CN102459224A - 5-炔基-吡啶 - Google Patents
5-炔基-吡啶 Download PDFInfo
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- CN102459224A CN102459224A CN2010800276562A CN201080027656A CN102459224A CN 102459224 A CN102459224 A CN 102459224A CN 2010800276562 A CN2010800276562 A CN 2010800276562A CN 201080027656 A CN201080027656 A CN 201080027656A CN 102459224 A CN102459224 A CN 102459224A
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- ethyl
- pyridine
- pyridin
- compound
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/73—Unsubstituted amino or imino radicals
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
本发明涉及通式(1)的化合物,其中,R1至R4、m和n如权利要求1所定义,所述化合物适于治疗特征在于过度或异常细胞增殖的疾病;以及所述化合物用于制备具有上述性质的药物中的用途。
Description
本发明涉及新的通式(1)的5-炔基-吡啶
其中基团R1至R4、m和n具有权利要求和说明书中给出的含义;涉及其异构体,涉及制备这些炔基-吡啶的方法以及它们作为药物的用途。
发明背景
很多蛋白激酶已被证实为用于治疗性干预各种适应症的合适的靶标分子,例如癌症、炎症以及自身免疫性疾病。由于很多编码激酶的基因参与了癌症的发展,因此这些酶也就成为了尤其用于癌症的治疗的引人注目的靶标分子。
磷脂酰肌醇-3-激酶(PI3-激酶)为脂激酶(lipid kinase)的亚家族,其催化磷酸基转移至磷酸肌醇中肌醇环的3’-位。
磷酸肌醇3-激酶(PI3K)途径在大量的人类癌症中被活化。其既可通过PI3K的突变造成激酶活化而发生,或间接地通过灭活磷酸酶与张力蛋白同系物(PTEN)抑制因子。两种情况下,信号级联均被诱导活化,促进了细胞在体内与体外的转化。在所述级联之中,酶的PI3K家族与mTOR激酶起着关键作用。PI3K家族包含15种脂激酶,具有独特的底物特异性、表达形式和调节模式。它们在很多细胞过程(例如细胞生长和分化过程、细胞骨架改变的控制和胞内运输过程的调节)中发挥重要作用。基于其体内对特定磷酸肌醇底物的特异性,PI3-激酶可分为不同的类型。哺乳动物中雷帕霉素的靶点(mTOR)为与PI3-激酶家族脂激酶相关的丝氨酸/苏氨酸激酶。其存在于两种复合物即mTORC1和mTORC2中(两者被调节的方式不同),具有不同的底物特异性,并且对雷帕霉素的敏感性不同。mTOR控制细胞生长和存活关键途径的核心作用激起了人们对于发现mTOR抑制剂的兴趣,所述mTOR抑制剂结合于ATP位点并且因此以mTORC2与mTORC1作为靶点。其结果是,抑制PI3K途径,尤其通过PI3Kα和mTOR调节,成为了癌症治疗的引人注目的靶点。在很多细胞过程(例如细胞生长和分化过程、细胞骨架改变的控制和胞内运输过程的调节)中发挥重要作用。基于其体内对特定磷酸肌醇底物的特异性,PI3-激酶可分为不同的类型。
5-炔基-嘧啶在专利WO2006044823中被公开为,例如,抑制蛋白激酶的化合物。
发明详述
目前惊奇地发现通式(1)的化合物(其中基团R1至R4、m和n具有下面给出的定义)具有激酶抑制剂的作用。因此,根据本发明的化合物可用于治疗例如与激酶活性相关的和特征在于过度或异常细胞增殖的疾病。
本发明涉及通式(1)的化合物
其中
R1和R4各自独立地表示选自Ra、Rb和被一个或多个相同或不同的Rb和/或Rc取代的Ra的基团;或
一个R1与吡啶一起形成9-10元杂芳环,其任选被一个或多个相同或不同的Rb和/或Rc取代;和
R2和R3各自独立地表示选自C1-6烷基、C3-8环烷基、3-8元杂环烷基、C6-10芳基和5-12元杂芳基的基团,其任选被一个或多个相同或不同的R5取代,和
每个R5表示选自Ra、Rb和被一个或多个相同或不同的Rb和/或Rc取代的Ra的基团;和
每个Ra各自独立地表示任选被一个或多个相同或不同的Rb和/或Rc取代的基团,所述基团选自C1-6烷基、2-6元杂烷基、C1-6卤代烷基、C3-10环烷基、C4-16环烷基烷基、C6-10芳基、C7-16芳基烷基、5-12元杂芳基、6-18元杂芳基烷基、3-14元杂环烷基和4-14元杂环烷基烷基,
每个Rb表示合适的基团,其各自独立地选自=O、-ORc、C1-3卤代烷基氧基、-OCF3、=S、-SRc、=NRc、=NORc、=NNRcRc、=NN(Rg)C(O)NRcRc、-NRcRc、-ONRcRc、-N(ORc)Rc、-N(Rg)NRcRc、卤素、-CF3、-CN、-NC、-OCN、-SCN、-NO、-NO2、=N2、-N3、-S(O)Rc、-S(O)ORc、-S(O)2Rc、-S(O)2ORc、-S(O)NRcRc、-S(O)2NRcRc、-OS(O)Rc、-OS(O)2Rc、-OS(O)2ORc、-OS(O)NRcRc、-OS(O)2NRcRc、-C(O)Rc、-C(O)ORc、-C(O)SRc、-C(O)NRcRc、-C(O)N(Rg)NRcRc、-C(O)N(Rg)ORc、-C(NRg)NRcRc、-C(NOH)Rc、-C(NOH)NRcRc、-OC(O)Rc、-OC(O)ORc、-OC(O)SRc、-OC(O)NRcRc、-OC(NRg)NRcRc、-SC(O)Rc、-SC(O)ORc、-SC(O)NRcRc、-SC(NRg)NRcRc、-N(Rg)C(O)Rc、-N[C(O)Rc]2、-N(ORg)C(O)Rc、-N(Rg)C(NRg)Rc、-N(Rg)N(Rg)C(O)Rc、-N[C(O)Rc]NRcRc、-N(Rg)C(S)Rc、-N(Rg)S(O)Rc、-N(Rg)S(O)ORc、-N(Rg)S(O)2Rc、-N[S(O)2Rc]2、-N(Rg)S(O)2ORc、-N(Rg)S(O)2NRcRc、-N(Rg)[S(O)2]2Rc、-N(Rg)C(O)ORc、-N(Rg)C(O)SRc、-N(Rg)C(O)NRcRc、-N(Rg)C(O)NRgNRcRc、-N(Rg)N(Rg)C(O)NRcRc、-N(Rg)C(S)NRcRc、-[N(Rg)C(O)]2Rc、-N(Rg)[C(O)]2Rc、-N{[C(O)]2Rc}2、-N(Rg)[C(O)]2ORc、-N(Rg)[C(O)]2NRcRc、-N{[C(O)]2ORc}2、-N{[C(O)]2NRcRc}2、-[N(Rg)C(O)]2ORc、-N(Rg)C(NRg)ORc、-N(Rg)C(NOH)Rc、-N(Rg)C(NRg)SRc、-N(Rg)C(NRg)NRcRc和-N=C(Rg)NRcRc,和
每个Rc各自独立地表示氢或任选被一个或多个相同或不同的Rd和/或Re取代的基团,所述基团选自C1-6烷基、2-6元杂烷基、C1-6卤代烷基、C3-10环烷基、C4-16环烷基烷基、C6-10芳基、C7-16芳基烷基、5-12元杂芳基、6-18元杂芳基烷基、3-14元杂环烷基和4-14元杂环烷基烷基,和
每个Rd表示合适的基团,其各自独立地选自=O、-ORe、C1-3卤代烷基氧基、-OCF3、=S、-SRe、=NRe、=NORe、=NNReRe、=NN(Rg)C(O)NReRe、-NReRe、-ONReRe、-N(Rg)NReRe、卤素、-CF3、-CN、-NC、-OCN、-SCN、-NO、-NO2、=N2、-N3、-S(O)Re、-S(O)ORe、-S(O)2Re、-S(O)2ORe、-S(O)NReRe、-S(O)2NReRe、-OS(O)Re、-OS(O)2Re、-OS(O)2ORe、-OS(O)NReRe、-OS(O)2NReRe、-C(O)Re、-C(O)ORe、-C(O)SRe、-C(O)NReRe、-C(O)N(Rg)NReRe、-C(O)N(Rg)ORe、-C(NRg)NReRe、-C(NOH)Re、-C(NOH)NReRe、-OC(O)Re、-OC(O)ORe、-OC(O)SRe、-OC(O)NReRe、-OC(NRg)NReRe、-SC(O)Re、-SC(O)ORe、-SC(O)NReRe、-SC(NRg)NReRe、-N(Rg)C(O)Re、-N[C(O)Re]2、-N(ORg)C(O)Re、-N(Rg)C(NRg)Re、-N(Rg)N(Rg)C(O)Re、-N[C(O)Re]NReRe、-N(Rg)C(S)Re、-N(Rg)S(O)Re、-N(Rg)S(O)ORe、-N(Rg)S(O)2Re、-N[S(O)2Re]2、-N(Rg)S(O)2ORe、-N(Rg)S(O)2NReRe、-N(Rg)[S(O)2]2Re、-N(Rg)C(O)ORe、-N(Rg)C(O)SRe、-N(Rg)C(O)NReRe、-N(Rg)C(O)NRgNReRe、-N(Rg)N(Rg)C(O)NReRe、-N(Rg)C(S)NReRe、-[N(Rg)C(O)]2Re、-N(Rg)[C(O)]2Re、-N{[C(O)]2Re}2、-N(Rg)[C(O)]2ORe、-N(Rg)[C(O)]2NReRe、-N{[C(O)]2ORe}2、-N{[C(O)]2NReRe}2、-[N(Rg)C(O)]2ORe、-N(Rg)C(NRg)ORe、-N(Rg)C(NOH)Re、-N(Rg)C(NRg)SRe、-N(Rg)C(NRg)NReRe和-N=C(Rg)NReRe,
每个Re各自独立地表示氢或任选被一个或多个相同或不同的Rf和/或Rg取代的基团,所述基团选自C1-6烷基、2-6元杂烷基、C1-6卤代烷基、C3-10环烷基、C4-16环烷基烷基、C6-10芳基、C7-16芳基烷基、5-12元杂芳基、6-18元杂芳基烷基、3-14元杂环烷基和4-14元杂环烷基烷基,和
每个Rf表示合适的基团,其在各种情况下各自独立地选自=O、-ORg、C1-3卤代烷基氧基、-OCF3、=S、-SRg、=NRg、=NORg、=NNRgRg、=NN(Rh)C(O)NRgRg、-NRgRg、-ONRgRg、-N(Rh)NRgRg、卤素、-CF3、-CN、-NC、-OCN、-SCN、-NO、-NO2、=N2、-N3、-S(O)Rg、-S(O)ORg、-S(O)2Rg、-S(O)2ORg、-S(O)NRgRg、-S(O)2NRgRg、-OS(O)Rg、-OS(O)2Rg、-OS(O)2ORg、-OS(O)NRgRg、-OS(O)2NRgRg、-C(O)Rg、-C(O)ORg、-C(O)SRg、-C(O)NRgRg、-C(O)N(Rh)NRgRg、-C(O)N(Rh)ORg、-C(NRh)NRgRg、-C(NOH)Rg、-C(NOH)NRgRg、-OC(O)Rg、-OC(O)ORg、-OC(O)SRg、-OC(O)NRgRg、-OC(NRh)NRgRg、-SC(O)Rg、-SC(O)ORg、-SC(O)NRgRg、-SC(NRh)NRgRg、-N(Rh)C(O)Rg、-N[C(O)Rg]2、-N(ORh)C(O)Rg、-N(Rh)C(NRh)Rg、-N(Rh)N(Rh)C(O)Rg、-N[C(O)Rg]NRgRg、-N(Rh)C(S)Rg、-N(Rh)S(O)Rg、-N(Rh)S(O)ORg、-N(Rh)S(O)2Rg、-N[S(O)2Rg]2、-N(Rh)S(O)2ORg、-N(Rh)S(O)2NRgRg、-N(Rh)[S(O)2]2Rg、-N(Rh)C(O)ORg、-N(Rh)C(O)SRg、-N(Rh)C(O)NRgRg、-N(Rh)C(O)NRhNRgRg、-N(Rh)N(Rh)C(O)NRgRg、-N(Rh)C(S)NRgRg、-[N(Rh)C(O)]2Rg、-N(Rh)[C(O)]2Rg、-N{[C(O)]2Rg}2、-N(Rh)[C(O)]2ORg、-N(Rh)[C(O)]2NRgRg、-N{[C(O)]2ORg}2、-N{[C(O)]2NRgRg}2、-[N(Rh)C(O)]2ORg、-N(Rh)C(NRh)ORg、-N(Rh)C(NOH)Rg、-N(Rh)C(NRh)SRg、-N(Rh)C(NRh)NRgRg;和-N=C(Rh)NRhRh;和
每个Rg各自独立地表示氢或任选被一个或多个相同或不同的Rh取代的基团,所述基团选自C1-6烷基、2-6元杂烷基、C1-6卤代烷基、C3-10环烷基、C4-16环烷基烷基、C6-10芳基、C7-16芳基烷基、5-12元杂芳基、6-18元杂芳基烷基、3-14元杂环烷基和4-14元杂环烷基烷基;和
每个Rh各自独立地选自氢、C1-6烷基、2-6元杂烷基、C1-6卤代烷基、C3-10环烷基、C4-16环烷基烷基、C6-10芳基、C7-16芳基烷基、5-12元杂芳基、6-18元杂芳基烷基、3-14元杂环烷基和4-14元杂环烷基烷基;和
m表示0、1或2;和
n表示0、1、2或3;和
任选以其前药、互变异构体、外消旋体、对映异构体、非对映异构体、前药及混合物的形式,以及任选为其药理学上可接受的盐。
本发明的一个方面涉及通式(1)的化合物,其中R3表示任选被一个或多个相同或不同的R5取代的C6-10芳基或5-12元杂芳基。
本发明的另一方面涉及通式(1)的化合物,其中R3表示任选被一个或多个相同或不同的R5取代的苯基。
本发明的另一方面涉及通式(1)的化合物,其中R3表示任选被一个或多个相同或不同的R5取代的吡啶基。
本发明的另一方面涉及通式(1)的化合物,其中R3表示任选被一个或多个相同或不同的R5取代的吡唑基。
本发明的另一方面涉及通式(1)的化合物,其中R2表示甲基或乙基。
本发明的另一方面涉及通式(1)的化合物,其中n表示1或2。
本发明的另一方面涉及通式(1)的化合物,其中R1表示甲基、乙基或-NRcRc。
本发明的另一方面涉及通式(1)的化合物,其中R1选自-NH2、-NH-CH3和-N(CH3)2。
本发明的另一方面涉及通式(1)的化合物,其中Ra选自氢、甲基、乙基和环丙基。
本发明的另一方面涉及通式(1)的化合物,其中Rb选自-F、-Cl、-CH3、-OCH3、-CF3、-C(O)-Rc、-C(O)NRcRc、-C(O)OH、-C(O)OCH3、-C(O)-NH2、-C(O)-NHCH3、-C(O)-N(CH3)2、-S(O)2CH3、-2-丙基-Rc。
本发明的另一方面涉及通式(1)的化合物,其中Rc选自-H、-CN、-甲基、-乙基、-(CH2)2-OCH3、哌嗪基、哌啶基、吡咯烷基和吗啉基。
本发明的另一方面涉及通式(1)的化合物,其中R3为被一个或多个R5取代的苯基,其中至少一个R5为-C(O)Rc且其中Rc为
本发明的另一方面涉及通式(1)的化合物,其中Rd选自-H、-甲基、-乙基、-丙基、-OH、-OCH3和-C(O)CH3。
本发明的另一方面涉及通式(1)的化合物,其中Re选自-环丙基、环戊基、环氧乙烷基(oxiranyl)、四氢吡喃基和吗啉基。
本发明的另一方面涉及通式(1)的化合物,其中R3选自下列基团:
本发明的一个方面涉及通式(1)的化合物或其药理学有效的盐,其作为药物。
本发明的一个方面涉及通式(1)的化合物或其药理学有效的盐,其用于制备具有抗增殖活性的药物。
本发明的一个方面是药物制剂,其包含作为活性物质的一个或多个通式(1)的化合物,或其药理学有效的盐,任选与常规的赋形剂和/或载体组合。
本发明的一个方面是通式(1)的化合物在制备用于治疗和/或预防癌症、感染、炎症和自身免疫性疾病的药物中的用途。
本发明的一个方面是药物制剂,其包含通式(1)化合物以及至少一种不同于式(1)的其他细胞抑制或细胞毒活性物质,任选以互变异构体、外消旋体、对映异构体、非对映异构体及其混合物的形式,以及任选其药学可接受的盐。
定义
如本文中所使用,除非另有说明,否则采用以下定义。
烷基取代基在各情况下是指饱和的、不饱和的、直链的或支链的脂肪烃基(烷基),其包括饱和烷基与不饱和烯基和炔基。烯基取代基在各情况下为具有至少一个双键的直链或支链的不饱和烷基。炔基取代基在各情况下为具有至少一个叁键的直链或支链的不饱和烷基。
术语杂烷基广义上指衍生自上文定义的烷基的基团,其通过基团-OH、-SH或-NH2彼此独立地替换烃链中一个或多个-CH3基团,用基团-O-、-S-或-NH--彼此独立地替换一个或多个-CH2-基团,
用基团=N-替换一个或多个=CH-基团,用基团=NH替换一个或多个=CH2基团或用≡N替换一个或多个≡CH基团而得到,同时一个杂烷基中总共仅可存在最多三个杂原子,在两个氧原子之间及两个硫原子之间或一个氧原子与一个硫原子之间必须至少存在一个碳原子,且该基团整体上必须具有化学稳定性。
由烷基间接定义/衍生而得到的杂烷基,是由具有杂原子的饱和烃链、杂烯基和杂炔基的子群组成,同时可进一步细分为直链(非支链)及支链。若假设杂烷基经取代,则该取代可彼此独立地在各情况下在所有带有氢的氧、硫、氮和/或碳原子上进行单取代或多取代。杂烷基自身可作为取代基同时经碳原子和杂原子键连至分子。
列出以下代表化合物作为实例:二甲基氨基甲基;二甲基氨基乙基(1-二甲基氨基乙基;2-二甲基-氨基乙基);二甲基氨基丙基(1-二甲基氨基丙基,2-二甲基氨基丙基,3-二甲基氨基丙基);二乙基氨基甲基;二乙基氨基乙基(1-二乙基氨基乙基,2-二乙基氨基乙基);二乙基氨基丙基(1-二乙基氨基丙基,2-二乙基氨基-丙基,3-二乙基氨基丙基);二异丙基氨基乙基(1-二异丙基氨基乙基,2-二-异丙基氨基乙基);双-2-甲氧基乙基氨基;[2-(二甲基氨基-乙基)-乙基-氨基]-甲基;3-[2-(二甲基氨基-乙基)-乙基-氨基]-丙基;羟基甲基;2-羟基-乙基;3-羟基丙基;甲氧基;乙氧基;丙氧基;甲氧基甲基;2-甲氧基乙基等等。
卤代烷基是指一个或多个氢原子被卤原子取代的烷基。卤代烷基包括饱和烷基与不饱和烯基和炔基,例如-CF3、-CHF2、-CH2F、-CF2CF3、-CHFCF3、-CH2CF3、-CF2CH3、-CHFCH3、-CF2CF2CF3、-CF2CH2CH3、-CF=CF2、-CCl=CH2、-CBr=CH2、-CI=CH2、-C≡C-CF3、-CHFCH2CH3和-CHFCH2CF3。
卤素是指氟、氯、溴和/或碘原子。
环烷基是指单环或双环,且该环状体系可为饱和环的或不饱和的非芳香环,其还可任选含有双键,如环丙基、环丙烯基、环丁基、环丁烯基、环戊基、环戊烯基、环己基、环己烯基、降冰片基和降冰片烯基。
环烷基烷基包括键连至碳原子(通常键连至末端C原子)的氢原子被环烷基取代的非环状烷基。
芳基是指具有6-10个碳原子的单环或双环芳香环,如苯基和萘基。
芳基烷基包括键连至碳原子(通常键连至末端C原子)的氢原子被芳基取代的非环状烷基。
杂芳基是指单环或双环芳香环,其含有一个或多个相同或不同的杂原子(如氮、硫或氧原子)代替一个或多个碳原子。实例包括呋喃基、噻吩基、吡咯基、唑基、噻唑基、异唑基、异噻唑基、吡唑基、咪唑基、三唑基、四唑基、二唑基、噻二唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基和三嗪基。双环杂芳基的实例为吲哚基、异吲哚基、苯并呋喃基、苯并噻吩基、苯并唑基、苯并噻唑基、苯并异唑基、苯并异噻唑基、苯并咪唑基、苯并吡唑基、吲唑基、异喹啉基、喹啉基、喹喔啉基、噌嗪基、酞嗪基、喹唑啉基和苯并三嗪基、吲嗪基、唑并吡啶基、咪唑并吡啶基、萘啶基、吲哚满基(indolinyl)、异色满基、色满基、四氢异喹啉基、异吲哚满基(isoindolinyl)、异苯并四氢呋喃基、异苯并四氢噻吩基、异苯并噻吩基、苯并唑基、吡啶并吡啶基、苯并四氢呋喃基、苯并四氢噻吩基、嘌呤基、苯并二氧杂环戊烯基(benzodioxolyl)、三嗪基、吩嗪基(phenoxazinyl)、吩噻嗪基、蝶啶基、苯并噻唑基、咪唑并吡啶基、咪唑并噻唑基、二氢苯并异嗪基、苯并异嗪基、苯并嗪基、二氢苯并异噻嗪基、苯并吡喃基、苯并噻喃基、香豆素基、异香豆素基、色酮基、色满酮基(Chromanonyl)、吡啶基-N-氧化物、四氢喹啉基、二氢喹啉基、二氢喹啉酮基、二氢异喹啉酮基、二氢香豆素基、二氢异香豆素基、异吲哚满酮基、苯并二烷基、苯并唑啉酮基、吡咯基-N-氧化物、嘧啶基-N-氧化物、哒嗪基-N-氧化物、吡嗪基-N-氧化物、喹啉基-N-氧化物、吲哚基-N-氧化物、吲哚满基-N-氧化物、异喹啉基-N-氧化物、喹唑啉基-N-氧化物、喹喔啉基-N-氧化物、酞嗪基-N-氧化物、咪唑基-N-氧化物、异唑基-N-氧化物、唑基-N-氧化物、噻唑基-N-氧化物、吲嗪基-N-氧化物、吲唑基-N-氧化物、苯并噻唑-N-氧化物、苯并咪唑基-N-氧化物、吡咯基-N-氧化物、二唑基-N-氧化物、噻二唑基-N-氧化物、三唑基-N-氧化物、四唑基-N-氧化物、苯并噻喃基-S-氧化物及苯并噻喃基-S,S-二氧化物。
杂芳基烷基包含键连至碳原子(通常键连至末端C原子)的氢原子被杂芳基取代的非环烷基。
杂环烷基是指包含3-12个碳原子的饱和的或不饱和的非芳香单环、双环或桥联的双环,其带有杂原子如氮、氧或硫代替一个或多个碳原子。该等杂环烷基的实例为四氢呋喃基、吡咯烷基、吡咯啉基、咪唑烷基、咪唑啉基、吡唑烷基、吡唑啉基、哌啶基、哌嗪基、吲哚满基、异吲哚满基、吗啉基、硫代吗啉基、高吗啉基、高哌啶基、高哌嗪基、高硫代吗啉基、硫代吗啉基-S-氧化物、硫代吗啉基-S,S-二氧化物、四氢吡喃基、四氢噻吩基、高硫代吗啉基-S,S-二氧化物、唑烷酮基(oxazolidinonyl)、二氢吡唑基、二氢吡咯基、二氢吡嗪基、二氢吡啶基、二氢嘧啶基、二氢呋喃基、二氢吡喃基、四氢噻吩基-S-氧化物、四氢噻吩基-S,S-二氧化物、高硫代吗啉基-S-氧化物、2-氧杂-5-氮杂双环[2.2.1]庚烷、8-氧杂-3-氮杂-双环[3.2.1]辛烷、3.8-二氮杂-双环[3.2.1]辛烷、2,5-二氮杂-双环[2.2.1]庚烷、3,8-二氮杂-双环[3.2.1]辛烷、3,9-二氮杂-双环[4.2.1]壬烷及2,6-二氮杂-双环[3.2.2]壬烷。
杂环烷基烷基是指键连至碳原子(通常键连至末端C原子)的氢原子被杂环烷基取代的非环状烷基。
以下实施例示例性地说明本发明而并非限制其范围。
通用方法1(GP1):Sonogashira反应
将卤化物(1.0当量)溶于DMF或THF并加入PdCl2(PPh3)2(0.1当量)和CuI(0.1当量)。随后,添加三乙胺(10.0当量),最后添加炔烃(1.5当量),并在55-65C搅拌该反应混合物。通过LC-MS监测该反应。若4小时后碘化物没有完全转化,则分小份额外添加炔烃。
通用方法2(GP2):炔烃的去硅烷基化
将TMS-炔烃(1.0当量)溶解于MeOH中,一次性添加K2CO3(0.5当量),并在室温搅拌反应混合物直至转化完全(3-16小时)。在真空中除去溶剂,将粗产物溶解于乙酸乙酯中,用水萃取有机相。用MgSO4干燥有机相、滤出且在真空中除去溶剂。粗产物不作进一步纯化直接使用或通过硅胶色谱使用DCM/MeOH或(环)己烷/乙酸乙酯纯化后使用。
通用方法3(GP3):Suzuki偶联
将4-氯吡啶(1.0当量)溶解于二烷中,添加硼酸(2.0当量)、K3PO4(1.2当量)、Pd2(dba)3(0.1当量)及二环己基(2′,4′,6′-三异丙基联苯-2-基)膦(Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphan,即2-二环己基磷-2′,4′,6′-三异丙基联苯)(“X-Phos”,0.3当量),反应混合物在回流搅拌3-16小时或在150℃在微波辐射下搅拌60-180分钟。若起始原料未完全转化,则额外地添加硼酸及Pd-催化剂并重新进行反应。
通用方法4(GP4):酯的皂化将酯溶解于THF或二烷中,添加1.0-2.0当量的1N NaOH,回流下加热混合物直至反应控制显示起始原料已完全转化。产物自反应混合物中沉淀(例如在酸化后)且不再经额外纯化步骤直接使用,或可通过色谱进一步纯化。
通用方法5(GP5):与胺形成酰胺
将0.21mmol起始原料、0.31mmol TBTU或HATU和0.42mmol的Huenig碱在2mL DMSO或THF或NMP中的混合物搅拌5分钟。添加0.31mmol胺且在室温将所得混合物搅拌过夜。由制备型RP-HPLC或通过硅胶色谱纯化,在蒸发溶剂之后,得到所需产物。
通用方法6(GP6):与酰氯形成酰胺
向0.13mmol起始原料及67μL的Huenig碱在2mL THF的混合物中添加0.26mmol酰氯。反应混合物在室温搅拌过夜。蒸发溶剂且将残余物溶解于1mL DMSO中,滤出不溶物,由制备型RP-HPLC或通过硅胶色谱纯化所得溶液,在蒸发溶剂之后,得到所需产物。
通用方法7(GP7):与异氰酸酯形成脲
向0.16mmol起始原料及64.4μL的Huenig碱在2mL THF的混合物中添加0.49mmol异氰酸酯。反应混合物在室温搅拌过夜。蒸发溶剂且将残余物溶于1mL DMSO中,滤出不溶物质,由制备型RP-HPLC或通过硅胶色谱纯化所得溶液,在蒸发溶剂之后,得到所需产物。
通用方法8(GP8):通过胺的预活化形成脲
将0.34mmol胺及0.34mmol N,N′-羰基二咪唑及0.34mmol 1,8-二氮杂双环[5.4.0]十一碳-7-烯的混合物在室温搅拌10分钟。一次性添加0.32mmol起始原料。反应混合物于微波中在100℃加热1小时。蒸发溶剂且将残余物溶于1mL DMSO中,滤出不溶物质,由制备型RP-HPLC或通过硅胶色谱纯化所得溶液,得到所需产物。
通用方法9(GP9):与碳酸形成酰胺
将0.62mmol碳酸、0.93mmol TBTU及1.2mmol的Huenig碱在2mLDMSO中的混合物搅拌5分钟。添加0.31mmol起始原料,在室温将所得混合物搅拌过夜。由制备型RP-HPLC或通过硅胶色谱进行纯化,在蒸发溶剂之后,得到所需产物。
中间体A
A-1)5-碘-3-三氟甲基-吡啶-2-基胺
根据通用方法1(GP1)合成标题化合物,起始于5.0g(31mmol)的3-三氟甲基-2-氨基吡啶和6.9g(31mmol)NIS。从反应混合物中沉淀后的产量:6.78g(76%)。
A-2)2-甲基-5-三甲基硅基乙炔基-吡啶
根据通用方法2(GP2)合成标题化合物,起始于2.0g(11.6mmol)的5-溴-2-甲基-吡啶和2.3mL(16.3mmol)的1-三甲基硅基-乙炔,使用18mL无水THF中的68mg(0.36mmol)CuI、305mg(1.2mmol)三苯基膦、213mg(0.30mmol)PdCl2(PPh3)2和18mL(127mmol)三乙胺。对于后处理,用乙酸乙酯稀释反应混合物,用水和盐水萃取有机相。通过硅胶色谱用己烷/乙酸乙酯梯度纯化产物。产量:1.5g(68%)。注:在40℃/40毫巴观察到产物升华。
A-3)5-三甲基硅基乙炔基-吡啶-2-基胺
根据通用方法2(GP2)合成标题化合物,起始于5.0g(28.9mmol)的5-溴-2-氨基-吡啶和5.7mL(40.5mmol)的1-三甲基硅基-乙炔,使用40mL无水THF中的168mg(0.88mmol)CuI、758mg(2.9mmol)三苯基膦、533mg(0.76mmol)PdCl2(PPh3)2和40mL(288mmol)三乙胺。对于后处理,用乙酸乙酯和少量的环己烷稀释反应混合物,用水和盐水萃取有机相。通过硅胶色谱用己烷/乙酸乙酯(10/1v/v)纯化产物。产量:5.0g(91%)。
A-4)甲基-(5-三甲基硅基乙炔基-吡啶-2-基)-胺
根据通用方法2(GP2)合成标题化合物,起始于4.3g(23.0mmol)的5-溴-2-甲基氨基-吡啶和4.5mL(32.2mmol)的1-三甲基硅基-乙炔,使用40mL无水THF中的134mg(0.71mmol)CuI、601mg(2.3mmol)三苯基膦、420mg(0.60mmol)PdCl2(PPh3)2和32mL(101mmol)三乙胺。对于后处理,用乙酸乙酯和少量的环己烷稀释反应混合物,用水和盐水萃取有机相。通过硅胶色谱用己烷/乙酸乙酯梯度纯化产物。产量:4.0g(85%)。注:在40℃/40毫巴观察到产物升华。
A-5)乙基-(5-三甲基硅基乙炔基-吡啶-2-基)-胺
根据通用方法2(GP2)合成标题化合物,起始于909mg(4.5mmol)的5-溴-2-乙基氨基-吡啶和0.89mL(6.3mmol)1-三甲基硅基-乙炔,使用7mL无水THF中的26mg(0.13mmol)CuI、118mg(0.45mmol)三苯基膦、82mg(0.12mmol)PdCl2(PPh3)2和6.3mL(45.0mmol)三乙胺。对于后处理,用乙酸乙酯和少量的环己烷稀释反应混合物,用水和盐水萃取有机相。通过硅胶色谱用己烷/乙酸乙酯梯度纯化产物。
产量:980mg(99%)。
A-6)5-三甲基硅基乙炔基-吡啶-3-醇
根据通用方法2(GP2)合成标题化合物,起始于2.0g(11.6mmol)的5-溴-3-羟基-吡啶和2.3mL(16.2mmol)1-三甲基硅基-乙炔,使用20mL无水THF中的66mg(0.3mmol)CuI、303mg(1.2mmol)三苯基膦、243mg(0.3mmol)PdCl2(PPh3)2和19mL(139mmol)三乙胺。对于后处理,用乙酸乙酯和少量的环己烷稀释反应混合物,用水和盐水萃取有机相。通过硅胶色谱用DCM/MeOH梯度纯化产物。产量:2.0g(91%)。
A-7)5-三甲基硅基乙炔基-吡啶-3-基胺
根据通用方法2(GP2)合成标题化合物,起始于2.0g(11.6mmol)的5-溴-3-氨基-吡啶和2.3mL(16.2mmol)1-三甲基硅基-乙炔,使用20mL无水THF中的66mg(0.3mmol)CuI、303mg(1.2mmol)三苯基膦、243mg(0.3mmol)PdCl2(PPh3)2和19mL(139mmol)三乙胺。对于后处理,用乙酸乙酯和少量的环己烷稀释反应混合物,用水和盐水萃取有机相。通过硅胶色谱用DCM/MeOH梯度纯化产物。产物沉淀于柱上,并且随后用纯MeOH从硅胶中提取。产量:2.0g(91%)。
A-8)5-三甲基硅基乙炔基-1H-吡唑并[3,4-b]吡啶
根据通用方法2(GP2)合成标题化合物,起始于1.0g(5.1mmol)的5-溴-1H-吡唑并[4,5-B]吡啶和1.0mL(7.1mmol)1-三甲基硅基-乙炔,使用8mL无水THF中的29mg(0.15mmol)CuI、133mg(0.51mmol)三苯基膦、106mg(0.15mmol)PdCl2(PPh3)2和8.4mL(60.6mmol)三乙胺。滤出形成的沉淀,并通过RP-HPLC用ACN/H2O梯度纯化产物。产量:542mg(50%)。
A-9)5-三甲基硅基乙炔基-1H-吡咯并[2,3-b]吡啶
根据通用方法2(GP2)合成标题化合物,起始于3.0g(15.2mmol)的5-溴-1H-吡咯并[2,3-B]吡啶和3.0mL(21.3mmol)的1-三甲基硅基-乙炔,使用25mL无水THF中的87mg(0.46mmol)CuI、400mg(1.5mmol)三苯基膦、312mg(0.46mmol)PdCl2(PPh3)2和25.4mL(182mmol)三乙胺。滤出形成的沉淀,并通过硅胶色谱用DCM/MeOH梯度纯化产物。产量:3.05g(94%)。
A-10)6-三甲基硅基乙炔基-3H-咪唑并[4,5-b]吡啶
根据通用方法2(GP2)合成标题化合物,起始于1.2g(6.1mmol)的5-溴-3H-咪唑并[4,5-B]吡啶和1.2mL(8.4mmol)的1-三甲基硅基-乙炔,使用10mL无水THF中的34mg(0.18mmol)CuI、159mg(0.61mmol)三苯基膦、128mg(0.18mmol)PdCl2(PPh3)2和10.1mL(72.7mmol)三乙胺。滤出形成的沉淀,通过RP-HPLC用ACN/H2O梯度纯化产物。产量:606mg(46%)。
A-11)5-乙炔基-2-甲基-吡啶
根据通用方法3(GP3)合成标题化合物,起始于13mL MeOH中的2.2g(11.6mmol)2-甲基-5-三甲基硅基乙炔基-吡啶(A4)和802mg(5.8mmol)K2CO3。通过硅胶色谱用环己烷/乙酸乙酯梯度纯化粗产物。由于在40℃/40毫巴观察到升华,将产物用1N HCl从有机相萃取并在冻干后作为盐酸盐而分离。产量:1.3g(73%)。
A-12)5-乙炔基-2-氨基-吡啶
根据通用方法3(GP3)合成标题化合物,起始于30mL MeOH中的5.5g(28.9mmol)的5-三甲基硅基乙炔基-吡啶-2-基胺(A5)和2.0mg(14.4mmol)K2CO3。产量:经硅胶色谱纯化之后为2.89mg(85%)。
A-13)(5-乙炔基-吡啶-2-基)-甲基-胺
根据通用方法3(GP3)合成标题化合物,起始于10mL MeOH中的1.5g(7.3mmol)甲基-(5-三甲基硅基乙炔基-吡啶-2-基)-胺(A6)和507mg(3.7mmol)K2CO3。产量:经硅胶色谱纯化之后为698mg(56%)。
A-14)(5-乙炔基-吡啶-2-基)-乙基-胺
根据通用方法3(GP3)合成标题化合物,起始于6mL MeOH中的980mg(4.5mmol)TMS-炔烃和310mg(2.3mmol)K2CO3。
产量:经硅胶色谱纯化之后为388mg(59%)。
A-15)5-乙炔基-吡啶-3-醇
根据通用方法3(GP3)合成标题化合物,起始于10mL MeOH中的2.0g(10.5mmol)TMS-炔烃和722mg(5.2mmol)K2CO3。产量:经硅胶色谱纯化之后为804mg(49%)。
A-16)5-乙炔基-吡啶-3-基胺
根据通用方法3(GP3)合成标题化合物,起始于10mL MeOH中的2.0g(10.5mmol)TMS-炔烃和722mg(5.2mmol)K2CO3。产量:经硅胶色谱纯化以及从二烷/HCl中沉淀之后为1.2g(74%)。
A-17)5-乙炔基-1H-吡唑并[3,4-b]吡啶
根据通用方法3(GP3)合成标题化合物,起始于6mL MeOH中的542mg(2.5mmol)TMS-炔烃和174mg(1.3mmol)K2CO3。
产量:经萃取后为330mg(92%)。
A-18)5-乙炔基-1H-吡咯并[2,3-b]吡啶
根据通用方法3(GP3)合成标题化合物,起始于15mL MeOH中的3.05g(14.2mmol)TMS-炔烃和983mg(7.1mmol)K2CO3。产量:经硅胶色谱纯化之后为1.23g(61%)。
A-19)6-乙炔基-3H-咪唑并[4,5-b]吡啶
根据通用方法3(GP3)合成标题化合物,起始于6mL MeOH中的706mg(3.3mmol)TMS-炔烃和227mg(1.6mmol)K2CO3。产量:经萃取后为491mg(94%)。
A-20)3-碘-2-甲基-吡啶-4-醇
向10g(91.6mmol)2-甲基-吡啶-4-醇在100mL水中的溶液一次性加入20.6g(91.6mmol)NIS。在室温搅拌该反应混合物,直到通过LC-MS的反应控制显示起始原料完全转化。将沉淀滤出,用水洗涤并干燥。所分离的固体包含所需产物与双碘化的起始原料(推测为4-羟基-3,5-二碘-2-甲基-吡啶)的混合物,不需进一步纯化而用于下一步骤。产量:17.6g。
A-21)4-氯-3-碘-2-甲基-吡啶
惰性气氛下将碘化反应所得的粗产物溶于300mL乙腈。加入82g(898mmol)POCl3在50mL乙腈中的溶液以及催化量的P2O5,然后将反应混合物回流下加热2小时。LC-MS显示起始原料完全转化。冷却至室温后该混合物在真空下浓缩至体积约为50mL。滤出形成的沉淀并丢弃。通过加入KOH将溶液的pH调节至约1。再一次将沉淀滤出并丢弃。加入额外的KOH至pH约为7。将从反应混合物沉淀的产物滤出,用水洗涤并在40℃真空干燥。产量:8.1g(43%,经2步)。
A-22)2-乙基-吡啶-1-氧化物
向500g(4.7mol)2-乙基吡啶在2.0L乙酸中的溶液加入H2O2(1586.0g,13.900mol)。然后将该混合物加热至80℃过夜。冷却至室温后,该混合物倾倒入碎冰中,并用DCM(8×1.0L)萃取。合并DCM层,用饱和Na2SO3溶液洗涤,无水Na2SO4干燥。在真空除去溶剂得到标题化合物。
产量:573.8g(100%)。
A-23)2-乙基-4-硝基-吡啶-1-氧化物
在0℃将浓硫酸(1826.0g,18.660mol)和发烟硝酸(1174.0g,18.640mol)混合。然后经1小时将573.8g(4.7mol)2-乙基-吡啶-1-氧化物加入该混合物。所得混合物在80℃加热3小时。冷却至室温后,将该混合物缓慢倾倒入碎冰中,伴随剧烈搅拌。用DCM(6×1.0L)萃取水层,合并的层经无水Na2SO4干燥。在真空除去溶剂得到标题化合物。产量:700.0g(89%)。
A-24)2-乙基-吡啶-4-基胺
将388.0g(2.3mol)2-乙基-4-硝基-吡啶-1-氧化物在3.0L EtOH和1.0L饱和NH4Cl溶液(1.0L)中的溶液与647.5g(11.6mol)铁粉共同搅拌。将该混合物回流3小时。用滤出铁粉,并在真空从滤液除去溶剂得到粗品油。将所述油用DCM/MeOH(1.0L,10∶1)稀释,并通过过滤除去未溶解的NH4Cl,在真空干燥滤液得到标题化合物。产量:200.0g(71%)。
A-25)2-乙基-吡啶-4-醇
将282.1g(2.3mol)2-乙基-吡啶-4-基胺溶于浓硝酸(789mL,11.561mol)和H2O(1.5L)中。然后在0℃经2小时将NaNO2(238.9g,3.468mol)在H2O(600mL)中的溶液缓慢加入该溶液。加入之后,该混合物温热至室温并且再搅拌2小时。反应混合物在-2℃储存过夜。通过过滤收集沉淀,并在真空干燥得到标题化合物。产量:155.1g,(54%)。
A-26)2-乙基-3-碘-吡啶-4-醇
经1小时向72.0g(0.58mol)2-乙基-吡啶-4-醇在1.0L H2O中的溶液分10份加入130.0g(0.58mol)NIS。该混合物在室温搅拌过夜。一次性加入乙酸(1.5L)。通过过滤除去所形成的沉淀。用硅胶色谱(DCM∶MeOH约30∶1)纯化滤液得到标题化合物。产量:9.0g(6%)。
A-27)4-氯-2-乙基-3-碘-吡啶
在室温将165.1g(1.08mol)POCl3在100mL CH3CN中的溶液滴加入27.1g(108mmol)2-乙基-3-碘-吡啶-4-醇在150mL CH3CN中的溶液。然后经20分钟缓慢加入Et3N(21.9g,216mmol),接着将反应混合物在60℃加热3小时。将反应混合物在真空蒸发得到油。将该粗品油倾倒入碎冰中,水相用石油醚/EtOAc(3×,200mL;10∶1)萃取。收集有机相,用无水Na2SO4干燥。在真空除去溶剂得到所需产物。产量:22.0g(76%)。
A-28)5-(4-氯-2-甲基-吡啶-3-基乙炔基)-吡啶-2-基胺
根据通用方法1(GP1)合成标题化合物,起始于1.0g(4.0mmol)的4-氯-3-碘-2-甲基-吡啶和513mg(4.3mmol)2-氨基-5-乙炔基-吡啶,使用40mL无水DMF中的75mg(0.40mmol)CuI、276mg(0.40mmol)PdCl2(PPh3)2和5.4mL(39.5mmol)三乙胺。反应完成后真空下除去溶剂并通过硅胶色谱用DCM/MeOH梯度(100∶0至90∶10)纯化产物。产量:617mg(64%)。
A-29)[5-(4-氯-2-甲基-吡啶-3-基乙炔基)-吡啶-2-基]-甲基-胺
根据通用方法1(GP1)合成标题化合物,起始于20mg(0.08mmol)的4-氯-3-碘-2-甲基-吡啶和11mg(0.09mmol)(5-乙炔基-吡啶-2-基)-甲基-胺,使用1mL无水DMF中的1.5mg(0.01mmol)CuI、5.5mg(0.01mmol)PdCl2(PPh3)2和0.11mL(0.8mmol)三乙胺。反应完成后通过RP-HPLC用ACN/H2O梯度(95∶5至70∶30)纯化产物。产量:20mg(98%)。
A-30)5-(4-氯-2-乙基-吡啶-3-基乙炔基)-吡啶-2-基胺
根据通用方法1(GP1)合成标题化合物,起始于1.0g(3.7mmol)的4-氯-3-碘-2-乙基-吡啶和485mg (4.1mmol)2-氨基-5-乙炔基-吡啶,使用25mL无水DMF中的36mg(0.40mmol)CuI、131mg(0.40mmol)PdCl2(PPh3)2和5.2mL(39.5mmol)三乙胺。反应完成后将反应混合物滴加入水。将沉淀滤出并溶于异丙醇。产物残留于溶液中,而副产物(Glaser-自身偶联所得的炔烃二聚物)形成沉淀并被滤出。母液在真空下浓缩。产量:718mg(75%)。
A-31)4-[3-(6-氨基-吡啶-3-基乙炔基)-2-甲基-吡啶-4-基]-2-氟-苯甲酸甲酯
根据通用方法3(GP3)合成标题化合物,起始于500mg(2.1mmol)的5-(4-氯-2-甲基-吡啶-3-基乙炔基)-吡啶-2-基胺,使用4mL二烷中的812mg(4.1mmol)的3-氟-4-甲氧基羰基苯基硼酸、188mg(0.21mmol)Pd2(dba)3、293mg(0.62mmol)X-Phos和567mg(2.5mmol)K3PO4。微波辐射下将反应混合物在150℃搅拌180分钟。通过硅胶色谱用DCM/MeOH梯度(99∶1至90∶10,20分钟)纯化产物。产量:52mg(70%)。
A-32)4-[3-(6-氨基-吡啶-3-基乙炔基)-2-甲基-吡啶-4-基]-2-氟-苯甲酸
根据通用方法4(GP4)合成标题化合物,起始于300mg(0.83mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-甲基-吡啶-4-基]-2-氟-苯甲酸甲酯,使用5mL THF中的0.83mL(0.83mmoL)的1N NaOH。通过过滤收集沉淀并用THF洗涤。产量:280mg(97%)。
A-33)4-[3-(6-氨基-吡啶-3-基乙炔基)-2-甲基-吡啶-4-基]-苯甲酸甲酯
根据通用方法3(GP3)合成标题化合物,起始于1.5g(6.2mmol)的5-(4-氯-2-甲基-吡啶-3-基乙炔基)-吡啶-2-基胺,使用25mL二烷中的2.2g(12.3mmol)的4-甲氧基羰基苯基硼酸、281mg(0.31mmol)Pd2(dba)3、440mg(0.92mmol)X-Phos和1.7g(7.4mmol)K3PO4。反应混合物在100℃搅拌过夜。冷却至室温后将反应混合物滴加入水中,将沉淀滤出。将该固体溶于异丙醇,搅拌数分钟,滤出并在真空下干燥。产量:2.0g(95%,残留Pd)。
A-34)4-[3-(6-氨基-吡啶-3-基乙炔基)-2-甲基-吡啶-4-基]-苯甲酸
根据通用方法4(GP4)合成标题化合物,起始于2.0g(5.8mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-甲基-吡啶-4-基]-苯甲酸甲酯,使用8mL THF中的11.6mL(11.6mmoL)的1N NaOH。反应完成后用1.0N HCl将pH调节至约5。通过过滤收集沉淀,用水洗涤并在真空下干燥。将该固体溶于异丙醇,搅拌数分钟,然后通过过滤分离该固体并在40℃真空下干燥。产量:1.9g(99%)。
A-35)4-[3-(6-氨基-吡啶-3-基乙炔基)-2-甲基-吡啶-4-基]-2-氯-苯甲酸甲酯
根据通用方法3(GP3)合成标题化合物,起始于300mg(1.2mmol)的5-(4-氯-2-甲基-吡啶-3-基乙炔基)-吡啶-2-基胺,使用4mL二烷中的527mg(2.4mmol)的3-氯-4-甲氧基羰基苯基硼酸、112mg(0.12mmol)Pd2(dba)3、176mg(0.37mmol)X-Phos和340mg(1.5mmol)K3PO4。反应混合物在140℃微波辐射下搅拌60分钟。减压下除去溶剂,之后加入DMF并滤出形成的沉淀。通过RP-HPLC色谱用ACN/H2O梯度从母液分离产物。产量:300mg(65%)。
A-36)4-[3-(6-氨基-吡啶-3-基乙炔基)-2-甲基-吡啶-4-基]-2-氯-苯甲酸
根据通用方法4(GP4)合成标题化合物,起始于460mg(1.2mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-甲基-吡啶-4-基]-2-氯-苯甲酸甲酯,使用10mL THF中的2.4mL(2.4mmoL)的1N NaOH。通过硅胶色谱用DCM/MeOH梯度(100∶0至90∶10,NH3)纯化产物。产量:420mg(95%)。
A-37)4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸甲酯
根据通用方法3(GP3)合成标题化合物,起始于3.2g(12.3mmol)的5-(4-氯-2-乙基-吡啶-3-基乙炔基)-吡啶-2-基胺(A-30),使用60mL 1,2-二甲氧基乙烷和10mL水的混合物中的3.6g(18.4mmol)的3-氟-4-甲氧基羰基苯基硼酸、561mg(0.61mmol)Pd2(dba)3、877mg(1.84mmol)X-Phos、519mg(12.3mmol)LiCl和3.39g(14.7mmol)K3PO4。反应混合物在95℃搅拌16小时。反应完成后,将该混合物倾倒入水,所形成的沉淀通过过滤收集。通过硅胶色谱用DCM/MeOH-混合物(3%MeOH,流速55mL/分钟)纯化产物。产量:2.46g(53%)。
A-38)4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸
根据通用方法4(GP4)合成标题化合物,起始于2.36g(6.3mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸甲酯(A-37),使用40mL THF中的9.4mL(9.4mmoL)的1N NaOH。反应混合物在95℃搅拌2小时。减压下除去溶剂,将粗产物溶于水并用1N HCl将pH调节至5。通过过滤收集沉淀。干燥后的产量:2.2g(97%)。
A-39)4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氯-苯甲酸甲酯
根据通用方法3(GP3)合成标题化合物,起始于2.0g(7.8mmol)的5-(4-氯-2-乙基-吡啶-3-基乙炔基)-吡啶-2-基胺(A-30),使用100mL DME和20mL水的混合物中的2.5g(11.6mmol)的3-氯-4-甲氧基羰基苯基硼酸、335mg(0.39mmol)Pd2(dba)3、555mg(1.2mmol)X-Phos和2.7g(11.6mmol)K3PO4。反应混合物回流下搅拌4日。减压下除去DME并用乙酸乙酯萃取水层。有机相用Na2SO4干燥,过滤并在真空下除去溶剂。通过硅胶色谱用DCM/MeOH梯度纯化产物。产量:0.59g(19%)。
A-40)4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氯-苯甲酸
根据通用方法4(GP4)合成标题化合物,起始于1.1g(2.8mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氯-苯甲酸甲酯(A-39),使用100mL THF和20mL水的混合物中的134mg(5.6mmoL)LiOH。反应完成后,减压下除去THF,水溶液用1N HCl酸化至pH约为1,之后用饱和NaHCO3水溶液将pH调节至6。通过过滤收集沉淀的产物,用水和甲醇洗涤。产量:760mg(72%)。
A-41)4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-甲氧基-苯甲酸甲酯
根据通用方法3(GP3)合成标题化合物,起始于1.5g(5.0mmol)的5-(4-氯-2-乙基-吡啶-3-基乙炔基)-吡啶-2-基胺(A-30),使用20mL二烷中的1.6g(7.4mmol)的3-甲氧基-4-甲氧基羰基苯基硼酸、135mg(0.15mmol)Pd2(dba)3、354mg(0.74mmol)X-Phos和2.2g(9.4mmol)K3PO4。反应混合物回流下搅拌过夜。减压下除去溶剂,之后加水,并通过过滤收集所形成的沉淀。通过硅胶色谱用DCM/MeOH梯度纯化产物。产量:1.07g(56%)。
A-42)4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-甲氧基-苯甲酸
根据通用方法4(GP4)合成标题化合物,起始于1.07g(2.77mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-甲氧基-苯甲酸甲酯(A-41),使用30mL THF中的2.4mL(2.4mmoL)的1N NaOH。反应混合物搅拌过夜,起始原料完全消耗后用1N HCl将pH调节至4。由于没有沉淀形成,用DCM萃取水相。然而,加入DCM后的产物沉淀则通过过滤收集。通过用1N NaOH将pH调节至6,从母液沉淀出另外的产物。合并级分的产量:990mg (96%)。
A-43)4-[3-(6-氨基-2-乙基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸甲酯
根据通用方法3(GP3)合成标题化合物,起始于1.29g(4.5mmol)的5-(4-氯-2-乙基-吡啶-3-基乙炔基)-6-乙基-吡啶-2-基胺(A-30),使用1,2-二甲氧基乙烷和2.25mL水的混合物中的1.34mg(6.8mmol)的3-氟-4-甲氧基羰基苯基硼酸、1.4g(0.9mmol)Pd(PPh3)4和1.19g(8.6mmol)K2CO3。反应混合物在130℃微波辐射下搅拌两次,每次30分钟。产物通过加入水而沉淀,将其滤出并通过硅胶色谱用环己烷/乙酸乙酯梯度纯化。产量:944mg(52%)。
A-44)4-[3-(6-氨基-2-乙基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸
根据通用方法4(GP4)合成标题化合物,起始于944mg(2.34mmol)的4-[3-(6-氨基-2-乙基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸甲酯(A-43),使用25mL THF中的3.5mL(3.5mmoL)的1N NaOH。反应混合物用水稀释,用DCM萃取产物。分离有机相并在减压下除去溶剂。粗产物不需进一步纯化而使用。产量:945mg(>100%)。
A-45)4-[2-乙基-3-(6-甲基氨基-吡啶-3-基乙炔基)-吡啶-4-基]-2-氟-苯甲酸甲酯
根据通用方法3(GP3)合成标题化合物,起始于770mg(2.8mmol)的5-(4-氯-2-乙基-吡啶-3-基乙炔基)-吡啶-2-基]-甲基-胺(A-30),使用7.5mL 1,2-二甲氧基乙烷和1.5mL水混合中的841mg(4.3mmol)的3-氟-4-甲氧基羰基苯基硼酸、882mg(0.57mmol)Pd(PPh3)4和752mg(5.4mmol)K2CO3。反应混合物在180℃微波辐射下搅拌30分钟。滤出反应混合物,产物通过加水而从溶液中沉淀出来。过滤后,通过硅胶色谱用DCM/MeOH梯度纯化产物。产量:850mg(77%)。
A-46)4-[2-乙基-3-(6-甲基氨基-吡啶-3-基乙炔基)-吡啶-4-基]-2-氟-苯甲酸
根据通用方法4(GP4)合成标题化合物,起始于850mg(2.18mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸甲酯(A-45),使用22mL THF中的3.3mL(3.3mmoL)的1N NaOH。反应混合物在65℃搅拌72小时。产物通过加水沉淀,通过过滤收集。干燥后的产量:747mg(91%)。
实施例1-130
实施例化合物根据通用方法3(GP3)(Suzuki偶联)或GP5-9(酰胺或脲的形成)合成,如下面所述。合成所需的合适的起始原料可以从实施例的表中推测出来。所有构建块和试剂均为市售可得或可通过文献中已知的方法合成。
表1:实施例
实施例19:
2-{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-苯基}-2-甲基-丙腈
根据通用方法3(GP3)合成标题化合物,起始于100mg(0.39mmol)的5-(4-氯-2-乙基-吡啶-3-基乙炔基)-吡啶-2-基胺(A-30),使用1.0mL DME和0.2mL水的混合物中的110mg(0.58mmoL)的4-(2-氰基丙-2-基)苯硼酸、22mg(0.02mmol)Pd(PPh3)4和103mg(0.74mmol)K2CO3。反应混合物微波辐射下在130℃搅拌两次,每次30分钟。反应完成后,加入水并通过过滤收集沉淀。通过硅胶色谱用DCM/MeOH梯度纯化粗产物。由于所得产物纯度不足,其通过RP-HPLC用H2O/ACN梯度再次纯化。产量:30mg(21%)。
MW=366.5;[M+H]+=367;保留时间(tRet)=1.83分钟。
实施例20:
5-(2,2′-二乙基-[4,4′]联吡啶-3-基乙炔基)-吡啶-2-基胺
根据通用方法3(GP3)合成标题化合物,起始于100mg(0.39mmol)的5-(4-氯-2-乙基-吡啶-3-基乙炔基)-吡啶-2-基胺(A-30),使用6.0mL DME混合物中的146mg(约60%纯度,0.58mmoL)2-乙基-吡啶-4-基硼酸、18mg(0.02mmol)Pd2(dba)3、28mg(0.06mmol)XPhos和107mg(0.47mmol)K3PO4。反应混合物微波辐射下在190℃搅拌两次,每次300分钟。反应混合物在真空浓缩并通过硅胶色谱用DCM/MeOH梯度纯化粗产物。产量:9mg(7%)。
MW=328.4;[M+H]+=329;tRet=1.61分钟。
实施例21:
5-(2-乙基-2′,6′-二甲基-[4,4′]联吡啶-3-基乙炔基)-吡啶-2-基胺
根据通用方法3(GP3)合成标题化合物,起始于100mg(0.39mmol)的5-(4-氯-2-乙基-吡啶-3-基乙炔基)-吡啶-2-基胺(A-30),使用6.0mL DME混合物中的88mg(0.58mmoL)2,6-甲基-吡啶-4-基硼酸、18mg(0.02mmol)Pd2(dba)3、28mg(0.06mmol)XPhos和107mg(0.47mmol)K3PO4。反应混合物微波辐射下在190℃搅拌两次,每次300分钟。反应混合物在真空浓缩并通过硅胶色谱用DCM/MeOH梯度纯化粗产物。产量:17mg(14%)。
MW=328.4;[M+H]+=329;tRet=1.61分钟。
实施例22:
5-(6-环丙基-2′-乙基-[3,4′]联吡啶-3′-基乙炔基)-吡啶-2-基胺
根据通用方法3(GP3)合成标题化合物,起始于150mg(0.58mmol)的5-(4-氯-2-乙基-吡啶-3-基乙炔基)-吡啶-2-基胺(A-30),使用6.0mL DME和1.5mL水的混合物中的142mg(0.87mmoL)2-环丙基-吡啶-5-基硼酸、4.5mg(0.03mmol)PdPd(PPh3)4和154mg(1.11mmol)K2CO3。反应混合物微波辐射下在150℃搅拌两次,每次120分钟。反应混合物在真空浓缩并通过硅胶色谱用DCM/MeOH梯度纯化粗产物。产量:68mg(34%)。
MW=340.4;[M+H]+=341;tRet=1.51分钟。
实施例23:
5-(2′-乙基-6-三氟甲基-[3,4′]联吡啶-3′-基乙炔基)-吡啶-2-基胺
根据通用方法3(GP3)合成标题化合物,起始于150mg(0.58mmol)的5-(4-氯-2-乙基-吡啶-3-基乙炔基)-吡啶-2-基胺(A-30),使用6.0mL DME和1.5mL水的混合物中的167mg(0.87mmoL)2-三氟甲基-吡啶-5-基硼酸、4.5mg(0.03mmol)PdPd(PPh3)4和154mg(1.11mmol)K2CO3。反应混合物微波辐射下在150℃搅拌两次,每次120分钟。反应混合物在真空浓缩并通过硅胶色谱用DCM/MeOH梯度纯化粗产物。产量:15mg(7%)。
MW=368.4;[M+H]+=369;tRet=1.56分钟。
实施例24:
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯基}-吗啉-4-基-甲酮
根据通用方法5(GP5)合成标题化合物,起始于120mg(0.33mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸(A-38),使用1.2mL DMF中的43mg(0.50mmoL)吗啉、139mg(0.37mmol)HATU和96μLDIEA。反应完成后,减压下除去DMF并通过硅胶色谱纯化产物用DCM/MeOH梯度。产量:66mg(46%)。
MW=430.5;[M+H]+=431;tRet=1.60分钟。
实施例25:
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯基}-哌嗪-1-基-甲酮
根据通用方法5(GP5)合成标题化合物,起始于100mg(0.28mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸(A-38),使用1mL DMF中的29mg(0.33mmoL)哌嗪、116mg(0.30mmol)HATU和81μLDIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/MeOH梯度从所得溶液分离产物。产量:8mg(6%)。
MW=429.5;[M+H]+=430;tRet=1.29分钟。
实施例26:
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯基}-(4-甲基-哌嗪-1-基)-甲酮
根据通用方法5(GP5)合成标题化合物,起始于120mg(0.33mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸(A-38),使用1.2mL DMF中的55μL(0.50mmoL)N-甲基哌嗪、139mg(0.37mmol)HATU和96μLDIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/MeOH梯度从所得溶液分离产物。产量:55mg(37%)。
MW=443.5;[M+H]+=444;tRet=1.68分钟。
实施例27:
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氯-苯基}-(4-甲基-哌嗪-1-基)-甲酮
根据通用方法5(GP5)合成标题化合物,起始于100mg(0.27mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氯-苯甲酸(A-40),使用1.2mL DMF中的40mg(0.40mmoL)N-甲基哌嗪、102mg(0.53mmol)EDC,72mg(0.53mmol)HOBt和68mg(0.53mmol)DIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/ACN梯度从所得溶液分离产物。产量:66mg(54%)。
MW=460.0;[M+H]+=460/62;tRet=1.64分钟。
实施例28:
{4-[2-乙基-3-(6-甲基氨基-吡啶-3-基乙炔基)-吡啶-4-基]-2-氟-苯基}-(4-甲基-哌嗪-1-基)-甲酮
根据通用方法5(GP5)合成标题化合物,起始于100mg(0.27mmol)的4-[2-乙基-3-(6-甲基氨基-吡啶-3-基乙炔基)-吡啶-4-基]-2-氟-苯甲酸(A-46),使用1.5mL DMF中的50μL(0.45mmoL)N-甲基哌嗪、101mg(0.27mmol)HATU和50μL(0.29mmol)DIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/ACN梯度从所得溶液分离产物。产量:70mg(58%)。
MW=457.6;[M+H]+=458;tRet=1.70分钟。
实施例29:
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-甲氧基-苯基}-(4-甲基-哌嗪-1-基)-甲酮
根据通用方法5(GP5)合成标题化合物,起始于70mg(0.19mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-甲氧基-苯甲酸(A-42),使用1.0mL DMF中的42μL(0.38mmoL)N-甲基哌嗪、71mg(0.19mmol)HATU和35μL(0.21mmol)DIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/ACN梯度从所得溶液分离产物。产量:81mg(95%)。
MW=455.6;[M+H]+=456;tRet=1.57分钟。
实施例30:
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯基}-(4-乙基-哌嗪-1-基)-甲酮
根据通用方法5(GP5)合成标题化合物,起始于100mg(0.28mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸(A-38),使用1mL DMF中的38mg(0.33mmoL)N-乙基哌嗪、116mg(0.30mmol)HATU和81μL DIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/MeOH梯度从所得溶液分离产物。产量:36mg(28%)。
MW=457.6;[M+H]+=458;tRet=1.66分钟。
实施例31:
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氯-苯基}-(4-乙基-哌嗪-1-基)-甲酮
根据通用方法5(GP5)合成标题化合物,起始于100mg(0.27mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氯-苯甲酸(A-40),使用1.2mL DMF中的40mg(0.40mmoL)N-乙基哌嗪、102mg(0.53mmol)EDC、72mg(0.53mmol)HOBt和68mg(0.53mmol)DIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/ACN梯度从所得溶液分离产物。产量:67mg(53%)。
MW=474.0;[M+H]+=474/476;tRet=1.73分钟。
实施例32:
{4-[2-乙基-3-(6-甲基氨基-吡啶-3-基乙炔基)-吡啶-4-基]-2-氟-苯基}-(4-乙基-哌嗪-1-基)-甲酮
根据通用方法5(GP5)合成标题化合物,起始于100mg(0.28mmol)的4-[2-乙基-3-(6-甲基氨基-吡啶-3-基乙炔基)-吡啶-4-基]-2-氟-苯甲酸(A-46),使用1.5mL DMF中的55μL(0.33mmoL)N-乙基哌嗪、101mg(0.27mmol)HATU和50μL DIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/ACN梯度从所得溶液分离产物。产量:82mg(65%)。
MW=471.6;[M+H]+=472;tRet=1.79分钟。
实施例33:
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-甲氧基-苯基}-(4-乙基-哌嗪-1-基)-甲酮
根据通用方法5(GP5)合成标题化合物,起始于70mg(0.19mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-甲氧基-苯甲酸(A-42),使用1.0mL DMF中的42mg(0.38mmoL)N-乙基哌嗪、71mg(0.19mmol)HATU和35μL(0.21mmol)DIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/ACN梯度从所得溶液分离产物。产量:85mg(97%)。
MW=469.6;[M+H]+=470;tRet=1.64分钟。
实施例34:
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯基}-(4-环丙基-哌嗪-1-基)-甲酮
根据通用方法5(GP5)合成标题化合物,起始于120mg(0.33mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸(A-38),使用1.2mL DMF中的63mg(0.50mmoL)N-环丙基哌嗪、139mg(0.37mmol)HATU和96μL DIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/ACN梯度从所得溶液分离产物。产量:30mg(20%)。
MW=469.6;[M+H]+=470;tRet=1.82分钟。
实施例35:
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯基}-[4-(四氢-吡喃-4-基)-哌嗪-1-基]-甲酮
根据通用方法5(GP5)合成标题化合物,起始于320mg(0.89mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸(A-38),使用3mL DMF中的181mg(1.06mmoL)的1-四氢-吡喃-4-基哌嗪、370mg(0.97mmol)HATU和258μLDIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/MeOH梯度从所得溶液分离产物。产量:90mg(20%)。
MW=513.6;[M+H]+=514;tRet=1.62分钟。
实施例36:
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氯-苯基}-(4-吗啉-4-基-哌啶-1-基)-甲酮
根据通用方法5(GP5)合成标题化合物,起始于100mg(0.27mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氯-苯甲酸(A-40),使用1.2mL DMF中的68mg(0.40mmoL)的4-哌啶-4-基吗啉、102mg(0.53mmol)EDC、72mg(0.53mmol)HOBt和68mg(0.53mmol)DIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/ACN梯度从所得溶液分离产物。产量:73mg(51%)。
MW=530.1;[M+H]+=530/532;tRet=1.66分钟。
实施例37:
{4-[2-乙基-3-(6-甲基氨基-吡啶-3-基乙炔基)-吡啶-4-基]-2-氟-苯基}-[4-(四氢-吡喃-4-基)-哌嗪-1-基]-甲酮
根据通用方法5(GP5)合成标题化合物,起始于100mg(0.27mmol)的4-[2-乙基-3-(6-甲基氨基-吡啶-3-基乙炔基)-吡啶-4-基]-2-氟-苯甲酸(A-46),使用1.5mL DMF中的68mg(0.40mmoL)四氢-吡喃-4-基哌嗪、101mg(0.27mmol)HATU和50μL DIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/ACN梯度从所得溶液分离产物。产量:59mg(42%)。
MW=527.6;[M+H]+=528;tRet=1.81分钟。
实施例38:
1-(4-{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酰基}-哌嗪-1-基)-乙酮
根据通用方法5(GP5)合成标题化合物,起始于100mg(0.28mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸(A-38),使用1mL DMF中的46mg(0.36mmoL)N-乙酰基哌嗪、116mg(0.30mmol)HATU和81μLDIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/ACN梯度从所得溶液分离产物。产量:69mg(53%)。
MW=471.5;[M+H]+=472;tRet=1.52分钟。
实施例39:
4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-N-(2-甲氧基-乙基)-N-甲基-苯甲酰胺
根据通用方法5(GP5)合成标题化合物,起始于320mg(0.89mmol)的4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酸(A-38),使用3mL DMF中的95mg(1.06mmoL)2-甲氧基甲基胺、370mg(0.97mmol)HATU和258μL DIPEA。反应完成后,过滤反应混合物且通过RP-HPLC用H2O/ACN梯度从所得溶液分离产物。产量:130mg(34%)。
MW=432.5;[M+H]+=433;tRet=1.62分钟。
表1:实施例(续)
分析方法
HPLC: Agilent 1100 Series
MS: Agilent LC/MSD SL
柱: Phenomenex,Mercury Gemini C18,3μm,2.0×20mm,
物品号00M-4439-B0-CE
溶剂A:5mM NH4HCO3/20mM NH3
B:HPLC级乙腈
检测: MS: 正离子和负离子
质量范围: 120-700m/z
毛细管出口电压:70
增益EMV: 1
阈值: 150
步长: 0.25
UV: 315nm
带宽: 170nm
参照: 关
范围: 210-400nm
范围步长: 2.00nm
峰宽: <0.01分钟
狭缝: 2nm
进样:5μL
流速:1.00mL/分钟
柱温:40℃
梯度:0.00分钟 5%B
0.00-2.50分钟 5%→95%B
2.50-2.80分钟 95%B
2.81-3.10分钟 95%→5%B
分析方法2
仪器:Agilent 1100-SL:包括ELSD/DAD/MSD
色谱:
“Acid”方法:
洗脱剂A: 0.1%甲酸的乙腈溶液
洗脱剂B: 0.1%甲酸的水溶液
线性梯度程序: t0=2%A,t3.5分钟=98%A,t6分钟=98%A
流速: 1mL/分钟
柱温箱温度: 35℃
“Base”方法:
洗脱剂A: 10mM氨的乙腈溶液
洗脱剂B: 10mM氨的水溶液
线性梯度程序: t0=2%A,t3.5分钟=98%A,t6分钟=98%A
流速: 1mL/分钟
柱温箱温度: 35℃
蒸发光散射检测器(ELSD):
仪器: Polymer Laboratories PL-ELS 2100
喷雾器气体流速: 1.1L/分钟N2
喷雾器温度: 50℃
蒸发温度: 80℃
灯: 蓝色LED 480nm
二极管阵列检测器(DAD):
仪器: Agilent G1316A
样品波长: 220-320nm
参照物波长: 关
质谱分析(MSD):
仪器: Agilent LC/MSD-SL
电离: ESI(正和负)
质量范围: 100-800
所用缩写
下述实施例描述本发明化合物的生物活性,并不是将本发明限于这些实施例中。
增殖的抑制:CyQuant PC-3
描述:
CyQuant NF分析基于通过荧光染料结合测量细胞DNA含量。由于细胞DNA含量是高度调节的,其与细胞数约成正比。增殖的程度通过比较药物处理的样品与未处理的对照的细胞计数而测定。该分析不依赖于表现出细胞数-非依赖差异的生理活性。
在该分析中,使用DNA-结合染料与原生质透膜剂(plasma membranepermeabilization reagent)的组合。吸出培养基并以染料结合溶液替换,将细胞孵育30-60分钟,然后测定荧光(在485nm激发,在530nm检测发射)。数据以荧光发射强度单位表示,其为孵育时间的函数。
细胞和试剂:
设备:
96孔板 平底(Falcon,Cat.No.:353072)
96孔板 U形(Costar,Cat.No.:3799)
CO2-培养箱
微量培养板读数器,Wallac Victor
操作:
第0天:将150μl培养基中的3000PC-3细胞(培养于F-12K/10%FCS中)
接种于平底96孔板(包括空白培养基)。将板于CO2培养箱中在
37℃孵育过夜。
第1天:在96孔板中在培养基中稀释化合物至浓度为80μM→1∶5,7步
稀释步骤。
每孔中加入每个稀释液各50μl(总体积为每孔200μl;化合物
终浓度:20μM→1∶5)。若需要,测试其他稀释液。
所有浓度均一式两份或三份测试。
对照: 细胞w/o化合物(+50μl培养基+DMSO)。
细胞与化合物一起孵育3天。
第4天:吸出培养基并以100μl的1x染料结合溶液(将22μl CyQuant NF
染料试剂加入11ml的1x HBSS缓冲液)替换。覆盖微量培养板
并孵育30-60分钟,以使染料-DNA的结合平衡。在微量培养板
读数器(在485nm激发,在530nm检测发射)测定荧光强度。
评价: 用GraphPad Prism(Fifty)计算IC50
mTOR-诱导的p-4E-BP1磷酸化的抑制(TR-FRET mTOR活性试剂盒;Invitrogen)
材料:
-GFP-4E-BP1底物;Invitrogen序号PV4759
-Lanthascreen Tb-抗-p4E-BP1(pThr46)抗体试剂盒;Invitrogen序号PV4758
-FRAP1(mTOR)激酶;Invitrogen序号PV4753
-ATP 10mM
-5x分析缓冲液(250mM HEPES pH7.5,0.05%聚山梨醇酯20,5mM EGTA,50mM MnCl2)
-EDTA500mM
确定试验化合物的IC50值:
激酶反应条件:
400nM GFP-4E-BP1,8μMATP,约150ng/mL mTOR,50mM HEPES pH7.5,0.01%聚山梨醇酯20,1mM EGTA,10mM MnCl2,以及变化量的测试化合物。
反应物的制备:
注:在进行稀释前,将mTOR、底物、ATP和抗体解冻并在冰上保持。在使用当天,这些化合物的稀释可短期地保持在室温。
1.将2ml的5X分析缓冲液加入8mL水中,制备10ml的1X分析缓冲液。
注:1X分析缓冲液的浓度为:50mM HEPES pH 7.5,0.01%聚山梨醇酯20,1mM EGTA,及10mM MnCl2。
2.制备抗体/EDTA溶液:首先将2.75μl的Tb-抗-p4E-BP1抗体加入2397μl的LanthaScreenTM TR-FRET稀释缓冲液中。然后加入100μl的0.5M EDTA。
3.制备4X底物/酶溶液:首先将72μl的GFP-4E-BP1(22μM)加入926μl的1X分析缓冲液中。然后加入1.6μl的mTOR(0.45mg/mL)。
4.制备ATP溶液:将3.2μl的10mM ATP加入1997μl的1X分析缓冲液中。
抑制剂的系列稀释(16点曲线):
注:抑制剂推荐用DMSO系列稀释,然后用1X分析缓冲液稀释至4X工作浓度。下面的操作描述了将化合物在96孔板中的稀释,然后转移至384孔板进行激酶分析。该操作需要将化合物在96孔板的相邻两列中稀释,这在用8通道移液器转移至384孔板单一的列时将使样品以浓度的顺序排列。
1.对每个化合物,将40μl的DMSO分别加在96孔板的相邻两列中(例如列1和2)。
2.将10μl的抑制剂储备液(10mM)加入第一列的第一个孔(A1)中并混合。
3.从A1转移10μl至下一列中相邻的孔(B1)并混合。
4.从B1转移10μl至第一列中下一个孔(B2)并混合。
5.重复这样的稀释模式直到孔H1,而最后一个孔H2中仅有DMSO。
6.在96孔板中将4μl稀释的化合物转移加入至96μl的1X分析缓冲液中,成为4X化合物稀释液。
激酶反应:
1.从96孔板的第一列取2.5μl的4X化合物稀释液,用8通道移液器加入384孔板第一列每隔一个的孔中。列2和3也如此重复。
2.从96孔板的第二列取2.5μl的4X化合物稀释液,用8通道移液器加入384孔板第一列空白的孔中。列2和3也如此重复。
注:该程序使化合物稀释液以浓度的顺序排列。
3.将2.5μl的4X酶/底物溶液加入列1-6。
4.在室温(振荡器)预孵育30分钟。
5.向所有孔中加入5μl的ATP溶液以开启反应。
6.在板振荡器上振摇分析板30秒。
7.在室温(20-25℃)孵育分析板1小时。
停止步骤与荧光检测:
1.将10μl的抗体/EDTA溶液加入列1-9的每个孔。
2.在板振荡器上振摇分析板30秒。
3.在室温(20-25℃)孵育分析板1小时。
4.在荧光板读数器(例如Perkin Elmer Envision)上测定GFP(FRET)和铽(参比)发射信号。
数据分析:
1.通过以铽(参比)信号区分GFP(FRET)信号计算发射比。
2.绘制每个化合物的浓度对发射比的图。确定达到最大信号的50%所需的化合物浓度(IC50)。IC50值的确定,可以使用GraphPad的Prism软件通过曲线拟合(S形剂量响应,可变斜率)来得到。
表2:生物学数据
表2:生物学数据(续)
表2:生物学数据(续)
表2:生物学数据(续)
表2:生物学数据(续)
本发明的物质为PI3激酶途径抑制剂,特别是丝氨酸/苏氨酸激酶mTOR和/或脂激酶家庭Pi3K的成员。基于它们的生理活性,通式(1)新的化合物及其异构体及其生理上耐受的盐适于治疗以过度或异常细胞增殖为特征的疾病。这些疾病包括如:病毒感染(如HIV及卡波西氏(Kaposi′s)肉瘤);炎症及自身免疫疾病(如结肠炎、关节炎、阿尔兹海默氏病(Alzheimer′s disease)、肾小球肾炎及伤口愈合);细菌、真菌和/或寄生虫感染;白血病、淋巴瘤及实体肿瘤;皮肤病(如牛皮癣);骨病;心血管疾病(如再狭窄及过度增大)。此外,所述化合物适用于保护增殖细胞(如毛细胞、肠细胞、血细胞及祖细胞)免受由于照射、UV治疗和/或抑制细胞治疗所致的DNA损伤(Davis等人,2001)。
例如,本发明的化合物可治疗(但不限于)以下癌症:脑肿瘤,如听神经瘤、星形细胞瘤(如毛样星形细胞瘤、原纤维星形细胞瘤、原生质性星形细胞瘤、饲肥星形细胞瘤、退行发育性星形细胞瘤)及神经胶母细胞瘤、脑淋巴瘤、脑转移瘤、垂体瘤例如泌乳素瘤、产生HGH(人生长激素)的肿瘤及产生ACTH(促肾上腺皮质激素)的肿瘤、颅咽管瘤、成神经管细胞瘤、脑脊膜瘤及少突神经胶质瘤;神经瘤(新生肿瘤),例如植物神经系统瘤,例如,成交感神经母细胞瘤、神经节瘤、副神经节瘤(嗜铬细胞瘤(pheochromocytoma、chromaffinoma))及颈动脉球瘤,外周神经系统瘤,例如截肢性神经瘤、神经纤维瘤、神经鞘瘤(neurilemmoma、schwannoma)及恶性神经鞘瘤,以及中枢神经系统瘤,例如脑瘤及脊髓瘤;肠癌,例如直肠癌、结肠癌、肛门癌、小肠癌及十二指肠癌;眼睑瘤例如基底细胞癌;胰癌或胰脏癌瘤;膀胱癌或膀胱癌瘤;肺癌(支气管癌),例如小细胞支气管肺癌(燕麦细胞癌)及非小细胞支气管肺癌,例如扁平上皮癌(squamous epithelium carcinoma)、腺癌及大细胞支气管肺癌;乳腺癌,例如:乳房癌瘤,如浸润性导管癌、胶样癌、浸润性小叶癌、小管癌、腺样囊性癌及乳头状癌;非霍奇金淋巴瘤(NHL),例如伯基特氏淋巴瘤(Burkitt’s lymphoma)、低度恶性非霍奇金淋巴瘤(NHL)及粘样霉菌病(mucosisfungoides);子宫癌或子宫内膜癌或子宫体癌;CUP综合症(原发位不明癌);卵巢癌例如粘蛋白癌、子宫内膜癌或浆液性癌;胆囊癌;胆管癌,例如肝门胆管癌(Klatskin’s tumor);睾丸癌,例如睾丸精原细胞瘤及非睾丸精原细胞瘤;淋巴瘤(淋巴肉瘤),例如恶性淋巴瘤、霍奇金病、非霍奇金淋巴瘤(NHL)例如慢性淋巴细胞白血症、毛细胞白血病(hair cell leukaemia)、免疫细胞瘤、浆细胞瘤(多发性骨髓瘤)、淋巴母细胞癌、伯基特氏淋巴瘤、T-区粘样霉菌病、大细胞未分化淋巴母细胞癌(large-cell anaplastic lymphoblastoma)及淋巴母细胞瘤;喉癌,例如声带瘤、声门上瘤、声门瘤及声门下喉瘤;骨癌,例如骨软骨瘤、软骨瘤、成软骨细胞瘤、软骨粘液样纤维瘤、骨瘤、骨样骨瘤、骨母细胞瘤、骨嗜酸性肉芽肿、巨细胞瘤、软骨肉瘤、骨肉瘤、尤因氏肉瘤(Ewing′ssarcoma)、网状细胞肉瘤、浆细胞瘤、纤维性发育不良、青少年骨囊肿及动脉瘤骨囊肿;头颈瘤,例如唇瘤、舌瘤、口底瘤、口腔瘤、齿龈瘤、腭瘤、唾液腺瘤、喉瘤、鼻腔瘤、鼻旁窦瘤、喉瘤及中耳瘤;肝癌,例如肝细胞癌(HCC);白血病,例如急性白血病,例如,急性淋巴/成淋巴细胞性白血病(ALL)、急性髓细胞样白血病(AML);慢性白血病例如慢性淋巴性白血病(CLL)、慢性髓细胞样白血病(CML);胃癌,例如乳突状癌、管状癌及黏蛋白腺癌、印戒细胞癌、腺样鳞状细胞癌(adenoid squamous cell carcinoma)、小细胞癌及未分化癌;黑素瘤,例如浅表性扩散(superficially spreading)、恶性小结节雀斑痣(nodular malignant lentigo)及肢端黑色素瘤;肾癌,例如肾细胞癌或肾上腺样瘤或葛维兹瘤(Grawitz’s tumor);食道癌;阴茎癌;前列腺癌;咽喉癌,例如鼻咽癌、口咽癌及咽下部癌;视网膜母细胞癌;例如阴道癌;板上皮癌、腺癌、原位癌、恶性黑色素瘤及肉瘤;甲状腺癌,例如乳突状、小囊及甲状腺髓样癌,及未分化癌;皮肤的棘细胞癌(spinalioma)、鳞状细胞癌(prickle cellcarcinoma)及鳞状上皮癌(squamous epidormoid carcinoma);胸腺瘤、尿道癌及外阴癌。
所述新化合物可用于预防或短期或长期治疗上述疾病,适当时包括与其它现代技术化合物组合,如其它抗肿瘤物质、细胞毒性物质、细胞增殖抑制剂、抗血管生成物质、类固醇或抗体。
通式(1)化合物可单独使用或与本发明的其它活性化合物组合使用,和适当时可与其它药理活性化合物组合。可与本发明的化合物组合给予的化学治疗剂包括(但不限于)激素、激素类似物及抗激素(如他莫昔芬、托瑞米芬、雷洛昔芬、氟维司群、甲地孕酮、氟他胺、尼鲁米特、比卡鲁胺、氨鲁米特、醋酸环丙孕酮、非那雄胺、醋酸布舍瑞林、氟氢可的松、氟甲睾酮、甲羟孕酮、奥曲肽)、芳香酶抑制剂(例如阿那曲唑、来曲唑、利阿唑、伏氯唑、依西美坦、阿他美坦)、LHRH激动剂及拮抗剂(例如醋酸性瑞林、亮丙瑞林(luprolide))、生长因子抑制剂(生长因子,例如“血小板衍生生长因子”及“肝细胞生长因子”,抑制剂为例如“生长因子”抗体、“生长因子受体”抗体及酪氨酸激酶抑制剂,例如吉非替尼、伊马替尼、拉帕替尼、及曲妥珠单杭);抗代谢物(例如,叶酸拮抗剂例如甲氨蝶呤、雷替曲塞,嘧啶类似物例如5-氟尿嘧啶、卡培他滨及吉西他滨,嘌呤及腺苷类似物例如巯基嘌呤、硫鸟嘌呤、克拉屈滨及喷司他丁、阿糖胞苷、氟达拉滨);抗肿瘤抗生素(例如蒽环素类例如多柔比星、柔红霉素、表柔比星及伊达比星、丝裂霉素C、博莱霉素、放线菌素D、普卡霉素、链佐星);铂衍生物(例如顺式铂、奥沙利铂、卡铂);烷化剂(例如雌莫司汀、氮芥(meclorethamine)、美法仑、苯丁酸氮芥、白消安、达卡巴嗪、环磷酰胺、异环磷酰胺、替莫唑胺、亚硝基脲,例如卡莫司汀及洛莫司汀、塞替派);抗有丝分裂剂(例如长春花生物碱,例如长春花碱、长春地辛、长春瑞宾及长春新碱;及紫杉烷类例如紫杉醇、西紫杉醇);拓朴异构酶抑制剂(例如表鬼白毒素,例如依托泊苷及凡毕复、替尼泊苷、安吖啶、拓扑替康、伊立替康、米托蒽醌)及不同的化疗剂例如胺磷汀、阿那格雷、氯膦酸盐、非格司亭(filgrastin)、干扰素-α、亚叶酸钙、利妥昔单抗、丙卡巴肼、左旋咪唑、美司钠、米托坦、帕米膦酸盐及卟菲尔钠。
适用形式的实施例包括如片剂、胶囊、栓剂、溶液(特定而言,注射(皮下、静脉内、肌内)用溶液及输注用溶液)、糖浆、乳液或分散性粉剂。在此方面,医药活性化合物的比例应分别占总组合物的0.1-90重量%、优选0.5-50重量%的范围内,即其量应足以达到以下指定的剂量范围。必要时,可一天给予若干次所述剂量。
如可通过混合活性化合物与已知辅助物质来获得适当片剂,这些已知辅助物质如惰性稀释剂,如碳酸钙、磷酸钙或乳糖;崩解剂,如玉米淀粉或海藻酸;黏合剂,如淀粉或明胶;润滑剂,如硬脂酸镁或滑石和/或用以达成储积效应(depot effect)的试剂,如羧甲基纤维素、邻苯二甲酸乙酸纤维素或聚乙酸乙烯酯。片剂亦可包含若干层。
相应地,糖衣片剂可使用常用于糖衣的制剂涂布类似片剂制法所制备的核而制得,如可力酮(collidone)或虫胶、阿拉伯胶、滑石、二氧化钛或糖。所述核亦可包含若干层,以达成储积效应或避免不兼容性。同样地,糖衣亦可包含若干层以达成储积效应,可使用上文在片剂的情况下所述辅助物质。
本发明的活性化合物或活性化合物组合的糖浆可另外包含甜味剂,如糖精、环己胺磺酸盐、甘油或糖,以及味道改良剂,如调味剂,如香草精或橙萃取物。其也可包含悬浮佐剂或增稠剂,如羧甲基纤维素钠;湿润剂,如脂肪醇与氧化乙烯的缩合产物;或防腐剂,如对羟基苯甲酸酯。
注射及输注溶液按照惯用方式制得,如添加等渗剂、防腐剂(如对羟基苯甲酸酯)或稳定剂(如乙二胺四乙酸的碱金属盐),适当时可使用乳化剂和/或分散剂,使用水作为稀释剂时如可使用有机溶剂(若适当)作为增溶剂或辅助溶剂,并将溶液等分至注射瓶或安瓿或输液瓶中。
包含一或多种活性化合物或活性化合物组合的胶囊例如可通过将活性化合物与如乳糖或山梨糖醇的惰性载体混合,并将混合物囊封至明胶胶囊中而制得。合适的栓剂例如可通过与预期用于此目的的赋形剂(如中性脂肪或聚乙二醇或其衍生物)混合而制得。
可提及的辅助物质如水;医药学上不排斥的有机溶剂,如石蜡(如石油馏份)、植物油(如花生油或芝麻油)、单官能醇或多官能醇(如EtOH或甘油);载体物质,如天然矿物粉末(例如高岭土、黏土、滑石及白垩)、合成矿物粉末(如高分散性硅酸及硅酸盐)、糖(如蔗糖、乳糖及葡萄糖)、乳化剂(如木质素、亚硫酸盐废液(sulphite waste liquors)、甲基纤维素、淀粉及聚乙烯吡咯烷酮)及助流剂(如硬脂酸镁、滑石、硬脂酸及月桂基硫酸钠)。
施药以惯用方式进行,优选经口或经皮,更优选经口。在经口使用的情况下,除上述载体物质之外,片剂当然也可包含添加剂,如柠檬酸钠、碳酸钙及磷酸二钙,以及多种其它物质,如淀粉(优选马铃薯淀粉)、明胶及其类似物。此外亦可使用如硬脂酸镁、月桂基硫酸钠及滑石的助流剂来制锭。在水性悬浮液的情况下,除上述辅助物质之外也可将多种味道改良剂或着色剂添加至活性化合物中。
对于非经肠施药,可在使用适宜液体载体物质的同时使用活性化合物的溶液。静脉内施药的剂量为每小时1-1000mg,优选每小时在5到500mg之间。
尽管如此,适当时可能必须偏离上述量,其视体重、施药途径的性质、个体对药物的反应、制剂的性质及在进行施药的时间或时间间隔而定。因此,在一些情况下,小于先前所述最低量可能足以生效,然而在其它情况下必须超过上述的上限。当以相对较大量施药时,宜将其分为若干单一剂量,于给药当日内给予。
以下制剂实施例示例性地说明本发明,而并非限制其范围。
药物制剂实施例
将细粉状活性化合物、乳糖及一部分玉米淀粉相互混合。将混合物过筛,接着以聚乙烯吡咯烷酮的水溶液湿润,捏合,湿法造粒且干燥。将颗粒物质,剩余玉米淀粉及硬脂酸镁过筛且相互混合。将混合物压制成具有适当形状及尺寸的片剂。
将细粉状活性化合物、一部分玉米淀粉、乳糖、微晶纤维素及聚乙烯基吡咯烷酮相互混合,接着将混合物过筛且连同剩余玉米淀粉及水加工成颗粒物质,将该颗粒物质干燥且过筛。随后将羧甲基淀粉钠及硬脂酸镁添加至颗粒物质中且与其混合,并将混合物压缩成具有适当尺寸的片剂。
C)安瓿溶液
式(1)活性化合物 50mg
氯化钠 50mg
注射用水 5mL
将活性化合物在其原有pH值或(若适当)在pH 5.5-6.5下溶解于水中,接着添加氯化钠作为等渗剂。通过过滤使所得溶液无热原质,并在无菌条件下将滤液等分至安瓿中,随后灭菌且通过熔融密封。安瓿含有5mg、25mg及50mg的活性物质。
Claims (22)
1.通式(1)的化合物,
其中
R1和R4各自独立地表示选自Ra、Rb和被一个或多个相同或不同的Rb和/或Rc取代的Ra的基团;或
一个R1与吡啶一起形成9-10元杂芳环,其任选被一个或多个相同或不同的Rb和/或Rc取代;和
R2和R3各自独立地表示选自C1-6烷基、C3-8环烷基、3-8元杂环烷基、C6-10芳基和5-12元杂芳基的基团,其任选被一个或多个相同或不同的R5取代,和
每个R5表示选自Ra、Rb和被一个或多个相同或不同的Rb和/或Rc取代的Ra的基团;和
每个Ra各自独立地表示任选被一个或多个相同或不同的Rb和/或Rc取代的基团,所述基团选自C1-6烷基、2-6元杂烷基、C1-6卤代烷基、C3-10环烷基、C4-16环烷基烷基、C6-10芳基、C7-16芳基烷基、5-12元杂芳基、6-18元杂芳基烷基、3-14元杂环烷基和4-14元杂环烷基烷基,
每个Rb表示合适的基团,其各自独立地选自=O、-ORc、C1-3卤代烷基氧基、-OCF3、=S、-SRc、=NRc、=NORc、=NNRcRc、=NN(Rg)C(O)NRcRc、-NRcRc、-ONRcRc、-N(ORc)Rc、-N(Rg)NRcRc、卤素、-CF3、-CN、-NC、-OCN、-SCN、-NO、-NO2、=N2、-N3、-S(O)Rc、-S(O)ORc、-S(O)2Rc、-S(O)2ORc、-S(O)NRcRc、-S(O)2NRcRc、-OS(O)Rc、-OS(O)2Rc、-OS(O)2ORc、-OS(O)NRcRc、-OS(O)2NRcRc、-C(O)Rc、-C(O)ORc、C(O)SRc、-C(O)NRcRc、-C(O)N(Rg)NRcRc、-C(O)N(Rg)ORc、-C(NRg)NRcRc、-C(NOH)Rc、-C(NOH)NRcRc、-OC(O)Rc、-OC(O)ORc、-OC(O)SRc、-OC(O)NRcRc、-OC(NRg)NRcRc、-SC(O)Rc、-SC(O)ORc、-SC(O)NRcRc、-SC(NRg)NRcRc、-N(Rg)C(O)Rc、-N[C(O)Rc]2、-N(ORg)C(O)Rc、-N(Rg)C(NRg)Rc、-N(Rg)N(Rg)C(O)Rc、-N[C(O)Rc]NRcRc、-N(Rg)C(S)Rc、-N(Rg)S(O)Rc、-N(Rg)S(O)ORc、-N(Rg)S(O)2Rc、-N[S(O)2Rc]2、-N(Rg)S(O)2ORc、-N(Rg)S(O)2NRcRc、-N(Rg)[S(O)2]2Rc、-N(Rg)C(O)ORc、-N(Rg)C(O)SRc、-N(Rg)C(O)NRcRc、-N(Rg)C(O)NRgNRcRc、-N(Rg)N(Rg)C(O)NRcRc、-N(Rg)C(S)NRcRc、-[N(Rg)C(O)]2Rc、-N(Rg)[C(O)]2Rc、-N{[C(O)]2Rc}2、-N(Rg)[C(O)]2ORc、-N(Rg)[C(O)]2NRcRc、-N{[C(O)]2ORc}2、-N{[C(O)]2NRcRc}2、-[N(Rg)C(O)]2ORc、-N(Rg)C(NRg)ORc、-N(Rg)C(NOH)Rc、-N(Rg)C(NRg)SRc、-N(Rg)C(NRg)NRcRc和-N=C(Rg)NRcRc,和
每个Rc各自独立地表示氢或任选被一个或多个相同或不同的Rd和/或Re取代的基团,所述基团选自C1-6烷基、2-6元杂烷基、C1-6卤代烷基、C3-10环烷基、C4-16环烷基烷基、C6-10芳基、C7-16芳基烷基、5-12元杂芳基、6-18元杂芳基烷基、3-14元杂环烷基和4-14元杂环烷基烷基,和
每个Rd表示合适的基团,其各自独立地选自=O、-ORe、C1-3卤代烷基氧基、-OCF3、=S、-SRe、=NRe、=NORe、=NNReRe、=NN(Rg)C(O)NReRe、-NReRe、-ONReRe、-N(Rg)NReRe、卤素、-CF3、-CN、-NC、-OCN、-SCN、-NO、-NO2、=N2、-N3、-S(O)Re、-S(O)ORe、-S(O)2Re、-S(O)2ORe、-S(O)NReRe、-S(O)2NReRe、-OS(O)Re、-OS(O)2Re、-OS(O)2ORe、-OS(O)NReRe、-OS(O)2NReRe、-C(O)Re、-C(O)ORe、-C(O)SRe、-C(O)NReRe、-C(O)N(Rg)NReRe、-C(O)N(Rg)ORe、-C(NRg)NReRe、-C(NOH)Re、-C(NOH)NReRe、-OC(O)Re、-OC(O)ORe、-OC(O)SRe、-OC(O)NReRe、-OC(NRg)NReRe、-SC(O)Re、-SC(O)ORe、-SC(O)NReRe、-SC(NRg)NReRe、-N(Rg)C(O)Re、-N[C(O)Re]2、-N(ORg)C(O)Re、-N(Rg)C(NRg)Re、-N(Rg)N(Rg)C(O)Re、-N[C(O)Re]NReRe、-N(Rg)C(S)Re、-N(Rg)S(O)Re、-N(Rg)S(O)ORe、-N(Rg)S(O)2Re、-N[S(O)2Re]2、-N(Rg)S(O)2ORe、-N(Rg)S(O)2NReRe、-N(Rg)[S(O)2]2Re、-N(Rg)C(O)ORe、-N(Rg)C(O)SRe、-N(Rg)C(O)NReRe、-N(Rg)C(O)NRgNReRe、-N(Rg)N(Rg)C(O)NReRe、-N(Rg)C(S)NReRe、-[N(Rg)C(O)]2Re、-N(Rg)[C(O)]2Re、-N{[C(O)]2Re}2、-N(Rg)[C(O)]2ORe、-N(Rg)[C(O)]2NReRe、-N{[C(O)]2ORe}2、-N{[C(O)]2NReRe}2、-[N(Rg)C(O)]2ORe、-N(Rg)C(NRg)ORe、-N(Rg)C(NOH)Re、-N(Rg)C(NRg)SRe、-N(Rg)C(NRg)NReRe和-N=C(Rg)NReRe,
每个Re各自独立地表示氢或任选被一个或多个相同或不同的Rf和/或Rg取代的基团,所述基团选自C1-6烷基、2-6元杂烷基、C1-6卤代烷基、C3-10环烷基、C4-16环烷基烷基、C6-10芳基、C7-16芳基烷基、5-12元杂芳基、6-18元杂芳基烷基、3-14元杂环烷基和4-14元杂环烷基烷基,和
每个Rf表示合适的基团,其在各种情况下各自独立地选自=O、-ORg、C1-3卤代烷基氧基、-OCF3、=S、-SRg、=NRg、=NORg、=NNRgRg、=NN(Rh)C(O)NRgRg、-NRgRg、-ONRgRg、-N(Rh)NRgRg、卤素、-CF3、-CN、-NC、-OCN、-SCN、-NO、-NO2、=N2、-N3、-S(O)Rg、-S(O)ORg、-S(O)2Rg、-S(O)2ORg、-S(O)NRgRg、-S(O)2NRgRg、-OS(O)Rg、-OS(O)2Rg、-OS(O)2ORg、-OS(O)NRgRg、-OS(O)2NRgRg、-C(O)Rg、-C(O)ORg、-C(O)SRg、-C(O)NRgRg、-C(O)N(Rh)NRgRg、-C(O)N(Rh)ORg、-C(NRh)NRgRg、-C(NOH)Rg、-C(NOH)NRgRg、-OC(O)Rg、-OC(O)ORg、-OC(O)SRg、-OC(O)NRgRg、-OC(NRh)NRgRg、-SC(O)Rg、-SC(O)ORg、-SC(O)NRgRg、-SC(NRh)NRgRg、-N(Rh)C(O)Rg、-N[C(O)Rg]2、-N(ORh)C(O)Rg、-N(Rh)C(NRh)Rg、-N(Rh)N(Rh)C(O)Rg、-N[C(O)Rg]NRgRg、-N(Rh)C(S)Rg、-N(Rh)S(O)Rg、-N(Rh)S(O)ORg、-N(Rh)S(O)2Rg、-N[S(O)2Rg]2、-N(Rh)S(O)2ORg、-N(Rh)S(O)2NRgRg、-N(Rh)[S(O)2]2Rg、-N(Rh)C(O)ORg、-N(Rh)C(O)SRg、-N(Rh)C(O)NRgRg、-N(Rh)C(O)NRhNRgRg、-N(Rh)N(Rh)C(O)NRgRg、-N(Rh)C(S)NRgRg、-[N(Rh)C(O)]2Rg、-N(Rh)[C(O)]2Rg、-N{[C(O)]2Rg}2、-N(Rh)[C(O)]2ORg、-N(Rh)[C(O)]2NRgRg、-N{[C(O)]2ORg}2、-N{[C(O)]2NRgRg}2、-[N(Rh)C(O)]2ORg、-N(Rh)C(NRh)ORg、-N(Rh)C(NOH)Rg、-N(Rh)C(NRh)SRg、-N(Rh)C(NRh)NRgRg和-N=C(Rh)NRhRh;和
每个Rg各自独立地表示氢或任选被一个或多个相同或不同的Rh取代的基团,所述基团选自C1-6烷基、2-6元杂烷基、C1-6卤代烷基、C3-10环烷基、C4-16环烷基烷基、C6-10芳基、C7-16芳基烷基、5-12元杂芳基、6-18元杂芳基烷基、3-14元杂环烷基和4-14元杂环烷基烷基;和
每个Rh各自独立地选自氢、C1-6烷基、2-6元杂烷基、C1-6卤代烷基、C3-10环烷基、C4-16环烷基烷基、C6-10芳基、C7-16芳基烷基、5-12元杂芳基、6-18元杂芳基烷基、3-14元杂环烷基和4-14元杂环烷基烷基;和
m表示0、1或2;和
n表示0、1、2或3;和
任选以其前药、互变异构体、外消旋体、对映异构体、非对映异构体、前药及混合物的形式,以及任选为其药理学上可接受的盐。
2.权利要求1的化合物,其中R3表示任选被一个或多个相同或不同的R5取代的C6-10芳基或5-12元杂芳基。
3.权利要求2的化合物,其中R3表示任选被一个或多个相同或不同的R5取代的苯基。
4.权利要求2的化合物,其中R3表示任选被一个或多个相同或不同的R5取代的吡啶基。
5.权利要求2的化合物,其中R3表示任选被一个或多个相同或不同的R5取代的吡唑基。
6.权利要求1至5中任一项的化合物,其中R2表示甲基或乙基。
7.权利要求1至6中任一项的化合物,其中n表示1或2。
8.权利要求1至7中任一项的化合物,其中R1表示甲基、乙基或-NRcRc。
9.权利要求1至8中任一项的化合物,其中R1选自-NH2、-NH-CH3和-N(CH3)2。
10.权利要求1至9中任一项的化合物,其中Ra选自氢、甲基、乙基和环丙基。
11.权利要求1至10中任一项的化合物,其中Rb选自-F、-Cl、-CH3、-OCH3、-CF3、-C(O)-Rc、-C(O)NRcRc、-C(O)OH、-C(O)OCH3、-C(O)-NH2、-C(O)-NHCH3、-C(O)-N(CH3)2、-S(O)2CH3、-2-丙基-Rc。
12.权利要求1至11中任一项的化合物,其中Rc选自-H、-CN、-甲基、-乙基、-(CH2)2-OCH3、哌嗪基、哌啶基、吡咯烷基和吗啉基。
14.权利要求1至13中任一项的化合物,其中Rd选自-H、-甲基、-乙基、-丙基、-OH、-OCH3、-C(O)CH3。
15.权利要求1至14中任一项的化合物,其中Re选自-环丙基、环戊基、环氧乙烷基、四氢吡喃基和吗啉基。
17.化合物,其选自:
2-{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-苯基}-2-甲基-丙腈
5-(2,2′-二乙基-[4,4′]联吡啶-3-基乙炔基)-吡啶-2-基胺
5-(2-乙基-2′,6′-二甲基-[4,4′]联吡啶-3-基乙炔基)-吡啶-2-基胺
5-(6-环丙基-2′-乙基-[3,4′]联吡啶-3′-基乙炔基)-吡啶-2-基胺
5-(2′-乙基-6-三氟甲基-[3,4′]联吡啶-3′-基乙炔基)-吡啶-2-基胺
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯基}-吗啉-4-基-甲酮
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯基}-哌嗪-1-基-甲酮
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯基}-(4-甲基-哌嗪-1-基)-甲酮
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氯-苯基}-(4-甲基-哌嗪-1-基)-甲酮
{4-[2-乙基-3-(6-甲基氨基-吡啶-3-基乙炔基)-吡啶-4-基]-2-氟-苯基}-(4-甲基-哌嗪-1-基)-甲酮
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-甲氧基-苯基}-(4-甲基-哌嗪-1-基)-甲酮
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯基}-(4-乙基-哌嗪-1-基)-甲酮
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氯-苯基}-(4-乙基-哌嗪-1-基)-甲酮
{4-[2-乙基-3-(6-甲基氨基-吡啶-3-基乙炔基)-吡啶-4-基]-2-氟-苯基}-(4-乙基-哌嗪-1-基)-甲酮
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-甲氧基-苯基}-(4-乙基-哌嗪-1-基)-甲酮
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯基}-(4-环丙基-哌嗪-1-基)-甲酮
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯基}-[4-(四氢-吡喃-4-基)-哌嗪-1-基]-甲酮
{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氯-苯基}-(4-吗啉-4-基-哌啶-1-基)-甲酮
{4-[2-乙基-3-(6-甲基氨基-吡啶-3-基乙炔基)-吡啶-4-基]-2-氟-苯基}-[4-(四氢-吡喃-4-基)-哌嗪-1-基]-甲酮
1-(4-{4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-苯甲酰基}-哌嗪-1-基)-乙酮
4-[3-(6-氨基-吡啶-3-基乙炔基)-2-乙基-吡啶-4-基]-2-氟-N-(2-甲氧基-乙基)-N-甲基-苯甲酰胺。
18.权利要求1至17中任一项的化合物或其药理学有效的盐,其作为药物。
19.权利要求1至17中任一项的化合物或其药理学有效的盐,其用于制备具有抗增殖活性的药物。
20.药物制剂,其包含作为活性物质的一个或多个权利要求1至17中任一项的通式(1)的化合物或其药理学有效的盐,任选与常规的赋形剂和/或载体组合。
21.权利要求1至17中任一项的通式(1)的化合物在制备用于治疗和/或预防癌症、感染、炎症和自身免疫性疾病的药物中的用途。
22.药物制剂,其包含权利要求1至17中任一项的通式(1)的化合物以及至少一种不同于式(1)的其他细胞抑制或细胞毒活性物质,任选以互变异构体、外消旋体、对映异构体、非对映异构体及其混合物的形式,以及任选其药理学上可接受的盐。
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CN101128199A (zh) * | 2004-04-23 | 2008-02-20 | 布里斯托尔-迈尔斯斯奎布公司 | 作为激酶抑制剂的单环杂环 |
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Also Published As
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ECSP11011454A (es) | 2011-12-30 |
PE20120637A1 (es) | 2012-05-26 |
EP2421846A1 (en) | 2012-02-29 |
AP2011005894A0 (en) | 2011-10-31 |
IL215161A0 (en) | 2011-12-29 |
SG175272A1 (en) | 2011-11-28 |
CA2759368A1 (en) | 2010-10-28 |
JP2012524750A (ja) | 2012-10-18 |
EA201101517A1 (ru) | 2012-05-30 |
TN2011000531A1 (en) | 2013-05-24 |
US9090564B2 (en) | 2015-07-28 |
KR20120004529A (ko) | 2012-01-12 |
UY32565A (es) | 2010-11-30 |
AR076332A1 (es) | 2011-06-01 |
CO6460762A2 (es) | 2012-06-15 |
JP5635592B2 (ja) | 2014-12-03 |
MA33222B1 (fr) | 2012-04-02 |
EP2421846B1 (en) | 2016-01-06 |
MX2011011021A (es) | 2011-11-02 |
US20110098275A1 (en) | 2011-04-28 |
US20130196975A1 (en) | 2013-08-01 |
BRPI1013716A2 (pt) | 2016-04-05 |
WO2010122069A1 (en) | 2010-10-28 |
TW201103905A (en) | 2011-02-01 |
AU2010240963A1 (en) | 2011-10-13 |
CL2011002625A1 (es) | 2012-04-20 |
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