药学学报

Compd.	Yield/%	mp/℃		Compd.	Yield/%	mp/℃
7a'a	96.3	170.0-172.1		7a'n	54.1	194.0-195.1
7a'b	49.7	191.7-193.2	7a'o	24.0	166.7-167.8
7a'c	29.8	196.0-197.1	7a'p	29.6	188.6-189.8
7a'd	94.5	210.4-211.7	7a'q	33.8	175.1-176.2
7a'e	76.7	202.1-202.8	7a'r	53.1	196.1-197.2
7a'f	87.5	202.9-203.1	7b'a	89.3	215.3-216.4
7a'g	66.8	198.1-199.7	7b'b	48.0	182.1-183.6
7a'h	72.8	108.4-109.5	7b'c	37.3	185.4-186.6
7a'i	89.8	195.1-196.2	7b'd	84.9	194.2-195.6
7a'j	20.7	193.4-194.5	7b'e	85.5	228.5-229.6
7a'k	58.1	168.5-169.2	7b'f	60.2	233.1-234.5
7a'l	92.4	212.5-213.0	7b'g	63.3	198.6-198.9
7a'm	50.1	196.5-197.8

Compd.	Yield/%	mp/℃		Compd.	Yield/%	mp/℃
7a'a	96.3	170.0-172.1		7a'n	54.1	194.0-195.1
7a'b	49.7	191.7-193.2	7a'o	24.0	166.7-167.8
7a'c	29.8	196.0-197.1	7a'p	29.6	188.6-189.8
7a'd	94.5	210.4-211.7	7a'q	33.8	175.1-176.2
7a'e	76.7	202.1-202.8	7a'r	53.1	196.1-197.2
7a'f	87.5	202.9-203.1	7b'a	89.3	215.3-216.4
7a'g	66.8	198.1-199.7	7b'b	48.0	182.1-183.6
7a'h	72.8	108.4-109.5	7b'c	37.3	185.4-186.6
7a'i	89.8	195.1-196.2	7b'd	84.9	194.2-195.6
7a'j	20.7	193.4-194.5	7b'e	85.5	228.5-229.6
7a'k	58.1	168.5-169.2	7b'f	60.2	233.1-234.5
7a'l	92.4	212.5-213.0	7b'g	63.3	198.6-198.9
7a'm	50.1	196.5-197.8

Compd.	¹H NMR, ¹³C NMR, HR-ESI-MS
7a'a	¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H, Ph-NH-CO), 7.71 (dd, J = 8.2, 1.8 Hz, 2H, ArH), 7.56 (ddt, J = 6.8, 5.0, 1.8 Hz, 2H, ArH), 7.27-7.21 (m, 2H, ArH), 7.13 (td, J = 8.9, 1.9 Hz, 2H, ArH), 3.87 (s, 2H, S-CH₂), 2.98-2.85 (m, 1H, CH(CH₃)₂), 1.21 (d, J = 1.7 Hz, 3H, CH₃), 1.19 (d, J = 1.8 Hz, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.4, 167.1, 167.1, 159.1, 158.0 (¹J_CF = 238 Hz), 150.9, 135.6 (⁴J_CF = 2 Hz), 134.6, 128.4 (2C), 126.1 (2C), 120.5 (2C, ³J_CF = 8 Hz), 119.2, 115.4 (2C, ²J_CF = 22 Hz), 90.2, 35.2, 33.4, 23.7 (2C); HR-ESI-MS: m/z calcd. for C₂₂H₁₉FN₄O₂S [M+H]⁺ 423.124 6, found 423.124 8
7a'b	¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H, Ph-NH-CO), 7.63 (d, J = 7.8 Hz, 1H, ArH), 7.57 (td, J = 7.4, 5.8, 2.7 Hz, 3H, ArH), 7.45 (q, J = 7.1, 6.5 Hz, 1H, ArH), 7.33 (t, J = 8.7 Hz, 1H, ArH), 7.13 (td, J = 9.0, 2.0 Hz, 2H, ArH), 3.91 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6, 166.9, 165.8, 165.7, 161.8 (¹J_CF = 242 Hz), 158.0 (¹J_CF = 237 Hz), 139.2 (³J_CF = 8 Hz), 135.51 (⁴J_CF = 3 Hz), 130.3 (³J_CF = 8 Hz), 124.5 (⁴J_CF = 3 Hz), 120.6 (2C, ³J_CF = 8 Hz), 118.6, 117.2 (²J_CF = 21 Hz), 115.4 (2C, ²J_CF = 22 Hz), 115.0 (²J_CF = 23 Hz), 91.4, 35.3; HR-ESI-MS: m/z calcd. for C₁₉H₁₂F₂N₄O₂S [M+H]⁺ 399.068 3, found 399.068 6
7a'c	¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s, 1H, Ph-NH-CO), 7.58 (dd, J = 8.3, 5.0 Hz, 2H, ArH), 7.54 (d, J = 5.0 Hz, 2H, ArH), 7.29 (td, J = 9.6, 9.0, 6.8 Hz, 2H, ArH), 7.18-7.08 (m, 2H, ArH), 3.81 (s, 2H, S-CH₂), 2.30 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 170.0, 167.6, 167.5, 157.9 (¹J_CF = 238 Hz), 137.4, 137.3, 135.6 (⁴J_CF = 3 Hz), 130.4, 128.6, 128.0, 125.4, 120.5 (2C, ³J_CF = 8 Hz), 119.7, 115.4 (2C, ²J_CF = 22 Hz), 89.5, 35.1, 20.9; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₂S [M+H]⁺ 395.093 3, found 395.093 5
7a'd	¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H, Ph-NH-CO), 7.65-7.44 (m, 4H, ArH), 7.22-7.02 (m, 3H, ArH), 3.85 (s, 2H, S-CH₂), 2.25 (s, 3H, CH₃), 2.19 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6, 168.9, 167.3, 167.3, 157.9 (¹J_CF = 239 Hz), 138.7, 136.1, 135.6 (¹J_CF = 3 Hz), 134.7, 129.2 (2C), 125.8, 120.5 (2C, ³J_CF = 7 Hz), 119.3, 115.3 (2C, ²J_CF = 22 Hz), 89.7, 35.2, 19.3 (2C); HR-ESI-MS: m/z calcd. for C₂₁H₁₇FN₄O₂S [M+H]⁺ 409.109 0, found 409.109 2
7a'e	¹H NMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H, Ph-NH-CO), 10.87-10.72 (m, 1H, OH), 10.54 (s, 1H, Ar-NH), 8.35 (dd, J = 7.9, 1.7 Hz, 1H, ArH), 7.75 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H, ArH), 7.67-7.60 (m, 2H, ArH), 7.52 (d, J = 8.3 Hz, 1H, ArH), 7.44 (t, J = 7.6 Hz, 1H, ArH), 7.14 (t, J = 8.9 Hz, 2H, ArH), 4.04 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 177.2, 169.0, 166.7, 165.8, 157.9 (¹J_CF = 238 Hz), 157.4, 151.5, 135.5 (⁴J_CF = 3 Hz), 133.9, 125.9, 125.0, 120.7 (2C, ³J_CF = 8 Hz), 118.7, 116.9, 115.3 (2C, ²J_CF = 22 Hz), 94.7, 35.6; HR-ESI-MS: m/z calcd. for C₁₉H₁₃FN₄O₃S [M+H]⁺ 397.072 6, found 397.073 0
7a'f	¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H, Ph-NH-CO), 7.73 (d, J = 7.8 Hz, 2H, ArH), 7.64-7.50 (m, 2H, ArH), 7.29-7.03 (m, 4H, ArH), 3.94 (s, 2H, S-CH₂), 2.63 (q, J = 7.6 Hz, 2H, CH₂-CH₃), 1.17 (t, J = 7.6 Hz, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.5, 167.1, 166.7, 161.9, 158.0 (¹J_CF = 239 Hz), 146.7, 135.5 (⁴J_CF = 2 Hz), 134.0, 128.5 (2C), 127.6 (2C), 120.6 (2C, ³J_CF = 8 Hz), 118.4, 115.4 (2C, ²J_CF = 22 Hz), 90.3, 35.3, 28.1, 15.4; HR-ESI-MS: m/z calcd. for C₂₁H₁₇FN₄O₂S [M+H]⁺ 409.109 0, found 409.109 4
7a'g	¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H, Ph-NH-CO), 10.77 (s, 1H, Ar-NH), 7.72 (dd, J = 8.5, 2.1 Hz, 2H, ArH), 7.58 (ddd, J = 9.1, 4.8, 2.1 Hz, 4H, ArH), 7.13 (td, J = 8.9, 2.1 Hz, 2H, ArH), 3.89 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6, 168.1, 167.0, 166.1, 157.9 (¹J_CF = 238 Hz), 136.1, 135.5 (⁴J_CF = 3 Hz), 131.2 (2C), 130.4 (2C), 123.8, 120.5 (2C, ³J_CF = 8 Hz), 118.8, 115.3 (2C, ²J_CF = 22 Hz), 90.1, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₂BrFN₄O₂S [M+H]⁺ 459.982 8, found 459.982 9
7a'h	¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H, Ph-NH-CO), 8.06 (d, J = 5.1 Hz, 2H, ArH), 7.85 (d, J = 7.8 Hz, 1H, ArH), 7.66 (t, J = 8.0 Hz, 1H, ArH), 7.59 (ddt, J = 6.9, 4.9, 1.8 Hz, 2H, ArH), 7.13 (td, J = 8.9, 2.0 Hz, 2H, ArH), 3.86 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 169.2, 167.3, 165.7, 157.9 (¹J_CF = 238 Hz), 138.2, 135.6 (⁴J_CF =3 Hz), 132.3, 129.5, 129.0 (²J_CF = 32 Hz), 126.6, 124.6 (³J_CF = 4 Hz), 124.0 (¹J_CF = 271 Hz), 120.6 (2C, ³J_CF = 8 Hz), 119.2, 115.4 (2C, ²J_CF= 22 Hz), 90.0, 35.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₂F₄N₄O₂S [M+H]⁺ 449.065 1, found 449.064 7
7a'i	¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H, Ph-NH-CO), 7.94 (d, J = 7.9 Hz, 2H, ArH), 7.75 (d, J = 8.1 Hz, 2H, ArH), 7.58 (ddt, J = 6.9, 4.9, 1.9 Hz, 2H, ArH), 7.13 (tt, J = 9.0, 4.6 Hz, 2H, ArH), 3.88 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.2, 168.6, 167.2, 165.9, 157.9 (¹J_CF = 239 Hz), 141.1, 135.6 (⁴J_CF = 2 Hz), 130.1 (²J_CF = 31 Hz), 129.1 (2C), 125.1 (2C, ³J_CF = 3 Hz), 124.0 (¹J_CF = 271 Hz), 120.5 (2C, ³J_CF = 7 Hz), 118.9, 115.3 (2C, ²J_CF = 22 Hz), 90.4, 35.3; HR-ESI-MS: m/z calcd. for C₂₀H₁₂F₄N₄O₂S [M+H]⁺ 449.056 1, found 499.055 8
7a'j	¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H, Ph-NH-CO), 7.63-7.50 (m, 2H, ArH), 7.33 (dtd, J = 6.1, 3.7, 3.2, 1.2 Hz, 3H, ArH), 7.20-7.09 (m, 2H, ArH), 7.08-6.98 (m, 1H, ArH), 3.84 (s, 2H, S-CH₂), 3.76 (s, 3H, -OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.4, 169.8, 167.4, 167.1, 158.9, 157.9 (¹J_CF = 239 Hz), 138.6, 135.6 (⁴J_CF= 3 Hz), 129.3, 120.5, 120.5 (2C, ³J_CF = 8 Hz), 119.5, 115.6, 115.3 (2C, ²J_CF = 22 Hz), 113.6, 89.6, 55.2, 35.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₃S [M+H]⁺ 411.088 2, found 411.088 5
7a'k	¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H, Ph-NH-CO), 7.74 (d, J = 2.4 Hz, 3H, ArH), 7.64–7.55 (m, 2H, ArH), 7.13 (td, J = 8.9, 1.9 Hz, 2H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.8, 169.4, 167.3, 164.3, 157.9 (¹J_CF =238 Hz), 140.6, 135.6 (⁴J_CF = 3 Hz), 134.0 (2C, Ph), 129.3, 126.8 (2C, Ph), 120.6 (2C, ³J_CF = 7 Hz), 119.1, 115.3 (2C, ²J_CF = 22 Hz), 89.8, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₁Cl₂FN₄O₂S [M+H]⁺ 449.993 4, found 449.993 5
7a'l	¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H, Ph-NH-CO), 7.70 (dd, J = 8.2, 1.8 Hz, 2H, ArH), 7.58 (ddt, J = 6.8, 4.9, 1.7 Hz, 2H, ArH), 7.24-7.09 (m, 4H, ArH), 3.91 (s, 2H, S-CH₂), 2.34 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.8, 167.1, 166.9, 163.8, 157.9 (¹J_CF = 238 Hz), 140.3, 135.6 (⁴J_CF = 2 Hz), 133.9, 128.8 (2C), 128.4 (2C), 120.6 (2C, ³J_CF = 7 Hz), 118.8, 115.4 (2C, ²J_CF = 22 Hz), 90.1, 35.2, 21.0; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₂S [M+H]⁺ 395.093 3, found 395.093 6
7a'm	¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H, Ph-NH-CO), 7.83 (ddd, J = 8.3, 5.5, 2.1 Hz, 2H, ArH), 7.59 (ddt, J = 7.4, 5.0, 2.1 Hz, 2H, ArH), 7.24 (td, J = 8.9, 2.2 Hz, 2H, ArH), 7.14 (td, J = 9.1, 2.2 Hz, 2H, ArH), 3.83 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.4, 169.7, 167.5, 166.1, 163.0 (¹J_CF = 246 Hz), 157.9 (¹J_CF = 238 Hz), 135.6 (⁴J_CF = 3 Hz), 133.8 (⁴J_CF = 3 Hz), 130.6 (2C, ³J_CF = 8 Hz), 120.5 (2C, ³J_CF = 8 Hz), 119.6, 115.4 (2C, ²J_CF = 22 Hz), 115.1 (2C, ²J_CF = 21 Hz), 89.4, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₂F₂N₄O₂S [M+H]⁺ 399.068 3, found 399.068 7
7a'n	¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H, Ph-NH-CO), 7.79 (d, J = 8.4 Hz, 2H, ArH), 7.59 (dd, J = 8.4, 4.9 Hz, 2H, ArH), 7.14 (t, J = 8.5 Hz, 2H, ArH), 6.94 (d, J = 8.4 Hz, 2H, ArH), 3.85 (s, 2H, S-CH₂), 3.79 (s, 3H, -OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.5, 169.0, 167.3, 166.5, 160.9, 157.9 (¹J_CF = 238 Hz), 135.6 (⁴J_CF = 3 Hz), 130.0 (2C), 129.3, 120.5 (2C, ³J_CF = 8 Hz), 119.6, 115.4 (2C, ²J_CF = 22 Hz), 113.50 (2C), 89.0, 55.3, 35.2; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₃S [M+H]⁺ 411.088 2, found 411.088 4
7a'o	¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 1H, Ph-NH-CO), 7.78 (ddd, J = 11.8, 7.9, 2.2 Hz, 1H, ArH), 7.70–7.63 (m, 1H, ArH), 7.63-7.55 (m, 2H, ArH), 7.49 (dt, J = 10.7, 8.5 Hz, 1H, ArH), 7.18–7.08 (m, 2H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 169.4, 167.3, 164.7, 157.9 (¹J_CF = 238 Hz), 150.3 (¹J_CF = 242 Hz, ²J_CF = 12 Hz), 149.1 (¹J_CF = 246 Hz, ²J_CF = 12 Hz), 135.5 (⁴J_CF = 2 Hz), 130.8 (³J_CF = 6 Hz), 125.4 (⁴J_CF = 3 Hz), 120.5 (2C, ³J_CF = 8 Hz), 119.3, 117.4 (²J_CF = 18 Hz), 117.31 (²J_CF = 17 Hz), 115.3 (2C, ²J_CF = 22 Hz), 89.6, 35.1; HR-ESI-MS: m/z calcd. for C₁₉H₁₁F₃N₄O₂S [M+H]⁺ 417.058 8, found 417.058 6
7a'p	¹H NMR (400 MHz, DMSO-d₆) δ 10.93 (s, 1H, Ph-NH-CO), 7.62-7.52 (m, 2H, ArH), 7.36-7.24 (m, 2H, ArH), 7.22 (dd, J = 3.8, 0.9 Hz, 2H, ArH), 7.18-7.09 (m, 2H, ArH), 3.81 (s, 2H, S-CH₂), 2.21 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.3, 169.8, 169.4, 167.4, 157.9 (¹J_CF = 238 Hz), 137.8, 135.5 (⁴J_CF = 3 Hz), 134.9, 130.1, 128.7, 128.3, 125.5, 120.5 (2C, ³J_CF = 8 Hz), 118.9, 115.3 (2C, ²J_CF = 22 Hz), 91.9, 35.1, 19.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₂S [M+H]⁺ 395.093 3, found 395.093 6
7a'q	¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H, Ph-NH-CO), 7.64-7.54 (m, 2H, ArH), 7.49-7.32 (m, 3H, ArH), 7.13 (t, J = 8.9 Hz, 2H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.8, 169.5, 167.4, 164.5, 162.0 (2C, ¹J_CF = 245 Hz, ³J_CF = 13 Hz), 157.9 (¹J_CF = 238 Hz), 140.8 (³J_CF = 9 Hz), 135.6 (⁴J_CF = 2 Hz), 120.5 (2C, ³J_CF = 8 Hz), 119.2, 115.3 (2C, ²J_CF = 22 Hz), 111.5 (2C, ²J_CF = 26 Hz), 105.29 (²J_CF = 25 Hz), 89.7, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₁F₃N₄O₂S [M+H]⁺ 417.058 8, found 417.059 1
7a'r	¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H, Ph-NH-CO), 7.57 (ddt, J = 6.9, 5.0, 2.8 Hz, 2H, ArH), 7.44-7.35 (m, 1H, ArH), 7.25-7.06 (m, 4H, ArH), 6.93 (t, J = 7.4 Hz, 1H, ArH), 3.78 (s, 2H, S-CH₂), 3.76 (s, J = 1.7 Hz, 3H, -OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.2, 169.2, 167.6, 166.9, 157.9 (¹J_CF = 238 Hz), 156.2, 135.6 (⁴J_CF = 2 Hz), 130.6, 129.6, 127.1, 120.5 (2C, ³J_CF = 7 Hz), 120.1, 118.9, 115.3 (2C, ²J_CF = 22 Hz), 111.6, 93.1, 55.4, 35.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₃S [M+H]⁺ 411.088 2, found 411.088 6
7b'a	¹H NMR (400 MHz, DMSO-d₆) δ 11.38 (s, 1H, Ph-NH-CO), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.31-7.19 (m, 4H, ArH), 6.89 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.83 (s, 2H, S-CH₂), 2.91 (p, J = 6.9 Hz, 1H, -CH(CH₃)₂), 1.21 (d, J = 6.9 Hz, 6H, -CH(CH₃)₂; ¹³C NMR (100 MHz, DMSO-d₆) δ 171.1, 169.7, 168.4, 167.1, 162.6 (¹J_CF = 241 Hz), 162.4 (¹J_CF = 241 Hz), 150.6, 141.6 (³J_CF = 14 Hz), 134.9, 128.3 (2C), 126.05 (2C), 119.6, 101.7 (2C, ²J_CF = 29 Hz), 98.2 (²J_CF = 26 Hz), 89.4, 35.3, 33.3, 23.7 (2C); HR-ESI-MS: m/z calcd. for C₂₂H₁₈F₂N₄O₂S [M+H]⁺ 441.115 2, found 441.115 0
7b'b	¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (s, 1H, Ph-NH-CO), 7.64-7.57 (m, 1H, ArH), 7.54-7.42 (m, 2H, ArH), 7.29 (pd, J = 8.0, 7.4, 2.6 Hz, 3H, ArH), 6.88 (tt, J = 9.3, 2.4 Hz, 1H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 169.7, 168.3, 165.8, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 242 Hz), 161.8 (¹J_CF = 243 Hz), 141.5 (³J_CF = 14 Hz), 139.7 (³J_CF = 7 Hz), 130.2 (³J_CF = 8 Hz), 124.4 (⁴J_CF=2 Hz), 119.4, 116.8 (²J_CF = 20 Hz), 114.9 (²J_CF = 23 Hz), 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.8, 35.3; HR-ESI-MS: m/z calcd. for C₁₉H₁₁F₃N₄O₂S [M+H]⁺ 417.058 8, found 417.059 2
7b'c	¹H NMR (400 MHz, DMSO-d₆) δ 11.43 (s, 1H, Ph-NH-CO), 7.53 (dd, J = 6.4, 1.7 Hz, 2H, ArH), 7.34–7.22 (m, 4H, ArH), 6.88 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.83 (s, 2H, S-CH₂), 2.30 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.3, 170.0, 168.5, 167.5, 162.6 (¹J_CF = 242 Hz), 162.5 (¹J_CF = 242 Hz), 141.6 (³J_CF = 14 Hz), 137.4, 137.4, 130.5, 128.6, 128.0, 125.4, 119.6, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.7, 35.3, 20.9; HR-ESI-MS: m/z calcd. for C₂₀H₁₄F₂N₄O₂S [M+H]⁺ 413.083 9, found 413.083 7
7b'd	¹H NMR (400 MHz, DMSO-d₆) δ 11.45 (s, 1H, Ph-NH-CO), 7.56-7.45 (m, 2H, ArH), 7.29-7.13 (m, 3H, ArH), 6.88 (tt, J = 9.3, 2.4 Hz, 1H, ArH), 3.83 (s, 2H, S-CH₂), 2.25 (s, 3H, CH₃), 2.20 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.0, 169.7, 168.4, 167.4, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 242 Hz), 141.6 (³J_CF = 14 Hz), 138.5, 136.0, 134.9, 129.2, 129.1, 125.7, 119.6, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.5, 35.3, 19.3 (2C); HR-ESI-MS: m/z calcd. for C₂₁H₁₆F₂N₄O₂S [M+H]⁺ 427.099 6, found 427.099 3
7b'e	¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H, Ph-NH-CO), 10.94 (s, 1H, -OH), 8.32 (dd, J = 7.9, 1.6 Hz, 1H, ArH), 7.75 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H, ArH), 7.52 (d, J = 8.4 Hz, 1H, ArH), 7.42 (t, J = 7.6 Hz, 1H, ArH), 7.38-7.27 (m, 2H, ArH), 6.90 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 4.05 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 176.9, 169.0, 167.6, 165.8, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 242 Hz), 157.4, 151.6, 141.6 (³J_CF = 13 Hz), 133.9, 125.8, 125.0, 118.7, 116.9, 101.9 (2C, ²J_CF = 29 Hz), 98.4 (²J_CF = 26 Hz), 94.9, 35.7; HR-ESI-MS: m/z calcd. for C₁₉H₁₂F₂N₄O₃S [M+H]⁺ 415.063 2, found 415.063 6
7b'f	¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (s, 1H, Ph-NH-CO), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.30–7.18 (m, 4H, ArH), 6.88 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.84 (s, 2H, S-CH₂), 2.63 (q, J = 7.6 Hz, 2H, -CH₂CH₃), 1.18 (t, J = 7.5 Hz, 3H, -CH₂CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.0, 169.5, 168.4, 167.2, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 241 Hz), 146.1, 141.6 (³J_CF = 13 Hz), 134.7, 128.3 (2C), 127.5 (2C), 119.5, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.5, 35.3, 28.1, 15.4; HR-ESI-MS: m/z calcd. for C₂₁H₁₆F₂N₄O₂S [M+H]⁺ 427.099 6, found 427.100 0
7b'g	¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (s, 1H, Ph-NH-CO), 7.73-7.67 (m, 2H, ArH), 7.61 (d, J = 8.6 Hz, 2H, ArH), 7.32-7.24 (m, 2H, ArH), 6.89 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.4, 169.6, 168.3, 166.1, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 241 Hz), 141.6 (³J_CF = 13 Hz), 136.5, 131.2 (2C), 130.3 (2C), 123.5, 119.4, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.6, 35.3; HR-ESI-MS: m/z calcd. for C₁₉H₁₁BrF₂N₄O₂S [M+H]⁺ 422.973 4, found 422.973 8

Compd.	¹H NMR, ¹³C NMR, HR-ESI-MS
7a'a	¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H, Ph-NH-CO), 7.71 (dd, J = 8.2, 1.8 Hz, 2H, ArH), 7.56 (ddt, J = 6.8, 5.0, 1.8 Hz, 2H, ArH), 7.27-7.21 (m, 2H, ArH), 7.13 (td, J = 8.9, 1.9 Hz, 2H, ArH), 3.87 (s, 2H, S-CH₂), 2.98-2.85 (m, 1H, CH(CH₃)₂), 1.21 (d, J = 1.7 Hz, 3H, CH₃), 1.19 (d, J = 1.8 Hz, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.4, 167.1, 167.1, 159.1, 158.0 (¹J_CF = 238 Hz), 150.9, 135.6 (⁴J_CF = 2 Hz), 134.6, 128.4 (2C), 126.1 (2C), 120.5 (2C, ³J_CF = 8 Hz), 119.2, 115.4 (2C, ²J_CF = 22 Hz), 90.2, 35.2, 33.4, 23.7 (2C); HR-ESI-MS: m/z calcd. for C₂₂H₁₉FN₄O₂S [M+H]⁺ 423.124 6, found 423.124 8
7a'b	¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H, Ph-NH-CO), 7.63 (d, J = 7.8 Hz, 1H, ArH), 7.57 (td, J = 7.4, 5.8, 2.7 Hz, 3H, ArH), 7.45 (q, J = 7.1, 6.5 Hz, 1H, ArH), 7.33 (t, J = 8.7 Hz, 1H, ArH), 7.13 (td, J = 9.0, 2.0 Hz, 2H, ArH), 3.91 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6, 166.9, 165.8, 165.7, 161.8 (¹J_CF = 242 Hz), 158.0 (¹J_CF = 237 Hz), 139.2 (³J_CF = 8 Hz), 135.51 (⁴J_CF = 3 Hz), 130.3 (³J_CF = 8 Hz), 124.5 (⁴J_CF = 3 Hz), 120.6 (2C, ³J_CF = 8 Hz), 118.6, 117.2 (²J_CF = 21 Hz), 115.4 (2C, ²J_CF = 22 Hz), 115.0 (²J_CF = 23 Hz), 91.4, 35.3; HR-ESI-MS: m/z calcd. for C₁₉H₁₂F₂N₄O₂S [M+H]⁺ 399.068 3, found 399.068 6
7a'c	¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s, 1H, Ph-NH-CO), 7.58 (dd, J = 8.3, 5.0 Hz, 2H, ArH), 7.54 (d, J = 5.0 Hz, 2H, ArH), 7.29 (td, J = 9.6, 9.0, 6.8 Hz, 2H, ArH), 7.18-7.08 (m, 2H, ArH), 3.81 (s, 2H, S-CH₂), 2.30 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 170.0, 167.6, 167.5, 157.9 (¹J_CF = 238 Hz), 137.4, 137.3, 135.6 (⁴J_CF = 3 Hz), 130.4, 128.6, 128.0, 125.4, 120.5 (2C, ³J_CF = 8 Hz), 119.7, 115.4 (2C, ²J_CF = 22 Hz), 89.5, 35.1, 20.9; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₂S [M+H]⁺ 395.093 3, found 395.093 5
7a'd	¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H, Ph-NH-CO), 7.65-7.44 (m, 4H, ArH), 7.22-7.02 (m, 3H, ArH), 3.85 (s, 2H, S-CH₂), 2.25 (s, 3H, CH₃), 2.19 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6, 168.9, 167.3, 167.3, 157.9 (¹J_CF = 239 Hz), 138.7, 136.1, 135.6 (¹J_CF = 3 Hz), 134.7, 129.2 (2C), 125.8, 120.5 (2C, ³J_CF = 7 Hz), 119.3, 115.3 (2C, ²J_CF = 22 Hz), 89.7, 35.2, 19.3 (2C); HR-ESI-MS: m/z calcd. for C₂₁H₁₇FN₄O₂S [M+H]⁺ 409.109 0, found 409.109 2
7a'e	¹H NMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H, Ph-NH-CO), 10.87-10.72 (m, 1H, OH), 10.54 (s, 1H, Ar-NH), 8.35 (dd, J = 7.9, 1.7 Hz, 1H, ArH), 7.75 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H, ArH), 7.67-7.60 (m, 2H, ArH), 7.52 (d, J = 8.3 Hz, 1H, ArH), 7.44 (t, J = 7.6 Hz, 1H, ArH), 7.14 (t, J = 8.9 Hz, 2H, ArH), 4.04 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 177.2, 169.0, 166.7, 165.8, 157.9 (¹J_CF = 238 Hz), 157.4, 151.5, 135.5 (⁴J_CF = 3 Hz), 133.9, 125.9, 125.0, 120.7 (2C, ³J_CF = 8 Hz), 118.7, 116.9, 115.3 (2C, ²J_CF = 22 Hz), 94.7, 35.6; HR-ESI-MS: m/z calcd. for C₁₉H₁₃FN₄O₃S [M+H]⁺ 397.072 6, found 397.073 0
7a'f	¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H, Ph-NH-CO), 7.73 (d, J = 7.8 Hz, 2H, ArH), 7.64-7.50 (m, 2H, ArH), 7.29-7.03 (m, 4H, ArH), 3.94 (s, 2H, S-CH₂), 2.63 (q, J = 7.6 Hz, 2H, CH₂-CH₃), 1.17 (t, J = 7.6 Hz, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.5, 167.1, 166.7, 161.9, 158.0 (¹J_CF = 239 Hz), 146.7, 135.5 (⁴J_CF = 2 Hz), 134.0, 128.5 (2C), 127.6 (2C), 120.6 (2C, ³J_CF = 8 Hz), 118.4, 115.4 (2C, ²J_CF = 22 Hz), 90.3, 35.3, 28.1, 15.4; HR-ESI-MS: m/z calcd. for C₂₁H₁₇FN₄O₂S [M+H]⁺ 409.109 0, found 409.109 4
7a'g	¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H, Ph-NH-CO), 10.77 (s, 1H, Ar-NH), 7.72 (dd, J = 8.5, 2.1 Hz, 2H, ArH), 7.58 (ddd, J = 9.1, 4.8, 2.1 Hz, 4H, ArH), 7.13 (td, J = 8.9, 2.1 Hz, 2H, ArH), 3.89 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6, 168.1, 167.0, 166.1, 157.9 (¹J_CF = 238 Hz), 136.1, 135.5 (⁴J_CF = 3 Hz), 131.2 (2C), 130.4 (2C), 123.8, 120.5 (2C, ³J_CF = 8 Hz), 118.8, 115.3 (2C, ²J_CF = 22 Hz), 90.1, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₂BrFN₄O₂S [M+H]⁺ 459.982 8, found 459.982 9
7a'h	¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H, Ph-NH-CO), 8.06 (d, J = 5.1 Hz, 2H, ArH), 7.85 (d, J = 7.8 Hz, 1H, ArH), 7.66 (t, J = 8.0 Hz, 1H, ArH), 7.59 (ddt, J = 6.9, 4.9, 1.8 Hz, 2H, ArH), 7.13 (td, J = 8.9, 2.0 Hz, 2H, ArH), 3.86 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 169.2, 167.3, 165.7, 157.9 (¹J_CF = 238 Hz), 138.2, 135.6 (⁴J_CF =3 Hz), 132.3, 129.5, 129.0 (²J_CF = 32 Hz), 126.6, 124.6 (³J_CF = 4 Hz), 124.0 (¹J_CF = 271 Hz), 120.6 (2C, ³J_CF = 8 Hz), 119.2, 115.4 (2C, ²J_CF= 22 Hz), 90.0, 35.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₂F₄N₄O₂S [M+H]⁺ 449.065 1, found 449.064 7
7a'i	¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H, Ph-NH-CO), 7.94 (d, J = 7.9 Hz, 2H, ArH), 7.75 (d, J = 8.1 Hz, 2H, ArH), 7.58 (ddt, J = 6.9, 4.9, 1.9 Hz, 2H, ArH), 7.13 (tt, J = 9.0, 4.6 Hz, 2H, ArH), 3.88 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.2, 168.6, 167.2, 165.9, 157.9 (¹J_CF = 239 Hz), 141.1, 135.6 (⁴J_CF = 2 Hz), 130.1 (²J_CF = 31 Hz), 129.1 (2C), 125.1 (2C, ³J_CF = 3 Hz), 124.0 (¹J_CF = 271 Hz), 120.5 (2C, ³J_CF = 7 Hz), 118.9, 115.3 (2C, ²J_CF = 22 Hz), 90.4, 35.3; HR-ESI-MS: m/z calcd. for C₂₀H₁₂F₄N₄O₂S [M+H]⁺ 449.056 1, found 499.055 8
7a'j	¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H, Ph-NH-CO), 7.63-7.50 (m, 2H, ArH), 7.33 (dtd, J = 6.1, 3.7, 3.2, 1.2 Hz, 3H, ArH), 7.20-7.09 (m, 2H, ArH), 7.08-6.98 (m, 1H, ArH), 3.84 (s, 2H, S-CH₂), 3.76 (s, 3H, -OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.4, 169.8, 167.4, 167.1, 158.9, 157.9 (¹J_CF = 239 Hz), 138.6, 135.6 (⁴J_CF= 3 Hz), 129.3, 120.5, 120.5 (2C, ³J_CF = 8 Hz), 119.5, 115.6, 115.3 (2C, ²J_CF = 22 Hz), 113.6, 89.6, 55.2, 35.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₃S [M+H]⁺ 411.088 2, found 411.088 5
7a'k	¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H, Ph-NH-CO), 7.74 (d, J = 2.4 Hz, 3H, ArH), 7.64–7.55 (m, 2H, ArH), 7.13 (td, J = 8.9, 1.9 Hz, 2H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.8, 169.4, 167.3, 164.3, 157.9 (¹J_CF =238 Hz), 140.6, 135.6 (⁴J_CF = 3 Hz), 134.0 (2C, Ph), 129.3, 126.8 (2C, Ph), 120.6 (2C, ³J_CF = 7 Hz), 119.1, 115.3 (2C, ²J_CF = 22 Hz), 89.8, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₁Cl₂FN₄O₂S [M+H]⁺ 449.993 4, found 449.993 5
7a'l	¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H, Ph-NH-CO), 7.70 (dd, J = 8.2, 1.8 Hz, 2H, ArH), 7.58 (ddt, J = 6.8, 4.9, 1.7 Hz, 2H, ArH), 7.24-7.09 (m, 4H, ArH), 3.91 (s, 2H, S-CH₂), 2.34 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.8, 167.1, 166.9, 163.8, 157.9 (¹J_CF = 238 Hz), 140.3, 135.6 (⁴J_CF = 2 Hz), 133.9, 128.8 (2C), 128.4 (2C), 120.6 (2C, ³J_CF = 7 Hz), 118.8, 115.4 (2C, ²J_CF = 22 Hz), 90.1, 35.2, 21.0; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₂S [M+H]⁺ 395.093 3, found 395.093 6
7a'm	¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H, Ph-NH-CO), 7.83 (ddd, J = 8.3, 5.5, 2.1 Hz, 2H, ArH), 7.59 (ddt, J = 7.4, 5.0, 2.1 Hz, 2H, ArH), 7.24 (td, J = 8.9, 2.2 Hz, 2H, ArH), 7.14 (td, J = 9.1, 2.2 Hz, 2H, ArH), 3.83 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.4, 169.7, 167.5, 166.1, 163.0 (¹J_CF = 246 Hz), 157.9 (¹J_CF = 238 Hz), 135.6 (⁴J_CF = 3 Hz), 133.8 (⁴J_CF = 3 Hz), 130.6 (2C, ³J_CF = 8 Hz), 120.5 (2C, ³J_CF = 8 Hz), 119.6, 115.4 (2C, ²J_CF = 22 Hz), 115.1 (2C, ²J_CF = 21 Hz), 89.4, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₂F₂N₄O₂S [M+H]⁺ 399.068 3, found 399.068 7
7a'n	¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H, Ph-NH-CO), 7.79 (d, J = 8.4 Hz, 2H, ArH), 7.59 (dd, J = 8.4, 4.9 Hz, 2H, ArH), 7.14 (t, J = 8.5 Hz, 2H, ArH), 6.94 (d, J = 8.4 Hz, 2H, ArH), 3.85 (s, 2H, S-CH₂), 3.79 (s, 3H, -OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.5, 169.0, 167.3, 166.5, 160.9, 157.9 (¹J_CF = 238 Hz), 135.6 (⁴J_CF = 3 Hz), 130.0 (2C), 129.3, 120.5 (2C, ³J_CF = 8 Hz), 119.6, 115.4 (2C, ²J_CF = 22 Hz), 113.50 (2C), 89.0, 55.3, 35.2; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₃S [M+H]⁺ 411.088 2, found 411.088 4
7a'o	¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 1H, Ph-NH-CO), 7.78 (ddd, J = 11.8, 7.9, 2.2 Hz, 1H, ArH), 7.70–7.63 (m, 1H, ArH), 7.63-7.55 (m, 2H, ArH), 7.49 (dt, J = 10.7, 8.5 Hz, 1H, ArH), 7.18–7.08 (m, 2H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 169.4, 167.3, 164.7, 157.9 (¹J_CF = 238 Hz), 150.3 (¹J_CF = 242 Hz, ²J_CF = 12 Hz), 149.1 (¹J_CF = 246 Hz, ²J_CF = 12 Hz), 135.5 (⁴J_CF = 2 Hz), 130.8 (³J_CF = 6 Hz), 125.4 (⁴J_CF = 3 Hz), 120.5 (2C, ³J_CF = 8 Hz), 119.3, 117.4 (²J_CF = 18 Hz), 117.31 (²J_CF = 17 Hz), 115.3 (2C, ²J_CF = 22 Hz), 89.6, 35.1; HR-ESI-MS: m/z calcd. for C₁₉H₁₁F₃N₄O₂S [M+H]⁺ 417.058 8, found 417.058 6
7a'p	¹H NMR (400 MHz, DMSO-d₆) δ 10.93 (s, 1H, Ph-NH-CO), 7.62-7.52 (m, 2H, ArH), 7.36-7.24 (m, 2H, ArH), 7.22 (dd, J = 3.8, 0.9 Hz, 2H, ArH), 7.18-7.09 (m, 2H, ArH), 3.81 (s, 2H, S-CH₂), 2.21 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.3, 169.8, 169.4, 167.4, 157.9 (¹J_CF = 238 Hz), 137.8, 135.5 (⁴J_CF = 3 Hz), 134.9, 130.1, 128.7, 128.3, 125.5, 120.5 (2C, ³J_CF = 8 Hz), 118.9, 115.3 (2C, ²J_CF = 22 Hz), 91.9, 35.1, 19.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₂S [M+H]⁺ 395.093 3, found 395.093 6
7a'q	¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H, Ph-NH-CO), 7.64-7.54 (m, 2H, ArH), 7.49-7.32 (m, 3H, ArH), 7.13 (t, J = 8.9 Hz, 2H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.8, 169.5, 167.4, 164.5, 162.0 (2C, ¹J_CF = 245 Hz, ³J_CF = 13 Hz), 157.9 (¹J_CF = 238 Hz), 140.8 (³J_CF = 9 Hz), 135.6 (⁴J_CF = 2 Hz), 120.5 (2C, ³J_CF = 8 Hz), 119.2, 115.3 (2C, ²J_CF = 22 Hz), 111.5 (2C, ²J_CF = 26 Hz), 105.29 (²J_CF = 25 Hz), 89.7, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₁F₃N₄O₂S [M+H]⁺ 417.058 8, found 417.059 1
7a'r	¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H, Ph-NH-CO), 7.57 (ddt, J = 6.9, 5.0, 2.8 Hz, 2H, ArH), 7.44-7.35 (m, 1H, ArH), 7.25-7.06 (m, 4H, ArH), 6.93 (t, J = 7.4 Hz, 1H, ArH), 3.78 (s, 2H, S-CH₂), 3.76 (s, J = 1.7 Hz, 3H, -OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.2, 169.2, 167.6, 166.9, 157.9 (¹J_CF = 238 Hz), 156.2, 135.6 (⁴J_CF = 2 Hz), 130.6, 129.6, 127.1, 120.5 (2C, ³J_CF = 7 Hz), 120.1, 118.9, 115.3 (2C, ²J_CF = 22 Hz), 111.6, 93.1, 55.4, 35.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₃S [M+H]⁺ 411.088 2, found 411.088 6
7b'a	¹H NMR (400 MHz, DMSO-d₆) δ 11.38 (s, 1H, Ph-NH-CO), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.31-7.19 (m, 4H, ArH), 6.89 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.83 (s, 2H, S-CH₂), 2.91 (p, J = 6.9 Hz, 1H, -CH(CH₃)₂), 1.21 (d, J = 6.9 Hz, 6H, -CH(CH₃)₂; ¹³C NMR (100 MHz, DMSO-d₆) δ 171.1, 169.7, 168.4, 167.1, 162.6 (¹J_CF = 241 Hz), 162.4 (¹J_CF = 241 Hz), 150.6, 141.6 (³J_CF = 14 Hz), 134.9, 128.3 (2C), 126.05 (2C), 119.6, 101.7 (2C, ²J_CF = 29 Hz), 98.2 (²J_CF = 26 Hz), 89.4, 35.3, 33.3, 23.7 (2C); HR-ESI-MS: m/z calcd. for C₂₂H₁₈F₂N₄O₂S [M+H]⁺ 441.115 2, found 441.115 0
7b'b	¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (s, 1H, Ph-NH-CO), 7.64-7.57 (m, 1H, ArH), 7.54-7.42 (m, 2H, ArH), 7.29 (pd, J = 8.0, 7.4, 2.6 Hz, 3H, ArH), 6.88 (tt, J = 9.3, 2.4 Hz, 1H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 169.7, 168.3, 165.8, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 242 Hz), 161.8 (¹J_CF = 243 Hz), 141.5 (³J_CF = 14 Hz), 139.7 (³J_CF = 7 Hz), 130.2 (³J_CF = 8 Hz), 124.4 (⁴J_CF=2 Hz), 119.4, 116.8 (²J_CF = 20 Hz), 114.9 (²J_CF = 23 Hz), 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.8, 35.3; HR-ESI-MS: m/z calcd. for C₁₉H₁₁F₃N₄O₂S [M+H]⁺ 417.058 8, found 417.059 2
7b'c	¹H NMR (400 MHz, DMSO-d₆) δ 11.43 (s, 1H, Ph-NH-CO), 7.53 (dd, J = 6.4, 1.7 Hz, 2H, ArH), 7.34–7.22 (m, 4H, ArH), 6.88 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.83 (s, 2H, S-CH₂), 2.30 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.3, 170.0, 168.5, 167.5, 162.6 (¹J_CF = 242 Hz), 162.5 (¹J_CF = 242 Hz), 141.6 (³J_CF = 14 Hz), 137.4, 137.4, 130.5, 128.6, 128.0, 125.4, 119.6, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.7, 35.3, 20.9; HR-ESI-MS: m/z calcd. for C₂₀H₁₄F₂N₄O₂S [M+H]⁺ 413.083 9, found 413.083 7
7b'd	¹H NMR (400 MHz, DMSO-d₆) δ 11.45 (s, 1H, Ph-NH-CO), 7.56-7.45 (m, 2H, ArH), 7.29-7.13 (m, 3H, ArH), 6.88 (tt, J = 9.3, 2.4 Hz, 1H, ArH), 3.83 (s, 2H, S-CH₂), 2.25 (s, 3H, CH₃), 2.20 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.0, 169.7, 168.4, 167.4, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 242 Hz), 141.6 (³J_CF = 14 Hz), 138.5, 136.0, 134.9, 129.2, 129.1, 125.7, 119.6, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.5, 35.3, 19.3 (2C); HR-ESI-MS: m/z calcd. for C₂₁H₁₆F₂N₄O₂S [M+H]⁺ 427.099 6, found 427.099 3
7b'e	¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H, Ph-NH-CO), 10.94 (s, 1H, -OH), 8.32 (dd, J = 7.9, 1.6 Hz, 1H, ArH), 7.75 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H, ArH), 7.52 (d, J = 8.4 Hz, 1H, ArH), 7.42 (t, J = 7.6 Hz, 1H, ArH), 7.38-7.27 (m, 2H, ArH), 6.90 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 4.05 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 176.9, 169.0, 167.6, 165.8, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 242 Hz), 157.4, 151.6, 141.6 (³J_CF = 13 Hz), 133.9, 125.8, 125.0, 118.7, 116.9, 101.9 (2C, ²J_CF = 29 Hz), 98.4 (²J_CF = 26 Hz), 94.9, 35.7; HR-ESI-MS: m/z calcd. for C₁₉H₁₂F₂N₄O₃S [M+H]⁺ 415.063 2, found 415.063 6
7b'f	¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (s, 1H, Ph-NH-CO), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.30–7.18 (m, 4H, ArH), 6.88 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.84 (s, 2H, S-CH₂), 2.63 (q, J = 7.6 Hz, 2H, -CH₂CH₃), 1.18 (t, J = 7.5 Hz, 3H, -CH₂CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.0, 169.5, 168.4, 167.2, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 241 Hz), 146.1, 141.6 (³J_CF = 13 Hz), 134.7, 128.3 (2C), 127.5 (2C), 119.5, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.5, 35.3, 28.1, 15.4; HR-ESI-MS: m/z calcd. for C₂₁H₁₆F₂N₄O₂S [M+H]⁺ 427.099 6, found 427.100 0
7b'g	¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (s, 1H, Ph-NH-CO), 7.73-7.67 (m, 2H, ArH), 7.61 (d, J = 8.6 Hz, 2H, ArH), 7.32-7.24 (m, 2H, ArH), 6.89 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.4, 169.6, 168.3, 166.1, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 241 Hz), 141.6 (³J_CF = 13 Hz), 136.5, 131.2 (2C), 130.3 (2C), 123.5, 119.4, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.6, 35.3; HR-ESI-MS: m/z calcd. for C₁₉H₁₁BrF₂N₄O₂S [M+H]⁺ 422.973 4, found 422.973 8

Compd.	R₁	R₂	EC₅₀ /μmol·L^-1	CC₅₀ /μmol·L^-1	TI
7a'a	4'-F	4'-iPr	> 50	> 200
7a'b	4'-F	3'-F	> 50	> 200
7a'c	4'-F	3'-Me	> 50	> 200
7a'd	4'-F	3', 4'-diMe	> 50	> 200
7a'e	4'-F	2'-OH	21.23	> 200	> 9.42
7a'f	4'-F	4'-Et	20.21	> 200	> 9.90
7a'g	4'-F	4'-Br	19.13	> 200	> 10.45
7a'h	4'-F	3'-CF₃	18.29	> 200	> 10.93
7a'i	4'-F	4'-CF₃	> 50	> 200
7a'j	4'-F	3'-OCH₃	> 50	> 200
7a'k	4'-F	3', 5'-diCl	7.86	> 200	> 25.45
7a'l	4'-F	4'-Me	> 50	> 200
7a'm	4'-F	4'-F	> 50	> 200
7a'n	4'-F	4'-OCH₃	> 50	> 200
7a'o	4'-F	3', 4'-diF	> 50	> 200
7a'p	4'-F	2'-Me	> 50	> 200
7a'q	4'-F	3', 5'-diF	> 50	> 200
7a'r	4'-F	2'-Ome	> 50	> 200
7b'a	3', 5'-diF	4'-iPr	> 50	158.61
7b'b	3', 5'-diF	3'-F	> 50	> 200
7b'c	3', 5'-diF	3'-Me	> 50	> 200
7b'd	3', 5'-diF	3', 4'-diMe	> 50	> 200
7b'e	3', 5'-diF	2'-OH	> 50	> 200
7b'f	3', 5'-diF	4'-Et	> 50	> 200
7b'g	3', 5'-diF	4'-Br	> 50	> 200
Ribavirin			18.07 ± 0.36	> 200	> 11.07

Compd.	R₁	R₂	EC₅₀ /μmol·L^-1	CC₅₀ /μmol·L^-1	TI
7a'a	4'-F	4'-iPr	> 50	> 200
7a'b	4'-F	3'-F	> 50	> 200
7a'c	4'-F	3'-Me	> 50	> 200
7a'd	4'-F	3', 4'-diMe	> 50	> 200
7a'e	4'-F	2'-OH	21.23	> 200	> 9.42
7a'f	4'-F	4'-Et	20.21	> 200	> 9.90
7a'g	4'-F	4'-Br	19.13	> 200	> 10.45
7a'h	4'-F	3'-CF₃	18.29	> 200	> 10.93
7a'i	4'-F	4'-CF₃	> 50	> 200
7a'j	4'-F	3'-OCH₃	> 50	> 200
7a'k	4'-F	3', 5'-diCl	7.86	> 200	> 25.45
7a'l	4'-F	4'-Me	> 50	> 200
7a'm	4'-F	4'-F	> 50	> 200
7a'n	4'-F	4'-OCH₃	> 50	> 200
7a'o	4'-F	3', 4'-diF	> 50	> 200
7a'p	4'-F	2'-Me	> 50	> 200
7a'q	4'-F	3', 5'-diF	> 50	> 200
7a'r	4'-F	2'-Ome	> 50	> 200
7b'a	3', 5'-diF	4'-iPr	> 50	158.61
7b'b	3', 5'-diF	3'-F	> 50	> 200
7b'c	3', 5'-diF	3'-Me	> 50	> 200
7b'd	3', 5'-diF	3', 4'-diMe	> 50	> 200
7b'e	3', 5'-diF	2'-OH	> 50	> 200
7b'f	3', 5'-diF	4'-Et	> 50	> 200
7b'g	3', 5'-diF	4'-Br	> 50	> 200
Ribavirin			18.07 ± 0.36	> 200	> 11.07

5-氰基-2-硫乙酰芳氨嘧啶酮类DENV NS5 RdRp抑制剂的设计、合成及活性研究

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王靖博 ¹^,^# , 李春艳 ²^,³^,⁴^,^# , 赵子衿 ¹ , 杨柳萌 ² , 张洪彬 ¹^,^* , 郑永唐 ²^,^* , 何严萍 ¹^,^*

药学学报 | 研究论文 2023,58(11): 3379-3388

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药学学报 | 研究论文 2023, 58(11): 3379-3388

5-氰基-2-硫乙酰芳氨嘧啶酮类DENV NS5 RdRp抑制剂的设计、合成及活性研究

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王靖博¹^,^#, 李春艳²^,³^,⁴^,^#, 赵子衿¹, 杨柳萌², 张洪彬¹^,^*, 郑永唐²^,^*, 何严萍¹^,^*

作者信息

1.云南大学化学科学与工程学院, 自然资源药物化学重点实验室, 云南昆明 650091

2.中国科学院昆明动物研究所, 中国科学院动物模型与人类疾病机理重点实验室, 云南昆明 650223

3.大理大学药学院, 云南大理 671000

4.中国药科大学基础与临床学院, 江苏南京 211100

通讯作者:

*张洪彬, Tel/Fax: 86-871-65031119, E-mail: zhanghb@ynu.edu.cn;

郑永唐, Tel/Fax: 86-871-5195684, E-mail: zhengyt@mail.kiz.ac.cn;

何严萍, Tel/Fax: 86-871-65031119, E-mail: yphe@ynu.edu.cn

Design, synthesis, and activity of 5-cyano-2-thiacetyl aromatic pyrimidinone as DENV NS5 RdRp inhibitors

Jing-bo WANG¹, Chun-yan LI²^,³^,⁴, Zi-jin ZHAO¹, Liu-meng YANG², Hong-bin ZHANG¹^,^*, Yong-tang ZHENG²^,^*, Yan-ping HE¹^,^*

Affiliations

1. Key Laboratory of Medicinal Chemistry for Natural Resource Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China

2. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China

3. College of Pharmacy, Dali University, Dali 671000, China

4. School of Basic Medicine and Clinic Pharmacy, China Pharmaceutical University, Nanjing 211100, China

出版时间: 2023-11-12 doi: 10.16438/j.0513-4870.2023-0197

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摘要

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为了筛选新型的抗登革热病毒(DENV) NS5 RdRp酶抑制剂, 本论文采用分子杂合的方法, 基于嘧啶酮类HCV NS5B RdRp抑制剂3jc和ZIKV NS5 RdRp抑制剂4w的结构, 设计合成了一系列5-氰基-2-硫乙酰芳基嘧啶酮化合物。通过MTT法及噬斑法体外抗DENV活性筛选发现其中5个化合物显示了抗DENV活性, 其中活性最高的化合物7a'k的抗病毒活性优于阳性对照物利巴韦林(EC₅₀ = 7.86 μmol·L^-1 vs EC₅₀ = 18.07 μmol·L^-1), 其余4个化合物与利巴韦林活性相当。最后通过分子对接分析了可能的结合模式, 为该类新型DENV NS5 RdRp酶抑制剂进一步研究提供了思路。

关键词

登革热病毒NS5 RdRp酶抑制剂 / 合成 / 抗登革热病毒活性 / 分子对接

Abstract

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To screen novel anti-dengue virus (DENV) NS5 RdRp enzyme inhibitors, a series of 5-cyano-2-thiacetoaryl pyrimidinone compounds were designed and synthesized by molecular hybridization method with HCV NS5B RdRp inhibitor 3jc and ZIKV NS5 RdRp inhibitor 4w as lead compounds. The anti-DENV activity of these compounds was evaluated by MTT assay and plaque assay and five compounds showed anti-DENV activity. The most active compound 7a'k showed better anti-DENV activity than that of the positive control ribavirin (EC₅₀ = 7.86 μmol·L^-1 vs EC₅₀ = 18.07 μmol·L^-1), and the other four compounds showed almost the same anti-DENV activity as ribavirin. Finally, the prediction and simulation of the binding mode through molecular provided new ideas for the further development of this new DENV NS5 RdRp inhibitor.

Key words

dengue virus NS5 RdRp inhibitor / synthesis / anti- dengue virus activity / molecular docking

引用本文

王靖博, 李春艳, 赵子衿, 杨柳萌, 张洪彬, 郑永唐, 何严萍. 5-氰基-2-硫乙酰芳氨嘧啶酮类DENV NS5 RdRp抑制剂的设计、合成及活性研究. 药学学报, 2023 , 58 (11) : 3379 -3388 . DOI: 10.16438/j.0513-4870.2023-0197

Jing-bo WANG, Chun-yan LI, Zi-jin ZHAO, Liu-meng YANG, Hong-bin ZHANG, Yong-tang ZHENG, Yan-ping HE. Design, synthesis, and activity of 5-cyano-2-thiacetyl aromatic pyrimidinone as DENV NS5 RdRp inhibitors[J]. Acta Pharmaceutica Sinica, 2023 , 58 (11) : 3379 -3388 . DOI: 10.16438/j.0513-4870.2023-0197

正文

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登革热是由登革热病毒(DENV) 引起的, 由雌性伊蚊携带并传播的病毒性疾病, DENV病毒与黄病毒(HCV)、寨卡病毒(ZIKV) 同属于黄病毒科, 是黄病毒属的一个血清亚群^[1-3]。据估计, 每年约有4亿人感染DENV病毒^{[4, 5]}。感染者通常会伴随出现头痛、关节痛、皮疹、白细胞减少等症状。并可能出现轻度无症状登革热(DF) 或者严重登革出血热(DHF), 更严重者甚至会出现伴有休克的登革休克综合征(DSS)^[6]。此外, DENV有4种血清型DENV (1~4), 同一个体可以多次感染DENV病毒^{[7, 8]}, 这为登革热疫苗和特效药的研发带来了巨大的困难。因此, 研究高效低毒的抗DENV药物具有重大意义。

DENV病毒有3种结构蛋白和7种非结构蛋白, 结构蛋白影响着病毒的进入、组装和在宿主细胞中的释放, 非结构蛋白参与病毒RNA复制病毒组装和宿主免疫反应 ^[9-12]。其中非结构蛋白NS5由900个氨基酸残基组成, 是最大的黄病毒蛋白, 也是病毒蛋白中最保守的^{[13, 14]}。NS5蛋白的N端(残基1~296) 为甲基转移酶(MT) 结构域, 负责给病毒RNA加帽^{[15, 16]}; C端(残基320~900) 为RNA依赖性RNA聚合酶(RdRp) 结构域, 负责病毒RNA的合成^{[17, 18]}。RdRp酶是黄病毒科中常见的一类酶, 不同黄病毒属病毒的NS5 RdRp酶有很高的同源性^[19], 其结构被比作右手: 由拇指、手指、手掌3个结构子域组成^[20-22]。由于宿主细胞中不存在RdRp类似结构的蛋白, 所以RdRp酶抑制剂将具有很好的病毒特异性, 是开发抗登革病毒药物研究的重要靶点^[23]。

本课题组长期从事多取代嘧啶酮类抗病毒新药研究^[24-28], 最近报道了一系列新型的5-烷基-2-硫乙酰芳胺嘧啶酮类抗ZIKV活性化合物^[29], 其中化合物4w靶向ZIKV NS5 RdRp, 主要和NS5 RdRp的手掌结构域结合, 其抑制活性IC₅₀为7.65 μmol·L^-1 (图 1B)。有趣的是, 将化合物4w与DENV NS5 RdRp酶(PDB: 5K5M) 进行分子对接发现, 化合物4w与NS5 RdRp有较好的结合, 其嘧啶酮环和C-6环己烷伸入了由Trp-803、Ala-799、Met-761等残基组成的疏水口袋—“N口袋”, 该疏水口袋位于NS5 RdRp酶的拇指结构域中, Zhou等^[29-31]研究发现, 抑制剂小分子与该口袋的结合的强弱对RdRp酶活性有重要影响。4w嘧啶酮环的1-NH和C-4羰基分别与拇指区“N口袋”中Ser-796、Arg-729形成了氢键, C-2侧链则与手掌区残基Asp-664形成了氢键(图 1A)。另外, Ding等^{[23, 33]}报道了通过高通量筛选及结构修饰后得到的HCV NS5 RdRp酶抑制剂3jc, 其IC₅₀为3.8 μmol·L^-1 (图 1B)。4w与3jc同为2, 5, 6-三取代的嘧啶酮类衍生物, 结构上具有一定的相似性, 且它们同样作用于黄病毒中保守的NS5 RdRp酶。DENV、ZIKV及HCV同属黄病毒, 基于它们NS5 RdRp酶的高度同源性, 推断该类型化合物也可能具有抗DENV活性。因此, 为了筛选新骨架的抗DENV抑制剂, 本文采用分子杂合的方法, 在保留嘧啶酮母环的基础上, 将4w的C-2位硫乙酰芳胺侧链及3jc的C-6位取代苯环、C-5氰基拼合以构建目标化合物的结构, 对R₁取代位, 保留了4'-F和3', 5'-2F的优势基团, 而在R₂位置引入多种不同的取代基以增加结构多样性, 从而设计合成了一系列新型的5-氰基-2-硫乙酰芳氨嘧啶酮类目标化合物7 (图 1B)。并采用噬斑法和MTT法对其抗DENV活性和细胞毒性进行了检测, 最后结合分子对接的方法对筛选到的抗DENV活性化合物的结合模式进行分析, 为新型骨架DENV NS5 RdRp抑制剂的研究提供了基础。

结果与讨论

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1 化学实验

目标化合物的合成如合成路线1所示: 首先苯胺1和溴乙酰溴2通过亲核取代反应得到2-溴乙酰苯胺3。另外, 取代苯甲醛4、氰基乙酸乙酯5和硫脲经比吉内利一锅法合成5-氰基-6芳基-嘧啶酮6。最后, 3和6在K₂CO₃催化下经S-烷基化反应得到5-氰基-2-硫乙酰芳氨嘧啶酮类化合物7。

通过上述方法共合成了25个目标新化合物, 并通过¹H NMR、¹³C NMR谱和HR-ESI-MS进行了结构表征, 其理化性质和谱学数据见表 1和表 2。

2 抗DENV活性评价

以临床使用的广谱抗病毒药物利巴韦林(ribavirin) 为阳性对照, 采用噬斑法和MTT法评估了化合物7(a'a~a'r, b'a~b'g) 的体外抗DENV病毒活性和细胞毒性(表 3)。由表 3中可见, 目标化合物均具有较小的细胞毒性, 除了化合物7b'a的CC₅₀为158.6 μmol·L^-1外, 其余化合物的CC₅₀值均大于200 μmol·L^-1。25个目标化合物中有5个化合物7a'k、7a'e、7a'f、7a'g、7a'h表现出了抗DENV活性, 其中化合物7a'k活性最高, 其EC₅₀ = 7.86 μmol·L^-1, 治疗指数TI > 25.45, 较阳性对照物利巴韦林(TI > 11.07) 提高了2倍。其余4个化合物活性与阳性对照物利巴韦林活性(EC₅₀= 18.07 ± 0.36 μmol·L^-1) 相当。

另外, 由表 3可见5个抗DENV-2活性化合物的R₁取代基均为4'-F, 而R₁为3', 5'-diF取代基的7b′系列化合物均未显示出抗DENV活性。对于R₁为4'-F的7a'系列化合物, 在C-6苯环上引入了18种不同取代基(R₂), 而其中只有5种显示了抗DENV病毒活性, 可见R₁和R₂取代基均对活性有影响, 且它们之间可能存在某种协同关系。对此采用分子对接的方法对该类化合物与NS5 RdRp可能的作用方式进行了探讨(PDB: 5K5M)。首先, 选择R₂取代基相同, R₁取代基不同的7a'e和7b'e、7a'f和7b'f、7a'g和7b'g3组化合物的复合物模型进行了比较。如图 2A-1、B-1、C-1所示, 3个有抗DENV活性化合物7a'e、7a'f和7a'g与NS5 RdRp酶的结合模式和先导化合物4w相似, 它们的嘧啶环和C-6取代苯环均指向“N口袋”, 并通过嘧啶环的C-5-CN与“N口袋”内Tyr-765上羟基间形成氢键作用从而稳定与“N口袋”的结合。同时, 7a'e和7a'f的C-2侧链上的NH和嘧啶环上的3-NH与活性位点残基Thr-793形成双重氢键作用, 进一步加强了其与NS5 RdRp的结合。而7a'g则通过C-2β羰基与Tyr-758间的氢键作用加强这种结合。而由图 2A-2、B-2、C-2所示的7b'e、7b'f、7b'g复合物模型可见, C-2侧链末端3', 5'-diF取代苯基使这3个化合物的C-2侧链形成特定的空间走向, 且和Asn-406、Ser-791、Leu-754等氨基酸残基形成多种氢键作用, 从而拉扯化合物分子不能进入到“N口袋”中, 这种远离“N口袋”的无效结合不能对NS5 RdRp活性产生影响。

图 2D、E显示了化合物7a'h和7a'k与DENV NS5 RdRp的相互作用, 由图 2D可见, 7a'h的嘧啶环和C-6苯环同样指向“N口袋”, 但因R₂取代基的差异, 7a'h采取与化合物7a'e、7a'f、7a'g不同的结合构象, 该构象使7a'h以C-4羰基与Arg-727间的氢键作用替代7a'e、7a'f、7a'g中C-5-CN与Tyr-765间的氢键作用, 并使C-6苯环上的4'-CF₃更深入“N口袋”内部, 保证抑制剂小分子与NS5 RdRp稳定结合, 因而7a'h具有略高于与7a'e、7a'f、7a'g活性。在R₁取代基相同的情况下(R₁=4'-F), C-6苯环上3', 5'-diCl取代基的引入(R₂=3', 5'-diCl)使化合物7a'k与NS5 RdRp的结合模式发生了变化。如图 2E所示, 进入到“N口袋”内部的是7a'k的C-2侧链, 其嘧啶酮上的C-4位羰基和C-2β位羰基与“N口袋”内的Arg-729形成较强的双重氢键(d = 1.9Å及2.0Å), 这种加强的有效结合使7a'k具有最高的抗DENV活性。以上分子对接分析表明, 与NS5 RdRp“N口袋”内活性位点残基的有效结合是该类化合物具有抗DENV活性的关键, 而R₁和R₂取代基间通过某种协同作用对该类化合物与NS5 RdRp的结合方式产生影响。虽然目前R₁和R₂取代基的构效关系尚未表现出明显的规律性, 但在上述结合模型的指导下, 可尝试在5-氰基-2-硫乙酰芳氨嘧啶酮基本骨架上, 进一步丰富R₁和R₂取代基, 构建结构多样性分子, 通过分子模拟寻找能与NS5 RdRp“N口袋”加强结合的分子并加以合成, 以发现更优活性的抗DENV化合物。

小结

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为了筛选新型的抗DENV NS5 RdRp酶抑制剂, 本文基于嘧啶酮类HCV NS5B RdRp抑制剂3jc和ZIKV NS5 RdRp抑制剂4w的结构, 采用分子杂合的方法, 设计合成系列5-氰基-2-硫乙酰芳基嘧啶酮化合物, 并通过噬斑法从中筛选到5个抗DENV活性化合物, 最后通过对该类化合物与DENV NS5 RdRp分子对接发现该类化合物具有抗DENV活性的关键在于与NS5 RdRp“N口袋”结合, 同时指出R₁和R₂取代基间对化合物的结合方式产生协同影响, 从而为该类化合物的进一步结构优化设计提供理论指导。

实验部分

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市售分析纯(AR) 或试剂级(RG) 或是根据反应所需自行制备得到。常压柱色谱所用硅胶(100/200~300目) 购自青岛海洋化工。薄层色谱(TLC) 板购自乳山市太阳干燥剂有限公司。Bruker DRX 400 (¹H: 400 MHz, ¹³C: 100 MHz) 购自德国Bruker公司, 内标TMS, 溶剂DMSO-d₆购自中国扬格赛公司; Manon MP430全自动熔点仪, 邢台润联公司; Agilent LC/MSD TOF质谱仪, 购自美国Agilent公司。

利巴韦林(ribavirin) 购自广州昂飞生物科技有限公司; N, N-二甲基甲酰胺(N, N-dimethyl formamine, DMF) 购自西陇化工股份有限公司; MTT、硫酸链霉素(streptomycin sulfate)、青霉素(penicillin)、DMSO购自美国Sigma公司; 多聚甲醛购自天津光复精细化工研究所; 结晶紫购自北京索莱宝; DMEM高糖培养基、胎牛血清购自美国Thermo Fisher公司; 小牛血清、胰酶购自美国Gibco公司; 低熔点琼脂糖购自美国Amresco公司。

倒置显微镜(TS-100F) 购自日本Nikon公司; 离心机(Allegra X-30) 购自美国Beckman公司; 酶联斑点分析仪(Immunospot S6 Universal) 购自美国CTL公司; 酶标仪(ELX800) 购自美国Bioteck公司; 生物安全柜(1287)、细胞培养箱(311) 购自美国Thermo Fisher公司。4 ℃冰箱(HYC-360) 购自Haier公司。

所有化合物均用DMSO溶解, 终浓度为50 mmol·L^-1, 避光至于4 ℃冰箱保存, 使用时DMEM培养基稀释至所需浓度。

1 化合物的合成

1.1 2-溴乙酰苯胺(3) 的合成

将取代苯胺1 (10 mmol, 1 eq.)、三乙胺(15 mmol, 1.5 eq.) 和溴乙酰溴2 (15 mmol, 1.5 eq.) 溶于150 mL二氯甲烷中, 在0 ℃反应2 h后, 用二氯甲烷(100 mL×3) 萃取, 合并有机相, 有机相用饱和氯化钠溶液洗涤, 无水硫酸钠干燥, 蒸发得到粗品, 粗品重结晶, 过滤得到2-溴乙酰苯胺3纯品, 产率为88%~92%。

1.2 5-氰基-6-芳基-2-巯基嘧啶酮类化合物(6) 的合成

依次将氰基乙酸乙酯5 (10 mmol, 1 eq.)、取代苯甲醛4 (10 mmol, 1 eq.)、硫脲(10 mmol, 1 eq.) 和无水碳酸钾(10 mmol, 1 eq.) 加入乙醇溶液中, 回流反应10~14 h。TLC跟踪反应结束后, 将溶液冷却至室温, 过滤, 固体用无水乙醇洗涤, 溶于200 mL 80 ℃水中, 冷却至室温, 用乙酸调节溶液pH至5~6, 析出白色或黄色固体, 将固体过滤, 干燥, 重结晶或柱色谱分离得到5-氰基-6-芳基-2-巯基嘧啶酮6, 产率为38%~75%。

1.3 目标化合物7的合成

将5-氰基-6-芳基-2-巯基嘧啶酮6 (1 mmol, 1 eq.) 溶解于15 mL DMF溶液中, 加入无水碳酸钾(1.2 mmol, 1.2 eq.) 搅拌0.5 h后, 加入2-溴乙酰苯胺3 (1 mmol, 1eq.), 室温下反应0.5 h。用TLC跟踪反应完成后用乙酸乙酯(80 mL×3) 萃取, 合并有机相, 饱和氯化钠溶液洗涤, 无水硫酸钠干燥。将有机相减压浓缩得到粗产品, 通过柱色谱或重结晶得到目标化合物。产率为21%~92%。

2 目标化合物抗DENV活性测试

通过上述合成方法合成了共25个目标化合物, 本实验采用噬斑法和MTT法分别测试目标分子的抑制DENV活性(EC₅₀) 和对细胞毒性(CC₅₀)。其中抗DENV活性以抗病毒药物利巴韦林为阳性对照。

2.1 噬斑法测试抗DENV活性

将Vero细胞铺种于12孔细胞培养板中(每孔3×10⁵个), 培养过夜后向其加入DENV (MOI = 0.5), 吸附2~4 h, 1×PBS洗涤后, 加入含梯度稀释待测化合物的2%低熔点琼脂糖-DEME (2% FBS) 培养基, 在37 ℃、5% CO₂培养箱中条件下培养5天。用4%多聚甲醛固定10 min, 清洗3次, 加入0.8%结晶紫对其进行染色。利用酶联斑点分析仪对细胞板中的噬斑数进行图像分析并计算半数有效浓度EC₅₀。

2.2 MTT法检测细胞分子毒性

将Vero细胞铺种于96孔细胞培养板中(每孔4×10⁴个), 在37 ℃、5% CO₂培养箱条件下培养至细胞成长呈单层状, 弃去上清。随后, 加入含有梯度稀释待测化合物(终浓度为200 μmol·L^-1), 每个梯度浓度设置3复孔, 同时设置正常对照组、空白对照组。培养5天后, 每孔加入20 μL MTT (5 mg·mL^-1), 37 ℃、5% CO₂培养箱中孵育4 h后弃去100 μL上清液, 每孔加入100 μL SDS-DMF (12% SDS-50% DMF) 溶液。将细胞培养板置于37 ℃、5% CO₂培养箱中孵育过夜, 待其结晶完全溶解后, 震荡均匀, 利用Bio-TEK酶标仪检测OD值(检测波长: 570 nm、参考波长: 630 nm), 并计算半数细胞毒性浓度CC₅₀。

2.3 治疗指数(TI) 值的计算

依据MTT检测法实验结果绘制剂量-反应曲线, 利用Reed & Muench法计算有效抑制50%细胞感染病毒的药物浓度(EC₅₀) 和使50%的细胞发生病变时的药物浓度(CC₅₀)。利用TI = CC₅₀/EC₅₀获得药物的TI值。

3 分子对接

使用Autodock 4.2程序进行分子对接, 所有用于对接的分子采用Sybyl/Minimize分子力学程序进行能量优化, 迭代6 000次, 直到能量梯度收敛至0.005 kcal·mol^-1。所选DENV-2 NS5 RdRp的3D晶体结构检索自RCSBB蛋白数据库(PDB: 5K5M)。使用AutoDock Tools (ADT) 处理小分子和蛋白质, 从配合物中提取结合配体, 除去水分子, 自动添加氢原子, 使用Lamarckian GA对接算法对目标分子执行50次对接计算, 最后根据抑制剂与酶相互作用能量大小和几何构型匹配程度来确定抑制剂的结合构象, 并用Pymol软件显示对接结果。

作者贡献: 王靖博负责化合物的合成和分子对接及文章撰写; 李春艳负责体外抗DENV活性测试; 赵子衿负责数据的整理及文章部分撰写; 杨柳萌协助活性测试和文章的修改; 何严萍、郑永唐、张洪彬负责课题规划、实验指导及文章修改及校对。

利益冲突: 无利益冲突。

基金

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国家自然科学基金(21967020)
国家自然科学基金(82273820)
国家自然科学基金(U1702286)
云南省重点研发计划(202103AC100005)
云南省重点研发计划(202103AQ100001)
国家重点研发计划(2019YFE0109200)

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Yokokawa F, Nilar S, Noble CG, et al. Discovery of potent non-nucleoside inhibitors of dengue viral RNA-dependent RNA polymerase from a fragment hit using structure-based drug design[J]. J Med Chem, 2016, 59: 3935-3952.

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Tang ZL, Li XX, Yao Y, et al. Design, synthesis, fungicidal activity and molecular docking studies of novel 2-((2-hydroxyphenyl)methylamino)acetamide derivatives[J]. Bioorg Med Chem, 2019, 27: 2572-2578.

https://doi.org/10.1016/j.bmc.2019.03.040

2023年第58卷第11期

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doi: 10.16438/j.0513-4870.2023-0197

接收时间：2023-02-20
首发时间：2025-11-21
出版时间：2023-11-12

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收稿日期：2023-02-20
修回日期：2023-03-17

基金

国家自然科学基金(21967020)

国家自然科学基金(82273820)

国家自然科学基金(U1702286)

云南省重点研发计划(202103AC100005)

云南省重点研发计划(202103AQ100001)

国家重点研发计划(2019YFE0109200)

作者信息

1.云南大学化学科学与工程学院, 自然资源药物化学重点实验室, 云南昆明 650091

2.中国科学院昆明动物研究所, 中国科学院动物模型与人类疾病机理重点实验室, 云南昆明 650223

3.大理大学药学院, 云南大理 671000

4.中国药科大学基础与临床学院, 江苏南京 211100

通讯作者:

*张洪彬, Tel/Fax: 86-871-65031119, E-mail: zhanghb@ynu.edu.cn;

郑永唐, Tel/Fax: 86-871-5195684, E-mail: zhengyt@mail.kiz.ac.cn;

何严萍, Tel/Fax: 86-871-65031119, E-mail: yphe@ynu.edu.cn

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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/℃		Compd.	Yield/%	mp/℃
7a'a	96.3	170.0-172.1		7a'n	54.1	194.0-195.1
7a'b	49.7	191.7-193.2	7a'o	24.0	166.7-167.8
7a'c	29.8	196.0-197.1	7a'p	29.6	188.6-189.8
7a'd	94.5	210.4-211.7	7a'q	33.8	175.1-176.2
7a'e	76.7	202.1-202.8	7a'r	53.1	196.1-197.2
7a'f	87.5	202.9-203.1	7b'a	89.3	215.3-216.4
7a'g	66.8	198.1-199.7	7b'b	48.0	182.1-183.6
7a'h	72.8	108.4-109.5	7b'c	37.3	185.4-186.6
7a'i	89.8	195.1-196.2	7b'd	84.9	194.2-195.6
7a'j	20.7	193.4-194.5	7b'e	85.5	228.5-229.6
7a'k	58.1	168.5-169.2	7b'f	60.2	233.1-234.5
7a'l	92.4	212.5-213.0	7b'g	63.3	198.6-198.9
7a'm	50.1	196.5-197.8

Compd.

Yield/%

mp/℃

Compd.

Yield/%

mp/℃

7a'a

96.3

170.0-172.1

7a'n

54.1

194.0-195.1

7a'b

49.7

191.7-193.2

7a'o

24.0

166.7-167.8

7a'c

29.8

196.0-197.1

7a'p

29.6

188.6-189.8

7a'd

94.5

210.4-211.7

7a'q

33.8

175.1-176.2

7a'e

76.7

202.1-202.8

7a'r

53.1

196.1-197.2

7a'f

87.5

202.9-203.1

7b'a

89.3

215.3-216.4

7a'g

66.8

198.1-199.7

7b'b

48.0

182.1-183.6

7a'h

72.8

108.4-109.5

7b'c

37.3

185.4-186.6

7a'i

89.8

195.1-196.2

7b'd

84.9

194.2-195.6

7a'j

20.7

193.4-194.5

7b'e

85.5

228.5-229.6

7a'k

58.1

168.5-169.2

7b'f

60.2

233.1-234.5

7a'l

92.4

212.5-213.0

7b'g

63.3

198.6-198.9

7a'm

50.1

196.5-197.8

Compd.	¹H NMR, ¹³C NMR, HR-ESI-MS
7a'a	¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H, Ph-NH-CO), 7.71 (dd, J = 8.2, 1.8 Hz, 2H, ArH), 7.56 (ddt, J = 6.8, 5.0, 1.8 Hz, 2H, ArH), 7.27-7.21 (m, 2H, ArH), 7.13 (td, J = 8.9, 1.9 Hz, 2H, ArH), 3.87 (s, 2H, S-CH₂), 2.98-2.85 (m, 1H, CH(CH₃)₂), 1.21 (d, J = 1.7 Hz, 3H, CH₃), 1.19 (d, J = 1.8 Hz, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.4, 167.1, 167.1, 159.1, 158.0 (¹J_CF = 238 Hz), 150.9, 135.6 (⁴J_CF = 2 Hz), 134.6, 128.4 (2C), 126.1 (2C), 120.5 (2C, ³J_CF = 8 Hz), 119.2, 115.4 (2C, ²J_CF = 22 Hz), 90.2, 35.2, 33.4, 23.7 (2C); HR-ESI-MS: m/z calcd. for C₂₂H₁₉FN₄O₂S [M+H]⁺ 423.124 6, found 423.124 8
7a'b	¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H, Ph-NH-CO), 7.63 (d, J = 7.8 Hz, 1H, ArH), 7.57 (td, J = 7.4, 5.8, 2.7 Hz, 3H, ArH), 7.45 (q, J = 7.1, 6.5 Hz, 1H, ArH), 7.33 (t, J = 8.7 Hz, 1H, ArH), 7.13 (td, J = 9.0, 2.0 Hz, 2H, ArH), 3.91 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6, 166.9, 165.8, 165.7, 161.8 (¹J_CF = 242 Hz), 158.0 (¹J_CF = 237 Hz), 139.2 (³J_CF = 8 Hz), 135.51 (⁴J_CF = 3 Hz), 130.3 (³J_CF = 8 Hz), 124.5 (⁴J_CF = 3 Hz), 120.6 (2C, ³J_CF = 8 Hz), 118.6, 117.2 (²J_CF = 21 Hz), 115.4 (2C, ²J_CF = 22 Hz), 115.0 (²J_CF = 23 Hz), 91.4, 35.3; HR-ESI-MS: m/z calcd. for C₁₉H₁₂F₂N₄O₂S [M+H]⁺ 399.068 3, found 399.068 6
7a'c	¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s, 1H, Ph-NH-CO), 7.58 (dd, J = 8.3, 5.0 Hz, 2H, ArH), 7.54 (d, J = 5.0 Hz, 2H, ArH), 7.29 (td, J = 9.6, 9.0, 6.8 Hz, 2H, ArH), 7.18-7.08 (m, 2H, ArH), 3.81 (s, 2H, S-CH₂), 2.30 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 170.0, 167.6, 167.5, 157.9 (¹J_CF = 238 Hz), 137.4, 137.3, 135.6 (⁴J_CF = 3 Hz), 130.4, 128.6, 128.0, 125.4, 120.5 (2C, ³J_CF = 8 Hz), 119.7, 115.4 (2C, ²J_CF = 22 Hz), 89.5, 35.1, 20.9; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₂S [M+H]⁺ 395.093 3, found 395.093 5
7a'd	¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H, Ph-NH-CO), 7.65-7.44 (m, 4H, ArH), 7.22-7.02 (m, 3H, ArH), 3.85 (s, 2H, S-CH₂), 2.25 (s, 3H, CH₃), 2.19 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6, 168.9, 167.3, 167.3, 157.9 (¹J_CF = 239 Hz), 138.7, 136.1, 135.6 (¹J_CF = 3 Hz), 134.7, 129.2 (2C), 125.8, 120.5 (2C, ³J_CF = 7 Hz), 119.3, 115.3 (2C, ²J_CF = 22 Hz), 89.7, 35.2, 19.3 (2C); HR-ESI-MS: m/z calcd. for C₂₁H₁₇FN₄O₂S [M+H]⁺ 409.109 0, found 409.109 2
7a'e	¹H NMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H, Ph-NH-CO), 10.87-10.72 (m, 1H, OH), 10.54 (s, 1H, Ar-NH), 8.35 (dd, J = 7.9, 1.7 Hz, 1H, ArH), 7.75 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H, ArH), 7.67-7.60 (m, 2H, ArH), 7.52 (d, J = 8.3 Hz, 1H, ArH), 7.44 (t, J = 7.6 Hz, 1H, ArH), 7.14 (t, J = 8.9 Hz, 2H, ArH), 4.04 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 177.2, 169.0, 166.7, 165.8, 157.9 (¹J_CF = 238 Hz), 157.4, 151.5, 135.5 (⁴J_CF = 3 Hz), 133.9, 125.9, 125.0, 120.7 (2C, ³J_CF = 8 Hz), 118.7, 116.9, 115.3 (2C, ²J_CF = 22 Hz), 94.7, 35.6; HR-ESI-MS: m/z calcd. for C₁₉H₁₃FN₄O₃S [M+H]⁺ 397.072 6, found 397.073 0
7a'f	¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H, Ph-NH-CO), 7.73 (d, J = 7.8 Hz, 2H, ArH), 7.64-7.50 (m, 2H, ArH), 7.29-7.03 (m, 4H, ArH), 3.94 (s, 2H, S-CH₂), 2.63 (q, J = 7.6 Hz, 2H, CH₂-CH₃), 1.17 (t, J = 7.6 Hz, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.5, 167.1, 166.7, 161.9, 158.0 (¹J_CF = 239 Hz), 146.7, 135.5 (⁴J_CF = 2 Hz), 134.0, 128.5 (2C), 127.6 (2C), 120.6 (2C, ³J_CF = 8 Hz), 118.4, 115.4 (2C, ²J_CF = 22 Hz), 90.3, 35.3, 28.1, 15.4; HR-ESI-MS: m/z calcd. for C₂₁H₁₇FN₄O₂S [M+H]⁺ 409.109 0, found 409.109 4
7a'g	¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H, Ph-NH-CO), 10.77 (s, 1H, Ar-NH), 7.72 (dd, J = 8.5, 2.1 Hz, 2H, ArH), 7.58 (ddd, J = 9.1, 4.8, 2.1 Hz, 4H, ArH), 7.13 (td, J = 8.9, 2.1 Hz, 2H, ArH), 3.89 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6, 168.1, 167.0, 166.1, 157.9 (¹J_CF = 238 Hz), 136.1, 135.5 (⁴J_CF = 3 Hz), 131.2 (2C), 130.4 (2C), 123.8, 120.5 (2C, ³J_CF = 8 Hz), 118.8, 115.3 (2C, ²J_CF = 22 Hz), 90.1, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₂BrFN₄O₂S [M+H]⁺ 459.982 8, found 459.982 9
7a'h	¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H, Ph-NH-CO), 8.06 (d, J = 5.1 Hz, 2H, ArH), 7.85 (d, J = 7.8 Hz, 1H, ArH), 7.66 (t, J = 8.0 Hz, 1H, ArH), 7.59 (ddt, J = 6.9, 4.9, 1.8 Hz, 2H, ArH), 7.13 (td, J = 8.9, 2.0 Hz, 2H, ArH), 3.86 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 169.2, 167.3, 165.7, 157.9 (¹J_CF = 238 Hz), 138.2, 135.6 (⁴J_CF =3 Hz), 132.3, 129.5, 129.0 (²J_CF = 32 Hz), 126.6, 124.6 (³J_CF = 4 Hz), 124.0 (¹J_CF = 271 Hz), 120.6 (2C, ³J_CF = 8 Hz), 119.2, 115.4 (2C, ²J_CF= 22 Hz), 90.0, 35.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₂F₄N₄O₂S [M+H]⁺ 449.065 1, found 449.064 7
7a'i	¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H, Ph-NH-CO), 7.94 (d, J = 7.9 Hz, 2H, ArH), 7.75 (d, J = 8.1 Hz, 2H, ArH), 7.58 (ddt, J = 6.9, 4.9, 1.9 Hz, 2H, ArH), 7.13 (tt, J = 9.0, 4.6 Hz, 2H, ArH), 3.88 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.2, 168.6, 167.2, 165.9, 157.9 (¹J_CF = 239 Hz), 141.1, 135.6 (⁴J_CF = 2 Hz), 130.1 (²J_CF = 31 Hz), 129.1 (2C), 125.1 (2C, ³J_CF = 3 Hz), 124.0 (¹J_CF = 271 Hz), 120.5 (2C, ³J_CF = 7 Hz), 118.9, 115.3 (2C, ²J_CF = 22 Hz), 90.4, 35.3; HR-ESI-MS: m/z calcd. for C₂₀H₁₂F₄N₄O₂S [M+H]⁺ 449.056 1, found 499.055 8
7a'j	¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H, Ph-NH-CO), 7.63-7.50 (m, 2H, ArH), 7.33 (dtd, J = 6.1, 3.7, 3.2, 1.2 Hz, 3H, ArH), 7.20-7.09 (m, 2H, ArH), 7.08-6.98 (m, 1H, ArH), 3.84 (s, 2H, S-CH₂), 3.76 (s, 3H, -OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.4, 169.8, 167.4, 167.1, 158.9, 157.9 (¹J_CF = 239 Hz), 138.6, 135.6 (⁴J_CF= 3 Hz), 129.3, 120.5, 120.5 (2C, ³J_CF = 8 Hz), 119.5, 115.6, 115.3 (2C, ²J_CF = 22 Hz), 113.6, 89.6, 55.2, 35.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₃S [M+H]⁺ 411.088 2, found 411.088 5
7a'k	¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H, Ph-NH-CO), 7.74 (d, J = 2.4 Hz, 3H, ArH), 7.64–7.55 (m, 2H, ArH), 7.13 (td, J = 8.9, 1.9 Hz, 2H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.8, 169.4, 167.3, 164.3, 157.9 (¹J_CF =238 Hz), 140.6, 135.6 (⁴J_CF = 3 Hz), 134.0 (2C, Ph), 129.3, 126.8 (2C, Ph), 120.6 (2C, ³J_CF = 7 Hz), 119.1, 115.3 (2C, ²J_CF = 22 Hz), 89.8, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₁Cl₂FN₄O₂S [M+H]⁺ 449.993 4, found 449.993 5
7a'l	¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H, Ph-NH-CO), 7.70 (dd, J = 8.2, 1.8 Hz, 2H, ArH), 7.58 (ddt, J = 6.8, 4.9, 1.7 Hz, 2H, ArH), 7.24-7.09 (m, 4H, ArH), 3.91 (s, 2H, S-CH₂), 2.34 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.8, 167.1, 166.9, 163.8, 157.9 (¹J_CF = 238 Hz), 140.3, 135.6 (⁴J_CF = 2 Hz), 133.9, 128.8 (2C), 128.4 (2C), 120.6 (2C, ³J_CF = 7 Hz), 118.8, 115.4 (2C, ²J_CF = 22 Hz), 90.1, 35.2, 21.0; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₂S [M+H]⁺ 395.093 3, found 395.093 6
7a'm	¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H, Ph-NH-CO), 7.83 (ddd, J = 8.3, 5.5, 2.1 Hz, 2H, ArH), 7.59 (ddt, J = 7.4, 5.0, 2.1 Hz, 2H, ArH), 7.24 (td, J = 8.9, 2.2 Hz, 2H, ArH), 7.14 (td, J = 9.1, 2.2 Hz, 2H, ArH), 3.83 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.4, 169.7, 167.5, 166.1, 163.0 (¹J_CF = 246 Hz), 157.9 (¹J_CF = 238 Hz), 135.6 (⁴J_CF = 3 Hz), 133.8 (⁴J_CF = 3 Hz), 130.6 (2C, ³J_CF = 8 Hz), 120.5 (2C, ³J_CF = 8 Hz), 119.6, 115.4 (2C, ²J_CF = 22 Hz), 115.1 (2C, ²J_CF = 21 Hz), 89.4, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₂F₂N₄O₂S [M+H]⁺ 399.068 3, found 399.068 7
7a'n	¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H, Ph-NH-CO), 7.79 (d, J = 8.4 Hz, 2H, ArH), 7.59 (dd, J = 8.4, 4.9 Hz, 2H, ArH), 7.14 (t, J = 8.5 Hz, 2H, ArH), 6.94 (d, J = 8.4 Hz, 2H, ArH), 3.85 (s, 2H, S-CH₂), 3.79 (s, 3H, -OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.5, 169.0, 167.3, 166.5, 160.9, 157.9 (¹J_CF = 238 Hz), 135.6 (⁴J_CF = 3 Hz), 130.0 (2C), 129.3, 120.5 (2C, ³J_CF = 8 Hz), 119.6, 115.4 (2C, ²J_CF = 22 Hz), 113.50 (2C), 89.0, 55.3, 35.2; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₃S [M+H]⁺ 411.088 2, found 411.088 4
7a'o	¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 1H, Ph-NH-CO), 7.78 (ddd, J = 11.8, 7.9, 2.2 Hz, 1H, ArH), 7.70–7.63 (m, 1H, ArH), 7.63-7.55 (m, 2H, ArH), 7.49 (dt, J = 10.7, 8.5 Hz, 1H, ArH), 7.18–7.08 (m, 2H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 169.4, 167.3, 164.7, 157.9 (¹J_CF = 238 Hz), 150.3 (¹J_CF = 242 Hz, ²J_CF = 12 Hz), 149.1 (¹J_CF = 246 Hz, ²J_CF = 12 Hz), 135.5 (⁴J_CF = 2 Hz), 130.8 (³J_CF = 6 Hz), 125.4 (⁴J_CF = 3 Hz), 120.5 (2C, ³J_CF = 8 Hz), 119.3, 117.4 (²J_CF = 18 Hz), 117.31 (²J_CF = 17 Hz), 115.3 (2C, ²J_CF = 22 Hz), 89.6, 35.1; HR-ESI-MS: m/z calcd. for C₁₉H₁₁F₃N₄O₂S [M+H]⁺ 417.058 8, found 417.058 6
7a'p	¹H NMR (400 MHz, DMSO-d₆) δ 10.93 (s, 1H, Ph-NH-CO), 7.62-7.52 (m, 2H, ArH), 7.36-7.24 (m, 2H, ArH), 7.22 (dd, J = 3.8, 0.9 Hz, 2H, ArH), 7.18-7.09 (m, 2H, ArH), 3.81 (s, 2H, S-CH₂), 2.21 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.3, 169.8, 169.4, 167.4, 157.9 (¹J_CF = 238 Hz), 137.8, 135.5 (⁴J_CF = 3 Hz), 134.9, 130.1, 128.7, 128.3, 125.5, 120.5 (2C, ³J_CF = 8 Hz), 118.9, 115.3 (2C, ²J_CF = 22 Hz), 91.9, 35.1, 19.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₂S [M+H]⁺ 395.093 3, found 395.093 6
7a'q	¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H, Ph-NH-CO), 7.64-7.54 (m, 2H, ArH), 7.49-7.32 (m, 3H, ArH), 7.13 (t, J = 8.9 Hz, 2H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.8, 169.5, 167.4, 164.5, 162.0 (2C, ¹J_CF = 245 Hz, ³J_CF = 13 Hz), 157.9 (¹J_CF = 238 Hz), 140.8 (³J_CF = 9 Hz), 135.6 (⁴J_CF = 2 Hz), 120.5 (2C, ³J_CF = 8 Hz), 119.2, 115.3 (2C, ²J_CF = 22 Hz), 111.5 (2C, ²J_CF = 26 Hz), 105.29 (²J_CF = 25 Hz), 89.7, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₁F₃N₄O₂S [M+H]⁺ 417.058 8, found 417.059 1
7a'r	¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H, Ph-NH-CO), 7.57 (ddt, J = 6.9, 5.0, 2.8 Hz, 2H, ArH), 7.44-7.35 (m, 1H, ArH), 7.25-7.06 (m, 4H, ArH), 6.93 (t, J = 7.4 Hz, 1H, ArH), 3.78 (s, 2H, S-CH₂), 3.76 (s, J = 1.7 Hz, 3H, -OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.2, 169.2, 167.6, 166.9, 157.9 (¹J_CF = 238 Hz), 156.2, 135.6 (⁴J_CF = 2 Hz), 130.6, 129.6, 127.1, 120.5 (2C, ³J_CF = 7 Hz), 120.1, 118.9, 115.3 (2C, ²J_CF = 22 Hz), 111.6, 93.1, 55.4, 35.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₃S [M+H]⁺ 411.088 2, found 411.088 6
7b'a	¹H NMR (400 MHz, DMSO-d₆) δ 11.38 (s, 1H, Ph-NH-CO), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.31-7.19 (m, 4H, ArH), 6.89 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.83 (s, 2H, S-CH₂), 2.91 (p, J = 6.9 Hz, 1H, -CH(CH₃)₂), 1.21 (d, J = 6.9 Hz, 6H, -CH(CH₃)₂; ¹³C NMR (100 MHz, DMSO-d₆) δ 171.1, 169.7, 168.4, 167.1, 162.6 (¹J_CF = 241 Hz), 162.4 (¹J_CF = 241 Hz), 150.6, 141.6 (³J_CF = 14 Hz), 134.9, 128.3 (2C), 126.05 (2C), 119.6, 101.7 (2C, ²J_CF = 29 Hz), 98.2 (²J_CF = 26 Hz), 89.4, 35.3, 33.3, 23.7 (2C); HR-ESI-MS: m/z calcd. for C₂₂H₁₈F₂N₄O₂S [M+H]⁺ 441.115 2, found 441.115 0
7b'b	¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (s, 1H, Ph-NH-CO), 7.64-7.57 (m, 1H, ArH), 7.54-7.42 (m, 2H, ArH), 7.29 (pd, J = 8.0, 7.4, 2.6 Hz, 3H, ArH), 6.88 (tt, J = 9.3, 2.4 Hz, 1H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 169.7, 168.3, 165.8, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 242 Hz), 161.8 (¹J_CF = 243 Hz), 141.5 (³J_CF = 14 Hz), 139.7 (³J_CF = 7 Hz), 130.2 (³J_CF = 8 Hz), 124.4 (⁴J_CF=2 Hz), 119.4, 116.8 (²J_CF = 20 Hz), 114.9 (²J_CF = 23 Hz), 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.8, 35.3; HR-ESI-MS: m/z calcd. for C₁₉H₁₁F₃N₄O₂S [M+H]⁺ 417.058 8, found 417.059 2
7b'c	¹H NMR (400 MHz, DMSO-d₆) δ 11.43 (s, 1H, Ph-NH-CO), 7.53 (dd, J = 6.4, 1.7 Hz, 2H, ArH), 7.34–7.22 (m, 4H, ArH), 6.88 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.83 (s, 2H, S-CH₂), 2.30 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.3, 170.0, 168.5, 167.5, 162.6 (¹J_CF = 242 Hz), 162.5 (¹J_CF = 242 Hz), 141.6 (³J_CF = 14 Hz), 137.4, 137.4, 130.5, 128.6, 128.0, 125.4, 119.6, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.7, 35.3, 20.9; HR-ESI-MS: m/z calcd. for C₂₀H₁₄F₂N₄O₂S [M+H]⁺ 413.083 9, found 413.083 7
7b'd	¹H NMR (400 MHz, DMSO-d₆) δ 11.45 (s, 1H, Ph-NH-CO), 7.56-7.45 (m, 2H, ArH), 7.29-7.13 (m, 3H, ArH), 6.88 (tt, J = 9.3, 2.4 Hz, 1H, ArH), 3.83 (s, 2H, S-CH₂), 2.25 (s, 3H, CH₃), 2.20 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.0, 169.7, 168.4, 167.4, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 242 Hz), 141.6 (³J_CF = 14 Hz), 138.5, 136.0, 134.9, 129.2, 129.1, 125.7, 119.6, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.5, 35.3, 19.3 (2C); HR-ESI-MS: m/z calcd. for C₂₁H₁₆F₂N₄O₂S [M+H]⁺ 427.099 6, found 427.099 3
7b'e	¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H, Ph-NH-CO), 10.94 (s, 1H, -OH), 8.32 (dd, J = 7.9, 1.6 Hz, 1H, ArH), 7.75 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H, ArH), 7.52 (d, J = 8.4 Hz, 1H, ArH), 7.42 (t, J = 7.6 Hz, 1H, ArH), 7.38-7.27 (m, 2H, ArH), 6.90 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 4.05 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 176.9, 169.0, 167.6, 165.8, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 242 Hz), 157.4, 151.6, 141.6 (³J_CF = 13 Hz), 133.9, 125.8, 125.0, 118.7, 116.9, 101.9 (2C, ²J_CF = 29 Hz), 98.4 (²J_CF = 26 Hz), 94.9, 35.7; HR-ESI-MS: m/z calcd. for C₁₉H₁₂F₂N₄O₃S [M+H]⁺ 415.063 2, found 415.063 6
7b'f	¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (s, 1H, Ph-NH-CO), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.30–7.18 (m, 4H, ArH), 6.88 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.84 (s, 2H, S-CH₂), 2.63 (q, J = 7.6 Hz, 2H, -CH₂CH₃), 1.18 (t, J = 7.5 Hz, 3H, -CH₂CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.0, 169.5, 168.4, 167.2, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 241 Hz), 146.1, 141.6 (³J_CF = 13 Hz), 134.7, 128.3 (2C), 127.5 (2C), 119.5, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.5, 35.3, 28.1, 15.4; HR-ESI-MS: m/z calcd. for C₂₁H₁₆F₂N₄O₂S [M+H]⁺ 427.099 6, found 427.100 0
7b'g	¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (s, 1H, Ph-NH-CO), 7.73-7.67 (m, 2H, ArH), 7.61 (d, J = 8.6 Hz, 2H, ArH), 7.32-7.24 (m, 2H, ArH), 6.89 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.4, 169.6, 168.3, 166.1, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 241 Hz), 141.6 (³J_CF = 13 Hz), 136.5, 131.2 (2C), 130.3 (2C), 123.5, 119.4, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.6, 35.3; HR-ESI-MS: m/z calcd. for C₁₉H₁₁BrF₂N₄O₂S [M+H]⁺ 422.973 4, found 422.973 8

Compd.

¹H NMR, ¹³C NMR, HR-ESI-MS

7a'a

¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H, Ph-NH-CO), 7.71 (dd, J = 8.2, 1.8 Hz, 2H, ArH), 7.56 (ddt, J = 6.8, 5.0, 1.8 Hz, 2H, ArH), 7.27-7.21 (m, 2H, ArH), 7.13 (td, J = 8.9, 1.9 Hz, 2H, ArH), 3.87 (s, 2H, S-CH₂), 2.98-2.85 (m, 1H, CH(CH₃)₂), 1.21 (d, J = 1.7 Hz, 3H, CH₃), 1.19 (d, J = 1.8 Hz, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.4, 167.1, 167.1, 159.1, 158.0 (¹J_CF = 238 Hz), 150.9, 135.6 (⁴J_CF = 2 Hz), 134.6, 128.4 (2C), 126.1 (2C), 120.5 (2C, ³J_CF = 8 Hz), 119.2, 115.4 (2C, ²J_CF = 22 Hz), 90.2, 35.2, 33.4, 23.7 (2C); HR-ESI-MS: m/z calcd. for C₂₂H₁₉FN₄O₂S [M+H]⁺ 423.124 6, found 423.124 8

7a'b

¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H, Ph-NH-CO), 7.63 (d, J = 7.8 Hz, 1H, ArH), 7.57 (td, J = 7.4, 5.8, 2.7 Hz, 3H, ArH), 7.45 (q, J = 7.1, 6.5 Hz, 1H, ArH), 7.33 (t, J = 8.7 Hz, 1H, ArH), 7.13 (td, J = 9.0, 2.0 Hz, 2H, ArH), 3.91 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6, 166.9, 165.8, 165.7, 161.8 (¹J_CF = 242 Hz), 158.0 (¹J_CF = 237 Hz), 139.2 (³J_CF = 8 Hz), 135.51 (⁴J_CF = 3 Hz), 130.3 (³J_CF = 8 Hz), 124.5 (⁴J_CF = 3 Hz), 120.6 (2C, ³J_CF = 8 Hz), 118.6, 117.2 (²J_CF = 21 Hz), 115.4 (2C, ²J_CF = 22 Hz), 115.0 (²J_CF = 23 Hz), 91.4, 35.3; HR-ESI-MS: m/z calcd. for C₁₉H₁₂F₂N₄O₂S [M+H]⁺ 399.068 3, found 399.068 6

7a'c

¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s, 1H, Ph-NH-CO), 7.58 (dd, J = 8.3, 5.0 Hz, 2H, ArH), 7.54 (d, J = 5.0 Hz, 2H, ArH), 7.29 (td, J = 9.6, 9.0, 6.8 Hz, 2H, ArH), 7.18-7.08 (m, 2H, ArH), 3.81 (s, 2H, S-CH₂), 2.30 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 170.0, 167.6, 167.5, 157.9 (¹J_CF = 238 Hz), 137.4, 137.3, 135.6 (⁴J_CF = 3 Hz), 130.4, 128.6, 128.0, 125.4, 120.5 (2C, ³J_CF = 8 Hz), 119.7, 115.4 (2C, ²J_CF = 22 Hz), 89.5, 35.1, 20.9; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₂S [M+H]⁺ 395.093 3, found 395.093 5

7a'd

¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H, Ph-NH-CO), 7.65-7.44 (m, 4H, ArH), 7.22-7.02 (m, 3H, ArH), 3.85 (s, 2H, S-CH₂), 2.25 (s, 3H, CH₃), 2.19 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6, 168.9, 167.3, 167.3, 157.9 (¹J_CF = 239 Hz), 138.7, 136.1, 135.6 (¹J_CF = 3 Hz), 134.7, 129.2 (2C), 125.8, 120.5 (2C, ³J_CF = 7 Hz), 119.3, 115.3 (2C, ²J_CF = 22 Hz), 89.7, 35.2, 19.3 (2C); HR-ESI-MS: m/z calcd. for C₂₁H₁₇FN₄O₂S [M+H]⁺ 409.109 0, found 409.109 2

7a'e

¹H NMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H, Ph-NH-CO), 10.87-10.72 (m, 1H, OH), 10.54 (s, 1H, Ar-NH), 8.35 (dd, J = 7.9, 1.7 Hz, 1H, ArH), 7.75 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H, ArH), 7.67-7.60 (m, 2H, ArH), 7.52 (d, J = 8.3 Hz, 1H, ArH), 7.44 (t, J = 7.6 Hz, 1H, ArH), 7.14 (t, J = 8.9 Hz, 2H, ArH), 4.04 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 177.2, 169.0, 166.7, 165.8, 157.9 (¹J_CF = 238 Hz), 157.4, 151.5, 135.5 (⁴J_CF = 3 Hz), 133.9, 125.9, 125.0, 120.7 (2C, ³J_CF = 8 Hz), 118.7, 116.9, 115.3 (2C, ²J_CF = 22 Hz), 94.7, 35.6; HR-ESI-MS: m/z calcd. for C₁₉H₁₃FN₄O₃S [M+H]⁺ 397.072 6, found 397.073 0

7a'f

¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H, Ph-NH-CO), 7.73 (d, J = 7.8 Hz, 2H, ArH), 7.64-7.50 (m, 2H, ArH), 7.29-7.03 (m, 4H, ArH), 3.94 (s, 2H, S-CH₂), 2.63 (q, J = 7.6 Hz, 2H, CH₂-CH₃), 1.17 (t, J = 7.6 Hz, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.5, 167.1, 166.7, 161.9, 158.0 (¹J_CF = 239 Hz), 146.7, 135.5 (⁴J_CF = 2 Hz), 134.0, 128.5 (2C), 127.6 (2C), 120.6 (2C, ³J_CF = 8 Hz), 118.4, 115.4 (2C, ²J_CF = 22 Hz), 90.3, 35.3, 28.1, 15.4; HR-ESI-MS: m/z calcd. for C₂₁H₁₇FN₄O₂S [M+H]⁺ 409.109 0, found 409.109 4

7a'g

¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H, Ph-NH-CO), 10.77 (s, 1H, Ar-NH), 7.72 (dd, J = 8.5, 2.1 Hz, 2H, ArH), 7.58 (ddd, J = 9.1, 4.8, 2.1 Hz, 4H, ArH), 7.13 (td, J = 8.9, 2.1 Hz, 2H, ArH), 3.89 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6, 168.1, 167.0, 166.1, 157.9 (¹J_CF = 238 Hz), 136.1, 135.5 (⁴J_CF = 3 Hz), 131.2 (2C), 130.4 (2C), 123.8, 120.5 (2C, ³J_CF = 8 Hz), 118.8, 115.3 (2C, ²J_CF = 22 Hz), 90.1, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₂BrFN₄O₂S [M+H]⁺ 459.982 8, found 459.982 9

7a'h

¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H, Ph-NH-CO), 8.06 (d, J = 5.1 Hz, 2H, ArH), 7.85 (d, J = 7.8 Hz, 1H, ArH), 7.66 (t, J = 8.0 Hz, 1H, ArH), 7.59 (ddt, J = 6.9, 4.9, 1.8 Hz, 2H, ArH), 7.13 (td, J = 8.9, 2.0 Hz, 2H, ArH), 3.86 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 169.2, 167.3, 165.7, 157.9 (¹J_CF = 238 Hz), 138.2, 135.6 (⁴J_CF =3 Hz), 132.3, 129.5, 129.0 (²J_CF = 32 Hz), 126.6, 124.6 (³J_CF = 4 Hz), 124.0 (¹J_CF = 271 Hz), 120.6 (2C, ³J_CF = 8 Hz), 119.2, 115.4 (2C, ²J_CF= 22 Hz), 90.0, 35.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₂F₄N₄O₂S [M+H]⁺ 449.065 1, found 449.064 7

7a'i

¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H, Ph-NH-CO), 7.94 (d, J = 7.9 Hz, 2H, ArH), 7.75 (d, J = 8.1 Hz, 2H, ArH), 7.58 (ddt, J = 6.9, 4.9, 1.9 Hz, 2H, ArH), 7.13 (tt, J = 9.0, 4.6 Hz, 2H, ArH), 3.88 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.2, 168.6, 167.2, 165.9, 157.9 (¹J_CF = 239 Hz), 141.1, 135.6 (⁴J_CF = 2 Hz), 130.1 (²J_CF = 31 Hz), 129.1 (2C), 125.1 (2C, ³J_CF = 3 Hz), 124.0 (¹J_CF = 271 Hz), 120.5 (2C, ³J_CF = 7 Hz), 118.9, 115.3 (2C, ²J_CF = 22 Hz), 90.4, 35.3; HR-ESI-MS: m/z calcd. for C₂₀H₁₂F₄N₄O₂S [M+H]⁺ 449.056 1, found 499.055 8

7a'j

¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H, Ph-NH-CO), 7.63-7.50 (m, 2H, ArH), 7.33 (dtd, J = 6.1, 3.7, 3.2, 1.2 Hz, 3H, ArH), 7.20-7.09 (m, 2H, ArH), 7.08-6.98 (m, 1H, ArH), 3.84 (s, 2H, S-CH₂), 3.76 (s, 3H, -OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.4, 169.8, 167.4, 167.1, 158.9, 157.9 (¹J_CF = 239 Hz), 138.6, 135.6 (⁴J_CF= 3 Hz), 129.3, 120.5, 120.5 (2C, ³J_CF = 8 Hz), 119.5, 115.6, 115.3 (2C, ²J_CF = 22 Hz), 113.6, 89.6, 55.2, 35.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₃S [M+H]⁺ 411.088 2, found 411.088 5

7a'k

¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H, Ph-NH-CO), 7.74 (d, J = 2.4 Hz, 3H, ArH), 7.64–7.55 (m, 2H, ArH), 7.13 (td, J = 8.9, 1.9 Hz, 2H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.8, 169.4, 167.3, 164.3, 157.9 (¹J_CF =238 Hz), 140.6, 135.6 (⁴J_CF = 3 Hz), 134.0 (2C, Ph), 129.3, 126.8 (2C, Ph), 120.6 (2C, ³J_CF = 7 Hz), 119.1, 115.3 (2C, ²J_CF = 22 Hz), 89.8, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₁Cl₂FN₄O₂S [M+H]⁺ 449.993 4, found 449.993 5

7a'l

¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1H, Ph-NH-CO), 7.70 (dd, J = 8.2, 1.8 Hz, 2H, ArH), 7.58 (ddt, J = 6.8, 4.9, 1.7 Hz, 2H, ArH), 7.24-7.09 (m, 4H, ArH), 3.91 (s, 2H, S-CH₂), 2.34 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.8, 167.1, 166.9, 163.8, 157.9 (¹J_CF = 238 Hz), 140.3, 135.6 (⁴J_CF = 2 Hz), 133.9, 128.8 (2C), 128.4 (2C), 120.6 (2C, ³J_CF = 7 Hz), 118.8, 115.4 (2C, ²J_CF = 22 Hz), 90.1, 35.2, 21.0; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₂S [M+H]⁺ 395.093 3, found 395.093 6

7a'm

¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H, Ph-NH-CO), 7.83 (ddd, J = 8.3, 5.5, 2.1 Hz, 2H, ArH), 7.59 (ddt, J = 7.4, 5.0, 2.1 Hz, 2H, ArH), 7.24 (td, J = 8.9, 2.2 Hz, 2H, ArH), 7.14 (td, J = 9.1, 2.2 Hz, 2H, ArH), 3.83 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.4, 169.7, 167.5, 166.1, 163.0 (¹J_CF = 246 Hz), 157.9 (¹J_CF = 238 Hz), 135.6 (⁴J_CF = 3 Hz), 133.8 (⁴J_CF = 3 Hz), 130.6 (2C, ³J_CF = 8 Hz), 120.5 (2C, ³J_CF = 8 Hz), 119.6, 115.4 (2C, ²J_CF = 22 Hz), 115.1 (2C, ²J_CF = 21 Hz), 89.4, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₂F₂N₄O₂S [M+H]⁺ 399.068 3, found 399.068 7

7a'n

¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H, Ph-NH-CO), 7.79 (d, J = 8.4 Hz, 2H, ArH), 7.59 (dd, J = 8.4, 4.9 Hz, 2H, ArH), 7.14 (t, J = 8.5 Hz, 2H, ArH), 6.94 (d, J = 8.4 Hz, 2H, ArH), 3.85 (s, 2H, S-CH₂), 3.79 (s, 3H, -OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.5, 169.0, 167.3, 166.5, 160.9, 157.9 (¹J_CF = 238 Hz), 135.6 (⁴J_CF = 3 Hz), 130.0 (2C), 129.3, 120.5 (2C, ³J_CF = 8 Hz), 119.6, 115.4 (2C, ²J_CF = 22 Hz), 113.50 (2C), 89.0, 55.3, 35.2; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₃S [M+H]⁺ 411.088 2, found 411.088 4

7a'o

¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 1H, Ph-NH-CO), 7.78 (ddd, J = 11.8, 7.9, 2.2 Hz, 1H, ArH), 7.70–7.63 (m, 1H, ArH), 7.63-7.55 (m, 2H, ArH), 7.49 (dt, J = 10.7, 8.5 Hz, 1H, ArH), 7.18–7.08 (m, 2H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 169.4, 167.3, 164.7, 157.9 (¹J_CF = 238 Hz), 150.3 (¹J_CF = 242 Hz, ²J_CF = 12 Hz), 149.1 (¹J_CF = 246 Hz, ²J_CF = 12 Hz), 135.5 (⁴J_CF = 2 Hz), 130.8 (³J_CF = 6 Hz), 125.4 (⁴J_CF = 3 Hz), 120.5 (2C, ³J_CF = 8 Hz), 119.3, 117.4 (²J_CF = 18 Hz), 117.31 (²J_CF = 17 Hz), 115.3 (2C, ²J_CF = 22 Hz), 89.6, 35.1; HR-ESI-MS: m/z calcd. for C₁₉H₁₁F₃N₄O₂S [M+H]⁺ 417.058 8, found 417.058 6

7a'p

¹H NMR (400 MHz, DMSO-d₆) δ 10.93 (s, 1H, Ph-NH-CO), 7.62-7.52 (m, 2H, ArH), 7.36-7.24 (m, 2H, ArH), 7.22 (dd, J = 3.8, 0.9 Hz, 2H, ArH), 7.18-7.09 (m, 2H, ArH), 3.81 (s, 2H, S-CH₂), 2.21 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.3, 169.8, 169.4, 167.4, 157.9 (¹J_CF = 238 Hz), 137.8, 135.5 (⁴J_CF = 3 Hz), 134.9, 130.1, 128.7, 128.3, 125.5, 120.5 (2C, ³J_CF = 8 Hz), 118.9, 115.3 (2C, ²J_CF = 22 Hz), 91.9, 35.1, 19.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₂S [M+H]⁺ 395.093 3, found 395.093 6

7a'q

¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H, Ph-NH-CO), 7.64-7.54 (m, 2H, ArH), 7.49-7.32 (m, 3H, ArH), 7.13 (t, J = 8.9 Hz, 2H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.8, 169.5, 167.4, 164.5, 162.0 (2C, ¹J_CF = 245 Hz, ³J_CF = 13 Hz), 157.9 (¹J_CF = 238 Hz), 140.8 (³J_CF = 9 Hz), 135.6 (⁴J_CF = 2 Hz), 120.5 (2C, ³J_CF = 8 Hz), 119.2, 115.3 (2C, ²J_CF = 22 Hz), 111.5 (2C, ²J_CF = 26 Hz), 105.29 (²J_CF = 25 Hz), 89.7, 35.2; HR-ESI-MS: m/z calcd. for C₁₉H₁₁F₃N₄O₂S [M+H]⁺ 417.058 8, found 417.059 1

7a'r

¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H, Ph-NH-CO), 7.57 (ddt, J = 6.9, 5.0, 2.8 Hz, 2H, ArH), 7.44-7.35 (m, 1H, ArH), 7.25-7.06 (m, 4H, ArH), 6.93 (t, J = 7.4 Hz, 1H, ArH), 3.78 (s, 2H, S-CH₂), 3.76 (s, J = 1.7 Hz, 3H, -OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.2, 169.2, 167.6, 166.9, 157.9 (¹J_CF = 238 Hz), 156.2, 135.6 (⁴J_CF = 2 Hz), 130.6, 129.6, 127.1, 120.5 (2C, ³J_CF = 7 Hz), 120.1, 118.9, 115.3 (2C, ²J_CF = 22 Hz), 111.6, 93.1, 55.4, 35.1; HR-ESI-MS: m/z calcd. for C₂₀H₁₅FN₄O₃S [M+H]⁺ 411.088 2, found 411.088 6

7b'a

¹H NMR (400 MHz, DMSO-d₆) δ 11.38 (s, 1H, Ph-NH-CO), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.31-7.19 (m, 4H, ArH), 6.89 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.83 (s, 2H, S-CH₂), 2.91 (p, J = 6.9 Hz, 1H, -CH(CH₃)₂), 1.21 (d, J = 6.9 Hz, 6H, -CH(CH₃)₂; ¹³C NMR (100 MHz, DMSO-d₆) δ 171.1, 169.7, 168.4, 167.1, 162.6 (¹J_CF = 241 Hz), 162.4 (¹J_CF = 241 Hz), 150.6, 141.6 (³J_CF = 14 Hz), 134.9, 128.3 (2C), 126.05 (2C), 119.6, 101.7 (2C, ²J_CF = 29 Hz), 98.2 (²J_CF = 26 Hz), 89.4, 35.3, 33.3, 23.7 (2C); HR-ESI-MS: m/z calcd. for C₂₂H₁₈F₂N₄O₂S [M+H]⁺ 441.115 2, found 441.115 0

7b'b

¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (s, 1H, Ph-NH-CO), 7.64-7.57 (m, 1H, ArH), 7.54-7.42 (m, 2H, ArH), 7.29 (pd, J = 8.0, 7.4, 2.6 Hz, 3H, ArH), 6.88 (tt, J = 9.3, 2.4 Hz, 1H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.5, 169.7, 168.3, 165.8, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 242 Hz), 161.8 (¹J_CF = 243 Hz), 141.5 (³J_CF = 14 Hz), 139.7 (³J_CF = 7 Hz), 130.2 (³J_CF = 8 Hz), 124.4 (⁴J_CF=2 Hz), 119.4, 116.8 (²J_CF = 20 Hz), 114.9 (²J_CF = 23 Hz), 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.8, 35.3; HR-ESI-MS: m/z calcd. for C₁₉H₁₁F₃N₄O₂S [M+H]⁺ 417.058 8, found 417.059 2

7b'c

¹H NMR (400 MHz, DMSO-d₆) δ 11.43 (s, 1H, Ph-NH-CO), 7.53 (dd, J = 6.4, 1.7 Hz, 2H, ArH), 7.34–7.22 (m, 4H, ArH), 6.88 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.83 (s, 2H, S-CH₂), 2.30 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.3, 170.0, 168.5, 167.5, 162.6 (¹J_CF = 242 Hz), 162.5 (¹J_CF = 242 Hz), 141.6 (³J_CF = 14 Hz), 137.4, 137.4, 130.5, 128.6, 128.0, 125.4, 119.6, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.7, 35.3, 20.9; HR-ESI-MS: m/z calcd. for C₂₀H₁₄F₂N₄O₂S [M+H]⁺ 413.083 9, found 413.083 7

7b'd

¹H NMR (400 MHz, DMSO-d₆) δ 11.45 (s, 1H, Ph-NH-CO), 7.56-7.45 (m, 2H, ArH), 7.29-7.13 (m, 3H, ArH), 6.88 (tt, J = 9.3, 2.4 Hz, 1H, ArH), 3.83 (s, 2H, S-CH₂), 2.25 (s, 3H, CH₃), 2.20 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.0, 169.7, 168.4, 167.4, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 242 Hz), 141.6 (³J_CF = 14 Hz), 138.5, 136.0, 134.9, 129.2, 129.1, 125.7, 119.6, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.5, 35.3, 19.3 (2C); HR-ESI-MS: m/z calcd. for C₂₁H₁₆F₂N₄O₂S [M+H]⁺ 427.099 6, found 427.099 3

7b'e

¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H, Ph-NH-CO), 10.94 (s, 1H, -OH), 8.32 (dd, J = 7.9, 1.6 Hz, 1H, ArH), 7.75 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H, ArH), 7.52 (d, J = 8.4 Hz, 1H, ArH), 7.42 (t, J = 7.6 Hz, 1H, ArH), 7.38-7.27 (m, 2H, ArH), 6.90 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 4.05 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 176.9, 169.0, 167.6, 165.8, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 242 Hz), 157.4, 151.6, 141.6 (³J_CF = 13 Hz), 133.9, 125.8, 125.0, 118.7, 116.9, 101.9 (2C, ²J_CF = 29 Hz), 98.4 (²J_CF = 26 Hz), 94.9, 35.7; HR-ESI-MS: m/z calcd. for C₁₉H₁₂F₂N₄O₃S [M+H]⁺ 415.063 2, found 415.063 6

7b'f

¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (s, 1H, Ph-NH-CO), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.30–7.18 (m, 4H, ArH), 6.88 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.84 (s, 2H, S-CH₂), 2.63 (q, J = 7.6 Hz, 2H, -CH₂CH₃), 1.18 (t, J = 7.5 Hz, 3H, -CH₂CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.0, 169.5, 168.4, 167.2, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 241 Hz), 146.1, 141.6 (³J_CF = 13 Hz), 134.7, 128.3 (2C), 127.5 (2C), 119.5, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.5, 35.3, 28.1, 15.4; HR-ESI-MS: m/z calcd. for C₂₁H₁₆F₂N₄O₂S [M+H]⁺ 427.099 6, found 427.100 0

7b'g

¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (s, 1H, Ph-NH-CO), 7.73-7.67 (m, 2H, ArH), 7.61 (d, J = 8.6 Hz, 2H, ArH), 7.32-7.24 (m, 2H, ArH), 6.89 (tt, J = 9.4, 2.4 Hz, 1H, ArH), 3.84 (s, 2H, S-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.4, 169.6, 168.3, 166.1, 162.6 (¹J_CF = 242 Hz), 162.4 (¹J_CF = 241 Hz), 141.6 (³J_CF = 13 Hz), 136.5, 131.2 (2C), 130.3 (2C), 123.5, 119.4, 101.7 (2C, ²J_CF = 29 Hz), 98.3 (²J_CF = 26 Hz), 89.6, 35.3; HR-ESI-MS: m/z calcd. for C₁₉H₁₁BrF₂N₄O₂S [M+H]⁺ 422.973 4, found 422.973 8

Compd.	R₁	R₂	EC₅₀ /μmol·L^-1	CC₅₀ /μmol·L^-1	TI
7a'a	4'-F	4'-iPr	> 50	> 200
7a'b	4'-F	3'-F	> 50	> 200
7a'c	4'-F	3'-Me	> 50	> 200
7a'd	4'-F	3', 4'-diMe	> 50	> 200
7a'e	4'-F	2'-OH	21.23	> 200	> 9.42
7a'f	4'-F	4'-Et	20.21	> 200	> 9.90
7a'g	4'-F	4'-Br	19.13	> 200	> 10.45
7a'h	4'-F	3'-CF₃	18.29	> 200	> 10.93
7a'i	4'-F	4'-CF₃	> 50	> 200
7a'j	4'-F	3'-OCH₃	> 50	> 200
7a'k	4'-F	3', 5'-diCl	7.86	> 200	> 25.45
7a'l	4'-F	4'-Me	> 50	> 200
7a'm	4'-F	4'-F	> 50	> 200
7a'n	4'-F	4'-OCH₃	> 50	> 200
7a'o	4'-F	3', 4'-diF	> 50	> 200
7a'p	4'-F	2'-Me	> 50	> 200
7a'q	4'-F	3', 5'-diF	> 50	> 200
7a'r	4'-F	2'-Ome	> 50	> 200
7b'a	3', 5'-diF	4'-iPr	> 50	158.61
7b'b	3', 5'-diF	3'-F	> 50	> 200
7b'c	3', 5'-diF	3'-Me	> 50	> 200
7b'd	3', 5'-diF	3', 4'-diMe	> 50	> 200
7b'e	3', 5'-diF	2'-OH	> 50	> 200
7b'f	3', 5'-diF	4'-Et	> 50	> 200
7b'g	3', 5'-diF	4'-Br	> 50	> 200
Ribavirin			18.07 ± 0.36	> 200	> 11.07

Compd.

R₁

R₂

EC₅₀ /μmol·L^-1

CC₅₀ /μmol·L^-1

7a'a

4'-F

4'-iPr

> 50

> 200

7a'b

4'-F

3'-F

> 50

> 200

7a'c

4'-F

3'-Me

> 50

> 200

7a'd

4'-F

3', 4'-diMe

> 50

> 200

7a'e

4'-F

2'-OH

21.23

> 200

> 9.42

7a'f

4'-F

4'-Et

20.21

> 200

> 9.90

7a'g

4'-F

4'-Br

19.13

> 200

> 10.45

7a'h

4'-F

3'-CF₃

18.29

> 200

> 10.93

7a'i

4'-F

4'-CF₃

> 50

> 200

7a'j

4'-F

3'-OCH₃

> 50

> 200

7a'k

4'-F

3', 5'-diCl

7.86

> 200

> 25.45

7a'l

4'-F

4'-Me

> 50

> 200

7a'm

4'-F

> 50

> 200

7a'n

4'-F

4'-OCH₃

> 50

> 200

7a'o

4'-F

3', 4'-diF

> 50

> 200

7a'p

4'-F

2'-Me

> 50

> 200

7a'q

4'-F

3', 5'-diF

> 50

> 200

7a'r

4'-F

2'-Ome

> 50

> 200

7b'a

3', 5'-diF

4'-iPr

> 50

158.61

7b'b

3', 5'-diF

3'-F

> 50

> 200

7b'c

3', 5'-diF

3'-Me

> 50

> 200

7b'd

3', 5'-diF

3', 4'-diMe

> 50

> 200

7b'e

3', 5'-diF

2'-OH

> 50

> 200

7b'f

3', 5'-diF

4'-Et

> 50

> 200

7b'g

3', 5'-diF

4'-Br

> 50

> 200

Ribavirin

18.07 ± 0.36

> 200

> 11.07