Journal of Medicinal Chemistry
Article
washed with brine, dried (MgSO4), and evaporated in vacuo. The
residue (100.7 mg) was purified by MDAP (method A). The required
fractions were combined and evaporated in vacuo to give 28w (66 mg,
39%) as an off-white foam: LCMS (system A) RT = 0.85 min, 100%,
1.67−1.57 (2H, m), 1.40−1.32 (1H, m), 0.90−0.85 (2H, m), 0.66−
0.62 (2H, m); 13C NMR (DMSO-d6, 151 MHz) 173.7, 157.2, 155.7,
151.1, 144.3, 144.2, 136.0, 115.5, 112.3, 111.5, 110.2, 109.8, 66.1,
61.9, 59.1, 53.1, 48.6, 41.5, 40.6, 40.4, 36.5, 35.7, 34.8, 30.1, 25.9,
21.0, 15.4, 9.0. HRMS (ESI) calcd for C31H43N4O3 519.3335 (M +
H)+, found 519.3333. Anal. chiral HPLC RT = 17.0 min, 99.5% on a
Chiralpak AD-H column (250 mm × 4.6 mm) eluting with 40%
EtOH (containing 0.2% isopropylamine)−heptane, flow rate = 1 mL/
min, detecting at 215 nm.
(S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-morpholino-
phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-
ethyl)pyrrolidin-1-yl)butanoic Acid (28ch). Prepared from (R)-
26ch: LCMS (system A) RT = 0.85 min, 98%, ES+ve m/z 573 (M +
1
ES+ve m/z 494 (M + H)+; H NMR (CDCl3, 400 MHz) 7.24−7.16
(2H, m), 6.80−6.74 (3H, m), 6.29 (1H, d, J 7 Hz), 4.51−4.44 (1H,
m), 4.02−3.95 (2H, m), 3.62−3.54 (2H, m), 3.50−3.34 (3H, m),
3.15−3.05 (1H, m), 3.02−2.93 (1H, m), 2.79−2.67 (6H, m), 2.56−
2.46 (1H, m), 2.28−2.16 (1H, m), 2.16−2.06 (1H, m), 2.06−1.97
(2H, m), 1.96−1.73 (6H, m), 1.71−1.60 (1H, m), 1.58−1.47 (1H,
m).
(3S)-4-((R)-3-(2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)-
ethyl)pyrrolidin-1-yl)-3-(3-(tetrahydrofuran-3-yl)phenyl)-
butanoic Acids (28x Isomer 1 and 28x Isomer 2). Prepared from
(R)-17. 28x Isomer 1: LCMS (system A) RT = 0.84 min, 100%, ES
+ve m/z 464 (M + H)+; 1H NMR (DMSO-d6, 600 MHz) 7.22 (1H, t,
J 7.5 Hz), 7.14 (1H, s), 7.10 (1H, br d, J 7.5 Hz), 7.07 (1H, br d, J 7.5
Hz), 7.02 (1H, br d, J 7 Hz), 6.30−6.20 (2H, m), 4.04−3.99 (1H, m),
3.96−3.90 (1H, m), 3.82−3.75 (1H, m), 3.52 (1H, br t, J 8 Hz),
3.37−3.30 (1H, m), 3.26−3.21 (2H, m), 3.20−3.14 (1H, m), 2.91−
2.83 (1H, m), 2.82−2.74 (2H, m), 2.74−2.68 (1H, m), 2.62−2.57
(2H, m), 2.60−2.53 (1H, m), 2.52−2.47 (1H, m), 2.43−2.38 (2H,
m), 2.41−2.36 (1H, m), 2.36−2.31 (1H, m), 2.31−2.24 (1H, m),
2.08−1.99 (1H, m), 1.95−1.85 (2H, m), 1.78−1.71 (2H, m), 1.67−
1.55 (2H, m), 1.40−1.30 (1H, m); 13C NMR (DMSO-d6, 151 MHz)
173.6, 157.1, 155.7, 143.7, 142.5, 136.0, 128.4, 126.3, 125.2, 125.1,
112.3, 109.8, 73.8, 67.6, 61.8, 59.2, 53.1, 44.1, 40.9, 40.6, 40.1, 36.5,
35.7, 34.8, 33.9, 30.1, 25.9, 21.0.
+
1
H) ; IR imax (neat) 3300−2500, 1678, 1595, 1118, 725 cm−1; H
NMR (DMSO-d6, 600 MHz) 7.02 (1H, d, J 7.3 Hz), 6.86 (1H, s),
6.79 (1H, m), 6.75 (1H, s), 6.25 (1H, s), 6.26 (1H, d, J 7.3 Hz), 6.03
(1H, s), 3.76−3.71 (4H, m), 3.27−3.20 (4H, m), 3.18−3.13 (4H, m),
2.96−2.88 (1H, m), 2.83−2.78 (2H, m), 2.75−2.68 (1H, m), 2.63−
2.54 (3H, m), 2.45−2.38 (2H, m), 2.36−2.32 (1H, m), 2.26 (3H, s),
2.16 (3H, s), 2.10−1.98 (1H, m), 1.94−1.87 (1H, m), 1.76−1.71
(2H, m), 1.67−1.55 (2H, m), 1.39−1.32 (1H, m); 13C NMR
(DMSO-d6, 151 MHz) 173.7, 157.6, 156.3, 151.7, 147.6, 145.3, 140.7,
139.5, 136.5, 114.3, 113.2, 112.8, 110.3, 109.3, 107.2, 66.4, 62.1, 59.7,
53.7, 48.6, 41.3, 41.1, 40.8, 37.0, 36.3, 35.3, 30.5, 26.5, 21.4, 13.6,
12.5. HRMS (ESI) calcd for C33H45N6O3 573.3548 (M + H)+, found
573.3534.
́
(R)-3-(3-Morpholinophenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-
1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid
(30c). Similarly prepared to 28c from 26c. LCMS (system A) RT
Prepared from (R)-17. 28x Isomer 2: LCMS (system A) RT =
1
= 0.79 min, 100%, ES+ve m/z 479 (M + H)+; H NMR (CD3OD,
1
0.84 min, 100%, ES+ve m/z 464 (M + H)+; H NMR (DMSO-d6,
400 MHz) 7.23 (1H, t, J 7.5 Hz), 7.14 (1H, d, J 7.3 Hz), 6.90−6.84
(2H, m), 6.77 (1H, d, J 7.5 Hz), 6.39 (1H, d, J 7.3 Hz), 3.86−3.80
(4H, m), 3.61−3.49 (2H, m), 3.43−3.34 (4H, m), 3.30−3.20 (2H,
m), 3.19−3.12 (4H, m), 2.91−2.77 (2H, m), 2.70 (2H, t, J 6 Hz),
2.66−2.51 (3H, m), 2.42−2.30 (1H, m), 2.26−2.15 (1H, m), 1.92−
1.83 (2H, m), 1.82−1.66 (3H, m).
600 MHz) 7.24−7.19 (1H, m), 7.13 (1H, s), 7.10 (1H, d, J 7.5 Hz),
7.07 (1H, d, J 7.5 Hz), 7.02 (1H, d, J 7.0 Hz), 6.27−6.23 (2H, m),
4.01 (1H, t, J 8 Hz), 3.93 (1H, td, J 8, 4.5 Hz), 3.78 (1H, q, J 8 Hz),
3.52 (2H, t, J 8 Hz), 3.33 (1H, quin, J 8 Hz), 3.25−3.21 (2H, m),
3.20−3.14 (1H, m), 2.86 (1H, dd, J 12, 10 Hz), 2.81−2.74 (2H, m),
2.73−2.67 (1H, m), 2.60 (2H, t, J 6 Hz), 2.56 (1H, td, J 9, 5.5 Hz),
2.49−2.47 (1H, m), 2.43−2.35 (3H, m), 2.33 (1H, dd, J 9, 7 Hz),
2.28 (1H, dtd, J 12, 8, 4.5 Hz), 2.07−1.98 (1H, m), 1.94−1.86 (2H,
m), 1.74 (2H, quin, J 6 Hz), 1.67−1.54 (2H, m), 1.39−1.30 (1H, m);
13C NMR (DMSO-d6, 151 MHz) 173.6, 157.2, 155.7, 143.8, 142.5,
(S)-3-(3-Morpholinophenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-
1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid
(ent-30c). These are the data for the title compound prepared
according to a similar route to that shown in Scheme 1. LCMS
1
(system A) RT = 0.79 min, 100%, ES+ve m/z 479 (M + H)+; H
136.0, 128.4, 126.3, 125.1, 125.1, 112.3, 109.8, 73.8, 67.6, 61.9, 59.2,
53.1, 44.2, 40.9, 40.6, 40.2, 36.5, 35.7, 34.9, 33.9, 30.1, 25.9, 21.0.
(S)-4-((R)-3-(2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)-
ethyl)pyrrolidin-1-yl)-3-(3-(tetrahydro-2H-pyran-4-yl)phenyl)-
butanoic Acid (28y). Prepared from (R)-17: LCMS (system A) RT
NMR (CD3OD, 600 MHz) 7.21 (1H, t, J 7.8 Hz), 7.13 (1H, d, J 7.3
Hz), 6.87−6.82 (2H, m), 6.74 (1H, d, J 7.5 Hz), 6.37 (1H, d, J 7.3
Hz), 3.84−3.77 (4H, m), 3.54 (1H, dd, J 12.7, 9.4 Hz), 3.40−3.37
(1H, m), 3.37−3.34 (2H, m), 3.34−3.30 (1H, m), 3.32−3.27 (2H,
m), 3.20 (1H, dd, J = 12.7, 3.8 Hz), 3.15−3.10 (4H, m), 3.00 (1H, br
s), 2.80 (1H, dd, J 16.4, 10.5 Hz), 2.68 (2H, t, J 6.2 Hz), 2.59 (1H,
dd, J 16.3, 2.4 Hz), 2.54 (2H, t, J 7.3 Hz), 2.32 (1H, spt, J 7.9 Hz),
2.19 (1H, dq, J 13.1, 6.6 Hz), 1.89−1.83 (2H, m), 1.82−1.72 (2H,
m), 1.66 (1H, dq, J 13.0, 8.6 Hz); 13C NMR (CD3OD, 151 MHz)
180.3, 157.4, 157.3, 153.6, 144.8, 138.8, 131.0, 119.6, 116.0, 115.9,
115.8, 112.2, 68.1, 63.4, 59.9, 55.1, 50.7, 46.2, 42.5, 41.3, 38.2, 36.4,
34.7, 31.0, 27.5, 22.5.
(R)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-
(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-
yl)butanoic Acid (30h). Similarly prepared to 28h from 26h via the
following sequence. A solution of (R)-tert-butyl 4-((R)-3-(2-(1,8-
naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-3-(3-(3,5-dimethyl-1H-pyra-
zol-1-yl)phenyl)butanoate30 (60 mg, 0.111 mmol) in EtOH (5 mL)
was hydrogenated over 5% Pd/C (24 mg, 0.011 mmol) for 18 h. The
catalyst was removed by passing through a Celite cartridge (10 g) and
the filtrate was concentrated in vacuo to give (R)-tert-butyl 3-(3-(3,5-
dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-
1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoate (51 mg, 84%)
as a colorless gum: LCMS (system A) RT = 1.44 min, 81%, ES+ve m/
z 544 (M + H)+; 1H NMR (CDCl3, 400 MHz) 7.30−7.38 (m, 1H),
7.24−7.29 (m, 2H), 7.20 (d, J = 7.81 Hz, 1H), 7.04 (d, J = 7.30 Hz,
1H), 6.31 (d, J = 7.30 Hz, 1H), 5.97 (s, 1H), 3.35−3.41 (m, 2H),
3.26−3.33 (m, 1H), 2.79−2.88 (m, 2H), 2.56−2.71 (m, 5H), 2.38−
2.55 (m, 5H), 2.29 (s, 3H), 2.27 (s, 3H), 2.00−2.13 (m, 2H), 1.84−
1.98 (m, 3H), 1.64−1.72 (m, 2H), 1.30 (s, 9H).
1
= 0.90 min, 98%, ES+ve m/z 478 (M + H)+; H NMR (DMSO-d6,
600 MHz) 7.20 (1H, t, J 8 Hz), 7.11 (1H, s), 7.07 (1H, d, J 8 Hz),
7.06−7.03 (1H, m), 7.01 (1H, d, J 7.3 Hz), 6.26−6.23 (2H, m), 3.93
(2H, dt, J 11, 3 Hz), 3.44−3.38 (2H, m), 3.24−3.21 1H, (m, 1H),
3.21−3.14 (1H, m), 2.85 (1H, dd, J 12, 10 Hz), 2.78−2.67(4H, m),
2.63−2.51 (3H, m), 2.45−2.28 (4H, m), 2.06−1.97 (1H, m), 1.93−
1.84 (1H, m), 1.76−1.71 (2H, m), 1.68−1.55 (6H, m), 1.34 (1H, br
dd, J 12, 8 Hz); 13C NMR (DMSO-d6, 151 MHz) 173.7, 157.2, 155.7,
145.8, 143.8, 136.0, 128.2, 125.8, 124.9, 124.5, 112.2, 109.8, 67.3,
61.9, 59.3, 56.0, 53.2, 41.1, 40.6, 40.6, 40.0, 36.5, 35.7, 34.9, 33.5,
33.5, 30.1, 25.9, 21.0. HRMS (ESI) calcd for C29H40N3O3 478.3064
(M + H)+, found 478.3058. Anal. chiral HPLC RT = 7.5 min, 99.5%
on a Chiralpak AD-H column (250 mm × 4.6 mm) eluting 50%
EtOH (containing 0.2% isopropylamine)−heptane, flow rate = 1.0
mL/min, detecting at 215 nm.
(S)-3-(3-Cyclopropyl-5-morpholinophenyl)-4-((R)-3-(2-
(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-
yl)butanoic Acid (28bc). Prepared from (R)-17: LCMS (system A)
RT = 0.95 min, 94%, ES+ve m/z 519 (M + H)+; 1H NMR (DMSO-
d6, 600 MHz) 7.01 (1H, d, J 7.3 Hz), 6.56 (1H, s), 6.43 (1H, s), 6.40
(1H, s), 6.27−6.24 (2H, m), 3.74−3.69 (4H, m), 3.26−3.21 (m,
obscured by water), 3.09−3.04 (4H, m), 2.89 (1H, t, J 11 Hz), 2.81−
2.70 (3H, m), 2.63−2.56 (3H, m), 2.54−2.46 (m, obscured by
solvent), 2.41 (2H, t, J 8 Hz), 2.38−2.32 (2H, m), 2.07−2.00 (1H,
m), 1.95−1.88 (1H, m), 1.84−1.79 (1H, m), 1.78−1.73 (2H, m),
W
J. Med. Chem. XXXX, XXX, XXX−XXX