CN103923072B - 作为具有激酶抑制剂活性的取代的吲唑衍生物 - Google Patents
作为具有激酶抑制剂活性的取代的吲唑衍生物 Download PDFInfo
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- CN103923072B CN103923072B CN201410135406.0A CN201410135406A CN103923072B CN 103923072 B CN103923072 B CN 103923072B CN 201410135406 A CN201410135406 A CN 201410135406A CN 103923072 B CN103923072 B CN 103923072B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
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Abstract
本发明公开了如说明书中定义的式(I)的取代的吲唑衍生物及其药学可接受的盐、它们的制备方法和包含它们的药物组合物;本发明的化合物可用于在治疗与蛋白激酶活性失调有关的疾病例如癌症中的治疗方法。
Description
本申请是同名发明名称的中国专利申请第200880025455.1号的分案申请,原案国际申请号为PCT/EP2008/058861,国际申请日为2008年7月8日。
技术领域
本发明涉及某些取代吲唑化合物,其调节蛋白质激酶的活性。因此,本发明的化合物可用于治疗由蛋白激酶活性失调引起的疾病。本发明还提供制备这些化合物的方法、包括这些化合物的药物组合物、以及利用包括这些化合物的药物组合物治疗疾病的方法。
背景技术
蛋白激酶(PK)的功能失常是许多疾病的标志。与人类癌症有关的致癌基因和原癌基因有一大部分编码PK。增强的PK活性还与许多非恶性病有关,例如良性前列腺增生、家族性腺瘤病、息肉病、神经纤维瘤病、银屑病、与动脉粥样硬化有关的血管平滑细胞增殖、肺纤维化、关节炎、肾小球肾炎和手术后的狭窄和再狭窄。
PK还与炎症性状况以及病毒和寄生虫的增殖有关。PK可能还在神经变性疾病的发病机理和发展中起到重要作用。
关于PK故障或失调的一般参考文献,参见例如Current Opinion in ChemicalBiology1999,3,459-465。
一组PK是一组具有内在蛋白酪氨酸激酶活性(RPTK)的膜受体。在结合生长因子时,RPTK变活化并且使其自身和一系列细胞质中的底物磷酸化。通过这一机理,它们可以转导用于增殖、分化或其它生物学改变的细胞内信号传导。RTPK的结构异常、超表达和活化通常在人肿 瘤中观察到,从而提示导致细胞增殖的信号转导的组成型灼热(constitutiveignition)可以导致恶性肿瘤转化。间变性淋巴瘤酶(ALK)是属于RTK的胰岛素受体亚家族的酪氨酸激酶受体:所述ALK基因位于染色体2上并且主要在神经元细胞,尤其是在发育过程中的神经元细胞上表达。ALK基因涉及一大组间变性大细胞淋巴瘤(ALCL)中与染色体5上的核磷蛋白(NPM)基因平衡的染色体易位。在ALK+ALCL中,由于易位,NPM遍在启动子驱动融合蛋白的异位表达,其中NPM部分二聚化且ALK激酶结构域进行自磷酸化并且变成组成型活性的。
来自文献的许多数据证明了NPM-ALK融合蛋白具有强的致癌潜力并且其异位表达是细胞转化的原因。此外,人NPM-ALK在小鼠T细胞淋巴细胞中的组成型表达足以用于在转基因动物中在短的潜伏期后发展为淋巴瘤形成。
ALCL是一类确定的疾病,其特征在于,细胞分化抗原CD30(Ki-1)的表面表达,并且是2%的成年人和13%的儿科非霍奇金氏淋巴瘤的原因,主要影响年轻的男性患者。ALK+ALCL占所有ALCL的70%,并且是伴有系统信号的侵蚀性疾病,并且是常见的结节外发病(extranodal involvment)(骨髓、皮肤、骨、软组织)。
发现大约15-20%的表达ALK的ALCL带有一个不同的染色体易位,涉及ALK的细胞质部分,具有不同的N-末端部分,所有这些引起ALK激酶结构域的组成型激活。
此外,发现从外胚层来源的实体瘤(如黑素瘤、乳腺瘤、以及神经母细胞瘤、胶质母细胞瘤、尤因肉瘤、视网膜母细胞瘤)建立的细胞系表达ALK受体。
总之,干扰ALK信号转导可能代表了用于在ALCL和可能的其它适应症中阻断肿瘤细胞增殖的特异性的和有效的方法。
胰岛素样生长因子1型受体(IGF-1R,IGF1R)也是RTK的胰岛素受体亚家族的成员。
存在几个系列的证据提示IGF-1R信号传导可以促成肿瘤发生并 且干扰IGF-1R功能代表了对癌症的有效治疗选择。就IGF和IGF-1R信号传导的综述、生理功能、以及支持该系统在上文概述的人癌症和其它病理学中的关联的证据的详细描述而言,读者可以参考关于这个主题的许多综述和其中包含的参考文献,例如Baserga R.等,Biochim BiophysActa vol.1332,F105-F126页,1997;Khandwala H.M.等,Endocr Rev vol.21,215-44页,2000;Le Roith D.等,Endocr Rev vol.22,页53-74,2001;Valentinis B.等,Mol Patholvol.54,133-7页,2001;Wang Y.等,Curr Cancer Drug Targets vol.2,191-207页,2002;Laron,Z.J Clin Endocrinol Metab vol.89,1031-1044页,2004;Hofmann F等,DrugDiscov Today vol.10,1041-7页,2005。
发明内容
在Aventis Pharma SA名下的WO2006003276,WO2004022544和WO2003078403中披露了用于治疗神经变性疾病、脑血管意外、肥胖、心血管疾病和癌症的3-氨基和3-酰基氨基吲唑衍生物。
在SmithKline Beecham P.L.C.名下的WO2003051847中披露了用于治疗糖尿病、神经变性疾病,例如阿尔茨海默病和帕金森病的吲唑基酰胺衍生物。
在Merck GMBH名下的WO2008003396中披露了用于治疗肿瘤疾病、病毒病、移植中的免疫抑制、囊性纤维化和与血管发生相关的疾病的吲唑衍生物。
尽管有了这些研发,但是仍然存在对治疗这类疾病的更有效活性剂的需求。
我们目前已经发现一系列吲唑类化合物是有效的蛋白激酶抑制剂且由此用于抗癌疗法。
因此,本发明的第一个方面在于提供由式(I)表示的取代的吲唑化合物,
其中:
X是-CH2-,-CH(OH)-,-CH(OR')-或-C(R'R'')-,其中:
R'是任选进一步被取代的直链或支链C1-C6烷基,R''是氢或任选进一步被取代的直链或支链C1-C6烷基;
Ar是任选被一个或多个选自如下的取代基取代的芳基或杂芳基:卤素,C2-C6烯基,C2-C6炔基,氰基,硝基,NHCOR4,COR4,NR5R6,NR5COR4,OR7,SR7,SOR10,SO2R10,NHSOR10,NHSO2R10,R8R9N-C1-C6烷基,R8O-C1-C6烷基,任选进一步被取代的直链或支链C1-C6烷基,C3-C6环烷基,杂环基,芳基和杂芳基,其中:
R4是氢,C2-C6烯基,C2-C6炔基,NR5R6,OR7,SR7,R8R9N-C1-C6烷基,R8O-C1-C6烷基,任选进一步被取代的直链或支链C1-C6烷基,C3-C6环烷基,杂环基,芳基或杂芳基;
R5和R6独立地是氢,C2-C6烯基,C2-C6炔基,R8R9N-C2-C6烷基,R8O-C2-C6烷基,任选进一步被取代的直链或支链C1-C6烷基,C3-C6环烷基,杂环基,芳基或杂芳基,或R5和R6与所键合的氮原子一起形成任选被取代的杂环基;
R7是氢,C2-C6烯基,C2-C6炔基,COR4,SOR10,SO2R10,R8R9N-C2-C6烷基,R8O-C2-C6烷基,任选进一步被取代的直链或支链C1-C6烷基,C3-C6环烷基,杂环基,芳基或杂芳基,其中R4为如上述定义的;
R8和R9独立地是氢,C2-C6烯基,C2-C6炔基,COR4,任选进一步被取代的直链或支链C1-C6烷基,C3-C6环烷基,杂环基,芳基或杂芳基,或R8和R9与所键合的氮原子一起形成任选被取代的杂环基,其中R4为如上述定义的;
R10是氢,C2-C6烯基,C2-C6炔基,NR5R6,OR7,R8R9N-C1-C6烷基, R8O-C1-C6烷基,任选进一步被取代的直链或支链C1-C6烷基,C3-C6环烷基,杂环基,芳基或杂芳基,其中R5,R6,R7,R8和R9为如上述定义的;
R是任选被取代的直链或支链C1-C6烷基,C3-C6环烷基,杂环基,芳基或杂芳基;
R1,R2和R3独立地是氢,卤素,硝基,任选被取代的直链或支链C1-C6烷基,NR5R6或OR7,其中R5,R6和R7为如上述定义的;
或其异构体、互变体、前药或药学可接受的盐。
本发明还提供通过由标准合成转化组成的方法制备的式(I)的取代吲唑衍生物的合成方法。
本发明还提供治疗由蛋白激酶活性失调引起的和/或与之相关的疾病的方法,所述蛋白激酶特别是PLK家族、不同同工型的蛋白激酶C、Met,PAK-4,PAK-5,ZC-1,STLK-2,DDR-2,Aurora1,Aurora2,Bub-1,Chk1,Chk2,HER2,raf1,MEK1,MAPK,EGF-R,PDGF-R,FGF-R,FLT3,JAK2,IGF-R,ALK,PI3K,weel激酶,Src,Abl,Akt,MAPK,ILK,MK-2,IKK-2,Cdc7,Nek,Cdk/细胞周期蛋白激酶家族,更特别地是Aurora2,IGF-1R和ALK活性,以及进一步特别地是ALK活性,所述方法包括对有此需要的哺乳动物给予有效量的上述定义的式(I)表示的取代吲唑化合物。
本发明的优选方法是治疗由蛋白激酶活性失调引起的和/或与之相关的疾病,所述疾病选自癌症和细胞增殖疾病。
本发明的另一种优选方法是治疗具体类型的癌症,包括癌、鳞状细胞癌、骨髓样或淋巴样谱系的造血性肿瘤,间质来源的肿瘤,中枢和外周神经系统肿瘤,黑素瘤,精原细胞瘤,畸胎癌,骨肉瘤,着色性干皮病,角膜眦疣,甲状腺毛囊癌和卡波西肉瘤。
本发明的另一种优选的方法是治疗具体类型的癌症,例如,但不限于乳腺癌,肺癌,结直肠癌,前列腺癌,卵巢癌,子宫内膜癌,胃癌,透明细胞肾细胞癌,眼色素层黑素瘤,多发性骨髓瘤,横纹肌肉瘤,尤因肉瘤,卡波西肉瘤,和髓母细胞瘤。
本发明的另一种优选的方法是治疗ALK+间变性大细胞淋巴瘤(ALCL)或其中ALK活性可能起作用的其它可能的适应征,如神经母细胞瘤,横纹肌肉瘤,胶质母细胞瘤,炎性成肌纤维细胞瘤和某些类型的黑素瘤,乳腺癌,尤因肉瘤,视网膜母细胞瘤和非小细胞肺癌(NSCLC)。
本发明的另一种优选的方法是治疗细胞增殖疾病,例如,但不限于良性前列腺增生,家族性腺瘤病,息肉病,神经纤维瘤病,银屑病,动脉粥样硬化和与血管平滑细胞增殖和新生内膜形成有关的疾病,例如血管成形术或手术后的再狭窄、肺纤维化、关节炎、肾小球肾炎,视网膜病变,包括糖尿病性和新生儿视网膜病变和老年性黄斑变性,移植血管疾病(例如可能在血管或器官移植后发生),肢端肥大症和肢端肥大症继发性病症,以及涉及IGF/IGF-1R信号传导的其它肥大性疾病,例如纤维化肺疾病,涉及慢性或急性氧化性应激的病理学情况或高氧症诱发的组织损伤,和其中涉及升高的IGF水平或IGF-1R活性的代谢障碍,例如肥胖。
另外,本发明的方法还提供对肿瘤血管生成和转移的抑制。
在另一个优选的实施方案中,本发明的方法进一步包括对有此需要的哺乳动物进行放疗或化疗方案与至少一种细胞生长抑制剂或细胞毒素剂的组合。
本发明还提供了抑制活性ALK蛋白的方法,包括使所述蛋白质接触有效量的式(I)的化合物。
本发明还提供药物组合物,其包括一种或多种式(I)的化合物或其药学可接受的盐以及药学可接受的赋形剂、载体或稀释剂。
本发明另外提供与一种或多种化疗剂或放射疗法组合的包括式(I)的化合物的药物组合物。这种药物可以包括但不限于抗激素药(例如抗雌激素药、抗雄激素药、和芳香酶抑制剂)、拓扑异构酶I抑制剂、拓扑异构酶II抑制剂、靶向微管的药物、铂类药物、烷化剂、DNA损伤或嵌入剂、抗肿瘤抗代谢药、其它激酶抑制剂、其它抗血管生成因子、驱动蛋白的抑制剂、治疗用单克隆抗体、mTOR的抑制剂、组蛋白脱乙 酰基酶抑制剂、法尼基转移酶抑制剂、和缺氧响应的抑制剂。
另外,本发明提供了产品或试剂盒,其包含如上述定义的式(I)的化合物或其药学可接受的盐或其药物组合物和一种或多种化疗剂作为在抗癌疗法中同时、分开或依次使用的联合制剂。
本发明在另一个方面中提供了如上述定义的式(I)的化合物或其药学可接受的盐,用作药物。
本发明还提供了如上述定义的式(I)的化合物或其药学可接受的盐在制备具有抗肿瘤活性的药物中的应用。
最终,本发明提供了如上述定义的式(I)的化合物或其药学可接受的盐在治疗癌症方法中的应用。
具体实施方式
式(I)的化合物可以具有一个或多个不对称中心,并且由此可以作为单独的光学异构体或外消旋混合物存在。因此,式(I)的化合物的所有可能的异构体、以及它们的混合物都在本发明范围内。
在哺乳动物中代谢来源的式(I)的化合物的衍生物、以及式(I)的化合物的药学可接受的生物前体(或者称为前药)也在本发明范围内。
除了上述的以外,如本领域技术人员已知的,式(I)的化合物的吡唑环上未取代的氮在溶液中迅速地平衡,形成为互变异构体混合物,如下所述:
其中X,Ar,R,R1,R2和R3为如上述定义的。
因此,在本发明中,在只表示了式(I)的化合物的一种互变异构体时,另一种互变异构体(Ia)也在本发明范围内,除非明确地注明不是这样。
除非另作陈述,否则本文所用的一般术语具有如下报告的含义。
术语“直链或支链C1-C6烷基”意旨饱和脂族烃基,包括1-6个碳原子的直链和支链基团,例如甲基,乙基,丙基,2-丙基,正-丁基,异-丁基,叔丁基,戊基等。烷基可以被取代或未被取代。当被取代时,取代基优选1-3个,它们独立地选自卤素,C2-C6烯基,C2-C6炔基,氰基,硝基,NHCOR4,COR4,NR5R6,NR5COR4,OR7,SR7,SOR10,SO2R10,NHSOR10,NHSO2R10,R8R9N-C1-C6烷基,R8O-C1-C6烷基,任选进一步被取代的C3-C6环烷基,杂环基和芳基,其中R4,R5,R6,R7,R8,R9和R10为如上述定义的。
术语“C3-C6环烷基”意旨3-至6-元全碳单环,其可以包含一个或多个双键,但不具有完全共轭的π-电子系统。环烷基的实例是环丙基基,环丁基,环戊基,环戊烯基,环己基,环己烯基和环己二烯基,但不限于此。环烷基可以被取代或未被取代。当被取代时,取代基优选为1或2个取代基,它们独立地选自卤素,C2-C6烯基,C2-C6炔基,氰基,硝基,NHCOR4,COR4,NR5R6,NR5COR4,OR7,SR7,SOR10,SO2R10,NHSOR10,NHSO2R10,R8R9N-C1-C6烷基,R8O-C1-C6烷基,任选进一步被取代的直链或支链C1-C6烷基,C3-C6环烷基,杂环基和芳基,其中R4,R5,R6,R7,R8,R9和R10为如上述定义的。
术语“杂环基”意旨3-至7-元饱和或部分不饱和碳环,其中一个或多个碳原子被杂原子,例如氮,氧和硫替代。杂环基的非限制性实例是,例如环氧乙烷基、氮丙定基、环氧丙烷基、氮杂环丁烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基、吡喃基、二氢吡喃基、四氢吡喃基、四氢硫代吡喃基、哌啶基、吡唑啉基、异唑烷基、异唑啉基、噻唑烷基、噻唑啉基、异噻唑啉基、二烷基、哌嗪基、吗啉基、硫代吗啉基、六亚甲基亚胺基(examethyleneiminyl)、高哌嗪基等。杂环基可以被取代或未被取代。当被取代时,取代基优选为1或2个取代基,它们独立地选自卤素,C2-C6烯基,C2-C6炔基,氰基,硝基,NHCOR4,COR4,NR5R6,NR5COR4,OR7,SR7,SOR10,SO2R10,NHSOR10,NHSO2R10,R8R9N-C1-C6烷基,R8O-C1-C6烷基,任选进一步被取代的直链或支链C1-C6烷基,C3-C6环烷基,杂环基和芳基,其中R4,R5,R6,R7,R8,R9和R10为如上述定义的。
术语“芳基”意旨具有1-4个环系的单-,双-或多-碳环烃,其中各个环任选进一步被稠合或通过单键彼此连接,其中至少一个碳环是“芳族的”,其中术语“芳族”意旨完全共轭的π-电子键系统。这类芳基的非限制性实例是苯基,α-或β-萘基或联苯基。
术语“杂芳基”意旨芳族杂环,一般是具有1-3个选自N,O或S的杂原子的5-至7-元杂环;该杂环可以任选进一步与芳族和非芳族的碳环和杂环稠合或连接。这类杂芳基的非限制性实例是,例如吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、咪唑基、噻唑基、异噻唑基、吡咯基、苯基-吡咯基、呋喃基、苯基-呋喃基、唑基、异唑基、吡唑基、噻吩基、苯并噻吩基、异二氢吲哚基、苯并咪唑基、喹啉基、异喹啉基、1,2,3-三唑基、1-苯基-1,2,3-三唑基、2,3-二氢吲哚基、2,3-二氢苯并呋喃基、2,3-二氢苯并噻吩基;苯并吡喃基,2,3-二氢苯丙嗪基、2,3-二氢喹喔啉基等。
芳基和杂芳基可以任选被一个或多个,优选1、2或3个取代基取代,所述取代基独立地选自卤素,C2-C6烯基,C2-C6炔基,氰基,硝基,NHCOR4,COR4,NR5R6,NR5COR4,OR7,SR7,SOR10,SO2R10,NHSOR10,NHSO2R10,R8R9N-C1-C6烷基,R8O-C1-C6烷基,任选进一步被取代的直链或支链C1-C6烷基,C3-C6环烷基,杂环基和芳基,其中R4,R5,R6,R7,R8,R9和R10为如上述定义的。
术语“卤素”表示氟、氯、溴或碘。
术语“C2-C6烯基”表示包含至少一个碳-碳双键并且可以是直链或支链的脂族C2-C6烃链。有代表性的实例包括,但不限于乙烯基,1-丙烯基,2-丙烯基,1-或2-丁烯基等。
术语“C2-C6炔基”表示包含至少一个碳-碳三键并且可以是直链或支链的脂族C2-C6烃链。有代表性的实例包括,但不限于乙炔基,1-丙炔基,2-丙炔基,1-或2-丁炔基等。
术语“氰基”表示-CN残基。
术语“硝基”表示-NO2基团。
术语式(I)的化合物的“药学可接受的盐”是指保持母体化合物的生物有效性和性质的那些盐。这种盐包括意旨那些保持母体化合物的生物有效性和特性的盐。这类盐的实例包括:与无机酸或与有机酸形成的酸加成盐,所述的无机酸例如盐酸、氢溴酸、硝酸、磷酸、硫酸、高氯酸等,所述的有机酸例如乙酸、三氟乙酸、丙酸、乙醇酸、乳酸、(D)或(L)苹果酸、马来酸、甲磺酸、乙磺酸、苯甲酸、对-甲苯磺酸、水杨酸、肉桂酸、扁桃酸、酒石酸、柠檬酸、琥珀酸、丙二酸等;在存在于式(I)的化合物中的酸性质子被金属离子替代或与有机碱配位时形成的盐,所述金属离子例如为碱金属离子,例如钠或钾,或例如为碱土金属离子,例如钙或镁,所述有机碱例如为乙醇胺、二乙醇胺、三乙醇胺、氨基丁三醇、N-甲基葡糖胺等。
式(I)的化合物由通式(IA)表示,其中X是-CH2-:
式(I)的化合物由通式(IB)表示,其中X是-CH(OH)-:
式(I)的化合物由通式(IC)表示,其中X是-CH(OR')-:
式(I)的化合物由通式(ID)表示,其中X是-C(R'R'')-:
式(I)的化合物的优选类型是以下化合物,其中:
X是-CH2-,-CH(OH)-,-CH(OR')-或-C(R'R'')-,其中R'是C1-C3烷基且R''是氢或C1-C3烷基;
R是任选取代的C3-C6环烷基,杂环基,芳基或杂芳基,且
R1,R2和R3独立地是氢,卤素或羟基。
式(I)的化合物的另一种优选类型是以下化合物,其中:
X是-CH2-,-CH(OH)-,-CH(OR')-或-C(R'R'')-,其中R'是甲基且R''是氢或甲基,且
R1,R2和R3是氢。
式(I)的化合物的另一种优选类型是以下化合物,其中:
R是任选取代的芳基或杂芳基。
式(I)的化合物的更优选类型是以下化合物,其中:
Ar是下式的基团:
其中Ra,Rb和Rc独立地是氢,卤素,C2-C6烯基,C2-C6炔基,氰基,硝基,NHCOR4,COR4,NR5R6,NR5COR4,OR7,SR7,SOR10,SO2R10,NHSOR10,NHSO2R10,R8R9N-C1-C6烷基,R8O-C1-C6烷基,任选进一步 被取代的直链或支链C1-C6烷基,C3-C6环烷基,杂环基,芳基或杂芳基,其中R4,R5,R6,R7,R8,R9和R10为如上述定义的,且
R是任选取代的芳基。
式(I)的化合物的另一种更优选类型是以下化合物,其中:
Ar是下式的基团:
其中Ra和Rb为如上述定义的。
式(I)的化合物的最优选类型是以下化合物,其中:
Ar是下式的基团:
其中Ra是氢,卤素,硝基,NHCOR4或NR5R6,且Rb是氢,硝基,NR5R6,OR7或R8R9N-C1-C6烷基,其中R4,R5,R6,R7,R8和R9为如上述定义的。
本发明的具体化合物(cpd.)如下所列:
1.N-(5-苄基-1H-吲唑-3-基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
2.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
3.N-[5-(2,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)苯甲酰胺;
4.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)苯甲酰胺;
5.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-硝基苯甲酰胺;
6.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪 -1-基)-2-硝基-苯甲酰胺;
7.2-氨基-N-[5-(3-氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
8.2-氨基-N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
9.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺;
10.N-[5-(2,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺;
11.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺;
12.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(1-甲基-哌啶-4-基氨基)-苯甲酰胺;
13.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(1-甲基-哌啶-4-基氨基)-苯甲酰胺;
14.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-2-(2-甲氧基-1-甲氧基甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺:
15.N-[5-(2,5-二氟-苄基)-1H-吲唑-3-基]-2-(2-甲氧基-1-甲氧基甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
16.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-(2-甲氧基-1-甲氧基甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
17.2-环己基氨基-N-[5-(3-氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
18.2-环己基氨基-N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
19.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-2-(4-羟基-环己基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
20.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-(4-羟基-环己基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
21.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-2-异丁基氨基-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
22.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-异丁基氨基-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
23.2-苄基氨基-N-[5-(3-氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
24.2-苄基氨基-N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
25.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-2-(2-甲氧基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
26.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-(2-甲氧基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
27.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-2-(2-甲氧基-1-甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
28.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-(2-甲氧基-1-甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
29.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-2-((S)-2-甲氧基-1-甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
30.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-((S)-2-甲氧基-1-甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
31.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-2-((R)-2-甲氧基-1-甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
32.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-((R)-2-甲氧基-1-甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
33.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-2-(2-甲氧基-1,1-二甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
34.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-(2-甲氧基-1,1-二甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
35.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-2-(3-甲氧基-丙基氨 基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
36.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-(3-甲氧基-丙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
37.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-2-(2-氟-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
38.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-(2-氟-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
39.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-2-(3-氟-丙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
40.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-(3-氟-丙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
41.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-苯基氨基-苯甲酰胺;
42.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-苯基氨基-苯甲酰胺;
43.1H-吡咯-2-甲酸[2-[5-(3-氟-苄基)-1H-吲唑-3-基氨基甲酰基]-5-(4-甲基-哌嗪-1-基)-苯基]-酰胺;
44.1H-吡咯-2-甲酸[2-[5-(3,5-二氟-苄基)-1H-吲唑-3-基氨基甲酰基]-5-(4-甲基-哌嗪-1-基)-苯基]-酰胺;
45.1H-吡咯-3-甲酸[2-[5-(3-氟-苄基)-1H-吲唑-3-基氨基甲酰基]-5-(4-甲基-哌嗪-1-基)-苯基]-酰胺;
46.1H-吡咯-3-甲酸[2-[5-(3,5-二氟-苄基)-1H-吲唑-3-基氨基甲酰基]-5-(4-甲基-哌嗪-1-基)-苯基]-酰胺;
47.N-[5-(3-氟-苄基)-1H-吲唑-3-基]-2-甲磺酰基氨基-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
48.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-甲磺酰基氨基-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
49.2-氟-N-[5-(3-氟-苄基)-1H-吲唑-3-基]-5-(四氢-吡喃-4-基氨基)-苯甲酰胺;
50.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-氟-5-(四氢-吡喃-4-基氨基)-苯甲酰胺;
51.2-氟-N-[5-(3-氟-苄基)-1H-吲唑-3-基]-5-(2-甲氧基-乙基氨基)-苯甲酰胺;
52.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-氟-5-(2-甲氧基-乙基氨基)-苯甲酰胺;
53.4-[(3-二甲基氨基-丙基)-甲基-氨基]-N-[5-(3-乙氧基-苄基)-1H-吲唑-3-基]-2-硝基-苯甲酰胺;
54.2-氨基-4-[(3-二甲基氨基-丙基)-甲基-氨基]-N-[5-(3-乙氧基-苄基)-1H-吲唑-3-基]-苯甲酰胺;
55.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-(四氢-吡喃-4-基氨基)-苯甲酰胺;
56.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-(2-甲氧基-1-甲氧基甲基-乙基氨基)-苯甲酰胺;
57.2-氨基-N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-[(3-二甲基氨基-丙基)-甲基-氨基]-苯甲酰胺;
58.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-[(3-二甲基氨基-丙基)-甲基-氨基]-苯甲酰胺;
59.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-硝基-苯甲酰胺;
60.N-{5-[(3,5-二氟-苯基)-羟基-甲基]-1H-吲唑-3-基}-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺;
61.N-{5-[(3,5-二氟-苯基)-羟基-甲基]-1H-吲唑-3-基}-2-(2-甲氧基-1-甲氧基甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
62.N-{5-[(3,5-二氟-苯基)-羟基-甲基]-1H-吲唑-3-基}-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
63.N-{5-[(3,5-二氟-苯基)-羟基-甲基]-1H-吲唑-3- 基}-2-(2-甲氧基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
64.N-{5-[(3,5-二氟-苯基)-羟基-甲基]-1H-吲唑-3-基}-2-(3-甲氧基-丙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
65.N-{5-[(3,5-二氟-苯基)-羟基-甲基]-1H-吲唑-3-基}-2-(2-甲氧基-1,1-二甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
66.N-{5-[(3,5-二氟-苯基)-羟基-甲基]-1H-吲唑-3-基}-2-(2-氟-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
67.N-{5-[(3-乙氧基-苯基)-羟基-甲基]-1H-吲唑-3-基}-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺;
68.N-{5-[(3,5-二氟-苯基)-甲氧基-甲基]-1H-吲唑-3-基}-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺;
69.N-{5-[(3,5-二氟-苯基)-甲氧基-甲基]-1H-吲唑-3-基}-2-(2-甲氧基-1-甲氧基甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
70.N-{5-[(3,5-二氟-苯基)-甲氧基-甲基]-1H-吲唑-3-基}-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
71.N-{5-[(3,5-二氟-苯基)-甲氧基-甲基]-1H-吲唑-3-基}-2-(2-甲氧基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
72.N-{5-[(3,5-二氟-苯基)-甲氧基-甲基]-1H-吲唑-3-基}-2-(3-甲氧基-丙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
73.N-{5-[(3,5-二氟-苯基)-甲氧基-甲基]-1H-吲唑-3-基}-2-(2-甲氧基-1,1-二甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
74.N-{5-[(3,5-二氟-苯基)-甲氧基-甲基]-1H-吲唑-3-基}-2-(2-氟-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
75.N-{5-[1-(3,5-二氟-苯基)-乙基]-1H-吲唑-3-基}-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺;
76.N-{5-[1-(3,5-二氟-苯基)-乙基]-1H-吲唑-3-基}-2-(2-甲 氧基-1-甲氧基甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
77.N-{5-[(3,5-二氟-苯基)-乙基]-1H-吲唑-3-基}-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
78.N-{5-[(3,5-二氟-苯基)-乙基]-1H-吲唑-3-基}-2-(2-甲氧基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
79.N-{5-[(3,5-二氟-苯基)-乙基]-1H-吲唑-3-基}-2-(3-甲氧基-丙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
80.N-{5-[(3,5-二氟-苯基)-乙基]-1H-吲唑-3-基}-2-(2-甲氧基-1,1-二甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
81.N-{5-[(3,5-二氟-苯基)-乙基]-1H-吲唑-3-基}-2-(2-氟-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
82.N-{5-[1-(3,5-二氟-苯基)-1-甲基-乙基]-1H-吲唑-3-基}-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺;
83.N-{5-[1-(3,5-二氟-苯基)-1-甲基-乙基]-1H-吲唑-3-基}-2-(2-甲氧基-1-甲氧基甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
84.N-{5-[1-(3,5-二氟-苯基)-1-甲基-乙基]-1H-吲唑-3-基}-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
85.N-{5-[1-(3,5-二氟-苯基)-1-甲基-乙基]-1H-吲唑-3-基}-2-(2-甲氧基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
86.N-{5-[1-(3,5-二氟-苯基)-1-甲基-乙基]-1H-吲唑-3-基}-2-(3-甲氧基-丙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
87.N-{5-[1-(3,5-二氟-苯基)-1-甲基-乙基]-1H-吲唑-3-基}-2-(2-甲氧基-1,1-二甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
88.N-{5-[1-(3,5-二氟-苯基)-1-甲基-乙基]-1H-吲唑-3-基}-2-(2-氟-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
89.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基-1,4-二氮杂环庚烷-1-基)-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
90.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-[(2-二甲基氨基-乙基)-甲基-氨基]-2-(四氢-吡喃-4-基氨基)-苯甲酰胺;
91.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[4-(二甲基氨基)哌啶-1-基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
92.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
93.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-3-(4-甲基哌嗪-1-基)苯甲酰胺;
94.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2S)-1-甲基吡咯烷-2-基]甲氧基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
95.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[(1-甲基哌啶-4-基)氧基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
96.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[2-(二甲基氨基)乙氧基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
97.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(3S)-1-甲基吡咯烷-3-基]氧基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
98.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(哌嗪-1-基)-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
99.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基哌嗪-1-基)-2-{[顺式-4-(三氟甲基)环己基]氨基}苯甲酰胺;
100.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基哌嗪-1-基)-2-{[反式-4-(三氟甲基)环己基]氨基}苯甲酰胺;
101.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-氟-4-(4-甲基哌嗪-1-基)苯甲酰胺;
102.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-1-(哌啶-4-基)-1H-吡唑-4-甲酰胺;
103.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-[(顺式-4-羟基环己基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酰胺;
104.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-[(反式-4-羟基环 己基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酰胺;
105.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-[(2-羟基乙基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酰胺;
106.2-[(氮杂环丁烷-3-基甲基)氨基]-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基哌嗪-1-基)苯甲酰胺;
107.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-{[(1-甲基氮杂环丁烷-3-基)甲基]氨基}-4-(4-甲基哌嗪-1-基)苯甲酰胺;
108.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[(1-甲基哌啶-4-基)氨基]-2-[四氢-2H-吡喃-4-基氨基]苯甲酰胺;
109.4-[(氮杂环丁烷-3-基甲基)氨基]-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
110.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-[(1-甲基哌啶-4-基)氨基]苯甲酰胺;
111.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-[(1-甲基哌啶-4-基)氨基]-4-(吗啉-4-基)苯甲酰胺;
112.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-甲氧基-4-(4-甲基哌嗪-1-基)苯甲酰胺;
113.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-5-(4-甲基哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)吡啶-2-甲酰胺;
114.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-6-(4-甲基哌嗪-1-基)-2-(四氢-2H-吡喃-4-基氨基)吡啶-3-甲酰胺;
115.1-[4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-3-(四氢-2H-吡喃-4-基氨基)苄基]哌啶;
116.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2-甲氧基乙基)(甲基)氨基]甲基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
117.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(吡咯烷-1-基甲基)-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
118.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(吗啉-4-基甲基)-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
119.4-(氮杂环丁烷-1-基甲基)-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
120.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-氟-5-(4-甲基-哌嗪-1-基甲基)-苯甲酰胺;
121.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-氟-5-{[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]甲基}苯甲酰胺;
122.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-氟-5-(吗啉-4-基甲基)苯甲酰胺;
123.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-氟-5-((S)-2-吡咯烷-1-基甲基-吡咯烷-1-羰基)-苯甲酰胺;
124.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2R)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}苯甲酰胺;
125.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}苯甲酰胺;
126.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[4-(吡咯烷-1-基)哌啶-1-基]羰基}苯甲酰胺;
127.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
128.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2R)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
129.N1-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-N4-[2-(二甲基氨基)乙基]-N4-甲基-2-(四氢-2H-吡喃-4-基氨基)苯-1,4-二甲酰胺;
130.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[4-(丙-2-基)哌嗪-1-基]羰基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
131.N1-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-N4-[2-(二甲基氨基)乙基]-2-(四氢-2H-吡喃-4-基氨基)苯-1,4-二甲酰胺;
132.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[(4-甲基哌嗪-1- 基)羰基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
133.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[4-(二甲基氨基)哌啶-1-基]羰基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
134.N1-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-N4-(1-甲基哌啶-4-基)-2-(四氢-2H-吡喃-4-基氨基)苯-1,4-二甲酰胺;
135.N-[5-(2-甲基-5-氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺;
136.4-(4-甲基哌嗪-1-基)-N-[5-(吡啶-3-基甲基)-1H-吲唑-3-基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
137.N-[5-苄基-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺;
138.4-{[2-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-5-(4-甲基哌嗪-1-基)苯基]氨基}哌啶-1-甲酸乙酯;
139.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基哌嗪-1-基)-2-(哌啶-4-基氨基)苯甲酰胺;
140.5-(3,5-二氟苄基)-3-({[4-(4-甲基哌嗪-1-基)-2-(四氢-2H-吡喃-4-基氨基)苯基]羰基}氨基)-1H-吲唑-1-甲酸乙酯;
141.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-((S)-2-甲氧基-1-甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺;
142.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[(2R)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
143.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2R)-1-甲基吡咯烷-2-基]甲氧基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
144.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(3R)-1-甲基吡咯烷-3-基]氧基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺;
145.N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-氟-5-{[(2R)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]甲基}苯甲酰胺,和
146.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-氟-5-((R)-2-吡咯烷-1-基甲基-吡咯烷-1-羰基)-苯甲酰胺。
本发明优选的具体化合物是:
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺。
本发明还提供了制备如上述定义的式(I)的化合物的方法,其特征在于,该方法包括:
i)还原式(II)的羰基化合物:
其中Ar,R,R1,R2,和R3为如上述定义的,得到式(IA),(IB)或(IC)的化合物:
其中Ar,R,R1,R2,R3和R'为如上述定义的;
或
i')使式(IIIA),(IIIB),(IIIC)或(IIID)的化合物:
其中R,R1,R2,R3,R'和R''为如上述定义的,与式(IV)的化合物反应:
其中Ar为如上述定义的且Y表示羟基或适当的离去基,例如卤素,得到如上述定义的式(I)的化合物;
或
i'')使式(XXIIA),(XXIIC)或(XXIID)的化合物脱保护:
其中Ar,R,R1,R2,R3,R'和R''为如上述定义的且PG是合适的保护基,例如苄基,p-甲氧基苄基,o,p-二甲氧基苄基或三苯基甲基,得到式(IA),(IC)或(ID)的化合物:
其中Ar,R,R1,R2,R3,R'和R''为如上述定义的,任选将得到的化合物分离为单一异构体,将式(I)的化合物转化为不同的式(I)的化合物,和/或如果需要转化为药学可接受的盐。
本发明进一步提供了制备如上述定义的式(IA),(IB)或(IC)的化合物的方法,其特征在于,根据下列步骤制备如上述定义的式(II)的化合物:
a)使式(XII)的化合物:
其中R1,R2和R3为如上述定义的,与式RMgZ(XIII)的有机金属化合物(即格利雅试剂)反应,其中R为如上述定义的且Z是卤素,得到式(XI)的化合物:
其中R,R1,R2和R3为如上述定义的;
b)氧化得到的式(XI)的化合物,得到式(X)的化合物:
其中R,R1,R2和R3为如上述定义的;
c)使得到的式(X)的化合物与水合肼反应,得到式(IX)的化合物:
其中R,R1,R2和R3为如上述定义的;
d)保护得到的式(IX)的化合物,得到式(VIII)的化合物:
其中R,R1,R2和R3为如上述定义的,且PG1是合适的保护基,例如三氟乙酰基;
e)保护得到的式(VIII)的化合物,得到式(VII)的化合物:
其中R,R1,R2,R3,PG和PG1为如上述定义的;
f)从得到的式(VII)的化合物上除去保护基PG1,得到式(VI)的化合物:
其中R,R1,R2,R3和PG为如上述定义的;
g)使得到的式(VI)的化合物与如上述定义的式(IV)的化合物反应,得到式(V)的化合物:
其中Ar,R,R1,R2,R3和PG为如上述定义的;
h)使得到的式(V)的化合物脱包含,得到如上述定义的式(II)的 化合物。
本发明进一步提供了制备如上述定义的式(IA)的化合物的方法,其特征在于,根据下列步骤制备如上述定义的式(IIIA)的化合物:
j)在适当的试剂,例如NaI和Me3SiCl的存在下还原如上述定义的式(XI)的化合物,得到式(XIV)的化合物:
其中R,R1,R2和R3为如上述定义的;
或
k)使式(XV)的硼酸化合物:
其中R1,R2和R3为如上述定义的,与式(XVI)的化合物反应:
其中R为如上述定义的且W表示卤原子,例如溴或碘或合适的离去基,如磺酸酯类,例如甲磺酸酯或三氟甲磺酸酯,或磷酸酯,该反应在适当的催化剂,例如钯催化剂存在下进行,得到如上述定义的式(XIV)的化合物;
l)使得到的式(XIV)的化合物与水合肼反应,得到如上述定义的式(IIIA)的化合物。
本发明进一步提供了制备如上述定义的式(IB)的化合物的方法,其特征在于,根据下列步骤制备如上述定义的式(IIIB)的化合物:
l')使如上述定义的式(XI)的化合物与水合肼反应,得到如上述定义的式(IIIB)的化合物。
本发明进一步提供了制备如上述定义的式(IC)的化合物的方法,其特征在于,根据下列步骤制备如上述定义的式(IIIC)的化合物:
m)使如上述定义的式(XI)的化合物与式(XVIII)的亲电子烷化剂反应:
R'-W'
(XVIII)
其中R'为如上述定义的且W'表示卤原子,例如氯、溴或碘或适当的离去基,如磺酸酯类,例如甲磺酸酯或三氟甲磺酸酯,得到式(XVII)的化合物:
其中R,R1,R2,R3和R'为如上述定义的;
l'')使得到的式(XVII)的化合物与水合肼反应,得到如上述定义的式(IIIC)的化合物。
本发明进一步提供了制备如上述定义的式(ID)的化合物的方法,其特征在于,根据下列步骤制备式(IIID1)的化合物,其中R''是氢:
其中R,R1,R2,R3和R'为如上述定义的:
n)使如上述定义的式(XIV)的化合物与如上述定义的式(XVIII)的化合物反应;
l''')使得到的式(XIXD1)的化合物:
其中R,R1,R2,R3和R'如上述所定义,与水合肼反应,得到如上述定义的式(IIID1)的化合物;
或
o)使式(XXI)的化合物:
其中R1,R2,R3和R'为如上述定义的,与如上述定义的式(XIII)的化合物反应,得到式(XX)的化合物:
其中R,R1,R2,R3和R'为如上述定义的;
p)还原得到的式(XX)的化合物,得到如上述定义的式XIXD1的化合物。
本发明进一步提供了制备如上述定义的式(ID)的化合物的方法,其特征在于,根据下列步骤制备具有下式的式(IIID2)的化合物,其中R''为如上述定义的,但不是氢:
其中R,R1,R2,R3和R'为如上述定义的:
q)使如上述定义的式(XIXD1)的化合物与式(XXIII)的亲电子的烷化剂反应:
R''-W'
(XXIII)
其中R''和W'为如上述定义的,得到式(XIXD2)的化合物:
其中R,R1,R2,R3和R'为如上述定义的,且R''为如上述定义的,但不是氢;
liv)使得到的式(XIXD2)的化合物与水合肼反应,得到如上述定义的式(IIID2)的化合物。
本发明进一步提供了制备如上述定义的式(IA),(IC)或(ID)的化合物的方法,其特征在于,根据下列步骤制备如上述定义的式(XXIIA),(XXIIC)或(XXIID)的化合物:
r)保护如上述定义的式(IIIA),(IIIC)或(IIID)的化合物,得到式(XXIVA),(XXIVC)或(XXIVD)的化合物:
其中R,R1,R2,R3,R,R''和PG1为如上述定义的;
s)保护得到的式(XXIVA),(XXIVC)或(XXIVD)的化合物,得到式(XXVA),(XXVC)或(XXVD)的化合物:
其中R,R1,R2,R3,R,R'',PG和PG1为如上述定义的;
t)从得到的式(XXVA),(XXVC)或(XXVD)的化合物上除去保护基PG1,得到式(XXVIA),(XXVIC)或(XXVID)的化合物:
其中R,R1,R2,R3,R,R''和PG为如上述定义的;
u)使得到的式(XXVIA),(XXVIC)或(XXVID)的化合物与如上述定义的式(IV)的化合物反应,得到如上述定义的式(XXIIA),(XXIIC)或(XXIID)的化合物。
注意如上述定义的式(V)的化合物可以是其异构体形式a或b或两者的混合物的任一种:
同样地,如上述定义的式(XXIIA),(XXIIC),(XXIID),(XXVA),(XXVC),(XXVD),(XXVIA),(XXVIC)和(XXVID)的化合物可以是其异构体形式a或b的任一种。
可以将式(II),(V),(XXIIA),(XXIIC),和(XXIID)的化合物转化 为另一种式(II),(V),(XXIIA),(XXIIC)和(XXIID)的化合物,所述转化通过一种或多种下列反应进行:
1)还原式(II),(V),(XXIIA),(XXIIC)和(XXIID)的化合物,其中Ar是取代的芳基且取代基之一是NO2,得到式(II),(V),(XXIIA),(XXIIC)和(XXIID)的化合物,其中该取代基是NH2;
2)酰化式(II),(V),(XXIIA),(XXIIC)和(XXIID)的化合物,其中Ar是取代的芳基且取代基之一是NH2,通过与式(XXVII)或(XXVIII)的酰化剂反应来进行:
其中R4和Y为如上述定义的,得到式(II),(V),(XXIIA),(XXIIC)和(XXIID)的化合物,其中该取代基是NHCOR4或NHSO2R4残基,其中R4为如上述定义的;
3)使式(II),(V),(XXIIA),(XXIIC)和(XXIID)的化合物,其中Ar是取代的芳基且取代基之一是NH2,与适当的醛或酮在还原剂存在下反应,得到式(II),(V),(XXIIA),(XXIIC)和(XXIID)的化合物,其中该取代基是NR5R6基团,其中R5或R6中的一个是氢且另一个是任选进一步被取代的直链或支链C1-C6烷基,C3-C6环烷基,杂环基,芳基,R8R9N-C2-C6烷基,R8O-C2-C6烷基,其中R8和R9为如上述定义的。
可以将式(I)的化合物转化为另一种式(I)的化合物,所述转化通过一种或多种下列反应进行:
4)还原式(I)的化合物,其中Ar是取代的芳基且取代基之一是NO2,得到式(I)的化合物,其中该取代基是NH2;
5)酰化式(I)的化合物,其中Ar是取代的芳基且取代基之一是NH2,通过与如上述定义的式(XXVII)或(XXVIII)的化合物反应、随后使吡唑环上的酰基选择性脱保护来进行,从而得到式(I)的化合物,其中该取代基是NHCOR4或NHSO2R4残基,其中R4为如上述定义的;
6)使式(I)的化合物,其中Ar是取代的芳基且取代基之一是NH2,与适当的醛或酮在还原剂存在下反应而得到式(I)的化合物,其中该取 代基是NR5R6基团,其中R5或R6中的一个是如转化3)中所定义的。
根据上述的合成过程,式(I)的化合物的合成可以以逐步的方式进行,由此,将每个中间体分离并且在实施随后的反应之前通过标准纯化技术例如柱色谱法来纯化。做为选择,所述合成顺序的两个或更多个步骤可以以所谓的“一步法”操作进行,如本领域中已知的,由此,只分离和纯化得自所述两个或更多个步骤的化合物。
如下所示的方案1-4表示式(I)的化合物的制备,其中X,Ar,R,R1,R2和R3具有上述含义。
方案1
方案2
方案3
方案4
根据步骤i),可以通过本领域公知的各种方式和实验条件还原式(II)的化合物得到式(IA),(IB)或(IC)的化合物。优选在硼氢化钠,氰基硼氢化钠,硼氢化钠/三氟乙酸,锌/盐酸,氯化锡/乙酸的存在下在适当的溶剂中进行上述还原,所述适当的溶剂例如为甲苯,二氯甲烷,氯仿,乙醚,四氢呋喃,1,4-二烷,甲醇,乙醇,异丙醇,乙酸,反应温度为从约-10℃至回流温度,且反应时间在约1小时-约96小时之间改变。根据实验条件,可以将式(IA),(IB)或(IC)的化合物分离作为主要产物。
根据步骤i'),可以通过使式(IIIA),(IIIB),(IIIC)或(IIID)的化合物与式(IV)的化合物按照本领域广泛已知的用于缩合反应的各种方式和实验条件反应,得到式(IA),(IB),(IC)或(ID)的化合物。优选在亚硫酰氯或草酰氯存在下,在适当的溶剂中将式(IV)的化合物(其中Y是羟基)转化为其相应的酰氯(其中Y是氯),所述适当的溶剂例如为甲苯,二氯甲烷,氯仿,乙醚,四氢呋喃,1,4-二烷,反应温度为从约-10℃至回流温度,反应时间在约1小时至约96小时之间 改变。通过蒸发溶剂来分离酰氯并且进一步与(IIIA),(IIIB),(IIIC)或(IIID)在例如吡啶、三乙胺或N-乙基二异丙胺等碱的存在下在适当的溶剂中反应,所述适当的溶剂例如为甲苯,二氯甲烷,氯仿,乙醚,四氢呋喃,1,4-二烷,反应温度从约-40℃至回流温度,反应时间在约1小时至约96小时。或者,使式(IV)的化合物与式(IIIA),(IIIB),(IIIC)或(IIID)的化合物在活化剂存在下反应,所述活化剂例如为羟基苯并三唑,二环己基碳二亚胺,二异丙基碳二亚胺,1-乙基-3-(3'-二甲基氨基)碳二亚胺盐酸盐。优选该反应在适当的溶剂中和在质子清除剂存在下进行,所述溶剂例如为四氢呋喃,二氯甲烷,甲苯,1,4-二烷,且所述质子清除剂例如为吡啶,三乙胺,N,N-二异丙基乙胺,反应温度从约室温至回流,反应时间为约30分钟至约96小时。
根据步骤i''),可以通过本领域广泛已知的各种方式和实验条件使式(XXIIA),(XXIIC)或(XXIID)的化合物脱保护而得到式(IA),(IC)或(ID)的化合物。优选就酰基残基而言,该反应在碱性条件下,例如在氢氧化钠、氢氧化钾、氢氧化锂或氢氧化钡或叔胺,例如三乙胺或二异丙基乙胺或肼存在下和在适当的溶剂,例如甲醇,乙醇,四氢呋喃,N,N-二甲基甲酰胺,水及其混合物中进行。一般而言,该反应在室温至回流温度下进行约30分钟至约96小时时间范围。在PG表示适当的保护基,例如苄基,p-甲氧基苄基,o,p-二甲氧基苄基或三苯基甲基时,转化可以根据与步骤h)中报告的同样的条件下进行。
根据步骤a),可以根据文献中广泛已知的常规方法,通过使用式(XIII)的格利雅试剂,在各种方式和实验条件中,将式(XII)的化合物转化为式(XI)的化合物。优选式(XII)的化合物与有机金属试剂的反应在适当的溶剂,例如,四氢呋喃,1,4-二烷和乙醚中,在-78℃至室温的温度下进行约30分钟至96小时。
根据步骤b),可以在各种方式中,根据将醇类化合物氧化成酮类化合物的常规方法来将式(XI)的化合物氧化成式(X)的化合物。优选该反应在适当的溶剂中和在适当的氧化剂和催化剂存在下进行,所述溶剂例如为甲醇,乙醇,叔丁醇,水,四氢呋喃,1,4-二烷,甲苯, 乙酸,三氟乙酸,二氯甲烷,二氯乙烷,乙腈,二甲亚砜或其混合物,所述氧化剂例如为3-氯过苯甲酸,过氧化氢,戴斯-马丁氧化剂(Dess-Martin periodinane),臭氧,高锰酸钾,高碘酸钠,高碘酸,且所述催化剂是氧化铬(VI),过钌酸四丙基铵,氯化钌。一般而言,该反应在-78℃至回流温度下进行约30分钟至约96小时。
根据步骤c),可以通过本领域广泛已知的用于制备3-氨基吲唑类化合物的各种方式和实验条件将式(X)的化合物转化为式(IX)的化合物。优选式(X)的化合物与肼的反应在适当的溶剂,例如,甲苯,四氢呋喃,1,4-二烷,二甲亚砜,乙腈,甲醇,乙醇或正-丁醇中和在0℃至回流温度下进行约1小时至约96小时。为了催化该反应,可能需要添加酸,例如优选盐酸或乙酸。
根据步骤d),可以通过本领域广泛已知的用于保护伯氨基的各种方式和实验条件将式(IX)的化合物转化为式(VIII)的化合物。优选通过在适当的溶剂,例如乙腈,四氢呋喃,甲苯,二氯甲烷中用过量的三氟乙酸酐或三氟乙酰氯处理来进行该反应。一般而言,该反应在0℃至约110℃的温度下进行约30分钟至约96小时。用质子溶剂,例如,水,甲醇,乙醇或其混合物或用碳酸氢钠的水溶液对该反应混合物进行后处理导致对吲唑环上的三氟乙酰基进行选择性水解。就邻苯二甲酰亚胺衍生物的制备而言,通过用邻苯二甲酸酐在碱性条件下,例如在1,8-二氮杂双环[5.4.0]十一-7-烯,N,N-二甲基氨基吡啶,吡啶,三乙胺的存在下和在适当的溶剂,例如乙腈,四氢呋喃,N,N-二甲基甲酰胺,甲苯,二氯甲烷,水及其混合物中处理来进行该反应。一般而言,该反应在室温至约110℃的温度下进行约30分钟至约96小时。
根据步骤e),由式(VIII)的化合物得到式(VII)的化合物的反应可以在各种方式和实验条件中进行。当PG是三苯基甲基时,该反应优选通过在适当的溶剂中和在质子清除剂存在下用三苯甲基氯处理来进行,所述溶剂例如为四氢呋喃,二氯甲烷,甲苯,1,4-二烷,所述质子清除剂例如优选为1,8-二氮杂双环[5.4.0]十一-7-烯,三乙胺,N,N-二异丙基乙胺,吡啶,反应温度在室温至回流温度,反应时间约 30分钟至约96小时。
根据步骤f),可以根据常规方法,通过除去适当的保护基,例如三氟乙酰基将式(VII)的化合物转化为式(VI)的化合物。优选通过用有机或无机碱在适当的溶剂中处理来进行该反应,所述碱例如为碳酸钾,氢氧化钠,氨,三乙胺,N,N-二异丙基乙胺,所述溶剂例如为四氢呋喃,二氯甲烷,甲苯,1,4-二烷,甲醇,乙醇,水或其混合物。反应温度在室温至回流温度,反应时间约30分钟至约96小时。
根据步骤g),可以在本领域中广泛已知的用于缩合反应的各种方式和实验条件中将式(VI)的化合物转化为式(V)的化合物。优选该反应按照与步骤i')中报告的同样的方式进行。
根据步骤h),可以根据能够选择性水解苄基、4-甲氧基苄基、2,4-二甲氧基苄基和三苯基甲基保护基的常规方法使内环吲唑氮原子脱保护,从而将式(V)的化合物转化为式(II)的化合物。优选该反应在酸性条件下和在适当的溶剂中进行,所述酸性条件优选在无机或有机酸,例如盐酸,三氟乙酸或甲磺酸的存在下,所述溶剂例如为二氯甲烷、1,4-二烷、低级醇(例如甲醇或乙醇),反应温度在室温至约80℃,反应时间约1小时至约48小时。在可替代方案中,该反应在还原条件下和适当的溶剂中进行,所述还原条件例如在氢和氢化催化剂存在下,所述溶剂例如为乙醇,甲醇,乙酸乙酯或其混合物。催化剂通常是金属,最常见的是钯衍生物,例如氢氧化钯或钯黑。
根据步骤j),可以在各种方式中,根据用于将醇类化合物还原成烷的常规方法,将式(XI)的化合物还原成式(XIV)的化合物。优选该反应在适当的溶剂中和适当还原系统存在下进行,所述溶剂例如为甲醇,乙醇,四氢呋喃,1,4-二烷,乙酸,二氯甲烷,乙腈或其混合物,所述还原系统例如为三甲基甲硅烷基氯/碘化钠,二氯二甲基硅烷/碘化钠,三乙基硅烷/三氟乙酐,硼氢化钠/三氟乙酸。一般而言,该反应在-10℃至回流的温度下进行约30分钟至约96小时。
根据步骤k),可以在各种方式中,根据用于硼-衍生物偶联,即Suzuki-样反应的常规方法在式(XVI)的化合物存在下将式(XV)的化合 物转化为式(XIV)的化合物。优选该反应在适当的溶剂中和在适当碱存在下进行,所述溶剂例如为乙醇,水,四氢呋喃,二烷,丙酮,N,N-二甲基甲酰胺,二甲氧基乙烷,甲苯,二甲苯或其混合物,所述碱例如为三乙胺,二异丙基乙胺,碳酸钠,碳酸钾或碳酸铯,磷酸钾,氢氧化钠或氟化铯,反应温度在-20℃至回流温度,反应时间在约1小时至约96小时。催化剂通常是适当配体(所述配体例如是三苯膦)存在下的金属,最常见的是钯衍生物,例如氯化钯、乙酸钯。
根据步骤l),可以在各种方式和实验条件中将式(XIV)的化合物转化为式(IIIA)的化合物。优选该反应在与对步骤c)报告的同样的方式中进行。
根据步骤l')可以在各种方式和实验条件中将式(XI)的化合物转化为式(IIIB)的化合物。优选该反应在与对步骤c)报告的同样的方式中进行。
根据步骤m),可以在各种方式中,根据用于O-烷基化反应的常规方法,在式(XVIII)的化合物存在下将式(XI)的化合物转化为式(XVII)的化合物。优选该反应在适当的溶剂中和适当碱存在下进行,所述溶剂例如为四氢呋喃,二烷,N,N-二甲基甲酰胺,二甲氧基乙烷,所述碱例如为三乙胺,二异丙基乙胺,碳酸钠,碳酸钾或碳酸铯,氢化钠,反应温度在-78℃至回流温度,反应时间约1小时至约96小时。烷化剂通常是卤素或磺酸酯衍生物;最常见的离去基是碘,溴,三氟甲磺酸酯,或甲磺酸酯。
根据步骤l''),可以在各种方式和实验条件中将式(XVII)的化合物转化为式(IIIC)的化合物。优选该反应在与对步骤c)报告的同样的方式中进行。
根据步骤n),可以在各种方式中,根据用于C-烷基化反应的常规方法,在式(XVIII)的化合物存在下将式(XIV)的化合物转化为式(XIXD1)的化合物。优选该反应在与对步骤m)报告的同样的方式中进行。
根据步骤l''')可以在各种方式和实验条件中将式(XIXD1)的化 合物转化为式(IIID1)的化合物。优选该反应在与对步骤c)报告的同样的方式中进行。
根据步骤o),可以在各种方式和实验条件中,在式(XIII)的化合物的存在下,将式(XXI)的化合物转化为式(XX)的化合物。优选该反应在与对步骤a)报告的同样的方式中进行。
根据步骤p),可以在各种方式和实验条件中将式(XX)的化合物转化为式(XIXD1)的化合物。优选该反应在与对步骤j)报告的同样的方式中进行。
根据步骤q),可以在各种方式和实验条件中在式(XXIII)的化合物存在下,将式(XIXD1)的化合物转化为式(XIXD2)的化合物。优选该反应在与对步骤m)报告的同样的方式中进行。
根据步骤lIV),可以在各种方式和实验条件中将式(XIXD2)的化合物转化为式(IIID2)的化合物。优选该反应在与对步骤c)报告的同样的方式中进行。
根据步骤r),可以在本领域广泛已知的用于保护伯氨基的各种方式和实验条件中,将式(IIIA),(IIIC)或(IIID)的化合物转化为式(XXIVA),(XXIVC)或(XXIVD)的化合物。优选该反应在与对步骤d)报告的同样的方式中进行。
根据步骤s),可以在各种方式和实验条件中进行由式(XXIVA),(XXIVC)或(XXIVD)的化合物得到式(XXVA),(XXVC)或(XXVD)的化合物的反应。优选该反应在与对步骤e)报告的同样的方式中进行。
根据步骤t),可以通过根据常规方法除去适当的保护基,例如三氟乙酰基,将式(XXVA),(XXVC)或(XXVD)的化合物转化为式(XXVIA),(XXVIC)或(XXVID)的化合物。优选该反应在与对步骤f)报告的同样的方式中进行。
根据步骤u),可以在本领域广泛已知的用于缩合反应的各种方式和实验条件中将式(XXVIA),(XXVIC)或(XXVID)的化合物转化为式(XXIIA),(XXIIC)或(XXIID)的化合物。优选该反应在与对步骤i')报告的同样的方式中进行。
根据1)中所述的转化,在各种方式中,根据文献中众所周知的常规方法,将式(II),(V),(XXIIA),(XXIIC)或(XXIID)的化合物,其中Ar是取代的芳基且取代基之一是硝基,还原成式(II),(V),(XXIIA),(XXIIC)或(XXIID)的化合物,其中该取代基是氨基。优选该转化在适当的溶剂中和适当还原剂存在下进行,所述溶剂例如为甲醇,乙醇,水,四氢呋喃,1,4-二烷,N,N-二甲基甲酰胺,乙酸或其混合物,所述还原剂例如为氢和氢化催化剂,或该转化通过用环己烯或环己二烯或甲酸或甲酸铵和氢化催化剂或金属,例如铁或锌在无机酸,例如盐酸存在下处理或通过用氯化锡(II)处理来进行,反应温度在0℃至回流温度,反应时间约1小时至约96小时。所述氢化催化剂通常是金属,最常见的是钯,它可以直接使用或负载在碳上使用。
根据2)中所述的转化,在各种方式中,根据文献中众所周知的常规方法,通过与式(XXVII)或(XXVIII)的乙酰化剂反应来酰化式(II),(V),(XXIIA),(XXIIC)或(XXIID)的化合物,其中Ar是取代的芳基且取代基之一是氨基,得到式(II),(V),(XXIIA),(XXIIC)或(XXIID)的化合物,其中该取代基是NHCOR4或NHSO2R4残基。优选该转化在与对步骤i')报告的同样的条件下进行。
根据3)中所述的转化,在各种方式中,根据用于进行还原烷基化的常规方法,通过与适当的醛或酮反应使式(II),(V),(XXIIA),(XXIIC)或(XXIID)的化合物(其中Ar是取代的芳基且取代基之一是氨基)还原氨基化。优选该反应在适当的溶剂中和在适当的还原剂的存在下和酸性催化剂存在下进行,所述溶剂例如为甲醇,N,N-二甲基甲酰胺,二氯甲烷,四氢呋喃或其混合物,所述还原剂例如为硼氢化钠,四烷基硼氢化铵,氰基硼氢化钠,三乙酰氧基硼氢化钠,三乙酰氧基四甲基硼氢化铵,且所述酸性催化剂例如为乙酸或三氟乙酸,反应温度在约0℃至回流温度,反应时间在约1小时至约96小时之间改变。
根据4)中所述的转化,在各种方式中,根据文献中已知的常规方法将式(I)的化合物,其中Ar是取代的芳基且取代基之一是硝基,还原成式(I)的化合物,其中该取代基是氨基。优选该转化在与转化1) 报告的同样的条件下进行。
根据5)中所述的转化,在各种方式中,根据文献中众所周知的常规方法,通过与式(XXVII)或(XXVIII)的乙酰化剂反应,酰化式(I)的化合物,其中Ar是取代的芳基且取代基之一是氨基,得到式(I)的化合物,其中该取代基是NHCOR4或NHSO2R4残基。优选该转化在与转化2)报告的同样的条件下进行。
根据6)中所述的转化,在各种方式中,根据用于进行还原烷基化的常规方法,通过与适当的醛或酮反应,对式(I)的化合物进行还原氨基化,式(I)的化合物中,Ar是取代的芳基且取代基之一是氨基。优选该转化在与转化3)报告的同样的条件下进行。
本领域技术人员已知当式(IV)或式(XXVII)的化合物携带可能干扰酰化反应的官能团时,在进行反应前必须保护这类基团。特别地,当式(IV)或式(XXVII)的化合物被通式NR5R6,OR7,SR7,R8R9N-C1-C6烷基或R8O-C1-C6烷基的残基取代时,其中R7或至少一个R5和R6或至少一个R8和R9表示氢,这类基团可以如本领域公知的被保护。本领域技术人员还已知可以在反应刚结束后或合成过程的后期阶段除去这类保护基。
可以在各种方式中根据用于使氨基脱保护的常规方法使式(I),(XXIIA),(XXIIC或(XXIID)的化合物脱保护,其中,Ar是取代的芳基且取代基之一是被保护的氨基。根据氨基保护基的不同,该反应可以在不同方式中进行。在一个方面中,这类反应可以通过在适当的溶剂中用无机酸或有机酸处理来进行,所述无机酸例如为盐酸、硫酸或高氯酸,所述有机酸例如为三氟乙酸或甲磺酸,所述溶剂例如为水,甲醇,乙醇,1,4-二烷,四氢呋喃,乙醚,二异丙基醚,乙腈,N,N-二甲基甲酰胺,二氯甲烷或其混合物,反应温度在-10℃至80℃,反应时间在30分钟至48小时。在另一个方面中,这类反应可以通过在适当的溶剂中用无机碱或有机碱处理或使用无水肼或水合肼处理来进行,所述无机碱例如为氢氧化锂或氢氧化钠或氢氧化钾,或碳酸钠或碳酸钾或碳酸铯,所述有机碱例如为三乙胺或N,N-二异丙基乙胺,所 述溶剂例如为水,甲醇,乙醇,1,4-二烷,四氢呋喃,乙醚,二异丙基醚,乙腈,N,N-二甲基甲酰胺,二氯甲烷或其混合物,反应温度在-10℃至80℃,反应时间在30分钟至72小时。
可以使用例如Smith,Michael-March's Advanced Organic Chemistry:reactions mechanisms and structure-第5版,Michael B.Smith和Jerry March,JohnWiley&Sons Inc.,New York(NY),2001中报告的有机合成中的标准方法制备取代的吲唑衍生物。本领域技术人员已知将一种化学官能团转化为另一种化学官能团可能需要在含这一官能团的化合物上有一个或多个反应中心被保护,以避免不需要的副反应。可以按照例如在:Green,Theodora W.和Wuts,Peter G.M.-Protective Groups in Organic Synthesis,Third Edition,John Wiley&Sons Inc.,New York(NY),1999中所述的标准方法保护这类反应中心并且在随后的合成转化结束时脱保护。
就其中式(I)的化合物包含一个或多个不对称中心的情况而言,可以通过本领域技术人员公知的方法将该化合物分离为单一异构体。这类方法包括标准色谱技术,包括使用手性固定相的色谱法或结晶法。例如,在Jacques,Jean;Collet,André;Wilen,SamuelH.,-Enantiomers,Racemates,和Resolutions,John Wiley&Sons Inc.,New York(NY),1981中报告了包含一个或多个不对称中心的化合物的一般分离方法。
还可以根据本领域技术人员公知的标准方法将式(I)的化合物转化为药学可接受的盐。或者,还可以根据本领域技术人员公知的标准方法将作为盐得到的式(I)的化合物转化为游离碱或游离酸。
本发明方法的原料物质,即式(XII),(XIII),(XV),(XVI),(XVIII),(XXIII)和(XXI)的化合物是商购的或可以通过使用众所周知的方法制备。
例如,易于根据本领域技术人员广泛已知的用于格氏试剂反应的常规方法得到式(XIII)的化合物,如下列方案中报告的:
RZ+Mg→RMgZ
(XIII)
例如,易于由相应的卤素衍生物制备式(XV)的化合物,如下列方案中报告的(例如,参见WANG,X.-J.等.;Org Lett2006,8(2),305-307):
例如,易于通过经根据常规合成方法操作精制相应的醇类衍生物而得到式(XVI)的化合物。
例如,易于通过经根据常规合成方法操作氧化相应的醇类衍生物而得到式(XXI)的化合物。
本发明的另一个目的在于提供式(IIIA'),(IIIB'),(IIIC')或(IIID')的中间体:
其中R是任选取代的C3-C6环烷基,芳基或杂芳基,且
R1,R2,R3,R'和R''为如上述定义的,条件是不包括下列化合物:
-6-(3-氨基-1H-吲唑-5-基甲基)-3-异丙基-1-(2,4,6-三氯-苯基)-1,7-二氢-吡唑并[3,4-d]嘧啶-4-酮,和
-1-[(3-氨基-1H-吲唑-5-基)甲基]-3-({1-[2-(二甲基氨基)乙基]-1H-苯并咪唑-2-基}甲基)-1,3-二氢-2H-苯并咪唑-2-酮。
本发明的另一个目的在于提供式(XIIA),(XXIIC)或(XXIID)的中间体:
其中Ar,R,R1,R2,R3,R',R''和PG为如上述定义的。
本发明的另一个目的在于提供式(XXVII)的化合物:
其中Ar,R,R1,R2和R3为如上述定义的且PG2是乙氧基羰基或2-甲氧基乙基羰基。
本发明进一步提供了制备如上述定义的式(XXVII)的化合物的方法,其特征在于,该方法包括:
v)保护如上述定义的式(I)的化合物,得到式(XXVII)的化合物:
其中R,R1,R2,R3和PG2为如上述定义的。
根据步骤v),将式(I)的化合物保护为式(XXVII)的化合物可以在各种方式和实验条件中进行。优选该反应通过在适当的溶剂中用碱处理来进行,所述碱例如为二异丙基氨基锂,氢化钠或双(三甲基甲硅烷基)氨基锂、双(三甲基甲硅烷基)氨基钠或双(三甲基甲硅烷基)氨基钾,所述溶剂例如为甲苯,四氢呋喃,1,4-二烷,乙醚,N,N-二甲基甲酰胺,二甲氧基乙烷,反应温度在-78℃至室温,反应时间为约 10分钟至约96小时。亲电子试剂通常是氯甲酸酯衍生物,例如,氯甲酸乙酯或氯甲酸2-甲氧基乙酯。
药理学
本文中使用的简略形式和缩写具有以下含义:
Ci 居里
DMSO 二甲亚砜
ID 身份
KDa 千道尔顿
microCi 微居里
mg 毫克
microg 微克
mL 毫升
microL 微升
M 摩尔
mM 毫摩尔
μM 微摩尔
nM 纳摩尔
试验
在生化测定中对本发明的化合物进行试验,如下所述。
用于生化试验的ALK胞浆区的制备
克隆和表达
从人睾丸cDNA文库进行PCR扩增对应于残基1060-1620(所述氨基酸残基的数目参考基因库登记号NP 004295.2)的ALK胞浆区。
使用正向寡核苷酸: 5'GGGGACAAGTTTGTACAAAAAAGCAGGCTTACTGGAAGTTCTGTTCCAGGGGCCCCGCCGGAAGCACCAGGAGCTG -3'
和反向寡核苷酸:5'GGGGACCACTTTGTACAAGAAAGCTGGGTTTCAGGGCCCAGGCTGGTTCATGCTATT-3'进行扩增。
对于克隆的目的,寡核苷酸包括attB位点,以使用Gateway技术 (Invitrogen),得到适合于克隆的含attB-侧翼的PCR产物。此外,对于纯化的目的,正向引物包括PreScission切割位点(Amersham Biosciences)。将得到的PCR产物克隆到经过Gateway-修饰的杆状病毒表达载体pVL1393(Invitrogen)中。对于表达和纯化的目的,向ALK胞浆区的N-末端添加GST标签。克隆根据在Gateway手册(Invitrogen)中所述的流程进行。
通过使用BaculoGoldTM转染试剂盒(Pharmingen)、用表达载体和病毒DNA共转染Sf9昆虫细胞而生成杆状病毒。
在5天之后回收病毒上清液并且经过三轮扩增,以增加病毒滴定度。
通过在27℃振荡的条件下用每十亿细胞30mL的病毒上清液以1x106细胞/mL的密度感染Sf21昆虫细胞,以产生重组蛋白质。在感染48小时之后,回收细胞,形成团粒并且在-80℃冷冻。
蛋白质纯化
将细胞再混悬在溶胞缓冲液(Tris-HCl50mM pH8,NaCl150mM,CHAPS0.2%,DTT20mM,甘油20%,“完全的”蛋白酶抑制剂混合物(Roche Diagnostics),Na3VO41mM中,并且通过用Gaulin匀浆器(Niro Soavi Italy)将液体挤出来进行溶胞。通过以20000g离心30分钟使溶胞产物澄清,将其加载在谷胱甘肽琼脂糖凝胶4B(Amersham Biosciences)柱上。
在彻底洗涤之后,将重组蛋白质用含10mM谷胱甘肽的100mM Tris-HCl pH8,10%甘油来洗脱。
将亲合性纯化的GST-ALK加载在Heparin SepharoseTMFF(Amersham Biosciences)柱上,并且用50mM NaCl,25mM TRIS pH7.5,2mM DTT,20%甘油洗脱。
将洗脱的级分合并,并且用150mM NaCl,50mM Tris-HCl pH7.4,2mM DTT,20%甘油来透析。
在用于生化试验之前,将纯化的蛋白质储存在-80℃。
用于ALK激酶活性抑制剂的生化试验
ALK酶需要预活化,以使反应动力学线性化。
i.用于ALK的激酶缓冲液(KB)
激酶缓冲液由50mM HEPES pH7.5组成,其包含1mM MnCl2,5mM MgCl2,1mM DTT,3μMNa3VO4,和0.2mg/mL BSA。3X KB是具有与KB相同组成和pH的缓冲液,但是每种成分的浓度是其三倍。
ii.试验条件
所述激酶试验在8μM ATP,1nM33P-γ-ATP和2μM MBP的存在下用20nM的最终酶浓度进行。MPB购自Sigma-Aldrich,St.Louis,MO,USA。
关于ALK激酶活性抑制剂的基于细胞的试验
在Karpas-299,SR-786和SUP-M2间变性大细胞淋巴瘤细胞系中的ALK和STAT3磷酸化的蛋白印迹分析
将Karpas-299,SR-786和SUP-M2细胞(DSMZ,Braunschwiegh,Germany)以5x105细胞/mL接种在6-孔组织培养板中的RPMI-1640培养基+2mM谷氨酰胺+10%-15%FCS(EuroClone,Italy)中,并且在37℃,5%CO2,100%相对湿度下培养过夜。培养之后,将细胞用所需浓度的化合物在37℃处理2小时。通过在248x g离心5分钟收集细胞,用冷的PBS洗涤,再次在248x g离心5分钟,然后在100mMTris-HCl pH7.4,2%SDS,1mM Na3VO4,蛋白酶抑制剂混合物[Sigma-Aldrich product#P8340],磷酸酶抑制剂混合物[Sigma-Aldrichproducts#P2850+#P5726])中裂解。在短暂的声处理之后,通过在10,000xg室温离心20分钟使细胞溶胞产物澄清,并且用MOPS流动缓冲液使20μg/通路的澄清的溶胞产物蛋白质在NuPAGE凝胶(NuPAGE4-12%10-通路Bis-Tris凝胶,Invitrogen)上运行,然后使用MiniPROTEAN II腔(Bio-Rad Laboratories,Hercules,CA,USA)转移到Hybond-ECL硝化纤维素滤器(Amersham Biosciences,Little Chalfont,Buckinghamshire,UK)上。将带有转移的蛋白质的过滤器在封闭缓冲液(TBS+5%脱脂奶粉[#1706404 Bio-rad,Hercules,CA,USA]+0.1%Tween20)中孵育1小时并且在4℃,在包含1/500抗-磷酸-ALK Tyr1604抗体(产品#3341Cell Signaling Technology,Beverly,MA,USA)的TBS+5%BSA+0.1%Tween20中引入探针过夜,用于检测磷酸化的ALK,或者在包含1/500小鼠抗-ALK抗体(产品#35-4300,ZymedLaboratories,South San Francisco,CA,USA)的TBS+5%BSA+0.1%Tween20中引入探针过夜,用于检测总的ALK,或者在包含1/500小鼠抗-磷酸STAT3Tyr705抗体(产品#612357,BDTransduction Laboratories,Canada)的TBS+5%BSA+0.1%Tween20中引入探针过夜,用于检测磷酸化的STAT3,或者在包含1/1000小鼠抗-STAT3抗体(产品#610190BDTransductionLaboratories,Canada)的TBS+5%BSA+0.1%Tween20中引入探针过夜,用于检测总的STAT3。
在所有情况下,都是随后将过滤器用更换几次的TBS+0.1%Tween20洗涤20分钟,并且在包含1/10000稀释度的辣根过氧化酶轭合的抗-兔或小鼠IgG(Amersham,产品#NA934)的TBS+5%脱脂奶粉+0.1%Tween20中孵育1小时,然后再次洗涤并且根据生产商的建议使用ECL化学发光系统(Amersham)显影。除非另有说明,使用的试剂来自Sigma-Aldrich,St.Louis,MO,USA。
用于ALK激酶活性抑制剂的体外细胞增殖试验
将人ALCL细胞系Karpas-299,SR-786和SUP-M2以1x105细胞/mL接种在96孔板(PerkinElmer,Wellesley,MA,USA)中的RPMI-1640培养基+2mM谷氨酰胺+10%-15%FCS(EuroClone,Italy),(100μL/孔)中,并且保持在37℃、5%CO2、100%相对湿度条件下。第二天,将培养板用适当稀释度的化合物一式两份进行处理,所述稀释从在DMSO(最终的DMSO浓度为0.1%)中的10mM储备液开始。每个培养板中包括八个未经处理的对照孔。在处理72小时之后,向每个孔加入50μL的CellTiter-Glo Assay试剂(Promega,Madison,WI,USA),并且在搅拌之后使用Envision Detector检测器(PerkinElmer Wellesley,MA,USA)测量发光信号。
使用Microsoft Excel S形曲线拟合来进行LSW/数据分析,计算IC50值。
用于生化试验的IGF-1R的制备
克隆和表达
将人cDNA用作模板,用于通过将包括整个激酶结构域的IGF-1R(前体蛋白的氨基酸残基960-1367;参见NCBI Entrez Protein Accession#P08069)的预测的胞质部分的聚合酶链式反应(PCR)进行扩增。使用正向引物序列5'-CTCGGATCCAGAAAGAGAAATAACAGCAGGCTG-3'和反向引物序列5'-CTCGGATCCTCAGCAGGTCGAAGACTGGGGCAGCGG-3'进行PCR。为了便于随后的克隆步骤,两种引物都包括BamHI限制性核酸内切酶位点序列。使用BamHI粘性端在壳框中将这个PCR产物克隆到杆状病毒表达系统pVL1392(Pharmingen)的转移载体中,所述转移载体预先通过插入到编码谷胱甘肤S-转移酶(GST)融合蛋白的序列的pVL1392多重克隆位点、PreScission蛋白酶切割位点和得自pGex-6P质粒(Amersham BioSciences)的部分MCS盒中而进行过修饰。将上述的IGF-1R PCR产物插入到经过修饰的pVL1392载体的pGex-6P衍生的BamHI位点,产生对应于pGEX-6P GST蛋白和与人IGF-1R胞浆区融合的PreScission肽的开放阅读框。为了得到融合蛋白,将Sf21昆虫细胞(Invitrogen)用2微克的纯化质粒和1微克的病毒DNA(BaculoGoldTM Transfection Kit,Pharmingen)共转染,如Baculovirus Instruction manual(Pharmingen)中所述。病毒的首次扩增使用600微升的共转染病毒,在12mL培养基(TNM-FH Grace培养基-Pharmingen)中在单层培养的6x106Sf21上进行。在3天之后,收集培养基,离心并且转移到无菌管中。用相同方法使用在40mL培养基中稀释的3x107细胞上的2mL来制备第二次扩增。对于病毒的第三次扩增,对于在40mL培养基中稀释的每3x107细胞,使用得自第二轮的1mL上清液。
在用14mL病毒/1x109昆虫细胞(MOI=1.5)感染的H5昆虫细胞中进行蛋白表达,在27℃在振荡下进行65小时。通过在1200xg离 心10分钟收获细胞。
蛋白质纯化
将细胞再混悬在磷酸盐缓冲盐溶液(PBS),20mM二硫苏糖醇(DTT),0.2%CHAPS,20%甘油,1mM OVA,“完全的”蛋白酶抑制剂混合物(1片/50mL缓冲液;Roche Diagnostics,Milan,Italy)中,并且通过用Gaulin匀浆器(Niro Soavi,Italy)将液体挤出来进行溶胞。将溶胞产物在14000xg离心45分钟并将上清液加载在包含10mL谷胱甘肽琼脂糖凝胶(Amersham Biosciences)的柱子上。将柱子首先用5倍柱体积的PBS缓冲液洗涤,然后用5倍柱体积的100mM Tris pH8.0,20%甘油洗涤,最后用含10mM谷胱甘肽的100mM Tris pH8.0,20%甘油洗脱。收集10mL的级分并将富含蛋白质的级分合并。典型地,从1x109细胞回收20mg的融合蛋白,通过SDS-PAGE和随后的Coomassie染色判断其典型地为>85%的纯度。在用于生化试验之前,将纯化的蛋白质储存在-80℃。
关于IGF-1R激酶活性抑制剂的生化试验
使用转磷酸作用试验测定推定的激酶抑制剂的抑制活性以及所选化合物的效力。
在含痕量的33P-γ-ATP(γ磷酸盐标记的,RedivueTM编码号AH9968,1000-3000Ci/mmole,Amersham Biosciences Piscataway,NJ,USA)的ATP、最理想的辅助因子和试验化合物的存在下在适当的缓冲条件下将特异性底物与激酶一起培养。
在磷酸化反应结束时,通过过量的Dowex离子交换树脂捕获超过98%冷的和放射性的ATP。通过重力使树脂沉淀到反应孔的底部。随后收回包含底物肽的上清液并且转移到计数板中,并且通过β-计数评价放射性活度(对应于并入到肽中的磷酸盐)。
试剂/试验条件
i.Dowex树脂的制备
将500g的湿树脂(SIGMA,常规制备的DOWEX树脂1x8200-400 目,2.5Kg)称重并且稀释到2L的150mM甲酸钠,pH3.00中。
使树脂沉淀几小时,然后将上清液抛弃。在两天内重复这个洗涤操作三次。最后,使树脂沉淀,抛弃上清液并且加入两倍体积(相对于树脂体积)的150mM甲酸钠缓冲液。最终的pH是大约3.0。将经过洗涤的树脂保持在4℃备用,并且其可以稳定超过一周。
ii.激酶缓冲液(KB)
激酶缓冲液由50mM HEPES pH7.9组成,包含3mM MgCl2,1mMDTT,3μM Na3VO4,和0.2mg/mL BSA。3X KB是具有与KB相同的组成和pH的缓冲液,但是每种成分的浓度都是KB的三倍。
iii.酶预活化和3X酶混合物的制备。
在开始激酶抑制试验之前,将IGF-1R预磷酸化,以使反应动力学线性化。为此,在包含100μM ATP的KB中以360nM的酶浓度制备所需总量的酶,并将该制备物在28℃孵育30分钟。通过将该预活化的酶在3X KB中稀释20倍得到3X酶混合物。
iv.试验条件
所述激酶试验用6nM的最终酶浓度进行,在6μM ATP,1nM33P-γ-ATP和10μM底物、具有序列:KKKSPGEYVNIEFGGGGGK-生物素的羧基末端的生物素化的肽的存在下进行。所述肽以>95%的肽纯度分批得自American Peptide Company,Inc.(Sunnyvale,CA,USA)。
自动化的Dowex试验
在21μL的总的最终容积中进行试验反应,所述反应包括:
a)7μL/孔的3X酶混合物(在3X激酶缓冲液中的18nM预活化的酶),
b)7μL/孔的3x底物/ATP混合物(在双蒸馏水(ddH2O)中的30μM底物,18μM ATP,3nM33P-γ-ATP),
c)7μL/孔的稀释到ddH2O-3%DMSO中的3X试验化合物。
化合物稀释和试验方案报告如下
i.化合物的稀释
将试验化合物在100%DMSO中的10mM储备液分配在96孔12x8 格式的微量滴定板中。
对于抑制%的研究,在100%DMSO中制备1mM、100μM和10μM的稀释板,然后在ddH2O,3%DMSO中稀释到3X最终所需浓度(30,3和0.3μM)。将Multimek96(Beckman Coulter,Inc.4300N.Harbor Boulevard,P.O.Box3100Fullerton,CA92834-3100USA)用来将化合物移液到试验板中。
对于IC50测定,从1mM/100%DMSO储备液得到在3%DMSO中的30μM化合物的起始溶液。将这些30μM的起始溶液用来在ddH2O,3%DMSO中生成另外的9个连续的1/3稀释,得到3X最终试验浓度的10-点稀释曲线。使用Biomek2000(Beckman Coulter)系统在96孔板中进行连续稀释。制备7化合物/板的稀释曲线,并且每个板还包括星状孢子素的10-点稀释曲线以及若干阴性和阳性对照孔。
ii.试验方案
将7μL的每种试验化合物(或对照)在ddH2O,3%DMSO中的稀释液移液到384孔的V形底试验板中的每个孔中,然后将其转移到PlateTrak12自动化工作站(Perkin Elmer,45William Street Wellesley,MA02481-4078,USA)上,所述PlateTrak12自动化工作站装备有一个用于启动试验的384个端部的移液头、以及一个用于分配树脂的96个端部的头部,备有包含用以完成试验过程的足够的3X酶混合物和3X ATP混合物(3X)的储库。
在试验开始时,液体处理系统吸出7μL的ATP混合物,在端部内引入空气间隙(5μL),然后吸出7μL的3X酶混合物。为了起动反应,将端部内容物分配到已经包含7μL试验化合物(为3X所需最终浓度)的试验孔中,随后进行3个混合循环,以重建所有反应组分的所需最终浓度。
将板在室温孵育60分钟,然后通过将70μL的Dowex树脂混悬液移液到反应混合物中中止反应,随后进行三个混合循环。在终止反应之后,将板放置1小时以使ATP的捕获最大化。这时,将20μL的上清液从每个孔转移到包含70μL/孔的Microscint40(Perkin Elmer)的384-Optiplates(Perkin Elmer)的孔中;在轨道振荡5分钟之后,将板放在Perkin-ElmerTop Count放射性活度计数器上读数。
iii.数据分析
使用“Assay Explorer”软件包的专业版本(Elsevier MDL,San Leandro,CA94577)分析数据。对于单独的化合物浓度,抑制活性典型地表示为与没有抑制剂时得到的酶的总活度相比的、在化合物的存在下获得的抑制%。
对表现出所需抑制效果的化合物进行进一步分析,以通过IC50计算来研究抑制剂的效力。在这种情况中,使用抑制剂的系列稀释液得到的抑制数据通过非线性回归拟合,使用以下方程:
其中νb为基线速度,ν为观察到的反应速度,νo为在没有抑制剂存在下的速度,且[I]为抑制剂浓度。
关于IGF-1R激酶活性抑制剂的基于细胞的试验
在MCF-7人乳腺癌细胞中在用IGF-1刺激之后的受体磷酸化的蛋白印迹分析
将MCF-7细胞(ATCC#HTB-22)以2x105细胞/孔接种在12-孔组织培养板中的E-MEM培养基(MEM+Earle's BSS+2mM谷氨酰胺+0.1mM非必需氨基酸)+10%FCS,并且在37℃、5%CO2、100%相对湿度下培养过夜。然后通过用E-MEM+0.1%BSA替换E-MEM+10%FCS使细胞饥饿,并且培养过夜。在培养之后,将各孔用所需浓度的化合物在37℃处理1小时,然后用10nM重组人IGF-1(Invitrogen,Carlsbad,CA,USA)在37℃刺激10分钟。然后将细胞用PBS洗涤并且在100μL/孔的细胞溶解缓冲液(M-PER哺乳动物蛋白质提取试剂[产品#78501,Pierce,Rockford,IL,USA]+10mM EDTA+蛋白酶抑制剂混合物[Sigma-Aldrich product#P8340]+磷酸酶抑制剂混合物[Sigma-Aldrich products#P2850+#P5726])中溶解。通过以 10,000xg离心5分钟使细胞溶胞产物澄清,并且用MOPS流动缓冲液使10μg/通路的澄清的溶胞产物蛋白质在NuPAGE凝胶(NuPAGE4-12%10-通路Bis-Tris凝胶,Invitrogen)上运行,然后使用Mini PROTEAN II腔(Bio-Rad Laboratories,Hercules,CA,USA)转移到Hybond-ECL硝化纤维素滤器(Amersham Biosciences,Little Chalfont,Buckinghamshire,UK)上。将带有转移的蛋白质的过滤器在封闭缓冲液(TBS+5%BSA+0.15%Tween20)中孵育1小时,并且在包含1/1000兔抗-磷酸IGF-1R Tyr1131/InsR Tyr1146抗体(产品#3021,Cell SignalingTechnology,Beverly,MA,USA)的相同缓冲液中引入探针2小时,用于检测磷酸化的IGF-1R,或者在包含1/1000稀释度的兔IGF-Irβ(H-60)抗体(产品#sc-9038,Santa CruzBiotechnology,Inc.,Santa Cruz,CA,USA)的相同缓冲液中引入探针2小时,用于检测总的IGF-1Rβ链。在两种情况下,都是随后将过滤器用更换几次的TBS+0.15%Tween20洗涤30分钟,并且在包含1/5000稀释度的辣根过氧化酶轭合的抗-兔IgG(Amersham,产品#NA934)的洗涤缓冲液中孵育1小时,然后再次洗涤并且根据生产商的介绍使用ECL化学发光系统(Amersham)显影。除非另有说明,所用的试剂来自Sigma-Aldrich,St.Louis,MO,USA。
在初级的人成纤维细胞中的生长因子诱导的S6核糖体蛋白磷酸化
使用S6核糖体蛋白在响应于正常人皮肤成纤维细胞(NHDF)的生长因子刺激中的磷酸化作用来评价化合物抑制细胞中IGF-1诱导的信号传导的效力,以及对EGF和PDGF刺激的选择性。将得自PromoCell(Heidelberg,Germany)的NHDF细胞在37℃保持在含5%CO2的湿润气氛中在完全成纤维细胞生长培养基(complete Fibroblast Growth Medium,PromoCell)中。对于试验,将NHDF以5000细胞/孔的密度接种在384孔组织培养板(透明的平底黑色板;Matrix Technologies Inc.,Hudson,NH,USA)中的包含0.1%牛血清白蛋白(BSA)的无血清培养基中并且培养5天。将饥饿的细胞用所需剂量的化合物处理1小时,然后用10nM IGF-1(Invitrogen Corp.,CA,USA),10nM EGF(Gibco BRL,USA)或1nM PDGF-B/B(Roche Diagnostics GmbH,Germany)再刺激2小时。然后将细胞在PBS/3.7%多聚甲醛中在室温固定20分钟,用PBS洗涤2次,并且用PBS/0.3%Triton X-100渗透化处理15分钟。然后将孔用PBS/1%脱脂奶粉(Bio-Rad Laboratories,Hercules,CA,USA)饱和1小时,然后在PBS/1%奶/0.3%Tween20中在37℃用1/200稀释度的抗-磷酸-S6(Ser235/236)抗体(CellSignaling Technology,Beverly,MA,USA,cat.#2211)引入探针。然后将孔用PBS洗涤两次,并且在37℃与PBS/1%奶/0.3%Tween20+1μg/mL DAPI(4,6-二脒基-2-苯基吲哚)+1/500山羊抗-兔Cy5TM-结合的二次抗体(Amersham Biosciences,Little Chalfont,Buckinghamshire,UK)孵育1小时。然后将孔用PBS洗涤2次,并将40μL PBS分配在每个孔中,用于免疫荧光分析。自动获得在DAPI和Cy5TM通道中的荧光图像,使用CellomicsArrayScanTM IV仪器(Cellomics,Pittsburgh,USA)储存和分析;使用CellomicsCytotoxicity Algorithm以每种细胞使用10场/孔来量化与磷酸-S6(Cy5TM信号参数:“MeanLyso Mass-pH”)有关的胞质荧光,并且最终表示为平均种群数值。除非另有说明,试剂来自Sigma-Aldrich,St.Louis,MO,USA。
关于Aurora-2激酶活性抑制剂的生化试验
以与对于IGF-1R所述相同的方法进行体外激酶抑制试验。然而,与IGF-1R的不同之处在于,Aurora-2酶不需要预先活化。
i.用于Aurora-2的激酶缓冲液(KB)
所述激酶缓冲液由50mM HEPES,pH7.0,10mM MgCl2,1mM DTT,3μM Na3VO4,和0.2mg/mL BSA组成。
ii.用于Aurora-2的试验条件(最终浓度)
激酶试验使用2.5nM的酶浓度,10μM ATP,1nM33P-γ-ATP和8μM底物进行,由4个LRRWSLG重复组成
关于Aurora-2激酶活性抑制剂的基于细胞的试验
关于Aurora-2激酶活性抑制剂的体外细胞增殖试验
将人结肠癌细胞系HCT-116以5000细胞/cm2接种在24孔板(Costar)中,使用补充有10%FCS(EuroClone,Italy)2mM L-谷氨酰胺和1%青霉素/链霉素的F12培养基(Gibco),并且保持在37℃、5%CO2和96%相对湿度的条件下。第二天,将板用5mL的适当稀释度的化合物一式两份进行处理,所述稀释度从在DMSO中的10mM储备液开始。每个板中包括两个未经处理的对照孔。在处理72小时之后,将培养基抽出并使用0.5mL的0.05%(w/v)Trypsin,0.02%(w/v)EDTA(Gibco)使细胞从每个孔脱离。将样品用9.5mL的Isoton(Coulter)稀释并且使用Multisizer3细胞计数器(Beckman Coulter)计数。将数据作为对照孔的百分比进行评价:
CTR的%=(受处理的-空白)/(对照-空白)。
使用Microsoft Excel S形曲线拟合来进行LSW/数据分析,计算IC50值。
从上述试验中得出结论,本发明式(I)的化合物导致具有显著的蛋白激酶抑制活性,一般具有低于10μM的IC50。
例如,参见下表1,其中报告了在生化试验中作为ALK、IGF-1R和Aurora-2激酶抑制剂测定的本发明某些有代表性的化合物的实验数据(IC50μM)。
表1.
从所有上述结果中可以看出,本发明的新的式(I)化合物在因蛋白 激酶活性失调导致的疾病,例如癌症的疗法中表现为特别有利。
本发明的化合物可以作为单独的活性剂给药,或者做为选择,与已知的抗癌疗法例如放射治疗或化疗方案组合,例如与抗激素药(例如抗雌激素药、抗雄激素药、和芳香酶抑制剂)、拓扑异构酶I抑制剂、拓扑异构酶II抑制剂、靶向微管的药物、铂类药物、烷化剂、DNA损伤或嵌入剂、抗肿瘤药、抗代谢药、其它激酶抑制剂、其它抗血管生成因子、驱动蛋白的抑制剂、治疗用单克隆抗体、mTOR的抑制剂、组蛋白脱乙酰基酶抑制剂、法尼基转移酶抑制剂、和缺氧响应的抑制剂相组合。
如果配制为固定剂量,这种组合产品在如下所述的剂量范围内使用本发明的化合物以及在批准的剂量范围内使用其它药学活性剂。
在不适合使用组合制剂时,式(I)的化合物可以与已知的抗癌剂依次地使用。
适合于对哺乳动物给药(例如,对人给药)的本发明的式(I)的化合物可以通过常用的途径给药,并且剂量水平取决于患者的年龄、体重和病况以及给药途径。
例如,用于式(I)的化合物口服给药的合适剂量可以是大约10到大约500mg每剂量,每天1-5次。本发明的化合物可以以多种剂型给药,例如以片剂、胶囊、糖衣片或薄膜衣片、液体溶液或混悬液的形式口服给药;以栓剂的形式直肠给药;非肠道给药例如,肌内注射,或者通过静脉内和/或鞘内和/或脊柱内注射或输注给药。
本发明还包括药物组合物,其包括与药学可接受的赋形剂结合的式(I)的化合物或其药学可接受的盐,所述赋形剂可以是载体或稀释剂。
包含本发明化合物的药物组合物通常根据常规方法制备并且以合适的药物形式给药。
例如,固体口服形式可以包含活性化合物、以及稀释剂,例如,乳糖、葡萄糖、二糖、蔗糖、纤维素、玉米淀粉或马铃薯淀粉;润滑剂,例如,二氧化硅、滑石粉、硬脂酸、硬脂酸镁或硬脂酸钙、和/ 或聚乙二醇;粘合剂,例如,淀粉、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素或聚乙烯基吡咯烷酮;崩解剂,例如,淀粉、海藻酸、藻酸盐、或淀粉羟乙酸钠;泡腾混合物;染料;甜味剂;润湿剂,例如卵磷脂,聚山梨酯、月桂基硫酸盐;和通常用于药物制剂中的无毒的和药理学无活性的物质。这些药物制剂可以通过已知的方式生产,例如通过混合、制粒、压片、包糖衣、或包薄膜衣的方法。
用于口服给药的液体分散体可以是例如,糖浆、乳剂和混悬剂。
例如,糖浆可以包含作为载体的蔗糖或蔗糖与甘油和/或甘露醇和山梨醇。
混悬剂和乳剂可以包含作为载体的例如天然胶、琼脂、海藻酸钠、果胶、甲基纤维素、羧甲基纤维素、或聚乙烯醇。
用于肌肉注射的混悬液或溶液可以包含活性化合物以及药学可接受的载体,例如,无菌水、橄榄油、油酸乙酯、二醇,例如,丙二醇,和在需要的情况下包含适量的盐酸利多卡因。
用于静脉注射或输注的溶液可以包含作为载体的无菌水,或者优选它们可以是无菌的、含水的、等渗的盐水溶液形式,或者它们可以包含丙二醇作为载体。
栓剂可以包含活性化合物以及药学可接受的载体,例如,可可脂、聚乙二醇、聚氧乙烯山梨糖醇酐脂肪酸酯表面活性剂或卵磷脂。
实验部分
对于本发明任意具体的式(I)的化合物、其任选的药学可接受的盐形式,参见实验部分和权利要求。就如下的实施例而言,使用本文所述的方法或本领域众所周知的其它方法合成本发明的化合物。
本文所用的短语和缩写具有如下含义:
为了更好地示例本发明,而非做出对其的任何限定,给出了下列实施例。
本文所用的符号以及在方法、方案和实施例中使用的规定与现有科学文献,例如Journal of the American Chemical Society或Journal of Biological Chemistry中使用的那些一致。
除非另有注解,否则所有原料均获自商品供应商,具有最佳等级并且无需进一步纯化使用。无水溶剂,例如DMF,THF,CH2Cl2和甲苯获自Aldrich化学公司。所有涉及空气或湿度敏感性的化合物的反应均在氮气或氩气环境中进行。
一般的纯化和分析方法
在硅胶(Merck grade9395,60A)上进行快速色谱法。HPLC在Waters X Terra RP18(4.6x50mm,3.5μm)柱上进行,使用装备有996Waters PDA检测器和Micromass mod.ZQ单四极质谱仪的Waters2790HPLC系统,所述质谱仪装备有电喷射(ESI)离子源。流 动相A是乙酸铵5mM缓冲液(用乙酸-乙腈95:5调节pH5.5),流动相B是水-乙腈(5:95)。梯度为在8分钟内从10-90%B,在90%B保持2分钟。在220nm和254nm进行UV检测。流速为1mL/min。注射体积为10μL。从100-800amu的质量范围进行全扫描。毛细管电压是2.5KV;源温度是120℃;锥电压是10V。保留时间(HPLC,室温)以分钟给出,在220nm或在254nm。质量表示为m/z比。
如果需要,通过在Waters Symmetry C18(19x50mm,5μm)柱或在Waters X TerraRP18(30x150mm,5μm)柱上进行制备型HPLC来纯化化合物,使用装备有996Waters PDA检测器和Micromass mod.ZMD单四极质谱仪的Waters制备型HPLC600进行,使用电喷雾电离,阳极模式。使用:酸性法∶流动相A是水-0.01%三氟乙酸,流动相B是乙腈;梯度为在8分钟内从10-90%的B,在90%B保持2分钟;流速为20mL/min。或者,碱性法∶流动相A是水-0.1%NH3,流动相B是乙腈;梯度为在8分钟内从10-100%的B,在100%的B保持2分钟;流速为20mL/min。
1H-NMR谱测定在装备有5mm双共振探针[1H(15N-31P)ID_PFGVarian]的以400.45MHz操作的Mercury VX400上进行。
实施例1
步骤a
5-[(3,5-二氟-苯基)-羟基-甲基]-2-氟-苄腈[(XI),R1=R2=R3=H,R=3,5-二氟苯基]
向在氩气环境中的搅拌的镁粉(2.6g,109mmol)在无水四氢呋喃中的混悬液(10mL)中缓慢加入1-溴-3,5-二氟-苯(21g,109mmol)在干四氢呋喃(90mL)中的溶液。搅拌该反应混合物并且在90℃下加热至全部镁耗尽(1小时)。此后,将该反应体系在-10℃下冷却并且在30min过程中加入2-氟-5-甲酰基-苄腈(13.5g,90.6mmol)在100mL无水四氢呋喃中的溶液。1小时后,通过滴加200mL20%氯化铵溶液使该反应混合物骤冷。加入乙酸乙酯,分离各层并且用乙酸乙酯萃 取水层两次。收集有机层,用盐水洗涤、干燥并蒸发。将粗产物与异丙基醚/己烷1:1(100mL)一起研磨,过滤并且用相同的混合物(50mL)洗涤而得到16g终产物。通过硅胶色谱法纯化得到的有机相(己烷/EtOAc4:1),得到4.5g标题化合物(总量20.5g,87%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):5.82(d,J=4.02Hz,1H)6.41(d,J=4.02Hz,1H)7.05-7.12(m,1H)7.12-7.18(m,2H)7.46-7.50(m,1H)7.80(td,J=5.76,2.62Hz,1H)7.97(dd,J=6.34,2.19Hz,1H)
按照同样方式操作获得下列化合物:
5-(苯基-羟基-甲基)-2-氟-苄腈[(XI),R1=R2=R3=H,R=苯基]
ESI(+)MS:m/z245(MNH4 +)。
步骤b
5-(3,5-二氟-苯甲酰基)-2-氟-苄腈[(X),R1=R2=R3=H,R=3,5-二氟苯基]
将5-[(3,5-二氟-苯基)-羟基-甲基]-2-氟-苄腈(2.68g,10.2mmol),4-甲基吗啉N-氧化物一水合物(2.02g,15mmol)和过钌酸四丙基铵(35mg,0.1mmol)在干二氯甲烷(50mL)中的混合物在室温下搅拌2小时。蒸发该反应混合物,将残余物再溶于乙酸乙酯。用10%亚硫酸氢钠和饱和氯化铵洗涤有机相、干燥并蒸发。粗产物通过硅胶色谱法纯化(EtOAc/己烷),得到2.05g标题化合物(77%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.43-7.50(m,2H)7.61-7.68(m,1H)7.72(t,J=9.02Hz,1H)8.17(ddd,J=8.84,5.30,2.32Hz,1H)8.35(dd,J=6.22,2.20Hz,1H)
按照同样方式操作获得下列化合物:
5-苯甲酰基-2-氟-苄腈[(X),R1=R2=R3=H,R=苯基]
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.59(t,J=7.81Hz,2H)7.72(m,2H)7.78(dd,J=8.30,1.46Hz,2H)8.13(ddd,J=8.79,5.37,2.20Hz,1H)8.28(dd,J=6.10,2.20Hz,1H)
步骤c
(3-氨基-1H-吲唑-5-基)-(3,5-二氟-苯基)-甲酮[(IX),R1=R2=R3=H,R=3,5-二氟苯基]
将5-(3,5-二氟-苯甲酰基)-2-氟-苄腈(2.05g,7.84mmol)和水合肼(0.73mL,15.7mmol)在干四氢呋喃(100mL)中的混合物在室温下搅拌2小时。用37%盐酸(1.3mL,15.7mmol)将该反应混合物处理30分钟,然后部分蒸发挥发性物质。然后用水(100mL)稀释该反应混合物并且加入NH3水以达到中性pH。过滤得到的固体,用水充分洗涤并且在真空中和60℃下干燥。得到标题化合物,为黄色固体(1.75g,80%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):5.75(br.s.,2H)7.33-7.36(m,1H)7.36-7.40(m,2H)7.52-7.59(m,1H)7.75(dd,J=8.84,1.65Hz,1H)8.27(dd,J=1.59,0.73Hz,1H)11.95(br.s.,1H)
按照同样方式操作获得下列化合物:
(3-氨基-1H-吲唑-5-基)-(3-乙氧基-苯基)-甲酮[(IX),R1=R2=R3=H,R=3-乙氧基苯基]
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.36(t,J=7.01Hz,3H)4.11(q,J=6.95Hz,2H)7.20-7.24(m,2H)7.25-7.28(m,1H)7.41(dd,J=8.84,0.55Hz,1H)7.48(td,J=7.68,0.61Hz,1H)7.80(dd,J=8.78,1.59Hz,1H)8.34(d,J=0.85Hz,1H)12.24(br.s.,1H)
(3-氨基-1H-吲唑-5-基)-苯基-甲酮[(IX),R1=R2=R3=H,R=苯基]
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.40(dd,J=8.78,0.61Hz,1H)7.57(tt,J=7.68,1.59Hz,2H)7.66(tt,J=7.32,2.07Hz,1H)7.72(dt,J=6.83,1.34Hz,2H)7.78(dd,J=8.78,1.59Hz,1H)8.31(m,1H)12.15(br.s.,1H)
步骤d
N-[5-(3,5-二氟-苯甲酰基)-1H-吲唑-3-基]-2,2,2-三氟-乙酰胺[(VIII),R1=R2=R3=H,R=3,5-二氟苯基,PG1=三氟乙酰基]
用三氟乙酐(4.2mL,30mmol)处理(3-氨基-1H-吲唑-5-基)-(3,5-二氟-苯基)-甲酮(2.73g,10mmol)在干四氢呋喃(120mL)中的混悬液并且在室温下搅拌1小时。蒸发该溶液,用甲醇处理并且进一步蒸发至干。将残余物再溶于乙酸乙酯并且用碳酸氢盐水溶液洗涤。分离有机相、干燥并蒸发。将该固体与少量二氯甲烷一起研磨并且过滤而得到3.25g(88%收率)标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.39-7.46(m,2H)7.56-7.64(m,1H)7.68(dd,J=8.84,0.67Hz,1H)7.86(dd,J=8.84,1.65Hz,1H)8.28-8.32(m,1H)12.16(s,1H)13.50(s,1H)
按照同样方式操作获得下列化合物:
N-[5-(3-乙氧基-苯甲酰基)-1H-吲唑-3-基]-2,2,2-三氟-乙酰胺[(VIII),R1=R2=R3=H,R=3-乙氧基苯基,PG1=三氟乙酰基]
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.34(t,J=6.95Hz,3H)4.10(q,J=6.95Hz,2H)7.19-7.25(m,2H)7.28(d,J=7.56Hz,1H)7.43-7.50(m,1H)7.67(d,J=8.90Hz,1H)7.85(dd,J=8.84,1.52Hz,1H)8.26(s,1H)12.14(s,1H)13.46(s,1H)
步骤e
N-[5-(3,5-二氟-苯甲酰基)-1-三苯甲基-1H-吲唑-3-基]-2,2,2-三氟-乙酰胺[(VII),R1=R2=R3=H,R=3,5-二氟苯基,PG=三苯基甲基,PG1=三氟乙酰基]
用氯代三苯基甲烷(14.72g,52.8mmol)和三乙胺(14.55mL,103.5mmol)处理在干二氯甲烷(300mL)中的N-[5-(3,5-二氟-苯甲酰基)-1H-吲唑-3-基]-2,2,2-三氟-乙酰胺(19.11g,51.76mmol)。在室温下搅拌2天后,用NH4Cl溶液洗涤该反应体系、干燥并蒸发。通过硅胶色谱法(DCM/MeOH)纯化粗产物,得到27.32g标题化合物(86%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):6.57(d,J=8.90Hz,1H)7.20(m,6H)7.29-7.40(m,11H)7.58(m,2H)8.22(d, J=1.10Hz,1H)12.27(s,1H)
按照同样方式操作获得下列化合物:
N-[5-(3-乙氧基-苯甲酰基)-1-三苯甲基-1H-吲唑-3-基]-2,2,2-三氟-乙酰胺[(VII),R1=R2=R3=H,R=3-乙氧基苯基,PG=三苯基甲基,PG1=三氟乙酰基]
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.33(t,J=6.95Hz,3H)4.10(q,J=6.95Hz,2H)6.56(d,J=9.02Hz,1H)7.17-7.39(m,18H)7.41-7.47(m,1H)7.54(dd,J=9.08,1.65Hz,1H)8.18(d,J=0.98Hz,1H)12.25(s,1H)
步骤f
(3-氨基-1-三苯甲基-1H-吲唑-5-基)-(3,5-二氟-苯基)-甲酮[(VI),R1=R2=R3=H,R=3,5-二氟苯基,PG=三苯基甲基]
将N-[5-(3,5-二氟-苯甲酰基)-1-三苯甲基-1H-吲唑-3-基]-2,2,2-三氟-乙酰胺(6.12g,10mmol)在100℃下,在异丙醇/四氢呋喃8:2(100mL)和三乙胺(12.2mL)的混合物中加热48小时。部分蒸发挥发性物质,冷却并过滤得到的混合物。用乙醚洗涤该固体。在真空中和70℃下干燥后,得到标题化合物,为白色固体(5.1g,99%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):5.98(br.s.,2H)6.35(d,J=8.90Hz,1H)7.20-7.37(m,17H)7.48(dd,J=9.08,1.77Hz,1H)7.50-7.57(m,1H)8.23(d,J=1.10Hz,1H)
按照同样方式操作获得下列化合物:
(3-氨基-1-三苯甲基-1H-吲唑-5-基)-(3-乙氧基-苯基)-甲酮[(VI),R1=R2=R3=H,R=3-乙氧基苯基,PG=三苯基甲基]
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.33(t,J=6.95Hz,3H)4.07(q,J=6.95Hz,2H)5.93(s,2H)6.36(d,J=9.02Hz,1H)7.12-7.34(m,18H)7.40-7.46(m,2H)8.22(d,J=1.10Hz,1H)
步骤g
N-[5-(3,5-二氟-苯甲酰基)-1-三苯甲基-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺[(V),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-硝基-苯基,PG=三苯基甲基]
向4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酸盐酸盐(1.5g,4.97mmol)在干四氢呋喃(80mL)中的混悬液中加入草酰氯(1.4mL,19.9mmol)和N,N-二甲基甲酰胺(1-2滴)。将该混合物在室温下搅拌过夜,然后蒸发至干。将得到的粗的酰氯溶于甲苯并且再次蒸发,然后溶于干四氢呋喃(180mL)。将(3-氨基-1-三苯甲基-1H-吲唑-5-基)-(3,5-二氟-苯基)-甲酮(1.83g.3.55mmol)和N,N-二异丙基乙胺(2.5mL,14.22mmol)在干四氢呋喃(15mL)中的溶液加入到该反应混合物中。将该混合物在室温下搅拌过夜,然后在75℃下搅拌2小时。蒸发挥发性物质,将残余物溶于二氯甲烷,用盐水洗涤。用硫酸钠干燥有机相并且蒸发至干。通过硅胶色谱法(DCM/MeOH)纯化粗产物,得到2.51g标题化合物,为黄色粉末(92%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.22(s,3H)2.40-2.45(m,4H)3.26-3.36(m,4H)6.50(d,J=8.17Hz,1H)7.19-7.50(m,21H)7.56(dd,J=9.15,1.71Hz,1H)8.28-8.30(m,1H)11.22(br.s.,1H)
按照同样方式操作获得下列化合物:
N-[5-(3-乙氧基-苯甲酰基)-1-三苯甲基-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺[(V),R1=R2=R3=H,R=3-乙氧基苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-硝基-苯基,PG=三苯基甲基]
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.34(t,J=6.95Hz,3H)2.24(m,3H)2.45(m,4H)3.27(m,4H)4.08(q,J=6.95Hz,2H)6.51(d,J=8.17Hz,1H)7.20-7.46(m,22H)7.53(dd,J=9.15,1.71Hz,1H)8.30(m,1H)11.22(br.s.,1H)
步骤h
N-[5-(3,5-二氟-苯甲酰基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺[(II),R1=R2=R3=H,R=3,5-二氟苯基, Ar=4-(4-甲基-哌嗪-1-基)-2-硝基-苯基]
将N-[5-(3,5-二氟-苯甲酰基)-1-三苯甲基-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺(2.76g,3.62mmol),三氟乙酸(5.6mL)和二氯甲烷(56mL)的混合物在室温下搅拌2小时。蒸发挥发性物质,将残余物溶于二氯甲烷,用饱和碳酸氢钠溶液洗涤。将有机相蒸发至干。将残余物再溶于乙酸乙酯并且用盐水洗涤两次。用硫酸钠干燥得到的有机相并且蒸发至干。通过硅胶色谱法(DCM/MeOH)纯化粗产物,从乙醚中研磨由此得到的化合物,从而得到1.47g标题化合物(78%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.25(br.s.,3H)2.47(br.s.,4H)3.29-3.38(m,4H)7.26(dd,J=8.84,2.50Hz,1H)7.37-7.43(m,2H)7.45(d,J=2.44Hz,1H)7.51-7.59(m,1H)7.63(dd,J=8.84,0.55Hz,1H)7.66(br.s.,1H)7.86(dd,J=8.84,1.65Hz,1H)8.36(s,1H)11.13(s,1H)13.21(s,1H)
按照同样方式操作获得下列化合物:
N-[5-(3-乙氧基-苯甲酰基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺[(II),R1=R2=R3=H,R=3-乙氧基苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-硝基-苯基]
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.34(t,J=6.95Hz,3H)2.26-2.34(m,3H)2.46-2.59(m,4H)3.28-3.35(m,4H)4.10(q,J=6.95Hz,2H)7.18-7.21(m,1H)7.24-7.26(m,1H)7.27(dd,J=9.33,1.89Hz,1H)7.29-7.32(m,1H)7.45(t,J=7.87Hz,1H)7.46(d,J=2.32Hz,1H)7.62(d,J=9.02Hz,1H)7.66(d,J=9.88Hz,1H)7.84(dd,J=8.78,1.59Hz,1H)8.39(s,1H)11.13(br.s.,1H)13.17(s,1H)
4-[(3-二甲基氨基-丙基)-甲基-氨基]-N-[5-(3-乙氧基-苯甲酰基)-1H-吲唑-3-基]-2-硝基-苯甲酰胺[(II),R1=R2=R3=H,R=3-乙氧基苯基,Ar=4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-硝基-苯基]
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.33(t,J=6.95Hz, 3H)1.60-1.78(m,2H)2.22(s,6H)2.29-2.37(m,2H)3.01(s,3H)3.48(t,J=7.01Hz,2H)4.09(q,J=6.99Hz,2H)6.98(dd,J=8.84,2.50Hz,1H)7.16-7.21(m,2H)7.22-7.25(m,1H)7.27-7.32(m,1H)7.45(t,J=7.93Hz,1H)7.58-7.66(m,2H)7.83(dd,J=8.78,1.59Hz,1H)8.36(s,1H)11.04(s,1H)13.14(s,1H)
步骤i
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-硝基-苯基]cpd.(化合物)6
在氩气环境中将N-[5-(3,5-二氟-苯甲酰基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺(3.61g,6.93mmol)溶于DCM(150mL)并且在搅拌下加入三氟乙酸(150mL)。在72小时过程中逐步加入硼氢化钠颗粒(2.62g,69.3mmol)。蒸发该反应混合物,溶于混合物MeOH/丙酮并且搅拌1小时。将得到的混合物蒸发至干,再溶于MeOH并且加入NaOH8N至达到碱性pH。蒸发粗产物并且加入冰/水,过滤由此形成的固体,用水洗涤并且在真空中和80℃下干燥,得到3.22g标题化合物(92%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.23(s,3H)2.42-2.47(m,4H)3.33-3.38(m,4H)4.05(s,2H)6.91-6.97(m,2H)6.97-7.05(m,1H)7.24(dd,J=8.60,1.52Hz,1H)7.27(br.s.,1H)7.41(d,J=8.66Hz,1H)7.44(br.s.,1H)7.63(s,1H)7.66-7.73(m,1H)10.81(br.s.,1H)12.70(s,1H)
按照同样方式操作得到下列化合物:
4-[(3-二甲基氨基-丙基)-甲基-氨基]-N-[5-(3-乙氧基-苄基)-1H-吲唑-3-基]-2-硝基-苯甲酰胺[(IA),R1=R2=R3=H,R=3-乙氧基苯基,Ar=4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-硝基-苯基]cpd.53
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.26-1.31(m,3H)1.69(t,J=6.77Hz,2H)2.19(s,6H)2.28(br.s.,2H)3.02(s,3H)3.45-3.51(m,2H)3.93-4.00(m,2H)3.96(s,2H)6.70-6.73(m,1H)6.76-6.80(m,1H)6.77(d,J=1.59Hz,1H)6.98(d,J=8.90Hz,1H)7.14-7.19(m,1H)7.19-7.23(m,2H)7.38(d,J=8.66Hz,1H)7.61(s,1H)7.67(d,J=10.00Hz,1H)10.72(br.s.,1H)12.65(s,1H)
N-{5-[(3,5-二氟-苯基)-羟基-甲基]-1H-吲唑-3-基}-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺[(IB),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.60
将N-[5-(3,5-二氟-苯甲酰基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺(130mg,0.226mmol)和硼氢化钠(15mg,0.39mmol)的混合物在室温下溶于异-丙醇(20mL)。将该反应混合物搅拌4小时,用甲醇骤冷并且蒸发至干。将粗产 物再溶于DCM并且用盐水洗涤。在与乙醚一起研磨后,回收59mg标题化合物(45%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.26-1.41(m,2H)1.89-1.99(m,2H)2.23(s,3H)2.39-2.47(m,4H)3.21-3.29(m,4H)3.45-3.55(m,2H)3.63-3.74(m,1H)3.76-3.86(m,2H)5.81(d,J=4.15Hz,1H)6.12(d,J=4.15Hz,1H)6.14(d,J=2.07Hz,1H)6.24(dd,J=9.08,2.26Hz,1H)6.96-7.04(m,1H)7.05-7.12(m,2H)7.27-7.36(m,1H)7.37-7.43(m,1H)7.64(s,1H)7.80(d,J=9.15Hz,1H)8.31(d,J=7.56Hz,1H)10.09(s,1H)12.63(s,1H)
N-{5-[(3-乙氧基-苯基)-羟基-甲基]-1H-吲唑-3-基}-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺[(IB),R1=R2=R3=H,R=3-乙氧基苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-硝基-苯基]cpd.67
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.29(t,J=6.95Hz,3H)2.24(s,3H)2.42-2.47(m,4H)3.36(m,4H)3.97(q,J=6.95Hz,2H)5.70(d,J=3.90Hz,1H)5.85(d,J=3.90Hz,1H)6.72(ddd,J=8.17,2.56,0.73Hz,1H)6.90(d,J=7.68Hz,1H)6.93(dd,J=2.20,1.46Hz,1H)7.17(t,J=7.87Hz,1H)7.26(d,J=8.78Hz,1H)7.28(dd,J=8.72,1.40Hz,1H)7.36(d,J=8.78Hz,1H)7.44(d,J=2.07Hz,1H)7.70(d,J=6.71Hz,1H)7.81(br.s.,1H)10.80(br.s.,1H)12.65(s,1H)。
实施例2
步骤j
5-(3,5-二氟-苄基)-2-氟-苄腈[(XIV),R1=R2=R3=H,R=3,5-二 氟苯基]
在氮气环境中和60℃下的乙腈(50mL)中搅拌5-[(3,5-二氟-苯基)-羟基-甲基]-2-氟-苄腈(3.5g,13.3mmol)和碘化钠(20g,133mmol)。在8小时内向该反应混合物中逐步加入氯代三甲基硅烷(17mL,134mmol)。用乙酸乙酯稀释该混合物并且用水、饱和碳酸氢钠水溶液、10%硫代硫酸钠水溶液和盐水洗涤。通过硅胶色谱法纯化粗产物(EtOAc/己烷5:100),得到3.1g标题化合物(88%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.02(s,2H)7.02-7.11(m,3H)7.47(t,J=9.08Hz,1H)7.68-7.74(m,1H)7.90(dd,J=6.22,2.19Hz,1H)
按照同样方式操作获得下列化合物:
5-苄基-2-氟-苄腈[(XIV),R1=R2=R3=H,R=苯基]
ESI(+)MS:m/z229(MNH4 +)。
步骤k
5-(3,5-二氟-苄基)-2-氟-苄腈[(XIV),R1=R2=R3=H,R=3,5-二氟苯基]
在氩气环境中的烘干烧瓶中加入3-氰基-4-氟苯基硼酸(1.649g,10mmol),磷酸钾粉末(4.254g,20mmol)和Pd(PPh3)4(231mg,0.2mmol)。将烧瓶抽真空并且反充氩气三次,然后在搅拌下通过注射器经筛格塞加入甲苯(30mL)和3,5-二氟苄基溴(1.295mL,10mmol)。在半小时内将该反应混合物加热至100℃并且维持在该温度下1.5小时。将黑色混合物溶于乙醚(200mL),用饱和氯化铵水溶液(2x20mL)、盐水(3x30mL)洗涤,用硫酸钠干燥并且蒸发至干而得到3.21g黄色油状物。通过硅胶快速色谱法纯化粗产物,用正-己烷/乙酸乙酯95:5洗脱,得到1.89g(收率76.4%)带白色的固体。
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.02(s,2H)7.02-7.11(m,3H)7.47(t,J=9.08Hz,1H)7.68-7.74(m,1H)7.90(dd,J=6.22,2.19Hz,1H)
按照同样方法制备下列化合物:
5-(2,5-二氟-苄基)-2-氟-苄腈
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.01(s,2H),7.09-7.17(m,1H),7.20-7.27(m,2H),7.46(t,J=9.08Hz,1H),7.64(m,1H),7.82(dd,J=6.22,2.19Hz,1H)
2-氟-5-(5-氟-2-甲基-苄基)-苄腈
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.18(s,3H),4.01(s,2H),7.00(m,2H),7.22(m,1H),7.48(t,J=9.08Hz,1H),7.56(m,1H),7.75(dd,J=6.22,2.19Hz,1H)
2-氟-5-(3-氟-苄基)-苄腈
1H-NMR(400MHz),δ(ppm,DMSO-d6):3.98(s,2H),6.95-7.15(m,3H),7.27-7.38(m,1H),7.38-7.48(t,1H),7.61-7.70(m,1H),7.81-7.87(dd,J=6.22,2.19Hz.1H)。
2-氟-5-吡啶-3-基甲基-苄腈
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.03(s,2H)7.33(ddd,J=7.83,4.79,0.79Hz,1H)7.47(t,J=9.02Hz,1H)7.65-7.68(m,1H)7.68-7.72(m,1H)7.89(dd,J=6.28,2.01Hz,1H)8.44(dd,J=4.76,1.59Hz,1H)8.54(d,J=1.71Hz,1H)
步骤l
5-(3,5-二氟-苄基)-1H-吲唑-3-基胺[(IIIA),R1=R2=R3=H,R=3,5-二氟苯基]
将5-(3,5-二氟-苄基)-2-氟-苄腈(20g,80.9mmol)和水合肼(19.6mL,404mmol)在正-丁醇(200mL)中的混合物在120℃下加热过夜。用水/乙酸乙酯稀释该反应混合物,并用盐水将有机相洗涤两次、干燥并蒸发。将粗产物与乙醚一起研磨并且过滤而得到13gr终产物。通过硅胶色谱法纯化得到的有机相(DCM/EtOH95:5),得到6.3g标题化合物(总量19.2g,92%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.01(s,2H)5.23(s,2H)6.89-6.98(m,2H)7.03(tt,J=9.43,2.33Hz,1H)7.11-7.15(m,1H)7.16-7.20(m,1H)7.53(s,1H)11.30(s,1H)
按照同样方法制备下列化合物:
5-(2,5-二氟-苄基)-1H-吲唑-3-基胺
1H-NMR(400MHz),δ(ppm,DMSO-d6):3.99(s,2H),5.28(m,2H),7.05-7.25(m,5H),7.51(s,1H),11.30(bs,1H)。
5-(5-氟-2-甲基-苄基)-1H-吲唑-3-基胺
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.21(s,3H),3.97(s,2H),5.22(bs,2H),7.43(s,1H),7.14-7.20(m,2H),7.06(dd,1H),6.87-6.97(m,2H),11.27(bs,1H)。
5-(3-氟-苄基)-1H-吲唑-3-基胺
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.00(s,2H),5.22(bs,2H),6.96-7.09(m,3H),7.11(m,1H),7.15(m,1H),7.29-7.37(m,1H),7.53(s,1H),11.27(s,1H)。
5-吡啶-3-基甲基-1H-吲唑-3-基胺
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.01(s,2H)5.23(br.s.,2H)7.08-7.15(m,1H)7.15-7.19(m,1H)7.25-7.34(m,1H)7.53(s,1H)7.60(dt,J=7.86,1.92Hz,1H)8.40(dd,J=4.69,1.65Hz,1H)8.51(d,J=1.83Hz,1H)11.28(s,1H)
5-苄基-1H-吲唑-3-基胺
1H-NMR(400MHz),δ(ppm,DMSO-d6):3.97(s,2H)5.21(s,2H)7.07-7.11(m,1H)7.13-7.16(m,1H)7.16-7.20(m,1H)7.20-7.24(m,2H)7.25-7.31(m,2H)7.52(s,1H)11.25(s,1H)。
步骤n
5-[1-(3,5-二氟-苯基)-乙基]-2-氟-苄腈[(XIXD1),R1=R2=R3=H,R=3,5-二氟苯基,R'=甲基]
在氮气环境中和-20℃下将5-(3,5-二氟-苄基)-2-氟-苄腈(450mg,1.82mmol)溶于干THF(14mL)并且在搅拌下加入碘甲烷(0.17mL,2.73mmol)。逐步加入双-(三甲基甲硅烷基)-氨基锂在THF中1.0M(0.684ml,3.64mmol)的溶液。20分钟后,通过添加KHSO410%溶液使反应猝灭并且用乙酸乙酯萃取。用KHSO410%水溶液和盐水洗涤有机相,用硫酸钠干燥并且蒸发至干。通过硅胶快速色谱法纯化粗产物,使用己烷/乙酸乙酯98/2作为洗脱剂。分离标题产物,为油状物(400mg,84%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.59(d,J=7.32Hz,3H)4.31(q,J=7.19Hz,1H)7.08(m,3H)7.46(t,J=9.15Hz,1H)7.73(m,1H)7.95(dd,J=6.22,2.44Hz,1H)
步骤l'''
5-[1-(3,5-二氟-苯基)-乙基]-1H-吲唑-3-基胺[(IIID1),R1=R2=R3=H,R=3,5-二氟苯基,R'=甲基]
将5-[1-(3,5-二氟-苯基)-乙基]-2-氟-苄腈(324mg,1.24mmol)溶于正-丁醇(3mL)并且加入水合肼(0.301mL,6.20mmol)。将该反应混合物在120℃下搅拌22小时,然后通过添加水/乙酸乙酯骤冷。分离有机相,用水和盐水洗涤,用硫酸钠干燥并且蒸发至干。通过硅胶色谱法纯化粗产物,用DCM/EtOH99/1-98/2梯度洗脱。分离标题产物,为油状物(96mg,39%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.61(d,J=7.19Hz,3H)4.25(q,J=7.32Hz,1H)5.26(br.s,5.26,2H)6.99(m,3H)7.12(dd,J=8.66,1.59Hz,1H)7.16(dd,J=8.54,0.73Hz,1H)7.62(br.s,1H)11.29(s,1H)
步骤i'
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.11
向4-(4-甲基-哌嗪-1-基)-2-[(四氢-吡喃-4-基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸三氟乙酸盐(10g,22.1mmol)在干二氯甲烷(300mL)中的混悬液中加入草酰氯(3.58mL,42.3mmol)和N,N-二甲基甲酰胺(1-2滴)。将该混合物在室温下搅拌2小时,然后蒸发至干。将所得粗的酰基氯溶于甲苯并且再次蒸发,然后在-20℃下溶于干四氢呋喃(130mL)。将5-(3,5-二氟-苄基)-1H-吲唑-3-基胺(5g.19.28mmol)和N,N-二异丙基乙胺(12.8mL,73.3mmol)在干THF(40mL)中的溶液加入到冷却的反应混合物中。将该混合物在-20℃下搅拌4小时,然后通过添加水/乙酸乙酯骤冷。用饱和碳酸氢钠溶液洗涤有机相,用硫酸钠干燥并且蒸发至干。
通过硅胶快速色谱法纯化粗产物,使用二氯甲烷/乙醇100:10作为洗脱剂,得到中间体N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-[(四氢-吡喃-4-基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酰胺,为淡黄色固体。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.25-1.41(m,1H)1.48-1.61(m,1H)1.66(d,J=9.02Hz,1H)1.92(d,J=9.15Hz,1H)2.25(s,3H)2.43-2.49(m,4H)3.23-3.41(m,6H)3.77(dd,J=10.91,4.21Hz,1H)3.87(dd,J=11.65,3.96Hz,1H)4.02(s,2H)4.37-4.49(m,1H)6.89(d,J=2.44Hz,1H)6.90-6.98(m,2H)7.02(tt,J=9.42,2.29Hz,1H)7.09(dd,J=8.78,2.44 Hz,1H)7.27(dd,J=8.72,1.40Hz,1H)7.41-7.43(m,2H)7.83(d,J=8.78Hz,1H)10.52(s,1H)12.69(s,1H)
或者,可以将预先未纯化的粗反应混合物在三乙胺(60mL)存在下溶于甲醇(375mL)并且在65℃下搅拌2小时。减压除去溶剂并且用水/乙酸乙酯处理残余物。用硫酸钠干燥有机相并且蒸发至干。通过硅胶色谱法(DCM/EtOH/在MeOH中的NH35N=1000/50/5)纯化粗产物并且使由此得到的化合物从EtOAc/己烷中结晶,得到8.4g标题化合物,为白色固体(78%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.26-1.43(m,2H)1.86-2.02(m,2H)2.23(s,3H)2.42-2.46(m,4H)3.23-3.29(m,4H)3.45-3.54(m,2H)3.62-3.75(m,1H)3.82(dt,J=11.61,3.83Hz,2H)4.05(s,2H)6.14(d,J=2.07Hz,1H)6.24(dd,J=8.90,2.19Hz,1H)6.94-7.06(m,3H)7.26(dd,J=8.66,1.46Hz,1H)7.41(d,J=8.66Hz,1H)7.50(d,1H)7.80(d,J=9.15Hz,1H)8.29(d,J=7.68Hz,1H)10.08(s,1H)12.63(s,1H)。
按照同样方式操作获得下列化合物:
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-(3-甲氧基-丙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-(3-甲氧基-丙基氨基)-苯基]cpd.36
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.80(五重峰,J=6.49Hz,2H)2.24(s,3H)2.42-2.47(m,4H)3.16-3.21(m,2H)3.23(s,3H)3.26-3.32(m,4H)3.41(t,J=6.16Hz,2H)4.04(s,2H)6.07(d,J=2.19Hz,1H)6.24(dd,J=9.02,2.19Hz, 1H)6.95-7.00(m,2H)6.99-7.04(m,1H)7.24(dd,J=8.66,1.59Hz,1H)7.41(d,J=8.54Hz,1H)7.51(s,1H)7.80(d,J=9.15Hz,1H)8.19(t,J=5.12Hz,1H)10.07(s,1H)12.62(s,1H)
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-苯基]cpd.4
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.23(s,3H)2.44-2.49(m,4H)3.28-3.32(m,4H)4.05(s,2H)6.90-7.00(m,3H)7.02(d,J=9.15Hz,2H)7.24(dd,J=8.66,1.59Hz,1H)7.41(d,J=0.49Hz,1H)7.59(s,1H)7.97(d,J=9.02Hz,2H)10.39(s,1H)12.67(s,1H)
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-((R)-2-甲氧基-1-甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-((R)-2-甲氧基-1-甲基-乙基氨基)-苯基]cpd.32
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.14(d,J=6.34Hz,3H)2.23(s,3H)2.41-2.47(m,4H)3.24-3.31(m,4H)3.27(s,3H)3.32-3.40(m,2H)3.74-3.83(m,1H)4.05(s,2H)6.13(d,J=2.19Hz,1H)6.24(dd,J=9.02,2.20Hz,1H)6.94- 7.04(m,3H)7.25(dd,J=8.66,1.59Hz,1H)7.41(d,J=8.54Hz,1H)7.49(s,1H)7.78(d,J=9.02Hz,1H)8.20(d,J=7.68Hz,1H)10.04(s,1H)12.63(s,1H)
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-(2-甲氧基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-(2-甲氧基-乙基氨基)-苯基]cpd.26
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.25(s,3H)2.44-2.49(m,4H)3.26(s,3H)3.27-3.31(m,6H)3.54(t,J=5.37Hz,2H)4.05(s,2H)6.09(d,J=1.95Hz,1H)6.25(dd,J=8.96,2.01Hz,1H)6.94-7.00(m,2H)6.99-7.05(m,1H)7.24(dd,J=8.60,1.52Hz,1H)7.41(d,J=8.66Hz,1H)7.51(s,1H)7.79(d,J=9.15Hz,1H)8.23(t,J=5.12Hz,1H)10.06(s,1H)12.63(s,1H)
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-硝基-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-硝基-苯基]cpd.59
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.68(m,2H)2.15(m, 6H)2.25(t,J=6.58Hz,2H)3.02(s,3H)3.48(t,J=7.07Hz,2H)4.05(s,2H)6.93-7.05(m,4H)7.19(d,J=2.44Hz,1H)7.26(dd,J=8.54,1.46Hz,1H)7.42(d,J=8.54Hz,1H)7.62(s,1H)7.68(bs,1H)10.73(s,1H)12.69(s,1H)
2-环己基氨基-N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-环己基氨基-苯基]cpd.18
1H-NMR(400MHz),δ(ppm,DMSO-d6):12.61(s,1H)10.04(s,1H)8.26(d,1H)7.77(d,1H)7.48(s,1H)7.40(d,1H)7.25(dd,1H)6.90-7.00(m,3H)6.21(dd,1H)6.08(d,1H)4.03(s,2H)3.45(m,1H)3.25(m,4H)2.45(bs,4H)2.24(s,3H)1.88-1.23(m,10H)
N-{5-[1-(3,5-二氟-苯基)-乙基]-1H-吲唑-3-基}-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺[(ID),R1=R2=R3=R''=H,R=3,5-二氟苯基,R'=甲基,Ar=4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.75
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.29-1.43(m,2H)1.60(d,J=7.19Hz,3H)1.89-1.99(m,2H)2.29(br.s.,3H)2.45-2.57(m,4H)3.22-3.38(m,4H)3.45-3.55(m,2H)3.64-3.76(m,1H)3.78-3.85(m,2H)4.31(q,J=7.40Hz,1H)6.15 (d,J=1.95Hz,1H)6.25(dd,J=8.90,2.19Hz,1H)6.94-7.06(m,3H)7.28(dd,J=8.78,1.59Hz,1H)7.40(d,J=8.54Hz,1H)7.52(s,1H)7.81(d,J=9.15Hz,1H)8.32(d,J=7.68Hz,1H)10.09(s,1H)12.62(s,1H)
通过制备型手性-HPLC,通过使用Daicel Chiralpak AD250x20mm10μm作为柱系统,使用己烷/2-丙醇40:60作为洗脱剂,获得单一对映异构体。
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-[(1-甲氧基-2-甲基丙-2-基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-[(1-甲氧基-2-甲基丙-2-基)氨基]-苯基]cpd.34
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.31(s,6H)2.27(br.s.,3H)2.50(m,4H)3.26(m,7H)3.35(s,2H)4.05(s,2H)6.27(dd,J=9.02,2.32Hz,1H)6.31(d,J=2.32Hz,1H)6.93-7.05(m,3H)7.25(dd,J=8.60,1.52Hz,1H)7.41(d,J=8.54Hz,1H)7.51-7.53(m,1H)7.76(d,J=8.90Hz,1H)8.26(s,1H)10.14(s,1H)12.63(s,1H)
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-(2-甲氧基-1-甲氧基甲基-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-(2-甲氧基-1-甲氧基甲基-乙基氨基)-苯基]cpd.16
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.42(br.s.,3H)2.70(br.s.,4H)3.26(s,6H)3.30(m,4H)3.41(d,J=5.00Hz,4H)3.85(m,J=8.17,5.00,5.00,5.00,5.00Hz,1H)4.04(s,2H)6.20(d,J=1.95Hz,1H)6.26(dd,J=8.96,2.01Hz,1H)6.94-7.04(m,3H)7.24(dd,J=8.66,1.46Hz,1H)7.41(d,J=8.54Hz,1H)7.48(br.s.,1H)7.79(d,J=9.02Hz,1H)8.32(d,J=8.29Hz,1H)10.06(s,1H)12.64(s,1H)
2-苄基氨基-N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-苄基氨基-苯基]cpd.24
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.22(s,3H)2.41(br.s.,4H)3.19-3.24(m,4H)4.04(s,2H)4.39(d,J=5.49Hz,2H)6.09(d,J=2.19Hz,1H)6.26(dd,J=9.02,2.32Hz,1H)6.92-6.98(m,2H)6.98-7.04(m,1H)7.21-7.27(m,2H)7.30-7.36(m,2H)7.36-7.39(m,2H)7.40(d,J=9.02Hz,1H)7.51(s,1H)7.81(d,J=9.02Hz,1H)8.60(t,J=5.55Hz,1H)10.11(s,1H)12.63(s,1H)
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-(2-氟-乙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-(2-氟-乙基氨基)-苯基]cpd. 38
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.24(s,3H)2.43-2.48(m,4H)3.26-3.31(m,4H)3.49(dq,J=27.68,5.12Hz,2H)4.04(s,2H)4.60(dt,J=47.68,4.76Hz,2H)6.12(d,J=2.23Hz,1H)6.28(dd,J=8.99,2.23Hz,1H)6.94-7.00(m,2H)6.99-7.04(m,1H)7.24(dd,J=8.57,1.52Hz,1H)7.41(d,J=8.57Hz,1H)7.51(s,1H)7.81(d,J=8.99Hz,1H)8.37(t,J=5.43Hz,1H)10.11(s,1H)12.63(s,1H)
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-(2-氟-丙基氨基)-4-(4-甲基-哌嗪-1-基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-(2-氟-丙基氨基)-苯基]cpd.40
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.86-2.04(m,2H)2.26(br.s.,3H)2.48(br.s.,4H)3.21-3.37(m,6H)4.04(s,2H)4.44-4.66(dt,J=47.43,5.73Hz,2H)6.09(d,J=1.95Hz,1H)6.26(dd,J=9.02,2.20Hz,1H)6.94-7.05(m,3H)7.25(dd,J=8.60,1.40Hz,1H)7.41(d,J=8.66Hz,1H)7.50(d,J=1.71Hz,1H)7.81(d,J=9.02Hz,1H)8.22(t,J=5.24Hz,1H)10.09(s,1H)12.63(s,1H)
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-[(3-二甲基氨基-丙 基)-甲基-氨基]-2-(四氢-吡喃-4-基氨基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-(四氢-吡喃-4-基氨基)-苯基]cpd.55
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.32-1.44(m,2H)1.67(quin,J=6.98Hz,2H)1.93-1.98(m,2H)2.17(s,6H)2.26(t,J=6.65Hz,2H)2.96(s,3H)3.36-3.43(m,2H)3.44-3.53(m,2H)3.58-3.69(m,1H)3.79-3.87(m,2H)4.05(s,2H)5.87(d,J=2.19Hz,1H)6.04(dd,J=9.02,2.32Hz,1H)6.96-7.05(m,3H)7.25(dd,J=8.60,1.52Hz,1H)7.41(d,J=8.54Hz,1H)7.49(s,1H)7.77(d,J=9.15Hz,1H)8.35(d,J=7.32Hz,1H)9.96(s,1H)12.60(s,1H)
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-苯基氨基-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-苯基氨基-苯基]cpd.42
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.24(s,3H)2.46(br.s.,4H)3.22(br.s.,4H)4.05(s,2H)6.53(dd,J=9.02,2.19Hz,1H)6.74(d,J=2.32Hz,1H)6.95-7.02(m,4H)7.19(d,J=7.56Hz,2H)7.25(dd,J=8.66,1.46Hz,1H)7.29-7.35(m,2H)7.40-7.44(m,1H)7.55(s,1H)7.91(d,J=9.15Hz,1H) 10.03(s,1H)10.39(s,1H)12.69(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基-1,4-二氮杂环庚烷-1-基)-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-1,4-二氮杂环庚烷-1-基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.89
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.31-1.42(m,2H)1.83-1.98(m,4H)2.28(s,3H)2.44-2.49(m,2H)2.63(d,J=4.51Hz,2H)3.44-3.59(m,6H)3.65(d,J=11.46Hz,1H)3.78-3.85(m,2H)4.04(s,2H)5.87(d,J=2.32Hz,1H)6.05(dd,J=9.08,2.26Hz,1H)6.96-7.04(m,3H)7.25(dd,J=8.59,1.52Hz,1H)7.41(d,J=8.53Hz,1H)7.49(s,1H)7.77(d,J=9.14Hz,1H)8.36(d,J=7.68Hz,1H)9.96(s,1H)12.60(s,1H)
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-[(2-二甲基氨基-乙基)-甲基-氨基]-2-(四氢-吡喃-4-基氨基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-[(2-二甲基氨基-乙基)-甲基-氨基]-2-(四氢-吡喃-4-基氨基)-苯基]cpd.90
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.32-1.43(m,2H)1.96(d,1H)2.19-2.22(m,6H)2.40(t,J=7.19Hz,2H)2.98(s,3H)3.41-3.51(m,4H)3.56-3.65(m,1H)3.80-3.87(m,2H)4.04(s,2H)5.87(d,J=2.32Hz,1H)6.02(dd,J=9.08,2.38Hz,1H)6.96-7.04(m,3H)7.25(dd,J=8.59,1.52Hz,1H)7.41(d,J=8.53Hz,1H)7.49(s,1H)7.78(d,J=9.14Hz,1H)8.35(d,J=7.31Hz,1H)9.97(s,1H)12.60(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[4-(二甲基氨基)哌啶-1-基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-[4-(二甲基氨基)哌啶-1-基]-2-(四氢-吡喃-4-基氨基)-苯基]cpd.91
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.43(m,4H)1.82(d,J=12.32Hz,2H)1.93(dq,J=12.74,2.77Hz,2H)2.20(s,6H)2.29(m,1H)2.78(td,J=12.38,2.19Hz,2H)3.49(ddd,J=11.86,9.91,2.26Hz,2H)3.62-3.72(m,1H)3.81(dt,J=11.74,4.07Hz,2H)3.87(d,J=12.56Hz,2H)4.04(s,2H)6.12(d,J=2.19Hz,1H)6.23(dd,J=8.96,2.26Hz,1H)6.99(m,3H)7.25(dd,J=8.60,1.52Hz,1H)7.40(d,J=8.54Hz,1H)7.48(br.s.,1H)7.78(d,J=9.15Hz,1H)8.28(d,J=7.56Hz,1H)10.05(s,1H)12.61(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]-2-(四氢-吡喃-4-基氨基)-苯基]cpd.92
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.36(m,2H)1.72(m,4H)1.99(m,6H)2.43(m,3H)2.63(m,2H)3.16(m,2H)3.39-3.47(m,3H)3.58(br.s.,1H)3.82-3.90(m,2H)3.90(br.s.,1H)4.04(s,2H)5.82(d,J=1.59Hz,1H)5.90(dd,J=8.90,2.07Hz,1H)6.98(m,3H)7.24(dd,J=8.60,1.52Hz,1H)7.40(d,J=8.90Hz,1H)7.48(br.s.,1H)7.77(d,J=9.02Hz,1H)8.36(d,J=7.32Hz,1H)9.95(s,1H)12.60(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-3-(4-甲基哌嗪-1-基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=3-(4-甲基哌嗪-1-基)苯基]cpd.93
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.26(s,3H)2.47-2.54(m,4H)3.22-3.27(m,4H)4.06(s,2H)6.92-6.99(m,2H)6.99-7.06(m,1H)7.15-7.20(m,1H)7.26(dd,J=8.66,1.59Hz,1H)7.36(t,J=7.93Hz,1H)7.42-7.45(m,1H)7.47(d,J=7.80Hz,1H)7.60-7.63(m,2H)10.65(s,1H)12.73(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(哌嗪-1-基)-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(哌嗪-1-基)-2-(四氢-2H-吡喃-4-基氨基)苯基]cpd.98
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.30-1.41(m,2H)1.88-2.01(m,2H)2.81-2.88(m,4H)3.17-3.22(m,4H)3.45-3.54(m,2H)3.62-3.73(m,1H)3.78-3.85(m,2H)4.05(s,2H)6.12(d,J=2.19Hz,1H)6.23(dd,J=8.96,2.26Hz,1H)6.94-7.04(m,3H)7.26(dd,J=8.65,1.58Hz,1H)7.39-7.43(m,1H)7.49(s,1H)7.80(d,J=9.02Hz,1H)8.29(d,J=7.68Hz,1H)10.07(s,1H)12.63(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基哌嗪-1-基)-2-{[顺式-4-(三氟甲基)环己基]氨基}苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-{[顺式-4-(三氟甲基)环己基]氨基}苯基]cpd.99
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.39-1.53(m,2H)1.58-1.73(m,4H)1.84-1.91(m,2H)2.25(s,3H)2.28-2.40(m,1H)2.47(br.s.,4H)3.25-3.33(m,4H)3.82-3.90(m,1H)4.01(s,2H)6.10(d,J=1.95Hz,1H)6.24(dd,J=9.15,2.19Hz,1H)6.90-6.96(m,2H)6.96-7.03(m,1H)7.24(dd,J=8.60,1.52Hz,1H)7.42(d,J=8.54Hz,1H)7.52(s,1H)7.83(d,J=9.02Hz,1H)8.69(d,J=7.80Hz,1H)10.10(s,1H)12.65(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基哌嗪-1-基)-2-{[反式-4-(三氟甲基)环己基]氨基}苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-{[反式-4-(三氟甲基)环己基]氨基}苯基]cpd.100
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.10-1.23(m,2H)1.44-1.57(m,2H)1.86-1.94(m,2H)2.06-2.15(m,2H)2.25(s,3H)2.29-2.34(m,1H)2.46(br.s.,4H)3.24-3.31(m,4H)3.39-3.51(m,1H)4.05(s,2H)6.15(d,J=2.07Hz,1H)6.23(dd,J=8.90,2.07Hz,1H)6.95-7.00(m,2H)7.00-7.06(m,1H)7.25(dd,J=8.60,1.52Hz,1H)7.41(d,J=8.54Hz,1H)7.48(s,1H)7.78(d,J=9.02Hz,1H)8.14(d,J=8.05Hz,1H)10.05(s,1H)12.62(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-氟-4-(4-甲基哌嗪-1-基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-氟-苯基]cpd.101
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.26(s,3H)2.45-2.50(m,4H)3.29-3.36(m,4H)4.06(s,2H)6.78-6.89(m,2H)6.94-6.98(m,2H)6.98-7.06(m,1H)7.25(dd,J=8.54,1.59Hz,1H)7.42(d,J=8.66Hz,1H)7.64(s,1H)7.68(t, J=8.90Hz,1H)10.08(d,J=3.41Hz,1H)12.68(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-[(1-甲基哌啶-4-基)氨基]苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=2-[(1-甲基哌啶-4-基)氨基]-苯基]cpd.110
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.35-1.49(m,H)1.94(d,H)2.20(br.s.,5H)2.60-2.73(m,2H)3.38-3.47(m,1H)4.05(s,2H)6.58-6.64(m,1H)6.80(d,J=8.29Hz,1H)6.95-7.00(m,2H)7.00-7.05(m,1H)7.27(dd,J=8.65,1.58Hz,1H)7.32-7.37(m,1H)7.44(d,J=8.53Hz,1H)7.53(s,1H)7.85-7.88(m,1H)7.89(dd,J=8.05,1.34Hz,1H)10.44(s,1H)12.72(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-[(1-甲基哌啶-4-基)氨基]-4-(吗啉-4-基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(吗啉-4-基)-2-[(1-甲基哌啶-4-基)氨基]-苯基]cpd.111
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.38-1.50(m,2H)1.91-2.01(m,2H)2.27(m,5H)2.72(m,2H)3.20-3.26(m,4H)3.50(br.s.,1H)3.72-3.78(m,4H)4.05(s,2H)6.11(d,J=2.19Hz,1H)6.25(dd,J=9.08,2.13Hz,1H)6.92-7.08(m,3H)7.26(dd,J=8.59,1.52Hz,1H)7.42(d,J=8.53Hz,1H)7.50 (s,1H)7.82(d,J=9.02Hz,1H)8.28(d,J=7.31Hz,1H)10.10(s,1H)12.64(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-甲氧基-4-(4-甲基哌嗪-1-基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-甲氧基-氨基}苯基]cpd.112
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.25(s,3H)2.47(br.s.,4H)3.33-3.38(m,4H)4.02(s,3H)4.06(s,2H)6.63(d,J=1.95Hz,1H)6.67(dd,J=8.96,2.13Hz,1H)6.96(dd,J=8.72,2.13Hz,2H)6.99-7.05(m,1H)7.24(dd,J=8.66,1.59Hz,1H)7.40(d,J=8.66Hz,1H)7.76(s,1H)7.88(d,J=8.78Hz,1H)9.99(s,1H)12.65(s,1H)
N-[5-(2,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺[(IA),R1=R2=R3=H,R=2,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.10
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.29-1.42(m,2H)1.90-1.98(m,2H)2.27(br.s.,3H)2.49(br.s.,4H)3.24-3.32(m,4H)3.45-3.56(m,2H)3.64-3.74(m,1H)3.82(ddd,J=11.80,3.96,3.75Hz,2H)4.04(s,2H)6.14(d,J=1.83Hz,1H)6.24(dd,J=8.90,1.95Hz,1H)7.04-7.12(m,1H)7.15- 7.23(m,2H)7.24-7.27(m,1H)7.41(d,J=8.66Hz,1H)7.46(s,1H)7.80(d,J=9.02Hz,1H)8.30(d,J=7.68Hz,1H)10.08(s,1H)12.63(s,1H)
N-[5-(2-甲基-5-氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺[(IA),R1=R2=R3=H,R=2-甲基-5-氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.135
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.29-1.41(m,2H)1.94(dd,J=13.35,2.86Hz,2H)2.22(s,3H)2.25(s,3H)2.46(br.s.,4H)3.24-3.30(m,4H)3.46-3.54(m,2H)3.63-3.73(m,1H)3.78-3.86(m,2H)4.03(s,2H)6.13(d,J=1.95Hz,1H)6.23(dd,J=9.02,2.07Hz,1H)6.89-6.98(m,2H)7.14-7.21(m,2H)7.38(s,1H)7.41(d,J=8.65Hz,1H)7.79(d,J=9.02Hz,1H)8.31(d,J=7.80Hz,1H)10.07(s,1H)12.61(s,1H)
N-[5-(2-氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺[(IA),R1=R2=R3=H,R=2-氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.9
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.29-1.42(m,2H)1.89-1.98(m,2H)2.24(s,3H)2.45(br.s.,4H)3.24-3.30(m,4H)3.47-3.55(m,2H)3.64-3.74(m,1H)3.77-3.87(m,2H)4.04(s,2H)6.14(d,J=2.19Hz,1H)6.24(dd,J=8.96,2.26Hz,1H)6.95-7.02(m,1H)7.04-7.09(m,1H)7.10(d,J=7.56Hz,1H)7.24(dd,J=8.66,1.46Hz,1H)7.31(td,J=7.80,6.34Hz,1H)7.40(d,J=8.53Hz,1H)7.46(s,1H)7.79(d,J=9.02Hz,1H)8.28(d,J=7.80Hz,1H)10.07(s,1H)12.61(s,1H)
4-(4-甲基哌嗪-1-基)-N-[5-(吡啶-3-基甲基)-1H-吲唑-3-基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=吡啶-3-基,Ar=4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.136
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.30-1.42(m,2H)1.95(d,2H)2.26(s,3H)2.47(br.s.,4H)3.25-3.30(m,4H)3.47-3.54(m,2H)3.64-3.74(m,1H)3.79-3.86(m,2H)4.05(s,2H)6.14(d,J=2.07Hz,1H)6.24(dd,J=8.90,2.19Hz,1H)7.24(dd,J=8.60,1.52Hz,1H)7.29(ddd,J=7.80,4.76,0.73Hz,1H)7.41(d,J=8.90Hz,1H)7.47(s,1H)7.63(dt,J=7.87,1.92Hz,1H)7.79(d,J=9.15Hz,1H)8.27(d,J=7.80Hz,1H)8.39(dd,J=4.76,1.59Hz,1H)8.52(d,J=1.71Hz,1H)10.07(s,1H)12.62(s,1H)
N-[5-苄基-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺[(IA),R1=R2=R3=H,R=苯基,Ar=4-(4-甲基 -哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.137
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.31-1.42(m,2H)1.90-1.99(m,2H)2.24(s,3H)2.42-2.47(m,4H)3.24-3.31(m,4H)3.46-3.55(m,2H)3.64-3.76(m,1H)3.78-3.87(m,2H)4.01(s,2H)6.14(d,J=2.07Hz,1H)6.24(dd,J=8.96,2.26Hz,1H)7.17-7.27(m,6H)7.38(d,J=8.90Hz,1H)7.44(s,1H)7.79(d,J=9.02Hz,1H)8.28(d,J=7.68Hz,1H)10.05(s,1H)12.59(s,1H)。
实施例3
步骤r
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2,2,2-三氟-乙酰胺[(XXIVA),R1=R2=R3=H,R=3,5-二氟苯基,PG1=三氟乙酰基]
向在剧烈搅拌下和冷却至0℃的5-(3,5-二氟-苄基)-1H-吲唑-3-基胺(0.5g,1.93mmol)在无水二氯甲烷(20mL)中的混悬液中滴加三氟乙酐,将浓稠的浆液搅拌3.5小时。将该反应混合物倾入3%NaHCO3溶液并且用二氯甲烷萃取。用盐水洗涤有机层,用Na2SO4干燥并且浓缩至得到粗的白色固体,将其直接用于下一步。
ESI(+)MS m/z356(100,MH+);HRMS(ESI)对C16H10F5N3O+H+的计算值:356.0817;实测值:356.0820
步骤s
N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-2,2,2-三氟-乙酰胺[(XXVA),R1=R2=R3=H,R=3,5-二氟苯基,PG=三苯基甲基,PG1=三氟乙酰基]
将粗的N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2,2,2-三氟-乙 酰胺混悬于二氯甲烷(25mL)中并且用三苯甲基氯(0.72g,2.58mmol)在搅拌下处理。将该混悬液冷却至0℃并且加入纯的1,8-二氮杂双环[5.4.0]十一-7-烯(0.42mL,2.78mmol),产生中间体增溶。在0℃下搅拌3小时后,将该反应混合物倾入含1N HCl(5mL)的50mL冰中,并且用二氯甲烷萃取。用NaHCO3、盐水洗涤有机层,干燥并且浓缩至得到粗物质,通过快速色谱法(洗脱剂:DCM)纯化该粗产物。得到所需的产物,为白色固体(450mg,两步内收率40%)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):3.98(s,2H)6.34(d,J=8.78Hz,1H)6.93-7.07(m,4H)7.16-7.20(m,6H)7.25-7.39(m,9H)7.52(s,1H)11.99(s,1H)
步骤t
5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基胺[(XXVIA),R1=R2=R3=H,R=3,5-二氟苯基,PG=三苯基甲基]
将N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-2,2,2-三氟-乙酰胺(450mg,0.75mmol)溶于甲醇(6mL)和三乙胺(1.5mL),将该溶液回流3小时。减压除去溶剂并且通过快速色谱法纯化残余物(洗脱剂:DCM)。得到标题化合物,为白色泡沫(300mg,收率80%)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):3.91(s,2H)5.53(s,2H)6.24(d,J=8.78Hz,1H)6.87-6.93(m,3H)6.97-7.07(m,1H)7.17-7.23(m,3H)7.27(t,J=7.50Hz,6H)7.34(d,J=1.59Hz,6H)7.48(s,1H)
步骤u
N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺[(XXIIA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-硝基-苯基,PG=三苯基甲基]
将4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酸(150mg,0.5mmol)混悬于无水二氯甲烷(10mL)中,加入1滴DMF,随后加入草酰氯(0.2mL,2mmol)。在室温下搅拌2小时后,在减压下充分干燥该混合物而得到酰氯,为白色粉末。将120mg酰氯(0.4mmol)溶于无水四氢呋喃(3mL)并且加入5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基胺(200mg,0.4mmol)。将所得溶液在搅拌下液冷却至0℃。在添加二异丙基乙胺(0.2mL,1.2mmol)后,将该反应混合物搅拌18小时,同时使温度逐步从0℃升高至室温。在蒸发挥发性物质后,通过快速色谱法纯化粗产物(洗脱剂:DCM/MeOH10:1)。分离标题化合物,为浅黄色固体(200mg,收率67%)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.24(s,3H)2.45(br.s.,4H)3.31-3.39(m,4H)3.96(s,2H)6.29(br.s.,1H)6.98(m,4H)7.29(m,17H)7.58(s,1H)7.70(br.s.,1H)10.96(br.s.,1H)
步骤i”
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺盐酸盐[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-硝基-苯基]cpd.6
向N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺(28.5mg,0.04mmol)在二烷(1mL)中的溶液中加入在二烷中的4M HCl(0.1mL),将该混合物在室温下搅拌1小时。在浓缩后,将残余物混悬于乙醚/MeOH1:1中,搅拌20分钟,过滤,用相同的溶剂混合物洗涤并且干燥。得到所需产物,为盐酸盐衍生物(19mg,87%)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.85(d,J=4.02Hz,3H)3.08-3.31(m,4H)3.53(d,J=11.71Hz,2H)4.06(s,2H)4.13(d,J=13.17Hz,2H)6.91-6.99(m,2H)6.99-7.08(m,1H)7.26(dd,J=8.54,1.34Hz,1H)7.37(d,J=6.95Hz, 1H)7.43(d,J=8.66Hz,1H)7.58(br.s.,1H)7.64(s,1H)7.78(d,J=7.44Hz,1H)10.39(br.s.,1H)10.91(br.s.,1H)12.74(br.s.,1H)
按照同样方式操作获得下列化合物:
2-氨基-N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺盐酸盐[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-氨基-苯基]cpd.8
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.84(d,J=4.39Hz,3H)3.05-3.20(m,4H)3.44-3.53(m,2H)3.85-3.94(m,2H)4.05(s,2H)6.30(d,J=1.95Hz,1H)6.36(dd,J=8.96,2.13Hz,1H)6.93-7.00(m,2H)6.99-7.05(m,1H)7.24(dd,J=8.66,1.46Hz,1H)7.41(d,J=8.41Hz,1H)7.53(s,1H)7.81(d,J=9.02Hz,1H)10.11(br.s.,1H)10.37(br.s.,1H)12.66(br.s.,1H)
实施例4
转化1
2-氨基-N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺[(XXIIA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-氨基-苯基,PG=三苯基甲基]
将N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺(170mg,0.236mmol),10%Pd-C(10mg)和甲酸铵(25mg,0.4mmol)在甲醇(5mL)中的混合物在室温下搅拌18小时。过滤出催化剂并且浓缩溶液。将残余物溶于二氯甲烷,用NaHCO3水溶液洗涤,干燥并且浓缩至得到标题化合物(145mg,87%)。
ESI(+)MS m/z243(100,三苯甲基+),719(16,MH+);HRMS(ESI)对C45H40F2N6O+H+的计算值:719.3304;实测值:719.3309
按照同样方式操作获得下列化合物:
2-氨基-N-[5-(3-乙氧基-苯甲酰基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺[(II),R1=R2=R3=H,R=3-乙氧基苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-氨基-苯基]
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.33(t,J=6.95Hz,3H)2.22(s,3H)2.40-2.45(m,4H)3.16-3.22(m,4H)4.09(q,J=6.95Hz,2H)6.17(d,J=2.44Hz,1H)6.23(dd,J=9.02,2.44Hz,1H)6.53(s,2H)7.18(ddd,J=8.23,2.62,0.85Hz,1H)7.24(dd,J=2.44,1.46Hz,1H)7.29(dt,J=7.68,1.10Hz,1H)7.44(t,J=7.93Hz,1H)7.59(dd,J=8.84,0.55Hz,1H)7.71(d,J=9.15Hz,1H)7.83(dd,J=8.78,1.59Hz,1H)8.20(br.s.,1H)10.30(s,1H)13.05(s,1H)
2-氨基-N-[5-(3,5-二氟-苯甲酰基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺[(II),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-氨基-苯基]
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.30(br.s.,3H)2.56(m,4H)3.22(m,4H)6.18(d,J=2.32Hz,1H)6.24(dd,J=9.08,2.38Hz,1H)6.57(s,2H)7.42(m,2H)7.54(tt,J=9.15,2.38Hz,1H)7.61(dd,J=8.90,0.61Hz,1H)7.73(d,J=9.02Hz,1H)7.83(dd,J=8.84,1.65Hz,1H)8.26(d,J=0.98Hz,1H)10.36(s,1H)13.11(s,1H)
实施例5
转化2+步骤i”
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-甲磺酰基氨基-4-(4-甲基-哌嗪-1-基)-苯甲酰胺盐酸盐[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-甲磺酰基氨基-苯基]cpd.48
向2-氨基-N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺(29mg,0.04mmol)在无水二氯甲烷(2mL)和干吡啶(0.05mL)中的溶液中加入甲磺酰氯(14.7mg,0.01mL,0.13mmol),将该反应混合物在室温下搅拌8小时。将该混合物倾入冰并且用二氯甲烷萃取。用0.1N HCl、再用水洗涤有机层,用无水Na2SO4干燥并且浓缩至得到粗的带白色的固体,将其混悬于二 烷(1mL)中。添加在二烷(0.1mL)中的4MHCl,然后将该混悬液搅拌过夜。在浓缩后,将残余物混悬于乙醚/MeOH1:1中,搅拌20分钟,过滤,用相同的溶剂混合物洗涤并且干燥。得到所需产物,为盐酸盐(15mg,0.025mmol,63%)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.86(d,J=4.27Hz,3H)3.17(s,3H)3.14-3.27(m,4H)3.55(m,2H)4.02(m,2H)4.06(s,2H)6.92(dd,J=9.02,2.32Hz,1H)6.97-7.03(m,3H)7.05(d,J=2.56Hz,1H)7.28(dd,J=8.66,1.46Hz,1H)7.45(d,J=8.54Hz,1H)7.55(s,1H)8.12(d,J=9.15Hz,1H)10.56(s,1H)10.76(s,1H)11.42(s,1H)12.84(s,1H)
按照同样方式操作获得下列化合物:
N-[2-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-5-(4-甲基哌嗪-1-基)苯基]-1H-吡咯-2-甲酰胺盐酸盐[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基哌嗪-1-基)-2-(1H-吡咯-2-氨基甲酰基)-苯基]cpd.44
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.74(br.s.,3H)4.04(s,2H)6.09(dt,J=3.60,2.41Hz,1H)6.65(dt,J=3.87,1.78Hz,1H)6.82(dd,J=9.02,2.32Hz,1H)6.97(m,4H)7.28(dd,J=8.66,1.46Hz,1H)7.46(d,J=8.66Hz,1H)7.59(br.s.,1H)8.09(d,J=9.15Hz,1H)8.38(d,J=2.44Hz,1H)9.99(br.s.,1H)10.71(s,1H)11.69(br.s.,1H)12.51(s,1H)12.82(s,1H)
实施例6
转化4
2-氨基-N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-氨基-苯基]cpd.8
将N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酰胺(3.21g,6.33mmol),环己烯(20mL),二烷(200mL)和10%Pd/C(0.8g)的混合物在100℃下搅拌2小时。用硅藻土垫过滤该反应混合物,用THF和MeOH充分洗涤。在蒸发有机相后,通过硅胶色谱法纯化粗产物(DCM/MeOH95/5),得到2.51g标题化合物(83%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.23(s,3H)2.44(br. s.,4H)3.20(t,J=4.76Hz,4H)4.04(s,2H)6.18(d,J=2.44Hz,1H)6.24(dd,J=8.96,2.38Hz,1H)6.53(s,2H)6.97(m,3H)7.22(dd,J=8.66,1.59Hz,1H)7.39(d,J=8.66Hz,1H)7.52(br.s.,1H)7.72(d,J=9.02Hz,1H)10.01(s,1H)12.60(s,1H)
按照同样方式操作获得下列化合物:
2-氨基-4-[(3-二甲基氨基-丙基)-甲基-氨基]-N-[5-(3-乙氧基-苄基)-1H-吲唑-3-基]-苯甲酰胺[(IA),R1=R2=R3=H,R=3-乙氧基苯基,Ar=4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-氨基-苯基]cpd.54
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.27(t,J=6.95Hz,3H)1.67(d,J=7.19Hz,2H)2.19(s,6H)2.28(t,J=6.04Hz,2H)2.90(s,3H)3.24-3.40(m,2H)3.96(q,J=6.95Hz,2H)3.95(s,2H)5.94(d,J=2.56Hz,1H)6.04(dd,J=9.02,2.56Hz,1H)6.52(s,2H)6.68-6.72(m,1H)6.76-6.79(m,1H)6.77(s,1H)7.13-7.17(m,1H)7.18(dd,J=8.60,1.65Hz,1H)7.33-7.38(m,1H)7.47(s,1H)7.69(d,J=9.02Hz,1H)9.88(s,1H)12.53(s,1H)
2-氨基-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}苯甲酰胺
1H-NMR(400MHz),δ(ppm,DMSO-d6):3.29-3.48(m,2H)4.06(s,2H)4.29(br.s.,1H)6.63(br.s.,3H)6.85(br.s.,1H)6.92-7.05(m,3H)7.26(dd,J=8.66,1.34Hz,1H)7.43(d,J=8.54Hz,1H)7.57(s,1H)7.85(d,J=8.17Hz,1H)10.46(s,1H)12.72(s,1H)
2-氨基-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2R)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}苯甲酰胺
ESI(+)MS:m/z559(MH+)。
2-氨基-N1-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-N4-[2-(二甲基氨基)乙基]-N4-甲基苯-1,4-二甲酰胺
ESI(+)MS:m/z507(MH+)。
2-氨基-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[4-(丙-2-基)哌嗪-1-基]羰基}苯甲酰胺
1H-NMR(400MHz),δ(ppm,DMSO-d6):0.99(d,J=6.46Hz,6H)2.43(m,4H)2.70(d,1H)3.58(m,4H)4.06(s,2H)6.54(dd,J=8.05,1.46Hz,1H)6.65(s,2H)6.75(d,J=1.46Hz,1H)6.92-7.01(m,2H)6.99-7.05(m,1H)7.26(dd,J=8.59,1.52Hz,1H)7.43(d,J=8.65Hz,1H)7.57(s,1H)7.85(d,J=8.17Hz,1H)10.45(s,1H)12.71(s,1H)
2-氨基-N1-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-N4-[2-(二甲基氨基)乙基]苯-1,4-二甲酰胺
ESI(+)MS:m/z493(MH+)。
2-氨基-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[(4-甲基哌嗪-1-基)羰基]苯甲酰胺
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.06(s,2H)6.60(d,J=8.29Hz,1H)6.68(s,2H)6.80(d,J=1.46Hz,1H)6.93-7.00(m,2H)7.00-7.06(m,1H)7.26(dd,J=8.53,1.58Hz,1H)7.44(d,J=8.65Hz,1H)7.55(s,1H)7.88(d,J=8.17Hz,1H)10.48(s,1H)12.73(s,1H)
2-氨基-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[4-(二甲基氨基)哌啶-1-基]羰基}苯甲酰胺
ESI(+)MS:m/z533(MH+)。
2-氨基-N1-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-N4-(1-甲基哌啶-4-基)苯-1,4-二甲酰胺
ESI(+)MS:m/z519(MH+)。
实施例7
转化6
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.11
向2-氨基-N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-苯甲酰胺(1.9g,3.98mmol)在二氯甲烷(80mL)中的溶液中加入四氢-吡喃-4-酮(0.55mL,5.98mmol),三氟乙酸(4mL)和三乙酰氧基硼氢化四甲基铵(1.57g,5.98mmol)。将该混合物在室温下搅拌过夜,然后再加入三乙酰氧基硼氢化四甲基铵(1.57g)。在室温下再搅拌3小时后,用二氯甲烷稀释该混合物,用2N氢氧化钠和盐水洗涤,用硫酸钠干燥并且蒸发至干。通过硅胶快速色谱法纯化粗产物,使用二氯甲烷/甲醇/在MeOH中的NH35N(96:4:0.5)作为洗脱剂,得到1.61g标题化合物(72%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.26-1.43(m,2H)1.86-2.02(m,2H)2.23(s,3H)2.42-2.46(m,4H)3.23-3.29(m,4H)3.45-3.54(m,2H)3.62-3.75(m,1H)3.82(dt,J=11.61,3.83Hz,2H)4.05(s,2H)6.14(d,J=2.07Hz,1H)6.24(dd,J=8.90,2.19Hz,1H)6.94-7.06(m,3H)7.26(dd,J=8.66,1.46Hz,1H)7.41(d,J=8.66Hz,1H)7.50(d,1H)7.80(d,J=9.15Hz,1H)8.29(d,J=7.68Hz,1H)10.08(s,1H)12.63(s,1H)
N-{5-[(3,5-二氟-苯基)-甲氧基-甲基]-1H-吲唑-3-基}-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺[(IC),R1=R2=R3=H,R=3,5-二氟苯基,R'=甲基,Ar=4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.68
在将从上述报导的N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺的制备中的柱色谱法纯化得到的混合级分进行制备型HPLC纯化的过程中,将标题化合物分离为副产物(约15%)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.31-1.44(m,2H)1.91-2.01(m,2H)2.79(br.s.,3H)3.32(m,11H)3.45-3.56(m,2H)3.68-3.78(m,1H)3.80-3.88(m,2H)5.48(s,1H)6.22(d,J=2.07Hz,1H)6.30(d,J=9.02Hz,1H)7.04-7.12(m,3H)7.32(dd,J=8.78,1.46Hz,1H)7.45(d,J=8.90Hz,1H)7.64(s,1H)7.86(d,J=9.02Hz,1H)8.35(d,J=7.80Hz,1H)10.20(s,1H)12.73(s,1H)
按照同样方式操作获得下列化合物:
2-[(2-{[叔丁基(二甲基)甲硅烷基]氧基}乙基)氨基]-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基哌嗪-1-基)苯甲酰胺
ESI(+)MS:m/z635(MH+)。
3-({[2-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-5-(4-甲基哌嗪-1-基)苯基]氨基}甲基)氮杂环丁烷-1-甲酸叔丁酯
ESI(+)MS:m/z646(MH+)。
1-[4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-3-(四氢-2H-吡喃-4-基氨基)苄基]哌啶三氟乙酸盐[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-哌啶-1-基甲基-2-(四氢-吡喃-4-基氨基)-苯基]cpd.115
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.32-1.46(m,3H)1.65-1.93(m,5H)1.96-2.04(m,2H)2.81-2.96(m,2H)3.32(br.s.,2H)3.44-3.54(m,2H)3.63-3.74(m,1H)3.82-3.91(m,2H)4.06(s,2H)4.23(d,J=5.37Hz,2H)6.75-6.81(m,1H)6.94-7.06(m,2H)7.13(s,1H)7.29(dd,J=8.66,1.46Hz,1H)7.45(d,J=8.54Hz,1H)7.50(s,1H)7.96(d,J=8.05Hz,1H)8.00(br.s.,1H)10.14(br.s.,1H)10.54(s,1H)12.77(br.s.,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2-甲氧基乙基)(甲基)氨基]甲基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-{[(2-甲氧基乙基)(甲基)氨基]甲基}-2-(四氢-吡喃-4-基氨基)-苯基]cpd.116
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.31-1.45(m,2H)1.95(d,J=11.83Hz,2H)2.22(s,3H)2.52-2.57(m,2H)3.26(s,3H)3.43-3.53(m,6H)3.64(dd,J=6.95,2.93Hz,1H)3.80 -3.88(m,2H)4.05(s,2H)6.58(d,J=7.93Hz,1H)6.79(s,1H)6.95-7.06(m,3H)7.27(dd,J=8.66,1.46Hz,1H)7.43(d,J=8.54Hz,1H)7.52(s,1H)7.86(d,J=8.05Hz,1H)7.96(d,J=7.56Hz,1H)10.39(s,1H)12.71(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(吡咯烷-1-基甲基)-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(吡咯烷-1-基甲基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.117
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.31-1.45(m,2H)1.67-1.78(m,4H)1.90-1.98(m,2H)2.47(br.s.,2H)3.44-3.54(m,2H)3.56(br.s.,4H)3.59-3.71(m,1H)3.83(dt,J=11.65,3.69Hz,2H)4.05(s,2H)6.59(d,J=8.66Hz,1H)6.77(s,1H)6.92-7.07(m,3H)7.27(dd,J=8.66,1.59Hz,1H)7.42(d,J=0.49Hz,1H)7.52(s,1H)7.85(d,J=8.17Hz,1H)7.95(d,J=7.80Hz,1H)10.39(s,1H)12.71(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(吗啉-4-基甲基)-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(吗啉-4-基甲基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.118
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.30-1.44(m,2H)1.88-2.01(m,2H)2.39(br.s.,4H)3.45-3.46(m,2H)3.46-3.54(m,2H)3.61(br.s.,4H)3.65(d,1H)3.84(d,J=12.32Hz,2H)4.05(s,2H)6.60(d,J=8.41Hz,1H)6.79(s,1H)6.89-7.09(m,3H)7.28(dd,J=8.72,1.16Hz,1H)7.43(d,J=8.78Hz,1H)7.51(s,1H)7.87(d,J=8.05Hz,1H)7.95(d,J=7.80Hz,1H)10.40(s,1H)12.71(s,1H)
4-(氮杂环丁烷-1-基甲基)-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(氮杂环丁烷-1-基甲基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.119
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.31-1.43(m,2H)1.90-1.98(m,2H)1.98-2.06(m,2H)3.15(t,J=6.95Hz,4H)3.46-3.54(m,4H)3.61-3.70(m,1H)3.79-3.88(m,2H)4.05(s,2H)6.53(dd,J=8.11,1.16Hz,1H)6.72(s,1H)6.94-7.05(m,3H)7.27(dd,J=8.60,1.52Hz,1H)7.43(d,J=8.66Hz,1H)7.51(s,1H)7.83(d,J=8.17Hz,1H)7.94(d,J=7.80Hz,1H)10.38(s,1H)12.70(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-{[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}-2-(四氢-吡喃-4-基氨基)-苯基]cpd.127
1H-NMR(400MHz),δ(ppm,DMSO-d6):ppm3.44-3.56(m,2H)3.61-3.75(m,1H)3.78-3.88(m,2H)4.06(s,2H)4.26(br.s.,1H)6.66(s,1H)6.83(s,1H)6.95-7.06(m,3H)7.28(dd,J=8.66,1.46Hz,1H)7.44(d,J=8.78Hz,1H)7.53(s,1H)7.93(d,J=8.17Hz,1H)7.97(br.s.,1H)10.55(s,1H)12.75(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2R)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-{[(2R)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}-2-(四氢-吡喃-4-基氨基)-苯基]cpd.128
1H-NMR(400MHz),δ(ppm,DMSO-d6):ppm3.44-3.56(m,2H)3.61-3.75(m,1H)3.78-3.88(m,2H)4.06(s,2H)4.26(br.s.,1H)6.66(s,1H)6.83(s,1H)6.95-7.06(m,3H)7.28(dd,J=8.66,1.46Hz,1H)7.44(d,J=8.78Hz,1H)7.53(s,1H)7.93(d,J=8.17Hz,1H)7.97(br.s.,1H)10.55(s,1H)12.75(s,1H)
N1-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-N4-[2-(二甲基氨基)乙 基]-N4-甲基-2-(四氢-2H-吡喃-4-基氨基)苯-1,4-二甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-({N-[2-(二甲基氨基)乙基]-N-甲基}羰基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.129
1H-NMR(400MHz),δ(ppm,DMSO-d6):旋转异构体混合物1.31-1.44(m,2H)1.87-1.97(m,2H)3.45-3.52(m,2H)3.62-3.72(m,1H)3.79-3.88(m,2H)4.06(s,2H)6.56(d,J=7.68Hz,1H)6.76(br.s.,1H)6.95-7.05(m,3H)7.28(dd,J=8.59,1.52Hz,1H)7.44(d,J=8.65Hz,1H)7.54(s,1H)7.91-7.99(m,2H)10.56(s,1H)12.75(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[4-(丙-2-基)哌嗪-1-基]羰基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-{[4-(丙-2-基)哌嗪-1-基]羰基}-2-(四氢-吡喃-4-基氨基)-苯基]cpd.130
1H-NMR(400MHz),δ(ppm,DMSO-d6):0.99(d,J=6.46Hz,6H)1.32-1.43(m,2H)1.89-1.97(m,2H)2.36-2.54(m,4H)2.66-2.75(m,1H)3.28-3.37(m,2H)3.49(td,J=11.18,2.13Hz,2H)3.61(br.s.,2H)3.65-3.74(m,1H)3.80-3.87 (m,2H)4.06(s,2H)6.58(dd,J=7.98,1.28Hz,1H)6.77(d,J=0.85Hz,1H)6.95-7.05(m,3H)7.28(dd,J=8.59,1.52Hz,1H)7.44(d,J=8.65Hz,1H)7.53(s,1H)7.91-7.95(m,1H)7.94-7.96(m,1H)10.56(s,1H)12.75(s,1H)
N1-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-N4-[2-(二甲基氨基)乙基]-2-(四氢-2H-吡喃-4-基氨基)苯-1,4-二甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-({N-[2-(二甲基氨基)乙基]}羰基)-2-(四氢-吡喃-4-基氨基)-苯基]cpd.131
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.33-1.47(m,2H)1.93-2.00(m,2H)2.30(br.s.,6H)2.51-2.60(m,2H)3.37-3.44(m,2H)3.46-3.54(m,2H)3.73(d,1H)3.85(dt,J=11.61,3.76Hz,2H)4.06(s,2H)6.95-7.05(m,3H)7.07(dd,J=8.17,1.46Hz,1H)7.23(d,J=1.22Hz,1H)7.28(dd,J=8.65,1.58Hz,1H)7.44(d,J=8.53Hz,1H)7.54(s,1H)7.93(d,J=7.68Hz,1H)7.96(d,J=8.29Hz,1H)8.47(t,J=4.94Hz,1H)10.60(s,1H)12.76(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[(4-甲基哌嗪-1-基)羰基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-[(4-甲基哌嗪-1-基)羰基]-2-(四氢-吡喃-4-基氨基)-苯基]cpd.132
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.32-1.43(m,2H)1.93(d,J=11.70Hz,2H)2.22(s,3H)2.33(m,4H)3.45-3.53(m,2H)3.65-3.73(m,1H)3.80-3.86(m,2H)4.06(s,2H)6.57(dd,J=7.98,1.28Hz,1H)6.77(d,J=0.98Hz,1H)6.96-7.05(m,3H)7.28(dd,J=8.59,1.52Hz,1H)7.44(d,J=8.53Hz,1H)7.52(s,1H)7.92-7.95(m,1H)7.94-7.97(m,1H)10.56(s,1H)12.75(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[4-(二甲基氨基)哌啶-1-基]羰基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-{[4-(二甲基氨基)哌啶-1-基]羰基}-2-(四氢-吡喃-4-基氨基)-苯基]cpd.133
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.25-1.46(m,4H)1.73(m,1H)1.84(m,1H)1.93(d,J=11.46Hz,2H)2.20(s,6H)2.34(m,1H)2.82(m,1H)3.04(m,1H)3.42-3.55(m,2H)3.65-3.76(m,2H)3.78-3.88(m,2H)4.06(s,2H)4.43(m,1H)6.58(dd,J=8.05,1.34Hz,1H)6.78(d,J=0.85Hz,1H)6.94-7.06(m,3H)7.28(dd,J=8.65,1.58Hz,1H)7.44(d,J=8.53Hz,1H)7.53(s,1H)7.90-7.96(m,2H)10.55(s,1H) 12.74(s,1H)
N1-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-N4-(1-甲基哌啶-4-基)-2-(四氢-2H-吡喃-4-基氨基)苯-1,4-二甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-[N-(1-甲基哌啶-4-基)-羰基]-2-(四氢-吡喃-4-基氨基)-苯基]cpd.134
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.32-1.47(m,2H)1.56-1.70(m,2H)1.74-1.83(m,2H)1.92-1.99(m,2H)2.02(br.s.,2H)2.21(s,3H)2.82(d,J=13.17Hz,2H)3.46-3.54(m,2H)3.67-3.80(m,2H)3.79-3.88(m,2H)4.06(s,2H)6.96-7.05(m,3H)7.08(dd,J=8.17,1.46Hz,1H)7.21(d,J=1.22Hz,1H)7.28(dd,J=8.65,1.46Hz,1H)7.42-7.46(m,1H)7.54(s,1H)7.92-7.97(m,2H)8.26(d,J=7.80Hz,1H)10.60(s,1H)12.77(s,1H)。
实施例8
4-{[(2S)-1-甲基吡咯烷-2-基]甲氧基}-2-硝基苯甲酸叔丁酯的制备
在氩气气氛下,在圆底三颈瓶中加入甲苯(15ml),CsCO3(1.6g,5mmol),膦配体2-(二叔丁基膦基)-1,1'-联萘(331mg,0.83mmol)和Pd(dba)2(380mg,0.66mmol)。给该混合物脱气而发氩气泡5分钟。然后加入4-溴-2-硝基苯甲酸叔丁酯(1g,3.31mmol)和(S)-(-)-1-甲基-2-吡咯烷甲醇(0.78ml,6.62mmol),将该混合物加热至100℃下18h。将该反应体系冷却至室温,用30ml水骤冷并且用25ml AcOEt萃取两次。收集有机相,用Na2SO4干燥并且蒸发溶剂,得到红色油状物,在Biotage SP1自动化系统(90:10DCM/MeOH(等 度洗脱)上对其进行色谱纯化,得到纯的标题化合物,为淡黄色油状物(460mg,1.36mmol,41%收率)
ESI(+)MS:m/z337(MH+)。
按照同样方式操作获得下列化合物:
4-[(1-甲基哌啶-4-基)氧基]-2-硝基苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.48(9H,s)1.68(m,2H)1.95(m,2H)2.20(m,5H)2.61(m,2H)4.60(m,1H)7.30(dd,J=8.78,2.56Hz,1H)7.54(d,J=2.56Hz,1H)7.79(d,J=8.78Hz,1H)
4-[2-(二甲基氨基)乙氧基]-2-硝基苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.49(9H,s)2.22(s,6H)2.65(t,J=5.61Hz,2H)4.21(t,J=5.63Hz,2H)7.30(dd,J=8.78,2.56Hz,1H)7.52(d,J=2.56Hz,1H)7.80(d,J=8.78Hz,1H)
4-{[(3S)-1-甲基吡咯烷-3-基]氧基}-2-硝基苯甲酸叔丁酯
ESI(+)MS:m/z323(MH+)。
2-氨基-4-{[(2S)-1-甲基吡咯烷-2-基]甲氧基}苯甲酸叔丁酯的制备
将硝基-衍生物4-{[(2S)-1-甲基吡咯烷-2-基]甲氧基}-2-硝基苯甲酸叔丁酯(460mg,1.37mmol)溶于20ml MeOH,在氩气环境下加入130mg Pd/C5%和700mg(6.3mmol)HCOONH4。将该混合物在80℃下回流1h,然后冷却至室温并且通过小硅藻土垫过滤,用MeOH洗涤。然后蒸馏出溶剂,将残余物溶于20ml DCM,用20ml NaHCO3(10%)洗涤两次。用Na2SO4干燥收集的有机萃取物,过滤并且蒸发至干而得到褐色油状物(400mg,1.31mmol,95%收率),将其不经任何进一步纯化而用于下一步。
ESI(+)MS:m/z307(MH+)。
按照同样方式操作获得下列化合物:
2-氨基-4-[(1-甲基哌啶-4-基)氧基]苯甲酸叔丁酯
ESI(+)MS:m/z307(MH+)。
2-氨基-4-[2-(二甲基氨基)乙氧基]苯甲酸叔丁酯
1NMR(400MHz),δ(ppm,DMSO-d6):1.51(s,9H)2.21(s,6H)2.61(t,J=5.79Hz,2H)4.00(t,J=5.79Hz,2H)6.11(dd,J=8.96,2.50Hz,1H)6.25(d,J=2.56Hz,1H)6.60(s,2H)7.56(d,J=8.90Hz,1H)
2-氨基-4-{[(3S)-1-甲基吡咯烷-3-基]氧基}苯甲酸叔丁酯
ESI(+)MS:m/z293(MH+)。
4-{[(2S)-1-甲基吡咯烷-2-基]甲氧基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酸叔丁酯的制备
在氩气环境中将2-氨基-4-{[(2S)-1-甲基吡咯烷-2-基]甲氧基}苯甲酸叔丁酯(400mg,1.3mmol)溶于20ml DCM。加入四氢-4H-吡喃-4-酮(0.19ml,2.05mmol),TFA(0.29ml,3.69mmol)和Me4BH(OAc)3(540mg,2.05mmol)。将得到的浆液在室温下搅拌过夜,然后用15ml NaHCO310%骤冷并且用20ml DCM萃取两次。然后用Na2SO4干燥有机层,过滤并且浓缩至得到黄色油状物(448mg,1.15mmol,88%),将其不经任何进一步纯化而用于下一步。
ESI(+)MS:m/z391(MH+)。
按照同样方式操作获得下列化合物:
4-[(1-甲基哌啶-4-基)氧基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酸叔丁酯
ESI(+)MS:m/z391(MH+)。
4-[2-(二甲基氨基)乙氧基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酸叔丁酯
ESI(+)MS:m/z365(MH+)。
4-{[(3S)-1-甲基吡咯烷-3-基]氧基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酸叔丁酯
ESI(+)MS:m/z377(MH+)。
4-{[(2S)-1-甲基吡咯烷-2-基]甲氧基}-2-[四氢-2H-吡喃-4-基 (三氟乙酰基)氨基]苯甲酸叔丁酯的制备
将4-{[(2S)-1-甲基吡咯烷-2-基]甲氧基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酸叔丁酯(448mg,1.15mmol)溶于20ml DCM。加入TEA(0.18ml,1.3mmol)和TFAA(0.27ml,1.7mmol),将该反应混合物在室温下搅拌2小时并且用15ml NaHCO310%骤冷。用20ml DCM将得到的混合物萃取两次,用Na2SO4干燥,过滤并且在真空中浓缩。对粗产物进行硅胶色谱纯化(DCM/MeOH95:5),得到黄色油状物(481mg,1mmol,87%)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.00(qd,J=12.25,4.82Hz,1H)1.47(s,9H)1.51-1.64(m,1H)1.98(d,J=12.68Hz,2H)3.83(ddd,J=31.46,11.34,4.02Hz,2H)4.51(tt,J=11.95,3.90Hz,1H)7.02(br.s.,1H)7.21(d,J=6.95Hz,1H)7.95(d,J=8.78Hz,1H)
按照同样方式操作获得下列化合物:
4-[(1-甲基哌啶-4-基)氧基]-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸叔丁酯
ESI(+)MS:m/z487(MH+)。
4-[2-(二甲基氨基)乙氧基]-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸叔丁酯
ESI(+)MS:m/z461(MH+)。
4-{[(3S)-1-甲基吡咯烷-3-基]氧基}-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸叔丁酯
ESI(+)MS:m/z473(MH+)。
4-{[(2S)-1-甲基吡咯烷-2-基]甲氧基}-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸三氟乙酸盐的制备
将4-{[(2S)-1-甲基吡咯烷-2-基]甲氧基}-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸叔丁酯(480mg,1mmol)溶于20ml DCM。加入在二烷中的无水HCl4M(2.5ml,10mmol)。将该反应体系在室温下搅拌5天,然后HPLC分析显示形成所需产物,但含有约30%的 脱三氟乙酰基化副产物。在真空中除去溶剂,将得到的黄色粉末混悬于15ml DCM并且加入TFAA(0.28ml,2mmol)。该固体即刻溶解,将该混合物搅拌2小时,然后HPLC分析显示副产物完全消失。将溶剂蒸发至干而得到深黄色固体,将其不经任何进一步纯化而用于下一合成步骤。
ESI(+)MS:m/z431(MH+)。
按照同样方式操作获得下列化合物:
4-[(1-甲基哌啶-4-基)氧基]-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸三氟乙酸叔丁酯
ESI(+)MS:m/z431(MH+)。
4-[2-(二甲基氨基)乙氧基]-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸三氟乙酸叔丁酯
ESI(+)MS:m/z405(MH+)。
4-{[(3S)-1-甲基吡咯烷-3-基]氧基}-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸三氟乙酸叔丁酯
ESI(+)MS:m/z417(MH+)。
步骤i'
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2S)-1-甲基吡咯烷-2-基]甲氧基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-{[(2S)-1-甲基吡咯烷-2-基]甲氧基}-2-(四氢-2H-吡喃-4-基氨基)-苯基]cpd.94的制备
在氮气环境中将4-{[(2S)-1-甲基吡咯烷-2-基]甲氧基}-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸三氟乙酸盐(1mmol,531mg)溶于DCM中并且加入2滴无水DMF。加入草酰氯(0.17ml,2mmol), 将该混合物在室温下搅拌2小时。蒸发溶剂而得到黄色粉末。在氩气环境中将该固体再溶于THF并且在-20℃下冷却。加入DIPEA(0.56ml,3.2mmol)。然后在15'内滴加溶于10mL干THF的5-(3,5-二氟苄基)-1H-吲唑-3-胺。将该反应混合物保持在-20℃下6小时,然后使温度在室温下升高过夜。用15mL NaHCO35%使反应猝灭并且用AcOEt(15ml)萃取两次。然后蒸发溶剂,将残余物再溶于20ml MeOH。加入TEA(10mmol,1.5ml),将该混合物加热至65℃下3hr。然后将反应体系冷却至室温并且除去溶剂而得到粗产物,通过硅胶快速色谱法纯化(AcOEt/MeOH/NH3Aq.85:15:05),得到标题化合物,为白色粉末(258mg,0.45mmol,45%)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.28-1.44(m,2H)1.94(d,J=12.07Hz,2H)3.44-3.56(m,3H)3.59-3.73(m,1H)3.77-3.87(m,2H)4.05(s,2H)6.23(dd,1H)6.28(d,J=2.19Hz,1H)6.92-7.06(m,3H)7.27(dd,J=8.66,1.59Hz,1H)7.42(d,J=8.90Hz,1H)7.50(s,1H)7.88(d,J=8.90Hz,1H)8.27(d,J=7.80Hz,1H)10.24(s,1H)12.68(s,1H)
按照同样方式操作获得下列化合物:
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[(1-甲基哌啶-4-基)氧基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-[(1-甲基哌啶-4-基)氧基]-2-(四氢-2H-吡喃-4-基氨基)-苯基]cpd.95
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.36(ddd,J=9.82,3.66,3.48Hz,2H)1.70(m,2H)1.85-2.00(m,4H)2.22-2.30(m,5H)2.64-2.79(m,2H)3.44-3.54(m,2H)3.58-3.72(m,1H)3.82(dt,J=11.65,3.69Hz,2H)4.05(s,2H)4.51(br.s.,1H)6.20-6.30(m,2H)6.94-7.07(m,3H)7.27(dd,J=8.60,1.52Hz,1H)7.42(d,J=8.54Hz,1H)7.50(d,J=2.32Hz,1H)7.88(d,J=9.51Hz,1H)8.22(d,J=7.68Hz,1H)10.24(s,1H)12.68(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[2-(二甲基氨基)乙氧基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-[2-(二甲基氨基)乙氧基]-2-(四氢-2H-吡喃-4-基氨基)-苯基]cpd.96
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.31-1.44(m,2H)1.94(d,J=10.73Hz,2H)2.42(br.s.,6H)2.89(br.s.,2H)3.49(t,J=9.88Hz,2H)3.60-3.73(m,1H)3.78-3.88(m,2H)4.05(s,2H)4.19(t,J=5.24Hz,2H)6.25(dd,J=8.84,2.38Hz,1H)6.29(d,J=2.32Hz,1H)6.93-7.06(m,3H)7.27(dd,J=8.60,1.52Hz,1H)7.43(d,J=8.78Hz,1H)7.50(s,1H)7.90(d,J=8.78Hz,1H)8.27(d,J=7.44Hz,1H)10.26(s,1H)12.68(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(3S)-1-甲基吡咯烷-3-基]氧基}-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-{[(3S)-1-甲基吡咯烷-3-基]氧基}-2-(四氢-2H-吡喃-4-基氨基)-苯基]cpd.97
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.29-1.44(m,2H)1.75-1.86(m,1H)1.93(d,J=10.49Hz,2H)2.32(s,4H)2.44(br.s.,1H)2.65-2.78(m,2H)2.79-2.88(m,1H)3.44-3.54(m,2H)3.58-3.71(m,1H)3.82(d,J=11.58Hz,2H)4.05(s,2H)4.96-5.01(m,1H)6.15-6.19(m,1H)6.19-6.20(m,1H)6.94-7.06(m,3H)7.26(dd,J=8.66,1.59Hz,1H)7.42(d,J=8.54Hz,1H)7.50(d,J=1.59Hz,1H)7.87(d,J=8.90Hz,1H)8.23(d,J=7.68Hz,1H)10.24(s,1H)12.67(s,1H)。
实施例9
步骤u
N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-2-氟-5-甲酰基-苯甲酰胺的制备
用亚硫酰氯(1.59mL,21.87mmol)处理在甲苯(22mL)中的2-氟-5-甲酰基-苯甲酸(368mg,2.187mmol),在回流温度下搅拌4小时。蒸发挥发性物质,将残余物溶于甲苯(4mL)并且蒸发至干,得到灰白色固体,将其溶于干THF(5mL)并且滴加到5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基胺(843mg,1.68mmol)和DIPEA(0.88mL,5.04mmol)在THF(10mL)中的溶液中,冷却至4℃。使该反应体系逐步达到室温。一夜后,蒸发挥发性物质。将粗产物溶于DCM(150mL)并且用NaHCO3水溶液(100mL),然后用水、再用盐水洗涤。在用硫酸钠干燥,蒸发并且用硅胶纯化(洗脱剂:DCM)后,得到868mg标题化合物,为白色固体,收率79%。
1H-NMR(400MHz),δ(ppm,DMSO-d6):3.98(s,2H)6.34(d,J=8.66Hz,1H)6.89-7.09(m,3H)7.22-7.34(m,15H)7.53 -7.64(m,1H)7.66(s,1H)8.14(br.s.,1H)8.32(d,J=4.51Hz,1H)10.05(s,1H)11.08(br.s.,1H)
步骤i”
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-氟-5-甲酰基-苯甲酰胺的制备
用在二烷(2.8mL)中的4N HCl处理在干二烷(25mL)中的N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-2-氟-5-甲酰基-苯甲酰胺(740mg,1.137mmol)。将该反应体系在室温下搅拌2天。将挥发性成分蒸发至干,将残余物溶于Et2O(10mL),搅拌1小时,通过抽吸过滤,用Et2O(10mL)洗涤,在50℃下和真空中干燥,得到358mg标题化合物,为白色固体,收率77%。
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.08(s,2H)6.88-7.09(m,3H)7.22-7.31(m,1H)7.45(d,J=8.41Hz,1H)7.62(t,J=9.57Hz,1H)7.71(s,1H)8.12-8.19(m,1H)8.35(d,J=5.61Hz,1H)10.08(s,1H)10.92(s,1H)12.80(br.s.,1H)
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-氟-5-(4-甲基-哌嗪-1-基甲基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=2-氟-5-(4-甲基-哌嗪-1-基甲基)-苯基]cpd.120的制备
在氮气环境中和室温下,用N-甲基哌嗪(0.039mL,0.367mmol)、然后用乙酸(0.024mL,0.422mmol)处理在THF(4mL)中的N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-氟-5-甲酰基-苯甲酰胺(150mg,0.367mmol)。0.5小时后,加入三乙酰氧基硼氢化钠,将该反应体系搅拌过夜。加入EtOAc(25mL)和水(25mL),用浓NH4OH将pH调节至11。分离有机层并且用EtOAc(2x10mL)将水层萃取两次。用硫酸钠干燥合并的有机萃取物,蒸发至干并且用硅胶纯化(洗脱剂:DCM: 在MeOH中的7N NH3=96:4),得到177mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.18(br.s.,3H)2.30-2.46(m,8H)3.51(br.s.,2H)4.07(s,2H)6.92-7.00(m,2H)6.99-7.06(m,1H)7.28(s,1H)7.28-7.35(m,1H)7.44(d,J=8.53Hz,1H)7.47-7.54(m,1H)7.65(br.s.,1H)7.67(br.s.,1H)10.66(br.s.,1H)12.75(br.s.,1H)
按照同样方式操作获得下列化合物:
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-氟-5-{[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]甲基}苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=2-氟-5-{[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]甲基}-苯基]cpd.121
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.67(m,6H)1.92(m,1H)2.14(m,1H)2.63(m,2H)2.82(m,1H)3.23-3.37(m,2H)4.07(s,2H)4.17(d,J=14.26Hz,1H)6.93-6.99(m,2H)6.99-7.07(m,1H)7.25-7.28(m,1H)7.28-7.33(m,1H)7.44(d,J=8.65Hz,1H)7.50(br.s.,1H)7.66(br.s.,2H)10.64(br.s.,1H)12.75(br.s.,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-氟-5-(吗啉-4-基甲基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=2-氟-5-(吗啉-4-基甲基)-苯基]cpd.122
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.40(br.s.,4H)3.52(br.s.,2H)3.60(br.s.,4H)4.07(s,2H)6.94-6.99(m, 2H)6.99-7.07(m,1H)7.27(d,J=8.65Hz,1H)7.33(d,J=8.53Hz,1H)7.44(d,J=8.53Hz,1H)7.53(br.s.,1H)7.67(br.s.,2H)10.67(br.s.,1H)12.75(br.s.,1H)。
实施例10
N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-4-氟-异酞氨酸的制备
在室温下,首先用2-甲基-2-丁烯(0.079mL,1.082mmol)、然后用亚氯酸钠(37mg,0.405mmol)和磷酸二氢钠水溶液(0.8mL)滴加处理在叔丁醇(1.8mL)中的N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-2-氟-5-甲酰基-苯甲酰胺(88mg,0.135mmol)。将该反应体系搅拌过夜,然后加入EtOAc(30mL)并且用水(25mL)洗涤。用EtOAc(2x10mL)将水层萃取两次。用盐水洗涤合并的有机层,蒸发至干而得到106mg标题化合物,无需进一步纯化,直接在如下步骤中使用。
1H-NMR(400MHz),δ(ppm,DMSO-d6):3.98(s,2H)6.33(d,J=8.53Hz,1H)6.78(br.s.,1H)6.90-7.07(m,3H)7.20-7.35(m,15H)7.43-7.54(m,1H)7.65(br.s.,1H)8.13(br.s.,1H)8.29(d,J=3.66Hz,1H)11.01(s,1H)13.12(br.s.,1H)
N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-2-氟-5-((S)-2-吡咯烷-1-基甲基-吡咯烷-1-羰基)-苯甲酰胺的制备
用1-羟基苯并三唑(25mg,0.181mmol)、EDCI(35mg,0.181mmol)和(S)-(+)-1-(2-吡咯烷基甲基)吡咯烷(0.03mL,0.1813mmol)处理在DCM(1.4mL)中的N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-4-氟-异酞氨酸(93mg,0.139mmol)。1小时后,用DCM(25mL)稀释该反应体系并且用NaHCO3水溶液(5mL),水(5mL)且最终用盐水洗涤。在用硫酸钠干燥后,蒸发溶剂并且用硅胶纯化(洗脱剂:DCM,在MeOH中的7N NH395:5),得到92mg标题化合物,两步内收率85%。
1H-NMR(400MHz),δ(ppm,DMSO-d6):3.97(s,2H)4.26(br.s.,1H)6.33(d,J=8.41Hz,1H)6.86-7.09(m,4H)7.15-7.35 (m,15H)7.38-7.46(m,1H)7.63(s,1H)7.68(br.s.,1H)7.82(br.s.,1H)10.96(br.s.,1H)
步骤i”
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-氟-5-((S)-2-吡咯烷-1-基甲基-吡咯烷-1-羰基)-苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=2-氟-5-((S)-2-吡咯烷-1-基甲基-吡咯烷-1-羰基)-苯基]cpd.123
用TFA(0.17mL,2.24mmol)处理在DCM(1mL)中的N-[5-(3,5-二氟-苄基)-1-三苯甲基-1H-吲唑-3-基]-2-氟-5-((S)-2-吡咯烷-1-基甲基-吡咯烷-1-羰基)-苯甲酰胺(90mg,0.112mmol)。在室温下2小时后,加入DCM(25mL)并且用NaHCO3水溶液、水和盐水洗涤有机相。用硫酸钠干燥、蒸发并且用硅胶纯化粗产物(洗脱剂:DCM/MeOH/在MeOH中的7N NH3=9:1:0.1),得到42mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.07(s,2H)4.29(br.s.,1H)6.93-6.99(m,2H)6.99-7.06(m,1H)7.27(dd,J=8.53,1.34Hz,1H)7.42(br.s.,1H)7.65-7.74(m,2H)7.85(br.s.,1H)10.80(br.s.,1H)12.77(br.s.,1H)。
实施例11
步骤i'
4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-3-硝基苯甲酸甲酯的制备
将4-(甲氧基羰基)-2-硝基苯甲酸(4.8g,21.3mmol)和亚硫酰氯(15.5mL)在干THF(130mL)中和70℃下搅拌2小时。蒸发挥发性物质并且在0℃下将残余物溶于干吡啶(100mL)。将5-(3,5-二氟-苄基)-1H-吲唑-3-基胺(4.6mg,17.76mmol)在干吡啶(10mL)中的溶液加入到冷却的反应混合物中。使温度达到室温过夜。用NaHCO3 饱和溶液使反应停止,并用乙酸乙酯萃取。用Na2SO4干燥收集的有机相,过滤并且蒸发至干。通过硅胶柱色谱法纯化残余物(DCM/EtOH/在MeOH中7N NH3=95/5/0.5),得到5.4gr(65%收率)标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):3.97(s,3H)4.08(s,2H)6.89-7.00(m,2H)6.99-7.07(m,1H)7.29(dd,J=8.66,1.46Hz,1H)7.45(d,J=8.66Hz,1H)7.76(s,1H)8.01(d,J=7.93Hz,1H)8.40(dd,J=7.93,1.59Hz,1H)8.58(d,J=1.46Hz,1H)11.22(s,1H)12.81(s,1H)
按照同样方式操作获得下列化合物:
4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}苯甲酸甲酯
ESI(+)MS:m/z422(MH+)。
4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-3-硝基苯甲酸的制备
将4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-3-硝基苯甲酸甲酯(5.4g,11.6mmol)溶于THF(78mL)和水(52mL)中,在室温下用LiOH水合物(730mg)处理24小时。蒸发THF并且用5%KHSO4水溶液(100mL)处理得到的水相。过滤出由此沉淀的物质并且在真空中和60℃下干燥,得到标题化合物,无需任何进一步的纯化。
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.08(s,2H)6.92-7.00(m,2H)7.00-7.07(m,1H)7.27(dd,J=8.59,1.40Hz,1H)7.44(d,J=8.65Hz,1H)7.76(s,1H)7.85(d,J=7.68Hz,1H)8.30(dd,J=7.74,1.28Hz,1H)8.50(d,J=1.22Hz,1H)11.08(s,1H)12.77(s,1H)
按照同样方式操作获得下列化合物:
4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}苯甲酸
ESI(+)MS:m/z408(MH+)。
N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-羰基)-2-硝基-苯甲酰胺的制备
用1-羟基苯并三唑(195mg,1.44mmol)、EDCI(276mg,1.44mmol) 和1-甲基哌嗪(0.16mL,1.44mmol)处理在DMF(10mL)中的4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-3-硝基苯甲酸(500mg,1.11mmol)。将该反应体系在室温下保持过夜。通过蒸发除去挥发性物质,在搅拌下将残余物滴加到冰水(25mL)中。用DCM(2x25mL)萃取得到的黄色固体。用硫酸钠干燥合并的有机层并且蒸发而得到590mg标题化合物,将其不经任何进一步纯化而用于下一步。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.23(s,3H)2.34(m,2H)2.45(m,2H)3.39(m,2H)3.67(m,2H)4.08(s,2H)6.93-6.99(m,2H)6.99-7.07(m,1H)7.28(dd,J=8.59,1.40Hz,1H)7.45(d,J=8.53Hz,1H)7.74(s,1H)7.87-7.90(m,1H)7.90-7.93(m,1H)8.15(d,J=0.85Hz,1H)11.10(s,1H)12.78(s,1H)
按照同样方式操作获得下列化合物:
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2R)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-{[(2R)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}-苯基]cpd.124
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.06(s,2H)4.30(br.s.,1H)6.94-7.00(m,2H)6.99-7.06(m,1H)7.27(dd,J=8.66,1.59Hz,1H)7.44(d,J=8.54Hz,1H)7.61(d,2H)7.63(s,1H)8.11(d,J=8.29Hz,2H)10.81(s,1H)12.77(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-{[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]羰基}-苯基] cpd.125
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.06(s,2H)4.30(br.s.,1H)6.94-7.00(m,2H)6.99-7.06(m,1H)7.27(dd,J=8.60,1.52Hz,1H)7.44(d,J=8.90Hz,1H)7.59-7.65(m,3H)8.11(d,J=8.17Hz,2H)10.81(s,1H)12.77(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[4-(吡咯烷-1-基)哌啶-1-基]羰基}苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-{[4-(吡咯烷-1-基)哌啶-1-基]羰基}-苯基]cpd.126
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.41(m,2H)1.70(m,4H)1.94(m,2H)2.33(m,1H)2.53(m,4H)3.06(m,2H)3.52(m,1H)4.06(s,2H)4.30m,1H)6.94-7.00(m,2H)7.00-7.05(m,1H)7.27(dd,J=8.66,1.59Hz,1H)7.42-7.46(m,1H)7.54(d,J=8.29Hz,2H)7.62(s,1H)8.12(d,J=8.17Hz,2H)10.81(s,1H)12.77(s,1H)。
实施例12
2-硝基-对苯二甲酸1-叔丁酯4-甲酯的制备
用叔丁醇(4.05mL,42.99mmol)、二碳酸二叔丁酯(12.19g, 55.87g)和DMAP(0.79g,6.45mmol)处理在DCM(54mL)中的商购2-硝基-对苯二甲酸4-甲酯(4.84g,21.49mmol)。在室温下4天后,用DCM(100mL)稀释该反应体系,用1N HCl(100mL)、NaHCO3水溶液且最终用水洗涤。在用硫酸钠干燥并且蒸发挥发性物质后,得到标题化合物,为淡褐色油状物,超过了定量收率(6.51g)。将粗产物不经进一步纯化而用于下一步。
ESI(+)MS:m/z282(MH+)。
2-硝基-对苯二甲酸1-叔丁酯的制备
将2-硝基-对苯二甲酸1-叔丁酯4-甲酯(21.49mmol)溶于THF(143mL)中,并且用在水(97mL)中的氢氧化锂一水合物(1.35g,32.24mmol)处理。将该反应体系在室温下搅拌2小时,然后部分蒸发,用冰/水浴冷却并且通过滴加1N HCl(35mL)处理。产生固体沉淀。然后用DCM(150mL和2X50mL)萃取该混合物。用1N HCl(10mL)进一步处理水相并且用DCM(2X50mL)萃取。然后用水且最终用盐水洗涤合并的有机层。在用硫酸钠干燥并且蒸发后,得到5.34g标题化合物,为淡红色固体,总收率93%。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.53(s,9H)7.93(d,J=7.92Hz,1H)8.31(dd,J=7.92,1.58Hz,1H)8.42(d,J=1.34Hz,1H)13.78(s,1H)
2-硝基-4-(哌啶-1-羰基)-苯甲酸叔丁酯的制备
用1-羟基苯并三唑(0.39g,2.43mmol),EDCI(0.47g,2.43mmol)和哌啶(0.24mL,2.43mmol)处理在DCM(18mL)中的2-硝基-对苯二甲酸1-叔丁酯(500mg,1.88mmol)。3小时后,用DCM(50mL)稀释该反应体系并且用NaHCO3水溶液(30mL)、水(30mL)且最终用盐水洗涤。用硫酸钠干燥并且蒸发溶剂后,得到定量收率的标题化合物,为无色油状物。将粗产物不经任何进一步纯化而用于如下反应。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.45(br.s.,6H)1.51(s,9H)3.19-3.27(m,2H)3.59(br.s.,2H)7.76-7.81(m,1H)7.85-7.89(m,1H)8.01(d,J=1.22Hz,1H)
按照与上述同样的方式操作获得下列化合物:
4-[(2-甲氧基乙基)(甲基)氨基甲酰基]-2-硝基苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):旋转异构体混合物1.52(s,9H)7.77-7.83(m,1H)7.84-7.91(m,1H)8.03(d,J=0.61Hz,1H)
2-硝基-4-(吡咯烷-1-基羰基)苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.52(s,9H)1.78-1.94(m,4H)3.37-3.43(m,2H)3.49(t,J=6.70Hz,2H)7.84-7.90(m,1H)7.91-7.96(m,1H)8.12(d,J=1.34Hz,1H)
4-(氮杂环丁烷-1-基羰基)-2-硝基苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.52(s,9H)2.29(dt,J=15.51,7.79Hz,2H)4.06-4.12(m,2H)4.31-4.38(m,2H)7.88(d,J=7.92Hz,1H)8.01(dd,J=7.92,1.58Hz,1H)8.16(d,J=1.34Hz,1H)
4-(吗啉-4-基羰基)-2-硝基苯甲酸叔丁酯
ESI(+)MS:m/z337(MH+)。
2-硝基-4-哌啶-1-基甲基-苯甲酸盐酸盐的制备
在室温下和氮气环境中和搅拌下将2-硝基-4-(哌啶-1-羰基)-苯甲酸叔丁酯(1.87mmol)溶于干THF并且滴加到3.7mL硼烷四氢呋喃复合物的1.0M溶液中。然后将该反应体系回流6小时,冷却至室温并且谨慎用2N HCl(10mL)处理。在搅拌15分钟后,逐份加入固体K2CO3(1.75g)。用EtOAc(3x25mL)萃取该混合物。用硫酸钠干燥合并的有机层并且蒸发而得到油状物,对其进行HPLC-MS分析显示所得到的为叔胺和相应硼烷复合物的4:6混合物。将该混合物溶于DCM(1mL)并且用在二烷中的4N HCl(7mL)处理。在室温下4天后,形成灰白色,过滤,用二烷(5mL)洗涤并且在50℃下和真空中干燥。得到0.40g标题化合物,总收率70%。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.37-1.80(m,5H)2.90(br.s.,4H)4.42(s,2H)7.92-7.99(m,2H)8.24(d,J=0.85 Hz,1H)9.99(br.s.,1H)
4-{[(2-甲氧基乙基)(甲基)氨基]甲基}-2-硝基苯甲酸盐酸盐
ESI(+)MS:m/z269(MH+)。
2-硝基-4-(吡咯烷-1-基甲基)苯甲酸盐酸盐
ESI(+)MS:m/z251(MH+)。
4-(吗啉-4-基甲基)-2-硝基苯甲酸盐酸盐
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.39(t,J=4.51Hz,4H)3.59(t,J=4.63Hz,4H)3.62(s,2H)7.72(dd,J=7.87,1.28Hz,1H)7.82(d,J=7.80Hz,1H)7.87(d,J=0.98Hz,1H)
4-(氮杂环丁烷-1-基甲基)-2-硝基苯甲酸盐酸盐
ESI(+)MS:m/z237(MH+)。
步骤i'
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-硝基-4-(哌啶-1-基甲基)苯甲酰胺的制备
用亚硫酰氯(5mL)处理2-硝基-4-哌啶-1-基甲基-苯甲酸盐酸盐(440mg,1.46mmol)并且回流1小时。通过蒸发除去过量试剂,随后从甲苯(2x5mL)中蒸发。在真空中进一步干燥固体。用干吡啶(7mL)处理酰氯,冷却至4℃并且在氮气环境中和搅拌下加入在干吡啶(3mL)中的5-(3,5-二氟-苄基)-1H-吲唑-3-基胺(315mg,1.22mmol)。在搅拌几小时后,将该反应体系保持在0℃下过夜。加入EtOAc(50mL)和水(50mL),用浓NH4OH将pH调节至9。分离有机层,用硫酸钠干燥,蒸发至干并且用硅胶(DCM:MeOH=95:5)纯化,得到266mg标题化合物,收率43%。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.54(br.s.,6H)2.39(br.s.,4H)3.61(s,2H)4.07(s,2H)6.92-6.99(m,2H)6.99-7.06(m,1H)7.26-7.29(m,1H)7.44(d,J=8.53Hz,1H)7.73(s,1H)7.79(s,2H)8.04(s,1H)11.01(s,1H)12.75(s,1H)
按照与上述同样的方式操作获得下列化合物:
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2-甲氧基乙基)(甲 基)氨基]甲基}-2-硝基苯甲酰胺
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.24(s,3H)2.60(t,J=5.67Hz,2H)3.26(s,3H)3.50(t,J=5.73Hz,2H)3.70(s,2H)4.07(s,2H)6.96(d,J=6.70Hz,2H)6.99-7.07(m,1H)7.24-7.30(m,1H)7.44(d,J=8.53Hz,1H)7.73(s,1H)7.80(s,2H)8.07(s,1H)11.02(s,1H)12.75(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-硝基-4-(吡咯烷-1-基甲基)苯甲酰胺
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.75(br.s.,4H)2.46-2.56(m,4H)3.77(br.s.,2H)4.07(s,2H)6.96(d,J=6.58Hz,2H)6.99-7.06(m,1H)7.25-7.30(m,1H)7.44(d,J=8.54Hz,1H)7.73(s,1H)7.80(s,2H)8.05(s,1H)11.02(s,1H)12.75(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(吗啉-4-基甲基)-2-硝基苯甲酰胺
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.40-2.46(m,4H)3.60-3.65(m,4H)3.66(s,2H)4.07(s,2H)6.90-6.99(m,2H)6.99-7.07(m,1H)7.24-7.29(m,1H)7.44(d,J=8.54Hz,1H)7.73(s,1H)7.81(s,2H)8.07(s,1H)11.02(s,1H)12.75(s,1H)
4-(氮杂环丁烷-1-基甲基)-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-硝基苯甲酰胺
ESI(+)MS:m/z478(MH+)。
转化4
2-氨基-N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-哌啶-1-基甲基苯甲酰胺的制备
将N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-2-硝基-4-哌啶-1-基甲基-苯甲酰胺(255mg,0.505mmol)混悬于DCM(7mL)中并且用nBu4NCl(95mg,0.343mmol)处理。在搅拌下滴加在水(3.4mL)中的 Na2S2O4(659mg,3.029mmol)。2小时后,通过蒸发除去挥发性物质,从水相中过滤固体并且在真空中干燥。用在二烷中的4N HCl(12mL)处理固体,然后通过蒸发除去溶剂。将固体溶于DCM(100mL),用K2CO3水溶液、然后用盐水洗涤。在用硫酸钠干燥并且除去溶剂后,得到248mg标题化合物,超过定量收率。将粗产物不经进一步纯化而用于下一步。
ESI(+)MS:m/z476(MH+)。
按照与上述同样的方式操作获得下列化合物:
2-氨基-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-{[(2-甲氧基乙基)(甲基)氨基]甲基}-苯甲酰胺
ESI(+)MS:m/z480(MH+)。
2-氨基-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(吡咯烷-1-基甲基)苯甲酰胺
ESI(+)MS:m/z462(MH+)。
2-氨基-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(吗啉-4-基甲基)-苯甲酰胺
ESI(+)MS:m/z478(MH+)。
2-氨基-4-(氮杂环丁烷-1-基甲基)-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-苯甲酰胺
ESI(+)MS:m/z448(MH+)。
实施例13
4-(4-甲基哌嗪-1-基)-2-[(1-甲基哌啶-4-基)氨基]苯甲酸叔丁酯的制备
在氮气环境中将2-氨基-4-(4-甲基哌嗪-1-基)苯甲酸叔丁酯(1.5g,5.15mmol)溶于干二烷(25mL)。加入N-甲基哌啶酮(0.72g,6.18mmol,1.2eq),随后加入三氟乙酸(1.03mL,13.39mmol,2.6eq)和三乙酰氧基硼氢化钠(1.72g,7.73mmol,1.5eq)。将该混合物在室温下搅拌26小时。在此过程中,再加入额外份数的N-甲基哌啶酮(0.5mL,0.75eq)和三乙酰氧基硼氢化钠(1.72g,7.73 mmol,1.5eq)。然后加入NaHCO3饱和水溶液,将该反应混合物在减压下浓缩。加入10%氢氧化铵至pH10,用二氯甲烷萃取水相。用盐水洗涤有机相,用Na2SO4干燥并且在减压下蒸发。通过硅胶色谱法纯化(DCM/MeOH/在MeOH中的NH37%=90:8:2),得到1.025g标题化合物,为灰白色固体(51%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.36-1.47(m,2H)1.50(s,9H)1.88-1.98(m,2H)2.09-2.16(m,2H)2.18(s,3H)2.21(s,3H)2.38-2.44(m,4H)2.59-2.68(m,2H)3.20-3.26(m,4H)3.37-3.50(m,1H)6.01(d,J=1.95Hz,1H)6.18(dd,J=9.08,2.26Hz,1H)7.56(d,J=9.02Hz,1H)7.68(d,J=7.56Hz,1H)
按照同样方式操作获得下列化合物:
4-{[2-(叔丁氧基羰基)-5-(4-甲基哌嗪-1-基)苯基]氨基}哌啶-1-甲酸乙酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.19(t,J=7.50Hz,3H)1.24-1.34(m,2H)1.50(s,9H)1.89-2.00(m,2H)2.22(s,3H)2.39-2.45(m,4H)3.03-3.16(m,2H)3.20-3.29(m,4H)3.66-3.76(m,1H)3.80-3.90(m,2H)4.05(q,J=7.07Hz,2H)6.07(d,J=2.07Hz,1H)6.20(dd,J=9.15,2.19Hz,1H)7.57(d,J=9.02Hz,1H)7.70(d,J=7.93Hz,1H)
4-(4-甲基哌嗪-1-基)-2-[(1-甲基哌啶-4-基)(三氟乙酰基)氨基]苯甲酸叔丁酯的制备
在氮气环境中将4-(4-甲基哌嗪-1-基)-2-[(1-甲基哌啶-4-基)氨基]苯甲酸叔丁酯(1.02g,2.625mmol)溶于干二氯甲烷(10mL),将该溶液冷却至0℃。加入三乙胺(0.548mL,3.938mmol,1.5eq),随后加入三氟乙酐(0.445mL,3.15mmol,1.2eq),将该混合物在0℃下搅拌2小时。然后用二氯甲烷稀释并且用水洗涤两次。用二氯甲烷反萃取水相。用Na2SO4干燥合并的有机相,在减压下浓缩,得到1.18g粗产物(93%收率),将其不经进一步纯化而用于下一步。
1H-NMR(400MHz),δ(ppm,DMSO-d6):0.93-1.07(m,2H)1.45(s,9H)1.48-1.64(m,2H)1.85-2.05(m,2H)2.11(s,3H)2.23(s,3H)2.41-2.47(m,4H)2.66-2.87(m,2H)3.27-3.35(m,4H)4.10-4.26(m,1H)6.78(d,J=2.44Hz,1H)7.05(dd,J=9.02,2.56Hz,1H)7.81(d,J=9.02Hz,1H)
按照同样方式操作获得下列化合物:
4-{[2-(叔-丁氧基羰基)-5-(4-甲基哌嗪-1-基)苯基](三氟乙酰基)氨基}哌啶-1-甲酸乙酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):0.77-0.93(m,1H)1.13(t,J=7.07Hz,3H)1.34-1.44(m,1H)1.46(s,9H)1.56-1.63(m,1H)2.01-2.10(m,1H)2.22(s,3H)2.40-2.44(m,4H)2.78-2.97(m,2H)3.27-3.36(m,4H)3.91-4.06(m,2H)3.94-4.01(m,2H)4.37-4.47(m,1H)6.78(d,J=2.44Hz,1H)7.04(dd,J=9.02,2.56Hz,1H)7.81(d,J=9.02Hz,1H)
4-(4-甲基哌嗪-1-基)-2-[(1-甲基哌啶-4-基)(三氟乙酰基)氨基]苯甲酸二盐酸盐的制备
在氮气环境中将4-(4-甲基哌嗪-1-基)-2-[(1-甲基哌啶-4-基)(三氟乙酰基)氨基]苯甲酸叔丁酯(1.18g,2.435mmol)溶于干二氯甲烷(3mL)。然后滴加4M HCl在二烷中的溶液(9.1mL,36.4mmol,15eq),将该混合物搅拌1.5小时。形成粘性固体。加入5个以上当量的HCl,将该混合物搅拌2小时以上。过滤固体,用DCM(10mL)和乙醚(10mL)洗涤,在真空中和60℃下干燥2小时。得到1.06g标题化合物,为浅褐色粉末(87%收率)。
ESI(+)MS:m/z429(MH+)。
按照同样方式操作获得下列化合物:
2-{[1-(乙氧基羰基)哌啶-4-基](三氟乙酰基)氨基}-4-(4-甲基哌嗪-1-基)苯甲酸盐酸盐
1H-NMR(400MHz),δ(ppm,DMSO-d6):0.83-0.98(m,1H)1.13(t,J=7.01Hz,3H)1.34-1.47(m,1H)1.63(d,J=10.85Hz, 1H)2.04(d,J=13.66Hz,1H)2.84(s,3H)2.88(m,2H)3.16(m,4H)3.52(m,2H)3.94-4.02(m,2H)4.05(m,4H)4.34-4.48(m,1H)6.96(d,J=2.32Hz,1H)7.11(dd,J=8.90,2.56Hz,1H)7.91(d,J=8.90Hz,1H)10.26(br.s.,1H)12.79(br.s.,1H)
步骤i'
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基哌嗪-1-基)-2-[(1-甲基哌啶-4-基)氨基]苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基哌嗪-1-基)-2-[(1-甲基哌啶-4-基]氨基)-苯基]cpd.13的制备
在氮气环境中将4-(4-甲基哌嗪-1-基)-2-[(1-甲基哌啶-4-基)(三氟乙酰基)氨基]苯甲酸二盐酸盐(251mg,0.501mmol,1.3eq)混悬于干THF(4mL)中。加入亚硫酰氯(0.365mL,1.0mmol,2.6eq),将该混合物在70℃下搅拌1.5小时。然后将该混合物蒸发至干,溶于甲苯,再蒸发至干,然后在室温下和高度真空中保持2小时。然后将酰氯混悬于干吡啶(2mL)中并且冷却至0℃。滴加5-(3,5-二氟苄基)-1H-吲唑-3-胺(100mg,0.386mmol,1eq)在干吡啶(1.2mL)中的溶液,将该混合物在0℃下搅拌2小时,然后在4℃下保持过夜。然后用水和乙酸乙酯稀释。用30%氢氧化铵将水相碱化至pH10,用乙酸乙酯萃取。用Na2SO4干燥合并的有机层并且蒸发至干,得到290mg粗的三氟乙酰胺。将粗产物溶于甲醇(7mL),加入三乙胺(1.3mL,9.34mmol,24eq),将该溶液回流1.5小时。将该反应混合物蒸发至干并且通过硅胶色谱法纯化(DCM/MeOH/在MeOH中的NH37%=83:17:1)。然后在室温下将产物在乙醚(1mL)中搅拌成浆液30分钟,然后过滤并 且在45℃下和高度真空中干燥3小时。得到153mg标题化合物,为淡黄色粉末(69%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.33-1.50(m,2H)1.92(dd,J=9.51,4.02Hz,2H)2.18(br.s.,3H)2.21(br.s.,2H)2.23(s,3H)2.44(t,J=4.60Hz,4H)2.61(br.s.,2H)3.25(t,J=4.90Hz,4H)3.41-3.52(m,1H)4.04(s,2H)6.08(d,J=1.95Hz,1H)6.22(dd,J=8.96,2.13Hz,1H)6.98(m,3H)7.24(dd,J=8.65,1.46Hz,1H)7.40(d,J=8.53Hz,1H)7.49(s,1H)7.78(d,J=9.02Hz,1H)8.26(d,J=7.44Hz,1H)10.06(s,1H)12.62(s,1H)
按照同样方式操作获得下列化合物:
4-{[2-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-5-(4-甲基哌嗪-1-基)苯基]氨基}哌啶-1-甲酸乙酯[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基哌嗪-1-基)-2-{(1-(乙氧基羰基)哌啶-4-基]氨基}-苯基]cpd.138
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.17(t,J=7.07Hz,3H)1.21-1.34(m,2H)1.87-1.98(m,2H)2.26(br.s.,3H)2.45-2.49(m,4H)3.07-3.21(m,2H)3.25-3.35(m,4H)3.64-3.73(m,1H)3.76(ddd,J=13.57,4.18,3.96Hz,2H)4.02(q,J=7.03Hz,2H)4.04(s,2H)6.15(d,J=2.10Hz,1H)6.25(dd,J=9.11,2.10Hz,1H)6.92-7.05(m,3H)7.25(dd,J=8.57,1.52Hz,1H)7.41(d,J=8.57Hz,1H)7.47(s,1H)7.80(d,J=9.11Hz,1H)8.31(d,J=7.93Hz,1H)10.09(s,1H)12.63(s, 1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基哌嗪-1-基)-2-(哌啶-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基哌嗪-1-基)-2-[(哌啶-4-基)氨基]-苯基]cpd.139的制备
在螺旋帽pirex管内将4-{[2-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-5-(4-甲基哌嗪-1-基)苯基]氨基}哌啶-1-甲酸乙酯(198mg,0.313mmol)溶于62%HBr水溶液(4mL)并且在70℃下搅拌1小时。然后用水和30%氢氧化铵稀释该混合物,并且用乙酸乙酯萃取。用Na2SO4干燥有机相并且浓缩至干。通过硅胶色谱法纯化(DCM/MeOH/在MeOH中的NH37%=80:10:10),得到127mg纯的产物(72%收率)。将产物与乙酸乙酯一起搅拌成浆液,过滤,用正-己烷洗涤并且在45℃下和高度真空中干燥3小时,得到88mg标题化合物,为白色固体。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.16-1.31(m,J=12.50,10.20,10.20,3.66Hz,2H)1.89(dq,J=12.50,3.40Hz,2H)2.22(s,3H)2.43(t,J=4.76Hz,4H)2.63(ddd,J=12.59,10.27,2.62Hz,2H)2.92(dt,J=12.53,3.92Hz,2H)3.25(t,J=4.63Hz,4H)3.46-3.57(m,1H)4.04(s,2H)6.09(d,J=2.07Hz,1H)6.22(dd,J=9.02,2.07Hz,1H)6.93-7.04(m,3H)7.24(dd,J=8.66,1.59Hz,1H)7.40(d,J=8.66Hz,1H)7.48(br.s.,1H)7.78(d,J=9.02Hz,1H)8.24(d,J=7.80Hz,1H)10.04(s,1H)12.62(s,1H)。
实施例14
1-[1-(叔-丁氧基羰基)哌啶-4-基]-1H-吡唑-4-甲酸的制备
在氮气环境中和0℃下,将1H-吡唑-4-甲酸乙酯(700mg,5mmol)和NaH60%(6mmol)的混合物在干DMF(15mL)中搅拌1小时。加入溶于4mL干DMF的4-[(甲基磺酰基)氧基]哌啶-1-甲酸叔丁酯(1.53g,5.5mmol),将得到的溶液在100℃下加热过夜。用水使反应混合物骤冷并且用乙酸乙酯萃取(x3)。用Na2SO4干燥收集的有机相,过滤并且蒸发至干。将残余物溶于MeOH(20mL)和水(5mL)并且加入KOH(1.12g,20mmol)。将得到的溶液在室温下搅拌24小时,然后减压除去溶剂。将残余物溶于AcOEt和KHSO45%溶液。用EtOAc将水相萃取几次。用Na2SO4干燥收集的有机相,过滤并且蒸发至干而得到600mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.42(s,9H)1.73-1.87(m,2H)1.96-2.03(m,2H)2.82-2.99(m,2H)4.04(d,J=12.93Hz,2H)4.34-4.47(m,1H)7.81(s,1H)8.29(s,1H)12.26(br.s.,1H)
步骤i'
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-1-(哌啶-4-基)-1H-吡唑-4-甲酰胺盐酸盐[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=(哌啶-4-基)-1H-吡唑]cpd.102的制备
将1-[1-(叔丁氧基羰基)哌啶-4-基]-1H-吡唑-4-甲酸(134mg,0.45mmol)和草酰氯(0.6mmol)在干DCM(5mL)中和在室温下搅拌过夜。蒸发挥发性物质并且在0℃下将残余物溶于干吡啶(5mL)。将5-(3,5-二氟-苄基)-1H-吲唑-3-基胺(100mg,0.38mmol)在干吡啶(2mL)中的溶液加入到冷却的反应混合物中。1小时后,用NaHCO3饱和溶液使反应猝灭并且用乙酸乙酯萃取。用Na2SO4干燥收集的有机相, 过滤并且蒸发至干。通过硅胶柱色谱法纯化残余物(DCM/EtOH/在MeOH中的NH35N=1000/50/1),得到87mg Boc-保护的衍生物,将其溶于2mL二烷并且用0.4mL在二烷中的4M HCl处理。蒸发挥发性物质而得到65mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.10-2.23(m,2H)2.22-2.31(m,2H)3.03-3.19(m,2H)3.32-3.49(m,2H)4.05(s,2H)4.54-4.63(m,1H)6.92-6.98(m,2H)6.98-7.05(m,1H)7.25(dd,J=8.59,1.65Hz,1H)7.40-7.44(m,1H)7.63(d,J=0.61Hz,1H)8.16(s,1H)8.49(s,1H)8.65-8.77(m,1H)8.82-8.96(m,1H)10.44(s,1H)12.71(br.s.,1H)
实施例15
步骤i'
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-[(顺式-4-羟基环己基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-[(顺式-4-羟基环己基)氨基]-苯基]cpd.103的制备
将4-(4-甲基哌嗪-1-基)-2-[{顺式-4-[(苯基羰基)氧基]环己基}(三氟乙酰基)氨基]苯甲酸盐酸盐(1.03g,1.94mmol)和草酰氯(3.88mmol)在干DCM(20mL)和几滴干DMF中和0℃下搅拌,使温度在2小时内达到室温。蒸发挥发性物质,在0℃下将残余物溶于干吡啶(25mL)。将5-(3,5-二氟-苄基)-1H-吲唑-3-基胺(387mg,1.49mmol)在干吡啶(6mL)中的溶液加入到冷却的反应混合物中。使温度达到室温下过夜。用NaHCO3饱和溶液使反应停止并且用乙酸乙酯萃取。用Na2SO4干燥收集的有机相,过滤并且蒸发至干。通过硅胶柱色谱法 纯化残余物(DCM/AcOEt/EtOH=100/10/15)。将由此得到的衍生物溶于MeOH(200mL)和水(20mL)并且在60℃下用LiOH水合物(160mg,3.8mmol)处理4小时。蒸发MeOH并且用EtOAc萃取得到的水相。用Na2SO4干燥收集的有机相,过滤并且蒸发至干。通过硅胶柱色谱法纯化残余物(DCM/EtOH/在MeOH中的NH35N=100/10/2),得到233mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.41-1.70(m,8H)2.24(s,3H)2.45(br.s.,4H)3.22-3.29(m,4H)3.58(d,J=10.61Hz,2H)4.05(s,2H)4.43(d,J=3.78Hz,1H)6.09(d,J=1.95Hz,1H)6.22(dd,J=8.96,2.13Hz,1H)6.94-7.04(m,3H)7.25(dd,J=8.65,1.58Hz,1H)7.41(d,J=8.53Hz,1H)7.51(s,1H)7.79(d,J=9.14Hz,1H)8.39(d,J=7.68Hz,1H)10.04(s,1H)12.63(s,1H)
按照与上述同样的方式操作获得下列化合物:
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-[(反式-4-羟基环己基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-[(反式-4-羟基环己基)氨基]-苯基]cpd.104
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.10-1.22(m,2H)1.29-1.41(m,2H)1.78-1.83(m,2H)1.94-2.03(m,2H)2.24(s,3H)2.42-2.48(m,4H)3.23-3.28(m,4H)3.34-3.42(m,1H)3.43-3.52(m,1H)4.04(s,2H)4.53(d,J=4.14Hz,1H)6.09(d,J=2.07Hz,1H)6.21(dd,J=9.02,2.19Hz,1H)6.95-7.04(m,3H)7.25(dd,J=8.53,1.58Hz,1H)7.40(d,J=8.53Hz, 1H)7.48(s,1H)7.77(d,J=9.14Hz,1H)8.17(d,J=7.80Hz,1H)10.04(s,1H)12.61(s,1H)
实施例16
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-[(2-羟基乙基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-[(2-羟基乙基)氨基]-苯基]cpd.105的制备
将2-[(2-{[叔丁基(二甲基)甲硅烷基]氧基}乙基)氨基]-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基哌嗪-1-基)苯甲酰胺(126mg,0.2mmol)溶于干THF(3mL)并且在0℃下加入在THF中的1M TBAF(0.24mL)。将得到的溶液在室温下搅拌过夜。用水使反应停止并且用乙酸乙酯萃取。用Na2SO4干燥收集的有机相,过滤并且蒸发至干。通过硅胶柱色谱法纯化残余物(DCM/EtOH/在MeOH中的NH35N=85/15/1),得到83mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.34(br.s.,3H)2.51-2.65(m,4H)3.20(q,J=5.57Hz,2H)3.25-3.36(m,4H)3.60(q,J=5.53Hz,2H)4.05(s,2H)4.74(t,J=5.18Hz,1H)6.09(d,J=2.07Hz,1H)6.25(dd,J=8.90,2.19Hz,1H)6.94-6.99(m,2H)6.99-7.04(m,1H)7.23(dd,J=8.66,1.58Hz,1H)7.41(d,J=8.65Hz,1H)7.51(s,1H)7.79(d,J=9.02Hz,1H)8.22(t,J=5.18Hz,1H)10.06(s,1H)12.62(s,1H)
实施例17
2-[(氮杂环丁烷-3-基甲基)氨基]-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基哌嗪-1-基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5- 二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-[(氮杂环丁烷-3-基甲基)氨基]-苯基]cpd.106的制备
将3-({[2-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-5-(4-甲基哌嗪-1-基)苯基]氨基}甲基)氮杂环丁烷-1-甲酸叔丁酯(289mg,0.45mmol)溶于DCM(3mL)并且加入TFA(0.7mL)。将得到的反应溶液在室温下搅拌过夜。用DCM稀释该混合物并且用10%NH3水萃取。蒸发有机相。进行反相柱色谱纯化,得到104mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.24(s,3H)2.42-2.47(m,4H)2.80-2.90(m,1H)3.26-3.38(m,4H)3.58(t,J=7.86Hz,2H)4.04(s,2H)6.08(d,J=2.32Hz,1H)6.25(dd,J=8.96,2.13Hz,1H)6.94-7.00(m,2H)6.98-7.04(m,1H)7.25(dd,J=8.65,1.58Hz,1H)7.39-7.43(m,1H)7.49(d,J=0.61Hz,1H)7.80(d,J=8.90Hz,1H)8.16(t,J=5.06Hz,1H)10.07(br.s.,1H)12.63(br.s.,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-{[(1-甲基氮杂环丁烷-3-基)甲基]氨基}-4-(4-甲基哌嗪-1-基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基-哌嗪-1-基)-2-[(1-甲基氮杂环丁烷-3-基甲基)氨基]-苯基]cpd.107的制备
向2-[(氮杂环丁烷-3-基甲基)氨基]-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-(4-甲基哌嗪-1-基)苯甲酰胺(100mg,0.14mmol)在二氯甲烷(2mL)中的溶液中加入37wt.%在水中的甲醛(0.014mL,0.168mmol),TEA(0.4mmol)和三乙酰氧基硼氢化钠(45mg,0.21mmol)。将该混合物在室温下搅拌过夜,用二氯甲烷稀释,用NaHCO3饱和水溶液、水和盐水洗涤。用硫酸钠干燥有机相并且蒸发至干。通过硅胶快速色谱法纯化粗产物,使用二氯甲烷/甲醇/在MeOH中的NH35N(100:10:1)作为洗脱剂,得到5mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.26(s,3H)2.47(br.s.,4H)2.62(s,3H)2.84-2.99(m,1H)3.27-3.34(m,4H)3.36-3.46(m,2H)3.52-3.62(m,2H)3.80-3.90(m,2H)4.04(s,2H)6.09(d,J=2.07Hz,1H)6.28(dd,J=9.02,2.07Hz,1H)6.93-6.99(m,2H)6.99-7.05(m,1H)7.25(dd,J=8.59,1.52Hz,1H)7.41(d,J=8.65Hz,1H)7.50(s,1H)7.81(d,J=9.14Hz,1H)8.25(t,J=5.49Hz,1H)10.12(s,1H)12.64(s,1H)。
实施例18
4-硝基-2-(四氢-吡喃-4-基氨基)-苯甲酸的制备
在60℃下将4-硝基-2-(四氢-吡喃-4-基氨基)-苯甲酸乙酯(11.2g,38mmol)溶于200mL乙醇,然后加入2N NaOH(40mL,80mmol)。将该混合物在60℃下搅拌4小时,然后减压除去溶剂。将残余物溶于200mL水,用2N HCl(35mL)使该混合物到达酸性pH。过滤沉淀的黄色固体,用大量水洗涤并且在烘箱内、在40℃下干燥,得到标题化合物(9.3g)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):13.49(bs,1H),8.17(bd,1H),8.04(d,J=8.7Hz,1H),7.54(d,J=2.2Hz,1H),7.32(dd,J1=8.7HZ,J2=2.2Hz,1H),3.90-3.78(m,3H),3.54(m,2H),1.98(m,2H),1.46(m,2H)。
4-硝基-2-[(四氢-吡喃-4-基)-(2,2,2-三氟-乙酰基)-氨基]-苯 甲酸的制备
在室温下向30mL三氟乙酐中分小部分加入4-硝基-2-(四氢-吡喃-4-基氨基)-苯甲酸(9.1g,34.2mmol)。将该混合物在室温下搅拌1小时,然后蒸发至干。用200mL水处理残余物(褐色油)并且在室温下剧烈搅拌3小时。过滤由此形成的白色固体,用大量水洗涤并且在烘箱内和40℃下干燥,得到标题化合物(11.8g)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):13.52(bs,1H),8.45(dd,J1=8.5Hz,J2=2.3Hz,1H),8.32(d,J=2.3Hz,1H),8.26(d,J=8.5Hz,1H),4.58(m,1H),3.84(m,2H),3.45-3.2(m,2H),1.98(m,1H),1.59(m,1H),1.49(m,1H),1.14(m,1H)。
步骤i'
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-硝基-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酰胺的制备
将4-硝基-2-[(四氢-吡喃-4-基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸(3.62g,10mmol)和草酰氯(3.8mL,30mmol)在干DCM(120mL)和几滴干DMF中,在室温下搅拌2小时。蒸发挥发性物质并且在0℃下将残余物溶于干吡啶(50mL)。将5-(3,5-二氟-苄基)-1H-吲唑-3-基胺(2g,7.72mmol)在干吡啶(20mL)中的溶液在氮气环境中加入到冷却的反应混合物中。使得到的混合物在室温下反应过夜,然后减压除去溶剂。将残余物溶于EtOAc并且用NaHCO3饱和水溶液、水和盐水洗涤。用硫酸钠干燥有机相并且蒸发至干。通过硅胶快速色谱法纯化粗产物,使用AcOEt/己烷7:3作为洗脱剂,得到3.9g标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.38-1.57(m,2H)1.65-1.74(m,1H)1.91-1.98(m,1H)3.25-3.44(m,2H)3.70-3.78(m,1H)3.87(dd,J=11.92,4.09Hz,1H)4.04(s,2H)4.47-4.58(m,1H)6.98(d,J=1.34Hz,2H)6.99-7.06(m,1H)7.31(dd,J=8.68,1.47Hz,1H)7.45(d,J=8.56Hz,1H)7.54(s,1H)8.20(d,J=8.56Hz,1H)8.36(d,J=2.32Hz,1H)8.51(dd, J=8.56,2.08Hz,1H)11.28(s,1H)12.85(s,1H)
转化4
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-氨基-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酰胺的制备
将N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-硝基-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酰胺(3.86g,6.4mmol),环己烯(10mL),二烷(70mL)和10%Pd/C(0.42g)的混合物在100℃下搅拌4小时。用硅藻土垫过滤该反应混合物,用THF和MeOH充分洗涤。在蒸发有机相后,通过硅胶色谱法纯化粗产物(DCM/EtOH9/1),得到2.75g标题化合物(82%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.29(qd,J=12.28,4.63Hz,1H)1.56(qd,J=12.19,4.51Hz,1H)1.62(ddd,J=12.93,3.47,2.01Hz,1H)1.84(ddd,J=12.47,3.93,2.01Hz,1H)3.33(m,2H)3.77(dd,J=11.58,4.39Hz,1H)3.88(dd,J=11.65,4.33Hz,1H)4.00(s,2H)4.43(tt,J=11.93,3.86Hz,1H)5.96(s,2H)6.50(d,J=2.32Hz,1H)6.68(dd,J=8.47,2.26Hz,1H)6.89-6.97(m,2H)7.01(tt,J=9.43,2.33Hz,1H)7.25(dd,1H)7.39(m,2H)7.68(d,J=8.54Hz,1H)10.33(s,1H)12.64(s,1H)
转化6
3-{[(4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-3-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯基)氨基]甲基}氮杂环丁烷-1-甲酸叔丁酯的制备
向N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-氨基-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酰胺(240mg,0.42mmol)在二氯甲烷(20mL)中的溶液中加入3-甲酰基氮杂环丁烷-1-甲酸叔丁酯(116mg,0.63mmol),三氟乙酸(0.32mL)和三乙酰氧基硼氢化四甲基铵(165mg g,0.63mmol)。将该混合物在室温下搅拌过夜,然后用二氯甲烷稀释,用NaHCO3饱和溶液和盐水洗涤,用硫酸钠干燥并且蒸发至干。
ESI(+)MS:m/z743(MH+)。
按照与上述同样的方式操作获得下列化合物:
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[(1-甲基哌啶-4-基)氨基]-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酰胺
ESI(+)MS:m/z671(MH+)。
3-({[4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-3-(四氢-2H-吡喃-4-基氨基)苯基]氨基}甲基)氮杂环丁烷-1-甲酸叔丁酯的制备
将3-{[(4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-3-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯基)氨基]甲基}氮杂环丁烷-1-甲酸叔丁酯(760mg,1.02mmol)溶于MeOH(12mL)和TEA(4mL)中,在室温下搅拌过夜。蒸发挥发性物质,将残余物溶于DCM,用盐水洗涤。用硫酸钠干燥有机相并且蒸发至干。
ESI(+)MS:m/z647(MH+)。
按照与上述同样的方式操作获得下列化合物:
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-4-[(1-甲基哌啶-4-基)氨基]-2-[四氢-2H-吡喃-4-基氨基]苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-[(1-甲基哌啶-4-基)氨基]-2-[四氢-2H-吡喃-4-基氨基]-苯基]cpd.108
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.28-1.50(m,4H)1.80-1.99(m,4H)2.06(t,J=12.54Hz,2H)2.19(s,3H)2.75(d,J=12.19Hz,2H)3.40(m,1H)3.45(ddd,J=11.83,10.12,2.32Hz,2H)3.83(dt,J=11.68,3.86Hz,2H)4.03(s,2H)5.87(d,J=1.71Hz,1H)5.90(dd,J=8.78,1.95Hz,1H)5.93(d,J=7.93 Hz,1H)5.95(s,1H)6.98(m,3H)7.24(dd,J=8.66,1.59Hz,1H)7.39(d,J=8.54Hz,1H)7.47(br.s.,1H)7.69(d,J=8.90Hz,1H)8.30(d,J=7.44Hz,1H)9.88(s,1H)12.57(s,1H)
4-[(氮杂环丁烷-3-基甲基)氨基]-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-[(氮杂环丁烷-3-基甲基)氨基]-2-[四氢-2H-吡喃-4-基氨基]苯基]cpd.109的制备
将3-({[4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-3-(四氢-2H-吡喃-4-基氨基)苯基]氨基}甲基)氮杂环丁烷-1-甲酸叔丁酯(738mg,1.1mmol)溶于DCM(12mL)并且加入TFA(3mL)。将得到的反应溶液在室温下搅拌3小时。用DCM稀释该混合物并且用10%NH3水萃取。用DCM将水相萃取几次。用盐水洗涤收集的有机相,用硫酸钠干燥并且蒸发至干。进行硅胶柱色谱纯化,使用二氯甲烷/甲醇/在MeOH中的NH35N(70:30:1)作为洗脱剂,得到150mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.30-1.42(m,2H)1.87-2.00(m,2H)2.77-2.88(m,1H)3.24-3.33(m,4H)3.42-3.53(m,2H)3.53-3.60(m,3H)3.78-3.88(m,2H)4.05(s,2H)5.86(s,1H)5.90(d,J=8.66Hz,1H)6.07-6.13(m,1H)6.95-7.04(m,3H)7.25(dd,J=8.60,1.52Hz,1H)7.40(d,J=8.66Hz,1H)7.48(s,1H)7.70(d,J=8.78Hz,1H)8.35(d,J=7.19Hz,1H)9.90(s,1H)12.59(br.s.,1H)。
实施例19
步骤i'
2,6-二氯-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]吡啶-3-甲酰胺的制备
将2,6-二氯吡啶-3-甲酸(480mg,2.5mmol)和亚硫酰氯(0.28mL,3.75mmol)在干甲苯(120mL)和几滴干DMF中,在90℃下加热2小时。蒸发挥发性物质,在0℃下和氮气环境中将残余物溶于干吡啶(15mL)。将5-(3,5-二氟-苄基)-1H-吲唑-3-基胺(518mg,2mmol)在干吡啶(7mL)中的溶液加入到冷却的反应混合物中。使得到的混合物在室温下反应过夜,然后减压除去溶剂。将残余物溶于EtOAc并且用NaHCO3饱和水溶液、水和盐水洗涤。用硫酸钠干燥有机相并且蒸发至干。通过硅胶快速色谱法纯化粗产物,用DCM/EtOH100:4作为洗脱剂,得到300mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.09(s,2H)6.93-7.01(m,2H)7.04(tt,J=9.39,2.32Hz,1H)7.29(dd,J=8.54,1.34Hz,1H)7.45(d,J=8.54Hz,1H)7.70(s,1H)7.75(d,J=8.05Hz,1H)8.24(d,J=7.93Hz,1H)11.04(s,1H)12.80(s,1H)
按照与上述同样的方式操作获得下列化合物:
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-3,5-二氟吡啶-2-甲酰胺
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.07(s,2H)6.93-6.99(m,2H)6.99-7.06(m,1H)7.28(dd,J=8.66,1.46Hz,1H)7.45(d,J=8.41Hz,1H)7.68(s,1H)8.12-8.23(m,1H)8.68(s,1H)10.78(s,1H)12.81(s,1H)
6-氯-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-2-(四氢-2H-吡喃-4-基氨基)吡啶-3-甲酰胺的制备
将2,6-二氯-N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]吡啶-3-甲酰胺(80mg,0.18mmol)在二烷(1mL)中的溶液在100℃和在DIPEA(0.1mL,0.55mmol)和四氢-2H-吡喃-4-胺(28mg,0.28mmol)存在下加热24小时。用EtOAc稀释反应混合物并且用水洗涤。用硫酸钠干燥有机层,过滤并且蒸发。通过硅胶快速色谱法纯化粗产物,用DCM/EtOH95:5作为洗脱剂,得到57mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.37-1.52(m,2H)1.94(dd,J=13.05,2.80Hz,2H)3.47(td,J=11.16,2.19Hz,2H)3.80-3.87(m,2H)4.06(s,2H)4.07-4.15(m,1H)6.73(d,J=8.05Hz,1H)6.93-7.07(m,3H)7.28(dd,J=8.66,1.59Hz,1H)7.44(dd,J=8.54,0.49Hz,1H)7.55(s,1H)8.29(d,J=8.17Hz,1H)8.60(d,J=7.32Hz,1H)10.74(s,1H)12.79(s,1H)
按照与上述同样的方式操作获得下列化合物:
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-5-氟-3-(四氢-2H-吡喃-4-基氨基)吡啶-2-甲酰胺
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.34-1.52(m,2H)1.95(d,J=10.36Hz,2H)3.45-3.54(m,2H)3.68-3.77(m,1H)3.82-3.89(m,2H)4.07(s,2H)6.97-7.05(m,3H)7.28(dd,J=8.66,1.59Hz,1H)7.37(dd,J=12.44,2.32Hz,1H)7.43(d,J=8.54Hz,1H)7.65(s,1H)7.88(d,J=2.32Hz,1H)8.55(d,J=6.95Hz,1H)10.46(s,1H)12.76(s,1H)
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-5-(4-甲基哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)吡啶-2-甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=5-(4-甲基哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)吡啶]cpd.113的制备
将N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-5-氟-3-(四氢-2H-吡喃-4-基氨基)吡啶-2-甲酰胺(925mg,1.92mmol)和N-甲基哌嗪(20mL)的溶液在60℃下搅拌48小时。然后用EtOAc稀释该反应混合物并且用饱和NaHCO3溶液洗涤。用硫酸钠干燥有机层,过滤并且蒸发。通过硅胶快速色谱法纯化粗产物,使用DCM/EtOH/在MeOH中的NH35N (100:5:0.5)作为洗脱剂,得到600mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.34-1.47(m,2H)1.92-2.00(m,2H)2.25(s,3H)2.44-2.49(m,4H)3.34-3.40(m,4H)3.48-3.56(m,2H)3.72-3.81(m,1H)3.82-3.88(m,2H)4.07(s,2H)6.54(d,J=2.20Hz,1H)6.95-7.07(m,3H)7.26(dd,J=8.66,1.59Hz,1H)7.41(d,J=8.54Hz,1H)7.72(s,1H)7.73(d,J=2.32Hz,1H)8.32(d,J=8.05Hz,1H)10.19(s,1H)12.66(s,1H)
按照同样方式操作获得下列化合物:
N-[5-(3,5-二氟苄基)-1H-吲唑-3-基]-6-(4-甲基哌嗪-1-基)-2-(四氢-2H-吡喃-4-基氨基)吡啶-3-甲酰胺[(IA),R1=R2=R3=H,R=3,5-二氟苯基,Ar=6-(4-甲基哌嗪-1-基)-2-(四氢-2H-吡喃-4-基氨基)吡啶]cpd.114
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.35-1.47(m,2H)1.90-2.00(m,2H)2.22(s,3H)2.36-2.40(m,4H)3.41-3.51(m,2H)3.57-3.63(m,4H)3.78-3.88(m,2H)4.05(s,2H)4.06-4.11(m,1H)6.10(d,J=8.90Hz,1H)6.96-7.05(m,3H)7.25(dd,J=8.66,1.59Hz,1H)7.41(d,J=8.66Hz,1H)7.50(s,1H)8.10(d,J=9.02Hz,1H)8.73(d,J=6.95Hz,1H)10.06(s,1H)12.63(s,1H)。
实施例20
步骤v
4-[4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-3-(四氢-2H-吡喃-4-基氨基)苯基]哌嗪-1-甲酸叔丁酯的制备
向N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-哌嗪-1-基-2-(四氢-吡喃-4-基氨基)-苯甲酰胺(71.7mg,0.131mmol)在无水二氯甲烷(3.0mL)和三乙胺(0.052mL,38.1mg,0.377mmol)中的溶液中加入二碳酸二叔丁基酯(34.5mg,0.157mmol),将该溶液在室温下搅拌40分钟。将该混合物蒸发至干并且通过快速硅胶柱色谱法纯化,用二氯甲烷/甲醇9:1洗脱,得到60mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.28-1.41(m,2H)1.44(s,9H)1.90-1.99(m,2H)3.24-3.30(m,4H)3.46(d,J=4.88Hz,4H)3.48-3.54(m,2H)3.64-3.74(m,1H)3.79-3.86(m,2H)4.05(s,2H)6.16(d,J=2.19Hz,1H)6.25(dd,J=8.90,2.19Hz,1H)6.95-7.04(m,3H)7.26(dd,J=8.66,1.46Hz,1H)7.41(d,J=8.90Hz,1H)7.49(s,1H)7.82(d,J=9.15Hz,1H)8.29(d,J=7.44Hz,1H)10.10(s,1H)12.64(s,1H)
5-(3,5-二氟苄基)-3-({[4-(哌嗪-1-基)-2-(四氢-2H-吡喃-4-基氨基)苯基]羰基}氨基)-1H-吲唑-1-甲酸乙酯的制备
在氩气环境中,向维持在-50℃下的4-[4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-3-(四氢-2H-吡喃-4-基氨基)苯基]哌嗪-1-甲酸叔丁酯(0.013mmol)在无水四氢呋喃(1.0mL)中的溶液中加入LiHMSD在无水四氢呋喃(0.015mL)中的1M溶液。在该温度下搅拌5分钟后,加入氯代碳酸乙酯(0.002mL,1.63mg,0.015mmol)。在-50℃下30分钟后,反应完成。在用二氯甲烷稀释后,用盐水洗涤该溶液,用硫酸钠干燥并且蒸发至干。将粗产物溶于二氯甲烷(1mL),加入三氟乙酸(0.1mL),将该混合物在室温下搅拌过夜。在用二氯甲烷稀释后,用碳酸氢钠、盐水洗涤该溶液,用硫酸钠干燥并且蒸发至干。
通过硅胶快速色谱法纯化粗产物,用二氯甲烷/甲醇9:1和0.5%的33%NH4OH水溶液洗脱,得到标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.30-1.38(m,2H)1.40(t,J=7.13Hz,3H)1.90-1.99(m,2H)2.79-2.86(m,4H)3.18 -3.23(m,4H)3.47-3.54(m,2H)3.63-3.76(m,1H)3.79-3.86(m,2H)4.11(s,2H)4.48(q,J=7.15Hz,2H)6.11(d,J=2.07Hz,1H)6.24(dd,J=9.15,2.19Hz,1H)6.97-7.07(m,3H)7.55(dd,J=8.66,1.59Hz,1H)7.67(d,J=0.73Hz,1H)7.80(d,J=9.02Hz,1H)8.07(d,J=8.66Hz,1H)8.24(d,J=7.56Hz,1H)10.65(br.s.,1H)
4-[4-{[5-(3,5-二氟苄基)-1H-吲唑-3-基]氨基甲酰基}-3-(四氢-2H-吡喃-4-基氨基)苯基]哌嗪-1-甲酸1-(乙酰氧基)乙酯的制备
在氮气环境中,向冷却至0℃的N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-哌嗪-1-基-2-(四氢-吡喃-4-基氨基)-苯甲酰胺在氯仿(5.0mL)中的溶液中,加入1,8-双(二甲基氨基)萘(21.4mg,0.1mmol)和(1-氯乙基)氯甲酸酯(0.011mL,14.3mg,0.1mmol)。在室温下搅拌2小时后,用二氯甲烷(30mL)稀释该混合物,用饱和碳酸氢钠溶液(3mL)、盐水(3x5mL)洗涤,用硫酸钠干燥并且蒸发至干。将粗产物溶于冰醋酸(2.0mL),加入乙酸汞(II)(31.9mg,0.1mmol),将该混合物在室温下搅拌1.5小时。在除去溶剂后,将粗产物溶于二氯甲烷,用饱和碳酸氢钠溶液(3x3mL)、盐水(3x5mL)洗涤,用硫酸钠干燥并且蒸发至干而得到50mg淡黄色泡沫,将其通过硅胶快速色谱法纯化,用乙酸乙酯和0.5%的33%NH4OH水溶液洗脱,得到35mg标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.29-1.42(m,2H)1.46(d,J=5.49Hz,3H)1.90-1.98(m,2H)2.03-2.06(m,3H)3.30-3.50(m,8H)3.45-3.52(m,2H)3.64-3.74(m,1H)3.79-3.86(m,2H)4.05(s,2H)6.16(d,J=2.07Hz,1H)6.25(dd,J=9.02,2.07Hz,1H)6.67-6.73(m,1H)6.94-7.05(m,3H)7.26(dd,J=8.66,1.59Hz,1H)7.41(d,J=8.66Hz,1H)7.49(s,1H)7.82(d,J=9.02Hz,1H)8.30(d,J=7.68Hz,1H)10.11(s,1H)12.64(s,1H)
5-(3,5-二氟苄基)-3-({[4-(4-甲基哌嗪-1-基)-2-(四氢-2H-吡 喃-4-基氨基)苯基]羰基}氨基)-1H-吲唑-1-甲酸乙酯[(XXVII),R1=R2=R3=H,R=3,5-二氟苯基,Ar=4-(4-甲基哌嗪-1-基)-2-(四氢-2H-吡喃-4-基氨基)苯基,PG=乙氧基羰基]cpd.140的制备
向维持在-50℃下和氮气环境中的N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺(200mg,0.356mmol)在无水四氢呋喃(9mL)中的溶液中加入LiHMSD在无水四氢呋喃(0.374mL)中的1M溶液。在该温度下搅拌5分钟后,加入氯甲酸乙酯(0.036mL,0.374mmol)。在-50℃下1小时后,反应完成。用水/EtOAc稀释该反应混合物,用盐水洗涤,用硫酸钠干燥并且蒸发至干。通过使用DCM/乙醇100:5的硅胶快速色谱法纯化粗产物,得到140mg(62%收率)标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.39(t,J=7.07Hz,3H)2.25(br.s.,3H)2.46(br.s.,4H)3.50(ddd,J=11.83,10.06,2.26Hz,1H)3.66-3.75(m,1H)3.81(dt,J=11.61,3.76Hz,2H)4.10(s,2H)4.47(q,J=7.15Hz,2H)6.13(d,J=1.95Hz,1H)6.25(dd,J=9.08,2.13Hz,1H)7.54(dd,J=8.66,1.59Hz,1H)7.66(dd,J=1.46,0.73Hz,1H)7.80(d,J=9.15Hz,1H)8.07(d,J=8.66Hz,1H)8.24(d,J=7.68Hz,1H)10.65(s,1H)
按照与上述同样的方式操作获得下列化合物:
5-(3,5-二氟苄基)-3-({[4-(4-甲基哌嗪-1-基)-2-(四氢-2H-吡喃-4-基氨基)苯基]羰基}氨基)-1H-吲唑-1-甲酸2-甲氧基乙酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.30-1.43(m,2H)1.90-2.00(m,2H)2.26(br.s.,3H)2.47(br.s.,4H)3.27-3.33(m,7H)3.46-3.55(m,2H)3.67-3.74(m,3H)3.79-3.85(m,2H)4.11(s,2H)4.54-4.59(m,2H)6.14(d,J=1.71Hz,1H)6.26(dd,J=9.02,2.19Hz,1H)6.97-7.09(m,3H)7.56(dd,J=8.72,1.52Hz,1H)7.67(d,J=0.85Hz,1H)7.81(d,J=9.15Hz,1H)8.07(d,J=8.54Hz,1H)8.25(d,J=7.56Hz,1H)10.68 (s,1H)
5-(3,5-二氟苄基)-3-[({4-[4-(乙氧基羰基)哌嗪-1-基]-2-(四氢-2H-吡喃-4-基氨基)苯基}羰基)氨基]-1H-吲唑-1-甲酸乙酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.22(t,J=7.07Hz,3H)1.30-1.38(m,2H)1.40(t,J=7.07Hz,3H)1.90-2.00(m,2H)3.48-3.54(m,2H)3.71(d,1H)3.78-3.86(m,2H)4.05-4.10(m,2H)4.11(s,2H)4.48(q,J=7.03Hz,2H)6.15(d,J=2.07Hz,1H)6.26(dd,J=9.15,2.19Hz,1H)6.95-7.07(m,2H)7.55(dd,J=8.66,1.59Hz,1H)7.67(d,J=0.85Hz,1H)7.83(d,J=9.15Hz,1H)8.08(d,J=8.78Hz,1H)8.25(d,J=7.80Hz,1H)10.68(s,1H)
实施例21
4-氟-2-硝基-苯甲酸叔丁酯的制备
将4-氟-2-硝基苯甲酸(10g,54mmol),(Boc)2O(2eq.,23.6g,108mmol)和4-(N,N-二甲基氨基)吡啶(0.3eq.,1.98g,16.2mmol)在叔丁醇(100mL)和二氯甲烷(100mL)中的溶液在室温下搅拌20小时。然后用乙酸乙酯(500mL)稀释该反应混合物,用1N HCl(500mL)、水(500mL)、盐水(500mL)洗涤,用硫酸钠干燥并且蒸发至干。得到标题化合物,为淡黄色油状物(定量),将其不经任何进一步纯化而用于下一步。
1H-NMR(400MHz),δ(ppm,DMSO-d6):8.04(dd,J=8.47,2.50Hz,1H)7.95(dd,J=8.66,5.37Hz,1H)7.71(ddd,J=8.66,8.17,2.56Hz,1H)1.51(s,9H)。
4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酸叔丁酯的制备
将4-氟-2-硝基-苯甲酸叔丁酯(13g,54mmol)和N-甲基哌嗪(17mL)的溶液在室温下搅拌6小时。然后用水(800mL)稀释该反应混合物并且维持在磁搅拌下20小时。过滤得到的固体,用水充分洗涤并且在真空中和40℃下干燥。得到标题化合物,为黄色固体(16.4g,94%收率),将其不经任何进一步纯化而用于下一步。
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.69(d,J=8.90Hz,1H)7.29(d,J=2.56Hz,1H),7.15(dd,J1=8.90Hz,J2=2.56Hz,1H),3.37(m,4H),2.44(m,4H),1.46(s,9H)。
按照同样方式操作获得下列化合物:
4-[(2-二甲基氨基-乙基)-甲基-氨基]-2-硝基-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.67(d,J=8.9Hz,1H),6.98(d,J=2.6Hz,1H),6.89(dd,J1=8.9Hz,J2=2.6Hz,1H),3.54(m,2H),3.02(s,3H),2.40(m,2H),2.19(s,6H),1.46(s,9H)。
4-(4-二甲基氨基-哌啶-1-基)-2-硝基-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.67(d,J=9.0Hz,1H),7.26(d,J=2.6Hz,1H),7.13(dd,J1=9.0Hz,J2=2.6Hz,1H),3.96(m,2H),2.93(m,2H),2.36(m,1H),2.20(s,6H),1.82(m,2H),1.46(s,9H),1.40(m,2H)。
4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-硝基-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.67(d,J=9.0Hz,1H),7.02(d,J=2.6Hz,1H),6.90(dd,J1=9.0Hz,J2=2.6Hz,1H),3.46(m,2H),3.00(s,3H),2.22(m,2H),2.14(s,6H),1.65(m,2H),1.45(s,9H)。
4-(4-甲基-1,4-二氮杂环庚烷-1-基)-2-硝基苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.44(s,9H)1.85(m,2H)2.25(s,3H)2.43(m,2H)2.60(m,2H)3.51(t,2H)3.60(t,2H)6.91(dd,J1=9.02Hz,J2=2.66Hz,1H)7.02(d,J=2.56Hz,1H)7.64(d,J=8.90Hz,1H)
2-硝基-4-(哌嗪-1-基)苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.46(m,9H)2.81(m,4H)3.33(m,4H)7.12(dd,J1=8.90Hz,J2=2.56Hz,1H)7.25(d,J=2.56Hz,1H)7.65(d,J=8.90Hz,1H)
2-硝基-4-[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]苯甲酸叔丁 酯
ESI(+)MS:m/z376(MH+)。
2-氨基-4-(4-甲基-哌嗪-1-基)-苯甲酸叔丁酯的制备
将4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酸叔丁酯(13.3g,41.5mmol),环己烷(45mL),乙醇(300mL)和10%Pd/C(0.4g)的混合物在80℃下搅拌7小时。再加入10%Pd/C(0.9g),将该混合物在80℃下再搅拌4小时。用硅藻土垫过滤该反应混合物,用乙醇充分洗涤,将滤液蒸发至干而得到标题化合物,为淡黄色固体(11.5g,95%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.47(d,J=9.0Hz,1H),6.40(bs,2H),6.18(dd,J1=9.0Hz,J2=2.4Hz,1H),6.11(d,J=2.4Hz,1H),3.16(m,4H),2.41(m,4H),2.21(s,3H),1.49(s,9H)。
按照同样方式操作获得下列化合物:
2-氨基-4-[(2-二甲基氨基-乙基)-甲基-氨基]-苯甲酸叔丁酯
ESI(+)MS:m/z294(MH+)。
2-氨基-4-[(3-二甲基氨基-丙基)-甲基-氨基]-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.45(d,J=9.0Hz,1H),6.36(bs,2H),5.99(dd,J1=9.0Hz,J2=2.6Hz,1H),5.86(d,J=2.6Hz,1H),3.31(m,2H),2.87(s,3H),2.22(m,2H),2.15(s,6H),1.62(m,2H),1.48(s,9H)。
2-氨基-4-[4-(三氟乙酰基)哌嗪-1-基]苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.51(s,9H)3.28-3.35(m,4H)3.66-3.74(m,4H)6.15(d,J=2.44Hz,1H)6.21(dd,J=9.14,2.44Hz,1H)6.47(br.s.,2H)7.50-7.53(m,1H)
2-氨基-4-[4-(二甲基氨基)哌啶-1-基]苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.31-1.45(m,2H)1.49-1.52(m,9H)1.75-1.81(m,2H)2.17(s,6H)2.20-2.30(m,1H)2.69-2.79(m,2H)3.71-3.80(m,2H)6.12(d,J=2.44Hz,1H)6.18(dd,J=9.14,2.44Hz,1H)6.39(s,2H)7.46(d,J=9.02 Hz,1H)
2-氨基-4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯甲酸叔丁酯
ESI(+)MS:m/z306(MH+)。
2-氨基-4-[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]苯甲酸叔丁酯
ESI(+)MS:m/z346(MH+)。
2-氨基-4-(吗啉-4-基)苯甲酸叔丁酯
ESI(+)MS:m/z279(MH+)。
4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酸叔丁酯的制备
向2-氨基-4-(4-甲基-哌嗪-1-基)-苯甲酸叔丁酯(11.5g,39.5mmol)在二氯甲烷(340mL)中的溶液中加入四氢-吡喃-4-酮(4.5mL,49.3mmol),三氟乙酸(8.2mL)和三乙酰氧基硼氢化四甲基铵(15.57g,59.2mmol)。将该混合物在室温下搅拌2小时,然后用0.5N盐酸、0.5N NaOH和NaHCO3饱和溶液洗涤。用硫酸钠干燥有机层并且蒸发至干而得到标题化合物,为淡黄色固体(13.3g,90%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.72(d,J=7.7Hz,1H),7.58(d,J=9.1Hz,1H),6.20(dd,J1=9.1Hz,J2=2.2Hz,1H),6.08(d,J=2.2Hz,1H),3.85(m,2H),3.70(m,1H),3.50(m,2H),3.27(m,4H),2.47(m,4H),2.26(bt,3H),1.96(m,2H),1.51(s,9H),1.39(m,2H)。
按照同样方式操作获得下列化合物:
4-[(2-二甲基氨基-乙基)-甲基-氨基]-2-(四氢-吡喃-4-基氨基)-苯甲酸叔丁酯
ESI(+)MS:m/z378(MH+)。
4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-(四氢-吡喃-4-基氨基)-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.70(bd,J=7.4Hz,1H),7.54(d,J=9.0Hz,1H),5.99(dd,J1=9.0Hz,J2=2.3Hz, 1H),5.79(d,J=2.3Hz,1H),3.86(m,2H),3.62(m,1H),3.47(m,2H),3.36(m,2H),2.93(s,3H),2.28(m,2H),2.18(bs,6H),1.97(m,2H),1.64(m,2H),1.49(s,9H),1.39(m,2H)。
2-(四氢-2H-吡喃-4-基氨基)-4-[4-(三氟乙酰基)哌嗪-1-基]苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.33-1.45(m,2H)1.51(s,9H)1.92-2.00(m,2H)3.36-3.42(m,4H)3.50(td,J=11.18,2.13Hz,2H)3.70(d,J=3.05Hz,5H)3.82-3.89(m,2H)6.10(d,J=2.32Hz,1H)6.21(dd,J=9.08,2.26Hz,1H)7.61(d,J=9.02Hz,1H)7.73(d,J=7.68Hz,1H)
4-[4-(二甲基氨基)哌啶-1-基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酸叔丁酯
ESI(+)MS:m/z404(MH+)。
4-(4-甲基-1,4-二氮杂环庚烷-1-基)-2-(四氢-2H-吡喃-4-基氨基)苯甲酸叔丁酯
ESI(+)MS:m/z390(MH+)。
4-[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]-2-(四氢-2H-吡喃-4-基氨基)苯甲酸叔丁酯
ESI(+)MS:m/z430(MH+)。
2-(环己基氨基)-4-(4-甲基哌嗪-1-基)苯甲酸叔丁酯
ESI(+)MS:m/z374(MH+)。
2-[(1,3-二甲氧基丙-2-基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸叔丁酯
ESI(+)MS:m/z394(MH+)。
2-(苄基氨基)-4-(4-甲基哌嗪-1-基)苯甲酸叔丁酯
ESI(+)MS:m/z382(MH+)。
4-(4-甲基哌嗪-1-基)-2-{[顺式-4-(三氟甲基)环己基]氨基}苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.40-1.50(m,2H)1.51 (s,9H)1.57-1.69(m,2H)1.70-1.78(m,2H)1.87(d,J=14.27Hz,2H)2.24(s,3H)2.32-2.39(m,1H)2.40-2.48(m,4H)3.27(br.s.,4H)3.83-3.94(m,1H)6.05(d,J=1.95Hz,1H)6.20(dd,J=9.21,2.26Hz,1H)7.57(d,J=9.02Hz,1H)8.04(d,J=8.05Hz,1H)
4-(4-甲基哌嗪-1-基)-2-{[反式-4-(三氟甲基)环己基]氨基}苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.18-1.31(m,2H)1.44-1.57(m,2H)1.50(s,9H)1.87-1.94(m,2H)2.07-2.13(m,2H)2.25(s,3H)2.28-2.38(m,1H)2.44(br.s.,4H)3.26(br.s.,4H)3.40-3.53(m,1H)6.07(d,J=2.07Hz,1H)6.18(dd,J=9.08,2.26Hz,1H)7.54-7.58(m,1H)7.62(d,J=7.93Hz,1H)
4-(4-甲基哌嗪-1-基)-2-({顺式-4-[(苯基羰基)氧基]环己基}氨基)苯甲酸叔丁酯
ESI(+)MS:m/z494(MH+)。
4-(4-甲基哌嗪-1-基)-2-({反式-4-[(苯基羰基)氧基]环己基}氨基)苯甲酸叔丁酯
ESI(+)MS:m/z494(MH+)。
2-[(1-甲基哌啶-4-基)氨基]苯甲酸叔丁酯
ESI(+)MS:m/z291(MH+)。
2-[(1-甲基哌啶-4-基)氨基]-4-(吗啉-4-基)苯甲酸叔丁酯
ESI(+)MS:m/z376(MH+)。
4-(4-甲基-哌嗪-1-基)-2-[(四氢-吡喃-4-基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸叔丁酯的制备
向在氩气环境中和0℃下的4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酸叔丁酯(13.3g,35.4mmol)在干二氯甲烷(350mL)中的溶液中加入三乙胺(7.5mL,53.1mmol)和三氟乙酐(6.5mL,46.1mmol)。将该混合物在0℃下搅拌20分钟,然后滴加水(350mL)。 分离各相并且用盐水洗涤有机相,用硫酸钠干燥并且蒸发至干。通过硅胶色谱法纯化粗残余物,用二氯甲烷/乙醇95:5作为洗脱剂,得到12.1g标题化合物,为淡黄色固体(73%收率)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.83(d,J=9.0Hz,1H),7.06(dd,J1=9.0Hz,J2=2.5Hz,1H),6.82(J=2.5Hz,1H),4.48(m,1H),3.85(m,2H),3.5-3.3(m,6H),2.49(m,4H),2.26(bs,3H),2.0(m,1H),1.59(m,1H),1.51(m,1H),1.46(s,9H),1.03(m,1H)。
按照同样方式操作获得下列化合物:
4-[(2-二甲基氨基-乙基)-甲基-氨基]-2-[(四氢-吡喃-4-基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.80(d,J=9.1Hz,1H),6.79(dd,J1=9.1Hz,J2=2.6Hz,1H),6.51(d,J=2.6Hz,1H),4.48(m,1H),3.86(m,1H),3.79(m,1H),3.52(m,2H),3.41-3.25(m,2H),3.00(s,3H),2.5-2.35(m,2H),2.21(s,6H),1.98(m,1H),1.64-1.45(m,3H),1.44(s,9H)。
4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-[(四氢-吡喃-4-基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.79(d,J=9.1Hz,1H),6.79(dd,J1=9.1Hz,J2=2.6Hz,1H),6.52(d,J=2.6Hz,1H),4.48(m,1H),3.87(m,1H),3.79(m,1H),3.51-3.32(m,4H),2.98(s,3H),2.22(m,2H),2.12(s,6H),1.99(m,1H),1.70-1.46(m,4H),1.44(s,9H),1.03(m,1H)。
2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]-4-[4-(三氟乙酰基)哌嗪-1-基]苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.45(s,9H)1.60(qd,J=12.21,4.94Hz,2H)3.73(t,J=5.12Hz,4H)4.48(tt,J=11.96,3.89Hz,1H)6.84(d,J=2.56Hz,1H)7.07(dd,J=8.96,2.62Hz,1H)7.85(d,J=9.02Hz,1H)
4-[4-(二甲基氨基)哌啶-1-基]-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸叔丁酯
ESI(+)MS:m/z500(MH+)。
4-(4-甲基-1,4-二氮杂环庚烷-1-基)-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸叔丁酯
ESI(+)MS:m/z486(MH+)。
4-[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸叔丁酯
ESI(+)MS:m/z526(MH+)。
2-[环己基(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸叔丁酯
ESI(+)MS:m/z470(MH+)。
2-[(1,3-二甲氧基丙-2-基)(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸叔丁酯
ESI(+)MS:m/z490(MH+)。
2-[苄基(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸叔丁酯
ESI(+)MS:m/z478(MH+)。
4-(4-甲基哌嗪-1-基)-2-{(三氟乙酰基)[顺式-4-(三氟甲基)环己基]氨基}苯甲酸叔丁酯
ESI(+)MS:m/z538(MH+)。
4-(4-甲基哌嗪-1-基)-2-{(三氟乙酰基)[反式-4-(三氟甲基)环己基]氨基}苯甲酸叔丁酯
ESI(+)MS:m/z538(MH+)。
4-(4-甲基哌嗪-1-基)-2-[{顺式-4-[(苯基羰基)氧基]环己基}(三氟乙酰基)氨基]苯甲酸叔丁酯
ESI(+)MS:m/z590(MH+)。
4-(4-甲基哌嗪-1-基)-2-[{反式-4-[(苯基羰基)氧基]环己基}(三氟乙酰基)氨基]苯甲酸叔丁酯
ESI(+)MS:m/z590(MH+)。
2-[(1-甲基哌啶-4-基)(三氟乙酰基)氨基]苯甲酸叔丁酯
ESI(+)MS:m/z387(MH+)。
2-[(1-甲基哌啶-4-基)(三氟乙酰基)氨基]-4-(吗啉-4-基)苯甲酸叔丁酯
ESI(+)MS:m/z472(MH+)。
4-(4-甲基哌嗪-1-基)-2-[苯基(三氟乙酰基)氨基]苯甲酸叔丁酯
ESI(+)MS:m/z464(MH+)。
4-(4-甲基-哌嗪-1-基)-2-[(四氢-吡喃-4-基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸三氟乙酸盐的制备
将4-(4-甲基-哌嗪-1-基)-2-[(四氢-吡喃-4-基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸叔丁酯(12.1g,25.7mmol)、三氟乙酸(48.5mL)和二氯甲烷(195mL)的混合物在室温下搅拌2小时。然后蒸发挥发性物质,将残余物溶于乙醚并且再次蒸发。将该操作重复5次,然后将固体与乙醚一起研磨,过滤并且在40℃下的烘箱中干燥,得到标题化合物,为浅褐色固体(13.4g)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):12.78(bs,1H),9.74(bs,1H),7.93(d,J=8.8Hz,1H),7.13(dd,J1=8.8Hz,J2=2.5Hz,1H),6.98(d,J=2.5Hz,1H),4.49(m,1H),4.11(m,2H),3.84(m,2H),3.6-3.0(m,8H),2.89(s,3H),1.98(m,1H),1.59(m,1H),1.53(m,1H),1.08(m,1H)。
按照同样方式操作获得下列化合物:
4-[(2-二甲基氨基-乙基)-甲基-氨基]-2-[(四氢-吡喃-4-基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸三氟乙酸盐
1H-NMR(400MHz),δ(ppm,DMSO-d6):12.56(bs,1H),9.49(bs,1H),7.88(d,J=8.9Hz,1H),8.92(dd,J1=8.9Hz,J2=2.6Hz,1H),6.63(d,J=2.6Hz,1H),4.49(m,1H),3.9-3.2(m,8H),3.02(s,3H),2.85(s,6H),1.98(m,1H),1.62-1.49(m,2H),1.08(m,1H)。
4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-[(四氢-吡喃-4- 基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸三氟乙酸盐
ESI(+)MS:m/z432(MH+)。
2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]-4-[4-(三氟乙酰基)哌嗪-1-基]苯甲酸
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.08(m,J=12.35,12.24,12.24,4.76Hz,1H)1.47-1.55(m,1H)1.56-1.67(m,1H)1.91-2.01(m,1H)3.38-3.53(m)3.73(t,J=5.12Hz,4H)3.78(dd,J=11.52,4.45Hz,1H)3.86(dd,J=11.40,4.57Hz,1H)4.46(tt,J=11.87,3.98Hz,1H)6.85(d,1H)7.06(dd,J=8.90,2.68Hz,1H)7.89(d,J=8.90Hz,1H)12.67(br.s.,1H)
4-(4-甲基-1,4-二氮杂环庚烷-1-基)-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸盐酸盐
1H-NMR(400MHz),δ(ppm,DMSO-d6):4.42-4.55(m,1H)6.91-6.96(m,1H)7.89(d,J=9.02Hz,1H)10.14(br.s.,1H)12.56(br.s.,1H)
4-[4-(二甲基氨基)哌啶-1-基]-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸盐酸盐
ESI(+)MS:m/z444(MH+)。
4-[(2S)-2-(吡咯烷-1-基甲基)吡咯烷-1-基]-2-[四氢-2H-吡喃-4-基(三氟乙酰基)氨基]苯甲酸盐酸盐
ESI(+)MS:m/z470(MH+)。
2-[环己基(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸盐酸盐
ESI(+)MS:m/z414(MH+)。
2-[(1,3-二甲氧基丙-2-基)(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸盐酸盐
ESI(+)MS:m/z434(MH+)。
2-[苄基(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸盐酸盐
ESI(+)MS:m/z422(MH+)。
4-(4-甲基哌嗪-1-基)-2-{(三氟乙酰基)[顺式-4-(三氟甲基)环己基]氨基}苯甲酸三氟乙酸盐
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.09-1.90(4m,8H)2.36-2.46(m,1H)2.88(br.s.,3H)2.99-3.25(m,4H)3.49(br.s.,2H)3.96-4.16(m,2H)4.27-4.37(m,1H)7.00(d,J=2.32Hz,1H)7.12(dd,J=8.90,2.44Hz,1H)7.92(d,J=8.90Hz,1H)9.67(br.s.,1H)12.80(s,1H)
4-(4-甲基哌嗪-1-基)-2-{(三氟乙酰基)[反式-4-(三氟甲基)环己基]氨基}苯甲酸三氟乙酸盐
ESI(+)MS:m/z482(MH+)。
4-(4-甲基哌嗪-1-基)-2-[{顺式-4-[(苯基羰基)氧基]环己基}(三氟乙酰基)氨基]苯甲酸盐酸盐
ESI(+)MS:m/z534(MH+)。
4-(4-甲基哌嗪-1-基)-2-[{反式-4-[(苯基羰基)氧基]环己基}(三氟乙酰基)氨基]苯甲酸盐酸盐
ESI(+)MS:m/z534(MH+)。
2-[(1-甲基哌啶-4-基)(三氟乙酰基)氨基]苯甲酸盐酸盐
ESI(+)MS:m/z331(MH+)。
2-[(1-甲基哌啶-4-基)(三氟乙酰基)氨基]-4-(吗啉-4-基)苯甲酸盐酸盐
ESI(+)MS:m/z416(MH+)。
4-(4-甲基哌嗪-1-基)-2-[苯基(三氟乙酰基)氨基]苯甲酸盐酸盐
ESI(+)MS:m/z408(MH+)。
实施例22
2,4-二氟-苯甲酸叔丁酯的制备
向2,4-二氟苯甲酸(5g,31.62mmol)在二氯甲烷(100mL)和t-BuOH(50mL)的混合物中的溶液中加入(Boc)2O(13.8g,63.24mmol)和N,N-二甲基氨基吡啶(1.16g,9.49mmol)。将该溶液在室温下搅 拌24小时,然后用二氯甲烷稀释,用1N HCl、NaHCO3饱和溶液、水(3次)和盐水洗涤两次。用硫酸钠干燥有机相,过滤并且蒸发而得到标题化合物(5.70g,84%),为淡黄色油状物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.91(m,1H),7.36(m,1H),7.20(m,1H),1.53(s,9H)。
4-氟-2-((S)-2-甲氧基-1-甲基-乙基氨基)-苯甲酸叔丁酯的制备
将2,4-二氟-苯甲酸叔丁酯(30g,140.05mmol)和(S)-2-甲氧基-1-甲基-乙胺(100mL)的混合物在65℃下搅拌2天。加入NaHCO3饱和溶液并且用二氯甲烷萃取该混合物(3次)。用水、然后用盐水洗涤有机相两次,用硫酸钠干燥、过滤并且蒸发至干而得到粗产物,通过硅胶柱色谱法纯化(己烷/乙酸乙酯9:1)。得到标题化合物(33.38g,84%),为油状物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.87(d,J=7.80Hz,1H),7.80(t,J=7.19Hz,1H),6.60(dd,J1=13.05Hz,J2=2.44Hz,1H),6.36(m,1H),3.80(m,1H),3.40(d,J=4.76Hz,2H),3.30(s,3H),1.53(s,9H),1.17(d,J=6.58Hz,3H)。
按照与上述同样的方式操作获得下列化合物:
4-氟-2-((R)-2-甲氧基-1-甲基-乙基氨基)-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.87(d,J=7.80Hz,1H),7.80(t,J=7.19Hz,1H),6.60(dd,J1=13.05Hz,J2=2.44Hz,1H),6.36(m,1H),3.80(m,1H),3.40(d,J=4.76Hz,2H),3.30(s,3H),1.53(s,9H),1.17(d,J=6.58Hz,3H)。
4-氟-2-(2-甲氧基-乙基氨基)-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.89(t,J=5.00Hz,1H),7.80(t,J=7.07Hz,1H),6.56(dd,J1=12.80Hz,J2=2.56Hz,1H),6.37(m,1H),3.55(t,J=5.37Hz,2H),3.33(m,2H),3.29(s,3H),1.53(s,9H)。
4-氟-2-[(3-甲氧基丙基)氨基]苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.51-1.53(m,9H)1.76 -1.85(m,2H)3.18-3.23(m,2H)3.25(s,3H)3.38-3.44(m,2H)6.32-6.39(m,1H)6.49(dd,J=12.80,2.44Hz,1H)7.79(dd,J=8.90,7.07Hz,1H)7.88(br.s.,1H)
4-氟-2-[(2-氟乙基)氨基]苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.54(s,9H)3.50(dd,J=27.00,5.00Hz,2H)4.63(dt,J=47.56,4.88Hz,2H)6.41(td,J=8.57,2.50Hz,1H)6.62(dd,J=12.62,2.38Hz,1H)7.82(dd,J=8.90,7.07Hz,1H)8.05(t,J=4.82Hz,1H)
4-氟-2-[(3-氟丙基)氨基]苯甲酸叔丁酯
ESI(+)MS:m/z272(MH+)。
4-氟-2-[(1-甲氧基-2-甲基丙-2-基)氨基]苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.34(s,6H)1.53(s,9H)3.33(br.s.,3H)3.40(s,2H)6.31-6.39(m,1H)6.67(dd,J=13.29,2.44Hz,1H)7.82(dd,J=8.84,7.38Hz,1H)8.22(s,1H)
4-氟-2-[((S)-2-甲氧基-1-甲基-乙基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸叔丁酯的制备
将4-氟-2-((S)-2-甲氧基-1-甲基-乙基氨基)-苯甲酸叔丁酯(1.54g,5.44mmol)在二氯甲烷(30mL)中的溶液冷却至0℃-5℃。加入三乙胺(1.11mL,8.16mmol)和三氟乙酐(1.15mL,8.16mmol)。在0℃-5℃下3小时后,用NaHCO3饱和溶液、水和盐水洗涤该混合物。用硫酸钠干燥有机层,过滤并且蒸发,得到标题化合物,为淡黄色油状物(2g,99%)。
1H-NMR(400MHz),δ(ppm,DMSO-d6):(互变体混合物)8.07(m,1H),7.53(m,1H),7.29(dd,J1=9.39Hz,J2=2.68Hz,1H),4.83(m,1H),3.44(m,1H),3.30(s,3H),1.49(s,9H),0.86(d,3H)。
按照与上述同样的方式操作获得下列化合物:
4-氟-2-[((R)-2-甲氧基-1-甲基-乙基)-(2,2,2-三氟-乙酰基)- 氨基]-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):(互变体混合物)8.07(m,1H),7.53(m,1H),7.29(dd,J1=9.39Hz,J2=2.68Hz,1H),4.83(m,1H),3.44(m,1H),3.30(s,3H),1.49(s,9H),0.86(d,3H)。
4-氟-2-[(2-甲氧基-乙基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):8.07(m,1H),7.50(m,1H),7.41(dd,J1=9.39Hz,J2=2.56Hz,1H),4.28(m,1H),3.55(m,1H),3.46(m,1H),3.38(m,1H),3.18(s,3H),1.49(s,9H)。
4-氟-2-[(3-甲氧基丙基)(三氟乙酰基)氨基]苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.48(s,9H)1.68-1.83(m,2H)3.18(s,3H)3.21-3.29(m,1H)3.33-3.38(m,2H)4.06-4.18(m,1H)7.46-7.52(m,1H)7.56(dd,J=9.27,2.68Hz,1H)8.06(dd,J=8.84,6.40Hz,1H)
4-氟-2-[(2-氟乙基)(三氟乙酰基)氨基]苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.50(s,9H)3.54-3.74(m,1H)4.26-4.45(m,1H)4.50-4.80(m,2H)7.47-7.55(m,2H)8.08(dd,J=9.27,6.46Hz,1H)
4-氟-2-[(3-氟丙基)(三氟乙酰基)氨基]苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.50(s,9H)1.80-2.07(m,2H)3.26-3.42(m,1H)4.21(ddd,J=13.78,8.90,6.71Hz,1H)4.42-4.60(m,2H)7.48-7.55(m,1H)7.60(dd,J=9.27,2.44Hz,1H)8.09(dd,J=8.84,6.40Hz,1H)
4-氟-2-[(1-甲氧基-2-甲基丙-2-基)(三氟乙酰基)氨基]苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.09(s,3H)1.47(s,3H)1.52(s,9H)3.17(s,3H)3.19(d,J=9.75Hz,1H)3.80(d, J=9.63Hz,1H)7.36(dd,J=9.45,2.62Hz,1H)7.47(td,J=8.41,2.68Hz,1H)7.93(dd,J=8.78,6.46Hz,1H)
2-[((S)-2-甲氧基-1-甲基-乙基)-(2,2,2-三氟-乙酰基)-氨基]-4-(4-甲基-哌嗪-1-基)-苯甲酸叔丁酯的制备
将4-氟-2-[((S)-2-甲氧基-1-甲基-乙基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸叔丁酯(2g,5.28mmol)和N-甲基哌嗪(5.86mL,52.8mmol)在四氢呋喃(20mL)中的溶液在60℃下搅拌7天。然后蒸发该溶液,加入NaHCO3饱和溶液并且用二氯甲烷萃取该混合物(3次)。用水、盐水洗涤有机层,用硫酸钠干燥、过滤并且蒸发而得到粗产物,通过硅胶柱色谱法纯化(二氯甲烷-甲醇93:7)。得到标题化合物(2.04g,84%),为淡黄色固体。
1H-NMR(400MHz),δ(ppm,DMSO-d6):(互变体混合物)7.81(d,J=9.15Hz,1H),7.06(dd,J1=9.15Hz,J2=2.56Hz,1H),6.79(d,J=2.56Hz,1H),4.80(m,1H),3.39(m,2H),3.34-3.28(m,7H),2.55(m,4H),2.29(bs,3H),1.46(s,9H),0.83(d,3H)。
按照与上述同样的方式操作获得下列化合物:
2-[((R)-2-甲氧基-1-甲基-乙基)-(2,2,2-三氟-乙酰基)-氨基]-4-(4-甲基-哌嗪-1-基)-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):(互变体混合物)7.81(d,J=9.15Hz,1H),7.06(dd,J1=9.15Hz,J2=2.56Hz,1H),6.79(d,J=2.56Hz,1H),4.80(m,1H),3.39(m,2H),3.34-3.28(m,7H),2.55(m,4H),2.29(bs,3H),1.46(s,9H),0.83(d,3H)。
2-[(2-甲氧基-乙基)-(2,2,2-三氟-乙酰基)-氨基]-4-(4-甲基-哌嗪-1-基)-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):(互变体混合物)7.83(d,J=9.02Hz,1H),7.05(dd,J1=9.02Hz,J2=2.68Hz,1H),6.86(d,J=2.68Hz,1H),4.31(m,1H),3.55(m,1H),3.40(m,1H),3.32(m,4H),3.25(m,1H),3.21(s,1H),2.44(t,J=5.12Hz,4H),2.22(bs,3H),1.46(s,9H)。
4-[(2-二甲基氨基-乙基)-甲基-氨基]-2-[(2-甲氧基-乙基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):7.81(d,J=8.9Hz,1H),6.78(dd,J1=8.9Hz,J2=2.8Hz,1H),6.60(d,J=2.8Hz,1H),4.40-4.31(m,1H),3.59-3.39(m,4H),3.23(s,3H),3.22-3.15(m,1H),3.00(s,3H),2.40(m,2H),2.19(bs,6H),1.46(s,9H)。
2-[(3-甲氧基丙基)(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.45(s,9H)1.68-1.84(m,2H)2.26(br.s.,3H)2.44-2.60(m,4H)3.12-3.23(m,1H)3.18(s,3H)3.25-3.48(m,6H)4.08(d,J=22.92Hz,1H)6.92(d,J=2.19Hz,1H)7.02(dd,J=9.02,2.44Hz,1H)7.81(d,J=9.02Hz,1H)
2-[(2-氟乙基)(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.46(s,9H)2.22(s,3H)2.43(t,J=4.76Hz,4H)3.25-3.31(m,4H)3.41-3.59(m,1H)4.27-4.46(m,1H)4.46-4.78(m,2H)6.90(d,J=2.07Hz,1H)7.05(dd,J=9.02,2.68Hz,1H)7.83(d,J=9.02Hz,1H)
2-[(3-氟丙基)(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.46(s,9H)1.80-2.05(m,2H)2.25(br.s.,3H)2.46(br.s.,4H)3.18-3.37(m,5H)4.10-4.24(m,1H)4.38-4.60(m,2H)6.95(d,J=2.44Hz,1H)7.04(dd,J=8.96,2.62Hz,1H)7.84(d,J=9.02Hz,1H)
2-[(1-甲氧基-2-甲基丙-2-基)(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸叔丁酯
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.04(s,3H)1.45(s, 3H)1.49(s,9H)2.22(s,3H)2.44(t,J=4.94Hz,4H)3.20(d,J=9.51Hz,1H)3.23(s,3H)3.25-3.30(m,4H)3.93(d,J=9.51Hz,1H)6.89(d,J=2.32Hz,1H)7.00(dd,J=8.96,2.62Hz,1H)7.70(d,J=8.90Hz,1H)
2-[((S)-2-甲氧基-1-甲基-乙基)-(2,2,2-三氟-乙酰基)-氨基]-4-(4-甲基-哌嗪-1-基)-苯甲酸三氟乙酸盐的制备
向2-[((S)-2-甲氧基-1-甲基-乙基)-(2,2,2-三氟-乙酰基)-氨基]-4-(4-甲基-哌嗪-1-基)-苯甲酸叔丁酯(2.03g,4.42mmol)在二氯甲烷(15mL)中的溶液中加入三氟乙酸(3.4mL,44.2mmol)。将该混合物在室温下搅拌15小时,然后蒸发该溶液至干而得到标题化合物,为油状物,将其不经任何进一步纯化而用于下一步。
1H-NMR(400MHz),δ(ppm,DMSO-d6):(互变体混合物)12.10(bs,1H),9.74(bs,1H),7.90(d,J=8.90Hz,1H),7.15(dd,J1=8.90Hz,J2=2.56Hz,1H),6.89(d,J=2.56Hz,1H),4.76(m,1H),4.03(t,2H),3.55(m,2H),3.37(m,2H),3.30(s,3H),3.18(m,2H),2.88(bs,3H),0.85(d,3H)。
按照与上述同样的方式操作获得下列化合物:
2-[((R)-2-甲氧基-1-甲基-乙基)-(2,2,2-三氟-乙酰基)-氨基]-4-(4-甲基-哌嗪-1-基)-苯甲酸三氟乙酸盐
1H-NMR(400MHz),δ(ppm,DMSO-d6):(互变体混合物)12.10(bs,1H),9.74(bs,1H),7.90(d,J=8.90Hz,1H),7.15(dd,J1=8.90Hz,J2=2.56Hz,1H),6.89(d,J=2.56Hz,1H),4.76(m,1H),4.03(t,2H),3.55(m,2H),3.37(m,2H),3.30(s,3H),3.18(m,2H),2.88(bs,3H),0.85(d,3H)。
2-[(2-甲氧基-乙基)-(2,2,2-三氟-乙酰基)-氨基]-4-(4-甲基-哌嗪-1-基)-苯甲酸三氟乙酸盐
1H-NMR(400MHz),δ(ppm,DMSO-d6):(互变体混合物)12.76(bs,1H),9.73(bs,1H),7.91(d,J=8.78Hz,1H),7.10(dd,J1=8.78Hz,J2=2.68Hz,1H),7.01(d,J=2.68Hz,1H),4.15(m, 1H),4.04(m,2H),3.54(m,2H),3.42(m,2H),3.38(m,2H),3.33(m,2H),3.19(s,3H),3.14(m,2H),2.86(bs,3H)。
4-[(2-二甲基氨基-乙基)-甲基-氨基]-2-[(2-甲氧基-乙基)-(2,2,2-三氟-乙酰基)-氨基]-苯甲酸盐酸盐
1H-NMR(400MHz),δ(ppm,DMSO-d6):12.59(bs,1H),10.00(bs,1H),7.88(d,J=8.9Hz,1H),6.92(dd,J1=8.9Hz,J2=2.8Hz,1H),6.74(8d,J=2.8Hz,1H),4.18(m,1H),3.79(m,2H),3.56(m,1H),3.47-3.36(m,2H),3.24(m,2H),3.21(s,3H),3.01(s,3H),2.84(bd,6H)。
2-[(3-甲氧基丙基)(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸盐酸盐
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.70-1.81(m,2H)2.84(d,J=2.93Hz,3H)3.06-3.40(m,7H)3.19(s,3H)3.52(d,J=10.36Hz,2H)3.96-4.06(m,1H)4.09(br.s.,2H)7.07(d,J=2.56Hz,1H)7.10(dd,J=8.90,2.68Hz,1H)7.93(d,J=8.78Hz,1H)10.27(br.s.,1H)12.76(br.s.,1H)
2-[(2-氟乙基)(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸盐酸盐
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.84(br.s.,3H)3.04-3.30(m,4H)3.47-3.56(m,2H)3.54-3.67(m,1H)4.06(d,2H)4.18-4.40(m,1H)4.46-4.79(m,2H)7.07(d,J=2.19Hz,1H)7.12(dd,J=8.96,2.62Hz,1H)7.91-7.97(m,1H)10.33(br.s.,1H)12.83(br.s.,1H)
2-[(3-氟丙基)(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸三氟乙酸盐
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.82-2.02(m,2H)2.87(s,3H)3.14(m,5H)3.44(m)4.09(m,3H)4.40-4.59(m,2H)7.08-7.15(m,2H)7.95(d,J=9.15Hz,1H)9.72(br.s.,1H)12.81(br.s.,1H)
2-[(1-甲氧基-2-甲基丙-2-基)(三氟乙酰基)氨基]-4-(4-甲基哌嗪-1-基)苯甲酸盐酸盐
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.07(s,3H)1.43(s,3H)2.84(s,3H)3.10-3.38(m,5H)3.25(s,3H)3.47-3.57(m,2H)3.92(d,J=9.51Hz,1H)3.95-4.02(m,2H)7.00(d,J=2.44Hz,1H)7.10(dd,J=8.84,2.50Hz,1H)7.84(d,J=8.78Hz,1H)10.25(br.s.,1H)12.77(br.s.,1H)
实施例23
4-(4-乙酰基哌嗪-1-基)-2-硝基苯甲酸叔丁酯的制备
向2-氨基-4-(哌嗪-1-基)苯甲酸叔丁酯(7.6g,24.7mmol)在二氯甲烷(120mL)中的溶液中加入三乙胺(13.46mL,98.7mmol)和三氟乙酐(6.87mL,49.35mmol)。1小时后蒸发挥发性物质,并且通过柱色谱法纯化粗产物(EtOAc/己烷3:7),得到9.46g(收率95%)标题化合物。
ESI(+)MS:m/z404(MH+)。
实施例24
4-(4-甲基哌嗪-1-基)-2-(苯基氨基)苯甲酸叔丁酯的制备
在氩气环境下的干燥Schlenk管中,将2-氨基-4-(4-甲基哌嗪-1-基)苯甲酸叔丁酯(800mg,2.745mmol)溶于干甲苯(14mL)。使氩气通过该混合物发泡几分钟,然后加入溴苯(0.32mL,3.02mmol,1.1eq),Cs2CO2(1.34g,4.118mmol,1.5eq),Pd(OAc)2(16mg,0.069mmol,2.5mol%)和Rac-BINAP(88mg,0.137mmol,5mol%)。然后将该混合物在100℃下搅拌21小时。将该混合物冷却至室温并且用二氯甲烷稀释。用硅藻土垫过滤盐,并且在减压下浓缩滤液。通过硅胶色谱法纯化粗产物(DCM/EtOH/在甲醇中的NH37%=95:5:0.5),得到1.13g标题化合物(定量收率),为灰白色固体。
1H-NMR(400MHz),δ(ppm,DMSO-d6):1.54(s,9H)2.21(s,3H)2.37-2.43(m,4H)3.15-3.20(m,4H)6.43(dd,J=9.15,2.44Hz,1H)6.60(d,J=2.44Hz,1H)7.02-7.07(m,1H)7.23 -7.27(m,2H)7.33-7.38(m,2H)7.69(d,J=9.02Hz,1H)9.50(s,1H)
实施例25
2-甲氧基-4-(4-甲基哌嗪-1-基)苯甲酸甲酯的制备
将2-甲氧基-4-氟-苯甲酸甲酯(1.6g,9.7mmol),K2CO3(1.3g,9.7mmol)和N-甲基哌嗪(1.3mL,11.7mmol)在100℃下在DMSO(5mL)中加热20小时。用DCM稀释反应混合物并且用水洗涤。用硫酸钠干燥有机相并且蒸发至干。用硅胶柱色谱纯化,使用二氯甲烷/甲醇95:5作为洗脱剂,得到1.7g(收率66%)标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.25(s,3H)2.45(br.s.,4H)3.26-3.34(m,4H)3.70(s,3H)3.80(s,3H)6.49(d,J=2.32Hz,1H)6.53(dd,J=8.84,2.38Hz,1H)7.61(d,J=8.78Hz,1H)
2-甲氧基-4-(4-甲基哌嗪-1-基)苯甲酸盐酸盐的制备
将2-甲氧基-4-(4-甲基哌嗪-1-基)苯甲酸甲酯(1.9g,7.2mmol)在40℃下,在2NNaOH(10mL)和MeOH(10mL)的混合物中加热2小时。蒸发MeOH并且用25%HCl将水层酸化至pH=6,用n-BuOH萃取。用硫酸钠干燥有机相并且蒸发至干,得到1.0g(收率61%)标题化合物。
1H-NMR(400MHz),δ(ppm,DMSO-d6):2.82(br.s.,3H)2.99-3.31(m,4H)3.47(br.s.,2H)3.83(s,3H)4.04(br.s.,2H)6.61(d,1H)6.59(s,1H)7.66(d,J=8.78Hz,1H)10.49(br.s.,1H)11.91(br.s.,1H)
实施例26
4-(4-甲基-哌嗪-1-基)-2-硝基苯甲酸盐酸盐的制备
将4-(4-甲基-哌嗪-1-基)-2-硝基-苯甲酸叔丁酯(16.4g,51mmol)和37%HCl(100mL)在1,4-二烷(200mL)中的混合物在室温下搅拌4小时。过滤得到的固体,用1,4-二烷充分洗涤并且在真空中和45℃下干燥。得到标题化合物,为淡黄色固体(13.45g,87.5%收率),将其不经任何进一步纯化而用于下一步。
1H-NMR(400MHz),δ(ppm,DMSO-d6):10.27(bs,1H),7.81(d,J=8.90Hz,1H),7.40(d,J=2.69Hz,1H),7.24(dd,J1=8.90Hz,J2=2.69Hz,1H),4.13(bs,2H),3.55-3.06(bs,6H),2.83(s,3H)。
按照同样方式操作获得下列化合物:
4-[(3-二甲基氨基-丙基)-甲基-氨基]-2-硝基-苯甲酸盐酸盐
1H-NMR(400MHz),δ(ppm,DMSO-d6):13.07(bs,1H),9.72(bs,1H),7.76(d,J=9.0Hz,1H),7.03(d,J=2.6Hz,1H),6.93(dd,J1=9.0Hz,J2=2.6Hz,1H),3.51(m,2H),3.08(m,2H),3.03(s,3H),2.77(s,6H),1.90(m,2H)。
Claims (11)
1.N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺或其药学上可接受的盐在制备用于治疗由蛋白激酶活性失调引起的疾病的药物中的用途。
2.权利要求1的用途,其中所述疾病是癌症。
3.权利要求2的用途,其中所述癌症选自非小细胞肺癌、结直肠癌、前列腺癌、乳腺癌、卵巢癌、尤因肉瘤、炎性成肌纤维细胞瘤、间变性大细胞淋巴瘤、横纹肌肉瘤、肾细胞癌、甲状腺毛囊癌、黑素瘤、骨髓样造血性肿瘤、淋巴样造血性肿瘤、鳞状细胞癌、胃癌、子宫内膜癌、多发性骨髓瘤、中枢和外周神经系统肿瘤、和视网膜母细胞瘤。
4.权利要求3的用途,其中所述中枢和外周神经系统肿瘤选自神经母细胞瘤、胶质母细胞瘤、和髓母细胞瘤。
5.下述化合物或其药学上可接受的盐:N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(哌嗪-1-基)-2-(四氢-吡喃-4-基氨基)-苯甲酰胺。
6.权利要求5的化合物或其药学上可接受的盐在制备用于治疗由蛋白激酶活性失调引起的疾病的药物中的用途。
7.权利要求6的用途,其中所述疾病是癌症。
8.权利要求7的用途,其中所述癌症选自非小细胞肺癌、结直肠癌、前列腺癌、乳腺癌、卵巢癌、尤因肉瘤、炎性成肌纤维细胞瘤、间变性大细胞淋巴瘤、横纹肌肉瘤、肾细胞癌、甲状腺毛囊癌、黑素瘤、骨髓样造血性肿瘤、淋巴样造血性肿瘤、鳞状细胞癌、胃癌、子宫内膜癌、多发性骨髓瘤、中枢和外周神经系统肿瘤、和视网膜母细胞瘤。
9.权利要求8的用途,其中所述中枢和外周神经系统肿瘤选自神经母细胞瘤、胶质母细胞瘤、和髓母细胞瘤。
10.式(I)的化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗癌症,所述癌症选自非小细胞肺癌、结直肠癌、前列腺癌、乳腺癌、卵巢癌、尤因肉瘤、炎性成肌纤维细胞瘤、间变性大细胞淋巴瘤、横纹肌肉瘤、肾细胞癌、甲状腺毛囊癌、黑素瘤、骨髓样造血性肿瘤、淋巴样造血性肿瘤、鳞状细胞癌、胃癌、子宫内膜癌、多发性骨髓瘤、中枢和外周神经系统肿瘤、和视网膜母细胞瘤,
其中:
X是-CH2-;
Ar是被一个或多个独立地选自NR5R6和杂环基的取代基取代的苯基,其中:
R5和R6独立地是氢、R8-O-C2-C6烷基、C3-C6环烷基、或杂环基,或者R5和R6与它们所键合的氮原子一起可形成任选被直链或支链C1-C6烷基取代的杂环基;
R8是直链或支链C1-C6烷基,
R是任选被一个或多个卤素取代的苯基,
R1、R2和R3是氢,
其中,所述杂环基是一个或两个碳原子被氮替代的5-7元碳环。
11.权利要求10的用途,其中所述中枢和外周神经系统肿瘤选自神经母细胞瘤、胶质母细胞瘤、和髓母细胞瘤。
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