Journal of Medicinal Chemistry
Article
MHz, CDCl3) δ 8.08 (dd, J = 8.0, 1.2 Hz, 1H), 7.55 (td, J = 7.5, 1.4
Hz, 1H), 7.47 (td, J = 7.8, 1.5 Hz, 1H), 7.34 (s, 4H), 7.26 (dd, J = 7.6,
1.4 Hz, 1H), 3.32 (d, J = 12.4 Hz, 2H), 2.70 (d, J = 11.6 Hz, 2H),
2.36−2.15 (m, 3H), 2.08 (td, J = 11.7, 2.5 Hz, 2H), 1.60 (s, 4H),
1.38−1.02 (m, 5H), 0.87 (d, J = 6.3 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 140.3, 138.1, 137.0, 133.8, 132.8, 132.4, 131.0, 130.3,
127.8, 127.6, 61.5, 49.3, 44.6, 34.5, 31.0, 27.3, 21.8. LC−MS (ESI)
calcd for C23H30ClN2O2S [M + H]+ 433.2, found 433.2.
1′-((4′-Methoxy-[1,1′-biphenyl]-2-yl)sulfonyl)-4-methyl-
1,4′-bipiperidine (53). Reaction of 30 with (4-methoxyphenyl)-
boronic acid (Procedure C) yielded 53 as a black gel (59%). 1H NMR
(400 MHz, CDCl3) δ 8.08 (dd, J = 7.9, 1.4 Hz, 1H), 7.52 (td, J = 7.5,
1.4 Hz, 1H), 7.44−7.40 (m, 1H), 7.35−7.31 (m, 2H), 7.30−7.23 (m,
1H), 6.93−6.87 (m, 2H), 3.81 (s, 3H), 3.31 (d, J = 12.9 Hz, 2H),
2.68 (d, J = 11.6 Hz, 2H), 2.34−2.12 (m, 3H), 2.06 (td, J = 11.6, 2.5
Hz, 2H), 1.57 (d, J = 12.5 Hz, 4H), 1.39−1.01 (m, 5H), 0.86 (d, J =
6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 159.2, 141.4, 137.1,
133.2, 132.2, 132.0, 130.9, 130.3, 128.5, 128.4, 127.2, 112.9, 61.6,
55.3, 49.3, 44.6, 34.6, 31.0, 27.3, 21.9. HRMS (ESI-TOF) calcd for
C24H33N2O3S [M + H]+ 429.2206, found 429.2199.
7.72 (m, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H),
7.04−6.88 (m, 2H), 3.88 (d, J = 12.0 Hz, 2H), 3.84 (s, 3H), 2.76 (d, J
= 11.6 Hz, 2H), 2.40−1.95 (m, 5H), 1.83 (d, J = 10.7 Hz, 2H), 1.71−
1.48 (m, 4H), 1.36−1.23 (m, 1H), 1.23−1.04 (m, 2H), 0.87 (d, J =
6.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 160.0, 145.1, 133.9,
131.6, 128.4, 128.2, 126.9, 114.5, 61.5, 55.4, 49.5, 46.2, 34.6, 31.0,
27.4, 21.9. HRMS (ESI-TOF) calcd for C24H33N2O3S [M + H]+
429.2206, found 429.2203.
1′-((2′-Methoxy-[1,1′-biphenyl]-4-yl)sulfonyl)-4-methyl-
1,4′-bipiperidine (59). Reaction of amine 1a with 2′-methoxy-[1,1′-
biphenyl]-4-sulfonyl chloride (Procedure A) yielded 59 as a colorless
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gel (88%). H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H),
7.66 (d, J = 8.4 Hz, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.29 (d, J = 7.5 Hz,
1H), 7.07−6.91 (m, 2H), 3.86 (d, J = 11.6 Hz, 2H), 3.80 (s, 3H),
2.77 (d, J = 11.4 Hz, 2H), 2.32 (t, J = 11.3 Hz, 2H), 2.22 (tt, J = 11.6,
3.7 Hz, 1H), 2.11 (t, J = 10.8 Hz, 2H), 1.83 (d, J = 11.2 Hz, 2H),
1.73−1.52 (m, 4H), 1.37−1.23 (m, 1H), 1.16 (qd, J = 11.9, 3.7 Hz,
2H), 0.87 (d, J = 6.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 156.3,
143.2, 134.2, 130.7, 130.0, 129.8, 128.6, 127.3, 121.0, 111.3, 61.4,
55.5, 49.4, 46.1, 34.5, 31.0, 27.3, 21.8. HRMS (ESI-TOF) calcd for
C24H33N2O3S [M + H]+ 429.2206, found 429.2205.
4-Methyl-1′-((4′-methyl-[1,1′-biphenyl]-2-yl)sulfonyl)-1,4′-
bipiperidine (54). Reaction of 30 with p-tolylboronic acid
1′-((2′-Fluoro-[1,1′-biphenyl]-4-yl)sulfonyl)-4-methyl-1,4′-
bipiperidine (60). Reaction of amine 1a with 2′-fluoro-[1,1′-
biphenyl]-4-sulfonyl chloride (Procedure A) yielded 60 as a colorless
gel (73%). 1H NMR (400 MHz, CDCl3) δ 7.85−7.76 (m, 2H), 7.72−
7.64 (m, 2H), 7.42 (td, J = 7.7, 1.8 Hz, 1H), 7.39−7.33 (m, 1H), 7.24
(dd, J = 6.3, 1.3 Hz, 1H), 7.22−7.12 (m, 1H), 3.87 (d, J = 12.0 Hz,
2H), 2.77 (d, J = 11.5 Hz, 2H), 2.42−2.17 (m, 3H), 2.11 (td, J = 11.7,
2.4 Hz, 2H), 1.84 (d, J = 13.6 Hz, 2H), 1.72−1.54 (m, 4H), 1.36−
1.23 (m, 1H), 1.24−1.09 (m, 2H), 0.87 (d, J = 6.3 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 159.6 (d, J = 249.1 Hz), 140.3 (d, J = 1.3
Hz), 135.2, 130.6 (d, J = 3.1 Hz), 130.2 (d, J = 8.3 Hz), 129.5 (d, J =
3.2 Hz), 127.8, 127.2 (d, J = 13.0 Hz), 124.7 (d, J = 3.7 Hz), 116.3 (d,
J = 22.6 Hz), 61.4, 49.4, 46.2, 34.5, 31.0, 27.3, 21.8. HRMS (ESI-
TOF) calcd for C23H30FN2O2S [M + H]+ 417.2007, found 417.1995.
1′-([1,1′-Biphenyl]-3-ylsulfonyl)-4-methyl-1,4′-bipiperidine
(61). Reaction of 29 with phenylboronic acid (Procedure C) yielded
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(Procedure C) yielded 54 as a brown gel (23%). H NMR (400
MHz, CDCl3) δ 8.08 (dd, J = 8.0, 1.4 Hz, 1H), 7.54 (td, J = 7.5, 1.4
Hz, 1H), 7.44 (td, J = 7.7, 1.5 Hz, 1H), 7.28 (d, J = 7.9 Hz, 3H), 7.18
(d, J = 7.8 Hz, 2H), 3.33 (d, J = 13.1 Hz, 2H), 2.84 (d, J = 10.7 Hz,
2H), 2.43 (t, J = 12.6 Hz, 1H), 2.37 (s, 3H), 2.22 (td, J = 12.6, 2.4 Hz,
4H), 1.76−1.58 (m, 4H), 1.47−1.19 (m, 5H), 0.90 (d, J = 4.8 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 141.7, 137.5, 136.9, 136.7,
133.1, 132.3, 130.2, 129.4, 128.2, 127.3, 62.0, 49.1, 44.2, 33.4, 30.6,
26.7, 21.5, 21.2. HRMS (ESI-TOF) calcd for C24H33N2O2S [M + H]+
413.2257, found 413.2264.
4-Methyl-1′-((4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-
sulfonyl)-1,4′-bipiperidine (55). Reaction of 30 with (4-
(trifluoromethyl)phenyl)boronic acid (Procedure C) yielded 55 as a
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black solid (12%). H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 8.0,
1.4 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.59 (tt, J = 7.5, 1.1 Hz, 1H),
7.56−7.49 (m, 3H), 7.29 (dd, J = 7.7, 1.4 Hz, 1H), 3.30 (d, J = 12.8
Hz, 2H), 2.73 (d, J = 11.0 Hz, 2H), 2.31 (td, J = 12.6, 2.4 Hz, 3H),
2.10 (t, J = 12.3 Hz, 2H), 1.64 (t, J = 12.4 Hz, 4H), 1.35−1.12 (m,
5H), 0.88 (d, J = 6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 143.4,
140.1, 136.9, 132.7, 132.5, 130.3, 130.1, 130.0, 129.8, 128.2, 124. 4 (q,
J = 3.7 Hz), 61.6, 49.3, 44.5, 34.3, 30.9, 27.1, 21.7. HRMS (ESI-TOF)
calcd for C24H30F3N2O2S [M + H]+ 467.1975, found 467.1967.
1′-([1,1′-Biphenyl]-4-ylsulfonyl)-4-methyl-1,4′-bipiperidine
(56). Reaction of 17 with phenylboronic acid (Procedure C) yielded
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61 as a black gel (58%). H NMR (400 MHz, CDCl3) δ 7.94 (t, J =
1.8 Hz, 1H), 7.79 (ddd, J = 7.8, 1.9, 1.1 Hz, 1H), 7.71 (ddd, J = 7.8,
1.8, 1.1 Hz, 1H), 7.62−7.55 (m, 3H), 7.50−7.43 (m, 1H), 7.43−7.36
(m, 1H), 3.87 (d, J = 12.0 Hz, 2H), 2.77 (d, J = 11.7 Hz, 2H), 2.28
(td, J = 12.0, 2.5 Hz, 2H), 2.20 (td, J = 8.1, 4.1 Hz, 1H), 2.11 (td, J =
11.5, 2.4 Hz, 2H), 1.83 (d, J = 11.6 Hz, 2H), 1.72−1.54 (m, 4H),
1.37−1.23 (m, 1H), 1.17 (qd, J = 12.1, 3.8 Hz, 2H), 0.87 (d, J = 6.3
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 142.3, 139.2, 136.7, 131.3,
129.4, 129.1, 128.3, 127.2, 126.2, 126.1, 61.4, 49.4, 46.2, 34.4, 31.0,
27.3, 21.8. HRMS (ESI-TOF) calcd for C23H31N2O2S [M + H]+
399.2101, found 399.2096.
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56 as a white solid (21%); mp 178−181 °C. H NMR (400 MHz,
CDCl3) δ 7.81 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.64−
7.56 (m, 2H), 7.52−7.45 (m, 2H), 7.45−7.37 (m, 1H), 3.90 (d, J =
12.1 Hz, 2H), 2.84 (d, J = 10.8 Hz, 2H), 2.32 (td, J = 12.1, 2.5 Hz,
3H), 2.20 (t, J = 11.9 Hz, 2H), 1.91 (d, J = 12.6 Hz, 2H), 1.77−1.57
(m, 4H), 1.42−1.12 (m, 3H), 0.90 (d, J = 5.9 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 145.6, 139.2, 134.6, 129.1, 129.1, 128.5, 128.2,
127.6, 127.3, 61.6, 49.4, 46.1, 34.1, 30.8, 27.1, 21.7. HRMS (ESI-
TOF) calcd for C23H31N2O2S [M + H]+ 399.2101, found 399.2097.
1′-((4′-Chloro-[1,1′-biphenyl]-4-yl)sulfonyl)-4-methyl-1,4′-
bipiperidine (57). Reaction of amine 1a with 4′-chloro-[1,1′-
biphenyl]-4-sulfonyl chloride (Procedure A) yielded 57 as a white
solid (87%); mp 205−207 °C. 1H NMR (400 MHz, CDCl3) δ 7.88−
7.75 (m, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.43
(d, J = 8.5 Hz, 2H), 3.87 (d, J = 12.0 Hz, 2H), 2.76 (d, J = 10.9 Hz,
2H), 2.41−2.02 (m, 5H), 1.83 (dd, J = 12.3, 3.6 Hz, 2H), 1.70−1.46
(m, 4H), 1.37−1.05 (m, 3H), 0.87 (d, J = 6.3 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 144.2, 137.7, 135.1, 134.7, 129.2, 128.5, 128.3,
127.4, 61.4, 49.5, 46.2, 34.6, 31.0, 27.3, 21.8. HRMS (ESI-TOF) calcd
for C23H30ClN2O2S [M + H]+ 433.1711, found 433.1706.
1′-((4′-Chloro-[1,1′-biphenyl]-3-yl)sulfonyl)-4-methyl-1,4′-
bipiperidine (62). Reaction of 29 with 4-(chlorophenyl)boronic
acid (Procedure C) yielded 62 as a pink solid (58%); mp 124−126
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°C. H NMR (400 MHz, CDCl3) δ 7.89 (t, J = 1.8 Hz, 1H), 7.72
(ddt, J = 15.7, 7.9, 1.4 Hz, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.54−7.48
(m, 2H), 7.45−7.39 (m, 2H), 3.86 (d, J = 12.1 Hz, 2H), 2.80 (dt, J =
11.5, 3.1 Hz, 2H), 2.27 (td, J = 12.1, 2.4 Hz, 3H), 2.13 (t, J = 10.6 Hz,
2H), 1.86 (d, J = 13.3 Hz, 2H), 1.72−1.52 (m, 4H), 1.38−1.14 (m,
3H), 0.87 (d, J = 6.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 141.1,
137.6, 136.9, 134.5, 131.1, 129.6, 129.2, 128.5, 126.5, 125.8, 61.5,
49.4, 46.1, 34.2, 30.8, 27.1, 21.7. HRMS (ESI-TOF) calcd for
C23H30ClN2O2S [M + H]+ 433.1711, found 433.1705.
1′-((4′-Methoxy-[1,1′-biphenyl]-3-yl)sulfonyl)-4-methyl-
1,4′-bipiperidine (63). Reaction of 29 with (4-methoxyphenyl)-
boronic acid (Procedure C) yielded 63 as a yellow solid (44%); mp
107−109 °C. 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.74 (d, J
= 7.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.58−7.47 (m, 3H), 6.98 (d,
J = 8.5 Hz, 2H), 3.87 (d, J = 12.2 Hz, 2H), 3.84 (s, 3H), 2.80 (d, J =
10.0 Hz, 2H), 2.27 (td, J = 12.0, 2.4 Hz, 3H), 2.15 (t, J = 11.9 Hz,
2H), 1.87 (d, J = 11.7 Hz, 2H), 1.75−1.53 (m, 4H), 1.38−1.19 (m,
3H), 0.88 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 159.9,
141.9, 136.6, 131.6, 130.8, 129.4, 128.3, 125.6, 125.5, 114.5, 61.5,
1′-((4′-Methoxy-[1,1′-biphenyl]-4-yl)sulfonyl)-4-methyl-
1,4′-bipiperidine (58). Reaction of amine 1a with 4′-methoxy-[1,1′-
biphenyl]-4-sulfonyl chloride (Procedure A) yielded 58 as a white
solid (92%); mp 195−198 °C. 1H NMR (400 MHz, CDCl3) δ 7.85−
P
J. Med. Chem. XXXX, XXX, XXX−XXX