CN113354617A - Egfr和pi3k的小分子抑制剂 - Google Patents
Egfr和pi3k的小分子抑制剂 Download PDFInfo
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- CN113354617A CN113354617A CN202110299508.6A CN202110299508A CN113354617A CN 113354617 A CN113354617 A CN 113354617A CN 202110299508 A CN202110299508 A CN 202110299508A CN 113354617 A CN113354617 A CN 113354617A
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- cancer
- reaction mixture
- quinazolin
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- pi3k
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Abstract
本发明属于药物化学领域。具体地说,本发明涉及一类新的具有喹唑啉结构或喹啉结构的小分子,所述小分子充当EGFR蛋白和PI3K蛋白的双重抑制剂;以及其作为治疗癌症和其他疾病的治疗剂的用途。
Description
关于联邦资助的研究或开发的声明
本发明根据由美国国立卫生研究院(National Institutes of Health)授予的拨款号R01 CA155198在政府支持下进行。政府具有本发明的某些权利。
发明领域
本发明属于药物化学领域。具体地说,本发明涉及一类新的具有喹唑啉结构或喹啉结构的小分子,所述小分子充当EGFR蛋白和PI3K蛋白的双重抑制剂;以及其作为治疗癌症和其他疾病的治疗剂的用途。
前言
结肠直肠癌是美国第三最普遍的恶性肿瘤,估计2005年大约有145,000例新诊断和56,000例死亡(参见例如,Cancer Facts and Figures 2005,Surveillance Research(Washington,D.C.:American Cancer Society,Inc.),2005)。外科手术是用于治疗结肠直肠癌的主要手段,但复发频发。结肠直肠癌已证明对化学疗法具有抗性,尽管使用5-氟尿嘧啶与左旋咪唑的组合已经取得了有限成功。外科手术对存活的影响最大,并且在一些患有有限疾病的患者中实现治愈。然而,外科手术移除大部分肿瘤,留下微观残留疾病,其最终导致复发。
需要用于预防和/或治疗结肠直肠癌的改进的方法。
发明内容
在开发本发明的实施方案过程期间进行的实验合成了用于调节(例如,抑制)磷酸肌醇3′OH激酶家族(PIK3)的蛋白质(例如,PIK3Cα、PIK3δ、PIK3β、PIK3Cγ、PI3Kα)的活性或功能和调节(例如,抑制))表皮生长因子EGFR家族的蛋白质(例如,ERBB受体酪氨酸激酶家族(例如,ERBB1、ERBB2、ERBB4、ERBB1))的活性或功能的喹唑啉衍生物和喹啉衍生物。具体地说,利用从已知的PI3K和EGFR抑制剂中收集的x射线晶体结构和结构-活性关系,此类实验分别引起了PI3K抑制剂的“活性核心”的鉴别,从而促进针对PI3K的高抑制活性;以及EGFR抑制剂的“活性核心”的鉴别,从而促进针对EGFR的高抑制活性(参见实施例I)。因此,合成了本发明的喹唑啉化合物和喹啉化合物,以靶向PI3K的“活性核心”和EGFR的“活性核心”,从而使得此类化合物呈现为具有针对PI3K和EGFR的“双重效力”。
PI3K通过磷酸酶和张力蛋白同源物(PTEN)负调控(参见例如,Hamada K,等人,2005Genes Dev 19(17):2054-65)。许多研究已经证明了PIK3CA突变/PTEN丧失与导致较差总存活的EGFR靶向抗性之间的联系(参见例如,Atreya CE,Sangale Z,Xu N,等人CancerMed.2013;2:496-506;Sawai H,等人,BMC Gastroenterol.2008;8:56;Bethune G,等人,JThorac Dis.2010;2:48-51;Spano JP,等人,Ann Oncol.2005;16:189-194;HeimbergerAB,等人,J Transl Med.2005;3:38)。在开发本发明的实施方案过程期间合成的喹唑啉化合物和喹啉化合物是基于以下中心假说设计的:EGFR和PIK3CA的双重靶向在EGFR阳性和PIK3CA突变或无效PTEN表达子的结肠直肠癌患者中将是有效的(参见例如,Psyrri A,等人,Am Soc Clin Oncol Educ Book.2013:246-255;Lui VW,等人,Cancer Discov.2013;3:761-769;Jin G,等人,Lung Cancer.2010;69:279-283;Buck E,等人,Mol CancerTher.2006;5:2676-2684;Fan QW,等人,Cancer Res.2007;67:7960-7965;Gadgeel SM,等人,Clin Lung Cancer.2013;14:322-332。
因此,本发明涉及一类新的具有喹唑啉结构或喹啉结构的小分子,所述小分子充当EGFR蛋白和PI3K蛋白的双重抑制剂;以及其作为治疗以异常EGFR和PI3K表达为特征的病状(例如,癌症和其他疾病(例如,自身免疫性病症、炎性疾病、心血管疾病、神经变性疾病、过敏、哮喘、胰腺炎、多器官衰竭、肾病、血小板聚集、精子能动性、移植排斥、移植物排斥、肺损伤等))的治疗剂的用途。实际上,通过靶向EGFR和PI3K,本发明的化合物适用于治疗患有在PI3Kα中具有活化突变或为PTEN缺失的EGFR阳性结肠直肠癌的受试者。
因此,本发明设想使患有以异常EGFR蛋白活性(例如,ERBB1)和PI3K蛋白活性(例如,PI3Kα)为特征的病状(例如,癌症(例如,和/或癌症相关病症))的动物(例如,人)暴露于治疗有效量的具有喹唑啉结构的药物(例如,具有喹唑啉结构的小分子)或具有喹啉结构的药物(例如,具有喹啉结构的小分子),所述药物抑制EGFR和PI3K两者的活性,所述暴露将抑制以异常EGFR和PI3K蛋白表达为特征的细胞(例如,具有异常EGFR和PI3K蛋白表达的结肠直肠癌细胞)的生长和/或使此类细胞呈现为对另外治疗药物(例如,癌症治疗药物或放射疗法)的细胞死亡诱导的活性更敏感的群体。本发明设想当作为单一疗法施用以诱导此类细胞(例如癌细胞)的细胞生长抑制、细胞凋亡和/或细胞周期停滞,或当以与另外的药剂(如其他细胞死亡诱导或细胞周期破坏治疗药物(例如,癌症治疗药物或放射疗法)的时间关系施用(组合疗法)以便与仅单独用治疗药物或放射疗法治疗的动物中相应比例的细胞相比,使更大比例的细胞(例如,癌细胞)或支持性细胞易于执行细胞凋亡程序时,EGFR和PI3K两者的抑制剂满足用于治疗以异常EGFR和PI3K活性为特征的多种病状(例如,癌症)的未满足的需求。
在本发明的某些实施方案中,其中所治疗的病状是以异常EGFR蛋白活性(例如,ERBB1)和PI3K蛋白活性(例如,PI3Kα)为特征的癌症(例如,结肠直肠癌),用治疗有效量的本发明的化合物和抗癌剂疗程组合治疗动物与单独用所述化合物或抗癌药物/放射治疗的那些动物相比在此类动物中产生更大的肿瘤响应和临床益处。由于所有批准的抗癌药物和放射治疗的剂量是已知的,因此本发明设想它们与本发明化合物的各种组合。
如所述,本申请人已经发现,某些喹唑啉化合物和喹啉化合物充当EGFR和PI3K两者的抑制剂,并且用作治疗癌症和其他疾病的治疗剂。因此,本发明涉及适用于抑制EGFR和PI3K活性(例如,由此促进细胞凋亡)且增加细胞对细胞凋亡和/或细胞周期停滞的诱导剂的敏感性的喹唑啉化合物和喹啉化合物。本发明的某些喹唑啉化合物和喹啉化合物可作为立体异构体(包括光学异构体)存在。本发明包括所有立体异构体,作为纯的单独立体异构体制剂和各自的富集制剂两者,以及此类立体异构体的外消旋混合物以及可根据本领域的技术人员熟知的方法分离的单独非对映异构体和对映异构体。
式I和II不限于R1和R2的特定化学部分。在一些实施方案中,R1和R2的特定化学部分独立地包括允许所得到的化合物抑制EGFR蛋白(例如,ERBB1)且抑制PI3K蛋白(例如,PI3Kα)的任何化学部分。
在一些实施方案中,R1是取代的或未取代的芳基部分。在一些实施方案中,R1选自
在一些实施方案中,R2是取代的或未取代的芳基部分。在一些实施方案中,R2选自
在一些实施方案中,对于式I和II设想以下化合物:
本发明还提供用于制备本发明的化合物中的任一种的方法。
本发明还提供化合物在以异常EGFR蛋白活性(例如,ERBB1)和PI3K蛋白活性(例如,PI3Kα)为特征的细胞中诱导细胞周期停滞和/或细胞凋亡的用途。本发明还涉及化合物用于使细胞对另外的药剂如细胞凋亡和/或细胞周期停滞的诱导剂敏感以及通过在用化学治疗剂治疗之前诱导细胞周期停滞来化学保护正常细胞的用途。
本发明的化合物适用于治疗、改善或预防病症,如对诱导凋亡细胞死亡响应的那些病症,例如以细胞凋亡调节异常为特征的病症,包括过度增生性疾病,如以细胞异常EGFR蛋白活性(例如,ERBB1)和PI3K蛋白活性(例如,PI3Kα)为特征的癌症(例如,结肠直肠癌)。在某些实施方案中,所述化合物可用于治疗、改善或预防以对癌症疗法有抗性为特征的此类类型的癌症(例如,结肠直肠癌)(例如,为化疗抗性、放射抗性、激素抗性等的那些癌细胞)。在某些实施方案中,癌症是结肠直肠癌、头颈癌、多形性胶质母细胞瘤和/或非小细胞肺癌(NSCLC)。在其他实施方案中,所述化合物可用于治疗以EGFR和PI3K蛋白的异常表达为特征的其他病症(例如,自身免疫性病症、炎性疾病、心血管疾病、神经变性疾病、过敏、哮喘、胰腺炎、多器官衰竭、肾病、血小板聚集、精子能动性、移植排斥、移植物排斥、肺损伤等)。
本发明还提供药物组合物,其包含在药学上可接受的载体中的本发明的化合物。
本发明还提供试剂盒,其包括本发明的化合物和用于将所述化合物施用至动物的说明书。所述试剂盒可任选地含有其他治疗剂,例如抗癌剂或细胞凋亡调节剂。
此外,本发明提供用于通过使细胞暴露于本发明的一种或多种喹唑啉或喹啉化合物来同时抑制此类细胞中的EGFR蛋白活性和PI3K蛋白活性的方法。
附图简述
图1A-C示出EGFR抑制剂。
图2A-E示出PI3K抑制剂。
图3示出拉帕替尼(Lapatinib)(PDB代码:1XKK)和HKI-272(PDB代码:3W2Q)的在EGFR(蛋白激酶的ATP竞争位点)中的X射线晶体喹诺酮结合模式。
图4A示出GSK2126458(PDB代码:3L08)与EGFR和PI3K的X射线晶体结合模式,PF-04979064(PDB代码:4HVB)与PI3K的X射线晶体结合模式,以及拉帕替尼与EGFR的X射线晶体结合模式。
图4B示出BEZ235在PI3K中的结合模式。
图4C示出对于拉帕替尼和GSK2126458(PDB代码:3L08),喹啉的脂质与蛋白激酶结合模式的比较。
图5A示出在单次口服剂量的MOL-162给药后两小时时,发现EGFR的磷酸化在HCT-116肿瘤(100mg/kg)中被完全抑制。
图5B示出对于MOL-160、MOL-161、MOL-162和MOL-163的细胞增殖的测量。
图5C示出对于各种化合物的HCT-116细胞活力。
图5D示出在处理2小时的HCT-116细胞中MOL-162对pAKT和pEGFR的影响。
图6示出各种化合物针对EGFR和PIK3CA的IC50。
图7示出在10μM下选定化合物针对化合物的NCI-60比较组的生长%。
图8A、8B、8C、8D和8E示出MOL-201针对HCT-116、A431、COL-205、SK-MEL5和MDA-MB-468异种移植物的体内功效。
定义
如本文所用的术语“抗癌剂”是指用于治疗过度增生性疾病如癌症(例如,哺乳动物中,例如人中)的任何治疗剂(例如,化学治疗化合物和/或分子治疗化合物)、反义疗法、放射疗法或外科手术干预。
如本文所用的术语“前药”是指在目标生理系统内需要生物转化(例如,自发的或酶促的)以释放或将前药转化(例如,酶促地、生理学地、机械地,电磁地)成活性药物的母体“药物”分子的药理学无活性衍生物。前药被设计为克服与稳定性、水溶性、毒性、缺乏特异性或有限生物利用度相关的问题。示例性前药包含活性药物分子本身和化学掩蔽基团(例如,可逆地抑制药物的活性的基团)。一些前药是具有在代谢条件下可裂解的基团的化合物的变体或衍生物。前药可使用本领域中已知的方法从母体化合物容易地制备,如在以下文献中描述的那些方法:A Textbook of Drug Design and Development,Krogsgaard-Larsen和H.Bundgaard(编著),Gordon&Breach,1991,具体地第5章:″Design andApplications of Prodrugs″;Design of Prodrugs,H.Bundgaard(编著),Elsevier,1985;Prodrugs:Topical and Ocular Drug Delivery,K.B.Sloan(编著),Marcel Dekker,1998;Methods in Enzymology,K.Widder等人(编著),第42卷,Academic Press,1985,具体地第309-396页;Burger′s Medicinal Chemistry and Drug Discovery,第5版,M.Wolff(编著),John Wiley&Sons,1995,具体地第1卷和第172-178页和第949-982页;Pro-Drugs asNovel Delivery Systems,T.Higuchi和V.Stella(编著),Am.Chem.Soc.,1975;以及Bioreversible Carriers in Drug Design,E.B.Roche(编著),Elsevier,1987。
当它们在生理条件下经历溶剂分解或经历酶降解或其他生物化学转化(例如,磷酸化、氢化、脱氢、糖基化)时,示例性前药在体内或体外变得具有药学活性。前药通常在哺乳动物生物体中提供水溶性、组织相容性或延迟释放的优点。(参见例如,Bundgard,Designof Prodrugs,第7-9、21-24页,Elsevier,Amsterdam(1985);和Silverman,The OrganicChemistry of Drug Design and Drug Action,第352-401页,Academic Press,SanDiego,CA(1992))。常见前药包括酸衍生物,如通过母体酸与合适的醇(例如,低级烷醇)的反应制备的酯或通过母体醇与合适的羧酸(例如,氨基酸)的反应制备的酯;通过母体酸化合物与胺的反应制备的酰胺;碱性基团反应以形成酰化碱衍生物(例如,低级烷基酰胺);或含磷衍生物,例如磷酸酯、膦酸酯和氨基磷酸酯,包括环状磷酸酯、膦酸酯和氨基磷酸酯(参见例如,美国专利申请公布号US 2007/0249564 A1;以引用的方式整体并入本文)。
如本文所用的术语“药学上可接受的盐”是指在目标动物(例如,哺乳动物)中生理上耐受的本发明化合物的任何盐(例如,通过与酸或碱反应获得)。本发明化合物的盐可从无机或有机酸和碱来获得。酸的实例包括但不限于盐酸、氢溴酸、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、乙酸、柠檬酸、甲磺酸、乙磺酸、甲酸、苯甲酸、丙二酸、磺酸、萘-2-磺酸、苯磺酸等。其他酸如草酸虽然本身不是药学上可接受的,但是可用于制备盐,所述盐在获得本发明的化合物及其药学上可接受的酸加成盐时适用作中间体。
碱的实例包括但不限于碱金属(例如,钠)氢氧化物、碱土金属(例如,镁)氢氧化物、氨和式NW4 +的化合物,其中W是C1-4烷基等。
盐的实例包括但不限于:乙酸盐、己二酸盐、海藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、延胡索酸盐、葡萄糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、氯化物、溴化物、碘化物、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、棕榈酸盐(palmoate)、果胶酸盐(pectinate)、过硫酸盐、苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一酸盐等。盐的其他实例包括与合适阳离子如Na+、NH4 +和NW4 +(其中W是C1-4烷基)等化合的本发明化合物的阴离子。就治疗用途而言,本发明化合物的盐预期为药学上可接受的。然而,非药学上可接受的酸和碱的盐也可适用于例如制备或纯化药学上可接受的化合物。
如本文所用的术语“溶剂合物”是指本发明的化合物与一种或多种溶剂分子(无论是有机的还是无机的)的物理缔合。这种物理缔合通常包括氢键。在某些情况下,溶剂合物能够分离,例如当一个或多个溶剂合物分子并入结晶固体的晶格中时。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括水合物、乙醇化物和甲醇化物。
如本文所用的术语“治疗有效量”是指足以导致病症的一种或多种症状的改善或预防病症进展或引起病症消退的治疗剂的量。例如,关于癌症的治疗,在一个实施方案中,治疗有效量将是指使肿瘤生长速率降低、使肿瘤质量降低、使转移数量减少、使肿瘤进展时间增加或使存活时间增加至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%或至少100%的治疗剂的量。
如本文所用的术语“致敏(sensitize/sensitizing)”是指通过施用第一药剂(例如,本发明的喹唑啉化合物),使动物或动物内的细胞对第二药剂的生物效应(例如,促进或延迟细胞功能的方面,包括但不限于细胞分裂、细胞生长、增殖、侵袭、血管生成、坏死或细胞凋亡)更敏感或响应更强。第一药剂对靶细胞的致敏作用可被测量为在施用和不施用第一药剂的情况下施用第二药剂时观察到的预期生物效应的差异(例如,促进或延迟细胞功能的方面,包括但不限于细胞生长、增殖、侵袭、血管生成或细胞凋亡)。致敏细胞的反应可相对于在第一药剂不存在下的响应增加至少约10%、至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%、至少约100%、至少约150%、至少约200%、至少约250%、至少300%、至少约350%、至少约400%、至少约450%或至少约500%。
如本文使用的术语“细胞凋亡的调节异常”是指细胞通过凋亡经历细胞死亡的能力(例如,倾向性)的任何异常。细胞凋亡的调节异常与各种病状相关或由各种病状诱导,所述病状的非限制性实例包括自身免疫性病症(例如,系统性红斑狼疮、类风湿性关节炎、移植物抗宿主病、重症肌无力或肖格伦综合征)、慢性炎性病状(例如,银屑病、哮喘或克罗恩氏病)、过度增生性病症(例如,肿瘤、B细胞淋巴瘤或T细胞淋巴瘤)、病毒感染(例如,疱疹、乳头状瘤或HIV)以及其他病状如骨关节炎和动脉粥样硬化。
如本文所用的术语“过度增生性疾病”是指动物中局部增殖细胞群体不受正常生长的通常限制控制的任何病状。过度增生性病症的实例包括肿瘤、赘生物、淋巴瘤等。如果赘生物不经历侵袭或转移则被认为是良性的,并且如果赘生物确实经历侵袭或转移中的任一者则被认为是恶性的。“转移性”细胞是指细胞可侵入并破坏邻近的身体结构。增生是细胞增殖的一种形式,其涉及组织或器官中细胞数量的增加而无结构或功能的显著改变。化生是受控的细胞生长的一种形式,其中一种类型的完全分化细胞取代另一种类型的分化细胞。
活化的淋巴细胞的病理性生长通常导致自身免疫性病症或慢性炎性病状。如本文所用,术语“自身免疫性病症”是指生物体产生识别生物体的自身分子、细胞或组织的抗体或免疫细胞的任何病状。自身免疫性病症的非限制性实例包括自身免疫性溶血性贫血、自身免疫性肝炎、伯杰氏病(Berger’s disease)或IgA肾病、乳糜泻、慢性疲劳综合征、克罗恩氏病、皮肌炎、纤维肌痛、移植物抗宿主病、格雷夫氏病(Grave’s disease)、桥本氏甲状腺炎(Hashimoto′s thyroiditis)、特发性血小板减少性紫癜、扁平苔藓、多发性硬化、重症肌无力、银屑病、风湿热、风湿性关节炎、硬皮病、肖格伦综合征、系统性红斑狼疮、1型糖尿病、溃疡性结肠炎、白癜风等。
如本文使用的术语“瘤性疾病”是指为良性(非癌性)或恶性(癌性)的细胞的任何异常生长。
如本文使用的术语“正常细胞”是指不经历异常生长或分裂的细胞。正常细胞是非癌性的并且不是任何过度增生性疾病或病症的一部分。
如本文使用的术语“抗肿瘤剂”是指延迟靶向(例如,恶性)瘤的增殖、生长或扩散的任何化合物。
如本文所用的术语“预防(prevent)”、“预防(preventing)”和“预防(prevention)”是指动物中病理细胞(例如,过度增殖细胞或瘤细胞)的出现减少。预防可以是完全的,例如,受试者中完全不存在病理细胞。预防也可以是部分的,以使得受试者中病理细胞的出现少于在无本发明的情况下将出现的病理细胞。
术语“药学上可接受的载体”或“药学上可接受的媒介物”涵盖标准药物载体、溶剂、表面活性剂或媒介物中的任一种。合适的药学上可接受的媒介物包括水性媒介物和非水性媒介物。标准药物载体及其制剂描述于Remington′s Pharmaceutical Sciences,MackPublishing Co.,Easton,PA,第19版1995中。
发明详述
不管PI3K/AKT途径活化导致对EGFR靶向药剂的抗性的强有力的证据,研究人员仅最近才试图在临床前和临床上将EGFR靶向剂与PI3K/AKT/MTOR途径抑制剂组合。例如,Buck等人证明,mTOR抑制剂雷帕霉素与EGFR抑制剂埃罗替尼在对单独埃罗替尼治疗有抗性的几种细胞系中协同作用(例如,Ratushny V,等人,Cell Signal.2009;21:1255-1268)。然而,这种协同组合的全部潜力并未实现,因为雷帕霉素诱导AKT的磷酸化,从而导致途径再活化(例如,Ratushny V,等人,Cell Signal.2009;21:1255-1268)。其他人已经探索了几种细胞系和癌组织分型中EGFR和PI3K/AKT途径的双重抑制,从而为这种组合治疗策略提供进一步的支持(参见例如,Eichhorn PJ,等人,Cancer Res.2008;68:9221-9230)。本发明的化合物克服此类限制,并且代表EGFR蛋白活性(例如,ERBB1)和PI3K蛋白活性(例如,PI3Kα)的双重效力抑制剂。具体地说,利用从已知的PI3K和EGFR抑制剂中收集的x射线晶体结构和结构-活性关系,此类实验分别引起了PI3K抑制剂的“活性核心”的鉴别,从而促进针对PI3K的高抑制活性;以及EGFR抑制剂的“活性核心”的鉴别,从而促进针对EGFR的高抑制活性(参见,实施例I)。因此,合成了本发明的喹唑啉和喹啉化合物,以靶向PI3K的“活性核心”和EGFR的“活性核心”,从而使此类化合物呈现为具有针对EGFR蛋白活性(例如,ERBB1)和PI3K蛋白活性(例如,P13Kα)的“双重效力”。
因此,本发明涉及充当EGFR蛋白活性(例如,ERBB1)和PI3K蛋白活性(例如,PI3Kα)的抑制剂的化合物。通过抑制EGFR蛋白活性(例如,ERBB1)和PI3K蛋白活性(例如,PI3Kα)的活性,这些化合物使细胞对细胞凋亡和/或细胞周期停滞的诱导剂敏感,并且在一些情况下本身诱导细胞凋亡和/或细胞周期停滞。因此,本发明涉及使细胞对细胞凋亡和/或细胞周期停滞的诱导剂敏感的方法以及诱导细胞中的细胞凋亡和/或细胞周期停滞的方法,所述方法包括使所述细胞与本发明的化合物单独或与另外的药剂(例如,细胞凋亡的诱导剂或细胞周期破坏剂)组合接触。
本发明还涉及治疗、改善或预防患者中以具有异常EGFR蛋白活性(例如,ERBB1)和PI3K蛋白活性(例如,PI3Kα)的细胞为特征的病状的方法,所述病状如对细胞凋亡的诱导有响应的那些病状,所述方法包括向所述患者施用本发明的化合物和另外的药剂,例如细胞凋亡的诱导剂。此类病症包括特征在于细胞凋亡调节异常的那些和特征在于具有异常EGFR蛋白活性(例如,ERBB1)和PI3K蛋白活性(例如,PI3Kα)的细胞的增殖的那些(例如,结肠直肠癌)。实际上,通过靶向EGFR和PI3K,本发明的化合物适用于治疗患有在PI3Kα中具有活化突变或为PTEN缺失的EGFR阳性结肠直肠癌的受试者。
式I和II不限于R1和R2的特定化学部分。在一些实施方案中,R1和R2的特定化学部分独立地包括允许所得到的化合物抑制EGFR蛋白(例如,ERBB1)且抑制PI3K蛋白(例如,PI3Kα)的任何化学部分。
在一些实施方案中,R1是取代的或未取代的芳基部分。在一些实施方案中,R1选自
在一些实施方案中,R2是取代的或未取代的芳基部分。在一些实施方案中,R2选自
在一些实施方案中,对于式I和II设想以下化合物:
本发明的一个重要方面是本发明的化合物诱导细胞周期停滞和/或细胞凋亡,并且还单独或响应于另外的凋亡诱导信号而增强诱导细胞周期停滞和/或细胞凋亡。因此,预期这些化合物使细胞对细胞周期停滞和/或细胞凋亡的诱导敏感,包括对此类诱导刺激物具有抗性的细胞。本发明的EGFR和PI3K抑制剂(例如,喹唑啉化合物)(例如,喹啉化合物)可用于诱导可通过诱导细胞凋亡治疗、改善或预防的任何病症中的细胞凋亡。
在一些实施方案中,本发明的组合物和方法用于治疗动物(例如,哺乳动物患者,包括但不限于人和兽医动物)中的患病细胞、组织、器官或病理病状和/或疾病状态。就这一点而言,各种疾病和病理适于使用本发明的方法和组合物治疗或预防。这些疾病和病状的非限制性示例性列表包括但不限于结肠直肠癌、非小细胞肺癌、头或颈癌、多形性成胶质细胞瘤癌、胰腺癌、乳腺癌、前列腺癌、淋巴瘤、皮肤癌、结肠癌、黑素瘤、恶性黑素瘤、卵巢癌、脑癌、原发性脑癌、头颈癌、神经胶质瘤、成胶质细胞瘤、肝癌、膀胱癌、非小细胞肺癌、乳腺癌、卵巢癌、肺癌、小细胞肺癌、威尔姆斯瘤、宫颈癌、睾丸癌、膀胱癌、胰腺癌、胃癌、结肠癌、前列腺癌、泌尿生殖器癌、甲状腺癌、食管癌、骨髓瘤、多发性骨髓瘤、肾上腺癌、肾细胞癌、子宫内膜癌、肾上腺皮质癌、恶性胰腺胰岛瘤、恶性类癌、绒毛膜癌、蕈样真菌病、恶性高钙血症、宫颈增生、白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性粒细胞性白血病、急性粒细胞性白血病、毛细胞白血病、成神经细胞瘤、横纹肌肉瘤、卡波济氏肉瘤、真性红细胞增多症、原发性血小板增多症、霍奇金氏病、非霍奇金氏淋巴瘤、软组织肉瘤、成骨性肉瘤、原发性巨球蛋白血症以及成视网膜细胞瘤等、T和B细胞介导的自身免疫性疾病;炎性疾病;感染;过度增生性疾病;AIDS;退行性病状、血管疾病等。在一些实施方案中,所治疗的癌细胞是转移性的。在其他实施方案中,所治疗的癌细胞对抗癌剂具有抗性。
在其他实施方案中,所述病症是具有有异常EGFR蛋白活性(例如,ERBB1)和PI3K蛋白活性(例如,PI3Kα)的细胞的任何病症(例如,自身免疫性病症、炎性疾病、心血管疾病、神经变性疾病、过敏、哮喘、胰腺炎、多器官衰竭、肾病、血小板聚集、精子能动性、移植排斥、移植物排斥、肺损伤等)。
本发明的一些实施方案提供用于施用有效量的本发明的化合物和至少一种另外的治疗剂(包括但不限于,化学治疗性抗肿瘤剂、凋亡调节剂、抗微生物剂、抗病毒剂、抗真菌剂和抗炎剂)和/或治疗技术(例如,外科手术和/或放射疗法)的方法。在一个具体实施方案中,另外的治疗剂是抗癌剂。
许多合适的抗癌剂被考虑用于本发明的方法中。实际上,本发明设想但不限于施用许多抗癌剂,如:诱导细胞凋亡的药剂;多核苷酸(例如,反义、核酶、siRNA);多肽(例如,酶和抗体);生物模拟物;生物碱;烷化剂;抗肿瘤抗生素;抗代谢药物;激素;铂化合物;单克隆或多克隆抗体(例如,与抗癌药物、毒素、防御素缀合的抗体);毒素;放射性核素;生物响应调节剂(例如,干扰素(例如,IFN-α)和白介素(例如,IL-2));过继性免疫治疗剂;造血生长因子;诱导肿瘤细胞分化的药剂(例如,全反式视黄酸);基因治疗试剂(例如,反义治疗试剂和核苷酸);肿瘤疫苗;血管生成抑制剂;蛋白酶抑制剂;NF-KB调节剂;抗CDK化合物;HDAC抑制剂等。适用于与所公开的化合物共同施用的化学治疗化合物和抗癌疗法的许多其他实例是本领域的技术人员已知的。
在某些实施方案中,抗癌剂包括诱导或刺激细胞凋亡的药剂。诱导细胞凋亡的药剂包括但不限于放射(例如,X射线、γ射线、UV);肿瘤坏死因子(TNF)相关因子(例如,TNF家族受体蛋白、TNF家族配体、TRAIL、TRAIL-R1或TRAIL-R2的抗体);激酶抑制剂(例如,表皮生长因子受体(EGFR)激酶抑制剂、血管生长因子受体(VGFR)激酶抑制剂、成纤维细胞生长因子受体(FGFR)激酶抑制剂、血小板源性生长因子受体(PDGFR)激酶抑制剂和Bcr-Ab1激酶抑制剂(如GLEEVEC));反义分子;抗体(例如,HERCEPTIN、RITUXAN、ZEVALIN和AVASTIN);抗雌激素(例如,雷洛昔芬和他莫昔芬);抗雄激素(例如,氟他胺、比卡鲁胺、非那雄胺、氨鲁米特、酮康唑和皮质类固醇);环氧合酶2(COX-2)抑制剂(例如,塞来昔布、美洛昔康、NS-398和非类固醇抗炎药(NSAID));抗炎药(例如,布他酮、DECADRON、DELTASONE、地塞米松、地塞米松浓缩口服液、DEXONE、HEXADROL、羟氯喹、METICORTEN、ORADEXON、ORASONE、羟基保泰松、PEDIAPRED、苯基丁氮酮、PLAQUENIL、泼尼松龙、泼尼松、PRELONE和TANDEARIL);以及癌症化学治疗药物(例如,伊立替康(CAMPTOSAR)、CPT-11、氟达拉滨(FLUDARA)、达卡巴嗪(DTIC)、地塞米松、米托蒽醌、MYLOTARG、VP-16、顺铂、卡铂、奥沙利铂、5-FU、阿霉素、吉西他滨、硼替佐米、吉非替尼、贝伐单抗、TAXOTERE或TAXOL);细胞信号传导分子;神经酰胺和细胞因子;星孢菌素等。
在其他实施方案中,本发明的组合物和方法提供本发明的化合物和至少一种选自烷化剂、抗代谢物和天然产物(例如,草药和其他植物和/或动物源性化合物)的抗过度增生或抗肿瘤剂。
适用于本发明组合物和方法的烷化剂包括但不限于:1)氮芥(例如,二氯甲基二乙胺、环磷酰胺、异环磷酰胺、美法仑(L-沙可来新(sarcolysin));和苯丁酸氮芥);2)乙烯亚胺和甲基蜜胺(例如,六甲基密胺和噻替派);3)烷基磺酸酯(例如,白消安);4)亚硝基脲(例如,卡莫司汀(BCNU);洛莫司汀(CCNU);司莫司汀(甲基-CCNU));以及链佐星(链脲霉素));和5)三氮烯(例如,达卡巴嗪(DTIC;二甲基三嗪并咪唑甲酰胺)。
在一些实施方案中,适用于本发明组合物和方法中的抗代谢物包括但不限于:1)叶酸类似物(例如,甲氨蝶呤(氨甲蝶呤));2)嘧啶类似物(例如,氟尿嘧啶(5-氟尿嘧啶;5-FU)、氟尿苷(氟脱氧尿苷;FudR)和阿糖胞苷(胞嘧啶阿拉伯糖苷));和3)嘌呤类似物(例如,巯基嘌呤(6-巯基嘌呤;6-MP)、硫鸟嘌呤(6-硫鸟嘌呤;TG)和喷司他丁(2′-脱氧柯福霉素))。
在其他实施方案中,适用于本发明的组合物和方法中的化学治疗剂包括但不限于:1)长春花生物碱(例如,长春花碱(VLB)、长春新碱));2)表鬼臼毒素(例如,依托泊苷和替尼泊苷);3)抗生素(例如,更生霉素(放线菌素D)、柔红霉素(道诺霉素;红比霉素)、阿霉素、博来霉素、普卡霉素(光辉霉素)和丝裂霉素(丝裂霉素C));4)酶(例如,L-天冬酰胺酶);5)生物响应调节剂(例如,干扰素-α);6)铂配位复合物(例如,顺铂(cis-DDP)和卡铂);7)蒽二酮类(例如,米托蒽醌);8)取代的脲(例如,羟基脲);9)甲基肼衍生物(例如,丙卡巴肼(N-甲基肼;MIH));10)肾上腺皮质抑制剂(例如,米托坦(o,p’-DDD)和氨鲁米特);11)肾上腺皮质类固醇(例如,泼尼松);12)孕激素(例如,己酸羟孕酮、乙酸甲羟孕酮和乙酸甲地孕酮);13)雌激素(例如,己烯雌酚和乙炔雌二醇);14)抗雌激素(例如,他莫昔芬);15)雄激素(例如,丙酸睾酮和氟甲睾酮);16)抗雄激素(例如,氟他胺);以及17)促性腺激素释放激素类似物(例如,亮丙瑞林)。
在癌症治疗情形中常规使用的任何溶瘤剂可用于本发明的组合物和方法中。例如,美国食品与药品管理局维持被批准在美国使用的溶瘤剂的处方集。U.S.F.D.A.的国际合作机构维持类似的处方集。表1提供被批准在美国使用的示例性抗肿瘤剂的列表。本领域的技术人员将理解,所有美国批准的化学治疗剂所需的“产品标签”描述所述示例性药剂的经批准的适应症、给药信息、毒性数据等。
表1.
抗癌剂还包括已被鉴定为具有抗癌活性的化合物。实例包括但不限于3-AP、12-O-十四烷酰佛波醇-13-乙酸酯、17AAG、852A、ABI-007、ABR-217620、ABT-751、ADI-PEG20、AE-941、AG-013736、AGRO100、阿拉诺新、AMG 706、抗体G250、抗瘤酮(antineoplaston)、AP23573、阿帕兹醌(apaziquone)、APC8015、阿替莫德(atiprimod)、ATN-161、安贝生坦(atrasenten)、阿扎胞苷、BB-10901、BCX-1777、贝伐单抗、BG00001、比卡鲁胺、BMS 247550、硼替佐米、苔藓抑素-1、布舍瑞林、骨化三醇、CCI-779、CDB-2914、头孢克肟、西妥昔单抗、CG0070、西仑吉肽、氯法拉滨、考布他汀A4磷酸酯、CP-675,206、CP-724,714、CpG 7909、姜黄素、地西他滨、DENSPM、度骨化醇、E7070、E7389、海鞘素743、乙丙昔罗、依氟鸟氨酸、EKB-569、恩斯他瑞(enzastaurin)、埃罗替尼、依昔舒林、芬维A胺、夫拉平度、氟达拉滨、氟他胺、福莫司汀、FR901228、G17DT、加利昔单抗、吉非替尼、染料木素、葡磷酰胺、GTI-2040、组氨瑞林、HKI-272、高三尖杉酯碱、HSPPC-96、hu14.18-白介素-2融合蛋白、HuMax-CD4、伊洛前列素、咪喹莫特、英夫利昔单抗、白介素-12、IPI-504、伊洛福芬、伊沙匹隆、拉帕替尼、来那度胺、来他替尼(lestaurtinib)、亮丙瑞林、LMB-9免疫毒素、洛那法尼、鲁昔单抗(luniliximab)、马磷酰胺、MB07133、MDX-010、MLN2704、单克隆抗体3F8、单克隆抗体J591、莫特沙芬、MS-275、MVA-MUC1-IL2、尼鲁米特、硝基喜树碱、诺拉曲塞二盐酸盐、诺瓦得士(nolvadex)、NS-9、O6-苄基鸟嘌呤、奥利默森钠、ONYX-015、奥戈伏单抗、OSI-774、帕尼单抗、伯尔定、PD-0325901、培美曲塞、PHY906、吡格列酮、吡非尼酮、PS-341、PSC 833、PXD101、吡唑啉吖啶、R115777、RAD001、豹蛙酶(ranpirnase)、蝴蝶霉素类似物、rhu血管抑素蛋白、rhuMab 2C4、罗格列酮、鲁比替康、S-1、S-8184、沙铂(satraplatin)、SB-、15992、SGN-0010、SGN-40、索拉非尼、SR31747A、ST1571、SU011248、辛二酰苯胺异羟肟酸、苏拉明、他来博斯塔(talabostat)、他仑帕奈(talampanel)、塔瑞奎达(tariquidar)、替西罗莫司、TGFa-PE38免疫毒素、沙利度胺、胸腺法新、替吡法尼、替拉扎明、TLK286、曲贝替定、葡糖醛酸三甲曲沙、TroVax、UCN-1、丙戊酸、长春氟宁、VNP40101M、伏洛昔单抗、伏立诺他、VX-680、ZD1839、ZD6474、齐留通和唑喹达三盐酸盐。
为了更详细地描述抗癌剂和其他治疗剂,本领域的技术人员参考任何数量的指导手册,包括但不限于,Physician′s Desk Reference and to Goodman and Gilman′s″Pharmaceutical Basis of Therapeutics″tenth edition,编著.Hardman等人,2002。
本发明提供用于施用本发明的化合物与放射疗法的方法。本发明不受用于将治疗剂量的放射递送至动物的类型、量或递送和施用系统的限制。例如,动物可接收光子放射疗法、粒子束放射疗法、其他类型的放射疗法及其组合。在一些实施方案中,使用线性加速器将放射递送至动物。在其他实施方案中,使用γ刀递送放射。
放射源可以在动物的外部或内部。外部放射疗法是最常见的,并且涉及使用例如线性加速器将高能放射束通过皮肤引导至肿瘤部位。当放射束定位于肿瘤部位时,几乎不可能避免正常健康组织的暴露。然而,外部放射通常被动物良好耐受。内部放射疗法包括在身体内部或在肿瘤部位处或附近植入放射发射源,如珠粒、线、小球、胶囊、颗粒等,包括使用特异性地靶向癌细胞的递送系统(例如,使用连接至癌细胞结合配体的颗粒)。此类植入物可在治疗后移除,或者不活动地留在身体中。内部放射疗法的类型包括但不限于短距离放射治疗、组织间照射、腔内照射、放射免疫疗法等。
动物可任选地接受放射增敏剂(例如,甲硝唑、米索硝唑,动脉内Budr、静脉内碘脱氧尿苷(IudR)、硝基咪唑、5-取代的-4-硝基咪唑、2H-异吲哚二酮、[[(2-溴乙基)-氨基]甲基]-硝基-1H-咪唑-1-乙醇、硝基苯胺衍生物、DNA亲和低氧选择性细胞毒素、卤化DNA配体、1,2,4苯并三嗪氧化物、2-硝基咪唑衍生物、含氟硝基唑类衍生物、苯甲酰胺、烟酰胺、吖啶-嵌入剂、5-硫代四唑衍生物、3-硝基-1,2,4-三唑、4,5-二硝基咪唑衍生物、羟基化德克萨卟啉(texaphrin)、顺铂、丝裂霉素、替拉扎明、亚硝基脲、巯基嘌呤、甲氨蝶呤、氟尿嘧啶、博来霉素、长春新碱、卡铂、表柔比星、阿霉素、环磷酰胺、长春地辛、依托泊苷、紫杉醇、热(过热)等)、放射保护剂(例如,半胱胺、氨基烷基二氢硫代磷酸酯、氨磷汀(WR 2721)、IL-1、IL-6等)。放射增敏剂增强肿瘤细胞的杀伤。放射保护剂保护健康组织免受放射的有害作用。
任何类型的放射可施用至动物,只要放射的剂量被动物耐受而没有不可接受的不利副作用。放射疗法的合适类型包括例如电离(电磁)放射疗法(例如,X射线或γ射线)或粒子束放射疗法(例如,高线性能量放射)。电离放射被定义为包含具有足够能量以产生电离的粒子或光子的放射,即电子的增益或损失(例如像以引用的方式整体并入本文的U.S.5,770,581中所描述)。放射的影响可以被临床医生至少部分地控制。在一个实施方案中,为了最大靶细胞暴露和毒性降低,将放射剂量分次给予。
在一个实施方案中,施用至动物的总放射剂量是约.01戈瑞(Gy)至约100Gy。在另一个实施方案中,在治疗过程内施用约10Gy至约65Gy(例如,约15Gy、20Gy、25Gy、30Gy、35Gy、40Gy、45Gy、50Gy、55Gy或60Gy)。虽然在一些实施方案中可在一天的过程内施用完整剂量的放射,但是总剂量理想地分次并在几天内施用。理想地,在至少约3天,例如至少5、7、10、14、17、21、25、28、32、35、38、42、46、52或56天(约1-8周)的过程内施用放射疗法。因此,每日放射剂量将包含大约1-5Gy(例如,约1Gy、1.5Gy、1.8Gy、2Gy、2.5Gy、2.8Gy、3Gy、3.2Gy、3.5Gy、3.8Gy、4Gy、4.2Gy或4.5Gy)或1-2Gy(例如,1.5-2Gy)。每日放射剂量应足以诱导靶细胞的破坏。在一个实施方案中,如果在一段时间内延续,并非每天施用放射,从而允许动物休息并实现所述疗法的作用。例如,放射期望连续5天施用,并且对于每周治疗在2天不施用,从而允许每周休息2天。然而,取决于动物的响应性和任何潜在的副作用,放射可以1天/周、2天/周、3天/周、4天/周、5天/周、6天/周或全部7天/周施用。可在治疗期中的任何时间开始放射疗法。在一个实施方案中,放射在第1周或第2周开始,并且在治疗期的剩余持续时间内施用。例如,放射在包括6周的治疗期的第1-6周或第2-6周内施用,以用于治疗例如实体肿瘤。或者,放射在包括5周的治疗期的第1-5周或第2-5周内施用。然而,这些示例性放射疗法施用方案并不旨在限制本发明。
抗微生物治疗剂也可用作本发明中的治疗剂。可使用可杀死、抑制或以其他方式减弱微生物生物体的功能的任何试剂,以及预期具有此类活性的任何试剂。抗微生物剂包括但不限于单独使用或组合使用的天然和合成抗生素、抗体、抑制蛋白(例如,防御素)、反义核酸、膜破坏剂等。实际上,可使用任何类型的抗生素,包括但不限于抗菌剂、抗病毒剂、抗真菌剂等。
在本发明的一些实施方案中,本发明的化合物和一种或多种治疗剂或抗癌剂在一种或多种以下条件下施用至动物:以不同的周期、以不同的持续时间、不同的浓度、通过不同的施用途径等。在一些实施方案中,化合物在治疗剂或抗癌剂之前施用,例如在施用治疗剂或抗癌剂之前0.5、1、2、3、4、5、10、12或18小时,1、2、3、4、5或6天,或者1、2、3或4周。在一些实施方案中,化合物在治疗剂或抗癌剂之后施用,例如在施用抗癌剂之后0.5、1、2、3、4、5、10、12或18小时,1、2、3、4、5或6天,或者1、2、3或4周。在一些实施方案中,化合物和治疗剂或抗癌剂同时施用但按不同的时间表,例如,每天施用化合物,而治疗剂或抗癌剂每周一次、每两周一次、每三周一次或每四周一次施用。在其他实施方案中,化合物每周一次施用,而治疗剂或抗癌剂每天、每周一次、每两周一次、每三周一次或每四周一次施用。
本发明范围内的组合物包括其中本发明的化合物以有效于实现其预期目的量包含的所有组合物。虽然个体需求不同,但确定每种组分的有效量的最佳范围在本领域的技术范围内。通常,化合物可以每天0.0025至50mg/kg针对对诱导细胞凋亡有响应的病症所治疗的哺乳动物的体重的剂量或等效量的其药学上可接受的盐口服施用至哺乳动物,例如人。在一个实施方案中,口服施用约0.01至约25mg/kg以治疗、改善或预防此类病症。对于肌内注射,剂量通常为口服剂量的约一半。例如,合适的肌内剂量将是约0.0025至约25mg/kg,或约0.01至约5mg/kg。
单位口服剂量可包括约0.01至约1000mg,例如约0.1至约100mg的化合物。单位剂量可作为一个或多个片剂或胶囊每天一次或多次施用,所述片剂或胶囊各自含有约0.1至约10mg,通常约0.25至50mg的化合物或其溶剂合物。
在局部制剂中,化合物可以每克载体约0.01至100mg的浓度存在。在一个实施方案中,化合物以约0.07-1.0mg/ml,例如约0.1-0.5mg/ml,且在一个实施方案中约0.4mg/ml的浓度存在。
除了作为原料化学品施用化合物之外,本发明的化合物还可作为包含合适的药学上可接受的载体的药物制剂的一部分施用,所述药学上可接受的载体包括有助于将化合物加工成药学上可使用的制剂的赋形剂和助剂。制剂(特别是可口服或局部施用并且可用于一种施用方式的那些制剂,如片剂、糖锭剂、缓释锭剂和胶囊、口腔清洗剂和漱口水、凝胶剂、液体悬浮液、洗发剂、发胶、洗发水,以及还有可直肠施用的制剂,如栓剂以及用于通过静脉输注、注射、局部或口服施用的合适溶液)含有约0.01%至99%,在一个实施方案中约0.25%至75%的活性化合物连同赋形剂。
本发明的药物组合物可施用至可能经历本发明化合物的有益作用的任何患者。此类患者中最重要的是哺乳动物,例如人,但是本发明不旨在限于此。其他患者包括兽医动物(牛、羊、猪、马、狗、猫等)。
化合物及其药物组合物可通过实现其预期目的的任何方式施用。例如,可通过胃肠外、皮下、静脉内、肌内、腹膜内、透皮、口腔、鞘内、颅内、鼻内或局部途径施用。或者或同时,可通过口服途径进行施用。所施用的剂量将取决于接受者的年龄、健康和体重,同时治疗的种类(如果存在),治疗的频率以及所需作用的性质。
本发明的药物制剂以本身已知的方式制造,例如通过常规混合、制粒、糖锭剂制备、溶解或冻干方法。因此,可通过以下步骤来获得用于口服使用的药物制剂:将活性化合物与固体赋形剂组合,任选地研磨所得到的混合物,并且在添加合适的助剂之后(如果需要或必要)加工颗粒的混合物,以便获得片剂或糖锭剂核心。
合适的赋形剂具体地是填充剂,如糖,例如乳糖或蔗糖、甘露醇或山梨醇;纤维素制剂和/或磷酸钙,例如磷酸三钙或磷酸氢钙;以及粘合剂如淀粉糊,使用例如玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮。如果需要,可添加崩解剂,如上述淀粉以及还有羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂或藻酸或其盐,如藻酸钠。助剂尤其是流动调节剂和润滑剂,例如二氧化硅、滑石、硬脂酸或其盐如硬脂酸镁或硬脂酸钙和/或聚乙二醇。糖锭剂核心被提供有合适的包衣,如果需要所述包衣是耐胃液的。为此目的,可使用浓缩的糖溶液,所述浓缩的糖溶液可任选包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、漆溶液、以及合适的有机溶剂或溶剂混合物。为了产生耐胃液的包衣,使用合适的纤维素制剂如邻苯二甲酸乙酰纤维素或邻苯二甲酸羟丙基甲基纤维素的溶液。可将染料或颜料添加至片剂或糖锭剂包衣(例如)用于鉴别或以便表征活性化合物剂量的不同组合。
可口服使用的其他药物制剂包括由明胶制成的推入配合型胶囊(push-fitcapsule)以及由明胶和增塑剂(如甘油或山梨糖醇)制成的软密封型胶囊。推入配合型胶囊可包含呈颗粒形式的活性化合物,所述活性化合物可与填充剂(如乳糖)、粘合剂(如淀粉)和/或润滑剂(如滑石或硬脂酸镁)以及任选的稳定剂混合。在软胶囊中,活性化合物在一个实施方案中溶解或悬浮在合适的液体(如脂肪油或液体石蜡)中。此外,可添加稳定剂。
可直肠使用的可能的药物制剂包括例如栓剂,其由一种或多种活性化合物与栓剂基质的组合组成。合适的栓剂基质是例如天然或合成甘油三酸酯或石蜡烃。此外,还可能使用由活性化合物与基质的组合组成的明胶直肠胶囊。可能的基质材料包括例如液体甘油三酸酯、聚乙二醇或石蜡烃。
用于胃肠外施用的合适制剂包括呈水溶性形式的活性化合物的水溶液,例如水溶性盐和碱性溶液。此外,可施用作为适当的油性注射悬浮液的活性化合物的悬浮液。合适的亲脂性溶剂或媒介物包括脂肪油,例如芝麻油,或合成脂肪酸酯,例如油酸乙酯或甘油三酯或聚乙二醇-400。水性注射悬浮液可含有增加悬浮液粘度的物质,包括例如羧甲基纤维素钠、山梨糖醇和/或葡聚糖。任选地,悬浮液还可含有稳定剂。
在一个实施方案中,通过选择适当的载体将本发明的局部组合物配制为油、乳膏、洗剂、软膏等。合适的载体包括植物油或矿物油、白凡士林(白软石蜡)、支链脂肪或油、动物脂肪和高分子量醇(大于C12)。载体可以是其中活性成分可溶的那些。如果需要,还可包括乳化剂、稳定剂、湿润剂和抗氧化剂,以及赋予颜色或香味的试剂。此外,透皮渗透增强剂可用于这些局部制剂中。此类增强剂的实例可在美国专利号3,989,816和4,444,762中找到;其各自以引用的方式并入本文。
可通过将植物油(如杏仁油)中的活性成分的溶液与温和的软石蜡混合并使混合物冷却来配制软膏。这种软膏的典型实例是包含约30重量%的杏仁油和约70重量%的白色软石蜡的一种软膏。可通过将活性成分溶解在合适的高分子量醇如丙二醇或聚乙二醇中来方便地制备洗剂。
本领域的普通技术人员将容易地认识到,前述内容仅仅代表本发明的某些优选实施方案的详细描述。上述组合物和方法的各种修改和改变可使用本领域可获得的专门技术容易地实现,并且在本发明的范围内。
实施例
以下实施例说明但并非限制本发明的化合物、组合物和方法。在临床治疗中通常遇到并且对本领域技术人员而言显而易见的各种条件和参数的其他合适的修改和改变在本发明的精神和范围内。
实施例1.
利用从化合物数据库收集的x射线晶体结构和结构-活性关系,产生了所有验证的文献EGFR抑制剂(图1A-C)和PI3K抑制剂(图2A-E)的汇编数据库。
接下来,单独产生每个靶标的“活性核心”,并且将此类核心与针对两种激酶的高活性比较。对交叉检查此类核心的选择性。鉴别了三个“选择性”核心。分析活性和选择性核心的X射线晶体结构的结合模式。
图3示出拉帕替尼(PDB代码:1XKK)和HKI-272(PDB代码:3W2Q)在EGFR(蛋白激酶的ATP竞争位点)中的X射线晶体喹诺酮结合模式。对于拉帕替尼,喹啉氮与铰链主链MET793形成氢键。喹唑啉环体系的6位离开相对于喹啉的PI3K结合模式翻转的溶剂。对于HKI-272(具有3-腈的喹啉),维持与喹唑啉核心类似的结合模式,但与PI3K结合模式相比时翻转。两个系列之间的SAR预计会会聚。
图4A示出GSK2126458(PDB代码:3L08)与EGFR和PI3K的X射线晶体结合模式,PF-04979064(PDB代码:4HVB)与PI3K的X射线晶体结合模式,以及拉帕替尼与EGFR的X射线晶体结合模式。如所示,结合PI3K喹啉氮的GSK2126458(3L08)的X射线晶体结构与铰链主链缬氨酸形成氢键。6位的吡啶基位于PI3K特异性口袋内。磺酰胺与LYS833相互作用,并且芳香族基团位于磷酸盐结合口袋内。
图4B示出BEZ235在PI3K中的结合模式。在PI3K喹啉氮中结合的BEZ235模型与铰链主链缬氨酸形成氢键。6位的第二个喹啉位于PI3K特异性口袋内。腈与LYS833相互作用,并且芳香族基团是核糖结合口袋与磷酸盐结合口袋之间的桥。
图4C示出对于拉帕替尼和GSK2126458(PDB代码:3L08),喹啉的脂质与蛋白激酶结合模式的比较。如所示,喹啉(喹唑啉)核心的结合模式在PI3K中相对于EGFR翻转。
基于这种结合信息,合成了针对PI3K和EGFR的双重效力的新化合物。选择了共同核心(例如,(BEZ235))(例如,(埃罗替尼))(例如,(培利替尼))并且针对EGFR和PIK3CA的效力设计了配体。分子的对应核心部分展示具有针对PIK3CA或EGFR的活性的共同核心结构的结构基序。这些共同的核心充当用于设计具有针对EGFR和PI3K两者的潜在活性的新分子的基础。利用此类核心在EGFR和PI3K的其各自活性位点中的已知分子的结合模式,从而产生具有针对两者的活性的新颖配体的设计(参见图4C)。
设计了许多具有针对EGFR和PIK3CA的纳摩尔效力的命中。出人意料地,当分子针对一组广泛的39种激酶(涵盖各种酪氨酸、丝氨酸/苏氨酸和脂质激酶)进行表达谱分析时,只有ERBB(ERBB1、ERBB2和ERBB4)和PI3K(PIK3a、P110γ、P110δ、MTOR和DNA-PK)家族在10μM下被均匀地抑制>50%。MOL-162的代表性数据证明了纯化的EGFR和PIK3CA的有效双重抑制,伴随对针对KRAS突变型HCT-116细胞的途径和细胞毒性的细胞调节。针对这两种生化靶标均示出这些药剂的结构-活性关系。此外,证明了针对其他HER家族成员以及MTOR的选择性。基于针对PI3K家族成员的此类结果,预期此类化合物将是针对除PIK3CA以外的PI3K的其他同种型同样有效的,因此将治疗效用扩展到结直肠癌以外。
MOL-153的干净激酶分布引起此化合物针对皮下HCT-116肿瘤的体内药效动力学活性的评估。虽然腹膜内施用100mg/kg此化合物导致pAKT的抑制,但是未检测到pEGFR的抑制,推测这是由于针对EGFR的不足效力(349nM)所致。接下来合成密切相关的类似物,所述类似物将具有针对主要靶标的改进的双重效力并且还展现口服活性。比MOL-153显著更易溶解的MOL-162从这些努力中出现。如图5A中所示,在单次口服剂量的MOL-162给药后两小时,发现EGFR的磷酸化在HCT-116肿瘤中被完全抑制(100mg/kg)。AKT的磷酸化未被强烈抑制。然而,需要MOL-162的另外合成以允许进行完整药效动力学时程研究来确定在单次和重复每日给药后两种靶标的靶标抑制的最大程度。
图5B示出对于MOL-160、MOL-161、MOL-162和MOL-163的细胞增殖的测量。使用CellTiter Glo测定(Promega,Madison,WI)来测定细胞增殖。将细胞系在96孔板中以每孔2,000与5,000个细胞之间的密度接种。在接种二十四小时后,将细胞用不同浓度的药物作为单一药剂或组合给药。给药后72或96小时测定Cell Titer Glo的信号。
图5C示出各种化合物的HCT-116细胞活力。
图5D示出在处理2小时的HCT-116细胞中MOL-162对pAKT和pEGFR的影响。
图7示出在10μM下选定化合物针对化合物的NCI-60比较组的生长%。双重EGFR和PIK3CA抑制剂在体外抑制NCI-60细胞组的肿瘤生长。MOL-201在所述组内表现出广泛的细胞杀伤(在10uM下的负生长)。所述方法在实施例2-NCI比较组中概述。
图8A、8B、8C、8D和8E示出MOL-201针对HCT-116、A431、COL-205、SK-MEL5和MDA-MB-468异种移植物的体内功效。MOL-201被小鼠良好耐受,其中在20和100mg/kg下每天处理持续10天没有毒性的临床观察结果。在HCT-116、A431、SK-MEL5和COL-205异种移植物中在较高剂量下观察到抗肿瘤活性,如由T/C和T-C值所指示。MOL-201在20mg/kg的较低剂量下引发抗肿瘤活性。所述方法在实施例2-异种移植物研究中概述。
实施例2.
描述了用于实施例1的材料和方法。
测定:生物化学测定采用基于荧光的偶联酶形式,并且基于磷酸化和非磷酸化肽对蛋白水解裂解的差异敏感性(图6)。肽底物用两个荧光团标记-在每个末端处一个-其构成FRET对。在初级反应中,激酶将ATP的γ-磷酸转移至合成FRET肽中的单个酪氨酸、丝氨酸或苏氨酸残基。在次级反应中,位点特异性蛋白酶识别并裂解非磷酸化FRET肽。FRET-肽的磷酸化抑制了由开发试剂引起的裂解。裂解破坏FRET-肽上的供体荧光团(即香豆素)与受体荧光团(即荧光素)之间的FRET,而未裂解的、磷酸化的FRET-肽维持FRET。计算在400nm处供体荧光团激发后供体发射与受体发射的比率(发射比)的比率计法用于定量反应进程。
用于定量反应进程的这种比率计法的显著益处是消除FRET肽浓度和信号强度的孔间变化。因此,在低磷酸化百分比下,所述测定产生非常高的Z′因子值(>0.7)。
裂解和未裂解的FRET-肽均促成荧光信号,且因此促成发射比。FRET-肽的磷酸化程度可从发射比计算。如果FRET肽被磷酸化(即,没有激酶抑制),则发射比将保持较低,且如果FRET-肽未被磷酸化(即激酶抑制),则发射比将保持较高。
酶:ADAPTA通用激酶测定是一种用于检测ADP的基于荧光的均相免疫测定。与ATP消耗测定相比,ADAPTA测定对ADP形成非常敏感,以使得大多数信号改变发生在ATP至ADP的转化的前10%-20%中。这使得ADAPTA通用激酶测定非常适合用于低活性激酶。
ADAPTA通用激酶测定的原理在以下概述。测定本身可分为两个阶段:激酶反应阶段和ADP检测阶段。在激酶反应阶段,将激酶反应所需的所有组分添加至孔中,并且使反应物孵育60分钟。在反应之后,将由铕标记的抗-ADP抗体、Alexa647标记的ADP示踪剂和EDTA(用于终止激酶反应)组成的检测溶液添加至测定孔中。通过激酶反应形成的ADP(在不存在抑制剂的情况下)将置换来自抗体的Alexa647标记的ADP示踪剂,从而导致TR-FRET信号的降低。在抑制剂存在下,通过激酶反应形成的ADP的量减少,并且所得到的完整抗体-示踪剂相互作用产生高TR-FRET信号。
测试化合物测试化合物在孔中在1%DMSO(最终)中筛选。对于10点滴定,从客户选择的起始浓度开始进行3倍连续稀释。
肽/激酶混合物将所有肽/激酶混合物在适当的激酶缓冲液中稀释至2X工作浓度。
显色试剂溶液将显色试剂稀释在显色缓冲液中。
10X新型PKC脂质混合物:2mg/ml磷脂酰丝氨酸,0.2mg/ml DAG于20mM HEPES(pH7.4)中,0.3%CHAPS。对于5mL 10X新型PKC脂质混合物:1.将10mg磷脂酰丝氨酸(AvantiPolar Lipids Part#8400032C或840039C)和1mg DAG(Avanti Polar Lipids Part#800811C)添加至玻璃管中。2.通过在氮气流下蒸发至透明的薄膜来从脂质混合物中除去氯仿。以一定角度连续旋转管以确保脂质溶液的最大表面积将促进最薄薄膜。3.向干燥的脂质混合物中添加5mL再悬浮缓冲液(20mM HEPES,0.3%CHAPS,pH 7.4)。4.轻轻加热至50℃-60℃持续1-2分钟,且以短时间间隔涡旋直到脂质溶解至透明或稍微混浊溶液。在2-3次热/涡旋循环后,脂质通常在溶液中。5.冷却至室温,等分成单次使用体积,并储存在-20℃下。
测定方案:条形码Corning,低体积NBS,黑色384孔板(Corning Cat.#4514)1.2.5μL-4X测试化合物或100nL 100X加2.4μL激酶缓冲液。2.5μL-2X肽/激酶混合物。3.2.5μL-4XATP溶液。4.30秒板振荡。5.在室温下60分钟激酶反应孵育。6.5μL-显色试剂溶液。7.30秒板振荡。8.在室温下60分钟显色反应孵育。9.在荧光板读数器上读取并分析数据。
通过从测定孔计算发射比来确定ADP形成。通过将示踪剂(受体)发射的强度除以如以下等式中所示的在615nm处的Eu(供体)发射的强度来计算发射比。
由于ADAPTA技术测量ADP形成(即ATP转化为ADP),因此它可用于测量任何类型的ATP水解,包括激酶的固有ATP酶活性。在这种情况下,底物是水,而不是脂质或肽。服务以这种方式筛选CHUK,因此激酶反应中不包含底物。以下提供使用固有ATP酶活性来筛选激酶抑制剂的参考。
测试化合物:测试化合物在孔中在1%DMSO(最终)中筛选。对于10点滴定,从客户选择的起始浓度开始进行3倍连续稀释。
底物/激酶混合物:将所有底物/激酶混合物在适当的激酶缓冲液中稀释至2X工作浓度(参见章节激酶特异性测定条件以获得完整的描述)。
检测混合物:在TR-FRET稀释缓冲液中制备检测混合物。检测混合物由EDTA(30mM)、Eu-抗-ADP抗体(6nM)和ADP示踪剂组成。对于5-150μMATP,检测混合物含有EC60浓度的示踪剂。
测定方案:条形码Corning,低体积,白色384孔板(Corning Cat.#4512)1.2.5μL-4X测试化合物在30mM HEPES或100nL 100X在100%DMSO加2.4μL 30mM HEPES中。2.2.5μL-4X ATP溶液。3.5μL-2X底物/激酶混合物。4.30秒板振荡。5.在1000x g下1分钟离心。6.在室温下60分钟激酶反应孵育。7.5μL-检测混合物。8.30秒板振荡。9.在1000x g下1分钟离心。10.在室温下60分钟检测混合物平衡。11.在荧光板读数器上读取并分析数据。
蛋白质溶解产物的制备和蛋白质印迹[50mmol/L Tris-HCl(pH8.0),150mmol/LNaCl,1%NP40,0.5%脱氧胆酸钠,0.1%SDS,含有蛋白酶(P8340,Sigma,St.Louis,MO)和磷酸酶(P5726,Sigma)抑制剂混合物]。通过微量牛血清白蛋白测定(Pierce,Rockford,IL)来测定可溶性蛋白质浓度。通过SDS-PAGE分离蛋白质电泳转移至硝酸纤维素、与抗体孵育和化学发光第二步检测(PicoWest,Pierce)来进行蛋白质免疫检测。抗体包括EGFR、磷酸-EGFR(Y1068)、磷酸-p42/p44、磷酸-Akt(473)、磷酸-Akt(308)、总Akt、磷酸-S6(235/236)和总S6。所有抗体均获自Cell Signaling Technologies(Danvers,MA)。
处理研究为了分析本文公开的分子对下游信号传导蛋白的磷酸化的影响,使细胞系生长至70%汇合,此时以指定浓度添加MOL-162和/或类似化合物,并且将细胞在37C下孵育1或2小时。如果指出,添加10ng/mL EGF配体5分钟。除去培养基,用PBS洗涤细胞两次,并且如前所述裂解细胞。
蛋白质印迹通过洗涤剂溶解[25mmol/L Tris-HCl(pH 7.6)、150mmol/L NaCl、1%Nonidet P-40、10%甘油、1mM EDTA、1mmol/L二硫苏糖醇(DTT)以及蛋白酶和磷酸酶抑制剂制备细胞提取物,在4℃下振动30分钟,并在4℃下以14,000rpm离心20分钟。通过BioRad蛋白测定来测定蛋白质浓度,且随后对溶解产物进行SDS凝胶电泳。将蛋白质转移至聚偏二氟乙烯(PVDF)膜并用识别EGFR、磷酸-EGFR(Y1068)、磷酸-p42/p44、磷酸化-Akt(473)、磷酸-Akt(308)、总Akt和GAPDH(Abcam)的一抗探测。在用抗兔HRP或抗小鼠HRP连接的二抗(Jackson ImmunoResearch Laboratories,Inc.)孵育后,使用化学发光(GE Healthcare)检测蛋白质。
NCI比较组.使癌筛选组的人肿瘤细胞系在含有5%胎牛血清和2mM L-谷氨酰胺的RPMI1640培养基中生长。对于典型的筛选实验,取决于单个细胞系的倍增时间,将细胞以5,000至40,000个细胞/孔的接种密度以100μL接种到96孔微量滴定板中。在细胞接种后,将微量滴定板在37℃、5%CO2、95%空气和100%相对湿度下孵育24小时,然后添加实验药物。
在24小时后,将每个细胞系的两个板用TCA原位固定,以代表药物添加时每个细胞系的细胞群体的测量值(Tz)。将实验药物以400倍所需的最终最大测试浓度溶解在二甲亚砜中,并且在使用前冷冻保存。在添加药物时,将冷冻浓缩物的等分试样解冻并用含有50μg/ml庆大霉素的完全培养基稀释至所需最终最大测试浓度的两倍。进行另外四次10倍或1/2log连续稀释以提供总计五种药物浓度加对照。将100μl这些不同药物稀释液的等分试样添加至已经含有100μl培养基的适当微量滴定孔中,从而得到所需的最终药物浓度。
在药物添加后,将板在37℃、5%CO2、95%空气和100%相对湿度下再孵育48小时。对于贴壁细胞,通过添加冷TCA终止测定。通过轻轻添加50μl冷50%(w/v)TCA(最终浓度,10%TCA)并在4℃下孵育60分钟来将细胞固定在原位。丢弃上清液,并且将板用自来水洗涤五次且空气干燥。将1%乙酸中的0.4%(w/v)的磺酰罗丹明B(SRB)溶液(100μl)添加到每个孔中,并且将板在室温下孵育10分钟。在染色后,通过用1%乙酸洗涤5次来除去未结合的染料并且使板空气干燥。随后将结合的染色剂用10mM trizma碱溶解,并且在波长为515nm的自动读板器上读取吸光度。对于悬浮细胞,方法是相同的,除了通过轻轻添加50μl of 80%TCA(最终浓度,16%TCA)而将沉降的细胞固定在孔的底部来终止测定。使用七种吸光度测量[时间零(Tz),对照生长(C),和在五种浓度水平的药物存在下的测试生长(Ti)],在每种药物浓度水平下计算生长百分比。百分比生长抑制计算如下:
对于Ti>/=Tz的浓度,[(Ti-Tz)/(C-Tz)]x100
对于Ti<Tz的浓度,[(Ti-Tz)/Tz]x100
对单剂量测定报告的数量是相对于无药物对照,并且相对于时间零数目的细胞的生长。这允许检测生长抑制(0与100之间的值)和致死率(小于0的值)。例如,值100表示没有生长抑制。值40意味着60%生长抑制。值0表示在实验过程中没有净生长。值-40将意味着40%致死率。值-100表示所有细胞都死亡。来自单剂量平均值图的信息可用于比较分析。热图详述绿色(生长%<0,生长%>0%但小于50%,生长%>50%。
异种移植物研究.对雌性6-7周龄NCR裸鼠(CrTac:来自Taconic的NCr-Foxnlnu)6-7周龄,皮下植入在1∶1无血清培养基/混合物中的1x106至1x107个细胞至右侧腋下的区域中。将小鼠随机分入处理组,且当肿瘤达到100至200mg时开始处理。基于个体动物体重(0.2ml/20g),通过口服管饲法每日一次,以5%DMSO/95%PEG300中的透明黄色溶液施用MTX-201持续10天。每周测量皮下肿瘤体积和体重两至三次。通过用卡尺测量两个垂直直径并使用以下公式计算肿瘤体积:肿瘤体积=(长度x宽度2)/2。在停止处理后保持小鼠直到肿瘤负荷达到约1000mg,以允许计算肿瘤生长延迟。在处理的最后一天,通过将中值处理的肿瘤重量除以中值对照肿瘤重量并乘以100来计算处理/对照百分比(%T/C)。通过将处理组的达到评估大小(750mg)的中值时间减去对照组的达到评估大小的中值时间来计算肿瘤生长延迟(T-C)。部分消退(PR)被定义为消退至<=基线肿瘤体积的50%的肿瘤。完全响应(CR)被定义为低于触诊极限(<40mg)的肿瘤。
实施例3.
此实施例显示密歇根大学喹唑啉库3-实验(MOL-160-163和MOL-165的合成)。
N-(5-(4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺,MOL-160。
向由2-丙醇(30mL)中的6-溴-4-氯喹唑啉(0.3g,1.30mmol)组成的溶液中添加3-氯-4-氟苯胺(0.189g,1.30mmol)。将反应混合物加热(80℃)并在N2流下搅拌过夜。将反应混合物冷却至室温,且然后将反应混合物通过熔结漏斗过滤。将过滤的固体用过量2-丙醇冲洗并在高真空下干燥以得到呈灰白色固体的6-溴-N-(3-氯-4-氟苯基)喹唑啉-4-胺(3A)(350mg,85%严率)。MS:(ESI+m/z353.9,ESI-m/z351.9)将由无水乙醇(3mL)中的6-溴-N-(3-氯-4-氟苯基)喹唑啉-4-胺(0.185g,0.526mmol)组成的溶液置于含有搅拌棒的5mL微波反应小瓶中。接着添加5-(甲基磺酰胺基)吡啶-3-基硼酸频哪醇酯(4,0.164g,0.553mmol),然后添加SiliCat DPP-Pd(5mol%,0.26mmol/g负载,0.101g)和10%碳酸钾水溶液(2当量,0.76mL,1.05mmol)。将反应混合物置于N2气氛下,封盖,且然后在Biotage EmrysOptimizer微波中在125℃下加热1小时。使反应混合物冷却至室温,且然后通过熔结漏斗过滤以收集SiliCat DPP-Pd。将过滤的固体用过量乙醇冲洗,且将滤液在减压下浓缩以得到粗产物。使用庚烷中4%-100%乙酸乙酯、然后二氯甲烷中0%-10%甲醇的梯度通过Biotage Isolera快速色谱法纯化粗产物,得到呈白色固体的N-(5-(4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺(5A,MOL-160,96mg,41%产率,96%纯度);1H NMR(400MHz,DMSO-d6)δ10.17(br.s,1H),10.03(s,1H),8.83-8.87(m,2H),8.66(s,1H),8.49(d,J=2.38Hz,1H),8.13-8.20(m,2H),7.90-7.98(m,2H),7.83(ddd,J=2.65,4.25,9.01Hz,1H),7.47(t,J=9.15Hz,1H),3.14(s,3H);MS:(ESI+m/z444.1,ESI-m/z442.0);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.32。
N-(5-(4-((3-氯苯基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺,MOL-162
向由2-丙醇(10mL)中的6-溴-4-氯喹唑啉(0.448g,1.84mmol)组成的溶液中添加3-氯苯胺(0.246g,1.93mmol)。将反应混合物加热(80℃)并在N2流下搅拌过夜。将反应混合物冷却至室温,且然后将反应混合物通过熔结漏斗过滤。将过滤的固体用过量2-丙醇冲洗并在高真空下干燥以得到呈灰白色固体的6-溴-N-(3-氯苯基)喹唑啉-4-胺(3B)(490mg,79%产率,98%纯度)。MS(ESI+m/z335.9,ESI-m/z333.9.)将由无水乙醇(3mL)中的6-溴-N-(3-氯苯基)喹唑啉-4-胺(0.200g,0.597mmol)组成的溶液置于含有搅拌棒的5mL微波反应小瓶中。接着添加5-(甲基磺酰胺基)吡啶-3-基硼酸频哪醇酯(4,0.187g,0.627mmol),然后添加SiliCat DPP-Pd(5mol%,0.26mmol/g负载,0.115g)和10%碳酸钾水溶液(2当量,0.87mL,1.20mmol)。将反应混合物置于N2气氛下,封盖,且然后在Biotage EmrysOptimizer微波中在100℃下加热30分钟。将反应混合物冷却至室温,且然后通过熔结漏斗过滤以收集SiliCat DPP-Pd。将过滤的固体用过量乙醇冲洗,且将滤液在减压下浓缩以得到粗产物。使用庚烷中4%-100%乙酸乙酯、然后二氯甲烷中0%-10%甲醇的梯度通过Biotage Isolera快速色谱法纯化粗产物得到呈白色固体的N-(5-(4-((3-氯苯基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺(5B,MOL-162,78mg,31%产率,97%纯度);1H NMR(400MHz,DMSO-d6)δ10.20(br.s.,1H),10.04(s,1H),8.89(dd,J-1.74,13.45 Hz,1H),8.70(s,1H),8.50(d,J=2.38Hz,1H),8.19(dd,J=1.65,8.60 Hz,1H),8.11(t,J=2.01Hz,1H),7.91-8.04(m,1H),7.67-7.91(m,1H),7.45(t,J=8.14Hz,1H),7.22(m,1H),3.16(s,3H);MS:(ESI+m/z426.1,ESI-m/z424.0);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.49。
N-(5-(4-((5-氯吡啶-3-基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺,MOL-163
向由2-丙醇(10mL)中的6-溴-4-氯喹唑啉(0.448g,1.84mmol)组成的溶液中添加3-氨基-5-氯吡啶(0.248g,1.93mmol)。将反应混合物加热(80℃)并在N2流下搅拌过夜。将反应混合物冷却至室温,且然后将反应混合物通过熔结漏斗过滤。将过滤的固体用过量2-丙醇冲洗并在高真空下干燥以得到呈灰白色固体的6-溴-N-(5-氯吡啶-3-基)喹唑啉-4-胺(3C)(575mg,93%产率,93%纯度)。MS(ESI+m/z336.9,ESI-m/z334.9)。将由无水乙醇(3mL)中的6-溴-N-(5-氯吡啶-3-基)喹唑啉-4-胺(0.136g,0.405mmol)组成的溶液置于含有搅拌棒的5mL微波反应小瓶中。接着添加5-(甲基磺酰胺基)吡啶-3-基硼酸频哪醇酯(4,0.127g,0.425mmol),然后添加SiliCat DPP-Pd(5mol%,0.26mmol/g负载,0.082g)和10%碳酸钾水溶液(2当量,0.59mL,0.81mmol)。将反应混合物置于N2气氛下,封盖,且然后在BiotageEmrys Optimizer微波中在100℃下加热30分钟。将反应混合物冷却至室温,且然后通过熔结漏斗过滤以收集SiliCat DPP-Pd。将过滤的固体用过量乙醇冲洗,且将滤液在减压下浓缩以得到粗产物。使用庚烷中4%-100%乙酸乙酯、然后二氯甲烷中0%-10%甲醇的梯度通过Biotage Isolera快速色谱法纯化粗产物得到呈白色固体的N-(5-(4-((5-氯吡啶-3-基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺(5C,MOL-163,70mg,40%产率,98%纯度);1H NMR(400MHz,DMSO-d6)δ10.21(br.s.,2H),8.94-9.03(m,1H),8.86-8.88(d,J=4.65Hz,2H),8.73(s,1H),8.59(s,1H),8.50(d,J=2.01Hz,1H),8.32-8.44(m,1H),8.20(d,J=8.97Hz,1H),7.90-8.04(m,2H),3.15(s,3H);MS:(ESI+m/z427.0,ESI-m/z425.0);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.47。
N-(5-(4-((5-溴吡啶-3-基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺,MOL-165
向由2-丙醇(10mL)中的6-溴-4-氯喹唑啉(0.448g,1.84mmol)组成的溶液中添加3-溴苯胺(0.332g,1.93mmol)。将反应混合物加热(80℃)并在N2流下搅拌过夜。将反应混合物冷却至室温,且然后将反应混合物通过熔结漏斗过滤。将过滤的固体用过量2-丙醇冲洗并在高真空下干燥以得到呈灰白色固体的6-溴-N-(5-溴吡啶-3-基)喹唑啉-4-胺(3D)(605mg,87%产率,98%纯度)。MS(ESI+m/z379.9,ESI-m/z377.8)。将由无水乙醇(4mL)中的6-溴-N-(5-溴吡啶-3-基)喹唑啉-4-胺(0.150g,0.395mmol)组成的溶液置于含有搅拌棒的5mL微波反应小瓶中。接着添加5-(甲基磺酰胺基)吡啶-3-基硼酸频哪醇酯(4,0.120g,0.400mmol),然后添加SiliCat DPP-Pd(5mol%,0.26mmol/g负载,0.080g)和10%碳酸钾水溶液(2当量,0.60mL,0.79mmol)。将反应混合物置于N2气氛下,封盖,且然后在BiotageEmrys Optimizer微波中在100℃下加热30分钟。将反应混合物冷却至室温,且然后通过熔结漏斗过滤以收集SiliCat DPP-Pd。将过滤的固体用过量乙醇冲洗,且将滤液在减压下浓缩以得到粗产物。使用庚烷中4%-100%乙酸乙酯、然后二氯甲烷中0%-10%甲醇的梯度通过Biotage Isolera快速色谱法纯化粗产物得到呈白色固体的N-(5-(4-((5-溴吡啶-3-基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺(5D,MOL-165,39mg,21%产率,85%纯度);此产物是5D:5D-BN-(5′-((6-溴喹唑啉-4-基)氨基)-[3,3′-联吡啶]-5-基)甲磺酰胺的85:15混合物,其如通过来自铃木(Suzuki)偶联反应的产物一样发生。1H NMR(400MHz,DMSO-d6)δ10.17(br.s.,1H),10.00(s,lH),8.84-8.94(m,2H),8.70(s,1H),8.51(d,J=2.38Hz,1H),8.15-8.25(m,2H),7.89-8.03(m,2H),7.33-7.41(m,2H),3.16(s,3H);MS:(ESI+m/z470,472);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.62。
N-(5-(4-((3-乙炔基苯基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺,MOL-161
向由30mL的1,4-二噁烷中的6-溴-4-氯喹唑啉(1.2g,4.9mmol)和3-((三甲基甲硅烷基)乙炔基)苯胺(1.1g,5.9mmol,如由Ute F.Rohrig,JMC,2012,55(11),5270-5290描述而制备)组成的溶液在90℃下加热3小时。将反应混合物冷却至室温,用乙醚稀释并通过熔结玻璃过滤。将固体在20mL异丙醇中研磨,过滤并干燥以得到呈固体的6-溴-N-(3-((三甲基甲硅烷基)乙炔基)苯基)喹唑啉-4-胺(3E)(940mg,48%);1H NMR(400MHz,DMSO-d6)δ11.8(br s,1H),9.29(d,J=1.7Hz,1H),9.00(s,1H),8.26(dd,J=1.7,8.8Hz,1H),7.95(d,J=8.9Hz,1H),7.89(s,1H),7.81(d,J=8.1Hz,1H),7.51(t,J=7.9Hz,1H),7.41(d,J=7.7Hz,1H),0.25(s,9H)。将由无水乙醇(4mL)中的6-溴-N-(3-((三甲基甲硅烷基)乙炔基)苯基)喹唑啉-4-胺(0.250g,0.631mmol)组成的溶液置于含有搅拌棒的5mL微波反应小瓶中。接着添加5-(甲基磺酰胺基)吡啶-3-基硼酸频哪醇酯(4,0.200g,0.662mmol),然后添加SiliCatDPP-Pd(5mol%,0.26mmol/g负载,0.126g)和10%碳酸钾水溶液(2当量,0.91mL,1.26mmol)。将反应混合物置于N2气氛下,封盖,且然后在Biotage Emrys Optimizer微波中在100℃下加热5分钟。将反应混合物冷却至室温,且然后通过熔结漏斗过滤以收集SiliCatDPP-Pd。将过滤的固体用过量乙醇冲洗,且在减压下浓缩滤液以得到粗产物。使用庚烷中5%-65%乙酸乙酯、然后二氯甲烷中0%-10%甲醇的梯度通过Biotage Isolera快速色谱法纯化粗产物得到5E与TMS保护的5E的混合物。将此混合物溶于甲醇中,且然后用过量10%碳酸钾(1mL)处理。将溶液加热至35℃,且然后通过TLC(90∶10∶0.5,DCM∶MeOH∶NH4OH)除去TMS。在反应完成后,将溶液酸化(1N HCl)至pH约5,且然后用DCM∶MeOH(90∶10混合物,75mL)萃取三次。将有机层在减压下浓缩以得到粗产物。使用二氯甲烷中1%-13%甲醇的梯度通过Biotage Isolera快速色谱法纯化脱保护的粗产物得到呈黄色固体的N-(5-(4-((3-乙炔基苯基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺(5E,MOL-161,68mg,26%产率,97.5%纯度)。1H NMR(400MHz,DMSO-d6)δ10.16(br.s.,1H),9.97(s,1H),8.75-8.94(m,2H),8.66(s,1H),8.48(d,J=2.38Hz,1H),8.16(dd,J=1.65,8.60Hz,1H),8.04(s,1H),7.85-7.98(m,4H),7.42(t,J=7.87Hz,1H),7.42(d,J=7.69Hz,1H),4.21(s,1H),3.13(s,3H);MS:(ESI+m/z416.1,ESI-m/z414.0);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.6。
实施例4.
此实施例显示密歇根大学喹唑啉实验(MOL-166-167和MOL-153的合成)。
N-(5-(4-((4-(吡啶-4-基氧基)苯基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺,
MOL-166
向由2-丙醇(10mL)中的6-溴-4-氯喹唑啉(0.448g,1.84mmol)组成的溶液中添加4-(吡啶-4-基氧基)苯胺(0.360g,1.93mmol)。将反应混合物加热(80℃)并在N2流下搅拌过夜。将反应混合物冷却至室温,且然后将反应混合物通过熔结漏斗过滤。将过滤的固体用过量2-丙醇冲洗并在高真空下干燥以得到呈灰白色固体的6-溴-N-(4-(吡啶-4-基氧基)苯基)喹唑啉-4-胺(3F)(313mg,43%产率,97%纯度)。MS(ESI+m/z394.0,ESI-m/z392.0)。接着将由无水乙醇(10mL)中的6-溴-N-(4-(吡啶-4-基氧基)苯基)喹唑啉-4-胺(0.306g,0.77mmol)组成的溶液置于含有搅拌棒的20mL微波反应小瓶中。接着,添加3-氨基吡啶-5-硼酸频哪醇酯(6,0.176g,0.80mmol),然后添加SiliCat DPP-Pd(5mol%,0.26mmol/g负载,0.150g)和10%碳酸钾水溶液(2当量,1.15mL,1.6mmol)。将反应混合物置于N2气氛下,封盖,且然后在Biotage Emrys Optimizer微波中在125℃下加热1小时。将反应混合物冷却至室温,且然后通过熔结漏斗过滤以收集SiliCat DPP-Pd。将过滤的固体用过量乙醇冲洗,且在减压下浓缩滤液以得到粗产物。使用庚烷中4%-100%乙酸乙酯、然后二氯甲烷中0%-10%甲醇的梯度通过Biotage Isolera快速色谱法纯化粗产物得到呈灰白色固体的7F6-(5-氨基吡啶-3-基)-N-(4-(吡啶-4-基氧基)苯基)喹唑啉-4-胺(50mg,15%产率,92%纯度)。MS(ESI+m/z407.1,ESI-m/z405.1)。向6-(5-氨基吡啶-3-基)-N-(4-(吡啶-4-基氧基)苯基)喹唑啉-4-胺(50mg,0.12mmol)于吡啶(3mL)中的室温溶液添加甲磺酰氯(56mg,0.5mmol)。反应混合物变成暗红色,其持续且搅拌15分钟。将反应混合物倒入饱和碳酸氢钠溶液中,且用乙酸乙酯萃取有机物。将有机相用水和盐水洗涤,经硫酸镁干燥,过滤且在真空下浓缩。将粗固体溶解在甲醇中,并且“干法负载”到用1/9至3/7甲醇/乙酸乙酯梯度洗脱的硅胶柱上以得到呈固体的N-(5-(4-((4-(吡啶-4-基氧基)苯基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺(5F,MOL-166,20mg,33%产率,96%纯度)。1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.91(s,1H),8.79(d,J=1.9Hz,1H),8.62(s,1H),8.4-8.5(m,3H),8.15(dd,J=1.7,8.6Hz,1H),7.85-8.0(m,4H),7.24(d,J=8.9Hz,2H),6.94(d,J=4.7Hz,2H),3.08(s,3H);MS:(ESI+m/z485.1,ESI-m/z483.0)。
5G,N-(5-(4-(苄基氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺,MOL-167
将6-溴-4-氯喹唑啉(1.2g,4.9mmol)和苄胺(633mg,5.9mmol)在30mL1,4-二噁烷中的混合物在45℃下加热2小时,然后在90℃下加热1小时。添加另外量的苄胺(500mg,4.7mmol),且将反应混合物在90℃下再加热2小时。将反应混合物冷却至室温,用乙醚稀释并通过熔结玻璃过滤。在真空下浓缩滤液,且在异丙醇下研磨粗固体,过滤并干燥以得到呈固体的N-苄基-6-溴喹唑啉-4-胺(3G)(950mg,62%严率)。1H NMR(400MHz,DMSO-d6)δ8.91(t,J=5.9Hz,1H),8.60(d,J=2.2Hz,1H),8.46(s,1H),7.88(dd,J=2.2,8.9Hz,1H),7.62(d,J=8.9Hz,1H),7.25-7.40(m,4H),7.23(t,J=9Hz,1H),4.75(d,J=5.8Hz,2H)。接着将由无水乙醇(10mL)中的N-苄基-6-溴喹唑啉-4-胺(0.314g,1.0mmol)组成的溶液置于含有搅拌棒的20mL微波反应小瓶中。接着,添加3-氨基吡啶-5-硼酸频哪醇酯(6,0.231g,1.05mmol),然后添加SiliCat DPP-Pd(5mol%,0.26mmol/g负载,0.200g)和10%碳酸钾水溶液(2当量,1.5mL,1.26mmol)。将反应混合物置于N2气氛下,封盖,且然后在BiotageEmrys Optimizer微波中在100℃下加热5分钟。使反应混合物冷却至室温,且然后通过熔结漏斗过滤以收集SiliCat DPP-Pd。将过滤的固体用过量乙醇冲洗,且在减压下浓缩滤液以得到粗产物。使用庚烷中4%-100%乙酸乙酯、然后二氯甲烷中0%-10%甲醇的梯度通过Biotage Isolera快速色谱法纯化粗产物得到呈白色固体的6-(5-氨基吡啶-3-基)-N-苄基喹唑啉-4-胺(7G)(59mg,18%产率,85%纯度);MS:(ESI+m/z328.1,ESI-m/z326.1)。向6-(5-氨基吡啶-3-基)-N-苄基喹唑啉-4-胺(59mg,0.18mmol)于吡啶(4mL)中的室温溶液添加甲磺酰氯(83mg,0.72mmol)。反应混合物变成暗红色,其持续且搅拌1小时。将反应混合物倒入饱和碳酸氢钠溶液中,且用乙酸乙酯萃取有机物。将有机相用水和盐水洗涤,经硫酸镁干燥,过滤且在真空下浓缩。将粗固体溶解在甲醇中,且“干法负载”到用1/9至3/7甲醇/乙酸乙酯梯度洗脱的硅胶柱上,从而产生部分纯化的淡黄色固体。将此粗固体在2-丙醇/二氯甲烷/乙酸乙酯的溶液下研磨,过滤并干燥以得到呈白色粉末的N-(5-(4-(苄基氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺(5G,MOL-167,6mg,8%产率,96%纯度);MS:(ESI+m/z406.1,ESI-m/z404.1)。
5H,N-(5-(4-((3-氯-4-甲氧基苯基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺,
MOL-153
将6-溴-4-氯喹唑啉(1.65g,6.5mmol)和3-氯-4-甲氧基苯胺(1.2g,7.8mmol)于40mL1,4-二噁烷中的混合物在90℃下加热3小时。将反应混合物冷却至室温,用乙醚稀释并通过熔结玻璃过滤。将固体用乙醚洗涤并干燥以得到呈黄色-金色固体的6-溴-N-(3-氯-4-甲氧基苯基)喹唑啉-4-胺(3H)(2.1g,89%);1H NMR(400MHz,DMSO-d6)δ11.5(br s,1H),9.15(s,1H),8.92(s,1H),8.21(d,J=9Hz,1H),7.8-8.0(m,2H),7.66(dd,J=8.9,2.3Hz,1H),7.25(d,J=8.9Hz,1H),3.95(s,3H);MS:(ESI+m/z364.0,366.0(Br同位素),ESI-m/z362.0,364.0(Br同位素))。将6-溴-N-(3-氯-4-甲氧基苯基)喹唑啉-4-胺(1.85g,5.08mmol)和3-氨基吡啶-5-硼酸频哪醇酯(6,932mg,4.23mmol)于1,4-二噁烷(90mL)和水(7.6mL)中的溶液脱气。向所述溶液中添加碳酸铯(6.9g,21.1mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)(366mg)。将反应混合物在N2下在90℃-95℃下加热4小时。将反应混合物用乙酸乙酯、二氯甲烷和甲醇稀释,用饱和碳酸氢钠、水和盐水洗涤,经硫酸镁干燥,过滤且在真空下浓缩。将粗物质通过硅胶柱色谱法,用2/98至25/75甲醇/乙酸乙酯的梯度洗脱来纯化以得到呈灰白色固体的6-(5-氨基吡啶-3-基)-N-(3-氯-4-甲氧基苯基)喹唑啉-4-胺(7H)(524mg,33%产率)。向6-(5-氨基吡啶-3-基)-N-(3-氯-4-甲氧基苯基)喹唑啉-4-胺(250mg,0.66mmol)于吡啶(15mL)中的室温溶液添加甲磺酰氯(303mg,2.65mmol)。反应混合物变成暗红色,其持续且搅拌1小时。将反应混合物倒入饱和碳酸氢钠溶液中,且用乙酸乙酯萃取有机物。将有机相用水和盐水洗涤,经硫酸镁干燥,过滤且在真空下浓缩。将粗的黄色固体溶解于甲醇中。添加乙酸乙酯和乙醚直到观察到浑浊。将混合物搅拌1小时且过滤所得固体,用乙酸乙酯洗涤且干燥以得到呈亮黄色粉末的N-(5-(4-((3-氯-4-甲氧基苯基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺(5H,MOL-153,120mg,40%产率,94%纯度);1HNMR(400MHz,DMSO-d6)δ11.6(br s,1H),10.3(br s,1H),9.17(s,1H),8.95(s,1H),8.88(brs,1H),8.52(br s,1H),8.40(dd,J=1.3,8.6Hz,1H),8.0-8.1(m,1H),7.89(d,J=2.6Hz,1H),7.66(dd,J=2.6,8.9Hz,1H),7.28(d,J=9.0Hz,1H),3.90(s,3H),3.16(s,3H);MS:(ESI+m/z456)。
实施例5.
此实施例显示密歇根大学喹唑啉实验(MOL-154的合成)。
8,(N-(5-(4-((3-氯-4-甲氧基苯基)氨基)喹唑啉-6-基)吡啶-3-基)-3-氟苯磺酰
胺,MOL-154)
向6-(5-氨基吡啶-3-基)-N-(3-氯-4-甲氧基苯基)喹唑啉-4-胺(7H,250mg,0.66mmol)于吡啶(15mL)中的室温溶液添加3-氟苯磺酰氯(516mg,2.65mmol)。反应混合物变成暗红色,其持续且搅拌1小时。将反应混合物倒入饱和碳酸氢钠溶液中,且用乙酸乙酯萃取有机物。将有机相用水和盐水洗涤,经硫酸镁干燥,过滤且在真空下浓缩。与庚烷一起旋转蒸发得到粗的黄色固体,将所述固体在甲醇和乙酸乙酯以及乙醚的混合物下研磨1小时,且将所得固体过滤并干燥以得到呈黄色粉末的N-(5-(4-((3-氯-4-甲氧基苯基)氨基)喹唑啉-6-基)吡啶-3-基)-3-氟苯磺酰胺(8,MOL-154,120mg,34%产率,100%纯度);1HNMR(400MHz,DMSO-d6)δ10.8(br s,1H),10.0(br s,1H),8.82(s,2H),8.62(s,1H),8.29(d,J=2.2Hz,1H),8.07(d,J=7.5Hz,1H),7.96(d,J=2.3Hz,1H),7.93(d,J=1.9Hz,1H),7.87(d,J=8.9Hz,1H),7.72(dd,J=2.4,8.9Hz,1H),7.6-7.7(m,2H),7.45-7.55(m,1H),7.28(d,J=9.0Hz,1H),3.88(s,3H);MS:(ESI+m/z536)。
实施例6.
此实施例显示密歇根大学喹唑啉文4-实验(MOL-171-177、MOL-181-186和MOL-191-196的合成)。
10A,6-(2-氨基嘧啶-5-基)-N-(3-氯苯基)喹唑啉-4-胺,MOL-171
将由无水乙醇(4mL)中的6-溴-N-(3-氯苯基)喹唑啉-4-胺(3B,0.115g,0.343mmol)组成的溶液置于含有搅拌棒的5mL微波反应小瓶中。接着,添加(2-氨基嘧啶-5-基)硼酸(9A,0.50g,0.361mmol),然后添加SiliCat DPP-Pd(5mol%,0.26mmol/g负载,0.068g)和10%碳酸钾水溶液(2当量,0.50mL,0.68mmol)。将反应混合物置于N2气氛下,封盖,且然后在Biotage Emrys Optimizer微波中在100℃下加热15分钟。将反应混合物冷却至室温,且然后通过熔结漏斗过滤以收集SiliCat DPP-Pd。将过滤的固体用过量乙醇冲洗,且在减压下浓缩滤液以得到粗产物。使用庚烷中4%-100%乙酸乙酯、然后二氯甲烷中0%-10%甲醇的梯度通过Biotage Isolera快速色谱法纯化粗产物得到呈白色固体的6-(2-氨基嘧啶-5-基)-N-(3-氯苯基)喹唑啉-4-胺(10A,MOL-171,26.4mg,22%产率,95%纯度);1HNMR(400MHz,DMSO-d6)δ9.88(s,1H),8.83(s,1H),8.76(m,1H),8.65(s,1H),8.20(dd,J=1.65,8.60Hz,1H),8.10(t,J=1.92Hz,1H),7.73-7.99(m,2H),7.45(t,J=8.14Hz,1H),7.07-7.31(m,1H),6.95(s,2H);MS:(ESI+m/z348.8,ESI-m/z346.8);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.52。
除非另外指出,否则以下(10B-10F)中的每一个以针对10A描述的方式制备。
10B,N-(3-氯苯基)-6-(1H-吡咯并[2,3-b]吡啶-5-基)喹唑啉-4-胺,MOL-172
使用5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吡咯并[2,3-b]吡啶9B代替9A以得到呈灰白色固体的标题化合物(0.022g,20%产率,97%纯度);1H NMR(400MHz,DMSO-d6)δ11.81(br.s.,1H),10.06(br.s.,1H),8.86(s,1H),8.75(d,J=1.83Hz,1H),8.56(br.s.,1H),8.42(d,J=2.01Hz,1H),8.22(d,J=8.05Hz,1H),8.05(br.s.,1H),7.68-7.93(m,2H),7.56(d,J=3.29Hz,1H),7.40(t,J=8.14Hz,1H),7.12(d,J=7.14Hz,1H),6.56(d,J=5.51Hz,1H);MS:(ESI+m/z371.8,ESI-m/z369.8);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.54。
10C,1-(4-(4-((3-氯苯基)氨基)喹唑啉-6-基)苯基)-3-甲基脲,MOL-173
使用1-甲基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯基)脲9C代替9A以得到呈灰白色固体的标题化合物(0.037g,28%产率,96%纯度);1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.77(d,J=1.83Hz,1H),8.71(s,1H),8.64(s,1H),8.14-8.41(m,1H),8.01-8.14(m,1H),7.69-7.96(m,2H),7.59(d,J=8.60Hz,1H),7.45(t,J=8.14Hz,1H),7.06-7.31(m,1H),6.07(d,J=4.57Hz,1H),3.33(s,3H);MS:(ESI+m/z403.8,ESI-m/z401.8);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.54。
10D,N-(3-(4-((3-氯苯基)氨基)喹唑啉-6-基)苯基)甲磺酰胺,MOL-174
使用N-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯基)甲磺酰胺脲9D代替9A以得到呈灰白色固体的标题化合物(0.049g,39%产率,96%纯度);1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.91(s,1H),8.81(d,J=1.83Hz,1H),8.68(s,1H),8.02-8.22(m,2H),7.75-8.01(m,2H),7.59-7.67(m,1H),7.50-7.59(m,1H),7.45(t,J=8.14Hz,1H),7.31(d,J=8.60Hz,1H),7.20(dd,J=1.74,7.78Hz,1H)3.07(s,3H);MS:(ESI+m/z425.8,ESI-m/z423.7);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.62。
10E,6-(3-(1H-四唑-5-基)苯基)-N-(3-氯苯基)喹唑啉-4-胺,MOL-175
使用(3-(2H-四唑-5-基)苯基)硼酸9E代替9A以得到呈灰白色固体的标题化合物(0.049g,21%产率,98%纯度);1H NMR(400MHz,DMSO-d6)δ10.10(br.s.,1H),8.94(s,1H),8.54(s,1H),8.29(d,J=8.78Hz,1H),8.03-8.19(m,2H),7.96(d,J=8.60Hz,1H),7.64-7.92(m,2H),7.46(t,J=8.05Hz,1H),7.22(dd,J=1.30,7.90Hz,1H);MS:(ESI+m/z400.0,ESI-m/z398.1);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.56。
10F,N-(3-氯苯基)-6-(1H-吡唑-4-基)喹唑啉-4-胺,MOL-176
使用(1H-吡唑-4-基)硼酸9F代替9A以得到呈白色固体的标题化合物(0.010g,9%产率,98%纯度);1H NMR(400MHz,DMSO-d6)δ13.11(br.s.,1H),9.80(s,1H),8.72(s,1H),8.62(s,1H),8.35(br.s.,1H)8.09-8.21(m,2H),7.88(dd,J=1.80,8.00Hz,1H),7.80(d,J=8.78Hz,1H),7.46(t,J=8.14Hz,1H),7.20(dd,J=1.80,8.34Hz,1H);MS:(ESI+m/z322.0,ESI-m/z320.0);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.54。
N-(3-氯苯基)-6-(1H-吡唑并[3,4-b]吡啶-5-基)喹唑啉-4-胺,MOL-177
向由含有搅拌棒的2mL微波反应小瓶中的6-溴-N-(3-氯苯基)喹唑啉-4-胺(0.133g,0.36mmol)和1H-吡唑并[3,4-b]吡啶-5-硼酸频哪醇酯(0.133g,0.54mmol)于1,4-二噁烷(2mL)中的溶液添加2M K2CO3(0.72mL,1.44mmol)。使混合物脱气(真空/氮气,3次),之后添加SiliCat DPP-Pd(0.10g,0.26mmol/g负载),且然后在Biotage Emrys Optimizer微波中在140℃下加热三次20分钟。使反应混合物冷却至室温,用一次性移液管移除水层,且将剩余的有机相通过熔结漏斗过滤以收集SiliCat DPP-Pd。将过滤的固体用室温甲醇冲洗,且将滤液放在一边。然后将过滤的固体用热甲醇充分洗涤,并将滤液在减压下浓缩以得到呈淡黄色固体的标题化合物(43mg,32%,94.9%纯度);TLC Rf0.10(溶剂体系:7∶3v/v乙酸乙酯-庚烷);MS(ES-API+)m/z373.0(M+1),375.0(Cl同位素),(ES-API-)m/z371.0(M-1),373.0(Cl同位素);1H NMR(400MHz,DMSO-d6)δ9.01(d,J=1.28Hz,1H),8.86(s,1H),8.62(s,1H),8.53(s,1H),8.18-8.25(m,2H),8.01(s,1H),7.80(d,J=8.69Hz,1H),7.75(br d,J=8.23Hz,1H),7.37(t,J=7.96Hz,1H),7.09(br d,J=7.87Hz,1H)。
11A,6-(2-氨基嘧啶-5-基)-N-(3-氯-4-氟苯基)喹唑啉-4-胺,MOL-181
将由无水乙醇(4mL)中的6-溴-N-(3-氯-4-氟苯基)喹唑啉-4-胺(3A,0.150g,0.425mmol)组成的溶液置于含有搅拌棒的5mL微波反应小瓶中。接着,添加(2-氨基嘧啶-5-基)硼酸(9A,0.62g,0.447mmol),然后添加SiliCat DPP-Pd(5mol%,0.26mmol/g负载,0.085g)和10%碳酸钾水溶液(2当量,0.62mL,0.85mmol)。将反应混合物置于N2气氛下,封盖,且然后在Biotage Emrys Optimizer微波中在100℃下加热15分钟。使反应混合物冷却至室温,且然后通过熔结漏斗过滤以收集SiliCat DPP-Pd。将过滤的固体用过量乙醇冲洗,且在减压下浓缩滤液以得到粗产物。使用庚烷中4%-100%乙酸乙酯、然后二氯甲烷中0%-10%甲醇的梯度通过Biotage Isolera快速色谱法纯化粗产物得到呈白色固体的6-(2-氨基嘧啶-5-基)-N-(3-氯-4-氟苯基)喹唑啉-4-胺(11A,MOL-181,75mg,48%产率,95%纯度);1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.82(s,1H),8.69-8.78(m,1H),8.63(s,1H),8.04-8.29(m,1H),7.78-7.92(m,1H),7.49(t,J=9.06Hz,1H),6.96(s,2H);MS:(ESI+m/z367.0,ESI-m/z365.0);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.58。
除非另外指出,否则以下(11B-11F)中的每一个以针对11A描述的方式制备。
11B,N-(3-氯-4-氟苯基)-6-(1H-吡咯并[2,3-b]吡啶-5-基)喹唑啉-4-胺,MOL-
182
使用5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吡咯并[2,3-b]吡啶9B代替9A以得到呈灰白色固体的标题化合物(0.067g,41%产率,98%纯度);1H NMR(400MHz,DMSO-d6)δ11.84(br.s.,1H),10.01(s,1H),8.83-8.99(m,1H),8.78(d,J=2.01Hz,1H),8.65(s,1H),8.44(d,J=2.01Hz,1H),8.17-8.37(m,2H),7.83-7.95(m,1H),7.57(t,J=2.93Hz,1H),7.49(t,J=9.15Hz,1H),6.41-6.67(m,1H);MS:(ESI+m/z390.1,ESI-m/z388.1);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.63
11C,1-(4-(4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基)苯基)-3-甲基脲,MOL-183
使用1-甲基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯基)脲9C代替9A以得到呈灰白色固体的标题化合物(0.022g,13%产率,100%纯度);1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.75(d,J=1.40 Hz,1H),8.71(s,1H),8.63(s,1H),8.06-8.27(m,1H),7.70-7.91(m,2H),7.59(d,J=8.60Hz,1H),7.49(t,J=9.06Hz,1H),6.08(d,J=4.76Hz,1H),3.33(s,3H),2.67(d,J=4.57Hz,2H);MS:(ESI+m/z422.1,ESI-m/z420.1);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.58。
11D,N-(3-(4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基)苯基)甲磺酰胺,MOL-184
使用N-(3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯基)甲磺酰胺脲9D代替9A以得到呈灰白色固体的标题化合物(0.056g,30%产率,96%纯度);1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.91(s,1H),8.77(s,1H),8.66(s,1H),8.19(dd,J=2.47,6.86Hz,1H),8.11(dd,J=1.37,8.69Hz,1H),7.72-7.99(m,2H),7.41-7.65(m,3H),7.30(d,J=7.87Hz,1H),3.07(s,3H);MS:(ESI+m/z443.1,ESI-m/z441.1);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.66。
11E,6-(3-(1H-四唑-5-基)苯基)-N-(3-氯-4-氟苯基)喹唑啉-4-胺,MOL-185
使用(3-(2H-四唑-5-基)苯基)硼酸9E代替9A以得到呈灰白色固体的标题化合物(0.007g,4%产率,83%纯度);1H NMR(400MHz,DMSO-d6)δ10.24(br.s.,1H),9.03(s,1H),8.66(m,2H),8.28(m,2H),8.10(d,J=7.32Hz,1H),7.81-8.03(m,2H),7.68(t,J=7.32Hz,1H),7.48(t,J=9.00Hz,1H);MS:(ESI+m/z418.0,ESI-m/z416.0);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.22。
11F,N-(3-氯-4-氟苯基)-6-(1H-吡唑-4-基)喹唑啉-4-胺,MOL-186
使用(1H-吡唑-4-基)硼酸9F代替9A以得到呈白色固体的标题化合物(0.022g,15%产率,97%纯度);1H NMR(400MHz,DMSO-d6)δ13.11(br.s.,1H),9.80(s,1H),8.69(s,1H),8.59(s,1H),8.35(br.s.,1H)8.02-8.28(m,2H),7.80-7.92(m,1H),7.79(d,J=8.78Hz,1H),7.49(t,J=9.14Hz,1H),7.20(dd,J=1.80,8.34Hz,1H);MS:(ESI+m/z340.0,ESI-m/z338.0);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.54。
3-(4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基)-N-环丙基苯磺酰胺,MOL-214
使由3mL的1,4-二噁烷中的6-溴-N-(3-氯苯基)喹唑啉-4-胺-HCl(100mg,0.26mmol)、(3-(N-环丙基氨磺酰基)苯基)硼酸(94mg,0.39mmol)和1.4M K2CO3(1.1mL)组成的混合物脱气(真空/氮,3次)。向反应混合物中添加SiliCat DPP-Pd(50mg,0.26mmol/g负载)。将反应混合物密封并在Biotage Emrys Optimizer微波中在100℃下加热12分钟。向反应混合物中添加另外的2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯胺(40mg,0.16mmol)和SiliCat DPP-Pd(30mg)。将反应混合物在120℃下再次加热15分钟并冷却。移除水相,且将剩余的有机相通过玻璃熔结料过滤。将固体用甲醇洗涤。在减压下浓缩滤液。使用干法负载方法将白色固体残余物施加至40g硅胶柱,且用4∶6乙酸乙酯-庚烷至100%乙酸乙酯的梯度洗脱以得到呈淡黄色固体的20mg(16%,纯度96%)的标题化合物;MS(ES-API+)m/z469.0(M+1),471.0(Cl同位素);1H NMR(400 MHz,DMSO-d6)δ10.13(s,1H),8.87(s,1H),8.67(s,1H),8.14-8.27(m,4H),8.01(d,J=2.65Hz,1H),7.95(d,J=8.69Hz,1H),7.87-7.92(m,1H),7.79-7.87(m,2H),7.49(t,J=9.06Hz,1H),2.17(dt,J=3.34,6.75Hz,1H),0.37-0.54(m,4H)。
13N-(3-氯-4-氟苯基)-6-(6-甲氧基吡啶-3-基)喹唑啉-4-胺,MOL-151
使6-溴-N-(3-氯-4-氟苯基)喹唑啉-4-胺(3A,275mg,0.78mmol)和(6-甲氧基吡啶-3-基)硼酸(9G,119mg,0.78mmol)于1,4-二噁烷(15mL)和水(1.4mL)中的溶液脱气。向所述溶液中添加碳酸铯(1.0g,3.1mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)(44mg)。将反应混合物在N2下在80℃下加热2小时。将反应混合物用甲苯稀释,且在真空下除去挥发物,并将粗物质通过硅胶柱色谱法,用3/7至6/4乙酸乙酯/庚烷的梯度洗脱进行纯化以得到呈黄色固体的N-(3-氯-4-氟苯基)-6-(6-甲氧基吡啶-3-基)喹唑啉-4-胺(13,MOL-151,40mg,13%,HPLC纯度95%);1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),8.77(d,J=1.5Hz,1H),8.69(d,J=2.6Hz,1H),8.63(s,1H),8.1-8.24(m,3H),7.78-7.92(m,2H),7.46(t,J=9.15Hz,1H),7.00(d,J=8.8Hz,1H),3.92(s,3H);MS:(ESI+m/z381.1,ESI-m/z379.1)。
12A,6-(2-氨基嘧啶-5-基)-N-(5-氯吡啶-3-基)喹唑啉-4-胺,MOL-191
将由无水乙醇(4mL)中的6-溴-N-(5-氯吡啶-3-基)喹唑啉-4-胺(3C,0.150g,0.447mmol)组成的溶液置于含有搅拌棒的5mL微波反应小瓶中。接着,添加(2-氨基嘧啶-5-基)硼酸(9A,0.65g,0.469mmol),然后添加SiliCat DPP-Pd(5mol%,0.26mmol/g负载,0.090g)和10%碳酸钾水溶液(2当量,0.65mL,0.89mmol)。将反应混合物置于N2气氛下,封盖,且然后在Biotage Emrys Optimizer微波中在100℃下加热15分钟。使反应混合物冷却至室温,且然后通过熔结漏斗过滤以收集SiliCat DPP-Pd。将过滤的固体用过量乙醇冲洗,且在减压下浓缩滤液以得到粗产物。使用庚烷中4%-100%乙酸乙酯、然后二氯甲烷中0%-10%甲醇的梯度通过Biotage Isolera快速色谱法纯化粗产物得到呈白色固体的6-(2-氨基嘧啶-5-基)-N-(5-氯吡啶-3-基)喹唑啉-4-胺(12A,MOL-191,44mg,28%产率,95%纯度);1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.01(s,1H),8.83(s,1H),8.70(s,1H),8.62(br.s.,1H),8.39(d,J=1.50Hz,1H),8.23(d,J=8.23Hz1H),7.89(d,J=8.60Hz,1H),6.97(s,2H);MS:(ESI+m/z350.0,ESI-m/z348.0);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.40。
除非另外指出,否则以下(12B-12F)中的每一个以针对12A描述的方式制备。
12B,N-(5-氯吡啶-3-基)-6-(1H-吡咯并[2,3-b]吡啶-5-基)喹唑啉-4-胺,MOL-
192
使用5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吡咯并[2,3-b]吡啶9B代替9A以得到呈灰白色固体的标题化合物(0.052g,31%产率,98%纯度);1H NMR(400MHz,DMSO-d6)δ11.84(br.s.,1H),10.16(s,1H),9.03(d,J=2.01Hz,1H),8.89(m,lH),8.78(d,J=2.01Hz,1H),8.71(s,1H),8.63(t,J=2.01Hz,1H),8.44(d,J=2.01Hz,1H),8.14-8.41(m,2H),7.93(d,J=8.60Hz,1H),7.57(t,J=2.93Hz,1H),6.57(dd,J=1.83,3.48Hz,1H);MS:(ESI+m/z373.1,ESI-m/z371.1);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.50。
12C,1-(4-(4-((5-氯吡啶-3-基)氨基)喹唑啉-6-基)苯基)-3-甲基脲,MOL-193
使用1-甲基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯基)脲9C代替9A以得到呈白色固体的标题化合物(0.016g,9%产率,98%纯度);1H NMR(400MHz,DMSO-d6)δ10.14(br.s.,1H),9.02(br.s.,1H),8.65-8.88(m,2H),8.62(br.s.,1H),8.38(br.s.,1H),8.21(d,J=8.78Hz,1H),7.88(d,J=8.42Hz,1H),7.79(d,J=8.42Hz,1H),7.59(d,J=8.42Hz,1H),6.08(d,J=4.76Hz,1H),3.33(s,3H),2.67(d,J=4.21Hz,2H);MS:(ESI+m/z405.1,ESI-m/z403.1);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.49。
12D,N-(3-(4-((5-氯吡啶-3-基)氨基)喹唑啉-6-基)苯基)甲磺酰胺,MOL-194
使用N-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯基)甲磺酰胺脲9D代替9A以得到呈白色固体的标题化合物(0.049g,26%产率,97%纯度);1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),9.93(s,1H),9.00(s,1H),8.80(s,1H),8.73(s,1H),8.61(br.s.,1H),8.39(d,J=2.01Hz,lH),8.14(dd,J=1.37,8.69Hz,lH),7.95(d,J=8.78Hz,1H),7.43-7.65(m,2H),7.32(d,J=7.87Hz,1H),3.08(s,3H);MS:(ESI+m/z426.0,ESI-m/z424.0);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.51。
12E,6-(3-(1H-四唑-5-基)苯基)-N-(5-氯吡啶-3-基)喹唑啉-4-胺,MOL-195
使用(3-(2H-四唑-5-基)苯基)硼酸9E代替9A以得到呈灰白色固体的标题化合物(0.030g,17%产率,95%纯度);1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.01(d,J=1.83Hz,1H),8.93(s,1H),8.74(s,1H),8.61(t,J=1.83Hz,2H),8.54(s,1H),8.40(d,J=2.01Hz,1H),8.32(dd,J=1.46,8.78Hz,1H),8.10(dd,J=8.05,13.91Hz,2H),7.99(t,J=8.60Hz,1H),7.81(t,J=7.78Hz,1H);MS:(ESI+m/z401.0,ESI-m/z399.1);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.08。
12F,N-(5-氯吡啶-3-基)-6-(1H-吡唑-4-基)喹唑啉-4-胺,MOL-196
使用(1H-吡唑-4-基)硼酸9F代替9A以得到呈白色固体的标题化合物(0.010g,7%产率,99%纯度);1H NMR(400MHz,DMSO-d6)δ13.12(br.s.,1H),9.98(s,1H),9.01(br.s.,1H),8.60-8.72(m,3H),8.38(d,J=2.01Hz,1H),8.18(d,J=8.42Hz,2H),7.83(d,J=8.23Hz,1H),7.68(s,1H);MS:(ESI+m/z323.0,ESI-m/z321.0);TLC:(90∶10∶0.5,DCM∶MeOH∶NH4OH)Rf=0.37。
实施例7.
此实施例显示EMD喹唑啉实验(EMD-151的合成)
13N-(3-氯-4-氟苯基)-6-(6-甲氧基吡啶-3-基)喹唑啉-4-胺,EMD-151
使6-溴-N-(3-氯-4-氟苯基)喹唑啉-4-胺(3A,275mg,0.78mmol)和(6-甲氧基吡啶-3-基)硼酸(9G,119mg,0.78mmol)于1,4-二噁烷(15mL)和水(1.4mL)中的溶液脱气。向所述溶液中添加碳酸铯(1.0g,3.1mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)(44mg)。将反应混合物在N2下在80℃下加热2小时。将反应混合物用甲苯稀释,且在真空下除去挥发物,并将粗物质通过硅胶柱色谱法,用3/7至6/4乙酸乙酯/庚烷的梯度洗脱进行纯化以得到呈黄色固体的N-(3-氯-4-氟苯基)-6-(6-甲氧基吡啶-3-基)喹唑啉-4-胺(13,EMD-151,40mg,13%,HPLC纯度95%);1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),8.77(d,J=1.5Hz,1H),8.69(d,J=2.6Hz,1H),8.63(s,1H),8.1-8.24(m,3H),7.78-7.92(m,2H),7.46(t,J=9.15Hz,1H),7.00(d,J=8.8Hz,1H),3.92(s,3H);MS:(ESI+m/z381.1,ESI-m/z379.1)。
实施例8.
此实施例描述本发明的另外基于喹唑啉的化合物的合成。
6-(5-氨基-6-氯吡啶-3-基)-N-(3-氯苯基)喹唑啉-4-胺(3B),MOL-200
向由1,4-二噁烷(250mL)中的6-溴-N-(3-氯苯基)喹唑啉-4-胺(10.0g,26.9mmol)和2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶-3-胺(9H)(6.8g,26.9mmol)组成的溶液添加1.4M K2CO3(58mL,81mmol)。使混合物脱气(真空/氮气,3次),之后添加SiliCat DPP-Pd(3.5g,0.26mmol/g负载),且然后在95℃下在搅拌下加热过夜。使反应混合物冷却至室温且用乙酸乙酯、甲醇和二氯甲烷稀释。将混合物用水洗涤洗涤两次,然后用盐水洗涤。将有机相经硫酸镁干燥,过滤且在减压下浓缩。将残余物在溶剂50mL乙酸乙酯、40mL二氯甲烷、10mL甲醇、0.25mL氢氧化铵的混合物中研磨1小时并过滤。将固体用乙酸乙酯洗涤且在高真空中干燥以得到标题化合物(5.92g,57%)。将滤液施加至用2∶35∶63甲醇-乙酸乙酯-二氯甲烷洗脱的硅胶柱以得到呈白色固体的另一批标题化合物(0.2g,100%纯度)。TLC Rf0.16(溶剂体系:65∶35v/v乙酸乙酯-庚烷);MS(ES-API+)m/z382.1(M+1),384.1(Cl同位素),(ES-API-)m/z380.0(M-1),382.0(Cl同位素);1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.82(d,J=1.74Hz,1H),8.67(s,1H),8.05-8.15(m,3H),7.89(d,J=8.60Hz,1H),7.82-7.87(m,1H),7.51(d,J=2.20Hz,1H),7.43(t,J=8.14Hz,1H),7.15-7.22(m,1H),5.74(s,2H)。
N-(2-氯-5-(4-((3-氯苯基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺,MOL-201
向由吡啶(25mL)中的6-(5-氨基-6-氯吡啶-3-基)-N-(3-氯苯基)喹唑啉-4-胺(1.99g,5.2mmol)组成的混合物中添加甲磺酰氯(0.35g,3.0mmol),然后在3小时后再添加甲磺酰氯(0.35g,3.0mmol),且在30分钟后再添加(0.46mg,4.0mmol)。将反应混合物在室温下搅拌过夜。向冰冷反应混合物中添加2N NaOH(5mL,10mmol),使其温至室温,然后在3小时后在0℃下再添加(5mL,10mmol)。使混合物搅拌1小时,同时温至至室温,且添加1N HCl(3mL,3mmol)和盐水。将有机物质用乙酸乙酯-甲醇(8∶2)萃取两次。将合并的有机相用盐水洗涤,经硫酸镁干燥,过滤且在减压下浓缩。将残余物悬浮于甲苯中并浓缩,然后悬浮于乙酸乙酯中并浓缩以得到接近白色的固体。将固体在20mL/30mL甲醇/乙酸乙酯中研磨过夜并过滤以得到呈灰白色固体的标题化合物(1.55g,65%,99.6%纯度)。MS(ES-API+)m/z460.0(M+1),462.0(Cl同位素),(ES-API-)m/z457.9(M-1),459.9(Cl同位素);1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.93(br s,1H),8.88(s,1H),8.67(s,1H),8.60(s,1H),8.14-8.23(m,2H),8.09(t,J=1.92Hz,1H),7.91(d,J=8.69Hz,1H),7.83(dd,J=1.01,8.33Hz,1H),7.43(t,J=8.10Hz,1H),7.19(d,J=8.14Hz,1H),3.07(s,3H)。
N-(2-氯-5-(4-((3-氯苯基)氨基)喹唑啉-6-基)吡啶-3-基)-N-(甲基磺酰基)甲
磺酰胺,MOL-201B
向由吡啶(1.2mL)中的6-(5-氨基-6-氯吡啶-3-基)-N-(3-氯苯基)喹唑啉-4-胺(255mg,0.67mmol)组成的混合物中以小部分添加甲磺酰氯(458mL,4.0mmol)。将反应混合物在室温下搅拌5小时,然后在3℃下储存过夜。将结晶物质过滤,用2mL甲醇洗涤,并在5mL甲醇下研磨3小时。将固体过滤并在高真空下干燥以得到标题化合物(125mg,23%,纯度88%);MS(ES-API+)m/z538(M+1),541(Cl同位素),(ES-API-)m/z535.9(M-1),537.9(Cl同位素);1H NMR(400MHz,DMSO-d6)δ11.47(br s,1H),9.57(s,1H),9.20(d,J=2.29Hz,1H),8.97(d,J=2.29Hz,1H),8.87(s,1H),8.52(dd,J=1.60,8.74Hz,1H),8.14(t,J=1.88Hz,1H),8.02(d,J=8.78Hz,1H),7.93(d,J=7.64Hz,1H),7.49(t,J=8.10Hz,1H),7.30(d,J=7.57Hz,1H),3.76(s,6H)。
6-(5-氨基-6-甲氧基吡啶-3-基)-N-(3-氯苯基)喹唑啉-4-胺(10I),MOL202A
使由10mL的1,4-二噁烷中的6-溴-N-(3-氯苯基)喹唑啉-4-胺-HCl(800mg,2.15mmol)、2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶-3-胺(550mg,2.20mmol)和1.4M K2CO3(6.1mL)组成的混合物脱气(真空/氮,3次)。向反应混合物中添加SiliCat DPP-Pd(250mg,0.26mmol/g负载)。将反应混合物密封并在Biotage EmrysOptimizer微波中在100℃下加热8分钟。将反应混合物冷却,移除水相,且将剩余的有机相通过玻璃熔结料过滤。将固体用甲醇洗涤。此反应程序重复9次。将合并的滤液在减压下浓缩。将残余物在乙酸乙酯、甲醇、二氯甲烷和庚烷的混合物中研磨过夜。过滤悬浮液以在高真空下干燥后得到2.46g的呈灰棕色固体的标题化合物。将滤液施加至120g硅胶柱,且将所述柱用1∶1乙酸乙酯-庚烷至100%乙酸乙酯的梯度洗脱以得到1.20g的呈暗黄色固体的标题化合物。总计:3.66g(45%);MS(ES-API+)m/z378.1(M+1),380.1(Cl同位素);1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.74(d,J=1.55Hz,1H),8.64(s,1H),8.10(t,J=1.92Hz,1H),8.05(d,J=8.69Hz,1H),7.81-7.90(m,3H),7.42(t,J=8.14Hz,1H),7.30(d,J=2.20Hz,1H),7.17(d,J=7.67Hz,1H),5.13(s,2H),3.92(s,3H)。
N-(5-(4-((3-氯苯基)氨基)喹唑啉-6-基)-2-甲氧基吡啶-3-基)甲磺酰胺,MOL-
202
向由吡啶(2mL)中的6-(5-氨基-6-甲氧基吡啶-3-基)-N-(3-氯苯基)喹唑啉-4-胺(300mg,0.79mmol)组成的混合物中添加甲磺酰氯(121mg,1.06mmol)。将反应混合物在室温下搅拌2.75小时。将反应混合物过滤,且将固体用乙酸乙酯洗涤并在2-丙醇下研磨3小时。将混合物过滤并在高真空下干燥以得到呈淡灰白色固体的标题化合物(267mg,74%);TLCRf0.25(溶剂体系:1∶1v/v乙酸乙酯-庚烷);MS(ES-API+)m/z456(M+1),458(Cl同位素),(ES-API-)m/z453.9(M-1),456.0(Cl同位素);1H NMR(400MHz,DMSO-d6)δ12.35(br s,1H),9.62(br s,1H),9.40(s,1H),8.89(s,1H),8.72(d,J=2.29Hz,1H),8.39(br d,J=8.87Hz,1H),8.17(d,J=2.10Hz,1H),8.12(d,J=8.60Hz,1H),8.03(s,1H),7.86(br d,J=8.33Hz,1H),7.48(t,J=8.14Hz,1H),7.34(br d,J=8.42Hz,1H),3.98(s,3H),3.17(s,3H)。
N-(5-(4-((3-氯苯基)氨基)喹唑啉-6-基)-2-甲氧基吡啶-3-基)-N-(甲基磺酰
基)甲磺酰胺,MOL-202B
向由吡啶(0.5mL)中的N-(5-(4-((3-氯苯基)氨基)喹唑啉-6-基)-2-甲氧基吡啶-3-基)甲磺酰胺(150mg,0.33mmol)组成的混合物中添加甲磺酰氯(227mg,1.98mmol)。将反应混合物在室温下搅拌2小时,然后在40℃下搅拌4小时。将反应混合物在0℃下储存过夜,用1mL二氯甲烷和3滴吗啉稀释,(添加吗啉得到均质溶液)且直接施加至25g硅胶柱以用于纯化。将柱用4∶6至8∶2v/v乙酸乙酯-庚烷的梯度洗脱以分离呈淡棕色固体的标题化合物(18mg,10%);TLC Rf0.36(溶剂体系:1∶1v/v乙酸乙酯-庚烷);MS(ES-API+)m/z534(M+1),536(Cl同位素),(ES-API-)m/z532(M-1),534(Cl同位素)。
N-(5-(4-((3-氯苯基)氨基)喹唑啉-6-基)-2-甲氧基吡啶-3-基)环丙烷磺酰胺,
MOL-204
向由吡啶(0.8mL)中的6-(5-氨基-6-甲氧基吡啶-3-基)-N-(3-氯苯基)喹唑啉-4-胺(200mg,0.53mmol)组成的混合物中以两个相等部分相隔1小时添加环丙烷磺酰氯(278mg,1.98mmol)。将反应混合物在室温下搅拌另外2.25小时。向反应混合物中添加1mL二氯甲烷和3滴吗啉中的甲醇(185mg,5.3mmol),(添加吗啉得到均质溶液)且将混合物直接施加至40g硅胶柱以用于纯化。将柱用0∶100至10∶90v/v甲醇-乙酸乙酯的梯度洗脱以分离呈固体的标题化合物(45mg,18%);TLC Rf0.25(溶剂体系:1∶1v/v乙酸乙酯-庚烷);MS(ES-API+)m/z482(M+1),484(Cl同位素),(ES-API-)m/z480(M-1),482(Cl同位素);1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),9.44(s,1H),8.80(s,1H),8.65(s,1H),8.53(d,J=2.10Hz,1H),8.17(dd,J=1.33,8.74Hz,1H),8.05-8.11(m,2H),7.88(d,J=8.69Hz,1H),7.80-7.86(m,1H),7.43(t,J=8.10Hz,1H),7.15-7.21(m,1H),3.99(s,3H),2.69-2.79(m,1H),1.96(s,1H),0.83-0.98(m,4H)。
N-(5-(4-((3-氯苯基)氨基)喹唑啉-6-基)-2-甲氧基吡啶-3-基)-2-吗啉代乙烷-
1-磺酰胺,MOL-205
在两个分开的反应容器中:向包括6-(5-氨基-6-甲氧基吡啶-3-基)-N-(3-氯苯基)喹唑啉-4-胺(300mg,0.79mmol)和N-甲基吗啉(239mg,2.37mmol)于二氯甲烷(20mL)中的悬浮液的两个反应容器各自缓慢添加2-氯乙磺酰氯(258mg,1.58mmol)。在室温下搅拌4小时后,添加2-氯乙磺酰氯(280mg,1.7mmol)和N-甲基吗啉(276mg,2.7mmol)。在约3小时后,向两种反应混合物中添加吗啉(241mg,2.8mmol),且将反应物在室温下搅拌过夜。将反应混合物合并并直接负载到已用乙酸乙酯-庚烷(8∶2v/v)平衡的120克硅胶柱上,并使用足够的二氯甲烷以帮助将粗物质保持在溶液中。用甲醇-乙酸乙酯(0∶100v/v至10∶90v/v)的梯度洗脱硅胶柱。将来自适当级分的部分浓缩的所得沉淀物过滤以得到呈接近白色固体的标题化合物(125mg,28%);TLC Rf0.13(溶剂体系:乙酸乙酯);MS(ES-API+)m/z555(M+1),557(Cl同位素),(ES-API-)m/z553(M-1),555(Cl同位素);1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),9.47(br s,1H),8.79(s,1H),8.65(s,1H),8.51(d,J=2.01Hz,1H),8.15(dd,J=1.46,8.69Hz,1H),8.05-8.12(m,2H),7.88(d,J=8.69Hz,1H),7.80-7.86(m,1H),7.84(dd,J=1.88,8.19Hz,1H),7.43(t,J=8.14Hz,1H),7.18(dd,J=2.01,7.96Hz,1H),3.99(s,3H),3.49(t,J=4.48Hz,4H),3.34-3.42(m,2H),2.76(br t,J=7.18Hz,2H),2.37(m,4H)。
N-(5-(4-((3-氯苯基)氨基)喹唑啉-6-基)-2-甲氧基吡啶-3-基)-4-甲基哌嗪-1-
磺酰胺,MOL-207
向由吡啶(0.5mL)中的6-(5-氨基-6-甲氧基吡啶-3-基)-N-(3-氯苯基)喹唑啉-4-胺(25mg,0.07mmol)组成的混合物中添加4-甲基哌嗪-1-磺酰氯(40mg,0.20mmol)。将反应混合物在40℃下搅拌过夜,冷却至室温且闲置44天。将混合物过滤,用2mL甲醇洗涤,并在高真空下在室温下干燥以得到呈固体的标题化合物(13mg,34%);MS(ES-API+)m/z540.1(M+1),542.1(Cl同位素),(ES-API-)m/z538.0(M-1),540.0(Cl同位素);1H NMR(400MHz,DMSO-d6和D2O)δ8.80(s,1H),8.64(s,1H),8.53(d,J=1.95Hz,1H),8.12-8.20(m,1H),8.10(d,J=1.95Hz,1H),8.03(s,1H),7.90(d,J=8.99Hz,1H),7.80(br d,J=7.82Hz,1H),7.43(t,J=8.01Hz,1H),7.19(br d,J=8.21Hz,1H),3.31-3.50(m,4H),3.00(br t,J=11.14Hz,2H),2.75(s,3H),2.67(br t,J=12.51Hz,2H)。
6-(5-氨基-6-氯吡啶-3-基)-N-(3-氯-4-氟苯基)喹唑啉-4-胺(11H),MOL-210
使由15mL的l,4-二噁烷中的6-溴-N-(3-氯苯基)喹唑啉-4-胺-HCl(700mg,1.80mmol)、2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶-3-胺(467mg,1.80mmol)和1.4M K2CO3(5.1mL)组成的混合物脱气(真空/氮,3次)。向反应混合物中添加SiliCat DPP-Pd(300mg,0.26mmol/g负载)。将反应混合物密封并在Biotage EmrysOptimizer微波中在100℃下加热10分钟。将反应混合物冷却,移除水相,且将剩余的有机相通过玻璃熔结料过滤。将固体用甲醇洗涤。在减压下浓缩滤液。将残余物溶解于乙酸乙酯、甲醇、二氯甲烷和庚烷的混合物中,并且施加至120g硅胶柱上,且将所述柱用35∶65至75∶25乙酸乙酯-庚烷的梯度洗脱以得到399mg(55%)的呈固体的标题化合物;MS(ES-API+)m/z400.0(M+1),402.0(Cl同位素),(ES-API-)m/z397.9(M-1),400.0(Cl同位素);1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.78(s,1H),8.64(s,1H),8.18(dd,J=2.61,6.91Hz,1H),8.04-8.12(m,2H),7.88(d,J=8.69Hz,1H),7.80-7.86(m,1H),7.50(d,J=2.20Hz,1H),7.41-7.48(t,1H),5.74(s,2H)。
N-(2-氯-5-(4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基)吡啶-3-基)甲磺酰胺,MOL-
211
向由3mL吡啶中的6-(5-氨基-6-氯吡啶-3-基)-N-(3-氯-4-氟苯基)喹唑啉-4-胺(300mg,0.75mmol)组成的搅拌室温混合物中相隔4小时添加两部分的甲磺酰氯(92mg,0.6mmol(2x))。然后将反应混合物搅拌过夜。向反应混合物中添加2N NaOH(1.0mL,2mmol),并将其搅拌30分钟。将反应混合物用饱和氯化铵溶液和1mL的1N HCl(pH=9)稀释。将混合物用乙酸乙酯萃取。将有机相用饱和氯化铵溶液洗涤,然后用盐水洗涤,经硫酸镁干燥,过滤并浓缩。将固体残余物在80g用7∶3乙酸乙酯-庚烷至100%乙酸乙酯的梯度洗脱的硅胶柱上进行色谱分析。将从适当级分获得的固体物质在乙酸乙酯(4mL)和甲醇(2mL)中研磨,过滤并在高真空中干燥以得到167mg(46%,纯度95%)的标题化合物;MS(ES-API+)m/z478.0(M+1),480.0(Cl同位素),(ES-API-)m/z476.0(M-1),478.0(Cl同位素);1H NMR(400MHz,DMSO-d6)δ10.05(br s,1H),9.96(br s,1H),8.88(s,1H),8.80(d,J=2.10Hz,1H),8.67(s,1H),8.28(d,J=2.10Hz,1H),8.22-8.27(m,1H),8.18(dd,J=2.38,6.86Hz,1H),7.93(d,J=8.69Hz,1H),7.77-7.89(m,1H),7.49(t,J=9.06Hz,1H),3.19(s,3H)。
6-(3-氨基-4-氯苯基)-N-(3-氯-4-氟苯基)喹唑啉-4-胺(11J),MOL-212
使由10mL的1,4-二噁烷中的6-溴-N-(3-氯苯基)喹唑啉-4-胺-HCI(350mg,0.90mmol)、2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯胺(251mg,0.99mmol)和1.4M K2CO3(2.8mL)组成的混合物脱气(真空/氮,3次)。向反应混合物中添加SiliCat DPP-Pd(150mg,0.26mmol/g负载)。将反应混合物密封并在Biotage EmrysOptimizer微波中在100℃下加热12分钟。向反应混合物中添加另外的2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯胺(40mg,0.16mmol)和SiliCat DPP-Pd(30mg)。将反应混合物在100℃下再次加热6分钟并冷却。移除水相,且将剩余的有机相通过玻璃熔结料过滤。将固体用甲醇洗涤。在减压下浓缩滤液。将残余物施加至120g硅胶柱,且用35∶65至75∶25乙酸乙酯-庚烷的梯度洗脱以得到126mg(35%)的呈无色固体的标题化合物;MS(ES-API+)m/z399.0(M+1),401.0(Cl同位素),(ES-API-)m/z397.0(M-1),399.0(Cl同位素);1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.73(d,J=1.74Hz,1H),8.64(s,1H),8.20(dd,J=2.65,6.86Hz,1H),8.06(dd,J=1.83,8.69Hz,1H),7.83-7.90(m,2H),7.47(t,J=9.10Hz,1H),7.37(d,J=8.23Hz,1H),7.23(d,J=2.20Hz,1H),7.03(dd,J=2.20,8.23Hz,1H),5.51(s,2H)。
N-(2-氯-5-(4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基)苯基)甲磺酰胺,MOL-213
向由1.5mL吡啶中的6-(3-氨基-4-氯苯基)-N-(3-氯-4-氟苯基)喹唑啉-4-胺(126mg,0.32mmol)组成的搅拌室温混合物中添加甲磺酰氯(45mg,0.39mmol)。然后将反应混合物搅拌过夜。向反应混合物中添加2N NaOH(1.0mL,2mmol),并将其搅拌10分钟。将反应混合物用饱和氯化铵溶液和0.5mL的1N HCl稀释。将混合物用乙酸乙酯萃取。将有机相用饱和氯化铵溶液洗涤,然后用盐水洗涤,经硫酸镁干燥、过滤并浓缩。将固体残余物在乙酸乙酯(4mL)和甲醇(2mL)中研磨20小时,过滤并在高真空中干燥以得到83mg(54%,纯度97%)的标题化合物;MS(ES-API+)m/z477.0(M+1),479.0(Cl同位素),(ES-API-)m/z474.9(M-1),477.0(Cl同位素);1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),9.67(s,1H),8.79(d,J=1.56Hz,1H),8.64(s,1H),8.12-8.19(m,2H),7.84-7.92(m,2H),7.81(ddd,J=2.74,4.30,9.06Hz,1H),7.73-7.78(m,1H),7.68-7.73(m,1H),7.46(t,J=9.10Hz,1H),3.10(s,3H)。
6-溴-N-(3-氯-4-(吡啶-2-基甲氧基)苯基)喹唑啉-4-胺盐酸盐
将由40mL1,4-二噁烷中的6-溴-4-氯喹唑啉(1.0g,4.1mmol)和3-氯-4-(吡啶-2-基甲氧基)苯胺(1.15g,4.9mmol)组成的混合物在80℃下加热过夜。将反应混合物冷却至室温,用20mL乙醚稀释并过滤。将固体在高真空中干燥以得到1.98g(100%,纯度90%)的标题化合物;MS(ES-API+)m/z441.0(M+1)443.0(Cl/Br同位素),(ES-API-)m/z439.0(M-1)441.0(Cl/Br同位素);1H NMR(400MHz,DMSO-d6)δ11.49(br s,1H),9.15(d,J=1.92Hz,1H),8.91(s,1H),8.61(d,J=5.03Hz,1H),8.20(dd,J=2.01,8.87Hz,1H),7.90-7.96(m,2H),7.87(d,J=8.97Hz,1H),7.59-7.69(m,2H),7.41(dd,J=4.99,6.54Hz,1H),7.34(d,J=9.06Hz,1H),5.34(s,2H)。
6-(5-氨基-6-氯吡啶-3-基)-N-(3-氯-4-(吡啶-2-基甲氧基)苯基)喹唑啉-4-胺
使由15mL1,4-二噁烷中的6-溴-N-(3-氯-4-(吡啶-2-基甲氧基)苯基)喹唑啉-4-胺-HCl(900mg,1.88mmol)、2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶-3-胺(832mg,4.3mmol)和2.0M K2CO3(4.4mL)组成的混合物脱气(真空/氮,3次)。向反应混合物中添加SiliCat DPP-Pd(450mg,0.26mmol/g负载)。将反应混合物密封并在Biotage Emrys Optimizer微波中在100℃下加热20分钟。将反应混合物冷却,移除水相,且将混合物通过玻璃熔结料过滤。将固体用甲醇洗涤,然后用热甲醇洗涤。在减压下浓缩滤液。将残余物用甲醇和乙酸乙酯稀释,在减压下浓缩以得到固体。将固体悬浮于20mL乙酸乙酯中。添加2mL甲醇产生均质溶液。缓慢添加15mL庚烷产生固体沉淀,且将悬浮液搅拌30分钟且过滤并干燥以得到530mg的呈浅绿色/棕色固体的标题化合物。将母液放置过夜并产生沉淀,将所述沉淀过滤以得到300mg的另外淡绿色固体。总计:880mg(96%,纯度90%);MS(ES-API+)m/z489.1(M+1),491.0(Cl同位素),(ES-API-)m/z487.0(M-1),489.0(Cl同位素);1H NMR(400MHz,DMSO-d6)(br s,1H),8.79(br s,1H),8.58(br d,J=4.39Hz,1H),8.50(br s,1H),8.07(br d,J=1.65Hz,1H),7.95-8.04(m,2H),7.82-7.90(m,1H),7.78(br d,J=8.88Hz,1H),7.69(br d,J=7.69Hz,1H),7.53-7.60(m,2H),7.30-7.38(m,1H),7.24(br d,J=8.78Hz,1H),5.73(s,2H),5.27(s,2H)。
N-(2-氯-5-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)喹唑啉-6-基)吡啶-3-
基)甲磺酰胺,MOL-215
向由3.5mL吡啶中的6-(5-氨基-6-氯吡啶-3-基)-N-(3-氯-4-(吡啶-2-基甲氧基)苯基)喹唑啉-4-胺(300mg,0.61mmol)组成的搅拌室温混合物中相隔2小时添加两部分的甲磺酰氯(140mg,2.45mmol(2x))。将反应混合物搅拌过夜。向反应混合物添加2N NaOH(1.5mL,3mmol)。在0.5小时时,添加另外量的2N NaOH(0.5mL,1mmol),并继续搅拌另外0.5小时。向反应中添加2N NaOH(2.0mL,4mmol),且在30分钟后,通过TLC显示反应(水解)完成。将反应混合物用饱和碳酸氢钠溶液和乙酸乙酯稀释,并在分液漏斗中振荡。向混合物中添加水、盐水、甲醇和异丙醇(25mL)以制动(brake)乳液。将混合物用乙酸乙酯萃取两次。将合并的有机相用盐水洗涤,经硫酸镁干燥,过滤且在减压下浓缩。将残余物吸收在甲苯中并浓缩。将固体吸收在甲醇/乙酸乙酯中,过滤并将滤液施加到用9∶1乙酸乙酯-庚烷至100%乙酸乙酯至1∶9甲醇-乙酸乙酯洗脱的120g硅胶柱上以得到140mg(40%,纯度97%)的呈黄色固体的标题化合物;MS(ES-API+)m/z567.0(M+1),569.1(Cl同位素),(ES-API-)m/z565.0(M-1),567.0(Cl同位素);1H NMR(400MHz,DMSO-d6)δ9.96(br s,2H),8.88(s,1H),8.81(d,J=2.10Hz,1H),8.62(s,1H),8.60(br d,J=4.39Hz,1H),8.29(d,J=2.01Hz,1H),8.24(brd,J=8.78Hz,1H),8.02(d,J=2.47Hz,1H),7.86-7.93(m,2H),7.72(dd,J=2.38,8.87Hz,1H),7.59(d,J=7.87Hz,1H),7.34-7.41(m,1H),7.31(d,J=9.06Hz,1H),5.31(s,2H),3.20(s,3H)。
6-(5-氨基吡啶-3-基)-N-(3-氯苯基)喹唑啉-4-胺,MOL-310
使由15mL的1,4-二噁烷中的6-溴-N-(3-氯苯基)喹唑啉-4-胺-HCl(500mg,1.49mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶-3-胺(274mg,1.24mmol)和2.0M K2CO3(3.1mL)组成的混合物脱气(真空/氮,3次)。向反应混合物中添加SiliCat DPP-Pd(60mg,0.26mmol/g负载)。将反应混合物密封并在95℃下加热1.25小时。向反应中添加5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶-3-胺(90mg,0.41mmol),并在95℃下再次加热过夜。将反应混合物冷却并通过玻璃熔结料过滤。将固体用乙醇洗涤。在减压下浓缩滤液。使用干式负载方法将残余物在40g硅胶柱上进行色谱分析且用1∶99至15∶85甲醇-乙酸乙酯的梯度洗脱以得到126mg(24%,纯度97.4%)的标题化合物;MS(ES-API+)m/z348.0(M+1),350.0(Cl同位素),(ES-API-)m/z346.0(M-1),348.0(Cl同位素);1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.81(d,J=1.65Hz,1H),8.66(s,1H),8.24(d,J=1.92Hz,1H),8.05-8.14(m,2H),7.99(d,J=2.47Hz,1H),7.81-7.93(m,2H),7.42(t,J=8.10Hz,1H),7.29(t,J=2.29Hz,1H),7.18(d,J=8.18Hz,1H),5.48(s,2H)。
6-(5-(1H-四唑-1-基)吡啶-3-基)-N-(3-氯苯基)喹唑啉-4-胺,MOL-311
向由2mL乙酸中的6-(5-氨基吡啶-3-基)-N-(3-氯苯基)喹唑啉-4-胺(100mg,0.29mmol)组成的混合物中添加原甲酸三甲酯(92mg,0.86mmol)和叠氮化钠(56mg,0.86mmol)。将反应混合物在80℃下加热4小时。用饱和碳酸氢钠溶液淬灭反应且用乙酸乙酯萃取。将有机相经硫酸镁干燥,过滤且在减压下浓缩至黄色固体。将固体在4∶1二氯甲烷-乙酸乙酯下研磨,然后在二氯甲烷-乙酸乙酯-四氢呋喃下研磨,并过滤以得到40mg(34,纯度91%)的标题化合物;MS(ES-API+)m/z401.1(M+1),403.0(Cl同位素),(ES-API-)m/z399.0(M-1),401.0(Cl同位素);1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),10.00(s,1H),9.33(s,1H),9.19(d,J=2.10Hz,1H),9.01(s,1H),8.76-8.88(m,1H),8.69(s,1H),8.38(d,J=8.60Hz,1H),8.08(s,1H),7.95(d,J=8.60Hz,1H),7.84(br d,J=8.23Hz,1H),7.44(t,J=8.10Hz,1H),7.20(d,J=7.96Hz,1H)。
5-(4-((3-氯苯基)氨基)喹唑啉-6-基)烟腈,MOL-312
使由15mL的1,4-二噁烷中的6-溴-N-(3-氯苯基)喹唑啉-4-胺-HCl(500mg,1.49mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)烟腈(286mg,1.24mmol)和2.0M K2CO3(3.1mL)组成的混合物脱气(真空/氮,3次)。向反应混合物中添加SiliCat DPP-Pd(70mg,0.26mmol/g负载)。将反应混合物密封并在95℃下加热4小时。将反应混合物冷却并通过玻璃熔结料过滤。将固体用乙醇洗涤。在减压下浓缩滤液。将甲苯添加至残余物中并在减压下浓缩。使用干式负载方法将残余物在40g硅胶柱上进行色谱分析且用25∶75至95∶5乙酸乙酯-二氯甲烷的梯度洗脱,然后添加在95∶5乙酸乙酯-二氯甲烷体系中5%甲醇至9%甲醇以得到147mg(33%)的淡黄色固体的呈标题化合物;MS(ES-API+)m/z358.0(M+1),360.0(Cl同位素),(ES-API-)m/z356.0(M-1),358.0(Cl同位素);1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),9.41(d,J=2.20Hz,1H),9.08(d,J=1.83Hz,1H),8.94(d,J=1.74Hz,1H),8.82(t,J=2.10Hz,1H),8.69(s,1H),8.34(dd,J=1.83,8.69Hz,1H),8.07(t,J=1.97Hz,1H),7.92(d,J=8.69Hz,1H),7.84(dd,J=1.19,8.23Hz,1H),7.44(t,J=8.14Hz,1H),7.20(dd,J=1.33,7.91Hz,1H)。
6-(5-(1H-四唑-5-基)吡啶-3-基)-N-(3-氯苯基)喹唑啉-4-胺,MOL-313
将由5-(4-((3-氯苯基)氨基)喹唑啉-6-基)烟腈(50mg,0.14mmol)、叠氮化钠(18mg,0.28mmol)、氯化铵(15mg,0.28mmol)和氯化锂(1.2mg)组成的混合物在100℃下加热过夜。将反应冷却,添加甲苯且将混合物在减压下浓缩至小于1mL。向残余物添加0.5∶5∶95乙酸-甲醇-二氯甲烷的混合物,并将混合物过滤。将滤液施加至25g硅胶柱,所述柱用0.5∶10∶90至0.5∶40∶60乙酸-甲醇-二氯甲烷的梯度洗脱,以得到34mg(60%,纯度96%)的呈固体的标题化合物;MS(ES-API+)m/z401.0(M+I),403.1(Cl同位素);1H NMR(400MHz,DMSO-d6)δ10.25(br s,1H),9.18(s,1H),9.03(s,1H),9.01(s,1H),8.71(s,1H),8.67(s,1H),8.29(d,J=8.69Hz,1H),8.13(s,1H),7.92(d,J=8.69Hz,1H),7.88(br d,J=8.42Hz,1H),7.42(t,J=8.10Hz,1H),7.18(d,J=7.96Hz,1H)。
实施例9.
此实施例显示用于本发明的另外基于喹啉的化合物的合成程序。
4-((3-4-氟苯基)氨基)-6-(6-甲氧基吡啶-3-基)喹啉-3-甲腈,MOL-150
将6-溴-4-氯喹啉-3-甲腈(14,200mg,0.75mmol)和3-氯-4-氟苯胺(2A,130mg,0.90mmol)于4mL的1,4-二噁烷中的混合物在90℃下加热2小时。将反应混合物冷却至室温,用乙醚稀释,冷却至0℃并通过熔结玻璃过滤。将固体用乙醚洗涤并干燥以得到呈暗黄色固体的6-溴-4-((3-氯-4-氟苯基)氨基)喹啉-3-甲腈(15,280mg,100%)。使6-溴-4-((3-氯-4-氟苯基)氨基)喹啉-3-甲腈(278mg,0.77mmol)和(6-甲氧基吡啶-3-基)硼酸(9G,118mg,0.77mmol)于1,4-二噁烷(15mL)和水(1.4mL)中的溶液脱气。向所述溶液中添加碳酸铯(1.0g,3.1mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)(44mg)。将反应混合物在N2下在80℃下加热2小时。将反应混合物用甲苯稀释且在真空下除去挥发物,并且将粗物质通过硅胶柱色谱,用3/7至7/3乙酸乙酯/庚烷的梯度洗脱进行纯化。将黄色固体在二氯甲烷/乙醚中研磨,过滤并干燥以得到呈白色固体的4-((3-氯-4-氟苯基)氨基)-6-(6-甲氧基吡啶-3-基)喹啉-3-甲腈(16,MOL-150,44mg,14%,100%纯度);1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.75(d,J=1.9Hz,1H),8.70(d,J=1.9Hz,1H),8.58(s,1H),8.21(t,J=6.2Hz,2H),7.99(d,J=8.4Hz,1H),7.64(d,J=6.6Hz,1H),7.48(t,J=8.8Hz,1H),7.3-7.4(m,1H),6.99(d,J=8.5Hz,1H),3.91(s,3H);MS:(ESI+m/z405.1,ESI-m/z403.1)。
6-溴-4-((4-(吡啶-4-基氧基)苯基)氨基)喹啉-3-甲腈盐酸盐,MOL-400
将由3mL乙氧基乙醇中的6-溴-4-氯喹啉-3-甲腈(440mg,1.64mmol)和4-(吡啶-4-基氧基)苯胺(291mg,1.56mmol)组成的混合物在125℃下在密封容器中加热2小时。将反应混合物冷却至室温并过滤以得到193mg的呈浅棕色固体的标题化合物。将滤液用乙酸乙酯稀释,且用饱和碳酸氢钠溶液洗涤。将水相用乙酸乙酯萃取两次。将合并的有机相用盐水洗涤,经硫酸镁干燥,过滤且在减压下浓缩。将残余物在25g的用45∶55乙酸乙酯-庚烷至100%乙酸乙酯至2∶98甲醇-乙酸乙酯的梯度洗脱的二氧化硅上进行色谱分析以得到160mg的呈棕褐色固体的标题化合物。总计:353mg(54%,)。将浅棕色固体的样品大部分溶解在5mL的2∶8甲醇-二氯甲烷中,且在搅拌时添加15mL乙醚和5mL庚烷。将悬浮液搅拌过夜并过滤。将滤液置于室温下且过滤所形成的结晶物质以得到接近白色固体(99.9%纯);MS(ES-API+)m/z417.0(M+1)419.0(Br同位素),(ES-API-)m/z414.9(M-1)417.0(Br同位素);1H NMR(400MHz,DMSO-d6)δ10.03(br s,1H),8.78(d,J=1.92Hz,1H),8.57(s,1H),8.44-8.51(m,2H),7.97(dd,J=2.10,8.87Hz,1H),7.85(d,J=8.87Hz,1H),7.45(d,J=8.69Hz,2H),7.21-7.30(m,2H),6.97-7.03(m,2H)。
6-(3-(羟甲基)苯基)-4-((4-(吡啶-4-基氧基)苯基)氨基)喹啉-3-甲腈,MOL-402
使由2mL的1,4-二噁烷和1mL乙醇中的6-溴-4-((4-(吡啶-4-基氧基)苯基)氨基)喹啉-3-甲腈盐酸盐(40mg,0.096mmol)、(3-(羟甲基)苯基)硼酸(19mg,0.125mmol)和2.0MK2CO3(0.24mL)组成的混合物脱气(真空/氮,3次)。向反应混合物中添加SiliCat DPP-Pd(25mg,0.26mmol/g负载)。将反应混合物密封并在95℃下加热2小时。将反应混合物冷却并通过玻璃熔结料过滤。将固体用乙醇洗涤。在减压下浓缩滤液。将残余物在1.5mL甲醇中研磨并过滤以得到25mg(58%,纯度98.4%)的呈固体的标题化合物;MS(ES-API+)m/z445.2(M+1),(ES-API-)m/z443.2(M-1);1H NMR(400MHz,DMSO-d6)δ10.11(br s,1H),8.75-8.88(m,1H),8.54(s,1H),8.44(d,J=5.37Hz,2H),8.17(dd,J=1.69,8.65Hz,1H),7.99(d,J=8.60Hz,1H),7.83(s,1H),7.76(br d,J=7.96Hz,1H),7.43-7.54(m,3H),7.38(d,J=7.50Hz,1H),7.26(d,J=8.78Hz,2H),6.93-7.02(m,2H),5.28(t,J=5.67Hz,1H),4.60(d,J=5.58Hz,2H)。
N-(5-(3-氰基-4-((4-(吡啶-4-基氧基)苯基)氨基)喹啉-6-基)吡啶-3-基)甲磺
酰胺,MOL-401
使由4mL的1,4-二噁烷和2mL乙醇中的6-溴-4-((4-(吡啶-4-基氧基)苯基)氨基)喹啉-3-甲腈盐酸盐(80mg,0.19mmol)、N-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶-3-基)甲磺酰胺(74mg,0.25mmol)和2.0M K2CO3(0.47mL)组成的混合物脱气(真空/氮,3次)。向反应混合物中添加SiliCat DPP-Pd(50mg,0.26mmol/g负载)。将反应混合物密封并在95℃下加热2小时。将反应混合物冷却并通过玻璃熔结料过滤。将固体用乙醇洗涤。在减压下浓缩滤液。将残余物在12g用100%乙酸乙酯至25:75的甲醇-乙酸乙酯的梯度洗脱的硅胶柱上进行色谱分析以得到65mg的黄色固体。将固体在甲醇-乙酸乙酯-二氯甲烷的混合物中研磨并过滤以得到32mg的呈黄色固体的标题化合物(33%,纯度91%);MS(ES-API+)m/z509.1(M+1),(ES-API-)m/z507.0(M-1);1H NMR(400MHz,DMSO-d6)δ10.14(s,2H),8.86(s,2H),8.58(s,1H),8.44-8.51(m,3H),8.13-8.22(m,1H),8.13-8.22(m,1H),8.05(br d,J=8.60Hz,1H),8.00(t,J=2.10Hz,1H),7.49(br d,J=8.33Hz,2H),7.27(d,J=8.69Hz,2H),6.98(d,J=5.37Hz,2H),3.13(s,3H)。
6-(3-羟苯基)-4-((4-(吡啶-4-基氧基)苯基)氨基)喹啉-3-甲腈,MOL-403
使由4mL的1,4-二噁烷和2mL乙醇中的6-溴-4-((4-(吡啶-4-基氧基)苯基)氨基)喹啉-3-甲腈盐酸盐(80mg,0.19mmol)、(3-羟苯基)硼酸(34mg,0.25mmol)和2.0M K2CO3(0.47mL)组成的混合物脱气(真空/氮,3次)。向反应混合物中添加SiliCat DPP-Pd(50mg,0.26mmol/g负载)。将反应混合物密封并在95℃下加热2小时。将反应混合物冷却并通过玻璃熔结料过滤。将固体用乙醇洗涤。将滤液用甲苯稀释并在减压下浓缩。将残余物在12g用8∶2乙酸乙酯-二氯甲烷至100%乙酸乙酯、然后至1∶9甲醇-乙酸乙酯的梯度洗脱的硅胶柱上进行色谱分析以得到15mg(18%,纯度95.9%)的标题化合物;MS(ES-API+)m/z431.1(M+1),(ES-API-)m/z429.1(M-1);1H NMR(400MHz,DMSO-d6)δ9.91-10.48(br s,1H),9.47-9.91(br s,1H),8.75(s,1H),8.38-8.52(m,3H),8.07(br d,J=7.96Hz,1H),7.92(br d,J=8.69Hz,1H),7.41(br d,J=8.05Hz,2H),7.25-7.36(m,3H),7.22(br d,J=8.60Hz,2H),6.96(d,J=6.13Hz,2H),6.82(br d,J=7.23Hz,1H)。
6-溴-4-((3-氯-4-氟苯基)氨基)喹啉-3-甲腈盐酸盐
将由40mL1,4-二噁烷中的6-溴-4-氯喹唑啉-3-甲腈(1.0g,3.7mmol)和3-氯-4-氟苯胺(653mg,4.5mmol)组成的混合物在80℃下加热过夜。将反应混合物冷却至室温,用20mL乙醚稀释并过滤。将固体在高真空中干燥以得到1.36g(89%)的标题化合物;MS(ES-API+)m/z376.0(M+1)378.0(Cl/Br同位素),(ES-API-)m/z373.9(M-1)375.9(Cl/Br同位素);1HNMR(400MHz,DMSO-d6) 8.99(s,1H),8.16(dd,J=1.92,8.97Hz,1H),8.00(d,J=8.88Hz,1H),7.75(dd,J=2.52,6.63Hz,1H),7.50-7.59(m,1H),7.43-7.50(m,1H)。
6-(5-氨基-6-氯吡啶-3-基)-4-((3-氯-4-氟苯基)氨基)喹啉-3-甲腈
将由15mL1,4-二噁烷中的6-溴-4-((3-氯-4-氟苯基)氨基)喹啉-3-甲腈-HCl(1.2g,2.9mmol)、2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶-3-胺(1.1g,4.3mmol)和2.0M K2CO3(5.8mL)组成的混合物脱气(真空/氮,3次)。向反应混合物中添加SiliCat DPP-Pd(650mg,0.26mmol/g负载)。将反应混合物密封并在Biotage EmrysOptimizer微波中在100℃下加热20分钟。将反应混合物冷却并通过玻璃熔结料过滤。将固体用甲醇洗涤,然后用热甲醇洗涤。在减压下浓缩滤液。将残余物用甲苯稀释,在减压下浓缩,然后在乙酸乙酯中研磨1小时。将固体过滤并干燥以得到2.98g的呈固体的标题化合物;MS(ES-API+)m/z424.0(M+1),426.0(Cl同位素),(ES-API-)m/z422.0(M-1),423.9(Cl同位素);1H NMR(400MHz,DMSO-d6) 7.88(d,J=2.01Hz,1H),7.78(s,1H),7.62-7.68(m,1H),7.38-7.50(m,2H),7.08(t,J=9.24Hz,1H),6.77(br d,J=6.68Hz,1H),6.60-6.69(m,1H),5.61(s,2H)。
N-(2-氯-5-(4-((3-氯-4-氟苯基)氨基)-3-氰基喹啉-6-基)吡啶-3-基)甲磺酰
胺,MOL-216
向由12mL吡啶中的6-(5-氨基-6-氯吡啶-3-基)-4-((3-氯-4-氟苯基)氨基)喹啉-3-甲腈(1.00g,2.35mmol)组成的搅拌室温混合物中相隔2小时添加两部分的甲磺酰氯(0.54g,9.4mmol(2x))。将反应混合物总计搅拌5小时。向反应混合物添加2N NaOH(5.0mL,10mmol)。在1.5小时时,添加另外量的2N NaOH(3mL,6mmol),并继续搅拌另外0.5小时。向深橙色/红色反应混合物中逐滴添加6N HCl(1mL,6mmol)。将红色/棕色反应混合物用饱和氯化钠溶液稀释,且将混合物用乙酸乙酯萃取两次。将合并的有机相用盐水洗涤,经硫酸镁干燥,过滤且浓缩。将固体残余物在甲醇和乙酸乙酯的混合物中研磨并过滤。将母液施加至120g用65∶35乙酸乙酯-庚烷至100%乙酸乙酯至15∶85甲醇-乙酸乙酯的梯度洗脱的硅胶柱上。合并含有产物的纯净级分且使淡黄色固体沉淀。将其过滤并干燥以得到30mg(2.5%)的标题化合物。将上述过滤的固体溶解于热甲醇-乙酸乙酯(9∶1,250mL)中。向溶液中添加25g的二氧化硅,并且此混合物用于将样品干式负载到220g用65:35乙酸乙酯-庚烷至100%乙酸乙酯至1∶9甲醇-乙酸乙酯的梯度洗脱的硅胶柱上。将含有纯净产物的级分在减压下浓缩以得到52mg(4.2%)的呈灰白色固体的标题化合物。MS(ES-API+)m/z502.0(M+1),504.0(Cl同位素),(ES-API-)m/z500.0(M-1),501.9(Cl同位素);1H NMR(400MHz,DMSO-d6)9.93(br s,1H),8.84(s,1H),8.80(s,1H),8.62(s,1H),8.28(s,1H),8.24(br d,J=9.15Hz,1H),8.05(br d,J=8.51Hz,1H),7.67(br d,J=4.67Hz,1H),7.45-7.54(m,1H),7.42(br s,1H),3.16(s,3H)。
现在已经充分描述了本发明,本领域的技术人员应理解,本发明可在广泛和等效范围的条件、制剂和其他参数内进行,而不会影响本发明的范围或其任何实施方案。本文中引用的所有专利、专利申请和公布全部以引用的方式整体并入。
以引用的方式并入
本文提及的专利文件和科学文章中的每个的全部公开内容出于所有目的以引用的方式并入。
等效案
在不脱离本发明的精神或基本特征的情况下,本发明可以其他具体形式来实施。因此,前述实施方案在所有方面都应被视为说明性的,而非限制本文中描述的本发明。本发明的范围因此由所附权利要求书而不是前述说明书指示,因此属于权利要求书的含义和等效范围内的所有变化意图被包含在其中。
Claims (11)
2.如权利要求1所述的化合物,其中所述EGFR蛋白是ERBB1、ERBB2、和ERBB4中的一种或多种,和其中所述PI3K蛋白是PIK3Cα、PIK3δ、PIK3β、PIK3Cγ和PI3Kα中的一种或多种。
4.如权利要求1-3中任一项所述的化合物在制备用于治疗或缓解有需要的患者中涉及NSCLC、头颈癌、多形性胶质母细胞瘤或结肠直肠癌的症状的药物中的用途。
5.如权利要求4所述的用途,其中所述治疗还包括向所述患者施用一种或多种抗癌剂。
6.如权利要求5所述的用途,其中所述抗癌剂是化学治疗剂。
7.如权利要求6所述的用途,其中所述抗癌剂是放射疗法。
8.如权利要求7所述的用途,其中所述化合物能够抑制EGFR活性和PI3IK活性。
9.一种药盒,其包括如权利要求1-3中任一项所述的化合物以及用于将所述化合物施用至患者的说明书,所述患者患有NSCLC、头颈癌、多形性胶质母细胞瘤或结肠直肠癌。
10.如权利要求9所述的药盒,其还包括一种或多种抗癌剂。
11.如权利要求10所述的药盒,其中所述化合物将与一种或多种抗癌剂一起施用。
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CA3081443A1 (en) | 2016-06-23 |
US20210023085A1 (en) | 2021-01-28 |
EP3233085B1 (en) | 2022-09-07 |
NZ732511A (en) | 2018-11-30 |
KR20200091954A (ko) | 2020-07-31 |
WO2016100347A2 (en) | 2016-06-23 |
US10206924B2 (en) | 2019-02-19 |
US20170360788A1 (en) | 2017-12-21 |
AU2019202604B2 (en) | 2020-09-24 |
KR20170095328A (ko) | 2017-08-22 |
HK1248520A1 (zh) | 2018-10-19 |
JP2019206549A (ja) | 2019-12-05 |
CN107531665A (zh) | 2018-01-02 |
AU2019202604A1 (en) | 2019-05-02 |
WO2016100347A3 (en) | 2016-08-18 |
EP3233085A2 (en) | 2017-10-25 |
US11607414B2 (en) | 2023-03-21 |
AU2015362670A1 (en) | 2017-06-29 |
CA2969974A1 (en) | 2016-06-23 |
KR102139496B1 (ko) | 2020-07-30 |
JP2017537959A (ja) | 2017-12-21 |
JP2021088580A (ja) | 2021-06-10 |
US10842791B2 (en) | 2020-11-24 |
JP6559785B2 (ja) | 2019-08-14 |
CN107531665B (zh) | 2021-03-30 |
EP3233085A4 (en) | 2018-06-13 |
CA2969974C (en) | 2020-08-04 |
US20190167686A1 (en) | 2019-06-06 |
AU2015362670B2 (en) | 2019-01-24 |
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