CN106279150B - 吡啶稠环类化合物及其制备方法和用途 - Google Patents
吡啶稠环类化合物及其制备方法和用途 Download PDFInfo
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- CN106279150B CN106279150B CN201510315361.XA CN201510315361A CN106279150B CN 106279150 B CN106279150 B CN 106279150B CN 201510315361 A CN201510315361 A CN 201510315361A CN 106279150 B CN106279150 B CN 106279150B
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- Prior art keywords
- pyridine
- cyanoanilino
- phenoxy
- dimethyl
- cyanoethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- 239000012312 sodium hydride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
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- 239000007921 spray Substances 0.000 description 1
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- 239000008223 sterile water Substances 0.000 description 1
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- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及吡啶稠环类化合物及其制备方法和用途,具体涉及式Ⅰ所示的化合物或其可药用盐,其药物组合物,及其用于制备预防和或治疗与HIV感染有关的疾病或病症的药物的用途。本发明化合物结构新颖,具有较高的抗HIV活性,并且能有效抵抗HIV病毒株的耐药性,是一类具有较高应用潜力的非核苷类HIV逆转录酶抑制剂。
Description
技术领域
本发明涉及医药领域,具体涉及吡啶稠环类化合物及其制备方法和用途,所述化合物作为非核苷类HIV逆转录酶抑制剂可用于预防或治疗与HIV感染相关的疾病。
背景技术
艾滋病病毒(即人类免疫缺陷病毒,Human Immunodeficiency Virus,HIV)是一种RNA病毒,该病毒的表面是一层双脂膜。膜中包裹着2个单链RNA和一些重要的酶(如逆转录酶、蛋白水解酶、整合酶)以及结构蛋白质(p24,p17,p7等)。病毒的膜表面有两个重要的糖蛋白GP120和GP41。GP120在膜的外部,GP41横跨双脂膜并与GP120形成一个复合体。它们的主要功能是识别和进攻人体免疫系统中具有CD4表面受体的细胞,如淋巴细胞(T细胞)、巨噬细胞等。HIV在体外不能繁殖,必须借助于人体细胞才能复制再生。HIV的复制周期与一般的逆转录病毒类似:结合靶细胞受体,包膜与细胞膜融合、病毒核心进入细胞浆、反转录、病毒DNA进入细胞核和整合入宿主DNA中、病毒RNA转录和出核、翻译病毒蛋白质以及装配病毒颗粒、出芽和成熟等过程。艾滋病病毒以这样的一个循环过程不断的复制,感染人体免疫细胞,破坏人体免疫系统,最终导致人体免疫功能丧失,使病人处于各类感染而毫无抵抗能力的危险中。理论上讲,药物只要阻断病毒复制过程中的任何一个环节,都会达到抑制病毒、治疗疾病的目的。
目前为止,批准上市的用于临床抗HIV感染和治疗艾滋病的化学药物以及组合已有30多种。现有药物按其作用机制可分为五类:核苷类逆转录酶抑制剂(NRTIs)、非核苷类逆转录酶抑制剂(NNRTIs)、蛋白水解酶抑制剂(PIs)、融合酶抑制剂(Enfuvirtide)和进入抑制剂(Maraviroc)。
非核苷类逆转录酶抑制剂具有结构多样性,高效低毒、靶点和作用机制清楚和非竞争性抑制剂等优越之处,在抗HIV组合疗法中占有重要的位置。目前,有5个上市的非核苷类逆转录酶抑制剂:奈韦拉平(nevirapine),地拉韦啶(delavirdine),依非韦伦(Efavirenz)、依曲韦伦(Entravirine)和利匹韦林(rilpivirine)。
现有药物单独或者联合使用虽可有效抑制病毒在体内的复制,但共同面对的问题是耐药性。HIV病毒在与药物作用一段时间后会产生某种变异。变异的病毒可不再受药物的抑制作用,仍然像用药以前一样继续在体内复制大量的病毒。因此,开发新型结构的非核苷类逆转录酶抑制剂对于筛选出能够有效抑制野生型和多种耐药性HIV病毒,例如E138K突变病毒株的药物具有深远意义和良好的应用前景。
发明内容
本发明的发明人意外地发现一类新型化合物,其具有良好的抗HIV活性,较高的安全性,并能有效抑制HIV病毒株的耐药性,本发明即基于以上发现而完成。
本发明第一方面涉及式Ⅰ化合物或其可药用盐,
其中,
稠环为吡啶并环A,环A为5、6或7元杂环,环A上有一个或两个以上R1;
R1和R2分别独立地选自H、=O、卤素、-OH、-NRR’、-CN、-NO2、-CF3、-COOR、-CONRR’、-SO3H、-SO2NRR’、C1-6烷基、C3-6环烷基、C1-6烷氧基、取代的C1-6烷基、取代的C1-6烷氧基、取代的C1-6烷氨基、5、6或7元杂环基,所述取代基选自卤素、-OH、-NH2;
R4和R5分别独立地选自卤素、-OH、-NH2、-CF3、C1-6烃基(例如C1-6烷基)、C1-6烷氧基、-COOR;
R6选自H、-CN、卤素、C1-6烃基(例如C1-6烷基、C2-6烯基或C2-6炔基)、取代的C1-6烷基、取代的C2-6烯基、取代的C2-6炔基、C1-6烷氧基、-COOH、-CONRR’、-CF3、-SO3H、-SO2NRR’,-COOR’、含1-3个选自N、O、S的杂原子的五元或者六元杂芳基,并任选在其环上带有醛基、酮基、氰基、α,β不饱和氰基、烯基、炔基、醛基或者酮基,其中所述取代基选自-CN、-NO2、-NH2或-N3;
R和R’各自独立地选自H或者C1-6烃基;
X选自-NH-、-O-、-S-、-NR-;
Y选自C、N、O、S。
根据本发明第一方面任一项所述的式Ⅰ化合物或其可药用盐,其中,
稠环为吡啶并环A,环A为5、6或7元杂环,环A上有一个或两个以上R1;
R1为H;
R2选自H、=O、卤素、-OH、-NRR’、-CN、-NO2、-CF3、-COOR、-CONRR’、-SO3H、-SO2NRR’、C1-6烷基、C3-6环烷基、C1-6烷氧基、取代的C1-6烷基、取代的C1-6烷氧基、取代的C1-6烷氨基、5、6或7元杂环基,所述取代基选自卤素、-OH、-NH2;
R4和R5分别独立地选自卤素、-OH、-NH2、-CF3、C1-6烃基(例如C1-6烷基)、C1-6烷氧基、-COOR;
R6选自H、-CN、卤素、C1-6烃基(例如C1-6烷基、C2-6烯基或C2-6炔基)、取代的C1-6烷基、取代的C2-6烯基、取代的C2-6炔基、C1-6烷氧基、-COOH、-CONRR’、-CF3、-SO3H、-SO2NRR’,-COOR’、含1-3个选自N、O、S的杂原子的五元或者六元杂芳基,并任选在其环上带有醛基、酮基、氰基、α,β不饱和氰、烯基、炔基、醛基或者酮基,其中所述取代基选自-CN、-NO2、-NH2或-N3;
R和R’各自独立地选自H或者C1-6烃基;
X选自-NH-、-O-、-S-、-NR-;
Y选自C、N、O、S。
在本发明的一个实施方案中,R4和R5均为甲基,或R4和R5各自独立地选自卤素、C1-6烷氧基;
X为-O-。
根据本发明第一方面任一项所述的式Ⅰ化合物或其可药用盐,其中,
稠环为吡啶并环A,环A为5、6或7元杂环,环A上有一个或两个以上R1;
R1选自H、=O、卤素、-OH、-NRR’、-CN、-NO2、-CF3、-COOR、-CONRR’、-SO3H、-SO2NRR’、C1-6烷基、C3-6环烷基、C1-6烷氧基、取代的C1-6烷基、取代的C1-6烷氧基、取代的C1-6烷氨基、5、6或7元杂环基,所述取代基选自卤素、-OH、-NH2;
R2为H;
R4和R5分别独立地选自卤素、-OH、-NH2、-CF3、C1-6烃基(例如C1-6烷基)、C1-6烷氧基、-COOR’;
R6选自H、-CN、卤素、C1-6烃基(例如C1-6烷基、C2-6烯基或C2-6炔基)、取代的C1-6烷基、取代的C2-6烯基、取代的C2-6炔基、C1-6烷氧基、-COOH、-CONRR’、-CF3、-SO3H、-SO2NRR’,-COOR’、含1-3个选自N、O、S的杂原子的五元或者六元杂芳基,并任选在其环上带有醛基、酮基、氰基、α,β不饱和氰、烯基、炔基、醛基或者酮基,其中所述取代基选自-CN、-NO2、-NH2或-N3;
R和R’各自独立地选自H或者C1-6烃基;
X选自-NH-、-O-、-S-、-NR-;
Y选自C、N、O、S。
在本发明的一个实施方案中,R4和R5均为甲基,X为-O-。
根据本发明第一方面任一项所述的式Ⅰ化合物或其可药用盐,其中,
稠环为吡啶并环A,环A为5、6或7元杂环,环A上有一个或两个以上R1;
R1和R2均为H;
R4和R5分别独立地选自卤素、-OH、-NH2、-CF3、C1-6烃基(例如C1-6烷基)、C1-6烷氧基、-COOR;
R6选自H、-CN、卤素、C1-6烃基(例如C1-6烷基、C2-6烯基或C2-6炔基)、取代的C1-6烷基、取代的C2-6烯基、取代的C2-6炔基、C1-6烷氧基、-COOH、-CONRR’、-CF3、-SO3H、-SO2NRR’,-COOR’、含1-3个选自N、O、S的杂原子的五元或者六元杂芳基,并任选在其环上带有醛基、酮基、氰基、α,β不饱和氰、烯基、炔基、醛基或者酮基,其中所述取代基选自-CN、-NO2、-NH2或-N3;
R和R’各自独立地选自H或者C1-6烃基;
X选自-NH-、-O-、-S-、-NR-;
Y选自C、N、O、S。
在本发明的一个实施方案中,R4和R5均为甲基,或R4和R5各自独立地选自卤素、C1-6烷氧基,X为-O-。
根据本发明第一方面任一项所述的式Ⅰ化合物或其可药用盐,其中,
稠环为吡啶并环A,环A为咪唑环、噻唑环、咪唑烷-2-酮环、吡咯环、吡咯烷环、嘧啶环、吡嗪环、哌嗪环、嘧啶环或哒嗪环,环A上有一个或两个以上R1;;
R1和R2分别独立地选自H、=O、卤素、-OH、-NRR’、-CN、-NO2、-CF3、-COOR、-CONRR’、-SO3H、-SO2NRR’、C1-6烷基、C3-6环烷基、C1-6烷氧基、取代的C1-6烷基、取代的C1-6烷氧基、取代的C1-6烷氨基、5、6或7元杂环基,所述取代基选自卤素、-OH、-NH2;
R4和R5分别独立地选自卤素、-OH、-NH2、-CF3、C1-6烃基(例如C1-6烷基)、C1-6烷氧基、-COOR;
R6选自H、-CN、卤素、C1-6烃基(例如C1-6烷基、C2-6烯基或C2-6炔基)、取代的C1-6烷基、取代的C2-6烯基、取代的C2-6炔基、C1-6烷氧基、-COOH、-CONRR’、-CF3、-SO3H、-SO2NRR’,-COOR’、含1-3个选自N、O、S的杂原子的五元或者六元杂芳基,并任选在其环上带有醛基、酮基、氰基、α,β不饱和氰、烯基、炔基、醛基或者酮基,其中所述取代基选自-CN、-NO2、-NH2或-N3;
R和R’各自独立地选自H或者C1-6烃基;
X选自-NH-、-O-、-S-、-NR-;
Y选自C、N、O、S。
根据本发明第一方面任一项所述的式Ⅰ化合物或其可药用盐,其选自以下化合物:
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-1);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰基-苯氧基)-7-溴-3H-咪唑并[4,5-c]吡啶(I-2);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰基-苯氧基)-1,3-二氢咪唑并[4,5-c]吡啶-2-酮(I-3);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-4);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-溴-3H-咪唑并[4,5-c]吡啶(I-5);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-甲氧基-3H-咪唑并[4,5-c]吡啶(I-8);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-乙氧基-3H-咪唑并[4,5-c]吡啶(I-9);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-(2-羟基乙氧基)-3H-咪唑并[4,5-c]吡啶(I-12);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-硝基-3H-咪唑并[4,5-c]吡啶(I-14);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-甲氨基-3H-咪唑并[4,5-c]吡啶(I-16);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-二乙氨基-3H-咪唑并[4,5-c]吡啶(I-18);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-(3-羟基丙氨基)-3H-咪唑并[4,5-c]吡啶(I-19);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-哌嗪-1-基-3H-咪唑并[4,5-c]吡啶(I-20);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-吡咯烷-1-基-3H-咪唑并[4,5-c]吡啶(I-21);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-咪唑-1-基-3H-咪唑并[4,5-c]吡啶(I-22);
4-(4-氰基苯胺基)-6-(2-溴-6-甲氧基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-23);
4-(4-氰基苯胺基)-6-(2-溴-6-甲氧基-4-氰乙基-苯氧基)-7-氯-3H-咪唑并[4,5-c]吡啶(I-24);
4-(4-氰基苯胺基)-6-(2,6-二氟-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-25);
2-丙氧基-4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-26);
2-甲基-4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-28);
1-乙氧甲酰基-4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-29);
5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-吡嗪并[4,3-b]吡啶(I-30);
2-羟基-5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-吡嗪并[4,3-b]吡啶(I-31);
2,3-二羟基-5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-吡嗪并[4,3-b]吡啶(I-32);
5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-8-溴-吡嗪并[4,3-b]吡啶(I-33);
5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰乙基-苯氧基)-吡嗪并[4,3-b]吡啶(I-34);
2,3-二羟基-5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-吡啶并[4,3-b]吡啶(I-35);
5-(4-氰基苯胺基)-7-(2,6-二甲氧基-4-氰乙基-苯氧基)-吡嗪并[4,3-b]吡啶(I-36);
5-(4-氰基苯胺基)-7-(2,6-二氟-4-氰乙基-苯氧基)-吡嗪并[4,3-b]吡啶(I-37);
5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰乙基-苯氧基)-8-溴-吡嗪并[4,3-b]吡啶(I-38);
5-(4-氰基苯胺基)-7-[2,6-二甲基-4-(2-氰基乙烯基)-苯氧基]-吡嗪并[4,3-b]吡啶(I-39);
5-(4-氰基苯胺基)-7-(2,6-二氟-苯氧基)-吡嗪并[4,3-b]吡啶(I-41);
5-(4-氰基苯胺基)-7-(2,4,6-三溴-苯氧基)-吡嗪并[4,3-b]吡啶(I-42);
5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰乙基-苯氧基)-8-溴-哌啶并[4,3-b]吡啶(I-44);
5-(4-氰基苯胺基)-7-(2-溴-6-甲氧基-4-氰乙基-苯氧基)-吡嗪并[4,3-b]吡啶(I-45);
5-(4-氰基苯胺基)-7-(2-溴-6-甲氧基-4-氰乙基-苯氧基)-8-氯-吡嗪并[4,3-b]吡啶(I-46);
5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰乙基-苯氧基)-8-氯-吡嗪并[4,3-b]吡啶(I-47)。
本发明第二方面涉及本发明第一方面任一项所述的式Ⅰ化合物或其可药用盐的制备方法,其包含以下步骤:
1)式II的2,6-二卤代吡啶类化合物与式Ⅲ的对氰基苯胺反应,生成式IV的2-(4-氰基苯胺基)多取代吡啶类化合物;
2)式IV化合物与式Ⅴ化合物进行偶联反应,生成式VI的2-(4-氰基苯胺基)多取代吡啶类化合物;
3)式VI化合物进行关环反应,生成式I化合物;
其中,R1’选自-NO2,-NH2;R2’选自-NO2,-NH2,-CN,-COOH,-COOCH3,-CONHR’,卤素,OH,SH;R1,R2,R4,R5,R6,R’,X和Y的定义如本发明第一方面所述。
在本发明的一个实施方案中,中间体IV可通过如下方法合成:
在碱如叔丁醇钾、氢氧化钠、吡啶、氢化钠、三乙胺、N,N-二甲胺基吡啶、碳酸钠、碳酸氢钠、碳酸铯、碳酸钾或碳酸钾/卤化亚铜存在下,使2,6-二卤代吡啶Ⅱ和对氰基苯胺在溶剂例如但不限于甲醇、乙醇、乙腈、DMF、叔丁醇或DMSO中在室温至140℃以下,反应5分钟~24小时,生成2-(4-氰基苯胺基)多取代吡啶Ⅳ。反应物Ⅱ/Ⅲ的投料摩尔比为:1:1~1:2。
该反应也可在微波作用下,以DMF,DMA或DMSO为溶剂,温度可以在110℃~180℃之间,反应5~30分钟,得到中间体Ⅳ,所用碱以及化合物Ⅱ和Ⅲ的物料比同上所述。
该反应也可以使Ⅱ和Ⅲ在惰性气体保护下,50~180℃直接无溶剂反应,Ⅱ和Ⅲ物料比同上所述。
在本发明的一个实施方案中,当通式中X为-O-时,中间体Ⅵ可通过如下方法合成:
方法1:使2-(4-氰基苯胺基)多取代吡啶Ⅳ与三取代苯酚V以DMF,DMSO,DMA等为溶剂,以碳酸钾为碱,在铜或亚铜试剂(CuI,CuBr,CuCl)为催化剂存在下,氮气保护,加热至100~150℃,反应2~8小时,或者无催化剂条件下,于130~150℃反应2~24小时。
方法2:在干燥乙醚中,使式V的三取代苯酚与NaH或者叔丁醇钾反应成钠盐或钾盐,其盐与Ⅳ在DMF或DMA中回流0.5~10小时;
方法3:使中间体Ⅳ在DMF,DMA或者DMSO中与V的钠盐或者钾盐在微波条件下反应5~30分钟;
方法4:以DMF为溶剂,使中间体Ⅳ与三取代苯酚V及碳酸钾微波反应例如5-30分钟。
在本发明的一个实施方案中,当目标化合物通式中X为-NH-时,中间体Ⅵ的合成方法可以是:
方法(1):使中间体Ⅳ与三取代苯胺V在非质子极性溶剂(DMA,DMF,DMSO)中,以铜或亚铜试剂(CuI,CuBr,CuCl)为催化剂,以碳酸钾为碱,氮气保护,温度130~160℃反应2~24小时。
方法(2):以钯试剂为催化剂,甲苯为溶剂,碳酸铯为碱,氮气保护,使中间体Ⅳ与三取代苯胺V在例如100℃左右反应例如1~24小时。
方法(3):将中间体Ⅳ与三取代苯胺V混合,无溶剂状态下,加热至100~180℃,反应2~24小时;
方法(4):如果三取代苯胺V为液体,则以此苯胺溶剂,微波反应,温度在此苯胺沸点温度反应15~30分钟。
方法(5):以DMSO或NMP为溶剂,三取代苯胺V与中间体Ⅳ摩尔比为4:1,在叔丁醇钾存在下,温度200~250℃,微波反应15~30分钟。
当X为本发明定义的其它基团时,本领域技术人员可根据上述方法或本领域公知方法合成通式Ⅵ化合物,例如X为-S-,-NR”-,其中R”为甲基,乙基,丙基等。
在本发明的实施方案中,式I化合物可通过如下方法合成:
在本发明的一个实施方案中,当通式Ⅵ中R1’为硝基,R2’为氨基时,采用Fe/NH4Cl法,保险粉法,氢气还原法等硝基还原方法,将硝基还原为氨基,然后与乙二醛在乙醇中回流,生成吡啶并哒嗪化合物。
采用上述方法将硝基还原为氨基,然后与原甲酸三乙酯,在DMF,DMSO或者DMA中,酸性催化下,生成吡啶并咪唑类化合物。
类似地,通过上述方法可合成本发明其它定义的式I化合物,例如当R2’为-OH,-SH或-COOH等。
本发明合成式I化合物的方法中,反应所用的各种原料是本领域技术人员根据已有知识可以制备得到的,或者是可以通过文献公知的方法制得的,或者是可以通过商业购得的。以上方案中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术人员已有知识可以做适当改变的。或者,本领域技术人员也可以根据本发明第二方面方法合成本发明未具体列举的其他式I化合物。
本发明第三方面涉及药物组合物,其包含本发明第一方面任一项所述的式Ⅰ化合物或其可药用盐,以及药学上可接受的载体或赋形剂。
本发明第四方面涉及本发明第一方面任一项所述的式Ⅰ化合物或其可药用盐,或本发明三方面任一项所述的药物组合物用于制备预防和/或治疗与HIV病毒感染有关的疾病或病症的药物中的用途。
在本发明的实施方案中,所述疾病或病症为艾滋病。
在本发明的实施方案中,所述HIV病毒为HIV-1或HIV-2病毒。
在本发明的实施方案中,所述HIV病毒为野生型或突变型HIV病毒。
在本发明的实施方案中,所述突变型HIV病毒为非核苷逆转录酶抑制剂的耐药突变病毒。
本发明的第五方面涉及预防和/或治疗与HIV病毒感染有关的疾病或病症的方法,其包含向有需要的受试者给予本发明第一方面任一项所述的式Ⅰ化合物或其可药用盐,或本发明三方面任一项所述的药物组合物的步骤。
在本发明的实施方案中,所述疾病或病症为艾滋病。
在本发明的实施方案中,所述HIV病毒为HIV-1或HIV-2病毒。
在本发明的实施方案中,所述HIV病毒为野生型或突变型HIV病毒。
在本发明的实施方案中,所述突变型HIV病毒为非核苷逆转录酶抑制剂的耐药突变病毒。
本发明第六方面涉及本发明第一方面任一项所述的式Ⅰ化合物或其可药用盐,或本发明三方面任一项所述的药物组合物,其用于预防和/或治疗与HIV病毒感染有关的疾病或病症。
在本发明的实施方案中,所述疾病或病症为艾滋病。
在本发明的实施方案中,所述HIV病毒为HIV-1或HIV-2病毒。
在本发明的实施方案中,所述HIV病毒为野生型或突变型HIV病毒。
在本发明的实施方案中,所述突变型HIV病毒为非核苷逆转录酶抑制剂的耐药突变病毒。
本发明第七方面涉及用于杀死细胞中HIV病毒或抑制细胞中HIV病毒增殖的方法,其包括给所述的细胞施用有效量的第一方面任一项所述的式Ⅰ化合物或其可药用盐,或本发明三方面任一项所述的药物组合物。
在本发明的实施方案中,所述方法在体外进行。
在本发明的实施方案中,所述方法在体内进行。
根据本发明第七方面任一项所述的方法,所述细胞为细胞系,或者来自受试者的细胞,例如HIV病毒感染的细胞。
在本发明的实施方案中,所述HIV病毒为HIV-1或HIV-2病毒。
在本发明的实施方案中,所述HIV病毒为野生型或突变型HIV病毒。
在本发明的实施方案中,所述病毒为非核苷逆转录酶抑制剂的耐药突变病毒。
本发明第八方面涉及本发明第一方面任一项所述的式Ⅰ化合物或其可药用盐,或本发明三方面任一项所述的药物组合物用于制备非核苷类逆转录酶抑制剂的用途,所述抑制剂用于抑制细胞中逆转录酶的表达。
在本发明的实施方案中,所述逆转录酶为HIV病毒的逆转录酶。
在本发明的实施方案中,所述HIV病毒为HIV-1或HIV-2病毒。
在本发明的实施方案中,所述逆转录酶为野生型或突变型HIV病毒的逆转录酶。
在本发明的实施方案中,所述抑制剂用于体外方法中。
在本发明的实施方案中,所述抑制剂用于体内方法中。
在本发明的实施方案中,所述细胞为细胞系,或来自受试者的细胞,例如HIV感染的细胞。
本发明第九方面涉及本发明第一方面任一项所述的式Ⅰ化合物或其可药用盐,或本发明三方面任一项所述的药物组合物,其用于抑制细胞中逆转录酶的表达。
在本发明的实施方案中,其用于体外方法中。
在本发明的实施方案中,其用于体内方法中。
在本发明的实施方案中,所述细胞为细胞系,或来自受试者的细胞,例如HIV病毒感染的细胞。
在本发明的实施方案中,所述HIV病毒为HIV-1或HIV-2病毒。
在本发明的实施方案中,所述HIV病毒为野生型或突变型HIV病毒。
在本发明的实施方案中,所述病毒为非核苷逆转录酶抑制剂的耐药突变病毒。
一种抑制细胞中逆转录酶表达的试剂盒,所述试剂盒包括本发明第一方面任一项所述的式Ⅰ化合物或其可药用盐,或本发明第三方面任一项所述的药物组合物,且,任选地还包括使用说明。
本文所用术语“杂环”是指任选地含有1-3个选自N、O、S的杂原子(例如含有1个N原子、2个N原子、3个N原子、1个O原子、2个O原子、1个S原子、1个N原子和1个O原子、或者1个N原子和1个S原子等)的脂肪或芳香环系,例如含有5-7个原子的杂环,典型的例子包括但不限于吡咯烷环、四氢呋喃环、吡咯环、呋喃环、噻吩环、咪唑环、咪唑啉环、恶唑环、噻唑环、咪唑烷-2-酮环、吡咯烷环、哌啶环、吡啶环、哌嗪环、吡嗪环、嘧啶环或哒嗪环等。
本发明中所提到的术语“卤素”,“卤”,“Hal”或“卤代”是指氟,氯,溴和碘。
本发明中所采用的术语“烃基”是指烃类分子中失去一个氢原子而得到的基团,所述烃类分子是指由碳原子和氢原子构成的分子,主要包含脂肪烃和芳香烃,常见的如烷烃、烯烃、炔烃、环烃和芳烃等。上述烃类分子失去一个氢原子形成所述“烃基”,例如烷基(例如支链烷基,直链烷基)、环烷基、烯基和炔基。在本发明一个实施方案中,本发明所述“C1-6烃基”例如包括C1-6烷基,C2-6烯基,C2-6炔基,C3-6环烷基,C3-6环烯基。
本发明中所使用的术语“烷基”是指直链或支链一价饱和烃基,例如为C1-6烷基、C1-4烷基。术语“C1-6烷基”意指具有1~6,即1、2、3、4、5或6个碳原子的直链或支链烷基,典型地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基和己基等。相似地,术语“C1-4烷基”意指具有1、2、3或4个碳原子的直链或支链烷基,即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。当所述烷基被选自-CN、-NO2、-NH2或-N3等的基团取代后得到所述取代烷基,例如“取代的C1-6烷基”,“取代的C1-4烷基”等,具体的例子包括但不限于2-氰基乙基等。
本发明中所使用的术语“C1-6烷氧基”是指上述的C1-6烷基与氧原子连接后生成的基团,具体的例子包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基。当所述C1-6烷氧基被选自卤素、羟基、氨基的基团取代后得到所述“取代的C1-6烷氧基”,具体的例子包括但不限于2-羟基乙氧基等。
本发明中所使用的术语“C1-6烷氨基”是指上述的C1-6烷基与氮原子连接后生成的基团,当有两个所述C1-6烷基连在同一个氮原子上形成所述“二C1-6烷氨基”,具体的例子包括但不限于甲氨基、二甲胺基、二乙胺基等。当所述C1-6烷氨基被选自卤素、羟基、氨基的基团取代后得到所述“取代的C1-6烷氨基”,具体的例子包括但不限于3-羟基丙胺基等。
本发明中使用的术语“C2-6烯基”是指具有2-6个碳原子的烯基,所述烯基具有1、2或3个碳碳双键,当具有一个以上的碳碳双键时,所述碳碳双键共轭或非共轭。本发明中的C2-6烯基的实例包括乙烯基,丙烯基。当所述C2-6烯基被选自-CN、-NO2、-NH2或-N3的基团取代时,得到所述的“取代的C2-6烯基”,具体的例子包括但不限于2-氰基乙烯基等。
本发明中使用的术语“α,β不饱和氰、烯基、炔基、醛基或者酮基”是指所述氰基、烯基、炔基、醛基或者酮基与碳碳双键形成1,4共轭体系,具体结构如下所示:-C=C-CN、-C=C-C=C-、-C=C-C≡C-、-C=C-CHO或其中不饱和的碳原子上还可连接氢,卤素,硝基,氰基等,在本发明的实施方案中,所述α,β不饱和炔基或者酮基通过其α端连接到式I化合物R6的五元或者六元杂芳基上。
本发明中使用的术语“C2-6炔基”是指具有2-6个碳原子的炔基,所述炔基具有1、2或3个碳碳三键,当具有一个以上的碳碳三键时,所述碳碳三键共轭或非共轭。本发明中的C2-6炔基的实例包括乙炔基,丙炔基。当所述C2-6炔基被选自-CN、-NO2、-NH2或-N3的基团取代时,得到所述的“取代的C2-6炔基”,具体的例子包括但不限于2-氰基乙炔基等。
本发明中使用的术语“耐药突变”是指病毒在药物环境下产生的突变,这种突变使得药物作用靶点的生化或结构特征发生改变,从而导致该病毒对药物产生了耐受。在本发明的实施方案中,所述耐药突变是指HIV病毒对非核苷类逆转录酶抑制剂的耐药突变,具体地,耐药突变的位点可选自E138K、K103N/S、A98G、L100I、K101E/P/Q、V106A/M/N、V108I、T139I、T181C、G190A/S/E、F227C/L、P236L、P225H、Y181C/I/V、Y188L/C/H、M230L、K238T、V179D/F/I、L234I、L318F、L283I和I135T/M。例如,所述耐药突变位点可为E138K或K103N/Y181C。在本发明的实施方案中,野生型HIV病毒选自NL4-3、Bal或IIIB等。
本发明化合物既可以其本身也可以其药用盐的形式使用。式I化合物的可药物盐包括与药学上可以接受的无机酸或者有机酸、或者无机碱或有机碱形成的常规盐。合适的酸加成盐的例子包括盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟基萘甲酸、氢碘酸、苹果酸、鞣酸等形成的盐。合适的碱加成盐的例子包括钠、钾、镁、锂、铝、钙、锌、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因等形成的盐。本文中涉及到本发明化合物时,包括式I化合物及其可药用盐。
本发明式I化合物或其可药用盐还可以包括其异构体、消旋体、对映体、非对映体、对映体富集物或酯(当其存在时),本发明式I化合物以及它的异构体、消旋体、对映体、非对映体、对映体富集物或酯还可以形成溶剂合物,例如水合物、醇合物等。上述化合物还可以是前药或可在体内代谢变化后释放出所述活性成分的形式,因此本发明也包括本发明化合物的前药和活性代谢物。选择和制备适当的前药衍生物是本领域技术人员公知技术。例如,在“Design Of Prodrugs”,H Bund Saard,Elsevier编辑,1985年版中描述了选择和制备适宜前药衍生物的常规方法。一般来说,基于能够实现本发明的目的,与药学可接受的溶剂如水、乙醇等的溶剂合物的形式与非溶剂合物形式相当。
本文所用的术语“药物组合物”意指包括包含指定量的各指定成分的药品,以及直接或间接从指定量的各指定成分的组合产生的药品。本发明式I化合物可与常规药物载体或赋形剂组成药物组合物。这里的载体包括但不限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血白蛋白,缓冲物质如磷酸盐,甘油,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态二氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛脂。
本发明的化合物或药物组合物可按本领域常规方法制备成各种剂型,包括但不限于片剂、胶囊、溶液、悬浮液、颗粒剂或注射剂等,经口服、直肠、胃肠外、池内、阴道内、腹膜内、局部(如通过散剂、软膏剂或滴剂)、口颊给予人类或其他哺乳动物,或者作为口腔喷雾剂或鼻腔喷雾剂给予。本文所用术语“胃肠外”指包括静脉内、肌肉内、腹膜内、胸骨内、皮下和关节内注射和输液的给药方式。
适合于胃肠外注射的本发明化合物或药物组合物可包括生理上可接受的无菌含水或非水溶液剂、分散剂、混悬剂、或乳剂,及供重构成无菌可注射溶液剂或分散剂的无菌散剂。合适的含水或非水载体、稀释剂、溶剂或媒介物的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)植物油(如橄榄油)、可注射有机酯如油酸乙酯以及它们的合适混合物。
这些化合物或药物组合物也可含有辅料,如防腐剂、湿润剂、乳化剂和分散剂。通过各种抗细菌剂和抗真菌剂,例如尼泊金酯类、三氯叔丁醇、苯酚、山梨酸等,可确保防止微生物的作用。还期望包括等渗剂,例如糖类、氯化钠等。通过使用能延迟吸收的物质,例如单硬脂酸铝和明胶,可达到可注射药物形式的延长吸收。
混悬剂中除活性化合物外还可含有悬浮剂,例如乙氧基化异十八醇、聚氧乙烯山梨醇和聚氧乙烯失水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄耆胶或者这些物质的混合物等。
在一些情况下,为延长药物的作用,期望减慢皮下或肌肉内注射药物的吸收。这可通过使用水溶性差的晶体或无定形物质的液体混悬剂来实现。这样,药物的吸收速度取决于其溶解速度,而溶解速度又取决于晶体大小和晶型。或者,胃肠外给药的药物形式的延长吸收通过将该药物溶解于或悬浮于油媒介物中来实现。
可注射贮库制剂形式可通过在生物可降解聚合物如聚丙交酯-聚乙交酯中形成药物的微胶囊基质来制备。可根据药物与聚合物之比和所采用的具体聚合物的性质,对药物释放速度加以控制。其他生物可降解聚合物得到实例包括聚原酸酯类和聚酐类。可注射贮库制剂也可通过将药物包埋于能与身体组织相容的脂质体或微乳中来制备。
可注射制剂可例如通过用滤菌器过滤或通过掺入无菌固体组合物形式的灭菌剂来灭菌,所述固体组合物可在临用前溶解或者分散于无菌水或其他无菌可注射介质。
本发明化合物或其药物组合物可用口服方法或非胃肠道给药方式。口服给药可以是片剂、胶囊剂、包衣剂,肠道外用药制剂有注射剂和栓剂等。这些制剂是按照本领域的技术人员所熟悉的方法制备的。为了制造片剂、胶囊剂、包衣剂所用辅料是常规的辅料,例如淀粉、明胶、阿拉伯胶、硅石、聚乙二醇,液体剂型所用的溶剂如水、乙醇、丙二醇、植物油(如玉米油、花生油、橄榄油等)。含有本发明化合物的制剂中还有其他辅料,例如表面活性剂,润滑剂,崩解剂,防腐剂,矫味剂和色素等。在片剂、胶囊剂、包衣剂、注射剂和栓剂中含有本发明式I化合物的剂量是以单元剂型中存在的化合物的量计算的。在单元剂型中本发明式I化合物一般含量为1-5000mg,优选的单元剂型含有10-500mg,更优选的单元剂型含有20-300mg。
具体地说,本发明可以提供的供口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在此类固体剂型中,活性化合物可与至少一种惰性的药物可接受赋形剂或载体如柠檬酸钠或磷酸二钙和/或以下物质混合:a)填充剂或增量剂如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸;b)粘合剂如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯树胶;c)保湿剂如甘油;d)崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)溶液阻滞剂如石蜡;f)吸收加速剂如季胺化合物;g)湿润剂如鲸蜡醇和甘油单硬脂酸酯;h)吸附剂如高岭土和膨润土;i)润滑剂如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠和它们的混合物。在胶囊剂、片剂和丸剂的情况下,所述剂型中也可包含缓冲剂。
相似类型的固体组合物使用赋形剂例如乳糖剂高分子量聚乙二醇等,也可用作软胶囊和硬胶囊中的填充物。
片剂、糖衣丸剂、胶囊剂、丸剂和颗粒剂的固体剂型可与包衣和壳料如肠溶衣材和医药制剂领域公知的其他衣材一起制备。这些固体剂型可任选含有遮光剂,且其组成还可使其只是或优先地在肠道的某个部位任选以延迟方式释放活性成分。可以使用的包埋组合物的实例包括高分子物质和蜡类。如果合适,活性化合物也可与一种或多种上述赋形剂配成微胶囊形式。
供口服给药的液体剂型包括药物可接受的乳剂、溶液剂、混悬剂、糖浆剂和酏剂。液体剂型除含有活性化合物外还可含有本领域常用的惰性稀释剂,例如水或其他溶剂,增溶剂和乳化剂例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油类(如玉米油、花生油、棉籽油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯及它们的混合物。口服组合物除包含惰性稀释剂外还可包含辅料,例如湿润剂、乳化和悬浮剂、甜味剂、矫味剂和香味剂。
供直肠或阴道给药的组合物优选是栓剂。栓剂可通过将发明化合物与合适的飞刺激性赋形剂或载体例如可可脂、聚乙二醇或栓剂蜡混合来制备,它们在室温下为固体,但在体温下为液体,因此可在直肠腔或阴道腔内融化而释放出活性化合物。
本发明的化合物及其组合物还考虑用于局部给药。供局部给予本发明化合物的剂量形式包括散剂、喷雾剂、软膏剂和吸入剂。在无菌条件下将活性化合物与药学可接受的载体和任何所需的防腐剂、缓冲剂或推进剂混合。眼用制剂、眼软膏剂、散剂和溶液剂也被考虑在本发明范围内。
本发明化合物也可以脂质体形式给药。如本领域所公知,脂质体通常用磷脂或其他脂类物质制得。脂质体由分散于含水介质中的单层或多层水化液晶所形成。任何能够形成脂质体的无毒、生理上可接受和可代谢的脂质均可使用。脂质体形式的本发明组合物除含有本发明化合物外,还可含有稳定剂、防腐剂、赋形剂等。优选的式天然和合成的磷脂和磷脂酰胆碱(卵磷脂),它们可以单独或者一起使用,形成脂质体的方法是本领域公知的。
当用于上述预防和/或治疗时,预防和/或治疗有效量的一种本发明化合物可以以纯形式应用,或者以药学可接受的酯或前药形式(在存在这些形式的情况下)应用。或者,所述化合物可以以含有该项目的化合物与一种或多种药物可接受的载体或赋形剂的药物组合物给药。术语“预防和/或治疗”的本发明化合物指以适用于任何医学预防和/或治疗的合理效果/风险比治疗障碍的足够量的化合物。但应认识到,本发明化合物和药物组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定,对于任何具体的患者,具体的治疗有效剂量水平须根据多种因素而定,所述因素包括所治疗的疾病或障碍和该疾病或障碍的严重程度;所采用的具体化合物的活性;所采用的具体组合;患者的年龄、体重、一般健康状况、性别和饮食;所采用的具体化合物的给药时间、给药途径、和排泄率;治疗持续时间;所采用的具体化合物组合使用或同时使用的药物;及医疗领域公知的类似因素。例如,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。一般说来,本发明式I化合物用于哺乳动物特别是人的剂量可以介于0.001-1000mg/kg体重/天,例如介于0.01-100mg/kg体重/天,例如介于0.01-10mg/kg体重/天。
本发明化合物结构新颖,具有较高的抗HIV活性,并且能有效抵抗HIV突变病毒株的耐药性,是一类具有较高应用潜力的非核苷类HIV逆转录酶抑制剂。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
制备实施例1 2-(4-氰基苯胺基)-3-硝基-4-氨基-6-氯-吡啶(IV-1)
2,6-二氯-3-硝基-4-氨基吡啶(II-1,416mg,2.0mmol)和对氰基苯胺(III-1,472mg,4.0mmol),无溶剂反应,100℃反应过夜,加入DMF溶解,导入水中pH=3.0,搅拌10分钟,抽滤,滤出固体在碳酸氢钠水溶液中搅拌15分钟,抽滤,水洗,干燥,中压柱分离纯化(二氯甲烷,乙酸乙酯为洗脱剂),得黄色固体491.3mg,产率85%。
制备实施例2 2-(4-氰基苯胺基)-3-硝基-4-氨基-5-溴-6-氯-吡啶(IV-2)
以4-氨基-3-硝基-2,6-二氯-5-溴吡啶为原料,制备方法同IV-1,产率90%。
制备实施例3 2-(4-氰基苯胺基)-3-硝基-4-氨基-5,6-二氯吡啶(IV-3)
以4-氨基-3-硝基-2,5,6-三氯吡啶为原料,制备方法同IV-1,产率92.75%。
制备实施例4 2-(4-氰基苯胺基)-3-硝基-4-氨基-5-碘-6-氯-吡啶(IV-4)
以4-氨基-3-硝基-2,6-二氯-5-碘吡啶为原料,制备方法同IV-1,产率40%。
制备实施例5 2-(4-氰基苯胺基)-3,5-二硝基-4-氨基-6-氯-吡啶(IV-5)
以4-氨基-3,5-二硝基-2,6-二氯吡啶为原料,制备方法同IV-1,产率89%。
制备实施例6 2-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰基-苯氧基)-3-硝基-4-氨基吡啶(VI-1)
将化合物IV-1(319mg,1.1mmol)与2,6-二甲基-4-氰基苯酚(294mg,2.0mmol),溶于4mL DMF中,加入碳酸钾(276mg,2.0mmol),140℃,微波反应25分钟。倒入水中,加入饱和氯化钠水溶液,搅拌30分钟,抽滤,水洗,干燥,中压柱分离(二氯甲烷,乙酸乙酯为洗脱剂),得到黄色固体315mg,产率:71.20%。
制备实施例7 2-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰基-苯氧基)-3-硝基-4-氨基-5-溴吡啶(VI-2)
以化合物Ⅳ-2和2,6-二甲基-4-氰基苯酚为原料,制备方法同VI-1,产率85%。
制备实施例8 2-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3-硝基-4-氨基吡啶(VI-3)
以化合物IV-1和2,6-二甲基-4-氰乙基苯酚为原料,制备方法同VI-1,产率76%。
制备实施例9 2-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3-硝基-4-氨基-5-溴吡啶(VI-4)
以化合物IV-2和2,6-二甲基-4-氰乙基苯酚为原料,制备方法同VI-1,产率77%。
制备实施例10 2-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3-硝基-4-氨基-5-氯吡啶(VI-5)
以化合物IV-3和2,6-二甲基-4-氰乙基苯酚为原料,制备方法同VI-1,产率96.91%。
制备实施例11 2-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3-硝基-4-氨基-5-碘吡啶(VI-6)
以化合物IV-4和2,6-二甲基-4-氰乙基-苯酚为原料,制备方法同VI-1,产率89.35%。
制备实施例12 2-(4-氰基苯胺基)-6-(2,6-二甲基-4-丙烯氰基-苯氧基)-3-硝基-4-氨基吡啶(VI-7)
以化合物IV-1和2,6-二甲基-4-(2-氰基乙烯基)苯酚为原料,制备方法同VI-1,产率77%。
制备实施例13 2-(4-氰基苯胺基)-6-[2,6-二甲基-4-(2-氰基乙烯基)-苯氧基]-3-硝基-4-氨基-5-溴吡啶(VI-8)
以化合物IV-2和2,6-二甲基-4-(2-氰基乙烯基)苯酚为原料,制备方法同VI-1,产率77%。
制备实施例14 2-(4-氰基苯胺基)-6-(2-溴-4-氰乙基-6-甲氧基-苯氧基)-3-硝基-4-氨基吡啶(VI-9)
以化合物IV-1和4-(2-氰基乙烯基)-2-甲氧基-6-溴苯酚为原料,制备方法同VI-1,产率77%。
制备实施例15 2-(4-氰基苯胺基)-6-(2-溴-4-氰乙基-6-甲氧基-苯氧基)-3-硝基-4-氨基-5-氯吡啶(VI-10)
以化合物IV-3和4-氰乙基-2-甲氧基-6-溴苯酚为原料,制备方法同VI-1,产率67%。
制备实施例16 2-(4-氰基苯胺基)-6-(2,6-二氟-4-氰乙基-苯氧基)-3-硝基-4-氨基吡啶(VI-11)
以化合物IV-1和4-氰乙基-2,6-二氟苯酚为原料,制备方法同VI-1,产率77.10%。
制备实施例17 2-(4-氰基苯胺基)-6-(2,6-二甲氧基-4-氰乙基-苯氧基)-3-硝基-4-氨基吡啶(VI-12)
以化合物IV-1和4-氰乙基-2,6-二甲氧基苯酚为原料,制备方法同VI-1,产率77.05%。
制备实施例18 2-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3,5-二硝基-4-氨基吡啶(VI-13)
以化合物IV-5和4-氰乙基-2,6-二甲基苯酚为原料,制备方法同VI-1,产率77.05%。
制备实施例19 2-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3-硝基-4-乙酰氨基吡啶(VI-14)
化合物VI-3在醋酸酐中回流过夜,产率77.05%。
实施例1 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-1)
VI-1(100mg,0.25mmol)溶于THF/甲醇/水(5ml/5ml/2ml)中,还原铁粉(139mg,2.5mmol),NH4Cl(135mg,2.5mmol),回流3小时,硅藻土抽滤,THF洗,减压除去溶剂,剩余物真空干燥,加入DMF(3ml),加入0.2ml原甲酸三乙酯,0.5ml盐酸乙醚,室温搅拌3小时。加入0.5mL三乙胺,倒入30ml冰水中,搅拌10分钟,乙酸乙酯提取,水洗,饱和食盐水洗,无水硫酸钠干燥,旋干,得粗品,中压柱分离(二氯甲烷和甲醇为洗脱剂),得白色固体58.5mg,产率61.64%。1H NMR(DMSO-d6)δppm 2.05(6H,s,2×CH3),6.65(1H,s,ArH-3),7.30(2H,d,J=8.4Hz,ArH-2’,6’),7.56(2H,d,J=8.4Hz,ArH-3’,5’),7.74(2H,s,ArH-3”,5”),8.17(1H,s,ArH-6),9.80(1H,s,NH-1’),12.68(1H,s,NH-6).MS m/z(%)381.3(M+1,100).
实施例2 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰基-苯氧基)-7-溴-3H-咪唑并[4,5-c]吡啶(I-2)
制备方法同I-1,VI-2为原料,产率65.43%,1H NMR(DMSO-d6)δppm2.07(6H,s,2×CH3),7.28(2H,d,J=8.4Hz,ArH-2’,6’),7.46(2H,d,J=8.4Hz,ArH-3’,5’),7.78(2H,s,ArH-3”,5”),8.17(1H,s,ArH-6),9.94(1H,s,NH-1’),13.26(1H,s,NH-6).MS m/z(%)459(M+1,100).
实施例3 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰基-苯氧基)-1,3-二氢咪唑并[4,5-c]吡啶-2-酮(I-3)
VI-1(100mg,0.25mmol)溶于THF/甲醇/水(5ml/5ml/2ml)中,还原铁粉(139mg,2.5mmol),NH4Cl(135mg,2.5mmol),回流3小时,硅藻土抽滤,THF洗,减压除去溶剂,剩余物真空干燥,溶于二氯甲烷(5ml)中,加入三光气(120mg,0.4mmol),室温搅拌30分钟,减压除去二氯甲烷,剩余物加入3ml水,搅拌15分钟,抽滤,水洗,得白色固体75mg,产率75.76%。1HNMR(DMSO-d6)δppm 2.09(6H,s,2×CH3),6.33(1H,s,pyridine-H),7.22(2H,d,J=8.4Hz,ArH-2’,6’),7.35(2H,d,J=8.4Hz,ArH-3’,5’),7.76(2H,s,ArH-3”,5”),8.97(1H,s,NH),10.25(1H,s,NH-1’),11.18(1H,s,NH-6).MSm/z(%)397(M+1,100).
实施例4 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-4)
方法同I-1,VI-3为原料,产率60.15%,1H NMR(DMSO-d6)δppm 2.08(6H,s,2×CH3),2.89(4H,br,2×CH2),6.52(1H,s,ArH-3),7.13(2H,s,ArH-3”,5”),7.38(2H,d,J=8.4Hz,ArH-2’,6’),7.75(2H,d,J=8.4Hz,ArH-3’,5’),8.17(1H,s,ArH-6),9.75(1H,s,NH-1’),12.61(1H,s,NH-6).MSm/z(%)381.3(M+1,100).
实施例5 4-(4-氰基苯胺)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-溴-3H-咪唑并[4,5-c]吡啶(I-5)
制备方法同I-1,VI-4为原料,产率67.32%,1H NMR(DMSO-d6)δppm2.06(6H,s,2×CH3),2.89(4H,br,2×CH2),6.52(1H,s,ArH-3),7.17(2H,s,ArH-3”,5”),7.33(2H,d,J=8.4Hz,ArH-2’,6’),7.60(2H,d,J=8.4Hz,ArH-3’,5’),8.27(1H,s,ArH-6),9.88(1H,s,NH-1’),13.21(1H,s,NH-6).MS m/z(%)487.5(M+1,100).
实施例6 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-甲氧基-3H-咪唑并[4,5-c]吡啶(I-8)
将NaH(50mg),投入甲醇(2ml)中,室温搅拌10分钟,加入I-5(50mg,0.1mmol),在140℃微波反应15min,倒入pH=3.0的冰水中,搅拌15分钟,析出固体,抽滤,水洗,干燥,得到灰白粗品40mg,以二氯甲烷和甲醇为洗脱剂,中压柱分离纯化,得到白色固体24.2mg,产率:55.31%。1H NMR(DMSO-d6)δppm 2.07(6H,s,2×CH3),2.91(4H,dt,2×CH2),4.00(3H,s,OCH3),7.15(2H,s,ArH-3”,5”),7.28(2H,d,J=8.4Hz,ArH-2’,6’),7.57(2H,d,J=8.4Hz,ArH-3’,5’),9.59(1H,s,NH-1’),13.15(1H,s,NH-3).MS m/z(%)439.2(M+1,100).
实施例7 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-乙氧基-3H-咪唑并[4,5-c]吡啶(I-9)
以化合物I-5为原料,制备方法同I-8,将其中的甲醇换为乙醇,产率:44.58%。1HNMR(DMSO-d6)δppm 1.45(3H,t,J=5.8Hz,CH3),2.12(6H,s,2×Ar-CH3),2.94(4H,dt,2×CH2),4.33(2H,q,OCH2),7.20(2H,s,ArH-3”,5”),7.33(2H,d,J=8.8Hz,ArH-2’,6’),7.64(2H,d,J=8.8Hz,ArH-3’,5’),8.26(1H,s,Imidazole-H),9.68(1H,s,NH-1’),13.12(1H,s,NH-3).MS m/z(%)453.4(M+1,100).
实施例8 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-(2-羟基乙氧基)-3H-咪唑并[4,5-c]吡啶(I-12)
以化合物I-5为原料,制备方法同I-8,将其中的甲醇换为乙二醇,产率:36.62%。1H NMR(DMSO-d6)δppm 2.06(6H,s,2×CH3),2.91(4H,dt,2×CH2),4.00(3H,s,OCH3),7.14(2H,s,ArH-3”,5”),7.27(2H,d,J=8.4Hz,ArH-2’,6’),7.57(2H,d,J=8.4Hz,ArH-3’,5’),8.21(1H,s,Imidazole-H),9.62(1H,s,NH-1’),12.93(1H,s,NH-3).MS m/z(%)469.3(M+1,100).
实施例9 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-硝基-3H-咪唑并[4,5-c]吡啶(I-14)
将VI-13(100mg,0.23mmol),溶于DMF(5ml)中,室温下,加入原甲酸三乙酯(0.2ml),加入盐酸乙醚(1ml),搅拌2小时,反应完毕。倒入冰水中,搅拌10分钟,抽滤,水洗,干燥,得黄色固体88.88mg,以二氯甲烷和甲醇为洗脱剂,中压分离,得黄色固体66.14mg,产率:64.68%。1H NMR(DMSO-d6)δppm 2.07(6H,s,2×CH3),2.90(4H,dt,2×CH2),7.21(2H,s,ArH-3”,5”),7.39(2H,d,J=8.4Hz,ArH-2’,6’),7.61(2H,d,J=8.4Hz,ArH-3’,5’),8.32(1H,s,imidazole-H),10.74(1H,s,NH-1’),13.43(1H,s,NH-3).MS m/z(%)454.2(M+1,100).
实施例10 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-甲氨基-3H-咪唑并[4,5-c]吡啶(I-16)
将I-5(60mg,0.12mmol)投入甲胺水溶液(1.5ml)和甲醇(1.5ml)的混和溶液中,140℃微波反应40分钟,倒入水中,抽滤,水洗,干燥,得粗品48mg。以二氯甲烷和甲醇为洗脱剂,中压柱分离,得到白色固体21.23mg,产率:39.35%。1H NMR(DMSO-d6)δppm 2.07(6H,s,2×CH3),2.88(4H,dt,2×CH2),3.00(3H,s,NHCH3),7.12(2H,s,ArH-3”,5”),7.27(2H,d,J=8.8Hz,ArH-2’,6’),7.56(2H,d,J=8.8Hz,ArH-3’,5’),8.17(1H,s,imidazole-H),9.38(1H,s,NH-1’),12.63(1H,s,NH-3).MS m/z(%)438.2(M+1,100).
实施例11 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-二乙氨基-3H-咪唑并[4,5-c]吡啶(I-18)
以化合物I-5为原料,制备方法同I-16,将其中的甲胺水溶液换为二乙胺,产率:46.33%。1H NMR(DMSO-d6)δppm 1.05(6H,t,J=7.2Hz,CH3),2.13(6H,s,2×CH3),2.96(4H,dt,2×CH2),3.29(4H,q,J=8.8Hz,N(CH2)2),7.20(2H,s,ArH-3”,5”),7.31(2H,d,J=8.8Hz,ArH-2’,6’),7.62(2H,d,J=8.8Hz,ArH-3’,5’),8.16(1H,s,imidazole-H),9.69(1H,s,NH-1’),12.79(1H,s,NH-3).MS m/z(%)480.4(M+1,100).
实施例12 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-(3-羟基丙氨基)-3H-咪唑并[4,5-c]吡啶(I-19)
以化合物I-5为原料,制备方法同I-16,将其中的甲胺水溶液换为3-氨基丙醇,产率:28.63%。1H NMR(DMSO-d6)δppm 1.05(6H,t,J=7.2Hz,CH3),2.13(6H,s,2×CH3),2.96(4H,dt,2×CH2),3.29(4H,q,J=8.8Hz,N(CH2)2),7.20(2H,s,ArH-3”,5”),7.31(2H,d,J=8.8Hz,ArH-2’,6’),7.62(2H,d,J=8.8Hz,ArH-3’,5’),8.16(1H,s,imidazole-H),9.69(1H,s,NH-1’),12.79(1H,s,NH-3).MS m/z(%)482.2(M+1,100).
实施例13 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-哌嗪-1-基-3H-咪唑并[4,5-c]吡啶(I-20)
以化合物I-5为原料,制备方法同I-16,将其中的甲胺水溶液换为哌嗪,产率:35.56%。1H NMR(DMSO-d6)δppm 2.08(6H,s,2×CH3),2.96(4H,dt,2×CH2),3.30(4H,br,piperizine H),3.43(4H,br,2CH2of piperizene near Ar),7.16(2H,s,ArH-3”,5”),7.27(2H,d,J=8.4Hz,ArH-2’,6’),7.57(2H,d,J=8.4Hz,ArH-3’,5’),8.23(1H,s,imidazole-H),8.95(1H,s,piperizine-NH),9.68(1H,s,NH-1’),12.88(1H,s,NH-3).MS m/z(%)493.4(M+1,100).
实施例14 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-吡咯烷-1-基-3H-咪唑并[4,5-c]吡啶(I-21)
以化合物I-5为原料,制备方法同I-16,将其中的甲胺水溶液换为吡咯烷,产率:53.82%。1H NMR(DMSO-d6)δppm 2.15(6H,s,2×CH3),2.50(4H,br,pyrole-H),2.93(4H,dt,2×CH2),3.99(4H,br,pyrole-H),7.20(2H,s,ArH-3”,5”),7.39(2H,d,J=8.8Hz,ArH-2’,6’),7.54(2H,d,J=8.4Hz,ArH-3’,5’),8.59(1H,s,imidazole-H),10.63(1H,s,NH-1’).MSm/z(%)478.2(M+1,100).
实施例15 4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-咪唑-1-基-3H-咪唑并[4,5-c]吡啶(I-22)
以化合物I-5为原料,制备方法同I-16,将其中的甲胺水溶液换为咪唑,产率:61.25%。1H NMR(DMSO-d6)δppm 2.08(6H,s,2×CH3),2.91(4H,dt,2×CH2),7.14(2H,s,ArH-3”,5”),7.19(1H,s),7.34(2H,d,J=8.0Hz,ArH-2’,6’),7.52(1H,s),7.65(2H,d,J=8.0Hz,ArH-3’,5’),8.00(1H,s),8.23(1H,s,imidazole-H),9.97(1H,s,NH-1’),13.11(1H,s,NH-3).MS m/z(%)475.1(M+1,100).
实施例16 4-(4-氰基苯胺基)-6-(2-溴-6-甲氧基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-23)
制备方法同I-1,VI-9为原料,产率:70.19%。1H NMR(DMSO-d6)δppm2.96(4H,dt,2×CH2),3.70(3H,s,OCH3),6.60(1H,s,pyridine-H),7.24(1H,s,ArH-5”),7.29(1H,s,ArH-3”),7.41(2H,d,J=8.8Hz,ArH-2’,6’),7.72(2H,d,J=8.8Hz,ArH-3’,5’),8.18(1H,s,imidazole-H),9.75(1H,s,NH-1’),12.64(1H,s,NH-3).MS m/z(%)489.0,491.0(M+1,100).
实施例17 4-(4-氰基苯胺基)-6-(2-溴-6-甲氧基-4-氰乙基-苯氧基)-7-氯-3H-咪唑并[4,5-c]吡啶(I-24)
制备方法同I-1,VI-10为原料,产率:61.21%。1H NMR(DMSO-d6)δppm2.96(4H,dt,2×CH2),3.72(3H,s,OCH3),7.30(2H,d,J=8.8Hz,ArH-2’,6’),7.41(2H,d,J=8.8Hz,ArH-3’,5’),7.58(1H,s,ArH-5”),7.62(1H,s,ArH-3”),8.31(1H,s,imidazole-H),9.89(1H,s,NH-1’),13.35(1H,s,NH-3).MS m/z(%)525.2(M+1,100).
实施例18 4-(4-氰基苯胺基)-6-(2,6-二氟-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-25)
制备方法同I-1,VI-11为原料,产率:63.65%。1H NMR(DMSO-d6)δppm2.96(2H,t,J=6.4Hz,CH2CN),3.20(2H,t,J=6.4Hz,ArCH2),6.75(1H,s,ArH-3),7.34(2H,d,J=8.8Hz,ArH-3”,5”),7.42(2H,d,J=8.8Hz,ArH-2’,6’),7.69(2H,d,J=8.8Hz,ArH-3’,5’),8.18(1H,s,imidazole-H),9.89(1H,s,NH-1’).MS m/z(%)417.2(M+1,100).
实施例19 2-丙氧基-4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-26)
将NaH(50mg)在0℃下,分批投入丙醇(2.0ml)中,搅拌5分钟后将I-5(50mg,0.1mmol)投入混和溶液中,于100℃下微波反应25分钟,倒入水中,抽滤,水洗,干燥,纯化,得到白色固体8.05mg,产率:18.66%。1H NMR(DMSO-d6)δppm(CDCl3)1.05(3H,t,J=7.6Hz,CH3),1.87(2H,m,CH2),2.13(6H,s,2×CH3),2.69(3H,t,J=7.2Hz,CH2CN),2.99(2H,t,J=7.2Hz,ArCH2),4.44(2H,t,J=7.2Hz,OCH2),6.31(1H,s,ArH-3),7.01(2H,s,ArH-3”,5”),7.30(2H,d,J=8.8Hz,ArH-2’,6’),7.36(1H,s,NH),7.46(2H,d,J=8.8Hz,ArH-3’,5’),8.31(1H,s,NH-1’).MS m/z(%)467.2(M+1,100).
实施例20 2-甲基-4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-28)
将化合物VI-14溶于醋酸中,加入铁粉,110℃反应2小时,得I-28,产率:80.25%。1H NMR(DMSO-d6)δppm 2.08(6H,s,2×CH3),2.59(3H,s,CH3),2.89(4H,dt,2×CH2),6.60(1H,s,ArH-3),7.13(2H,s,ArH-3”,5”),7.39(2H,d,J=8.8Hz,ArH-2’,6’),7.61(2H,d,J=8.8Hz,ArH-3’,5’),9.62(1H,s,NH-1’).MS m/z(%)423.0(M+1,100).
实施例21 1-乙氧甲酰基-4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-29)
将化合物VI-3溶于丙酮中,加入碳酸钾,0℃加入氯甲酸乙酯,反应2小时,抽滤,旋干。所得粗品溶于乙酸乙酯中,加入Pd/C,氢气还原硝基,抽滤,旋干,所得剩余物加入DMF溶解,加入原甲酸三乙酯,盐酸乙醚,室温搅拌1小时,得I-29,产率45.16%。
1H NMR(DMSO-d6)δppm 1.27(3H,t,J=7.2Hz,CH3),2.07(6H,s,2×CH3),2.87(4H,dt,2×CH2),4.20(2H,q,J=7.2Hz,OCH2),7.10(2H,s,ArH-3”,5”),7.48(1H,s,pyiridine-H),7.93(2H,d,J=8.8Hz,ArH-2’,6’),8.06(1H,s,NH),8.85(1H,s,NH-1’),10.18(1H,s,NH-6).MS m/z(%)481.4(M+1,100).
实施例22 5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-吡嗪并[4,3-b]并吡啶(I-30)
VI-1(200mg,0.5mmol)溶于THF/甲醇/水(10ml/10ml/4ml)中,还原铁粉(278mg,5.0mmol),NH4Cl(270mg,5.0mmol),回流3小时,硅藻土抽滤,THF洗,减压除去大部分溶剂,加入1.0ml(40%乙二醛水溶液),加入乙醇(10mL),回流4小时,冷却至室温,反应液倒入冰水中,乙酸乙酯提取,饱和食盐水洗,无水硫酸钠干燥。中压柱分离(二氯甲烷与石油醚梯度洗脱)得黄色固体108.0mg,产率55.10%。1H NMRδppm(CDCl3)2.22(6H,s,2×CH3),6.85(1H,s,ArH-3),7.45(2H,d,J=8.4Hz,ArH-2’,6’),7.53(2H,s,ArH-3”,5”),7.54(2H,d,J=8.4Hz,ArH-3’,5’),8.60(1H,d,J=1.6Hz,ArH-6),8.94(1H,d,J=1.6Hz,ArH-5),9.08(1H,s,NH-1’).MS m/z(%)393.2(M+1,100).
实施例23 2-羟基-5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-吡嗪并[4,3-b]并吡啶(I-31)
以化合物VI-1为原料,制备方法同I-30,乙二醛用乙醛酸乙酯替代,产率87.32%,1H NMRδppm(DMSO-d6)2.12(6H,s,2×CH3),6.30(1H,s,ArH-3),7.38(2H,d,J=8.8Hz,ArH-2’,6’),7.58(2H,d,J=8.8Hz,ArH-3’,5’),7.80(2H,s,ArH-3”,5”),7.94(1H,s,ArH-6),9.92(1H,s,NH-1’),12.63(1H,s,OH).MS m/z(%)409.0(M+1,100).
实施例24 2,3-二羟基-5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-吡嗪并[4,3-b]并吡啶(I-32)
以化合物VI-1为原料,制备方法同I-30,乙二醛用草酸二乙酯替代,产率60.04%,1H NMRδppm(DMSO-d6)2.05(6H,s,2×CH3),6.33(1H,s,ArH-3),7.24(2H,d,J=8.8Hz,ArH-2’,6’),7.34(2H,d,J=8.8Hz,ArH-3’,5’),7.74(2H,s,ArH-3”,5”),9.12(1H,s,NH-1’),11.59(1H,s,OH-6),12.20(1H,s,OH-5).MS m/z(%)425.2(M+1,100).
实施例25 5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-8-溴-吡嗪并[4,3-b]并吡啶(I-33)
以VI-2为原料,制备方法同I-30,产率94.83%,1H NMRδppm(CDCl3)2.24(6H,s,2×CH3),7.33(2H,d,J=8.8Hz,ArH-2’,6’),7.38(2H,d,J=8.8Hz,ArH-3’,5’),7.57(2H,s,ArH-3”,5”),8.67(1H,d,J=1.6Hz,ArH-6),9.04(1H,s,NH),9.12(1H,d,J=1.6Hz,ArH-5).MS m/z(%)473.2(M+1,100).
实施例26 5-(4-氰基苯胺)-7-(2,6-二甲基-4-氰乙基-苯氧基)-吡嗪并[4,3-b]并吡啶(I-34)
以VI-3为原料,制备方法同I-30,产率61.23%,1H NMRδppm(CDCl3)2.16(6H,s,2×CH3),2.70(2H,t,J=7.6Hz,CH2CN),2.98(2H,t,J=7.6Hz,ArCH2),6.73(1H,s,ArH-3),7.04(2H,s,ArH-3”,5”),7.45(2H,d,J=8.4Hz,ArH-2’,6’),7.67(2H,d,J=8.4Hz,ArH-3’,5’),8.54(1H,d,J=1.6Hz,ArH-6),8.88(1H,d,J=1.6Hz,ArH-5),9.05(1H,s,NH).MS m/z(%)421.4(M+1,100).
实施例27 2,3-二羟基-5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-吡嗪并[4,3-b]吡啶(I-35)
以VI-3为原料,制备方法同I-30,乙二醛用草酸二乙酯替代,产率53.14%,1H NMRδppm(DMSO-d6)2.00(6H,s,2×CH3),2.82(2H,t,J=6.0Hz,CH2CN),2.85(2H,t,J=6.0Hz,ArCH2),6.23(1H,s,ArH-3),7.09(2H,s,ArH-3”,5”),7.34(2H,d,J=9.6Hz,ArH-2’,6’),7.37(2H,d,J=9.6Hz,ArH-3’,5’),8.93(1H,s,NH-1’),11.49(1H,s,OH-6),12.13(1H,s,OH-5).MSm/z(%)453.2(M+1,100).
实施例28 5-(4-氰基苯胺基)-7-(2,6-二甲氧基-4-氰乙基-苯氧基)-吡嗪并[4,3-b]吡啶(I-36)
以VI-12为原料,制备方法同I-30,产率86.19%。1H NMR(DMSO-d6)δppm 2.96(4H,dt,2×CH2),3.70(6H,s,2×OCH3),6.76(1H,s,ArH-3),6.86(2H,s,ArH-3”,5”),7.56(2H,d,J=8.8Hz,ArH-2’,6’),7.93(2H,d,J=8.8Hz,ArH-3’,5’),8.76(1H,d,J=1.6Hz,ArH-6),9.03(1H,d,J=1.6Hz,ArH-5),10.40(1H,s,NH).MS m/z(%)453.2(M+1,100),475.1(M+23,50).
实施例29 5-(4-氰基苯胺基)-7-(2,6-二氟-4-氰乙基-苯氧基)-吡嗪并[4,3-b]吡啶(I-37)
以VI-11为原料,制备方法同I-30,产率67.62%。1H NMR(DMSO-d6)δppm 2.98(4H,dt,2×CH2),7.06(1H,s,ArH-3),7.41(2H,s,ArH-3”,5”),7.58(2H,d,J=8.8Hz,ArH-2’,6’),7.84(2H,d,J=8.8Hz,ArH-3’,5’),8.84(1H,d,J=1.6Hz,ArH-6),9.10(1H,d,J=1.6Hz,ArH-5),10.57(1H,s,NH).MS m/z(%)429.2(M+1,100).
实施例30 5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰乙基-苯氧基)-8-溴-吡嗪并[4,3-b]吡啶(I-38)
以VI-4为原料,制备方法同I-30,产率87.32%,1H NMRδppm(CDCl3)2.17(6H,s,2×CH3),2.72(2H,t,J=7.6Hz,CH2CN),2.98(2H,t,J=7.6Hz,ArCH2),7.08(2H,s,ArH-3”,5”),7.33(2H,d,J=8.4Hz,ArH-2’,6’),7.41(2H,d,J=8.4Hz,ArH-3’,5’),8.61(1H,d,J=1.6Hz,ArH-6),8.98(1H,s,NH-1’),9.07(1H,d,J=1.6Hz,ArH-5).MS m/z(%)499.3(M+1,100).
实施例31 5-(4-氰基苯胺基)-7-[2,6-二甲基-4-(2-氰基乙烯基)-苯氧基]-吡嗪并[4,3-b]吡啶(I-39)
以VI-7为原料,制备方法同I-30,产率85.81%。1H NMR(DMSO-d6)δppm 2.12(6H,s,2×CH3),6.53(1H,d,J=16.8Hz,=CHCN),6.89(1H,s,pyridine-H),7.40(2H,d,J=8.4Hz,ArH-2’,6’),7.59(2H,s,ArH-3”,5”),7.74(1H,d,J=16.8Hz,ArCH2=),7.79(2H,d,J=8.4Hz,ArH-3’,5’),8.79(1H,d,J=1.6Hz,ArH-6),9.06(1H,d,J=1.6Hz,ArH-5),10.47(1H,s,NH-1’).MS m/z(%)419.1(M+1,100).
实施例32 5-(4-氰基苯胺基)-7-(2,6-二氟-苯氧基)-吡嗪并[4,3-b]吡啶(I-41)
以IV-1和2,6-二氟苯酚为原料,制备中间体,制备方法同VI-1,此中间体制备I-41,制备方法同I-30,产率:87.63%。1H NMR(DMSO-d6)δppm 7.09(1H,s,ArH-3),7.42(2H,d,J=8.4Hz,ArH-3”,5”),7.50(2H,d,J=8.8Hz,ArH-2’,6’),7.53(1H,t,J=8.4Hz,ArH-4”),7.79(2H,d,J=8.8Hz,ArH-3’,5’),8.85(1H,d,J=1.6Hz,ArH-6),9.11(1H,d,J=1.6Hz,ArH-5),10.58(1H,s,NH).MS m/z(%)376.1(M+1,100).
实施例33 5-(4-氰基苯胺基)-7-(2,4,6-三溴-苯氧基)-吡嗪并[4,3-b]吡啶(I-42)
以IV-1和2,4,6-三溴苯酚为原料,制备中间体,制备方法同VI-1,此中间体制备I-42,制备方法同I-30,产率90.13%。1H NMR(DMSO-d6)δppm 7.06(1H,s,ArH-3),7.50(2H,d,J=8.4Hz,ArH-2’,6’),7.76(2H,d,J=8.4Hz,ArH-3’,5’),8.22(2H,s,ArH-3”,5”),8.84(1H,d,J=1.6Hz,ArH-6),9.10(1H,d,J=1.6Hz,ArH-5),10.58(1H,s,NH-1’).MS m/z(%)573.2(M+1,100).
实施例34 5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰乙基-苯氧基)-8-溴-哌嗪并[4,3-b]吡啶(I-44)
将I-38(100mg,0.2mmol)溶于THF(5ml)中,分批投入硼氢化钠(40mg),滴入三氟乙酸(0.5ml),室温反应1小时。倒入20ml水中,加入碳酸钾调节pH为弱碱,搅拌20分钟,静置,抽滤,水洗,干燥,得淡黄色粗品98.08mg.中压柱分离纯化(以二氯甲烷与乙酸乙酯为脱剂),得到淡黄色固体86.16mg,产率85.49%。1H NMRδppm(CDCl3)2.13(6H,s,2×CH3),2.67(2H,t,J=7.2Hz,CH2CN),2.98(2H,t,J=7.2Hz,ArCH2),3.49(4H,m,2×CH2),6.99(2H,s,ArH-3”,5”),7.18(2H,br,NH),7.27(4H,s,ArH-3’,5’and ArH-2’,6’).MS m/z(%)503.2(M+1,100).
实施例35 5-(4-氰基苯胺基)-7-(2-溴-6-甲氧基-4-氰乙基-苯氧基)-吡嗪并[4,3-b]吡啶(I-45)
以VI-9为原料,制备方法同I-30,产率:75.23%。1H NMR(DMSO-d6)δppm 2.96(2H,t,J=7.6Hz,CH2CN),3.01(2H,t,J=7.6Hz,ArCH2),3.72(3H,s,OCH3),6.89(1H,s,ArH-3),7.29(1H,d,J=1.6Hz,ArH-3”),7.34(1H,d,J=1.6Hz,ArH-5”),7.54(2H,d,J=8.4Hz,ArH-2’,6’),7.86(2H,d,J=8.4Hz,ArH-3’,5’),8.80(1H,d,J=1.6Hz,ArH-6),9.06(1H,d,J=1.6Hz,ArH-5),10.45(1H,s,NH-1’).MS m/z(%)523.1,525.2(M+23,100).
实施例36 5-(4-氰基苯胺基)-7-(2-溴-6-甲氧基-4-氰乙基-苯氧基)-8-氯-吡嗪并[4,3-b]吡啶(I-46)
以VI-10为原料,制备方法同I-30,产率:75.83%。1H NMR(DMSO-d6)δppm 2.96(2H,t,J=7.6Hz,CH2CN),3.01(2H,t,J=7.6Hz,ArCH2),3.74(3H,s,OCH3),7.34(1H,d,J=1.6Hz,ArH-3”),7.36(1H,d,J=1.6Hz,ArH-5”),7.52(2H,d,J=8.4Hz,ArH-2’,6’),7.75(2H,d,J=8.4Hz,ArH-3’,5’),8.90(1H,d,J=1.6Hz,ArH-6),9.21(1H,d,J=1.6Hz,ArH-5),10.58(1H,s,NH-1’).MS m/z(%)536.0(M+1,100).
实施例37 5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰乙基-苯氧基)-8-氯-吡嗪并[4,3-b]吡啶(I-47)
以VI-5为原料,制备方法同I-30,产率77.21%。1H NMR(DMSO-d6)δppm 2.10(6H,s,2×CH3),2.92(2H,t,J=6.4Hz,CH2CN),2.96(2H,t,J=6.4Hz,ArCH2),7.21(2H,s,ArH-3”,5”),7.44(2H,d,J=8.4Hz,ArH-2’,6’),7.73(2H,d,J=8.4Hz,ArH-3’,5’),8.89(1H,d,J=1.6Hz,ArH-6),9.20(1H,s,NH-1’),10.53(1H,d,J=1.6Hz,ArH-5).MS m/z(%)455.2(M+1,100).
实施例38本申请化合物抗HIV活性试验(MT-2TZM-bl细胞模型)
Rilpivirine(参照专利US20070191407A1方法制备)为阳性对照物,试验方法参照文献(Dang,Z,et al.J.Med.Chem.2009,52,7887-7891)进行。
EC50值的测定方法1:在96孔细胞培养板中,分别将待测化合物的不同浓度溶液与用200TCID50的HIV-1的NL4-3病毒或E138K突变病毒(Surgical Oncology ResearchFacility,Duke University Medical Center提供)感染的TZM-bl细胞(来自美国国家卫生研究院,NIH)混合。2天后,取出培养基并向每个孔中加入100μl的Bright Glo试剂,用Victor 2照度计检测细胞的荧光量。用CalcuSyn软件计算化合物的半数有效浓度(EC50)。
EC50值的测定方法2:参照文献(Jiang,S.et al.Antimicrob.AgentsChemother.2004,48,4349-4345)。在96孔细胞培养板中,将50μl不同浓度的化合物溶液与等体积HIV-1ⅢB、A17或Bal病毒株(来自美国纽约血液中心)(5×105/ml)混合,在37℃温育30分钟,然后加入100μl的MT-2细胞(1×105/ml,含10%血清的RPIM 1640培养液),混合均匀,37℃温育过夜。第二天,吸去150μl的上清液,补入等体积新鲜培养液,37℃继续温育3天,于第四天记录细胞病变(CPE)效应。然后吸取100μl的培养上清液,用5%的Triton X-100裂解病毒颗粒,采用ELSA方法检测其中的p24抗原。用HIVIG(2μg/ml)包被酶标板,再用1%的无脂牛奶封闭,然后加入病毒裂解液,37℃温育60分钟。在充分洗板之后,先后加入抗p24单抗-183-12H-5C,生物素标记的羊抗鼠抗体及卵白素标记的辣根过氧化物酶。然后用TMB显色,在450nm处检测光密度,用CalcuSyn软件计算化合物的半数有效浓度(EC50)。
CC50值的测定方法1:在96孔细胞培养板中,将100μl不同浓度的化合物1-47的溶液与等体积TZM-bl细胞(来自美国国家卫生研究院,NIH)(5×105/ml)混合,在37℃温育4天,加入50μl新鲜配制的含0.02μM PMS的XTT溶液(1mg/ml),4小时后检测450nm处的光密度。用用CalcuSyn软件计算化合物的半数细胞毒性浓度(CC50)。
CC50值的测定方法2:参照文献(Jiang,S.et al.Antimicrob.AgentsChemother.2004,48,4349-4345)。在96孔细胞培养板中,将50μl不同浓度的化合物溶液与等体积PBS混合,在37℃温育30分钟,然后加入100μl的MT-2细胞(1×105/ml,含10%血清的RPIM 1640培养液),混合均匀,37℃温育过夜。第二天,吸去150μl的上清液,补入等体积新鲜培养液,37℃继续温育3天,于第四加入新鲜配制的含PMS的XTT溶液(1mg/ml)。4小时后,检测450nm处的密度,用CalcuSyn软件计算化合物的半数细胞毒性浓度(CC50)。
各数值结果见表1。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (18)
1.式Ⅰ化合物或其可药用盐,
其中,
稠环为吡啶并环A,环A为5或6元杂环,环A上有一个或两个以上R1;
R1选自H、=O、-OH、-COOR、C1-6烷基和C1-6烷氧基;
R2选自H、卤素、-OH、-NRR’、-NO2、-COOR、C1-6烷基、C1-6烷氧基、取代的C1-6烷基、取代的C1-6烷氧基、取代的C1-6烷氨基、5或6元杂环基,所述取代基选自卤素、-OH、-NH2;
R4和R5分别独立地选自卤素、-OH、C1-6烷基、C1-6烷氧基;
R6选自H、-CN、卤素、C1-6烷基、C2-6烯基、取代的C1-6烷基、取代的C2-6烯基、C1-6烷氧基,其中所述取代基为-CN;
R和R’各自独立地选自H或者C1-6烃基;
X为-O-;
Y为N。
2.权利要求1的式Ⅰ化合物或其可药用盐,其中,
R1为H,其余各基团的定义如权利要求1所述。
3.权利要求2的式Ⅰ化合物或其可药用盐,其中,
R4和R5均为甲基,或R4和R5各自独立地选自卤素、C1-6烷氧基,X为-O-。
4.权利要求1的式Ⅰ化合物或其可药用盐,其中,
R2为H,其余各基团的定义如权利要求1所述。
5.权利要求4的式Ⅰ化合物或其可药用盐,其中,
R4和R5均为甲基,X为-O-。
6.权利要求1的式Ⅰ化合物或其可药用盐,其中,
R1和R2均为H,其余各基团的定义如权利要求1所述。
7.权利要求6的式Ⅰ化合物或其可药用盐,其中,
R4和R5均为甲基,或R4和R5各自独立地选自卤素、C1-6烷氧基,X为-O-。
8.权利要求1的式Ⅰ化合物或其可药用盐,其中,
环A选自咪唑环、咪唑啉环、噻唑环、咪唑烷-2-酮环、吡咯环、吡咯烷环、嘧啶环、吡嗪环、哌嗪环、嘧啶环和哒嗪环,其余各基团的定义如权利要求1所述。
9.权利要求1-8任一项的式Ⅰ化合物或其可药用盐,其选自以下化合物:
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-1);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰基-苯氧基)-7-溴-3H-咪唑并[4,5-c]吡啶(I-2);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰基-苯氧基)-1,3-二氢咪唑并[4,5-c]吡啶-2-酮(I-3);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-4);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-溴-3H-咪唑并[4,5-c]吡啶(I-5);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-甲氧基-3H-咪唑并[4,5-c]吡啶(I-8);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-乙氧基-3H-咪唑并[4,5-c]吡啶(I-9);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-(2-羟基乙氧基)-3H-咪唑并[4,5-c]吡啶(I-12);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-硝基-3H-咪唑并[4,5-c]吡啶(I-14);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-甲氨基-3H-咪唑并[4,5-c]吡啶(I-16);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-二乙氨基-3H-咪唑并[4,5-c]吡啶(I-18);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-(3-羟基丙氨基)-3H-咪唑并[4,5-c]吡啶(I-19);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-哌嗪-1-基-3H-咪唑并[4,5-c]吡啶(I-20);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-吡咯烷-1-基-3H-咪唑并[4,5-c]吡啶(I-21);
4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-7-咪唑-1-基-3H-咪唑并[4,5-c]吡啶(I-22);
4-(4-氰基苯胺基)-6-(2-溴-6-甲氧基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-23);
4-(4-氰基苯胺基)-6-(2-溴-6-甲氧基-4-氰乙基-苯氧基)-7-氯-3H-咪唑并[4,5-c]吡啶(I-24);
4-(4-氰基苯胺基)-6-(2,6-二氟-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-25);
2-丙氧基-4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-26);
2-甲基-4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-28);
1-乙氧甲酰基-4-(4-氰基苯胺基)-6-(2,6-二甲基-4-氰乙基-苯氧基)-3H-咪唑并[4,5-c]吡啶(I-29);
5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-吡嗪并[4,3-b]吡啶(I-30);
2-羟基-5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-吡嗪并[4,3-b]吡啶(I-31);
2,3-二羟基-5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-吡嗪并[4,3-b]吡啶(I-32);
5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-8-溴-吡嗪并[4,3-b]吡啶(I-33);
5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰乙基-苯氧基)-吡嗪并[4,3-b]吡啶(I-34);
2,3-二羟基-5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰基-苯氧基)-吡啶并[4,3-b]吡啶(I-35);
5-(4-氰基苯胺基)-7-(2,6-二甲氧基-4-氰乙基-苯氧基)-吡嗪并[4,3-b]吡啶(I-36);
5-(4-氰基苯胺基)-7-(2,6-二氟-4-氰乙基-苯氧基)-吡嗪并[4,3-b]吡啶(I-37);
5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰乙基-苯氧基)-8-溴-吡嗪并[4,3-b]吡啶(I-38);
5-(4-氰基苯胺基)-7-[2,6-二甲基-4-(2-氰基乙烯基)-苯氧基]-吡嗪并[4,3-b]吡啶(I-39);
5-(4-氰基苯胺基)-7-(2,6-二氟-苯氧基)-吡嗪并[4,3-b]吡啶(I-41);
5-(4-氰基苯胺基)-7-(2,4,6-三溴-苯氧基)-吡嗪并[4,3-b]吡啶(I-42);
5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰乙基-苯氧基)-8-溴-哌啶并[4,3-b]吡啶(I-44);
5-(4-氰基苯胺基)-7-(2-溴-6-甲氧基-4-氰乙基-苯氧基)-吡嗪并[4,3-b]吡啶(I-45);
5-(4-氰基苯胺基)-7-(2-溴-6-甲氧基-4-氰乙基-苯氧基)-8-氯-吡嗪并[4,3-b]吡啶(I-46);
5-(4-氰基苯胺基)-7-(2,6-二甲基-4-氰乙基-苯氧基)-8-氯-吡嗪并[4,3-b]吡啶(I-47)。
10.权利要求1的式Ⅰ化合物或其可药用盐的制备方法,其包含以下步骤:
1)式II的2,6-二卤代吡啶类化合物与式Ⅲ的对氰基苯胺反应,生成式IV的2-(4-氰基苯胺基)多取代吡啶类化合物;
2)式IV化合物与式Ⅴ化合物偶联生成式VI的2-(4-氰基苯胺基)多取代吡啶类化合物;
3)式VI化合物关环生成式I化合物;
其中,R1’为-NO2,-NH2;R2’为-NO2或-NH2;R1,R2,R4,R5,R6,R’,X和Y的定义如权利要求1所述。
11.药物组合物,其包含权利要求1-9任一项所述的式Ⅰ化合物或其可药用盐,以及药学上可接受的载体或赋形剂。
12.权利要求1-9任一项的式Ⅰ化合物或其可药用盐或权利要求11的药物组合物用于制备预防和或治疗与HIV病毒感染有关的疾病或病症的药物的用途。
13.权利要求12的用途,其中所述与HIV病毒感染有关的疾病或病症为艾滋病。
14.权利要求12或13的用途,所述HIV病毒为野生型或突变型HIV病毒。
15.权利要求14的用途,所述突变型HIV病毒为非核苷逆转录酶抑制剂的耐药突变病毒。
16.权利要求1-9任一项的式Ⅰ化合物或其可药用盐或权利要求11的药物组合物用于制备非核苷类逆转录酶抑制剂的用途。
17.权利要求16的用途,其中所述逆转录酶为HIV病毒的逆转录酶。
18.权利要求16或17的用途,所述逆转录酶为野生型或耐药突变型HIV病毒的逆转录酶。
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