CN108697684A - 趋化因子受体的调节剂 - Google Patents
趋化因子受体的调节剂 Download PDFInfo
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- CN108697684A CN108697684A CN201680068079.9A CN201680068079A CN108697684A CN 108697684 A CN108697684 A CN 108697684A CN 201680068079 A CN201680068079 A CN 201680068079A CN 108697684 A CN108697684 A CN 108697684A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
提供具有式(A)的化合物作为趋化因子抑制剂:
Description
相关申请的交叉引用
本申请是根据35U.S.C.§119(e)要求2015年11月19日提交的美国临时申请号62/257,389和2016年1月12日提交的美国临时申请号62/277,711的优先权的申请,其各自在此通过引用全部并入本文。
联邦资助研发下作出发明的权属声明
不适用
引用“序列表”、表格或以光盘形式提交的计算机程序列表附件
不适用
发明背景
趋化因子是趋化细胞因子,其被各种细胞释放以将巨噬细胞、淋巴细胞、嗜酸性粒细胞、嗜碱性粒细胞和嗜中性粒细胞吸引到炎症部位(综述于Schall,细胞因子(Cytokine),3:165-183(1991),Schall等人,Curr Opin.Immunol.6:865-873(1994)和Murphy,Rev.Immun.,12:593-633(1994))。除刺激趋化作用之外,在应答细胞中,趋化因子可以选择性诱导其他变化,包括细胞形状的变化、细胞内游离钙离子([Ca2+])浓度的瞬时升高、颗粒胞吐作用、整联蛋白上调、生物活性脂质(例如白三烯)的形成和呼吸爆发,这与白细胞活化有关。因此,趋化因子是炎性反应的早期触发因素,引起炎症介质释放、趋化作用和外渗至感染或炎症部位。
存在两个主要类别的趋化因子,CXC(α)和CC(β),取决于前两个半胱氨酸是被单个氨基酸(C-X-C)分开还是相邻的(C-C)。α-趋化因子如CXCL1(GROα)和CXCL8(白介素-8,IL-8)主要对嗜中性粒细胞具有趋化性,而β-趋化因子如CCL5(RANTES)和CCL20(LARC,MIP-3α)则对T细胞、B细胞、巨噬细胞、嗜酸性粒细胞和嗜碱性粒细胞具有趋化性(Deng等,Nature,381:661-666(1996))。趋化因子结合属于G蛋白偶联的七跨膜域蛋白家族的特异性细胞表面受体(综述于Horuk,Trends Pharm.Sci.,15:159-165(1994)),其被称为“趋化因子受体”。
结合它们的同源的配体后,趋化因子受体通过相关的三聚G蛋白转换胞内信号,从而导致胞内钙浓度快速增加。有至少11种人趋化因子受体结合β趋化因子或对之起反应,有至少7种人趋化因子受体结合α趋化因子。此外,CX3CR1(分形趋化因子(fractalkine)受体)可结合分形趋化因子,其因前两个半胱氨酸之间的一系列三氨基酸而区分。趋化因子受体是炎性和免疫调节性紊乱和疾病,包括哮喘和变应性疾病,以及自身免疫疾病,例如风湿性关节炎和动脉粥样硬化的重要介质。
已知趋化因子受体CCR6通过记忆(而非原初)CD4T细胞、分泌IL17的αβT细胞、分泌IL17的γδT细胞、调节性T细胞、B细胞和树突细胞来表达。其唯一已知的配体是CCL20(MIP-3α,LARC),对其它显示出强结合。它在大约30-60%的成人外周血效应子/记忆CD4+T细胞上表达。CCR6参与白细胞归巢至炎症组织,特别是皮肤、肺和肠;并且在具有皮肤归巢表型的T细胞子集(即表达皮肤淋巴细胞抗原(CLA)和CCR4的T细胞)上共表达。因此CCR6可能是白细胞参与皮肤病变的重要参与者。
CCR6表达与银屑病有关。在人类中,外周血中大多数表达IL17的皮肤归巢CD4T细胞表达CCR6(Homey等,JI,2000)。在几种炎症性疾病中,IL17分泌细胞为中枢媒介。T细胞,例如γδT细胞和TH17T细胞,在激活之后产生IL17。IL17的致病效应与人类疾病有关,例如,类风湿性关节炎(Patel DD等.,Ann Rheum Dis2013)、多发性硬化(Zepp J,Wu L,和X Li,Trends Immunol 2011)和银屑病(Martin DA等,J.Invest Dermatol 2012)。IL17与银屑病之间的强有力联系的证据包括全基因组关联研究,该研究表明银屑病与IL17信号通路的上游基因(IL-23)或下游基因(NFb)密切相关,以及与在临床环境中靶向IL17的效力密切相关(Martin DA等,J.Invest Dermat.2012;Papp等,NEJM,2012;Papp等,NEJM,2012)。除了增强的CCL20-介导的趋化性,与健康对照组相比,分离自银屑病患者的CCR6+T细胞优先分泌IL-17A、IL22和TNFα(Kagami等,J.Invest.Dermatol.,2010)。最终,在病灶性银屑病皮肤样本中,CCL20mRNA上调表达(Homey等,JI,2000;Dieu-Nosjean等,JEM,2000)。在小鼠内,CCR6基因敲除小鼠免于IL-23所驱动的银屑病(Hedrick M.N.等人.JCI,2009)。因此,大量小鼠和人体内证据都表明CCR6阻滞在银屑病和银屑病样模型中的保护性作用。
CCR6也在其发育的关键阶段由树突细胞表达,并且对于它们通过组织的迁移是重要的(Sozzani等人,J Leuk Biol,66:1,1999)。树突状细胞负责将抗原提呈给淋巴结内的T细胞,因此抑制树突状细胞运输可以对T细胞介导的炎症反应具有抑制作用(Banchereau和Steinman,Nature,392:245,1998)。
CCR6由B细胞表达,并且最近已证明CCR6介导的B细胞迁移是B细胞对可溶性抗原的记忆应答所必需的(Elgueta等,J Immunol,194:505,2015)。因此通过CCR6阻断抑制这种B细胞迁移可能潜在地抑制B细胞介导的(和因此抗体介导的)在疾病如狼疮、类风湿性关节炎和天疱疮中的炎症反应。
CCR6通常由结直肠癌(CRC)细胞表达。该受体的高表达与CRC患者的不良结果相关,并且已经提出CCR6本身有助于导致转移的CRC细胞的迁移(Liu J.等人,Plosone 20149(6):e101137)。
与单独的受体CXCR2结合的趋化因子促进嗜中性粒细胞的积聚和活化。这些趋化因子涉及广泛的急性和慢性炎症疾病,例如银屑病、类风湿性关节炎、放射诱导的纤维化肺病、自身免疫性大疱性皮肤病(AIBD)、慢性阻塞性肺病(COPD)和臭氧诱导的气道炎症(参见,Baggiolini等,Febs Lett.307:97(1992);Miller等人,Crit.Rev.Immunol.12:17(1992);Oppenheim等人,annu.Rev.Immunol.9:617(1991);Seitz等,J.Clin.Invest.87:463(1991);Miller等人,Ann.Rev.Respir.Dis.146:427(1992);和Donnely等,Lancet 341:643(1993),Fox&Haston,Radiation Oncology,85:215(2013),Hirose等,J.Genet.Syndr.Genet.Ther.S3:005(2013),Miller等人,Eur.J.DrugMetab.Pharmacokinet.39:173(2014),Lazaar等,Br.J.Clin.Pharmacol.,72:282(2011))。
除了炎性疾病之外,包括CXCL1、CXCL2、CXCL3和CXCL5在内的一些CXCR2配体趋化因子也参与诱导肿瘤血管生成(Strieter等.JBC 270:27348-27357(1995))。在缺血性中风期间,一些CXCR2配体趋化因子是恶化剂(Connell等,Neurosci.Lett.,15:30111(2015)。它们的血管生成活性可能是由趋化因子在周围血管的血管内皮细胞(ECs)表面上表达的CXCR2的激活所致。
已知许多类型的肿瘤产生CXCR2配体趋化因子。这些趋化因子的产生与更具攻击性的表型相关(Inoue等,Clin Cancer Res 6:2104-2119(2000))和不良预后(Yoneda等人,J Nat Cancer Inst 90:447-454(1998))。由于趋化因子是EC趋化的强有力的趋化因子,因此它们可能诱导内皮细胞趋向肿瘤中它们的生产部位的作用。这可能是诱导肿瘤血管生成的关键步骤。CXCR2抑制剂将抑制ELR-CXC趋化因子的血管生成活性并因此阻断肿瘤生长。对CXCL8(Arenberg等,J Clin Invest 97:2792-2802(1996))、ENA-78(Arenberg等,J ClinInvest 102:465-72(1998))和CXCL1(Haghnegahdar等,J.Leukoc Biology 67:53-62(2000))的抗体的这种抗肿瘤活性已得到证实。
许多肿瘤细胞表达CXCR2,肿瘤细胞可通过分泌ELR-CXC趋化因子刺激其自身生长。因此,除了减少肿瘤内的血管生成之外,CXCR2抑制剂可以直接抑制肿瘤细胞的生长。
CXCR2通常在肿瘤微环境中由髓源阻抑细胞(MDSC)表达。MDSC涉及抑制肿瘤免疫应答,并且MDSC对CXCR2配体趋化因子的迁移最有可能负责将这些细胞吸引到肿瘤中(Marvel和Gabrilovich,J.Clin.Invest.13:1(2015)和Mackall等人,Sci.Trans.Med.6:237(2014))。因此,CXCR2抑制剂可逆转抑制过程并由此使免疫细胞更有效地排斥肿瘤。实际上,阻断CXC-趋化因子受体的激活已被证明可用作抑制肿瘤生长中与检查点抑制剂的联合治疗,表明CXCR2阻断也可与其他抗肿瘤治疗(包括但不限于疫苗或传统的细胞毒性化学疗法)联合使用增强肿瘤排斥(参见Highfill等,Science Translational Medicine,6:237(2014))。
CCR6和CXCR2的活性各自与某些癌症类型(包括CRC)的不良结果相关联,但其可能通过不同的潜在的互补机制发挥作用(Nandi等,PLoS One,9:e97566,2014;Liu等,PLoSOne,9:e101137,2014;Cheluvappa,Int J Colorectal Dis,29:1181,2014;Zhang,BiomedPharmacother.69:242,2014;Lee等,Int J Cancer,135:232,2014;Wang和DuBois,Oncoimmunology,29:e28581,2014;Wu等,Int J Clin Exp Med,8:5883,2015)。
鉴于CCR6和CXCR2的临床重要性,鉴定调节这两种受体中的一种或两种的功能的化合物代表了开发新的治疗剂的有吸引力的途径。本文提供了这些化合物及其使用方法。
发明内容
本文描述了具有式(A)的化合物:
其中R3、R4、R5a、R5b、R6a、R6b、R7、B和下标n具有在下面的具体描述中提供的含义。该化合物可用于治疗至少部分由CCR6调节的疾病或病症,并且还可用于治疗至少部分由CXCR2调节的疾病或病症。
还提供了式(A)化合物的药物组合物。
在本公开中进一步提供了用于合成式(A)化合物的制备方法,以及用于制备的选择的中间体。
附图说明
图1A-1AJ提供了本文所述化合物的结构和生物学活性。
图2提供了化合物1.023在IL-23诱导的耳肿胀模型中。
图3提供了在咪喹莫特诱导的银屑病模型中用化合物1.129处理的小鼠中的PASI评分。
图4提供了在咪喹莫特诱导的银屑病模型中与用载体处理的小鼠相比,用化合物1.129处理的小鼠的厚度、红斑和脱皮评分≥3。
发明详述
在进一步描述本发明之前,应该理解的是,本发明不限于在此阐述的特定实施例,并且还应该理解,在此使用的术语仅用于描述特定实施例的目的,并且并非意在限制。
在提供一定范围的值的情况下,应该理解的是本发明包含在该范围的上限和下限之间的每个中间值,以及该陈述范围内任何其他规定的或中间值,除非上下文另有明确规定,否则精确到下限单位的十分之一。这些较小范围的上限和下限可以独立地包括在较小范围内,并且也包含在本发明内,受限于所述范围内的任何特别排除的限制。在所述范围包括一个或两个限制的情况下,排除那些所包括的限制中的任一个或两个的范围也包括在本发明中。除非另外定义,否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。
必须注意的是,除非上下文另外清楚地指出,否则如本文和所附权利要求中所使用的,单数形式“一”,“一个”和“该”包括复数指示物。进一步指出,可以起草权利要求来排除任何可选元素。因此,本陈述旨在结合权利要求元素的陈述用作诸如“仅仅”、“仅”等排他性术语的使用或“否定”限制的使用的先行基础。
本文讨论的出版物仅因其公开在本申请的提交日期之前而提供。此外,提供的出版日期可能与实际出版日期不同,可能需要独立确认。
概述
本发明源自发现式(A),(A1),(A2),(I)和(Ia1)的化合物作为CCR6受体和/或CXCR2受体的有效拮抗剂。该化合物具有体内抗炎活性并具有优异的药代动力学性质。因此,本文提供的化合物可用于药物组合物,治疗CCR6介导的疾病和/或CXCR2介导的疾病的方法,以及用于鉴定CCR6和/或CXCR2拮抗剂的测定中的对照。
缩略语和定义
除非另有说明,下列术语意图具有以下所述的含义。其他术语在整个说明书的其他地方定义。
除非另有表述,术语“烷基”本身或作为另一取代基的一部分是指具有指定碳原子数(即,C1-8表示1-8个碳)的直链或支链烃基。烷基的例子包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基等。
术语“环烷基”是指具有指定环原子数(例如,C3-6环烷基)并且完全饱和的或在环顶点之间具有不超过一个双键的烃环。“环烷基”也表示双环和多环烃环,例如双环[2.2.1]庚烷、双环[2.2.2]辛烷等。
术语“环杂烷基”指具有指定数量的环顶点(或成员)并具有1-5个选自N、O和S的杂原子的环烷基环,所述杂原子取代1-5个碳顶点,并且其中氮和硫原子是任选被氧化,并且氮原子任选被季铵化。环杂烷基可以是单环、双环或多环环系。环杂烷基的非限制性例子包括吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑烷酮、乙内酰脲、二氧戊环、邻苯二甲酰亚胺、哌啶、1,4-二噁烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S、S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环等。环杂烷基可以通过环碳或杂原子与分子的其余部分连接。
如本文所用,在本文描述的任何化学结构中,横贯单键、双键或三键的波浪线表示该单键、双键或三键与分子的其余部分的连接点。此外,延伸到环中心的键(例如苯环)意味着指示在任何可用的环顶点处的连接。本领域技术人员将理解,显示为连接到环上的多个取代基将占据提供稳定化合物的环顶点并且在其他方面是空间上相容的。对于二价组分,表示意味着包括任一取向(正向或反向)。例如,基团“-C(O)NH”意味着包括任何一种取向的连接:-C(O)NH-或–NHC(O)-,和类似地,“-O-CH2CH2-”意在包括-O-CH2CH2-和-CH2CH2-O-。
术语"烷氧基"、"烷基氨基"和"烷硫基"(或硫代烷氧基)以其常规意义使用,指代分别经氧原子、氨基或硫原子连接于分子的其余部分的那些烷基。此外,对于二烷基氨基,烷基部分可以相同或不同,也可和与各烷基相连的氮原子组合形成3-7元环。因此,二烷基氨基或-NRaRb所示基团表示包括哌啶基、吡咯烷基、吗啉基、氮杂环丁烷基(azetidinyl)等。
除非另有表述,术语“卤代”或“卤素”本身或作为另一取代基的一部分是指氟、氯、溴、或碘原子。此外,诸如“卤代烷基”等术语表示包括单卤代烷基或多卤代烷基。例如,术语“C1-4卤代烷基”表示包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
除非另有表述,术语“芳基”表示多不饱和的(通常表示芳香性)的烃基,其可以是单环或稠合在一起或共价连接的多环(最多三个环)。芳基的非限制性实例包括苯基、萘基和联苯。
术语"杂芳基"是指含有1-5个选自N、O和S的杂原子的芳基(或环),其中氮和硫原子任选被氧化,一个或多个氮原子任选被季铵化。杂芳基可通过杂原子连接于分子的其余部分。杂芳基的非限制性例子包括吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基、苯并三嗪基(benzotriazinyl)、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异噁唑基、异苯并呋喃基(isobenzofuryl)、异吲哚基、中氮茚基(indolizinyl)、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基等等。杂芳基环的取代基可以选自下面描述的可接受的取代基。
在一些实施方案中,上述术语(例如“烷基”,“芳基”和“杂芳基”)将被任选取代。下面提供了每种类型基团的选择的取代基。
烷基(包括通常称为亚烷基,烯基,炔基和环烷基的那些基团)的可选取代基可以是选自下组的各种基团:卤素、-OR’、-NR’R”、-SR’、-SIR’R”R”’、-OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR’-C(O)NR”R”’、-NR”C(O)2R’、-NH-C(NH2)=NH、-NR’C(NH2)=NH、-NH-C(NH2)=NR’、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、-NR’S(O)2R”、-CN和-NO2,数量从零到(2m’+1),其中m’是这种基团中的碳原子总数。R’、R”和R”’各自独立地表示氢、未取代的C1-8烷基、未取代的芳基、被1-3个卤素取代的芳基、未取代的C1-8烷基、C1-8烷氧基或C1-8硫代烷氧基、或未取代的芳基-C1-4烷基。当R’和R”连接到相同的氮原子时,它们可以与氮原子结合形成3-、4-、5-、6-或7-元环。例如,-NR’R”是指包括1-吡咯烷基和4-吗啉基。
类似地,芳基和杂芳基的可选取代基是多种的,并且通常选自:-卤素、-OR’、-OC(O)R’、-NR’R”、-SR’、-R’、-CN、-NO2、-CO2R’、-CONR’R”、-C(O)R’、-OC(O)NR’R”、-NR”C(O)R’、-NR”C(O)2R’、-NR’-C(O)NR”R”’、-NH-C(NH2)=NH、-NR’C(NH2)=NH、-NH-C(NH2)=NR’、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、-NR’S(O)2R”、-N3、全氟(C1-C4)烷氧基和全氟(C1-C4)烷基,数量从零到芳香环体系上的开放化合价的总数;其中R’、R”和R”’独立地选自氢、C1-8烷基、C1-8卤烷基、C3-6环烷基、C2-8烯基和C2-8炔基。其它合适的取代基包括通过1-4个碳原子的亚烷基链连接到环原子上的每一个上述芳基取代基。
芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-T-C(O)-(CH2)q-U-的取代基取代,其中T和U独立地为-NH-、-O-、-CH2-或单键,且q是0至2的整数。或者,芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-A-(CH2)r-B-,其中A和B独立地是-CH2-、-O-、-NH-、-S-、-S(O)-、-S(O)2-、-S(O)2NR’-或单键,且r是1至3的整数。由此形成的新环中的一个单键可以任选地被双键取代。或者,芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-(CH2)s-X-(CH2)t-的取代基替代,其中s和t独立地为0至3的整数,并且X是-O-、-NR’-、-S-、-S(O)-、-S(O)2-、或-S(O)2NR’-。-NR'-和-S(O)2NR'-中的取代基R'选自氢或未取代的C1-6烷基。
如本文所用,术语“杂原子”意在包括氧(O)、氮(N)、硫(S)和硅(Si)。
当变量(例如R1或Ra)在任何化合物或取代基中出现多于一次时,其每次出现时的定义与其它情况下的定义无关。另外,只有当这样的组合产生稳定的化合物时,才允许取代基和/或变量的组合。
术语"药学上可接受的盐"意在包括与相对无毒的酸或碱制备的活性化合物的盐,其取决于本文所述化合物的具体的取代基。当本发明化合物含有相对酸性的官能团时,可通过将中性形式的此类化合物与足量的所需碱(纯净的或在合适的惰性溶剂中的)接触来获得碱加成盐。衍生自药学上可接受的无机碱的盐的例子包括铝、铵、钙、铜、铁,亚铁、锂、镁、锰,亚锰、钾、钠、锌盐等。衍生自药学上可接受的有机碱的盐包括伯胺、仲胺和叔胺的盐,包括取代的胺、环状胺、自然产生的胺等等,例如精氨酸、甜菜碱、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺(glucamine)、葡萄糖胺(glucosamine)、组氨酸、海巴明(hydrabamine)、异丙胺、赖氨酸、甲葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等等。当本发明化合物含有相对碱性的官能团时,可通过将中性形式的此类化合物与足量的所需酸(纯净的或在合适的惰性溶剂中的)接触来获得酸加成盐。药学上可接受的酸加成盐的例子包括那些衍生自无机酸的盐,例如盐酸、氢溴酸、硝酸、碳酸、单氢碳酸(monohydrogencarbonic)、磷酸、单氢磷酸(monohydrogenphosphoric)、二氢磷酸(dihydrogenphosphoric)、硫酸、单氢硫酸(monohydrogensulfuric)、氢碘酸、或亚磷酸等等;以及衍生自相对无毒的有机酸的盐,例如乙酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、扁桃酸、苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸,酒石酸、甲磺酸等等。还包括氨基酸的盐,例如精氨酸盐等等,和有机酸,例如葡萄糖醛酸(glucuronic acid)或半乳糖醛酸(galactunoric acid)等的盐(参见,例如Berge,S.M.等,“药用盐”,Journal of Pharmaceutical Science,1977,66,1-19)。本发明的某些具体化合物同时含有碱性和酸性官能团,从而能将化合物转换成碱加成盐或酸加成盐。
通过将盐与碱或酸接触并以常规方式分离母体化合物,可以再生该化合物的中性形式。化合物的母体形式与各种盐形式在某些物理性能(例如在极性溶剂中的溶解度)上不同,但除此之外,就本发明的目的而言,那些盐与母体形式化合物是等价的。
除盐的形式外,本发明提供前药形式的化合物。本文所述的化合物的前药是在生理条件下很容易经历化学变化以提供本发明化合物的那些化合物。另外,前药可以在离体环境中通过化学或生物化学方法转变为本发明化合物。例如,当置于含合适的酶或化学试剂的经皮贴片贮器中时,前药可缓慢转变为本发明的化合物。
本发明的某些化合物可以非溶剂化形式以及溶剂化形式存在,包括含水形式。溶剂化形式通常与非溶剂化形式等价,应包括在本发明范围内。本发明的某些化合物可以多晶型或无定形形式存在。就本发明所考虑的应用而言,所有物理形式通常是等价的,应包括在本发明范围内。
本发明的某些化合物拥有不对称碳原子(光学中心)或双键;消旋体、非对映体、几何异构体、区域异构体和单独的异构体(例如,分离的对映体)均应包括在本发明范围内。当显示立体化学描述时,意思是指其中存在一种异构体且基本上不含另一种异构体的化合物。“基本上不含”另一种异构体表示两种异构体的至少80/20比例,更优选90/10或95/5或更多。在一些实施方案中,异构体中的一种将以至少99%的量存在。
本发明化合物还可在构成此类化合物的一个或多个原子处含有非天然比例的原子同位素。某同位素的非天然比例可以定义为从所讨论原子的天然发现的量到100%该原子的量。例如,化合物可以掺入放射性同位素,例如氚(3H)、碘-125(125I)或碳-14(14C),或非放射性同位素,例如氘(2H)或碳-13(13C)。除了本申请所述的那些用途,此类同位素变体可提供额外的用途。例如,本发明化合物的同位素变体可以有额外的用途,包括但不限于作为诊断的和/或成像试剂,或作为细胞毒性/放射毒性治疗剂。另外,本发明化合物的同位素变体可具有改变的药代动力学和药效学特征,从而有助于增加治疗期间的安全性、耐受性或疗效。无论是否有放射性,本发明化合物的所有同位素变体均应包括在本发明范围内。
术语“患者”或“受试者”可互换使用以指代人类或非人类动物(例如哺乳动物)。
当它们适用于例如受试者、细胞、组织、器官或生物流体时,术语“施用”、“给予”等是指例如CCR6和/或CXCR2的拮抗剂、包含其的药物组合物、或诊断剂与受试者、细胞、组织、器官或生物流体的接触。在细胞的情况下,给药包括将试剂与细胞接触(例如体外或离体),以及试剂与流体接触,其中流体与细胞接触。
术语“治疗、医治、诊治”(treat,treating,treatment)”等是指在疾病、病况或病症、或其症状已经被诊断、观察等后开始的作用的过程(例如施用CCR6和/或CXCR2的拮抗剂或包含其的药物组合物),以便暂时或永久地消除、减轻、抑制、减缓或改善疾病、病况或病症、或折磨受试者的病症、或至少一种与疾病、病症、折磨受试者的病症有关的症状的至少一种潜在原因。因此,治疗包括抑制(例如阻止疾病、病况或病症或与其相关的临床症状的发展或进一步发展)活动性疾病。
如本文所用的术语“需要治疗”是指由医师或其他护理人员做出的对象需要或将从治疗中受益的判断。这种判断是基于医生或护理人员专业领域中的各种因素作出的。
术语“预防(prevent,preventing,prevention)”等是指以某种方式(例如,在疾病、病况、病症或其症状发作前)启动的作用过程(例如,施用CCR6和/或CXCR2拮抗剂或包含其的药物组合物),从而暂时或永久地预防、阻抑、抑制或减轻患者发生疾病、病况或病症等(如通过没有临床症状确定)的风险,或延迟其发作,通常在受试者倾向于患有特定疾病、病况或病症的情况下。在某些情况下,这些术语还指减缓疾病、病况或病症的进展或抑制其发展成有害的或其他不希望的状态。
如本文所用的术语“需要预防”是指由医师或其他护理人员作出的受试者需要或将从预防护理中受益的判断。这种判断是基于医生或护理人员专业领域中的各种因素而作出的。
短语“治疗有效量”是指将药剂单独或作为药物组合物的一部分施用于受试者,并且以单次剂量或作为一系列剂量的一部分,当对受试者施用时,以能够对疾病、病况或病情的任何症状、方面或病症具有任何可检测的、积极作用的量。通过测量相关的生理效应可以确定治疗有效量,并且可以结合受试者病症的诊断分析和给药方案等来调整治疗有效量。举例而言,在施用后特定时间测量CCR6和/或CXCR2拮抗剂(或例如其代谢物)的血清水平可指示是否已使用治疗有效量。
短语“足以实现改变的量”意味着在施用特定疗法之前(例如,基线水平)和之后测量的指标水平之间存在可检测的差异。指标包括任何客观参数(例如血清浓度)或主观参数(例如,受试者的幸福感)。
术语“小分子”是指具有小于约10kDa,小于约2kDa或小于约1kDa的分子量的化学化合物。小分子包括但不限于:无机分子,有机分子,含有无机组分的有机分子,含有放射性原子的分子和合成分子。治疗上,小分子可能对细胞更易渗透,不易降解,而且比大分子不易引发免疫反应。
术语“抑制剂”和“拮抗剂”或“激活剂”和“激动剂”分别是指例如用于激活例如配体、受体、辅因子、基因、细胞、组织或器官的抑制或活化分子。抑制剂是减少、阻断、阻止、延迟激活、失活、脱敏或下调例如基因、蛋白质、配体、受体或细胞的分子。激活剂是增加、激活、促进、增强激活、敏化或上调例如基因、蛋白质、配体、受体或细胞的分子。抑制剂也可以定义为减少、阻断或灭活组成性活性的分子。“激动剂”是与靶标相互作用以引起或促进靶标活化增加的分子。“拮抗剂”是一种反对激动剂作用的分子。拮抗剂阻止、降低、抑制或中和激动剂的活性,并且拮抗剂还可以预防、抑制或降低靶标例如靶标受体的组成性活性,即使在没有鉴定的激动剂的情况下。
术语“调节(modulate),调整(modulation)”等是指分子(例如激活剂或抑制剂)直接或间接增加或降低CCR6和/或CXCR2的功能或活性的能力。调节剂可以单独作用,或者其可以使用辅因子例如蛋白质、金属离子或小分子。
分子的“活性”可以描述或指代分子与受体的结合;催化活性;刺激基因表达或细胞信号传导、分化或成熟的能力;抗原活性;调节其他分子的活性等等。
如本文所用,“可比较的”、“可比较的活性”、“与......可比较的活性”、“可比较的效果”、“与......可比较的效果”等是可以定量和/或定性观察的相对术语。这些术语的含义通常取决于它们的使用环境。举例来说,从定性角度来看,两种激活受体的药物可被视为具有可比较的效果,但从定量的角度来看,如在本领域接受的测定(例如,剂量-反应测定)中或在本领域接受的动物模型中确定的,如果一个药物仅能够达到其他药物的活性的20%,则可将两种药物视为缺乏可比较的效果。当比较一个结果与另一个结果(例如,一个结果与参考标准)时,“可比较的”经常(尽管不总是)意味着一个结果与参考标准的偏差小于35%、小于30%、小于25%、小于20%、小于15%、小于10%、小于7%、小于5%、小于4%、小于3%、小于2%、或小于1%。在特定的实施方案中,如果一个结果与参考标准的偏差小于15%、小于10%或小于5%,那么其结果与参考标准是可比较的。作为例子而非限制,活性或效果可以指效力、稳定性、溶解度或免疫原性。
“基本纯”表示一组分占大于组合物总含量的约50%,并且通常大于组合物总含量的约60%。更典型地,“基本上纯”是指其中全部组合物的至少75%、至少85%、至少90%或更多是目标组分的组合物。在一些情况下,目标组分将占大于组合物总含量的约90%或约95%。
化合物
本文提供具有式(I)的化合物:
或其任何盐、溶剂合物、水合物、N-氧化物、互变异构体或旋转异构体,
其中,
B选自下组:呋喃基、恶唑基、苯基、吡啶基、嘧啶基和吡嗪基,其各自任选地被R1a、R1b和R2取代,R1a、R1b和R2独立地选自下组:卤素、CN、C1-4烷基、C1-4烷氧基和C1-4卤代烷基;
R3是选自H和D的成员;
R4是选自H、C1-8烷基和Y的成员;其中,C1-8烷基任选地被卤素、-CN、-CO2Ra、-CONRaRb、-C(O)Ra、OC(O)NRaRb、-NRaC(O)Rb、-NRaC(O)2Rc、-NRaC(O)NRaRb、-NRaRb、-ORa、-S(O)2NRaRb、-NRaS(O)2Rb或Y取代,其中各Ra和Rb独立地选自:氢、C1-4烷基、C1-4羟基烷基和C1-4卤代烷基,Rc选自:C1-4烷基、C1-4羟基烷基和C1-4卤代烷基;并且Y是5元或6元芳基或杂芳基,任选地被1至4个选自卤素、-CN、-C1-4烷基、-C1-4烷氧基、-C1-4羟基烷基、-C1-4卤代烷基、OCF3、-CO2Ra、-CONRaRb、-C(O)Ra、-OC(O)NRaRb、-NRaC(O)Rb、-CH2CO2Ra的取代基取代;
R5a和R5b是各自独立地选自H、卤素、C1-4烷基、C1-4烷氧基、CO2H和CN的成员;
R6a和R6b是各自独立地选自H、C1-4烷基、C1-4羟基烷基和C1-4卤代烷基的成员;或任选地R6a和R6b一起形成氧基(=O);和
下标n是1或2。
在一些实施方案中,式I化合物为一化合物,其中B为呋喃基或恶唑基,其任选被R1a和R1b取代,所述R1a和R1b独立地选自下组:卤素、CN、C1-4烷基、C1-4烷氧基和C1-4卤代烷基。在这组实施方案中,某些选择的实施方案是其中R1a是CH3的那些。在其他选择的实施方案中,R3为H。在其他选择的实施方案中,R5a和R5b中的每一个独立地选自H、Cl和F。在其他选择的实施方案中,R6a和R6b中的每一个独立地选自H和C1-4烷基。在其他选择的实施方案中,R4是Y。在其他选择的实施方案中,R4选自H和任选取代的芳基或杂芳基。在具体的实施方案中,R1a选自CH3和Cl;并且R1b不存在或为CH3。
在一组选定的实施方案中,提供具有式(Ia1)的化合物:
或其药学上可接受的盐、溶剂化物或水合物,其中R1a选自CH3和Cl;R1b不存在(被H取代)或是CH3;R3是H或D;R4是H或任选地取代的芳基或杂芳基;R5a和R5b各自独立地选自H、F、Cl、Br和CH3;并且R6a和R6b各自独立地选自H和CH3。
在某些实施方案中,提供了式(Ia1)的化合物、或其药学上可接受的盐、溶剂化物或水合物,其中R1a是CH3;R1b不存在(被H取代)或是CH3;R3是H或D;R4是H或任选地取代的芳基或杂芳基;R5a是H或Cl或Br;R5b是H或F;且R6a和R6b各自为H。
在一些选定的实施方案中,提供了选自图1中的那些化合物的式(I)的化合物。
本文还提供具有式(A)的化合物、或其任何药学上可接受的盐、溶剂化物、水合物、N-氧化物、互变异构体或旋转异构体:
其中,
B选自下组:呋喃基、噻吩基、恶唑基、苯基、吡啶基、嘧啶基和吡嗪基,其各自任选地被R1a、R1b和R2取代,R1a、R1b和R2独立地选自下组:卤素、CN、C1-4烷基、C1-4烷氧基和C1-4卤代烷基;
R3是选自H和D的成员;
R4是选自H、C1-8烷基、OH、-NRaRb、-C1-4烷氧基和Y的成员;其中,C1-8烷基任选地被卤素、-CN、-CO2Ra、-CONRaRb、-C(O)Ra、OC(O)NRaRb、-NRaC(O)Rb、-NRaC(O)2Rc、-NRaC(O)NRaRb、-NRaRb、-ORa、-S(O)2NRaRb、-NRaS(O)2Rb和Y取代,其中Y是4至8元环杂烷基或3至8元环烷基或5元或6元芳基或杂芳基,其任一个任选地被1至4个选自卤素、氧基、-CN、-C1-6烷基、-C1-6烷氧基、-C1-6羟基烷基、-C1-6卤代烷基、O-C1-6卤代烷基、-C1-4烷基-O-C1-4烷基、-C1-6烷基-NRaRb、-C1-6烷基-CO2H、-C1-6烷基-CO2Ra、-C1-6烷基-CONRaRb、-C1-6烷基-C(O)Ra、-C1-6烷基-OC(O)NRaRb、-C1-6烷基-NRaC(O)Rb、-C1-6烷基-NRaC(O)2Rc、-C1-6烷基-NRaC(O)NRaRb、-C1-6烷基-ORa、-C1-6烷基-S(O)2NRaRb、-C1-6烷基-NRaS(O)2Rb、-CO2Ra、-CONRaRb、-C(O)Ra、-OC(O)NRaRb、-NRaC(O)Rb、-NRaC(O)2Rc、-NRaC(O)NRaRb、-NRaRb、-ORa、-S(O)2NRaRb、-NRaS(O)2Rb、-CH2CO2Ra的取代基取代;每个Ra和Rb独立地选自氢、C1-4烷基、C1-4羟基烷基和C1-4卤代烷基,并且Rc选自C1-4烷基、C1-4羟基烷基和C1-4卤代烷基;并且其中4至8元环杂烷基和3至8元环烷基可以另外任选地被氧基取代;
R5a和R5b是各自独立地选自H、卤素、C1-4烷基、-C1-4卤代烷基、O-C1-4卤代烷基、C1-4烷氧基、CO2H和CN的成员;
R6a和R6b是各自独立地选自H、C1-4烷基、C1-4羟基烷基和C1-4卤代烷基的成员;或任选地R6a和R6b一起形成氧基(=O)或4-6元环杂烷基或3-6元环烷基;
R7是选自甲基、乙基和C1-2卤代烷基的成员;和
下标n是1或2。
在一些实施方案中,B选自下组:
在一些实施方案中,B选自下组:
在一些实施方案中,B为呋喃基或恶唑基,其各自任选被独立地选自卤素、CN、C1-4烷基、C1-4烷氧基和C1-4卤代烷基的R1a和R1b取代。
在一些实施方案中,B为被为CH3或Cl的R1a取代并且任选地被为CH3的R1b取代的呋喃基。
在一些实施方案中,R3是H。
在一些实施方案中,R5a和R5b中的每一个独立地选自H、CH3、Cl和F。
在一些实施方案中,选自下组:
在一些实施方案中,选自下组:
在一些实施方案中,每个R6a和R6b独立地选自H和C1-2烷基。
在一些实施方案中,独立地选自下组
在一些实施方案中,独立地选自下组
在一些实施方案中,R4为H、C1-3烷基或Y,其中C1-3烷基被四唑基或四唑酮基取代,其中四唑基或四唑酮基任选被C1-6烷基、C1-6羟基烷基或C1-4烷基-O-C1-4烷基取代,其中Y选自下组:吡啶基、吡唑基和苯基,其中吡啶基、吡唑基和苯基具有1-3个独立地选自-C1-4烷基、-C1-4烷氧基和-CO2H的取代基。
在一些实施方案中,R4是H。
在一些实施方案中,R4为C1-6烷基,其中C1-6烷基被四唑基或四唑酮基取代,其中四唑基或四唑酮基任选被-C1-6烷基、-C1-6烷氧基、-C1-6羟基烷基、-C1-6卤代烷基、O-C1-6卤代烷基、-C1-4烷基-O-C1-4烷基、-C1-6烷基-NRaRb、-C1-6烷基-CO2H、-C1-6烷基-CO2Ra、-C1-6烷基-CONRaRb、-C1-6烷基-C(O)Ra、-C1-6烷基-OC(O)NRaRb、-C1-6烷基-NRaC(O)Rb、-C1-6烷基-NRaC(O)2Rc、-C1-6烷基-NRaC(O)NRaRb、-C1-6烷基-ORa、-C1-6烷基-S(O)2NRaRb或-C1-6烷基-NRaS(O)2Rb。
在一些实施方案中,R4为C1-3烷基,其中C1-3烷基被四唑基或四唑酮基取代,其中四唑基或四唑酮基任选被-C1-6烷基、-C1-6烷氧基、-C1-6羟基烷基、-C1-6卤代烷基、-C1-4烷基-O-C1-4烷基、-C1-6烷基-NRaRb或-C1-6烷基-CO2H。
在一些实施方案中,R4为C1-3烷基,其中C1-3烷基被四唑基或四唑酮基取代,其中四唑基或四唑酮基任选被C1-3烷基、C1-3羟基烷基或C1-3烷基-O-C1-3烷基取代。
在一些实施方案中,R4选自吡啶基、吡唑基和苯基,其中吡啶基、吡唑基和苯基具有1-3个独立地选自-C1-4烷基、-C1-4烷氧基和-CO2H的取代基。
在一些实施方案中,R4为被四唑基或四唑酮基取代的C1-3烷基,其中四唑基或四唑酮基任选被C1-3烷基取代。
在一些实施方案中,R4选自下组:
在一些实施方案中,R7选自甲基、乙基和CF3。在一些实施方案中,R7是甲基。
在一些实施方案中,提供了式(A1)的化合物、或其药学上可接受的盐、溶剂化物或水合物:
其中R1a选自CH3和Cl;R1b不存在或为CH3;R3是H或D;R4是H或Y;R5a和R5b各自独立地选自H、F、Cl、Br和CH3;R6a和R6b各自独立地选自H和CH3;和R7是甲基或乙基。
在一些实施方案中,R1a是CH3;R1b不存在或为CH3;R3是H或D;R4是H;R5a是H、F、Me或Cl或Br;R5b是H或F;R6a和R6b各自为H;和R7是甲基或乙基;或其药学上可接受的盐、溶剂化物或水合物。
在一些实施方案中,所述化合物在携带R3的碳原子处基本上不含其他异构体。
在一些实施方案中,R4是Y。
在一些实施方案中,提供了式(A2)的化合物、或其药学上可接受的盐、溶剂化物或水合物:
其中R1a选自CH3和Cl;R1b是H或CH3;R3是H或D;R4a和R4b独立地选自卤素、-CN、-C1-4烷基、-C1-4烷氧基、-C1-4羟基烷基、-C1-4卤代烷基、OCF3,-CO2Ra、-CONRaRb、-C(O)Ra、-OC(O)NRaRb、-NRaC(O)Rb、-CH2CO2Ra,和Ra和Rb独立地选自氢、C1-4烷基、C1-4羟基烷基和C1-4卤代烷基;R5a和R5b各自独立地选自H、F、Cl、Br和CH3;R6a和R6b各-自独立地选自H和CH3;和R7选自甲基、乙基和C1-2卤代烷基。
在一些实施方案中,提供了选自下组的化合物或其药学上可接受的盐:
在一些实施方案中,提供了选自下组的化合物或其药学上可接受的盐:
在一些实施方案中,提供了选自下组的化合物或其药学上可接受的盐:
化合物的制备
以下实施例中的方案提供了某些可遵循以获得本发明某些化合物的合成路线。其他路线或下述路线的更改对本领域技术人员是显而易见的,都在本发明的保护范围内。
药物组合物
除在上文提供的化合物外,用于调节人和动物中CCR6和/或CXCR2活性的组合物通常含有药物载体或稀释剂。
本文所用的术语"组合物"应包括含有特定量的特定成分的产品,以及直接或间接由特定量的特定成分组合产生的任何产品。"药学上可接受的"表示载体、稀释剂或赋形剂必须与制剂的其它成分相兼容并且对其接受者无害。
用于本发明化合物给药的药物组合物可以方便地以单位剂型存在,并可通过医学和药物递送领域中熟知的任何方法制备。所有方法包括将活性成分与组成一种或多种辅助成分的载体结合的步骤。药物组合物一般是通过将活性成分与液体载体或细分的固体载体或二者均匀和紧密地结合来制备,然后,如果需要,将产品形成所需制剂。在药物组合物中,活性目标化合物的含量足以对疾病的过程或状况产生所需效果。
含有活性成分的药物组合物可以是适于口服应用的形式,例如作为片剂、锭剂、软糖、水性或油性悬液、可分散粉末或颗粒,乳液和自乳化液(如美国专利申请6,451,339所述),硬或软胶囊剂、糖浆、酏剂、溶液、口腔贴剂、口服凝胶、咀嚼胶、可咀嚼片剂、泡腾粉末和泡腾片剂。用于口服使用的组合物可以根据药物组合物制备领域已知的任何方法制备,此类组合物可含有选自甜味剂、调味剂、着色剂、抗氧化剂和防腐剂中的一种或多种试剂,以提供药学上上等和爽口的制品。片剂含有与无毒的药学上可接受的赋形剂相混合的活性成分,这些赋形剂适用于片剂的制备。这些赋形剂可以是,例如惰性稀释剂,如纤维素、二氧化硅、氧化铝、碳酸钙、碳酸钠、葡萄糖、甘露醇、山梨醇、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如玉米淀粉或藻酸;粘合剂,如PVP、纤维素、PEG、淀粉、明胶或阿拉伯胶,和润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。那些片剂可以是无包衣的或它们可通过已知技术经肠溶性或其它包衣以延迟在胃肠道的崩解和吸收,从而在较长的时期提供持续作用。例如,可利用的延时材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯。还可通过美国专利号4,256,108;4,166,452和4,265,874所述的技术对它们包衣,以便形成渗透性治疗片剂来控制释放。
口服应用的制剂也可以是硬明胶胶囊,其中活性成分与惰性固体稀释剂,例如碳酸钙、磷酸钙或高岭土混合,或是软明胶胶囊,其中活性成分与水或油性介质,例如花生油,液体石蜡,或橄榄油混合。此外,乳液可用非水可混溶成分,例如油来制备,并用表面活化剂,例如单甘油酯-甘油二酯,PEG酯等进行稳定。
水性悬浮液含有与适合制备水性悬浮液的赋形剂相混合的活性成分。此类赋形剂是悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍树胶和阿拉伯胶;分散或润湿剂可以是天然产生的磷脂,例如卵磷脂,或环氧烷与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂肪醇的缩合产物,例如十七烷基亚乙基氧基鲸蜡醇(heptadecaethyleneoxycetanol),或环氧乙烷与源自脂肪酸与己糖醇的偏酯,如聚氧乙烯山梨醇单油酸酯的缩合产物,或环氧乙烷与源自脂肪酸与己糖醇酐的偏酯,如聚乙烯脱水山梨醇单油酸酯的缩合产物。水性悬浮液也可包含一种或多种防腐剂,如对羟基苯甲酸乙酯或正丙酯,一种或多种着色剂,一种或多种调味剂和一种或多种甜味剂,如蔗糖或糖精。
油性悬浮液可将活性成分悬浮于例如花生油、橄榄油、芝麻油或椰油的植物油或例如液体石蜡的矿物油中配制而成。油性悬浮液可包含增稠剂,如蜂蜡、硬石蜡或鲸蜡醇。还可加入如上所述的甜味剂和调味剂以提供可口的口服制品。这些组合物可通过加入抗氧化剂,如抗坏血酸进行防腐。
适用于通过加入水制备水性悬浮液的可分散粉末和颗粒提供了与分散剂或润湿剂、悬浮剂和一种或多种防腐剂相混合的活性成分。适宜的分散剂或润滑剂和悬浮剂的实例为上文提及的那些。也可存在其它赋形剂,如甜味剂、调味剂和着色剂。
本发明的药物组合物也可以是水包油乳液形式。油相可为植物油,如橄榄油或花生油,或矿物油,如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的树胶,如阿拉伯胶或黄蓍树胶,天然产生的磷脂,如大豆,卵磷脂和衍生自脂肪酸与己糖醇酐的酯或偏酯,如脱水山梨醇单油酸酯,和所述偏酯与环氧乙烷的缩合物,如聚氧乙烯脱水山梨醇单油酸酯。乳液也可包含甜味剂和调味剂。
糖浆和酏剂可用甜味剂配制,如甘油、丙二醇、山梨醇或蔗糖。这种制剂还可包含缓和剂,防腐剂,调味剂和/或着色剂。口服溶液剂可与例如环糊精、PEG和表面活化剂组合制备。
药物组合物可为无菌可注射水性或油性悬浮液形式。这种悬浮液可按照公知技术,采用上文所述的合适分散剂或润湿剂和悬浮剂来配制。无菌可注射制品也可以是无毒的胃肠外可接受的稀释剂或溶剂配制的无菌可注射溶液或悬浮液,例如1,3-丁二醇溶液。在可接受的载体和溶剂中,可采用水,林格氏溶液和等渗氯化钠溶液。此外,无菌的不挥发性油常规用作溶剂或悬浮介质。为此目的,可利用任何温和的不挥发性油,包括合成的单或二甘油酸酯。此外,脂肪酸,如油酸可用于制备可注射剂。
本发明化合物也可以栓剂形式以直肠给药。可通过将药物与适宜的无刺激性赋形剂混合来制备这些组合物,所述赋形剂在常温下为固体,但在直肠温度下为液体,从而在直肠内熔化释放出药物。这种物质包括椰子油和聚乙二醇。此外,可借助溶液或软膏,通过眼部递送给予化合物。还有,可借助离子渗透贴剂等实现本发明化合物的经皮给药。就局部使用而言,可利用含有本发明化合物的乳膏、软膏、凝胶剂、溶液或悬浮液等。如本文所用,局部应用也意在包括采用漱口剂和漱口药。
本发明化合物可放置于医疗器械中进行配制,所述医疗器械可包括任何各种常规的移植物、支架,包括覆膜支架、导管、球囊、筐或其他可配置或永久植入体腔内的器械。如一个特定的实施例,希望具有能够递送本发明化合物至已经经介入治疗的身体部位的器械或方法。
在示例性的实施例中,本发明的抑制剂可放置于医疗器械中,例如支架,并且递送至身体某部位的治疗位点用于治疗。
支架已被用作递送治疗剂(即,药物)的载体。血管内支架通常永久地植入冠状或周围血管中。支架设计包括美国专利号4,733,655(Palmaz)、4,800,882(Gianturco)、或4,886,062(Wiktor)中的那些。这些设计包括金属和聚合物支架,以及自膨胀和球囊膨胀支架。所述支架也可用于在与血管接触的部位递送药物,如在美国专利5,102,417(Palmaz)以及国际专利申请WO91/12779(美敦力公司(Medtronic,Inc.))和WO90/13332(雪松西奈医学中心(Cedars-SanaiMedicalCenter))、美国专利5,419,760(Narciso,Jr.)和美国专利5,429,634(Narciso,Jr.)中所公开的。所述支架也用于递送病毒至内腔壁用于基因传递,如美国专利5,833,651(Donovan等)中所公布的。
在一个实施例中,所述抑制剂可在医疗器械(例如支架)的生物相容涂层形成过程中与聚合物组合物相结合。由这些组分制得的涂层通常是均匀的,可用于涂覆一些植入装置。
所述聚合物可以是非降解性的或生物可吸收的聚合物,这取决于期望的释放速率或期望的聚合物稳定性程度,但是生物可吸收的聚合物是优选的实施方式,不同于非降解性的聚合物,生物可吸收的聚合物在植入后不会存在很久,以免引起任何不良反应及慢性局部反应。可使用的生物可吸收聚合物包括但不限于:聚(L-乳酸)、聚己内酯、聚乙交酯(PGA)、聚(丙交酯-共-乙交酯)(PLLA/PGA)、聚(羟基丁酸酯)、聚(羟基丁酸酯-共-戊酸酯)、聚二噁烷酮、聚原酸酯、聚酐、聚(乙醇酸)、聚(D-乳酸)、聚(L-乳酸)、聚(D、L-乳酸)、聚(D、L-丙交酯)(PLA)、聚(L-丙交酯)(PLLA)、聚(乙醇酸-共-三亚甲基碳酸酯)(PGA/PTMC)、聚环氧乙烷(PEO)、聚二噁烷酮(PDS)、聚磷酸酯、聚磷酸酯氨基甲酸乙酯、聚(氨基酸)、氰基丙烯酸酯、聚(三亚甲基碳酸酯)、聚(亚氨基碳酸酯)、共聚(醚-酯)(例如、PEO/PLA)、聚亚烷基草酸盐、聚磷腈和生物分子(例如纤维蛋白、纤维蛋白原、纤维素、淀粉、胶原和透明质酸)、聚ε己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯、水凝胶的交联或两亲嵌段共聚物、以及本领域中已知的其它合适的生物可吸收聚合物。此外,可以使用具有相对低的慢性组织反应的非降解性聚合物,例如聚氨酯、有机硅以及聚酯;也可以使用其他聚合物,如果这些聚合物可以在医疗器械上溶解、固化或聚合,例如聚烯烃、聚异丁烯和乙烯-α烯烃共聚物,丙烯酸聚合物和共聚物、乙烯基卤化物聚合物和共聚物,如聚氯乙烯;聚乙烯吡咯烷酮;聚乙烯醚,如聚乙烯基甲醚;聚偏二卤乙烯,如聚偏二氟乙烯和聚偏二氯乙烯;聚丙烯腈、聚乙烯酮;聚乙烯基芳烃,例如聚苯乙烯、聚乙烯酯,例如聚醋酸乙烯酯;乙烯基单体彼此间的共聚物,以及,烯烃,例如乙烯-甲基丙烯酸甲酯共聚物、丙烯腈-苯乙烯共聚物、ABS树脂和乙烯-乙酸乙烯酯共聚物;吡喃共聚物、聚羟基丙基甲基丙烯酰胺-苯酚;聚羟基乙基-天冬酰胺-苯酚;棕榈酰残基取代的聚环氧乙烷-聚赖氨酸;聚酰胺,例如尼龙66和聚己内酰胺;醇酸树脂、聚碳酸酯;聚甲醛;聚酰亚胺;聚醚;环氧树脂、聚氨酯;人造纤维;人造纤维-三醋酸酯;纤维素、醋酸纤维素、丁酸纤维素;乙酸丁酸纤维素;玻璃纸;硝酸纤维素;丙酸纤维素;纤维素醚;和羧甲基纤维素。
聚合物和半渗透聚合物基质可加工成成型制品,例如瓣膜、支架、导管、假体等。
在本发明的一个实施例中,本发明的抑制剂偶联至聚合物或半渗透聚合物基质,所述半渗透聚合物基质形成为支架或支架型移植物器械。
典型地,聚合物可通过旋转涂布、浸渍或喷涂应用到可植入器械的表面。本领域已知的其他方法也可以用于此目的。喷涂的方法包括传统的方法,以及带有喷墨型分配器的微沉积技术。额外地,可使用图片图形化将所述聚合物沉积于可植入器械上,使得聚合物仅放置于器械的特定部分。所述器械的涂层提供环绕器械的均匀的层,考虑到不同分析物通过器械涂覆的增强的扩散。
在本发明的优选实施例中,配制所述抑制剂用于从聚合物涂层释放到该医疗器械所放置的环境中。优选地,通过使用几种公知的涉及聚合物载体或涂层以控制洗脱的技术中的至少一种技术,使所述抑制剂以受控的方式在延长的时间范围(如,月)内释放。一些此类技术此前在美国专利申请20040243225A1中被描述。
此外,如美国专利6,770,729中所描述,聚合物组合物的试剂和反应条件可控,以便控制来自聚合物涂层的抑制剂的释放。例如,可以调节一个或多个聚合物涂层的扩散系数以控制来自聚合物涂层的抑制剂的释放。在该主题的变化中,可以控制一个或多个聚合物涂层的扩散系数以调节存在于医疗器械所放置的环境中的分析物水平(例如,促进一部分聚合物的分解或水解的分析物),以得到聚合物组成中的一种或多种组分(例如,从而调节抑制剂从聚合物涂层的释放)。然而,本发明另一个实施例包括具有多个聚合物涂层的器械,每一个涂层具有多个扩散系数。在本发明此类实施例中,抑制剂从聚合物涂层的释放可通过多个聚合物涂层释放。
在本发明的另一个实施例中,抑制剂从聚合物涂层的释放通过调节所述聚合物组合物的一个或多个性质来控制,例如,一种或多种内源或外源性化合物的存在,或者,聚合物组合物的pH。例如,某些聚合物组合物可设计为释放所述抑制剂,响应于所述聚合物组合物pH的下降。可替代地,某些聚合物组合物可设计为释放所述抑制剂,响应于氢过氧化物的存在。
在一些实施方案中,提供了包含本发明化合物的药物组合物。在一些实施方案中,所述药物组合物还包含一种或多种另外的治疗剂。在一些实施方案中,所述一种或多种另外的治疗剂选自细胞毒性化疗、抗癌或抗肿瘤疫苗、抗免疫细胞因子疗法、免疫细胞因子疗法、嵌合抗原受体(CAR)的T细胞受体、基因转移治疗、检查点抑制剂、皮质类固醇、类维生素A样药剂、抗肿瘤药物和干扰素类似物。在一些实施方案中,所述一种或多种另外的治疗剂选自下组:TNFα配体抑制剂、TNF结合剂、IL-1配体抑制剂、IL-6配体抑制剂、IL-8配体抑制剂;IL-17拮抗剂、钙调神经磷酸酶抑制剂、TNF拮抗剂、视黄酸受体γ拮抗剂、IL-17A配体抑制剂;IL-17F配体抑制剂、RIP-1激酶抑制剂、神经鞘氨醇-1-磷酸受体-1拮抗剂、神经鞘氨醇-1-磷酸受体-1调节剂、Rho相关蛋白激酶2抑制剂、IL-12拮抗剂;IL-23拮抗剂、II型TNF受体调节剂、IL-23A抑制剂、PDE4抑制剂、JAK酪氨酸激酶抑制剂、Jak1酪氨酸激酶抑制剂;Jak3酪氨酸激酶抑制剂、组胺H1受体拮抗剂、视黄酸受体激动剂、膜铜胺氧化酶抑制剂、PI3K调节剂、磷酸肌醇-3激酶δ抑制剂、线粒体10kDa热休克蛋白刺激剂、腺苷A3受体激动剂、半乳糖凝集素-3抑制剂、F1F0ATP合酶调节剂、GM-CSF配体抑制剂、维生素D3受体激动剂、糖皮质激素激动剂、组胺H4受体拮抗剂、CCR3趋化因子拮抗剂、嗜酸细胞活化趋化因子配体抑制剂、神经鞘氨醇-1-磷酸受体-1调节剂、磷脂酶A2抑制剂、PDE4抑制剂、白蛋白调节剂、TLR-7拮抗剂、TLR-8拮抗剂、TLR-9拮抗剂、CD40配体受体拮抗剂、Src酪氨酸激酶抑制剂、微管蛋白结合剂、白介素-1α配体抑制剂、组蛋白脱乙酰酶-1抑制剂、组蛋白脱乙酰酶-2抑制剂、组蛋白脱乙酰酶-3抑制剂、组蛋白脱乙酰酶-6抑制剂、核苷逆转录酶抑制剂、核因子κB抑制剂、STAT-3抑制剂、甲状旁腺激素配体抑制剂;维生素D3受体激动剂、T细胞表面糖蛋白CD28刺激剂、组胺H4受体拮抗剂、TGFβ激动剂、P-选择素糖蛋白配体-1刺激剂、DHFR抑制剂、视黄酸受体γ调节剂、胞质磷脂酶A2抑制剂、类视色素X受体调节剂、β-连环蛋白抑制剂、CREB结合蛋白抑制剂、TrkA受体拮抗剂、T细胞分化抗原CD6抑制剂、ADP核糖基环化酶-1抑制剂、白介素-1β配体调节剂;胰岛素受体底物-1抑制剂、DHFR抑制剂、IL-8拮抗剂、阻断CTLA-4(CD152)、PD-1(CD279)、PDL-1(CD274)、TIM-3、LAG-3(CD223)、VISTA、KIR、NKG2A、BTLA、PD-1H、TIGIT、CD96、4-1BB(CD137)、4-1BBL(CD137L)、GARP、CSF-1R、A2AR、CD73、CD47、色氨酸2,3-双加氧酶(TDO)或吲哚胺2,3双加氧酶(IDO)活性的药物、以及OX40、GITR、4-1BB、ICOS、STING或CD40的激动剂。
由CCR6和/或CXCR2调节的疾病的治疗方法
一方面,本发明提供治疗或预防CCR6介导的病症或疾病和/或CXCR2介导的病症或疾病的方法,所述方法给予具有此类病症或疾病的对象治疗有效量的本发明的任意化合物。用于本方法的优选化合物是本文作为优选实施方式的那些化合物,以及在下文实施例中专门列出的化合物;以及本文提供的特定结构的化合物。本文将"对象"定义为包括动物,例如哺乳动物,包括但不限于灵长类动物(例如,人)、奶牛、绵羊、山羊、马、狗、猫、家兔、大鼠、小鼠等等。在优选的实施方式中,所述对象是人。
如本文所用,短语"CCR6介导的病症或疾病"和相关的短语及术语是指以不适当的(例如,小于或大于正常的)CCR6功能活性为特征的某种病症或疾病。不适当的CCR6功能活性可因正常情况下不表达CCR6的细胞表达CCR6,CCR6表达增加(导致,例如炎性和免疫调节性紊乱和疾病)或CCR6表达降低所致。不适当的CCR6功能活性也可因通常情况下不分泌CCL20的细胞分泌CCL20,CCL20表达增加(导致,例如炎性和免疫调节性紊乱和疾病)或CCL20表达降低所致。不适当的CCR6功能活性可以完全或部分介导CCR6介导的病症或疾病。然而,CCR6介导的病症或疾病是调节CCR6对潜在的病症或疾病产生某些疗效的病症或疾病(例如,CCR6拮抗剂导致至少一些患者的患者舒适程度有某些改进)。
类似地,短语“CXCR2介导的病症或疾病”和相关的短语和术语是指以不当的,例如小于或高于正常的CXCR2功能活性为特征的的病症或疾病。不适当的CXCR2功能活性可能由于通常不表达CXCR2的细胞中的CXCR2表达、CXCR2表达增加(导致例如炎症和免疫调节障碍和疾病)或CXCR2表达下降而引起。CXCR2介导的病症或疾病可能完全或部分由不适当的CXCR2功能活性介导。然而,CXCR2介导的病症或疾病是调节CXCR2对潜在的病症或疾病产生某些疗效的病症或疾病(例如,CXCR2拮抗剂导致至少一些患者的患者舒适程度有某些改善)。
术语"治疗有效量"表示标的化合物的用量,其会引起研究人员,兽医、医师或其他临床医师所探寻组织、系统、动物或人的生物学或医学反应。
与炎症、感染和癌症相关的疾病和病症可用本发明化合物和组合物治疗或预防。在一组实施方式中,包括慢性病的人或其他物种的疾病或病症可以用CCR6功能的抑制剂治疗。这些疾病或病症包括:(1)变应性疾病,例如全身过敏性或超敏性反应,药品过敏、昆虫叮咬过敏和食物过敏,(2)炎性肠病,例如克罗恩病、溃疡性结肠炎、回肠炎和肠炎,(3)阴道炎,(4)银屑病和炎性皮肤病,例如皮炎、湿疹、特应性皮炎、变应性接触性皮炎、荨麻疹和瘙痒症、白癜风,(5)脉管炎,(6)脊椎关节病,(7)硬皮病,(8)哮喘和呼吸变应性疾病,例如过敏性哮喘、过敏性鼻炎,超敏性肺病等,(9)自身免疫性疾病,例如关节炎(包括类风湿性和银屑病性)、以及例如桥本氏甲状腺炎和格雷夫斯病、多发性硬化症、全身性红斑狼疮、I型糖尿病、肾小球肾炎等,(10)移植物排斥(包括同种异体移植物排斥和移植物抗宿主病),(11)需要抑制不良炎症的其它疾病,例如动脉粥样硬化、肌炎、神经变性疾病(例如,阿耳茨海默病)、脑炎、脑膜炎、肝炎、肾炎、脓毒病、结节病、变态反应性结膜炎、耳炎、慢性阻塞性肺病、鼻窦炎、贝赫切特综合征和痛风。
优选地,本方法的方法涉及选自下组的疾病或病症的治疗:过敏性疾病、银屑病、皮肤病症(如特异性皮炎)和哮喘和硬皮病。
在另一组实施方式中,可调节依赖于CCR6调节的调节性T细胞运输以治疗包括以下的疾病或病症:癌症、感染性疾病(病毒感染,例如HIV感染,和细菌感染)和免疫抑制性疾病,例如器官移植状况和皮移植状况。术语"器官移植状况"意在包括骨髓移植状况和实体器官(例如,肾、肝、肺、心脏、胰脏或其组合)移植状况。
考虑到它们抑制CXCR2的结合,本发明化合物可用于治疗由CXCR2介导的病症或疾病,例如炎性或过敏性病症或疾病,特别是慢性阻塞性肺气道或肺部疾病(COPD、COAD或COLD),包括慢性支气管炎或与之相关的呼吸困难、肺气肿、闭塞性细支气管炎综合征和严重哮喘。
本发明化合物还可用于治疗各种疾病,例如癌症,例如结直肠癌、卵巢癌、前列腺癌、包括转移性黑素瘤的黑素瘤、肺癌(例如非小细胞肺癌)、肾细胞癌;肿瘤血管生成、缺血/再灌注损伤、移植物功能延迟、骨关节炎、伴有骨髓纤维化的骨髓化生、子宫肌腺症、接触性过敏(皮肤),并在伤口愈合。根据本发明的治疗可以是症状性或预防性的。
治疗慢性支气管炎或COPD的预防效果将通过降低频率或严重程度来证明,将提供症状缓解和减轻疾病进展,改善肺功能。其进一步可以通过减少对其他症状性治疗(即用于或打算限制或中止出现的症状发作的治疗,例如抗炎(例如皮质类固醇)或支气管扩张)的要求来证明。
本发明适用的其他炎症或阻塞性气道疾病和病症包括急性肺损伤(ALI)、急性/成人呼吸窘迫综合征(ARDS)、特发性肺纤维化、纤维性肺、气道高反应性、呼吸困难、肺纤维化、过敏性气道炎症、小气道疾病、肺癌、患有镰状细胞病和肺高血压患者中的急性胸部综合征、以及由于其他药物治疗(特别是其他吸入药物治疗)导致的气道高反应性恶化。本发明还适用于治疗任何类型或起因的支气管炎,包括例如急性、花生仁吸入性、卡他性、格鲁布性(croupus)、慢性或结核性支气管炎。本发明适用的进一步的炎症性或阻塞性气道疾病包括任何类型或起因的肺尘症(炎症,通常是职业性肺部疾病,无论是慢性还是急性常伴有气道阻塞以及由于反复吸入粉尘引起),其包括例如矾土肺、炭肺、石棉沉着病、石末沉着病、驼鸟毛尘肺、肺铁末沉着病、硅肺病、烟尘肺和棉尘肺。
本发明化合物还可用于治疗呼吸道病毒感染,其加剧诸如哮喘、慢性支气管炎、COPD、中耳炎和鼻窦炎等潜在慢性病症。所治疗的呼吸道病毒感染可能与继发性细菌感染有关,如中耳炎、鼻窦炎或肺炎。
本发明化合物还可用于治疗皮肤的炎性病症,例如银屑病、特应性皮炎、红斑狼疮和其他皮肤的炎性或过敏性病症。
本发明化合物也可用于治疗其他疾病或病症,特别是具有炎症成分的疾病或病症,例如影响鼻子的疾病(包括过敏性鼻炎,例如萎缩性、慢性或季节性鼻炎)、胃肠道的炎性病症(例如炎性肠病,如溃疡性结肠炎和克罗恩病)、骨和关节疾病(包括类风湿性关节炎、银屑病性关节炎)和其他疾病,如动脉粥样硬化、多发性硬化症、和急性及慢性同种异体移植排斥(例如心脏、肾脏、肝脏、肺脏或骨髓移植后)。
本发明化合物还可用于治疗内毒素性休克、肾小球性肾炎、大脑和心脏缺血、阿尔茨海默氏病、囊性纤维化、病毒感染和与其相关的恶化、获得性免疫缺陷综合征(AIDS)、多发性硬化症(MS)、幽门螺杆菌相关性胃炎和癌症(特别是卵巢癌的生长)。
本发明的化合物还可用于治疗人类中病毒感染引起的症状,其由人鼻病毒、其他肠病毒、冠状病毒、疱疹病毒、流感病毒、副流感病毒、呼吸道合胞病毒或腺病毒引起。本发明的化合物也可用于治疗胰腺炎。
本发明化合物抑制炎性病症例如炎性气道疾病的有效性可以在气道炎症或其他炎性病症的动物模型(例如小鼠、大鼠或兔模型)中证实,例如由Wada等人,J.Exp.Med 180:1135-40(1994);Sekido等,Nature 365:654-57(1993);Modelska等人,Am.J.Respir.Crit.Care.Med 160:1450-56(1999);和Laffon等人,Am.J.Respir.Crit.CareMed.160:1443-49(1999)的描述。
在一些实施方案中,本文提供了用于治疗由CXCR2介导的病症或疾病的方法,例如炎性或过敏性病症,特别是炎性或阻塞性气道疾病,其包括向所需受试者(特别是人)给予有效量的游离形式或如上文所述的药学上可接受的盐形式的式(A)、(A1)、(A2)、(I)或(Ia1)化合物。在另一方面,本发明提供了如上所述的以游离形式或药学上可接受的盐形式的式(A)、(A1)、(A2)、(I)或(Ia1)化合物的用途,用于制备用于治疗由CXCR2介导的病症或疾病(例如炎性或过敏性病症或疾病,特别是炎性或阻塞性气道疾病)的药物。
本文所述的式(A)、(A1)、(A2)、(I)和(Ia1)化合物还可用作与其他药物(例如抗炎药、支气管扩张药、抗组胺药或止咳药物)组合使用的共治疗化合物,特别是用于治疗例如上文提及的那些阻塞性或炎性气道疾病,例如作为这类药物治疗活性的增强剂或作为减少所需剂量或这些药物的潜在副作用的手段。本发明的化合物可以与其他药物混合于固定的药物组合物中,或者其可以单独地在另一种药物之前、同时或之后给予。
取决于待治疗的疾病和对象的条件,本发明化合物可以通过口服、胃肠外(例如,肌肉内、腹膜内、静脉内、ICV、脑池内注射或输注、皮下注射或植入)、吸入剂、经鼻、经鞘、经直肠、舌下、或局部给药途径给予,可以单独或一起配制成含有适合各给药途径的常规无毒药学上可接受载体、佐剂和运载体的合适剂量单位制剂。本发明也考虑利用长效制剂给予本发明化合物。
本领域的技术人员将理解调节CCR6活性的药剂可在治疗方案中与其它治疗剂和/或化疗剂或辐射组合。在一些病例中,如果不与本发明的组合物一起提供,化疗剂或辐射的用量将为亚治疗的。本领域的技术人员会知道"组合"可以涉及治疗方法的组合(即,两种或多种药品作为混合物施用,或至少同时或至少在不同时间引入对象,但使得二者同时在对象的血流中)。另外,本发明的组合物可以在第二治疗方案之前或之后给予,例如在某剂量的化疗或放疗之前或之后。
本发明化合物可相应地用于多种炎症和免疫调节紊乱和疾病的预防和治疗中。
在治疗或预防需要趋化因子受体调节的病症中,合适的剂量水平通常是每天约0.001到100mg/kg患者体重,所述剂量可以在一剂或多剂中给予。优选地,剂量水平是每天约0.01到约25mg/kg;更优选地,每天约0.05到约10mg/kg。合适的剂量水平可以是每天约0.01到25mg/kg,每天约0.05到10mg/kg,或每天约0.1到5mg/kg。在该范围内,剂量可以是每天0.005到0.05、0.05到0.5或0.5到5.0mg/kg。对于口服给药,优选以片剂的形式给予组合物,所述片剂含有1.0到1000毫克活性成分,特别是1.0、5.0、10.0、15.0、20.0、25.0、50.0、75.0、100.0、150.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0和1000.0毫克活性成分,用于对待治疗患者的病症调节剂量。所述组合物可以每天1-4次的方案给予,优选每天1次或2次。
然而,应该理解,任何具体患者的特定剂量水平和剂量频率可以变化,取决于各种因素,包括所用具体化合物的活性、该化合物的代谢稳定性和作用长度、对象的年龄、体重、遗传特征、总体健康状况、性别和饮食,以及给药方式和时间、排出率,药物组合和所治疗对象的特定状况的严重程度。
与炎症、免疫紊乱、感染和癌症相关的疾病和病症可用本发明的化合物、组合物以及方法治疗或预防。
本发明所述化合物和组合物可以与具有相关用途的其他化合物和组合物联用以预防和治疗感兴趣的病症和疾病,例如炎症或自身免疫紊乱、病症和疾病,包括炎症性肠病、类风湿性关节炎、骨关节炎、银屑病关节炎、多发性关节炎、多发性硬化症、过敏性疾病、银屑病、特应性皮炎和哮喘,以及上面提到的那些病状。
例如,在治疗或预防炎症或自身免疫疾病或例如与骨质疏松有关的关节炎中,本发明化合物与组合物可与抗炎剂或止痛剂(如阿片激动剂、脂氧合酶抑制剂(如5-脂肪氧合酶抑制剂)、环氧合酶抑制剂(如环加氧酶-2抑制剂)、白介素抑制剂(例如白介素-1抑制剂)、NMDA拮抗剂、一氧化氮的抑制剂或一氧化氮的合成抑制剂、非甾体抗炎剂、或细胞因子抑制抗炎剂)一起使用,例如与化合物(诸如对乙酰氨基酚、阿司匹林、可待因、芬太尼、布洛芬、吲哚美辛、酮咯酸、吗啡、萘普生、非那西丁、吡罗昔康、类固醇止痛剂、舒芬太尼、苏林酸、替尼达普等)一起使用。同样地,本发明化合物和组合物可以与上面列出的止痛剂一起施用;与增效剂,如咖啡因,H2拮抗剂(例如,雷尼替丁)、二甲基硅油,氢氧化铝或氢氧化镁,一起施用;与解充血剂,如苯肾上腺素、苯丙醇胺、伪麻黄碱、羟甲唑啉、肾上腺素(ephinephrine)、萘甲唑啉、赛洛唑啉、六氢脱氧麻黄硷、或者左旋脱氧麻黄碱,一起施用;与镇咳药,如可待因、二氢可待因酮、咳美芬、咳必清、或右美沙芬,一起施用;与利尿剂一起施用;以及与镇静或非镇静抗组胺药一起施用。
同样地,本发明化合物和组合物可以与其他药品联用,所述其他药品用于治疗、预防、抑制或改善本发明化合物和组合物有用的疾病或病症。此类其他药物可以通过常用的途径和用量,与本发明化合物或组合物同时或顺序给予。当本发明化合物或组合物与一种或多种其他药物同时使用时,除本发明化合物或组合物之外,含有此类其他药物的药物组合物是优选的。所以,本发明的药物组合物包括除本发明的化合物或组合物之外,还含有一种或多种其他活性成分或治疗剂的那些。可与本发明化合物或组合物联用的,分别给予或在同一药物组合物中给予的其它治疗剂的例子包括但不限于:(a)VLA4拮抗剂,(b)皮质类固醇,例如氯地米松、甲基氢化泼尼松、倍他米松、强的松、泼尼松龙、地塞米松、氟替卡松、氢化可的松、布地奈德、曲安奈德、沙美特罗、沙美特罗、舒喘宁、福莫特罗;(c)免疫抑制剂,例如环孢菌素(环胞菌素A、)、他克莫司(FK506,)、雷帕霉素(西罗莫司,)、托法替尼和其他FK-506型免疫抑制剂,和麦考酚酯,例如,麦考酚酸乙酯(d)抗组胺药(H1-组胺拮抗剂),例如溴苯吡胺、氯芬胺、右氯苯那敏、曲普立啶、氯马斯汀、苯海拉明、二苯拉林、曲吡那敏、羟嗪、甲吡咯嗪、异丙嗪、三甲泼拉嗪、哌吡庚啶、赛庚啶、安他心、非尼拉敏吡拉明、阿司咪唑、特非那定、氯雷他定、西替利嗪、非索非那定、脱碳乙氧基氯雷他定等;(e)非甾体抗哮喘剂(例如,特布他林、奥西那林、非诺特罗、异他林、舒喘灵、比托特罗和吡布特罗)、茶碱、色甘酸钠、阿托品、异丙托溴铵、白三烯拮抗药(例如,扎氟普汀(zafmlukast)、孟鲁司特、普仑司特、伊拉司特、泊比司特和SKB-106、203)、白三烯生物合成抑制剂(齐留通,BAY-1005);(f)非甾体抗炎药(NSAID),例如丙酸衍生物(例如,阿明洛芬、苯恶洛芬、布氯酸、卡洛芬、芬布芬、非诺洛芬、氟洛芬、氟联苯丙酸、异丁苯丙酸、吲哚洛芬、酮洛芬、咪洛芬(niroprofen)、萘普生、奥沙普秦、吡咯芬、普拉洛芬、舒洛芬、噻洛芬酸和硫恶洛芬)、乙酸衍生物(例如,吲哚美辛、阿西美辛、阿氯芬酸、环氯茚酸、双氯芬酸、芬氯酸、芬克洛酸、芬替酸、呋罗芬酸、异丁芬酸、伊索克酸、奥普平酸(oxpinac)、舒林酸、硫平酸、托美丁、齐多美辛及佐美酸)、芬那酸衍生物(例如,氟芬那酸、甲氯芬那酸、甲芬那酸、尼氟酸及托芬那酸),联苯羧酸衍生物(例如,二氟尼柳及氟苯柳)、昔康类(例如,伊索昔康、吡罗昔康、舒多昔康及替诺昔康)、水杨酸酯(例如,乙酰水杨酸及柳氮磺胺吡啶)及吡唑啉酮(例如,阿扎丙宗、贝吡龙(bezpiperylon)、非普拉宗、莫非布宗、羟布宗及保泰松);(g)环氧合酶-2(COX-2)抑制剂,例如,塞来考昔和罗非考昔(h)IV型磷酸二酯酶(PDEIV)的抑制剂;(i)金化合物,例如,金诺芬及金硫葡糖;(j)依那西普(k)抗体治疗剂,例如,奥素克隆(OKT3)、达珠单抗巴利昔单抗英夫利昔阿达木单抗高利单抗利妥昔单抗托珠单抗(l)趋化因子受体(特别是CCR5、CXCR2、CXCR3、CCR2、CCR3、CCR4、CCR7、CX3CR1和CXCR6)的其他拮抗剂;(m)润滑剂或软化剂,例如矿脂和羊毛脂;(n)角质层分离剂(例如,他佐罗汀);(o)维生素D3衍生物,例如,卡泊三烯或卡泊三醇(p)PUVA;(q)地蒽酚(r)依曲替酯和异维A酸;和(s)多发性硬化症治疗剂,例如干扰素β-1β干扰素(β-1α咪唑硫嘌呤格拉默醋酸盐糖皮质激素(例如,泼尼松龙)和环磷酰胺;(t)DMARDS,例如甲氨蝶呤和来氟米特,(u)其他化合物,例如5-氨基水杨酸和其前药;羟化氯喹;D-青霉胺;抗代谢物,例如咪唑硫嘌呤、6-巯嘌呤和甲氨蝶呤;DNA合成抑制剂,例如羟基脲和微管破坏剂,例如秋水仙碱和蛋白酶体抑制剂例如硼替佐米(v)抗CTLA-4、PD1或PD-L1的抗体。可改变本发明化合物与第二活性成份的重量比,取决于各成份的有效剂量。一般而言,使用各成份的有效剂量。因此,例如,当本发明化合物与NSAID组合时,本发明化合物与NSAID的重量比通常为约1000∶1至约1∶1000,优选约200∶1至约1∶200。本发明化合物与其它活性成份的组合通常也处于上述范围内,但在各情况下,应使用各活性成份的有效剂量。
在一些实施方案中,提供了在有需要的受试者中治疗CXCR2和/或CCR6介导的疾病或病症的方法,所述方法包括施用有效量的本发明的化合物或其药学上可接受的盐、或包含本公开化合物的药物组合物给予所述受试者。在一些实施方案中,疾病或病症是急性或慢性炎性病症。在一些实施方案中,急性或慢性炎性病症为银屑病、干眼病、动脉粥样硬化、盘状红斑狼疮、类风湿性关节炎、狼疮、辐射诱导的纤维化肺病、自身免疫性大疱性皮肤病(AIBD)、慢性阻塞性肺病或臭氧诱导的气道炎症。在一些实施方案中,急性或慢性炎症是银屑病。
在一些实施方案中,该疾病是癌症。在一些实施方案中,所述癌症选自下组:皮肤T细胞淋巴瘤、非霍奇金淋巴瘤、蕈样肉芽肿、佩吉特样网状细胞增多症、塞泽里综合征、肉芽肿松弛皮肤、淋巴瘤样丘疹病、慢性苔藓样糠疹、急性苔藓痘疮样糠疹、CD30+皮肤T细胞淋巴瘤、继发性皮肤CD30+大细胞淋巴瘤、非蕈样肉芽肿CD30皮肤大T细胞淋巴瘤、多形性T细胞淋巴瘤、伦纳特淋巴瘤、皮下T细胞淋巴瘤、血管中心淋巴瘤、母细胞性NK细胞淋巴瘤(blastic NK-cell lymphoma)、B细胞淋巴瘤、霍奇金淋巴瘤(HL)、头颈部肿瘤;鳞状细胞癌、横纹肌肉瘤、路易士肺癌(LLC)、非小细胞肺癌、食管鳞状细胞癌、食道腺癌、肾细胞癌(RCC)、结肠直肠癌(CRC)、急性髓细胞样白血病(AML)、乳腺癌、胃癌、前列腺小细胞神经内分泌癌(SCNC)、肝癌、成胶质细胞瘤、肝癌、口腔鳞状细胞癌、胰腺癌、甲状腺乳头状癌、肝内胆管细胞癌、肝细胞癌、骨癌、转移和鼻咽癌。在一些实施方案中,该疾病是结肠直肠癌。在一些实施方案中,该疾病是皮肤T细胞淋巴瘤。
在一些实施方案中,化合物单独使用或与一种或多种其他抗癌疗法组合使用。在一些实施方案中,所述化合物与细胞毒性化疗、抗癌疫苗、抗肿瘤疫苗、抗免疫细胞因子疗法、免疫细胞因子疗法、检查点抑制剂和嵌合抗原受体(CAR)T细胞受体、基因转移治疗中的一种或多种联合使用。在一些实施方案中,该化合物与至少一种检查点抑制剂组合使用。在一些实施方案中,所述化合物与一种或多种阻断CTLA-4(CD152)、PD-1(CD279)、PDL-1(CD274)、TIM-3、LAG-3(CD223)、VISTA、KIR、NKG2A、BTLA、PD-1H、TIGIT、CD96、4-1BB(CD137)、4-1BBL(CD137L)、GARP、CSF-1R、A2AR、CD73、CD47、色氨酸2,3-双加氧酶(TDO)或吲哚胺2,3双加氧酶(IDO)活性的化合物组合使用。在一些实施方案中,所述化合物与一种或多种OX40、GITR、4-1BB、ICOS、STING或CD40的激动剂组合使用。
在一些实施方案中,给予本发明的化合物或其药学上可接受的盐和/或其前药或本发明的组合物以治疗结直肠癌、转移、晚期皮肤T细胞淋巴瘤、胰腺癌、非霍奇金淋巴瘤、蕈样肉芽肿、佩吉特样网状细胞增多症、塞泽里综合征、肉芽肿松弛皮肤、淋巴瘤样丘疹病、慢性苔藓样糠疹、急性苔藓痘疮样糠疹、CD30+皮肤T细胞淋巴瘤、继发性皮肤CD30+大细胞淋巴瘤、非蕈样肉芽肿CD30-皮肤大T细胞淋巴瘤、多形性T细胞淋巴瘤、伦纳特淋巴瘤、皮下T细胞淋巴瘤、血管中心淋巴瘤、母细胞性NK细胞淋巴瘤、B细胞淋巴瘤、霍奇金淋巴瘤(HL)、干眼病、动脉粥样硬化或盘状红斑狼疮。
在一些实施方案中,给予本发明的化合物或其药学上可接受的盐和/或其前药或本公开的组合物以治疗胰岛素依赖性糖尿病、膀胱炎、胰岛细胞移植排斥;肾移植排斥;肝移植排斥;肺移植排斥、COPD或流感。
在一些实施方案中,给予本发明的化合物或其药学上可接受的盐和/或其前药或本发明的组合物以治疗黑素瘤、成胶质细胞瘤、食道肿瘤、鼻咽癌、葡萄膜黑素瘤、淋巴瘤、淋巴球淋巴瘤、原发性CNS淋巴瘤、T细胞淋巴瘤、弥漫性大B细胞淋巴瘤、原发性纵隔大B细胞淋巴瘤、前列腺癌、阉割抵抗性前列腺癌、慢性髓细胞白血病、卡波西肉瘤纤维肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、血管肉瘤、淋巴管肉瘤、滑膜瘤、脑膜瘤、平滑肌肉瘤、横纹肌肉瘤、软组织肉瘤、肉瘤、脓毒症、胆管肿瘤、基底细胞癌、胸腺瘤、甲状腺癌、甲状旁腺癌、子宫癌、肾上腺癌、肝脏感染、默克尔细胞癌、神经肿瘤、滤泡中心淋巴瘤、结肠癌、霍奇金氏病、非霍奇金氏淋巴瘤、白血病、慢性或急性白血病(包括急性骨髓性白血病、慢性骨髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病)、多发性骨髓瘤、卵巢肿瘤、骨髓增生异常综合征、皮肤或眼内恶性黑素瘤、肾细胞癌、小细胞肺癌、肺癌、间皮瘤、乳腺癌、鳞状非小细胞肺癌(SCLC)、非鳞状NSCLC、结肠直肠癌、卵巢癌、胃癌、肝细胞癌、胰腺癌、胰腺癌、胰腺导管腺癌、头颈鳞状细胞癌、头颈癌、胃肠道、胃癌、骨癌、皮肤癌、直肠癌、肛门区癌症、睾丸癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、食管癌、小肠癌、内分泌系统癌症、尿道癌、阴茎癌、膀胱癌、肾癌、输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、肿瘤血管生成、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、表皮样癌、石棉肺、癌、腺癌、乳头状癌、囊腺癌、支气管癌、肾细胞癌、移行细胞癌、绒毛膜癌、精原细胞瘤、胚胎性癌、威尔姆氏肿瘤(wilm'stumor)、多形性腺瘤、肝细胞乳头状瘤、肾小管腺瘤、囊腺瘤、乳头状瘤、腺瘤、平滑肌瘤、横纹肌瘤、血管瘤、淋巴管瘤、骨瘤、软骨瘤、脂肪瘤和/或纤维瘤。
联合疗法
本发明的化合物可以单独供应或与一种或多种其他药物一起供应。可能的组合伴侣可以包括另外的抗血管生成因子和/或化学治疗剂(例如细胞毒性剂)或辐射、癌症疫苗、免疫调节剂、检查点抑制剂、抗血管剂、信号转导抑制剂、抗增殖剂、细胞凋亡诱导剂、烷基化剂、亚硝基脲剂、抗代谢物、抗癌抗生素、植物源性生物碱、拓扑异构酶抑制剂、激素药、激素拮抗剂、芳香酶抑制剂、P-糖蛋白抑制剂、铂络合物衍生物、抗纤维化剂、放射疗法、放射治疗剂和基因表达调节剂。
可与本发明的化合物或组合物组合使用的其它治疗剂(单独或在相同药物组合物中施用)的实例包括但不限于:CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCR11、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、CXCR6、CXCR7、CX3CR1、ChemR23、C5aR、C5a和C5的调节剂、或其任何组合。在一些实施方案中,调节剂是拮抗剂。
可与本发明化合物或组合物组合的其他治疗剂(单独或在相同药物组合物中施用)的实例包括但不限于:治疗性抗体、双特异性抗体和“抗体样”治疗性蛋白质(如Fab衍生物)、抗体-药物偶联物(ADC)、病毒、溶瘤病毒、基因修饰剂或编辑剂如CRISPR(包括CRISPRCas9)、锌指核酸酶或合成核酸酶(TALEN)、CAR(嵌合抗原受体)T细胞免疫治疗剂、细胞因子、疫苗、疫苗佐剂、GM-CSF、M-CSF、G-CSF、干扰素-a、β或γ、IL-1、IL-2、IL-3、IL-12、聚(I:C)、CPG、环磷酰胺、环磷酰胺类似物、抗TGF和伊马替尼(Gleevac)、有丝分裂抑制剂、激酶抑制剂、紫杉醇、舒尼替尼(Sutent)、抗血管生成剂、芳香酶抑制剂、来曲唑、A2a腺苷受体(A2AR)拮抗剂、腺苷受体调节剂、A3腺苷受体调节剂、血管生成抑制剂、蒽环类药物、奥沙利铂、多柔比星、TLR4拮抗剂、IL-18拮抗剂、Btk酪氨酸激酶抑制剂、Erbb2酪氨酸激酶受体抑制剂;Erbb4酪氨酸激酶受体抑制剂、mTOR抑制剂、胸苷酸合成酶抑制剂、EGFR酪氨酸激酶受体抑制剂、表皮生长因子拮抗剂、Fyn酪氨酸激酶抑制剂、Kit酪氨酸激酶抑制剂、Lyn酪氨酸激酶抑制剂、NK细胞受体调节剂、PDGF受体拮抗剂、PARP抑制剂、聚ADP核糖聚合酶抑制剂、聚ADP核糖聚合酶1抑制剂、聚ADP核糖聚合酶2抑制剂、聚ADP核糖聚合酶3抑制剂、半乳糖基转移酶调节剂、二氢嘧啶脱氢酶抑制剂、乳清酸磷酸核糖基转移酶抑制剂、端粒酶调节剂、粘蛋白1抑制剂、粘蛋白抑制剂、促胰液素激动剂、TNF相关凋亡诱导配体调节剂、IL17基因刺激剂、白细胞介素17E配体、神经激肽受体激动剂、细胞周期蛋白G1抑制剂、检查点抑制剂、PD-1抑制剂、PD-L1抑制剂、CTLA4抑制剂、拓扑异构酶I抑制剂、Alk-5蛋白激酶抑制剂、结缔组织生长因子配体抑制剂、Notch-2受体拮抗剂、Notch-3受体拮抗剂、透明质酸酶刺激剂、MEK-1蛋白激酶抑制剂、磷酸肌醇-3激酶抑制剂、MEK-2蛋白激酶抑制剂、GM-CSF受体调节剂;TNFα配体调节剂、间皮素调节剂、天冬酰胺酶刺激剂、CSF2基因刺激剂、胱天蛋白酶-3刺激剂;胱天蛋白酶-9刺激剂、PKN3基因抑制剂、刺猬蛋白抑制剂、平滑受体拮抗剂、AKT1基因抑制剂、DHFR抑制剂、胸苷激酶刺激剂、CD29调节剂、纤连蛋白调节剂、白细胞介素-2配体、丝氨酸蛋白酶抑制剂、D40LG基因刺激剂;TNFSF9基因刺激剂、2-酮戊二酸脱氢酶抑制剂、TGF-βII型受体拮抗剂、Erbb3酪氨酸激酶受体抑制剂、胆囊收缩素CCK2受体拮抗剂、维尔姆斯肿瘤蛋白质调节剂、RasGTP酶调节剂、组蛋白脱乙酰酶抑制剂、RafB蛋白激酶抑制剂、细胞周期蛋白-依赖性激酶4抑制剂A调节剂、雌激素受体β调节剂、4-1BB抑制剂、4-1BBL抑制剂、PD-L2抑制剂、B7-H3抑制剂、B7-H4抑制剂、BTLA抑制剂、HVEM抑制剂、TIM3抑制剂、TIGIT抑制剂、NKG2A抑制剂、GAL9抑制剂、LAG3抑制剂、PD-1H抑制剂、PD96抑制剂、VISTA抑制剂、KIR抑制剂、2B4抑制剂、CD160抑制剂、CD66e调节剂、血管紧张素II受体拮抗剂、结缔组织生长因子配体抑制剂、Jak1酪氨酸激酶抑制剂、Jak2酪氨酸激酶抑制剂、双重Jak1/Jak2酪氨酸激酶抑制剂、血管紧张素转化酶2刺激剂、生长激素受体拮抗剂、半乳糖凝集素-3抑制剂、检查点激酶2调节剂、钠葡萄糖转运蛋白-2抑制剂、内皮素ET-A拮抗剂、盐皮质激素受体拮抗剂、内皮素ET-B拮抗剂、高级糖基化产物受体拮抗剂、促肾上腺皮质激素配体、法尼酯(Farnesoid)X受体激动剂、G蛋白偶联胆汁酸受体1激动剂、醛糖还原酶抑制剂、黄嘌呤氧化酶抑制剂、PPARγ激动剂、前列腺素受体拮抗剂、FGF受体拮抗剂、PDGF受体拮抗剂、TGFβ拮抗剂、P3蛋白调节剂、p38MAP激酶抑制剂、VEGF-1受体拮抗剂、蛋白酪氨酸磷酸酶β抑制剂、Tek酪氨酸激酶受体刺激剂、PDE5抑制剂、盐皮质激素受体拮抗剂、ACE抑制剂、I-κB激酶抑制剂、NFE2L2基因刺激剂物、核因子κB抑制剂、STAT3基因抑制剂、NADPH氧化酶1抑制剂、NADPH氧化酶4抑制剂、PDE4抑制剂、肾素抑制剂、FURIN基因抑制剂、MEKK-5蛋白激酶抑制剂、膜铜胺氧化酶抑制剂、整联蛋白α-V/β-3拮抗剂、胰岛素敏化剂、激肽释放酶1调节剂、环氧酶抑制剂、补体C3调节剂、微管蛋白结合剂、巨噬细胞甘露糖受体1调节剂、苯丙氨酸羟化酶刺激剂、地尼白介素、贝沙罗汀、伏立诺他、罗米地辛、普拉曲沙、泼尼松、泼尼松龙、CCX354、CCX9588、CCX140、CCX872、CCX598、CCX6239、CCX9664、CCX2553、CCX2991、CCX282、CCX025、CCX507、CCX430、CCX765、CCX224、CCX662、CCX650、CCX832、CCX168、CCX168-M1、巴维昔单抗、IMM-101、CAP1-6D、雷克辛-G(Rexin-G)、染料木素、CVac、MM-D37K、PCI-27483、TG-01、莫替司他(mocetinostat)、LOAd-703、CPI-613、乌帕姆诺斯特(upamostat)、CRS-207、诺瓦卡普(NovaCaps)、曲美替尼(trametinib)、Atu-027、索尼得吉(sonidegib)、GRASPA、特拉贝德森(trabedersen)、纳特莱泽派(nastorazepide)、树突状细胞免疫疗法(Vaccell)、奥戈伏单抗、伊斯蒂单抗(istiratumab)、雷法替尼(refametinib)、瑞格拉非尼、拉帕替尼、司美替尼、瑞卡帕布、佩拉雷奥雷派(pelareorep)、他雷单抗(tarextumab)、聚乙二醇化的透明质酸酶、瓦利替尼(varlitinib)、阿格马基因贝萨诺克(aglatimagenebesadenovec)、GBS-01、GI-4000、WF-10、高路瑟尼(galunisertib)、阿法替尼、RX-0201、FG-3019、帕妥珠单抗、DCVax-Direct、塞利那瑟(selinexor)、葡磷酰胺、维如利金、钇(90Y)西瓦图单抗特踹齐坦(clivatuzumabtetraxetan)、溴夫定、尼妥珠单抗、阿尔甘盼图赛-L(algenpantucel-L)、替加氟+吉莫斯特+氧嗪酸钾+亚叶酸钙、奥拉帕尼、依鲁替尼、吡柔比星、Rh-Apo2L、特脱莫肽(tertomotide)、替加氟+吉莫斯特+奥替拉西钾、替加氟+吉莫斯特+奥替拉西钾、马西替尼(masitinib)、雷克辛-G、丝裂霉素(mitomycin)、厄洛替尼、阿霉素、地塞米松、长春新碱、环磷酰胺、氟尿嘧啶、拓扑替康(topotecan)、紫杉酚、干扰素、铂衍生物、紫杉烷、紫杉醇、长春花生物碱、长春碱、蒽环类、多柔比星、表鬼臼毒素类、依托泊苷、顺铂、雷帕霉素、氨甲喋呤、放线菌素D、多拉司他汀10(dolastati10)、秋水仙碱、吐根碱、三甲曲沙、氯苯氨啶、环孢素、柔红霉素、替尼泊苷、两性霉素、烷化剂、苯丁酸氮芥、5-氟尿嘧啶、喜树碱、顺铂、甲硝唑、格列卫、阿瓦斯汀、帕尼单抗、阿巴瑞克、阿地白介素、阿仑单抗、阿利维A酸、别嘌醇、六甲蜜胺、氨磷汀、阿那曲唑、三氧化二砷、天冬酰胺酶、阿扎胞苷、AZD9291、卡介苗活菌、贝伐单抗、氟尿嘧啶、蓓萨罗丁、博来霉素、硼替佐米、白消安、卡普睾酮、卡培他滨、喜树碱、卡铂、卡莫司汀、塞来昔布、西妥昔单抗、苯丁酸氮芥、克拉屈滨、氯法拉滨、环磷酰胺、阿糖胞苷、更生霉素、阿法达贝泊汀柔红霉素、地尼白(denileukin)、右雷佐生、多西他赛、多柔比星(中性)、盐酸阿霉素、屈他雄酮丙酸酯、表柔比星、阿法依泊汀、雌莫司汀、依托泊苷磷酸盐、依托泊苷、依西美坦、非格司亭、氟尿苷氟达拉滨、氟维司群、吉非替尼、吉西他滨、吉妥单抗、醋酸戈舍瑞林、组氨瑞林醋酸盐、羟基脲、替伊莫单抗、伊达比星、异环磷酰胺、甲磺酸伊马替尼、干扰素α-2a、干扰素α-2b、伊立替康、来那度胺、来曲唑、亚叶酸钙、醋酸亮丙瑞林、左旋咪唑、洛莫司汀、醋酸甲地孕酮、美法仑、巯基嘌呤、6-MP、美司钠、氨甲喋呤、甲氧沙林、丝裂霉素C、米托坦、米托蒽醌、诺龙、奈拉滨、诺非单抗(nofetumomab)、奥普瑞白介素、奥沙利铂、白蛋白结合型紫杉醇、帕利夫明、帕米膦酸二钠、培加酶、天门冬酰胺酶、培非司亭、培美曲塞二钠、喷司他丁、哌泊溴烷、普利霉素、卟菲尔钠、甲基苄肼、阿的平、拉布立酶、利妥昔单抗、洛昔替尼(rociletinib)、沙格司亭、索拉非尼、链脲霉素、马来酸舒尼替尼、滑石、他莫昔芬、替莫唑胺、替尼泊苷、VM-26、睾内脂、硫鸟嘌呤、6-TG、塞替派、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、维A酸、ATRA、尿嘧啶芥末、戊柔比星、长春碱、长春新碱、长春瑞滨、唑来膦酸、唑来膦酸、派姆单抗、纳武单抗、IBI-308、mDX-400、BGB-108、MEDI-0680、SHR-1210、PF-06801591、PDR-001、GB-226、STI-1110、德瓦鲁单抗、阿替珠单抗、阿维单抗、BMS-936559、ALN-PDL、TSR-042、KD-033、CA-170、STI-1014、FOLFIRINOX、KY-1003、奥美沙坦酯、坎地沙坦、PBI-4050、巴瑞克替尼、GSK-2586881、氯沙坦、达格列净丙二醇、培维索孟、GR-MD-02、卡格列净、厄贝沙坦、FG-3019、阿曲生坦、菲涅任侬(finerenone)、斯帕森坦(sparsentan)、波生坦、去纤维蛋白多核苷酸、非马沙坦、阿泽里拉贡(azeliragon)、吡哆胺、促肾上腺皮质激素、INT-767、依帕司他、托匹司他、SER-150-DN、吡非尼酮、VEGFR-1mAb、AKB-9778、PF-489791、SHP-627、CS-3150、咪达普利、培哚普利、卡托普利、依那普利、赖诺普利、佐芬普利、赖诺普利、喹那普利、贝那普利、群多普利、西拉普利、福辛普利、雷米普利、甲基巴多索隆、厄贝沙坦+丙亢、GKT-831、MT-3995、TAK-648、TAK-272、GS-4997、DW-1029M、ASP-8232、VPI-2690B、DM-199、大黄酸、PHN-033、GLY-230、和沙丙蝶呤、舒洛地昔、利利单抗(lirilumab)、IPH-4102、IPH-2101、IMP-321、BMS-986016、MGD-013、LAG-525、德罗瓦单抗(durvalumab)、莫奈株单抗(monalizumab)、MCLA-134、MBG-453、CA-170、AUPM-170、AUPM-327、瑞米斯他(resminostat)、伊匹单抗(ipilimumab)、BGB-A317、曲美目单抗(tremelimumab)、REGN-2810、AZD-5069、马赛替尼(masitinib)、比尼替尼(binimetinib)、曲美替尼、鲁索替尼(ruxolitinib)、达拉菲尼(dabrafenib)、利那洛肽(linaclotide)、伊匹单抗、阿帕替尼(apatinib)、尼达尼布(nintedanib)、卡博替尼(cabozantinib)、帕唑替尼(pazopanib)、贝林司他(belinostat)、帕尼单抗(panitumumab)、瓜地西他滨(guadecitabine)、维莫德吉(vismodegib)、威罗菲尼(vemurafenib)、达沙替尼(dasatinib)、曲美目单抗、贝伐珠单抗(bevacizumab)、奥沙利铂、阿柏西普(aflibercept)、凡德他尼(vandetanib)、依维莫司(everolimus)、沙利窦达(thalidomide)、维利帕尼(veliparib)、恩科菲尼(encorafenib)、奈布森(napabucasin)、奥派利斯(alpelisib)、阿西替尼(axitinib)、西地尼布(cediranib)、奈昔木单抗(necitumumab)、雷莫芦单抗(ramucirumab)、依洛福芬(irofulven)、曲氟尿苷(trifluridine)+地匹福林(tipiracil)、道那菲尼(donafenib)、帕克替尼(pacritinib)、派克斯-威克(pexastimogene devacirepvec)、提瓦替尼(tivantinib)、GNR-011、他拉泊芬(talaporfin)、皮里诺森(piclidenoson)、地西他滨(decitabine)、盖尼塔单抗(ganitumab)、帕比司他(panobinostat)、雷他莫德(rintatolimod)、泊马昔布(polmacoxib)、左亚药酸(levofolinate)、法米替尼(famitinib)、沃图莫单抗(votumumab)、替莫扎尼(tivozanib)、恩替诺特(entinostat)、普利肽新(plitidepsin)、来非莫德(lefitolimod)、OSE-2101、维特斯朋(vitespen)、TroVax、溴隐停(bromocriptine)、米哚妥林(midostaurin)、福他布林(fosbretabulin)、呋喹替尼(fruquintinib)、盖那特匹(ganetespib)、布立尼布(brivanib)、安罗替尼(anlotinib)、L19-TNF-α、拉妥木单抗(racotumomab)、乐复能(Novaferon)、雷替曲塞(raltitrexed)、恩扎妥林(enzastaurin)、GM-CT-01、阿西莫单抗(arcitumomab)、地尼白介素、贝沙罗汀、伏立诺他、罗米地辛、普拉曲沙、泼尼松、泼尼松龙、或其任何组合。
可与本发明的化合物或组合物组合的其他治疗剂(单独或在相同药物组合物中施用)的实例包括但不限于:MP-1032、苏金单抗(secukinumab)、倍他米松、环孢素、赛妥珠单抗(certolizumab)、聚乙二醇化赛妥珠单抗(certolizumab pegol)、VTP-43742、比麦珠单抗(bimekizumab)、GSK-2982772、阿米莫德(amiselimod)、KD-025、优特克单抗(ustekinumab)、依那西普、库赛珠单抗(guselkumab)、阿普斯特(apremilast)、富马酸二甲酯+富马酸单乙基酯钙盐+富马酸单乙基酯镁盐-富马酸单乙基酯锌盐、英利昔单抗、瑞萨珠单抗(risankizumab)、一刻珠单抗(ixekizumab)、莫米松、布罗达单抗、阿达木单抗、托法替尼、奥洛他定、他扎罗汀、富马酸二甲酯、猪鞭虫卵子(Trichuris suis ova)、BTT-1023、沃克普林(voclosporin)、塞莱斯布(seletalisib)、INV-103、皮里诺森(piclidenoson)、GR-MD-02、PRX-167700、LYC-30937EC、那米鲁单抗(namilumab)、LY-3074828、LEO-32731、阿维A、卡泊三醇、WBI-1001、丙酸氯倍他索、倍他米松、ZPL-389、柏替木单抗(bertilimumab)、AKP-11、ZPL-521、克立萨硼(crisaborole)、CLS-008、IMO-8400、博莱鲁单抗(bleselumab)、卡泊三醇、替可珠单抗(tildrakizumab)、KX-01、18C3、DSXS-1411、DLX-105、瑞孟斯他(remetinostat)、普如索尔(Prurisol)、S-414114、GLG-801、伊奈骨化醇(inecalcitol)、马沙骨化醇+倍他米松、TAB-08、阿法西普(alefacept)、乌倍他索、托瑞福特(toreforant)、卡泊三醇、二丙酸倍他米松、曲加珠单抗(tregalizumab)、CJM-112、内湖珠单抗(neihulizumab)、戊酸倍他米松、P-3072、P-3073、氨甲喋呤、GSK2981278A、卡泊三醇+二丙酸倍他米松、LEO-124249、AVX-001、卡泊三醇+二丙酸倍他米松、富马酸二甲酯、丙酸卤倍他索+他扎罗汀、卡泊三醇、卡泊三醇+倍他米松、阿立维A、DFD-06、孟加拉玫瑰红钠、C-82、TU-2100、CT-327、帕立骨化醇(pefcalcitol)、醋酸氟轻松、丙酸氯倍他索+维甲酸、GK-664-S、他扎罗汀+倍他米松、伊立珠单抗(itolizumab)、戊酸倍他米松、IMO-3100、PUR-0110、LEO-29102、奥瑞莫德(orilotimod)、马沙骨化醇(maxacalcitol)、IR-502、烟酸肉豆蔻酯、阿加尼生(aganirsen)、甲氨喋呤、糠酸莫米松、BCG多糖+核酸注射液、琥珀酸锂、奥瑞莫德、LAS-41004、骨化三醇、GMDP、糠酸莫米松、MOL-4249、氨基蝶呤、他卡考醇、地蒽酚、卤米松、安波(anapsos)、塔格瑞斯(osimertinib)和AGEN-1884。
试剂盒和包装
术语“试剂盒”和“药物试剂盒”是指商品试剂盒或包装,其在一个或多个合适的容器中包含一种或多种药物组合物及其使用说明。在一个实施方案中,提供了包含式(A)、(A1)、(A2)、(I)或(Ia1)化合物或其药学上可接受的盐的试剂盒及其施用说明书。在一个实施方案中,提供了包含式(A)、(A1)、(A2)、(I)和(Ia1)化合物或其药学上可接受的盐与一种或多种(例如,一种、两种、三种、一种或两种、或一种至三种)额外的治疗剂的试剂盒及其施用说明书。
在一个实施方案中,将本发明的化合物配制成包装在单一包装中的给药单元。单一包装包括但不限于瓶子、儿童防护瓶、安瓿和管子。在一个实施方案中,将本发明的化合物和任选的另外的治疗剂配制成给药单位,并且将每个单一给药单位分别包装在单个包装中。这种单独包装的单元可以含有任何形式的药物组合物,包括但不限于液体形式、固体形式、粉末形式、颗粒形式、泡腾粉末或片剂、硬胶囊或软胶囊、乳剂、混悬剂、糖浆剂、栓剂、片剂、锭剂、菱形锭剂、溶液、口腔贴剂、薄膜、口腔凝胶、咀嚼片、口香糖和一次性注射器。这种独立包装的单元可以组合在由一种或多种纸、卡纸板、纸板、金属箔和塑料箔制成的包装中,例如泡罩包装。一个或多个施用单位可以每天施用一次或数次。一个或多个施用单位可以一天服用三次。一个或多个施用单位可以每天施用两次。一个或多个施用单位可以在第一天施用,并且一个或多个施用单位可以在随后的日子施用。
一般合成程序
实施方案还涉及可用于制备主题化合物或其药学上可接受的盐的方法和中间体。
现在将通过参考本文的一般制备的说明性合成方案和以下具体实施例来描述可用于实施方案的方法中的示例性化学实体。本领域技术人员将认识到,为了获得本文中的各种化合物,可以适当选择起始材料,使得最终期望的取代将通过反应方案进行,适当地进行或不进行保护以产生期望的产物。或者,在最终希望的取代基的位置,可能需要或希望使用合适的基团,其可以通过反应方案进行并且适当地用期望的取代基替换。此外,本领域的技术人员将认识到,下面的方案中示出的变换可以以与特定侧基的功能兼容的任何顺序执行。
本公开化合物的代表性合成描述于下面的方案和下面的具体实施例中。提供方案1和2作为本公开的进一步实施方案,并且说明用于制备包括化学式(A)、(A1)、(A2)、(I)和(Ia1)化合物的本公开化合物的一般方法,并且其可用于制备化学式(A)、(A1)、(A2)、(I)和(Ia1)的另外的化合物。该方法与各种功能兼容。
方案1
B1的氨基可以与3,4-二甲氧基环丁-3-烯-1,2-二酮反应以得到B2。B2然后可以与B3的氨基反应以提供B4。
方案2
B7可以通过B6中的氰基的还原,例如通过氢化,然后环化获得。或者,B5(其中X表示离去基团,例如卤素或甲苯磺酸酯,并且其中R是烷基)可以与NH3反应形成环化的产物B7。B7可以与HNO3反应以在诸如硫酸的酸存在下引入硝基,得到B8。通过例如氢化随后还原B8中的硝基可以提供B9。
实施例
提供以下实施例来说明但不限制要求保护的发明。
可以从商业来源例如奥尔德里奇化学有限公司(密尔沃基,威斯康星州,美国)获得以下用的试剂和溶剂。在瓦里安汞(Varian Mercury)400MHz核磁共振光谱仪上记录1H-NMR。相对于TMS提供显著的峰,并按照以下顺序列表:多重性(s,单重峰;d,双重峰;t,三重峰;q,四重峰;m,多重峰)和质子的数量。质谱分析法的结果以质量与电荷的比率报告,其次以每个离子的相对丰度(作为插入成分)报告。在表中,报告含有最常见的原子同位素的M+H(或者,如记录的,M-H)离子的单个m/e值。同位素模式在所有情况下对应于预期的公式。使用配备有用于样品输送的安捷伦ZORBAX柱(SB-C18,2.1X50mm,5μ柱)的HP1100HPLC在休利特-帕卡德MSD电喷雾质谱仪上进行电喷雾离子化(ESI)质谱分析。通常,将分析物以0.1mg/mL溶解于甲醇中,并将1微升与递送溶剂一起注入质谱仪中,所述质谱仪扫描100至1500道尔顿。所有化合物可以以ESI正离子模式,使用含1%甲酸的乙腈/水作为递送溶剂进行分析。下面提供的化合物也可以以ESI负离子模式,使用2mM NH4OAc的乙腈/水作为递送系统进行分析。
在实施例和整个本发明的描述中使用以下缩写:
HPLC,高压液相色谱;DMF,二甲基甲酰胺;TFA,三氟乙酸;THF,四氢呋喃;EtOAc,乙酸乙酯;BOC2O,二叔丁基二碳酸酯或BOC酸酐;HPLC,高压液相色谱;DIPEA,二异丙基乙胺;HBTU,O-(苯并三唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐;dppf,1,1'-双(二苯基膦基)二茂铁;Pd2(dba)3,三(二亚苄基丙酮)二钯(0);DIPEA,二异丙基乙胺;DMP,邻苯二甲酸二甲酯;Me,甲基;Et,乙基;DCM,二氯甲烷。
可以使用本领域技术人员已知的各种反应合成如下所述本发明范围内的化合物。本领域技术人员还将认识到,可以采用替代方法来合成本发明的目标化合物,并且本文中所述的方法并不是详尽的,但的确提供了目标化合物的广泛适用和实用的途径。
本专利中要求保护的某些分子可以以不同的对映体和非对映体形式存在,并且这些化合物的所有的这些变体被要求保护。
在本文中,对用于合成关键化合物的实验步骤的详细描述导致分子由鉴别它们的物理数据以及与它们相关的结构描述描写。
本领域技术人员还将认识到,在有机化学的标准后处理过程中,经常使用酸和碱。在本专利所述的实验步骤中,如果它们具有必要的内在酸性或碱性,母体化合物的盐有时会产生。
实施例1:3-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]-4-乙氧基-环丁-3-烯-1,2-二酮的合成
步骤a:在装配有机械搅拌器的5L三颈圆底烧瓶中,向二氯甲烷(1.5L)加入(R)-2-甲基丙烷-2-亚磺酰胺(100g,0.825mol),2,2-二甲基丙醛(78.2g,0.907mol)和四乙氧基钛(414.1g,1.815mol)。将反应混合物在室温下搅拌12小时,然后加入十水合硫酸钠(260g),然后加入硅藻土(500g)。将混合物在室温下搅拌5小时,通过硅藻土过滤并用二氯甲烷(1L)冲洗。将滤液在真空下浓缩并在真空下干燥过夜,得到棕色油状的[N(E),S(R)]-N-(2,2-二甲基亚丙烷)-2-甲基-丙烷-2-亚磺酰胺(150g,96%),将其不经进一步纯化用于下一步。1HNMR(400MHz,CD3OD)δ7.80(s,1H),1.10(s,9H),1.08(s,9H);MS:C19H19NOS的(ES)m/z计算值是190.1,实测值是190.1。
步骤b:向装配加料漏斗的1L三颈烧瓶中加入2-甲基呋喃(31.1mL,345.1mmol,1.5当量)和无水Et2O(300mL),然后在冰浴中冷却。在接近35分钟内滴加己烷中的n-BuLi(2.5M,120mL,299mmol,1.3当量)。将混合物在0℃下搅拌30分钟,然后在室温下搅拌40分钟,然后再次冷却至0℃。加入固体MgBr2x Et2O(77.2g,299.1mmol,1.3当量)并将该混合物在0℃下搅拌30分钟,然后在室温下搅拌20分钟。
在装配机械搅拌器和内部温度计的5L三颈烧瓶中,将来自步骤a的亚胺(43.5g,230.1mmol)溶于无水甲苯(1.2L)中并将其冷却至-70℃的内部温度。在56分钟内加入上述段落的锂盐溶液,保持内部温度在-70至-67.8℃之间。加完后,将反应混合物在-70℃下搅拌1小时,然后在室温下过夜。将反应混合物用饱和NH4Cl溶液(400mL)和水(400mL)缓慢淬灭,然后在室温下搅拌15分钟。将有机层分离并用盐水(200mL)洗涤。用乙酸乙酯(300mL)萃取合并的水层。有机相用MgSO4干燥,过滤并蒸发,得到橙色油状物。将粗产物溶于己烷(500mL)中并使其在-20℃结晶过夜,得到黄色固体。过滤固体,将母液蒸发并再次从己烷(50mL)中结晶,得到产物(51.9g,83%),产物为纯净的非对映体。MS:C14H26NO2S[M+H]+的(ES)m/z计算值为272.2,实测值272.2。
步骤c:将来自之前步骤的N-[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]-2-甲基-丙烷-2-亚磺酰胺(51.9g,191.5mmol)溶解在甲醇(100mL)中并在冰浴中冷却,然后加入2M HCl的乙醚(191.5mL,383.0mmol,2当量)。除去冷却浴并将反应混合物在室温下搅拌2小时。真空除去溶剂,并将无水乙醚(300mL)加入到残余物中。过滤所得混合物。向固体中加入水(100mL)和1M NaOH水溶液(200mL)。产物用二氯甲烷(3x 100mL)萃取,合并的有机层用MgSO4干燥,过滤并蒸发,得到黄色油状物(27.2g,85%)。MS:C10H15O[(M–NH3)+H]+的(ES)m/z计算值为151.1,实测值151.1。
步骤d:将3,4-二乙氧基环丁-3-烯-1,2-二酮(15.9g,93.5mmol,1.05当量)溶于无水乙醇(150mL)中并在冰浴中冷却。然后滴加(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙烷-1-胺(14.9g,89.0mmol)的无水乙醇(50mL)溶液,将反应混合物在室温下搅拌过夜。蒸发过量的溶剂并将残余物与己烷(500mL)一起搅拌直至固体沉淀。过滤固体,用己烷(100mL)洗涤并在高真空下干燥,得到标题化合物(24.4g,94%)。MS:C16H22NO4[M+H]+的(ES)m/z计算值为292.1,实测值292.1。
实施例2:2-[4-氯-7-[[2-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]苯甲酸的合成
步骤a:将含有3-氯-2-甲基-苯甲酸(100.0g,0.586mole)的浓H2SO4(500mL)的4L锥形烧瓶冰浴冷却。滴加70%HNO3(45.2mL,0.703mole,1.2当量),将反应混合物在0℃下搅拌2小时,然后小心地用冰淬灭并用冷水稀释至4L。过滤白色固体,用水洗涤并在高真空下干燥(127g,定量),得到3-氯-2-甲基-6-硝基-苯甲酸和3-氯-2-甲基-5-硝基-苯甲酸比例为3:1的混合物。MS:C8H5ClNO4[M-H]-的(ES)m/z计算值为214.0,实测值:214.0。
步骤b:将来自之前步骤的同分异构酸混合物(50g,232.0mmol)溶于无水DMF(200mL)中,加入无水Na2CO3(27.0g,255.2mmol,1.1当量),并将反应在室温下搅拌持续30分钟。加入甲烷碘(15.9mL,255.2mmol,1.1当量),并在室温下继续搅拌3h。反应混合物用水(1.2L)稀释,产物用Et2O(3×250mL)萃取。将合并的有机层用盐水(4x 100mL)洗涤,用MgSO4干燥,过滤并蒸发,得到黄色油状物(49.7g,93%)。
步骤c:将来自之前步骤的同分异构酯的混合物(49.7g,216.5mmol)溶于CCl4(400mL)中并加入N-溴代丁二酰亚胺(57.8g,324.7mmol,1.5当量),接着加入过氧化苯甲酰(10.4g,43.2mmol,0.20当量)。将反应混合物回流搅拌过夜,然后冷却至室温并过滤。蒸发滤液,残余物通过硅胶层析(100:0至9:1的己烷:乙酸乙酯)纯化,得到黄色的单一异构体固体(44.1g,66%)。1H NMR(400MHz,CDCl3)δ8.07(d,J=9.2Hz,1H),7.65(d,J=9.2Hz,1H),4.63(s,2H),4.01(s,3H)。
步骤d:将来自之前步骤的产物(616mg,2mmol)、邻氨基苯甲酸甲酯(302mg,2mmol)和K2CO3(553mg,4mmol)溶于无水乙腈中的悬浮液在40mL封闭反应小瓶中加热至85℃过夜。然后将反应物冷却至室温,用乙酸乙酯稀释并过滤。浓缩滤液得到未环化的粗产物(800mg)。将该粗产物溶于乙酸(5mL)中并加热至120℃过夜,得到环化产物。环化产物用乙酸乙酯稀释,用水和饱和NaHCO3水溶液洗涤,然后干燥(Na2SO4),过滤并浓缩。将残余物吸附在二氧化硅上并通过硅胶层析(0-50%乙酸乙酯的己烷)纯化,得到所需产物(350mg,50%)。MS:C16H11ClN2O[M+H]+的(ES)m/z计算值为347.0,实测值347.0。
步骤e:在室温下向2-(4-氯-7-硝基-1-氧代-异吲哚啉-2-基)苯甲酸甲酯(347mg,1mmol)在乙醇的搅拌混合物中加入铁粉(224mg,4mmol),随后加入4M HCl的二噁烷溶液(2mL,8mmol)。将反应混合物在室温下搅拌1小时,然后真空浓缩。残余物用乙酸乙酯稀释并用饱和碳酸氢钠溶液中和并用乙酸乙酯(2×5mL)萃取。将合并的有机层干燥(Na2SO4),过滤并真空浓缩。通过硅胶层析(0-100%乙酸乙酯的己烷)纯化粗产物,得到呈黄色粉末状的2-(7-氨基-4-氯-1-氧代-异吲哚啉-2-基)苯甲酸甲酯(200mg,0.63mmol,63%)。MS:C16H13ClN2O3[M+H]+的(ES)m/z计算值为317.0,实测值317.0。
步骤f:将2-(7-氨基-4-氯-1-氧代-异吲哚啉-2-基)苯甲酸甲酯(109mg,0.34mmol)和3-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]-4-乙氧基-环丁-3-烯-1,2-二酮(100mg,0.34mmol)的二氯甲烷溶液在0℃搅拌,加入2M三甲基铝的甲苯溶液(0.68mL,1.36mmol)。将溶液在0℃搅拌1小时,然后温热至室温并再搅拌1小时。将反应混合物冷却至0℃,用5%盐酸溶液淬灭并用水稀释,然后用乙酸乙酯(2×5mL)萃取。将有机层干燥(Na2SO4),过滤并真空浓缩。通过HPLC纯化粗产物得到2-[4-氯-7-[[2-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]苯甲酸甲酯(65mg,0.12mmol,34%)。MS:C30H28ClN3O6[M-H]+的(ES)m/z计算值为560.0,实测值是560.0。
步骤g:向2-[4-氯-7-[[2-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]苯甲酸甲酯(56mg,0.1mmol)的四氢呋喃(1mL)和甲醇(0.1mL)和水(0.1mL)的溶液中加入过量的氢氧化锂。将所得混合物在室温下搅拌1小时。反应用5%盐酸溶液酸化并用乙酸乙酯萃取。将有机层干燥(Na2SO4),过滤并真空浓缩。粗产物经HPLC纯化,得到黄色固体状的2-[4-氯-7-[[2-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]苯甲酸固体(30mg,0.05mmol,50%)。1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),9.06(d,J=10Hz,1H),7.85(dd,J=7.6,1.6Hz,1H),7.65–7.41(m,5H),6.10(d,J=2.6Hz,1H),5.95(d,J=2.6Hz,1H),5.03(d,J=10.4Hz,1H),4.80(dd,J=20,10Hz,2H),2.20(s,3H),0.87(s,9H).MS:C29H26ClN3O6[M-H]-的(ES)m/z计算值为546.0,实测值546.0。
实施例3:3-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]-4-[(5-氟-3-氧代-异吲哚啉-4-基)氨基]环丁-3-烯-1,2-二酮
步骤a:向500mL圆底烧瓶中加入2-溴-5-氟苯甲酸甲酯(48g,206mmol),氰化亚铜(37g,412mmmol)和DMF(200mL)。将混合物在110℃加热过夜,然后冷却至室温。加入乙醚(1.5L)和硅藻土(100g),并将混合物在室温下搅拌30分钟。过滤固体,滤液用盐水(3×200mL)洗涤,然后用MgSO4干燥。减压蒸发溶剂,得到所需产物,其为无色固体(31g,84%)。MS:C9H7FNO2[M+H]+的(ES)m/z计算值180.1,实测值180.1。
步骤b:在室温下向2-氰基-5-氟苯甲酸甲酯(10g,56mmol)的甲醇(200mL)溶液中加入10%Pd-C(1.0g)。将所得混合物在氢气(50psi)气氛下搅拌过夜。将反应混合物通过硅藻土过滤并将滤液减压浓缩,得到所需产物,其为无色固体(8.0g,90%)。MS:C8H7FNO[M+H]+的(ES)m/z计算值为152,实测值152。
步骤c:向6-氟异吲哚啉-1-酮(8.0g,5.3mmol)的浓H2SO4的0℃悬浮液中滴加浓H2SO4(26mL)和硝酸(6mL)的预冷混合物,同时保持反应混合物低于5℃。滴加完后,将反应混合物缓慢温热至室温过夜。将冰(50g)加入到混合物中,收集固体并干燥,然后用MTBE(50mL)和乙酸乙酯(50mL)洗涤,得到所需产物,其为淡黄色固体(5.1g,50%)。MS:C8H6FN2O3[M+H]+的(ES)m/z计算值为197.2,实测值是197.2。
步骤d:将6-氟-7-硝基异吲哚啉-1-酮(11.3g,57mmol)和10%Pd/C(50%湿度,6.2g,2.9mmol,0.05当量)的THF(300mL)溶液在氢气氛(气球)下搅拌过夜。通过硅藻土过滤固体,减压浓缩滤液,得到无色固体,将其通过硅胶层析(100%乙酸乙酯)纯化,得到所需产物,其为白色固体(6.4g,67%)。MS:C8H9FN2O[M+H]+的(ES)m/z计算值为168.1,实测值168.1。
步骤e:7-氨基-6-二氟-异吲哚啉-1-酮(4.4g,26mmole)和3,4-二甲氧基环丁-3-烯-1,2-二酮(7.4g,52mmole)的无水甲醇(30mL)混合物在60℃下搅拌过夜,然后在80℃搅拌5小时。将反应混合物蒸发并在50℃下将残余物在乙酸乙酯(200mL)中搅拌30分钟,然后冷却至室温。过滤混合物并干燥,得到淡黄色固体(5.0g,70%)。MS:C13H10FN2O4[M+H]+的(ES)m/z计算值是277.2,实测值277.2。
步骤f:将无水乙醇(10mL)加入到3-[(7-氟-3-氧代-异吲哚啉-4-基)氨基]-4-甲氧基-环丁-3-烯-1,2-二酮(1.5g,5.4mmol)和(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙烷-1-胺(1.1g,6.5mmol)的混合物,并将该混合物在60℃下搅拌过夜。使反应物冷却至室温,溶于最小量的二氯甲烷中,并吸附到硅胶上。产物通过硅胶层析(40%乙酸乙酯的二氯甲烷)纯化,得到白色固体(800mg,45%)。1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.65(s,1H),8.35(d,J=10.4Hz,1H),7.41(dd,J=11.6,8.4Hz,1H),6.18(dd,J=4.0,8.4Hz,1H),6.12(d,J=3.2Hz,1H),5.98(d,J=2.0Hz,1H),4.97(d,J=4.10Hz,1H),4.26(s,2H),2.22(s,3H),0.90(s,9H)。MS:C22H22FN3O4[M-H]-的(ES)m/z计算值410.0,实测值410.0。
实施例4:3-[(5,7-二氟-3-氧代-异吲哚啉-4-基)氨基]-4-[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]环丁-3-烯-1,2-二酮的合成
步骤a:将3,5-二氟-2-甲基-苯甲酸(5.2g,30.2mmol)溶于无水DMF(30mL)中。加入无水Na2CO3(3.5g,33.2mmol,1.1当量)并将反应在室温下搅拌30分钟。加入碘甲烷(2.1mL,33.2mmol,1.1当量)并将混合物在室温下搅拌4小时,然后将反应用水(200mL)稀释并将产物用Et2O(3×50mL)萃取。将合并的有机层用盐水(4×30mL)洗涤,用MgSO4干燥,过滤并蒸发,得到黄色油状物(5.4g,96%)。
步骤b:将步骤a的产物(5.4g,29.0mmol)溶于四氯化碳(60mL)中,加入N-溴代丁二酰亚胺(7.7g,43.5mmol,1.5当量),然后加入过氧化苯甲酰(1.4g,5.8mmol,0.20当量)。将反应混合物回流搅拌过夜,然后冷却至室温并过滤。蒸发滤液,残余物通过柱层析法(硅胶,100%的己烷至9:1的己烷:乙酸乙酯)纯化,得到为黄色油状(7.4g,96%)的产物。
步骤c:将甲醇中的NH3(7M,45mL,6.4mmol)冷却至0℃,加入步骤b的产物(6g,22.6mmol)。将反应混合物在0℃下搅拌10分钟,然后在室温下过夜。蒸发过量溶剂,残余物用水(50mL)稀释。过滤得到的固体,用水(2×20mL)洗涤,然后用己烷(20mL)洗涤,得到产物(3.4g,89%)。MS:C8H6F2NO[M+H]+的(ES)m/z计算值为170.0,实测值为170.3。
步骤d:将来自步骤c的4,6-二氟异吲哚啉-1-酮(3.4g,20.1mmol)溶于浓H2SO4(40mL)中并冷却到0℃。滴加70%HNO3(1.5mL,24.1mmol,1.2当量),并将反应混合物在0℃下搅拌10分钟,然后历经1小时温热至室温并搅拌过夜。加入冰,然后用冷水(100mL)稀释混合物。过滤得到的黄色固体,用水(2×50mL)洗涤,然后用己烷(50mL)洗涤并真空干燥(3.4g,79%)。MS:C8H5F2N2O3[M+H]+的(ES)m/z计算值为215.0,实测值为215.2。
步骤e:将得自步骤d的4,6-二氟-7-硝基-异吲哚啉-1-酮(3.4g,15.9mmol)用THF(50mL),在氮气的气氛下加入50%湿度的10%Pd/C(1.7g,0.8mmol,5%mmol)。在室温下,将反应混合物在H2(气球)气氛下剧烈搅拌1天,然后通过硅藻土过滤并蒸发,得到固体产物(2.7g,92%)。MS:C8H7F2N2O[M+H]+的(ES)m/z计算值为185.1,实测值为185.3。
步骤f:将得自步骤e的7-氨基-4,6-二氟-异吲哚啉-1-酮(2.3g,12.5mmol)和3,4-二甲氧基环丁-3-烯-1,2-二酮(3.5g,25.0mmol,2.0当量)在无水MeOH(15mL)中的混合物在60℃下搅拌过夜。将反应混合物蒸发并将残余物用MTBE:EtOAc(1:1,200mL)稀释并在50℃下搅拌30分钟,然后冷却至室温。过滤固体产物,用MTBE洗涤,然后溶于MeOH:DCM(1:1,200mL)中并通过硅藻土过滤。蒸发滤液,得到灰色固体(2.0g,54%)。MS:C13H9F2N2O4[M+H]+的(ES)m/z计算值为295.1,实测值为295.2。
步骤g:将无水甲醇(30mL)加入到得自步骤f的3-[(5,7-二氟-3-氧代-异吲哚啉-4-基)氨基]-4-甲氧基-环丁-3-烯-1,2-二酮(1.5g,5.1mmol)和(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙烷-1-胺(852mg,5.1mmol)的混合物中,在60℃下,搅拌该混合物1天。使反应物冷却至室温,溶于最少量的二氯甲烷中,并吸附在硅胶上。通过硅胶层析(100:0至50:50的二氯甲烷:乙酸乙酯)纯化产物,得到棕色固体(1.4g,64%)。1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.92(s,1H),8.37(d,J=10.2Hz,1H),7.62(dd,J=10.9,8.6Hz,1H),6.18(d,J=3.1Hz,1H),6.04(d,J=3.1Hz,1H),5.01(d,J=10.2Hz,1H),4.41(s,2H),2.27(s,3H),0.96(s,9H)。MS:C22H21F2N3O4[M-H]-的(ES)m/z计算值为428.1,实测值为428.1。
实施例5:2-[4-氯-7-[2-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]-4-甲氧基-苯甲酸
步骤a:包含有4-氯异吲哚啉-1-酮(25.0g,0.149mole)的浓H2SO4(50mL)的1L圆底烧瓶在冰浴中冷却。滴加浓H2SO4(50mL)与70%HNO3(10mL,0.16mole,0.16当量)的混合物并将反应混合物在0℃下搅拌2h,然后小心地用冰淬灭并用冷水稀释至1L。过滤固体,用水洗涤并在高真空下干燥,得到4-氯-7-硝基-异吲哚啉-1-酮(23g,73%)。MS:C8H5ClN2O3[M-H]-的(ES)m/z计算值为212.0,实测值212.0。
步骤b:在室温下,向4-氯-7-硝基-异吲哚啉-1-酮(23g,108mmol)的乙醇搅拌混合物中加入铁粉(18.2g,324mmol),然后加入4M HCl的二噁烷(162mL,648mmole)。将反应混合物在室温下搅拌1小时,然后真空浓缩。将残余物用乙酸乙酯稀释,用饱和碳酸氢钠溶液中和并用乙酸乙酯(2×500mL)萃取。将合并的有机层干燥(Na 2SO4)、过滤并真空浓缩,得到7-氨基-4-氯-异吲哚啉-1-酮(16.5g,72%)。MS:C8H7ClN2O[M+H]+的(ES)m/z计算值是183.2,实测值是183.2。
步骤c:向含有7-氨基-4-氯-异吲哚啉-1-酮(250mg,1.37mmol)的二噁烷(10mL)的反应小瓶中加入2-溴-5-甲氧基-苯甲酸甲酯(502mg,2.05mmol),碳酸铯(893mg,2.74mmol),碘化亚铜(104mg,0.55mmol)和(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(156mg,1.1mmol)。用氮气吹扫混合物,然后温热至110℃。将反应在110℃下搅拌1小时,并通过LC-MS监测反应。完成后,使反应冷却,然后通过硅藻土过滤并用乙酸乙酯冲洗。通过硅胶层析(0-50%乙酸乙酯/己烷)纯化粗产品,得到2-(7-氨基-4-氯-1-氧代-异吲哚啉-2-基)-5-甲氧基-苯甲酸甲酯,其为白色固体(284mg,60%)。MS:C17H15ClN2O4[M+H]+的(ES)m/zC计算值为347.1,实测值347.1。
步骤d:将2-(7-氨基-4-氯-1-氧代-异吲哚啉-2-基)-5-甲氧基-苯甲酸甲酯(160mg,0.46mmol)和3,4-二甲氧基环丁烷-1,2-二酮(131mg,0.92mmol)的无水甲醇(5mL)混合物在60℃下搅拌过夜。将反应混合物蒸发,在50℃下,将残余物在乙酸乙酯(5mL)中在搅拌30分钟,然后使其冷却至室温。过滤混合物并干燥,得到产物2-[4-氯-7-[(2-甲氧基-3,4-二氧代-环丁基)氨基]-1-氧代-异吲哚啉-2-基]-5-甲氧基-苯甲酸甲酯,其为浅黄色固体(170mg,81%)。MS:C22H17ClN2O7[M+H]+的(ES)m/z计算值为457.1,实测值457.1。
步骤e:将无水甲醇(10mL)加入到2-[4-氯-7-[(2-甲氧基-3,4-二氧代-环丁基)氨基]-1-氧代-异吲哚啉-2-基]-5-甲氧基-苯甲酸甲酯(170mg,0.37mmol)和(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙烷-1-胺(62mg,0.37mmol)的混合物,并且该混合物为在60℃下搅拌过夜。然后浓缩反应物,且粗2-[4-氯-7-[[2-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]-4-甲氧基-苯甲酸甲酯(218mg,0.37mmol)不经进一步纯化用于下一步。
步骤f:向2-[4-氯-7-[[2-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]-4-甲氧基-苯甲酸甲酯(218mg,0.37mmol)的四氢呋喃(4.0mL),甲醇(0.5mL)和水(0.5mL)溶液中加入氢氧化锂(78mg,1.85mmol)。所得混合物在60℃下搅拌6小时。反应用5%盐酸溶液酸化并用乙酸乙酯萃取。将有机层干燥(Na2SO4),过滤并真空浓缩。通过反相色谱法纯化粗产物,得到黄色的2-[4-氯-7-[[2-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]-4-甲氧基-苯甲酸固体(37mg,17%)。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.12(d,J=10Hz,1H),7.90(d,J=9.2,1H),7.66(d,J=8.8,1H),7.49(d,J=9.2,1H),7.19(d,J=2.4,1H),7.04(dd,J=8.8,2.4,1H),6.16(d,J=3.2Hz,1H),6.02(d,J=1.6Hz,1H),5.09(d,J=10Hz,1H),4.78(dd,J=23,5.6Hz,2H),3.83(s,3H),2.24(s,3H),0.87(s,9H)。MS:C30H28ClN3O7[M-H]-的(ES)m/z计算值为576.0,实测值576.0。
实施例6:2-[4-氯-7-[[2-[[(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]-4-甲氧基-苯甲酸
步骤a:向配备有加料漏斗的1L三颈烧瓶中加入2,3-二甲基呋喃(30.0g,312.5mmol,1.3当量)和无水Et2O(300mL),然后在冰浴中冷却。在约35分钟内,滴加n-BuLi的己烷(2.5M,125mL,312.5mmol,1.3当量)。将混合物在0℃下搅拌30分钟,然后在室温下搅拌40分钟,然后再次冷却至0℃。加入固体MgBr2x Et2O(80.6g,312.5mmol,1.3当量)并将混合物在0℃下搅拌30分钟,然后在室温下搅拌20分钟。
在配有机械搅拌器和内部温度计的5L三颈烧瓶中,将亚胺(45.4g,240.4mmol)溶于无水甲苯(1.2L)中并将其冷却至-70℃的内部温度。在56分钟内加入上述段落的锂盐溶液,保持内部温度在-70至-67.8℃之间。加完后,将反应混合物在-70℃下搅拌1小时,然后在室温下过夜。将反应混合物用饱和NH4Cl水溶液(400mL)和水(400mL)缓慢淬灭,然后在室温下搅拌15分钟。然后分离有机层并用盐水(200mL)洗涤。用乙酸乙酯(300mL)萃取合并的水层。将有机物用MgSO4干燥,过滤并浓缩,得到黄色油状物。通过硅胶层析(0-10%MTBE/DCM)纯化粗产物,得到作为单一非对映异构体的产物(18.0g,26%)。MS:C15H28NO2S[M+H]+的(ES)m/z的计算值286.1,实测值为286.1。
步骤b:来自之前步骤的N-[(1R)-2,2-二甲基-1-(4,5-二甲基-2-呋喃基)丙基]-2-甲基-丙烷-2-亚磺酰胺(18g,63.1mmol)溶于甲醇(200mL)并在冰浴中冷却,然后加入2MHCl的乙醚溶液(31.5mL,126.2mmol,2当量)。除去冷却浴并将反应混合物在室温下搅拌2小时。真空下除去溶剂,向残余物中加入无水乙醚(100mL)。过滤所得混合物。向固体中加入水(100mL)和1M NaOH水溶液(100mL)。产物用二氯甲烷(3×100mL)萃取,合并的有机层用MgSO4干燥,过滤并蒸发,得到(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙烷-1-胺,其为黄色油状物(9.7g,85%)。MS:C11H17O[(M–NH3)+H]+的(ES)m/z计算值为165.1,实测值为165.1。
步骤c:将无水甲醇(1mL)加入到2-[4-氯-7-[(2-甲氧基-3,4-二氧代-环丁基)氨基]-1-氧代-异吲哚啉-2-基]-5-甲氧基-苯甲酸甲酯(60mg,0.13mmol)和(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙烷-1-胺(24mg,0.13mmol)的混合物。该混合物在60℃下搅拌3小时。将反应浓缩至干,并将粗2-[4-氯-7-[[2-[(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]-4-甲氧基-苯甲酸甲酯(78mg,0.13mmol)没有进一步纯化用于下一步中。
步骤d:向2-[4-氯-7-[[2-[[(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]-4-甲氧基-苯甲酸甲酯(78mg,0.13mmol)的四氢呋喃(1.0mL),甲醇(0.1mL),水(0.1mL)溶液中加入氢氧化锂(27mg,0.65mmol)。将所得混合物在室温下搅拌过夜。反应用5%盐酸溶液酸化并用乙酸乙酯萃取。将有机层干燥(Na2SO4),过滤并真空浓缩。通过反相色谱法纯化粗产物,得到黄色的2-[4-氯-7-[[2-[[(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]-4-甲氧基-苯甲酸固体(12mg,15%)。1HNMR(400MHz,DMSO-d6)δ9.93(s,1H),9.09(d,J=10Hz,1H),7.90(d,J=9.2,1H),7.66(d,J=8.8,1H),7.49(d,J=9.2,1H),7.19(d,J=2.4,1H),7.04(dd,J=8.8,2.4,1H),6.06(d,J=3.2Hz,1H),5.04(d,J=10Hz,1H),4.83(dd,J=23,5.6Hz,2H),3.83(s,3H),2.15(s,3H),1.85(s,3H),0.87(s,9H).MS:C31H30ClN3O7[M-H]-的(ES)m/z计算值为590.2,实测值590.2。
实施例7:2-[4-氯-7-[[2-[[(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]-4-甲基-苯甲酸
步骤a:向含有7-氨基-4-氯-异吲哚啉-1-酮(305mg,1.67mmol)的二噁烷(10mL)的反应小瓶中加入2-溴-5-甲基-苯甲酸甲酯(575mg,2.51mmol),碳酸铯(1.63g,5mmol),碘化亚铜(190mg,1.0mmol)和(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(285mg,2.0mmol)。用氮气吹扫混合物,然后温热至110℃。将反应在110℃下搅拌1小时并通过LC-MS监测。完成后,使反应冷却,然后通过硅藻土过滤并用EtOAc冲洗。通过硅胶层析(0-50%乙酸乙酯/己烷)纯化粗品,得到2-(7-氨基-4-氯-1-氧代-异吲哚啉-2-基)-5-甲基-苯甲酸甲酯,其为白色固体(345mg,62%)。MS:C17H15ClN2O3[M+H]+的(ES)m/z C计算值为331.1,实测值331.1。
步骤b:向2-(7-氨基-4-氯-1-氧代-异吲哚啉-2-基)-5-甲基-苯甲酸甲酯(689mg,2.08mmol)的四氢呋喃(10mL)、甲醇(1mL)和水(1mL)的溶液中加入氢氧化锂(874mg,20.83mmol)。所得混合物在60℃下搅拌过夜。然后使反应冷却,然后用1N盐酸溶液酸化至pH=5并用乙酸乙酯/MeOH(10:1)萃取。将有机层干燥(Na2SO4),过滤并真空浓缩。将己烷加入到粗产物中,过滤所得固体,用己烷冲洗,得到黄色的2-(7-氨基-4-氯-1-氧代-异吲哚啉-2-基)-4-甲基-苯甲酸固体(572mg,87%)。
步骤c:将2-(7-氨基-4-氯-1-氧代-异吲哚啉-2-基)-4-甲基-苯甲酸(570mg,1.80mmol)和3,4-二甲氧基环丁烷-1,2-二酮(307mg,2.16mmol)的无水甲醇(5mL)溶液在60℃下搅拌过夜。然后使反应混合物冷却至室温并过滤。然后将固体用EtOAc洗涤并干燥,得到黄色的2-[4-氯-7-[(2-甲氧基-3,4-二氧代-环丁烯-1-基)氨基]-1-氧代-异吲哚啉-2-基]-4-甲基-苯甲酸固体(565mg,71%)。MS:C21H15ClN2O6[M+H]+的(ES)m/z计算值为427.1,实测值为427.1。
步骤d:将无水甲醇(2mL)加入到2-[4-氯-7-[(2-甲氧基-3,4-二氧代-环丁烯-1-基)氨基]-1-氧代-异吲哚啉-2-基]-4-甲基-苯甲酸(60mg,0.14mmol)和(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙烷-1-胺(27mg,0.15mmol)的混合物,并将该混合物在60℃下搅拌过夜。然后浓缩反应物,通过反相层析纯化粗产物品,得到2-[4-氯-7-[[2-[[(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]-4-甲基-苯甲酸(30mg,37%)。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.09(d,J=10Hz,1H),7.81(d,J=9.2,1H),7.66(d,J=8.8,1H),7.49(d,J=9.2,1H),7.42(d,J=2.4,1H),7.30(dd,J=8.8,2.4,1H),6.07(d,J=3.2Hz,1H),5.04(d,J=10Hz,1H),4.83(dd,J=23,5.6Hz,2H),2.38(s,3H),2.15(s,3H),1.85(s,3H),0.87(s,9H).MS:C31H30ClN3O6[M-H]-的(ES)m/z计算值为574.0,实测值574.0。
实施例8:3-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丁基]氨基]-4-[(5-氟-3-氧代-异吲哚啉-4-基)氨基]环丁-3-烯-1,2-二酮的合成
步骤a:将2,2-二甲基丁醛(5.0g,50mmol)和(R)-叔丁基亚磺酰胺(6.36g,52.5mmol)溶于CH2Cl2(100mL)中并且加入Ti(OEt)4(85-95%,22.81g,~90mmol)。将反应在室温下搅拌过夜。然后用CH2Cl2(200mL)稀释反应物,然后在剧烈搅拌下加入硅藻土和H2O(90mL)。搅拌混合物5小时,然后通过硅藻土过滤,用CH2Cl2冲洗滤饼。将滤液浓缩并硅胶纯化(1%至30%EtOAc的己烷),得到产物。
步骤b:将2-甲基呋喃(5.06mL,56.2mmol)的Et2O在冰上冷却。滴加N-BuLi(2.5M,22.5mL,56.3mmol),将反应物在冰上搅拌15分钟,然后除去浴,并在室温继续搅拌1小时。然后将反应物再次在冰上冷却,且一次性加入MgBr2(14.5g,56.2mmol)。将反应在冰上搅拌20分钟,然后除去浴,并在室温继续搅拌50分钟。然后将反应物在-78℃浴中冷却,并向其中滴加入(R,E)-N-(2,2-二甲基丁烯基)-2-甲基-丙烷-2-亚磺酰胺(7.6g,37.4mmol)的Et2O。使反应缓慢温热至室温过夜。加入饱和NH4Cl水溶液淬灭,剧烈搅拌混合物,然后用H2O稀释并用EtOAc(3×150mL)萃取。将合并的有机层用MgSO4干燥,过滤并浓缩,得到粗品。然后将其在硅胶上(5%至40%EtOAc的己烷)纯化,得到纯的同分异构产物。
步骤c:向N-[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丁基]-2-甲基-丙烷-2-亚磺酰胺(6.0g,21mmol)中加入MeOH和HCl的二噁烷(4M,21mL,84mmol)。将其在室温下搅拌45分钟。然后浓缩反应物并真空干燥,得到产物。
步骤d:环丁烯(72mg,0.26mmol)和(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丁烷-1-胺盐酸盐(57mg,0.26mmol)的MeOH(1.3mL)混合物中加入Et3N(0.072mL,0.52mmol)。将反应在60℃下搅拌4小时,然后在室温下过夜。将硅胶加入到反应中,浓缩混合物,并通过硅胶层析(1%至10%MeOH的CH2Cl2)纯化得到产物。1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.71(s,1H),8.39(d,J=10.2Hz,1H),7.47(dd,J=11.2,8.2Hz,1H),7.33(dd,J=8.3,3.8Hz,1H),6.17(d,J=3.1Hz,1H),6.06–
6.02(m,1H),5.11(d,J=10.2Hz,1H),4.32(s,2H),2.27(s,3H),1.36-1.21(m,2H),0.94(s,3H),0.88(s,3H),0.83(t,J=7.5Hz,
3H)。MS:C23H25FN3O4[M+H]+的(ES)m/z C的计算值是426.2,实测值是426.2。
实施例9:3-[[(1R)-1-(5-氯-2-呋喃基)-2,2-二甲基-丙基]氨基]-4-[(7-氯-3-氧代-异吲哚啉-4-基)氨基]环丁-3-烯-1,2-二酮的合成
步骤a:将5-氯呋喃-2-甲醛(5.0g,38mmol)和(R)-叔丁基亚磺酰胺(4.2g,35mmol)溶于CH2Cl2(75mL)中,并加入Ti(OEt)4(85-95%,17.6g,77mmol)。将反应在室温下搅拌过夜。然后将反应物用CH2Cl2(150mL)稀释,加入Na2SO4·10H2O(100g),并将混合物搅拌90分钟。然后将其通过硅藻土过滤,用CH2Cl2(200mL)冲洗滤饼。滤液浓缩得到产物。
步骤b:(R,E)-N-[(5-氯-2-呋喃基)亚甲基]-2-甲基-烷-2-亚磺酰胺(7.65g,32.7mmol)溶于CH2Cl2(131mL)并在氮气气氛下,在-78℃浴中冷却。在30分钟内经由加料漏斗加入t-BuMgCl(2M的Et2O,33mL,66mmol),然后将反应物搅拌4小时。加入饱和NH4Cl水溶液,使混合物温热至室温。然后加入H2O(50mL),并将混合物用CH2Cl2(2x)萃取,用Na2SO4干燥,过滤并浓缩,得到非对映异构体的混合物。将粗产物吸附到硅胶上并通过柱层析法(10%甲基叔丁基醚的CH2Cl2)进行纯化。收集早期洗脱的非对映异构体并对其浓缩,得到产物。
步骤c:将N-[(1R)-1-(5-氯-2-呋喃基)-2,2-二甲基-丙基]-2-甲基-丙烷-2-亚磺酰胺(0.98g,3.4mmol)溶于MeOH(3.4mL),加入HCl(2M HCl的Et2O,3.4mL,6.8mmol)。将反应搅拌过夜,然后浓缩。加入Et2O(25mL)并将混合物搅拌30分钟,然后过滤。将固体用Et2O(2x)洗涤,然后加入KOH水溶液(3M,5mL),并将产物用CH2Cl2(3x)萃取。将合并的有机层用KOH水溶液(1.5M)洗涤两次,用Na2SO4干燥,过滤并浓缩得到产物。
步骤d:将3-[(7-氯-3-氧代-异吲哚啉-4-基)氨基]-4-甲氧基-环丁-3-烯-1,2-二酮(59mg,0.2mmol)和(1R)-1-(5-氯-2-呋喃基)-2,2-二甲基-丙烷-1-胺(38mg,0.2mmol)在MeOH(0.2mL)中合并,并将混合物在室温下搅拌过夜。将反应浓缩,然后通过反相层析(MeCN:含0.1%TFA的H2O,作为洗脱剂)纯化,得到产物。1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.17(d,J=10.0Hz,1H),8.95(s,1H),7.61(d,J=8.7Hz,1H),7.45(d,J=8.7Hz,1H),6.53–6.43(m,2H),5.17(d,J=9.9Hz,1H),4.38(s,2H),3.17(s,1H),0.99(s,9H).MS:C21H20Cl2N3O4[M+H]+的(ES)m/z计算值448.1,实测值448.1。
实施例10:(R)-3-(2,2-二甲基-1-(5-甲基呋喃-2-基)丙基)氨基)-4-((5-氟-7-甲基-3-氧代异吲哚啉-4-基)氨基)环丁-3-烯-1,2-二酮
步骤a:在室温下,向在水浴中的7-氨基-6-氟异吲哚啉-1-酮(2.4g,14.4mmol)的AcOH(30mL)中分批加入N-碘代丁二酰亚胺(4.55g,20.2mmol)。将所得混合物在水浴中搅拌30分钟,用水(20mL)淬灭,并用乙酸乙酯(100mL)萃取。有机层用盐水(100mL)洗涤,然后用MgSO4.干燥。减压蒸发溶剂,得到棕色固体,将其通过硅胶层析(0-60%乙酸乙酯的己烷)纯化,得到产物。MS:C8H6FIN2O[M+H]+的(ES)m/z计算值为293.0实测值为293.0。
步骤b:向7-氨基-6-氟-4-碘异吲哚啉-1-酮(2.2g,7.53mmol)的二噁烷(44mL)溶液中加入CsF(4.57g,30.1mmol),2,4,6-三甲基-1,3,5,2,4,6-三氧杂三硼烷(1.35g,22.6mmol)和[1,1'-双(二苯膦基)二茂铁]二氯化钯(II)(551mg,0.753mmol)。所得混合物在80℃下搅拌过夜。然后将反应物在水(100mL)和乙酸乙酯(100mL)之间分配,并将有机层用盐水(80mL)洗涤,然后用MgSO4干燥。减压蒸发溶剂,得到棕色固体,将其通过硅胶层析(0-80%乙酸乙酯的己烷)纯化,得到产物。MS:C9H9FN2O[M+H]+的(ES)m/z计算值是181.1,实测值是181.1。
步骤c:将7-氨基-6-氟-4-甲基异吲哚啉-1-酮(200mg,1.11mmol)和3,4-二甲氧基环丁-3-烯-1,2-二酮(189.3mg,1.33mmol)在无水甲醇(3mL)的混合物在60℃搅拌过夜,然后在80℃搅拌5小时。将反应混合物蒸发并通过硅胶层析(0-100%乙酸乙酯的己烷)纯化,得到产物。MS:C14H11FN2O4[M+H]+的(ES)m/z计算值是291.1,实测值291.1。
步骤d:将无水甲醇(2mL)加入到3-((5-氟-7-甲基-3-氧代异吲哚啉-4-基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮(95mg,0.327mmol)和(R)-2,2-二甲基-1-(5-甲基呋喃-2-基)丙烷-1-胺(55mg,0.329mmol)的混合物,并将该混合物在60℃下搅拌过夜。使反应物冷却至室温,溶于最小量的二氯甲烷中,并吸附到硅胶上。产物通过硅胶层析(40%乙酸乙酯的二氯甲烷)纯化,得到产物。1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.61(s,1H),8.24(d,J=10.4Hz,1H),7.21(d,J=11.6Hz,1H),6.07(d,J=2.4Hz,1H),5.94(d,J=2.4Hz,1H),4.90(s,2H),2.16(s,3H),2.15(s,3H),0.90(s,9H)。MS:C23H24FN3O4[M-H]-的(ES)m/z计算值是426.2,实测值是426.2。
实施例11:(R)-3-((1-(4,5-二甲基呋喃-2-基-2,2-二甲基丁基)氨基)-4-((5-氟-1,1,7三甲基-3-氧代-异吲哚啉-4-基)氨基)环丁-3-烯-1,2-二酮
步骤a:在0℃下,向装有2-(溴甲基)-5-氟苯甲酸甲酯(25g,101mmol)和THF(300mL)的500mL圆底烧瓶中缓慢加入4-甲氧基苄胺(34.7g,253mmol)。使混合物温热至室温过夜。将反应物用乙酸乙酯(300mL)和HCl(1N水溶液,200mL)倒入2L的分液漏斗中。将有机层用盐水(2×200mL)洗涤,然后用MgSO4干燥,过滤,浓缩,并通过硅胶层析(0-30%乙酸乙酯的己烷)纯化,得到6-氟-2-(4-甲氧基苄基)异吲哚啉-1-酮。MS:C16H14FNO2[M+H]+的(ES)m/z计算值为272.1,实测值272.1。
步骤b:在0℃下,向6-氟-2-(4-甲氧基苄基)异吲哚啉-1-酮(10g,36.9mmol)的THF(50mL)溶液中加入NaH(7.4g,184.5mmol)。所得混合物在氮气下搅拌30分钟。在0℃下,向反应混合物中加入甲基碘(31.4g,221.2mmol),然后将其在70℃加热过夜,冷却至室温,用水(40mL)淬灭,并用乙酸乙酯(100mL)萃取。有机层用盐水(100mL)洗涤并用MgSO4干燥。浓缩溶剂得到粗产物,将其通过硅胶层析(0-80%乙酸乙酯的己烷)纯化,得到6-氟-2-(4-甲氧基苄基)-3,3-二甲基异吲哚啉-1-酮。MS:C18H18FNO2[M+H]+的(ES)m/z计算值300.1,实测值300.1。
步骤c:将6-氟-2-(4-甲氧基苄基)-3,3-二甲基异吲哚啉-1-酮(5g,16.7mmol)的TFA(25mL)和苯甲醚(5mL)溶液在100℃加热过夜。将反应混合物倒入冰(20g)中,用饱和NaHCO3水溶液(50mL)中和,并用乙酸乙酯(100mL)萃取。有机层用盐水(100mL)洗涤,然后用MgSO4.干燥。减压蒸发溶剂,得到粗产物,将其通过硅胶层析(0-100%乙酸乙酯的己烷)纯化,得到6-氟-3,3-二甲基异吲哚啉-1-酮。MS:C10H10FNO[M+H]+的(ES)m/z计算值是180.1,实测值是180.1。
步骤d:向0℃的6-氟-3,3-二甲基异吲哚啉-1-酮(3.1g,17.3mmol)的浓H2SO4(12mL)悬浮液中滴加硝酸(1.34mL),同时保持反应混合物低于5C。加完后,将反应混合物缓慢温热至室温过夜。向混合物中加入冰(20g),过滤固体,然后用MTBE(50mL)和乙酸乙酯(50mL)洗涤,得到6-氟-3,3-二甲基-7-硝基异吲哚啉-1-酮。MS:C10H9FN2O3[M+H]+的(ES)m/z计算值是225.1,实测值是225.1。
步骤e:将6-氟-3,3-二甲基-7-硝基异吲哚啉-1-酮(2.0g,8.93mmol)和10%Pd/C(50%湿度,0.89g,0.45mmol,0.05当量)的MeOH(50mL)溶液在氢气气氛(35psi)下振摇2小时。通过硅藻土过滤固体,减压浓缩滤液,得到的产物通过硅胶层析(100%乙酸乙酯)纯化,得到7-氨基-6-氟-3,3-二甲基异吲哚啉-1-酮。MS:C10H11FN2O[M+H]+的(ES)m/z计算值195.1,实测值195.1。
步骤f:在室温下,向在室温水浴中的7-氨基-6-氟-3,3-二甲基异吲哚啉-1-酮(150mg,0.77mmol)的AcOH(2mL)溶液中分批加入N-碘代丁二酰亚胺(244mg,1.08mmol)药剂。将所得混合物在水浴中搅拌30分钟,用水(1mL)淬灭并用乙酸乙酯(10mL)萃取。将有机层用盐水(10mL)洗涤,然后用MgSO4干燥。减压蒸发溶剂,得到粗产物,将其通过硅胶层析(0-60%乙酸乙酯的己烷)纯化,得到7-氨基-6-氟-4-碘-3,3-二甲基异吲哚啉-1-酮。MS:C10H10FIN2O[M+H]+的(ES)m/z计算值321.0,实测值321.0。
步骤g:向7-氨基-6-氟-4-碘-3,3-二甲基异吲哚啉-1-酮(370mg,1.16mmol)的二噁烷(12mL)溶液中加入CsF(705mg,4.64mmol),2,4,6-三甲基-1,3,5,2,4,6-三氧杂三硼烷(435mg,3.47mmol)和[1,1'-双(二苯膦基)二茂铁]二氯化钯(II)(95mg,0.116mmole)。将所得混合物在80℃下搅拌过夜,然后冷却至室温。将反应物在水(20mL)和乙酸乙酯(30mL)之间分配。将有机层用盐水(20mL)洗涤,然后用MgSO4干燥,过滤并浓缩,得到粗产物,将其通过硅胶层析(0-80%乙酸乙酯的己烷)纯化,得到7-氨基-6-氟-3,3,4-三甲基异吲哚啉-1-酮。MS:C11H13FN2O[M+H]+的(ES)m/z计算值209.1,实测值209.1。
步骤h:将7-氨基-6-氟-3,3,4-三甲基异吲哚啉-1-酮(129mg,0.62mmol)和3,4-二甲氧基环丁-3-烯-1,2-二酮(176.3mg,1.24mmol)mmol)的无水甲醇(2.5mL)混合物在60℃下搅拌过夜,然后在80℃下搅拌5小时。将反应混合物浓缩,通过硅胶层析(0-100%乙酸乙酯的己烷)纯化粗产物,得到3-((5-氟-1,1,7-三甲基-3-氧代异吲哚啉-4-基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮。MS:C16H15FN2O4[M+H]+的(ES)m/z计算值是319.1,实测值是319.1。
步骤i:将无水甲醇(2mL)加入3-((5-氟-1,1,7-三甲基-3-氧代异吲哚啉-4-基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮(22mg,0.07mmol)和(R)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丁-1-胺(15mg,0.077mmol)的混合物,在60℃下,搅拌该混合物过夜。使反应冷却至室温,溶解于最小量的二氯甲烷中,并吸附至硅胶上。将其通过硅胶层析(40%乙酸乙酯的二氯甲烷)纯化,得到标题化合物。1H NMR(400MHz,Cd3OD)δ7.21(d,J=12Hz,1H),6.04(s,1H),5.16(d,J=4.10Hz,1H),2.47(s,3H),2.19(s,3H),1.92(s,3H),1.60(s,6H),1.40(q,J=7.6Hz,2H),1.03(s,3H),0.97(s,3H),0.91(t,J=7.6Hz,3H)。MS:C27H32FN3O4[M-H]-的(ES)m/z计算值是482.2,实测值是482.2。
实施例12:(R)-3-((7-氯-2-(3-甲基-1H-吡唑-5-基)-3-氧代异吲哚啉-4-基)氨基)-4-((2,2-二甲基-1-(5-甲基呋喃-2-基)丙基)氨基)环丁-3-烯-1,2-二酮的合成。
步骤a:向2-(溴甲基)-3-氯-6-硝基苯甲酸甲酯(500mg,1.62mmol)和3-甲基-1H-吡唑-5-胺(158mg,1.62mmol)的无水四氢呋喃溶液(3ml)中加入三乙胺(0.5ml,3.56mmol)。将所得反应溶液在封闭的40mL反应小瓶中加热至60℃持续1小时。反应过程中固体沉淀。然后将反应物冷却至室温,并过滤。用二氯甲烷冲洗固体得到产物。MS:C12H9ClN4O3[M+H]+的(ES)m/z计算值为293.0,实测值293.0。
步骤b:在室温下,向4-氯-2-(3-甲基-1H-吡唑-5-基)-7-硝基异吲哚啉-1-酮(266mg,0.91mmol)的乙醇搅拌混合物中加入铁粉(203mg,3.60mmol),随后加入含有4M HCl的二噁烷(0.91ml,3.64mmol)。将反应混合物在室温下搅拌1小时,然后浓缩至干燥。残余物用乙酸乙酯稀释,并用饱和碳酸氢钠溶液中和,用乙酸乙酯(2×5ml)萃取。将合并的有机层干燥(Na2SO4),过滤并真空浓缩。通过硅胶柱层析(0-100%乙酸乙酯的己烷)纯化粗产物,得到产物。MS:C12H11ClN4O[M+H]+的(ES)m/z计算值是263.0,测测值263.0。
步骤c:向7-氨基-4-氯-2-(3-甲基-1H-吡唑-5-基)异吲哚啉-1-酮(200mg,0.76mmol)和3,4-二甲氧基环丁-3-烯-1-酮(130mg,0.91mmol)的甲醇(1ml)悬浮液中加入4M HCl的二噁烷(0.19ml,0.76mmol)。将反应混合物温热至60℃并搅拌1小时。然后将其冷却至室温,过滤并用甲醇冲洗以得到产物。MS:C17H13ClN4O4[M+H]+的(ES)m/z计算值为373.0,实测值373.0。
步骤d:向3-((7-氯-2-(3-甲基-1H-吡唑-5-基)-3-氧代异吲哚啉-4-基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮(100mg,0.27mmol)的甲醇(1ml)悬浮液中加入(R)-2,2-二甲基-1-(5-甲基呋喃-2-基)丙烷-1-胺(45mg,0.27mmol)和三乙胺(0.04ml,0.27mmol)。将所得混合物在室温下搅拌过夜,然后用二氯甲烷稀释。过滤除去固体,将滤液浓缩至干。将其通过反相层析纯化得到产物。1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),10.00(s,1H),9.13(d,J=10Hz,1H),7.63(d,J=10Hz,1H),7.46(d,J=10Hz,1H),6.56(s,1H),6.20(d,J=3.2Hz,1H),6.04(d,J=3.2Hz,1H),5.12(d,J=10Hz,1H),4.85(s,2H),2.28(s,3H),2.25(s,3H),0.97(s,9H)。MS:C26H26ClN5O4[M-H]-的(ES)m/z计算值为506.1,实测值506.1。
实施例13:(R)-3-((7-氯-5-氟-1,1-二甲基-3-氧代异吲哚啉-4-基)氨基)-4-((2,2-二甲基-1-(5-甲基呋喃-2-基)丙基)氨基)环丁-3-烯-1,2-二酮的合成
步骤a:将2-溴-5-氟苯甲酸甲酯(5.00g,21.5mmol)和氰化亚铜(2.12g,23.6mmol)在DMF中的混合物在90℃下加热1天,然后冷却至室温,用乙酸乙酯(300mL)稀释并过滤。将滤液用盐水(5×50mL)洗涤,然后用饱和NaHCO3水溶液(50mL)洗涤。有机层用MgSO4干燥,过滤并真空浓缩。该产物不经进一步纯化而用于下一步。MS:C9H6FNO2[M+H]+的(ES)m/z计算值是180.0,实测值是180.0。
步骤b:在0℃下,向2-氰基-5-氟苯甲酸甲酯(3.85g,21.5mmol)的四氢呋喃(30mL)和水(3mL)搅拌溶液中加入一水氢氧化锂(1.11g,26.5mmol)。将反应温热至室温并搅拌1小时。然后蒸发溶剂,残余物用水(100mL)和2M HCl水溶液(20mL)稀释。过滤收集固体,真空干燥得到所需产物。MS:C8H4FNO2[M+H]+的(ES)m/z计算值为166.0,实测值为166.0。
步骤c:在-78℃下,向2-氰基-5-氟苯甲酸(1.70g,10.3mmol)的无水四氢呋喃(105mL)搅拌溶液中滴加包含1.6M甲基锂的乙醚溶液(25.74mL,41.2mmol)。将混合物在-78℃搅拌1小时,然后缓慢温热至室温,用饱和氯化铵水溶液淬灭,并用乙酸乙酯萃取。通过硅胶层析(0-100%乙酸乙酯的己烷)纯化有机层,得到6-氟-3,3-二甲基异吲哚啉-1-酮。MS:C10H10FNO[M+H]+的(ES)m/z计算值是180.0,实测值是180.0。
步骤d:将含有6-氟-3,3-二甲基异吲哚啉-1-酮(620mg,3.46mmol)的浓H2SO4(1mL)的反应小瓶在冰浴中冷却。滴加含有70%HNO3(0.25mL,3.8mmol)的浓H2SO4(1mL)混合物,并将反应混合物在0℃下搅拌2h,然后小心地用冰淬灭并用冷水稀释至10mL。过滤固体,用水洗涤并真空干燥,得到6-氟-3,3-二甲基-7-硝基异吲哚啉-1-酮。MS:C10H9FN2O3[M+H]+的(ES)m/z计算值是225.0,实测值是225.0。
步骤e:在室温下向6-氟-3,3-二甲基-7-硝基异吲哚啉-1-酮(0.56g,2.50mmol)的乙醇(10mL)和水(1mL)溶液中加入铁粉(0.58g,10.38mmol)和氯化铵(1.90g,34.6mmol)。将反应混合物温热至90℃并搅拌1小时。然后使反应冷却至室温,通过硅藻土过滤并用甲醇(20ml)冲洗。将滤液浓缩至干,残余物用乙酸乙酯稀释,然后用水和盐水洗涤。将合并的有机层干燥((Na2SO4),过滤、真空浓缩,并通过硅胶层析(0-100%乙酸乙酯的己烷)纯化,得到7-氨基-6-氟-3,3-二甲基异吲哚啉-1-酮。MS:C10H11FN2O[M+H]+的(ES)m/z计算值195.0,实测值195.0。
步骤f:在室温下向7-氨基-6-氟-3,3-二甲基异吲哚啉-1-酮(116mg,0.59mmol)的乙酸(1mL)溶液中加入N-氯代丁二酰亚胺(80mg,0.59mmol)。将反应混合物温热至45℃并搅拌过夜。然后将其冷却至室温,用乙酸乙酯稀释,并用水和盐水洗涤。将合并的有机层干燥(Na2SO4),过滤并真空浓缩。通过硅胶层析(0-30%乙酸乙酯的己烷)纯化粗产物,得到7-氨基-4-氯-6-氟-3,3-二甲基异吲哚啉-1-酮。MS:C10H10ClFN2O[M+H]+的(ES)m/z计算值是229.0,实测值229.0。
步骤g:向7-氨基-4-氯-6-氟-3,3-二甲基异吲哚啉-1-酮(73mg,0.32mmol)和3,4-二甲氧基环丁-3-烯-1,2-二酮(540.38mmol)的甲醇(3mL)悬浮液中加入4M HCl的二噁烷(0.08mL,0.32mmol)。将反应混合物温热至60℃并搅拌1小时。然后将其冷却至室温并用二氯甲烷(2ml)稀释以产生澄清溶液。该溶液真空浓缩。通过硅胶层析(0-10%甲醇的二氯甲烷)纯化粗产物以提供所需产物。MS:C15H12ClFN2O4[M+H]+的(ES)m/z计算值是338.0,实测值是338.0。
步骤h:向3-((7-氯-5-氟-1,1-二甲基-3-氧代异吲哚啉-4-基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮(71mg,0.21mmol)的甲醇(2mL)悬浮液加入(R)-2,2-二甲基-1-(5-甲基呋喃-2-基)丙烷-1-胺(35mg,0.21mmol)和三乙胺(0.03mL,0.21mmol)。将所得混合物在室温下搅拌过夜,然后用二氯甲烷稀释。然后通过硅胶层析(0-10%甲醇的二氯甲烷)纯化,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.97(s,1H),8.40(d,J=10Hz,1H),7.62(d,J=10Hz,1H),6.10(d,J=2.6Hz,1H),5.95(d,J=2.6Hz,1H),4.92(d,J=10Hz,1H),2.19(s,3H),1.46(s,6H),0.87(s,9H)。MS:C24H25ClFN3O4[M-H]-的(ES)m/z计算值是472.0,实测值472.0。
实施例14:3-[(7-氯-5-氟-1,1-二甲基-3-氧代-异吲哚啉-4-基)氨基]-4-[[(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]氨基]环丁-3-烯-1,2-二酮的合成
向3-((7-氯-5-氟-1,1-二甲基-3-氧代异吲哚啉-4-基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮(15mg,0.04mmol)的甲醇(2mL)悬浮液加入(R)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丙烷-1-胺(11mg,0.05mmol)和三乙胺(0.01ml,0.05mmol)。将所得混合物在室温下搅拌过夜并浓缩至干燥。粗产物通过反相层析纯化得到产物。1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.06(s,1H),8.44(d,J=10Hz,1H),7.70(d,J=10Hz,1H),6.08(s,1H),4.94(d,J=10Hz,1H),2.17(s,3H),1.87(s,3H),1.54(s,6H),0.94(s,9H)。MS:C25H27ClFN3O4[M-H]-的(ES)m/z计算值是486.0,实测值486.0。
实施例15:3-[[7-氯-3-氧代-2-[2-(5-氧代-1H-四唑-4-基)乙基]异吲哚啉-4-基]氨基]-4-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]环丁-3-烯-1,2-二酮的合成
步骤a:向2-(溴甲基)-3-氯-6-硝基苯甲酸甲酯(10.0g,32.4mmol)和3-氨基丙酸乙酯盐酸盐(5.5g,35.6mmol)的四氢呋喃(120ml)混合物中加入三乙胺(10ml,71.3mmol)。将反应混合物在室温下搅拌过夜。然后用乙酸乙酯稀释反应物,并用水和盐水洗涤。将合并的有机层干燥((Na2SO4),过滤并真空浓缩,得到产物,其不经进一步纯化即可使用。MS:C13H13ClN2O5[M+H]+的(ES)m/z计算值为313.0,实测值313.0。
步骤b:在室温下向3-(4-氯-7-硝基-1-氧代异吲哚啉-2-基)丙酸乙酯(10.1g,32.4mmol)的乙醇(90ml)和水(10ml)溶液中加入铁粉(6.0g,97.2mmol)和氯化铵(9.0g,162mmol)。将反应混合物温热至90℃并搅拌1小时。然后使其冷却至室温,通过硅藻土过滤并用甲醇(120ml)冲洗。将滤液浓缩至干,残余物用乙酸乙酯稀释,用水洗涤,然后用盐水洗涤。将合并的有机层干燥(Na2SO4),过滤并真空浓缩,得到产物,其不经进一步纯化即可使用。MS:C13H15ClN2O3[M+H]+的(ES)m/z计算值为283.0,实测值283.0。
步骤c:室温下向3-(7-氨基-4-氯-1-氧代异吲哚啉-2-基)丙酸乙酯(6.60g,23.2mmol)的四氢呋喃(40ml)溶液中加入二碳酸二叔丁酯(12.67g g,58.0mmol)和4-二(甲基氨基)吡啶(142mg,1.16mmol)。将反应混合物温热至100℃并搅拌过夜。然后使其冷却至室温,用饱和NaHCO3水溶液(100ml)稀释并搅拌20分钟。然后将反应混合物用乙酸乙酯稀释,并依次用水和盐水洗涤。将合并的有机层干燥(Na2SO4),过滤并真空浓缩。通过硅胶层析(0-40%乙酸乙酯的己烷)纯化粗产物以提供产物。MS:C23H31ClN2O7[M+Na]+的(ES)m/z计算值505.0,实测值505.0。
步骤d:向3-[7-[双(叔丁氧基羰基)氨基]-4-氯-1-氧代-异吲哚啉-2-基]丙酸乙酯(7.43g,15.4mmol)的四氢呋喃(40ml)、甲醇(4mL)和水(4ml)溶液中加入一水氢氧化锂(1.9g,46.2mmol)。将反应混合物搅拌过夜,然后浓缩至干燥,残余物用1M HCl酸化至pH=4。然后混合物用乙酸乙酯萃取,并用水和盐水洗涤。将合并的有机层干燥(Na2SO4),过滤并真空浓缩,得到产物,其不经进一步纯化即可使用。MS:C21H27ClN2O7[M+H]+的(ES)m/z计算值为455.0,实测值455.0。
步骤e:在0℃下,向3-[7-[双(叔丁氧基羰基)氨基]-4-氯-1-氧代-异吲哚啉-2-基]丙酸(4.66g,10.2mmol)的二氯甲烷(40ml)悬浮液滴加乙二酰氯(1.3ml,15.4mmol)。加完后,加入两滴DMF。将反应混合物在0℃下搅拌10分钟,然后温热至室温持续3小时。将所得溶液浓缩至干燥。将残余物溶于二氯甲烷(40ml)中并再次浓缩至干燥以除去过量的乙二酰氯。粗产物未经进一步纯化即用于下一步。
步骤f:在室温下,将叠氮基三甲基硅烷在氮气气氛下一次性加入到上述酰氯中。将混合物加热至100℃持续2小时,然后冷却至室温。然后将该混合物浓缩至干燥以除去过量的叠氮基三甲基硅烷。将粗产物用乙酸乙酯稀释,并用1M HCl水溶液酸化至pH=3。有机层用水洗涤,然后用盐水洗涤。将合并的有机层干燥(Na2SO4),过滤并真空浓缩。通过硅胶层析(0-100%乙酸乙酯的己烷)纯化粗产物以提供产物。MS:C21H27ClN6O6[M+Na]+的(ES)m/z计算值517.0,实测值517.0。
步骤g:在室温下,向N-叔丁氧基羰基-N-[7-氯-3-氧代-2-[2-(5-氧代-1H-四唑-4-基)乙基]异吲哚啉-4-基]氨基甲酸叔丁酯(135mg,0.27mmol)的二氯甲烷(1ml)溶液中加入三氟乙酸(0.25ml)。将反应混合物在室温下搅拌1小时,然后用饱和NaHCO3水溶液中和。用二氯甲烷萃取混合物,然后用水和盐水洗涤有机层。将合并的有机层干燥(Na2SO4),过滤并真空浓缩。通过硅胶层析(0-100%乙酸乙酯的己烷)纯化粗产物以提供产物。MS:C11H11ClN6O2[M+H]+的(ES)m/z计算值为295.0,实测值295.0。
步骤h:向7-氨基-4-氯-2-(2-(5-氧代-4,5-二氢-1H-四唑-1-基)乙基)异吲哚啉-1-酮(60mg,0.21mmol)和3,4-二甲氧基环丁-3-烯-1,2-二酮(44mg,0.31mmol)的甲醇(1ml)悬浮液中加入含有4M HCl的二噁烷(0.05ml,0.21mmol)。将所得澄清溶液温热至60℃并搅拌1小时,在此期间固体沉淀。使反应混合物冷却至室温,过滤固体并用乙酸乙酯(2ml)冲洗以提供产物。MS:C16H13ClN6O5[M-H]-的(ES)m/z计算值为403.0,实测值403.0。
步骤i:向3-((7-氯-3-氧代-2-(2-(5-氧代-4,5-二氢-1H-四唑-1-基)乙基)异吲哚啉-4-基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮(40mg,0.10mmol)的甲醇(2ml)悬浮液中加入(R)-2,2-二甲基-1-(5-甲基呋喃-2-基)丙烷-1-胺(20mg,0.12mmol)和一滴三乙胺。将所得混合物在室温下搅拌过夜,然后浓缩至干。通过硅胶层析(0-100%乙酸乙酯的己烷)纯化粗产物,得到产物。1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.11(d,J=10Hz,1H),7.58(d,J=8Hz,1H),7.42(d,J=8Hz,1H),6.18(d,J=2.6Hz,1H),6.03(d,J=2.6Hz,1H),5.10(d,J=10.4Hz,1H),4.54(s,2H),4.22(t,J=5.6,5.6Hz,2H),3.85(t,J=5.6,5.6Hz,2H),2.27(s,3H),0.95(s,9H)。MS:C25H26ClN7O5[M-H]-的(ES)m/z计算值为538.0,实测值538.0。
实施例16:(R)-3-((7-氯-2-(2-(4-甲基-5-氧代-4,5-二氢-1H-四唑-1-基)乙基)-3-氧代异吲哚啉-4-基)氨基)-4-((2,2-二甲基-1-(5-甲基呋喃-2-基)丙基)氨基)环丁-3-烯-1,2-二酮的合成
步骤a:在室温下,向叔丁基N-叔丁氧基羰基-N-[7-氯-3-氧代-2-[2-(-氧代-1H-四唑-4-基)乙基]异吲哚啉-4-基](100mg,0.20mmol)的DMF(1ml)溶液中加入碳酸钾(70mg,0.51mmol)和碘甲烷。将反应混合物在室温下搅拌2小时,然后用水淬灭。固体沉淀并过滤,然后用水和己烷冲洗。收集的固体在真空下干燥以提供产物。MS:C22H29ClN6O6[M+H]+的(ES)m/z计算值为509.0,实测值509.0。
步骤b:在室温下,向N-叔丁氧基羰基-N-[7-氯-2-[2-(4-甲基-5-氧代-四唑-1-基)乙基]-3-氧代-异吲哚啉-4-基]氨基甲酸叔丁酯(80mg,0.16mmol)的二氯甲烷(1ml)溶液中加入三氟乙酸(0.25ml)。将反应混合物在室温下搅拌1小时,然后用饱和NaHCO3水溶液中和。混合物用二氯甲烷萃取,有机层用水和盐水洗涤。将合并的有机层干燥(Na2SO4),过滤并真空浓缩。通过硅胶层析(0-100%乙酸乙酯的己烷)纯化粗产物以提供产物。MS:C12H13ClN6O2[M+H]+的(ES)m/z计算值是309.0,实测值309.0。
步骤c:向7-氨基-4-氯-2-(2-(4-甲基-5-氧代-4,5-二氢-1H-四唑-1-基)乙基)异吲哚啉-1-酮(31mg,0.10mmol)和3,4-二甲氧基环丁-3-烯-1,2-二酮(21mg,0.15mmol)的甲醇(1ml)悬浮液中加入4M HCl的二噁烷(0.025ml,0.10mmol)。将所得澄清溶液温热至60℃并搅拌1小时。使反应混合物冷却至室温,过滤固体沉淀,然后用乙酸乙酯(2ml)冲洗以提供产物。MS:C17H15ClN6O5[M-H]-的(ES)m/z计算值为417.0,实测值417.0。
步骤d:向3-((7-氯-2-(2-(4-甲基-5-氧代-4,5-二氢-1H-四唑-1-基)乙基)-3-氧代异吲哚啉-4-基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮(32mg,0.076mmol)的甲醇(2ml)悬浮液中加入(R)-2,2-二甲基-1-(5-甲基呋喃-2-基)丙烷-1-胺(15mg,0.09mmol)和一滴三乙胺。将所得混合物在室温下搅拌过夜并浓缩至干。通过硅胶层析(0-100%乙酸乙酯的己烷)纯化粗产物,得到产物。1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),9.10(d,J=10Hz,1H),7.59(d,J=8.8Hz,1H),7.44(d,J=8.8Hz,1H),6.18(d,J=2.8Hz,1H),6.03(d,J=2.8Hz,1H),5.10(d,J=10.4Hz,1H),4.54(s,2H),4.22(t,J=5.6,5.6Hz,2H),3.86(t,J=5.6,5.6Hz,2H),2.27(s,3H),0.95(s,9H)。MS:C26H28ClN7O5[M-H]-的(ES)m/z计算值为552.0,实测值552.0。
实施例17:2-[4-氯-7-[[2-[[(1R)-1-(5-氯-2-呋喃基)-2,2-二甲基-丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]-6-甲氧基-吡啶-3-甲酸的合成
步骤a:向含有7-氨基-4-氯-异吲哚啉-1-酮(365mg,2.0mmol)的二噁烷(2.0mL)的反应小瓶中加入2-氯-6-甲氧基烟酸甲酯(603mg,3.0mmol),碳酸铯(1.3g,4.0mmol),碘化亚铜(152mg,80mmol)和(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(227mg,1.6mmol)。用氮气吹扫混合物,然后温热至110℃。反应在110℃下搅拌并通过LC-MS监测。完成后,使反应冷却,然后通过硅藻土过滤并用乙酸乙酯冲洗。通过硅胶层析(0-50%乙酸乙酯/己烷)纯化粗产物,得到产物。
步骤b:向2-(7-氨基-4-氯-1-氧代-异吲哚啉-2-基)-6-甲氧基-吡啶-3-羧酸甲酯(440mg,1.27mmol)的四氢呋喃(5.0mL)、甲醇(0.5mL)和水(0.5mL)的溶液中加入氢氧化锂(533mg,12.7mmol)。所得混合物在室温下搅拌。完成后,使用1N HCl水溶液将反应酸化至pH5-7,并用乙酸乙酯萃取。有机层用盐水洗涤,干燥((Na2SO4),过滤并真空浓缩,得到产物。
步骤c:将2-(7-氨基-4-氯-1-氧代-异吲哚啉-2-基)-6-甲氧基-吡啶-3-羧酸(334mg,1.00mmol)和3,4-二甲氧基环丁-3-烯-1,2-二酮(156mg,1.10mmol)的无水甲醇(5mL)混合物在60℃下搅拌3小时。然后过滤反应混合物,并且固体用乙酸乙酯洗涤,然后干燥得到产物。
步骤d:将Et3N(0.08mL,0.6mmol)加入到2-[4-氯-7-[(2-甲氧基-3,4-二氧代-环丁烯-1-基)氨基]-1-氧代-异吲哚啉-2-基]-6-甲氧基-吡啶-3-羧酸(97mg,0.22mmol)和(1R)-1-(5-氯-2-呋喃基)-2,2-二甲基-丙烷-1-胺(45mg,0.24mmol)在MeOH(3.0mL)混合物中。将反应在60℃下搅拌4小时,然后浓缩。通过反相层析(MeCN:含0.1%TFA的H2O,作为洗脱液)纯化所得粗产物以得到产物。1H NMR(400MHz,甲醇-d4)δ8.20(d,J=8.5Hz,1H),7.94(d,J=8.9Hz,1H),7.62(d,J=8.8,1H),6.81(d,J=8.6Hz,1H),6.39(s,1H),6.25(d,J=3.5Hz,1H),5.28(s,1H),5.17(s,2H),4.02(s,3H),1.06(s,9H)。MS:C28H23Cl2N4O7[M-H]-的(ES)m/z计算值是597.1,实测值是597.1。
实施例18:2-[4-氯-7-[[2-[[(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]氨基]-3,4-二氧代-环丁烯-1-基]氨基]-1-氧代-异吲哚啉-2-基]-6-甲氧基-吡啶-3-甲酸的合成
将Et3N(0.08mL,0.6mmol)加入到2-[4-氯-7-[(2-甲氧基-3,4-二氧代-环丁烯-1-基)氨基]-1-氧代-异吲哚啉-2-基]-6-甲氧基-吡啶-3-羧酸(90mg,0.15mmol)和(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙烷-1-胺盐酸盐(45mg,0.23mmol)的MeOH(3.0mL)混合物中。将反应在60℃下搅拌4小时,然后浓缩。通过反相层析(MeCN:含0.1%TFA的H2O,作为洗脱液)纯化所得粗产物以得到产物。1H NMR(400MHz,甲醇-d4)δ8.19(d,J=8.5Hz,1H),7.92(d,J=9.1Hz,1H),7.61(d,J=8.8Hz,1H),6.80(d,J=8.6Hz,1H),6.06(s,1H),5.24–5.09(m,3H),4.02(s,3H),2.18(s,3H),1.91(s,3H),1.04(s,9H)。MS:C30H28ClN4O7[M-H]-的(ES)m/z计算值为591.2,实测值591.1。
实施例19:3-[[(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]氨基]-4-[(5-氟-3-氧代-异吲哚啉-4基)氨基]环丁-3-烯-1,2-二酮的合成
将Et3N(0.08mL,0.6mmol)加入到3-[(5-氟-3-氧代-异吲哚啉-4-基)氨基]-4-甲氧基-环丁-3-烯-1,2-二酮(81mg,0.30mmol)和(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丁烷-1-胺盐酸(72mg,0.33mmol)的MeOH混合物中。将反应在60℃下搅拌4小时。将反应浓缩,然后通过反相层析(MeCN:含0.1%TFA的H2O,作为洗脱剂)纯化,得到产物。1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.72(s,1H),8.39(d,J=10.2Hz,1H),7.47(dd,J=11.2,8.2Hz,1H),7.33(dd,J=8.3,3.8Hz,1H),6.07(s,1H),4.97(d,J=10.2Hz,1H),4.32(s,2H),2.18(s,3H),1.87(s,3H),0.95(s,9H)。
实施例20:3-[(7'-氯-5'-氟-3'-氧代-螺[环戊烷-1,1'-异吲哚啉]-4'-基)氨基]-4-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]环丁-3-烯-1,2-二酮的合成
步骤a:将2-溴-5-氟苯甲酸甲酯(2.5g,10.8mmol),2-环戊烯基-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(2.3g,11.9mmol)和K2CO3(3.7g,27.0mmol)在1,2-二甲氧基乙烷(27mL)和H2O(3.0mL)中的混合物用N2吹扫2分钟。然后在室温下加入Pd(PPh3)4(0.62g,0.54mmol)。将所得混合物加热至95℃持续14小时,反应完成后,使混合物冷却至室温。将反应混合物用EtOAc(100mL)稀释,将有机层用H2O洗涤,然后用盐水洗涤,然后用Na2SO4干燥,过滤并浓缩。通过硅胶层析(0-20%乙酸乙酯的己烷)纯化粗化合物,得到2-环戊烯基-5-氟苯甲酸甲酯。
步骤b:向2-环戊烯基-5-氟苯甲酸甲酯(2.2g,10.0mmol)的MeOH(25mL)溶液中加入PtO2(448mg,2.0mmol)。在H2(40psi)下震荡3小时。将混合物通过硅藻土过滤并用MeOH(40mL)洗涤,并将滤液减压浓缩。粗产物无需进一步纯化直接用于下一步。
步骤c:在室温下,向2-环戊基-5-氟苯甲酸甲酯(2.0g,14.9mmol)的THF/H2O(20:6mL)搅拌溶液中加入LiOH·2H2O(1.89g,61.0mmol)。将反应混合物搅拌16小时。完成后,反应用2N HCl水溶液(4mL)淬灭以调节至pH=7。将水溶液用乙酸乙酯(2×75mL)萃取,并将合并的有机层用盐水洗涤,经Na2SO4,干燥,过滤并浓缩。粗产物无需进一步纯化直接用于下一步。MS:C12H13FO2[M+H]+的(ES)m/z计算值209.1,实测值是209.1。
步骤d:在0℃向2-环戊基-5-氟苯甲酸(3.0g,14.4mmol)的二氯甲烷(30mL)搅拌溶液中加入DMF(2滴)。然后在5分钟内滴加乙二酰氯(2.27g,18.0mmol),并将反应混合物在室温下搅拌16小时。反应完成后,减压除去溶剂,残余物真空干燥2小时,得到2-环戊基-5-氟苯甲酰氯。
在0℃将上述得到的2-环戊基-5-氟苯甲酰氯(3.0g,13.2mmol)的5ml乙酸乙酯加入到O-甲基羟胺盐酸盐(1.32g,15.8mmol)和K2CO3(3.6g,26.4mmol)在EtOAc和H2O(32:10mL)中的冷溶液中。然后将反应混合物在室温下搅拌14小时。反应完成后,混合物用乙酸乙酯(2×50mL)萃取,合并的有机层用盐水溶液洗涤,用Na2SO4干燥,过滤并真空浓缩。通过硅胶层析(10-40%乙酸乙酯的己烷)纯化粗化合物,得到2-环戊基-5-氟-N-甲氧基苯甲酰胺。MS:C13H16FNO2[M+H]+的(ES)m/z C计算值是238.2,实测值是238.1。
步骤e:在室温下,向2-环戊基-5-氟-N-甲氧基苯甲酰胺(2.0g,8.4mmol)和mCPBA(2.16g,12.6mmol)的六氟丙醇(3.5mL)混合物中加入2-碘联苯(468mg,1.68mmol)。将反应混合物在室温下搅拌1小时。完成后,将反应混合物用饱和NaHCO3水溶液淬灭,并用乙酸乙酯(100mL)稀释。将有机层用H2O洗涤,然后用盐水溶液洗涤,用Na2SO4干燥,过滤并浓缩。通过硅胶层析(10-60%乙酸乙酯的己烷)纯化粗化合物,得到5'-氟-2'-甲氧基螺[环戊烷-1,1'-异吲哚啉]-3'-酮。MS:C13H14FNO2[M+H]+的(ES)m/z C计算值是236.1,实测值是236.0。
步骤f:室温下,向搅拌的5'-氟-2'-甲氧基螺-[环戊烷-1,1'-异吲哚啉]-3'-酮(0.95g,4.04mmol)的DMF(3.5mL)溶液中加入60%NaH(185mg,8.08mmol)。将所得混合物加热至95℃持续3小时,然后将混合物冷却至室温。将反应混合物用乙酸乙酯(75mL)稀释,并将有机层用H2O洗涤,然后盐水洗涤,用Na2SO4干燥,过滤并浓缩。粗产物无需进一步纯化直接用于下一步。
步骤g:将来自步骤f的5'-氟螺[环戊烷-1,1'-异吲哚啉]-3'-酮(0.75g,3.65mmol)溶于浓H2SO4(5mL)中并冷却至0℃。滴加70%HNO3(0.46g,7.31mmol,2.0当量)并将反应混合物在0℃搅拌10分钟,然后温热至室温并搅拌过夜。加入冰,然后用冷水(10mL)稀释混合物。将反应混合物用EtOAc(2×25mL)萃取,用H2O洗涤,然后用盐水溶液洗涤,用Na2SO4干燥,过滤并浓缩。粗品无需进一步纯化(0.55g)而直接用于下一步。MS:C12H11FN2O3[M+H]+的(ES)m/z计算值是251.1,实测值是251.0。
步骤h:5'-氟-4'-硝基螺[环戊烷-1,1'-异吲哚啉]-3'-酮(0.55g,1.32mmol)和10%Pd/C(50%湿度,200mg)的MeOH(20mL)在氢气气氛(40psi)下搅拌1小时。将混合物通过硅藻土过滤并用MeOH(40mL)洗涤,并将滤液减压浓缩,得到粗产物,将其通过硅胶层析(20-100%乙酸乙酯的己烷)纯化,得到4'-氨基-5'-氟螺[环戊烷-1,1'-异吲哚啉]-3'-酮(0.45g,56%)。MS:C12H13FN2O[M+H]+的(ES)m/z计算为221.0,实测值为221.0。
步骤i:室温下,向搅拌的7'-氨基-6'-氟-螺[环戊烷-1,3'-异吲哚啉]-1'-酮(135mg,0.61mmol)的AcOH(1.5mL)溶液中加入N-氯代丁二酰亚胺(89mg,0.67mmol)。将所得混合物加热至45℃持续16小时,然后冷却至室温。反应混合物用EtOAc(50mL)稀释。将有机层用H2O洗涤,然后用盐水溶液洗涤,用Na2SO4干燥,过滤并浓缩。粗产物无需进一步纯化直接用于下一步。
步骤j:室温下,向4'-氨基-7'-氯-5'-氟螺[环戊烷-1,1'-异吲哚啉]-3'-酮(125mg,0.490mmol)和3,4-二甲氧基环丁-3-烯-1,2-二酮(104mg,0.735mmol)的无水甲醇(2mL)混合物中加入4N HCl的二噁烷(0.122μl,0.490mmol)。将反应混合物在60℃下搅拌3小时,然后浓缩。向残余物中加入乙酸乙酯(5mL),并将其在50℃下搅拌10分钟,然后冷却至室温。过滤混合物并干燥,得到3-((7'-氯-5'-氟-3'-氧代螺-[环戊烷-1,1'-异吲哚啉]-4'-基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮。MS:C17H14ClFN2O4[M+H]+的(ES)m/z计算值是365.1,实测值是365.0。
步骤k:室温下,向来自步骤i的3-((7'-氯-5'-氟-3'-氧代螺[环戊烷-1,1'-异吲哚啉]-4'-基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮(70mg,0.205mmol)和(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙烷-1-胺(32mg,0.205mmol)的甲醇(2.0mL)混合物中加入三乙胺(114mg,0.41mmol,2.0当量)。将混合物在60℃搅拌3小时,然后冷却至室温。减压除去溶剂,通过硅胶层析(20-100%乙酸乙酯的己烷)纯化粗化合物,得到(R)-3-((7'-氯-5'-氟-3'-氧代螺[环戊烷-1,1'-异吲哚啉]-4'-基)氨基)-4-((2,2-二甲基-1-(5-甲基呋喃-2-基)丙基)氨基)环丁-3-烯-1,2-二酮。1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),9.42(s,1H),8.50(d,J=10.2Hz,1H),7.70(d,J=8.6Hz,1H),6.19(d,J=4.2Hz,1H),6.03-6.01(m,1H),5.02(d,J=10.2Hz,1H),2.27(s,3H),1.95-1.80(m,6H),1.70-1.80(m,2H),0.95(s,9H)。MS:C26H27ClFN3O4[M+H]+的(ES)m/z计算值是500.2,实测值是500.2。
实施例21:3-[(7-氯-2-羟基-3-氧代-异吲哚啉-4-基)氨基]-4-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]氨基]环丁-3-烯-1,2-二酮的合成
步骤a:将三乙胺(983mg,9.71mmol)加入到2-(溴甲基)-3-氯-6-硝基-苯甲酸甲酯(1.5g,4.87mmol)和N-羟基氨基甲酸叔丁酯(710mg,5.35mmol)的THF(10mL)混合物中,并将该混合物加热至65℃持续16小时。完成后,反应物用EtOAc稀释并用H2O(3x)洗涤。将有机层用Na2SO4,干燥,过滤并浓缩,得到产物,将其立即用于下一步。
步骤b:将EtOH:H2O以8:2的混合物(24mL)加入来自前步骤的4-氯-2-羟基-7-硝基-异吲哚啉-1-酮粗产品中。向该溶液中加入NH4Cl(2.67g,49.9mmol)和铁粉(800mg,14.3mmol)。将反应加热至85℃。一旦完成,将反应浓缩以除去EtOH,并加入EtOAc和H2O。过滤混合物以除去铁,然后用H2O洗涤,用Na2SO4干燥,过滤并浓缩。向粗产品中加入含HCl的MeOH(4M,2.0mL),过滤收集固体,得到产物。
步骤c:3,4-二甲氧基环丁-3-烯-1,2-二酮(80mg,0.56mmol)在无水甲醇(2.5mL)中的混合物(75mg,0.38mmol)在60℃下搅拌过夜。过滤反应混合物,固体用MeOH冲洗,然后真空干燥得到粗产物。
步骤d:得自前一步骤的粗3-[(7-氯-2-羟基-3-氧代-异吲哚啉-4-基)氨基]-4-甲氧基-环丁-3-烯-1,2-二酮和(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙烷-1-胺盐酸盐(66mg,0.40mmol)在MeOH(2.0mL)中合并并加入三乙胺(76mg,0.76mmol)。将混合物在室温下搅拌过夜。将反应浓缩并依次通过硅胶层析和反相层析(MeCN:含有0.1%TFA的H2O,作为洗脱剂)纯化,得到产物。1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),10.42(s,1H),9.19(d,J=9.7Hz,1H),7.65(d,J=9.0Hz,1H),7.39(d,J=9.0Hz,1H),6.22-6.18(m,1H),6.05-6.03(m,1H),5.09-5.15(m,3H),2.26(s,3H),0.95(s,9H)。MS:C22H22ClN3O5[M+Na]+的(ES)m/z计算值是464.1,实测值是464.0。
实施例22:3-[(2-氨基-7-氯-3-氧代-异吲哚啉-4-基)氨基]-4-[[(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]氨基]环丁-3-烯-1,2-二酮的合成
步骤a:将2-(溴甲基)-3-氯-6-硝基-苯甲酸甲酯(1.5g,4.87mmol)和N-氨基甲酸叔丁酯(670mg,5.11mmol)的THF(10mL)混合物加热至65℃持续3小时。完成后,反应物用EtOAc稀释并用H2O(3x)洗涤。将有机层用Na2SO4干燥,过滤并浓缩,得到粗产物,将其通过硅胶层析纯化得到产物。
步骤b:将MeOH(15mL)加入到来自之前步骤的N-(4-氯-7-硝基-1-氧代-异吲哚啉-2-基)氨基甲酸叔丁酯(1.6g,4.9mmol)中。向该溶液中加入PtO2(221mg,0.97mmol),并将该混合物在氢化装置中在H2(30psi)下在震动。反应完成后,将混合物过滤并真空干燥得到产物。
步骤c:将N-(7-氨基-4-氯-1-氧代-异吲哚啉-2-基)氨基甲酸叔丁酯(420mg,1.84mmol)和3,4-二甲氧基环丁-3-烯-1,2-二酮(392mg,2.7mmol)的无水甲醇(5.0mL)混合物在60℃下搅拌12小时。过滤反应混合物,通过硅胶层析纯化固体,得到产物。
步骤d:N-[4-氯-7-[(2-甲氧基-3,4-二氧代-环丁烯-1-基)氨基]-1-氧代-异吲哚啉-2-基]氨基甲酸叔丁酯(50mg,0.12mmol)和(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙烷-1-胺盐酸盐(27mg,0.13mmol)在MeOH(4.0mL)中合并,并加入三乙胺(24mg,0.244mmol)。将混合物在65℃下搅拌过夜。然后将该反应浓缩,得到粗产品,将其不进一步纯化用于下一步。
步骤e:将来自之前步骤的粗产物溶于MeOH(2.0mL)中,加入含有HCl的二噁烷(4M,10滴),并将反应在室温下搅拌。完成后,将反应浓缩并通过反相层析(MeCN:含有0.1%TFA的H2O,作为洗脱液)纯化,得到产物。1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),9.01(d,J=10.2Hz,1H),8.05(d,J=6.0Hz,2H),7.43(d,J=9.0Hz,1H),7.23(d,J=9.0Hz,1H),6.1(d,J=3.2Hz,1H),5.04(d,J=4.2Hz,1H),4.40(d,J=11.2Hz,2H),2.09(s,3H),1.79(s,3H),0.86(s,9H)。MS:C23H25ClN4O4[M+H]+的(ES)m/z计算值457.2,实测值是457.0。
实施例23:3-[(7-氯-2-甲氧基-3-氧代-异吲哚啉-4-基)氨基]-4-[[(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]氨基]环丁-3-烯-1,2-二酮的合成
步骤a:将2-(溴甲基)-3-氯-6-硝基-苯甲酸甲酯(5.0g,16.2mmol)和O-甲基羟胺盐酸盐(2.12g,17.9mmol)的THF(30mL)混合物加热至65℃持续2个小时。完成后,反应物用EtOAc稀释并用H2O(3x)洗涤。将有机层用Na2SO4干燥,过滤并浓缩,得到产物,将其不经进一步纯化用于下一步。
步骤b:向来自之前步骤的产物中加入以8:2的EtOH:H2O混合物(26mL)。向该溶液中加入NH4Cl(9.0g,170mmol)和铁粉(2.27g,40.6mmol),并将混合物加热至85℃。一旦完成,浓缩反应物以除去EtOH,然后加入EtOAc和H2O。过滤混合物以除去铁,然后用H2O洗涤,用Na2SO4干燥,过滤并浓缩。通过硅胶层析(10%至80%EtOAc的己烷)纯化粗产物以得到产物。
步骤c:将7-氨基-4-氯-2-甲氧基-异吲哚啉-1-酮(1.0g,4.1mmol)和3,4-二甲氧基环丁-3-烯-1,2-二酮(0.88g,6.2mmol)在无水甲醇(10mL)的混合物在60℃下搅拌过夜。然后将其过滤并将固体用MeOH冲洗并在真空下干燥以得到产物。
步骤d:3-[(7-氯-2-甲氧基-3-氧代-异吲哚啉-4-基)氨基]-4-甲氧基-环丁-3-烯-1,2-二酮(125mg,0.39mmol)和(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙烷-1-胺盐酸盐在MeOH(4.0mL)中合并,并加入三乙胺(117mg,1.15mmol)。将混合物在60℃下搅拌过夜。然后浓缩反应物,得到粗产物,将其通过硅胶层析(CH2Cl2:MeOH)纯化得到产物。1HNMR(400MHz,DMSO-d6)δ9.87(s,1H),9.01(d,J=10.2Hz,1H),7.63(d,J=9.0Hz,1H),7.42(d,J=9.0Hz,1H),6.09(s,1H),5.04(d,J=10.1Hz,1H),4.73(s,2H),3.86(s,3H),2.18(s,3H),1.87(s,3H),0.95(s,9H)。MS:C24H26ClN3O5[M-H]-的(ES)m/z计算值是470.2,实测值是470.1。
实施例24:3-(((R)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丙基)氨基)-4-(((S)-5-氟-1-甲基-3-氧代异吲哚啉-4-基)氨基)环丁-3-烯-1,2-二酮和3-(((R)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丙基)氨基)-4-(((R)-5-氟-1-甲基-3-氧代异吲哚啉-4-基))氨基)环丁-3-烯-1,2-二酮的合成
步骤a:在室温下,向搅拌的6-氟异吲哚啉-1-酮(10g,66.2mmol)的无水二氯甲烷(100mL)中加入三乙胺(16.72,165.5mmol,21.8mL),二碳酸二叔丁酯(17.3g,79.4%mmol)和催化DMAP(100mg)。将反应混合物在室温下搅拌16小时。完成后,将其用CH2Cl2稀释,用H2O洗涤,然后用饱和NaHCO3水溶液洗涤。有机层用Na2SO4干燥,过滤并真空浓缩。通过硅胶层析(0-30%乙酸乙酯的己烷)纯化粗化合物,得到产物。MS:C13H14FNO3[M+H]+的(ES)m/z计算值是252.3,实测值252.3。
步骤b:1)在-78℃,N2气氛下,向6-氟-1-氧代异吲哚啉-2-羧酸叔丁酯(5.0g,19.9mmol)的无水THF(40mL)搅拌溶液中滴加LiHMDS(21.89mL,21.89mmol)。搅拌30分钟后,将碘甲烷(2.82g,19.92mmol)在THF(5mL)中的溶液加入到混合物中。将反应混合物在-78℃搅拌1小时,然后温热至室温并搅拌2小时。完成后,将反应混合物用饱和NH4Cl水溶液淬灭,用EtOAc(100mL)稀释,将有机层用H2O然后用盐水溶液洗涤。然后将有机层用Na2SO4干燥、过滤并真空浓缩。粗产物无需进一步纯化直接用于下一步。2)向5-氟-1-甲基-3-氧代异吲哚啉-2-羧酸叔丁酯(6.2g,66.2mmol)的MeOH(60mL)的搅拌溶液中加入含4N HCl的二噁烷(79.6mmol,20mL)。将其在室温下搅拌3小时。反应完成后,除去溶剂并将反应混合物用EtOAc(3×50mL)稀释。用H2O洗涤,然后用饱和NaHCO3水溶液洗涤。然后将有机层用Na2SO4干燥,过滤并浓缩。通过硅胶层析(10-80%乙酸乙酯的己烷)纯化粗化合物,得到产物。MS:C9H8FNO[M+H]+的(ES)m/z计算值是166.2,实测值是166.2。
步骤c:1)在-78℃,N2气氛下,向6-氟-3-甲基异吲哚啉-1-酮(2.5g,15.1mmol)的无水THF(25mL)的搅拌溶液中滴加n-BuLi(6.64mL,16.61mmol,2.5M的己烷),将反应混合物在-78℃搅拌30分钟。然后向该混合物中加入(1R,2S,5R)-2-异丙基-5-甲基环已氯甲酸酯(3.96g,18.18mmol)的THF(5mL),并将其在-78℃搅拌30分钟。然后使反应混合物温热至室温并搅拌3小时。反应完成后,将反应混合物用饱和NH4Cl水溶液淬灭,用EtOAc(2×75mL)萃取,然后将合并的有机层用H2O洗涤,然后用盐水溶液洗涤,用Na2SO4干燥,真空下过滤并浓缩。通过硅胶层析纯化粗化合物,分别得到(1S)-(1R,2S,5R)-2-异丙基-5-甲基环己基-5-氟-1-甲基-3-氧代异吲哚啉-2-羧酸盐和(1R)-(1R,2S,5R)-2-异丙基-5-甲基环己基-5-氟-1-甲基-3-氧代异吲哚啉-2-羧酸盐。2)在室温下,向上述得到的一个非对映异构体(1.2g,3.45mmol)的MeOH(10mL)搅拌溶液中加入含Mg(OMe)2(10-12wt%)的MeOH(17.2mmol,10mL)。将反应混合物在室温下搅拌2小时。反应完成后,除去溶剂并将反应混合物用饱和NH4Cl水溶液淬灭,并用EtOAc(2×75mL)萃取。将合并的有机层用H2O洗涤,然后用盐水溶液洗涤,用Na2SO4干燥,过滤并真空浓缩。通过硅胶层析(20-60%乙酸乙酯的己烷)纯化粗化合物,得到所需的产物。MS:C9H8FNO[M+H]+的(ES)m/z计算值是166.2,实测值166.2。另一种非对映异构体被类似地处理以得到另一所需产物。
步骤d:1)将从步骤c获得的一种化合物(0.45g,2.72mmol)溶于浓H2SO4(5mL)并冷却至0℃。滴加70%HNO3(0.34g,24.1mmol,2.0当量),并将反应混合物在0℃搅拌10分钟,然后温热至室温并搅拌过夜。加入冰,然后用冷水(10mL)稀释混合物并用EtOAc(2×25mL)萃取。将合并的有机层用H2O洗涤,然后用盐水溶液洗涤,然后用Na2SO4干燥,过滤并浓缩。粗产物无需进一步纯化直接用于下一步。MS:C9H7F2N2O3[M+H]+的(ES)m/z计算值为211.0,实测值为211.2。另一种对映异构体被类似地处理以得到另一所需产物。2)在氢气气氛(40psi)下,将上述获得的一种化合物(0.35g,1.32mmol)和10%Pd/C(50%湿度,100mg)在MeOH(25mL)溶液中搅拌1小时。将混合物通过硅藻土过滤并用MeOH(40mL)洗涤。将滤液减压浓缩,得到粗产物,将其通过硅胶层析(20-100%乙酸乙酯/己烷)纯化,得到所需产物。MS:C9H9FN2O[M+H]+的(ES)m/z计算值为181.1,实测值181.2。另一种对映异构体被类似地处理以得到另一所需产物。
步骤e:在60℃下,将步骤d中获得的一种化合物(170mg,0.939mmol)和3,4-二甲氧基环丁-3-烯-1,2-二酮(200mg,1.40mmol)的无水甲醇(4mL)混合物搅拌3小时。将反应混合物蒸发并在50℃下,将残余物在乙酸乙酯(10mL)中搅拌30分钟,然后冷却至室温。过滤混合物并干燥,得到所需产物。MS:C14H11FN2O4[M+H]+的(ES)m/z计算值是291.1,实测值是291.2。另一种对映异构体被类似地处理以得到另一所需产物。
步骤f:(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙烷-1-胺盐酸盐(62mg,0.288mmol,1.05当量)的甲醇(2.5mL)溶液中加入三乙胺(75mg,0.687mmol,2.5当量)。将混合物在室温下搅拌10分钟以变成澄清溶液,然后在室温下加入上述获得的一种化合物。所得溶液在60℃下搅拌3小时。完成后,使反应冷却至室温。减压除去溶剂,粗产物通过制备HPLC(乙腈-含有0.1%TFA的水)纯化,得到所需产物。1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.79(s,1H),8.38(d,J=10.2Hz,1H),7.46(dd,J=11.4,8.2Hz,1H),7.34(dd,J=3.9,8.2Hz,1H),6.07(s,1H),4.95(d,J=10.1Hz,1H),4.58(q,J=6.6Hz,1H),2.18(s,3H),1.87(s,3H),1.33(d,J=6.6Hz,3H),0.95(s,9H)。MS:C24H26FN3O4[M-H]-的(ES)m/z计算值是438.2,实测值是438.0。另一个非对映异构体的获得是相似的。1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.79(s,1H),8.37(d,J=10.2Hz,1H),7.44(dd,J=11.0,8.2Hz,1H),7.33(dd,J=3.9,8.8Hz,1H),6.07(s,1H),4.95(d,J=10.1Hz,1H),4.56(q,J=6.3Hz,1H),2.18(s,3H),1.87(s,3H),1.33(d,J=6.6Hz,3H),0.95(s,9H)。MS:C24H26FN3O4[M-H]的(ES)m/z计算值是438.2,实测值438.0。
实施例25:3-(((R)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丁基)氨基)-4-(((S)-5-氟-1,7-二甲基-3-氧代异吲哚啉-4-基)氨基)环丁-3-烯-1,2-二酮和3-(((R)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丁基)氨基)-4-(((R)-5-氟-1,7-二甲基-3-氧代异吲哚啉-4-基)氨基)环丁-3-烯-1,2-二酮
步骤a:在室温下,向7-氨基-6-氟-3-甲基异吲哚啉-1-酮(200mg,1.11mmol)的一种对映体的AcOH(2.2mL)的室温水浴溶液中分批加入N-碘代丁二酰亚胺(350mg,1.56mmole)。将所得混合物在水浴中搅拌30分钟,用水(1mL)淬灭,然后用乙酸乙酯(10mL)萃取。将有机层用盐水(10mL)洗涤,然后用MgSO4干燥,过滤并浓缩。通过硅胶层析(0-60%乙酸乙酯的己烷)纯化粗产物,得到所需产物。MS:C9H8FIN2O[M+H]+的(ES)m/z计算值307.0,实测值307.0。另一种对映异构体被类似地处理以得到另一所需产物。
步骤b:向步骤a所得的一种化合物(248mg,0.81mmol)的二噁烷(8.1mL)溶液中加入CsF(493mg,3.24mmol),2,4,6-三甲基-1,3,5,2,4,6-三氧杂三硼环己烷(305mg,2.43mmol)和[1,1'-双(二苯基膦基)二茂铁]-二氯化钯(II)(66mg,0.08mmol)。所得混合物在80℃下搅拌过夜。将反应物在水(20mL)和乙酸乙酯(30mL)之间分配。将有机层用盐水(20mL)洗涤,然后用MgSO4干燥,过滤并浓缩。通过硅胶层析(0-80%乙酸乙酯的己烷)纯化粗产物,得到所需产物。MS:C10H11FN2O[M+H]+的(ES)m/z计算值195.1,实测值195.1。另一种对映异构体被类似地处理以得到另一所需产物。
步骤c:在60℃下,对从步骤b中获得的一种化合物(127mg,0.65mmol)和3,4-二甲氧基环丁-3-烯-1,2-二酮(186mg,1.3mmol)的无水甲醇(3mL)混合物搅拌过夜,然后在80℃下持续5小时。将反应混合物浓缩并通过硅胶层析(0-100%乙酸乙酯的己烷)纯化,得到所需产物。MS:C15H13FN2O4[M+H]+的(ES)m/z计算值是305.1,实测值是305.1。另一种对映异构体被类似地处理以得到另一所需产物。
步骤d:将无水甲醇(2mL)加入步骤c所得的一种化合物(40mg,0.13mmol)和(R)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丁基-1-胺(33.6mg,0.145mmol)的混合物中,并将该混合物在60℃下搅拌过夜。使反应物冷却至室温,溶于最小量的二氯甲烷中,并吸附到硅胶上。将其通过硅胶层析(40%乙酸乙酯的二氯甲烷)纯化,得到所需产物。1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),8.78(s,1H),8.32(d,J=10.0Hz,1H),7.29(d,J=11.6Hz,1H),6.06(s,1H),5.05(d,J=10.4Hz,1H),4.63(q,J=6.8Hz,1H),2.31(s,3H),2.18(s,3H),1.87(s,3H),1.34(d,J=6.8Hz,3H),1.26(q,J=7.2Hz,2H),0.93(s,3H),0.88(s,3H),0.82(t,J=7.2Hz,3H)。MS:C26H30FN3O4[M-H]-的(ES)m/z计算值是468.2,实测值是468.2。另一个非对映异构体的获得是相似的。
实施例26:3-(((R)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丙基)氨基)-4-(((S)-5-氟-1,7-二甲基-3-氧代异吲哚啉-4-基)氨基)环丁-3-烯-1,2-二酮和3-(((R)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丙基)氨基)-4-(((R)-5-氟-1,7-二甲基-3-氧代异吲哚啉-4-基)氨基)环丁-3-烯-1,2-二酮
将无水甲醇(2mL)加入到3-((5-氟-1,7-二甲基-3-氧代异吲哚啉-4-基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮的一种对映体(40mg,0.13mmol)和(R)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丁基-1-胺(31.6mg,0.145mmol)的混合物并将该混合物在60℃下搅拌过夜。使反应物冷却至室温,溶于最小量的二氯甲烷中,并吸附到硅胶上。将其通过硅胶层析(40%乙酸乙酯的二氯甲烷)纯化,得到所需产物。1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),8.74(s,1H),8.34(d,J=10.4Hz,1H),7.28(d,J=11.6Hz,1H),6.06(s,1H),4.95(d,J=10.0Hz,1H),4.61(q,J=6.8Hz,1H),2.31(s,3H),2.16(s,3H),1.86(s,3H),1.33(d,J=6.8Hz,3H),0.94(s,9H)。MS:C25H28FN3O4[M-H]-的(ES)m/z计算值是454.2,实测值是454.2。另一个非对映异构体的获得是相似的。
实施例27:3-(((R)-2,2-二甲基-1-(5-甲基呋喃-2-基)丙基)氨基)-4-(((S)-5-氟-1-甲基-3-氧代异吲哚啉-4-基)氨基)环丁-3-烯-1,2-二酮和3-(((R)-2,2-二甲基-1-(5-甲基呋喃-2-基)丙基)氨基)-4-(((R)-5-氟-1-甲基-3-氧代异吲哚啉-4-基)氨基)环丁-3-烯-1,2-二酮的合成
在室温下,向3-((5-氟-1-甲基-3-氧代异吲哚啉-4-基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮的一个对映体(50mg,0.171mmol)和(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙烷-1-胺(30mg,0.180mmol)的甲醇(3.0mL)混合物中加入三乙胺(43mg,0.42mmol,2.5当量)。将混合物在60℃搅拌3小时,然后冷却至室温。减压除去溶剂,粗产物通过制备HPLC(乙腈-0.1%TFA的水)纯化,得到所需产物。1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.80(s,1H),8.42(d,J=10.1Hz,1H),7.46(dd,J=3.1,8.4Hz,1H),7.36(dd,J=3.9,8.2Hz,1H),6.18(d,J=3.2,Hz,1H),6.03(d,J=2.4Hz,1H),5.00(d,J=10.5Hz,1H),4.56(q,J=7.1Hz,1H),2.27(s,3H),1.33(d,J=6.6Hz,3H),0.95(s,9H)。MS:C23H24FN3O4[M-H]-的(ES)m/z计算值是424.2,实测值是424.0。另一个非对映异构体是相似的。1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.79(s,1H),8.40(d,J=10.5Hz,1H),7.46(dd,J=11.3,8.6Hz,1H),7.34(dd,J=3.9,8.2Hz,1H),6.17(d,J=3.2,Hz,1H),6.04-6.03(m,1H),5.00(d,J=10.1Hz,1H),4.56(q,J=6.6Hz,1H),2.27(s,3H),1.33(d,J=6.6Hz,3H),0.95(s,9H)。MS:C23H24FN3O4[M+H]+的(ES)m/z计算值是426.2,实测值是426.0。
实施例28:3-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丁基]氨基]-4-[[(1S)-5-氟-1-甲基-3-氧代-异吲哚啉-4-基]氨基]环丁-3-烯-1,2-二酮和3-[[(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丁基]氨基]-4-[[(1R)-5-氟-1-甲基-3-氧代-异吲哚啉-4-基]氨基]环丁-3-烯-1,2-二酮的合成
将三乙胺(0.025mL,0.18mmol)加入到3-((5-氟-1-甲基-3-氧代异吲哚啉-4-基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮的一种对映体(26mg,0.09mmol)和(1R)-2,2-二甲基-1-(5-甲基-2-呋喃基)丁烷-1-胺盐酸盐(20mg,0.09mmol)的MeOH(1.0mL)混合物中。将反应在室温下搅拌18小时。然后将硅胶加入到反应中,浓缩混合物,并将其通过硅胶层析(含1%至10%MeOH的CH2Cl2)纯化。然后通过反相层析(MeCN:含0.1%TFA的H2O,作为洗脱液)纯化产物,得到最终产物。1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.79(s,1H),8.40(d,J=10.2Hz,1H),7.47(dd,J=11.1,8.2Hz,1H),7.35(dd,J=8.3,3.8Hz,1H),6.17(d,J=3.1Hz,1H),6.06–6.01(m,1H),5.10(d,J=10.2Hz,1H),4.58(q,J=6.6Hz,1H),2.27(s,3H),1.34(d,J=6.7Hz,3H),1.32–1.24(m,2H),0.94(s,3H),0.88(s,3H),0.83(t,J=7.4Hz,3H)。MS:C24H27FN3O4[M+H]+的(ES)m/z计算值是440.2,实测值是440.4。另一个非对映异构体是相似的。
使用如本文所述的类似合成方法和适当的试剂制备以下化合物,并且通过表1中所示的MS(质谱)和/或NMR表征。
表1.化合物的表征
生物活性
生物学实施例1:CXCR2活性配体结合试验
使用配体结合试验来确定潜在CXCR2拮抗剂阻断CXCR2与其任何配体之间的相互作用的能力。将稳定表达CXCR2的HEK-293细胞或表达CXCR2的人嗜中性粒细胞在检测缓冲液(20mM HEPES pH 7.1,140mM NaCl,1mM CaCl2,5mM MgCl2,0.1%叠氮化钠和0.1%牛血清白蛋白)离心并重悬至5×105个细胞/mL的浓度。结合试验设置如下:用于筛选的化合物从最多20μM连续稀释,并且将0.1mL含有5x 104个细胞(对于HEK-293细胞)或3x 104个细胞(对于人嗜中性粒细胞)的细胞加入到含有化合物的每个孔中。然后加入0.1mL在检测缓冲液中稀释至的终浓度,产生/孔的125I标记的CXCL8(得自珀金埃尔默;沃尔瑟姆,美国马萨诸塞州),板被密封并在25℃下,在摇床上温育约3小时。在真空细胞收集器(帕卡德仪器;梅里登,康涅狄格州)上将反应物抽吸到预先浸泡在0.3%聚乙烯亚胺(PEI)溶液中的GF/B玻璃滤器上。将闪烁液(50μL;微闪(Microscint)20,帕卡德仪器)加入到每个孔中,板被密封并在Top Count闪烁计数器(帕卡德仪器)中测量放射性。仅含有稀释剂的对照孔(总计数)或20μM化合物用于计算化合物总抑制百分比。GraphPad股份有限公司(圣地亚哥,加利福尼亚)的计算机程序Prism被用于计算IC50值。IC50值是将标记的CXCR8与受体结合减少50%所需的浓度。图1中,在结合测定中,将具有小于100nM的IC50值的化合物标记为(+++);;从100-1000nM的化合物标记为(++);并且小于或等于20μM但高于1000nM的化合物被标记为(+)。
生物学实施例2:CXCR2活性的迁移性/趋化性测定
血清趋化性试验可用于确定潜在受体拮抗剂在阻断通过趋化因子受体如CXCR2介导的迁移中的功效。该测定通常使用具有5μm孔径聚碳酸酯膜的微室系统进行。开始是这样测定的,通过在室温下以400×g离心收集表达趋化因子受体的细胞(本例子中是分离来自人全血的嗜中性粒细胞),然后以400万/ml悬浮于人血清中。从最大终浓度10μM(或其等量的溶剂(DMSO))连续稀释待测化合物,然后加入到细胞/血清混合物中。单独地,将在其EC50浓度(10nM)的重组人CXCL5(ENA-78)置于板的较低孔中。将5-μm(孔径)聚碳酸酯膜置于板上,并将20μL的细胞/化合物混合物转移到膜的每个孔上。将平板在37℃温育45分钟,然后除去聚碳酸酯膜,并将5μl DNA插入剂CyQUANT(英杰公司,卡尔斯巴德,加利福尼亚)加入到较低孔中。使用光谱荧光增强(Spectrafluor Plus)平板读数器(帝肯,圣何塞,加利福尼亚)测量对应于迁移细胞数量的荧光量。
生物学实施例3:CCR6活性的迁移性/趋化性测定
使用血清趋化性试验来确定潜在受体拮抗剂在阻断通过趋化因子受体,如CCR6介导的迁移中的功效。该测定通常使用具有5μm孔径聚碳酸酯膜的微室系统进行。开始是这样测定的,通过在室温以400×g离心收集表达趋化因子受体的细胞(本例子是KHYG-1细胞,八木田等,白血病,14:922,2000),然后以400万/ml在人血清中悬浮。从10μM的最大终浓度(或其等效体积的溶剂(DMSO))中连续稀释待测化合物,然后加入到细胞/血清混合物中。单独地,将在其EC50浓度(10nM)的重组人CCL20(MIP-3α/LARC)置于板的较低孔中。将5-μm(孔径)聚碳酸酯膜置于平板上,并将20μL细胞/化合物混合物转移到膜的每个孔上。将平板在37℃温育45分钟,然后除去聚碳酸酯膜,并将5μl DNA插入剂CyQUANT(英杰公司,卡尔斯巴德,加利福尼亚)加入到较低孔中。使用光谱荧光增强(SpectrafluorPlus)平板读数器(帝肯,圣何塞,加利福尼亚)测量对应于迁移细胞数量的荧光量。在图1,在趋化检测中,具有小于100nM的IC50值的化合物标记为(+++);100-1000nM的标记为(++);小于或等于20μM但高于1000nM的被标记(+)。
生物学实例4:在IL-23诱导的银屑病耳肿胀模型中的体内功效
向小鼠耳朵皮内注射IL-23可造成CCR6依赖性的耳肿胀(亨德里克梅等。临床调查杂志,2009.119:2317-2329)。C57Bl/6小鼠在右耳被皮内注射IL-23,左耳被皮内注射PBS作为对照。化合物1.023(实施例6中合成)通过皮下途径给药。在3次皮内注射IL-23并开始中度耳肿胀后,化合物以治疗方式给药。使用卡尺测量肿胀程度。化合物1.023能够完全抑制IL-23诱导的耳肿胀并且能够减少肿胀至回基线水平(图2)。
生物学实例5:咪喹莫特诱导的银屑病样模型中的体内功效
将咪喹莫特乳膏局部应用于小鼠剃光的背部导致类似于人类银屑病变的特征的银屑病发展,即皮肤红斑,皮肤厚度和脱皮。(范得菲茨L.等,2009.免疫学杂志182:5836-5845)。Balb/c小鼠用咪喹莫特乳膏局部应用于剃光的背部皮肤。化合物1.129通过口服途径预防性给药以实现在整个研究中达到合适的血浆浓度。以盲目方式通过测量皮肤疾病的3个方面,即红斑程度,皮肤脱皮影响的皮肤百分比和由卡尺测量的皮肤厚度确定银屑病样皮损的发展。每个测量分配一个在0(无疾病)和4(最大疾病)之间的疾病分数,从而计算累积的PASI(银屑病活动严重性指数)评分,最高评分为12分。化合物1.129能够通过抑制红斑,脱皮和皮肤厚度来降低累积PASI评分的严重程度。与载体处理的小鼠相比(图3),在用化合物1.129给药组中,表现出严重症状(每次读数的分数≥3)的小鼠的百分比减少。
本文在此描述了本发明的特定实施例,包括发明人已知的用于实施本发明的最佳模式。在阅读前述说明后,所公开的实施方案的变化对于本领域的技术人员而言可能变得明显,并且预期那些技术人员可以适当地采用这样的变化。因此,本发明旨在以不同于本文具体描述的方式来实施,并且本发明包括适用法律允许的所附权利要求中所述主题的所有修改和等同物。此外,除非本文另有说明或者与上下文明显矛盾,否则本发明涵盖上述要素在其所有可能变型中的任何组合。
说明书中引用的所有出版物,专利申请,登录号和其他参考文献均通过引用并入本文,如同每个单独的出版物或专利申请被具体且单独地指示为通过引用并入。
Claims (36)
1.具有式(A)的化合物、或其任何药学上可接受的盐、溶剂化物、水合物、N-氧化物、互变异构体或旋转异构体,
其中,
B选自下组:呋喃基、噻吩基、恶唑基、苯基、吡啶基、嘧啶基和吡嗪基,其各自任选地被R1a、R1b或R2取代,R1a、R1b和R2独立地选自下组:卤素、CN、C1-4烷基、C1-4烷氧基和C1-4卤代烷基;
R3是选自H和D的成员;
R4是选自H、C1-8烷基、OH、-NRaRb、-C1-4烷氧基和Y的成员;其中,C1-8烷基任选地被卤素、-CN、-CO2Ra、-CONRaRb、-C(O)Ra、OC(O)NRaRb、-NRaC(O)Rb、-NRaC(O)2Rc、-NRaC(O)NRaRb、-NRaRb、-ORa、-S(O)2NRaRb、-NRaS(O)2Rb或Y取代,其中Y是4至8元环杂烷基或3至8元环烷基或5元或6元芳基或杂芳基,其任一个任选地被1至4个选自卤素、氧基、-CN、-C1-6烷基、-C1-6烷氧基、-C1-6羟基烷基、-C1-6卤代烷基、O-C1-6卤代烷基、-C1-4烷基-O-C1-4烷基、-C1-6烷基-NRaRb、-C1-6烷基-CO2H、-C1-6烷基-CO2Ra、-C1-6烷基-CONRaRb、-C1-6烷基-C(O)Ra、-C1-6烷基-OC(O)NRaRb、-C1-6烷基-NRaC(O)Rb、-C1-6烷基-NRaC(O)2Rc、-C1-6烷基-NRaC(O)NRaRb、-C1-6烷基-ORa、-C1-6烷基-S(O)2NRaRb、-C1-6烷基-NRaS(O)2Rb、-CO2Ra、-CONRaRb、-C(O)Ra、-OC(O)NRaRb、-NRaC(O)Rb、-NRaC(O)2Rc、-NRaC(O)NRaRb、-NRaRb、-ORa、-S(O)2NRaRb、-NRaS(O)2Rb、-CH2CO2Ra的取代基取代;每个Ra和Rb独立地选自氢、C1-4烷基、C1-4羟基烷基和C1-4卤代烷基,并且Rc选自C1-4烷基、C1-4羟基烷基和C1-4卤代烷基;并且其中4至8元环杂烷基和3至8元环烷基可以另外任选地被氧基取代;
R5a和R5b是各自独立地选自H、卤素、C1-4烷基、-C1-4卤代烷基、O-C1-4卤代烷基、C1-4烷氧基、CO2H和CN的成员;
R6a和R6b是各自独立地选自H、C1-4烷基、C1-4羟基烷基和C1-4卤代烷基的成员;或任选地R6a和R6b一起形成氧基(=O)或4-6元环杂烷基或3-6元环烷基;
R7是选自甲基、乙基和C1-2卤代烷基的成员;和
下标n是1或2。
2.如权利要求1的化合物具有式(I),或其任何盐、溶剂合物、水合物、N-氧化物、互变异构体或旋转异构体:
其中,
B选自下组:呋喃基、恶唑基、苯基、吡啶基、嘧啶基和吡嗪基,其各自任选被R1a、R1b或R2取代,R1a、R1b和R2独立地选自下组:卤素、CN、C1-4烷基、C1-4烷氧基和C1-4卤代烷基;
R3是选自H和D的成员;
R4是选自下组:H、C1-8烷基和Y的成员;其中,C1-8烷基任选地被卤素、-CN、-CO2Ra、-CONRaRb、-C(O)Ra、OC(O)NRaRb、-NRaC(O)Rb、-NRaC(O)2Rc、-NRaC(O)NRaRb、-NRaRb、-ORa、-S(O)2NRaRb、-NRaS(O)2Rb或Y取代,其中Y是5或6元芳基或杂芳基,其具有1-4个选自卤素、-CN、-C1-4烷基、-C1-4烷氧基、-C1-4羟基烷基、-C1-4卤代烷基、OCF3、-CO2Ra、-CONRaRb、-C(O)Ra、-OC(O)NRaRb、-NRaC(O)Rb、-CH2CO2Ra的取代基;且各Ra和Rb独立地选自:氢、C1-4烷基、C1-4羟基烷基和C1-4卤代烷基,且Rc选自C1-4烷基、C1-4羟基烷基和C1-4卤代烷基;
R5a和R5b是各独立地选自下组:H、卤素、C1-4烷基、C1-4烷氧基、CO2H和CN的成员;
R6a和R6b是各独立地选自下组:H、C1-4烷基、C1-4羟基烷基和C1-4卤代烷基的成员;或任选地R6a和R6b一起形成氧基(=O);和
下标n是1或2。
3.如权利要求1的化合物、或其任何药学上可接受的盐、溶剂合物、水合物、N-氧化物、互变异构体或旋转异构体,其中B选自下组:
4.如权利要求1-3中任一项的化合物、或其任何药学上可接受的盐、溶剂化物、水合物、N-氧化物、互变异构体或旋转异构体,其中B选自下组:
5.如权利要求1或2中任一项的化合物、或其任何药学上可接受的盐、溶剂合物、水合物、N-氧化物、互变异构体或旋转异构体,其中B为呋喃基或恶唑基,其各自任选被R1a或R1b取代,R1a和R1b独立地选自下组:卤素、CN、C1-4烷基、C1-4烷氧基和C1-4卤代烷基。
6.如权利要求5的化合物、或其任何药学上可接受的盐、溶剂合物、水合物、N-氧化物、互变异构体或旋转异构体,其中B为被R1a取代和任选地被R1b取代的呋喃基,R1a为CH3或Cl,R1b为CH3。
7.如权利要求1至6中任一项的化合物、或其任何药学上可接受的盐、溶剂化物、水合物、N-氧化物、互变异构体或旋转异构体,其中R3为H。
8.如权利要求1至7中任一项的化合物、或其任何药学上可接受的盐、溶剂合物、水合物、N-氧化物、互变异构体或旋转异构体,其中各R5a和R5b独立地选自下组:H、CH3、Cl和F。
9.如权利要求1至7中任一项所述的化合物、或其任何药学上可接受的盐、溶剂合物、水合物、N-氧化物、互变异构体或旋转异构体,其中选自下组:
10.如权利要求1至7中任一项所述的化合物、或其任何药学上可接受的盐、溶剂合物、水合物、N-氧化物、互变异构体或旋转异构体,其中选自下组:
11.如权利要求1至10中任一项的化合物、或其任何药学上可接受的盐、溶剂化物、水合物、N-氧化物、互变异构体或旋转异构体,其中R6a和R6b各独立地选自H和C1-2烷基。
12.如权利要求1或3至10中任一项的化合物、或其任何药学上可接受的盐、溶剂合物、水合物、N-氧化物、互变异构体或旋转异构体,其中,
独立地选自下组:
13.如权利要求1至10或12中任一项所述的化合物、或其任何药学上可接受的盐、溶剂合物、水合物、N-氧化物、互变异构体或旋转异构体,其中,
独立地选自下组:
14.如权利要求1或3-13中任一项的化合物、或其任何药学上可接受的盐、溶剂化物、水合物、N-氧化物、互变异构体或旋转异构体,其中R4为H、C1-3烷基或Y,其中C1-3烷基被四唑基或四唑酮基(tetrazolonyl)取代,其中四唑基或四唑酮基任选被C1-6烷基、C1-6羟基烷基或C1-4烷基-O-C1-4烷基取代,其中Y选自下组:吡啶基、吡唑基和苯基,其中吡啶基、吡唑基和苯基具有1-3个独立地选自-C1-4烷基、-C1-4烷氧基和-CO2H的取代基。
15.如权利要求1或3-14中任一项的化合物、或其任何药学上可接受的盐、溶剂化物、水合物、N-氧化物、互变异构体或旋转异构体,其中R4选自下组:
16.如权利要求1或3-15中任一项的化合物、或其任何药学上可接受的盐、溶剂合物、水合物、N-氧化物、互变异构体或旋转异构体,其中R7选自下组:甲基、乙基和CF3。
17.如权利要求1的化合物具有式(A1),或其药学上可接受的盐、溶剂化物或水合物:
其中R1a选自CH3和Cl;R1b不存在或为CH3;R3是H或D;R4是H或Y;R5a和R5b各自独立地选自H、F、Cl、Br和CH3;R6a和R6b各自独立地选自H和CH3;和R7是甲基或乙基。
18.如权利要求17的化合物、或其任何药学上可接受的盐、溶剂化物、水合物、N-氧化物、互变异构体或旋转异构体,其中,R1a是CH3;R1b不存在或为CH3;R3是H或D;R4是H;R5a是H、F、Me或Cl或Br;R5b是H或F;R6a和R6b各自为H;和R7是甲基或乙基;或其药学上可接受的盐、溶剂化物或水合物。
19.如权利要求17的化合物、或其任何药学上可接受的盐、溶剂化物、水合物、N-氧化物、互变异构体或旋转异构体,所述化合物在携带R3的碳原子处基本上不含其他异构体。
20.如权利要求17的化合物、或其任何药学上可接受的盐、溶剂合物、水合物、N-氧化物、互变异构体或旋转异构体,其中R4是Y。
21.如权利要求1的化合物具有式(A2),或其药学上可接受的盐、溶剂化物或水合物:
其中R1a选自CH3和Cl;R1b是H或CH3;R3是H或D;R4a和R4b独立地选自卤素、-CN、-C1-4烷基、-C1-4烷氧基、-C1-4羟基烷基、-C1-4卤代烷基、OCF3,-CO2Ra、-CONRaRb、-C(O)Ra、-OC(O)NRaRb、-NRaC(O)Rb、-CH2CO2Ra,和Ra和Rb独立地选自氢、C1-4烷基、C1-4羟基烷基和C1-4卤代烷基;R5a和R5b各自独立地选自H、F、Cl、Br和CH3;R6a和R6b各自独立地选自H和CH3;和R7选自下组:甲基、乙基和C1-2卤代烷基。
22.如权利要求1的化合物、或其药学上可接受的盐,选自下组:
23.如权利要求1的化合物、或其药学上可接受的盐,选自下组:
24.一种药物组合物,其包含权利要求1至23中任一项的化合物。
25.如权利要求24所述的药物组合物,其进一步包含一种或多种另外的治疗剂。
26.如权利要求25所述的药物组合物,其中,所述一种或多种另外的治疗剂选自下组:细胞毒性化疗、抗癌或抗肿瘤疫苗、抗免疫细胞因子疗法、免疫细胞因子疗法、嵌合抗原受体(CAR)T细胞受体、基因转移疗法、检查点抑制剂、皮质类固醇、类维生素A样药剂、抗肿瘤药物和干扰素类似物。
27.如权利要求25所述的药物组合物,其中,所述一种或多种另外的治疗剂选自下组:TNFα配体抑制剂、TNF结合剂、IL-1配体抑制剂;IL-6配体抑制剂、IL-8配体抑制剂;IL-17拮抗剂、TNF拮抗剂、视黄酸受体γ拮抗剂、IL-17A配体抑制剂;IL-17F配体抑制剂、神经鞘氨醇-1-磷酸受体-1拮抗剂、神经鞘氨醇-1-磷酸受体-1调节剂、IL-12拮抗剂;IL-23拮抗剂、II型TNF受体调节剂、IL-23A抑制剂、PDE 4抑制剂、JAK酪氨酸激酶抑制剂、Jak1酪氨酸激酶抑制剂;Jak3酪氨酸激酶抑制剂、视黄酸受体激动剂、神经鞘氨醇-1-磷酸受体-1调节剂或TLR-7拮抗剂、TLR-8拮抗剂、TLR-9拮抗剂、IL-8拮抗剂、阻断CTLA-4(CD152)、PD-1(CD279)、PDL-1(CD274)、TIM-3、LAG-3(CD223)、VISTA、KIR、NKG2A、BTLA、PD-1H、TIGIT、CD96、4-1BB(CD137)、4-1BBL(CD137L)、GARP、CSF-1R、A2AR、CD73、CD47、色氨酸2,3-双加氧酶(TDO)或吲哚胺2,3双加氧酶(IDO)的活性的药物、及OX40、GITR、4-1BB、ICOS、STING或CD40的激动剂。
28.一种治疗所需受试者中CXCR2和/或CCR6介导的疾病或病症的方法,所述方法包括:给予所述受试者有效量的如权利要求1至23中任一项的化合物或其药学上可接受的盐或如权利要求24至27中任一项的药物组合物。
29.如权利要求28的方法,其中所述疾病或病症是急性或慢性炎性病症。
30.如权利要求29的方法,其中所述急性或慢性炎性病症为银屑病、干眼病、动脉粥样硬化、盘状红斑狼疮、类风湿性关节炎、狼疮、辐射诱导的纤维化肺病、自身免疫性大疱性皮肤病(AIBD)、慢性阻塞性肺病或臭氧引起的气道炎症。
31.如权利要求28的方法,其中所述疾病是选自下组的癌症:皮肤T细胞淋巴瘤、非霍奇金淋巴瘤、蕈样肉芽肿、佩吉特样网状细胞增多症、塞泽里综合征、肉芽肿松弛皮肤、淋巴瘤样丘疹病、慢性苔藓样糠疹、急性苔藓痘疮样糠疹、CD30+皮肤T细胞淋巴瘤、继发性皮肤CD30+大细胞淋巴瘤、非蕈样肉芽肿CD30皮肤大T细胞淋巴瘤、多形性T细胞淋巴瘤、伦纳特淋巴瘤、皮下T细胞淋巴瘤、血管中心淋巴瘤、母细胞性NK细胞淋巴瘤、B细胞淋巴瘤、霍奇金淋巴瘤(HL)、头颈部肿瘤;鳞状细胞癌、横纹肌肉瘤、路易士肺癌(LLC)、非小细胞肺癌、食管鳞状细胞癌、食道腺癌、肾细胞癌(RCC)、结肠直肠癌(CRC)、急性髓细胞样白血病(AML)、乳腺癌、胃癌、前列腺小细胞神经内分泌癌(SCNC)、肝癌、成胶质细胞瘤、肝癌、口腔鳞状细胞癌、胰腺癌、甲状腺乳头状癌、肝内胆管细胞癌、肝细胞癌、骨癌、转移和鼻咽癌。
32.如权利要求31的方法,其中所述化合物单独使用或与一种或多种其它抗癌疗法组合使用。
33.如权利要求32的方法,其中所述化合物与以下中一种或多种组合使用:细胞毒性化学疗法、抗癌疫苗、抗肿瘤疫苗、抗免疫细胞因子疗法、免疫细胞因子疗法、检查点抑制剂和嵌合抗原受体(CAR)T细胞受体、基因转移疗法。
34.如权利要求32的方法,其中所述一种或多种其它抗癌疗法选自下组:阻断CTLA-4(CD152)、PD-1(CD279)、PDL-1(CD274)、TIM-3、LAG-3(CD223)、VISTA、KIR、NKG2A、BTLA、PD-1H、TIGIT、CD96、4-1BB(CD137)、4-1BBL(CD137L)、GARP、CSF-1R、A2AR、CD73、CD47、色氨酸2,3-双加氧酶(TDO)或吲哚胺2,3双加氧酶(IDO)的活性的药物,以及OX40、GITR、4-1BB、ICOS、STING或CD40的激动剂。
35.如权利要求30的方法,其中所述化合物单独使用或与一种或多种其他治疗剂组合使用。
36.如权利要求35的方法,其中所述化合物与以下中一种或多种组合使用:皮质类固醇、类维生素A样药剂、抗肿瘤剂和干扰素类似物、TNFα配体抑制剂、TNF结合剂、IL-1配体抑制剂;IL-6配体抑制剂、IL-8配体抑制剂;IL-17拮抗剂、TNF拮抗剂、视黄酸受体γ拮抗剂、IL-17A配体抑制剂;IL-17F配体抑制剂、神经鞘氨醇-1-磷酸受体-1拮抗剂、神经鞘氨醇-1-磷酸受体-1调节剂、IL-12拮抗剂;IL-23拮抗剂、II型TNF受体调节剂、IL-23A抑制剂、PDE 4抑制剂、JAK酪氨酸激酶抑制剂、Jak1酪氨酸激酶抑制剂;Jak3酪氨酸激酶抑制剂、视黄酸受体激动剂、神经鞘氨醇-1-磷酸受体-1调节剂、TLR-7拮抗剂、TLR-8拮抗剂、TLR-9拮抗剂或IL-8拮抗剂。
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- 2016-11-17 CN CN201680068079.9A patent/CN108697684A/zh active Pending
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CN112190708A (zh) * | 2019-07-08 | 2021-01-08 | 上海交通大学医学院附属瑞金医院 | 趋化因子受体ccr6抑制剂在预防银屑病复发中的新应用 |
CN112190708B (zh) * | 2019-07-08 | 2023-09-05 | 上海交通大学医学院附属瑞金医院 | 趋化因子受体ccr6抑制剂在预防银屑病复发中的新应用 |
CN113018438A (zh) * | 2019-12-24 | 2021-06-25 | 四川大学 | Cxcr2抑制剂在制备治疗鼻咽癌的药物中的用途 |
CN113018438B (zh) * | 2019-12-24 | 2022-06-17 | 四川大学 | Cxcr2抑制剂在制备治疗鼻咽癌的药物中的用途 |
CN113713092A (zh) * | 2021-08-05 | 2021-11-30 | 齐鲁工业大学 | 趋化因子受体ccr6在制备抗肿瘤药物中的应用 |
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US20220009912A1 (en) | 2022-01-13 |
CA3005656A1 (en) | 2017-05-26 |
JP2018538266A (ja) | 2018-12-27 |
MA43382A (fr) | 2018-10-10 |
US11820759B2 (en) | 2023-11-21 |
SG11201804133PA (en) | 2018-06-28 |
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KR20180100116A (ko) | 2018-09-07 |
EP3383386A1 (en) | 2018-10-10 |
AU2016357413A1 (en) | 2018-06-14 |
EP3383386B8 (en) | 2024-03-20 |
MX2018006150A (es) | 2019-05-27 |
US20170144997A1 (en) | 2017-05-25 |
EA201891209A1 (ru) | 2018-12-28 |
BR112018009880A2 (pt) | 2018-11-13 |
TW201720817A (zh) | 2017-06-16 |
NZ742809A (en) | 2022-09-30 |
PH12018501096A1 (en) | 2018-12-17 |
EA035666B1 (ru) | 2020-07-23 |
US10336736B2 (en) | 2019-07-02 |
US20180141934A1 (en) | 2018-05-24 |
AU2016357413B2 (en) | 2021-03-04 |
US9834545B2 (en) | 2017-12-05 |
IL259342A (en) | 2018-07-31 |
US10988464B2 (en) | 2021-04-27 |
US20200039969A1 (en) | 2020-02-06 |
WO2017087607A1 (en) | 2017-05-26 |
TWI734715B (zh) | 2021-08-01 |
JP6923522B2 (ja) | 2021-08-18 |
IL259342B (en) | 2021-09-30 |
EP3383386B1 (en) | 2024-02-14 |
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