CN112574207B - Erk1/2蛋白激酶抑制剂及其用途 - Google Patents
Erk1/2蛋白激酶抑制剂及其用途 Download PDFInfo
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- CN112574207B CN112574207B CN201910942430.8A CN201910942430A CN112574207B CN 112574207 B CN112574207 B CN 112574207B CN 201910942430 A CN201910942430 A CN 201910942430A CN 112574207 B CN112574207 B CN 112574207B
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- amino
- chloro
- pyrimidin
- hydroxyethyl
- triazin
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Abstract
本发明提供一种由式(Ⅰ)表示的化合物,或其异构体、药学上可接受的盐,以及其用于制备ERK1/2介导的疾病药物的用途。
Description
技术领域
本发明属于化学医药领域,具体涉及一种ERK1/2蛋白激酶抑制剂及其用途。
背景技术
细胞外信号调节激酶(ERK1/2)是广泛表达的蛋白丝氨酸/苏氨酸激酶,是丝裂原活化蛋白激酶(MAPK)家族的重要亚族之一。MAPK通路是进化保守的细胞信号通路,调节各种细胞过程,包括细胞周期进程、细胞迁移、细胞生存、分化、代谢、增殖和转录。ERK/MAPK信号通路对细胞表面受体酪氨酸激酶(RTK)的细胞外刺激做出响应。激活RTK时,RAS GTP酶(K-RAS、N-RAS和H-RAS)从未活化GDP-结合状态转化为活化的GTP-结合状态。活化的RAS通过磷酸化下游RAF effector蛋白,从而激活RAF(A-RAF、B-RAF和C-RAF)的激酶活性,它们转而又磷酸化,激活双特异性激酶MEK(MEK1/2)。然后,活化的MEK磷酸化,并激活ERK1/2。磷酸化激活的ERK1/2由胞质转位到核内,进而介导Elk-1,ATF,NF-κB,Ap-1,c-fos和c-Jun的转录活化,参与多种生物学反应,包括细胞增殖与分化、细胞形态维持、细胞骨架的构建、细胞凋亡和细胞的恶变等。
ERK及其信号途径在肿瘤侵袭和转移过程中起中介和放大信号的作用,在许多人类的癌症中都可以发现ERK信号通路上多个蛋白突变引起的异常激活而最终导致ERK激酶活性的过度激活。大约30%的人类癌症包含活化RAS突变(Roberts and Der,Oncogene.2007;26:3291-3310)。KRAS是最常见的突变亚型,在22%的肿瘤中突变。KRAS突变在胰腺癌(70~90%)、非小细胞肺癌(10~20%)和结肠直肠癌(25~35%)中尤其普遍(Neuzilletetal.,2014.Pharmacol.Ther.141;160-171)。分别在8%和3%的癌症中出现N-RAS突变和H-RAS突变(Prior et al.,Cancer Res.2012;72(10);2457-2467)。值得指出的是,据报道,15-20%的黑色素瘤病例存在活化N-RAS突变。此外,所有肿瘤中有8%出现B-RAF突变,B-RAF绝大部分突变形式为B-RAFV600E突变,这种突变在黑色素瘤(50-60%)、乳头状甲状腺癌(40~60%)、结肠直肠癌(5~10%)和非小细胞肺癌(3~5%)中尤其普遍存在(Neuzillet et al.,2014.Pharmacol.Ther.141;160-171),这使得B-RAF可以不需要RAS磷酸化激活而处于持续活化的状态。目前已有多个特异性靶向B-RAFV600E突变的抗肿瘤药物上市,在黑色素瘤等疾病领域表现出良好的疗效。然而目前为止尚无针对作为整个MAPK信号通路最下游的关键激酶ERK的特异性靶向药物上市。另外一方面,目前已经上市的所有靶向B-RAFV600E突变药物均在治疗不到一年的时间内出现了较为严重的的耐药性。大量临床研究表明,除常见的耐药突变以外,ERK激酶活性的异常重新激活是此类药物耐药的重要机理。因此开发新型特异性ERK抑制剂既可以作为一种新型抗肿瘤药物,与此同时又可以作为多种B-RAFV600E突变抑制剂药物耐药后的二线药物,在抗肿瘤治疗中有着非常重要的临床和市场价值。
临床进展较快的ERK1/2抑制剂如Ulixertinib(Phase II)、ASTX-029等已显示出良好的生物学活性。然而Ulixertinib在药物代谢方面的缺陷导致较高的临床剂量以及更为频繁的给药方式对其进一步临床开发带来了较大限制。而ASTX-029对B-RAF野生型肿瘤细胞增殖的抑制活性也较强,进而有可能在临床上表现出较强的毒性。
发明内容
本发明公开了一类可作为ERK1/2蛋白激酶抑制剂的化合物以及其在制备ERK2介导的疾病药物中的用途。
一方面,本发明提供式(Ⅰ)化合物:
或其异构体、药学上可接受的盐;
其中,X和Y分别独立的选自C或N;
R1选自C1-6烷基、3元至9元环烷基、包含1-3个N或O的3元至9元杂环烷基、芳基、包含1-3个N或O的5元至6元杂芳基;所述烷基、环烷基、杂环烷基、芳基、杂芳基可选的被一个或多个R6取代,R6选自C1-6烷基,卤素、羟基、羰基、氨基、氰基、烷氧基、-(CH2)nCOOH、-(CO)(CH2)nCH3;
R2选自氢、卤素、烷氧基或可选的被一个或多个氟原子取代的C1-6烷基;
R3选自可选的被0-3个R7取代的芳基或5至6元杂芳基,R7选自卤素、烷氧基、可选的被一个或多个氟原子取代的C1-6烷基;
R4选自-(CH2)n OH、-COOH;
R5选自C1-6烷基;
每个n各自独立的为0-3之间的整数。
在一些实施方案中,式(Ⅰ)是式(Ⅰa):
其中:R2选自氢、卤素或可选的被一个或多个氟原子取代的C1-6烷基;R3选自可选的被0-3个R7取代的芳基,R7选自卤素、烷氧基、可选的被一个或多个氟原子取代的C1-6烷基;R4为-(CH2)n OH;每个n各自独立的为0-3之间的整数。
在另一些实施方案中,式(Ⅰ)是式(Ⅰb):
R2选自氢、氯或三氟甲基;R7选自卤素、甲基、甲氧基或三氟甲基;R1、X、Y具有前述定义的含义。
在另一些实施方案中,式(Ⅰb)是式(Ⅰb-1):
其中R1、R2、R7具有前述所定义的含义。
在另一些实施方案中,式(Ⅰb)是式(Ⅰb-2):
其中R1、R2、R7具有前述所定义的含义。
在另一些实施方案中,式(Ⅰb)是式(Ⅰb-3):
其中R1、R2、R7具有前述所定义的含义。
在另一些实施方案中,式(Ⅰb)是式(Ⅰb-4):
其中R1、R2、R7具有前述所定义的含义。
前述杂环烷基即单环或多环(包括2个或更多个稠合在一起的环,包括螺、稠合或桥连系统,例如双环系统)、饱和或不饱和的非芳族4至15元环系统,包含1至14个成环碳原子和1至10个成环杂原子,所述成环杂原子彼此独立地选自O、S、N、P和B。杂环烷基基团还可任选地含有一个或多个氧代(即,=O)或硫羰(即,=S)基团。例如,4至12元杂环烷基是单环或多环、饱和或不饱和的非芳族4至12元环系统,其包含一个或多个成环杂原子。
前述芳基即具有共轭π电子系统的全碳单环或稠环多环芳族基团。芳基基团在一个或多个环中可具有6至10个碳原子。最常见的是,芳基基团在环中具有6个碳原子。例如,C6-10芳基是含有6至10个碳原子的芳族基团,例如苯基或萘基。
前述杂芳基,即在至少一个环中具有一个或多个杂原子环成员(成环原子)的单环或稠环多环芳族杂环基团,所述杂原子环成员彼此独立地选自O、S和N。杂芳基基团具有5至14个成环原子,包括1至13个碳原子和1至8个选自O、S和N的杂原子。在一些实施方案中,杂芳基基团具有5至10个成环原子,包括一至四个杂原子。杂芳基基团还可含有一至三个氧代或硫羰(即,=S)基团。在一些实施方案中,杂芳基基团具有5至8个成环原子,包括一个、两个或三个杂原子。例如,5元杂芳基基团是如上定义的单环杂芳基基团,在单环杂芳基环中具有5个成环原子;6元杂芳基是如上定义的单环杂芳基基团,在单环杂芳基环中具有6个成环原子;5~10元杂芳基是如上定义的单环或双环杂芳基基团,在单环或双环杂芳基环中具有5、6、7、8、9或10个成环原子。
在另一些实施方案中,所述化合物是以下化合物中的一种:
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)吡啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺;
(R)-N-((S)-2-羟基-1-(间甲苯基)乙基)-2-(4-氧代-6-(2-((四氢-2H-吡喃-4-基)氨基)-5-(三氟甲基)嘧啶-4-基)吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)丙酰胺;
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(3-(三氟甲基)苯基)乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3,5-二甲基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3,5-二甲基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-苯乙基)丙酰胺;
(S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-苯乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((4,4-二氟环己基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺;
(S)-2-(6-(5-氯-2-((4,4-二氟环己基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺;
(2R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-(1-(3-氯苯基)-2-羟乙基)丙酰胺;
(2S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-(1-(3-氯苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-(异丙基氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(异丙基氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2-(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2-(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(2R)-2-(6-(2-((8-氧杂双环[3.2.1]辛-3-基)氨基)-5-氯嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(2S)-2-(6-(2-((8-氧杂双环[3.2.1]辛-3-基)氨基)-5-氯嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-(((R)-3,3-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(((R)-3,3-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((2-氯-4-氟苯基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氯-5-氟苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-((2-氯-4-氟苯基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氯-5-氟苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-(((R)-2,2-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(((R)-2,2-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(4-氧代-6-(2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)丙酰胺;
(R)-2-(6-(5-氯-2-(((3S,4R)-3-甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(((3S,4R)-3-甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-(((1S,3R)-3-羟基环戊基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(((1S,3R)-3-羟基环戊基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((3,3-二氟环)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-((3,3-二氟环)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(6-(5-甲基-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)丙酰胺;
(S)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(6-(5-甲基-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)丙酰胺;
2-(6-(5-氯-2-((1-甲基-2-氧代哌啶-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
2-(6-(2-((1-乙酰基哌啶-4-基)氨基)-5-氯嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3-(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-(((1r,4R)-4-甲氧基环己基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(((1r,4S)-4-甲氧基环己基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
2-(6-(5-氯-2-(((3S,4R)-3-甲氧基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
2-(6-(5-氯-2-(((3S,4R)-3-羟基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-(((3R,4R)-3-羟基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(((3R,4R)-3-羟基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(7-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
2-(3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环丁基)乙酸;
4-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环己烷-1-羧酸;
(1R,3S)-3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环己烷-1-羧酸;
(1R,3S)-3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环戊烷-1-羧酸;
3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙烷-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环丁烷-1-羧酸;
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺;
(R)-2-(7-(5-氯-2-(异丙基氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(2R)-2-(7-(5-氯-2-((3,3-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(2R)-2-(7-(5-氯-2-((2,2-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(7-(5-氯-2-(((3R,4R)-3-甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(1-氧代-7-(2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺;
(R)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2-(1H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺;
(R)-2-(7-(5-氯-2-(((1S,3R)-3-羟基环戊基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2-(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺。
前述化合物可用于制备预防或治疗ERK2介导的疾病药物,所述ERK2介导的疾病为癌症,具体可以为非小细胞肺癌、胰腺癌、结肠癌、胃癌、淋巴瘤或黑色素瘤。
在一些实施方案中,化合物可作为立体异构体,诸如阻转异构体、外消旋体、对映异构体或非对映异构体存在。用于制备/分离单个对映异构体的常规技术包括从合适的光学纯前体手性合成或使用例如手性高效液相色谱法(HPLC)拆分外消旋体。可替代地,外消旋体(或外消旋前体)可与合适的光学活性化合物(例如,乙醇)反应,或在化合物含有酸性或碱性部分的情况下,与酸或碱(诸如酒石酸或1-苯基乙胺)反应。所得的非对映异构体混合物可通过色谱法和/或分级结晶分离,并且非对映异构体中的一者或两者可通过本领域技术人员熟知的手段转化为一种或多种对应的纯对映异构体。手性化合物(及其手性前体)可使用色谱法(通常为HPLC)在具有流动相的不对称树脂上以对映异构体富集形式获得,所述流动相由烃(通常为庚烷或己烷)组成,含有0%至50%2-丙醇(通常为2%至20%)和0%至5%烷基胺(通常为0.1%二乙基胺)。浓缩洗脱液得到富集的混合物。立体异构体聚集体20可通过本领域技术人员已知的常规技术来分离。合适的立体选择性技术是本领域普通技术人员熟知的。对于含有烯基或亚烯基基团的式(I)的化合物,几何顺式/反式(或Z/E)异构体是可能的。顺式/反式异构体可通过本领域技术人员熟知的常规技术分离,例如色谱法和分级结晶。
本发明还提供一种药物组合物,其包含治疗有效量的式(I)的化合物或其药学上可接受的盐、异构体;药学上可接受的载体或赋形剂。药学上可接受的载体或赋形剂可包含任何常规药物载体或赋形剂。合适的药物载体包括惰性稀释剂或填充剂、水以及各种有机溶剂诸如水合物和溶剂。如果需要,药物组合物可含有另外的成分,诸如调味剂、粘合剂、赋形剂等。
本发明还提供一种式(Ⅱ)化合物:
其中,R8选自卤素、硼酸基或频那醇硼烷基;R9选自C1-6烷基;Y选自C或N。
在一些实施方案中,式(Ⅱ)可以是式(Ⅱa):
R8选自卤素、硼酸基或频那醇硼烷基;R9选自C1-6烷基;Y选自C或N。
在一些实施方案中,R8选自氟、氯、溴、碘、硼酸基或频那醇硼烷基,R9选自甲基、乙基、异丙基或正丁基;Y选自C或N。
本发明还提供一种式(Ⅲ)化合物:
其中,R11选自卤素或-NHR1,R10选自氢或C1-6烷基;X、Y、R1、R2具有前述所定义的含义。
在一些实施方案中,式(Ⅲ)是式(Ⅲa):
R11选自卤素或-NHR1,R10选自氢或C1-6烷基;X、Y、R1、R2具有权利要求1所定义的含义。
在一些实施方案中,R11选自氟、氯、溴、碘或-NHR1;R10选自氢、甲基、乙基、异丙基或正丁基;X、Y、R1、R2具有权利要求1所定义的含义。
所述式(Ⅱ)、式(Ⅱa)、式(Ⅲ)、式(Ⅲa)化合物可用于制备前述式(Ⅰ)化合物。
本发明提供的化合物具有明显的ERK抑制剂活性,良好的细胞增殖抑制活性,可同时抑制EKR1/2及下游通路的磷酸化,相对于阳性药具有明显的细胞选择性及药物代谢动力学性质的优势。
具体实施方式
本发明所涉及化合物可参考如下通用方法制得:方法I
试剂和条件:(a)2,4-二硝基苯基羟胺,NaH,DMF,0℃;(b)N,N-二甲基甲酰胺二甲基缩醛,60℃,3h;(c)LiOH,THF/H2O,60℃;(d)(R)-2-叔丁基-2-氨基丙酸盐酸盐,HATU,DIPEA,DMF;(e)乙酸/乙腈,70℃;(f)联硼频哪醇酯,乙酸钾,Pd(dppf)Cl2,二氧六环,90℃;(g)2,4-二氯-5-R2-嘧啶,Na2CO3,Pd(dppf)Cl2,二氧六环,90℃;(h)TFA,DCM;(i)NH2R1,Na2CO3,二氧六环,90℃或NH2R1,Pd2(dba)3,Xantphos,Cs2CO3,二氧六环,100℃;(j)HATU,DIPEA,DMF,NHR3R4。
上述合成方法I主要用于合成4-氧代吡咯并[2,1-f][1,2,4]三嗪类分子,其中当R1为烷基或者环烷基类分子时合成方法为NH2R1,Na2CO3,二氧六环,90℃,当R1为芳基或杂环芳基时合成成方法为NH2R1,Pd2(dba)3,Xantphos,Cs2CO3,二氧六环,100℃。
方法II
试剂和条件:(a)2-溴-1,1-二乙氧基乙烷,NaH,DMF;(b)LiOH,THF/H2O,60℃;(c)(R)-2-叔丁基-2-氨基丙酸盐酸盐,HATU,DIPEA,DMF;(d)乙酸/乙腈,70℃;(e)联硼频哪醇酯,乙酸钾,Pd(dppf)Cl2,二氧六环,90℃;(f)2,4-二氯-5-R2-嘧啶,Na2CO3,Pd(dppf)Cl2,二氧六环,90℃;(g)TFA,DCM;(h)NH2R1,Na2CO3,二氧六环,90℃或NH2R1,Pd2(dba)3,Xantphos,Cs2CO3,二氧六环,100℃;(i)HATU,DIPEA,DMF,NHR3R4。
上述合成方法II主要用于合成1-氧代吡咯并[1,2-a]吡嗪类分子,其中当R1为烷基或者环烷基类分子时合成方法为NH2R1,Na2CO3,二氧六环,90℃,当R1为芳基或杂环芳基时合成成方法为NH2R1,Pd2(dba)3,Xantphos,Cs2CO3,二氧六环,100℃。
方法Ⅲ
试剂和条件:(a)2-溴丙酸叔丁酯,NaH,DMF,0℃;(b)联硼频哪醇酯,乙酸钾,Pd(dppf)Cl2,二氧六环,90℃;(c)2,4-二氯-5-R2-嘧啶,Na2CO3,Pd(dppf)Cl2,二氧六环,90℃;(d)TFA,DCM;(e)NH2R1,Na2CO3,二氧六环,90℃或NH2R1,Pd2(dba)3,Xantphos,Cs2CO3,二氧六环,100℃;(f)HATU,DIPEA,DMF,NHR3R4
上述合成方法III主要用于合成消旋4-氧代吡咯并[2,1-f][1,2,4]三嗪类分子,通过制备分离后可以获得单一构型,其中当R1为烷基或者环烷基类分子时合成方法为NH2R1,Na2CO3,二氧六环,90℃,当R1为芳基或杂环芳基时合成成方法为NH2R1,Pd2(dba)3,Xantphos,Cs2CO3,二氧六环,100℃。
实施例1(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物1)
在0℃下,向4-溴-2-甲氧羰基吡咯(10.00g,48.80mmol,1.00eq.)的DMF(500mL)溶液中,加入NaH(11.66g,58.56mmol,1.20eq.),搅拌30分钟,加入2,4-二硝基苯基羟胺(11.66g,58.56mmol,1.20eq.),加完在室温下搅拌12小时。用水和乙酸乙酯稀释反应。分离各相,水相用乙酸乙酯(2×200mL)萃取。合并的有机提取物用饱和氯化钠(200mL)洗涤,MgSO4干燥,并浓缩至干,得到中间体1.1(10.9g,94.3%产率)。
将中间体1.1(10.00g,50.22mmol,1.00eq.)加入N,N-二甲基甲酰胺二甲基缩醛(150mL)中,然后在60℃下搅拌3小时。用TLC监测反应完成后,浓缩溶剂,得到中间体1.2(11.0g,88%收率),为棕色油状物,未经进一步纯化,直接用于下一步骤。1H NMR(400MHz,DMSO-d6)δ(ppm)7.95(s,1H),7.16(d,J=2.2Hz,1H),6.75(d,J=2.2Hz,1H),3.68(s,3H),2.92(d,J=32.9Hz,6H)。
将中间体1.2(11.00g,40.13mmol,1.00eq.)置于THF/水混合物(100mL/50mL)中并向其中加入LiOH.H2O(5.05g,120.39mmol,3.00eq.)。然后搅拌混合物并加热至60℃保持12小时。用TLC确认反应完成后,真空除去溶剂,用1.5N HCl将残余物中和至pH 6~7。过滤白色固体,用水洗涤并干燥得中间体1.3(7g,产率67.3%)。1H NMR(400MHz,DMSO-d6)δ(ppm)12.75(s,1H),8.09(s,1H),7.26(d,J=2.2Hz,1H),6.72(d,J=2.2Hz,1H),2.94(d,J=46.4Hz,6H)。
向中间体1.3(3.00g,11.53mmol,1.00eq.)的DMF(100mL)的溶液中加入(R)-2-叔丁基-2-氨基丙酸盐酸盐(2.30g,12.68mmol,1.10eq.)和DIPEA(4.47g,34.59mmol,3.00eq.)。搅拌15分钟后,加入HATU(4.82g,12.68mmol,1.10eq.),并将混合物在室温下搅拌1小时。将反应用水(300mL)和EtOAc(150mL)稀释。分离各相,水相用EtOAc(3×100mL)萃取。将合并的有机萃取液用盐水(200mL)洗涤。将醚溶液干燥(MgSO4),过滤并浓缩,得到中间体1.4(3.5g,78.4%产率),为黄色固体,其未进一步纯化并直接用于下一步骤。1H NMR(400MHz,DMSO-d6)δ(ppm)9.03(d,J=7.0Hz,1H),8.28(s,1H),7.38(d,J=2.2Hz,1H),6.63(d,J=2.2Hz,1H),4.34(p,J=7.1Hz,1H),3.00(d,J=36.9Hz,6H),1.42(s,9H),1.34(d,J=7.1Hz,3H).
将中间体1.4(3.50g,9.04mmol,1.00eq.)置于乙腈(20mL)和乙酸(10mL)的混合溶液中,将混合物在70℃下搅拌12小时。将反应用水(50mL)和EtOAc(50mL)稀释。分离各相,水相用EtOAc(3×50mL)萃取。用NaHCO3(3×50mL)洗涤合并的有机萃取物。将有机相用MgSO4干燥,过滤,并浓缩至干。通过柱层析(硅胶,PE/EA=10/1~3/1)纯化残余物,得到中间体1.5(1.8g,60%产率),为类白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm)8.19(s,1H),7.90(d,J=1.8Hz,1H),7.08(d,J=1.8Hz,1H),5.11(d,J=7.3Hz,1H),1.61(d,J=7.3Hz,3H),1.39(s,9H)。
将中间体1.5(1.80g,5.26mmol,1.00eq.)的二氧六环(30.0mL)溶液中加入联硼频哪醇酯(1.60g,6.31mmol,1.20eq.),乙酸钾(1.55g,15.78mmol,3.00eq.)和Pd(dppf)Cl2(0.38g,0.53mmol,0.10eq.)。将反应加热至90℃并在氮气下搅拌6小时,冷却至室温后,真空除去溶剂,将残余物在EtOAc(100mL)和水(100mL),收集有机相并用盐水(100mL)洗涤。将有机溶液用MgSO4干燥,过滤,并浓缩至干。通过柱层析(硅胶,PE/EA=10/1~3/1)纯化残余物,得到中间体1.6(1.1g,53.9%产率),为类白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm)8.14(s,1H),7.77(d,J=1.6Hz,1H),7.04(d,J=1.6Hz,1H),5.12(d,J=7.3Hz,1H),2.26–2.20(m,1H),1.61(d,J=7.3Hz,3H),1.39(s,9H),1.29(s,12H)。
将中间体1.6(1.10g,15.49mmol,1.00eq.),2,4,5-三氯嘧啶(0.78g,4.25mmol,1.50eq.),Pd(dppf)Cl2(0.38g,0.53mmol,0.10eq.)和2.0M Na2CO3(2.8mL,5.66mmol,2.00eq.)加入到20mL二氧六环中,将混合物加热至90℃搅拌6小时。将反应用水(60mL)和EtOAc(30mL)稀释。分离各相,水相用EtOAc(2×50mL)萃取。将合并的有机萃取液用盐水(50mL)洗涤,将有机溶液用MgSO4干燥,过滤,并浓缩至干。通过柱层析(硅胶,PE/EA=10/1~3/1)纯化残余物,得到中间体1.7(0.8g,72.7%产率),为类白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm)δ8.91(s,1H),8.50(d,J=1.9Hz,1H),8.32(s,1H),7.68(d,J=1.9Hz,1H),5.16(d,J=7.3Hz,1H),1.64(d,J=7.3Hz,3H),1.41(s,9H)。
将三氟乙酸(333.51mg,29.25mmol,15.00eq.)滴加到中间体1.7(800.00mg,1.95mmol,1.00eq.)的DCM(10mL)溶液中,并将混合物在室温下搅拌12小时,将混合物浓缩至干,得到中间体1.8(650mg,94.2%产率),为无色油状物。其未进一步纯化并直接用于下一步骤。
将中间体1.8(650.00mg,1.84mmol,1.00eq.),4-氨基四氢吡喃盐酸盐(759.83mg,5.52mmol,3.00eq.)和碳酸钠(2M,3.7mL,7.36mmol,4.00eq.)加入到20mL二氧六环中,将混合物加热至90℃搅拌6小时。冷却反应,加入盐酸(1M水溶液,2mL),立即形成浓稠的无色沉淀。过滤浆液,滤饼用水(20mL)洗涤。将所得固体在40℃下真空干燥,得到中间体1.9(600.00mg,77.9%产率),为黄色固体。
将DIPEA(279.16mg,2.16mmol,3.00eq.)加入到中间体1.9(300.00mg,0.72mmol,1.00eq.)和(2S)-2-氨基-2-(5-氟-3-甲氧基苯基)乙-1-醇(146.68mg,0.79mmol,1.10eq.)的DMF(20mL)溶液中。搅拌15分钟后,加入HATU(300.38mg,0.79mmol,1.10eq.),并将混合物在室温下搅拌1小时。将反应用水(60mL)和EtOAc(30mL)稀释。分离各相,水相用EtOAc(2×50mL)萃取。将合并的有机萃取液用盐水(50mL)洗涤,用MgSO4干燥并浓缩。通过柱层析硅胶,DCM/MeOH=50/1~20/1)纯化残余物,得到化合物1(200mg,47.6%产率),为类白色固体。MS:[M+H]+=586/588。1H NMR(400MHz,DMSO-d6)δ(ppm)8.82(s,1H),8.46–8.07(m,3H),7.61(d,J=1.6Hz,1H),6.88–6.55(m,3H),5.52(d,J=7.4Hz,1H),4.97(t,J=5.5Hz,1H),4.82(d,J=7.1Hz,1H),3.92(dd,J=29.5,9.1Hz,3H),3.77(s,3H),3.57(s,2H),3.43(s,1H),1.81(dd,J=43.1,11.4Hz,2H),1.62(t,J=11.9Hz,3H),1.53(ddd,J=15.5,12.5,4.2Hz,2H)。
实施例2(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)吡啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺(化合物2)
搅拌下,将5-氯-2-氟-4-碘吡啶(3.00g,11.65mmol,1.00eq.)和4-氨基四氢吡喃盐酸盐(3.21g,23.30mmol,2.00eq.)溶于30mL乙醇中。加入N,N-二异丙基乙胺(4.52g,34.95mmol,3.00eq.)在90℃反应12小时。将反应用水稀释并用EtOAc萃取。将合并的有机层用饱和盐水洗涤,经MgSO4干燥,并浓缩至干。通过柱色谱(硅胶,PE/EtOAc=5/1~3/1)纯化残余物,得到中间体2.1(2.50g,64%产率),为白色固体。
中间体2.2使用实施例1中化合物1.7相似的合成步骤,以中间体2.1作为起始原料制得。MS:[M+H]+=552/554。1H NMR(400MHz,DMSO-d6)δ(ppm)8.22(s,1H),8.10–7.87(m,2H),7.27(d,J=1.8Hz,1H),6.72(s,1H),6.67(d,J=7.7Hz,1H),5.15(q,J=7.3Hz,1H),3.90(ddd,J=11.4,9.2,5.1Hz,3H),3.57–3.35(m,2H),1.96–1.78(m,2H),1.63(d,J=7.3Hz,3H),1.53–1.48(m,1H),1.41(s,9H)。
化合物2使用实施例1中化合物1相似的合成步骤,以中间体2.2作为起始原料制得。MS:[M+H]+=552/554。1H NMR(400MHz,DMSO-d6)δ(ppm)8.73(dd,J=42.9,8.1Hz,1H),8.16(d,J=10.1Hz,1H),8.04(dd,J=5.2,2.9Hz,2H),7.37–7.12(m,2H),7.17–6.92(m,3H),6.69(dd,J=10.0,4.5Hz,2H),5.64–5.37(m,1H),4.99–4.87(m,1H),4.79(dt,J=8.1,4.0Hz,1H),3.56(dt,J=8.5,5.4Hz,2H),3.41(t,J=11.5Hz,2H),2.29(d,J=12.5Hz,3H),1.87(d,J=12.5Hz,2H),1.63(dd,J=19.4,7.4Hz,3H),1.53–1.31(m,2H)。
实施例3(R)-N-((S)-2-羟基-1-(间甲苯基)乙基)-2-(4-氧代-6-(2-((四氢-2H-吡喃-4-基)氨基)-5-(三氟甲基)嘧啶-4-基)吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)丙酰胺(化合物3)
中间体3.1使用实施例2中化合物2.1相似的合成步骤,以起始原料2,4-二氯-5-(三氟甲基)嘧啶制得。1H NMR(400MHz,DMSO-d6)δ(ppm)8.60(dd,J=18.5,7.9Hz,2H),4.11–3.91(m,1H),3.97–3.76(m,2H),3.54–3.34(m,2H),1.80(dd,J=12.5,2.0Hz,2H),1.69–1.40(m,2H)。
化合物3使用实施例2中化合物2相似的合成步骤,以中间体3.1作为起始原料制得。MS:[M+H]+=586。1H NMR(400MHz,DMSO-d6)δ(ppm)8.79(d,J=6.0Hz,1H),8.63(d,J=22.5Hz,1H),8.22(s,1H),8.04(dd,J=27.7,20.4Hz,2H),7.32(s,1H),7.22(t,J=7.5Hz,1H),7.17–6.86(m,3H),5.53(q,J=7.1Hz,1H),4.92(t,J=5.4Hz,1H),4.80(d,J=6.6Hz,1H),4.06(dd,J=16.9,9.8Hz,1H),3.89(d,J=11.4Hz,2H),3.55(t,J=6.7Hz,2H),3.51–3.35(m,2H),2.30(s,3H),1.86(t,J=13.0Hz,2H),1.59(t,J=13.3Hz,3H),1.27(d,J=13.5Hz,3H)。
实施例4(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(3-(三氟甲基)苯基)乙基)丙酰胺(化合物4)
化合物4使用实施例1中化合物1相似的合成步骤,以(2S)-2-氨基-2-(3-三氟甲基-苯基)-乙醇作为起始原料制得。MS:[M+H]+=606/608。1H NMR(400MHz,DMSO-d6)δ(ppm)8.95(d,J=8.0Hz,1H),8.45–8.25(m,2H),8.19(d,J=21.8Hz,1H),7.68(s,1H),7.65–7.52(m,3H),7.41(d,J=7.7Hz,1H),5.51(dd,J=14.9,7.5Hz,1H),5.03(t,J=5.4Hz,1H),4.94(dd,J=13.8,6.0Hz,1H),4.11–3.90(m,1H),3.89(d,J=11.1Hz,1H),3.60(dd,J=14.1,8.3Hz,1H),3.43(s,1H),1.91–1.70(m,1H),1.66–1.54(m,1H),1.62–1.40(m,2H)。
实施例5(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3,5-二甲基苯基)-2-羟乙基)丙酰胺(化合物5A)和(S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3,5-二甲基苯基)-2-羟乙基)丙酰胺(化合物5B)
将DIPEA(279.16mg,2.16mmol,3.00eq.)加入到中间体1.9(300.00mg,0.72mmol,1.00eq.)和(2S)-2-氨基-2-(3,5-二甲基苯基)乙-1-醇(130.54mg,0.79mmol,1.10eq.)的DMF(20mL)溶液中。搅拌15分钟后,加入HATU(300.38mg,0.79mmol,1.10eq.),并将混合物在室温下搅拌1小时。将反应用水(60mL)和EtOAc(30mL)稀释。分离各相,水相用EtOAc(2×50mL)萃取。将合并的有机萃取液用盐水(50mL)洗涤,用MgSO4干燥并浓缩。通过柱层析硅胶,DCM/MeOH=50/1~20/1)纯化残余物,得到5A(50mg,12.3%产率,Rf=0.4,EA),为类白色固体。MS:[M+H]+=566/568。1H NMR(400MHz,DMSO-d6)δ(ppm)8.75(d,J=8.0Hz,1H),8.33(d,J=20.4Hz,2H),8.22(d,J=4.6Hz,1H),7.60(dd,J=5.9,1.8Hz,1H),7.40(d,J=7.7Hz,1H),6.89(d,J=10.3Hz,3H),5.52(q,J=7.3Hz,1H),4.88(t,J=5.5Hz,1H),4.75(dd,J=13.3,7.3Hz,1H),4.02(dt,J=17.0,8.5Hz,1H),3.87(dd,J=21.5,13.5Hz,2H),3.63–3.48(m,2H),3.43(s,2H),2.31–2.19(m,3H),2.51(s,6H),1.86(d,J=10.6Hz,2H),1.59(t,J=11.9Hz,3H),1.53(dd,J=11.8,3.7Hz,2H)。
经过柱层析纯化上述残余物,得到5B(40mg,9.8%产率,Rf=0.3,EA),为类白色固体。MS:[M+H]+=566/568。1H NMR(400MHz,DMSO-d6)δ(ppm)8.64(d,J=8.2Hz,1H),8.33(d,J=19.1Hz,2H),8.18(s,1H),7.58(d,J=1.8Hz,1H),7.39(t,J=9.4Hz,1H),6.87(d,J=15.6Hz,3H),5.46(q,J=7.3Hz,1H),4.88(t,J=5.6Hz,1H),4.75(dd,J=13.4,7.5Hz,1H),3.97(s,1H),3.88(d,J=11.4Hz,2H),3.55(qd,J=11.0,5.8Hz,2H),3.42(s,2H),2.24(d,J=12.5Hz,4H),2.51(s,6H),1.86(d,J=10.1Hz,2H),1.65(d,J=7.4Hz,3H),1.53(dd,J=20.1,9.2Hz,2H)。
实施例6(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-苯乙基)丙酰胺(化合物6A)和(S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-苯乙基)丙酰胺(化合物6B)
将DIPEA(279.16mg,2.16mmol,3.00eq.)加入到中间体1.9(300.00mg,0.72mmol,1.00eq.)和(2S)-2-氨基-2-苯基乙-1-醇(72.49mg,0.79mmol,1.10eq.)的DMF(20mL)溶液中。搅拌15分钟后,加入HATU(300.38mg,0.79mmol,1.10eq.),并将混合物在室温下搅拌1小时。将反应用水(60mL)和EtOAc(30mL)稀释。分离各相,水相用EtOAc(2×50mL)萃取。将合并的有机萃取液用盐水(50mL)洗涤,用MgSO4干燥并浓缩。通过柱层析硅胶,DCM/MeOH=50/1~20/1)纯化残余物,得到6A(40mg,9.5%产率,Rf=0.35,EA),为类白色固体。MS:[M+H]+=538/540。1H NMR(400MHz,DMSO-d6)δ(ppm)8.83(d,J=8.0Hz,1H),8.33(d,J=20.8Hz,2H),8.21(s,1H),7.61(d,J=1.7Hz,1H),7.49–7.11(m,6H),5.67–5.45(m,1H),4.93(t,J=5.5Hz,1H),4.92–4.74(m,1H),4.01(dd,J=18.3,11.1Hz,1H),3.89(d,J=11.2Hz,2H),3.57(dd,J=9.1,4.1Hz,2H),3.43(s,2H),1.87(d,J=11.4Hz,2H),1.67–1.55(m,3H),1.59–1.46(m,2H)。
经过柱层析纯化上述残余物,得到6B(40mg,9.5%产率,Rf=0.3,EA),为类白色固体。MS:[M+H]+=538/540。1H NMR(400MHz,DMSO-d6)δ(ppm)8.72(d,J=8.1Hz,1H),8.32(d,J=20.7Hz,2H),8.20(s,1H),7.58(d,J=1.6Hz,1H),7.49–7.12(m,6H),5.48(q,J=7.3Hz,1H),4.91(dd,J=17.9,12.4Hz,1H),4.84(dd,J=13.5,7.4Hz,1H),4.01(dd,J=20.1,12.9Hz,1H),3.88(d,J=11.2Hz,2H),3.69–3.52(m,2H),3.42(s,2H),1.86(d,J=11.2Hz,2H),1.64(t,J=20.0Hz,3H),1.60–1.44(m,2H)。
实施例7(R)-2-(6-(5-氯-2-((4,4-二氟环己基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺(化合物7A)和(S)-2-(6-(5-氯-2-((4,4-二氟环己基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺(化合物7B)
化合物7A使用实施例1中化合物1.8及实施例5中化合物5A相似的合成步骤,以4,4-二氟环己胺盐酸盐作为起始原料制得。MS:[M+H]+=586/588。1H NMR(400MHz,DMSO-d6)δ(ppm)8.79(d,J=8.0Hz,1H),8.36(s,2H),8.21(s,1H),7.64(s,1H),7.43(d,J=7.7Hz,1H),7.22(t,J=7.5Hz,1H),7.08(dd,J=16.6,8.2Hz,3H),5.53(q,J=7.3Hz,1H),4.90(t,J=5.5Hz,1H),4.80(dd,J=13.4,7.1Hz,1H),4.15–3.89(m,1H),3.66–3.46(m,2H),2.30(s,3H),1.99(dd,J=30.5,18.8Hz,5H),1.61(d,J=7.4Hz,4H)。
化合物7B使用实施例1中化合物1.8及实施例5中化合物5B相似的合成步骤制得。MS:[M+H]+=586/588。1H NMR(400MHz,DMSO-d6)δ(ppm)8.69(d,J=8.2Hz,1H),8.35(s,2H),8.19(s,1H),7.61(s,1H),7.43(d,J=7.6Hz,1H),7.19(t,J=7.5Hz,1H),7.14–6.96(m,3H),5.47(d,J=7.4Hz,1H),4.90(t,J=5.6Hz,1H),4.79(dd,J=13.5,7.3Hz,1H),3.98(t,J=6.6Hz,1H),3.58(dt,J=11.5,5.7Hz,2H),2.29(d,J=12.0Hz,3H),1.99(dd,J=31.6,17.9Hz,5H),1.74–1.57(m,4H)。
实施例8(2R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-(1-(3-氯苯基)-2-羟乙基)丙酰胺(化合物8A)和(2S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-(1-(3-氯苯基)-2-羟乙基)丙酰胺(化合物8B)
化合物8A使用实施例5中化合物5A相似的合成步骤,以2-氨基-2-(3-氯-苯基)-乙醇作为起始原料制得。MS:[M+H]+=572/574。1H NMR(400MHz,DMSO-d6)δ(ppm)8.78(dd,J=49.0,8.0Hz,1H),8.48–8.23(m,1H),8.14(d,J=64.8Hz,2H),7.61(d,J=1.7Hz,1H),7.54–7.12(m,4H),6.90(dd,J=4.3,1.5Hz,0.5H),6.57(dd,J=4.2,2.7Hz,0.5H),5.60–5.32(m,1H),4.98(dd,J=10.9,5.4Hz,1H),4.83(dd,J=15.4,7.1Hz,1H),3.99(dd,J=38.5,20.0Hz,1H),3.89(d,J=11.1Hz,2H),3.55(d,J=26.4Hz,2H),3.43(s,1H),1.85(s,2H),1.74–1.51(m,3H),1.54(d,J=8.2Hz,2H)。
化合物8B使用实施例5中化合物5B相似的合成步骤制得。MS:[M+H]+=572/574。1HNMR(400MHz,DMSO-d6)δ(ppm)8.74(d,J=8.1Hz,1H),8.33(d,J=19.2Hz,2H),8.19(s,1H),7.87(d,J=9.3Hz,1H),7.72–7.53(m,2H),7.50–7.21(m,4H),5.44(d,J=7.3Hz,1H),4.98(t,J=5.5Hz,1H),4.84(dd,J=14.0,6.5Hz,1H),4.03–3.93(m,1H),3.88(d,J=11.2Hz,2H),3.67–3.51(m,2H),3.43(s,2H),3.02(s,3H),2.79(s,3H),1.86(d,J=12.1Hz,2H),1.66(d,J=7.3Hz,3H),1.53(d,J=11.6Hz,2H)。
实施例9(R)-2-(6-(5-氯-2-(异丙基氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物9A)和(S)-2-(6-(5-氯-2-(异丙基氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物9B)
在0℃下,向6-溴-3H-吡咯并[2,1-f][1,2,4]三嗪-4-酮(40.00g,186.90mmol,1.00eq.)的DMF(500mL)溶液中,加入NaH(8.97g,224.28mmol,1.20eq.),搅拌30分钟,滴加2-溴丙酸叔丁酯(42.98g,205.59mmol,1.10eq.),加毕在室温下搅拌2小时。用水和乙酸乙酯稀释反应。分离各相,水相用乙酸乙酯(2×200mL)萃取。合并的有机提取物用饱和氯化钠(200mL)洗涤,MgSO4干燥,并浓缩至干,得到中间体9.1(50.0g,79.3%产率),为类白色固体。1HNMR(400MHz,DMSO-d6)δ(ppm)8.19(s,1H),8.00–7.77(m,1H),7.07(s,1H),5.12(q,J=7.0Hz,1H),1.61(d,J=7.2Hz,3H),1.40(d,J=1.4Hz,9H)。
将中间体9.1(50.00g,146.12mmol,1.00eq.)的二氧六环(500.0mL)溶液中加入联硼频哪醇酯(44.53g,175.34mmol,1.20eq.),乙酸钾(43.02g,438.36mmol,3.00eq.)和Pd(dppf)Cl2(10.69g,14.61mmol,0.10eq.)。将反应加热至90℃并在氮气下搅拌6小时,冷却至室温后,真空除去溶剂,将残余物在EtOAc(100mL)和水(100mL),收集有机相并用盐水(100mL)洗涤。将有机溶液用MgSO4干燥,过滤,并浓缩至干。通过柱层析(硅胶,PE/EA=10/1~3/1)纯化残余物,得到中间体9.2(23.0g,40.4%产率),为类白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm)8.14(s,1H),7.77(d,J=1.6Hz,1H),7.04(d,J=1.6Hz,1H),5.12(d,J=7.3Hz,1H),2.26–2.20(m,1H),1.61(d,J=7.3Hz,3H),1.39(s,7H),1.29(s,10H)。
将中间体9.2(10.00g,25.69mmol,1.00eq.),2,4,5-三氯嘧啶(7.07g,38.54mmol,1.50eq.)和2.0M Na2CO3(25.7mL,51.38mmol,2.00eq.)加入到200mL二氧六环中,将混合物加热至90℃搅拌6小时。将反应用水(200mL)和EtOAc(100mL)稀释。分离各相,水相用EtOAc(2×50mL)萃取。将合并的有机萃取液用盐水(50mL)洗涤,将有机溶液用MgSO4干燥,过滤,并浓缩至干。通过柱层析(硅胶,PE/EA=10/1~3/1)纯化残余物,得到中间体9.3(6.7g,63.8%产率),为类白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm)δ8.91(s,1H),8.50(d,J=1.9Hz,1H),8.32(s,1H),7.68(d,J=1.9Hz,1H),5.16(d,J=7.3Hz,1H),1.64(d,J=7.3Hz,3H),1.41(s,9H)。
将中间体9.3(500.00mg,1.22mmol,1.00eq.),异丙胺(216.34mg,3.66mmol,3.00eq.)和2.0M Na2CO3(2.5mL,4.88mmol,4.00eq.)加入到二氧六环(20mL)中,将混合物加热至90℃搅拌6小时。将反应用水(60mL)和EtOAc(30mL)稀释。分离各相,水相用EtOAc(2×50mL)萃取。将合并的有机萃取液用盐水(50mL)洗涤,将有机溶液用MgSO4干燥,过滤,并浓缩至干。通过柱层析(硅胶,PE/EA=5/1~1/1)纯化残余物,得到中间体9.4(300.00g,56.8%产率),为类白色固体。
将三氟乙酸(1180.11mg,10.35mmol,15.00eq.)滴加到中间体9.4(300.00mg,0.69mmol,1.00eq.)的DCM(10mL)溶液中,并将混合物在室温下搅拌12小时将混合物浓缩至干,得到中间体9.5(180.00mg,69.4%产率),为淡黄色固体。
化合物9A使用实施例5中化合物5A相似的合成步骤,以中间体9.5和(2S)-2-氨基-2-(5-氟-3-甲氧基苯基)乙-1-醇作为起始原料制得。MS:[M+H]+=544/546。1H NMR(400MHz,DMSO-d6)δ(ppm)8.80(d,J=8.1Hz,1H),8.32(d,J=15.1Hz,2H),8.23(s,1H),7.61(d,J=1.7Hz,1H),7.24(d,J=7.7Hz,1H),6.91–6.56(m,3H),5.52(q,J=7.3Hz,1H),4.96(t,J=5.5Hz,1H),4.83(dd,J=13.6,6.4Hz,1H),4.08(s,1H),3.77(s,3H),3.57(t,J=5.2Hz,2H),1.63(d,J=7.4Hz,3H),1.21(t,J=13.8Hz,6H)。
化合物9B使用实施例5中化合物5B相似的合成步骤制得。MS:[M+H]+=544/546。1HNMR(400MHz,DMSO)δ8.72(d,J=8.1Hz,1H),8.46–7.95(m,3H),7.58(d,J=1.7Hz,1H),7.24(d,J=7.6Hz,1H),7.02–6.39(m,3H),5.45(q,J=7.1Hz,1H),4.97(t,J=5.5Hz,1H),4.81(dd,J=13.1,6.9Hz,1H),4.00(d,J=54.0Hz,1H),3.89–3.56(m,3H),3.58(dd,J=11.4,5.7Hz,2H),1.66(d,J=7.4Hz,2H),1.21(t,J=14.8Hz,6H)。
实施例10(R)-2-(6-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物10A)和(S)-2-(6-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物10B)
将中间体9.3(500.00mg,1.22mmol,1.00eq.)溶于10mL甲苯中,加入1-甲基-1H-吡唑-5-胺(142.10mg,1.46mmol,1.20eq.),碳酸铯(795.00mg,2.44mmol,2.00eq.),氮气保护下,加入催化量的Pd2(dba)3、Xantphos加毕升温至100℃下,反应12h,将反应液旋干,加入50mL水中,加入50mL EA,分液水相用EA萃取,将合并的有机萃取液用盐水(50mL)洗涤,将有机溶液用MgSO4干燥,过滤,并浓缩至干。通过柱层析(硅胶,DCM/MeOH=5 0/1~20/1)纯化残余物,得到中间体10.1(300.00g,52.3%产率),为类白色固体。
化合物10A使用实施例9中化合物9A相似的合成步骤,以中间体10.1作为起始原料制得。MS:[M+H]+=582/584。1H NMR(400MHz,DMSO-d6)δ(ppm)9.64(s,1H),8.88(d,J=7.9Hz,1H),8.55(s,1H),8.31(d,J=1.8Hz,1H),8.24(s,1H),7.57(s,1H),7.39(d,J=1.9Hz,1H),6.83–6.54(m,3H),6.28(d,J=1.8Hz,1H),5.52(d,J=7.4Hz,1H),4.99(t,J=5.5Hz,1H),4.81(dd,J=13.4,6.3Hz,1H),3.77(s,3H),3.70(s,3H),3.58(d,J=5.3Hz,2H),1.64(d,J=7.4Hz,3H)。
化合物10B使用实施例9中化合物9B相似的合成步骤制得。MS:[M+H]+=582/584。1HNMR(400MHz,DMSO-d6)δ(ppm)9.62(s,1H),8.72(d,J=8.1Hz,1H),8.55(s,1H),8.31(d,J=1.8Hz,1H),8.22(s,1H),7.52(d,J=20.3Hz,1H),7.39(d,J=1.8Hz,1H),6.83–6.55(m,3H),6.28(d,J=1.6Hz,1H),5.44(q,J=7.2Hz,1H),4.96(t,J=5.6Hz,1H),4.81(dd,J=13.3,6.8Hz,1H),3.76(d,J=6.9Hz,3H),3.70(s,3H),3.58(dd,J=11.4,5.5Hz,2H),1.66(d,J=7.4Hz,3H)。
实施例11(R)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2-(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物11A)和(S)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2-(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物11B)
在0℃下,向4-溴-2-甲氧羰基吡咯(30.00g,147.04mmol,1.00eq.)的500mL DMF溶液中,加入NaH(7.06g,176.45mmol,1.20eq.),搅拌30分钟,滴加溴代乙醛缩二乙醇(31.86g,161.74mmol,1.10eq.),加完在室温下搅拌12小时。用水和乙酸乙酯稀释反应。分离各相,水相用乙酸乙酯(2×200mL)萃取。合并的有机提取物用饱和氯化钠(200mL)洗涤,MgSO4干燥,并浓缩至干,得到中间体11.1(33.0g,70.2%产率)。1H NMR(400MHz,DMSO-d6)δ(ppm)7.16(d,J=1.4Hz,1H),6.81(d,J=1.5Hz,1H),4.64(t,J=5.3Hz,1H),3.77(s,3H),3.69–3.56(m,2H),3.52(dd,J=9.5,7.0Hz,2H),3.45(d,J=5.3Hz,2H),1.13(t,J=7.0Hz,6H)。
将中间体11.1(33.00g,103.06mmol,1.00eq.)置于THF/水混合物(200mL/100mL)中并向其中加入LiOH.H2O(12.97g,309.18mmol,3.00eq.)。然后搅拌混合物并加热至60℃保持12小时。用TLC确认反应完成后,真空除去溶剂,用1.5N HCl将残余物中和至pH6~7。过滤白色固体,用水洗涤并干燥得中间体11.2(20.2g,产率63.5%)。1H NMR(400MHz,DMSO-d6)δ(ppm)12.59(S,1H),7.19(d,J=1.9Hz,1H),6.82(d,J=1.9Hz,1H),4.64(t,J=5.4Hz,1H),4.34(d,J=5.4Hz,2H),3.60(dd,J=9.6,7.1Hz,2H),3.35(dd,J=9.6,7.0Hz,2H),1.04(t,J=7.0Hz,6H)。
向中间体11.2(20.20g,65.98mmol,1.00eq.)的DMF(300mL)的溶液中加入(R)-2-叔丁基-2-氨基丙酸盐酸盐(13.18g,72.58mmol,1.10eq.)和DIPEA(25.58g,197.94mmol,3.00eq.)。搅拌15分钟后,加入HATU(27.60g,72.58mmol,1.10eq.),并将混合物在室温下搅拌1小时。将反应用水(300mL)和EtOAc(150mL)稀释。分离各相,水相用EtOAc(3×100mL)萃取。将合并的有机萃取液用盐水(200mL)洗涤。将醚溶液干燥(MgSO4),过滤并浓缩,得到中间体11.3(23.5g,83.9%产率),为黄色固体,其未进一步纯化并直接用于下一步骤。1H NMR(400MHz,DMSO-d6)δ(ppm)7.26(dd,J=4.6,2.0Hz,1H),6.88(dd,J=5.2,2.0Hz,1H),4.64(dd,J=5.3,2.4Hz,1H),4.35(d,J=5.4Hz,2H),4.22(d,J=7.1Hz,1H),3.65–3.59(m,3H),3.34(dd,J=11.5,4.6Hz,3H),1.27(t,J=7.1Hz,2H),1.12(d,J=7.6Hz,8H),1.04(t,J=7.0Hz,6H)。
将中间体11.3(23.50g,54.23mmol,1.00eq.)置于乙腈(60mL)和乙酸(30mL)中的混合溶液中,将混合物在70℃下搅拌12小时。将反应用水(50mL)和EtOAc(50mL)稀释。分离各相,水相用EtOAc(3×50mL)萃取。用NaHCO3(3×50mL)洗涤合并的有机萃取物。将有机相用MgSO4干燥,过滤,并浓缩至干。通过柱层析(硅胶,PE/EA=10/1~3/1)纯化残余物,得到中间体11.4(12g,64.8%产率),为类白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm)7.64(d,J=1.6Hz,1H),7.39(d,J=6.0Hz,1H),6.99(d,J=1.2Hz,1H),6.89(d,J=6.0Hz,1H),5.14(q,J=7.3Hz,1H),1.52(d,J=7.3Hz,3H),1.39(s,9H)。
将中间体11.4(12.00g,35.17mmol,1.00eq.)的二氧六环(150.0mL)溶液中加入联硼频哪醇酯(10.72g,42.20mmol,1.20eq.),乙酸钾(10.35g,105.51mmol,3.00eq.)和Pd(dppf)Cl2(2.57g,3.52mmol,0.10eq.)。将反应加热至90℃并在氮气下搅拌6小时,冷却至室温后,真空除去溶剂,将残余物在EtOAc(200mL)和水(200mL),收集有机相并用盐水(200mL)洗涤。将有机溶液用MgSO4干燥,过滤,并浓缩至干。通过柱层析(硅胶,PE/EA=10/1~3/1)纯化残余物,得到中间体11.5(7.5g,55.15%产率),为类白色固体。1H NMR(400MHz,DMSO-d6)δ(ppm)7.68(d,J=1.5Hz,1H),7.40(d,J=5.9Hz,1H),7.02(d,J=0.7Hz,1H),6.83(d,J=6.1Hz,1H),5.14(q,J=7.3Hz,1H),1.52(t,J=8.5Hz,3H),1.38(s,9H),1.29(d,J=8.4Hz,12H)。
将中间体11.5(7.50g,15.93mmol,1.00eq.),2,4,5-三氯嘧啶(4.38g,23.89mmol,1.50eq.),Pd(dppf)Cl2(0.38g,0.53mmol,0.10eq.)和2.0M Na2CO3(15.9mL,31.86mmol,2.00eq.)加入到50mL二氧六环中,将混合物加热至90℃搅拌6小时。将反应用水(60mL)和EtOAc(30mL)稀释。分离各相,水相用EtOAc(2×50mL)萃取。将合并的有机萃取液用盐水(50mL)洗涤,将有机溶液用MgSO4干燥,过滤,并浓缩至干。通过柱层析(硅胶,PE/EA=10/1~3/1)纯化残余物,得到中间体11.6(5.0g,76.9%产率),为类白色固体。
将三氟乙酸(20.88g,183.15mmol,15.00eq.)滴加到中间体11.6(5.00g,12.21mmol,1.00eq.)的DCM(50mL)溶液中,并将混合物在室温下搅拌12小时将混合物浓缩至干,得到中间体11.7(3.80g,88.2%产率),为无色油状物。其未进一步纯化并直接用于下一步骤。
将中间体11.7(3.80g,10.76mmol,1.00eq.),4-氨基四氢吡喃盐酸盐(4.44g,32.28mmol,3.00eq.)和碳酸钠(2M,21.5mL,43.04mmol,4.00eq.)加入到二氧六环(30mL)中,将混合物加热至90℃搅拌6小时。冷却反应,加入盐酸(1M水溶液,10mL),立即形成浓稠的无色沉淀。过滤浆液,滤饼用水(50mL)洗涤。将所得固体在40℃下真空干燥,得到中间体11.8(3.90g,86.6%产率),为黄色固体。
将DIPEA(3.62g,27.99mmol,3.00eq.)加入到中间体11.8(3.90g,9.33mmol,1.00eq.)和(2S)-2-氨基-2-(5-氟-3-甲氧基苯基)乙-1-醇(1.90g,10.26mmol,1.10eq.)的DMF(20mL)溶液中。搅拌15分钟后,加入HATU(3.90g,10.26mmol,1.10eq.),并将混合物在室温下搅拌1小时。将反应用水(60mL)和EtOAc(30mL)稀释。分离各相,水相用EtOAc(2×50mL)萃取。将合并的有机萃取液用盐水(50mL)洗涤,用MgSO4干燥并浓缩。经过手性分离制备化合物11A和11B。
色谱柱:waters SFC200
柱规格:ChiralPak AS,250×30mm I.D.,5μm
进样量:将化合物溶于150mL MEOH中,每次注射17mL
流动相:A为CO2,B为甲醇(0.1%NH3H2O)
流速:70mL/min
波长:UV 254nm
化合物11A(4.2g,77.06%产率)保留时间3.87min,e.e.>98%,为类白色固体。MS:[M+H]+=585/587。1H NMR(400MHz,DMSO-d6)δ(ppm)8.64(d,J=8.1Hz,1H),8.32(d,J=15.9Hz,2H),7.62(s,1H),7.51(d,J=6.1Hz,1H),7.35(d,J=7.6Hz,1H),6.96(d,J=6.2Hz,1H),6.83–6.42(m,3H),5.53(q,J=7.2Hz,1H),4.91(t,J=5.5Hz,1H),4.81(dd,J=14.0,6.3Hz,1H),3.93(d,J=16.0Hz,1H),3.89(d,J=11.2Hz,2H),3.77(s,3H),3.56(t,J=5.9Hz,2H),3.43(s,2H),1.87(d,J=11.3Hz,2H),1.53(d,J=15.7Hz,2H),1.50(d,J=7.3Hz,3H).
化合物11B(0.2g,3.6%产率)保留时间4.61min,e.e.>98%,为类白色固体。MS:[M+H]+=585/587。1H NMR(400MHz,DMSO-d6)δ(ppm)8.56(d,J=8.1Hz,1H),8.32(d,J=13.2Hz,2H),7.61(d,J=1.0Hz,1H),7.51(d,J=6.1Hz,1H),7.36(d,J=7.6Hz,1H),6.88(d,J=6.1Hz,1H),6.78–6.53(m,3H),5.48(q,J=7.1Hz,1H),4.92(t,J=5.7Hz,1H),4.81(dd,J=13.8,6.5Hz,1H),4.02–3.83(m,3H),3.75(d,J=13.8Hz,3H),3.64–3.50(m,2H),3.44(d,J=10.8Hz,2H),1.87(d,J=9.9Hz,2H),1.54(t,J=11.2Hz,5H).
实施例12(2R)-2-(6-(2-((8-氧杂双环[3.2.1]辛-3-基)氨基)-5-氯嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物12A)和(2S)-2-(6-(2-((8-氧杂双环[3.2.1]辛-3-基)氨基)-5-氯嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物12B)
化合物12A使用实施例9中化合物9A相似的合成步骤,以8-氧杂二环[3.2.1]辛烷-3-胺盐酸作为起始原料制得。MS:[M+H]+=612/614。1H NMR(400MHz,DMSO-d6)δ(ppm)8.80(d,J=8.0Hz,1H),8.31(d,J=22.2Hz,2H),8.22(s,1H),7.60(d,J=1.5Hz,1H),7.30(s,1H),6.71(dd,J=15.7,6.9Hz,3H),5.51(q,J=7.3Hz,1H),4.96(t,J=5.5Hz,1H),4.83(dd,J=13.6,6.4Hz,1H),4.36(s,2H),4.22(s,1H),3.77(s,3H),3.58(d,J=5.6Hz,2H),1.92(d,J=56.6Hz,6H),1.62(t,J=9.8Hz,3H),1.59(s,2H)。
化合物12B使用实施例9中化合物9B相似的合成步骤制得。MS:[M+H]+=612/614。1HNMR(400MHz,DMSO-d6)δ(ppm)8.71(d,J=8.0Hz,1H),8.46–8.21(m,2H),8.24–8.05(m,1H),7.57(s,1H),7.31(d,J=12.3Hz,1H),6.85–6.57(m,3H),5.44(q,J=7.2Hz,1H),4.96(t,J=5.5Hz,1H),4.81(dd,J=13.2,6.6Hz,1H),4.36(s,2H),4.21(s,1H),3.75(s,3H),3.66–3.47(m,2H),1.83(s,6H),1.65(t,J=9.9Hz,3H),1.59(t,J=11.8Hz,2H)。
实施例13(R)-2-(6-(5-氯-2-(((R)-3,3-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物13A)和(S)-2-(6-(5-氯-2-(((R)-3,3-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物13B)
化合物13A使用实施例9中化合物9A相似的合成步骤,以4-氨基-3,3-二甲基四氢吡喃盐酸盐作为起始原料制得。MS:[M+H]+=614/616。1H NMR(400MHz,DMSO-d6)δ(ppm)8.80(d,J=8.0Hz,1H),8.34(s,2H),8.23(s,1H),7.63(s,1H),7.15(s,1H),6.71(dd,J=14.9,6.3Hz,3H),5.52(q,J=7.3Hz,1H),4.95(t,J=5.4Hz,1H),4.82(dd,J=13.6,6.4Hz,1H),3.89(d,J=10.3Hz,1H),3.77(s,3H),3.57(dd,J=8.9,3.8Hz,2H),3.43(d,J=11.2Hz,2H),3.19(s,1H),1.79–1.68(m,1H),1.63(d,J=7.4Hz,3H),1.57(s,1H),0.98(s,3H),0.81(s,3H)。
化合物13B使用实施例9中化合物9B相似的合成步骤制得。MS:[M+H]+=614/616。1HNMR(400MHz,DMSO-d6)δ(ppm)8.71(d,J=8.0Hz,1H),8.33(s,2H),8.20(s,1H),7.61(s,1H),7.15(s,1H),6.77–6.60(m,3H),5.45(q,J=7.2Hz,1H),4.96(t,J=5.5Hz,1H),4.81(dd,J=13.2,6.8Hz,1H),3.89(d,J=10.0Hz,1H),3.75(s,3H),3.58(dd,J=11.4,5.7Hz,2H),3.43(d,J=11.2Hz,2H),3.18(s,1H),1.78–1.70(m,1H),1.66(d,J=7.3Hz,3H),1.58(d,J=11.6Hz,1H),0.98(s,3H),0.80(s,3H)。
实施例14(R)-2-(6-(5-氯-2-((2-氯-4-氟苯基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氯-5-氟苯基)-2-羟乙基)丙酰胺(化合物14A)和(S)-2-(6-(5-氯-2-((2-氯-4-氟苯基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氯-5-氟苯基)-2-羟乙基)丙酰胺(化合物14B)
化合物14A使用实施例9中化合物9A相似的合成步骤,以2-氯-4-氟-苯氨作为起始原料制得。制备方法同实施例10,保留时间3.54min,e.e.=99%,为类白色固体。MS:[M+H]+=630/632。1H NMR(400MHz,DMSO-d6)δ(ppm)9.21(s,1H),8.70(d,J=8.1Hz,1H),8.49(s,1H),8.26(d,J=1.8Hz,1H),8.20(s,1H),7.70(dd,J=9.0,5.8Hz,1H),7.56–7.49(m,2H),7.30–7.23(m,1H),6.76–6.64(m,3H),5.43(q,J=7.3Hz,1H),4.95(t,J=5.5Hz,1H),4.81(dd,J=13.4,7.0Hz,1H),3.75(s,3H),3.58(dd,J=11.4,5.9Hz,2H),1.66(d,J=7.4Hz,3H)。
化合物14B使用实施例9中化合物9B相似的合成步骤制得,制备方法同实施例10,保留时间2.85min,e.e.=100%。MS:[M+H]+=630/632。1H NMR(400MHz,DMSO-d6)δ(ppm)9.21(s,1H),8.79(d,J=8.0Hz,1H),8.49(s,1H),8.27(d,J=1.8Hz,1H),8.23(s,1H),7.70(dd,J=9.0,5.8Hz,1H),7.54(td,J=4.9,3.0Hz,2H),7.32–7.24(m,1H),6.76–6.67(m,3H),5.51(q,J=7.3Hz,1H),4.95(s,1H),4.82(dd,J=13.8,6.3Hz,1H),3.77(s,3H),3.57(d,J=5.2Hz,2H),1.63(d,J=7.4Hz,3H)。
实施例15(R)-2-(6-(5-氯-2-(((R)-2,2-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物15A)和(S)-2-(6-(5-氯-2-(((R)-2,2-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物15B)
化合物15A使用实施例9中化合物9A相似的合成步骤,以4-氨基-2,2-二甲基四氢吡喃盐酸盐作为起始原料制得。MS:[M+H]+=614/616。1H NMR(400MHz,DMSO-d6)δ(ppm)8.85(d,J=7.9Hz,1H),8.33(d,J=20.8Hz,2H),8.22(s,1H),7.61(s,1H),7.31(s,1H),6.71(dd,J=16.2,7.0Hz,3H),5.51(q,J=7.1Hz,1H),4.98(t,J=5.5Hz,1H),4.82(dd,J=13.4,6.4Hz,1H),4.13(s,1H),3.77(s,3H),3.68(s,2H),3.58(d,J=5.6Hz,2H),3.38(s,1H),1.83(d,J=11.1Hz,1H),1.64(d,J=7.3Hz,3H),1.42(s,1H),1.16(s,3H),1.11(s,3H)。
化合物15B使用实施例9中化合物9B相似的合成步骤制得。MS:[M+H]+=614/616。1HNMR(400MHz,DMSO-d6)δ(ppm)8.84(s,1H),8.32(d,J=18.6Hz,2H),8.19(s,1H),7.58(s,1H),7.30(s,1H),6.79–6.58(m,3H),5.45(s,1H),5.03(s,1H),4.80(s,1H),4.08(d,J=33.0Hz,2H),3.75(s,3H),3.68(s,2H),3.59(s,2H),1.83(s,1H),1.68(s,3H),1.42(s,1H),1.25(s,3H),1.15(s,3H)。
实施例16N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(4-氧代-6-(2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)丙酰胺(化合物16)
化合物16合成方法同化合物9类似,以2,4-二氯嘧啶作为起始原料制得。MS:[M+H]+=552。1H NMR(400MHz,DMSO-d6)δ(ppm)8.76(dd,J=37.2,8.1Hz,1H),8.26(dd,J=5.0,2.7Hz,2H),8.17(d,J=12.4Hz,1H),7.50(dd,J=10.7,1.7Hz,1H),7.06(dd,J=7.5,4.9Hz,2H),6.83–6.53(m,3H),5.49(dq,J=27.5,7.2Hz,1H),4.96(t,J=5.4Hz,1H),4.82(dt,J=12.9,6.4Hz,1H),4.05–3.99(m,1H),3.88(d,J=11.3Hz,2H),3.76(d,J=7.1Hz,3H),3.63–3.50(m,2H),3.43(s,2H),1.86(d,J=11.4Hz,2H),1.64(dd,J=11.8,7.4Hz,3H),1.54(dd,J=19.9,11.1Hz,2H)。
实施例17(R)-2-(6-(5-氯-2-(((3S,4R)-3-甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物17A)和(S)-2-(6-(5-氯-2-(((3S,4R)-3-甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物17B)
化合物17A使用实施例9中化合物9A相似的合成步骤,以(3R,4S)-3-甲基-哌啶-4-基胺盐酸盐作为起始原料制得。MS:[M+H]+=600/602。1H NMR(400MHz,DMSO-d6)δ(ppm)8.81(d,J=8.0Hz,1H),8.33(s,2H),8.22(s,1H),7.61(d,J=1.8Hz,1H),7.34(d,J=8.6Hz,1H),6.78–6.62(m,3H),5.52(q,J=7.3Hz,1H),4.96(t,J=5.5Hz,1H),4.82(dd,J=13.7,6.3Hz,1H),3.89(d,J=7.9Hz,1H),3.81(dd,J=11.6,4.4Hz,1H),3.77(s,3H),3.73–3.67(m,1H),3.57(dt,J=7.4,3.8Hz,2H),3.43(s,1H),1.86(s,1H),1.80–1.71(m,1H),1.64(d,J=7.4Hz,3H),1.50(ddd,J=24.0,12.4,4.5Hz,1H),0.80(d,J=6.5Hz,3H)。
化合物17B使用实施例9中化合物9B相似的合成步骤制得。MS:[M+H]+=600/602。1HNMR(400MHz,DMSO-d6)δ(ppm)8.71(d,J=7.6Hz,1H),8.32(s,2H),8.19(s,1H),7.58(s,1H),7.33(d,J=8.4Hz,1H),6.70(dd,J=20.5,10.5Hz,3H),5.45(d,J=7.2Hz,1H),4.95(s,1H),4.81(d,J=6.3Hz,1H),3.88(d,J=8.7Hz,1H),3.83–3.78(m,1H),3.75(s,3H),3.58(d,J=5.3Hz,2H),3.40(s,1H),3.08(s,1H),1.86(s,1H),1.79–1.71(m,1H),1.66(d,J=7.1Hz,3H),1.50(d,J=8.3Hz,1H),0.80(d,J=6.3Hz,3H)。
实施例18(R)-2-(6-(5-氯-2-(((1S,3R)-3-羟基环戊基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物18A)和(S)-2-(6-(5-氯-2-(((1S,3R)-3-羟基环戊基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物18B)
化合物18A使用实施例9中化合物9A相似的合成步骤,以(1S,3S)-3-氨基环戊-1-醇盐酸盐作为起始原料制得。MS:[M+H]+=586/588。1H NMR(400MHz,DMSO-d6)δ(ppm)8.79(d,J=8.0Hz,1H),8.32(d,J=8.7Hz,2H),8.22(s,1H),7.61(d,J=1.4Hz,1H),7.28(d,J=6.9Hz,1H),6.77–6.65(m,3H),5.52(q,J=7.3Hz,1H),4.95(t,J=5.5Hz,1H),4.82(dd,J=13.7,6.4Hz,1H),4.63(d,J=4.0Hz,1H),4.27–4.09(m,2H),3.77(s,3H),3.57(dd,J=9.1,3.9Hz,2H),2.22(s,1H),1.95(s,1H),1.81–1.66(m,2H),1.63(d,J=7.4Hz,3H),1.53–1.42(m,1H)。
化合物18B使用实施例9中化合物9B相似的合成步骤制得。MS:[M+H]+=586/588。1HNMR(400MHz,DMSO-d6)δ(ppm)8.70(d,J=8.1Hz,1H),8.32(d,J=9.8Hz,2H),8.19(s,1H),7.59(d,J=1.6Hz,1H),7.28(d,J=7.0Hz,1H),6.76–6.65(m,4H),5.45(q,J=7.3Hz,1H),4.95(t,J=5.6Hz,1H),4.83–4.75(m,1H),4.63(d,J=4.1Hz,1H),4.14(d,J=4.5Hz,2H),3.64–3.48(m,3H),2.22(s,1H),1.94(s,1H),1.80–1.70(m,1H),1.66(d,J=7.3Hz,3H),1.59(dd,J=7.7,3.7Hz,1H),1.53–1.44(m,1H)。
实施例19(R)-2-(6-(5-氯-2-((3,3-二氟环)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物19A)和(S)-2-(6-(5-氯-2-((3,3-二氟环)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物19B)
化合物19A使用实施例9中化合物9A相似的合成步骤,以3,3-二氟环丁胺盐酸盐作为起始原料制得。MS:[M+H]+=592/594。1H NMR(400MHz,DMSO-d6)δ(ppm)8.90–8.81(m,1H),8.55–8.26(m,2H),8.23(s,1H),7.90(d,J=6.3Hz,1H),7.65(d,J=16.6Hz,1H),6.80–6.60(m,3H),5.53(q,J=7.0Hz,1H),4.98(t,J=5.4Hz,1H),4.82(dd,J=13.3,6.6Hz,1H),4.26(s,1H),3.77(s,3H),3.56(t,J=14.2Hz,2H),2.99(s,2H),2.69(d,J=10.9Hz,2H),1.64(d,J=7.3Hz,3H)。
化合物19B使用实施例9中化合物9B相似的合成步骤制得。MS:[M+H]+=592/594。1HNMR(400MHz,DMSO-d6)δ(ppm)8.71(d,J=8.1Hz,1H),8.46–8.21(m,2H),8.23(d,J=20.3Hz,1H),7.90(d,J=6.2Hz,1H),7.62(d,J=14.9Hz,1H),6.70(dd,J=19.2,10.0Hz,3H),5.45(q,J=7.1Hz,1H),4.96(t,J=5.5Hz,1H),4.81(dd,J=13.4,6.8Hz,1H),4.26(s,1H),3.76(s,3H),3.66–3.49(m,2H),2.99(s,2H),2.77–2.58(m,2H),1.66(d,J=7.3Hz,3H)。
实施例20(R)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(6-(5-甲基-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)丙酰胺(化合物20A)和(S)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(6-(5-甲基-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)丙酰胺(化合物20B)
化合物20A使用实施例9中化合物9A相似的合成步骤,以2,4-二氯-5-甲基嘧啶为起始原料制得。MS:[M+H]+=566。1H NMR(400MHz,DMSO-d6)δ(ppm)8.81(d,J=8.0Hz,1H),8.13(dd,J=33.5,9.1Hz,3H),7.43(d,J=1.7Hz,1H),6.83(d,J=7.7Hz,1H),6.71(dd,J=15.3,6.7Hz,3H),5.52(q,J=7.3Hz,1H),4.96(t,J=5.5Hz,1H),4.82(dd,J=13.6,6.3Hz,1H),4.03–3.93(m,1H),3.92–3.84(m,2H),3.77(s,3H),3.57(t,J=5.4Hz,2H),3.42(t,J=10.9Hz,2H),2.31(s,3H),1.87(d,J=11.4Hz,2H),1.63(d,J=7.4Hz,3H),1.52(ddd,J=15.5,12.4,4.2Hz,2H)。
化合物20B使用实施例9中化合物9B相似的合成步骤制得。MS:[M+H]+=566。1H NMR(400MHz,DMSO-d6)δ(ppm)8.71(d,J=8.1Hz,1H),8.15(d,J=7.3Hz,2H),8.08(d,J=1.5Hz,1H),7.40(d,J=1.7Hz,1H),6.83(d,J=7.7Hz,1H),6.77–6.65(m,3H),5.45(q,J=7.3Hz,1H),4.96(t,J=5.6Hz,1H),4.81(dd,J=13.4,6.8Hz,1H),4.00–3.93(m,1H),3.88(d,J=11.2Hz,2H),3.75(s,3H),3.65–3.53(m,2H),3.42(t,J=10.9Hz,2H),2.30(s,3H),1.86(d,J=11.4Hz,2H),1.66(d,J=7.4Hz,3H),1.58–1.46(m,2H)。
实施例21 2-(6-(5-氯-2-((1-甲基-2-氧代哌啶-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物21)
化合物21合成方法同化合物1类似,以4-氨基-1-甲基-哌啶-2-酮作为起始原料制得。MS:[M+H]+=613/615。1H NMR(400MHz,DMSO-d6)δ(ppm)8.76(dd,J=39.1,7.6Hz,1H),8.49–8.04(m,3H),7.56(dd,J=41.7,8.7Hz,2H),7.07–6.53(m,4H),5.48(dd,J=28.7,7.3Hz,1H),4.96(s,1H),4.81(s,1H),3.89–3.65(m,3H),3.54(d,J=22.0Hz,2H),2.85(d,J=10.6Hz,3H),2.60(s,1H),2.30(dd,J=16.7,9.1Hz,1H),2.09(s,1H),1.80(s,1H),1.72–1.54(m,3H)。
实施例22 2-(6-(2-((1-乙酰基哌啶-4-基)氨基)-5-氯嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3-(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物22)
化合物22合成方法同化合物1类似,1-(4-氨基-哌啶-1-基)-乙酮作为起始原料制得。MS:[M+H]+=627。1H NMR(400MHz,DMSO-d6)δ(ppm)8.76(dd,J=39.1,7.6Hz,1H),8.29(dd,J=58.7,13.5Hz,3H),7.61(d,J=10.2Hz,1H),7.51(d,J=7.3Hz,1H),6.69(d,J=28.2Hz,4H),5.48(dd,J=28.7,7.3Hz,1H),4.96(s,1H),4.81(s,1H),3.93–3.65(m,3H),3.54(d,J=22.0Hz,2H),2.85(d,J=10.6Hz,3H),2.60(s,1H),2.30(dd,J=16.7,9.1Hz,2H),2.09(s,1H),1.80(s,1H),1.68–1.42(m,3H)。
实施例23(R)-2-(6-(5-氯-2-(((1r,4R)-4-甲氧基环己基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物23A)和(S)-2-(6-(5-氯-2-(((1r,4S)-4-甲氧基环己基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物23B)
化合物23A使用实施例9中化合物9A相似的合成步骤,以trans-4-甲氧基-环己基-1-氨盐酸盐作为起始原料制得。MS:[M+H]+=614/616。1H NMR(400MHz,DMSO-d6)δ(ppm)8.80(d,J=8.1Hz,1H),8.33–8.22(m,3H),7.59(d,J=1.8Hz,1H),7.27(d,J=7.6Hz,1H),6.74–6.68(m,3H),5.51(q,J=7.3Hz,1H),4.96(s,1H),4.82(dd,J=13.5,6.9Hz,1H),3.76(s,3H),3.57–3.56(m,2H),3.23(s,3H),3.12(s,1H),2.00(dd,J=18.6,13.1Hz,3H),1.63(d,J=7.4Hz,3H),1.26(dd,J=22.7,12.9Hz,4H)。
化合物23B使用实施例9中化合物9B相似的合成步骤制得。MS:[M+H]+=614/616。1H NMR(400MHz,DMSO-d6)δ(ppm)8.71(d,J=8.1Hz,1H),8.48–7.88(m,3H),7.57(d,J=1.8Hz,1H),7.27(d,J=7.6Hz,1H),6.91–6.38(m,3H),5.44(q,J=7.3Hz,1H),4.96(s,1H),4.81(dd,J=13.5,6.9Hz,1H),3.75(s,3H),3.67–3.45(m,2H),3.25(s,3H),3.13(s,1H),2.00(dd,J=18.6,13.1Hz,3H),1.66(d,J=7.4Hz,3H),1.29(dd,J=22.7,12.9Hz,4H)。
实施例24 2-(6-(5-氯-2-(((3S,4R)-3-甲氧基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物24)
化合物24使用实施例9中类似合成步骤,以(3S,4R)-4-氨基-3-甲氧基四氢吡喃盐酸盐作为起始原料制得。MS:[M+H]+=616/618。1H NMR(400MHz,DMSO-d6)δ(ppm)8.76(dd,J=37.8,8.0Hz,1H),8.45–8.12(m,3H),7.60(dd,J=11.5,1.8Hz,1H),7.49(d,J=7.9Hz,1H),6.86–6.58(m,3H),5.48(dq,J=29.1,7.2Hz,1H),4.96(t,J=5.6Hz,1H),4.82(dd,J=12.9,6.6Hz,1H),4.10–3.92(m,2H),3.79(dd,J=17.8,9.5Hz,4H),3.58–3.49(m,2H),3.38(s,3H),3.15(s,1H),1.96(s,1H),1.65(dd,J=10.8,7.4Hz,3H),1.52(d,J=10.8Hz,1H)。
实施例25 2-(6-(5-氯-2-(((3S,4R)-3-羟基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物25)
化合物25使用实施例9中合成步骤类似,以(3S,4R)-4-氨基-3-羟基四氢吡喃盐酸盐作为起始原料制。MS:[M+H]+=602/604。1H NMR(400MHz,DMSO-d6)δ(ppm)8.75(dd,J=37.7,8.1Hz,1H),8.53–8.11(m,3H),7.60(dd,J=10.9,1.8Hz,1H),7.29(d,J=7.9Hz,1H),6.90–6.53(m,3H),5.50(dt,J=21.7,7.2Hz,1H),4.95(dd,J=12.4,5.5Hz,2H),4.83(dd,J=13.7,6.3Hz,1H),3.94–3.66(m,6H),3.66–3.42(m,3H),3.09(s,1H),1.98(d,J=15.9Hz,1H),1.78–1.54(m,3H),1.57–1.38(m,1H)。
实施例26(R)-2-(6-(5-氯-2-(((3R,4R)-3-羟基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物26A)和(S)-2-(6-(5-氯-2-(((3R,4R)-3-羟基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物26B)
化合物26A使用实施例9中化合物9A相似的合成步骤,以(3R,4R)-4-氨基-3-羟基四氢吡喃盐酸盐作为起始原料制得。MS:[M+H]+=602/604。1H NMR(400MHz,DMSO-d6)δ(ppm)8.83(d,J=8.0Hz,1H),8.33(d,J=10.7Hz,2H),8.22(s,1H),7.62(d,J=1.8Hz,1H),7.29(d,J=7.9Hz,1H),6.78–6.60(m,3H),5.52(q,J=7.3Hz,1H),5.02–4.89(m,2H),4.82(dd,J=13.7,6.3Hz,1H),3.83(dd,J=11.0,5.1Hz,2H),3.77(s,3H),3.57(dt,J=7.2,3.8Hz,2H),3.53–3.46(m,1H),3.09(s,1H),2.03–1.87(m,1H),1.64(d,J=7.4Hz,3H),1.50(ddd,J=15.7,12.9,4.5Hz,1H)。
化合物26B使用实施例9中化合物9B相似的合成步骤制得。MS:[M+H]+=602/604。1HNMR(400MHz,DMSO-d6)δ(ppm)8.72(d,J=8.1Hz,1H),8.32(d,J=12.9Hz,2H),8.20(s,1H),7.59(d,J=1.8Hz,1H),7.29(d,J=8.0Hz,1H),6.79–6.63(m,3H),5.45(q,J=7.3Hz,1H),5.02–4.91(m,2H),4.81(dd,J=13.3,6.8Hz,1H),3.82(dd,J=11.0,4.9Hz,2H),3.76(d,J=6.8Hz,3H),3.59(dt,J=11.7,5.8Hz,2H),3.54–3.46(m,2H),3.08(s,2H),1.96(s,1H),1.66(d,J=7.4Hz,3H),1.55–1.42(m,1H)。
实施例27(R)-2-(7-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺(化合物27)
化合物27使用实施例11中类似合成步骤,以中间体11.6作为起始原料制得。MS:[M+H]+=581/582。1H NMR(400MHz,DMSO-d6)δ(ppm)9.59(s,1H),8.66(d,J=8.0Hz,1H),8.53(s,1H),8.34(d,J=1.3Hz,1H),7.70–7.49(m,2H),7.39(d,J=1.7Hz,1H),6.97(d,J=6.1Hz,1H),6.71(dd,J=17.4,6.6Hz,3H),6.29(s,1H),5.53(q,J=7.2Hz,1H),4.93(t,J=5.5Hz,1H),4.83–4.73(m,1H),3.77(s,3H),3.69(d,J=13.1Hz,3H),3.55(dd,J=14.4,8.6Hz,2H),1.50(d,J=7.3Hz,3H)。
实施例28 2-(3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环丁基)乙酸(化合物28)
化合物28合成方法同化合物9类似,以(3-氨基-环丁基)-乙酸盐酸盐作为起始原料制得。MS:[M-H]-=612/614。1H NMR(400MHz,DMSO-d6)δ(ppm)11.98(s,1H),8.77(dd,J=39.9,8.0Hz,1H),8.33(s,2H),8.21(d,J=11.8Hz,1H),7.60(d,J=7.1Hz,2H),6.80–6.63(m,3H),5.49(ddd,J=29.9,14.5,7.2Hz,1H),4.97(t,J=5.3Hz,1H),4.88–4.76(m,1H),4.44(s,
1H),4.26(s,1H),3.76(d,J=6.7Hz,3H),3.58(d,J=5.5Hz,2H),2.33(t,J=13.7Hz,2H),2.19(d,J=6.9Hz,1H),2.08(s,1H),1.69(s,1H),1.65(dd,J=10.7,7.4Hz,3H)。
实施例29 4-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环己烷-1-羧酸(化合物29)
化合物29合成方法同化合物9类似,以4-氨基-环己烷羧酸盐酸盐作为起始原料制得。MS:[M-H]-=626/628。1H NMR(400MHz,DMSO-d6)δ(ppm)12.09(s,1H),8.78(dd,J=38.3,8.0Hz,1H),8.38–8.23(m,2H),8.21(d,J=11.3Hz,1H),7.59(dd,J=11.1,1.5Hz,1H),7.31(d,J=6.3Hz,1H),6.79–6.59(m,3H),5.48(dq,J=29.6,7.3Hz,1H),4.98(t,J=5.2Hz,1H),4.86–4.72(m,1H),3.85(s,1H),3.76(d,J=7.1Hz,3H),3.62–3.51(m,2H),2.45(s,1H),1.97(d,J=14.6Hz,2H),1.72(s,2H),1.65(dd,J=10.5,7.5Hz,7H)。
实施例30(1R,3S)-3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环己烷-1-羧酸(化合物30)
化合物30合成方法同化合物9类似,以(1R,3S)-3-氨基环己烷-1-羧酸盐酸盐作为起始原料制得。MS:[M-H]-=626/628。1H NMR(400MHz,DMSO-d6)δ(ppm)11.98(s,1H),8.80(dd,J=31.9,7.5Hz,1H),8.25(t,J=29.3Hz,3H),7.59(d,J=10.0Hz,1H),7.34(d,J=7.8Hz,1H),6.94–6.52(m,3H),5.48(dq,J=29.8,7.4Hz,1H),5.01(s,1H),4.87–4.70(m,1H),3.76(d,J=7.2Hz,3H),3.65–3.50(m,2H),2.34(s,1H),2.14(d,J=12.0Hz,1H),1.83(dd,J=33.0,12.6Hz,2H),1.64(dd,J=9.6,7.6Hz,2H),1.53–1.04(m,4H)。
实施例31(1R,3S)-3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环戊烷-1-羧酸(化合物31)
化合物31合成方法同化合物9类似,以(1R,3S)-3-氨基环戊烷-1-羧酸盐酸盐作为起始原料制得。MS:[M-H]-=612/614。1H NMR(400MHz,DMSO-d6)δ(ppm)11.97(s,1H)8.81(dd,J=35.0,8.0Hz,1H),8.53–8.04(m,3H),7.60(d,J=10.6Hz,1H),7.51(s,1H),5.49(dd,J=30.2,7.1Hz,1H),5.01(s,1H),4.91–4.58(m,1H),4.23(s,2H),3.76(d,J=7.3Hz,3H),3.67–3.50(m,2H),2.73(d,J=37.0Hz,1H),2.29(d,J=35.8Hz,1H),1.93–1.77(m,2H),1.66(dd,J=20.6,12.5Hz,3H)。
实施例32 3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙烷-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环丁烷-1-羧酸(化合物32)
化合物32合成方法同化合物9类似,以3-氨基-环丁烷羧酸盐酸盐作为起始原料制得。MS:[M-H]-=598/600。1H NMR(400MHz,DMSO-d6)δ(ppm)8.79(dd,J=39.2,8.0Hz,1H),8.41–8.25(m,2H),8.25–8.15(m,1H),7.75(dd,J=22.0,7.1Hz,1H),7.66–7.52(m,1H),6.78–6.60(m,3H),5.57–5.40(m,1H),4.98(t,J=5.1Hz,1H),4.88–4.73(m,1H),4.59–4.42(m,1H),4.34(s,1H),3.76(d,J=6.9Hz,3H),3.58(d,J=5.3Hz,2H),2.97(s,1H),2.81(d,J=7.8Hz,1H),2.31(dd,J=21.6,5.6Hz,1H),2.15(dd,J=18.7,9.1Hz,1H),1.65(dd,J=10.6,7.5Hz,3H)。
实施例33(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺(化合物33)
化合物33使用实施例1中化合物1相似的合成步骤,以(2S)-2-氨基-2-(3-甲基苯基)乙-1-醇作为起始原料制得。MS:[M+H]+=552/554。1H NMR(400MHz,DMSO)δ8.82(d,J=8.0Hz,1H),8.48–8.10(m,2H),7.61(d,J=1.6Hz,1H),7.41(t,J=9.9Hz,1H),7.22(t,J=7.5Hz,1H),7.08(dd,J=15.5,8.1Hz,2H),5.53(q,J=7.3Hz,1H),4.91(dd,J=28.8,23.4Hz,1H),4.79(dd,J=13.4,7.0Hz,1H),4.02(dt,J=19.2,9.6Hz,1H),3.88(d,J=11.2Hz,2H),3.64–3.45(m,2H),3.43(s,2H),2.37–2.15(m,3H),1.85(s,2H),1.66–1.48(m,3H),1.60–1.42(m,2H)。
实施例34参考实施例11或实施例27的制备方法,采用不同中间体或其盐形式合成化合物34-40,见表1。
表1
实施例35ERK2酶抑制试验
ERK2在大肠杆菌系统中表达,大肠杆菌系统购自Carna Biosciences,Inc.(Japan,CK)。ULight-MBP Peptide、Europium-anti-phospho-Myelin Basic Protein(Thr232)antibody和LANCE Detection Buffer购自PerkinElmer(Waltham,MA)。高纯度的ATP、DTT、EDTA、EGTA、Tween-20、DMSO和Tris buffer购自Sigma。
实验所用的assay buffer由50mM Tris(pH 7.5)、1mM EGTA、10mM MgCl2、0.01%Tween-20和2mM DTT组成。4%DMSO的化合物、ERK2酶和ULight-MBP Peptide/ATP混合溶液使用assay buffer配制,配制完成后,2.5μL 4%DMSO的化合物、5μL的ERK2和2.5μL的ULight-MBP Peptide/ATP混合液分别加入Opti Plate-384 White孔板中,盖膜,800转1min,室温孵育1.5h。ERK2、ULight-MBP Peptide、ATP和DMSO的最终浓度分别为2nM,30nM,5μM and 1%。1.5h后,将5μL 40mM EDTA(detection buffer配制)加入反应混合物中终止反应,终止时间5min。然后加入5μL检测抗体(最终浓度2nM,detection buffer配制),室温孵育1h。在TECAN(Switzerland)的SPARK多功能酶标仪器上读取平板,激发光波长为320nm,发射光波长为665nm。在Prism 7(LaJolla,CA)中使用S形剂量反应模型(可变斜率,四个参数)确定化合物使细胞成活率抑制50%的浓度(IC50值)。
本文所述的代表性化合物的ERK2酶抑制试验结果在表2中示出。
表2
化合物 | IC50(nM) | 化合物 | IC50(nM) |
1 | 0.93 | 16 | 4 |
2 | 3.57 | 17A | 3 |
3 | N/A | 17B | 140 |
4 | N/A | 18A | 5 |
5A | 2.52 | 18B | 320 |
5B | N/A | 19A | 8 |
6A | N/A | 19B | 1360 |
6B | N/A | 20A | 1.49 |
7A | N/A | 20B | 81.33 |
7B | N/A | 21 | 6.14 |
8A | 4.91 | 22 | 9.19 |
8B | N/A | 23A | 5.69 |
9A | 5.43 | 23B | 303 |
9B | N/A | 24 | 4.24 |
10A | 1.19 | 25 | 6.33 |
10B | N/A | 26A | 6.67 |
11A | 0.95 | 26B | 116.4 |
11B | N/A | 27 | 1.99 |
12A | 2.25 | 28 | 42.46 |
12B | 602 | 29 | 568.8 |
13A | 35.8 | 30 | 91.35 |
13B | 2670 | 31 | 24.13 |
14A | 27.5 | 32 | 83.13 |
14B | 2518 | 33 | 0.86 |
15A | 10 | Ulixertinib | 0.54 |
15B | 1880 | ASTX-029 | 0.55 |
从表2测试结果分析,此类化合物大多数具有明显ERK2抑制活性,同时其中部分化合物的ERK抑制活性同现有阳性参照具有相近的结果,尤其是化合物1,化合物10A,化合物11化合物12A及化合物33。
实施例36非B-RAF突变WT细胞增殖抑制试验
材料和细胞系
NCI-H508、SW-48和MKN-45细胞购自中国科学院细胞库(上海)。DMEM培养基、RPMI1640培养基、青霉素-链霉素双抗和0.5%的胰酶(10X)购自ThermoFisher(Waltham,MA,USA)。经认证的胎牛血清(FBS)购自Biological Industries(Israel)。康宁96和384孔细胞培养板购自CORNING(USA)。Cell-Titer购自Promega Corporation(Madison,WI,USA)。
为了评估合成化合物对胃癌MKN-45细胞,人结肠癌NCI-H508和SW-48细胞增殖的抑制能力,将MKN-45和NCI-H508指数增长的细胞接种于含10%牛血清和1%青霉素-链霉素双抗的RPMI1640培养基,SW-48指数增长的细胞接种于含10%牛血清和1%青霉素-链霉素双抗的DMEM培养基,密度分别为125000、100000和300000个细胞/mL,384孔板,每孔20μL,并放置在37℃,5%CO2的培养箱中过夜。将化合物在DMSO中稀释至12个点、3倍系列稀释液,从6mM开始。将化合物储备板的1μL DMSO溶液添加到99μL细胞培养基(测定中化合物的最终最高浓度为30μM,并且DMSO的最终浓度为0.5%)。将培养基中的20μL化合物溶液加到MKN-45、NCI-H508和SW-48细胞板的每个孔中。在加入化合物溶液后,将384孔板放置于37℃,5%CO2培养箱中孵育4天。采用Promega(Madison,WI,USA)的CellTiter-Glo检测试剂盒,通过定量细胞培养中存在的ATP,测定细胞活力。20分钟的孵育后使用TECAN公司的SPARK多功能酶标仪在化学发光的程序下进行读数。在Prism 7(LaJolla,CA)中使用S形剂量反应模型(可变斜率,四个参数)确定化合物使细胞成活率抑制50%的浓度(IC50值)。
本文所述的代表性化合物的非B-RAF突变细胞增殖抑制试验结果在表3中示出。
表3
由表3结果分析,本发明化合物对于MKN-45(WT)、NCI-H508(WT)、SW-48(WT)等非B-RAF突变的WT细胞增殖抑制活性远低于ASTX-029,针对BRAF突变的敏感细胞的选择性明显高于所列两个阳性化合物。
实施例37磷酸化ERK1/2(Thr202/Tyr204)试验
p-ERK细胞实验使用advance phospho-ERK1/2Kit试剂盒(Cisbio),参照生产商使用方法,步骤如下:A375细胞(5000cells/well)和Colo205细胞(50000cells/well)分别接种到96孔培养板中,37℃,5%CO2的培养箱中过夜(A375),Colo205细胞无需过夜。后加入ERK1/2的抑制剂,并在37℃,5%CO2的培养箱中孵育30min,ERK抑制剂的浓度为30,10,3.3,1.1,0.37,0.12,0.04,0.01,0.005,0.002,0.0005和0.0002μM。终止孵育通过加入supplemented lysis buffer,并室温震荡至少30min。待细胞完全裂解后,轻轻上下吸打混匀,从96孔板吸16μL细胞裂解液到OptiPlate-384 White孔板中,然后加入4μl等体积混合的检测抗体(detection buffer配制),盖膜,室温孵育4h。在TECAN(Switzerland)的SPARK多功能酶标仪器上读取平板,激发光波长为320nm,发射光波长为665nm。在Prism 7(LaJolla,CA)中使用S形剂量反应模型(可变斜率,四个参数)确定化合物使细胞成活率抑制50%的浓度(IC50值)。
本文所述的代表性化合物的磷酸化ERK1/2(Thr202/Tyr204)试验结果在表4中示出。
表4
由表4中实验结果表明,本发明化合物可以同时抑制ERK1/2下游的磷酸化及ERK1/2自身的磷酸化。
实施例38药物代谢动力学实验
将雄性CD-1小鼠(购自JH Laboratory Animal Co.LTD;19-27g;6-8周;n=18,每种给药途径9只,每个时间点3只动物)在测试化合物单一剂量条件下分别通过尾部静脉注射(2mg/kg)和口服饲喂(10mg/kg)进行给药处理,所用化合物溶液均在含5%N,N-二甲基亚砜(DMSO)和10%聚乙二醇15羟硬脂酸酯(Solutol HS15)的含20%羟丙基-β-环糊精(HP-β-CD)的生理盐水中配制。口服给药组动物在给药前一天禁食过夜并在给药之后4小时进食。静脉给药组动物给药后可自由获取食物和饮水。所述研究符合实验动物管理评估和认可协会(国际AAALAC)和美国国立卫生研究院的指南和标准。在指定的取样时间点,使用异氟烷麻醉动物后,通过面部静脉或心脏穿刺,在异氟醚吸入麻醉状态下采用交错出血的方式采集大约110μL的血液样品到EDTA-2K管中存储。所采集血液样品保持在湿冰中并且在采样后15分钟内离心,以获得血浆(2000g,4℃,5min)。将血浆样品储存在大约-70℃冷冻条件下,直至分析。在分析所采集血浆样品前,将30μL未稀释的血浆样品的等分试样加入200μL IS(含300ng/mL双氯芬酸或者20ng/mL格列甲嗪的乙腈溶液)。将混合物在750rpm条件下涡旋10min并在6000rpm下离心10min。取3μL上清液的等分试样,采用UPLC-MS/MS-010(API-4000)进行化合物浓度定量分析。通过分析含有双氯芬酸(300ng/mL)或者格列甲嗪(20ng/mL)作为内参的3.0-3,000ng/mL测试化合物的一系列对照血浆等分式样来构建标准校准曲线。对于10倍稀释的血浆样品,将3μL血液样品的等分试样加入27μL空白稀释血浆,稀释因子为10。随后的操作与上述未稀释的血浆样品相同。
本文所述的代表性化合物的PK结果见表5和表6。
表5
*参考文献数值
表6
由表5、表6实验结果显示,此类化合物PK数据大都优于阳性药Ulixertinib和阳性药ASTX-029,尤以化合物1,10A,11,27较为明显,其生物利用度同阳性药相近,但是体内清除率低于Ulixertinib,而远低于ASTX-029。Cmax及AUC明显优于阳性药Ulixertinib和阳性药ASTX-029。更优的药代动力学性质,结合优异的酶活抑制活性,更高的敏感细胞选择性,会在体内药效上体现出远优于阳性化合物的治疗窗口,更好的临床药效和安全性。
Claims (23)
1.式(Ⅰ)化合物:
或其立体异构体、药学上可接受的盐;
其中,X和Y分别独立的选自C或N;
R1选自C1-6烷基、3元至9元环烷基、包含1-3个N或O的3元至9元杂环烷基、6元至10元芳基、包含1-3个N或O的5元至6元杂芳基;所述烷基、环烷基、杂环烷基、芳基、杂芳基可选的被一个或多个R6取代,R6选自C1-6烷基,卤素、羟基、氨基、氰基、-(CH2)nCOOH或-(CO)(CH2)nCH3;
R2选自氢、卤素或可选的被一个或多个氟原子取代的C1-6烷基;
R3选自可选的被0-3个R7取代的6元至10元芳基或5至6元杂芳基,R7选自卤素、甲氧基、可选的被一个或多个氟原子取代的C1-6烷基;
R4选自-(CH2)n OH、-COOH;
R5选自C1-6烷基;
每个n各自独立的为0-3之间的整数。
3.根据权利要求2所述的化合物,其中:R2选自氢、卤素或可选的被一个或多个氟原子取代的C1-6烷基;R3选自可选的被0-3个R7取代的6元至10元芳基,R7选自卤素、甲氧基或可选的被一个或多个氟原子取代的C1-6烷基;R4为-(CH2)n OH;每个n各自独立的为0-3之间的整数。
9.一种化合物,选自:
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)吡啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺;
(R)-N-((S)-2-羟基-1-(间甲苯基)乙基)-2-(4-氧代-6-(2-((四氢-2H-吡喃-4-基)氨基)-5-(三氟甲基)嘧啶-4-基)吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)丙酰胺;
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(3-(三氟甲基)苯基)乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3,5-二甲基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3,5-二甲基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-苯乙基)丙酰胺;
(S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-苯乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((4,4-二氟环己基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺;
(S)-2-(6-(5-氯-2-((4,4-二氟环己基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺;
(2R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-(1-(3-氯苯基)-2-羟乙基)丙酰胺;
(2S)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-(1-(3-氯苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-(异丙基氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(异丙基氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2-(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2-(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(2R)-2-(6-(2-((8-氧杂双环[3.2.1]辛-3-基)氨基)-5-氯嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(2S)-2-(6-(2-((8-氧杂双环[3.2.1]辛-3-基)氨基)-5-氯嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-(((R)-3,3-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(((R)-3,3-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((2-氯-4-氟苯基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氯-5-氟苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-((2-氯-4-氟苯基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氯-5-氟苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-(((R)-2,2-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(((R)-2,2-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(4-氧代-6-(2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)丙酰胺;
(R)-2-(6-(5-氯-2-(((3S,4R)-3-甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(((3S,4R)-3-甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-(((1S,3R)-3-羟基环戊基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(((1S,3R)-3-羟基环戊基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-((3,3-二氟环)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-((3,3-二氟环)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(6-(5-甲基-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)丙酰胺;
(S)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(6-(5-甲基-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)丙酰胺;
2-(6-(5-氯-2-((1-甲基-2-氧代哌啶-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
2-(6-(2-((1-乙酰基哌啶-4-基)氨基)-5-氯嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3-(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-(((1r,4R)-4-甲氧基环己基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(((1r,4S)-4-甲氧基环己基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
2-(6-(5-氯-2-(((3S,4R)-3-甲氧基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
2-(6-(5-氯-2-(((3S,4R)-3-羟基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(6-(5-氯-2-(((3R,4R)-3-羟基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(S)-2-(6-(5-氯-2-(((3R,4R)-3-羟基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(7-(5-氯-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
2-(3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环丁基)乙酸;
4-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环己烷-1-羧酸;
(1R,3S)-3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环己烷-1-羧酸;
(1R,3S)-3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环戊烷-1-羧酸;
3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙烷-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环丁烷-1-羧酸;
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺;
(R)-2-(7-(5-氯-2-(异丙基氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(2R)-2-(7-(5-氯-2-((3,3-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(2R)-2-(7-(5-氯-2-((2,2-二甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-2-(7-(5-氯-2-(((3R,4R)-3-甲基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
(R)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(1-氧代-7-(2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)吡咯并[1,2-a]吡嗪-2(1H)-基)丙酰胺;
(R)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2-(1H)-基)-N-((S)-2-羟基-1-(间甲苯基)乙基)丙酰胺;
(R)-2-(7-(5-氯-2-(((1S,3R)-3-羟基环戊基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2-(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺。
10.根据权利要求9所述的化合物,其为:
N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)-2-(4-氧代-6-(2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)丙酰胺;
2-(6-(5-氯-2-((1-甲基-2-氧代哌啶-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
2-(6-(2-((1-乙酰基哌啶-4-基)氨基)-5-氯嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3-(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
2-(6-(5-氯-2-(((3S,4R)-3-甲氧基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
2-(6-(5-氯-2-(((3S,4R)-3-羟基四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺;
2-(3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环丁基)乙酸;
4-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环己烷-1-羧酸;
(1R,3S)-3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环己烷-1-羧酸;
(1R,3S)-3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环戊烷-1-羧酸;
3-((5-氯-4-(3-(1-(((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)氨基)-1-氧代丙烷-2-基)-4-氧代-3,4-二氢吡咯并[2,1-f][1,2,4]三嗪-6-基)嘧啶-2-基)氨基)环丁烷-1-羧酸。
11.根据权利要求9所述的化合物,其为:
(R)-2-(6-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-4-氧代吡咯并[2,1-f][1,2,4]三嗪-3(4H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺。
12.根据权利要求9所述的化合物,其为:
(R)-2-(7-(5-氯-2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-1-氧代吡咯并[1,2-a]吡嗪-2-(1H)-基)-N-((S)-1-(3-氟-5-甲氧基苯基)-2-羟乙基)丙酰胺。
13.权利要求1-12任一项所述的化合物用于制备预防或治疗ERK1/2介导的疾病药物的用途。
14.根据权利要求13所述的用途,其中所述ERK1/2介导的疾病为癌症。
15.根据权利要求14所述的用途,其中所述癌症为非小细胞肺癌、胰腺癌、结肠癌、胃癌、淋巴瘤或黑色素瘤。
16.一种药物组合物,其包含治疗有效量的根据权利要求1-12所述的化合物以及药学上可接受的载体或赋形剂。
19.根据权利要求17或18所述的化合物,其中R8选自氟、氯、溴、碘、硼酸基或频那醇硼烷基,R9选自甲基、乙基、异丙基或正丁基;Y选自C或N。
22.根据权利要求20或21所述的化合物,其中R11选自氟、氯、溴、碘或-NHR1;R10选自氢、甲基、乙基、异丙基或正丁基;X、Y、R1、R2具有权利要求1所定义的含义。
23.权利要求17至22任一项化合物用于制备权利要求1所述化合物的用途。
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