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Compd	Yield /%	mp /℃	¹H NMR	¹³C NMR	HR-ESI-MS (m/z) Formula Calcd. Found
4a	35	254-256	(500 MHz, DMSO-d₆) δ 10.35 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 8.9, 2.3 Hz, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.9 Hz, 1H), 6.45 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 16.9, 2.0 Hz, 1H), 5.75 (dd, J = 10.1, 2.0 Hz, 1H), 4.51 (t, J = 5.8 Hz, 2H), 2.87 (qt, J = 11.2, 5.7 Hz, 2H)	(126 MHz, DMSO-d₆) δ 164.0, 163.2, 152.9 (d, J = 5.04 Hz), 139.0 (d, J = 6.30 Hz), 138.1, 133.8 (d, J = 3.78 Hz), 133.5, 131.9, 131.0, 130.3 (d, J = 16.38 Hz), 127.5, 126.6, 126.2, 125.3, 124.6 (d, J = 5.04 Hz), 124.1 (d, J = 16.38 Hz), 117.7 (dd, J = 31.50 Hz, 3.78 Hz), 115.1 (d, J = 15.12 Hz), 63.0, 32.4 (q, J = 28.98 Hz)	[M+H]⁺ C₂₀H₁₆F₆N₃O₅ 492.098 9, 492.098 5
5b	91	146-147	(600 MHz, DMSO-d₆) δ 9.91 (s, 1H), 7.86 (s, 1H), 7.66 (d, J = 6.3 Hz, 1H), 7.29-7.22 (m, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 5.39 (s, 2H), 4.88 (s, 2H), 4.25 (t, J = 5.9 Hz, 2H), 2.86 (dd, J = 11.4, 5.7 Hz, 2H)	(151 MHz, DMSO-d₆) δ 165.2, 147.3, 142.2, 137.5, 128.2 (d, J = 42.28 Hz), 127.6, 126.1, 125.9 (d, J = 15.10 Hz), 124.1, 118.1 (q, J = 6.04 Hz), 116.9, 116.0, 113.3, 110.8, 110.2 (q, J = 28.69 Hz), 61.3 (d, J = 3.02 Hz), 32.8 (q, J = 27.18 Hz)	[M+H]⁺ C₁₇H₁₆F₆N₃O₂ 408.114 1, 408.112 4
5c	15	202-204	(500 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.74 (s, 1H), 9.29 (s, 1H), 8.67 (s, 1H), 8.26 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.69-6.60 (m, 1H), 6.59-6.50 (m, 1H), 6.28 (t, J = 17.1 Hz, 2H), 5.79 (t, J = 10.2 Hz, 2H), 4.40 (t, J = 6.1 Hz, 2H), 2.93 (dt, J = 11.7, 6.0 Hz, 2H)	(126 MHz, DMSO-d₆) δ 165.1, 164.3, 163.3, 151.4, 137.8, 131.1, 130.7, 129.8, 128.6, 127.6, 127.0, 126.7, 125.4, 125.2, 124.8, 124.4, 123.9, 122.2, 117.5 (d, J = 2.52 Hz), 111.7, 62.0, 41.4, 33.7 (q, J = 27.72 Hz)	[M+H]⁺ C₂₃H₂₀F₆N₃O₄ 516.135 3, 516.133 1
6a	12	211-212	(500 MHz, DMSO-d₆) δ 10.35 (s, 1H), 10.16 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 8.9, 2.3 Hz, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.9 Hz, 1H), 6.45 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 16.9, 2.0 Hz, 1H), 5.75 (dd, J = 10.1, 2.0 Hz, 1H), 4.51 (t, J = 5.8 Hz, 2H), 2.81-2.93 (m, 2H)	(126 MHz, DMSO-d₆) δ 162.7 (d, J = 41.58 Hz), 152.6, 138.9, 135.0, 134.4, 133.6, 131.8, 127.5, 127.2, 126.6, 125.3, 124.4, 120.9 (2), 119.5 (2), 114.9, 62.9 (d, J = 3.78 Hz), 32.5 (q, J = 27.72 Hz)	[M+H]⁺ C₁₉H₁₇F₃N₃O₅ 424.111 5, 424.109 9
6b	45	228-230	(600 MHz, DMSO-d₆) δ 10.38 (s, 1H), 10.30 (s, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.29 (dd, J = 8.7, 2.4 Hz, 1H), 7.74 (t, J = 7.1 Hz, 3H), 7.58 (d, J = 8.8 Hz, 1H), 5.76 (d, J = 3.6 Hz, 1H), 5.68 (d, J = 3.6 Hz, 1H), 5.42 (dd, J = 15.6, 3.6 Hz, 1H), 4.54-4.45 (m, 2H), 2.87 (tt, J = 11.3, 5.7 Hz, 2H)	(151 MHz, DMSO-d₆) δ 165.3, 162.6, 157.4, 157.1 (q, J = 12.08 Hz), 155.2, 152.6, 139.0, 135.2, 133.6, 127.3, 127.1, 125.5, 124.4, 121.0, 120.6, 114.8, 99.6 (d, J = 15.10 Hz), 63.0 (q, J = 3.02 Hz), 32.5 (q, J = 28.18 Hz)	[M+H]⁺ C₁₉H₁₆F₄N₃O₅ 442.102 1, 442.100 3
6c	20	191-193	(600 MHz, DMSO-d₆) δ 9.93 (s, 1H), 9.25 (s, 1H), 7.53 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 6.70 (dt, J = 15.4, 5.9 Hz, 1H), 6.24 (d, J = 15.4 Hz, 1H), 3.04 (s, 1H), 2.94 (s, 1H), 2.17 (s, 5H), 1.47 (s, 8H)	(151 MHz, DMSO-d₆) δ 162.7, 153.9, 152.7, 149.1, 140.7 (2), 135.0, 133.6, 126.0 (2), 119.6 (2), 118.4, 106.6, 78.7, 59.7, 44.8 (d, J = 87.58 Hz, 2C), 38.5, 28.0 (3)	[M+H]⁺ C₂₂H₂₄F₃N₄O₅ 481.169 3, 481.169 0
6d	55	74-76	(600 MHz, DMSO-d₆) δ 10.20 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.27 (dd, J = 8.9, 2.4 Hz, 1H), 7.98 (dd, J = 16.1, 2.2 Hz, 1H), 7.75 (ddd, J = 15.0, 8.5, 2.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.49 (t, J = 8.8 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.51 (d, J = 8.2 Hz, 1H), 4.66-4.62 (m, 1H), 4.51 (d, J = 5.7 Hz, 1H), 4.49 (d, J = 9.1 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 3.60 (s, 1H), 2.99-2.85 (m, 6H)	(151 MHz, DMSO-d₆) δ 166.6 (d, J = 13.59 Hz), 162.2 (d, J = 4.53 Hz), 152.5, 151.0 (d, J = 7.55 Hz), 147.2, 142.7, 141.9, 139.1 (d, J = 34.73 Hz), 133.5, 133.0 (d, J = 7.55 Hz), 131.1, 128.4 (d, J = 13.59 Hz), 127.3 (d, J = 7.55 Hz), 125.5, 124.0 (d, J = 6.04 Hz), 121.6, 118.7, 116.1, 114.9 (dd, J = 30.20 Hz, 4.53 Hz), 62.9 (dd, J = 18.12 Hz, 3.02 Hz), 32.5 (q, J = 28.69 Hz)	[M+2H]²⁺ C₂₁H₂₅F₃N₃O₄ 439.170 7, 439.168 9
6e	14	178-180	(500 MHz, DMSO-d₆) δ 9.97 (s, 1H), 7.99 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.41 (dd, J = 16.9, 10.1 Hz, 2H), 6.22 (d, J = 16.9 Hz, 1H), 5.70 (d, J = 10.3 Hz, 1H), 4.47 (s, 1H), 3.73 (s, 3H), 3.56 (s, 1H), 3.14 (s, 4H), 2.84 (qt, J = 11.6, 5.8 Hz, 2H), 1.23 (s, 1H)	(126 MHz, DMSO-d₆) δ 166.6, 162.4, 151.0, 146.9, 139.2, 133.0, 131.9, 131.4, 128.3, 127.5, 126.0, 125.3, 124.0, 123.1, 120.2 (2), 116.3 (2), 115.0, 62.8 (d, J = 3.78 Hz), 48.8 (2), 47.1, 32.5 (q, J = 27.72 Hz)	[M+2H]²⁺ C₂₄H₂₆F₃N₃O₅ 493.181 4, 493.179 6
7b	92	151-153	(600 MHz, DMSO-d₆) δ 9.84 (s, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.64 (dd, J = 8.8, 2.5 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.3, 2.3 Hz, 1H), 6.84 (t, J = 9.1 Hz, 2H), 5.37 (s, 2H), 4.83 (s, 2H), 3.88 (d, J = 6.9 Hz, 2H), 1.32-1.21 (m, 1H), 0.58 (dt, J = 8.0, 3.0 Hz, 2H), 0.36 (dt, J = 4.8, 2.9 Hz, 2H)	(151 MHz, DMSO-d₆) δ 165.2, 148.1, 142.2, 137.4, 128.3, 127.2, 126.0, 118.0 (q, J = 6.04 Hz), 116.9, 116.0, 113.1, 110.7, 110.2 (q, J = 30.2 Hz), 72.3, 39.9, 10.1, 3.0 (2)	[M+H]⁺ C₁₈H₁₉F₃N₃O₂ 366.142 4, 366.140 8
7c	16	105-107	(500 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.73 (s, 1H), 9.43 (s, 1H), 8.61 (s, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.09 (dd, J = 8.8, 2.4 Hz, 1H), 7.81 (dd, J = 8.6, 2.4 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.73 (dd, J = 16.8, 10.1 Hz, 2H), 6.54 (ddd, J = 14.1, 10.2, 4.0 Hz, 2H), 6.34-6.23 (m, 2H), 5.78 (d, J = 10.3 Hz, 1H), 4.04 (s, 1H), 1.37-1.26 (m, 1H), 0.60 (d, J = 8.1 Hz, 2H), 0.40 (d, J = 4.8 Hz, 2H)	(126 MHz, DMSO-d₆) δ 165.1, 164.3, 163.4, 152.5, 137.9, 136.2, 131.8, 130.7, 130.1, 129.7, 127.0, 126.9 (d, J = 5.05 Hz), 126.0, 125.2, 124.9, 124.4, 123.9, 122.8, 117.4 (d, J = 5.04 Hz), 111.9, 73.1, 9.9, 3.2 (2)	[M+H]⁺ C₂₄H₂₃F₃N₃O₄ 474.163 5, 474.161 3
8a	11	200-202	(500 MHz, DMSO-d₆) δ 9.96 (s, 1H), 8.35 (s, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.7, 2.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.40 (dd, J = 16.9, 10.1 Hz, 1H), 6.21 (dd, J = 17.0, 2.1 Hz, 1H), 5.70 (dd, J = 10.1, 2.1 Hz, 1H), 4.09 (d, J = 7.0 Hz, 2H), 1.25 (t, J = 7.6 Hz, 1H), 0.59 (d, J = 8.0 Hz, 2H), 0.36 (d, J = 4.7 Hz, 2H)	(126 MHz, DMSO-d₆) δ 166.6, 162.4, 151.8, 146.8, 139.1, 132.9, 131.9, 131.4, 127.4, 126.0, 123.9, 120.2, 116.2, 115.1, 73.8, 48.7 (2), 9.6, 2.9 (2)	[M+H]⁺ C₂₀H₂₀N₃O₅ 382.139 8, 382.137 8
8b	13	242-243	(600 MHz, DMSO-d₆) δ 10.34 (s, 1H), 8.51 (s, 1H), 8.27-8.22 (m, 1H), 7.72 (q, J = 8.3 Hz, 4H), 7.49 (d, J = 8.9 Hz, 1H), 5.77-5.73 (m, 1H), 5.69-5.65 (m, 1H), 5.42 (dd, J = 15.4, 3.8 Hz, 1H), 4.14 (d, J = 7.0 Hz, 2H), 1.27 (ddt, J = 12.1, 7.7, 3.8 Hz, 1H), 0.60 (d, J = 8.1 Hz, 2H), 0.39 (q, J = 6.1 Hz, 2H)	(151 MHz, DMSO-d₆) δ 162.7, 157.3, 157.1 (d, J = 12.08 Hz), 155.2, 153.5, 138.9, 135.2, 133.5, 126.4, 124.3, 121.0 (2), 120.6 (2), 115.0, 99.6 (d, J = 15.10 Hz), 74.0, 9.6, 3.0 (2)	[M+H]⁺ C₂₀H₁₉FN₃O₅ 400.130 3, 400.128 9
8c	11	200-202	(500 MHz, DMSO-d₆) δ 9.96 (s, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.7, 2.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.40 (dd, J = 16.9, 10.1 Hz, 1H), 6.21 (dd, J = 16.9, 2.1 Hz, 1H), 5.70 (dd, J = 10.1, 2.1 Hz, 1H), 4.09 (d, J = 7.0 Hz, 2H), 3.45-3.85 (m, 5H), 3.14 (s, 4H), 1.24 (td, J = 7.5, 3.7 Hz, 1H), 0.59 (dt, J = 8.2, 3.1 Hz, 2H), 0.36 (dt, J = 6.3, 4.4 Hz, 2H)	(126 MHz, DMSO-d₆) δ 166.7, 162.5, 151.9, 146.9, 139.1, 133.0 (2), 131.9, 131.5, 127.5, 126.0, 124.0 (2), 120.3 (2), 116.3 (2), 115.2, 73.8, 48.7 (2), 47.0, 9.6, 3.0 (2)	[M+H]⁺ C₂₅H₂₈N₃O₅ 450.202 4, 450.199 9

Compd

Yield /%

mp /℃

¹H NMR

¹³C NMR

HR-ESI-MS
(m/z)
Formula
Calcd.
Found

254-256

(500 MHz, DMSO-d₆) δ 10.35 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 8.9, 2.3 Hz, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.9 Hz, 1H), 6.45 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 16.9, 2.0 Hz, 1H), 5.75 (dd, J = 10.1, 2.0 Hz, 1H), 4.51 (t, J = 5.8 Hz, 2H), 2.87 (qt, J = 11.2, 5.7 Hz, 2H)

(126 MHz, DMSO-d₆) δ 164.0, 163.2, 152.9 (d, J = 5.04 Hz), 139.0 (d, J = 6.30 Hz), 138.1, 133.8 (d, J = 3.78 Hz), 133.5, 131.9, 131.0, 130.3 (d, J = 16.38 Hz), 127.5, 126.6, 126.2, 125.3, 124.6 (d, J = 5.04 Hz), 124.1 (d, J = 16.38 Hz), 117.7 (dd, J = 31.50 Hz, 3.78 Hz), 115.1 (d, J = 15.12 Hz), 63.0, 32.4 (q, J = 28.98 Hz)

[M+H]⁺
C₂₀H₁₆F₆N₃O₅
492.098 9,
492.098 5

146-147

(600 MHz, DMSO-d₆) δ 9.91 (s, 1H), 7.86 (s, 1H), 7.66 (d, J = 6.3 Hz, 1H), 7.29-7.22 (m, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 5.39 (s, 2H), 4.88 (s, 2H), 4.25 (t, J = 5.9 Hz, 2H), 2.86 (dd, J = 11.4, 5.7 Hz, 2H)

(151 MHz, DMSO-d₆) δ 165.2, 147.3, 142.2, 137.5, 128.2 (d, J = 42.28 Hz), 127.6, 126.1, 125.9 (d, J = 15.10 Hz), 124.1, 118.1 (q, J = 6.04 Hz), 116.9, 116.0, 113.3, 110.8, 110.2 (q, J = 28.69 Hz), 61.3 (d, J = 3.02 Hz), 32.8 (q, J = 27.18 Hz)

[M+H]⁺
C₁₇H₁₆F₆N₃O₂
408.114 1,
408.112 4

202-204

(500 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.74 (s, 1H), 9.29 (s, 1H), 8.67 (s, 1H), 8.26 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.69-6.60 (m, 1H), 6.59-6.50 (m, 1H), 6.28 (t, J = 17.1 Hz, 2H), 5.79 (t, J = 10.2 Hz, 2H), 4.40 (t, J = 6.1 Hz, 2H), 2.93 (dt, J = 11.7, 6.0 Hz, 2H)

(126 MHz, DMSO-d₆) δ 165.1, 164.3, 163.3, 151.4, 137.8, 131.1, 130.7, 129.8, 128.6, 127.6, 127.0, 126.7, 125.4, 125.2, 124.8, 124.4, 123.9, 122.2, 117.5 (d, J = 2.52 Hz), 111.7, 62.0, 41.4, 33.7 (q, J = 27.72 Hz)

[M+H]⁺
C₂₃H₂₀F₆N₃O₄
516.135 3,
516.133 1

211-212

(500 MHz, DMSO-d₆) δ 10.35 (s, 1H), 10.16 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 8.9, 2.3 Hz, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.9 Hz, 1H), 6.45 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 16.9, 2.0 Hz, 1H), 5.75 (dd, J = 10.1, 2.0 Hz, 1H), 4.51 (t, J = 5.8 Hz, 2H), 2.81-2.93 (m, 2H)

(126 MHz, DMSO-d₆) δ 162.7 (d, J = 41.58 Hz), 152.6, 138.9, 135.0, 134.4, 133.6, 131.8, 127.5, 127.2, 126.6, 125.3, 124.4, 120.9 (2), 119.5 (2), 114.9, 62.9 (d, J = 3.78 Hz), 32.5 (q, J = 27.72 Hz)

[M+H]⁺
C₁₉H₁₇F₃N₃O₅
424.111 5,
424.109 9

228-230

(600 MHz, DMSO-d₆) δ 10.38 (s, 1H), 10.30 (s, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.29 (dd, J = 8.7, 2.4 Hz, 1H), 7.74 (t, J = 7.1 Hz, 3H), 7.58 (d, J = 8.8 Hz, 1H), 5.76 (d, J = 3.6 Hz, 1H), 5.68 (d, J = 3.6 Hz, 1H), 5.42 (dd, J = 15.6, 3.6 Hz, 1H), 4.54-4.45 (m, 2H), 2.87 (tt, J = 11.3, 5.7 Hz, 2H)

(151 MHz, DMSO-d₆) δ 165.3, 162.6, 157.4, 157.1 (q, J = 12.08 Hz), 155.2, 152.6, 139.0, 135.2, 133.6, 127.3, 127.1, 125.5, 124.4, 121.0, 120.6, 114.8, 99.6 (d, J = 15.10 Hz), 63.0 (q, J = 3.02 Hz), 32.5 (q, J = 28.18 Hz)

[M+H]⁺
C₁₉H₁₆F₄N₃O₅
442.102 1,
442.100 3

191-193

(600 MHz, DMSO-d₆) δ 9.93 (s, 1H), 9.25 (s, 1H), 7.53 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 6.70 (dt, J = 15.4, 5.9 Hz, 1H), 6.24 (d, J = 15.4 Hz, 1H), 3.04 (s, 1H), 2.94 (s, 1H), 2.17 (s, 5H), 1.47 (s, 8H)

(151 MHz, DMSO-d₆) δ 162.7, 153.9, 152.7, 149.1, 140.7 (2), 135.0, 133.6, 126.0 (2), 119.6 (2), 118.4, 106.6, 78.7, 59.7, 44.8 (d, J = 87.58 Hz, 2C), 38.5, 28.0 (3)

[M+H]⁺
C₂₂H₂₄F₃N₄O₅
481.169 3,
481.169 0

74-76

(600 MHz, DMSO-d₆) δ 10.20 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.27 (dd, J = 8.9, 2.4 Hz, 1H), 7.98 (dd, J = 16.1, 2.2 Hz, 1H), 7.75 (ddd, J = 15.0, 8.5, 2.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.49 (t, J = 8.8 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.51 (d, J = 8.2 Hz, 1H), 4.66-4.62 (m, 1H), 4.51 (d, J = 5.7 Hz, 1H), 4.49 (d, J = 9.1 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 3.60 (s, 1H), 2.99-2.85 (m, 6H)

(151 MHz, DMSO-d₆) δ 166.6 (d, J = 13.59 Hz), 162.2 (d, J = 4.53 Hz), 152.5, 151.0 (d, J = 7.55 Hz), 147.2, 142.7, 141.9, 139.1 (d, J = 34.73 Hz), 133.5, 133.0 (d, J = 7.55 Hz), 131.1, 128.4 (d, J = 13.59 Hz), 127.3 (d, J = 7.55 Hz), 125.5, 124.0 (d, J = 6.04 Hz), 121.6, 118.7, 116.1, 114.9 (dd, J = 30.20 Hz, 4.53 Hz), 62.9 (dd, J = 18.12 Hz, 3.02 Hz), 32.5 (q, J = 28.69 Hz)

[M+2H]²⁺
C₂₁H₂₅F₃N₃O₄
439.170 7,
439.168 9

178-180

(500 MHz, DMSO-d₆) δ 9.97 (s, 1H), 7.99 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.41 (dd, J = 16.9, 10.1 Hz, 2H), 6.22 (d, J = 16.9 Hz, 1H), 5.70 (d, J = 10.3 Hz, 1H), 4.47 (s, 1H), 3.73 (s, 3H), 3.56 (s, 1H), 3.14 (s, 4H), 2.84 (qt, J = 11.6, 5.8 Hz, 2H), 1.23 (s, 1H)

(126 MHz, DMSO-d₆) δ 166.6, 162.4, 151.0, 146.9, 139.2, 133.0, 131.9, 131.4, 128.3, 127.5, 126.0, 125.3, 124.0, 123.1, 120.2 (2), 116.3 (2), 115.0, 62.8 (d, J = 3.78 Hz), 48.8 (2), 47.1, 32.5 (q, J = 27.72 Hz)

[M+2H]²⁺
C₂₄H₂₆F₃N₃O₅
493.181 4,
493.179 6

151-153

(600 MHz, DMSO-d₆) δ 9.84 (s, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.64 (dd, J = 8.8, 2.5 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.3, 2.3 Hz, 1H), 6.84 (t, J = 9.1 Hz, 2H), 5.37 (s, 2H), 4.83 (s, 2H), 3.88 (d, J = 6.9 Hz, 2H), 1.32-1.21 (m, 1H), 0.58 (dt, J = 8.0, 3.0 Hz, 2H), 0.36 (dt, J = 4.8, 2.9 Hz, 2H)

(151 MHz, DMSO-d₆) δ 165.2, 148.1, 142.2, 137.4, 128.3, 127.2, 126.0, 118.0 (q, J = 6.04 Hz), 116.9, 116.0, 113.1, 110.7, 110.2 (q, J = 30.2 Hz), 72.3, 39.9, 10.1, 3.0 (2)

[M+H]⁺
C₁₈H₁₉F₃N₃O₂
366.142 4,
366.140 8

105-107

(500 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.73 (s, 1H), 9.43 (s, 1H), 8.61 (s, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.09 (dd, J = 8.8, 2.4 Hz, 1H), 7.81 (dd, J = 8.6, 2.4 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.73 (dd, J = 16.8, 10.1 Hz, 2H), 6.54 (ddd, J = 14.1, 10.2, 4.0 Hz, 2H), 6.34-6.23 (m, 2H), 5.78 (d, J = 10.3 Hz, 1H), 4.04 (s, 1H), 1.37-1.26 (m, 1H), 0.60 (d, J = 8.1 Hz, 2H), 0.40 (d, J = 4.8 Hz, 2H)

(126 MHz, DMSO-d₆) δ 165.1, 164.3, 163.4, 152.5, 137.9, 136.2, 131.8, 130.7, 130.1, 129.7, 127.0, 126.9 (d, J = 5.05 Hz), 126.0, 125.2, 124.9, 124.4, 123.9, 122.8, 117.4 (d, J = 5.04 Hz), 111.9, 73.1, 9.9, 3.2 (2)

[M+H]⁺
C₂₄H₂₃F₃N₃O₄
474.163 5,
474.161 3

200-202

(500 MHz, DMSO-d₆) δ 9.96 (s, 1H), 8.35 (s, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.7, 2.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.40 (dd, J = 16.9, 10.1 Hz, 1H), 6.21 (dd, J = 17.0, 2.1 Hz, 1H), 5.70 (dd, J = 10.1, 2.1 Hz, 1H), 4.09 (d, J = 7.0 Hz, 2H), 1.25 (t, J = 7.6 Hz, 1H), 0.59 (d, J = 8.0 Hz, 2H), 0.36 (d, J = 4.7 Hz, 2H)

(126 MHz, DMSO-d₆) δ 166.6, 162.4, 151.8, 146.8, 139.1, 132.9, 131.9, 131.4, 127.4, 126.0, 123.9, 120.2, 116.2, 115.1, 73.8, 48.7 (2), 9.6, 2.9 (2)

[M+H]⁺
C₂₀H₂₀N₃O₅
382.139 8,
382.137 8

242-243

(600 MHz, DMSO-d₆) δ 10.34 (s, 1H), 8.51 (s, 1H), 8.27-8.22 (m, 1H), 7.72 (q, J = 8.3 Hz, 4H), 7.49 (d, J = 8.9 Hz, 1H), 5.77-5.73 (m, 1H), 5.69-5.65 (m, 1H), 5.42 (dd, J = 15.4, 3.8 Hz, 1H), 4.14 (d, J = 7.0 Hz, 2H), 1.27 (ddt, J = 12.1, 7.7, 3.8 Hz, 1H), 0.60 (d, J = 8.1 Hz, 2H), 0.39 (q, J = 6.1 Hz, 2H)

(151 MHz, DMSO-d₆) δ 162.7, 157.3, 157.1 (d, J = 12.08 Hz), 155.2, 153.5, 138.9, 135.2, 133.5, 126.4, 124.3, 121.0 (2), 120.6 (2), 115.0, 99.6 (d, J = 15.10 Hz), 74.0, 9.6, 3.0 (2)

[M+H]⁺
C₂₀H₁₉FN₃O₅
400.130 3,
400.128 9

200-202

(500 MHz, DMSO-d₆) δ 9.96 (s, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.7, 2.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.40 (dd, J = 16.9, 10.1 Hz, 1H), 6.21 (dd, J = 16.9, 2.1 Hz, 1H), 5.70 (dd, J = 10.1, 2.1 Hz, 1H), 4.09 (d, J = 7.0 Hz, 2H), 3.45-3.85 (m, 5H), 3.14 (s, 4H), 1.24 (td, J = 7.5, 3.7 Hz, 1H), 0.59 (dt, J = 8.2, 3.1 Hz, 2H), 0.36 (dt, J = 6.3, 4.4 Hz, 2H)

(126 MHz, DMSO-d₆) δ 166.7, 162.5, 151.9, 146.9, 139.1, 133.0 (2), 131.9, 131.5, 127.5, 126.0, 124.0 (2), 120.3 (2), 116.3 (2), 115.2, 73.8, 48.7 (2), 47.0, 9.6, 3.0 (2)

[M+H]⁺
C₂₅H₂₈N₃O₅
450.202 4,
450.199 9

Compd	Yield /%	mp /℃	¹H NMR	¹³C NMR	HR-ESI-MS (m/z) Formula Calcd. Found
4a	35	254-256	(500 MHz, DMSO-d₆) δ 10.35 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 8.9, 2.3 Hz, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.9 Hz, 1H), 6.45 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 16.9, 2.0 Hz, 1H), 5.75 (dd, J = 10.1, 2.0 Hz, 1H), 4.51 (t, J = 5.8 Hz, 2H), 2.87 (qt, J = 11.2, 5.7 Hz, 2H)	(126 MHz, DMSO-d₆) δ 164.0, 163.2, 152.9 (d, J = 5.04 Hz), 139.0 (d, J = 6.30 Hz), 138.1, 133.8 (d, J = 3.78 Hz), 133.5, 131.9, 131.0, 130.3 (d, J = 16.38 Hz), 127.5, 126.6, 126.2, 125.3, 124.6 (d, J = 5.04 Hz), 124.1 (d, J = 16.38 Hz), 117.7 (dd, J = 31.50 Hz, 3.78 Hz), 115.1 (d, J = 15.12 Hz), 63.0, 32.4 (q, J = 28.98 Hz)	[M+H]⁺ C₂₀H₁₆F₆N₃O₅ 492.098 9, 492.098 5
5b	91	146-147	(600 MHz, DMSO-d₆) δ 9.91 (s, 1H), 7.86 (s, 1H), 7.66 (d, J = 6.3 Hz, 1H), 7.29-7.22 (m, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 5.39 (s, 2H), 4.88 (s, 2H), 4.25 (t, J = 5.9 Hz, 2H), 2.86 (dd, J = 11.4, 5.7 Hz, 2H)	(151 MHz, DMSO-d₆) δ 165.2, 147.3, 142.2, 137.5, 128.2 (d, J = 42.28 Hz), 127.6, 126.1, 125.9 (d, J = 15.10 Hz), 124.1, 118.1 (q, J = 6.04 Hz), 116.9, 116.0, 113.3, 110.8, 110.2 (q, J = 28.69 Hz), 61.3 (d, J = 3.02 Hz), 32.8 (q, J = 27.18 Hz)	[M+H]⁺ C₁₇H₁₆F₆N₃O₂ 408.114 1, 408.112 4
5c	15	202-204	(500 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.74 (s, 1H), 9.29 (s, 1H), 8.67 (s, 1H), 8.26 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.69-6.60 (m, 1H), 6.59-6.50 (m, 1H), 6.28 (t, J = 17.1 Hz, 2H), 5.79 (t, J = 10.2 Hz, 2H), 4.40 (t, J = 6.1 Hz, 2H), 2.93 (dt, J = 11.7, 6.0 Hz, 2H)	(126 MHz, DMSO-d₆) δ 165.1, 164.3, 163.3, 151.4, 137.8, 131.1, 130.7, 129.8, 128.6, 127.6, 127.0, 126.7, 125.4, 125.2, 124.8, 124.4, 123.9, 122.2, 117.5 (d, J = 2.52 Hz), 111.7, 62.0, 41.4, 33.7 (q, J = 27.72 Hz)	[M+H]⁺ C₂₃H₂₀F₆N₃O₄ 516.135 3, 516.133 1
6a	12	211-212	(500 MHz, DMSO-d₆) δ 10.35 (s, 1H), 10.16 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 8.9, 2.3 Hz, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.9 Hz, 1H), 6.45 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 16.9, 2.0 Hz, 1H), 5.75 (dd, J = 10.1, 2.0 Hz, 1H), 4.51 (t, J = 5.8 Hz, 2H), 2.81-2.93 (m, 2H)	(126 MHz, DMSO-d₆) δ 162.7 (d, J = 41.58 Hz), 152.6, 138.9, 135.0, 134.4, 133.6, 131.8, 127.5, 127.2, 126.6, 125.3, 124.4, 120.9 (2), 119.5 (2), 114.9, 62.9 (d, J = 3.78 Hz), 32.5 (q, J = 27.72 Hz)	[M+H]⁺ C₁₉H₁₇F₃N₃O₅ 424.111 5, 424.109 9
6b	45	228-230	(600 MHz, DMSO-d₆) δ 10.38 (s, 1H), 10.30 (s, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.29 (dd, J = 8.7, 2.4 Hz, 1H), 7.74 (t, J = 7.1 Hz, 3H), 7.58 (d, J = 8.8 Hz, 1H), 5.76 (d, J = 3.6 Hz, 1H), 5.68 (d, J = 3.6 Hz, 1H), 5.42 (dd, J = 15.6, 3.6 Hz, 1H), 4.54-4.45 (m, 2H), 2.87 (tt, J = 11.3, 5.7 Hz, 2H)	(151 MHz, DMSO-d₆) δ 165.3, 162.6, 157.4, 157.1 (q, J = 12.08 Hz), 155.2, 152.6, 139.0, 135.2, 133.6, 127.3, 127.1, 125.5, 124.4, 121.0, 120.6, 114.8, 99.6 (d, J = 15.10 Hz), 63.0 (q, J = 3.02 Hz), 32.5 (q, J = 28.18 Hz)	[M+H]⁺ C₁₉H₁₆F₄N₃O₅ 442.102 1, 442.100 3
6c	20	191-193	(600 MHz, DMSO-d₆) δ 9.93 (s, 1H), 9.25 (s, 1H), 7.53 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 6.70 (dt, J = 15.4, 5.9 Hz, 1H), 6.24 (d, J = 15.4 Hz, 1H), 3.04 (s, 1H), 2.94 (s, 1H), 2.17 (s, 5H), 1.47 (s, 8H)	(151 MHz, DMSO-d₆) δ 162.7, 153.9, 152.7, 149.1, 140.7 (2), 135.0, 133.6, 126.0 (2), 119.6 (2), 118.4, 106.6, 78.7, 59.7, 44.8 (d, J = 87.58 Hz, 2C), 38.5, 28.0 (3)	[M+H]⁺ C₂₂H₂₄F₃N₄O₅ 481.169 3, 481.169 0
6d	55	74-76	(600 MHz, DMSO-d₆) δ 10.20 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.27 (dd, J = 8.9, 2.4 Hz, 1H), 7.98 (dd, J = 16.1, 2.2 Hz, 1H), 7.75 (ddd, J = 15.0, 8.5, 2.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.49 (t, J = 8.8 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.51 (d, J = 8.2 Hz, 1H), 4.66-4.62 (m, 1H), 4.51 (d, J = 5.7 Hz, 1H), 4.49 (d, J = 9.1 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 3.60 (s, 1H), 2.99-2.85 (m, 6H)	(151 MHz, DMSO-d₆) δ 166.6 (d, J = 13.59 Hz), 162.2 (d, J = 4.53 Hz), 152.5, 151.0 (d, J = 7.55 Hz), 147.2, 142.7, 141.9, 139.1 (d, J = 34.73 Hz), 133.5, 133.0 (d, J = 7.55 Hz), 131.1, 128.4 (d, J = 13.59 Hz), 127.3 (d, J = 7.55 Hz), 125.5, 124.0 (d, J = 6.04 Hz), 121.6, 118.7, 116.1, 114.9 (dd, J = 30.20 Hz, 4.53 Hz), 62.9 (dd, J = 18.12 Hz, 3.02 Hz), 32.5 (q, J = 28.69 Hz)	[M+2H]²⁺ C₂₁H₂₅F₃N₃O₄ 439.170 7, 439.168 9
6e	14	178-180	(500 MHz, DMSO-d₆) δ 9.97 (s, 1H), 7.99 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.41 (dd, J = 16.9, 10.1 Hz, 2H), 6.22 (d, J = 16.9 Hz, 1H), 5.70 (d, J = 10.3 Hz, 1H), 4.47 (s, 1H), 3.73 (s, 3H), 3.56 (s, 1H), 3.14 (s, 4H), 2.84 (qt, J = 11.6, 5.8 Hz, 2H), 1.23 (s, 1H)	(126 MHz, DMSO-d₆) δ 166.6, 162.4, 151.0, 146.9, 139.2, 133.0, 131.9, 131.4, 128.3, 127.5, 126.0, 125.3, 124.0, 123.1, 120.2 (2), 116.3 (2), 115.0, 62.8 (d, J = 3.78 Hz), 48.8 (2), 47.1, 32.5 (q, J = 27.72 Hz)	[M+2H]²⁺ C₂₄H₂₆F₃N₃O₅ 493.181 4, 493.179 6
7b	92	151-153	(600 MHz, DMSO-d₆) δ 9.84 (s, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.64 (dd, J = 8.8, 2.5 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.3, 2.3 Hz, 1H), 6.84 (t, J = 9.1 Hz, 2H), 5.37 (s, 2H), 4.83 (s, 2H), 3.88 (d, J = 6.9 Hz, 2H), 1.32-1.21 (m, 1H), 0.58 (dt, J = 8.0, 3.0 Hz, 2H), 0.36 (dt, J = 4.8, 2.9 Hz, 2H)	(151 MHz, DMSO-d₆) δ 165.2, 148.1, 142.2, 137.4, 128.3, 127.2, 126.0, 118.0 (q, J = 6.04 Hz), 116.9, 116.0, 113.1, 110.7, 110.2 (q, J = 30.2 Hz), 72.3, 39.9, 10.1, 3.0 (2)	[M+H]⁺ C₁₈H₁₉F₃N₃O₂ 366.142 4, 366.140 8
7c	16	105-107	(500 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.73 (s, 1H), 9.43 (s, 1H), 8.61 (s, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.09 (dd, J = 8.8, 2.4 Hz, 1H), 7.81 (dd, J = 8.6, 2.4 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.73 (dd, J = 16.8, 10.1 Hz, 2H), 6.54 (ddd, J = 14.1, 10.2, 4.0 Hz, 2H), 6.34-6.23 (m, 2H), 5.78 (d, J = 10.3 Hz, 1H), 4.04 (s, 1H), 1.37-1.26 (m, 1H), 0.60 (d, J = 8.1 Hz, 2H), 0.40 (d, J = 4.8 Hz, 2H)	(126 MHz, DMSO-d₆) δ 165.1, 164.3, 163.4, 152.5, 137.9, 136.2, 131.8, 130.7, 130.1, 129.7, 127.0, 126.9 (d, J = 5.05 Hz), 126.0, 125.2, 124.9, 124.4, 123.9, 122.8, 117.4 (d, J = 5.04 Hz), 111.9, 73.1, 9.9, 3.2 (2)	[M+H]⁺ C₂₄H₂₃F₃N₃O₄ 474.163 5, 474.161 3
8a	11	200-202	(500 MHz, DMSO-d₆) δ 9.96 (s, 1H), 8.35 (s, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.7, 2.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.40 (dd, J = 16.9, 10.1 Hz, 1H), 6.21 (dd, J = 17.0, 2.1 Hz, 1H), 5.70 (dd, J = 10.1, 2.1 Hz, 1H), 4.09 (d, J = 7.0 Hz, 2H), 1.25 (t, J = 7.6 Hz, 1H), 0.59 (d, J = 8.0 Hz, 2H), 0.36 (d, J = 4.7 Hz, 2H)	(126 MHz, DMSO-d₆) δ 166.6, 162.4, 151.8, 146.8, 139.1, 132.9, 131.9, 131.4, 127.4, 126.0, 123.9, 120.2, 116.2, 115.1, 73.8, 48.7 (2), 9.6, 2.9 (2)	[M+H]⁺ C₂₀H₂₀N₃O₅ 382.139 8, 382.137 8
8b	13	242-243	(600 MHz, DMSO-d₆) δ 10.34 (s, 1H), 8.51 (s, 1H), 8.27-8.22 (m, 1H), 7.72 (q, J = 8.3 Hz, 4H), 7.49 (d, J = 8.9 Hz, 1H), 5.77-5.73 (m, 1H), 5.69-5.65 (m, 1H), 5.42 (dd, J = 15.4, 3.8 Hz, 1H), 4.14 (d, J = 7.0 Hz, 2H), 1.27 (ddt, J = 12.1, 7.7, 3.8 Hz, 1H), 0.60 (d, J = 8.1 Hz, 2H), 0.39 (q, J = 6.1 Hz, 2H)	(151 MHz, DMSO-d₆) δ 162.7, 157.3, 157.1 (d, J = 12.08 Hz), 155.2, 153.5, 138.9, 135.2, 133.5, 126.4, 124.3, 121.0 (2), 120.6 (2), 115.0, 99.6 (d, J = 15.10 Hz), 74.0, 9.6, 3.0 (2)	[M+H]⁺ C₂₀H₁₉FN₃O₅ 400.130 3, 400.128 9
8c	11	200-202	(500 MHz, DMSO-d₆) δ 9.96 (s, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.7, 2.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.40 (dd, J = 16.9, 10.1 Hz, 1H), 6.21 (dd, J = 16.9, 2.1 Hz, 1H), 5.70 (dd, J = 10.1, 2.1 Hz, 1H), 4.09 (d, J = 7.0 Hz, 2H), 3.45-3.85 (m, 5H), 3.14 (s, 4H), 1.24 (td, J = 7.5, 3.7 Hz, 1H), 0.59 (dt, J = 8.2, 3.1 Hz, 2H), 0.36 (dt, J = 6.3, 4.4 Hz, 2H)	(126 MHz, DMSO-d₆) δ 166.7, 162.5, 151.9, 146.9, 139.1, 133.0 (2), 131.9, 131.5, 127.5, 126.0, 124.0 (2), 120.3 (2), 116.3 (2), 115.2, 73.8, 48.7 (2), 47.0, 9.6, 3.0 (2)	[M+H]⁺ C₂₅H₂₈N₃O₅ 450.202 4, 450.199 9

Compd

Yield /%

mp /℃

¹H NMR

¹³C NMR

HR-ESI-MS
(m/z)
Formula
Calcd.
Found

254-256

[M+H]⁺
C₂₀H₁₆F₆N₃O₅
492.098 9,
492.098 5

146-147

[M+H]⁺
C₁₇H₁₆F₆N₃O₂
408.114 1,
408.112 4

202-204

[M+H]⁺
C₂₃H₂₀F₆N₃O₄
516.135 3,
516.133 1

211-212

[M+H]⁺
C₁₉H₁₇F₃N₃O₅
424.111 5,
424.109 9

228-230

[M+H]⁺
C₁₉H₁₆F₄N₃O₅
442.102 1,
442.100 3

191-193

(151 MHz, DMSO-d₆) δ 162.7, 153.9, 152.7, 149.1, 140.7 (2), 135.0, 133.6, 126.0 (2), 119.6 (2), 118.4, 106.6, 78.7, 59.7, 44.8 (d, J = 87.58 Hz, 2C), 38.5, 28.0 (3)

[M+H]⁺
C₂₂H₂₄F₃N₄O₅
481.169 3,
481.169 0

74-76

[M+2H]²⁺
C₂₁H₂₅F₃N₃O₄
439.170 7,
439.168 9

178-180

[M+2H]²⁺
C₂₄H₂₆F₃N₃O₅
493.181 4,
493.179 6

151-153

(151 MHz, DMSO-d₆) δ 165.2, 148.1, 142.2, 137.4, 128.3, 127.2, 126.0, 118.0 (q, J = 6.04 Hz), 116.9, 116.0, 113.1, 110.7, 110.2 (q, J = 30.2 Hz), 72.3, 39.9, 10.1, 3.0 (2)

[M+H]⁺
C₁₈H₁₉F₃N₃O₂
366.142 4,
366.140 8

105-107

[M+H]⁺
C₂₄H₂₃F₃N₃O₄
474.163 5,
474.161 3

200-202

(126 MHz, DMSO-d₆) δ 166.6, 162.4, 151.8, 146.8, 139.1, 132.9, 131.9, 131.4, 127.4, 126.0, 123.9, 120.2, 116.2, 115.1, 73.8, 48.7 (2), 9.6, 2.9 (2)

[M+H]⁺
C₂₀H₂₀N₃O₅
382.139 8,
382.137 8

242-243

(151 MHz, DMSO-d₆) δ 162.7, 157.3, 157.1 (d, J = 12.08 Hz), 155.2, 153.5, 138.9, 135.2, 133.5, 126.4, 124.3, 121.0 (2), 120.6 (2), 115.0, 99.6 (d, J = 15.10 Hz), 74.0, 9.6, 3.0 (2)

[M+H]⁺
C₂₀H₁₉FN₃O₅
400.130 3,
400.128 9

200-202

(126 MHz, DMSO-d₆) δ 166.7, 162.5, 151.9, 146.9, 139.1, 133.0 (2), 131.9, 131.5, 127.5, 126.0, 124.0 (2), 120.3 (2), 116.3 (2), 115.2, 73.8, 48.7 (2), 47.0, 9.6, 3.0 (2)

[M+H]⁺
C₂₅H₂₈N₃O₅
450.202 4,
450.199 9


4a	NO₂		> 200	> 200	-
5b	NH₂	NH₂	0.51 ± 0.03	1.85 ± 0.16	4
5c			2.75 ± 0.18	21.1 ± 0.55	8
6a	NO₂		7.33 ± 1.08	> 200	> 27
6b	NO₂		2.52 ± 0.04	73.2 ± 6.4	29
6c	NO₂		20.5 ± 5.10	> 200	> 10
6d	NO₂		28.4 ± 4.64	> 200	> 7
6e	NO₂		10.0 ± 2.80	92.8 ± 1.04	9
7b	NH₂	NH₂	0.44 ± 0.03	17.6 ± 1.73	40
7c			13.3 ± 0.47	38.6 ± 3.36	3
8a	NO₂		> 72.6	72.6 ± 20.3	-
8b	NO₂		> 3.45	3.45 ± 0.06	-
8c	NO₂		57.0 ± 5.14	> 200	> 4
8h			2.13 ± 0.41	67.0 ± 13.9	31.5
Mpv			0.44 ± 0.11	153.95 ± 4.35	350

Compd

R₁

R₂

R₃

EC₅₀/μmol·L^-1

CC₅₀/μmol·L^-1

NO₂

> 200

NH₂

0.51 ± 0.03

1.85 ± 0.16

2.75 ± 0.18

21.1 ± 0.55

NO₂

7.33 ± 1.08

> 200

> 27

NO₂

2.52 ± 0.04

73.2 ± 6.4

NO₂

20.5 ± 5.10

> 200

> 10

NO₂

28.4 ± 4.64

> 200

> 7

NO₂

10.0 ± 2.80

92.8 ± 1.04

NH₂

0.44 ± 0.03

17.6 ± 1.73

13.3 ± 0.47

38.6 ± 3.36

NO₂

> 72.6

72.6 ± 20.3

NO₂

> 3.45

3.45 ± 0.06

NO₂

57.0 ± 5.14

> 200

> 4

2.13 ± 0.41

67.0 ± 13.9

31.5

Mpv

0.44 ± 0.11

153.95 ± 4.35

350


4a	NO₂		> 200	> 200	-
5b	NH₂	NH₂	0.51 ± 0.03	1.85 ± 0.16	4
5c			2.75 ± 0.18	21.1 ± 0.55	8
6a	NO₂		7.33 ± 1.08	> 200	> 27
6b	NO₂		2.52 ± 0.04	73.2 ± 6.4	29
6c	NO₂		20.5 ± 5.10	> 200	> 10
6d	NO₂		28.4 ± 4.64	> 200	> 7
6e	NO₂		10.0 ± 2.80	92.8 ± 1.04	9
7b	NH₂	NH₂	0.44 ± 0.03	17.6 ± 1.73	40
7c			13.3 ± 0.47	38.6 ± 3.36	3
8a	NO₂		> 72.6	72.6 ± 20.3	-
8b	NO₂		> 3.45	3.45 ± 0.06	-
8c	NO₂		57.0 ± 5.14	> 200	> 4
8h			2.13 ± 0.41	67.0 ± 13.9	31.5
Mpv			0.44 ± 0.11	153.95 ± 4.35	350

Compd

R₁

R₂

R₃

EC₅₀/μmol·L^-1

CC₅₀/μmol·L^-1

NO₂

> 200

NH₂

0.51 ± 0.03

1.85 ± 0.16

2.75 ± 0.18

21.1 ± 0.55

NO₂

7.33 ± 1.08

> 200

> 27

NO₂

2.52 ± 0.04

73.2 ± 6.4

NO₂

20.5 ± 5.10

> 200

> 10

NO₂

28.4 ± 4.64

> 200

> 7

NO₂

10.0 ± 2.80

92.8 ± 1.04

NH₂

0.44 ± 0.03

17.6 ± 1.73

13.3 ± 0.47

38.6 ± 3.36

NO₂

> 72.6

72.6 ± 20.3

NO₂

> 3.45

3.45 ± 0.06

NO₂

57.0 ± 5.14

> 200

> 4

2.13 ± 0.41

67.0 ± 13.9

31.5

Mpv

0.44 ± 0.11

153.95 ± 4.35

350

基于丙烯酰胺共价弹头的双芳基酰胺衍生物设计合成及抗冠状病毒机制探究

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吴志云 , 李妍红 , 李健蕊 , 刘永华 , 李迎红 , 彭宗根 , 宋丹青 ^*

药学学报 | 研究论文 2025,60(9): 2849-2857

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药学学报 |研究论文 2025 , 60 (9) : 2849 -2857

基于丙烯酰胺共价弹头的双芳基酰胺衍生物设计合成及抗冠状病毒机制探究

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吴志云, 李妍红, 李健蕊, 刘永华, 李迎红, 彭宗根, 宋丹青^*

作者信息

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 100050

通讯作者:

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

作者简介:

作者贡献:

吴志云负责目标化合物的合成、分子对接以及初稿的撰写; 李妍红负责酶活抑制试验; 李健蕊负责测定目标化合物活性结果; 刘永华负责试验方法的设计和化合物合成路线的确证; 李迎红对实验过程中出现的问题及论文撰写提供了有益的指导; 彭宗根对生物实验部分进行了有益的指导; 宋丹青对实验过程中出现的问题及论文撰写提供了有益的指导, 并负责实验设计和把关、稿件修改等工作。

Design, synthesis and mechanism against coronavirus of biaryl amide derivatives based on acrylamide covalent warhead

Zhi-yun WU, Yan-hong LI, Jian-rui LI, Yong-hua LIU, Ying-hong LI, Zong-gen PENG, Dan-qing SONG^*

Affiliations

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2025-09-12 doi: 10.16438/j.0513-4870.2025-0726

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摘要

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本研究设计合成了一系列含丙烯酰胺共价弹头等基团的全新双芳基酰胺类衍生物, 采用CCK-8法评价了目标物对抗人类β-冠状病毒HCoV-OC43的活性。其中, 含2-氟丙烯酰胺共价弹头的化合物6b具有良好活性, EC₅₀值为2.52 μmol·L^-1, 治疗指数(selectivity index, SI) 值为29。分子对接结果显示, 6b可通过共价键合作用抑制宿主跨膜丝氨酸蛋白酶2 (transmembrane serine protease 2, TMPRSS2) 和病毒3-胰凝乳蛋白酶样蛋白酶(3-chymotrypsin like protease, 3CL^pro) 活性而发挥抗冠状病毒作用。研究结果拓展了此类化合物的结构类型及其抗冠状病毒用途, 为发展一类全新抗冠状病毒共价药物提供了理想先导物。

关键词

双芳基酰胺类 / β-冠状病毒 / 丙烯酰胺共价弹头 / 跨膜丝氨酸蛋白酶2 / 3-胰凝乳蛋白酶样蛋白酶

Abstract

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In this study, a series of novel biaryl amide derivatives featuring an acrylamide covalent warhead were designed and synthesized. The antiviral efficacy of these synthesized compounds against the human β-coronavirus HCoV-OC43 were evaluated using the CCK-8 assay. Among them, compound 6b, containing a 2-fluoroacrylamide covalent warhead, exhibited significant antiviral activity with an EC₅₀ value of 2.52 μmol·L^-1 and a selectivity index (SI) of 29, suggesting a reasonable therapeutic window. Molecular docking studies revealed that compound 6bcould inhibit the activities of host transmembrane serine protease 2 (TMPRSS2) and viral 3-chymotrypsin like protease (3CL^pro) through covalent bond formation, thereby exerting its antiviral effects. These findings not only expand the structural diversity of this class of compounds but also highlight their potential applications in antiviral therapy. Compound 6brepresents an ideal lead compound for the development of a new class of covalent antiviral drugs against coronaviruses.

Key words

biaryl amide derivative / β-coronavirus / acrylamide covalent warhead / transmembrane serine protease 2 / 3-chymotrypsin like protease

引用本文

吴志云, 李妍红, 李健蕊, 刘永华, 李迎红, 彭宗根, 宋丹青. 基于丙烯酰胺共价弹头的双芳基酰胺衍生物设计合成及抗冠状病毒机制探究. 药学学报, 2025 , 60 (9) : 2849 -2857 . DOI: 10.16438/j.0513-4870.2025-0726

Zhi-yun WU, Yan-hong LI, Jian-rui LI, Yong-hua LIU, Ying-hong LI, Zong-gen PENG, Dan-qing SONG. Design, synthesis and mechanism against coronavirus of biaryl amide derivatives based on acrylamide covalent warhead[J]. Acta Pharmaceutica Sinica, 2025 , 60 (9) : 2849 -2857 . DOI: 10.16438/j.0513-4870.2025-0726

正文

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由SARS-CoV-2引发的新型冠状病毒感染(COVID-19) 给人类生命健康和社会经济发展造成了极为严重的影响^[1-5]。虽然目前新冠已处于低流行趋势, 但由于病毒的持续变异, 现有疫苗和治疗药物效果下降, 公共卫生安全风险仍然存在^{[4, 6]}。因此, 研发具有全新作用机制、高成药性的小分子抗新冠药物作为储备, 仍具有重要意义^[5-8]。

共价药物最早可追溯到17世纪末的aspirin, 目前已广泛应用于抗癌、抗病毒等领域^[9-11], 成为发现创新药物的有效策略。相较于非共价药物, 共价药物具有诸多优势, 包括提高药物效力和靶向性, 与靶蛋白产生更持久的抑制效果, 以及可靶向不可成药靶点, 解决耐药性问题等^[11-14]。共价药物主要通过共价弹头与靶蛋白活性腔周围的亲核氨基酸残基发生共价键合作用, 其中丙烯酰胺作为最经典的共价弹头广泛应用于共价药物的设计中^{[11, 13]}。

双芳基酰胺类衍生物具有广泛的药理活性, 如抗菌、抗炎、抗肿瘤与抗病毒等活性, 显示出该类化合物潜在的研究与应用价值。其中的马赛替尼、卡莫斯他、氯硝柳胺等均具有较好的抗冠状病毒活性(图1), 提示双芳基酰胺是一个良好的抗冠状病毒结构单元^{[15, 16]}。

作者前期研究发现具有双芳基酰胺母核骨架的化合物8h具有良好的抗冠状病毒活性, 可抑制宿主跨膜丝氨酸蛋白酶2 (transmembrane serine protease 2, TMPRSS2) 和病毒3-胰凝乳蛋白酶样蛋白酶(3-chymotrypsin like protease, 3CL^pro) 的活性, 通过独特的双靶点机制发挥抗冠状病毒活性^{[15, 16]}。本研究在此工作基础上, 以8h为先导物, 通过引入丙烯酰胺共价弹头的共价修饰策略, 开展多轮结构修饰, 以期获得共价或可逆共价全新双芳基酰胺抗冠状病毒衍生物。继而采用CCK-8法在H460细胞上评价了它们对HCoV-OC43的抗病毒活性, 探究不同结构类型的丙烯酰胺弹头对冠状病毒的影响, 并对活性化合物作用机制进行初步探讨。

结果与讨论

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1　化合物的合成

目标化合物的合成路线如合成路线1所示^{[15, 16]}。以4-羟基-3-硝基苯甲酸甲酯为起始原料, 在碱性条件下与相应的卤代烷反应得到苯甲酸酯衍生物2a和2b, 酯基水解后得到羧酸衍生物3a和3b, 两步总收率为10%~25%, 延长反应时间及升高温度均对产率无明显影响。含共价弹头等基团的苯胺衍生物由N-Boc-4-氨基-3-三氟甲基苯胺或N-Boc-对氨基苯胺为起始原料, 经过酰胺缩合及脱Boc反应得到苯胺衍生物4、10、11与12, 两步总收率为25%~55%, 该步由于原料反应性不同, 产率存在差异。再将3a和3b与对应的苯胺衍生物缩合得到对应的目标化合物4a、5b、5c、6a~e、7b、7c及8a~c, 产率为12%~92%。5b、7b由于结构简单且催化氢化反应损失较少, 后处理步骤简单等原因, 其产率较高; 其余化合物由于空间位阻及电子效应等影响, 导致产率较低。

所有目标化合物的结构均经¹H NMR、¹³C NMR以及HRMS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　目标化合物抗冠状病毒构效关系

鉴于SARS-CoV-2为β-冠状病毒属成员, 作者以H460细胞为宿主, 选用与新冠病毒同属的人类β-冠状病毒HCoV-OC43感染, 以市售药物莫诺拉韦(molnupiravir, Mpv) 为阳性对照^{[17, 18]}, 采用CCK-8法考察化合物的半数有效浓度(median effect concentration, EC₅₀) 和细胞半数毒性浓度(median cytotoxic concentration, CC₅₀), 目标化合物的结构与活性结果见表2。

首先, 保留先导物8h的母核骨架, 将B环上的二甲氨基氮杂环丁烷替换为丙烯酰胺共价弹头, 化合物4a活性消失, 将A环R₂位置硝基进行替换氨基等、将三氟丙基用环丙基甲基替换, 同时将二甲氨基氮杂环丁烷分别替换为氨基和丙烯酰胺基团, 所得化合物7b、7c以及5b、5c的活性下降或保留; 其次, 保留A环的三氟丙基或环丙基甲基侧链, 移除了B环的-CF₃使其成为单取代, 分别引入丙烯酰胺及2-氟丙烯酰胺等共价弹头, 以及可逆共价弹头二甲氨基丁-2-烯酰胺, 由此设计合成一系列类似物。其中, 除化合物8a、8c外, 大部分化合物均具有较低的EC₅₀值, 具有较高的CC₅₀值。尤其含2-氟丙烯酰胺弹头化合物6b的活性与安全性均较佳, EC₅₀和治疗指数(selectivity index, SI) 分别为2.52 μmol·L^-1和29, 与先导物8h相当, 且可能具有全新的共价作用机制, 因此将其作为代表性化合物进行下一步研究。

3　分子对接

鉴于8h可作用于宿主TMPRSS2和病毒3CL^pro两个靶标蛋白, 采用分子对接软件将6b分别与靶点TMPRSS2 (PDB ID: 7MEQ) 和3CL^pro (PDB ID: 7RFW) 进行对接, 观察是否可能形成共价键结合。结果显示, 与先导物8h相似, 6b可分别与TMPRSS2 (图2A、B, docking score: 3.54) 活性腔的Gly439和Ser441残基, 以及3CL^pro (图2C、D, docking score: 4.45) 活性口袋的Thr26、His41、Ser46和Gly143残基形成氢键; 6b还可与TMPRSS2的His296残基形成π-阳离子相互作用。在此非共价结合基础上, 化合物6b的2-氟丙烯酰胺基团可与TMPRSS2活性腔外围的Ser441残基发生Michael加成形成共价键; 类似地, 6b也可与3CL^pro活性腔的Cys145残基发生相似的反应。提示6b与这两种蛋白均可形成共价结合作用。

4　化合物6b对TMPRSS2和3CL^pro的酶活抑制试验

基于以上结果, 进一步考察了6b与靶蛋白TMPRSS2和3CL^pro之间的相互作用^{[16, 19]}。采用荧光共振能量转移(fluorescence resonance energy transfer, FRET) 法测定了抑酶活性(图3)。结果显示, 6b对TMPRSS2和3CL^pro具有中等的抑制活性, 半抑制浓度(half maximal inhibitory concentration, IC₅₀) 分别为5.14和14.81 μmol·L^-1, 相当或优于8h(3.37和38.27 μmol·L^-1)。

鉴于共价抑制剂的IC₅₀值与时间具有相关性, 选择了抑酶活性更好的TMPRSS2开展时间相关研究, 设计了6b在不同时间点(1、2、4 h) 对TMPRSS2活性的抑制效果^{[20, 21]}。结果显示, 随时间的延长, IC₅₀值随之降低, 推测可能与6b和TMPRSS2形成共价键有关, 也可能为更多的化合物与蛋白结合, 从而增强了抑制效果, 详尽的作用机制尚待进一步验证。

结论

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本研究设计合成了一系列含(或不含) 丙烯酰胺共价弹头全新的双芳基酰胺类化合物, 初步总结了抗HCoV-OC43的构效关系。其中带有2-氟丙烯酰胺弹头的代表性化合物6b表现出良好的抗冠状病毒活性和较低的细胞毒性, 与先导物8h相当。分子对接结果显示, 化合物6b可通过共价键合抑制TMPRSS2和3CL^pro活性, 继而发挥良好抗冠状病毒活性。尤其含氟原子丙烯酰胺弹头的引入增强了吸电子效应, 使6b更易与靶蛋白的亲核氨基酸残基发生Michael加成, 形成稳定的共价键。虽然分子对接结果显示共价键合的可能性, 但后续还将通过蛋白质谱及点突变实验等手段进一步验证。该研究结果拓展了双芳基酰胺类化合物的结构类型, 为发展一类全新抗冠状病毒共价药物提供了理想先导物。

实验部分

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1　化学合成

使用MP90熔点仪(Mettler-Toledo, 瑞士Greifensee公司) 获得熔点(mp), 未经校正; 以DMSO-d₆为溶剂, TMS为内标, 在QONE光谱仪(500 MHz, 中科牛津) 和Bruker Avance光谱仪(600 MHz, 美国Varian公司) 上记录¹H NMR和¹³C NMR波谱; 在AutospecUltima-TOF光谱仪(英国Micromass公司) 上记录ESI高分辨率质谱(HR-MS); Flash柱分离纯化用Combiflash Rf 200 (美国Teledyne公司) 快速制备液相; 薄层层析(TLC) 采用Merck 60 F254和国产GF254薄层层析硅胶板; 紫外检测用手提紫外检测灯(ZF-7A, 上海宝山顾村电光仪器厂); 所用试剂购自乐研、泰坦、毕得、通广等试剂公司的分析纯或化学纯试剂, 所有化学试剂和溶剂均从商业来源获得并且无需进一步纯化即可使用。

1.1　目标化合物4a的合成

在冰浴下向CH₂Cl₂ (20 mL) 中依次加入N-Boc-4-氨基-3-三氟甲基苯胺(5 mmol)、三乙胺(triethylamine, TEA, 15 mmol) 和丙烯酰氯(6 mmol), 在0 ℃搅拌反应, 随后升至室温继续反应12 h, TLC点板监测反应完全后, 反应液中加入60 mL CH₂Cl₂、40 mL饱和食盐水, 有机相用饱和食盐水洗3次(30 mL × 3), 用硅胶匀化, 以石油醚(petroleum ether, PE) 和乙酸乙酯(ethyl acetate, EA) 为流动相经flash纯化, 得到的产物用5%的三氟乙酸(trifluoroacetic acid, TFA) 的CH₂Cl₂溶液脱Boc, 得到化合物4。

向3-硝基-4-羟基苯甲酸甲酯(10 mmol) 的N, N-二甲基甲酰胺(dimethylformamide, DMF) 溶液(20 mL) 中加入K₂CO₃ (20 mmol) 和1, 1, 1-三氟碘丙烷(15 mmol), 反应温度维持65 ℃, 反应8 h, TLC点板监测。反应液中加入EA 20 mL, 有机相用1 mol·L^-1盐酸中和, 水相用EA萃取3次(20 mL×3), 有机相用饱和食盐水洗3次(30 mL×3), 用硅胶匀化, 以PE和EA为流动相经flash纯化, 得到2a。将2a(2 mmol) 加入四氢呋喃(tetrahydrofuran, THF) 和水的混合溶液中(体积比为1∶1), 冰浴下加入LiOH (4 mmol), 反应2 h, TLC监测反应完成, 旋蒸除去THF, 加入EA 50 mL, 调节pH至2~3, 有机相用饱和食盐水洗3次(20 mL×3), 无水硫酸钠干燥, 旋除溶剂得到化合物3a。

向3a(2 mmol) 的CH₂Cl₂溶液(10 mL) 中加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI, 4 mmol)、4-二甲氨基吡啶(DMAP, 2 mmol) 和化合物4(2 mmol), 0 ℃搅拌, 升至室温, 反应12 h, TLC点板监测反应完全后, 反应液中加入20 mL CH₂Cl₂、20 mL饱和氯化铵溶液, 有机相分别用饱和氯化铵溶液和饱和食盐水洗3次(20 mL×3), 无水硫酸钠干燥, 用硅胶匀化, 以PE和EA为流动相经flash纯化, 得到目标物4a。

1.2　目标化合物5b和5c的合成

参照方法1.1, 得到化合物5a。

将5a(1 mmol) 溶于10 mL MeOH中, 加入Pd/C (10%, 0.1 mmol), 置于氢气氛围中, 室温反应10 h, TLC监测反应完成, 用硅藻土滤除钯碳, 将滤液旋干得到目标物5b。

向化合物5b(0.5 mmol) 的CH₂Cl₂ (10 mL) 溶液中加入TEA (1.5 mmol), 在冰浴下加入丙烯酰氯(1 mmol), 0 ℃搅拌1 h后, 升至室温继续反应8 h。反应液用水淬灭, 并加入10 mL CH₂Cl₂, 有机相用饱和食盐水洗3次(10 mL × 3), 无水硫酸钠干燥, 用硅胶匀化, 以PE和EA为流动相经flash纯化, 得到目标物5c。

1.3　目标化合物6a~6e的合成

参照方法1.1, 得到目标物6a~6e。

1.4　目标化合物7b、7c的合成

参照方法1.2, 得到目标物7b、7c。

1.5　目标化合物8a~8c的合成

参照方法1.1, 得到目标物8a~8c。

2　活性测定

H460细胞以每孔1.5×10⁴个细胞的密度接种至96孔板, 24 h后给药同时感染HCoV-OC43病毒, 72 h后用CCK-8法测细胞病变。吸弃细胞上清后加100 μL预混的CCK-8测试液, 37 ℃培养1 h, 测定450 nm下的吸光度值(OD₄₅₀)。

3　分子对接

TMPRSS2和3CL^pro蛋白结构分别来自PDB数据库(PDB ID: 7MEQ和7RFW)。

使用Schrӧdinger (Maestro 12.8) 软件自带模块处理蛋白并进行能量最小化, 设置pH为7.4; 配体化合物6b通过软件默认设置进行处理; TMPRSS2和3CL^pro对接盒子选用其PDB蛋白结构中配体分子所处活性口袋; 使用covalent docking模块进行对接, 反应类型设置为Michael加成, 其余选项均为默认设置。

4　酶活实验

使用FRET法检测化合物6b对TMPRSS2和3CL^pro的抑制活性, 该试剂盒监测存在和不存在抑制剂的情况下荧光底物的裂解。蛋白(TMPRSS2: 50 nmol·L^-1, 3CL^pro: 80 nmol·L^-1) 与化合物6b共孵育30 min后, 将肽底物(30 μmol·L^-1) 加入反应体系, 测定液的总体积为50 μL。

将TMPRSS2与化合物6b分别孵育1、2、4 h后, 将肽底物(30 μmol·L^-1) 加入反应体系, 测定液总体积为50 μL。通过多功能酶分析仪在380/460 nm的吸收/发射波长下记录荧光强度, 进行终点分析。

终点分析采用多功能酶分析仪记录340/490 nm吸收/发射波长处的相对荧光单位(relative fluorescence unit, RFU)。抑制率计算公式为抑制率(%) = (RFU_{100%酶活性} - RFU_样品) / (RFU_{100%酶活性} - RFU_空白对照) × 100%。IC₅₀采用GraphPad Prism 8测定。

参考文献

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文献

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2025年第60卷第9期

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doi: 10.16438/j.0513-4870.2025-0726

接收时间：2025-06-27
首发时间：2026-09-20
出版时间：2025-09-12

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收稿日期：2025-06-27
修回日期：2025-07-17

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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 100050

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宋丹青，Tel/Fax: 86-10-63165268, E-mail: songdanqingsdq@sina.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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Compd	Yield /%	mp /℃	¹H NMR	¹³C NMR	HR-ESI-MS (m/z) Formula Calcd. Found
4a	35	254-256	(500 MHz, DMSO-d₆) δ 10.35 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 8.9, 2.3 Hz, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.9 Hz, 1H), 6.45 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 16.9, 2.0 Hz, 1H), 5.75 (dd, J = 10.1, 2.0 Hz, 1H), 4.51 (t, J = 5.8 Hz, 2H), 2.87 (qt, J = 11.2, 5.7 Hz, 2H)	(126 MHz, DMSO-d₆) δ 164.0, 163.2, 152.9 (d, J = 5.04 Hz), 139.0 (d, J = 6.30 Hz), 138.1, 133.8 (d, J = 3.78 Hz), 133.5, 131.9, 131.0, 130.3 (d, J = 16.38 Hz), 127.5, 126.6, 126.2, 125.3, 124.6 (d, J = 5.04 Hz), 124.1 (d, J = 16.38 Hz), 117.7 (dd, J = 31.50 Hz, 3.78 Hz), 115.1 (d, J = 15.12 Hz), 63.0, 32.4 (q, J = 28.98 Hz)	[M+H]⁺ C₂₀H₁₆F₆N₃O₅ 492.098 9, 492.098 5
5b	91	146-147	(600 MHz, DMSO-d₆) δ 9.91 (s, 1H), 7.86 (s, 1H), 7.66 (d, J = 6.3 Hz, 1H), 7.29-7.22 (m, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 5.39 (s, 2H), 4.88 (s, 2H), 4.25 (t, J = 5.9 Hz, 2H), 2.86 (dd, J = 11.4, 5.7 Hz, 2H)	(151 MHz, DMSO-d₆) δ 165.2, 147.3, 142.2, 137.5, 128.2 (d, J = 42.28 Hz), 127.6, 126.1, 125.9 (d, J = 15.10 Hz), 124.1, 118.1 (q, J = 6.04 Hz), 116.9, 116.0, 113.3, 110.8, 110.2 (q, J = 28.69 Hz), 61.3 (d, J = 3.02 Hz), 32.8 (q, J = 27.18 Hz)	[M+H]⁺ C₁₇H₁₆F₆N₃O₂ 408.114 1, 408.112 4
5c	15	202-204	(500 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.74 (s, 1H), 9.29 (s, 1H), 8.67 (s, 1H), 8.26 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.69-6.60 (m, 1H), 6.59-6.50 (m, 1H), 6.28 (t, J = 17.1 Hz, 2H), 5.79 (t, J = 10.2 Hz, 2H), 4.40 (t, J = 6.1 Hz, 2H), 2.93 (dt, J = 11.7, 6.0 Hz, 2H)	(126 MHz, DMSO-d₆) δ 165.1, 164.3, 163.3, 151.4, 137.8, 131.1, 130.7, 129.8, 128.6, 127.6, 127.0, 126.7, 125.4, 125.2, 124.8, 124.4, 123.9, 122.2, 117.5 (d, J = 2.52 Hz), 111.7, 62.0, 41.4, 33.7 (q, J = 27.72 Hz)	[M+H]⁺ C₂₃H₂₀F₆N₃O₄ 516.135 3, 516.133 1
6a	12	211-212	(500 MHz, DMSO-d₆) δ 10.35 (s, 1H), 10.16 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 8.9, 2.3 Hz, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.9 Hz, 1H), 6.45 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 16.9, 2.0 Hz, 1H), 5.75 (dd, J = 10.1, 2.0 Hz, 1H), 4.51 (t, J = 5.8 Hz, 2H), 2.81-2.93 (m, 2H)	(126 MHz, DMSO-d₆) δ 162.7 (d, J = 41.58 Hz), 152.6, 138.9, 135.0, 134.4, 133.6, 131.8, 127.5, 127.2, 126.6, 125.3, 124.4, 120.9 (2), 119.5 (2), 114.9, 62.9 (d, J = 3.78 Hz), 32.5 (q, J = 27.72 Hz)	[M+H]⁺ C₁₉H₁₇F₃N₃O₅ 424.111 5, 424.109 9
6b	45	228-230	(600 MHz, DMSO-d₆) δ 10.38 (s, 1H), 10.30 (s, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.29 (dd, J = 8.7, 2.4 Hz, 1H), 7.74 (t, J = 7.1 Hz, 3H), 7.58 (d, J = 8.8 Hz, 1H), 5.76 (d, J = 3.6 Hz, 1H), 5.68 (d, J = 3.6 Hz, 1H), 5.42 (dd, J = 15.6, 3.6 Hz, 1H), 4.54-4.45 (m, 2H), 2.87 (tt, J = 11.3, 5.7 Hz, 2H)	(151 MHz, DMSO-d₆) δ 165.3, 162.6, 157.4, 157.1 (q, J = 12.08 Hz), 155.2, 152.6, 139.0, 135.2, 133.6, 127.3, 127.1, 125.5, 124.4, 121.0, 120.6, 114.8, 99.6 (d, J = 15.10 Hz), 63.0 (q, J = 3.02 Hz), 32.5 (q, J = 28.18 Hz)	[M+H]⁺ C₁₉H₁₆F₄N₃O₅ 442.102 1, 442.100 3
6c	20	191-193	(600 MHz, DMSO-d₆) δ 9.93 (s, 1H), 9.25 (s, 1H), 7.53 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 6.70 (dt, J = 15.4, 5.9 Hz, 1H), 6.24 (d, J = 15.4 Hz, 1H), 3.04 (s, 1H), 2.94 (s, 1H), 2.17 (s, 5H), 1.47 (s, 8H)	(151 MHz, DMSO-d₆) δ 162.7, 153.9, 152.7, 149.1, 140.7 (2), 135.0, 133.6, 126.0 (2), 119.6 (2), 118.4, 106.6, 78.7, 59.7, 44.8 (d, J = 87.58 Hz, 2C), 38.5, 28.0 (3)	[M+H]⁺ C₂₂H₂₄F₃N₄O₅ 481.169 3, 481.169 0
6d	55	74-76	(600 MHz, DMSO-d₆) δ 10.20 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.27 (dd, J = 8.9, 2.4 Hz, 1H), 7.98 (dd, J = 16.1, 2.2 Hz, 1H), 7.75 (ddd, J = 15.0, 8.5, 2.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.49 (t, J = 8.8 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.51 (d, J = 8.2 Hz, 1H), 4.66-4.62 (m, 1H), 4.51 (d, J = 5.7 Hz, 1H), 4.49 (d, J = 9.1 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 3.60 (s, 1H), 2.99-2.85 (m, 6H)	(151 MHz, DMSO-d₆) δ 166.6 (d, J = 13.59 Hz), 162.2 (d, J = 4.53 Hz), 152.5, 151.0 (d, J = 7.55 Hz), 147.2, 142.7, 141.9, 139.1 (d, J = 34.73 Hz), 133.5, 133.0 (d, J = 7.55 Hz), 131.1, 128.4 (d, J = 13.59 Hz), 127.3 (d, J = 7.55 Hz), 125.5, 124.0 (d, J = 6.04 Hz), 121.6, 118.7, 116.1, 114.9 (dd, J = 30.20 Hz, 4.53 Hz), 62.9 (dd, J = 18.12 Hz, 3.02 Hz), 32.5 (q, J = 28.69 Hz)	[M+2H]²⁺ C₂₁H₂₅F₃N₃O₄ 439.170 7, 439.168 9
6e	14	178-180	(500 MHz, DMSO-d₆) δ 9.97 (s, 1H), 7.99 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.41 (dd, J = 16.9, 10.1 Hz, 2H), 6.22 (d, J = 16.9 Hz, 1H), 5.70 (d, J = 10.3 Hz, 1H), 4.47 (s, 1H), 3.73 (s, 3H), 3.56 (s, 1H), 3.14 (s, 4H), 2.84 (qt, J = 11.6, 5.8 Hz, 2H), 1.23 (s, 1H)	(126 MHz, DMSO-d₆) δ 166.6, 162.4, 151.0, 146.9, 139.2, 133.0, 131.9, 131.4, 128.3, 127.5, 126.0, 125.3, 124.0, 123.1, 120.2 (2), 116.3 (2), 115.0, 62.8 (d, J = 3.78 Hz), 48.8 (2), 47.1, 32.5 (q, J = 27.72 Hz)	[M+2H]²⁺ C₂₄H₂₆F₃N₃O₅ 493.181 4, 493.179 6
7b	92	151-153	(600 MHz, DMSO-d₆) δ 9.84 (s, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.64 (dd, J = 8.8, 2.5 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.3, 2.3 Hz, 1H), 6.84 (t, J = 9.1 Hz, 2H), 5.37 (s, 2H), 4.83 (s, 2H), 3.88 (d, J = 6.9 Hz, 2H), 1.32-1.21 (m, 1H), 0.58 (dt, J = 8.0, 3.0 Hz, 2H), 0.36 (dt, J = 4.8, 2.9 Hz, 2H)	(151 MHz, DMSO-d₆) δ 165.2, 148.1, 142.2, 137.4, 128.3, 127.2, 126.0, 118.0 (q, J = 6.04 Hz), 116.9, 116.0, 113.1, 110.7, 110.2 (q, J = 30.2 Hz), 72.3, 39.9, 10.1, 3.0 (2)	[M+H]⁺ C₁₈H₁₉F₃N₃O₂ 366.142 4, 366.140 8
7c	16	105-107	(500 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.73 (s, 1H), 9.43 (s, 1H), 8.61 (s, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.09 (dd, J = 8.8, 2.4 Hz, 1H), 7.81 (dd, J = 8.6, 2.4 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.73 (dd, J = 16.8, 10.1 Hz, 2H), 6.54 (ddd, J = 14.1, 10.2, 4.0 Hz, 2H), 6.34-6.23 (m, 2H), 5.78 (d, J = 10.3 Hz, 1H), 4.04 (s, 1H), 1.37-1.26 (m, 1H), 0.60 (d, J = 8.1 Hz, 2H), 0.40 (d, J = 4.8 Hz, 2H)	(126 MHz, DMSO-d₆) δ 165.1, 164.3, 163.4, 152.5, 137.9, 136.2, 131.8, 130.7, 130.1, 129.7, 127.0, 126.9 (d, J = 5.05 Hz), 126.0, 125.2, 124.9, 124.4, 123.9, 122.8, 117.4 (d, J = 5.04 Hz), 111.9, 73.1, 9.9, 3.2 (2)	[M+H]⁺ C₂₄H₂₃F₃N₃O₄ 474.163 5, 474.161 3
8a	11	200-202	(500 MHz, DMSO-d₆) δ 9.96 (s, 1H), 8.35 (s, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.7, 2.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.40 (dd, J = 16.9, 10.1 Hz, 1H), 6.21 (dd, J = 17.0, 2.1 Hz, 1H), 5.70 (dd, J = 10.1, 2.1 Hz, 1H), 4.09 (d, J = 7.0 Hz, 2H), 1.25 (t, J = 7.6 Hz, 1H), 0.59 (d, J = 8.0 Hz, 2H), 0.36 (d, J = 4.7 Hz, 2H)	(126 MHz, DMSO-d₆) δ 166.6, 162.4, 151.8, 146.8, 139.1, 132.9, 131.9, 131.4, 127.4, 126.0, 123.9, 120.2, 116.2, 115.1, 73.8, 48.7 (2), 9.6, 2.9 (2)	[M+H]⁺ C₂₀H₂₀N₃O₅ 382.139 8, 382.137 8
8b	13	242-243	(600 MHz, DMSO-d₆) δ 10.34 (s, 1H), 8.51 (s, 1H), 8.27-8.22 (m, 1H), 7.72 (q, J = 8.3 Hz, 4H), 7.49 (d, J = 8.9 Hz, 1H), 5.77-5.73 (m, 1H), 5.69-5.65 (m, 1H), 5.42 (dd, J = 15.4, 3.8 Hz, 1H), 4.14 (d, J = 7.0 Hz, 2H), 1.27 (ddt, J = 12.1, 7.7, 3.8 Hz, 1H), 0.60 (d, J = 8.1 Hz, 2H), 0.39 (q, J = 6.1 Hz, 2H)	(151 MHz, DMSO-d₆) δ 162.7, 157.3, 157.1 (d, J = 12.08 Hz), 155.2, 153.5, 138.9, 135.2, 133.5, 126.4, 124.3, 121.0 (2), 120.6 (2), 115.0, 99.6 (d, J = 15.10 Hz), 74.0, 9.6, 3.0 (2)	[M+H]⁺ C₂₀H₁₉FN₃O₅ 400.130 3, 400.128 9
8c	11	200-202	(500 MHz, DMSO-d₆) δ 9.96 (s, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.7, 2.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.40 (dd, J = 16.9, 10.1 Hz, 1H), 6.21 (dd, J = 16.9, 2.1 Hz, 1H), 5.70 (dd, J = 10.1, 2.1 Hz, 1H), 4.09 (d, J = 7.0 Hz, 2H), 3.45-3.85 (m, 5H), 3.14 (s, 4H), 1.24 (td, J = 7.5, 3.7 Hz, 1H), 0.59 (dt, J = 8.2, 3.1 Hz, 2H), 0.36 (dt, J = 6.3, 4.4 Hz, 2H)	(126 MHz, DMSO-d₆) δ 166.7, 162.5, 151.9, 146.9, 139.1, 133.0 (2), 131.9, 131.5, 127.5, 126.0, 124.0 (2), 120.3 (2), 116.3 (2), 115.2, 73.8, 48.7 (2), 47.0, 9.6, 3.0 (2)	[M+H]⁺ C₂₅H₂₈N₃O₅ 450.202 4, 450.199 9

Compd

Yield /%

mp /℃

¹H NMR

¹³C NMR

HR-ESI-MS
(m/z)
Formula
Calcd.
Found

254-256

[M+H]⁺
C₂₀H₁₆F₆N₃O₅
492.098 9,
492.098 5

146-147

[M+H]⁺
C₁₇H₁₆F₆N₃O₂
408.114 1,
408.112 4

202-204

[M+H]⁺
C₂₃H₂₀F₆N₃O₄
516.135 3,
516.133 1

211-212

[M+H]⁺
C₁₉H₁₇F₃N₃O₅
424.111 5,
424.109 9

228-230

[M+H]⁺
C₁₉H₁₆F₄N₃O₅
442.102 1,
442.100 3

191-193

(151 MHz, DMSO-d₆) δ 162.7, 153.9, 152.7, 149.1, 140.7 (2), 135.0, 133.6, 126.0 (2), 119.6 (2), 118.4, 106.6, 78.7, 59.7, 44.8 (d, J = 87.58 Hz, 2C), 38.5, 28.0 (3)

[M+H]⁺
C₂₂H₂₄F₃N₄O₅
481.169 3,
481.169 0

74-76

[M+2H]²⁺
C₂₁H₂₅F₃N₃O₄
439.170 7,
439.168 9

178-180

[M+2H]²⁺
C₂₄H₂₆F₃N₃O₅
493.181 4,
493.179 6

151-153

(151 MHz, DMSO-d₆) δ 165.2, 148.1, 142.2, 137.4, 128.3, 127.2, 126.0, 118.0 (q, J = 6.04 Hz), 116.9, 116.0, 113.1, 110.7, 110.2 (q, J = 30.2 Hz), 72.3, 39.9, 10.1, 3.0 (2)

[M+H]⁺
C₁₈H₁₉F₃N₃O₂
366.142 4,
366.140 8

105-107

[M+H]⁺
C₂₄H₂₃F₃N₃O₄
474.163 5,
474.161 3

200-202

(126 MHz, DMSO-d₆) δ 166.6, 162.4, 151.8, 146.8, 139.1, 132.9, 131.9, 131.4, 127.4, 126.0, 123.9, 120.2, 116.2, 115.1, 73.8, 48.7 (2), 9.6, 2.9 (2)

[M+H]⁺
C₂₀H₂₀N₃O₅
382.139 8,
382.137 8

242-243

(151 MHz, DMSO-d₆) δ 162.7, 157.3, 157.1 (d, J = 12.08 Hz), 155.2, 153.5, 138.9, 135.2, 133.5, 126.4, 124.3, 121.0 (2), 120.6 (2), 115.0, 99.6 (d, J = 15.10 Hz), 74.0, 9.6, 3.0 (2)

[M+H]⁺
C₂₀H₁₉FN₃O₅
400.130 3,
400.128 9

200-202

(126 MHz, DMSO-d₆) δ 166.7, 162.5, 151.9, 146.9, 139.1, 133.0 (2), 131.9, 131.5, 127.5, 126.0, 124.0 (2), 120.3 (2), 116.3 (2), 115.2, 73.8, 48.7 (2), 47.0, 9.6, 3.0 (2)

[M+H]⁺
C₂₅H₂₈N₃O₅
450.202 4,
450.199 9


4a	NO₂		> 200	> 200	-
5b	NH₂	NH₂	0.51 ± 0.03	1.85 ± 0.16	4
5c			2.75 ± 0.18	21.1 ± 0.55	8
6a	NO₂		7.33 ± 1.08	> 200	> 27
6b	NO₂		2.52 ± 0.04	73.2 ± 6.4	29
6c	NO₂		20.5 ± 5.10	> 200	> 10
6d	NO₂		28.4 ± 4.64	> 200	> 7
6e	NO₂		10.0 ± 2.80	92.8 ± 1.04	9
7b	NH₂	NH₂	0.44 ± 0.03	17.6 ± 1.73	40
7c			13.3 ± 0.47	38.6 ± 3.36	3
8a	NO₂		> 72.6	72.6 ± 20.3	-
8b	NO₂		> 3.45	3.45 ± 0.06	-
8c	NO₂		57.0 ± 5.14	> 200	> 4
8h			2.13 ± 0.41	67.0 ± 13.9	31.5
Mpv			0.44 ± 0.11	153.95 ± 4.35	350

Compd

R₁

R₂

R₃

EC₅₀/μmol·L^-1

CC₅₀/μmol·L^-1

NO₂

> 200

NH₂

0.51 ± 0.03

1.85 ± 0.16

2.75 ± 0.18

21.1 ± 0.55

NO₂

7.33 ± 1.08

> 200

> 27

NO₂

2.52 ± 0.04

73.2 ± 6.4

NO₂

20.5 ± 5.10

> 200

> 10

NO₂

28.4 ± 4.64

> 200

> 7

NO₂

10.0 ± 2.80

92.8 ± 1.04

NH₂

0.44 ± 0.03

17.6 ± 1.73

13.3 ± 0.47

38.6 ± 3.36

NO₂

> 72.6

72.6 ± 20.3

NO₂

> 3.45

3.45 ± 0.06

NO₂

57.0 ± 5.14

> 200

> 4

2.13 ± 0.41

67.0 ± 13.9

31.5

Mpv

0.44 ± 0.11

153.95 ± 4.35

350