CN116102553A - 一种芳香稠环亚胺类化合物及其制备方法和应用 - Google Patents
一种芳香稠环亚胺类化合物及其制备方法和应用 Download PDFInfo
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- CN116102553A CN116102553A CN202211509299.4A CN202211509299A CN116102553A CN 116102553 A CN116102553 A CN 116102553A CN 202211509299 A CN202211509299 A CN 202211509299A CN 116102553 A CN116102553 A CN 116102553A
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- tetrahydrocyclohexyl
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Abstract
本发明涉及一种芳香稠环亚胺类化合物及其制备方法和应用。所述芳香稠环亚胺类化合物，具有刚性的平面结构和多个氢键受体及供体，其刚性平面结构能够与几丁质酶结合口袋中暴露于溶液的芳香氨基酸残基发生π‑π堆积作用，其氢键受体(如羰基氧原子)和氢键供体能够与结合口袋里的氨基酸产生直接或者水介导的氢键作用，从而产生对几丁质酶的抑制效果，通过对其抑制效果、选择性进行评价研究可知，该芳香稠环亚胺类化合物对亚洲玉米螟、人类、秀丽隐杆线虫、马来丝虫、烟曲霉菌、粘质沙雷氏菌几丁质酶均表现出抑制活性，在生物学和生物化学领域具有广泛的应用场景。
Description
技术领域
本发明涉及药物化学领域，尤其是涉及一种芳香稠环亚胺类化合物及其制备方法和应用。
背景技术
几丁质(Chitin)是以N-乙酰-β-D-葡萄糖胺(GlcNAc)为基本单元，通过β—1，4糖苷键连接的天然线性直链多糖，是昆虫外骨骼和中肠围食膜、线虫卵壳、软体动物的外壳、真菌细胞壁的重要组成部分，其合成和降解对这些生物的生长发育具有重要作用。GH18家族几丁质酶是水解几丁质的关键酶，抑制昆虫、线虫蜕皮相关的几丁质酶，如玉米螟来源的几丁质酶OfChi-h和OfChtI、线虫几丁质酶CeCht1、马来丝虫几丁质酶BmCht1，会导致昆虫、线虫无法蜕皮、生长抑制、化蛹失败而死亡，可以作为潜在的农药研发靶点。人体表达两种几丁质酶和多种类几丁质酶蛋白，其中人壳三糖几丁质酶HsChit1的表达与肺纤维化有关，可作为治疗特异性肺纤维化的潜在靶点；人类酸性哺乳动物酶AMCase的过量表达与哮喘有关，可作为治疗哮喘的潜在靶点。近年来，多种几丁质酶晶体结构的解析取得重要进展，为农用、医用小分子几丁质酶抑制剂的合理设计提供了重要的理论基础。
几丁质酶在真菌侵染、昆虫蜕皮、线虫孵化和人类哮喘、肺纤维化疾病中发挥重要的功能，因此，针对几丁质酶的抑制剂在抗真菌剂、杀虫剂、杀线虫剂和肺部疾病药物开发等方面具有良好的应用前景和积极的研究意义。
发明内容
本发明的目的是提供一种芳香稠环亚胺类化合物及其制备方法和应用，本发明化合物在抑制农业害虫、用于特异性肺纤维化、抗真菌感染和抑制细菌生长等方面具有广泛的应用前景。
本发明的目的可以通过以下技术方案来实现：
一种如通式(Ⅰ)结构的芳香稠环亚胺类化合物，或所述化合物的光学异构体、顺反异构体或其药学、农药学上可以接受的盐或溶剂合物：
其中，Y为无，或具有1-10个碳原子的取代或末取代的亚烷基或亚烷基-O-，所述的亚烷基为直链或支链的亚烷基；
M选自下组：NH，O或S；
R1为位于
环上的一个或多个H或C1-C4烷基或卤素；
R2，R3各自独立地选自下组：氢，氘，任意取代或未取代烷基，任意取代或未取代的烯基，任意取代或未取代的炔基，任意取代或未取代的烷氧基，任意取代或未取代环烷基，羟基，氨基，巯基，膦基，硝基，任意取代或未取代的芳基，任意取代或未取代的杂芳基中的一个或多个；
R4选自下组：氢，卤素，羟基，硝基，氨基，氰基，羰基，取代或未取代C2-C12烯基，取代或未取代C2-C12炔基，羧基，取代或未取代C1-C12烷基或烷氧基，取代或未取代C1-C12烷胺基，取代或未取代C3-C9环烷基，取代或为取代C5-7环烯基，取代或未取代的C2-C9非杂芳基，取代或未取代的3～12元杂环，取代或未取代的C6-C12芳基，取代或未取代的C4-C12杂芳基，取代或未取代苯基，取代或未取代萘基，取代或未取代5元或6元杂环基，或取代或未取代8-12元杂芳二环基；
环A为取代或未取代的8-12元杂芳二环环系，取代或未取代的8-12元杂芳三环环系，取代或未取代5-12元芳环环系，取代或未取代5-12元杂环环系，取代或未取代的5-12元芳环，取代或未取代的5-12元杂芳环，或取代或未取代5-12元杂环(包括全部或部分不饱和的杂环)；
R5为位于环A任意一个或多个位置上各自独立的取代基,且R5选自下组:卤素、氰基、硝基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、或取代或未取代的C3-7环烷基、取代或未取代的C5-7环烯基、三甲基硅烷基乙炔基、取代或未取代的苯基、取代或未取代的萘基、三甲基硅烷基乙炔基、取代或未取代的5元或6元杂环基、取代或未取代的8元至12元杂芳二环环系、OR'、Si(R')3、NR'R"、C(O)R'、C(O)OR'、C(O)NR'R"、SR'、S(O)mR'、S(O)2NR'R"、OC(O)R'、OC(O)NR'R"、OS(O)2R'、OS(O)2NR'R"、N(R")C(O)R'、NCH2R'、N(R")C(O)NR'R"、N(R")S(O)2R'或N(R')S(O)2NR'R"；
其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基所取代：卤素，羟基，硝基，氨基，氰基，羰基，羧基，C1-C6烷基，C1-C6烷氧基，C1-C6烷胺基，羟基C1-C6烷基，氨基C1-C6烷基，羰基C1-C6烷基，OR'、Si(R')3、NR'R"、C(O)R'、C(O)OR'、C(O)NR'R"、SR'、S(O)mR'、S(O)2NR'R"、OC(O)R'、OC(O)NR'R"、OS(O)2R'、OS(O)2NR'R"、N(R")C(O)R'、NCH2R'、N(R")C(O)NR'R"、N(R")S(O)2R'或N(R')S(O)2NR'R"，C3-C9环烷基，C6-C12芳基，3～12元杂环，C4-C12杂芳基；
其中R'、R"各自独立地为：H、C1-6烷基、C1-6卤代烷基、C3-6卤代环烷基、C2-6烯基、C2-6卤代烯基、C2-6炔基、C2-6卤代炔基，或取代或未取代的C3-7环烷基、取代或未取代的C5-7环烯基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的5元或6元饱和或不饱和杂环基、或取代或未取代的8元至12元杂芳二环环系；其中，R'、R"上的取代基是选自下组的一个或多个基团所取代:氧基(＝0)、卤素、氰基、硝基、C1-6烷基或环烷基、C1-6卤代烷基、C2-6烯基、C2-6卤代烯基、C2-6炔基、C2-6卤代炔基、羟基、羟基C1-4烷基。
所述化合物具有如式(Ⅱ)、式(Ⅲ)、式(Ⅳ)或式(Ⅴ)所示的结构：
其中，Y为无，或具有1-10个碳原子的未取代的直链亚烷基或亚烷基-O-；
M选自下组：NH，O或S；
n为0,1，2，3；
R1选自下组：氢，氟，氯，溴，碘，甲基，甲氧基，乙基，丙基，异丙基，环丙基，正丁基或者叔丁基；
R2，R3各自独立地选自下组：氢，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基，正戊基，异戊基，新戊基，丙烯基，烯丙基，丁烯基，戊烯基，己烯基，丙炔基，丁炔基，戊炔基，己炔基，环丙基，环丁基，环戊基，环己基，异丁羟基，氨基，巯基，膦基，硝基，苯基，苄基，吡啶基，呋喃基，噻吩基，甲氧苯基，乙基苯基，三氟甲基苯基，硝基苯基，1,2-二氯苯基，1,3-二氯苯基，1,4-二氯苯基，1,2-二溴苯基，1,3-二溴苯基，1,4-二溴苯基，1,2-二氟苯基，1,3-二氟苯基，1,4-二氟苯基，1,2-二甲基苯基，1,3-二甲基苯基，1,4-二甲基苯基，1,2,4,5-四氟苯基，1,2,3,4-四氟苯基，1,2,3,5-四氟苯基，1,2,4,5-四溴苯基，1,2,3,4-四溴苯基，1,2,3,5-四溴苯基，1,2,4,5-四氯苯基，1,2,3,4-四氯苯基，1,2,3,5-四氯苯基；
R4，R5各自独立地选自下组：氢，氟，氯，溴，碘，羟基，硝基，氰基，羰基，氨基，甲氧基，乙氧基，丙氨基，异氧丙基，正丁氧基，叔丁氧基，环己基氧基，N-(N，N-二甲基)取代基，N-(N，N-二乙基)取代基，N-(N，N-二丙基)取代基，N-(N，N-二丁基)取代基，N-(N-甲基-N-乙基)取代基，N-(N-甲基-N-丙基)取代基，N-(N-甲基-N-丁基)取代基，N-(N-乙基-N-丙基)取代基，N-(N-乙基-N-丁基)取代基，N-(N-丙基-N-丁基)取代基，环丙基，环丁基，环戊基，环己基，环庚基，2，3或4-甲基环己基，2，3或4-乙基环己基，2，3或4-羟基环己基，2，3或4-羧基环己基，2，3或4-氰基环己基，2，3或4-氨基环己基，2或3-四氢呋喃基，2或3-四氢噻吩基，N，2或3-四氢吡咯基，2，3或4-四氢吡喃基，N，2，3或4-哌啶基，N，2或3-吗啉基，N或2-哌嗪基，N，2或3-(N-甲基哌嗪基)，N，2或3-(N-苄基哌嗪基)苯基，2，3或4-甲基苯基，2，3或4-甲氧基苯基，2，3或4-氨基苯基，2，3或4-氰基苯基，2，3或4-羧基苯基，2，3或4-硝基苯基，2，3或4-羟基苯基，萘基，2或3-呋喃基，2或3-噻吩基，N，2或3-吡咯基，2，3或4-吡啶基，N，2或3-(N-吗啉基)苯基，吲哚基。
在本发明的一个实施例中，所述化合物具有如下所示结构：
Y为无，或具有1，2，3个碳原子的未取代的直链亚烷基；
R4，R5各自独立地选自下组：氢，氟，氯，溴，碘，羟基，硝基，氰基，羰基，氨基，甲氧基，乙氧基，丙氨基，异氧丙基，正丁氧基，叔丁氧基，环己基氧基，N-(N，N-二甲基)取代基，N-(N，N-二乙基)取代基，N-(N，N-二丙基)取代基，N-(N，N-二丁基)取代基，N-(N-甲基-N-乙基)取代基，N-(N-甲基-N-丙基)取代基，N-(N-甲基-N-丁基)取代基，N-(N-乙基-N-丙基)取代基，N-(N-乙基-N-丁基)取代基，N-(N-丙基-N-丁基)取代基，环丙基，环丁基，环戊基，环己基，环庚基，2，3或4-甲基环己基，2，3或4-乙基环己基，2，3或4-羟基环己基，2，3或4-羧基环己基，2，3或4-氰基环己基，2，3或4-氨基环己基，2或3-四氢呋喃基，2或3-四氢噻吩基，N，2或3-四氢吡咯基，2，3或4-四氢吡喃基，N，2，3或4-哌啶基，N，2或3-吗啉基，N或2-哌嗪基，N，2或3-(N-甲基哌嗪基)，N，2或3-(N-苄基哌嗪基)苯基，2，3或4-甲基苯基，2，3或4-甲氧基苯基，2，3或4-氨基苯基，2，3或4-氰基苯基，2，3或4-羧基苯基，2，3或4-硝基苯基，2，3或4-羟基苯基，萘基，2或3-呋喃基，2或3-噻吩基，N，2或3-吡咯基，2，3或4-吡啶基，N，2或3-(N-吗啉基)苯基，吲哚基。
在本发明的一个实施例中，所述化合物具有如下所示结构：
R4，R5各自独立地选自下组：氢，氟，氯，溴，碘，羟基，硝基，氰基，羰基，氨基，甲氧基，乙氧基，丙氨基，异氧丙基，正丁氧基，叔丁氧基，环己基氧基，N-(N，N-二甲基)取代基，N-(N，N-二乙基)取代基，N-(N，N-二丙基)取代基，N-(N，N-二丁基)取代基，N-(N-甲基-N-乙基)取代基，N-(N-甲基-N-丙基)取代基，N-(N-甲基-N-丁基)取代基，N-(N-乙基-N-丙基)取代基，N-(N-乙基-N-丁基)取代基，N-(N-丙基-N-丁基)取代基，环丙基，环丁基，环戊基，环己基，环庚基，2，3或4-甲基环己基，2，3或4-乙基环己基，2，3或4-羟基环己基，2，3或4-羧基环己基，2，3或4-氰基环己基，2，3或4-氨基环己基，2或3-四氢呋喃基，2或3-四氢噻吩基，N，2或3-四氢吡咯基，2，3或4-四氢吡喃基，N，2，3或4-哌啶基，N，2或3-吗啉基，N或2-哌嗪基，N，2或3-(N-甲基哌嗪基)，N，2或3-(N-苄基哌嗪基)苯基，2，3或4-甲基苯基，2，3或4-甲氧基苯基，2，3或4-氨基苯基，2，3或4-氰基苯基，2，3或4-羧基苯基，2，3或4-硝基苯基，2，3或4-羟基苯基，萘基，2或3-呋喃基，2或3-噻吩基，N，2或3-吡咯基，2，3或4-吡啶基，N，2或3-(N-吗啉基)苯基，吲哚基。
在本发明的一个实施例中，所述化合物具有如下所示的结构：
Y为无，或具有1，2，3个碳原子的未取代的直链亚烷基；
R4选自下组：氢，氟，氯，溴，碘，羟基，硝基，氰基，羰基，氨基，甲氧基，乙氧基，丙氨基，异氧丙基，正丁氧基，叔丁氧基，环己基氧基，N-(N，N-二甲基)取代基，N-(N，N-二乙基)取代基，N-(N，N-二丙基)取代基，N-(N，N-二丁基)取代基，N-(N-甲基-N-乙基)取代基，N-(N-甲基-N-丙基)取代基，N-(N-甲基-N-丁基)取代基，N-(N-乙基-N-丙基)取代基，N-(N-乙基-N-丁基)取代基，N-(N-丙基-N-丁基)取代基，环丙基，环丁基，环戊基，环己基，环庚基，2，3或4-甲基环己基，2，3或4-乙基环己基，2，3或4-羟基环己基，2，3或4-羧基环己基，2，3或4-氰基环己基，2，3或4-氨基环己基，2或3-四氢呋喃基，2或3-四氢噻吩基，N，2或3-四氢吡咯基，2，3或4-四氢吡喃基，N，2，3或4-哌啶基，N，2或3-吗啉基，N或2-哌嗪基，N，2或3-(N-甲基哌嗪基)，N，2或3-(N-苄基哌嗪基)苯基，2，3或4-甲基苯基，2，3或4-甲氧基苯基，2，3或4-氨基苯基，2，3或4-氰基苯基，2，3或4-羧基苯基，2，3或4-硝基苯基，2，3或4-羟基苯基，萘基，2或3-呋喃基，2或3-噻吩基，N，2或3-吡咯基，2，3或4-吡啶基，N，2或3-(N-吗啉基)苯基，吲哚基。
在本发明的一个实施例中，所述化合物具有如下所示的结构：
Y为无，或具有1，2，3个碳原子的未取代的直链亚烷基；
R4选自下组：氢，氟，氯，溴，碘，羟基，硝基，氰基，羰基，氨基，甲氧基，乙氧基，丙氨基，异氧丙基，正丁氧基，叔丁氧基，环己基氧基，N-(N，N-二甲基)取代基，N-(N，N-二乙基)取代基，N-(N，N-二丙基)取代基，N-(N，N-二丁基)取代基，N-(N-甲基-N-乙基)取代基，N-(N-甲基-N-丙基)取代基，N-(N-甲基-N-丁基)取代基，N-(N-乙基-N-丙基)取代基，N-(N-乙基-N-丁基)取代基，N-(N-丙基-N-丁基)取代基，环丙基，环丁基，环戊基，环己基，环庚基，2，3或4-甲基环己基，2，3或4-乙基环己基，2，3或4-羟基环己基，2，3或4-羧基环己基，2，3或4-氰基环己基，2，3或4-氨基环己基，2或3-四氢呋喃基，2或3-四氢噻吩基，N，2或3-四氢吡咯基，2，3或4-四氢吡喃基，N，2，3或4-哌啶基，N，2或3-吗啉基，N或2-哌嗪基，N，2或3-(N-甲基哌嗪基)，N，2或3-(N-苄基哌嗪基)苯基，2，3或4-甲基苯基，2，3或4-甲氧基苯基，2，3或4-氨基苯基，2，3或4-氰基苯基，2，3或4-羧基苯基，2，3或4-硝基苯基，2，3或4-羟基苯基，萘基，2或3-呋喃基，2或3-噻吩基，N，2或3-吡咯基，2，3或4-吡啶基，N，2或3-(N-吗啉基)苯基，吲哚基。
在本发明的一个实施例中，所述化合物具有如下所示的结构：
R2，R3各自独立地选自下组：氢，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基，正戊基，异戊基，新戊基，丙烯基，烯丙基，丁烯基，戊烯基，己烯基，丙炔基，丁炔基，戊炔基，己炔基，环丙基，环丁基，环戊基，环己基，异丁羟基，氨基，巯基，膦基，硝基，苯基，苄基，吡啶基，呋喃基，噻吩基，甲氧苯基，乙基苯基，三氟甲基苯基，硝基苯基，1,2-二氯苯基，1,3-二氯苯基，1,4-二氯苯基，1,2-二溴苯基，1,3-二溴苯基，1,4-二溴苯基，1,2-二氟苯基，1,3-二氟苯基，1,4-二氟苯基，1,2-二甲基苯基，1,3-二甲基苯基，1,4-二甲基苯基，1,2,4,5-四氟苯基，1,2,3,4-四氟苯基，1,2,3,5-四氟苯基，1,2,4,5-四溴苯基，1,2,3,4-四溴苯基，1,2,3,5-四溴苯基，1,2,4,5-四氯苯基，1,2,3,4-四氯苯基，1,2,3,5-四氯苯基；
R4，R5各自独立地选自下组：氢，氟，氯，溴，碘，羟基，硝基，氰基，羰基，氨基，甲氧基，乙氧基，丙氨基，异氧丙基，正丁氧基，叔丁氧基，环己基氧基，N-(N，N-二甲基)取代基，N-(N，N-二乙基)取代基，N-(N，N-二丙基)取代基，N-(N，N-二丁基)取代基，N-(N-甲基-N-乙基)取代基，N-(N-甲基-N-丙基)取代基，N-(N-甲基-N-丁基)取代基，N-(N-乙基-N-丙基)取代基，N-(N-乙基-N-丁基)取代基，N-(N-丙基-N-丁基)取代基，环丙基，环丁基，环戊基，环己基，环庚基，2，3或4-甲基环己基，2，3或4-乙基环己基，2，3或4-羟基环己基，2，3或4-羧基环己基，2，3或4-氰基环己基，2，3或4-氨基环己基，2或3-四氢呋喃基，2或3-四氢噻吩基，N，2或3-四氢吡咯基，2，3或4-四氢吡喃基，N，2，3或4-哌啶基，N，2或3-吗啉基，N或2-哌嗪基，N，2或3-(N-甲基哌嗪基)，N，2或3-(N-苄基哌嗪基)苯基，2，3或4-甲基苯基，2，3或4-甲氧基苯基，2，3或4-氨基苯基，2，3或4-氰基苯基，2，3或4-羧基苯基，2，3或4-硝基苯基，2，3或4-羟基苯基，萘基，2或3-呋喃基，2或3-噻吩基，N，2或3-吡咯基，2，3或4-吡啶基，N，2或3-(N-吗啉基)苯基，吲哚基。
在本发明的一个实施例中，所述的Y、R1、R2、R3、R4、R5、M和环A各自独立地为实施例中具体化合物所对应的基团。
上述更进一步地，所述的R5选自氢或甲基。
上述更进一步地，所述的R1为位于
环上的一个甲基。
本发明提供的一类通式(Ⅰ)优选化合物，包括但不限于如表1中芳香稠环亚胺类化合物01-98的结构。
一种芳香稠环亚胺类化合物的制备方法，具体步骤如下：
在惰性溶剂中，用式Ⅰ-ⅤA化合物和式Ⅰ-ⅤB化合物反应，得到式Ⅰ-Ⅴ化合物。
一种芳香稠环亚胺类化合物，或所述化合物的光学异构体、顺反异构体或其药学、农药学上可以接受的盐或溶剂合物，在制备几丁质酶抑制剂中的应用，用于抑制18家族几丁质酶活性，所述化合物在抑制18家族几丁质酶活性中使用的终浓度不低于1μM。
进一步地，选自以下应用：应用于延缓鳞翅目害虫生长发育和线虫卵孵化方面；应用于特异性肺纤维化、哮喘、抗真菌感染和抑制细菌生长方面。
一种芳香稠环亚胺类衍生物，基于所述的芳香稠环亚胺类化合物，所述的衍生物为式(Ⅰ)、(Ⅱ)、(Ⅲ)、(Ⅳ)、(Ⅴ)化合物的光学异构体、顺反异构体、药学、农药学上可以接受的盐或溶剂合物，所述盐或溶剂合物应用于农业害虫或人类、真菌或细菌的几丁质酶方面。
进一步地，所述农业害虫是鳞翅目昆虫、线虫。
上述更进一步地，所述鳞翅目昆虫包括麦蛾，棉红铃虫，马铃薯块茎蛾，甘薯麦蛾，棉褐带卷蛾，大豆食心虫，梨大食心虫，亚洲玉米螟，大造桥虫，菜粉蝶，棉铃虫，舞毒蛾，玉带风蝶，金凤蝶，舟形毛虫，黄腹灯蛾，美国白蛾，葡萄天蛾和稻苞虫等；线虫为秀丽隐杆线虫，马来丝虫，根结线虫，孢囊线虫，异皮线虫，种瘤线虫，松线虫，根腐线虫，锥线虫。
进一步地，所述人类几丁质酶为壳三糖几丁质酶，酸性哺乳动物酶；真菌几丁质酶为烟曲霉菌几丁质酶；细菌几丁质酶为粘质沙雷氏菌几丁质酶。
进一步地，所述在防治农业害虫方面的应用是在延缓鳞翅目害虫生长发育和线虫卵孵化等方面的应用，在防治人类几丁质酶或真菌、细菌的几丁质酶的应用是在特异性肺纤维化、哮喘、抗真菌感染和抑制细菌生长等方面的应用。
一种药物组合物，所述的药物组合物包括含有治疗有效量的所述芳香稠环亚胺类化合物，其药学、农药学上可以接受的盐或药学，农药学上可以接受的溶剂合物作为活性成分，药学、农药学上可接受的载体。
与现有技术相比，本发明优点如下：
1)本发明中的芳香稠环亚胺类化合物具有几丁质酶(如玉米螟几丁质酶OfChi-h、秀丽隐杆线虫几丁质酶CeCht1、马来丝虫几丁质酶BmCht1和人壳三糖几丁质酶HsChit1等)抑制活性，通过对其抑制效果、选择性进行评价研究可知，该芳香稠环亚胺类化合物对亚洲玉米螟、人类、秀丽隐杆线虫、马来丝虫、烟曲霉菌、粘质沙雷氏菌几丁质酶均表现出抑制活性，在生物学和生物化学领域具有广泛的应用场景；
2)通过抑制剂的抑制活性所获得的数据，包括抑制百分数、抑制常数测定，结果表明该类结构表现出了广泛的抑制活性，对OfChi-h、OfChtI、SmChiB、CeCht1、HsChit1、AmCase、和BmCht1都表现出一定的抑制活性；
3)特别地对应表中的化合物08对OfChi-h、CeCht1、HsChit1和AmCase抑制率都在90％以上，且化合物08对亚洲玉米螟几丁质酶OfChi-h的Ki为40.7nM，对人HsChit1的Ki为12.1nM，对人AmCase的Ki为64.1nM，对秀丽隐杆线虫几丁质酶CeCht1的Ki为18.8nM；
4)本发明中的芳香稠环亚胺类化合物，具有刚性的平面结构和多个氢键受体及供体，其刚性平面结构能够与几丁质酶结合口袋中暴露于溶液的芳香氨基酸残基发生π-π堆积作用，其氢键受体(如羰基氧原子)和氢键供体能够与结合口袋里的氨基酸产生直接或者水介导的氢键作用，从而产生对几丁质酶的抑制效果。
附图说明
图1为08对亚洲玉米螟几丁质酶OfChi-h的抑制活性测试图；
图2为08对人壳三糖几丁质酶HsChit1的抑制活性测试图；
图3为08对秀丽隐杆线虫几丁质酶CeCht1的抑制活性测试图；
图4为08对酸性哺乳动物酶AMCase的抑制活性测试图。
具体实施方式
下面结合附图和具体实施例对本发明进行详细说明。
除非另有定义，本发明所用的技术和科学上的术语，与本发明所属领域的通用技术的一般理解具有相同的意义。
术语“C1-6烷基”指具有1～6个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基,或类似基团。
术语“C1-C6烷氧基”指形如“具有1～6个碳原子的直链或支链烷基-氧基”结构的取代基,如乙氧基、丙氧基、丁氧基，或类似基团。
术语“C1-C6烷胺基”指形如“具有1～6个碳原子的直链或支链烷基-胺基”结构的取代基,如乙胺基、丙胺基、二甲胺基,或类似基团。
术语“亚烷基”指如上文所述的烷基失去一个氢原子之后形成的基团，例如-CH2-、-CH2-CH2-,或类似基团。
术语“C2-C12烯基”指具有2-12个碳原子的烯烃直链或支链的烯基,包括乙烯基、丙烯基、正烯基,或类似基团。
术语“C3-C9环烷基”指具有3-9个碳原子的环烷基,如环丙烷、环已烷等。
术语“卤素”指F、C1、Br和I。术语“卤代的”指被相同或不同的一个或多个上述卤原子取代的基团，例如三氟甲基、五氟乙基、七氟异丙基，或类似基团。
术语“环”或“环系”指碳环或杂环。
术语“杂环”指形成所述杂环骨架的原子中至少一个原子不是碳，为氮、氧或硫。通常，杂环包含不超过4个氮、不超过2个氧和/或不超过2个硫。除非另外指明，杂环可以是饱和的、部分不饱和的或完全不饱和的环。在本发明的一个优选的实施方式中，所述杂环中包含1-4个独立选自N、S、和O的杂原子。
术语“环系”指两个或更多个环并在一起的稠环。
术语“5元或6元杂环基”指含一个或多个选自氮、氧或硫的杂原子的五元或六元环，例如吡啶基、噻唑基、异噻唑基、噻吩基、呋喃基、吡咯基、吡唑基、嘧啶基、四氢呋喃基、4,5-二氢噻唑-2-基、2-氰基亚胺基-4-氧-1,3-噻唑烷-3-基、2-氰基亚胺基-4-氧-1,3-噻嗪烷-3-基、噁唑基、异噁唑基、1H-四基、1H-1,2,3-三唑基、4H-1,2,4-三唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基或四唑基等。术语“C4-C12杂芳基”指具有4-12个碳原子,且具有一个或多个选自0、S、N或P的杂原子的非饱和环系取代基,如吡啶基、噻吩基，或类似基团。
术语“杂环环系”指环系中的至少一个环是杂环的环系。
术语“杂芳环环系”指环系中的至少一个环为芳族环的体系。
术语“8元至12元杂芳二环环系”或“8元至14元杂芳二环或三环环系”可选自下组：苯并呋喃、苯并[b]噻吩、吲哚、喹啉、异喹啉、1H-吲唑、1H-苯并[d]咪唑、苯并[d]噻唑、苯并[d]噁唑、苯并[d]异噁唑、苯并[d][1,2,3]噻二唑、2,3-二氢咪唑并[1,2-a]吡啶、喹唑啉、喹喔啉、噌啉、酞嗪、1,8-萘啶、4,5,6,7-四氢苯并[b]噻吩、苯并[b]噻吩-1,1-二氧烷、8H-茚并[2,1-b]噻吩、7,8-二氢-6H-环戊[4,5]噻吩并[2,3-d]嘧啶、3,5,6,7-四氢-4H-环戊[4,5]噻吩并[2,3-d]嘧啶-4-酮、螺[吲哚啉-3,2'-[1,3]二氧戊环]-2-酮、螺[吲哚啉-3,2'-[1,3]二氧六环]-2-酮、或吲哚啉-2,3-二酮等。
术语“烷基”是指烷烃分子中少掉一个氢原子而成的基团；术语“亚烷基”是指烷烃分子中少掉两个氢原子而成的基团。类似地，“亚烯基”、“亚炔基”、“亚环烷基”、“亚环烯基”、“亚苯基”、“亚萘基”、“亚杂环基”或“亚杂芳二环或三环环系”的定义类似。
本发明所述的基团除非特别说明是“取代或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：卤素、氰基、硝基、C1-C6烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6卤代烯基、C2-C6炔基、C2-C6卤代炔基、羟基、羟基C1-C4烷基、OR3、NR3R4、C(O)R3、C(O)OR3、C(O)NR3R4、SR3、S(O)mR5、S(O)2NR3R4、OC(O)R5、OC(O)NR3R4、OS(O)2R5、OS(O)2NR3R4、N(R6)C(O)R5、N(R6)C(O)NR3R4、N(R6)S(O)2R5或N(R6)S(O)2NR3R4等，其中，所述的R3、R4、R5、R6的定义同前，m为1或2。
本发明的化合物可以含有一个或多个不对称中心，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物和纯或部分纯的化合物包括在本发明的范围之内。本发明包括化合物的所有异构形式，各种晶型形式，药学、农药学上可接受的盐、水合物或溶剂合物。
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸、苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
惰性溶剂指的是不与原料发生反应的各种溶剂，包括各种直链、支链或环状的醇、醚或酮、卤代烷、1,4-二氧六环、乙腈、四氢呋喃、N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)等。
药物组合物和施用方法：
由于本发明化合物具有优异的对几丁质酶的抑制活性，因此本发明化合物及其各种晶型，药学、农药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解农业害虫导致的田间灾害。根据现有技术，本发明化合物可用于治疗、预防鳞翅目类农业害虫，还可用于治疗特异性肺纤维化等等。
本发明的式(Ⅰ)、(Ⅱ)、(Ⅲ)、(Ⅳ)、(Ⅴ)化合物可用于药物组合物中，药物组合物包含安全有效量范围内的本发明式(Ⅰ)、(Ⅱ)、(Ⅲ)、(Ⅳ)、(Ⅴ)化合物、抗生素或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学、农药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：医药部分：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药；农药部分：喷雾法、喷粉法、土壤处理法、注射法、涂抹法、毒饵法和拌种法。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂,例如，甘油；(d)崩解剂,例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂,例如，石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如，鲸蜡醇和单硬脂酸甘油酯:(h)吸附剂,例如，高岭土:和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂,增溶剂和乳化剂，例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂，例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学、农药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1～2000mg,优选5～500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
实施例：
结合附图说明如下：图1为08对亚洲玉米螟几丁质酶OfChi-h的抑制活性测试图，图1显示08对亚洲玉米螟几丁质酶OfChi-h的Ki为40.7nM；图2为08对人壳三糖几丁质酶HsChit1的抑制活性测试图，图2显示08对人壳三糖几丁质酶HsChit1的Ki为12.1nM；图3为08对秀丽隐杆线虫几丁质酶CeCht1的抑制活性测试图，图3显示08对秀丽隐杆线虫几丁质酶CeCht1的Ki为18.8nM；图4为08对酸性哺乳动物酶AMCase的抑制活性测试图，图4显示08对酸性哺乳动物酶AMCase的Ki为64.1nM。
采用以下方法制备芳香稠环亚胺类化合物，
式Ⅰ-ⅤA化合物和等量的式Ⅰ-ⅤB化合物在惰性溶剂中，110℃温度下反应1h，TLC跟踪反应结束后，使用旋转蒸发仪除去反应液中的惰性溶剂，柱层析DCM：MeOH＝25：1得到目标化合物。
取2-氨基-N-苄基-10-甲基-5-氧代-5H-吡啶并[1,2-a:2',3'-d]嘧啶-3-甲酰胺360mg，N,N-二甲基甲酰胺二甲基缩醛(DMFDMA)120mg，加入到5ml甲苯中，110℃下反应1h，TLC跟踪反应结束后，使用旋转蒸发仪除去反应液中的甲苯，柱层析DCM：MeOH＝25：1得到目标化合物08，黄绿色固体，产率58.9％，1H NMR(400MHz,CDCl3)δ11.44(s,1H),9.55(s,1H),9.12(s,1H),8.83(d,J＝6.9Hz,1H),8.58(d,J＝1.9Hz,1H),8.47–8.35(m,1H),7.77(dt,J＝8.1,1.7Hz,1H),7.52(d,J＝6.6Hz,1H),7.25–7.21(m,1H),6.87(t,J＝7.0Hz,1H),3.31(s,3H),3.21(s,3H),2.66(s,3H),1.51–1.33(m,4H)ppm。
其他化合物可以通过类似的方法，使用相应的原料，按照合成反应通式合成，核磁数据列于下表。
表1芳香稠环亚胺类化合物结构及其核磁
实施例中所用到的OfChi-h、OfChtI、CeCht1、HsChit1、AmCase、AfChiB1、SmChiA参考下述参考文献：
Liu,T.,Chen,L.,Zhou,Y.,Jiang,X.,Duan,Y.,&Yang,Q.(2017).Structure,cat-alysis,an d inhi bition of Of Chi-h,the lepid optera-exclusive insectchitinase.Journal of Biological Chemistry,292(6),2080-2088.
Chen,L.,Zhou,Y.,Qu,M.,Zhao,Y.,&Yang,Q.(2014).Fully deacetylatedchitooligosaccharides act as efficient glycoside hydrolase family 18chitinaseinhibitors.Journal of Biological Chemistry,289(25),17932-17940.
Chen,Q.,Chen,W.,Kumar,A.,Jiang,X.,Janezic,M.,Zhang,K.Y.,&Yang,Q.(2021).Crystal Structure and Structure-Based Discovery of Inhibitors of the NematodeChitinase Ce Cht1.Journal of Agricultural and Food Chemistry,69(11),3519-3526.
Schüttelkopf,A.W.,Andersen,O.A.,Rao,F.V.,Allwood,M.,Rush,C.L.,Eggleston,I.M.,&van Aalten,D.M.(2011).Bisdionin C A Rationally Designed,Submicromolar Inhibitor of Family 18Chitinases.ACS medicinal chemistryletters,2(6),428-432.
抑制率测试方法：将待测化合物溶解在二甲基亚砜(DMSO)中，配置成10mM母液。
反应体系：总体积100μL的反应体系中含有适量的几丁质酶、20μM MU-(GlcNAc)2、2％(v/v)DMSO、10mM NaH2PO4、10mM Na2HPO4(pH 6.0)和不同浓度的抑制剂。
在30℃条件下，首先将待测几丁质酶和相应的化合物孵育10min，然后加入底物MU-(GlcNAc)2，继续反应20min后，加入100μL的0.5M的碳酸钠溶液终止反应，通过酶标仪(Tecan Infinite 200Pro)测定荧光强度，激发波长360nm，发射波长440nm。实验组荧光强度记做FE，不含底物的阴性对照组荧光强度记做FN，不含化合物的阳性对照组荧光强度记做FP，空白对照荧光强度记做FB，通过如下公式计算抑制活性。
抑制率＝[1-(FE-FN)/(FP-FB)]×100％
抑制常数Ki值的测定：在三个不同的底物浓度下，测定不同浓度化合物的抑制活性，以反应速率的倒数为纵坐标，化合物浓度为横坐标，通过Dixon plots法计算化合物的Ki值。
表2芳香稠环亚胺类化合物对不同几丁质酶在1μM浓度下的抑制活性
Claims (10)
1.一种如通式(Ⅰ)结构的芳香稠环亚胺类化合物，或所述化合物的光学异构体、顺反异构体或其药学、农药学上可以接受的盐或溶剂合物：
其中，Y为无，或具有1-10个碳原子的取代或末取代的亚烷基或亚烷基-O-，所述的亚烷基为直链或支链的亚烷基；
M选自下组：NH，O或S；
R1为位于
环上的一个或多个H或C1-C4烷基或卤素；
R2，R3各自独立地选自下组：氢，氘，任意取代或未取代烷基，任意取代或未取代的烯基，任意取代或未取代的炔基，任意取代或未取代的烷氧基，任意取代或未取代环烷基，羟基，氨基，巯基，膦基，硝基，任意取代或未取代的芳基，任意取代或未取代的杂芳基中的一个或多个；
R4选自下组：氢，卤素，羟基，硝基，氨基，氰基，羰基，取代或未取代C2-C12烯基，取代或未取代C2-C12炔基，羧基，取代或未取代C1-C12烷基或烷氧基，取代或未取代C1-C12烷胺基，取代或未取代C3-C9环烷基，取代或为取代C5-7环烯基，取代或未取代的C2-C9非杂芳基，取代或未取代的3～12元杂环，取代或未取代的C6-C12芳基，取代或未取代的C4-C12杂芳基，取代或未取代苯基，取代或未取代萘基，取代或未取代5元或6元杂环基，或取代或未取代8-12元杂芳二环基；
环A为取代或未取代的8-12元杂芳二环环系，取代或未取代的8-12元杂芳三环环系，取代或未取代5-12元芳环环系，取代或未取代5-12元杂环环系，取代或未取代的5-12元芳环，取代或未取代的5-12元杂芳环，或取代或未取代5-12元杂环(包括全部或部分不饱和的杂环)；
R5为位于环A任意一个或多个位置上各自独立的取代基,且R5选自下组:卤素、氰基、硝基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、或取代或未取代的C3-7环烷基、取代或未取代的C5-7环烯基、三甲基硅烷基乙炔基、取代或未取代的苯基、取代或未取代的萘基、三甲基硅烷基乙炔基、取代或未取代的5元或6元杂环基、取代或未取代的8元至12元杂芳二环环系、OR'、Si(R')3、NR'R"、C(O)R'、C(O)OR'、C(O)NR'R"、SR'、S(O)mR'、S(O)2NR'R"、OC(O)R'、OC(O)NR'R"、OS(O)2R'、OS(O)2NR'R"、N(R")C(O)R'、NCH2R'、N(R")C(O)NR'R"、N(R")S(O)2R'或N(R')S(O)2NR'R"；
其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基所取代：卤素，羟基，硝基，氨基，氰基，羰基，羧基，C1-C6烷基，C1-C6烷氧基，C1-C6烷胺基，羟基C1-C6烷基，氨基C1-C6烷基，羰基C1-C6烷基，OR'、Si(R')3、NR'R"、C(O)R'、C(O)OR'、C(O)NR'R"、SR'、S(O)mR'、S(O)2NR'R"、OC(O)R'、OC(O)NR'R"、OS(O)2R'、OS(O)2NR'R"、N(R")C(O)R'、NCH2R'、N(R")C(O)NR'R"、N(R")S(O)2R'或N(R')S(O)2NR'R"，C3-C9环烷基，C6-C12芳基，3～12元杂环，C4-C12杂芳基；
其中R'、R"各自独立地为：H、C1-6烷基、C1-6卤代烷基、C3-6卤代环烷基、C2-6烯基、C2-6卤代烯基、C2-6炔基、C2-6卤代炔基，或取代或未取代的C3-7环烷基、取代或未取代的C5-7环烯基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的5元或6元饱和或不饱和杂环基、或取代或未取代的8元至12元杂芳二环环系；其中，R'、R"上的取代基是选自下组的一个或多个基团所取代:氧基(＝0)、卤素、氰基、硝基、C1-6烷基或环烷基、C1-6卤代烷基、C2-6烯基、C2-6卤代烯基、C2-6炔基、C2-6卤代炔基、羟基、羟基C1-4烷基。
2.根据权利要求1所述的芳香稠环亚胺类化合物，或其药学、农药学上可以接受的盐或溶剂合物，其特征在于，所述化合物具有如式(Ⅱ)、式(Ⅲ)、式(Ⅳ)或式(Ⅴ)所示的结构：
其中，Y为无，或具有1-10个碳原子的未取代的直链亚烷基或亚烷基-O-；
M选自下组：NH，O或S；
n为0,1，2，3；
R1选自下组：氢，氟，氯，溴，碘，甲基，甲氧基，乙基，丙基，异丙基，环丙基，正丁基或者叔丁基；
R2，R3各自独立地选自下组：氢，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基，正戊基，异戊基，新戊基，丙烯基，烯丙基，丁烯基，戊烯基，己烯基，丙炔基，丁炔基，戊炔基，己炔基，环丙基，环丁基，环戊基，环己基，异丁羟基，氨基，巯基，膦基，硝基，苯基，苄基，吡啶基，呋喃基，噻吩基，甲氧苯基，乙基苯基，三氟甲基苯基，硝基苯基，1,2-二氯苯基，1,3-二氯苯基，1,4-二氯苯基，1,2-二溴苯基，1,3-二溴苯基，1,4-二溴苯基，1,2-二氟苯基，1,3-二氟苯基，1,4-二氟苯基，1,2-二甲基苯基，1,3-二甲基苯基，1,4-二甲基苯基，1,2,4,5-四氟苯基，1,2,3,4-四氟苯基，1,2,3,5-四氟苯基，1,2,4,5-四溴苯基，1,2,3,4-四溴苯基，1,2,3,5-四溴苯基，1,2,4,5-四氯苯基，1,2,3,4-四氯苯基，1,2,3,5-四氯苯基；
R4，R5各自独立地选自下组：氢，氟，氯，溴，碘，羟基，硝基，氰基，羰基，氨基，甲氧基，乙氧基，丙氨基，异氧丙基，正丁氧基，叔丁氧基，环己基氧基，N-(N，N-二甲基)取代基，N-(N，N-二乙基)取代基，N-(N，N-二丙基)取代基，N-(N，N-二丁基)取代基，N-(N-甲基-N-乙基)取代基，N-(N-甲基-N-丙基)取代基，N-(N-甲基-N-丁基)取代基，N-(N-乙基-N-丙基)取代基，N-(N-乙基-N-丁基)取代基，N-(N-丙基-N-丁基)取代基，环丙基，环丁基，环戊基，环己基，环庚基，2，3或4-甲基环己基，2，3或4-乙基环己基，2，3或4-羟基环己基，2，3或4-羧基环己基，2，3或4-氰基环己基，2，3或4-氨基环己基，2或3-四氢呋喃基，2或3-四氢噻吩基，N，2或3-四氢吡咯基，2，3或4-四氢吡喃基，N，2，3或4-哌啶基，N，2或3-吗啉基，N或2-哌嗪基，N，2或3-(N-甲基哌嗪基)，N，2或3-(N-苄基哌嗪基)苯基，2，3或4-甲基苯基，2，3或4-甲氧基苯基，2，3或4-氨基苯基，2，3或4-氰基苯基，2，3或4-羧基苯基，2，3或4-硝基苯基，2，3或4-羟基苯基，萘基，2或3-呋喃基，2或3-噻吩基，N，2或3-吡咯基，2，3或4-吡啶基，N，2或3-(N-吗啉基)苯基，吲哚基。
3.根据权利要求2所述的芳香稠环亚胺类化合物，或其药学、农药学上可以接受的盐或溶剂合物，其特征在于，所述化合物具有如下所示结构：
Y为无，或具有1，2，3个碳原子的未取代的直链亚烷基；
R4选自下组：氢，氟，氯，溴，碘，羟基，硝基，氰基，羰基，氨基，甲氧基，乙氧基，丙氨基，异氧丙基，正丁氧基，叔丁氧基，环己基氧基，N-(N，N-二甲基)取代基，N-(N，N-二乙基)取代基，N-(N，N-二丙基)取代基，N-(N，N-二丁基)取代基，N-(N-甲基-N-乙基)取代基，N-(N-甲基-N-丙基)取代基，N-(N-甲基-N-丁基)取代基，N-(N-乙基-N-丙基)取代基，N-(N-乙基-N-丁基)取代基，N-(N-丙基-N-丁基)取代基，环丙基，环丁基，环戊基，环己基，环庚基，2，3或4-甲基环己基，2，3或4-乙基环己基，2，3或4-羟基环己基，2，3或4-羧基环己基，2，3或4-氰基环己基，2，3或4-氨基环己基，2或3-四氢呋喃基，2或3-四氢噻吩基，N，2或3-四氢吡咯基，2，3或4-四氢吡喃基，N，2，3或4-哌啶基，N，2或3-吗啉基，N或2-哌嗪基，N，2或3-(N-甲基哌嗪基)，N，2或3-(N-苄基哌嗪基)苯基，2，3或4-甲基苯基，2，3或4-甲氧基苯基，2，3或4-氨基苯基，2，3或4-氰基苯基，2，3或4-羧基苯基，2，3或4-硝基苯基，2，3或4-羟基苯基，萘基，2或3-呋喃基，2或3-噻吩基，N，2或3-吡咯基，2，3或4-吡啶基，N，2或3-(N-吗啉基)苯基，吲哚基。
4.根据权利要求2所述的芳香稠环亚胺类化合物，或其药学、农药学上可以接受的盐或溶剂合物，其特征在于，所述化合物具有如下所示结构：
R4，R5各自独立地选自下组：氢，氟，氯，溴，碘，羟基，硝基，氰基，羰基，氨基，甲氧基，乙氧基，丙氨基，异氧丙基，正丁氧基，叔丁氧基，环己基氧基，N-(N，N-二甲基)取代基，N-(N，N-二乙基)取代基，N-(N，N-二丙基)取代基，N-(N，N-二丁基)取代基，N-(N-甲基-N-乙基)取代基，N-(N-甲基-N-丙基)取代基，N-(N-甲基-N-丁基)取代基，N-(N-乙基-N-丙基)取代基，N-(N-乙基-N-丁基)取代基，N-(N-丙基-N-丁基)取代基，环丙基，环丁基，环戊基，环己基，环庚基，2，3或4-甲基环己基，2，3或4-乙基环己基，2，3或4-羟基环己基，2，3或4-羧基环己基，2，3或4-氰基环己基，2，3或4-氨基环己基，2或3-四氢呋喃基，2或3-四氢噻吩基，N，2或3-四氢吡咯基，2，3或4-四氢吡喃基，N，2，3或4-哌啶基，N，2或3-吗啉基，N或2-哌嗪基，N，2或3-(N-甲基哌嗪基)，N，2或3-(N-苄基哌嗪基)苯基，2，3或4-甲基苯基，2，3或4-甲氧基苯基，2，3或4-氨基苯基，2，3或4-氰基苯基，2，3或4-羧基苯基，2，3或4-硝基苯基，2，3或4-羟基苯基，萘基，2或3-呋喃基，2或3-噻吩基，N，2或3-吡咯基，2，3或4-吡啶基，N，2或3-(N-吗啉基)苯基，吲哚基。
5.根据权利要求2所述的芳香稠环亚胺类化合物，或其药学、农药学上可以接受的盐或溶剂合物，其特征在于，所述化合物具有如下所示的结构：
Y为无，或具有1，2，3个碳原子的未取代的直链亚烷基；
R4选自下组：氢，氟，氯，溴，碘，羟基，硝基，氰基，羰基，氨基，甲氧基，乙氧基，丙氨基，异氧丙基，正丁氧基，叔丁氧基，环己基氧基，N-(N，N-二甲基)取代基，N-(N，N-二乙基)取代基，N-(N，N-二丙基)取代基，N-(N，N-二丁基)取代基，N-(N-甲基-N-乙基)取代基，N-(N-甲基-N-丙基)取代基，N-(N-甲基-N-丁基)取代基，N-(N-乙基-N-丙基)取代基，N-(N-乙基-N-丁基)取代基，N-(N-丙基-N-丁基)取代基，环丙基，环丁基，环戊基，环己基，环庚基，2，3或4-甲基环己基，2，3或4-乙基环己基，2，3或4-羟基环己基，2，3或4-羧基环己基，2，3或4-氰基环己基，2，3或4-氨基环己基，2或3-四氢呋喃基，2或3-四氢噻吩基，N，2或3-四氢吡咯基，2，3或4-四氢吡喃基，N，2，3或4-哌啶基，N，2或3-吗啉基，N或2-哌嗪基，N，2或3-(N-甲基哌嗪基)，N，2或3-(N-苄基哌嗪基)苯基，2，3或4-甲基苯基，2，3或4-甲氧基苯基，2，3或4-氨基苯基，2，3或4-氰基苯基，2，3或4-羧基苯基，2，3或4-硝基苯基，2，3或4-羟基苯基，萘基，2或3-呋喃基，2或3-噻吩基，N，2或3-吡咯基，2，3或4-吡啶基，N，2或3-(N-吗啉基)苯基，吲哚基。
6.根据权利要求2所述的芳香稠环亚胺类化合物，或其药学、农药学上可以接受的盐或溶剂合物，其特征在于，所述化合物具有如下所示的结构：
Y为无，或具有1，2，3个碳原子的未取代的直链亚烷基；
R4选自下组：氢，氟，氯，溴，碘，羟基，硝基，氰基，羰基，氨基，甲氧基，乙氧基，丙氨基，异氧丙基，正丁氧基，叔丁氧基，环己基氧基，N-(N，N-二甲基)取代基，N-(N，N-二乙基)取代基，N-(N，N-二丙基)取代基，N-(N，N-二丁基)取代基，N-(N-甲基-N-乙基)取代基，N-(N-甲基-N-丙基)取代基，N-(N-甲基-N-丁基)取代基，N-(N-乙基-N-丙基)取代基，N-(N-乙基-N-丁基)取代基，N-(N-丙基-N-丁基)取代基，环丙基，环丁基，环戊基，环己基，环庚基，2，3或4-甲基环己基，2，3或4-乙基环己基，2，3或4-羟基环己基，2，3或4-羧基环己基，2，3或4-氰基环己基，2，3或4-氨基环己基，2或3-四氢呋喃基，2或3-四氢噻吩基，N，2或3-四氢吡咯基，2，3或4-四氢吡喃基，N，2，3或4-哌啶基，N，2或3-吗啉基，N或2-哌嗪基，N，2或3-(N-甲基哌嗪基)，N，2或3-(N-苄基哌嗪基)苯基，2，3或4-甲基苯基，2，3或4-甲氧基苯基，2，3或4-氨基苯基，2，3或4-氰基苯基，2，3或4-羧基苯基，2，3或4-硝基苯基，2，3或4-羟基苯基，萘基，2或3-呋喃基，2或3-噻吩基，N，2或3-吡咯基，2，3或4-吡啶基，N，2或3-(N-吗啉基)苯基，吲哚基。
7.根据权利要求2所述的化合物，或其药学、农药学上可以接受的盐或溶剂合物，其特征在于，所述化合物具有如下所示的结构：
R2，R3各自独立地选自下组：氢，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基，正戊基，异戊基，新戊基，丙烯基，烯丙基，丁烯基，戊烯基，己烯基，丙炔基，丁炔基，戊炔基，己炔基，环丙基，环丁基，环戊基，环己基，异丁羟基，氨基，巯基，膦基，硝基，苯基，苄基，吡啶基，呋喃基，噻吩基，甲氧苯基，乙基苯基，三氟甲基苯基，硝基苯基，1,2-二氯苯基，1,3-二氯苯基，1,4-二氯苯基，1,2-二溴苯基，1,3-二溴苯基，1,4-二溴苯基，1,2-二氟苯基，1,3-二氟苯基，1,4-二氟苯基，1,2-二甲基苯基，1,3-二甲基苯基，1,4-二甲基苯基，1,2,4,5-四氟苯基，1,2,3,4-四氟苯基，1,2,3,5-四氟苯基，1,2,4,5-四溴苯基，1,2,3,4-四溴苯基，1,2,3,5-四溴苯基，1,2,4,5-四氯苯基，1,2,3,4-四氯苯基，1,2,3,5-四氯苯基；
R4，R5各自独立地选自下组：氢，氟，氯，溴，碘，羟基，硝基，氰基，羰基，氨基，甲氧基，乙氧基，丙氨基，异氧丙基，正丁氧基，叔丁氧基，环己基氧基，N-(N，N-二甲基)取代基，N-(N，N-二乙基)取代基，N-(N，N-二丙基)取代基，N-(N，N-二丁基)取代基，N-(N-甲基-N-乙基)取代基，N-(N-甲基-N-丙基)取代基，N-(N-甲基-N-丁基)取代基，N-(N-乙基-N-丙基)取代基，N-(N-乙基-N-丁基)取代基，N-(N-丙基-N-丁基)取代基，环丙基，环丁基，环戊基，环己基，环庚基，2，3或4-甲基环己基，2，3或4-乙基环己基，2，3或4-羟基环己基，2，3或4-羧基环己基，2，3或4-氰基环己基，2，3或4-氨基环己基，2或3-四氢呋喃基，2或3-四氢噻吩基，N，2或3-四氢吡咯基，2，3或4-四氢吡喃基，N，2，3或4-哌啶基，N，2或3-吗啉基，N或2-哌嗪基，N，2或3-(N-甲基哌嗪基)，N，2或3-(N-苄基哌嗪基)苯基，2，3或4-甲基苯基，2，3或4-甲氧基苯基，2，3或4-氨基苯基，2，3或4-氰基苯基，2，3或4-羧基苯基，2，3或4-硝基苯基，2，3或4-羟基苯基，萘基，2或3-呋喃基，2或3-噻吩基，N，2或3-吡咯基，2，3或4-吡啶基，N，2或3-(N-吗啉基)苯基，吲哚基。
8.根据权利要求1所述的化合物，或其药学、农药学上可以接受的盐或溶剂合物，其特征在于，所述化合物部分代表结构为下列化合物中的一种化合物：
9.一种如权利要求1至8中任一所述的芳香稠环亚胺类化合物，或所述化合物的光学异构体、顺反异构体或其药学、农药学上可以接受的盐或溶剂合物，在制备几丁质酶抑制剂中的应用。
10.一种药物组合物，所述的药物组合物包括含有治疗有效量的如权利要求1-8中任一所述的芳香稠环亚胺类化合物，其药学、农药学上可以接受的盐或药学，农药学上可以接受的溶剂合物作为活性成分，药学、农药学上可接受的载体。
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