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No.	Yield /%	mp/℃ (Dec.)	¹H NMR	¹³C NMR	HR-ESI-MS m/z
3a	33	125.3-126.9	¹H NMR (DMSO-d₆) δ 12.29 (s, 1H), 8.09 (d, J = 6.6 Hz, 2H), 7.53 (s, 1H), 7.52 (s, 2H), 7.34 (s, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.97 (s, 1H), 6.96 (s, 1H), 3.95 (s, 5H), 3.86 (s, 3H), 3.82 (s, 3H), 3.00 (t, J = 5.4 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 156.5, 150.3, 150.2, 148.6, 148.5, 135.8, 130.2, 128.9 (4), 128.1 (2), 127.7, 126.8, 121.9, 120.9, 114.5, 114.1, 111.2, 108.5, 106.7, 96.6, 56.5, 56.4, 56.1, 43.1, 27.5	C₂₈H₂₅N₂O₃Cl [M-Cl]⁺: 437.186 0, Found: 437.186 7
3b	47	180.7-183.2	¹H NMR (DMSO-d₆) δ 12.14 (s, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.52-7.32 (m, 4H), 7.01 (s, 1H), 6.97 (s, 1H), 4.24 (t, J = 6.0 Hz, 2H), 4.05 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.04 (t, J = 6.0 Hz, 2H), 2.45 (s, 3H)	¹³C NMR (DMSO-d₆) δ 153.6, 151.1, 150.4, 148.3, 143.4, 141.7, 135.8, 129.8, 129.2 (2), 128.9, 128.6 (2), 127.5, 126.6, 120.4, 119.5, 117.0 (2), 110.7, 109.4, 108.4, 98.4, 56.7, 56.0, 55.7, 44.5, 26.5, 21.0	C₂₉H₂₇N₂O₃Cl [M-Cl]⁺: 451.201 6, Found: 451.201 8
3c	45	186.9-189.0	¹H NMR (DMSO-d₆) δ 12.61 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 7.8, 1.8 Hz, 1H), 6.99 (s, 1H), 6.78 (s, 1H), 4.14 (t, J = 6.0 Hz, 2H), 4.00 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 3.02 (t, J = 6.0 Hz, 2H), 2.39 (s, 3H), 2.34 (s, 3H)	¹³C NMR (DMSO-d₆) δ 154.6, 151.1, 150.4, 148.3, 143.4, 140.0, 136.1, 135.7, 131.0, 130.9, 129.4, 128.9, 127.5, 126.7, 126.3, 120.4, 119.6, 116.9 (2), 110.7, 109.4, 108.4, 100.4, 56.6, 56.0, 55.7, 44.4, 26.5, 20.8, 19.5	C₃₀H₂₉N₂O₃Cl [M-Cl]⁺: 465.217 3, Found: 465.216 0
3d	36	183.1-185.3	¹H NMR (DMSO-d₆) δ 12.09 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.67-7.62 (m, 2H), 7.44 (d, J = 9.6 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 4.24 (t, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.06 (t, J = 6.0 Hz, 2H), 2.37 (s, 3H), 2.36 (s, 3H)	¹³C NMR (DMSO-d₆) δ 153.7, 151.1, 150.4, 148.3, 143.4, 140.5, 136.7, 135.8, 130.0, 129.6, 129.3, 128.8, 127.5, 126.6, 126.1, 120.4, 119.4, 117.0 (2), 110.8, 109.3, 108.4, 98.3, 56.7, 55.97, 55.8, 44.4, 26.5, 19.4, 19.3	C₃₀H₂₉N₂O₃Cl [M-Cl]⁺: 465.217 3, Found: 465.217 7
3e	53	190.6-193.4	¹H NMR (DMSO-d₆) δ 11.99 (s, 1H), 7.70 (s, 1H), 7.670 (s, 1H), 7.54-7.30 (m, 4H), 7.15 (s, 1H), 6.98 (s, 1H), 6.98 (s, 1H), 4.23 (s, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.86 (s, 6H), 3.82 (s, 3H), 3.04 (s, 2H)	¹³C NMR (DMSO-d₆) δ 152.9, 151.2, 150.5, 149.8, 147.9, 147.7, 142.8, 135.2, 128.3, 126.9, 126.0, 124.3, 121.7, 119.9, 118.8, 116.6 (2), 111.7, 111.1, 110.4, 108.9, 107.9, 97.7, 56.7, 55.9, 55.9, 55.8, 55.6, 44.2, 26.2	C₃₀H₂₉N₂O₅Cl [M-Cl]⁺: 497.207 1, Found: 497.2071
3f	43	192.2-193.9	¹H NMR (DMSO-d₆) δ 8.22 (d, J = 8.4 Hz, 2H), 7.55 (dt, J = 7.8, 2.4 Hz, 2H), 7.31 (s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.02-6.84 (m, 4H), 3.92 (s, 3H), 3.86 (s, 5H), 3.82 (s, 3H), 2.99 (t, J = 6.0 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 155.5, 149.6, 149.4, 149.2, 148.0, 140.1, 138.2, 135.1, 133.8, 128.8 (2), 128.2 (2), 127.0, 126.2, 121.7, 120.7, 113.1, 112.5, 110.8, 108.0, 105.1, 94.9, 55.9, 55.8, 55.6, 42.0, 27.2	C₂₈H₂₄N₂O₃Cl₂ [M-Cl]⁺: 471.147 0, Found: 471.147 5
3g	34	207.3-209.4	¹H NMR (DMSO-d₆) δ 12.34 (s, 1H), 7.90-7.81 (m, 4H), 7.76 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.01 (d, J = 4.8 Hz, 2H), 4.24 (t, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.05 (t, J = 6.0 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 152.7, 151.2, 150.5, 148.3, 143.4, 135.8, 131.9, 131.5 (2), 130.8 (2), 129.0, 127.5, 126.7, 125.1, 120.4, 119.6, 117.1 (2), 110.8, 109.7, 108.4, 99.0, 56.7, 56.0, 55.7, 44.6, 26.4	C₂₈H₂₄N₂O₃BrCl [M-Cl]⁺: 515.096 5, Found: 515.095 3
3h	39	174.9-177.1	¹H NMR (DMSO-d₆) δ 12.46 (s, 1H), 8.40 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.80 (dt, J = 8.4, 3.0 Hz, 1H), 7.73 (dd, J = 9.0, 3.0 Hz, 1H), 7.65 (d, J = 3.0 Hz, 1H), 7.44 (dd, J = 9.0, 3.0 Hz, 1H), 7.38 (d, J = 3.0 Hz, 1H), 7.05 (d, J = 3.0 Hz, 1H), 6.99 (d, J = 3.0 Hz, 1H), 4.25 (d, J = 6.6 Hz, 2H), 4.06 (d, J = 3.0 Hz, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.05 (d, J = 6.6 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 151.7, 151.1, 150.4, 148.3, 143.5, 135.7, 134.6, 133.7, 133.6, 132.7, 129.6, 129.1, 127.4, 126.7, 120.3, 119.7, 118.2, 117.1, 117.1, 111.5, 110.7, 109.8, 108.3, 99.4, 56.7, 56.0, 55.7, 44.6, 26.4	C₂₉H₂₄N₃O₃Cl [M-Cl]⁺: 462.181 2, Found: 462.181 4
3i	42	228.3-230.3	¹H NMR (DMSO-d₆) δ 8.43-8.35 (m, 2H), 8.01-7.91 (m, 2H), 7.32 (s, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.06 (s, 1H), 6.96 (d, J = 3.6 Hz, 2H), 6.92 (d, J = 7.8 Hz, 1H), 3.93 (s, 3H), 3.90-3.84 (m, 5H), 3.82 (s, 3H), 3.00 (t, J = 6.0 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 154.9, 149.7, 149.5, 149.3, 148.0, 143.9, 135.1, 132.3 (2), 129.6, 127.8 (2), 127.1, 126.2, 121.6, 121.0, 118.9, 113.3, 112.5, 111.3, 110.8, 108.0, 105.2, 95.4, 55.9, 55.8, 55.6, 42.0, 27.2	C₂₉H₂₄N₃O₃Cl [M-Cl]⁺: 462.181 2, Found: 462.181 5
3j	48	234.0-236.2	¹H NMR (CDCl₃, CD₃OD) δ 7.90 (dd, J = 1.2, 0.6 Hz, 1H), 7.71 (dd, J = 3.6, 0.6 Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 7.08 (s, 1H), 6.90 (s, 1H), 6.80 (dd, J = 3.6, 1.8 Hz, 1H), 4.24 (t, J = 6.0 Hz, 2H), 4.17 (s, 3H), 3.99 (s, 3H), 3.96 (s, 3H), 3.15 (t, J = 6.0 Hz, 2H)	¹³C NMR (CDCl₃, CD₃OD) δ 152.4, 152.0, 149.7, 147.8, 145. 8, 144.2, 143.2, 137.2, 128.7, 128.2, 127.7, 121.5, 120.4, 118.6, 117.3, 116.3, 114.2, 111.1, 110.6, 109.0, 94.6, 57.1, 56.8, 56.5, 45.8, 27.9	C₂₆H₂₃N₂O₄Cl [M-Cl]⁺: 427.165 2, Found: 427.166 3
3k	41	206.8-209.1	¹H NMR (DMSO-d₆) δ 12.77 (s, 1H), 11.19 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 7.34-7.27 (m, 2H), 7.14 (s, 1H), 6.99 (s, 1H), 6.36 (s, 1H), 4.19 (t, J = 5.4Hz, 2H), 4.04 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.05 (t, J = 5.4 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 163.5, 151.0, 150.8, 148.7, 145.6, 136.2, 127.9, 126.8, 125.8, 121.1, 118.9 (2), 117.2, 117.0, 115.4, 111.2, 111.2, 108.7, 108.7, 108.5, 94.2, 57.1, 56.4, 56.1, 44.7, 27.0	C₂₆H₂₄N₃O₃Cl [M-Cl]⁺: 426.181 2, Found: 426.182 0
3l	35	167.1-169.3	¹H NMR (DMSO-d₆) δ 8.23 (d, J = 9.6 Hz, 2H), 7.71 (s, 1H), 7.66 (s, 1H), 7.40 (s, 2H), 7.32 (s, 1H), 7.01 (s, 1H), 4.24 (s, 2H), 4.06 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.06 (s, 2H)	¹³C NMR (DMSO-d₆) δ 151.1, 150.3, 148.1, 146.9, 144.3, 135.9, 127.3, 126.7 126.2, 126.1, 120.2, 120.0, 117.0, 116.8, 116.7, 110.6, 110.1, 108.2, 99.4, 97.4, 56.7, 55.9, 55.6, 44.7, 26.3	C₂₅H₂₂N₃O₃SCl [M-Cl]⁺: 444.137 6, Found: 444.137 7
3m	53	186.7-189.2	¹H NMR (CD₃OD) δ 7.68 (d, J = 8.4 Hz, 1H), 7.51-7.45 (m, 2H), 7.33 (s, 1H), 6.86 (s, 1H), 6.72 (s, 1H), 4.15-4.09 (m, 5H), 3.96 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.09 (t, J = 6.0 Hz, 2H), 2.53 (s, 3H), 2.48 (s, 3H)	¹³C NMR (CD₃OD) δ 153.2, 152.6, 150.3, 147.6, 147.0, 145.2, 144.4, 137.6, 130.5, 129.0, 128.5, 122.2, 121.3, 118.8, 117.6, 114.7, 111.7, 111.2, 109.7, 101.6, 57.4, 57.0, 56.5, 46.3, 36.4, 28.2, 11.6, 10.5	C₂₈H₂₉N₄O₃Cl [M-Cl]⁺: 469.223 4, Found: 469.223 8
3n	34	150.3-151.9	¹H NMR (CD₃OD) δ 7.68 (d, J = 8.4 Hz, 1H), 7.51-7.45 (m, 2H), 7.34 (s, 1H), 6.87 (s, 1H), 6.72 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.17-4.08 (s, 5H), 3.89 (s, 3H), 3.86 (s, 3H), 3.09 (t, J = 6.0 Hz, 2H), 2.54 (s, 3H), 2.48 (s, 3H), 1.50 (t, J = 6.6 Hz, 3H)	¹³C NMR (CD₃OD) δ 153.2, 152.6, 150.3, 147.8, 147.4, 145.2, 143.3, 137.7, 130.5, 129.0, 128.5, 122.2, 121.3, 118.8, 117.6, 114.7, 111.7, 111.2, 109.7, 101.6, 57.4, 57.0, 56.6, 46.3, 45.4, 28.2, 15.3, 11.7, 10.4	C₂₉H₃₁N₄O₃Cl [M-Cl]⁺: 483.239 1, Found: 483.239 9
3o	31	188.7-191.2	¹H NMR (DMSO-d₆) δ 8.55 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.34-7.21 (m, 3H), 7.14 (s, 1H), 6.80 (s, 1H), 4.18 (t, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.05 (t, J = 6.0 Hz, 2H), 2.44 (s, 3H)	¹³C NMR (DMSO-d₆) δ 153.5, 152.7, 151.3, 150.3, 148.9, 144.8, 144.4, 139.8, 139.4, 137.9, 128.9, 128.3, 123.0, 121.8, 121.4, 118.6, 117.6, 111.6, 111.3, 109.6, 101.4, 96.2, 57.5, 57.0, 56.6, 46.5, 28.1, 18.5	C₂₈H₂₆N₃O₃Cl [M-Cl]⁺: 452.196 9, Found: 452.194 8
3p	35	187.1-188.9	¹H NMR (CDCl₃, CD₃OD) δ 9.71 (d, J = 1.2 Hz, 1H), 8.95-8.90 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 6.94 (s, 1H), 4.39 (t, J = 6.0 Hz, 2H), 4.22 (s, 3H), 4.01 (s, 3H), 3.98 (s, 3H), 3.20 (t, J = 6.0 Hz, 2H)	¹³C NMR (CDCl₃, CD₃OD) δ 153.1, 152.2, 149.9, 148.2, 146.6, 145.0, 144.1 (2), 143.5, 137.8, 128.8, 128.3, 128.0, 121.7, 121.4, 118.7, 117.7, 111.9, 111.2, 109.1, 97.2, 57.3, 56.9, 56.6, 46.3, 27.9	C₂₆H₂₃N₄O₃Cl [M-Cl]⁺: 439.176 5, Found: 439.176 7
3q	36	208.1-210.2	¹H NMR (DMSO-d₆) δ 12.79 (s, 1H), 9.42 (s, 1H), 9.27 (s, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.43 (s, 1H), 7.19 (s, 1H), 7.01 (s, 1H), 4.25 (s, 2H), 4.08 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.06 (s, 2H)	¹³C NMR (DMSO-d₆) δ 160.3, 157.3 (3), 151.6, 150.9, 149.2, 148.8, 143.9, 136.3, 129.7, 128.0, 127.7, 127.3, 120.8, 120.4, 117.7, 111.2, 110.6, 108.8, 100.6, 57.3, 56.5, 56.2, 45.2, 26.9	C₂₆H₂₃N₄O₃Cl [M-Cl]⁺: 439.176 5, Found: 439.176 9
3r	42	200.0-201.9	¹H NMR (CDCl₃, CD₃OD) δ 8.20 (s, 1H), 7.95 (d, J = 5.4 Hz, 1H), 7.60 (d, J = 3.6 Hz, 1H), 7.57 (d, J = 6.0 Hz, 1H), 7.42 (s, 1H), 7.39-7.33 (m, 2H), 7.29 (s, 1H), 7.25 (s, 1H), 6.92 (s, 1H), 6.89 (s, 1H), 4.18 (s, 5H), 4.00 (s, 3H), 3.97 (s, 3H), 3.18 (s, 2H)	¹³C NMR (CDCl₃, CD₃OD) δ 152.2, 151.8, 150.9, 149.6, 144.2, 138.1, 137.1, 130.0, 129.2, 128.0, 127.4, 124.8, 124.1, 122.8, 121.8, 119.7, 119.0, 118.1, 116.5, 113.7, 111.1, 109.4, 109.3, 109.0, 96.1, 57.2, 56.9, 56.5, 45.5, 28.1	C₃₀H₂₆N₃O₃Cl [M-Cl]⁺: 476.196 9, Found: 476.197 3

No.	Yield /%	mp/℃ (Dec.)	¹H NMR	¹³C NMR	HR-ESI-MS m/z
3a	33	125.3-126.9	¹H NMR (DMSO-d₆) δ 12.29 (s, 1H), 8.09 (d, J = 6.6 Hz, 2H), 7.53 (s, 1H), 7.52 (s, 2H), 7.34 (s, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.97 (s, 1H), 6.96 (s, 1H), 3.95 (s, 5H), 3.86 (s, 3H), 3.82 (s, 3H), 3.00 (t, J = 5.4 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 156.5, 150.3, 150.2, 148.6, 148.5, 135.8, 130.2, 128.9 (4), 128.1 (2), 127.7, 126.8, 121.9, 120.9, 114.5, 114.1, 111.2, 108.5, 106.7, 96.6, 56.5, 56.4, 56.1, 43.1, 27.5	C₂₈H₂₅N₂O₃Cl [M-Cl]⁺: 437.186 0, Found: 437.186 7
3b	47	180.7-183.2	¹H NMR (DMSO-d₆) δ 12.14 (s, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.52-7.32 (m, 4H), 7.01 (s, 1H), 6.97 (s, 1H), 4.24 (t, J = 6.0 Hz, 2H), 4.05 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.04 (t, J = 6.0 Hz, 2H), 2.45 (s, 3H)	¹³C NMR (DMSO-d₆) δ 153.6, 151.1, 150.4, 148.3, 143.4, 141.7, 135.8, 129.8, 129.2 (2), 128.9, 128.6 (2), 127.5, 126.6, 120.4, 119.5, 117.0 (2), 110.7, 109.4, 108.4, 98.4, 56.7, 56.0, 55.7, 44.5, 26.5, 21.0	C₂₉H₂₇N₂O₃Cl [M-Cl]⁺: 451.201 6, Found: 451.201 8
3c	45	186.9-189.0	¹H NMR (DMSO-d₆) δ 12.61 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 7.8, 1.8 Hz, 1H), 6.99 (s, 1H), 6.78 (s, 1H), 4.14 (t, J = 6.0 Hz, 2H), 4.00 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 3.02 (t, J = 6.0 Hz, 2H), 2.39 (s, 3H), 2.34 (s, 3H)	¹³C NMR (DMSO-d₆) δ 154.6, 151.1, 150.4, 148.3, 143.4, 140.0, 136.1, 135.7, 131.0, 130.9, 129.4, 128.9, 127.5, 126.7, 126.3, 120.4, 119.6, 116.9 (2), 110.7, 109.4, 108.4, 100.4, 56.6, 56.0, 55.7, 44.4, 26.5, 20.8, 19.5	C₃₀H₂₉N₂O₃Cl [M-Cl]⁺: 465.217 3, Found: 465.216 0
3d	36	183.1-185.3	¹H NMR (DMSO-d₆) δ 12.09 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.67-7.62 (m, 2H), 7.44 (d, J = 9.6 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 4.24 (t, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.06 (t, J = 6.0 Hz, 2H), 2.37 (s, 3H), 2.36 (s, 3H)	¹³C NMR (DMSO-d₆) δ 153.7, 151.1, 150.4, 148.3, 143.4, 140.5, 136.7, 135.8, 130.0, 129.6, 129.3, 128.8, 127.5, 126.6, 126.1, 120.4, 119.4, 117.0 (2), 110.8, 109.3, 108.4, 98.3, 56.7, 55.97, 55.8, 44.4, 26.5, 19.4, 19.3	C₃₀H₂₉N₂O₃Cl [M-Cl]⁺: 465.217 3, Found: 465.217 7
3e	53	190.6-193.4	¹H NMR (DMSO-d₆) δ 11.99 (s, 1H), 7.70 (s, 1H), 7.670 (s, 1H), 7.54-7.30 (m, 4H), 7.15 (s, 1H), 6.98 (s, 1H), 6.98 (s, 1H), 4.23 (s, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.86 (s, 6H), 3.82 (s, 3H), 3.04 (s, 2H)	¹³C NMR (DMSO-d₆) δ 152.9, 151.2, 150.5, 149.8, 147.9, 147.7, 142.8, 135.2, 128.3, 126.9, 126.0, 124.3, 121.7, 119.9, 118.8, 116.6 (2), 111.7, 111.1, 110.4, 108.9, 107.9, 97.7, 56.7, 55.9, 55.9, 55.8, 55.6, 44.2, 26.2	C₃₀H₂₉N₂O₅Cl [M-Cl]⁺: 497.207 1, Found: 497.2071
3f	43	192.2-193.9	¹H NMR (DMSO-d₆) δ 8.22 (d, J = 8.4 Hz, 2H), 7.55 (dt, J = 7.8, 2.4 Hz, 2H), 7.31 (s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.02-6.84 (m, 4H), 3.92 (s, 3H), 3.86 (s, 5H), 3.82 (s, 3H), 2.99 (t, J = 6.0 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 155.5, 149.6, 149.4, 149.2, 148.0, 140.1, 138.2, 135.1, 133.8, 128.8 (2), 128.2 (2), 127.0, 126.2, 121.7, 120.7, 113.1, 112.5, 110.8, 108.0, 105.1, 94.9, 55.9, 55.8, 55.6, 42.0, 27.2	C₂₈H₂₄N₂O₃Cl₂ [M-Cl]⁺: 471.147 0, Found: 471.147 5
3g	34	207.3-209.4	¹H NMR (DMSO-d₆) δ 12.34 (s, 1H), 7.90-7.81 (m, 4H), 7.76 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.01 (d, J = 4.8 Hz, 2H), 4.24 (t, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.05 (t, J = 6.0 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 152.7, 151.2, 150.5, 148.3, 143.4, 135.8, 131.9, 131.5 (2), 130.8 (2), 129.0, 127.5, 126.7, 125.1, 120.4, 119.6, 117.1 (2), 110.8, 109.7, 108.4, 99.0, 56.7, 56.0, 55.7, 44.6, 26.4	C₂₈H₂₄N₂O₃BrCl [M-Cl]⁺: 515.096 5, Found: 515.095 3
3h	39	174.9-177.1	¹H NMR (DMSO-d₆) δ 12.46 (s, 1H), 8.40 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.80 (dt, J = 8.4, 3.0 Hz, 1H), 7.73 (dd, J = 9.0, 3.0 Hz, 1H), 7.65 (d, J = 3.0 Hz, 1H), 7.44 (dd, J = 9.0, 3.0 Hz, 1H), 7.38 (d, J = 3.0 Hz, 1H), 7.05 (d, J = 3.0 Hz, 1H), 6.99 (d, J = 3.0 Hz, 1H), 4.25 (d, J = 6.6 Hz, 2H), 4.06 (d, J = 3.0 Hz, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.05 (d, J = 6.6 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 151.7, 151.1, 150.4, 148.3, 143.5, 135.7, 134.6, 133.7, 133.6, 132.7, 129.6, 129.1, 127.4, 126.7, 120.3, 119.7, 118.2, 117.1, 117.1, 111.5, 110.7, 109.8, 108.3, 99.4, 56.7, 56.0, 55.7, 44.6, 26.4	C₂₉H₂₄N₃O₃Cl [M-Cl]⁺: 462.181 2, Found: 462.181 4
3i	42	228.3-230.3	¹H NMR (DMSO-d₆) δ 8.43-8.35 (m, 2H), 8.01-7.91 (m, 2H), 7.32 (s, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.06 (s, 1H), 6.96 (d, J = 3.6 Hz, 2H), 6.92 (d, J = 7.8 Hz, 1H), 3.93 (s, 3H), 3.90-3.84 (m, 5H), 3.82 (s, 3H), 3.00 (t, J = 6.0 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 154.9, 149.7, 149.5, 149.3, 148.0, 143.9, 135.1, 132.3 (2), 129.6, 127.8 (2), 127.1, 126.2, 121.6, 121.0, 118.9, 113.3, 112.5, 111.3, 110.8, 108.0, 105.2, 95.4, 55.9, 55.8, 55.6, 42.0, 27.2	C₂₉H₂₄N₃O₃Cl [M-Cl]⁺: 462.181 2, Found: 462.181 5
3j	48	234.0-236.2	¹H NMR (CDCl₃, CD₃OD) δ 7.90 (dd, J = 1.2, 0.6 Hz, 1H), 7.71 (dd, J = 3.6, 0.6 Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 7.08 (s, 1H), 6.90 (s, 1H), 6.80 (dd, J = 3.6, 1.8 Hz, 1H), 4.24 (t, J = 6.0 Hz, 2H), 4.17 (s, 3H), 3.99 (s, 3H), 3.96 (s, 3H), 3.15 (t, J = 6.0 Hz, 2H)	¹³C NMR (CDCl₃, CD₃OD) δ 152.4, 152.0, 149.7, 147.8, 145. 8, 144.2, 143.2, 137.2, 128.7, 128.2, 127.7, 121.5, 120.4, 118.6, 117.3, 116.3, 114.2, 111.1, 110.6, 109.0, 94.6, 57.1, 56.8, 56.5, 45.8, 27.9	C₂₆H₂₃N₂O₄Cl [M-Cl]⁺: 427.165 2, Found: 427.166 3
3k	41	206.8-209.1	¹H NMR (DMSO-d₆) δ 12.77 (s, 1H), 11.19 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 7.34-7.27 (m, 2H), 7.14 (s, 1H), 6.99 (s, 1H), 6.36 (s, 1H), 4.19 (t, J = 5.4Hz, 2H), 4.04 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.05 (t, J = 5.4 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 163.5, 151.0, 150.8, 148.7, 145.6, 136.2, 127.9, 126.8, 125.8, 121.1, 118.9 (2), 117.2, 117.0, 115.4, 111.2, 111.2, 108.7, 108.7, 108.5, 94.2, 57.1, 56.4, 56.1, 44.7, 27.0	C₂₆H₂₄N₃O₃Cl [M-Cl]⁺: 426.181 2, Found: 426.182 0
3l	35	167.1-169.3	¹H NMR (DMSO-d₆) δ 8.23 (d, J = 9.6 Hz, 2H), 7.71 (s, 1H), 7.66 (s, 1H), 7.40 (s, 2H), 7.32 (s, 1H), 7.01 (s, 1H), 4.24 (s, 2H), 4.06 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.06 (s, 2H)	¹³C NMR (DMSO-d₆) δ 151.1, 150.3, 148.1, 146.9, 144.3, 135.9, 127.3, 126.7 126.2, 126.1, 120.2, 120.0, 117.0, 116.8, 116.7, 110.6, 110.1, 108.2, 99.4, 97.4, 56.7, 55.9, 55.6, 44.7, 26.3	C₂₅H₂₂N₃O₃SCl [M-Cl]⁺: 444.137 6, Found: 444.137 7
3m	53	186.7-189.2	¹H NMR (CD₃OD) δ 7.68 (d, J = 8.4 Hz, 1H), 7.51-7.45 (m, 2H), 7.33 (s, 1H), 6.86 (s, 1H), 6.72 (s, 1H), 4.15-4.09 (m, 5H), 3.96 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.09 (t, J = 6.0 Hz, 2H), 2.53 (s, 3H), 2.48 (s, 3H)	¹³C NMR (CD₃OD) δ 153.2, 152.6, 150.3, 147.6, 147.0, 145.2, 144.4, 137.6, 130.5, 129.0, 128.5, 122.2, 121.3, 118.8, 117.6, 114.7, 111.7, 111.2, 109.7, 101.6, 57.4, 57.0, 56.5, 46.3, 36.4, 28.2, 11.6, 10.5	C₂₈H₂₉N₄O₃Cl [M-Cl]⁺: 469.223 4, Found: 469.223 8
3n	34	150.3-151.9	¹H NMR (CD₃OD) δ 7.68 (d, J = 8.4 Hz, 1H), 7.51-7.45 (m, 2H), 7.34 (s, 1H), 6.87 (s, 1H), 6.72 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.17-4.08 (s, 5H), 3.89 (s, 3H), 3.86 (s, 3H), 3.09 (t, J = 6.0 Hz, 2H), 2.54 (s, 3H), 2.48 (s, 3H), 1.50 (t, J = 6.6 Hz, 3H)	¹³C NMR (CD₃OD) δ 153.2, 152.6, 150.3, 147.8, 147.4, 145.2, 143.3, 137.7, 130.5, 129.0, 128.5, 122.2, 121.3, 118.8, 117.6, 114.7, 111.7, 111.2, 109.7, 101.6, 57.4, 57.0, 56.6, 46.3, 45.4, 28.2, 15.3, 11.7, 10.4	C₂₉H₃₁N₄O₃Cl [M-Cl]⁺: 483.239 1, Found: 483.239 9
3o	31	188.7-191.2	¹H NMR (DMSO-d₆) δ 8.55 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.34-7.21 (m, 3H), 7.14 (s, 1H), 6.80 (s, 1H), 4.18 (t, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.05 (t, J = 6.0 Hz, 2H), 2.44 (s, 3H)	¹³C NMR (DMSO-d₆) δ 153.5, 152.7, 151.3, 150.3, 148.9, 144.8, 144.4, 139.8, 139.4, 137.9, 128.9, 128.3, 123.0, 121.8, 121.4, 118.6, 117.6, 111.6, 111.3, 109.6, 101.4, 96.2, 57.5, 57.0, 56.6, 46.5, 28.1, 18.5	C₂₈H₂₆N₃O₃Cl [M-Cl]⁺: 452.196 9, Found: 452.194 8
3p	35	187.1-188.9	¹H NMR (CDCl₃, CD₃OD) δ 9.71 (d, J = 1.2 Hz, 1H), 8.95-8.90 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 6.94 (s, 1H), 4.39 (t, J = 6.0 Hz, 2H), 4.22 (s, 3H), 4.01 (s, 3H), 3.98 (s, 3H), 3.20 (t, J = 6.0 Hz, 2H)	¹³C NMR (CDCl₃, CD₃OD) δ 153.1, 152.2, 149.9, 148.2, 146.6, 145.0, 144.1 (2), 143.5, 137.8, 128.8, 128.3, 128.0, 121.7, 121.4, 118.7, 117.7, 111.9, 111.2, 109.1, 97.2, 57.3, 56.9, 56.6, 46.3, 27.9	C₂₆H₂₃N₄O₃Cl [M-Cl]⁺: 439.176 5, Found: 439.176 7
3q	36	208.1-210.2	¹H NMR (DMSO-d₆) δ 12.79 (s, 1H), 9.42 (s, 1H), 9.27 (s, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.43 (s, 1H), 7.19 (s, 1H), 7.01 (s, 1H), 4.25 (s, 2H), 4.08 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.06 (s, 2H)	¹³C NMR (DMSO-d₆) δ 160.3, 157.3 (3), 151.6, 150.9, 149.2, 148.8, 143.9, 136.3, 129.7, 128.0, 127.7, 127.3, 120.8, 120.4, 117.7, 111.2, 110.6, 108.8, 100.6, 57.3, 56.5, 56.2, 45.2, 26.9	C₂₆H₂₃N₄O₃Cl [M-Cl]⁺: 439.176 5, Found: 439.176 9
3r	42	200.0-201.9	¹H NMR (CDCl₃, CD₃OD) δ 8.20 (s, 1H), 7.95 (d, J = 5.4 Hz, 1H), 7.60 (d, J = 3.6 Hz, 1H), 7.57 (d, J = 6.0 Hz, 1H), 7.42 (s, 1H), 7.39-7.33 (m, 2H), 7.29 (s, 1H), 7.25 (s, 1H), 6.92 (s, 1H), 6.89 (s, 1H), 4.18 (s, 5H), 4.00 (s, 3H), 3.97 (s, 3H), 3.18 (s, 2H)	¹³C NMR (CDCl₃, CD₃OD) δ 152.2, 151.8, 150.9, 149.6, 144.2, 138.1, 137.1, 130.0, 129.2, 128.0, 127.4, 124.8, 124.1, 122.8, 121.8, 119.7, 119.0, 118.1, 116.5, 113.7, 111.1, 109.4, 109.3, 109.0, 96.1, 57.2, 56.9, 56.5, 45.5, 28.1	C₃₀H₂₆N₃O₃Cl [M-Cl]⁺: 476.196 9, Found: 476.197 3


BBR	/	> 266	27.0	> 9.89	142
3a	C₆H₅	44.8	4.06	11.0	17.5
3b	p-CH₃C₆H₄	33.7	12.1	2.8	16.8
3c	o, p-(CH₃)₂C₆H₃	15.2	13.0	1.2	16.2
3d	m, p-(CH₃)₂C₆H₃	5.1	4.5	1.1	4.2
3e	m, p-(OCH₃)₂C₆H₃	5.1	5.2	0.99	7.33
3f	p-ClC₆H₄	14.8	15.7	0.94	19.4
3g	p-BrC₆H₄	13.7	16.5	0.83	15.0
3h	m-CNC₆H₄	5.51	2.96	1.86	12.0
3i	p-CNC₆H₄	25.8	29.3	0.87	34.0
3j	2′-Furyl	5.46	4.63	1.18	4.23
3k	2′-Pyrryl	13.1	13.1	1.00	11.1
3l	2′-Thiazolyl	25.2	46.7	0.54	22.4
3m		36.0	1.61	22.2	31.7
3n		94.3	10.2	9.27	35.3
3o		5.93	6.18	0.86	6.88
3p	2′-Pyrazinyl	8.96	4.79	1.87	5.46
3q	5′-Pyrimidyl	58.2	71.2	0.82	24.7
3r	3′-Indolyl	6.00	6.97	0.86	6.80


BBR	/	> 266	27.0	> 9.89	142
3a	C₆H₅	44.8	4.06	11.0	17.5
3b	p-CH₃C₆H₄	33.7	12.1	2.8	16.8
3c	o, p-(CH₃)₂C₆H₃	15.2	13.0	1.2	16.2
3d	m, p-(CH₃)₂C₆H₃	5.1	4.5	1.1	4.2
3e	m, p-(OCH₃)₂C₆H₃	5.1	5.2	0.99	7.33
3f	p-ClC₆H₄	14.8	15.7	0.94	19.4
3g	p-BrC₆H₄	13.7	16.5	0.83	15.0
3h	m-CNC₆H₄	5.51	2.96	1.86	12.0
3i	p-CNC₆H₄	25.8	29.3	0.87	34.0
3j	2′-Furyl	5.46	4.63	1.18	4.23
3k	2′-Pyrryl	13.1	13.1	1.00	11.1
3l	2′-Thiazolyl	25.2	46.7	0.54	22.4
3m		36.0	1.61	22.2	31.7
3n		94.3	10.2	9.27	35.3
3o		5.93	6.18	0.86	6.88
3p	2′-Pyrazinyl	8.96	4.79	1.87	5.46
3q	5′-Pyrimidyl	58.2	71.2	0.82	24.7
3r	3′-Indolyl	6.00	6.97	0.86	6.80

Code	Absn risk ^a	CYP risk ^b	Rat-TD₅₀^c/mg·kg^-1·d^-1	ADMET risk^d
3m	0.83	1	12.1	4.83

Code	Absn risk ^a	CYP risk ^b	Rat-TD₅₀^c/mg·kg^-1·d^-1	ADMET risk^d
3m	0.83	1	12.1	4.83

N-环化小檗碱衍生物合成及抗SARS-CoV-2假病毒活性研究

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范田运 ¹ , 吴佳静 ² , 李迎红 ¹ , 黄维金 ² , 郭茜茜 ¹ , 赵丽萍 ¹ , 汪燕翔 ¹ , 王佑春 ² , 宋丹青 ¹^,^*

药学学报 | 研究论文 2021,56(6): 1663-1669

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药学学报 | 研究论文 2021, 56(6): 1663-1669

N-环化小檗碱衍生物合成及抗SARS-CoV-2假病毒活性研究

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范田运¹, 吴佳静², 李迎红¹, 黄维金², 郭茜茜¹, 赵丽萍¹, 汪燕翔¹, 王佑春², 宋丹青¹^,^*

作者信息

1.中国医学科学院、北京协和医学院医药生物技术研究所, 北京市抗感染重点实验室, 北京 100050

2.中国食品药品检定研究院, 北京 102629

通讯作者:

*宋丹青, Tel/Fax: 86-10-63165268, E-mail: songdanqingsdq@hotmail.com

Synthesis and evaluation of N-cycloberberine derivatives as a novel class of anti-SARS-CoV-2 pseudovirus agents

Tian-yun FAN¹, Jia-jing WU², Ying-hong LI¹, Wei-jin HUANG², Xi-xi GUO¹, Li-ping ZHAO¹, Yan-xiang WANG¹, You-chun WANG², Dan-qing SONG¹^,^*

Affiliations

1. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

2. National Institute for Food and Drug Control, Beijing 102629, China

出版时间: 2021-06-12 doi: 10.16438/j.0513-4870.2021-0203

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摘要

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目前临床尚无治疗COVID-19的特效药物。传统天然药物小檗碱（BBR）具有中度抗SARS-CoV-2假病毒活性。本研究以BBR为先导物，设计合成了18个全新骨架N-环化BBR衍生物，评价了它们体外抗SARS-CoV-2假病毒活性。构效关系表明9-位引入适当的杂环利于活性提高。其中，化合物3m的EC₅₀为1.61 μmol·L^-1，SI为22.2，明显优于BBR。时间添加（time-of-addition）实验结果显示，化合物3m作用于病毒入侵宿主细胞的多个阶段，包括进入、吸附及膜融合过程，提示此类化合物通过多靶点的协同作用抑制SARS-CoV-2。研究结果为寻找抗SARS-CoV-2候选物提供了一类全新的先导物。

关键词

N-环化小檗碱 / SARS-CoV-2 / 构效关系 / 时间添加实验

Abstract

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There is no specific drug against COVID-19, but berberine (BBR) has moderate anti-SARS-CoV-2 pseudovirus activity. Taking BBR as the lead, 18 novel N-cycloberberine derivatives were synthesized and evaluated for their anti-SARS-CoV-2 pseudovirus activities in vitro. Structure-activity relationship analysis revealed that introducing an appropriate heterocyclic group at position 9 might be beneficial for potency. Among the tested compounds, compound 3m showed the most potent activity against SARS-CoV-2, with EC₅₀ value of 1.61 μmol·L^-1 and SI value of 22.2, much better than that of BBR. Additional experiment indicated that 3m had inhibitory activity on multiple processes in viral invasion, including adsorption and membrane fusion, suggesting a multi-target synergistic mechanism of action. These results provide a novel family of lead compounds for the discovery of anti-SARS-CoV-2 candidates.

Key words

N-cycloberberine / SARS-CoV-2 / structure-activity relationship / time-of-addition

引用本文

范田运, 吴佳静, 李迎红, 黄维金, 郭茜茜, 赵丽萍, 汪燕翔, 王佑春, 宋丹青. N-环化小檗碱衍生物合成及抗SARS-CoV-2假病毒活性研究. 药学学报, 2021 , 56 (6) : 1663 -1669 . DOI: 10.16438/j.0513-4870.2021-0203

Tian-yun FAN, Jia-jing WU, Ying-hong LI, Wei-jin HUANG, Xi-xi GUO, Li-ping ZHAO, Yan-xiang WANG, You-chun WANG, Dan-qing SONG. Synthesis and evaluation of N-cycloberberine derivatives as a novel class of anti-SARS-CoV-2 pseudovirus agents[J]. Acta Pharmaceutica Sinica, 2021 , 56 (6) : 1663 -1669 . DOI: 10.16438/j.0513-4870.2021-0203

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严重急性呼吸综合征冠状病毒2 (SARS-CoV-2) 具有高传染性和高隐蔽性传播特征, 其引发的疾病(COVID-19) 在2019年底爆发, 随即以惊人的速度席卷到全球180多个国家/地区, 导致全球性大流行^{[1, 2]}。近期出现的COVID-19病毒新变种传染性更强, 使疫情防控更加复杂化和具有挑战性^[3]。虽然RNA聚合酶抑制剂瑞德西韦(remdesivir) 批准上市用于重症患者的治疗, 但其治疗COVID-19的安全性和有效性尚待进一步验证^[4-6]。因此, 寻找抗SARS-CoV-2候选物是全球性公益需求, 更是为应对我国突发性传染性疾病的防控提供充足的战略物资储备, 意义重大。

天然产物历来是抗病毒药物发现的重要源泉, 对具有广谱抗病毒活性的天然产物进行抗SARS-CoV-2活性筛选, 是发现全新抗SARS-CoV-2候选物的重要策略^{[7, 8]}。小檗碱(berberine, BBR) 是中药黄连的有效成分, 具有多种抗病毒活性, 如抗柯萨奇病毒、抗丙肝病毒、抗人巨细胞病毒、抗甲病毒及抗甲型流感病毒等^[9-16]。基于此, 利用已构建的SARS-CoV-2假病毒模型对我国传统天然药物小檗碱(BBR) 及其4个主要代谢产物(图 1), 包括9-羟基小檗碱(M1)、10-羟基小檗碱(M2)、2, 3-二羟基小檗碱(M3) 和3-羟基小檗碱(M4) 进行了活性筛选^[17]。研究发现仅BBR显示中度抗SARS-CoV-2假病毒活性, 其EC₅₀值为27.0 μmol·L^-1, 选择性指数(SI) 大于9.9, 但4个代谢产物均没有活性, 该结果提示, 对BBR的A环和D环的传统结构修饰可能不利于活性的提高。为此, 本论文针对BBR及其类似物巴马汀(palmatine, PMT) 的8, 9-位进行环合, 由此构建了一类全新骨架的N-环化小檗碱衍生物(图 1)。随后评价了它们抗SARS-CoV-2假病毒活性, 发现BBR 8, 9-位环合, 同时亚甲二氧环打开(即PMT的8, 9-位环合) 的衍生物具有一定的抗SARS-CoV-2假病毒活性。在此总结了PMT的8, 9-位环合衍生物的构效关系(structure-activity relationship, SAR), 对代表性化合物开展了初步安全性与抗SARS-CoV-2假病毒作用机制研究。

结果和讨论

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1 化合物的合成

目标化合物3a~3r均以市售PMT为起始原料, 经胺化保护、脱保护以及环合反应合成得到(合成路线1)。首先, 100 ℃条件下, PMT与2, 4-二甲氧基苄胺经胺化反应, 得到关键中间体1, 收率为49%。然后将1置于盐酸甲醇溶液中, 脱去2, 4-二甲氧基苄基保护基, 以83%收率得到9-氨基巴马汀2^[18-20]。最后以不同于文献报道的全新合成方法, 将2与相应的α-甲基酮在碱性条件下, 经曼尼希反应和分子内加成环合得到新型的N-环化小檗碱衍生物3a~3r^[21], 收率31%~53%。所有目标化合物结构经¹H NMR、¹³C NMR以及HR-MS分析确证。目标化合物的收率、理化参数和波谱数据见表 1。

2 抗SARS-CoV-2假病毒的SAR研究

采用已构建的含荧光素酶报告系统的SARS-CoV-2假病毒模型评价目标物活性^[17]。该模型首先在293T细胞中转染质粒pcDNA3.1.S2, 24 h后感染含荧光素酶报告系统的G*ΔG-VSV假病毒; 病毒感染24 h后通过检测荧光素酶信号值即可定量分析SARS-CoV-2假病毒的复制能力。同时评价了目标物对G*ΔG-VSV假病毒的抑制活性, 用以排除化合物是通过抑制G*ΔG-VSV假病毒的活性而导致的假阳性结果。所有目标物的结构、细胞毒、抗SARS-CoV-2假病毒(EC₅₀-SARS-CoV-2) 和抗G*ΔG-VSV假病毒(EC₅₀-G*ΔG-VSV) 的活性见表 2。

SAR主要考察衍生物9-位不同取代基对抗SARS-CoV-2假病毒活性的影响。首先, 对9-位引入苯基, 所得化合物3a对SARS-CoV-2假病毒的EC₅₀为4.06 μmol·L^-1, 活性优于BBR, SI值与BBR相当。随后, 在9-位苯基上分别引入供电子甲基(3b~3d)、甲氧基(3e)、氯(3f) 和溴(3g) 和吸电子基氰基(3h~3i), 结果显示, 除化合物3i的活性弱于先导物外, 其他目标物的活性均强于BBR, 但其SI值均小于先导物。以上结果提示: 在9-位引入含不同取代的苯基不利于衍生物SI值提高。

接下来在9-位引入不同杂环取代基(3j~3r), 结果显示, 当9-位取代基为吡咯基、噻唑基和嘧啶基时, 衍生物3k、3l和3q的EC₅₀均大于13.0 μmol·L^-1; 当9-位取代基为呋喃基、取代的吡啶基、吡嗪基和吲哚基时, 虽然化合物3j、3o、3p和3r的抗SARS-CoV-2假病毒活性明显强于BBR, EC₅₀介于4.63和6.97 μmol·L^-1之间, 但是细胞毒性明显增大, SI低于先导物; 当9-位取代基为含不同取代的吡唑基时, 化合物3n活性强于BBR, EC₅₀为10.2 μmol·L^-1, SI值和BBR相当, 特别是化合物3m, 其EC₅₀仅为1.61 μmol·L^-1, SI为22.2, 抗病毒活性和SI均明显优于BBR, 并且3m对G*ΔG-VSV假病毒的EC₅₀为31.7 μmol·L^-1, 低于BBR的EC₅₀ 17.5 μmol·L^-1。因此, 选择3m为代表性化合物进行下一步研究。

3 时间添加实验

为初步探讨BBR与3m抗病毒机制, 设计了在不同的温度条件和时间点将3m或者BBR和病毒单独或同时加入宿主细胞的药物-病毒-宿主相互作用的时间添加实验^{[17, 22]}。如图 2A所示: 若病毒荧光降低, 提示a: 抑制病毒的入侵; b: 阻碍病毒对细胞膜表面的吸附; c: 阻断病毒与细胞膜表面受体结合; d: 抑制膜融合过程。结果如图 2B和2C所示: BBR对a、b和c过程的抑制率分别为60%、57%、69%, 提示BBR通过抑制病毒对宿主细胞的进入、吸附以及阻断病毒与受体的结合多个过程; 3m对a、b和d过程的抑制率分别为62%、76%、73%, 提示3m对病毒对宿主细胞的进入、吸附和膜融合阶段均有较好的抑制作用。上述结果提示, 3m和BBR均可能通过多靶点的协同作用机制产生抗病毒作用, 而母核骨架结构改变使两者作用机制不完全相同, 值得进一步深入研究。

4 成药性初步评价

4.1 化合物3m成药性预测

鉴于目标化合物具有新结构骨架, 使用ADMET Predictor 9.5软件对代表性化合物3m进行初步的成药性预测, 包括吸收、代谢和毒理性质进行打分, 了解其部分成药性质^[23] (表 3)。结果显示, 3m的预测分值均在软件设定的合理范围内, 提示化合物3m成药性良好。

4.2 化合物3m急性毒性

选用昆明小鼠, 以灌胃给药方式, 按照0、250、500和1 000 mg·kg^-1剂量, 将化合物3m一次性给药, 密切观察7天。结果显示, 不同剂量组小鼠生存状态均良好, 说明3m半数致死量(LD₅₀)大于1 000 mg·kg^-1。

小结

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本研究以BBR为先导物, 以抗SARS-CoV-2假病毒活性为导向, 共设计合成了18个全新结构骨架的N-环化BBR衍生物, 构效关系表明在9-位引入适当的杂环基团可以提高抗病毒活性。其中, 化合物3m显示出最优的抗病毒活性, 其EC₅₀仅为1.61 μmol·L^-1, SI为22.2, 明显优于BBR。时间添加实验提示BBR与3m均通过多靶点协同作用机制发挥抗病毒作用, 但因母核骨架结构改变使其作用机制发生变化。本研究结果为N-环化BBR衍生物发展成一类新颖的抗SARS-Co-2候选物提供了重要科学数据。

实验部分

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CXM-300型精密熔点仪测定目标物熔点, 温度未校正; 所有目标物的¹H NMR和¹³C NMR用Bruker Avance Ⅲ 600MHz核磁共振仪测定, 溶剂为DMSO-d₆、CD₃OD或者CD₃OD和CDCl₃混合溶剂; HR-ESI-MS用Autospec Ultima-TOF质谱测定仪测定; Flash柱分离纯化用Combiflash Rf 200快速制备液相, 试剂均为分析纯。

1 化合物合成

将PMT (5 g, 12.9 mmol) 加入到2, 4-二甲氧基苄胺25 mL中, 100 ℃条件下反应7 h。体系冷却至室温, 随后加入丙酮100 mL, 搅拌, 抽滤, 丙酮2×100 mL洗涤。滤渣经硅胶柱, 以二氯甲烷/甲醇为流动相分离纯化得红色化合物1。化合物1 (3 g, 5.74 mmol) 溶于10 mL甲醇中, 加入浓盐酸3 mL, 室温搅拌8 h, 抽滤, 沉淀以80%乙醇洗涤, 得红色化合物2。将化合物2 (300 mg, 0.81 mmol) 和相应的α-甲基酮(1.47 mmol) 置于无水甲醇(10 mL) 中, 加入甲醇钠调节反应体系始终为碱性, 60 ℃反应2~8 h, 将反应体系充分冷却, 用盐酸酸化, 减压旋干反应体系, 固体经硅胶柱以二氯甲烷/甲醇为流动相分离纯化得目标物3a~3r。

2 生物实验

2.1 体外细胞水平抗SARS-CoV-2假病毒活性评价

将每种化合物(终浓度200 μmol·L^-1) 的系列稀释液与1.3×10⁴ TCID₅₀ SARS-CoV-2假病毒混合于96孔Costar板中(Corning, Inc., 康宁, 纽约), 37 ℃下孵育1 h, 然后加入Huh 7细胞(每孔2×10⁴细胞), 孵育24 h。通过测量生物发光值来确定病毒感染性。根据剂量-反应曲线确定化合物抗病毒的EC₅₀值。同时, 在没有假病毒的情况下, 进行细胞毒性测试以确定每种测试化合物的CC₅₀值。

2.2 体外细胞水平抗G^*ΔG-VSV假病毒活性评价

将每种化合物(终浓度200 μmol·L^-1) 的系列稀释液与1.3×10⁴ TCID₅₀ G*ΔG-VSV假病毒混合于96孔Costar板(Corning, Inc., 康宁, 纽约), 37 ℃下孵育1 h, 然后加入Huh 7细胞(每孔2×10⁴细胞), 孵育24 h。通过测量生物发光值来确定病毒的感染性, EC₅₀由剂量反应曲线确定。

2.3 急性毒性实验

本部分动物实验遵循中国医学科学院药物研究所动物实验中心标准操作规程。以昆明种小鼠(18~20 g) 为动物模型, 称重后按照每组10只、雌雄各半随机分组。将化合物3m在研钵中充分研磨, 分别配制成0、25、50和100 mg·mL^-1混悬液, 给药前充分震荡, 使药物混悬均匀, 每只小鼠按照0、250、500和1 000 mg·kg^-1的剂量灌胃给药0.2 mL, 密切观察动物7天内的死亡情况, 计算LD₅₀。

2.4 时间添加实验

将Huh 7细胞在96孔板中培养24 h, 随后将化合物(终浓度25 μmol·L^-1) 在SARS-CoV-2假病毒感染前1 h (-1 h), 病毒感染中(0 h) 及病毒感染后(+1 h) 的不同时间段进行孵育。病毒感染后24 h检测生物发光值, 对化合物抗假病毒的效果进行分析^[14]。

作者贡献: 范田运负责所有目标物的合成、文献的调研整理及初稿的撰写; 吴佳静负责抗SARS-CoV-2假病毒活性筛选; 李迎红、黄维金、汪燕翔和王佑春教授负责实验把关及稿件修改等工作; 郭茜茜和赵丽萍帮助目标物的分离; 本文的通讯作者宋丹青教授负责实验设计和把关、稿件修改等工作。

利益冲突: 所有作者均声明不存在利益冲突。

基金

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中国医学科学院医学与健康科技创新工程重大协同创新项目(2020-I2M-2-010)
中国医学科学院医学与健康科技创新工程(2019-I2M-1-005)

参考文献

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2021年第56卷第6期

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doi: 10.16438/j.0513-4870.2021-0203

接收时间：2021-02-05
首发时间：2025-12-18
出版时间：2021-06-12

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收稿日期：2021-02-05
修回日期：2021-03-10

基金

中国医学科学院医学与健康科技创新工程重大协同创新项目(2020-I2M-2-010)

中国医学科学院医学与健康科技创新工程(2019-I2M-1-005)

作者信息

1.中国医学科学院、北京协和医学院医药生物技术研究所, 北京市抗感染重点实验室, 北京 100050

2.中国食品药品检定研究院, 北京 102629

通讯作者:

*宋丹青, Tel/Fax: 86-10-63165268, E-mail: songdanqingsdq@hotmail.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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No.	Yield /%	mp/℃ (Dec.)	¹H NMR	¹³C NMR	HR-ESI-MS m/z
3a	33	125.3-126.9	¹H NMR (DMSO-d₆) δ 12.29 (s, 1H), 8.09 (d, J = 6.6 Hz, 2H), 7.53 (s, 1H), 7.52 (s, 2H), 7.34 (s, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.97 (s, 1H), 6.96 (s, 1H), 3.95 (s, 5H), 3.86 (s, 3H), 3.82 (s, 3H), 3.00 (t, J = 5.4 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 156.5, 150.3, 150.2, 148.6, 148.5, 135.8, 130.2, 128.9 (4), 128.1 (2), 127.7, 126.8, 121.9, 120.9, 114.5, 114.1, 111.2, 108.5, 106.7, 96.6, 56.5, 56.4, 56.1, 43.1, 27.5	C₂₈H₂₅N₂O₃Cl [M-Cl]⁺: 437.186 0, Found: 437.186 7
3b	47	180.7-183.2	¹H NMR (DMSO-d₆) δ 12.14 (s, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.52-7.32 (m, 4H), 7.01 (s, 1H), 6.97 (s, 1H), 4.24 (t, J = 6.0 Hz, 2H), 4.05 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.04 (t, J = 6.0 Hz, 2H), 2.45 (s, 3H)	¹³C NMR (DMSO-d₆) δ 153.6, 151.1, 150.4, 148.3, 143.4, 141.7, 135.8, 129.8, 129.2 (2), 128.9, 128.6 (2), 127.5, 126.6, 120.4, 119.5, 117.0 (2), 110.7, 109.4, 108.4, 98.4, 56.7, 56.0, 55.7, 44.5, 26.5, 21.0	C₂₉H₂₇N₂O₃Cl [M-Cl]⁺: 451.201 6, Found: 451.201 8
3c	45	186.9-189.0	¹H NMR (DMSO-d₆) δ 12.61 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 7.8, 1.8 Hz, 1H), 6.99 (s, 1H), 6.78 (s, 1H), 4.14 (t, J = 6.0 Hz, 2H), 4.00 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 3.02 (t, J = 6.0 Hz, 2H), 2.39 (s, 3H), 2.34 (s, 3H)	¹³C NMR (DMSO-d₆) δ 154.6, 151.1, 150.4, 148.3, 143.4, 140.0, 136.1, 135.7, 131.0, 130.9, 129.4, 128.9, 127.5, 126.7, 126.3, 120.4, 119.6, 116.9 (2), 110.7, 109.4, 108.4, 100.4, 56.6, 56.0, 55.7, 44.4, 26.5, 20.8, 19.5	C₃₀H₂₉N₂O₃Cl [M-Cl]⁺: 465.217 3, Found: 465.216 0
3d	36	183.1-185.3	¹H NMR (DMSO-d₆) δ 12.09 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.67-7.62 (m, 2H), 7.44 (d, J = 9.6 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 4.24 (t, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.06 (t, J = 6.0 Hz, 2H), 2.37 (s, 3H), 2.36 (s, 3H)	¹³C NMR (DMSO-d₆) δ 153.7, 151.1, 150.4, 148.3, 143.4, 140.5, 136.7, 135.8, 130.0, 129.6, 129.3, 128.8, 127.5, 126.6, 126.1, 120.4, 119.4, 117.0 (2), 110.8, 109.3, 108.4, 98.3, 56.7, 55.97, 55.8, 44.4, 26.5, 19.4, 19.3	C₃₀H₂₉N₂O₃Cl [M-Cl]⁺: 465.217 3, Found: 465.217 7
3e	53	190.6-193.4	¹H NMR (DMSO-d₆) δ 11.99 (s, 1H), 7.70 (s, 1H), 7.670 (s, 1H), 7.54-7.30 (m, 4H), 7.15 (s, 1H), 6.98 (s, 1H), 6.98 (s, 1H), 4.23 (s, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.86 (s, 6H), 3.82 (s, 3H), 3.04 (s, 2H)	¹³C NMR (DMSO-d₆) δ 152.9, 151.2, 150.5, 149.8, 147.9, 147.7, 142.8, 135.2, 128.3, 126.9, 126.0, 124.3, 121.7, 119.9, 118.8, 116.6 (2), 111.7, 111.1, 110.4, 108.9, 107.9, 97.7, 56.7, 55.9, 55.9, 55.8, 55.6, 44.2, 26.2	C₃₀H₂₉N₂O₅Cl [M-Cl]⁺: 497.207 1, Found: 497.2071
3f	43	192.2-193.9	¹H NMR (DMSO-d₆) δ 8.22 (d, J = 8.4 Hz, 2H), 7.55 (dt, J = 7.8, 2.4 Hz, 2H), 7.31 (s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.02-6.84 (m, 4H), 3.92 (s, 3H), 3.86 (s, 5H), 3.82 (s, 3H), 2.99 (t, J = 6.0 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 155.5, 149.6, 149.4, 149.2, 148.0, 140.1, 138.2, 135.1, 133.8, 128.8 (2), 128.2 (2), 127.0, 126.2, 121.7, 120.7, 113.1, 112.5, 110.8, 108.0, 105.1, 94.9, 55.9, 55.8, 55.6, 42.0, 27.2	C₂₈H₂₄N₂O₃Cl₂ [M-Cl]⁺: 471.147 0, Found: 471.147 5
3g	34	207.3-209.4	¹H NMR (DMSO-d₆) δ 12.34 (s, 1H), 7.90-7.81 (m, 4H), 7.76 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.01 (d, J = 4.8 Hz, 2H), 4.24 (t, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.05 (t, J = 6.0 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 152.7, 151.2, 150.5, 148.3, 143.4, 135.8, 131.9, 131.5 (2), 130.8 (2), 129.0, 127.5, 126.7, 125.1, 120.4, 119.6, 117.1 (2), 110.8, 109.7, 108.4, 99.0, 56.7, 56.0, 55.7, 44.6, 26.4	C₂₈H₂₄N₂O₃BrCl [M-Cl]⁺: 515.096 5, Found: 515.095 3
3h	39	174.9-177.1	¹H NMR (DMSO-d₆) δ 12.46 (s, 1H), 8.40 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.80 (dt, J = 8.4, 3.0 Hz, 1H), 7.73 (dd, J = 9.0, 3.0 Hz, 1H), 7.65 (d, J = 3.0 Hz, 1H), 7.44 (dd, J = 9.0, 3.0 Hz, 1H), 7.38 (d, J = 3.0 Hz, 1H), 7.05 (d, J = 3.0 Hz, 1H), 6.99 (d, J = 3.0 Hz, 1H), 4.25 (d, J = 6.6 Hz, 2H), 4.06 (d, J = 3.0 Hz, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.05 (d, J = 6.6 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 151.7, 151.1, 150.4, 148.3, 143.5, 135.7, 134.6, 133.7, 133.6, 132.7, 129.6, 129.1, 127.4, 126.7, 120.3, 119.7, 118.2, 117.1, 117.1, 111.5, 110.7, 109.8, 108.3, 99.4, 56.7, 56.0, 55.7, 44.6, 26.4	C₂₉H₂₄N₃O₃Cl [M-Cl]⁺: 462.181 2, Found: 462.181 4
3i	42	228.3-230.3	¹H NMR (DMSO-d₆) δ 8.43-8.35 (m, 2H), 8.01-7.91 (m, 2H), 7.32 (s, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.06 (s, 1H), 6.96 (d, J = 3.6 Hz, 2H), 6.92 (d, J = 7.8 Hz, 1H), 3.93 (s, 3H), 3.90-3.84 (m, 5H), 3.82 (s, 3H), 3.00 (t, J = 6.0 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 154.9, 149.7, 149.5, 149.3, 148.0, 143.9, 135.1, 132.3 (2), 129.6, 127.8 (2), 127.1, 126.2, 121.6, 121.0, 118.9, 113.3, 112.5, 111.3, 110.8, 108.0, 105.2, 95.4, 55.9, 55.8, 55.6, 42.0, 27.2	C₂₉H₂₄N₃O₃Cl [M-Cl]⁺: 462.181 2, Found: 462.181 5
3j	48	234.0-236.2	¹H NMR (CDCl₃, CD₃OD) δ 7.90 (dd, J = 1.2, 0.6 Hz, 1H), 7.71 (dd, J = 3.6, 0.6 Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 7.08 (s, 1H), 6.90 (s, 1H), 6.80 (dd, J = 3.6, 1.8 Hz, 1H), 4.24 (t, J = 6.0 Hz, 2H), 4.17 (s, 3H), 3.99 (s, 3H), 3.96 (s, 3H), 3.15 (t, J = 6.0 Hz, 2H)	¹³C NMR (CDCl₃, CD₃OD) δ 152.4, 152.0, 149.7, 147.8, 145. 8, 144.2, 143.2, 137.2, 128.7, 128.2, 127.7, 121.5, 120.4, 118.6, 117.3, 116.3, 114.2, 111.1, 110.6, 109.0, 94.6, 57.1, 56.8, 56.5, 45.8, 27.9	C₂₆H₂₃N₂O₄Cl [M-Cl]⁺: 427.165 2, Found: 427.166 3
3k	41	206.8-209.1	¹H NMR (DMSO-d₆) δ 12.77 (s, 1H), 11.19 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 7.34-7.27 (m, 2H), 7.14 (s, 1H), 6.99 (s, 1H), 6.36 (s, 1H), 4.19 (t, J = 5.4Hz, 2H), 4.04 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.05 (t, J = 5.4 Hz, 2H)	¹³C NMR (DMSO-d₆) δ 163.5, 151.0, 150.8, 148.7, 145.6, 136.2, 127.9, 126.8, 125.8, 121.1, 118.9 (2), 117.2, 117.0, 115.4, 111.2, 111.2, 108.7, 108.7, 108.5, 94.2, 57.1, 56.4, 56.1, 44.7, 27.0	C₂₆H₂₄N₃O₃Cl [M-Cl]⁺: 426.181 2, Found: 426.182 0
3l	35	167.1-169.3	¹H NMR (DMSO-d₆) δ 8.23 (d, J = 9.6 Hz, 2H), 7.71 (s, 1H), 7.66 (s, 1H), 7.40 (s, 2H), 7.32 (s, 1H), 7.01 (s, 1H), 4.24 (s, 2H), 4.06 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.06 (s, 2H)	¹³C NMR (DMSO-d₆) δ 151.1, 150.3, 148.1, 146.9, 144.3, 135.9, 127.3, 126.7 126.2, 126.1, 120.2, 120.0, 117.0, 116.8, 116.7, 110.6, 110.1, 108.2, 99.4, 97.4, 56.7, 55.9, 55.6, 44.7, 26.3	C₂₅H₂₂N₃O₃SCl [M-Cl]⁺: 444.137 6, Found: 444.137 7
3m	53	186.7-189.2	¹H NMR (CD₃OD) δ 7.68 (d, J = 8.4 Hz, 1H), 7.51-7.45 (m, 2H), 7.33 (s, 1H), 6.86 (s, 1H), 6.72 (s, 1H), 4.15-4.09 (m, 5H), 3.96 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.09 (t, J = 6.0 Hz, 2H), 2.53 (s, 3H), 2.48 (s, 3H)	¹³C NMR (CD₃OD) δ 153.2, 152.6, 150.3, 147.6, 147.0, 145.2, 144.4, 137.6, 130.5, 129.0, 128.5, 122.2, 121.3, 118.8, 117.6, 114.7, 111.7, 111.2, 109.7, 101.6, 57.4, 57.0, 56.5, 46.3, 36.4, 28.2, 11.6, 10.5	C₂₈H₂₉N₄O₃Cl [M-Cl]⁺: 469.223 4, Found: 469.223 8
3n	34	150.3-151.9	¹H NMR (CD₃OD) δ 7.68 (d, J = 8.4 Hz, 1H), 7.51-7.45 (m, 2H), 7.34 (s, 1H), 6.87 (s, 1H), 6.72 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.17-4.08 (s, 5H), 3.89 (s, 3H), 3.86 (s, 3H), 3.09 (t, J = 6.0 Hz, 2H), 2.54 (s, 3H), 2.48 (s, 3H), 1.50 (t, J = 6.6 Hz, 3H)	¹³C NMR (CD₃OD) δ 153.2, 152.6, 150.3, 147.8, 147.4, 145.2, 143.3, 137.7, 130.5, 129.0, 128.5, 122.2, 121.3, 118.8, 117.6, 114.7, 111.7, 111.2, 109.7, 101.6, 57.4, 57.0, 56.6, 46.3, 45.4, 28.2, 15.3, 11.7, 10.4	C₂₉H₃₁N₄O₃Cl [M-Cl]⁺: 483.239 1, Found: 483.239 9
3o	31	188.7-191.2	¹H NMR (DMSO-d₆) δ 8.55 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.34-7.21 (m, 3H), 7.14 (s, 1H), 6.80 (s, 1H), 4.18 (t, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.05 (t, J = 6.0 Hz, 2H), 2.44 (s, 3H)	¹³C NMR (DMSO-d₆) δ 153.5, 152.7, 151.3, 150.3, 148.9, 144.8, 144.4, 139.8, 139.4, 137.9, 128.9, 128.3, 123.0, 121.8, 121.4, 118.6, 117.6, 111.6, 111.3, 109.6, 101.4, 96.2, 57.5, 57.0, 56.6, 46.5, 28.1, 18.5	C₂₈H₂₆N₃O₃Cl [M-Cl]⁺: 452.196 9, Found: 452.194 8
3p	35	187.1-188.9	¹H NMR (CDCl₃, CD₃OD) δ 9.71 (d, J = 1.2 Hz, 1H), 8.95-8.90 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 6.94 (s, 1H), 4.39 (t, J = 6.0 Hz, 2H), 4.22 (s, 3H), 4.01 (s, 3H), 3.98 (s, 3H), 3.20 (t, J = 6.0 Hz, 2H)	¹³C NMR (CDCl₃, CD₃OD) δ 153.1, 152.2, 149.9, 148.2, 146.6, 145.0, 144.1 (2), 143.5, 137.8, 128.8, 128.3, 128.0, 121.7, 121.4, 118.7, 117.7, 111.9, 111.2, 109.1, 97.2, 57.3, 56.9, 56.6, 46.3, 27.9	C₂₆H₂₃N₄O₃Cl [M-Cl]⁺: 439.176 5, Found: 439.176 7
3q	36	208.1-210.2	¹H NMR (DMSO-d₆) δ 12.79 (s, 1H), 9.42 (s, 1H), 9.27 (s, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.43 (s, 1H), 7.19 (s, 1H), 7.01 (s, 1H), 4.25 (s, 2H), 4.08 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.06 (s, 2H)	¹³C NMR (DMSO-d₆) δ 160.3, 157.3 (3), 151.6, 150.9, 149.2, 148.8, 143.9, 136.3, 129.7, 128.0, 127.7, 127.3, 120.8, 120.4, 117.7, 111.2, 110.6, 108.8, 100.6, 57.3, 56.5, 56.2, 45.2, 26.9	C₂₆H₂₃N₄O₃Cl [M-Cl]⁺: 439.176 5, Found: 439.176 9
3r	42	200.0-201.9	¹H NMR (CDCl₃, CD₃OD) δ 8.20 (s, 1H), 7.95 (d, J = 5.4 Hz, 1H), 7.60 (d, J = 3.6 Hz, 1H), 7.57 (d, J = 6.0 Hz, 1H), 7.42 (s, 1H), 7.39-7.33 (m, 2H), 7.29 (s, 1H), 7.25 (s, 1H), 6.92 (s, 1H), 6.89 (s, 1H), 4.18 (s, 5H), 4.00 (s, 3H), 3.97 (s, 3H), 3.18 (s, 2H)	¹³C NMR (CDCl₃, CD₃OD) δ 152.2, 151.8, 150.9, 149.6, 144.2, 138.1, 137.1, 130.0, 129.2, 128.0, 127.4, 124.8, 124.1, 122.8, 121.8, 119.7, 119.0, 118.1, 116.5, 113.7, 111.1, 109.4, 109.3, 109.0, 96.1, 57.2, 56.9, 56.5, 45.5, 28.1	C₃₀H₂₆N₃O₃Cl [M-Cl]⁺: 476.196 9, Found: 476.197 3

No.

Yield /%

mp/℃ (Dec.)

¹H NMR

¹³C NMR

HR-ESI-MS m/z

125.3-126.9

¹H NMR (DMSO-d₆) δ 12.29 (s, 1H), 8.09 (d, J = 6.6 Hz, 2H), 7.53 (s, 1H), 7.52 (s, 2H), 7.34 (s, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.97 (s, 1H), 6.96 (s, 1H), 3.95 (s, 5H), 3.86 (s, 3H), 3.82 (s, 3H), 3.00 (t, J = 5.4 Hz, 2H)

¹³C NMR (DMSO-d₆) δ 156.5, 150.3, 150.2, 148.6, 148.5, 135.8, 130.2, 128.9 (4), 128.1 (2), 127.7, 126.8, 121.9, 120.9, 114.5, 114.1, 111.2, 108.5, 106.7, 96.6, 56.5, 56.4, 56.1, 43.1, 27.5

C₂₈H₂₅N₂O₃Cl
[M-Cl]⁺: 437.186 0, Found:
437.186 7

180.7-183.2

¹H NMR (DMSO-d₆) δ 12.14 (s, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.52-7.32 (m, 4H), 7.01 (s, 1H), 6.97 (s, 1H), 4.24 (t, J = 6.0 Hz, 2H), 4.05 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.04 (t, J = 6.0 Hz, 2H), 2.45 (s, 3H)

¹³C NMR (DMSO-d₆) δ 153.6, 151.1, 150.4, 148.3, 143.4, 141.7, 135.8, 129.8, 129.2 (2), 128.9, 128.6 (2), 127.5, 126.6, 120.4, 119.5, 117.0 (2), 110.7, 109.4, 108.4, 98.4, 56.7, 56.0, 55.7, 44.5, 26.5, 21.0

C₂₉H₂₇N₂O₃Cl [M-Cl]⁺: 451.201 6, Found:
451.201 8

186.9-189.0

¹H NMR (DMSO-d₆) δ 12.61 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 7.8, 1.8 Hz, 1H), 6.99 (s, 1H), 6.78 (s, 1H), 4.14 (t, J = 6.0 Hz, 2H), 4.00 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 3.02 (t, J = 6.0 Hz, 2H), 2.39 (s, 3H), 2.34 (s, 3H)

¹³C NMR (DMSO-d₆) δ 154.6, 151.1, 150.4, 148.3, 143.4, 140.0, 136.1, 135.7, 131.0, 130.9, 129.4, 128.9, 127.5, 126.7, 126.3, 120.4, 119.6, 116.9 (2), 110.7, 109.4, 108.4, 100.4, 56.6, 56.0, 55.7, 44.4, 26.5, 20.8, 19.5

C₃₀H₂₉N₂O₃Cl [M-Cl]⁺: 465.217 3, Found:
465.216 0

183.1-185.3

¹H NMR (DMSO-d₆) δ 12.09 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.67-7.62 (m, 2H), 7.44 (d, J = 9.6 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 4.24 (t, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.06 (t, J =
6.0 Hz, 2H), 2.37 (s, 3H), 2.36 (s, 3H)

¹³C NMR (DMSO-d₆) δ 153.7, 151.1, 150.4, 148.3, 143.4, 140.5, 136.7, 135.8, 130.0, 129.6, 129.3, 128.8, 127.5, 126.6, 126.1, 120.4, 119.4, 117.0 (2), 110.8, 109.3, 108.4, 98.3, 56.7, 55.97, 55.8, 44.4, 26.5, 19.4, 19.3

C₃₀H₂₉N₂O₃Cl [M-Cl]⁺: 465.217 3, Found:
465.217 7

190.6-193.4

¹H NMR (DMSO-d₆) δ 11.99 (s, 1H), 7.70 (s, 1H), 7.670 (s, 1H), 7.54-7.30 (m, 4H), 7.15 (s, 1H), 6.98 (s, 1H), 6.98 (s, 1H), 4.23 (s, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.86 (s, 6H), 3.82 (s, 3H), 3.04 (s, 2H)

¹³C NMR (DMSO-d₆) δ 152.9, 151.2, 150.5, 149.8, 147.9, 147.7, 142.8, 135.2, 128.3, 126.9, 126.0, 124.3, 121.7, 119.9, 118.8, 116.6 (2), 111.7, 111.1, 110.4, 108.9, 107.9, 97.7, 56.7, 55.9, 55.9, 55.8, 55.6, 44.2, 26.2

C₃₀H₂₉N₂O₅Cl [M-Cl]⁺: 497.207 1, Found:
497.2071

192.2-193.9

¹H NMR (DMSO-d₆) δ 8.22 (d, J = 8.4 Hz, 2H), 7.55 (dt, J = 7.8, 2.4 Hz, 2H), 7.31 (s, 1H), 7.16 (d, J =
7.8 Hz, 1H), 7.02-6.84 (m, 4H), 3.92 (s, 3H), 3.86 (s, 5H), 3.82 (s, 3H), 2.99 (t, J = 6.0 Hz, 2H)

¹³C NMR (DMSO-d₆) δ 155.5, 149.6, 149.4, 149.2, 148.0, 140.1, 138.2, 135.1, 133.8, 128.8 (2), 128.2 (2), 127.0, 126.2, 121.7, 120.7, 113.1, 112.5, 110.8, 108.0, 105.1, 94.9, 55.9, 55.8, 55.6, 42.0, 27.2

C₂₈H₂₄N₂O₃Cl₂ [M-Cl]⁺: 471.147 0, Found:
471.147 5

207.3-209.4

¹H NMR (DMSO-d₆) δ 12.34 (s, 1H), 7.90-7.81 (m, 4H), 7.76 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.01 (d, J = 4.8 Hz, 2H), 4.24 (t, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.05 (t, J = 6.0 Hz, 2H)

¹³C NMR (DMSO-d₆) δ 152.7, 151.2, 150.5, 148.3, 143.4, 135.8, 131.9, 131.5 (2), 130.8 (2), 129.0, 127.5, 126.7, 125.1, 120.4, 119.6, 117.1 (2), 110.8, 109.7, 108.4, 99.0, 56.7, 56.0, 55.7, 44.6, 26.4

C₂₈H₂₄N₂O₃BrCl [M-Cl]⁺: 515.096 5, Found:
515.095 3

174.9-177.1

¹H NMR (DMSO-d₆) δ 12.46 (s, 1H), 8.40 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.80 (dt, J = 8.4, 3.0 Hz, 1H), 7.73 (dd, J = 9.0, 3.0 Hz, 1H), 7.65 (d, J = 3.0 Hz, 1H), 7.44 (dd, J = 9.0, 3.0 Hz, 1H), 7.38 (d, J = 3.0 Hz, 1H), 7.05 (d, J = 3.0 Hz, 1H), 6.99 (d, J = 3.0 Hz, 1H), 4.25 (d, J = 6.6 Hz, 2H), 4.06 (d, J = 3.0 Hz, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.05 (d, J = 6.6 Hz, 2H)

¹³C NMR (DMSO-d₆) δ 151.7, 151.1, 150.4, 148.3, 143.5, 135.7, 134.6, 133.7, 133.6, 132.7, 129.6, 129.1, 127.4, 126.7, 120.3, 119.7, 118.2, 117.1, 117.1, 111.5, 110.7, 109.8, 108.3, 99.4, 56.7, 56.0, 55.7, 44.6, 26.4

C₂₉H₂₄N₃O₃Cl [M-Cl]⁺: 462.181 2, Found:
462.181 4

228.3-230.3

¹H NMR (DMSO-d₆) δ 8.43-8.35 (m, 2H), 8.01-7.91 (m, 2H), 7.32 (s, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.06 (s, 1H), 6.96 (d, J = 3.6 Hz, 2H), 6.92 (d, J = 7.8 Hz, 1H), 3.93 (s, 3H), 3.90-3.84 (m, 5H), 3.82 (s, 3H), 3.00 (t, J = 6.0 Hz, 2H)

¹³C NMR (DMSO-d₆) δ 154.9, 149.7, 149.5, 149.3, 148.0, 143.9, 135.1, 132.3 (2), 129.6, 127.8 (2), 127.1, 126.2, 121.6, 121.0, 118.9, 113.3, 112.5, 111.3, 110.8, 108.0, 105.2, 95.4, 55.9, 55.8, 55.6, 42.0, 27.2

C₂₉H₂₄N₃O₃Cl [M-Cl]⁺: 462.181 2, Found:
462.181 5

234.0-236.2

¹H NMR (CDCl₃, CD₃OD) δ 7.90 (dd, J = 1.2, 0.6 Hz, 1H), 7.71 (dd, J = 3.6, 0.6 Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 7.08 (s, 1H), 6.90 (s, 1H), 6.80 (dd, J = 3.6, 1.8 Hz, 1H), 4.24 (t, J = 6.0 Hz, 2H), 4.17 (s, 3H), 3.99 (s, 3H), 3.96 (s, 3H), 3.15 (t, J = 6.0 Hz, 2H)

¹³C NMR (CDCl₃, CD₃OD) δ 152.4, 152.0, 149.7, 147.8, 145. 8, 144.2, 143.2, 137.2, 128.7, 128.2, 127.7, 121.5, 120.4, 118.6, 117.3, 116.3, 114.2, 111.1, 110.6, 109.0, 94.6, 57.1, 56.8, 56.5, 45.8, 27.9

C₂₆H₂₃N₂O₄Cl [M-Cl]⁺: 427.165 2, Found:
427.166 3

206.8-209.1

¹H NMR (DMSO-d₆) δ 12.77 (s, 1H), 11.19 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 7.34-7.27 (m, 2H), 7.14 (s, 1H), 6.99 (s, 1H), 6.36 (s, 1H), 4.19 (t, J = 5.4Hz, 2H), 4.04 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.05 (t, J = 5.4 Hz, 2H)

¹³C NMR (DMSO-d₆) δ 163.5, 151.0, 150.8, 148.7, 145.6, 136.2, 127.9, 126.8, 125.8, 121.1, 118.9 (2), 117.2, 117.0, 115.4, 111.2, 111.2, 108.7, 108.7, 108.5, 94.2, 57.1, 56.4, 56.1, 44.7, 27.0

C₂₆H₂₄N₃O₃Cl [M-Cl]⁺: 426.181 2, Found:
426.182 0

167.1-169.3

¹H NMR (DMSO-d₆) δ 8.23 (d, J = 9.6 Hz, 2H), 7.71 (s, 1H), 7.66 (s, 1H), 7.40 (s, 2H), 7.32 (s, 1H), 7.01 (s, 1H), 4.24 (s, 2H), 4.06 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.06 (s, 2H)

¹³C NMR (DMSO-d₆) δ 151.1, 150.3, 148.1, 146.9, 144.3, 135.9, 127.3, 126.7 126.2, 126.1, 120.2, 120.0, 117.0, 116.8, 116.7, 110.6, 110.1, 108.2, 99.4, 97.4, 56.7, 55.9, 55.6, 44.7, 26.3

C₂₅H₂₂N₃O₃SCl [M-Cl]⁺: 444.137 6, Found:
444.137 7

186.7-189.2

¹H NMR (CD₃OD) δ 7.68 (d, J = 8.4 Hz, 1H), 7.51-7.45 (m, 2H), 7.33 (s, 1H), 6.86 (s, 1H), 6.72 (s, 1H), 4.15-4.09 (m, 5H), 3.96 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.09 (t, J = 6.0 Hz, 2H), 2.53 (s, 3H), 2.48 (s, 3H)

¹³C NMR (CD₃OD) δ 153.2, 152.6, 150.3, 147.6, 147.0, 145.2, 144.4, 137.6, 130.5, 129.0, 128.5, 122.2, 121.3, 118.8, 117.6, 114.7, 111.7, 111.2, 109.7, 101.6, 57.4, 57.0, 56.5, 46.3, 36.4, 28.2, 11.6, 10.5

C₂₈H₂₉N₄O₃Cl [M-Cl]⁺: 469.223 4, Found:
469.223 8

150.3-151.9

¹H NMR (CD₃OD) δ 7.68 (d, J = 8.4 Hz, 1H), 7.51-7.45 (m, 2H), 7.34 (s, 1H), 6.87 (s, 1H), 6.72 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.17-4.08 (s, 5H), 3.89 (s, 3H), 3.86 (s, 3H), 3.09 (t, J = 6.0 Hz, 2H), 2.54 (s, 3H), 2.48 (s, 3H), 1.50 (t, J = 6.6 Hz, 3H)

¹³C NMR (CD₃OD) δ 153.2, 152.6, 150.3, 147.8, 147.4, 145.2, 143.3, 137.7, 130.5, 129.0, 128.5, 122.2, 121.3, 118.8, 117.6, 114.7, 111.7, 111.2, 109.7, 101.6, 57.4, 57.0, 56.6, 46.3, 45.4, 28.2, 15.3, 11.7, 10.4

C₂₉H₃₁N₄O₃Cl [M-Cl]⁺: 483.239 1, Found:
483.239 9

188.7-191.2

¹H NMR (DMSO-d₆) δ 8.55 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.34-7.21 (m, 3H), 7.14 (s, 1H), 6.80 (s, 1H), 4.18 (t, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.05 (t, J = 6.0 Hz, 2H), 2.44 (s, 3H)

¹³C NMR (DMSO-d₆) δ 153.5, 152.7, 151.3, 150.3, 148.9, 144.8, 144.4, 139.8, 139.4, 137.9, 128.9, 128.3, 123.0, 121.8, 121.4, 118.6, 117.6, 111.6, 111.3, 109.6, 101.4, 96.2, 57.5, 57.0, 56.6, 46.5, 28.1, 18.5

C₂₈H₂₆N₃O₃Cl [M-Cl]⁺: 452.196 9, Found:
452.194 8

187.1-188.9

¹H NMR (CDCl₃, CD₃OD) δ 9.71 (d, J = 1.2 Hz, 1H), 8.95-8.90 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 6.94 (s, 1H), 4.39 (t, J = 6.0 Hz, 2H), 4.22 (s, 3H), 4.01 (s, 3H), 3.98 (s, 3H), 3.20 (t, J = 6.0 Hz, 2H)

¹³C NMR (CDCl₃, CD₃OD) δ 153.1, 152.2, 149.9, 148.2, 146.6, 145.0, 144.1 (2), 143.5, 137.8, 128.8, 128.3, 128.0, 121.7, 121.4, 118.7, 117.7, 111.9, 111.2, 109.1, 97.2, 57.3, 56.9, 56.6, 46.3, 27.9

C₂₆H₂₃N₄O₃Cl [M-Cl]⁺: 439.176 5, Found:
439.176 7

208.1-210.2

¹H NMR (DMSO-d₆) δ 12.79 (s, 1H), 9.42 (s, 1H), 9.27 (s, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.43 (s, 1H), 7.19 (s, 1H), 7.01 (s, 1H), 4.25 (s, 2H), 4.08 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.06 (s, 2H)

¹³C NMR (DMSO-d₆) δ 160.3, 157.3 (3), 151.6, 150.9, 149.2, 148.8, 143.9, 136.3, 129.7, 128.0, 127.7, 127.3, 120.8, 120.4, 117.7, 111.2, 110.6, 108.8, 100.6, 57.3, 56.5, 56.2, 45.2, 26.9

C₂₆H₂₃N₄O₃Cl [M-Cl]⁺: 439.176 5, Found:
439.176 9

200.0-201.9

¹H NMR (CDCl₃, CD₃OD) δ 8.20 (s, 1H), 7.95 (d, J = 5.4 Hz, 1H), 7.60 (d, J = 3.6 Hz, 1H), 7.57 (d, J = 6.0 Hz, 1H), 7.42 (s, 1H), 7.39-7.33 (m, 2H), 7.29 (s, 1H), 7.25 (s, 1H), 6.92 (s, 1H), 6.89 (s, 1H), 4.18 (s, 5H), 4.00 (s, 3H), 3.97 (s, 3H), 3.18 (s, 2H)

¹³C NMR (CDCl₃, CD₃OD) δ 152.2, 151.8, 150.9, 149.6, 144.2, 138.1, 137.1, 130.0, 129.2, 128.0, 127.4, 124.8, 124.1, 122.8, 121.8, 119.7, 119.0, 118.1, 116.5, 113.7, 111.1, 109.4, 109.3, 109.0, 96.1, 57.2, 56.9, 56.5, 45.5, 28.1

C₃₀H₂₆N₃O₃Cl [M-Cl]⁺: 476.196 9, Found:
476.197 3


BBR	/	> 266	27.0	> 9.89	142
3a	C₆H₅	44.8	4.06	11.0	17.5
3b	p-CH₃C₆H₄	33.7	12.1	2.8	16.8
3c	o, p-(CH₃)₂C₆H₃	15.2	13.0	1.2	16.2
3d	m, p-(CH₃)₂C₆H₃	5.1	4.5	1.1	4.2
3e	m, p-(OCH₃)₂C₆H₃	5.1	5.2	0.99	7.33
3f	p-ClC₆H₄	14.8	15.7	0.94	19.4
3g	p-BrC₆H₄	13.7	16.5	0.83	15.0
3h	m-CNC₆H₄	5.51	2.96	1.86	12.0
3i	p-CNC₆H₄	25.8	29.3	0.87	34.0
3j	2′-Furyl	5.46	4.63	1.18	4.23
3k	2′-Pyrryl	13.1	13.1	1.00	11.1
3l	2′-Thiazolyl	25.2	46.7	0.54	22.4
3m		36.0	1.61	22.2	31.7
3n		94.3	10.2	9.27	35.3
3o		5.93	6.18	0.86	6.88
3p	2′-Pyrazinyl	8.96	4.79	1.87	5.46
3q	5′-Pyrimidyl	58.2	71.2	0.82	24.7
3r	3′-Indolyl	6.00	6.97	0.86	6.80

Compd.

CC₅₀/μmol·L^{-1 a}

EC₅₀-SARS-CoV-2/μmol·L^{-1 b}

SI^c

EC₅₀-G^*ΔG-VSV/μmol·L^-1

BBR

> 266

27.0

> 9.89

142

C₆H₅

44.8

4.06

11.0

17.5

p-CH₃C₆H₄

33.7

12.1

2.8

16.8

o, p-(CH₃)₂C₆H₃

15.2

13.0

1.2

16.2

m, p-(CH₃)₂C₆H₃

5.1

4.5

1.1

4.2

m, p-(OCH₃)₂C₆H₃

5.1

5.2

0.99

7.33

p-ClC₆H₄

14.8

15.7

0.94

19.4

p-BrC₆H₄

13.7

16.5

0.83

15.0

m-CNC₆H₄

5.51

2.96

1.86

12.0

p-CNC₆H₄

25.8

29.3

0.87

34.0

2′-Furyl

5.46

4.63

1.18

4.23

2′-Pyrryl

13.1

1.00

11.1

2′-Thiazolyl

25.2

46.7

0.54

22.4

36.0

1.61

22.2

31.7

94.3

10.2

9.27

35.3

5.93

6.18

0.86

6.88

2′-Pyrazinyl

8.96

4.79

1.87

5.46

5′-Pyrimidyl

58.2

71.2

0.82

24.7

3′-Indolyl

6.00

6.97

0.86

6.80

Code	Absn risk ^a	CYP risk ^b	Rat-TD₅₀^c/mg·kg^-1·d^-1	ADMET risk^d
3m	0.83	1	12.1	4.83

Code

Absn risk ^a

CYP risk ^b

Rat-TD₅₀^c/mg·kg^-1·d^-1

ADMET risk^d

0.83

12.1

4.83