Journal of Medicinal Chemistry
Article
133.2, 129.2, 128.6, 127.8, 126.6, 126.3, 126.2 (q), 126.0, 123.9,
117.5, 115.4, 96.2, 72.3, 46.4, 18.8 ppm; purity (UPLC-MS): 97%, tR:
3.39 min (method: gradient of 20% ACN to 90% within 5 min);
HRMS (MALDI): m/z calculated for C18H16F3N3O4 + K+ [M + K+]:
434.07245; found: 434.07242.
m/z calculated C20H18F3N3O3 + H+ [M + H+]: 406.13730; found:
406.13723.
3-(3-(1-Hydroxyureido)pent-1-yn-1-yl)-N-(2-(trifluoromethyl)-
benzyl)benzamide 7i. Procedure F; 80 mg (0.20 mmol) 15b, 30 mg
(0.22 mmol) 8e, 1 mg (0.004 mmol) Pd(ACN)2Cl2, 2 mg (0.01
mmol) CuI, 3 mg (0.01 mmol) PPh3, 0.1 mL (0.24 mmol, 1.2 equiv)
DIPA, 15 mL ethyl acetate, 43 h, further purification with column
chromatography (hexane/acetone 2:3), further purification with
preparative HPLC (linear gradient from 5% ACN to 90% within 10
min, 90% ACN for 6 min);white solid (58 mg, 0.14 mmol, 70%); 1H-
NMR (500 MHz, acetone-d6) δ = 8.67 (s, 1H), 8.43 (t, J = 6.0 Hz,
1H), 8.00 (t, J = 1.5 Hz, 1H), 7.94 (td, J = 1.5, 7.8 Hz, 1H), 7.74−
7.71 (m, 1H), 7.69−7.55 (m, 3H), 7.53−7.43 (m, 2H), 6.13 (s, 2H),
5.05 (t, J = 7.8 Hz, 1H), 4.83 (d, J = 5.7 Hz, 2H), 1.91−1.83 (m, 2H),
1.02 (t, J = 7.4 Hz, 3H) ppm; 13C-NMR (125 MHz, acetone-d6) δ =
166.9, 162.3, 138.6, 138.6, 135.7, 135.1, 133.3, 131.2, 129.8, 129.5,
128.2, 128.0, 126.7 (q), 126.6, 124.4, 89.9, 83.0, 53.3, 40.6 (q), 26.6,
11.1 ppm; purity (HPLC-MS): 97% tR: 10.03 min (method: gradient
of 10% ACN to 90% within 10 min, 90% ACN for 6 min); HRMS
(MALDI): m/z calculated C21H20F3N3O3 + H+ [M + H+]:
420.15295; found: 420.15279.
3-(3-(1-Hydroxyureido)but-1-yn-1-yl)-4-methyl-N-(2-
(trifluoromethyl)benzyl)-benzamide 7e. Procedure F; 90 mg (0.22
mmol) 15l, 31 mg (0.24 mmol) 8a, 1 mg (0.004 mmol, 0.03 equiv)
Pd(ACN)2Cl2, 2 mg (0.01 mmol, 0.04 equiv) CuI, 5 mg (0.01 mmol,
0.09 equiv) PPh3, 0.1 mL (0.26 mmol, 1.2 equiv) DIPA, 12 mL ethyl
acetate, 39 h, further purification with column chromatography (ethyl
acetate 100%); yellow solid (42 mg, 0.10 mmol, 47%); 1H-NMR (300
MHz, DMSO-d6) δ = 9.36 (s, 1H), 9.15 (t, J = 5.7 Hz, 1H), 7.94 (d, J
= 1.8 Hz, 1H), 7.85−7.33 (m, 6H), 6.59 (s, 2H), 5.18 (q, J = 7.0 Hz,
1H), 4.65 (d, J = 5.4 Hz, 2H), 2.41 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H)
ppm; 13C-NMR (75 MHz, DMSO-d6) δ = 165.7, 161.7, 143.3, 137.6
(d), 132.7, 131.6, 130.2, 129.6, 128.3, 127.3, 126.3, 125.9, 125.7 (q),
122.5, 94.6, 80.0, 46.1, 20.2, 18.8 ppm; purity (UPLC-MS): 98% tR:
3.99 min (method: gradient of 20% ACN to 90% within 5 min);
HRMS (MALDI): m/z calculated C21H20F3N3O3 + H+ [M + H+]:
420.15295; found: 420.15267.
3-(3-(1-Hydroxyureido)hex-1-yn-1-yl)-N-(2-(trifluoromethyl)-
benzyl)benzamide 7j. Procedure F; 80 mg (0.20 mmol) 15b, 30 mg
(0.22 mmol) 8f, 1 mg (0.004 mmol) Pd(ACN)2Cl2, 2 mg (0.01
mmol) CuI, 2 mg (0.01 mmol) PPh3, 0.1 mL (0.24 mmol, 1.2 equiv)
DIPA, 15 mL ethyl acetate, 43 h, further purification with column
chromatography (hexane/acetone 2:3), further purification with
preparative HPLC (linear gradient from 5% ACN to 90% within 10
min, 90% ACN for 6 min);white solid (57 mg, 0.13 mmol, 67%); 1H-
NMR (500 MHz, acetone-d6) δ = 8.65 (s, 1H), 8.43 (t, J = 5.5 Hz,
1H), 8.12−7.76 (m, 2H), 7.73 (d, J = 7.9 Hz, 1H), 7.69−7.55 (m,
3H), 7.52−7.34 (m, 2H), 6.12 (s, 2H), 5.16 (t, J = 7.7 Hz, 1H), 4.83
(d, J = 5.7 Hz, 2H), 1.83 (q, J = 7.7 Hz, 2H), 1.53−1.45 (m, 2H),
0.95 (t, J = 7.4 Hz, 3H) ppm; 13C-NMR (125 MHz, acetone-d6) δ =
166.9, 162.2, 138.6, 138.6, 135.7, 135.1, 133.3, 131.2, 129.8, 129.5,
128.2, 128.0, 126.8, 126.6 (q), 124.6, 124.4, 90.0, 82.9, 51.4, 40.6 (q),
35.3, 20.0, 13.9 ppm; purity (HPLC-MS): 97% tR: 10.51 min
(method: gradient of 10% ACN to 90% within 10 min, 90% ACN for
6 min); HRMS (MALDI): m/z calculated C22H22F3N3O3 + Na+ [M +
Na+]: 456.15055; found: 456.15027.
3-(3-(1-Hydroxyureido)-4-methylpent-1-yn-1-yl)-N-(2-
(trifluoromethyl)benzyl)-benzamide 7k. Procedure F; 100 mg (0.25
mmol) 15b, 42 mg (0.27 mmol) 8g, 1 mg (0.005 mmol)
Pd(ACN)2Cl2, 6 mg (0.03 mmol, 0.13 equiv) CuI, 11 mg (0.04
mmol, 0.17 equiv) PPh3, 0.1 mL (0.30 mmol, 1.2 equiv) DIPA, 15 mL
ethyl acetate, 39 h, further purification with column chromatography
(ethyl acetate 100%), further purification with preparative HPLC
(30% ACN for 3 min, linear gradient from 30% ACN to 80% within 8
min, 90% ACN for 6 min); white solid (20 mg, 0.05 mmol, 19%); 1H-
NMR (300 MHz, DMSO-d6) δ = 9.36−9.15 (m, 2H), 8.06−7.15 (m,
7H), 6.53 (s, 2H), 4.79−4.55 (m, 3H), 3.68−3.11 (m, 1H), 2.12−
1.97 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H) ppm;
13C-NMR (125 MHz, DMSO-d6) δ = 165.7, 161.8, 137.5 (d), 134.3,
3-(3-(1-Hydroxyureido)prop-1-yn-1-yl)-N-(2-(trifluoromethyl)-
benzyl)benzamide 7f. Procedure F; 100 mg (0.25 mmol) 15b, 30 mg
(0.27 mmol) 8b, 1 mg (0.005 mmol) Pd(ACN)2Cl2, 2 mg (0.01
mmol) CuI, 3 mg (0.01 mmol) PPh3, 0.1 mL (0.30 mmol, 1.2 equiv)
DIPA, 15 mL ethyl acetate, 39 h, further purification with column
chromatography (hexane/ethyl acetate 4:1−0:1);brown solid (50 mg,
0.13 mmol, 52%); 1H-NMR (300 MHz, DMSO-d6) δ = 9.62 (s, 1H),
9.23 (t, J = 5.7 Hz, 1H), 8.00 (t, J = 1.4 Hz, 1H), 7.92 (td, J = 1.3, 7.8
Hz, 1H), 7.77−7.43 (m, 6H), 6.56 (s, 2H), 4.66 (d, J = 5.4 Hz, 2H),
4.35 (s, 2H) ppm; 13C-NMR (75 MHz, DMSO-d6) δ = 165.7, 161.6,
137.4, 134.3 (d), 132.7, 132.1, 131.5 (d), 130.2, 128.9, 128.8, 128.7,
128.3, 127.5, 127.3, 126.3, 125.8 (q), 122.6, 87.1, 81.8 ppm; purity
(HPLC-MS): 97% tR: 7.62 min (method: gradient of 30% ACN to
90% within 10 min, 90% ACN for 6 min); HRMS (MALDI): m/z
calculated C19H16F3N3O3 + H+ [M + H+]: 392.12165; found:
392.12133.
(S)-3-(3-(1-Hydroxyureido)but-1-yn-1-yl)-N-(2-(trifluoromethyl)-
benzyl)benzamide 7g. Procedure F; 80 mg (0.20 mmol) 15b, 30 mg
(0.22 mmol) 8c, 1 mg (0.004 mmol) Pd(ACN)2Cl2, 2 mg (0.01
mmol) CuI, 3 mg (0.01 mmol) PPh3, 0.1 mL (0.24 mmol, 1.2 equiv)
DIPA, 11 mL ethyl acetate, 43 h, further purification with column
chromatography (hexane/acetone 2:3), further purification with
preparative HPLC (5% ACN to 90% within 10 min, 90% ACN for
1
6 min); white solid (27 mg, 0.07 mmol, 34%); H-NMR (500 MHz,
acetone-d6) δ = 8.69 (s, 1H), 8.42 (t, J = 5.3 Hz, 1H), 8.05−7.91 (m,
2H), 7.73 (d, J = 7.9 Hz, 1H), 7.70−7.54 (m, 3H), 7.53−7.43 (m,
2H), 6.13 (s, 2H), 5.27 (q, J = 7.0 Hz, 1H), 4.83 (d, J = 5.7 Hz, 2H),
1.45 (d, J = 7.0 Hz, 3H) ppm; 13C-NMR (125 MHz, acetone-d6) δ =
166.8, 162.0, 135.7, 133.4, 131.2, 129.8, 129.5, 128.2, 128.0, 126.6
(q), 124.4, 90.8, 82.2, 47.3, 40.6 (q), 18.6 ppm; purity (HPLC-MS):
97% tR: 9.66 min (method: gradient of 10% ACN to 90% within 10
min, 90% ACN for 6 min); HRMS (MALDI): m/z calculated
C20H18F3N3O3 + H+ [M + H+]: 406.13730; found: 406.13715.
(R)-3-(3-(1-Hydroxyureido)but-1-yn-1-yl)-N-(2-(trifluoromethyl)-
benzyl)benzamide 7h. Procedure F; 80 mg (0.20 mmol) 15b, 30 mg
(0.22 mmol) 8d, 1 mg (0.004 mmol) Pd(ACN)2Cl2, 2 mg (0.01
mmol) CuI, 3 mg (0.01 mmol) PPh3, 0.1 mL (0.24 mmol, 1.2 equiv)
DIPA, 15 mL ethyl acetate, 43 h, further purification with column
chromatography (hexane/acetone 2:3), further purification with
preparative HPLC (linear gradient from 5% ACN to 90% within 10
min, 90% ACN for 6 min); white solid (29 mg, 0.07 mmol, 36%); 1H-
NMR (500 MHz, acetone-d6) δ = 8.69 (s, 1H), 8.42 (t, J = 5.4 Hz,
1H), 8.02−7.91 (m, 2H), 7.76−7.52 (m, 4H), 7.52−7.43 (m, 2H),
6.14 (s, 2H), 5.27 (q, J = 7.0 Hz, 1H), 4.83 (d, J = 5.7 Hz, 2H), 1.45
(d, J = 7.0 Hz, 3H) ppm; 13C-NMR (125 MHz, acetone-d6) δ =
166.9, 162.0, 138.6, 138.6, 135.7, 135.1, 133.4, 131.2, 129.8, 129.5,
128.2, 128.0, 126.6 (q), 124.4, 90.8, 82.2, 47.3, 40.6 (q), 18.6 ppm;
purity (HPLC-MS): 97% tR: 9.65 min (method: gradient of 10%
ACN to 90% within 10 min, 90% ACN for 6 min); HRMS (MALDI):
134.2, 132.8, 130.1, 128.9, 128.3, 127.4 (d), 126.3, 125.8 (q), 122.8,
89.3, 82.5, 56.7, 30.5, 20.0, 19.4 ppm; purity (UPLC-MS): 99% tR:
3.93 min (method: gradient of 20% ACN to 90% within 5 min);
HRMS (MALDI): m/z calculated C22H22F3N3O3 + H+ [M + H+]:
434.16860; found: 434.16810.
3-(3-(1-Hydroxyureido)-5-methylhex-1-yn-1-yl)-N-(2-
(trifluoromethyl)benzyl)-benzamide 7l. Procedure F; 100 mg (0.25
mmol) 15b, 46 mg (0.27 mmol) 8h, 1 mg (0.005 mmol, 0.03 equiv)
Pd(ACN)2Cl2, 2 mg (0.01 mmol) CuI, 11 mg (0.04 mmol, 0.17
equiv) PPh3, 0.1 mL (0.30 mmol, 1.2 equiv) DIPA, 15 mL ethyl
acetate, 39 h, further purification with column chromatography
1
(DCM/MeOH 9:1); yellow solid (62 mg, 0.14 mmol, 56%); H-
NMR (300 MHz, DMSO-d6) δ = 9.33 (s, 1H), 9.24 (t, J = 5.8 Hz,
1H), 7.97−7.87 (m, 2H), 7.76−7.44 (m, 6H), 6.56 (s, 2H), 5.09 (t, J
= 7.8 Hz, 1H), 4.65 (d, J = 5.4 Hz, 2H), 1.81−1.59 (m, 3H), 0.92
(dd, J = 3.5, 6.5 Hz, 6H) ppm; 13C-NMR (125 MHz, DMSO-d6) δ =
165.7, 161.6, 137.4, 134.3, 134.2, 132.7, 130.1, 128.9, 128.3127.4 (d),
N
J. Med. Chem. XXXX, XXX, XXX−XXX