CN113646299A - 作为***素e2(pge2)受体调节剂的新型n-苄基-2-苯氧基苯甲酰胺衍生物 - Google Patents
作为***素e2(pge2)受体调节剂的新型n-苄基-2-苯氧基苯甲酰胺衍生物 Download PDFInfo
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- CN113646299A CN113646299A CN202080025513.1A CN202080025513A CN113646299A CN 113646299 A CN113646299 A CN 113646299A CN 202080025513 A CN202080025513 A CN 202080025513A CN 113646299 A CN113646299 A CN 113646299A
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- methyl
- fluorophenoxy
- benzoic acid
- biphenyl
- carboxamido
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Classifications
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Abstract
本发明涉及作为***素E2(PGE2)的EP4和/或EP2受体的调节剂的式(I)的新型的、任选地取代的N‑苄基‑2‑苯氧基苯甲酰胺衍生物,
Description
技术领域
本发明涉及作为***素E2(PGE2)的EP4和/或EP2受体调节剂的新型、任选地取代的N-苄基-2-苯氧基苯甲酰胺衍生物。
本发明的其他目的是提供制备这些化合物的方法;包括有效量的这些化合物的药物组合物,以及所述化合物用于治疗可以通过EP4和/或EP2受体的调节剂改善的病理病症或疾病,比如癌症疾病、疼痛和炎症病症,比如急性和慢性疼痛、骨关节炎、类风湿性关节炎疾病、子宫内膜异位症和肾脏疾病。
背景技术
***素E2(PGE2)参与多种生物过程,比如疼痛、发热、血管张力调节、肾功能、粘膜完整性、炎症、血管生成和肿瘤生长。PGE2经常引起复杂和不同的效应,这可归因于其四种所谓的E型***素受体(EP1到EP4)的激活。PGE2的生理活动由4个G蛋白偶联的质膜受体介导,其识别为E***素受体1-4(EP1、EP2、EP3和EP4),其各自可以激活不同的下游信号通路。(SUGIMOTO,Yukihiko;NARUMIYA,Shuh.Prostaglandin E receptors.Journal ofBiological Chemistry,2007,vol.282,no 16,p.11613-11617)。
PGE2是在炎症病症下检测到的主要类二十烷酸,并且此外,它还参与各种生理和/或病理病症,比如痛觉过敏、子宫收缩、消化蠕动、觉醒、抑制胃酸分泌、血压、血小板功能、骨代谢、血管生成、癌症转移等。类二十烷酸:(From Biotechnology to TherapeuticApplications,Folco,Samuelsson,Maclouf和Velo编辑,Plenum Press,New York,1996,第14章,p.137-154);(Journal of Lipid Mediators and Cell Signalling,14:83-87(1996)),(Prostaglandins and Other Lipid Mediators,69:557-573(2002))。
另一方面,据报道PGE2在不同类型癌症的癌组织中高表达,并且也阐明PGE2与癌症的发展和疾病病症有关。众所周知,PGE2与激活细胞增殖和抑制细胞死亡(细胞凋亡)有关,并且在癌症进展和转移过程中起着重要作用。
每个EP受体亚型在人体内都有特定的分布;EP1:子宫肌层、肺静脉、结肠、皮肤、肥大细胞;EP2:白细胞、平滑肌、中枢神经***(CNS)、生殖***、骨骼;EP3:中枢神经***、心血管***、生殖***、肾脏、膀胱;EP4:白细胞、平滑肌、心血管***和骨骼(SUGIMOTO,Yukihiko;NARUMIYA,Shuh.Journal of Biological Chemistry,2007,vol.282,no 16,p.11613-11617)和(Woodward,D.F.等人,(2011)International Union of Basic andClinical Pharmacology.LXXXIII:Pharmacol.Rev.63,471–538 5)。
EP2受体
使用EP2受体敲除小鼠的研究已经证明了EP2受体在恶性肿瘤中的作用,EP2受体缺陷小鼠在暴露于致癌促进剂后显著减少了肺、皮肤和乳腺肿瘤。EP2受体的遗传消融还减少了腺瘤性息肉病(APC)1309小鼠中肠息肉的大小和数量,这些小鼠在遗传上易受肠息肉发育的影响。此外,EP2受体已显示在包括结肠癌、***癌和乳腺癌的多种癌症中由肿瘤细胞表达(GUSTAFSSON,Annika等人International journal of cancer,2007,vol.121,no2,p.232-240)和(Chang SH等人,(2004).Proc Natl Acad Sci U S A 101:591–596)。
在***癌中,众所周知雄激素剥夺疗法(ADT)是一种主要的治疗方法,但该疾病经常复发并在几乎所有患者中变得去势抵抗性。从机制上讲,已经确定在雄激素剥夺后,升高的PGE2-EP2信号抑制了胸腺细胞中CD4的表达。在治疗上,用塞来昔布使PGE2信号失活,显著抑制了去势抵抗性***癌(CRPC)的发病。这些结果表明了将ADT与PGE2抑制相结合治疗***癌的新治疗途径(WANG,C.等人,Cell research,2018)。
PGE2-EP2信号传导作为慢性炎症的一个节点,塑造肿瘤微环境,并且因此是结直肠癌化学预防的有力候选目标(AOKI,Tomohiro;NARUMIYA,Shuh.Inflammation andregeneration,2017,vol.37,no 1,p.4.)。
此外,最近的一项研究表明,PGE2激活EP2受体可通过上调EMT关键诱导剂Snail的表达水平显著增强肝细胞癌细胞的侵袭和迁移能力(CHENG,Shan-Yu,et al.Oncologyreports,2014,vol.31,no 5,p.2099-2106.)和(ZANG,Shengbing等人Human pathology,2017,vol.63,p.120-127)。EP2受体也与乳腺癌的转移有关,部分原因是它能够改变细胞对TGF-β的反应(Tian M,Schiemann WP(2010).FASEB J 24:1105-1116)。
EP2对神经退行性疾病的拮抗作用
慢性炎症性神经退行性疾病,比如癫痫、阿尔茨海默病(AD)、帕金森病(PD)和肌萎缩侧索硬化症(ALS),导致相当一部分人口的死亡率和发病率。AD和PD与老年人的痴呆症状特别相关。然而,所有这些疾病都有一个共同的特征,即炎症通路过度激活。有趣的是,PGE2是这些疾病进展过程中产生的主要***素,并且已显示经由过EP2(并在较小程度上通过EP4)受体介导促炎功能。研究已经显示,施用有效且选择性的EP2拮抗剂TG4-15585,在毛果芸香碱癫痫持续状态模型中显著阻断海马中的神经元损伤(>60%的肺门,80%的CA3和>90%的CA1区域)。(JIANG,Jianxiong等人,Proceedings of the National Academy ofSciences,2012,vol.109,no 8,p.3149-3154)。
另一种有效的EP2拮抗剂TG6-10-186可抑制癫痫持续状态后小鼠的神经退行性、炎性细胞因子和趋化因子的上调以及神经胶质的激活,这表明EP2拮抗剂具有阻断癫痫发生的潜在治疗益处。(JIANG,Jianxiong等人,Proceedings of the National Academy ofSciences,2013,vol.110,no 9,p.3591-3596)。
基于在AD、PD和ALS的EP2基因敲除小鼠模型中观察到的有益效果(见上文),EP2受体拮抗剂可用作包括癫痫、阿尔茨海默病、帕金森病和肌萎缩性脊髓侧索硬化症的慢性炎症性神经退行性疾病的辅助治疗剂。(LIANG,Xibin等人,Annals of Neurology:OfficialJournal of the American Neurological Association and the Child NeurologySociety,2008,vol.64,no 3,p.304-314).(Liang X等人,J.Neurosci.2005;25:10180–10187);(Jin J等人,Journal of Neuroinflammation.2007)。
EP4受体
与EP2受体不同,EP4受体在包括免疫、骨关节、心血管、胃肠道和呼吸***以及癌细胞的多种组织和细胞中表达。最近的研究结果表明,EP4信号传导的调节可能涉及结肠癌(MUTOH,Michihiro等人,Cancer research,2002,vol.62,no 1,p.28-32.)、主动脉瘤(YOKOYAMA,Utako等人,PloS one,2012,vol.7,no 5,p.e36724.)、类风湿性关节炎(CHEN,Q.等人,British journal of pharmacology,2010,vol.160,no 2,p.292-310.)、骨质疏松症和自身免疫性疾病(YAO,Chengcan等人,Nature medicine,2009,vol.15,no 6,p.633.)的治疗策略。
因此,EP4信号传导的调节作为潜在的治疗靶标受到了更大的关注。
最近的报告表明,在某些类型的癌症中表达的EP4受体会促进肿瘤细胞的增殖和转移(YOKOYAMA等人,Pharmacological reviews,2013,vol.65,no 3,p.1010-1052)。
在乳腺癌中,研究表明肿瘤进展和转移由多种细胞事件导致,包括宿主抗肿瘤免疫细胞,比如天然杀伤(NK)和T细胞的失活,增加肿瘤相关巨噬细胞的免疫抑制功能,由于多种血管生成因子的上调,包括血管内皮生长因子(VEGF)-A、***生成增加(由于VEGF-C/D的上调)和干细胞的刺激,促进肿瘤细胞迁移、侵袭和肿瘤相关血管生成癌细胞中的样细胞(SLC)表型主要由激活肿瘤或宿主细胞上的***素(PG)E受体EP4介导,并且选择性EP4拮抗剂可以减轻所有这些在体外用细胞测试的事件以及体内表达COX-2的乳腺癌小鼠或携带COX-2过表达人乳腺癌异种移植物的免疫缺陷小鼠(MAJUMDER,Mousumi等人,International journal of molecular sciences,2018,vol.19,no 4,p.1019)。
EP4表达水平也与***癌细胞侵袭性相关,并且EP4特异性拮抗剂ONO-AE3-208可抑制细胞侵袭、迁移和骨转移(XU,Song等人,Cell biochemistry and biophysics,2014,vol.70,no 1,p.521-527)。
其他研究表明,抑制EP4通过下调CD24减弱肾细胞癌(RCC)血管内和转移,并且P-选择素参与肿瘤内渗(intravasation),这意味着这些分子有可能作为晚期RCC治疗的治疗靶标(ZHANG,Yushan等人,Cancer letters,2017,vol.391,p.50-58)。
EP4拮抗剂L-161,982在口腔鳞癌Tca8113细胞中诱导细胞凋亡、细胞周期停滞并抑制***素E2诱导的增殖(LI,Xiaohui等人,The Journal of Oral Pathology&Medicine,2017,vol.46,no 10,p.991-997)。
其他研究表明,EP4拮抗作用是一种对PGE2信号传导更具选择性的抑制作用,可减少肿瘤中癌症干细胞(CSC)的数量并增加肿瘤的化学敏感性。EP4拮抗作用通过触发细胞外囊泡/外泌体释放将CSC转化为对化疗敏感的非干细胞,并增强肿瘤对常规化疗的反应(LIN,Meng-Chieh等人,International Journal of Cancer,2018)。
此外,选择性EP4受体拮抗剂也有望通过抑制白细胞介素23(IL-23)产生和抑制T辅助细胞1(Th1)和T辅助细胞17(Th17)为自身免疫性疾病比如炎症性肠病(IBD)、类风湿性关节炎(RA)和多发性硬化症(MS)16-18提供有吸引力的治疗方法。
EP4受体在肝癌中的作用最近在非专利文献中有所报道。PGE2/EP4受体信号通过PKA/CREB激活上调c-Myc表达并导致体外HCC细胞中的细胞生长(XIA,Shukai等人,Oncology reports,2014,vol.32,no 4,p.1521-1530)。
PGE2激活的EP4受体信号可能涉及各种病理状态,比如疼痛(特别是炎症性、神经性和内脏)、炎症、神经保护、皮炎、骨病、睡眠的免疫***功能障碍促进、肾脏调节、胃或肠道粘液分泌和十二指肠碳酸氢盐分泌。研究表明,PGE2经由EP4受体抑制蛋白多糖合成并刺激骨关节炎软骨细胞中的基质降解。靶向EP4,而不是环氧化酶2,可能代表未来骨关节炎疾病改良的策略(ATTUR,Mukundan等人,The Journal of Immunology,2008,vol.181,no 7,p.5082-5088)。其他研究表明***素EP4受体的药理学阻断可能代表用于缓解骨关节炎和/或类风湿性关节炎的体征和症状的新型治疗策略(MURASE,Akio等人,Europeanjournal of pharmacology,2008,vol.580,no 1-2,p.116-121)。
另一方面,一些研究表明EP4受体在肾脏疾病发展中的作用。
从这个意义上说,最近的研究证明了PGE2 EP4受体选择性拮抗剂ASP7657在5/6肾切除大鼠(一种慢性肾脏疾病(CKD)模型)中的肾脏保护特性。这项研究表明ASP7657通过调节肾素释放和改善肾血流动力学来抑制慢性肾功能衰竭的进展(ELBERG,Dorit等人,Prostaglandins&other lipid mediators,2012,vol.98,no 1-2,p.11-16)。
其他研究公开了EP4拮抗剂可能主要通过减少肾小管细胞中Cxcl-5的产生从而减少肾嗜中粒细胞浸润来改善肾毒性血清肾炎NTS表型(ARINGER,Ida等人,AmericanJournal of Physiology-Renal Physiology,2018)。
在糖尿病和非糖尿病慢性肾脏疾病(CKD)的啮齿动物模型中,EP4抑制通过不同于广谱COX抑制或“标准护理”肾素血管紧张素***阻断的机制减轻肾损伤(THIEME,Karina等人,Scientific Reports,2017,vol.7,no 1,p.3442.)
最后,其他研究提到,在脂多糖(LPS)诱导的肾近端小管细胞损伤中,在帕立骨化醇预处理后,EP4通过Akt和NF-κB信号传导在抗炎和抗凋亡作用中发挥关键作用(HONG,YuAh等人,Kidney research and clinical practice,2017,vol.36,no 2,p.145)。
众所周知,***素E2(PGE2)有助于常染色体显性多囊肾脏疾病(ADPKD)的遗传非直系同源模型中的囊肿发生。PGE2激活缺乏多囊蛋白1(PC-1)的肾上皮细胞中的异常信号通路,这有助于ADPKD的增殖和分泌表型特征。拮抗EP4受体恢复了缺乏多囊蛋白-1(PC-1缺陷细胞)的肾上皮细胞的生长优势,暗示EP4受体在增殖中的核心作用(LIU,Yu等人,American Journal of Physiology-Renal Physiology,2012,vol.303,no 10,p.F1425-F1434)。
***素E2(PGE2)刺激人ADPKD细胞中的cAMP形成和囊肿形成。在分离的人ADPKD肾上皮细胞中进行的研究表明,PGE2的作用似乎是由EP2受体介导的,这表明EP2受体拮抗剂在治疗ADPKD的囊肿中具有治疗潜力。抑制EP2或EP4受体活性的***素E受体选择性拮抗剂可用作限制囊肿形成和ADPKD进展的药理学策略(ELBERG,Dorit等人,Prostaglandins&other lipid mediators,2012,vol.98,no 1-2,p.11-16)。
EP2和EP4受体调节也与多种疾病有关。
PGE2/EP2和PGE2/EP4信号通路的激活正调节肺癌患者浸润CD8+T细胞中的PD-1水平,从而在肺癌微环境中产生免疫耐受(WANG,Jinhong等人,Oncology letters,2018,vol.15,no 1,p.552-558)。
EP2/EP4激活与尿路上皮癌起始和生长的诱导以及化学抗性相关,大概是经由下调磷酸酶和张力蛋白同系物(PTEN)的表达。在BC系中,EP2/EP4拮抗剂和塞来昔布有效地抑制细胞活力和迁移,以及增强的PTEN表达(KASHIWAGI,Eiji等人,British journal ofcancer,2018,vol.118,no 2,p.213)。
众所周知,转移性乳腺癌细胞中S1P3受体的上调通过诱导PGE2和EP2/EP4激活来增加迁移和侵袭。(FILIPENKO,Iuliia等人,Biochimica et biophysica acta(BBA)-molecular and cell biology of lipids,2016,vol.1861,no 11,p.1840-1851)。
还已知人类***癌与EP4和EP2过表达和EP3表达降低有关(HUANG,Hosea FS等人,Significance of divergent expression of prostaglandin EP4 and EP3receptors in human prostate cancer.Molecular Cancer Research,2013,p.molcanres.0464.2012)。同样,其他研究表明,***素E2通过***素E2(EP2)介导和EP4介导的途径调节***癌中的肿瘤血管生成。(JAIN,Shalini等人,Cancer Research,2008,vol.68,no 19,p.7750-7759)。
其他研究提到PGE2通过包含EP2和EP4的信号通路增加SN12C细胞侵袭,促进肾癌细胞侵袭。(LI,Zhenyu等人,PGE2 promotes renal carcinoma cell invasion throughactivated RalA.Oncogene,2013,vol.32,no 11,p.1408)和(LI,Zhenyu等人,Oncogene,2013,vol.32,no11,p.1408)。
PGE2受体(EP2和EP4)激动剂促进黑素瘤细胞迁移,而PGE2受体拮抗剂抑制黑素瘤细胞的迁移能力,黑素瘤细胞是一种高度侵袭性的皮肤癌。(VAID,Mudit等人,Americanjournal of cancer research,2015,vol.5,no 11,p.3325)。
此外,已有证据表明EP2和EP4的抑制表明PGE2通过EP2和EP4受体在LoVo结肠癌细胞中诱导COX-2的蛋白表达。(HSU,Hsi-Hsien等人,International journal of molecularsciences,2017,vol.18,no 6,p.1132)。
其他研究表明,抑制EP2/EP4会降低子宫内膜异位症病变的生长和存活率;减少子宫内膜异位症病变的血管生成和神经支配;抑制背根神经节神经元的促炎性状态以减轻盆腔疼痛;减少子宫内膜和子宫内膜异位病变的促炎性、***主导和孕酮抗性分子环境;并通过多种机制恢复子宫内膜功能容受性(AROSH,Joe A.等人,Proceedings of theNational Academy of Sciences,2015,vol.112,no 31,p.9716-9721)(Banu,S.K.;Lee,J.;Speights,V.O.,Jr.;Starzinski-Powitz,A.;Arosh,J.A.Molecular Endocrinology2009,23,1291-1305),和新的选择性EP4拮抗剂已被确定用于治疗子宫内膜异位症Stefan等人,Identification of a Benzimidazolecarboxylic AcidDerivative(BAY 1316957)as a Potent and Selective Human Prostaglandin E2Receptor Subtype 4(hEP4-R)Antagonist for the Treatment ofEndometriosis.Journal of Medicinal Chemistry,2019)。
免疫反应中的EP2和EP4
在不同实体的肿瘤中,所有四种受体都是相关的,但EP2和EP4受体的表达在免疫细胞而不是组织驻留细胞上占主导地位。
PGE2诱导的EP2受体信号在抑制抗肿瘤免疫反应中也起着重要作用。事实上,PGE2对免疫细胞的大部分免疫调节作用是通过EP2和EP4受体信号传导的结果(KALINSKI,Pawel.The Journal of Immunology,2012,vol.188,no 1,p.21-28)。这可能是由于通过这两种受体的信号传导由相同的Gαs刺激蛋白转导,并且在激活后导致cAMP细胞内浓度增加。cAMP的这种增加被证明是抑制T辅助(TH)1细胞以及相关的IL-2和IFNγ减少的原因,这很重要,因为CD4+TH细胞代表癌症控制所需的适应性免疫***的关键效应臂。(O'CALLAGHAN,G.;HOUSTON,A.British journal of pharmacology,2015,vol.172,no 22,p.52)。
PGE2还以EP2和EP4受体介导的方式抑制NK细胞和细胞毒性T细胞(CTL)的活性(HOLT,Dawn等人,Journal of immunotherapy,2012,vol.35,no 2,p.179)两种细胞类型,它们也可以构成抗肿瘤免疫反应的一部分。此外,为了直接抑制免疫细胞的活性,通过EP2和EP4受体的信号传导促进了Treg细胞的发育。Treg细胞是免疫***的有效抑制剂,可抑制包括树突状细胞(DC)在内的众多免疫细胞的活性(NARENDRA,Bodduluru Lakshmi等人Inflammation Research,2013,vol.62,no 9,p.823-834)。DC在启动肿瘤特异性免疫反应中发挥核心作用,肿瘤中DC的存在与改善的预后相关。通过EP2(和EP4)受体的信号传导不仅通过Treg细胞的诱导阻断了DC的活性,而且还阻断了它们由单核细胞的生成,从而导致从单核细胞中发展出免疫抑制性MDSC(DE KEIJZER,Sandra等人,International journalof molecular sciences,2013,vol.14,no 4,p.6542-6555)。
PGE2/EP2和PGE2/EP4信号通路的激活正调节肺癌患者浸润CD8+T细胞中的PD-1水平。(WANG,Jinhong等人,Oncology letters,2018,vol.15,no 1,p.552-558)。
其他研究表明,甲状腺癌细胞产生的PGE2通过NK细胞上的EP2和EP4受体抑制NK激活受体的表达,抑制NK细胞的溶细胞活性。(PARK,Arum,et al.Frontiers in immunology,2018,vol.9)。
另一方面,已经表明EP4拮抗剂E704的特异性EP4阻断逆转了PGE2诱导的骨髓介导的免疫抑制,并且E7046与优先杀死Treg的IL-2-白喉毒素融合蛋白E7777结合协同减轻TME内的髓样和Treg衍生的免疫抑制,以促进强大的抗肿瘤免疫反应,提供可能有益于富含髓样和Treg细胞的肿瘤的癌症患者的联合疗法(ALBU,Diana I等人,Oncoimmunology,2017,vol.6,no 8,p.e1338239)。
因此,本发明要解决的问题是提供作为***素E2(PGE2)的EP4和/或EP2受体的调节剂的化合物。
本发明的作者发现了新型的N-苄基-2-苯氧基苯甲酰胺衍生物,它们可以方便地被取代为PGE2的EP4和/或EP2受体的有效调节剂。因此,该化合物可用于治疗通过调节EP4和/或EP2受体介导的疾病或病症,比如癌症、疼痛比如急性和慢性疼痛、炎症比如骨关节炎、类风湿性关节炎、神经退行性疾病、子宫内膜异位症和肾脏疾病。
发明内容
在第一方面(方面1)中,本发明涉及式(I)的新型的N-苄基-2-苯氧基苯甲酰胺衍生物和其药学上可接受的盐:
其中:
-A表示选自苯基和具有选自N、S和O的一个、两个或三杂原子的五元或六元杂芳基的基团,
-R1和R2独立地表示选自氢原子、卤素原子和C1-3烷基的基团,或R1和R2与它们所连接的碳原子一起形成C3-4环烷基基团,
-R3、R4、R5和每个R6独立地表示选自氢原子、卤素原子、氰基、直链或支链C1-3卤代烷基、直链或支链C1-3烷基、C3-4环烷基、直链或支链C1-3烷氧基和吡啶基的基团,
m是1至5的整数。
本发明的其他方面是:
方面2).用于制备方面1所述的化合物的方法。
方面3).包括治疗有效量的方面1所述的化合物的药物组合物。
方面4).根据方面3所述的药物组合物,进一步包括治疗有效量的化疗剂、消炎药、类固醇、免疫治疗剂和其他药剂比如治疗性抗体。
方面5).方面1所述的化合物,其用于治疗可通过调节***素E2(PGE2)的EP4和/或EP2受体而改善的疾病。
可通过调节EP4和/或EP2受体而改善的疾病可选自癌症、疼痛、炎症、神经退行性疾病和肾脏疾病。癌症优选地选自结肠癌、胃癌、***癌、肺癌、肝细胞癌、肾癌和乳腺癌。
方面6).方面1所述的化合物或方面3或4所述的药物组合物在制备用于治疗可通过调节EP4和/或EP2受体而改善的疾病的药物中的用途。
方面7).治疗或预防可通过调节EP4和/或EP2受体而改善的疾病的方法,其是通过向需要所述治疗的受试者施用方面1所述的化合物或方面3或4所述的药物组合物。
方面8).一种组合产物,其包括式(I)的化合物或其药学上可接受的盐和选自化疗剂、消炎药、类固醇、免疫抑制剂、治疗性抗体的一种或多种治疗剂,所述治疗剂可以用于与本申请的化合物组合用于治疗与调节***素E2的受体EP4和/或EP2相关的疾病、紊乱或病症。一种或多种另外的药物制剂可以同时或顺序地施用于患者。
示例性化疗剂包括蛋白酶体抑制剂(例如,硼替佐米),用于治疗CNS癌症的化疗剂,包括替莫唑胺、卡铂、卡莫司汀(BCNU)、顺铂、环磷酰胺、依托泊苷、依立替康、洛莫司汀(CCNU)、甲氨蝶呤、甲基苄肼、长春新碱和其他化疗剂比如沙利度胺、雷利度胺,和DNA损伤剂比如左旋溶肉瘤素、多柔比星、环磷酰胺、长春新碱、依托泊苷、卡莫司汀等。
示例性消炎化合物包括阿司匹林、水杨酸胆碱、塞来昔布、双氯芬酸钾、双氯芬酸钠、双氯芬酸钠与米索前列醇、二氟尼柳、依托度酸、非诺洛芬、氟比洛芬、布洛芬、酮洛芬、甲氯芬那酸钠、甲芬那酸、萘丁美酮、萘普生、萘普生钠、奥沙普秦、吡罗昔康、罗非考昔、双水杨酸、水杨酸钠、舒林酸、托美汀钠、伐地考昔等。
示例性类固醇包括皮质类固醇比如可的松、***、氢化可的松、甲基***龙、***龙、泼尼等。
示例性免疫抑制剂包括硫唑嘌呤、苯丁酸氮芥、环磷酰胺、环孢菌素、达利珠单抗、英夫利昔单抗、甲氨蝶呤、他克莫司等。
用于联合疗法的治疗性抗体的实例包括但不限于曲妥珠单抗(例如抗HER2)、雷珠单抗(例如抗VEGF-A)、贝伐单抗(例如抗VEGF)、帕尼单抗(例如抗EGFR)、西妥昔单抗(例如抗EGFR)、利妥昔单抗(抗CD20)和针对c-MET的抗体。
在仍另一方面,本发明涉及一种组合产物,其包括式(I)的化合物或其药学上可接受的盐,以及可用于治疗选自结肠癌、胃癌、***癌、肺癌和乳腺癌的癌症的一种或多种免疫治疗剂。
在优选的实施方式中,组合产物包括式(I)的化合物或其药学上可接受的盐,以及一种或多种免疫治疗剂,所述免疫治疗剂选自:抗CTLA4抗体,其选自伊匹单抗和曲美木单抗,抗PD1抗体比如纳武单抗、派姆单抗、西米普利单抗(cemiplimab)、匹利珠单抗、spartalizumab、MEDI0680、REGN2810和AMP-224,抗PDL1抗体比如阿特珠单抗(atezolizumab),阿维鲁单抗(avelumab)、杜伐鲁单抗(durvalumab)和MDX-1105,以及靶向糖脂GD2的单克隆抗体比如地努妥昔单抗。组合产物的组分在相同的制剂中或在分开的制剂中。
因此,本发明的衍生物和包括这种化合物和/或其盐的药学上可接受的盐和药物组合物可用于治疗人体的病理病症或疾病的方法中,该方法包括向需要所述治疗的受试者施用有效量的本发明的N-苄基-2-苯氧基苯甲酰胺衍生物或其药学上可接受的盐。
如前所述,本发明的N-苄基-2-苯氧基苯甲酰胺衍生物可用于治疗或预防已知易于通过用EP4调节剂和/或***素E2的EP2受体治疗而改善的疾病。这种疾病选自癌症,比如胃癌、结肠直肠癌、***癌、肺癌、肝细胞癌、肾癌和乳腺癌、疼痛、炎症、神经退行性疾病和肾脏疾病。
如本文使用的,术语卤素(halogen)原子包括氯、氟、溴或碘原子,优选地氟、氯或溴原子,更优选地氟或氯原子。当用作前缀时,术语卤代(halo)具有相同的含义。
如本文使用的,术语C1-3卤代烷基用于表示被一个或多个卤素原子,优选地一个、两个或三卤素原子取代的C1-3烷基。优选地,卤素原子选自氟或氯原子,更优选地氟原子。在优选的实施方式中,卤代烷基是被三个氟原子(三氟甲基)取代的C1烷基。
如本文使用的,术语C1-3烷基用于表示具有1至3个碳原子的直链或支链烃基(CnH2n+1)。实例包括甲基、乙基、正丙基、异丙基自由基。
如本文所使用的,术语Cn-Cm环烷基包括具有n至m个碳原子,例如3至6或3至4个碳原子的烃单环基团。这样的环烷基包括例如环丙基、环丁基、环戊基和环己基。
如本文所使用的,术语C1-3用于表示包含与氧原子连接的直链或支链C1-3烷基(CnH2n+1-O-)的基团。优选的烷氧基是甲氧基。
如本文所使用的,术语C3-4环烷氧基用于表示包含与氧原子连接的C3-4环烷基的基团(radical)。
如本文所使用的,术语五至六元杂芳基用于表示含有碳、氢和一个或多个,优选地选自N、O和S的一个、两个或三个杂原子作为环的一部分的杂芳环,比如呋喃、吡啶、嘧啶、吡嗪、吡咯、咪唑、吡唑、噁唑、噻唑和噻吩,优选地呋喃、吡啶、吡嗪、吡咯、咪唑、吡唑、噁唑、噻唑和噻吩。所述基团可以任选地被一个或多个根据在每种情况下定义的取代基取代。优选的基团是任选地取代的吡啶基、嘧啶基。当杂芳基带有两个或更多个取代基时,这些取代基可以相同或不同。
如本文所使用的,本发明的一般结构中存在的一些原子、基团、链或环是“任选地取代的”。这意味着这些原子、基团、链或环可以是未取代的或在任何位置被一个或多个,例如1、2、3或4个取代基取代,由此氢原子与未取代的原子、基团、链结合或环被化学上可接受的原子、自由基、链或环取代。当存在两个或更多个取代基时,每个取代基可以相同或不同。
如本文使用的,术语药学上可接受的盐用于表示与药学上可接受的碱结合的盐。药学上可接受的碱包括碱金属(例如钠或钾)、碱土金属(例如钙或镁)氢氧化物和有机碱,例如烷基胺、芳烷基胺和杂环胺。
术语“调节剂(modulator)”是指阻断或以其他方式干扰受体的特定生物活性的分子。
如本文所使用的,术语“Ki”是指引起对照特异性结合的半数最大抑制的浓度。Ki值可从IC50、测定中放射性配体的浓度和放射性配体对受体的亲和力估计。IC50值可以由适当的剂量反应曲线估计,更准确地说,IC50值可以使用非线性回归分析来确定。
根据本发明的一个实施方式,在式(I)化合物中,R1和R2独立地选自氢原子和C1-3烷基,或R1和R2与它们所连接的碳原子一起形成C3-4环烷基;R3选自氢原子和卤素原子;R4和R5表示氢原子。
根据本发明的一个实施方式,在式(I)的化合物中,R1、R2、R3、R4和R5表示氢原子。
根据本发明的一个实施方式,在式(I)的化合物中,A选自苯基、吡啶基、吡唑基、嘧啶基、苯硫基和呋喃基,优选地选自苯基、吡啶基、吡唑基、嘧啶基和苯硫基;更优选地选自苯基、吡啶基、嘧啶基和苯硫基;甚至更优选地选自苯基、吡啶基和苯硫基。
根据本发明的一个实施方式,A表示苯基。
在优选的实施方式中,每个R6独立地表示选自以下的基团:
a)氢原子,
b)卤素原子
c)氰基,
d)氨甲酰基(-CONH2)基,和
d)直链或支链C1-3卤代烷基。
在具体实施方式中,每个R6独立地表示选自以下的基团:
a)氢原子,
b)氟原子,
c)氯原子,
c)氰基,
d)氨甲酰基(-CONH2)基,和
d)三氟甲基。
在更优选的实施方式中,A表示苯基和每个R6独立地表示选自氟、三氟甲基和氰基的基团,并且m是1至4的整数。
根据本发明的另一个实施方式,A表示具有一个或两个N原子作为环的一部分的五元或六元杂芳环。在优选的实施方式中,A表示选自吡啶基或苯硫基的基团,每个R6独立地表示选自氟、三氟甲基和氰基的基团,并且m是1至4的整数。
根据本发明的另一个实施方式,R1、R2、R3、R4和R5表示氢原子,A表示苯基和每个R6独立地表示选自氟或三氟甲基的基团,和m是1至5的整数。
根据另一个实施方式,m是1至4的整数,优选地m是1至2的整数。
根据另一个实施方式,A表示选自苯基、吡啶基、嘧啶基、苯硫基的基团,R1、R2、R3、R4、R5是氢原子,每个R6独立地表示选自氢原子、氟、氯、氰基、三氟甲基和吡啶基的基团,并且m是1至2的整数。
本发明的具体单个化合物包括:
4-((2-(4-氟苯氧基)-5-(吡啶-4-基)苯甲酰胺基)甲基)苯甲酸
4-((4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((4'-氯-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((4'-氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((3'-氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((2'-氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((4'-氰基-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((3'-氰基-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(3-氟吡啶-4-基)苯甲酰胺基)甲基)苯甲酸)
4-((2-(4-氟苯氧基)-5-(吡啶-3-基)苯甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(3-氯吡啶-4-基)苯甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(嘧啶-5-基)苯甲酰胺基)甲基)苯甲酸
4-((3',4'-二氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((4-(4-氟苯氧基)-4'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((4-(4-氟苯氧基)-3'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(吡啶-2-基)苯甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(嘧啶-4-基)苯甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(苯硫-2-基)苯甲酰胺基)甲基)苯甲酸
4-((3',5'-二氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基))苯甲酸
4-((3'-氯-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((3'-氟-4-(4-氟苯氧基)-5'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((3'-氨甲酰基-5'-氯-4-(4-氟苯氧基)-[1,1'-联苯]-3-基甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(1H-吡唑-4-基)苯甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(1-甲基-1H-吡唑-4-基)苯甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(1-甲基-1H-吡唑-5-基)苯甲酰胺基)甲基)苯甲酸
4-((4-(4-氟苯氧基)-3'-(吡啶-4-基)-[1,1'-联苯]-3-基甲酰胺基)甲基)苯甲酸
4-((5-(5-氨基甲酰基呋喃-2-基)-2-(4-氟苯氧基)苯甲酰胺基)甲基)苯甲酸
3-氟-4-((4-(4-氟苯氧基)-3'-(三氟甲基)-[1,1'-联苯]-3-基甲酰胺基)甲基)苯甲酸
(R)-4-(1-(4-(4-氟苯氧基)-3'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)乙基)苯甲酸
4-(1-(4-(4-氟苯氧基)-3'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)环丙基)苯甲酸
4-((3'-氟-5'-氰基-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((3'-氯-5'-氰基-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸。
本发明的化合物可以通过使用下述方法制备。为便于描述过程,使用了具体的例子,但它们不以任何方式限制本发明的范围。
方案1
试剂和条件:(a)MeOH,H2SO4,70℃;b)NaH,DMF,120℃,过夜;c)NaOH,MeOH/H2O,室温,3小时;d)HATU,DIPEA,DCM,室温,过夜;e)[1,1′-双(二苯基膦)二茂铁]二氯钯(II),Cs2CO3,二噁烷/H2O,100℃,过夜,f)NaOH,MeOH/H2O,室温,过夜。
式(I)化合物可通过方案1中所述的合成路线来制备。
以式(II)的5-溴-2-氟苯甲酸衍生物开始,与甲醇反应生成酯(III),再与式(IV)的苯酚衍生物反应得到式(V)的化合物。
将式(V)的化合物在碱性含水条件下水解得到式(VI)的中间体,其在偶联剂比如HATU,式(VIII)前导化合物的存在下与式(VII)胺反应。通过在钯催化条件下与硼酸或硼酸酯反应,随后在碱性含水条件下水解,可以将式(VIII)的芳基溴转化为式(I)的化合物。
方案2
试剂和条件:g)[1,1′-双(二苯基膦)二茂铁]二氯钯(II),Cs2CO3,二噁烷/H2O,100℃,过夜,h)NaH,DMF,120℃,过夜;i)NaOH,MeOH/H2O,室温,过夜;)HATU,DIPEA,DCM,室温,过夜;k)NaOH,MeOH/H2O,室温,过夜。
在方案2中描述了式(I)的化合物的替代路线。在钯催化剂存在下将式(III)的芳基溴与硼酸、硼酸酯、锌试剂或三丁基锡烷试剂反应以产生式(X)的中间体。使用与方案1中描述的那些类似的反应,在碱性含水条件下将式(X)的化合物与苯酚(IV)水解后形成式(XI)的中间体,其在存在偶联剂比如HATU的情况下与式(VII)的胺反应以在碱性含水条件下水解后提供相应的式(I)的化合物。
本发明的化合物的合成通过以下实施例说明,包括中间体的制备,但不以任何方式限制本发明的范围。
缩写
在本申请中使用下述缩写,具有相应的定义:
RT:室温
HATU:N-[(二甲氨基)-1H-1,2,3-***并-[4,5-b]吡啶-1-基亚甲基]-N-甲基甲胺六氟磷酸盐N-氧化物
DIPEA:N,N-二异丙基乙胺
DMF:二甲基甲酰胺
DCM:二氯甲烷
THF:四氢呋喃
DMSO:二甲基亚砜
药理活性
结果
测定本发明化合物与人EP1、EP2、EP3和EP4受体的结合,并在几种浓度下测试IC50测定。
人类EP1受体中的竞争结合:
***素EP1受体竞争结合实验在具有结合缓冲液(Mes 10mM,EDTA 1mM,MgCl21mM,pH=6.0)的聚丙烯96孔微孔板中进行。在每个孔中温育10μg来自HEK-EP1细胞系并在我们实验室制备的膜(批号:A003/19-10-2011,蛋白质浓度=1756μg/ml)、3nM[3H]-***素E2(169.8Ci/mmol,0.1mCi/ml,Perkin Elmer NET428250UC)和研究的化合物以及标准品。在PGE2 10μM(Cayman 14010)存在下测定非特异性结合。将反应混合物(Vt:250μl/孔)在25℃下温育60分钟,过滤后将200μL转移至GF/C 96孔板(Millipore,Madrid,Spain)并用250μl洗涤缓冲液洗涤四次缓冲液(Mes 10mM,EDTA 1mM,MgCl2 1mM,pH=6.0),然后在微孔板β闪烁计数器(Microbeta Trilux,PerkinElmer,Madrid,Spain)中测量。(Abramovitz等人,Biochim Biophys Acta 2000;1483:285-293)。
人类EP2受体中的竞争结合:
***素EP2受体竞争结合实验在具有结合缓冲液(Hepes 50mM,CaCl2 1mM,MgCl25mM,pH=7.4)的聚丙烯96孔微孔板中进行。在每个孔中温育10μg来自EP2细胞系的膜(Millipore HTS185M,蛋白质浓度=2000μg/ml)、7.5nM[3H]-***素E2(169.8Ci/mmol,0.1mCi/ml,Perkin Elmer NET428250UC)和研究的化合物和标准品。在PGE2 200μM(Cayman14010)存在下测定非特异性结合。将反应混合物(Vt:250μl/孔)在25℃下温育90分钟,过滤后将200μL转移至GF/C 96孔板(Millipore,Madrid,Spain)并用250μl洗涤缓冲液(Hepes50mM,NaCl 500mM,pH=7.4)洗涤四次,然后在微孔板β闪烁计数器(Microbeta Trilux,PerkinElmer,Madrid,Spain)中测量。(Wilson等人,Br J Pharmacol 2006;148:326-339)。
人类EP3受体中的竞争结合:
***素EP3受体竞争结合实验在用结合缓冲液(Tris-HCl 50mM,MgCl2 10mM,EDTA 1mM,pH=7.4)预处理的多屏GF/C 96孔板(Millipore,Madrid,Spain)中进行。在每个孔中温育5μg来自EP3细胞系的膜(Millipore;HTS092M,蛋白质浓度=2000μg/ml)、1.5nM[3H]-***素E2(169.8Ci/mmol,0.1mCi/ml,Perkin Elmer NET428250UC)和研究的化合物和标准品。在PGE2 200μM(Cayman 14010)存在下测定非特异性结合。将反应混合物(Vt:250μl/孔)在25℃下温育90分钟,过滤后将200μl转移到GF/C 96孔板(Millipore,Madrid,Spain)并用250μl洗涤缓冲液(Tris-HCl 50mM,pH=7.4)洗涤四次,然后在微孔板β闪烁计数器(Microbeta Trilux,PerkinElmer,Madrid,Spain)中测量。(Audoly等人,MolPharmacol 1997;51:61-68)。
人类EP4受体中的竞争结合:
***素EP4受体竞争结合实验在用结合缓冲液(Mes 25mM,EDTA1mM,MgCl210mM,pH=6.0)预处理的多屏GF/B 96孔板(Millipore,Madrid,Spain)中进行。在每个孔中温育35μg来自HEK-EP4细胞系并在我们实验室制备的膜(批号:A003/27-04-2011,蛋白质浓度=2803μg/ml)、1nM[3H]-***素E2(169.8Ci/mmol,0.1mCi/ml,Perkin ElmerNET428250UC)和研究的化合物和标准品。在PGE2 10μM(Cayman 14010)存在下测定非特异性结合。将反应混合物(Vt:250μl/孔)在25℃下温育120分钟,过滤后将200μl转移到GF/B96孔板(Millipore,Madrid,Spain)并用250μl洗涤缓冲液(Mes 25mM,BSA 0.01%,pH=6.0)洗涤六次,然后在微孔板β闪烁计数器(Microbeta Trilux,PerkinElmer,Madrid,Spain)中测量。(Abramovitz等人,Biochim Biophys Acta 2000;1483:285-293)。
使用Cheng Prusoff方程计算抑制常数(Ki)
其中L=测定中放射性配体的浓度,和KD=放射性配体对受体的亲和力。使用scatchard图来确定KD。
本发明的化合物对受体EP1和EP3没有表现出任何显著的结合亲和力。
表1显示了本发明的一些化合物对受体EP2和EP4的Ki值。
Ki范围:A<0.1μM;0.1μM<=B<1μM;1μM<=C<10μM,D>=10μM
表1
从表1中描述的结果可以看出,本发明的化合物与***素E2的EP4和/或EP2受体有效结合。
本发明的化合物可用于治疗或预防已知易于通过调节EP4和/或EP2受体而改善的疾病。这种疾病选自癌症、疼痛、炎症、神经退行性疾病和肾脏疾病。
因此,本发明的化合物及其盐用于制备用于治疗或预防已知易于通过调节EP4和/或EP2受体而改善的疾病的药物。
因此,本发明的衍生物及其药学上可接受的盐和包含这种化合物和/或其盐的药物组合物可用于治疗或预防已知易于通过调节EP4和/或EP2受体而改善的人体病症的方法,所述方法包括向需要这种治疗或预防的受试者施用有效量的本发明的N-苄基-2-苯氧基苯甲酰胺衍生物或其药学上可接受的盐。
化合物、药物或药理活性剂的“有效量(effective amount)”或“治疗有效量(therapeutically effective amount)”是指无毒但足以提供所需效果的化合物、药物或药剂的量。“有效(effective)”的量将因个体而异,取决于个体的年龄和全身状况、特定的一种或多种活性剂等。因此,并不总是能够指定准确的“有效量”。然而,本领域普通技术人员可以使用常规实验来确定在任何个别情况下合适的“有效”量。
本发明化合物的一种治疗用途是治疗增殖性疾病或病症,例如癌症。癌症选自结肠癌、胃癌、***癌、肺癌、肝细胞癌、肾癌和乳腺癌。
本发明还提供了药物组合物,其包含作为活性成分的至少式(I)的N-苄基-2-苯氧基苯甲酰胺衍生物或与其他治疗剂和药学上可接受的赋形剂比如载体或稀释剂结合的其药学上可接受的盐。取决于制剂的性质以及在施用前是否要进一步稀释,按组合物的重量计,活性成分可以占0.001%至99%,优选地0.01%至90%。优选地,组合物制成适合于口服、局部、鼻、直肠、经皮或注射施用的形式。
与活性化合物或此类化合物的盐混合以形成本发明的组合物的药学上可接受的赋形剂本身是众所周知的,并且所使用的实际赋形剂取决于施用组合物的预期方法等等。
本发明的组合物优选适用于注射和经口施用。在这种情况下,用于口服施用的组合物可以采取片剂、缓凝剂(retard)片剂、舌下片剂、胶囊剂、吸入气雾剂、吸入溶液、干粉吸入剂或液体制剂的形式,比如混合物、酏剂、糖浆剂或混悬剂,均含有本发明的化合物;这种制剂可通过本领域众所周知的方法制备。
如果需要,可用于制备组合物的稀释剂包括与活性成分相容的那些液体和固体稀释剂,以及着色剂或调味剂。片剂或胶囊可方便地含有2至500mg活性成分或其等量的盐。
适于口服使用的液体组合物可以是溶液或悬浮液的形式。溶液可以是活性化合物的可溶性盐或其它衍生物与例如蔗糖结合以形成糖浆的水溶液。悬浮液可以包含与水结合的本发明的不溶性活性化合物或其药学上可接受的盐,以及悬浮剂或调味剂。
肠胃外注射组合物可由可溶性盐制备,其可以冷冻干燥或不冷冻干燥,并且可以溶解在无热原的水性介质或其他合适的肠胃外注射液中。
有效剂量通常在每天2-2000mg活性成分的范围内。日剂量可以以每天一次或多次治疗施用,优选地1到4次治疗。
本发明将通过以下实施例进一步说明。以下以说明的方式给出,并且无论如何不限制本发明的范围。
实施例
通用程序(General).试剂、溶剂和起始产物由商业来源获取。术语“浓缩”是指使用Büchi旋转蒸发仪进行真空蒸发。当指示时,反应产物通过硅胶(40-63μm)上的“快速”色谱法用指示的溶剂***纯化。光谱数据在Varian Mercury 400光谱仪中测量。HPLC-MS在Büchi 535仪器中测量。HPLC-MS在配备有Gilson 321活塞泵、Gilson 864真空脱气机、Gilson189进样模块、1/1000Gilson分流器、Gilson 307泵、Gilson 170检测器和ThermoquestFennigan aQa检测器的Gilson仪器上进行。
中间体1:4-(叠氮甲基)-3-氟苯甲酸甲酯
将4-(溴甲基)-3-氟苯甲酸甲酯(100mg,1.0eq)和叠氮化钠(29mg,1.2eq)在DMF(1.0mL)中的溶液在80℃下搅拌90min。一旦冷却,将反应物用盐水(3mL)稀释并用乙酸乙酯(3×10mL)萃取。将合并的有机溶液用水(25mL)和盐水(25mL)洗涤,经Na2SO4干燥,过滤并在减压下浓缩。获得呈浅黄色液体(定量)的期望的叠氮化物,其无需进一步纯化即可用于下一步。
1H-NMR(400MHz,DMSO-d6):δ=7.82(dd,1H),7.74(dd,1H),7.64(t,1H),4.62(s,2H),3.87(s,3H)。
HPLC-MS:Rt 2.65 m/z 182.0(MH+)
中间体2:4-(氨甲基)-3-氟苯甲酸甲酯
将4-(叠氮甲基)-3-氟苯甲酸甲酯(110mg,1.0eq)、三苯基膦(189mg,1.2eq)和水(0.9mL)在THF(2mL)中的溶液在室温下搅拌20小时。在减压下除去溶剂,并通过快速柱色谱法(二氯甲烷:甲醇,30:1)纯化,得到呈黄色蜡的4-(氨甲基)-3-氟苯甲酸甲酯(70mg,产率63.7%)。
1H-NMR(400MHz,DMSO-d6):δ=7.78(dd,1H),7.67(t,1H),7.61(dd,1H),3.85(s,3H),3.80(s,2H),1.96(s,2H)。
HPLC-MS:Rt 1.63 m/z 184.1(MH+)
中间体-3:4-氟-[1,1’-联苯]-3-羧酸甲酯
向4-氟-[1,1'-联苯]-3-羧酸(200.0mg,0.93mmol)在甲醇(1mL)中的溶液加入催化量的H2SO4,并将反应物在70℃下搅拌过夜。将溶液在水和乙酸乙酯之间分配,并用饱和NaHCO3和盐水洗涤有机层。经无水硫酸钠干燥,过滤并浓缩,以得到呈油状的中间体1(167.0mg,76.0%)。
1H-NMR(400MHz,DMSO-d6):δ=8.09(dd,1H),7.96(ddd,1H),7.68(d,2H),7.46(m,2H),3.89(s,3H)。
HPLC-MS:Rt 5.337 m/z 231.0(MH+)
使用针对中间体3所描述的程序合成以下中间体:
中间体4:5-溴-2-氟苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=7.98(dd,1H),7.87(m,1H),7.37(dd,1H),3.86(s,3H)。
中间体5:5-溴-2-(4-氟苯氧基)苯甲酸甲酯
向4-氟苯酚(481.0mg,4.29mmol)和***(171.6mg,4.29mmol)在N,N-二甲基甲酰胺中的搅拌溶液加入5-溴-2-氟苯甲酸甲酯(1000mg,4.29mmol)在N,N-二甲基甲酰胺中的溶液。将溶液在120℃下加热,并搅拌16小时。在冷却至室温之后,将混合物用水(20mL)稀释并用乙酸乙酯(3×20mL)萃取。将有机层经硫酸钠干燥,过滤并在减压下浓缩,以得到呈淡黄色油的标题化合物(1028.3mg,73.7%)。
1H-NMR(400MHz,DMSO-d6):δ=7.95(d,1H),7.75(dd,1H),7.22(m,2H),7.04(m,2H),6.95(d,1H),3.75(s,3H)。
HPLC-MS:Rt 5.602 m/z 326.9(MH+)
使用针对中间体5所描述的程序以及相应的甲酯和4-氟苯酚合成以下中间体:
中间体6:4-(4-氟苯氧基)-[1,1’-联苯]-3-羧酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=8.07(d,1H),7.88(dd,1H),7.68(d,2H),7.49(t,2H),7.39(t,1H),7.23(t,2H),7.10(s,1H),7.06(m,2H),3.77(s,3H)。
HPLC-MS:Rt 5.948 m/z 323.0(MH+)
中间体7:5-溴-2-(4-氟苯氧基)苯甲酸
向5-溴-2-(4-氟苯氧基)苯甲酸甲酯(1101.3mg,3.39mmol)在甲醇(8mL)和THF(8mL)中的溶液加入NaOH 2M(8.5mL,16.94mmol),并将混合物在室温下搅拌3小时。将溶液用水(15mL)稀释,并通过加入HCl 1M将pH值调节至4.0。将混合物用乙酸乙酯(3×50mL)萃取,并将合并的有机层用硫酸钠干燥并浓缩,用戊烷洗涤得到白色固体(823.5mg,78.1%)。
1H-NMR(400MHz,DMSO-d6):δ=13.24(s,1H),7.92(s,1H),7.72(d,1H),7.21(t,2H),7.01(s,2H),6.94(d,1H)。
HPLC-MS:Rt 3.087 m/z 312.9(MH+)
使用针对中间体7所描述的程序和相应的甲酯合成以下中间体:
中间体8:4-(4-氟苯氧基)-[1,1'-联苯]-3-羧酸
1H-NMR(400MHz,DMSO-d6):δ=13.04(s,1H),8.06(d,1H),7.84(dd,1H),7.68(d,2H),7.48(t,2H),7.39(t,1H),7.22(t,2H),7.04(m,3H)。
HPLC-MS:Rt 3.435 m/z 309.0(MH+)
中间体9:4-(4-氟苯氧基)-3'-(三氟甲基)-[1,1'-联苯]-3-羧酸
1H-NMR(400MHz,DMSO-d6):δ=13.09(s,1H),8.13(d,1H),7.95(m,4H),7.72(m,2H),7.23(m,2H),7.05(m,2H)。
HPLC-MS:Rt2.20 m/z 377.0(MH+)
中间体10:4-((5-溴-2-(4-氟苯氧基)苯甲酰胺基)甲基)苯甲酸甲酯
向5-溴-2-(4-氟苯氧基)苯甲酸(600mg,1.93mmol)在无水DCM(15mL)中的溶液加入HATU(880.0mg,2.30mmol)和DIPEA(1.31mL,7.71mmol)。在室温下在N2中将反应物搅拌15分钟之后,加入4-(氨甲基)苯甲酸甲酯盐酸盐(466.7mg,2.30mmol),并将反应物在室温下搅拌过夜。在加入20ml H2O之后,将水相用DCM 3×20mL萃取。将合并的有机相经无水硫酸钠干燥、过滤并浓缩,以得到白色固体(728.5mg,82.4%)。
1H-NMR(400MHz,DMSO-d6):δ=8.97(t,1H),7.85(d,2H),7.79(d,1H),7.63(dd,1H),7.38(d,2H),7.24(t,2H),7.11(dd,2H),6.86(d,1H),4.51(d,2H),3.83(s,3H)。
HPLC-MS:Rt 5.523 m/z 459.0(MH+)
使用针对中间体10所描述的程序和相应的化学试剂或衍生物合成以下中间体:
中间体11:(R)-4-(1-(5-溴-2-(4-氟苯氧基)苯甲酰胺基)乙基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=8.89(d,1H),7.84(d,2H),7.69(d,1H),7.62(dd,1H),7.45(d,2H),7.22(t,2H),7.07(m,2H),6.89(d,1H),5.08(p,1H),3.83(s,3H),1.38(d,3H)。
HPLC-MS:Rt 3.21 m/z 473.9(MH+)
中间体12:4-(1-(5-溴-2-(4-氟苯氧基)苯甲酰胺基)环丙基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.13(s,1H),7.78(s,1H),7.76(d,2H),7.65(dd,1H),7.24(m,4H),7.08(m,2H),6.95(d,1H),3.82(s,3H),1.28(m,2H),1.21(m,2H)。
HPLC-MS:Rt3.18 m/z 485.9(MH+)
中间体13:4-((4-(4-氟苯氧基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=8.96(t,1H),7.93(d,1H),7.86(d,2H),7.76(dd,1H),7.68(d,2H),7.48(t,2H),7.39(m,3H),7.25(t,2H),7.13(m,2H),7.00(d,1H),4.54(d,2H),3.84(s,3H)。
HPLC-MS:Rt 5.843 m/z 456.1(MH+)
中间体14:4-((5-溴-2-(4-氟苯氧基)苯甲酰胺基)甲基)苯甲酸
向4-((5-溴-2-(4-氟苯氧基)苯甲酰胺基)甲基)苯甲酸甲酯(200mg,1.0eq)在THF(2.0mL)和甲醇(2.0mL)中的溶液加入NaOH(2M)(1.1mL,5.0eq)),并将混合物在室温下搅拌20小时。在用水(10mL)稀释之后,将混合物用HCl水溶液中和,过滤,并用水和戊烷洗涤,以获得呈白色固体的酸(176mg,产率90.9%)。
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),8.98(t,1H),7.82(m,3H),7.63(dd,1H),7.32(m,2H),7.24(m,2H),7.12(m,2H),6.86(d,1H),4.49(d,2H)。
HPLC-MS:Rt 1.26 m/z 444.0(MH+)
中间体15:4-((2-(4-氟苯氧基)-5-(吡啶-4-基)苯甲酰胺基)甲基)苯甲酸甲酯
向4-((5-溴-2-(4-氟苯氧基)苯甲酰胺基)甲基)苯甲酸甲酯(70.0mg,0.15mmol)在二噁烷、吡啶-4-硼酸(37.6mg,0.31mmol)、[1,1′-双(二苯基膦)二茂铁]二氯钯(II)(7.5mg,0.009mmol)中的溶液加入Cs2CO3 2M(0.23mL,0.46mmol)。将混合物用N2脱气,并在100℃下搅拌过夜。然后,通过硅藻土过滤反应物,并用乙酸乙酯萃取。将有机部分用NaOH1M、饱和NaHCO3和盐水洗涤,并经无水硫酸钠干燥。在真空下除去溶剂并使用快速色谱法(己烷:乙酸乙酯1:1)纯化残余物。除去溶剂,用戊烷/二***洗涤,得到呈白色固体的产物(44.7mg,65.3%)。
1H-NMR(400MHz,DMSO-d6):δ=9.00(t,1H),8.65(d,2H),8.08(d,1H),7.89(m,3H),7.75(d,2H),7.42(d,2H),7.27(m,2H),7.17(m,2H),7.01(d,1H),4.56(d,2H),3.84(s,3H)。
HPLC-MS:Rt 4.875 m/z 457.1(MH+)
使用相应的化学试剂或衍生物,使用针对中间体15描述的程序合成以下中间体:
中间体16:4-((4’-氯-4-(4-氟苯氧基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=8.99(t,1H),7.92(d,1H),7.85(d,2H),7.74(m,3H),7.51(t,2H),7.39(d,2H),7.25(t,2H),7.12(m,2H),6.99(d,1H),4.53(d,2H),3.83(s,3H)。
HPLC-MS:Rt 6.203 m/z 490.1(MH+)
中间体17:4-((4’-氟-4-(4-氟苯氧基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=8.98(s,1H),7.86(m,3H),7.72(s,3H),7.37(m,2H),7.27(m,4H),7.12(s,2H),6.98(d,1H),4.53(d,2H),3.83(s,3H)。
HPLC-MS:Rt 5.945 m/z 474.1(MH+)
中间体18:4-((3’-氟-4-(4-氟苯氧基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=8.99(s,1H),7.95(d,1H),7.85(d,2H),7.80(dd,1H),7.53(t,3H),7.40(d,2H),7.24(dd,3H),7.13(dd,2H),6.98(d,1H),4.54(d,2H),3.83(s,3H)。
HPLC-MS:Rt 5.963 m/z 474.1(MH+)
中间体19:4-((2’-氟-4-(4-氟苯氧基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=8.99(s,1H),7.85(d,3H),7.64(d,1H),7.57(s,1H),7.40(d,3H),7.30(m,4H),7.17(s,2H),6.98(d,1H),4.54(d,2H),3.83(s,3H)。
HPLC-MS:Rt 5.936 m/z 474.1(MH+)
中间体20:4-((4’-氰基-4-(4-氟苯氧基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.01(t,1H),8.02(d,1H),7.93(m,4H),7.85(m,3H),7.41(d,2H),7.27(t,2H),7.16(m,2H),7.00(d,1H),4.55(d,2H),3.83(s,3H)。
HPLC-MS:Rt 5.649 m/z 481.1(MH+)
中间体21:4-((3’-氰基-4-(4-氟苯氧基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.00(t,1H),8.20(s,1H),8.04(dd,2H),7.85(t,4H),7.68(t,1H),7.41(d,2H),7.27(t,2H),7.15(dd,2H),7.00(d,1H),4.55(d,2H),3.84(s,3H)。
HPLC-MS:Rt 5.668 m/z 481.1(MH+)
中间体22:4-((2-(4-氟苯氧基)-5-(3-氟吡啶-4-基)苯甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.03(t,1H),8.67(d,1H),8.51(d,1H),7.97(s,1H),7.86(d,2H),7.77(d,1H),7.68(dd,1H),7.42(d,2H),7.29(dd,2H),7.20(m,2H),7.01(d,1H),4.56(d,2H),3.83(s,3H)。
HPLC-MS:Rt 5.199 m/z 475.1(MH+)
中间体23:4-((2-(4-氟苯氧基)-5-(吡啶-3-基)苯甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.00(t,1H),8.92(d,1H),8.58(dd,1H),8.11(m,1H),7.99(d,1H),7.84(m,3H),7.50(dd,1H),7.41(d,2H),7.26(t,2H),7.14(m,2H),7.02(d,1H),4.54(d,2H),3.83(s,3H)。
HPLC-MS:Rt 5.015 m/z 457.1(MH+)
中间体24:4-((2-(4-氟苯氧基)-5-(3-氯吡啶-4-基)苯甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.02(t,1H),8.75(s,1H),8.59(d,1H),7.86(d,2H),7.84(d,1H),7.64(dd,1H),7.53(d,1H),7.42(d,2H),7.30(t,2H),7.21(m,2H),6.98(d,1H),4.55(d,2H),3.83(s,3H)。
HPLC-MS:Rt 5.378 m/z 491.1(MH+)
中间体25:4-((2-(4-氟苯氧基)-5-(嘧啶-5-基)苯甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.18(m,3H),9.02(t,1H),8.08(d,1H),7.88(m,3H),7.42(d,2H),7.27(t,2H),7.15(m,2H),7.04(d,1H),4.55(d,2H),3.83(s,3H)。
HPLC-MS:Rt 4.715 m/z 458.1(MH+)
中间体26:4-((3’,4’-二氟-4-(4-氟苯氧基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=8.98(t,1H),7.95(d,1H),7.81(m,4H),7.53(m,2H),7.40(d,2H),7.26(t,2H),7.13(m,2H),6.98(d,1H),4.54(d,2H),3.83(s,3H)。
HPLC-MS:Rt 5.977 m/z 492.1(MH+)
中间体27:4-((4-(4-氟苯氧基)-4’-(三氟甲基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.02(t,1H),8.01(d,1H),7.93(d,2H),7.84(m,5H),7.41(d,2H),7.27(dd,2H),7.16(m,2H),7.01(d,1H),4.55(d,2H),3.83(s,3H)。
HPLC-MS:Rt 6.223 m/z 524.1(MH+)
中间体28:4-((4-(4-氟苯氧基)-3’-(三氟甲基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.00(t,1H),8.01(m,3H),7.85(d,3H),7.71(m,2H),7.40(d,2H),7.26(t,2H),7.15(dd,2H),7.01(d,1H),4.55(d,2H),3.83(s,3H)。
HPLC-MS:Rt 6.199 m/z 524.1(MH+)
中间体29:4-((2-(4-氟苯氧基)-5-(苯硫-2-基)苯甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=8.99(t,1H),7.90(d,1H),7.85(d,2H),7.74(dd,1H),7.56(d,1H),7.52(d,1H),7.39(d,2H),7.25(t,2H),7.13(m,3H),6.95(d,1H),4.52(d,2H),3.83(s,3H)。
HPLC-MS:Rt 3.21 m/z 462.1(MH+)
中间体30:4-((3’,5’-二氟-4-(4-氟苯氧基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.00(t,1H),8.00(d,1H),7.84(m,3H),7.48(m,2H),7.41(d,2H),7.25(m,3H),7.14(m,2H),6.97(d,1H),4.54(d,2H),3.83(s,3H)。
HPLC-MS:Rt 3.31 m/z 492.21(MH+)
中间体31:4-((3’-氯-4-(4-氟苯氧基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=8.99(t,1H),7.96(d,1H),7.86(d,2H),7.80(dd,1H),7.76(m,1H),7.66(d,1H),7.50(t,1H),7.43(m,3H),7.25(m,2H),7.14(m,2H),6.87(d,1H),4.54(d,2H),3.83(s,3H)。
HPLC-MS:Rt 3.41 m/z 490.16(MH+)
中间体32:4-((3’-氟-4-(4-氟苯氧基)-5’-(三氟甲基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.01(t,1H),8.06(d,1H),7.95(d,1H),7.88(m,4H),7.67(d,1H),7.41(d,2H),7.26(m,2H),7.15(m,2H),7.00(d,1H),4.55(d,2H),3.83(s,3H)。
HPLC-MS:Rt 3.48 m/z 542.21(MH+)
中间体33:4-((3’-氰基-5’-氟-4-(4-氟苯氧基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.00(t,1H),8.12(s,1H),8.07(d,1H),8.00(m,1H),7.88(m,4H),7.42(d,2H),7.26(m,2H),7.15(m,2H),6.99(d,1H),4.53(d,2H),3.83(s,3H)。
HPLC-MS:Rt 3.13 m/z 499.21(MH+)
中间体34:4-((3’-氯-5’-氰基-4-(4-氟苯氧基)-[1,1’-联苯]-3-甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.00(t,1H),8.22(d,1H),8.16(t,1H),8.05(m,2H),7.87(m,3H),7.42(d,2H),7.27(m,2H),7.15(m,2H),6.98(d,1H),4.55(d,2H),3.84(s,3H)。
HPLC-MS:Rt 3.26 m/z 515.1(MH+)
中间体35:4-((2-(4-氟苯氧基)-5-(1H-吡唑-4-基)苯甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=12.83(s,1H),8.99(t,1H),7.82(m,4H),7.62(m,2H),7.36(dd,2H),7.24(m,2H),7.12(m,2H),6.86(d,1H),4.50(d,2H),3.83(s,3H)。
HPLC-MS:Rt 2.03 m/z 446.0(MH+)
中间体36:4-((2-(4-氟苯氧基)-5-(1-甲基-1H-吡唑-4-基)苯甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=8.92(t,1H),8.18(s,1H),7.84(m,4H),7.64(dd,1H),7.37(d,2H),7.21(m,2H),7.06(m,2H),6.93(d,1H),4.51(d,2H),3.86(s,3H),3.83(s,3H)。
HPLC-MS:Rt 2.70 m/z 460.2(MH+)
中间体37:4-((2-(4-氟苯氧基)-5-(1-甲基-1H-吡唑-5-基)苯甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.01(t,1H),7.85(d,2H),7.77(d,1H),7.61(dd,1H),7.48(d,1H),7.40(d,2H),7.26(m,2H),7.17(m,2H),6.98(d,1H),6.43(d,1H),4.54(d,2H),3.86(s,3H),3.83(s,3H)。
HPLC-MS:Rt 2.73 m/z 460.13(MH+)
中间体38:4-((4-(4-氟苯氧基)-3’-(吡啶-4-基)-[1,1’-联苯]-3-基甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.00(t,1H),8.66(dd,2H),8.06(m,2H),7.85(m,7H),7.63(t,1H),7.40(d,2H),7.25(m,2H),7.14(m,2H),7.02(d,1H),4.55(d,2H),3.83(s,3H)。
HPLC-MS:Rt 3.06 m/z 533.2(MH+)
中间体39:4-((5-(5-氰基呋喃-2-基)-2-(4-氟苯氧基)苯甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.02(t,1H),8.10(s,1H),7.87(m,3H),7.42(m,3H),7.28(m,4H),7.18(m,2H),6.97(d,1H),4.55(d,2H),3.83(s,3H)。
HPLC-MS:Rt 3.08 m/z 471.1(MH+)
中间体40:3-氟-4-((4-(4-氟苯氧基)-3’-(三氟甲基)-[1,1’-联苯]-3-基甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.01(t,1H),8.01(m,2H),7.86(dd,1H),7.74(dd,2H),7.67(m,2H),7.44(t,1H),7.25(m,2H),7.15(m,2H),7.01(d,1H),4.55(d,2H),3.85(s,3H)。
中间体41:(R)-4-(1-(4-(4-氟苯氧基)-3’-(三氟甲基)-[1,1’-联苯]-3-甲酰胺基)乙基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=8.89(d,1H),8.01(m,2H),7.91(d,1H),7.84(m,3H),7.72(m,2H),7.48(d,2H),7.24(t,2H),7.11(m,2H),7.03(d,1H),5.14(p,1H),3.83(s,3H),1.41(d,3H)。
HPLC-MS:Rt3.51 m/z 538.0(MH+)
中间体42:4-(1-(4-(4-氟苯氧基)-3’-(三氟甲基)-[1,1’-联苯]-3-甲酰胺基)环丙基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.13(s,1H),8.04(d,2H),7.96(d,1H),7.86(dd,1H),7.75(m,4H),7.27(m,4H),7.13(dd,2H),7.09(d,1H),3.82(s,3H),1.32(t,2H),1.25(t,2H)。
HPLC-MS:Rt 3.48 m/z 550.0(MH+)
中间体43:4-((2-(4-氟苯氧基)-5-(吡啶-2-基)苯甲酰胺基)甲基)苯甲酸甲酯
向4-((5-溴-2-(4-氟苯氧基)苯甲酰胺基)甲基)苯甲酸甲酯(100.0mg,0.22mmol)和四(三苯基膦)钯(0)(15.1mg,0.013mmol)在干燥二噁烷(1.5mL)中的溶液加入2-(三丁基甲锡烷基)吡啶(113.4mg,0.26mmol)。将混合物用N2吹扫并在室温下搅拌2天。将反应物用乙酸乙酯稀释,并用NaOH 2M洗涤。将有机层经无水硫酸钠干燥、过滤并浓缩,并通过快速色谱法(己烷:乙酸乙酯1:1)纯化残余物,得到白色固体。将产物用戊烷/二***洗涤(40.3mg,40.5%)。
1H-NMR(400MHz,DMSO-d6):δ=9.00(t,1H),8.66(d,1H),8.39(d,1H),8.16(dd,1H),7.98(d,1H),7.90(dd,1H),7.86(d,2H),7.42(d,2H),7.36(dd,1H),7.27(t,2H),7.17(dd,2H),6.98(d,1H),4.56(d,2H),3.84(s,3H)。
HPLC-MS:Rt 5.308 m/z 457.1(MH+)
使用针对中间体43所描述的程序和相应的化学试剂或衍生物合成以下中间体:
中间体44:4-((2-(4-氟苯氧基)-5-(嘧啶-4-基)苯甲酰胺基)甲基)苯甲酸甲酯
1H-NMR(400MHz,DMSO-d6):δ=9.24(d,1H),9.04(t,1H),8.86(d,1H),8.51(d,1H),8.29(dd,1H),8.12(dd,1H),7.87(d,2H),7.44(d,2H),7.30(m,2H),7.22(m,2H),7.00(d,1H),4.57(d,2H),3.83(s,3H)。
HPLC-MS:Rt 4.890 m/z 458.1(MH+)
实施例1:4-((2-(4-氟苯氧基)-5-(吡啶-4-基)苯甲酰胺基)甲基)苯甲酸
向4-((2-(4-氟苯氧基)-5-(吡啶-4-基)苯甲酰胺基)甲基)苯甲酸甲酯(35.0mg,0.077mmol)在甲醇(0.5mL)和THF(0.5mL)中的溶液加入NaOH 2M(0.19mL,0.38mmol),并将混合物在室温下搅拌过夜。将溶液用水(15mL)稀释,并通过加入HCl 1M将pH值调节至4.0,并过滤沉淀物并用戊烷洗涤(27.8mg,82.0%)。
1H-NMR(400MHz,DMSO-d6):δ=12.85(s,1H),9.01(t,1H),8.64(d,2H),8.07(d,1H),7.90(dd,1H),7.84(d,2H),7.74(d,2H),7.39(d,2H),7.27(t,2H),7.17(dd,2H),7.01(d,1H),4.55(d,2H)。
HPLC-MS:Rt 3.362 m/z 443.1(MH+)
使用实施例1所描述的程序和相应的化学试剂或衍生物合成以下中间体:
实施例2:4-((4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.84(s,1H),8.95(s,1H),7.93(d,1H),7.83(d,2H),7.76(dd,1H),7.68(d,2H),7.48(t,2H),7.38(t,3H),7.25(t,2H),7.13(m,2H),7.00(d,1H),4.53(d,2H)。
HPLC-MS:Rt 3.867 m/z 442.1(MH+)
实施例3:4-((4'-氯-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),8.97(t,1H),7.93(d,1H),7.83(d,2H),7.75(m,3H),7.53(d,2H),7.37(d,2H),7.26(t,2H),7.13(m,2H),6.99(d,1H),4.53(d,2H)。
HPLC-MS:Rt 4.221 m/z 476.0(MH+)
实施例4:4-((4'-氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.87(s,1H),8.97(t,1H),7.90(d,1H),7.83(d,2H),7.73(m,3H),7.36(d,2H),7.29(m,4H),7.12(m,2H),6.99(d,1H),4.53(d,2H)。
HPLC-MS:Rt 4.029 m/z 460.1(MH+)
实施例5:4-((3'-氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),8.98(t,1H),7.96(d,1H),7.81(m,3H),7.53(m,3H),7.37(d,2H),7.22(m,3H),7.14(m,2H),6.99(d,1H),4.53(d,2H)。
HPLC-MS:Rt 4.033 m/z 460.1(MH+)
实施例6:4-((2'-氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.87(s,1H),8.98(s,1H),7.83(s,3H),7.64(d,1H),7.57(s,1H),7.34(m,7H),7.18(s,2H),6.99(d,1H),4.53(d,2H)。
HPLC-MS:Rt 4.001 m/z 460.1(MH+)
实施例7:4-((4'-氰基-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),9.00(t,1H),8.02(s,1H),7.91(m,4H),7.84(d,3H),7.38(d,2H),7.27(t,2H),7.16(m,2H),7.00(d,1H),4.54(d,2H)。
HPLC-MS:Rt 3.864 m/z 467.1(MH+)
实施例8:4-((3'-氰基-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),8.99(t,1H),8.20(s,1H),8.04(dd,2H),7.84(d,4H),7.68(t,1H),7.38(d,2H),7.27(t,2H),7.15(dd,2H),7.00(d,1H),4.54(d,2H)。
HPLC-MS:Rt 3.860 m/z 467.1(MH+)
实施例9:4-((2-(4-氟苯氧基)-5-(3-氟吡啶-4-基)苯甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),9.01(t,1H),8.67(d,1H),8.51(d,1H),7.97(s,1H),7.84(d,2H),7.77(d,1H),7.68(dd,1H),7.39(d,2H),7.29(t,2H),7.20(m,2H),7.01(d,1H),4.55(d,2H)。
HPLC-MS:Rt 3.495 m/z 461.1(MH+)
实施例10:4-((2-(4-氟苯氧基)-5-(吡啶-3-基)苯甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),8.99(s,1H),8.92(d,1H),8.58(dd,1H),8.11(m,1H),7.99(d,1H),7.83(m,3H),7.50(dd,1H),7.38(d,2H),7.26(t,2H),7.15(m,2H),7.02(d,1H),4.54(d,2H)。
HPLC-MS:Rt 3.390 m/z 443.1(MH+)
实施例11:4-((2-(4-氟苯氧基)-5-(3-氯吡啶-4-基)苯甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),9.01(t,1H),8.75(s,1H),8.59(d,1H),7.83(dd,3H),7.64(dd,1H),7.53(d,1H),7.39(d,2H),7.30(t,2H),7.21(dd,2H),6.98(d,1H),4.54(d,2H)。
HPLC-MS:Rt 3.624 m/z 477.0(MH+)
实施例12:4-((2-(4-氟苯氧基)-5-(嘧啶-5-基)苯甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),9.17(m,3H),9.01(t,1H),8.08(d,1H),7.88(m,3H),7.42(d,2H),7.27(t,2H),7.15(m,2H),7.04(d,1H),4.54(d,2H)。
HPLC-MS:Rt 3.147 m/z 444.1(MH+)
实施例13:4-((3',4'-二氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.89(s,1H),8.97(t,1H),7.95(d,1H),7.79(m,4H),7.54(m,2H),7.37(d,2H),7.26(t,2H),7.13(dd,2H),6.98(d,1H),4.53(d,2H)。
HPLC-MS:Rt 4.084 m/z 478.1(MH+)
实施例14:4-((4-(4-氟苯氧基)-4'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),9.00(t,1H),8.01(d,1H),7.93(d,2H),7.83(dd,5H),7.38(d,2H),7.27(t,2H),7.16(m,2H),7.02(d,1H),4.54(d,2H)。
HPLC-MS:Rt 2.53 m/z 510.57(MH+)
实施例15:4-((4-(4-氟苯氧基)-3'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=δ=12.88(s,1H),9.01(t,1H),8.01(dd,3H),7.84(dd,3H),7.72(q,2H),7.37(d,2H),7.60(m,2H),7.15(m,2H),7.01(d,1H),4.54(d,2H)。
HPLC-MS:Rt 2.47 m/z 510.51(MH+)
实施例16:4-((2-(4-氟苯氧基)-5-(吡啶-2-基)苯甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),8.99(t,1H),8.67(d,1H),8.39(d,1H),8.16(dd,1H),7.99(d,1H),7.89(m,1H),7.84(d,2H),7.39(d,2H),7.35(m,1H),7.27(t,2H),7.17(dd,2H),6.99(d,1H),4.55(d,2H)。
HPLC-MS:Rt 3.502 m/z 433.1(MH+)
实施例17:4-((2-(4-氟苯氧基)-5-(嘧啶-4-基)苯甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),9.24(d,1H),9.03(t,1H),8.86(d,1H),8.51(d,1H),8.28(dd,1H),8.12(dd,1H),7.85(d,2H),7.41(d,2H),7.30(m,2H),7.22(dd,2H),7.00(d,1H),4.56(d,2H)。
HPLC-MS:Rt 3.243 m/z 444.1(MH+)
实施例18:4-((2-(4-氟苯氧基)-5-(苯硫-2-基)苯甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),8.98(t,1H),7.90(d,1H),7.82(dd,2H),7.73(dd,1H),7.56(d,1H),7.53(dd,1H),7.35(,2H),7.24(t,2H),7.12(m,3H),6.96(d,1H),4.52(d,2H)。
HPLC-MS:Rt 2.18 m/z 448.1(MH+)
实施例19:4-((3',5'-二氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸。
1H-NMR(400MHz,DMSO-d6):δ=12.87(s,1H),8.99(t,1H),8.00(d,1H),7.83dd,3H),7.49(m,2H),7.38(d,2H),7.25(m,3H),7.14(m,2H),6.98(d,1H),4.54(d,2H)。
HPLC-MS:Rt 2.30 m/z 478.17(MH+)
实施例20:4-((3'-氯-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸。
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),8.99(t,1H),7.97(d,1H),7.80(m,4H),7.68(d,1H),7.51(t,1H),7.46(m,1H),7.39(d,2H),7.27(m,2H),7.15(m,2H),7.00(d,1H),4.55(d,2H)。
HPLC-MS:Rt 2.86 m/z 476.13(MH+)
实施例21:4-((3'-氟-4-(4-氟苯氧基)-5'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸。
1H-NMR(400MHz,DMSO-d6):δ=12.89(s,1H),9.01(t,1H),8.08(d,1H),7.96(d,1H),7.90(m,2H),7.84(d,2H),7.70(d,1H),7.39(d,2H),7.28(m,2H),7.17(m,2H),7.01(d,1H),4.56(d,2H)。
HPLC-MS:Rt 2.46 m/z 528.19(MH+)
实施例22:4-((3'-氨甲酰基-5'-氯-4-(4-氟苯氧基)-[1,1'-联苯]-3-基甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.89(s,1H),9.00(t,1H),8.26(s,1H),8.15(s,1H),8.05(d,1H),7.94(m,1H),7.88(m,1H),7.84(m,2H),7.63(s,1H),7.38(d,2H),7.26(m,2H),7.15(m,2H),7.01(d,1H),4.54(d,2H)。
HPLC-MS:Rt 1.96 m/z 519.07(MH+)
实施例23:4-((2-(4-氟苯氧基)-5-(1H-吡唑-4-基)苯甲酰胺基)甲基)苯甲酸。
1H-NMR(400MHz,DMSO-d6):δ=12.96(s,1H),8.90(t,1H),8.09(s,2H),7.85(d,1H),7.81(m,2H),7.69(dd,1H),7.33(m,2H),7.22(m,2H),7.06(m,2H),6.94(d,1H),4.49(d,2H)。
HPLC-MS:Rt 1.06 m/z 432.1(MH+)
实施例24:4-((2-(4-氟苯氧基)-5-(1-甲基-1H-吡唑-4-基)苯甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),8.91(t,1H),8.18(s,1H),7.88(s,1H),7.81(m,3H),7.64(dd,1H),7.33(d,2H),7.22(m,2H),7.06(m,2H),6.94(d,1H),4.50(d,2H),3.86(s,3H)。
HPLC-MS:Rt 1.78 m/z 446.10(MH+)
实施例25:4-((2-(4-氟苯氧基)-5-(1-甲基-1H-吡唑-5-基)苯甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),9.00(t,1H),7.83(d,2H),7.77(d,1H),7.61(dd,1H),7.48(d,1H),7.37(d,2H),7.27(m,2H),7.17(m,2H),6.98(d,1H),6.43(t,1H),4.53(d,2H),3.86(s,3H)。
HPLC-MS:Rt 1.82 m/z 446.10(MH+)
实施例26:4-((4-(4-氟苯氧基)-3'-(吡啶-4-基)-[1,1'-联苯]-3-基甲酰胺基)甲基)苯甲酸。
1H-NMR(400MHz,DMSO-d6):δ=12.88(s,1H),9.02(t,1H),8.92(d,1H),8.38(d,2H),8.25(s,1H),8.10(d,1H),7.98(d,1H),7.92(d,2H),7.83(d,2H),7.71(t,1H),7.38(d,2H),7.27(m,2H),7.15(m,2H),7.04(d,1H),4.54(d,2H)。
HPLC-MS:Rt 2.15 m/z 519.2(MH+)
实施例27:4-((5-(5-氨基甲酰基呋喃-2-基)-2-(4-氟苯氧基)苯甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=12.89(s,1H),9.00(t,1H),8.17(t,1H),8.02(s,1H),7.94(m,2H),7.45(s,2H),7.37(t,2H),7.26(m,2H),7.13(m,3H),6.99(d,1H),4.53(d,2H)。
HPLC-MS:Rt 1.74 m/z 475.0(MH+)
实施例28:3-氟-4-((4-(4-氟苯氧基)-3'-(三氟甲基)-[1,1'-联苯]-3-基甲酰胺基)甲基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=13.26(s,1H),9.00(t,1H),8.00(m,3H),7.86(dd,1H),7.73(m,2H),7.63(m,2H),7.41(t,1H),7.26(m,2H),7.15(m,2H),7.00(d,1H),4.54(d,2H)。
HPLC-MS:Rt 1.54 m/z 528.0(MH+)
实施例29:(R)-4-(1-(4-(4-氟苯氧基)-3'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)乙基)苯甲酸1H-NMR(400MHz,DMSO-d6):δ=12.86(s,1H),8.88(d,1H),8.06(m,2H),7.90(t,1H),7.84(dd,3H),7.72(q,2H),7.45(d,2H),7.25(t,2H),7.12(m,2H),7.03(d,1H),5.13(p,1H),1.40(t,3H)。
HPLC-MS:Rt 2.45 m/z 524.0(MH+)
实施例30:4-(1-(4-(4-氟苯氧基)-3'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)环丙基)苯甲酸
1H-NMR(400MHz,DMSO-d6):δ=9.09(s,1H),8.04(d,2H),7.95(s,1H),7.86(d,1H),7.73(d,4H),7.27(t,2H),7.18(d,2H),7.13(dd,2H),7.08(d,1H),1.27(t,2H),1.22(t,2H)。
HPLC-MS:Rt 2.79 m/z 536.0(MH+)
实施例31:4-((3'-氟-5'-氰基-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
在氮气气氛中向4-((5-溴-2-(4-氟苯氧基)苯甲酰胺基)甲基)苯甲酸(80mg,1.0eq)和(3-氰基-5-氟苯基)硼酸(59mg,2.0eq)在DMF(1.2mL)中的溶液加入2M Cs2CO3(0.27mL,3.0eq)和Pd(dppf)Cl2·DCM(9mg,0.06eq)。在110℃下搅拌之后20小时,将混合物通过硅藻土过滤,用乙酸乙酯(20mL)洗涤。将有机相用饱和碳酸氢钠(20mL)水溶液和盐水(20mL)洗涤,经Na2SO4干燥,过滤并在减压下浓缩。通过快速柱色谱法(己烷:乙酸乙酯,1:1)纯化粗物质,以获得呈白色固体的酸IV-484-536(22mg,产率25.2%)。
1H-NMR(400MHz,DMSO-d6):δ=12.86(s,1H),8.99(t,1H),8.12(s,1H),8.07(d,2H),8.01(dd,1H),7.89(dd,1H),7.84(d,2H),7.39(d,2H),7.27(m,2H),7.16(m,2H),6.99(d,1H),4.54(d,2H)。
HPLC-MS:Rt 2.23 m/z 485.1(MH+)
实施例32:4-((3'-氯-5'-氰基-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
向4-((3’-氰基-5’-氟-4-(4-氟苯氧基)-[1,1’-联苯]-3-基甲酰胺基)甲基)苯甲酸甲酯(100mg,1.0eq)在THF(1.0mL)中的溶液加入HCl(4M)(3.0mL),并将混合物在80℃下搅拌46小时。在用水(5mL)稀释之后,将混合物用乙酸乙酯(3×10mL)萃取,经Na2SO4干燥,过滤并在减压下浓缩。通过快速柱色谱法(己烷:乙酸乙酯,1:1)纯化粗物质,以获得呈白色固体的酸(18mg,产率18.6%)。
1H-NMR(400MHz,DMSO-d6):δ=12.87(s,1H),8.98(t,1H),8.22(s,1H),8.16(t,1H),8.07(d,1H),8.03(m,1H),7.89(dd,1H),7.84(d,2H),7.39(d,2H),7.27(m,2H),7.16(m,2H),6.99(d,1H),4.54(d,2H)。
HPLC-MS:Rt 2.34 m/z 501.1(MH+)
Claims (19)
2.根据权利要求1所述的化合物,其中R1、R2、R3、R4和R5表示氢原子。
3.根据权利要求1至2中任一项所述的化合物,其中A表示苯基。
4.根据权利要求3所述的化合物,其中每个R6独立地表示选自以下的基团:
a)氢原子,
b)卤素原子
c)氰基,
d)氨基甲酰基
e)直链或支链C1-3卤代烷基。
5.根据权利要求1至4中任一项所述的化合物,其中A表示苯基和每个R6独立地表示选自氟、三氟甲基和氰基的基团,和m是1至4的整数。
6.根据权利要求1至2中任一项所述的化合物,其中A表示五元或六元杂芳环。
7.根据权利要求6所述的化合物,其中A表示选自吡啶基或苯硫基的基团,每个R6独立地表示选自三氟甲基和氰基的基团,并且m是1至4的整数。
8.根据权利要求1所述的化合物,其中R1、R2、R3、R4和R5表示氢原子,A表示苯基和每个R6独立地表示选自氟和三氟甲基的基团,并且m是1至5的整数。
9.根据任一前述权利要求所述的化合物,其中m是1至2的整数。
10.根据权利要求1至2中任一项所述的化合物,其中A表示选自苯基、吡啶基、嘧啶基、苯硫基的基团,R1、R2、R3、R4、R5是氢原子,每个R6独立地表示选自氢原子、氟、氯、氰基、三氟甲基和吡啶基的基团,并且m是1至2的整数。
11.根据权利要求1所述的化合物,其为以下之一:
4-((2-(4-氟苯氧基)-5-(吡啶-4-基)苯甲酰胺基)甲基)苯甲酸
4-((4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((4'-氯-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((4'-氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((3'-氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((2'-氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((4'-氰基-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((3'-氰基-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(3-氟吡啶-4-基)苯甲酰胺基)甲基)苯甲酸)
4-((2-(4-氟苯氧基)-5-(吡啶-3-基)苯甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(3-氯吡啶-4-基)苯甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(嘧啶-5-基)苯甲酰胺基)甲基)苯甲酸
4-((3',4'-二氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((4-(4-氟苯氧基)-4'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((4-(4-氟苯氧基)-3'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(吡啶-2-基)苯甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(嘧啶-4-基)苯甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(苯硫-2-基)苯甲酰胺基)甲基)苯甲酸
4-((3',5'-二氟-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基))苯甲酸
4-((3'-氯-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((3'-氟-4-(4-氟苯氧基)-5'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((3'-氨甲酰基-5'-氯-4-(4-氟苯氧基)-[1,1'-联苯]-3-基甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(1H-吡唑-4-基)苯甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(1-甲基-1H-吡唑-4-基)苯甲酰胺基)甲基)苯甲酸
4-((2-(4-氟苯氧基)-5-(1-甲基-1H-吡唑-5-基)苯甲酰胺基)甲基)苯甲酸
4-((4-(4-氟苯氧基)-3'-(吡啶-4-基)-[1,1'-联苯]-3-基甲酰胺基)甲基)苯甲酸
4-((5-(5-氨基甲酰基呋喃-2-基)-2-(4-氟苯氧基)苯甲酰胺基)甲基)苯甲酸
3-氟-4-((4-(4-氟苯氧基)-3'-(三氟甲基)-[1,1'-联苯]-3-基甲酰胺基)甲基)苯甲酸
(R)-4-(1-(4-(4-氟苯氧基)-3'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)乙基)苯甲酸
4-(1-(4-(4-氟苯氧基)-3'-(三氟甲基)-[1,1'-联苯]-3-甲酰胺基)环丙基)苯甲酸
4-((3'-氟-5'-氰基-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸
4-((3'-氯-5'-氰基-4-(4-氟苯氧基)-[1,1'-联苯]-3-甲酰胺基)甲基)苯甲酸,
和其药学上可接受的盐。
12.根据权利要求1至11中任一项所限定的化合物,其用于治疗或预防可通过调节***素E2(PGE2)的EP4和/或EP2受体而改善的疾病或病理病症,其中所述疾病或病理病症选自癌症、疼痛、神经退行性疾病、骨关节炎、类风湿性关节炎、子宫内膜异位症和肾脏疾病。
13.根据权利要求1至11中任一项所限定的化合物,其用于治疗或预防癌症,特别是适合用免疫疗法治疗的癌症类型。
14.根据权利要求1至11中任一项所述的化合物在制造用于治疗或预防可通过调节***素E2(PGE2)的EP4和/或EP2受体而改善的疾病或病理病症的药物中的用途,其中所述疾病或病理病症选自癌症、疼痛、神经退行性疾病、骨关节炎、类风湿性关节炎、子宫内膜异位症和肾脏疾病。
15.根据权利要求1至11中任一项所述的化合物在制造用于治疗或预防癌症,特别是适合用免疫疗法治疗的癌症类型的药物中的用途。
16.一种治疗或预防可通过调节***素E2(PGE2)的EP4和/或EP2受体而改善的疾病或病理病症的方法,其中所述疾病或病理病症选自癌症、疼痛、神经退行性疾病、骨关节炎、类风湿性关节炎、子宫内膜异位症和肾脏疾病,所述方法包括向需要其的受试者施用有效量的根据权利要求1至11中任一项所述的化合物。
17.一种治疗或预防癌症,特别是适合用免疫疗法治疗的癌症类型的方法,所述方法包括向需要其的受试者施用有效量的根据权利要求1至11中任一项所述的化合物。
18.一种药物组合物,其包括根据权利要求1至11中任一项所述的化合物,药学上可接受的稀释剂或载体和任选地治疗有效量的其他化疗剂、消炎药、类固醇、免疫治疗剂和其他药剂比如治疗性抗体。
19.一种组合产物,其包括根据权利要求1至11中任一项所述的化合物或其药学上可接受的盐和至少一种治疗剂,所述治疗剂选自化疗剂、消炎药、类固醇、免疫抑制剂、免疫治疗剂、治疗性抗体和EP4和/或EP2调节剂,特别是选自以下的那些:选自伊匹单抗和曲美木单抗的抗CTLA4抗体,抗PD1抗体比如纳武单抗、派姆单抗、西米普利单抗、匹利珠单抗、spartalizumab、MEDI0680、REGN2810和AMP-224,抗PDL1抗体比如阿特珠单抗、阿维鲁单抗、杜伐鲁单抗和MDX-1105;卡铂、卡莫司汀(BCNU)、顺铂、环磷酰胺、依托泊苷、依立替康、洛莫司汀(CCNU)、甲氨蝶呤、甲基苄肼、替莫唑胺、长春新碱。
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WO2020161275A1 (en) | 2020-08-13 |
JP2022519719A (ja) | 2022-03-24 |
MX2021009519A (es) | 2021-09-08 |
US20220117962A1 (en) | 2022-04-21 |
EP3693359A1 (en) | 2020-08-12 |
BR112021015588A2 (pt) | 2021-10-05 |
ZA202105698B (en) | 2023-01-25 |
US11872226B2 (en) | 2024-01-16 |
EP3921310A1 (en) | 2021-12-15 |
CA3129502A1 (en) | 2020-08-13 |
AU2020218838A1 (en) | 2021-08-26 |
EA202192205A1 (ru) | 2021-11-08 |
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