TW201506011A - Nitrogenous heterocyclic derivatives and their application in drugs - Google Patents
Nitrogenous heterocyclic derivatives and their application in drugs Download PDFInfo
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本發明屬於藥物領域，並具體涉及一種新的含氮雜環化合物、藥物組合物、其製備方法及其作為藥物尤其是作為製備治療和預防組織纖維化的藥物的用途。 The present invention belongs to the field of medicine, and in particular relates to a novel nitrogen-containing heterocyclic compound, a pharmaceutical composition, a preparation method thereof and use thereof as a medicament, in particular as a medicament for the treatment and prevention of tissue fibrosis.
器官組織纖維化輕者稱為纖維化，重者引起組織結構破壞而發生器官硬化。組織纖維化不僅發生在肺、肝等器官，組織纖維化可累及人體幾乎所有的器官和系統，它是由於多種原因(如炎症，免疫、毒物、缺血及血流動力學改變等)引起實質細胞損傷，然後導致實質細胞的炎症變形、壞死、並啟動相應的巨噬細胞釋放多種細胞因數和生長因數，這些因數啟動靜息狀態的細胞外基質(extracellular martrix,ECM)產生細胞，使之轉化為肌成纖維細胞；肌成纖維細胞增殖，並分泌細胞因數，通過旁分泌方式再作用於巨噬細胞。肌成纖維細胞可合成大量膠原等ECM成分，同時ECM降解減少，從而造成器官或組織纖維化。因此器官或組織纖維化的發生和發展是細胞、細胞因數和ECM等相互作用、多因素參加的結果。鑒於ECM產生細胞在器官或組織纖維化形成中的重要作用，目前治療器官或組織纖維化的中藥靶標之一是抑制ECM產生細胞的增殖、活化和誘導其凋亡。 Organ tissue fibrosis is called fibrosis, and severe cases cause structural damage and organ sclerosis. Tissue fibrosis occurs not only in organs such as the lungs and liver, but tissue fibrosis can affect almost all organs and systems in the human body. It is caused by various causes (such as inflammation, immunity, poison, ischemia, and hemodynamic changes). Cell damage, which then leads to inflammatory deformation, necrosis of parenchymal cells, and activation of corresponding macrophages to release a variety of cytokines and growth factors that initiate resting extracellular matrix (ECM)-producing cells to transform Muscle fibroblasts; myofibroblasts proliferate and secrete cytokines, which act on macrophages by paracrine means. Myofibroblasts can synthesize a large amount of ECM components such as collagen, while ECM degradation is reduced, resulting in organ or tissue fibrosis. Therefore, the occurrence and development of organ or tissue fibrosis is the result of interaction, multi-factor participation of cells, cytokines and ECM. In view of the important role of ECM-producing cells in the formation of organ or tissue fibrosis, one of the current Chinese medicine targets for treating organ or tissue fibrosis is to inhibit the proliferation, activation and induce apoptosis of ECM-producing cells.
由於各器官或組織功能、形態的不同，以及各器官或組織主要組成細胞的不同，使得不同器官或組織的纖維化在其發病機理中既有共性、也有個性；以ECM主要產生細胞為例，肝臟中是肝星狀細胞，腎小球中為腎小球系膜細胞，腎間質中為腎間質成纖維細胞，肺臟中為肺成纖維細胞，心臟中為心成纖維細胞，腹膜中為腹膜間皮細胞。因此，在不同器官或組織纖維化的發病機制和治療靶點上也存在一定的差異。 Due to the different functions and morphologies of various organs or tissues, and the major constituent cells of various organs or tissues, the fibrosis of different organs or tissues has both commonality and individuality in its pathogenesis; taking ECM as the main producing cell as an example. Hepatic stellate cells in the liver, mesangial cells in the glomerulus, renal interstitial fibroblasts in the renal interstitium, lung fibroblasts in the lung, cardiac fibroblasts in the heart, and peritoneum For peritoneal mesothelial cells. Therefore, there are also some differences in the pathogenesis and therapeutic targets of different organs or tissue fibrosis.
EP1138329A公開已知的一種抗纖維化的藥物是吡非尼酮或稱 phifenidone,PFD，5-甲基-1-苯基-2-(1-氫)-吡啶酮。實驗表明，在腎纖維化、肺纖維化動物實驗和特異性肺纖維化病人的臨床治療中，PFD均具有阻止甚至逆轉ECM聚積的作用。 EP 1 138 329 A discloses that a known anti-fibrotic drug is pirfenidone or Phiffenidone, PFD, 5-methyl-1-phenyl-2-(1-hydro)-pyridinone. Experiments have shown that PFD has the effect of preventing or even reversing the accumulation of ECM in renal fibrosis, pulmonary fibrosis animal experiments and clinical treatment of patients with specific pulmonary fibrosis.
本發明提供一種化合物，或其藥物組合物，可以更加有效地阻止或治療人體或動物組織纖維化。一方面，本發明涉及一種如式(I)所示的化合物：
其中一些實施方案是，V1是N或CR1；V2是N或CR2；V3是N或CR3；V4是N或CR4；其中V1，V2，V3和V4至多有一個可以為N；X是一個鍵，或X為NR5，O，S，C1-10亞烷基，C2-10亞烯基，C2-10亞炔基，-R6-C(=Y)-，-R6-C(=Y)-O-，-R6-C(=Y)-N(R5)-，-R6-S(=O)t-，-R6-S(=O)t-N(R7)-，或-R6-Y-，其中t是1或2；Y是O或S；A為下述二價基團：亞雜環基，亞碳環基，亞稠合雙環基，亞稠合雜雙環基，亞螺雙環基，亞螺雜雙環基，亞芳基或亞雜芳基；B為烷氧基，羥基取代的烷氧基，-NR7R7a，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)t-，R7S(=O)t-，R7-S(=O)t-N(R7a)-，C4-12碳環基，C4-12環烷基，雜環基，芳基，雜芳基，稠合雙環基，稠合雜雙環基，螺雙環基，或螺雜雙環基；
或A，X和B可共同形成以下的子結構式(II)：
其中一些實施方案是，A獨立地為下述二價基團：C2-10亞雜環基，C3-10 亞碳環基，C5-12亞稠合雙環基，C5-12亞稠合雜雙環基，C5-12亞螺雙環基，C5-12亞螺雜雙環基，C6-10亞芳基，或C1-9亞雜芳基。 In some embodiments, A is independently the divalent group: C 2-10 heterocyclylene, C 3-10 carbocyclylene, C 5-12 subfused bicyclic, C 5-12 A fused heterobicyclic group, a C 5-12 sirobicyclo group, a C 5-12 spirobicyclo group, a C 6-10 arylene group, or a C 1-9 heteroarylene group.
另外一些實施方案是，A為以下的子結構式：
另外一些實施方案是，A為以下的子結構式：
另外一些實施方案是，A為以下的子結構式：
其中一些實施方案是，B獨立地為C1-6烷氧基，羥基取代的C1-6烷氧基，-NR7R7a，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)2-，R7S(=O)2-，R7S(=O)2N(R7a)-，C4-12碳環基，C4-12環烷基，C2-10雜環基，C6-10芳基，C1-9雜芳基，C5-12稠合雙環基，C5-12稠合雜雙環基，C5-12螺雙環基，或C5-12螺雜雙環基。 In some embodiments, B is independently C 1-6 alkoxy, hydroxy substituted C 1-6 alkoxy, -NR 7 R 7a , -C(=O)NR 7 R 7a , -OC(= O) NR 7 R 7a , -OC(=O)OR 7 , -N(R 7 )C(=O)NR 7 R 7a , -N(R 7 )C(=O)OR 7a , -N(R 7 ) C(=O)-R 7a , R 7 R 7a NS(=O) 2 -, R 7 S(=O) 2 -, R 7 S(=O) 2 N(R 7a )-, C 4 -12 carbocyclyl, C 4-12 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl, C 5-12 fused bicyclic, C 5-12 A fused heterobicyclic group, a C 5-12 spirobicyclic group, or a C 5-12 spirobicyclic group.
其中一些實施方案是，R1為H，F，Cl，Br，I，氰基，羥基，R7aR7N-，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)2-，R7S(=O)2-，R7S(=O)2N(R7a)-，R7aR7N-C1-6烷基，R7S(=O)-C1-6烷基，R7R7aN-C(=O)-C1-6烷基，R7aR7N-C1-6烷氧基，R7S(=O)-C1-6烷氧基，R7R7aN-C(=O)-C1-6烷氧基，C1-6脂肪族，C1-6烷氧基，C1-6羥基烷氧基，C1-6氨基烷氧基，C1-6羥基取代的氨基烷氧基，C1-6鹵代烷氧基，C1-6氨基取代的鹵代烷氧基，C1-6烷氨基C1-6鹵代烷氧基，羥基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6烷氧基，C1-6烷氧基C1-6烷氧基，C3-10環烷基氧基，C6-10芳基C1-6烷氧基，C6-10芳基C1-6烷氨基，C1-9雜芳基C1-6烷氧基，C1-9雜芳基C1-6烷氨基，C2-10雜環基C1-6烷氧基，C2-10雜環基C1-6烷氨基，C3-10環烷基氧基，C3-10環烷基氨基，C3-10碳環基C1-6烷氧基，C3-10碳環基C1-6烷氨基，C2-10雜環基(C1-6羥基烷氧基)，C3-10碳環基(C1-6羥基烷氧基)，C6-10芳基(C1-6羥基烷氧基)，C6-10芳氧基C1-6烷氧基，C6-10芳氧基，C1-9雜芳基氧基，C1-9雜芳基氧基C1-6烷氧基，C2-10雜環基氧基C1-6烷氧基，C3-10碳環基氧基C1-6烷氧基，C2-10雜環基氧基，C1-6疊氮基烷氧基，C5-12稠合雙環基，C5-12稠合雜雙環基，C5-12稠合雙環基C1-6脂肪族，C5-12稠合雜雙環基C1-6脂肪族，C5-12稠合雙環基氧基，C5-12 稠合雜雙環基氧基，C5-12稠合雙環基氨基，C5-12稠合雜雙環基氨基，C5-12稠合雙環基C1-6烷氧基，C5-12稠合雜雙環基C1-6烷氧基，C5-12稠合雙環基C1-6烷氨基，C5-12稠合雜雙環基C1-6烷氨基，C5-12稠合雙環基氧基C1-6烷氧基，C5-12稠合雜雙環基氧基C1-6烷氧基，C5-12稠合雙環基氨基C1-6烷氧基，C5-12稠合雜雙環基氨基C1-6烷氧基，C5-12稠合雙環基-C(=O)-，C5-12稠合雙環基-C(=O)O-，C5-12稠合雜雙環基-C(=O)-，C5-12稠合雜雙環基-C(=O)O-，C5-12稠合雙環基氨基-C(=O)-，C5-12稠合雜雙環基氨基-C(=O)-，C5-12稠合雙環基-C(=O)N(R7)-，C5-12稠合雜雙環基-C(=O)N(R7)-，C5-12螺雙環基，C5-12螺雜雙環基，C5-12螺雙環基C1-6脂肪族，C5-12螺雜雙環基C1-6脂肪族，C5-12螺雙環基氧基，C5-12螺雜雙環基氧基，C5-12螺雙環基氨基，C5-12螺雜雙環基氨基，C5-12螺雙環基C1-6烷氧基，C5-12螺雜雙環基C1-6烷氧基，C5-12螺雙環基C1-6烷氨基，C5-12螺雜雙環基C1-6烷氨基，C5-12螺雙環基氧基C1-6烷氧基，C5-12螺雜雙環基氧基C1-6烷氧基，C5-12螺雙環基氨基C1-6烷氧基，C5-12螺雜雙環基氨基C1-6烷氧基，C5-12螺雙環基-C(=O)-，C5-12螺雙環基-C(=O)O-，C5-12螺雜雙環基-C(=O)-，C5-12螺雜雙環基-C(=O)O-，C5-12螺雙環基氨基-C(=O)-，C5-12螺雜雙環基氨基-C(=O)-，C5-12螺雙環基-C(=O)N(R7)-，C5-12螺雜雙環基-C(=O)N(R7)-，C2-10雜環基，C3-10環烷基，C6-10芳基，C1-9雜芳基，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳基C1-6脂肪族，C1-9雜芳基C1-6脂肪族，C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-，其中G是O，S，NR5，S(=O)，S(=O)2，C(=O)，-C(=O)NH-，-OC(=O)NH-，-OC(=O)-，-NHC(=O)NH-，-HN-S(=O)t-，-OS(=O)t-，或-OS(=O)tNH-；t是1或2；p和m各自獨立地為0，1，2，3或4；或者其中C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-可以被一個或多個選自F，Cl，Br，I，C1-10烷基，C2-10烯基，C2-10炔基，C1-10烷氧基或氰基的取代基取代；R2為H，F，Cl，Br，I，氰基，羥基，R7aR7N-，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)2-，R7S(=O)2-，R7S(=O)2N(R7a)-，R7aR7N-C1-6 烷基，R7S(=O)-C1-6烷基，R7R7aN-C(=O)-C1-6烷基，R7aR7N-C1-6烷氧基，R7S(=O)-C1-6烷氧基，R7R7aN-C(=O)-C1-6烷氧基，C1-6脂肪族，C1-6烷氧基，C1-6羥基烷氧基，C1-6氨基烷氧基，羥基取代的C1-6氨基烷氧基，C1-6鹵代烷氧基，氨基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6鹵代烷氧基，羥基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6烷氧基，C1-6烷氧基C1-6烷氧基，C3-10環烷基氧基，C6-10芳基C1-6烷氧基，C6-10芳基C1-6烷氨基，C1-9雜芳基C1-6烷氧基，C1-9雜芳基C1-6烷氨基，C2-10雜環基C1-6烷氧基，C2-10雜環基C1-6烷氨基，C3-10環烷基氨基，C3-10碳環基C1-6烷氧基，C3-10碳環基C1-6烷氨基，C2-10雜環基(C1-6羥基烷氧基)，C3-10碳環基(C1-6羥基烷氧基)，C6-10芳基(C1-6羥基烷氧基)，C6-10芳氧基C1-6烷氧基，C6-10芳氧基，C1-9雜芳基氧基，C1-9雜芳基氧基C1-6烷氧基，C2-10雜環基氧基C1-6烷氧基，C3-10碳環基氧基C1-6烷氧基，C2-10雜環基氧基，C1-6疊氮基烷氧基，C5-12稠合雙環基，C5-12稠合雜雙環基，C5-12稠合雙環基C1-6脂肪族，C5-12稠合雜雙環基C1-6脂肪族，C5-12稠合雙環基氧基，C5-12稠合雜雙環基氧基，C5-12稠合雙環基氨基，C5-12稠合雜雙環基氨基，C5-12稠合雙環基C1-6烷氧基，C5-12稠合雜雙環基C1-6烷氧基，C5-12稠合雙環基C1-6烷氨基，C5-12稠合雜雙環基C1-6烷氨基，C5-12稠合雙環基氧基C1-6烷氧基，C5-12稠合雜雙環基氧基C1-6烷氧基，C5-12稠合雙環基氨基C1-6烷氧基，C5-12稠合雜雙環基氨基C1-6烷氧基，C5-12稠合雙環基-C(=O)-，C5-12稠合雙環基-C(=O)O-，C5-12稠合雜雙環基-C(=O)-，C5-12稠合雜雙環基-C(=O)O-，C5-12稠合雙環基氨基-C(=O)-，C5-12稠合雜雙環基氨基-C(=O)-，C5-12稠合雙環基-C(=O)N(R7)-，C5-12稠合雜雙環基-C(=O)N(R7)-，C5-12螺雙環基，C5-12螺雜雙環基，C5-12螺雙環基C1-6脂肪族，C5-12螺雜雙環基C1-6脂肪族，C5-12螺雙環基氧基，C5-12螺雜雙環基氧基，C5-12螺雙環基氨基，C5-12螺雜雙環基氨基，C5-12螺雙環基C1-6烷氧基，C5-12螺雜雙環基C1-6烷氧基，C5-12螺雙環基C1-6烷氨基，C5-12螺雜雙環基C1-6烷氨基，C5-12螺雙環基氧基C1-6烷氧基，C5-12螺雜雙環基氧基C5-12烷氧基，C5-12螺雙環基氨基C1-6烷氧基，C5-12螺雜雙環基氨基C1-6烷氧基，C5-12螺雙環基-C(=O)-，C5-12螺雙環基-C(=O)O-，C5-12螺雜雙環基-C(=O)-，C5-12螺雜雙環基-C(=O)O-，C5-12螺雙環基氨基-C(=O)-，C5-12螺雜雙環基氨基-C(=O)-，C5-12螺雙環基-C(=O)N(R7)-，C5-12螺雜雙環基-C(=O)N(R7)-，C2-10 雜環基，C3-10環烷基，C6-10芳基，C1-4雜芳基，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳基C1-6脂肪族，C1-9雜芳基C1-6脂肪族，C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-，其中G是O，S，NR5，S(=O)，S(=O)2，C(=O)，-C(=O)NH-，-OC(=O)NH-，-OC(=O)-，-NHC(=O)NH-，-HN-S(=O)t-，-OS(=O)t-，或-OS(=O)tNH-；t是1或2；p和m各自獨立地為0，1，2，3或4；R3為H，F，Cl，I，氰基，R7aR7N-，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)2-，R7S(=O)2-，R7S(=O)2N(R7a)-，R7aR7N-C1-6烷基，R7S(=O)-C1-6烷基，R7R7aN-C(=O)-C1-6烷基，R7aR7N-C1-6烷氧基，R7S(=O)-C1-6烷氧基，R7R7aN-C(=O)-C1-6烷氧基，C1-6脂肪族，C2-10鹵代烷基，C6-10芳基-C2-10烷氧基，C1-9雜芳基-C3-6烷氧基，C3-10環烷基-C2-10烷氧基，C5-10稠合雙環基-C2-10烷氧基，C2-10雜環基，C3-10環烷基，C1-4雜芳基，取代的C6-10芳基，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C1-4雜芳基C1-6脂肪族，C1-9雜芳基氧基C1-6烷氧基，取代的C6-10芳基C3-6烷基，C2-10雜環基C1-6烷基，C1-6烷氧基，C1-6羥基烷氧基，C1-6氨基烷氧基，羥基取代的C1-6氨基烷氧基，C1-6鹵代烷氧基，氨基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6鹵代烷氧基，羥基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6烷氧基，C1-6烷氧基C1-6烷氧基，C6-10芳基-C2-10烷氧基，C2-10雜環基C1-6烷氧基，C3-10碳環基C1-6烷氧基，C2-10雜環基(C1-6羥基烷氧基)，C3-10碳環基(C1-6羥基烷氧基)，C6-10芳基(C1-6羥基烷氧基)，C6-10芳氧基C1-6烷氧基，C6-10芳氨基C1-6烷氧基，C6-10芳氧基，C2-10雜環基氧基C1-6烷氧基，C3-10碳環基氧基C1-6烷氧基，C2-10雜環基氧基，C3-10環烷基氧基，C1-6疊氮基烷氧基，C5-12稠合雙環基，C5-12稠合雜雙環基，C5-12稠合雙環基C1-6脂肪族，C5-12稠合雜雙環基C1-6脂肪族，C5-12稠合雙環基氧基，C5-12稠合雜雙環基氧基，C5-12稠合雙環基氨基，C5-12稠合雜雙環基氨基，C5-12稠合雙環基C1-6烷氧基，C5-12稠合雜雙環基C1-6烷氧基，C5-12稠合雙環基C1-6烷氨基，C5-12稠合雜雙環基C1-6烷氨基，C5-12稠合雙環基氧基C1-6烷氧基，C5-12稠合雜雙環基氧基C1-6烷氧基，C5-12稠合雙環基氨基C1-6烷氧基，C5-12稠合雜雙環基氨基C1-6烷氧基， C5-12稠合雙環基-C(=O)-，C5-12稠合雙環基-C(=O)O-，C5-12稠合雜雙環基-C(=O)-，C5-12稠合雜雙環基-C(=O)O-，C5-12稠合雙環基氨基-C(=O)-，C5-12稠合雜雙環基氨基-C(=O)-，C5-12稠合雙環基-C(=O)NR7-，C5-12稠合雜雙環基-C(=O)NR7-，C5-12螺雙環基，C5-12螺雜雙環基，C5-12螺雙環基C1-6脂肪族，C5-12螺雜雙環基C1-6脂肪族，C5-12螺雙環基氧基，C5-12螺雜雙環基氧基，C5-12螺雙環基氨基，C5-12螺雜雙環基氨基，C5-12螺雙環基C1-6烷氧基，C5-12螺雜雙環基C1-6烷氧基，C5-12螺雙環基C1-6烷氨基，C5-12螺雜雙環基C1-6烷氨基，C5-12螺雙環基氧基C1-6烷氧基，C5-12螺雜雙環基氧基C1-6烷氧基，C5-12螺雙環基氨基C1-6烷氧基，C5-12螺雜雙環基氨基C1-6烷氧基，C5-12螺雙環基-C(=O)-，C5-12螺雙環基-C(=O)O-，C5-12螺雜雙環基-C(=O)-，C5-12螺雜雙環基-C(=O)O-，C5-12螺雙環基氨基-C(=O)-，C5-12螺雜雙環基氨基-C(=O)-，C5-12螺雙環基-C(=O)NR7-，C5-12螺雜雙環基-C(=O)NR7-，C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-，其中G是O，S，NR5，S(=O)，S(=O)2，C(=O)，-C(=O)NH-，-OC(=O)NH-，-OC(=O)-，-NHC(=O)NH-，-HN-S(=O)t-，-OS(=O)t-，或-OS(=O)tNH-；t是1或2；p和m各自獨立地為0，1，2，3或4；R4為H，F，I，氰基，羥基，R7aR7N-，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)-，R7S(=O)-，R7S(=O)N(R7a)-，R7aR7N-C1-6烷基，R7S(=O)-C1-6烷基，R7R7aN-C(=O)-C1-6烷基，R7aR7N-C1-6烷氧基，R7S(=O)-C1-6烷氧基，R7R7aN-C(=O)-C1-6烷氧基，C1-6脂肪族，C2-10烷氧基，C1-6羥基烷氧基，C1-6氨基烷氧基，羥基取代的C1-6氨基烷氧基，C1-6鹵代烷氧基，氨基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6鹵代烷氧基，羥基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6烷氧基，C1-6烷氧基C1-6烷氧基，C3-5環烷基氧基，C6-10芳基C1-6烷氧基，C1-9雜芳基C1-6烷氧基，C1-9雜芳基C1-6烷氨基，C2-10雜環基C1-6烷氧基，C2-10雜環基C1-6烷氨基，C7-10環烷基氧基，C3-10環烷基氨基，C3-10碳環基C1-6烷氧基，C3-10碳環基C1-6烷氨基，C2-10雜環基(C1-6羥基烷氧基)，C3-10碳環基(C1-6羥基烷氧基)，C6-10芳基(C1-6羥基烷氧基)，C6-10芳氧基C1-6烷氧基，C6-10芳氧基，C1-9雜芳基氧基，C1-9雜芳基氧基C1-6烷氧 基，C2-10雜環基氧基C1-6烷氧基，C3-10碳環基氧基C1-6烷氧基，C2-10雜環基氧基，C1-6疊氮基烷氧基，C5-12稠合雙環基，C5-12稠合雜雙環基，C5-12稠合雙環基C1-6脂肪族，C5-12稠合雜雙環基C1-6脂肪族，C5-12稠合雙環基氧基，C5-12稠合雜雙環基氧基，C5-12稠合雙環基氨基，C5-12稠合雜雙環基氨基，C5-12稠合雙環基C1-6烷氧基，C5-12稠合雜雙環基C1-6烷氧基，C5-12稠合雙環基C1-6烷氨基，C5-12稠合雜雙環基C1-6烷氨基，C5-12稠合雙環基氧基C1-6烷氧基，C5-12稠合雜雙環基氧基C1-6烷氧基，C5-12稠合雙環基氨基C1-6烷氧基，C5-12稠合雜雙環基氨基C1-6烷氧基，C5-12稠合雙環基-C(=O)-，C5-12稠合雙環基-C(=O)O-，C5-12稠合雜雙環基-C(=O)-，C5-12稠合雜雙環基-C(=O)O-，C5-12稠合雙環基氨基-C(=O)-，C5-12稠合雜雙環基氨基-C(=O)-，C5-12稠合雙環基-C(=O)NR7-，C5-12稠合雜雙環基-C(=O)NR7-，C5-12螺雙環基，C5-12螺雜雙環基，C5-12螺雙環基C1-6脂肪族，C5-12螺雜雙環基C1-6脂肪族，C5-12螺雙環基氧基，C5-12螺雜雙環基氧基，C5-12螺雙環基氨基，C5-12螺雜雙環基氨基，C5-12螺雙環基C1-6烷氧基，C5-12螺雜雙環基C1-6烷氧基，C5-12螺雙環基C1-6烷氨基，C5-12螺雜雙環基C1-6烷氨基，C5-12螺雙環基氧基C1-6烷氧基，C5-12螺雜雙環基氧基C1-6烷氧基，C5-12螺雙環基氨基C1-6烷氧基，C5-12螺雜雙環基氨基C1-6烷氧基，C5-12螺雙環基-C(=O)-，C5-12螺雙環基-C(=O)O-，C5-12螺雜雙環基-C(=O)-，C5-12螺雜雙環基-C(=O)O-，C5-12螺雙環基氨基-C(=O)-，C5-12螺雜雙環基氨基-C(=O)-，C5-12螺雙環基-C(=O)N(R7)-，C5-12螺雜雙環基-C(=O)N(R7)-，C2-10雜環基，C3-10環烷基，C6-10芳基，C1-9雜芳基，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳基C2-6脂肪族，C1-9雜芳基C1-6脂肪族，C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-，其中G是O，S，NR5，S(=O)，S(=O)2，C(=O)，-C(=O)NH-，-OC(=O)NH-，-OC(=O)-，-NHC(=O)NH-，-HN-S(=O)t-，-OS(=O)t-，或-OS(=O)tNH-；t是1或2；p和m各自獨立地為0，1，2，3或4。 In some embodiments, R 1 is H, F, Cl, Br, I, cyano, hydroxy, R 7a R 7 N-, -C(=O)NR 7 R 7a , -OC(=O)NR 7 R 7a , -OC(=O)OR 7 , -N(R 7 )C(=O)NR 7 R 7a , -N(R 7 )C(=O)OR 7a , -N(R 7 )C( =O)-R 7a , R 7 R 7a NS(=O) 2 -,R 7 S(=O) 2 -,R 7 S(=O) 2 N(R 7a )-,R 7a R 7 NC 1 -6 alkyl, R 7 S(=O)-C 1-6 alkyl, R 7 R 7a NC(=O)-C 1-6 alkyl, R 7a R 7 NC 1-6 alkoxy, R 7 S(=O)-C 1-6 alkoxy, R 7 R 7a NC(=O)-C 1-6 alkoxy, C 1-6 aliphatic, C 1-6 alkoxy, C 1 -6 hydroxyalkoxy, C 1-6 aminoalkoxy, C 1-6 hydroxy substituted aminoalkoxy, C 1-6 haloalkoxy, C 1-6 amino substituted haloalkoxy, C 1- 6 alkylamino C 1-6 haloalkoxy, hydroxy substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy , C 3-10 cycloalkyloxy, C 6-10 aryl C 1-6 alkoxy, C 6-10 aryl C 1-6 alkylamino, C 1-9 heteroaryl C 1-6 alkane Oxy, C 1-9 heteroaryl C 1-6 alkylamino, C 2-10 heterocyclyl C 1-6 alkoxy, C 2-10 heterocyclyl C 1-6 alkylamino, C 3-10 cycloalkyl group, C 3-10 cycloalkyl Amino group, C 3-10 carbon ring group C 1-6 alkoxy, C 3-10 carbocyclyl, C 1-6 alkylamino, C 2-10 heterocyclyl (C 1-6 hydroxyalkoxy), C 3-10 carbocyclyl (C 1-6 hydroxyalkoxy), C 6-10 aryl (C 1-6 hydroxyalkoxy), C 6-10 aryloxy C 1-6 alkoxy, C 6-10 aryloxy, C 1-9 heteroaryloxy, C 1-9 heteroaryloxy C 1-6 alkoxy, C 2-10 heterocyclyloxy C 1-6 alkoxy , C 3-10 carbocyclyloxy C 1-6 alkoxy, C 2-10 heterocyclyloxy, C 1-6 azidoalkoxy, C 5-12 fused bicyclic, C 5-12 fused heterobicyclic group, C 5-12 fused bicyclic C 1-6 aliphatic, C 5-12 fused heterobicyclic C 1-6 aliphatic, C 5-12 fused bicyclic oxy , C 5-12 fused heterobicycloyloxy, C 5-12 fused bicyclic amino group, C 5-12 fused heterobicyclic amino group, C 5-12 fused bicyclic C 1-6 alkoxy group, C 5-12 fused heterobicyclic C 1-6 alkoxy, C 5-12 fused bicyclic C 1-6 alkylamino, C 5-12 fused heterobicyclic C 1-6 alkylamino, C 5 -12 fused bicyclic oxy C 1-6 alkoxy, C 5-12 fused heterobicyclo oxy C 1-6 alkoxy, C 5-12 fused bicyclic amino C 1-6 alkoxy Base, C 5-12 fused heterobicyclic ring Alkylamino C 1-6 alkoxy, C 5-12 fused bicyclo-C(=O)-, C 5-12 fused bicyclo-C(=O)O-, C 5-12 fused Bicyclo-C(=O)-, C 5-12 fused heterobicyclo-C(=O)O-, C 5-12 fused bicyclic amino-C(=O)-, C 5-12 thick Heterobicycloamino-C(=O)-, C 5-12 fused bicyclo-C(=O)N(R 7 )-, C 5-12 fused heterobicyclo-C(=O)N (R 7 )-, C 5-12 spirobicyclo, C 5-12 spirobicyclo, C 5-12 spirobicyclic C 1-6 aliphatic, C 5-12 spiro bicyclic C 1-6 fat Family, C 5-12 spirobicycloyloxy, C 5-12 spirobicycloyloxy, C 5-12 spirobicyclic amino, C 5-12 spirobicyclic amino, C 5-12 spirobicyclic C 1-6 alkoxy, C 5-12 spirobicyclo C 1-6 alkoxy, C 5-12 spirobicyclo C 1-6 alkylamino, C 5-12 spirobicyclo C 1-6 alkane Amino, C 5-12 spirobicyclooxy C 1-6 alkoxy, C 5-12 spirobicyclooxy C 1-6 alkoxy, C 5-12 spirobicycloamino C 1-6 alkane Oxy, C 5-12 spirobicycloamino C 1-6 alkoxy, C 5-12 spirobicyclo-C(=O)-, C 5-12 spirobicyclo-C(=O)O- , C 5-12 spirobicyclo-C(=O)-, C 5-12 spirobicyclo-C(=O)O-, C 5-12 spirobicyclo Amino-C(=O)-, C 5-12 spirobicycloamino-C(=O)-, C 5-12 spirobicyclo-C(=O)N(R 7 )-, C 5-12 Spirobicyclo-C(=O)N(R 7 )-, C 2-10 heterocyclyl, C 3-10 cycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, C 2 -10 heterocyclyl C 1-6 aliphatic, C 3-10 cycloalkyl C 1-6 aliphatic, C 6-10 aryl C 1-6 aliphatic, C 1-9 heteroaryl C 1-6 Aliphatic, C 6-10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C 1-9 heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, C 2 -10 heterocyclyl group - (CH 2) p -G- ( CH 2) m -, C 3-10 cycloalkyl or - (CH 2) p -G- ( CH 2) m -, wherein G is O, S, NR 5 , S(=O), S(=O) 2 , C(=O), -C(=O)NH-, -OC(=O)NH-, -OC(=O)-, -NHC (= O) NH -, - HN-S (= O) t -, - OS (= O) t -, or -OS (= O) t NH-; t is 1 or 2; p and m are each Independently 0, 1, 2, 3 or 4; or wherein C 6-10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C 1-9 heteroaryl-(CH 2 ) p -G-(CH 2 ) m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 ) m -, or C 3-10 cycloalkyl-(CH 2 ) p -G- (CH 2 ) m - may be one or more selected from the group consisting of F, Cl, Br, I, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy Or cyano Substituent group; R 2 is H, F, Cl, Br, I, cyano, hydroxy, R 7a R 7 N -, - C (= O) NR 7 R 7a, -OC (= O) NR 7 R 7a, -OC(=O)OR 7 , -N(R 7 )C(=O)NR 7 R 7a , -N(R 7 )C(=O)OR 7a , -N(R 7 )C(=O) -R 7a , R 7 R 7a NS(=O) 2 -,R 7 S(=O) 2 -,R 7 S(=O) 2 N(R 7a )-,R 7a R 7 NC 1-6 alkane Base, R 7 S(=O)-C 1-6 alkyl, R 7 R 7a NC(=O)-C 1-6 alkyl, R 7a R 7 NC 1-6 alkoxy, R 7 S ( =O)-C 1-6 alkoxy, R 7 R 7a NC(=O)-C 1-6 alkoxy, C 1-6 aliphatic, C 1-6 alkoxy, C 1-6 hydroxy Alkoxy, C 1-6 aminoalkoxy, hydroxy substituted C 1-6 aminoalkoxy, C 1-6 haloalkoxy, amino substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 haloalkoxy, hydroxy-substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 3 -10 cycloalkyloxy, C 6-10 aryl C 1-6 alkoxy, C 6-10 aryl C 1-6 alkylamino, C 1-9 heteroaryl C 1-6 alkoxy, C 1-9heteroaryl C 1-6 alkylamino, C 2-10 heterocyclyl C 1-6 alkoxy, C 2-10 heterocyclyl C 1-6 alkylamino, C 3-10 cycloalkyl amino, C 3-10 carbocyclyl, C 1-6 alkoxy , C 3-10 carbocyclyl, C 1-6 alkylamino, C 2-10 heterocyclyl (C 1-6 hydroxyalkoxy), C 3-10 carbocyclyl (C 1-6 hydroxyalkoxy) , C 6-10 aryl (C 1-6 hydroxyalkoxy), C 6-10 aryloxy C 1-6 alkoxy, C 6-10 aryloxy, C 1-9 heteroaryloxy , C 1-9heteroaryloxy C 1-6 alkoxy, C 2-10heterocyclyloxy C 1-6 alkoxy, C 3-10 carbocyclyloxy C 1-6 alkoxy a C 2-10 heterocyclyloxy group, a C 1-6 azidoalkoxy group, a C 5-12 fused bicyclic group, a C 5-12 fused heterobicyclic group, a C 5-12 fused bicyclic group C 1-6 aliphatic, C 5-12 fused heterobicyclic C 1-6 aliphatic, C 5-12 fused bicyclic oxy, C 5-12 fused heterobicyclo oxy, C 5-12 a fused bicyclic amino group, a C 5-12 fused heterobicyclic amino group, a C 5-12 fused bicyclic C 1-6 alkoxy group, a C 5-12 fused heterobicyclic C 1-6 alkoxy group, C 5-12 fused bicyclic C 1-6 alkylamino, C 5-12 fused heterobicyclic C 1-6 alkylamino, C 5-12 fused bicyclic oxy C 1-6 alkoxy, C 5-12 fused heterobicyclooxy C 1-6 alkoxy, C 5-12 fused bicyclic amino C 1-6 alkoxy, C 5-12 fused heterobicyclic amino C 1-6 alkane alkoxy, C 5-12 fused Cycloalkyl group -C (= O) -, C 5-12 fused bicyclic group -C (= O) O-, C 5-12 fused bicyclic heteroaryl group -C (= O) -, C 5-12 fused Heterobicyclo-C(=O)O-, C 5-12 fused bicyclic amino-C(=O)-, C 5-12 fused heterobicyclic amino-C(=O)-, C 5- 12 fused bicyclic group -C(=O)N(R 7 )-, C 5-12 fused heterobicyclo-C(=O)N(R 7 )-, C 5-12 spirobicyclo, C 5 -12 spirobicyclo, C 5-12 spirobicyclic C 1-6 aliphatic, C 5-12 spirobicyclo C 1-6 aliphatic, C 5-12 spirobicyclooxy, C 5-12 Spirobicyclooxy, C 5-12 spirobicyclic amino, C 5-12 spirobicyclic amino, C 5-12 spirobicyclic C 1-6 alkoxy, C 5-12 spiro bicyclo C 1-6 alkoxy, C 5-12 spirobicyclo C 1-6 alkylamino, C 5-12 spirobicyclo C 1-6 alkylamino, C 5-12 spirobicyclooxy C 1-6 alkane Oxy, C 5-12 spirobicyclooxy C 5-12 alkoxy, C 5-12 spirobicycloamino C 1-6 alkoxy, C 5-12 spirobicycloamino C 1-6 Alkoxy, C 5-12 spirobicyclo-C(=O)-, C 5-12 spirobicyclo-C(=O)O-, C 5-12 spirobicyclo-C(=O)- , C 5-12 spiro bicyclic heteroaryl group -C (= O) O-, C 5-12 bicyclic spiro amino group -C (= O) -, C 5-12 spiro bicyclic heteroaryl group Group -C (= O) -, C 5-12 bicyclic spiro group -C (= O) N (R 7) -, C 5-12 spiro bicyclic heteroaryl group -C (= O) N (R 7) -, C 2-10 heterocyclic group, C 3-10 cycloalkyl group, C 6-10 aryl group, C 1-4 heteroaryl group, C 2-10 heterocyclic group C 1-6 aliphatic, C 3-10 ring Alkyl C 1-6 aliphatic, C 6-10 aryl C 1-6 aliphatic, C 1-9 heteroaryl C 1-6 aliphatic, C 6-10 aryl-(CH 2 ) p -G -(CH 2 ) m -,C 1-9heteroaryl- (CH 2 ) p -G-(CH 2 ) m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 m -, or C 3-10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m -, wherein G is O, S, NR 5 , S(=O), S(=O) 2 , C(=O), -C(=O)NH-, -OC(=O)NH-, -OC(=O)-, -NHC(=O)NH-,-HN-S(=O) t -, -OS(=O) t -, or -OS(=O) t NH-;t is 1 or 2; p and m are each independently 0,1,2,3 or 4; R 3 is H , F, Cl, I, cyano, R 7a R 7 N-, -C(=O)NR 7 R 7a , -OC(=O)NR 7 R 7a , -OC(=O)OR 7 ,-N (R 7 )C(=O)NR 7 R 7a , -N(R 7 )C(=O)OR 7a , -N(R 7 )C(=O)-R 7a ,R 7 R 7a NS(= O) 2 -, R 7 S(=O) 2 -, R 7 S(=O) 2 N(R 7a )-, R 7a R 7 NC 1-6 alkyl, R 7 S(=O)-C 1-6 alkyl, R 7 R 7a NC(=O)-C 1-6 alkyl, R 7a R 7 NC 1-6 alkoxy, R 7 S ( =O)-C 1-6 alkoxy, R 7 R 7a NC(=O)-C 1-6 alkoxy, C 1-6 aliphatic, C 2-10 haloalkyl, C 6-10 aryl -C 2-10 alkoxy, C 1-9heteroaryl -C 3-6 alkoxy, C 3-10 cycloalkyl-C 2-10 alkoxy, C 5-10 fused bicyclic group - C 2-10 alkoxy, C 2-10 heterocyclyl, C 3-10 cycloalkyl, C 1-4 heteroaryl, substituted C 6-10 aryl, C 2-10 heterocyclyl C 1 -6 aliphatic, C 3-10 cycloalkyl C 1-6 aliphatic, C 1-4 heteroaryl C 1-6 aliphatic, C 1-9 heteroaryloxy C 1-6 alkoxy, Substituted C 6-10 aryl C 3-6 alkyl, C 2-10 heterocyclyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxy alkoxy, C 1-6 Aminoalkoxy, hydroxy-substituted C 1-6 aminoalkoxy, C 1-6 haloalkoxy, amino-substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 haloalkoxy, Hydroxy-substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 6-10 aryl-C 2- 10 alkoxy, C 2-10 heterocyclyl C 1-6 alkoxy, C 3-10 carbocyclyl C 1-6 alkoxy, C 2-10 heterocyclyl (C 1-6 hydroxy alkoxy Base), C 3-10 carbocyclic (C 1-6 hydroxy alkoxy), C 6-10 aryl (C 1-6 hydroxy) Alkoxy), C 6-10 aryloxy C 1-6 alkoxy, C 6-10 arylamino C 1-6 alkoxy, C 6-10 aryloxy, C 2-10 heterocyclooxy Alkyl C 1-6 alkoxy, C 3-10 carbocyclyloxy C 1-6 alkoxy, C 2-10 heterocyclyloxy, C 3-10 cycloalkyloxy, C 1-6 Azidoalkoxy, C 5-12 fused bicyclic, C 5-12 fused heterobicyclic, C 5-12 fused bicyclic C 1-6 aliphatic, C 5-12 fused heterobicyclic C 1-6 aliphatic, C 5-12 fused bicyclic oxy, C 5-12 fused heterobicyclooxy, C 5-12 fused bicyclic amino, C 5-12 fused heterobicyclic amino , C 5-12 fused bicyclic C 1-6 alkoxy, C 5-12 fused heterobicyclic C 1-6 alkoxy, C 5-12 fused bicyclic C 1-6 alkylamino, C 5-12 fused heterobicyclic C 1-6 alkylamino, C 5-12 fused bicyclic oxy C 1-6 alkoxy, C 5-12 fused heterobicyclo oxy C 1-6 alkoxy , C 5-12 fused bicyclic amino C 1-6 alkoxy, C 5-12 fused heterobicyclic amino C 1-6 alkoxy, C 5-12 fused bicyclic-C (=O -, C 5-12 fused bicyclo-C(=O)O-, C 5-12 fused heterobicyclo-C(=O)-, C 5-12 fused heterobicyclo-C (= O) O-, C 5-12 fused bicyclic amino group -C (= O) -, C 5-12 fused bicyclic heteroaryl group -C (= O) -, C 5-12 fused bicyclic group -C (= O) NR 7 - , C 5-12 fused Heterobicyclo-C(=O)NR 7 -, C 5-12 spirobicyclo, C 5-12 spirobicyclo, C 5-12 spirobicyclic C 1-6 aliphatic, C 5-12 spiro Bicyclic C 1-6 aliphatic, C 5-12 spirobicycloyloxy, C 5-12 spirobicycloyloxy, C 5-12 spirobicyclic amino, C 5-12 spirobicyclic amino, C 5-12 spirobicyclo C 1-6 alkoxy, C 5-12 spirobicyclo C 1-6 alkoxy, C 5-12 spirobicyclo C 1-6 alkylamino, C 5-12 spiro Bicyclic C 1-6 alkylamino, C 5-12 spirobicyclooxy C 1-6 alkoxy, C 5-12 spirobicyclooxy C 1-6 alkoxy, C 5-12 spiro bicyclo Alkylamino C 1-6 alkoxy, C 5-12 spirobicycloamino C 1-6 alkoxy, C 5-12 spirobicyclo-C(=O)-, C 5-12 spirobicyclo- C(=O)O-, C 5-12 spirobicyclo-C(=O)-, C 5-12 spirobicyclo-C(=O)O-, C 5-12 spirobicycloamino- C(=O)-, C 5-12 spirobicycloamino-C(=O)-, C 5-12 spirobicyclo-C(=O)NR 7 -, C 5-12 spirobicyclo- C(=O)NR 7 -,C 6-10 aryl-(CH 2 ) p -G-(CH 2 ) m -,C 1-9heteroaryl- (CH 2 ) p - G-(CH 2 ) m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 ) m -, or C 3-10 cycloalkyl-(CH 2 ) p -G-( CH 2 ) m -, where G is O, S, NR 5 , S(=O), S(=O) 2 , C(=O), -C(=O)NH-, -OC(=O) NH -, - OC (= O ) -, - NHC (= O) NH -, - HN-S (= O) t -, - OS (= O) t -, or -OS (= O) t NH- ;t is 1 or 2; p and m are each independently 0,1,2,3 or 4; R 4 is H,F,I,cyano,hydroxy,R 7a R 7 N-,-C(=O )NR 7 R 7a , -OC(=O)NR 7 R 7a , -OC(=O)OR 7 , -N(R 7 )C(=O)NR 7 R 7a , -N(R 7 )C( =O)OR 7a , -N(R 7 )C(=O)-R 7a , R 7 R 7a NS(=O)-, R 7 S(=O)-, R 7 S(=O)N( R 7a )-, R 7a R 7 NC 1-6 alkyl, R 7 S(=O)-C 1-6 alkyl, R 7 R 7a NC(=O)-C 1-6 alkyl, R 7a R 7 NC 1-6 alkoxy, R 7 S(=O)-C 1-6 alkoxy, R 7 R 7a NC(=O)-C 1-6 alkoxy, C 1-6 aliphatic , C 2-10 alkoxy, C 1-6 hydroxyalkoxy, C 1-6 aminoalkoxy, hydroxy substituted C 1-6 aminoalkoxy, C 1-6 haloalkoxy, amino substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 haloalkoxy, hydroxy substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 alkoxy, C 1- 6 alkoxy C 1-6 alkoxy group, C 3-5 cycloalkyl group, C 6-10 aryl C 1-6 alkoxy, C 1-9 heteroaryl-C 1-6 alkoxy group, C 1 -9heteroaryl C 1-6 alkylamino, C 2-10 heterocyclyl C 1-6 alkoxy, C 2-10 heterocyclyl C 1-6 alkylamino, C 7-10 cycloalkyloxy , C 3-10 cycloalkylamino, C 3-10 carbocyclic C 1-6 alkoxy, C 3-10 carbocyclic C 1-6 alkylamino, C 2-10 heterocyclyl (C 1- 6 hydroxyalkoxy), C 3-10 carbocyclyl (C 1-6 hydroxyalkoxy), C 6-10 aryl (C 1-6 hydroxyalkoxy), C 6-10 aryloxy C 1-6 alkoxy, C 6-10 aryloxy, C 1-9 heteroaryloxy, C 1-9 heteroaryloxy C 1-6 alkoxy, C 2-10 heterocyclooxy Alkyl C 1-6 alkoxy, C 3-10 carbocyclyloxy C 1-6 alkoxy, C 2-10 heterocyclyloxy, C 1-6 azidoalkoxy, C 5- 12 fused bicyclic group, C 5-12 fused heterobicyclic group, C 5-12 fused bicyclic C 1-6 aliphatic, C 5-12 fused heterobicyclic C 1-6 aliphatic, C 5- 12 fused bicyclic oxy, C 5-12 fused heterobicyclooxy, C 5-12 fused bicyclic amino, C 5-12 fused heterobicyclic amino, C 5-12 fused bicyclic C 1-6 alkoxy, C 5-12 fused heterobicyclic C 1-6 alkoxy, C 5-12 fused bicyclic C 1-6 alkylamino, C 5-12 fused heterobicyclic C 1-6 alkylamino, C 5-12 fused bicyclic oxy C 1-6 alkoxy, C 5 -12 fused heterobicyclooxy C 1-6 alkoxy, C 5-12 fused bicyclic amino C 1-6 alkoxy, C 5-12 fused heterobicyclic amino C 1-6 alkoxy , C 5-12 fused bicyclic group -C(=O)-, C 5-12 fused bicyclic group -C(=O)O-, C 5-12 fused heterobicyclic group -C(=O) -, C 5-12 fused heterobicyclo-C(=O)O-, C 5-12 fused bicyclic amino-C(=O)-, C 5-12 fused heterobicyclic amino-C ( =O)-, C 5-12 fused bicyclo-C(=O)NR 7 -, C 5-12 fused heterobicyclo-C(=O)NR 7 -, C 5-12 spirobicyclo, C 5-12 spirobicyclo, C 5-12 spirobicyclic C 1-6 aliphatic, C 5-12 spirobicyclo C 1-6 aliphatic, C 5-12 spirobicyclooxy, C 5 -12 spirobicyclooxy, C 5-12 spirobicyclic amino, C 5-12 spirobicyclic amino, C 5-12 spirobicyclo C 1-6 alkoxy, C 5-12 spiro bicyclo Alkyl C 1-6 alkoxy, C 5-12 spirobicyclo C 1-6 alkylamino, C 5-12 spirobicyclo C 1-6 alkylamino, C 5-12 spirobicyclooxy C 1- 6 alkoxy, C 5-12 bicyclic heteroaryl group spiro-C 1-6 alkyl Group, C 5-12 bicyclic spiro amino C 1-6 alkoxy group, C 5-12 bicyclic heteroaryl group spiro C 1-6 alkoxy, C 5-12 bicyclic spiro group -C (= O) -, C 5-12 spirobicyclo-C(=O)O-, C 5-12 spirobicyclo-C(=O)-, C 5-12 spirobicyclo-C(=O)O-, C 5-12 spirobicycloamino-C(=O)-, C 5-12 spirobicycloamino-C(=O)-, C 5-12 spirobicyclo-C(=O)N(R 7 ) -, C 5-12 spirobicyclo-C(=O)N(R 7 )-, C 2-10 heterocyclyl, C 3-10 cycloalkyl, C 6-10 aryl, C 1-9 Heteroaryl, C 2-10 heterocyclyl C 1-6 aliphatic, C 3-10 cycloalkyl C 1-6 aliphatic, C 6-10 aryl C 2-6 aliphatic, C 1-9 hetero Aryl C 1-6 aliphatic, C 6-10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C 1-9 heteroaryl-(CH 2 ) p -G-(CH 2 m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 ) m -, or C 3-10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m - Where G is O, S, NR 5 , S(=O), S(=O) 2 , C(=O), -C(=O)NH-, -OC(=O)NH-, -OC (= O) -, - NHC (= O) NH -, - HN-S (= O) t -, - OS (= O) t -, or -OS (= O) t NH-; t is 1 or 2; p and m are each independently 0, 1, 2, 3 or 4.
其中一些實施方案是，各R5獨立地為氫，R7R7aNC(=O)-，R7OC(=O)-，R7C(=O)-，R7R7aNS(=O)-，R7OS(=O)-，R7S(=O)-，R7R7aNS(=O)2-，R7OS(=O)2-，R7S(=O)2-，C1-6脂肪族，C1-6鹵代脂肪族，C1-6羥基脂肪族，C1-6氨基脂肪 族，C1-6烷氧基C1-6脂肪族，C1-6烷氨基C1-6脂肪族，C1-6烷硫基C1-6脂肪族，C6-10芳基C1-6脂肪族，C1-9雜芳基C1-6脂肪族，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳氧基C1-6脂肪族，C2-10雜環基氧基C1-6脂肪族，C3-10環烷基氧基C1-6脂肪族，C6-10芳氨基C1-6脂肪族，C2-10雜環基氨基C1-6脂肪族，C3-10環烷基氨基C1-6脂肪族，C6-10芳基，C1-9雜芳基，C2-10雜環基或C3-10碳環基。 In some embodiments, each R 5 is independently hydrogen, R 7 R 7a NC(=O)-, R 7 OC(=O)-, R 7 C(=O)-, R 7 R 7a NS(= O)-, R 7 OS(=O)-, R 7 S(=O)-, R 7 R 7a NS(=O) 2 -, R 7 OS(=O) 2 -, R 7 S(=O 2 -, C 1-6 aliphatic, C 1-6 halogenated aliphatic, C 1-6 hydroxy aliphatic, C 1-6 amino aliphatic, C 1-6 alkoxy C 1-6 aliphatic, C 1-6 alkylamino C 1-6 aliphatic, C 1-6 alkylthio C 1-6 aliphatic, C 6-10 aryl C 1-6 aliphatic, C 1-9 heteroaryl C 1- 6 aliphatic, C 2-10 heterocyclic C 1-6 aliphatic, C 3-10 cycloalkyl C 1-6 aliphatic, C 6-10 aryloxy C 1-6 aliphatic, C 2-10 Heterocyclyloxy C 1-6 aliphatic, C 3-10 cycloalkyloxy C 1-6 aliphatic, C 6-10 arylamino C 1-6 aliphatic, C 2-10 heterocyclylamino C 1-6 aliphatic, C 3-10 cycloalkylamino C 1-6 aliphatic, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclic or C 3-10 carbocyclic base.
其中一些實施方案是，各R5a可以相同或不同，各自獨立地為H，羥基，氨基，F，Cl，Br，I，氰基，氧代(=O)，R7aR7N-，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)2-，R7S(=O)2-，R7S(=O)2N(R7a)-，R7aR7N-C1-6烷基，R7S(=O)-C1-6烷基，R7R7aN-C(=O)-C1-6烷基，R7aR7N-C1-6烷氧基，R7S(=O)-C1-6烷氧基，R7R7aN-C(=O)-C1-6烷氧基，C6-10芳基，C1-9雜芳基，C1-6烷氧基，C1-6烷基，C2-6烯基，C2-6炔基，C2-10雜環基，巰基，硝基，C6-10芳基C1-6烷基，C6-10芳基氨基，C1-9雜芳基氨基，C6-10芳基C1-6烷氨基，C1-9雜芳基C1-6烷氨基，C1-9雜芳基氧基，C1-9雜芳基C1-6烷基，C6-10芳基C1-6烷氧基，C1-9雜芳基C1-6烷氧基，C2-10雜環基氧基，C2-10雜環基C1-6烷氧基，C2-10雜環基氨基，C2-10雜環基C1-6烷氨基或C6-10芳氧基。 In some embodiments, each R 5a may be the same or different, each independently H, hydroxy, amino, F, Cl, Br, I, cyano, oxo (=O), R 7a R 7 N-,- C(=O)NR 7 R 7a , -OC(=O)NR 7 R 7a , -OC(=O)OR 7 , -N(R 7 )C(=O)NR 7 R 7a ,-N(R 7 ) C(=O)OR 7a , -N(R 7 )C(=O)-R 7a , R 7 R 7a NS(=O) 2 -,R 7 S(=O) 2 -,R 7 S (=O) 2 N(R 7a )-, R 7a R 7 NC 1-6 alkyl, R 7 S(=O)-C 1-6 alkyl, R 7 R 7a NC(=O)-C 1 -6 alkyl, R 7a R 7 NC 1-6 alkoxy, R 7 S(=O)-C 1-6 alkoxy, R 7 R 7a NC(=O)-C 1-6 alkoxy , C 6-10 aryl, C 1-9 heteroaryl, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-10 Cyclic, fluorenyl, nitro, C 6-10 aryl C 1-6 alkyl, C 6-10 arylamino, C 1-9 heteroarylamino, C 6-10 aryl C 1-6 alkylamino , C 1-9 heteroaryl C 1-6 alkylamino, C 1-9 heteroaryloxy, C 1-9 heteroaryl C 1-6 alkyl, C 6-10 aryl C 1-6 alkane Oxy, C 1-9 heteroaryl C 1-6 alkoxy, C 2-10 heterocyclyloxy, C 2-10 heterocyclyl C 1-6 alkoxy, C 2-10 heterocyclyl amino, C 2-10 heterocyclyl C 1-6 alkylamino or C 6-10 aryloxy .
其中一些實施方案是，各R7和R7a獨立地為H，C1-6脂肪族，C1-6鹵代脂肪族，C1-6羥基脂肪族，C1-6氨基脂肪族，C1-6烷氧基C1-6脂肪族，C1-6烷氨基C1-6脂肪族，C1-6烷硫基C1-6脂肪族，C6-10芳基C1-6脂肪族，C1-9雜芳基C1-6脂肪族，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳氧基C1-6脂肪族，C2-10雜環基氧基C1-6脂肪族，C3-10環烷基氧基C1-6脂肪族，C6-10芳氨基C1-6脂肪族，C2-10雜環基氨基C1-6脂肪族，C3-10環烷基氨基C1-6脂肪族，C6-10芳基，C1-9雜芳基，C2-10雜環基或C3-10碳環基；當R7和R7a連在同一個氮原子上，R7，R7a和氮原子可以任意地形成取代或非取代的3-8元環，C5-12稠合雙環或C5-12螺雙環。 In some embodiments, each of R 7 and R 7a is independently H, C 1-6 aliphatic, C 1-6 haloaliphatic, C 1-6 hydroxyaliphatic, C 1-6 aminoaliphatic, C 1-6 alkoxy C 1-6 aliphatic, C 1-6 alkylamino C 1-6 aliphatic, C 1-6 alkylthio C 1-6 aliphatic, C 6-10 aryl C 1-6 Aliphatic, C 1-9 heteroaryl C 1-6 aliphatic, C 2-10 heterocyclic C 1-6 aliphatic, C 3-10 cycloalkyl C 1-6 aliphatic, C 6-10 aromatic Oxy C 1-6 aliphatic, C 2-10 heterocyclooxy C 1-6 aliphatic, C 3-10 cycloalkyloxy C 1-6 aliphatic, C 6-10 arylamino C 1- 6 aliphatic, C 2-10 heterocyclylamino C 1-6 aliphatic, C 3-10 cycloalkylamino C 1-6 aliphatic, C 6-10 aryl, C 1-9 heteroaryl, C 2-10heterocyclyl or C 3-10 carbocyclyl; when R 7 and R 7a are bonded to the same nitrogen atom, R 7 , R 7a and the nitrogen atom may optionally form a substituted or unsubstituted 3-8 member. Ring, C 5-12 fused bicyclic or C 5-12 spiro bicyclic.
其中一些實施方案是，式(I)中的N，V1，V2，V3，V4和C(=Y)共同
所定義的子結構(III)為以下結構式：
其中一些實施方案是，式(I)中的N，V1，V2，V3，V4和C=Y共同所
定義的子結構(III)為以下結構式：
其中一些實施方案是，A為以下的子結構式：
其中一些實施方案是，式(I)中的A，X和B可共同形成以下的子結構式(II)：
其中一些實施方案是，本發明涉及如式(IV)所示的化合物，
其中一些實施方案是，B為-N(CH3)2，-N(CH2CH3)2，-N(CH2CH2CH3)2，-N(CH2CH2CH2CH3)2，或B為以下子結構式：
其中一些實施方案是，本發明涉及如式(V)所示的化合物，
其中一些實施方案是，本發明涉及如式(VI)所示的化合物，
其中一些實施方案，R1獨立地為H，F，Cl，Br，I，氰基，羥基，甲基，乙基，丙基，異丙基，丁基，叔丁基，C6-8芳基-(CH2)p-G-(CH2)m-或C4-6雜芳基-(CH2)p-G-(CH2)m-，其中G是NR5，O或S，p和m各自獨立地選自0，1，2或3；或者其中C6-8芳基-(CH2)p-G-(CH2)m-或C4-6雜芳基 -(CH2)p-G-(CH2)m-可以被一個或多個選自F，Cl，Br，甲基，乙基，丙基，乙炔基，丙炔基，丁炔基，甲氧基或者氰基的取代基取代；R3獨立地為H，F，Cl，I，氰基，羥基，甲基，乙基，丙基，異丙基，丁基，叔丁基，C6-8芳基-(CH2)p-G-(CH2)m-或C4-6雜芳基-(CH2)p-G-(CH2)m-，其中G是O或S，p和m各自獨立地選自0，1，2或3。 In some embodiments, R 1 is independently H, F, Cl, Br, I, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C 6-8 aryl -(CH 2 ) p -G-(CH 2 ) m - or C 4-6 heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, wherein G is NR 5 , O or S, p and m are each independently selected from 0, 1, 2 or 3; or wherein C 6-8 aryl-(CH 2 ) p -G-(CH 2 ) m - or C 4-6 heteroaryl-(CH) 2 ) p -G-(CH 2 ) m - may be selected from one or more selected from the group consisting of F, Cl, Br, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, methoxy or Substituted by a cyano substituent; R 3 is independently H, F, Cl, I, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C 6-8 -(CH 2 ) p -G-(CH 2 ) m - or C 4-6 heteroaryl-(CH 2 ) p -G-(CH 2 ) m - wherein G is O or S, p and m Each is independently selected from 0, 1, 2 or 3.
其中一些實施方案是，本發明涉及如式(VII)所示的化合物，
其中，R1為H，F，Cl，Br，I，氰基，羥基，C1-6烷基，C1-6鹵代烷基，C1-6烷氧基，C1-6羥基烷氧基，C1-6氨基烷氧基，C1-6鹵代烷氧基，C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-，其中G是O，S，NR5，C(=O)，-C(=O)NH-，-OC(=O)NH-，-OC(=O)-或-NHC(=O)NH-；p和m各自獨立地為0，1，2或3；或者其中C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-可以被一個或多個選自F，Cl，Br，I，乙基，丙基，乙烯基，丙烯基，乙炔基，丙炔基，丁炔基，甲氧基，乙氧基或氰基的取代基取代；R3為H，F，Cl，I，氰基，羥基，C1-6烷基，C1-6鹵代烷基，C1-6烷氧基，C1-6羥基烷氧基，C1-6氨基烷氧基，C1-6鹵代烷氧基，C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-，其中G是O，S，NR5，C(=O)，-C(=O)NH-，-OC(=O)NH-，-OC(=O)-或-NHC(=O)NH-；p和m各自獨立地為0，1，2或3；各R5獨立地為氫，R7R7aNC(=O)-，R7OC(=O)-，R7C(=O)-，C1-3烷基， C1-3鹵代烷基，C1-3羥基烷基，C1-3氨基烷基，C1-3烷氧基C1-3烷基，C1-3烷氨基C1-3烷基，C1-3烷硫基C1-3烷基，C6-10芳基C1-3烷基，C1-9雜芳基C1-3烷基，C2-10雜環基C1-3烷基，C3-10環烷基C1-3烷基，C6-10芳基，C1-9雜芳基，C2-10雜環基或C3-10碳環基；各R7獨立地為H，C1-6烷基，C1-6鹵代脂肪族，C1-6羥基脂肪族，C1-6氨基脂肪族，C1-6烷氧基C1-6脂肪族，C1-6烷氨基C1-6脂肪族，C1-6烷硫基C1-6脂肪族，C6-10芳基C1-6脂肪族，C1-9雜芳基C1-6脂肪族，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳基，C1-9雜芳基，C2-10雜環基或C3-10碳環基；各R7a獨立地為C1-6烷基，C1-6鹵代脂肪族，C1-6羥基脂肪族，C1-6氨基脂肪族，C1-6烷氧基C1-6脂肪族，C1-6烷氨基C1-6脂肪族，C1-6烷硫基C1-6脂肪族，C6-10芳基C1-6脂肪族，C1-9雜芳基C1-6脂肪族，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳基，C1-9雜芳基，C2-10雜環基或C3-10碳環基；當R7和R7a連在同一個氮原子上，R7，R7a和氮原子可以任意地形成取代或非取代的3-8元環；各R8a可以相同或不同，各自獨立地為H，羥基，氨基，F，Cl，Br，I，-N(CH3)2，氰基，硝基，巰基，C1-4烷基，三氟甲基，C1-4烷氧基，C1-4烷氨基，C1-4烷硫基，C6-10芳基，C6-10芳基C1-4烷基或C1-9雜芳基；和n是0，1，2或3。 Wherein R 1 is H, F, Cl, Br, I, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxy alkoxy , C 1-6 aminoalkoxy, C 1-6 haloalkoxy, C 6-10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C 1-9 heteroaryl-(CH 2 ) p -G-(CH 2 ) m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 ) m -, or C 3-10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m -, where G is O, S, NR 5 , C(=O), -C(=O)NH-, -OC(=O)NH-, -OC(=O) - or -NHC(=O)NH-; p and m are each independently 0, 1, 2 or 3; or wherein C 6-10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C 1-9heteroaryl- (CH 2 ) p -G-(CH 2 ) m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 ) m -, or C 3- 10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m - may be selected from one or more selected from the group consisting of F, Cl, Br, I, ethyl, propyl, vinyl, propenyl, ethynyl, Substituted with a propynyl, butynyl, methoxy, ethoxy or cyano substituent; R 3 is H, F, Cl, I, cyano, hydroxy, C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, C 1-6 aminoalkoxy, C 1-6 haloalkoxy, C 6-10 aryl - (CH 2 ) p -G-(CH 2 ) m -,C 1-9heteroaryl- (CH 2 ) p -G-(CH 2 ) m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 ) m -, or C 3-10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m -, wherein G is O, S, NR 5 , C(=O) , -C(=O)NH-, -OC(=O)NH-, -OC(=O)- or -NHC(=O)NH-; p and m are each independently 0, 1, 2 or 3 Each R 5 is independently hydrogen, R 7 R 7a NC(=O)-, R 7 OC(=O)-, R 7 C(=O)-, C 1-3 alkyl, C 1-3 haloalkane Base, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-3 alkylamino C 1-3 alkyl, C 1-3 alkane Thio C 1-3 alkyl, C 6-10 aryl C 1-3 alkyl, C 1-9 heteroaryl C 1-3 alkyl, C 2-10 heterocyclyl C 1-3 alkyl, C 3-10 cycloalkyl C 1-3 alkyl, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-10 carbocyclyl; each R 7 independently Is H, C 1-6 alkyl, C 1-6 halogenated aliphatic, C 1-6 hydroxy aliphatic, C 1-6 amino aliphatic, C 1-6 alkoxy C 1-6 aliphatic, C 1-6 alkylamino C 1-6 aliphatic, C 1-6 alkylthio C 1-6 aliphatic, C 6-10 aryl C 1-6 aliphatic, C 1-9 heteroaryl C 1-6 Aliphatic, C 2-10 heterocyclyl C 1-6 aliphatic, C 3-10 cycloalkyl C 1-6 Aliphatic, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-10 carbocyclyl; each R 7a is independently C 1-6 alkyl, C 1- 6 halogenated aliphatic, C 1-6 hydroxy aliphatic, C 1-6 amino aliphatic, C 1-6 alkoxy C 1-6 aliphatic, C 1-6 alkylamino C 1-6 aliphatic, C 1-6 alkylthio C 1-6 aliphatic, C 6-10 aryl C 1-6 aliphatic, C 1-9 heteroaryl C 1-6 aliphatic, C 2-10 heterocyclic C 1- 6 aliphatic, C 3-10 cycloalkyl C 1-6 aliphatic, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-10 carbocyclyl; R 7 and R 7a are bonded to the same nitrogen atom, and R 7 , R 7a and a nitrogen atom may be optionally substituted to form a substituted or unsubstituted 3-8 membered ring; each R 8a may be the same or different and each independently H. Hydroxy, amino, F, Cl, Br, I, -N(CH 3 ) 2 , cyano, nitro, decyl, C 1-4 alkyl, trifluoromethyl, C 1-4 alkoxy, C 1 -4 alkylamino, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl or C 1-9 heteroaryl; and n is 0, 1, 2 or 3.
其中一些實施方案，各R7獨立地為H，C1-6烷基，C1-4烷氧基C1-6烷基或以下結構：
本發明一方面涉及藥物組合物，包含本發明的化合物，或其立體異構體，幾何異構體，互變異構體，氮氧化物，水合物，溶劑化物，代謝產物，藥學上可接受的鹽或它們的前藥，或任選藥學上可接受的載體，賦形劑，稀釋劑，輔劑，媒介物，或它們的組合。 One aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention, or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite thereof, pharmaceutically acceptable Salts or their prodrugs, or optionally a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
本發明一方面涉及預防、處理、治療或減輕患者組織或器官纖維化疾病的方法，包括使用本發明化合物的藥物組合物藥學上可接受的有效劑量對患者進行給藥。 One aspect of the invention relates to a method of preventing, treating, treating or ameliorating a fibrotic disease in a tissue or organ of a patient comprising administering to the patient a pharmaceutically acceptable effective amount of a pharmaceutical composition of a compound of the invention.
本發明一方面涉及預防、處理、治療或減輕患者組織或器官纖維化疾病的方法，包括使用本發明化合物藥學上可接受的有效劑量對患者進行給藥。 One aspect of the invention relates to a method of preventing, treating, treating or ameliorating a fibrotic disease in a tissue or organ of a patient comprising administering to the patient a pharmaceutically acceptable effective amount of a compound of the invention.
本發明另一方面涉及本發明的化合物用於製備用於預防、處理、治療或減輕患者組織或器官纖維化疾病的藥物的用途。 Another aspect of the invention relates to the use of a compound of the invention for the manufacture of a medicament for the prevention, treatment, treatment or alleviation of a fibrotic disease in a tissue or organ of a patient.
本發明另一方面涉及使用一種包含本發明的化合物的藥物組合物用於製備用於預防、處理、治療或減輕患者組織或器官纖維化疾病的藥物的用途。 Another aspect of the invention relates to the use of a pharmaceutical composition comprising a compound of the invention for the manufacture of a medicament for the prevention, treatment, treatment or alleviation of a tissue or organ fibrotic disease in a patient.
另一方面，本發明涉及一種使用本發明之化合物或其藥物組合物在阻 止或治療人體或動物組織纖維化疾病中的用途，該用途包含使用本發明的化合物或其藥物組合物的藥學上可接受的有效治療量對人體或動物進行給藥。 In another aspect, the invention relates to the use of a compound of the invention or a pharmaceutical composition thereof Use in the treatment or treatment of a fibrotic disease in a human or animal tissue, the use comprising administering to a human or animal a pharmaceutically acceptable effective therapeutic amount of a compound of the invention or a pharmaceutical composition thereof.
其中一些實施例是，本發明所述的組織或器官纖維化疾病為腎間質纖維化、腎小球硬化、肝纖維化、肺纖維化、腹膜纖維化、心肌纖維化、皮膚纖維化、手術後黏連、良性前列腺肥大症、骨骼肌纖維化、硬皮病、多發性硬化症，胰腺纖維化，肝硬化，肌肉瘤，神經纖維瘤，肺間質纖維化，糖尿病腎病，阿爾茨海默病或血管纖維化疾病。另外一些實施例是，本發明所述的手術後黏連是指疤痕癒合。 In some embodiments, the tissue or organ fibrosis disease of the present invention is renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, surgery. Post-adhesion, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, muscle tumor, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, Alzheimer's disease Or vascular fibrosis. In other embodiments, post-operative adhesion as described herein refers to scar healing.
另一方面，本發明涉及式(I)，(V)，(VI)，(VII)或(IV)所包含的化合物的製備、分離和純化的方法。 In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula (I), (V), (VI), (VII) or (IV).
前面所述內容只概述了本發明的某些方面，但並不限於這些方面。這些方面及其他的方面的內容將在下面作更加具體完整的描述。 The foregoing description merely summarizes certain aspects of the invention, but is not limited thereto. These and other aspects are described in more detail below.
本發明將會把確定的具體化的內容所對應的文獻詳細列出，實施例都伴隨有結構式和化學式的圖解。本發明有預期地涵蓋所有的選擇餘地、變體和同等物，這些可能像申請專利範圍所定義的那樣包含在現有發明領域。所屬領域的技術人員將識別許多類似或等同於在此所描述的方法和物質，這些可以應用于本發明的實踐中去。本發明絕非限於方法和物質的描述。有很多文獻和相似的物質與本發明申請相區別或抵觸，其中包括但絕不限於術語的定義，術語的用法，描述的技術，或像本發明申請所控制的範圍。 The present invention will list the documents corresponding to the specific content of the determination, and the examples are accompanied by the diagrams of the structural formula and the chemical formula. The present invention is intended to cover all alternatives, modifications, and equivalents, which may be included in the field of the present invention as defined by the scope of the claims. Those skilled in the art will recognize many methods and materials that are similar or equivalent to those described herein, which can be used in the practice of the present invention. The invention is in no way limited to the description of methods and materials. There are many documents and similar materials that differ or contradict the application of the present invention, including but not limited to the definition of terms, the use of terms, the techniques described, or the scope as controlled by the present application.
本發明將應用以下定義除非其他方面表明。根據本發明的目的，化學元素根據元素週期表，CAS版本和化學藥品手冊，75，thEd，1994來定義。另外，有機化學一般原理見"Organic Chemistry," Thomas Sorrell,University Science Books,Sausalito：1999,and "March's Advanced Organic Chemistry," by Michael B.Smith and Jerry March,John Wiley&Sons,New York：2007，因此所有的內容都融合了參考文獻。 The invention will apply the following definitions unless otherwise indicated. For the purposes of the present invention, chemical elements are defined in accordance with the Periodic Table of the Elements, CAS version and Handbook of Chemicals , 75, th Ed, 1994 . In addition, the general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999 , and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 , so all The content is a fusion of references.
如本發明所描述的，本發明的化合物可以任選地被一個或多個取代基所取代，如上面的通式化合物，或者像實施例裡面特殊的例子，子類，和本發明所包含的一類化合物。應瞭解“任選取代的”這個術語與“取代或非取代的”這個術語可以交換使用。一般而言，術語“任選地”不論是否位於術語“取代的”之前，表示所給結構中的一個或多個氫原子被具體取代基所取代。除非其他方面表明，一個任選的取代基團可以有一個取代基在基團各個可取代的位置進行取代。當所給出的結構式中不只一個位置能被為具體基團的一個或多個取代基所取代，那麼取代基可以相同或不同地在各個位置取代。其中所述的取代基可以是，但並不限於，鹵代烷基，羥基，氨基，鹵素，氰基，芳基，雜芳基，烷氧基，烷氨基，烷硫基，烷基，烯基，炔基，雜環基，巰基，硝基，芳氧基，雜芳氧基，氧代(=O)，羧基，羥基取代的烷氧基，羥基取代的烷基-C(=O)-，烷基-C(=O)-，烷基-S(=O)-，烷基-S(=O)2-，羥基取代的烷基-S(=O)-，羥基取代的烷基-S(=O)2-，羧基烷氧基等等。 As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or as specific examples, subclasses, and inclusions of the present invention. A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "optionally" whether preceded by the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group. When more than one position in the given formula can be substituted by one or more substituents of a particular group, the substituents can be substituted at the various positions, either identically or differently. The substituents described therein may be, but are not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, Alkynyl, heterocyclyl, fluorenyl, nitro, aryloxy, heteroaryloxy, oxo (=O), carboxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, Alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl- S(=O) 2 -, carboxyalkoxy and the like.
本發明使用的術語“脂肪族”或“脂肪族基團”，表示直鏈(即非支鏈)或支鏈，取代或非取代的完全飽和或含有一個或多個不飽和度的烴鏈。除非另外詳細說明，脂肪族基團含有1-20個碳原子，其中一些實施例是，脂肪族基團含有1-10個碳原子，另外一些實施例是，脂肪族基團含有1-8個碳原子，另外一些實施例是，脂肪族基團含有1-6個碳原子，另外一些實施例是，脂肪族基團含有1-4個碳原子，另外一些實施例是，脂肪族基團含有1-3個碳原子。合適的脂肪族基團包括，但並不限於，直鏈或支鏈，取代或非取代的烷基，烯基或炔基，如甲基，乙基，丙基，異丙基，丁基，叔丁基，己基，異丁基，仲丁基，乙烯基等。 The term "aliphatic" or "aliphatic group" as used herein, denotes a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more degrees of unsaturation. Unless otherwise specified, an aliphatic group contains from 1 to 20 carbon atoms, some of which are, wherein the aliphatic group contains from 1 to 10 carbon atoms, and in other embodiments, the aliphatic group contains from 1 to 8 A carbon atom, in other embodiments, the aliphatic group contains 1-6 carbon atoms, and in other embodiments, the aliphatic group contains 1-4 carbon atoms, and in other embodiments, the aliphatic group contains 1-3 carbon atoms. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl or alkynyl groups such as methyl, ethyl, propyl, isopropyl, butyl, Tert-butyl, hexyl, isobutyl, sec-butyl, vinyl, and the like.
本發明使用的術語“鹵代脂肪族”表示脂肪族基團被一個或多個相同或不同的鹵原子所取代，其中脂肪族基團具有如本發明所述的含義，鹵原子即氟、氯、溴或碘，這樣的實例包括，但並不限於三氟甲基，三氟乙基，氯甲基，2-氯乙烯基等。 The term "haloaliphatic" as used in the present invention means that the aliphatic group is substituted by one or more of the same or different halogen atoms, wherein the aliphatic group has the meaning as described in the present invention, and the halogen atom is fluorine or chlorine. Examples of bromine or iodine include, but are not limited to, trifluoromethyl, trifluoroethyl, chloromethyl, 2-chlorovinyl and the like.
本發明使用的術語“羥基脂肪族”表示脂肪族基團被一個或多個羥基基團所取代，其中脂肪族基團具有如本發明所述的含義，這樣的實例包括， 但並不限於羥乙基，2-羥基丙基，羥甲基等。 The term "hydroxyaliphatic" as used herein means that the aliphatic group is substituted by one or more hydroxyl groups, wherein the aliphatic group has the meaning as described herein, such examples include However, it is not limited to hydroxyethyl, 2-hydroxypropyl, hydroxymethyl and the like.
本發明使用的術語“氨基脂肪族”表示脂肪族基團被一個或多個氨基基團所取代，其中脂肪族基團具有如本發明所述的含義，這樣的實例包括，但並不限於氨基甲基，2-氨基乙基，2-氨基異丙基等。 The term "aminoaliphatic" as used herein means that the aliphatic group is substituted by one or more amino groups, wherein the aliphatic group has the meaning as described herein, such examples include, but are not limited to, amino groups. Methyl, 2-aminoethyl, 2-aminoisopropyl and the like.
本發明使用的術語“烷基”包括1-20個碳原子，或1-10個碳原子，或1-6個碳原子，或1-4個碳原子，或1-3個碳原子飽和直鏈或支鏈的單價烴基，其中烷基可以獨立任選地被一個或多個本發明所描述的取代基所取代。烷基更進一步的實例包括，但並不限於，甲基(Me，-CH3)，乙基(Et，-CH2CH3)，正丙基(n-Pr，-CH2CH2CH3)，異丙基(i-Pr，-CH(CH3)2)，正丁基(n-Bu，-CH2CH2CH2CH3)，異丁基(i-Bu，-CH2CH(CH3)2)，仲丁基(s-Bu，-CH(CH3)CH2CH3)，叔丁基(t-Bu，-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)，正己基(-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基(-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)，正庚基，正辛基，等等。術語“烷基”和其首碼“烷”在此處使用，都包含直鏈和支鏈的飽和碳鏈。術語“烷撐”在此處使用，表示從直鏈或支鏈飽和碳氫化物消去兩個氫原子得到的飽和二價烴基，這樣的實例包括，但並不限於，亞甲基，次乙基，次異丙基等等。 The term "alkyl" as used herein, includes from 1 to 20 carbon atoms, or from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms, or from 1 to 3 carbon atoms. A chain or branched monovalent hydrocarbon group wherein the alkyl group can be independently and optionally substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1- Butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2), 2-methyl-3-pentyl (-CH (CH 2 CH 3) CH (CH 3) 2), 2,3- Methyl-2-butyl (-C (CH 3) 2 CH (CH 3) 2), 3,3- dimethyl-2-butyl (-CH (CH 3) C ( CH 3) 3), Positive heptyl, n-octyl, and so on. The term "alkyl" and its first "alkane" are used herein to encompass both straight-chain and branched saturated carbon chains. The term "alkylene" is used herein to mean a saturated divalent hydrocarbon radical derived by the elimination of two hydrogen atoms from a linear or branched saturated hydrocarbon, examples of which include, but are not limited to, methylene, hypoethyl , isopropyl and so on.
術語“亞烷基”表示烷基體系具有兩個連接點與分子其餘部分相連，其中烷基具有如本發明所述的含義。 The term "alkylene" means that the alkyl system has two points of attachment to the rest of the molecule, wherein the alkyl group has the meaning as described herein.
術語“鏈烯基”，或“烯基”表示2-12個碳原子，或2-8個碳原子，或2-6個碳原子，或2-4個碳原子直鏈或支鏈的一價烴基，其中至少一個位置為不飽和狀態，即一個C-C為sp2雙鍵，其中鏈烯基的基團可以獨立任選地被一個或多個本發明所描述的取代基所取代，包括基團有“反”“正”或"E" "Z"的定位，其中具體的實例包括，但並不限於，乙烯基(-CH=CH2)，烯丙基 (-CH2CH=CH2)，等等。 The term "alkenyl", or "alkenyl" denotes 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or a straight or branched chain of 2 to 4 carbon atoms. a valence hydrocarbon group wherein at least one position is in an unsaturated state, that is, one CC is a sp 2 double bond, wherein the alkenyl group may be independently and optionally substituted by one or more substituents described herein, including The group has the positioning of "anti", "positive" or "E""Z", and specific examples include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ),and many more.
術語“亞烯基”表示鏈烯基體系具有兩個連接點與分子其餘部分相連，其中鏈烯基具有如本發明所述的含義。 The term "alkenylene" means that the alkenyl system has two points of attachment to the rest of the molecule, wherein the alkenyl group has the meaning as described herein.
術語“炔基”表示2-12個碳原子，或2-8個碳原子，或2-6個碳原子，或2-4個碳原子直鏈或支鏈的一價烴基，其中至少一個位置為不飽和狀態，即一個C-C為sp三鍵，其中炔基基團可以獨立任選地被一個或多個本發明所描述的取代基所取代，具體的實例包括，但並不限於，乙炔基(-C三CH)，炔丙基(-CH2C三CH)，等等。 The term "alkynyl" means 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or a straight or branched monovalent hydrocarbon radical of 2 to 4 carbon atoms, at least one of which Is an unsaturated state, that is, one CC is a sp triple bond, wherein the alkynyl group may be independently and optionally substituted by one or more substituents described in the present invention, and specific examples include, but are not limited to, ethynyl groups. (-C tri CH), propargyl (-CH 2 C tri CH), and the like.
術語“亞炔基”表示炔基體系具有兩個連接點與分子其餘部分相連，其中炔基具有如本發明所述含義。 The term "alkynylene" means that the alkynyl system has two points of attachment to the rest of the molecule, wherein the alkynyl group has the meaning as described herein.
術語“羥基取代的烷基”表示烷基基團被一個或多個羥基基團所取代，其中烷基基團具有本發明所述的含義。這樣的實例包含，但並不限於羥甲基，羥乙基，1，2-二羥基乙基等。 The term "hydroxy substituted alkyl" denotes an alkyl group substituted by one or more hydroxy groups, wherein the alkyl group has the meanings indicated herein. Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl and the like.
術語“羧基取代的烷基”表示烷基基團被一個或多個羧基基團所取代，其中烷基基團具有本發明所述的含義。這樣的實例包含，但並不限於羧甲基，羧乙基等。 The term "carboxy-substituted alkyl" means that the alkyl group is substituted by one or more carboxy groups, wherein the alkyl group has the meaning as described herein. Such examples include, but are not limited to, carboxymethyl, carboxyethyl, and the like.
術語“環狀脂肪族”或“碳環”、“碳環基”、“環烷基”是指一價或多價，非芳香族，飽和或部分不飽和環，且不包含雜原子，其中包括3-12個碳原子的單環或7-12個碳原子的二環或三環。具有7-12個原子的雙碳環可以是二環[4,5]，[5,5]，[5,6]或[6,6]體系，同時具有9或10個原子的雙碳環可以是二環[5,6]或[6,6]體系。合適的環狀脂肪族基團包括，但並不限於，環烷基，環烯基和環炔基。環狀脂肪族基團的實例進一步包括，但絕不限於，環丙基，環丁基，環戊基，1-環戊基-1-烯基，1-環戊基-2-烯基，1-環戊基-3-烯基，環己基，1-環己基-1-烯基，1-環己基-2-烯基，1-環己基-3-烯基，環己二烯基，環庚基，環辛基，環壬基，環癸基，環十一烷基，環十二烷基，金剛烷基等等。並且所述環狀脂肪族”或“碳環”、“碳環基”、“環烷基”可以是取代或非取代的，其中取代基可以是，但並不限於，鹵代烷基，羥基，氨基，鹵素，氰基，芳基，雜芳基，烷氧基，烷氨基，烷基，烯基，炔基，雜環基，巰基，硝基，芳氧基，羥基取代的烷氧基，羥基取代的烷基-C(=O)-，烷基-C(=O)-，烷基-S(=O)-，烷基-S(=O)2-，羥基取代的烷基-S(=O)-，羥 基取代的烷基-S(=O)2-，羧基烷氧基等等。 The term "cyclic aliphatic" or "carbocyclic", "carbocyclyl", "cycloalkyl" refers to a monovalent or multivalent, non-aromatic, saturated or partially unsaturated ring and does not contain a hetero atom, wherein A monocyclic ring of 3 to 12 carbon atoms or a bicyclic or tricyclic ring of 7 to 12 carbon atoms. A double carbon ring having 7 to 12 atoms may be a bicyclo[4,5], [5,5], [5,6] or [6,6] system having a double carbon ring of 9 or 10 atoms. It may be a bicyclo[5,6] or [6,6] system. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of the cyclic aliphatic group further include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, Cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl and the like. And the cyclic aliphatic or "carbocyclic", "carbocyclyl", "cycloalkyl" may be substituted or unsubstituted, wherein the substituent may be, but not limited to, a halogenated alkyl group, a hydroxyl group, an amino group. , halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, fluorenyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy Substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy substituted alkyl-S (=O)-, hydroxy-substituted alkyl-S(=O) 2 -, carboxyalkoxy and the like.
術語“亞碳環基”表示碳環基體系具有兩個連接點與分子其餘部分相連，其中碳環基具有如本發明所述的含義。 The term "carbocyclylene" means that the carbocyclic group system has two points of attachment to the rest of the molecule, wherein the carbocyclic group has the meaning as described herein.
術語“碳環基(羥基烷氧基)”表示羥基烷氧基基團被一個或多個碳環基基團所取代，其中碳環基基團和羥基烷氧基具有如本發明所述的含義，這樣的實例包括，但並不限於環丙基羥甲基，環丙基羥乙基，環丙基羥丙基，環己基羥丙基，環己基羥甲基等。 The term "carbocyclyl (hydroxyalkoxy)" denotes that a hydroxyalkoxy group is substituted by one or more carbocyclyl groups, wherein the carbocyclyl group and the hydroxyalkoxy group have a By way of example, such examples include, but are not limited to, cyclopropylhydroxymethyl, cyclopropylhydroxyethyl, cyclopropylhydroxypropyl, cyclohexylhydroxypropyl, cyclohexylhydroxymethyl and the like.
術語“環烷基氧基”或“碳環基氧基”包括任選取代的環烷基或碳環基，如本發明所定義的，連接到氧原子上，並且由氧原子與其餘分子相連，這樣的實例包括，但並不限於環丙基氧基，環戊基氧基，環己基氧基，羥基取代的環丙基氧基等。 The term "cycloalkyloxy" or "carbocyclyloxy" includes an optionally substituted cycloalkyl or carbocyclyl group, as defined herein, attached to an oxygen atom, and attached to the remaining molecule by an oxygen atom. Examples of such include, but are not limited to, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropyloxy and the like.
術語“環烷基氨基”表示氨基基團被一個或兩個環烷基基團所取代，其中環烷基具有如本發明所述的含義，這樣的實例包括，但並不限於環丙基氨基，環戊基氨基，環己基氨基，羥基取代的環丙基氨基，二環己基氨基，二環丙基氨基等。 The term "cycloalkylamino" denotes an amino group substituted by one or two cycloalkyl groups, wherein cycloalkyl has the meaning as described herein, such examples include, but are not limited to, cyclopropylamino , cyclopentylamino, cyclohexylamino, hydroxy-substituted cyclopropylamino, dicyclohexylamino, dicyclopropylamino and the like.
術語“碳環基氧基烷氧基”表示烷氧基被一個或多個碳環基氧基基團所取代，其中烷氧基和碳環基氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於環丙基氧基甲氧基，環丙基氧基乙氧基，環戊基氧基乙氧基，環己基氧基乙氧基，環己烯基-3-氧基乙氧基等。 The term "carbocyclyloxyalkoxy" denotes that alkoxy is substituted by one or more carbocyclyloxy groups, wherein alkoxy and carbocyclyloxy groups have the meanings as described herein Such examples include, but are not limited to, cyclopropyloxymethoxy, cyclopropyloxyethoxy, cyclopentyloxyethoxy, cyclohexyloxyethoxy, cyclohexenyl- 3-oxyethoxy group and the like.
術語“環烷基氧基脂肪族”表示脂肪族基團被一個或多個環烷基氧基基團所取代，其中脂肪族基團和環烷基氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於環丙基氧基甲基，環丙基氧基乙基，環戊基氧基甲基，環戊基氧基乙基，環己基氧基乙基，鹵代環丙基氧基乙基等。 The term "cycloalkyloxyaliphatic" means that the aliphatic group is substituted by one or more cycloalkyloxy groups, wherein the aliphatic group and the cycloalkyloxy group have the same according to the invention Meaning, such examples include, but are not limited to, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxyethyl, Halocyclopropyloxyethyl and the like.
術語“環烷基氨基脂肪族”表示脂肪族基團被一個或多個環烷基氨基基團所取代，其中脂肪族基團和環烷基氨基基團具有如本發明所述的含義，這樣的實例包括，但並不限於環丙基氨基甲基，環丙基氨基乙基，環戊基氨基甲基，環戊基氨基乙基，環己基氨基乙基，鹵代環丙基氨基乙基等。 The term "cycloalkylaminoaliphatic" means that the aliphatic group is substituted by one or more cycloalkylamino groups, wherein the aliphatic group and the cycloalkylamino group have the meanings as described herein, such that Examples include, but are not limited to, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopentylaminomethyl, cyclopentylaminoethyl, cyclohexylaminoethyl, halocyclopropylaminoethyl Wait.
術語“環烷基脂肪族”或“碳環基脂肪族”表示脂肪族基團可被一個或多個環烷基基團或碳環基基團所取代，其中環烷基，或碳環基和脂肪族基團具有如本發明所述的含義，這樣的實例包括，但並不限於環丙基甲基，環 丙基乙基，環丙基丙基，環戊基甲基，環己基乙基等。 The term "cycloalkylaliphatic" or "carbocyclyl aliphatic" means that the aliphatic group may be substituted by one or more cycloalkyl groups or carbocyclyl groups, wherein cycloalkyl, or carbocyclyl And aliphatic groups have the meanings as described herein, such examples include, but are not limited to, cyclopropylmethyl, rings Propylethyl, cyclopropylpropyl, cyclopentylmethyl, cyclohexylethyl and the like.
術語“環烷基烷氧基”，或“碳環基烷氧基”表示烷氧基基團被一個或多個環烷基基團或碳環基基團所取代，其中環烷基基團或碳環基基團和烷氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於環丙基甲氧基，環丙基乙氧基，環戊基乙氧基，環己基乙氧基，環己基甲氧基，環丙基丙氧基等。 The term "cycloalkylalkoxy", or "carbocyclylalkoxy" denotes an alkoxy group substituted by one or more cycloalkyl groups or carbocyclyl groups, wherein a cycloalkyl group Or a carbocyclyl group and an alkoxy group have the meanings as described herein, such examples include, but are not limited to, cyclopropylmethoxy, cyclopropylethoxy, cyclopentylethoxy , cyclohexylethoxy, cyclohexylmethoxy, cyclopropylpropoxy and the like.
術語“環烷基烷氨基”或“碳環基烷氨基”表示烷氨基基團被一個或多個環烷基基團或碳環基基團所取代，其中環烷基基團或碳環基基團和烷氨基基團具有如本發明所述的含義，這樣的實例包括，但並不限於環丙基甲氨基，環丙基乙氨基，環戊基乙氨基，環己基乙氨基，環己基甲氨基，環丙基丙氨基等。 The term "cycloalkylalkylamino" or "carbocyclylalkylamino" denotes an alkylamino group substituted by one or more cycloalkyl groups or carbocyclyl groups, wherein a cycloalkyl group or a carbocyclic group The group and the alkylamino group have the meanings as described herein, such examples include, but are not limited to, cyclopropylmethylamino, cyclopropylethylamino, cyclopentylethylamino, cyclohexylethylamino, cyclohexyl Methylamino, cyclopropylpropylamino and the like.
術語“雜環”，“雜環基”，“雜脂環族”或“雜環的”在此處可交換使用，都是指單環，雙環，或三環體系，其中環上一個或多個原子獨立任選地被雜原子所取代，環可以是完全飽和的或包含一個或多個不飽和度，但絕不是芳香族類，只有一個連接點連接到其他分子上去。一個或多個環上的氫原子獨立任選地被一個或多個本發明所描述的取代基所取代。其中一些實施例是，“雜環”“雜環基”“雜脂環族”或“雜環的”基團是3-7元環的單環(1-6個碳原子和為N，O，P，S的1-3個雜原子，在此S或P任選地被一個或多個氧原子所取代得到像SO，SO2，PO，PO2的基團，當所述的環為三元環時，其中只有一個雜原子)，或7-10元的雙環(4-9個碳原子和為N，O，P，S的1-3個雜原子，在此S或P任選地被一個或多個氧原子所取代得到像SO，SO2，PO，PO2的基團)。 The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein to refer to a monocyclic, bicyclic, or tricyclic system wherein one or more rings are present. The atoms are independently and optionally substituted by a heteroatom, which may be fully saturated or contain one or more unsaturations, but is by no means aromatic, with only one point of attachment attached to the other. The hydrogen atoms on one or more of the rings are independently, optionally, substituted by one or more substituents described herein. In some embodiments, a "heterocyclic""heterocyclyl""heteroalicyclic" or "heterocyclic" group is a 3-7 membered ring of a single ring (1-6 carbon atoms and is N, O). , 1-3 heteroatoms of P, S, wherein S or P is optionally substituted with one or more oxygen atoms to give a group like SO, SO 2 , PO, PO 2 when the ring is When the three-membered ring, there is only one hetero atom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms of N, O, P, S, optional in this S or P) The ground is replaced by one or more oxygen atoms to give a group like SO, SO 2 , PO, PO 2 ).
雜環基可以是碳基或雜原子基。“雜環基”同樣也包括雜環基團與飽和或部分不飽和環或雜環併合所形成的基團。雜環的實例包括，但並不限於，吡咯烷基，四氫呋喃基，二氫呋喃基，四氫噻吩基，四氫吡喃基，二氫吡喃基，四氫噻喃基，呱啶基，嗎啉基，硫代嗎啉基，噻噁烷基，呱嗪基，高呱嗪基，氮雜環丁基，氧雜環丁基，硫雜環丁基，呱啶基，高呱啶基，環氧丙基，氮雜環庚基，氧雜環庚基，硫雜環庚基，4-甲氧基-呱啶-1-基，1,2,3,6-四氫吡啶-1-基，氧氮雜卓基，二氮雜卓基，硫氮雜卓基，吡咯啉-1-基，2-吡咯啉基，3-吡咯啉基，二氫吲哚基，2H-吡喃基，4H-吡喃基，二氧雜環 己基，1,3-二氧戊基，吡唑啉基，二噻烷基，二噻茂烷基，二氫噻吩基，吡唑烷基咪唑啉基，咪唑烷基，1，2，3，4-四氫異喹啉基，1,2,6-噻二嗪烷1,1-二氧-2-基，4-羥基-1,4-氮雜磷烷4-氧化物-1-基，2-羥基-1-(呱嗪-1-基)乙酮-4-基，2-羥基-1-(5,6-二氫-1,2,4-三嗪-1(4H)-基)乙酮-4-基，5,6-二氫-4H-1,2,4-噁二嗪-4-基，2-羥基-1-(5,6-二氫吡啶-1(2H)-基)乙酮-4-基，3-氮雜雙環[3.1.0]己基，3-氮雜雙環[4.1.0]庚基，氮雜雙環[2.2.2]己基，2-甲基-5,6,7,8-四氫-[1,2,4]三唑[1,5-c]嘧啶-6-基，4,5,6,7-四氫異噁唑[4,3-c]吡啶-5-基，3H-吲哚基2-氧-5-氮雜雙環[2.2.1]庚烷-5-基，2-氧-5-氮雜雙環[2.2.2]辛烷-5-基，喹嗪基和N-吡啶基尿素。雜環基團的實例還包括，1，1-二氧硫代嗎啉基，和其中環上兩個碳原子被氧原子所取代如嘧啶二酮基。並且所述雜環基可以是取代或非取代的，其中取代基可以是，但並不限於，鹵代烷基，氧代(=O)，羥基，氨基，鹵素，氰基，雜芳基，烷氧基，烷氨基，烷基，烯基，炔基，雜環基，巰基，硝基，芳氧基，羥基取代的烷氧基，羥基取代的烷基-C(=O)-，烷基-C(=O)-，烷基-S(=O)-，烷基-S(=O)2-，羥基取代的烷基-S(=O)-，羥基取代的烷基-S(=O)2-，羧基烷氧基等等。 The heterocyclic group may be a carbon group or a hetero atom group. "Heterocyclyl" also includes groups formed by the union of a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, acridinyl, Morpholinyl, thiomorpholinyl, thiazolidine, pyridazinyl, oxazinyl, azetidinyl, oxetanyl, thietanyl, acridinyl, homoacridinyl , epoxypropyl, azepanyl, oxetanyl, thietyl, 4-methoxy-acridin-1-yl, 1,2,3,6-tetrahydropyridine-1 -yl, oxazepine, diazepine, thiazepine, pyrrolin-1-yl, 2-pyrolinyl, 3-pyrrolyl, indanyl, 2H-pyran Base, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithiaalkyl, dithialimyl, dihydrothienyl, pyrazolidinyl imidazoline Base, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinidine 1,1-dioxo-2-yl, 4-hydroxy-1,4- Azaphosphazene 4-oxide-1-yl, 2-hydroxy-1-(pyridazin-1-yl)ethanone-4-yl, 2-hydroxy-1-(5,6-dihydro-1, 2,4-triazin-1(4H)-yl)ethanone-4-yl, 5,6-dihydro-4H-1,2,4-oxa Pyrazin-4-yl, 2-hydroxy-1-(5,6-dihydropyridine-1(2H)-yl)ethanone-4-yl, 3-azabicyclo[3.1.0]hexyl, 3-nitrogen Heterobicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7,8-tetrahydro-[1,2,4]triazole [1,5- c]pyrimidin-6-yl,4,5,6,7-tetrahydroisoxazole [4,3-c]pyridin-5-yl, 3H-indenyl 2-oxo-5-azabicyclo[2.2 .1] heptane-5-yl, 2-oxo-5-azabicyclo[2.2.2]octane-5-yl, quinolizinyl and N-pyridylurea. Examples of the heterocyclic group further include a 1,1-dioxothiomorpholinyl group, and wherein two carbon atoms in the ring are substituted with an oxygen atom such as a pyrimidinedione group. And the heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, a halogenated alkyl group, an oxo group (=O), a hydroxyl group, an amino group, a halogen group, a cyano group, a heteroaryl group, an alkoxy group. Base, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkyl- C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S (= O) 2 -, carboxy alkoxy and the like.
術語“亞雜環基”表示雜環基體系具有兩個連接點與分子其餘部分相連，其中雜環基具有如本發明所述的含義。 The term "heterocyclylene" means that the heterocyclyl system has two points of attachment to the rest of the molecule, wherein the heterocyclyl has the meaning as described herein.
術語“雜環基烷基”包括雜環基取代的烷基；術語“雜環基烷氧基”包括雜環基取代的烷氧基，其中氧原子與分子的其餘部分相連；術語“雜環基烷氨基”包括雜環基取代的烷氨基，其中氮原子與分子的其餘部分相連。其中雜環基，烷基，烷氧基和烷氨基具有如本發明所述的含義，這樣的實例包括，但並不限於吡咯-2-基甲基，嗎啉-4-基乙基，嗎啉-4-基乙氧基，呱嗪-4-基乙氧基，呱啶-4-基乙基氨基等。 The term "heterocyclylalkyl" includes heterocyclyl-substituted alkyl; the term "heterocyclylalkoxy" includes heterocyclyl-substituted alkoxy wherein the oxygen atom is attached to the remainder of the molecule; the term "heterocycle" The alkylamino group" includes a heterocyclic group-substituted alkylamino group in which a nitrogen atom is bonded to the remainder of the molecule. Wherein heterocyclyl, alkyl, alkoxy and alkylamino have the meanings as described herein, examples of which include, but are not limited to, pyrrol-2-ylmethyl, morpholin-4-ylethyl, Polin-4-ylethoxy, pyridazin-4-ylethoxy, acridin-4-ylethylamino and the like.
術語“雜環基脂肪族”表示雜環基取代的脂肪族基團，其中雜環基和脂肪族基團具有如本發明所述的含義，這樣的實例包括，但並不限於吡咯-2-甲基，呱啶-2-乙基，呱嗪-2-乙基，呱啶-2-甲基等。 The term "heterocyclyl aliphatic" denotes a heterocyclic substituted aliphatic group wherein the heterocyclyl and aliphatic groups have the meanings as described herein, examples of which include, but are not limited to, pyrrole-2- Methyl, acridine-2-ethyl, pyridazine-2-ethyl, acridine-2-methyl and the like.
術語“雜環基氧基”包括任選取代的雜環基，如本發明所定義的，連接到氧原子上，其中氧原子與分子的其餘部分相連，這樣的實例包括，但並不限於吡咯-2-氧基，吡咯-3-氧基，呱啶-2-氧基，呱啶-3-氧基，呱嗪-2-氧基，呱啶-4-氧基等。 The term "heterocyclyloxy" includes optionally substituted heterocyclyl, as defined herein, attached to an oxygen atom wherein the oxygen atom is attached to the remainder of the molecule, examples of which include, but are not limited to, pyrrole -2-oxy, pyrrol-3-oxy, acridine-2-oxy, acridine-3-oxy, pyridazin-2-oxy, acridine-4-yl and the like.
術語“雜環基氨基”表示氨基基團被一個或兩個雜環基基團所取代，其中氮原子與分子的其餘部分相連，並且雜環基具有如本發明所述的含義，這樣的實例包括，但並不限於吡咯-2-氨基，吡咯-3-氨基，呱啶-2-氨基，呱啶-3-氨基，呱啶-4-氨基，呱嗪-2-氨基，二吡咯-2-氨基等。 The term "heterocyclylamino" denotes an amino group substituted by one or two heterocyclyl groups, wherein the nitrogen atom is attached to the remainder of the molecule, and the heterocyclyl has the meaning as described herein, such an example Including, but not limited to, pyrrole-2-amino, pyrrole-3-amino, acridine-2-amino, acridine-3-amino, acridinium-4-amino, pyridazin-2-amino, dipyrrole-2 -Amino, etc.
術語“雜環基氧基烷氧基”表示烷氧基被一個或多個雜環基氧基基團所取代，其中烷氧基和雜環基氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於吡咯-2-氧基甲氧基，吡咯-3-氧基乙氧基，呱啶-2-氧基乙氧基，呱啶-3-氧基乙氧基，呱嗪-2-氧基甲氧基，呱啶-4-氧基乙氧基等。 The term "heterocyclyloxyalkoxy" denotes that alkoxy is substituted by one or more heterocyclyloxy groups, wherein alkoxy and heterocyclyloxy groups have the meanings as described herein Such examples include, but are not limited to, pyrrole-2-oxymethoxy, pyrrole-3-oxyethoxy, acridine-2-oxyethoxy, acridine-3-oxyethoxy Base, pyridazine-2-oxymethoxy, acridine-4-oxyethoxy, and the like.
術語“雜環基氧基脂肪族”表示脂肪族基團被一個或多個雜環基氧基基團所取代，其中脂肪族基團和雜環基氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於吡咯-2-氧基甲基，呱嗪-3-氧基乙基，呱嗪-2-氧基乙基，嗎啉-2-氧基甲基，呱啶-2-氧基乙基等。 The term "heterocyclyloxyaliphatic" means that the aliphatic group is substituted by one or more heterocyclyloxy groups, wherein the aliphatic group and the heterocyclyloxy group have a group according to the invention Meaning, such examples include, but are not limited to, pyrrole-2-oxymethyl, pyridazin-3-oxyethyl, pyridazin-2-oxyethyl, morpholin-2-oxymethyl, Acridine-2-oxyethyl and the like.
術語“雜環基氨基脂肪族”表示脂肪族基團被一個或多個雜環基氨基基團所取代，其中脂肪族基團和雜環基氨基基團具有如本發明所述的含義，這樣的實例包括，但並不限於吡咯-2-氨基甲基，呱嗪-3-氨基乙基，呱嗪-2-氨基乙基，呱啶-2-氨基乙基，嗎啉-2-氨基甲基等。 The term "heterocyclylaminoaliphatic" means that the aliphatic group is substituted by one or more heterocyclylamino groups, wherein the aliphatic group and the heterocyclylamino group have the meanings as described herein, such that Examples include, but are not limited to, pyrrole-2-aminomethyl, pyridazin-3-aminoethyl, pyridazin-2-aminoethyl, acridinium-2-aminoethyl, morpholine-2-amino Base.
術語“雜環基(羥基烷氧基)”表示羥基烷氧基被一個或多個雜環基基團所取代，其中雜環基基團和羥基烷氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於吡咯-2-基羥甲氧基，嗎啉-4-基羥甲氧基等。 The term "heterocyclyl (hydroxyalkoxy)" denotes a hydroxyalkoxy group substituted by one or more heterocyclyl groups, wherein the heterocyclyl group and the hydroxyalkoxy group have a group according to the invention Meaning, such examples include, but are not limited to, pyrrol-2-ylhydroxymethoxy, morpholin-4-ylhydroxymethoxy, and the like.
術語“雜原子”表示一個或多個O，S，N，P和Si，包括N，S和P任何氧化態的形式；伯、仲、叔胺和季銨鹽的形式；或者雜環中氮原子上的氫被取代的形式，例如，N(像3，4-二氫-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。 The term "heteroatom" denotes one or more of O, S, N, P and Si, including any of the forms of oxidation states of N, S and P; forms of primary, secondary, tertiary and quaternary ammonium salts; a form in which a hydrogen on a atom is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidine) NR in the base.
術語“鹵素”是指F，Cl，Br或I。 The term "halogen" means F, Cl, Br or I.
在本發明中所使用的術語“不飽和的”表示部分含有一個或多個不飽和度。 The term "unsaturated" as used in the present invention means that the moiety contains one or more degrees of unsaturation.
本發明中所使用的術語“烷氧基”，涉及到烷基，像本發明所定義的，通過氧原子(“烷氧基”)連接到主要的碳鏈上，這樣的實例包括，但並不限於甲氧基，乙氧基，丙氧基，丁氧基等。並且所述烷氧基可以是取代或非取代的，其中取代基可以是，但並不限於，羥基，氨基，鹵素，氰基，烷氧 基，烷基，烯基，炔基，巰基，硝基等等。 The term "alkoxy" as used in the present invention relates to an alkyl group, as defined in the present invention, attached to the main carbon chain through an oxygen atom ("alkoxy"), such examples include, but It is not limited to a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like. And the alkoxy group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, a hydroxyl group, an amino group, a halogen, a cyano group, an alkoxy group. Base, alkyl, alkenyl, alkynyl, decyl, nitro, and the like.
術語“羥基取代的烷氧基”或“羥基烷氧基”表示烷氧基基團被一個或多個羥基基團所取代，其中烷氧基具有如本發明所述的含義，這樣的實例包括，但並不限於羥甲氧基，2-羥基乙氧基，2-羥基丙氧基，2-羥基異丙氧等。 The term "hydroxy substituted alkoxy" or "hydroxyalkoxy" means that the alkoxy group is substituted by one or more hydroxyl groups, wherein the alkoxy group has the meaning as described herein, such examples include However, it is not limited to hydroxymethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxyisopropoxy and the like.
術語“氨基烷氧基”表示烷氧基基團被一個或多個氨基基團所取代，其中烷氧基具有如本發明所述的含義，這樣的實例包括，但並不限於氨甲氧基，2-氨基乙氧基，2-氨基丙氧基，2-氨基異丙氧基等。 The term "aminoalkoxy" denotes that the alkoxy group is substituted by one or more amino groups, wherein the alkoxy group has the meaning as described herein, such examples include, but are not limited to, aminomethoxy 2-aminoethoxy, 2-aminopropoxy, 2-aminoisopropoxy and the like.
術語“羥基取代的氨基烷氧基”表示氨基烷氧基基團被一個或多個羥基基團所取代，其中氨基烷氧基具有如本發明所述的含義，這樣的實例包括，但並不限於羥基氨甲氧基，2-羥基-2-氨基乙氧基等。 The term "hydroxy substituted aminoalkoxy" denotes an aminoalkoxy group substituted by one or more hydroxy groups, wherein the aminoalkoxy group has the meaning as described herein, such examples include, but are not It is limited to hydroxyaminomethoxy, 2-hydroxy-2-aminoethoxy and the like.
術語“疊氮基烷氧基”表示烷氧基被一個或多個疊氮基基團所取代，其中烷氧基具有如本發明所述的含義，這樣的實例包括，但並不限於2-疊氮基乙氧基，3-疊氮基丙氧基，2-疊氮基丙氧基等。 The term "azidoalkoxy" denotes that the alkoxy group is substituted by one or more azido groups, wherein the alkoxy group has the meaning as described herein, such examples include, but are not limited to, 2- Azidoethoxy, 3-azidopropoxy, 2-azidopropoxy, and the like.
術語“烷氧基烷氧基”表示烷氧基基團被一個或多個烷氧基基團所取代，其中烷氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於甲氧基甲氧基，甲氧基乙氧基，乙氧基甲氧基，乙氧基乙氧基，乙氧基丙氧基等。 The term "alkoxyalkoxy" denotes that the alkoxy group is substituted by one or more alkoxy groups, wherein the alkoxy group has the meaning as described herein, such examples include, but It is not limited to methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy and the like.
本發明所使用的術語“烷氧基脂肪族”表示脂肪族基團被一個或多個烷氧基基團所取代，其中脂肪族基團和烷氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於甲氧基甲基，乙氧基甲基，乙氧基乙基，乙氧基丙烯基等。 The term "alkoxy aliphatic" as used herein means that the aliphatic group is substituted by one or more alkoxy groups, wherein the aliphatic group and the alkoxy group have the meanings as described herein. Examples of such include, but are not limited to, methoxymethyl, ethoxymethyl, ethoxyethyl, ethoxypropenyl and the like.
本發明所使用的術語“烷氨基脂肪族”表示脂肪族基團被一個或多個烷氨基基團所取代，其中脂肪族基團和烷氨基基團具有如本發明所述的含義，這樣的實例包括，但並不限於二甲氨基乙基，甲氨基乙基，二乙氨基甲基，二乙氨基乙基等。 The term "alkylaminoaliphatic" as used herein means that the aliphatic group is substituted by one or more alkylamino groups, wherein the aliphatic group and the alkylamino group have the meanings as described herein, such Examples include, but are not limited to, dimethylaminoethyl, methylaminoethyl, diethylaminomethyl, diethylaminoethyl, and the like.
本發明所使用的術語“烷硫基脂肪族”表示脂肪族基團被一個或多個烷硫基基團所取代，其中脂肪族基團和烷硫基基團具有如本發明所述的含義，這樣的實例包括，但並不限於甲硫基乙基，甲硫基丙基，乙硫基乙基，甲硫基丙烯基等。 The term "alkylthioaliphatic" as used herein means that the aliphatic group is substituted by one or more alkylthio groups, wherein the aliphatic group and the alkylthio group have the meanings as described herein. Examples of such include, but are not limited to, methylthioethyl, methylthiopropyl, ethylthioethyl, methylthiopropenyl and the like.
術語“鹵代烷基”“鹵代烯基”和“鹵代烷氧基”表示烷基，烯基或烷氧基可以被一個或多個鹵素原子所取代的情況，這樣的實例包括，但並不限於三氟甲基，2-氯-乙烯基，三氟甲氧基等。 The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" denote alkyl, alkenyl or alkoxy which may be substituted by one or more halogen atoms, examples of which include, but are not limited to, three Fluoromethyl, 2-chloro-vinyl, trifluoromethoxy, and the like.
術語“氨基取代的鹵代烷氧基”表示鹵代烷氧基被一個或多個氨基基團所取代，其中鹵代烷氧基具有如本發明所述的含義，這樣的實例包括，但並不限於3-氨基-2-氯丙氧基等。 The term "amino-substituted haloalkoxy" denotes that haloalkoxy is substituted by one or more amino groups, wherein haloalkoxy has the meaning as described herein, such examples include, but are not limited to, 3-amino- 2-chloropropoxy group and the like.
術語“烷氨基烷氧基”表示烷氧基被一個或多個烷氨基基團所取代，其中烷氧基具有如本發明所述的含義，這樣的實例包括，但並不限於3-甲氨基-2-丙氧基等。 The term "alkylaminoalkoxy" denotes that alkoxy is substituted by one or more alkylamino groups, wherein alkoxy has the meaning as described herein, such examples include, but are not limited to, 3-methylamino -2-propoxy and the like.
術語“烷氨基鹵代烷氧基”表示鹵代烷氧基被一個或多個烷氨基基團所取代，其中鹵代烷氧基具有如本發明所述的含義，這樣的實例包括，但並不限於3-甲氨基-2-氯丙氧基等。 The term "alkylaminohaloalkoxy" denotes that haloalkoxy is substituted by one or more alkylamino groups, wherein haloalkoxy has the meaning as described herein, such examples include, but are not limited to, 3-methylamino -2-chloropropoxy and the like.
術語“羥基取代的鹵代烷氧基”表示鹵代烷氧基被一個或多個羥基基團所取代，其中鹵代烷氧基具有如本發明所述的含義，這樣的實例包括，但並不限於3-羥基-2-氟丙氧基，羥甲基三氟甲氧基等。 The term "hydroxy substituted haloalkoxy" denotes that haloalkoxy is substituted by one or more hydroxy groups, wherein haloalkoxy has the meaning as described herein, such examples include, but are not limited to, 3-hydroxy- 2-fluoropropoxy, hydroxymethyltrifluoromethoxy, and the like.
術語“芳基”可以單獨使用或作為“芳烷基”“芳烷氧基”或“芳氧基烷基”的一大部分，表示共含有6-14元環的單環，雙環，和三環的碳環體系，其中，至少一個環體系是芳香族的，其中每一個環體系包含3-7元環，且只有一個附著點與分子的其餘部分相連。術語“芳基”可以和術語“芳香環”交換使用，如芳香環可以包括苯基，萘基和蒽。並且所述芳基可以是取代或非取代的，其中取代基可以是，但並不限於，鹵代烷基，羥基，氨基，鹵素，氰基，芳基，雜芳基，烷氧基，烷氨基，烷基，烯基，炔基，雜環基，巰基，硝基，芳氧基，羥基取代的烷氧基，羥基取代的烷基-C(=O)-，烷基-C(=O)-，烷基-S(=O)-，烷基-S(=O)2-，羥基取代的烷基-S(=O)-，羥基取代的烷基-S(=O)2-，羧基烷氧基，等等。 The term "aryl" may be used alone or as a large part of "aralkyl""aralkyloxy" or "aryloxyalkyl", meaning a monocyclic, bicyclic, and tertiary ring containing a 6-14 membered ring. A cyclic carbocyclic ring system in which at least one ring system is aromatic, wherein each ring system comprises a 3-7 membered ring and only one attachment point is attached to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", such as an aromatic ring which may include phenyl, naphthyl and anthracene. And the aryl group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, a halogenated alkyl group, a hydroxyl group, an amino group, a halogen, a cyano group, an aryl group, a heteroaryl group, an alkoxy group, an alkylamino group, Alkyl, alkenyl, alkynyl, heterocyclyl, fluorenyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O) -, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) 2 -, Carboxylkoxy, and the like.
術語“氟代苯基”表示苯基基團被一個或多個氟原子所取代。 The term "fluorophenyl" means that the phenyl group is substituted by one or more fluorine atoms.
術語“亞芳基”表示芳基體系具有兩個連接點與分子其餘部分相連，其中芳基具有如本發明所述的含義。 The term "arylene" means that the aryl system has two points of attachment to the rest of the molecule, wherein the aryl group has the meaning as described herein.
術語“芳基脂肪族”表示脂肪族基團被一個或多個芳基基團所取代，其中脂肪族基團和芳基基團具有如本發明所述的含義，這樣的實例包括，但並 不限於苯乙基，苯甲基，對甲苯乙基，苯乙烯基等。 The term "arylaliphatic" means that the aliphatic group is substituted by one or more aryl groups, wherein the aliphatic group and the aryl group have the meanings as described herein, such examples include, but It is not limited to phenethyl, benzyl, p-toluethyl, styryl and the like.
術語“芳氧基”或“芳基氧基”包括任選取代的芳基，如本發明所定義的，連接到氧原子上，並且由氧原子與分子其餘部分相連，其中芳基基團具有如本發明所述的含義，這樣的實例包括，但並不限於苯氧基，甲苯氧基，乙苯氧基等。 The term "aryloxy" or "aryloxy" includes an optionally substituted aryl group, as defined herein, attached to an oxygen atom, and attached to the remainder of the molecule by an oxygen atom, wherein the aryl group has Such examples include, but are not limited to, phenoxy, tolyloxy, ethylphenoxy, and the like, as the meaning of the present invention.
術語“芳氨基”表示氨基基團被一個或兩個芳基基團所取代，其中芳基具有如本發明所述的含義，這樣的實例包括，但並不限於苯基氨基，對氟苯基氨基，二苯基氨基，二甲苯基氨基，二對甲苯基氨基等。 The term "arylamino" means that the amino group is substituted by one or two aryl groups, wherein the aryl group has the meaning as described herein, such examples include, but are not limited to, phenylamino, p-fluorophenyl Amino group, diphenylamino group, xylylamino group, di-p-tolylamino group and the like.
術語“芳氧基烷氧基”表示烷氧基被一個或多個芳氧基基團所取代，其中烷氧基和芳氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於苯氧基甲氧基，苯氧基乙氧基，苯氧基丙氧基等。 The term "aryloxyalkoxy" denotes that the alkoxy group is substituted by one or more aryloxy groups, wherein the alkoxy and aryloxy groups have the meanings as described herein, such examples include However, it is not limited to phenoxymethoxy, phenoxyethoxy, phenoxypropoxy and the like.
術語“雜芳基氧基烷氧基”表示烷氧基被一個或多個雜芳基氧基基團所取代，其中烷氧基和雜芳基氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於吡啶基氧基甲氧基，嘧啶基氧基乙氧基，噻唑基氧基丙氧基等。 The term "heteroaryloxyalkoxy" denotes an alkoxy group substituted by one or more heteroaryloxy groups, wherein the alkoxy and heteroaryloxy groups have the meanings as described herein Examples of such include, but are not limited to, pyridyloxymethoxy, pyrimidinyloxyethoxy, thiazolyloxypropoxy, and the like.
術語“芳氧基脂肪族”表示脂肪族基團被一個或多個芳氧基基團所取代，其中芳氧基和脂肪族基團具有如本發明所述的含義，這樣的實例包括，但並不限於苯氧基甲基，苯氧基乙基，甲苯氧基乙基，苯氧基丙基等。 The term "aryloxy aliphatic" means that the aliphatic group is substituted by one or more aryloxy groups, wherein the aryloxy group and the aliphatic group have the meanings as described herein, such examples include, but It is not limited to phenoxymethyl, phenoxyethyl, tolyloxyethyl, phenoxypropyl and the like.
術語“雜芳氧基脂肪族”表示脂肪族基團被一個或多個雜芳氧基基團所取代，其中雜芳氧基和脂肪族基團具有如本發明所述的含義，這樣的實例包括，但並不限於呋喃氧基甲基，嘧啶氧基乙基等。 The term "heteroaryloxyaliphatic" means that the aliphatic group is substituted by one or more heteroaryloxy groups, wherein the heteroaryloxy group and the aliphatic group have the meanings as described herein, such an example Including, but not limited to, furanyloxymethyl, pyrimidinyloxyethyl and the like.
術語“芳氨基脂肪族”表示表示脂肪族基團被一個或多個芳氨基基團所取代，其中芳氨基和脂肪族基團具有如本發明所述的含義，這樣的實例包括，但並不限於苯氨基甲基，苯氨基乙基，甲苯氨基乙基，苯氨基丙基，苯氨基烯丙基等。 The term "arylaminoaliphatic" means that the aliphatic group is substituted by one or more arylamino groups, wherein the arylamino group and the aliphatic group have the meanings as described herein, such examples include, but are not It is limited to phenylaminomethyl, phenylaminoethyl, toluidine aminoethyl, phenylaminopropyl, phenylaminoallyl and the like.
術語“芳基(羥基烷氧基)”表示羥基烷氧基被一個或多個芳基基團取代，其中芳基基團和羥基烷氧基具有如本發明所述的含義，這樣的實例包括，但並不限於苯基羥甲基，苯基羥乙基，對甲苯基羥乙基等。 The term "aryl(hydroxyalkoxy)" means that the hydroxyalkoxy group is substituted by one or more aryl groups, wherein the aryl group and the hydroxyalkoxy group have the meanings as described herein, such examples include However, it is not limited to phenylhydroxymethyl, phenylhydroxyethyl, p-tolylhydroxyethyl and the like.
術語“芳基烷氧基”表示烷氧基基團被一個或多個芳基所取代，其中芳基和烷氧基具有本發明所述的含義，這樣的實例包括，但並不限於苯基甲氧 基，苯基乙氧基，對甲苯基甲氧基，苯基丙氧基等。並且所述芳基可以是取代或非取代的，其中取代基可以是，但並不限於，鹵代烷基，羥基，氨基，鹵素，氰基，芳基，雜芳基，烷氧基，烷氨基，烷基，烯基，炔基，雜環基，巰基，硝基，芳氧基，羥基取代的烷氧基，羥基取代的烷基-C(=O)-，烷基-C(=O)-，烷基-S(=O)-，烷基-S(=O)2-，羥基取代的烷基-S(=O)-，羥基取代的烷基-S(=O)2-，羧基烷氧基等等。 The term "arylalkoxy" denotes an alkoxy group substituted by one or more aryl groups, wherein aryl and alkoxy have the meanings indicated herein, such examples include, but are not limited to, phenyl Methoxy, phenylethoxy, p-tolylmethoxy, phenylpropoxy and the like. And the aryl group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, a halogenated alkyl group, a hydroxyl group, an amino group, a halogen, a cyano group, an aryl group, a heteroaryl group, an alkoxy group, an alkylamino group, Alkyl, alkenyl, alkynyl, heterocyclyl, fluorenyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O) -, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) 2 -, Carboxylkoxy groups and the like.
術語“芳基烷氨基”表示烷氨基基團被一個或多個芳基基團所取代，其中芳基和烷氧基具有本發明所述的含義，這樣的實例包括，但並不限於苯基甲氨基，苯基乙氨基，苯基丙氨基，對甲苯基甲氨基等。 The term "arylalkylamino" denotes an alkylamino group substituted by one or more aryl groups, wherein aryl and alkoxy have the meanings described herein, such examples include, but are not limited to, phenyl Methylamino, phenylethylamino, phenylpropylamino, p-tolylmethylamino and the like.
術語“雜芳基”可以單獨使用或作為“雜芳基烷基”或“雜芳基烷氧基”的一大部分，表示共含有5-14元環的單環，雙環，和三環體系，其中至少一個環體系是芳香族的，且至少一個環體系包含一個或多個雜原子，其中每一個環體系包含3-7元環，且只有一個附著點與分子其餘部分相連。術語“雜芳基”可以與術語“芳雜環”或“雜芳族化合物”交換使用。並且所述雜芳基可以是取代或非取代的，其中取代基可以是，但並不限於，鹵代烷基，羥基，氨基，鹵素，氰基，芳基，雜芳基，烷氧基，烷氨基，烷基，烯基，炔基，雜環基，巰基，硝基，芳氧基，羥基取代的烷氧基，羥基取代的烷基-C(=O)-，烷基-C(=O)-，烷基-S(=O)-，烷基-S(=O)2-，羥基取代的烷基-S(=O)-，羥基取代的烷基-S(=O)2-，羧基烷氧基等等。 The term "heteroaryl" may be used alone or as a large part of "heteroarylalkyl" or "heteroarylalkoxy", meaning monocyclic, bicyclic, and tricyclic systems containing a 5-14 membered ring. Wherein at least one ring system is aromatic and at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring and only one attachment point is attached to the remainder of the molecule. The term "heteroaryl" can be used interchangeably with the terms "aromatic heterocycle" or "heteroaromatic". And the heteroaryl group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, a halogenated alkyl group, a hydroxyl group, an amino group, a halogen, a cyano group, an aryl group, a heteroaryl group, an alkoxy group, an alkylamino group. , alkyl, alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O -, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) 2 - , carboxy alkoxy and the like.
另外一些實施例是，芳雜環包括以下的單環，但並不限於這些單環：2-呋喃基，3-呋喃基，N-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基，3-異噁唑基，4-異噁唑基，5-異噁唑基，2-噁唑基，4-噁唑基，5-噁唑基，4-甲基異噁唑-5-基，N-吡咯基，2-吡咯基，3-吡咯基，2-吡啶基，3-吡啶基，4-吡啶基，2-嘧啶基，4-嘧啶基，嘧啶-5-基，噠嗪基(如3-噠嗪基)，2-噻唑基，4-噻唑基，5-噻唑基，四唑基(如5-四唑基)，三唑基(如2-三唑基和5-三唑基)，2-噻吩基，3-噻吩基，吡唑基(如2-吡唑基)，異噻唑基，1，2，3-噁二唑基，1，2，5-噁二唑基，1，2，4-噁二唑基，1，2，3-三唑基，1，2，3-硫代二唑基，1，3，4-硫代二唑基，1，2，5-硫代二唑基，1,3,4-噻二唑-2-基，吡嗪基，吡嗪-2-基，1，3，5-三嗪基，苯並[d]噻唑-2-基，咪唑並[1,5-a]吡啶-6-基；也包括以下的雙環，但絕不限於這些雙環：苯並咪唑 基，苯並呋喃基，苯並噻吩基，苯並噻唑基，吲哚基(如2-吲哚基)，嘌呤基，喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)，和異喹啉基(如1-異喹啉基，3-異喹啉基或4-異喹啉基)。 In other embodiments, the aromatic heterocycle includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazole- 5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, Pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (eg 5-tetrazolyl), triazolyl (eg 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (eg 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5- Oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl, benzo[ d] thiazol-2-yl, imidazo[1,5-a]pyridine-6-yl; also includes the following bicyclic rings, but is in no way limited to these bicyclic rings: benzene Imidazole Benzo, benzofuranyl, benzothienyl, benzothiazolyl, fluorenyl (eg 2-indenyl), fluorenyl, quinolinyl (eg 2-quinolinyl, 3-quinolinyl, 4 -quinolinyl), and isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolinyl).
術語“亞雜芳基”表示雜芳基體系具有兩個連接點與分子其餘部分相連，其中雜芳基具有本發明所述的含義。 The term "heteroarylene" means that the heteroaryl system has two points of attachment to the rest of the molecule, wherein the heteroaryl has the meaning as described herein.
術語“雜芳基氧基”包括任選取代的雜芳基，如本發明所定義的，連接到氧原子上，並且由氧原子與分子其餘部分相連，其中雜芳基基團具有如本發明所述的含義，這樣的實例包括，但並不限於吡啶-2-氧基，噻唑-2-氧基，咪唑-2-氧基，嘧啶-2-氧基等。 The term "heteroaryloxy" includes an optionally substituted heteroaryl group, as defined herein, attached to an oxygen atom, and attached to the remainder of the molecule by an oxygen atom, wherein the heteroaryl group has the invention By way of example, such examples include, but are not limited to, pyridin-2-yloxy, thiazol-2-oxy, imidazol-2-oxy, pyrimidin-2-oxy and the like.
術語“雜芳基氧基脂肪族”表示脂肪族基團被一個或多個雜芳基氧基基團所取代，其中脂肪族基團和雜芳基氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於吡啶-2-氧基乙基，噻唑-2-氧基甲基，咪唑-2-氧基乙基，嘧啶-2-氧基丙基等。術語“磺醯基”，無論是單獨使用還是和其他的術語像“烷基磺醯基”連用，分別表示二價的基團-SO2-。術語“烷基磺醯基”是指烷基取代的磺醯基基團，形成烷基磺醯基(-SO2CH3)。 The term "heteroaryloxyaliphatic" means that the aliphatic group is substituted by one or more heteroaryloxy groups, wherein the aliphatic group and the heteroaryloxy group have a group according to the invention Meaning, such examples include, but are not limited to, pyridin-2-oxyethyl, thiazol-2-oxymethyl, imidazole-2-oxyethyl, pyrimidin-2-oxypropyl and the like. The term "sulfo acyl", whether used alone or with other terms such as "alkylsulfonyl group" used in conjunction, respectively divalent radicals -SO 2 -. The term "alkylsulfonyl" refers to an alkyl-substituted sulfonyl group forming an alkylsulfonyl group (-SO 2 CH 3 ).
術語“氨磺醯”，“氨基磺醯基”和“氨磺醯基”表示氨基取代的磺醯基基團，形成氨磺醯基(-SO2NH2)。 The terms "ammoxime", "aminosulfonyl" and "aminosulfonyl" refer to an amino-substituted sulfonyl group to form a sulfonyl group (-SO 2 NH 2 ).
術語“羧基”，無論是單獨使用還是和其他術語連用，如“羧烷基”，表示-CO2H；術語“羰基”，無論是單獨使用還是和其他術語連用，如“氨基羰基”或“醯氧基”，表示-(C=O)-。 The term "carboxy", whether used alone or in conjunction with other terms, such as "carboxyalkyl", means -CO 2 H; the term "carbonyl", whether used alone or in conjunction with other terms, such as "aminocarbonyl" or ""醯oxy", which means -(C=O)-.
術語“羧基烷氧基”表示烷氧基基團被一個或多個羧基基團所取代，其中烷氧基和羧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於羧基甲氧基，羧基乙氧基等。 The term "carboxyalkoxy" denotes that the alkoxy group is substituted by one or more carboxy groups, wherein the alkoxy and carboxy groups have the meanings as described herein, such examples include, but are not limited to, Carboxymethoxy, carboxyethoxy, and the like.
術語“烷基羰基”包括任選取代的烷基，如本發明所定義的，與羰基連接，並由羰基與分子其餘部分相連，其中烷基具有如本發明所述的含義，這樣的實例包括，但不限於甲基羰基，乙基羰基等。 The term "alkylcarbonyl" includes an optionally substituted alkyl group, as defined herein, attached to a carbonyl group and attached to the remainder of the molecule by a carbonyl group, wherein the alkyl group has the meaning as described herein, such examples include However, it is not limited to methylcarbonyl, ethylcarbonyl and the like.
術語“羥基烷基羰基”包括羥基取代的烷基，如本發明所定義的，與羰基連接，並由羰基與分子其餘部分相連，其中羥基烷基具有如本發明所述的含義，這樣的實例包括，但不限於羥甲基羰基，1,2-二羥乙基羰基等。 The term "hydroxyalkylcarbonyl" embraces a hydroxy-substituted alkyl group, as defined herein, attached to a carbonyl group and attached to the remainder of the molecule by a carbonyl group, wherein the hydroxyalkyl group has the meaning as described herein, such an example These include, but are not limited to, hydroxymethylcarbonyl, 1,2-dihydroxyethylcarbonyl, and the like.
術語“芳烷基”或“芳基烷基”包括芳基取代的烷基基團。其中一些實施例 是，芳烷基基團是指“較低級的芳烷基”基團，即芳基基團連接到C1-6的烷基基團上。另外一些實施例是，芳烷基基團是指含C1-3的烷基的“苯烷撐”。其中具體實例包括苄基，二苯基甲基，苯乙基。芳烷基上的芳基可以進一步被鹵素，烷基，烷氧基，鹵代烷基和鹵代烷氧基所取代。 The term "aralkyl" or "arylalkyl" includes aryl substituted alkyl groups. In some of these embodiments, an aralkyl group refers to a "lower aralkyl" group, i.e., an aryl group attached to a C1-6 alkyl group. In other embodiments, an aralkyl group refers to a "phenylene support" comprising a C1-3 alkyl group. Specific examples thereof include a benzyl group, a diphenylmethyl group, and a phenethyl group. The aryl group on the aralkyl group may be further substituted with a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group and a halogenated alkoxy group.
術語“烷硫基”包括C1-10直鏈或支鏈的烷基連接到二價的硫原子上。其中一些實施例是，烷硫基是較低級的C1-3烷硫基，這樣的實例包括，但並不限於甲硫基(CH3S-)。 The term "alkylthio" includes a C1-10 straight or branched alkyl group attached to a divalent sulfur atom. In some of these embodiments, the alkylthio group is a lower C 1-3 alkylthio group, and such examples include, but are not limited to, methylthio (CH 3 S-).
術語“鹵代烷硫基”包括C1-10的鹵代烷基連接到二價硫原子上。其中一些實施例是，鹵代烷硫基是較低級的C1-3鹵代烷硫基，這樣的實例包括，但並不限於三氟甲硫基。 The term "haloalkylthio" includes a C 1-10 haloalkyl group attached to a divalent sulfur atom. In some of these embodiments, the haloalkylthio group is a lower C 1-3 haloalkylthio group, and such examples include, but are not limited to, trifluoromethylthio groups.
術語“烷基氨基”，或“烷氨基”，包括“N-烷基氨基”和“N，N-二烷基氨基”，其中氨基團分別獨立地被一個或兩個烷基基團所取代。其中一些實施例是，烷基氨基是一個或兩個C1-6烷基連接到氮原子上的較低級的烷基氨基基團。另外一些實施例是，烷基氨基是C1-3的較低級的烷基氨基基團。合適的烷基氨基基團可以是單烷基氨基或二烷基氨基，這樣的實例包括，但並不限於，N-甲氨基，N-乙氨基，N，N-二甲氨基，N，N-二乙氨基等等。 The term "alkylamino", or "alkylamino", includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently replaced by one or two alkyl groups. . In some embodiments, the alkylamino group is a lower alkylamino group having one or two C1-6 alkyl groups attached to the nitrogen atom. In other embodiments, the alkylamino group is a lower alkylamino group of C1-3 . Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N, N - Diethylamino and the like.
術語“烷氨基鹵代烷氧基”表示鹵代烷氧基被一個或多個烷氨基基團所取代，其中鹵代烷氧基和烷氨基基團具有如本發明所述的含義，這樣的實例包括，但並不限於甲氨基二氟代甲氧基，乙氨基三氟甲氧基等。 The term "alkylaminohaloalkoxy" denotes that haloalkoxy is substituted by one or more alkylamino groups, wherein haloalkoxy and alkylamino groups have the meanings as described herein, such examples include, but are not It is limited to methylaminodifluoromethoxy, ethylaminotrifluoromethoxy and the like.
術語“雜芳基氨基”表示氨基團被一個或兩個雜芳基所取代，其中雜芳基具有本發明所述的含義，這樣的實例包括，但並不限於N-噻吩基氨基等。其中一些實施例是，雜芳基氨基上的雜芳環可以進一步被取代。 The term "heteroarylamino" denotes an amino group substituted by one or two heteroaryl groups, wherein the heteroaryl group has the meanings described herein, such examples include, but are not limited to, N-thienylamino and the like. In some of these embodiments, the heteroaryl ring on the heteroarylamino group can be further substituted.
術語“雜芳基脂肪族”表示脂肪族基團被一個或多個雜芳基所取代，其中雜芳基和脂肪族基團具有本發明所述的含義，這樣的實例包括，但並不限於噻吩-2-丙烯基，吡啶-4-乙基，咪唑-2-甲基，呋喃-2-乙基，吲哚-3-甲基等。 The term "heteroarylaliphatic" means that the aliphatic group is substituted by one or more heteroaryl groups, wherein the heteroaryl and aliphatic groups have the meanings described herein, such examples include, but are not limited to, Thiophen-2-propenyl, pyridin-4-ethyl, imidazol-2-methyl, furan-2-ethyl, indole-3-methyl and the like.
術語“雜芳基烷基”表示烷基基團被一個或多個雜芳基所取代，其中雜芳基和烷基基團具有本發明所述的含義，這樣的實例包括，但並不限於咪唑-2-甲基，呋喃-2-乙基，吲哚-3-甲基等。 The term "heteroarylalkyl" denotes an alkyl group substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups have the meanings described herein, such examples include, but are not limited to, Imidazole-2-methyl, furan-2-ethyl, indole-3-methyl and the like.
術語“雜芳基烷氨基”包括含有氮原子的雜芳基烷基基團通過氮原子連 接到其他基團上，其中雜芳基烷基具有如本發明所述的含義，這樣的實例包括，但並不限於吡啶-2-基甲氨基，噻唑-2-基乙氨基，咪唑-2-基乙氨基，嘧啶-2-基丙氨基，嘧啶-2-基甲氨基等。 The term "heteroarylalkylamino" includes a heteroarylalkyl group containing a nitrogen atom through a nitrogen atom Attached to other groups wherein the heteroarylalkyl group has the meaning as described herein, such examples include, but are not limited to, pyridin-2-ylmethylamino, thiazol-2-ylethylamino, imidazole-2 -ethylethylamino, pyrimidin-2-ylpropylamino, pyrimidin-2-ylmethylamino and the like.
術語“氨基烷基”包括被一個或多個氨基所取代的C1-10直鏈或支鏈烷基基團。其中一些實施例是，氨基烷基是被一個或多個氨基基團所取代的C1-6“較低級的氨基烷基”，這樣的實例包括，但並不限於，氨甲基，氨乙基，氨丙基，氨丁基和氨己基。 The term "aminoalkyl" includes C1-10 straight or branched alkyl groups substituted with one or more amino groups. In some embodiments, the aminoalkyl group is a C1-6 "lower aminoalkyl group" substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, ammonia Ethyl, aminopropyl, aminobutyl and aminohexyl.
術語“烷基氨基烷基”包括被烷氨基取代的烷基基團。其中一些實施例是，烷基氨基烷基是C1-6較低級的烷氨基烷基。另外一些實施例是，烷基氨基烷基是C1-3較低級的烷氨基烷基。合適的烷氨基烷基基團可以是單烷基或二烷基取代的，這樣的實例包括，但並不限於，N-甲基氨基甲基，N，N-二甲基氨基乙基，N，N-二乙基氨基甲基等等。 The term "alkylaminoalkyl" includes alkyl groups substituted with alkylamino groups. In some of these embodiments, the alkylaminoalkyl group is a C1-6 lower alkylaminoalkyl group. In other embodiments, the alkylaminoalkyl group is a C1-3 lower alkylaminoalkyl group. Suitable alkylaminoalkyl groups may be monoalkyl or dialkyl substituted, examples of which include, but are not limited to, N-methylaminomethyl, N,N-dimethylaminoethyl, N , N-diethylaminomethyl and the like.
術語“烷基氨基烷氧基”包括被烷氨基取代的烷氧基基團。合適的烷氨基烷氧基可以被單烷基或二烷基所取代，這樣的實例包括，但並不限於，N-甲基氨基乙氧基，N，N-二甲基氨基乙氧基，N，N-二乙基氨基乙氧基等等。 The term "alkylaminoalkoxy" includes alkoxy groups substituted with alkylamino groups. Suitable alkylaminoalkoxy groups may be substituted by monoalkyl or dialkyl groups, examples of which include, but are not limited to, N-methylaminoethoxy, N,N-dimethylaminoethoxy, N , N-diethylaminoethoxy and the like.
術語“烷基氨基烷氧基烷氧基”表示被烷基氨基烷氧基所取代的烷氧基基團。合適的烷基氨基烷氧基烷氧基可以被單烷基或二烷基所取代，這樣的實例包括，但並不限於，N-甲基氨基甲氧基乙氧基，N-甲基氨基乙氧基乙氧基，N，N-二甲基氨基乙氧基乙氧基，N，N-二乙基氨基甲氧基甲氧基等等。 The term "alkylaminoalkoxyalkoxy" denotes an alkoxy group substituted by an alkylaminoalkoxy group. Suitable alkylaminoalkoxy alkoxy groups may be substituted by monoalkyl or dialkyl groups, examples of which include, but are not limited to, N-methylaminomethoxyethoxy, N-methylaminoethyl Oxyethoxy, N,N-dimethylaminoethoxyethoxy, N,N-diethylaminomethoxymethoxy, and the like.
術語“羧基烷基”包括可以被一個或多個羧基所取代的C1-10直鏈或支鏈烷基，這樣的實例包括，但並不限於，羧甲基，羧丙基等等。 The term "carboxyalkyl" includes C1-10 straight or branched alkyl groups which may be substituted by one or more carboxy groups, examples of which include, but are not limited to, carboxymethyl, carboxypropyl and the like.
術語“雜芳基烷氧基”包括含有氧原子的雜芳基烷基基團通過氧原子連接到其他基團上，其中雜芳基烷基具有如本發明所述的含義，這樣的實例包括，但並不限於吡啶-2-基甲氧基，噻唑-2-基乙氧基，咪唑-2-基乙氧基，嘧啶-2-基丙氧基，嘧啶-2-基甲氧基等。 The term "heteroarylalkoxy" includes a heteroarylalkyl group containing an oxygen atom attached to the other group through an oxygen atom, wherein the heteroarylalkyl group has the meaning as described herein, such examples include , but not limited to, pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, etc. .
術語“環烷基烷基”表示環烷基取代的烷基基團，這樣的實例包括，但並不限於環己基甲基。所述的環烷基可以進一步被鹵素，烷基，烷氧基和羥基所取代。 The term "cycloalkylalkyl" denotes a cycloalkyl-substituted alkyl group, examples of which include, but are not limited to, cyclohexylmethyl. The cycloalkyl group may be further substituted by a halogen, an alkyl group, an alkoxy group and a hydroxyl group.
術語“稠合雙環”，“稠環”，“稠合雙環基”，“稠環基”表示飽和或不飽和的稠環體系，涉及到非芳香族的雙環體系。這樣的體系可以包含獨立的或共軛的不飽和狀態，但其核心結構不包含芳香環或芳雜環(但是芳香族可以作為其上的取代基)。稠合雙環中的每一個環要麼是碳環要麼是雜脂環族，這樣的實例包括，但並不限於，六氫-呋喃並[3,2-b]呋喃，2,3,3a,4,7,7a-六氫-1H-茚，7-氮雜雙環[2.3.0]庚烷，稠合雙環[3.3.0]辛烷，稠合雙環[3.1.0]己烷，1,2,3,4,4a,5,8,8a-八氫萘，這些都包含在稠合雙環的體系之內。並且所述稠合雙環基可以是取代或非取代的，其中取代基可以是，但並不限於，鹵代烷基，氧代(=O)，羥基，氨基，鹵素，氰基，芳基，雜芳基，烷氧基，烷氨基，烷基，烯基，炔基，雜環基，巰基，硝基，芳氧基，羥基取代的烷氧基，羥基取代的烷基-C(=O)-，烷基-C(=O)-，烷基-S(=O)-，烷基-S(=O)2-，羥基取代的烷基-S(=O)-，羥基取代的烷基-S(=O)2-，羧基烷氧基等等。 The terms "fused bicyclic", "fused ring", "fused bicyclic", "fused ring" mean a saturated or unsaturated fused ring system involving a non-aromatic bicyclic system. Such a system may contain an independent or conjugated unsaturated state, but its core structure does not contain an aromatic ring or an aromatic heterocyclic ring (but an aromatic may serve as a substituent thereon). Each of the fused bicyclic rings is either a carbocyclic ring or a heteroalicyclic ring, and such examples include, but are not limited to, hexahydro-furo[3,2-b]furan, 2,3,3a,4 ,7,7a-hexahydro-1H-indole, 7-azabicyclo[2.3.0]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, 1,2 , 3, 4, 4a, 5, 8, 8a-octahydronaphthalene, these are all contained within the fused bicyclic system. And the fused bicyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, haloalkyl, oxo (=O), hydroxy, amino, halogen, cyano, aryl, heteroaryl Alkyl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)- , alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl -S(=O) 2 -, carboxyalkoxy and the like.
術語“亞稠合雙環基”表示稠合雙環基體系具有兩個連接點與分子其餘部分相連，其中稠合雙環基具有如本發明所述的含義。 The term "subfused bisbicyclo" means that the fused bicyclic radical system has two points of attachment to the rest of the molecule, wherein the fused bicyclic radical has the meaning as described herein.
術語“稠合雜雙環基”表示飽和或不飽和的稠環體系，涉及到非芳香族的雙環體系。這樣的體系可以包含獨立的或共軛的不飽和狀態，但其核心結構不包含芳香環或芳雜環(但是芳香族可以作為其上的取代基)。且至少一個環體系包含一個或多個雜原子，其中每一個環體系包含3-7元環，即包含1-6個碳原子和為N，O,p，S的1-3個雜原子，在此S或P任選地被一個或多個氧原子所取代得到像SO，SO2,pO,pO2的基團，這樣的實例包括，但並不限於六氫-呋喃並[3,2-b]呋喃，7-氮雜雙環[2.3.0]庚烷等。並且所述稠合雜雙環基可以是取代或非取代的，其中取代基可以是，但並不限於，鹵代烷基，氧代(=O)，羥基，氨基，鹵素，氰基，芳基，雜芳基，烷氧基，烷氨基，烷基，烯基，炔基，雜環基，巰基，硝基，芳氧基，羥基取代的烷氧基，羥基取代的烷基-C(=O)-，烷基-C(=O)-，烷基-S(=O)-，烷基-S(=O)2-，羥基取代的烷基-S(=O)-，羥基取代的烷基-S(=O)2-，羧基烷氧基等等。 The term "fused heterobicyclic" means a saturated or unsaturated fused ring system involving a non-aromatic bicyclic system. Such a system may contain an independent or conjugated unsaturated state, but its core structure does not contain an aromatic ring or an aromatic heterocyclic ring (but an aromatic may serve as a substituent thereon). And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, ie 1-3 heteroatoms comprising 1-6 carbon atoms and being N, O, p, S, Wherein S or P is optionally substituted with one or more oxygen atoms to give a group like SO, SO 2 , pO, pO 2 , such examples include, but are not limited to, hexahydro-furan [3, 2 -b] furan, 7-azabicyclo[2.3.0]heptane, and the like. And the fused heterobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, haloalkyl, oxo (=O), hydroxy, amino, halogen, cyano, aryl, hetero Aryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O) -, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkane Base-S(=O) 2 -, carboxyalkoxy and the like.
術語“亞稠合雜雙環基”表示稠合雜雙環基體系具有兩個連接點與分子其餘部分相連，其中稠合雜雙環基具有如本發明所述的含義。 The term "sub-fused heterobicyclic" means that the fused heterobicyclic system has two points of attachment to the rest of the molecule, wherein the fused heterobicyclic group has the meaning as described herein.
術語“稠合雙環基脂肪族”表示脂肪族基團被一個或多個稠合雙環基基 團所取代，其中脂肪族基團和稠合雙環基基團具有如本發明所述的含義，這樣的實例包括，但並不限於1,2,3,4,4a,5,8,8a-八氫萘基乙基，1,2,3,4,4a,5,8,8a-八氫萘基甲基，1,2,3,4,4a,5,8,8a-八氫萘基丙基，稠合雙環[3.3.0]辛烷基甲基，稠合雙環[3.1.0]己烷基乙基等。 The term "fused bicyclic aliphatic" means that the aliphatic group is bonded to one or more fused bicyclic groups. Substituted, wherein the aliphatic group and the fused bicyclic group have the meanings as described herein, such examples include, but are not limited to, 1, 2, 3, 4, 4a, 5, 8, 8a- Octahydronaphthalenylethyl, 1,2,3,4,4a,5,8,8a-octahydronaphthylmethyl, 1,2,3,4,4a,5,8,8a-octahydronaphthyl Propyl, fused bicyclo[3.3.0]octylmethyl, fused bicyclo[3.1.0]hexylethyl and the like.
術語“稠合雜雙環基脂肪族”表示脂肪族基團被一個或多個稠合雜雙環基基團所取代，其中脂肪族基團和稠合雜雙環基基團具有如本發明所述的含義，這樣的實例包括，但並不限於六氫-呋喃並[3,2-b]呋喃-2-基乙基，六氫-呋喃並[3,2-b]呋喃-2-基甲基，7-氮雜雙環[2.3.0]庚烷-2-基甲基，7-氮雜雙環[2.3.0]庚烷-2-基乙基，7-氮雜雙環[2.3.0]庚烷-4-基甲基等。 The term "fused heterobicyclic aliphatic" means that the aliphatic group is substituted by one or more fused heterobicyclic groups, wherein the aliphatic group and the fused heterobicyclic group have a group according to the invention Meaning, such examples include, but are not limited to, hexahydro-furo[3,2-b]furan-2-ylethyl, hexahydro-furo[3,2-b]furan-2-ylmethyl , 7-azabicyclo[2.3.0]heptan-2-ylmethyl, 7-azabicyclo[2.3.0]heptan-2-ylethyl, 7-azabicyclo[2.3.0]g Alkyl-4-ylmethyl and the like.
術語“稠合雙環基氧基”包括任選取代的稠合雙環基，像本發明所定義的，連接到氧原子上，並且由氧原子與分子其餘部分相連，這樣的實例包括，但並不限於1,2,3,4,4a,5,8,8a-八氫萘基氧基，稠合雙環[3.3.0]辛烷-2-氧基，稠合雙環[3.1.0]己烷-2-氧基等。 The term "fused bicyclic oxy" includes an optionally substituted fused bicyclic group, as defined herein, attached to an oxygen atom, and attached to the remainder of the molecule by an oxygen atom, examples of which include, but are not Limited to 1,2,3,4,4a,5,8,8a-octahydronaphthyloxy, fused bicyclo[3.3.0]octane-2-oxy, fused bicyclo[3.1.0]hexane -2-oxyl and the like.
術語“稠合雜雙環基氧基”包括任選取代的稠合雜雙環基，像本發明所定義的，連接到氧原子上，並且由氧原子與分子其餘部分相連，這樣的實例包括，但並不限於六氫-呋喃並[3,2-b]呋喃-2-基氧基，7-氮雜雙環[2.3.0]庚烷-2-基氧基，7-氮雜雙環[2.3.0]庚烷-4-基氧基等。 The term "fused heterobicyclooxy" includes an optionally substituted fused heterobicyclic group, as defined herein, attached to an oxygen atom, and attached to the remainder of the molecule by an oxygen atom, such examples include, but It is not limited to hexahydro-furo[3,2-b]furan-2-yloxy, 7-azabicyclo[2.3.0]heptan-2-yloxy, 7-azabicyclo[2.3. 0] heptane-4-yloxy and the like.
術語“稠合雙環基氨基”表示氨基基團被一個或兩個稠合雙環基所取代，其中稠合雙環基具有如本發明所述的含義，這樣的實例包括，但並不限於1,2,3,4,4a,5,8,8a-八氫萘基氨基，二(1,2,3,4,4a,5,8,8a-八氫萘基)氨基，稠合雙環[3.3.0]辛烷基氨基，稠合雙環[3.1.0]己烷基氨基等。 The term "fused bicyclic amino" means that the amino group is substituted by one or two fused bicyclic groups, wherein the fused bicyclic group has the meaning as described herein, such examples include, but are not limited to, 1,2 , 3,4,4a,5,8,8a-octahydronaphthylamino, bis(1,2,3,4,4a,5,8,8a-octahydronaphthyl)amino, fused bicyclo[3.3. 0] octylamino group, fused bicyclo[3.1.0]hexaneamino group and the like.
術語“稠合雜雙環基氨基”表示氨基基團被一個或兩個稠合雜雙環基所取代，其中稠合雜雙環基具有如本發明所述的含義，這樣的實例包括，但並不限於六氫-呋喃並[3,2-b]呋喃-2-基氨基，7-氮雜雙環[2.3.0]庚烷-2-基氨基，7-氮雜雙環[2.3.0]庚烷-4-基氨基等。 The term "fused heterobicyclic amino" means that the amino group is substituted by one or two fused heterobicyclic groups, wherein the fused heterobicyclic group has the meaning as described herein, such examples include, but are not limited to, Hexahydro-furo[3,2-b]furan-2-ylamino, 7-azabicyclo[2.3.0]heptan-2-ylamino, 7-azabicyclo[2.3.0]heptane- 4-ylamino and the like.
術語“稠合雙環基烷氨基”表示烷氨基基團被一個或多個稠合雙環基所取代，其中稠合雙環基具有如本發明所述的含義，這樣的實例包括，但並不限於1,2,3,4,4a,5,8,8a-八氫萘基甲氨基，二(1,2,3,4,4a,5,8,8a-八氫萘基)甲氨基，稠合雙環[3.3.0]辛烷基甲氨基，稠合雙環[3.1.0]己烷基甲氨基等。 The term "fused bicycloalkylamino" means that the alkylamino group is substituted by one or more fused bicyclic groups, wherein the fused bicyclic group has the meaning as described herein, such examples include, but are not limited to, , 2,3,4,4a,5,8,8a-octahydronaphthylmethylamino, bis(1,2,3,4,4a,5,8,8a-octahydronaphthyl)methylamino, fused Bicyclo[3.3.0]octylmethylamino, fused bicyclo[3.1.0]hexanemethylamino and the like.
術語“稠合雜雙環基烷氨基”表示烷氨基基團被一個或多個稠合雜雙環 基所取代，其中稠合雜雙環基具有如本發明所述的含義，這樣的實例包括，但並不限於六氫-呋喃並[3,2-b]呋喃-2-基甲氨基，7-氮雜雙環[2.3.0]庚烷-2-基甲氨基，7-氮雜雙環[2.3.0]庚烷-4-基甲氨基等。 The term "fused heterobicycloalkylamino" means that the alkylamino group is bonded to one or more heterobicyclic rings. Substituted, wherein the fused heterobicyclic group has the meaning as described herein, and such examples include, but are not limited to, hexahydro-furo[3,2-b]furan-2-ylmethylamino, 7- Azabicyclo[2.3.0]heptan-2-ylmethylamino, 7-azabicyclo[2.3.0]heptan-4-ylmethylamino and the like.
術語“稠合雙環基烷氧基”表示烷氧基被一個或多個稠合雙環基基團所取代，其中烷氧基和稠合雙環基具有如本發明所述的含義，這樣的實例包括，但並不限於1,2,3,4,4a,5,8,8a-八氫萘基甲氧基，1,2,3,4,4a,5,8,8a-八氫萘基乙氧基，稠合雙環[3.3.0]辛烷-乙氧基，稠合雙環[3.1.0]己烷-丙氧基等。 The term "fused bicycloalkoxy" denotes an alkoxy group substituted by one or more fused bicyclic groups, wherein alkoxy and fused bicyclic groups have the meanings as described herein, such examples include , but not limited to 1,2,3,4,4a,5,8,8a-octahydronaphthylmethoxy, 1,2,3,4,4a,5,8,8a-octahydronaphthyl Oxy, fused bicyclo[3.3.0]octane-ethoxy, fused bicyclo[3.1.0]hexane-propoxy, and the like.
術語“稠合雜雙環基烷氧基”表示烷氧基被一個或多個稠合雜雙環基基團所取代，其中烷氧基和稠合雜雙環基具有如本發明所述的含義，這樣的實例包括，但並不限於六氫-呋喃並[3,2-b]呋喃-2-基丙氧基，7-氮雜雙環[2.2.1]庚烷-2-基乙氧基，7-氮雜雙環[2.3.0]庚烷-4-基丙氧基，六氫-呋喃並[3,2-b]呋喃-2-基乙氧基，7-氮雜雙環[2.3.0]庚烷-2-基丙氧基，7-氮雜雙環[2.3.0]庚烷-4-基乙氧基等。 The term "fused heterobicycloalkoxy" means that the alkoxy group is substituted by one or more fused heterobicyclic groups, wherein the alkoxy group and the fused heterobicyclic group have the meanings as described herein, such that Examples include, but are not limited to, hexahydro-furo[3,2-b]furan-2-ylpropoxy, 7-azabicyclo[2.2.1]heptan-2-ylethoxy, 7 -azabicyclo[2.3.0]heptan-4-ylpropoxy, hexahydro-furo[3,2-b]furan-2-ylethoxy, 7-azabicyclo[2.3.0] Heptan-2-ylpropoxy, 7-azabicyclo[2.3.0]heptan-4-ylethoxy and the like.
術語“稠合雙環基氧基烷氧基”表示烷氧基被一個或多個稠合雙環基氧基基團所取代，其中烷氧基和稠合雙環基氧基具有如本發明所述的含義，這樣的實例包括，但並不限於1,2,3,4,4a,5,8,8a-八氫萘基氧基甲氧基，1,2,3,4,4a,5,8,8a-八氫萘基氧基乙氧基，稠合雙環[3.3.0]辛烷-2-氧基乙氧基，稠合雙環[3.1.0]己烷-2-氧基丙氧基等。 The term "fused bicyclic oxyalkoxy" means that the alkoxy group is substituted by one or more fused bicyclic oxy groups, wherein the alkoxy group and the fused bicyclic oxy group have a Meaning, such examples include, but are not limited to, 1,2,3,4,4a,5,8,8a-octahydronaphthyloxymethoxy, 1,2,3,4,4a,5,8 , 8a-octahydronaphthyloxyethoxy, fused bicyclo[3.3.0]octane-2-oxyethoxy, fused bicyclo[3.1.0]hexane-2-oxypropoxy Wait.
術語“稠合雜雙環基氧基烷氧基”表示烷氧基被一個或多個稠合雜雙環基氧基基團所取代，其中烷氧基和稠合雜雙環基氧基具有如本發明所述的含義，這樣的實例包括，但並不限於六氫-呋喃並[3,2-b]呋喃-2-基氧基丙氧基，7-氮雜雙環[2.2.1]庚烷-2-基氧基乙氧基，7-氮雜雙環[2.3.0]庚烷-4-基氧基丙氧基，六氫-呋喃並[3,2-b]呋喃-2-基氧基乙氧基，7-氮雜雙環[2.3.0]庚烷-2-基氧基丙氧基，7-氮雜雙環[2.3.0]庚烷-4-基氧基乙氧基等。 The term "fused heterobicyclic oxyalkoxy" denotes that alkoxy is substituted by one or more fused heterobicyclooxy groups, wherein alkoxy and fused heterobicyclooxy have the invention By way of example, such examples include, but are not limited to, hexahydro-furo[3,2-b]furan-2-yloxypropoxy, 7-azabicyclo[2.2.1]heptane- 2-yloxyethoxy, 7-azabicyclo[2.3.0]heptane-4-yloxypropoxy, hexahydro-furo[3,2-b]furan-2-yloxy Ethoxy, 7-azabicyclo[2.3.0]heptan-2-yloxypropoxy, 7-azabicyclo[2.3.0]heptan-4-yloxyethoxy, and the like.
術語“稠合雙環基氨基烷氧基”表示烷氧基被一個或多個稠合雙環基氨基所取代，其中烷氧基和稠合雙環基氨基具有如本發明所述的含義，這樣的實例包括，但並不限於1,2,3,4,4a,5,8,8a-八氫萘基氨基乙氧基，1,2,3,4,4a,5,8,8a-八氫萘基氨基丙氧基，二(1,2,3,4,4a,5,8,8a-八氫萘基)氨基丙氧基，稠合雙環[3.3.0]辛烷-2-氨基乙氧基，稠合雙環[3.1.0]己烷-2-氨基丙氧基等。 The term "fused bicyclic aminoalkoxy" means that the alkoxy group is substituted by one or more fused bicyclic amino groups, wherein the alkoxy group and the fused bicyclic amino group have the meanings as described herein, such an example Including, but not limited to, 1,2,3,4,4a,5,8,8a-octahydronaphthylaminoethoxy, 1,2,3,4,4a,5,8,8a-octahydronaphthalene Aminoaminopropoxy, bis(1,2,3,4,4a,5,8,8a-octahydronaphthyl)aminopropoxy, fused bicyclo[3.3.0]octane-2-aminoethoxy Base, fused bicyclo[3.1.0]hexane-2-aminopropoxy and the like.
術語“稠合雜雙環基氨基烷氧基”表示烷氧基被一個或多個稠合雜雙環基氨基所取代，其中烷氧基和稠合雜雙環基氨基具有如本發明所述的含義，這樣的實例包括，但並不限於7-氮雜雙環[2.2.1]庚烷-2-基氨基乙氧基，7-氮雜雙環[2.3.0]庚烷-4-基氨基丙氧基，六氫-呋喃並[3,2-b]呋喃-2-基氨基乙氧基，六氫-呋喃並[3,2-b]呋喃-2-基氨基丙氧基，六氫-呋喃並[3,2-b]呋喃-2-基氨基甲氧基等。 The term "fused heterobicyclic aminoalkoxy" means that the alkoxy group is substituted by one or more fused heterobicyclic amino groups, wherein the alkoxy group and the fused heterobicyclic amino group have the meanings as described herein. Such examples include, but are not limited to, 7-azabicyclo[2.2.1]heptan-2-ylaminoethoxy, 7-azabicyclo[2.3.0]heptan-4-ylaminopropoxy , hexahydro-furo[3,2-b]furan-2-ylaminoethoxy, hexahydro-furo[3,2-b]furan-2-ylaminopropoxy, hexahydro-furan [3,2-b]furan-2-ylaminomethoxy and the like.
術語“螺環基”，“螺環”，“螺雙環基”，“螺雙環”表示一個環起源於另一個環上特殊的環狀碳。例如，像下面所描述的，一個飽和的橋環體系(環B和B')被稱為“稠合雙環”，反之環A和環B在兩個飽和的環體系中共用一個碳原子，則被稱為“螺環”。螺環裡面的每一個環要麼是碳環要麼是雜脂環族。這樣的實例包括，但並不限於2,7-二氮雜螺[4.4]壬烷-2-基，7-氧-2-氮雜螺[4.5]癸烷-2-基，4-氮雜螺[2.4]庚烷-5-基，4-氧雜螺[2.4]庚烷-5-基，5-氮雜螺[2.4]庚烷-5-基，螺[2.4]庚烷基，螺[4.4]壬烷基，7-羥基-5-氮雜螺[2.4]庚烷-5-基等。並且所述螺雙環基可以是取代或非取代的，其中取代基可以是，但並不限於，鹵代烷基，氧代(=O)，羥基，氨基，鹵素，氰基，芳基，雜芳基，烷氧基，烷氨基，烷基，烯基，炔基，雜環基，巰基，硝基，芳氧基，羥基取代的烷氧基，羥基取代的烷基-C(=O)-，烷基-C(=O)-，烷基-S(=O)-，烷基-S(=O)2-，羥基取代的烷基-S(=O)-，羥基取代的烷基-S(=O)2-，羧基烷氧基等等。 The terms "spirocyclyl", "spirocyclic", "spirobicyclo", and "spirobicyclic" mean that one ring originates from a particular cyclic carbon on the other ring. For example, as described below, a saturated bridged ring system (rings B and B') is referred to as a "fused bicyclic ring", whereas ring A and ring B share a carbon atom in two saturated ring systems, Known as the "spiral ring." Each ring in the spiral ring is either a carbon ring or a heteroalicyclic ring. Such examples include, but are not limited to, 2,7-diazaspiro[4.4]decane-2-yl, 7-oxo-2-azaspiro[4.5]decane-2-yl, 4-aza Spiro[2.4]heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl, spiro[2.4]heptanyl, snail [4.4] Mercaptoalkyl, 7-hydroxy-5-azaspiro[2.4]heptane-5-yl and the like. And the spirobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, haloalkyl, oxo (=O), hydroxy, amino, halogen, cyano, aryl, heteroaryl , alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, Alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl- S(=O) 2 -, carboxyalkoxy and the like.
術語“亞螺雙環基”表示螺雙環基體系具有兩個連接點與分子其餘部分相連，其中螺雙環基具有如本發明所述的含義。 The term "spirabicyclo" refers to a spirobicyclic radical system having two points of attachment to the rest of the molecule, wherein the spirobicyclo group has the meaning as described herein.
術語“螺雜雙環基”表示一個環起源於另一個環上特殊的環狀碳。例如，像上面所描述的，一個飽和的橋環體系(環B和B')被稱為“稠合雙環”，反之環A和環B在兩個飽和的環體系中共用一個碳原子，則被稱為“螺環”。且至少一個環體系包含一個或多個雜原子，其中每一個環體系包含3-7元環，即包含1-6個碳原子和為N，O,P，S的1-3個雜原子，在此S或P任選地被一個 或多個氧原子所取代得到像SO，SO2,PO,PO2的基團，這樣的實例包括，但並不限於4-氮雜螺[2.4]庚烷-5-基，4-氧雜螺[2.4]庚烷-5-基，5-氮雜螺[2.4]庚烷-5-基，7-羥基-5-氮雜螺[2.4]庚烷-5-基等。並且所述螺雜雙環基可以是取代或非取代的，其中取代基可以是，但並不限於，鹵代烷基，氧代(=O)，羥基，氨基，鹵素，氰基，芳基，雜芳基，烷氧基，烷氨基，烷基，烯基，炔基，雜環基，巰基，硝基，芳氧基，羥基取代的烷氧基，羥基取代的烷基-C(=O)-，烷基-C(=O)-，烷基-S(=O)-，烷基-S(=O)2-，羥基取代的烷基-S(=O)-，羥基取代的烷基-S(=O)2-，羧基烷氧基等等。 The term "spirobicyclo" means that one ring originates from a particular cyclic carbon on the other ring. For example, as described above, a saturated bridged ring system (rings B and B') is referred to as a "fused bicyclic ring", whereas ring A and ring B share a carbon atom in two saturated ring systems, Known as the "spiral ring." And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, ie 1-3 heteroatoms containing 1-6 carbon atoms and being N, O, P, S, Wherein S or P is optionally substituted with one or more oxygen atoms to give a group like SO, SO 2 , PO, PO 2 , such examples include, but are not limited to, 4-azaspiro[2.4] Alkan-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl,7-hydroxy-5-azaspiro[2.4]heptane -5-based and the like. And the spiroheterobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, haloalkyl, oxo (=O), hydroxy, amino, halogen, cyano, aryl, heteroaryl Alkyl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)- , alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl -S(=O) 2 -, carboxyalkoxy and the like.
術語“亞螺雜雙環基”表示螺雜雙環基體系具有兩個連接點與分子其餘部分相連，其中螺雜雙環基具有如本發明所述的含義。 The term "aspynbicyclo" means that the spirobicyclo ring system has two points of attachment to the rest of the molecule, wherein the spiroheterobicyclic group has the meaning as described herein.
術語“螺雙環基脂肪族”表示脂肪族基團被一個或多個螺雙環基基團所取代，其中脂肪族基團和螺雙環基基團具有如本發明所述的含義，這樣的實例包括，但並不限於螺[2.4]庚烷基甲基，螺[2.4]庚烷基乙基，螺[2.4]庚烷基丙基，螺[4.4]壬烷基甲基，螺[4.4]壬烷基乙基，4-氮雜螺[2.4]庚烷-5-基甲基，4-氮雜螺[2.4]庚烷-5-基乙基，4-氧雜螺[2.4]庚烷-5-基乙基，5-氮雜螺[2.4]庚烷-5-基丙基，7-羥基-5-氮雜螺[2.4]庚烷-5-基丙基等。 The term "spirobicycloaliphatic" means that the aliphatic group is substituted by one or more spirobicyclo groups, wherein the aliphatic group and the spirobicyclo group have the meanings as described herein, such examples include , but not limited to spiro [2.4] heptylmethyl, spiro[2.4] heptylethyl, spiro[2.4]heptylpropyl, spiro[4.4]decylmethyl, snail [4.4]壬Alkylethyl, 4-azaspiro[2.4]heptane-5-ylmethyl, 4-azaspiro[2.4]heptane-5-ylethyl, 4-oxaspiro[2.4]heptane- 5-ylethyl, 5-azaspiro[2.4]heptane-5-ylpropyl, 7-hydroxy-5-azaspiro[2.4]heptane-5-ylpropyl and the like.
術語“螺雜雙環基脂肪族”表示脂肪族基團被一個或多個螺雜雙環基基團所取代，其中脂肪族基團和螺雜雙環基基團具有如本發明所述的含義，這樣的實例包括，但並不限於4-氮雜螺[2.4]庚烷-5-基甲基，4-氮雜螺[2.4]庚烷-5-基乙基，4-氧雜螺[2.4]庚烷-5-基乙基，5-氮雜螺[2.4]庚烷-5-基丙基，7-羥基-5-氮雜螺[2.4]庚烷-5-基丙基等。 The term "spirobicycloaliphatic" means that the aliphatic group is substituted by one or more spirobicyclo groups, wherein the aliphatic group and the spirobicyclo group have the meaning as described herein, such that Examples include, but are not limited to, 4-azaspiro[2.4]heptane-5-ylmethyl, 4-azaspiro[2.4]heptane-5-ylethyl, 4-oxaspiro[2.4] Heptane-5-ylethyl, 5-azaspiro[2.4]heptane-5-ylpropyl, 7-hydroxy-5-azaspiro[2.4]heptane-5-ylpropyl and the like.
術語“螺雙環基氧基”包括任選取代的螺雙環基，像本發明所定義的，連接到氧原子上，並且由氧原子與分子其餘部分相連，這樣的實例包括，但並不限於螺[2.4]庚烷-2-氧基，螺[2.4]庚烷-3-氧基，螺[2.4]庚烷-4-氧基，螺[4.4]壬烷-2-氧基，螺[4.4]壬烷-4-氧基，4-氮雜螺[2.4]庚烷-5-氧基等。 The term "spirobicyclooxy" includes an optionally substituted spirobicyclo group, as defined herein, attached to an oxygen atom, and attached to the remainder of the molecule by an oxygen atom, examples of which include, but are not limited to, spiro [2.4] heptane-2-oxy, spiro[2.4]heptane-3-oxy, spiro[2.4]heptane-4-oxy, spiro[4.4]decane-2-oxy, spiro[4.4 ] decane-4-oxy, 4-azaspiro[2.4]heptane-5-oxy and the like.
術語“螺雜雙環基氧基”包括任選取代的螺雜雙環基，像本發明所定義的，連接到氧原子上，並且由氧原子與分子其餘部分相連，這樣的實例包括，但並不限於4-氮雜螺[2.4]庚烷-5-基氧基，4-氧雜螺[2.4]庚烷-5-基氧基，5-氮雜螺[2.4]庚烷-5-基氧基等。 The term "spirobicyclooxy" includes an optionally substituted spirobicyclo group, as defined herein, attached to an oxygen atom, and attached to the remainder of the molecule by an oxygen atom, examples of which include, but are not Limited to 4-azaspiro[2.4]heptane-5-yloxy, 4-oxaspiro[2.4]heptane-5-yloxy, 5-azaspiro[2.4]heptane-5-yloxy Base.
術語“螺雙環基氨基”表示氨基基團被一個或兩個螺雙環基基團所取代 ，其中螺雙環基具有如本發明所述的含義，這樣的實例包括，但並不限於螺[2.4]庚烷-2-氨基，螺[2.4]庚烷-3-氨基，螺[2.4]庚烷-4-氨基，螺[4.4]壬烷-2-氨基，螺[4.4]壬烷-4-氨基，4-氮雜螺[2.4]庚烷-5-氨基等。 The term "spirobicycloamino" means that the amino group is replaced by one or two spirobicyclic groups. Wherein the spirobicyclic group has the meaning as described in the present invention, such examples include, but are not limited to, spiro[2.4]heptane-2-amino, spiro[2.4]heptane-3-amino, spiro[2.4]g Alkyl-4-amino, spiro[4.4]decane-2-amino, spiro[4.4]decane-4-amino, 4-azaspiro[2.4]heptane-5-amino and the like.
術語“螺雜雙環基氨基”表示氨基基團被一個或兩個螺雜雙環基基團所取代，其中螺雜雙環基具有如本發明所述的含義，這樣的實例包括，但並不限於4-氮雜螺[2.4]庚烷-5-基氨基，4-氮雜螺[2.4]庚烷-2-基氨基，4-氧雜螺[2.4]庚烷-5-基氨基，5-氮雜螺[2.4]庚烷-5-基氨基等。 The term "spirobicycloamino" means that the amino group is substituted by one or two spirobicyclo groups, wherein the spirobicyclo group has the meaning as described herein, such examples include, but are not limited to, 4 -azaspiro[2.4]heptane-5-ylamino, 4-azaspiro[2.4]heptan-2-ylamino, 4-oxaspiro[2.4]heptane-5-ylamino, 5-nitrogen Heterospiro[2.4]heptane-5-ylamino and the like.
術語“螺雙環基烷氧基”表示烷氧基基團被一個或多個螺雙環基所取代，其中螺雙環基和烷氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於螺[2.4]庚烷-2-甲氧基，螺[2.4]庚烷-3-乙氧基，螺[2.4]庚烷-4-乙氧基，螺[4.4]壬烷-2-甲氧基，螺[4.4]壬烷-4-丙氧基，4-氮雜螺[2.4]庚烷-5-甲氧基等。 The term "spirobicycloalkoxy" denotes that the alkoxy group is substituted by one or more spirobicyclo groups, wherein the spirobicyclo and alkoxy groups have the meanings as described herein, such examples include But not limited to spiro[2.4]heptane-2-methoxy, spiro[2.4]heptane-3-ethoxy, spiro[2.4]heptane-4-ethoxy, spiro[4.4]decane- 2-methoxy, spiro[4.4]decane-4-propoxy, 4-azaspiro[2.4]heptane-5-methoxy and the like.
術語“螺雜雙環基烷氧基”表示烷氧基基團被一個或多個螺雜雙環基所取代，其中螺雜雙環基和烷氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於4-氮雜螺[2.4]庚烷-5-基甲氧基，4-氮雜螺[2.4]庚烷-2-基乙氧基，4-氧雜螺[2.4]庚烷-5-基乙氧基，5-氮雜螺[2.4]庚烷-5-基丙氧基等。 The term "spirobicycloalkoxy" denotes that the alkoxy group is substituted by one or more spirobicyclo groups, wherein the spirobicyclo and alkoxy groups have the meanings as described herein, such Examples include, but are not limited to, 4-azaspiro[2.4]heptane-5-ylmethoxy, 4-azaspiro[2.4]heptan-2-ylethoxy, 4-oxaspiro[2.4 Heptane-5-ylethoxy, 5-azaspiro[2.4]heptane-5-ylpropoxy and the like.
術語“螺雙環基烷氨基”表示烷氨基基團被一個或多個螺雙環基所取代，其中螺雙環基和烷氨基基團具有如本發明所述的含義，這樣的實例包括，但並不限於螺[2.4]庚烷-2-甲氨基，螺[2.4]庚烷-3-乙氨基，螺[2.4]庚烷-4-乙氨基，螺[4.4]壬烷-2-甲氨基，螺[4.4]壬烷-4-丙氨基，4-氮雜螺[2.4]庚烷-5-甲氨基等。 The term "spirobicycloalkylamino" means that the alkylamino group is substituted by one or more spirobicyclic groups, wherein the spirobicyclo and alkano groups have the meanings as described herein, such examples include, but are not Limited to spiro [2.4] heptane-2-methylamino, spiro[2.4]heptane-3-ethylamino, spiro[2.4]heptane-4-ethylamino, spiro[4.4]decane-2-methylamino, snail [4.4] decane-4-propylamino, 4-azaspiro[2.4]heptane-5-methylamino and the like.
術語“螺雜雙環基烷氨基”烷氨基基團被一個或多個螺雜雙環基所取代，其中螺雜雙環基和烷氨基基團具有如本發明所述的含義，這樣的實例包括，但並不限於4-氮雜螺[2.4]庚烷-5-基甲氨基，4-氮雜螺[2.4]庚烷-2-基乙氨基，4-氧雜螺[2.4]庚烷-5-基乙氨基，5-氮雜螺[2.4]庚烷-5-基丙氨基等。 The term "spirobicycloalkylamino" alkylamino group is substituted by one or more spirobicyclo groups, wherein spirobicyclo and alkylamino groups have the meanings as described herein, such examples include, but It is not limited to 4-azaspiro[2.4]heptane-5-ylmethylamino, 4-azaspiro[2.4]heptan-2-ylethylamino, 4-oxaspiro[2.4]heptane-5- Ethylethylamino, 5-azaspiro[2.4]heptane-5-ylpropylamino and the like.
術語“螺雙環基氧基烷氧基”表示烷氧基被一個或多個螺雙環基氧基基團所取代，其中螺雙環基氧基和烷氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於螺[2.4]庚烷-2-氧基乙氧基，螺[2.4]庚烷-3-氧基丙氧基，螺[2.4]庚烷-4-氧基丙氧基，螺[4.4]壬烷-2-氧基乙氧基，螺[4.4]壬 烷-4-氧基丙氧基，4-氮雜螺[2.4]庚烷-5-氧基丙氧基等。 The term "spirobicyclooxyalkoxy" denotes that alkoxy is substituted by one or more spirobicyclooxy groups, wherein the spirobicyclooxy and alkoxy groups have the meanings as described herein Examples of such include, but are not limited to, spiro[2.4]heptane-2-oxyethoxy, spiro[2.4]heptane-3-oxypropoxy, spiro[2.4]heptane-4-oxo Propyloxy, spiro[4.4]decane-2-oxyethoxy, spiro[4.4]壬 Alkyl-4-oxypropoxy, 4-azaspiro[2.4]heptane-5-oxypropoxy and the like.
術語“螺雜雙環基氧基烷氧基”表示烷氧基被一個或多個螺雜雙環基氧基基團所取代，其中螺雜雙環基氧基和烷氧基基團具有如本發明所述的含義，這樣的實例包括，但並不限於4-氮雜螺[2.4]庚烷-5-基氧基乙氧基，4-氧雜螺[2.4]庚烷-5-基氧基乙氧基，5-氮雜螺[2.4]庚烷-5-基氧基乙氧基，4-氮雜螺[2.4]庚烷-5-基氧基丙氧基，4-氧雜螺[2.4]庚烷-5-基氧基丙氧基，5-氮雜螺[2.4]庚烷-5-基氧基丙氧基等等。 The term "spirobicyclooxyalkoxy" denotes that alkoxy is substituted by one or more spirobicyclooxy groups, wherein the spirobicyclooxy and alkoxy groups have the same as in the present invention Meaning of the description, such examples include, but are not limited to, 4-azaspiro[2.4]heptane-5-yloxyethoxy, 4-oxaspiro[2.4]heptane-5-yloxy B Oxy, 5-azaspiro[2.4]heptane-5-yloxyethoxy, 4-azaspiro[2.4]heptane-5-yloxypropoxy, 4-oxaspiro[2.4 Heptane-5-yloxypropoxy, 5-azaspiro[2.4]heptane-5-yloxypropoxy and the like.
術語“螺雙環基氨基烷氧基”表示烷氧基被一個或多個螺雙環基氨基所取代，其中烷氧基和螺雙環基氨基具有如本發明所述的含義，這樣的實例包括，但並不限於螺[2.4]庚烷-2-氨基乙氧基，螺[2.4]庚烷-3-氨基丙氧基，螺[2.4]庚烷-4-氨基乙氧基，螺[4.4]壬烷-2-氨基乙氧基，螺[4.4]壬烷-4-氨基丙氧基，4-氮雜螺[2.4]庚烷-5-氨基丙氧基等。 The term "spirobicycloaminoalkoxy" denotes that alkoxy is substituted by one or more spirobicyclic amino groups, wherein alkoxy and spirobicycloamino have the meanings as described herein, such examples include, but Not limited to spiro[2.4]heptane-2-aminoethoxy, spiro[2.4]heptane-3-aminopropoxy, spiro[2.4]heptane-4-aminoethoxy, spiro[4.4]壬Alkyl-2-aminoethoxy, spiro[4.4]decane-4-aminopropoxy, 4-azaspiro[2.4]heptane-5-aminopropoxy and the like.
術語“螺雜雙環基氨基烷氧基”表示烷氧基被一個或多個螺雜雙環基氨基所取代，其中烷氧基和螺雜雙環基氨基具有如本發明所述的含義，這樣的實例包括，但並不限於4-氮雜螺[2.4]庚烷-5-基氨基乙氧基，4-氮雜螺[2.4]庚烷-2-基氨基丙氧基，4-氧雜螺[2.4]庚烷-5-基氨基乙氧基，5-氮雜螺[2.4]庚烷-5-基氨基丙氧基等。 The term "spirobicycloaminoalkoxy" denotes an alkoxy group substituted by one or more spirobicycloamino groups, wherein alkoxy and spirobicycloamino have the meanings as described herein, such an example Including, but not limited to, 4-azaspiro[2.4]heptane-5-ylaminoethoxy, 4-azaspiro[2.4]heptan-2-ylaminopropoxy, 4-oxaspiro[ 2.4] Heptane-5-ylaminoethoxy, 5-azaspiro[2.4]heptane-5-ylaminopropoxy and the like.
如本發明所描述的，取代基畫一個鍵連接到中心的環上形成的環體系(如下式所示)代表取代基可以在環上任何可取代的位置進行取代。例如，式a代表A環或B環上任何可能被取代的位置均可被取代，如式b所示。 As described herein, a ring system formed by a substituent attached to a central ring (shown below) represents a substituent which may be substituted at any substitutable position on the ring. For example, the formula a represents that any position on the A ring or the B ring that may be substituted may be substituted, as shown in formula b.
像本發明所描述的，環體系裡面虛線鍵代表一個雙鍵或單鍵。例如，式c的結構代表式d裡面的任何一種結構。 As described in the present invention, the dashed key in the ring system represents a double bond or a single bond. For example, the structure of equation c represents any of the structures in equation d.
如本發明所描述的，體系中有兩個連接點與分子其餘部分相連，例如，式e所示，表示既可以是E端也可以是E’端與分子其餘部分相連，即兩端的連接方式可以互換。 As described in the present invention, there are two connection points in the system which are connected to the rest of the molecule, for example, as shown in the formula e, which means that the E terminal or the E' end can be connected to the rest of the molecule, that is, the connection manner at both ends. Can be interchanged.
除非其他方面表明，本發明所描述的結構式包括所有的同分異構形式(如對映異構，非對映異構，和幾何異構(或構象異構))：例如含有不對稱中心的R、S構型，雙鍵的(Z)、(E)異構體，和(Z)、(E)的構象異構體。因此，本發明的化合物的單個立體化學異構體或其對映異構體，非對映異構體，或幾何異構體(或構象異構體)的混合物都屬於本發明的範圍。 Unless otherwise indicated, the structural formulae described herein include all isomeric forms (eg, enantiomeric, diastereomeric, and geometric (or conformational)): for example, containing asymmetric centers The R, S configuration, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers thereof, or mixtures of geometric isomers (or conformational isomers) are within the scope of the invention.
本發明所使用的術語“前藥”，代表一個化合物在體內轉化為式(I)、(IV)、(V)所示的化合物。這樣的轉化受前體藥物在血液中水解或在血液或組織中經酶轉化為母體結構的影響。本發明前體藥物類化合物可以是酯，在現有的發明中酯可以作為前體藥物的有苯酯類，脂肪族(C1-24)酯類，醯氧基甲基酯類，碳酸酯，氨基甲酸酯類和氨基酸酯類。例如本發明裡的一個化合物包含羥基，即可以將其醯化得到前體藥物形式的化合物。其他的前體藥物形式包括磷酸酯，如這些磷酸酯類化合物是經母體上的羥基磷酸化得到的。關於前體藥物完整的討論可以參考以下文獻：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs：Design and Clinical Applications,Nature Review Drug Discovery,2008,7, 255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。 The term "prodrug" as used in the present invention denotes a compound which is converted in vivo to a compound of formula (I), (IV), (V). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug-like compound of the present invention may be an ester. In the prior invention, the ester may be used as a prodrug of a phenyl ester, an aliphatic (C 1-24 ) ester, a decyloxymethyl ester, a carbonate, Carbamates and amino acid esters. For example, a compound of the invention comprises a hydroxyl group, i.e., it can be deuterated to give a compound in the form of a prodrug. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent. For a discussion of the completeness of prodrugs, refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 , J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery , 2008 , 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry , 2008 , 51, 2328-2345.
除非其他方面表明，本發明的化合物的所有互變異構形式都包含在本發明的範圍之內。另外，除非其他方面表明，本發明所描述的化合物的結構式包括一個或多個不同的原子的富集同位素。 Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. Additionally, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.
“代謝產物”是指具體的化合物或其鹽在體內通過代謝作用所得到的產物。一個化合物的代謝產物可以通過所屬領域公知的技術來進行鑒定，其活性可以通過如本發明所描述的那樣採用試驗的方法進行表徵。這樣的產物可以是通過給藥化合物經過氧化，還原，水解，醯氨化，脫醯氨作用，酯化，脫脂作用，酶裂解等等方法得到。相應地，本發明包括化合物的代謝產物，包括將本發明的化合物與哺乳動物充分接觸一段時間所產生的代謝產物。 "Metabolic product" refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, hydrazine, deamination, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
本發明中立體化學的定義和慣例的使用通常參考以下文獻：S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994．本發明的化合物可以包含不對稱中心或手性中心，因此存在不同的立體異構體。本發明的化合物所有的立體異構形式，包括但絕不限於，非對映體，對映異構體，阻轉異構體，和它們的混合物，如外消旋混合物，組成了本發明的一部分。很多有機化合物都以光學活性形式存在，即它們有能力旋轉平面偏振光的平面。在描述光學活性化合物時，首碼D、L或R、S用來表示分子手性中心的絕對構型。首碼d、l或(+)、(-)用來命名化合物平面偏振光旋轉的符號，(-)或l是指化合物是左旋的，首碼(+)或d是指化合物是右旋的。這些立體異構體的化學結構是相同的，但是它們的立體結構不一樣。特定的立體異構體可以是對映體，異構體的混合物通常稱為對映異構體混合物。50：50的對映體混合物被稱為外消旋混合物或外消旋體，這可能導致化學反應過程中沒有立體選擇性或立體定向性。術語“外消旋混合物”和“外消旋體”是指等摩爾的兩個對映異構體的混合物，缺乏光學活性。 The use of the definitions and conventions of stereochemistry in the present invention is generally referred to the following documents: SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. , "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994 . The compounds of the invention may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention. portion. Many organic compounds exist in optically active forms, that is, they have the ability to rotate planes of plane polarized light. In describing an optically active compound, the first code D, L or R, S is used to indicate the absolute configuration of the molecular chiral center. The first code d, l or (+), (-) is used to name the symbol of the rotation of the plane polarized light of the compound, (-) or l means that the compound is left-handed, and the first code (+) or d means that the compound is right-handed. . The chemical structures of these stereoisomers are the same, but their stereostructures are different. A particular stereoisomer can be an enantiomer, and a mixture of isomers is often referred to as a mixture of enantiomers. The 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lack optical activity.
術語“互變異構體”或“互變異構的形式”是指不同能量的結構的同分異構體可以通過低能壘互相轉化。例如質子互變異構體(即質子移變的互變 異構體)包括通過質子遷移的互變，如酮式-烯醇式和亞胺-烯胺的同分異構化作用。原子價(化合價)互變異構體包括重組成鍵電子的互變。 The term "tautomer" or "tautomeric form" means that the isomers of the structure of different energies can be converted into each other by a low energy barrier. For example, proton tautomers (ie, proton shifts) Isomers include interconversions by proton transfer, such as keto-enol and imine-enamine isomerization. The valence (valence) tautomer includes the interconversion of recombination bond electrons.
本發明所使用的“藥學上可接受的鹽”是指本發明的化合物的有機鹽和無機鹽。藥學上可接受的鹽在所屬領域是為我們所熟知的，如文獻：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66：1-19,1977.所記載的。藥學上可接受的無毒的酸形成的鹽包括，但並不限於，與氨基基團反應形成的無機酸鹽有鹽酸鹽，氫溴酸鹽，磷酸鹽，硫酸鹽，高氯酸鹽，和有機酸鹽如乙酸鹽，草酸鹽，馬來酸鹽，酒石酸鹽，檸檬酸鹽，琥珀酸鹽，丙二酸鹽，或通過書籍文獻上所記載的其他方法如離子交換法來得到這些鹽。其他藥學上可接受的鹽包括己二酸鹽，藻酸鹽，抗壞血酸鹽，天冬氨酸鹽，苯磺酸鹽，苯甲酸鹽，重硫酸鹽，硼酸鹽，丁酸鹽，樟腦酸鹽，樟腦磺酸鹽，環戊基丙酸鹽，二葡萄糖酸鹽，十二烷基硫酸鹽，乙磺酸鹽，甲酸鹽，反丁烯二酸鹽，葡庚糖酸鹽，甘油磷酸鹽，葡萄糖酸鹽，半硫酸鹽，庚酸鹽，己酸鹽，氫碘酸鹽，2-羥基-乙磺酸鹽，乳糖醛酸鹽，乳酸鹽，月桂酸鹽，月桂基硫酸鹽，蘋果酸鹽，丙二酸鹽，甲磺酸鹽，2-萘磺酸鹽，煙酸鹽，硝酸鹽，油酸鹽，棕櫚酸鹽，撲酸鹽，果膠酸鹽，過硫酸鹽，3-苯基丙酸鹽，苦味酸鹽，特戊酸鹽，丙酸鹽，硬脂酸鹽，硫氰酸鹽，對甲苯磺酸鹽，十一酸鹽，戊酸鹽，等等。通過適當的堿得到的鹽包括鹼金屬，鹼土金屬，銨和N+(C1-4烷基)4的鹽。本發明也擬構思了任何所包含N的基團的化合物所形成的季銨鹽。水溶性或油溶性或分散產物可以通過季銨化作用得到。鹼金屬或鹼土金屬鹽包括鈉，鋰，鉀，鈣，鎂，等等。藥學上可接受的鹽進一步包括適當的、無毒的銨，季銨鹽和抗平衡離子形成的胺陽離子，如鹵化物，氫氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。 The "pharmaceutically acceptable salt" as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and Organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods such as ion exchange methods described in the literature. . Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphorate , camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate , gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malic acid Salt, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-benzene Propionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by appropriate hydrazine include salts of alkali metals, alkaline earth metals, ammonium and N + (C 1-4 alkyl) 4 . The present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1- 8 sulfonate and aromatic sulfonate.
本發明的“溶劑化物”是指一個或多個溶劑分子與本發明的化合物所形成的締合物。形成溶劑化物的溶劑包括，但並不限於，水，異丙醇，乙醇，甲醇，二甲亞碸，乙酸乙酯，乙酸，氨基乙醇。術語“水合物”是指溶劑分子是水所形成的締合物。 "Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl hydrazine, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" means that the solvent molecule is an association formed by water.
術語“保護基團”或“Pg”是指一個取代基與別的官能團起反應的時候，通 常用來阻斷或保護特殊的功能性。例如，“氨基的保護基團”是指一個取代基與氨基基團相連來阻斷或保護化合物中氨基的功能性，合適的氨基保護基團包括乙醯基，三氟乙醯基，叔丁氧羰基(BOC)，苄氧羰基(CBZ)和9-芴亞甲氧羰基(Fmoc)。相似地，“羥基保護基團”是指羥基的取代基用來阻斷或保護羥基的功能性，合適的保護基團包括乙醯基和甲矽烷基。“羧基保護基團”是指羧基的取代基用來阻斷或保護羧基的功能性，一般的羧基保護基包括-CH2CH2SO2Ph，氰基乙基，2-(三甲基矽烷基)乙基，2-(三甲基矽烷基)乙氧基甲基，2-(對甲苯磺醯基)乙基，2-(對硝基苯磺醯基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。對於保護基團一般的描述可參考文獻：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005. The term "protecting group" or "Pg" refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups. For example, "protecting group of an amino group" means a substituent which is bonded to an amino group to block or protect the functionality of an amino group in a compound. Suitable amino protecting groups include ethenyl, trifluoroethylidene, tert-butyl Oxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of a hydroxy group. Suitable protecting groups include ethenyl and carbaryl. "Carboxy protecting group" means a substituent of a carboxy group used to block or protect the functionality of a carboxy group. Typical carboxy protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylnonane) Ethyl, 2-(trimethyldecyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(di Phenylphosphino)ethyl, nitroethyl, and the like. A general description of protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 ; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005 .
本發明提供一種化合物，或其藥物組合物，可以更加有效地阻止或治療人體或動物組織纖維化。一方面，本發明涉及一種如式(I)所示的化合物：
其中一些實施方案是，V1是N或CR1；V2是N或CR2；V3是N或CR3；V4是N或CR4；其中V1，V2，V3和V4至多有一個可以為N；X是一個鍵，或X為NR5，O，S，C1-10亞烷基，C2-10亞烯基，C2-10亞炔基，-R6-C(=Y)-，-R6-C(=Y)-O-，-R6-C(=Y)-N(R5)-，-R6-S(=O)t-，-R6-S(=O)t-N(R7)-，或-R6-Y-，其中t是1或2；Y是O或S；A為下述二價基團：亞雜環基，亞碳環基，亞稠合雙環基，亞稠合雜雙
環基，亞螺雙環基，亞螺雜雙環基，亞芳基或亞雜芳基；B為烷氧基，羥基取代的烷氧基，-NR7R7a，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)t-，R7S(=O)t-，R7-S(=O)t-N(R7a)-，C4-12碳環基，C4-12環烷基，雜環基，芳基，雜芳基，稠合雙環基，稠合雜雙環基，螺雙環基，或螺雜雙環基；或A，X和B可共同形成以下的子結構式(II)：
其中一些實施方案是，A獨立地為下述二價基團：C2-10亞雜環基，C3-10亞碳環基，C5-12亞稠合雙環基，C5-12亞稠合雜雙環基，C5-12亞螺雙環基，C5-12亞螺雜雙環基，C6-10亞芳基，或C1-9亞雜芳基。 In some embodiments, A is independently the divalent group: C 2-10 heterocyclylene, C 3-10 carbocyclylene, C 5-12 subfused bicyclic, C 5-12 A fused heterobicyclic group, a C 5-12 sirobicyclo group, a C 5-12 spirobicyclo group, a C 6-10 arylene group, or a C 1-9 heteroarylene group.
另外一些實施方案是，A為以下的子結構式：
另外一些實施方案是，A為以下的子結構式：
另外一些實施方案是，A為以下的子結構式：
其中一些實施方案是，B獨立地為C1-6烷氧基，羥基取代的C1-6烷氧基，-NR7R7a，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)2-，R7S(=O)2-，R7S(=O)2N(R7a)-，C4-12碳環基，C4-12環烷基，C2-10雜環基，C6-10芳基，C1-9雜芳基，C5-12稠合雙環基，C5-12稠合雜雙環基，C5-12螺雙環基，或C5-12螺雜雙環基。 In some embodiments, B is independently C 1-6 alkoxy, hydroxy substituted C 1-6 alkoxy, -NR 7 R 7a , -C(=O)NR 7 R 7a , -OC(= O) NR 7 R 7a , -OC(=O)OR 7 , -N(R 7 )C(=O)NR 7 R 7a , -N(R 7 )C(=O)OR 7a , -N(R 7 ) C(=O)-R 7a , R 7 R 7a NS(=O) 2 -, R 7 S(=O) 2 -, R 7 S(=O) 2 N(R 7a )-, C 4 -12 carbocyclyl, C 4-12 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl, C 5-12 fused bicyclic, C 5-12 A fused heterobicyclic group, a C 5-12 spirobicyclic group, or a C 5-12 spirobicyclic group.
其中一些實施方案是，R1為H，F，Cl，Br，I，氰基，羥基，R7aR7N-，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)2-，R7S(=O)2-，R7S(=O)2N(R7a)-，R7aR7N-C1-6烷基，R7S(=O)-C1-6烷基，R7R7aN-C(=O)-C1-6烷基，R7aR7N-C1-6烷氧基，R7S(=O)-C1-6烷氧基，R7R7aN-C(=O)-C1-6烷氧基，C1-6脂肪族，C1-6烷氧基，C1-6羥基烷氧基，C1-6氨基烷氧基，C1-6羥基取代的氨基烷氧基，C1-6鹵代烷氧基，C1-6氨基取代的鹵代烷氧基，C1-6烷氨基C1-6鹵代烷氧基，羥基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6烷氧基，C1-6烷氧基C1-6烷氧基，C3-10環烷基氧基，C6-10芳基C1-6烷氧基，C6-10芳基C1-6烷氨基，C1-9雜芳基C1-6烷氧基，C1-9雜芳基C1-6烷氨基，C2-10雜環基C1-6烷氧基，C2-10雜環基C1-6烷氨基，C3-10環烷基氧基，C3-10環烷基氨基，C3-10碳環基C1-6烷氧基，C3-10碳環基C1-6烷氨基，C2-10雜環基(C1-6羥基烷氧基)，C3-10碳環基(C1-6羥基烷氧基)，C6-10芳基(C1-6羥基烷氧基)，C6-10芳氧基C1-6烷氧基，C6-10芳氧基，C1-9雜芳基氧基，C1-9雜芳基氧基C1-6烷氧基，C2-10 雜環基氧基C1-6烷氧基，C3-10碳環基氧基C1-6烷氧基，C2-10雜環基氧基，C1-6疊氮基烷氧基，C5-12稠合雙環基，C5-12稠合雜雙環基，C5-12稠合雙環基C1-6脂肪族，C5-12稠合雜雙環基C1-6脂肪族，C5-12稠合雙環基氧基，C5-12稠合雜雙環基氧基，C5-12稠合雙環基氨基，C5-12稠合雜雙環基氨基，C5-12稠合雙環基C1-6烷氧基，C5-12稠合雜雙環基C1-6烷氧基，C5-12稠合雙環基C1-6烷氨基，C5-12稠合雜雙環基C1-6烷氨基，C5-12稠合雙環基氧基C1-6烷氧基，C5-12稠合雜雙環基氧基C1-6烷氧基，C5-12稠合雙環基氨基C1-6烷氧基，C5-12稠合雜雙環基氨基C1-6烷氧基，C5-12稠合雙環基-C(=O)-，C5-12稠合雙環基-C(=O)O-，C5-12稠合雜雙環基-C(=O)-，C5-12稠合雜雙環基-C(=O)O-，C5-12稠合雙環基氨基-C(=O)-，C5-12稠合雜雙環基氨基-C(=O)-，C5-12稠合雙環基-C(=O)N(R7)-，C5-12稠合雜雙環基-C(=O)N(R7)-，C5-12螺雙環基，C5-12螺雜雙環基，C5-12螺雙環基C1-6脂肪族，C5-12螺雜雙環基C1-6脂肪族，C5-12螺雙環基氧基，C5-12螺雜雙環基氧基，C5-12螺雙環基氨基，C5-12螺雜雙環基氨基，C5-12螺雙環基C1-6烷氧基，C5-12螺雜雙環基C1-6烷氧基，C5-12螺雙環基C1-6烷氨基，C5-12螺雜雙環基C1-6烷氨基，C5-12螺雙環基氧基C1-6烷氧基，C5-12螺雜雙環基氧基C1-6烷氧基，C5-12螺雙環基氨基C1-6烷氧基，C5-12螺雜雙環基氨基C1-6烷氧基，C5-12螺雙環基-C(=O)-，C5-12螺雙環基-C(=O)O-，C5-12螺雜雙環基-C(=O)-，C5-12螺雜雙環基-C(=O)O-，C5-12螺雙環基氨基-C(=O)-，C5-12螺雜雙環基氨基-C(=O)-，C5-12螺雙環基-C(=O)N(R7)-，C5-12螺雜雙環基-C(=O)N(R7)-，C2-10雜環基，C3-10環烷基，C6-10芳基，C1-9雜芳基，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳基C1-6脂肪族，C1-9雜芳基C1-6脂肪族，C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-，其中G是O，S，NR5，S(=O)，S(=O)2，C(=O)，-C(=O)NH-，-OC(=O)NH-，-OC(=O)-，-NHC(=O)NH-，-HN-S(=O)t-，-OS(=O)t-，或-OS(=O)tNH-；t是1或2；p和m各自獨立地為0，1，2，3或4；或者其中C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-可以被一個或多個選自F，Cl，Br，I，C1-10烷基，C2-10烯基，C2-10炔基，C1-10烷氧基或氰基的取代基取代； R2為H，F，Cl，Br，I，氰基，羥基，R7aR7N-，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)2-，R7S(=O)2-，R7S(=O)2N(R7a)-，R7aR7N-C1-6烷基，R7S(=O)-C1-6烷基，R7R7aN-C(=O)-C1-6烷基，R7aR7N-C1-6烷氧基，R7S(=O)-C1-6烷氧基，R7R7aN-C(=O)-C1-6烷氧基，C1-6脂肪族，C1-6烷氧基，C1-6羥基烷氧基，C1-6氨基烷氧基，羥基取代的C1-6氨基烷氧基，C1-6鹵代烷氧基，氨基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6鹵代烷氧基，羥基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6烷氧基，C1-6烷氧基C1-6烷氧基，C3-10環烷基氧基，C6-10芳基C1-6烷氧基，C6-10芳基C1-6烷氨基，C1-9雜芳基C1-6烷氧基，C1-9雜芳基C1-6烷氨基，C2-10雜環基C1-6烷氧基，C2-10雜環基C1-6烷氨基，C3-10環烷基氨基，C3-10碳環基C1-6烷氧基，C3-10碳環基C1-6烷氨基，C2-10雜環基(C1-6羥基烷氧基)，C3-10碳環基(C1-6羥基烷氧基)，C6-10芳基(C1-6羥基烷氧基)，C6-10芳氧基C1-6烷氧基，C6-10芳氧基，C1-9雜芳基氧基，C1-9雜芳基氧基C1-6烷氧基，C2-10雜環基氧基C1-6烷氧基，C3-10碳環基氧基C1-6烷氧基，C2-10雜環基氧基，C1-6疊氮基烷氧基，C5-12稠合雙環基，C5-12稠合雜雙環基，C5-12稠合雙環基C1-6脂肪族，C5-12稠合雜雙環基C1-6脂肪族，C5-12稠合雙環基氧基，C5-12稠合雜雙環基氧基，C5-12稠合雙環基氨基，C5-12稠合雜雙環基氨基，C5-12稠合雙環基C1-6烷氧基，C5-12稠合雜雙環基C1-6烷氧基，C5-12稠合雙環基C1-6烷氨基，C5-12稠合雜雙環基C1-6烷氨基，C5-12稠合雙環基氧基C1-6烷氧基，C5-12稠合雜雙環基氧基C1-6烷氧基，C5-12稠合雙環基氨基C1-6烷氧基，C5-12稠合雜雙環基氨基C1-6烷氧基，C5-12稠合雙環基-C(=O)-，C5-12稠合雙環基-C(=O)O-，C5-12稠合雜雙環基-C(=O)-，C5-12稠合雜雙環基-C(=O)O-，C5-12稠合雙環基氨基-C(=O)-，C5-12稠合雜雙環基氨基-C(=O)-，C5-12稠合雙環基-C(=O)N(R7)-，C5-12稠合雜雙環基-C(=O)N(R7)-，C5-12螺雙環基，C5-12螺雜雙環基，C5-12螺雙環基C1-6脂肪族，C5-12螺雜雙環基C1-6脂肪族，C5-12螺雙環基氧基，C5-12螺雜雙環基氧基，C5-12螺雙環基氨基，C5-12螺雜雙環基氨基，C5-12螺雙環基C1-6烷氧基，C5-12螺雜雙環基C1-6烷氧基，C5-12螺雙環基C1-6烷氨基，C5-12螺雜雙環基C1-6烷氨基，C5-12螺雙環基氧基C1-6烷氧基，C5-12螺雜雙環基氧基C5-12烷氧基，C5-12螺雙環基氨基C1-6烷氧基，C5-12螺雜雙環基氨基C1-6烷氧基，C5-12螺雙 環基-C(=O)-，C5-12螺雙環基-C(=O)O-，C5-12螺雜雙環基-C(=O)-，C5-12螺雜雙環基-C(=O)O-，C5-12螺雙環基氨基-C(=O)-，C5-12螺雜雙環基氨基-C(=O)-，C5-12螺雙環基-C(=O)N(R7)-，C5-12螺雜雙環基-C(=O)N(R7)-，C2-10雜環基，C3-10環烷基，C6-10芳基，C1-4雜芳基，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳基C1-6脂肪族，C1-9雜芳基C1-6脂肪族，C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-，其中G是O，S，NR5，S(=O)，S(=O)2，C(=O)，-C(=O)NH-，-OC(=O)NH-，-OC(=O)-，-NHC(=O)NH-，-HN-S(=O)t-，-OS(=O)t-，或-OS(=O)tNH-；t是1或2；p和m各自獨立地為0，1，2，3或4；R3為H，F，Cl，I，氰基，R7aR7N-，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)2-，R7S(=O)2-，R7S(=O)2N(R7a)-，R7aR7N-C1-6烷基，R7S(=O)-C1-6烷基，R7R7aN-C(=O)-C1-6烷基，R7aR7N-C1-6烷氧基，R7S(=O)-C1-6烷氧基，R7R7aN-C(=O)-C1-6烷氧基，C1-6脂肪族，C2-10鹵代烷基，C6-10芳基-C2-10烷氧基，C1-9雜芳基-C3-6烷氧基，C3-10環烷基-C2-10烷氧基，C5-10稠合雙環基-C2-10烷氧基，C2-10雜環基，C3-10環烷基，C1-4雜芳基，取代的C6-10芳基，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C1-4雜芳基C1-6脂肪族，C1-9雜芳基氧基C1-6烷氧基，取代的C6-10芳基C3-6烷基，C2-10雜環基C1-6烷基，C1-6烷氧基，C1-6羥基烷氧基，C1-6氨基烷氧基，羥基取代的C1-6氨基烷氧基，C1-6鹵代烷氧基，氨基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6鹵代烷氧基，羥基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6烷氧基，C1-6烷氧基C1-6烷氧基，C6-10芳基-C2-10烷氧基，C2-10雜環基C1-6烷氧基，C3-10碳環基C1-6烷氧基，C2-10雜環基(C1-6羥基烷氧基)，C3-10碳環基(C1-6羥基烷氧基)，C6-10芳基(C1-6羥基烷氧基)，C6-10芳氧基C1-6烷氧基，C6-10芳氨基C1-6烷氧基，C6-10芳氧基，C2-10雜環基氧基C1-6烷氧基，C3-10碳環基氧基C1-6烷氧基，C2-10雜環基氧基，C3-10環烷基氧基，C1-6疊氮基烷氧基，C5-12稠合雙環基，C5-12稠合雜雙環基，C5-12稠合雙環基C1-6脂肪族，C5-12稠合雜雙環基C1-6脂肪族，C5-12稠合雙環基氧基，C5-12稠合雜雙環基氧基，C5-12稠合雙環基氨基，C5-12稠合雜雙環基氨基，C5-12稠合雙環基C1-6烷氧基，C5-12稠合雜 雙環基C1-6烷氧基，C5-12稠合雙環基C1-6烷氨基，C5-12稠合雜雙環基C1-6烷氨基，C5-12稠合雙環基氧基C1-6烷氧基，C5-12稠合雜雙環基氧基C1-6烷氧基，C5-12稠合雙環基氨基C1-6烷氧基，C5-12稠合雜雙環基氨基C1-6烷氧基，C5-12稠合雙環基-C(=O)-，C5-12稠合雙環基-C(=O)O-，C5-12稠合雜雙環基-C(=O)-，C5-12稠合雜雙環基-C(=O)O-，C5-12稠合雙環基氨基-C(=O)-，C5-12稠合雜雙環基氨基-C(=O)-，C5-12稠合雙環基-C(=O)NR7-，C5-12稠合雜雙環基-C(=O)NR7-，C5-12螺雙環基，C5-12螺雜雙環基，C5-12螺雙環基C1-6脂肪族，C5-12螺雜雙環基C1-6脂肪族，C5-12螺雙環基氧基，C5-12螺雜雙環基氧基，C5-12螺雙環基氨基，C5-12螺雜雙環基氨基，C5-12螺雙環基C1-6烷氧基，C5-12螺雜雙環基C1-6烷氧基，C5-12螺雙環基C1-6烷氨基，C5-12螺雜雙環基C1-6烷氨基，C5-12螺雙環基氧基C1-6烷氧基，C5-12螺雜雙環基氧基C1-6烷氧基，C5-12螺雙環基氨基C1-6烷氧基，C5-12螺雜雙環基氨基C1-6烷氧基，C5-12螺雙環基-C(=O)-，C5-12螺雙環基-C(=O)O-，C5-12螺雜雙環基-C(=O)-，C5-12螺雜雙環基-C(=O)O-，C5-12螺雙環基氨基-C(=O)-，C5-12螺雜雙環基氨基-C(=O)-，C5-12螺雙環基-C(=O)NR7-，C5-12螺雜雙環基-C(=O)NR7-，C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-，其中G是O，S，NR5，S(=O)，S(=O)2，C(=O)，-C(=O)NH-，-OC(=O)NH-，-OC(=O)-，-NHC(=O)NH-，-HN-S(=O)t-，-OS(=O)t-，或-OS(=O)tNH-；t是1或2；p和m各自獨立地為0，1，2，3或4；R4為H，F，I，氰基，羥基，R7aR7N-，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)-，R7S(=O)-，R7S(=O)N(R7a)-，R7aR7N-C1-6烷基，R7S(=O)-C1-6烷基，R7R7aN-C(=O)-C1-6烷基，R7aR7N-C1-6烷氧基，R7S(=O)-C1-6烷氧基，R7R7aN-C(=O)-C1-6烷氧基，C1-6脂肪族，C2-10烷氧基，C1-6羥基烷氧基，C1-6氨基烷氧基，羥基取代的C1-6氨基烷氧基，C1-6鹵代烷氧基，氨基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6鹵代烷氧基，羥基取代的C1-6鹵代烷氧基，C1-6烷氨基C1-6烷氧基，C1-6烷氧基C1-6烷氧基，C3-5環烷基氧基，C6-10芳基C1-6烷氧基，C1-9雜芳基C1-6烷氧基，C1-9雜芳基C1-6烷氨基，C2-10雜環基C1-6烷氧基，C2-10雜環基C1-6烷氨基，C7-10環烷基氧基，C3-10環烷基氨基， C3-10碳環基C1-6烷氧基，C3-10碳環基C1-6烷氨基，C2-10雜環基(C1-6羥基烷氧基)，C3-10碳環基(C1-6羥基烷氧基)，C6-10芳基(C1-6羥基烷氧基)，C6-10芳氧基C1-6烷氧基，C6-10芳氧基，C1-9雜芳基氧基，C1-9雜芳基氧基C1-6烷氧基，C2-10雜環基氧基C1-6烷氧基，C3-10碳環基氧基C1-6烷氧基，C2-10雜環基氧基，C1-6疊氮基烷氧基，C5-12稠合雙環基，C5-12稠合雜雙環基，C5-12稠合雙環基C1-6脂肪族，C5-12稠合雜雙環基C1-6脂肪族，C5-12稠合雙環基氧基，C5-12稠合雜雙環基氧基，C5-12稠合雙環基氨基，C5-12稠合雜雙環基氨基，C5-12稠合雙環基C1-6烷氧基，C5-12稠合雜雙環基C1-6烷氧基，C5-12稠合雙環基C1-6烷氨基，C5-12稠合雜雙環基C1-6烷氨基，C5-12稠合雙環基氧基C1-6烷氧基，C5-12稠合雜雙環基氧基C1-6烷氧基，C5-12稠合雙環基氨基C1-6烷氧基，C5-12稠合雜雙環基氨基C1-6烷氧基，C5-12稠合雙環基-C(=O)-，C5-12稠合雙環基-C(=O)O-，C5-12稠合雜雙環基-C(=O)-，C5-12稠合雜雙環基-C(=O)O-，C5-12稠合雙環基氨基-C(=O)-，C5-12稠合雜雙環基氨基-C(=O)-，C5-12稠合雙環基-C(=O)NR7-，C5-12稠合雜雙環基-C(=O)NR7-，C5-12螺雙環基，C5-12螺雜雙環基，C5-12螺雙環基C1-6脂肪族，C5-12螺雜雙環基C1-6脂肪族，C5-12螺雙環基氧基，C5-12螺雜雙環基氧基，C5-12螺雙環基氨基，C5-12螺雜雙環基氨基，C5-12螺雙環基C1-6烷氧基，C5-12螺雜雙環基C1-6烷氧基，C5-12螺雙環基C1-6烷氨基，C5-12螺雜雙環基C1-6烷氨基，C5-12螺雙環基氧基C1-6烷氧基，C5-12螺雜雙環基氧基C1-6烷氧基，C5-12螺雙環基氨基C1-6烷氧基，C5-12螺雜雙環基氨基C1-6烷氧基，C5-12螺雙環基-C(=O)-，C5-12螺雙環基-C(=O)O-，C5-12螺雜雙環基-C(=O)-，C5-12螺雜雙環基-C(=O)O-，C5-12螺雙環基氨基-C(=O)-，C5-12螺雜雙環基氨基-C(=O)-，C5-12螺雙環基-C(=O)N(R7)-，C5-12螺雜雙環基-C(=O)N(R7)-，C2-10雜環基，C3-10環烷基，C6-10芳基，C1-9雜芳基，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳基C2-6脂肪族，C1-9雜芳基C1-6脂肪族，C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-，其中G是O，S，NR5，S(=O)，S(=O)2，C(=O)，-C(=O)NH-，-OC(=O)NH-，-OC(=O)-，-NHC(=O)NH-，-HN-S(=O)t-，-OS(=O)t-，或-OS(=O)tNH-；t是1或2；p和m各自獨立地為0，1，2，3或4。 In some embodiments, R 1 is H, F, Cl, Br, I, cyano, hydroxy, R 7a R 7 N-, -C(=O)NR 7 R 7a , -OC(=O)NR 7 R 7a , -OC(=O)OR 7 , -N(R 7 )C(=O)NR 7 R 7a , -N(R 7 )C(=O)OR 7a , -N(R 7 )C( =O)-R 7a , R 7 R 7a NS(=O) 2 -,R 7 S(=O) 2 -,R 7 S(=O) 2 N(R 7a )-,R 7a R 7 NC 1 -6 alkyl, R 7 S(=O)-C 1-6 alkyl, R 7 R 7a NC(=O)-C 1-6 alkyl, R 7a R 7 NC 1-6 alkoxy, R 7 S(=O)-C 1-6 alkoxy, R 7 R 7a NC(=O)-C 1-6 alkoxy, C 1-6 aliphatic, C 1-6 alkoxy, C 1 -6 hydroxyalkoxy, C 1-6 aminoalkoxy, C 1-6 hydroxy substituted aminoalkoxy, C 1-6 haloalkoxy, C 1-6 amino substituted haloalkoxy, C 1- 6 alkylamino C 1-6 haloalkoxy, hydroxy substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy , C 3-10 cycloalkyloxy, C 6-10 aryl C 1-6 alkoxy, C 6-10 aryl C 1-6 alkylamino, C 1-9 heteroaryl C 1-6 alkane Oxy, C 1-9 heteroaryl C 1-6 alkylamino, C 2-10 heterocyclyl C 1-6 alkoxy, C 2-10 heterocyclyl C 1-6 alkylamino, C 3-10 cycloalkyl group, C 3-10 cycloalkyl Amino group, C 3-10 carbon ring group C 1-6 alkoxy, C 3-10 carbocyclyl, C 1-6 alkylamino, C 2-10 heterocyclyl (C 1-6 hydroxyalkoxy), C 3-10 carbocyclyl (C 1-6 hydroxyalkoxy), C 6-10 aryl (C 1-6 hydroxyalkoxy), C 6-10 aryloxy C 1-6 alkoxy, C 6-10 aryloxy, C 1-9 heteroaryloxy, C 1-9 heteroaryloxy C 1-6 alkoxy, C 2-10 heterocyclyloxy C 1-6 alkoxy , C 3-10 carbocyclyloxy C 1-6 alkoxy, C 2-10 heterocyclyloxy, C 1-6 azidoalkoxy, C 5-12 fused bicyclic, C 5-12 fused heterobicyclic group, C 5-12 fused bicyclic C 1-6 aliphatic, C 5-12 fused heterobicyclic C 1-6 aliphatic, C 5-12 fused bicyclic oxy , C 5-12 fused heterobicycloyloxy, C 5-12 fused bicyclic amino group, C 5-12 fused heterobicyclic amino group, C 5-12 fused bicyclic C 1-6 alkoxy group, C 5-12 fused heterobicyclic C 1-6 alkoxy, C 5-12 fused bicyclic C 1-6 alkylamino, C 5-12 fused heterobicyclic C 1-6 alkylamino, C 5 -12 fused bicyclic oxy C 1-6 alkoxy, C 5-12 fused heterobicyclo oxy C 1-6 alkoxy, C 5-12 fused bicyclic amino C 1-6 alkoxy Base, C 5-12 fused heterobicyclic ring Alkylamino C 1-6 alkoxy, C 5-12 fused bicyclo-C(=O)-, C 5-12 fused bicyclo-C(=O)O-, C 5-12 fused Bicyclo-C(=O)-, C 5-12 fused heterobicyclo-C(=O)O-, C 5-12 fused bicyclic amino-C(=O)-, C 5-12 thick Heterobicycloamino-C(=O)-, C 5-12 fused bicyclo-C(=O)N(R 7 )-, C 5-12 fused heterobicyclo-C(=O)N (R 7 )-, C 5-12 spirobicyclo, C 5-12 spirobicyclo, C 5-12 spirobicyclic C 1-6 aliphatic, C 5-12 spiro bicyclic C 1-6 fat Family, C 5-12 spirobicycloyloxy, C 5-12 spirobicycloyloxy, C 5-12 spirobicyclic amino, C 5-12 spirobicyclic amino, C 5-12 spirobicyclic C 1-6 alkoxy, C 5-12 spirobicyclo C 1-6 alkoxy, C 5-12 spirobicyclo C 1-6 alkylamino, C 5-12 spirobicyclo C 1-6 alkane Amino, C 5-12 spirobicyclooxy C 1-6 alkoxy, C 5-12 spirobicyclooxy C 1-6 alkoxy, C 5-12 spirobicycloamino C 1-6 alkane Oxy, C 5-12 spirobicycloamino C 1-6 alkoxy, C 5-12 spirobicyclo-C(=O)-, C 5-12 spirobicyclo-C(=O)O- , C 5-12 spirobicyclo-C(=O)-, C 5-12 spirobicyclo-C(=O)O-, C 5-12 spirobicyclo Amino-C(=O)-, C 5-12 spirobicycloamino-C(=O)-, C 5-12 spirobicyclo-C(=O)N(R 7 )-, C 5-12 Spirobicyclo-C(=O)N(R 7 )-, C 2-10 heterocyclyl, C 3-10 cycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, C 2 -10 heterocyclyl C 1-6 aliphatic, C 3-10 cycloalkyl C 1-6 aliphatic, C 6-10 aryl C 1-6 aliphatic, C 1-9 heteroaryl C 1-6 Aliphatic, C 6-10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C 1-9 heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, C 2 -10 heterocyclyl group - (CH 2) p -G- ( CH 2) m -, C 3-10 cycloalkyl or - (CH 2) p -G- ( CH 2) m -, wherein G is O, S, NR 5 , S(=O), S(=O) 2 , C(=O), -C(=O)NH-, -OC(=O)NH-, -OC(=O)-, -NHC (= O) NH -, - HN-S (= O) t -, - OS (= O) t -, or -OS (= O) t NH-; t is 1 or 2; p and m are each Independently 0, 1, 2, 3 or 4; or wherein C 6-10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C 1-9 heteroaryl-(CH 2 ) p -G-(CH 2 ) m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 ) m -, or C 3-10 cycloalkyl-(CH 2 ) p -G- (CH 2 ) m - may be one or more selected from the group consisting of F, Cl, Br, I, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy Or cyano Substituent group; R 2 is H, F, Cl, Br, I, cyano, hydroxy, R 7a R 7 N -, - C (= O) NR 7 R 7a, -OC (= O) NR 7 R 7a, -OC(=O)OR 7 , -N(R 7 )C(=O)NR 7 R 7a , -N(R 7 )C(=O)OR 7a , -N(R 7 )C(=O) -R 7a , R 7 R 7a NS(=O) 2 -,R 7 S(=O) 2 -,R 7 S(=O) 2 N(R 7a )-,R 7a R 7 NC 1-6 alkane Base, R 7 S(=O)-C 1-6 alkyl, R 7 R 7a NC(=O)-C 1-6 alkyl, R 7a R 7 NC 1-6 alkoxy, R 7 S ( =O)-C 1-6 alkoxy, R 7 R 7a NC(=O)-C 1-6 alkoxy, C 1-6 aliphatic, C 1-6 alkoxy, C 1-6 hydroxy Alkoxy, C 1-6 aminoalkoxy, hydroxy substituted C 1-6 aminoalkoxy, C 1-6 haloalkoxy, amino substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 haloalkoxy, hydroxy-substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 3 -10 cycloalkyloxy, C 6-10 aryl C 1-6 alkoxy, C 6-10 aryl C 1-6 alkylamino, C 1-9 heteroaryl C 1-6 alkoxy, C 1-9heteroaryl C 1-6 alkylamino, C 2-10 heterocyclyl C 1-6 alkoxy, C 2-10 heterocyclyl C 1-6 alkylamino, C 3-10 cycloalkyl Amino group, C 3-10 carbocyclic C 1-6 alkoxy Base, C 3-10 carbocyclyl C 1-6 alkylamino, C 2-10 heterocyclyl (C 1-6 hydroxyalkoxy), C 3-10 carbocyclyl (C 1-6 hydroxy alkoxy) ), C 6-10 aryl (C 1-6 hydroxyalkoxy), C 6-10 aryloxy C 1-6 alkoxy, C 6-10 aryloxy, C 1-9 heteroaryloxy Base, C 1-9 heteroaryloxy C 1-6 alkoxy, C 2-10 heterocyclyloxy C 1-6 alkoxy, C 3-10 carbocyclyloxy C 1-6 alkane Oxy, C 2-10 heterocyclyloxy, C 1-6 azidoalkoxy, C 5-12 fused bicyclic, C 5-12 fused heterobicyclic, C 5-12 fused bicyclic a C 1-6 aliphatic, C 5-12 fused heterobicyclic C 1-6 aliphatic, C 5-12 fused bicyclic oxy, C 5-12 fused heterobicyclooxy, C 5 12 fused bicyclic amino group, C 5-12 fused heterobicyclic amino group, C 5-12 fused bicyclic C 1-6 alkoxy group, C 5-12 fused heterobicyclic C 1-6 alkoxy group , C 5-12 fused bicyclic C 1-6 alkylamino, C 5-12 fused heterobicyclic C 1-6 alkylamino, C 5-12 fused bicyclic oxy C 1-6 alkoxy, C 5-12 fused heterobicyclooxy C 1-6 alkoxy, C 5-12 fused bicyclic amino C 1-6 alkoxy, C 5-12 fused heterobicyclic amino C 1-6 alkoxy, C 5-12 fused Cycloalkyl group -C (= O) -, C 5-12 fused bicyclic group -C (= O) O-, C 5-12 fused bicyclic heteroaryl group -C (= O) -, C 5-12 fused Heterobicyclo-C(=O)O-, C 5-12 fused bicyclic amino-C(=O)-, C 5-12 fused heterobicyclic amino-C(=O)-, C 5- 12 fused bicyclic group -C(=O)N(R 7 )-, C 5-12 fused heterobicyclo-C(=O)N(R 7 )-, C 5-12 spirobicyclo, C 5 -12 spirobicyclo, C 5-12 spirobicyclic C 1-6 aliphatic, C 5-12 spirobicyclo C 1-6 aliphatic, C 5-12 spirobicyclooxy, C 5-12 Spirobicyclooxy, C 5-12 spirobicyclic amino, C 5-12 spirobicyclic amino, C 5-12 spirobicyclic C 1-6 alkoxy, C 5-12 spiro bicyclo C 1-6 alkoxy, C 5-12 spirobicyclo C 1-6 alkylamino, C 5-12 spirobicyclo C 1-6 alkylamino, C 5-12 spirobicyclooxy C 1-6 alkane Oxy, C 5-12 spirobicyclooxy C 5-12 alkoxy, C 5-12 spirobicycloamino C 1-6 alkoxy, C 5-12 spirobicycloamino C 1-6 Alkoxy, C 5-12 spirobicyclo-C(=O)-, C 5-12 spirobicyclo-C(=O)O-, C 5-12 spirobicyclo-C(=O)- , C 5-12 spiro bicyclic heteroaryl group -C (= O) O-, C 5-12 bicyclic spiro amino group -C (= O) -, C 5-12 spiro bicyclic heteroaryl group Group -C (= O) -, C 5-12 bicyclic spiro group -C (= O) N (R 7) -, C 5-12 spiro bicyclic heteroaryl group -C (= O) N (R 7) -, C 2-10 heterocyclic group, C 3-10 cycloalkyl group, C 6-10 aryl group, C 1-4 heteroaryl group, C 2-10 heterocyclic group C 1-6 aliphatic, C 3-10 ring Alkyl C 1-6 aliphatic, C 6-10 aryl C 1-6 aliphatic, C 1-9 heteroaryl C 1-6 aliphatic, C 6-10 aryl-(CH 2 ) p -G -(CH 2 ) m -,C 1-9heteroaryl- (CH 2 ) p -G-(CH 2 ) m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 m -, or C 3-10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m -, wherein G is O, S, NR 5 , S(=O), S(=O) 2 , C(=O), -C(=O)NH-, -OC(=O)NH-, -OC(=O)-, -NHC(=O)NH-,-HN-S(=O) t -, -OS(=O) t -, or -OS(=O) t NH-;t is 1 or 2; p and m are each independently 0,1,2,3 or 4; R 3 is H , F, Cl, I, cyano, R 7a R 7 N-, -C(=O)NR 7 R 7a , -OC(=O)NR 7 R 7a , -OC(=O)OR 7 ,-N (R 7 )C(=O)NR 7 R 7a , -N(R 7 )C(=O)OR 7a , -N(R 7 )C(=O)-R 7a ,R 7 R 7a NS(= O) 2 -, R 7 S(=O) 2 -, R 7 S(=O) 2 N(R 7a )-, R 7a R 7 NC 1-6 alkyl, R 7 S(=O)-C 1-6 alkyl, R 7 R 7a NC(=O)-C 1-6 alkyl, R 7a R 7 NC 1-6 alkoxy, R 7 S (=O)-C 1-6 alkoxy, R 7 R 7a NC(=O)-C 1-6 alkoxy, C 1-6 aliphatic, C 2-10 haloalkyl, C 6-10 aryl -C 2-10 alkoxy, C 1-9heteroaryl -C 3-6 alkoxy, C 3-10 cycloalkyl-C 2-10 alkoxy, C 5-10 fused bicyclic -C 2-10 alkoxy, C 2-10 heterocyclyl, C 3-10 cycloalkyl, C 1-4 heteroaryl, substituted C 6-10 aryl, C 2-10 heterocyclyl C 1-6 aliphatic, C 3-10 cycloalkyl C 1-6 aliphatic, C 1-4 heteroaryl C 1-6 aliphatic, C 1-9 heteroaryloxy C 1-6 alkoxy , substituted C 6-10 aryl C 3-6 alkyl, C 2-10 heterocyclyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxy alkoxy, C 1- 6 aminoalkoxy, hydroxy substituted C 1-6 aminoalkoxy, C 1-6 haloalkoxy, amino substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 haloalkoxy , hydroxy-substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 6-10 aryl-C 2 -10 alkoxy, C 2-10 heterocyclyl C 1-6 alkoxy, C 3-10 carbocyclyl C 1-6 alkoxy, C 2-10 heterocyclyl (C 1-6 hydroxy alkane alkoxy), C 3-10 carbocyclyl (C 1-6 hydroxyalkoxy), C 6-10 aryl (C 1-6 hydroxyalkyl Alkoxy), C 6-10 aryl-C 1-6 alkoxy, C 6-10 aryl-amino-C 1-6 alkoxy, C 6-10 aryloxy, C 2-10 heterocyclyl-yloxy Alkyl C 1-6 alkoxy, C 3-10 carbocyclyloxy C 1-6 alkoxy, C 2-10 heterocyclyloxy, C 3-10 cycloalkyloxy, C 1-6 Azidoalkoxy, C 5-12 fused bicyclic, C 5-12 fused heterobicyclic, C 5-12 fused bicyclic C 1-6 aliphatic, C 5-12 fused heterobicyclic C 1-6 aliphatic, C 5-12 fused bicyclic oxy, C 5-12 fused heterobicyclooxy, C 5-12 fused bicyclic amino, C 5-12 fused heterobicyclic amino , C 5-12 fused bicyclic C 1-6 alkoxy, C 5-12 fused heterobicyclic C 1-6 alkoxy, C 5-12 fused bicyclic C 1-6 alkylamino, C 5-12 fused heterobicyclic C 1-6 alkylamino, C 5-12 fused bicyclic oxy C 1-6 alkoxy, C 5-12 fused heterobicyclo oxy C 1-6 alkoxy a C 5-12 fused bicyclic amino C 1-6 alkoxy group, a C 5-12 fused heterobicyclic amino C 1-6 alkoxy group, a C 5-12 fused bicyclic group-C (=O) -, C 5-12 fused bicyclo-C(=O)O-, C 5-12 fused heterobicyclo-C(=O)-, C 5-12 fused heterobicyclo-C (= O) O-, C 5-12 fused bicyclic amino group -C (= O) -, C 5-12 fused bicyclic heteroaryl group -C (= O) -, C 5-12 fused bicyclic group -C (= O) NR 7 - , C 5-12 fused Heterobicyclo-C(=O)NR 7 -, C 5-12 spirobicyclo, C 5-12 spirobicyclo, C 5-12 spirobicyclic C 1-6 aliphatic, C 5-12 spiro Bicyclic C 1-6 aliphatic, C 5-12 spirobicycloyloxy, C 5-12 spirobicycloyloxy, C 5-12 spirobicyclic amino, C 5-12 spirobicyclic amino, C 5-12 spirobicyclo C 1-6 alkoxy, C 5-12 spirobicyclo C 1-6 alkoxy, C 5-12 spirobicyclo C 1-6 alkylamino, C 5-12 spiro Bicyclic C 1-6 alkylamino, C 5-12 spirobicyclooxy C 1-6 alkoxy, C 5-12 spirobicyclooxy C 1-6 alkoxy, C 5-12 spiro bicyclo Alkylamino C 1-6 alkoxy, C 5-12 spirobicycloamino C 1-6 alkoxy, C 5-12 spirobicyclo-C(=O)-, C 5-12 spirobicyclo- C(=O)O-, C 5-12 spirobicyclo-C(=O)-, C 5-12 spirobicyclo-C(=O)O-, C 5-12 spirobicycloamino- C(=O)-, C 5-12 spirobicycloamino-C(=O)-, C 5-12 spirobicyclo-C(=O)NR 7 -, C 5-12 spirobicyclo- C(=O)NR 7 -,C 6-10 aryl-(CH 2 ) p -G-(CH 2 ) m -,C 1-9heteroaryl- (CH 2 ) p - G-(CH 2 ) m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 ) m -, or C 3-10 cycloalkyl-(CH 2 ) p -G-( CH 2 ) m -, where G is O, S, NR 5 , S(=O), S(=O) 2 , C(=O), -C(=O)NH-, -OC(=O) NH -, - OC (= O ) -, - NHC (= O) NH -, - HN-S (= O) t -, - OS (= O) t -, or -OS (= O) t NH- ;t is 1 or 2; p and m are each independently 0,1,2,3 or 4; R 4 is H,F,I,cyano,hydroxy,R 7a R 7 N-,-C(=O )NR 7 R 7a , -OC(=O)NR 7 R 7a , -OC(=O)OR 7 , -N(R 7 )C(=O)NR 7 R 7a , -N(R 7 )C( =O)OR 7a , -N(R 7 )C(=O)-R 7a , R 7 R 7a NS(=O)-, R 7 S(=O)-, R 7 S(=O)N( R 7a )-, R 7a R 7 NC 1-6 alkyl, R 7 S(=O)-C 1-6 alkyl, R 7 R 7a NC(=O)-C 1-6 alkyl, R 7a R 7 NC 1-6 alkoxy, R 7 S(=O)-C 1-6 alkoxy, R 7 R 7a NC(=O)-C 1-6 alkoxy, C 1-6 aliphatic , C 2-10 alkoxy, C 1-6 hydroxyalkoxy, C 1-6 aminoalkoxy, hydroxy substituted C 1-6 aminoalkoxy, C 1-6 haloalkoxy, amino substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 haloalkoxy, hydroxy substituted C 1-6 haloalkoxy, C 1-6 alkylamino C 1-6 alkoxy, C 1- 6 alkoxy C 1-6 alkoxy group, C 3-5 cycloalkyl group, C 6-10 aryl C 1-6 alkoxy, C 1-9 heteroaryl-C 1-6 alkoxy group, C 1 -9heteroaryl C 1-6 alkylamino, C 2-10 heterocyclyl C 1-6 alkoxy, C 2-10 heterocyclyl C 1-6 alkylamino, C 7-10 cycloalkyloxy , C 3-10 cycloalkylamino, C 3-10 carbocyclyl C 1-6 alkoxy, C 3-10 carbocyclic C 1-6 alkylamino, C 2-10 heterocyclyl (C 1- 6 hydroxyalkoxy), C 3-10 carbocyclyl (C 1-6 hydroxyalkoxy), C 6-10 aryl (C 1-6 hydroxyalkoxy), C 6-10 aryloxy C 1-6 alkoxy, C 6-10 aryloxy, C 1-9 heteroaryloxy, C 1-9 heteroaryloxy C 1-6 alkoxy, C 2-10 heterocyclooxy Alkyl C 1-6 alkoxy, C 3-10 carbocyclyloxy C 1-6 alkoxy, C 2-10 heterocyclyloxy, C 1-6 azidoalkoxy, C 5- 12 fused bicyclic group, C 5-12 fused heterobicyclic group, C 5-12 fused bicyclic C 1-6 aliphatic, C 5-12 fused heterobicyclic C 1-6 aliphatic, C 5- 12 fused bicyclic oxy, C 5-12 fused heterobicyclooxy, C 5-12 fused bicyclic amino, C 5-12 fused heterobicyclic amino, C 5-12 fused bicyclic C 1-6 alkoxy, C 5-12 fused heterobicyclic C 1-6 alkoxy, C 5-12 fused bicyclic C 1-6 alkylamino, C 5-12 fused heterobicyclic C 1-6 alkylamino, C 5-12 fused bicyclic oxy C 1-6 alkoxy, C 5-12 fused heterobicyclooxy C 1-6 alkoxy, C 5-12 fused bicyclic amino C 1-6 alkoxy, C 5-12 fused heterobicyclic amino C 1-6 alkane Oxy, C 5-12 fused bicyclo-C(=O)-, C 5-12 fused bicyclo-C(=O)O-, C 5-12 fused heterobicyclic-C (=O -, C 5-12 fused heterobicyclo-C(=O)O-, C 5-12 fused bicyclic amino-C(=O)-, C 5-12 fused heterobicyclic amino-C (=O)-, C 5-12 fused bicyclo-C(=O)NR 7 -, C 5-12 fused heterobicyclo-C(=O)NR 7 -, C 5-12 spirobicyclo , C 5-12 spirobicyclo, C 5-12 spirobicyclic C 1-6 aliphatic, C 5-12 spirobicyclo C 1-6 aliphatic, C 5-12 spirobicyclooxy, C 5-12 spirobicyclooxy, C 5-12 spirobicyclic amino, C 5-12 spirobicyclic amino, C 5-12 spirobicyclo C 1-6 alkoxy, C 5-12 spiro Bicyclic C 1-6 alkoxy, C 5-12 spirobicyclo C 1-6 alkylamino, C 5-12 spirobicyclo C 1-6 alkylamino, C 5-12 spirobicyclooxy C 1 -6 alkoxy, C 5-12 bicyclic heteroaryl group spiro-C 1-6 alkyl Group, C 5-12 bicyclic spiro amino C 1-6 alkoxy group, C 5-12 bicyclic heteroaryl group spiro C 1-6 alkoxy, C 5-12 bicyclic spiro group -C (= O) -, C 5-12 spirobicyclo-C(=O)O-, C 5-12 spirobicyclo-C(=O)-, C 5-12 spirobicyclo-C(=O)O-, C 5-12 spirobicycloamino-C(=O)-, C 5-12 spirobicycloamino-C(=O)-, C 5-12 spirobicyclo-C(=O)N(R 7 ) -, C 5-12 spirobicyclo-C(=O)N(R 7 )-, C 2-10 heterocyclyl, C 3-10 cycloalkyl, C 6-10 aryl, C 1-9 Heteroaryl, C 2-10 heterocyclyl C 1-6 aliphatic, C 3-10 cycloalkyl C 1-6 aliphatic, C 6-10 aryl C 2-6 aliphatic, C 1-9 hetero Aryl C 1-6 aliphatic, C 6-10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C 1-9 heteroaryl-(CH 2 ) p -G-(CH 2 m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 ) m -, or C 3-10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m - Where G is O, S, NR 5 , S(=O), S(=O) 2 , C(=O), -C(=O)NH-, -OC(=O)NH-, -OC (= O) -, - NHC (= O) NH -, - HN-S (= O) t -, - OS (= O) t -, or -OS (= O) t NH-; t is 1 or 2; p and m are each independently 0, 1, 2, 3 or 4.
其中一些實施方案是，各R5獨立地為氫，R7R7aNC(=O)-，R7OC(=O)-，R7C(=O)-，R7R7aNS(=O)-，R7OS(=O)-，R7S(=O)-，R7R7aNS(=O)2-，R7OS(=O)2-，R7S(=O)2-，C1-6脂肪族，C1-6鹵代脂肪族，C1-6羥基脂肪族，C1-6氨基脂肪族，C1-6烷氧基C1-6脂肪族，C1-6烷氨基C1-6脂肪族，C1-6烷硫基C1-6脂肪族，C6-10芳基C1-6脂肪族，C1-9雜芳基C1-6脂肪族，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳氧基C1-6脂肪族，C2-10雜環基氧基C1-6脂肪族，C3-10環烷基氧基C1-6脂肪族，C6-10芳氨基C1-6脂肪族，C2-10雜環基氨基C1-6脂肪族，C3-10環烷基氨基C1-6脂肪族，C6-10芳基，C1-9雜芳基，C2-10雜環基或C3-10碳環基。 In some embodiments, each R 5 is independently hydrogen, R 7 R 7a NC(=O)-, R 7 OC(=O)-, R 7 C(=O)-, R 7 R 7a NS(= O)-, R 7 OS(=O)-, R 7 S(=O)-, R 7 R 7a NS(=O) 2 -, R 7 OS(=O) 2 -, R 7 S(=O 2 -, C 1-6 aliphatic, C 1-6 halogenated aliphatic, C 1-6 hydroxy aliphatic, C 1-6 amino aliphatic, C 1-6 alkoxy C 1-6 aliphatic, C 1-6 alkylamino C 1-6 aliphatic, C 1-6 alkylthio C 1-6 aliphatic, C 6-10 aryl C 1-6 aliphatic, C 1-9 heteroaryl C 1- 6 aliphatic, C 2-10 heterocyclic C 1-6 aliphatic, C 3-10 cycloalkyl C 1-6 aliphatic, C 6-10 aryloxy C 1-6 aliphatic, C 2-10 Heterocyclyloxy C 1-6 aliphatic, C 3-10 cycloalkyloxy C 1-6 aliphatic, C 6-10 arylamino C 1-6 aliphatic, C 2-10 heterocyclylamino C 1-6 aliphatic, C 3-10 cycloalkylamino C 1-6 aliphatic, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclic or C 3-10 carbocyclic base.
其中一些實施方案是，各R5a可以相同或不同，各自獨立地為H，羥基，氨基，F，Cl，Br，I，氰基，氧代(=O)，R7aR7N-，-C(=O)NR7R7a，-OC(=O)NR7R7a，-OC(=O)OR7，-N(R7)C(=O)NR7R7a，-N(R7)C(=O)OR7a，-N(R7)C(=O)-R7a，R7R7aN-S(=O)2-，R7S(=O)2-，R7S(=O)2N(R7a)-，R7aR7N-C1-6烷基，R7S(=O)-C1-6烷基，R7R7aN-C(=O)-C1-6烷基，R7aR7N-C1-6烷氧基，R7S(=O)-C1-6烷氧基，R7R7aN-C(=O)-C1-6烷氧基，C6-10芳基，C1-9雜芳基，C1-6烷氧基，C1-6烷基，C2-6烯基，C2-6炔基，C2-10雜環基，巰基，硝基，C6-10芳基C1-6烷基，C6-10芳基氨基，C1-9雜芳基氨基，C6-10芳基C1-6烷氨基，C1-9雜芳基C1-6烷氨基，C1-9雜芳基氧基，C1-9雜芳基C1-6烷基，C6-10芳基C1-6烷氧基，C1-9雜芳基C1-6烷氧基，C2-10雜環基氧基，C2-10雜環基C1-6烷氧基，C2-10雜環基氨基，C2-10雜環基C1-6烷氨基或C6-10芳氧基。 In some embodiments, each R 5a may be the same or different, each independently H, hydroxy, amino, F, Cl, Br, I, cyano, oxo (=O), R 7a R 7 N-,- C(=O)NR 7 R 7a , -OC(=O)NR 7 R 7a , -OC(=O)OR 7 , -N(R 7 )C(=O)NR 7 R 7a ,-N(R 7 ) C(=O)OR 7a , -N(R 7 )C(=O)-R 7a , R 7 R 7a NS(=O) 2 -,R 7 S(=O) 2 -,R 7 S (=O) 2 N(R 7a )-, R 7a R 7 NC 1-6 alkyl, R 7 S(=O)-C 1-6 alkyl, R 7 R 7a NC(=O)-C 1 -6 alkyl, R 7a R 7 NC 1-6 alkoxy, R 7 S(=O)-C 1-6 alkoxy, R 7 R 7a NC(=O)-C 1-6 alkoxy , C 6-10 aryl, C 1-9 heteroaryl, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-10 Cyclic, fluorenyl, nitro, C 6-10 aryl C 1-6 alkyl, C 6-10 arylamino, C 1-9 heteroarylamino, C 6-10 aryl C 1-6 alkylamino , C 1-9 heteroaryl C 1-6 alkylamino, C 1-9 heteroaryloxy, C 1-9 heteroaryl C 1-6 alkyl, C 6-10 aryl C 1-6 alkane Oxy, C 1-9 heteroaryl C 1-6 alkoxy, C 2-10 heterocyclyloxy, C 2-10 heterocyclyl C 1-6 alkoxy, C 2-10 heterocyclyl amino, C 2-10 heterocyclyl C 1-6 alkylamino or C 6-10 aryloxy .
其中一些實施方案是，各R7和R7a獨立地為H，C1-6脂肪族，C1-6鹵代脂肪族，C1-6羥基脂肪族，C1-6氨基脂肪族，C1-6烷氧基C1-6脂肪族，C1-6烷氨基C1-6脂肪族，C1-6烷硫基C1-6脂肪族，C6-10芳基C1-6脂肪族，C1-9雜芳基C1-6脂肪族，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳氧基C1-6脂肪族，C2-10雜環基氧基C1-6脂肪族，C3-10環烷基氧基C1-6脂肪族，C6-10芳氨基C1-6脂肪族，C2-10雜環基氨基C1-6脂肪族，C3-10環烷基氨基C1-6脂肪族，C6-10芳基，C1-9雜芳基，C2-10雜環基或C3-10碳環基：；當R7和R7a連在同一個氮原子上，R7，R7a和氮原子可以任意地形成取代或非取代的3-8元環，C5-12稠合雙環或C5-12螺雙環。 In some embodiments, each of R 7 and R 7a is independently H, C 1-6 aliphatic, C 1-6 haloaliphatic, C 1-6 hydroxyaliphatic, C 1-6 aminoaliphatic, C 1-6 alkoxy C 1-6 aliphatic, C 1-6 alkylamino C 1-6 aliphatic, C 1-6 alkylthio C 1-6 aliphatic, C 6-10 aryl C 1-6 Aliphatic, C 1-9 heteroaryl C 1-6 aliphatic, C 2-10 heterocyclic C 1-6 aliphatic, C 3-10 cycloalkyl C 1-6 aliphatic, C 6-10 aromatic Oxy C 1-6 aliphatic, C 2-10 heterocyclooxy C 1-6 aliphatic, C 3-10 cycloalkyloxy C 1-6 aliphatic, C 6-10 arylamino C 1- 6 aliphatic, C 2-10 heterocyclylamino C 1-6 aliphatic, C 3-10 cycloalkylamino C 1-6 aliphatic, C 6-10 aryl, C 1-9 heteroaryl, C 2-10heterocyclyl or C 3-10carbocyclyl : when R 7 and R 7a are bonded to the same nitrogen atom, R 7 , R 7a and the nitrogen atom may be optionally substituted or unsubstituted 3-8 Yuan ring, C 5-12 fused bicyclic or C 5-12 spiro bicyclic.
其中一些實施方案是，式(I)中的N，V1，V2，V3，V4和C(=Y)共同
所定義的子結構(III)為以下結構式：
其中一些實施方案是，式(I)中的N，V1，V2，V3，V4和C(=Y)共同所定義的子結構(III)為以下結構式：
其中一些實施方案是，A為以下的子結構式：
其中一些實施方案是，式(I)中的A，X和B可共同形成以下的子結構式(II)：
其中一些實施方案是，本發明涉及如式(IV)所示的化合物，
其中一些實施方案是，B為-N(CH3)2，-N(CH2CH3)2，-N(CH2CH2CH3)2，-N(CH2CH2CH2CH3)2，或B為以下子結構式：
其中一些實施方案是，本發明涉及如式(V)所示的化合物，
其中一些實施方案是，本發明涉及如式(VI)所示的化合物，
其中一些實施方案，R1獨立地為H，F，Cl，Br，I，氰基，羥基，甲基，乙基，丙基，異丙基，丁基，叔丁基，C6-8芳基-(CH2)p-G-(CH2)m-或C4-6雜芳基-(CH2)p-G-(CH2)m-，其中G是NR5，O或S，p和m各自獨立地選自0，1，2或3；或者其中C6-8芳基-(CH2)p-G-(CH2)m-或C4-6雜芳基-(CH2)p-G-(CH2)m-可以被一個或多個選自F，Cl，Br，甲基，乙基，丙基，乙炔基，丙炔基，丁炔基，甲氧基或者氰基的取代基取代；R3獨立地為H，F，Cl，I，氰基，羥基，甲基，乙基，丙基，異丙基，丁基，叔丁基，C6-8芳基-(CH2)p-G-(CH2)m-或C4-6雜芳基-(CH2)p-G-(CH2)m-，其中G是O或S，p和m各自獨立地選自0，1，2或3。 In some embodiments, R 1 is independently H, F, Cl, Br, I, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C 6-8 aryl -(CH 2 ) p -G-(CH 2 ) m - or C 4-6 heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, wherein G is NR 5 , O or S, p and m are each independently selected from 0, 1, 2 or 3; or wherein C 6-8 aryl-(CH 2 ) p -G-(CH 2 ) m - or C 4-6 heteroaryl-(CH) 2 ) p -G-(CH 2 ) m - may be selected from one or more selected from the group consisting of F, Cl, Br, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, methoxy or Substituted by a cyano substituent; R 3 is independently H, F, Cl, I, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C 6-8 -(CH 2 ) p -G-(CH 2 ) m - or C 4-6 heteroaryl-(CH 2 ) p -G-(CH 2 ) m - wherein G is O or S, p and m Each is independently selected from 0, 1, 2 or 3.
其中一些實施方案是，本發明涉及如式(VII)所示的化合物，
其中，R1為H，F，Cl，Br，I，氰基，羥基，C1-6烷基，C1-6鹵代烷基，C1-6烷氧基，C1-6羥基烷氧基，C1-6氨基烷氧基，C1-6鹵代烷氧基，C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-，其中G是O，S，NR5，C(=O)，-C(=O)NH-，-OC(=O)NH-，-OC(=O)-或-NHC(=O)NH-；p和m各自獨立地為0，1，2或3；或者其中C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基 -(CH2)p-G-(CH2)m-可以被一個或多個選自F，Cl，Br，I，乙基，丙基，乙烯基，丙烯基，乙炔基，丙炔基，丁炔基，甲氧基，乙氧基或氰基的取代基取代；R3為H，F，Cl，I，氰基，羥基，C1-6烷基，C1-6鹵代烷基，C1-6烷氧基，C1-6羥基烷氧基，C1-6氨基烷氧基，C1-6鹵代烷氧基，C6-10芳基-(CH2)p-G-(CH2)m-，C1-9雜芳基-(CH2)p-G-(CH2)m-，C2-10雜環基-(CH2)p-G-(CH2)m-，或C3-10環烷基-(CH2)p-G-(CH2)m-，其中G是O，S，NR5，C(=O)，-C(=O)NH-，-OC(=O)NH-，-OC(=O)-或-NHC(=O)NH-；p和m各自獨立地為0，1，2或3；各R5獨立地為氫，R7R7aNC(=O)-，R7OC(=O)-，R7C(=O)-，C1-3烷基，C1-3鹵代烷基，C1-3羥基烷基，C1-3氨基烷基，C1-3烷氧基C1-3烷基，C1-3烷氨基C1-3烷基，C1-3烷硫基C1-3烷基，C6-10芳基C1-3烷基，C1-9雜芳基C1-3烷基，C2-10雜環基C1-3烷基，C3-10環烷基C1-3烷基，C6-10芳基，C1-9雜芳基，C2-10雜環基或C3-10碳環基；各R7獨立地為H，C1-6烷基，C1-6鹵代脂肪族，C1-6羥基脂肪族，C1-6氨基脂肪族，C1-6烷氧基C1-6脂肪族，C1-6烷氨基C1-6脂肪族，C1-6烷硫基C1-6脂肪族，C6-10芳基C1-6脂肪族，C1-9雜芳基C1-6脂肪族，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳基，C1-9雜芳基，C2-10雜環基或C3-10碳環基；各R7a獨立地為C1-6烷基，C1-6鹵代脂肪族，C1-6羥基脂肪族，C1-6氨基脂肪族，C1-6烷氧基C1-6脂肪族，C1-6烷氨基C1-6脂肪族，C1-6烷硫基C1-6脂肪族，C6-10芳基C1-6脂肪族，C1-9雜芳基C1-6脂肪族，C2-10雜環基C1-6脂肪族，C3-10環烷基C1-6脂肪族，C6-10芳基，C1-9雜芳基，C2-10雜環基或C3-10碳環基；當R7和R7a連在同一個氮原子上，R7，R7a和氮原子可以任意地形成取代或非取代的3-8元環；各R8a可以相同或不同，各自獨立地為H，羥基，氨基，F，Cl，Br，I，-N(CH3)2，氰基，硝基，巰基，C1-4烷基，三氟甲基，C1-4烷氧基，C1-4烷氨 基，C1-4烷硫基，C6-10芳基，C6-10芳基C1-4烷基或C1-9雜芳基；和n是0，1，2或3。 Wherein R 1 is H, F, Cl, Br, I, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxy alkoxy , C 1-6 aminoalkoxy, C 1-6 haloalkoxy, C 6-10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C 1-9 heteroaryl-(CH 2 ) p -G-(CH 2 ) m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 ) m -, or C 3-10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m -, where G is O, S, NR 5 , C(=O), -C(=O)NH-, -OC(=O)NH-, -OC(=O) - or -NHC(=O)NH-; p and m are each independently 0, 1, 2 or 3; or wherein C 6-10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C 1-9heteroaryl- (CH 2 ) p -G-(CH 2 ) m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 ) m -, or C 3- 10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m - may be selected from one or more selected from the group consisting of F, Cl, Br, I, ethyl, propyl, vinyl, propenyl, ethynyl, Substituted with a propynyl, butynyl, methoxy, ethoxy or cyano substituent; R 3 is H, F, Cl, I, cyano, hydroxy, C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, C 1-6 aminoalkoxy, C 1-6 haloalkoxy, C 6-10 aryl - (CH 2 ) p -G-(CH 2 ) m -,C 1-9heteroaryl- (CH 2 ) p -G-(CH 2 ) m -,C 2-10heterocyclyl- (CH 2 ) p -G-(CH 2 ) m -, or C 3-10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m -, wherein G is O, S, NR 5 , C(=O) , -C(=O)NH-, -OC(=O)NH-, -OC(=O)- or -NHC(=O)NH-; p and m are each independently 0, 1, 2 or 3 Each R 5 is independently hydrogen, R 7 R 7a NC(=O)-, R 7 OC(=O)-, R 7 C(=O)-, C 1-3 alkyl, C 1-3 haloalkane Base, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-3 alkylamino C 1-3 alkyl, C 1-3 alkane Thio C 1-3 alkyl, C 6-10 aryl C 1-3 alkyl, C 1-9 heteroaryl C 1-3 alkyl, C 2-10 heterocyclyl C 1-3 alkyl, C 3-10 cycloalkyl C 1-3 alkyl, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-10 carbocyclyl; each R 7 independently Is H, C 1-6 alkyl, C 1-6 halogenated aliphatic, C 1-6 hydroxy aliphatic, C 1-6 amino aliphatic, C 1-6 alkoxy C 1-6 aliphatic, C 1-6 alkylamino C 1-6 aliphatic, C 1-6 alkylthio C 1-6 aliphatic, C 6-10 aryl C 1-6 aliphatic, C 1-9 heteroaryl C 1-6 aliphatic, C 2-10 heterocyclyl C 1-6 aliphatic, C 3-10 cycloalkyl C 1-6 Fatty aliphatic, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-10 carbocyclyl; each R 7a is independently C 1-6 alkyl, C 1- 6 halogenated aliphatic, C 1-6 hydroxy aliphatic, C 1-6 amino aliphatic, C 1-6 alkoxy C 1-6 aliphatic, C 1-6 alkylamino C 1-6 aliphatic, C 1-6 alkylthio C 1-6 aliphatic, C 6-10 aryl C 1-6 aliphatic, C 1-9 heteroaryl C 1-6 aliphatic, C 2-10 heterocyclic C 1- 6 aliphatic, C 3-10 cycloalkyl C 1-6 aliphatic, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-10 carbocyclyl; R 7 and R 7a are bonded to the same nitrogen atom, and R 7 , R 7a and a nitrogen atom may be optionally substituted to form a substituted or unsubstituted 3-8 membered ring; each R 8a may be the same or different and each independently H. Hydroxy, amino, F, Cl, Br, I, -N(CH 3 ) 2 , cyano, nitro, decyl, C 1-4 alkyl, trifluoromethyl, C 1-4 alkoxy, C 1 -4 alkylamino, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl or C 1-9 heteroaryl; and n is 0, 1, 2 or 3.
其中一些實施方案，各R7獨立地為H，C1-6烷基，C1-4烷氧基C1-6烷基或以下結構：
在另外一些實施方案，本發明涉及到以下其中之一的化合物或它們的立體異構體，幾何異構體，互變異構體，氮氧化物，水合物，溶劑化物，或藥學上可接受的鹽，但絕不限於這些化合物：
本發明包含本發明化合物及其藥學上可接受的鹽的應用，用於生產醫藥產品治療患者組織或器官纖維化的疾病，包括那些本發明所描述的疾病。本發明包含藥物組合物，該藥物組合物包括式(I)，(V)，(VI)，(VII)或(IV)所代表的化合物與至少一種藥學上可接受的載體，賦形劑，稀釋劑，輔劑，媒介物的結合所需的有效治療量。 The present invention comprises the use of a compound of the present invention and a pharmaceutically acceptable salt thereof for the manufacture of a medicinal product for treating diseases of tissue or organ fibrosis in a patient, including those described in the present invention. The present invention comprises a pharmaceutical composition comprising a compound represented by formula (I), (V), (VI), (VII) or (IV) and at least one pharmaceutically acceptable carrier, excipient, The effective therapeutic amount required for the combination of diluent, adjuvant, and vehicle.
本發明同樣包含治療或減輕患者組織或器官纖維化的疾病，或對此病症敏感的方法，該方法包含使用式(I)，(V)，(VI)，(VII)或(IV)所代表化合物的治療有效量對患者進行治療。 The invention also encompasses a method of treating or ameliorating, or sensitizing to, a disease of a patient's tissue or organ fibrosis, the method comprising the use of formula (I), (V), (VI), (VII) or (IV) A therapeutically effective amount of a compound is administered to a patient.
本發明所述的組織或器官纖維化疾病為腎間質纖維化、腎小球硬化、 肝纖維化、肺纖維化、腹膜纖維化、心肌纖維化、皮膚纖維化、手術後黏連、良性前列腺肥大症、骨骼肌纖維化、硬皮病、多發性硬化症，胰腺纖維化，肝硬化，肌肉瘤，神經纖維瘤，肺間質纖維化，糖尿病腎病，阿爾茨海默病或血管纖維化疾病。其中手術後黏連是指疤痕癒合。 The tissue or organ fibrosis disease according to the present invention is renal interstitial fibrosis, glomerular sclerosis, Liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, postoperative adhesion, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, Muscle, neurofibromatosis, pulmonary interstitial fibrosis, diabetic nephropathy, Alzheimer's disease or vascular fibrosis. Among them, adhesion after surgery refers to scar healing.
除非其他方面表明，本發明的化合物所有的立體異構體，幾何異構體，互變異構體，氮氧化物，水合物，溶劑化物，代謝產物，鹽和藥學上可接受的前藥都屬於本發明的範圍。 Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are The scope of the invention.
具體地說，鹽是藥學上可接受的鹽。術語“藥學上可接受的”包括物質或組合物必須是適合化學或毒理學地，與組成製劑的其他組分和用於治療的哺乳動物有關。 In particular, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically relevant to the other components of the formulation and to the mammal being treated.
本發明的化合物的鹽還包括用於製備或純化式(I)，(V)，(VI)，(VII)或(IV)所示化合物的中間體或式(I)，(V)，(VI)，(VII)或(IV)所示化合物分離的對映異構體的鹽，但不一定是藥學上可接受的鹽。 Salts of the compounds of the invention also include intermediates or formula (I), (V), for the preparation or purification of compounds of formula (I), (V), (VI), (VII) or (IV), VI) The salt of the isolated enantiomer of the compound of (VII) or (IV), but not necessarily a pharmaceutically acceptable salt.
如果本發明的化合物是鹼性的，則想得到的鹽可以通過文獻上提供的任何合適的方法製備得到，例如，使用無機酸，如鹽酸，氫溴酸，硫酸，硝酸和磷酸等等。或者使用有機酸，如乙酸，馬來酸，琥珀酸，扁桃酸，富馬酸，丙二酸，丙酮酸，草酸，羥乙酸和水楊酸；吡喃糖酸，如葡萄糖醛酸和半乳糖醛酸；α-羥酸，如檸檬酸和酒石酸；氨基酸，如天門冬氨酸和谷氨酸；芳香族酸，如苯甲酸和肉桂酸；磺酸，如對甲苯磺酸，乙磺酸，等等。 If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like. Or use organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranoic acid such as glucuronic acid and galactose Aldehydic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and many more.
如果本發明的化合物是酸性的，則想得到的鹽可以通過合適的方法製備得到，如，使用無機堿或有機堿，如氨(伯氨，仲氨，叔氨)，鹼金屬氫氧化物或鹼土金屬氫氧化物，等等。合適的鹽包括，但並不限於，從氨基酸得到的有機鹽，如甘氨酸和精氨酸，氨，如伯氨、仲氨和叔氨，和環狀氨，如呱啶，嗎啉和呱嗪等，和從鈉，鈣，鉀，鎂，錳，鐵，銅，鋅，鋁和鋰得到無機鹽。 If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, for example, using an inorganic hydrazine or an organic hydrazine such as ammonia (primary ammonia, secondary ammonia, tertiary ammonia), an alkali metal hydroxide or an alkaline earth. Metal hydroxide, and so on. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as acridine, morpholine and pyridazine Etc., and inorganic salts are obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
根據另一方面，本發明的藥物組合物的特點包括式(I)，(V)，(VI)，(VII)或(IV)的化合物，本發明所列出的化合物，或實施例1-72的化合物，和藥學上可接受的載體，輔劑，或賦形劑。本發明的組合物中化合物的量能有效 地可探測地治療或減輕患者組織或器官纖維化的疾病。 According to another aspect, the pharmaceutical composition of the present invention comprises a compound of formula (I), (V), (VI), (VII) or (IV), a compound listed herein, or Example 1- a compound of 72, and a pharmaceutically acceptable carrier, adjuvant, or excipient. The amount of the compound in the composition of the present invention is effective A disease that can detect or alleviate the fibrosis of a patient's tissues or organs.
本發明的化合物存在自由形態，或合適的、作為藥學上可接受的衍生物。根據本發明，藥學上可接受的衍生物包括，但並不限於，藥學上可接受的前藥，鹽，酯，酯類的鹽，或能直接或間接地根據患者的需要給藥的其他任何加合物或衍生物，本發明其他方面所描述的化合物，其代謝產物或他的殘留物。 The compounds of the invention exist in free form or, as appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, ester salts, or any other agent which can be administered, directly or indirectly, depending on the needs of the patient. An adduct or derivative, a compound described in other aspects of the invention, a metabolite thereof or a residue thereof.
像本發明所描述的，本發明藥學上可接受的組合物進一步包含藥學上可接受的載體，輔劑，或賦形劑，這些像本發明所應用的，包括任何溶劑，稀釋劑，或其他液體賦形劑，分散劑或懸浮劑，表面活性劑，等滲劑，增稠劑，乳化劑，防腐劑，固體黏合劑或潤滑劑，等等，適合於特有的目標劑型。如以下文獻所描述的：In Remington：The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams& Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York，綜合此處文獻的內容，表明不同的載體可應用於藥學上可接受的組合物的製劑和它們公知的製備方法。除了任何常規的載體媒介與本發明的化合物不相容的範圍，例如所產生的任何不良的生物效應或與藥學上可接受的組合物的任何其他組分以有害的方式產生的相互作用，它們的用途也是本發明所考慮的範圍。 As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988- 1999, Marcel Dekker, New York, incorporating the contents of the literature, indicates that different carriers are useful in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. In addition to any conventional carrier medium that is incompatible with the compounds of the invention, such as any undesirable biological effects produced or interactions with any other component of a pharmaceutically acceptable composition in a detrimental manner, The use is also within the scope of the invention.
可作為藥學上可接受載體的物質包括，但並不限於，離子交換劑，鋁，硬脂酸鋁，卵磷脂，血清蛋白，如人血清蛋白，緩衝物質如磷酸鹽，甘氨酸，山梨酸，山梨酸鉀，飽和植物脂肪酸的部分甘油酯混合物，水，鹽或電解質，如硫酸魚精蛋白，磷酸氫二鈉，磷酸氫鉀，氯化鈉，鋅鹽，膠體矽，三矽酸鎂，聚乙烯吡咯烷酮，聚丙烯酸脂，蠟，聚乙烯-聚氧丙烯-阻斷聚合體，羊毛脂，糖，如乳糖，葡萄糖和蔗糖；澱粉如玉米澱粉和土豆澱粉；纖維素和它的衍生物如羧甲基纖維素鈉，乙基纖維素和乙酸纖維素；樹膠粉；麥芽；明膠；滑石粉；輔料如可哥豆脂和栓劑蠟狀物；油如花生油，棉子油，紅花油，麻油，橄欖油，玉米油和豆油；二醇類化合物，如丙二醇和聚乙二醇；酯類如乙基油酸酯和乙基月桂酸酯；瓊脂；緩衝劑如氫氧化鎂和氫氧化鋁；海藻酸；無熱原的水；等滲鹽；林格(氏)溶液； 乙醇，磷酸緩衝溶液，和其他無毒的合適的潤滑劑如月桂硫酸鈉和硬脂酸鎂，著色劑，釋放劑，包衣衣料，甜味劑，調味劑和香料，防腐劑和抗氧化劑。 Substances which may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbus Potassium acid, a partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal bismuth, magnesium tristearate, polyethylene Pyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymer, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Cellulose sodium, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talcum powder; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid Pyrogen-free water; isotonic saline; Ringer (s) solution; Ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and flavors, preservatives and antioxidants.
本發明的藥物組合物可以是口服給藥，注射給藥，噴霧吸入法，局部給藥，經直腸給藥，經鼻給藥，含服給藥，陰道給藥或通過植入性藥盒給藥。可以是膠囊，片劑，丸劑，粉劑、粒劑和水制懸浮液或溶液。 The pharmaceutical composition of the present invention may be administered orally, by injection, by inhalation, topically, rectally, nasally, buccally, vaginally or via an implantable kit. medicine. It may be a capsule, tablet, pill, powder, granule and aqueous suspension or solution.
口服給藥可以用如下形式：片劑、丸劑、膠囊、可分散的粉末、顆粒或懸浮液、糖漿、和酏劑，或以外用方式給藥：軟膏劑、凝膠、含藥膠布等，或者以無菌可注射溶液或懸浮液形式進行非腸胃給藥。 Oral administration can be carried out in the form of tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, and elixirs, or by external administration: ointments, gels, medicated tapes, etc., or Parenteral administration is carried out as a sterile injectable solution or suspension.
本發明化合物也可腸胃外或腹腔內給藥。也可在適當混合有表面活性劑(如羥丙基纖維素、聚乙烯吡咯烷酮)的水中製備這些活性化合物(作為游離堿或藥學上可接受的鹽)的溶液或懸浮液。還可在甘油、液體、聚乙二醇及其在油中的混合物中製備分散液。在常規儲存和使用條件下，這些製劑中含有防腐劑以防止微生物生長。 The compounds of the invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds (as free guanidine or pharmaceutically acceptable salts) can also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose, polyvinylpyrrolidone. Dispersions can also be prepared in glycerol, liquids, polyethylene glycols, and mixtures thereof in oils. These preparations contain preservatives to prevent microbial growth under normal conditions of storage and use.
適於注射的藥物形式包括：無菌水溶液或分散液和無菌粉(用於臨時製備無菌注射溶液或分散液)。在所有情況下，這些形式必須是無菌的且必須是流體以易於注射器排出流體。在製造和儲存條件下必須是穩定的，且必須能防止微生物(如細菌和真菌)的污染影響。載體可以是溶劑或分散介質，其中含有如水、醇(如甘油、丙二醇和液態聚乙二醇)、它們的適當混合物和植物油。 The pharmaceutical forms suitable for injection include: sterile aqueous solutions or dispersions and sterile powders (for the preparation of sterile injectable solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate the discharge of fluid from the syringe. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating effects of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, an alcohol such as glycerol, propylene glycol, and liquid polyethylene glycol, suitable mixtures thereof, and vegetable oils.
化合物可以以局部方式施用，而不以系統方式施用。例如通常以稀釋製劑或持續釋放製劑的形式將化合物直接注射至器官內。此外，含有本發明化合物的藥物組合物可以在靶向藥物傳遞系統中使用，例如在用器官特異性抗體包衣的脂質體重遞送。所述脂質體將靶向所述器官並被該器官選擇性攝取。此外，含有本發明化合物的組合物可以以快速釋放製劑、延時釋放製劑或即時釋放製劑的形式提供。 The compounds can be administered in a topical manner without being administered systemically. For example, the compound is usually injected directly into the organ in the form of a diluted formulation or a sustained release formulation. Furthermore, pharmaceutical compositions containing the compounds of the invention can be used in targeted drug delivery systems, for example, in the weight of lipids coated with organ-specific antibodies. The liposomes will target the organ and be selectively taken up by the organ. Furthermore, compositions containing a compound of the invention may be provided in the form of a rapid release formulation, a time release formulation or a ready release formulation.
對於吸入施用，本發明的化合物可以是氣溶膠、氣霧劑或粉末形式。本發明化合物的藥物組合物可以方便地以氣溶膠噴霧劑形式遞送，所述氣溶膠噴霧劑可以裝在壓力容器或霧化器中，使用合適的拋射劑例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合適的氣體。在壓 力氣溶膠的情況下，劑量單位可以通過閥門進行確定以遞送計量量。例如，以膠囊劑和藥筒為例，用於吸入器或吹藥器的明膠可以製備為含有所述化合物與適當粉末基質例如乳糖或澱粉的粉末混合物。 For administration by inhalation, the compounds of the invention may be in the form of an aerosol, aerosol or powder. The pharmaceutical compositions of the compounds of the invention may conveniently be delivered in the form of an aerosol spray which may be contained in a pressure vessel or nebulizer using a suitable propellant such as dichlorodifluoromethane or trichlorofluoride. Methane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Under pressure In the case of a force aerosol, the dosage unit can be determined by a valve to deliver a metered amount. For example, in the case of capsules and cartridges, gelatin for use in an inhaler or insufflator can be prepared to contain a powder mix of the compound with a suitable powder base such as lactose or starch.
本發明化合物還可以製備為直腸組合物例如灌腸劑、直腸凝膠劑、直腸泡沫劑、直腸氣溶膠、栓劑、凝膠栓劑(jelly suppository)或保留灌腸劑(retention enma)，其中含有常規的栓劑基質例如可哥脂或其他甘油酯以及合成聚合物例如聚乙烯吡咯烷酮、PEG等。在組合物的栓劑形式中，低熔點蠟例如但不限於脂肪酸甘油酯任選與可哥脂的混合物首先被熔化。 The compounds of the invention may also be prepared in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppository or retention enma containing conventional suppositories. The base is, for example, cognate or other glycerides and synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In the suppository form of the composition, a low melting wax such as, but not limited to, a fatty acid glyceride, optionally mixed with keto butter, is first melted.
此外，本發明化合物還可與其他治療纖維化的藥物聯用。具體包括，但不限於，Ivacaftor、羅氟斯特、吡非尼酮、美格魯特、洛沙坦、干擾素、阿拉法-鏈道酶、Veldona、ataluren、皮質激素、氨甲喋呤、他克莫司等。 In addition, the compounds of the invention may also be combined with other agents that treat fibrosis. Specifically included, but not limited to, Ivacaftor, Rofluent, Pirfenidone, Megruth, Losartan, Interferon, Arafat-Chainase, Veldona, ataluren, Corticosteroids, Methotrexate, Tacroom Secretary and so on.
可以根據常規方式用一種或多種生理學可接受的載體製備藥物組合物，其中包括可幫助將活性化合物加工為可藥用製劑的賦形劑和輔劑。所選擇的施用途徑決定適當的劑型。任何熟知的技術、載體和賦形劑都可以根據現有技術中的理解適當的使用。含有本發明化合物的藥物組合物可以根據常規方法製備，例如通過常規的混合、溶解、制粒、制錠、研磨、乳化、包囊、包封或壓制過程製備。 The pharmaceutical compositions may be prepared in a conventional manner using one or more physiologically acceptable carriers including excipients and adjuvants which may aid in the processing of the active compound into a pharmaceutically acceptable formulation. The route of administration chosen determines the appropriate dosage form. Any of the well-known techniques, carriers and excipients can be suitably employed in accordance with the understanding in the prior art. The pharmaceutical composition containing the compound of the present invention can be produced according to a conventional method, for example, by a conventional mixing, dissolving, granulating, tableting, grinding, emulsifying, encapsulating, encapsulating or pressing process.
藥物組合物將包含至少一種可藥用載體、稀釋劑或賦形劑和游離酸、游離堿或可藥用鹽形式的本發明的化合物作為活性成分。此外，藥物組合物還可包括其它醫學或藥學活性劑、載體、輔劑、例如防腐劑、穩定劑、濕潤劑或乳化劑、溶解促進劑、調節滲透壓的鹽或緩衝劑。此外，藥物組合物還可含有其它有治療價值的物質。 The pharmaceutical composition will comprise, as active ingredient, at least one pharmaceutically acceptable carrier, diluent or excipient and a compound of the invention in the form of the free acid, free oxime or pharmaceutically acceptable salt. In addition, the pharmaceutical compositions may also include other medical or pharmaceutically active agents, carriers, adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure or buffers. In addition, the pharmaceutical compositions may also contain other therapeutically valuable substances.
含有本文所述化合物的組合物的製備方法包括將化合物與一種或多種惰性的可藥用賦形劑或載體一起製備為固體、半固體或液體形式。固體組合物包括但不限於散劑、片劑、可分散顆粒劑、膠囊劑、扁囊劑和栓劑。液體組合物包括其中溶解有化合物的溶液劑、含有化合物的乳劑、含有包含本文公開化合物的脂質體、膠團或納米粒子的溶液劑。半固體組合物包括但不限於凝膠劑、混懸劑和乳膏劑。組合物可以是液體溶液劑或混懸劑形式、適合於在使用前溶解或懸浮在液體中的固體形式或乳劑形式。這些組合物還可以含有少量無毒的輔劑，例如濕潤劑或乳化劑、pH緩衝劑等。 A method of preparing a composition comprising a compound described herein comprises preparing the compound together with one or more inert pharmaceutically acceptable excipients or carriers in solid, semi-solid or liquid form. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, solutions containing liposomes, micelles or nanoparticles comprising the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The composition may be in the form of a liquid solution or suspension, in a solid form or in an emulsion form suitable for dissolution or suspension in a liquid prior to use. These compositions may also contain minor amounts of non-toxic adjuvants such as wetting or emulsifying agents, pH buffering agents and the like.
本發明的化合物優選地按製劑配方製備成劑量單位型以減輕給藥量和劑量的均勻性。術語“劑量單位型”在此處是指患者得到適當治療所需藥物的物理分散單位。然而，應瞭解本發明的化合物或組合物每日總的用法將通過主治醫生根據可靠的醫學範圍判斷來確定。具體的有效劑量水準對於任何一個特殊的患者或有機體將取決於許多因素包括被治療的病症和病症的嚴重性，具體化合物的活性，所用的具體組合物，患者的年齡、體重、健康狀況、性別和飲食習慣，給藥時間，給藥途徑和所用具體化合物的排泄速率，治療的持續時間，藥物應用于聯合用藥或與有特效的化合物聯用，以及其他一些藥學領域公知的因素。 The compounds of the present invention are preferably prepared in dosage unit form in a formulation to reduce the uniformity of administration and dosage. The term "dosage unit type" as used herein refers to the physically discrete unit of the drug required for the patient to receive appropriate treatment. However, it is to be understood that the total daily usage of the compounds or compositions of the present invention will be determined by the attending physician based on a reliable medical field judgment. The specific effective dosage level will depend on a number of factors for any particular patient or organism, including the severity of the condition and condition being treated, the activity of the particular compound, the particular composition employed, the patient's age, weight, health, sex And dietary habits, time of administration, route of administration and rate of excretion of the particular compound employed, duration of treatment, administration of the drug in combination or in combination with a compound having a specific effect, and other factors well known in the pharmaceutical arts.
所用的活性成分的有效劑量可隨所用的化合物、給藥的模式和待治療的疾病的嚴重程度而變化。然而，通常當本發明的化合物每天以約0.25-1000mg/kg動物體重的劑量給予時，能得到令人滿意的效果，較佳地每天以2-4次分開的劑量給予，或以緩釋形式給藥。對大部分大型哺乳動物而言，每天的總劑量約為1-100mg/kg，較佳地約為2-80mg/kg。適用於內服的劑量形式，包含與固態或液態藥學上可接受的載體密切混合的約0.25-500mg的活性化合物。可調節此劑量方案以提供最佳治療應答。另外，由於治療狀況的不同，可每天給予若干次分開的劑量，或將劑量按比例減少。 The effective dose of the active ingredient employed will vary depending upon the compound employed, the mode of administration, and the severity of the condition being treated. However, usually, when the compound of the present invention is administered at a dose of about 0.25 to 1000 mg/kg of animal body weight per day, a satisfactory effect can be obtained, preferably administered in 2-4 divided doses per day, or in a sustained release form. Dosing. For most large mammals, the total daily dose is about 1-100 mg/kg, preferably about 2-80 mg/kg. Dosage forms for internal administration comprise from about 0.25 to about 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide an optimal therapeutic response. In addition, several separate doses may be administered per day, or the dose may be proportionally reduced, depending on the condition being treated.
可以將本發明化合物通過附加適宜的官能團進行修飾以提高選擇性生物特性。這樣的修飾是本領域已知的並且包括向生物腔隙(例如血液、淋巴系統、中樞神經系統)滲透、提高口服有效性、提高溶解性以便可以通過注射給藥、改變代謝和改變排泄的修飾。 The compounds of the invention may be modified by the addition of suitable functional groups to enhance selective biological properties. Such modifications are known in the art and include infiltration into biological cavities (e.g., blood, lymphatic system, central nervous system), improving oral availability, increasing solubility so that administration can be by injection, alteration of metabolism, and alteration of excretion. .
可以將本發明化合物通過附加適宜的官能團進行修飾以提高選擇性生物特性。這樣的修飾是本領域已知的並且包括向生物腔隙(例如血液、淋巴系統、中樞神經系統)滲透、提高口服有效性、提高溶解性以便可以通過注射給藥、改變代謝和改變排泄的修飾。 The compounds of the invention may be modified by the addition of suitable functional groups to enhance selective biological properties. Such modifications are known in the art and include infiltration into biological cavities (e.g., blood, lymphatic system, central nervous system), improving oral availability, increasing solubility so that administration can be by injection, alteration of metabolism, and alteration of excretion. .
本發明涉及的化合物或者其藥用鹽或其水合物能有效用於預防、處理、治療或減輕患者組織或器官纖維化疾病，特別是能有效治療腎間質纖維化、腎小球硬化、肝纖維化、肺纖維化、腹膜纖維化、心肌纖維化、皮膚纖維化、手術後黏連、良性前列腺肥大症、骨骼肌纖維化、硬皮病、多發性硬化症，胰腺纖維化，肝硬化，肌肉瘤，神經纖維瘤，肺間質纖維化， 糖尿病腎病，阿爾茨海默病或血管纖維化的疾病。 The compound of the present invention or a pharmaceutically acceptable salt thereof or a hydrate thereof can be effectively used for preventing, treating, treating or ameliorating a fibrotic disease of a tissue or an organ of a patient, and particularly effective for treating renal interstitial fibrosis, glomerular sclerosis, liver Fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, postoperative adhesions, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, muscle Tumor, neurofibromatosis, pulmonary interstitial fibrosis, Diabetic nephropathy, Alzheimer's disease or vascular fibrosis.
一般地，本發明的化合物可以通過本發明所描述的方法製備得到，除非有進一步的說明，其中取代基的定義如式(I)，(V)，(VI)，(VII)或(IV)所示。下面的反應方案和實施例用於進一步舉例說明本發明的內容。 In general, the compounds of the invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formula (I), (V), (VI), (VII) or (IV). Shown. The following reaction schemes and examples are provided to further illustrate the contents of the present invention.
所屬領域的技術人員將認識到：本發明所描述的化學反應可以用來合適地製備本發明的其他化合物，且用於製備本發明的化合物的其它方法都被認為是在本發明的範圍之內。例如，根據本發明那些非例證的化合物的合成可以成功地被所屬領域的技術人員通過修飾方法完成，如適當的保護干擾基團，通過利用其他已知的試劑除了本發明所描述的，或將反應條件做一些常規的修改。另外，本發明所公開的反應或已知的反應條件也公認地適用于本發明其他化合物的製備。 Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. . For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modifications by those skilled in the art, such as appropriate protection of the interfering group, by the use of other known reagents in addition to those described herein, or The reaction conditions are subject to some conventional modifications. Additionally, the reactions or known reaction conditions disclosed herein are also recognized to be suitable for the preparation of other compounds of the invention.
下面所描述的實施例，除非其他方面表明所有的溫度定為攝氏度。試劑購買于商品供應商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用時都沒有經過進一步純化，除非其他方面表明。一般的試劑從汕頭西隴化工廠，廣東光華化學試劑廠，廣州化學試劑廠，天津好寓宇化學品有限公司，青島騰龍化學試劑有限公司，和青島海洋化工廠購買得到。 The examples described below, unless otherwise indicated, all temperatures are set to degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. The general reagents were purchased from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.
無水四氫呋喃，二氧六環，甲苯，乙醚是經過金屬鈉回流乾燥得到。無水二氯甲烷和氯仿是經過氫化鈣回流乾燥得到。乙酸乙酯，石油醚，正己烷，N，N-二甲基乙醯胺和N，N-二甲基甲醯胺是經無水硫酸鈉事先乾燥使用。 Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal. Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.
以下反應一般是在氮氣或氬氣正壓下或在無水溶劑上套一乾燥管(除非其他方面表明)，反應瓶都塞上合適的橡皮塞，底物通過注射器打入。玻璃器皿均是經過乾燥的。 The following reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe. The glassware is dried.
色譜柱是使用矽膠柱。矽膠(300-400目)購于青島海洋化工廠。核磁共振光譜以CDCl3,d6-DMSO,CD3OD或d6-丙酮為溶劑(報導以ppm為單位)，用TMS(0ppm)或氯仿(7.25ppm)作為參照標準。當出現多重峰的時候，將使用下面的縮寫：s(singlet，單峰)，d(doublet，雙峰)，t(triplet，三重峰)，m(multiplet，多重峰)，br(broadened，寬峰)，dd(doublet of doublets，四重 峰),dt(doublet of triplets，雙三重峰)。偶合常數，用赫茲(Hz)表示。 The column is a silicone column. Silicone rubber (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The nuclear magnetic resonance spectrum was measured by CDCl 3 , d 6 -DMSO, CD 3 OD or d 6 -acetone (reported in ppm) using TMS (0 ppm) or chloroform (7.25 ppm) as a reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide) Peak), dd (doublet of doublets), dt (doublet of triplets). Coupling constant, expressed in Hertz (Hz).
低解析度質譜(MS)資料通過配備G1312A二元泵和a G1316A TCC(柱溫保持在30℃)的Agilent 6320系列LC-MS的光譜儀來測定的，G1329A自動採樣器和G1315B DAD檢測器應用於分析，ESI源應用於LC-MS光譜儀。 Low-resolution mass spectrometry (MS) data was determined by a spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C) Agilent 6320 Series LC-MS. The G1329A autosampler and G1315B DAD detector were used. For analysis, the ESI source was applied to an LC-MS spectrometer.
低解析度質譜(MS)資料通過配備G1311A四元泵和G1316A TCC(柱溫保持在30℃)的Agilent 6120系列LC-MS的光譜儀來測定的，G1329A自動採樣器和G1315D DAD檢測器應用於分析，ESI源應用於LC-MS光譜儀。 Low-resolution mass spectrometry (MS) data were measured with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30 °C) Agilent 6120 Series LC-MS spectrometer, G1329A autosampler and G1315D DAD detector for analysis The ESI source was applied to an LC-MS spectrometer.
以上兩種光譜儀都配備了Agilent Zorbax SB-C18柱，規格為2.1×30mm，5μm。注射體積是通過樣品濃度來確定；流速為0.6mL/min；HPLC的峰值是通過在210nm和254nm處的UV-Vis波長來記錄讀取的。流動相為0.1%的甲酸乙腈溶液(相A)和0.1%的甲酸超純水溶液(相B)。梯度洗脫條件如表1所示：
化合物純化是通過Agilent 1100系列高效液相色譜(HPLC)來評價的，其中UV檢測在210nm和254nm處，Zorbax SB-C18柱，規格為2.1×30mm，4μm，10分鐘，流速為0.6mL/min，5-95%的(0.1%甲酸乙腈溶液)的(0.1%甲酸水溶液)，柱溫保持在40℃。 Compound purification was evaluated by Agilent 1100 Series High Performance Liquid Chromatography (HPLC) with UV detection at 210 nm and 254 nm, Zorbax SB-C18 column, size 2.1 x 30 mm, 4 μm, 10 min, flow rate 0.6 mL/min 5-95% (0.1% formic acid in acetonitrile) (0.1% aqueous formic acid), the column temperature was kept at 40 °C.
下面簡寫詞的使用貫穿本發明： The following abbreviations are used throughout the invention:
BPO 過氧化二苯甲醯 BPO benzoquinone peroxide
NH4Cl 氯化氨 NH 4 Cl ammonia chloride
BOC,Boc 叔丁氧基羰基 BOC, Boc tert-butoxycarbonyl
Cs2CO3 碳酸銫 Cs 2 CO 3 strontium carbonate
CHCl3 氯仿 CHCl 3 chloroform
CCl4 四氯化碳 CCl 4 carbon tetrachloride
CDCl3 氘代氯仿 CDCl 3 deuterated chloroform
CuI 碘化亞銅 CuI cuprous iodide
DMF N,N-二甲基甲醯胺 DMF N,N-dimethylformamide
DMAP 4-二甲氨基吡啶 DMAP 4-dimethylaminopyridine
DMSO 二甲基亞碸 DMSO dimethyl sulfoxide
EA,EtOAc 乙酸乙酯 EA, EtOAc ethyl acetate
g 克 g g
h 小時 h hours
HCl 鹽酸 HCl hydrochloric acid
H2 氫氣 H 2 hydrogen
MeOH,CH3OH 甲醇 MeOH, CH 3 OH methanol
CH2Cl2,DCM 二氯甲烷 CH 2 Cl 2 , DCM dichloromethane
mL,mL 毫升 mL, mL ml
N2 氮氣 N 2 nitrogen
Pd/C 鈀/碳 Pd/C palladium/carbon
PE 石油醚(60-90 0C) PE petroleum ether (60-90 0C)
K2CO3 碳酸鉀 K 2 CO 3 potassium carbonate
RT,rt 室溫 RT, rt room temperature
NaHCO3 碳酸氫鈉 NaHCO 3 sodium bicarbonate
NaCl 氯化鈉 NaCl sodium chloride
Na2SO4 硫酸鈉 Na 2 SO4 sodium sulfate
THF 四氫呋喃 THF tetrahydrofuran
Et3N,TEA 三乙胺 Et 3 N, TEA triethylamine
NBS N-溴丁二醯亞胺 NBS N-bromobutanediimine
H2O 水 H 2 O Water
AlMe3 三甲基鋁 AlMe 3 trimethyl aluminum
Lawesson’s Reagent(勞森試劑) 2,4-雙(4-甲氧基苯基)-1,3-二硫-2,4-膦烷-2,4-二硫化物 Lawesson’s Reagent 2,4-bis(4-methoxyphenyl)-1,3-disulfide-2,4-phosphane-2,4-disulfide
PFD 吡非尼酮 PFD pirfenidone
化合物1與化合物2於氮氣保護下，同堿(如碳酸鉀、碳酸銫、磷酸鉀等)、配體(如8-羥基喹啉、2-氧代環己基甲酸乙酯、N,N'-二甲基乙二胺等)在溶劑(如二氧六環、N,N-二甲基甲醯胺、二甲亞碸)中加熱(50℃-140℃)反應可得到目標化合物3，其中V1，V2，V3，V4，A，B和X具有本發明所述的含義。 Compound 1 and Compound 2 under the protection of nitrogen, the same (such as potassium carbonate, cesium carbonate, potassium phosphate, etc.), ligand (such as 8-hydroxyquinoline, ethyl 2-oxocyclohexylcarboxylate, N, N'- Dimethylethylenediamine, etc.) is heated in a solvent (such as dioxane, N,N-dimethylformamide, dimethyl hydrazine) (50 ° C - 140 ° C) to obtain the target compound 3 , wherein V 1 , V 2 , V 3 , V 4 , A, B and X have the meanings indicated in the present invention.
目標化合物6是通過含碘衍生物4與吡啶酮衍生物5於氮氣保護下，同堿(如碳酸鉀、碳酸銫、磷酸鉀等)、配體(如8-羥基喹啉、2-氧代環己基甲酸乙酯、N,N'-二甲基乙二胺等)在溶劑(如二氧六環、N,N-二甲基甲醯胺、二甲亞碸)中加熱(50-140℃)反應得到；其中R2、R4，X和B具有如本發明所述的含義。 The target compound 6 is obtained by the iodine-containing derivative 4 and the pyridone derivative 5 under the protection of nitrogen, the same (such as potassium carbonate, cesium carbonate, potassium phosphate, etc.), a ligand (such as 8-hydroxyquinoline, 2-oxo). Ethyl cyclohexylcarboxylate, N,N'-dimethylethylenediamine, etc.) are heated in a solvent (such as dioxane, N,N-dimethylformamide, dimethyl hydrazine) (50-140) °C) The reaction is obtained; wherein R 2 , R 4 , X and B have the meanings as described in the present invention.
噻唑衍生物7在NBS作用下得到含溴衍生物8，再與吡啶酮衍生物5於氮氣保護下，同堿(如碳酸鉀、碳酸銫、磷酸鉀等)、配體(如8-羥基喹啉、2-氧代環己基甲酸乙酯、N,N'-二甲基乙二胺等)在溶劑(如二氧六環、N,N- 二甲基甲醯胺、二甲亞碸)中加熱(50-140℃)反應得到如圖所示化合物9；其中R2、R4和B具有如本發明所述的含義。 Thiazole derivative 7 can obtain bromine derivative 8 under the action of NBS, and then under the protection of nitrogen with pyridone derivative 5 , such as potassium carbonate, cesium carbonate, potassium phosphate, etc., ligand (such as 8-hydroxyquine) Porphyrin, ethyl 2-oxocyclohexylcarboxylate, N,N'-dimethylethylenediamine, etc.) in a solvent (such as dioxane, N,N-dimethylformamide, dimethylhydrazine) The reaction in heating (50-140 ° C) gives compound 9 as shown; wherein R 2 , R 4 and B have the meanings as described herein.
硝基衍生物10通過催化氫化還原為胺類化合物11，然後與化合物12在三甲基鋁作用下於有機溶劑(二氯甲烷等)中反應得到目標化合物13；其中R1、R3和B具有如本發明所述的含義。 The nitro derivative 10 is reduced to the amine compound 11 by catalytic hydrogenation, and then reacted with the compound 12 under the action of trimethylaluminum in an organic solvent (dichloromethane or the like) to obtain the target compound 13 ; wherein R 1 , R 3 and B Has the meaning as described in the present invention.
噻唑衍生物7在強酸(濃硝酸、濃硫酸等)的作用下，生成化合物14，然後經過催化氫化還原為胺類化合物15，進而與化合物12在三甲基鋁作用下於有機溶劑(二氯甲烷等)中反應得到目標化合物16；其中R1、R3和B具有如本發明所述的含義。 The thiazole derivative 7 is formed into a compound 14 under the action of a strong acid (concentrated nitric acid, concentrated sulfuric acid, etc.), and then reduced to an amine compound 15 by catalytic hydrogenation, and further reacted with the compound 12 under trimethylaluminum in an organic solvent (dichloro The reaction in methane or the like gives the object compound 16 ; wherein R 1 , R 3 and B have the meanings as described in the present invention.
稠合三環化合物17與化合物12在三甲基鋁作用下於有機溶劑(二氯甲烷等)中反應得到目標化合物18；其中R1、R3，R5a，n和D具有如本發明所述的含義。 The fused tricyclic compound 17 and the compound 12 are reacted in an organic solvent (dichloromethane or the like) under the action of trimethylaluminum to obtain the target compound 18 ; wherein R 1 , R 3 , R 5a , n and D have the present invention The meaning of the description.
在氮氣保護下，2-氟-4-碘甲苯(23.60g,0.10mol)溶於CHCl3(1000mL)中，攪拌，BPO(0.55g,2.27mmol)和NBS(24.92g,0.14mol)加入該反應液中，加熱回流反應6h，冷卻過濾，減壓蒸去溶劑。在氮氣保護下將濃縮液加入嗎啉(43.56g,0.50mol)的乙醇溶液(1000mL)中，室溫攪拌過夜。減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=3/1)，得到白色固體(4.82g,15%)。 2-Fluoro-4-iodotoluene (23.60 g, 0.10 mol) was dissolved in CHCl 3 (1000 mL) under nitrogen, stirring, BPO (0.55 g, 2.27 mmol) and NBS (24.92 g, 0.14 mol) were added. The reaction mixture was heated to reflux for 6 hours, cooled and filtered, and evaporated. The concentrate was added to a solution of morpholine (43.56 g, 0.50 mol) in ethanol (1000 mL). The solvent was evaporated under reduced pressure. EtOAcjjjjjjjj
在氮氣保護下，CuI(0.19g,1mmol)，Cs2CO3(6.85g,20mmol)和2-氧代環己基甲酸乙酯(0.34g,2mmol)加入到DMSO(10mL)中，室溫攪拌30min。5-甲基吡啶酮(1.09g,10mmol)和4-(2-氟-4-碘苯甲基)嗎啉(3.21g,10mmol)的DMSO(12mL)溶液，注射加入。加熱至100℃過夜。冷卻至室溫，過濾，加入水(50mL)和二氯甲烷(50mL×3)，收集有機相，減壓減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=10/1)，得到白色固體(0.70g,23%)。 CuI (0.19 g, 1 mmol), Cs 2 CO 3 (6.85 g, 20 mmol) and ethyl 2-oxocyclohexylcarboxylate (0.34 g, 2 mmol) were added to DMSO (10 mL) and stirred at room temperature under nitrogen. 30min. A solution of 5-methylpyridone (1.09 g, 10 mmol) and 4-(2-fluoro-4-iodobenzyl)morpholine (3.21 g, 10 mmol) in DMSO (12 mL) Heat to 100 ° C overnight. After cooling to room temperature, filtration, water (50 mL) and dichloromethane (50 mL×3) were added, the organic phase was collected, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography ( petroleum ether / ethyl acetate /V) = 10/1) gave a white solid (0.70 g, 23%).
MS(ESI,pos.ion)m/z：303.2(M+1)；1H NMR(400MHz,CDCl3)：δ 2.06(s,3H),3.16-3.32(m,4H),3.86-3.97(m,4H),4.44(s,2H),6.47(d,1H,J=9.6Hz),7.39-7.44(m,2H),7.48(s,1H),7.52-7.55(m,1H),7.99(t,1H,.J=8.2Hz)。 MS (ESI, pos.) m/z: 303.2 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.06 (s, 3H), 3.16-3.32 (m, 4H), 3.86 - 3.97 ( m, 4H), 4.44 (s, 2H), 6.47 (d, 1H, J = 9.6 Hz), 7.39-7.44 (m, 2H), 7.48 (s, 1H), 7.52-7.55 (m, 1H), 7.99 (t, 1H,. J = 8.2 Hz).
在10mL圓底燒瓶中加入3,5-二甲基吡啶-2(H)-酮(0.22g,1.80mmol)，1-(2-氟-4-碘苄基)嗎啉(0.58g,1.80mmol)，碳酸鉀(2.48g,18mmol)，碘化亞銅(0.02g,0.1mmol)和DMF(3mL)。反應體系於氮氣保護下加熱至回流，TLC監測直至反應結束，將混合物冷至室溫，過濾，往濾液中加入水(10mL)和二氯甲烷(20mL)，分液。水層用二氯甲烷萃取(20mL×2)。有機層用無水硫酸鈉乾燥後，減壓蒸去溶劑；粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到白色固體(0.28g,50%)。 In a 10 mL round bottom flask was added 3,5-lutidine-2( H )-one (0.22 g, 1.80 mmol), 1-(2-fluoro-4-iodobenzyl)morpholine (0.58 g, 1.80) Methyl) potassium carbonate (2.48 g, 18 mmol), cuprous iodide (0.02 g, 0.1 mmol) and DMF (3 mL). The reaction was heated to reflux under N.sub.2, and then filtered and evaporated. The aqueous layer was extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate (MgSO4). .
MS(ESI,pos.ion)m/z：317.1(M+1)；1H NMR(400MHz CDCl3)：δ 2.06(s,3H),2.16(s,3H),2.61(s,2H),4.10(m,4H),4.32(m,4H),6.97(s,1H),7.09(s,1H),7.24(d,1H),7.31(d,1H),8.1(s,1H)。 MS (ESI, pos.ion) m / z: 317.1 (M + 1); 1 H NMR (400MHz CDCl 3): δ 2.06 (s, 3H), 2.16 (s, 3H), 2.61 (s, 2H), 4.10 (m, 4H), 4.32 (m, 4H), 6.97 (s, 1H), 7.09 (s, 1H), 7.24 (d, 1H), 7.31 (d, 1H), 8.1 (s, 1H).
2-氟-4-碘甲苯(0.94g,4.0mmol)在CCl4(40mL)中，在氮氣保護下攪拌，BPO(0.02g,0.08mmol)和NBS(0.78g,4.4mmol)加入該反應液中，加熱回流反應5h，冷卻。減壓蒸餾除去溶劑，得到第一步粗產品。甲基呱嗪(2.00g,20mmol)在乙醇(40mL)在氮氣保護下加入到上一步粗產品中，室溫攪拌過夜。減壓除去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=10/1)，得到白色固體(0.69g,52%)。 2-Fluoro-4-iodotoluene (0.94 g, 4.0 mmol) was added to CCl 4 (40 mL), stirred under nitrogen, and BPO (0.02 g, 0.08 mmol) and NBS (0.78 g, 4.4 mmol) were added to the reaction mixture. The reaction was heated to reflux for 5 h and cooled. The solvent was distilled off under reduced pressure to give a crude material. Methylpyridazine (2.00 g, 20 mmol) was added to the crude product of the previous step in EtOAc (40 mL). The solvent was removed under reduced pressure. EtOAc m.
在10mL圓底燒瓶中加入3,5-二甲基吡啶-2(H)-酮(0.07g,0.57mmol)，1-(2-氟-4-碘苄基)-4-甲基呱嗪(0.19g,0.57mmol)，碳酸鉀(0.08g,0.58mmol)，碘化亞銅(0.005g,0.026mmol)和DMF(1mL)。反應體系於氮氣保護下加熱至回流，TLC監測直至反應結束，將混合物冷至室溫，往有機層中加入水(5mL)和二氯甲烷(10mL×3)，分液。有機層用無水硫酸鈉乾燥後，減壓蒸去溶劑；粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到淡黃色固體(0.07g,37%)。 Add 3,5-lutidine-2(H)-one (0.07 g, 0.57 mmol), 1-(2-fluoro-4-iodobenzyl)-4-methylpyridazine to a 10 mL round bottom flask (0.19 g, 0.57 mmol), potassium carbonate (0.08 g, 0.58 mmol), cuprous iodide (0.005 g, 0.026 mmol) and DMF (1 mL). The reaction was heated to reflux under a nitrogen atmosphere, and then filtered and evaporated to dryness. The mixture was cooled to room temperature, and water (5 mL) and dichloromethane (10 mL×3) were added to the organic layer. The organic layer was dried over anhydrous sodium sulfate (MgSO4). ).
MS(ESI,pos.ion)m/z：317.1(M+1)；1H NMR(400MHz CDCl3)：δ 2.08(s,3H),2.17(s,3H),2.29(s,3H),2.46-2.54(m,8H),3.61(s,2H),6.97(s,1H),7.11-7.15(m,3H),7.47-7.511(m,1H)。 MS (ESI, pos.ion) m / z: 317.1 (M + 1); 1 H NMR (400MHz CDCl 3): δ 2.08 (s, 3H), 2.17 (s, 3H), 2.29 (s, 3H), 2.46-2.54 (m, 8H), 3.61 (s, 2H), 6.97 (s, 1H), 7.11-7.15 (m, 3H), 7.47-7.511 (m, 1H).
在250mL圓底燒瓶中加入2-氟-4-碘甲苯(2.83g,12mmol)並溶於四氯化碳(120mL)中，攪拌下向溶液中加入NBS(2.24g,12.6mmol)和BPO(0.06g,0.24mmol)，氮氣保護下反應體系加熱至回流反應9h。反應完畢，待冷卻至室溫，反應液減壓蒸去溶劑；粗產品經柱層析純化(淋洗劑為石油醚)，得到白色固體(2.16g,57%)。 2-Fluoro-4-iodotoluene (2.83 g, 12 mmol) was added to a 250 mL round bottom flask and dissolved in carbon tetrachloride (120 mL). NBS (2.24 g, 12.6 mmol) and BPO were added to the solution under stirring. 0.06 g, 0.24 mmol), the reaction system was heated to reflux for 9 h under nitrogen. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated to dryness.
在100mL兩口燒瓶中加入1-溴甲基-2-氟-4-碘苯(1.89g,6.0mmol)，氮氣保護下，加入二乙胺(2.19g,30mmol)溶於乙醇(60mL)溶液，室溫下攪拌反應過夜。反應完畢，減壓蒸去溶劑，剩餘物溶於乙酸乙酯(100mL)中，有機層分別用水(100mL×3)和飽和鹽水(100mL)洗滌。有機層減壓蒸去溶劑，得到無色油狀物(1.72g,94%)。 1-Bromomethyl-2-fluoro-4-iodobenzene (1.89 g, 6.0 mmol) was added to a 100 mL two-necked flask, and a solution of diethylamine (2.19 g, 30 mmol) in ethanol (60 mL) was added under nitrogen. The reaction was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated. mjjjjjjjjjjj The organic layer was evaporated to dryness crystall
在氮氣保護下，將3,5-二甲基吡啶酮(0.69g,5.60mmol)，N,N`-二甲基乙二胺(0.20g,2.24mmol)，碘化亞銅(0.21g,1.12mmol)和磷酸三鉀(2.38g,11.20mmol)加入N-乙基-N-(2-氟-4碘苯甲基)乙胺(1.72g,5.60mmol)溶於二氧六環(50mL)的溶液中，攪拌下加熱至110℃反應9h，反應完畢，將混合物冷至室溫，傾入二氯甲烷(200mL)中，用水(200mL×3)和飽和鹽水(200mL)洗滌。有機層減壓蒸去溶劑；粗產品經柱層析純化(二氯甲烷/甲醇(V/V)=10/1)，得到黃色固體(0.23g,14%)。 3,5-dimethylpyridone (0.69 g, 5.60 mmol), N,N'-dimethylethylenediamine (0.20 g, 2.24 mmol), cuprous iodide (0.21 g, under N2) 1.12 mmol) and tripotassium phosphate (2.38 g, 11.20 mmol) were added N-ethyl-N-(2-fluoro-4-iodobenzyl)ethylamine (1.72 g, 5.60 mmol) in dioxane (50 mL) The solution was heated to 110 ° C with stirring for 9 h. After the reaction was completed, the mixture was cooled to room temperature, poured into dichloromethane (200 mL), and washed with water (200 mL × 3) and saturated brine (200 mL). The organic layer was evaporated to dryness crystals crystals crystals crystals
MS(ESI,pos.ion)m/z：303.7(M+1)；1H NMR(400MHz CDCl3)：δ 1.06(t,6H,J=7.2Hz),2.07(s,3H),2.17(s,3H),2.53-2.58(m,4H),3.65(s,2H),6.98(s,1H),7.15-7.09(m,3H),7.55(t,1H,J=8.2Hz)。 MS (ESI, pos.) m/z: 303.7 (M + 1); 1 H NMR (400 MHz CDCl 3 ): δ 1.06 (t, 6H, J = 7.2 Hz), 2.07 (s, 3H), 2.17 ( s, 3H), 2.53-2.58 (m, 4H), 3.65 (s, 2H), 6.98 (s, 1H), 7.15-7.09 (m, 3H), 7.55 (t, 1H, J = 8.2 Hz).
1-甲基-2-氟-4-硝基苯(4.96g,32mmol)，NBS(6.05g,34mmol)加入到四氯化碳(80mL)中，攪拌溶解，再加入BPO(0.39g,1.60mmol)，68℃下攪拌反應5h。停止反應後，過濾，蒸去溶劑，粗產品經柱層析純化(乙酸乙酯/石油醚(V/V)=1/20)，得到黃色固體(4.53g,60%)。 1-methyl-2-fluoro-4-nitrobenzene (4.96 g, 32 mmol), NBS (6.05 g, 34 mmol) was added to carbon tetrachloride (80 mL), stirred and dissolved, then BPO (0.39 g, 1.60) Methyl), the reaction was stirred at 68 ° C for 5 h. After the reaction was quenched, EtOAc (EtOAc m.
1-溴甲基-2-氟-4-硝基苯(3.04g,13mmol)加入到二氯甲烷(50mL)中，再加入嗎啉(1.74g,20mmol)，三乙胺(2.63g,26mmol)。反應液加熱至回流，過夜。停止反應後蒸餾除去溶劑，粗產品經柱層析純化(乙酸乙酯/石油醚(V/V)=1/4)，得到黃色固體(2.05g,65%)。 1-Bromomethyl-2-fluoro-4-nitrobenzene (3.04 g, 13 mmol) was added to dichloromethane (50 mL), then morpholine (1.74 g, 20 mmol), triethylamine (2.63 g, 26 mmol) ). The reaction was heated to reflux overnight. After the reaction was quenched, the solvent was evaporated, mjjjjjjjj
4-(2-氟-4-硝基苄基)嗎啉(14.80g,62mmol)加入到甲醇(100mL)中，再加入鈀碳(4.00g)，加上氫氣球，在氫氣氛圍下室溫攪拌過夜。反應完後過濾除去鈀碳，蒸乾溶劑，粗產品經柱層析純化(乙酸乙酯/石油醚(V/V)=1/1)，得到棕黃色固體(11.27g,87%)。 4-(2-Fluoro-4-nitrobenzyl)morpholine (14.80 g, 62 mmol) was added to methanol (100 mL), then palladium carbon (4.00 g) was added, and a hydrogen balloon was added. Stir overnight. After completion of the reaction, the palladium carbon was removed by filtration, and the solvent was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
在氮氣保護下，向50mL三口燒瓶中加入3-氟-4-(嗎啉甲基)苯胺(0.21g,1.00mmol)，無水二氯甲烷(10mL)，1.0mol/L三甲基鋁的正庚烷溶液(4.5mL,4.5mmol)，室溫攪拌20分鐘；然後加3-(N-乙醯基氨基)巴豆酸甲酯(0.19g,1.20mmol)的二氯甲烷(5mL)溶液，室溫攪拌10h。向反應體系中加入飽和氯化銨溶液淬滅反應，二氯甲烷萃取；有機層經過飽和碳酸氫鈉溶液和飽和食鹽水洗滌後，無水硫酸鈉乾燥。減壓蒸去溶劑得粗產品，粗產品經柱層析純化(乙酸乙酯/石油醚(V/V)=1/1)，得到淡黃色固體(0.105g,30%)。 To a 50 mL three-necked flask, 3-fluoro-4-(morpholinyl)aniline (0.21 g, 1.00 mmol), anhydrous dichloromethane (10 mL), 1.0 mol/L trimethyl aluminum was added under a nitrogen atmosphere. Heptane solution (4.5 mL, 4.5 mmol), stirred at room temperature for 20 min; then a solution of methyl 3-(N-ethylamino) crotonate (0.19 g, 1.20 mmol) in dichloromethane (5 mL) Stir for 10h. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride, and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness crystals crystals crystals crystals crystals crystals
MS(ESI,pos.ion)m/z：318.2(M+1)；1H NMR(400MHz CDCl3)：δ 2.18(s,3H),2.31(s,3H),2.53(s,4H),3.62(m,2H),3.74(s,4H),6.3(s,1H),6.96(m,2H),7.61(s,1H)。 MS (ESI, pos.ion) m / z: 318.2 (M + 1); 1 H NMR (400MHz CDCl 3): δ 2.18 (s, 3H), 2.31 (s, 3H), 2.53 (s, 4H), 3.62 (m, 2H), 3.74 (s, 4H), 6.3 (s, 1H), 6.96 (m, 2H), 7.61 (s, 1H).
4-羥基硫代苯甲醯胺(30.64g,0.20mol)和2-溴-1,1-二甲氧基乙烷(31.00g,0.20mol)在乙醇(600mL)中室溫攪拌，對甲苯磺酸(34.44g,0.20mol)加入至反應液中。加熱至90℃反應24h。反應結束後冷卻至室溫，減壓蒸餾除去溶劑，加入水(200mL)，用飽和碳酸氫鈉溶液調pH值至8，二氯甲烷(200mL×3)萃取，合併有機相，減壓蒸餾濃縮得到黃色固體(21.3g,60%)。 4-Hydroxythiobenzamide (30.64 g, 0.20 mol) and 2-bromo-1,1-dimethoxyethane (31.00 g, 0.20 mol) in ethanol (600 mL) at room temperature, toluene Sulfonic acid (34.44 g, 0.20 mol) was added to the reaction solution. Heat to 90 ° C for 24 h. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated evaporated evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjj A yellow solid (21.3 g, 60%) was obtained.
2-(4-羥基苯基)噻唑(21.27g,0.12mol)和K2CO3(82.93g,0.60mol)在丙酮(1000mL)中室溫攪拌，溴乙烷(39.24g,0.36mol)加入至反應液中。60℃回流11h。冷卻至室溫，過濾，減壓蒸餾濃縮濾液後，得到白色固體(24.54g,100%)。 2-(4-Hydroxyphenyl)thiazole (21.27 g, 0.12 mol) and K 2 CO 3 (82.93 g, 0.60 mol) were stirred in acetone (1000 mL) at room temperature, and ethyl bromide (39.24 g, 0.36 mol) was added. Into the reaction solution. Reflow at 60 ° C for 11 h. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated evaporated.
2-(4-乙氧苯基)噻唑(1.03g,5.00mmol)在DCM(30mL)中，氮氣保護下室溫攪拌，NBS(0.98g,5.50mmol)和冰醋酸(0.3mL)加入反應液中。48℃反應3h。反應結束後冷卻至室溫，減壓蒸去溶劑；粗產品經柱層析純化(乙酸乙酯/石油醚(V/V)=1/1)，真空乾燥後，得到白色固體(1.34g,94%)。 2-(4-Ethoxyphenyl)thiazole (1.03 g, 5.00 mmol) in DCM (30 mL) EtOAc (EtOAc) in. The reaction was carried out at 48 ° C for 3 h. After completion of the reaction, the mixture was cooled to room temperature. EtOAc was evaporated. 94%).
在氮氣保護下，CuI(0.038g,0.20mmol)，Cs2CO3(0.98g,3.00mmol)和配體8-羥基喹啉(0.029g,0.20mmol)加入到DMSO(2mL)中，室溫攪拌30分鐘。用注射器加入溶於DMSO(2mL)的3,5-二甲基吡啶酮(0.30g,2.40mmol)和5-溴-2-(4-乙氧基苯基)噻唑(0.57g,2.00mmol)後，加熱至130℃反應12h。冷卻至室溫，過濾，水(10mL)和二氯甲烷(20mL×3)萃取，收集有機相，減壓蒸乾溶劑。粗產品柱層析純化(石油醚/乙酸乙酯(V/V)=1/10)，得到白色固體(0.17g,26%)。 Under nitrogen, CuI (0.038 g, 0.20 mmol), Cs 2 CO 3 (0.98 g, 3.00 mmol) and ligand 8-hydroxyquinoline (0.029 g, 0.20 mmol) were added to DMSO (2 mL) at room temperature Stir for 30 minutes. 3,5-Dimethylpyridone (0.30 g, 2.40 mmol) and 5-bromo-2-(4-ethoxyphenyl)thiazole (0.57 g, 2.00 mmol) dissolved in DMSO (2 mL) were added by syringe. Thereafter, the mixture was heated to 130 ° C for 12 h. After cooling to room temperature, filtration, water (10 mL) and dichloromethane (20 mL×3) were evaporated. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc:
MS(ESI,pos.ion)m/z：327(M+1)；1H NMR(400MHz CDCl3)：δ 1.44(t,3H,J=7.0Hz),2.15(s,3H),2.21(s,3H),4.07-4.12(m,2H),6.95(d,2H,J=8.8Hz),7.16(s,1H),7.36(s,1H),7.82(s,1H),7.88(d,2H,J=8.8Hz)。 MS (ESI, pos.) m/z: 327 (M + 1); 1 H NMR (400 MHz CDCl 3 ): δ 1.44 (t, 3H, J = 7.0 Hz), 2.15 (s, 3H), 2.21. s, 3H), 4.07-4.12 (m, 2H), 6.95 (d, 2H, J = 8.8 Hz), 7.16 (s, 1H), 7.36 (s, 1H), 7.82 (s, 1H), 7.88 (d) , 2H, J = 8.8Hz).
3,4-二氟硝基苯(20.0g,0.13mol)用滴液漏斗滴加入溶有嗎啉(12.04 g,0.14mol)和三乙胺(13.97g,0.14mol)的乙酸乙酯溶液(冰浴冷卻)，反應液緩慢升至室溫，攪拌過夜。混合物過濾，濾餅用水洗滌，真空乾燥。濾液分出有機相，水相用乙酸乙酯洗滌，無水硫酸鈉乾燥後，減壓蒸去溶劑得黃色固體。合併上述兩部分固體即得到產品黃色固體(28.0g,99%)。 3,4-Difluoronitrobenzene (20.0 g, 0.13 mol) was added dropwise with morpholine (12.04) using a dropping funnel. g, 0.14 mol) and a solution of triethylamine (13.97 g, 0.14 mol) in ethyl acetate (cooling in ice-bath), the reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was filtered and the filter cake was washed with water and dried in vacuo. The organic layer was separated, and the aqueous layer was washed with ethyl acetate. The product was obtained as a yellow solid (28.0 g, 99%).
鈀碳(3.0g)加入到4-(2-氟-4-硝基苯基)嗎啉(15.0g,66mmol)的四氫呋喃(100mL)溶液，混合物通入氫氣，室溫攪拌12h。將混合物用矽藻土過濾，濾液減壓蒸乾溶劑，得到白色固體(11.55g,89%)。 Palladium on carbon (3.0 g) was added to a solution of 4-(2-fluoro-4-nitrophenyl)morpholine (15.0 g, 66 mmol) in THF (100 mL). The mixture was filtered over EtOAc (EtOAc)EtOAc.
將2-氨基巴豆酸甲酯(100g,0.87mol)加入乙酸酐(300mL,3.04mol)中，攪拌下加熱至75℃反應3h，冷卻至室溫，減壓蒸乾溶劑，粗產品於乙醇(150mL)中重結晶，得到白色晶體(46g,34%)。 Methyl 2-aminocrotonate (100 g, 0.87 mol) was added to acetic anhydride (300 mL, 3.04 mol), heated to 75 ° C for 3 h with stirring, cooled to room temperature, and the solvent was evaporated to dryness. Recrystallization from 150 mL) gave white crystals (46 g, 34%).
在氮氣保護下，3-氟-4-嗎啉基苯胺(11.0g,56mmol)溶於二氯甲烷(200mL)。小心加入三甲基鋁的1M正庚烷溶液(168mL,168mmol)。滴加完畢，繼續攪拌20min。小心加入溶於二氯甲烷(30mL)的3-(N-乙醯基氨基)巴豆酸甲酯(10.57g,67mmol)。室溫攪拌5h。反應體系用飽和氯化銨溶液淬滅，水洗後，用無水硫酸鈉乾燥。減壓蒸去溶劑得粗品，粗品在乙酸乙酸中重結晶，得到淡黃色固體(11.39g,67%)。 3-Fluoro-4-morpholinylaniline (11.0 g, 56 mmol) was dissolved in dichloromethane (200 mL). A solution of trimethylaluminum in 1 M n-heptane (168 mL, 168 mmol) was carefully taken. After the addition was completed, stirring was continued for 20 min. Methyl 3-(N-ethylidenylamino)crotonate (10.57 g, 67 mmol) dissolved in dichloromethane (30 mL) was added. Stir at room temperature for 5 h. The reaction system was quenched with saturated aqueous ammonium chloride, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness crystals crystals crystals crystals crystals
MS(ESI,pos.ion)m/z：304.2(M+1)；1H NMR(400MHz,CDCl3)：δ 2.19(s,3H),2.30(s,3H),3.09-3.22(m,4H),3.88(t,4H,J=4.6Hz),6.28(s,1H),6.90-6.94(m,2H),7.01-7.06(m,1H)。 MS (ESI, pos.ion) m / z: 304.2 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.19 (s, 3H), 2.30 (s, 3H), 3.09-3.22 (m, 4H), 3.88 (t, 4H, J = 4.6 Hz), 6.28 (s, 1H), 6.90-6.94 (m, 2H), 7.01-7.06 (m, 1H).
冰浴條件下，將3,4-二氟硝基苯(5.00g,31.43mmol)緩慢滴加到二乙 胺(2.53g,34.59mmol)和三乙胺(3.82g,37.75mmol)的乙酸乙酯溶液(40mL)中，滴加過程持續約30分鐘。滴畢緩慢升至室溫，有固體析出。過濾，濾餅用適量水洗，乾燥得黃色固體。濾液用乙酸乙酯萃，取有機層，無水硫酸鈉乾燥，蒸乾乙酸乙酯得黃色固體，合併上述兩部分固體即到得黃色固體(7.20g,99%). 3,4-difluoronitrobenzene (5.00 g, 31.43 mmol) was slowly added dropwise to the second bath under ice bath A solution of the amine (2.53 g, 34.59 mmol) and triethylamine (3.82 g, 37.75 mmol) in ethyl acetate (40 mL). The dropping was slowly raised to room temperature, and a solid precipitated. Filtration, the filter cake was washed with an appropriate amount of water and dried to give a yellow solid. The filtrate was extracted with EtOAc. EtOAc (EtOAc m.
鈀/碳(1.50g)加入到含有N,N-二乙基-2-氟-4-硝基苯胺(4.00g,18.84mmol)的四氫呋喃(50mL)溶液中，室溫條件下，氫氣氛圍中反應12h。將反應液過濾。濾液減壓蒸乾溶劑，得到灰白色固體(3.20g,93%)。 Palladium/carbon (1.50 g) was added to a solution of N,N -diethyl-2-fluoro-4-nitroaniline (4.00 g, 18.84 mmol) in tetrahydrofuran (50 mL) at room temperature under hydrogen atmosphere Reaction for 12 h. The reaction solution was filtered. The filtrate was evaporated to dryness crystall
室溫，氮氣氛圍下，將N1,N1-二乙基-2-氟-1,4-苯二胺(1.50g,8.23mmol)溶於乾燥的二氯甲烷(60mL)中，緩慢滴加1M三甲基鋁庚烷溶液(33mL,33mmol)，滴畢繼續攪拌40分鐘。然後滴加3-(N-乙醯基氨基)巴豆酸甲酯(2.58g,16.40mmol)的乾燥二氯甲烷溶液(20mL)，滴畢繼續攪拌6h。緩慢加入適量水淬滅三甲基鋁，有機層飽和食鹽水洗，無水硫酸鈉乾燥。有機層經減壓蒸去溶劑得粗品，粗品在乙酸乙酸中重結晶，得到淡黃色固體(1.60g,67%)。 N 1 ,N 1 -diethyl-2-fluoro-1,4-phenylenediamine (1.50 g, 8.23 mmol) was dissolved in dry dichloromethane (60 mL) at room temperature under a nitrogen atmosphere. A 1 M solution of trimethylaluminum heptane (33 mL, 33 mmol) was added and stirring was continued for 40 min. Then, a solution of methyl 3-(N-acetamidoamino)crotonate (2.58 g, 16.40 mmol) in dichloromethane (20 mL) was evaporated. The trimethylaluminum was quenched by adding an appropriate amount of water, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was evaporated to dryness crystals crystals crystals
MS(ESI,pos.ion)m/z：290.2(M+1)；1H NMR(400MHz,DMSO)：δ 1.07(t,6H,J=7.04Hz),2.08(s,3H),2.19(s,3H),3.22-3.27(m,4H),6.22(s,1H),6.98-7.06(m,2H),7.16-7.20(m,1H)。 MS (ESI, pos.ion) m / z: 290.2 (M + 1); 1 H NMR (400MHz, DMSO): δ 1.07 (t, 6H, J = 7.04Hz), 2.08 (s, 3H), 2.19 ( s, 3H), 3.22-3.27 (m, 4H), 6.22 (s, 1H), 6.98-7.06 (m, 2H), 7.16-7.20 (m, 1H).
冰浴條件下，將3,4-二氟硝基苯(5.00g,31.43mmol)緩慢滴加到硫代嗎啡啉(3.57g,34.56mmol)和三乙胺(3.50g,34.56mmol)的乙酸乙酯溶液中，滴加過程持續約30分鐘。滴畢緩慢升至室溫，有固體析出。過濾， 濾餅用適量水洗，乾燥得到黃色固體。濾液用乙酸乙酯萃取，無水硫酸鈉乾燥有機相，蒸乾乙酸乙酯得到黃色固體。合併上述兩部分固體即得到黃色固體(5.50g,72%)。 3,4-Difluoronitrobenzene (5.00 g, 31.43 mmol) was slowly added dropwise to the thiomorpholine (3.57 g, 34.56 mmol) and triethylamine (3.50 g, 34.56 mmol) of acetic acid under ice bath. In the ethyl ester solution, the dropping process lasted for about 30 minutes. The dropping was slowly raised to room temperature, and a solid precipitated. filter, The filter cake was washed with an appropriate amount of water and dried to give a yellow solid. The filtrate was extracted with EtOAc. The two solids were combined to give a yellow solid (5.50 g, 72%).
鈀碳(1.30g)加入到含有3-氟-4-硫代嗎啡啉基硝基苯(4.00g,16.51mmol)的四氫呋喃溶液(50mL)中，室溫條件下，氫氣氛圍中反應12h。將反應液過濾。濾液減壓蒸乾溶劑，得到灰白色固體(3.40g,97%)。 Palladium carbon (1.30 g) was added to a solution of tetrafluorofuran (50 mL) containing 3-fluoro-4-thiomorpholinyl nitrobenzene (4.00 g, 16.51 mmol), and the mixture was reacted in a hydrogen atmosphere at room temperature for 12 h. The reaction solution was filtered. The filtrate was evaporated to dryness crystall
室溫，氮氣氛圍下，將3-氟-4-硫代嗎啡啉基苯胺(1.20g,5.65mmol)溶於乾燥的二氯甲烷(60mL)中，緩慢滴加1M三甲基鋁庚烷溶液(28.5mL,28.5mmol)，滴畢繼續攪拌40分鐘。然後滴加3-(N-乙醯基氨基)巴豆酸甲酯(2.66g,16.92mmol)的乾燥二氯甲烷溶液(20mL)，滴畢繼續攪拌6h。緩慢加入適量水淬滅三甲基鋁，飽和食鹽水洗，乾燥。減壓蒸乾溶劑，得到淡黃色固體(0.91g,67%)。 3-Fluoro-4-thiomorpholine phenylamine (1.20g, 5.65mmol) was dissolved in dry dichloromethane (60mL) at room temperature under nitrogen atmosphere, and 1M trimethylaluminum heptane solution was slowly added dropwise. (28.5 mL, 28.5 mmol), stirring was continued for 40 minutes. Then, a solution of methyl 3-(N-acetamidoamino)crotonate (2.66 g, 16.92 mmol) in dichloromethane (20 mL) was evaporated. Slowly add an appropriate amount of water to quench the trimethylaluminum, wash with saturated brine, and dry. The solvent was evaporated to dryness crystall
MS(ESI,pos.ion)m/z：320.2(M+1)；1H NMR(400MHz,CDCl3)：δ 2.07(s,3H),2.19(s,3H),2.77(t,4H,J=4.76Hz),3.33(d,4H,J=4.12Hz),6.23(s,1H),7.08-7.11(m,1H),7.16-7.20(m,1H),7.25-7.29(m,1H)。 MS (ESI, pos. ion) m/z: 320.2 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.07 (s, 3H), 2.19 (s, 3H), 2.77 (t, 4H, J = 4.76 Hz), 3.33 (d, 4H, J = 4.12 Hz), 6.23 (s, 1H), 7.08-7.11 (m, 1H), 7.16-7.20 (m, 1H), 7.25-7.29 (m, 1H) ).
將3,4-二氟硝基苯(3.18g,20mmol)加入到含有碳酸鉀(5.53g,40mmol)和1,1-二氧代硫代嗎啡啉鹽酸鹽(3.60g,21mmol)的DMSO(50mL)的懸濁液中，升溫至100℃反應12h。加入水(150mL)，二氯甲烷(100mL×2)萃取。無水硫酸鈉乾燥有機相，減壓蒸乾溶劑，得到黃色固體(6.04g,70%)。 3,4-Difluoronitrobenzene (3.18 g, 20 mmol) was added to DMSO containing potassium carbonate (5.53 g, 40 mmol) and 1,1-dioxothiomorpholine hydrochloride (3.60 g, 21 mmol). The suspension was heated to 100 ° C for 12 h in a suspension of (50 mL). Water (150 mL) was added and extracted with dichloromethane (100 mL×2). The organic phase was dried over anhydrous sodium sulfate and evaporated
鈀/碳(1.30g)加入到含有3-氟-4-(1,1-二氧代硫代嗎啡啉基)硝基苯(4.00g,14.58mmol)的四氫呋喃(50mL)溶液中，室溫條件下，氫氣氛圍中反應12h。將反應液過濾。將濾液減壓蒸乾，得到灰白色固體(2.40g,67%)。 Palladium on carbon (1.30 g) was added to a solution containing 3-fluoro-4-(1,1-dioxothiomorphinyl)nitrobenzene (4.00 g, 14.58 mmol) in tetrahydrofuran (50 mL), rt. Under the conditions, the reaction was carried out for 12 h in a hydrogen atmosphere. The reaction solution was filtered. The filtrate was evaporated to dryness crystall
室溫，氮氣氛圍下，將3-氟-4-(1,1-二氧代硫代嗎啉基)苯胺(1.20g,4.91mmol)溶於乾燥的二氯甲烷(100mL)中，緩慢滴加1M三甲基鋁庚烷溶液(28.5mL,28.5mmol)，滴畢繼續攪拌20分鐘。然後滴加3-(N-乙醯基氨基)巴豆酸甲酯(2.32g,14.76mmol)的乾燥二氯甲烷溶液(30mL)，滴畢繼續攪拌15h。緩慢加入適量水淬滅三甲基鋁，飽和食鹽水洗，無水硫酸鈉乾燥。減壓蒸乾溶劑，得到黃色固體(0.81g,47%)。 3-Fluoro-4-(1,1-dioxothiomorpholinyl)aniline (1.20 g, 4.91 mmol) was dissolved in dry dichloromethane (100 mL) at room temperature under nitrogen. A 1 M solution of trimethylaluminum heptane (28.5 mL, 28.5 mmol) was added and stirring was continued for 20 minutes. Then, a solution of methyl 3-(N-acetamidoamino)crotonate (2.32 g, 14.76 mmol) in dichloromethane (30 mL) was evaporated. The trimethylaluminum was quenched by adding an appropriate amount of water, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness crystall
MS(ESI,pos.ion)m/z：352.1(M+1)；1H NMR(400MHz,DMSO-d6)：δ 2.07(s,3H),2.20(s,3H),3.29(t,4H,J=4.4Hz),3.58(d,4H,J=4.4Hz),6.23(s,1H),7.13-7.11(m,1H),7.26-7.28(m,1H),7.31-7.35(m,1H)。 MS (ESI, pos.ion) m / z: 352.1 (M + 1); 1 H NMR (400MHz, DMSO-d 6): δ 2.07 (s, 3H), 2.20 (s, 3H), 3.29 (t, 4H, J = 4.4 Hz), 3.58 (d, 4H, J = 4.4 Hz), 6.23 (s, 1H), 7.13 - 7.11 (m, 1H), 7.26-7.28 (m, 1H), 7.31 - 7.35 (m , 1H).
呱啶(5.88g,69mmol)和三乙胺(6.98g,69mmol)溶解在乙酸乙酯(60mL)中，攪拌下將3,4-二氟硝基苯(10.00g,63mmol)滴加其中，室溫攪拌過夜。反應完後，反應液用飽和鹽水洗滌，無水硫酸鈉乾燥，減壓蒸餾除去溶劑，得到黃色固體(14.00g,99%)。 Acridine (5.88 g, 69 mmol) and triethylamine (6.98 g, 69 mmol) were dissolved in ethyl acetate (60 mL), and 3,4-difluoronitrobenzene (10.00 g, 63 mmol) was added dropwise with stirring. Stir at room temperature overnight. After the reaction, the reaction mixture was washed with EtOAc EtOAc m.
3-氟-4-呱啶基硝基苯(14.00g,62mmol)溶解在四氫呋喃(80mL)中，將鈀碳(3.00g)加入其中後，加上氫氣球，在氫氣的氛圍下室溫攪拌過 夜。過濾除去鈀碳，減壓蒸乾溶劑，得到棕黃色固體(11.00g,87%)。 3-Fluoro-4-acridinyl nitrobenzene (14.00 g, 62 mmol) was dissolved in tetrahydrofuran (80 mL), palladium carbon (3.00 g) was added thereto, and a hydrogen balloon was added thereto, and stirred at room temperature under a hydrogen atmosphere. Over night. The palladium carbon was removed by filtration, and the solvent was evaporated to dryness crystals crystals crystals
3-氟-4-呱啶基苯胺(10.00g,51mmol)溶解在乾燥的二氯甲烷(100mL)中，在氮氣保護下緩慢加入1M三甲基鋁甲苯溶液(155mL,155mmol)。室溫下攪拌20分鐘後，將溶解在乾燥的二氯甲烷(20mL)中的3-(N-乙醯基氨基)巴豆酸甲酯(9.72g,62mmol)滴加到反應液中。室溫下攪拌5小時。停止反應後，用飽和氯化銨溶液淬滅反應，用二氯甲烷萃取，飽和鹽水洗滌，有機相用無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(乙酸乙酯/石油醚(V/V)=1/2)，得到淡黃色固體(11.02g,71%)。 3-Fluoro-4-acridinylaniline (10.00 g, 51 mmol) was dissolved in dry dichloromethane (100 mL). After stirring at room temperature for 20 minutes, methyl 3-(N-ethylidinoamino)crotonate (9.72 g, 62 mmol) dissolved in dry dichloromethane (20 mL) was added dropwise. Stir at room temperature for 5 hours. After the reaction was stopped, the reaction was quenched with EtOAc EtOAc (EtOAc) Petroleum ether (V/V) = 1/2) gave a pale yellow solid (11.02 g, 71%).
MS(ESI,pos.ion)m/z：302.2(M+1)；1H NMR(400MHz,CDCl3)：δ 1.57-1.63(m,2H),1.78-1.72(m,4H),2.18(s,3H),2.29(s,3H),3.07-3.01(m,2H),3.11-3.16(m,2H),6.28(s,1H),6.86-6.88(m,1H),6.89-6.90(m,1H),7.02-7.06(m,1H)。 MS (ESI, pos.ion) m / z: 302.2 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 1.57-1.63 (m, 2H), 1.78-1.72 (m, 4H), 2.18 ( s, 3H), 2.29 (s, 3H), 3.07-3.01 (m, 2H), 3.11-3.16 (m, 2H), 6.28 (s, 1H), 6.86-6.88 (m, 1H), 6.89-6.90 ( m, 1H), 7.02-7.06 (m, 1H).
N-甲基呱嗪(6.91g,69mmol)和三乙胺(6.98g,69mmol)溶解在乙酸乙酯(60mL)中，攪拌下將3,4-二氟硝基苯(10.02g,63mmol)滴加其中，室溫攪拌過夜。反應完後，反應液用飽和鹽水洗滌，無水硫酸鈉乾燥，減壓蒸餾除去溶劑，得到黃色固體(14.75g,98%)。 N-methylpyridazine (6.91 g, 69 mmol) and triethylamine (6.98 g, 69 mmol) were dissolved in ethyl acetate (60 mL) and 3,4-difluoronitrobenzene (10.02 g, 63 mmol) It was added dropwise and stirred at room temperature overnight. After the reaction, the reaction mixture was washed with EtOAc EtOAcjjjjjjjjj
3-氟-4-(4-甲基呱嗪基)硝基苯(14.76g,61.70mmol)溶解在四氫呋喃(80mL)中，將鈀/碳(3.00g)加入其中後，加上氫氣球，在氫氣的氛圍下室溫攪拌過夜。過濾除去鈀碳，減壓蒸乾溶劑，得到灰白色固體(11.99g,93%)。 3-Fluoro-4-(4-methylpyridazinyl)nitrobenzene (14.76 g, 61.70 mmol) was dissolved in tetrahydrofuran (80 mL), palladium/carbon (3.00 g) was added thereto, and a hydrogen balloon was added thereto. Stir at room temperature overnight under a hydrogen atmosphere. The palladium on carbon was removed by filtration, and the solvent was evaporated to dryness crystall
3-氟-4-(4-甲基呱嗪基)苯胺(11.01g,52.60mmol)溶解在乾燥的二氯甲烷(200mL)中，在氮氣保護下緩慢加入1.0M三甲基鋁甲苯溶液(158mL,158mmol)。室溫下攪拌20分鐘後，將溶解在乾燥的二氯甲烷(20mL)中的3-(N-乙醯基氨基)巴豆酸甲酯(9.92g,63.10mmol)滴加到反應液中。室溫下攪拌5h。停止反應後，用飽和氯化銨溶液淬滅反應，用二氯甲烷萃取，飽和鹽水洗滌，有機相用無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(二氯甲烷/甲醇(V/V)=5/1)，得到白色固體(11.31g,68%)。 3-Fluoro-4-(4-methylpyridazinyl)aniline (11.01 g, 52.60 mmol) was dissolved in dry dichloromethane (200 mL). 158 mL, 158 mmol). After stirring at room temperature for 20 minutes, methyl 3-(N-acetamidoamino)crotonate (9.92 g, 63.10 mmol) dissolved in dry dichloromethane (20 mL) was added dropwise. Stir at room temperature for 5 h. After the reaction was stopped, the reaction was quenched with EtOAc EtOAc (EtOAc m. Methanol (V/V) = 5/1) gave a white solid (11.31 g, 68%).
MS(ESI,pos.ion)m/z：317.2(M+1)；1H NMR(400MHz,CDCl3)：δ 2.19(s,3H),2.29(s,3H),2.37(s,3H),2.61(s,4H),3.14-3.24(m,4H),6.28(s,1H),6.88-6.91(m,2H),7.05(t,1H,J=8.8Hz)。 MS (ESI, pos.ion) m / z: 317.2 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.19 (s, 3H), 2.29 (s, 3H), 2.37 (s, 3H) , 2.61 (s, 4H), 3.14 - 3.24 (m, 4H), 6.28 (s, 1H), 6.88 - 6.91 (m, 2H), 7.05 (t, 1H, J = 8.8 Hz).
將3,4,5-三氟硝基苯(4.00g,22.59mmol)加入到含有脯氨醇(2.74g,27.11mmol)和KOH(3.17g,56.47mmol)的DMSO(30mL)懸濁液中，然後升溫至65℃攪拌4h。反應畢，冷卻至室溫，加入水(150mL)，二氯甲烷萃取(100mL×2)。合併有機相，無水硫酸鈉乾燥，減壓蒸乾溶劑，得到黃色固體(5.00g,93%)。 3,4,5-Trifluoronitrobenzene (4.00 g, 22.59 mmol) was added to a suspension of valine (2.74 g, 27.11 mmol) and KOH (3.17 g, 56.47 mmol) in DMSO (30 mL) Then, the temperature was raised to 65 ° C and stirred for 4 h. After completion of the reaction, it was cooled to room temperature, and water (150 mL) was added, and dichloromethane (100 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate
鈀/碳(1.50g)加入到含有9-氟-7-硝基-2,3,3a,4-四氫-1H-苯[b]吡咯[1,2-d][1,4]惡嗪(4.00g,16.79mmol)的四氫呋喃(40mL)溶液中，室溫條件下，氫氣氛圍中反應12h。將反應液經矽藻土過濾。將濾液旋乾，得到灰白色固體(3.00g,85%)。 Palladium/carbon (1.50g) was added to contain 9-fluoro-7-nitro-2,3,3a,4-tetrahydro-1H-benzene[b]pyrrole[1,2-d][1,4] A solution of the oxazine (4.00 g, 16.79 mmol) in tetrahydrofuran (40 mL) was reacted in a hydrogen atmosphere at room temperature for 12 h. The reaction solution was filtered through celite. The filtrate was dried to give an off-white solid (3.
在室溫，氮氣氛圍下，將9-氟-2,3,3a,4-四氫-1H-苯[b]吡咯[1,2-d][1,4]惡 嗪-7-胺(2.00g,9.61mmol)溶於乾燥的二氯甲烷(50mL)中，緩慢滴加1M三甲基鋁庚烷溶液(48mL,48mmol)，滴畢繼續攪拌40分鐘。然後滴加3-(N-乙醯基氨基)巴豆酸甲酯(2.66g,16.92mmol)的乾燥二氯甲烷溶液(30mL)，滴畢繼續攪拌5h。緩慢加入適量水淬滅三甲基鋁，飽和食鹽水洗，無水硫酸鈉乾燥，過濾，有機層減壓蒸乾溶劑，得到白色固體(1.00g,33%)。 9-fluoro-2,3,3a,4-tetrahydro-1H-benzene[b]pyrrole[1,2-d][1,4] evil at room temperature under nitrogen atmosphere The oxazine-7-amine (2.00 g, 9.61 mmol) was dissolved in dry methylene chloride (50 mL), and then 1M trimethylaluminum heptane solution (48 mL, 48 mmol) was slowly added dropwise, and stirring was continued for 40 minutes. Then, a dry dichloromethane solution (30 mL) of methyl 3-(N-ethylidenylamino)crotonate (2.66 g, 16.92 mmol) was added dropwise, and stirring was continued for 5 h. Trimethylaluminum was quenched by the addition of aq. EtOAc (EtOAc).
MS(ESI,pos.ion)m/z：316.2(M+1)：1H NMR(400MHz,DMSO-d6)：δ 1.52-1.56(m,1H),1.88-1.90(m,2H),2.10(s,3H),2.18(s,3H),2.31(s,1H),3.12-3.18(q,1H),3.37-3.40(m,2H),3.79-3.84(m,1H),4.35(d,1H,J=9.5Hz),6.20(s,1H),6.71(s,1H),6.82(d,1H,J=1.7Hz)。 MS (ESI, pos.ion) m / z: 316.2 (M + 1): 1 H NMR (400MHz, DMSO-d 6): δ 1.52-1.56 (m, 1H), 1.88-1.90 (m, 2H), 2.10(s,3H), 2.18(s,3H), 2.31(s,1H),3.12-3.18(q,1H), 3.37-3.40(m,2H),3.79-3.84(m,1H), 4.35( d, 1H, J = 9.5 Hz), 6.20 (s, 1H), 6.71 (s, 1H), 6.82 (d, 1H, J = 1.7 Hz).
在500mL三口燒瓶中加入4-氨基苯甲醯胺(6.81g,50mmol)並溶解於DMF(70mL)中，然後加入NaI(22.48g,150mmol)和K2CO3(13.82g,100mmol)，最後在攪拌下加入溴乙烷(13.62g,125mmol)。反應體系加熱至110℃反應過夜。第二天再補加溴乙烷(13.62g,125mmol)，110℃繼續反應6h。反應完畢，將混合物冷至室溫，減壓除去DMF，加水(100mL)，攪拌10分鐘，混合物過濾，得到固體，乾燥得到黃色固體(7.40g,77%)。 4-Aminobenzamide (6.81 g, 50 mmol) was added to a 500 mL three-necked flask and dissolved in DMF (70 mL), then NaI (22.48 g, 150 mmol) and K 2 CO 3 (13.82 g, 100 mmol). Ethyl bromide (13.62 g, 125 mmol) was added with stirring. The reaction system was heated to 110 ° C to react overnight. The next day, additional ethyl bromide (13.62 g, 125 mmol) was added and the reaction was continued at 110 ° C for 6 h. After the reaction was completed, the mixture was cooled to EtOAc. EtOAc m.
在250mL三口燒瓶中加入4-(二乙胺基)苯甲醯胺(5.66g,29.43mmol)並溶解於四氫呋喃(80mL)中，反應體系加熱至50℃，1h內加入P2S5(9.81g,44.14mmol)，反應體系加熱至55℃反應8h，反應完畢，將混合物冷至室溫，過濾，減壓蒸乾濾液，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到黃色固體(1.23g,20%)。 4-(Diethylamino)benzamide (5.66 g, 29.43 mmol) was added to a 250 mL three-necked flask and dissolved in tetrahydrofuran (80 mL). The reaction was heated to 50 ° C, and P 2 S 5 (9.81) was added in 1 h. g, 44.14 mmol), the reaction system is heated to 55 ° C for 8 h, the reaction is completed, the mixture is cooled to room temperature, filtered, and the filtrate is evaporated to dryness under reduced pressure. The crude product is purified by column chromatography ( petroleum ether / ethyl acetate V) = 2/1) gave a yellow solid (1.23 g, 20%).
在250mL圓底燒瓶中加入4-(二乙胺基)硫代苯甲醯胺(2.29g,11mmol)溶解於乙醇(60mL)中，然後加入2-溴-1,1-二甲氧基乙烷(1.86g,11mmol)和對甲苯磺酸(1.89g,11mmol)，反應體系加熱至95℃反應過夜。反應完畢，將混合物冷至室溫，減壓蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯/三乙胺(V/V/V)=2/1/0.05)，得到白色固體(1.40g,55%)。 Add 4-(diethylamino) thiobenzamide (2.29 g, 11 mmol) to ethanol (60 mL) in a 250 mL round bottom flask, then add 2-bromo-1,1-dimethoxyB The alkane (1.86 g, 11 mmol) and p-toluenesulfonic acid (1.89 g, 11 mmol) were reacted to 95 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated to dryness. White solid (1.40 g, 55%).
在100mL三口燒瓶中加入N,N-二乙基-4-(噻唑-2-基)苯胺(1.39g,6.00mmol)和濃硫酸(10mL)，體系降溫至-10℃，然後加入濃硝酸(0.45mL)。反應體系升溫至0℃反應3小時。反應完畢，將混合物加入到冰水中，二氯甲烷萃取(30mL×3)，有機層無水硫酸鈉乾燥後，減壓蒸乾溶劑，粗產品經柱層析純化(石油醚/二氯甲烷(V/V)=1/1)，得到黃色固體(0.73g,44%)。 N,N-Diethyl-4-(thiazol-2-yl)aniline (1.39 g, 6.00 mmol) and concentrated sulfuric acid (10 mL) were added to a 100 mL three-necked flask, and the system was cooled to -10 ° C, then concentrated nitric acid ( 0.45 mL). The reaction system was warmed to 0 ° C for 3 hours. After completion of the reaction, the mixture was added to ice water, extracted with dichloromethane (30 mL × 3), dried over anhydrous sodium sulfate, and evaporated. /V) = 1/1) gave a yellow solid (0.73 g, 44%).
在100mL圓底燒瓶中加入N,N-二乙基-4-(5-硝基噻唑-2-基)苯胺(0.73g,2.64mmol)並溶解於甲醇(30mL)中，然後加入Pd/C(73mg)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=5/1)，得到白色固體(0.45g,69%)。 Add N,N-diethyl-4-(5-nitrothiazol-2-yl)aniline (0.73 g, 2.64 mmol) in a 100 mL round bottom flask and dissolve in methanol (30 mL) then Pd/C (73 mg) and passed H 2 . The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was evaporated.jjjjjjjjj
在100mL三口燒瓶中加入2-(4-(二乙胺基)苯基)噻唑-5-胺(0.45g,1.82mmol)並溶解於二氯甲烷(20mL)中，室溫下緩慢加入2M三甲基鋁甲苯溶液(4.5mL,9.0mmol)，反應體系在室溫下反應1h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(315mg,2.00mmol,5mL二氯甲烷溶解)，反應體系在室溫下反應3天。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中淬滅三甲基鋁，二氯甲烷萃取(50mL×3)，無水硫酸鈉乾燥，減壓蒸乾溶劑，粗產品經製備薄層純化，得到黃色固體(22mg,3%)。 Add 2-(4-(diethylamino)phenyl)thiazole-5-amine (0.45 g, 1.82 mmol) to a 100 mL three-neck flask and dissolve in dichloromethane (20 mL). Methyl aluminum toluene solution (4.5 mL, 9.0 mmol), and the reaction was allowed to react at room temperature for 1 h. Then, methyl 3-(N-acetamidoamino)crotonate (315 mg, 2.00 mmol, 5 mL of dichloromethane was dissolved) was slowly added, and the reaction was allowed to react at room temperature for 3 days. After the reaction is completed, a saturated ammonium chloride solution is slowly added to the system to quench the trimethylaluminum, extracted with dichloromethane (50 mL×3), dried over anhydrous sodium sulfate, and the solvent is evaporated to dryness under reduced pressure. , a yellow solid (22 mg, 3%).
MS(ESI,pos.ion)m/z：355.2(M+1)；1H NMR(400MHz,DMSO-d6)：δ 0.89(t,6H,J=12.0Hz),2.08(s,3H),2.23(s,3H),2.95-3.02(m,4H),6.33(s,1H),7.29(d,1H,J=12.0Hz),7.72-7.74(m,2H),7.87(d,1H,J=4.0Hz),7.95-7.98(m,1H)。 MS (ESI, pos.) m/z: 355.2 (M + 1); 1 H NMR (400 MHz, DMSO-d 6 ): δ 0.89 (t, 6H, J = 12.0 Hz), 2.08 (s, 3H) , 2.23 (s, 3H), 2.95-3.02 (m, 4H), 6.33 (s, 1H), 7.29 (d, 1H, J = 12.0 Hz), 7.72-7.74 (m, 2H), 7.87 (d, 1H) , J = 4.0 Hz), 7.95-7.98 (m, 1H).
在500mL三口燒瓶中加入4-氨基苯甲醯胺(6.81g,50mmol)並溶解於DMF(70mL)中，隨後加入NaI(22.48g,150mmol)和K2CO3(13.82g,100mmol)，體系加熱至140℃，然後加入二氯乙醚(14.30g,100mmol)。反應體系升溫到150℃反應5h。反應完畢，將混合物冷至室溫，加水(100mL)，攪拌10分鐘，混合物過濾，固體水洗，乾燥得到黃色固體(6.60g,64%)。 4-Aminobenzamide (6.81 g, 50 mmol) was added to a 500 mL three-neck flask and dissolved in DMF (70 mL), followed by NaI (22.48 g, 150 mmol) and K 2 CO 3 (13.82 g, 100 mmol), system Heat to 140 ° C, then dichloroethyl ether (14.30 g, 100 mmol) was added. The reaction system was heated to 150 ° C for 5 h. After the reaction was completed, the mixture was cooled to room temperature, EtOAc (EtOAc)
在250mL圓底燒瓶中加入4-(嗎啉基)苯甲醯胺(4.91g,23.80mmol)溶解於四氫呋喃(70mL)中，攪拌下加入Lawesson’s Reagent(10.60g,26.20mmol)，反應體系加熱至70℃反應4h。反應完畢，將混合物冷至室溫，減壓蒸乾溶劑，加入二氯甲烷(30mL)和水(100mL)，混合物過濾，所得的固體用水洗後，乾燥得到黃色固體(4.41g,83%)。 4-(morpholinyl)benzamide (4.91 g, 23.80 mmol) was added to tetrahydrofuran (70 mL) in a 250 mL round bottom flask, and Lawesson's Reagent (10.60 g, 26.20 mmol) was added with stirring, and the reaction system was heated to The reaction was carried out at 70 ° C for 4 h. After completion of the reaction, the mixture was cooled to room temperature. EtOAc was evaporated. .
在250mL圓底燒瓶中加入4-(嗎啉基)硫代苯甲醯胺(2.22g,10mmol)並溶解於乙醇(50mL)中，然後攪拌下加入2-溴-1,1-二甲氧基乙烷(1.69g,10mmol)和對甲苯磺酸(1.90g,10mmol)，反應體系加熱至95℃反應過夜。反應完畢，將混合物冷至室溫，過濾後得到固體，乾燥後得到黃色固體(2.00g,81%)。 4-(morpholinyl) thiobenzamide (2.22 g, 10 mmol) was added to a 250 mL round bottom flask and dissolved in ethanol (50 mL), then 2-bromo-1,1-dimethoxy was added with stirring. Ethylethane (1.69 g, 10 mmol) and p-toluenesulfonic acid (1.90 g, 10 mmol) were reacted to 95 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature and filtered to give a solid.
在100mL三口燒瓶中加入4-(4-(噻唑-2-基)苯基)嗎啉(2.00g,8.13mmol)和濃硫酸(25mL)，體系降溫至-10℃，然後加入濃硝酸(0.60mL)。反應體系升溫至0℃反應4.5h。反應完畢，將混合物加入到冰水中，二氯甲烷萃取(60mL×3)，有機層無水硫酸鈉乾燥，減壓蒸乾溶劑，得到黃色固體(0.70g,30%)。 4-(4-(thiazol-2-yl)phenyl)morpholine (2.00 g, 8.13 mmol) and concentrated sulfuric acid (25 mL) were added to a 100 mL three-necked flask, the system was cooled to -10 ° C, then concentrated nitric acid (0.60) was added. mL). The reaction system was warmed to 0 ° C for 4.5 h. After the reaction was completed, the mixture was poured into EtOAc EtOAc m.
在100mL圓底燒瓶中加入4-(4-(5-硝基噻唑-2-基)苯基)嗎啉(0.70g,2.44mmol)並溶解於二氯甲烷(20mL)中，然後加入Pd/C(70mg)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸乾溶劑，得到灰白色固體(0.20g,32%)。 Add 4-(4-(5-nitrothiazol-2-yl)phenyl)morpholine (0.70 g, 2.44 mmol) to a 100 mL round bottom flask and dissolve in dichloromethane (20 mL) then Pd/ C (70 mg) and passed H 2 . The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was evaporated.
在100mL三口燒瓶中加入2-(4-嗎啉苯基)噻唑-5-胺(0.20g,0.77mmol)並溶解於二氯甲烷(20mL)中，室溫下緩慢加入2M三甲基鋁的甲苯溶液(2.3mL,4.6mmol)，反應體系在室溫下反應1h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(132mg,0.84mmol,5mL二氯甲烷溶解)，反應體系在室溫下反應過夜。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中淬滅三甲基鋁，二氯甲烷萃取(50mL×3)，無水硫酸鈉乾燥，減壓蒸乾溶劑，粗產品經製備薄層純化，得到淡黃色(20mg,7%)。 2-(4-morpholinephenyl)thiazole-5-amine (0.20 g, 0.77 mmol) was added to a 100 mL three-necked flask and dissolved in dichloromethane (20 mL). 2M trimethylaluminum was slowly added at room temperature. A toluene solution (2.3 mL, 4.6 mmol) was reacted for 1 h at room temperature. Then, methyl 3-(N-acetamidoamino)crotonate (132 mg, 0.84 mmol, dissolved in 5 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature overnight. After the reaction is completed, a saturated ammonium chloride solution is slowly added to the system to quench the trimethylaluminum, extracted with dichloromethane (50 mL×3), dried over anhydrous sodium sulfate, and the solvent is evaporated to dryness under reduced pressure. , gave a pale yellow color (20 mg, 7%).
MS(ESI,pos.ion)m/z：369.1(M+1)；1H NMR(400MHz,DMSO-d6)：δ 2.20(s,3H),2.34(s,3H),2.62-2.84(m,2H),3.06-3.10(s,2H),3.63-3.66(m,4H),6.32(s,1H),7.26(d,1H,J=4.2Hz),7.32(d,2H,J=3.2Hz),7.77(d,1H,J=2.4Hz),7.84(d,1H,J=3.6Hz),8.02-8.05(m,1H)。 MS (ESI, pos.) m/z: 369.1 (M + 1); 1 H NMR (400 MHz, DMSO-d 6 ): δ 2.20 (s, 3H), 2.34 (s, 3H), 2.62. m, 2H), 3.06-3.10 (s, 2H), 3.63 - 3.66 (m, 4H), 6.32 (s, 1H), 7.26 (d, 1H, J = 4.2 Hz), 7.32 (d, 2H, J = 3.2 Hz), 7.77 (d, 1H, J = 2.4 Hz), 7.84 (d, 1H, J = 3.6 Hz), 8.02 - 8.05 (m, 1 H).
在250mL圓底燒瓶中加入5-硝基苯胺(6.91g,50mmol)並溶於四氫呋喃(150mL)中，攪拌下向溶液中加入Boc2O(13.10g,60mmol)和DMAP(1.53g,12.5mmol)，氮氣保護下反應體系加熱至回流反應過夜。反應完畢，待冷卻至室溫，反應液減壓蒸去溶劑，剩餘物溶於二氯甲烷(200mL)中 ，該溶液分別用水(200mL×3)和飽和鹽水(200mL)洗滌，無水硫酸鈉乾燥後，減壓蒸去溶劑；粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到淡黃色固體(10.75g,90%)。 5-Nitroaniline (6.91 g, 50 mmol) was added to a 250 mL round bottom flask and dissolved in tetrahydrofuran (150 mL). To the solution was added Boc 2 O (13.10 g, 60 mmol) and DMAP (1.53 g, 12.5 mmol). The reaction system was heated to reflux overnight under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated to dryness crystals.mjjjjjjjjjjjjjjjjjjjjjjjjjjjj After that, the solvent was evaporated under reduced pressure. EtOAcjjjjjjjj
在100mL圓底燒瓶中加入5-硝基叔丁氧羰基苯胺(10.75g,45.12mmol)溶於甲醇(150mL)中，加入10%鈀/碳(0.48g)，氫氣中室溫攪拌反應過夜。反應完畢，過濾，濾液減壓蒸去溶劑；粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到淡黃色固體(7.59g,81%)。 To a 100 mL round bottom flask, 5-nitro-tert-butoxycarbonylaniline (10.75 g, 45.12 mmol) was dissolved in methanol (150 mL), and 10% palladium/carbon (0.48 g) was added. After completion of the reaction, the mixture was filtered. EtOAcjjjjjjjjjj
在氮氣保護下，將5-氨基叔丁氧羰基苯胺(7.59g,36.40mmol)，碳酸鉀(10.06g,72.80mmol)和碘化鈉(16.37g,109.20mmol)懸浮於DMF(300mL)中並加熱至150℃，向上述反應體系中緩慢的加入2,2`-二氯乙醚(5.73g,40.1mmol)，加畢，保持150℃反應過夜。反應完畢，將混合物冷至室溫，傾入水(700mL)中，用二氯甲烷(200mL×3)萃取水溶液，合併有機層並用水(200mL×3)和飽和食鹽水(200mL)洗滌。有機層無水硫酸鈉乾燥後，減壓蒸去溶劑；粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到黃色固體(5.91g,58%)。 5-Amino-tert-butoxycarbonylaniline (7.59 g, 36.40 mmol), potassium carbonate (10.06 g, 72.80 mmol) and sodium iodide (16.37 g, 109.20 mmol) were suspended in DMF (300 mL). After heating to 150 ° C, 2,2'-dichloroethyl ether (5.73 g, 40.1 mmol) was slowly added to the above reaction system, and the reaction was continued at 150 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature, poured into water (700 mL), and the aqueous layer was extracted with dichloromethane (200 mL × 3), and the organic layer was combined and washed with water (200 mL × 3) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate ieldielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel
在100mL圓底燒瓶中加入5-嗎啉叔丁氧碳基苯胺(5.91g,21.20mmol)溶於1M的氯化氫甲醇溶液(106mL,106.0mmol)中，室溫下攪拌過夜。反應完畢，減壓蒸去溶劑，剩餘物加入水(100mL)中，攪拌至完全溶解，加入碳酸鈉的飽和水溶液將溶液調至鹼性，二氯甲烷(100mL×3)萃取水層，合併有機層並用飽和食鹽水(150mL)洗滌。有機層無水硫酸鈉乾燥後，減壓蒸去溶劑，得到淺棕色固體(3.42g,91%)。 To a 100 mL round bottom flask was added 5-morpholine tert-butoxycarbyl aniline (5.91 g, 21.20 mmol) in 1M MeOH (MeOH) After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was added to water (100 mL), and the mixture was stirred to dissolve completely. The solution was adjusted to basic with saturated aqueous sodium carbonate, and the aqueous layer was extracted with dichloromethane (100 mL×3). The layers were washed with saturated brine (150 mL). The organic layer was dried over anhydrous sodium sulfate.
在氮氣保護下，向500mL兩口燒瓶中加入5-嗎啉苯胺(3.42g,19.20mmol)溶於二氯甲烷(100mL)中，攪拌下小心的加入1mol/L三甲基鋁的甲苯溶液(96mL,96mmol)，加畢，反應體系在室溫下攪拌反應30min。小心的向反應體系中加入3-(N-乙醯基氨基)巴豆酸甲酯(3.29g,19.20mmol)的二氯甲烷(50mL)溶液，加畢，室溫下攪拌過夜。反應完畢，緩慢用氯 化氨飽和水溶液(200mL)淬滅反應，二氯甲烷(200mL×3)萃取，合併有機層並用飽和食鹽水(300mL)洗滌。有機層無水硫酸鈉乾燥後，減壓蒸去溶劑；粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(0.73g,13%)。 Under a nitrogen atmosphere, 5-morpholinaniline (3.42 g, 19.20 mmol) was added to dichloromethane (100 mL) in a 500 mL two-necked flask, and a 1 mol/L solution of trimethylaluminum in toluene (96 mL) was carefully added with stirring. , 96 mmol), after the addition, the reaction system was stirred at room temperature for 30 min. A solution of methyl 3-(N-ethylidenyl) crotonate (3.29 g, 19.20 mmol) in dichloromethane (50 mL) was evaporated. After the reaction is completed, slowly use chlorine The reaction was quenched with EtOAc (EtOAc) (EtOAc) The organic layer was dried over anhydrous sodium sulfate. EtOAcjjjjjjjjj
MS(ESI,pos.ion)m/z：286.3(M+1)；1H NMR(400MHz,CDCl3)：δ 2.19(s,3H),2.29(s,3H),3.17-3.19(m,4H),3.84(t,4H,J=4.8Hz),6.28(s,1H),6.66(d,2H,J=8.0Hz),6.98(d,1H,J=9.3Hz),7.40(t,1H,J=8.2Hz)。 MS (ESI, pos.) m/z: 286.3 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.19 (s, 3H), 2.29 (s, 3H), 3.17 - 3.19 (m, 4H), 3.84 (t, 4H, J = 4.8 Hz), 6.28 (s, 1H), 6.66 (d, 2H, J = 8.0 Hz), 6.98 (d, 1H, J = 9.3 Hz), 7.40 (t, 1H, J = 8.2 Hz).
在250mL圓底燒瓶中加入2-氟-5-硝基苯胺(4.68g,30mmol)並溶於四氫呋喃(150mL)中，攪拌下向溶液中加入Boc2O(9.82g,45mmol)和DMAP(7.33g,60mmol)，氮氣保護下反應體系加熱至回流反應過夜。反應完畢，待冷卻至室溫，反應液減壓蒸去溶劑，剩餘物溶於乙酸乙酯(250mL)中，有機層分別用水(200mL×3)和飽和鹽水(200mL)洗滌；粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=8/1)，得到淡黃色固體物(3.54g,40%)。 2-Fluoro-5-nitroaniline (4.68 g, 30 mmol) was added to a 250 mL round bottom flask and dissolved in tetrahydrofuran (150 mL). To the solution was added Boc 2 O (9.82 g, 45 mmol) and DMAP (7.33). g, 60 mmol), the reaction was heated to reflux overnight under nitrogen. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated to dryness. The residue was dissolved in ethyl acetate (250mL), and the organic layer was washed with water (200mL×3) and saturated brine (200mL); Purification by chromatography (EtOAc/EtOAc (EtOAc/EtOAc)
在100mL圓底燒瓶中加入2-氟-5-硝基叔丁氧羰基苯胺(3.54g,13.8mmol)溶於甲醇(100mL)中，加入.10%鈀碳(0.15g)，氫氣中室溫攪拌反應過夜。反應完畢，過濾，濾液減壓蒸去溶劑；粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到淡黃色固體(2.02g,65%)。 Add 2-fluoro-5-nitro-tert-butoxycarbonylaniline (3.54 g, 13.8 mmol) in methanol (100 mL) in a 100 mL round bottom flask, add .10% palladium on carbon (0.15 g), at room temperature in hydrogen. The reaction was stirred overnight. After completion of the reaction, the mixture was filtered. EtOAcjjjjjjjjjj
在氮氣保護下，將2-氟-5-氨基叔丁氧羰基苯胺(2.02g,8.93mmol)，碳酸鉀(2.47g,17.86mmol)和碘化鈉(4.02g,26.79mmol)溶於DMF(60 mL)中並加熱至150℃，向上述反應體系中緩慢的加入2,2`-二氯乙醚(1.28g,8.93mmol)，加畢，保持150℃反應過夜。反應完畢，將混合物冷至室溫，傾入水(200mL)中，用二氯甲烷(200mL×2)萃取水溶液，合併有機層並用水(200mL×2)和飽和食鹽水(200mL)洗滌。有機層無水硫酸鈉乾燥後，減壓蒸去溶劑；粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到黃色固體(0.93g,35%)。 2-Fluoro-5-amino-tert-butoxycarbonylaniline (2.02 g, 8.93 mmol), potassium carbonate (2.47 g, 17.86 mmol) and sodium iodide (4.02 g, 26.79 mmol) were dissolved in DMF under nitrogen. 60 In mL) and heating to 150 ° C, 2,2'-dichloroethyl ether (1.28 g, 8.93 mmol) was slowly added to the above reaction system, and the reaction was continued at 150 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature, poured into water (200 mL), and the aqueous layer was extracted with methylene chloride (200 mL × 2), and the organic layer was combined and washed with water (200 mL × 2) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4).
在100mL圓底燒瓶中加入2-氟-5-嗎啉叔丁氧羰基苯胺(0.93g,3.14mmol)溶於1mol/L的氯化氫甲醇溶液(31mL,31mmol)中，室溫下攪拌過夜。反應完畢，減壓蒸去溶劑，剩餘物加入水(150mL)中，攪拌至完全溶解，用碳酸鈉的飽和水溶液鹼化，二氯甲烷(100mL×3)萃取水層，合併有機層並用飽和食鹽水(150mL)洗滌。有機層無水硫酸鈉乾燥後，減壓蒸去溶劑，得到淺棕色固體(0.35g,57%)。 2-Fluoro-5-morpholine tert-butoxycarbonylaniline (0.93 g, 3.14 mmol) was added to a 1 mol/L methanolic hydrogen chloride solution (31 mL, 31 mmol) in a 100 mL round bottom flask and stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated under reduced pressure. the residue was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Wash with water (150 mL). The organic layer was dried over anhydrous sodium sulfate.
在氮氣保護下，向100mL兩口燒瓶中加入2-氟-5-嗎啉苯胺(0.35g,1.78mmol)溶於二氯甲烷(20mL)中，攪拌下小心的加入2M三甲基鋁的甲苯溶液(3.3mL,6.6mmol)，加畢，反應體系在室溫下攪拌反應20min。小心的向反應體系中加入3-(N-乙醯基氨基)巴豆酸甲酯(0.30g,1.78mmol)的二氯甲烷(10mL)溶液，加畢，室溫下攪拌過夜。反應完畢，緩慢的用氯化氨飽和水溶液(80mL)淬滅反應，二氯甲烷(100mL×3)萃取，合併有機層並用飽和食鹽水(150mL)洗滌。有機層無水硫酸鈉乾燥後，減壓蒸去溶劑；粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/2)，得到黃色固體(0.37g,69%)。 To a 100 mL two-necked flask, 2-fluoro-5-morpholinaniline (0.35 g, 1.78 mmol) was dissolved in dichloromethane (20 mL) under nitrogen, and 2 M trimethylaluminum in toluene was carefully added with stirring. (3.3 mL, 6.6 mmol), after completion, the reaction was stirred at room temperature for 20 min. A solution of methyl 3-(N-ethylidylamino)crotonate (0.30 g, 1.78 mmol) in dichloromethane (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was evaporated, mjjjjjjjjjjjj The organic layer was dried over anhydrous sodium sulfate (MgSO4).
MS(ESI,pos.ion)m/z：304.2(M+1)；1H NMR(400MHz,CDCl3)：δ 2.23(s,3H),2.30(s,3H),3.11-3.14(m,4H),3.85(t,4H,J=4.8Hz),6.29(s,1H),6.70-6.71(m,1H),6.96-7.00(m,1H),7.18(t,1H,J=9.0Hz)。 MS (ESI, pos. ion) m/z: 304.2 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.23 (s, 3H), 2.30 (s, 3H), 3.11-3.14 (m, 4H), 3.85 (t, 4H, J = 4.8 Hz), 6.29 (s, 1H), 6.70-6.71 (m, 1H), 6.96-7.00 (m, 1H), 7.18 (t, 1H, J = 9.0 Hz) ).
在100mL圓底燒瓶中加入3,4-二氟硝基苯(1.59g,10mmol)並溶解於DMSO(15mL)中，攪拌下加入K2CO3(3.04g,22mmol)和吡咯(0.74g,11mmol)，反應體系加熱至90℃反應18h。反應完畢，將混合物冷至室溫，加水(50mL)，過濾，乾燥得到黃色固體(2.00g,97%)。 3,4-difluoronitrobenzene (1.59 g, 10 mmol) was added to a 100 mL round bottom flask and dissolved in DMSO (15 mL), and K 2 CO 3 (3.04 g, 22 mmol) and pyrrole (0.74 g, 11 mmol), the reaction system was heated to 90 ° C for 18 h. After the reaction was completed, the mixture was cooled to EtOAc.
在100mL圓底燒瓶中加入1-(2-氟-4-硝基苯基)-1H-吡咯(2.00g,9.70mmol)並溶解於二氯甲烷(35mL)中，然後加入Pd/C(0.20g)並通入H2。反應體系在室溫下反應5h。反應完畢，過濾，減壓蒸乾溶劑，粗產品經柱層析純化(石油醚/二氯甲烷(V/V)=3/1)，得到白色固體(1.30g,76%)。 Add 1-(2-fluoro-4-nitrophenyl)-1 H -pyrrole (2.00 g, 9.70 mmol) to a 100 mL round bottom flask and dissolve in dichloromethane (35 mL) then Pd/C ( 0.20 g) and passed H 2 . The reaction system was reacted at room temperature for 5 h. After completion of the reaction, the mixture was evaporated.jjjjjlililililililililililili
在250mL三口燒瓶中加入3-氟-4-(1H-吡咯-1-基)苯胺(0.80g,4.55mmol)並溶解於二氯甲烷(30mL)中，室溫下緩慢加入1M三甲基鋁庚烷溶液(23mL,23mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(785mg,5.0mmol,10mL二氯甲烷溶解)，反應體系在室溫下反應3天。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中淬滅三甲基鋁，二氯甲烷萃取(100mL×3)，無水硫酸鈉乾燥，減壓蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=3/2)，得到淡黃色固體(450mg,35%)。 3-Fluoro-4-(1 H -pyrrol-1-yl)phenylamine (0.80 g, 4.55 mmol) was added to a 250 mL three-necked flask and dissolved in dichloromethane (30 mL). Aluminium heptane solution (23 mL, 23 mmol) was reacted at room temperature for 0.5 h. Then, methyl 3-(N-acetamidoamino)crotonate (785 mg, 5.0 mmol, dissolved in 10 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 3 days. After completion of the reaction, the saturated ammonium chloride solution was slowly added to the system to quench the trimethylaluminum, extracted with dichloromethane (100 mL×3), dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. (Petroleum ether/ethyl acetate (V/V) = 3/2) gave a pale yellow solid (450 mg, 35%).
MS(ESI,pos.ion)m/z：284.2(M+1)；1H NMR(400MHz,CDCl3)：δ 2.25(s,3H),2.32(s,3H),6.32(s,1H),6.40(t,2H,J=2.2Hz),7.08-7.11(m,3H),7.13(dd,1H,J 1 =2.2Hz,J 2 =10.8Hz),7.54(t,1H,J=8.4Hz)。 MS (ESI, pos.ion) m / z: 284.2 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.25 (s, 3H), 2.32 (s, 3H), 6.32 (s, 1H) , 6.40 (t, 2H, J = 2.2 Hz), 7.08-7.11 (m, 3H), 7.13 (dd, 1H, J 1 = 2.2 Hz, J 2 = 10.8 Hz), 7.54 (t, 1H, J = 8.4) Hz).
在100mL圓底燒瓶中加入3,4-二氟硝基苯(3.18g,20mmol)並溶解於DMSO(35mL)中，攪拌下加入K2CO3(6.08g,44mmol)和吡唑(1.50g,22mmol)，反應體系加熱至90℃反應18h。反應完畢，將混合物冷至室溫，加水(50mL)，過濾，濾液二氯甲烷萃取(50mL×3)，有機層濃縮後所得的粗產品經柱層析純化(石油醚/二氯甲烷(V/V)=1/1)，得到黃色固體(3.31g,80%)。 3,4-Difluoronitrobenzene (3.18 g, 20 mmol) was added to a 100 mL round bottom flask and dissolved in DMSO (35 mL). K 2 CO 3 (6.08 g, 44 mmol) and pyrazole (1.50 g) were added with stirring. , 22 mmol), the reaction system was heated to 90 ° C for 18 h. After completion of the reaction, the mixture was cooled to room temperature, water (50 mL) was added, filtered, and the filtrate was extracted with dichloromethane (50 mL×3). The crude product was concentrated and purified by column chromatography ( petroleum ether / dichloromethane (V) /V) = 1/1) gave a yellow solid (3.31 g, 80%).
在100mL圓底燒瓶中加入1-(2-氟-4-硝基苯基)-1H-吡唑(3.31g,16mmol)並溶解於二氯甲烷(60mL)中，然後加入Pd/C(0.33g)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸乾溶劑，粗產品經柱層析純化(石油醚/二氯甲烷(V/V)=1/1)，得到白色固體(1.30g,46%)。 Add 1-(2-fluoro-4-nitrophenyl)-1 H -pyrazole (3.31 g, 16 mmol) to a 100 mL round bottom flask and dissolve in dichloromethane (60 mL) then Pd/C ( 0.33 g) and passed H 2 . The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was evaporated.jjjjjjjjjjj
在250mL三口燒瓶中加入3-氟-4-(1H-吡唑-1-基)苯胺(0.65g,3.68mmol)並溶解於二氯甲烷(30mL)中，室溫下緩慢加入2M三甲基鋁庚烷溶液(18.4mL,36.8mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醚基氨基)巴豆酸甲酯(634mg,4.04mmol,10mL二氯甲烷溶解)，反應體系在室溫下反應3天。反應完畢，將飽和氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(100mL×3)，無水硫酸鈉乾燥，蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/2)，得到白色固體(400mg,38%)。 3-Fluoro-4-( 1H -pyrazol-1-yl)aniline (0.65 g, 3.68 mmol) was added to a 250 mL three-necked flask and dissolved in dichloromethane (30 mL). A solution of aluminum heptane (18.4 mL, 36.8 mmol) was reacted at room temperature for 0.5 h. Then, methyl 3-(N-diethylamino)crotonate (634 mg, 4.04 mmol, dissolved in 10 mL of dichloromethane) was added slowly, and the reaction was allowed to react at room temperature for 3 days. After completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, extracted with dichloromethane (100 mL × 3), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by column chromatography ( petroleum ether / ethyl acetate (V) /V) = 1/2) gave a white solid (400 mg, 38%).
MS(ESI,pos.ion)m/z：285.2(M+1)；1H NMR(400MHz,CDCl3)：δ 2.23(s,3H),2.32(s,3H),6.32(s,1H),6.54(t,1H,J=2.0Hz),7.13-7.19(m,2H),7.78(d,1H,J=4.0Hz),8.08(t,1H,J=2.0Hz),8.12-8.16(m,1H)。 MS (ESI, pos.ion) m / z: 285.2 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.23 (s, 3H), 2.32 (s, 3H), 6.32 (s, 1H) , 6.54 (t, 1H, J = 2.0 Hz), 7.13-7.19 (m, 2H), 7.78 (d, 1H, J = 4.0 Hz), 8.08 (t, 1H, J = 2.0 Hz), 8.12-8.16 ( m, 1H).
將3-氨基巴豆酸甲酯(3.20g,27.79mmol)和吡啶(2.64g,33.33mmol)加入到CH2Cl2(60mL)，然後降溫至-20℃攪拌20分鐘。將溴乙醯溴(5.61g,27.79mmol)的二氯甲烷溶液(20mL)逐滴加入。滴畢升至室溫攪拌2h，然後有機相用飽和食鹽水洗(100mL×3)，無水硫酸鈉乾燥，減壓蒸去溶劑。粗產品經柱層析純化(乙酸乙酯/石油醚(V/V)=1/5)，得到微紅色固體(0.99g,15%)。 Methyl 3-aminocrotonate (3.20 g, 27.79 mmol) and pyridine (2.64 g, 33.33 mmol) were added to CH 2 Cl 2 (60 mL), then cooled to -20 ° C and stirred for 20 min. A solution of bromoacetam bromide (5.61 g, 27.79 mmol) in dichloromethane (20 mL) was added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 2 hr, then the organic layer was washed with brine (100 mL×3) The crude product was purified by EtOAc EtOAc EtOAc (EtOAc:
將3-氟苯酚(0.30g,2.68mmol)和3-(N-(2-溴乙醯)氨基)巴豆酸甲酯(0.76g,3.22mmol)依次加入到含有碳酸鉀(0.37g,2.68mmol)的丙酮(10mL)懸濁液中，升溫至回流反應5h。降至室溫，蒸去丙酮。將殘留物溶於二氯甲烷(40mL)，飽和食鹽水(40mL×3)洗，乾燥，減壓蒸去溶劑，粗產品經柱層析純化(乙酸乙酯/石油醚(V/V)=1/10)，得到白色固體(0.50g,70%)。 3-Fluorophenol (0.30 g, 2.68 mmol) and 3-(N-(2-bromoacetamidine)amino)crotonic acid methyl ester (0.76 g, 3.22 mmol) were sequentially added to potassium carbonate (0.37 g, 2.68 mmol). The acetone (10 mL) suspension was heated to reflux for 5 h. At room temperature, the acetone was distilled off. The residue was dissolved in dichloromethane (40 mL), EtOAc (EtOAc m. 1/10) gave a white solid (0.50 g, 70%).
在室溫，氮氣氛圍下，將3-氟-4-嗎啡啉基苯胺(0.55g,2.80mmol)溶於乾燥的二氯甲烷(40mL)中，緩慢滴加2M三甲基鋁庚烷溶液(2mL,4mmol)，滴畢繼續攪拌30分鐘。然後滴加3-(N-(2-(3-氟苯氧基)乙醯)氨基)巴豆酸甲酯(0.75g,2.80mmol)的乾燥二氯甲烷溶液(10mL)，滴畢繼續攪拌7h。緩慢加入適量水淬滅三甲基鋁，飽和食鹽水洗兩遍，無水硫酸鈉乾燥有機相。減壓蒸乾溶劑，粗產品經柱層析純化(乙酸乙酯/石油醚(V/V)=1/1)，得到灰白色固體(0.24g,62%)。 3-Fluoro-4-morpholine phenylamine (0.55 g, 2.80 mmol) was dissolved in dry dichloromethane (40 mL) at room temperature under a nitrogen atmosphere, and 2M trimethylaluminum heptane solution was slowly added dropwise ( 2 mL, 4 mmol), stirring was continued for 30 minutes. Then a solution of methyl 3-(N-(2-(3-fluorophenoxy)acetam)amino)crotonate (0.75 g, 2.80 mmol) in dichloromethane (10 mL) . The trimethylaluminum was quenched by adding an appropriate amount of water slowly, washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated to dryness EtOAcjjjjjjjjjjjj
MS(ESI,pos.ion)m/z：414.3(M+1)； 1H NMR(400MHz,CDCl3)：δ 2.34(s,3H),3.03-3.14(m,4H),3.85(t,4H,J=4.8Hz),4.67(s,2H),6.38(s,1H),6.45-6.49(m,1H),6.53-6.55(m,1H),6.64-6.68(m,1H),6.95-6.98(m,3H),7.13-7.19(m,1H)。 MS (ESI, pos.) m/z: 414.3 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.34 (s, 3H), 3.03-3.14 (m, 4H), 3.85 (t, 4H, J = 4.8 Hz), 4.67 (s, 2H), 6.38 (s, 1H), 6.45-6.49 (m, 1H), 6.53-6.55 (m, 1H), 6.64-6.68 (m, 1H), 6.95 -6.98 (m, 3H), 7.13-7.19 (m, 1H).
在100mL圓底燒瓶中加入吡咯烷(0.78g,11mmol)並溶解於乙酸乙酯(15mL)和三乙胺(1.52g,15mmol)中，然後在冰浴下緩慢加入3,4-二氟硝基苯(1.59g,10mmol)，反應體系升溫至室溫反應過夜。反應完畢，混合物經過濾，所得的固體經水洗，乾燥得到黃色固體(1.60g,76%)。 Pyrrolidine (0.78 g, 11 mmol) was added to a 100 mL round bottom flask and dissolved in ethyl acetate (15 mL) and triethylamine (1.52 g, 15 mmol), then 3,4-difluoronitrobenzene was slowly added to the ice bath. Base benzene (1.59 g, 10 mmol), and the reaction was allowed to warm to room temperature overnight. After completion of the reaction, the mixture was filtered and evaporated, mjjjjjj
在250mL圓底燒瓶中加入1-(2-氟-4-硝基苯基)吡咯烷(1.60g,7.62mmol)並溶解於二氯甲烷(20mL)和甲醇(20mL)中，然後加入Pd/C(0.16g)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=5/1)，得到白色固體(1.20g,88%)。 Add 1-(2-fluoro-4-nitrophenyl)pyrrolidine (1.60 g, 7.62 mmol) to a 250 mL round bottom flask and dissolve in dichloromethane (20 mL) and methanol (20 mL) then Pd/ C (0.16 g) and passed H 2 . The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was evaporated.jjjjjjjjj
在250mL三口燒瓶中加入3-氟-4-(吡咯烷-1-基)苯胺(0.50g,2.78mmol)並溶解於二氯甲烷(20mL)中，室溫下緩慢加入1M三甲基鋁庚烷溶液(14mL,14mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(481mg,3.06mmol,10mL二氯甲烷溶解)，反應體系在室溫下反應3天。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中淬滅剩餘三甲基鋁，二氯甲烷萃取(100mL×3)，無水硫酸鈉乾燥，蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到淡黃色固體(300mg,38%)。 3-Fluoro-4-(pyrrolidin-1-yl)phenylamine (0.50 g, 2.78 mmol) was added to a 250 mL three-necked flask and dissolved in dichloromethane (20 mL). Alkane solution (14 mL, 14 mmol) was reacted for 0.5 h at room temperature. Then, methyl 3-(N-acetamidoamino)crotonate (481 mg, 3.06 mmol, dissolved in 10 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 3 days. After the reaction is completed, a saturated ammonium chloride solution is slowly added to the system to quench the remaining trimethylaluminum, extracted with dichloromethane (100 mL×3), dried over anhydrous sodium sulfate, and the solvent is evaporated to dryness. Petroleum ether/ethyl acetate (v/v) = 1/1) gave a pale yellow solid (300 mg, 38%).
MS(ESI,pos.ion)m/z：288.3(M+1)；1H NMR(400MHz,CDCl3)：δ 1.96-1.99(m,4H),2.21(s,3H),2.29(s,3H), 3.43-3.48(m,4H),6.28(s,1H),6.71(t,1H,J=8.8Hz),6.78-6.84(m,2H)。 MS (ESI, pos.) m/z: 288.3 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 1.96-1.99 (m, 4H), 2.21. (s, 3H), 2.29 (s, 3H), 3.43-3.48 (m, 4H), 6.28 (s, 1H), 6.71 (t, 1H, J = 8.8 Hz), 6.78-6.84 (m, 2H).
在100mL圓底燒瓶中加入3,4-二氟硝基苯(3.18g,20mmol)並溶解於DMSO(25mL)中，攪拌下加入K2CO3(6.08g,44mmol)和二正丁胺(2.84g,22mmol)，反應體系加熱至90℃反應過夜。反應完畢，將混合物冷至室溫，加水(100mL)，二氯甲烷萃取(8.0mL×3)，無水硫酸鈉乾燥，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/二氯甲烷(V/V)=10/1)，得到黃色油狀物(4.03g,75%)。 3,4-Difluoronitrobenzene (3.18 g, 20 mmol) was added to a 100 mL round bottom flask and dissolved in DMSO (25 mL). K 2 CO 3 (6.08 g, 44 mmol) and di-n-butylamine ( 2.84 g, 22 mmol), the reaction was heated to 90 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, water (100 mL), methylene chloride (EtOAc (EtOAc) (V/V) = 10/1) gave a yellow oil (4.03 g, 75%).
在250mL圓底燒瓶中加入N1,N1-二丁基-2-氟苯-1,4-二胺(4.03g,15mmol)並溶解於二氯甲烷(70mL)和甲醇(20mL)中，然後加入Pd/C(0.40g)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸乾溶劑，粗產品經柱層析純化(石油醚/二氯甲烷(V/V)=8/1)，得到無色油狀物(2.32g,65%)。 Add N 1 ,N 1 -dibutyl-2-fluorobenzene-1,4-diamine (4.03 g, 15 mmol) in a 250 mL round bottom flask and dissolve in dichloromethane (70 mL) and methanol (20 mL). was then added Pd / C (0.40g) and passed through H 2. The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
在250mL三口燒瓶中加入N1,N1-二丁基-2-氟苯-1,4-二胺(1.10g,4.62mmol)並溶解於二氯甲烷(20mL)中，室溫下緩慢加入1M三甲基鋁庚烷溶液(23mL,23mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(798mg,5.08mmol,10mL二氯甲烷溶解)，反應體系在室溫下反應3天。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中淬滅剩餘三甲基鋁，二氯甲烷萃取(100mL×3)，無水硫酸鈉乾燥，蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=3/2)，得到淡黃色油狀物(800mg,50%)。 Add N 1 ,N 1 -dibutyl-2-fluorobenzene-1,4-diamine (1.10 g, 4.62 mmol) to a 250 mL three-necked flask and dissolve in dichloromethane (20 mL) and slowly add at room temperature. 1M trimethylaluminum heptane solution (23 mL, 23 mmol), and the reaction was allowed to react at room temperature for 0.5 h. Then, methyl 3-(N-acetamidoamino)crotonate (798 mg, 5.08 mmol, dissolved in 10 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 3 days. After the reaction is completed, a saturated ammonium chloride solution is slowly added to the system to quench the remaining trimethylaluminum, extracted with dichloromethane (100 mL×3), dried over anhydrous sodium sulfate, and the solvent is evaporated to dryness. Petroleum ether/ethyl acetate (V/V) = 3/2) gave a pale yellow oil (800 mg, 50%).
MS(ESI,pos.ion)m/z：346.3(M+1)； 1H NMR(400MHz,CDCl3)：δ 0.93(t,6H,J=7.4Hz),1.26-1.36(m,4H),1.55(t,4H,J=8.0Hz),2.20(s,3H),2.29(s,3H),3.21(t,4H,J=7.6Hz),6.28(s,1H),6.80-6.85(m,2H),6.88-6.93(m,1H)。 MS (ESI, pos.) m/z: 346.3 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 0.93 (t, 6H, J = 7.4 Hz), 1.26-1.36 (m, 4H) , 1.55 (t, 4H, J = 8.0 Hz), 2.20 (s, 3H), 2.29 (s, 3H), 3.21 (t, 4H, J = 7.6 Hz), 6.28 (s, 1H), 6.80-6.85 ( m, 2H), 6.88-6.93 (m, 1H).
在100mL圓底燒瓶中加入3,4-二氟硝基苯(1.59g,10mmol)並溶解於DMSO(15mL)中，攪拌下加入K2CO3(3.04g,22mmol)和二異丁胺(1.42g,11mmol)，反應體系加熱至90℃反應過夜。反應完畢，將混合物冷至室溫，加水(50mL)，二氯甲烷萃取(50mL×3)，無水硫酸鈉乾燥，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=10/1)，得到黃色油狀物(0.80g,30%)。 3,4-Difluoronitrobenzene (1.59 g, 10 mmol) was added to a 100 mL round bottom flask and dissolved in DMSO (15 mL). K 2 CO 3 (3.04 g, 22 mmol) and diisobutylamine ( 1.42 g, 11 mmol), the reaction was heated to 90 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature, EtOAc (EtOAc) V/V) = 10/1) gave a yellow oil (0.80 g, 30%).
在250mL圓底燒瓶中加入N1,N1-二異丁基-2-氟苯-1,4-二胺(0.80g,3mmol)溶解於二氯甲烷(15mL)和甲醇(15mL)中，然後加入Pd/C(80mg)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=8/1)，得到淡黃色油狀物(0.40g,56%)。 N 2 ,N 1 -diisobutyl-2-fluorobenzene-1,4-diamine (0.80 g, 3 mmol) was dissolved in dichloromethane (15 mL) and methanol (15 mL). was then added Pd / C (80mg) and passed through H 2. The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
在250mL三口燒瓶中加入N1,N1-二異丁基-2-氟苯-1,4-二胺(0.40g,1.68mmol)並溶解於二氯甲烷(20mL)中，室溫下緩慢加入1M三甲基鋁庚烷溶液(8.4mL,8.4mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(290mg,1.85mmol,10mL二氯甲烷溶解)，反應體系在室溫下反應3天。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(100mL×3)，無水硫酸鈉乾燥，減壓蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色油狀物(280mg, 48%)。 Add N 1 ,N 1 -diisobutyl-2-fluorobenzene-1,4-diamine (0.40 g, 1.68 mmol) in a 250 mL three-necked flask and dissolve in dichloromethane (20 mL) slowly at room temperature A 1 M solution of trimethylaluminum heptane (8.4 mL, 8.4 mmol) was added and the reaction was allowed to react at room temperature for 0.5 h. Then, methyl 3-(N-ethylidylamino)crotonate (290 mg, 1.85 mmol, dissolved in 10 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 3 days. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, extracted with dichloromethane (100 mL×3), dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The ester (V/V) = 1/1) gave a yellow oil (280 mg, 48%).
MS(ESI,pos.ion)m/z：346.4(M+1)；1H NMR(400MHz,CDCl3)：δ 0.88-0.90(m,12H),1.87-1.94(m,2H),2.20(s,3H),2.29(s,3H),3.00-3.10(m,4H),6.28(s,1H),6.80-6.84(m,2H),6.95(t,1H,J=12.9Hz)。 MS (ESI, pos.) m/z: 346.4 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 0.88-0.90 (m, 12H), 1.87-1.94 (m, 2H), 2.20 ( s, 3H), 2.29 (s, 3H), 3.00-3.10 (m, 4H), 6.28 (s, 1H), 6.80-6.84 (m, 2H), 6.95 (t, 1H, J = 12.9 Hz).
在100mL圓底燒瓶中加入3,4-二氟硝基苯(1.59g,10mmol)並溶解於DMSO(15mL)中，攪拌下加入K2CO3(3.04g,22mmol)和二己胺(2.04g,11 mmol)，反應體系加熱至90℃反應過夜。反應完畢，將混合物冷至室溫，加水(50mL)，二氯甲烷萃取(50mL×3)，無水硫酸鈉乾燥，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/二氯甲烷(V/V)=10/1)，得到黃色油狀物(2.79g,86%)。 3,4-Difluoronitrobenzene (1.59 g, 10 mmol) was added to a 100 mL round bottom flask and dissolved in DMSO (15 mL). K 2 CO 3 (3.04 g, 22 mmol) and dihexylamine (2.04) were added with stirring. g, 11 mmol), the reaction was heated to 90 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL), dichloromethane (50 mL, 3), dried over anhydrous sodium sulfate V/V) = 10/1) gave a yellow oil (2.79 g, 86%).
在250mL圓底燒瓶中加入N,N-二己基-2-氟-4-硝基苯胺(2.79g,8.64mmol)並溶解於甲醇(50mL)中，然後加入Pd/C(0.28g)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=10/1)，得到淡黃色油狀物(1.60g,63%)。 Add N,N-dihexyl-2-fluoro-4-nitroaniline (2.79 g, 8.64 mmol) in a 250 mL round bottom flask and dissolve in methanol (50 mL), then add Pd/C (0.28 g) and pass Into H 2 . The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
在250mL三口燒瓶中加入N1,N1-二己基-2-氟苯-1,4-二胺(0.58g,1.97mmol)並溶解於二氯甲烷(20mL)中，室溫下緩慢加入2mol/L三甲基鋁庚烷溶液(9.9mL,19.8mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(341mg,2.17mmol,5mL二氯甲烷溶解)，反應體系在室溫下反應3天。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中淬滅剩餘三甲基鋁，二氯甲烷萃取(100mL×3)，無水硫酸鈉乾燥，減壓 蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到淡黃色油狀物(500mg,63%)。 Add N 1 ,N 1 -dihexyl-2-fluorobenzene-1,4-diamine (0.58 g, 1.97 mmol) in a 250 mL three-necked flask and dissolve in dichloromethane (20 mL), slowly add 2 mol at room temperature /L trimethylaluminum heptane solution (9.9 mL, 19.8 mmol), and the reaction was allowed to react at room temperature for 0.5 h. Then, methyl 3-(N-acetamidoamino)crotonate (341 mg, 2.17 mmol, dissolved in 5 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 3 days. After the reaction is completed, a saturated ammonium chloride solution is slowly added to the system to quench the remaining trimethylaluminum, extracted with dichloromethane (100 mL×3), dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. Purification (petroleum ether / ethyl acetate (v/v) = 2 / 1)
MS(ESI,pos.ion)m/z：402.3(M+1)；1H NMR(400MHz,CDCl3)：δ 0.89(t,6H,J=7.0Hz),1.31(t,12H,J=7.8Hz),1.55(t,4H,J=7.2Hz),2.20(s,3H),2.29(s,3H),3.18-3.21(m,4H),6.28(s,1H),6.79-6.82(m,2H),6.84-6.92(m,1H)。 MS (ESI, pos.ion) m / z: 402.3 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 0.89 (t, 6H, J = 7.0Hz), 1.31 (t, 12H, J = 7.8Hz), 1.55 (t, 4H , J = 7.2Hz), 2.20 (s, 3H), 2.29 (s, 3H), 3.18-3.21 (m, 4H), 6.28 (s, 1H), 6.79-6.82 ( m, 2H), 6.84-6.92 (m, 1H).
在500mL圓底燒瓶中，加入乙酸乙酯(200mL)、2-氯-5-硝基吡啶(3.17g,20mmol)、嗎啉(2.00g,23mmol)和三乙胺(2.43g,24mmol)。加熱回流3h後，冷至室溫，用水(100mL×3)洗滌，收集有機相，經無水硫酸鈉乾燥後，減壓蒸去溶劑，真空乾燥，得到黃色固體(3.89g,93%)。 In a 500 mL round bottom flask, ethyl acetate (200 mL), 2-chloro-5-nitropyridine (3.17 g, 20 mmol), morpholine (2.00 g, 23 mmol) and triethylamine (2.43 g, 24 mmol) were added. After heating to reflux for 3 h, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
在100mL圓底燒瓶中，4-(5-硝基吡啶-2-基)嗎啉(3.89g,18.60mmol)溶於THF(100mL)，加入鈀/碳(0.5g)後，通入H2，室溫攪拌過夜。混合物過濾後，收集濾液，減壓蒸去溶劑，真空乾燥得到棕紅色固體(3.30g,99%)。 In 100mL round bottom flask, 4- (5-nitropyridin-2-yl) morpholine (3.89g, 18.60mmol) was dissolved in of THF (100mL), after addition of Pd / C (0.5g), into H 2 Stir at room temperature overnight. After the mixture was filtered, the filtrate was evaporated,jjjjjjjj
在氮氣保護下，6-嗎啉吡啶-3-胺(1.79g,10mmol)溶於CH2Cl2(100mL)中，小心地滴加1M的三甲基鋁正庚烷溶液(40mL,40mmol)，滴加完畢，繼續攪拌30min。滴加溶於CH2Cl2(5mL)的3-(N-乙醯基氨基)巴豆酸甲酯(1.89g,12mmol)，滴加完畢，繼續室溫攪拌6h，用飽和氯化銨溶液(100mL)淬滅反應，分出有機相，經無水硫酸鈉乾燥後，減壓蒸去溶劑，粗產品用乙酸乙酯重結晶，得到淡黃色固體(1.11g,39%)。 Under nitrogen, 6-morpholin-pyridin-3-amine (1.79g, 10mmol) was dissolved in CH 2 Cl 2 (100mL) and carefully added dropwise 1M trimethylaluminum heptane solution (40mL, 40mmol) After the addition is completed, stirring is continued for 30 minutes. 3-(N-Ethylamino) crotonate methyl ester (1.89 g, 12 mmol) dissolved in CH 2 Cl 2 (5 mL) was added dropwise, and the mixture was stirred at room temperature for 6 h, with saturated ammonium chloride solution ( The reaction was quenched with EtOAc (EtOAc)EtOAc.
MS(ESI,pos.ion)m/z：287.2(M+1)； 1HNMR(400MHz,CDCl3)：δ 2.22(s,3H),2.30(s,3H),3.54-3.60(m,4H),3.83(t,4H,J=4.9Hz),6.29(s,1H),6.74(d,1H,J=8.8Hz),7.33(dd,1H,J 1 =2.1Hz,J 2=8.8Hz),8.00(d,1H,J=2.6Hz)。 MS (ESI, pos.) m/z: 287.2 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.22 (s, 3H), 2.30 (s, 3H), 3.54-3.60 (m, 4H) ), 3.83 (t, 4H, J = 4.9 Hz), 6.29 (s, 1H), 6.74 (d, 1H, J = 8.8 Hz), 7.33 (dd, 1H, J 1 = 2.1 Hz, J 2 = 8.8 Hz) ), 8.00 (d, 1H, J = 2.6 Hz).
在1000mL圓底燒瓶中，將3,4-二氟硝基苯(15.91g,0.10mol)加入4-羥基呱啶(11.11g,0.11mol)和三乙胺(12.14g,0.12mol)的乙酸乙酯(500mL)溶液。室溫攪拌24h。用水(200mL×4)洗滌，收集有機相，經無水硫酸鈉乾燥後，減壓蒸乾溶劑，真空乾燥得到橙色油狀物(19.35g,80%)。 In a 1000 mL round bottom flask, 3,4-difluoronitrobenzene (15.91 g, 0.10 mol) was added to 4-hydroxyacridine (11.11 g, 0.11 mol) and triethylamine (12.14 g, 0.12 mol) of acetic acid. Ethyl ester (500 mL) solution. Stir at room temperature for 24 h. After washing with water (200 mL × 4), EtOAc (EtOAc)
在250mL圓底燒瓶中，1-(2-氟-4-硝基苯基)呱啶-4-醇(2.67g,11mmol)溶於甲醇(100mL)，加入鈀/碳(1.00g)後，通入氫氣，室溫攪拌6h。混合物過濾，收集濾液，減壓蒸去溶劑，真空乾燥，得到粗產品(2.50g)直接用於下一步反應。 In a 250 mL round bottom flask, 1-(2-fluoro-4-nitrophenyl)acridin-4-ol (2.67 g, 11 mmol) was dissolved in methanol (100 mL) and palladium / carbon (1.00 g). Hydrogen was introduced and stirred at room temperature for 6 h. The mixture was filtered, and the filtrate was evaporated.
在氮氣保護下，1-(4-氨基-2-氟苯基)呱啶-4-醇(1.68g,8.00mmol)溶於CH2Cl2(20mL)中，小心地滴加2M的三甲基鋁正庚烷溶液(32mL,64mmol)，滴加完畢，繼續攪拌30min。滴加溶於CH2Cl2(5mL)的3-(N-乙醯基氨基)巴豆酸甲酯(1.40g,8.90mmol)，滴加完畢，繼續室溫攪拌5h，用飽和氯化銨(100mL)溶液淬滅反應，分出有機相，經無水硫酸鈉乾燥後，減壓蒸去溶劑，粗產品用乙酸乙酯重結晶，得到黃色固體(1.25g,50%)。 1-(4-Amino-2-fluorophenyl)acridin-4-ol (1.68 g, 8.00 mmol) was dissolved in CH 2 Cl 2 (20 mL). Base aluminum n-heptane solution (32 mL, 64 mmol) was added dropwise and stirring was continued for 30 min. Was added dropwise dissolved in CH 2 Cl 2 (5mL) of 3- (N- acetyl-ylamino) crotonate (1.40g, 8.90mmol), completion, stirring was continued 5h at room temperature, washed with saturated ammonium chloride ( The reaction was quenched with EtOAc (EtOAc)EtOAc.
MS(ESI,pos.ion)m/z：318.2(M+1)；1H NMR(400MHz,CDCl3)：δ 1.74-1.77(m,2H),2.02-2.05(m,2H),2.18(s,3H),2.29(s,3H),2.85-2.99(m,2H),3.36-3.48(m,2H),3.84-3.92(m,1H),6.28(s,1H),6.90(d,1H,J=1.2Hz),7.05(t,1H,J=0.8Hz)。 MS (ESI, pos.) m/z: 318.2 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 1.74-1.77 (m, 2H), 2.02-2.05 (m, 2H), 2.18 ( s, 3H), 2.29 (s, 3H), 2.85-2.99 (m, 2H), 3.36-3.48 (m, 2H), 3.84-3.92 (m, 1H), 6.28 (s, 1H), 6.90 (d, 1H, J = 1.2 Hz), 7.05 (t, 1H, J = 0.8 Hz).
在氮氣保護下，碳酸鉀(6.50g,47mmol)和嗎啉(3.75g,43mmol)溶於乙腈(30mL)中，冰浴冷卻，攪拌，2-溴乙腈(5.16g,43mmol)一次性加入該反應液中，升溫至室溫反應2h，過濾，減壓蒸去溶劑，得到黃色固體(5.41g,100%)。 Under a nitrogen atmosphere, potassium carbonate (6.50 g, 47 mmol) and morpholine (3.75 g, 43 mmol) were dissolved in acetonitrile (30 mL), cooled in ice-cooled, stirred, 2-bromoacetonitrile (5.16 g, 43 mmol) The reaction mixture was warmed to room temperature for 2 h, filtered, and the solvent was evaporated evaporated.
在冰浴冷卻下，四氫鋁鋰(3.19g,84mmol)一次性加入乾燥四氫呋喃(35mL)中，所得的反應液在0℃下攪拌20分鐘。逐滴加入2-嗎啉乙腈(3.50g,28mmol,10mL乾燥THF溶液)。滴畢，加熱至回流3h。冷卻至室溫後冰浴冷卻，向反應體系中緩慢加入水(20mL)，過濾，減壓蒸去溶劑，得到黃色油狀物(2.62g,72%)。 Lithium aluminum hydride (3.19 g, 84 mmol) was added in one portion to dry tetrahydrofuran (35 mL), and the obtained mixture was stirred at 0 ° C for 20 min. 2-morpholine acetonitrile (3.50 g, 28 mmol, 10 mL dry THF) was added dropwise. After the dropwise addition, it was heated to reflux for 3 h. After cooling to room temperature, it was cooled in an ice-bath, and water (20 mL) was slowly added to the reaction system, and the solvent was evaporated to give a yellow oil (2.62 g, 72%).
在氮氣保護下，2-嗎啉乙氨(0.90g,6.91mmol)，3,4-二氟硝基苯(1.10g,6.91mmol)和三乙胺(1.40g,13.82mmol)溶於乙酸乙酯(10mL)中，加熱至回流24h。冷卻至室溫，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到黃色油狀物(1.57g,84%)。 2-morpholineethylamine (0.90 g, 6.91 mmol), 3,4-difluoronitrobenzene (1.10 g, 6.91 mmol) and triethylamine (1.40 g, 13.82 mmol) were dissolved in acetic acid under nitrogen. The ester (10 mL) was heated to reflux for 24 h. After cooling to room temperature, the solvent was evaporated.jjjjjjjjjjj
在25mL圓底燒瓶中加入2-氟-N-(2-嗎啉乙基)-4-硝基苯(0.60g,2.23mmol)和四氫呋喃(8.0mL)，然後加入Pd/C(0.03g)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸去溶劑，得到黃色油狀物(0.50g,94%)。 Add 2-fluoro-N-(2-morpholinyl)-4-nitrobenzene (0.60 g, 2.23 mmol) and tetrahydrofuran (8.0 mL) to a 25 mL round bottom flask, then add Pd/C (0.03 g) And pass H 2 . The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was evaporated.
在100mL三口燒瓶中加入2-氟-N1-(2-嗎啉乙基)苯-1,4-二胺(0.50g,2.09mmol)和二氯甲烷(20mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(3.2mL,6.40mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯 基氨基)巴豆酸甲酯(0.65g,4.13mmol,5mL二氯甲烷溶解)，反應體系在室溫下反應36h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(100mL×3)，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(乙酸乙酯/甲醇(V/V)=30/1)，得到白色固體(0.50g,24%)。 Add 2-fluoro-N 1 -(2-morpholinethyl)benzene-1,4-diamine (0.50 g, 2.09 mmol) and dichloromethane (20 mL) to a 100 mL three-necked flask, and slowly add 2 M at room temperature. Trimethylaluminum toluene solution (3.2 mL, 6.40 mmol), and the reaction was allowed to react at room temperature for 0.5 h. Then, methyl 3-(N-acetamidoamino)crotonate (0.65 g, 4.13 mmol, dissolved in 5 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 36 h. After completion of the reaction, a saturated ammonium chloride solution was slowly added to the system, and extracted with dichloromethane (100 mL × 3), dried over anhydrous sodium sulfate, and evaporated. (V/V) = 30/1) gave a white solid (0.50 g, 24%).
MS(ESI,pos.ion)m/z：347.2(M+1)；1H NMR(400MHz,CDCl3)：δ 2.08(s,3H),2.18(m,3H),2.43(s,4H),2.57(s,2H),3.25(m,2H),3.58(t,4H,J=4.32Hz),5.52(s,1H),6.20(s,1H),6.79-6.83(m,1H),6.91-6.93(m,1H),7.08-7.12(m,1H)。 MS (ESI, pos.) m/z: 347.2 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.08 (s, 3H), 2.18 (m, 3H), 2.43 (s, 4H) , 2.57 (s, 2H), 3.25 (m, 2H), 3.58 (t, 4H, J = 4.32 Hz), 5.52 (s, 1H), 6.20 (s, 1H), 6.79-6.83 (m, 1H), 6.91-6.93 (m, 1H), 7.08-7.12 (m, 1H).
在25mL圓底燒瓶中加入3-(3-氟-4-((2-嗎啉乙基)氨基)苯基)-2,6-二甲基嘧啶-4(3H)-酮(0.24g,0.69mmol)，碳酸鉀(0.48g,3.47mmol)和乙腈(15mL)，室溫攪拌下緩慢加入碘甲烷(0.30g,2.11mmol)，反應體系在室溫下反應36h。反應完畢，過濾，減壓蒸去溶劑，粗產品經製備薄層板純化(乙酸乙酯/甲醇(V/V)=50/1)，得到白色固體(50mg,20%)。 In a 25 mL round bottom flask was added 3-(3-fluoro-4-((2-morpholinethyl)amino)phenyl)-2,6-dimethylpyrimidin-4(3H)-one (0.24 g, 0.69 mmol), potassium carbonate (0.48 g, 3.47 mmol) and acetonitrile (15 mL), methylene chloride (0.30 g, 2.11 mmol) was slowly added under stirring at room temperature, and the reaction was allowed to react at room temperature for 36 h. After completion of the reaction, the mixture was filtered,jjjjjjjjjjj
MS(ESI,pos.ion)m/z：361.2(M+1)；1H NMR(400MHz,CDCl3)：δ 1.26(s,3H),2.16(s,3H),2.26(s,3H),2.62(m,4H),3.48(m,2H),3.69-3.74(m,2H),4.00(m,4H),6.17(s,1H),6.755-6.84(m,2H),7.03(m,1H)。 MS (ESI, pos.ion) m / z: 361.2 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 1.26 (s, 3H), 2.16 (s, 3H), 2.26 (s, 3H) , 2.62 (m, 4H), 3.48 (m, 2H), 3.69-3.74 (m, 2H), 4.00 (m, 4H), 6.17 (s, 1H), 6.755-6.84 (m, 2H), 7.03 (m) , 1H).
在氮氣保護下，2-嗎啉乙氨(5.34g,41mmol)，1,4-二氯硝基苯(7.87g,41mmol)和碳酸銫(26.73g,82mmol)溶於乙腈(100mL)中，加熱至回 流6h。冷卻至室溫，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到黃色固體(5.90g,50%)。 2-morpholineethylamine (5.34 g, 41 mmol), 1,4-dichloronitrobenzene (7.87 g, 41 mmol) and cesium carbonate (26.73 g, 82 mmol) were dissolved in acetonitrile (100 mL). Heated back Flow 6h. After cooling to room temperature, the solvent was evaporated.jjjjjjjjjjjjj
在250mL圓底燒瓶中加入3-氯-N-(2-嗎啉乙基)-4-硝基苯(3.50g,12.25mmol)和乙酸乙酯(60mL)，然後加入Pd/C(0.73g)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸去溶劑，粗品未經進一步處理直接進行下一步反應。 3-Chloro-N-(2-morpholinethyl)-4-nitrobenzene (3.50 g, 12.25 mmol) and ethyl acetate (60 mL) were added to a 250 mL round bottom flask, then Pd/C (0.73 g) ) and pass H 2 . The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was filtered, and the solvent was evaporated under reduced pressure.
在100mL三口燒瓶中加入3-氯-N1-(2-嗎啉乙基)-1,4-苯二胺(0.70g,1.93mmol)和二氯甲烷(20mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(6.8mL,13.6mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(0.43g,2.74mmol,5mL二氯甲烷溶解)，反應體系在室溫下反應72h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×3)，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(乙酸乙酯/甲醇(V/V)=30/1)，得到淡黃色固體(0.33g,47%)。 3-Chloro-N 1 -(2-morpholinethyl)-1,4-phenylenediamine (0.70 g, 1.93 mmol) and dichloromethane (20 mL) were added to a 100 mL three-neck flask, and slowly added 2 M at room temperature. A solution of trimethylaluminum toluene (6.8 mL, 13.6 mmol) was reacted at room temperature for 0.5 h. Then, methyl 3-(N-acetamidoamino)crotonate (0.43 g, 2.74 mmol, dissolved in 5 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 72 h. After completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, extracted with dichloromethane (50 mL×3), dried over anhydrous sodium sulfate and evaporated. (V/V) = 30/1) gave a pale yellow solid (0.33 g, 47%).
MS(ESI,pos.ion)m/z：363.1(M+1)；1H NMR(400MHz,CDCl3)：δ 2.17(s,3H),2.33(s,3H),2.42-2.43(m,4H),2.50-2.64(m,2H),3.09-3.13(m,2H),3.59-3.63(m,4H),4.55-4.57(t,1H),6.32(s,1H),6.76-6.81(m,1H),6.80-6.81(m,1H),6.89-6.91(m,1H)。 MS (ESI, pos.) m/z: 363.1 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.17 (s, 3H), 2.33 (s, 3H), 2.42-2.43 (m, 4H), 2.50-2.64 (m, 2H), 3.09-3.13 (m, 2H), 3.59-3.63 (m, 4H), 4.55-4.57 (t, 1H), 6.32 (s, 1H), 6.76-6.81 ( m, 1H), 6.80-6.81 (m, 1H), 6.89-6.91 (m, 1H).
在氮氣保護下，1-溴-3-氯丙基(0.79g,5.00mmol)和碳酸鉀(1.38g,10.00mmol)溶於乙酸乙酯(20mL)中，室溫攪拌下，逐滴加入嗎啉(0.44g,5.05mmol,20mL乙酸乙酯溶解)，滴畢，反應體系在室溫下反應過夜。反應畢，過濾，減壓蒸去溶劑，粗品未經進一步處理直接進行下一步反應。 Under a nitrogen atmosphere, 1-bromo-3-chloropropyl (0.79 g, 5.00 mmol) and potassium carbonate (1.38 g, 10.00 mmol) were dissolved in ethyl acetate (20 mL). The morpholine (0.44 g, 5.05 mmol, 20 mL of ethyl acetate) was dissolved, and the reaction was allowed to react at room temperature overnight. After completion of the reaction, the mixture was filtered, and the solvent was evaporated under reduced pressure.
在氮氣保護下，4-(3-氯丙基)嗎啉(1.64g,10mmol)和碳酸鉀(4.14g,30mmol)溶於乙腈(20mL)中，室溫攪拌下，逐滴加入2-氟-4-硝基苯胺(1.56g,10mmol)，滴畢，反應體系在室溫下反應24h。反應畢，過濾，減壓蒸去溶劑，粗產品經柱層析純化(乙酸乙酯/石油醚(V/V)=1/1)，得到黃色油狀物(1.78g,63%)。 4-(3-Chloropropyl)morpholine (1.64 g, 10 mmol) and potassium carbonate (4.14 g, 30 mmol) were dissolved in acetonitrile (20 mL) under nitrogen. 4-Nitroaniline (1.56 g, 10 mmol), after completion, the reaction was allowed to react at room temperature for 24 h. After completion of the reaction, the title compound was evaporated, mjjjjjjjj
在50mL圓底燒瓶中加入2-氟-N-(3-嗎啉丙基)-4-硝基苯胺(1.78g,6.28mmol)，乙酸乙酯(15mL)和甲醇(15mL)，然後加入Pd/C(0.30g)並通入H2。反應體系在室溫下反應2h。反應完畢，過濾，減壓蒸去溶劑，粗品未經進一步處理直接進行下一步反應。 To a 50 mL round bottom flask was added 2-fluoro-N-(3-morpholinyl)-4-nitroaniline (1.78 g, 6.28 mmol), ethyl acetate (15 mL) and methanol (15 mL). /C (0.30g) and pass H 2 . The reaction system was reacted at room temperature for 2 h. After completion of the reaction, the mixture was filtered, and the solvent was evaporated under reduced pressure.
在100mL三口燒瓶中加入2-氟-N1-(3-嗎啉丙基)苯基-1,4-苯二胺(1.60g,6.23mmol)和二氯甲烷(30mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(22mL,44mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(1.98g,12.59mmol,10mL二氯甲烷溶解)，反應體系在室溫下反應過夜。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×3)，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到淡黃色固體(0.60g,27%)。 Add 2-fluoro-N 1 -(3-morpholinyl)phenyl-1,4-phenylenediamine (1.60 g, 6.23 mmol) and dichloromethane (30 mL) to a 100 mL three-neck flask, slowly at room temperature A 2 M solution of trimethylaluminum toluene (22 mL, 44 mmol) was added, and the reaction was allowed to react at room temperature for 0.5 h. Then, methyl 3-(N-acetamidoamino)crotonate (1.98 g, 12.59 mmol, dissolved in 10 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature overnight. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, extracted with dichloromethane (50 mL×3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography ( petroleum ether / ethyl acetate The ester (V/V) = 2/1) gave a pale yellow solid (0.60 g, 27%).
MS(ESI,pos.ion)m/z：361.2(M+1)；1H NMR(400MHz,CDCl3)：δ 1.85-1.88(m,2H),2.21(s,3H),2.29(s,3H),2.49(m,4H),2.53-2.56(t,2H),3.20-3.31(m,2H),3.75-3.77(t,4H),6.28(s,1H),6.70-6.74(t,1H),6.81-6.84(m,2H)。 MS (ESI, pos.) m/z: 361.2 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 1.85-1.88 (m, 2H), 2.21 (s, 3H), 2.29 (s, 3H), 2.49 (m, 4H), 2.53-2.56 (t, 2H), 3.20-3.31 (m, 2H), 3.75-3.77 (t, 4H), 6.28 (s, 1H), 6.70-6.74 (t, 1H), 6.81-6.84 (m, 2H).
在氮氣保護下，碳酸鉀(8.28g,60mmol)和嗎啉(4.35g,50mmol)溶於乙腈(50mL)中，室溫攪拌，4-溴丁腈(7.40g,50mmol)逐滴加入該反應液中，室溫反應6h，過濾，減壓蒸去溶劑，得到粗產品(7.26g,94%)。 Under a nitrogen atmosphere, potassium carbonate (8.28 g, 60 mmol) and morpholine (4.35 g, 50 mmol) were dissolved in acetonitrile (50 mL), stirred at room temperature, and 4-bromobutyronitrile (7.40 g, 50 mmol) was added dropwise to the reaction. The mixture was reacted at room temperature for 6 h, filtered, and evaporated, evaporated,
在冰浴冷卻下，四氫鋁鋰(5.37g,142mmol)一次性加入乾燥四氫呋喃(70mL)中，所得的反應液在0℃下攪拌20分鐘。逐滴加入4-嗎啉丁腈(7.26g,47mmol,40mL乾燥THF溶液)。滴畢，加熱至回流4h。冷卻至室溫後冰浴冷卻，向反應體系中緩慢加入水(20mL)，反應液過濾，濾液減壓蒸去溶劑，粗品未經進一步處理直接進行下一步反應。 Lithium aluminum hydride (5.37 g, 142 mmol) was added in one portion to dry tetrahydrofuran (70 mL), and the obtained mixture was stirred at 0 ° C for 20 min. 4-morpholine butyronitrile (7.26 g, 47 mmol, 40 mL dry THF solution) was added dropwise. After the dropwise addition, it was heated to reflux for 4 h. After cooling to room temperature, it was cooled in an ice bath, water (20 mL) was slowly added to the reaction system, the reaction liquid was filtered, and the solvent was evaporated under reduced pressure. The crude product was directly subjected to the next reaction without further treatment.
在氮氣保護下，4-嗎啉丁氨(0.63g,4.00mmol)，3,4-二氟硝基苯(0.64g,4.00mmol)和碳酸鉀(1.10g,8.00mmol)溶於乙腈(20mL)中，室溫反應19h。反應畢，抽濾，減壓蒸去溶劑，粗品未經進一步處理直接進行下一步反應。 4-morpholine butylamine (0.63 g, 4.00 mmol), 3,4-difluoronitrobenzene (0.64 g, 4.00 mmol) and potassium carbonate (1.10 g, 8.00 mmol) were dissolved in acetonitrile (20 mL). In the reaction at room temperature for 19 h. After completion of the reaction, the mixture was suction filtered, and the solvent was evaporated under reduced pressure.
在100mL圓底燒瓶中加入2-氟-N-(4-嗎啉丁基)-4-硝基苯胺(1.19g,4.00mmol)，乙酸乙酯(20mL)和甲醇(20mL)，然後加入Pd/C(0.30g)並通入H2。反應體系在室溫下反應2h。反應完畢，過濾，減壓蒸去溶劑，粗產品經柱層析純化(乙酸乙酯/甲醇(V/V)=10/1)，得到白色固體(1.07g,100%)。 To a 100 mL round bottom flask was added 2-fluoro-N-(4-morpholinyl)-4-nitroaniline (1.19 g, 4.00 mmol), ethyl acetate (20 mL) and methanol (20 mL). /C (0.30g) and pass H 2 . The reaction system was reacted at room temperature for 2 h. After completion of the reaction, the mixture was evaporated,jjjjjjjjjj
在100mL三口燒瓶中加入2-氟-N1-(4-嗎啉丁基)苯基-1,4-二胺(1.07g,4.00mmol)和二氯甲烷(30mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(14mL,28mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(1.30g,8.27mmol,5mL二氯甲烷溶解)，反應體系在室溫下反應過夜。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×3)，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到淡黃色固體(0.26g,17%)。 Add 2-fluoro-N 1 -(4-morpholinobutyl)phenyl-1,4-diamine (1.07 g, 4.00 mmol) and dichloromethane (30 mL) to a 100 mL three-necked flask and slowly add at room temperature. 2M trimethylaluminum toluene solution (14 mL, 28 mmol), and the reaction was allowed to react at room temperature for 0.5 h. Then, methyl 3-(N-ethylidylamino)crotonate (1.30 g, 8.27 mmol, dissolved in 5 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature overnight. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, extracted with dichloromethane (50 mL×3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography ( petroleum ether / ethyl acetate The ester (V/V) = 2/1) gave a pale yellow solid (0.26 g, 17%).
MS(ESI,pos.ion)m/z：375.2(M+1)；1H NMR(400MHz,CDCl3)：δ 1.63-1.74(m,4H),2.20(s,3H),2.29(s,3H), 2.39-2.426(t,2H),2.47(t,4H),3.19-3.22(m,2H),3.73-3.75(t,4H),6.28(s,1H),6.72-6.76(t,1H),6.81-6.83(d,2H)。 MS (ESI, pos.) m/z: 375.2 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 1.63-1.74 (m, 4H), 2.20 (s, 3H), 2.29 (s, 3H), 2.39-2.426(t,2H), 2.47(t,4H), 3.19-3.22(m,2H),3.73-3.75(t,4H),6.28(s,1H),6.72-6.76(t, 1H), 6.81-6.83 (d, 2H).
在氮氣保護下，2,2’-羥基二乙胺(4.21g,40mmol)溶於乙腈(50mL)中，室溫攪拌下，逐滴加入Boc酸酐(9.60g,44mmol,50mL乙腈溶解)，滴畢，反應體系在室溫下反應3.5h。反應畢，減壓蒸去溶劑，得到無色油狀物(8.20g,100%)。 2,2'-hydroxydiethylamine (4.21 g, 40 mmol) was dissolved in acetonitrile (50 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature, and then added with Boc anhydride (9.60 g, 44 mmol, 50 mL of acetonitrile). After completion, the reaction system was reacted at room temperature for 3.5 h. After completion of the reaction, the solvent was evaporated to dryness crystall
在氮氣保護下，N-叔丁氧羰基-2,2’-羥基二乙胺(8.20g,40mmol)溶於正己烷(30mL)中，室溫攪拌下，依次加入氫氧化鈉(8.00g,200mmol，溶解于30mL水中)，1-溴丙烷(9.84g,80mmol)和TBAB(1.00g)，反應體系加熱至回流反應過夜。反應畢，冷卻至室溫，將反應液傾入二氯甲烷(100mL)中，水洗滌(100mL×3)，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到無色油狀物(1.78g,15%)。 N-tert-butoxycarbonyl-2,2'-hydroxydiethylamine (8.20 g, 40 mmol) was dissolved in n-hexane (30 mL) under nitrogen, and sodium hydroxide (8.00 g, 200 mmol, dissolved in 30 mL of water), 1-bromopropane (9.84 g, 80 mmol) and TBAB (1.00 g), and the reaction was heated to reflux overnight. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was poured into dichloromethane (100 mL), washed with water (100 mL×3), dried over anhydrous sodium sulfate and evaporated. Ethyl acetate (V/V) = 4/1) gave a colourless oil (1.
將N-叔丁氧羰基-2,2’-丙氧基二乙胺(1.78g,6.15mmol)溶於2M氯化氫乙酸乙酯溶液(15mL,30mmol)中，反應體系在室溫下反應過夜。反應畢，減壓蒸去溶劑，得到無色油狀物(1.16g,100%)。 N-tert-Butoxycarbonyl-2,2'-propoxydiethylamine (1.78 g, 6.15 mmol) was dissolved in 2M aqueous ethyl hydrogen chloride (15 mL, 30 mmol). After completion of the reaction, the solvent was evaporated.
在100mL圓底燒瓶中加入3,4-二氟硝基苯(2.94g,18.45mmol)並溶解於DMF(30mL)中，攪拌下加入三乙胺(3.11g,30.75mmol)和2,2’-丙氧基二乙胺(1.16g,6.15mmol)，反應體系加熱至90℃反應過夜。反應完畢，待反應液冷至室溫，將反應液傾入二氯甲烷(100mL)中，水洗滌(100mL×3)，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=10/1)，得到黃色油狀物(1.47g,73%)。 3,4-Difluoronitrobenzene (2.94 g, 18.45 mmol) was added to a 100 mL round bottom flask and dissolved in DMF (30 mL). Triethylamine (3.11 g, 30.75 mmol) and 2,2' were added with stirring. -propoxydiethylamine (1.16 g, 6.15 mmol), and the reaction was heated to 90 ° C overnight. After completion of the reaction, the reaction solution was cooled to room temperature, and the reaction mixture was poured into dichloromethane (100 mL), washed with water (100 mL×3), dried over anhydrous sodium sulfate and evaporated. (Petroleum ether / ethyl acetate (V/V) = 10/1) gave a yellow oil (1. 7 g, 73%).
在100mL圓底燒瓶中加入2-氟-4-硝基-N,N-二(2-丙氧基乙基)胺(1.47g,4.48mmol)並溶解於甲醇(50mL)中，然後加入Pd/C(0.15g)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到微黑色油狀物(0.50g,34%)。 2-Fluoro-4-nitro-N,N-bis(2-propoxyethyl)amine (1.47 g, 4.48 mmol) was added to a 100 mL round bottom flask and dissolved in methanol (50 mL) then Pd. /C(0.15g) and passed through H 2. The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was filtered, evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
在100mL三口燒瓶中加入2-氟-N1,N1-二(2-丙氧基乙基)苯-1,4-二胺(0.50g,1.68mmol)和二氯甲烷(10mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(3.4mL,6.8mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(0.32g,2.02mmol,2mL二氯甲烷溶解)，反應體系在室溫下反應72h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×3)，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到淡黃色油狀物(0.53g,78%)。 In a 100 mL three-necked flask, 2-fluoro-N 1 ,N 1 -di(2-propoxyethyl)benzene-1,4-diamine (0.50 g, 1.68 mmol) and dichloromethane (10 mL) were added. 2M trimethylaluminum toluene solution (3.4 mL, 6.8 mmol) was slowly added under temperature, and the reaction system was reacted at room temperature for 0.5 h. Then, methyl 3-(N-acetamidoamino)crotonate (0.32 g, 2.02 mmol, dissolved in 2 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 72 h. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, extracted with dichloromethane (50 mL×3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography ( petroleum ether / ethyl acetate The ester (V/V) = 2/1) gave a pale yellow oil (0.53 g, 78%).
MS(ESI,pos.ion)m/z：406.2(M+1)；1H NMR(400MHz,DMSO-d6)：δ 0.83(t,6H,J=7.4Hz),1.42-1.51(m,4H),2.38(t,3H,J=4.4Hz),2.50-2.51(m,3H),3.32(t,4H,J=6.5Hz),3.50-3.54(m,8H),6.53(s,1H),7.07-7.09(m,1H),7.15(t,1H,J=9.2Hz),7.20-7.24(m,1H)。 MS (ESI, pos.) m/z: 406.2 (M + 1); 1 H NMR (400 MHz, DMSO-d 6 ): δ 0.83 (t, 6H, J = 7.4 Hz), 1.42-1.51 (m, 4H), 2.38 (t, 3H, J = 4.4 Hz), 2.50-2.51 (m, 3H), 3.32 (t, 4H, J = 6.5 Hz), 3.50-3.54 (m, 8H), 6.53 (s, 1H) ), 7.07-7.09 (m, 1H), 7.15 (t, 1H, J = 9.2 Hz), 7.20-7.24 (m, 1H).
在100mL圓底燒瓶中加入3,4-二氟硝基苯(3.18g,20mmol)並溶解於乙酸乙酯(50mL)中，攪拌下加入三乙胺(2.43g,24mmol)和正己胺(2.02g,20mmol)，反應體系加熱至回流反應過夜。反應完畢，將混合物冷至室溫，過濾，減壓蒸去溶劑，得到黃色油狀物(4.37g,91%)。 3,4-Difluoronitrobenzene (3.18 g, 20 mmol) was added to a 100 mL round bottom flask and dissolved in ethyl acetate (50 mL) and triethylamine (2.43 g, 24 mmol) and n-hexylamine (2.02) g, 20 mmol), the reaction was heated to reflux overnight. After the reaction was completed, the mixture was cooled to room temperature, filtered, evaporated, evaporated
在100mL圓底燒瓶中加入2-氟-N-己烷-4-硝基苯胺(4.37g,18.2mmol)並溶解於甲醇(50mL)中，然後加入Pd/C(0.50g)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到微黑色油狀物(3.36g,88%)。 Add 2-fluoro-N-hexane-4-nitroaniline (4.37 g, 18.2 mmol) to a 100 mL round bottom flask and dissolve in methanol (50 mL), then add Pd/C (0.50 g) and pass H 2 . The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was filtered and evaporated tolululululululululululululululululululululululululu
在250mL三口燒瓶中加入2-氟-N1-己基苯-1,4-二胺(3.36g,16mmol)和二氯甲烷(20mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(40mL,80mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(3.02g,19.2mmol,5mL二氯甲烷溶解)，反應體系在室溫下反應72h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(150mL×3)，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到淡黃色油狀物(1.57g,31%)。 2-Fluoro-N 1 -hexylbenzene-1,4-diamine (3.36 g, 16 mmol) and dichloromethane (20 mL) were added to a 250 mL three-necked flask, and 2 M trimethylaluminum toluene solution (40 mL) was slowly added at room temperature. , 80 mmol), the reaction system was reacted at room temperature for 0.5 h. Then, methyl 3-(N-acetamidoamino)crotonate (3.02 g, 19.2 mmol, dissolved in 5 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 72 h. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, extracted with dichloromethane (150 mL × 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography ( petroleum ether / acetic acid The ester (V/V) = 4/1) gave a pale yellow oil (1. 57 g, 31%).
MS(ESI,pos.ion)m/z：318.2(M+1)；1H NMR(400MHz,MeOD)：δ 0.92(t,3H,J=7.0Hz),1.17(t,1H,J=7.1Hz),1.35-1.37(m,4H),1.63-1.70(m,2H),2.45(s,3H),2.49(s,3H),3.22(t,2H,J=7.2Hz),3.30-3.31(m,3H),3.58-3.63(m,1H),6.54(s,1H),6.89(t,1H,J=8.7Hz),7.00-7.07(m,2H)。 MS (ESI, pos.) m/z: 318.2 (M + 1); 1 H NMR (400 MHz, MeOD): δ 0.92 (t, 3H, J = 7.0 Hz), 1.17 (t, 1H, J = 7.1 Hz), 1.35-1.37 (m, 4H), 1.63-1.70 (m, 2H), 2.45 (s, 3H), 2.49 (s, 3H), 3.22 (t, 2H, J = 7.2 Hz), 3.30-3.31 (m, 3H), 3.58-3.63 (m, 1H), 6.54 (s, 1H), 6.89 (t, 1H, J = 8.7 Hz), 7.00-7.07 (m, 2H).
在100mL圓底燒瓶中加入3,4-二氟硝基苯(6.36g,40mmol)並溶解於乙酸乙酯(60mL)中，攪拌下加入三乙胺(12.14g,120mmol)和3-乙氧基丙基-1-胺(4.54g,44mol)，反應體系加熱至回流反應過夜。反應完畢，將混合物冷至室溫，減壓蒸去溶劑，得到黃色油狀物(8.68g,90%)。 3,4-Difluoronitrobenzene (6.36 g, 40 mmol) was added to a 100 mL round bottom flask and dissolved in ethyl acetate (60 mL). Triethylamine (12.14 g, 120 mmol) and 3-ethoxy Propyl-1-amine (4.54 g, 44 mol), and the reaction was heated to reflux overnight. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was evaporated.
在100mL圓底燒瓶中加入N-(3-乙氧基丙基)-2-氟-4-硝基苯胺(8.68g,36mmol)並溶解於甲醇(50mL)中，然後加入Pd/C(0.87g)並通入H2。反 應體系在室溫下反應過夜。反應完畢，過濾，蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到微黑色油狀物(5.52g,72%)。 N-(3-Ethoxypropyl)-2-fluoro-4-nitroaniline (8.68 g, 36 mmol) was added to a 100 mL round bottom flask and dissolved in methanol (50 mL) then Pd/C (0.87) g) and pass H 2 . The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the title compound was evaporated, mjjjjjjjjjj
在250mL三口燒瓶中加入N1-(3-乙氧基丙基)-2-氟苯-1,4-二胺(5.52g,26mmol)和二氯甲烷(40mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(52mL,104mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(4.87g,31mmol,10mL二氯甲烷溶解)，反應體系在室溫下反應72h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(150mL×3)，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到淡黃色油狀物(2.22g,27%)。 Add N 1 -(3-ethoxypropyl)-2-fluorobenzene-1,4-diamine (5.52 g, 26 mmol) and dichloromethane (40 mL) to a 250 mL three-necked flask, and slowly add 2 M at room temperature. Trimethylaluminum toluene solution (52 mL, 104 mmol), and the reaction was allowed to react at room temperature for 0.5 h. Then, methyl 3-(N-acetamidoamino)crotonate (4.87 g, 31 mmol, dissolved in 10 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 72 h. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, extracted with dichloromethane (150 mL × 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography ( petroleum ether / acetic acid The ester (V/V) = 1/1) gave a pale yellow oil (2.22 g, 27%).
MS(ESI,pos.ion)m/z：320.2(M+1)；1H NMR(400MHz,CDCl3)：δ 1.23(t,3H,J=7.0Hz),1.91-1.97(m,2H),2.20(s,3H),2.28(s,3H),3.26-3.33(m,2H),3.47-3.52(m,2H),3.55-3.61(m,2H),4.74(brs,1H),6.27(s,1H),6.75(t,1H,J=8.5Hz),6.82(d,2H,J=9.3Hz)。 MS (ESI, pos.) m/z: 320.2 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 1.23 (t, 3H, J = 7.0 Hz), 1.91-1.97 (m, 2H) , 2.20 (s, 3H), 2.28 (s, 3H), 3.26-3.33 (m, 2H), 3.47-3.52 (m, 2H), 3.55-3.61 (m, 2H), 4.74 (brs, 1H), 6.27 (s, 1H), 6.75 (t, 1H, J = 8.5 Hz), 6.82 (d, 2H, J = 9.3 Hz).
在冰浴冷卻下，氫化鈉(60%，1.40g,35mmol)一次性加入乾燥四氫呋喃(25mL)中，所得的反應液升溫至室溫攪拌30分鐘。冰浴冷卻下，逐滴加入1H-咪唑(2.00g,30mmol,6mL乾燥THF溶液)，所得的反應液升溫至室溫攪拌1.5h，逐滴加入1-溴-3-氯丙烷(4.60g,30mmol)，反應體系在室溫下反應過夜。將甲醇(5mL)一次性加入反應體系，過濾，減壓蒸去溶劑，粗產品經柱層析純化(二氯甲烷/甲醇(V/V)=30/1)，得到淡黃色油狀物(3.10g,73%)。 Sodium hydride (60%, 1.40 g, 35 mmol) was added to dry tetrahydrofuran (25 mL) in vacuo, and the mixture was warmed to room temperature and stirred for 30 min. 1H-imidazole (2.00 g, 30 mmol, 6 mL dry THF solution) was added dropwise under ice-cooling, and the obtained mixture was warmed to room temperature and stirred for 1.5 h, and 1-bromo-3-chloropropane (4.60 g, 30 mmol), the reaction system was allowed to react at room temperature overnight. Methanol (5 mL) was added to the reaction mixture in one portion, and the solvent was evaporated. 3.10g, 73%).
冰浴冷卻下，1-(3-氯丙基)-1H-咪唑(1.90g,13.14mmol)，碳酸銫(4.28 g,13.14mmol)和催化量的碘化鉀溶於DMF(30mL)中，一次性加入2-氟-4-硝基苯胺(1.38g,8.84mmol)，滴畢，反應體系加熱至回流反應36h。反應完畢，將混合物冷至室溫，過濾，減壓蒸去溶劑，殘餘物加入水(50mL)中，二氯甲烷(20mL×2)萃取，有機相用飽和鹽水(20mL×2)洗滌，減壓蒸去溶劑，粗產品經柱層析純化(二氯甲烷/甲醇(V/V)=15/1)，得到黃色油狀物(2.85g,82%)。 1-(3-chloropropyl)-1H-imidazole (1.90 g, 13.14 mmol), cesium carbonate (4.28) under ice cooling g, 13.14 mmol) and a catalytic amount of potassium iodide were dissolved in DMF (30 mL), 2-fluoro-4-nitroaniline (1.38 g, 8.84 mmol) was added in one portion, and the reaction was heated to reflux for 36 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the solvent was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjj The solvent was evaporated to dryness crystals crystals crystals crystals crystals
在50mL圓底燒瓶中加入N-(3-(1-1H-咪唑基)丙基)-2-氟-4-硝基苯胺(1.20g,4.54mmol)和四氫呋喃(20mL)，然後加入Pd/C(0.30g)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸去溶劑，得到黃色油狀物(1.00g,94%)。 Add N-(3-(1-1H-imidazolyl)propyl)-2-fluoro-4-nitroaniline (1.20 g, 4.54 mmol) and tetrahydrofuran (20 mL) in a 50 mL round bottom flask, then add Pd/ C (0.30 g) and passed H 2 . The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was filtered.
在250mL三口燒瓶中加入N1-(3-(1-1H-咪唑基)丙基)-2-氟苯-1,4-二胺(1.00g,4.27mmol)和二氯甲烷(30mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(16.4mL,32.8mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(1.00g,6.36mmol,8mL二氯甲烷溶解)，反應體系在室溫下反應24h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×2)，有機層用飽和食鹽水(50mL×3)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(二氯甲烷/甲醇(V/V)=20/1)，得到淡黃色油狀物(0.22g,15%)。 N 1 -(3-(1-1H-imidazolyl)propyl)-2-fluorobenzene-1,4-diamine (1.00 g, 4.27 mmol) and dichloromethane (30 mL) were added to a 250 mL three-neck flask. A 2 M solution of trimethylaluminum toluene (16.4 mL, 32.8 mmol) was slowly added at room temperature, and the reaction was allowed to react at room temperature for 0.5 h. Then, methyl 3-(N-acetamidoamino)crotonate (1.00 g, 6.36 mmol, dissolved in 8 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 24 h. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, and the mixture was extracted with dichloromethane (50 mL×2). The organic layer was washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate The crude product was purified by EtOAc EtOAcjjjjjjj
MS(ESI,pos.ion)m/z：342.2(M+1)；1H NMR(400MHz,DMSO-d6)：δ 2.01(m,2H),2.07(s,3H),2.18(s,3H),3.07(t,2H,J=6.6Hz),4.07(t,2H,J=7.0Hz),6.19(s,1H),6.69-6.74(m,1H),6.89-6.91(m,2H),7.07-7.11(m,1H),7.20-7.21(m,1H),7.65(s,1H)。 MS (ESI, pos.ion) m / z: 342.2 (M + 1); 1 H NMR (400MHz, DMSO-d 6): δ 2.01 (m, 2H), 2.07 (s, 3H), 2.18 (s, 3H), 3.07 (t, 2H, J = 6.6 Hz), 4.07 (t, 2H, J = 7.0 Hz), 6.19 (s, 1H), 6.69-6.74 (m, 1H), 6.89-6.91 (m, 2H) ), 7.07-7.11 (m, 1H), 7.20-7.21 (m, 1H), 7.65 (s, 1H).
冰浴冷卻下，2-(1-呱啶基)乙胺(0.90g,7.02mmol)和碳酸鉀(0.97g,7.02mmol)懸浮於丙酮(30mL)中，一次性加入3,4-二氟硝基苯(1.11g,6.98mmol)，滴畢，反應體系加熱至回流反應過夜。反應完畢，將混合物冷至室溫，過濾，減壓蒸去溶劑，粗品未經進一步處理直接進行下一步反應。 2-(1-Acryl)ethylamine (0.90 g, 7.02 mmol) and potassium carbonate (0.97 g, 7.02 mmol) were suspended in acetone (30 mL) with ice-cooling, and 3,4-difluorobenzene was added in one portion. Nitrobenzene (1.11 g, 6.98 mmol) was added dropwise, and the reaction was heated to reflux overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure.
在50mL圓底燒瓶中加入2-氟-4-硝基-N-(2-(1-呱啶基)乙基)苯胺(1.87g,7.00mmol)和四氫呋喃(20mL)，然後加入Pd/C(0.50g)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸去溶劑，粗產品經柱層析純化(二氯甲烷/甲醇(V/V)=15/1)，得到黃色油狀物(1.50g,90%)。 Add 2-fluoro-4-nitro-N-(2-(1-acridinyl)ethyl)aniline (1.87 g, 7.00 mmol) and tetrahydrofuran (20 mL) in a 50 mL round bottom flask, then add Pd/C (0.50 g) and passed H 2 . The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was evaporated.jjjjjjjjjj
在250mL三口燒瓶中加入2-氟-N1-(2-(1-呱啶基)乙基)苯-1,4-二胺(1.00g,4.21mmol)和二氯甲烷(30mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(6.3mL,12.6mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(1.60g,10.18mmol,8mL二氯甲烷溶解)，反應體系在室溫下反應24h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×2)，有機層用飽和食鹽水(50mL×3)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(二氯甲烷/甲醇(V/V)=20/1)，得到淡黃色固體(70mg,5%)。 Add 2-fluoro-N 1 -(2-(1-acridinyl)ethyl)benzene-1,4-diamine (1.00 g, 4.21 mmol) and dichloromethane (30 mL) to a 250 mL three-neck flask. 2M trimethylaluminum toluene solution (6.3 mL, 12.6 mmol) was slowly added thereto, and the reaction system was reacted at room temperature for 0.5 h. Then, methyl 3-(N-acetamidoamino)crotonate (1.60 g, 10.18 mmol, dissolved in 8 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 24 h. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, and the mixture was extracted with dichloromethane (50 mL×2). The organic layer was washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate The crude product was purified by EtOAc EtOAcjjjjjjj
MS(ESI,pos.ion)m/z：345.3(M+1)；1H NMR(400MHz,DMSO-d6)：δ 1.43(s,2H),1.57(s,4H),2.08(s,3H),2.19(s,3H),2.45(m,4H),2.60(m,2H),3.35(m,2H),6.20(s,1H),6.81-6.86(m,1H),6.92-6.95(m,1H),7.10-7.13(m,1H)。 MS (ESI, pos.ion) m / z: 345.3 (M + 1); 1 H NMR (400MHz, DMSO-d 6): δ 1.43 (s, 2H), 1.57 (s, 4H), 2.08 (s, 3H), 2.19 (s, 3H), 2.45 (m, 4H), 2.60 (m, 2H), 3.35 (m, 2H), 6.20 (s, 1H), 6.81-6.86 (m, 1H), 6.92-6.95 (m, 1H), 7.10-7.13 (m, 1H).
在冰浴冷卻下，氫化鈉(0.70g,17.50mmol,60%)一次性加入乾燥DMF(25mL)中，所得的反應液升溫至室溫攪拌30分鐘。冰浴冷卻下，逐滴加入1H-四氮唑(1.00g,14.28mmol,6mL乾燥DMF溶液)，所得的反應液升溫至室溫攪拌1.5h，逐滴加入1-溴-3-氯丙烷(2.35g,14.93mmol)，反應體系在室溫下反應過夜。將甲醇(1mL)一次性加入反應體系，過濾，減壓蒸去溶劑，粗品未經進一步處理直接進行下一步反應。 Sodium hydride (0.70 g, 17.50 mmol, 60%) was added to dry DMF (25 mL). 1H-tetrazole (1.00 g, 14.28 mmol, 6 mL of dry DMF solution) was added dropwise under ice-cooling, and the obtained mixture was warmed to room temperature and stirred for 1.5 h, and 1-bromo-3-chloropropane was added dropwise. 2.35 g, 14.93 mmol), the reaction was allowed to react at room temperature overnight. Methanol (1 mL) was added to the reaction system in one portion, filtered, and the solvent was evaporated under reduced pressure.
冰浴冷卻下，1-(3-氯丙基)-1H-四氮唑(2.10g,14.33mmol)，碳酸銫(4.66g,14.33mmol)和催化量的碘化鉀溶於DMF(30mL)中，一次性加入2-氟-4-硝基苯胺(1.50g,9.61mmol)，滴畢，反應體系加熱至回流反應35h。反應完畢，將混合物冷至室溫，過濾，減壓蒸去溶劑，殘餘物加入水(50mL)中，二氯甲烷(20mL×2)萃取，有機相用飽和鹽水(20mL×2)洗滌，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到油狀物(360mg,10%)。 1-(3-Chloropropyl)-1H-tetrazole (2.10 g, 14.33 mmol), cesium carbonate (4.66 g, 14.33 mmol) and a catalytic amount of potassium iodide dissolved in DMF (30 mL). 2-Fluoro-4-nitroaniline (1.50 g, 9.61 mmol) was added in one portion, and the reaction was heated to reflux for 35 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the solvent was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjj The solvent was evaporated to dryness.
在50mL圓底燒瓶中加入N-(3-(1-1H-四氮唑)丙基)-2-氟-4-硝基苯胺(0.36g,1.35mmol)和四氫呋喃(10mL)，然後加入Pd/C(0.12g)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到紅色油狀物(0.20g,63%)。 Add N-(3-(1-1H-tetrazolyl)propyl)-2-fluoro-4-nitroaniline (0.36 g, 1.35 mmol) and tetrahydrofuran (10 mL) in a 50 mL round bottom flask, then add Pd /C (0.12g) and pass H 2 . The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was evaporated.jjjjjjjjjj
在100mL三口燒瓶中加入N1-(3-(1-1H-四氮唑)丙基)-2-氟苯-1,4-二胺(0.20g,0.85mmol)和二氯甲烷(20mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(1.3mL,2.6mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-乙醯基氨基)巴豆酸甲酯(0.20g,1.27mmol,5mL二氯甲烷溶解)，反應 體系在室溫下反應24h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(20mL×2)，有機層用飽和食鹽水(20mL×3)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到淡黃色固體(0.16g,55%)。 Add N 1 -(3-(1-1H-tetrazolyl)propyl)-2-fluorobenzene-1,4-diamine (0.20 g, 0.85 mmol) and dichloromethane (20 mL) in a 100 mL three-neck flask 2M trimethylaluminum toluene solution (1.3 mL, 2.6 mmol) was slowly added at room temperature, and the reaction system was reacted at room temperature for 0.5 h. Then, methyl 3-(N-ethylidylamino)crotonate (0.20 g, 1.27 mmol, dissolved in 5 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 24 h. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, and the mixture was extracted with dichloromethane (20 mL×2). The organic layer was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate The crude product was purified by EtOAc EtOAc EtOAc (EtOAc:
MS(ESI,pos.ion)m/z：344.1(M+1)；1H NMR(400MHz,DMSO-d6)：δ 2.08(s,3H),2.18(s,3H),2.24(m,2H),3.18(t,2H,J=6.60Hz),4.83(t,2H J=6.96Hz),6.20(s,1H),6.74-6.78(m,1H),6.89-6.91(m,1H),7.08-7.12(m,1H),8.97(s,1H)。 MS (ESI, pos.) m/z: 344.1 (M + 1); 1 H NMR (400 MHz, DMSO-d 6 ): δ 2.08 (s, 3H), 2.18 (s, 3H), 2.24 (m, 2H), 3.18 (t, 2H, J = 6.60 Hz), 4.83 (t, 2H J = 6.96 Hz), 6.20 (s, 1H), 6.74 - 6.78 (m, 1H), 6.89 - 6.91 (m, 1H) , 7.08-7.12 (m, 1H), 8.97 (s, 1H).
在氮氣保護下，3,4-二氟硝基苯(1.59g,10mmol)和碳酸鉀(6.90g,50mmol)溶於二氯甲烷(40mL)中，一次性加入2-(3-1H-吲哚)乙胺(1.96g,10mmol)，反應體系在室溫下反應24h。反應畢，過濾，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=10/1)，得到黃色固體(2.32g,78%)。 Under nitrogen, 3,4-difluoronitrobenzene (1.59 g, 10 mmol) and potassium carbonate (6.90 g, 50 mmol) were dissolved in dichloromethane (40 mL), and 2-(3-1H-吲) was added in one portion.哚) Ethylamine (1.96 g, 10 mmol), and the reaction was allowed to react at room temperature for 24 h. After the reaction was completed, EtOAc~~~~~~~~~
在100mL圓底燒瓶中加入N-(2-(3-1H-吲哚)乙基)-2-氟-4-硝基苯胺(2.32g,7.75mmol)，乙酸乙酯(25mL)和甲醇(25mL)，然後加入Pd/C(0.60g)並通入H2。反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸去溶劑，粗品未經進一步處理直接進行下一步反應。 N-(2-(3-1H-Indolyl)ethyl)-2-fluoro-4-nitroaniline (2.32 g, 7.75 mmol), ethyl acetate (25 mL) and methanol 25mL), followed by addition of Pd / C (0.60g) and passed through H 2. The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was filtered, and the solvent was evaporated under reduced pressure.
在250mL三口燒瓶中加入N1-(2-(3-1H-吲哚)乙基)-2-氟苯-1,4-二胺(2.09g,7.76mmol)和二氯甲烷(30mL)，室溫下緩慢加入2mol/L三甲基鋁甲苯溶液(19.4mL,38.8mmol)，反應體系在室溫下反應1h。然後緩慢加 入3-(N-乙醯基氨基)巴豆酸甲酯(2.44g,15.52mmol,10mL二氯甲烷溶解)，反應體系在室溫下反應72h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×2)，有機層用飽和食鹽水(50mL×3)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到淡黃色固體(0.95g,33%)。 N 2 -(2-(3-1H-Indolyl)ethyl)-2-fluorobenzene-1,4-diamine (2.09 g, 7.76 mmol) and dichloromethane (30 mL) were added to a 250 mL three-neck flask. A 2 mol/L solution of trimethylaluminum toluene (19.4 mL, 38.8 mmol) was slowly added at room temperature, and the reaction was allowed to react at room temperature for 1 h. Then, methyl 3-(N-acetamidoamino)crotonate (2.44 g, 15.52 mmol, dissolved in 10 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 72 h. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, and the mixture was extracted with dichloromethane (50 mL×2). The organic layer was washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate The crude product was purified with EtOAc EtOAcjjjjjjj
MS(ESI,pos.ion)m/z：377.2(M+1)；1H NMR(400MHz CDCl3)：δ 2.18(s,3H),2.28(s,3H),3.10-3.14(m,2H),3.48-3.53(m,2H),4.21-4.22(m,1H),6.28(s,1H),6.74-6.81(m,3H),7.03-7.04(d,1H),7.11-7.15(m,1H),7.18-7.23(m,1H),7.35-7.37(m,1H),7.60-7.62(d,1H)。 MS (ESI, pos. ion) m/z: 377.2 (M + 1); 1 H NMR (400 MHz CDCl 3 ): δ 2.18 (s, 3H), 2.28 (s, 3H), 3.10-3.14 (m, 2H) ), 3.48-3.53 (m, 2H), 4.21-4.22 (m, 1H), 6.28 (s, 1H), 6.74-6.81 (m, 3H), 7.03-7.04 (d, 1H), 7.11-7.15 (m , 1H), 7.18-7.23 (m, 1H), 7.35-7.37 (m, 1H), 7.60-7.62 (d, 1H).
在50mL圓底燒瓶中加入3-(3-氟-4-(呱嗪基)苯基)-2,6-二甲基嘧啶-4(3H)-酮(0.30g,1.00mmol)和碳酸鉀(0.69g,5.00mmol)並溶解於乙腈(15mL)中，攪拌下加入3-溴丙炔(0.12g,1.01mmol)，反應體系在室溫下反應36h。反應完畢，過濾，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到白色固體(150mg,44%)。 Add 3-(3-fluoro-4-(pyridazinyl)phenyl)-2,6-dimethylpyrimidin-4(3H)-one (0.30 g, 1.00 mmol) and potassium carbonate to a 50 mL round bottom flask (0.69 g, 5.00 mmol) and dissolved in acetonitrile (15 mL), 3-bromopropyne (0.12 g, 1.01 mmol), and the reaction was allowed to react at room temperature for 36 h. After completion of the reaction, the mixture was evaporated.jjjjjjjjjj
MS(ESI,pos.ion)m/z：341.3(M+1)；1H NMR(400MHz,CDCl3)：δ 2.18(s,3H),2.29(s,3H),2.29(s,1H),2.76-2.78(t,4H),3.17-3.38(m,4H),3.38(s,2H),6.28(s,1H),6.89-6.92(m,2H),7.03-7.05(m,1H)。 MS (ESI, pos.ion) m / z: 341.3 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.18 (s, 3H), 2.29 (s, 3H), 2.29 (s, 1H) , 2.76-2.78(t,4H), 3.17-3.38(m,4H), 3.38(s,2H),6.28(s,1H),6.89-6.92(m,2H),7.03-7.05(m,1H) .
在250mL圓底燒瓶中加入2-氯-1-氟-4-硝基苯(17.55g,0.10mol)並溶解於DMF(100mL)中，攪拌下加入K2CO3(27.64g,0.20mol)和二正己胺(18.54g,0.10mol)，反應體系加熱至90℃反應72小時。反應完畢，將混合物冷至室溫，過濾，將有機相濃縮至50mL，傾入二氯甲烷(150mL)中，用水(150mL×3)和飽和食鹽水(150mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=10/1)，得到黃色油狀物(23.64g,69%)。 2-Chloro-1-fluoro-4-nitrobenzene (17.55 g, 0.10 mol) was added to a 250 mL round bottom flask and dissolved in DMF (100 mL). K 2 CO 3 (27.64 g, 0.20 mol) was added with stirring. And di-n-hexylamine (18.54 g, 0.10 mol), and the reaction system was heated to 90 ° C for 72 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the organic phase was concentrated to 50 mL, and then evaporated to dichloromethane (150 mL), washed with water (150 mL×3) and brine (150 mL) The solvent was evaporated to dryness crystals crystals crystals crystals
在250mL圓底燒瓶中加入濃鹽酸(1.0mL)，水(50mL)，一次性加入鐵粉(5.58g,100mmol)，攪拌下加熱至65℃活化鐵粉15分鐘，然後後傾去水層，將N,N-二己基-2-氯-4-硝基苯胺(3.41g,10mmol,100mL甲醇溶解)加入上述鐵粉中，用鹽酸調pH=3，加熱至65℃反應45分鐘，反應畢，將混合物冷至室溫並用三乙胺調節pH=10，過濾，減壓蒸去甲醇，殘餘物溶解於二氯甲烷(150mL)，用水(100mL×3)和飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，得到無色油狀物(3.00g,97%)。 Concentrated hydrochloric acid (1.0 mL), water (50 mL) was added to a 250 mL round bottom flask, iron powder (5.58 g, 100 mmol) was added in one portion, and the iron powder was heated to 65 ° C for 15 minutes while stirring, and then the aqueous layer was decanted. Add N,N-dihexyl-2-chloro-4-nitroaniline (3.41 g, 10 mmol, 100 mL of methanol) to the above iron powder, adjust the pH to 3 with hydrochloric acid, and heat to 65 ° C for 45 minutes. The mixture was cooled to room temperature and adjusted to pH = 10 with triethylamine, filtered, and then evaporated to dryness m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The residue was dried over anhydrous sodium
在100mL圓底燒瓶中加入N1,N1-二己基-2-氯苯-1,4-二胺(3.11g,10mmol)並溶解於甲苯(50mL)中，攪拌下加入雙乙烯酮(1.68g,20mmol)，反應體系加熱至80℃反應過夜。反應完畢，將混合物冷至室溫，減壓蒸去溶劑，得到微黑色油狀物(3.94g,100%)。 N 1 ,N 1 -dihexyl-2-chlorobenzene-1,4-diamine (3.11 g, 10 mmol) was added to a 100 mL round bottom flask and dissolved in toluene (50 mL), and diketene (1.68 g, 20 mmol), the reaction system was heated to 80 ° C to react overnight. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was evaporated to drynessiel
在100mL圓底燒瓶中加入N-(3-氯-4-(二正己胺)苯基)-3-乙醯乙醯胺(3.94g,10mmol)，甲醇(50mL)和氨水(50mL)，反應體系在室溫下反應過夜。反應完畢，減壓蒸去溶劑，得黑色油狀物(3.94g,100%)。 Add N-(3-chloro-4-(di-n-hexylamine)phenyl)-3-acetamethyleneamine (3.94 g, 10 mmol), methanol (50 mL) and aqueous ammonia (50 mL) in a 100 mL round bottom flask. The system was allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated to dryness crystall
在250mL圓底燒瓶中加入(Z)-3-氨基-N-(3-氯-4-(二正己胺)苯基)丁醯胺 -2-烯(3.94g,10mmol)，原乙酸三乙酯(80mL)，反應體系加熱至150℃反應過夜。反應完畢，將混合物冷至室溫，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到淡黃色油狀物(1.36g,33%)。 Add (Z)-3-amino-N-(3-chloro-4-(di-n-hexylamine)phenyl)butanamine to a 250 mL round bottom flask 2-ene (3.94 g, 10 mmol), triethyl orthoacetate (80 mL), and the reaction was heated to 150 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated evaporated evaporated. mjjjjjjjjj , 33%).
MS(ESI,pos.ion)m/z：418.3(M+1)；1H NMR(400MHz DMSO-d6)：δ 0.83-0.89(m,6H),1.24-1.31(m,12H),1.46-1.51(m,4H),2.19(s,3H),2.29(s,3H),3.08-3.12(m,4H),6.28(s,1H),6.98-7.01(m,1H),7.14-7.19(m,1H),7.19(d,1H,J=2.5Hz)。 MS (ESI, pos.) m/z: 418.3 (M + 1); 1 H NMR (400 MHz DMSO-d 6 ): δ 0.83-0.89 (m, 6H), 1.24-1.31 (m, 12H), 1.46 -1.51 (m, 4H), 2.19 (s, 3H), 2.29 (s, 3H), 3.08-3.12 (m, 4H), 6.28 (s, 1H), 6.98-7.01 (m, 1H), 7.14-7.19 (m, 1H), 7.19 (d, 1H, J = 2.5 Hz).
在500mL三口瓶中，2-氟-5-硝基苯胺(9.45g,60.5mmol)和溴化銅(16.22g,72.6mmol)一次性加入乙腈(200mL)中，室溫攪拌下，逐滴加入叔丁基亞硝酸酯(10.8mL,90.1mmol)，反應體系加熱至回流反應3.5h。反應完畢，待混合物冷至室溫，將反應液傾入乙酸乙酯(200mL)中，有機相用2mol/L稀鹽酸(150mL×2)，水(150mL)和飽和食鹽水(150mL×2)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗品未經進一步處理直接進行下一步反應。 In a 500 mL three-necked flask, 2-fluoro-5-nitroaniline (9.45 g, 60.5 mmol) and copper bromide (16.22 g, 72.6 mmol) were added in one portion to acetonitrile (200 mL), and added dropwise at room temperature with stirring. Tert-butyl nitrite (10.8 mL, 90.1 mmol), and the reaction was heated to reflux for 3.5 h. After completion of the reaction, the mixture was cooled to room temperature, and the reaction mixture was poured into ethyl acetate (200 mL), and the organic phase was diluted with 2 mol/L of hydrochloric acid (150 mL×2), water (150 mL) and saturated brine (150 mL×2) After washing, it was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
在250mL圓底燒瓶中加入2-溴-1-氟-4-硝基苯(13.30g,60.5mmol)並溶解於DMF(100mL)中，攪拌下加入K2CO3(16.78g,121mmol)和二正己胺(11.22g,60.5mmol)，反應體系加熱至90℃反應48h。反應完畢，將混合物冷至室溫，過濾，將有機相濃縮至30mL，傾入二氯甲烷(150mL)中，用水(150mL×3)和飽和食鹽水(150mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=10/1)，得到黃色油狀物(9.28g,40%)。 2-Bromo-1-fluoro-4-nitrobenzene (13.30 g, 60.5 mmol) was added to a 250 mL round bottom flask and dissolved in DMF (100 mL). K 2 CO 3 (16.78 g, 121 mmol) and Di-n-hexylamine (11.22 g, 60.5 mmol), and the reaction system was heated to 90 ° C for 48 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the organic phase was concentrated to 30 mL, EtOAc (150 mL), washed with water (150 mL×3) and brine (150 mL) The solvent was evaporated to dryness crystals crystals crystals crystals crystals
在250mL圓底燒瓶中加入濃鹽酸(4.0mL)，水(100mL)，一次性加入鐵粉(13.44g,241mmol)，攪拌下加熱至65℃活化鐵粉15min，然後後傾去水層，將N,N-二己基-2-溴-4-硝基苯胺(9.28g,24.1mmol,150mL甲醇溶解)加入上述鐵粉中，用鹽酸調pH 3，加熱至65℃反應30min，反應畢，將混合物冷至室溫並用三乙胺調節pH=10，過濾，減壓蒸去甲醇，殘餘物溶解於二氯甲烷(150mL)，用水(100mL×3)和飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=20/1)，得到無色油狀物(4.40g,51%)。 Concentrated hydrochloric acid (4.0 mL), water (100 mL) was added to a 250 mL round bottom flask, iron powder (13.44 g, 241 mmol) was added in one portion, and the iron powder was heated to 65 ° C for 15 min with stirring, and then the aqueous layer was decanted. N,N-dihexyl-2-bromo-4-nitroaniline (9.28g, 24.1mmol, 150mL methanol dissolved) was added to the above iron powder, adjusted to pH 3 with hydrochloric acid, heated to 65 ° C for 30 min, the reaction was completed, The mixture was cooled to room temperature and adjusted to pH = 10 with triethylamine, filtered, and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The mixture was dried with EtOAc EtOAc EtOAc.
在250mL圓底燒瓶中加入N1,N1-二己基-2-溴苯-1,4-二胺(4.40g,12.4mmol)並溶解於乙酸乙酯(120mL)中，攪拌下加入雙乙烯酮(1.57g,18.7mmol)，反應體系加熱至80℃反應過夜。反應完畢，將混合物冷至室溫，減壓蒸去溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=10/1)，得到無色油狀物(5.10g,94%)。 N 2 ,N 1 -dihexyl-2-bromobenzene-1,4-diamine (4.40 g, 12.4 mmol) was added to a 250 mL round bottom flask and dissolved in ethyl acetate (120 mL). 1.57 g, 18.7 mmol), and the reaction was heated to 80 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated evaporated evaporated. mjjjjjjj %).
在250mL圓底燒瓶中加入N-(3-溴-4-(二正己胺)苯基)-3-乙醯乙醯胺(5.10g,11.6mmol)，甲醇(60mL)和氨水(60mL)，反應體系在室溫下反應過夜。反應完畢，減壓蒸去溶劑，得到黑色油狀物(5.10g,100%)。 Add N-(3-bromo-4-(di-n-hexylamine)phenyl)-3-acetamethyleneamine (5.10 g, 11.6 mmol), methanol (60 mL) and aqueous ammonia (60 mL) in a 250 mL round bottom flask. The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the solvent was evaporated to dryness crystall
在250mL圓底燒瓶中加入(Z)-3-氨基-N-(3-溴-4-(二正己胺)苯基)丁醯胺-2-烯(5.10g,11.6mmol)，原乙酸三乙酯(100mL)，反應體系加熱至150℃反應過夜。反應完畢，將混合物冷至室溫，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到淡黃色油狀物(1.74g,33%)。 In a 250 mL round bottom flask was added (Z)-3-amino-N-(3-bromo-4-(di-n-hexylamine)phenyl)butanamine-2-ene (5.10 g, 11.6 mmol), orthoacetic acid Ethyl acetate (100 mL), and the reaction was heated to 150 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated, evaporated, mjjjjjjjjjj , 33%).
MS(ESI,pos.ion)m/z：464.3(M+1)；1H NMR(400MHz DMSO-d6)：δ 0.81-0.84(m,6H),1.22-1.25(m,12H),1.40-1.42(m,4H),2.01(s,3H),2.19(s,3H),3.02-3.07(m,4H),6.23(s,1H),7.26-7.33(m,2H),7.61(d,1H,J=2.32Hz)。 MS (ESI, pos.) m/z: 464.3 (M + 1); 1 H NMR (400 MHz DMSO-d 6 ): δ 0.81-0.84 (m, 6H), 1.22-1.25 (m, 12H), 1.40 -1.42 (m, 4H), 2.01 (s, 3H), 2.19 (s, 3H), 3.02-3.07 (m, 4H), 6.23 (s, 1H), 7.26-7.33 (m, 2H), 7.61 (d) , 1H, J = 2.32Hz).
在100mL圓底燒瓶中加入2-氯-5-硝基-苯甲腈(1.83g,10.0mmol)並溶解於乙腈(20mL)中，攪拌下加入K2CO3(2.76g,20.0mmol)和二正己胺(1.85g,9.98mmol)，反應體系加熱至80℃反應40h。反應完畢，將混合物冷至室溫，傾入二氯甲烷(100mL)中，用水(100mL×3)和飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=125/2)，得到黃色油狀物(2.89g,87%)。 2-Chloro-5-nitro-benzonitrile (1.83 g, 10.0 mmol) was added to a 100 mL round bottom flask and dissolved in acetonitrile (20 mL). K 2 CO 3 (2.76 g, 20.0 mmol) and Di-n-hexylamine (1.85 g, 9.98 mmol), and the reaction system was heated to 80 ° C for 40 h. After completion of the reaction, the mixture was cooled to room temperature, poured into dichloromethane (100 mL), washed with water (100 mL × 3) and brine (100 mL), dried over anhydrous sodium sulfate Purification (petroleum ether / EtOAc (V/V) = EtOAc)
在100mL圓底燒瓶中加入N,N-二己基-2-腈基-4-硝基苯胺(2.89g,8.72mmol)和甲醇(30mL)，然後加入10%Pd/C(0.30g)並通入H2，反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸去溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=5/1)，得到無色油狀物(1.55g,59%)。 Add N,N-dihexyl-2-carbonitrile-4-nitroaniline (2.89 g, 8.72 mmol) and methanol (30 mL) in a 100 mL round bottom flask, then add 10% Pd/C (0.30 g) and pass Into H 2 , the reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was evaporated,jjjjjjjjjj
在100mL圓底燒瓶中加入N1,N1-二己基-2-腈基苯-1,4-二胺(1.55g,5.14mmol)並溶解於乙酸乙酯(30mL)中，攪拌下加入雙乙烯酮(0.52g,6.19mmol)，反應體系加熱至80℃反應過夜。反應完畢，將混合物冷至室溫，減壓蒸去溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到黃色油狀物(1.47g,74%)。 Add N 1 ,N 1 -dihexyl-2-cyanobenzene-1,4-diamine (1.55 g, 5.14 mmol) in a 100 mL round bottom flask and dissolve in ethyl acetate (30 mL). (0.52 g, 6.19 mmol), and the reaction was heated to 80 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was evaporated evaporated evaporated. %).
在50mL圓底燒瓶中加入N-(3-腈基-4-(二正己胺)苯基)-3-乙醯乙醯胺(1.47g,3.81mmol)，甲醇(15mL)和氨水(15mL)，反應體系在室溫下反應過夜。反應完畢，減壓蒸去溶劑，得到黑色油狀物(1.30g,88%)。 Add N-(3-cyano-4-(di-n-hexylamine)phenyl)-3-acetamethyleneamine (1.47 g, 3.81 mmol), methanol (15 mL) and aqueous ammonia (15 mL) in a 50 mL round bottom flask. The reaction system was allowed to react at room temperature overnight. After completion of the reaction, the solvent was evaporated to dryness crystall
在100mL圓底燒瓶中加入(Z)-3-氨基-N-(3-氯-4-(二正己胺)苯基)丁醯胺-2-烯(1.30g,3.38mmol)，原乙酸三乙酯(30mL)，反應體系加熱至150℃反應過夜。反應完畢，將混合物冷至室溫，減壓蒸去溶劑，粗產品經柱層析純化(二氯甲烷/甲醇(V/V)=50/1)，得到淡黃色油狀物(60mg,4%)。 In a 100 mL round bottom flask was added (Z)-3-amino-N-(3-chloro-4-(di-n-hexylamine)phenyl)butanamine-2-ene (1.30 g, 3.38 mmol), orthoacetic acid Ethyl acetate (30 mL), and the reaction was heated to 150 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated evaporated evaporated. mjjjjjjjjj %).
MS(ESI,pos.ion)m/z：409.3(M+1)；1H NMR(400MHz,DMSO-d6)：δ 0.88-0.91(m,6H),1.26-1.36(m,12H),1.63-1.67(m,4H),2.20(s,3H),2.29(s,3H),3.43(t,4H,J=7.8Hz),6.28(s,1H),6.90(d,1H,J=9.16Hz),7.14(dd,1H,J=2.68Hz,9.12Hz),7.29(d,1H,J=2.64Hz)。 MS (ESI, pos. ion) m/z: 409.3 (M + 1); 1 H NMR (400 MHz, DMSO-d 6 ): δ 0.88-0.91 (m, 6H), 1.26-1.36 (m, 12H), 1.63-1.67 (m, 4H), 2.20 (s, 3H), 2.29 (s, 3H), 3.43 (t, 4H, J = 7.8 Hz), 6.28 (s, 1H), 6.90 (d, 1H, J = 9.16 Hz), 7.14 (dd, 1H, J = 2.68 Hz, 9.12 Hz), 7.29 (d, 1H, J = 2.64 Hz).
在100mL圓底燒瓶中加入2-氟-4-硝基苯胺(2.34g,15.0mmol)、DMF(30mL)、K2CO3(4.2g,30.4mmol)、KI(0.5g,3.01mmol)和溴乙基金剛烷(3.65g,15.0mmol)，反應體系加熱至140℃反應12h。反應完畢，將混合物冷至室溫，過濾，加入二氯甲烷(150mL)，用水(50mL×3)和飽和氯化鈉溶液(150mL)洗滌，無水硫酸鈉乾燥，蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=8/1)，得到黃色固體(477mg,10%)。 To a 100 mL round bottom flask was added 2-fluoro-4-nitroaniline (2.34 g, 15.0 mmol), DMF (30 mL), K 2 CO 3 (4.2 g, 30.4 mmol), KI (0.5 g, 3.01 mmol) and Bromoethyl adamantane (3.65 g, 15.0 mmol), and the reaction system was heated to 140 ° C for 12 h. After completion of the reaction, the mixture was cooled to room temperature, filtered, dichloromethane (150 mL), washed with water (50mL×3) and saturated sodium chloride (150mL), dried over anhydrous sodium sulfate, evaporated Purification (petroleum ether / ethyl acetate (v/v) = 8/1) afforded a yellow solid (477mg, 10%).
在100mL圓底燒瓶中加入鐵粉(0.88g,15.8mmol)、水(50mL)，加熱至65℃，緩慢滴加HCl(1mL)，反應15min後，將水去除，向反應體系中加入N-(2-(金剛烷-1-基)乙基)-2-氟-4-硝基苯胺(0.5g,1.57mmol)、甲醇(50mL)，反應體系加熱至65℃反應0.5h。反應完畢，冷至室溫，過濾，蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到白色固體(382mg,84%)。 Iron powder (0.88g, 15.8mmol) and water (50mL) were added to a 100mL round bottom flask, heated to 65 ° C, and HCl (1mL) was slowly added dropwise. After 15 minutes of reaction, the water was removed and N- was added to the reaction system. (2-(adamantan-1-yl)ethyl)-2-fluoro-4-nitroaniline (0.5 g, 1.57 mmol), methanol (50 mL), and the reaction was heated to 65 ° C for 0.5 h. After completion of the reaction, the mixture was cooled to EtOAc.
在100mL圓底燒瓶中加入N-(2-(金剛烷-1-基)乙基)-2-氟-1,4-苯二胺(0.38g,1.32mmol)，乙酸乙酯(20mL)和雙乙烯酮(0.22g,2.62mmol)，反應體系加熱至90℃反應過夜，冷至室溫，蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得白色固體(317mg,64%)。 Add N-(2-(adamantan-1-yl)ethyl)-2-fluoro-1,4-phenylenediamine (0.38 g, 1.32 mmol) in ethyl acetate (20 mL) Diketene (0.22 g, 2.62 mmol), the reaction system was heated to 90 ° C overnight, cooled to room temperature, and the solvent was evaporated to dryness. The crude material was purified by column chromatography ( petroleum ether / ethyl acetate (V / V) = 4 / 1) , white solid (317 mg, 64%).
在100mL圓底燒瓶中加入N-(2-(金剛烷-1-基)乙基)氨基)-3-氟苯基)-3-乙醯乙醯苯胺(0.31g,0.83mmol)，甲醇(10mL)，氨水(10mL)，室溫下反應過夜。反應完畢，減壓蒸去溶劑，粗產物在沒有進一步純化的條件下進行下一步反應。 Add N-(2-(adamantan-1-yl)ethyl)amino)-3-fluorophenyl)-3-acetamidoaniline (0.31 g, 0.83 mmol) in methanol to a 100 mL round bottom flask. 10 mL), aqueous ammonia (10 mL), and allowed to react at room temperature overnight. After completion of the reaction, the solvent was evaporated under reduced pressure and the crude material was applied to the next step without further purification.
在100mL圓底燒瓶中加入N-(2-(金剛烷-1-基)乙基)氨基)-3-氟苯基)-3-氨基丁醯胺-2-烯(0.31g,0.83mmol)，原乙酸三乙酯(20mL)，反應體系加熱至150℃反應12h，冷至室溫，蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到紅棕色固體(10mg,3%)。 Add N-(2-(adamantan-1-yl)ethyl)amino)-3-fluorophenyl)-3-aminobutyramine-2-ene (0.31 g, 0.83 mmol) to a 100 mL round bottom flask. , triethyl orthoacetate (20mL), the reaction system is heated to 150 ° C for 12h, cooled to room temperature, the solvent is evaporated, the crude product is purified by column chromatography ( petroleum ether / ethyl acetate (V / V) = 4 / 1 ), a reddish brown solid (10 mg, 3%) was obtained.
MS(ESI,pos.ion)m/z：396.2(M+1)；1H NMR(400MHz,DMSO-d6)：δ 1.57(d,2H),1.58(m,6H),1.98(m,6H),2.22(m,6H),2.28(s,3H),3.17(d,2H),3.97(s,1H),6.28(s,1H),6.74-6.83(m,3H)。 MS (ESI, pos.) m/z: 396.2 (M + 1); 1 H NMR (400 MHz, DMSO-d 6 ): δ 1.57 (d, 2H), 1.58 (m, 6H), 1.98 (m, 6H), 2.22 (m, 6H), 2.28 (s, 3H), 3.17 (d, 2H), 3.97 (s, 1H), 6.28 (s, 1H), 6.74 - 6.83 (m, 3H).
在150mL圓底燒瓶中加入3-(2-呋喃)丙烯酸(11.0g,80.0mmol)和甲醇(110mL)，然後加入10% Pd/C(1.1g)並通入氫氣，反應體系在3MPa壓力下加熱至60℃反應過夜。反應完畢，將混合物冷卻至室溫，過濾，減壓蒸乾溶劑，粗品未經進一步純化直接用於下一步反應。 3-(2-furan)acrylic acid (11.0 g, 80.0 mmol) and methanol (110 mL) were added to a 150 mL round bottom flask, then 10% Pd/C (1.1 g) was added and hydrogen was introduced, and the reaction system was under a pressure of 3 MPa. The reaction was heated to 60 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered, and evaporated to dryness.
在500mL雙口瓶加入3-(四氫呋喃-2-基)丙酸(11.5g,80.0mmol)和乾燥四氫呋喃(200mL)，氮氣保護，在室溫下滴加1mol/L硼烷四氫呋喃絡合物(160mL,160mmol)，反應體系在室溫下反應過夜。反應完畢，加入甲 醇淬滅，減壓蒸乾溶劑，粗品未經進一步純化直接用於下一步反應。 3-(tetrahydrofuran-2-yl)propionic acid (11.5 g, 80.0 mmol) and dry tetrahydrofuran (200 mL) were added to a 500 mL two-necked flask, and nitrogen-protected, and a 1 mol/L borane tetrahydrofuran complex was added dropwise at room temperature ( 160 mL, 160 mmol), the reaction was allowed to react at room temperature overnight. After the reaction is completed, join A The alcohol was quenched and the solvent was evaporated evaporated evaporated.
在50mL圓底燒瓶中加入3-(四氫呋喃-2-基)丙-1-醇(3.90g,30.0mmol)，氮氣保護下慢慢滴加二氯亞碸(15mL)，反應體系加熱至回流，反應3.5h。將混合物冷卻至室溫，蒸乾溶劑，加入水，用二氯甲烷(30mL×4)萃取，有機相用飽和食鹽水(40mL×2)洗滌，無水硫酸鈉乾燥。過濾，減壓蒸乾溶劑，得到黃色液體，粗品未經進一步處理直接用於下一步反應。 3-(tetrahydrofuran-2-yl)propan-1-ol (3.90 g, 30.0 mmol) was added to a 50 mL round bottom flask, and dichlorohydrazine (15 mL) was slowly added dropwise under a nitrogen atmosphere, and the reaction was heated to reflux. The reaction was 3.5 h. The mixture was cooled to room temperature, and the solvent was evaporated, evaporated, evaporated, evaporated. Filtration and evaporation of the solvent under reduced pressure afforded a yellow liquid.
在250mL雙口瓶中加入2-氟-4-硝基苯胺(7.02g,45.0mmol)、碳酸銫(29.3g,90.0mmol)、碘化鉀(16.6g,100mmol)和DMF(100mL)，氮氣保護，在室溫下往反應體系中慢慢滴加2-(3-氯丙基)四氫呋喃(7.43g,50.0mmol)。滴加完，反應體系加熱至140℃，反應48h。反應完畢，將混合物冷卻至室溫，過濾，減壓蒸乾溶劑。加入水，用二氯甲烷萃取(30mL×4)萃取，有機相用飽和食鹽水(40mL×2)洗滌，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=20/1)，得到黃色固體(3.74g,31%)。 2-Fluoro-4-nitroaniline (7.02 g, 45.0 mmol), cesium carbonate (29.3 g, 90.0 mmol), potassium iodide (16.6 g, 100 mmol) and DMF (100 mL) were added to a 250 mL two-necked flask and protected with nitrogen. 2-(3-Chloropropyl)tetrahydrofuran (7.43 g, 50.0 mmol) was slowly added dropwise to the reaction mixture at room temperature. After the dropwise addition was completed, the reaction system was heated to 140 ° C and reacted for 48 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the solvent was evaporated. Water was added, and the mixture was extracted with dichloromethane (30 mL×4). The crude was purified by EtOAc EtOAc EtOAc (EtOAc:
在100mL圓底燒瓶中加入2-氟-4-硝基-N-(3-(四氫呋喃-2-基)丙基)苯胺(480mg,1.79mmol)、甲醇(40mL)和水(20mL)，然後加入鐵粉(504mg,9.03mmol)和氯化銨(193mg,3.61mmol)，反應體系加熱到60℃反應過夜。反應完畢，將混合物冷卻至室溫，加入飽和碳酸氫鈉溶液，過濾，濾液用二氯甲烷萃取(30mL×4)，有機相用飽和食鹽水洗滌(40mL×3)，無水硫酸鈉乾燥。蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到紅色液體(260mg,61%)。 Add 2-fluoro-4-nitro- N- (3-(tetrahydrofuran-2-yl)propyl)aniline (480 mg, 1.79 mmol), methanol (40 mL) and water (20 mL) to a 100 mL round bottom flask, then Iron powder (504 mg, 9.03 mmol) and ammonium chloride (193 mg, 3.61 mmol) were added, and the reaction system was heated to 60 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature, and then filtered and evaporated, evaporated, evaporated, evaporated. The solvent was evaporated to dryness crystals crystals crystals crystals
在100mL圓底燒瓶中加入2-氟-N1-(3-(四氫呋喃-2-基)丙基)-1,4-苯二胺(260mg,1.09mmol)、二乙烯酮(110mg,1.31mmol)和乙酸乙酯(10mL)，反應體系加熱至80℃，反應過夜。反應完畢，將混合物冷卻至室溫，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到黃色液體(83mg,24%)。 In a 100 mL round bottom flask was added 2-fluoro-N 1 -(3-(tetrahydrofuran-2-yl)propyl)-1,4-phenylenediamine (260 mg, 1.09 mmol), diketene (110 mg, 1.31 mmol). And ethyl acetate (10 mL), the reaction system was heated to 80 ° C and allowed to react overnight. After completion of the reaction, the mixture was cooled to EtOAc. EtOAc m.
在250mL圓底燒瓶中加入N-(3-氟-4-(3-(四氫呋喃-2-基)丙氨基)苯基)-3-羰基丁醯胺(250mg,0.78mmol)、乙醯胺(92mg,1.56mmol)、四異丙基鈦酸酯(1.9mL)和二甲苯(10mL)，反應體系加熱至165℃，反應24h。將反應體系冷卻至室溫，加入甲苯(60mL)和飽和氯化銨溶液(60mL)，室溫反應過夜。反應完畢，過濾，濾液用二氯甲烷萃取(15mL×3)。合併有機層，用飽和食鹽水洗滌(15mL×2)，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/2)，得到黃色固體(80mg,29%)。 In a 250 mL round bottom flask was added N- (3-fluoro-4-(3-(tetrahydrofuran-2-yl)propylamino)phenyl)-3-carbonylbutanamine (250 mg, 0.78 mmol), acetamide ( 92 mg, 1.56 mmol), tetraisopropyl titanate (1.9 mL) and xylene (10 mL). The reaction was heated to 165 ° C for 24 h. The reaction system was cooled to room temperature, and toluene (60 mL) and a saturated ammonium chloride solution (60 mL) were added, and the mixture was allowed to react at room temperature overnight. After the reaction was completed, it was filtered, and the filtrate was extracted with dichloromethane (15 mL×3). The organic layer was combined, washed with brine (15 mL? The crude was purified by EtOAc EtOAc EtOAc (EtOAc)
MS(ESI,pos.ion)m/z：346.2(M+1)；1H NMR(400MHz,CDCl3)：δ 1.52-1.43(m,2H),1.81-1.75(m,2H),1.94-1.87(m,2H),2.04-2.09(m,2H),2.20(s,3H),2.28(s,3H),3.23-3.19(t,2H,J=6.6Hz),3.76-3.73(m,1H),3.89-3.83(m,2H),4.29(brs,1H),6.27(s,1H),6.76-6.72(t,1H,J=8.7Hz),6.82-6.80(d,2H,J=9.1Hz)。 MS (ESI, pos.) m/z: 346.2 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 1.52-1.43 (m, 2H), 1.81-1.75 (m, 2H), 1.94 1.87 (m, 2H), 2.04-2.09 (m, 2H), 2.20 (s, 3H), 2.28 (s, 3H), 3.23-3.19 (t, 2H, J = 6.6 Hz), 3.76-3.73 (m, 1H), 3.89-3.83 (m, 2H), 4.29 (brs, 1H), 6.27 (s, 1H), 6.76-6.72 (t, 1H, J = 8.7 Hz), 6.82-6.80 (d, 2H, J = 9.1 Hz).
在100mL圓底燒瓶中加入2-甲基-1-(萘-2-基)丙烷-2-胺鹽酸鹽(5.9g,25.0mmol)，3-氯-4-氟硝基苯(5.27g,30.0mmol)，碳酸鉀(6.9g,50.0mmol)和DMSO(50mL)，反應體系加熱至140℃反應過夜，反應完畢，將反應液倒入水(150mL)中，用乙酸乙酸(50mL x 3)萃取，有機相無水硫酸鈉乾燥，過濾，蒸乾溶劑，粗品經柱層析純化(石油醚/二氯甲烷(V/V)=10/1)，得到黃色粉末(3.78g,43%)。 Add 2-methyl-1-(naphthalen-2-yl)propan-2-amine hydrochloride (5.9 g, 25.0 mmol), 3-chloro-4-fluoronitrobenzene (5.27 g) to a 100 mL round bottom flask. , 30.0 mmol), potassium carbonate (6.9 g, 50.0 mmol) and DMSO (50 mL), the reaction system was heated to 140 ° C overnight, the reaction was completed, the reaction solution was poured into water (150 mL), acetic acid acetic acid (50 mL x 3) The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness crystals .
在100mL圓底燒瓶中加入鐵粉(3.78g,67.7mmol)、水(50mL)，加熱至65℃，緩慢滴加濃鹽酸(1mL)，反應15min後，將水去除，向燒瓶中加入2-氯-N-(2-甲基-1-(萘-2-基)丙烷-2-基)-4-硝基苯胺(2.4g,6.76mmol)、 THF(50mL)，反應體系加熱至65℃反應0.5h。反應完畢，冷至室溫，過濾，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=8/1)，得到白色固體(1.86g,84%)。 Iron powder (3.78g, 67.7mmol), water (50mL) was added to a 100mL round bottom flask, heated to 65 ° C, concentrated hydrochloric acid (1mL) was slowly added dropwise, after 15min reaction, the water was removed, and 2 - 2 was added to the flask. Chloro-N-(2-methyl-1-(naphthalen-2-yl)propan-2-yl)-4-nitroaniline (2.4 g, 6.76 mmol), THF (50 mL), the reaction was heated to 65 ° C for 0.5 h. After completion of the reaction, the mixture was cooled to EtOAc EtOAc (mjjjjjj .
在100mL圓底燒瓶中加入2-氯-N1-(2-甲基-1-(萘-2-基)丙烷-2-基)-1,4-苯二胺(2.0g,6.16mmol)，乙酸乙酯(30mL)和雙乙烯酮(1.55g,1.84mmol)，反應體系加熱至90℃反應過夜，冷至室溫，蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到白色固體(2.00g,79%)。 Add 2-chloro-N 1 -(2-methyl-1-(naphthalen-2-yl)propan-2-yl)-1,4-phenylenediamine (2.0 g, 6.16 mmol) to a 100 mL round bottom flask Ethyl acetate (30 mL) and diketene (1.55 g, 1.84 mmol). The reaction was heated to 90 ° C overnight, cooled to room temperature and evaporated to dryness. /V) = 1/1) gave a white solid (2.00 g, 79%).
在100mL圓底燒瓶中加入N-(3-氯-4-((2-甲基-1-(萘-2-基)丙烷-2-基)氨基)苯基-3-乙醯乙醯苯胺(2.0g,4.89mmol)，甲醇(15mL)，氨水(15mL)，室溫下反應過夜，粗品未經進一步處理直接用於下一步反應。 Add N-(3-chloro-4-((2-methyl-1-(naphthalen-2-yl)propan-2-yl)amino)phenyl-3-acetamidanilide in a 100 mL round bottom flask (2.0 g, 4.89 mmol), methanol (15 mL), EtOAc (15 mL).
在100mL圓底燒瓶中加入(Z)-3-氨基-N-(3-氯-4-((2-甲基-1-(萘-2-基)丙烷-2-基)氨基)苯基丁醯胺-2-烯(2.0g,4.90mmol)，原乙酸三乙酯(20mL)，反應體系加熱至150℃反應12h，冷卻至室溫，蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到淡黃色固體(1.59g,76%)。 Add (Z)-3-amino-N-(3-chloro-4-((2-methyl-1-(naphthalen-2-yl)propan-2-yl)amino)phenyl) to a 100 mL round bottom flask Butaamine-2-ene (2.0g, 4.90mmol), triethyl orthoacetate (20mL), the reaction system is heated to 150 ° C for 12h, cooled to room temperature, the solvent is evaporated, the crude product is purified by column chromatography (oil Ether/ethyl acetate (v/v) = 1 / 1) gave pale yellow solid (1.
MS(ESI,pos.ion)m/z：432.3(M+1)；1H NMR(400MHz,CDCl3)：δ 1.43(s,6H),2.11(s,3H),2.19(s,3H),3.20(d,2H),4.63(s,1H),6.23(s,1H),7.11-7.83(m,10H)。 MS (ESI, pos.ion) m / z: 432.3 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 1.43 (s, 6H), 2.11 (s, 3H), 2.19 (s, 3H) , 3.20 (d, 2H), 4.63 (s, 1H), 6.23 (s, 1H), 7.11 - 7.83 (m, 10H).
在100mL圓底燒瓶中加入嗎啉(1.1mL,12.6mmol)並溶解於DMF(30 mL)中，攪拌下加入3-氯-4-氟硝基苯(1.76g,10.0mmol)和三乙胺(4.2mL,30.1mmol)，反應體系在室溫下反應過夜。反應完畢，過濾，將有機相傾入二氯甲烷(150mL)中，用水(150mL×3)和飽和食鹽水(150mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=10/1)，得到黃色固體(1.53g,63%)。 Add morpholine (1.1 mL, 12.6 mmol) to a 100 mL round bottom flask and dissolve in DMF (30) In mL), 3-chloro-4-fluoronitrobenzene (1.76 g, 10.0 mmol) and triethylamine (4.2 mL, 30.1 mmol) were added with stirring, and the reaction was allowed to react at room temperature overnight. After the completion of the reaction, the mixture was filtered and evaporated. mjjjjjjjjjjjjjjjjjjj (Petroleum ether / ethyl acetate (V/V) = 10/1) gave a yellow solid (l.
在100mL圓底燒瓶中加入濃鹽酸(1.0mL)，水(50mL)，一次性加入鐵粉(7.55g,135mmol)，攪拌下加熱至65℃活化鐵粉15min，然後後傾去水層，將4-(2-氯-4-硝基苯基)嗎啉(3.28g,13.5mmol,50mL甲醇溶解)加入上述鐵粉中，用鹽酸調pH=3，加熱至65℃反應45min，反應畢，將混合物冷至室溫並用三乙胺調節pH=10，過濾，減壓蒸去甲醇，殘餘物溶解於二氯甲烷(150mL)，用水(100mL×3)和飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，得到白色固體(2.05g,71%)。 Concentrated hydrochloric acid (1.0 mL), water (50 mL) was added to a 100 mL round bottom flask, iron powder (7.55 g, 135 mmol) was added in one portion, and iron powder was heated to 65 ° C for 15 min with stirring, and then the aqueous layer was decanted. 4-(2-Chloro-4-nitrophenyl)morpholine (3.28g, 13.5mmol, 50mL methanol dissolved) was added to the above iron powder, adjusted to pH=3 with hydrochloric acid, heated to 65 ° C for 45 min, and the reaction was completed. The mixture was cooled to room temperature and adjusted to pH = 10 with triethylamine, filtered, and evaporated, evaporated, evaporated, m.jjjjjjjjjjjjjjjjjjjjjjj The residue was dried over sodium sulfate (EtOAc m.
在100mL圓底燒瓶中加入3-氯-4-嗎啉基苯胺(2.05g,9.64mmol)並溶解於乙酸乙酯(30mL)中，攪拌下加入雙乙烯酮(1.62g,19.3mmol)，反應體系加熱至80℃反應過夜。反應完畢，將混合物冷至室溫，減壓蒸去溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=3/1)，得到淡黃色固體(2.59g,91%)。 3-chloro-4-morpholinylaniline (2.05 g, 9.64 mmol) was added to a 100 mL round bottom flask and dissolved in ethyl acetate (30 mL), and diketene (1.62 g, 19.3 mmol) was added with stirring, and the reaction system was heated. The reaction was carried out overnight at 80 °C. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was evaporated, evaporated,jjjjjjjjjjjjjjj ).
在100mL圓底燒瓶中加入N-(3-氯-4-(4-嗎啉)苯基)-3-乙醯乙醯胺(2.0g,6.74mmol)，甲醇(15mL)，氨水(15mL)，室溫下反應過夜。反應完畢，減壓蒸去溶劑，粗品未經進一步純化直接用於下一步反應。 Add N-(3-chloro-4-(4-morpholinyl)phenyl)-3-acetamethyleneamine (2.0 g, 6.74 mmol), methanol (15 mL), ammonia (15 mL) in a 100 mL round bottom flask. The reaction was allowed to proceed overnight at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure.
在100mL圓底燒瓶中加入(Z)-3-氨基-N-(3-氯-4-(嗎啉苯基)丁醯胺-2-烯(2.0g,6.76mmol)，原乙酸三乙酯(20mL)，反應體系加熱至150℃反應12h，冷至室溫，蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得淡黃色固體(1.63g,76%)。 In a 100 mL round bottom flask was added (Z)-3-amino-N-(3-chloro-4-(morpholinylphenyl)butanamine-2-ene (2.0 g, 6.76 mmol), triethyl orthoacetate. (20mL), the reaction system was heated to 150 ° C for 12h, cooled to room temperature, the solvent was evaporated to dryness, the crude was purified by column chromatography ( petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a pale yellow solid (1.63g, 76%).
MS(ESI,pos.ion)m/z：320.1(M+1)；1H NMR(400MHz,CDCl3)：δ 2.19(s,3H),2.30(s,3H),3.06(m,4H),3.88(t, 4H),6.28(s,1H),7.07-7.28(m,3H)。 MS (ESI, pos.ion) m / z: 320.1 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.19 (s, 3H), 2.30 (s, 3H), 3.06 (m, 4H) , 3.88 (t, 4H), 6.28 (s, 1H), 7.07-7.28 (m, 3H).
在100mL圓底燒瓶中加入1-氟-4-硝基-2-(三氟甲基)苯(4.18g,20.0mmol)、嗎啉(2.09g,24.0mmol)、三乙胺(6.07g,60.0mmol)和乙酸乙酯(30mL)，反應體系在室溫下反應5h。反應完畢，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(5.0g,91%)。 In a 100 mL round bottom flask was added 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (4.18 g, 20.0 mmol), morpholine (2.09 g, 24.0 mmol), triethylamine (6.07 g, 60.0 mmol) and ethyl acetate (30 mL), the reaction was allowed to react at room temperature for 5 h. After completion of the reaction, the solvent was evaporated to drynessjjjjjjjjjj
在100mL圓底燒瓶中加入4-(4-硝基-2-(三氟甲基)苯基)嗎啉(5.0g,18.1mmol)、甲醇(20mL)，然後加入10% Pd/C(500mg)並通入氫氣，反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到白色固體(4.01g,90%)。 Add 4-(4-nitro-2-(trifluoromethyl)phenyl)morpholine (5.0 g, 18.1 mmol), methanol (20 mL) in a 100 mL round bottom flask, then add 10% Pd/C (500 mg) And hydrogen gas was introduced, and the reaction system was allowed to react at room temperature overnight. After completion of the reaction, the mixture was evaporated,jjjjjjjjjjj
在100mL圓底燒瓶中加入4-嗎啉-3-(三氟甲基)苯胺(4.0g,16.2mmol)、二乙烯酮(2.73g,32.5mmol)和乙酸乙酯(30mL)，反應體系加熱至90℃反應過夜。反應完畢，將混合物冷卻至室溫，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(4.0g,75%)。 4-morpholine-3-(trifluoromethyl)aniline (4.0 g, 16.2 mmol), diketene (2.73 g, 32.5 mmol) and ethyl acetate (30 mL) were added to a 100 mL round bottom flask. The reaction was carried out overnight at 90 °C. After the reaction was completed, the mixture was cooled to room temperature. EtOAcjjjjjjjjjjj .
在100mL圓底燒瓶中加入N-(4-嗎啉-3-(三氟甲基)苯基)-3-乙醯乙醯苯胺(4.0g,12.1mmol)，甲醇(20mL)，氨水(20mL)，室溫下反應過夜，蒸乾溶劑，粗品未經進一步純化直接用於下一步反應。 Add N-(4-morpholin-3-(trifluoromethyl)phenyl)-3-acetamethylene anilide (4.0 g, 12.1 mmol) in methanol (20 mL), aqueous ammonia (20 mL) The reaction was carried out at room temperature overnight, and the solvent was evaporated to dryness.
在100mL圓底燒瓶中加入(Z)-3-氨基-N-(4-(嗎啉)-3-(三氟甲基)苯基)丁醯胺-2-烯(4.0g,12.1mmol)，原乙酸三乙酯(10mL)，反應體系加熱至150℃反應過夜，冷至室溫，蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸 乙酯(V/V)=1/1)，得到淡黃色固體(3.00g,70%)。 (Z)-3-Amino-N-(4-(morpholine)-3-(trifluoromethyl)phenyl)butanamine-2-ene (4.0 g, 12.1 mmol) was added to a 100 mL round bottom flask. , triethyl orthoacetate (10mL), the reaction system is heated to 150 ° C reaction overnight, cooled to room temperature, the solvent is evaporated, the crude product is purified by column chromatography (petroleum ether / acetic acid Ethyl ester (V/V) = 1/1) gave a pale yellow solid (3.00 g, 70%).
MS(ESI,pos.ion)m/z：354.2(M+1)；1H NMR(400MHz,CDCl3)：δ 2.05(s,3H),2.21(s,3H),2.92(t,4H),3.72(m,4H),6.26(s,1H),7.66-7.77(m,3H). MS (ESI, pos.ion) m / z: 354.2 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.05 (s, 3H), 2.21 (s, 3H), 2.92 (t, 4H) , 3.72 (m, 4H), 6.26 (s, 1H), 7.66-7.77 (m, 3H).
在100mL雙口瓶中加入60%氫化鈉(3.0g,75.0mmol)和DMF(20mL)，氮氣保護，在0℃下分別加入6-硝基-1H-吲哚(4.86g,30.0mmol,10mL DMF溶解)和3-羥基苯腈(3.57g,30.0mmol,10mL DMF溶解)，反應體系在室溫下反2h。在避光條件下，往反應體系中緩慢加入二碘甲烷的DMF溶液(7.5mL,90.0mmol,10mL DMF稀釋)，反應體系在室溫下反應20h。反應完畢，加水淬滅，過濾，濾液用二氯甲烷萃取(30mL×6)，有機相用飽和鹽水洗滌(50mL×3)，無水硫酸鈉乾燥。蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(4.47g,51%)。 60% sodium hydride (3.0 g, 75.0 mmol) and DMF (20 mL) were added to a 100 mL two-necked flask, and nitrogen-protected, and 6-nitro-1 H -indole (4.86 g, 30.0 mmol, respectively) was added at 0 °C. 10 mL of DMF was dissolved) and 3-hydroxybenzonitrile (3.57 g, 30.0 mmol, 10 mL of DMF dissolved) and the reaction was reversed at room temperature for 2 h. DMF solution of diiodomethane (7.5 mL, 90.0 mmol, diluted with 10 mL of DMF) was slowly added to the reaction system in the dark, and the reaction was allowed to react at room temperature for 20 h. After completion of the reaction, the mixture was stirred with EtOAc EtOAc EtOAc. The solvent was evaporated to dryness crystals crystals crystals crystals
在250mL圓底燒瓶中加入3-((6-硝基-1H-吲哚-1-基)苯氧基)苯腈(3.0g,10.2mmol)、四氫呋喃(80mL)和水(40mL)，然後加入鐵粉(2.86g,51.2mmol)和氯化銨(1.09g,20.4mmol)，反應體系加熱到64℃反應過夜。反應完畢，將混合物冷卻至室溫，加入飽和碳酸氫鈉溶液，過濾，濾液用乙酸乙酯萃取(30mL×4)，有機相用飽和食鹽水洗滌(40mL×3)，無水硫酸鈉乾燥。蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到黃色固體(1.76g,65%)。 Add 3-((6-nitro-1 H -indol-1-yl)phenoxy)benzonitrile (3.0 g, 10.2 mmol), tetrahydrofuran (80 mL) and water (40 mL) to a 250 mL round bottom flask. Iron powder (2.86 g, 51.2 mmol) and ammonium chloride (1.09 g, 20.4 mmol) were then added and the reaction was heated to 64 ° C overnight. After the completion of the reaction, the mixture was cooled to room temperature, and then filtered, evaporated, evaporated, evaporated, evaporated The solvent was evaporated to dryness crystals crystals crystals crystals
在100mL圓底燒瓶中加入3-((6-氨基-1H-吲哚-1-基)苯氧基)苯腈(2.62g,9.95mmol)、二乙烯酮(1.0g,11.9mmol)和乙酸乙酯(20mL)，反應體系加熱至80℃，反應過夜。反應完畢，將混合物冷卻至室溫，減壓蒸乾溶 劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(2.70g,78%)。 In a 100 mL round bottom flask was charged 3-((6-amino- 1H -indol-1-yl)phenoxy)benzonitrile (2.62 g, 9.95 mmol), diketene (1.0 g, 11.9 mmol) and Ethyl acetate (20 mL) was heated to 80 ° C and allowed to react overnight. After completion of the reaction, the mixture was cooled to EtOAc (mjqqqqqq .
在100mL圓底燒瓶中加入N-(1-((3-氰基苯氧基)甲基)-1H-吲哚-6-基)-3-羰基丁醯胺(1.04g,2.99mmol)、甲醇(20mL)和氨水(20mL)，反應體系在室溫下反應過夜。反應完畢，減壓蒸乾溶劑，粗品未經進一步純化直接用於下一步反應。 Add N- (1-((3-cyanophenoxy)methyl)-1 H -indol-6-yl)-3-carbonylbutanamine (1.04 g, 2.99 mmol) in a 100 mL round bottom flask Methanol (20 mL) and aqueous ammonia (20 mL) were reacted at room temperature overnight. After completion of the reaction, the solvent was evaporated to dryness.
在100mL圓底燒瓶中加入(Z)-3-氨基-N-(1-((3-氰基苯氧基)甲基)-1H-吲哚-6-基)丁醯胺-2-烯(1.04g,3.00mmol)和原乙酸三乙酯(20mL)，反應體系加熱至130℃反應過夜。反應完畢，將混合物冷卻至室溫，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(272mg,25%)。 Add (Z)-3-amino-N-(1-((3-cyanophenoxy)methyl)-1H-indol-6-yl)butanamine-2-ene to a 100 mL round bottom flask (1.04 g, 3.00 mmol) and triethyl orthoacetate (20 mL), and the reaction was heated to 130 ° C overnight. After completion of the reaction, the mixture was cooled to EtOAc. EtOAc m.
MS(ESI,pos.ion)m/z：371.1(M+1)；1H NMR(400MHz,DMSO-d6)：δ 2.05(s,3H),2.21(s,3H),6.25(s,1H),6.29(s,2H),6.64-6.63(d,1H,J=3.2Hz),7.01-6.99(dd,1H,J 1 =1.4Hz,J 2 =8.3Hz),7.39-7.37(m,1H),7.51-7.44(m,2H),7.63(s,1H),7.72-7.68(m,3H)。 MS (ESI, pos.ion) m / z: 371.1 (M + 1); 1 H NMR (400MHz, DMSO-d 6): δ 2.05 (s, 3H), 2.21 (s, 3H), 6.25 (s, 1H), 6.29 (s, 2H), 6.64-6.63 (d, 1H, J = 3.2 Hz), 7.01-6.99 (dd, 1H, J 1 = 1.4 Hz, J 2 = 8.3 Hz), 7.39-7.37 (m) , 1H), 7.51-7.44 (m, 2H), 7.63 (s, 1H), 7.72-7.68 (m, 3H).
將3,4-二氟苯酚(0.78g,6.00mmol)和2-溴乙醯氨基巴豆酸甲酯(1.18g,5.00mmol)加入到含有碳酸鉀(1.38g,10.0mmol)的丙酮(50mL)懸濁液中，升溫至回流反應5h。反應完畢，將混合物冷至室溫，過濾，蒸去 丙酮，加入二氯甲烷(100mL)，用水(100mL×2)和飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=5/1)，得到白色固體(0.85g,59%)。 Add 3,4-difluorophenol (0.78 g, 6.00 mmol) and methyl 2-bromoacetamidine amino crotonate (1.18 g, 5.00 mmol) to acetone (50 mL) containing potassium carbonate (1.38 g, 10.0 mmol) In the suspension, the temperature was raised to reflux for 5 hours. After the reaction is completed, the mixture is cooled to room temperature, filtered, and evaporated. Acetone was added to dichloromethane (100 mL), washed with water (100 mL×2) and brine (100 mL). V/V) = 5/1) gave a white solid (0.85 g, 59%).
在100mL三口燒瓶中加入3-氟-4-嗎啡啉基苯胺(0.39g,2.00mmol)和二氯甲烷(15mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(3.5mL,7.0mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-(2-(3,4-二氟苯氧基)乙醯)氨基)巴豆酸甲酯(0.57g,2.00mmol,5mL二氯甲烷溶解)，反應體系在室溫下反應12h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×2)，有機層用飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到淡棕色固體(0.50g,58%)。 3-Fluoro-4-morpholine phenylamine (0.39 g, 2.00 mmol) and dichloromethane (15 mL) were added to a 100 mL three-neck flask, and 2 M trimethylaluminum toluene solution (3.5 mL, 7.0 mmol) was slowly added at room temperature. The reaction system was reacted at room temperature for 0.5 h. Then slowly add 3-(N-(2-(3,4-difluorophenoxy)acetam)amino)crotonic acid methyl ester (0.57 g, 2.00 mmol, 5 mL dichloromethane dissolved), the reaction system at room temperature The reaction was carried out for 12 h. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, and the mixture was extracted with dichloromethane (50 mL×2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate Purification by column chromatography (EtOAc/EtOAc (EtOAc)
MS(ESI,pos.ion)m/z：432.1(M+1)；1H NMR(400MHz,CDCl3)：δ 2.35(s,3H),3.04-3.17(m,4H),3.86(t,4H,J=4.7Hz),4.65(s,2H),6.39(s,1H),6.46-6.51(m,1H),6.58-6.64(m,1H),6.95-6.98(m,3H),7.03(t,1H,J=9.4Hz). MS (ESI, pos.) m/z: 432.1 (M+l); 1 H NMR (400 MHz, CDCl 3 ): δ 2.35 (s, 3H), 3.04-3.17 (m, 4H), 3.86 (t, 4H, J = 4.7 Hz), 4.65 (s, 2H), 6.39 (s, 1H), 6.46-6.51 (m, 1H), 6.58-6.64 (m, 1H), 6.95-6.98 (m, 3H), 7.03 (t, 1H, J = 9.4 Hz).
將3,5-二氟苯酚(0.78g,6.00mmol)和2-溴乙醯氨基巴豆酸甲酯(1.18g,5.00mmol)加入到含有碳酸鉀(1.38g,10.0mmol)的丙酮(50mL)懸濁液中，加熱至回流反應5h。反應完畢，將混合物冷至室溫，過濾，蒸去丙酮，加入二氯甲烷(100mL)，用水(100mL×2)和飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗品經柱層析純化(石油醚/乙酸 乙酯(V/V)=5/1)，得到白色固體(1.18g,83%)。 3,5-Difluorophenol (0.78 g, 6.00 mmol) and 2-bromoacetamidomethylcrotonate (1.18 g, 5.00 mmol) were added to acetone (1. In the suspension, the mixture was heated to reflux for 5 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Purification by column chromatography (petroleum ether / acetic acid) Ethyl ester (V/V) = 5/1) gave white solid (1.
在100mL三口燒瓶中加入3-氟-4-嗎啡啉基苯胺(0.81g,4.13mmol)和二氯甲烷(15mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(6.2mL,12.4mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-(2-(3,5-二氟苯氧基)乙醯)氨基)巴豆酸甲酯(1.18g,4.14mmol,5mL二氯甲烷溶解)，反應體系在室溫下反應12h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×2)，有機層用飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到淡棕色固體(1.08g,61%)。 3-Fluoro-4-morpholine phenylamine (0.81 g, 4.13 mmol) and dichloromethane (15 mL) were added to a 100 mL three-necked flask, and 2 M trimethylaluminum toluene solution (6.2 mL, 12.4 mmol) was slowly added at room temperature. The reaction system was reacted at room temperature for 0.5 h. Then slowly add 3-( N- (2-(3,5-difluorophenoxy)acetamidine)amino)crotonic acid methyl ester (1.18 g, 4.14 mmol, 5 mL dichloromethane), the reaction system at room temperature The reaction was carried out for 12 h. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, and the mixture was extracted with dichloromethane (50 mL×2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate Purification by column chromatography (EtOAc/EtOAc (EtOAc:EtOAc)
MS(ESI,pos.ion)m/z：432.0(M+1)；1H NMR(400MHz,CDCl3)：δ 2.35(s,3H),3.05-3.16(m,4H),3.86(t,4H,J=4.6Hz),4.67(s,2H),6.30-6.33(m,2H),6.39(s,1H),6.39-6.45(m,1H),6.95-6.98(m,3H)。 MS (ESI, pos.) m/z: 432.0 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.35 (s, 3H), 3.05-3.16 (m, 4H), 3.86 (t, 4H, J = 4.6 Hz), 4.67 (s, 2H), 6.30-6.33 (m, 2H), 6.39 (s, 1H), 6.39-6.45 (m, 1H), 6.95-6.98 (m, 3H).
將3-氟苯硫酚(0.77g,6.01mmol)和2-溴乙醯氨基巴豆酸甲酯(1.18g,5.00mmol)加入到含有碳酸鉀(1.38g,10.0mmol)的丙酮(50mL)懸濁液中，加熱至回流反應5h。反應完畢，將混合物冷至室溫，過濾，蒸去丙酮，加入二氯甲烷(100mL)，用水(100mL×2)和飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=5/1)，得到白色固體(0.78g,55%)。 3-Fluorothiophenol (0.77 g, 6.01 mmol) and methyl 2-bromoacetamidine amino crotonate (1.18 g, 5.00 mmol) were added to acetone (50 mL) containing potassium carbonate (1.38 g, 10.0 mmol). In the turbid liquid, heat to reflux for 5 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The crude was purified by EtOAc EtOAc EtOAc (EtOAc)
在100mL三口燒瓶中加入3-氟-4-嗎啡啉基苯胺(0.54g,2.75mmol)和二氯甲烷(15mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(4.8mL,9.60mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-(2-(3-氟苯巰基)乙醯)氨基)巴豆酸甲酯(0.78g,2.75mmol,5mL二氯甲烷溶解)，反應體系在室溫下反應12h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×2)，有機層用飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到淡棕色固體(0.79g,67%)。 3-Fluoro-4-morpholine phenylamine (0.54 g, 2.75 mmol) and dichloromethane (15 mL) were added to a 100 mL three-necked flask, and 2 M trimethylaluminum toluene solution (4.8 mL, 9.60 mmol) was slowly added at room temperature. The reaction system was reacted at room temperature for 0.5 h. Then, methyl 3-( N- (2-(3-fluorophenylindenyl)ethyl)amino)crotonate (0.78 g, 2.75 mmol, 5 mL of dichloromethane) was added slowly, and the reaction was allowed to react at room temperature for 12 h. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, and the mixture was extracted with dichloromethane (50 mL×2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate Purification by column chromatography (EtOAc/EtOAc (EtOAc:EtOAc)
MS(ESI,pos.ion)m/z：430.3(M+1)；1H NMR(400MHz,CDCl3)：δ 2.26(s,3H),3.09-3.21(m,4H),3.81(s,2H),3.89(t,4H,J=4.7Hz),6.30(s,1H),6.91-7.03(m,4H),7.06-7.10(m,2H),7.20-7.24(m,1H)。 MS (ESI, pos.) m/z: 430.3 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.26 (s, 3H), 3.09-3.21 (m, 4H), 3.81 (s, 2H), 3.89 (t, 4H, J = 4.7 Hz), 6.30 (s, 1H), 6.91-7.03 (m, 4H), 7.06-7.10 (m, 2H), 7.20-7.24 (m, 1H).
氮氣保護下，在100mL圓底燒瓶中加入3-(3-氟苯基)丙酸(2.50g,14.9mmol)並溶解於二氯亞碸(10mL)中，反應體系加熱至回流反應3h。反應完畢，將混合物冷至室溫，減壓蒸去溶劑，粗品未經進一步處理直接進行下一步反應。 Under a nitrogen atmosphere, 3-(3-fluorophenyl)propionic acid (2.50 g, 14.9 mmol) was added to a 100 mL round bottom flask and dissolved in dichloromethane (10 mL). The reaction was heated to reflux for 3 h. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure.
將3-氨基巴豆酸甲酯(1.70g,14.8mmol)和吡啶(1.30g,16.4mmol)加入到二氯甲烷(25mL)中，室溫攪拌下，逐滴加入3-(3-氟苯基)丙醯氯(2.77g,14.8mmol,5mL二氯甲烷溶液)。滴畢，繼續攪拌反應1小時，然後有機相用飽和食鹽水洗(50mL×3)，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產 品經柱層析純化(石油醚/乙酸乙酯(V/V)=3/1)，得到白色固體(2.00g,51%)。 Methyl 3-aminocrotonate (1.70 g, 14.8 mmol) and pyridine (1.30 g, 16.4 mmol) were added to dichloromethane (25 mL), and stirred at room temperature, 3-(3-fluorophenyl) Propionyl chloride (2.77 g, 14.8 mmol, 5 mL dichloromethane solution). After the completion of the dropwise addition, the reaction was stirred for 1 hour, and the organic phase was washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate and evaporated. Purification by column chromatography (EtOAc/EtOAc (EtOAc/EtOAc)
在100mL三口燒瓶中加入3-氟-4-嗎啡啉基苯胺(1.10g,5.61mmol)和二氯甲烷(20mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(5.7mL,11.4mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-(3-(3-氟苯基)丙醯)氨基)巴豆酸甲酯(1.00g,3.77mmol,8mL二氯甲烷溶解)，反應體系在室溫下反應24h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×2)，有機層用飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(淋洗劑為乙酸乙酯)，得到橙色固體(1.10g,71%)。 3-Fluoro-4-morpholine phenylamine (1.10 g, 5.61 mmol) and dichloromethane (20 mL) were added to a 100 mL three-necked flask, and 2 M trimethylaluminum toluene solution (5.7 mL, 11.4 mmol) was slowly added at room temperature. The reaction system was reacted at room temperature for 0.5 h. Then, methyl 3-( N- (3-(3-fluorophenyl)propan)amino)crotonate (1.00 g, 3.77 mmol, dissolved in 8 mL of dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 24 h. After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, and the mixture was extracted with dichloromethane (50 mL×2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate Purification by column chromatography (eluent ethyl acetate) afforded an orange solid (1.10 g, 71%).
MS(ESI,pos.ion)m/z：412.3(M+1)；1H NMR(400MHz,CDCl3)：δ 2.25(s,3H),2.57(t,3H,J=7.5Hz),2.91(t,3H,J=7.8Hz),3.02-3.06(m,4H),3.75(t,4H,J=4.6Hz),6.26(s,1H),6.88-6.91(m,2H),6.96-7.01(m,1H),7.04-7.06(m,1H),7.10-7.14(m,1H),7.17-7.21(m,1H),7.24-7.29(m,1H)。 MS (ESI, pos.ion) m / z: 412.3 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.25 (s, 3H), 2.57 (t, 3H, J = 7.5Hz), 2.91 (t, 3H, J = 7.8 Hz), 3.02-3.06 (m, 4H), 3.75 (t, 4H, J = 4.6 Hz), 6.26 (s, 1H), 6.88-6.91 (m, 2H), 6.96- 7.01 (m, 1H), 7.04-7.06 (m, 1H), 7.10-7.14 (m, 1H), 7.17-7.21 (m, 1H), 7.24-7.29 (m, 1H).
在氮氣保護下，3-氟苯酚(6.00g,53.5mmol)，4-溴丁酸乙酯(15.70g,80.5mmol)和碳酸銫(26.20g,80.4mmol)溶於DMF(25mL)中，反應體系加熱至回流反應過夜。待混合物冷至室溫，將水(150mL)一次性加入反應體系中，二氯甲烷萃取(100mL×2)，有機層用飽和食鹽水(100mL×2)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸 乙酯(V/V)=10/1)，得到無色油狀物(12.0g,99%)。 3-Fluorophenol (6.00 g, 53.5 mmol), 4-bromobutyric acid ethyl ester (15.70 g, 80.5 mmol) and cesium carbonate (26.20 g, 80.4 mmol) were dissolved in DMF (25 mL) under nitrogen. The system was heated to reflux overnight. The mixture was cooled to room temperature, water (150 mL) was added to the reaction system in one portion, and extracted with dichloromethane (100 mL×2). The organic layer was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate Solvent removal, crude product purified by column chromatography (petroleum ether / acetic acid Ethyl ester (V/V) = 10/1) gave a colourless oil (12.0 g, 99%).
在氮氣保護下，氫氧化鉀(0.24g,4.28mmol)溶于水(3mL)和乙醇(3mL)中，室溫攪拌下，將4-(3-氟苯氧基)丁酸乙酯(0.30g,1.33mmol)一次性加入上述溶液，反應體系加熱至40℃反應4h。待混合物冷至室溫，將二氯甲烷(20mL)一次性加入反應體系中，有機層用飽和食鹽水(20mL×2)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，得到白色固體(0.25g,96%)。 Under a nitrogen atmosphere, potassium hydroxide (0.24 g, 4.28 mmol) was dissolved in water (3 mL) and ethanol (3 mL), and ethyl 4-(3-fluorophenoxy)butanoate (0.30) g, 1.33 mmol) The above solution was added in one portion, and the reaction system was heated to 40 ° C for 4 h. The mixture was cooled to room temperature, and dichloromethane (20 mL) was added to the reaction mixture. The organic layer was washed with brine (20 mL×2) and dried over anhydrous sodium sulfate. g, 96%).
氮氣保護下，在50mL圓底燒瓶中加入4-(3-氟苯氧基)丁酸(3.00g,15.1mmol)並溶解於二氯亞碸(15mL)中，反應體系加熱至回流反應3h。反應完畢，將混合物冷至室溫，減壓蒸去溶劑，粗品未經進一步處理直接進行下一步反應。 Under a nitrogen atmosphere, 4-(3-fluorophenoxy)butyric acid (3.00 g, 15.1 mmol) was added to a 50 mL round bottom flask and dissolved in dichloromethane (15 mL). The reaction was heated to reflux for 3 h. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure.
將3-氨基巴豆酸甲酯(1.70g,14.8mmol)和吡啶(1.20g,15.2mmol)加入到二氯甲烷(25mL)，室溫攪拌下，逐滴加入4-(3-氟苯氧基)丁醯氯(3.28g,15.1mmol,5mL二氯甲烷溶解)。滴畢，繼續攪拌反應1h，然後有機相用飽和食鹽水洗(50mL×3)，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=3/1)，得到白色固體(1.20g,28%)。 Methyl 3-aminocrotonate (1.70 g, 14.8 mmol) and pyridine (1.20 g, 15.2 mmol) were added to dichloromethane (25 mL), and stirred at room temperature, and 4-(3-fluorophenoxy) was added dropwise. Dibutyl chloride (3.28 g, 15.1 mmol, 5 mL of dichloromethane dissolved). After the completion of the dropwise addition, the reaction was stirred for 1 h, then the organic phase was washed with brine (50 mL×3), dried over anhydrous sodium sulfate and evaporated. ) = 3/1) gave a white solid (1.20 g, 28%).
在100mL三口燒瓶中加入3-氟-4-嗎啡啉基苯胺(0.36g,1.83mmol)和二氯甲烷(20mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(2.7mL,5.40mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-(4-(3-氟苯氧基)丁醯)氨基)巴豆酸甲酯(0.80g,2.71mmol,4mL二氯甲烷溶解)，反應體系在室溫下反應24h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×2)，有機層用飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(乙酸乙酯洗脫)，得到淡黃色固體(0.40g,49%)。 3-Fluoro-4-morpholine phenylamine (0.36 g, 1.83 mmol) and dichloromethane (20 mL) were added to a 100 mL three-neck flask, and a 2 M solution of trimethylaluminum toluene (2.7 mL, 5.40 mmol) was slowly added at room temperature. The reaction system was reacted at room temperature for 0.5 h. Then 3-( N- (4-(3-fluorophenoxy)butanyl)amino)crotonate methyl ester (0.80 g, 2.71 mmol, 4 mL dichloromethane) was added slowly, and the reaction was allowed to react at room temperature for 24 h. . After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, and the mixture was extracted with dichloromethane (50 mL×2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate Purification by column chromatography (EtOAc EtOAc)
MS(ESI,pos.ion)m/z：442.3(M+1)；1H NMR(400MHz,CDCl3)：δ 2.00(m,2H),2.22(s,3H),2.44(m,2H),3.07 (m,4H),3.76(t,4H,J=4.6Hz),3.95(t,2H,J=6.4Hz),6.22(s,1H),6.73-6.74(m,3H),7.07-7.08(m,2H),7.12-7.28(m,2H)。 MS (ESI, pos.) m/z: 442.3 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.00 (m, 2H), 2.22 (s, 3H), 2.44 (m, 2H) , 3.07 (m, 4H), 3.76 (t, 4H, J = 4.6 Hz), 3.95 (t, 2H, J = 6.4 Hz), 6.22 (s, 1H), 6.73 - 6.74 (m, 3H), 7.07- 7.08 (m, 2H), 7.12 - 7.28 (m, 2H).
在250mL雙口瓶中加入N-(3-氟-4-嗎啉苯基)-3-羰基丁醯胺(11.2g,40.0mmol)和醋酸(100mL)，氮氣保護，在室溫下緩慢滴加溴素(2.4mL)。滴加完後，反應體系在室溫下反應24h。反應完畢，減壓蒸乾大部分溶劑，加入水，用乙酸乙酯萃取(30mL×4)，有機相用飽和食鹽水洗滌(40mL×3)，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到黃色固體(6.80g,47%)。 Add N- (3-fluoro-4-morpholinylphenyl)-3-carbonylbutanamine (11.2 g, 40.0 mmol) and acetic acid (100 mL) to a 250 mL two-necked flask, nitrogen-protected, and slowly drip at room temperature Bromine (2.4 mL). After the completion of the dropwise addition, the reaction system was reacted at room temperature for 24 hours. After completion of the reaction, most of the solvent was evaporated to dryness, evaporated, evaporated, evaporated, evaporated. The crude was purified by EtOAc EtOAc EtOAc (EtOAc:
在100mL雙口瓶中加入3-氟苯酚(2.33g,20.8mmol)和乾燥四氫呋喃(20mL)，然後加入氫化鈉(909mg,22.7mmol)，反應體系在室溫下反應3h。往反應體系中滴加4-溴-N-(3-氟-4-嗎啉苯基)-3-羰基丁醯胺的四氫呋喃溶液(6.8g,18.9mmol,40mL四氫呋喃溶解)。滴加完，反應體系在室溫下反應過夜。反應完畢，把反應液緩慢加入到水(100mL)中，混合溶液用乙酸乙酯萃取(30mL×5)，有機相用飽和食鹽水洗滌(50mL×2)，無水硫酸鈉乾燥。減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到黃色固體(0.16g,2%)。 3-fluorophenol (2.33 g, 20.8 mmol) and dry tetrahydrofuran (20 mL) were added to a 100 mL two-necked flask, then sodium hydride (909 mg, 22.7 mmol) was added, and the reaction was allowed to react at room temperature for 3 h. A tetrahydrofuran solution of 4-bromo- N- (3-fluoro-4-morpholinylphenyl)-3-carbonylbutanamine (6.8 g, 18.9 mmol, 40 mL of tetrahydrofuran) was added dropwise to the reaction mixture. After the dropwise addition, the reaction system was allowed to react at room temperature overnight. After the completion of the reaction, the reaction mixture was slowly added to water (100 mL), and the mixture was evaporated to ethyl acetate (30 mL? The solvent was evaporated to dryness crystals crystals crystals crystals
在250mL圓底燒瓶中加入N-(3-氟-4-嗎啉苯基)-4-(3-氟苯氧基)-3-羰基丁醯胺(510mg,1.31mmol)、乙醯胺(154mg,2.61mmol)、四異丙基鈦酸酯(3.2mL)和二甲苯(10mL)，反應體系加熱至165℃，反應24h。將反應體系冷卻至室溫，加入甲苯(60mL)和飽和氯化銨溶液(60mL)，室溫反 應過夜。反應完畢，過濾，濾液用二氯甲烷萃取(20mL×4)。合併有機層，用飽和食鹽水洗滌(30mL×2)，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(0.09g,17%)。 In a 250 mL round bottom flask was added N- (3-fluoro-4-morpholinylphenyl)-4-(3-fluorophenoxy)-3-carbonylbutanamine (510 mg, 1.31 mmol), acetamide ( 154 mg, 2.61 mmol), tetraisopropyl titanate (3.2 mL) and xylene (10 mL) were heated to 165 ° C for 24 h. The reaction system was cooled to room temperature, and toluene (60 mL) and a saturated ammonium chloride solution (60 mL) were added, and the mixture was allowed to react at room temperature overnight. After the reaction was completed, it was filtered, and the filtrate was extracted with dichloromethane (20 mL × 4). The organic layer was combined, washed with brine (30 mL? The crude was purified by EtOAc EtOAc EtOAc (EtOAc:
MS(ESI,pos.ion)m/z：414.1(M+1)；1H NMR(400MHz,DMSO-d6)：δ 2.12(s,3H),3.07(d,4H,J=5.4Hz),3.76(t,4H,J=4.5Hz),4.97(s,2H),6.41(s,1H),6.84-6.80(m,1H),6.99-6.91(m,2H),7.16-7.14(m,2H),7.38-7.31(m,2H)。 MS (ESI, pos. ion) m/z: 414.1 (M + 1); 1 H NMR (400 MHz, DMSO-d 6 ): δ 2.12 (s, 3H), 3.07 (d, 4H, J = 5.4 Hz) , 3.76(t,4H, J =4.5Hz), 4.97(s,2H),6.41(s,1H),6.84-6.80(m,1H),6.99-6.91(m,2H),7.16-7.14(m , 2H), 7.38-7.31 (m, 2H).
在100mL三口燒瓶中加入3-氟-4-嗎啡啉基苯胺(0.63g,3.01mmol)和二氯甲烷(15mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(5.3mL,10.6mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-(2-(3-氟苯氧基)乙醯)氨基)巴豆酸甲酯(0.80g,2.99mmol,5mL二氯甲烷溶解)，反應體系在室溫下反應12h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×2)，有機層用飽和食鹽水(100mL)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到淡黃色固體(0.94g,73%)。 3-Fluoro-4-morpholine phenylamine (0.63 g, 3.01 mmol) and dichloromethane (15 mL) were added to a 100 mL three-neck flask, and 2 M trimethylaluminum toluene solution (5.3 mL, 10.6 mmol) was slowly added at room temperature. The reaction system was reacted at room temperature for 0.5 h. Then 3-( N- (2-(3-fluorophenoxy)ethyl)amino)crotonate methyl ester (0.80 g, 2.99 mmol, 5 mL dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 12 h. . After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, and the mixture was extracted with dichloromethane (50 mL×2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate Purification by column chromatography (EtOAc/EtOAc (EtOAc:EtOAc)
MS(ESI,pos.ion)m/z：427.2(M+1)；1H NMR(400MHz,CDCl3)：δ 2.34(s,3H),2.35(s,3H),2.58(t,4H,J=4.8Hz),3.08-3.16(m,4H),4.68(s,2H),6.38(d,1H,J=0.8Hz),6.49(tt,1H,J 1 =2.4Hz,J 2 =10.6Hz),6.54(dd,1H,J 1 =2.3Hz,J 2 =5.3Hz),6.64-6.60(m,1H),6.94-6.98(m,3H),7.14-7.20(m,1H)。 MS (ESI, pos.ion) m / z: 427.2 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.34 (s, 3H), 2.35 (s, 3H), 2.58 (t, 4H, J = 4.8 Hz), 3.08-3.16 (m, 4H), 4.68 (s, 2H), 6.38 (d, 1H, J = 0.8 Hz), 6.49 (tt, 1H, J 1 = 2.4 Hz, J 2 = 10.6) Hz), 6.54 (dd, 1H, J 1 = 2.3 Hz, J 2 = 5.3 Hz), 6.64-6.60 (m, 1H), 6.94-6.98 (m, 3H), 7.14-7.20 (m, 1H).
在500mL圓底燒瓶中加入2-溴乙醇(27.9g,223mmol)、嗎啉(40g,459mmol)、K2CO3(48.4g,350mmol)和CH3CN(30mL)，回流反應3h，反應完畢，將反應體系冷卻至室溫，過濾，蒸乾溶劑，粗品未經進一步處理直接用於下一步反應，得到黃色固體(24.40g,83%)。 2-Bromoethanol (27.9 g, 223 mmol), morpholine (40 g, 459 mmol), K 2 CO 3 (48.4 g, 350 mmol) and CH 3 CN (30 mL) were added to a 500 mL round bottom flask and refluxed for 3 h. The reaction system was cooled to room temperature, filtered, and evaporated to dryness.
在100mL圓底燒瓶中加入1,2-二氟-4-硝基苯(1.0g,6.29mmol)、2-嗎啉乙醇(1.0g,7.62mmol)、Cs2CO3(2.5g,7.67mmol)和DMF(10mL)，反應體系加熱至75℃反應12h，反應完畢，加水(30mL)，用二氯甲烷(30mL×2)萃取，有機相用飽和氯化鈉溶液(30mL×3)洗滌。蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到黃色油狀物(1.30g,76%)。 In a 100 mL round bottom flask, 1,2-difluoro-4-nitrobenzene (1.0 g, 6.29 mmol), 2-morpholineethanol (1.0 g, 7.62 mmol), Cs 2 CO 3 (2.5 g, 7.67 mmol) were added. And DMF (10 mL), the reaction was heated to 75 ° C for 12 h. After the reaction was completed, water (30 mL) was added and extracted with dichloromethane (30 mL×2), and the organic phase was washed with a saturated sodium chloride solution (30 mL×3). The solvent was evaporated to dryness crystallite crystal crystal crystal crystal crystal crystal crystal
在100mL圓底燒瓶中加入4-(2-(2-氟-4-硝基苯氧基)乙基)嗎啉(1.3g,4.81mmol)和THF(12mL)，然後加入10% Pd/C(0.4g)並通入氫氣，反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸乾溶劑，粗品未經進一步處理直接用於下一步反應。得到黃色油狀物(1.00g,86%)。 Add 4-(2-(2-fluoro-4-nitrophenoxy)ethyl)morpholine (1.3 g, 4.81 mmol) and THF (12 mL) to a 100 mL round bottom flask, then add 10% Pd/C (0.4 g) and hydrogen gas was introduced, and the reaction system was allowed to react at room temperature overnight. After the reaction was completed, the mixture was filtered, and the solvent was evaporated to dryness. A yellow oil (1.00 g, 86%) was obtained.
在100mL三口燒瓶中加入3-氟-4-(2-嗎啉乙氧基)苯胺(0.33g,1.37mmol)和二氯甲烷(20mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(2.7mL,5.40mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-(2-(3-氟苯氧基)乙醯)氨基)巴豆酸甲酯(0.37g,1.38mmol,5mL二氯甲烷溶解) ，反應體系在室溫下反應24h。反應完畢，將飽和的氯化銨溶液緩慢加入到體系中，二氯甲烷萃取(50mL×2)，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(二氯甲烷/甲醇(V/V)=30/1)，得到淡黃色固體(0.19g,30%)。 3-Fluoro-4-(2-morpholinoethoxy)aniline (0.33 g, 1.37 mmol) and dichloromethane (20 mL) were added to a 100 mL three-necked flask, and a 2 M solution of trimethylaluminum toluene was slowly added at room temperature ( 2.7 mL, 5.40 mmol), and the reaction was allowed to react at room temperature for 0.5 h. Then 3-( N- (2-(3-fluorophenoxy)acetam)amino)crotonate methyl ester (0.37 g, 1.38 mmol, 5 mL dichloromethane) was slowly added, and the reaction was allowed to react at room temperature for 24 h. . After the completion of the reaction, the saturated ammonium chloride solution was slowly added to the system, extracted with dichloromethane (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. (V/V) = 30/1) gave a pale yellow solid (0.19 g, 30%).
MS(ESI,pos.ion)m/z：458.1(M+1)；1H NMR(400MHz,CDCl3)：δ 2.24(s,3H),2.45(t,4H,J=4.34Hz),2.66(t,2H,J=5.58Hz),3.55(t,4H,J=4.56Hz),4.15(m,2H),4.72(s,2H),6.37(s,1H),6.63-6.75(m,3H),7.17-7.27(m,3H),7.38-7.41(m,1H)。 MS (ESI, pos.ion) m / z: 458.1 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.24 (s, 3H), 2.45 (t, 4H, J = 4.34Hz), 2.66 (t, 2H, J = 5.58 Hz), 3.55 (t, 4H, J = 4.56 Hz), 4.15 (m, 2H), 4.72 (s, 2H), 6.37 (s, 1H), 6.63 - 6.75 (m, 3H), 7.17-7.27 (m, 3H), 7.38-7.41 (m, 1H).
在100mL三口燒瓶中加入2-氟-N 1-(2-嗎啉乙基)苯-1,4-二胺(0.33g,1.38mmol)和二氯甲烷(20mL)，室溫下緩慢加入2M三甲基鋁甲苯溶液(2.1mL,4.2mmol)，反應體系在室溫下反應0.5h。然後緩慢加入3-(N-(2-(3-氟苯氧基)乙醯)氨基)巴豆酸甲酯(0.37g,1.38mmol,5mL二氯甲烷溶解)，反應體系在室溫下反應24h。反應完畢，將水(50mL)緩慢加入到體系中，二氯甲烷萃取(50mL×2)，飽和氯化鈉溶液(100mL×3)洗滌，無水硫酸鈉乾燥，減壓蒸去溶劑，粗產品經柱層析純化(淋洗劑為乙酸乙酯)，得到淡黃色固體(0.5g,79%)。 2-Fluoro- N 1 -(2-morpholinethyl)benzene-1,4-diamine (0.33 g, 1.38 mmol) and dichloromethane (20 mL) were added to a 100 mL three-necked flask, and 2 M was slowly added at room temperature. Trimethylaluminum toluene solution (2.1 mL, 4.2 mmol), and the reaction system was reacted at room temperature for 0.5 h. Then 3-( N- (2-(3-fluorophenoxy)ethyl)amino)crotonate methyl ester (0.37 g, 1.38 mmol, 5 mL dichloromethane) was added slowly, and the reaction was allowed to react at room temperature for 24 h. . After completion of the reaction, water (50 mL) was slowly added to the system, extracted with dichloromethane (50 mL×2), washed with saturated sodium chloride solution (100 mL×3), dried over anhydrous sodium sulfate and evaporated. Purification by column chromatography (EtOAc EtOAc)
MS(ESI,pos.ion)m/z：457.2(M+1)；1H NMR(400MHz,CDCl3)：δ 2.22(s,3H),2.44(m,4H),3.19(t,2H,J=3.19Hz),3.76(t,4H,J=2.24Hz),4.70(s,2H),6.34(s,1H),6.52-6.64(m,2H),6.53-6.56(m,1H),6.69-6.81(m,3H),6.98-7.01(m,1H),7.14-7.21(m,1H),7.21-7.28(m,1H)。 MS (ESI, pos.) m/z: 457.2 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.22 (s, 3H), 2.44 (m, 4H), 3.19 (t, 2H, J = 3.19 Hz), 3.76 (t, 4H, J = 2.24 Hz), 4.70 (s, 2H), 6.34 (s, 1H), 6.52-6.64 (m, 2H), 6.53-6.56 (m, 1H), 6.69-6.81 (m, 3H), 6.98-7.01 (m, 1H), 7.14-7.21 (m, 1H), 7.21-7.28 (m, 1H).
在100mL兩口燒瓶中加入環己醇(2.40g,24.0mmol)、Rh2(OAc)4(50mg,0.11mmol)和二氯甲烷(50mL)，室溫下緩慢滴入2-重氮乙酸乙酯(2.73g,23.9mmol)，反應體系在室溫下反應5min，過濾，蒸乾溶劑，粗產品經柱層析純化(石油醚/乙酸乙酯(V/V)=15/1)，得到無色液體(3.8g,85%)。 Add cyclohexanol (2.40 g, 24.0 mmol), Rh 2 (OAc) 4 (50 mg, 0.11 mmol) and dichloromethane (50 mL) to a 100 mL two-necked flask, and slowly add 2-ethyl diazoacetate at room temperature. (2.73g, 23.9mmol), the reaction system was reacted for 5 min at room temperature, filtered, and the solvent was evaporated to dryness. The crude product was purified by column chromatography ( petroleum ether/ethyl acetate (V/V)=15/1) to give colorless Liquid (3.8 g, 85%).
在100mL兩口燒瓶中加入NaOH(4.89g,122mmol)、H2O(20mL)和CH3OH(20mL)，在冰浴條件下緩慢滴加2-(環己氧基)乙酸乙酯(3.8g,20.4mmol,10mL甲醇溶解)，反應體系在室溫下反應2h。反應完畢，用濃鹽酸調pH至4，用二氯甲烷(20mL×2)萃取，有機相用飽和氯化鈉溶液洗(40mL×2)，蒸乾溶劑，粗產品經柱層析純化(淋洗劑為乙酸乙酯)，得到淡黃色油狀物(2.7g,84%)。 NaOH (4.89 g, 122 mmol), H 2 O (20 mL) and CH 3 OH (20 mL) were added to a 100 mL two-necked flask, and 2-(cyclohexyloxy)acetate (3.8 g) was slowly added dropwise under ice bath. 20.4 mmol, 10 mL of methanol was dissolved), and the reaction system was reacted at room temperature for 2 h. After completion of the reaction, the pH was adjusted to 4 with concentrated hydrochloric acid, extracted with dichloromethane (20 mL×2), the organic phase was washed with saturated sodium chloride solution (40 mL×2), and the solvent was evaporated to dryness. The solvent was obtained as a pale yellow oil (2.7 g, 84%).
在100mL圓底燒瓶中加入2-(環己基氧基)乙酸(0.90g,5.69mmol)和SOCl2(10mL)，體系加熱至回流反應2h，反應完畢，冷卻至室溫，減壓蒸乾SOCl2，得到黃色油狀物，粗品未經進一步處理直接用於下一步反應。 2-(cyclohexyloxy)acetic acid (0.90 g, 5.69 mmol) and SOCl 2 (10 mL) were added to a 100 mL round bottom flask, and the system was heated to reflux for 2 h. The reaction was completed, cooled to room temperature, and evaporated to dryness. 2 , a yellow oil was obtained, and the crude product was used for the next reaction without further treatment.
在100mL圓底燒瓶中加入NH4OH(25-28%，15mL)，在冰浴條件下加入2-(環己氧基)乙醯氯(1.01g,5.72mmol,2mL二氯甲烷溶解)，反應體系在室溫下反應5min，用二氯甲烷(20mL×3)萃取，有機相用飽和氯化鈉溶液(20mL×2)洗滌，蒸乾溶劑，得到白色固體(0.5g,56%)。 Add NH 4 OH (25-28%, 15 mL) to a 100 mL round bottom flask and add 2-(cyclohexyloxy)ethyl hydrazine chloride (1.01 g, 5.72 mmol, 2 mL dichloromethane) in ice bath. The reaction was allowed to react at room temperature for 5 min, EtOAc (EtOAc) (EtOAc)
在100mL三口瓶中加入2-(環己基氧基)乙醯胺(0.4g,2.54mmol)、N-(3-氟-4-嗎啉苯基)-3-乙醯乙醯苯胺(0.7g,2.50mmol)、四異丙基鈦酸酯(5.8g,20.4mmol)和二甲苯(16mL)，反應體系加熱至165℃，反應30h。反應完畢，將反應體系冷卻至室溫，加入乙酸乙酯(60mL)，水(10mL)，過濾，蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到黃色油狀物(0.16g,16%)。 Add 2-(cyclohexyloxy)acetamide (0.4 g, 2.54 mmol), N- (3-fluoro-4-morpholinylphenyl)-3-acetamidanilide (0.7 g) to a 100 mL three-necked flask. , 2.50 mmol), tetraisopropyl titanate (5.8 g, 20.4 mmol) and xylene (16 mL). The reaction was heated to 165 ° C for 30 h. After completion of the reaction, the reaction mixture was cooled to room temperature, ethyl acetate (60 mL), water (10 mL), filtered, evaporated and evaporated. /1) gave a yellow oil (0.16 g, 16%).
MS(ESI,pos.ion)m/z：402.2(M+1)；1H NMR(400MHz,CDCl3)：δ 1.04(m,6H),1.23(m,4H),2.21(s,3H),2.9m(m,1H),3.05(m,4H),3.76(t,4H,J=4.60Hz),4.07(s,2H),6.32(s,1H),7.08-7.15(m,2H),7.21-7.24(m,1H)。 MS (ESI, pos.ion) m / z: 402.2 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 1.04 (m, 6H), 1.23 (m, 4H), 2.21 (s, 3H) , 2.9m (m, 1H), 3.05 (m, 4H), 3.76 (t, 4H, J = 4.60Hz), 4.07 (s, 2H), 6.32 (s, 1H), 7.08-7.15 (m, 2H) , 7.21 - 7.24 (m, 1H).
在100mL兩口燒瓶中加入吡啶-3-醇(4.0g,42.1mmol)、K2CO3(6.96g,50.4mmol)和CH3CN(6mL)，在室溫條件下緩慢滴加2-溴乙腈(2.52g,21.0mmol)，反應體系在室溫條件下反應40h，反應完畢，過濾，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到黃色固體(0.45g,16%)。 Pyridine-3-ol (4.0 g, 42.1 mmol), K 2 CO 3 (6.96 g, 50.4 mmol) and CH 3 CN (6 mL) were added to a 100 mL two-necked flask, and 2-bromoacetonitrile was slowly added dropwise at room temperature. (2.52g, 21.0mmol), the reaction was carried out at room temperature for 40h, the reaction was completed, filtered, and the solvent was evaporated to dryness. 1) A yellow solid (0.45 g, 16%) was obtained.
在100mL兩口燒瓶中加入2-(吡啶-3-氧基)乙腈(100mg,0.75mmol)、K2CO3(103mg,0.75mmol)、DMSO(0.1mL)和H2O(2mL)，在冰浴條件下緩慢滴入H2O2(30%,0.1mL)，反應體系室溫下反應5min，蒸乾溶劑，粗品經柱層析純化(淋洗劑為乙酸乙酯)，得到白色固體(62.2mg,55%)。 Add 2-(pyridin-3-oxy)acetonitrile (100 mg, 0.75 mmol), K 2 CO 3 (103 mg, 0.75 mmol), DMSO (0.1 mL) and H 2 O (2 mL) in a 100 mL two-neck flask. Under the conditions of the bath, H 2 O 2 (30%, 0.1 mL) was slowly added dropwise, and the reaction was allowed to react at room temperature for 5 min, and the solvent was evaporated to dryness. 62.2 mg, 55%).
在100mL三口瓶中加入2-(吡啶-3-氧基)乙醯胺(120mg,0.79mmol)、N-(3-氟-4-嗎啉苯基)-3-乙醯乙醯苯胺(221.1mg,0.79mmol)、四異丙基鈦酸酯(1.79g,6.30mmol)和二甲苯(16mL)，反應體系加熱至165℃，反應50h。反應完畢，將反應體系冷卻至室溫，加入乙酸乙酯(30mL)，水(5mL)，過濾，蒸乾溶劑，粗品經柱層析純化(淋洗劑為乙酸乙酯)，得到黃色固體(0.90g,29%)。 2-(Pyridin-3-yloxy)acetamide (120 mg, 0.79 mmol), N- (3-fluoro-4-morpholinylphenyl)-3-acetamidanilide (221.1) was added to a 100 mL three-necked flask. Mg, 0.79 mmol), tetraisopropyl titanate (1.79 g, 6.30 mmol) and xylene (16 mL). The reaction was heated to 165 ° C for 50 h. After completion of the reaction, the reaction mixture was cooled to room temperature, ethyl acetate (30 mL), water (5 mL), filtered and evaporated. 0.90g, 29%).
MS(ESI,pos.ion)m/z：397.2(M+1)；1H NMR(400MHz,CDCl3)：δ 2.21(s,3H),2.97(m,4H),3.72(t,4H,J=4.62Hz),4.79(s,2H),6.37(s,1H),7.04-7.08(m,1H),7.17-7.20(m,1H),7.23-7.27(m,2H),7.32-7.35(m,1H),7.67-7.74(m,1H),8.14-8.15(m,2H)。 MS (ESI, pos.ion) m / z: 397.2 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.21 (s, 3H), 2.97 (m, 4H), 3.72 (t, 4H, J = 4.62 Hz), 4.79 (s, 2H), 6.37 (s, 1H), 7.04-7.08 (m, 1H), 7.17-7.20 (m, 1H), 7.23-7.27 (m, 2H), 7.32-7.35 (m, 1H), 7.67-7.74 (m, 1H), 8.14 - 8.15 (m, 2H).
在100mL圓底燒瓶中加入5-氟嘧啶-3-醇(0.95g,8.40mmol)、碳酸鉀(1.16g,8.40mmol)和乙腈(6mL)，在25℃下往反應體系中緩慢滴加2-溴乙腈(1.01g,8.42mmol)。滴加完，反應體系在室溫下反應40h。反應完畢，過濾，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=3/1)，得到黃色固體(0.55g,43%)。 Add 5-fluoropyrimidin-3-ol (0.95 g, 8.40 mmol), potassium carbonate (1.16 g, 8.40 mmol) and acetonitrile (6 mL) to a 100 mL round bottom flask, and slowly add 2 to the reaction system at 25 ° C. -Bromoacetonitrile (1.01 g, 8.42 mmol). After the dropwise addition, the reaction system was reacted at room temperature for 40 h. After completion of the reaction, EtOAc~~~~~~~~~~~~~~~~~~~
在100mL圓底燒瓶中加入2-((5-氟嘧啶-3-基)氧基)乙腈(0.55g,3.62mmol)、碳酸鉀(0.60g,4.34mmol)、DMSO(0.55mL)和水(8mL)，在冰浴下緩慢滴加30%過氧化氫(0.55mL)。滴加完，反應體系在室溫下反應5分鐘。反應完畢，減壓蒸乾溶劑，粗品經柱層析純化(乙酸乙酯洗脫)，得到白色固體(0.37g,60%)。 Add 2-((5-fluoropyrimidin-3-yl)oxy)acetonitrile (0.55 g, 3.62 mmol), potassium carbonate (0.60 g, 4.34 mmol), DMSO (0.55 mL) and water in a 100 mL round bottom flask. 8 mL), 30% hydrogen peroxide (0.55 mL) was slowly added dropwise under an ice bath. After the dropwise addition, the reaction system was allowed to react at room temperature for 5 minutes. After completion of the reaction, the solvent was evaporated.
在100mL圓底燒瓶中加入2-((5-氟嘧啶-3-基)氧基)乙醯胺(200mg,1.18mmol)、N-(3-氟-4-嗎啉苯基)-3-羰基丁醯胺(330mg,1.18mmol)和二甲苯(10mL)，然後在室溫下往反應體系中加入四異丙基鈦酸酯(2.7mg,9.5mmol)，反應體系加熱至回流，反應50h。將反應體系冷卻至室溫，加入水(10mL)和乙酸乙酯(60mL)，過濾，減壓蒸乾溶劑。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(130mg,27%)。 Add 2-((5-fluoropyrimidin-3-yl)oxy)acetamide (200 mg, 1.18 mmol), N- (3-fluoro-4-morpholinylphenyl)-3- in a 100 mL round bottom flask Benzyl amide (330 mg, 1.18 mmol) and xylene (10 mL), then tetraisopropyl titanate (2.7 mg, 9.5 mmol) was added to the reaction system at room temperature, and the reaction was heated to reflux for 50 h. . The reaction system was cooled to room temperature, water (10 mL) and ethyl acetate (60 mL) was evaporated. The crude was purified by EtOAc EtOAc EtOAc (EtOAc)
MS(ESI,pos.ion)m/z：415.2(M+1)；1H NMR(400MHz,DMSO-d6)：δ 2.21(s,3H),2.98(m,4H),3.73(t,4H,J=4.62Hz),4.84(s,2H),6.37(s,1H),7.04-7.08(m,1H),7.18-7.21(m,1H),7.32-7.37(m,2H),8.07-8.08(m,1H),8.16(m,1H)。 MS (ESI, pos.ion) m / z: 415.2 (M + 1); 1 H NMR (400MHz, DMSO-d 6): δ 2.21 (s, 3H), 2.98 (m, 4H), 3.73 (t, 4H, J = 4.62Hz), 4.84(s, 2H), 6.37(s, 1H), 7.04-7.08(m,1H), 7.18-7.21(m,1H),7.32-7.37(m,2H),8.07 -8.08 (m, 1H), 8.16 (m, 1H).
在100mL圓底燒瓶中加入3-氟苯酚(3.36g,30.0mmol)、2-溴-2-甲基丙酸乙酯(8.78g,45.0mmol)、碳酸鉀(6.22g,45.0mmol)和丙酮(50mL)，反應體系加熱至回流，反應過夜。反應完畢，將混合物冷卻至室溫，加入水(60mL)，二氯甲烷萃取(40mL×2)。有機層用飽和食鹽水洗滌(40mL×2)，用無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=4/1)，得到無色液體(3.20g,47%)。 3-fluorophenol (3.36 g, 30.0 mmol), 2-bromo-2-methylpropionic acid ethyl ester (8.78 g, 45.0 mmol), potassium carbonate (6.22 g, 45.0 mmol) and acetone were placed in a 100 mL round bottom flask. (50 mL), the reaction was heated to reflux and allowed to react overnight. After completion of the reaction, the mixture was cooled to room temperature, then water (60 mL) The organic layer was washed with brine (40 mL × 2) The crude was purified by EtOAc EtOAc EtOAc (EtOAc:
在250mL圓底燒瓶中加入氫氧化鉀(2.38g,42.4mmol)、水(50mL) 和乙醇(70mL)，然後一次性加入2-甲基-2-(3-氟苯氧基)丙酸乙酯(3.20g,14.1mmol)，反應體系加熱至40℃，反應2h。將混合物冷卻至0℃，加入濃鹽酸調至酸性pH 3，二氯甲烷萃取(20mL×2)。有機層用飽和食鹽水洗滌(20mL×2)，無水硫酸鈉乾燥。過濾，蒸乾溶劑，得到白色固體(1.70g,61%)。 Add potassium hydroxide (2.38 g, 42.4 mmol), water (50 mL) to a 250 mL round bottom flask. And ethanol (70 mL), then ethyl 2-methyl-2-(3-fluorophenoxy)propanoate (3.20 g, 14.1 mmol) was added in one portion, and the reaction was heated to 40 ° C for 2 h. The mixture was cooled to 0 ° C, concentrated aqueous hydrochloric acid was added to acid pH 3 and dichloromethane (20 mL×2). The organic layer was washed with brine (20 mL×2) Filtration and evaporation <RTI ID=0.0>
在50mL圓底燒瓶中加入2-甲基-2-(3-氟苯氧基)丙酸(1.70g,8.58mmol)，氮氣保護下緩慢滴加二氯亞碸(15mL)，反應體系加熱至回流，反應3h。將混合物冷卻至室溫，蒸乾溶劑，得到黃色液體，粗品未經進一步處理直接用於下一步反應。 2-Methyl-2-(3-fluorophenoxy)propionic acid (1.70 g, 8.58 mmol) was added to a 50 mL round bottom flask, and dichlorohydrazine (15 mL) was slowly added dropwise under nitrogen atmosphere, and the reaction system was heated to Reflow, reaction for 3 h. The mixture was cooled to room temperature, and the solvent was evaporated to dryness to give a yellow liquid.
在50mL雙口瓶中加入吡啶(0.80g,10.1mmol)、3-氨基巴豆酸甲酯(0.90g,7.82mmol)和二氯甲烷(20mL)，氮氣保護下緩慢滴加2-(3-氟苯氧基)-2-甲基丙醯氯(1.86g,8.59mmol)的二氯甲烷(5mL)溶液，反應體系在室溫下反應過夜。反應完畢，混合物用飽和食鹽水洗滌(20mL×3)，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=20/1)，得到黃色固體(1.13g,49%)。 Pyridine (0.80 g, 10.1 mmol), methyl 3-aminocrotonate (0.90 g, 7.82 mmol) and dichloromethane (20 mL) were added to a 50 mL two-necked flask, and 2-(3-fluoro) was slowly added dropwise under nitrogen. A solution of phenoxy)-2-methylpropionyl chloride (1.86 g, 8.59 mmol) in dichloromethane (5 mL). After completion of the reaction, the mixture was washed with brine (20 mL×3) The crude was purified by EtOAc EtOAc EtOAc (EtOAc:
在100mL雙口瓶中加入3-氟-4-嗎啉苯胺(0.50g,2.55mmol)和乾燥二氯甲烷(40mL)，氮氣保護，室溫下緩慢滴加2M三甲基鋁甲苯溶液(3.9mL,7.8mmol)，反應體系在室溫下反應0.5h。然後往反應體系中緩慢滴加3-(N-(2-(3-氟苯氧基)-2-甲基丙醯)氨基)巴豆酸甲酯(1.13g,3.83mmol,5mL二氯甲烷溶解)，反應體系在室溫下反應3天。反應完畢，將飽和的氯化銨溶液(50mL)緩慢加入到體系中，二氯甲烷萃取(30mL×3)，有機層用飽和食鹽水洗滌(30mL×3)，用無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=3/1)，得到黃色固體(0.17g,15%)。 3-Fluoro-4-morpholinaniline (0.50 g, 2.55 mmol) and dry dichloromethane (40 mL) were added to a 100 mL two-necked flask, and nitrogen-protected, and 2 M trimethylaluminum toluene solution (3.9) was slowly added dropwise at room temperature. mL, 7.8 mmol), the reaction was allowed to react at room temperature for 0.5 h. Then, 3-( N- (2-(3-fluorophenoxy)-2-methylpropionamidine)amino)crotonate methyl ester (1.13 g, 3.83 mmol, 5 mL dichloromethane) was slowly added dropwise to the reaction system. The reaction system was reacted at room temperature for 3 days. After completion of the reaction, a saturated ammonium chloride solution (50 mL) was slowly added to the mixture, and dichloromethane (30 mL × 3), and the organic layer was washed with brine (30 mL × 3) and dried over anhydrous sodium sulfate. The crude was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc
MS(ESI,pos.ion)m/z：442.2(M+1)；1H NMR(400MHz,CDCl3)：δ 1.55(s,3H),1.68-1.65(d,3H,J=12.8Hz),2.35(s,3H),3.17-3.06(m,4H),3.88-3.85(m,4H),6.24-6.20(dt,1H,J 1 =10.8Hz,J 2 =2.4Hz),6.31-6.28(dd,1H,J 1 =8.2Hz,J 2 =2.2Hz),6.35(s,1H),6.60-6.56(dd, 1H,J 1 =12.9Hz,J 2 =2.4Hz),6.71-6.65(m,2H),6.85-6.80(t,1H,J=8.8Hz),7.17-7.11(m,1H)。 MS (ESI, pos.) m/z: 442.2 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 1.55 (s, 3H), 1.68-1.65 (d, 3H, J = 12.8 Hz) , 2.35 (s, 3H), 3.17-3.06 (m, 4H), 3.88-3.85 (m, 4H), 6.24-6.20 (dt, 1H, J 1 = 10.8 Hz, J 2 = 2.4 Hz), 6.31-6.28 (dd, 1H, J 1 = 8.2 Hz, J 2 = 2.2 Hz), 6.35 (s, 1H), 6.60-6.56 (dd, 1H, J 1 = 12.9 Hz, J 2 = 2.4 Hz), 6.71-6.65 ( m, 2H), 6.85-6.80 (t, 1H, J = 8.8 Hz), 7.17-7.11 (m, 1H).
在100mL圓底燒瓶中加入2-氟-N 1 ,N 1 -二己基苯胺(2.94g,10.0mmol)、二乙烯酮(0.84g,10.0mmol)和甲苯(50mL)，反應體系加熱至80℃，反應過夜。反應完畢，將混合物冷卻至室溫，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/4)，得到黃色油狀物(2.67g,70%)。 2-fluoro- N 1 ,N 1 -dihexylaniline (2.94 g, 10.0 mmol), diketene (0.84 g, 10.0 mmol) and toluene (50 mL) were added to a 100 mL round bottom flask, and the reaction was heated to 80 ° C. , react overnight. After completion of the reaction, the mixture was cooled to room temperature. EtOAcjjjjjjjjj %).
在250mL圓底燒瓶中加入3-氟苯酚(11.2g,100mmol)、2-溴乙醯胺(13.8g,100mmol)、碳酸鉀(13.82g,100mmol)、碳酸銫(32.58g,100mmol)和丙酮(150mL)，反應體系加熱至回流，反應過夜。反應完畢，將混合物冷卻至室溫，過濾，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到白色固體(5.06g,30%)。 3-fluorophenol (11.2 g, 100 mmol), 2-bromoacetamide (13.8 g, 100 mmol), potassium carbonate (13.82 g, 100 mmol), cesium carbonate (32.58 g, 100 mmol) and acetone were placed in a 250 mL round bottom flask. (150 mL), the reaction was heated to reflux and allowed to react overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered, evaporated, evaporated,jjjjjjjjjjjjj %).
在100mL圓底燒瓶中加入N-(4-(二己氨基)-3-氟苯基)-3-羰基丁醯胺(2.67g,7.05mmol)、2-(3-氟苯氧基)乙醯胺(2.37g,14.0mmol)和二甲苯(20mL)，然後在室溫下往反應體系中加入四異丙基鈦酸酯(5.97g,21.0mmol)，反應體系加熱至165℃，反應24h。將反應體系冷卻至室溫，加入甲苯(120mL)和飽和氯化銨溶液(150mL)，反應體系在室溫下反應過夜。反應完畢，過濾，濾液用二氯甲烷(150mL×3)萃取。合併有機層，用無水 硫酸鈉乾燥。過濾，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=2/1)，得到黃色固體(0.95g,26%)。 Add N- (4-(dihexylamino)-3-fluorophenyl)-3-carbonylbutanamine (2.67 g, 7.05 mmol), 2-(3-fluorophenoxy)ethyl in a 100 mL round bottom flask Indoleamine (2.37 g, 14.0 mmol) and xylene (20 mL), then tetraisopropyl titanate (5.97 g, 21.0 mmol) was added to the reaction system at room temperature, and the reaction system was heated to 165 ° C for 24 h. . The reaction system was cooled to room temperature, and toluene (120 mL) and a saturated ammonium chloride solution (150 mL) were added, and the reaction system was allowed to react at room temperature overnight. The reaction was completed, filtered, and the filtrate was extracted with dichloromethane (150 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate. Filtration and evaporation <RTI ID=0.0></RTI> to EtOAc.
MS(ESI,pos.ion)m/z：512.3(M+1)；1H NMR(400MHz,DMSO-d6)：δ 0.88(t,6H,J=7.2Hz),1.25-1.30(m,16H),2.42(s,3H),3.62(t,4H,J=7.8Hz),4.84(s,2H),6.54(s,1H),6.54(s,1H),6.58-6.60(m,1H),6.64-6.66(m,1H),6.68-6.73(m,1H),7.21-7.27(m,1H),7.60(d,1H,J=8.6Hz),7.74-7.77(m,1H),7.96(t,1H,J=8.3Hz)。 MS (ESI, pos. ion) m/z: 512.3 (M + 1); 1 H NMR (400 MHz, DMSO-d 6 ): δ 0.88 (t, 6H, J = 7.2 Hz), 1.25-1.30 (m, 16H), 2.42 (s, 3H), 3.62 (t, 4H, J = 7.8 Hz), 4.84 (s, 2H), 6.54 (s, 1H), 6.54 (s, 1H), 6.58-6.60 (m, 1H) ), 6.64-6.66 (m, 1H), 6.68-6.73 (m, 1H), 7.21-7.27 (m, 1H), 7.60 (d, 1H, J = 8.6 Hz), 7.74-7.77 (m, 1H), 7.96 (t, 1H, J = 8.3 Hz).
在250mL圓底燒瓶中加入N-(3-氯-4-嗎啉苯基)-3-羰基丁醯胺(0.89g,3.00mmol)和二甲苯(20mL)，然後加入2-(3-氟苯氧基)乙醯胺(1.01g,5.97mmol)和四異丙基鈦酸酯(7.2mL)，反應體系加熱至165℃，反應24h。將反應體系冷卻至室溫，加入甲苯(45mL)和飽和氯化銨溶液(60mL)，室溫反應過夜。反應完畢，過濾，濾液用二氯甲烷萃取(60mL×3)。合併有機層，用飽和食鹽水洗滌，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(0.29g,23%)。 Add N- (3-chloro-4-morpholinylphenyl)-3-carbonylbutanamine (0.89 g, 3.00 mmol) and xylene (20 mL) in a 250 mL round bottom flask, then add 2-(3-fluoro Phenoxy)acetamide (1.01 g, 5.97 mmol) and tetraisopropyl titanate (7.2 mL) were heated to 165 ° C for 24 h. The reaction system was cooled to room temperature, and toluene (45 mL) and saturated aqueous ammonium chloride (60 mL) After the reaction was completed, it was filtered, and the filtrate was extracted with dichloromethane (60 mL×3). The organic layer was combined, washed with brine and dried over anhydrous sodium sulfate. The crude was purified by EtOAc EtOAc EtOAc (EtOAc:
MS(ESI,pos.ion)m/z：430.1(M+1)；1H NMR(400MHz,DMSO-d6)：δ 2.35(s,3H),3.00-3.06(m,4H),3.85-3.87(m,4H),4.68(d,J=5.12Hz,2H),6.39(s,1H),6.45-6.49(m,1H),6.54(dd,J=2.32Hz and 8.34Hz,1H),6.64-6.68(m,1H),7.07(s,1H),7.11-7.19(m,2H),7.29(d,J=2.4Hz,1H)。 MS (ESI, pos.) m/z: 430.1 (M + 1); 1 H NMR (400 MHz, DMSO-d 6 ): δ 2.35 (s, 3H), 3.00-3.06 (m, 4H), 3.85- 3.87 (m, 4H), 4.68 (d, J = 5.12 Hz, 2H), 6.39 (s, 1H), 6.45-6.49 (m, 1H), 6.54 (dd, J = 2.32 Hz and 8.34 Hz, 1H), 6.64-6.68 (m, 1H), 7.07 (s, 1H), 7.11-7.19 (m, 2H), 7.29 (d, J = 2.4 Hz, 1H).
在100mL圓底燒瓶中加入3-氯苯酚(2.57g,20.0mmol)、2-溴乙醯胺(2.76g,20.0mmol)、碳酸鉀(5.53g,40.0mmol)和丙酮(40mL)，反應體系加熱至70℃反應過夜。反應完畢，將混合物冷卻至室溫，過濾，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到白色固體(3.22g,87%)。 3-chlorophenol (2.57 g, 20.0 mmol), 2-bromoacetamide (2.76 g, 20.0 mmol), potassium carbonate (5.53 g, 40.0 mmol) and acetone (40 mL) were added to a 100 mL round bottom flask. Heat to 70 ° C to react overnight. After the reaction was completed, the mixture was cooled to room temperature, filtered, evaporated, evaporated, evaporated %).
在250mL圓底燒瓶中加入N-(3-氯-4-嗎啉苯基)-3-羰基丁醯胺(0.48mg,1.62mmol)、2-(3-氯苯氧基)乙醯胺(0.60g,3.24mmol)、四異丙基鈦酸酯(2.4mL)和二甲苯(10mL)，反應體系加熱至165℃，反應24h。將反應體系冷卻至室溫，加入甲苯(60mL)和飽和氯化銨溶液(60mL)，室溫反應過夜。反應完畢，過濾，濾液用二氯甲烷萃取(20mL×4)。合併有機層，用飽和食鹽水洗滌(30mL×2)，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(0.46g,64%)。 Add N-(3-chloro-4-morpholinylphenyl)-3-carbonylbutanamine (0.48 mg, 1.62 mmol), 2-(3-chlorophenoxy)acetamide in a 250 mL round bottom flask ( 0.60 g, 3.24 mmol), tetraisopropyl titanate (2.4 mL) and xylene (10 mL) were heated to 165 ° C for 24 h. The reaction system was cooled to room temperature, and toluene (60 mL) and a saturated ammonium chloride solution (60 mL) were added, and the mixture was allowed to react at room temperature overnight. After the reaction was completed, it was filtered, and the filtrate was extracted with dichloromethane (20 mL × 4). The organic layer was combined, washed with brine (30 mL? The crude was purified by EtOAc EtOAc EtOAc (EtOAc:
MS(ESI,pos.ion)m/z：446.1(M+1)；1H NMR(400MHz,CDCl3)：δ 2.35(s,3H),3.08-2.99(m,4H),3.87-3.85(t,4H,J=4.6Hz),4.69-4.68(d,2H,J=6.2Hz),6.39(s,1H),6.67-6.64(m,1H),6.75-6.74(t,1H,J=2.2Hz),6.95-6.92(m,1H),7.07-7.05(d,1H,J=8.5Hz),7.16-7.11(m,2H),7.29(s,1H)。 MS (ESI, pos.) m/z: 446.1 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.35 (s, 3H), 3.08-2.99 (m, 4H), 3.87-3.85 ( t, 4H, J = 4.6 Hz), 4.69-4.68 (d, 2H, J = 6.2 Hz), 6.39 (s, 1H), 6.67-6.64 (m, 1H), 6.75-6.74 (t, 1H, J = 2.2 Hz), 6.95-6.92 (m, 1H), 7.07-7.05 (d, 1H, J = 8.5 Hz), 7.16-7.11 (m, 2H), 7.29 (s, 1H).
在100mL圓底燒瓶中加入3-羥基苯腈(2.38g,20.0mmol)、2-溴乙醯胺(3.04g,22.0mmol)、碳酸鉀(5.53g,40.0mmol)和丙酮(20mL)，反應體系加熱至70℃反應17.5h。反應完畢，將混合物冷卻至室溫，過濾，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到白色固體(2.70g,77%)。 3-Hydroxybenzonitrile (2.38 g, 20.0 mmol), 2-bromoacetamide (3.04 g, 22.0 mmol), potassium carbonate (5.53 g, 40.0 mmol) and acetone (20 mL) were added to a 100 mL round bottom flask. The system was heated to 70 ° C for 17.5 h. After the reaction was completed, the mixture was cooled to EtOAc. %).
在250mL圓底燒瓶中加入N-(3-氯-4-嗎啉苯基)-3-羰基丁醯胺(0.59g,2.00mmol)、2-(3-氰基苯氧基)乙醯胺(0.71g,4.03mmol)、四異丙基鈦酸酯(4.8mL)和二甲苯(20mL)，反應體系加熱至165℃，反應24h。將反應體系冷卻至室溫，加入甲苯(30mL)和飽和氯化銨溶液(40mL)，室溫反應過夜。反應完畢，過濾，濾液用二氯甲烷萃取(50mL×3)。合併有機層，用無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(0.51g,59%)。 Add N- (3-chloro-4-morpholinylphenyl)-3-carbonylbutanamine (0.59 g, 2.00 mmol), 2-(3-cyanophenoxy)acetamide in a 250 mL round bottom flask (0.71 g, 4.03 mmol), tetraisopropyl titanate (4.8 mL) and xylene (20 mL). The reaction was heated to 165 ° C for 24 h. The reaction system was cooled to room temperature, and toluene (30 mL) and saturated aqueous ammonium chloride (40 mL) The reaction was completed, filtered, and the filtrate was extracted with dichloromethane (50mL×3). The organic layers were combined and dried over anhydrous sodium sulfate. The crude was purified by EtOAc EtOAc EtOAc (EtOAc:
MS(ESI,pos.ion)m/z：437.1(M+1)；1H NMR(400MHz,CDCl3)：δ 2.35(s,3H),2.98-3.11(m,4H),3.85-3.87(m,4H),4.68-4.76(m,2H),6.39(d,1H,J=0.84Hz),7.02-7.05(m,3H),7.13(dd,1H,J=2.36Hz and 8.52Hz),7.25-7.34(m,3H)。 MS (ESI, pos.) m/z: 437.1 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.35 (s, 3H), 2.98-3.11 (m, 4H), 3.85-3. m, 4H), 4.68-4.76 (m, 2H), 6.39 (d, 1H, J = 0.84 Hz), 7.02-7.05 (m, 3H), 7.13 (dd, 1H, J = 2.36 Hz and 8.52 Hz), 7.25-7.34 (m, 3H).
在250mL圓底燒瓶中加入3-氟苯酚(5.61g,50.0mmol)、2-溴乙醯胺(7.59g,55.0mmol)、碳酸鉀(13.82g,100mmol)和丙酮(80mL)，反應體系加熱至70℃反應過夜。反應完畢，將混合物冷卻至室溫，過濾，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到白色固體(7.89g,93%)。 In a 250 mL round bottom flask, 3-fluorophenol (5.61 g, 50.0 mmol), 2-bromoacetamide (7.59 g, 55.0 mmol), potassium carbonate (13.82 g, 100 mmol) and acetone (80 mL) were added, and the reaction system was heated. The reaction was carried out overnight at 70 °C. After the reaction was completed, the mixture was cooled to room temperature, filtered, evaporated, evaporated, evaporated, mjjjjjjjjjjjj %).
在250mL圓底燒瓶中加入3,4-二氟硝基苯(7.95g,50.0mmol)、3-嗎啉酮(5.06g,50.0mmol)、碳酸鉀(13.82g,100mmol)和DMF(80mL)，反應體系加熱至140℃反應過夜。反應完畢，將混合物冷卻至室溫，過濾，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=3/1)，得到黃色固體(5.00g,42%)。 Add 3,4-difluoronitrobenzene (7.95 g, 50.0 mmol), 3-morpholinone (5.06 g, 50.0 mmol), potassium carbonate (13.82 g, 100 mmol) and DMF (80 mL) to a 250 mL round bottom flask. The reaction system was heated to 140 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature, filtered, evaporated, evaporated, evaporated,jjjjjjjjjjjjjj %).
在250mL圓底燒瓶中加入鐵粉(8.8g,158mmol)、水(60mL)和鹽酸(2mL)，反應體系加熱至65℃。反應20min後，將混合物冷卻至室溫，倒掉反應溶劑，往反應瓶中加入4-(2-氟-4-硝基苯基)嗎啉-3-酮的甲醇溶液(3.8g,15.8mmol,100mL甲醇溶解)，用鹽酸調pH=2，反應體系加熱至65℃反應4h。反應完畢，將混合物冷卻至室溫，加入飽和碳酸氫鈉溶液調pH=8，過濾，減壓蒸乾大部分溶劑，剩餘物用乙酸乙酯萃取(20mL×3)，有機相用飽和食鹽水洗滌(20mL×4)，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/2)，得到白色固體(1.89g,57%)。 Iron powder (8.8 g, 158 mmol), water (60 mL) and hydrochloric acid (2 mL) were added to a 250 mL round bottom flask, and the reaction was heated to 65 °C. After reacting for 20 min, the mixture was cooled to room temperature, the reaction solvent was evaporated, and a solution of 4-(2-fluoro-4-nitrophenyl)morpholin-3-one in methanol (3.8 g, 15.8 mmol) was added to the reaction flask. , 100 mL of methanol was dissolved), pH was adjusted to 2 with hydrochloric acid, and the reaction system was heated to 65 ° C for 4 h. After completion of the reaction, the mixture was cooled to room temperature, and the mixture was adjusted to pH=8 with saturated sodium hydrogen carbonate solution, filtered, and evaporated to dryness. It was washed (20 mL × 4) and dried over anhydrous sodium sulfate. The crude was purified by EtOAc EtOAc EtOAc (EtOAc:
在100mL圓底燒瓶中加入4-(4-氨基-2-氟苯基)嗎啉-3-酮(2.51g,11.9mmol)、二乙烯酮(2.51g,29.9mmol)和乙酸乙酯(40mL)，反應體系加熱至80℃，反應24h。反應完畢，將混合物冷卻至室溫，減壓蒸乾溶劑，粗品 經柱層析純化(石油醚/乙酸乙酯(V/V)=1/4)，得到黃色固體(2.15g,61%)。 Add 4-(4-amino-2-fluorophenyl)morpholin-3-one (2.51 g, 11.9 mmol), diketene (2.51 g, 29.9 mmol) and ethyl acetate (40 mL) in a 100 mL round bottom flask. The reaction system was heated to 80 ° C and reacted for 24 h. After the reaction is completed, the mixture is cooled to room temperature, and the solvent is evaporated to dryness under reduced pressure. Purification by column chromatography (EtOAc/EtOAc (EtOAc)
在100mL圓底燒瓶中加入N-(3-氟-4-(3-羰基嗎啉)苯基))-3-羰基丁醯胺(0.59g,2.00mmol)、2-(3-氟苯氧基)乙醯胺(0.94g,5.56mmol)、四異丙基鈦酸酯(4.8mL)和二甲苯(10mL)，反應體系加熱至165℃，反應24h。將反應體系冷卻至室溫，加入甲苯(60mL)和飽和氯化銨溶液(60mL)，室溫反應過夜。反應完畢，過濾，濾液用二氯甲烷萃取(20mL×4)。合併有機層，用飽和食鹽水洗滌(30mL×2)，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/2)，得到黃色固體(0.06g,7%)。 Add N- (3-fluoro-4-(3-carbonylmorpholine)phenyl))-3-carbonylbutanamine (0.59 g, 2.00 mmol), 2-(3-fluorophenoxyl) to a 100 mL round bottom flask Ethylamine (0.94 g, 5.56 mmol), tetraisopropyl titanate (4.8 mL) and xylene (10 mL) were heated to 165 ° C for 24 h. The reaction system was cooled to room temperature, and toluene (60 mL) and a saturated ammonium chloride solution (60 mL) were added, and the mixture was allowed to react at room temperature overnight. After the reaction was completed, it was filtered, and the filtrate was extracted with dichloromethane (20 mL × 4). The organic layer was combined, washed with brine (30 mL? The crude was purified by EtOAc EtOAc EtOAc (EtOAc)
MS(ESI,pos.ion)m/z：428.1(M+1)；1H NMR(400MHz,CDCl3)：δ 2.36(s,3H),3.70(d,2H,J=3.12Hz),4.03(t,2H,J=4.6Hz),4.35(s,2H),4.73(s,2H),6.38(s,1H),6.55-6.53(m,2H),6.67(t,1H,J=7.3Hz),7.21-7.11(m,3H),7.44(t,1H,J=8.2Hz)。 MS (ESI, pos.) m/z: 428.1 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.36 (s, 3H), 3.70 (d, 2H, J = 3.12 Hz), 4.03 (t, 2H, J = 4.6 Hz), 4.35 (s, 2H), 4.73 (s, 2H), 6.38 (s, 1H), 6.55-6.53 (m, 2H), 6.67 (t, 1H, J = 7.3 Hz), 7.21 - 7.11 (m, 3H), 7.44 (t, 1H, J = 8.2 Hz).
在100mL圓底燒瓶中加入4-氯萘酚(3.57g,20.0mmol)、2-溴乙醯胺(2.76g,20.0mmol)、碳酸鉀(5.53g,40.0mmol)和丙酮(40mL)，反應體系加熱至70℃反應過夜。反應完畢，將混合物冷卻至室溫，過濾，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到白色固體(2.32g,49%)。 4-chloronaphthol (3.57 g, 20.0 mmol), 2-bromoacetamide (2.76 g, 20.0 mmol), potassium carbonate (5.53 g, 40.0 mmol) and acetone (40 mL) were added to a 100 mL round bottom flask. The system was heated to 70 ° C and allowed to react overnight. After the reaction was completed, the mixture was cooled to room temperature, filtered, evaporated, evaporated,jjjjjjjjjj %).
在250mL圓底燒瓶中加入N-(3-氯-4-嗎啉苯基)-3-羰基丁醯胺(0.59g, 2.0mmol)、2-(4-氯萘-1-氧基)乙醯胺(0.94g,4.0mmol)、四異丙基鈦酸酯(4.8mL)和二甲苯(10mL)，反應體系加熱至165℃，反應24h。將反應體系冷卻至室溫，加入甲苯(60mL)和飽和氯化銨溶液(60mL)，室溫反應過夜。反應完畢，過濾，濾液用二氯甲烷萃取(20mL×4)。合併有機層，用飽和食鹽水洗滌(30mL×2)，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(0.56g,56%)。 Add N- (3-chloro-4-morpholinylphenyl)-3-carbonylbutanamine (0.59 g, 2.0 mmol), 2-(4-chloronaphthalene-1-oxy)B in a 250 mL round bottom flask The guanamine (0.94 g, 4.0 mmol), tetraisopropyl titanate (4.8 mL) and xylene (10 mL) were heated to 165 ° C for 24 h. The reaction system was cooled to room temperature, and toluene (60 mL) and a saturated ammonium chloride solution (60 mL) were added, and the mixture was allowed to react at room temperature overnight. After the reaction was completed, it was filtered, and the filtrate was extracted with dichloromethane (20 mL × 4). The organic layer was combined, washed with brine (30 mL? The crude was purified by EtOAc EtOAc EtOAc (EtOAc:
MS(ESI,pos.ion)m/z：496.1(M+1)；1H NMR(400MHz,CDCl3)：δ 2.37(s,3H),2.96-2.86(m,4H),3.83-3.80(t,4H,J=4.6Hz),4.93-4.92(d,2H,J=4.9Hz),6.41(1H,s),6.62-6.60(d,1H,J=8.3Hz),6.89-6.87(d,1H,J=8.5Hz),7.09-7.07(dd,1H,J 1 =2.5Hz,J 2 =8.5Hz),7.27-7.26(m,1H),7.35-7.33(d,1H,J=8.2Hz),7.55-7.51(m,1H),7.64-7.60(m,1H),8.04-8.02(d,1H,J=8.3Hz),8.18-8.16(d,1H,J=8.2Hz)。 MS (ESI, pos.) m/z: 496.1 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.37 (s, 3H), 2.96 - 2.86 (m, 4H), 3.83 - 3.80 ( t, 4H, J = 4.6 Hz), 4.93-4.92 (d, 2H, J = 4.9 Hz), 6.41 (1H, s), 6.62-6.60 (d, 1H, J = 8.3 Hz), 6.89-6.87 (d , 1H, J = 8.5 Hz), 7.09-7.07 (dd, 1H, J 1 = 2.5 Hz, J 2 = 8.5 Hz), 7.27-7.26 (m, 1H), 7.35-7.33 (d, 1H, J = 8.2 Hz), 7.55-7.51 (m, 1H), 7.64-7.60 (m, 1H), 8.04-8.02 (d, 1H, J = 8.3 Hz), 8.18-8.16 (d, 1H, J = 8.2 Hz).
在100mL圓底燒瓶中加入3-羥基苯乙炔(3.31g,28.0mmol)、丙酮(50mL)、2-溴乙醯胺(2.36g,17.1mmol)和K2CO3(5.53g,40.0mmol)，反應體系加熱至70℃反應7h。將混合物冷至室溫，過濾，蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到白色固體(2.70g,90%)。 3-Hydroxyphenylacetylene (3.31 g, 28.0 mmol), acetone (50 mL), 2-bromoacetamide (2.36 g, 17.1 mmol) and K 2 CO 3 (5.53 g, 40.0 mmol) were placed in a 100 mL round bottom flask. The reaction system was heated to 70 ° C for 7 h. The mixture was cooled to room temperature, filtered, and then evaporated tolululululululululululululululululululu
在250mL圓底燒瓶中加入N-(3-氟-4-嗎啉苯基)-3-羰基丁醯胺(0.80g,2.85mmol)、2-(3-乙炔苯氧基)乙醯胺(1.0g,5.71mmol)、四異丙基鈦酸酯(6.76mL)和二甲苯(20mL)，反應體系加熱至165℃，反應24h。將反應體 系冷卻至室溫，加入甲苯(50mL)和飽和氯化銨溶液(60mL)，室溫反應過夜。反應完畢，過濾，濾液用二氯甲烷萃取(150mL×3)。合併有機層，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(0.60g,50%)。 In a 250 mL round bottom flask was added N- (3-fluoro-4-morpholinylphenyl)-3-carbonylbutanamine (0.80 g, 2.85 mmol), 2-(3-ethynylphenoxy)acetamide ( 1.0 g, 5.71 mmol), tetraisopropyl titanate (6.76 mL) and xylene (20 mL) were heated to 165 ° C for 24 h. The reaction system was cooled to room temperature, and toluene (50 mL) and a saturated ammonium chloride solution (60 mL) were added, and the mixture was allowed to react at room temperature overnight. The reaction was completed, filtered, and the filtrate was extracted with dichloromethane (150 mL, 3). The organic layers were combined and dried over anhydrous sodium sulfate. The crude was purified by EtOAc EtOAc EtOAc (EtOAc:
MS(ESI,pos.ion)m/z：420.1(M+1)；1H NMR(400MHz,CDCl3)：δ 2.34(s,3H),3.03-3.11(m,5H),3.83(t,4H),4.68(s,2H),6.38(s,1H),6.76-7.19(m,7H)。 MS (ESI, pos.) m/z: 420.1 (M + 1); 1 H NMR (400 MHz, CDCl 3 ): δ 2.34 (s, 3H), 3.03-3.11 (m, 5H), 3.83 (t, 4H), 4.68 (s, 2H), 6.38 (s, 1H), 6.76-7.19 (m, 7H).
在100mL圓底燒瓶中加入3-氟苯酚(2.24g,20.0mmol)、甲醇(20mL)、2-溴-2,2-二氟乙酸乙酯(8.12g,40.0mmol)和碳酸鉀(6.91g,50.0mmol),反應體系加熱至70℃反應過夜。將混合物冷至室溫，過濾，蒸乾溶劑，粗品未經進一步處理直接用於下一步反應。 3-fluorophenol (2.24 g, 20.0 mmol), methanol (20 mL), ethyl 2-bromo-2,2-difluoroacetate (8.12 g, 40.0 mmol) and potassium carbonate (6.91 g) were placed in a 100 mL round bottom flask. , 50.0 mmol), and the reaction system was heated to 70 ° C to react overnight. The mixture was cooled to room temperature, filtered, and the solvent was evaporated evaporated.
在20mL封管中加入2,2-二氟-2-(3-氟苯氧基)乙酸乙酯(3.5g,14.9mmol)、甲醇(10mL)和氨水(5.09g)，反應體系加熱至100℃反應24h。將混合物冷至室溫，蒸乾溶劑，粗品未經進一步處理直接用於下一步反應。 2,2-difluoro-2-(3-fluorophenoxy)acetic acid ethyl acetate (3.5 g, 14.9 mmol), methanol (10 mL) and aqueous ammonia (5.09 g) were added to a 20 mL sealed tube, and the reaction system was heated to 100. °C reaction for 24h. The mixture was cooled to room temperature, and the solvent was evaporated to dryness.
在250mL圓底燒瓶中加入N-(3-氟-4-嗎啉苯基)-3-羰基丁醯胺(0.60g,2.14mmol)、2,2-二氟-2-(3-氟苯氧基)乙醯胺(0.88g,4.29mmol)、四異丙基鈦酸酯(4.87g,17.1mmol)和二甲苯(20mL)，反應體系加熱至165℃，反應24h。將反應體系冷卻至室溫，加入甲苯(60mL)和飽和氯化銨溶液 (80mL)，室溫反應過夜。反應完畢，過濾，濾液用二氯甲烷萃取(150mL×3)。合併有機層，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(0.38g,40%)。 Add N- (3-fluoro-4-morpholinylphenyl)-3-carbonylbutanamine (0.60 g, 2.14 mmol), 2,2-difluoro-2-(3-fluorobenzene) to a 250 mL round bottom flask Ethyl acetamide (0.88 g, 4.29 mmol), tetraisopropyl titanate (4.87 g, 17.1 mmol) and xylene (20 mL) were heated to 165 ° C for 24 h. The reaction system was cooled to room temperature, and toluene (60 mL) and a saturated aqueous solution The reaction was completed, filtered, and the filtrate was extracted with dichloromethane (150 mL, 3). The organic layers were combined and dried over anhydrous sodium sulfate. The crude was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc
MS(ESI,pos.ion)m/z：450.1(M+1)；1H NMR(400MHz,CDCl3)：δ 2.43(s,3H),3.15(t,4H),3.85(m,4H),6.36-7.27(m,8H)。 MS (ESI, pos.ion) m / z: 450.1 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.43 (s, 3H), 3.15 (t, 4H), 3.85 (m, 4H) , 6.36-7.27 (m, 8H).
在100mL圓底燒瓶中加入1,2,3-三氟-5-硝基苯(3.54g,20.0mmol)、嗎啉(2.0mL,23.0mmol)、三乙胺(8.5mL,61.0mmol)和乙酸乙酯(30mL)，反應體系在室溫下反應5h。反應完畢，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=8/1)，得到黃色固體(4.76g,98%)。 In a 100 mL round bottom flask, 1,2,3-trifluoro-5-nitrobenzene (3.54 g, 20.0 mmol), morpholine (2.0 mL, 23.0 mmol), triethylamine (8.5 mL, 61.0 mmol) and Ethyl acetate (30 mL) was reacted at room temperature for 5 h. After completion of the reaction, the solvent was evaporated to drynessjjjjjjjjjjjjj
在100mL圓底燒瓶中加入4-(2,6-二氟-4-硝基苯基)嗎啉(4.71g,19.3mmol)、四氫呋喃(30mL)和乙醇(30mL)，然後加入10% Pd/C(2.0g)並通入氫氣，反應體系在室溫下反應過夜。反應完畢，過濾，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=8/1)，得到黃色固體(3.62g,88%)。 Add 4-(2,6-difluoro-4-nitrophenyl)morpholine (4.71 g, 19.3 mmol), tetrahydrofuran (30 mL) and ethanol (30 mL) to a 100 mL round bottom flask, then add 10% Pd/ C (2.0 g) was passed through hydrogen, and the reaction was allowed to react at room temperature overnight. After completion of the reaction, the mixture was evaporated,jjjjjjjjjj
在100mL圓底燒瓶中加入3,5-二氟-4-嗎啉苯胺(3.42g,16.0mmol)、二乙烯酮(1.61g,19.2mmol)和乙酸乙酯(20mL)，反應體系加熱至83℃反應過夜。反應完畢，將混合物冷卻至室溫，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(3.10g,65%)。 3,5-difluoro-4-morpholinaniline (3.42 g, 16.0 mmol), diketene (1.61 g, 19.2 mmol) and ethyl acetate (20 mL) were added to a 100 mL round bottom flask, and the reaction was heated to 83. The reaction was carried out overnight at °C. After completion of the reaction, the mixture was cooled to EtOAc (mjqqqqq .
在100mL圓底燒瓶中加入3-羥基苯腈(2.38g,20.0mmol)、2-溴乙醯胺(3.04g,22.0mmol)、碳酸鉀(5.53g,40.0mmol)和丙酮(30mL)，反應體系加熱至75℃反應過夜。反應完畢，將混合物冷卻至室溫，過濾，減壓蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到白色固體(1.00g,28%)。 3-Hydroxybenzonitrile (2.38 g, 20.0 mmol), 2-bromoacetamide (3.04 g, 22.0 mmol), potassium carbonate (5.53 g, 40.0 mmol) and acetone (30 mL) were added to a 100 mL round bottom flask. The system was heated to 75 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature, filtered, evaporated, evaporated, evaporated %).
在250mL圓底燒瓶中加入N-(3,5-二氟-4-嗎啉苯基)-3-羰基丁醯胺(0.79g,2.65mmol)、2-(3-氰基苯氧基)乙醯胺(0.93g,5.28mmol)、四異丙基鈦酸酯(6.3mL)和二甲苯(25mL)，反應體系加熱至165℃，反應24h。將反應體系冷卻至室溫，加入甲苯(60mL)和飽和氯化銨溶液(60mL)，室溫反應過夜。反應完畢，過濾，濾液用二氯甲烷萃取(20mL×4)。合併有機層，用飽和食鹽水洗滌(30mL×2)，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/2)，得到黃色固體(0.29g,25%)。 Add N- (3,5-difluoro-4-morpholinylphenyl)-3-carbonylbutanamine (0.79 g, 2.65 mmol), 2-(3-cyanophenoxy) to a 250 mL round bottom flask. Acetamide (0.93 g, 5.28 mmol), tetraisopropyl titanate (6.3 mL) and xylene (25 mL) were heated to 165 ° C for 24 h. The reaction system was cooled to room temperature, and toluene (60 mL) and a saturated ammonium chloride solution (60 mL) were added, and the mixture was allowed to react at room temperature overnight. After the reaction was completed, it was filtered, and the filtrate was extracted with dichloromethane (20 mL × 4). The organic layer was combined, washed with brine (30 mL? The crude was purified by EtOAc EtOAc EtOAc (EtOAc)
MS(ESI,pos.ion)m/z：439.1(M+1)；1H NMR(400MHz,CDCl3)：δ 2.34(s,3H),3.20(s,4H),3.80-3.77(t,4H,J=4.4Hz),4.77(s,2H),6.37(s,1H),6.83-6.81(d,2H,J=8.9Hz),7.08-7.06(dd,2H,J 1 =7.5Hz,J 2 =1.0Hz),7.29-7.27(d,1H,J=6.4Hz),7.39-7.35(m,1H)。 MS (ESI, pos.ion) m / z: 439.1 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.34 (s, 3H), 3.20 (s, 4H), 3.80-3.77 (t, 4H, J = 4.4 Hz), 4.77 (s, 2H), 6.37 (s, 1H), 6.83-6.81 (d, 2H, J = 8.9 Hz), 7.08-7.06 (dd, 2H, J 1 = 7.5 Hz, J 2 = 1.0 Hz), 7.29-7.27 (d, 1H, J = 6.4 Hz), 7.39-7.35 (m, 1H).
在100mL圓底燒瓶中加入3-甲氧基苯酚(2.48g,20.0mmol)、丙酮(30mL)、溴乙醯胺(3.31g,24.0mmol)和碳酸鉀(5.53g,40.0mmol)，反應體 系加熱至70℃反應9h。將混合物冷至室溫，過濾，蒸乾溶劑，粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到白色固體(3.0g,83%)。 3-methoxyphenol (2.48 g, 20.0 mmol), acetone (30 mL), bromoacetamide (3.31 g, 24.0 mmol) and potassium carbonate (5.53 g, 40.0 mmol) were added to a 100 mL round bottom flask. The mixture was heated to 70 ° C for 9 h. The mixture was cooled to room temperature, filtered and evaporated to drynessjjjjjjjjjjjjj
在250mL圓底燒瓶中加入N-(3-氟-4-嗎啉苯基)-3-羰基丁醯胺(1.0g,3.57mmol)、2-(3-甲氧基苯氧基)乙醯胺(1.29g,7.12mmol)、四異丙基鈦酸酯(8.11g,28.5mmol)和二甲苯(30mL)，反應體系加熱至165℃，反應24h。將反應體系冷卻至室溫，加入甲苯(80mL)和飽和氯化銨溶液(100mL)，室溫反應過夜。反應完畢，過濾，濾液用二氯甲烷萃取(150mL×3)。合併有機層，無水硫酸鈉乾燥。粗品經柱層析純化(石油醚/乙酸乙酯(V/V)=1/1)，得到黃色固體(0.61g,40%)。 Add N- (3-fluoro-4-morpholinylphenyl)-3-carbonylbutanamine (1.0 g, 3.57 mmol), 2-(3-methoxyphenoxy)acetamidine to a 250 mL round bottom flask. Amine (1.29 g, 7.12 mmol), tetraisopropyl titanate (8.11 g, 28.5 mmol) and xylene (30 mL), and the reaction was heated to 165 ° C for 24 h. The reaction system was cooled to room temperature, and toluene (80 mL) and a saturated ammonium chloride solution (100 mL) were added, and the mixture was allowed to react at room temperature overnight. The reaction was completed, filtered, and the filtrate was extracted with dichloromethane (150 mL, 3). The organic layers were combined and dried over anhydrous sodium sulfate. The crude was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc
MS(ESI,pos.ion)m/z：426.1(M+1)；1H NMR(400MHz,CDCl3)：δ 2.25(s,3H),2.97(t,4H),3.69(s,3H),3.71(m,4H),4.69(s,2H),6.33-7.31(m,8H)。 MS (ESI, pos.ion) m / z: 426.1 (M + 1); 1 H NMR (400MHz, CDCl 3): δ 2.25 (s, 3H), 2.97 (t, 4H), 3.69 (s, 3H) , 3.71 (m, 4H), 4.69 (s, 2H), 6.33 - 7.31 (m, 8H).
在500mL圓底燒瓶中加入4-溴-1-氯-2-氟苯(20.90g,100.0mmol)、乙醯丙酮(30mL,300.0mmol)和二甲基亞碸(100mL)，加入磷酸三鉀(63.70g,300.0mmol)和碘化亞銅(3.00g,15.80mmol)，氮氣保護下加熱至110℃反應23小時。反應畢，冷卻至室溫，加入2M鹽酸(300mL)，體系用乙酸乙酯(100mL x 3)萃取，有機相用飽和食鹽水(100mL x 2)洗滌，無水硫酸鈉(50g)乾燥。過濾，減壓蒸去溶劑，粗產品矽膠柱層析(石油醚/乙酸乙酯(v/v)=10/1)純化，得到黃色液體(9.02g,48.2%)。 4-Bromo-1-chloro-2-fluorobenzene (20.90 g, 100.0 mmol), acetamidineacetone (30 mL, 300.0 mmol) and dimethyl hydrazine (100 mL) were added to a 500 mL round bottom flask, and tripotassium phosphate was added. (63.70 g, 300.0 mmol) and cuprous iodide (3.00 g, 15.80 mmol) were heated to 110 ° C under nitrogen for 23 hours. After the reaction was completed, the mixture was cooled to room temperature, then 2M hydrochloric acid (300 mL) was evaporated, and ethyl acetate (100 mL x 3), and the organic phase was washed with saturated brine (100 mL x 2) and dried over anhydrous sodium sulfate (50 g). Filtration and evaporation of the solvent <RTI ID=0.0>: </RTI> EtOAc (EtOAc:EtOAc
在250mL兩口瓶中加入甲基溴化鎂(100mL,100.0mmol,1.0M四氫呋喃溶液)，氮氣保護下冷卻至0℃，緩慢滴加1-(4-氯-3-氟苯基)丙-2-酮(9.00g,48.20mmol)的四氫呋喃溶液(20mL)。滴加完，反應體系加熱至76℃反應12小時。冷卻至室溫，飽和氯化銨溶液(50mL)淬滅反應，溶液倒入水(200mL)中稀釋，體系用乙酸乙酯(100mL x 4)萃取，合併有機相，飽和食鹽水(100mL x 2)洗滌，無水硫酸鈉(50g)乾燥。過濾，減壓蒸去溶劑，粗產品矽膠柱層析(石油醚/乙酸乙酯(v/v)=8/1)純化，得到黃色液體(8.61g,88.2%)。 Add methyl magnesium bromide (100 mL, 100.0 mmol, 1.0 M tetrahydrofuran solution) to a 250 mL two-necked flask, cool to 0 ° C under nitrogen, and slowly add 1-(4-chloro-3-fluorophenyl)propane-2 a solution of ketone (9.00 g, 48.20 mmol) in tetrahydrofuran (20 mL). After the dropwise addition was completed, the reaction system was heated to 76 ° C for 12 hours. After cooling to room temperature, the reaction was quenched with a saturated aqueous solution of ammonium chloride (50 mL), and the mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL x 4), and the organic phase was combined with saturated brine (100 mL x 2) Washed and dried over anhydrous sodium sulfate (50 g). Filtration and evaporation of the solvent <RTI ID=0.0></RTI></RTI> <RTI ID=0.0></RTI>
在250mL圓底燒瓶中加入1-(4-氯-3-氟苯基)-2-甲基丙-2-醇(8.61g,42.50mmol)、乙腈(13mL,255.0mmol)和醋酸(80mL)，往體系中滴加硫酸(13mL)，滴加完，體系加熱至65℃反應5小時。反應畢，將混合物冷卻至室溫，倒進冰水(400mL)中，用氫氧化鈉調節pH>11，體系用乙酸乙酯(150mL x 3)萃取，有機相用飽和食鹽水(150mL x 2)洗滌，無水硫酸鈉(40g)乾燥。過濾，減壓蒸去溶劑，粗產品矽膠柱層析(石油醚/乙酸乙酯(v/v)=2/1)純化，得到黃色固體(4.38g,42.1%)。 Add 1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-ol (8.61 g, 42.50 mmol), acetonitrile (13 mL, 255.0 mmol) and acetic acid (80 mL) to a 250 mL round bottom flask. Sulfuric acid (13 mL) was added dropwise to the system, and the mixture was added dropwise, and the system was heated to 65 ° C for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, poured into ice water (400 mL), adjusted to pH >11 with sodium hydroxide, and extracted with ethyl acetate (150 mL x 3). Washed and dried over anhydrous sodium sulfate (40 g). Filtration and evaporation of EtOAc EtOAc (EtOAc)
MS(ESI，pos.ion)m/z：244.2(M+1)；C12H15ClFNO的計算精確品質：243.081H NMR(400MHz,CDCl3)δ 7.29(dd,J=10.7,5.2Hz,1H),6.94(dd,J=10.2,1.9Hz,1H),6.87(dd,J=8.1,1.5Hz,1H),5.21(s,1H),3.08(s,2H),1.95(s,3H),1.32(s,6H)。 MS (ESI, pos. ion) m/z: 244.2 (M + 1); C 12 H 15 ClFNO Calculated Accuracy: 243.08 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (dd, J = 10.7, 5.2 Hz , 1H), 6.94 (dd, J = 12.2, 1.9 Hz, 1H), 6.87 (dd, J = 8.1, 1.5 Hz, 1H), 5.21 (s, 1H), 3.08 (s, 2H), 1.95 (s, 3H), 1.32 (s, 6H).
在100mL圓底燒瓶中加入N-(1-(4-氯-3-氟苯基)-2-甲基丙-2-基)乙醯胺(3.36g,13.80mmol)和濃鹽酸(60mL)，體系加熱至120℃反應16.5小時。反應畢，將混合物冷卻至室溫，倒進冰水中，用氫氧化鈉調節pH>12，體系用乙酸乙酯(80mL x 5)萃取，有機相用飽和食鹽水(100mL x 2)洗滌，無水硫酸鈉(20g)乾燥。過濾，減壓蒸去溶劑，剩餘物再次溶於濃鹽酸(60mL)中，體系加熱至120℃反應20小時。反應畢，將混合物冷卻至室溫，加入水(100mL)，用乙酸乙酯(50mL x 3)洗滌，水相用氫氧化鈉調節pH>11，體系用乙酸乙酯(50mL x 3)萃取，有機相用飽和食鹽水(80 mL x 2)洗滌，無水硫酸鈉(20g)乾燥。過濾，減壓蒸去溶劑，粗產品經真空乾燥，得到黃色固體(0.484g,17.4%)。 Add N- (1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-yl)acetamide (3.36 g, 13.80 mmol) and concentrated hydrochloric acid (60 mL) to a 100 mL round bottom flask. The system was heated to 120 ° C for 16.5 hours. After completion of the reaction, the mixture was cooled to room temperature, poured into ice water, adjusted to pH > 12 with sodium hydroxide, the mixture was extracted with ethyl acetate (80 mL x 5), and the organic phase was washed with saturated brine (100 mL x 2) Sodium sulfate (20 g) was dried. Filtration, the solvent was evaporated under reduced pressure, and the residue was again dissolved in concentrated hydrochloric acid (60 mL), and the mixture was heated to 120 ° C for 20 hours. After completion of the reaction, the mixture was cooled to room temperature, water (100 mL) was added, washed with ethyl acetate (50 mL x 3), the aqueous phase was adjusted to pH <11> with sodium hydroxide, and the system was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with brine (80 mL×2) and dried over anhydrous sodium sulfate Filtration and evaporation of the solvent <RTI ID=0.0>
MS(ESI，pos.ion)m/z：202.1(M+1)；C10H13ClFN的計算精確品質：201.07 MS (ESI, pos.ion) m / z: 202.1 (M + 1); C 10 H 13 ClFN calculation Accurate quality: 201.07
在100mL圓底燒瓶中加入3-氯-4-氟硝基苯(421mg,2.40mmol)、1-(4-氯-3-氟苯基)-2-甲基丙-2-胺(484mg,2.40mmol)和二甲基亞碸(10mL)，氮氣保護下反應體系加熱至90℃反應3小時。冷卻至室溫，攪拌反應38.5小時。加熱至90℃繼續反應81.5小時。反應完畢，冷卻至室溫，加入水(80mL)，用乙酸乙酯(30mL x 3)萃取，有機相用飽和食鹽水(30mL x 2)洗滌，無水硫酸鈉(10g)乾燥。過濾，減壓蒸去溶劑，粗產品矽膠柱層析(石油醚/乙酸乙酯(v/v)=20/1)純化，得到黃色油狀物(490mg,57.2%)。 In a 100 mL round bottom flask was added 3-chloro-4-fluoronitrobenzene (421 mg, 2.40 mmol), 1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-amine (484 mg, 2.40 mmol) and dimethyl hydrazine (10 mL) were heated to 90 ° C for 3 hours under nitrogen atmosphere. After cooling to room temperature, the reaction was stirred for 38.5 hours. The reaction was continued for 81.5 hours by heating to 90 °C. After completion of the reaction, the mixture was cooled to room temperature, water (EtOAc) was evaporated, ethyl acetate (30mL, 3), and the organic phase was washed with saturated brine (30mL) and dried over anhydrous sodium sulfate (10g). Filtration and evaporation of EtOAc EtOAc (EtOAc)
MS(ESI，pos.ion)m/z：357.2(M+1)；C16H15Cl2FN2O2的計算精確品質：356.051H NMR(400MHz,CDCl3)δ 8.24(d,J=2.6Hz,1H),8.10(dd,J=9.2,2.6Hz,1H),7.34-7.26(m,1H),7.04-6.98(m,1H),6.86(dd,J=9.9,2.0Hz,1H),6.77(dd,J=8.2,1.5Hz,1H),5.00(s,1H),3.04(s,2H),1.48(s,6H)。 MS (ESI, pos. ion) m/z: 357.2 (M + 1); C 16 H 15 Cl 2 FN 2 O 2 Calculated Accuracy: 356.05 1 H NMR (400 MHz, CDCl 3 ) δ 8.24 (d, J = 2.6 Hz, 1H), 8.10 (dd, J = 9.2, 2.6 Hz, 1H), 7.34-7.26 (m, 1H), 7.04-6.98 (m, 1H), 6.86 (dd, J = 9.9, 2.0 Hz, 1H), 6.77 (dd, J = 8.2, 1.5 Hz, 1H), 5.00 (s, 1H), 3.04 (s, 2H), 1.48 (s, 6H).
在100mL圓底燒瓶中加入20mL水和鐵粉(697mg,12.50mmol)，往體系中滴加濃鹽酸(0.2mL)，攪拌下加熱至65℃活化鐵粉15分鐘，然後傾去水層，將2-氯-N-(1-(4-氯-3-氟苯基)-2-甲基丙-2-基)-4-硝基苯胺(446mg,1.25mmol)溶於甲醇(20mL)的溶液加入上述鐵粉中，用鹽酸調pH 2~3，加熱至65℃反應20分鐘。反應畢，將混合物冷卻至室溫並用三乙胺調節pH 11，過濾，減壓蒸去溶劑，剩餘物溶於乙酸乙酯(100mL)，依次用水(30mL x 3)，飽和食鹽水(30mL x 2)洗滌，無水硫酸鈉(10g)乾燥。過濾，減壓蒸去溶液，粗品未經進一步純化直接用於下一步反應。 20 mL of water and iron powder (697 mg, 12.50 mmol) were added to a 100 mL round bottom flask, concentrated hydrochloric acid (0.2 mL) was added dropwise to the system, and the iron powder was heated to 65 ° C for 15 minutes with stirring, and then the aqueous layer was decanted. 2-Chloro- N- (1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-yl)-4-nitroaniline (446 mg, 1.25 mmol) dissolved in methanol (20 mL) The solution was added to the above iron powder, adjusted to pH 2 to 3 with hydrochloric acid, and heated to 65 ° C for 20 minutes. After completion of the reaction, the mixture was cooled to room temperature and adjusted to pH 11 with triethylamine, filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), and then water (30mL x 3), saturated brine (30mL) 2) Washed and dried over anhydrous sodium sulfate (10 g). Filtration and evaporation of the solution under reduced pressure.
MS(ESI，pos.ion)m/z：327.1(M+1)；C16H17Cl2FN2的計算精確品質：326.08 MS (ESI, pos. ion) m/z: 327.1 (M + 1); C 16 H 17 Cl 2 FN 2 Calculated Accuracy: 326.08
在氮氣保護下，2-氯-N 1-(1-(4-氯-3-氟苯基)-2-甲基丙-2-基)苯-1,4-二胺(408mg,1.25mmol)溶於15mL甲苯中，小心地滴加三甲基鋁(2.5mL,5.00mmol,2.0M甲苯溶液)，滴加完畢，室溫繼續攪拌30分鐘。滴加溶於5mL 甲苯的3-(N-乙醯基氨基)巴豆酸甲酯(295mg,1.88mmol)，滴加完畢，繼續室溫攪拌22小時。補加三甲基鋁(2.0mL,4.00mmol,2.0M甲苯溶液)，攪拌30分鐘，補加溶於甲苯(3mL)的3-(N-乙醯基氨基)巴豆酸甲酯(295mg,1.88mmol)，室溫下繼續反應18小時。飽和氯化銨溶液(50mL)淬滅反應，過濾，濾液分出有機相，水相用乙酸乙酯(30mL x 3)萃取，合併有機相，飽和食鹽水(30mL x 2)洗滌，經無水硫酸鈉(15g)乾燥後，減壓蒸去溶劑，粗產品矽膠柱層析(石油醚/乙酸乙酯(v/v)=2/3)純化，得到黃色固體(183mg,33.7%)。 2-Chloro- N 1 -(1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-yl)benzene-1,4-diamine (408 mg, 1.25 mmol) under N2 Dissolved in 15 mL of toluene, carefully added trimethylaluminum (2.5 mL, 5.00 mmol, 2.0 M solution in toluene), and the mixture was stirred at room temperature for 30 minutes. Methyl 3-( N -ethylmercaptoamino)crotonate (295 mg, 1.88 mmol) dissolved in 5 mL of toluene was added dropwise, and the mixture was stirred at room temperature for 22 hours. Add trimethylaluminum (2.0 mL, 4.00 mmol, 2.0 M solution in toluene), stir for 30 minutes, and add methyl 3-( N -ethylmercaptoamino)crotonate dissolved in toluene (3 mL) (295 mg, 1.88) Methyl) The reaction was continued for 18 hours at room temperature. The reaction was quenched with a saturated aqueous solution of ammonium chloride (50 mL), filtered, and the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was combined and washed with saturated brine (30 mL x 2) After the sodium (15 g) was dried, EtOAcjjjjjjjjj
MS(ESI，pos.ion)m/z：434.2(M+1)；C22H22Cl2FN3O的計算精確品質：433.111H NMR(400MHz,CDCl3)δ 7.31(t,J=8.0Hz,1H),7.16(d,J=2.5Hz,1H),7.11(d,J=8.7Hz,1H),6.98(dd,J=8.7,2.5Hz,1H),6.90(dd,J=10.1,1.9Hz,1H),6.83(dd,J=8.2,1.5Hz,1H),6.30(d,J=9.9Hz,1H),4.48(s,1H),3.01(dd,J=32.3,13.6Hz,2H),2.33(s,3H),2.27(s,3H),1.44(s,3H),1.42(s,3H)。 MS (ESI, pos. ion) m/z: 434.2 (M + 1); C 22 H 22 Cl 2 FN 3 O Calculated Accuracy: 433.11 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 2.5 Hz, 1H), 7.11 (d, J = 8.7 Hz, 1H), 6.98 (dd, J = 8.7, 2.5 Hz, 1H), 6.90 (dd, J = 10.1, 1.9 Hz, 1H), 6.83 (dd, J = 8.2, 1.5 Hz, 1H), 6.30 (d, J = 9.9 Hz, 1H), 4.48 (s, 1H), 3.01 (dd, J = 32.3, 13.6) Hz, 2H), 2.33 (s, 3H), 2.27 (s, 3H), 1.44 (s, 3H), 1.42 (s, 3H).
取指數生長期的BHK-21細胞，待細胞生長融合85~95%時，常規傳代方法消化收集細胞，細胞計數，調整細胞密度至2×104個/mL，接種于96孔細胞培養板中，100μl/孔，在37℃，5% CO2條件下孵育。 Take BHK-21 cells in the exponential growth phase. When the cell growth is 85~95%, the cells are collected by conventional passage method, the cells are counted, the cell density is adjusted to 2×10 4 cells/mL, and the cells are seeded in a 96-well cell culture plate. In 100 μl/well, incubate at 37 ° C, 5% CO 2 .
待細胞接種貼壁24h後，棄上清，換含上述配製的各化合物濃度梯度的培養液100μl/孔，每個濃度組3個複孔，加藥後繼續培養48h。 After the cells were inoculated for 24 hours, the supernatant was discarded, and 100 μl/well of the culture solution containing the concentration gradient of each compound prepared above was used, and 3 replicate wells of each concentration group were further cultured for 48 hours.
加藥48h後，每孔加入10μl(培養液體積的1/10)CCK-8溶液，培養箱中孵育2h後，酶標儀450nm處檢測各孔的吸光度(A)值。根據所測A值計算每個化合物的細胞增殖抑制率，細胞增殖抑制率(inhibition ratio,IR)=(1-實驗組(Ai)值/對照組(Ao)值)×100%，資料處理軟體分別計算各化合物在48h的IC50值。 After 48 hours of dosing, 10 μl (1/10 of the volume of the culture solution) of CCK-8 solution was added to each well, and after incubating for 2 hours in the incubator, the absorbance (A) value of each well was measured at 450 nm. The cell proliferation inhibition rate of each compound was calculated according to the measured A value, and the inhibition ratio (IR) = (1 - experimental group (A i ) value / control group (A o ) value) × 100%, data The processing software calculates the IC 50 value of each compound at 48 h.
表2 活性數據
器官纖維化的共同特徵是細胞外基質(ECM)過度沉積，器官組織結構改建，其中許多細胞因數參與了這一過程。經過體外細胞實驗篩選，本發明中大部分化合物活性高於吡非尼酮，部分化合物的體外活性可以達到吡非尼酮的20倍以上；且本發明中的化合物可以避免吡非尼酮產生的光毒性反應，在抗纖維化方面具有很好的應用前景。 A common feature of organ fibrosis is the excessive deposition of extracellular matrix (ECM) and the alteration of organ structure, many of which are involved in this process. After in vitro cell assay screening, most of the compounds in the present invention have higher activity than pirfenidone, and some compounds can achieve 20 times more activity than pirfenidone; and the compounds of the present invention can avoid the production of pirfenidone. Phototoxic reaction has a good application prospect in anti-fibrosis.
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