Journal of Medicinal Chemistry
Article
1
4
8
H), 3.11−3.23 (m, 1 H), 3.85 (s, 2 H), 4.26−4.45 (m, 2 H), 4.69−
.81 (2m, 1 H), 6.89 (d, J = 9.54 Hz, 1 H), 8.00 (d, J = 10.04 Hz, 1 H),
.09 (dd, J = 11.04, 2.01 Hz, 1 H), 8.21 (d, J = 1.51 Hz, 1 H), 8.61 (d,
H), 2.19−2.42 (m, 1 H), 2.57 (t, J = 6.69 Hz, 3 H), 2.90 (d, J = 11.30
Hz, 1 H), 3.02−3.22 (m, 1 H), 3.71 (d, J = 3.39 Hz, 2 H), 4.30 (tq, J =
13.10, 6.77 Hz, 2 H), 4.60 (s, 1 H), 4.64−4.79 (d, J = 45 Hz 1 H), 6.83
(d, J = 9.61 Hz, 1 H), 7.02 (d, J = 8.10 Hz, 1 H), 7.30 (d, J = 8.10 Hz,
1 H), 7.95 (d, J = 9.80 Hz, 1 H), 7.99−8.11 (m, 1 H), 8.56 (d, J = 2.07
J = 2.51 Hz, 1 H), 8.73 (d, J = 2.01 Hz, 1 H); HRMS m/z (ES+)
+
4
39.206 23 (MH ) for C H F N O.
23 24 2 6
+
5
-(((3S,4R)-3-Fluoro-1-(2-(7-methoxy-2-oxo-1,5-naphthyri-
Hz, 1 H), 11.19 (s, 1 H); HRMS m/z (ES+) 471.196 93 (MH ) for
din-1(2H)-yl)ethyl)piperidin-4-ylamino)methyl)-2-methylnico-
tinonitrile (17). In a 500 mL round-bottomed flask, 16 (8.50 g, 19.39
mmol) and sodium methoxide (4.19 g, 77.54 mmol) were taken up in
MeOH (150 mL) to give a yellow solution. The resulting reaction
mixture was heated to reflux for 2 h. Solvent was evaporated from the
reaction mixture, and water was added to the residue. This was
extracted using 10% methanol in DCM (3 × 200 mL), and the
combined organic layers were concentrated and purified by silica gel
chromatography using 0−10% methanol in DCM to yield 17 (5.5 g)
as off white solid, which was low-melting and hygroscopic. Therefore,
the free base was dissolved in DCM (60 mL), and HCl in ether (85
mL) was added to it. The precipitated solid was stirred at rt for 2 h and
filtered. The filtered solid was further triturated with methanol/
C H F N O .
23
24
2
6
3
6
-(((3S,4R)-3-Fluoro-1-(2-(7-methoxy-2-oxo-1,5-naphthyri-
din-1(2H)-yl)ethyl)piperidin-4-ylamino)methyl)-2H-pyrido[3,2-
b][1,4]oxazin-3(4H)-one (21). In a 50 mL round-bottomed flask,
28c (350 mg, 1.17 mmol), 29b (803 mg, 1.29 mmol), DIPEA (0.615
mL, 3.52 mmol), and sodium carbonate (249 mg, 2.35 mmol) were
taken up in DMF (5 mL) to give a yellowish solution under nitrogen
atmosphere that was heated to 70 °C for 1 h. Solvent was evaporated
from the reaction mixture. Water was added to the residue and
extracted using 10% methanol in DCM (3 × 25 mL). The combined
organic layers were concentrated to dryness and purified by
1
preparative HPLC to yield 21 (120 mg, 21.20%) as white solid: H
NMR (300 MHz, DMSO-d ) δ 1.46−1.74 (m, 2 H), 2.16 (t, J = 10.27
Hz, 1 H), 2.24−2.45 (m, 2 H), 2.59 (t, J = 6.88 Hz, 3 H), 2.86−2.98
(m, 1 H), 3.08−3.17 (m, 1 H), 3.73 (s, 2 H), 3.99 (s, 3 H), 4.27−4.44
(m, 2 H), 4.61 (s, 2 H), 4.65−4.82 (2m, 1 H), 6.66 (d, J = 9.61 Hz, 1
H), 7.02 (d, J = 8.10 Hz, 1 H), 7.30 (d, J = 7.91 Hz, 1 H), 7.42 (d, J =
2.26 Hz, 1 H), 7.87 (d, J = 9.61 Hz, 1 H), 8.28 (d, J = 2.26 Hz, 1 H),
6
acetonitrile, filtered, and dried to give the HCl salt of 17 (6.50 g,
1
6
2
4
4.1%) as pale yellow solid: H NMR (300 MHz, DMSO-d ) δ 2.18−
6
.47 (m, 2 H), 2.72 (s, 3 H), 3.23−3.75 (m, 7 H), 4.07 (s, 3 H), 4.26−
.46 (m, 2 H), 4.63−4.86 (m, 2 H), 5.50−5.66 (d, J = 45 Hz 1H), 6.73
d, J = 9.80 Hz, 1 H), 7.75 (s, 1 H), 7.95 (d, J = 9.80 Hz, 1 H), 8.34 (d,
(
+
J = 2.07 Hz, 1 H), 8.57 (d, J = 2.07 Hz, 1 H), 8.95 (d, J = 2.07 Hz, 1
11.15 (br s, 1 H); HRMS m/z (ES+) 483.215 93 (MH ) for
H), 10.22−10.33 (2 br s, 2 H), 11.25 (br s, 1 H); HRMS m/z (ES+)
C H FN O .
24
27
6
4
+
4
51.225 43 (MH ) for C H FN O ·2HCl.
6-(((3R,4S)-3-Fluoro-1-(2-(7-methoxy-2-oxo-1,5-naphthyri-
24
27
6
2
5-(((3S,4R)-3-Methoxy-1-(2-(7-methoxy-2-oxo-1,5-naphthyr-
din-1(2H)-yl)ethyl)piperidin-4-ylamino)methyl)-2H-pyrido[3,2-
b][1,4]oxazin-3(4H)-one (22). In a 100 mL round-bottomed flask,
22a (1.5 g, 3.19 mmol) was dissolved in MeOH (30 mL), and sodium
methoxide (0.689 g, 12.75 mmol) was added. The mixture was heated
to 80 °C overnight. The solvent was evaporated under vacuum, the
idin-1(2H)-yl)ethyl)piperidin-4-ylamino)methyl)-2-methylnico-
tinonitrile (18). In a 50 mL round-bottomed flask, 18b (150 mg, 0.45
mmol) was dissolved in DMF (5 mL), sodium carbonate (143 mg,
1
.35 mmol) was added, and the mixture was stirred for 2 min. Then 32
(
102 mg, 0.45 mmol) was added to the reaction and heated to 70 °C
residue was basified with saturated NaHCO solution and extracted
with 10% MEOH/DCM, and the solvent was evaporated to get the
3
for 2 h. The reaction mixture was concentrated under vacuum, and the
residue was basified with saturated NaHCO solution, concentrated
under vacuum, and purified by preparative HPLC to give 18 (30.0 mg,
crude compound, which was purified by preparative HPLC to give 22
3
1
(1.2 g, 78%): H NMR (300 MHz, DMSO-d ) δ 1.46−1.76 (m, 2 H),
6
1
1
2.42%) as a gum: H NMR (300 MHz, DMSO-d ) δ 1.35−1.52 (m, 1
1.96−2.22 (m, 2 H), 2.22−2.45 (m, 1 H), 2.57 (t, J = 6.78 Hz, 3 H),
2.93 (d, J = 11.30 Hz, 1 H), 3.15 (br s, 1 H), 3.72 (s, 2 H), 3.92−4.09
(m, 3 H), 4.35 (t, J = 6.22 Hz, 2 H), 4.60 (s, 2 H), 4.63−4.88 (d, J =
51 Hz, 1 H), 6.66 (d, J = 9.61 Hz, 1 H), 7.02 (d, J = 8.10 Hz, 1 H),
7.30 (d, J = 8.10 Hz, 1 H), 7.42 (s, 1 H), 7.87 (d, J = 9.61 Hz, 1 H),
6
H), 1.58−1.74 (m, 1 H), 1.97−2.11 (m, 1 H), 2.20−2.44 (m, 2 H),
2
(
.54−2.61 (m, 2 H), 2.61−2.85 (m, 6 H), 3.17 (s, 3 H), 3.25−3.32
m, 1 H), 3.74 (d, J = 4.33 Hz, 2 H), 3.98 (s, 3 H), 4.27−4.44 (m, 2
H), 6.66 (d, J = 9.61 Hz, 1 H), 7.43 (s, 1 H), 7.86 (d, J = 9.80 Hz, 1
H), 8.17 (s, 1 H), 8.27 (d, J = 2.07 Hz, 1 H), 8.67 (s, 1 H); HRMS m/
+
8.28 (s, 1 H), 11.19 (s, 1 H); HRMS m/z (ES+) 483.216 40 (MH )
+
z (ES+) 463.245 32 (MH ) for C H N O .
for C24H27FN O .
6 4
25
30
6
3
6
-(((3S,4R)-3-Fluoro-1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-
(2H)-yl)ethyl)piperidin-4-ylamino)methyl)-2H-pyrido[3,2-b]-
1,4]oxazin-3(4H)-one (19). In a 250 mL round-bottomed flask, 28b
7.86 g, 27.47 mmol), 29b (7.00 g, 24.97 mmol), and sodium
6-(((3S,4R)-3-Methoxy-1-(2-(7-methoxy-2-oxo-1,5-naphthyr-
idin-1(2H)-yl)ethyl)piperidin-4-ylamino)methyl)-2H-pyrido-
[3,2-b][1,4]oxazin-3(4H)-one (23). In a 250 mL round-bottomed
flask, 23c (2.300 g, 4.77 mmol) and sodium methoxide (1.288 g, 23.83
mmol) were taken up in MeOH (50 mL) to give a white solution
under nitrogen atmosphere and heated to 70 °C for 2 h. The solvent
was evaporated from the reaction mixture. Water was added to the
residue and extracted using 10% methanol in DCM (3 × 100 mL).
The combined organic layers were concentrated to dryness and
purified by silica gel chromatography using 0−10% methanol in DCM
1
[
(
carbonate (5.29 g, 49.95 mmol) were taken up in DMF (50 mL) to
give a yellowish solution under nitrogen atmosphere that was heated
to 70 °C for 1 h. Solvent was evaporated from the reaction mixture.
Water was added to the residue and it was extracted using 10%
methanol in DCM (5 × 75 mL). The combined organic layers were
concentrated to dryness and purified by silica gel column using 0−12%
1
1
methanol in DCM to yield 19 (5.40 g, 46.0%) as a white solid: H
and 0.1% ammonia to yield 23 (0.350 g, 14.85%) as off white solid: H
NMR (300 MHz, DMSO-d ) δ 1.44−1.68 (m, 2 H), 2.2−2.39 (m, 3
NMR (300 MHz, DMSO) δ 1.73 (br s, 2 H), 1.99−2.20 (m, 2 H),
2.51−2.71 (m, 2 H), 2.99 (br s, 1 H), 3.09−3.23 (m, 4 H), 3.62 (br s,
1H), 3.94 (s, 3 H), 3.95−4.10 (m, 3 H), 4.21−4.47 (m, 2 H), 4.63 (s,
2 H), 6.61 (d, J = 9.61 Hz, 1 H), 7.06 (d, J = 7.91 Hz, 1 H), 7.30−7.47
(m, 2 H), 7.83 (d, J = 9.61 Hz, 1 H), 8.24 (d, J = 2.07 Hz, 1H), 8.75
(br s, 1H), 11.30 (s, 1H); HRMS m/z (ES+) 495.230 61 (MH ) for
C H N O .
25 30 6 5
6
H), 2.57 (t, J = 6.59 Hz, 2 H), 2.84−2.97 (m, 1 H), 3.06−3.20 (m, 1
H), 3.60−3.82 (m, 2 H), 4.14−4.43 (m, 2 H), 4.61 (s, 3 H), 4.63−4.79
(
d, J = 45 Hz, 1 H), 6.83 (d, J = 9.80 Hz, 1 H), 7.02 (d, J = 8.10 Hz, 1
H), 7.30 (d, J = 7.91 Hz, 1 H), 7.95 (d, J = 9.80 Hz, 1 H), 8.04 (dd, J =
1.21, 2.17 Hz, 1 H), 8.56 (d, J = 2.26 Hz, 1 H), 11.20 (s, 1 H);
+
1
+
HRMS m/z (ES+) 471.196 74 (MH ) for C H F N O .
23
24
2
6
3
6
-(((3R,4S)-3-Fluoro-1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-
(2H)-yl)ethyl)piperidin-4-ylamino)methyl)-2H-pyrido[3,2-b]-
1,4]oxazin-3(4H)-one (20). In a 250 mL round-bottomed flask, 29c
1
[
ASSOCIATED CONTENT
■
* Supporting Information
Sythetic schemes and procedures for intermediates; primary
sequence alignment of Mtb GyrA and Sau GyrA; Overlay of
secondary structures of Mtb GyrA model and Sau GyrA;
comparison of active site residues of Mtb GyrA model and Sau
GyrA crystal structure; docked poses of compounds 1a, 2a, and
(
(
(
3.50 g, 12.49 mmol) was dissolved in DMF (50 mL) and Na CO
3.97 g, 37.46 mmol) was added. The mixture stirred for 2 min, 28b
4.29 g, 14.98 mmol) was added, and the reaction was heated to 70 °C
2 3
S
for 2 h. The reaction mixture was concentrated under vacuum, and the
residue was basified with sat. NaHCO solution, concentrated under
3
vacuum, and purified by preparative HPLC to give 20 (2.90 g, 49.4%):
1
H NMR (300 MHz, DMSO) δ 1.41−1.70 (m, 2 H), 1.93−2.19 (m, 3
O
dx.doi.org/10.1021/jm500432n | J. Med. Chem. XXXX, XXX, XXX−XXX