Journal of Medicinal Chemistry
Article
Supporting Information, Figure S37) δ 164.0, 163.9, 161.5, 161.4,
160.5, 160.4, 158.1, 158.0, 149.6, 144.6, 129.5, 1289.41, 128.38,
129.32, 125.8, 125.7, 110.7, 110.6, 110.4, 110.0, 103.7, 103.4, 103.2,
73.6, 73.5, 63.04, 62.99, 58.3, 56.1, 56.0, 53.7, 52.8, 31.6, 29.28, 29.27,
29.23, 29.17, 29.0, 27.2, 25.9, 22.3, 13.0. LRMS m/z calcd for
C26H41F2N5O 477.3, found 478.3 [M + H]+. Purity of the com-
pound was further confirmed by RP-HPLC by using method 2:
Rt = 16.06 min (96% pure; Supporting Information, Figure S38).
2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(4-
dodecylpiperazine)propan-2-ol (22). To a solution of compound 14
(50 mg, 0.21 mmol) in EtOH (3 mL), compound 7 (81 mg,
0.32 mmol) and Et3N (0.04 mL, 0.32 mmol) were added. The reaction
mixture was stirred at 80 °C for 12 h, and progress of the reaction was
monitored by TLC (1:9/MeOH:CH2Cl2, Rf 0.50). The organic layer
was removed under reduced pressure, and the residue was purified by
flash column chromatography (SiO2, 1:19/MeOH:CH2Cl2) to afford
compound 22 (80 mg, 80%) as a colorless liquid. 1H NMR (400 MHz,
CDCl3, Supporting Information, Figure S39) δ 8.10 (s, 1H), 7.76
(s, 1H), 7.53−7.46 (m, 1H), 6.83−6.74 (m, 2H), 4.50 (s, 2H), 3.05
(d, J = 13.6 Hz, 1H), 2.65 (d, J = 13.6 Hz, 1H), 2.60−2.28 (m, 8H),
1.45−1.43 (m, 2H), 1.28−1.19 (m, 20H), 0.85 (t, J = 6.6 Hz, 3H).
13C NMR (100 MHz, CDCl3, Supporting Information, Figure S40)
δ 164.0, 163.9, 161.5, 161.4, 160.1, 160.0, 157.7, 157.6, 151.0, 144.6,
129.34, 129.28, 129.24, 129.19, 126.19, 126.16, 126.1, 126.0, 111.62,
111.59, 111.41, 111.38, 104.5, 104.3, 104.2, 104.0, 72.01, 71.95, 62.22,
62.18, 58.5, 56.31, 56.26, 54.0, 53.1, 31.9, 29.59, 29.57, 29.53, 29.49,
29.4, 29.3, 27.4, 26.5, 22.6, 14.1. LRMS m/z calcd for C27H43F2N5O
491.3, found 492.3 [M + H]+. Purity of the compound was further
confirmed by RP-HPLC by using method 1: Rt = 3.12 min (97% pure;
2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(4-
tridecylpiperazine)propan-2-ol (23). To a solution of compound 14
(100 mg, 0.42 mmol) in EtOH (5 mL), compound 8 (169 mg,
0.63 mmol) and Et3N (0.09 mL, 0.63 mmol) were added. The reaction
mixture was stirred at 80 °C for 12 h, and progress of the reaction was
monitored by TLC (1:19/MeOH:CH2Cl2, Rf 0.48). The organic layer
was removed under reduced pressure, and the residue was purified by
flash column chromatography (SiO2, 1:19/MeOH:CH2Cl2) to afford
compound 23 (132 mg, 62%) as a yellow liquid. 1H NMR (400 MHz,
CD3OD, Supporting Information, Figure S42) δ 8.31 (s, 1H), 7.72
(s, 1H), 7.47−7.40 (m, 1H), 6.93−6.79 (m, 2H), 4.66 (d, J = 14.2 Hz,
1H), 4.57 (d, J = 14.2 Hz, 1H), 2.97 (d, J = 13.8 Hz, 1H), 2.77 (d, J =
13.8 Hz, 1H), 2.50−2.45 (m, 4H), 2.45−2.32 (m, 4H), 2.30−2.24
(m, 2H), 1.48−1.39 (m, 2H), 1.33−1.20 (m, 20H), 0.87 (t, J = 6.6 Hz,
3H). 13C NMR (100 MHz, CD3OD, Supporting Information,
Figure S43) δ 164.0, 163.9, 161.5, 161.4, 160.6, 160.4, 158.1, 158.0,
149.6, 144.6, 129.5, 129.42, 129.38, 129.32, 125.83, 125.79, 125.70,
125.67, 110.7, 110.6, 110.5, 110.4, 103.7, 103.44, 103.42, 103.2, 73.6,
73.5, 63.04, 63.00, 58.3, 56.1, 56.0, 53.8, 52.8, 31.6, 29.32, 29.30, 29.24,
29.21, 29.15, 29.0, 27.2, 25.9, 22.3, 13.0. LRMS m/z calcd for
C28H45F2N5O 505.4, found 506.3 [M + H]+. Purity of the compound
was further confirmed by RP-HPLC by using method 2: Rt = 16.82 min
129.3, 125.83, 125.80, 125.70, 125.67, 110.69, 110.65, 110.5, 110.4,
103.7, 103.5, 103.2, 73.6, 73.5, 63.1, 63.0, 58.3, 56.1, 56.0, 53.8, 52.8,
31.7, 29.36, 29.34, 29.32, 29.26, 29.24, 29.20, 29.18, 29.06, 27.2, 26.0,
22.3, 13.0. LRMS m/z calcd for C29H47F2N5O 519.4, found 520.3
[M + H]+. Purity of the compound was further confirmed by
RP-HPLC by using method 1: Rt = 3.47 min (96% pure; Supporting
2-(2,4-Dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(4-
decylpiperazine)propan-2-ol (25). To a solution of compound 15
(50 mg, 0.19 mmol) in EtOH (3 mL), compound 5 (55 mg,
0.24 mmol) and Et3N (0.03 mL, 0.24 mmol) were added. The reaction
mixture was stirred at 80 °C for 12 h, and progress of the reaction was
monitored by TLC (1:9/MeOH:CH2Cl2, Rf 0.40). The organic layer
was removed under reduced pressure, and the residue was purified by
flash column chromatography (SiO2, 1:19/MeOH:CH2Cl2) to afford
1
compound 25 (48 mg, 52%) as a yellow liquid. H NMR (400 MHz,
CD3OD, Supporting Information, Figure S48) δ 8.31 (s, 1H), 7.74
(s, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.20
(dd, J1 = 8.6 Hz, J2 = 2.2 Hz, 1H), 4.97 (d, J = 14.3 Hz, 1H), 4.67
(d, J = 14.3 Hz, 1H), 3.41 (d, J = 14.0 Hz, 1H), 2.83 (d, J = 14.0 Hz,
1H), 2.75−2.35 (m, 10H), 1.55−1.45 (m, 2H), 1.35−1.21 (m, 14H),
0.87 (t, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CD3OD,
Supporting Information, Figure S49) δ 149.7, 144.8, 138.4, 133.9,
131.5, 130.3, 130.0, 126.8, 74.9, 61.2, 57.5, 54.9, 52.3, 31.6, 29.3,
29.2, 29.1, 29.01, 28.97, 26.8, 24.9, 22.3, 13.0. LRMS m/z calcd for
C25H39Cl2N5O 495.3, found 496.3 [M + H]+. Purity of the compound
was further confirmed by RP-HPLC by using method 1: Rt = 3.45 min
2-(2,4-Dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(4-
dodecylpiperazine)propan-2-ol (26). To a solution of compound 15
(50 mg, 0.19 mmol) in EtOH (3 mL), compound 7 (61 mg,
0.24 mmol) and Et3N (0.03 mL, 0.24 mmol) were added. The reaction
mixture was stirred at 80 °C for 12 h, and progress of the reaction was
monitored by TLC (1:9/MeOH:CH2Cl2, Rf 0.50). The organic layer
was removed under reduced pressure, and the residue was purified by
flash column chromatography (SiO2, 1:19/MeOH:CH2Cl2) to afford
1
compound 26 (44 mg, 45%) as a yellow liquid. H NMR (400 MHz,
CD3OD, Supporting Information, Figure S51) δ 8.31 (s, 1H), 7.74
(s, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.20
(dd, J1 = 8.6 Hz, J2 = 2.1 Hz, 1H), 4.98 (d, J = 14.3 Hz, 1H), 4.68
(d, J = 14.3 Hz, 1H), 3.43 (d, J = 14.0 Hz, 1H), 2.86 (d, J = 14.0 Hz,
1H), 2.78−2.43 (m, 10H), 1.58−1.51 (m, 2H), 1.35−1.18 (m, 18H),
0.87 (t, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CD3OD, Supporting
Information, Figure S52) δ 149.8, 144.7, 138.3, 133.9, 131.5, 130.3,
130.1, 126.8, 75.1, 61.2, 57.3, 54.9, 52.1, 52.0, 31.6, 29.3 (2C), 29.2,
29.1, 29.0, 28.9, 26.6, 24.6, 22.3, 13.0. LRMS m/z calcd for
C27H43Cl2N5O 523.3, found 524.3 [M + H]+. Purity of the compound
was further confirmed by RP-HPLC by using method 1: Rt = 3.46 min
2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(mopholine)-
propan-2-ol (27). To a solution of compound 14 (50 mg, 0.21 mmol)
in EtOH (3 mL), morpholine (0.073 mL, 0.32 mmol) and Et3N
(0.04 mL, 0.32 mmol) were added. The reaction mixture was stirred at
80 °C for 12 h, and progress of the reaction was monitored by TLC
(1:10/MeOH: CH2Cl2, Rf 0.02). The organic layer was removed
under reduced pressure, and the residue was purified by column
chromatography (SiO2, 1:20/MeOH: CH2Cl2) to afford compound 27
(60 mg, 88%) as a white solid. 1H NMR (400 MHz, CDCl3,
Supporting Information, Figure S54) δ 8.12 (s, 1H), 7.77 (s, 1H),
7.55−7.53 (m, 1H), 6.82−6.76 (m, 2H), 5.11 (d, J = 8.2 Hz, 1H), 4.55
(d, J = 14.2 Hz, 1H), 4.48 (d, J = 14.2 Hz, 1H), 3.55 (m, 4H), 3.07
(d, J = 13.6 Hz, 1H), 2.61 (d, J = 12.8 Hz, 1H), 2.32 (m, 4H), 1.60
(br s, 1H). 13C NMR (100 MHz, CDCl3, Supporting Information,
Figure S55) δ 164.0, 163.9, 161.6, 161.4, 160.1, 160.0, 157.7, 157.6,
151.1, 144.7, 129.35, 129.29, 129.26, 129.20, 111.8, 111.7, 111.6,
111.5, 104.6, 104.3, 104.1, 72.2, 72.1, 66.8, 63.0, 62.9, 56.2, 56.1, 54.7.
LRMS m/z calcd for C15H18F2N4O2 324.1, found 325.1 [M + H]+.
Purity of the compound was further confirmed by RP-HPLC by
using method 1: Rt = 2.85 min (99% pure; Supporting Information,
2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(4-
tetradecylpiperazine)propan-2-ol (24). To a solution of compound
14 (50 mg, 0.21 mmol) in EtOH (3 mL), compound 9 (89 mg,
0.32 mmol), and Et3N (0.04 mL, 0.32 mmol) were added. The reaction
mixture was stirred at 80 °C for 12 h, and progress of the reaction was
monitored by TLC (1:9/MeOH:CH2Cl2, Rf 0.40). The organic layer
was removed under reduced pressure, and the residue was purified by
flash column chromatography (SiO2, 1:19/MeOH:CH2Cl2) to afford
1
compound 24 (91 mg, 83%) as a yellow solid. H NMR (400 MHz,
CD3OD, Supporting Information, Figure S45) δ 8.33 (s, 1H), 7.75
(s, 1H), 7.49−7.43 (m, 1H), 6.95−6.81 (m, 2H), 4.68 (d, J = 14.3 Hz,
1H), 4.59 (d, J = 14.3 Hz, 1H), 2.98 (dd, J1 = 13.8 Hz, J2 = 1.6 Hz,
1H), 2.79 (d, J = 13.8 Hz, 1H), 2.55−2.45 (m, 4H), 2.45−2.32
(m, 4H), 2.31−2.27 (m, 2H), 1.46 (p, J = 7.4 Hz, 2H), 1.34−1.28
(m, 22H), 0.90 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CD3OD,
Supporting Information, Figure S46) δ 164.0, 163.9, 161.5, 161.4,
160.6, 160.4, 158.1, 158.0, 150.7, 149.6, 144.6, 129.5, 129.42, 129.39,
L
J. Med. Chem. XXXX, XXX, XXX−XXX