Journal of Medicinal Chemistry
Article
4.14 (m, 1H), 3.70−3.58 (m, 1H), 3.06 (d, 1H, J = 11.7 Hz), 2.95 (t, 1H,
J = 10.5 Hz), 2.71 (d, 2H, J = 10.6 Hz), 2.56 (t, 1H, J = 11.3 Hz), 2.45−
2.18 (m, 3H), 2.21 (s, 3H), 2.07−1.93 (m, 1H), 1.00−0.91 (m, 6H),
0.81 (d, 3H, J = 6.4 Hz); 13C NMR (CDCl3) δ 167.5, 160.2, 157.2, 151.4,
145.7, 142.1, 130.5, 129.9, 129.2, 128.8, 128.8, 126.2, 120.9, 116.9, 116.7,
108.8, 106.7, 103.8, 58.6, 57.9, 54.4, 51.4, 51.0, 43.9, 30.9, 20.6, 18.9,
18.0, 12.9; MS (ESI) m/z 504.6 (M + H)+.
N. 12d free base: 1H NMR (CDCl3) δ 7.42 (s, 1H), 7.23−7.10 (m, 2H),
7.01 (t, 1H, J = 7.8 Hz), 6.93 (d, 1H, J = 7.4 Hz), 6.77 (s, 1H), 6.71 (t,
2H, J = 8.7 Hz), 6.55 (bs, 1H), 6.45−6.32 (m, 3H), 4.33−4.19 (m, 1H),
3.52 (bs, 1H), 3.12−3.02 (m, 1H), 2.96−2.83 (m, 1H), 2.67−2.47 (m,
4H), 2.39−2.25 (m, 3H), 2.29 (s, 3H), 2.01−1.88 (m, 1H), 1.00−0.91
(m, 6H), 0.81 (d, 3H, J = 6.3 Hz); 13C NMR (CDCl3) δ 168.0, 157.3,
156.1, 151.5, 147.4, 146.9, 140.3, 131.1, 129.8, 129.7, 124.9, 119.2, 119.1,
119.1, 118.1, 115.7, 115.6, 107.7, 58.9, 53.9, 51.4, 51.2, 31.2, 21.4, 19.1,
19.1, 17.9, 13.8; MS (ESI) m/z 504.5 (M + H)+.
4-(3,5-Dimethylphenoxy)-N-[(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3-
methylpiperazin-1-yl]methyl}-2-methylpropyl]benzamide (11q) Di-
hydrochloride. General procedure B using acid 25q afforded 37 mg
(61%) of 11q·2HCl as a white powder: mp 117−120 °C (fusion);
3-Chloro-N-[(2S)-1-[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-
1-yl]-3-methylbutan-2-yl]-4-(3-methylphenoxy)benzamide (12e) Di-
hydrochloride. General procedure B using acid 26e afforded 25 mg
[α]25 +66.4° (c 0.66, CH3OH). Anal. (C31H41Cl2N3O3·2H2O) C, H,
D
N. 11q free base: 1H NMR (CDCl3) δ 7.75 (d, 2H, J = 8.7 Hz), 7.03 (t,
1H, J = 8.0 Hz), 6.95 (d, 2H, J = 8.7 Hz), 6.79 (s, 1H), 6.63 (s, 2H),
6.43−6.24 (m, 4H), 4.29−4.16 (m, 1H), 3.83−3.72 (m, 1H), 3.20−3.11
(m 1H), 3.09−2.97 (m, 1H), 2.95−2.72 (m, 2H), 2.61 t, 1H, J = 11 Hz),
2.51−2.30 (m, 3H), 2.28 (s, 6H), 2.11−1.98 (m, 1H), 1.03−0.93 (m,
6H), 0.88 (d, 3H, J = 6.5 Hz); 13C NMR (CDCl3) δ 166.2, 159.4, 156.0,
154.8, 150.2, 138.7, 128.7, 127.9, 127.6, 124.8, 116.6, 116.2, 107.4, 105.3,
102.4, 57.3, 56.7, 53.3, 50.1, 49.7, 42.4, 29.7, 20.1, 17.7, 16.9, 11.7; MS
(ESI) m/z 502.8 (M + H)+.
(41%) of 12e·2HCl as a white powder: mp 154−158 °C (fusion); [α]25
D
+63.2° (c 0.95, CH3OH). Anal. (C30H38Cl3N3O3·H2O) C, H, N. 12e
free base: 1H NMR (CDCl3) δ 7.87 (s, 1H), 7.60 (d, 1H, J = 8.5 Hz),
7.23 (t, 1H, J = 7.7 Hz), 7.04 (t, 1H, J = 8.0 Hz), 6.97 (d, 1H, J = 7.4 Hz),
6.88 (d, 1H, J = 8.5 Hz), 6.84−6.76 (m, 2H), 6.40 (d, 1H, J = 8.2 Hz),
6.35−6.25 (m, 3H), 4.26−4.12 (m, 1H), 3.85−3.74 (m, 1H), 3.17 (d,
1H, J = 11.7 Hz), 3.04 (t, 1H, J = 10.0 Hz), 2.77 (t, 2H, J = 8.8 Hz), 2.64−
2.52 (m, 1H), 2.48−2.29 (m, 3H), 2.33 (s, 3H), 2.11−1.97 (m, 1H),
1.05−0.93 (m, 6H), 0.89 (d, 3H, J = 6.4 Hz); 13C NMR (CDCl3) δ
166.2, 157.0, 155.7, 151.4, 140.3, 130.7, 129.9, 129.7, 129.5, 126.7, 125.2,
125.1, 119.7, 119.0, 116.0, 108.6, 106.3, 103.4, 58.5, 57.9, 54.5, 51.5,
50.9, 43.6, 30.8, 21.4, 18.9, 18.1, 12.8; MS (ESI) m/z 522.4 (M + H)+.
N-[(1S)-1-{[(3S)-4-(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]-
methyl}-2-methylpropyl]-2-methyl-4-(3-methylphenoxy)benzamide
(12f) Dihydrochloride. General procedure B with acid 26f afforded 13
mg (22%) of 12f·2HCl as a white powder: mp 164−167 °C (fusion);
[α]25D +46.6° (c 0.35, CH3OH). Anal. (C31H41Cl2N3O3·H2O) C, H, N.
12f free base: 1H NMR (CDCl3) δ 7.39 (d, 1H, J = 8.2 Hz), 7.22 (t, 1H, J
= 8.0 Hz), 7.06 (t, 1H, J = 8.0 Hz), 6.95 (d, 1H, J = 7.4 Hz), 6.85−6.74
(m, 3H), 6.43 (dd, 1H, J = 8.3, 1.6 Hz), 6.36 (s, 1H), 6.29 (dd, 1H, J =
7.9, 1.8 Hz), 5.81 (bd, 1H, J = 6.8 Hz), 4.30−4.16 (m, 1H), 3.89−3.77
(m, 1H); 13C NMR (CDCl3) δ 169.8, 158.7, 156.9, 156.5, 151.5, 140.1,
138.7, 129.9, 129.6, 128.5, 124.6, 120.8, 120.0, 116.4, 115.4, 108.8, 106.3,
103.6, 59.4, 58.4, 54.6, 51.2, 51.0, 43.9, 30.6, 21.4, 20.2, 19.1, 17.8, 13.1;
MS (ESI) m/z 502.8 (M + H)+.
N-(1S)-1-{[(3S)-4-(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]-
methyl}-2-methylpropyl-3-methyl-4-phenoxybenzamide (12a) Di-
hydrochloride. General procedure B using acid 26a afforded 31.9 mg
(45%) of 12a·2HCl as a pale-yellow solid: mp 88 °C (fusion); [α]25
D
+62.1° (c 1.51, CH3OH). Anal. (C30H39Cl2N3O3·H2O) C, H, N. 12a
free base: 1H NMR (CDCl3) δ 7.70 (s, 1H), 7.56 (d, 1H, J = 8.5 Hz),
7.32 (t, 2H, J = 8.3 Hz), 7.09 (t, 1H, J = 7.5 Hz), 7.03 (t, 1H, J = 7.9 Hz),
6.92 (d, 2H, J = 8.1 Hz), 6.81 (d, 1H, J = 8.4 Hz), 6.46 (br s, 1H), 6.41−
6.28 (m, 3H), 4.32−4.17 (m, 1H), 3.83−3.69 (m, 1H), 3.18−2.95 (m,
2H), 2.86−2.58 (m, 3H), 2.52−2.32 (m, 3H), 2.27 (s, 3H), 2.10−1.96
(m, 1H), 1.02−0.93 (m, 6H), 0.89 (d, 3H, J = 6.4 Hz); 13C NMR
(CDCl3) δ 167.6, 157.9, 157.3, 151.3, 130.3, 129.9, 129.7, 129.7, 129.5,
126.0, 123.4, 118.4, 118.1, 108.7, 106.8, 103.9, 103.2, 96.8, 58.5, 57.9,
54.3, 51.2, 50.9, 30.9, 18.9, 18.0, 16.2, 12.9; MS (ESI) m/z 488.6 (M +
H)+.
N-[(2S)-1-[(3S)-4-(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]-3-
methylbutan-2-yl]-3-methyl-4-(3-methylphenoxy)benzamide (12b)
Dihydrochloride. General procedure B with acid 26b afforded 42.9 mg
(70%) of 12b·2HCl as a white powder: mp 124−130 °C (fusion);
[α]25D 46.6° (c 0.50, CH3OH). Anal. (C31H41Cl2N3O3·2H2O) C, H, N.
12b free base: 1H NMR (CDCl3) δ 7.68 (s, 1H), 7.55 (d, 2H, J = 8.4
Hz), 7.19 (t, 1H, J = 7.7 Hz), 7.03 (t, 1H, J = 8.0 Hz), 6.91 (d, 1H, J = 7.5
Hz), 6.81 (d, 1H, J = 8.4 Hz), 6.75 (s, 1H), 6.42−6.28 (m, 5H), 4.29−
4.15 (m, 1H), 3.84−3.72 (m, 1H), 3.15 (d, 1H, J = 11.4 Hz), 3.03 (t, 1H,
J = 10.3 Hz), 2.84−2.72 (m 2H), 2.65−2.53 (m, 1H), 2.47−2.32 (m,
3H), 2.31 (s, 3H), 2.27 (s, 3H), 2.12−1.98 (m, 1H), 1.02−0.95 (m, 6H),
0.90 (d, 3H, J = 6.4 Hz); 13C NMR (CDCl3) δ 167.6, 157.9, 157.2, 156.8,
151.4, 140.1, 130.3, 129.9, 129.7, 129.6, 129.5, 125.9, 124.2, 119.1, 118.1,
115.4, 108.5, 106.5, 103.6, 58.6, 57.9, 54.5, 51.3, 50.9, 43.7, 30.8, 21.4,
18.9, 18.1, 16.3, 12.8; MS (ESI) m/z 502.8 (M + H)+.
N-[(1S)-1-{[(3S)-4-(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]-
methyl}-2-methylpropyl]-2-methoxy-4-(3-methylphenoxy)-
benzamide (12g) Dihydrochloride. General procedure B with acid 26g
afforded 35 mg (58%) of 12g·2HCl as a white powder: mp 99−102 °C
(fusion); [α]2 5 +82.3° (c 0.265, CH3 OH). Anal.
D
(C31H41Cl2N3O4·0.5H2O) C, H, N. 12g free base: 1H NMR (CDCl3)
δ 8.11 (d, 1H, J = 8.7 Hz), 7.83 (d, 1H, J = 8.4 Hz), 7.29−7.19 (m, 1H),
7.07−6.95 (m, 2H, 6.89−6.80 (m, 2H), 6.64−6.53 (m, 2H), 6.42−6.26
(m, 3H), 4.37−4.25 (m, 1H), 3.89 (s, 3H), 3.82−3.70 (m, 1H); 13C
NMR (CDCl3) δ 165.1, 161. 6, 158.9, 157.4, 155.7, 151.5, 140.2, 133.8,
129.8, 129.7, 125.2, 120.5, 116.9, 116.5, 110.2, 108.4, 106.4, 103. 7,
101.7, 59.5, 58.7, 56.1, 54.0, 51.5, 51.1, 43.8, 43.8, 30.0, 21.4, 19.4, 17.3,
12.7; MS (ESI) m/z 518.7 (M + H)+.
2-Hydroxy-N-[(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3-methylpipera-
zin-1-yl]methyl}-2-methylpropyl]-4-(3-methylphenoxy)benzamide
(12h) Dihydrochloride. General procedure B with acid 26h afforded 65
mg (43%) of 12h·2HCl as a white powder: mp 119−123 °C (fusion);
N-[(2S)-1-[(3S)-4-(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]-3-
methylbutan-2-yl]-3-methoxy-4-(3-methylphenoxy)benzamide
(12c) Dihydrochloride. General procedure B with acid 26c afforded
46.7 mg (75%) of 12c·2HCl as a white powder: mp 128−131 °C; [α]25
[α]25 +81.8° (c 0.08, CH3OH). Anal. (C30H39Cl2N3O4·1.25H2O) C,
D
D
54.0° (c 0.73, CH3OH). Anal. (C31H41Cl2N3O4·2H2O) C, H, N. 12c
free base: 1H NMR (CDCl3) δ 7.53 (d, 1H, J = 1.9 Hz), 7.27−7.14 (m,
2H), 7.03 (t, 1H, J = 8.0 Hz), 6.90 (d, 1H, J = 7.6 Hz), 6.86 (d, 1H, J = 8.3
Hz), 6.81−6.71 (m, 2H), 6.42−6.28 (m, 4H), 4.28−4.16 (m, 1H), 3.84
(s, 3H), 3.83−3.72 (m, 1H), 3.14 (d, 1H, J = 11.8 Hz), 3.01 (t, 1H, J =
10.7 Hz), 2.83−2.71 (m, 2H), 2.64−2.52 (m, 1H), 2.47−2.27 (m, 3H),
2.30 (s, 3H), 2.11−1.98 (m, 1H), 1.03−0.94 (m, 6H), 0.90 (d, 3H, J =
6.4 Hz); 13C NMR (CDCl3) δ 167.5, 157.3, 156.8, 151.4, 151.1, 148.7,
139.9, 130.8, 129.9, 129.4, 124.2, 119.1, 118.9, 118.9, 115.2, 112.3, 108.5,
106.6, 103.7, 58.6, 57.9, 56.6, 54.5, 51.5, 50.9, 43.7, 30.8, 21.4, 18.9, 18.1,
12.8; MS (ESI) m/z 518.7 (M + H)+.
3-Hydroxy-N-[(2S)-1-[(3S)-4-(3-hydroxyphenyl)-3-methylpipera-
zin-1-yl]-3-methylbutan-2-yl]-4-(3-methylphenoxy)benzamide
(12d) Dihydrochloride. General procedure B with acid 26d afforded
38.6 mg (64%) of 12d·2HCl as a pale-yellow powder: mp 195−200 °C;
[α]25D 58.5° (c 1.07, CH3OH). Anal. (C30H39Cl2N3O4·1.5H2O) C, H,
H, N. 12h free base: 1H NMR (CDCl3) δ 7.37 (d, 1H, J = 8.6 Hz), 7.24
(t, 1H, J = 7.7 Hz), 7.07 (t, 1H, J = 8.1 Hz), 6.99 (d, 1H, J = 7.6 Hz),
6.91−6.82 (m, 2H), 6.50−6.40 (m, 3H), 6.32 (t, 1H, J = 2.2 Hz), 6.27
(dd, 1H, J = 7.9, 2.0 Hz), 4.23−4.10 (m, 1H), 3.90−3.80 (m, 1H), 3.26−
3.16 (m, 1H), 3.08 (td, 1H, J = 11.3, 2.5 Hz), 2.89−2.72 (m, 2H), 2.68−
2.56 (m, 1H), 2.5−2.33 (m, 3H), 2.34 (s, 3H), 2.16−2.02 (m, 1H),
1.01−0.95 (m, 6H), 0.92 (d, 3H, J = 6.5 Hz); 13C NMR (CDCl3) 170.1,
163.6, 163.1, 156.8, 155.3, 151.6, 140.4, 130.3, 129.9, 127.1, 125.7, 121.3,
117.6, 109.4, 108.9, 108.9, 106.2, 106.2, 103.3, 58.2, 57.9, 54.8, 51.0,
50.9, 43.5, 30.8, 21.6, 18.9, 18.4, 12.9; MS (ESI) m/z 504.6 (M + H)+.
4-(2-Hydroxyphenoxy)-N-[(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3-
methylpiperazin-1-yl]methyl}-2-methylpropyl]-3-methoxybenza-
mide (12i) Dihydrochloride. General procedure B using acid 26i
afforded 38.5 mg (42%) of 12i·2HCl as an off-white powder: mp 95−97
°C (fusion); [α]2 5 +55.2° (c 0.29, CH3 OH). Anal.
D
1
(C30H39Cl2N3O5·H2O) C, H, N. 12i free base: H NMR (CDCl3) δ
K
dx.doi.org/10.1021/jm400275h | J. Med. Chem. XXXX, XXX, XXX−XXX