H. Liu et al. / European Journal of Medicinal Chemistry 86 (2014) 628e638
635
with dichloromethane and methanol (35:1, v/v) to get the title
compounds 9b1e10 (33.5e46.8%) as off-white and yellow solids.
3.83 (3H, s, OeCH3) 3.75 (1H, m), 3.08 (2H, m), 1.96e1.78 (2H, m,
fluorocyclopropyl CH). MS-ESI (m/z): 393.69 (MþH)þ. HRMS-ESI
(m/z): Calcd. for
C
18H19O4N4F2 (MþH)þ: 393.13689; Found:
4.2.5.1. 7-[3-Amino-4-(methoxyimino)piperidin-1-yl]-6-fluoro-1-
[(1R, 2S)-2- fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid 9b1. The title compound 9b1 was obtained from
8b and 3-aminopiperidin-4-one O-methyl oxime dihydrochloride
as a yellow solid (42.7%). ½aꢄ2D0 ¼ þ14.63 (c 0.082, CH3OH), 1H NMR
393.13584.
4.2.5.6. 7-[(S)-2-(aminomethyl)-3-(ethoxyimino)azetidin-1-yl]-6-
fluoro-1-[(1R, 2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-
3-carboxylic acid 9b6. The title compound 9b6 was obtained from
8b and (S)-2-(aminomethyl)azetidin-3-one O-ethyl oxime dihy-
drochloride [23] as an off-white solid (37.9%). ½aꢄ2D0 ¼ þ52.78 (c
(400 MHz, CDCl3)
d
8.76 (1H, s, C2eH), 8.04 (1H, d, J ¼ 13.2 Hz,
C5eH), 7.21 (1H, s, C8eH), 5.12 (1H, d, J ¼ 65.8 Hz, fluorocyclopropyl
CH), 3.91 (3H, s, OeCH3), 3.82 (1H, s), 3.73 (1H, m), 3.57e3.49 (2H,
m), 3.47e3.26 (2H, m), 3.25e3.07 (1H, m), 2.66e2.58 (1H, m),
1.81e1.74 (2H, m, fluorocyclopropyl CH). MS-ESI (m/z): 407.31
(MþH)þ. HRMS-ESI (m/z): Calcd. for C19H21O4N4F2 (MþH)þ:
407.15254; Found 407.15103.
0.036, CH3OH), 1H NMR (400 MHz, DMSO-d6)
d 8.74 (1H, s, C2eH),
7.94 (1H, d, J ¼ 12.0 Hz, C5eH), 7.24 (1H, m, C8eH), 5.51e5.40 (2H,
m), 4.94 (2H, m), 4.13 (2H, q, J ¼ 8.0 Hz, OeCH2CH3), 3.37 (1H, s),
3.33e3.24 (2H, m), 1.94e1.80 (2H, m, fluorocyclopropyl CH), 1.23
(3H, t, J ¼ 8.0 Hz, OCH2eCH3). MS-ESI (m/z): 407.82 (MþH)þ. HRMS-
ESI (m/z): Calcd. for C19H21O4N4F2 (MþH)þ: 407.15254; Found:
407.15128.
4.2.5.2. 7-[3-(Aminomethyl)-4-(methoxyimino)pyrrolidin-1-yl)-6-
fluoro-1-[(1R, 2S)-2- fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-
3-carboxylic acid 9b2. The title compound 9b2 was obtained from
8b and 4-aminopyrrolidin-3-one O-methyl oxime dimesylate [34]
as an off-white solid (39.6%). ½aꢄ2D0 ¼ þ4.76 (c 0.042, CH3OH), 1H
4.2.5.7. 7-[(S)-2-(aminomethyl)-3-(benzyloxyimino)azetidin-1-yl]-
6-fl uo ro- 1- [ ( 1 R , 2 S) - 2 -fluoro cyclopropyl]-4-ox o-1, 4-
dihydroquinoline-3-carboxylic acid 9b7. The title compound 9b7
was obtained from 8b and (S)-2-(aminomethyl)azetidin-3-one O-
benzyl oxime dihydrochloride [23] as an off-white solid (43.5%).
½aꢄ2D0 ¼ þ46.55 (c 0.058, CH3OH), 1H NMR (400 MHz, DMSO-d6)
NMR (400 MHz, DMSO-d6)
d 8.71 (1H, s, C2eH), 7.89 (1H, d,
J ¼ 14.2 Hz, C5eH), 7.15 (1H, d, J ¼ 7.3 Hz, C8eH), 5.37 (1H, d,
J ¼ 64.8 Hz, fluorocyclopropyl CH), 4.40 (2H, s), 4.03e3.91 (1H, m),
3.86 (4H, m), 3.76e3.60 (1H, m), 3.15 (1H, s), 2.94e2.76 (2H, m),
1.96e1.83 (1H, m, fluorocyclopropyl CH), 1.85e1.70 (1H, m, fluo-
rocyclopropyl CH). MS-ESI (m/z): 407.50 (MþH)þ. HRMS-ESI (m/z):
Calcd. for C19H21O4N4F2 (MþH)þ: 407.15254; Found 407.15106.
d
8.69 (1H, s, C2eH), 7.89 (1H, d, J ¼ 12.0 Hz, C5eH), 7.40e7.27 (6H,
m, C8eH, AreH), 5.48e5.25 (2H, m), 5.10 (2H, s, OeCH2Ar),
4.97e4.89 (2H, m), 3.78 (1H, m), 3.31e3.10 (2H, m), 1.90e1.74 (2H,
m, fluorocyclopropyl CH). MS-ESI (m/z): 469.35 (MþH)þ. HRMS-ESI
(m/z): Calcd. for
419.16635.
C
24H23O4N4F2 (MþH)þ: 469.16819; Found:
4.2.5.3. 7-[3-(Aminomethyl)-4-(ethoxyimino)pyrrolidin-1-yl]-6-
fluoro-1-[(1R, 2S)-2- fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-
3-carboxylic acid 9b3. The title compound 9b3 was obtained from
8b and 4-aminopyrrolidin-3-one O-ethyl oxime dimesylate as an
off-white solid (34.6%). ½aꢄ2D0 ¼ þ11.11 (c 0.056, CH3OH), 1H NMR
4.2.5.8. 7-[(R)-2-(aminomethyl)-3-(methoxyimino)azetidin-1-yl]-6-
fluoro-1-[(1R, 2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-
3-carboxylic acid 9b8. The title compound 9b8 was obtained from
8b and (R)-2-(aminomethyl)azetidin-3-one O-methyl oxime dihy-
drochloride [23] as an off-white solid (46.2%). ½aꢄ2D0 ¼ þ8.82 (c
(400 MHz, DMSO-d6)
d
8.70 (1H, s, C2eH), 7.88 (1H, d, J ¼ 14.2 Hz,
C5eH), 7.15 (1H, d, J ¼ 7.3 Hz, C8eH), 5.36 (1H, d, J ¼ 64.2 Hz, flu-
orocyclopropyl CH), 4.41 (2H, s), 4.11 (2H, q, J ¼ 8.0 Hz, OeCH2CH3),
3.91 (1H, m), 3.78 (1H, m), 3.66 (1H, m), 3.11 (1H, s), 2.89e2.78 (2H,
m), 1.95e1.81 (1H, m, fluorocyclopropyl CH), 1.78e1.70 (1H, m,
fluorocyclopropyl CH), 1.23 (3H, t, J ¼ 8.0 Hz, OCH2eCH3). MS-ESI
(m/z): 421.15 (MþH)þ. HRMS-ESI (m/z): Calcd. for C20H23O4N4F2
(MþH)þ: 421.16853; Found 421.16819.
0.068, CH3OH), 1H NMR (400 MHz, DMSO-d6)
d 8.70 (1H, s, C2eH),
7.89 (1H, d, J ¼ 12.0 Hz, C5eH), 7.38 (1H, m, C8eH), 5.48e5.24 (2H,
m), 5.22e5.15 (1H, m), 4.95e4.84 (2H, m), 3.83 (3H, s, OeCH3) 3.78
(1H, m), 3.13 (2H, m), 1.91e1.76 (2H, m). MS-ESI (m/z): 393.33
(MþH)þ. HRMS-ESI (m/z): Calcd. for C18H19O4N4F2 (MþH)þ:
393.13689; Found: 393.13592.
4.2.5.4. 7-[3-(Aminomethyl)-4-(benzyloxyimino)pyrrolidin-1-yl]-6-
fluoro-1-[(1R, 2S)- 2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-
3-carboxylic acid 9b4. The title compound 9b4 was obtained from
8b and 4-aminopyrrolidin-3-one O-benzyl oxime dimesylate [34]
as an off-white solid (46.7%). ½aꢄ2D0 ¼ þ6.25 (c 0.048, CH3OH), 1H
4.2.5.9. 7-[(R)-2-(aminomethyl)-3-(ethoxyimino)azetidin-1-yl]-6-
fluoro-1-[(1R, 2S)-2- fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-
3-carboxylic acid 9b9. The title compound 9b9 was obtained from
8b and (R)-2-(aminomethyl)azetidin-3-one O-ethyl oxime dihy-
drochloride [23] as an off-white solid (35.2%). ½aꢄ2D0 ¼ þ7.84 (c 0.102,
NMR (400 MHz, DMSO-d6)
d
8.70 (1H, s, C2eH), 7.89 (1H, d,
CH3OH), 1H NMR (400 MHz, DMSO-d6)
d 8.69 (1H, s, C2eH), 7.88
J ¼ 14.2 Hz, C5eH), 7.38e7.31 (5H, m, AreH), 7.15 (1H, d, J ¼ 7.8 Hz,
C8eH), 5.36 (1H, d, J ¼ 64.2 Hz, fluorocyclopropyl CH), 5.13 (2H, s,
OeCH2Ar), 3.87 (2H, m), 3.87 (2H, m), 3.69 (1H, m), 3.07 (1H, s),
2.85e2.72 (2H, m), 1.97e1.70 (2H, m, fluorocyclopropyl CH),
1.78e1.70 (1H, m, fluorocyclopropyl CH). MS-ESI (m/z): 483.32
(MþH)þ. HRMS-ESI (m/z): Calcd. for C25H25O4N4F2 (MþH)þ:
483.18384; Found: 483.18179.
(1H, d, J ¼ 12.0 Hz, C5eH), 7.25 (1H, m, C8eH), 5.48e5.25 (2H, m),
4.95e4.75 (2H, m), 4.08 (2H, q, J ¼ 8.0 Hz, OeCH2CH3), 3.78 (1H, s),
3.30e3.12 (2H, m), 1.94e1.78 (2H, m, fluorocyclopropyl CH), 1.23
(3H, t, J ¼ 8.0 Hz, OCH2eCH3). MS-ESI (m/z): 407.15 (MþH)þ. HRMS-
ESI (m/z): Calcd. for C19H21O4N4F2 (MþH)þ: 407.15254; Found:
407.15247.
4.2.5.10. 7-[(R)-2-(aminomethyl)-3-(benzyloxyimino)azetidin-1-yl]-
6-fl uo ro- 1- [ ( 1 R , 2 S) - 2 -fluoro cyclopropyl]-4-ox o-1, 4-
dihydroquinoline-3-carboxylic acid 9b10. The title compound 9b10
was obtained from 8b and (R)-2-(aminomethyl)azetidin-3-one O-
benzyl oxime dihydrochloride [23] as an off-white solid (46.8%).
4.2.5.5. 7-[(S)-2-(aminomethyl)-3-(methoxyimino)azetidin-1-yl]-6-
fluoro-1-[(1R, 2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-
3-carboxylic acid 9b5. The title compound 9b5 was obtained from
8b and (S)-2-(aminomethyl)azetidin-3-one O-methyl oxime dihy-
drochloride as an off-white solid (33.5%). ½aꢄ2D0 ¼ þ27.94 (c 0.068,
½aꢄ2D0 ¼ þ6.12 (c 0.050, CH3OH), 1H NMR (400 MHz, DMSO-d6)
d 8.71
CH3OH), 1H NMR (400 MHz, DMSO-d6)
d
8.67 (1H, s, C2eH), 7.87
(1H, s, C2eH), 7.90 (1H, d, J ¼ 12.0 Hz, C5eH), 7.39e7.31 (6H, m,
C8eH, AreH), 5.42e5.24 (2H, m), 5.11 (2H, s, OeCH2Ar), 4.95e4.85
(2H, m), 3.79 (1H, m), 3.28e3.12 (2H, m), 1.91e1.76 (2H, m,
(1H, d, J ¼ 12.0 Hz, C5eH), 7.34 (1H, d, J ¼ 7.8 Hz, C8eH), 5.38 (1H, d,
J ¼ 64.2 Hz, fluorocyclopropyl CH), 5.22e5.15 (1H, m), 4.90 (2H, m),