CN105051043A - 用作激酶活性调节剂的新颖的杂环类衍生物 - Google Patents
用作激酶活性调节剂的新颖的杂环类衍生物 Download PDFInfo
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- CN105051043A CN105051043A CN201380069718.XA CN201380069718A CN105051043A CN 105051043 A CN105051043 A CN 105051043A CN 201380069718 A CN201380069718 A CN 201380069718A CN 105051043 A CN105051043 A CN 105051043A
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- piperazine
- ethyl
- phenyl
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Abstract
本发明提供了通式(I)所示的新的杂环类衍生物,它们的制备及其用于治疗过度增殖性疾病诸如癌症的用途,其中R1、R2、W、X1、X2、X3、X4和n具有如说明书中通式(I)指明的含义。
Description
相关申请
本申请要求2012年11月16日提交的美国专利申请号61/727,298的优先权,其内容全部纳入此处作为参考。
技术领域
本发明涉及一系列可用于治疗哺乳动物的过度增殖性疾病诸如癌症的杂环类化合物。本发明还包括所述化合物在治疗哺乳动物尤其是人的过度增殖性疾病的用途,以及包含所述化合物的药物组合物。
发明背景
蛋白激酶组成一大族担负细胞内多种信号转导过程控制的结构相关酶(Hardie,G.和Hanks,S.(1995)TheProteinKinaseFactsBook.I和II,AcademicPress,SanDiego,CA)。通过它们磷酸化的底物(例如蛋白-酪氨酸、蛋白-丝氨酸/苏氨酸、脂质等),可将激酶分成多族。已确定了一般对应于这些激酶各族的序列模体(例如,Hanks,S.K.,Hunter,T.,FASEBJ.,9:576-596(1995);Knighton,等人,Science,253:407-414(1991);Hiles等人,Cell,70:419-429(1992);Kunz等人,Cell,73:585-596(1993);Garcia-Bustos,等人,EMBOJ.,13:2352-2361(1994))。
蛋白激酶可由其调节机制表征。这些机制包括例如自磷酸化作用、由其它激酶转磷酸作用、蛋白质-蛋白质相互作用、蛋白质-脂质相互作用和蛋白质-多核苷酸相互作用。单个蛋白激酶可由多于一种机制调节。
通过将磷酸基团加到靶蛋白,激酶可调节很多不同的细胞过程,包括但不限于增殖、分化、细胞凋亡、运动性、转录、翻译及其他信号传导过程。这些磷酸化事件充当能够调节或调整靶蛋白生物功能的分子通断开关。靶蛋白的磷酸化响应于多种胞外信号(激素、神经递质、生长和分化因子等)、细胞周期事件、环境或营养应激等而发生。适合的蛋白激酶在信号传导通路中起作用以活化或钝化(直接或间接)例如代谢酶、调节蛋白、受体、细胞骨架蛋白、离子通道或泵或转录因子。由蛋白磷酸化控制缺陷导致的不受控的信号传导涉及多种疾病,包括例如炎症、癌症、过敏/哮喘、免疫系统疾病和病症、中枢神经系统疾病和病症及血管生成。
蛋白激酶70S6K,即70kDa核糖体蛋白激酶p70S6K(也称为SK6、p70/p85S6激酶、p70/p85核糖体S6激酶和pp70S6K)是蛋白激酶的AGC亚家族的成员。p70S6K是丝氨酸-苏氨酸激酶,其是磷脂酰肌醇3激酶(PI3K)/AKT通路的组成部分。p70S6K为PI3K的下游部分,且通过响应多种有丝分裂原、激素和生长因子在多个位点的磷酸化而被激活。由于雷帕霉素起到抑制p70S6K活性的作用,p70S6K活性也受包含mTOR的复合物(TORC1)的控制。p70S6K通过PI3K下游靶点AKT和PKCζ调节。Akt直接磷酸化并钝化TSC2,由此激活mTOR。此外,对于被渥曼青霉素抑制而不被雷帕霉素抑制的p70S6K的突变体等位基因的研究表明PI3K通路可以不依赖mTOR活性的调节而对p70S6K产生作用。
酶p70S6K通过S6核糖体蛋白的磷酸化而调控蛋白合成。S6磷酸化与翻译装置(translationalapparatus)的mRNA编码组件的翻译的增加相关,所述翻译装置包括核糖体蛋白和翻译延伸因子(其表达增加对细胞生长和增殖是必不可少的)。这些mRNA在其5'转录起始端(称为5'TOP)包含寡嘧啶片段,已证明这对于其在翻译水平的调节是必不可少的。
除了参与翻译之外,p70S6K激活还涉及细胞周期控制、神经细胞分化、在肿瘤转移中重要的细胞运动性和细胞响应的调节、免疫应答和组织修复。p70S6K抗体破坏了大鼠成纤维细胞进入S期所驱动的促有丝分裂响应,这就表明了p70S6K功能在细胞周期中从G1期至S期的进程中是必不可少的。此外,已经确定在细胞周期的G1期至S期雷帕霉素对细胞周期增殖的抑制是其抑制生成过度磷酸化的激活形式的p70S6K的结果。
p70S6K肿瘤细胞增殖和保护细胞免于细胞凋亡中的作用受到支持,这是基于其在肿瘤组织中参与生长因子受体信号转导、过表达和激活。例如,RNA印迹分析和蛋白质印迹分析表明,PS6K基因的扩增分别伴有mRNA和蛋白质表达的相应增加(CancerRes.(1999)59:1408-11-PS6K在乳腺癌中定位于染色体区17q23及其扩增的测定(LocalizationofPS6KtoChromosomalRegion17q23andDeterminationofItsAmplificationinBreastCancer))。
染色体17q23在以下肿瘤和癌症中扩增:高达20%的原发性乳腺肿瘤、87%含有BRCA2突变的乳腺肿瘤和50%含有BRCA1突变的肿瘤以及其它癌症类型,例如胰腺癌、膀胱癌和成神经细胞瘤(参见M.Barlund,O.Monni,J.Kononen,R.Cornelison,J.Torhorst,G.Sauter,O.-P.Kallioniemi和KallioniemiA.,CancerRes.,2000,60:5340-5346)。研究表明,17q23在乳腺癌中的扩增涉及PAT1、RAD51C、PS6K和SIGMA1B基因(CancerRes.(2000):60,第5371-5375页)。
p70S6K基因已被鉴定为这些部位扩增和过表达的靶点,并且观察到扩增和预后不良之间在统计上显着相关。在用上游激酶mTOR的抑制剂CCI-779(雷帕霉素酯)治疗的肾癌患者中,观察到p70S6K激活的临床抑制。据报道,疾病进程和p70S6K活性抑制之间有显着的线性相关性。在响应能量应激时肿瘤抑制因子LKB1激活AMPK,AMPK磷酸化TSC1/2复合物,并使得其钝化mTOR/p70S6K通路。LKB1中的突变引起波伊茨-耶格综合征(Peutz-JegherssyndromePJS),患有PJS的患者发展为的癌症可能性是一般人群的15倍。此外,1/3的肺腺癌潜伏有未激活的LKB1突变。p70S6K涉及代谢疾病和障碍。据报道,缺乏p70S6K避免患年龄和饮食诱发的肥胖症并同时提高胰岛素敏感性。基于这些发现,支持了p70S6K在肥胖症、糖尿病、代谢综合征、胰岛素抵抗、高血糖、高氨基酸血症和高脂血症等代谢疾病和障碍中的作用。
在WO03/064397,WO04/092154,WO05/054237,WO05/056014,WO05/033086,WO05/117909,WO05/039506,WO06/120573,WO06/136821,WO06/071819,WO06/131835,WO08/140947,WO10/056563,WO10/093419,WO12/013282,WO12/016001以及WO12/069146中公开了被描述为适于抑制p70S6K的化合物。
发明内容
本发明提供通式I所示的化合物,其可用于治疗与p70S6K相关的疾病。
本发明的目的是提供调节激酶活性的新化合物。该蛋白激酶调节包括但不限于p70S6K抑制和AKT抑制,其用于治疗过度增殖性疾病,尤其是与以上提及的蛋白激酶的活动过度相关的那些,诸如哺乳动物中的癌症,所述化合物在活性以及溶解度、代谢清除率和生物利用度特性方面具有优良的药理性质。
因此,本发明提供了新的杂环类衍生物及其可药用盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以全部比例混合的混合物,这些化合物都是激酶抑制剂且可用于治疗以上提及的疾病。
本发明涉及通式(I)化合物及其可药用盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以所有比例混合的混合物,
式中:
X1是N或者CH,
X2是CH2或者NH,
X3是CH2或者CO,
X4是O、CH2或者NH,
W是N或者CH,
R1是Ar或者Het,
R2是[C(R3)2]pHet1或者[C(R3)2]pN(R3)2,
R3是H或者是任选地被取代的具有1、2、3或4个碳原子的烷基,
Ar是苯基,所述苯基未被取代或被Hal、A、苯基、CON(R3)2、COOR3、NHCOA、NHSO2A、CHO、COA、SO2N(R3)2、SO2A、[C(R3)2]pOR3、[C(R3)2]p-N(R3)2和/或[C(R3)2]p-CN单取代、二取代或三取代,
Het是呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噁二唑基、噻唑基、三唑基、四唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吲哚基、异吲哚基、苯并咪唑基、吲唑基或者喹啉基,所述基团未被取代或被Hal、A、[C(R3)2]pOR3、[C(R3)2]pN(R3)2、NO2、CN、[C(R3)2]pCOOR3、CON(R3)2、NR3COA、NR3SO2A、SO2N(R3)2、S(O)mA和/或O[C(R3)2]qN(R3)2单取代、二取代或三取代,
Het1是二氢吡咯基、吡咯烷基、氮杂环丁烷基、氧杂环丁烷基、四氢咪唑基、二氢吡唑基、四氢吡唑基、四氢呋喃基、二氢吡啶基、四氢吡啶基、哌啶基、氮杂环庚烷基、吗啉基、六氢哒嗪基、六氢嘧啶基、[1,3]二氧杂环戊烷基、四氢吡喃基、吡啶基或者哌嗪基,所述基团未被取代或被A单取代或二取代,
A是具有1-10个碳原子的无支链的或有支链的烷基,其中1个或2个非相邻的CH-和/或CH2-基团可以被N-、O-和/或S-原子所替代,且其中1-7个H原子可以被F或者Cl所替代,
Hal是F、Cl、Br或者I,
每个m独立地是0、1或者2,
每个n独立地是0、1或者2,
每个p独立地是0、1、2、3或者4,
每个q独立地是2、3或者4。
本发明还涉及这些化合物的光学活性形式(立体异构体)、对映异构体、外消旋体、非对映异构体以及水合物和溶剂化物。
本发明还涉及通式I所示化合物的盐的溶剂化物,例如盐酸盐的单水合物或双水合物。
此外,本发明涉及通式I所示化合物的药学上可接受的衍生物。
术语“化合物的溶剂化物”用来表示这些化合物与惰性溶剂分子由于彼此引力作用而形成的加合物。溶剂化物是,例如,单水合物或双水合物或醇化物。
术语“药学上可接受的衍生物”用来表示,例如,本发明的化合物的盐类和所谓的前体药物化合物。
除非另有指明,此处所用的术语“前体药物”用来表示通式I化合物的衍生物,其在生物条件下(体内或体外)能够水解、氧化或通过其它反应来提供活性化合物,尤其是通式I化合物的衍生物。前体药物的例子包括但不限于:包含可生物水解部分的通式I化合物的衍生物和代谢物,其中可生物水解部分例如是可生物水解的酰胺、可生物水解的酯、可生物水解的氨基甲酸酯、可生物水解的碳酸盐、可生物水解的酰脲、以及可生物水解的磷酸盐类似物。在某些实施例中,含有羧酸官能团的化合物的前体药物是羧酸的低烷基酯。将分子中的任一羧酸部分酯化,可方便地形成羧酸酯。前体药物一般通过已知的方法制备,例如Burger'sMedicinalChemistryandDrugDiscovery(第六版)(DonaldJ.Abrahamed.,2001,Wiley)以及DesignandApplicationofProdrugs(H.Bundgaard1985版,HarwoodAcademicPublishersGmfh)描述的那些方法制备。
用语“有效量”表示可引起组织、系统、动物或人体产生一种例如研究人员或医生所寻求或期望的生物学或医学反应的药物或药物活性成分的量。
此外,用语“治疗有效量”表示与未接受此量的相应患者相比,该量产生如下结果:
治疗改善,治愈,预防或消除疾病、综合征、疾病状况、患者主诉、病变或副作用或也减缓疾病、主诉或病变的进程。
用语“治疗有效量”也涵盖了对增进正常生理功能有效的量。
本发明也涉及通式I化合物的混合物的用途,例如两种非对映体的混合物,例如混合比例为1:1,1:2,1:3,1:4,1:5,1:10,1:100或1:1000。
这些混合物特别优选立体异构体化合物的混合物。
“互变异构体”指的是彼此保持平衡状态的化合物的异构形式。异构形式的浓度取决于化合物所处的环境,例如,视乎化合物是固体或者处于有机溶液或水溶液中,异构形式的浓度可以不同。
本发明的化合物的代谢产物也落入本发明的范围之内。
当本发明化合物或其前体药物的互变异构(例如,酮-烯醇互变异构)现象存在时,既要求保护它们分别的单个形式(例如,酮或烯醇形式),也要求保护其任意比例的混合物。这同样适用于它们的立体异构体,例如,对映异构体、顺/反异构体、构象异构体等。如有需要,异构体可根据本领域已知的方法(例如液相色谱法)分离。这同样适用于它们的对映异构体,例如,采用手性固定相分离。此外,对映异构体可通过转化为非对映异构体进行分离,即与对映异构纯的辅助化合物偶连,随后分离所得的非对映异构体并裂解辅助残基。或者,本发明化合物的任何对映异构体可用光学纯原料由立体选择性合成获得。
术语"取代的"指的是被上述取代基执行的取代,除非另有说明,可进行多个不同程度的取代。
这些化合物的全部生理学上可接受的盐、衍生物、溶剂化物、盐的溶剂化物以及立体异构体,包括其所有比例的混合物也符合本发明。
本发明涉及通式I的化合物及其盐,并涉及制备通式(I)化合物、其药学可用盐、溶剂化物、盐的溶剂化物、互变异构体和立体异构体,包括其所有比例的混合物,的方法,其特征在于:
a)通式(II)所示的化合物,
式中,X1、X2、X3、X4和n具有通式I中指明的含义,
与通式(III)所示的化合物反应,
式中,W、R1和R2具有通式I中指明的含义,
或者
b)为制备通式I所示的化合物,式中X3是CO且X4是NH,
使通式(IV)所示的化合物进行环化反应,
式中,R1、R2、W、X1、X2和n具有通式I中指明的含义,并且A'是含有1、2、3、或4个碳原子的烷基。
和/或
将通式(I)化合物的碱或酸转换为它们的一种盐。
在上下文中,基团R1、R2、W、X1、X2、X3、X4和n具有与通式I下标明的意义相同的定义,除非另有明确规定。
“A”表示烷基,是无支链(直链)或支链的,且含有1、2、3、4、5、6、7、8、9或10个碳原子。A较佳为表示甲基,还可以是乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,也可以是戊基、1-,2-或3-甲基丁基、1,1-,1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-,2-,3-或4-甲基戊基、1,1-,1,2-,1,3-,2,2-,2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基,更优选地为例如三氟甲基。
特别优选的是,“A”表示含有1、2、3、4、5或6个碳原子的烷基,优选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、三氟甲基、五氟乙基或1,1,1-三氟乙基。
此外“A”表示例如CH2OCH3、CH2CH2OH、OCH2CH2NH2、CH2NHCH2或NHCH2CH3。
Cyc较佳地表示环丙基、环丁基、环戊基、环己基或者环庚基。
R1较佳地表示Ar。
R3较佳地表示H或含有1、2、3或4个碳原子的烷基,更优选地为H或甲基。
Ar表示例如邻、间、对位-甲苯基,邻、间、对位-乙苯基,邻、间、对位-丙苯基,邻、间、对位-异丙苯基,邻、间、对位-叔丁苯基,邻、间、对位-羟基苯基,邻、间、对位-硝基苯基,邻、间、对位-氨基苯基,邻、间、对位-(N-甲基氨基)苯基,邻、间、对位-(N-甲基氨基羰基)苯基,邻、间、对位-甲氧基苯基,邻、间、对位-乙氧基苯基,邻、间、对位-乙氧基羰基苯基,邻、间、对位-(N,N-二甲基氨基)苯基,邻、间、对位-(N,N-二甲基氨基羰基)苯基,邻、间、对位-(乙基氨基)苯基,邻、间、对位-(N,N-二乙基氨基)苯基,邻、间、对位-氟代苯基,邻、间、对位-溴代苯基,邻、间、对位-氯代苯基,邻、间、对位-(甲基磺酰胺基)苯基,邻、间、对位-(甲基磺酰基)苯基,邻、间、对位-氰基苯基,邻、间、对位-羧酸基苯基,邻、间、对位-甲氧基羰基苯基,邻、间、对位-甲酰基苯基,邻、间、对位-乙酰基苯基,邻、间、对位-氨基磺酰基苯基,邻、间、对位-[2-(吗啉-4-基)乙氧基]苯基,邻、间、对位-[3-(N,N-二乙基氨基)丙氧基]苯基,还优选2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二氟代苯基,2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二氯代苯基,2,4-,2,5-,2,6-,3,4-或3,5-二溴代苯基,2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二硝基苯基,2,5-或3,4-二甲氧基苯基,3-哨基-4-氯代苯基,3-氨基-4-氯代-,2-氨基-3-氯代-,2-氨基-4-氯代-,2-氨基-5-氯代-或2-氨基-6-氯代苯基,2-硝基-4-N,N-二甲基氨基-或3-硝基-4-N,N-二甲基氨基苯基,2,3-二氨基苯基,2,3,4-,2,3,5-,2,3,6-,2,4,6-或3,4,5-三氯苯基,2,4,6-三甲氧基苯基,2-羟基-3,5-二氯代苯基,对位碘代苯基,3,6-二氯代-4-氨基-苯基,4-氟-3-氯代苯基,2-氟-4-溴苯基,2,5-二氟-4-溴苯基,3-溴-6-甲氧基苯基,3-氯-6-甲氧基苯基,3-氯-4-乙酰氨基苯基,3-氟-4-甲氧基苯基,3-氨基-6-甲基苯基,3-氯-4-乙酰氨基苯基,或2,5-二甲基-4-氯代苯基。
优选的是,Ar表示苯基,所述苯基是未取代的或者被Hal和/或A单取代或二取代。
特别优选的是,Ar表示苯基,所述苯基被CF3、F或者Cl单取代。
Het优选地表示吡啶基或嘧啶基,上述每个基团是未取代的或者被“A”单取代。
Het1优选地表示吡咯烷基、氮杂环丁烷基或哌啶基。
Hal优选地表示F、Cl或Br,但也可以是I,特别优选是F或Cl。
在整个本发明中,对于所有不止出现一次的所有基团,可以是同样的或不同的,即它们是相互独立的。
通式I所示的化合物可以有一个或多个手性中心,因此可以不同的立体异构体形式出现。通式I涵盖了所有这些形式。
因此,本发明特别涉及的是通式I的化合物,其中至少一个上述基团具有如上所示的优选意义。化合物的某些优选基团可用以下子结构式Ia到Ie表示,它们符合通式I,并且在没有指定更详细的含义时这些基团具有如通式I下所指定的意义,但是在
Ia中R3是H或甲基;
Ib中Ar是苯基,所述苯基未被取代或者被Hal和/或A单取代或二取代;
Ic中Het是吡啶基或者嘧啶基,上述每个基团是未取代的或者被A单取代;
Id中Het1是吡咯烷基、氮杂环丁烷基或者哌啶基;
Ie中X1是N或者CH,
X2是CH2或者NH,
X3是CH2或者CO,
X4是CH2或者NH,
R1是Ar;
R2是[C(R3)2]pHet1或者[C(R3)2]pN(R3)2,
R3是H或者甲基,
Ar是苯基,所述苯基未被取代或被Hal和/或A单取代或二取代,
Het1是吡咯烷基、氮杂环丁烷基或者哌啶基,
A是具有1-10个碳原子的无支链的或有支链的烷基,其中1个或2个非相邻的CH-和/或CH2-基团可以被N-和/或O-原子所替代,且其中1-7个H原子可以被F、Cl或者Cyc所替代,
Cyc是具有3-7个碳原子的环状烷基,
Hal是F、Cl、Br或者I,
每个n独立地是0或者1,
每个p独立地是0、1、2、3或者4;
及其药学上可接受的盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以所有比例混合的混合物。
在某些实施例中,此处所给出的任一通式所示的化合物,其中R1选自以下组内:
在某些实施例中,此处所给出的任一通式所示的化合物,其中R2选自以下组内:
在某些实施例中,此处所给出的任一通式所示的化合物,其中环选自以下组内:
在某些实施例中,本发明提供通式I-f所示的化合物及其药学上可接受的盐、溶剂化物、盐的溶剂化物、互变异构体和立体异构体,包括它们以所有比例混合的混合物,
式中,R1和R2如上所定义。
在某些实施例中,本发明提供通式I-g所示的化合物及其药学上可接受的盐、溶剂化物、盐的溶剂化物、互变异构体和立体异构体,包括它们以所有比例混合的混合物,
式中,R1和R2如上所定义。
在某些实施例中,本发明提供通式I-h所示的化合物及其药学上可接受的盐、溶剂化物、盐的溶剂化物、互变异构体和立体异构体,包括它们以所有比例混合的混合物,
式中,R1和R2如上所定义。
在某些实施例中,本发明提供通式I-i所示的化合物及其药学上可接受的盐、溶剂化物、盐的溶剂化物、互变异构体和立体异构体,包括它们以所有比例混合的混合物,
式中,R1和R2如上所定义。
在某些实施例中,本发明提供通式I-j所示的化合物及其药学上可接受的盐、溶剂化物、盐的溶剂化物、互变异构体和立体异构体,包括它们以所有比例混合的混合物,
式中,R1和R2如上所定义。
在某些实施例中,本发明提供通式I-k所示的化合物及其药学上可接受的盐、溶剂化物、盐的溶剂化物、互变异构体和立体异构体,包括它们以所有比例混合的混合物,
式中,R1和R2如上所定义。
在通式I-f至I-k中任一通式所示的某些实施例中,其中R1选自以下组内:
在通式I-f至I-k中任一通式所示的某些实施例中,其中R2选自以下组内:
通式I化合物及其合成用的起始原料,按照文献所述,由已知的方法(例如标准的著作,如Houben-Weyl,MethodenderorganischenChemie[有机化学方法],Georg-Thieme-Verlag,斯图加特),在已知的并适合上述反应的反应条件下进行制备。也可以使用本身已知但在本说明书中没有更详细提及的变体。
通式II与通式III所示的起始化合物通常是已知的。如果是新颖的,那么也可以由本身已知的方法制备。
也可以将通式II化合物与通式III化合物反应来制备通式I所示的化合物。
此外,较佳地可以通过环化通式IV所示的化合物获得通式I所示的化合物。
在本领域技术人员所公知的适于反应的条件下进行反应。
根据采取的反应条件,反应时间一般为几分钟至14天之间,反应温度在0℃和160℃之间,通常为20℃和150℃之间,优选约60℃和约140℃之间。
通常,在酸结合剂存在下进行反应,酸结合剂优选是有机碱例如DIPEA、三乙胺、二甲基苯胺、吡啶或喹啉。
有利的是碱金属或碱土金属氢氧化物、碳酸盐或碳酸氢盐或者碱金属或碱土金属的弱酸的另一种盐,优选是钾、钠、钙或铯。
合适的惰性溶剂的例子有:烃类,如正己烷、石油醚、苯、甲苯或二甲苯;氯代烃,如三氯乙烯、1,2-二氯乙烷、四氯甲烷、氯仿或二氯甲烷;醇类,如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚类,如乙醚、异丙醚、四氢呋喃(THF)或二氧六环;乙二醇醚,如乙二醇单甲醚或单乙醚或乙二醇二甲醚(diglyme);酮,如丙酮或丁酮;酰胺,如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈,如乙腈;亚砜,如二甲基亚砜(DMSO);二硫化碳;羧酸,如甲酸或乙酸;硝基化合物,如硝基甲烷或硝基苯;酯类,如乙酸乙酯,或上述溶剂的混合物。特别优选的是DMF、DMSO或NMP。
药用盐类和其他形式
本发明的所述化合物可以其最终的非盐形式使用。另一方面,本发明还涉及这些化合物以其药学上可接受的盐的形式使用,可以采用本技术领域的专业人员已知的程序,从各种有机和无机的酸和碱衍生而来。通式I化合物的药学上可接受的盐形式,绝大部分是用传统方法合成的。如果通式I化合物含有羧基,其合适的盐之一可以通过此化合物与合适的碱反应而生成相应的碱加成盐。这样的碱包括,如碱金属氢氧化物,包括氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钠或乙醇钾和丙醇钠或丙醇钾;以及各种有机碱,如哌啶、二乙醇胺和N–甲基谷氨酰胺。通式I所示化合物的铝盐也同样包括在内。对于通式I中包含碱性中心的某些化合物的情况,可以将这些化合物与药学上可接受的有机酸和无机酸作用形成它们的酸加成盐,例如卤化氢,如氯化氢、溴化氢或碘化氢;其他矿物酸及其相应的盐,如硫酸盐、硝酸盐和磷酸盐等;和烷基-和单芳基-磺酸,如乙基磺酸、对甲苯磺酸和苯磺酸,以及其他有机酸及其相应的盐,如醋酸盐、三氟醋酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等。因此,通式I化合物药学上可接受的酸加成盐包括以下盐:醋酸盐、己二酸盐、藻酸盐、精氨酸盐、天门冬氨酸盐、苯甲酸盐、苯磺酸盐(besylate)、硫酸氢盐、亚硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、氯化物、氯苯甲酸盐、柠檬酸盐、环戊烷丙酸盐、葡萄糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙烷磺酸盐、富马酸盐、粘液酸盐(从粘液酸制得)、半乳糖醛酸盐、葡庚糖酸盐、葡萄糖酸盐、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2–羟基乙磺酸盐、碘化物、羟乙基磺酸盐、异丁酸盐、乳酸盐、乳糖酸钠、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲磺酸盐、甲基苯甲酸盐、磷酸氢盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、palmoate、果胶酸盐、过硫酸盐、苯基乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐,但这并不代表仅限于此。
此外,本发明的化合物的碱式盐包括铝盐、铵盐、钙盐、铜盐、铁(III)盐、亚铁(Ⅱ)盐、锂盐、镁盐、锰(III)盐、亚锰(II)盐、钾盐、钠盐和锌盐,但这并不代表仅限于此。在上述盐中,优先考虑铵盐,碱金属盐钠盐和钾盐,和碱土金属盐钙盐和镁盐。通式I所示化合物与药学上可接受的无毒有机碱形成的盐包括下列胺的盐,即伯、仲和叔胺、取代胺,也包括自然存在的取代胺、环胺和碱性离子交换树脂,例如精氨酸、甜菜碱、咖啡因、氯普鲁卡因、胆碱、N,N'-二苄基乙二胺(苄星)、二环己胺、二乙醇胺、二乙基胺、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、葡萄糖胺、组氨酸、哈胺、异丙胺、利多卡因、赖氨酸、葡甲胺、N-甲基-D-葡萄糖胺、吗啉、哌嗪、哌啶、聚酰胺树脂、普鲁卡因、嘌呤、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三(羟甲基)甲胺(氨丁三醇),但这并不代表仅限于此。
含有碱性氮基团的本发明化合物,可以使用诸如(C1-C4)卤代烃的试剂进行季铵化,例如甲基、乙基、异丙基和叔丁基氯化物、溴化物和碘化物;二(C1-C4)烷基硫酸盐,例如二甲基、二乙基和二戊基硫酸盐;(C10-C18)卤代烃,例如癸烷基、十二烷基、月桂基、十四烷基和十八烷基氯化物、溴化物和碘化物;以及芳基-(C1-C4)烷基卤化物,例如氯化苄和苯乙基溴。这些盐类化合物可以用来制备水溶性和油溶性的本发明化合物。
上述较优选的药用盐类包括醋酸盐、三氟醋酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡萄糖酸盐、半琥珀酸盐、马尿酸盐、盐酸盐、氢溴酸盐、羟乙基磺酸盐、扁桃酸盐、葡甲胺盐、硝酸盐、油酸盐、膦酸盐、特戊酸盐、磷酸钠盐、硬脂酸盐、硫酸盐、磺酰基水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨丁三醇,但这并不代表仅限于此。
特别优选的是盐酸盐、二氢氯化物、溴酸盐、马来酸盐、甲磺酸盐、磷酸盐、硫酸盐和琥珀酸盐。
通式I所示碱性化合物的酸加成盐,通过将游离碱的形式与足够量的所需酸混合接触的方法制备,使按照常规方式生成相应的盐类。这种游离碱是可以再生的,通过使盐类形式与碱接触,用常规方式分离游离碱。这种游离碱的形式在某种意义上与其相应的盐形式在某些物理特性上是不同的,如在极性溶剂中的溶解性;但是,出于本发明的目的,这些盐类在另一方面也对应于其各自的游离碱形式。
如上所述,通式I化合物的药学上可接受的碱加成盐,通过与金属或胺的反应生成,如碱金属和碱土金属或有机胺。优选的金属是钠、钾、镁和钙。优选的有机胺为N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基-D-葡萄糖胺和普鲁卡因。
本发明的酸性化合物的碱加成盐,通过将游离酸的形式与足够量的所需碱混合接触的方法制备,使按照常规方式生成相应的盐类。这种游离酸是可以再生的,通过使盐类形式与酸接触,用常规方式分离游离酸。这种游离酸的形式在某种意义上与其相应的盐形式在某些物理特性上是不同的,如在极性溶剂中的溶解性;但是,出于本发明的目的,这些盐类在另一方面也对应于其各自的游离酸形式。
如果某个本发明化合物上含有不止一个可以形成这种类型药学上可接受盐的基团,本发明也包括复盐。典型的复盐的形式包括,例如,二酒石酸盐、二醋酸盐、二富马酸盐,二葡甲胺盐、二磷酸盐、二钠盐和三盐酸盐,但这并不代表仅限于此。
根据上面所述可以看出,术语“药学上可接受的盐”一词在本说明书前后关联中是指一种活性成分,包括以盐形式之一存在的通式I化合物,特别是如果这种盐的形式赋予了活性成分较其游离形式或任何前面使用的活性成分的其他盐形式更为改善的药代动力学特性。该活性成分的药学上可接受的盐的形式也可以是首次给活性成分提供这种理想的药代动力学性质,这种性质是它以前所没有的,并对于其体内疗效来说,它甚至可以对该活性成分的药效学产生积极的影响。
同位素
具有通式I的化合物还应包括其同位素标记形式。具有通式I的化合物的同位素标记形式与所述化合物的区别仅在于所述化合物的一个或多个原子被原子量或质量数与通常是天然存在的原子的原子量或质量数不同的一个或多个原子取代。市场上容易买到且可通过已知方法被结合到具有通式I的化合物中的同位素的例子包括氢、碳、氮、氧、磷、氟和氯,例如分别为2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F和36CI。含有一或多个上述同位素和/或其他原子的同位素的通式I化合物、其前体药物或它们中任一个的药学上可接受的盐都应理解为本发明的一部分。可以多种有利的方式使用同位素标记的通式I化合物。例如,结合了诸如3H或14C的放射性同位素的同位素标记的通式1化合物可用于药物和/或底物组织分布试验。由于其制备简单及可检测性良好而尤其优选这两种放射性同位素,即氚(3H)和碳-14(14C)。由于诸如氘(2H)的较重的同位素具有较高的代谢稳定性,将这种同位素标记化合物结合到通式I化合物中在治疗上是有好处的。较高的代谢稳定性直接导致体内半衰期延长或剂量减少,这在多数情况下代表了本发明的优选实施例。通常可通过进行本文本的实施例部分和制备部分中的合成方案和相关描述中公开的步骤来制备同位素标记的通式I化合物,用容易得到的同位素标记反应物代替非同位素标记反应物。
为了通过一级动力学同位素效应控制化合物的氧化代谢,可将氘(2H)结合到所述化合物中。一级动力学同位素效应是由于同位素核的替换而导致化学反应速率发生变化,这是由于所述同位素替换之后形成共价键所需的基态能量的变化而引起的。较重的同位素的替换通常导致化学键的基态能量降低,从而引起速率限制的键断裂反应的速率降低。如果键断裂发生在沿着多产物反应的坐标的鞍点区中或其附近,产物分布比率可被显着改变。解释如下:如果氘被键合到碳原子的非可替换位置上,通常速率差异km/kd=2-7。如果该速率差异被成功地应用于易于氧化的通式I化合物,则该化合物在体内的性质可被显着地改变,从而改善药物动力学特性。
在发现和开发治疗剂时,本领域技术人员尝试在保持有利的体外特性的同时优化药物动力学参数。可以合理地认为,许多药物动力学性质差的化合物易于被氧化代谢。现有的体外肝微粒体试验提供了关于这种类型的氧化代谢过程的有价值的信息,这些信息使得可以合理地设计具有通式I的含氘化合物,使其由于抗氧化代谢而提高稳定性。因此,通式I化合物的药物动力学性质显着地改善了,这种改善可用体内半衰期(t/2)的延长、疗效最好的浓度(Cmax)、剂量响应曲线下的面积(AUC)以及F来定量地表示,也可用降低的清除率、剂量和材料成本来定量地表示。
以下阐述用于说明上述内容:把通式I化合物制备成一系列类似物,其中所述通式I化合物具有多个氧化代谢可能攻击的位点,例如苯甲基氢原子和与氮原子键合的氢原子,在所述类似物中各种组合的氢原子被氘原子取代,因此所述氢原子中的一部分、大多数或全部被氘原子取代。半衰期的确定使得可以有利地及准确地确定对氧化代谢的抵抗能力提高的程度。通过这种方式确定了,由于这种类型的氘-氢替换,母化合物的半衰期可被提高高达100%。
通式I化合物中的氘-氢替换也可被用来有利地改变起始化合物的代谢物谱,以减少或消除不良有毒代谢物。例如,如果通过氧化性碳-氢(C-H)键断裂产生了有毒代谢物,可以合理地认为,含氘类似物将会显着地减少或消除不良代谢物的产生,即使该具体的氧化反应并不是速率决定步骤。更多现有技术中关于氘-氢替换的信息可参见例如Hanzlik等,J.Org.Chem.55,3992-3997,1990,Reider等,J.Org.Chem.52,3326-3334,1987,Foster,Adv.DrugRes.14,1-40,1985,Gilletteetal,Biochemistry33(10)2927-2937,1994,andJarman等Carcinogenesis16(4),683-688,1993。
因为本发明化合物的外消旋物或立体异构体的药学活性可能存在差异,可能需要使用对映体。在这些情况下,可采用本领域技术人员已知的或甚至在合成上直接采用的化学或物理方法将终产物甚至中间体拆分成为对映异构化合物。
在分子结构中存在外消旋胺的情况下,混合物可与光学活性拆分试剂形成非对映体。合适的拆分试剂实例为具有光学活性的酸类,如R型或S型的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸和乳酸,合适的N-保护氨基酸类(例如N-苯甲酰脯氨酸或N苯磺酰脯氨酸),或各种光学活性的樟脑磺酸。借助于光学活性拆分剂(例如固定在硅胶上的二硝基苯甲酰苯基甘氨酸、三醋酸纤维素或碳水化合物的其他衍生物或手性衍生化甲基丙烯酸聚合物)的对映体的色谱拆分法也具有优势。为此目的所使用的合适洗脱剂为含水或含醇的溶剂混合物,例如乙烷/异丙醇/腈,例如比例为82∶15∶3。一种拆分包含酯基(例如乙酰基酯)的外消旋物的巧妙的方法是使用酶、特别是酯酶类。
本发明还涉及药物组合物,所述药物组合物包含至少一种通式I化合物和/或其药学上可接受的盐、溶剂化物、互变异构体和立体异构体,包括它们的所有比例的混合物,并任选地包含赋形剂和/或佐剂。
“药物组合物”是指一种或多种活性成分和组成载体的一种或多种惰性组分以及由下列直接或间接获得的任意产物:任意两种或多种组分组合、复合、聚集,或者一种或多种组分解离,或者一种或多种组分的其它类型的反应或相互作用。因此,本发明药物组合物包括通过本发明化合物和可药用载体混合而制得的任意组合物。
本发明药物组合物可另外含有一种或多种作为活性成分的其它化合物,例如一种或多种另外的本发明化合物、前体药物化合物或其它p70S6K抑制剂。
药物组合物包括经口、直肠、局部、肠胃外(包括皮下、肌肉内和静脉内)、眼球(眼)、肺(鼻或颊吸入)或鼻给药的适宜组合物,在任何已知的情况中最适宜的途径取决于治疗的病症的性质和严重性以及活性组分的性质。它们可方便地以单位剂量形式存在并采用药物领域已知的任意方法制备。
在一个实施方案中,所述化合物和药物组合物用于治疗以下疾病:癌症,例如脑癌、肺癌、结肠癌、表皮样癌、鳞状细胞癌、膀胱癌、胃癌、胰腺癌、乳腺癌、头癌、颈癌、肾癌、肾的癌、肝癌、卵巢癌、前列腺癌、结直肠癌、子宫癌、直肠癌、食管癌、睾丸癌、妇科癌、甲状腺癌、黑素瘤、恶性血液病,诸如急性髓性白血病、多发性骨髓瘤、慢性髓性白血病、骨髓细胞白血病、神经胶质瘤、卡波西肉瘤,或其它任何类型的实体或液体肿瘤。优选地,治疗的癌症选自乳腺癌、结直肠癌、肺癌、前列腺癌或胰腺癌或成胶质细胞瘤。
采用本发明的化合物治疗的示范性疾病包括:前列腺癌,甲状腺癌,肝癌,肺癌,乳腺癌,结肠癌,前列腺癌,垂体瘤,膀胱癌,乳腺癌,结肠癌(例如结肠直肠癌如结肠腺癌和结肠腺瘤),肾癌,表皮癌,肝癌,肺癌,例如上述器官的腺癌,小细胞肺癌和非小细胞肺癌,食道癌,胆囊癌,卵巢癌,胰腺癌如外分泌胰腺癌,胃癌,子宫颈癌,子宫内膜癌,甲状腺癌,前列腺癌,或皮肤癌(例如鳞状细胞癌);淋巴系统的造血肿瘤(例如白血病、急性淋巴细胞性白血病、慢性成淋巴细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、毛细胞淋巴瘤或伯基特淋巴瘤);骨髓系统的造血肿瘤(例如白血病、急性和慢性骨髓性白血病、骨髓增生综合征、骨髓增生异常综合征或早幼粒细胞白血病);多发性骨髓瘤;甲状腺滤泡癌;源自间叶细胞的肿瘤(例如纤维肉瘤和眼眶横纹肌肉瘤);中枢或周围神经系统肿瘤(例如星细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤);黑素瘤;精原细胞瘤;畸胎癌;骨肉瘤;着色性干皮病;角化棘皮瘤;甲状腺滤泡状癌或卡波氏肉瘤。
在某些实施方案中,所述疾病是膀胱癌,乳腺癌,宫颈癌,结肠癌,表皮癌,胆囊癌,肾癌,肝癌,肺癌,垂体瘤,食道癌,卵巢癌,胰腺癌,前列腺癌,胃癌,甲状腺癌,白血病,B细胞淋巴瘤,T细胞淋巴瘤,何杰金氏淋巴瘤,非何杰金氏淋巴瘤,毛细胞淋巴瘤,伯基特淋巴瘤,急性和慢性髓细胞性白血病,骨髓增生综合征,骨髓增生异常综合征,髓细胞性白血病;多发性骨髓瘤,甲状腺滤泡癌;星细胞瘤,成神经细胞瘤,神经胶质瘤,神经鞘瘤,黑素瘤或卡波氏肉瘤。
在某些实施方案中,所述疾病是多发性骨髓瘤,骨髓增生性疾病,子宫内膜癌,前列腺癌,膀胱癌,肺癌,卵巢癌,乳腺癌,胃癌,结肠直肠癌,以及口腔鳞状细胞癌。在某些实施例中,所述疾病是多发性骨髓瘤,膀胱癌,子宫颈癌,前列腺癌,甲状腺癌,肺癌,乳腺癌,或结肠癌。
本发明还涉及本发明化合物在制备药物中的用途,所述药物用于治疗哺乳动物中与p70S6K活动过度有关的过度增殖性疾病以及由p70S6K级联所调节的疾病,或用于治疗异常增殖介导的病症,例如癌症和炎症。
本发明还涉及用于治疗哺乳动物中与血管发生或血管生成有关的疾病的化合物或药物组合物,其包含治疗有效量的本发明化合物或其可药用盐、前体药物或水合物以及可药用的载体。
在一个实施方案中,所述化合物或药物组合物可以用于治疗下列疾病:肿瘤血管生成、慢性炎症(例如类风湿性关节炎、炎性肠疾病)、动脉粥样硬化、皮肤病(例如银屑病、湿疹和硬皮病)、糖尿病、糖尿病性视网膜病、早产儿视网膜病和年龄相关性黄斑变性。
本发明还涉及用于抑制哺乳动物中异常细胞生长的化合物或药物组合物,其包含一定量的本发明化合物或其可药用盐或溶剂化物或前体药物以及一定量的另外的抗癌治疗药物,其中所述化合物、盐、溶剂化物或前体药物的量与化学治疗剂的量一起对抑制异常细胞生长是有效的。许多抗癌治疗药物目前在本领域内中是已知的。在一个实施方案中,所述抗癌治疗药物是选自以下的化学治疗剂:有丝分裂抑制剂、烷化剂、抗代谢药、嵌入抗生素(intercalatingantibiotics)、生长因子抑制剂、细胞周期抑制剂、酶、拓扑异构酶抑制剂、生物学应答调节剂、抗激素、血管生成抑制剂和抗雄激素。在另一个实施方案中,所述抗癌治疗药物是选自以下的抗体:贝伐单抗、CD40-特异性抗体、chTNT-1/B、地舒单抗、扎木单抗、IGF1R-特异性抗体、林妥珠单抗、依决洛单抗、WXG250、利妥昔单抗、替西木单抗、曲妥单抗和西妥昔单抗。在另一个实施方案中,所述抗癌治疗药物是另一种蛋白激酶的抑制剂,所述蛋白激酶诸如Akt、Axl、AuroraA、AuroraB、dyrk2、epha2、fgfr3、igf1r、IKK2、JNK3、Vegfr1、Vegfr2、Vegfr3(也称为Flt-4)、KDR、MEK、MET、Plk1、RSK1、Src、TrkA、Zap70、cKit、bRaf、EGFR、Jak2、PI3K、NPM-Alk、c-Abl、BTK、FAK、PDGFR、TAK1、LimK、Flt-3、PDK1和Erk。
本申请公开的通式I所示的化合物可与包括抗癌药物在内的已知的治疗剂联用。此处所用的术语“抗癌药物”涉及给予癌症患者用于治疗癌症的任何药物。
以上定义的抗癌治疗可作为单一疗法应用,或者除了本文公开的此处公开的通式I所示的化合物之外可包括常规手术或放射疗法或药物治疗。这种药物治疗例如化疗或靶向治疗,可包括一种或多种,但是优选地为一种以下抗肿瘤药物:
烷化剂:例如六甲密胺、苯达莫司汀、白消安、卡莫司汀、苯丁酸氮芥、氮芥、环磷酰胺、氮烯唑胺、异环磷酰胺、甲磺丙胺、洛莫司汀、美法仑、二溴甘露醇、二溴卫矛醇、尼莫司汀、雷莫司汀、替莫唑胺、噻替派、苏消安、二氯甲基二乙胺、卡波醌、阿帕齐醌、福莫司汀、葡磷酰胺、帕利伐米、哌血生、曲磷胺、尿啼陡氮芥、TH-3024、VAL-0834;
铂化合物:例如卡铂、顺铂、依铂、米铂水合物、奥沙利铂、洛铂、奈达铂、吡铂、沙铂;洛铂、奈达铂、吡铂、赛特铂;
DNA改性剂:例如氨柔比星、蒽双咪腙、地西他滨、米托蒽醌、甲基苄肼、曲贝替定、氯法拉滨;安吖啶、溴他里辛、匹杉琼、laromustine1,3;
拓扑异构酶抑制剂:例如依托泊苷、伊立替康、雷佐生、索布佐生、替尼泊苷、托泊替康;氨萘非特、贝洛替、依利醋铵、伏利拉辛(voreloxin);
微管改性剂:例如卡巴他赛、多西他赛、艾日布尔、伊沙匹隆、紫杉醇、长春碱、长春新碱、长春瑞滨、长春地辛、长春氟宁;康普瑞汀A4前体药物(fosbretabulin)、替司他赛;
抗代谢药物:例如天冬酰胺酶3、阿扎胞苷、左亚叶酸钙、卡培他滨、克拉屈滨、阿糖胞苷、依诺他滨、氟尿苷、氟达拉滨、氟尿嘧啶、吉西他滨、巯嘌呤、甲氨蝶呤、奈拉滨、培美曲塞、普拉曲沙、硫唑嘌呤、硫鸟嘌呤、卡莫氟;脱氧氟尿苷、艾西拉滨、雷替曲塞、沙帕他滨、替加氟2,3、三甲曲沙;
抗癌抗生素:例如博来霉素,更生霉素、阿霉素、表阿霉素、伊达比星、左旋咪唑、米替福新、丝裂霉素C、罗米地辛、链佐星、戊柔比星、净司他丁、佐柔比星、柔红霉素、普卡霉素;阿柔比星、派来霉素、吡柔比星;
激素/拮抗剂:例如阿巴瑞克、阿比特龙、比卡鲁胺、布舍瑞林、卡普睾酮、氯烯雌醚、地加瑞克、地塞米松、雌二醇、氟可龙、甲睾酮、氟他胺、氟维司群、戈舍瑞林、组氨瑞林、亮丙瑞林、甲地孕酮、米托坦、那法瑞林、诺龙、尼鲁米特、奥曲肽、泼尼松龙、雷洛昔芬、他莫昔芬、促甲状腺激素阿尔法、托瑞米芬、曲洛司坦、曲普瑞林、二乙基己烯雌酚;阿考比芬、达那唑、洛瑞林、环硫雄醇、orteronel、恩杂鲁胺1,3;
芳香酶抑制剂:例如氨基格鲁米特、阿那曲唑、依西美坦、法倔、来曲唑、睾内酯、福美坦;
小分子激酶抑制剂:例如克唑替尼、达沙替尼、厄洛替尼、伊马替尼、拉帕替尼、尼洛替尼、帕唑帕尼、瑞格非尼、鲁索利替尼、索拉非尼、舒尼替尼、凡德他尼、维罗非尼、博舒替尼、吉非替尼、阿西替尼、阿法替尼、alisertib、达拉菲尼、达可替尼、dinaciclib、多韦替尼、恩扎妥林、尼达尼布、乐伐替尼、利尼伐尼、linsitinib、马赛替尼、米哚妥林、莫特塞尼、来那替尼(neratinib)、orantinib、哌立福辛、普纳替尼、拉多替尼、rigosertib、替批法尼、tivantinib、tivozanib、曲美替尼、pimasertib、丙氨酸布立尼布、西地尼布、阿帕替尼、卡波替尼S-苹果酸盐1,3、依鲁替尼1,3、埃克替尼4,buparlisib2,西帕替尼4,cobimetinib1,3,艾德利布1,3,fedratinib1,XL-6474
光敏剂:例如甲氧沙林3、吓吩姆钠、他拉泊芬、替莫泊芬;
抗体:例如阿仑单抗、贝西索单抗、贝伦妥单抗-维多汀、西妥昔单抗、迪诺塞麦、易普利单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、群司珠单抗、贝伐单抗2,3、卡妥索单抗、elotuzumab、依帕珠单抗、farletuzumab、mogamulizumab、necitumumab、尼妥珠单抗、奥奴珠单抗、ocaratuzumab、奥戈伏单抗、雷莫芦单抗、利妥木单抗、司妥昔单抗、托珠单抗、扎鲁木单抗、扎木单抗、马妥珠单抗、达妥珠单抗1,2,3、onartuzumab1,3、雷妥莫单抗1、tabalumab1,3,EMD-5257974,纳武单抗(nivolumab1,3);
细胞因子:例如阿地白介素、干扰素α2、干扰素α2a3、干扰素α2b2,3、西莫白介素、他索纳明、替西白介素、奥普瑞白介素1,3、重组白介素β-1a4;
药物轭合物:例如地尼白介素-毒素连接物、替伊莫单抗、碘苄胍1123、松龙苯芥、曲妥珠单抗-emtansine、雌莫司汀、吉妥珠单抗、奥唑米星、阿柏西普、cintredekinbesudotox、依多曲肽、奥英妥珠单抗、那莫单抗、莫奥珠单抗、锝(99mTc)阿西莫单抗、vintafolide1,3;
疫苗:例如前列腺癌疫苗(sipuleucel3)、维特斯朋3、emepepimut-S3、结肠癌疫苗(oncoVAX4)、rindopepimut3、troVax4、MGN-16014、MGN-17034;以及
其它药物:阿利维甲酸、贝沙罗汀、硼替佐米、依维莫司、伊班膦酸、咪喹莫特、来那度胺、蘑菇多糖、甲酪氨酸、米伐木肽、帕米磷酸、培加帕酶、喷司他丁、sipuleucel3、西佐糖、他米巴罗汀、替西莫司、沙利度胺、维A酸、维莫德吉、唑来膦酸、沙利度胺、伏立诺他、塞来考昔、西仑吉肽、恩替诺特、依他硝唑、ganetespib、idronoxil、iniparib、ixazomib、氯尼达明、尼莫唑、帕比司他、培瑞维A酸、plitidepsin、泊马度胺、procodazol、ridaforolimus、他喹莫德、telotristat、胸腺法新、替拉扎明、托多司他、trabedersen、乌苯美司、伐司朴达多、今又生(gendicine4)、溶链菌4、reolysin4、盐酸瑞他霉素1,3、trebananib2,3、维鲁利秦4、卡非佐米1,3,血管内皮抑制素4,immucothel4,贝利司他3,MGN-17034。
(1Prop.INN(建议采用的国际非专有名称);2Rec.INN(推荐采用的国际非专有名称);3USAN(美国采用的名称);4noINN(没有国际非专有名称))。
本发明还涉及抑制哺乳动物中异常细胞生长或治疗过度增殖性疾病的方法,该方法包括向哺乳动物施用一定量的本发明化合物或其可药用盐或溶剂化物或前体药物,与手术或放射治疗联合使用,其中所述化合物、盐、溶剂化物或前体药物的量联合放射治疗对抑制哺乳动物中的异常细胞生长或治疗过度增殖性疾病是有效的。施用放射治疗的技术在本领域中是已知的,并且这些技术可用于本文中所述的联合治疗中。在该联合治疗中,本发明化合物的施用可如本文所述确定。一般认为,本发明化合物可以使得异常细胞对放射治疗更为敏感,从而可以杀死和/或抑制此类细胞生长。
因此,本发明还涉及使哺乳动物中的异常细胞对放射治疗敏感化的方法,该方法包括向哺乳动物施用一定量的本发明化合物或其可药用盐、溶剂化物或前体药物,所述量可以有效地使得异常细胞对放射治疗敏感化。本方法中化合物、盐或溶剂化物的量可根据本文所述的确定所述化合物的有效量的方法进行测定。本发明还涉及抑制哺乳动物中异常细胞生长的方法,其包括一定量的本发明化合物或其可药用盐、溶剂化物、前体药物或同位素标记的衍生物以及一定量的一种或多种选自抗血管生成剂、信号传导抑制剂和抗增殖性药物。
在实际应用中,根据常规药物配制技术,本发明化合物作为活性成分可以与药用载体结合为紧密混合物。所述载体可根据施用(例如,经口或胃肠外(包括静脉内的))所需的制剂形式而采用多种形式。在制备口服剂型组合物时,可使用任何常规药用介质,例如,水、乙二醇、油类、醇类、矫味剂、防腐剂、着色剂等。在口服液体制剂的情况中,可使用任何常规药用介质,例如,混悬剂、酏剂和溶液剂;或载体例如淀粉、糖、微晶纤维素、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。在口服固体制剂情况下,组合物可作为例如粉剂、硬和软胶囊以及片剂形式存在,相对液体剂型来说,优选固体口服剂型。
因为片剂和胶囊容易给药,所以片剂和胶囊代表最有益的口服单位剂型,在此情况下,明显可以采用固体药物载体。如有需要,片剂可通过标准含水或不含水技术包衣。所述组合物和制剂应包含至少0.1%的活性化合物。当然,活性化合物在这些组合物中的百分比可变化,可以有益地在约2%到约60%的单位重量范围内。在所述治疗有用的组合物中的活性化合物的量为能够获得有效剂量的量。活性化合物同样可经鼻内给药,例如,液体滴剂或喷雾剂。
片剂、丸剂、胶囊等可同样包含:粘合剂,例如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂,例如磷酸二钙;崩解剂,例如玉米淀粉、土豆淀粉、海藻酸;润滑剂,例如硬脂酸镁;和甜味剂,例如蔗糖、乳糖或糖精。单位剂型为胶囊时,可包含除上述类型材料之外的液体载体,例如脂肪油。
各种不同的其它物质可以作为包衣材料存在,或用于改变单位剂量的物理形式。例如,片剂可用虫胶、糖衣或两者一起包衣。除了活性组分外,糖浆剂或酏剂还可包含:作为甜味剂的蔗糖、作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、着色剂和矫味剂(例如樱桃或橙子口味)。
本发明化合物也可以经肠胃外给药。这些活性化合物的溶液或悬浮液可通过在水中与表面活性剂(例如羟基-丙基纤维素)适当地混合来制备。分散液可由甘油、液态聚乙二醇以及其在油中的混合物制备。在储存和使用的常规条件下,这些制剂可以包含防腐剂以防止微生物的生长。
适宜于注射使用的药物形式包括用于即时制备无菌注射溶液或分散体的无菌注射水溶液或分散体和无菌粉末。在所有情况中,该形式必须为无菌的并必须具有足够的流动性使它们易于注射。在制备和储存的情况下,所述形式必须稳定并且必须能够对抗微生物(例如细菌和真菌)的污染。载体可包括溶剂或分散介质,例如水、乙醇、多元醇(例如,甘油、丙二醇和液态聚乙二醇)、其适宜的混合物和植物油。
任何适宜的给药途径可以提供哺乳动物(尤其是人类)有效剂量的本发明化合物。例如,可经口、直肠、局部、肠胃外、眼、肺、鼻等给药。剂型包括片剂、口含片剂、分散剂、混悬剂、溶液剂、胶囊剂、霜剂、软膏剂、气雾剂等。优选本发明化合物经口给药。
施用的活性组分的有效量可取决于该施用的具体化合物、施用模式、待治疗的病症以及待治疗病症的严重性。所述剂量可很容易被本领域技术人员确定。
治疗或预防作为本发明化合物的适应症的癌症、炎症或其它增殖性疾病时,在给予日剂量为约0.01mg到约100mg/kg动物体重时即可以获得大致满意的结果,优选给予单一日剂量。对于大型哺乳动物而言,总的日剂量为约0.1mg到约1000mg,优选为约0.2mg到约50mg。在70kg的成年人情况中,总的日剂量大致为约0.2mg到200mg。所述剂量方案可以调整从而能提供最佳治疗响应。
本发明还涉及药盒(套盒),该药盒包含下列独立包装:
a)有效量的本发明的化合物和/或其可药用盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以所有比例混合的混合物;以及
b)有效量的另外的药物活性成分。
所述药盒包含适当的容器,例如盒子、独立瓶子、袋子或安瓿。药盒可包括例如独立安瓿,每一个含有有效量的本发明化合物和/或其药学上可用的衍生物、溶剂化物和立体异构体(包括其所有比例的混合物)以及溶解形式或冻干形式的有效量的另外的药物活性成分。
具体实施方式
实验部分
在本申请中可能出现的某些缩写如下:
缩写
名称 | |
ACN | 乙腈 |
AcOH | 乙酸 |
AIBN | 偶氮二异丁腈 |
ATP | 三磷酸腺苷 |
b | 宽峰 |
Bop-Cl | 双(2-氧代-3-噁唑烷基)次磷酰氯 |
Conc. | 浓缩 |
d | 双峰 |
DCM | 二氯甲烷 |
DCE | 二氯乙烷 |
DMAP | 二甲氨基吡啶 |
DMF | 二甲基甲酰胺 |
DMSO | 二甲基亚砜 |
DIEA/DIPEA | N,N-二异丙基乙胺 |
DTT | 二硫苏糖醇 |
EDTA | 乙二胺四乙酸 |
equiv./eq. | 当量 |
Et | 乙基 |
h | 小时 |
HEPES | 4-(2-羟基乙基)-1-哌嗪乙磺酸 |
HPLC | 高压液相色谱法 |
LC/MS | 液相色谱法-质谱法 |
LiOH | 氢氧化锂 |
m | 多重峰 |
M | 分子离子 |
m/z | 质荷比 |
Me | 甲基 |
甲醇 | 甲醇 |
min | 分钟 |
MS | 质谱法 |
N | 当量(浓度单位) |
NaOH | 氢氧化钠 |
NBS | N-溴代琥珀酰亚胺 |
NMO | 4-甲基吗啉N-氧化物 |
NMP | N-甲基-2-吡咯烷酮 |
NMR | 核磁共振 |
PG | 保护基团 |
psi | 磅/平方英寸 |
q | 四重峰 |
Rf | 保留因子 |
RT/rt | 室温 |
Rt. | 保留时间 |
s | 单峰 |
T3P | 丙基磷酸环酐 |
TBAF | 四丁基氟化铵 |
Tert | 叔 |
TEA | 三乙胺 |
TFA | 三氟乙酸 |
THAB | 四己基溴化铵 |
THF | 四氢呋喃 |
UV | 紫外 |
VIS | 可见 |
本发明化合物可以根据下文流程和实施例中的方法采用适当的物质制备,在下面的具体的实施例中进一步举例说明。
此外,通过使用本文所述方法,结合本领域的常规技术,可容易地制备本文所要求的其它化合物。然而,不能将实施例中说明的化合物理解为是作为本发明的唯一类型。实施例还说明了本发明化合物的制备的详细描述。本领域技术人员容易理解,下列制备方法的条件和过程的已知变通方法能用于制备这些化合物。
本发明化合物通常以其可药用盐形式分离,诸如如上所述的那些。相应于分离的盐的作为游离胺的碱可以用适宜的碱中和制得,所述碱诸如碳酸氢钠、碳酸钠、氢氧化钠和氢氧化钾水溶液,将释放的作为游离胺的碱用有机溶剂萃取,然后蒸发。通过所述方式分离的作为游离胺的可通过将其溶解于有机溶剂中,然后加入适当的酸,最终蒸发、沉淀或结晶而进一步转化为其它可药用的盐。
通过以下流程和实施例中所述的具体实施方案阐述但不限制本发明。除非在流程中另外说明,否则任何变量具有如上所述的同样意义。
除非另外说明,所有的原料来自商业供应商,且未经进一步纯化地使用。除非另外说明,所有的温度以℃表示,且所有的反应在室温进行。化合物通过二氧化硅色谱或制备型HPLC纯化。
本发明还涉及根据下文所述流程和操作实施例制备通式(I)的化合物的方法。
通用合成流程I
双环骨架(1)与胺(2)在碱性条件下反应,生成通式(3)所示的化合物。除非另有指明,通用合成流程I中的取代基对应通式I中定义的那些取代基。
通用合成流程II
步骤1
在某些实施例中,由4-氨基-6-氯-嘧啶-5-醇与1,2-二溴-乙烷在碱性条件下反应,制备双环骨架。
步骤2
在优选实施例中,双环骨架(4)与胺(5)(WO13/40044)在碱性条件下反应,生成通式I所表示的化合物(6)。除非另有指明,通用合成流程I中的取代基对应通式I中定义的那些取代基。
通用合成流程III
4,6-二氯-5-硝基-嘧啶与试剂(7)在碱性条件下反应,得到氯化物中间体(8)。将氯化物(8)与取代的胺(4)反应,得到化合物(9)。将化合物(9)进行氢化反应,得到化合物(10),通过化合物(10)的环闭合反应,得到一环闭合产物,使所述环闭合产物脱boc保护,生成双环化合物(11)。化合物(11)在碱存在下进行烷基化反应,得到所希望的化合物(12)。
分析方法
使用以下三种方法进行分析性LC/MS:
方法A:使用DiscoveryC18,5μm,3x30mm柱,流速400μL/分钟,进样环5μL,流动相(A)含0.1%甲酸的水,流动相(B)含0.1%甲酸的甲醇;保留时间以分钟计。方法详述:(I)使用QuaternaryPumpG1311A(Agilent),备有UV/VIS二极管阵列检测器G1315B(Agilent)和FinniganLCQDuoMS检测器(ESI+模式),UV-检测在254和280nm,梯度:15-95%(B)3.2分钟线性梯度,(II)在95%(B)保持1.4分钟,(III)从95-15%(B)0.1分钟线性梯度,(IV)在15%(B)保持2.3分钟。
方法B:使用WatersSymmetryC18,3.5μm,4.6x75mm柱,流速1mL/分钟,进样环10μL,流动相(A)为含0.05%TFA的水,流动相(B)为含0.05%TFA的ACN;保留时间以分钟计。方法详述:(I)使用BinaryPumpG1312A(Agilent),备有UV/Vis二极管阵列检测器G1315B(Agilent)和AgilentG1956B(SL)MS检测器(ESI+模式),UV-检测在254和280nm,梯度:20-85%(B)10分钟线性梯度,(II)在85%(B)保持1分钟,(III)从85-20%(B)0.2分钟线性梯度,(IV)在20%(B)保持3.8分钟。
方法C:梯度:4.2分钟/流速:2ml/分钟99∶01-0∶100水+0.1%(体积)TFA;乙腈+0.1%(体积)TFA;0.0至0.2分钟:99∶01;0.2至3.8分钟:99∶01→0∶100;3.8至4.2分钟:0∶100;柱:ChromolithPerformanceRP18e;长度100mm,直径3mm;波长:220nm。
分析型手性HPLC
使用来自DaicelChemicalIndustries,Ltd.的ChiralPakAD-H柱(250X4.6mm)在Agilent1100系列系统进行分析型手性HPLC。该方法使用5.0μL进样体积,流速1mL/分钟,使用100%甲醇在25℃运行15分钟,且UV-检测在254和280nm。
制备型HPLC
使用WatersAtlantisdC18OBDTM10μM(30X250mm)柱或WatersSunfirePrepC18OBD10μM(30X250mm)柱进行制备型HPLC。所述柱在装备有进样环(10mL)和ISCOUA-6UV/Vis检测器的WatersPrepLC4000System以60mL/分钟的流速使用。流动相从含有(A)水和(B)HPLC-级乙腈的两个溶剂瓶中吸入。通常的制备使用线性梯度(例如,0-60%溶剂B经历60分钟)。
实施例
以下操作实施例旨在阐明本发明的具体实施方案,并不意欲以任何方式限制说明书或权利要求的范围。
实施例1
按照通用合成流程II合成通式(I)化合物
2-(1-(5,6,7,8-四氢-1,8-萘啶-4-基)哌啶-4-基)-2-(4-(三氟甲基)苯基)乙胺(“A1”)
步骤1:4-(2-(4-硝基苯基磺酰氨基)-1-(4-(三氟甲基)苯基)-乙基)哌啶-1-羧酸叔丁酯
0℃下向4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-羧酸叔丁酯(1000.00mg;2.68mmol;1.00eq.)和二异丙基乙胺(0.58ml;3.21mmol;1.2eq.)在30mlDCM中的溶液加入4-硝基-苯磺酰氯(593.50mg;2.68mmol;1.0eq.)。得到的混合物室温搅拌2小时。移除溶剂后,将残留物送入snap柱(洗脱液为0-50%乙酸乙酯的己烷溶液)洗脱,生成4-(2-(4-硝基苯基磺酰氨基)-1-(4-(三氟甲基)苯基)乙基)哌啶-1-羧酸叔丁酯(1050mg,70%得率)。
步骤2:4-硝基-N-(2-(哌啶-4-基)-2-(4-(三氟甲基)苯基)乙基)-苯磺酰胺
4-(2-(4-硝基苯基磺酰氨基)-1-(4-(三氟甲基)苯基)乙基)哌啶-1-羧酸叔丁酯(1050.0mg;1.88mmol;1.0eq.)和5ml4MHCl的二噁烷溶液在5ml甲醇中的反应混合物搅拌2小时。移除溶剂后,残留物用醚处理,收集到固体,为标题化合物的盐酸盐(814mg,81.5%得率)。
步骤3:4-硝基-N-(2-(1-(5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4-基)哌啶-4-基)-2-(4-(三氟甲基)苯基)乙基)苯磺酰胺
5-氯-1,2,3,4-四氢-[1,8]萘啶(50.0mg;0.3mmol;1.0eq.)、4-硝基-N-(2-(哌啶-4-基)-2-(4-(三氟甲基)苯基)乙基)-苯磺酰胺(157.56mg;0.30mmol;1.0eq.)和二异丙基乙胺(0.27ml;1.5mmol;5.0eq.)在1mlNMP中的反应混合物在140℃搅拌36小时。粗产物经制备型HPLC提纯,得到标题化合物(100mg);LC-MS(M+H=590,obsd.=591)。
步骤4:2-(1-(5,6,7,8-四氢-1,8-萘啶-4-基)哌啶-4-基)-2-(4-(三氟甲基)苯基)乙胺
4-硝基-N-[2-[4-(5,6,7,8-四氢-[1,8]萘啶-4-基)-哌嗪-1-基]-2-(4-三氟甲基-苯基)-乙基]-苯磺酰胺(100.0mg;0.17mmol;1.0eq.)、苯硫酚(93.2mg;0.85mmol;5.0eq.)和碳酸铯(551.6mg;1.69mmol;10.0eq.)在5ml乙腈中的反应混合物在40℃搅拌3小时。经lc-ms发现少量产物,另外加入0.1ml苯硫酚,搅拌过夜。粗产物经制备型HPLC提纯,得到标题化合物,为白色固体(9.7mg);LC-MS(M+H=405,obsd.=406)。
2-(1-(2,3-二氢-1H-吡咯并[2,3-b]吡啶-4-基)哌啶-4-基)-2-(4-(三氟甲基)苯基)乙胺(“A2”)
步骤1:2-(1-(7-(4-甲氧基苄基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)哌啶-4-基)-2-(4-(三氟甲基)苯基)乙胺
4-氯-7-(4-甲氧基-苄基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶(60.0mg;0.22mmol;1.0eq.)、2-(哌嗪-1-基)-2-(4-(三氟甲基)苯基)乙胺三盐酸盐(83.27mg;0.22mmol;1.0eq.)和碳酸钾(0.42ml;2.18mmol;10.0eq.)在1.5mlDMF中的反应混合物在120℃下搅拌60小时。粗产物经制备型HPLC提纯,得到标题化合物(50mg,31%得率);LC-MS(M+H=511,obsd.=512)。
步骤2:2-(1-(2,3-二氢-1H-吡咯并[2,3-b]吡啶-4-基)哌啶-4-基)-2-(4-(三氟甲基)苯基)乙胺
向在密封小管中的2-(1-(7-(4-甲氧基苄基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)哌啶-4-基)-2-(4-(三氟甲基)苯基)乙胺二(2,2,2-三氟乙酸盐)(50.00mg;0.07mmol;1.00eq.)加入三氟乙酸(1.00ml;8.77mmol;129.91eq.),反应混合物在80℃搅拌过夜。粗产物经制备型HPLC提纯,得到标题化合物(5mg,11.9%得率);LC-MS(M+H=391,obsd.=392);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.19(s,1H),6.82-6.84(d,2H),6.57-6.59(d,2H),3.09-3.29(m,1H),3.07-3.09(m,4H),2.93-2.97(m,3H),2.93-2.99(m,3H),1.87-1.91(m,2H),1.24-1.59(m,2H)。
2-(1-(6,7-二氢-5H-环戊烷并[b]吡啶-4-基)哌啶-4-基)-2-(4-(三氟甲基)苯基)乙胺(“A3”)
4-氯-6,7-二氢-5H-环戊烷并嘧啶(50.0mg;0.32mmol;1.0eq.)、2-(哌嗪-1-基)-2-(4-(三氟甲基)苯基)乙胺三盐酸盐(148.52mg;0.39mmol;1.20eq.)和碳酸钾(268.19mg;1.94mmol;6.0eq.)在1.5mlDMF中的反应混合物在120℃下搅拌过夜。粗产物经制备型HPLC提纯,得到标题化合物(50mg,21%得率);LC-MS(M+H=390,obsd.=391);
1HNMR(400MHz,DMSO-d6)δ[ppm]:8.63(s,1H),7.94-8.01(d,3H),7.75-7.77(d,2H),7.50-7.52(d,2H),4.04-4.08(m,4H),3.69-3.71(m,1H),3.03-3.07(m,3H),2.90-2.91(m,2H),2.63-2.64(m,2H),2.31-2.33(m,2H),2.01-2.03(m,2H)。
{2-(4-氯苯基)-2-[4-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌嗪-1-基]-乙基}-二甲胺(“A4”)
步骤1:4-氯-7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪
4-氨基-6-氯-嘧啶-5-醇(500.0mg;3.44mmol;1.0eq.)、碳酸铯(2238mg;6.87mmol;2.0eq.)和1,2-二溴-乙烷(645.3mg;3.44mmol;1.0eq.)在10ml丙酮中的反应混合物在65℃搅拌14小时。向反应溶液加入50mL乙酸乙酯,先后用水和盐水洗涤,干燥。移除溶剂后得到残留物,该残留物用醚处理,搅拌30分钟,过滤,得到4-氯-7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪,为黄色固体(227mg,38.5%得率)。LC-MS(M+H=172,obsd.=172/174)。
步骤2:{2-(4-氯苯基)-2-[4-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌嗪-1-基]-乙基}-二甲胺
[2-(4-氯-苯基)-2-哌嗪-1-基-乙基]-二甲胺(300.0mg;1.03mmol;1.00eq.)、4-氯-7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪(196.49mg;1.13mmol;1.10eq.)和碳酸钾(363.37mg;2.58mmol;2.50eq.)在DMSO(3.00ml)中的混合物于190℃微波辐射3小时。反应混合物冷却至室温,用水(20mL)稀释,DCM(3x20mL)萃取。有机层合并,用盐水溶液洗涤,Na2SO4干燥,真空浓缩。得到褐色粗残留物,该残留物经Biotage柱提纯,洗脱液为DCM/甲醇,得到褐色胶状物。该胶状固体在二乙醚(3mL)中研磨,过滤,在抽吸下干燥,得到标题化合物,为褐色固体(36.00mg,8.2%得率)。LC-MS(M+H=403,obsd.=403);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.63(s,1H),7.37-7.35(m,2H),7.29-7.26(m,2H),6.98(bs,1H),3.99(t,J=4.2Hz,2H),3.67(bs,1H),3.44(bs,4H),3.33(bs,2H),2.75(bs,1H),2.37(bs,4H),2.10(bs,6H)。
[2-[4-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌嗪-1-基]-2-(4-三氟甲基苯基)-乙基]-二 甲胺(“A5”)
采用[2-(4-三氟甲基苯基)-2-哌嗪-1-基-乙基]-二甲胺为起始材料,依据A4的制备方法合成标题化合物。LC-MS(M+H=437,obsd.=437);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.67(d,J=7.4Hz,2H),7.63(s,1H),7.49(d,J=8.1Hz,2H),6.98(bs,1H),3.99(t,J=4.2Hz,2H),3.76(bs,1H),3.43-3.42(m,4H),3.32(bs,2H),2.81(bs,1H),2.59(bs,1H),2.39(bs,4H),2.10(bs,6H)。
[2-[4-(6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-2-(4-三氟甲基苯基)-乙基]-二甲 胺(“A6”)
二甲基-[2-哌嗪-1-基-2-(4-三氟甲基-苯基)-乙基]-胺(300.00mg;0.96mmol;1.00eq.)、4-氯-6,7-二氢-5H-吡咯并[2,3-d]嘧啶(156.52mg;0.96mmol;1.00eq.)和碳酸钾(336.95mg;2.39mmol;2.50eq.)在干DMSO(3.00ml)中的混合物于190℃辐射3小时。反应混合物冷却至室温,用水(25mL)稀释,DCM(3x20mL)萃取。有机层合并,用盐水溶液洗涤,Na2SO4干燥,真空浓缩。得到褐色粗残留物,该残留物经Biotage柱提纯,洗脱液为DCM/甲醇,得到褐色胶状物。该胶状固体与二乙醚(2x10ml)共沸,得到泡沫状固体。该固体再用二乙醚/乙烷混合物(1:1,5ml)处理。用注射器洗涤以除去溶剂部分,剩下的固体在真空下进一步干燥,得到标题化合物,为褐色固体(34.00mg,8.2%得率)。LC-MS(M+H=421,obsd.=421);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.80(s,1H),7.67(d,J=7.7Hz,2H),7.50(d,J=8.1Hz,2H),6.56(bs,1H),3.76(s,1H),3.50-3.48(m,4H),3.37(bs,2H),3.01(t,J=8.6Hz,2H),2.79(bs,2H),2.50-2.49(m,1H),2.39(bs,4H),2.10(bs,6H)。
{2-(4-氯苯基)-2-[4-(6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙基}-二甲胺(“A7”)
采用[2-(4-氯苯基)-2-哌嗪-1-基-乙基]-二甲胺为起始材料,依据A6的制备方法合成标题化合物。LC-MS(M+H=387,obsd.=387);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.80(s,1H),7.35(d,J=8.4Hz,2H),7.28(d,J=8.5Hz,2H),6.56(bs,1H),3.66-3.63(m,1H),3.51-3.43(m,4H),3.37-3.36(m,2H),3.01(t,J=8.7Hz,2H),2.73-2.66(m,1H),2.60-2.57(m,1H),2.40-2.32(m,4H),2.09(s,6H)。
{2-(4-氯苯基)-2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙基}-二甲胺(“A8”)
[2-(4-氯-苯基)-2-哌嗪-1-基-乙基]-二甲胺(300.00mg;1.03mmol;1.00eq.)、4-氯-5,6,7,8-四氢-吡啶并[2,3-d]嘧啶(184.01mg;1.03mmol;1.00eq.)和碳酸钾(363.37mg;2.58mmol;2.50eq.)在干DMSO(3.00ml;10.00V)中的混合物于190℃辐射3小时。反应混合物冷却至室温,用水(25mL)稀释,DCM(3x20mL)萃取。有机层合并,用水、盐水溶液洗涤,Na2SO4干燥,真空浓缩。得到的残留物经Biotage柱提纯,洗脱液为DCM/甲醇,得到褐色胶状物。该胶状物与二乙醚(2x10ml)共沸,得到泡沫状固体。该固体再用二乙醚/乙烷混合物(1:1,5ml)处理,过滤,抽吸下干燥,得到标题化合物,为浅褐色固体(66.00mg,15.6%得率)。LC-MS(M+H=401,obsd.=401);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.87(s,1H),7.37(d,J=8.2Hz,2H),7.29(d,J=8.5Hz,2H),6.86(bs,1H),3.68(bs,1H),3.17-3.15(m,2H),3.10(bs,4H),2.76(bs,1H),2.37(bs,4H),2.36-2.32(m,2H),2.11(bs,6H),1.62-1.59(m,2H)。
二甲基-[2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-2-(4-三氟甲基-苯基)-乙 基]-胺(“A9”)
采用[2-(4-三氟甲基苯基)-2-哌嗪-1-基-乙基]-二甲胺为起始材料,依据A8的制备方法合成标题化合物。LC-MS(M+H=435,obsd.=435);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.87(s,1H),7.68(d,J=8.1Hz,2H),7.51(d,J=8.0Hz,2H),6.87(s,1H),3.79-3.75(m,1H),3.16-3.15(m,2H),3.10(bs,4H),2.84-2.78(m,1H),2.50-2.49(m,1H),2.37-2.34(m,6H),2.11(s,6H),1.60(bs,2H)。
2-[4-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌嗪-1-基]-2-(4-三氟甲基苯基)-乙胺(“A10”)
2-哌嗪-1-基-2-(4-三氟甲基苯基)-乙胺二盐酸盐(500mg;1.1mmol;1.0eq.)、4-氯-7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪(200mg;1.1mmol;1.0eq.)和碳酸钾(804mg;5.7mmol;5.0eq.)在干DMSO(5.00ml)中的混合物于100℃加热3天。反应混合物冷却至室温,用水(100mL)稀释,DCM(2x100mL)萃取。有机层合并,用水(50mL)、盐水溶液洗涤,Na2SO4干燥,真空浓缩。得到的残留物经Biotage柱提纯,洗脱液为DCM的甲醇溶液;得到的产物再经制备型HPLC提纯,得到标题化合物,为黄色固体(14.0mg;2.9%得率)。LC-MS(M+H=409,obsd.=409);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.69(d,J=8.1Hz,2H),7.64(s,1H),7.47(d,J=8.0Hz,2H),7.00(s,1H),3.99(t,J=4.2Hz,2H),3.98-3.43(m,7H),3.07-3.02(m,1H),2.84-2.79(m,1H),2.37-2.32(m,4H),1.55(brs,1H)。
2-(4-氯苯基)-2-[4-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌嗪-1-基]-乙胺(“A11”)
采用2-(4-氯苯基)-2-哌嗪-1-基-乙胺二盐酸盐为起始材料,依据A10的制备方法合成标题化合物。LC-MS(M+H=375,obsd.=375);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.63(s,1H),7.38(d,J=8.4Hz,2H),7.26(d,J=8.4Hz,2H),6.99(brs,1H),3.99(t,J=4.3Hz,2H),3.49-3.48(m,1H),3.47-3.45(m,4H),3.40-3.38(m,2H),3.06-3.01(m,1H),2.77-2.72(m,1H),2.39-2.30(m,5H)。
[2-[4-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌嗪-1-基]-2-(3-氟-4-三氟甲基苯基)-乙 基]-二甲胺(“A12”)
采用[2-(3-氟-4-三氟甲基-苯基)-2-哌嗪-1-基-乙基]-二甲胺为起始材料,依据A4的制备方法合成标题化合物。LC-MS(M+H=455,obsd.=455);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.77(d,J=6.2Hz,1H),7.74(s,1H),7.46(d,J=12.0Hz,1H),7.32(d,J=8.0Hz,1H),7.00(s,1H),3.99(t,J=4.2Hz,3H),3.47(s,4H),3.00(brs,2H),2.45-2.44(m,4H),2.37(brs,6H)。
2-(4-氯-苯基)-2-[4-(6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙胺(“A13”)
采用2-(4-氯苯基)-2-哌嗪-1-基-乙胺二盐酸盐和4-氯-6,7-二氢-5H-吡咯并[2,3-d]嘧啶为起始材料,依据A10的制备方法合成标题化合物。LC-MS(M+H=359,obsd.=359);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.80(s,1H),7.38(d,J=8.4Hz,2H),7.26(d,J=8.4Hz,2H),6.57(brs,1H),3.51-3.49(m,5H),3.49-3.48(m,1H),3.04-2.99(m,3H),2.78-2.73(m,1H),2.37-2.32(m,5H),1.69(brs,2H)。
2-[4-(6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-2-(4-氟苯基)-乙胺(“A14”)
采用2-(4-氟苯基)-2-哌嗪-1-基-乙胺二盐酸盐为起始材料,依据A13的制备方法合成标题化合物。LC-MS(M+H=343,obsd.=343)。
{2-(4-氯-3-氟-苯基)-2-[4-(6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙基}-二甲胺(“A15”)
采用[2-(4-氯-3-氟-苯基)-2-哌嗪-1-基-乙基]-二甲胺为起始材料,依据A13的制备方法合成标题化合物。LC-MS(M+H=405,obsd.=405);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.80(s,1H),7.51(t,J=8.00Hz,1H),7.34(dd,J=1.72,10.68Hz,1H),7.14(dd,J=1.68,8.26Hz,1H),6.57(s,1H),3.73(s,1H),3.48(dd,J=4.16,Hz,4H),3.39-3.40(m,2H),3.02(t,J=8.88Hz,2H),2.74-2.78(m,1H),2.50-2.55(m,1H),2.37(s,4H),2.11(s,6H)。
2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-2-(4-三氟甲基-苯基)-乙胺(“A16”)
采用4-氯-5,6,7,8-四氢-吡啶并[2,3-d]嘧啶为起始材料,依据A10的制备方法合成标题化合物。LC-MS(M+H=407,obsd.=407);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.88(s,1H),7.70(d,J=8.1Hz,2H),7.49(d,J=7.9Hz,2H),6.88(s,1H),3.48(t,J=6.5Hz,2H),3.17-3.13(m,6H),3.13-3.03(m,1H),2.84-2.79(m,2H),2.41-2.32(m,5H),1.62-1.61(m,3H)。
2-(4-氯-苯基)-2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙胺(“A17”)
采用2-(4-氯苯基)-2-哌嗪-1-基-乙胺二盐酸盐为起始材料,依据A16的制备方法合成标题化合物。LC-MS(M+H=373,obsd.=373);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.87(s,1H),7.39(d,J=8.4Hz,2H),7.27(d,J=8.4Hz,2H),6.87(brs,1H),3.40-3.37(m,1H),3.17-3.15(m,2H),3.15-3.12(m,4H),3.05-3.00(m,1H),2.41-2.35(m,6H),1.62-1.59(m,4H)。
{2-(4-氯-3-氟-苯基)-2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙基}-二甲胺(“A18”)
采用[2-(4-氯-3-氟-苯基)-2-哌嗪-1-基-乙基]-二甲胺为起始材料,依据A16的制备方法合成标题化合物。LC-MS(M+H=419,obsd.=419)。
{2-(3-氟-4-三氟甲基-苯基)-2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙基}- 二甲胺(“A19”)
采用[2-(3-氟-4-三氟甲基-苯基)-2-哌嗪-1-基-乙基]-二甲胺为起始材料,依据A16的制备方法合成标题化合物。LC-MS(M+H=453,obsd.=453);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.87(s,1H),7.73(t,J=7.8Hz,1H),7.46(d,J=12.1Hz,1H),7.34(d,J=8.2Hz,1H),6.87(s,1H),3.82(s,1H),3.17-3.11(m,6H),2.86(t,J=9.8Hz,1H),2.38-2.35(m,6H),2.11(s,6H),1.61(t,J=4.68Hz,2H)。
[2-[4-(6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-2-(3-氟-4-三氟甲基-苯基)-乙基]- 二甲胺(“A20”)
采用[2-(3-氟-4-三氟甲基-苯基)-2-哌嗪-1-基-乙基]-二甲胺为起始材料,依据A6的制备方法合成标题化合物。LC-MS(M+H=439,obsd.=439);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.80(s,1H),7.71(t,J=7.9Hz,1H),7.45(d,J=12.0Hz,1H),7.33(d,J=8.1Hz,1H),6.58(s,1H),3.82-3.79(m,1H),3.49(t,J=3.8Hz,4H),3.37-3.33(m,2H),3.04-3.00(m,2H),2.86-2.81(m,1H),2.50-2.48(m,1H),2.40-2.38(m,4H),2.10(s,6H)。
2-(4-氟-苯基)-2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙胺(“A21”)
采用2-(4-氟苯基)-2-哌嗪-1-基-乙胺二盐酸盐为起始材料,依据A16的制备方法合成标题化合物。LC-MS(M+H=357,obsd.=357)。
2-[1-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌啶-4-基]-2-(4-三氟甲基-苯基)-乙胺(“A22”)
采用2-哌啶-4-基-2-(4-三氟甲基-苯基)-乙胺三盐酸盐为起始材料,依据A16的制备方法合成标题化合物。LC-MS(M+H=406,obsd.=406);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.99(s,1H),7.66(s,2H),7.42-7.40(d,J=8.0Hz,2H),6.82(s,1H),3.65-3.61(d,J=12.6Hz,1H),3.51-3.33(m,1H),3.18(s,2H),2.99-2.84(m,1H),2.82-2.50(m,1H),2.40-2.37(m,4H),1.89-1.86(d,J=12.28Hz,2H),1.79-1.77(d,J=8.48Hz,2H),1.63-1.61(d,J=10.48Hz,2H),1.33-1.22(m,3H),1.05-1.02(m,1H)。
2-[1-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌啶-4-基]-2-(4-三氟甲基-苯基)-乙胺(“A23”)
采用2-哌啶-4-基-2-(4-三氟甲基-苯基)-乙胺三盐酸盐为起始材料,依据A10的制备方法合成标题化合物。LC-MS(M+H=408,obsd.=408);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.66-7.63(m,1H),7.41-7.39(d,J=8.1Hz,2H),6.9(s,1H),4.29-4.27(d,1H),4.17-4.14(d,1H),4.00-3.98(m,2H),2.98-2.88(m,1H),2.85-2.82(m,1H),2.71-2.66(m,3H),1.88-1.81(m,2H),1.23-1.23(m,3H),1.01-0.93(m,1H),0.87-0.85(m,1H)。
按照通用合成流程III合成通式(I)的实施例化合物
4-{4-[2-二甲基氨基-1-(4-氟-苯基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A24”)
步骤1:(6-氯-5-硝基-嘧啶-4-基氨基)-乙酸乙酯
向在干DMF(26mL)中的氨基-乙酸乙酯盐酸盐(1439.15mg;10.31mmol;1.00eq.)和4,6-二氯-5-硝基-嘧啶(2000.00mg;10.31mmol;1.00eq.)加入乙基-二异丙胺(3997.72mg;30.93mmol;3.00eq.),混合物搅拌3小时。LC-MS显示反应完成。移除DMF,加入乙酸乙酯。混合物用盐水洗涤,MgSO4干燥,经快速硅胶色谱法提纯(洗脱液为乙酸乙酯的己烷溶液,0%至30%),得到(6-氯-5-硝基-嘧啶-4-基氨基)-乙酸乙酯2.1g,78%得率;LC/MS:261(M+H)。
步骤2:4-[6-(乙氧基羰基甲基-氨基)-5-硝基-嘧啶-4-基]-哌嗪-1-羧酸叔丁酯
哌嗪-1-羧酸叔丁酯(800.00mg;4.30mmol;1.00eq.)、(6-氯-5-硝基-嘧啶-4-基氨基)-乙酸乙酯(1119.49mg;4.30mmol;1.00eq.)和碳酸钾(1.78g;12.89mmol;3.00eq.)在无水DMF(5mL)中的混合物于60℃搅拌5小时。LC/MS显示反应完成。倒入水中后,沉淀出固体,过滤和干燥,得到1.4g固体,79%得率;LC-MS(M+1:411,obsd:411)。
步骤3:4-[5-氨基-6-(乙氧基羰基甲基-氨基)-嘧啶-4-基]-哌嗪-1-羧酸叔丁酯
4-[6-(乙氧基羰基甲基-氨基)-5-硝基-嘧啶-4-基]-哌嗪-1-羧酸叔丁酯(1400.00mg;3.41mmol;1.00eq.)和Pd/C(300mg)在甲醇(30mL)中的混合物在压力20psi下进行加氢反应2小时。过滤后,移除溶剂,粗产物用于下一个反应中(1.0g,77%得率);LC-MS(M+1:381,obsd:381)。
步骤4:4-哌嗪-1-基-7,8-二氢-5H-蝶啶-6-酮盐酸盐
4-[5-氨基-6-(乙氧基羰基甲基-氨基)-嘧啶-4-基]-哌嗪-1-羧酸叔丁酯(700.00mg;1.84mmol;1.00eq.)在乙醇(20mL)中的溶液回流15小时。浓缩后,得到粗产物,用于下一个反应中。
将上述粗产物悬于10mLHCl的二噁烷溶液(4.0M),搅拌1小时。LC/MS显示反应完成。移除溶剂,加入醚,过滤出固体,干燥;得到400mg固体,80%得率;LC-MS(M+1:235,obsd:235)。
步骤5:4-{4-[2-二甲基氨基-1-(4-氟-苯基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮
使在密封小瓶中的[2-氯-2-(4-氟-苯基)-乙基]-二甲胺盐酸盐(50.00mg;0.21mmol;1.00eq.)、4-哌嗪-1-基-7,8-二氢-5H-蝶啶-6-酮盐酸盐(56.84mg;0.21mmol;1.00eq.)和乙基-二异丙胺(0.19ml;1.05mmol;5.00eq.)在ACN(5mL)中的混合物于70℃搅拌过夜。得到的产物经反相HPLC提纯。得到18mg产物,21%得率;LC-MS(M+1:400,obsd:400);
1HNMR(400MHz,DMSO-d6)δ[ppm]:2.26(6H),2.63(1H),2.84(1H),2.88(1H),3.95(2H),4.14(1H),7.19(2H),7.27(2H),8.14(1H)。
4-{4-[2-二甲基氨基-1-(3-氟-苯基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A25”)
采用2-氯-2-(3-氟-苯基)-乙基]-二甲胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=400,obsd.=400);
1HNMR(400MHz,DMSO-d6)δ[ppm]:2.27(6H),2.65(1H),2.86(1H),2.87(1H),3.98(2H),4.16(1H),6.83(1H),7.06(2H),7.38(1H),8.14(1H)。
4-{4-[2-二甲基氨基-1-(4-氯-苯基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A26”)
采用2-氯-2-(4-氯-苯基)-乙基]-二甲胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=400,obsd.=400);
1HNMR(400MHz,DMSO-d6)δ[ppm]:2.24(6H),2.61(1H),2.82(1H),2.89(1H),3.95(2H),4.14(1H),7.44(2H),7.48(2H),8.14(1H)。
4-{4-[2-二甲基氨基-1-(3-氯-苯基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A27”)
采用2-氯-2-(3-氯-苯基)-乙基]-二甲胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=400,obsd.=400);
1HNMR(400MHz,DMSO-d6)δ[ppm]:2.27(6H),2.65(1H),2.86(1H),2.87(1H),3.98(2H),4.16(1H),7.17(1H),7.31-7.34(2H),7.49(1H),8.14(1H)。
4-{4-[2-二甲基氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A28”)
采用2-氯-2-(4-三氟甲基-苯基)-乙基]-二甲胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=450,obsd.=450);
1HNMR(400MHz,DMSO-d6)δ[ppm]:2.26(6H),2.63(1H),2.84(1H),2.88(1H),3.95(2H),4.14(1H),7.22(2H),7.57(2H),8.14(1H)。
4-{4-[1-(4-氟-苯基)-2-(吡咯烷-基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A29”)
采用2-氯-2-(4-氟-苯基)-乙基]-吡咯烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=426,obsd.=426);
1HNMR(400MHz,DMSO-d6)δ[ppm]:1.68(4H),2.26(4H),2.63(1H),2.86(1H),2.89(1H),3.98(2H),4.16(1H),7.19(2H),7.28(2H),8.14(1H)。
4-{4-[1-(4-氯-苯基)-2-(吡咯烷-基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A30”)
采用2-氯-2-(4-氯-苯基)-乙基]-吡咯烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=442,obsd.=442);
1HNMR(400MHz,DMSO-d6)δ[ppm]:1.67(4H),2.26(4H),2.65(1H),2.80(1H),2.84(1H),3.98(2H),4.17(1H),7.44(2H),7.48(2H),8.14(1H)。
4-{4-[1-(4-氟-苯基)-2-(哌啶-基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A31”)
采用2-氯-2-(4-氟-苯基)-乙基]-哌啶盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=440,obsd.=440);
1HNMR(400MHz,DMSO-d6)δ[ppm]:1.53(4H),1.59(2H),2.46(4H),2.63(1H),2.86(1H),2.89(1H),3.98(2H),4.16(1H),7.19(2H),7.28(2H),8.14(1H)。
4-{4-[1-(4-氯-苯基)-2-(哌啶-基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A32”)
采用2-氯-2-(4-氯-苯基)-乙基]-哌啶盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=457,obsd.=457);
1HNMR(400MHz,DMSO-d6)δ[ppm]:1.52(4H),1.60(2H),2.47(4H),2.62(1H),2.86(1H),2.89(1H),3.98(2H),4.16(1H),7.44(2H),7.48(2H),8.14(1H)。
4-{4-[1-(4-三氟-苯基)-2-(哌啶-基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A33”)
采用2-氯-2-(4-三氟-苯基)-乙基]-哌啶盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=490,obsd.=490);
1HNMR(400MHz,DMSO-d6)δ[ppm]:1.50(4H),1.57(2H),2.43(4H),2.65(1H),2.85(1H),2.90(1H),3.98(2H),4.16(1H),7.26(2H),7.59(2H),8.14(1H)。
4-{4-[2-吡咯烷-1-基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A34”)
采用2-氯-2-(4-三氟甲基-苯基)-乙基]-吡咯烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=476,obsd.=476);
1HNMR(400MHz,DMSO-d6)δ[ppm]:1.68(4H),2.28(4H),2.66(1H),2.81(1H),2.86(1H),3.98(2H),4.17(1H),7.29(2H),7.63(2H),8.14(1H)。
4-(4-(1-(2-氟苯基)-2-(吡咯烷-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A35”)
采用2-氯-2-(2-氯苯基)-乙基]-吡咯烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=426,obsd.=426);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.72(s,1H),7.38(d,J=7.4Hz,1H),7.28(d,J=20.9Hz,1H),7.14(t,J=6.5Hz,1H),7.05(t,J=10.8Hz,1H),3.94(s,3H),3.13-3.02(m,5H),2.89-2.85(m,1H),2.56-2.54(m,4H),2.40-2.37(m,4H),2.29-2.28(m,4H)。
4-(4-(2-(二甲基氨基)-1-(2-氟苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A36”)
采用2-氯-2-(2-氟苯基)-N,N-二甲基乙胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=400,obsd.=400);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.63(s,1H),7.81(s,1H),7.36(t,J=7.0Hz,2H),7.28(s,1H),7.23(d,J=7.1Hz,2H),3.79(s,5H),3.33(s,1H),3.19(s,6H),2.66(s,1H),2.59(s,2H),2.49(t,J=1.60Hz,2H),2.32(s,2H)。
4-(4-(2-(氮杂环丁烷-1-基)-1-(2-氟苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A37”)
采用1-(2-氯-2-(2-氟苯基)-乙基)-氮杂环丁烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=412,obsd.=412);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.57(s,1H),7.83(s,1H),7.44-7.40(m,1H),7.26(dd,J=11.5,16.2Hz,2H),7.17-7.09(m,2H),3.79(t,J=1.2Hz,3H),3.12-3.02(m,8H),2.50-2.48(m,5H),2.35-2.31(m,1H),1.90(t,J=6.8Hz,2H)
4-(4-(1-(2-氟苯基)-2-(哌啶-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A38”)
采用1-(2-氯-2-(2-氟苯基)-乙基)-哌啶盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=440,obsd.=440);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.61(s,1H),7.81(s,1H),7.37(t,J=6.7Hz,1H),7.28(d,J=8.1Hz,2H),7.15(dd,J=7.1,17.1Hz,2H),4.04(t,J=7.0Hz,1H),3.78(s,2H),3.16(s,4H),2.66(s,3H),2.49(s,3H),2.30(t,J=10.68Hz,2H),1.31(s,8H)。
4-(4-(2-氨基-1-(2-氯苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A39”)
采用2-氯-2-(2-氯苯基)-乙胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=388,obsd.=388);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.62(s,1H),7.86(s,1H),7.75(dd,J=1.5,7.7Hz,1H),7.38-7.30(m,3H),7.26-7.22(m,1H),4.50(dd,J=3.5,9.5Hz,1H),3.82(s,2H),3.25(s,5H),2.69-2.66(m,1H),2.50-2.48(m,1H),2.32(d,J=3.60Hz,1H),2.25(t,J=9.80Hz,2H)。
4-(4-(1-(2-氯苯基)-2-(二甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A40”)
采用2-氯-2-(2-氯苯基)-N,N-二甲基乙胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=416,obsd.=416);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.62(s,1H),7.82(s,1H),7.46(d,J=0.0Hz,2H),7.35(s,1H),7.31(t,J=7.4Hz,2H),4.22(s,1H),3.79(s,2H),3.15(s,4H),2.59(s,2H),2.49(s,4H),2.12(s,6H)。.
4-(4-(1-(2-氯苯基)-2-(甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A41”)
采用2-氯-2-(2-氯苯基)-N-甲基乙胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。TLC-MS:(M+1=402,obsd.=402);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.63(s,1H),8.17(s,1H),7.86(s,1H),7.66(s,1H),7.64(t,J=6.2Hz,1H),7.42-7.31(m,1H),7.29-7.25(m,2H),4.20(dd,J=4.4,9.0Hz,1H),3.82(s,2H),3.29-3.24(m,4H),3.19(d,J=0.00Hz,2H),2.50-2.49(m,2H),2.38-2.31(m,2H),2.19(s,3H)。
4-(4-(2-(氮杂环丁烷-1-基)-1-(2-氯苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A42”)
采用1-(2-氯-2-(2-氯苯基)-乙基)-氮杂环丁烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=428,obsd.=428);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.77(s,1H),7.93(s,1H),7.66-7.59(m,2H),7.49-7.45(m,3H),5.15(d,J=5.6Hz,1H),4.18(d,J=8.1Hz,2H),4.04(t,J=7.7Hz,2H),3.87(s,2H),3.28(s,4H),2.89(s,1H),2.77(s,2H),2.50-2.48(m,3H),2.36-2.30(m,2H)。
4-(4-(1-(2-氯苯基)-2-(吡咯烷-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A43”)
采用1-(2-氯-2-(2-氯苯基)-乙基)-吡咯烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=442,obsd.=442);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.62(s,1H),7.82(s,1H),7.47-7.41(m,2H),7.33(t,J=6.4Hz,1H),7.26(t,J=7.6Hz,2H),4.21(d,J=7.0Hz,1H),3.79(s,2H),3.15(s,4H),2.93(t,J=12.0Hz,1H),2.79(s,1H),2.66-2.60(m,2H),2.50-2.49(m,8H),1.59(s,4H)。
4-(4-(1-(2-氯苯基)-2-(哌啶-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A44”)
采用1-(2-氯-2-(2-氯苯基)-乙基)-哌啶盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=456,obsd.=456);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.62(s,1H),7.82(s,1H),7.47-7.40(m,1H),7.32(t,J=7.0Hz,1H),7.27(d,J=11.9Hz,3H),4.18(s,1H),3.79(s,2H),3.15(s,4H),2.71(s,1H),2.67-2.61(m,4H),2.32(t,J=1.80Hz,4H),1.43-0.00(m,7H)。
4-(4-(2-(二甲基氨基)-1-(邻甲苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A45”)
采用2-氯-N,N-二甲基-2-(邻甲苯基)-乙胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=396,obsd.=396);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.58(s,1H),7.82(s,1H),7.28(s,2H),7.15(s,3H),3.80(d,J=1.2Hz,4H),3.15(s,5H),2.66(t,J=1.8Hz,4H),2.36(s,3H),2.12(s,6H)。
4-(4-(2-(吡咯烷-1-基)-1-(邻甲苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A46”)
采用1-(2-氯-2-(邻甲苯基)乙基)-吡咯烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=422,obsd.=422);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.58(s,1H),7.82(s,1H),7.29(d,J=12.6Hz,2H),7.12(d,J=14.5Hz,3H),3.80(s,5H),3.15(s,4H),2.95(s,1H),2.66(s,3H),2.49(t,J=1.7Hz,4H),2.41(s,3H),1.61(s,4H)。
4-(4-(2-(哌啶-1-基)-1-(邻甲苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A47”)
采用1-(2-氯-2-(邻甲苯基)乙基)-哌啶盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=436,obsd.=436);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.59(s,1H),7.82(s,1H),7.30(d,J=10.9Hz,2H),7.14-7.10(m,4H),3.80(s,3H),3.33(s,4H),3.14(s,5H),2.51-2.48(m,3H),2.34(s,4H),1.41(s,4H),1.32(s,2H)。
4-(4-(2-氨基)-1-(3,4-二氟苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A48”)
采用2-氯-2-(3,4-二氟苯基)-乙胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=390,obsd.=390);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.60(s,1H),7.85(s,1H),7.47-7.42(m,1H),7.37-7.33(m,2H),7.26(d,J=31.5Hz,1H),4.09-4.05(m,1H),3.82(s,2H),3.22(s,6H),2.50-2.48(m,6H)。
4-(4-(1-(3,4-二氟苯基)-2-(二甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A49”)
采用2-氯-2-(3,4-二氟苯基)-N,N-二甲基-乙胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=418,obsd.=418);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.59(s,1H),7.81(s,1H),7.39-7.32(m,2H),7.27(s,1H),7.12(s,1H),3.79(s,2H),3.74-3.70(m,2H),3.14(d,J=3.6Hz,4H),2.85-2.80(m,1H),2.50-2.45(m,4H),2.10(s,6H)。
4-(4-(1-(3,4-二氟苯基)-2-(甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A50”)
采用2-氯-2-(3,4-二氟苯基)-N-甲基-乙胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=404,obsd.=404);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.61(s,1H),8.28(s,1H),7.85(s,1H),7.40-7.30(m,3H),7.19(s,1H),3.82(s,2H),3.68-3.65(m,1H),3.23(s,4H),2.66(t,J=1.8Hz,2H),2.50(s,3H),2.26-2.22(m,1H),2.14(s,3H)。
4-(4-(2-(氮杂环丁烷-1-基)-1-(3,4-二氟苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮
(“A51”)
采用1-(2-氯-2-(3,4-二氟苯基)-乙基)-氮杂环丁烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=430,obsd.=430);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.97(s,1H),7.40-7.31(m,2H),7.25(s,1H),4.06(s,4H),3.54(s,1H),3.45-3.23(m,8H),3.09-3.07(m,1H),3.00(s,1H),2.34(s,6H)。
4-(4-(1-(3,4-二氟苯基)-2-(吡咯烷-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A52”)
采用1-(2-氯-2-(3,4-二氟苯基)-乙基)-吡咯烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=444,obsd.=444);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.74(s,1H),7.25-7.11(m,3H),3.99(s,2H),3.66(s,1H),3.11-3.02(m,4H),2.89(d,J=6.9Hz,2H),2.62-2.55(m,4H),2.38(d,J=7.0Hz,4H),1.63(d,J=3.5Hz,4H)。
4-(4-(1-(3,4-二氟苯基)-2-(哌啶-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A53”)
采用1-(2-氯-2-(3,4-二氟苯基)-乙基)-哌啶盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=458,obsd.=458);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.60(s,1H),7.82(s,1H),7.37(t,J=7.9Hz,2H),7.28(s,1H),7.13(s,1H),3.79(s,3H),3.15(s,4H),2.65-2.64(m,3H),2.40(s,2H),2.29(s,3H),1.32(s,8H)。
4-(4-(1-(3-氯-4-氟苯基)-2-(二甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A54”)
采用2-氯-2-(3-氯-4-氟苯基)-N,N-二甲基-乙胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=432,obsd.=432);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.60(s,1H),7.81(s,1H),7.51-7.49(m,1H),7.38-7.30(m,1H),7.29(t,J=2.0Hz,2H),3.77(t,J=11.7Hz,4H),3.15(d,J=3.3Hz,5H),2.86(t,J=12.0Hz,1H),2.50-2.45(m,3H),2.12(s,6H)。
4-(4-(2-(氮杂环丁烷-1-基)-1-(3-氯-4-氟苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮
(“A55”)
采用1-(2-氯-2-(3-氯-4-氟苯基)-乙基)-氮杂环丁烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=446,obsd.=446);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.71(s,1H),7.90(s,1H),7.73(d,J=5.9Hz,1H),7.59-7.51(m,5H),4.81(s,1H),4.09-4.02(m,4H),3.86(s,2H),3.04(s,4H),2.75(s,2H),2.50-2.48(m,2H),2.32-2.26(m,2H)。
4-(4-(1-(3-氯-4-氟苯基)-2-(吡咯烷-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A56”)
采用1-(2-氯-2-(3-氯-4-氟苯基)-乙基)-吡咯烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=460,obsd.=460);
1HNMR(400MHz,DMSO-d6)δ[ppm]:8.12(s,1H),7.48-7.45(m,1H),7.31-7.22(m,2H),3.99(s,2H),3.83(s,1H),3.04(q,J=6.9Hz,1H),2.65-2.57(m,8H),1.81(s,4H),1.41(s,1H)。
4-(4-(1-(3-氯-4-氟苯基)-2-(吡咯烷-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A57”)
采用1-(2-氯-2-(3-氯-4-氟苯基)-乙基)-哌啶盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=474,obsd.=474);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.59(s,1H),7.81(s,1H),7.50(dd,J=1.5,7.3Hz,1H),7.38-7.27(m,3H),3.76(t,J=11.1Hz,3H),3.15(s,4H),2.72(d,J=8.5Hz,1H),2.66(s,1H),2.50-2.48(m,5H),2.40(s,2H),1.36-1.32(m,6H),1.23(s,1H)。
4-(4-(1-(4-氯-3-氟苯基)-2-(二甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A58”)
采用2-氯-2-(4-氯-3-氟苯基)-N,N-二甲基-乙胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=432,obsd.=432);
1HNMR(400MHz,DMSO-d6)δ[ppm]:9.60(s,1H),7.82(s,1H),7.53(d,J=6.8Hz,1H),7.37(d,J=10.3Hz,2H),7.15(d,J=7.2Hz,1H),3.79(s,3H),3.15(s,4H),2.68(s,1H),2.49(s,1H),2.22(s,4H),2.08(s,6H)。
4-(4-(1-(4-氯-3-氟苯基)-2-(甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A59”)
采用2-氯-2-(4-氯-3-氟苯基)-N-甲基-乙胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=420,obsd.=420);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.91(d,J=3.1Hz,1H),7.72(d,J=8.1Hz,1H),7.69-7.61(m,1H),7.42-7.40(m,1H),4.63(s,1H),3.88(s,2H),3.70(s,1H),3.36(s,4H),3.23(s,1H),2.93(s,3H),2.50-2.49(m,2H),2.41(s,3H)。
4-(4-(2-(氮杂环丁烷-1-基)-1-(4-氯-3-氟苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮
(“A60”)
采用1-(2-氯-2-(4-氯-3-氟苯基)-乙基)-氮杂环丁烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=446,obsd.=446);
1HNMR(400MHz,DMSO-d6)δ[ppm]:8.28(s,2H),7.80(s,1H),7.49(t,J=8.1Hz,1H),7.30(dd,J=1.7,10.5Hz,1H),7.17(dd,J=1.4,8.3Hz,1H),3.80(d,J=9.9Hz,2H),3.60(t,J=6.2Hz,1H),3.22(d,J=6.9Hz,2H),3.19-3.07(m,6H),2.49(t,J=1.8Hz,3H),2.41-2.29(m,3H),1.97(s,2H)。
4-(4-(1-(4-氯-3-氟苯基)-2-(吡咯烷-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A61”)
采用1-(2-氯-2-(4-氯-3-氟苯基)-乙基)-吡咯烷盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=460,obsd.=460);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.70(s,1H),7.44(t,J=8.0Hz,1H),7.12(dd,J=1.8,10.1Hz,1H),7.01(t,J=8.2Hz,1H),4.00-3.99(m,3H),3.80(t,J=12.6Hz,1H),3.38(dd,J=6.4,13.0Hz,1H),3.29(s,4H),3.22(s,4H),2.56-2.40(m,4H),1.93(s,4H)。
4-(4-(1-(4-氯-3-氟苯基)-2-(哌啶-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A62”)
采用1-(2-氯-2-(4-氯-3-氟苯基)-乙基)-哌啶盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=474,obsd.=474);
1HNMR(400MHz,DMSO-d6)δ[ppm]:7.79(s,1H),7.49(t,J=8.0Hz,1H),7.30(dd,J=1.4,10.7Hz,1H),7.13(d,J=8.2Hz,1H),3.79(s,3H),3.15(s,4H),2.50-2.49(m,7H),2.44(s,2H),1.32(d,J=21.6Hz,6H)。
4-(4-(2((2-(二甲基氨基)乙基)氨基)-1-(4-(三氟甲基)苯基)-乙基)哌嗪-1-基)-7,8-二氢蝶啶-
6(5H)-酮(“A63”)
采用N1-(2-氯-2-(4-(三氟甲基)苯基)乙基)-N2,N2-二甲基乙烷-1,2-二胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=493,obsd.=493);
1HNMR(400MHz,DMSO-d6)δ[ppm]:δ8.33(s,1H),7.77(s,1H),7.64(d,J=8.1Hz,2H),7.46(d,J=8.0Hz,2H),4.00-3.94(m,4H),3.16(s,5H),2.98-2.89(m,5H),2.74-2.51(m,11H)。
4-(4-(2-((2-(二甲基氨基)乙基)氨基)-1-(3-(三氟甲基)苯基)-乙基)哌嗪-1-基)-7,8-二氢蝶啶-
6(5H)-酮(“A64”)
采用N1-(2-氯-2-(3-(三氟甲基)苯基)乙基)-N2,N2-二甲基乙烷-1,2-二胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=493,obsd.=493);
1HNMR(400MHz,DMSO-d6)δ[ppm]:δ9.63(s,1H),8.19(s,1H),7.86(s,1H),7.73-7.61(m,2H),7.59-7.53(m,2H),7.31(s,1H),3.94-3.90(m,1H),3.83(s,2H),3.23(s,4H),2.67-2.63(m,2H),2.54-2.41(m,6H),2.39-2.28(m,8H)。
4-(4-(2-((2-(二甲基氨基)乙基)氨基)-1-(对甲苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮
(“A65”)
采用N1-(2-氯-2-(对甲苯基)苯基)-乙基)-N2,N2-二甲基乙烷-1,2-二胺盐酸盐为起始材料,依据A24的制备方法合成标题化合物。LC-MS:(M+1=439,obsd.=439);
1HNMR(400MHz,DMSO-d6)δ[ppm]:δ9.62(s,1H),8.14(s,1H),7.86(s,1H),7.29(t,J=8.4Hz,3H),7.15(d,J=7.9Hz,2H),3.90(s,1H),3.83(s,2H),3.16(s,5H),2.72(s,4H),2.50-2.48(m,3H),2.29(d,J=6.56Hz,11H)。
生物活性
参照以下有关p70S6K和AKT酶试验的方案获得实施例部分的化合物的IC50值。
P70S6K酶试验
将P70S6K抑制剂化合物稀释,并铺于96孔板中。将包含以下组分的反应混合液加入该化合物板中以开始酶反应;将P70S6K(3nM,T412E突变体,Millipore)与24μMATP在试验缓冲液中混合,所述缓冲液包含100mMHepes(pH7.5)、5mMMgCl2、1mMDTT、0.015%Brij和1μM底物肽FITC-AHA-AKRRRLSSLRA-OH(源自S6核糖体蛋白质序列,FITC=异硫氰酸荧光素,AHA=6-氨基己酸)。将该反应物在25℃孵育90分钟,之后加入10mMEDTA以停止该反应。在CaliperLifeSciencesLabChip3000分析底物和产物(磷酸化的)肽的比例,压力为-1.4psi,下游电压和下游电压分别为-3000和-700。在获得色谱图上,解析出产物峰在底物峰之前。
表1列出了实施例部分中选定的化合物在P70S6K酶抑制试验中获得的值,这些值是本发明描述的选定化合物的功能数据。
AKT酶试验
采用TTPMosquito液体处理仪器,在384孔板的每个孔内放置125nl在100%DMSO中适当浓度的抑制剂(用于绘制剂量反应曲线)。向该反应加入各组分至终浓度为12.5μl:
0.1ng/μlHis-AKT(全长),(Invitrogen,Part#P2999,Lot#641228C)
160uMATP(Fluka,02055)
1mMDTT(Sigma,D0632)
1mMMgCl2(Sigma,M1028)
1μM底物肽(序列FITC-AHA-GRPRTSSFAEG-NH2),由TuftsPeptideSynthesisservice合成
100mMHEPESpH7.5(Calbiochem,391338)
0.015%Brij-35(Sigma,B4184)
反应在25℃培育90分钟,然后加入70μl终止缓冲液(100mMHEPESpH7.5,0.015%Brij-35,10mMEDTA(Sigma,E7889))终止反应。
用CaliperLC3000读取孔板,读取格式为芯片外迁移率试验格式(Off-Chipmobilityshiftassayformat),采用具有12个吸入针的芯片,参数如下:筛选压力–2.3psi,上游电压–500,下游电压–3000。这些条件使得未磷酸化底物和磷酸化产物以不同峰分辨出来,因此可以直接测量底物转化为产物的百分比。将转化百分比与抑制剂浓度绘制成曲线,得到S形剂量应答曲线,基于该S形曲线可以计算IC50值。
表1列出了实施例部分中选定的化合物在P70S6K和AKT酶抑制试验中获得的值。
表中的数据的含义如下:
+++++:<25nM;
++++:25-100nM;
+++:101nM–500nM;
++:501nM–1000nM;
+:>1M。
表1:通式(I)所示的化合物对p70S6K和AKT酶的抑制
以下实施例涉及药物:
实施例A:注射液瓶
将100g通式I所示的化合物作为活性成分与5g磷酸二氢钠在3L再蒸馏水中的溶液用2N盐酸调它的pH至6.5,无菌过滤,转移到注射瓶中,无菌条件下冻干,并在无菌条件下密封。每个注射液瓶含有5mg活性成分。
实施例B:栓剂
将20g通式I所示的化合物作为活性成分与100g大豆卵磷脂和1400g可可油混合,倒入模中,冷却。每片栓剂含20mg活性成分。
实施例C:溶液制剂
由1g作为活性成分的通式I所示的化合物、9.38gNaH2PO4·2H2O、28.48gNa2HPO4·12H2O和0.1g苯扎氯铵在940mL再蒸馏水中制成一种溶液。将该溶液的pH调至6.8,再将该溶液配至1L,放射灭菌。该溶液以眼药水形式使用。
实施例D:软膏
在无菌条件下将500mg通式I所示的化合物作为活性成分与99.5g凡士林混合。
实施例E:片剂
将1kg通式I所示的化合物作为活性成分、4kg乳糖、1.2kg马铃薯粉、0.2kg滑石和0.1kg硬脂酸镁按照常规方法压成片剂,以致于每片含10mg活性成分。
实施例F:包衣片剂
类似实施例E压成片剂,然后按照常规方法用蔗糖包衣、马铃薯粉、滑石、黄芪胶和染料来包衣片剂。
实施例G:胶囊剂
将2kg通式I所示的化合物作为活性成分按照常规方法导入硬胶囊中,以致于每个胶囊含20mg活性成分。
实施例H:安瓿剂
将1kg通式I所示的化合物作为活性成分在60L再蒸馏水中的溶液无菌过滤,转移到安瓿中,无菌条件下冻干,并在无菌条件下密封。每个安瓿含有10mg活性成分。
Claims (10)
1.如以下通式(I)所示的化合物及其可药用盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以所有比例混合的混合物,
X1是N或者CH,
X2是CH2或者NH,
X3是CH2或者CO,
X4是O、CH2或者NH,
W是N或者CH,
R1是Ar或者Het,
R2是[C(R3)2]pHet1或者[C(R3)2]pN(R3)2,
R3是H或者是任选地被取代的具有1、2、3或4个碳原子的烷基,
Ar是苯基,所述苯基未被取代或被Hal、A、苯基、CON(R3)2、COOR3、NHCOA、NHSO2A、CHO、COA、SO2N(R3)2、SO2A、[C(R3)2]pOR3、[C(R3)2]p-N(R3)2和/或[C(R3)2]p-CN单取代、二取代或三取代,
Het是呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噁二唑基、噻唑基、三唑基、四唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吲哚基、异吲哚基、苯并咪唑基、吲唑基或者喹啉基,所述基团未被取代或被Hal、A、[C(R3)2]pOR3、[C(R3)2]pN(R3)2、NO2、CN、[C(R3)2]pCOOR3、CON(R3)2、NR3COA、NR3SO2A、SO2N(R3)2、S(O)mA和/或O[C(R3)2]qN(R3)2单取代、二取代或三取代,
Het1是二氢吡咯基、吡咯烷基、氮杂环丁烷基、氧杂环丁烷基、四氢咪唑基、二氢吡唑基、四氢吡唑基、四氢呋喃基、二氢吡啶基、四氢吡啶基、哌啶基、氮杂环庚烷基、吗啉基、六氢哒嗪基、六氢嘧啶基、[1,3]二氧杂环戊烷基、四氢吡喃基、吡啶基或者哌嗪基,所述基团未被取代或被A单取代或二取代,
A是具有1-10个碳原子的无支链的或有支链的烷基,其中1个或2个非相邻的CH-和/或CH2-基团可以被N-、O-和/或S-原子所替代,且其中1-7个H原子可以被F或者Cl所替代,
Hal是F、Cl、Br或者I,
每个m独立地是0、1或者2,
每个n独立地是0、1或者2,
每个p独立地是0、1、2、3或者4,
每个q独立地是2、3或者4。
2.如权利要求1所述的化合物及其可药用盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以所有比例混合的混合物,其中:
X1是N或者CH,
X2是CH2或者NH,
X3是CH2或者CO,
X4是CH2或者NH,
W是N或者CH,
R1是Ar;
R2是[C(R3)2]pHet1或者[C(R3)2]pN(R3)2,
R3是H或者甲基,
Ar是苯基,所述苯基未被取代或被Hal和/或A单取代或二取代,
Het1是吡咯烷基、氮杂环丁烷基或者哌啶基,
A是具有1-10个碳原子的无支链的或有支链的烷基,其中1个或2个非相邻的CH-和/或CH2-基团可以被N-和/或O-原子所替代,且其中1-7个H原子可以被F、Cl或者Cyc所替代,
Cyc是具有3-7个碳原子的环状烷基,
Hal是F、Cl、Br或者I,
每个n独立地是0或者1,
每个p独立地是0、1、2、3或者4。
3.如权利要求1所述的化合物及其可药用盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以所有比例混合的混合物,其中所述化合物选自以下组内:
2-(1-(5,6,7,8-四氢-1,8-萘啶-4-基)哌啶-4-基)-2-(4-(三氟甲基)苯基)乙胺(“A1”)
2-(1-(2,3-二氢-1H-吡咯并[2,3-b]吡啶-4-基)哌啶-4-基)-2-(4-(三氟-甲基)苯基)乙胺(“A2”)
2-(1-(6,7-二氢-5H-环戊烷并[b]吡啶-4-基)哌啶-4-基)-2-(4-(三氟甲基)苯基)乙胺(“A3”)
{2-(4-氯苯基)-2-[4-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌嗪-1-基]-乙基}-二甲胺(“A4”)
[2-[4-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌嗪-1-基]-2-(4-三氟甲基苯基)-乙基]-二甲胺(“A5”)
[2-[4-(6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-2-(4-三氟甲基苯基)-乙基]-二甲胺(“A6”)
{2-(4-氯苯基)-2-[4-(6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙基}-二甲胺(“A7”)
{2-(4-氯苯基)-2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙基}-二甲胺(“A8”)
二甲基-[2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-2-(4-三氟甲基-苯基)-乙基]-胺(“A9”)
2-[4-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌嗪-1-基]-2-(4-三氟甲基苯基)-乙胺(“A10”)
2-(4-氯苯基)-2-[4-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌嗪-1-基]-乙胺(“A11”)
[2-[4-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌嗪-1-基]-2-(3-氟-4-三氟甲基苯基)-乙基]-二甲胺(“A12”)
2-(4-氯-苯基)-2-[4-(6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙胺(“A13”)
2-[4-(6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-2-(4-氟苯基)-乙胺(“A14”)
{2-(4-氯-3-氟-苯基)-2-[4-(6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙基}-二甲胺(“A15”)
2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-2-(4-三氟甲基-苯基)-乙胺(“A16”)
2-(4-氯-苯基)-2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙胺(“A17”)
{2-(4-氯-3-氟-苯基)-2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙基}-二甲胺(“A18”)
{2-(3-氟-4-三氟甲基-苯基)-2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙基}-二甲胺(“A19”)
2-(4-氟苯基)-2-[4-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌嗪-1-基]-乙胺(“A20”)
[2-[4-(6,7-二氢-5H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-2-(3-氟-4-三氟甲基-苯基)-乙基]-二甲胺(“A21”)
2-(4-氟-苯基)-2-[4-(5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-4-基)-哌嗪-1-基]-乙胺(“A22”)
2-[1-(7,8-二氢-6H-嘧啶并[5,4-b][1,4]噁嗪-4-基)-哌啶-4-基]-2-(4-三氟甲基-苯基)-乙胺(“A23”)
4-{4-[2-二甲基氨基-1-(4-氟-苯基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A24”)
4-{4-[2-二甲基氨基-1-(3-氟-苯基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A25”)
4-{4-[2-二甲基氨基-1-(4-氯-苯基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A26”)
4-{4-[2-二甲基氨基-1-(3-氯-苯基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A27”)
4-{4-[2-二甲基氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A28”)
4-{4-[1-(4-氟-苯基)-2-(吡咯烷-基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A29”)
4-{4-[1-(4-氯-苯基)-2-(吡咯烷-基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A30”)
4-{4-[1-(4-氟-苯基)-2-(哌啶-基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A31”)
4-{4-[1-(4-氯-苯基)-2-(哌啶-基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A32”)
4-{4-[1-(4-三氟-苯基)-2-(哌啶-基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A33”)
4-{4-[2-吡咯烷-1-基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-7,8-二氢-5H-蝶啶-6-酮(“A34”)
4-(4-(1-(2-氟苯基)-2-(吡咯烷-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A35”)
4-(4-(2-(二甲基氨基)-1-(2-氟苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A36”)
4-(4-(2-(氮杂环丁烷-1-基)-1-(2-氟苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A37”)
4-(4-(1-(2-氟苯基)-2-(哌啶-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A38”)
4-(4-(2-氨基-1-(2-氯苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A39”)
4-(4-(1-(2-氯苯基)-2-(二甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A40”)
4-(4-(1-(2-氯苯基)-2-(甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A41”)
4-(4-(2-(氮杂环丁烷-1-基)-1-(2-氯苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A42”)
4-(4-(1-(2-氯苯基)-2-(吡咯烷-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A43”)
4-(4-(1-(2-氯苯基)-2-(哌啶-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A44”)
4-(4-(2-(二甲基氨基)-1-(邻甲苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A45”)
4-(4-(2-(吡咯烷-1-基)-1-(邻甲苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A46”)
4-(4-(2-(哌啶-1-基)-1-(邻甲苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A47”)
4-(4-(2-氨基)-1-(3,4-二氟苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A48”)
4-(4-(1-(3,4-二氟苯基)-2-(二甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A49”)
4-(4-(1-(3,4-二氟苯基)-2-(甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A50”)
4-(4-(2-(氮杂环丁烷-1-基)-1-(3,4-二氟苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A51”)
4-(4-(1-(3,4-二氟苯基)-2-(吡咯烷-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A52”)
4-(4-(1-(3,4-二氟苯基)-2-(哌啶-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A53”)
4-(4-(1-(3-氯-4-氟苯基)-2-(二甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A54”)
4-(4-(2-(氮杂环丁烷-1-基)-1-(3-氯-4-氟苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A55”)
4-(4-(1-(3-氯-4-氟苯基)-2-(吡咯烷-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A56”)
4-(4-(1-(3-氯-4-氟苯基)-2-(吡咯烷-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A57”)
4-(4-(1-(4-氯-3-氟苯基)-2-(二甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A58”)
4-(4-(1-(4-氯-3-氟苯基)-2-(甲基氨基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A59”)
4-(4-(2-(氮杂环丁烷-1-基)-1-(4-氯-3-氟苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A60”)
4-(4-(1-(4-氯-3-氟苯基)-2-(吡咯烷-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A61”)
4-(4-(1-(4-氯-3-氟苯基)-2-(哌啶-1-基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A62”)
4-(4-(2((2-(二甲基氨基)乙基)氨基)-1-(4-(三氟甲基)苯基)-乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A63”)
4-(4-(2-((2-(二甲基氨基)乙基)氨基)-1-(3-(三氟甲基)苯基)-乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A64”)
4-(4-(2-((2-(二甲基氨基)乙基)氨基)-1-(对甲苯基)乙基)哌嗪-1-基)-7,8-二氢蝶啶-6(5H)-酮(“A65”)。
4.一种制备方法,用于制备通式(I)所示的化合物及其可药用盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以所有比例混合的混合物,所述方法的特征在于,
a)通式(II)所示的化合物,
式中、X1、X2、X3、X4和n具有权利要求1中指明的含义,
与通式(III)所示的化合物反应,
式中,W、R1和R2具有权利要求1中指明的含义,
或者
b)为制备通式(I)所示的化合物,式中X3是CO且X4是NH,
使通式(IV)所示的化合物进行环化反应,
式中,R1、R2、W、X1、X2和n具有权利要求1中指明的含义,并且A'是含有1、2、3、或4个碳原子的烷基。
和/或
将通式(I)化合物的碱或酸转换为它们的一种盐。
5.一种药物组合物,所述药物组合物包含至少一种通式(I)所示的化合物和/或其可药用盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以所有比例混合的混合物,以及任选地包含可药用载体、赋形剂或媒介物。
6.通式(I)所示的化合物和/或其可药用盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以所有比例混合的混合物,其中,所述化合物用于治疗癌症。
7.通式(I)所示的化合物和/或其可药用盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以所有比例混合的混合物,其中,所述化合物用于治疗肿瘤,其中给予治疗有效量的通式(I)所示的化合物,并结合放射性治疗及联用以下化合物:第1)组:细胞毒性剂,及第2)组:抗增殖剂。
8.通式(I)所示的化合物和/或其可药用盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以所有比例混合的混合物,其中,所述化合物用于治疗癌症、败血性休克、原发性开角型青光眼(POAG)、增生、类风湿关节炎、牛皮癣,动脉粥样硬化、视网膜病、骨关节炎、子宫内膜异位症、慢性炎症和/或神经变性疾病。
9.通式(I)所示的化合物和/或其可药用盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以所有比例混合的混合物,其中,所述化合物用于治疗肿瘤,其中给予治疗有效量的通式(I)所示的化合物,并结合使用以下化合物:第1)组:雌激素受体调节剂,第2)组:雄激素受体调节剂,第3)组:类视黄醇受体调节剂,第4)组:细胞毒性剂,第5)组:抗增殖剂,第6)组:异戊二烯基–蛋白转移酶抑制剂,第7)组:HMG-CoA还原酶抑制剂,第8)组:HIV蛋白酶抑制剂,第9)组:逆转录酶抑制剂,以及第10)组:其它血管生成抑制剂。
10.一种药盒(套盒),该药盒包含下列独立包装:
a)有效量的通式(I)所示的化合物和/或其可药用盐、溶剂化物、盐的溶剂化物、互变异构体或立体异构体,包括它们以所有比例混合的混合物;以及
b)有效量的另外的药物活性成分。
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US9850255B2 (en) | 2017-12-26 |
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