药学学报

Compd.	Appearance	Yield/%	mp/℃
Ⅲa	White solid	66	161-162
Ⅲb	White solid	68	165-166
Ⅲc	White solid	70	179-180
Ⅲd	White solid	75	171-172
Ⅲe	White solid	80	167-169
Ⅲf	White solid	87	169-170
Ⅲg	White solid	78	222-224
Ⅲh	White solid	65	213-214
Ⅲi	White solid	80	214-215
Ⅲj	White solid	61	192-193
Ⅲk	White solid	90	187-188
Ⅲl	White solid	89	182-183
Ⅲm	White solid	68	185-187
Ⅲn	White solid	69	188-189
Ⅲo	White solid	60	188-190

Compd.

Appearance

Yield/%

mp/℃

Ⅲa

White solid

161-162

Ⅲb

White solid

165-166

Ⅲc

White solid

179-180

Ⅲd

White solid

171-172

Ⅲe

White solid

167-169

Ⅲf

White solid

169-170

Ⅲg

White solid

222-224

Ⅲh

White solid

213-214

Ⅲi

White solid

214-215

Ⅲj

White solid

192-193

Ⅲk

White solid

187-188

Ⅲl

White solid

182-183

Ⅲm

White solid

185-187

Ⅲn

White solid

188-189

Ⅲo

White solid

188-190

Compd.	Appearance	Yield/%	mp/℃
Ⅲa	White solid	66	161-162
Ⅲb	White solid	68	165-166
Ⅲc	White solid	70	179-180
Ⅲd	White solid	75	171-172
Ⅲe	White solid	80	167-169
Ⅲf	White solid	87	169-170
Ⅲg	White solid	78	222-224
Ⅲh	White solid	65	213-214
Ⅲi	White solid	80	214-215
Ⅲj	White solid	61	192-193
Ⅲk	White solid	90	187-188
Ⅲl	White solid	89	182-183
Ⅲm	White solid	68	185-187
Ⅲn	White solid	69	188-189
Ⅲo	White solid	60	188-190

Compd.

Appearance

Yield/%

mp/℃

Ⅲa

White solid

161-162

Ⅲb

White solid

165-166

Ⅲc

White solid

179-180

Ⅲd

White solid

171-172

Ⅲe

White solid

167-169

Ⅲf

White solid

169-170

Ⅲg

White solid

222-224

Ⅲh

White solid

213-214

Ⅲi

White solid

214-215

Ⅲj

White solid

192-193

Ⅲk

White solid

187-188

Ⅲl

White solid

182-183

Ⅲm

White solid

185-187

Ⅲn

White solid

188-189

Ⅲo

White solid

188-190

Compd.	¹H NMR, ¹³C NMR and MS
Ⅲa	¹H NMR (400 MHz, CDCl₃) δ: 9.28 (s, 1H, CONH), 7.49 (d, 2H, J = 8.0 Hz, ArH), 7.32-7.37 (m, 3H, ArH), 6.63 (s, 1H, ArH), 6.30 (s, 2H, NH₂), 5.70 (dd, 1H, J = 8.0, 8.0 Hz, PCH), 3.88 (s, 3H, CH₃), 3.73 (d, 3H, J = 8.0 Hz, CH₃), 3.65 (d, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 169.9, 163.3, 160.7, 148.3, 142.3, 133.7, 132.6, 128.2, 128.0, 127.9, 110.1, 61.5, 53.2, 53.0, 48.4. ESI MS (m/z): 399.1 [M+H]⁺.
Ⅲb	¹H NMR (400 MHz, CDCl₃) δ: 9.21 (s, 1H, CONH), 7.62 (t, 1H, J=12.0 Hz, ArH), 7.33-7.36 (m, 1H, ArH), 7.18-7.23 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.32 (s, 2H, NH₂), 5.84 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.73 (s, 3H, CH₃), 3.65 (d, 3H, J = 12.0 Hz, CH₃), 3.53 (d, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.8, 162.6, 160.7 (J_C-F = 77 Hz), 158.4, 149.4, 143.3, 130.5, 125.0, 122.7, 115.7, 115.6, 109.8, 62.3, 55.3, 54.2, 53.7. ESI MS (m/z): 417.1 [M+H]⁺.
Ⅲc	¹H NMR (400 MHz, CDCl₃) δ: 9.29 (s, 1H, CONH), 7.51 (d, J = 16.0 Hz, 2H, ArH), 7.08-7.13 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.28 (s, 2H, NH₂), 5.70 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.88 (s, 3H, CH₃), 3.74 (d, 3H, J = 12.0 Hz, CH₃), 3.67 (d, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 170.0, 163.9, 163.2 (J_C-F = 12 Hz), 161.4, 148.3, 142.3, 130.1, 130.0, 115.1, 114.9, 110.0, 61.5, 53.3, 53.0, 49.3. ESI MS (m/z): 417.1 [M+H]⁺.
Ⅲd	¹H NMR (400 MHz, CDCl₃) δ: 9.26 (s, 1H, CONH), 7.49 (d, 2H, J = 8.0 Hz, ArH), 7.34-7.37 (m, 3H, ArH), 6.63 (s, 1H, ArH), 6.32 (s, 2H, NH₂), 5.64 (dd, 1H, J = 8.0, 8.0 Hz, PCH), 3.92-4.01 (m, 4H, 2CH₂), 3.89 (s, 3H, CH₃), 1.25 (t, 3H, J = 12.0 Hz, CH₃), 1.18 (t, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 169.8, 163.3, 161.6, 148.3, 142.4, 133.9, 132.8, 128.2, 128.1, 127.9, 110.2, 63.5, 63.3, 61.5, 50.6, 15.3, 15.1. ESI MS (m/z): 427.1 [M+H]⁺.
Ⅲe	¹H NMR (400 MHz, CDCl₃) δ: 9.23 (s, 1H, CONH), 7.62 (t, 1H, J = 8.0 Hz, ArH), 7.33-7.35 (m, 1H, ArH), 7.11-7.20 (m, 2H, ArH), 6.59 (s, 1H, ArH), 6.33 (s, 2H, NH₂), 5.79 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.82-4.02 (m, 4H, 2CH₂), 3.72 (s, 3H, CH₃), 1.16 (t, 3H, J = 12.0 Hz, CH₃), 1.03 (t, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.8, 162.7, 160.9 (J_C-F = 98 Hz), 158.5, 149.4, 143.4, 130.6, 124.9, 122.8, 115.6, 115.4, 109.9, 63.3, 63.0, 62.3, 53.7, 16.7, 16.5. ESI MS (m/z): 445.2 [M+H]⁺.
Ⅲf	¹H NMR (400 MHz, CDCl₃) δ: 9.28 (s, 1H, CONH), 7.50-7.54 (m, 2H, ArH), 7.08-7.13 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.31 (s, 2H, NH₂), 5.64 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.99-4.12 (m, 4H, 2CH₂), 3.90 (s, 3H, CH₃), 1.25 (d, 3H, J = 16.0 Hz, CH₃), 1.20 (d, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.7, 163.2, 162.5 (J_C-F = 9 Hz), 160.6, 149.5, 143.5, 130.8, 130.7, 115.5, 115.3, 109.9, 63.1, 62.9, 62.3, 48.2, 16.6, 16.5. ESI MS (m/z): 445.1 [M+H]⁺.
Ⅲg	¹H NMR (400 MHz, CDCl₃) δ: 9.66 (s, 1H, CONH), 7.46-7.48 (m, 2H, ArH), 7.27-7.34 (m, 3H, ArH), 6.61 (s, 1H, ArH), 6.33 (s, 2H, NH₂), 5.49 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.63-4.75 (m, 1H, CH), 4.49-4.57 (m, 1H, CH), 3.75 (s, 3H, CH₃), 1.07-1.36 (m, 12H, 4CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.7, 162.6, 161.4, 143.6, 135.4, 128.8, 128.7, 128.5, 128.1, 114.9, 109.9, 72.8, 72.6, 61.5, 56.5, 23.0, 22.9, 22.7, 22.2. ESI MS (m/z): 455.2 [M+H]⁺.
Ⅲh	¹H NMR (400 MHz, CDCl₃) δ: 9.25 (s, 1H, CONH), 7.58-7.62 (m, 1H, ArH), 7.33-7.37 (m, 1H, ArH), 7.11-7.21 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.31 (s, 2H, NH₂), 5.94 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 4.69-4.73 (m, 1H, CH), 4.50-4.55 (m, 1H, CH), 3.85 (s, 3H, CH₃), 1.07-1.34 (m, 12H, 4CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 169.9, 163.3, 161.3 (J_C-F = 74 Hz), 158.8, 148.4, 142.3, 130.0, 129.7, 124.0, 114.9, 110.2, 72.8, 72.5, 61.5, 56.5, 23.0, 22.9, 22.7, 22.2. ESI MS (m/z): 473.2 [M+H]⁺.
Ⅲi	¹H NMR (400 MHz, CDCl₃) δ: 9.01 (s, 1H, CONH), 7.58-7.61 (m, 2H, ArH), 6.95-6.99 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.22 (s, 2H, NH₂), 5.60 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.68-4.74 (m, 1H, CH), 4.24-4.32 (m, 1H, CH), 3.69 (s, 3H, CH₃), 1.18-1.38 (m, 12H, 4CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 163.8, 161.6 (J_C-F = 7 Hz), 161.3, 147.0, 143.6, 131.4, 129.6, 115.3, 115.1, 110.5, 73.2, 72.3, 61.9, 58.3, 24.2, 24.1, 23.9, 22.9. ESI MS (m/z): 473.2 [M+H]⁺.
Ⅲj	¹H NMR (400 MHz, CDCl₃) δ: 9.25 (s, 1H, CONH), 7.63 (d, 2H, J = 8.0 Hz, ArH), 7.22-7.30 (m, 3H, ArH), 6.63 (s, 1H, ArH), 6.26 (s, 2H, NH₂), 5.70 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.05-4.27 (m, 2H, CH₂), 3.46-3.75 (m, 2H, CH₂), 3.22 (s, 3H, CH₃), 1.65-1.72 (m, 2H, CH₂), 1.38-1.45 (m, 2H, CH₂), 1.30-1.35 (m, 2H, CH₂), 1.09-1.22 (m, 2H, CH₂), 0.89 (t, 3H, J = 16.0 Hz, CH₃), 0.74 (t, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 163.3, 161.9, 146.9, 143.8, 133.0, 128.2, 126.6, 125.3, 122.6, 110.1, 67.5, 67.3, 61.9, 49.0, 32.4, 32.2, 18.7, 18.4, 13.6, 13.4. ESI MS (m/z): 483.2 [M+H]⁺.
Ⅲk	¹H NMR (400 MHz, CDCl₃) δ: 9.17 (s, 1H, CONH), 7.31-7.46 (m, 1H, ArH), 7.21-7.26 (m, 1H, ArH), 7.10-7.14 (m, 1H, ArH), 6.98-7.02 (m, 1H, ArH), 6.67 (s, 1H, ArH), 6.16-6.23 (m, 3H, PCH+NH₂), 4.08-4.36 (m, 2H, CH₂), 3.60-3.72 (m, 2H, CH₂), 3.31 (s, 3H, CH₃), 1.67-1.74 (m, 2H, CH₂), 1.33-1.46 (m, 4H, 2CH₂), 1.11-1.23 (m, 2H, CH₂), 0.90 (t, 3H, J = 16.0 Hz, CH₃), 0.75 (t, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 162.2, 161.9 (J_C-F = 81 Hz), 154.4, 143.6, 129.7, 126.6, 125.3, 122.6, 114.7, 110.3, 67.7, 67.3, 62.0, 53.4, 32.4, 32.2, 18.4, 18.3, 13.6, 13.4. ESI MS (m/z): 501.2 [M+H]⁺.
Ⅲl	¹H NMR (400 MHz, CDCl₃) δ: 9.31 (s, 1H, CONH), 7.64 (d, 2H, J = 8.0 Hz, ArH), 6.96-6.98 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.31 (s, 2H, NH₂), 5.69 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.04-4.28 (m, 2H, CH₂), 3.52-3.78 (m, 2H, CH₂), 3.23 (s, 3H, CH₃), 1.65-1.72 (m, 2H, CH₂), 1.33-1.45 (m, 4H, 2CH₂), 1.11-1.22 (m, 2H, CH₂), 0.89 (t, 3H, J = 16.0 Hz, CH₃), 0.76 (t, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.3, 163.7, 161.9 (J_C-F = 10 Hz), 146.9, 143.7, 131.4, 126.6, 125.3, 115.4, 115.2, 110.1, 67.6, 67.5, 61.9, 48.2, 32.4, 32.2, 18.7, 18.4, 13.6, 13.4. ESI MS (m/z): 501.2 [M+H]⁺.
Ⅲm	¹H NMR (400 MHz, CDCl₃) δ: 9.29 (s, 1H, CONH), 7.63 (d, 2H, J = 4.0 Hz, ArH), 7.22-7.32 (m, 3H, ArH), 6.62 (s, 1H, ArH), 6.30 (s, 2H, NH₂), 5.71 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 3.80-4.12 (m, 2H, CH₂), 3.50-3.71 (m, 2H, CH₂), 3.42 (s, 3H, CH₃), 1.94-2.00 (m, 1H, CH), 1.58-1.65 (m, 1H, CH), 0.94-0.96 (m, 6H, 2CH₃), 0.67 (t, 6H, J = 16.0 Hz, 2CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 161.9, 146.9, 143.7, 128.3, 128.1, 126.6, 125.3, 122.6, 121.3, 110.0, 73.5, 73.3, 61.9, 49.0, 29.2, 29.0, 18.8, 18.7, 18.4, 18.3. ESI MS (m/z): 511.2 [M+H]⁺.
Ⅲn	¹H NMR (400 MHz, CDCl₃) δ: 9.26 (s, 1H, CONH), 8.01-8.03 (m, 1H, ArH), 7.19-7.23 (m, 1H, ArH), 7.08-7.11 (m, 1H, ArH), 6.96-7.00 (m, 1H, ArH), 6.64 (s, 1H, ArH), 6.30 (s, 2H, NH₂), 6.17 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.12-4.18 (m, 1H, CH₂), 3.83-3.88 (m, 1H, CH₂), 3.55-3.61 (m, 1H, CH₂), 3.33-3.39 (m, 1H, CH₂), 3.27 (s, 3H, CH₃), 1.93-2.01 (m, 1H, CH), 1.60-1.67 (m, 1H, CH), 0.95-0.97 (m, 6H, 2CH₃), 0.69 (t, 6H, J = 12.0 Hz, 2CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.3, 161.9 (J_C-F = 89 Hz), 158.4, 146.9, 143.6, 131.9, 129.8, 125.3, 121.3, 114.7, 110.1, 73.7, 73.2, 61.9, 42.1, 29.2, 29.0, 18.8, 18.7, 18.3, 18.2. ESI MS (m/z): 529.2 [M+H]⁺.
Ⅲo	¹H NMR (400 MHz, CDCl₃) δ: 9.25 (s, 1H, CONH), 7.62-7.65 (m, 2H, ArH), 6.96-7.00 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.26 (s, 2H, NH₂), 5.69 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.07-4.12 (m, 1H, CH₂), 3.80-3.85 (m, 1H, CH₂), 3.54-3.60 (m, 1H, CH₂), 3.29-3.33 (m, 1H, CH₂), 3.26 (s, 3H, CH₃), 1.94-2.02 (m, 1H, CH), 1.62-1.69 (m, 1H, CH), 0.95-0.97 (m, 6H, 2CH₃), 0.71 (t, 6H, J = 12.0 Hz, 2CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.3, 163.8, 161.8 (J_C-F = 7 Hz), 161.3, 146.9, 143.6, 131.3, 129.0, 115.4, 115.2, 110.1, 73.6, 73.4, 61.8, 48.2, 29.2, 29.0, 18.8, 18.7, 18.4, 18.3. ESI MS (m/z): 529.2 [M+H]⁺.

Compd.

¹H NMR, ¹³C NMR and MS

Ⅲa

¹H NMR (400 MHz, CDCl₃) δ: 9.28 (s, 1H, CONH), 7.49 (d, 2H, J = 8.0 Hz, ArH), 7.32-7.37 (m, 3H, ArH), 6.63 (s, 1H, ArH), 6.30 (s, 2H, NH₂), 5.70 (dd, 1H, J = 8.0, 8.0 Hz, PCH), 3.88 (s, 3H, CH₃), 3.73 (d, 3H, J = 8.0 Hz, CH₃), 3.65 (d, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 169.9, 163.3, 160.7, 148.3, 142.3, 133.7, 132.6, 128.2, 128.0, 127.9, 110.1, 61.5, 53.2, 53.0, 48.4. ESI MS (m/z): 399.1 [M+H]⁺.

Ⅲb

¹H NMR (400 MHz, CDCl₃) δ: 9.21 (s, 1H, CONH), 7.62 (t, 1H, J=12.0 Hz, ArH), 7.33-7.36 (m, 1H, ArH), 7.18-7.23 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.32 (s, 2H, NH₂), 5.84 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.73 (s, 3H, CH₃), 3.65 (d, 3H, J = 12.0 Hz, CH₃), 3.53 (d, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.8, 162.6, 160.7 (J_C-F = 77 Hz), 158.4, 149.4, 143.3, 130.5, 125.0, 122.7, 115.7, 115.6, 109.8, 62.3, 55.3, 54.2, 53.7. ESI MS (m/z): 417.1 [M+H]⁺.

Ⅲc

¹H NMR (400 MHz, CDCl₃) δ: 9.29 (s, 1H, CONH), 7.51 (d, J = 16.0 Hz, 2H, ArH), 7.08-7.13 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.28 (s, 2H, NH₂), 5.70 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.88 (s, 3H, CH₃), 3.74 (d, 3H, J = 12.0 Hz, CH₃), 3.67 (d, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 170.0, 163.9, 163.2 (J_C-F = 12 Hz), 161.4, 148.3, 142.3, 130.1, 130.0, 115.1, 114.9, 110.0, 61.5, 53.3, 53.0, 49.3. ESI MS (m/z): 417.1 [M+H]⁺.

Ⅲd

¹H NMR (400 MHz, CDCl₃) δ: 9.26 (s, 1H, CONH), 7.49 (d, 2H, J = 8.0 Hz, ArH), 7.34-7.37 (m, 3H, ArH), 6.63 (s, 1H, ArH), 6.32 (s, 2H, NH₂), 5.64 (dd, 1H, J = 8.0, 8.0 Hz, PCH), 3.92-4.01 (m, 4H, 2CH₂), 3.89 (s, 3H, CH₃), 1.25 (t, 3H, J = 12.0 Hz, CH₃), 1.18 (t, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 169.8, 163.3, 161.6, 148.3, 142.4, 133.9, 132.8, 128.2, 128.1, 127.9, 110.2, 63.5, 63.3, 61.5, 50.6, 15.3, 15.1. ESI MS (m/z): 427.1 [M+H]⁺.

Ⅲe

¹H NMR (400 MHz, CDCl₃) δ: 9.23 (s, 1H, CONH), 7.62 (t, 1H, J = 8.0 Hz, ArH), 7.33-7.35 (m, 1H, ArH), 7.11-7.20 (m, 2H, ArH), 6.59 (s, 1H, ArH), 6.33 (s, 2H, NH₂), 5.79 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.82-4.02 (m, 4H, 2CH₂), 3.72 (s, 3H, CH₃), 1.16 (t, 3H, J = 12.0 Hz, CH₃), 1.03 (t, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.8, 162.7, 160.9 (J_C-F = 98 Hz), 158.5, 149.4, 143.4, 130.6, 124.9, 122.8, 115.6, 115.4, 109.9, 63.3, 63.0, 62.3, 53.7, 16.7, 16.5. ESI MS (m/z): 445.2 [M+H]⁺.

Ⅲf

¹H NMR (400 MHz, CDCl₃) δ: 9.28 (s, 1H, CONH), 7.50-7.54 (m, 2H, ArH), 7.08-7.13 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.31 (s, 2H, NH₂), 5.64 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.99-4.12 (m, 4H, 2CH₂), 3.90 (s, 3H, CH₃), 1.25 (d, 3H, J = 16.0 Hz, CH₃), 1.20 (d, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.7, 163.2, 162.5 (J_C-F = 9 Hz), 160.6, 149.5, 143.5, 130.8, 130.7, 115.5, 115.3, 109.9, 63.1, 62.9, 62.3, 48.2, 16.6, 16.5. ESI MS (m/z): 445.1 [M+H]⁺.

Ⅲg

¹H NMR (400 MHz, CDCl₃) δ: 9.66 (s, 1H, CONH), 7.46-7.48 (m, 2H, ArH), 7.27-7.34 (m, 3H, ArH), 6.61 (s, 1H, ArH), 6.33 (s, 2H, NH₂), 5.49 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.63-4.75 (m, 1H, CH), 4.49-4.57 (m, 1H, CH), 3.75 (s, 3H, CH₃), 1.07-1.36 (m, 12H, 4CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.7, 162.6, 161.4, 143.6, 135.4, 128.8, 128.7, 128.5, 128.1, 114.9, 109.9, 72.8, 72.6, 61.5, 56.5, 23.0, 22.9, 22.7, 22.2. ESI MS (m/z): 455.2 [M+H]⁺.

Ⅲh

¹H NMR (400 MHz, CDCl₃) δ: 9.25 (s, 1H, CONH), 7.58-7.62 (m, 1H, ArH), 7.33-7.37 (m, 1H, ArH), 7.11-7.21 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.31 (s, 2H, NH₂), 5.94 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 4.69-4.73 (m, 1H, CH), 4.50-4.55 (m, 1H, CH), 3.85 (s, 3H, CH₃), 1.07-1.34 (m, 12H, 4CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 169.9, 163.3, 161.3 (J_C-F = 74 Hz), 158.8, 148.4, 142.3, 130.0, 129.7, 124.0, 114.9, 110.2, 72.8, 72.5, 61.5, 56.5, 23.0, 22.9, 22.7, 22.2. ESI MS (m/z): 473.2 [M+H]⁺.

Ⅲi

¹H NMR (400 MHz, CDCl₃) δ: 9.01 (s, 1H, CONH), 7.58-7.61 (m, 2H, ArH), 6.95-6.99 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.22 (s, 2H, NH₂), 5.60 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.68-4.74 (m, 1H, CH), 4.24-4.32 (m, 1H, CH), 3.69 (s, 3H, CH₃), 1.18-1.38 (m, 12H, 4CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 163.8, 161.6 (J_C-F = 7 Hz), 161.3, 147.0, 143.6, 131.4, 129.6, 115.3, 115.1, 110.5, 73.2, 72.3, 61.9, 58.3, 24.2, 24.1, 23.9, 22.9. ESI MS (m/z): 473.2 [M+H]⁺.

Ⅲj

¹H NMR (400 MHz, CDCl₃) δ: 9.25 (s, 1H, CONH), 7.63 (d, 2H, J = 8.0 Hz, ArH), 7.22-7.30 (m, 3H, ArH), 6.63 (s, 1H, ArH), 6.26 (s, 2H, NH₂), 5.70 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.05-4.27 (m, 2H, CH₂), 3.46-3.75 (m, 2H, CH₂), 3.22 (s, 3H, CH₃), 1.65-1.72 (m, 2H, CH₂), 1.38-1.45 (m, 2H, CH₂), 1.30-1.35 (m, 2H, CH₂), 1.09-1.22 (m, 2H, CH₂), 0.89 (t, 3H, J = 16.0 Hz, CH₃), 0.74 (t, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 163.3, 161.9, 146.9, 143.8, 133.0, 128.2, 126.6, 125.3, 122.6, 110.1, 67.5, 67.3, 61.9, 49.0, 32.4, 32.2, 18.7, 18.4, 13.6, 13.4. ESI MS (m/z): 483.2 [M+H]⁺.

Ⅲk

¹H NMR (400 MHz, CDCl₃) δ: 9.17 (s, 1H, CONH), 7.31-7.46 (m, 1H, ArH), 7.21-7.26 (m, 1H, ArH), 7.10-7.14 (m, 1H, ArH), 6.98-7.02 (m, 1H, ArH), 6.67 (s, 1H, ArH), 6.16-6.23 (m, 3H, PCH+NH₂), 4.08-4.36 (m, 2H, CH₂), 3.60-3.72 (m, 2H, CH₂), 3.31 (s, 3H, CH₃), 1.67-1.74 (m, 2H, CH₂), 1.33-1.46 (m, 4H, 2CH₂), 1.11-1.23 (m, 2H, CH₂), 0.90 (t, 3H, J = 16.0 Hz, CH₃), 0.75 (t, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 162.2, 161.9 (J_C-F = 81 Hz), 154.4, 143.6, 129.7, 126.6, 125.3, 122.6, 114.7, 110.3, 67.7, 67.3, 62.0, 53.4, 32.4, 32.2, 18.4, 18.3, 13.6, 13.4. ESI MS (m/z): 501.2 [M+H]⁺.

Ⅲl

¹H NMR (400 MHz, CDCl₃) δ: 9.31 (s, 1H, CONH), 7.64 (d, 2H, J = 8.0 Hz, ArH), 6.96-6.98 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.31 (s, 2H, NH₂), 5.69 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.04-4.28 (m, 2H, CH₂), 3.52-3.78 (m, 2H, CH₂), 3.23 (s, 3H, CH₃), 1.65-1.72 (m, 2H, CH₂), 1.33-1.45 (m, 4H, 2CH₂), 1.11-1.22 (m, 2H, CH₂), 0.89 (t, 3H, J = 16.0 Hz, CH₃), 0.76 (t, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.3, 163.7, 161.9 (J_C-F = 10 Hz), 146.9, 143.7, 131.4, 126.6, 125.3, 115.4, 115.2, 110.1, 67.6, 67.5, 61.9, 48.2, 32.4, 32.2, 18.7, 18.4, 13.6, 13.4. ESI MS (m/z): 501.2 [M+H]⁺.

Ⅲm

¹H NMR (400 MHz, CDCl₃) δ: 9.29 (s, 1H, CONH), 7.63 (d, 2H, J = 4.0 Hz, ArH), 7.22-7.32 (m, 3H, ArH), 6.62 (s, 1H, ArH), 6.30 (s, 2H, NH₂), 5.71 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 3.80-4.12 (m, 2H, CH₂), 3.50-3.71 (m, 2H, CH₂), 3.42 (s, 3H, CH₃), 1.94-2.00 (m, 1H, CH), 1.58-1.65 (m, 1H, CH), 0.94-0.96 (m, 6H, 2CH₃), 0.67 (t, 6H, J = 16.0 Hz, 2CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 161.9, 146.9, 143.7, 128.3, 128.1, 126.6, 125.3, 122.6, 121.3, 110.0, 73.5, 73.3, 61.9, 49.0, 29.2, 29.0, 18.8, 18.7, 18.4, 18.3. ESI MS (m/z): 511.2 [M+H]⁺.

Ⅲn

¹H NMR (400 MHz, CDCl₃) δ: 9.26 (s, 1H, CONH), 8.01-8.03 (m, 1H, ArH), 7.19-7.23 (m, 1H, ArH), 7.08-7.11 (m, 1H, ArH), 6.96-7.00 (m, 1H, ArH), 6.64 (s, 1H, ArH), 6.30 (s, 2H, NH₂), 6.17 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.12-4.18 (m, 1H, CH₂), 3.83-3.88 (m, 1H, CH₂), 3.55-3.61 (m, 1H, CH₂), 3.33-3.39 (m, 1H, CH₂), 3.27 (s, 3H, CH₃), 1.93-2.01 (m, 1H, CH), 1.60-1.67 (m, 1H, CH), 0.95-0.97 (m, 6H, 2CH₃), 0.69 (t, 6H, J = 12.0 Hz, 2CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.3, 161.9 (J_C-F = 89 Hz), 158.4, 146.9, 143.6, 131.9, 129.8, 125.3, 121.3, 114.7, 110.1, 73.7, 73.2, 61.9, 42.1, 29.2, 29.0, 18.8, 18.7, 18.3, 18.2. ESI MS (m/z): 529.2 [M+H]⁺.

Ⅲo

¹H NMR (400 MHz, CDCl₃) δ: 9.25 (s, 1H, CONH), 7.62-7.65 (m, 2H, ArH), 6.96-7.00 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.26 (s, 2H, NH₂), 5.69 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.07-4.12 (m, 1H, CH₂), 3.80-3.85 (m, 1H, CH₂), 3.54-3.60 (m, 1H, CH₂), 3.29-3.33 (m, 1H, CH₂), 3.26 (s, 3H, CH₃), 1.94-2.02 (m, 1H, CH), 1.62-1.69 (m, 1H, CH), 0.95-0.97 (m, 6H, 2CH₃), 0.71 (t, 6H, J = 12.0 Hz, 2CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.3, 163.8, 161.8 (J_C-F = 7 Hz), 161.3, 146.9, 143.6, 131.3, 129.0, 115.4, 115.2, 110.1, 73.6, 73.4, 61.8, 48.2, 29.2, 29.0, 18.8, 18.7, 18.4, 18.3. ESI MS (m/z): 529.2 [M+H]⁺.

Compd.	¹H NMR, ¹³C NMR and MS
Ⅲa	¹H NMR (400 MHz, CDCl₃) δ: 9.28 (s, 1H, CONH), 7.49 (d, 2H, J = 8.0 Hz, ArH), 7.32-7.37 (m, 3H, ArH), 6.63 (s, 1H, ArH), 6.30 (s, 2H, NH₂), 5.70 (dd, 1H, J = 8.0, 8.0 Hz, PCH), 3.88 (s, 3H, CH₃), 3.73 (d, 3H, J = 8.0 Hz, CH₃), 3.65 (d, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 169.9, 163.3, 160.7, 148.3, 142.3, 133.7, 132.6, 128.2, 128.0, 127.9, 110.1, 61.5, 53.2, 53.0, 48.4. ESI MS (m/z): 399.1 [M+H]⁺.
Ⅲb	¹H NMR (400 MHz, CDCl₃) δ: 9.21 (s, 1H, CONH), 7.62 (t, 1H, J=12.0 Hz, ArH), 7.33-7.36 (m, 1H, ArH), 7.18-7.23 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.32 (s, 2H, NH₂), 5.84 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.73 (s, 3H, CH₃), 3.65 (d, 3H, J = 12.0 Hz, CH₃), 3.53 (d, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.8, 162.6, 160.7 (J_C-F = 77 Hz), 158.4, 149.4, 143.3, 130.5, 125.0, 122.7, 115.7, 115.6, 109.8, 62.3, 55.3, 54.2, 53.7. ESI MS (m/z): 417.1 [M+H]⁺.
Ⅲc	¹H NMR (400 MHz, CDCl₃) δ: 9.29 (s, 1H, CONH), 7.51 (d, J = 16.0 Hz, 2H, ArH), 7.08-7.13 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.28 (s, 2H, NH₂), 5.70 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.88 (s, 3H, CH₃), 3.74 (d, 3H, J = 12.0 Hz, CH₃), 3.67 (d, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 170.0, 163.9, 163.2 (J_C-F = 12 Hz), 161.4, 148.3, 142.3, 130.1, 130.0, 115.1, 114.9, 110.0, 61.5, 53.3, 53.0, 49.3. ESI MS (m/z): 417.1 [M+H]⁺.
Ⅲd	¹H NMR (400 MHz, CDCl₃) δ: 9.26 (s, 1H, CONH), 7.49 (d, 2H, J = 8.0 Hz, ArH), 7.34-7.37 (m, 3H, ArH), 6.63 (s, 1H, ArH), 6.32 (s, 2H, NH₂), 5.64 (dd, 1H, J = 8.0, 8.0 Hz, PCH), 3.92-4.01 (m, 4H, 2CH₂), 3.89 (s, 3H, CH₃), 1.25 (t, 3H, J = 12.0 Hz, CH₃), 1.18 (t, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 169.8, 163.3, 161.6, 148.3, 142.4, 133.9, 132.8, 128.2, 128.1, 127.9, 110.2, 63.5, 63.3, 61.5, 50.6, 15.3, 15.1. ESI MS (m/z): 427.1 [M+H]⁺.
Ⅲe	¹H NMR (400 MHz, CDCl₃) δ: 9.23 (s, 1H, CONH), 7.62 (t, 1H, J = 8.0 Hz, ArH), 7.33-7.35 (m, 1H, ArH), 7.11-7.20 (m, 2H, ArH), 6.59 (s, 1H, ArH), 6.33 (s, 2H, NH₂), 5.79 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.82-4.02 (m, 4H, 2CH₂), 3.72 (s, 3H, CH₃), 1.16 (t, 3H, J = 12.0 Hz, CH₃), 1.03 (t, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.8, 162.7, 160.9 (J_C-F = 98 Hz), 158.5, 149.4, 143.4, 130.6, 124.9, 122.8, 115.6, 115.4, 109.9, 63.3, 63.0, 62.3, 53.7, 16.7, 16.5. ESI MS (m/z): 445.2 [M+H]⁺.
Ⅲf	¹H NMR (400 MHz, CDCl₃) δ: 9.28 (s, 1H, CONH), 7.50-7.54 (m, 2H, ArH), 7.08-7.13 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.31 (s, 2H, NH₂), 5.64 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.99-4.12 (m, 4H, 2CH₂), 3.90 (s, 3H, CH₃), 1.25 (d, 3H, J = 16.0 Hz, CH₃), 1.20 (d, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.7, 163.2, 162.5 (J_C-F = 9 Hz), 160.6, 149.5, 143.5, 130.8, 130.7, 115.5, 115.3, 109.9, 63.1, 62.9, 62.3, 48.2, 16.6, 16.5. ESI MS (m/z): 445.1 [M+H]⁺.
Ⅲg	¹H NMR (400 MHz, CDCl₃) δ: 9.66 (s, 1H, CONH), 7.46-7.48 (m, 2H, ArH), 7.27-7.34 (m, 3H, ArH), 6.61 (s, 1H, ArH), 6.33 (s, 2H, NH₂), 5.49 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.63-4.75 (m, 1H, CH), 4.49-4.57 (m, 1H, CH), 3.75 (s, 3H, CH₃), 1.07-1.36 (m, 12H, 4CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.7, 162.6, 161.4, 143.6, 135.4, 128.8, 128.7, 128.5, 128.1, 114.9, 109.9, 72.8, 72.6, 61.5, 56.5, 23.0, 22.9, 22.7, 22.2. ESI MS (m/z): 455.2 [M+H]⁺.
Ⅲh	¹H NMR (400 MHz, CDCl₃) δ: 9.25 (s, 1H, CONH), 7.58-7.62 (m, 1H, ArH), 7.33-7.37 (m, 1H, ArH), 7.11-7.21 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.31 (s, 2H, NH₂), 5.94 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 4.69-4.73 (m, 1H, CH), 4.50-4.55 (m, 1H, CH), 3.85 (s, 3H, CH₃), 1.07-1.34 (m, 12H, 4CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 169.9, 163.3, 161.3 (J_C-F = 74 Hz), 158.8, 148.4, 142.3, 130.0, 129.7, 124.0, 114.9, 110.2, 72.8, 72.5, 61.5, 56.5, 23.0, 22.9, 22.7, 22.2. ESI MS (m/z): 473.2 [M+H]⁺.
Ⅲi	¹H NMR (400 MHz, CDCl₃) δ: 9.01 (s, 1H, CONH), 7.58-7.61 (m, 2H, ArH), 6.95-6.99 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.22 (s, 2H, NH₂), 5.60 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.68-4.74 (m, 1H, CH), 4.24-4.32 (m, 1H, CH), 3.69 (s, 3H, CH₃), 1.18-1.38 (m, 12H, 4CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 163.8, 161.6 (J_C-F = 7 Hz), 161.3, 147.0, 143.6, 131.4, 129.6, 115.3, 115.1, 110.5, 73.2, 72.3, 61.9, 58.3, 24.2, 24.1, 23.9, 22.9. ESI MS (m/z): 473.2 [M+H]⁺.
Ⅲj	¹H NMR (400 MHz, CDCl₃) δ: 9.25 (s, 1H, CONH), 7.63 (d, 2H, J = 8.0 Hz, ArH), 7.22-7.30 (m, 3H, ArH), 6.63 (s, 1H, ArH), 6.26 (s, 2H, NH₂), 5.70 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.05-4.27 (m, 2H, CH₂), 3.46-3.75 (m, 2H, CH₂), 3.22 (s, 3H, CH₃), 1.65-1.72 (m, 2H, CH₂), 1.38-1.45 (m, 2H, CH₂), 1.30-1.35 (m, 2H, CH₂), 1.09-1.22 (m, 2H, CH₂), 0.89 (t, 3H, J = 16.0 Hz, CH₃), 0.74 (t, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 163.3, 161.9, 146.9, 143.8, 133.0, 128.2, 126.6, 125.3, 122.6, 110.1, 67.5, 67.3, 61.9, 49.0, 32.4, 32.2, 18.7, 18.4, 13.6, 13.4. ESI MS (m/z): 483.2 [M+H]⁺.
Ⅲk	¹H NMR (400 MHz, CDCl₃) δ: 9.17 (s, 1H, CONH), 7.31-7.46 (m, 1H, ArH), 7.21-7.26 (m, 1H, ArH), 7.10-7.14 (m, 1H, ArH), 6.98-7.02 (m, 1H, ArH), 6.67 (s, 1H, ArH), 6.16-6.23 (m, 3H, PCH+NH₂), 4.08-4.36 (m, 2H, CH₂), 3.60-3.72 (m, 2H, CH₂), 3.31 (s, 3H, CH₃), 1.67-1.74 (m, 2H, CH₂), 1.33-1.46 (m, 4H, 2CH₂), 1.11-1.23 (m, 2H, CH₂), 0.90 (t, 3H, J = 16.0 Hz, CH₃), 0.75 (t, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 162.2, 161.9 (J_C-F = 81 Hz), 154.4, 143.6, 129.7, 126.6, 125.3, 122.6, 114.7, 110.3, 67.7, 67.3, 62.0, 53.4, 32.4, 32.2, 18.4, 18.3, 13.6, 13.4. ESI MS (m/z): 501.2 [M+H]⁺.
Ⅲl	¹H NMR (400 MHz, CDCl₃) δ: 9.31 (s, 1H, CONH), 7.64 (d, 2H, J = 8.0 Hz, ArH), 6.96-6.98 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.31 (s, 2H, NH₂), 5.69 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.04-4.28 (m, 2H, CH₂), 3.52-3.78 (m, 2H, CH₂), 3.23 (s, 3H, CH₃), 1.65-1.72 (m, 2H, CH₂), 1.33-1.45 (m, 4H, 2CH₂), 1.11-1.22 (m, 2H, CH₂), 0.89 (t, 3H, J = 16.0 Hz, CH₃), 0.76 (t, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.3, 163.7, 161.9 (J_C-F = 10 Hz), 146.9, 143.7, 131.4, 126.6, 125.3, 115.4, 115.2, 110.1, 67.6, 67.5, 61.9, 48.2, 32.4, 32.2, 18.7, 18.4, 13.6, 13.4. ESI MS (m/z): 501.2 [M+H]⁺.
Ⅲm	¹H NMR (400 MHz, CDCl₃) δ: 9.29 (s, 1H, CONH), 7.63 (d, 2H, J = 4.0 Hz, ArH), 7.22-7.32 (m, 3H, ArH), 6.62 (s, 1H, ArH), 6.30 (s, 2H, NH₂), 5.71 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 3.80-4.12 (m, 2H, CH₂), 3.50-3.71 (m, 2H, CH₂), 3.42 (s, 3H, CH₃), 1.94-2.00 (m, 1H, CH), 1.58-1.65 (m, 1H, CH), 0.94-0.96 (m, 6H, 2CH₃), 0.67 (t, 6H, J = 16.0 Hz, 2CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 161.9, 146.9, 143.7, 128.3, 128.1, 126.6, 125.3, 122.6, 121.3, 110.0, 73.5, 73.3, 61.9, 49.0, 29.2, 29.0, 18.8, 18.7, 18.4, 18.3. ESI MS (m/z): 511.2 [M+H]⁺.
Ⅲn	¹H NMR (400 MHz, CDCl₃) δ: 9.26 (s, 1H, CONH), 8.01-8.03 (m, 1H, ArH), 7.19-7.23 (m, 1H, ArH), 7.08-7.11 (m, 1H, ArH), 6.96-7.00 (m, 1H, ArH), 6.64 (s, 1H, ArH), 6.30 (s, 2H, NH₂), 6.17 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.12-4.18 (m, 1H, CH₂), 3.83-3.88 (m, 1H, CH₂), 3.55-3.61 (m, 1H, CH₂), 3.33-3.39 (m, 1H, CH₂), 3.27 (s, 3H, CH₃), 1.93-2.01 (m, 1H, CH), 1.60-1.67 (m, 1H, CH), 0.95-0.97 (m, 6H, 2CH₃), 0.69 (t, 6H, J = 12.0 Hz, 2CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.3, 161.9 (J_C-F = 89 Hz), 158.4, 146.9, 143.6, 131.9, 129.8, 125.3, 121.3, 114.7, 110.1, 73.7, 73.2, 61.9, 42.1, 29.2, 29.0, 18.8, 18.7, 18.3, 18.2. ESI MS (m/z): 529.2 [M+H]⁺.
Ⅲo	¹H NMR (400 MHz, CDCl₃) δ: 9.25 (s, 1H, CONH), 7.62-7.65 (m, 2H, ArH), 6.96-7.00 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.26 (s, 2H, NH₂), 5.69 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.07-4.12 (m, 1H, CH₂), 3.80-3.85 (m, 1H, CH₂), 3.54-3.60 (m, 1H, CH₂), 3.29-3.33 (m, 1H, CH₂), 3.26 (s, 3H, CH₃), 1.94-2.02 (m, 1H, CH), 1.62-1.69 (m, 1H, CH), 0.95-0.97 (m, 6H, 2CH₃), 0.71 (t, 6H, J = 12.0 Hz, 2CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.3, 163.8, 161.8 (J_C-F = 7 Hz), 161.3, 146.9, 143.6, 131.3, 129.0, 115.4, 115.2, 110.1, 73.6, 73.4, 61.8, 48.2, 29.2, 29.0, 18.8, 18.7, 18.4, 18.3. ESI MS (m/z): 529.2 [M+H]⁺.

Compd.

¹H NMR, ¹³C NMR and MS

Ⅲa

Ⅲb

Ⅲc

Ⅲd

Ⅲe

Ⅲf

Ⅲg

Ⅲh

Ⅲi

Ⅲj

Ⅲk

Ⅲl

Ⅲm

Ⅲn

Ⅲo

Compd.	R	R₁	MIC/μg·mL^-1
Ⅲa	H	CH₃	256	256	1 024	512
Ⅲb	2-F	CH₃	128	128	128	512
Ⅲc	4-F	CH₃	32	64	128	64
Ⅲd	H	C₂H₅	32	128	32	128
Ⅲe	2-F	C₂H₅	8	16	8	32
Ⅲf	4-F	C₂H₅	1	8	4	16
Ⅲg	H	CH(CH₃)₂	64	64	64	64
Ⅲh	2-F	CH(CH₃)₂	32	16	32	32
Ⅲi	4-F	CH(CH₃)₂	4	4	16	8
Ⅲj	H	(CH₂)₃CH₃	1 024	1 024	> 1 024	> 1 024
Ⅲk	2-F	(CH₂)₃CH₃	512	1 024	1 024	1 024
Ⅲl	4-F	(CH₂)₃CH₃	256	512	256	512
Ⅲm	H	(CH₂)₂CH(CH₃)₂	> 1 024	1 024	> 1 024	> 1 024
Ⅲn	2-F	(CH₂)₂CH(CH₃)₂	1 024	512	> 1 024	512
Ⅲo	4-F	(CH₂)₂CH(CH₃)₂	1 024	256	> 1 024	1 024
Oxacillin			0.5	16	256	64

Compd.

R₁

MIC/μg·mL^-1

S. aureus

E. coli

MRSA

FREC

Ⅲa

CH₃

256

1 024

512

Ⅲb

2-F

CH₃

128

512

Ⅲc

4-F

CH₃

128

Ⅲd

C₂H₅

128

Ⅲe

2-F

C₂H₅

Ⅲf

4-F

C₂H₅

Ⅲg

CH(CH₃)₂

Ⅲh

2-F

CH(CH₃)₂

Ⅲi

4-F

CH(CH₃)₂

Ⅲj

(CH₂)₃CH₃

1 024

> 1 024

Ⅲk

2-F

(CH₂)₃CH₃

512

1 024

Ⅲl

4-F

(CH₂)₃CH₃

256

512

256

512

Ⅲm

(CH₂)₂CH(CH₃)₂

> 1 024

1 024

> 1 024

Ⅲn

2-F

(CH₂)₂CH(CH₃)₂

1 024

512

> 1 024

512

Ⅲo

4-F

(CH₂)₂CH(CH₃)₂

1 024

256

> 1 024

1 024

Oxacillin

0.5

256

Compd.	R	R₁	MIC/μg·mL^-1
Ⅲa	H	CH₃	256	256	1 024	512
Ⅲb	2-F	CH₃	128	128	128	512
Ⅲc	4-F	CH₃	32	64	128	64
Ⅲd	H	C₂H₅	32	128	32	128
Ⅲe	2-F	C₂H₅	8	16	8	32
Ⅲf	4-F	C₂H₅	1	8	4	16
Ⅲg	H	CH(CH₃)₂	64	64	64	64
Ⅲh	2-F	CH(CH₃)₂	32	16	32	32
Ⅲi	4-F	CH(CH₃)₂	4	4	16	8
Ⅲj	H	(CH₂)₃CH₃	1 024	1 024	> 1 024	> 1 024
Ⅲk	2-F	(CH₂)₃CH₃	512	1 024	1 024	1 024
Ⅲl	4-F	(CH₂)₃CH₃	256	512	256	512
Ⅲm	H	(CH₂)₂CH(CH₃)₂	> 1 024	1 024	> 1 024	> 1 024
Ⅲn	2-F	(CH₂)₂CH(CH₃)₂	1 024	512	> 1 024	512
Ⅲo	4-F	(CH₂)₂CH(CH₃)₂	1 024	256	> 1 024	1 024
Oxacillin			0.5	16	256	64

Compd.

R₁

MIC/μg·mL^-1

S. aureus

E. coli

MRSA

FREC

Ⅲa

CH₃

256

1 024

512

Ⅲb

2-F

CH₃

128

512

Ⅲc

4-F

CH₃

128

Ⅲd

C₂H₅

128

Ⅲe

2-F

C₂H₅

Ⅲf

4-F

C₂H₅

Ⅲg

CH(CH₃)₂

Ⅲh

2-F

CH(CH₃)₂

Ⅲi

4-F

CH(CH₃)₂

Ⅲj

(CH₂)₃CH₃

1 024

> 1 024

Ⅲk

2-F

(CH₂)₃CH₃

512

1 024

Ⅲl

4-F

(CH₂)₃CH₃

256

512

256

512

Ⅲm

(CH₂)₂CH(CH₃)₂

> 1 024

1 024

> 1 024

Ⅲn

2-F

(CH₂)₂CH(CH₃)₂

1 024

512

> 1 024

512

Ⅲo

4-F

(CH₂)₂CH(CH₃)₂

1 024

256

> 1 024

1 024

Oxacillin

0.5

256

含氨基噻唑肟结构的膦酸酯衍生物的合成与抗菌活性研究

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陈阳密 , 安艳 , 董向涛 , 卢子聪 , 杨家强 ^*

药学学报 | 研究论文 2024,59(1): 161-165

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药学学报 | 研究论文 2024, 59(1): 161-165

含氨基噻唑肟结构的膦酸酯衍生物的合成与抗菌活性研究

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陈阳密, 安艳, 董向涛, 卢子聪, 杨家强^*

作者信息

遵义医科大学药学院, 贵州遵义 563000

通讯作者:

^*杨家强, Tel: 86-851-28642339, E-mail: yjqcn@126.com

Synthesis and antibacterial activities of phosphonate derivatives containing aminothiazoloxime fragment

Yang-mi CHEN, Yan AN, Xiang-tao DONG, Zi-cong LU, Jia-qiang YANG^*

Affiliations

School of Pharmacy, Zunyi Medical University, Zunyi 563000, China

出版时间: 2024-01-12 doi: 10.16438/j.0513-4870.2023-0790

文章导航

摘要

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采用分子杂合原理, 将氨基噻唑肟与膦酸酯片段组合, 设计合成了15个目标物进行抗菌活性研究。结果显示: 该类衍生物对所测试细菌有较好的抑制作用, 尤以化合物Ⅲf和Ⅲi的抗金葡菌(S. aureus)、大肠杆菌(E. coli)、耐甲氧西林金葡菌(MRSA) 和耐氟喹诺酮大肠杆菌(FREC) 活性最为显著, 前者的最小抑菌浓度(MIC) 分别为1、8、4和16 μg·mL^-1, 后者的MIC分别为4、4、16和8 μg·mL^-1, 抗S. aureus活性略低于苯唑西林, 抗E. coli、MRSA和FREC活性优于对照药苯唑西林, 值得进一步深入研究。

关键词

氨基噻唑肟 / 膦酸酯 / 分子杂合 / 合成 / 抗菌活性

Abstract

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Based on the principle of molecular hybridization, fifteen compounds were designed and synthesized through the combination of aminothiazoloxime and phosphonate fragment. The results showed that these compounds had better inhibitory effects on the tested bacteria. In particular, the activities of compounds Ⅲf and Ⅲi against S. aureus, E. coli, methicillin-resistant S. aureus (MRSA) and fluoroquinolone-resistant E. coli (FREC) were the most significant, the minimal inhibitory concentration (MIC) of Ⅲf was 1, 8, 4, 16 μg·mL^-1 respectively, and the MIC of Ⅲi was 4, 4, 16, 8 μg·mL^-1 respectively, which were slightly lower than that of the control drug oxacillin, and their anti-E. coli, MRSA and FREC activities were superior to that of the control drug oxacillin. Their activities to S. aureus were close to that of oxacillin, and to E. coli, MRSA and FREC were superior to that of oxacillin, which is worthy of further study.

Key words

aminothiazole oxime / phosphonate / molecular hybridization / synthesis / antibacterial activity

引用本文

陈阳密, 安艳, 董向涛, 卢子聪, 杨家强. 含氨基噻唑肟结构的膦酸酯衍生物的合成与抗菌活性研究. 药学学报, 2024 , 59 (1) : 161 -165 . DOI: 10.16438/j.0513-4870.2023-0790

Yang-mi CHEN, Yan AN, Xiang-tao DONG, Zi-cong LU, Jia-qiang YANG. Synthesis and antibacterial activities of phosphonate derivatives containing aminothiazoloxime fragment[J]. Acta Pharmaceutica Sinica, 2024 , 59 (1) : 161 -165 . DOI: 10.16438/j.0513-4870.2023-0790

正文

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在有机磷化学中, α-氨基膦酸酯作为天然氨基酸的结构类似物, 具有抗菌^[1]、抗真菌^[2]、抗肿瘤^[3]、抗病毒^[4]、抗氧化^[5]和抗阿尔茨海默病^[6]等多种生物活性, 在医学、制药及农业等领域应用广泛^{[7, 8]}, 受到化学家和生物学家的极大关注。研究表明, α-氨基膦酸酯衍生物对革兰阳性菌、革兰阴性菌和耐药菌等多种细菌有抑制作用。2020年, Poola等^[9]设计合成了含不同官能团的α-氨基膦酸酯衍生物, 一些化合物对金葡菌、枯草芽孢杆菌、肺炎克雷伯菌和大肠杆菌的活性显著, 有望成为新的抗菌候选化合物; 2022年, K'tir等^[10]设计合成了含噁噻唑烷的新型α-氨基膦酸酯, 对革兰阳性菌和阴性菌有较优的活性, 作用机制研究表明对YpDHPS靶点有潜在抑制作用, 可进一步开发为抑制DHPS的候选化合物; 另外, 2023年, Yang等^[11]报道含香豆素结构的α-氨基膦酸酯衍生物对金葡菌也有显著的抑制活性, 能够破坏细菌细胞膜的完整性, 从而导致蛋白质的代谢抑制。

在药物分子结构中, 氨基噻唑常作为一种优势骨架^[12-14], 已上市的药物中, 有许多以其为核心结构, 如法莫替丁、头孢替安、美洛司康等。其中, 2-氨基噻唑肟作为氨基噻唑的衍生结构, 近年来, 在抗菌药物研发中具有明显优势^[15-17], 尤其是在第三、四代半合成头孢菌素类抗生素的设计和改造中, 通过引入2-氨基噻唑肟片段, 能扩大抗菌谱、增强活性、改善耐药性等作用, 对其药效学和动力学均有着重要影响, 如头孢噻肟、头孢匹罗、头孢喹肟等。

基于此, 本文采用分子杂合策略, 将优势骨架“2-氨基噻唑肟”与“α-氨基膦酸酯”活性片段结合, 设计合成系列含氨基噻唑肟结构的新型膦酸酯衍生物进行抗菌活性研究。目标物的合成路线如路线1所示。

结果与讨论

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1 化合物的合成

按实验部分“1.1”方法, 优化中间体I的合成方法。首先, 考察溶剂对其收率的影响, 以乙腈和二氯甲烷为溶剂, 收率分别为73%和79%; 以四氢呋喃和1, 2-二氯乙烷为溶剂, 收率分别为85%和88%。接着, 考察反应温度对其收率的影响, 在-5 ℃, 无反应, 在0 ℃和5 ℃, 收率较低, 分别为41%和66%; 随着温度由10 ℃升高到15 ℃, 收率由76%逐渐达到88%; 但当温度超过20 ℃, 溶液就会变稠, 颜色也会有所加深, 生成的副产物较多, 收率明显降低。最后, 考察脱水剂对其收率的影响, 以无机酸浓硫酸和浓磷酸为脱水剂, 收率较低, 约50%左右, 而采用有机脱水剂三苯基膦和亚磷酸三乙酯, 收率分别为84%和88%, 收率有很大提高。综上, 中间体Ⅰ的最优合成条件为: 在15 ℃下, 以亚磷酸三乙酯为催化剂, 1, 2-二氯乙烷为溶剂。

目标物结构经¹H NMR、¹³C NMR及MS得以确证, 理化数据见表 1和表 2。

2 活性评价

由表 3可知, 该类衍生物具有潜在抗菌活性, 部分化合物的活性较为显著。其中, 化合物Ⅲc、Ⅲd、Ⅲe、Ⅲf、Ⅲh和Ⅲi对S. aureus的MIC分别为32、32、8、1、32和4 μg·mL^-1, Ⅲf和Ⅲi的活性略低于苯唑西林(MIC = 0.5 μg·mL^-1); 化合物Ⅲe、Ⅲf、Ⅲh和Ⅲi对E. coli的MIC分别为16、8、16和4 μg·mL^-1, Ⅲe和Ⅲh的活性与苯唑西林(MIC = 16 μg·mL^-1) 相当, Ⅲf和Ⅲi的活性优于苯唑西林; 化合物Ⅲd、Ⅲe、Ⅲf、Ⅲh和Ⅲi对MRSA的MIC分别为32、8、4、32和16 μg·mL^-1, 优于苯唑西林(MIC = 256 μg·mL^-1); 化合物Ⅲe、Ⅲf、Ⅲh和Ⅲi对FREC的MIC分别为32、16、32和8 μg·mL^-1, 优于苯唑西林(MIC = 64 μg·mL^-1)。综合来看, 在所设计合成的衍生物中, 目标物Ⅲf和Ⅲi对S. aureus、E. coli、MRSA和FREC的活性最为突出, 且具有广谱性。

构效关系分析: ① R为氟原子取代且位于苯环对位的目标物通常有更好的抗菌活性, 可能与靶标的结合位点或作用力有关; ②取代基R₁为甲基、丁基和异戊基时, 抗菌活性都不佳, 为乙基和异丙基时, 抗菌活性较为显著, 推测取代基R₁需要合适的大小, 可能与空间效应有关。

3 小结

依据分子杂合策略, 设计合成的含氨基噻唑肟结构的膦酸酯衍生物有较好的抗菌活性, 尤其是化合物Ⅲf和Ⅲi对S. aureus和E. coli的活性与对照药相当, 对MRSA和FREC的活性优于对照药。后续有必要以此结合体为基础, 进一步丰富取代基或官能团的类型和位置, 进行结构优化与深入研究。

实验部分

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用SGW X-4显微熔点仪测定熔点; NMR用Bruker Avance 400型核磁共振仪测定; 质谱数据用Agilent 6460质谱仪测得。

氨基噻肟酸、二硫化二苯并噻唑、亚磷酸三乙酯、三乙胺、苯甲醛、邻氟苯甲醛、对氟苯甲醛、三氟甲磺酸铝、亚磷酸二甲酯、亚磷酸二乙酯、亚磷酸二异丙酯、亚磷酸二丁酯、亚磷酸二异戊酯、三苯基膦均为化学纯, 购于百灵威试剂有限公司; 其余溶剂或试剂均为分析纯, 购于安徽优昇生物科技有限公司。

1 化合物的合成

1.1 中间体Ⅰ的合成

在15 ℃下, 依次将二硫化二苯并噻唑6.75 mmol和1, 2-二氯乙烷20 mL加入50 mL反应瓶中, 反应20 min, 再加入氨基噻肟酸5 mmol, 反应30 min, 再加入三乙胺2.5 mmol, 反应60 min, 再加入亚磷酸三乙酯6.75 mmol, 反应4 h, 减压过滤, 干燥, 得淡黄色粉末, 即中间体Ⅰ。

1.2 中间体Ⅱ的合成

依次称取芳香甲醛2.4 mmol、乙酸铵2 mmol和亚磷酸酯2 mmol于50 mL反应瓶中, 室温反应10 min, 再加入三氟甲磺酸铝0.01 mmol, 在95 ℃下反应, 薄层色谱法跟踪, 完毕, 加20 mL蒸馏水; 接着, 用1 mol·L^-1的盐酸酸化至pH 1, 用环己烷萃取4次, 乙酸乙酯萃取4次, 1 mol·L^-1的氢氧化钠碱化至pH 7~8; 最后, 用乙酸乙酯萃取6次, 合并萃取液, 减压浓缩, 得中间体Ⅱ。

1.3 目标物Ⅲ的合成

取中间体Ⅱ 0.5 mmol、四氢呋喃20 mL和三乙胺0.3 g于50 mL反应瓶中, 搅拌下, 将中间体I 0.6 mmol加至反应瓶中, 室温反应, 薄层色谱法跟踪, 完毕, 减压过滤, 再用四氢呋喃重结晶, 制得目标物Ⅲ。

2 体外抗菌活性测试

金葡菌、大肠埃希菌源于北京北纳创联生物技术研究院; 耐药菌株: 耐甲氧西林金葡菌和耐氟喹诺酮大肠杆菌, 由遵义医科大学附属医院分离提供。以oxacillin对照药, 采用两倍稀释法测定目标物的MIC, 测试方法参照文献[18]。

作者贡献: 陈阳密负责活性研究、数据整理与撰写等; 安艳负责化学合成; 董向涛和卢子聪参与数据整理和构效关系分析; 杨家强负责指导与修改等工作。

利益冲突: 本文作者声明无任何利益冲突。

基金

收起

贵州省科技厅国际合作项目基金资助(黔科合外G字[2014]7013)
遵义市科技计划项目(遵市科合HZ字[2020]41号)

参考文献

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文献

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参考文献引证文献

排序方式：

[1]

Yang JQ, Wang Y, Zhou XR, et al. Synthesis and antibacterial activities of novel sulfonamide derivatives containing a fused-ring [J]. Acta Pharm Sin (药学学报), 2021, 56: 835-840.

[2]

Cordero-Díaz A, Robledo-Leal E, Hernández-Fernández E, et al. Novel α-aminophosphonates and α-aminophosphonic acids: synthesis, molecular docking and evaluation of antifungal activity against scedosporium species [J]. Molecules, 2022, 27: 3886.

[3]

Yang JQ, Zeng FK, Yang X, et al. Synthesis and antitumor activity of phosphonate derivatives containing amino acid [J]. Acta Pharm Sin (药学学报), 2016, 51: 1105-1109.

[4]

Hkiri S, Mekni-Toujani M, Üstün E, et al. Synthesis of novel 1, 3, 4-oxadiazole-derived α-aminophosphonates/α-aminophosphonic acids and evaluation of their in vitro antiviral activity against the avian coronavirus infectious bronchitis virus [J]. Pharmaceutics, 2023, 15: 114.

[5]

Kandula M, Gundluru M, Nemallapudi BR, et al. Synthesis, antioxidant activity, and α‐glucosidase enzyme inhibition of α‐aminophosphonate derivatives bearing piperazine‐1, 2, 3‐triazole moiety [J]. J Heterocyclic Chem, 2020, 58: 172-181.

[6]

Yelamanda RK, Jeelan BS, Monika K, et al. Synthesis and anti-Alzheimer potential of novel α-aminophosphonate derivatives and probing their molecular interaction mechanism with acetylcholinesterase [J]. Eur J Med Chem, 2023, 253: 115288.

[7]

Zhang GP, Hao GF, Pan JK, et al. Asymmetric synthesis and bioselective activities of α-aminophosphonates based on the dufulin motif [J]. J Agric Food Chem, 2016, 64: 4207-4213.

[8]

Ali OM, Alotaibi MT, Zaki YH, et al. Design, synthesis, and spectroscopic studies of some new α-aminophosphonate analogues derived from 4-hydroxybenzaldehyde with special reference to anticancer activity [J]. Drug Des Devel Ther, 2022, 16: 2589-2599.

[9]

Poola S, Nagaripati S, Tellamekala S, et al. Green synthesis, antibacterial, anti-viral and molecular docking studies of α-aminophosphonates [J]. Synthetic Commun, 2020, 50: 1-18.

[10]

K'tir H, Amira A, Benzaid C, et al. Synthesis, bioinformatics and biological evaluation of novel α-aminophosphonates as antibacterial agents: DFT, molecular docking and ADME/T studies [J]. J Mol Struct, 2022, 1250: 131635.

[11]

Yang XC, Zeng CM, Avula SR, et al. Novel coumarin aminophosphonates as potential multitargeting antibacterial agents against Staphylococcus aureus [J]. Eur J Med Chem, 2023, 245: 114891.

[12]

Das D, Sikdar P, Bairagi M. Recent developments of 2-aminothiazoles in medicinal chemistry [J]. Eur J Med Chem, 2016, 109: 89-98.

[13]

Wang LL, Battini N, Bheemanaboina R, et al. Design and synthesis of aminothiazolyl norfloxacin analogues as potential antimicrobial agents and their biological evaluation [J]. Eur J Med Chem, 2019, 167: 105e123.

[14]

Tabei A, Ejtemaei R, Mahboubi A, et al. Synthesis of new 2-(5-(5-nitrofuran-2-yl)-1, 3, 4-thiadiazol-2-ylimino) thiazolidin-4-one derivatives as anti-MRSA and anti-H. pylori agents [J]. BMC Chem, 2022, 16: 38.

[15]

Chen GH, Yang Y, Lin C, et al. Synthesis and antibacterial activity of 7β-[2-(2-substituted aminothiazol-4-yl)-(Z)-2-methoxyiminoacetylamido]-3-quaternaryammoniummethyl-cephalosporins [J]. Acta Pharm Sin (药学学报), 2009, 44: 366-370.

[16]

Li ZW, Lu X, Wang YX, et al. Synthesis and antibacterial evaluation against resistant Gram-negative bacteria of monobactams bearing various substituents on oxime residue [J]. Bioorg Chem, 2020, 94: 103487.

[17]

Shen ZW, Xu W, Yu JF, et al. Synthesis and in vitro antibacterial activity of new aminothiazole-oximepiperidone cephalosporins [J]. Bioorg Med Chem Lett, 2021, 40: 127928.

[18]

Shen GX. Microbiology and Immunology (微生物与免疫学) [M]. Beijing: People's Medical Publishing House, 2007: 326-328.

2024年第59卷第1期

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doi: 10.16438/j.0513-4870.2023-0790

接收时间：2023-06-27
首发时间：2025-11-28
出版时间：2024-01-12

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收稿日期：2023-06-27
修回日期：2023-08-15

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贵州省科技厅国际合作项目基金资助(黔科合外G字[2014]7013)

遵义市科技计划项目(遵市科合HZ字[2020]41号)

作者信息

遵义医科大学药学院, 贵州遵义 563000

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^*杨家强, Tel: 86-851-28642339, E-mail: yjqcn@126.com

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2种不同金属材料的力学参数

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

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Compd.	Appearance	Yield/%	mp/℃
Ⅲa	White solid	66	161-162
Ⅲb	White solid	68	165-166
Ⅲc	White solid	70	179-180
Ⅲd	White solid	75	171-172
Ⅲe	White solid	80	167-169
Ⅲf	White solid	87	169-170
Ⅲg	White solid	78	222-224
Ⅲh	White solid	65	213-214
Ⅲi	White solid	80	214-215
Ⅲj	White solid	61	192-193
Ⅲk	White solid	90	187-188
Ⅲl	White solid	89	182-183
Ⅲm	White solid	68	185-187
Ⅲn	White solid	69	188-189
Ⅲo	White solid	60	188-190

Compd.

Appearance

Yield/%

mp/℃

Ⅲa

White solid

161-162

Ⅲb

White solid

165-166

Ⅲc

White solid

179-180

Ⅲd

White solid

171-172

Ⅲe

White solid

167-169

Ⅲf

White solid

169-170

Ⅲg

White solid

222-224

Ⅲh

White solid

213-214

Ⅲi

White solid

214-215

Ⅲj

White solid

192-193

Ⅲk

White solid

187-188

Ⅲl

White solid

182-183

Ⅲm

White solid

185-187

Ⅲn

White solid

188-189

Ⅲo

White solid

188-190

Compd.	¹H NMR, ¹³C NMR and MS
Ⅲa	¹H NMR (400 MHz, CDCl₃) δ: 9.28 (s, 1H, CONH), 7.49 (d, 2H, J = 8.0 Hz, ArH), 7.32-7.37 (m, 3H, ArH), 6.63 (s, 1H, ArH), 6.30 (s, 2H, NH₂), 5.70 (dd, 1H, J = 8.0, 8.0 Hz, PCH), 3.88 (s, 3H, CH₃), 3.73 (d, 3H, J = 8.0 Hz, CH₃), 3.65 (d, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 169.9, 163.3, 160.7, 148.3, 142.3, 133.7, 132.6, 128.2, 128.0, 127.9, 110.1, 61.5, 53.2, 53.0, 48.4. ESI MS (m/z): 399.1 [M+H]⁺.
Ⅲb	¹H NMR (400 MHz, CDCl₃) δ: 9.21 (s, 1H, CONH), 7.62 (t, 1H, J=12.0 Hz, ArH), 7.33-7.36 (m, 1H, ArH), 7.18-7.23 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.32 (s, 2H, NH₂), 5.84 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.73 (s, 3H, CH₃), 3.65 (d, 3H, J = 12.0 Hz, CH₃), 3.53 (d, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.8, 162.6, 160.7 (J_C-F = 77 Hz), 158.4, 149.4, 143.3, 130.5, 125.0, 122.7, 115.7, 115.6, 109.8, 62.3, 55.3, 54.2, 53.7. ESI MS (m/z): 417.1 [M+H]⁺.
Ⅲc	¹H NMR (400 MHz, CDCl₃) δ: 9.29 (s, 1H, CONH), 7.51 (d, J = 16.0 Hz, 2H, ArH), 7.08-7.13 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.28 (s, 2H, NH₂), 5.70 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.88 (s, 3H, CH₃), 3.74 (d, 3H, J = 12.0 Hz, CH₃), 3.67 (d, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 170.0, 163.9, 163.2 (J_C-F = 12 Hz), 161.4, 148.3, 142.3, 130.1, 130.0, 115.1, 114.9, 110.0, 61.5, 53.3, 53.0, 49.3. ESI MS (m/z): 417.1 [M+H]⁺.
Ⅲd	¹H NMR (400 MHz, CDCl₃) δ: 9.26 (s, 1H, CONH), 7.49 (d, 2H, J = 8.0 Hz, ArH), 7.34-7.37 (m, 3H, ArH), 6.63 (s, 1H, ArH), 6.32 (s, 2H, NH₂), 5.64 (dd, 1H, J = 8.0, 8.0 Hz, PCH), 3.92-4.01 (m, 4H, 2CH₂), 3.89 (s, 3H, CH₃), 1.25 (t, 3H, J = 12.0 Hz, CH₃), 1.18 (t, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 169.8, 163.3, 161.6, 148.3, 142.4, 133.9, 132.8, 128.2, 128.1, 127.9, 110.2, 63.5, 63.3, 61.5, 50.6, 15.3, 15.1. ESI MS (m/z): 427.1 [M+H]⁺.
Ⅲe	¹H NMR (400 MHz, CDCl₃) δ: 9.23 (s, 1H, CONH), 7.62 (t, 1H, J = 8.0 Hz, ArH), 7.33-7.35 (m, 1H, ArH), 7.11-7.20 (m, 2H, ArH), 6.59 (s, 1H, ArH), 6.33 (s, 2H, NH₂), 5.79 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.82-4.02 (m, 4H, 2CH₂), 3.72 (s, 3H, CH₃), 1.16 (t, 3H, J = 12.0 Hz, CH₃), 1.03 (t, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.8, 162.7, 160.9 (J_C-F = 98 Hz), 158.5, 149.4, 143.4, 130.6, 124.9, 122.8, 115.6, 115.4, 109.9, 63.3, 63.0, 62.3, 53.7, 16.7, 16.5. ESI MS (m/z): 445.2 [M+H]⁺.
Ⅲf	¹H NMR (400 MHz, CDCl₃) δ: 9.28 (s, 1H, CONH), 7.50-7.54 (m, 2H, ArH), 7.08-7.13 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.31 (s, 2H, NH₂), 5.64 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 3.99-4.12 (m, 4H, 2CH₂), 3.90 (s, 3H, CH₃), 1.25 (d, 3H, J = 16.0 Hz, CH₃), 1.20 (d, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.7, 163.2, 162.5 (J_C-F = 9 Hz), 160.6, 149.5, 143.5, 130.8, 130.7, 115.5, 115.3, 109.9, 63.1, 62.9, 62.3, 48.2, 16.6, 16.5. ESI MS (m/z): 445.1 [M+H]⁺.
Ⅲg	¹H NMR (400 MHz, CDCl₃) δ: 9.66 (s, 1H, CONH), 7.46-7.48 (m, 2H, ArH), 7.27-7.34 (m, 3H, ArH), 6.61 (s, 1H, ArH), 6.33 (s, 2H, NH₂), 5.49 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.63-4.75 (m, 1H, CH), 4.49-4.57 (m, 1H, CH), 3.75 (s, 3H, CH₃), 1.07-1.36 (m, 12H, 4CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.7, 162.6, 161.4, 143.6, 135.4, 128.8, 128.7, 128.5, 128.1, 114.9, 109.9, 72.8, 72.6, 61.5, 56.5, 23.0, 22.9, 22.7, 22.2. ESI MS (m/z): 455.2 [M+H]⁺.
Ⅲh	¹H NMR (400 MHz, CDCl₃) δ: 9.25 (s, 1H, CONH), 7.58-7.62 (m, 1H, ArH), 7.33-7.37 (m, 1H, ArH), 7.11-7.21 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.31 (s, 2H, NH₂), 5.94 (dd, 1H, J = 12.0, 12.0 Hz, PCH), 4.69-4.73 (m, 1H, CH), 4.50-4.55 (m, 1H, CH), 3.85 (s, 3H, CH₃), 1.07-1.34 (m, 12H, 4CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 169.9, 163.3, 161.3 (J_C-F = 74 Hz), 158.8, 148.4, 142.3, 130.0, 129.7, 124.0, 114.9, 110.2, 72.8, 72.5, 61.5, 56.5, 23.0, 22.9, 22.7, 22.2. ESI MS (m/z): 473.2 [M+H]⁺.
Ⅲi	¹H NMR (400 MHz, CDCl₃) δ: 9.01 (s, 1H, CONH), 7.58-7.61 (m, 2H, ArH), 6.95-6.99 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.22 (s, 2H, NH₂), 5.60 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.68-4.74 (m, 1H, CH), 4.24-4.32 (m, 1H, CH), 3.69 (s, 3H, CH₃), 1.18-1.38 (m, 12H, 4CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 163.8, 161.6 (J_C-F = 7 Hz), 161.3, 147.0, 143.6, 131.4, 129.6, 115.3, 115.1, 110.5, 73.2, 72.3, 61.9, 58.3, 24.2, 24.1, 23.9, 22.9. ESI MS (m/z): 473.2 [M+H]⁺.
Ⅲj	¹H NMR (400 MHz, CDCl₃) δ: 9.25 (s, 1H, CONH), 7.63 (d, 2H, J = 8.0 Hz, ArH), 7.22-7.30 (m, 3H, ArH), 6.63 (s, 1H, ArH), 6.26 (s, 2H, NH₂), 5.70 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.05-4.27 (m, 2H, CH₂), 3.46-3.75 (m, 2H, CH₂), 3.22 (s, 3H, CH₃), 1.65-1.72 (m, 2H, CH₂), 1.38-1.45 (m, 2H, CH₂), 1.30-1.35 (m, 2H, CH₂), 1.09-1.22 (m, 2H, CH₂), 0.89 (t, 3H, J = 16.0 Hz, CH₃), 0.74 (t, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 163.3, 161.9, 146.9, 143.8, 133.0, 128.2, 126.6, 125.3, 122.6, 110.1, 67.5, 67.3, 61.9, 49.0, 32.4, 32.2, 18.7, 18.4, 13.6, 13.4. ESI MS (m/z): 483.2 [M+H]⁺.
Ⅲk	¹H NMR (400 MHz, CDCl₃) δ: 9.17 (s, 1H, CONH), 7.31-7.46 (m, 1H, ArH), 7.21-7.26 (m, 1H, ArH), 7.10-7.14 (m, 1H, ArH), 6.98-7.02 (m, 1H, ArH), 6.67 (s, 1H, ArH), 6.16-6.23 (m, 3H, PCH+NH₂), 4.08-4.36 (m, 2H, CH₂), 3.60-3.72 (m, 2H, CH₂), 3.31 (s, 3H, CH₃), 1.67-1.74 (m, 2H, CH₂), 1.33-1.46 (m, 4H, 2CH₂), 1.11-1.23 (m, 2H, CH₂), 0.90 (t, 3H, J = 16.0 Hz, CH₃), 0.75 (t, 3H, J = 16.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 162.2, 161.9 (J_C-F = 81 Hz), 154.4, 143.6, 129.7, 126.6, 125.3, 122.6, 114.7, 110.3, 67.7, 67.3, 62.0, 53.4, 32.4, 32.2, 18.4, 18.3, 13.6, 13.4. ESI MS (m/z): 501.2 [M+H]⁺.
Ⅲl	¹H NMR (400 MHz, CDCl₃) δ: 9.31 (s, 1H, CONH), 7.64 (d, 2H, J = 8.0 Hz, ArH), 6.96-6.98 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.31 (s, 2H, NH₂), 5.69 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.04-4.28 (m, 2H, CH₂), 3.52-3.78 (m, 2H, CH₂), 3.23 (s, 3H, CH₃), 1.65-1.72 (m, 2H, CH₂), 1.33-1.45 (m, 4H, 2CH₂), 1.11-1.22 (m, 2H, CH₂), 0.89 (t, 3H, J = 16.0 Hz, CH₃), 0.76 (t, 3H, J = 12.0 Hz, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.3, 163.7, 161.9 (J_C-F = 10 Hz), 146.9, 143.7, 131.4, 126.6, 125.3, 115.4, 115.2, 110.1, 67.6, 67.5, 61.9, 48.2, 32.4, 32.2, 18.7, 18.4, 13.6, 13.4. ESI MS (m/z): 501.2 [M+H]⁺.
Ⅲm	¹H NMR (400 MHz, CDCl₃) δ: 9.29 (s, 1H, CONH), 7.63 (d, 2H, J = 4.0 Hz, ArH), 7.22-7.32 (m, 3H, ArH), 6.62 (s, 1H, ArH), 6.30 (s, 2H, NH₂), 5.71 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 3.80-4.12 (m, 2H, CH₂), 3.50-3.71 (m, 2H, CH₂), 3.42 (s, 3H, CH₃), 1.94-2.00 (m, 1H, CH), 1.58-1.65 (m, 1H, CH), 0.94-0.96 (m, 6H, 2CH₃), 0.67 (t, 6H, J = 16.0 Hz, 2CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.2, 161.9, 146.9, 143.7, 128.3, 128.1, 126.6, 125.3, 122.6, 121.3, 110.0, 73.5, 73.3, 61.9, 49.0, 29.2, 29.0, 18.8, 18.7, 18.4, 18.3. ESI MS (m/z): 511.2 [M+H]⁺.
Ⅲn	¹H NMR (400 MHz, CDCl₃) δ: 9.26 (s, 1H, CONH), 8.01-8.03 (m, 1H, ArH), 7.19-7.23 (m, 1H, ArH), 7.08-7.11 (m, 1H, ArH), 6.96-7.00 (m, 1H, ArH), 6.64 (s, 1H, ArH), 6.30 (s, 2H, NH₂), 6.17 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.12-4.18 (m, 1H, CH₂), 3.83-3.88 (m, 1H, CH₂), 3.55-3.61 (m, 1H, CH₂), 3.33-3.39 (m, 1H, CH₂), 3.27 (s, 3H, CH₃), 1.93-2.01 (m, 1H, CH), 1.60-1.67 (m, 1H, CH), 0.95-0.97 (m, 6H, 2CH₃), 0.69 (t, 6H, J = 12.0 Hz, 2CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.3, 161.9 (J_C-F = 89 Hz), 158.4, 146.9, 143.6, 131.9, 129.8, 125.3, 121.3, 114.7, 110.1, 73.7, 73.2, 61.9, 42.1, 29.2, 29.0, 18.8, 18.7, 18.3, 18.2. ESI MS (m/z): 529.2 [M+H]⁺.
Ⅲo	¹H NMR (400 MHz, CDCl₃) δ: 9.25 (s, 1H, CONH), 7.62-7.65 (m, 2H, ArH), 6.96-7.00 (m, 2H, ArH), 6.62 (s, 1H, ArH), 6.26 (s, 2H, NH₂), 5.69 (dd, 1H, J = 16.0, 16.0 Hz, PCH), 4.07-4.12 (m, 1H, CH₂), 3.80-3.85 (m, 1H, CH₂), 3.54-3.60 (m, 1H, CH₂), 3.29-3.33 (m, 1H, CH₂), 3.26 (s, 3H, CH₃), 1.94-2.02 (m, 1H, CH), 1.62-1.69 (m, 1H, CH), 0.95-0.97 (m, 6H, 2CH₃), 0.71 (t, 6H, J = 12.0 Hz, 2CH₃). ¹³C NMR (101 MHz, CDCl₃) δ: 168.3, 163.8, 161.8 (J_C-F = 7 Hz), 161.3, 146.9, 143.6, 131.3, 129.0, 115.4, 115.2, 110.1, 73.6, 73.4, 61.8, 48.2, 29.2, 29.0, 18.8, 18.7, 18.4, 18.3. ESI MS (m/z): 529.2 [M+H]⁺.

Compd.

¹H NMR, ¹³C NMR and MS

Ⅲa

Ⅲb

Ⅲc

Ⅲd

Ⅲe

Ⅲf

Ⅲg

Ⅲh

Ⅲi

Ⅲj

Ⅲk

Ⅲl

Ⅲm

Ⅲn

Ⅲo

Compd.	R	R₁	MIC/μg·mL^-1
Ⅲa	H	CH₃	256	256	1 024	512
Ⅲb	2-F	CH₃	128	128	128	512
Ⅲc	4-F	CH₃	32	64	128	64
Ⅲd	H	C₂H₅	32	128	32	128
Ⅲe	2-F	C₂H₅	8	16	8	32
Ⅲf	4-F	C₂H₅	1	8	4	16
Ⅲg	H	CH(CH₃)₂	64	64	64	64
Ⅲh	2-F	CH(CH₃)₂	32	16	32	32
Ⅲi	4-F	CH(CH₃)₂	4	4	16	8
Ⅲj	H	(CH₂)₃CH₃	1 024	1 024	> 1 024	> 1 024
Ⅲk	2-F	(CH₂)₃CH₃	512	1 024	1 024	1 024
Ⅲl	4-F	(CH₂)₃CH₃	256	512	256	512
Ⅲm	H	(CH₂)₂CH(CH₃)₂	> 1 024	1 024	> 1 024	> 1 024
Ⅲn	2-F	(CH₂)₂CH(CH₃)₂	1 024	512	> 1 024	512
Ⅲo	4-F	(CH₂)₂CH(CH₃)₂	1 024	256	> 1 024	1 024
Oxacillin			0.5	16	256	64

Compd.

R₁

MIC/μg·mL^-1

S. aureus

E. coli

MRSA

FREC

Ⅲa

CH₃

256

1 024

512

Ⅲb

2-F

CH₃

128

512

Ⅲc

4-F

CH₃

128

Ⅲd

C₂H₅

128

Ⅲe

2-F

C₂H₅

Ⅲf

4-F

C₂H₅

Ⅲg

CH(CH₃)₂

Ⅲh

2-F

CH(CH₃)₂

Ⅲi

4-F

CH(CH₃)₂

Ⅲj

(CH₂)₃CH₃

1 024

> 1 024

Ⅲk

2-F

(CH₂)₃CH₃

512

1 024

Ⅲl

4-F

(CH₂)₃CH₃

256

512

256

512

Ⅲm

(CH₂)₂CH(CH₃)₂

> 1 024

1 024

> 1 024

Ⅲn

2-F

(CH₂)₂CH(CH₃)₂

1 024

512

> 1 024

512

Ⅲo

4-F

(CH₂)₂CH(CH₃)₂

1 024

256

> 1 024

1 024

Oxacillin

0.5

256