Journal of Medicinal Chemistry
Article
+
4
°
81.2597 [M + H] . HPLC purity 98% (R = 12.5 min), mp 298−303
HPLC: method B, R = 29.8 min. The product was obtained as a white
t
t
1
C. 0.3 Equiv Et N and 1 equiv CH CO H-salt: H NMR (600 MHz,
DMSO-d ): δ (ppm) = 9.41 (s, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 8.13 (s,
H), 7.91 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 7.9 Hz, 2H), 7.52 (d, J = 8.4
Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 3.19 (d, J = 12.1 Hz, 2H), 2.80−2.74
m, 2H), 2.43 (q, J = 7.1 Hz, (0.3 equiv Et N), 3H), 1.85 (s, 3H ),
acetate salt by lyophilization (1 equiv CH
3
CO
MS (ESI, m/z) 509.2 [M + H] . ESI-HRMS calcd for C27H N O F
24 4 3 3
2
H-salt, 2.63 mg, 84%).
3
3
2
+
6
+
1
509.1801, found 509.1817 [M + H] . HPLC purity 96% (R
t
= 12.3 min),
): δ (ppm) = 9.52 (s,
6
1
mp 274−280 °C. H NMR (400 MHz, DMSO-d
(
1
(
1H), 8.35 (s, 1H), 8.23 (s, 1H), 8.15−8.05 (m, 3H), 7.72 (d, J = 8.0 Hz,
2H), 7.52 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 3.09 (d, J = 12.1
Hz, 2H), 2.71−2.64 (m, 3H), 1.85 (s, 3Hacetate), 1.77 (d, J = 12.1 Hz,
3
acetate
.85−1.79 (m, 2H), 1.79−1.67 (m, 2H), 1.33 (s, 9H), 0.93 (t, J = 7.1 Hz,
13
0.3 equiv Et N), 3H). 1 Equiv CH CO H-salt: C NMR (150 MHz,
3 3 2
13
2
H), 1.61 (qd, J = 4.0, 12.1 Hz, 2H). C NMR (125 MHz, DMSO-d ): δ
DMSO-d ): δ (ppm) = 151.1, 147.7, 141.0, 137.8, 137.1, 128.4, 128.1,
27.8 (2C), 127.3, 127.4 (2C), 126.2 (2C), 125.6 (2C), 120.0, 119.8,
19.5, 40.5 (2C), 34.9 (2C), 31.6 (3C).
6
6
(
(
ppm) = 167.6, 148.5, 146.9, 146.5, 141.2, 137.7, 137.0, 130.4, 127.9
2C), 127.7 (2C), 127.6, 127.4 (2C), 122.3 (2C), 122.2 (q, JC−F = 260.4
1
1
Hz), 120.9, 119.7, 118.3, 46.5 (2C), 42.1, 40.7, 40.6, 33.7 (2C), 22.4.
5-(4-(3-(Trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)-4′-(pi-
peridin-4-yl)-[1,1′-biphenyl]-3-carboxylic Acid (85). Semipreparative
5
-(4-(3-(Trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)-4′-(piperi-
din-4-yl)-[1,1′-biphenyl]-3-carboxylic Acid (80). Semipreparative
HPLC: method B, R = 27.6 min. The product was obtained as a
t
HPLC: method B, R = 29.2 min. The product was obtained as a white
white solid by lyophilization (0.5 equiv CH CO H-salt, 2.53 mg, 48%).
MS (ESI, m/z) 493.1 [M + H] . ESI-HRMS calcd for C H N O F
93.1851, found 493.1851 [M + H] . HPLC purity 99% (R = 11.8 min),
t
3
2
+
acetate salt by lyophilization (0.5 equiv CH CO H-salt, 3.63 mg, 66%).
3
2
2
7
24
4
2 3
+
+
MS (ESI, m/z) 509.2 [M + H] . ESI-HRMS calcd for C H N O F
09.1801, found 509.1798 [M + H] . HPLC purity 98% (R = 12.4 min).
t
H NMR (500 MHz, DMSO-d ): δ (ppm) = 9.63 (s, 1H), 8.40 (s, 1H),
4
27 24 4 3 3
t
+
1
5
mp 277−284 °C. H NMR (500 MHz, DMSO-d ): δ (ppm) = 9.70 (s,
6
1
1
(
(
H), 8.41 (s, 1H), 8.32 (s, 2H), 8.28 (s, 1H), 8.16 (s, 1H), 7.79−7.72
m, 4H), 7.41 (d, J = 7.9 Hz, 2H), 3.20 (d, J = 12.0 Hz, 2H), 2.88−2.68
m, 3H), 1.99−1.63 (m, (1.5H
), 5H). 13C NMR (125 MHz,
6
8.30 (s, 1H), 8.15 (t, J = 2.0 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.94 (s,
1H), 7.75 (d, J = 7.9 Hz, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.9 Hz,
2H), 7.38 (dd, J = 2.4, 8.1 Hz, 1H), 3.24 (d, J = 11.8 Hz, 2H), 2.88−2.75
acetate
DMSO-d ): δ (ppm) = 172.5, 167.6, 146.1, 145.8, 143.3, 140.8, 137.2,
6
13
1
1
36.6, 131.5, 130.3, 130.0, 129.8, 129.0, 127.4 (2C), 127.0, 126.9 (2C),
25.9 (q, JC−F = 274 Hz, 1C), 124.7, 121.8, 120.8, 119.0, 118.0, 45.7, 45.2
(m, 3H), 1.88 (s, 1.5Hacetate), 1.86−1.79 (m, 4H). C NMR (125 MHz,
DMSO-d ): δ (ppm) = 171.9, 166.6, 148.5, 145.3, 140.2, 136.7, 135.9,
6
(
2C), 40.8, 32.1 (2C), 29.0, 21.8, 11.7.
132.2, 130.7, 126.8 (2C), 126.4 (2C), 123.7, 120.2, 120.0, 119.5, 118.8
(q, JC−F = 257.4 Hz), 117.1, 45.1 (2C), 40.7, 32.1 (2C), 21.1.
5
-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-4′-(piperidin-4-yl)-
[
1,1′-biphenyl]-3-carboxylic Acid (81). Semipreparative HPLC:
5-(4-(3-Chlorophenyl)-1H-1,2,3-triazol-1-yl)-4′-(piperidin-4-yl)-
method B, R = 23.0 min. The product was obtained as a white solid
[1,1′-biphenyl]-3-carboxylic Acid (86). Semipreparative HPLC:
t
by lyophilization (1 equiv CH CO H-salt, 2.14 mg, 73%). MS (ESI, m/
z) 455.2 [M + H] . ESI-HRMS calcd for C H N O 455.2083, found
4
method B, R
= 21.2 min. The product was obtained as a white solid
t
3
2
+
by lyophilization (1 equiv CH
CO
459.2 [M + H] . ESI-HRMS calcd for C26H24 ClN O 459.1588, found
4 2
H-salt, 2.2 mg, 68%). MS (ESI, m/z)
27
27
4
3
3
2
+
1
+
35
55.2086 [M + H] . HPLC purity 97% (R = 10.1 min). H NMR (500
t
+
1
MHz, DMSO-d ): δ (ppm) = 9.35 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H),
459.1583 [M + H] . HPLC purity 98% (R
t
= 11.1 min). H NMR (500
6
7
2
2
1
.92 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 7.9 Hz,
H), 7.07 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H), 3.07 (d, J = 11.8 Hz, 2H),
.70−2.57 (m, 3H), 1.84−1.68 (m, (3Hacetate), 5H), 1.58 (qd, J = 4.0,
MHz, DMSO-d ): δ (ppm) = 9.59 (s, 1H), 8.36 (s, 1H), 8.22 (s, 1H),
8.10 (s, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.55 (t, J =
6
7.9 Hz, 1H), 7.45 (dd, J = 2.1, 8.1 Hz, 1H), 7.38 (d, J = 7.9 Hz, 2H), 2.66
2.0 Hz, 2H). 13C NMR (125 MHz, DMSO-d ): δ (ppm) = 173.8
13
(s, 3H), 1.67 (m, (3Hacetate), 7H). C NMR (125 MHz, DMSO-d
): δ
6
6
(1Cacetate), 167.8, 159.9, 147.9, 147.3, 144.7, 141.3, 137.9, 137.3, 128.1
(2C), 127.6 (2C), 127.5, 127.4 (2C), 123.7, 119.7, 119.5, 118.3, 115.1
(2C), 55.9, 47.1 (2C), 42.7, 34.5 (2C), 29.8, 23.6 (1Cacetate).
(ppm) = 167.1, 146.9, 146.1, 140.8, 137.4, 136.6, 134.0, 132.9, 131.2,
128.1, 127.6 (2C), 127.3 (2C), 127.0, 125.3, 124.0, 120.8, 119.4, 117.7,
46.8, 42.4 (2C), 34.4 (2C), 29.2.
5
-(4-(4-(Pentyloxy)phenyl)-1H-1,2,3-triazol-1-yl)-4′-(piperidin-4-
5-(4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-4′-(piperidin-4-yl)-
yl)-[1,1′-biphenyl]-3-carboxylic Acid (82). Semipreparative HPLC:
[1,1′-biphenyl]-3-carboxylic Acid (87). Semipreparative HPLC:
method B, R = 34.1 min. The product was obtained as a white solid by
method B, R = 20.6 min. The product was obtained as a salt by
t
t
lyophilization (1 equiv CH CO H-salt, 5.3 mg, 99%). MS (ESI, m/z)
lyophilization (0.5 equiv CH CO H-salt, 3.06 mg, 99%). MS (ESI, m/z)
3
2
3
2
+
+
5
5
11.3 [M + H] . ESI-HRMS calcd for C H N O 511.2709, found
443.2 [M + H] . ESI-HRMS calcd for C H FN O 443.1883, found
31
35
4
3
26 24 4 2
+
1
+
1
11.2703 [M + H] . HPLC purity 99% (R = 14.4 min). H NMR (500
443.1890 [M + H] . HPLC purity 96% (R = 10.8 min). H NMR (400
t
t
MHz, DMSO-d ): δ (ppm) = 9.40 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H),
MHz, DMSO-d ): δ (ppm) = 9.46 (s, 1H), 8.36 (s, 1H), 8.23 (s, 1H),
6
6
8
.16 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 7.8 Hz, 2H), 7.45 (d, J
7.9 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 4.08 (t, J = 6.5 Hz, 2H), 3.20 (d, J
8.10 (s, 1H), 8.06−7.95 (m, 2H), 7.71 (d, J = 7.7 Hz, 2H), 7.40−7.33
=
=
(m, 4H), 3.11−3.01 (m, 2H), 2.70−2.57 (m, 3H), 1.75 (m, 4H), 1.63−
11.8 Hz, 2H), 2.83−2.68 (m, 3H), 1.94 (s, 3H
), 1.89−1.78 (m,
1.50 (m, 2H). 13C NMR (150 MHz, DMSO-d ): δ (ppm) = 163.2,
acetate
6
4H), 1.77−1.65 (m, 3H), 1.52−1.38 (m, 4H), 0.97 (t, J = 7.2 Hz, 3H).
161.2, 147.0, 146.8, 141.1, 137.6, 137.0, 127.8 (2C), 127.5 (2C), 127.3,
120.2, 119.9, 118.2, 116.5 (2C), 116.3 (2C), 72.7, 70.8, 60.7, 46.6, 42.3
(2C), 40.5, 34.2 (2C), 29.4, 20.7.
1
3
C NMR (125 MHz, DMSO-d ): δ (ppm) = 137.0, 126.9 (2C), 126.3
6
(
2C), 126.2 (2C), 120.6 (2C), 119.2, 118.8, 118.0, 114.4, 77.0, 72.3,
67.0, 46.7 (2C), 27.9, 27.2, 21.4, 13.5.
5-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-4′-(piperidin-4-yl)-
[
1,1′-biphenyl]-3-carboxylic Acid (88). Semipreparative HPLC:
5
-(4-(2-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-4′-(piperidin-4-yl)-
[
1,1′-biphenyl]-3-carboxylic Acid (83). Semipreparative HPLC:
method B, R
salt by lyophilization (0.5 equiv CH
t
= 21.5 min. The product was obtained as a white acetate
CO H-salt, 3.4 mg, 84%). MS (ESI,
m/z) 443.1 [M + H] . ESI-HRMS calcd for C26 443.1883,
method B, R = 23.0 min. The product was obtained as a white solid
3
2
t
+
by lyophilization (1 equiv CH CO H-salt, 3.05 mg, 52%). MS (ESI, m/
z) 455.2 [M + H] . ESI-HRMS calcd for C H N O 455.2083, found
4
H24FN O
4 2
3
2
+
+
1
found 443.1884 [M + H] . HPLC purity 98.2% (R
= 10.5 min). H
2
7
27
4
3
t
+
1
55.2086 [M + H] . HPLC purity 98% (R = 10.44 min). H NMR (600
NMR (500 MHz, DMSO-d ): δ (ppm) = 9.57 (s, 1H), 8.37 (s, 1H), 8.27
6
t
MHz, DMSO-d ): δ (ppm) = 9.02 (s, 1H), 8.33 (s, 1H), 8.24 (s, 1H),
(s, 1H), 8.13 (s, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.79 (dt, J = 2.6, 10.2 Hz,
1H), 7.75 (d, J = 7.9 Hz, 2H), 7.56 (td, J = 6.0, 8.0 Hz, 1H), 7.41 (d, J =
7.9 Hz, 2H), 7.22 (td, J = 2.6, 8.6 Hz, 1H), 3.19 (d, J = 11.8 Hz, 2H),
6
8
(
3
.22 (d, J = 7.5 Hz, 1H), 8.10 (s, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.43−7.34
m, 3H), 7.18 (d, J = 8.3 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 3.98 (s, 3H),
.14 (d, J = 12.0 Hz, 3H), 2.74−2.67 (m, 3H), 1.86 (s, 3Hacetate), 1.79 (d,
1
3
2.82−2.69 (m, 3H), 1.89 (s, 1.5H
), 1.86−1.69 (m, 4H). C NMR
acetate
13
J = 12.0 Hz, 2H), 1.73−1.62 (m, 2H). C NMR (150 MHz, DMSO-d ):
δ (ppm) = 173.1 (1C
(125 MHz, DMSO-d ): δ (ppm) = 173.5, 167.5, 163.01 (d, J = 243.6
6
6 C−F
), 167.9, 156.0, 146.7, 143.7, 143.2, 141.1,
Hz), 146.8, 146.5, 144.3, 141.0, 137.5, 136.8, 133.2, 133.2, 131.6, 131.5,
127.8 (2C), 127.4 (2C), 127.2, 121.7, 120.9, 119.4, 118.2, 115.3, 115.2,
112.4, 112.2, 46.4 (2C), 42.1, 33.8 (2C), 23.3.
acetate
137.6, 137.1, 129.7, 127.7 (2C), 127.4 (2C), 127.3, 122.2, 121.0, 120.0,
119.1, 118.9, 111.9, 55.9, 46.3 (2C), 41.9, 40.4, 33.6 (2C), 22.4
(
1Cacetate).
-(4-(4-(Trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)-4′-(pi-
peridin-4-yl)-[1,1′-biphenyl]-3-carboxylic Acid (84). Semipreparative
5-(4-(2-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-4′-(piperidin-4-yl)-
5
[1,1′-biphenyl]-3-carboxylic Acid (89). Semipreparative HPLC:
method B, R = 24.3 min. The product was obtained as a white salt by
t
N
J. Med. Chem. XXXX, XXX, XXX−XXX