CN101633645A - 作为mek抑制剂的n3烷基化苯并咪唑衍生物 - Google Patents
作为mek抑制剂的n3烷基化苯并咪唑衍生物 Download PDFInfo
- Publication number
- CN101633645A CN101633645A CN200910149291A CN200910149291A CN101633645A CN 101633645 A CN101633645 A CN 101633645A CN 200910149291 A CN200910149291 A CN 200910149291A CN 200910149291 A CN200910149291 A CN 200910149291A CN 101633645 A CN101633645 A CN 101633645A
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- CN
- China
- Prior art keywords
- fluoro
- benzoglyoxaline
- chloro
- phenyl amino
- bromo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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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
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Abstract
本发明涉及式I的化合物及其药物学上可接受的盐和前药,其中W、R1、R2、R7、R8、R9和R10如说明书中所定义。此等化合物是MEK抑制剂,并且可用于治疗哺乳动物中过度增殖性疾病,如癌症和炎症。本发明还公开了使用所述化合物治疗哺乳动物中过度增殖性疾病的方法以及包含所述化合物的药物组合物。
Description
本申请是2003年3月13日提交的第03810754.6号发明名称为“作为MEK抑制剂的N3烷基化苯并咪唑衍生物”的中国专利申请的分案申请。
技术领域
本发明涉及一系列烷基化的(1H-苯并咪唑-5-基)-(4-取代的苯基)-胺衍生物,其可用于治疗哺乳动物中的过度增殖性疾病,如癌症和炎症。本发明还涉及在治疗哺乳动物、特别是人中的过度增殖性疾病时使用所述化合物的方法,还涉及包含这些化合物的药物组合物。
背景技术
通过生长因子受体和蛋白质激酶进行细胞信号传递是细胞生长、增殖和分化中的重要调节剂。在正常的细胞生长中,通过受体活化,生长因子(如PDGF或EGF等)激活MAP激酶通道。在正常和非受控细胞生长中最重要而且也是最被了解的MAP激酶通道之一是Ras/Raf激酶通道。活性GTP所结合的Ras导致Raf激酶的活化和间接磷酸化。Raf接着使两个丝氨酸残基上的MEK1和2磷酸化(对于MEK1是S218和S222,而对于MEK2是S222和S226(Ahn等人,Methods in Enzymology2001,332,417-431)。经活化的MEK然后使其已知的底物--MAP激酶(ERK1和2)磷酸化。由MEK产生的ERK磷酸化对于ERK1是发生在Y204和T202上,而对于ERK2是发生在Y185和T183上(Ahn等人,Methods in Enzymology 2001,332,417-431)。被磷酸化的ERK发生二聚合,然后移位至细胞核中,并在此累积(Khokhlatchev等人,Cell1998,93,605-615)。在该细胞核中,ERK参与数种重要的细胞功能中,包括但不限于核转运、信号传导、DNA修复、核小体组装和移位、以及mRNA加工和翻译(Ahn等人,Molecular Cell 2000,6,1343-1354)。总之,用生长因子处理细胞导致ERK1和2的活化,这又导致增殖,而且在某些情况下导致分化(Lewis等人,Adv.Cancer Res.1998,74,49-139)。
在增殖性疾病中,ERK激酶通道所涉及的生长因子受体、下游信号蛋白或蛋白激酶的基因突变和/或过度表达导致非受控的细胞增殖,并最终导致肿瘤形成。例如,一些癌症所包含的突变由于连续形成生长因子而导致该通道的连续活化。其他突变可在已活化的结合GTP的Ras复合物的去活化中导致缺陷产生,这又导致MAP激酶通道的活化。在50%的结肠和90%以上的胰腺癌,以及许多其他类型的癌症中都发现了突变、致癌性的Ras(Kohl等人,Science 1993,260,1834-1837)。最近,在60%以上的恶性黑素瘤中鉴别出bRaf突变(Davies,H.等人.Nature 2002,417,949-954)。bRaf中的这些突变导致组成性的活性MAP激酶级联。原生肿瘤样品和细胞系的研究也已表明胰腺、结肠、肺、卵巢和肾的癌症中MAP激酶通道的组成性或过度活化(Hoshino,R.等人,Oncogene 1999,18,813-822)。由此,在癌症和由于基因突变导致的过度活性的MAP激酶通道之间存在强烈的关联性。
因为MAP激酶级联的组成性或过度活化在细胞增殖和分化中起着重要的作用,相信抑制该通道在过度增殖性疾病中是有益的。因为在Ras和Raf的下游,MEK在该通道中是一个关键的因素。另外,其是一个具有吸引力的治疗目标,因为对于MEK磷酸化已知的底物是MAP激酶--ERK1和2。在多个研究中已表明抑制MEK具有潜在的治疗作用。例如,已表明小分子的MEK抑制剂在无毛鼠异种移植中抑制人肿瘤生长(Sebolt-Leopold等人,Nature-Medicine 1999,5(7),810-816;Trachet等人,AACR April 6-10,2002,Poster #5426;Tecle,H.IBC 2ndInternational Conference of Protein kinases,September 9-10,2002)、在动物中阻断静态异常性疼痛(2001年1月25日公布的WO 01/05390)、以及抑制极性髓性白血病细胞的生长(Milella等人,J Clin Invest 2001,108(6),851-859)。
已公开了MEK的小分子抑制剂。在过去的数年中,至少有13个专利申请:1995年1月24日申请的US 5,525,625;1998年10月8日公布的WO 98/43960;1999年1月14日公布的WO 99/01421;1999年1月14日公布的WO 99/0142;2000年7月20日公布的WO 00/41505;2000年7月20日公布的WO 00/42002,2000;2000年7月20日公布的WO00/42003;2000年7月20日公布的WO 00/41994;2000年7月20日公布的WO 00/42022;2000年7月20日公布的WO 00/42029;2000年11月16日公布的WO 00/68201;2001年9月20日公布的WO 01/68619;以及2002年1月24日公布的WO 02/06213。
发明内容
本发明提供式I的烷基化(1H-苯并咪唑-5-基)-(4-取代的苯基)-胺化合物及其药物学上可接受的盐和前药,它们可用于治疗过度增殖性疾病。具体而言,本发明涉及用作MEK抑制剂的式I化合物。本发明还提供治疗癌症的方法。本发明还提供包含式I的化合物的制剂以及使用该化合物治疗患者的方法。另外,本发明还描述了制备式I的抑制剂化合物的方法。
因此,本发明提供式I的化合物及其药物学上可接受的盐、前药和溶剂化物:
其中:
------是任选的键,条件是:环中有且仅有一个氮是双键的;
R1、R2、R9和R10独立地选自于氢、卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-OR3、-C(O)R3、-C(O)OR3、-NR4C(O)OR6、-OC(O)R3、-NR4SO2R6、-SO2NR3R4、-NR4C(O)R3、-C(O)NR3R4、-NR5C(O)NR3R4、-NR5C(NCN)NR3R4、-NR3R4,以及
C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、C3-C10环烷基烷基、-S(O)j(C1-C6烷基)、-S(O)j(CR4R5)m-芳基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基、-O(CR4R5)m-芳基、-NR4(CR4R5)m-芳基、-O(CR4R5)m-杂芳基、-NR4(CR4R5)m-杂芳基、-O(CR4R5)m-杂环基以及-NR4(CR4R5)m-杂环基,其中每个烷基、烯基、炔基、环烷基、芳基、杂芳基和杂环基部分可任选地被1-5个独立地选自于以下组中的基团取代:氧代、卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-NR4SO2R6、-SO2NR3R4、-C(O)R3、-C(O)OR3、-OC(O)R3、-NR4C(O)OR6、-NR4C(O)R3、-C(O)NR3R4、-NR3R4、-NR5C(O)NR3R4、-NR5C(NCN)NR3R4、-OR3、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基、和杂环基烷基;
R3选自于氢、三氟甲基、以及
C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、C3-C10环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、和杂环基烷基,其中每个烷基、烯基、炔基、环烷基、芳基、杂芳基和杂环基部分可任选地被1-5个独立地选自于以下组中的基团取代:氧代、卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-NR′SO2R″″、-SO2NR′R″、-C(O)R′、-C(O)OR′、-OC(O)R′、-NR′C(O)OR″″、-NR′C(O)R″、-C(O)NR′R″、-SR′、-S(O)R″″、-SO2R″″、-NR′R″、-NR′C(O)NR″R″′、-NR′C(NCN)NR″R″′、-OR′、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基、和杂环基烷基;
R′、R″和R″′独立地选自于氢、低级烷基、低级烯基、芳基和芳基烷基;
R″″选自于低级烷基、低级烯基、芳基和芳基烷基;或者
R′、R″、R″′或R″″中的任意两个可与它们所连接的原子一起形成4-10元碳环、杂芳基或杂环,这些基团中每一个都可任选地被1-3个独立地选自于以下组中的基团取代:卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基、和杂环基烷基;或者
R3和R4与它们所连接的原子一起形成4-10元碳环、杂芳基或杂环,这些基团中每一个都可任选地被1-3个独立地选自于以下组中的基团取代:卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-NR′SO2R″″、-SO2NR′R″、-C(O)R′、-C(O)OR′、-OC(O)R′、-NR′C(O)OR″″、-NR′C(O)R″、-C(O)NR′R″、-SO2R″″、-NR′R″、-NR′C(O)NR″R″′、-NR′C(NCN)NR″R″′、-OR′、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基、和杂环基烷基;或者
R4和R5独立地代表氢或C1-C6烷基;或者
R4和R5与它们所连接的原子一起形成4-10元碳环、杂芳基或杂环,这些基团中每一个都可任选地被1-3个独立地选自于以下组中的基团取代:卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-NR′SO2R″″、-SO2NR′R″、-C(O)R″″、-C(O)OR′、-OC(O)R′、-NR′C(O)OR″″、-NR′C(O)R″、-C(O)NR′R″、-SO2R″″、-NR′R″、-NR′C(O)NR″R″′、-NR′C(NCN)NR″R″′、-OR′、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基、和杂环基烷基;
R6选自于三氟甲基、以及
C1-C10烷基、C3-C10环烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基,其中每个烷基、环烷基、芳基、杂芳基和杂环基部分可任选地被1-5个独立地选自于以下组中的基团取代:氧代、卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-NR′SO2R″″、-SO2NR′R″、-C(O)R′、-C(O)OR′、-OC(O)R′、-NR′C(O)O R″″、-NR′C(O)R″、-C(O)NR′R″、-SO2R″″、-NR′R″、-NR′C(O)NR″R″′、-NR′C(NCN)NR″R″′、-OR′、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基、和杂环基烷基;
R7选自于氢、以及
C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、C3-C10环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基,其中每个烷基、烯基、炔基、环烷基、芳基、杂芳基和杂环基部分可任选地被1-5个独立地选自于以下组中的基团取代:氧代、卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-NR4SO2R6、-SO2NR3R4、-C(O)R3、-C(O)OR3、-OC(O)R3、-NR4C(O)OR6、-NR4C(O)R3、-C(O)NR3R4、-SO2R6、-NR3R4、-NR5C(O)NR3R4、-NR5C(NCN)NR3R4、-OR3、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基、和杂环基烷基;
W选自于杂芳基、杂环基、-C(O)OR3、-C(O)NR3R4、-C(O)NR4OR3、-C(O)R4OR3、-C(O)(C3-C10环烷基)、-C(O)(C1-C10烷基)、-C(O)(芳基)、-C(O)(杂芳基)和-C(O)(杂环基),这些基团中的每一个都可任选地被1-5个独立地选自于以下组中的基团取代:
-NR3R4、-OR3、-R2、以及
C1-C10烷基、C2-C10烯基、和C2-C10炔基,它们中的每一个都任选地被1或2个选自于-NR3R4和-OR3中的基团取代;
R8选自于氢、-SCF3、-Cl、-Br、-F、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-OR3、-C(O)R3、-C(O)OR3、-NR4C(O)OR6、-OC(O)R3、-NR4SO2R6、-SO2NR3R4、-NR4C(O)R3、-C(O)NR3R4、-NR5C(O)NR3R4、-NR3R4、以及
C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、C3-C10环烷基烷基、-S(O)j(C1-C6烷基)、-S(O)j(CR4R5)m-芳基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基、-O(CR4R5)m-芳基、-NR4(CR4R5)m-芳基、-O(CR4R5)m-杂芳基、-NR4(CR4R5)m-杂芳基、-O(CR4R5)m-杂环基和-NR4(CR4R5)m-杂环基,其中每个烷基、烯基、炔基、环烷基、芳基、杂芳基和杂环基部分可任选地被1-5个独立地选自于以下组中的基团取代:氧代、卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-NR4SO2R6、-SO2NR3R4、-C(O)R3、-C(O)OR3、-OC(O)R3、-NR4C(O)OR6、-NR4C(O)R3、-C(O)NR3R4、-NR3R4、-NR5C(O)NR3R4、-NR5C(NCN)NR3R4、-OR3、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基、和杂环基烷基;
m是0、1、2、3、4或5;以及
j是1或2。
具体实施方式
本发明中包括的新化合物是那些如上述通式I所描述的化合物、及其药物学上可接受的盐和前药。
本发明还提供式I的化合物,其中R7是C1-C10烷基、C3-C7环烷基、C3-C7环烷基烷基、C3-C7杂环烷基或C3-C7杂环烷基烷基,它们中的每一个可任选地被1-3个独立地选自于以下组中的基团取代:氧代、卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-NR4SO2R6、-SO2NR3R4、-C(O)R3、-C(O)OR3、-OC(O)R3、-SO2R3、-NR4C(O)OR6、-NR4C(O)R3、-C(O)NR3R4、-NR3R4、-NR5C(O)NR3R4、-NR5C(NCN)NR3R4、-OR3、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基、和杂环基烷基。
本发明还提供式I的化合物其中R8是-OCF3、-Br或-Cl,R2是氢,而R1是低级烷基或卤素。
本发明还提供式I的化合物,其中R9是氢或卤素,而R10是氢。
本发明还提供式I的化合物,其中W是-C(O)OR3或-C(O)NR4OR3。
本发明还提供式II的化合物:
其中W、R1、R7、R8、R9和R10如以上式I所述。
本发明还提供式II的化合物,其中R7是C1-C10烷基、C3-C7环烷基或C3-C7环烷基烷基,这些基团中的每一个都可任选地被1-3个独立地选自于以下组中的基团取代:氧代、卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-NR4SO2R6、-SO2NR3R4、-C(O)R3、-C(O)OR3、-OC(O)R3、-SO2R3、-NR4C(O)OR6、-NR4C(O)R3、-C(O)NR3R4、-NR3R4、-NR5C(O)NR3R4、-NR5C(NCN)NR3R4、-OR3、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基、和杂环基烷基。
本发明还提供式II的化合物,其中R8是-OCF3、-Br或-Cl,而R1是低级烷基或卤素。
本发明还提供式II的化合物,其中R9是氢或卤素,而R10是氢。
本发明还提供式II的化合物,其中W是-C(O)OR3或-C(O)NR4OR3。
本发明还提供式III的化合物:
其中W、R1、R7、R8、R9和R10如以上式I所述,而A是-OR3或-NR4OR3,其中R3和R4如以上式I所述。
本发明还提供式III的化合物,其中R7是C1-C10烷基、C3-C7环烷基或C3-C7环烷基烷基,这些基团中的每一个都可任选地被1-3个独立地选自于以下组中的基团取代:氧代、卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-NR4SO2R6、-SO2NR3R4、-C(O)R3、-C(O)OR3、-OC(O)R3、-SO2R3、-NR4C(O)OR6、-NR4C(O)R3、-C(O)NR3R4、-NR3R4、-NR5C(O)NR3R4、-NR5C(NCN)NR3R4、-OR3、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基、和杂环基烷基。
本发明还提供式III的化合物,其中R8是-OCF3、-Br或-Cl,R2是氢,而R1是低级烷基或卤素。
本发明还提供式III的化合物,其中R9是氢或卤素。
本发明还提供式III的化合物,其中当A是-OR3时,R3是氢或低级烷基;以及当A是-NR4OR3时,R4是氢。
本发明还提供式IIIa的化合物:
其中R1、R2、R7、R8和R9如以上式I所述,而A是-OR3或-NR4OR3,其中R3和R4如以上式I所述。
本发明还提供式IIIa的化合物,其中R7是C1-C10烷基、C3-C7环烷基或C3-C7环烷基烷基,这些基团中的每一个都可任选地被1-3个独立地选自于以下组中的基团取代:氧代、卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-NR4SO2R6、-SO2NR3R4、-C(O)R3、-C(O)OR3、-OC(O)R3、-SO2R3、-NR4C(O)OR6、-NR4C(O)R3、-C(O)NR3R4、-NR3R4、-NR5C(O)NR3R4、-NR5C(NCN)NR3R4、-OR3、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基、和杂环基烷基。
本发明还提供式IIIa的化合物,其中R8是-OCF3、-Br或-Cl,R2是氢,而R1是低级烷基或卤素。
本发明还提供式IIIa的化合物,其中R9是氢或卤素。
本发明还提供式IIIa的化合物,其中当A是-OR3时,R3是氢或低级烷基;以及当A是-NR4OR3时,R4是氢。
本发明还提供式IIIb的化合物:
其中R1、R7、R8和R9如以上式I所述,而A是-OR3或-NR4OR3,其中R3和R4如以上式I所述。
本发明还提供式IIIb的化合物,其中R7是C1-C10烷基、C3-C7环烷基或C3-C7环烷基烷基,这些基团中的每一个都可任选地被1-3个独立地选自于以下组中的基团取代:氧代、卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-NR4SO2R6、-SO2NR3R4、-C(O)R3、-C(O)OR3、-OC(O)R3、-SO2R3、-NR4C(O)OR6、-NR4C(O)R3、-C(O)NR3R4、-NR3R4、-NR5C(O)NR3R4、-NR5C(NCN)NR3R4、-OR3、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基、和杂环基烷基。
本发明还提供式IIIb的化合物,其中R8是-OCF3、-Br或-Cl,而R1是低级烷基或卤素。
本发明还提供式IIIb的化合物,其中R9是氟或氯。
本发明还提供式IIIb的化合物,其中当A是-OR3时,R3是氢或低级烷基;以及当A是-NR4OR3时,R4是氢。
除非另有明确定义外,在本发明的说明书中使用的术语采用以下定义。
本发明中术语“C1-C10烷基”、“烷基”和“低级烷基”是指具有1-10个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、n-丁基、sec-丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基、3-己基、3-甲基戊基、庚基、辛基等。优选的烷基是C1-6烷基。更优选的烷基是C1-3烷基。
术语“C2-C10烯基”、“低级烯基”和“烯基”是指具有2-10个碳原子以及至少一个双键的烃基,并且包括乙烯基、丙烯基、1-丁-3-烯基、1-戊-3-烯基、1-己-5-烯基等。更优选的是具有3-5个碳原子的低级烯基。
术语“C2-C10炔基”、“低级炔基”和“炔基”是指具有2-10个碳原子以及至少一个叁键的烃基,并且包括乙炔基、丙炔基、丁炔基、戊炔-2-基等。更优选的是具有3-5个碳原子的炔基。
在本发明中术语“卤素”是指氟、溴、氯和碘。
术语“芳基”是指具有单环(如苯基)、多环(如联苯基)或其中至少一个是芳香环的多个稠合环(如1,2,3,4-四氢萘基、萘基)的芳香碳环基,其任选被例如卤素、低级烷基、低级烷氧基、三氟甲基、芳基、杂芳基、和羟基单、二或三取代。
术语“杂芳基”是指5-、6-或7-元环的一个或多个芳香环系,其包括稠合环系(其中至少一个是芳香性的),具有5-10个原子,其中有至少一个并最多4个选自于氮、氧或硫的杂原子。杂芳基的例子有吡啶基、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、噌啉基、吲唑基、中氮茚基、2,3-二氮杂萘基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、三唑基、噻二唑基、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、喹喔啉基、1,5-二氮杂萘基、以及呋喃并吡啶基。螺环部分也包括在该定义的范围内。杂芳基任选地被例如卤素、低级烷基、低级烷氧基、卤代烷基、芳基、杂芳基、和羟基单、二或三取代。
在此所用术语“碳环”、“碳环基”、“环烷基”或“C3-C10环烷基”是指具有3-10个碳原子的饱和碳环基团。该环烷基可以是单环或者多环稠合系统,而且可以稠合在芳香环上。此等基团的例子包括环丙基、环丁基、环戊基和环己基。该环烷基在此可以是未取代的,或者如详细说明,可在一个或者多个合适的位置处被各种基团取代。例如,此等环烷基可任选地被例如以下基团取代:C1-C6烷基、C1-C6烷氧基、卤素、羟基、氰基、硝基、氨基、单(C1-C6)烷基氨基、二(C1-C6)烷基氨基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6卤代烷氧基、氨基(C1-C6)烷基、单(C1-C6)烷基氨基(C1-C6)烷基或二(C1-C6)烷基氨基(C1-C6)烷基。
术语“杂环”或“杂环基”是指5-、6-或7-元环的一个或者多个碳环环系,其包括稠合环系,具有4-10个原子,其中包含至少1个至最多4个选自于氮、氧或硫的杂原子,其条件是:该基团的环不包含两个相邻的O或S原子。稠合环系可以是稠合在芳香基团上的杂环。优选的杂环包括但不限于吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢硫代吡喃基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、哌嗪基、高哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、高哌啶基、氧杂环戊烷基(oxepanyl)、硫杂环戊烷基(thiepanyl)、氧氮杂卓(oxazepinyl)、二氮杂卓、硫氮杂卓(thiazepinyl)、1,2,3,6-四氢吡啶基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二噁烷基、1,3-二氧戊环基、吡唑啉基、二噻烷基、二硫戊环基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基咪唑啉基、咪唑啉基、3-氮杂二环[3.1.0]己烷基、3-氮杂二环[4.1.0]庚烷基、氮杂二环[2.2.2]己烷基、3H-吲哚基和喹嗪基。螺环部分也包括在该定义的范围内。如有可能,衍生于上述基团的基团可以是C-连接的或N-连接的。例如,衍生于吡咯基的基团可以吡咯-1-基(N-连接的)或吡咯-3-基(C-连接的)。另外,衍生于咪唑的基团可以是咪唑-1-基(N-连接的)或咪唑-3-基(C-连接的)。其中2个环碳原子被氧代基团(=O)取代杂环基的例子是1,1-二氧代-卤代吗啉基。杂环基在此可以是未取代的,或者如详细说明,可在一个或者多个合适的位置处被各种基团取代。例如,此等杂环基可任选地被例如以下基团取代:C1-C6烷基、C1-C6烷氧基、卤素、羟基、氰基、硝基、氨基、单(C1-C6)烷基氨基、二(C1-C6)烷基氨基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6卤代烷氧基、氨基(C1-C6)烷基、单(C1-C6)烷基氨基(C1-C6)烷基或二(C1-C6)烷基氨基(C1-C6)烷基。
术语“芳基烷基”是指被一个或者多个(如上定义的)芳基取代的(如上定义的)烷基。更优选的芳基烷基是芳基-C1-3-烷基。其例子包括苄基、苯基乙基等。
术语“杂芳基烷基”是指被一个或者多个(如上定义的)杂芳基取代的(如上定义的)烷基。更优选的杂芳基烷基是5-或6-元杂芳基-C1-3-烷基。其例子包括噁唑基甲基、吡啶基乙基等。
术语“杂环基烷基”是指被一个或者多个(如上定义的)杂环基取代的(如上定义的)烷基。更优选的杂环基烷基是5或6元杂环基-C1-3-烷基。其例子包括四氢呋喃基甲基。
术语“环烷基烷基”是指被一个或者多个(如上定义的)环烷基取代的(如上定义的)烷基。更优选的环烷基烷基是5或6元环烷基-C1-3-烷基。其例子包括环丙基甲基。
术语“Me”代表甲基,“Et”代表乙基,“Bu”代表丁基,而“Ac”代表乙酰基。
除非另有说明,在此所用术语“药物学上可接受的盐”包括在本发明化合物中存在的酸性和碱性基团的盐。本身为碱性的本发明化合物能够与各种无机和有机酸形成各种盐。可用于制备本发明碱性化合物的药物学上可接受的酸加成盐的酸是那些能够形成无毒性酸加成盐的酸,即、包含药物学上可接受的阴离子的盐,如乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、钙、樟脑磺酸盐(camsylate)、碳酸盐、氯化物、clavulanate、柠檬酸盐、二盐酸盐、edislyate、estolate、乙磺酸盐、乙基琥珀酸盐、富马酸盐、gluceptate、葡糖酸盐、谷氨酸盐、乙醇酰阿散酸盐、己基resorcinate、hydrabamine、氢溴酸盐、盐酸盐、碘化物、isothionate、乳酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、粘酸盐、萘磺酸盐、硝酸盐、油酸盐、草酸盐、pamoate(embonate)、棕榈酸盐、泛酸盐、磷酸盐/磷酸氢盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、碱式乙酸盐、琥珀酸盐、单宁酸盐、酒石酸盐、teoclate、甲苯磺酸盐、triethiodode、以及戊酸盐。因为本发明的单个化合物可包括一个以上的酸性或碱性基团,所以本发明的化合物在单个化合物中有可能包括单、二或三盐。
如果在本发明的化合物中存在酸性基团,则可通过用碱性化合物处理本发明的化合物来形成盐,特别是用无机碱。优选的无机盐是那些用碱金属和碱土金属形成的盐,如锂、钠、钾、钡和钙。优选的有机碱盐包括例如铵、二苄基铵、苄基铵、2-羟基乙基铵、二(2-羟基乙基)铵、苯基乙基苄基胺、二苄基-亚乙基二胺等盐。酸性基团的其他盐包括例如那些用以下物质形成的盐:普鲁卡因、奎宁和N-甲基葡糖胺,以及与碱性氨基酸形成的盐,如甘氨酸、鸟氨酸、组氨酸、苯基甘氨酸、赖氨酸和精氨酸。特别优选的盐是本发明化合物的钠或钾盐。
对于碱性基团,所述盐是用酸性化合物、特别是无机酸处理本发明的化合物而形成的盐。优选的该类型的无机盐包括例如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐等。优选的该类型的有机盐包括例如与以下有机酸形成的盐:甲酸、乙酸、琥珀酸、柠檬酸、乳酸、马来酸、富马酸、棕榈酸、胆酸、粘酸、D-谷氨酸、D-樟脑酸、戊二酸、乙醇酸盐、邻苯二甲酸、酒石酸、月桂酸、硬脂酸、水杨酸、甲磺酸、苯磺酸、对甲苯磺酸、山梨酸、puric、苯甲酸、肉桂酸等。特别优选的该类型的盐是本发明化合物的盐酸盐或硫酸盐。
在本发明的化合物中,在使用诸如(CR4R5)m或(CR4R5)t的术语时,R4和R5可随着1以上的m或t而变化。例如,如果m或t是2,术语(CR4R5)m或(CR4R5)t可等于-CH2CH2-或-CH(CH3)C(CH2CH3)(CH2CH2CH3)-或任意数量的在R4和R5定义范围内的类似基团。
本发明的某些化合物可具有不对称中心,并且因此以不同对映体的形式存在。本发明化合物所有可能的异构体和立体异构体、以及它们的混合物也被认为是在本发明的范围之内。对于本发明的化合物,本发明包括外消旋体、一种或多种对映体、一种或多种非对映异构体、或者它们的混合物的应用。本发明的化合物也可为互变异构体的形式。本发明涉及所有此等互变异构体及其混合物的应用。
本发明还包括经同位素标记的化合物,该化合物与本发明的化合物是相同的,但是其中一个或者多个原子被具有与天然原子量或原子数不同的原子量或原子数的原子置换。可掺入在本发明化合物中的同位素的例子包括氢、碳、氮、氧、鳞、硫、氟和氯的同位素,如分别是2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F、和36Cl。本发明的化合物、其前药、以及包含上述同位素和/或其他原子的同位素的所述化合物或所述前药的药物学上可接受的盐也在本发明的范围内。某些经同位素标记的本发明的化合物,例如那些掺入放射性同位素如3H和14C的化合物,可用于药物和/或底物组织分布分析中。氚化的(即3H)以及碳-14(即14C)同位素对于制备和可检测性是特别优选的。另外,用更重的同位素如氘(即2H)取代,由于具有更高的代谢稳定性,可提供某些有利的治疗价值,如增加体内半衰期或降低所需的剂量,并因此在某些情况下是优选的。经同位素标记的本发明的化合物及其前药通常可通过用易于得到的经同位素标记的试剂替代未被同位素标记的试剂按照以下合成路线和/或实施例和制备例中描述的方法来制备。
本发明还包括包含式I-IIIb化合物的药物组合物以及通过给药本发明的化合物的前药来治疗增殖性疾病或异常细胞生长的方法。具有游离氨基、酰胺基、羟基或羧基的本发明化合物可转化为前药。该前药包括以下化合物:氨基酸残基或由一个或多个(如2、3或4个)氨基酸残基组成的多肽链通过酰胺或酯键共价连接在本发明化合物的游离氨基、羟基或羧基上。氨基酸残基包括但不限于20个通常用3个字母符号表示的天然氨基酸,而且还包括4-羟基脯氨酸、羟基赖氨酸、demosine、isodemosine、3-甲基组氨酸、正缬氨酸、β-丙氨酸、γ-氨基丁酸、cirtulline、高半胱氨酸、高丝氨酸、鸟氨酸和氮氨酸砜。也包括其他类型的前药。例如,游离羧基可衍生为酰胺或烷基酯。如Advanced DrugDelivery Reviews 1996,19,115中所述,游离羟基通过使用以下基团来进行衍生化,所述基团包括但不限于半琥珀酸酯、磷酸酯、二甲基氨基乙酸酯和磷酰基氧基甲基氧基羰基。羟基和氨基的氨基甲酸酯前药,以及羟基的碳酸酯前药、磺酸酯和硫酸酯,也包括在内。还包括羟基的衍生化如(酰基氧基)甲基和(酰基氧基)乙基醚,其中所述酰基可以是烷基酯,任选被包括但不限于醚、胺和羧酸官能团的基团取代,或者其中所述酰基是如上所述的氨基酸酯。该类型的前药描述在以下文献中:J.Med.Chem.1996,39,10。游离胺也可被衍生为酰胺、磺酰胺或膦酰胺。所有这些其他部分可掺入包括但不限于醚、胺和羧酸官能团的基团。
应理解的是,如果两个或者更多的基团被连续地用于限定连接在结构上的取代基,则第一个命名的基团被认为是端基,而最后命名的基团被认为是连接在所需的结构上。因此,例如,芳基烷基是通过烷基连接在所需的结构上。
本发明还涉及用于治疗哺乳动物中过度增殖性疾病的药物组合物,该组合物包括治疗有效量的本发明的化合物或其药物学上可接受的盐、前药或水合物,以及药物学上可接受的载体。在一个实施方案中,所述药物组合物是用于治疗癌症,如脑、肺、鳞状细胞、膀胱、胃、胰腺、乳腺、头、颈、肾、卵巢、前列腺、结肠直肠、食管、睾丸、妇科或甲状腺癌。在另一个实施方案中,所述药物组合物是用于治疗非癌症性的过度增殖性疾病,如良性的皮肤(如牛皮癣)、再狭窄、或前列腺(如良性的前列腺肥大(BPH))增生。
本发明还涉及用于治疗哺乳动物中胰腺炎或肾疾病(包括增殖性肾小球肾炎和糖尿病诱发的肾疾病)或者治疗哺乳动物疼痛的药物组合物,其包括治疗有效量的本发明的化合物或其药物学上可接受的盐、前药或水合物,以及药物学上可接受的载体。
本发明还涉及用于预防哺乳动物中胚细胞移植的药物组合物,其包括治疗有效量的本发明的化合物或其药物学上可接受的盐、前药或水合物,以及药物学上可接受的载体。
本发明还涉及用于治疗哺乳动物中与血管发生或血管形成有关的疾病的药物组合物,其包括治疗有效量的本发明的化合物或其药物学上可接受的盐、前药或水合物,以及药物学上可接受的载体。在一个实施方案中,所述药物组合物是用于治疗选自于以下组中的疾病:肿瘤血管发生,慢性炎性疾病如类风湿性关节炎,动脉硬化,炎性肠疾病,皮肤疾病如牛皮癣、疹、和硬皮病,糖尿病,糖尿病性视网膜炎,早熟性视网膜炎,与年龄有关的肌肉减退,血管瘤,神经胶质瘤,黑素瘤,卡波济肉瘤,以及卵巢、乳腺、肺、胰腺、前列腺、结肠和表皮癌。
本发明还涉及治疗哺乳动物中过度增殖性疾病的方法,其包括向所述哺乳动物给药治疗有效量的本发明的化合物或其药物学上可接受的盐、前药或水合物。在一个实施方案中,所述方法涉及治疗以下疾病:癌症,如脑、肺、鳞状细胞、膀胱、胃、胰腺、乳腺、头、颈、肾、卵巢、前列腺、结肠直肠、食管、睾丸、妇科或甲状腺癌。在另一个实施方案中,所述方法是用于治疗非癌症性的过度增殖性疾病,如良性的皮肤(如牛皮癣)、再狭窄、或前列腺(如良性的前列腺肥大(BPH))增生。
本发明还涉及治疗哺乳动物中过度增殖性疾病的方法,其包括向所述哺乳动物给药治疗有效量的本发明的化合物或其药物学上可接受的盐、前药或水合物以及选自于以下组中的抗肿瘤剂:有丝分裂抑制剂、烷基化剂、抗代谢药物、插入抗生素、生长因子抑制剂、细胞周期抑制剂、酶抑制剂、拓扑异构酶抑制剂、生物反应调节剂、抗激素药、血管发生抑制剂、以及抗雄激素。
本发明还涉及治疗哺乳动物中胰腺炎和肾疾病的方法,其包括向所述哺乳动物给药治疗有效量的本发明的化合物或其药物学上可接受的盐、前药或水合物。
本发明还涉及预防哺乳动物中胚细胞移植的方法,其包括向所述哺乳动物给药治疗有效量的本发明的化合物或其药物学上可接受的盐、前药或水合物。
本发明还涉及治疗哺乳动物中与血管发生或血管形成有关的疾病的方法,其包括向所述哺乳动物给药治疗有效量的本发明的化合物或其药物学上可接受的盐、前药或水合物。在一个实施方案中,所述方法是用于治疗选自于以下组中的疾病:肿瘤血管发生,慢性炎性疾病如类风湿性关节炎,动脉硬化,炎性肠疾病,皮肤疾病如牛皮癣、疹、和硬皮病,糖尿病,糖尿病性视网膜炎,早熟性视网膜炎,与年龄有关的肌肉减退,血管瘤,神经胶质瘤,黑素瘤,卡波济肉瘤,以及卵巢、乳腺、肺、胰腺、前列腺、结肠和表皮癌。
根据本发明的方法,可用本发明的化合物或其药物学上可接受的盐、前药和水合物治疗的患者包括例如已被诊断患有以下疾病的患者:牛皮癣,再狭窄,动脉粥样硬化,BPH,肺癌,骨癌,CMML,胰腺癌,皮肤癌,头和颈的,皮肤或眼内黑素瘤,子宫癌,卵巢癌,直肠癌,肛门区域的癌症,胃癌,结肠癌,乳腺癌,睾丸癌,妇科肿瘤(如子宫肌瘤、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌或外阴癌),何杰金(Hodgkin)氏病,食管癌,小肠癌,内分泌系统的癌症(如甲状腺癌、甲状旁腺癌或肾上腺癌),软组织的肉瘤,尿道癌,阴茎癌,前列腺癌,慢性或急性白血病,儿童实体瘤,淋巴细胞的淋巴瘤,膀胱癌,肾或输尿管癌(如肾细胞癌、肾盂癌),或者中枢神经系统的癌症(如原发性CNS淋巴瘤、脊椎轴肿瘤、脑干神经胶质瘤或垂体腺癌)。
本发明还涉及用于抑制哺乳动物中异常细胞生长的药物组合物,其包括本发明的化合物或其药物学上可接受的盐、前药或水合物以及化疗剂,其中本发明化合物、其盐、溶剂化物或前药的量以及所述化疗剂的量在一起能够有效地抑制异常细胞生长。目前在本领域中已知许多的化疗剂。在一个实施方案中,所述化疗剂选自于以下组中:有丝分裂抑制剂、烷基化剂、抗代谢药物、插入抗生素、生长因子抑制剂、细胞周期抑制剂、酶抑制剂、拓扑异构酶抑制剂、生物反应调节剂、抗激素药、血管发生抑制剂、以及抗雄激素。
本发明还涉及用于抑制哺乳动物中异常细胞生长或者治疗过度增殖性疾病的方法,其包括向所述哺乳动物给药一定量的本发明的化合物或其药物学上可接受的盐、前药或水合物并联合放射疗法,其中本发明化合物、其盐、溶剂化物或前药的量以及放射疗法在一起能够在哺乳动物中有效地抑制异常细胞生长或者治疗过度增殖性疾病。给药放射治疗剂的技术在本领域中是已知的,而且这些技术都可用于以上联合疗法中。在该组合疗法中本发明化合物的给药量可如下所述进行确定。
据信,本发明的化合物能够使异常细胞对于用于杀死和/或抑制此等细胞生长的放射治疗更为敏感。因此,本发明还涉及用于使哺乳动物中的异常细胞对于放射治疗更加敏感的方法,其包括向所述哺乳动物给药一定量的本发明化合物或其药物学上可接受的盐或溶剂化物或前药,其中所述量对于增加异常细胞对放射治疗的敏感性是有效的。在该方法中,本发明化合物、其盐或溶剂化物的量可根据如下所述的用于测定这些化合物的有效量的方法来确定。
本发明还涉及抑制哺乳动物中异常细胞生长的方法和药物组合物,其包括一定量的本发明的化合物或其药物学上可接受的盐或溶剂化物、前药、或同位素标记的衍生物,以及一定量的一种或多种选自于抗血管发生剂、信号传导抑制剂、和抗增殖剂的物质。
抗血管发生剂如MMP-2(基质-金属蛋白酶2)抑制剂、MMP-9(基质-金属蛋白酶9)抑制剂和COX-II(环加氧酶II)抑制剂可与本发明的化合物以及药物组合物联合使用。有用的COX-II抑制剂的例子包括CELEBREXTM(alecoxib)、伐地考昔、和罗非考昔。有用的基质金属蛋白酶抑制剂的例子描述在以下文献中:WO 96/33172(1996年10月24日公开)、WO 96/27583(1996年3月7日公开)、第97304971.1号欧洲专利申请(1997年7月8日申请)、第99308617.2号欧洲专利申请(1999年10月29日申请)、WO 98/07697(1998年2月26日公开)、WO 98/03516(1998年1月29日公开)、WO98/34918(1998年8月13日公开)、WO 98/34915(1998年8月13日公开)、WO 98/33768(1998年8月16日公开)、第606,046号欧洲专利公布(1994年7月13日公开)、第931,788号欧洲专利公布(1999年7月28日公开)、WO 90/05719(1990年5月31日公开)、WO99/52910(1999年10月21日公开)、WO 99/52889(1999年10月21日公开)、WO 99/29667(1999年6月17日公开)、第PCT/IB98/01113号PCT国际申请(1998年7月21日申请)、第99302232.1号欧洲专利申请(1999年3月25日申请)、第9912961.1号英国专利申请(1999年6月3日申请)、第60/148,464号美国临时专利申请(1999年8月12日申请)、第5,863,949号美国专利(1999年1月26日授权)、第5,861,510号美国专利(1999年1月19日授权)、以及第号欧洲专利公布780,386(1997年6月25日公开),所有以上文献的内容在此全部并入作为参考。优选的MMP-2和MMP-9抑制剂是那些在抑制MMP-1方面几乎没有或者根本没有活性的抑制剂。更优选的是那些相对于其他基质-金属蛋白酶(即、MMP-1、MMP-3、MMP-4、MMP-5、MMP-6、MMP-7、MMP-8、MMP-10、MMP-11、MMP-12、和MMP-13)选择性抑制MMP-2和/或MMP-9的抑制剂。
一些可用于本发明中的MMP抑制剂的具体例子是AG-3340、RO32-3555、和RS 13-0830。
术语“异常细胞生长”和“过度增殖性疾病”在本申请是可以相互交换使用的。
除非另有说明,在此所用术语“异常细胞生长”是指独立于正常细胞调节机制(如接触抑制作用丢失)的细胞生长。这例如包括以下的异常生长:(1)通过表达突变的酪氨酸激酶或者受体酪氨酸激酶的过度表达而增殖的肿瘤细胞(肿瘤);(2)其中发生异常酪氨酸激酶活化的其他增殖性疾病的良性和恶性细胞;(3)任何通过受体酪氨酸激酶增殖的肿瘤;(4)任何通过异常丝氨酸/苏氨酸激酶活化而增殖的肿瘤;以及(5)其中发生异常丝氨酸/苏氨酸激酶活化的其他增殖性疾病的良性和恶性细胞。
除非另有说明,在此所用术语“治疗”是指反转、缓解、抑制该术语所适用的疾病或病症、或者所述疾病或病症的一种或多种症状。
包括在本发明中的代表性的本发明化合物包括但不限于实施例中的化合物及其药物学上可接受的酸或碱加成盐或前药。
以下实施例仅是用于说明本发明的具体实施方案,而绝不是用于限制本发明说明书以及所附权利要求书的范围。
本发明的化合物的制备显示在以下合成路线1-4中。
合成路线1
合成路线1a
合成路线2
合成路线3
合成路线4
合成路线5
PCT专利申请WO 00/42022(2000年7月20日公开)提供了制备一些本发明化合物的总合成方法。上述专利申请的整个内容在此并入作为参考。
仅是用于说明本发明的具体实施方案,而绝不是用于限制本发明说明书以及所附权利要求书的范围。
本发明的化合物的制备方法示于以下合成路线1-4中。
合成路线1显示了本发明化合物的合成。在步骤1中,使用标准的条件,优选在H2SO4中的发烟硝酸,是所述酸硝酸化。在步骤2中,在室温下于水中用NH4OH置换氟,然后小心地用浓的无机酸酸化至pH接近0,由此制备所述苯胺。在步骤3中,通过标准的方法,包括但不限于Fisher酯化(MeOH、H2SO4),然后在合适的有机溶剂如PhMe/MeOH或THF/MeOH中与TMSCHN2反应,由此制备所述酯。在步骤4中,使所述酯与过滤的合适苯胺或者在有机溶剂如二甲苯中进行加热(60-200℃),由此制备二苯胺基衍生物。例如,如果R1=Me且R2=H,优选的方法是在二甲苯中于回流下搅拌所述酯和10当量的苯胺,直至反应完全。在步骤5中,通过标准反应条件,包括但不限于在有机溶剂如EtOH或THF中用H2、或Pd/C或Pd(OH)2/C或Raney镍,在AcOH中用Fe,在AcOH中用Zn,或者在MeOH中用Zn、NH4Cl(aq),还原所述硝基芳烃,以产生二胺。在步骤6中,仅与甲酸一起加热或者在合适的溶剂如EtOH中与甲醚乙酸盐一起加热,由此使所述二胺环化。或者,当R1或R2不是卤素时,在甲酸中与Pd(OH)2/C或其他钯源如Pd/C一起加热,由此将硝基芳烃直接转化为苯并咪唑。在步骤8中,通过标准方法,包括但不限于在有机辅助溶剂如THF和MeOH中使用NBS或NCS和pTsOH,可加入卤化物。在步骤9中,使苯并咪唑烷基化,以形成N1和N3产物接近相同的混合物,它们可通过标准技术分离,包括例如色谱法和研磨。烷基化反应是在合适的有机溶剂如DMF或THF中于0-80℃的温度下使用烷基化剂如烷基卤和碱如NaH或K2CO3而完成的。R7可通过本领域已知的如下所述的各种合成方法进行改性。在步骤10中,所述酯通过标准的皂化方法进行水解。接着在步骤11中通过标准的偶联方法将酸转化为所希望的异羟肟酸盐,所述偶联方法包括但不限于在合适的有机溶剂如DMF、THF或二氯甲烷中使用EDCI、HOBt或PyBOP以及合适的羟胺。
合成路线2显示了其中在与硝基酯偶联之前R8取代基在苯胺上的实施例。反应描述与合成路线1相同,区别在于不需要加入R8取代基,因为其在开始时就已存在于苯胺上。
在合成路线3中显示了N3烷基氨基苯并咪唑衍生物的制备。在步骤1中,使用合适的氧化剂如在合适溶剂中的OsO4或者KMnO4或I2、AgOAc、AcOH、水,使N3烷基化苯并咪唑异羟肟酸盐的端烯烃二羟基化。该二醇在步骤2中在合适的二相混合物中用NaIO4或Pb(OAc)4进一步氧化,形成醛。或者(步骤3),所述烯烃可通过标准方法直接转化为醛,所述方法包括但不限于臭氧/Me2S、NaIO4/OsO4或KMnO4。在步骤4中,在有或没有AcOH的情况下,在合适的溶剂如二氯甲烷、乙腈或THF中,使用标准方法如Na(CN)BH3、Na(OAc)3BH、NMe4BH(OAc)3,通过还原性胺化反应制备胺。优选的还原胺化反应是用胺、Me4NBH(OAc)3和乙酸在MeCN中于室温下处理所述醛。
合成路线4显示了其中W是杂环的本发明化合物的制备。在步骤1中,在合适的溶剂如EtOH中于50-100℃的温度下与肼一起搅拌,由此将甲基酯转化为酰肼。通过与合适的试剂环化制备所希望的杂环衍生物。对于噁二唑21,所述酰肼在合适的有机溶剂如EtOH中于升高的温度(50-100℃)下用原甲酸酯如原甲酸三乙酯、以及酸催化剂如pTsOH处理。对于羟基噁二唑22,所述酰肼可在合适的溶剂如甲苯中于50-120℃的温度下与光气或光气等价物如三光气或羰基二咪唑环化。巯基噁二唑23可通过在合适的有机溶剂如EtOH中于升高的温度(50-100℃)下与二硫化碳、和碱如KOH反应来制备。氨基噁二唑24可通过在两相溶剂系统如二噁烷和水中于室温下与BrCN和碱如NaHCO3的反应来制备。最后,取代的氨基噁二唑25可如下制备:首先使所述酰肼与合适的异硫氰酸酯在合适的有机溶剂DMF或THF中于25-100℃的温度下反应。中间产物可分离或者通过在合适的有机溶剂如THF和DMF中于室温-80℃的温度下用EDCI或其他碳二亚胺处理而进行环化。
在合成路线5中描述了酮基苯并咪唑衍生物的制备。在步骤1中,通过标准的还原方法,优选0℃下在THF中的LAH或者室温下在EtOH:THF中的NaBH4,将甲基酯转化为苄基醇。在步骤2中,在丙酮:THF中于50℃下用MnO2进行氧化,形成醛。在步骤3中,在THF中于低温(如-78℃)下向所述醛中添加有机金属试剂如有机锂试剂和格氏试剂,形成取代的苄基醇。在步骤4中,在标准的条件下,如Swern或Dess-Martin氧化反应,氧化所述苄基醇,由此制备所述酮基衍生物。
本发明的化合物有可能具有不对称的碳原子。基于它们的物理活性性质的差异,通过本领域技术人员已知的方法,例如色谱法或分级结晶法,可将非对映异构体混合物分离为单个非对映异构体。通过与合适旋光化合物(如醇)的反应,将对映体混合物转化为非对映异构体混合物,分离所述非对映异构体并转化(例如水解)所述单个非对映异构体为相应纯的对映体。所有此等异构体,包括非对映异构体混合物和纯的对映体,都被认为是本发明的一部分。
本发明化合物的活性可通过以下方法进行测定。在E.coli中表达N-端6His标记的、组成性活性MEK1(2-393),然后通过常规方法纯制该蛋白(Ahn等人,Science 1994,265,966-970)。MEK1的活性通过以下方法进行评估:在MEK1存在下,测量来源于γ-33P-ATP中的γ-33P-磷酸酯在N-端His标记的ERK2上的掺入,该N-端His标记的ERK2是在E.coli中表达的并通过常规方法纯制的。该实验是在96孔聚丙烯板上进行的。温育混合物(100μL)包括25mM Hepes,pH 7.4、10mMMgCl2、5mMβ-甘油磷酸盐、100μM原钒酸钠、5mM DTT、5nMMEK1、和1μM ERK2。将抑制剂悬浮在DMSO中,然后所有的反应(包括对照)都是在1%DMSO的最终浓度下进行的。添加10μM ATP(0.5μCiγ-33P-ATP/孔),由此使反应开始,然后在室温下温育45分钟。添加等体积的25%TCA,以使反应停止,并使蛋白沉淀。沉淀出的蛋白收集在玻璃纤维B过滤板上,并用Tomtec MACH III收集器洗除过量的经标记的ATP。在添加30μL/孔的Packard Microscint 20之前,使所述板进行空气干燥,然后使用Packard TopCount对这些板进行计数。在该实验中,本发明的化合物表现出不超过50μM的IC50。
以下化合物代表了具有此等活性的化合物。
化合物# |
8n |
11b |
11c |
11p |
18i |
29c |
29i |
29s |
29t |
29bb |
29lll |
29mmm |
本发明的化合物(以下称为“活性化合物”)的给药可通过任何能够将该化合物转运至作用部位的方法来实现。这些方法包括口服途径、十二指肠内途径、非胃肠道注射(包括静脉、皮下、肌肉内、血管内或输注)、局部和直肠给药。
活性化合物的给药量将取决于所治疗的患者、疾病或病症的严重程度、给药率、化合物的处置、处方医生的感觉。但是,有效剂量范围是约0.001-100mg/kg体重/天,优选约1-35mg/kg/day,可在单个剂量中或者分为多个剂量。对于70kg的人,该剂量相当于约0.05-7g/天,优选为约0.05-2.5g/天。在某些情况下,低于上述剂量范围下限的剂量水平有可能已是足够的,而在其他情况下,在不产生任何有害副作用的情况下可使用更高的剂量,其条件是此等更大的剂量首先被分为数个小的剂量,用于整天的给药。
活性化合物可以单独给药或者与一种或多种其他抗肿瘤物质组合使用,这些其他的抗肿瘤物质例如选自于有丝分裂抑制剂,如长春碱;烷基化剂,如顺铂、卡铂和环磷酰胺;抗代谢药,如5-氟尿嘧啶、阿糖胞苷、和羟基脲,或者例如在第239362号欧洲专利申请中公开的优选抗代谢药之一,如N-(5-[N-(3,4-二氢-2-甲基-4-氧代喹唑啉-6-基甲基)-N-甲基氨基]-2-噻吩甲酰基)-L-谷氨酸;生长因子抑制剂;细胞周期抑制剂;插入抗生素,如阿霉素和博来霉素;酶,如干扰素;以及抗激素,例如,抗雌激素,如NolvadexTM(他莫昔芬),或者例如,抗雄激素如CasodexTM(4’-氰基-3-(4-氟苯基磺酰基)-2-羟基-2-甲基-3’-(三氟甲基)-N-丙酰苯胺)。此等组合治疗可通过同时、顺序或分开给药各单独治疗成分来实现。
本发明的组合物例如可为使用口服给药的形式,如片剂、胶囊、丸剂、缓释制剂、溶液、混悬液,用于非胃肠道注射的形式,如无菌溶液、混悬液或乳液,用于局部给药的形式,如软膏或乳膏,或者是用于直肠给药的形式,如栓剂。该药物组合物可以是适用于单独给药精确剂量的单元剂量剂型。该药物组合物将包括常规的药物载体或赋形剂以及作为活性成分的本发明化合物。另外,其还可包含其他的药物或药剂、载体、辅剂等。
示例性的非胃肠道给药剂型包括活性化合物在无菌水溶液(例如丙二醇水溶液或葡萄糖水溶液)中的溶液或混悬液。如果需要,此等进行可进行合适的缓冲。
合适的药物载体包括惰性稀释剂或填料、水和各种有机溶剂。如果需要,该药物组合物可包含其他成分,如调味剂、粘合剂、赋形剂等。因此,对于口服给药,可使用包含各种赋形剂如柠檬酸、各种崩解剂如淀粉、藻酸和某些复合硅酸盐、以及粘合剂如蔗糖、明胶和阿拉伯胶的片剂。另外,对于成片,润滑剂通常是非常有用的,例如硬脂酸镁、月桂基硫酸钠和滑石。类似类型的固体组合物也可以软和硬填充明胶胶囊的形式使用。因此,优选的材料包括乳糖和高分子量聚乙二醇。如果需要口服给药含水混悬液或酏剂时,其中的活性化合物可与甜味剂或调味剂、着色剂或染料组合使用,而且,如果需要,还可添加乳化剂或悬浮剂、以及稀释剂如水、乙醇、丙二醇、甘油和它们的混合物。
制备各种具有特定含量的活性化合物的药物组合物的方法是已知的,或者对于本领域技术人员是显而易见的。例如可参见:Remington’s Pharmaceutical Sciences,Mack Publishing Company,Ester,Pa.,15th Edition(1975)。
以下提供的实施例和制备方法进一步说明本发明的化合物以及制备这些化合物的方法。应理解的是,本发明的范围不仅局限于这些实施例和制备方法中。在以下实施例中,除非另有说明,具有单个手性中心的分子是以外消旋混合物的形式存在。除非另有说明,那些具有两个或者更多个手性中心的分子则以非对映异构体的外消旋混合物的形式存在。单个的对映体/非对映异构体可通过本领域技术人员已知的方法得到。
所有文章和参考文献(包括专利)的内容都并入本申请中作为参考。
将通过以下实施例进一步说明本发明,但是这些实施例绝不意味着是对本发明范围或精神的限制。
起始物和各种中间体可市售得到、由市售得到的化合物制备、或者使用已知的合成方法进行制备。
以下是制备本发明的中间体的方法的代表性例子。
实施例
实施例1
7-氟-6-(4-溴-2-甲基-苯基氨基)-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺(11a)
步骤A:2,3,4-三氟-5-硝基-苯甲酸2
在一个3升三口圆底烧瓶中加入125ml H2SO4。添加发烟硝酸(8.4ml,199mmol),然后轻柔地搅拌混合物。在90分钟的时间内,按照每次5g的量添加2,3,4-三氟苯甲酸1(25g,142mmol)。暗棕黄色的溶液在反应完成时搅拌60分钟。将反应混合物倾倒在1升的冰:水混合物中,并用乙醚(3x600ml)萃取。合并的有机萃取液进行干燥(MgSO4),然后减压浓缩,得到黄色固体。将该固体悬浮在己烷中并搅拌30分钟,之后过滤,得到29g(92%)纯净的所希望的产物,其为淡黄色固体:经检测MS APCI(-)m/z 220(M-1)。
步骤B:4-氨基-2,3-二氟-5-硝基-苯甲酸3
在0℃下将氢氧化铵溶液(~30%水溶液)(35ml,271mmol)添加至2,3,4-三氟-5-硝基-苯甲酸2(15g,67.8mmol)在30ml水中的溶液内,同时进行搅拌。氢氧化铵添加完成后,将反应混合物温热至室温,同时进行搅拌。2.5小时后,将反应混合物冷却至0℃,然后小心地添加浓盐酸,直至反应混合物的pH接近0。反应混合物用水(30ml)稀释,然后用乙醚(3x50ml)萃取。合并的有机萃取液进行干燥(MgSO4),然后减压浓缩,得到14g(95%)纯的标题化合物:经检测为MS APCI(-)m/z217(M-1)。
步骤C:4-氨基-2,3-二氟-5-硝基-苯甲酸甲基酯4
于0℃和氮气氛下将2M的TMS重氮甲烷己烷溶液(6.88ml,13.75mmol)添加至4-氨基-2,3-二氟-5-硝基-苯甲酸3(2.00g,9.17mmol)在25ml 4∶1THF∶MeOH内的悬浮液中。添加完成后,反应混合物温热至室温。0.5小时后,通过小心地添加乙酸破坏过量的TMS重氮甲烷。减压浓缩反应混合物,然后真空干燥,得到1.95g(92%)纯的标题化合物:经检测MS APCI(-)m/z 231(M-1)。
步骤D:4-氨基-3-氟-5-硝基-2-o-甲苯基氨基-苯甲酸甲基酯5a
4-氨基-2,3-二氟-5-硝基-苯甲酸甲基酯4(12.0g,51.7mmol)悬浮在二甲苯(60ml)中,然后添加ortho-甲胺苯(55.2ml,517mmol)。在氮气氛下将反应混合物加热至回流,同时进行搅拌。36小时后,将反应混合物冷却至室温,用乙醚稀释,然后用10%盐酸水溶液洗涤。含水洗涤液用乙醚萃取。合并的有机萃取液减压浓缩。残留物溶解在二氯甲烷中,然后通过玻璃漏斗中的硅胶过滤,用二氯甲烷洗涤。回收三该部分。第一个部分(2升)通过HPLC纯制。第二个部分(1升)和第三个部分(1升)仅是部分纯的。第一个部分减压浓缩并用乙醚研磨,得到11.2g(68%)纯净的所希望的产物,其是亮黄色的固体:经检测MSAPCI(-)m/z 318(M-1)。
步骤E:7-氟-6-o-甲苯基氨基-1H-苯并咪唑-5-羧酸甲基酯7a
4-氨基-3-氟-5-硝基-2-o-甲苯基氨基-苯甲酸甲基酯5a(1.57g,4.92mmol)、甲酸(25ml,26.5mmol)和20%Pd(OH)2/C(1.57g,2.95mmol)在25ml EtOH中加热至95℃,并同时进行搅拌。16小时后,将反应混合物冷却至室温,然后添加0.5g 20%Pd(OH)2/C和10ml甲酸。将反应混合物加热至95℃,同时进行搅拌。16小时后,将反应混合物冷却至室温,通过Celite过滤,并用EtOH洗涤。减压浓缩滤液,直至沉淀出所希望的产物。过滤收集所希望的产物。重新浓缩滤液,直至沉淀出更多的所希望的产物。过滤收集产物。重复EtOH浓缩、产物过滤数次。回收1.09g(74%)纯的所希望的产物:经检测MS APCI(+)m/z 300(M+1);经检测MS APCI(-)m/z 298(M-1)。
步骤F:7-氟-6-(4-溴-2-甲基-苯基氨基)-1H-苯并咪唑-5-羧酸甲基酯8a
在氮气氛下将7-氟-6-o-甲苯基氨基-1H-苯并咪唑-5-羧酸甲基酯7a(2.00g,6.68mmol)悬浮在1∶1THF∶MeOH混合物(60ml)中并冷却至-78℃。添加NBS(1.20g,6.75mmol)在1∶1THF/MeOH(5ml)中的溶液,然后添加TsOH·H2O(1.9g,10.0mmol)的MeOH(5ml)溶液。30分钟,使反应混合物温热至0℃,并在1小时后温热至室温。16小时后,进一步添加NBS(0.12g,0.67mmol),并搅拌反应混合物3小时。添加10%Na2S2O4溶液,由此淬灭反应混合物。30分钟后,反应混合物用水和乙酸乙酯稀释,然后分层。含水层用乙酸乙酯萃取。合并的有机萃取液进行干燥(Na2SO4),然后减压浓缩。回收的固体用二氯甲烷研磨,得到2.00g(79%)纯的所希望的产物:经检测MS APCI(+)m/z 380,378(M+1Br图形)。
步骤G:7-氟-6-(4-溴-2-甲基-苯基氨基)-1H-苯并咪唑-5-羧酸10a
将7-氟-6-(4-溴-2-甲基-苯基氨基)-1H-苯并咪唑-5-羧酸甲基酯8a(63mg,0.167mmol)悬浮在MeOH(1.5ml)中,然后添加20%NaOH(400μl)溶液。16小时后,反应混合物冷却至0℃,然后滴加1N HCl溶液直至pH为2-3。反应混合物用乙酸乙酯和水稀释,然后分层。有机层用盐水洗涤,干燥(Na2SO4),然后减压浓缩,得到58mg(95%)所希望的产物:经检测MS APCI(+)m/z 366,364(M+1Br图形);经检测MS APCI(-)m/z364,362(M-1Br图形)。
步骤H:7-氟-6-(4-溴-2-甲基-苯基氨基)-1H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11a
将7-氟-6-(4-溴-2-甲基-苯基氨基)-1H-苯并咪唑-5-羧酸10a(48mg,0.132mmol)溶解在1∶1THF∶二氯甲烷(1ml)中,添加Hunig碱(0.23μl,1.32mmol),然后再添加PyBOP(82mg,0.158mmol)。数分钟后,添加环丙基甲基羟胺盐酸盐(20mg,0.158mmol)(WO 0042022)。反应完成后,混合物在二氯甲烷和饱和NaHCO3溶液之间分配。分层,并用饱和NaHCO3和盐水洗涤有机层。有机层进行干燥(Na2SO4),然后减压浓缩。通过FCC(用洗脱20∶1二氯甲烷∶MeOH)纯制后,分离出25mg(45%)纯的标题化合物:经检测MS ESI(+)m/z 435,433(M+1Br图形);经检测MS ESI(-)m/z 433,431(M-1Br图形);1H NMR(400MHz,CDCl3)δ8.15(s,1H),8.02(s,1H),7.28(s,1H),7.43(d,1H),7.07(dd,1H),6.36(m,1H),3.70(d,2H),2.38(s,3H),0.86(m,1H),0.41(m,2H),0.13(m,2H);19F NMR(376MHz,CDCl3)-134.05(s).
实施例2
7-氟-6-苯基氨基-3H-苯并咪唑-5-羧酸甲基酯(27a)
步骤A:4-氨基-3-氟-5-硝基-2-苯基氨基-苯甲酸甲基酯26a
将4-氨基-2,3-二氟-5-硝基-苯甲酸甲基酯4(23.48g,101.1mmol)--实施例1步骤C的产物悬浮在中二甲苯(125mL)中,然后添加苯胺(92mL,1011mmol)。反应混合物在125℃和氮气氛下搅拌16小时。将反应混合物冷却至室温,并从溶液中沉淀出固体。.过滤收集该固体,并先后用二甲苯和乙醚洗涤。回收的22.22g(72.78mmol)黄色固体是纯的所希望的产物。减压浓缩滤液,重新溶解在二氯甲烷中,并由硅胶柱中用二氯甲烷洗脱。减压浓缩所希望的部分,得到棕色固体,其用乙醚研磨,得到5.47g(17.91mmol)黄色固体,其是纯的所希望的产物。合并产物的产量为27.69g(90%)。经检测MS APCI(-)m/z 304(M-1)。
步骤B:7-氟-6-苯基氨基-3H-苯并咪唑-5-羧酸甲基酯27a
在乙醇(250mL)中于40℃和氮气氛下搅拌4-氨基-3-氟-5-硝基-2-苯基氨基-苯甲酸甲基酯26a(16.70g,54.71mmol)、甲酸(250mL,6.63mol)和20%Pd(OH)2/C(9.00g,16.91mmol)共2小时,然后在95℃下16小时。将反应混合物冷却至室温,并通过Celite过滤,用乙酸乙酯洗涤。滤液减压浓缩,得到黄色固体。该固体用乙醚研磨,得到13.47g(86%)棕黄色固体状的所希望的产物。经检测MS APCI(+)m/z 286(M+1);经检测MS APCI(-)m/z 284(M-1)。
实施例3
6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯(8b)
步骤A:6-(4-溴-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯28a
将7-氟-6-苯基氨基-3H-苯并咪唑-5-羧酸甲基酯27a(4.99g,17.51mmol)溶解在N,N-二甲基甲酰胺(275mL)中。在室温和氮气氛下添加固体状的N-溴代琥珀酰亚胺(3.15g,17.70mmol),并搅拌反应混合物。30分钟后,添加饱和亚硫酸氢钠水溶液,由此淬灭反应混合物。将反应混合物倾倒在分离漏斗中,用水和乙酸乙酯稀释,然后分层。含水层用乙酸乙酯萃取。合并的有机萃取液用水洗涤3次,用盐水洗涤1次,接着干燥(Na2SO4),然后减压浓缩,产生6.38g(100%)纯的所希望的产物,其为棕黄色固体。经检测MS ESI(+)m/z 364,366(M+Br图形)。
步骤B:6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯8b
将6-(4-溴-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯28a(6.38g,17.51mmol)溶解在N,N-二甲基甲酰胺(275mL)。在室温和氮气氛下添加固体状的N-氯琥珀酰亚胺(2.36g,17.70mmol),并搅拌反应混合物,直至反应完全(5-6天)。添加饱和亚硫酸氢钠水溶液,由此淬灭反应混合物,得到一悬浮液。过滤收集所得的固体,用水和乙醚洗涤,然后在减压下干燥,产生6.07g(87%)纯的所希望的产物,其为米黄色固体。经检测MS ESI(+)m/z 398,400(M+Br图形)。
实施例4
6-(2,4-二氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯(8c)
在氮气氛下将7-氟-6-苯基氨基-3H-苯并咪唑-5-羧酸甲基酯27a(1.00g,3.51mmol)悬浮在1∶1四氢呋喃/甲醇(20mL)中并冷却至-78℃。先后添加TsOH·H2O(3.00g,10.50mmol)和N-氯琥珀酰亚胺(0.95g,7.08mmol)。10分钟后,将反应混合物温热至0℃,得到一溶液,并在30分钟后温热至室温。搅拌16小时后,反应完全。添加饱和亚硫酸氢钠水溶液,由此淬灭反应混合物,用乙酸乙酯和水稀释,然后分层。含水层用乙酸乙酯萃取。合并的有机萃取液用盐水洗涤,干燥(Na2SO4),然后减压浓缩。所得固体残留物用二氯甲烷研磨,产生的白色固体通过过滤收集,得到1.05g(85%)纯的所希望的产物。经检测MS ESI(+)m/z355,357(M+Cl图形)。
实施例5
6-(4-溴-2-氟-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯(8d)
步骤A:4-氨基-3-氟-2-(2-氟-苯基氨基)-5-硝基-苯甲酸甲基酯5b
将4-氨基-2,3-二氟-5-硝基-苯甲酸甲基酯4(1.50g,6.46mmol)悬浮在二甲苯(7.5mL)中,然后添加2-氟-苯基胺(6.24mL,64.6mmol)。反应混合物在140℃和氮气氛下搅拌。搅拌6天后,反应完全。将反应混合物冷却至室温,用二氯甲烷稀释,在硅胶柱上用二氯甲烷(1L)洗脱过滤,得到橙色滤液。该滤液浓缩至干,然后用乙醚研磨,产生亮黄色固体。重复进行研磨。收集黄色固体,得到1.08g(52%)纯的所希望的产物。经检测MS APCI(-)m/z 322(M-1)。
步骤B:6-(4-溴-2-氟-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯8d
通过已描述的还原/环化和溴化步骤,转化4-氨基-3-氟-2-(2-氟-苯基氨基)-5-硝基-苯甲酸甲基酯5b,得到所希望的产物。经检测MS ESI(+)m/z 382,384(M+,Br图形)。
实施例6
6-(4-氯-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯(8e)
通过已描述的溴化反应步骤,转化7-氟-6-o-甲苯基氨基-3H-苯并咪唑-5-羧酸甲基酯7a,不同之处在于使用N-氯琥珀酰亚胺替代N-溴代琥珀酰亚胺,得到所希望的产物。经检测MS ESI(+)m/z 334,336(M+,Cl图形)。
实施例7
7-氟-6-(2-甲基-4-三氟甲氧基-苯基氨基)-3H-苯并咪唑-5-羧酸甲基酯(8f)
步骤A.4-氨基-3-氟-2-(2-甲基-4-三氟甲氧基-苯基氨基)-5-硝基-苯甲酸甲基酯12a
将4-氨基-2,3-二氟-5-硝基-苯甲酸甲基酯4(0.50g,2.15mmol)悬浮在二甲苯(3mL)中,然后添加2-甲基-4-三氟甲氧基-苯基胺(1.00g,5.23mmol)。反应混合物在140℃和氮气氛下搅拌。搅拌7天后,反应产物是起始物和产物的混合物。将反应混合物冷却至室温。将反应混合物倾倒在分离漏斗中,添加乙醚和10%盐酸水溶液,然后分层。含水相用三份乙醚萃取。合并的乙醚层干燥(MgSO4),然后减压浓缩。残留物重新溶解在二氯甲烷中,然后在硅胶柱上用二氯甲烷进行洗脱过滤。滤液减压浓缩,得到亮黄色固体。该固体用乙醚洗涤,而滤液减压浓缩,残留物通过FCC(用100%二氯甲烷洗脱)进一步纯制,得到0.39g(45%)黄色固体状所希望的纯产物。经检测MS APCI(-)m/z 402(M-1)。
步骤B.7-氟-6-(2-甲基-4-三氟甲氧基-苯基氨基)-3H-苯并咪唑-5-羧酸甲基酯8f
通过已描述的还原/环化步骤转化4-氨基-3-氟-2-(2-甲基-4-三氟甲氧基-苯基氨基)-5-硝基-苯甲酸甲基酯12a,产生所希望的产物。经检测MS APCI(+)m/z 384(M+1);经检测MS APCI(-)m/z 382(M-1)。
实施例8
羟胺的制备
用于合成本发明化合物的羟胺可如下制备。
(i)O-(2-甲氧基-乙基)-羟胺
步骤A:2-(2-甲氧基-乙氧基)-异吲哚-1,3-二酮
将DEAD(10mL,63mmol)添加至2-甲氧基乙醇(5.0mL,63mmol)、PPh3(17g,63mmol)、和N-羟基邻苯二甲酰亚胺(10g,62mmol)在THF(170mL)中的混合物内。所得的橙色溶液在室温下搅拌16小时。真空浓缩反应混合物,过滤出固体并用CHCl3洗涤。浓缩滤液,过滤出固体并用CHCl3洗涤。重复该辅助,直至没有沉淀物形成。最终的黄色固体由乙醇中重结晶,得到所希望的产物(7.7g,55%)。
步骤B:O-(2-甲氧基-乙基)-羟胺
在室温下向2-(2-甲氧基-乙氧基)-异吲哚-1,3-二酮(7.7g,35mmol)在CH2Cl2(30mL)中的溶液内添加甲基肼(2.0mL,36mmol)。所得的溶液在室温下搅拌16小时。过滤出白色的固体。在减压下小心地蒸馏出溶剂,浓缩物进行真空蒸馏(20torr,57-58℃),得到所希望的产物(2.2g,68%)。
(ii)使用合适的醇如上所述制备以下羟胺。异吲哚-1,3-二酮中间体通过快速色谱纯制。
O-(2-甲基硫烷基-乙基)-羟胺通过真空蒸馏(76-78℃,20torr)进行纯制。
(iii)由合适的异吲哚-1,3-二酮用臭氧进行氧化(Tetrahedron Lett.1981,22,1287),然后如上所述脱保护,由此制备以下羟胺。
O-(2-苯磺酰基-乙基)-羟胺通过快速色谱(1%MeOH,在CH2Cl2中)进行纯制。
由PhSCH2CH2CH2Br和N-羟基邻苯二甲酰亚胺制备O-(3-苯基硫烷基-丙基)-羟胺,无需纯制直接使用。
(v)O-(2-吗啉-4-基-乙基)-羟胺二盐酸盐
步骤A:O-(2-溴-乙基)-羟胺氢溴酸盐
如WO 0018790所述,由1,2-二溴乙烷和N-羟基邻苯二甲酰亚胺制备2-(2-溴-乙氧基)-异吲哚-1,3-二酮,然后进行文献J.Org.Chem.1963,28,1604中描述的方法,产生所希望的产物。
步骤B:(2-溴-乙氧基)-氨基甲酸叔丁基酯
在室温下向O-(2-溴-乙基)-羟胺氢溴酸盐(100mg,0.45mmol)和二t-丁基二碳酸酯(110mg,0.49mmol)在CH2Cl2(1mL)中的溶液内添加Et3N(0.08mL,0.56mmol)。所得的悬浮液在室温下搅拌16小时。反应混合物用EtOAc稀释,用1N aq HCl和盐水洗涤,在MgSO4上干燥,过滤,浓缩,然后通过快速色谱(100%CH2Cl2)进行纯制,得到所希望的产物(81mg,75%)。
步骤C:(2-吗啉-4-基-乙氧基)-氨基甲酸叔丁基酯
在室温下向(2-溴-乙氧基)-氨基甲酸叔丁基酯(252mg,1.05mmol)在DMF(2mL)中的溶液内添加吗啉(0.14mL,1.6mmol)。反应混合物在50℃下搅拌7小时。反应混合物用EtOAc稀释,然后用水洗涤。有机层在MgSO4上干燥,过滤,浓缩,然后通过快速色谱(2%MeOH,在CH2Cl2)中进行纯制,得到所希望的产物(118mg,46%):经检测MSAPCI(+)m/z 247。
步骤D:O-(2-吗啉-4-基-乙基)-羟胺二盐酸盐
在室温下向(2-吗啉-4-基-乙氧基)-氨基甲酸叔丁基酯(118mg,0.48mmol)在MeOH(1mL)中的溶液内添加4M盐酸的二噁烷溶液(2.4mL,9.60mmol)。所得的溶液在室温下搅拌16小时。添加额外的HCl(2.4mL)并搅拌4小时后,真空浓缩反应混合物,得到黄色固体(82mg,78%)。
(vi)按照J.Heterocyclic Chem.2000,37,827-830中描述的方法,由合适的烷基卤化物和N-羟基邻苯二甲酰亚胺制备以下羟胺的异吲哚-1,3-二酮中间体。这些异吲哚-1,3-二酮通过如上所述的步骤脱保护:O-丁-3-烯基-羟胺、O-(四氢呋喃-2-基甲基)-羟胺、O-(3-甲氧基-丙基)-羟胺、和O-(3-苄氧基-丙基)-羟胺。
(vii)如WO 0206213中所述制备以下羟胺:O-(2-乙烯基氧基-乙基)-羟胺、2-氨基氧基-2-甲基-丙烷-1-醇、1-氨基氧基-2-甲基-丙烷-2-醇、3-氨基氧基-丙烷-1-醇、和(2-氨基氧基-乙基)-甲基-氨基甲酸叔丁基酯。
实施例9
6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺(11b)
步骤A:4-氨基-2-(2-氯-苯基氨基)-3-氟-5-硝基-苯甲酸甲基酯5b
将4-氨基-2,3-二氟-5-硝基-苯甲酸甲基酯4(2.00g,8.62mmol)悬浮在二甲苯(15ml)中,然后添加2-氯苯胺(9.06ml,86.15mmol)。在氮气氛下将反应混合物加热至140℃。6天后,将反应混合物冷却至室温,并用乙酸乙酯稀释。反应混合物用水、10%HCl溶液和盐水洗涤。有机层干燥(MgSO4),然后减压浓缩。粗产物用乙醚研磨两次,得到0.35g(12%)纯的所希望的产物,其为棕色固体。
步骤B:4,5-二氨基-2-(2-氯-苯基氨基)-3-氟-苯甲酸甲基酯6a
将4-氨基-2-(2-氯-苯基氨基)-3-氟-5-硝基-苯甲酸甲基酯5b(0.30g,0.88mmol)悬浮在AcOH(5ml)中,然后添加锌粉(0.29g,4.42mmol)。15分钟后,反应完全。反应混合物用乙酸乙酯稀释,然后通过Celite过滤。滤液用水、饱和NaHCO3、10%K2CO3和盐水洗涤。有机层干燥(MgSO4),然后减压浓缩,得到0.13g(48%)纯的所希望的产物,其为发白的棕色泡沫。
步骤C:6-(2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯7b
将4,5-二氨基-2-(2-氯-苯基氨基)-3-氟-苯甲酸甲基酯6a(0.125g,0.404mmol)悬浮在EtOH(2ml)中,然后添加甲脒乙酸盐(63mg,0.605mmol)。将反应混合物加热至回流。16小时后,反应混合物冷却至室温并用乙酸乙酯稀释。有机层用水、饱和NaHCO3、10%K2CO3和盐水洗涤。有机层干燥(MgSO4),然后减压浓缩,得到0.109g(85%)纯的所希望的产物。
步骤D:6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯8b
在氮气氛下将6-(2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯7b(55mg,0.172mmol)溶解在1∶1THF∶MeOH(2ml)中并冷却至-78℃。先后添加TsOH·H2O(49mg,0.258mmol)和NBS(31mg,0.174mmol)。10分钟后,反应混合物温热至0℃,并在2小时后温热至室温。16小时后,添加10%Na2S2O3,由此淬灭反应混合物,并用乙酸乙酯和水稀释。分层,而含水层用乙酸乙酯萃取。合并的有机萃取液进行干燥(MgSO4),然后减压浓缩。粗产物用二氯甲烷研磨,得到58mg(85%)纯的标题化合物,其为棕黄色固体。
步骤E:6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸10b
将6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯8b(58mg,0.146mmol)悬浮在EtOH(2ml)中,然后添加1ml 2N NaOH。16小时后,反应混合物用乙酸乙酯、水、和10%HCl溶液稀释。分层,而有机层用盐水洗涤。有机层干燥(MgSO4),然后减压浓缩。用MeOH研磨,得到22mg(39%)纯的所希望的产物。
步骤F:6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺(11b)
将6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸10b(22mg,0.057mmol)溶解在DMF(1ml),并先后添加HOBt(9mg,0.062mmol)和三乙基胺(18μl,0.132mmol)。先后添加环丙基甲基羟胺盐酸盐(8mg,0.062mmol)和EDCI(14mg,0.074mmol)。16小时后,反应混合物用乙酸乙酯和水稀释,然后分层。有机层用饱和NH4Cl、盐水、饱和NaHCO3、水和盐水洗涤。有机层干燥(MgSO4),然后减压浓缩,得到23mg(89%)纯的所希望的产物。经检测MS APCI(+)m/z 455,453(M+Br图形);经检测MS APCI(-)m/z 453,451(M-Br图形);1H NMR(400MHz,DMSO-d6)δ11.69(br s,1H),8.43(s,1H),7.62(d,1H),7.28(dd,1H),6.42(m,1H),3.63(d,2H),1.03(m,1H),0.48(m,2H),0.19(m,2H);19F NMR(376MHz,DMSO-d6)-132.95(s).
类似于实施例1和实施例9中描述的方法,使用合适的羧酸和羟胺制备以下化合物:
实施例10
6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺(29c)
步骤A.6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸甲基酯9a和6-(4-溴-2-氯-苯基氨基)-7-氟-1-甲基-1H-苯并咪唑-5-羧酸甲基酯
在75℃下搅拌6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯8b(150mg,0.38mmol)、碘甲烷(28μL,0.45mmol)和碳酸钾(78mg,0.56mmol)在二甲基甲酰胺(1.5mL)中的溶液1小时。反应混合物用乙酸乙酯稀释,用饱和碳酸钾水溶液(2x)、盐水洗涤,然后干燥(Na2SO4)。进行快速色谱(20∶1二氯甲烷/乙酸乙酯)纯制,得到56mg(36%)更易于移动的6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸甲基酯9a,其为白色固体。19F NMR(376MHz,CD3OD)-133.5(s)。经检测MS APCI(+)m/z 412,414(M+,Br图形)。还分离出54mg(35%)的6-(4-溴-2-氯-苯基氨基)-7-氟-1-甲基-1H-苯并咪唑-5-羧酸甲基酯,其为白色固体。19F NMR(376MHz,CD3OD)-139.9(s)。经检测MSAPCI(+)m/z 412,414(M+,Br图形)。
步骤B.6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸10c
将6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸甲基酯9a(56mg,0.14mmol)溶解在2∶1THF/水(3mL)中,然后添加NaOH(0.55mL,1.0M水溶液,0.55mmol)。搅拌2小时后,通过旋转蒸发使溶液物减少至初始体积的斯分之一,残留物用水稀释至50mL。该水溶液通过添加1.0M盐水水溶液而被酸化至pH 2,用1∶1四氢呋喃/乙酸乙酯(3x)萃取,干燥(Na2SO4),然后减压浓缩,得到43mg(79%)浅白色固体状的纯羧酸。经检测MS ESI(+)m/z 397,398(M+,Br图形)。
步骤C:6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-乙烯基氧基-乙氧基)-酰胺29a
将6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸10c(2.00g,5.0mmol)、O-(2-乙烯基氧基-乙基)-羟胺(0.776g,7.5mmol)、HOBt(0.88g,6.5mmol)、三乙基胺(1.61mL,2.3mmol)和EDCI(1.3g,6.5mmol)溶解在二甲基甲酰胺(52mL)中,然后在室温下搅拌48小时。反应混合物用乙酸乙酯稀释,用水(3x)、饱和碳酸钾(2x)、饱和氯化铵(2x)、盐水洗涤,干燥(Na2SO4),然后减压浓缩,得到浅白色固体。用乙醚研磨该固体,得到2.18g(90%)浅白色固体状的希望产物。经检测MS ESI(+)m/z 483,485(M+Br图形)。
步骤D:6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺29c
将盐酸(14mL,1.0M水溶液,14mmol)添加至6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-乙烯基氧基-乙氧基)-酰胺29a(2.18g,4.50mmol)在乙醇(50mL)中的悬浮液内,搅拌反应混合物24小时。通过旋转蒸发浓缩反应混合物至干,固体在3∶1乙酸乙酯/四氢呋喃和饱和碳酸钾之间分配。含水相用3∶1乙酸乙酯/四氢呋喃(3x)萃取,合并的有机物干燥(Na2SO4),然后浓缩,得到2.11g(100%)6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺,其为浅白色固体。经检测MS ESI(+)m/z 457,459(M+,Br图形)。1H NMR(400MHz,MeOH-d4)8.26(s,1H),7.78(s,1H),7.57(d,1H),7.24(dd,1H),6.40(dd,1H),3.86(s,3H),3.79(m,2H),3.49(m,2H)。19F NMR(376MHz,MeOH-d4)-133.68(s).
实施例11
类似于实施例10中描述的方法,使用甲基酯8b以及合适的烷基化剂(步骤A)和合适的羟胺(步骤C)制备以下化合物:
实施例12
6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2,3-二羟基-丙氧基)-酰胺(29hhh)
向6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸烯丙基氧基-酰胺29tt(20mg,0.04mmol)在0.50mL 4∶1四氢呋喃/水中的溶液内先后添加OsO4(41μL,0.054M的t-BuOH溶液,0.002mmol)和NMO(7mg,0.06mmol)。溶液在室温下搅拌8小时,之后HPLC分析显示完全转化为产物。该溶液接着与饱和NaHSO3一起搅拌,并用乙酸乙酯稀释。有机相干燥(Na2SO4)。通过FCC(DCM->20∶1 DCM/MeOH)纯制,得到16mg所希望的产物,其为浅白色固体。经检测MS ESI(+)m/z487,489(M+,Br图形)。
实施例13
6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(3,4-二羟基-丁氧基)-酰胺(29iii)
6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸丁-3-烯基氧基-酰胺29uu进行如实施例12中描述的二羟基化方法。经检测MSAPCI(+)m/z 501,503(M+Br图形)。
实施例14
6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-甲基氨基-乙氧基)-酰胺TFA盐(29jjj)
由(2-{[6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羰基]-氨基氧基}-乙基)-甲基-氨基甲酸叔丁基酯29ww起始,在二氯甲烷中进行三氟乙酸脱保护,由此制得标题化合物。经检测MS APCI(+)m/z470,472(M+,Br图形);1H NMR(400MHz,CD3OD)δ8.31(s,1H),7.74(s,1H),7.51(d,1H),7.19(dd,1H),6.39(dd,1H),4.11(m,2H),3.97(s,3H),3.12(m,2H),2.72(s,3H);19F NMR(376MHz,CD3OD)-77.41(s,3F),-134.79(s,1F).
实施例15
类似于实施例10中描述的方法,使用甲基酯8a以及合适的烷基化剂(步骤A)和合适的羟胺(步骤C)制备以下化合物:
实施例16
类似于实施例10中描述的方法,使用甲基酯8e以及合适的烷基化剂(步骤A)和合适的羟胺(步骤C)制备以下化合物:
实施例17
类似于实施例10中描述的方法,使用甲基酯8c以及合适的烷基化剂(步骤A)和合适的羟胺(步骤C)制备以下化合物:
实施例18
类似于实施例10中描述的方法,使用甲基酯8d以及合适的烷基化剂(步骤A)和合适的羟胺(步骤C)制备以下化合物:
实施例19
6-(4-溴-2-甲基-苯基氨基)-7-氟-3-[4-(4-甲基-哌嗪-1-基)-丁基]-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺(11o)
步骤A:6-(4-溴-2-甲基-苯基氨基)-7-氟-3-戊-4-烯基-3H-苯并咪唑-5-羧酸甲基酯9b
在氮气氛下将7-氟-6-(4-溴-2-甲基-苯基氨基)-1H-苯并咪唑-5-羧酸甲基酯8a(0.915g,2.419mmol)悬浮在DMF(18ml)中。添加溴戊烯(0.430ml,3.629mmol)和K2CO3(0.502g,3.629mmol),然后将反应混合物温热至80℃。1后,将反应混合物冷却至室温,然后倾倒在100ml的1∶1乙酸乙酯∶乙醚中。有机层用水和盐水洗涤,干燥(Na2SO4),然后减压浓缩。N3和N1烷基化产物通过快速柱色谱分离,用20∶1二氯甲烷∶乙酸乙酯洗脱。进行两次色谱分离,由此得到完全分离的异构体。更高Rf的产物是N3产物9b,而较低Rf的产物是N1产物。回收得到的N3产物9b为0.415g(38%):经检测LC/MS ESI(+)m/z 448,446(M+1Br图形)。回收得到的N1产物是0.486g(45%):经检测LC/MS ESI(+)m/z448,446(M+1Br图形)。
步骤B:6-(4-溴-2-甲基-苯基氨基)-7-氟-3-戊-4-烯基-3H-苯并咪唑-5-羧酸10d
将6-(4-溴-2-甲基-苯基氨基)-7-氟-3-戊-4-烯基-3H-苯并咪唑-5-羧酸甲基酯9b溶解在1∶1THF∶MeOH(10ml)中,然后添加1N NaOH溶液(2.3ml)。5小时后,减压除去有机溶剂,而残留物用水和100ml 1∶1 THF∶乙酸乙酯稀释。分层,而含水层用乙酸乙酯萃取。合并的有机萃取液进行干燥(Na2SO4),然后减压浓缩,得到0.39g(100%)纯净的希望产物,其为亮黄色固体。
步骤C:6-(4-溴-2-甲基-苯基氨基)-7-氟-3-戊-4-烯基-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11f
将6-(4-溴-2-甲基-苯基氨基)-7-氟-3-戊-4-烯基-3H-苯并咪唑-5-羧酸10d(0.390g,0.902mmol)溶解在1∶1THF∶二氯甲烷(6ml)中,并先后添加Hunig碱(0.346ml,1.985mmol)和PyBOP(0.563g,1.083mmol)。10分钟后,添加环丙基甲基羟胺盐酸盐(0.134g,1.083mmol)。16小时后,反应混合物用乙酸乙酯稀释,并用0.1N HCl、饱和NaHCO3、和盐水洗涤。有机层干燥(Na2SO4),然后减压浓缩。粗的黄色残留物通过FCC纯制,其中用乙酸乙酯洗脱,得到0.315g(70%)纯的所希望的产物,其为黄色固体:经检测MS APCI(+)m/z 503,501(M+1Br图形)。
步骤D:6-(4-溴-2-甲基-苯基氨基)-3-(4,5-二羟基-戊基)-7-氟-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11m
将6-(4-溴-2-甲基-苯基氨基)-7-氟-3-戊-4-烯基-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11f(0.307g,0.612mmol)溶解在4∶1THF∶水(8ml)中,并先后添加1.134ml(0.061mmol)0.054M OsO4在t-BuOH中的溶液和NMO(0.093g,0.796mmol)。5小时后,添加10%NaHS2O3溶液,由此淬灭反应混合物。10分钟后,反应混合物通过Celite过滤并用乙酸乙酯和二氯甲烷洗涤。滤液用稀释乙酸乙酯并用0.01N HCl、和盐水洗涤。有机层干燥(Na2SO4),然后减压浓缩。粗产物通过FCC纯制,其中用9∶1乙酸乙酯∶MeOH洗脱,得到0.244g(74%)纯的所希望的产物。
步骤E:6-(4-溴-2-甲基-苯基氨基)-7-氟-3-(4-氧代-丁基)-3H苯并咪唑-5-羧酸环丙基甲氧基-酰胺11n
向6-(4-溴-2-甲基-苯基氨基)-3-(4,5-二羟基-戊基)-7-氟-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11m(0.244g,0.456mmol)、THF(5ml)和pH 7磷酸盐缓冲液(3ml)的混合物中添加高碘酸钠(0.195g,0.911mmol)。16小时后,反应混合物用乙酸乙酯稀释并用NaHCO3、和盐水洗涤。有机层干燥(Na2SO4),然后减压浓缩,得到橙色固体。通过FCC纯制,其中用4∶1二氯甲烷∶MeOH洗脱,得到0.189g(82%)纯的所希望的产物,其为黄色固体:经检测MS APCI(+)m/z 505,503(M+1Br图形);经检测MS APCI(-)m/z 503,501(M-1Br图形)。
步骤F:6-(4-溴-2-甲基-苯基氨基)-7-氟-3-[4-(4-甲基-哌嗪-1-基)-丁基]-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11o
将6-(4-溴-2-甲基-苯基氨基)-7-氟-3-(4-氧代-丁基)-3H苯并咪唑-5-羧酸环丙基甲氧基-酰胺11n(15mg,0.030mmol)溶解在MeCN(500μl)中,并先后添加甲基哌嗪(10μl,0.089mmol)和AcOH(5μl,0.089mmol)。5分钟后,添加四甲基三乙酰氧基硼氢化铵(12mg,0.045mmol)。5分钟后,反应混合物用乙酸乙酯稀释并用NaHCO3和盐水洗涤。有机层干燥(Na2SO4),然后减压浓缩,得到12mg(69%)纯的标题化合物,其为白色固体。经检测MS APCI(-)m/z 587,585(M-1Br图形);1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.98(s,1H),7.30(d,1H),7.08(dd,1H),6.30(d,1H),6.1(broad singlet,1H),4.26(t,2H),3.64(d,2H),3.37(s,1H),2.45(br,8H),2.41(s,3H),2.38(t,2H),2.28(s,3H),1.95(quin,2H),1.55(quin,2H),0.98(m,1H),0.50(qt,2H),0.22(qt,2H).
实施例20
类似于实施例19中描述的方法,在还原胺化(步骤F)中使用合适的烯基取代的苯并咪唑以及合适的胺,制备以下化合物:
实施例21
6-(4-溴-2-甲基-苯基氨基)-3-[4-(1,1-二氧代-1λ6-硫代吗啉-4-基)-丁基]-7-氟-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺(18cc)
向6-(4-溴-2-甲基-苯基氨基)-7-氟-3-(4-硫代吗啉-4-基-丁基)-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺18l(8mg,0.014mmol)在1∶1∶1水/丙酮/MeOH(1mL)中的溶液内添加NMO(1.6mg,0.014mmol)和四氧化饿(250μL,0.054M的t-BuOH溶液,0.014mmol)。搅拌24小时后,溶液用饱和硫代硫酸钠溶液稀释,搅拌10分钟并用乙酸乙酯稀释。溶液用盐水(2x)洗涤,干燥(Na2SO4),然后减压浓缩。,得到灰色固体。FCC(10∶1二氯甲烷/甲醇)产生6mg(71%)所希望的产物,其为浅白色固体。经检测MS ESI(+)m/z 622,624(M+,Br图形)。
实施例22
6-(4-溴-2-氯-苯基氨基)-7-氟-3-[4-(4-甲基-哌嗪-1-基)-丁基]-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺(18dd)
在85℃下搅拌6-(4-溴-2-氯-苯基氨基)-3-(4-氯-丁基)-7-氟-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺18ee(10mg,0.018mmol)、碘化钠(14mg,0.092mmol)、以及1-甲基-哌嗪(10μL,0.092mmol)共3小时。反应混合物用乙酸乙酯稀释,并用水洗涤3次,用饱和碳酸钾水溶液洗涤2次,干燥(Na2SO4),然后减压浓缩,得到黄色油。快速色谱纯制(1∶1二氯甲烷/甲醇,接着甲醇,然后20∶1甲醇/三乙基胺),得到纯净的产物(8mg,72%),其为浅白色泡沫。经检测MS ESI(+)m/z 607,609(M+,Br图形)。1H NMR(400MHz,DMSO-d6)8.37(s,1H),7.71(s,1H),7.49(d,1H),7.18(dd,1H),6.40(dd,1H),4.38(t,2H),3.62(d,2H),2.45(br,8H),2.41(t,2H),2.28(s,3H),1.96(m,2H),1.54(m,2H),1.07(m,1H),0.50(d,2H),0.22(d,2H).
实施例23
类似于实施例22中描述的方法,使用合适的胺和伯烷基氯化物制备以下化合物。
实施例24
6-(4-氯-2-甲基-苯基氨基)-7-氟-3-噁唑-5-基甲基-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺(18ggg)
将6-(4-氯-2-甲基-苯基氨基)-7-氟-3-(2-氧代-乙基)-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺(0.020g,0.046mmol)溶解在甲醇(2mL)中。添加碳酸钾(0.013g,0.093mmol)和1-异氰基甲磺酰基-4-甲基-苯(0.010g,0.051mmol)。反应混合物在回流和氮气氛下搅拌16小时,然后减压浓缩。残留物溶解在乙酸乙酯中,然后倾倒在分离漏斗中并用水和盐水洗涤。合并的含水层重新用乙酸乙酯(2x)萃取。合并的乙酸乙酯层干燥(Na2SO4,),然后减压浓缩。所得的固体通过快速柱色谱进行纯制(用15∶1二氯甲烷∶甲醇洗脱),得到0.011g(50%)所希望的产物。经检测MS APCI(+)m/z 470,472(M+,Cl图形);1H NMR(400MHz,CDCl3)δ10.51(br s,1H),8.07(s,1H),8.02(s,1H),7.89(s,1H),7.23(s,1H),7.15(d,1H),6.92(dd,1H),6.31(d,1H),6.11(br s,1H),5.45(s,2H),3.62(d,2H),2.40(s,3H),0.87(m,1H),0.49(m,2H),0.20(m,2H).19F NMR(376MHz,CDCl3)-134.54(s).
实施例25
6-(4-溴-2-氯-苯基氨基)-7-氟-3-(3-氧代-3-吡咯烷-1-基-丙基)-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺(18hhh)
步骤A:6-(4-溴-2-氯-苯基氨基)-3-(2-叔丁氧基羰基-乙基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯
在氮气氛下将6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯8b(0.50g,1.25mmol)溶解在DMF(8ml),并先后添加K2CO3(0.26g,1.88mmol)和丙烯酸t-丁基酯(1.84ml,12.54mmol)。将反应混合物加热至90℃,同时进行搅拌。4小时后,反应混合物冷却至室温,并用乙酸乙酯稀释。有机层用水(3x)和盐水洗涤,干燥(MgSO4),然后减压浓缩。通过柱色谱纯制,其中用19∶1二氯甲烷∶乙酸乙酯洗脱,得到0.41g(62%)希望的产物。
步骤B:6-(4-溴-2-氯-苯基氨基)-3-(2-羧基-乙基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯TFA盐
将6-(4-溴-2-氯-苯基氨基)-3-(2-叔丁氧基羰基-乙基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯(0.050g,0.095mmol)溶解在二氯甲烷(0.5ml)中,然后添加TFA(0.5ml)。45分钟后,浓缩反应混合物至干,得到0.49g(88%)所希望的产物:经检测LC/MS ESI(+)m/z 472,470(M+Br图形);1H NMR(400MHz,DMSO-d6)8.51(s,1H),8.20(s,1H),8.13(s,1H),7.64(d,1H),7.29(dd,1H),6.45(dd,1H),4.55(t,2H),2.89(t,2H).
步骤C:6-(4-溴-2-氯-苯基氨基)-7-氟-3-(3-氧代-3-吡咯烷-1-基-丙基)-3H-苯并咪唑-5-羧酸甲基酯
在室温下向6-(4-溴-2-氯-苯基氨基)-3-(2-羧基-乙基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯(60mg,0.13mmol)在DMF(1.8mL)中的溶液内添加HOBt-H2O(24mg,0.16mmol)、Et3N(0.043mL,0.31mmol)、吡咯烷(0.011mL,0.13mmol)、和EDCI(34mg,0.18mmol)。所得的黄色溶液在室温下搅拌16小时。反应混合物用EtOAc和水稀释,用饱和NH4Cl水溶液、盐水、饱和NaHCO3水溶液、和盐水洗涤。有机层在MgSO4上干燥,过滤,然后真空浓缩,得到的粗产物通过快速色谱纯制(3%MeOH,在CH2Cl2中),得到45mg(67%)所希望的产物:经检测MSAPCI(+)m/z 523,525(M+,Br图形)。
步骤D:6-(4-溴-2-氯-苯基氨基)-7-氟-3-(3-氧代-3-吡咯烷-1-基-丙基)-3H-苯并咪唑-5-羧酸
在室温下向6-(4-溴-2-氯-苯基氨基)-7-氟-3-(3-氧代-3-吡咯烷-1-基-丙基)-3H-苯并咪唑-5-羧酸甲基酯(41mg,0.079mmol)在THF/H2O(1.5mL/0.75mL)中的溶液内添加0.20mL(0.20mmol)1N LiOH水溶液。所得的溶液搅拌16小时。反应混合物用1N aq HCl酸化(pH~2-3),然后用EtOAc稀释。有机层在MgSO4上干燥,过滤,然后真空浓缩,粗产物(42mg),其无需进一步纯制就直接使用。
步骤E:6-(4-溴-2-氯-苯基氨基)-7-氟-3-(3-氧代-3-吡咯烷-1-基-丙基)-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺18hhh
按照步骤A中描述的标准偶联步骤,由6-(4-溴-2-氯-苯基氨基)-7-氟-3-(3-氧代-3-吡咯烷-1-基-丙基)-3H-苯并咪唑-5-羧酸和O-环丙基甲基-羟胺盐酸盐制备标题化合物:经检测MS APCI(+)m/z 578,580(M+,Br图形);1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.42(s,1H),8.01(s,1H),7.76(s,1H),7.62(s,1H),7.28(d,1H),6.39(m,1H),4.52(t,2H),3.66(d,2H),3.33(t,2H),3.28(t,2H),2.89(t,2H),1.83(m,2H),1.76(m,2H),1.06(m,1H),0.49(m,2H),0.22(m,2H);19F NMR(376MHz,DMSO-d6)-132.94(s,1F).
实施例26
按照类似于实施例25中描述的方法,使用甲基酯8b以及合适的胺制备以下化合物:
实施例27
6-(4-溴-2-氯-苯基氨基)-7-氟-3-(四氢吡喃-2-基甲基)-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺(11p)
步骤A:6-(4-溴-2-氯-苯基氨基)-7-氟-3-(四氢吡喃-2-基甲基)-3H-苯并咪唑-5-羧酸甲基酯11q
将6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯8b(0.25g,0.63mmol)溶解在N,N-二甲基甲酰胺(5mL)中。添加2-溴甲基-四氢吡喃(0.34g,1.88mmol)和碳酸钾(0.26g,1.88mmol),并在60℃和氮气氛下搅拌反应混合物12小时。将反应混合物倾倒在中分离漏斗中,用乙酸乙酯和水稀释,然后分层。乙酸乙酯层用水和盐水洗涤,干燥(Na2SO4),然后减压浓缩。所得固体残留物用研磨乙醚,得到淡黄色固体(通过NMR确定为N3区域异构体)和黄色滤液(通过NMR确定为N1和N3区域异构体的混合物)。收集这些固体并用乙醚洗涤,得到0.12g(37%)所希望的纯的N3区域异构体产物,其为淡黄色固体。经检测MS ESI(+)m/z 496,498(M+,Br图形)。
步骤B:6-(4-溴-2-氯-苯基氨基)-7-氟-3-(四氢吡喃-2-基甲基)-3H-苯并咪唑-5-羧酸11r
将6-(4-溴-2-氯-苯基氨基)-7-氟-3-(四氢吡喃-2-基甲基)-3H-苯并咪唑-5-羧酸甲基酯11q悬浮在4∶1四氢呋喃/水(2.5mL)中,然后添加1MLiOH水溶液(2.5mL)。在室温下搅拌16小时后,反应混合物为均相的,而且反应完全。反应混合物冷却至0℃,用水稀释,然后滴加2MHCI水溶液,直至该溶液的pH为1-2,此时变为悬浮液。将反应混合物倾倒在中分离漏斗并用乙酸乙酯/四氢呋喃和水稀释,然后分层。含水层用萃取乙酸乙酯。合并的有机层用盐水洗涤,干燥(Na2SO4),然后减压浓缩,得到0.11g(100%)纯的所希望的产物,其为白色固体。经检测MS ESI(+)m/z 482,484(M+,Br图形)。
步骤C:6-(4-溴-2-氯-苯基氨基)-7-氟-3-(四氢吡喃-2-基甲基)-3H-苯并咪唑-5-羧酸(2-乙烯基氧基-乙氧基)-酰胺11s
将6-(4-溴-2-氯-苯基氨基)-7-氟-3-(四氢吡喃-2-基甲基)-3H-苯并咪唑-5-羧酸11r(0.11g,0.23mmol)溶解在N,N-二甲基甲酰胺(2mL)中。添加HOBT(0.037g,0.27mmol)和三乙基胺(0.094mL,0.68mmol)。接着在室温和氮气氛下添加O-(2-乙烯基氧基-乙基)-羟胺(0.028g,0.27mmol)和EDCI(0.056g,0.29mmol),并搅拌反应混合物,直至HPLC显示反应完全(2-天)。将反应混合物倾倒在中分离漏斗,用乙酸乙酯和水稀释,然后分层。乙酸乙酯层顺序地用饱和NH4Cl水溶液(2x)、盐水(1x)、饱和碳酸氢钠水溶液(2x)、水(1x)、和盐水(1x)洗涤,干燥(Na2SO4),然后减压浓缩。所得的固体通过FCC纯制(用15∶1二氯甲烷∶甲醇洗脱),得到0.039g(79%)纯的所希望的产物,其为浅白色固体。经检测MS ESI(+)m/z 567,569(M+,Br图形)。
步骤D:6-(4-溴-2-氯-苯基氨基)-7-氟-3-(四氢吡喃-2-基甲基)-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺11p
将6-(4-溴-2-氯-苯基氨基)-7-氟-3-(四氢吡喃-2-基甲基)-3H-苯并咪唑-5-羧酸(2-乙烯基氧基-乙氧基)-酰胺11s(0.039g,0.068mmol)溶解在乙醇(2mL)中,然后添加2M HCl水溶液(200μL)。反应混合物在室温下搅拌30分钟。反应混合物用水稀释,并用2M NaOH水溶液(~200μL)中和至pH 7,然后减压浓缩。在分离漏斗中,残留物在乙酸乙酯和盐水之间分配,然后分层。乙酸乙酯层干燥(Na2SO4),然后减压浓缩,得到0.034g(91%)纯的所希望的产物,其为浅白色固体。经检测MSESI(+)m/z 541,543(M+,Br图形);1H NMR(400MHz,CD3OD)δ8.29(s,1H),7.75(s,1H),7.49(d,1H),7.18(dd,1H),6.40(dd,1H),4.40(dd,A ofABX图形,1H),4.28(dd,B of ABX图形,1H),3.92(m,X of ABX图形,1H),3.66(t,2H),3.35(m,1H),1.89(m,1H),1.76(m,1H),2.28(s,3H),1.54(m,3H),1.30(m,1H).19F NMR(376MHz,CD3OD)-134.87(s).
实施例28
按照类似于实施例27中描述的方法,使用合适的甲基酯和烷基化剂(步骤A)以及合适的羟胺(步骤C)制备以下化合物。
实施例29
6-(4-溴-2-氯-苯基氨基)-7-氟-3-(2-甲磺酰基-乙基)-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺(11bb)
步骤A:6-(4-溴-2-氯-苯基氨基)-7-氟-3-(2-甲磺酰基-乙基)-3H-苯并咪唑-5-羧酸甲基酯11cc
在氮气氛下将6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯8b(1.55g,3.89mmol)溶解在15ml DMF中。先后添加K2CO3(0.70g,5.06mmol)和甲基乙烯基砜(0.41ml,4.67mmol)。在室温下搅拌16小时后,反应混合物用稀释乙酸乙酯和水。分层,有机层用水(3x)和盐水洗涤。合并的含水洗涤液用乙酸乙酯萃取。合并的有机萃取液溶解在二氯甲烷中并用乙醚沉淀,重复数次,由此进行纯制,得到1.16g(59%)纯的所希望的产物,其为黄色固体:MS APCI(+)m/z 506,504(M+Br图形)和400,398(M-甲基乙基砜Br图形)。
步骤B:6-(4-溴-2-氯-苯基氨基)-7-氟-3-(2-甲磺酰基-乙基)-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11bb
使6-(4-溴-2-氯-苯基氨基)-7-氟-3-(2-甲磺酰基-乙基)-3H-苯并咪唑-5-羧酸甲基酯11cc进行如上所述的方法,得到6-(4-溴-2-氯-苯基氨基)-7-氟-3-(2-甲磺酰基-乙基)-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺:经检测MS APCI(+)m/z 561,559(M+Br图形)和MS APCI(-)m/z 559,557(M-Br图形);1H NMR(400MHz,DMSO-d6)11.75(s,1H),8.47(s,1H),8.04(s,1H),7.77(s,1H),7.62(d,1H),7.28(dd,1H),6.40(dd,1H),4.78(t,2H),3.82(t,2H),3.62(d,2H),3.07(s,3H),1.02(m,1H),0.49(m,2H),0.21(m,2H);19F NMR(376MHz,DMSO-d6)-132.66(s)。
实施例30
使用合适的甲基酯和Michael受体以及如上所述的方法制备以下化合物。
实施例31
[6-(5-氨基-[1,3,4]噁二唑-2-基)-4-氟-1H-苯并咪唑-5-基]-(4-溴-2-甲基-苯基)-胺(24a)
步骤A:6-(4-溴-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸酰肼20a
将6-(4-溴-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯8a(0.051g,0.135mmol)悬浮在EtOH(5ml)中,然后添加水合肼(0.118g,2.023mmol)。反应混合物在回流下加热16小时。反应混合物减压浓缩并通过FCC进行纯制,其中用97∶3乙酸乙酯∶MeOH洗脱,得到0.041g(81%)纯净的希望产物:经检测LC/MS ESI(+)m/z 378,380(M+Br图形)。
步骤B:[6-(5-氨基-[1,3,4]噁二唑-2-基)-4-氟-1H-苯并咪唑-5-基]-(4-溴-2-甲基-苯基)-胺24a
将6-(4-溴-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸酰肼20a(0.041g,0.109mmol)悬浮在1,4-二噁烷(1.5ml)中,然后添加36μl 3M溴化氰在二氯甲烷中的溶液。接着添加NaHCO3(9mg,0.109mmol)在水(1.5ml)中的溶液。16小时后,反应混合物用水和盐水稀释,然后用THF萃取。合并的有机萃取液进行干燥(Na2SO4),然后减压浓缩。通过FCC进行纯制,其中用98∶2乙酸乙酯∶MeOH洗脱,得到24mg(55%)纯的标题化合物,其为黄色固体:经检测LC/MS ESI(+)m/z 403,405(M+Br图形);1H-NMR(400MHz,DMSO-d6)12.97(s,1H),8.42(s,1H),7.94(s,1H),7.74(s,1H),7.36(s,2H),7.33(d,1H),7.15(d,1H),6.40(bs,1H),2.34(s,3H).
实施例32
[6-(5-氨基-[1,3,4]噁二唑-2-基)-4-氟-1H-苯并咪唑-5-基]-(4-氯-2-甲基-苯基)-胺(24b)
如实施例31所述,由6-(4-氯-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯8e起始,制备[6-(5-氨基-[1,3,4]噁二唑-2-基)-4-氟-1H-苯并咪唑-5-基]-(4-氯-2-甲基-苯基)-胺24b。经检测LC/MS ESI(+)m/z 359,361(M+Cl图形);1H NMR(400MHz,DMSO-d6)8.42(s,1H),8.00(bs,1H),7.78(bs,1H)7.48(s,2H),7.22(s,1H),7.04(d,1H),6.48(bs,1H),2.37(s,3H).
实施例33
[6-(5-氨基-[1,3,4]噁二唑-2-基)-4-氟-1H-苯并咪唑-5-基]-(4-溴-2-氯-苯基)-胺(24c)
如实施例31所述,由6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯8b起始,制备[6-(5-氨基-[1,3,4]噁二唑-2-基)-4-氟-1H-苯并咪唑-5-基]-(4-溴-2-氯-苯基)-胺24c。经检测MS APCI(+)m/z 425,423(M+Br图形)和MS APCI(-)m/z 423,421(M-Br图形).
实施例34
6-(4-氯-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸酰肼(20b)
如实施例31之步骤A所述,由6-(4-氯-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯8e起始,制备6-(4-氯-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸酰肼20b。经检测LC/MS ESI(+)m/z 334,336(M+Cl图形);1H NMR(400MHz,DMSO-d6)13.09(bs,1H),9.98(s,1H),8.40(s,1H),8.17(bs,1H),7.64(bs,1H),7.20(s,1H),7.03(d,1H),6.41(bs,1H),4.49(s,2H),2.23(s,3H).
实施例35
5-16-(4-氯-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-[1,3,4]噁二唑-2-醇(22a)
将6-(4-氯-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸酰肼20b(0.050g,0.150mmol)悬浮在PhMe(2ml)中,然后添加20%光气在PhMe中的溶液(0.24ml,0.45mmol)。反应混合物在回流和氮气氛下搅拌1小时,然后冷却至室温。添加THF和10%HCl的1∶1混合物(20ml),由此淬灭反应混合物。分层,而含水层用THF(3x)萃取。合并的有机层用盐水洗涤,干燥(Na2SO4),然后减压浓缩,得到54mg(99%)所希望的产物,其为黄色固体:经检测LC/MS ESI(+)m/z 360,362(M+Cl图形);1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),8.83(s,1H),7.88(s,1H),7.30(s,1H),7.20(d,1H),7.00(dd,1H),6.38(dd,1H),2.30(s,3H).
实施例36
(4-氯-2-甲基-苯基)-(4-氟-6-[1,3,4]噁二唑-2-基-1H-苯并咪唑-5-基)-胺(21a)
将6-(4-氯-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸酰肼20b(0.048g,0.144mmol)悬浮在3ml无水EtOH中,并先后添加HC(OEt)3(0.60ml,3.54mmol)和催化剂pTsOH·H2O。在氮气氛下将反应混合物加热至回流。2小时后,将反应混合物冷却至室温,然后减压浓缩。通过快速柱色谱纯制(97∶3乙酸乙酯∶MeOH),得到36mg(73%)所希望的产物,其为亮黄色固体。经检测LC/MS ESI(+)m/z 344,346(M+Cl图形);1H NMR(400MHz,DMSO-d6)13.10(bs,1H),9.39(s,1H),8.49(s,1H),8.10(bs,1H),7.78(bs,1H),7.20(d,1H),7.00(dd,1H),6.41(bs,1H),2.18(s,3H).
实施例37
5-[6-(4-氯-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-[1,3,4]噁二唑-2-硫醇(23a)
在氮气氛下将6-(4-氯-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸酰肼20b(0.050g,0.150mmol)悬浮在3ml无水EtOH中,然后冷却至0℃。先后添加CS2(26mg,0.346mmol)和KOH粉末(8mg,0.150mmol)。在0℃下搅拌30分钟后,将反应混合物加热至回流。3.5小时后,添加水,然后添加乙酸乙酯和1N HCl,由此淬灭反应混合物。分层,而含水层用乙酸乙酯萃取。合并的有机萃取液进行干燥(Na2SO4),然后减压浓缩,得到所希望的产物,其为黄色固体:经检测LC/MS ESI(+)m/z 376,378(M+Cl图形);1H NMR(400MHz,DMSO-d6)8.51(s,1H),7.92(s,1H),7.19(s,1H),7.12(s,1H),6.98(d,1H),6.29(d,1H),2.28(s,3H).
实施例38
6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酰胺(11oo)
将6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸10c(0.029g,0.076mmol)溶解在N,N-二甲基甲酰胺(1.1mL)中。在室温下向反应混合物中顺序地添加HOBT(0.016g,0.10mmol)、三乙基胺(0.028mL,0.20mmol)、甲基胺(0.059mL,0.12mmol,2M四氢呋喃溶液)、以及EDCI(0.019g,0.10mmol)。溶液在室温和氮气氛下搅拌16小时。反应混合物将倾倒在中分离漏斗并用乙酸乙酯和水稀释,然后分层。乙酸乙酯层顺序地用饱和NH4Cl水溶液(2x)、盐水(1x)、饱和碳酸氢钠水溶液(2x)、水(1x)、和盐水(1x)洗涤,干燥(MgSO4),然后减压浓缩。所得的固体通过FCC纯制(用19∶1二氯甲烷∶甲醇洗脱),得到0.013g(42%)纯的所希望的产物。经检测MS APCI(+)m/z 397,399(M+,Br图形);1HNMR(400MHz,DMSO-d6)δ8.76(br s,1H),8.69(m,1H),8.41(s,1H),7.76(s,1H),7.63(d,1H),7.30(dd,1H),6.50(dd,1H),2.76和2.75(s和s,总共3H,酰胺rotamers).19F NMR(376MHz,DMSO-d6)-132.69(s).
实施例39
按照类似于实施例38中描述的方法,使用合适的羧酸和酰胺,制备以下化合物。如果包含两个胺官能团,则在偶联反应中使用合适的单Boc保护的胺,而Boc基团在最终的步骤中在标准的TFA脱保护条件下除去。
实施例40
[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-甲醇(10e)
将6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸甲基酯8b(1.06g,2.65mmol)悬浮在四氢呋喃(25mL)中,然后冷却至-78℃。向反应混合物中滴加氢化铝锂(8.03mL,8.03mmol,1M四氢呋喃溶液)。在-78℃下搅拌10分钟后,将反应混合物温热至0℃,并变为均匀的溶液。反应混合物在0℃下搅拌5分钟,然后冷却至-778℃。用MeOH淬灭反应混合物,用Rochelle′s盐稀释,温热至室温并搅拌1小时。将反应混合物倾倒在分离漏斗中,用乙酸乙酯稀释,然后分层。含水相用乙酸乙酯萃取。合并的乙酸乙酯层干燥(Na2SO4),然后减压浓缩,得到0.98g(100%)纯的所希望的产物,其为淡黄色固体。经检测MS ESI(+)m/z370,372(M+,Br图形)。
实施例41
6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-甲醛(10f)
将[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-甲醇10e(0.96g,2.58mmol)溶解在四氢呋喃/丙酮(1∶1,15mL)中,然后添加MnO2(2.24g,25.8mmol)。反应混合物在50℃和氮气氛下搅拌10小时。通过硅胶过滤反应混合物,并用二氯甲烷/甲醇(10∶1,1L)洗脱。滤液减压浓缩至小的体积,通过Acrodisc注射过滤器进行过滤,除去少量的由硅胶中通过的MnO2。滤液减压浓缩,而残留物通过快速柱色谱纯制(用20∶1二氯甲烷∶甲醇洗脱),得到0.81g(85%)纯的所希望的产物,其为亮黄色固体。经检测MS ESI(+)m/z 368,370(M+,Br图形)。
实施例42
1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-基]-2-羟基-乙烷酮(10g)
步骤A:1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-基]-2-甲氧基甲氧基-乙醇10i
在-78℃下向三丁基-甲氧基甲氧基甲基-锡烷(864mg,2.37mmol,根据J.Org.Chem.1988,53,4131中描述的方法制备的)在THF(8mL)中的溶液内添加n-BuLi(0.94mL,2.35mmol,2.5M己烷溶液)。搅拌3分钟后,在-78℃下添加6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-甲醛10h(59mg,0.15mmol)在THF(2mL)中的溶液。在-78℃下搅拌40分钟后,反应溶液在-78℃下用饱和氯化铵水溶液淬灭,温热至室温,并用EtOAc稀释。有机层用盐水洗涤,在MgSO4上干燥,过滤,浓缩,然后通过快速色谱纯制(1.5%MeOH在CH2Cl2中),得到所希望的产物(45mg,64%):经检测MS APCI(+)m/z 458,460(M+,Br图形)。
步骤B:1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-基]-2-甲氧基甲氧基-乙烷酮10j
在室温下搅拌1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-基]-2-甲氧基甲氧基-乙醇10i(44mg,0.096mmol)和Dess-Martinperiodinane(49mg,0.12mmol)在CH2Cl2(1.5mL)中的混合物共1.5小时。反应混合物用醚(3mL)稀释。添加饱和的NaHCO3水溶液(1mL),其中包含硫代硫酸钠五水合物(74mg)。所得的混合物搅拌10分钟,并用EtOAc稀释。有机层用饱和NaHCO3水溶液和盐水洗涤,在MgSO4上干燥,过滤,然后真空浓缩,得到的粗产物通过快速色谱纯制(1.5%MeOH在CH2Cl2中),得到所希望的产物(31mg,71%):经检测MSAPCI(+)m/z 456,458(M+,Br图形)。
步骤C:1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-基]-2-羟基-乙烷酮10g
在室温下搅拌1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-基]-2-甲氧基甲氧基-乙烷酮10j(15mg,0.033mmol)、10%HCl水溶液(0.3mL)、甲醇(0.01mL)、和水(0.05mL)的混合物共3天。用饱和NaHCO3水溶液中和反应混合物,用EtOAc稀释。有机层用盐水洗涤,在MgSO4上干燥,过滤,真空浓缩,然后通过快速色谱纯制(1.5%MeOH在CH2Cl2中),得到所希望的产物(7.3mg,54%):经检测MSAPCI(+)m/z 412,414(M+,Br图形);1H NMR(400MHz,丙酮-d6)δ8.64(s,1H),8.34(s,1H),8.16(s,1H),7.58(d,1H),7.31(dd,1H),6.59(dd,1H),4.94(s,2H),4.06(s,3H);19F NMR(376MHz,丙酮-d6)-132.45(s,1F).
实施例43
1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-羟基-乙烷酮(10k)
步骤A:1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-甲氧基甲氧基-乙醇10l
根据实施例42之步骤A中描述的方法用三丁基-甲氧基甲氧基甲基-锡烷处理6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-甲醛10f,得到化合物10l。经检测MS APCI(+)m/z 444,446(M+,Br图形)。
步骤B:1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-甲氧基甲氧基-乙烷酮10m
在-78℃下向草酰氯(0.11mL,0.22mmol)在CH2Cl2(1mL)中的溶液内添加DMSO(0.016mL,0.22mmol)。搅拌3分钟后,添加1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-甲氧基甲氧基-乙醇10l(25mg,0.056mmol)在二氯甲烷(1mL)中的溶液。所得的溶液在-78℃下搅拌30分钟。添加TEA(0.1mL,0.71mmol)。反应混合物缓慢温热至室温,在室温搅拌5分钟,然后用水和CH2Cl2稀释。分离有机层,在MgSO4上干燥,过滤并浓缩,得到的粗产物无需进一步纯制即直接使用。
步骤C:1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-羟基-乙烷酮10k
根据实施例42之步骤C中描述的方法,使1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-甲氧基甲氧基-乙烷酮10m脱保护,得到化合物10k。经检测MS APCI(+)m/z 398,400(M+,Br图形);1H NMR(400MHz,CD3OD)δ8.38(s,1H),8.04(s,1H),7.52(d,1H),7.22(dd,1H),6.53(dd,1H),4.90(m,2H);19F NMR(376MHz,CD3OD)-133.96(s,1F).
实施例44
1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-乙氧基-乙烷酮(10n)
步骤A:1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-乙氧基-乙醇10o
在-78℃下向锂甲基乙基醚在THF(6mL)中的溶液(根据Tetrahedron 1996,52,1643中的方法由4,4’-二叔丁基联苯(585mg,2.20mmol)、Li(18mg,2.59mmol)、和EtOCH2Cl(0.20mL,2.05mmol)制得的)内添加6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-甲醛10f(29mg,0.080mmol)在THF(1mL)中的溶液。所得的溶液在-78℃下搅拌1小时,然后用饱和氯化铵水溶液淬灭,温热至室温,并用EtOAc萃取。有机层用洗涤盐水,在MgSO4上干燥,过滤,真空浓缩,然后通过快速色谱纯制(100%CH2Cl2-3%-5%MeOH在CH2Cl2中),得到所希望的产物(15mg,44%):经检测MS APCI(+)m/z 428,430(M+,Br图形)。
步骤B:1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-乙氧基-乙烷酮10n
根据实施例42之步骤B中描述的方法,由1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-乙氧基-乙醇10o制备标题化合物,不同之处在于,反应混合物不用包含硫代硫酸钠五水合物的饱和碳酸氢钠水溶液处理。经检测MS APCI(+)m/z 426,428(M+,Br图形);1H NMR(400MHz,CD3OD)δ8.36(s,1H),8.04(s,1H),7.51(d,1H),7.21(dd,1H),6.51(dd,1H),4.76(s,2H),3.57(q,2H),1.19(t,3H);19F NMR(376MHz,CD3OD)-133.96(s).
实施例45
1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-甲氧基-乙烷酮(10p)
按照实施例44中描述的方法,由6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-甲醛10f和锂甲基甲基醚制备1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-甲氧基-乙烷酮10p。经检测MS APCI(+)m/z412,414(M+,Br图形)。
实施例46
2-苄氧基-1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-乙烷酮(10q)
步骤A:2-苄氧基-1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-乙醇10r
在-78℃下向苄氧基甲基锂在THF中的水溶液(2mL,根据J.Am.Chem.Soc.1978,100,1481中描述的方法,由n-Bu3SnCH2OBn(505mg,1.23mmol)和n-BuLi(0.49mL,1.22mmol,2.5M己烷溶液)制备的)内添加6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-甲醛10f(51mg,0.14mmol)在THF(3mL)中的溶液。所得的溶液在-78℃下搅拌1小时。用饱和氯化铵水溶液淬灭反应,并用EtOAc萃取。有机层在MgSO4上干燥,过滤,真空浓缩,然后通过快速色谱纯制(100%CH2Cl2-3%MeOH在CH2Cl2中),得到所希望的产物(46mg,68%):经检测MSAPCI(+)m/z 490,492(M+,Br图形)。
步骤B:2-苄氧基-1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-乙烷酮10q
根据实施例42之步骤B中描述的方法,由2-苄氧基-1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-乙醇10r制备标题化合物,不同之处在于,反应混合物不用包含硫代硫酸钠五水合物的饱和碳酸氢钠水溶液处理。经检测MS APCI(+)m/z 488,490(M+,Br图形);1H NMR(400MHz,CD3OD)δ8.37(s,1H),8.02(s,1H),7.51(d,1H),7.26(m,5H),7.19(dd,1H),6.46(dd,1H),4.77(s,2H),4.58(s,2H);19F NMR(376MHz,CD3OD)-134.52(s).
实施例47
1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-甲磺酰基-乙烷酮(10s)
步骤A:1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-甲磺酰基-乙醇10t
在-78℃下向甲基砜(65mg,0.68mmol)在THF(1.5mL)中的溶液内添加n-BuLi溶液(0.27mL,0.68mmol,2.5M己烷溶液)。搅拌5分钟后,添加HMPA(0.1mL)。另外搅拌10分钟后,添加6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-甲醛10f(26mg,0.069mmol)在THF(1mL)中的溶液。所得的溶液在-78℃下搅拌1.5小时。用饱和氯化铵水溶液淬灭反应,温热至室温,并用EtOAc稀释。有机层用水洗涤,在MgSO4上干燥,过滤,真空浓缩,然后通过快速色谱纯制(3%MeOH在CH2Cl2中),得到粗的希望产物(31mg,96%),其未经进一步纯制直接使用:经检测MS APCI(+)m/z 462,464(M+,Br图形)。
步骤B:1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-甲磺酰基-乙烷酮10s
根据实施例42之步骤B中描述的方法,由1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-甲磺酰基-乙醇10t制备标题化合物,不同之处在于,反应混合物不用包含硫代硫酸钠五水合物的饱和碳酸氢钠水溶液处理。经检测MS APCI(+)m/z 460,462(M+,Br图形);1H NMR(400MHz,丙酮-d6)δ8.44(s,1H),8.33(s,1H),7.59(s,1H),7.32(d,1H),6.68(dd,1H),5.00(s,1H),3.15(s,3H);19F NMR(376MHz,丙酮-d6)-132.97(s).
实施例48
1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-乙烷-1,2-二醇(10u)
步骤A:1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-(异丙氧基-二甲基-硅烷基)-乙醇10v
在-78℃下向由Mg和氯甲基二甲基异丙氧基硅烷制得的格氏试剂(Org.Synth.1992,69,96)[4.4mL,3.26mmol,0.74M溶液(基于90%纯度)]在THF中的溶液内添加6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-甲醛10f(200mg,0.54mmol)在THF(1mL)中的溶液。-78℃下搅拌1小时后,用饱和氯化铵水溶液淬灭反应,并用EtOAc萃取。有机层在MgSO4上干燥,过滤,真空浓缩,得到粗的希望产物,其未经纯制即直接使用。
步骤B:1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-乙烷-1,2-二醇10u
在室温下向粗的1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-(异丙氧基-二甲基-硅烷基)-乙醇10v在MeOH-THF(5mL-5mL)中的溶液内添加KHCO3(54mg,0.54mmol)、KF(74mg,1.27mmol)、以及30%H2O2水溶液(0.20mL)。在室温下搅拌3.5小时后,反应混合物用水稀释,并用EtOAc萃取。有机层在MgSO4上干燥,过滤,真空浓缩,然后通过快速色谱纯制(8%-10%MeOH,在CH2Cl2中),得到所希望的产物(74mg,34%):经检测MS APCI(+)m/z 400,402(M+,Br图形);1HNMR(400MHz,CD3OD)δ8.20(s,1H),7.62(broad s,1H),7.47(d,1H),7.14(dd,1H),6.30(d,1H),4.96(t,1H),3.64(m,2H);19F NMR(376MHz,CD3OD)-136.87(s).
实施例49
[6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-基]-吡啶-2-基-甲醇(10w)
在-78℃下向2-溴吡啶(0.10mL,1.04mmol)在THF(3mL)中的溶液内添加n-BuLi(0.39mL,0.98mmol,2.5M己烷溶液)。在-78℃下搅拌10分钟后,添加6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-甲醛10h(25mg,0.064mmol)在THF(1mL)中的溶液。所得的反应混合物在-78℃下搅拌1.5小时,用饱和氯化铵水溶液淬灭,并用EtOAc萃取。有机层在MgSO4上干燥,过滤,真空浓缩,然后通过快速色谱纯制(2.5%MeOH,在CH2Cl2中),得到所希望的产物(18mg,62%):经检测MSAPCI(+)m/z 461,463(M+,Br图形);1H NMR(400MHz,CD3OD)δ8.31(d,1H),8.16(s,1H),7.65(m,3H),7.38(d,1H),7.10(m,1H),7.00(dd,1H),6.11(dd,1H),6.05(s,1H),3.94(s,3H);19F NMR(376MHz,CD3OD)-135.79(s).
实施例50
(4-溴-2-氯-苯基)-(4-氟-6-噁唑-5-基-1H-苯并咪唑-5-基)-胺(10x)
步骤A:[6-(4-溴-2-氯-苯基氨基)-7-氟-3-(2-甲磺酰基-乙基)-3H-苯并咪唑-5-基]-甲醇10y
在氮气氛下将6-(4-溴-2-氯-苯基氨基)-7-氟-3-(2-甲磺酰基-乙基)-3H-苯并咪唑-5-羧酸甲基酯11cc(0.300g,0.594mmol)悬浮在EtOH(6ml)和THF(4ml)的混合物中。添加NaBH4(0.112g,2.97mmol)。搅拌约4天后,添加AcOH直至反应混合物达到pH为7,由此淬灭反应混合物。反应混合物减压浓缩至干,而残留物在乙酸乙酯和水之间分配。分层,而有机层用水(3x)、盐水、和干燥(Na2SO4)洗涤。有机层减压浓缩,直至形成白色沉淀物,其通过过滤收集,得到0.225g(79%)纯净的希望产物:经检测LC/MS ESI(+)m/z 478,476(M+Br图形)。
步骤B:6-(4-溴-2-氯-苯基氨基)-7-氟-3-(2-甲磺酰基-乙基)-3H-苯并咪唑-5-甲醛10z
在氮气氛下将[6-(4-溴-2-氯-苯基氨基)-7-氟-3-(2-甲磺酰基-乙基)-3H-苯并咪唑-5-基]-甲醇10y(0.050,0.105mmol)溶解在1∶1THF∶丙酮(2ml)中,然后添加MnO2(0.046g,0.524mmol)。反应混合物在室温下搅拌16小时,然后在55℃下加热5小时。添加额外的MnO2(0.046g,0.524mmol),并且反应混合物在55℃下搅拌2小时。反应混合物浓缩至干,而残留物溶解在10∶1二氯甲烷∶MeOH中。溶液通过硅胶柱过滤,其中用10∶1二氯甲烷∶MeOH洗脱。所得的滤液减压浓缩,得到41mg(82%)所希望的产物,其为亮黄色固体。
步骤C:(4-溴-2-氯-苯基)-(4-氟-6-噁唑-5-基-1H-苯并咪唑-5-基)-胺10x
将6-(4-溴-2-氯-苯基氨基)-7-氟-3-(2-甲磺酰基-乙基)-3H-苯并咪唑-5-甲醛10z(0.025g,0.053mmol)悬浮在MeOH(2ml)和K2CO3(0.015g,0.105mmol)中,然后添加甲苯磺酰基甲基异氰化物(0.011g,0.058mmol)。在氮气氛下将反应混合物加热至回流16小时。冷却后,添加额外的甲苯磺酰基甲基异氰化物(0.011g,0.058mmol),并在氮气氛下加热反应混合物至回流16小时。将反应混合物冷却至室温,减压浓缩,然后溶解在乙酸乙酯中。有机溶液用水和盐水洗涤。合并的含水洗涤液用乙酸乙酯萃取。合并的有机萃取液进行干燥(Na2SO4),然后减压浓缩。通过快速柱色谱纯制,其中用20∶1二氯甲烷∶MeOH洗脱,得到4mg(18%)所希望的产物10x和1mg(4%)(4-溴-2-氯-苯基)-[4-氟-1-(2-甲磺酰基-乙基)-6-噁唑-5-基-1H-苯并咪唑-5-基]-胺。
(4-溴-2-氯-苯基)-(4-氟-6-噁唑-5-基-1H-苯并咪唑-5-基)-胺10x.经检测LC/MS ESI(+)m/z 409,407(M+Br图形);1H NMR(400MHz,MeOH-d4)8.33(s,1H),8.24(s,1H),7.94(bs,1H),7.51(d,1H),7.33(s,1H),7.07(dd,1H),6.14(dd,1H).
(4-溴-2-氯-苯基)-[4-氟-1-(2-甲磺酰基-乙基)-6-噁唑-5-基-1H-苯并咪唑-5-基]-胺。经检测LC/MS ESI(+)m/z 515,513(M+Br图形);1HNMR(400MHz,MeOH-d4)8.39(s,1H),8.28(s,1H),8.03(s,1H),7.52(d,1H),7.37(s,1H),7.07(m,1H),6.14(dd,1H),3.83(t,2H),2.99(s,3H),1.18(t,2H).
实施例51
(4-溴-2-氯-苯基)-[4-氟-6-(3H-咪唑-4-基)-1H-苯并咪唑-5-基]-胺(10aa)
步骤A:(4-溴-2-氯-苯基)-{4-氟-1-(2-甲磺酰基-乙基)-6-[4-(甲苯-4-磺酰基)-4,5-二氢-噁唑-5-基]-1H-苯并咪唑-5-基}-胺10bb
在氮气氛下将6-(4-溴-2-氯-苯基氨基)-7-氟-3-(2-甲磺酰基-乙基)-3H-苯并咪唑-5-甲醛10z(0.050g,0.107mmol)悬浮在EtOH(0.5ml)中,并先后添加甲苯磺酰基甲基异氰化物(0.020g,0.105mmol)和催化量的NaCN(~1mg)。2小时后,添加2ml THF,以有助于溶解。在室温下搅拌16小时后,添加第二个当量的甲苯磺酰基甲基异氰化物(0.020g,0.105mmol)。8小时后,反应混合物减压浓缩并用于下一步反应中:经检测LC/MS ESI(+)m/z 671,669(M+Br图形)。
步骤B:(4-溴-2-氯-苯基)-[4-氟-6-(3H-咪唑-4-基)-1H-苯并咪唑-5-基]-胺10aa
在密封的压力管中(4-溴-2-氯-苯基)-{4-氟-1-(2-甲磺酰基-乙基)-6-[4-(甲苯-4-磺酰基)-4,5-二氢-噁唑-5-基]-1H-苯并咪唑-5-基}-胺10bb(0.072g,0.107mmol)用2.4ml的2.0M NH3MeOH溶液处理。将反应混合物加热至90℃,同时进行搅拌20小时,然后在室温下继续搅拌3天。将反应混合物转移至圆底烧瓶中,然后减压浓缩。通过快速柱色谱纯制两次,其中用10∶1二氯甲烷∶MeOH洗脱,然后顺序地用二氯甲烷和乙醚研磨,得到3mg(7%)所希望的产物:经检测LC/MS ESI(+)m/z408,406(M+Br图形);1H NMR(400MHz,MeOH-d4)8.23(s,1H),7.87(s,1H),7.74(s,1H),7.46(m,1H),7.32(d,1H),7.05(m,1H),6.20(dd,1H).
实施例52
6-(4-溴-2-氯-苯基氨基)-7-氯-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺(10cc)
步骤A:3-氯-2,4-二氟-5-硝基-苯甲酸2a
将3-氯-2,4-二氟-苯甲酸1a(3.00g,15.6mmol)添加至浓H2SO4(16mL)和发烟硝酸(0.85mL,20.3mmol)的搅拌溶液中。3小时后形成沉淀。将黄色浆液倾倒在冰水(100mL)上。含水混合物用乙醚(3x)萃取。有机萃取液干燥(Na2SO4),然后减压浓缩,得到3.50g(95%)纯净的希望产物,其为淡黄色固体。
步骤B:4-氨基-3-氯-2-氟-5-硝基-苯甲酸3a
在0℃下将氢氧化铵溶液(6.88g,~30%in水,58.9mmol)添加至3-氯-2,4-二氟-5-硝基-苯甲酸2a(3.5g,14.7mmol)在水(16mL)中的溶液内,同时进行搅拌。氢氧化铵添加完全后,将反应混合物温热至室温。5小时后,将反应混合物冷却至0℃,并小心地添加浓HCl,直至反应混合物的pH接近0。过滤收集固体,并用水和乙醚洗涤。将固体溶解在MeOH和EtOAc中,转移至圆底烧瓶中,然后减压浓缩,得到2.96g的黄色固体。滤液在乙醚和水之间分配,而有机层用洗涤盐水。合并的有机萃取液进行干燥(Na2SO4),然后减压浓缩,得到0.65g的产物。总共回收到3.61g(104%)纯的标题化合物,其没有进一步纯制就继续使用。
步骤C:4-氨基-3-氯-2-氟-5-硝基-苯甲酸甲基酯4a
向4-氨基-3-氯-2-氟-5-硝基-苯甲酸3a(3.61g,15.4mmol)在THF(30mL)和MeOH(10mL)中的搅拌溶液内添加TMS重氮甲烷(9.23mL,2.0M己烷溶液,18.5mmol)。反应完全后,通过旋转蒸发浓缩反应混合物,而乙酸保留在阱中。回收的油状固体用乙醚研磨,得到1.51g的黄色固体。滤液浓缩并用乙醚研磨,得到另外0.69g的黄色固体。总共回收2.20g(57%)纯的标题化合物。
步骤D:4-氨基-3-氯-5-硝基-2-苯基氨基-苯甲酸甲基酯5c
将4-氨基-3-氯-2-氟-5-硝基-苯甲酸甲基酯4a(2.20g,8.84mmol)悬浮在MeOH(9.4mL)中,然后添加苯胺(3.22mL,35.4mmol)。在氮气氛下将反应混合物加热至回流,同时进行搅拌。19小时后,反应完全。将蒸馏水(3.22mL)添加至反应混合物中并继续回流1小时。在冰浴中将反应混合物冷却至0℃共20分钟。反应混合物过滤,并用3∶10蒸馏水/MeOH(总共65mL)洗涤,然后用MeOH洗涤。将固体溶解在CH2Cl2中,然后减压浓缩,得到2.40g(84%)纯的标题化合物。经检测MS APCI(-)m/z 320.3(M-1)。
步骤E:4,5-二氨基-3-氯-2-苯基氨基-苯甲酸甲基酯6b
将4-氨基-3-氯-5-硝基-2-苯基氨基-苯甲酸甲基酯5c(0.50g,1.55mmol)溶解在2∶1EtOH/MeOH(15.5mL)中。饱和的NH4Cl水溶液(15mL)、Zn粉(1.02g,15.6mmol)、和THF(10mL)。搅拌20小时后,反应混合物用CH2Cl2/THF和水稀释。有机层用水(3x)洗涤。合并的有机萃取液进行干燥(Na2SO4),然后减压浓缩.该固体用醚研磨,得到0.32g(70%)纯净的希望产物。
步骤F:7-氯-6-苯基氨基-3H-苯并咪唑-5-羧酸甲基酯7c
使4,5-二氨基-3-氯-2-苯基氨基-苯甲酸甲基酯6b(0.32g,1.09mmol)和甲脒乙酸盐(72mg,1.64mmol)在EtOH(36mL)中加热至80℃,同时进行搅拌。44小时后,将反应混合物冷却至室温并用EtOAc稀释,然后用水(3x)、饱和NaHCO3、以及盐水洗涤。合并的有机萃取液进行干燥(Na2SO4),然后减压浓缩,得到0.33g(99%)纯净的希望产物,其为固体。经检测MS APCI(+)m/z 302.3(M+1)。
步骤G:6-(4-溴-苯基氨基)-7-氯-3H-苯并咪唑-5-羧酸甲基酯8g
将7-氯-6-苯基氨基-3H-苯并咪唑-5-羧酸甲基酯7c(0.327g,1.08mmol)溶解在DMF(16mL)中,然后添加NBS(0.193g,1.08mmol)。1小时后,添加饱和NaHSO3水溶液,由此淬灭反应混合物。使反应混合物在EtOAc/THF和水之间分配。有机层用水和盐水洗涤。合并的有机萃取液进行干燥(Na2SO4),然后减压浓缩.回收的固体用醚研磨,得到0.225g(54%)纯的所希望的产物。经检测MS ESI(+)m/z 382,384(M+,Br图形)。
步骤H:6-(4-溴-2-氯-苯基氨基)-7-氯-3H-苯并咪唑-5-羧酸甲基酯10dd
将6-(4-溴-苯基氨基)-7-氯-3H-苯并咪唑-5-羧酸甲基酯8g(0.225g,0.591mmol)溶解在DMF(2mL)中,然后添加NCS(79mg,0.591mmol)。NCS溶解后,添加浓HCl(0.005mL,0.059mmol)。2小时后,将碳酸氢钠、水和NaHSO3添加至反应混合物中。过滤固体,并用水和醚洗涤,得到0.141g(57%)纯净的希望产物,其为棕黄色固体。经检测MS APCI(-)m/z 414,416(M-,Br图形)。
步骤I:6-(4-溴-2-氯-苯基氨基)-7-氯-3-甲基-3H-苯并咪唑-5-羧酸甲基酯10ee
将6-(4-溴-2-氯-苯基氨基)-7-氯-3H-苯并咪唑-5-羧酸甲基酯10dd(0.141g,0.34mmol)、碳酸钾(0.141g,1.02mmol)、和碘甲烷(0.063mL,1.02mmol)溶解在二甲基甲酰胺(3mL)中。20小时后,反应混合物用EtOAc稀释,然后用水(3x)、碳酸钾、和盐水洗涤。有机层干燥(Na2SO4)并浓缩,形成棕色油。通过快速色谱(EtOAc)分离N3和N1烷基化区域异构体。回收到的N3烷基化区域异构体为20.4mg(28%)。经检测MS ESI(+)m/z 428,430(M+,Br图形)。
步骤J:6-(4-溴-2-氯-苯基氨基)-7-氯-3-甲基-3H-苯并咪唑-5-羧酸10ff
将6-(4-溴-2-氯-苯基氨基)-7-氯-3-甲基-3H-苯并咪唑-5-羧酸甲基酯10ee(21mg,0.048mmol)溶解在2∶1THF/水(1.2mL)中,然后添加NaOH(0.190mL,1.0M水溶液,0.190mmol)。搅拌4小时后,反应物用水稀释,然后通过添加1.0M HCl而酸化至pH 2。混合物用3∶1EtOAc/THF(3x)萃取,干燥(Na2SO4)并浓缩,得到定量产量的希望产物,其为白色固体。经检测MS APCI(+)m/z 414,416(M+,Br图形)。
步骤K:6-(4-溴-2-氯-苯基氨基)-7-氯-3-甲基-3H-苯并咪唑-5-羧酸(2-乙烯基氧基-乙氧基)-酰胺10gg
在室温和氮气氛下将6-(4-溴-2-氯-苯基氨基)-7-氯-3-甲基-3H-苯并咪唑-5-羧酸10ff(32mg,0.077mmol)、O-(2-乙烯基氧基-乙基)-羟胺(0.010mL,0.092mmol)、HOBt(13mg,0.093mmol)、三乙基胺(0.011mL,0.077mmol)、和EDCI(19mg,0.10mmol)溶解在二甲基甲酰胺(1.0mL)中,然后搅拌24小时。反应混合物用EtOAc稀释,用水(3x)、10%碳酸钾(2x)、饱和氯化铵、盐水洗涤,干燥(Na2SO4),然后减压浓缩,得到39mg的85%纯物质。经检测MS APCI(-)m/z 497,501(M-,Br图形)。
步骤L:6-(4-溴-2-氯-苯基氨基)-7-氯-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺10cc
将盐酸(0.78mL,1.0M水溶液,0.78mmol)添加至6-(4-溴-2-氯-苯基氨基)-7-氯-3-甲基-3H-苯并咪唑-5-羧酸10gg(2-乙烯基氧基-乙氧基)-酰胺(39mg,0.078mmol)在MeOH(1mL)中的悬浮液内。1小时后,将反应混合物中和至pH 7,然后减压浓缩。将固体溶解在EtOAc中,用盐水洗涤,干燥(Na2SO4),然后减压浓缩。进行快速色谱纯制(20∶1CH2Cl2/MeOH),得到9mg(23%)的纯产物:经检测MS APCI(+)m/z473,475(M+,Br图形);1H NMR(400MHz,CDCl3)δ8.30(s,1H),8.08(s,1H),7.57(d,1H),7.15(dd,1H),6.21(d,1H),3.97(s,3H)3.86(m,2H),3.57(m,2H).
实施例53
6-(4-溴-2-氯-苯基氨基)-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺(10hh)
类似于实施例52的方法制备以上化合物,但消除步骤I。经检测MS APCI(-)m/z 457,461(M-,Br图形);1H NMR(400MHz,CD3OD)δ8.40(s,1H),7.85(s,1H),7.50(d,1H),7.14(dd,1H),6.21(d,1H),3.84(m,2H),3.61(m,2H).
实施例54
6-(4-溴-2-氯-苯基氨基)-7-氟-2-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺(10ii)
步骤A:4,5-二氨基-3-氟-2-苯基氨基-苯甲酸甲基酯6c
将4-氨基-3-氟-5-硝基-2-苯基氨基-苯甲酸甲基酯26a(11.44g,37.48mmol)悬浮在乙醇(400mL)中,然后添加甲酸铵(11.80g,187.0mmol)和20%Pd(OH)2/C(10.00g,18.79mmol)。反应混合物在95℃和氮气氛下搅拌30分钟。将反应混合物冷却至室温并通过celite过滤,用乙醇洗涤。滤液减压浓缩,得到9.63g(93%)纯的所希望的产物,其为紫色/红色固体。经检测MS ESI(+)m/z 276(M+1)。
步骤B:7-氟-2-甲基-6-苯基氨基-3H-苯并咪唑-5-羧酸甲基酯31a
将4,5-二氨基-3-氟-2-苯基氨基-苯甲酸甲基酯6c(0.20g,0.73mmol)悬浮在乙醇(3mL)中,并添加5M HCl水溶液(1mL.,5.00mmol)。反应混合物在氮气氛下回流,然后添加2,4-戊烷二酮(0.150mL,1.45mmol)。反应混合物在回流下搅拌60分钟。将反应混合物冷却至室温,然后用饱和碳酸氢钠水溶液处理,直至反应混合物的pH为7,并接着减压浓缩至干。残留物用乙酸乙酯和水稀释,倾倒在分离漏斗中,然后分层。乙酸乙酯层用盐水洗涤,干燥(Na2SO4),然后减压浓缩。红色的固体残留物用乙醚研磨,得到亮棕色的固体和红色滤液。收集固体并用乙醚洗涤,得到0.20g(91%)纯的所希望的产物,其为亮棕色固体。经检测MS ESI(+)m/z 300(M+1)。
步骤C:6-(4-溴-2-氯-苯基氨基)-7-氟-2-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺10ii
按照以上描述的溴化、氯化、水解、偶联、和水解方法,转化7-氟-2-甲基-6-苯基氨基-3H-苯并咪唑-5-羧酸甲基酯31a,得到纯的所希望的产物,其为浅白色固体。经检测MS ESI(+)m/z 457,459(M+,Br图形);1H NMR(400MHz,CD3OD)δ7.58(s,1H),7.49(d,1H),7.18(dd,1H),6.41(m,1H),3.91(t,2H),3.65(t,2H),2.61(s,3H);19F NMR(376MHz,CD3OD)-135.84(s).
实施例55
6-(4-氰基-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺(11yy)
步骤A:7-氟-6-(4-碘-2-甲基-苯基氨基)-1H-苯并咪唑-5-羧酸甲基酯10jj
在氮气氛下将7-氟-6-o-甲苯基氨基-1H-苯并咪唑-5-羧酸甲基酯7a(1.47g,4.92mmol)悬浮在1∶1THF∶MeOH混合物(44ml)中,然后冷却至-78℃。先后添加NIS(1.66g,7.39mmol)在THF(2ml)中的溶液和TsOH·H2O(1.87g,9.84mmol)的MeOH(2ml)溶液。30分钟,反应混合物温热至0℃并添加1ml二氯甲烷。在16小时的时间内缓慢使反应混合物温热至室温,同时进行搅拌。添加10%Na2S2O4溶液,由此淬灭反应混合物。反应混合物用水和乙酸乙酯稀释,然后分层。含水层用乙酸乙酯萃取。合并的有机萃取液进行干燥(Na2SO4),然后减压浓缩。回收的固体用MeOH研磨,得到1.45g(69%)纯的所希望的产物:经检测MS ESI(+)m/z 426(M+1);经检测MS ESI(-)m/z 424(M-1)。
步骤B:7-氟-6-(4-碘-2-甲基-苯基氨基)-(2-三甲基硅烷基-乙氧基甲基)-苯并咪唑-5-羧酸甲基酯10kk
在氮气氛下将7-氟-6-(4-碘-2-甲基-苯基氨基)-1H-苯并咪唑-5-羧酸甲基酯10jj(0.200g,0.470mmol)悬浮在DMF(2ml)中,然后在冰水浴中冷却至0℃。添加NaH(60%油分散液,0.018g,0.470mmol)。10分钟后,反应混合物温热至室温并搅拌30分钟。冷却至0℃后,添加SEMCl(0.087ml,0.494mmol),然后使反应物温热至室温,同时进行搅拌过夜。添加水和盐水,由此淬灭反应混合物。反应混合物用乙酸乙酯萃取。合并的有机萃取液用水和盐水洗涤,并干燥(MgSO4),然后减压浓缩。通过快速柱色谱纯制,其中用1∶1己烷∶乙酸乙酯洗脱,得到0.182g(70%)所希望的白色泡沫状产物,其是N1和N3异构体的1∶1混合物。
步骤C:6-(4-氰基-2-甲基-苯基氨基)-7-氟-(2-三甲基硅烷基-乙氧基甲基)-苯并咪唑-5-羧酸甲基酯10ll
在室温和氮气氛下向7-氟-6-(4-碘-2-甲基-苯基氨基)-(2-三甲基硅烷基-乙氧基甲基)-苯并咪唑-5-羧酸甲基酯10jj(0.060g,0.108mmol)的N1∶N3异构体1∶1混合物在1ml DMF中的搅拌溶液内添加dppf(2mg,0.004mmol),然后添加Pd2dba3(2mg,0.002mmol)和Zn(CN)2(8mg,0.065mmol)(Tetrahedron Lett.1999,40,8193-8195)。将反应混合物加热至120℃共45分钟。将反应混合物冷却至室温,然后通过添加5ml的饱和NH4Cl溶液∶浓NH4OH溶液∶水的4∶1∶5混合物进行淬灭。含水层用萃取乙酸乙酯。合并的有机萃取液用水(3x)、盐水洗涤,干燥(MgSO4),然后减压浓缩。通过快速柱色谱纯制,其中用1∶1己烷∶乙酸乙酯洗脱,得到38mg(77%)所希望的产物,其是N1和N3异构体的1∶1混合物:经检测APCI MS(+)m/z 455(M+1)。
步骤D:6-(4-氰基-2-甲基-苯基氨基)-7-氟-(2-三甲基硅烷基-乙氧基甲基)-苯并咪唑-5-羧酸10mm
如前所述用氢氧化钠水溶液使6-(4-氰基-2-甲基-苯基氨基)-7-氟-(2-三甲基硅烷基-乙氧基甲基)-苯并咪唑-5-羧酸甲基酯10ll(31mg,0.068mmol)的N 1∶N3异构体的1∶1混合物水解,得到26mg(87%)所希望的产物。
步骤E:6-(4-氰基-2-甲基-苯基氨基)-7-氟-(2-三甲基硅烷基-乙氧基甲基)-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11zz
如前所述,使6-(4-氰基-2-甲基-苯基氨基)-7-氟-(2-三甲基硅烷基-乙氧基甲基)-苯并咪唑-5-羧酸10mm(26mg,0.059mmol)的N1∶N3异构体的1∶1混合物与EDCI和环丙基甲基羟胺盐酸盐偶联,得到28mg(93%)所希望的产物:经检测APCI MS(+)m/z 510(M+1)。
步骤F:6-(4-氰基-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11yy
向6-(4-氰基-2-甲基-苯基氨基)-7-氟-(2-三甲基硅烷基-乙氧基甲基)-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11zz(28mg,0.055mmol)的N1∶N3异构体的1∶1混合物在0.5ml EtOH中的浆液内添加0.5ml 10%HCl。将反应混合物加热至50℃,同时进行搅拌过夜(Whitten等人,JOC 1986,51,1891-1894)。添加另外的0.5ml 10%HCl,并在70℃下搅拌反应混合物过夜。将反应混合物冷却至室温,然后用1.5ml 1N NaOH中和至pH~8。反应混合物用萃取乙酸乙酯,干燥(MgSO4),然后减压浓缩,得到14mg(60%)90%纯的产物,其是rotatomer的混合物:经检测MS APCI(+)m/z 380(M+1);经检测MS APCI(-)m/z 378(M-1);1HNMR(400MHz,MeOH-d4)δ8.41(bs,1H),7.75(m,1H),7.50(s,1H),7.38(d,1H),6.51(m,1H),3.72(d,0.5H),3.65(d,1.5H),2.41(s,3H),0.98(1H,m),0.58(d,1.5H),0.40(d,0.5H),0.25(d,1.5H),0.19(d,0.5H).
实施例56
6-(4-乙炔基-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11aaa
步骤A.7-氟-6-(2-甲基-4-三甲基硅烷基乙炔基-苯基氨基)-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11bbb
将7-氟-6-(4-碘-2-甲基-苯基氨基)-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11ccc(0.025g,0.052mmol)溶解在1∶1乙腈/三乙基胺(0.50mL)中。在60℃和氮气氛下连续地添加乙炔基-三甲基硅烷(0.013mL,0.092mmol)、Pd(PPh3)2Cl2(0.004g,0.006mmol)、和CuI(0.002g,0.011mmol),并搅拌反应混合物1小时。将反应混合物冷却至室温,然后减压浓缩。残留物通过FCC纯制(用20∶1二氯甲烷∶甲醇洗脱),得到0.020g(87%)所希望的产物。
步骤B:6-(4-乙炔基-2-甲基-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11aaa
将7-氟-6-(2-甲基-4-三甲基硅烷基乙炔基-苯基氨基)-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺11bbb(0.020g,0.044mmol)溶解在四氢呋喃(0.50mL)中,然后使反应溶液冷却至0℃。添加TBAF(50uL,0.050mmol,1M四氢呋喃溶液)。将反应混合物温热至室温,并添加另外的TBAF(25uL,0.025mmol,1M四氢呋喃溶液)。反应混合物在50℃和氮气氛下搅拌2小时。将反应混合物冷却至室温,添加几滴H2O,然后减压浓缩。残留物通过FCC纯制(用洗脱20∶1二氯甲烷∶甲醇),得到0.011g(65%)纯的所希望的产物。经检测MS APCI(-)m/z 377(M-1);1HNMR(400MHz,CDCl3)δ10.56(broad s,1H),8.12(s,1H),7.99(s,1H),7.28(s,1H),7.11(d,1H),6.42(broad,1H),3.70(br s,2H),2.96(d,1H),2.37(s,3H),0.85(m,1H),0.50(m,2H),0.22(m,2H).
现已完全、清楚、简明和准确地描述了本发明以及制备和使用方式和方法,以是本领域技术人员能够实施本发明。应理解的是,本发明以上部分描述了优选实施方案,而且在不偏离如权利要求书限定的本发明的精神和范围的情况下还可进行许多改进。为具体地指出以及明确地要求保护,以下权利要求书包括该说明书。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109336824A (zh) * | 2012-10-19 | 2019-02-15 | 诺华股份有限公司 | Mek抑制剂的制备和包含mek抑制剂的制剂 |
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