乙氧基环丁基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-环丁基-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-(2-(2-甲氧基乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;2-(1H-吡唑-3-基)-N-(3-(吡啶-2-基)-1-(2-(2,2,2-三氟乙氧基)乙基)-1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-(2-(2,2-二氟乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(3-(3,6-二氟吡啶-2-基)-1-((1r,3r)-3-乙氧基环丁基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-((1r,4r)-4-羟基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-((1r,4r)-4-乙氧基环己基)-3-(3,5,6-三氟吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(3-(4,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-((1r,4r)-4-吗啉基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-((1r,4r)-4-乙氧基环己基)-3-(3-氟-6-(三氟甲基)吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(5-氟-1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-((1r,3r)-3-吗啉基环丁基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-((1s,3s)-3-吗啉基环丁基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;2-(3-氟-1H-吡唑-4-基)-N-(1-((1r,4r)-4-吗啉基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺甲酸盐;N-(3-(3,6-二氟吡啶-2-基)-1-((1s,4s)-4-(4-甲基哌嗪-1-基)环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-((1s,3s)-3-羟基环丁基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;和2-(3-氟-1H-吡唑-4-基)-N-(1-((1r,4r)-4-吗啉基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺。
在某些实施方式中,化合物不是2-(1-(环丙基甲基)-1H-吡唑-4-基)-N-(1-甲基-3-(吡啶-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺;2-(1H-吡唑-4-基)-N-(3-(吡啶-2-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-(2-乙氧基乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-((1s,3s)-3-乙氧基环丁基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-环丁基-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-(2-(2-甲氧基乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-(2-(2,2-二氟乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(1-(2-(2,2-二氟乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;N-(3-氨甲酰基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;或2-(1H-吡唑-3-基)-N-(3-(吡啶-2-基)-1-(2-(2,2,2-三氟乙氧基)乙基)-1H-吡唑-4-基)噁唑-4-甲酰胺。
根据本发明的化合物还可以配制成包含一种或多种式1-12中任一项的化合物和药学上可接受的赋形剂的组合物。此类组合物还可包含另外的治疗剂。
还公开了制备和使用这些化合物和组合物的方法。例如,使用式1-12化合物的方法的一个公开实施方式包括给予有需要的对象有效量的根据式1-12中任一项或所有项的化合物,两种或更多种化合物,或包含至少一种化合物的组合物。该方法可特别适用于治疗指示IRAK抑制剂的疾病或病症,包括IRAK1,IRAK2,IRAK3和/或IRAK4抑制剂。这种疾病可能是自身免疫性疾病,炎性疾病,心血管疾病,神经变性疾病,过敏性疾病,多器官衰竭,肾脏疾病,血小板聚集病,癌症,移植,精子活力,红细胞缺乏,移植物排斥,肺损伤,呼吸系统疾病,缺血性病症,细菌感染,病毒感染,免疫调节障碍或其组合。
使用根据式1-12的化合物的方法的公开实施方式还包括通过使IRAK蛋白质与有效量的式1-12中任一项或所有项的一种或多种化合物或包含一种或多种化合物的组合物接触来抑制IRAK蛋白质,其中化合物的EC50为大于0至5μM,通常为0至1μM,并且许多公开的化合物具有显著低于1μM的EC50。IRAK蛋白可以在对象中,或者该方法可以包括在体外接触IRAK蛋白。
美国专利申请15/136,508提供了本发明公开实施方式的其他特征,该专利申请通过引用结合于此。
根据以下详细说明,本文所述发明的这些和其它目的、特征和优点将变得更显而易见。
具体实施方式
I.定义
提供如下定义和方法,以更好地限定本发明,并且指导本领域普通技术人员实践本发明。单数形式“一个/一种”(a/an)和“该”(the)是指一个/一种或多于一个/一种,除非上下文另外明确指示。术语“或”是指陈述的可替代性元素的单个元素或者两个或更多个元素的组合,除非上下文另外明确指示。如在此使用,“包含”意指“包括”。因此,“包含A或B,”意指“包括A、B、或A和B”而不排除另外的元素。在此引用的所有参考文献(包括专利和专利申请)通过引用并入。
除非另有说明,所有表示组分、分子量、百分比、温度、时间等的量的数字,如在说明书或权利要求书中使用的将被理解为由术语“约”进行修饰。因此,除非明确地或隐含地另外说明,提出的数值参数是可能取决于所希望的所需性能和/或在标准测试条件/方法下的检测限度的近似值。当直接地或明确地区别实施例和所讨论的现有技术时,实施例的数量不是近似的,除非引用词语“约”。
除非另外解释,否则在此所使用的所有技术和科学术语具有与本披露所属领域的普通技术人员通常所理解相同的含义。虽然在本发明的实施或测试中可以采用类似于或等同于本文所述的那些方法和材料,但下文描述了合适的方法和材料。材料、方法和实施例都仅是说明性的,不构成限制。
当描绘或描述化学结构时,除非另外清楚地说明,假定所有碳包括氢以致于每个碳符合四价化合价。例如,在以下示意图的左手边的结构中,暗示有九个氢原子。该九个氢原子描绘在右手边结构中。
有时结构中的特定原子在本文的化学式中描述为具有氢或氢原子,例如-CH2CH2-。本领域普通技术人员将会理解,上述描述的技术在化学领域中是常见的,以提供有机结构的描述的简洁性和简单性。
如果基团R被描绘为“漂浮”在环系统上,例如在以下基团中:
那么,除非另有定义,否则取代基R可以存在于稠合双环系统的任何原子上,不包括带有带符号的键的原子,只要形成稳定的结构即可。在所示的实例中,R基团可以位于吲哚基环系统的5元环或6元环中的原子上。
如果存在多于一个这样描述的“漂浮”基团,例如在以下通式中:
其中有两个基团(即R和指示连接于母体结构的键);那么,除非另有定义,“漂浮”基团可以驻留在环系统的任何原子上,同样假设各自替换环系统上描绘的、隐含的或明确定义的氢,并且通过这样的排列形成化学稳定的化合物。
如果基团R被描绘为存在于含有饱和碳的环系统上时,例如在以下通式中:
其中,在该实例中,y可以大于1,假设各自替换环上当前描绘的、隐含的或明确定义的氢;那么,除非另有定义,否则两个R可以位于相同的碳上。一个简单的例子是当R是甲基时。所描绘的结构可以作为所示环的碳(“环状”碳)上的孪生二甲基存在。在另一个实例中,在相同碳上的两个R,包括相同的碳,可以形成环,从而产生螺环(“螺环基”)结构。例如,如下所示,两个R可以与环己烷形成螺环排列的哌啶环,如
如本文使用,术语“取代的”是指术语中所有后来的修饰部分,例如在术语“取代的芳基C1-8烷基”中取代可以发生在芳基C1-8烷基基团的“C1-8烷基”部分、“芳基”部分或两个部分上。
当用于修饰特定的基团或部分时,“取代的”是指特定基团或部分的至少一个,可能两个或更多个氢原子独立地被如下定义的相同或不同的取代基取代。在一个具体实施方案中,基团、部分或取代基可以是取代的或未取代的,除非明确定义为“未取代的”或“取代的”。因此,本文中指定的任何基团可以是未取代的或取代的。在特定的实施方案中,取代基可以或可以不明确定义为取代的,但仍考虑任选被取代。例如,“烷基”或“吡唑基”部分可以是未取代的或取代的,但“未取代的烷基”或“未取代的吡唑基”未被取代。
除非另有说明,否则用于取代特定基团或部分中的饱和碳原子上的一个或多个氢原子的“取代基”或“取代基”是-R60,卤素,=O,-OR70,-SR70,-N(R80)2,卤代烷基,全卤代烷基,-CN,-NO2,=N2,-N3,-SO2R70,-SO3 –M+,-SO3R70,-OSO2R70,-OSO3 –M+,-OSO3R70,-P(O)(O–)2(M+)2,-P(O)(O–)2M2+,-P(O)(OR70)O–M+,-P(O)(OR70)2,-C(O)R70,-C(S)R70,-C(NR70)R70,-CO2 –M+,-CO2R70,-C(S)OR70,
-C(O)N(R80)2,-C(NR70)(R80)2,-OC(O)R70,-OC(S)R70,-OCO2 -M+,-OCO2R70,-OC(S)OR70,-NR70C(O)R70,-NR70C(S)R70,-NR70CO2 –M+,-NR70CO2R70,-NR70C(S)OR70,
-NR70C(O)N(R80)2,-NR70C(NR70)R70和-NR70C(NR70)N(R80)2,其中R60是C1-10脂族,杂脂族或环脂族,通常是C1-6脂族基,更通常是C1-6烷基,其中R60任选地可以被取代;每次出现时,R70各自独立地是氢或R60;每次出现时,R80各自独立地是R70,或者两个R80基团与它们所键合的氮原子一起形成3-至7-元杂环脂族,其任选地包括1至4个相同或不同的另外的选自O、N和S的杂原子,其中N任选地具有R70取代,例如H或C1-C3烷基取代;并且每个M+是具有净单个正电荷的反离子。每次出现时,M+各自独立地是例如碱金属离子(如K+、Na+、Li+);铵离子(如+N(R60)4);质子化氨基酸离子(如赖氨酸离子或精氨酸离子);或碱土金属离子(如[Ca2+]0.5、[Mg2+]0.5或[Ba2+]0.5)(下标“0.5”指这类二价碱土金属离子的抗衡离子之一可以是本发明化合物的离子化形式且另一个可以是典型的抗衡离子(如氯),或者两种离子化的本发明化合物可作为这类二价碱土金属离子的抗衡离子,或者双离子化的化合物可作为这类二价碱土金属离子的抗衡离子)。作为具体实例,-N(R80)2包括-NH2,-NH-烷基,-NH-吡咯烷-3-基,N-吡咯烷基,N-哌嗪基,4N-甲基-哌嗪-1-基,N-吗啉基等。在单个碳上的任何两个氢原子也可以被=O、=NR70、=N-OR70、=N2或=S代替。
除非另外指明,用于在含有不饱和碳的基团的不饱和碳原子上替代氢原子的取代基基团是-R60,卤代,
-O-M+,-OR70,-SR70,-S–M+,-N(R80)2,卤代烷基,全卤代烷基,-CN,-OCN,-SCN,-NO,-NO2,
-N3,-SO2R70,-SO3 –M+,-SO3R70,-OSO2R70,-OSO3 –M+,-OSO3R70,-PO3 -2(M+)2,
-PO3 -2M2+,-P(O)(OR70)O–M+,-P(O)(OR70)2,-C(O)R70,-C(S)R70,-C(NR70)R70,
-CO2 –M+,-CO2R70,-C(S)OR70,-C(O)NR80R80,-C(NR70)N(R80)2,
-OC(O)R70,-OC(S)R70,-OCO2 –M+,-OCO2R70,-OC(S)OR70,-NR70C(O)R70,
-NR70C(S)R70,-NR70CO2 –M+,-NR70CO2R70,-NR70C(S)OR70,-NR70C(O)N(R80)2,
-NR70C(NR70)R70和-NR70C(NR70)N(R80)2,其中R60、R70、R80和M+是如先前所定义的,条件是在取代的烯烃或炔烃的情况下,这些取代基不是-O-M+、-OR70、-SR70或-S-M+。
除非另外指明,用于在含有此类氮原子的基团中的氮原子上替换氢原子的取代基基团是-R60,-O-M+,-OR70,-SR70,-S-M+,-N(R80)2,卤代烷基,全卤代烷基,-CN,-NO,-NO2,
-S(O)2R70,-SO3 -M+,-SO3R70,-OS(O)2R70,-OSO3 -M+,-OSO3R70,-PO3 2-(M+)2,
-PO3 2-
M2+,-P(O)(OR70)O-M+,-P(O)(OR70)(OR70),-C(O)R70,-C(S)R70,-C(NR70)R70,
-CO2R70,-C(S)OR70,-C(O)NR80R80,-C(NR70)NR80R80,-OC(O)R70,-OC(S)R70,-OCO2R70,
-OC(S)OR70,-NR70C(O)R70,-NR70C(S)R70,-NR70CO2R70,-NR70C(S)OR70,-NR70C(O)N(R80)2,-NR70C(NR70)R70和-NR70C(NR70)N(R80)2,其中R60、R70、R80和M+如先前所定义。
在一个实施方式中,取代的基团具有至少一个取代基,直至特定部分可能的取代基数目,例如1个取代基,2个取代基,3个取代基或4个取代基。
另外,在基团或部分被取代的取代基取代的实施方案中,这种取代的取代基的嵌套限于三个,从而防止形成聚合物。因此,在包含第一基团的基团或部分中,该第一基团是在第二基团上的取代基,该第二基团本身是在第三基团上的取代基,该基团或部分附接至母体结构,该第一(最外面的)基团仅可被未取代的取代基取代。例如,在包含-(芳基-1)-(芳基-2)-(芳基-3)的基团中,芳基-3仅可以被本身不被取代的取代基取代。
本文定义的任何基团或部分可以与公开结构的任何其他部分连接,例如母体或核心结构,如本领域普通技术人员所理解的,例如通过考虑化合价规则,与示例性的物质比较,和/或考虑功能性,除非明确说明基团或部分与结构的其他部分的连接,或者由上下文暗示。
“酰基”是指基团–C(O)R,其中R是H,脂族,杂脂族,杂环或芳族。示例性的酰基部分包括但不限于:-C(O)H、-C(O)烷基、-C(O)C1-C6烷基、-C(O)C1-C6卤代烷基-C(O)环烷基、-C(O)烯基、-C(O)环烯基、-C(O)芳基、-C(O)杂芳基或-C(O)杂环基。具体的实例包括-C(O)H、-C(O)Me、-C(O)Et或-C(O)环丙基。
“脂族”是指基本上基于烃的基团或部分。脂族基团或部分可以是无环的,包括烷基、烯基或炔基,其环状形式,例如环脂族基团或部分,包括环烷基、环烯基或环炔基,并且还包括直链和支链排列,以及所有立体和位置异构体。除非另有明确说明,否则对于五环脂族基团或部分,脂族基团含有1至25个(C1-25)碳原子;例如,1至15个(C1-15),1至10个(C1-10),1至6个(C1-6),或1至4个(C1-4)碳原子,或者对于环脂族基团或部分,脂族基团含有3至15个(C3-15),3至10个(C3-10),3至6个(C3-6),或3至4个(C3-4)碳原子。脂族基团可以是取代的或未取代的,除非明确地称为“未取代的脂族”或“取代的脂族基”。脂族基团可以被一个或多个取代基取代(脂族链中的每个亚甲基碳至多两个取代基,或者对于脂族链中C=C双键的每个碳至多一个取代基,或者对于末端次甲基的碳至多一个取代基)。
“低级脂族”是指含有1-10个碳原子(C1-10)的脂族基团,例如1-6个(C1-6),或1-4个(C1-4)碳原子;或者对于低级环脂族基团,可以是3至10个(C3-10),例如3至6个(C3-6)碳原子。
“烷氧基”是指基团-OR,其中R是取代或未取代的烷基或取代或未取代的环烷基。在某些实例中,R是C1-6烷基或C3-6环烷基。甲氧基(-OCH3)和乙氧基(-OCH2CH3)是示例性的烷氧基。在取代的烷氧基中,R是取代的烷基或取代的环烷基,其在本发明公开的化合物中的实例包括卤代烷氧基,如-OCF2H。
“烷氧基烷基”是指基团-烷基-OR-,其中R是取代或未取代的烷基或取代或未取代的环烷基;–CH2CH2-O-CH2CH3是示例性的烷氧基烷基。
“烷基”是指具有1至至少25个(C1-25)碳原子,更通常1至10个(C1-10)碳原子,例如1至6个(C1-6)碳原子的饱和脂族烃基。烷基部分可以是取代或未取代的。举例来说,该术语包括直链和支链烃基,例如甲基(CH3),乙基(-CH2CH3),正丙基(-CH2CH2CH3),异丙基(-CH(CH3)2),正丁基(-CH2-CH2CH2CH3),异丁基(-CH2CH2(CH3)2),仲丁基(-CH(CH3)(CH2CH3),叔丁基(-C(CH3)3),正戊基(-CH2CH2CH2CH2CH3)和新戊基(-CH2C(CH3)3)。
“氨基”是指基团-NH2,-NHR或-NRR,其中每个R独立地选自H,脂族,杂脂族,芳族,包括芳基和杂芳基,或杂环脂族,或两个R基团以及与其连接的氮一起形成杂环。这种杂环的实例包括其中两个R基团与它们所连接的氮一起形成–(CH2)2-5–环的那些,任选地被一个或两个杂原子基团间隔,例如-O-或-N(Rg),例如在基团中,其中Rg是R70,-C(O)R70,-C(O)OR60或-C(O)N(R80)2。
“酰胺”或“甲酰胺”是指基团-N(R)酰基或C(O)氨基,其中R是氢,杂脂族或脂族基,例如烷基,特别是C1-6烷基。
“芳族”是指除非另有说明,具有单个环(例如苯基,吡啶基或吡唑基)或多个稠环的5至15个环原子的环状共轭基团或部分,其中至少一个环是芳族的(例如,萘基,吲哚基或吡唑并吡啶基),即至少一个环,和任选的多个稠合环,具有连续的离域π电子系统。通常,平面外π电子的数量对应于Hückel规则(4n+2)。与母体结构的连接点通常是通过稠环系统的芳香部分。例如,然而,在某些实例中,上下文或明确公开可指示连接点是通过稠环系统的非芳族部分。例如,/>芳族基团或部分可以仅包含环中的碳原子,例如芳基或部分,或者它可以包含一个或多个环碳原子和一个或多个包含孤对电子的环杂原子(例如S,O,N,P或Si),例如在杂芳基或部分中。除非另有说明,否则芳族基团可以是取代的或未取代的。
“芳基”是指除非另有说明,具有单个环(例如苯基)或多个稠环的6至15个碳原子的芳族碳环基团,其中至少一个环是芳族的(例如1,2,3,4-四氢喹啉,苯并二氧杂环戊环等)。如果任何芳环部分含有杂原子,则该基团是杂芳基而不是芳基。芳基可以是例如单环,双环,三环或四环。除非另有说明,否则芳基可以是取代的或未取代的。
“芳脂族”是指通过脂族部分与母体连接的芳基。芳脂族基团包括芳烷基或芳基烷基基团,例如苄基和苯乙基。
“羧基”或“羧酸盐”是指–CO2H、-C(O)O-或其盐。
“羧基酯”或“羧酸酯”是指基团–C(O)OR,其中R是脂族,杂脂族,环状,杂环和芳族,包括芳基和杂芳基。
“氰基”是指基团–CN。
“环脂族”是指具有单个环(例如环己基)或多个环的环状脂族基团,例如在稠合,桥接或螺环系统中,其中至少一个是脂族的。通常,与母体结构的连接点是通过多环系统的脂族部分。环脂族包括饱和和不饱和体系,包括环烷基,环烯基和环炔基。环脂族基团可含有三至二十五个碳原子;例如,3至15,3至10,或3至6个碳原子。除非另有说明,否则环脂族基团可以是取代的或未取代的。示例性的环脂族基团包括但不限于:环丙基,环丁基,环戊基,环己基,环庚基,环戊烯基或环己烯基。
“卤代”,“卤化物”或“卤素”是指氟,氯,溴或碘。
“卤代烷基”是指被一个或多个卤素取代的烷基部分。示例性的卤代烷基部分包括–CH2F,-CHF2和-CF3。
“杂脂族”是指具有至少一个杂原子和至少一个碳原子的脂族化合物或基团,即包含至少两个碳原子的脂族化合物或基团的一个或多个碳原子已经被具有至少一对孤对电子的原子(通常是氮,氧,磷,硅或硫)取代。杂脂族化合物或基团可以是取代或未取代的,支链或非支链的,手性或非手性的,和/或无环的或环状的,例如杂环脂族基团。
除非另有说明,“杂芳基”是指包含至少一个碳原子和至少一个杂原子(例如N,S,O,P或Si)的5至15个环原子的芳族基团或部分。杂芳基或部分可包含单个环(例如,吡啶基,嘧啶基或吡唑基)或多个稠合环(例如吲哚基,苯并吡唑基或吡唑并吡啶基)。杂芳基基团或部分可以是例如单环,双环,三环或四环。除非另有说明,否则杂芳基或部分可以是取代的或未取代的。
“杂环基”和“杂环”是指芳族和非芳族环系统,更具体地是指包含至少一个碳原子且通常为多个碳原子以及至少一个(例如一至五个杂原子)的稳定的三至十五元环部分。杂原子可以是氮,磷,氧,硅或硫原子。杂环基部分可以是单环部分,或可以包含多个环,例如在双环或三环体系中,条件是至少一个环含有杂原子。这种多环部分可包括稠合或桥环系统以及螺环系统;并且杂环基部分中的任何氮,磷,碳,硅或硫原子可任选被氧化成各种氧化态。为方便起见,氮,特别是但不限于那些定义为环状芳族氮的那些,意味着包括它们相应的N-氧化物形式,尽管在特定实例中没有明确定义。因此,对于具有例如吡啶基环的化合物,包括相应的吡啶基-N-氧化物作为本发明的另一种化合物,除非明确排除或在上下文中排除。另外,环状氮原子可任选被季铵化。杂环包括杂芳基部分和杂脂环基或杂环脂族部分,它们是部分或完全饱和的杂环基环。杂环基的实例包括但不限于:氮杂环丁烷基,氧杂环丁烷基,吖啶基,苯并二氧杂环戊烯基,苯并二噁烷基,苯并呋喃基,咔唑基,噌啉基,二氧戊环基,吲嗪基,萘啶基,全氢吖庚基(perhydroazepinyl),吩嗪基,吩噻嗪基,吩噁嗪基,酞嗪基,蝶啶基,嘌呤基,喹唑啉基,喹喔啉基,喹啉基(quinolinyl),异喹啉基,四唑基,四氢异喹啉基,哌啶基,哌嗪基,2-氧代哌嗪基,2-氧代哌啶基,2-氧代吡咯烷基,2-氧代氮杂环庚基,氮杂环庚基,吡咯基,4-哌啶酮基,吡咯烷基,吡唑基,吡唑烷基,咪唑基,咪唑啉基,咪唑烷基,二氢吡啶基,四氢吡啶基,吡啶基,吡嗪基,嘧啶基,哒嗪基,噁唑基,噁唑啉基,噁唑烷基,三唑基,异噁唑基,异噁唑烷基,吗啉基,噻唑基,噻唑啉基,噻唑烷基,异噻唑基,喹唑啉基,异噻唑烷基,吲哚基,异吲哚基,二氢吲哚基,异二氢吲哚基,八氢吲哚基,八氢异吲哚基,喹啉基(quinolyl),异喹啉基,十氢异喹啉基,苯并咪唑基,噻二唑基,苯并吡喃基,苯并噻唑基,苯并噁唑基,呋喃基,二氮杂双环庚烷,二氮杂环庚烷,二氮杂四氢呋喃基,四氢吡喃基,噻吩基,苯并噻吩基,硫代吗啉基,硫代吗啉基亚砜,硫代吗啉基砜,二氧磷杂环戊烷基(dioxaphospholanyl)和噁二唑基。
“羟基”是指基团-OH。
“硝基”是指基团–NO2。
“磷酸酯”是指基团–O-P(O)(OR’)2,其中-OR'各自独立地为-OH;-O-脂族,例如-O-烷基或-O-环烷基;-O-芳族,包括-O-芳基和-O-杂芳基;-O-芳烷基;或-OR'是-O-M+,其中每个M+是带正电荷的反离子。举例来说,M+可以是碱离子,例如K+,Na+,Li+;铵离子,例如+N(R”)4,其中R”是H,脂族,杂环基或芳基;或碱土离子,例如[Ca2+]0.5,[Mg2+]0.5,或[Ba2+]0.5。磷酰氧基烷基是指基团-烷基-磷酸酯/盐,例如-CH2OP(O)(OH)2,或其盐,例如-CH2OP(O)(O-Na+)2,(((二烷氧基磷酰基)氧基)烷基)是指磷酰氧基烷基的二烷基酯,例如-CH2OP(O)(O-叔丁基)2。
“膦酸酯”是指基团-P(O)(OR’)2,其中-OR'各自独立地为-OH;-O-脂族,例如-O-烷基或-O-环烷基;-O-芳族,包括-O-芳基和-O-杂芳基;或-O-芳烷基;或-OR'是-O-M+,其中M+是带正电荷的反离子。举例来说,M+可以是碱金属离子,例如K+,Na+,Li+;铵离子,例如+N(R”)4,其中R”是H,脂族,杂环基或芳基;或碱土金属离子,例如[Ca2+]0.5,[Mg2+]0.5,或[Ba2 +]0.5。膦酰氧基烷基是指基团-烷基-膦酸酯/盐,例如-CH2P(O)(OH)2,或-CH2P(O)(O-Na+)2,(((二烷氧基膦酰基)氧基)烷基)是指膦酰烷基的二烷基酯,例如-CH2P(O)(O-叔丁基)2。
“患者”或“对象”是指哺乳动物和其他动物,尤其是人类。因此,本发明的方法适用于人类治疗和兽医应用。
“药学上可接受的赋形剂”是指包含在活性成分制剂中的除活性成分之外的物质。如本文所用,赋形剂可以掺入药物组合物的颗粒内,或者它可以与药物组合物的颗粒物理混合。赋形剂可用于例如稀释活性剂和/或改变药物组合物的性质。赋形剂可包括但不限于:抗粘附剂,粘合剂,包衣,肠溶包衣,崩解剂,调味剂,甜味剂,着色剂,润滑剂,助流剂,吸附剂,防腐剂,佐剂,载体或运载体。赋形剂可以是淀粉和改性淀粉,纤维素和纤维素衍生物,糖类及其衍生物,例如二糖,多糖和糖醇,蛋白质,合成聚合物,交联聚合物,抗氧化剂,氨基酸或防腐剂。示例性的赋形剂包括但不限于:硬脂酸镁,硬脂酸,植物性硬脂酸甘油酯,蔗糖,乳糖,淀粉,羟丙基纤维素,羟丙基甲基纤维素,木糖醇,山梨糖醇,麦芽糖醇,明胶,聚乙烯吡咯烷酮(PVP),聚乙二醇(PEG),生育酚聚乙二醇1000琥珀酸酯(也称维生素E TPGS或TPGS),羧甲基纤维素,二棕榈酰磷脂酰胆碱(DPPC),维生素A,维生素E,维生素C,棕榈酸视黄酯,硒,半胱氨酸,蛋氨酸,柠檬酸,柠檬酸钠,对羟基苯甲酸甲酯,对羟基苯甲酸丙酯,糖,二氧化硅,滑石,碳酸镁,羟基乙酸淀粉钠,酒石黄,阿斯巴甜,苯扎氯铵,芝麻油,没食子酸丙酯,偏亚硫酸氢钠或羊毛脂。
“佐剂”是改变其他药剂(通常是活性成分)的作用的赋形剂。佐剂通常是药理学和/或免疫学试剂。佐剂可以通过增加免疫应答来改变活性成分的作用。佐剂也可以作为制剂的稳定剂。示例性佐剂包括但不限于氢氧化铝,明矾,磷酸铝,灭活细菌,角鲨烯,洗涤剂,细胞因子,石蜡油和组合佐剂,例如弗氏完全佐剂或弗氏不完全佐剂。
“药学上可接受的载体”是指作为载体或运载体的赋形剂,例如悬浮助剂,增溶助剂或雾化助剂。Remington:The Science and Practice of Pharmacy[雷明顿:药学科学与实践],费城科学大学,编辑:Lippincott,Williams和Wilkins,宾夕法尼亚州费城,第21版(2005),通过引用并入本文,描述了适合于药物递送一种或多种治疗组合物和另外的药学试剂的组合物和制剂。
通常,载体的性质取决于所采用的特定给药方式。例如,胃肠外制剂通常包含可注射的流体,其包括药学上和生理学上可接受的流体,例如水,生理盐水,平衡盐溶液,葡萄糖水溶液,甘油等作为运载体。在一些实例中,药学上可接受的载体可以是无菌的以适合给予对象(例如,通过胃肠外,肌内或皮下注射)。除生物中性载体外,待施用的药物组合物可含有少量无毒辅助物质,例如润湿剂或乳化剂,防腐剂和pH缓冲剂等,例如乙酸钠或脱水山梨糖醇单月桂酸酯。
“药学上可接受的盐”是指化合物的药学上可接受的盐,其衍生自本领域普通技术人员已知的各种有机和无机抗衡离子,并且仅举例来说,包括钠,钾,钙,镁,铵,四烷基铵等;当分子含有碱性官能团时,有机或无机酸的盐,如盐酸盐,氢溴酸盐,酒石酸盐,甲磺酸盐,乙酸盐,马来酸盐,草酸盐等。“药学上可接受的酸加成盐”是通过酸配伍形成的同时保留游离碱的生物有效性的“药学上可接受的盐”的子集。特别地,所公开的化合物与各种药学上可接受的酸形成盐,包括但不限于无机酸,例如盐酸,氢溴酸,硫酸,硝酸,磷酸等,以及有机酸,例如有机酸。作为甲酸,乙酸,三氟乙酸,丙酸,乙醇酸,丙酮酸,草酸,马来酸,丙二酸,琥珀酸,富马酸,酒石酸,柠檬酸,苯甲酸,肉桂酸,扁桃酸,苯磺酸,羟乙基磺酸,甲磺酸,乙磺酸,对甲苯磺酸,水杨酸,羟萘甲酸等。“药学上可接受的碱加成盐”是衍生自无机碱(如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等)的“药学上可接受的盐”的子集。示例性盐是铵、钾、钠、钙、和镁盐。衍生自药学上可接受的有机碱的盐包括但不限于,如下物质的盐:伯胺,仲胺和叔胺,取代胺(包括天然存在的取代胺),环胺以及碱性离子交换树脂,例如异丙基胺,三甲胺,二乙胺,三乙胺,三丙胺,三(羟甲基)氨基甲烷(Tris),乙醇胺,2-二甲氨基乙醇,2-二乙氨基乙醇,二环己胺,赖氨酸,精氨酸,组氨酸,咖啡因,普鲁卡因,氢胺,胆碱,甜菜碱,乙二胺,氨基葡萄糖,甲葡糖胺,可可碱,嘌呤,哌嗪,哌啶,N-乙基哌啶,聚胺树脂等。示例性有机碱是异丙胺,二乙胺,三(羟甲基)氨基甲烷(Tris),乙醇胺,三甲胺,二环己胺,胆碱和咖啡因。(参见例如,S.M.Berge等人,“Pharmaceutical Salts”[药用盐],J.Pharm.Sci.[药物科学杂志]1977;66:1-19,将其通过引用结合在此)。在具体公开的实施方式中,化合物可以是甲酸盐,三氟乙酸盐,盐酸盐或钠盐。
关于化合物或组合物的“有效量”是指足以获得特定所需结果的化合物或组合物的量,例如抑制蛋白质或酶,特别是IRAK激酶;在组织,系统,对象或患者中引起所需的生物或医学反应;治疗特定的疾病或疾病;改善或根除其一种或多种症状;和/或预防疾病或病症的发生。构成“有效量”的化合物的量可以根据化合物,所需结果,疾病状态及其严重程度,待治疗患者的年龄等而变化。
“前药”是指在体内转化以产生生物活性化合物,特别是母体化合物的化合物,例如通过肠道水解或酶促转化。前药部分的常见实例包括但不限于具有带羧酸部分的活性形式的化合物的酯和酰胺形式。本发明化合物的药学上可接受的酯的实例包括但不限于:磷酸酯/盐基团和羧酸的酯,例如脂族酯,特别是烷基酯(例如C1-6烷基酯)。其他前药部分包括磷酸酯/盐,例如-CH2–O-P(O)(OR')2或其盐,其中R'是H或C1-6烷基。可接受的酯还包括环烷基酯和芳烷基酯,例如但不限于苄基。本发明化合物的药学上可接受的酰胺的实例包括但不限于伯酰胺和仲烷基酰胺和叔烷基酰胺(例如具有约1至约6个碳原子)。可以根据常规方法制备根据本发明的化合物的公开的示例性实施方案的酰胺和酯。前药的一般概述参见Higuchi和V.Stella,《作为新型递送系统的前药》(Pro drugs as Novel DeliverySystems),美国化学学会研讨会系列第14卷和Edward B.Roche编撰,《药物设计中的生物可逆性载体》(Bioreversible Carriers in Drug Design),美国药学协会和培格曼出版社(American Pharmaceutical Association and Pergamon Press),1987,两者都通过引用并入本文。
“溶剂化物”是指通过溶剂分子与溶质的分子或离子的组合形成的复合物。溶剂可以是有机溶剂,无机溶剂或两者的混合物。溶剂的一些实例包括但不限于:醇,例如甲醇,乙醇,丙醇;酰胺类如N,N-二脂族酰胺,如N,N-二甲基甲酰胺;四氢呋喃;烷基亚砜,如二甲亚砜;水;及其组合。当与药学上可接受或不是药学上可接受的溶剂(例如水,乙醇等)组合时,本文所述的化合物可以以非溶剂化形式以及溶剂化形式存在。本发明公开的化合物的溶剂化形式在本文公开的实施方案的范围内。
“磺酰胺”是指基团或部分-SO2氨基或-N(R)磺酰基,其中R是H,脂族,杂脂族,环状,杂环,包括芳族,芳基和杂芳基。
“硫烷基”是指基团或-SH,-S-脂族,-S-杂脂族,-S-环,-S-杂环基,包括-S-芳族,-S-芳基和-S-杂芳基。
“亚磺酰基”是指基团或部分–S(O)H,–S(O)脂族,-S(O)杂脂族,-S(O)环,-S(O)杂环基,包括芳族,-S(O)芳基和-S(O)杂芳基。
“磺酰基”是指基团:–SO2H,–SO2脂族,-SO2杂脂族,-SO2环,–SO2杂环基,包括芳族磺酰基,包括-SO2芳基和-SO2杂芳基。
如本文所用的“治疗”或“处理”涉及治疗或处理患有感兴趣的疾病或病症的患者或对象(特别是人)的疾病或病症,并且包括作为实例,但不限于:
(i)预防患者或对象中发生所述疾病或病症,特别是在该患者或对象易于患上该病症但尚未被诊断患有该病症时;
(ii)抑制该疾病或病症,例如阻止或减缓其发展;
(iii)缓解该疾病或病症,例如使该疾病或病症或其症状消退;或者
(iv)稳定该疾病或病症。
本文中所用术语“疾病”和“病症”可以互换使用,或者可以是不同的,因为特定的疾病或病症可能不具有已知的致病物(因此尚未确定病因),并且因此其尚未被视作疾病而仅仅是作为一种不希望的病症或综合征,其中由临床医师或多或少地鉴定出了具体的一组症状。
上述定义和下列通式不包括不允许的取代模式(例如,被5个氟基取代的甲基)。本领域普通技术人员容易认识到这种不允许的取代模式。
本文提及的任何基团可任选地被至少一个,可能两个或更多个如本文所定义的取代基取代。也就是说,取代基团具有至少一个,可能的两个或更多个可取代的氢被本文所定义的取代基取代,除非上下文另有说明或特定结构式排除取代。
本领域普通技术人员将理解,化合物可表现出互变异构现象,构象异构现象,几何异构现象和/或光学异构现象。例如,某些公开的化合物可包括一个或多个手性中心和/或双键,因此可以作为立体异构体存在,例如双键异构体(即几何异构体),对映异构体,非对映异构体及其混合物,例如外消旋混合物。作为另一个实例,某些公开的化合物可以以几种互变异构形式存在,包括烯醇形式,酮形式和它们的混合物。由于说明书和权利要求书中的各种化合物名称,化学式和化合物图仅可表示可能的互变异构,构象异构,光学异构或几何异构形式中的一种,本领域普通技术人员将理解所公开的化合物包括本文所述化合物的任何互变异构,构象异构,光学异构和/或几何异构形式,以及这些各种不同异构形式的混合物。在旋转受限的情况下,例如在酰胺键周围或两个直接连接的环如吡唑环和吡啶环之间,阻转异构体也是可能的,并且也特别包括在本发明的化合物中。
在任何实施方案中,化合物中存在的任何或所有氢,或化合物内的特定基团或部分中的氢可以被氘或氚代替。因此,烷基的叙述包括氘代烷基,其中存在的一个至最大数目的氢可以被氘代替。例如,乙基可以是C2H5或者其中1至5个氢被氘代替的C2H5,例如在C2DxH5-x中。
II.IRAK活性化合物和含有IRAK活性化合物的组合物
A.噁唑
本文公开了噁唑化合物,制备该化合物的方法,以及使用该化合物的方法。在一个实施方案中,公开的化合物是酪氨酸激酶抑制剂。在一个具体实施方案中,所述化合物可用于阻断一种或多种细胞因子信号传导途径,例如IL-17信号传导途径。对于某些实施方案,噁唑化合物可用于治疗其中白细胞介素-1受体相关激酶(IRAK)途径的抑制在治疗上有用的病症。在一些实施方案中,化合物直接抑制IRAK蛋白,例如IRAK1,IRAK2,IRAK3,IRAK4或其组合。
在本发明范围内的示例性噁唑化合物具有通式1
和/或其盐,前药,N-氧化物或溶剂化物。参考式1,R1和R2中的至少一个是芳族的,例如杂芳基。在一些实施方案中,R1和R2中的一个是杂芳基,并且可以是含氮杂芳基,例如吡啶,嘧啶或吡嗪,R1和R2中的另一个是H,烷基,卤代烷基,硝基,氰基,酰胺,氨基,羟基,羧基,羧基酯或酰基。在某些公开的实施例中,R1和R2中的一个是H。在一些实施例中,R1和R2中的一个是6元含氮杂芳基,另一个是H。在某些实施方案中,R1是6元含氮杂芳基,R2是H。
R3是H;脂族基团,包括烷基、烯基、炔基、环烷基和环烯基;杂脂族基团;芳族基团,包括芳基和杂芳基;杂环基,如杂环脂族基团;酰胺;芳基;或芳脂族基团。在式1的一些实施方案中,R3是H,烷基,环脂族基团,通常是环烷基,例如环丙基、环丁基、环戊基或环己基,杂脂族基团或杂环脂族基团。
在一些实施方案中,R3是环己基,任选地被OH、烷氧基或杂环脂族基团取代。
在其他实施方案中,R3是环丁基,任选地被OH、烷氧基或杂环脂族基团取代。
在具体的实施方案中,R1和R2中的一个是选自吡啶基、嘧啶基或吡嗪基的6元含氮杂芳基,R1和R2中的另一个是H,并且R3是C1-6烷基,四氢吡喃,未取代的杂脂族,被卤素取代的杂脂族,未取代的环丁基,被-OH、烷氧基或杂环脂族取代的环丁基,或被-OH、烷氧基或杂环脂族取代的环己基。
R4是H,脂族基团,例如烷基,包括C1-6烷基,或杂脂族基团。或者,R1或R2中的一个与R4一起,并与它们所连接的原子一起形成具有3,4,5,6,7,8或更多个环原子(特别是5,6或7个环原子)的环,例如杂环基环。
在具体的实施方案中,R1和R2中的一个是选自吡啶基、嘧啶基或吡嗪基的6元含氮杂芳基,R1和R2中的另一个是H;R3是C1-6烷基,四氢吡喃,未取代的杂脂族,被卤素取代的杂脂族,未取代的环丁基,被-OH、烷氧基或杂环脂族取代的环丁基,或被-OH、烷氧基或杂环脂族取代的环己基;并且R4是H。
R5是H;脂族基团,包括烷基、烯基、炔基或卤代脂族基团。R5可以是H,烷基,例如C1-6烷基,或卤代烷基,如氟代烷基。并且在一些实施方案中,R5是H。
在具体的实施方案中,R1和R2中的一个是选自吡啶基、嘧啶基或吡嗪基的6元含氮杂芳基,R1和R2中的另一个是H;R3是C1-6烷基,四氢吡喃,未取代的杂脂族,被卤素取代的杂脂族,未取代的环丁基,被-OH、烷氧基或杂环脂族取代的环丁基,或被-OH、烷氧基或杂环脂族取代的环己基;R4是H;并且R5是H。
环A是杂环基团,例如杂芳基或杂环脂族基团。在一些实施方案中,环A是杂芳基,并且可以是含氮杂芳基,例如5元含氮杂芳基。在任何上述实施方案中,环A可以是吡唑基。
在一些实施方案中,环A是未取代的。在其他实施方案中,环A被取代,并且可以被所讨论的特定系统上的一个至多个可能的取代基取代,例如1至2,3或4个取代基。环A可能的取代基包括但不限于:卤素,包括F、Cl、Br或I,脂族基团,包括烷基、烯基和炔基,烷基磷酸酯,烷基膦酸酯,或其盐。
在具体的实施方案中,R1和R2中的一个是选自吡啶基、嘧啶基或吡嗪基的6元含氮杂芳基,R1和R2中的另一个是H;R3是C1-6烷基,四氢吡喃,未取代的杂脂族,被卤素取代的杂脂族,未取代的环丁基,被-OH、烷氧基或杂环脂族取代的环丁基,或被-OH、烷氧基或杂环脂族取代的环己基;R4是H;R5是H;并且环A是吡唑基,任选被以下基团取代:卤素,脂族基团,包括烷基、烯基和炔基,烷基磷酸酯,烷基膦酸酯,和/或其盐。
在某些实施方案中,R3是Ra,Rb,被1、2或3个Rb取代的Ra,被Rb和Rc取代的Ra,被Rc取代的Ra,–(CRaRa)n-Ra,-(CH2)n-Ra,-(CRaRa)n-Rb,-(CH2)n-Rb,-[(CH2)m-O-]n-Ra,-[(CH2)m-O-]n-[被1、2或3个Rb取代的Ra],或-(CH2)m-O-(CH2)m-O-Ra,其中m和n各自独立地是1、2或3;
在一些实施方案中,R4是Ra,-(CRaRa)m-O-Ra,-(CH2)m-O-Ra,-(CRaRa)m-O-(CRaRa)m-O-Ra,-[(CH2)m-O-]n-Ra或-(CH2)m-O-(CH2)m-O-Ra,其中m和n各自独立地是1、2或3;
R5是Ra或Rb;
对于每次出现,Ra独立地是H,D,C1-6烷基,C1-6卤代烷基,C3-6环烷基,C3-6杂脂环基, 其中Y和Z独立地是–CH2、-CHRb、O或NRd。
对于每次出现,Rb独立地是-OH,-CF3,-ORc,-NRdRd或卤素;
对于每次出现,Rc独立地是C1-6烷基,C3-6杂脂环基,被1、2或3个Re取代的C1-6烷基,或被1、2或3个Re取代的C3-6杂脂环基;
对于每次出现,Rd独立地是–C(O)Ra,任选地被1、2或3个Re取代的C1-6烷基,或者两个Rd基团与它们所连接的氮一起形成任选地被C1-6烷基取代并且任选地含有一或两个–O–或–N(Rg)的C3-6杂脂环基部分(其中Rg是R70);和
对于每次出现,Re独立地是C1-6烷基或-ORa。
关于式1,R1可以是:1A)杂芳基;1B)含氮杂芳基;1C)6元含氮杂芳基;1D)吡啶基;1E)嘧啶基;1F)吡嗪基;1G)吡啶-2-基;1H)嘧啶-2-基;1I)嘧啶-4-基;1J)吡嗪-2-基;1K)至少在6位取代的吡嗪-2-基;1L)至少在3位取代的吡啶-2-基;1M)6-(二氟甲基)吡啶-2-基;1N)3-氟-6-(三氟甲基)吡啶-2-基;1O)3,6-二氟吡啶-2-基;1P)3,5-二氟吡啶-2-基;1Q)3,5,6-三氟吡啶-2-基;或1R)4,6-二氟吡啶-2-基。
关于R1是1A至1R的实施方案,R3可以是与1A至1R的任何组合:2A)脂族;2B)环脂族;2C)环烷基;2E)被O-烷基、杂环基或OH取代的环烷基;2F)环己基;2G)环丁基;2H)被O-C1-6烷基取代的环己基;2I)被O-C1-6烷基取代的环丁基;2J)被杂脂环基取代的环己基;2K)被OH取代的环己基;2L)被OH取代的环丁基;2M)被杂脂族基取代的环丁基;2M)(1r,4r)-4-吗啉基环己基;2N)(1s,4s)-4-吗啉基环己基;2O)(1r,3r)-3-乙氧基环丁基;2P)(1s,3s)-3-乙氧基环丁基;2Q)(1r,4r)-4-乙氧基环己基;2S)(1s,4s)-4-乙氧基环己基;2T)(1r,4r)-4-羟基环己基;2U)(1s,4s)-4-羟基环己基;2V)((1R,4r)-4-(2R,6S)-2,6-二甲基吗啉基)环己基;2W)(1r,3r)-3-吗啉基环丁基;2X)(1s,3s)-3-吗啉基环丁基;2Y)(1s,4s)-4-(4-甲基哌嗪-1-基)环己基;2Z)(1r,4r)-4-(4-甲基哌嗪-1-基)环己基;2AA)(1r,3r)-3-羟基环丁基;或2AB)(1s,3s)-3-羟基环丁基。
本领域普通技术人员将理解,2A至2AB中的任何一个可以与1A至1R中的任何一个组合以形成这些取代基之间的任何和所有组合。
关于R1是1A至1R且R3是2A至2AB的实施方案,环A可以与1A至1R和2A至2AB的任何组合:3A)杂芳基;3B)含氮杂芳基;3C)5元杂芳基;3D)吡唑基;3E)吡唑-4-基;3F)1-((膦酰氧基)甲基)吡唑-4-基;3G)1-((膦酰氧基)甲基)吡唑-4-基钠盐;3H)5-氟吡唑-4-基;或3I)3-氟吡唑-4-基。
本领域普通技术人员将理解,3A至3I中的任何一个可以与1A至1R中的任何一个和2A至2AB中的任何一个组合,以形成这些取代基之间的任何和所有组合。
关于R1是1A至1R、R3是2A至2AB且环A是3A至3I的实施方案,R2,R4和R5可以是H。
在式1的一些实施方案中,化合物具有通式2
和/或其盐,前药,N-氧化物或溶剂化物,其中R1,R2,R3,R4,R5和环A如上文关于式1所定义。
在式1和2的一些实施方案中,环A是吡唑基。在式1和2的某些实施方案中,该化合物具有通式3
和/或其盐,前药,N-氧化物或溶剂化物。关于式3,R1,R2,R3,R4和R5如先前关于式1和2所定义。R6各自独立地是H,卤素,例如F、Cl、Br或I,脂族,杂脂族,芳基,-O-脂族,例如烷氧基,芳脂族,例如芳烷基,杂环基,磺酰基,硝基,OH,卤代烷基,羧基酯,氰基,酰基,氨基,烷基磷酸酯或烷基膦酸酯。在一些实施方案中,至少一个R6是烷基膦酸盐,或其盐,例如钠盐。在其他实施方案中,一个、两个或所有三个R6是H。在某些实施方案中,至少一个R6是卤素,例如F。
R6可以是Ra,Rb,被–OP(O)(Rf)2取代的Ra,被1、2或3个Rb取代的Ra,被Rc取代的Ra,被C1-6环烷基取代的Ra,被–P(O)(Rf)2取代的Ra,芳烷基,-(CRaRa)n-Ra,-(CH2)n-Ra或-C(O)C(Ra)2NRaRb,其中n、Ra、Rb和Rc如前定义,Rf在每次出现时独立地是-ORa,-O-M+其中每个M+独立地是碱金属离子,例如K+,Na+,Li+或铵离子,例如+NH4或+N(Ra)4,或–O-[M2+]0.5其中M2+是碱土金属离子,例如Mg2+,Ca2+或Ba2+。在具体实施方案中,R6是烷基膦酸酯或环丙基甲基,并且在其他实施方案中,R6是H。在某些公开的实施例中,R6是CH2OP(O)(OH)2或其盐。
在式3的具体实施方案中,化合物和/或其盐,前药,N-氧化物或其溶剂化物具有通式4
关于式4,R1,R2,R3,R4和R5如先前关于式1、2和3所定义。R7、R8和R9各自独立地是H,卤素,脂族,杂脂族,芳基,-O-脂族基,例如烷氧基,芳脂族基,例如芳烷基,杂环基,磺酰基,硝基,OH,卤代烷基,羧基酯,氰基,酰基,氨基,烷基磷酸酯或烷基膦酸酯。R7可以是H,脂族,-O-脂族,如烷氧基,杂脂族,羧基酯,酰基,芳脂族,如芳烷基,NO2,CN,OH,卤代烷基,如CF3,烷基磷酸酯或烷基膦酸酯。在一些实施例中,R7是H,烷基,羧基酯,酰基,烷基磷酸酯,烷基膦酸酯,杂环烷基或芳烷基。在具体实施方案中,R7是H,烷基,羧基酯,酰基,烷基磷酸酯或烷基膦酸酯。
R7可以是Ra,Rb,被–OP(O)(Rf)2取代的Ra,被1、2或3个Rb取代的Ra,被Rc取代的Ra,被–P(O)(Rf)2取代的Ra,芳烷基,-(CRaRa)n-Ra,-(CH2)n-Ra或-C(O)C(Ra)2NRaRb,其中n、Ra、Rb和Rc如前定义,Rf在每次出现时独立地是-ORa,-O-M+其中每个M+独立地是碱金属离子,例如K+,Na+,Li+或铵离子,例如+NH4或+N(Ra)4,或–O-[M2+]0.5其中M2+是碱土金属离子,例如Mg2+,Ca2+或Ba2+。在具体实施方案中,R7是烷基膦酸酯,并且在其他实施方案中,R7是H。在某些公开的实施例中,R7是CH2OP(O)(OH)2或其盐。
R8和R9独立地是Ra或Rb。
在某些实施例中,R8和R9各自独立地是H,卤素,例如F,烷基或卤代烷基,例如三氟甲基,并且在具体实施方案中,R8和R9均为H;R8和R9中的一个是H,另一个是低级烷基,例如甲基,卤素或三氟甲基;或者R8和R9均为低级烷基。在具体实施方案中,R8和R9中的一个是H而另一个是F。
在式1-4的一些实施方案中,R1是吡啶基,嘧啶基或吡嗪基,并且R2是H。在式1-4的其他实施方案中,R2是吡啶基,嘧啶基或吡嗪基,并且R1是H。在式1-4的一些实施方案中,R1是吡啶基,嘧啶基或吡嗪基,并且R2,R4和R5是H。在任何这些实施方案中,嘧啶基可以是嘧啶-2-基或嘧啶-4-基,并且可以是取代或未取代的;吡嗪基可以是吡嗪-2-基,并且可以是取代或未取代的;吡啶基可以是吡啶-2-基,并且可以是未取代或取代的,例如卤代烷基,卤素或其组合。在某些实施方案中,吡啶基是取代的吡啶-2-基,并且可以是6-(二氟甲基)吡啶-2-基,3-氟-6-(三氟甲基)吡啶-2-基,3,6-二氟吡啶-2-基,3,5-二氟吡啶-2-基,3,5,6-三氟吡啶-2-基或4,6-二氟吡啶-2-基。在任何这些实施方案中,R3可以是1,4-取代的环己基,或1,3-取代的环丁基。
在其他实施方案中,R1和R2中的一个是H,另一个是吡啶-3-基或吡啶-4-基。
在式1-4的一些实施方案中,R1是吡嗪基,并且R2是H。在式1-4的其他实施方案中,R1是嘧啶基,例如嘧啶-2-基,并且R2是H。在其他实施方案中,R1是吡啶基,并且R2是H。
在式1-4的一些实施方案中,R3是1,4-取代的环己基,R2是H,并且R1是吡嗪基。在式1-4的其他实施方案中,R3是1,4-取代的环己基,R2是H,并且R1是嘧啶-2-基。在式1-4的其他实施方案中,R3是1.3-取代的环丁基,R2是H,并且R1是吡嗪基。在式1-4的其他实施方案中,R3是1.3-取代的环丁基,R2是H,并且R1是嘧啶-2-基。在式1-4的其他实施方案中,R3是1,4-取代的环己基,R2是H,并且R1是吡啶-2-基。在式1-4的其他实施方案中,R3是1,4-取代的环丁基,R2是H,并且R1是吡啶-2-基。
在式1-4的任何上述实施方案中,R1可以是
其中Z1,Z2,Z3和Z4独立地是N或CR10,其中每个R10独立地是H,卤素或脂族,例如烷基,并且Z1,Z2,Z3和Z4中至少一个(例如一个、两个、三个或四个)是N。在一些实施方案中,每个R10独立地是H,卤素或卤代烷基,例如H,F,CF3或CF2。
在一些实施方案中,Z1是N,并且Z2,Z3和Z4中没有一个是N或者有一个是N。在某些实施方案中,Z1和Z2是N,并且Z3和Z4是CR10。在其他实施方案中,Z1和Z3是N,并且Z2和Z4是CR10。在其他实施方案中,Z1和Z4是N,并且Z2和Z3是CR10。
在式1-4的一些实施方案中,化合物和/或其盐,前药,N-氧化物或其溶剂化物具有选自式5-8的通式:
关于式5-8,R2,R3,R4,R5,R6,R7,R8,R9,R10,Z1,Z2,Z3,Z4和环A,如果存在,如前面对式1-4所定义。
在式1-8的一些实施方案中,化合物和/或其盐,前药,N-氧化物或其溶剂化物具有选自式5-8的通式:
关于式9-12,R2,R3,R4,R5,R7,R8和R9如对式1-8所定义,并且R11,R12,R13和R14(如果存在的话)独立地是H,卤素,或脂族基团,例如烷基。在某些实施方案中,R11,R12,R13和R14(如果存在的话)独立地是H,卤素或卤代烷基,并且独立地可以是H,F,CF3或CF2。
在式1-12的一些实施方案中,R4是H,R5是H,或者R4和R5均为H。
在式1-12的一些实施方案中,R3是C5-10环烷基,并且在某些实施方案中,R3是环己基,例如1,4-取代的环己基。在式1-12的其他实施方案中,R3是环丁基,例如1,3-取代的环丁基。
根据式1的示例性化合物包括:
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在某些实施方案中,根据式1的示例性化合物包括:
I-1:N-(1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-2:N-(1-((1r,4r)-4-吗啉基环己基)-3-(嘧啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-3:N-(1-((1r,4r)-4-乙氧基环己基)-3-(嘧啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-4:N-(3-(6-(二氟甲基)吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-5:N-(3-(6-(二氟甲基)吡啶-2-基)-1-((1R,4r)-4-((2R,6S)-2,6-二甲基吗啉基)环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-6:N-(1-((1r,4r)-4-乙氧基环己基)-3-(嘧啶-4-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-7:N-(3-(3-氟-6-(三氟甲基)吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-8:(4-(4-((3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基磷酸钠;
I-9:N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-10:N-(3-(3,6-二氟吡啶-2-基)-1-((1s,3s)-3-乙氧基环丁基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-11:N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-羟基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-12:磷酸二氢(4-(4-((3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基酯;
I-13:N-(3-(3,5-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-14:N-(5-(3,6-二氟吡啶-2-基)-1-((1r,4R)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-15:2-(1H-吡唑-4-基)-N-(3-(吡啶-2-基)-1-(2-(2,2,2-三氟乙氧基)乙基)-1H-吡唑-4-基)噁唑-4-甲酰胺;
I-16:((4-(4-((1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基)磷酸二叔丁酯;
I-17:磷酸二氢(4-(4-((1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基酯;
I-18:(4-(4-((1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基磷酸钠;
I-19:2-(1-(环丙基甲基)-1H-吡唑-4-基)-N-(1-甲基-3-(吡啶-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺;
I-20:2-(1H-吡唑-4-基)-N-(3-(吡啶-2-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)噁唑-4-甲酰胺;
I-21:N-(1-(2-乙氧基乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-22:N-(1-((1s,3s)-3-乙氧基环丁基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-23:N-(1-环丁基-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-24:N-(1-(2-(2-甲氧基乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-25:N-(1-(2-(2,2-二氟乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-26:N-(3-(3,6-二氟吡啶-2-基)-1-((1r,3r)-3-乙氧基环丁基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-27:N-(1-((1r,4r)-4-羟基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-28:N-(1-((1r,4r)-4-乙氧基环己基)-3-(3,5,6-三氟吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-29:N-(3-(4,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-30:N-(1-((1r,4r)-4-吗啉基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-31:N-(1-((1r,4r)-4-乙氧基环己基)-3-(3-氟-6-(三氟甲基)吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-32:N-(1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(5-氟-1H-吡唑-4-基)噁唑-4-甲酰胺;
I-33:N-(1-((1r,3r)-3-吗啉基环丁基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-34:N-(1-((1s,3s)-3-吗啉基环丁基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-35:2-(3-氟-1H-吡唑-4-基)-N-(1-((1r,4r)-4-吗啉基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺甲酸盐;
I-36:N-(3-(3,6-二氟吡啶-2-基)-1-((1s,4s)-4-(4-甲基哌嗪-1-基)环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-37:N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
I-38:N-(1-((1s,3s)-3-羟基环丁基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;或
I-39:2-(3-氟-1H-吡唑-4-基)-N-(1-((1r,4r)-4-吗啉基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺。
根据式1的一些示例性化合物包括:
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根据式1的示例性化合物包括:
II-1:N-(1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-2:N-(1-((1r,4r)-4-吗啉基环己基)-3-(嘧啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-3:N-(1-((1r,4r)-4-乙氧基环己基)-3-(嘧啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-4:N-(3-(6-(二氟甲基)吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-5:N-(3-(6-(二氟甲基)吡啶-2-基)-1-((1R,4r)-4-((2R,6S)-2,6-二甲基吗啉基)环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-6:N-(1-((1r,4r)-4-乙氧基环己基)-3-(嘧啶-4-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-7:N-(3-(3-氟-6-(三氟甲基)吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-8:(4-(4-((3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基磷酸钠;
II-9:N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-10:N-(3-(3,6-二氟吡啶-2-基)-1-((1s,3s)-3-乙氧基环丁基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-11:N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-羟基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-12:磷酸二氢(4-(4-((3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基酯;
II-13:N-(3-(3,5-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-14:N-(5-(3,6-二氟吡啶-2-基)-1-((1r,4R)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-15:2-(1H-吡唑-4-基)-N-(3-(吡啶-2-基)-1-(2-(2,2,2-三氟乙氧基)乙基)-1H-吡唑-4-基)噁唑-4-甲酰胺;
II-16:((4-(4-((1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基)磷酸二叔丁酯;
II-17:磷酸二氢(4-(4-((1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基酯;
II-18:(4-(4-((1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基磷酸钠;
II-19:N-(3-(3,6-二氟吡啶-2-基)-1-((1r,3r)-3-乙氧基环丁基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-20:N-(1-((1r,4r)-4-羟基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-21:N-(1-((1r,4r)-4-乙氧基环己基)-3-(3,5,6-三氟吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-22:N-(3-(4,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-23:N-(1-((1r,4r)-4-吗啉基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-24:N-(1-((1r,4r)-4-乙氧基环己基)-3-(3-氟-6-(三氟甲基)吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-25:N-(1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(5-氟-1H-吡唑-4-基)噁唑-4-甲酰胺;
II-26:N-(1-((1r,3r)-3-吗啉基环丁基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-27:N-(1-((1s,3s)-3-吗啉基环丁基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-28:2-(3-氟-1H-吡唑-4-基)-N-(1-((1r,4r)-4-吗啉基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺甲酸盐;
II-29:N-(3-(3,6-二氟吡啶-2-基)-1-((1s,4s)-4-(4-甲基哌嗪-1-基)环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-30:N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-31:N-(1-((1s,3s)-3-羟基环丁基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;或
II-32:2-(3-氟-1H-吡唑-4-基)-N-(1-((1r,4r)-4-吗啉基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺。
根据式1的其他示例性化合物可包括:
根据式1的另外的示例性化合物可包括:
III-1:2-(1-(环丙基甲基)-1H-吡唑-4-基)-N-(1-甲基-3-(吡啶-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺;
III-2:2-(1H-吡唑-4-基)-N-(3-(吡啶-2-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)噁唑-4-甲酰胺;
III-3:N-(1-(2-乙氧基乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
III-4:N-(1-((1s,3s)-3-乙氧基环丁基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
III-5:N-(1-环丁基-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
III-6:N-(1-(2-(2-甲氧基乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;或
III-7:N-(1-(2-(2,2-二氟乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺。
在式1-12的一些实施方案中,化合物不是:
2-(1-(环丙基甲基)-1H-吡唑-4-基)-N-(1-甲基-3-(吡啶-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺;
2-(1H-吡唑-4-基)-N-(3-(吡啶-2-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)噁唑-4-甲酰胺;
N-(1-(2-乙氧基乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
N-(1-((1s,3s)-3-乙氧基环丁基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
N-(1-环丁基-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
N-(1-(2-(2-甲氧基乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
N-(1-(2-(2,2-二氟乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
N-(3-氨甲酰基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
2-(1H-吡唑-3-基)-N-(3-(吡啶-2-基)-1-(2-(2,2,2-三氟乙氧基)乙基)-1H-吡唑-4-基)噁唑-4-甲酰胺;或
N-(1-(2-(2-甲氧基乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-3-基)噁唑-4-甲酰胺。
B.合成
所公开的噁唑化合物可以如下面举例说明的方式制备,并且如本领域普通技术人员在有机合成中所理解的。示例性合成可包括根据方案1的以下第一反应步骤。
方案1
乙酰基化合物2在合适的反应温度(例如约85℃至约130℃)与二甲基甲酰胺二甲基缩醛4反应,形成中间体化合物6。然后中间体化合物6与水合肼8反应,形成吡唑化合物10。该反应在合适的溶剂中进行,例如醇,如乙醇,甲醇或异丙醇,并且通常加热,例如加热回流。
以下根据方案2提供示例性合成中的第二反应步骤:
方案2
使用适合的硝化剂或硝化剂混合物12使化合物10发生硝化以形成化合物14。适合的硝化条件包括使化合物10与硝酸(如发烟硝酸)反应(任选地在硫酸的存在下)。典型地,缓慢地添加化合物10和硝酸,一个添加至另一个。可以使用冷却(如通过冰浴)将反应温度维持在适合的范围内,如从约0℃至小于50℃、从0℃至20℃、或从0℃至10℃。完成添加后,允许反应进行直至反应基本上完全,并可以允许其温热至室温以促进该反应。任选地,可以添加另外的硝化剂或硝化剂的混合物以促进该反应进行完全。然后将该反应淬灭,如通过添加水和/或冰,并将产物从水性溶液中分离或萃取,并且如果需要的话进行纯化。适合用于纯化本文公开的任何反应得到的产物的纯化技术包括但不限于:结晶、蒸馏和/或色谱法。
继续参考方案2,然后使化合物14与化合物16反应形成化合物18。化合物16包含所需的R1部分和合适的离去基团LG。合适的离去基团包括将充当离去基团以促进将R1部分添加至化合物14的任何基团。合适的离去基团包括但不限于:卤素,通常为溴,氯或碘,以及甲苯磺酸酯或甲磺酸酯基团。化合物14在合适的溶剂中并且通常在碱存在下与化合物16反应。合适的溶剂包括促进反应的任何溶剂,例如非质子溶剂。合适的溶剂包括但不限于:DMF(二甲基甲酰胺),THF(四氢呋喃),DMSO(二甲亚砜),乙腈,氯化溶剂如二氯甲烷和氯仿,DMA(二甲基乙酰胺),二噁烷,N-甲基吡咯烷酮或其组合。合适的碱包括任何有助于反应的碱,例如氢化物,通常是氢化钠,或碳酸盐,例如碳酸钾,碳酸钠或碳酸铯。反应可以在室温下进行,或者可以根据需要将反应混合物加热,例如加热至50℃,100℃或更高。然后从反应混合物中分离化合物18,并在需要时纯化。
然后使化合物18与适于将硝基部分还原成胺的还原剂20反应。合适的还原剂包括但不限于:在催化剂(例如钯催化剂)存在下的氢气;硼氢化钠,例如硼氢化钠,任选地在催化剂(例如镍催化剂)存在下;乙酸中的锌金属;或在水中或水和酸中的铁粉。在某些实施方案中,氢气与钯/碳催化剂和合适的溶剂如乙酸乙酯或甲醇组合使用。在一些实施方案中,使用还原剂和/或技术的组合。例如,可以首先使用包含第一还原剂和/或技术的第一方法进行还原,但得到产物的混合物。可以重复第一种方法,和/或可以执行第二种方法,包括第二还原剂和/或技术。一旦反应完成,如通过分析技术如LC-MS,TLC或HPLC所示,分离并纯化产物化合物22(如果需要的话)。
以下根据方案3提供示例性反应顺序的第三步骤。
方案3
化合物22与羧酸24反应形成化合物26。羧酸24通过任何合适的方法活化,然后与化合物22上的胺反应。合适的活化方法包括但不限于:形成酰氯,例如用亚硫酰氯处理;用1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓-3-氧化六氟磷酸酯(HATU)和碱如二异丙基乙胺(DIPEA)处理;用羰基二咪唑(CDI)处理;或用碳二亚胺处理,例如二环己基碳二亚胺(DCC)或1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC)。
然后使用适于在两个环之间形成键的任何偶联反应将化合物26与化合物28偶联以形成化合物30。在方案3的实例中,使用硼酸28显示硼酸偶联,其中化合物26上的离去基团LG通常是溴或碘。其他合适的偶联官能团包括三烷基锡或硼酸酯。偶联反应通常在合适的催化剂存在下进行。对于硼酸偶联,催化剂通常是钯催化剂,例如PdCl2(dppf)2,d[P(Ph)3]2Cl2,乙酸钯和三苯基膦,或四(苯基膦)(0)。反应在碱如碳酸钠、碳酸钾或碳酸铯的存在下进行,并在合适的溶剂或溶剂混合物中进行,例如二噁烷,二噁烷/水或DME(乙二醇二甲醚)/乙醇/水。反应可在合适的温度下加热,例如加热至高于室温一直到所选溶剂的沸点的温度范围,例如在50℃至125℃的温度,通常约100℃的温度,和/或搅拌合适的时间,例如1小时至3天,6小时至24小时,或12小时至18小时,以促进反应进行至完成。然后从反应混合物中分离化合物30并通过合适的技术纯化。
替代的示例性合成可包括根据方案4的以下第一反应步骤。
方案4
使用合适的硝化试剂或硝化剂混合物34对化合物32进行硝化以形成化合物36。适合的硝化条件包括使化合物32与硝酸(如发烟硝酸)反应(任选地在硫酸的存在下)。典型地,缓慢地添加化合物32和硝酸,一个添加至另一个。可以使用冷却(如通过冰浴)将反应温度维持在适合的范围内,如从约0℃至小于50℃、从0℃至20℃、或从0℃至10℃。完成添加后,允许反应进行直至反应基本上完全,并可以允许其温热至室温以促进该反应。任选地,可以添加另外的硝化剂或硝化剂的混合物以促进该反应进行完全。然后将该反应淬灭,如通过添加水和/或冰,并将产物从水相分离或萃取,并且如果需要的话进行纯化。适合用于纯化本文公开的任何反应得到的产物的纯化技术包括但不限于:结晶、蒸馏和/或色谱法。
继续参考方案4,然后使化合物36与化合物38反应形成化合物40。化合物38包含所需的环(例如环丁基、环戊基或环己基环)和合适的离去基团LG。合适的离去基团包括将充当离去基团以促进将环添加至化合物36的任何基团。合适的离去基团包括但不限于:卤素,通常为溴,氯或碘,以及甲苯磺酸酯或甲磺酸酯基团。化合物36在合适的溶剂中并且通常在碱存在下与化合物38反应。合适的溶剂包括促进反应的任何溶剂,例如非质子溶剂。合适的溶剂包括但不限于:DMF,THF,DMSO,乙腈,氯化溶剂如二氯甲烷和氯仿,DMA,二噁烷,N-甲基吡咯烷酮或其组合。合适的碱包括任何有助于反应的碱,例如氢化物,通常是氢化钠,或碳酸盐,例如碳酸钾,碳酸钠或碳酸铯。反应可在室温下进行,或反应混合物可加热,例如加热至高于室温一直到所选溶剂的沸点的温度范围,例如50℃,100℃或更高(如果需要的话)。然后从反应混合物中分离化合物40,并在需要时纯化。
然后使化合物40与适于将羰基部分还原为羟基的还原剂42反应。合适的还原剂包括但不限于硼氢化钠,二异丁基氢化铝或氢化铝锂。反应在适于促进反应的溶剂中进行,例如醇,特别是甲醇或乙醇,THF或乙醚。反应可在室温下进行,或反应混合物可加热,例如加热至高于室温一直到所选溶剂的沸点的温度范围,例如50℃,100℃或更高的温度。或者,可以根据需要冷却反应混合物,例如低于20℃,低于10℃或低于0℃。一旦反应完成,如通过分析技术如LC-MS,TLC或HPLC所示,通过合适的技术(例如柱色谱),分离和纯化产物化合物44(如果需要的话)。或者或另外,可以分离化合物45。
任选地,化合物44和/或化合物45可以与化合物46反应形成化合物48和/或化合物49。化合物46包含所需的Rx部分和合适的离去基团LG。合适的离去基团包括将充当离去基团以促进将Rx部分添加至化合物44和/或化合物45的任何基团。合适的离去基团包括但不限于:卤素,通常为溴,氯或碘,以及甲苯磺酸酯或甲磺酸酯基团。化合物44/45在合适的溶剂中并且通常在促进反应的碱或其他试剂的存在下,与化合物46反应。合适的溶剂包括促进反应的任何溶剂,例如非质子溶剂。合适的溶剂包括但不限于:DMF,THF,DMSO,乙腈,氯化溶剂如二氯甲烷和氯仿,DMA,二噁烷,N-甲基吡咯烷酮或其组合。促进反应的合适的碱或试剂包括但不限于:三氟甲磺酸银,2,6-二叔丁基吡啶,氢化钠或其组合。通常,将化合物46缓慢加入反应混合物中。可以使用冷却(如通过冰浴)将反应温度维持在适合的范围内,如从约0℃至小于50℃、从0℃至20℃、或从0℃至10℃。在加完46之后,使反应进行直至反应基本完成,并可使其温热至室温,或可将反应加热至高于室温一直到所选溶剂的沸点的温度范围,例如50℃,100℃或更高,以促进反应。一旦反应完成,如通过分析技术如LC-MS,TLC或HPLC所示,通过合适的技术(例如柱色谱),分离和纯化产物化合物48和/或化合物49(如果需要的话)。
化合物48和/或化合物49的另一种示例性合成路线示于方案5中。
方案5
参考方案5,在冷却的同时将化合物36溶解在合适的溶剂中,并用碱如氢化钠处理。合适的溶剂包括但不限于:非质子溶剂,例如1,4-二噁烷,THF,DMF,乙腈,醚或其组合。加入具有4-硝基苯砜离去基团(nosyl或Nos)的环己基化合物37,并在适于促进反应的温度下加热反应,例如在高于室温一直到所选溶剂的沸点的温度范围,例如50℃至200℃或更高,通常为90℃至150℃。可以搅拌反应,例如通过摇动或搅拌。如果需要,可以加入另外的化合物37,以促进反应进行完成。
淬灭反应混合物,例如通过加入碳酸氢钠溶液,将产物萃取到有机溶剂如乙酸乙酯或氯仿中。化合物48和49可以通过任何合适的技术或技术的组合分离和/或纯化,例如色谱法或研磨。
4-硝基苯磺酸盐化合物37可根据方案6的示例性合成路线制备。
方案6
参考方案6,首先用碱(例如氢化钠或叔丁醇钾)在合适的溶剂中处理1,4-二氧杂螺[4.5]癸-8-醇37-1,然后用Rx-LG处理,形成化合物37-2,其中LG是合适的离去基团,例如氯化物,溴化物,碘化物,甲苯磺酸酯或甲磺酸酯。合适的溶剂包括但不限于:非质子溶剂,例如THF,DMF,乙腈,二噁烷,醚或其组合。在反应基本完成后,加入含水酸如HCl以淬灭反应并形成化合物37-3。
然后用还原剂处理化合物37-3,形成化合物37-4。化合物37-4可以基本上是一种异构体,或者,化合物37-4可以是顺式和反式异构体的混合物,并且在一些实施方案中,化合物37-4包含约2:1的顺式:反式异构体混合物。还原剂可以是能够将羰基部分还原为醇部分的任何试剂。合适的还原剂包括但不限于:氢化铝锂,二异丁基氢化铝,硼烷-THF或硼氢化物试剂,例如硼氢化钠。适于促进反应的溶剂包括但不限于:THF,醚或其组合。
然后在碱存在下用4-硝基苯磺酰氯(nosyl)处理化合物37-4,形成化合物37。碱可以是促进反应的任何合适的碱,并且可以是有机碱,例如三甲胺,1,4-二氮杂双环[2.2.2]辛烷(DABCO),吡啶或胡尼碱;或无机碱,例如碳酸钾,碳酸钠或碳酸铯。反应可在合适的溶剂中进行,通常是非质子溶剂,如吡啶,THF或氯化溶剂,如二氯甲烷或氯仿。化合物37可以基本上是一种异构体,或者,化合物37可以是异构体的混合物。异构体的比例可以通过合适的技术改变,例如色谱法或研磨。在一些实施方案中,通过研磨将异构体的比例纯化至约8:1。
或者,化合物40可以根据方案7通过示例性合成路线制备。
方案7
关于方案7,化合物36与化合物50反应形成化合物52。化合物50包含所需的环,例如环丁基、环戊基或环己基环,合适的离去基团LG和保护的羰基部分,例如缩醛或缩酮。在上面的实施例中,显示了环状缩酮部分。合适的离去基团包括将作为离去基团以促进将环添加至化合物36的任何基团,并且包括但不限于:卤素,通常是溴、氯或碘,以及甲苯磺酸酯或甲磺酸酯基团。化合物36与化合物50在合适的溶剂中并且通常在碱存在下反应。合适的溶剂包括促进反应的任何溶剂,例如非质子溶剂。合适的溶剂包括但不限于:DMF,THF,DMSO,乙腈,氯化溶剂如二氯甲烷和氯仿,DMA,二噁烷,N-甲基吡咯烷酮或其组合。合适的碱包括任何有助于反应的碱,例如氢化物,通常是氢化钠,或碳酸盐,例如碳酸钾,碳酸钠或碳酸铯。反应可在室温下进行,或反应混合物可加热,例如加热至高于室温一直到所选溶剂的沸点的温度范围,例如50℃,100℃或更高(如果需要的话)。然后从反应混合物中分离化合物52,并通过合适的技术如柱色谱法纯化(如果需要的话)。
然后使化合物52与合适的试剂54反应以形成化合物40。试剂54可以是适于除去保护基团和/或形成羰基部分的任何试剂。在方案5中所示的示例性合成中,保护基团是环状缩酮,合适的试剂54包括但不限于:甲苯磺酸吡啶鎓(PPTS),对甲苯磺酸,盐酸或乙酸。反应在适于促进反应的溶剂或溶剂混合物中进行,例如丙酮,THF,乙酸,水或其组合。反应可在室温下进行,或反应混合物可加热,例如加热至高于室温一直到所选溶剂的沸点的温度范围,例如50℃,100℃或更高(如果需要的话)。然后从反应混合物中分离化合物40,并通过合适的技术如柱色谱法纯化(如果需要的话)。
以下根据方案8提供示例性反应顺序的第二步骤。
方案8
使化合物48与适于将硝基部分还原成胺的还原剂56反应。在所需产物化合物包含羟基部分的某些实施方案中,化合物44可用于代替化合物48。合适的还原剂包括但不限于:在催化剂(例如钯催化剂)存在下的氢气;硼氢化钠,例如硼氢化钠,任选地在催化剂(例如镍催化剂)存在下;乙酸中的锌金属;或在水中或水和酸中的铁粉。在某些实施方案中,在钯/碳催化剂存在下并且在合适的溶剂如乙酸乙酯或甲醇中使用氢气。在一些实施方案中,使用还原剂和/或技术的组合。例如,可以首先使用包含第一还原剂和/或技术的第一方法进行还原,但得到产物的混合物。可以重复第一种方法,和/或可以执行第二种方法,包括第二还原剂和/或技术。一旦反应完成,如通过分析技术如LC-MS,TLC或HPLC所示,分离并纯化产物化合物58(如果需要的话)。
化合物58与羧酸60反应形成酰胺62。羧酸60通过任何合适的方法活化,然后与化合物58的胺官能团反应。合适的活化方法包括但不限于:通过用亚硫酰氯处理形成酰氯;用1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓-3-氧化六氟磷酸酯(HATU)和碱如二异丙基乙胺(DIPEA)处理;用羰基二咪唑(CDI)处理;或用碳二亚胺处理,例如二环己基碳二亚胺(DCC)或1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC)。
然后使用适于在两个环之间形成键的任何偶联反应将化合物62与化合物64偶联以形成化合物66。在上面的实施例中,显示了硼酸酯偶联,其中化合物62上的离去基团LG通常是溴或碘。其他合适的偶联官能团包括三烷基锡或硼酸。偶联反应通常在合适的催化剂存在下进行。对于硼酸酯或硼酸偶联,催化剂通常是钯催化剂,例如PdCl2(dppf)2,d[P(Ph)3]2Cl2,乙酸钯和三苯基膦,或四(苯基膦)(0)。反应在碱如碳酸钠、碳酸钾或碳酸铯的存在下进行,并在合适的溶剂或溶剂混合物中进行,例如二噁烷,二噁烷/水或DME/乙醇/水。反应可在合适的温度下加热,例如50℃至125℃,通常约100℃,和/或搅拌合适的时间,例如1小时至3天,6小时至24小时,或12小时至18小时,以促进反应进行完成。然后从反应混合物中分离化合物66并通过合适的技术纯化。
某些实施方案可包含磷酸酯部分。方案9提供了某些这样的实施方案的示例性合成。
方案9
化合物68与化合物70反应形成化合物72。化合物70包含所需的Ry部分和合适的离去基团LG。典型的Ry部分包括但不限于:脂族基团,例如烷基(通常是甲基,乙基,丙基,异丙基或叔丁基);芳基;杂脂族基团;或杂环基团。两个Ry部分可以相同或不同。合适的离去基团包括但不限于:卤素,通常为溴,氯或碘,以及甲苯磺酸酯或甲磺酸酯基团。化合物68在合适的溶剂中并且通常在碱存在下与化合物70反应。合适的溶剂包括促进反应的任何溶剂,例如非质子溶剂。合适的溶剂包括但不限于:DMF,THF,DMSO,乙腈,氯化溶剂如二氯甲烷和氯仿,DMA,二噁烷,N-甲基吡咯烷酮或其组合。合适的碱包括任何有助于反应的碱,例如氢化物,通常是氢化钠,或碳酸盐,例如碳酸钾,碳酸钠或碳酸铯。反应可在室温下进行,或反应混合物可加热,例如加热至高于室温一直到所选溶剂的沸点的温度范围,例如50℃,100℃或更高(如果需要的话)。然后从反应混合物中分离化合物72,并在需要时纯化。
然后化合物72与化合物74反应形成化合物76。化合物74可以是适于在化合物76中形成酸部分的任何化合物。化合物74可以是酸性试剂,如三氟乙酸、盐酸或氢溴酸,或它可以是碱性试剂,例如氢氧化钠、氢氧化锂或氢氧化钾。合适的溶剂包括但不限于:氯化溶剂,例如二氯甲烷和氯仿,醇,例如甲醇和乙醇,水,或其组合。反应可在室温下进行,或反应混合物可加热,例如加热至高于室温一直到所选溶剂的沸点的温度范围,例如50℃,100℃或更高(如果需要的话)。也可以将反应混合物冷却,例如低于20℃,低于10℃,低于0℃或更低。一旦反应完成,如通过分析技术如LC-MS,TLC或HPLC所示,通过合适的技术分离和纯化产物化合物76(如果需要的话),例如通过在合适的溶剂或溶剂体系中进行搅动,例如通过搅拌或超声处理。合适的溶剂或溶剂体系包括但不限于:丙酮/水,丙酮,乙醚或醇/水。
然后使化合物76与化合物78反应形成盐化合物80。化合物78可以是为盐化合物80提供合适的抗衡离子(CI)的任何化合物,例如氢氧化钙,氢氧化钠,氢氧化钾,氢氧化锂,氨,三甲胺,三(羟甲基)氨基甲烷,或氨基酸如赖氨酸或精氨酸。本领域普通技术人员将理解,如果抗衡离子CI具有单个正电荷,如在Na+,K+,Li+或NH4 +中,那么化合物80将包含两个CI离子,而如果抗衡离子CI具有两个正电荷,如在CI2+中,那么化合物80将包含一个CI离子。
C.治疗剂的组合
本发明的噁唑化合物可以单独使用,彼此组合使用,或作为其他已建立的疗法的辅助或与其他已建立的疗法组合使用。另一方面,本发明化合物可与其它可用于治疗特定病症或病症的治疗剂组合使用。这些化合物可以同时、以任何顺序依次、通过相同的给药途径或不同的给药途径进行给予。
在一些实施方案中,第二治疗剂是抗炎剂,抗生素,抗凝血剂,抗体,抗炎剂,免疫抑制剂,鸟苷酸环化酶-C激动剂,肠促分泌剂,抗病毒剂,抗癌剂,抗真菌剂,或其组合。抗炎剂可以是甾体或非甾体抗炎剂。在某些实施方案中,非甾体抗炎剂选自:氨基水杨酸盐、环氧合酶抑制剂、双氯芬酸、依托度酸、法莫替丁、非诺洛芬、氟比洛芬、酮洛芬、酮咯酸、布洛芬、吲哚美辛、甲氯芬那酸、甲芬那酸、美洛昔康、萘普酮、萘普生、奥沙普秦、吡罗昔康、双水杨酯、舒林酸、托美丁、或其组合。在一些实施方案中,免疫抑制剂是巯嘌呤,皮质类固醇,烷化剂,钙调神经磷酸酶抑制剂,肌苷一磷酸脱氢酶抑制剂,抗淋巴细胞球蛋白,抗胸腺细胞球蛋白,抗T细胞抗体,或其组合。在一个实施方案中,抗体是英夫利昔单抗。
在一些实施方案中,本发明化合物可与其他抗癌剂或细胞毒剂一起使用。各种类型的抗癌和抗肿瘤化合物包括但不限于:烷化剂,抗代谢物,BCL-2抑制剂,长春花生物碱,紫杉烷,抗生素,酶,细胞因子,铂配位络合物,蛋白酶体抑制剂,取代的脲,激酶抑制剂,激素和激素拮抗剂,以及低甲基化剂,例如DNMT抑制剂,例如阿扎胞苷和地西他滨。示例性的烷化剂包括但不限于:甲氯胺,环磷酰胺,异环磷酰胺,美法仑,苯丁酸氮芥,乙烯亚胺,甲基三聚氰胺,烷基磺酸盐(例如白消安)和卡莫司汀。示例性抗代谢物包括,例如但不限于,叶酸类似物甲氨蝶呤;嘧啶类似物氟尿嘧啶,胞嘧啶核苷;嘌呤类似物巯基嘌呤,硫鸟嘌呤和硫唑嘌呤。示例性的长春花生物碱包括,例如但不限于,长春碱,长春新碱,紫杉醇和秋水仙碱。示例性抗生素包括,例如但不限于,放线菌素D,柔红霉素和博来霉素。有效作为抗肿瘤剂的示例性酶包括L-天冬酰胺酶。示例性配位化合物包括,例如但不限于,顺铂和卡铂。示例性激素和激素相关化合物包括,例如但不限于,肾上腺皮质激素泼尼松和地塞米松;芳香酶抑制剂氨基谷氨酰胺,福美坦和阿那曲唑;孕激素化合物羟孕酮己内酯,甲羟孕酮;和抗雌激素化合物他莫昔芬。
这些和其他有用的抗癌剂化合物描述在Merck Index[默克索引],第13版,(O'Neil M.J.等人编辑)Merck Publishing Group[默克出版集团](2001);以及Goodman和Gilman,The Pharmacological Basis of Therapeutics[治疗的药理学基础],第12版,Brunton L.L.编辑,第60-63章,McGraw Hill[麦格劳-希尔集团],(2011),两者均通过引用结合在此。
在CTLA 4抗体中可以与本文公开的抑制剂组合使用的是由百时美施贵宝公司(Bristol-Myers Squibb)以出售的伊匹木单抗。
用于组合的其他化疗剂包括免疫肿瘤试剂,如检查点途径抑制剂,例如PD-1抑制剂(如纳武单抗(nivolumab)和兰波单抗(lambrolizumab))和PD-L1抑制剂(如派姆单抗(pembrolizumab)、MEDI-4736和MPDL3280A/RG7446)。用于与本文公开的化合物组合的另外的检查点抑制剂包括抗-LAG-3试剂,如BMS-986016(MDX-1408)。
用于与本发明公开的抑制剂组合的另外的化疗剂包括抗-SLAMF7试剂(如人源化单克隆抗体埃罗妥珠单抗(elotuzumab)(BMS-901608))、抗-KIR试剂(如抗-KIR单克隆抗体利瑞单抗(lirilumab)(BMS-986015))和抗-CD137试剂(如完全人源性单克隆抗体尤尔单抗(urelumab)(BMS-663513)。
与本发明的化合物组合有用的另外的抗增殖化合物包括,例如但不限于,针对生长因子受体(例如抗-Her2)的抗体;和细胞因子(如干扰素-α和干扰素-γ、白介素-2和GM-CSF)。
可与本发明的噁唑化合物组合使用的另外的化疗剂包括蛋白酶体抑制剂,例如硼替佐米,卡非佐米,麻瑞佐米(marizomib)等。
与本文公开的化合物组合有用(特别是在治疗恶性肿瘤中)的激酶抑制剂的实例包括:Btk抑制剂(如依鲁替尼)、CDK抑制剂(如帕博西尼)、EGFR抑制剂(如阿法替尼、埃罗替尼、吉非替尼、拉帕替尼、奥斯替尼和凡德替尼(vandetinib))、Mek抑制剂(如曲美替尼)、Raf抑制剂(如达拉菲尼、索拉非尼和威罗菲尼)、VEGFR抑制剂(如阿西替尼、乐伐替尼、尼达尼布、帕唑帕尼)、BCR-Abl抑制剂(如博舒替尼、达沙替尼、伊马替尼和尼罗替尼)、Syk抑制剂(如福他替尼(fostamatinib))、和JAK抑制剂(如鲁索利替尼(ruxolitinib))。在其他实施方案中,第二治疗剂可选自以下任何一种:
镇痛药-吗啡、芬太尼、氢吗啡酮、羟考酮、可待因、醋氨酚、氢可酮、丁丙诺啡、曲马多、文拉法辛、氟吡汀、哌替啶、喷他佐辛、右吗拉胺、地匹哌酮;
抗生素-氨基糖苷类(例如阿米卡星、庆大霉素、卡那霉素、新霉素、奈替米星、妥布霉素、和巴龙霉素)、碳青霉烯类(例如厄他培南、多利培南、亚胺培南、西司他丁、和美罗培南)、头孢菌素(例如头孢羟氨苄、头孢唑啉、头孢噻吩、头孢氨苄、头孢克洛、头孢羟唑、头孢西丁、头孢丙烯、头孢呋辛、头孢克肟、头孢地尼、头孢托仑、头孢哌酮、头孢噻肟、头孢泊肟、头孢他啶、头孢布烯、头孢唑肟、头孢曲松、头孢吡肟和头孢吡普(cefobiprole))、糖肽(例如替考拉宁、万古霉素和特拉万星)、林可酰胺(例如克林霉素和林可霉素)、脂肽(例如达托霉素)、大环内酯类(阿奇霉素、克拉霉素、地红霉素、红霉素、罗红霉素、醋竹桃霉素、泰利霉素和大观霉素)、单环β-内酰胺类(例如氨曲南)、硝基呋喃(例如呋喃唑酮和呋喃妥因)、青霉素(例如阿莫西林、氨苄青霉素、阿洛西林、羧苄西林、氯唑西林、双氯西林、氟氯西林、美洛西林、甲氧西林、萘夫西林、苯唑西林、青霉素G、青霉素V、哌拉西林、替莫西林和替卡西林))、青霉素组合物(例如阿莫西林/克拉维酸、氨苄青霉素/舒巴坦、哌拉西林/他唑巴坦、和替卡西林/克拉维酸)、多肽(例如杆菌肽、粘菌素和多粘菌素B)、喹诺酮(例如环丙沙星、依诺沙星、加替沙星、左氧氟沙星、洛美沙星、莫西沙星、萘啶酸、诺氟沙星、氧氟沙星、曲伐沙星、格雷沙星、司帕沙星和替马沙星)、磺酰胺(例如磺胺米隆、磺酰氨基柯衣定(sulfonamidochrysoidine)、磺胺醋酰、磺胺嘧啶、磺胺嘧啶银、磺胺甲二唑、磺胺甲噁唑、磺胺、柳氮磺胺吡啶、磺胺异噁唑、甲氧苄氨嘧啶、和甲氧苄氨嘧啶-磺胺甲噁唑)、四环素(例如地美环素、强力霉素、二甲胺四环素、氧四环素和四环素)、抗分支杆菌化合物(例如氯法齐明、氨苯砜、卷曲霉素、环丝氨酸、乙胺丁醇、乙硫异烟胺、异烟肼、吡嗪酰胺、利福平(rifampicin、rifampin)、利福布汀、利福喷丁、和链霉素)、以及其他(如胂凡纳明、氯霉素、磷霉素、梭链孢酸、利奈唑胺、甲硝唑、莫匹罗星、平板霉素、奎奴普汀(quinuprisin)/达福普汀、利福昔明、甲砜霉素、替加环素和替硝唑);
抗体-抗-TNF-α抗体,例如英利昔单抗(RemicadeTM)、阿达木单抗、戈利木单抗、赛妥珠单抗;抗-B细胞抗体,例如利妥昔单抗;抗-IL-6抗体,例如托珠单抗;抗-IL-1抗体,例如阿那白滞素;抗PD-1和/或抗-PD-L1抗体,例如纳武单抗、派姆单抗、佩蒂单抗(pidilizumab)、BMS-936559、MPDL3280A、AMP-224、MEDI4736;艾克司单抗(ixekizumab)、布朗德柳单抗(brodalumab)、奥法木单抗、斯瑞克单抗(sirukumab)、克立昔单抗、克拉扎克单抗(clazakiumab)、斐扎克单抗(fezakinumab)、斐替克单抗(fletikumab)、马瑞林单抗(mavrilimumab)、奥瑞珠单抗(ocrelizumab)、三瑞林单抗(sarilumab)、赛库克单抗(secukinumab)、托利珠单抗(toralizumab)、扎木单抗;
抗凝剂-华法林(CoumadinTM),苊香豆醇、苯丙香豆素、裂盒蕈色素、苯茚二酮、肝素、磺达肝癸钠、艾卓肝素(idraparinux)、利伐沙班、阿哌沙班、水蛭素、来匹卢定、比伐卢定、阿加曲班(argatrobam)、达比加群、西米拉坦、巴曲酶、裂纤酶;
抗炎剂-类固醇(例如布地奈德)、非类固醇抗炎剂(例如氨基水杨酸盐(例如柳氮磺胺吡啶、美沙拉嗪、奥沙拉秦、和巴柳氮)、环氧合酶抑制剂(COX-2抑制剂,如罗非考昔、塞来昔布)、双氯芬酸、依托度酸、法莫替丁、非诺洛芬、氟比洛芬、酮洛芬、酮咯酸、布洛芬、吲哚美辛、甲氯芬那酸、甲芬那酸、美洛昔康、萘普酮、萘普生、奥沙普秦、吡罗昔康、双水杨酯、舒林酸、托美丁);
免疫抑制剂-巯基嘌呤、皮质类固醇(如地塞米松、氢化可的松、强的松、甲基强的松龙、和泼尼松龙)、烷化剂(例如环磷酰胺)、钙调神经磷酸酶抑制剂(例如环孢霉素、西罗莫司以及他克莫司)、肌苷一磷酸脱氢酶(IMPDH)抑制剂(例如麦考酚酯、吗替麦考酚酯和硫唑嘌呤)、以及设计用于抑制细胞免疫同时保留接受者的体液免疫反应完整的药剂,包括各种抗体(例如抗淋巴细胞球蛋白(ALG)、抗胸腺细胞球蛋白(ATG)、单克隆抗-T-细胞抗体(OKT3))以及放射。硫唑嘌呤目前可从Salix制药公司以商品名Azasan获得;巯基嘌呤目前可从Gate制药公司以商品名Purinethol获得;泼尼松和泼尼松龙目前可从罗克珊实验室公司(Roxane Laboratories,Inc.)获得;甲基泼尼松龙目前可从辉瑞公司(Pfizer)获得;西罗莫司(雷帕霉素)目前可从惠氏-斯特公司(Wyeth-Ayerst)以商品名Rapamune获得;他克莫司目前可从藤泽公司(Fujisawa)以商品名Prograf获得;环孢霉素目前可从诺华公司(Novartis)以商品名Sandimmune和雅培公司(Abbott)以商品名Gengraf获得;IMPDH抑制剂(例如吗替麦考酚酯和麦考酚酸)目前可从罗氏公司(Roche)以商品名Cellcept下和诺华公司(Novartis)以商品名Myfortic获得;硫唑嘌呤目前可从葛兰素史克公司(Glaxo SmithKline)以商品名Imuran获得;并且抗体目前可从奥托生物技术公司(Ortho Biotech)以商品名Orthoclone下、诺华公司(Novartis)以商品名Simulect(巴利昔单抗)下以及罗氏公司(Roche)以商品名Zenapax(达利珠单抗)获得;以及
鸟苷酸环化酶C受体激动剂或肠促分泌素--例如以商品名Linzess销售的利那洛肽(linaclotide)。
这些各种药剂可以按照其标准或常用剂量使用,如商业上可获得的药物形式的处方信息中所规定的(参见2006年医生案头参考[The Physician’s Desk Reference]中的处方信息),其公开内容在此引入作为参考。
D.包含噁唑化合物的组合物
所公开的噁唑化合物可以单独使用,以任何组合使用,或与至少一种第二治疗剂组合使用或辅助使用,并且噁唑化合物和至少一种第二治疗剂可以与对于形成给予对象的组合物有用的任何合适的添加剂组合使用。添加剂可以包括在药物组合物中用于各种目的,例如用于稀释组合物以递送至对象,用于促进制剂的加工,为制剂提供有利的材料性质,用于促进从递送装置分散,用于稳定制剂(例如,抗氧化剂或缓冲剂),为制剂提供令人愉快或可口的味道或稠度,等等。典型的添加剂包括,例如但不限于:药学上可接受的赋形剂;药学上可接受的载体;和/或佐剂,如单糖、二糖、和多糖、糖醇和其他多元醇,如乳糖、葡萄糖、棉子糖、松三糖、乳糖醇、麦芽糖醇、海藻糖、蔗糖、甘露醇、淀粉、或其组合;表面活性剂,如山梨醇、双磷脂酰胆碱、和卵磷脂;膨胀剂;缓冲液,如磷酸盐和柠檬酸缓冲液;抗粘附剂,如硬脂酸镁;粘合剂,如糖类(包括二糖类,如蔗糖和乳糖)、多糖(如淀粉、纤维素、微晶纤维素、纤维素酯(如羟丙基纤维素)、明胶、合成的聚合物(如聚乙烯吡咯烷酮、聚烯二醇);包衣(如纤维素醚,包括羟丙基甲基纤维素、虫胶、玉米蛋白质玉米醇溶蛋白、和明胶);释放助剂(如肠溶包衣);崩解剂(如交聚维酮、交联的羧甲基纤维钠、和羟基乙酸淀粉钠);填充剂(如二碱式磷酸钙、植物油脂、乳糖、蔗糖、葡萄糖、甘露醇、山梨醇、碳酸钙、和硬脂酸镁);调味剂和甜味剂(如薄荷、樱桃、大茴香、桃、杏或甘草、覆盆子、和香草;润滑剂(例如矿物油,如滑石或二氧化硅、脂肪(如植物硬脂)、硬脂酸镁或硬脂酸);防腐剂(如抗氧化剂,例如维生素A、维生素E、维生素C、棕榈酸视黄醇、和硒、氨基酸(例如半胱氨酸和甲硫氨酸)、柠檬酸和柠檬酸钠、对羟基苯甲酸酯类(例如对羟基苯甲酸甲酯和对羟基苯甲酸丙酯);着色剂;压缩助剂;乳化剂;包封剂;树胶;造粒剂;及其组合。
III.使用方法
A.疾病/障碍
所公开的噁唑化合物以及其组合和/或组合物可用于改善、治疗或预防多种疾病和/或病症。在具体的实施方案中,噁唑化合物,噁唑化合物的组合或其组合物可用于治疗其中白细胞介素-1受体相关激酶(IRAK)途径的抑制在治疗上有用的病症。在一些实施方案中,化合物直接抑制IRAK蛋白,例如IRAK1,IRAK2,IRAK3或IRAK4。在某些实施方案中,公开的噁唑化合物可用于治疗、预防或改善自身免疫疾病,炎性疾病,心血管疾病,神经障碍,神经变性疾病,过敏性疾病,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,红细胞缺乏,移植物排斥,肺损伤,呼吸系统疾病,缺血性疾病以及细菌和病毒感染。
在一些实施方案中,噁唑化合物,噁唑化合物的组合或其组合物可用于治疗或预防过敏性疾病,肌萎缩性侧索硬化症(ALS),全身性红斑狼疮,类风湿性关节炎,I型糖尿病,炎性肠病,胆汁性肝硬化,葡萄膜炎,多发性硬化症,克罗恩病,溃疡性结肠炎,大疱性类天疱疮,肉状瘤病,银屑病,自身免疫性肌炎,韦格纳肉芽肿病,鱼鳞病,格雷夫斯眼病或哮喘。
噁唑化合物,噁唑化合物的组合或其组合物也可用于改善、治疗或预防与骨髓或器官移植排斥或移植物抗宿主疾病相关的免疫调节障碍。可以用本发明化合物治疗的炎性和免疫调节障碍的实例包括但不限于:器官或组织的移植、通过移植带来的移植物-与-宿主疾病、自身免疫综合征,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、全身性硬化症、重症肌无力、I型糖尿病、葡萄膜炎、后葡萄膜炎、过敏性脑脊髓炎、肾小球肾炎、感染后自身免疫性疾病(包括风湿热和感染后肾小球肾炎)、炎性和增生性皮肤疾病、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、血管神经性水肿、血管炎、红斑、皮肤嗜酸性粒细胞增多、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、格雷夫斯眼病、伏格特-小柳-原田三氏综合征、肉状瘤病、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、尘埃性哮喘、慢性或根深哮喘、晚期哮喘和气道高反应、支气管炎、胃溃疡、由缺血性疾病和血栓引起的血管损伤、缺血性肠病、炎性肠病、坏死性小肠结肠炎、与热烧伤有关的肠道病变、乳糜泻、直肠炎、嗜酸细胞性胃肠炎、肥大细胞增多症、克罗恩病、溃疡性结肠炎、偏头痛、鼻炎、湿疹、间质性肾炎、肺出血肾炎综合征、溶血性尿毒症综合征、糖尿病性肾病、多发性肌炎、格林-巴利综合征、美尼尔氏病、多发神经炎、多神经炎、单神经炎、神经根病、甲状腺机能亢进、巴塞多氏病、纯红细胞发育不全、再生障碍性贫血、再生不良性贫血、特发性血小板减少性紫癜、自身免疫性溶血性贫血、粒性白血球缺乏症、恶性贫血、巨成红细胞性贫血、红细胞发生不能、骨质疏松症、肉状瘤病、纤维化肺、特发性间质性肺炎、皮肌炎、寻常性白斑病、寻常性鱼鳞癣、光变应性敏感(photoallergic sensitivity)、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、结节性多动脉炎、心肌病、硬皮病、韦格纳氏肉芽肿病、肖格伦综合征、肥胖病、嗜酸性筋膜炎、齿龈病变、牙周组织、牙槽骨、骨质牙(substantiaossea dentis)、肾小球肾炎、通过预防脱毛或提供头发发生和/或促进头发生成和头发生长的男性型脱发或脱发秃发症、肌肉萎缩症、脓皮病和塞扎里氏综合征(Sezary'ssyndrome)、爱迪生氏病、器官保存后发生的缺血再灌注损伤、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、铁尘肺、色素性视网膜炎、老年性黄斑变性、玻璃体疤痕、角膜碱性烧伤、皮炎多形性红斑、线性IgA大疱皮炎和水泥皮炎、齿龈炎、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、癌转移和低气压病、由组胺或白三烯-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、肝部分切除、急性肝坏死、毒素引起的坏死、病毒性肝炎、休克、或缺氧症、B型病毒性肝炎、非A型/非B型肝炎、肝硬化、酒精性肝病(包括酒精性肝硬化)、非酒精性脂肪性肝炎(NASH)、肝功能衰竭、暴发性肝功能衰竭、晚发性肝功能衰竭、“慢加急”肝功能衰竭、化疗效果增加、巨细胞病毒感染、HCMV感染、AIDS、癌症、老年性痴呆、帕金森氏病、创伤、或慢性细菌感染。
在某些实施方案中,本发明化合物可用于治疗神经疼痛,包括神经性疼痛和炎症引起的疼痛。
在某些实施方案中,噁唑化合物,噁唑化合物的组合或其组合物可用于治疗和/或预防类风湿性关节炎、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、骨质疏松症、全身性硬化症、多发性硬化症、银屑病(特别是脓疱性银屑病)、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、冷吡啉蛋白相关周期性综合征、施尼茨勒综合征、系统性幼年型特发性关节炎、成人发作斯蒂尔氏病(adult's onset Still's disease)、痛风、痛风发作、假痛风、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受体拮抗剂的缺乏)、阿尔茨海默病、帕金森氏病。
可以通过噁唑化合物,噁唑化合物的组合或其组合物治疗的增殖性疾病包括良性或恶性肿瘤、实体瘤、脑癌、肾癌、肝癌、肾上腺癌、膀胱癌、乳腺癌、胃癌、胃肿瘤、卵巢癌、结肠癌、直肠癌、前列腺癌、胰腺癌、肺癌、阴道癌、宫颈癌、睾丸癌、泌尿生殖道癌、食道癌、喉癌、皮肤癌、骨癌或甲状腺癌、肉瘤、恶性胶质瘤、成神经细胞瘤、多发性骨髓瘤、胃肠癌(尤其是结肠癌或结肠直肠腺瘤)、头颈肿瘤、表皮增生、牛皮癣、前列腺增生、瘤形成、上皮性瘤形成、腺瘤、腺癌、角化棘皮瘤、鳞状细胞癌、大细胞癌、非小细胞肺癌、淋巴瘤、霍奇金和非霍奇金、乳腺癌、滤泡性癌、未分化癌、乳头状癌、精原细胞瘤、黑色素瘤、IL-1驱动的障碍、MyD88驱动的障碍(如ABC弥散性大B细胞淋巴瘤(DLBCL)、瓦尔登斯特伦巨球蛋白血症(macroglobulinemia)、霍奇金氏淋巴瘤、原发性皮肤T淋巴细胞瘤或慢性淋巴细胞白血病)、郁积或无痛多发性骨髓瘤、或血液恶性肿瘤(包括白血病、急性髓性白血病(AML)、DLBCL、ABC DLBCL、慢性淋巴细胞白血病(CLL)、慢性淋巴细胞性淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病、急性淋巴细胞白血病、B细胞幼淋巴细胞白血病、淋巴浆细胞性淋巴瘤、骨髓增生异常综合征(MDS)、骨髓纤维化、真性红细胞增多症、卡波西氏肉瘤、瓦尔登斯特伦巨球蛋白血症(WM)、脾边缘区淋巴瘤、多发性骨髓瘤、浆细胞瘤、血管内大B细胞淋巴瘤)。具体说,本发明的化合物可用于治疗耐药性恶性肿瘤,例如对JAK抑制剂依鲁替尼耐药的恶性肿瘤,包括依鲁替尼耐药的血液恶性肿瘤,如依鲁替尼耐药的CLL和依鲁替尼耐药的瓦尔登斯特伦巨球蛋白血症。
可以使用噁唑化合物,噁唑化合物的组合或其组合物治疗的过敏性疾病的实例包括但不限于:哮喘(例如过敏性哮喘、过敏性哮喘、特应性支气管IgE介导的哮喘、非特应性哮喘、支气管哮喘、非过敏性哮喘、特发性气喘、真气喘、由病理生理紊乱引起的内源性哮喘、未知或不明显原因引起的特发性气喘、肺气肿哮喘、运动诱发的哮喘、情绪诱发的哮喘、由环境因素引起的外源性哮喘、冷空气诱发的哮喘、职业性气喘、由细菌、真菌、原生动物或病毒感染引起或与之相关的感染性哮喘、早期哮喘、气喘婴儿综合征、毛细支气管炎、咳嗽变异性哮喘或药物性哮喘)、过敏性支气管肺曲霉病(ABPA)、过敏性鼻炎、常年性过敏性鼻炎、常年性鼻炎、血管运动性鼻炎、鼻液倒流、脓性或非脓性鼻窦炎、急性或慢性鼻窦炎、以及筛骨、额骨、上颌骨、或蝶骨窦炎。
作为另一个例子,类风湿性关节炎(RA)通常导致整个身体的目标关节肿胀,疼痛,运动丧失和压痛。RA的特征在于密集淋巴细胞的慢性发炎性滑膜。滑膜通常是一个细胞层厚,变成强烈的细胞并呈现类似于淋巴组织的形式,包括树突细胞,T细胞,B细胞和NK细胞,巨噬细胞和浆细胞簇。该过程以及包括抗原-免疫球蛋白复合物形成在内的过多免疫病理学机制最终导致关节完整性的破坏,导致关节处或附近的畸形,功能的永久丧失和/或骨侵蚀。噁唑化合物,噁唑化合物的组合或其组合物可用于治疗、改善或预防RA的任何一种,几种或所有这些症状。因此,在RA的情况下,当实现通常与RA相关的任何症状的减轻或改善时,认为该化合物提供治疗益处,无论该治疗是否导致对潜在RA的伴随治疗和/或减少循环类风湿因子(“RF”)的量。
美国风湿病学会(ACR)已经制定了确定RA改善和临床缓解的标准。一旦采用这样的参数,ACR 20(20%临床改善的ACR标准)要求使拉伸和肿胀关节计数提高20%,以及以下5个参数中的3个提高20%:患者整体评价、医师整体评价、患者疼痛评价、残疾程度和急性期反应物水平。这些标准已经扩大,ACR50和ACR70分别提高了50%和70%。其他标准包括Paulu的标准和放射学进展(例如Sharp评分)。
在一些实施方案中,当患者表现出ACR20时,实现患有RA的患者的治疗益处。在特定实施例中,可以实现ACRC50或甚至ACR70的ACR改进。
B.制剂和给药
包含本发明的活性化合物的药物组合物(或其前药)可以通过常规混合、溶解、造粒、造糖衣片、研磨、乳化、封装、包埋或冻干过程来制造。可以使用一种或多种生理学上可接受的赋形剂、稀释剂、载体、佐剂或助剂配制组合物,以提供可以药学上使用的制剂。
活性化合物或前药能够以药物组合物本身,或以水合物、溶剂化物、N-氧化物或药学上可接受的盐的形式进行配制。通常,这种盐比对应的游离酸和碱更易溶于水溶液,但是也可以形成比对应的游离酸和碱具有更低的溶解度的盐。
本发明的药物组合物可以采取适合于几乎任何给药方式的形式,包括例如局部、眼部、口服、经颊、全身、鼻内、注射(如腹腔内或静脉内)、透皮、直肠、阴道等,或采取适合通过吸入或吹入给予的形式。
对于局部给予来说,活性化合物、水合物、溶剂化物、N-氧化物或药学上可接受的盐或前药可以配制为如本领域熟知的溶液、凝胶、软膏、乳膏、悬浮液等。
全身给药剂型包括注射给药,如皮下注射,静脉注射,肌肉注射,鞘内注射或腹腔注射,以及透皮,透粘膜,口腔或肺部给药。
有用的可注射制剂包括水性或油性运载体中的活性化合物的无菌悬浮液、溶液或乳液。这些组合物还可以包含配制试剂,如悬浮剂、稳定剂和/或分散剂。用于注射的制剂可以以单位剂型存在,例如,在安瓿瓶或在多剂量容器中,并且可以包含添加的防腐剂。
或者,可注射制剂可以粉末形式提供,用于在使用前用合适的运载体重建,包括但不限于无菌,无热原的水,缓冲液,右旋糖溶液等。为此,活性化合物可以通过任何本领域已知的技术干燥,例如冻干,并在使用前重建。
对于经粘膜给药,在适合于待渗透屏障的制剂中采用渗透剂。这种渗透剂是本领域已知的。
对于口服给药,药物组合物可以采取以下形式:例如通过常规手段用药学上可接受的赋形剂(例如粘合剂(例如预凝胶化的玉米淀粉、聚乙烯吡咯烷酮、或羟丙基甲基纤维素);填充剂(例如乳糖、微晶纤维素或磷酸氢钙);润滑剂(例如硬脂酸镁、滑石或二氧化硅);崩解剂(例如马铃薯淀粉或淀粉羟基乙酸钠);和/或润湿剂(例如十二烷基硫酸钠))制备的锭剂、片剂或胶囊。这些片剂可以通过本领域中熟知的方法例如用糖、膜或肠溶包衣进行包衣。
用于口服给予的液体制剂可以是(例如)酏剂、溶液剂、糖浆剂或混悬剂的形式,或者可制成临用前用水或其它合适的载体进行重建的干燥产品。可通过常规方式用药学上可接受的添加剂如助悬剂(如,山梨糖醇糖浆、纤维素衍生物或氢化食用脂肪);乳化剂(如,卵磷脂或阿拉伯胶);非水性载体(如,杏仁油、油性酯、乙醇、cremophoreTM或分馏植物油);和防腐剂(如,对羟基苯甲酸甲酯或丙酯,或山梨酸)配制这类液体制剂。该制剂还可适当地含有缓冲盐、防腐剂、调味剂、着色剂和甜味剂。
如众所周知的,口服给药的制剂可以适当配制以提供活性化合物或前药的控制释放。
对于含服给药,组合物可采用常规方式配制的片剂或锭剂的形式。
对于直肠和阴道给药途径,活性化合物可以配制成溶液(用于滞留型灌肠剂)栓剂或含有常规栓剂基质(例如可可脂或其他甘油酯)的软膏。
对于鼻腔给药或通过吸入或吹入给药,活性化合物、水合物、溶剂化物、N-氧化物、药学上可接受的盐或前药可以使用适合的推进剂从加压包装或喷雾器中以喷雾剂的形式方便地递送,所示推进剂例如是二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、碳氟化合物、二氧化碳或其他适合的气体。在增压式气溶胶的情况下,剂量单位可通过提供阀以递送计量的量来确定。可以配制用于在吸入器或吹入器中使用的胶囊或药筒(例如包括明胶的胶囊和药筒),这些胶囊或药筒包含该化合物和适合的粉末基质(例如乳糖或淀粉)的粉末混合物。
适用于使用市售鼻喷雾装置进行鼻腔给药的含水悬浮液制剂的具体实例包括以下成分:活性化合物或前药(0.5 20mg/ml);苯扎氯铵(0.1 0.2mg/mL);聚山梨醇酯80(80;0.5 5mg/ml);羧甲基纤维素钠或微晶纤维素(1 15mg/ml);苯乙醇(1 4mg/ml);和葡萄糖(20 50mg/ml)。最终悬浮液的pH可以调节至约pH 5至pH7,典型的pH约为5.5。
适于通过吸入给予化合物的水性悬浮液的另一具体实例包含20mg/mL噁唑化合物或前药、1%(v/v)聚山梨醇酯80(80)、50mM柠檬酸和/或0.9%氯化钠。
对于眼部给药,可将活性噁唑化合物或前药配制成适于给予眼睛的溶液、乳液、悬浮液等。适用于向眼睛施用化合物的各种运载体是本领域已知的。具体的非限制性实例描述于美国专利美国专利6,261,547;6,197,934;6,056,950;5,800,807;5,776,445;5,698,219;5,521,222;5,403,841;5,077,033;4,882,150;和4,738,851,在此引入作为参考。
为了延长递送,可以将活性噁唑化合物或前药配制成用于通过植入或肌内注射给药的长效制剂。活性成分可以用合适的聚合或疏水材料(例如,作为可接受油中的乳液)或离子交换树脂配制,或配制成微溶衍生物,例如微溶盐。或者,可以使用制造为粘附盘或贴剂的透皮递送系统,其缓慢释放活性化合物用于经皮吸收。为此,渗透增强剂可用于促进活性化合物的透皮渗透。合适的透皮贴剂描述于例如美国专利5,407,713;5,352,456;5,332,213;5,336,168;5,290,561;5,254,346;5,164,189;5,163,899;5,088,977;5,087,240;5,008,110;和4,921,475,它们通过引用并入本文。
或者,可以使用其他药物递送系统。脂质体和乳剂是众所周知的可用于递送活性化合物或前药的递送运载体的实例。也可以使用某些有机溶剂,例如二甲亚砜(DMSO),但通常以更大的毒性为代价。
如果需要,可将药物组合物装入包装或分配装置中,所述包装或分配装置可包含一个或多个含有活性化合物的单位剂型。例如,该包装可包括金属或塑料薄片,如泡罩包装。所述包装或分配装置可附有给药说明书。
C.剂量
噁唑化合物或噁唑化合物的组合通常以有效实现预期结果的量使用,例如,以有效治疗、预防或改善特定病症的量使用。噁唑化合物或其组合物可以治疗性给药以获得治疗益处或预防性给药以实现预防益处。治疗益处意指根除或改善正在治疗的潜在病症和/或根除或改善与潜在病症相关的一种或多种症状,使得患者报告感觉或状况改善,尽管患者可能仍然受到折磨与潜在的疾病。例如,向患有过敏症的患者施用化合物不仅在根除或改善潜在的过敏反应时提供治疗益处,而且当患者报告接触过敏原后与过敏相关的症状的严重性或持续时间减少时也提供治疗益处。作为另一个例子,哮喘背景下的治疗益处包括哮喘发作开始后呼吸的改善或哮喘发作的频率或严重程度的降低。治疗益处还包括停止或减缓疾病的进展,无论是否实现了改善。
如本领域普通技术人员所知,噁唑化合物的优选剂量可取决于各种因素,包括患者或治疗对象的年龄,体重,一般健康状况和病情的严重程度。当通过吸入给药时,剂量也可能需要适合个体的性别和/或个体的肺活量。也可以调整剂量以适应患有一种以上病症的个体或具有影响肺活量和正常呼吸能力的其他病症(例如肺气肿,支气管炎,肺炎和呼吸道感染)的个体。噁唑化合物或其组合物的剂量和给药频率还取决于噁唑化合物是否配制用于治疗病症的急性发作或用于疾病的预防性治疗。本领域普通技术人员将能够确定特定个体的最佳剂量。
对于预防性给药,噁唑化合物,噁唑化合物的组合或其组合物可以给予患有前述病症之一风险的患者或对象。例如,如果不知道患者或对象是否对特定药物过敏,则可以在给予药物之前给予噁唑化合物,噁唑化合物的组合或其组合物以避免或改善对该药物的过敏反应。或者,预防性给药可用于避免或改善诊断患有潜在病症的患者的症状发作。例如,可以在预期暴露于过敏原之前将噁唑化合物或其组合物给予过敏患者。噁唑化合物、噁唑化合物的组合或其组合物也可以预防性地给予健康个体,所述健康个体反复暴露于上述疾病之一已知的药剂以预防疾病的发作。例如,噁唑化合物,噁唑化合物的组合或其组合物可以给予反复暴露于已知会引起过敏的过敏原(例如乳胶)的健康个体,以防止个体发生过敏。或者,噁唑化合物,噁唑化合物的组合或其组合物可以在参与引发哮喘发作的活动之前给予患有哮喘的患者,以减轻哮喘发作的严重性或完全避免哮喘发作。
最初可以从体外测定估计有效剂量。例如,可以配制用于对象的初始剂量以实现如在体外测定中测量的等于或高于特定化合物的IC50或EC50的活性化合物的循环血液或血清浓度。考虑到特定化合物的生物利用度,可以计算剂量以达到这种循环血液或血清浓度。Fingl和Woodbury,"General Principles"[一般原则],在:Goodman和Gilman的ThePharmaceutical Basis of Therapeutics[药物治疗基础],第1章,第1-46页,PergamonPress[培格曼出版社],以及其中引用的参考文献,提供了关于有效剂量的另外的指导。
在一些实施方案中,所公开的化合物具有从大于0至20μM(如从大于0至10μM、从大于0至5μM、从大于0至1μM、从大于0至0.5μM、从大于0至0.1μM、从大于0至0.01μM,例如从大于0至0.004μM)的EC50。
初始剂量也可以从体内数据(例如动物模型)估计。用于测试化合物治疗或预防上述各种疾病的功效的动物模型是本领域熟知的。合适的超敏反应或过敏反应动物模型描述于Foster,(1995)Allergy[过敏],50(增刊21):6-9,讨论34-38;以及Tumas等人,(2001),J.Allergy Clin.Immunol.[过敏临床免疫学杂志]107(6):1025-1033。适合的过敏性鼻炎的动物模型描述于:Szelenyi等人,(2000),Arzneimittelforschung[药物研究]50(11):1037-42;Kawaguchi等人(1994),Clin.Exp.Allergy[临床与实验变态反应]24(3):238-244;以及Sugimoto等人,(2000),Immunopharmacology[免疫药理学]48(1):1-7中。本领域普通技术人员可以调整这些信息以确定适合人类给予的剂量。
所公开的噁唑化合物的剂量将典型地在从约大于0mg/kg/天(如0.0001mg/kg/天或0.001mg/kg/天或0.01mg/kg/天)一直到至少约100mg/kg/天的范围内。更典型地,该剂量(或有效量)可以在至少每天一次给予的从约0.0025mg/kg至约1mg/kg的范围内,例如从0.01mg/kg至约0.5mg/kg、或从约0.05mg/kg至约0.15mg/kg。总日剂量通常为每天从约0.1mg/kg至约5mg/kg或至约20mg/kg的范围内,例如每天从0.5mg/kg至约10mg/kg或从每天约0.7mg/kg至约2.5mg/kg。除了其他因素之外,剂量可以更高或更低,取决于该噁唑化合物的活性、其生物利用度、给予方式以及以上讨论的各种因素。
可以针对个体调整剂量和剂量间隔以提供足以维持治疗或预防效果的噁唑化合物的血浆水平。例如,化合物可以每天给药一次,每天一次,每周一次,每周多次(例如,每隔一天),每月一次,每月多次,或每年一次给药,取决于给药方式、治疗的具体适应症和处方医师的判断等。本领域普通技术人员将能够优化有效的局部剂量而无需过多的实验。
包含一种或多种所公开的噁唑化合物的组合物通常包含按总重量百分比计大于0一直到99%的噁唑化合物或化合物和/或其他治疗剂。更典型地,包含一种或多种所公开的噁唑化合物的组合物包含约1至约20重量%的噁唑化合物和其他治疗剂,和约80至约99重量%的药学上可接受的添加剂。
优选地,噁唑化合物,噁唑化合物的组合或其组合物将提供治疗或预防益处而不会引起实质毒性。噁唑化合物的毒性可使用标准药学方法测定。毒性和治疗(或预防)效果之间的剂量比是治疗指数。具有高治疗指数的噁唑化合物是优选的。
IV.实施例
实施例1
制备3-氟-2-(1H-吡唑-3-基)-6-(三氟甲基)吡啶102
圆底烧瓶中加入2-溴-3-氟-6-(三氟甲基)吡啶(20.7g,84.7mM),3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑(32.8g,169mM)和Pd(Ph3)4(9.79g,8.47mM)。Na2CO3(44.9g,423mM)溶解在H2O(200ml)中,与二噁烷(500ml)一起加入反应烧瓶中。将反应混合物在100℃下加热4小时;在此期间,反应变成黄色悬浮液。通过TLC和LCMS分析表明完全转化;使用旋转蒸发器在减压下除去溶剂。将水(400ml)加入到粗产物中,并用EtOAc(3×200ml)萃取混合物。将合并的有机相通过Na2SO4过滤,并将硅胶加入滤液中。将混合物浓缩至干,将粗产物吸附在硅胶上。CombiFlash色谱法用DCM/MeOH-NH3(2M)洗脱(梯度0至2%),得到18.4g(94%产率)标题化合物3-氟-2-(1H-吡唑-3-基)-6-(三氟甲基)吡啶102,为灰白色固体。
1H NMR(400MHz,CDCl3)δ8.39(s,1H),7.90(dd,J=8.6,3.6Hz,1H),7.77(t,J=8.8Hz,1H);MS(ESI)(m/z):232[M+H]+。
实施例2
制备3-氟-2-(4-硝基-1H-吡唑-3-基)-6-(三氟甲基)
吡啶104
3-氟-2-(1H-吡唑-3-基)-6-(三氟甲基)吡啶102(18.4g,79.6mM)溶解在浓H2SO4(90ml)中并冷却至0℃。使用滴液漏斗滴加发烟HNO3(17ml,398mM)。将反应混合物温热至室温过夜。然后将混合物缓慢倒在碎冰上,用饱和NaOH水溶液中和,同时在整个加入过程中保持冰浴冷却。当混合物接近pH 5-6时,大量固体开始沉淀。将pH调节至约7,然后用EtOAc(2×300ml)萃取混合物。将合并的有机层通过Na2SO4过滤,加入硅胶并在减压下除去溶剂。将所得材料加载到CombiFlash柱上,用己烷/EtOAc(梯度0至100%)洗脱进一步纯化。得到所需产物,为白色固体(20.6g,94%收率)。
1H NMR(400MHz,CDCl3)δ10.39(s,1H),7.75(d,J=2.0Hz,1H),7.66(d,J=2.3Hz,1H),7.65(s,1H),6.99(s,1H);MS(ESI)(m/z):277[M+H]+。
实施例3
制备3-氟-2-(4-硝基-1-(1,4-二氧杂螺[4.5]癸烷-8-基)-1H-吡唑-3-基)-6-(三氟甲基)吡啶106
在双颈圆底烧瓶中加入3-氟-2-(4-硝基-1H-吡唑-3-基)-6-(三氟甲基)吡啶104(20.6g,74.6mM)。加入无水二噁烷(500ml),搅拌混合物直至变成澄清溶液。将反应烧瓶脱气并用氮气回填。随后,在室温下分批缓慢加入NaH(在矿物油中,60重量%)(4.47g,111.9mM),并将灰色悬浮液搅拌约10分钟。分批加入4-甲基苯磺酸1,4-二氧杂螺[4.5]癸烷-8-基酯(69.9g,224mM),将反应混合物回流2天。冷却至室温后,用MeOH(100ml)淬灭反应,减压除去溶剂。将水(300ml)加入到粗产物中,并用EtOAc(2×300ml)萃取混合物。将有机层通过Na2SO4过滤,将粗产物吸附到硅胶上。用己烷/EtOAc(梯度0至30%)洗脱,通过快速色谱法分离所需产物106(灰白色固体,18.3g,59%产率)。
1H NMR(400MHz,CDCl3)δ8.32(d,J=0.4Hz,1H),7.82(dd,J=8.6,3.6Hz,1H),7.68(td,J=8.4,0.7Hz,1H),4.32(tt,J=11.6,4.0Hz,1H),3.98–3.92(m,4H),2.24(dddd,J=10.2,4.2,2.8,1.6Hz,2H),2.11(tdd,J=12.9,11.5,3.9Hz,2H),1.95–1.84(m,2H),1.72(td,J=13.3,4.3Hz,2H);MS(ESI)(m/z):417[M+H]+。
实施例4
制备4-(3-(3-氟-6-(三氟甲基)吡啶-2-基)-4-硝基-1H-吡唑-1-基)环己烷-1-酮108
3-氟-2-(4-硝基-1-(1,4-二氧杂螺[4.5]癸烷-8-基)-1H-吡唑-3-基)-6-(三氟甲基)吡啶106(18.0g,43.2mM)溶解在丙酮(400ml)中,然后加入水(100ml)和对甲苯磺酸一水合物(20.6g,108mM)。将混合物在80℃加热6小时。减压除去丙酮,加入饱和NaHCO3水溶液(200ml)。水相用EtOAc(2×300ml)萃取,合并的有机层用Na2SO4干燥。通过快速色谱法进一步纯化粗产物,用己烷/EtOAc(梯度0至50%)洗脱。得到标题化合物108,为灰白色固体(12.5g,78%收率)。
1H NMR(400MHz,CDCl3)δ8.36(d,J=0.4Hz,1H),7.86(dd,J=8.6,3.6Hz,1H),7.71(td,J=8.4,0.7Hz,1H),4.75(tt,J=10.8,3.5Hz,1H),2.73–2.47(m,7H),2.45–2.27(m,2H);MS(ESI)(m/z):373[M+H]+。
实施例5
制备4-((1r,4r)-4-(3-(3-氟-6-(三氟甲基)吡啶-2-基)-4-硝基-1H-吡唑-1-基)环己基)吗啉110
将来自实施例4的酮108(12.5g,33.6mM)溶解在无水DCM(500ml)中并加入吗啉(35ml,402mM)。加入NaBH(OAc)3(14.2g,67.2mM),并将淡黄色悬浮液搅拌3天。加入饱和的水溶液(400ml),用DCM(2×300ml)萃取混合物。将有机层通过Na2SO4过滤并在减压下除去溶剂。通过CombiFlash色谱法纯化粗产物,用DCM/MeOH-NH3(2M)(梯度0至2%)洗脱,得到3.86g(26%产率)标题化合物110,为灰白色固体。
1H NMR(400MHz,CDCl3)δ8.29(d,J=0.4Hz,1H),7.84(dd,J=8.6,3.6Hz,1H),7.69(td,J=8.4,0.7Hz,1H),4.23(tt,J=12.0,3.9Hz,1H),3.82–3.62(m,4H),2.59(dd,J=6.5,3.0Hz,4H),2.48–2.27(m,3H),2.16(dq,J=12.8,3.5Hz,2H),1.95–1.75(m,3H),1.46(qd,J=13.2,3.4Hz,2H);MS(ESI)(m/z):444[M+H]+。
实施例6
制备3-(3-氟-6-(三氟甲基)吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-胺112
将来自实施例5的硝基化合物110(3.22g,7.79mM)溶解在EtOAc(100ml)中并与Pd/C(湿支持物,载量10重量%,德固赛型E101NE/W,644mg)一起置于Parr压力容器中。将混合物脱气并用氢气回填三次。使用Parr振荡器氢化装置将反应混合物保持在60psi(磅/平方英寸)氢气压下。3小时后,还原完成,用装有硅藻土的玻璃料滤除催化剂。减压蒸发溶剂,得到所需产物112(2.94g,91%收率),为棕褐色固体。
1H NMR(400MHz,DMSO-d6)δ7.97(ddd,J=10.8,8.5,0.8Hz,1H),7.78(dd,J=8.5,3.1Hz,1H),4.96(s,2H),4.06(tt,J=11.9,4.0Hz,1H),3.63–3.47(m,4H),2.47(ddt,J=9.3,4.7,2.4Hz,4H),2.27(tt,J=11.6,3.5Hz,1H),2.09–1.99(m,2H),1.95–1.86(m,2H),1.80–1.66(m,2H),1.37(tdd,J=13.8,11.8,3.4Hz,2H);MS(ESI)(m/z):414[M+H]+。
实施例7
制备2-氯-N-(3-(3-氟-6-(三氟甲基)吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-基)噁唑-4-甲酰胺114
2-氯噁唑-4-羧酸(1.33g,9.02mM),HATU(4.56g,12.0mM),Hünig碱(6ml,34.4mM)置于圆底烧瓶中,加入无水DCM(500ml)。然后用实施例6的胺112(3.22g,7.79mM)处理澄清溶液。将混合物在室温下搅拌两天。加入饱和NaHCO3水溶液(400ml),用DCM(2×300ml)萃取混合物。将有机层通过Na2SO4过滤并在减压下除去溶剂。通过CombiFlash色谱法纯化粗产物,用DCM/MeOH-NH3(2M)(梯度0至3%)洗脱,得到4.05g(96%产率)标题化合物114,为灰白色固体。
1H NMR(400MHz,CDCl3)δ11.27(s,1H),8.46(d,J=0.8Hz,1H),8.20(d,J=0.3Hz,1H),7.75–7.56(m,2H),4.22(tt,J=12.0,3.9Hz,1H),3.83–3.68(m,4H),2.72–2.53(m,4H),2.48–2.25(m,2H),2.23–2.04(m,2H),1.89(qd,J=12.9,3.4Hz,2H),1.60–1.35(m,2H);MS(ESI)(m/z):543[M+H]+。
实施例8
制备N-(3-(3-氟-6-(三氟甲基)吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺II-7
将来自实施例8的噁唑氯化物116(3.70g,6.82mM)溶解在二噁烷(400ml)中,得到澄清的黄色溶液。将溶解在H2O(80ml)中的(1H-吡唑-4-基)硼酸(3.05g,27.3mM),四(三苯基膦)钯(630mg,8mol%)和Na2CO3(3.61g,34.1mM)加入烧瓶中。将反应混合物脱气,用氮气回填,然后回流2小时。通过TLC和LCMS分析显示完全转化,在减压下除去溶剂。加入水(400ml),用EtOAc(6×500ml)萃取混合物。产物在有机溶剂中溶解度低;因此需要大量的EtOAc。将合并的有机相通过Na2SO4过滤,加入硅胶并在减压下除去溶剂。通过CombiFlash色谱进一步纯化,用DCM/MeOH-NH3(3.5M)(梯度0至5%)洗脱,得到3.71g(93%产率)标题化合物II-7,为灰白色固体。
1H NMR(400MHz,DMSO-d6)δ13.52(s,1H),10.82(s,1H),8.76(s,1H),8.69–8.47(m,1H),8.49–8.23(m,1H),8.25–7.92(m,2H),4.31(tt,J=11.7,4.0Hz,1H),3.57(t,J=4.6Hz,4H),2.41–2.29(m,1H),2.14(d,J=11.4Hz,2H),1.96(d,J=12.2Hz,2H),1.91–1.78(m,2H),1.43(q,J=11.9,11.3Hz,2H);MS(ESI)(m/z):575[M+H]+。
实施例9
制备1-(3,6-二氟吡啶-2-基)乙烷-1-酮118
根据J.Med.Chem.56(5),2013,1799-1810的方法(在此引入作为参考),制备1-(3,6-二氟吡啶-2-基)乙烷-1-酮118。简言之,在装有顶置式搅拌器的三颈烧瓶中制备DABCO(49.7g,442.8mmol)在TBME(600mL)中的悬浮液。冷却至-78℃后,用滴液漏斗在90分钟内加入正丁基锂溶液(2.5M在己烷中,164mL)。2小时后,同时将温度保持在-78℃,用30分钟通过滴液漏斗滴加2,5-二氟吡啶(40g,340.6mmol)的TBME(20mL)溶液。在-78℃下再过一小时后,用滴液漏斗在20分钟内加入N-甲酰基-N-甲基乙酰胺(44.3mL,341.8mmol)的TBME(45mL)溶液。两小时后,基于LC-MS反应完成。小心地用饱和NH4Cl溶液(400mL)淬灭反应,然后用乙酸乙酯(400mL)稀释。将水层用乙酸乙酯进一步萃取两次。将合并的有机相用饱和NaHCO3溶液、盐水洗涤,用固体硫酸钠干燥,然后真空浓缩。高真空干燥后,得到47.2g 1-(3,6-二氟吡啶-2-基)乙烷-1-酮118。
1H NMR(300MHz,氯仿-d)δ7.69(td,J=8.9,5.8Hz,1H),7.23–7.14(m,1H),2.66(s,3H);LCMS(m/z):158.1(MH+)。
实施例10
制备(E)-1-(3,6-二氟吡啶-2-基)-3-(二甲基氨基)丙-2-烯-1-酮120
1-(3,6-二氟吡啶-2-基)乙烷-1-酮118(47.2g,300.2mmol)在N,N-二甲甲酰胺二甲基缩醛(80.0mL,600.4mmol)中的溶液在103℃回流。1小时后,基于LC-MS反应完成。将溶液真空浓缩并在高真空下干燥,得到61.6g(E)-1-(3,6-二氟吡啶-2-基)-3-(二甲基氨基)丙-2-烯-1-酮120,为深橙色固体。
1H NMR(300MHz,氯仿-d)δ7.81(d,J=12.6Hz,1H),7.63–7.51(m,1H),7.02–6.94(m,1H),5.89(d,J=12.6Hz,1H),3.16(s,3H),2.94(s,3H);LCMS(m/z):213.1(MH+)。
实施例11
制备3,6-二氟-2-(1H-吡唑-3-基)吡啶122
(E)-1-(3,6-二氟吡啶-2-基)-3-(二甲基氨基)丙-2-烯-1-酮120(61.6g,290.3mmol)在水合肼(64%肼,18.3mL)中于98℃加热30分钟。真空浓缩并在高真空下干燥过夜。将残留物用异丙醇研磨两次,得到37.3g 3,6-二氟-2-(1H-吡唑-3-基)吡啶122,为褐色固体。
1H NMR(300MHz,氯仿-d)δ7.76(d,J=2.0Hz,1H),7.62(td,J=8.9,6.0Hz,1H),6.95(dd,J=3.7,2.0Hz,1H),6.88(ddd,J=8.8,3.7,2.8Hz,1H);LCMS(m/z):182.1(MH+)。
实施例12
制备3,6-二氟-2-(4-硝基-1H-吡唑-3-基)吡啶124
向冷却至0℃的3,6-二氟-2-(1H-吡唑-3-基)吡啶122(37.3g,205.9mmol)的180mLH2SO4溶液中于40分钟内逐滴加入HNO3(90%发烟,19.4mL)。将反应物逐渐升温至室温过夜。将溶液倒在冰上,用NaOH水溶液中和至pH8。过滤固体,然后加入乙酸乙酯中。将水层用乙酸乙酯萃取两次,将合并的有机层用盐水洗涤一次,然后经硫酸钠干燥。将其与第一乙酸乙酯溶液合并,过滤,并真空浓缩。将得到的固体用乙酸乙酯和己烷研磨,得到39.9g3,6-二氟-2-(4-硝基-1H-吡唑-3-基)吡啶124,为浅黄色固体。
1H NMR(300MHz,氯仿-d)δ8.46(s,1H),7.72(td,J=8.2,5.8Hz,1H),7.15(dt,J=8.9,3.3Hz,1H),1.25(s,1H);LCMS(m/z):227.1(MH+)。
实施例13
制备2-(1-((1r,4r)-4-乙氧基环己基)-4-硝基-1H-吡唑-3-基)-3,6-二氟吡啶126
向冷却至0℃的3,6-二氟-2-(4-硝基-1H-吡唑-3-基)吡啶124(39.8g,176mmol)在1L二噁烷的溶液中加入NaH(60%矿物油中的分散体,10.56g,264mmol)。使其温热至室温2小时后,分批加入4-硝基苯磺酸4-乙氧基环己基酯(2:1比率的1s,4s:1r,4r;69.5g,221mmol)。将反应加热至温和回流48小时。冷却至室温后,将反应用冰淬灭并真空浓缩。通过硅胶色谱法纯化粗物质,用乙酸乙酯和己烷洗脱,然后进一步用乙酸乙酯研磨,得到30.1g 2-(1-((1r,4r)-4-乙氧基环己基)-4-硝基-1H-吡唑-3-基)-3,6-二氟吡啶126,为浅黄色固体。
1H NMR(300MHz,氯仿-d)δ8.26(s,1H),7.64(ddd,J=8.9,7.7,5.9Hz,1H),7.06(ddd,J=8.8,3.6,2.9Hz,1H),4.25(tt,J=11.8,3.9Hz,1H),3.54(q,J=7.0Hz,2H),3.34(tt,J=10.6,4.1Hz,1H),2.36–2.19(m,4H),1.94–1.79(m,2H),1.52–1.38(m,2H),1.21(t,J=7.0Hz,3H);LCMS(m/z):353.2(MH+)。
实施例14
制备3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-胺盐酸盐128
装有溶解在乙酸乙酯(200mL)中的2-(1-((1r,4r)-4-乙氧基环己基)-4-硝基-1H-吡唑-3-基)-3,6-二氟吡啶126(6.24g,17.7mmol)的Parr摇瓶中加入10%钯炭(627mg)。将混合物在氢气下40psi振荡过夜。将混合物通过硅藻土过滤到含有HCl(1.46mL 12.1N水溶液)的接收烧瓶中。通过旋转蒸发浓缩并在高真空下干燥过夜后,得到3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-胺盐酸盐128(6.2g),为浅黄色固体。LCMS(m/z):323.2(MH+)。
实施例15
制备2-溴-N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)噁唑-4-甲酰胺130
在小瓶中合并在CH2Cl2(4mL)中的3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-胺盐酸盐128(110mg,0.306mmol),2-溴噁唑-4-羧酸(73mg,0.369mmol),N,N-二异丙基乙胺(160μL,0.920mmol)和HATU(175mg,0.461mmol)。3小时后,将反应混合物用乙酸乙酯和水稀释。将有机相用水洗涤两次,然后用盐水溶液洗涤,用硫酸钠干燥,过滤,然后浓缩。通过硅胶色谱法纯化化合物,用乙酸乙酯和己烷洗脱,得到2-溴-N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)噁唑-4-甲酰胺130(148mg,0.298mmol),为白色固体。
1H NMR(300MHz,氯仿-d)δ11.43(s,1H),8.41(s,1H),8.28(s,1H),7.64(ddd,J=9.4,8.8,6.1Hz,1H),6.86(ddd,J=8.8,3.7,2.6Hz,1H),4.26(tt,J=11.9,3.7Hz,1H),3.56(q,J=7.0Hz,2H),3.37(tt,J=10.5,3.9Hz,1H),2.25(t,J=14.9Hz,4H),1.96–1.81(m,2H),1.54–1.39(m,2H),1.22(t,J=7.0Hz,3H);LCMS(m/z):497.9(MH+)。
实施例16
制备2-氯-N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)噁唑-4-甲酰胺132
采用2-氯噁唑-4-羧酸,根据实施例16的方法制备化合物132。
1H NMR(300MHz,氯仿-d)δ11.38(s,1H),8.40(s,1H),8.22(s,1H),7.64(ddd,J=9.4,8.8,6.0Hz,1H),6.85(ddd,J=8.8,3.7,2.6Hz,1H),4.26(tt,J=11.9,3.8Hz,1H),3.56(q,J=7.0Hz,2H),3.36(tt,J=10.6,4.0Hz,1H),2.24(t,J=14.6Hz,4H),1.96–1.80(m,2H),1.54–1.38(m,2H),1.22(t,J=7.0Hz,3H);LCMS(m/z):452.2(MH+)。
实施例17
制备N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺II-9
在微波小瓶中合并在3mL二噁烷中的2-溴-N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)噁唑-4-甲酰胺130(148mg,0.298mmol),4-吡唑硼酸频哪醇酯(116mg,0.596mmol)和2M Na2CO3水溶液(447μL)。将混合物在氮气下吹扫,然后加入四(三苯基膦)钯(0)(34mg,0.03mmol)。将该组合物在120℃下微波加热30分钟。通过硅藻土过滤固体,浓缩滤液。通过硅胶色谱法纯化化合物,用乙酸乙酯和己烷洗脱,得到N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺II-9(97.7mg,0.202mmol),为白色固体。
1H NMR(300MHz,氯仿-d)δ11.68(s,1H),8.44(s,1H),8.27–8.17(m,3H),7.66(td,J=9.1,6.1Hz,1H),6.92–6.83(m,1H),4.36–4.19(m,1H),3.57(q,J=7.0Hz,2H),3.44–3.32(m,1H),2.36–2.16(m,4H),1.97–1.82(m,2H),1.55–1.40(m,2H),1.23(t,J=7.0Hz,3H);LCMS(m/z):484.1(MH+)。
实施例18
制备((4-(4-((1-(反式-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基)磷酸二叔丁酯II-16
在圆底烧瓶中,室温下向N-(1-(反式-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺I-1(897mg,2mmol)的DMF(8mL)溶液中加入Cs2CO3(977.5mg,3mmol),30分钟后,加入(氯甲基)磷酸二叔丁酯(1.03g,4mmol)。在23小时,通过LC-MS,仍有7%的I-1存在。加入另外的(氯甲基)磷酸二叔丁酯(0.4g,1.5mmol)和Cs2CO3(0.2g,0.6mmol),再过24小时后,剩余约3%的I-1。在冰浴冷却下,通过逐滴加入水(24mL)淬灭反应,并将混合物在室温下搅拌30分钟。过滤收集沉淀物,用水洗涤,并在高真空下进一步干燥。得到化合物((4-(4-((1-(反式-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基)磷酸二叔丁酯II-16,为浅米色固体:1.33g(99%收率)。
1H NMR(400MHz,氯仿-d)δ11.56(s,1H),9.34(d,J=1.6Hz,1H),8.68(dd,J=2.7,1.6Hz,1H),8.50(dd,J=2.7,0.3Hz,1H),8.40(s,1H),8.36(d,J=0.6Hz,1H),8.23(s,1H),8.12(d,J=0.6Hz,1H),5.95(d,J=12.7Hz,2H),4.21(tt,J=11.8,3.8Hz,1H),3.57(q,J=7.0Hz,2H),3.38(tt,J=10.6,4.0Hz,1H),2.30–2.20(m,4H),1.97–1.88(m,2H),1.50–1.43(m,重叠,2H),1.454(s,9H),1.452(s,9H),1.23(t,J=7.0Hz,3H);LRMS(M+Na)m/z 693.36。
实施例19
制备磷酸二氢(4-(4-((1-(反式-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基酯II-17
在圆底烧瓶中,向((4-(4-((1-(反式-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基)磷酸二叔丁酯II-16(671mg,1mmol)的DCM(5mL)溶液中加入TFA(0.613mL,8mmol),并将混合物在室温下搅拌22小时。通过LC-MS监测反应完成。过滤收集黄色固体,用DCM洗涤,随后悬浮在二噁烷-H2O(10mL-1mL)中,通过离心除去溶剂,随后除去上清液。该过程重复3次,并用丙酮-H2O(10mL-1mL)再重复3次。将固体进一步真空干燥。得到化合物磷酸二氢(4-(4-((1-(反式-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基酯II-17,为亮黄色固体:145mg。
1H NMR(400MHz,DMSO-d6)δ11.46(br s,2H),11.45(s,1H),9.19(d,J=1.5Hz,1H),8.89(dd,J=2.7,1.6Hz,1H),8.79(s,1H),8.66(d,J=0.6Hz,1H),8.61(d,J=2.7Hz,1H),8.45(s,1H),8.22(d,J=0.7Hz,1H),5.90(d,J=10.6Hz,2H),4.34(br t,J=11.9Hz,1H),3.48(q,J=7.0Hz,2H),3.38–3.33(m,partially重叠with H2O,1H),2.11–2.07(m,4H),1.93–1.84(m,2H),1.40–1.30(m,2H),1.10(t,J=7.0Hz,3H);LRMS(M+H)m/z 559.19.
在除去大部分有机溶剂并通过过滤收集沉淀物后,从上清液中获得第二部分化合物:273.4mg,与第一批相同的纯度。合并产率为75%。
实施例20
制备(4-(4-((1-(反式-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基磷酸钠II-18
在冰浴上,向磷酸二氢(4-(4-((1-(反式-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基酯II-17(418mg,0.65mmol)在CH3CN(3mL)和H2O(2mL)的悬浮液中逐滴加入1N NaOH溶液(1.3mL,1.3mmol)。在室温下继续搅拌10分钟。加入另外的1mL水,混合物变成澄清的淡黄色溶液。通过冷冻干燥除去溶剂。得到化合物(4-(4-((1-(反式-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基磷酸钠,为浅黄色固体:399mg(>99%收率)。
1H NMR(400MHz,氧化氘)δ8.26(d,J=1.4Hz,1H),8.19(dd,J=2.6,1.5Hz,1H),8.12(d,J=2.6Hz,1H),7.95(s,1H),7.76(s,1H),7.69(s,1H),7.38(s,1H),5.57(d,J=6.6Hz,2H),3.90(tt,J=11.8,3.9Hz,1H),3.55(q,J=7.1Hz,2H),3.40(tt,J=11.0,3.9Hz,1H),2.14–2.09(m,2H),2.03–1.97(m,2H),1.66–1.56(m,2H),1.34–1.24(m,2H),1.10(t,J=7.0Hz,3H);LRMS(M+H)m/z559.23。
实施例21
制备2-(1-(反式-4-乙氧基环己基)-4-硝基-1H-吡唑-3-基)吡嗪136作为异构体的混合物
在氮气气氛下,向2-L双颈圆底烧瓶中加入2-(4-硝基-1H-吡唑-3-基)吡嗪132(17.5g,91.6mmol),然后加入1,4-二噁烷(450mL,0.2M)。用冰浴冷却,分批加入NaH(60%在矿物油中的分散体,5.5g,137mmol)。移去冰浴,将悬浮液在35℃下搅拌3小时。加入化合物4-乙氧基环己基4-硝基苯磺酸酯134(36.2g,110mmol,顺式/反式比率≥2),将反应混合物在110℃下温和回流搅拌。24小时后再加入约0.4当量(12克)的134。在第4天,通过LC-MS,132:136≈2:3。用约20mL饱和NaHCO3水溶液淬灭反应,并通过旋转蒸发除去大部分二噁烷。加入EtOAc(700mL)和饱和NaHCO3–H2O水溶液(约1:1,共700mL),并充分混合。分离两层,水层用EtOAc(400mL×2)萃取。合并有机层,干燥(Na2SO4),过滤,并通过旋转蒸发除去溶剂。通过硅胶色谱法纯化产物,然后用己烷-EtOAc(2:1)研磨。得到化合物2-(1-(反式-4-乙氧基环己基)-4-硝基-1H-吡唑-3-基)吡嗪136,为浅黄色固体:9.6g(33%收率);1H NMR(300MHz,氯仿-d)δ9.00(d,J=1.5Hz,1H),8.71(dd,J=2.5,1.5Hz,1H),8.65(d,J=2.5Hz,1H),4.26(tt,J=11.7,3.8Hz,2H),3.56(q,J=7.0Hz,2H),3.36(tt,J=10.6,4.1Hz,2H),2.36–2.21(m,4H),1.95–2.21(m,2H),1.54–1.40(m,2H),1.22(t,J=7.0Hz,3H);LRMS(M+H)m/z318.2。
实施例22
制备8-乙氧基-1,4-二氧杂螺[4.5]癸烷138
在圆底烧瓶中的氢化钠(60%在矿物油中的分散体,74.3g,1.858mol)用己烷洗涤四次。制备THF(1L)悬浮液并冷却至0℃。逐渐加入1,4-二氧杂螺[4.5]癸烷-8-醇(150g,929mmol),使反应温热至室温(rt)。2小时后,将反应冷却回0℃,用滴液漏斗在1小时内加入碘乙烷。逐渐使反应温热至室温,然后安装回流冷凝器。通过TLC(1:1乙酸乙酯的己烷溶液)监测反应。完成后,用冰淬灭反应,在真空中减少溶剂的体积,然后用乙酸乙酯和水稀释。用乙酸乙酯萃取两次后,将合并的有机层用盐水洗涤,用硫酸钠干燥,过滤,并真空浓缩。高真空干燥后,得到166.9g 8-乙氧基-1,4-二氧杂螺[4.5]癸烷138,为黄色油状物。
1H NMR(300MHz,氯仿-d)δ3.90(t,J=2.2Hz,4H),3.45(q,J=7.0Hz,2H),3.40–3.32(m,1H),1.82–1.62(m,6H),1.56–1.46(m,2H),1.16(t,J=7.0Hz,3H)。
实施例23
制备4-乙氧基环己烷-1-酮140
向8-乙氧基-1,4-二氧杂螺[4.5]癸烷138(166.9g,896.1mmol)的THF(700mL)溶液中加入3M HCl水溶液(aq)(597mL)。用附带的回流冷凝器将溶液加热至90℃,保持2小时。通过TLC(1:1乙酸乙酯的己烷溶液)监测反应,取等分试样用NaOH水溶液淬灭,并萃取到乙酸乙酯中。完成后,将溶剂体积真空浓缩并用4M NaOH溶液调节至pH8。将其用乙酸乙酯萃取两次,将合并的有机相用盐水洗涤,用固体硫酸钠干燥,过滤,并真空浓缩。在高真空下干燥后,得到124.2g所需的4-乙氧基环己烷-1-酮140,为黄色油状物。
1H NMR(300MHz,氯仿-d)δ3.74–3.61(m,1H),3.53(q,J=7.0Hz,2H),2.63–2.46(m,2H),2.30–2.15(m,2H),2.12–1.82(m,4H),1.21(t,J=7.0Hz,3H)。
实施例24
制备(1s,4s)-4-乙氧基环己烷-1-醇142
将4-乙氧基环己烷-1-酮140(121.6g,855mmol)在750mL THF中的溶液冷却至-78℃。在1小时内分批加入固体LiAlH4(95%,51.2g,1.28mol),然后逐渐升温至-10℃。一小时后,取出等分试样并在1:1乙酸乙酯的己烷溶液中淬灭进行TLC分析,显示反应完成。将反应冷却回-78℃并逐滴加入4M NaOH溶液(641mL)淬灭。将混合物稀释并用乙酸乙酯洗涤三次,倾析出溶剂。将合并的有机相用1M NaOH,盐水洗涤,用固体硫酸钠干燥,过滤,并真空浓缩。在高真空下干燥后,得到117.9g的4-乙氧基环己烷-1-醇142(~2:1比率的1s,4s和2s,4s异构体),为黄色油状物。
1H NMR(300MHz,氯仿-d)δ3.76–3.61(m,1H),3.52–3.38(m,2H),3.34(dp,J=6.3,3.2Hz,1H),3.27–3.18(m,~0.5H),2.01–1.92(m,1H),1.84–1.47(m,6H),1.33–1.25(m,1H),1.17(td,J=7.0,2.5Hz,3H)。
实施例25
制备4-硝基苯磺酸(1r,4r)-4-乙氧基环己基酯144
向冷却至0℃的4-乙氧基环己烷-1-醇144(~2:1比率的1s,4s和2s,4s异构体;112.9g,782.9mmol)的CH2Cl2(800mL)溶液中加入1,4-二氮杂双环[2.2.2]辛烷(105.4g,939.5mmol)。在0℃下在1小时内分批加入4-硝基苯磺酰氯,然后将反应物逐渐升温至室温过夜。当在1:1乙酸乙酯的己烷溶液中通过TLC分析显示反应完成时,通过加入NaHCO3饱和水溶液淬灭反应。在用CH2Cl2和水进一步稀释后,分离有机相并用NaHCO3溶液,水和盐水进一步洗涤。用固体硫酸钠干燥后,过滤溶液,真空浓缩,高真空干燥。将得到的固体用乙酸乙酯和己烷研磨,得到160.8g 4-硝基苯磺酸4-乙氧基环己基酯146(1r,4r和1s,4s的混合物),为灰白色固体。
1H NMR(300MHz,氯仿-d)δ8.51–8.31(m,2H),8.17–8.03(m,2H),4.73(dtt,J=11.7,8.1,4.0Hz,1H),3.44(qd,J=7.0,1.5Hz,2H),3.34(tt,J=6.7,3.1Hz,1H),1.99–1.87(m,2H),1.81–1.53(m,6H),1.16(td,J=7.0,2.8Hz,3H)。
使用实施例1-21的方法制备以下示例性化合物。下面提供这些另外的化合物的表征数据。
II-1
N-(1-(反式-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(300MHz,DMSO-d6)δ13.52(s,1H),11.43(s,1H),9.19(s,1H),8.91(m,1H),8.74(s,1H),8.60(m,1H),8.54(s,1H),8.45(s,1H),8.15(s,1H),4.34(m,1H),3.48(q,J=7.0Hz,2H),3.35(m,1H),2.09(m,4H),1.89(q,J=10.2Hz,2H),1.35(q,J=10.5Hz,2H),1.10(t,J=6.9Hz,3H);LCMS:purity:100%;MS(m/e):449.17(MH+).
II-15
2-(1H-吡唑-4-基)-N-(3-(吡啶-2-基)-1-(2-(2,2,2-三氟乙氧基)乙基)-1H-吡唑-4-基)噁唑-4-甲酰胺
1HNMR(300MHz,DMSO-d6)δ13.50(br s,1H),12.03(s,1H),8.87(d,J=6.7Hz,1H),8.74(s,1H),8.51(br s,1H),8.46(s,1H),8.14(br s,1H),8.01–7.94(m,2H),7.43–7.39(m,1H),4.44(t,J=6.7Hz,2H),4.13–4.01(m,4H);LCMS(m/z):448.17(MH+).
II-19
N-(3-(3,6-二氟吡啶-2-基)-1-((1r,3r)-3-乙氧基环丁基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(400MHz,DMSO-d6)1H NMR(400MHz,DMSO-d6)δ13.50(s,1H),11.38(s,1H),8.71(s,1H),8.49(d,J=0.7Hz,1H),8.36(s,1H),8.07(ddd,J=9.9,8.9,6.2Hz,1H),8.05–8.00(m,1H),7.27(ddd,J=8.8,3.3,2.5Hz,1H),5.06(ttd,J=8.5,5.5,0.8Hz,1H),4.26(dddd,J=11.3,5.1,4.3,2.1Hz,1H),3.36(q,J=7.0Hz,2H),2.72–2.61(m,1H),2.53–2.40(m,1H),1.20(dd,J=9.4,6.9Hz,2H),1.11(t,J=7.0Hz,3H);MS(ESI)(m/z):456[M+H]+.
II-20
N-(1-(反式-4-羟基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),9.19(d,J=1.6Hz,1H),8.90(dd,J=2.6,1.6Hz,1H),8.74(s,1H),8.60(d,J=2.6Hz,1H),8.44(s,1H),8.35(br s,2H),4.29(tt,J=11.5,4.0Hz,1H),3.53(tt,J=10.7,4.0Hz,1H),2.10–2.01(m,2H),1.98–1.82(m,4H),1.44–1.30(m,2H);LRMS(M+H)m/z:421.3.
II-21
N-(1-(反式-4-乙氧基环己基)-3-(3,5,6-三氟吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(400MHz,氯仿-d)δ11.39(s,1H),8.43(s,1H),8.22(s,2H),7.56(dd,J=8.5,8.5Hz,1H),4.26(tt,J=11.8,3.9Hz,1H),3.57(q,J=7.0Hz,2H),3.37(tt,J=10.6,3.9Hz,1H),2.31–2.19(m,4H),1.94–1.83(m,2H),1.52–1.41(m,2H),1.23(t,J=7.0Hz,3H);LRMS(M+H)m/z 502.2.
II-22
N-(3-(4,6-二氟吡啶-2-基)-1-(反式-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(400MHz,氯仿-d)δ11.63(s,1H),8.38(s,1H),8.23(s,3H),7.67(dd,J=8.9,2.0Hz,1H),6.59(ddd,J=8.2,1.8,1.8Hz,1H),4.18(tt,J=11.8,3.7Hz,1H),3.57(q,J=7.0Hz,2H),3.37(tt,J=10.6,3.9Hz,1H),2.24(td,J=14.3,3.7Hz,4H),1.96–1.84(m,2H),1.53–1.40(m,2H),1.23(t,J=7.0Hz,3H);LRMS(M+H)m/z 484.2.
II-23
N-(1-((1r,4r)-4-吗啉基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(400MHz,DMSO-d6)δ13.51(s,1H),11.42(s,1H),9.17(d,J=1.5Hz,1H),8.89(dd,J=2.7,1.6Hz,1H),8.73(s,1H),8.59(d,J=2.6Hz,1H),8.43(s,1H),7.72(s,1H),7.66(s,1H),4.25(tt,J=11.7,3.9Hz,1H),3.57–3.50(m,4H),2.48–2.42(m,3H),2.30(tt,J=11.5,3.4Hz,1H),2.10(dt,J=9.7,3.2Hz,2H),1.96–1.86(m,3H),1.81(td,J=12.4,3.4Hz,2H),1.37(qd,J=12.8,3.3Hz,2H);MS(ESI)(m/z):490[M+H]+.
II-24
N-(1-((1r,4r)-4-乙氧基环己基)-3-(3-氟-6-(三氟甲基)吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(400MHz,DMSO-d6)δ13.48(s,1H),10.78(s,1H),8.72(s,1H),8.55(d,J=0.7Hz,1H),8.17(s,2H),8.11(ddd,J=10.6,8.6,0.8Hz,1H),7.96(dd,J=8.6,3.2Hz,1H),4.33(tt,J=11.6,3.4Hz,1H),3.44(q,J=6.9Hz,2H),2.10–2.02(m,4H),1.91–1.76(m,2H),1.36(d,J=9.9Hz,1H),1.36–1.26(m,1H),1.07(t,J=7.0Hz,3H);MS(ESI)(m/z):534[M+H]+.
II-26
N-(1-((1r,3r)-3-吗啉基环丁基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(400MHz,DMSO-d6)1H NMR(400MHz,DMSO-d6)δ13.50(s,1H),11.40(s,1H),9.22(d,J=1.6Hz,1H),8.88(dd,J=2.7,1.6Hz,1H),8.71(s,1H),8.59(d,J=2.6Hz,1H),8.46(s,1H),8.32(s,2H),5.02–4.91(m,1H),3.58(t,J=4.6Hz,4H),3.05–2.94(m,1H),2.59–2.50(m,1H),2.50(dd,J=7.9,2.1Hz,1H);MS(ESI)(m/z):462[M+H]+.
II-27
N-(1-((1s,3s)-3-吗啉基环丁基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(400MHz,DMSO-d6)1H NMR(400MHz,DMSO-d6)δ13.50(s,1H),11.40(s,1H),9.20(d,J=1.5Hz,1H),8.88(dd,J=2.6,1.6Hz,1H),8.72(s,1H),8.59(d,J=2.6Hz,1H),8.51(s,1H),8.45(s,1H),8.13(s,1H),5.71(s,1H),4.78–4.66(m,1H),3.57(t,J=4.6Hz,4H),2.64–2.49(m,3H),2.36–2.25(m,6H);MS(ESI)(m/z):462[M+H]+.
II-28
2-(3-氟-1H-吡唑-4-基)-N-(1-((1r,4r)-4-吗啉基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺
MS(ESI)(m/z):508[M+H]+.
II-29
N-(3-(3,6-二氟吡啶-2-基)-1-(顺-4-(4-甲基哌嗪-1-基)环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(400MHz,DMSO-d6)δ13.52(s,1H),11.41(s,1H),8.73(s,1H),8.43(s,1H),8.21(s,2H),8.08(ddd,J=9.3,9.3,6.1Hz,1H),7.27(ddd,J=8.8,2.8,2.8Hz,1H),4.41(tt,J=8.3,4.2Hz,1H),2.44–2.07(m,14H),1.98–1.76(m,4H),1.62–1.50(m,2H);LRMS(M+H)m/z 538.4.
II-30
N-(3-(3,6-二氟吡啶-2-基)-1-(反式-4-吗啉基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(400MHz,DMSO-d6)δ13.52(s,1H),11.41(s,1H),8.74(s,1H),8.46(s,1H),8.22(br s,1H),8.14–7.93(m,1H),7.27(ddd,J=8.8,2.9,2.9Hz,1H),4.27(tt,J=11.8,4.0Hz,1H),3.59–3.51(m,4H),2.49–2.44(m,4H),2.38–2.27(m,1H),2.16–2.07(m,2H),1.98–1.89(m,2H),1.83(qd,J=12.8,3.4Hz,2H),1.40(qd,J=12.8,3.4Hz,2H);LRMS(M+H)m/z 525.3.
II-31
N-(1-((1s,3s)-3-羟基环丁基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(400MHz,DMSO-d6)δ12.68(s,1H),11.41(d,J=4.1Hz,1H),9.22(dd,J=5.2,1.6Hz,1H),8.90(dd,J=2.7,1.6Hz,1H),8.73(s,1H),8.60(d,J=2.6Hz,1H),8.49(s,1H),8.33(s,2H),5.32(d,J=7.0Hz,1H),4.50(tt,J=9.1,7.3Hz,1H),4.02–3.89(m,1H),2.84–2.71(m,2H),2.39(tdt,J=9.0,7.9,2.7Hz,2H);MS(ESI)(m/z):393[M+H]+.
III-1
2-(1-(环丙基甲基)-1H-吡唑-4-基)-N-(1-甲基-3-(吡啶-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(300MHz,DMSO-d6)δ11.99(s,1H),8.82(d,J=4.8Hz,1H),8.72(s,1H),8.52(s,1H),8.38(s,1H),8.08(s,1H),7.98–7.88(m,2H),7.40–7.36(m,1H),4.09(d,J=6.9Hz,2H),3.93(s,3H),1.32(m,1H),0.59–0.53(m,2H),0.45–0.40(m,2H);LCMS:purity:100%;MS(m/e):390.59(MH+).
III-2
2-(1H-吡唑-4-基)-N-(3-(吡啶-2-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(300MHz,DMSO-d6)δ13.54(s,1H),12.04(s,1H),8.86(ddd,J=5.0,1.7,0.9Hz,1H),8.74(s,1H),8.61–8.49(m,1H),8.46(s,1H),8.26–8.08(m,1H),8.04–7.98(m,1H),7.93(td,J=7.7,1.8Hz,1H),7.44–7.34(m,1H),4.67–4.42(m,1H),4.06–3.95(m,2H),3.55–3.42(m,2H),2.04(h,J=5.0,4.3Hz,4H);MS(ESI)(m/z):406[M+H]+.
III-3
N-(1-(2-乙氧基乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1HNMR(300MHz,DMSO-d6)δ12.02(s,1H),8.86(d,J=6.7Hz,2H),8.74(s,1H),8.44(s,1H),8.34(s,1H),8.01–7.90(m,2H),7.42–7.38(m,1H),4.37(t,J=6.7Hz,2H),3.79(t,J=6.7Hz,2H),3.46(q,J=6.7Hz,2H),1.09(t,J=6.7Hz,3H);LCMS(m/z):394.21(MH+).
III-4
N-(1-((1s,3s)-3-乙氧基环丁基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1HNMR(300MHz,DMSO-d6)δ12.01(s,1H),8.86(d,J=6.7Hz,1H),8.74(s,1H),8.45(s,1H),8.33(s,1H),8.06–8.03(m,1H),7.97–7.92(m,1H),7.43–7.39(m,1H),4.65–4.59(m,1H),3.87–3.82(m,1H),3.42(q,J=6.7Hz,2H),2.86–2.77(m,2H),2.45–2.41(m,1H),1.15(t,J=6.7Hz,3H);LCMS(m/z):420.21(MH+).
III-5
N-(1-环丁基-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺作为甲酸盐
LCMS(m/z):376.20(MH+).
III-6
N-(1-(2-(2-甲氧基乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-3-基)噁唑-4-甲酰胺
1HNMR(300MHz,DMSO-d6)δ12.02(s,1H),8.86(d,J=6.7Hz,1H),8.74(s,1H),8.44(s,1H),8.34(s,1H),8.01–7.90(m,2H),7.42–7.38(m,1H),4.37(t,J=6.7Hz,2H),3.84(t,J=6.7Hz,2H),3.56–3.53(m,2H);3.44–3.41(m,2H);3.22(s,3H);LCMS(m/z):424.24(MH+).
III-7
N-(1-(2-(2,2-二氟乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺
1H NMR(400MHz,DMSO-d6)δ13.53(s,1H),12.04(s,1H),8.84(ddd,J=5.0,1.8,1.0Hz,1H),8.71(s,1H),8.46(s,1H),7.98(dt,J=8.0,1.1Hz,1H),7.89(ddd,J=8.1,7.4,1.8Hz,1H),7.36(ddd,J=7.4,4.9,1.3Hz,1H),6.11(tt,J=54.9,3.7Hz,1H),4.40(t,J=5.2Hz,2H),3.96(t,J=5.3Hz,2H),3.72(td,J=15.2,3.7Hz,2H).
MS(ESI)(m/z):430[M+H]+
实施例26
LPS诱导的IL23p19在THP-1细胞(用IFNγ引发)中的测定
材料和设备
THP-1细胞(ATCC公司,目录号TIB-202)、二甲亚砜(DMSO)(西格玛奥德里奇公司(Sigma-Aldrich),目录号D2650)、RPMI 1640(Cellgro公司,目录号10-040-CM)、胎牛血清(西格玛奥德里奇公司(Sigma-Aldrich),目录号F4135)、来自牛血清的白蛋白(BSA)(西格玛奥德里奇公司(Sigma-Aldrich),目录号A7906)、LPS(血清型K-235,西格玛公司(Sigma),产品编号L 2143)、IFNγ(派普泰克公司(Peprotech),目录号300-02)
捕获抗体:人IL-23p19ELISA(e-生物科学公司(e-Bioscience),目录号14-7238-85),检测抗体:原代小鼠生物素化抗人IL-12(p40/p70)(e-生物科学公司(e-Bioscience),目录号13-7129-85),第二HRP-轭合的链霉亲和素(R&D系统公司(R&D Systems),目录号DY998)、1x PBST洗涤缓冲液(PBS-吐温片剂)(VWR国际(VWR International)目录号80058-558)、ELISA阻断缓冲液(具有1%BSA的PBS)、ELISA稀释缓冲液(具有1%BSA的PBS),384孔平底、MaxiSorp黑色免疫板(赛默科技公司(Thermo Scientific),目录号12-565-346),384孔平底、白色组织培养板(赛默科技公司(Thermo Scientific),目录号12-565-343),超级信号ELISA微小化学发光底物(赛默科技公司(Thermo Scientific),目录号37070),CellTiter Glo试剂(普洛麦格公司(Promega),目录号G7573),阳性对照、IKK2VI抑制剂(卡巴开公司(Calbiochem),目录号401483)、AquaMax 4000洗板机(分子装置公司(MolecularDevices),光度计、Wallac Victor2 1420多标签计数器。
方法
THP-1细胞刺激:
在第1天,在具有10%FBS的RPMI培养基中,在384-孔板中接种50K/孔THP-1细胞并用IFNγ(50ng/mL)引发约18小时。在第2天,将化合物从5mM以3-倍稀释在DMSO中连续地稀释,然后在具有10%FBS的RPMI培养基中以1:125进行稀释。50μ在384孔组织培养板中,将50μL/孔2x化合物一式两份添加至50μL/孔THP-1细胞(用IFNy引发的)中。将细胞与化合物在37℃、5%CO2下预孵育1小时,然后添加10μL/孔11x LPS以给出终浓度1ug/mL LPS。第3天,在37℃、5%CO2下刺激18小时之后,将测定板离心并收获70μL/孔上清液。通过夹心ELISA测量70μL/孔上清液中的IL-23p19蛋白,向残留的细胞中添加25μl/孔的Cell Titer Glo试剂以测量化合物毒性。
人IL-23p19夹心ELISA:
Maxisorp免疫ELISA板在室温下用PBS中25μL/孔的抗-IL-23p19捕获抗体(2.5ug/mL)预涂覆过夜。在用1x PBST洗涤之后,在室温下,将板使用在PBS中的100μL/孔的1%BSA阻断2小时。将板用1x PBST洗涤三次,并添加70μL/孔上清液。将板在室温下伴随振荡孵育2小时,并用1x PBST洗涤三次。添加在具有1%BSA的PBS中的25μL/孔的生物素标记的抗-IL-12(p40/p70)检测抗体(100ng/mL),并将板在室温下伴随振荡孵育2小时。在用1x PBST洗涤三次之后,添加在具有1%BSA的PBS中的25μL/孔的链霉亲和素-HRP(1:200),并将板在室温下伴随振荡孵育20分钟。将板用1x PBST洗涤三次,并添加25μL/孔的超级信号ELISA微小化学发光底物。用光度计读取板,并将化学发光值输入雅典娜公司(Athena)(Rigel)进行曲线拟合、EC50计算和数据库存储。结果列于表1。
实施例27
使用DC细胞进行化合物筛选
材料
人PBMC细胞(所有细胞公司(All Cells),目录号PB002)
含有10%FBS的RPMI生长培养基
IFNγ(派普泰克公司(Peprotech),目录号300-02)
GMCSF(派普泰克公司(Peprotech),目录号300-03)和IL4(派普泰克公司(Peprotech),目录号200-04)
白色透明瓶96孔板(费希尔公司(Fisher),目录号07-200-587,康宁公司(Corning)#3903)
LPS(制成在PBS中的2.5mg/ml储备液),来自西格玛奥德里奇公司(Sigma-Aldrich)(目录号L2018-5MG)
Cell Titer Glo试剂(普洛麦格公司(Promega),目录号G7573)
阳性对照、IKK2VI抑制剂(卡巴开公司(Calbiochem),目录号401483)
方案
I.PBMC至DC细胞的分化:
将从供应商获得的人PBMC细胞(400百万)转移至含有15mL RPMI培养基(10%FBS)的T-175烧瓶并在37℃下孵育2小时。在2小时之后,将含有漂浮细胞的培养基小心地吸出并添加含有GMCSF(100ng/ml)和IL4(20ng/ml)的12mL新鲜RPMI培养基(10%FBS),并将烧瓶保持在37℃培养箱中持续7天。
在3天之后,将新鲜GMCSF(100ng/ml)和IL4(20ng/ml)添加至烧瓶中并继续孵育。在7天之后,通过旋转(1200rpm(转/分钟/5分钟)和吸出培养基来收获完全分化的细胞。将细胞悬浮在含有50ng/ml IFNγ(1000U/ml)的新鲜RPMI培养基(10%FBS)中,然后铺板(50K/孔,在100μl中)在白色透明瓶96孔板中并放置在37℃培养箱中持续24小时。
II.化合物的添加:
在孵育24小时之后,将含有每孔2X浓缩的测试化合物的100μl的RPMI培养基添加至上述细胞培养基(终浓度变为1X),并在用LPS刺激之前将板在37℃下预孵育1小时。
在化合物预孵育1小时后,添加在RPMI培养基中每孔20X浓缩的LPS溶液10μl以给出1μg/ml的终浓度。将混合物振荡并将板在37℃下另外孵育18小时。
从每个孔小心地收获155μl上清液(不用尖端接触孔的底部),并向剩下的50μl/孔的细胞培养板中添加50μl的Cell Titer Glo试剂。将混合物在振荡器上孵育1-2分钟,读取板的发光强度以确定化合物细胞毒性。将上述收集的细胞培养物上清液用于进行如下文描述的IL23ELISA(65μl-上清液)和IL10ELISA(90μl-上清液)。
实施例28
人IL-23(p19/p40)ELISA方案(e-生物科学公司(e-Biosciences))
材料:
96-孔高结合不透明白色板(来自皮尔斯公司(Pierce),目录号15042);
1X PBS;1X TBST洗涤缓冲液;
阻断溶液:在PBS中的0.5%酪蛋白(来自BDH公司,目录号440203H);
稀释溶液:在PBS中的1%BSA(10%BSA,来自费希尔公司(Fisher),目录号37525);
捕获抗体:鼠抗人IL-23(p19)(e-生物科学公司(e-Biosciences),目录号14-7238-85);
检测抗体:原代小鼠生物素化的抗人IL-12(p40/p70)(e-生物科学公司(e-Biosciences),目录号13-7129-85);
第二HRP-轭合的链霉亲和素(R&D系统公司(R&D Systems),目录号DY998);
r人-IL-23(e-生物科学公司(e-Biosciences),目录号34-8239)(推荐的起始浓度=5ng/ml,在RPMI细胞培养基中);
细胞培养上清液(65μl,来自用IFNγ引发(50ng/ml-1000U/ml)并用0.01%SAC刺激的THP-1细胞);
超级信号ELISA微小化学发光底物[皮尔斯公司(Pierce),目录号37069]。
涂覆板:
向添加50μl的抗-IL23(p19)的10.5mLPBS中添加捕获抗体(2.5μg/ml)。将混合物充分混合,并将100μl的涂覆溶液添加至来自皮尔斯公司(Pierce)的96孔白色板的每孔。将孔覆盖并在4℃下孵育过夜。
阻断板:
将抗-IL23(p19)-抗体-涂覆的板用TBST洗涤2次(用洗板机),并使用200μl的0.5%酪蛋白在室温下伴随振荡阻断1.5-2小时。
添加上清液并检测:
将板使用TBST洗涤2次,并将上清液(65μl/孔)转移至以上预阻断的/IL23(p19)-抗体-涂覆的96孔板上,并在室温下伴随振荡孵育1.5小时。
使用TBST将板洗涤4次(洗板机),并添加从在11mL 1%BSA/PBS溶液(1-5000稀释)中的2μl生物素标记的抗-IL-12(p40/p70)抗体制备的100μl/孔检测抗体溶液。将板在室温下伴随振荡孵育1小时。
再次,将板用TBST洗涤4次,并添加100μl的HRP标记的链霉亲和素(R&D系统公司(R&D Systems))溶液(10μl/10mL 1%BSA溶液),并将板在室温下伴随振荡孵育另外45分钟。
在45分钟之后,将板用TBST洗涤4次,并添加来自皮尔斯公司(Pierce)的100ul/孔超级信号ELISA微小化学发光底物(3.5mL A+3.5mL B+3.5mL MQ水)。将板振荡1-2分钟,然后在读板器上读数。
来自实施例26-28中描述的测定的EC50结果显示在表1-3中。本领域普通技术人员理解,实施例26和28中描述的测定可预测体内测定的结果。
表1
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*ND表示由于化合物不溶性,测定中的伪影和/或其他因素,可能未产生准确的抑制曲线。
表2
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*ND表示由于化合物不溶性,测定中的伪影和/或其他因素,可能未产生准确的抑制曲线。
表3
V.示例性实施方案
以下编号的段落示出了所公开技术的示例性实施例。
段1.一种化合物,具有式1
或其盐,其中:
R1和R2中的至少一个是芳族,并且剩余的R1或R2是H、烷基、卤代烷基、硝基、氰基、酰胺、氨基、羟基、羧基、羧基酯或酰基;
R3是H、脂族、杂脂族、杂环基、酰胺、芳族或芳脂族;
R4是H、脂族、杂脂族,或R1和R2中的一个与R4以及与它们所连接的原子一起形成杂环;
R5是H或脂族;并且
环A是杂环基环。
段2.如段1所述的化合物,其中,R1和R2中的一个是含氮杂芳基,R1和R2中的另一个是H、烷基,卤代烷基、硝基、氰基、酰胺、氨基、羟基、羧基、羧基酯或酰基。
段3.如段1或2所述的化合物,其中,R1和R2中的一个是吡啶基、嘧啶基或吡嗪基,R1和R2中的另一个是H。
段4.如段1-3中任一项所述的化合物,其中,R3是H,烷基,环烷基,杂脂族或杂环脂族。
段5.如段1-4中任一项所述的化合物,其中,R3是H、C1-6烷基、环丙基、环丁基、环戊基或环己基。
段6.如段1-4中任一项所述的化合物,其中,R3是C1-6烷基,四氢吡喃,未取代的杂脂族,被卤素取代的杂脂族,未取代的环丁基,被-OH、烷氧基或杂环脂族取代的环丁基,未取代的环己基,或被-OH、烷氧基或杂环脂族取代的环己基。
段7.如段1-6中任一项所述的化合物,其中,R3是4-乙氧基环己基、4-吗啉基环己基、3-乙氧基环丁基、4-羟基环己基、(2,6-二甲基吗啉基)环己基、3-吗啉基环丁基、4-(4-甲基哌嗪-1-基)环己基或3-羟基环丁基。
段8.如段1-7中任一项所述的化合物,其中,R4是H或C1-6烷基。
段9.如段1-8中任一项所述的化合物,其中:
R1和R2中的一个选自吡啶基、嘧啶基或吡嗪基,R1和R2中的另一个是H;
R3是C1-6烷基,四氢吡喃,未取代的杂脂族,被卤素取代的杂脂族,未取代的环丁基,被烷氧基取代的环丁基,环己基,或被-OH、烷氧基或杂环脂族取代的环己基;并且
R4是H。
段10.如段1-9中任一项所述的化合物,其中,R5是H、烷基或卤代烷基。
段11.如段1-10中任一项所述的化合物,其中,R5是H或C1-6烷基。
段12.如段11中任一项所述的化合物,其中:
R1和R2中的一个选自:吡啶基、嘧啶基或吡嗪基,R1和R2中的另一个是H;
R3是C1-6烷基,四氢吡喃,未取代的杂脂族,被卤素取代的杂脂族,未取代的环丁基,被烷氧基取代的环丁基,环己基,或被-OH、烷氧基或杂环脂族取代的环己基;
R4是H;并且
R5是H。
段13.如段1-12中任一项所述的化合物,其中,环A是杂芳基。
段14.如段13所述的化合物,其中,环A是含氮杂芳基。
段15.如段13所述的化合物,其中,环A是5元含氮杂芳基。
段16.如段13所述的化合物,其中,环A是吡唑基。
段17.如段13-16中任一项所述的化合物,其中,环A是未取代的。
段18.如段13-16中任一项所述的化合物,其中,环A被1-4个取代基取代。
段19.如段18所述的化合物,其中,环A被至少一个选自以下的取代基取代:卤素、脂族取代基、烷基磷酸酯或烷基膦酸酯。
段20.如段13-18中任一项所述的化合物,其中:
R1和R2中的一个选自吡啶基、嘧啶基或吡嗪基,R1和R2中的另一个是H;
R3是C1-6烷基,四氢吡喃,未取代的杂脂族,被卤素取代的杂脂族,未取代的环丁基,被OH、烷氧基或杂环脂族取代的环丁基,未取代的环己基,或被-OH、烷氧基或杂环脂族取代的环己基;
R4是H;
R5是H;并且
环A是吡唑基。
段21.如段1-20中任一项所述的化合物,具有式2
段22.如段21所述的化合物,其中:
R1和R2中的一个选自吡啶基、嘧啶基或吡嗪基,R1和R2中的另一个是H;
R3是C1-6烷基,四氢吡喃,未取代的杂脂族,被卤素取代的杂脂族,未取代的环丁基,被-OH、烷氧基或杂环脂族取代的环丁基,未取代的环己基,或被-OH、烷氧基或杂环脂族取代的环己基;
R4是H或C1-6烷基;
R5是H或C1-6烷基;并且
环A是吡唑基。
段23.如段1-22中任一项所述的化合物,具有式3
3;并且
每个R6独立地是H、脂族、杂脂族、芳基、-O-脂族、芳脂族、杂环基、磺酰基、卤素、硝基、OH、卤代烷基、羧基酯、氰基、酰基、氨基、烷基磷酸酯或烷基膦酸酯。
段24.如段23所述的化合物,其中:
R1和R2中的一个选自吡啶基、嘧啶基或吡嗪基,R1和R2中的另一个是H;
R3是C1-6烷基,四氢吡喃,未取代的杂脂族,被卤素取代的杂脂族,未取代的环丁基,被-OH、烷氧基或杂环脂族取代的环丁基,未取代的环己基,或被-OH、烷氧基或杂环脂族取代的环己基;
R4是H或C1-6烷基;
R5是H或C1-6烷基;并且
环A是吡唑基。
段25.如段1-24中任一项所述的化合物,其中,所述化合物具有式4
4;并且
R7,R8和R9各自独立地是H、脂族、杂脂族、芳基、-O-脂族、芳脂族、杂环基、卤素、磺酰基、硝基、OH、卤代烷基、羧基酯、氰基、酰基、氨基、烷基磷酸酯或烷基膦酸酯。
段26.如段25所述的化合物,其中,R7是H、烷基,羧基酯、酰基、烷基磷酸酯、烷基膦酸酯、杂环烷基或芳烷基。
段27.如段25-26中任一项所述的化合物,其中,R7是H或-CH2OP(O)(OH)2或其盐。
段28.如段25-27中任一项所述的化合物,其中,R8和R9各自独立地是H、卤素、烷基或卤代烷基。
段29.如段28所述的化合物,其中,R8和R9是H。
段30.如段28所述的化合物,其中,R8和R9中的一个是F而另一个是H。
段31.如段25-30中任一项所述的化合物,其中:
R1和R2中的一个选自吡啶基、嘧啶基或吡嗪基,R1和R2中的另一个是H;
R3是C1-6烷基,四氢吡喃,未取代的杂脂族,被卤素取代的杂脂族,未取代的环丁基,被烷氧基取代的环丁基,环己基,或被-OH、烷氧基或杂环脂族取代的环己基;
R4是H或C1-6烷基;
R5是H或C1-6烷基;并且
环A是吡唑基。
段32.如段1-31中任一项所述的化合物,其中:
R1和R2中的一个是杂芳基,R1或R2中的另一个是H、烷基,卤代烷基、硝基、氰基、酰胺、氨基、羟基、羧基、羧基酯或酰基;
R3是Ra,Rb,被1、2或3个Rb取代的Ra,被Rb和Rc取代的Ra,被Rc取代的Ra,–(CRaRa)n-Ra,-(CH2)n-Ra,-(CRaRa)n-Rb,-(CH2)n-Rb,-[(CH2)m-O-]n-Ra,-[(CH2)m-O-]n-[被1、2或3个Rb取代的Ra],或-(CH2)m-O-(CH2)m-O-Ra,其中m和n各自独立地是1、2或3;
R4是Ra,-(CRaRa)m-O-Ra,-(CH2)m-O-Ra,-(CRaRa)m-O-(CRaRa)m-O-Ra,-[(CH2)m-O-]n-Ra或-(CH2)m-O-(CH2)m-O-Ra,其中m和n各自独立地是1、2或3;
R5是Ra或Rb;
对于每次出现,Ra独立地是H,D,C1-6烷基,C1-6卤代烷基C3-6环烷基,C3-6杂脂环基, 其中Y和Z独立地是–CH2、-CHRb、O或NRd;
对于每次出现,Rb独立地是-OH,-CF3,-ORc,-NRdRd或卤素;
对于每次出现,Rc独立地是C1-6烷基,C3-6杂脂环基,被1、2或3个Re取代的C1-6烷基,被1、2或3个Re取代的C3-6环烷基,或被1、2或3个Re取代的C3-6杂脂环基;
对于每次出现,Rd独立地是H,任选地被1、2或3个Re取代的C1-6烷基,或者两个Rd基团与它们所连接的氮一起形成任选地被C1-6烷基取代并且任选地含有一或两个–O–或–N(Rg)的C3-6杂脂环基部分,其中Rg是R70;并且
对于每次出现,Re独立地是C1-6烷基或-ORa。
段33.如段23所述的化合物,其中:
R1和R2中的一个是杂芳基,R1和R2中的另一个是H、烷基、卤代烷基、硝基、氰基、酰胺、氨基、羟基、羧基、羧基酯或酰基;
R3是Ra,Rb,被1、2或3个Rb取代的Ra,被Rb和Rc取代的Ra,被Rc取代的Ra,–(CRaRa)n-Ra,-(CH2)n-Ra,-(CRaRa)n-Rb,-(CH2)n-Rb,-[(CH2)m-O-]n-Ra,-[(CH2)m-O-]n-[被1、2或3个Rb取代的Ra],或-(CH2)m-O-(CH2)m-O-Ra,其中m和n各自独立地是1、2或3;
R4是Ra,-(CRaRa)m-O-Ra,-(CH2)m-O-Ra,-(CRaRa)m-O-(CRaRa)m-O-Ra,-[(CH2)m-O-]n-Ra或-(CH2)m-O-(CH2)m-O-Ra,其中m和n各自独立地是1、2或3;
R5是Ra或Rb;
R6是Ra,Rb,被–OP(O)(Rf)2取代的Ra,被1、2或3个Rb取代的Ra,被Rc取代的Ra,被C1-6环烷基取代的Ra,被–P(O)(Rf)2取代的Ra,芳烷基,-(CRaRa)n-Ra,-(CH2)n-Ra或-C(O)C(Ra)2NRaRb;
n和m独立地是1、2或3;
对于每次出现,Ra独立地是H,D,C1-6烷基,C1-6卤代烷基C3-6环烷基,C3-6杂脂环基, 其中Y和Z独立地是–CH2、-CHRb、O或NRd;
对于每次出现,Rb独立地是-OH,-CF3,-ORc,-NRdRd,或卤素;
对于每次出现,Rc独立地是C1-6烷基,C3-6杂脂环基,被1、2或3个Re取代的C1-6烷基,被1、2或3个Re取代的C3-6环烷基,或被1、2或3个Re取代的C3-6杂脂环基;
对于每次出现,Rd独立地是H,被1、2或3个Re取代的C1-6烷基,或者两个Rd基团与它们所连接的氮一起形成任选地被C1-6烷基取代并且任选地含有一或两个–O–或–N(Rg)的C3-6杂脂环基部分,其中Rg是R70;
对于每次出现,Re独立地是C1-6烷基或-ORa;并且
对于每次出现,Rf独立地是-ORa,-O-M+,其中每个M+独立地是碱金属离子或铵离子。
段34.如段25所述的化合物,其中:
R1和R2中的一个是杂芳基,R1或R2中的另一个是H、烷基、卤代烷基、硝基、氰基、酰胺、氨基、羟基、羧基、羧基酯或酰基;
R3是Ra,Rb,被1、2或3个Rb取代的Ra,被Rb和Rc取代的Ra,被Rc取代的Ra,–(CRaRa)n-Ra,-(CH2)n-Ra,-(CRaRa)n-Rb,-(CH2)n-Rb,-[(CH2)m-O-]n-Ra,-[(CH2)m-O-]n-[被1、2或3个Rb取代的Ra],或-(CH2)m-O-(CH2)m-O-Ra,其中m和n各自独立地是1、2或3;
R4是Ra,-(CRaRa)m-O-Ra,-(CH2)m-O-Ra,-(CRaRa)m-O-(CRaRa)m-O-Ra,-[(CH2)m-O-]n-Ra或-(CH2)m-O-(CH2)m-O-Ra,其中m和n各自独立地是1、2或3;
R5是Ra或Rb;
R6是Ra,Rb,被–OP(O)(Rf)2取代的Ra,被1、2或3个Rb取代的Ra,被Rc取代的Ra,被C1-6环烷基取代的Ra,被–P(O)(Rf)2取代的Ra,芳烷基,-(CRaRa)n-Ra,-(CH2)n-Ra或-C(O)C(Ra)2NRaRb;
R7是Ra,Rb,被–OP(O)(Rf)2取代的Ra,被1、2或3个Rb取代的Ra,被Rc取代的Ra,被–P(O)(Rf)2取代的Ra,芳烷基,-(CRaRa)n-Ra,-(CH2)n-Ra或-C(O)C(Ra)2NRaRb;
R8和R9独立地是Ra或Rb;
n和m独立地是1、2或3;
对于每次出现,Ra独立地是H,D,C1-6烷基,C1-6卤代烷基C3-6环烷基,C3-6杂脂环基, 其中Y和Z独立地是–CH2、-CHRb、O或NRd;
对于每次出现,Rb独立地是-OH,-CF3,-ORc,-NRdRd,或卤素;
对于每次出现,Rc独立地是C1-6烷基,C3-6杂脂环基,被1、2或3个Re取代的C1-6烷基,被1、2或3个Re取代的C3-6环烷基,或被1、2或3个Re取代的C3-6杂脂环基;
对于每次出现,Rd独立地是H,被1、2或3个Re取代的C1-6烷基,或者两个Rd基团与它们所连接的氮一起形成任选地被C1-6烷基取代并且任选地含有一或两个–O–或–N(Rg)的C3-6杂脂环基部分,其中Rg是R70;
对于每次出现,Re独立地是C1-6烷基或-ORa;并且
对于每次出现,Rf独立地是-ORa,-O-M+,其中每个M+独立地是碱金属离子或铵离子。
段35.如段1-34中任一项所述的化合物,其中,R1和R2中的一个是嘧啶-2-基、嘧啶-4-基、吡嗪-2-基、6-(二氟甲基)吡啶-2-基、3-氟-6-(三氟甲基)吡啶-2-基、3,6-二氟吡啶-2-基、或3,5-二氟吡啶-2-基。
段36.如段1-35中任一项所述的化合物,其中,所述化合物不是:
2-(1-(环丙基甲基)-1H-吡唑-4-基)-N-(1-甲基-3-(吡啶-2-基)-1H-吡唑-4-基)噁唑-4-甲酰胺;
2-(1H-吡唑-4-基)-N-(3-(吡啶-2-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)噁唑-4-甲酰胺;
N-(1-(2-乙氧基乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
N-(1-((1s,3s)-3-乙氧基环丁基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
N-(1-环丁基-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
N-(1-(2-(2-甲氧基乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
N-(1-(2-(2,2-二氟乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
N-(3-氨甲酰基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
2-(1H-吡唑-3-基)-N-(3-(吡啶-2-基)-1-(2-(2,2,2-三氟乙氧基)乙基)-1H-吡唑-4-基)噁唑-4-甲酰胺;或
N-(1-(2-(2-甲氧基乙氧基)乙基)-3-(吡啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-3-基)噁唑-4-甲酰胺。
段37.一种化合物,选自I-1至I-39。
段38.一种化合物,选自II-1至II-32。
段39.一种化合物,选自III-1至III-7。
段40.一种组合物,包含段1-39中任一项所述的化合物和药学上可接受的赋形剂。
段41.如段40所述的组合物,还包含另外的治疗剂。
段42.一种方法,包括给予有需要的对象有效量的段1-39中任一项所述的化合物或段40-41中任一项所述的组合物。
段43.如段42所述的方法,用于治疗指示IRAK抑制剂的疾病或病症。
段44.如段43所述的方法,其中,所述疾病是自身免疫性疾病,炎性疾病,心血管疾病,神经变性疾病,过敏性疾病,多器官衰竭,肾脏疾病,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,呼吸系统疾病,缺血性病症,细菌感染,病毒感染,免疫调节障碍或其组合。
段45.如段43所述的方法,其中,所述疾病是肌萎缩性侧索硬化症(ALS),全身性红斑狼疮,慢性类风湿性关节炎,I型糖尿病,炎性肠病,胆汁性肝硬化,葡萄膜炎,多发性硬化症,克罗恩病,溃疡性结肠炎,大疱性类天疱疮,肉状瘤病,银屑病,自身免疫性肌炎,胰腺炎,卡波西氏肉瘤,骨髓增生异常综合征,韦格纳肉芽肿病,鱼鳞病,格雷夫斯眼病或哮喘。
段46.如权利要求44所述的方法,其中,所述免疫调节障碍是
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,全身性硬化病,重症肌无力,I型糖尿病,葡萄膜炎,后葡萄膜炎,过敏性脑脊髓炎,肾小球肾炎,感染后自身免疫性疾病,包括风湿热和感染后肾小球肾炎,炎性和增生性皮肤疾病,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,大疱性表皮松解症,荨麻疹,血管神经性水肿,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,格雷夫斯眼病,伏格特-小柳-原田三氏综合征,肉状瘤病,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,尘埃性哮喘,慢性或根深哮喘,晚期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,与热烧伤有关的肠道病变,乳糜泻,直肠炎,嗜酸细胞性胃肠炎,肥大细胞增多症,克罗恩病,溃疡性结肠炎,偏头痛,鼻炎,湿疹,间质性肾炎,肺出血肾炎综合征,溶血性尿毒症综合征,糖尿病性肾病,多发性肌炎,格林-巴利综合征,美尼尔氏病,多发神经炎,多神经炎,单神经炎,神经根病,甲状腺机能亢进,巴塞多氏病,纯红细胞发育不全,再生障碍性贫血,再生不良性贫血,特发性血小板减少性紫癜,自身免疫性溶血性贫血,粒性白血球缺乏症,恶性贫血,巨成红细胞性贫血,红细胞发生不能,骨质疏松症,肉状瘤病,纤维化肺,特发性间质性肺炎,皮肌炎,寻常性白斑病,寻常性鱼鳞癣,光变应性敏感(photoallergic sensitivity),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,结节性多动脉炎,心肌病,硬皮病,韦格纳氏肉芽肿病,肖格伦综合征,肥胖病,嗜酸性筋膜炎,齿龈病变,牙周组织,牙槽骨,骨质牙(substantia osseadentis),肾小球肾炎,通过预防脱毛或提供头发发生和/或促进头发生成和头发生长的男性型脱发或脱发秃发症,肌肉萎缩症,脓皮病和塞扎里氏综合征(Sezary's syndrome),爱迪生氏病,器官保存后发生的缺血再灌注损伤,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,铁尘肺,色素性视网膜炎,老年性黄斑变性,玻璃体疤痕,角膜碱性烧伤,皮炎多形性红斑,线性IgA大疱皮炎和水泥皮炎,齿龈炎,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,癌转移和低气压病,由组胺或白三烯-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,肝部分切除,急性肝坏死,毒素引起的坏死,病毒性肝炎,休克,或缺氧症,B型病毒性肝炎,非A型/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,晚发性肝功能衰竭,“慢加急”肝功能衰竭,化疗效果增加,巨细胞病毒感染,HCMV感染,AIDS,癌症,老年性痴呆,帕金森氏病,创伤,或慢性细菌感染。
段47.一种抑制IRAK蛋白的方法,包括使IRAK蛋白与有效量的段1-39中任一项所述的化合物或段40-41中任一项所述的组合物接触。
段48.如段46所述的方法,其中,所述化合物的EC50大于0至5μM。
段49.如段46所述的方法,其中,所述化合物的EC50大于0至1μM。
段50.如段47-49中任一项所述的方法,其中,所述IRAK蛋白在对象中。
段51.如段47-50中任一项所述的方法,其中,接触IRAK蛋白包括体外接触IRAK蛋白。
鉴于可以应用所公开发明的原理的许多可能的实施例,应该认识到,所示实施例仅是本发明的优选示例,不应被视为限制本发明的范围。相反,本发明的范围由以下权利要求限定。因此,我们声称所有这些都属于这些权利要求的范围和精神。
Claims (17)
1.一种化合物,具有式4
和/或其盐,其中:
R1和R2中的一个是嘧啶-2-基、嘧啶-4-基、吡嗪-2-基、6-(二氟甲基)吡啶-2-基、3-氟-6-(三氟甲基)吡啶-2-基、3,6-二氟吡啶-2-基或3,5-二氟吡啶-2-基,并且R1和R2中的另一个是H;
R3是C1-6烷基,四氢吡喃,未取代的C1-6杂脂族,被卤素取代的C1-6杂脂族,未取代的环丁基,被-OH、C1-6烷氧基或C1-6杂环脂族取代的环丁基,未取代的环己基,或被-OH、C1-6烷氧基或C1-6杂环脂族取代的环己基;
R4是H或C1-6烷基;
R5是H或C1-6烷基;并且
R7,R8和R9各自独立地是H、卤素或烷基磷酸酯。
2.如权利要求1所述的化合物,其中:
R2是H;或
它们的组合。
3.如权利要求1或2所述的化合物,其中,R3是4-乙氧基环己基、4-吗啉基环己基、3-乙氧基环丁基、4-羟基环己基、(2,6-二甲基吗啉基)环己基、3-吗啉基环丁基、4-(4-甲基哌嗪-1-基)环己基或3-羟基环丁基。
4.如权利要求1中所述的化合物,其中:
吡唑是未取代的;或者
吡唑被至少一个选自以下的取代基取代:烷基磷酸酯。
5.如权利要求1所述的化合物,其中,R7是H、或-CH2OP(O)(OH)2,或其盐。
6.如权利要求1和5中任一项所述的化合物,其中:
R8和R9是H;或者
R8和R9中的一个是F而另一个是H。
7.如权利要求1所述的化合物,所述化合物选自:
II-1:N-(1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-2:N-(1-((1r,4r)-4-吗啉基环己基)-3-(嘧啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-3:N-(1-((1r,4r)-4-乙氧基环己基)-3-(嘧啶-2-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-4:N-(3-(6-(二氟甲基)吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-5:N-(3-(6-(二氟甲基)吡啶-2-基)-1-((1R,4r)-4-((2R,6S)-2,6-二甲基吗啉基)环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-6:N-(1-((1r,4r)-4-乙氧基环己基)-3-(嘧啶-4-基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-7:N-(3-(3-氟-6-(三氟甲基)吡啶-2-基)-1-((1r,4r)-4-吗啉基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-8:(4-(4-((3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基磷酸钠;
II-9:N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-10:N-(3-(3,6-二氟吡啶-2-基)-1-((1s,3s)-3-乙氧基环丁基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-11:N-(3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-羟基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-12:磷酸二氢(4-(4-((3-(3,6-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基酯;
II-13:N-(3-(3,5-二氟吡啶-2-基)-1-((1r,4r)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-14:N-(5-(3,6-二氟吡啶-2-基)-1-((1r,4R)-4-乙氧基环己基)-1H-吡唑-4-基)-2-(1H-吡唑-4-基)噁唑-4-甲酰胺;
II-15:2-(1H-吡唑-4-基)-N-(3-(吡啶-2-基)-1-(2-(2,2,2-三氟乙氧基)乙基)-1H-吡唑-4-基)噁唑-4-甲酰胺;
II-16:((4-(4-((1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基)磷酸二叔丁酯;
II-17:磷酸二氢(4-(4-((1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基酯;或
II-18:(4-(4-((1-((1r,4r)-4-乙氧基环己基)-3-(吡嗪-2-基)-1H-吡唑-4-基)氨甲酰基)噁唑-2-基)-1H-吡唑-1-基)甲基磷酸钠。
8.一种组合物,包含权利要求1-7中任一项所述的化合物和药学上可接受的赋形剂。
9.如权利要求1-7中任一项所述的化合物或权利要求8所述的组合物在制备用于治疗与IRAK相关的疾病或病症的药物中的用途。
10.如权利要求1-7中任一项所述的化合物或权利要求8所述的组合物在制备用于治疗指示IRAK抑制剂的疾病或病症的药物中的用途。
11.如权利要求10所述的用途,其中,所述疾病或病症是自身免疫性疾病,炎性疾病,心血管疾病,神经变性疾病,过敏性疾病,多器官衰竭,肾脏疾病,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,呼吸系统疾病,缺血性病症,细菌感染,病毒感染,免疫调节障碍或其组合。
12.如权利要求9所述的用途,其中所述药物用于治疗增殖性疾病。
13.如权利要求12所述的用途,其中所述增殖性疾病选自良性或恶性肿瘤、实体瘤。
14.如权利要求12所述的用途,其中所述增殖性疾病选自脑癌、肾癌、肝癌、肾上腺癌、膀胱癌、乳腺癌、胃癌、胃肿瘤、卵巢癌、结肠癌、直肠癌、前列腺癌、胰腺癌、肺癌、阴道癌、宫颈癌、睾丸癌、泌尿生殖道癌、食道癌、喉癌、皮肤癌、骨癌或甲状腺癌;肉瘤、恶性胶质瘤、成神经细胞瘤、多发性骨髓瘤、胃肠癌、结肠癌、结肠直肠腺瘤、头颈肿瘤、表皮增生、牛皮癣、前列腺增生、瘤形成、上皮性瘤形成、腺瘤、腺癌、角化棘皮瘤、鳞状细胞癌、大细胞癌、非小细胞肺癌、淋巴瘤、霍奇金和非霍奇金、乳腺癌、滤泡性癌、未分化癌、乳头状癌、精原细胞瘤、黑色素瘤、IL-1驱动的障碍、MyD88驱动的障碍、ABC弥散性大B细胞淋巴瘤(DLBCL)、瓦尔登斯特伦巨球蛋白血症、霍奇金氏淋巴瘤、原发性皮肤T淋巴细胞瘤、慢性淋巴细胞白血病、郁积或无痛多发性骨髓瘤。
15.如权利要求12所述的用途,其中所述增殖性疾病为血液恶性肿瘤。
16.如权利要求15所述的用途,其中所述血液恶性肿瘤选自白血病、急性髓性白血病(AML)、DLBCL、ABC DLBCL、慢性淋巴细胞白血病(CLL)、慢性淋巴细胞性淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病、急性淋巴细胞白血病、B细胞幼淋巴细胞白血病、淋巴浆细胞性淋巴瘤、骨髓增生异常综合征(MDS)、骨髓纤维化、真性红细胞增多症、卡波西氏肉瘤、瓦尔登斯特伦巨球蛋白血症(WM)、脾边缘区淋巴瘤、多发性骨髓瘤、浆细胞瘤或血管内大B细胞淋巴瘤。
17.如权利要求15所述的用途,其中所述血液恶性肿瘤是骨髓增生异常综合征。
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