R.A. Lippa et al. / European Journal of Medicinal Chemistry 208 (2020) 112719
19
6.1 Hz, 1H), 2.34 (s, 3H), 2.23e2.13 (m, 1H), 2.06e1.94 (m, 1H),
1.93e1.84 (m, 2H), 1.77e1.62 (m, 2H), 1.47e1.36 (m, 1H); 13C NMR
(101 MHz, CDCl3)
128.9, 128.2, 127.5, 125.4, 117.6, 108.9, 49.8, 46.9, 43.7, 41.7, 40.6,
38.5, 33.4, 32.4, 31.1, 25.9, 21.5, 19.8; IR (neat): 3261, 2937, 2861,
1683, 1623, 1564 cmꢁ1; LC-MS (For): 0.66 min (422) ([MþH]þ,
100%); HRMS: calculated for C25H32N3Oþ3 ([MþH]þ) 422.2438,
found 422.2448.
(S)-3-(3-Cyclopropylphenyl)-4-oxo-4-((R)-3-(2-(5,6,7,8-
tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)buta-
noic acid 17b: Prepared according to General Procedure F using aryl
bromide 6b (150 mg, 0.308 mmol, 1.0 eq.), cyclopropylboronic acid
(1.5 eq.), 2 M NaOH (0.6 eq.), and methanol (15 mL), heating at
120 ꢂC for 4 h. HPLC using Mass Directed Autopurification (Xselect
CSH C18 column eluting with 15e55% acetonitrile in water with
10 mM ammonium bicarbonate modifier) afforded the title com-
modifier) afforded the title compound (5 mg,10.5
m
mol, 6% yield) as
a white amorphous solid. ½a D20
ꢅ
(c ¼ 0.37, MeOH): þ33; 1H NMR
d
¼ 179.8, 174.3, 153.8, 150.3, 140.5, 139.1, 137.9,
(700 MHz, CDCl3)
d
¼ 10.61 (br s, 1H), 7.36e7.28 (m, 2H), 7.25e7.20
(m, 1H), 7.17 (d, J ¼ 7.2 Hz, 1H), 7.11 (d, J ¼ 7.6 Hz, 1H), 6.24 (d,
J ¼ 7.2 Hz, 1H), 4.80 (d, J ¼ 9.7 Hz, 1H), 4.39 (dd, J ¼ 12.1, 1.9 Hz, 1H),
3.56 (td, J ¼ 12.0, 7.4 Hz, 1H), 3.48e3.36 (m, 3H), 3.32e3.26 (m, 1H),
3.02e2.95 (m, 1H), 2.83 (t, J ¼ 12.5 Hz, 1H), 2.70 (t, J ¼ 6.1 Hz, 2H),
2.63e2.56 (m, 1H), 2.47 (td, J ¼ 12.7, 6.4 Hz, 1H), 2.27e2.14 (m, 2H),
2.11e1.96 (m, 4H), 1.89 (quin, J ¼ 5.9 Hz, 2H), 1.85e1.77 (m, 2H),
1.76e1.56 (m, 5H), 1.46e1.39 (m, 1H); 13C NMR (176 MHz, CDCl3)
d
¼ 179.9, 174.2, 153.8, 150.3, 146.5, 140.4, 139.1, 128.2, 127.3, 125.7,
125.4, 117.6, 108.9, 49.8, 47.0, 46.0, 43.7, 41.9, 40.6, 38.5, 34.7, 34.6,
33.4, 32.4, 31.1, 25.9, 25.5 (2C), 19.8; IR (neat): 3424, 2939, 2867,
1683, 1626, 1565 cmꢁ1; LC-MS (For): 0.86 min (476) ([MþH]þ,
100%); HRMS: calculated for C29H38N3Oþ3 ([MþH]þ) 476.2908,
found 476.2911.
pound (4 mg, 8.94
m
mol, 3% yield) as a white amorphous solid. ½a D20
ꢅ
(R)-3-(5-methylthiophen-2-yl)-4-oxo-4-((R)-3-(2-(5,6,7,8-
tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)buta-
noic acid 19: Prepared according to General Procedure G using aryl
bromide 6i (200 mg, 0.406 mmol, 1.0 eq.) and trimethylboroxine
(5.0 eq.) in 1,4-dioxane (8 mL)/water (2 mL). After stirring for 4 h at
90 ꢂC, the reaction mixture was filtered through Celite and
concentrated in vacuo. HPLC using Mass Directed Autopurification
(Xselect CSH C18 column eluting with 15e55% acetonitrile in water
with 10 mM ammonium bicarbonate modifier) afforded the title
compound (14 mg, 0.033 mmol, 8% yield) as a white amorphous
solid. Room temperature 1H and 13C NMR spectra in CDCl3 show
(c ¼ 1.10, MeOH): þ81; 1H NMR (400 MHz, CDCl3)
d
¼ 10.59 (br s,
1H), 7.27e7.13 (m, 4H), 6.90e6.84 (m, 1H), 6.22 (d, J ¼ 7.3 Hz, 1H),
4.77 (d, J ¼ 9.8 Hz, 1H), 4.36 (dd, J ¼ 12.2, 2.4 Hz, 1H), 3.54 (td,
J ¼ 12.0, 7.3 Hz, 1H), 3.45e3.32 (m, 4H), 3.26 (dd, J ¼ 12.2, 9.3 Hz,
1H), 2.80 (td, J ¼ 13.0, 2.0 Hz, 1H), 2.67 (t, J ¼ 6.1 Hz, 2H), 2.55 (dd,
J ¼ 16.6, 2.9 Hz, 1H), 2.46 (td, J ¼ 12.7, 6.4 Hz, 1H), 2.21e2.11 (m, 1H),
2.04e1.81 (m, 4H), 1.75e1.59 (m, 2H), 1.47e1.34 (m, 1H), 0.96e0.87
(m, 2H), 0.75e0.63 (m, 2H); 13C NMR (101 MHz, CDCl3)
d
¼ 179.7,
174.0, 153.7, 150.1, 143.9,140.4,139.1, 128.2,126.0,125.3,123.5,117.5,
108.9, 49.7, 46.8, 43.7, 41.8, 40.5, 38.4, 33.3, 32.3, 31.0, 25.8, 19.7,
15.3, 9.1, 9.1; IR (neat): 3405, 2923, 2862,1679,1623,1564 cmꢁ1; LC-
MS (For): 0.73 min (448) ([MþH]þ, 100%); HRMS: calculated for
complex mix of rotamers. ½a D20
ꢅ
(c ¼ 1.13, MeOH): þ25; 1H NMR
(400 MHz, DMSO‑d6, 393 K)
d
¼
d 8.15 (s, 1H), 7.29e7.13 (m, 1H),
C
27H34N3O3 ([MþH]þ) 448.2595, found 448.2602.
6.77e6.69 (m, 1H), 6.63e6.57 (m, 1H), 6.46e6.37 (m, 1H), 4.39e4.15
(m, 1H), 3.68e3.44 (m, 2H), 3.39e3.20 (m, 3H), 3.08e2.92 (m, 2H),
2.68 (t, J ¼ 6.4 Hz, 2H), 2.63e2.52 (m, 3H), 2.41e2.37 (m, 3H),
2.20e2.08 (m, 1H), 2.06e1.94 (m, 1H), 1.83 (quin, J ¼ 6.0 Hz, 2H),
1.76e1.64 (m, 2H), 1.61e1.45 (m, 1H); 13C NMR (101 MHz, CDCl3,
(S)-3-(3-(Cyclopent-1-en-1-yl)phenyl)-4-oxo-4-((R)-3-(2-
(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)
butanoic acid 17c: Prepared according to General Procedure F us-
ing aryl bromide 6b (67 mg, 0.140 mmol, 1.0 eq.), cyclopent-1-en-1-
ylboronic acid (1.2 eq.), 2 M NaOH (0.6 eq.), and methanol (15 mL),
heating at 120 ꢂC for 30 min. HPLC using Mass Directed Autopur-
ification (Xselect CSH C18 column eluting with 15e55% acetonitrile
in water with 10 mM ammonium bicarbonate modifier) afforded
the title compound (24 mg, 0.051 mmol, 37% yield) as an off-white
303 K)
d
¼ 179.5, 179.2, 174.0, 173.4, 153.7, 153.7, 150.1, 149.7, 141.1,
140.2, 139.2, 139.1, 138.5, 138.4, 124.5, 124.3, 124.1, 117.9, 117.6, 108.9,
108.8, 49.6, 48.4, 44.3, 43.8, 43.3, 43.1, 42.7, 41.5, 40.6, 40.6, 38.5,
35.5, 33.4, 32.3, 31.6, 31.5, 31.1, 30.5, 25.9, 25.9, 19.8, 19.7, 15.2; IR
(neat): 3390e2151, 1679, 1631, 1564 cmꢁ1; LC-MS (TFA): 0.69 min
(428) ([MþH]þ, 100%); HRMS: calculated for C23H30N3O3Sþ
([MþH]þ) 428.2002, found 428.2002.
amorphous solid. ½a D20
ꢅ
(c ¼ 0.45, MeOH): þ53; 1H NMR (700 MHz,
CDCl3)
d
¼ 10.62 (br s, 1H), 7.55e7.46 (m, 1H), 7.39e7.28 (m, 2H),
7.26e7.23 (m, 1H), 7.20e7.15 (m, 1H), 6.26e6.16 (m, 2H), 4.80 (d,
J ¼ 9.7 Hz, 1H), 4.40 (dd, J ¼ 12.1, 2.3 Hz, 1H), 3.56 (td, J ¼ 12.0,
7.4 Hz, 1H), 3.47e3.38 (m, 4H), 3.28 (dd, J ¼ 12.1, 9.5 Hz, 1H),
2.86e2.80 (m, 1H), 2.78e2.64 (m, 4H), 2.59 (dd, J ¼ 17.0, 2.5 Hz, 1H),
2.56e2.50 (m, 2H), 2.48 (td, J ¼ 12.9, 6.4 Hz, 1H), 2.21e2.15 (m, 1H),
2.04e1.96 (m, 3H), 1.92e1.86 (m, 2H), 1.75e1.63 (m, 2H), 1.43 (td,
Compounds 20 and 21 were prepared as previously reported
3-(5-(3-(Pyridin-2-ylamino)propoxy)-1H-indol-1-yl)prop-
anoic acid 20: 1H NMR (400 MHz, DMSO‑d6)
d
¼ 7.99e7.94 (m, 1H),
7.38e7.31 (m, 2H), 7.27 (d, J ¼ 3.2 Hz, 1H), 7.04 (d, J ¼ 2.3 Hz, 1H),
6.79 (dd, J ¼ 8.9, 2.3 Hz, 1H), 6.51 (t, J ¼ 5.4 Hz, 1H), 6.48e6.40 (m,
2H), 6.29 (d, J ¼ 3.2 Hz,1H), 4.34 (t, J ¼ 6.8 Hz, 2H), 4.04 (t, J ¼ 6.6 Hz,
2H), 3.39 (q, J ¼ 6.6 Hz, 2H), 2.70 (t, J ¼ 6.8 Hz, 2H), 1.98 (quin,
J ¼ 13.1, 5.9 Hz, 1H); 13C NMR (176 MHz, CDCl3)
d
¼ 179.7, 174.1,
153.7, 150.2, 142.5, 140.5, 139.1, 136.9, 128.3, 126.8, 126.1, 125.5,
124.1, 117.6, 108.9, 49.8, 47.0, 43.8, 41.8, 40.6, 38.5, 33.4, 33.3, 33.2,
32.4, 31.1, 25.9, 23.4, 19.8; IR (neat): 3259, 2938, 2865, 1678, 1625,
1564 cmꢁ1; LC-MS (For): 0.85 min (474) ([MþH]þ, 100%); HRMS:
calculated for C29H36N3Oþ3 ([MþH]þ) 474.2751, found 474.2752.
(S)-3-(3-Cyclopentylphenyl)-4-oxo-4-((R)-3-(2-(5,6,7,8-
J ¼ 6.6 Hz, 2H); 13C NMR (101 MHz, DMSO‑d6)
¼ 172.5,158.9,152.7,
d
147.5, 136.4,130.8,128.9,128.5,111.6, 111.3, 110.3,108.0,103.4,100.2,
66.1, 41.7, 37.8, 34.9, 28.9; IR (neat): 3275, 2856, 1683, 1616,
1488 cmꢁ1; LC-MS: (HpH): 0.67 min (340) ([MþH]þ, 99%).
3-(5-(2-(6-(Methylamino)pyridin-2-yl)ethoxy)-1H-indol-1-
tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)buta-
noic acid 18: Prepared according to General Procedure F using aryl
bromide 6b (89 mg, 0.183 mmol, 1.0 eq.), cyclopent-1-en-1-
ylboronic acid (1.3 eq.), 2 M NaOH (0.7 eq.), and methanol
(15 mL), heating at 120 ꢂC for 30 min. The reaction was filtered,
washed with methanol (15 mL) and hydrogenated using an H-
cube® Pro (40 ꢂC, 40 bar, 1 mL/min flow rate. 5% Pd/C cartridge) and
the reaction mixture was concentrated in vacuo. HPLC using Mass
Directed Autopurification (Xselect CSH C18 column eluting with
15e55% acetonitrile in water with 10 mM ammonium bicarbonate
yl)propanoic acid 21: 1H NMR (400 MHz, DMSO‑d6)
d
¼ 12.20 (br s,
1H), 7.35 (d, J ¼ 8.8 Hz, 1H), 7.30 (dd, J ¼ 8.3, 7.1 Hz, 1H), 7.27 (d,
J ¼ 3.2 Hz, 1H), 7.06 (d, J ¼ 2.2 Hz, 1H), 6.75 (dd, J ¼ 8.9, 2.3 Hz, 1H),
6.45 (d, J ¼ 7.1 Hz, 1H), 6.35e6.28 (m, 2H), 6.27 (d, J ¼ 8.3 Hz, 1H),
4.34 (t, J ¼ 6.7 Hz, 2H), 4.28 (t, J ¼ 6.9 Hz, 2H), 2.96 (t, J ¼ 6.9 Hz, 2H),
2.75 (d, J ¼ 4.9 Hz, 3H), 2.71 (t, J ¼ 6.7 Hz, 2H); 13C NMR (101 MHz,
DMSO‑d6)
d
¼ 172.4, 159.2, 156.2, 152.6, 136.9, 130.8, 128.9, 128.5,
111.6, 110.5, 110.3, 104.9, 103.4, 100.3, 67.5, 41.6, 37.5, 34.7, 27.9; IR
(neat): 3264, 2914, 1689, 1619, 1542, 1239, 1159 cmꢁ1; LC-MS:
(HpH): 0.67 min (340) ([MþH]þ, 97%).