Journal of Medicinal Chemistry
Article
3H); 13C NMR (100 MHz, DMSO-d6) δ 159.6, 137.4, 129.8, 127.7,
121.0, 114.0, 81.5, 73.2, 56.7, 55.2, 44.2, 39.3. Anal. Calcd for
C14H17NO·HCl (MW = 251.75): C, 66.79%; H, 7.21%; N, 5.56%.
Found: C, 66.36%; H, 7.09%; N, 5.51%.
118.2, 114.2, 80.6, 73.8, 59.7, 48.3, 45.9, 40.8; HRMS (ESI+) m/z
+
calcd for C20H23N2 [M + H]+ 291.1856, found 291.1856. Purity by
HPLC (condition C) 97%.
2-(3-((3-Fluorobenzyl)oxy)phenyl)-N-methyl-N-(prop-2-yn-1-yl)-
prop-2-en-1-aminium Carboxyformate (35). Following method B,
the title compound was isolated as a white solid (87%): mp 107−109
°C; 1H NMR (400 MHz, DMSO-d6) δ 7.47−7.41 (m, 1H), 7.31−7.23
(m, 3H), 7.18−7.10 (m, 3H), 6.95−6.93 (m, 1H), 5.53 (d, J = 1.6 Hz,
1H), 5.26 (d, J = 1.6 Hz, 1H), 5.14 (s, 2H), 3.45 (s, 2H), 3.34 (d, J =
2.4 Hz, 2H), 3.22 (t, J = 2.4 Hz, 1H), 2.22 (s, 3H); 13C NMR (101
MHz, DMSO-d6) δ 162.2 (d, J = 243.6 Hz), 161.3, 158.0, 143.5, 140.7,
140.1 (d, J = 7.4 Hz), 130.4 (d, J = 8.3 Hz), 129.2, 123.5 (d, J = 2.7
Hz), 119.0, 116.5, 114.5 (d, J = 20.9 Hz), 114.2 (d, J = 21.8 Hz),
113.9, 112.9, 78.2, 76.6, 68.3 (d, J = 1.7 Hz), 59.3, 44.4, 40.6. Anal.
Calcd for C20H20FNO·(COOH)2 (MW = 399.41): C, 66.16%; H,
5.55%; N, 3.51%. Found: C, 65.97%; H, 5.21%; N, 3.59%.
2-(3-(Benzyloxy)phenyl)-N-methyl-N-(prop-2-yn-1-yl)prop-2-en-
1-aminium Carboxyformate (29). Following method B, the title
compound was isolated (73%): mp 112−113 °C; 1H NMR (400 MHz,
methanol-d4) δ 7.48−7.31 (m, 6H), 7.16−7.15 (m, 1H), 7.12−7.09
(m, 1H), 7.03 (ddd, J = 8.0, 2.4, 0.8 Hz, 1H), 5.75 (d, J = 0.8 Hz, 1H),
5.61 (d, J = 0.8 Hz, 1H), 5.13 (s, 2H), 4.22 (s, 2H), 3.92 (d, J = 2.4
Hz, 2H), 3.27 (t, J = 2.4 Hz, 1H), 2.77 (s, 3H); 13C NMR (101 MHz,
methanol-d4) δ 165.9, 160.7, 140.8, 140.2, 138.6, 131.2, 129.5, 129.0,
128.6, 123.7, 120.2, 116.5, 114.5, 80.7, 73.7, 71.1, 59.6, 45.9, 40.7;
HRMS (ESI+) m/z calcd for C20H22NO+ [M + H]+ 292.1696, found
292.1689. Anal. Calcd for C20H21NO·(COOH)2 (MW = 381.42): C,
69.28%; H, 6.08%; N, 3.67%. Found: C, 69.25%; H, 6.07%; N, 3.52%.
2-(4-(Benzyloxy)phenyl)-N-methyl-N-(prop-2-yn-1-yl)prop-2-en-
1-aminium Carboxyformate (30). Following method B, the title
compound was isolated (66%): mp 138−139 °C; 1H NMR (400 MHz,
DMSO-d6) δ 7.49−7.30 (m, 7H), 6.97 (d, J = 8.8 Hz, 2H), 5.45 (d, J =
1.2 Hz, 1H), 5.16 (d, J = 0.4 Hz, 1H), 5.11 (s, 2H), 3.46 (s, 2H), 3.37
(d, J = 2.4 Hz, 2H), 3.24 (t, J = 2.4 Hz, 1H), 2.24 (s, 3H); 13C NMR
(101 MHz, DMSO-d6) δ 161.4, 158.0, 142.7, 137.1, 131.4, 128.4,
127.8, 127.6, 127.4, 114.6, 114.4, 78.0, 76.7, 69.2, 59.3, 44.3, 40.6;
HRMS (ESI+) m/z calcd for C20H22NO+ [M + H]+ 292.1696, found
292.1697. Purity by HPLC (condition A) >99%.
2-(3-((4-Fluorobenzyl)oxy)phenyl)-N-methyl-N-(prop-2-yn-1-yl)-
prop-2-en-1-aminium Carboxyformate (36). Following method B,
the title compound was isolated as a white solid (68%): mp 117.6−
1
118.9 °C; H NMR (400 MHz, methanol-d4) δ 7.50−7.45 (m, 2H),
7.34 (t, J = 8.0 Hz, 1H), 7.15 (t, J = 1.8 Hz, 1H), 7.13−7.07 (m, 3H),
7.04−7.01 (m, 1H), 5.75 (s, 1H), 5.61 (s, 1H), 5.11 (s, 2H), 4.20 (s,
2H), 3.91 (d, J = 2.8 Hz, 2H), 3.27 (t, J = 2.8 Hz, 1H), 2.76 (s, 3H);
13C NMR (101 MHz, methanol-d4) δ 165.8, 163.9 (d, J = 244.7 Hz),
160.6, 141.0, 140.3, 134.6 (d, J = 3.1 Hz), 131.2, 130.7 (d, J = 8.3 Hz),
123.4, 120.3, 116.4, 116.2 (d, J = 21.7 Hz), 114.5, 80.5, 73.9, 70.4, 59.7,
45.9, 40.8; HRMS (ESI+) m/z calcd for C20H21FNO+ [M + H]+
310.1602, found 310.1589. Anal. Calcd for C20H20FNO·(COOH)2
(MW = 399.41): C, 66.16%; H, 5.55%; N, 3.76%. Found: C, 66.16%;
H, 5.31%; N, 3.61%.
N-Methyl-2-(3-(phenoxymethyl)phenyl)-N-(prop-2-yn-1-yl)prop-
2-en-1-aminium Carboxyformate (31). Following method B, the title
1
compound was isolated as a white solid (85%): mp 125−126 °C; H
NMR (400 MHz, DMSO-d6) δ 7.60 (br, 1H), 7.50−7.47 (m, 1H),
7.37−7.35 (m, 2H), 7.31−7.27 (m, 2H), 7.03−7.00 (m, 2H), 6.96−
6.92 (m, 1H), 5.55 (d, J = 1.2 Hz, 1H), 5.29 (d, J = 1.2 Hz, 1H), 5.10
(s, 2H), 3.50 (s, 2H), 3.37 (d, J = 2.3 Hz, 2H), 3.23 (t, J = 2.3 Hz,
1H), 2.25 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 161.3, 158.3,
143.6, 139.2, 137.0, 129.5, 128.3, 127.0, 125.7, 125.6, 120.7, 116.3,
114.8, 78.2, 76.5, 69.1, 59.2, 44.4, 40.7. Anal. Calcd for C20H21NO·
(COOH)2 (MW = 381.42): C, 69.28%; H, 6.08%; N, 3.67%. Found:
C, 69.21%; H, 5.72%; N, 3.74%.
2-(3-((3-Methoxybenzyl)oxy)phenyl)-N-methyl-N-(prop-2-yn-1-
yl)prop-2-en-1-aminium Carboxyformate (37). Following method B,
the title compound was isolated as a white solid (68%): mp 113.9−
1
114.3 °C; H NMR (400 MHz, DMSO-d6) δ 7.30 (app t, 1H), 7.24
(app t, 1H), 7.16−7.15 (m, 1H), 7.11−7.09 (m, 1H), 7.03−7.01 (m,
2H), 6.94−6.92 (m, 1H), 6.90−6.88 (m, 1H), 5.52 (d, J = 1.2 Hz,
1H), 5.25 (d, J = 1.2 Hz, 1H), 5.08 (s, 2H), 3.76 (s, 3H), 3.44 (s, 2H),
3.34 (d, J = 2.4 Hz, 2H), 3.21 (t, J = 2.4 Hz, 1H), 2.22 (s, 3H); 13C
NMR (101 MHz, DMSO-d6) δ 161.3, 159.3, 158.2, 143.6, 140.6,
138.7, 129.5, 129.2, 119.8, 118.8, 116.4, 113.9, 113.2, 113.0, 78.3, 76.5,
69.0, 59.3, 55.0, 44.4, 40.7. Anal. Calcd for C21H23NO2·(COOH)2
(MW = 411.45): C, 67.14%; H, 6.12%; N, 3.40%. Found: C, 66.98%;
H, 6.21%; N, 3.07%.
N-Methyl-2-(4-(phenoxymethyl)phenyl)-N-(prop-2-yn-1-yl)prop-
2-en-1-aminium Carboxyformate (32). Following method B, the title
1
compound was isolated as a white solid (75%): mp 150−151 °C; H
NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 8.3 Hz, 2H), 7.41 (d, J =
8.3 Hz, 2H), 7.32−7.26 (m, 2H), 7.00 (dd, J = 8.7, 0.9 Hz, 2H), 6.93
(t, J = 7.3 Hz, 1H), 5.55 (d, J = 1.6 Hz, 1H), 5.27 (d, J = 1.6 Hz, 1H),
5.09 (s, 2H), 3.49 (s, 2H), 3.36 (d, J = 2.3 Hz, 2H), 3.23 (t, J = 2.3 Hz,
1H), 2.24 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 161.3, 158.3,
143.3, 138.5, 136.5, 129.5, 127.5, 126.3, 120.7, 116.3, 114.7, 78.1, 76.6,
68.7, 59.2, 44.3, 40.6; HRMS (ESI+) m/z calcd for C20H22NO+ [M +
H]+ 292.1696, found 292.1691. Anal. Calcd for C20H21NO·(COOH)2
(MW = 381.42): C, 69.28%; H, 6.08%; N, 3.67%. Found: C, 68.52%;
H, 6.16%; N, 3.29%.
2-(3-((4-Methoxybenzyl)oxy)phenyl)-N-methyl-N-(prop-2-yn-1-
yl)prop-2-en-1-aminium Carboxyformate (38). Following method B,
the title compound was isolated as a white solid (57%): mp 104−105
°C; 1H NMR (400 MHz, methanol-d4) δ 7.38−7.31 (m, 3H), 7.13 (s,
1H), 7.10 (d, J = 7.7 Hz, 1H), 7.02 (dd, J = 8.2, 2.1 Hz, 1H), 6.94−
6.91 (m, 2H), 5.74 (s, 1H), 5.60 (br d, 1H), 5.05 (s, 2H), 4.19 (br,
2H), 3.90 (br, 2H), 3.80 (s, 3H), 3.26 (t, J = 2.4 Hz, 1H), 2.75 (s,
3H); 13C NMR (100 MHz, methanol-d4) δ 165.8, 161.0, 160.7, 141.4,
140.3, 131.2, 130.5, 130.4, 122.9, 120.1, 116.4, 114.9, 114.5, 80.2, 74.2,
N-Methyl-2-(3-((phenylamino)methyl)phenyl)-N-(prop-2-yn-1-
yl)prop-2-en-1-aminium Carboxyformate (33). Following method B,
+
1
70.9, 59.9, 55.7, 45.9, 40.9; HRMS (ESI+) m/z calcd for C21H24NO2
the title compound was isolated (80%): mp 152−154 °C; H NMR
[M + H]+ 322.1802, found 322.1801. Anal. Calcd for C21H23NO2·
(COOH)2 (MW = 411.45): C, 67.14%; H, 6.12%; N, 3.40%. Found:
C, 66.96%; H, 5.89%; N, 3.39%.
(400 MHz, methanol-d4) δ 7.54 (s, 1H), 7.45−7.33 (m, 3H), 7.09 (dd,
J = 8.4, 7.6 Hz, 2H), 6.73−6.59 (m, 3H), 5.77 (s, 1H), 5.63 (s, 1H),
4.38 (s, 2H), 4.28 (s, 2H), 3.94 (d, J = 2.4 Hz, 2H), 3.29 (t, J = 2.4 Hz,
1H), 2.78 (s, 3H); 13C NMR (101 MHz, methanol-d4) δ 165.0, 149.4,
142.4, 140.5, 138.7, 130.3, 130.1, 129.3, 126.7, 126.2, 124.1, 118.7,
114.7, 81.2, 73.2, 59.5, 46.0, 40.7; HRMS (ESI+) m/z calcd for
2-(3-((3-Fluorophenoxy)methyl)phenyl)-N-methyl-N-(prop-2-yn-
1-yl)prop-2-en-1-aminium Carboxyformate (39). Following method
B, the title compound was isolated as a white solid (65%): mp 126.1−
1
+
C20H23N2 [M + H]+ 291.1856, found 291.1861. Purity by HPLC
127.0 °C; H NMR (400 MHz, methanol-d4) δ 7.62 (br, 1H), 7.52−
7.43 (m, 3H), 7.30−7.24 (m, 1H), 6.84−6.81 (m, 1H), 6.77 (dt, J =
11.1, 2.4 Hz, 1H), 6.70−6.65 (m, 1H), 5.78 (d, J = 0.8 Hz, 1H), 5.63
(d, J = 0.8 Hz, 1H), 5.13 (s, 2H), 4.23 (s, 2H), 3.91 (d, J = 2.8 Hz,
2H), 3.24 (t, J = 2.8 Hz, 1H), 2.77 (s, 3H); 13C NMR (100 MHz,
methanol-d4) δ 164.8 (d, J = 183.0 Hz), 161.6 (d, J = 11.0 Hz), 141.3,
139.3, 139.2, 131.6 (d, J = 10.1 Hz), 130.3, 129.1, 127.3, 126.8, 123.2,
112.0 (d, J = 3.0 Hz), 108.6 (d, J = 21.5 Hz), 103.5 (d, J = 25.2 Hz),
80.2, 74.2, 71.0, 59.8, 46.0, 40.9; HRMS (ESI+) m/z calcd for
C20H21FNO+ [M + H]+ 310.1602, found 310.1599. Anal. Calcd for
(condition C) 96%.
N-Methyl-2-(4-((phenylamino)methyl)phenyl)-N-(prop-2-yn-1-
yl)prop-2-en-1-aminium Carboxyformate (34). Following method B,
1
the title compound was isolated (85%): mp 139−140 °C; H NMR
(400 MHz, methanol-d4) δ 7.49 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4
Hz, 2H), 7.06 (dd, J = 8.8, 7.2 Hz, 2H), 6.64−6.55 (m, 3H), 5.74 (s,
1H), 5.58 (s, 1H), 4.35 (s, 2H), 4.21 (s, 2H), 3.91 (d, J = 2.4 Hz, 2H),
3.26 (t, J = 2.4 Hz, 1H), 2.76 (s, 3H); 13C NMR (101 MHz, methanol-
d4) δ 165.8, 149.7, 142.9, 140.8, 137.2, 130.0, 129.0, 127.7, 122.9,
Q
J. Med. Chem. XXXX, XXX, XXX−XXX