药学学报

Compd.	Yield/%	mp/°C	HR-ESI-MS (m/z)
8a	62	180-182	282.112 0	282.112 5
8b	58	166-168	282.112 0	282.112 5
9a	71	155-158	332.027 4	332.028 1
9b	65	221-223	409.939 1	409.938 6
9c	61	208-210	322.039 7	322.039 6
10a	52	141-143	385.082 0	385.082 8
10b	69	156-158	349.115 0	349.115 8
10c	44	165-166	371.066 5	371.067 2
10d	58	136-137	335.099 2	335.100 2
10e	67	183-184	385.082 2	385.082 8
10f	51	153-156	349.115 4	349.115 8
10g	39	171-172	371.066 5	371.067 2
10h	56	193-195	335.099 5	335.100 2
10i	37	150-151	317.095 0	317.095 4

Compd.	Yield/%	mp/°C	HR-ESI-MS (m/z)
8a	62	180-182	282.112 0	282.112 5
8b	58	166-168	282.112 0	282.112 5
9a	71	155-158	332.027 4	332.028 1
9b	65	221-223	409.939 1	409.938 6
9c	61	208-210	322.039 7	322.039 6
10a	52	141-143	385.082 0	385.082 8
10b	69	156-158	349.115 0	349.115 8
10c	44	165-166	371.066 5	371.067 2
10d	58	136-137	335.099 2	335.100 2
10e	67	183-184	385.082 2	385.082 8
10f	51	153-156	349.115 4	349.115 8
10g	39	171-172	371.066 5	371.067 2
10h	56	193-195	335.099 5	335.100 2
10i	37	150-151	317.095 0	317.095 4

Compd.	¹H NMR and ¹³C NMR data
8a	¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.90 (s, 1H), 7.52 (d, J = 6.9 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.1 Hz, 1H), 7.00 (t, J = 7.1 Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 6.76 (s, 1H), 3.76 (t, J = 5.8 Hz, 2H), 2.82 (t, J = 5.8 Hz, 2H), 1.96 (t, J = 5.8 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.44, 166.68, 138.63, 136.89, 132.39, 131.69, 130.82, 130.69, 129.00, 128.54, 128.53, 125.52, 125.13, 124.57, 44.46, 26.28, 23.65.
8b	¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.4 Hz, 1H), 7.00 (t, J = 7.7 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.75 (s, 1H), 3.75 (t, J = 6.4 Hz, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.00-1.90 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.53, 166.76, 140.71, 138.49, 131.72, 129.17 (2C), 128.56, 128.23 (2C), 125.52 (2C), 125.03, 124.64, 44.38, 26.25, 23.58.
9a	¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.12 (dd, J = 2.1, 8.4 Hz, 1H), 7.00 (td, J = 1.2, 7.4 Hz, 1H), 6.93 (td, J = 1.5, 7.9 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 3.73 (t, J = 6.4 Hz, 2H), 2.79 (t, J = 6.6 Hz, 2H), 1.99-1.88 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.80, 155.79, 139.16, 133.48, 131.39, 129.46, 128.47, 128.27, 125.51, 124.96, 124.24, 115.47, 108.66, 44.45, 26.27, 23.70.
9b	¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 7.44 (s, 2H), 7.21 (d, J = 7.3 Hz, 1H), 7.03 (td, J = 1.3, 7.4 Hz, 1H), 6.96 (td, J = 1.6, 7.8 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 3.73 (t, J = 6.5 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 1.99-1.89 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.23, 152.28, 138.66, 132.59 (2C), 131.72, 130.12, 128.50, 125.56, 125.06, 124.58, 111.04 (2C), 44.53, 26.24, 23.61.
9c^[15]	¹H NMR (400 MHz, DMSO-d₆) δ 10.70 (s, 1H), 7.27 (s, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.03 (td, J = 1.3, 7.4 Hz, 1H), 6.95 (td, J = 1.6, 7.8 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 3.73 (t, J = 6.5 Hz, 2H), 2.81 (t, J = 6.6 Hz, 2H), 2.00-1.88 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.55, 150.66, 138.69, 131.72, 128.91 (2C), 128.72, 128.51, 125.57, 125.02, 124.56, 121.58 (2C), 44.51, 26.24, 23.60.
10a	¹H NMR (400 MHz, Acetone-d₆) δ 10.13 (s, 1H), 7.59-7.47 (m, 2H), 7.26-7.20 (m, 3H), 7.06-6.91 (m, 3H), 3.84 (t, J = 6.4 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H), 2.08-2.02 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 168.73, 138.45, 135.67, 132.14, 131.97, 130.15, 128.87, 126.28, 125.84, 125.62, 125.26, 124.95, 122.94, 119.92 (q, J = 323.0 Hz), 44.97, 26.87, 24.01.
10b	¹H NMR (400 MHz, DMSO-d₆) δ 11.29 (s, 1H), 7.51-7.41 (m, 2H), 7.35-7.05 (m, 4H), 6.99 (t, J = 7.3 Hz, 1H), 6.96-6.83 (m, 1H), 3.70 (brs, 2H), 2.79 (t, J = 6.6 Hz, 2H), 1.97-1.90 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.83, 154.94 (q, J = 37.0 Hz), 138.27, 132.87, 130.35 (2C), 129.16, 128.52, 126.63, 126.09, 125.35 (2C), 124.53, 124.36, 115.90 (q, J = 288.6 Hz), 39.52, 26.33, 23.21.
10c	¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (d, J = 8.2 Hz, 1H), 7.56-7.44 (m, 2H), 7.41-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.11-7.03 (m, 1H), 3.82 (t, J = 8.4 Hz, 2H), 3.04 (t, J = 8.4 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.37, 142.64, 135.24, 132.74, 130.52, 127.75, 127.63, 127.02 (2C), 124.96 (2C), 124.08, 119.69 (q, J = 325.2 Hz), 116.75, 49.83, 27.70.
10d	¹H NMR (400 MHz, DMSO-d₆) δ 11.32 (s, 1H), 8.04 (d, J = 6.4 Hz, 1H), 7.64 (d, J = 6.4 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 7.1 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.21 (brs, 1H), 7.11-6.76 (m, 1H), 3.97 (t, J = 8.2 Hz, 2H), 3.07 (t, J = 8.2 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.99, 155.16 (q, J = 36.8 Hz), 142.79, 132.72, 131.87, 130.34, 127.67, 127.08 (2C), 126.99, 126.28, 124.93, 123.99, 116.81, 115.87 (q, J = 288.5 Hz), 50.16, 27.83.
10e	¹H NMR (400 MHz, CDCl₃) δ 9.65 (s, 1H), 7.61 (s, 1H), 7.41 (ddd, J = 0.8, 2.2, 8.2 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 7.05 (td, J = 1.0, 7.5 Hz, 1H), 6.89 (t, J = 6.3 Hz, 2H), 6.66 (brs, 1H), 3.95 (t, J = 6.6 Hz, 2H), 2.85 (t, J = 6.6 Hz, 2H), 2.12-2.04 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.23, 138.58, 137.87, 135.02, 131.72, 129.57, 128.47, 125.97, 125.51, 124.87, 124.59, 123.71, 121.83, 119.65 (q, J = 324.1 Hz), 44.37, 26.21, 23.63.
10f	¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 7.79 (t, J = 1.7 Hz, 1H), 7.72 (dd, J = 1.6, 7.8 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 7.01 (td, J = 1.0, 7.4 Hz, 1H), 6.97-6.89 (m, 1H), 6.83 (d, J = 7.4 Hz, 1H), 3.75 (t, J = 6.4 Hz, 2H), 2.81 (t, J = 6.6 Hz, 2H), 1.99-1.91 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.68, 154.58 (q, J = 37.0 Hz), 138.67, 137.36, 136.49, 131.44, 128.82, 128.57, 125.52, 125.05, 124.90, 124.49, 122.27, 120.53, 115.71 (q, J = 288.7 Hz), 44.63, 26.25, 23.62.
10g	¹H NMR (400 MHz, Acetone-d₆) δ 10.44 (brs, 1H), 8.10 (brs, 1H), 7.62-7.53 (m, 4H), 7.26 (d, J = 8.6 Hz, 1H), 7.16 (s, 1H), 7.04 (t, J = 7.4 Hz, 1H), 4.06 (t, J = 8.3 Hz, 2H), 3.14 (t, J = 8.3 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 168.67, 141.94, 137.40, 135.64, 132.43, 129.94, 127.91, 125.52, 125.46, 124.99, 124.56, 122.29, 120.01 (q, J = 322.9 Hz), 118.42, 51.42, 28.50.
10h	¹H NMR (400 MHz, DMSO-d₆) δ 11.42 (s, 1H), 8.07 (brs, 1H), 7.88 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.56-7.51 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.18 (brs, 1H), 7.07-7.01 (m, 1H), 4.01 (t, J = 8.2 Hz, 2H), 3.09 (t, J = 8.2 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.28, 154.70 (q, J = 37.1 Hz), 142.52, 137.68, 136.52, 132.75, 129.34, 126.91, 125.07, 124.05 (2C), 122.57, 119.55 (2C), 115.75 (q, J = 288.7 Hz), 50.45, 27.77.
10i	¹H NMR (400 MHz, CDCl₃) δ 8.22 (brs, 1H), 7.55 (s, 1H), 7.47-7.37 (m, 3H), 7.36-7.29 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.04 (brs, 1H), 4.05 (brs, 2H), 3.12 (t, J = 8.2 Hz, 2H), 2.98 (s, 3H). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.48, 142.60, 138.66, 138.03, 132.81, 129.63, 126.89, 125.08, 123.98, 122.02, 120.95, 117.75, 116.88, 50.53, 50.38, 27.72.

Compd.	¹H NMR and ¹³C NMR data
8a	¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.90 (s, 1H), 7.52 (d, J = 6.9 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.1 Hz, 1H), 7.00 (t, J = 7.1 Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 6.76 (s, 1H), 3.76 (t, J = 5.8 Hz, 2H), 2.82 (t, J = 5.8 Hz, 2H), 1.96 (t, J = 5.8 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.44, 166.68, 138.63, 136.89, 132.39, 131.69, 130.82, 130.69, 129.00, 128.54, 128.53, 125.52, 125.13, 124.57, 44.46, 26.28, 23.65.
8b	¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.4 Hz, 1H), 7.00 (t, J = 7.7 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.75 (s, 1H), 3.75 (t, J = 6.4 Hz, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.00-1.90 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.53, 166.76, 140.71, 138.49, 131.72, 129.17 (2C), 128.56, 128.23 (2C), 125.52 (2C), 125.03, 124.64, 44.38, 26.25, 23.58.
9a	¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.12 (dd, J = 2.1, 8.4 Hz, 1H), 7.00 (td, J = 1.2, 7.4 Hz, 1H), 6.93 (td, J = 1.5, 7.9 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 3.73 (t, J = 6.4 Hz, 2H), 2.79 (t, J = 6.6 Hz, 2H), 1.99-1.88 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.80, 155.79, 139.16, 133.48, 131.39, 129.46, 128.47, 128.27, 125.51, 124.96, 124.24, 115.47, 108.66, 44.45, 26.27, 23.70.
9b	¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 7.44 (s, 2H), 7.21 (d, J = 7.3 Hz, 1H), 7.03 (td, J = 1.3, 7.4 Hz, 1H), 6.96 (td, J = 1.6, 7.8 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 3.73 (t, J = 6.5 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 1.99-1.89 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.23, 152.28, 138.66, 132.59 (2C), 131.72, 130.12, 128.50, 125.56, 125.06, 124.58, 111.04 (2C), 44.53, 26.24, 23.61.
9c^[15]	¹H NMR (400 MHz, DMSO-d₆) δ 10.70 (s, 1H), 7.27 (s, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.03 (td, J = 1.3, 7.4 Hz, 1H), 6.95 (td, J = 1.6, 7.8 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 3.73 (t, J = 6.5 Hz, 2H), 2.81 (t, J = 6.6 Hz, 2H), 2.00-1.88 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.55, 150.66, 138.69, 131.72, 128.91 (2C), 128.72, 128.51, 125.57, 125.02, 124.56, 121.58 (2C), 44.51, 26.24, 23.60.
10a	¹H NMR (400 MHz, Acetone-d₆) δ 10.13 (s, 1H), 7.59-7.47 (m, 2H), 7.26-7.20 (m, 3H), 7.06-6.91 (m, 3H), 3.84 (t, J = 6.4 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H), 2.08-2.02 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 168.73, 138.45, 135.67, 132.14, 131.97, 130.15, 128.87, 126.28, 125.84, 125.62, 125.26, 124.95, 122.94, 119.92 (q, J = 323.0 Hz), 44.97, 26.87, 24.01.
10b	¹H NMR (400 MHz, DMSO-d₆) δ 11.29 (s, 1H), 7.51-7.41 (m, 2H), 7.35-7.05 (m, 4H), 6.99 (t, J = 7.3 Hz, 1H), 6.96-6.83 (m, 1H), 3.70 (brs, 2H), 2.79 (t, J = 6.6 Hz, 2H), 1.97-1.90 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.83, 154.94 (q, J = 37.0 Hz), 138.27, 132.87, 130.35 (2C), 129.16, 128.52, 126.63, 126.09, 125.35 (2C), 124.53, 124.36, 115.90 (q, J = 288.6 Hz), 39.52, 26.33, 23.21.
10c	¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (d, J = 8.2 Hz, 1H), 7.56-7.44 (m, 2H), 7.41-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.11-7.03 (m, 1H), 3.82 (t, J = 8.4 Hz, 2H), 3.04 (t, J = 8.4 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.37, 142.64, 135.24, 132.74, 130.52, 127.75, 127.63, 127.02 (2C), 124.96 (2C), 124.08, 119.69 (q, J = 325.2 Hz), 116.75, 49.83, 27.70.
10d	¹H NMR (400 MHz, DMSO-d₆) δ 11.32 (s, 1H), 8.04 (d, J = 6.4 Hz, 1H), 7.64 (d, J = 6.4 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 7.1 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.21 (brs, 1H), 7.11-6.76 (m, 1H), 3.97 (t, J = 8.2 Hz, 2H), 3.07 (t, J = 8.2 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.99, 155.16 (q, J = 36.8 Hz), 142.79, 132.72, 131.87, 130.34, 127.67, 127.08 (2C), 126.99, 126.28, 124.93, 123.99, 116.81, 115.87 (q, J = 288.5 Hz), 50.16, 27.83.
10e	¹H NMR (400 MHz, CDCl₃) δ 9.65 (s, 1H), 7.61 (s, 1H), 7.41 (ddd, J = 0.8, 2.2, 8.2 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 7.05 (td, J = 1.0, 7.5 Hz, 1H), 6.89 (t, J = 6.3 Hz, 2H), 6.66 (brs, 1H), 3.95 (t, J = 6.6 Hz, 2H), 2.85 (t, J = 6.6 Hz, 2H), 2.12-2.04 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.23, 138.58, 137.87, 135.02, 131.72, 129.57, 128.47, 125.97, 125.51, 124.87, 124.59, 123.71, 121.83, 119.65 (q, J = 324.1 Hz), 44.37, 26.21, 23.63.
10f	¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 7.79 (t, J = 1.7 Hz, 1H), 7.72 (dd, J = 1.6, 7.8 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 7.01 (td, J = 1.0, 7.4 Hz, 1H), 6.97-6.89 (m, 1H), 6.83 (d, J = 7.4 Hz, 1H), 3.75 (t, J = 6.4 Hz, 2H), 2.81 (t, J = 6.6 Hz, 2H), 1.99-1.91 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.68, 154.58 (q, J = 37.0 Hz), 138.67, 137.36, 136.49, 131.44, 128.82, 128.57, 125.52, 125.05, 124.90, 124.49, 122.27, 120.53, 115.71 (q, J = 288.7 Hz), 44.63, 26.25, 23.62.
10g	¹H NMR (400 MHz, Acetone-d₆) δ 10.44 (brs, 1H), 8.10 (brs, 1H), 7.62-7.53 (m, 4H), 7.26 (d, J = 8.6 Hz, 1H), 7.16 (s, 1H), 7.04 (t, J = 7.4 Hz, 1H), 4.06 (t, J = 8.3 Hz, 2H), 3.14 (t, J = 8.3 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 168.67, 141.94, 137.40, 135.64, 132.43, 129.94, 127.91, 125.52, 125.46, 124.99, 124.56, 122.29, 120.01 (q, J = 322.9 Hz), 118.42, 51.42, 28.50.
10h	¹H NMR (400 MHz, DMSO-d₆) δ 11.42 (s, 1H), 8.07 (brs, 1H), 7.88 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.56-7.51 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.18 (brs, 1H), 7.07-7.01 (m, 1H), 4.01 (t, J = 8.2 Hz, 2H), 3.09 (t, J = 8.2 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.28, 154.70 (q, J = 37.1 Hz), 142.52, 137.68, 136.52, 132.75, 129.34, 126.91, 125.07, 124.05 (2C), 122.57, 119.55 (2C), 115.75 (q, J = 288.7 Hz), 50.45, 27.77.
10i	¹H NMR (400 MHz, CDCl₃) δ 8.22 (brs, 1H), 7.55 (s, 1H), 7.47-7.37 (m, 3H), 7.36-7.29 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.04 (brs, 1H), 4.05 (brs, 2H), 3.12 (t, J = 8.2 Hz, 2H), 2.98 (s, 3H). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.48, 142.60, 138.66, 138.03, 132.81, 129.63, 126.89, 125.08, 123.98, 122.02, 120.95, 117.75, 116.88, 50.53, 50.38, 27.72.

Compd.	Inhibition/10^-5 mol·L^-1	IC₅₀/10^-6 mol·L^-1
8a	NA	ND
8b	NA	ND
9a	68%	ND
9b	99%	0.061
9c^*	94%	0.182
10a	62%	ND
10b	NA	ND
Lesinurad	ND	39
URC-102	ND	0.023^[16]
10c	47%	ND
10d	NA	ND
10e	82%	1.51
10f	NA	ND
10g	77%	2.19
10h	NA	ND
10i	NA	ND
Benzbromarone	ND	0.49

Compd.	Inhibition/10^-5 mol·L^-1	IC₅₀/10^-6 mol·L^-1
8a	NA	ND
8b	NA	ND
9a	68%	ND
9b	99%	0.061
9c^*	94%	0.182
10a	62%	ND
10b	NA	ND
Lesinurad	ND	39
URC-102	ND	0.023^[16]
10c	47%	ND
10d	NA	ND
10e	82%	1.51
10f	NA	ND
10g	77%	2.19
10h	NA	ND
10i	NA	ND
Benzbromarone	ND	0.49

尿酸盐转运体1抑制剂的设计、合成及活性研究

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王永成 , 杨亚军 , 候现新 , 杨颖 , 肖志艳 ^*

药学学报 | 研究论文 2019,54(6): 1069-1074

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药学学报 | 研究论文 2019, 54(6): 1069-1074

尿酸盐转运体1抑制剂的设计、合成及活性研究

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王永成, 杨亚军, 候现新, 杨颖, 肖志艳^*

作者信息

中国医学科学院、北京协和医学院药物研究所, 活性物质发现与适药化研究北京市重点实验室, 北京 100050

通讯作者:

*肖志艳，Tel / Fax: 86-10-63189228, E-mail: xiaoz@imm.ac.cn

Design, synthesis and biological evaluation of inhibitors of urate transporter 1 (URAT1)

Yong-cheng WANG, Ya-jun YANG, Xian-xin HOU, Ying YANG, Zhi-yan XIAO^*

Affiliations

Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2019-06-12 doi: 10.16438/j.0513-4870.2019-0208

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摘要

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尿酸盐转运体1（urate transporter 1，URAT1）是抗高尿酸血症的有效靶点。基于目前处于临床Ⅱ期的URAT1抑制剂URC-102的结构，设计合成了14个URC-102类似物，其中4个化合物（9b、9c、10e、10g）显示较强的URAT1抑制活性，化合物9b对URAT1的半数抑制浓度IC₅₀达到0.061 μmol·L^-1，显著强于雷西纳德和苯溴马隆。初步的构效关系研究为后续结构优化提供了依据。

关键词

URAT1抑制剂 / 高尿酸血症 / 痛风 / URC-102类似物

Abstract

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Urate transporter 1 (URAT1) is a validated target for the treatment of hyperuricemia. Based on the structure of URC-102, which is currently under a phase Ⅱ clinical trial, fourteen novel analogs were designed and synthesized. Among them, four compounds (9b, 9c, 10e and 10g) exhibited substantial inhibitory effect against URAT1. The most active compound 9b showed an IC₅₀ value of 0.061 μmol·L^-1, which is significantly more potent than Lesinurad and Benzbromarone. Preliminary SAR was drawn, providing clues for further structural optimization.

Key words

URAT1 inhibitors / hyperuricemia / gout / URC-102 analogs

引用本文

王永成, 杨亚军, 候现新, 杨颖, 肖志艳. 尿酸盐转运体1抑制剂的设计、合成及活性研究. 药学学报, 2019 , 54 (6) : 1069 -1074 . DOI: 10.16438/j.0513-4870.2019-0208

Yong-cheng WANG, Ya-jun YANG, Xian-xin HOU, Ying YANG, Zhi-yan XIAO. Design, synthesis and biological evaluation of inhibitors of urate transporter 1 (URAT1)[J]. Acta Pharmaceutica Sinica, 2019 , 54 (6) : 1069 -1074 . DOI: 10.16438/j.0513-4870.2019-0208

正文

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高尿酸血症是由体内嘌呤代谢紊乱造成的血清中尿酸盐(serum urate, sUA)浓度过高的代谢性疾病^[1]。高尿酸血症是痛风形成的直接诱因, 当血清尿酸浓度持续过高, 尿酸盐出现结晶沉积在软组织或关节, 继而引起炎症反应, 诱发痛风。目前, 痛风在北美和欧洲等发达国家的发病率超过1%^[2]。随着生活水平的提高, 我国的高尿酸血症和痛风发病率也在持续增高, 已经成为影响人们健康和生活质量的重要疾病之一^[3]。

高尿酸血症通常是由于尿酸产生过多和(或)尿酸排泄减少引起, 其中后者在高尿酸血症患者中约占90%^[4]。因此, 通过增加尿酸排泄的途径来降低sUA是行之有效的降尿酸治疗(urate-lowering therapy)方法。尿酸盐转运体1 (urate transporter 1, URAT1)是调控尿酸重吸收的重要蛋白^[5]。URAT1抑制剂通过抑制尿酸重吸收来增加尿酸排泄, 从而降低sUA。目前, 已上市的促尿酸排泄药物主要有丙磺舒(Probenecid)、苯溴马隆(Benzbromarone)和雷西纳德(Lesinurad) (图 1)。但是丙磺舒活性弱, 半衰期短, 会降低肾小球滤过率, 而且与常用药物(如:非甾体类抗炎药、β-内酰胺类、肝素等)之间存在显著的药物相互作用, 这些缺点限制了其临床应用^{[6, 7]}。苯溴马隆活性较强, 但由于肝毒性等原因, 2003年已经在欧洲撤市^{[8, 9]}。URAT1抑制剂雷西纳德于2015年12月上市, 联合黄嘌呤氧化酶抑制剂用于高尿酸血症和痛风的治疗^[10]。雷西纳德的上市也有力促进了新型URAT1抑制剂的研究和开发, Verinurad (RDEA3170)、SHR4640、URC-102 (图 1)等URAT1抑制剂先后进入了临床研究阶段^[11-14]。

URAT1为跨膜阴离子转运蛋白, 其结构目前尚未被解析。由已上市和处于临床研究的URAT1抑制剂(图 1)可知: URAT1抑制剂结构中都存在羧基、酚羟基或是三氟甲基磺酰胺等在体内正常生理情况下可以去离子化形成一个阴离子中心的结构单元, 而此阴离子中心是URAT1抑制剂保持活性的必需药效团。因此, 本文以目前处于临床Ⅱ期的URAT1抑制剂URC-102为模板, 设计得到了一系列URC-102的类似物(图 2)。首先通过生物电子等排将URC-102结构中的吡啶环替换为苯环, 并将吗啉环替换为哌啶环或吡咯烷环, 以实现骨架跃迁。进一步对N-苯甲酰基进行衍生化, 依据药效团要求, 在苯环上引入羧基(8)、酚羟基(9)或三氟甲基磺酰胺(10a、10c、10e及10g)等可形成阴离子的片段, 然后将三氟甲基磺酰胺结构替换为三氟乙酰胺(10b、10d、10f及10h)和甲基磺酰胺(10i)。本文共设计合成了14个URC-102类似物, 并初步研究了该类化合物的构效关系。

采用三条不同的合成路线得到了14个URC-102类似物。如路线1所示, 目标化合物8a、8b、9a~9c均由四氢喹啉(1a)与相应的苯甲酸衍生物形成酰胺(中间体2和5), 并进一步水解得到。化合物10a~10i则由四氢喹啉(1a)或吲哚啉(1b)与硝基苯甲酸形成酰胺类化合物(6), 并经Pd-C催化下的氢化还原得到7, 化合物7通过N-酰化得到化合物10b、10d、10f和10h, N-磺酰化得到10a、10c、10e、10g和10i。

结果与讨论

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1 目标化合物的结构确证

采用上述合成路线共合成了14个URC-102衍生物, 除化合物9c外, 所有化合物均未见文献报道。目标化合物结构均经¹H NMR和HR-ESI-MS确证, 其理化性质和谱学数据见表 1和表 2。

2 目标化合物的URAT1抑制活性

本文以雷西纳德和苯溴马隆为阳性对照, 测定了所有目标化合物在10 μmol·L^-1浓度下对URAT1的抑制活性, 对部分活性较好的化合物测试了其IC₅₀值。活性结果如表 3所示。

由表 3可知:将URC-102结构中的吡啶环和吗啉环分别替换为苯环和哌啶环, 对URAT1的抑制活性影响不大(URC-102 vs 9b), 将吡啶环进一步缩环为吡咯烷环, 活性依旧保持(10a vs 10c; 10e vs 10g)。但N-苯甲酰基结构中苯环上的取代基对活性有至关重要的影响, 取代基的类型及取代基位置都能显著影响此类化合物对URAT1的抑制强度。苯环上为羧基取代时, 无论羧基在苯环的间位(8a)还是对位(8b), 其活性都较差; 苯环上存在酚羟基时, 含有双卤素取代的化合物活性优于单卤素取代的化合物(9b vs 9a), 且双溴取代优于双氯取代(9b vs 9c); 苯环上为三氟甲基磺酰胺基取代时活性较好(10a、10c、10e及10g), 若替换为三氟乙酰胺基(10b、10d、10f及10h)和甲基磺酰胺基(10i)则活性丧失; 三氟甲磺酰胺基间位取代时活性优于邻位取代(10e vs 10a, 10g vs 10c)。

3 小结

本文以处于Ⅱ期临床研究的URC-102分子为模板, 通过生物电子等排及骨架跃迁的策略, 设计合成了14个目标化合物, 并测定了它们对URAT1的抑制活性。其中4个化合物(9b、9c、10e、10g)显示出较好的抑制率, 化合物9b对URAT1的半数抑制浓度IC₅₀达到0.061 μmol·L^-1, 活性优于雷西纳德和苯溴马隆。初步的构效关系研究表明, URC-102结构中的吡啶并吗啉环结构允许一定的结构变化(如:可替换为苯环并哌啶环及苯环并吡咯烷环), 但N-苯甲酰基结构中苯环上的取代基(包括取代基的类型及取代基位置)对活性有至关重要的影响。苯环上存在可形成阴离子中心的取代基为保持URAT1抑制作用的必要但不充分条件。上述构效关系为URAT1小分子抑制剂的发现和结构优化提供了参考。

实验部分

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熔点采用Fisher Scientific显微熔点仪测定, 温度未校正, 核磁氢谱采用VarianMercury 400型核磁共振仪测定, TMS为内标。质谱采用LC/MDC-MS串联质谱仪(Thermo, USA)测定。柱色谱分离采用硅胶H (200~300目), 薄层色谱硅胶为烟台江友硅胶开发有限公司所产的GF 254型硅胶板。实验所用试剂为化学纯或分析纯, 购买后未作进一步处理, 直接使用。所用溶剂均为分析纯, 其中无水溶剂均经美国创新科技(Innovative Technology)无水溶剂纯化系统除水后使用, 其他溶剂未特别指出则未经处理。

1 化合物的合成

1.1 中间体2a的制备

将间羧基苯甲酸甲酯(216 mg, 1.2 mmol)溶于无水二氯甲烷5 mL中, 加入3滴DMF, 然后缓慢加入草酰氯(254 mg, 2.0 mmol)室温反应1 h。减压浓缩除去反应溶剂和过量的草酰氯, 再将其溶于无水二氯甲烷5 mL中备用。将原料1a (133 mg, 1.0 mmol)溶解于无水二氯甲烷中, 加入三乙胺(202 mg, 2.0 mmol), 然后在冰浴下缓慢加入上述制备的酰氯, 室温下反应2 h。TLC监测反应完全, 将反应液用50 mL二氯甲烷稀释, 然后水洗, 有机相用无水硫酸钠干燥, 蒸除溶剂后柱色谱分离(石油醚-乙酸乙酯10:1)得到化合物2a, 收率: 61%。¹H NMR (400 MHz, CDCl₃) δ 8.10~8.06 (m, 1H), 8.03~7.96 (m, 1H), 7.48~7.41 (m, 1H), 7.35~7.27 (m, 1H), 7.14 (t, J = 6.8 Hz, 1H), 7.01~6.93 (m, 1H), 6.88~6.78 (m, 1H), 6.66 (brs, 1H), 3.93~3.81 (m, 5H), 2.88~2.80 (m, 2H), 2.10~1.97 (m, 2H)。

采用类似方法合成了中间体2b、5及6。

1.2 中间体4c的制备

将化合物3c (2 070 mg, 10 mmol)加入无水四氢呋喃30 mL中, 加入三乙胺(1 515 mg, 15 mmol), 然后在冰浴下缓慢加入乙酰氯(942 mg, 12 mmol), 室温下反应2 h。TLC监测反应完全, 向反应液中缓慢加入冰水50 mL将其淬灭, 然后用乙酸乙酯萃取3次, 饱和氯化钠洗1次, 有机相用无水硫酸钠干燥, 减压浓缩得到化合物4c, 可直接用于下一步, 收率: 92%。¹H NMR (400 MHz, DMSO-d₆) δ 13.71 (s, 1H), 8.03 (s, 2H), 2.45 (s, 3H)。

采用类似的方法合成了中间体4a、4b。

1.3 中间体5c的制备

制备方法与中间体2a的类似, 不同之处在于将原料相应的替换, 收率: 56%。HR-MS (ESI) m/z: Calcd. for C₁₈H₁₆Cl₂NO₃[M+H]⁺ 364.044 1, Found 364.043 2。

采用类似的方法合成了中间体5a、5b。

1.4 中间体7的制备

将化合物6 (268 mg, 1.0 mmol)加入甲醇5 mL中, 然后缓慢加入10%钯碳50 mg, 将反应体系用氢气置换3次, 室温反应4 h。TLC监测反应完全, 将反应液用硅藻土过滤, 减压浓缩干燥得到化合物7, 可直接用于下一步。

1.5 目标化合物8a的制备

将化合物2a (295 mg, 1.0 mmol)加入四氢呋喃-甲醇-水(2:2:1)的混合溶剂10 mL中, 然后加入氢氧化钠(80 mg, 2.0 mmol), 室温反应2 h。TLC监测反应完全, 减压浓缩除去反应体系中大部分的有机溶剂, 然后加水稀释, 用1 mol·L^-1盐酸缓慢调节pH至3~4, 析出固体, 抽滤干燥得粗品, 然后用乙醇-水体系重结晶得到目标化合物3a。

采用类似方法合成了8b、9a、9b、9c。目标化合物8a、8b、9a、9b、9c的理化性质和谱学数据见表 1和2。

1.6 目标化合物10g的制备

将相应的中间体7 (119 mg, 0.5 mmol)加入无水二氯甲烷5 mL中, 再加入吡啶(79 mg, 1.0 mmol), 然后在冰浴下缓慢滴加三氟甲磺酸酐(169 mg, 0.6 mmol), 室温反应2 h。TLC监测反应完全, 将反应液用二氯甲烷稀释, 水洗, 无水硫酸钠干燥, 减压浓缩, 柱色谱分离(石油醚-乙酸乙酯5:1)得到目标化合物10g。

采用类似方法合成了10a~10f、10h、10i。目标化合物10a~10i的理化性质和谱学数据见表 1和2。

2 体外URAT1抑制活性实验

培养稳定表达hURAT1的HEK-293T细胞株(DMEM培养基+10%胎牛血清+500 μg·mL^-1 G418+1% P/S), 将细胞接种到96孔细胞培养板中, 培养12~24 h。化合物用DMSO配成10 mmol·L^-1浓度的母液, 再用缓冲液稀释成1 mmol·L^-1, 进一步进行4倍等比稀释。待96孔板中细胞培养贴壁后即可进行¹⁴C-尿酸在稳定表达hURAT1细胞中的吸收试验。每孔加入50 μL相应化合物和0.1 Ci·mL^-114C-尿酸溶液, 在37 ℃培养箱中孵育5 min后, 立即加入150 μL冰冷的缓冲液以终止吸收。每孔加入50 μL的裂解液到所有孔中, 置于振荡器上以900 r·min^-1的速度振荡5 min; 每孔加入150 μL闪烁液Microsint 40, 以900 r·min^-1的速度振荡5 min; 采用MicroBeta Trilux (PerkinElmer公司生产)仪器测定放射活性, 并用XL-fit软件进行分析数据。

基金

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国家自然科学基金资助项目(21871295)

参考文献

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doi: 10.16438/j.0513-4870.2019-0208

接收时间：2019-03-27
首发时间：2026-01-26
出版时间：2019-06-12

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收稿日期：2019-03-27
修回日期：2019-04-15

基金

国家自然科学基金资助项目(21871295)

作者信息

中国医学科学院、北京协和医学院药物研究所, 活性物质发现与适药化研究北京市重点实验室, 北京 100050

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*肖志艳，Tel / Fax: 86-10-63189228, E-mail: xiaoz@imm.ac.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/°C	HR-ESI-MS (m/z)
8a	62	180-182	282.112 0	282.112 5
8b	58	166-168	282.112 0	282.112 5
9a	71	155-158	332.027 4	332.028 1
9b	65	221-223	409.939 1	409.938 6
9c	61	208-210	322.039 7	322.039 6
10a	52	141-143	385.082 0	385.082 8
10b	69	156-158	349.115 0	349.115 8
10c	44	165-166	371.066 5	371.067 2
10d	58	136-137	335.099 2	335.100 2
10e	67	183-184	385.082 2	385.082 8
10f	51	153-156	349.115 4	349.115 8
10g	39	171-172	371.066 5	371.067 2
10h	56	193-195	335.099 5	335.100 2
10i	37	150-151	317.095 0	317.095 4

Compd.

Yield/%

mp/°C

HR-ESI-MS (m/z)

Found [M+H]⁺

Calcd. [M+H]⁺

180-182

282.112 0

282.112 5

166-168

282.112 0

282.112 5

155-158

332.027 4

332.028 1

221-223

409.939 1

409.938 6

208-210

322.039 7

322.039 6

10a

141-143

385.082 0

385.082 8

10b

156-158

349.115 0

349.115 8

10c

165-166

371.066 5

371.067 2

10d

136-137

335.099 2

335.100 2

10e

183-184

385.082 2

385.082 8

10f

153-156

349.115 4

349.115 8

10g

171-172

371.066 5

371.067 2

10h

193-195

335.099 5

335.100 2

10i

150-151

317.095 0

317.095 4

Compd.	¹H NMR and ¹³C NMR data
8a	¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.90 (s, 1H), 7.52 (d, J = 6.9 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.1 Hz, 1H), 7.00 (t, J = 7.1 Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 6.76 (s, 1H), 3.76 (t, J = 5.8 Hz, 2H), 2.82 (t, J = 5.8 Hz, 2H), 1.96 (t, J = 5.8 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.44, 166.68, 138.63, 136.89, 132.39, 131.69, 130.82, 130.69, 129.00, 128.54, 128.53, 125.52, 125.13, 124.57, 44.46, 26.28, 23.65.
8b	¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.4 Hz, 1H), 7.00 (t, J = 7.7 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.75 (s, 1H), 3.75 (t, J = 6.4 Hz, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.00-1.90 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.53, 166.76, 140.71, 138.49, 131.72, 129.17 (2C), 128.56, 128.23 (2C), 125.52 (2C), 125.03, 124.64, 44.38, 26.25, 23.58.
9a	¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.12 (dd, J = 2.1, 8.4 Hz, 1H), 7.00 (td, J = 1.2, 7.4 Hz, 1H), 6.93 (td, J = 1.5, 7.9 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 3.73 (t, J = 6.4 Hz, 2H), 2.79 (t, J = 6.6 Hz, 2H), 1.99-1.88 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.80, 155.79, 139.16, 133.48, 131.39, 129.46, 128.47, 128.27, 125.51, 124.96, 124.24, 115.47, 108.66, 44.45, 26.27, 23.70.
9b	¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 7.44 (s, 2H), 7.21 (d, J = 7.3 Hz, 1H), 7.03 (td, J = 1.3, 7.4 Hz, 1H), 6.96 (td, J = 1.6, 7.8 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 3.73 (t, J = 6.5 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 1.99-1.89 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.23, 152.28, 138.66, 132.59 (2C), 131.72, 130.12, 128.50, 125.56, 125.06, 124.58, 111.04 (2C), 44.53, 26.24, 23.61.
9c^[15]	¹H NMR (400 MHz, DMSO-d₆) δ 10.70 (s, 1H), 7.27 (s, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.03 (td, J = 1.3, 7.4 Hz, 1H), 6.95 (td, J = 1.6, 7.8 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 3.73 (t, J = 6.5 Hz, 2H), 2.81 (t, J = 6.6 Hz, 2H), 2.00-1.88 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.55, 150.66, 138.69, 131.72, 128.91 (2C), 128.72, 128.51, 125.57, 125.02, 124.56, 121.58 (2C), 44.51, 26.24, 23.60.
10a	¹H NMR (400 MHz, Acetone-d₆) δ 10.13 (s, 1H), 7.59-7.47 (m, 2H), 7.26-7.20 (m, 3H), 7.06-6.91 (m, 3H), 3.84 (t, J = 6.4 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H), 2.08-2.02 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 168.73, 138.45, 135.67, 132.14, 131.97, 130.15, 128.87, 126.28, 125.84, 125.62, 125.26, 124.95, 122.94, 119.92 (q, J = 323.0 Hz), 44.97, 26.87, 24.01.
10b	¹H NMR (400 MHz, DMSO-d₆) δ 11.29 (s, 1H), 7.51-7.41 (m, 2H), 7.35-7.05 (m, 4H), 6.99 (t, J = 7.3 Hz, 1H), 6.96-6.83 (m, 1H), 3.70 (brs, 2H), 2.79 (t, J = 6.6 Hz, 2H), 1.97-1.90 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.83, 154.94 (q, J = 37.0 Hz), 138.27, 132.87, 130.35 (2C), 129.16, 128.52, 126.63, 126.09, 125.35 (2C), 124.53, 124.36, 115.90 (q, J = 288.6 Hz), 39.52, 26.33, 23.21.
10c	¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (d, J = 8.2 Hz, 1H), 7.56-7.44 (m, 2H), 7.41-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.11-7.03 (m, 1H), 3.82 (t, J = 8.4 Hz, 2H), 3.04 (t, J = 8.4 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.37, 142.64, 135.24, 132.74, 130.52, 127.75, 127.63, 127.02 (2C), 124.96 (2C), 124.08, 119.69 (q, J = 325.2 Hz), 116.75, 49.83, 27.70.
10d	¹H NMR (400 MHz, DMSO-d₆) δ 11.32 (s, 1H), 8.04 (d, J = 6.4 Hz, 1H), 7.64 (d, J = 6.4 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 7.1 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.21 (brs, 1H), 7.11-6.76 (m, 1H), 3.97 (t, J = 8.2 Hz, 2H), 3.07 (t, J = 8.2 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.99, 155.16 (q, J = 36.8 Hz), 142.79, 132.72, 131.87, 130.34, 127.67, 127.08 (2C), 126.99, 126.28, 124.93, 123.99, 116.81, 115.87 (q, J = 288.5 Hz), 50.16, 27.83.
10e	¹H NMR (400 MHz, CDCl₃) δ 9.65 (s, 1H), 7.61 (s, 1H), 7.41 (ddd, J = 0.8, 2.2, 8.2 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 7.05 (td, J = 1.0, 7.5 Hz, 1H), 6.89 (t, J = 6.3 Hz, 2H), 6.66 (brs, 1H), 3.95 (t, J = 6.6 Hz, 2H), 2.85 (t, J = 6.6 Hz, 2H), 2.12-2.04 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.23, 138.58, 137.87, 135.02, 131.72, 129.57, 128.47, 125.97, 125.51, 124.87, 124.59, 123.71, 121.83, 119.65 (q, J = 324.1 Hz), 44.37, 26.21, 23.63.
10f	¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 7.79 (t, J = 1.7 Hz, 1H), 7.72 (dd, J = 1.6, 7.8 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 7.01 (td, J = 1.0, 7.4 Hz, 1H), 6.97-6.89 (m, 1H), 6.83 (d, J = 7.4 Hz, 1H), 3.75 (t, J = 6.4 Hz, 2H), 2.81 (t, J = 6.6 Hz, 2H), 1.99-1.91 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.68, 154.58 (q, J = 37.0 Hz), 138.67, 137.36, 136.49, 131.44, 128.82, 128.57, 125.52, 125.05, 124.90, 124.49, 122.27, 120.53, 115.71 (q, J = 288.7 Hz), 44.63, 26.25, 23.62.
10g	¹H NMR (400 MHz, Acetone-d₆) δ 10.44 (brs, 1H), 8.10 (brs, 1H), 7.62-7.53 (m, 4H), 7.26 (d, J = 8.6 Hz, 1H), 7.16 (s, 1H), 7.04 (t, J = 7.4 Hz, 1H), 4.06 (t, J = 8.3 Hz, 2H), 3.14 (t, J = 8.3 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 168.67, 141.94, 137.40, 135.64, 132.43, 129.94, 127.91, 125.52, 125.46, 124.99, 124.56, 122.29, 120.01 (q, J = 322.9 Hz), 118.42, 51.42, 28.50.
10h	¹H NMR (400 MHz, DMSO-d₆) δ 11.42 (s, 1H), 8.07 (brs, 1H), 7.88 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.56-7.51 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.18 (brs, 1H), 7.07-7.01 (m, 1H), 4.01 (t, J = 8.2 Hz, 2H), 3.09 (t, J = 8.2 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.28, 154.70 (q, J = 37.1 Hz), 142.52, 137.68, 136.52, 132.75, 129.34, 126.91, 125.07, 124.05 (2C), 122.57, 119.55 (2C), 115.75 (q, J = 288.7 Hz), 50.45, 27.77.
10i	¹H NMR (400 MHz, CDCl₃) δ 8.22 (brs, 1H), 7.55 (s, 1H), 7.47-7.37 (m, 3H), 7.36-7.29 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.04 (brs, 1H), 4.05 (brs, 2H), 3.12 (t, J = 8.2 Hz, 2H), 2.98 (s, 3H). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.48, 142.60, 138.66, 138.03, 132.81, 129.63, 126.89, 125.08, 123.98, 122.02, 120.95, 117.75, 116.88, 50.53, 50.38, 27.72.

Compd.

¹H NMR and ¹³C NMR data

¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.90 (s, 1H), 7.52 (d, J = 6.9 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.1 Hz, 1H), 7.00 (t, J = 7.1 Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 6.76 (s, 1H), 3.76 (t, J = 5.8 Hz, 2H), 2.82 (t, J = 5.8 Hz, 2H), 1.96 (t, J = 5.8 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.44, 166.68, 138.63, 136.89, 132.39, 131.69, 130.82, 130.69, 129.00, 128.54, 128.53, 125.52, 125.13, 124.57, 44.46, 26.28, 23.65.

¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.4 Hz, 1H), 7.00 (t, J = 7.7 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.75 (s, 1H), 3.75 (t, J = 6.4 Hz, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.00-1.90 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.53, 166.76, 140.71, 138.49, 131.72, 129.17 (2C), 128.56, 128.23 (2C), 125.52 (2C), 125.03, 124.64, 44.38, 26.25, 23.58.

¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.12 (dd, J = 2.1, 8.4 Hz, 1H), 7.00 (td, J = 1.2, 7.4 Hz, 1H), 6.93 (td, J = 1.5, 7.9 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 3.73 (t, J = 6.4 Hz, 2H), 2.79 (t, J = 6.6 Hz, 2H), 1.99-1.88 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.80, 155.79, 139.16, 133.48, 131.39, 129.46, 128.47, 128.27, 125.51, 124.96, 124.24, 115.47, 108.66, 44.45, 26.27, 23.70.

¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 7.44 (s, 2H), 7.21 (d, J = 7.3 Hz, 1H), 7.03 (td, J = 1.3, 7.4 Hz, 1H), 6.96 (td, J = 1.6, 7.8 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 3.73 (t, J = 6.5 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 1.99-1.89 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.23, 152.28, 138.66, 132.59 (2C), 131.72, 130.12, 128.50, 125.56, 125.06, 124.58, 111.04 (2C), 44.53, 26.24, 23.61.

9c^[15]

¹H NMR (400 MHz, DMSO-d₆) δ 10.70 (s, 1H), 7.27 (s, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.03 (td, J = 1.3, 7.4 Hz, 1H), 6.95 (td, J = 1.6, 7.8 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 3.73 (t, J = 6.5 Hz, 2H), 2.81 (t, J = 6.6 Hz, 2H), 2.00-1.88 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.55, 150.66, 138.69, 131.72, 128.91 (2C), 128.72, 128.51, 125.57, 125.02, 124.56, 121.58 (2C), 44.51, 26.24, 23.60.

10a

¹H NMR (400 MHz, Acetone-d₆) δ 10.13 (s, 1H), 7.59-7.47 (m, 2H), 7.26-7.20 (m, 3H), 7.06-6.91 (m, 3H), 3.84 (t, J = 6.4 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H), 2.08-2.02 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 168.73, 138.45, 135.67, 132.14, 131.97, 130.15, 128.87, 126.28, 125.84, 125.62, 125.26, 124.95, 122.94, 119.92 (q, J = 323.0 Hz), 44.97, 26.87, 24.01.

10b

¹H NMR (400 MHz, DMSO-d₆) δ 11.29 (s, 1H), 7.51-7.41 (m, 2H), 7.35-7.05 (m, 4H), 6.99 (t, J = 7.3 Hz, 1H), 6.96-6.83 (m, 1H), 3.70 (brs, 2H), 2.79 (t, J = 6.6 Hz, 2H), 1.97-1.90 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.83, 154.94 (q, J = 37.0 Hz), 138.27, 132.87, 130.35 (2C), 129.16, 128.52, 126.63, 126.09, 125.35 (2C), 124.53, 124.36, 115.90 (q, J = 288.6 Hz), 39.52, 26.33, 23.21.

10c

¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (d, J = 8.2 Hz, 1H), 7.56-7.44 (m, 2H), 7.41-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.11-7.03 (m, 1H), 3.82 (t, J = 8.4 Hz, 2H), 3.04 (t, J = 8.4 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.37, 142.64, 135.24, 132.74, 130.52, 127.75, 127.63, 127.02 (2C), 124.96 (2C), 124.08, 119.69 (q, J = 325.2 Hz), 116.75, 49.83, 27.70.

10d

¹H NMR (400 MHz, DMSO-d₆) δ 11.32 (s, 1H), 8.04 (d, J = 6.4 Hz, 1H), 7.64 (d, J = 6.4 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 7.1 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.21 (brs, 1H), 7.11-6.76 (m, 1H), 3.97 (t, J = 8.2 Hz, 2H), 3.07 (t, J = 8.2 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 165.99, 155.16 (q, J = 36.8 Hz), 142.79, 132.72, 131.87, 130.34, 127.67, 127.08 (2C), 126.99, 126.28, 124.93, 123.99, 116.81, 115.87 (q, J = 288.5 Hz), 50.16, 27.83.

10e

¹H NMR (400 MHz, CDCl₃) δ 9.65 (s, 1H), 7.61 (s, 1H), 7.41 (ddd, J = 0.8, 2.2, 8.2 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 7.05 (td, J = 1.0, 7.5 Hz, 1H), 6.89 (t, J = 6.3 Hz, 2H), 6.66 (brs, 1H), 3.95 (t, J = 6.6 Hz, 2H), 2.85 (t, J = 6.6 Hz, 2H), 2.12-2.04 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.23, 138.58, 137.87, 135.02, 131.72, 129.57, 128.47, 125.97, 125.51, 124.87, 124.59, 123.71, 121.83, 119.65 (q, J = 324.1 Hz), 44.37, 26.21, 23.63.

10f

¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 7.79 (t, J = 1.7 Hz, 1H), 7.72 (dd, J = 1.6, 7.8 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 7.01 (td, J = 1.0, 7.4 Hz, 1H), 6.97-6.89 (m, 1H), 6.83 (d, J = 7.4 Hz, 1H), 3.75 (t, J = 6.4 Hz, 2H), 2.81 (t, J = 6.6 Hz, 2H), 1.99-1.91 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.68, 154.58 (q, J = 37.0 Hz), 138.67, 137.36, 136.49, 131.44, 128.82, 128.57, 125.52, 125.05, 124.90, 124.49, 122.27, 120.53, 115.71 (q, J = 288.7 Hz), 44.63, 26.25, 23.62.

10g

¹H NMR (400 MHz, Acetone-d₆) δ 10.44 (brs, 1H), 8.10 (brs, 1H), 7.62-7.53 (m, 4H), 7.26 (d, J = 8.6 Hz, 1H), 7.16 (s, 1H), 7.04 (t, J = 7.4 Hz, 1H), 4.06 (t, J = 8.3 Hz, 2H), 3.14 (t, J = 8.3 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 168.67, 141.94, 137.40, 135.64, 132.43, 129.94, 127.91, 125.52, 125.46, 124.99, 124.56, 122.29, 120.01 (q, J = 322.9 Hz), 118.42, 51.42, 28.50.

10h

¹H NMR (400 MHz, DMSO-d₆) δ 11.42 (s, 1H), 8.07 (brs, 1H), 7.88 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.56-7.51 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.18 (brs, 1H), 7.07-7.01 (m, 1H), 4.01 (t, J = 8.2 Hz, 2H), 3.09 (t, J = 8.2 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.28, 154.70 (q, J = 37.1 Hz), 142.52, 137.68, 136.52, 132.75, 129.34, 126.91, 125.07, 124.05 (2C), 122.57, 119.55 (2C), 115.75 (q, J = 288.7 Hz), 50.45, 27.77.

10i

¹H NMR (400 MHz, CDCl₃) δ 8.22 (brs, 1H), 7.55 (s, 1H), 7.47-7.37 (m, 3H), 7.36-7.29 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.04 (brs, 1H), 4.05 (brs, 2H), 3.12 (t, J = 8.2 Hz, 2H), 2.98 (s, 3H). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.48, 142.60, 138.66, 138.03, 132.81, 129.63, 126.89, 125.08, 123.98, 122.02, 120.95, 117.75, 116.88, 50.53, 50.38, 27.72.

Compd.	Inhibition/10^-5 mol·L^-1	IC₅₀/10^-6 mol·L^-1
8a	NA	ND
8b	NA	ND
9a	68%	ND
9b	99%	0.061
9c^*	94%	0.182
10a	62%	ND
10b	NA	ND
Lesinurad	ND	39
URC-102	ND	0.023^[16]
10c	47%	ND
10d	NA	ND
10e	82%	1.51
10f	NA	ND
10g	77%	2.19
10h	NA	ND
10i	NA	ND
Benzbromarone	ND	0.49

Compd.

Inhibition/10^-5 mol·L^-1

IC₅₀/10^-6 mol·L^-1

68%

99%

0.061

9c^*

94%

0.182

10a

62%

10b

Lesinurad

URC-102

0.023^[16]

10c

47%

10d

10e

82%

1.51

10f

10g

77%

2.19

10h

10i

Benzbromarone

0.49