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标题:Design, synthesis and biological evaluation of pyridone–aminal derivatives as MNK1/2 inhibitors
时间:2020-07-07 13:30:29
DOI:10.1016/j.bmc.2019.02.007
大小:4399 kb
页数:16 PAGES
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目录:
  • Design, synthesis and biological evaluation of pyridone–aminal derivatives as MNK1/2 inhibitors
    • Introduction
    • Results and discussion
      • Chemistry
      • In vitro enzymatic inhibitory activities
      • Anti-proliferative effects against cancer cell lines
      • Western Blot assay and selectivity profiling of compound 42i
      • In vivo antitumor efficacy of compound 42i
    • Conclusion
    • Experimental section
      • Chemistry
        • General synthetic procedures
        • 4.1.1.1 General procedure A
        • 4.1.1.2 General procedure B
        • 4.1.1.3 General procedure C
        • 4.1.1.4 General procedure D
        • Synthesis of 5-bromo-3-methylpicolinonitrile (6)
        • Synthesis of ethyl 5-bromo-3-methylpicolinate (8)
        • Synthesis of 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (11)
        • Synthesis of 6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (12)
        • Synthesis of targets 13a–i
        • 8′-methyl-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (13a)
        • 8′-methyl-6′-(pyridin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (13b)
        • 8′-methyl-6′-(pyridin-2-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (13c)
        • 8′-methyl-6′-(pyridin-3-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (13d).
        • 8′-methyl-6′-(pyrimidin-2-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (13e).
        • 8′-methyl-6′-(pyrazin-2-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (13f).
        • 8′-methyl-6′-(pyridazine-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (13g).
        • 8′-methyl-6′-(pyridazin-3-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (13h).
        • 8′-methyl-6′-((6-methylpyridin-2-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (13i).
        • 8′-methyl-6′-((2-methylpyridin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (13j)
        • 8′-methyl-6′-((3-methylpyridin-2-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (13k).
        • Synthesis of intermediate 17a–17d
        • (4-azidopyridin-2-yl)-bis-carbamic acid tert-butyl ester (16a).
        • (4-aminopyridin-2-yl)-bis-carbamic acid tert-butyl ester (17a).
        • (2-azidopyridin-4-yl)-bis-carbamic acid tert-butyl ester (16b).
        • (2-aminopyridin-4-yl)-bis-carbamic acid tert-butyl ester (17b).
        • (4-azidopyrimidin-2-yl)-bis-carbamic acid tert-butyl ester (16c).
        • (4-aminopyrimidin-2-yl)-bis-carbamic acid tert-butyl ester (17c).
        • (2-azidopyrimidin-4-yl)-bis-carbamic acid tert-butyl ester (16d).
        • (2-aminopyrimidin-4-yl)-bis-carbamic acid tert-butyl ester (17d).
        • Synthesis of targets 19a–19d
        • 8′-methyl-6′-(2-(N,N-diBoc-amino)-pyridin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (18a)
        • 8′-methyl-6′-(2-aminopyridin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (19a)
        • 8′-methyl-6′-(4-(N,N-diBoc-amino)-pyridin-2-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (18b)
        • 8′-methyl-6′-(4-aminopyridin-2-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (19b)
        • 8′-methyl-6′-(2-(N,N-diBoc-amino)-pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (18c)
        • 8′-methyl-6′-(4-aminopyridin-2-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (19c)
        • 8′-methyl-6′-(4-(N,N-diBoc-amino)-pyrimidin-2-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (18d)
        • 8′-methyl-6′-(4-aminopyridin-2-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (19d)
        • Synthesis of (6-chloropyrazin-2-yl)-bis-carbamic acid tert-butyl ester (21)
        • Synthesis of (6-(cyclopropanecarboxamido)pyrazine-2-yl)- bis-carbamic acid tert-butyl ester (22)
        • Synthesis of N-(6-aminopyrazin-2-yl)cyclopropanecarboxamide (23)
        • Synthesis of target 8′-methyl-6′-(6-aminopyrazin-2-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo [1,5-a]pyridine]-1′,5′-dione (25)
        • Synthesis of methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (27)
        • Synthesis of 1-methyl-4-nitro-1H-pyrazole-3-carboxamide (28)
        • Synthesis of 1-methyl-4-nitro-1H-pyrazole-3-carbonitrile (29)
        • Synthesis of 4-amino-1-methyl-1H-pyrazole-3-carbonitrile (30)
        • Synthesis of (1-methyl-4-nitro-1H-pyrazol-3-yl)methanol (31)
        • Synthesis of 1-methyl-4-nitro-1H-pyrazole-3-carbaldehyde (32)
        • Synthesis of 3-(difluoromethyl)-1-methyl-4-nitro-1H-pyrazole (33)
        • Synthesis of 3-(difluoromethyl)-1-methyl-1H-pyrazol-4-amine (34)
        • Synthesis of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (35)
        • Synthesis of (1-methyl-4-nitro-1H-pyrazole-3-yl)-bis-carbamic acid tert-butyl ester (36)
        • Synthesis of (1-methyl-4-amino-1H-pyrazole-3-yl)-bis-carbamic acid tert-butyl ester (37)
        • Synthesis of 38a–38b and 39
        • Synthesis of 1-methyl-4-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)-1H-pyrazole-3-carbonitrile (38a).
        • Synthesis of 6′-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (38b).
        • Synthesis of 6′-((3-(N,N-diBoc-amino)-1-methyl-1H-pyrazol-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (38c).
        • Synthesis of 6′-((3-amino-1-methyl-1H-pyrazol-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (39).
        • Synthesis of 41a–41g
        • Synthesis of 6-morpholinopyrimidin-4-amine (41a)
        • Synthesis of 6-(piperidin-1-yl)pyrimidin-4-amine (41b)
        • Synthesis of tert-butyl 4-((6-aminopyrimidin-4-yl)amino)piperidine-1-carboxylate (41c)
        • Synthesis of tert-butyl (1-(6-aminopyrimidin-4-yl)piperidin-4-yl)carbamate (41d)
        • Synthesis of tert-butyl 4-(6-aminopyrimidin-4-yl)piperazine-1-carboxylate (41e)
        • Synthesis of 6-(4-methylpiperazin-1-yl)pyrimidin-4-amine (41f)
        • Synthesis of 6-(4-acetylpiperazin-1-yl)pyrimidin-4-amine (41g)
        • Synthesis of 6-(4-(3-(dimethylamino)ethyl)piperazin-1-yl)pyrimidin-4-amine (41h)
        • Synthesis of 6-(4-(3-(dimethylamino)propyl)piperazin-1-yl)pyrimidin-4-amine (41i)
        • Synthesis of 42a-42i
        • Synthesis of 8′-methyl-6′-((6-morpholinopyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (42a)
        • Synthesis of 8′-methyl-6′-((6-(piperidin-1-yl)pyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (42b)
        • Synthesis of tert-butyl 4-((6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate (42c)
        • Synthesis of tert-butyl 4-((6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylate (42d)
        • Synthesis of tert-butyl 4-(6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)piperazine-1-carboxylate (42e)
        • Synthesis of 8′-methyl-6′-((6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (42f)
        • Synthesis of 8′-methyl-6′-((6-(4-acetylpiperazin-1-yl)pyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (42g)
        • Synthesis of 6′-((6-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)pyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (42h)
        • Synthesis of 6′-((6-(4-(3-(dimethylamino)propyl)piperazin-1-yl)pyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (42i)
        • Synthesis of 43a–43c
        • Synthesis of 8′-methyl-6′-((6-(piperidin-4-ylamino)pyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione 43a
        • Synthesis of 6′-((6-(4-aminopiperidin-1-yl)pyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione 43b
        • Synthesis of 8′-methyl-6′-((6-(piperazin-1-yl)pyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione 43c
      • Enzyme activity using ADP-Glo™ kinase assay kit
      • Enzyme activity using HTRF method
      • Cell line culture
      • MTT assay
      • Western Blot analysis
      • In vivo antitumor activity assay
      • Docking studies
    • Acknowledgements
    • Supplementary data
    • References

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