CN111606887A - 一种新型激酶抑制剂 - Google Patents
一种新型激酶抑制剂 Download PDFInfo
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- CN111606887A CN111606887A CN201910139510.XA CN201910139510A CN111606887A CN 111606887 A CN111606887 A CN 111606887A CN 201910139510 A CN201910139510 A CN 201910139510A CN 111606887 A CN111606887 A CN 111606887A
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- phenyl
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- C—CHEMISTRY; METALLURGY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
本发明提供一种新型的pan‑RAF激酶抑制剂,其包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物、或前药。本发明还提供式(I)的化合物用于预防或治疗与RAF和/或RAS激酶活性相关的病症的用途和方法。
Description
技术领域
本文提供了激酶抑制剂化合物、包含所述化合物的药物组合物、以及所述化合物在治疗中的用途。特别地,本文公开了适用于抑制RAF和/或RAS激酶和用于治疗由RAF和/或RAS激酶介导的病症的吡唑或咪唑类衍生物。
技术背景
RAF基因家族包含BRAF、ARAF和CRAF。BRAF是一种癌基因,位于7号染色体的长臂上,编码766个氨基酸残基的蛋白质,是一种丝/苏氨酸特异性激酶,是RAS/RAF/MEK/ERK信号通路中重要的转导因子。BRAF蛋白被RAS激酶磷酸化之后,BRAF蛋白才有了激酶活性,才能激活下游的MEK蛋白,MEK蛋白再激活ERK蛋白,ERK蛋白进入到细胞核内部,再激活下游的各种蛋白,启动下游的各种基因的转录,实现细胞的增殖和分裂。当BRAF发生V600E突变时,BRAF的第600个氨基酸残基由缬氨酸变成谷氨酸,BRAF蛋白一直都处于激活状态。在RAS突变的肿瘤中,RAS蛋白的持续活化导致下游BRAF-BRAF同二聚体,或者BRAF-CRAF异二聚体的形成,从而往下传递活化信号,促进肿瘤细胞的恶性增殖。因此,开发靶向pan-RAF的小分子靶向药物能够同时抑制由BRAF V600E突变以及RAS突变引起的癌症。
目前BRAF抑制剂Vemurafenib、Dabrafenib和LGX818已经获批用于治疗携带BRAF突变的黑色素瘤。但是,这两个药物在携带RAS突变的肿瘤中不起作用。主要原因是RAS突变能够导致BRAF和CRAF的二聚物形成,抑制BRAF反而能够激活CRAF;其次是由于上市的BRAF抑制剂对CRAF的抑制作用较弱,从而使BRAF抑制剂失去抗癌作用。因此,开发具有同时能够作用在BRAF及CRAF蛋白上并且能够有效抑制下游的MEK和ERK活性的Pan-RAF抑制剂,成为目前RAF抑制剂研发的热点。
发明内容
本发明提供一种选择性的激酶抑制剂,包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
其中,
Y和Z中一个为碳,另一个为氮,优选Y为氮而Z为碳;
R1、R2和R3各自独立地选自H、氰基、C1-6烷基、C1-6烷氧基、C1-6羟基烷基、C1-6羟基烷氧基、C3-6环烷基C1-6烷氧基、C1-6烷氧基C1-6烷氧基、苯基、吡啶基、苯基C1-6烷氧基、呋喃基C1-6烷氧基、任选地被R6取代的杂环烷基、任选地被R6取代的杂环烷基苯基、任选地被R6取代的杂环烷基羰基、任选地被R6取代的杂环烷基氧基、任选地被R6取代的杂环烷基C1-6烷氧基、任选地被R6取代的杂环烷基C1-6烷酰氨基、C3-6环烷基C1-6烷酰氨基、和C1-6烷基氨基羰基C1-6烷氧基,其中R1、R2和R3不同时为H;
R4和R5各自独立地选自H、C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、和任选地被R6取代的杂环烷基C1-6烷基,且R4和R5不同时为H;
R6独立地选自氧代、C1-6烷基、C2-6烷酰基、C1-6烷基砜基、和C1-6烷基氨基C2-6烷酰基。
上文所述的“杂环烷基”优选4至6元含氧和/或氮原子的杂环烷基,例如吡咯烷基、吗啉基、哌嗪基、四氢吡喃基、四氢呋喃基、氧杂环丁烷基、氮杂环丁烷基等,且这些杂环烷基上的氮原子或碳原子可任选地被选自氧代(=O)、C1-6烷基、C2-6烷酰基、C1-6烷基砜基、和C1-6烷基氨基C2-6烷酰基的R6基团取代。
在本发明优选的实施方式中,R1、R2和R3各自独立地选自H、氰基、C1-6烷基(例如甲基、乙基、正丙基、异丙基、正丁基、叔丁基等)、C1-6羟基烷氧基(例如羟基甲氧基、2-羟基乙氧基、3-羟基丙氧基、4-羟基丁氧基等)、C3-6环烷基C1-6烷氧基(例如环戊基甲氧基等)、C1-6烷氧基C1-6烷氧基(例如2-甲氧基乙氧基等)、苯基、吡啶基(例如2-吡啶基、3-吡啶基、4-吡啶基)、苯基C1-6烷氧基(例如苯基甲氧基等)、呋喃基C1-6烷氧基(例如呋喃-3-基甲氧基等)、任选地被R6取代的杂环烷基(例如N-吗啉基、哌嗪-1-基、4-甲基-哌嗪-1-基等)、任选地被R6取代的杂环烷基苯基(例如4-甲基-哌嗪-1-基苯基等)、任选地被R6取代的杂环烷基羰基(例如4-甲基-哌嗪-1-基羰基等)、任选地被R6取代的杂环烷基氧基(例如四氢吡喃-4-基氧基、四氢呋喃-3-基氧基、氧杂环丁烷-3-基氧基、氮杂环丁烷-3-基氧基等)、任选地被R6取代的杂环烷基C1-6烷氧基(例如2-吗啉代乙氧基、3-吗啉代丙氧基、四氢呋喃-2-基甲氧基、四氢呋喃-3-基甲氧基、四氢吡喃-4-基甲氧基、氧杂环丁烷-3-基甲氧基、吡咯烷-3-基甲氧基等)、任选地被R6取代的杂环烷基C1-6烷酰氨基(例如四氢吡喃-4-基甲酰氨基、四氢呋喃-3-基甲酰氨基、四氢吡喃-4-基乙酰氨基、四氢呋喃-3-基乙酰氨基、3-甲基-氧杂环丁烷-3-基甲酰氨基、3-氧杂二环[3.1.0]己烷-6-基甲酰氨基等)、C3-6环烷基C1-6烷酰氨基(例如环丙基甲酰氨基等)、和C1-6烷基氨基羰基C1-6烷氧基(例如二甲氨基羰基甲氧基等),其中R1、R2和R3不同时为H。
在本发明的又一优选实施方式中,提供一种选择性的pan-RAF激酶抑制剂,包括式(Ia)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
其中,R1、R2、R3、R4和R5如上文所定义。
在更优选的实施方式中,
R1选自H、吡啶基、杂环烷基、任选地被C1-6烷基取代的杂环烷基苯基、杂环烷基氧基、杂环烷基C1-6烷氧基、和C1-6烷基氨基羰基C1-6烷氧基;
R2选自H、C1-6烷基、C1-6羟基烷氧基、C1-6烷氧基C1-6烷氧基、杂环烷基氧基、和杂环烷基C1-6烷氧基;
R3选自H、和C3-6环烷基C1-6烷酰氨基;
其中R1、R2和R3不同时为H;
R4选自C1-6卤代烷基、和C1-6氰基烷基;
R5选自H、C1-6烷基、和任选地被C1-6烷基取代的杂环烷基C1-6烷基。
在特别优选的实施方式中,R1选自3-吡啶基、4-吡啶基、N-吗啉基、杂环烷基氧基、杂环烷基C1-6烷氧基、和C1-6烷基氨基羰基C1-6烷氧基;R4选自C1-6卤代烷基、和C1-6氰基烷基;R2、R3和R5均为H。
在另外特别优选的实施方式中,R2选自C1-6羟基烷氧基、C1-6烷氧基C1-6烷氧基、杂环烷基氧基、和杂环烷基C1-6烷氧基;R4选自C1-6卤代烷基、和C1-6氰基烷基;R1、R3和R5均为H。
在又一个方面,本发明提供一种药物组合物,其包括本发明所述的激酶抑制剂、和药学上可接受的载体或赋形剂、以及任选的其它治疗剂。
本发明还涉及采用本发明所述的激酶抑制剂在制备用于抑制酪氨酸激酶RAF和/或RAS活性的药物中的用途,以及在制备用于治疗、预防或改善由酪氨酸激酶RAF和/或RAS活性调节的或者受其影响的或者其中涉及酪氨酸激酶RAF和/或RAS活性的疾病、障碍或病症的药物中的用途。
附图说明
图1a至1b示出测试化合物在A375细胞肿瘤移植小鼠模型中的肿瘤抑制效果。
图2a至2c示出测试化合物在Calu-6细胞肿瘤移植小鼠模型中的肿瘤抑制效果。
图3a至3b示出测试化合物在HCT116细胞肿瘤移植小鼠模型中的肿瘤抑制效果。
图4a至4b示出测试化合物在COLO205细胞肿瘤移植小鼠模型中的肿瘤抑制效果。
图5a至5b示出测试化合物在BxPC3细胞肿瘤移植小鼠模型中的肿瘤抑制效果。
具体实施方式
术语
除非另外定义,所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员一般理解相同的含义。
除非另有说明,本发明采用本领域技术范围内的质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学等常规方法。除非提供具体的定义,否则与本文描述的分析化学、合成有机化学、以及医学和药物化学等化学上相关的命名和实验室操作和技术,是本领域技术人员已知的。一般而言,前述技术和步骤可以通过本领域众所周知的和在各种一般文献和更具体文献中描述的常规方法来实施,这些文献在本说明书中被引用和讨论。
术语“烷基”是指脂肪族烃基团,可以是支链或直链的烷基。根据结构,烷基可以是单价基团或双价基团(即亚烷基)。在本发明中,烷基优选是具有1-8个碳原子的烷基,更优选具有1-6个碳原子的“低级烷基”,甚至更优选具有1-4个碳原子的烷基。典型的烷基包括但不限于甲基、乙基、丙基、丁基、戊基、己基等。应理解,本文提到的“烷基”包括可能存在的所有构型和构象的该烷基,例如本文提到的“丙基”包括正丙基和异丙基,“丁基”包括正丁基、异丁基和叔丁基,“戊基”包括正戊基、异丙基、新戊基、叔戊基、和戊-3-基等。
术语“烷氧基”是指-O-烷基,其中烷基如本文中定义。典型的烷氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。
术语“烷氧基烷基”是指本文定义的烷基被本文定义的烷氧基取代。
术语“环烷基”是指单环或多环基,其仅含有碳和氢。环烷基包括具有3-12个环原子的基团。根据结构,环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中,环烷基优选是具有3-8个碳原子的环烷基,更优选具有3-6个碳原子的“低级环烷基”。环烷基的例子包括但不限于,环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环戊烯基、环己烯基、环庚烯基和金刚烷基。
术语“烷基(环烷基)”或“环烷基烷基”是指本文定义的烷基被本文定义的环烷基取代。非限制性的环烷基烷基包括环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基等。
术语“芳香基”是指平面环具有离域的π电子系统并且含有4n+2个π电子,其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原子构成。芳香基可以是任选取代的。术语“芳香基”包括碳环芳基(例如苯基)和杂环芳基(或“杂芳基”或“杂芳香基”)基团(例如吡啶)。该术语包括单环或稠环多环(即共用相邻的碳原子对的环)基团。
本文使用的术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构,芳基可以是单价基团或双价基团(即亚芳基)。
术语“芳氧基”是指-O-芳基,其中芳基如本文中定义。
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构,杂芳基可以是单价基团或双价基团(即亚杂芳基)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。
术语“烷基(芳基)”或“芳烷基”是指本文定义的烷基被本文定义的芳基取代。非限制性的烷基(芳基)包括苄基、苯乙基等。
术语“烷基(杂芳基)”或“杂芳基烷基”是指本文定义的烷基被本文定义的杂芳基取代。
本文使用的术语“杂烷基”是指本文定义的烷基中的一个或多个骨架链原子是杂原子,例如氧、氮、硫、硅、磷或它们的组合。所述杂原子(一个或多个)可以位于杂烷基内部的任意位置或在杂烷基与分子的其余部分相连的位置。
本文使用的术语“杂环烷基”或“杂环基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基环可以是由三、四、五、六、七、八、九或多于九个原子构成的单环或多环。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胺、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1,3-二噁英、1,3-二噁烷、1,4-二噁英、1,4-二噁烷、哌嗪、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,4-氧硫杂环己烷、四氢-1,4-噻嗪、2H-1,2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1,3,5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷、咪唑烷,吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1,3-二氧杂环戊烯、1,3-二氧杂环戊烷、1,3-二硫杂环戊烯、1,3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1,3-氧硫杂环戊烷。根据结构,杂环烷基可以是单价基团或双价基团(即亚杂环烷基)。
术语“烷基(杂环烷基)”或“杂环烷基烷基”是指本文定义的烷基被本文定义的杂环烷基取代。
术语“烷氧基(杂环烷基)”或“杂环烷基烷氧基”是指本文定义的烷氧基被本文定义的杂环烷基取代。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“卤代烷基”、“卤代烷氧基”和“卤代杂烷基”包括烷基、烷氧基或杂烷基的结构,其中至少一个氢被卤原子置换。在某些实施方式中,如果两个或更多氢原子被卤原子置换,所述卤原子彼此相同或不同。
术语“羟基”是指-OH基团。
术语“氰基”是指-CN基团。
术语“酯基”是指具有式-COOR的化学部分,其中R选自烷基、环烷基、芳基、杂芳基(通过环碳连接)和杂环基(通过环碳连接)。
术语“氨基”是指-NH2基团。
术语“氨酰基”是指-CO-NH2基团。
术语“烷基氨酰基”是指-CO-NH-R基团,其中R为本文定义的烷基。
术语“酰胺基”或“酰氨基”是指-NR-CO-R’,其中R和R’各自独立地为氢或烷基。
术语“烷基氨基”是指进一步被一个或两个烷基取代的氨基取代基,具体是指基团-NRR’,其中R和R’各自独立地选自氢或低级烷基,条件是-NRR’不是-NH2。“烷基氨基”包括其中-NH2的氮连接至少一个烷基基团的化合物的基团。烷基氨基基团的例子包括但不限于,甲基氨基、乙基氨基等。“二烷基氨基”包括其中-NH2的氮连接至少两个其它烷基基团的基团。二烷基氨基基团的例子包括但不限于,二甲基氨基、二乙基氨基等。
术语“烷基氨基烷基”是指本文定义的烷基被本文定义的烷基氨基取代。
术语“氨基烷基”是指进一步被一个或多个氨基取代的烷基取代基。
术语“氨基烷氧基”是指进一步被一个或多个氨基取代的烷氧基取代基。
术语“羟烷基”或“羟基烷基”是指进一步被一个或多个羟基取代的烷基取代基。
术语“氰基烷基”是指进一步被一个或多个氰基取代的烷基取代基。
术语“酰基”是指有机或无机含氧酸去掉羟基后剩下的一价原子团,通式为R-M(O)-,其中M通常为C。
术语“羰基”是由碳和氧两种原子通过双键连接而成的有机官能团(C=O)。
术语“烷酰基”或“烷基羰基”是指进一步被一个烷基取代的羰基。典型的烷酰基包括但不限于乙酰基、丙酰基、丁酰基、戊酰基、己酰基等。
术语“芳基羰基”是指本文定义的羰基被本文定义的芳基取代。
术语“烷氧基羰基”是指进一步被一个烷氧基取代的羰基。
术语“杂环烷基羰基”是指进一步被一个杂环烷基取代的羰基。
术语“烷基氨基羰基”、“环烷基氨基羰基”、“芳基氨基羰基”、“芳烷基氨基羰基”、“杂芳基氨基羰基”分别是指本文定义的羰基分别被本文定义的烷基氨基、环烷基氨基、芳基氨基、芳烷基氨基、或杂芳基氨基取代。
术语“烷基羰基烷基”或“烷酰基烷基”是指进一步被一个烷基羰基取代的烷基。
术语“烷基羰基烷氧基”或“烷酰基烷氧基”是指进一步被一个烷基羰基取代的烷氧基。
术语“砜基”或“磺酰基”是指磺酸失去羟基后的官能团,具体是指-S(=O)2-基团。
术语“烷基砜基”或“烷基磺酰基”是指-S(=O)2-R,其中R为烷基。
术语“任选”指后面描述的一个或多个事件可以发生或可以不发生,并且包括发生的事件和不发生的事件两者。术语“任选取代的”或“取代的”是指所提及的基团可以被一个或多个额外的基团取代,所述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、杂环基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基、甲磺酰基、烷基羰基、烷氧基羰基、杂芳基烷基、杂环烷基烷基、氨酰基、氨基保护基等。其中,氨基保护基优选选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧苄基、烯丙氧羰基、和三氟乙酰基等。
本文使用的术语“酪氨酸蛋白激酶(tyrosine protein kinase,TPK)”是一类催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶,能催化多种底物蛋白质酪氨酸残基磷酸化,在细胞生长、增殖、分化中具有重要作用。
本文使用的术语激酶的“抑制”、“抑制的”或“抑制剂”,是指磷酸转移酶活性被抑制。
本文公开的化合物的“代谢物”是当该化合物被代谢时形成的化合物的衍生物。术语“活性代谢物”是指当该化合物被代谢时形成的化合物的生物活性衍生物。本文使用的术语“被代谢”,是指特定物质被生物体改变的过程总和(包括但不限于水解反应和由酶催化的反应,例如氧化反应)。因此,酶可以产生特定的结构转变为化合物。例如,细胞色素P450催化各种氧化和还原反应,同时二磷酸葡萄糖甘酸基转移酶催化活化的葡萄糖醛酸分子至芳香醇、脂肪族醇、羧酸、胺和游离的巯基的转化。新陈代谢的进一步的信息可以从《ThePharmacological Basis of Therapeutics》,第九版,McGraw-Hill(1996)获得。本文公开的化合物的代谢物可以通过将化合物给予宿主并分析来自该宿主的组织样品、或通过将化合物与肝细胞在体外孵育并且分析所得化合物来鉴别。这两种方法都是本领域已知的。在一些实施方式中,化合物的代谢物是通过氧化过程形成并与相应的含羟基化合物对应。在一些实施方式中,化合物被代谢为药物活性代谢物。本文使用的术语“调节”,是指直接或间接与靶标相互作用,以改变靶标的活性,仅仅举例来说,包括增强靶标的活性、抑制靶标的活性、限制靶标的活性或者延长靶标的活性。
本文使用的术语“靶蛋白”是指能被选择性结合化合物所结合的蛋白质分子或部分蛋白质。在某些实施方式中,靶蛋白是酪氨酸激酶RAF(野生型或各种突变或其组合)、酪氨酸激酶RAS(野生型或各种突变或其组合)、BCR/ABL(野生型或各种突变或其组合)、ABL(野生型或各种突变或其组合)、KIT(野生型或各种突变或其组合)、EGFR(野生型或各种突变或其组合)、FLT3(野生型或各种突变或其组合)、VEGFR2(野生型或各种突变或其组合)、RET(野生型或各种突变或其组合)、PDGFRα(野生型或各种突变或其组合)、PDGFRβ(野生型或各种突变或其组合)、FGFR1(野生型或各种突变或其组合)、FGFR2(野生型或各种突变或其组合)、FGFR3(野生型或各种突变或其组合)、FGFR4(野生型或各种突变或其组合)。
本文使用的IC50是指在测量这样的效应的分析中获得最大效应的50%抑制的特定测试化合物的量、浓度或剂量。
本文使用的EC50是指测定化合物的剂量、浓度或量,其引起特定测定化合物诱导、刺激或加强的特定反应的50%的最大表达的剂量依赖反应。
本文使用的GI50是指使50%细胞生长被抑制所需的药物浓度,即药物使50%细胞(如癌细胞)的生长得到抑制或控制时的药物浓度。
本发明新型的激酶抑制剂
本发明提供一种选择性的pan-RAF激酶抑制剂,包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
其中,
Y和Z中一个为碳,另一个为氮;
R1、R2和R3各自独立地选自H、氰基、C1-6烷基、C1-6烷氧基、C1-6羟基烷基、C1-6羟基烷氧基、C3-6环烷基C1-6烷氧基、C1-6烷氧基C1-6烷氧基、苯基、吡啶基、苯基C1-6烷氧基、呋喃基C1-6烷氧基、任选地被R6取代的杂环烷基、任选地被R6取代的杂环烷基苯基、任选地被R6取代的杂环烷基羰基、任选地被R6取代的杂环烷基氧基、任选地被R6取代的杂环烷基C1-6烷氧基、任选地被R6取代的杂环烷基C1-6烷酰氨基、C3-6环烷基C1-6烷酰氨基、和C1-6烷基氨基羰基C1-6烷氧基,其中R1、R2和R3不同时为H;
R4和R5各自独立地选自H、C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、和任选地被R6取代的杂环烷基C1-6烷基,且R4和R5不同时为H;
R6独立地选自氧代(=O)、C1-6烷基、C2-6烷酰基、C1-6烷基砜基、和C1-6烷基氨基C2-6烷酰基。
在优选的方面,式(I)中Y为氮且Z为碳。
在某些实施方式中,R2和R3为H;且R1选自苯基、吡啶基、任选地被C1-6烷基取代的杂环烷基、任选地被C1-6烷基取代的杂环烷基苯基、任选地被C1-6烷基取代的杂环烷基羰基、杂环烷基氧基、杂环烷基C1-6烷氧基、和C1-6烷基氨基羰基C1-6烷氧基。
在另外的实施方式中,R1为H;R2选自H、氰基、C1-6烷基、C1-6羟基烷氧基、C3-6环烷基C1-6烷氧基、C1-6烷氧基C1-6烷氧基、苯基C1-6烷氧基、呋喃基C1-6烷氧基、任选地被R6基团取代的杂环烷基氧基、任选地被R6基团取代的杂环烷基C1-6烷氧基、任选地被C1-6烷基取代的杂环烷基C1-6烷酰氨基、和C1-6烷基氨基羰基C1-6烷氧基,其中R6独立地选自氧代(=O)、C2-6烷酰基、C1-6烷基砜基、C1-6烷基氨基C2-6烷酰基;R3选自H和C3-6环烷基C1-6烷酰氨基;且R2和R3不同时为H。
在本发明中,当提到“杂环烷基”,优选4至6元含氧和/或氮原子的杂环烷基,例如吡咯烷基、吗啉基、哌嗪基、四氢吡喃基、四氢呋喃基、氧杂环丁烷基、氮杂环丁烷基等,且这些杂环烷基上的氮原子或碳原子可任选地被选自氧代(=O)、C1-6烷基、C2-6烷酰基、C1-6烷基砜基、和C1-6烷基氨基C2-6烷酰基的R6基团取代。
在本发明优选的实施方式中,R1、R2和R3各自独立地选自H、氰基、C1-6烷基(例如甲基、乙基、正丙基、异丙基、正丁基、叔丁基等)、C1-6羟基烷氧基(例如羟基甲氧基、2-羟基乙氧基、3-羟基丙氧基、4-羟基丁氧基等)、C3-6环烷基C1-6烷氧基(例如环戊基甲氧基等)、C1-6烷氧基C1-6烷氧基(例如2-甲氧基乙氧基等)、苯基、吡啶基(例如2-吡啶基、3-吡啶基、4-吡啶基)、苯基C1-6烷氧基(例如苯基甲氧基等)、呋喃基C1-6烷氧基(例如呋喃-3-基甲氧基等)、任选地被R6取代的杂环烷基(例如N-吗啉基、哌嗪-1-基、4-甲基-哌嗪-1-基等)、任选地被R6取代的杂环烷基苯基(例如4-甲基-哌嗪-1-基苯基等)、任选地被R6取代的杂环烷基羰基(例如4-甲基-哌嗪-1-基羰基等)、任选地被R6取代的杂环烷基氧基(例如四氢吡喃-4-基氧基、四氢呋喃-3-基氧基、氧杂环丁烷-3-基氧基、氮杂环丁烷-3-基氧基等)、任选地被R6取代的杂环烷基C1-6烷氧基(例如2-吗啉代乙氧基、3-吗啉代丙氧基、四氢呋喃-2-基甲氧基、四氢呋喃-3-基甲氧基、四氢吡喃-4-基甲氧基、氧杂环丁烷-3-基甲氧基、吡咯烷-3-基甲氧基等)、任选地被R6取代的杂环烷基C1-6烷酰氨基(例如四氢吡喃-4-基甲酰氨基、四氢呋喃-3-基甲酰氨基、四氢吡喃-4-基乙酰氨基、四氢呋喃-3-基乙酰氨基、3-甲基-氧杂环丁烷-3-基甲酰氨基、3-氧杂二环[3.1.0]己烷-6-基甲酰氨基等)、C3-6环烷基C1-6烷酰氨基(例如环丙基甲酰氨基等)、和C1-6烷基氨基羰基C1-6烷氧基(例如二甲氨基羰基甲氧基等),其中R1、R2和R3不同时为H。
在本发明的又一优选实施方式中,提供一种选择性的pan-RAF激酶抑制剂,包括式(Ia)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
其中,R1、R2、R3、R4和R5如上文所定义。
在更优选的实施方式中,
R1选自H、吡啶基(例如3-吡啶基、4-吡啶基)、杂环烷基(例如N-吗啉基、哌嗪-1-基)、任选地被C1-6烷基取代的杂环烷基苯基(例如4-甲基-哌嗪-1-基苯基)、杂环烷基氧基(例如四氢吡喃-4-基氧基、氧杂环丁烷-3-基氧基)、杂环烷基C1-6烷氧基(例如2-吗啉代乙氧基、3-吗啉代丙氧基、四氢呋喃-3-基甲氧基)、和C1-6烷基氨基羰基C1-6烷氧基(例如二甲氨基羰基甲氧基);
R2选自H、C1-6烷基(例如甲基)、C1-6羟基烷氧基(例如2-羟基乙氧基、3-羟基丙氧基、4-羟基丁氧基)、C1-6烷氧基C1-6烷氧基(例如2-甲氧基乙氧基)、杂环烷基氧基(例如四氢吡喃-4-基氧基、四氢呋喃-3-基氧基、氧杂环丁烷-3-基氧基、氮杂环丁烷-3-基氧基)、和杂环烷基C1-6烷氧基(例如2-吗啉代乙氧基、四氢呋喃-2-基甲氧基、四氢呋喃-3-基甲氧基、四氢吡喃-4-基甲氧基、氧杂环丁烷-3-基甲氧基、吡咯烷-3-基甲氧基);
R3选自H、和C3-6环烷基C1-6烷酰氨基(例如环丙基甲酰氨基);
其中R1、R2和R3不同时为H;
R4选自C1-6卤代烷基(例如三氟甲基)、和C1-6氰基烷基(例如2-氰基乙-2-基、2-氰基丙-2-基);
R5选自H、C1-6烷基(例如甲基)、和任选地被C1-6烷基取代的杂环烷基C1-6烷基(例如4-甲基-哌嗪-1-基甲基)。
在特别优选的实施方式中,R1选自3-吡啶基、4-吡啶基、N-吗啉基、杂环烷基氧基(优选氧杂环丁烷-3-基氧基)、杂环烷基C1-6烷氧基(优选3-吗啉代丙氧基、四氢呋喃-3-基甲氧基)、和C1-6烷基氨基羰基C1-6烷氧基(优选二甲氨基羰基甲氧基);R4选自C1-6卤代烷基(优选三氟甲基)、和C1-6氰基烷基(优选2-氰基乙-2-基、2-氰基丙-2-基);R2、R3和R5均为H。
在另外特别优选的实施方式中,R2选自C1-6羟基烷氧基(优选3-羟基丙氧基、4-羟基丁氧基)、C1-6烷氧基C1-6烷氧基(优选2-甲氧基乙氧基)、杂环烷基氧基(优选四氢吡喃-4-基氧基、四氢呋喃-3-基氧基、氧杂环丁烷-3-基氧基)、和杂环烷基C1-6烷氧基(优选四氢吡喃-4-基甲氧基、氧杂环丁烷-3-基甲氧基);R4选自C1-6卤代烷基(优选三氟甲基)、和C1-6氰基烷基(优选2-氰基乙-2-基、2-氰基丙-2-基);R1、R3和R5均为H。
在优选的实施方式中,本发明提供以下化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
对于各个变量,上述基团的任意组合也在本文考虑之中。可以理解的是:本文所提供的化合物上的取代基和取代模式可以由本领域技术人员进行选择,以便提供化学上稳定的且可以使用本领域已知的技术以及本文阐述的技术合成的化合物。
本文描述的是新型的激酶抑制剂。本文也描述了此化合物的药学可接受的盐、溶剂化物、酯、酸、药物活性代谢物和前药。
在另外的或进一步的实施方式中,将本文描述的化合物给予有需要的生物体后在其体内代谢产生代谢物,所产生的代谢物然后用于产生期望的效果,包括期望的治疗效果。
本文描述的化合物可以被制成和/或被用作药学可接受的盐。药学可接受的盐的类型包括但不限于:(1)酸加成盐,通过将化合物的游离碱形式与药学可接受的无机酸反应形成,所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等;或与有机酸反应形成,所述有机酸如乙酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、柠檬酸、琥珀酸、马来酸、酒石酸、反丁烯二酸、三氟乙酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、甲苯磺酸、4-甲基双环-[2.2.2]辛-2-烯-1-甲酸、2-萘磺酸、叔丁基乙酸、葡庚糖酸、4,4′-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、水杨酸、羟基萘酸、硬脂酸、粘康酸等;(2)碱加成盐,其在母体化合物中的酸性质子被金属离子置换时形成,例如碱金属离子(例如锂、钠、钾)、碱土金属离子(例如镁或钙)或铝离子;或与有机碱或无机碱配位,可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺等,可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠、氢氧化钠等。
药学可接受的盐的相应的平衡离子可以使用各种方法分析和鉴定,所述方法包括但不限于离子交换色谱、离子色谱、毛细管电泳、电感耦合等离子体、原子吸收光谱、质谱或它们的任何组合。
使用以下技术的至少一种回收所述盐:过滤、用非溶剂沉淀接着过滤、溶剂蒸发、或水溶液的情况下使用冻干法。
筛选和表征药学可接受的盐、多晶型和/或溶剂化物可以使用多种技术完成,所述技术包括但不限于热分析、X射线衍射、光谱、显微镜方法、元素分析。使用的各种光谱技术包括但不限于Raman、FTIR、UVIS和NMR(液体和固体状态)。各种显微镜技术包括但不限于IR显微镜检术和拉曼(Raman)显微镜检术。
本发明的药物组合物
本申请还提供药物组合物,其包含至少一种式(I)或(Ia)的化合物或所述化合物的药学可接受的盐、溶剂化物、酯、酸、药物活性代谢物或前药、以及药学可接受的载体或赋形剂、以及者任选的其它治疗剂。
在治疗过程中,可以根据情况单独或与一种或多种其它的治疗剂组合使用。可以通过注射、口服、吸入、直肠和经皮施用中的至少一种将包含本发明化合物的药物施用给患者。其它的治疗剂可以选自以下药物:免疫抑制剂(例如他克莫司、环抱菌素、雷帕霉素、甲氨蝶岭、环磷酰胺、硫唑嘌呤、巯嘌呤、麦考酚酯或FTY720)、糖皮质激素类药(例如泼尼松、醋酸可的松、泼尼松龙、甲泼尼龙、地塞米松、倍他米松、曲安西龙、氢羟强的松龙、倍氯米松、醋酸氟氢可的松、醋酸脱氧皮质酮、醛固酮)、非甾体抗炎药(例如水杨酸盐、芳基烷酸、2-芳基丙酸、N-芳基邻氨基苯甲酸、昔康类、考昔类或硫酰替苯胺)、变态反应疫苗、抗组胺药、抗白三烯药、β-激动剂、茶碱、抗胆碱药或其它选择性激酶抑制剂(例如mTOR抑制剂、c-Met抑制剂)或her2抗体-药物。另外,所提及的其它治疗剂还可以是雷帕霉素(Rapamycin)、克唑替尼(Crizotinib)、他莫昔芬、雷洛昔芬、阿那曲唑、依西美坦、来曲唑、赫赛汀TM(曲妥珠单抗)、格列卫TM(伊马替尼)、紫杉醇TM(紫杉醇)、环磷酰胺、洛伐他汀、美诺四环素(Minosine)、阿糖胞苷、5-氟尿嘧啶(5-FU)、甲氨蝶呤(MTX)、紫杉特尔TM(多西他赛)、诺雷德TM(戈舍瑞林)、长春新碱、长春碱、诺考达唑、替尼泊苷、依托泊苷、健择TM(吉西他滨)、埃博霉素(Epothilone)、诺唯本、喜树碱、柔红霉素(Daunonibicin)、更生霉素、米托蒽醌、安吖啶、多柔比星(亚德里亚霉素)、表柔比星或伊达比星。或者,其它治疗剂也可以是细胞因子例如G-CSF(粒细胞集落刺激因子)。或者,其它治疗剂也可以是,例如但不限于,CMF(环磷酰胺、甲氨蝶呤和5-氟尿嘧啶)、CAF(环磷酰胺、亚德里亚霉素和5-氟尿嘧啶)、AC(亚德里亚霉素和环磷酰胺)、FEC(5-氟尿嘧啶、表柔比星和环磷酰胺)、ACT或ATC(亚德里亚霉素、环磷酰胺和紫杉醇)或CMFP(环磷酰胺、甲氨蝶呤、5-氟尿嘧啶和泼尼松)。
在本发明的实施方式中,在根据本发明对患者进行治疗时,给定药物的量取决于诸多因素,如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重),但是,根据特定的周围情况,包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主,施用剂量可由本领域已知的方法常规决定。通常,就成人治疗使用的剂量而言,施用剂量典型地在0.02-5000mg/天,例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量,例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是,尽管给出了上述剂量范围,但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
本发明的药物的用途
本发明的化合物能包括其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药、或药物组合物抑制一种用于抑制酪氨酸激酶RAF(野生型或各种突变或其组合)和/或RAS(野生型或各种突变或其组合)活性。本发明的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,或其药物组合物可用于治疗、预防或改善一种或多种选自下组的疾病:实体瘤(包括良性或者尤其恶性类型)、尤其肉瘤、胃肠道间质肿瘤(Gastrointestinal StromalTumors,GIST)、结直肠癌(colon cancer)、急性粒细胞白血病(Acute MyeloblasticLeukemia,AML)、慢性髓性白血病(Chronic Myelogenous Leukemia,CML)、瘤形成、系统性肥大细胞病、嗜酸性粒细胞增多综合征、纤维变性、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、睾丸上皮内瘤形成、黑色素瘤、乳癌、神经母细胞瘤、乳头状/滤泡型甲状腺癌、恶性淋巴瘤、非霍奇金淋巴瘤、2型多发性内分泌瘤形成、嗜铬细胞瘤、甲状腺癌、甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、以及其他增生性或增殖性疾病或类似疾病、或其组合。特别优选治疗:头颈癌、甲状腺癌(thyroid carcinoma)、黑色素瘤、结直肠癌(colorectal cancer)、肺癌、乳腺癌、胰腺癌、食管癌、肝癌、白血病(Leukemia)、瘤形成或类似疾病,或其组合。
化合物的制备
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描述的方法组合,可以合成本发明的化合物。另外,本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导,也可以利用以下的合成方法。
所述反应可以按顺序使用,以提供本文描述的化合物;或它们可以用于合成片段,所述片段通过本文描述的方法和/或本领域已知的方法随后加入。
在某些实施方式中,本文提供的是本文描述的酪氨酸激酶抑制剂化合物的制备方法及其使用方法。在某些实施方式中,本文描述的化合物可以使用以下合成的方案合成。可以使用与下述类似的方法,通过使用适当的可选择的起始原料,合成化合物。
用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。本文描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本文公开的化合物的一般方法可以来自本领域已知的反应,并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改,以引入本文提供的分子中的各种部分。
如果需要,反应产物可以使用常规技术分离和纯化,包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法表征,包括物理常数和图谱数据。
实施例1:N-(3-(4-([3,3′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-4-甲基-3-(三氟甲基)苯甲酰胺1
步骤1. 4-溴-1-(2-甲基-5-硝基苯基)-1H-吡唑a的合成:
将化合物4-溴吡唑(5g,1eq)、2-氟-1-甲基-4-硝基苯(5.5g,1.05eq)、碳酸钾(13.1,3eq)混合于DMF(50ml)中,于氮气氛围中120℃下搅拌过夜,后冷却浓缩。加入乙酸乙酯(200ml),依次水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,柱层析得黄色产品a(5.2g)。
步骤2. 1-(2-甲基-5-硝基苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑b的合成:
将化合物a(5g,1eq)、联硼酸频那醇酯(5.8g,1.3eq)、醋酸钾(3.5g,2eq)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(0.72g,0.05eq)混合于1,4-二氧六环(50ml)中,于氮气氛围中100℃下搅拌过夜,后浓缩,柱层析得黄色产品b(4.0g)。
步骤3. 5-(1-(2-甲基-5-硝基苯基)-1H-吡唑-4-基)-3,3′-联吡啶c的合成:
将化合物b(4.0g,1.1eq)、5-溴-3,3′-联吡啶(2.6g,1eq)、碳酸钾(3.0g,2eq)、四三苯基膦钯(0.6g,0.05eq)混合于1,4-二氧六环(40ml)和水(4ml)中,于氮气氛围中90℃下搅拌过夜,后浓缩,柱层析得黄色产品c(2.8g)。
步骤4. 3-(4-([3,3′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯胺d的合成:
将化合物c(2.8g,1eq)、钯碳(0.5g)混合于甲醇(30ml)中,于氢气氛围中,室温下搅拌2小时,后加入二氯甲烷(100ml)稀释,过滤,浓缩得浅绿色产品d(2.1g)。
步骤5.N-(3-(4-([3,3′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-4-甲基-3-(三氟甲基)苯甲酰胺1的合成:
将化合物d(0.05g,1eq)、4-甲基-3-(三氟甲基)苯甲酸(0.031g,1eq)、HATU(0.064,1.1eq)、二异丙基乙胺(0.020g,1eq)混合于DMF(2ml)中,室温搅拌0.5小时,后加入乙酸乙酯(50ml)稀释,依次水洗,饱和食盐水洗,无水硫酸钠干燥,过滤浓缩,HPLC得产品1(0.07g)。Exact Mass(计算值):513.17;MS(ESI)m/z(M+1)+:514.17。
实施例2:N-(3-(4-([3,3′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺2
化合物2的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):499.16;MS(ESI)m/z(M+1)+:500.16。
实施例3:N-(3-(4-([3,3′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(2-氰基丙烷-2-基)苯甲酰胺3
化合物3的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):498.21;MS(ESI)m/z(M+1)+:499.21。
实施例4:N-(3-(4-([3,3′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(叔丁基)异噁唑-3-甲酰胺4
化合物4的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):478.21;MS(ESI)m/z(M+1)+:479.21。
实施例5:N-(3-(4-([3,4′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(2-氰基丙烷-2-基)苯甲酰胺5
化合物5的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):498.21;MS(ESI)m/z(M+1)+:499.21。
实施例6:N-(3-(4-([3,4′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(1-氰基乙基)苯甲酰胺6
化合物6的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):484.20;MS(ESI)m/z(M+1)+:484.20。
实施例7:N-(3-(4-([3,4′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-4-甲基-3-(三氟甲基)苯甲酰胺7
化合物7的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):513.17;MS(ESI)m/z(M+1)+:514.17。
实施例8:N-(3-(4-([3,4′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酰胺8
化合物8的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):611.26;MS(ESI)m/z(M+1)+:612.26。
实施例9:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(5-吗啉代吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺9
化合物9的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):506.24;MS(ESI)m/z(M+1)+:507.24。
实施例10:3-(1-氰基乙基)-N-(4-甲基-3-(4-(5-吗啉代吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺10
化合物10的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):492.22;MS(ESI)m/z(M+1)+:493.22。
实施例11:4-甲基-N-(4-甲基-3-(4-(5-吗啉代吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺11
化合物11的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):521.20;MS(ESI)m/z(M+1)+:522.20。
实施例12:N-(4-甲基-3-(4-(5-吗啉代吡啶-3-基)-1H-吡唑-1-基)苯基)-4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酰胺12
化合物12的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):619.28;MS(ESI)m/z(M+1)+:620.28。
实施例13:N-(3-(4-([3,4′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺13
化合物13的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):499.16;MS(ESI)m/z(M+1)+:500.16。
实施例14:N-(3-(4-([3,4′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(叔丁基)异噁唑-3-甲酰胺14
化合物14的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):478.21;MS(ESI)m/z(M+1)+:479.21。
实施例15:1-(3-(4-([3,4′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(5-(叔丁基)异噁唑-3-基)脲15
步骤1.(5-(叔丁基)异噁唑-3-基)氨基甲酸苯酯e的合成
将5-(叔丁基)异噁唑-3-胺(5g,1eq)、DIEPA(5.1g,1.1eq)和THF(20ml)混合于氮气的氛围中于0℃下,滴加氯甲酸苯酯(5.9g,1.05eq)后于此温度下反应0.5小时,后加乙酸乙酯(120ml)稀释,依次用水洗,饱和食盐水洗,无水硫酸钠干燥,过滤浓缩,固体用正己烷洗,过滤得白色固体e(7g)。
步骤2. 1-(3-(4-([3,4′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(5-(叔丁基)异噁唑-3-基)脲15的合成
化合物f的合成通过使用类似于实施例1中所述的步骤完成。将化合物e(0.05g,1eq)和化合物f(0.055g,1eq)、DMSO(2ml)混合,于80℃下搅拌4小时,后加入乙酸乙酯(50ml),依次用水洗,饱和食盐水洗,无水硫酸钠干燥,过滤浓缩,HPLC得化合物12(0.06g)。Exact Mass(计算值):493.22;MS(ESI)m/z(M+1)+:494.22。
实施例16:N-(4-甲基-3-(4-(5-吗啉代吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺16
化合物16的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):507.18;MS(ESI)m/z(M+1)+:508.18。
实施例17:5-(叔丁基)-N-(4-甲基-3-(4-(5-吗啉代吡啶-3-基)-1H-吡唑-1-基)苯基)异噁唑-3-甲酰胺17
化合物17的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):486.23;MS(ESI)m/z(M+1)+:487.23。
实施例18:1-(5-(叔丁基)异噁唑-3-基)-3-(4-甲基-3-(4-(5-吗啉代吡啶-3-基)-1H-吡唑-1-基)苯基)脲18
化合物18的合成通过使用类似于实施例1和15中所述的步骤完成。Exact Mass(计算值):501.24;MS(ESI)m/z(M+1)+:502.24。
实施例19:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(5-(4-甲基哌嗪-1-羰基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺19
化合物19的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):547.26;MS(ESI)m/z(M+1)+:548.26。
实施例20:3-(1-氰基乙基)-N-(4-甲基-3-(4-(5-(4-甲基哌嗪-1-羰基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺20
化合物20的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):533.25;MS(ESI)m/z(M+1)+:534.25。
实施例21:N-(4-甲基-3-(4-(5-(4-甲基哌嗪-1-羰基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺21
化合物21的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):548.21;MS(ESI)m/z(M+1)+:549.21。
实施例22:5-(叔丁基)-N-(4-甲基-3-(4-(5-(4-甲基哌嗪-1-羰基)吡啶-3-基)-1H-吡唑-1-基)苯基)异噁唑-3-甲酰胺22
化合物22的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):527.26;MS(ESI)m/z(M+1)+:528.26。
实施例23:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(5-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺23
化合物23的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):519.27;MS(ESI)m/z(M+1)+:520.27。
实施例24:3-(1-氰基乙基)-N-(4-甲基-3-(4-(5-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺24
化合物24的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):505.26;MS(ESI)m/z(M+1)+:506.27。
实施例25:N-(4-甲基-3-(4-(5-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺25
化合物25的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):520.21;MS(ESI)m/z(M+1)+:521.21。
实施例26:5-(叔丁基)-N-(4-甲基-3-(4-(5-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡唑-1-基)苯基)异噁唑-3-甲酰胺26
化合物26的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):499.26;MS(ESI)m/z(M+1)+:500.26。
实施例27:1-(5-(叔丁基)异噁唑-3-基)-3-(4-甲基-3-(4-(5-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡唑-1-基)苯基)脲27
化合物27的合成通过使用类似于实施例1和15中所述的步骤完成。Exact Mass(计算值):514.28;MS(ESI)m/z(M+1)+:515.28。
实施例28:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(5-苯基吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺28
化合物28的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):497.22;MS(ESI)m/z(M+1)+:498.22。
实施例29:N-(4-甲基-3-(4-(5-苯基吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺29
化合物29的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):498.16;MS(ESI)m/z(M+1)+:499.16。
实施例30:N-(4-甲基-3-(4-(5-(4-(4-甲基哌嗪-1-基)苯基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(2-氰基丙烷-2-基)苯甲酰胺30
化合物30的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):595.31;MS(ESI)m/z(M+1)+:596.31
实施例31:N-(4-甲基-3-(4-(5-(4-(4-甲基哌嗪-1-基)苯基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺31
化合物31的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):596.25;MS(ESI)m/z(M+1)+:597.26。
实施例32:N-(4-甲基-3-(4-(5-(4-(4-甲基哌嗪-1-基)苯基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺32
化合物32的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):610.26;MS(ESI)m/z(M+1)+:611.26。
实施例33:5-(叔丁基)-N-(4-甲基-3-(4-(5-(4-(4-甲基哌嗪-1-基)苯基)吡啶-3-基)-1H-吡唑-1-基)苯基)异噁唑-3-甲酰胺33
化合物33的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):575.30;MS(ESI)m/z(M+1)+:576.30。
实施例34:N-(4-甲基-3-(4-(5-吗啉代吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺54
化合物34的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):521.20;MS(ESI)m/z(M+1)+:522.20。
实施例35:3-(2-氰基丙烷-2-基)-N-(3-(4-(6-(环丙烷甲酰氨基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺35
化合物35的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):504.22;MS(ESI)m/z(M+1)+:505.22。
实施例36:N-(3-(4-(6-(环丙烷甲酰氨基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺36
化合物36的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):505.17;MS(ESI)m/z(M+1)+:506.17。
实施例37:N-(5-(1-(2-甲基-5-(2-(3-(三氟甲基)苯基)乙酰氨基)苯基)-1H-吡唑-4-基)吡啶-2-基)环丙烷甲酰胺37
化合物37的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):519.18;MS(ESI)m/z(M+1)+:520.18。
实施例38:3-(2-氰基丙烷-2-基)-N-(3-(4-(6-(环丙烷甲酰氨基)-4-甲基吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺38
化合物38的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):518.24;MS(ESI)m/z(M+1)+:519.24。
实施例39:N-(3-(4-(6-(环丙烷甲酰氨基)-4-甲基吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺39
化合物39的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):519.18;MS(ESI)m/z(M+1)+:520.18。
实施例40:N-(4-甲基-5-(1-(2-甲基-5-(2-(3-(三氟甲基)苯基)乙酰氨基)苯基)-1H-吡唑-4-基)吡啶-2-基)环丙烷甲酰胺40
化合物40的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):533.20;MS(ESI)m/z(M+1)+:534.20。
实施例41:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(5-(2-吗啉代乙氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺41
步骤1. 4-(2-((5-溴吡啶-3-基)氧基)乙基)吗啉g的合成
将2-吗啉乙醇(3g,1eq)、DIEPA(3.2g,1.1eq)、THF(15ml)混合,于0℃下滴加甲基磺酰氯(2.7g,1.1eq),后于室温下搅拌6小时。反应液浓缩,乙酸乙酯(100ml)稀释,依次用水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩得产品2-吗啉代乙基甲磺酸酯(3.8g,1eq)。产物与5-溴吡啶-3-醇(2.8g,0.9eq)、碳酸钾(3.7g,2eq)混合,于DMF(30ml)中70℃搅拌5小时。后浓缩,乙酸乙酯稀释(150ml),依次用水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩得产品4-(2-((5-溴吡啶-3-基)氧基)乙基)吗啉g(3.2g)。
步骤2.化合物41的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):550.26;MS(ESI)m/z(M+1)+:551.26。
实施例42:N-(4-甲基-3-(4-(5-(2-吗啉代乙氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺42
化合物42的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):551.21;MS(ESI)m/z(M+1)+:552.21。
实施例43:N-(4-甲基-3-(4-(5-(2-吗啉代乙氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺43
化合物43的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):565.23;MS(ESI)m/z(M+1)+:566.23。
实施例44:N-(3-(4-(4-氰基-6-(环丙烷甲酰氨基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(2-氰基丙烷-2-基)苯甲酰胺44
化合物44的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):529.22;MS(ESI)m/z(M+1)+:530.22。
实施例45:N-(3-(4-(4-氰基-6-(环丙烷甲酰氨基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺45
化合物45的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):530.16;MS(ESI)m/z(M+1)+:531.16。
实施例46:N-(4-氰基-5-(1-(2-甲基-5-(2-(3-(三氟甲基)苯基)乙酰氨基)苯基)-1H-吡唑-4-基)吡啶-2-基)环丙烷甲酰胺46
化合物46的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):544.18;MS(ESI)m/z(M+1)+:545.18。
实施例47:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(5-(3-吗啉代丙氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺47
化合物47的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):564.28;MS(ESI)m/z(M+1)+:565.28。
实施例48:N-(4-甲基-3-(4-(5-(3-吗啉代丙氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺48
化合物48的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):565.23;MS(ESI)m/z(M+1)+:566.23。
实施例49:N-(4-甲基-3-(4-(5-(3-吗啉代丙氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺49
化合物49的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):579.24;MS(ESI)m/z(M+1)+:580.24。
实施例50:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(5-((四氢-2H-吡喃-4-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺50
化合物50的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):521.24;MS(ESI)m/z(M+1)+:522.24。
实施例51:N-(4-甲基-3-(4-(5-((四氢-2H-吡喃-4-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺51
化合物51的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):522.18;MS(ESI)m/z(M+1)+:523.18。
实施例52:N-(4-甲基-3-(4-(5-((四氢-2H-吡喃-4-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺52
化合物52的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):536.20;MS(ESI)m/z(M+1)+:537.20。
实施例53:3-(2-氰基丙烷-2-基)-N-(3-(4-(5-(2-(二甲基氨基)-2-氧代乙氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺53
化合物53的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):522.23;MS(ESI)m/z(M+1)+:523.23。
实施例54:N-(3-(4-(5-(2-(二甲基氨基)-2-氧代乙氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺54
化合物54的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):523.18;MS(ESI)m/z(M+1)+:524.18。
实施例55:N,N-二甲基-2-((5-(1-(2-甲基-5-(2-(3-(三氟甲基)苯基)乙酰氨基)苯基)-1H-吡唑-4-基)吡啶-3-基)氧基)乙酰胺55
化合物55的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):537.19;MS(ESI)m/z(M+1)+:538.19。
实施例56:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-((四氢-2H-吡喃-4-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺56
化合物56的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):521.24;MS(ESI)m/z(M+1)+:522.24。
实施例57:N-(4-甲基-3-(4-(4-((四氢-2H-吡喃-4-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺57
化合物57的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):522.19;MS(ESI)m/z(M+1)+:523.20。
实施例58:N-(4-甲基-3-(4-(4-((四氢-2H-吡喃-4-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺58
化合物58的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):536.20;MS(ESI)m/z(M+1)+:537.20。
实施例59:3-(2-氰基丙烷-2-基)-N-(3-(4-(4-(2-(二甲基氨基)-2-氧代乙氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺59
化合物59的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):522.23;MS(ESI)m/z(M+1)+:523.23。
实施例60:N-(3-(4-(4-(2-(二甲基氨基)-2-氧代乙氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺60
化合物60的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):522.23;MS(ESI)m/z(M+1)+:523.23。
实施例61:N,N-二甲基-2-((3-(1-(2-甲基-5-(2-(3-(三氟甲基)苯基)乙酰氨基)苯基)-1H-吡唑-4-基)吡啶-4-基基)氧基)乙酰胺61
化合物61的合成通过使用类似于实施例61中所述的步骤完成。Exact Mass(计算值):537.19;MS(ESI)m/z(M+1)+:538.19。
实施例62:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺62
化合物62的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):521.24;MS(ESI)m/z(M+1)+:522.24。
实施例63:N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺63
化合物63的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):522.18;MS(ESI)m/z(M+1)+:523.18。
实施例64:N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺64
化合物64的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):536.20;MS(ESI)m/z(M+1)+:537.20。
实施例65:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(5-((四氢呋喃-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺65
化合物65的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):521.24;MS(ESI)m/z(M+1)+:522.24。
实施例66:N-(4-甲基-3-(4-(5-((四氢呋喃-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺66
化合物66的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):522.18;MS(ESI)m/z(M+1)+:523.18。
实施例67:N-(4-甲基-3-(4-(5-((四氢呋喃-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺67
化合物67的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):536.20;MS(ESI)m/z(M+1)+:537.20。
实施例68:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺68
化合物68的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):507.22;MS(ESI)m/z(M+1)+:508.22。
实施例69:N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺69
化合物69的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):508.17;MS(ESI)m/z(M+1)+:509.17。
实施例70:N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺70
化合物70的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):522.18;MS(ESI)m/z(M+1)+:523.18。
实施例71:N-(3-(4-([3,4′-联吡啶]-5-基)-1H-吡唑-1-基)-4-甲基苯基)-2-(3-(三氟甲基)苯基)乙酰胺71
化合物71的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):513.17;MS(ESI)m/z(M+1)+:514.17。
实施例72:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-((四氢-2H-吡喃-4-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺72
化合物72的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):535.25;MS(ESI)m/z(M+1)+:536.25。
实施例73:3-(1-氰基乙基)-N-(4-甲基-3-(4-(4-((四氢-2H-吡喃-4-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺73
化合物73的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):521.24;MS(ESI)m/z(M+1)+:522.25。
实施例74:N-(4-甲基-3-(4-(4-((四氢-2H-吡喃-4-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺74
化合物74的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):536.20;MS(ESI)m/z(M+1)+:537.20。
实施例75:N-(4-甲基-3-(4-(4-((四氢-2H-吡喃-4-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺75
化合物75的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):550.21;MS(ESI)m/z(M+1)+:551.21。
实施例76:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-(2-吗啉代乙氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺76
化合物76的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):550.26;MS(ESI)m/z(M+1)+:551.26。
实施例77:3-(1-氰基乙基)-N-(4-甲基-3-(4-(4-(2-吗啉代乙氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺77
化合物77的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):536.25;MS(ESI)m/z(M+1)+:537.25。
实施例78:N-(4-甲基-3-(4-(4-(2-吗啉代乙氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺78
化合物78的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):565.23;MS(ESI)m/z(M+1)+:566.23。
实施例79:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-(氧杂环丁烷-3-基氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺79
化合物79的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):493.21;MS(ESI)m/z(M+1)+:494.21。
实施例80:3-(1-氰基乙基)-N-(4-甲基-3-(4-(4-(氧杂环丁烷-3-基氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺80
化合物80的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):479.19;MS(ESI)m/z(M+1)+:480.19。
实施例81:N-(4-甲基-3-(4-(4-(2-吗啉代乙氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺81
化合物81的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):521.21;MS(ESI)m/z(M+1)+:522.22。
实施例82:N-(4-甲基-3-(4-(4-(氧杂环丁烷-3-基氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺82
化合物82的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):494.15;MS(ESI)m/z(M+1)+:495.15。
实施例83:N-(4-甲基-3-(4-(4-(氧杂环丁烷-3-基氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺83
化合物83的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):508.17;MS(ESI)m/z(M+1)+:509.18。
实施例84:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(5-(氧杂环丁烷-3-基氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺84
化合物84的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):493.21;MS(ESI)m/z(M+1)+:494.21。
实施例85:3-(1-氰基乙基)-N-(4-甲基-3-(4-(5-(氧杂环丁烷-3-基氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺85
化合物85的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):479.19;MS(ESI)m/z(M+1)+:480.19。
实施例86:N-(4-甲基-3-(4-(5-(氧杂环丁烷-3-基氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺86
化合物86的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):508.17;MS(ESI)m/z(M+1)+:509.17。
实施例87:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-(氧杂环丁烷-3-基甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺87
化合物87的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):507.22;MS(ESI)m/z(M+1)+:508.22。
实施例88:3-(1-氰基乙基)-N-(4-甲基-3-(4-(4-(氧杂环丁烷-3-基甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺88
化合物88的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):493.21;MS(ESI)m/z(M+1)+:494.21。
实施例89:N-(4-甲基-3-(4-(4-(氧杂环丁烷-3-基甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺89
化合物89的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):508.17;MS(ESI)m/z(M+1)+:509.17。
实施例90:N-(4-甲基-3-(4-(4-(氧杂环丁烷-3-基甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺90
化合物90的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):522.18;MS(ESI)m/z(M+1)+:523.18。
实施例91:N-(3-(4-(4-(苄氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(2-氰基丙烷-2-基)苯甲酰胺91
化合物91的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):527.23;MS(ESI)m/z(M+1)+:528.24。
实施例92:N-(3-(4-(4-(苄氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺92
化合物92的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):528.17;MS(ESI)m/z(M+1)+:529.17。
实施例93:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-((四氢呋喃-2-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺93
化合物93的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):521.24;MS(ESI)m/z(M+1)+:522.24。
实施例94:3-(1-氰基乙基)-N-(4-甲基-3-(4-(4-((四氢呋喃-2-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺94
化合物94的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):507.22;MS(ESI)m/z(M+1)+:508.22。
实施例95:N-(4-甲基-3-(4-(4-((四氢呋喃-2-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺95
化合物95的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):522.18;MS(ESI)m/z(M+1)+:523.18。
实施例96:N-(4-甲基-3-(4-(4-((四氢呋喃-2-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺96
化合物96的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):536.20;MS(ESI)m/z(M+1)+:537.20。
实施例97:3-(2-氰基丙烷-2-基)-N-(3-(4-(4-(环戊基甲氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺97
化合物97的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):519.26;MS(ESI)m/z(M+1)+:520.26。
实施例98:3-(1-氰基乙基)-N-(3-(4-(4-(环戊基甲氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺98
化合物98的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):505.24;MS(ESI)m/z(M+1)+:506.24。
实施例99:N-(3-(4-(4-(环戊基甲氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺99
化合物99的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):520.20;MS(ESI)m/z(M+1)+:521.20。
实施例100:N-(3-(4-(4-(环戊基甲氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-2-(3-(三氟甲基)苯基)乙酰胺100
化合物100的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):534.22;MS(ESI)m/z(M+1)+:535.22。
实施例101:3-(2-氰基丙烷-2-基)-N-(3-(4-(4-(呋喃-3-基甲氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺101
化合物101的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):517.21;MS(ESI)m/z(M+1)+:518.21。
实施例102:3-(1-氰基乙基)-N-(3-(4-(4-(呋喃-3-基甲氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺102
化合物102的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):503.19;MS(ESI)m/z(M+1)+:504.19。
实施例103:N-(3-(4-(4-(呋喃-3-基甲氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺103
化合物103的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):518.15;MS(ESI)m/z(M+1)+:519.15。
实施例104:N-(3-(4-(4-(呋喃-3-基甲氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-2-(3-(三氟甲基)苯基)乙酰胺104
化合物104的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):532.17;MS(ESI)m/z(M+1)+:533.17。
实施例105:(S)-3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺105
化合物105的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):507.22;MS(ESI)m/z(M+1)+:508.22。
实施例106:(R)-3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺106
化合物106的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):507.22;MS(ESI)m/z(M+1)+:508.22。
实施例107:(S)-N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺107
化合物107的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):508.17;MS(ESI)m/z(M+1)+:509.17。
实施例108:(R)-N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺108
化合物108的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):508.17;MS(ESI)m/z(M+1)+:509.17。
实施例109:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(5-吗啉代吡啶-3-基)-1H-咪唑-1-基)苯基)苯甲酰胺109
化合物109的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):506.24;MS(ESI)m/z(M+1)+:507.24。
实施例110:N-(4-甲基-3-(4-(5-(氧杂环丁烷-3-基氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺110
化合物110的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):506.24:MS(ESI)m/z(M+1)+:507.24。
实施例111:N-(4-甲基-3-(4-(5-吗啉代吡啶-3-基)-1H-咪唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺111
化合物111的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):507.18;MS(ESI)m/z(M+1)+:508.18。
实施例112:(S)-3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺112
化合物112的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):521.24;MS(ESI)m/z(M+1)+:522.24。
实施例113:(R)-3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺113
化合物113的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):521.24;MS(ESI)m/z(M+1)+:522.24。
实施例114:(S)-N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺114
化合物114的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):522.18;MS(ESI)m/z(M+1)+:523.18。
实施例115:(R)-N-(4-甲基-3-(4-(4-((四氢呋喃-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺115
化合物115的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):522.18;MS(ESI)m/z(M+1)+:523.18。
实施例116:N-(3-(4-(4-((1-乙酰吡咯烷-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(2-氰基丙烷-2-基)苯甲酰胺116
化合物116的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):562.26;MS(ESI)m/z(M+1)+:563.26。
实施例117:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-((1-(甲基磺酰基)吡咯烷-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺117
化合物117的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):598.23;MS(ESI)m/z(M+1)+:599.23。
实施例118:3-(2-氰基丙烷-2-基)-N-(3-(4-(4-((1-(2-(二甲基氨基)乙酰基)吡咯烷-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺118
化合物118的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):605.31;MS(ESI)m/z(M+1)+:606.31。
实施例119:N-(3-(4-(4-((1-乙酰基吡咯烷-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺119
化合物119的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):563.21;MS(ESI)m/z(M+1)+:564.21。
实施例120:N-(4-甲基-3-(4-(4-((1-(甲基磺酰基)吡咯烷-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺120
化合物120的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):599.18;MS(ESI)m/z(M+1)+:600.18。
实施例121:N-(3-(4-(4-((1-(2-(二甲基氨基)乙酰基)吡咯烷-3-基)甲氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺121
化合物121的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):606.25;MS(ESI)m/z(M+1)+:607.25。
实施例122:(S)-3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-((5-氧代四氢呋喃-2-基)甲氧基)吡啶-3-基)-H-吡唑-1-基)苯基)苯甲酰胺122
化合物122的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):535.22;MS(ESI)m/z(M+1)+:536.22。
实施例123:N-(3-(4-(4-((1-乙酰基氮杂-3-基)氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基))-3-(三氟甲基)苯甲酰胺123
化合物123的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):535.18;MS(ESI)m/z(M+1)+:536.18。
实施例124:N-(4-甲基-3-(4-(4-((1-(甲基磺酰基)氮杂环丁烷-3-基)氧基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺124
化合物124的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):571.15;MS(ESI)m/z(M+1)+:572.15。
实施例125:N-(3-(1-(5-(3-(2-氰基丙烷-2-基)苯甲酰氨基)-2-甲基苯基)-1H-吡唑-4-基)吡啶-4-基)四氢-2H-吡喃-4-甲酰胺125
步骤1.N-(3-溴吡啶-4-基)四氢-2H-吡喃4-甲酰胺h的合成
将3-溴吡啶-4-胺(1.0g,1eq)、四氢-2H-吡喃-4-羧酸(0.75g,1eq)、HATU(2.4g,1.1eq)、DIPEA(0.75)和DMF(5mL)混合,于室温下搅拌0.5小时,后加乙酸乙酯(150mL)稀释,依次用水洗,饱和食盐水洗,无水硫酸钠干燥,过滤浓缩得产品h(1.3g),直接下一步。
步骤2.最终化合物125的合成通过使用类似于实施例1中所述的步骤完成。ExactMass(计算值):548.25;MS(ESI)m/z(M+1)+:549.25。
实施例126:N-(3-(1-(2-甲基-5-(3-(三氟甲基)苯甲酰氨基)苯基)-1H-吡唑-4-基)吡啶-4-基)四氢-2H-吡喃-4-甲酰胺126
化合物126的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):549.19;MS(ESI)m/z(M+1)+:550.19。
实施例127:N-(3-(1-(2-甲基-5-(2-(3-(三氟甲基)苯基)乙酰氨基)苯基)-1H-吡唑-4-基)吡啶-4-基)四氢-2H-吡喃-4-甲酰胺127
化合物127的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):563.24;MS(ESI)m/z(M+1)+:564.24。
实施例128:N-(3-(1-(2-甲基-5-(3-(3-(三氟甲基)苯基)脲基)苯基)-1H-吡唑-4-基)吡啶-4-基)四氢-2H-吡喃-4-甲酰胺128
化合物128的合成通过使用类似于实施例1和125和15中所述的步骤完成。ExactMass(计算值):564.20;MS(ESI)m/z(M+1)+:565.20。
实施例129:N-(3-(1-(5-(3-(5-(叔丁基)异噁唑-3-基)脲基)-2-甲基苯基)-1H-吡唑-4-基)吡啶-4-基)四氢-2H-吡喃-4-甲酰胺129
化合物129的合成通过使用类似于实施例1和125和15中所述的步骤完成。ExactMass(计算值):543.25;MS(ESI)m/z(M+1)+:544.25。
实施例130:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-(2-(四氢-2H-吡喃-4-基)乙酰氨基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺130
化合物130的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):562.26;MS(ESI)m/z(M+1)+:563.26。
实施例131:N-(4-甲基-3-(4-(4-(2-(四氢-2H-吡喃-4-基)乙酰氨基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺131
化合物131的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):563.21;MS(ESI)m/z(M+1)+:564.21。
实施例132:N-(4-甲基-3-(4-(4-(2-(四氢-2H-吡喃-4-基)乙酰氨基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺132
化合物132的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):577.23;MS(ESI)m/z(M+1)+:578.23。
实施例133:N-(3-(1-(2-甲基-5-(3-(3-(三氟甲基)苯基)脲基)苯基)-1H-吡唑-4-基)吡啶-4-基)-2-(四氢-2H-吡喃-4-基)乙酰胺133
化合物133的合成通过使用类似于实施例1和125和15中所述的步骤完成。ExactMass(计算值):578.22;MS(ESI)m/z(M+1)+:579.22。
实施例134:N-(3-(1-(5-(3-(5-(叔丁基)异噁唑-3-基)脲基)-2-甲基苯基)-1H-吡唑-4-基)吡啶-4-基)-2-(四氢-2H-吡喃-4-基)乙酰胺134
化合物134的合成通过使用类似于实施例1和125和15中所述的步骤完成。ExactMass(计算值):557.27;MS(ESI)m/z(M+1)+:558.27。
实施例135:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(4-(2-(四氢呋喃-3-基)乙酰氨基)吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺135
化合物135的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):548.25;MS(ESI)m/z(M+1)+:549.25。
实施例136:N-(4-甲基-3-(4-(4-(2-(四氢呋喃-3-基)乙酰氨基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺136
化合物136的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):549.19;MS(ESI)m/z(M+1)+:550.19。
实施例137:N-(4-甲基-3-(4-(4-(2-(四氢呋喃-3-基)乙酰氨基)吡啶-3-基)-1H-吡唑-1-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺137
化合物137的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):563.21;MS(ESI)m/z(M+1)+:564.21。
实施例138:N-(3-(1-(2-甲基-5-(3-(3-(三氟甲基)苯基)脲基)苯基)-1H-吡唑-4-基)吡啶-4-基)-2-(四氢呋喃-3-基)乙酰胺138
化合物138的合成通过使用类似于实施例1和125和15中所述的步骤完成。ExactMass(计算值):564.20;MS(ESI)m/z(M+1)+:565.20。
实施例139:N-(3-(1-(5-(3-(5-(叔丁基)异噁唑-3-基)脲基)-2-甲基苯基)-1H-吡唑-4-基)吡啶-4-基)-2-(四氢呋喃-3-基)乙酰胺139
化合物139的合成通过使用类似于实施例1和125和15中所述的步骤完成。ExactMass(计算值):543.25;MS(ESI)m/z(M+1)+:544.25。
实施例140:N-(3-(1-(5-(3-(2-氰基丙烷-2-基)苯甲酰氨基)-2-甲基苯基)-1H-吡唑-4-基)吡啶-4-基)四氢呋喃-3-甲酰胺140
化合物140的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):534.23;MS(ESI)m/z(M+1)+:535.23。
实施例141:N-(3-(1-(2-甲基-5-(3-(三氟甲基)苯甲酰氨基)苯基)-1H-吡唑-4-基)吡啶-4-基)四氢呋喃-3-甲酰胺141
化合物141的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):535.18;MS(ESI)m/z(M+1)+:536.18。
实施例142:N-(3-(1-(2-甲基-5-(2-(3-(三氟甲基)苯基)乙酰氨基)苯基)-1H-吡唑-4-基)吡啶-4-基)四氢呋喃-3-甲酰胺142
化合物142的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):549.19;MS(ESI)m/z(M+1)+:550.19。
实施例143:N-(3-(1-(2-甲基-5-(3-(3-(三氟甲基)苯基)脲基)苯基)-1H-吡唑-4-基)吡啶-4-基)-3-四氢呋喃甲酰胺143的合成
化合物143的合成通过使用类似于实施例1和125和15中所述的步骤完成。ExactMass(计算值):550.19;MS(ESI)m/z(M+1)+:551.19。
实施例144:N-(3-(1-(5-(3-(5-(叔丁基)异噁唑-3-基)脲基)-2-甲基苯基)-1H-吡唑-4-基)吡啶-4-基)四氢呋喃-3-甲酰胺144
化合物144的合成通过使用类似于实施例1和125和15中所述的步骤完成。ExactMass(计算值):529.24;MS(ESI)m/z(M+1)+:530.24。
实施例145:N-(3-(1-(5-(3-(2-氰基丙烷-2-基)苯甲酰氨基)-2-甲基苯基)-1H-吡唑-4-基)吡啶-4-基)-3-甲基氧杂环丁烷-3-甲酰胺145
化合物145的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):534.23;MS(ESI)m/z(M+1)+:535.23。
实施例146:3-甲基-N-(3-(1-(2-甲基-5-(3-(三氟甲基)苯甲酰氨基)苯基)-1H-吡唑-4-基)吡啶-4-基)氧杂环丁烷-3-甲酰胺146
化合物146的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):535.18;MS(ESI)m/z(M+1)+:536.18。
实施例147:3-甲基-N-(3-(1-(2-甲基-5-(2-(3-(三氟甲基)苯基)乙酰氨基)苯基)-1H-吡唑-4-基)吡啶-4-基)氧杂环丁烷-3-甲酰胺147
化合物147的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):549.19;MS(ESI)m/z(M+1)+:550.19。
实施例148:3-甲基-N-(3-(1-(2-甲基-5-(3-(3-(三氟甲基)苯基)脲基)苯基)-1H-吡唑-4-基)吡啶-4-基)氧杂环丁烷-3-甲酰胺148
化合物148的合成通过使用类似于实施例1和125和15中所述的步骤完成。ExactMass(计算值):550.19;MS(ESI)m/z(M+1)+:551.19。
实施例149:N-(3-(1-(5-(3-(5-(叔丁基)异噁唑-3-基)脲基)-2-甲基苯基)-1H-吡唑-4-基)吡啶-4-基)-3-甲基氧杂环丁烷-3-甲酰胺149
化合物149的合成通过使用类似于实施例1和125和15中所述的步骤完成。ExactMass(计算值):529.24;MS(ESI)m/z(M+1)+:530.24。
实施例150:N-(3-(1-(5-(3-(2-氰基丙烷-2-基)苯甲酰氨基)-2-甲基苯基)-1H-吡唑-4-基)吡啶-4-基)-3-氧杂二环[3.1.0]己烷-6-甲酰胺150
化合物150的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):546.23;MS(ESI)m/z(M+1)+:547.23。
实施例151:N-(3-(1-(2-甲基-5-(3-(三氟甲基)苯甲酰氨基)苯基)-1H-吡唑-4-基)吡啶-4-基)-3-氧杂二环[3.1.0]己烷-6-甲酰胺151
化合物151的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):547.18;MS(ESI)m/z(M+1)+:548.18。
实施例152:N-(3-(1-(2-甲基-5-(2-(3-(三氟甲基)苯基)乙酰氨基)苯基)-1H-吡唑-4-基)吡啶-4-基)-3-氧杂二环[3.1.0]己烷-6-甲酰胺152
化合物152的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):561.19;MS(ESI)m/z(M+1)+:562.19。
实施例153:N-(3-(1-(2-甲基-5-(3-(3-(三氟甲基)苯基)脲基)苯基)-1H-吡唑-4-基)吡啶-4-基)-3-氧杂二环[3.1.0]己烷-6-甲酰胺153
化合物153的合成通过使用类似于实施例1和125和15中所述的步骤完成。ExactMass(计算值):562.19;MS(ESI)m/z(M+1)+:563.19。
实施例154:N-(3-(1-(5-(3-(5-(叔丁基)异噁唑-3-基)脲基)2-甲基苯基)-1H-吡唑-4-基)吡啶-4-基)-3-氧杂二环[3.1.0]己烷-6-甲酰胺154
化合物154的合成通过使用类似于实施例1和125和15中所述的步骤完成。ExactMass(计算值):541.24;MS(ESI)m/z(M+1)+:542.24。
实施例155:3-(2-氰基丙烷-2-基)-N-(3-(4-(4-(2-羟基乙氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺155
化合物155的合成通过使用类似于实施例1和125中所述的步骤完成。Exact Mass(计算值):481.21;MS(ESI)m/z(M+1)+:482.21。
实施例156:N-(3-(4-(4-(2-羟基乙氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺156
化合物156的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):482.15;MS(ESI)m/z(M+1)+:483.15。
实施例157:1-(5-(叔丁基)异噁唑-3-基)-3-(3-(4-(4-(2-羟基乙氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)脲157
化合物157的合成通过使用类似于实施例1和41中所述的步骤完成。Exact Mass(计算值):476.21;MS(ESI)m/z(M+1)+:477.21。
实施例158:1-(3-(4-(4-(2-羟基乙氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(3-(三氟甲基)苯基)脲158
化合物158的合成通过使用类似于实施例1和41中所述的步骤完成。Exact Mass(计算值):497.16;MS(ESI)m/z(M+1)+:498.16。
实施例159:3-(2-氰基丙烷-2-基)-N-(3-(4-(4-(2-甲氧基乙氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺159
化合物159的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):495.22;MS(ESI)m/z(M+1)+:496.22。
实施例160:N-(3-(4-(4-(2-甲氧基乙氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺160
化合物160的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):496.17;MS(ESI)m/z(M+1)+:497.17。
实施例161:3-(2-氰基丙烷-2-基)-N-(3-(4-(4-(3-羟基丙氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺161
化合物161的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):495.22;MS(ESI)m/z(M+1)+:496.22。
实施例162:N-(3-(4-(4-(3-羟基丙氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺162
化合物162的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):496.17;MS(ESI)m/z(M+1)+:497.17。
实施例163:3-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4-(5-(哌嗪-1-基)吡啶-3-基)1H-吡唑-1-基)苯基)苯甲酰胺163
化合物163的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):505.25;MS(ESI)m/z(M+1)+:506.25。
实施例164:N-(4-甲基-3-(4-(5-(哌嗪-1-基)吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺164
化合物164的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):506.20;MS(ESI)m/z(M+1)+:507.20。
实施例165:3-(2-氰基丙烷-2-基)-N-(3-(4-(4-(4-羟基丁氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺165
化合物165的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):509.24;MS(ESI)m/z(M+1)+:510.24。
实施例166:N-(3-(4-(4-(4-羟基丁氧基)吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺166
化合物166的合成通过使用类似于实施例41中所述的步骤完成。Exact Mass(计算值):510.18;MS(ESI)m/z(M+1)+:511.18。
对比例1:3-三氟甲基-N-(4-甲基-3-(4-(吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺
对比化合物1的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):422.14;MS(ESI)m/z(M+1)+:423.14。
对比例2:3-氯-N-(4-甲基-3-(4-(吡啶-3-基)-1H-吡唑-1-基)苯基)苯甲酰胺
对比化合物2的合成通过使用类似于实施例1中所述的步骤完成。Exact Mass(计算值):388.11;MS(ESI)m/z(M+1)+:389.12。
实施例167:对癌细胞增殖的影响
通过测试本发明的化合物对癌细胞生长的影响(表2),进一步评估文中化合物对癌细胞增殖的抑制作用、及其对抑制癌细胞增殖的选择性。
本实施例中选用了小鼠原B细胞BaF3(购自ATCC)、小鼠BaF3-FL-BRAF-V600E(稳定表达全长BRAF-V600E突变型激酶)、黑色素瘤细胞A375(表达BRAF-V600E突变型激酶,购自南京科佰生物科技有限公司)、结直肠癌细胞COLO205(表达BRAF-V600E突变型激酶,购自美国ATCC)、人急性白血病细胞OCI-AML-3(表达NRAS-Q61L突变型激酶,购自南京科佰生物科技有限公司)、和人急性白血病细胞NB4(表达KRAS-A18D突变型激酶,购自美国ATCC)。上述BaF3-FL-BRAF-V600E突变细胞系的构建方法为:经PCR扩增人类全长BRAF-V600E突变激酶区序列,并插入到MSCV-Puro载体(购自Clontech),通过逆转录病毒方法,稳定转入小鼠BaF3细胞,并且撤除IL-3生长因子,最终得到依赖全长BRAF-V600E各种突变转入蛋白的细胞系。
在实施例中将不同浓度(0.000508μM、0.00152μM、0.00457μM、0.0137μM、0.0411μM、0.123μM、0.370μM、1.11μM、3.33μM、10μM于DMSO中)的测试化合物分别加入到上述细胞中,并孵育72小时,用Cell Titer-Glo(Promega,美国)细胞活力检测试剂盒,通过对活细胞中的ATP进行定量测定来检测活细胞数目。确定本发明的化合物针对各测试细胞的GI50值(单位),实验结果见表2。
表2
实验表明,本发明的化合物对表达BRAF-V600E的细胞系BaF3-FL-BRAF-V600E、A375、和COLO205能够达到与对比化合物1相当甚至更好的抑制活性,并且达到与对比化合物2相比更好的抑制活性。在表达NRAS或KRAS突变的OCI-AML-3和NB4细胞中,本发明的化合物也表现出与对比化合物1以及对比化合物2相当或更佳的抑制活性。
实施例168:蛋白酶活实验
化合物16和对照化合物PLX4032(MedChem Express,中国)对BRAF、BRAF V599E、RAF1(cRAF)Y340靶点活性是由Invitrogen公司(Carlsbad,美国)检测。
数据表明本发明的化合物16对BRAF蛋白、BRAF-V600E蛋白以及RAF1(CRAF)Y340D蛋白在体外均有较强的抑制作用,优于对照化合物PLX4032。
表3.化合物16和对照化合物PLX4032对蛋白BRAF、BRAF-V600E、RAF1(CRAF)Y340D体外酶活检测
IC<sub>50</sub>(nM) | 化合物16 | PLX4032 |
BRAF | 5.9 | 17.5 |
BRAF-V600E | 5.89 | 41.7 |
RAF1(CRAF)Y340D | 3.55 | 23.5 |
实施例169:大鼠药代动力学参数研究
实施例使用SD大鼠,180-220g,雄性(购于安徽医科大学实验动物中心,中国)。动物饲养在独立送风笼具中,每笼6只。饲养条件如下:温度为20~26℃,湿度为35-75%,光照为12小时照明,12小时黑暗,玉米芯垫料每周更换一次,自由取食,自由饮水,尾部数字标记。在实验过程中,动物饲养与使用将严格遵循国际实验动物评估认证管理委员会的规定。
化合物16以及对比化合物1的配制方法如下。精密称取待测化合物10mg置于无菌小瓶,然后用少量的DMSO对其进行溶解,然后加入5%葡萄糖溶液定容至5ml,得浓度为2mg/mL的灌胃供试溶液;精密量取0.5ml的2mg/mL的上述灌胃供试溶液,加入4.5ml 5%葡萄糖溶液定容至5ml,得浓度为0.2mg/mL的静脉注射供试溶液。在实验当前现配现用。
6只SD大鼠随机分为两组,分别灌胃和尾静脉注射给予合成的化合物。灌胃组于给药前0h及给药后5min、15min、30min、1h、1.5h、2h、4h、6h、9h、12h、24h;尾静脉组于给药前0h及给药后2min、5min、15min、30min、1h、2h、4h、6h、9h、12h自眼眶后静脉丛采集血样约0.3mL置于加有肝素(Sigma,美国)的1.5mL的离心管中,6000rpm离心3min分离血浆,然后取上层100μL的血浆于新的1.5mL的离心管中,存放于-80℃保存,待测定。
精密称取待测化合物标准品10mg于10mL的容量瓶中,加甲醇溶解定容混匀,即得到1mg/mL的储备液。然后用甲醇逐级稀释得到浓度分别为0.01、0.02、0.05、0.1、0.2、0.5、1、2、5、10、20μg/mL的系列工作液,放入4℃冰箱备用。
取离心管11个,分别加入上述工作液10μL,然后加入空白大鼠血浆90μL,混匀,使大鼠血浆中化合物的浓度分别为1、2、5、10、20、50、100、200、500、1000、2000ng/mL,然后加20μL的内标咖啡因溶液(200ng/mL)(中国食品药品检定研究院),涡旋10s,然后加入400μL的甲醇,涡旋10min,16000rpm离心5min后,取上清液70μL于进样瓶的内插管中,进样5μL进行LC-MS/MS分析测定。以样品和内标峰面积比As/Ais为纵坐标,浓度C(μg/mL)为横坐标,以1/C2为权重系数进行线性回归,获得大鼠血浆中化合物的标准曲线。
取-80℃保存的待测大鼠血浆100μL,加20μL的内标咖啡因溶液(200ng/mL),涡旋10s,然后加入400μL的甲醇,涡旋10min,16000rpm离心5min后,取上清液70μl于进样瓶的内插管中,进样5μl进行LC-MS/MS分析测定。
LC-MS/MS测定方法如下。实验仪器:API 4000三重四级杆检测器(AB SCIEX公司,美国),操作软件为Analyst 1.5.1(美国应用生物系统有限公司);岛津LC-30AD液相泵,岛津DGU-20A脱气单元,岛津CTO-30A柱温箱,SIL-30AC自动进样器(日本岛津公司)。色谱条件:色谱柱为汉邦Hedera ODS-2(江苏汉邦科技有限公司,中国),Dim.(mm):150×2.1,Pro.No:H18100205.15;Ser.No:C981210513;柱温40℃;流动相A为水相(含0.1%甲酸),流动相B为甲醇,梯度洗脱0-0.5min,B 10%;0.5-1.0min,B 90%;1.0-5.0min,B 90%;5.0-5.5min,B 10%;5.5-7min,B 10%。流速为0.3mL/min。进样量:5μL。质谱条件:离子源为Turbo Spray源,CAD为10;帘气(CUR)为25;加热温度为500℃;离子源气体GS1为45;离子源气体GS2为45;喷雾电压5500V;源内温度为500℃。
结果如下表4-7所示。结果显示化合物16无论静脉注射还是灌胃方式给药,其在血液内的最高浓度Cmax均比对比化合物1高。当灌胃给药时,化合物16在大鼠体内最大药物吸收为1482ng/ml,体内累计药物浓度AUC0-t为10930hr*ng/ml,口服利用度F%为144.1%,而对比化合物1在大鼠体内最大药物吸收为575.7ng/ml,体内累计药物浓度AUC0-t为1012hr*ng/ml,口服利用度F%为110.7%。因此,通过在吡啶基上引入取代基,本发明的化合物在大鼠体内吸收有很大的提高,并且口服利用度也有一定提高。
表4.化合物16静脉注射1mg/kg(n=3)
表5.化合物16口服给药10mg/kg(n=3)
表6.对比化合物1静脉注射1mg/kg(n=3)
表7.对比化合物1口服给药10mg/kg(n=3)
实施例170:动物药效实验
在本实施例中,分别测试化合物16、对比化合物1、和对照化合物LY30019120(购自MedChemExpress,中国)、PLX4032(购自MedChemExpress,中国)和RAF709(购自MedChemExpress,中国)、RAF265(购自MedChemExpress,中国)和PLX8394(购自MedChemExpress,中国)在人退行性肺癌Calu-6(表达KRAS Q61K突变激酶,购自南京科佰生物科技有限公司)、黑色素瘤细胞A375(表达BRAF-V600E突变型激酶,购自南京科佰生物科技有限公司)、胰腺癌细胞BxPC3(表达KRAS野生型,BRAF V487-P492>A缺失突变型激酶,购自南京科佰生物科技有限公司)、结直肠癌细胞HCT116(表达KRAS G13D突变型激酶,购自美国ATCC)、结直肠癌细胞COLO205(表达BRAF-V600E突变型激酶,购自美国ATCC)的小鼠模型中的实验结果。
实验步骤如下:
(1)从北京维通利华实验动物有限责任公司购买饲养4-6周龄的SCID小鼠(A375/COLO205)、裸鼠(HCT116/Calu-6/BxPC3)雌性小鼠,饲养于SPF级实验室中,饮水及垫料均经高压消毒无菌处理,有关小鼠的所有操作均在无菌条件下进行。
(2)第0天分别在小鼠左侧背部皮下分别注入约5×106个非小细胞肺癌Calu-6、结直肠癌HCT116、结直肠癌COLO205、黑色素瘤A375、胰腺癌BxPC3细胞。
(3)从第14天开始,每天使对应小鼠口服给药蓖麻油∶乙醇∶水(1∶1∶6)溶媒(5只小鼠);对于A375移植瘤剂量为50mg/kg、100mg/kg的化合物16、100mg/kg的PLX4032;对于Calu-6移植瘤剂量为50mg/kg、100mg/kg、200mg/kg的化合物16、100mg/kg的RAF709、60mg/kg LY30019120、以及100mg/kg的对比化合物1;对于HCT116移植瘤剂量为50mg/kg、100mg/kg的化合物16、100mg/kg的RAF709以及60mg/kg LY30019120;对于COLO205移植瘤剂量为25mg/kg、50mg/kg、100mg/kg的化合物16、100mg/kg的PLX4032;对于BxPC3移植瘤剂量为50mg/kg、100mg/kg、200mg/kg的化合物16、100mg/kg的LY3009120、100mg/kg的RAF265、和100mg/kg的PLX8394。从第15天开始,每天使对应小鼠口服给蓖麻油∶乙醇∶水(1∶1∶6)溶媒。
(4)分别从第15天开始,每天用游标卡尺测量皮下肿瘤的长/宽,并每天记录小鼠体重,分别确定化合物16对小鼠体重的影响;
(5)对于各模型组分别于第36、42、26、35或42天处死小鼠;
(6)统计内皮下肿瘤生长趋势,肿瘤体积计算方法:长×宽×宽/2mm3。
实验表明,在表达KRAS、BRAF或者NRAS突变的不同癌症细胞的小鼠移植瘤模型中,本发明的化合物16比对照化合物有更好的抑制作用。和对比化合物1相比在calu6细胞的移植瘤模型上,对比化合物1具有很强的毒性,在第八天小鼠全部死亡,而化合物16没有任何毒性,这也证明了本发明的化合物在吡啶基上引入吗啉取代基后在小鼠体内产生预料不到的药效,并且没有产生显著的毒性。
工业应用性
本发明提供一种新型的pan-RAF激酶抑制剂,其包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物、或前药,本发明还提供式(I)的化合物用于预防或治疗与RAF和/或RAS激酶活性相关的病症的用途和方法。因而,可将上述抑制剂制成相应的药物,适于工业应用。
尽管本文对本发明作了详细说明,但本发明不限于此,本技术领域的技术人员可以根据本发明的原理进行修改,因此,凡按照本发明的原理进行的各种修改都应当理解为落入本发明的保护范围。
Claims (16)
1.一种激酶抑制剂,包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
其中,
Y和Z中一个为碳,另一个为氮;
R1、R2和R3各自独立地选自H、氰基、C1-6烷基、C1-6烷氧基、C1-6羟基烷基、C1-6羟基烷氧基、C3-6环烷基C1-6烷氧基、C1-6烷氧基C1-6烷氧基、苯基、吡啶基、苯基C1-6烷氧基、呋喃基C1-6烷氧基、任选地被R6取代的杂环烷基、任选地被R6取代的杂环烷基苯基、任选地被R6取代的杂环烷基羰基、任选地被R6取代的杂环烷基氧基、任选地被R6取代的杂环烷基C1-6烷氧基、任选地被R6取代的杂环烷基C1-6烷酰氨基、C3-6环烷基C1-6烷酰氨基、和C1-6烷基氨基羰基C1-6烷氧基,其中R1、R2和R3不同时为H;
R4和R5各自独立地选自H、C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、和任选地被R6取代的杂环烷基C1-6烷基,且R4和R5不同时为H;
R6独立地选自氧代、C1-6烷基、C2-6烷酰基、C1-6烷基砜基、和C1-6烷基氨基C2-6烷酰基。
2.根据权利要求1所述的激酶抑制剂,其中Y为氮,Z为碳。
4.根据权利要求1所述的激酶抑制剂,其中R2和R3为H;且R1选自苯基、吡啶基、任选地被C1-6烷基取代的杂环烷基、任选地被C1-6烷基取代的杂环烷基苯基、任选地被C1-6烷基取代的杂环烷基羰基、杂环烷基氧基、杂环烷基C1-6烷氧基、和C1-6烷基氨基羰基C1-6烷氧基。
5.根据权利要求1所述的激酶抑制剂,其中R1为H;R2选自H、氰基、C1-6烷基、C1-6羟基烷氧基、C3-6环烷基C1-6烷氧基、C1-6烷氧基C1-6烷氧基、苯基C1-6烷氧基、呋喃基C1-6烷氧基、任选地被R6基团取代的杂环烷基氧基、任选地被R6基团取代的杂环烷基C1-6烷氧基、任选地被C1-6烷基取代的杂环烷基C1-6烷酰氨基、和C1-6烷基氨基羰基C1-6烷氧基,其中R6独立地选自氧代、C2-6烷酰基、C1-6烷基砜基、C1-6烷基氨基C2-6烷酰基;R3选自H和C3-6环烷基C1-6烷酰氨基;且R2和R3不同时为H。
7.根据权利要求6所述的激酶抑制剂,其中
R1选自H、吡啶基、杂环烷基、任选地被C1-6烷基取代的杂环烷基苯基、杂环烷基氧基、杂环烷基C1-6烷氧基、和C1-6烷基氨基羰基C1-6烷氧基;
R2选自H、C1-6烷基、C1-6羟基烷氧基、C1-6烷氧基C1-6烷氧基、杂环烷基氧基、和杂环烷基C1-6烷氧基;
R3选自H、和C3-6环烷基C1-6烷酰氨基;
其中R1、R2和R3不同时为H;
R4选自C1-6卤代烷基、和C1-6氰基烷基;
R5选自H、C1-6烷基、和任选地被C1-6烷基取代的杂环烷基C1-6烷基。
8.根据权利要求6所述的激酶抑制剂,其中
R1选自H、3-吡啶基、4-吡啶基、N-吗啉基、哌嗪-1-基、4-甲基-哌嗪-1-基苯基、四氢吡喃-4-基氧基、氧杂环丁烷-3-基氧基、2-吗啉代乙氧基、3-吗啉代丙氧基、四氢呋喃-3-基甲氧基、和二甲氨基羰基甲氧基;
R2选自H、甲基、2-羟基乙氧基、3-羟基丙氧基、4-羟基丁氧基、2-甲氧基乙氧基、四氢吡喃-4-基氧基、四氢呋喃-3-基氧基、氧杂环丁烷-3-基氧基、氮杂环丁烷-3-基氧基、2-吗啉代乙氧基、四氢呋喃-2-基甲氧基、四氢呋喃-3-基甲氧基、四氢吡喃-4-基甲氧基、氧杂环丁烷-3-基甲氧基、和吡咯烷-3-基甲氧基;
R3选自H、和环丙基甲酰氨基;
其中R1、R2和R3不同时为H;
R4选自三氟甲基、2-氰基乙-2-基、和2-氰基丙-2-基;
R5选自H、甲基、和4-甲基-哌嗪-1-基甲基。
9.根据权利要求6所述的激酶抑制剂,其中R1选自3-吡啶基、4-吡啶基、N-吗啉基、杂环烷基氧基、杂环烷基C1-6烷氧基、和C1-6烷基氨基羰基C1-6烷氧基;R4选自C1-6卤代烷基、和C1-6氰基烷基;R2、R3和R5均为H。
10.根据权利要求6所述的激酶抑制剂,其中R2选自C1-6羟基烷氧基、C1-6烷氧基C1-6烷氧基、杂环烷基氧基、和杂环烷基C1-6烷氧基;R4选自C1-6卤代烷基、和C1-6氰基烷基;R1、R3和R5均为H。
12.一种药物组合物,其包括如权利要求1-11中任一项所述的激酶抑制剂、和药学上可接受的载体或赋形剂、以及任选的其它治疗剂。
13.如权利要求1-11中任一项所述的激酶抑制剂在制备用于抑制酪氨酸激酶RAF和/或RAS活性的药物中的用途。
14.如权利要求1-11中任一项所述的激酶抑制剂在制备用于治疗、预防或改善由酪氨酸激酶RAF和/或RAS活性调节的或者受其影响的或者其中涉及酪氨酸激酶RAF和/或RAS活性的疾病、障碍或病症的药物中的用途。
15.如权利要求14所述的用途,其中所述疾病、障碍或病症选自以下增殖性疾病:实体瘤、肉瘤、胃肠道间质瘤、结直肠癌、急性粒细胞白血病、慢性髓性白血病、甲状腺癌、系统性肥大细胞病、嗜酸性粒细胞增多综合征、纤维变性、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、睾丸上皮内瘤形成、黑色素瘤、乳癌、神经母细胞瘤、乳头状/滤泡型甲状腺癌、恶性淋巴瘤、非霍奇金淋巴瘤、2型多发性内分泌瘤形成、嗜铬细胞瘤、甲状腺癌、甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、瘤形成或其组合。
16.如权利要求14所述的用途,其中所述疾病、障碍或病症选自以下增殖性疾病:头颈癌、甲状腺癌、黑色素瘤、结直肠癌、肺癌、乳腺癌、胰腺癌、食管癌、肝癌、白血病、瘤形成或其组合。
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