Isothiazoloquinolones as Antistaphylococcals
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2 205
99.4% purity (method 1); tR 10.67 min, 99.7% purity (method 2).
Anal. (C19H14FN3O2S‚HCl‚1.8H2O) C, H, N.
9-Cyclopropyl-6-fluoro-8-methoxy-7-pyridin-4-yl-9H-isothia-
zolo[5,4-b]quinoline-3,4-dione Hydrochloride (7f). Yield: 51%.
1H NMR (DMSO-d6): δ 1.11 (m, 2H), 1.19 (m, 2H), 3.44 (s, 3H),
3.83 (m, 1H), 7.86 (d, JH-F ) 9.5 Hz, 1H), 8.07 (d, JH-H ) 5.5
Hz, 1H), 9.00 (d, JH-H ) 5.5 Hz, 1H). 19F NMR (DMSO-d6): δ
-119.1 (s). HPLC: tR 7.34 min, 98.9% purity (method 1); tR 10.84
min, 99.9% purity (method 2). Anal. (C19H14FN3O3S‚HCl‚1.2H2O)
C, H, N.
9-Cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-
9H-isothiazolo[5,4-b]quinoline-3,4-dione Hydrochloride (7g).
Yield: 45%. 1H NMR (DMSO-d6): δ 1.01 (m, 2H), 1.10 (m, 2H),
2.50 (s, 3H), 3.37 (s, 3H), 3.76 (m, 1H), 7.28 (d, JH-H ) 5.0 Hz,
9-Cyclopropyl-7-(2,6-dimethylpyridin-4-yl)-6-fluoro-9H-isothi-
azolo[5,4-b]quinoline-3,4-dione Hydrochloride (5h). Yield: 42%.
1H NMR (DMSO-d6): δ 1.18 (m, 2H), 1.31 (m, 2H), 2.52 (s, 6H),
3.48 (m, 1H), 7.33 (s, 2H), 8.00 (d, JH-F ) 11.0 Hz, 1H), 8.07 (d,
JH-F ) 6.5 Hz, 1H). 19F NMR (DMSO-d6): δ -124.5 (s). HPLC:
tR 7.41 min, 96.5% purity (method 1); tR 10.77 min, 96.7% purity
(method 2).
9-Cyclopropyl-6-fluoro-7-pyridin-4-yl-9H-1-thia-2,8,9-triaza-
cyclopenta[b]naphthalene-3,4-dione Hydrochloride (6f). Yield:
1
60%. H NMR (DMSO-d6): δ 1.27 (m, 2H), 1.35 (m, 2H), 3.54
1H), 7.35 (s, 1H), 7.75 (d, JH-F ) 9.5 Hz, 1H), 8.55 (d, JH-H
)
(m, 1H), 8.26 (m, 2H), 8.52 (d, J ) 10.5 Hz, 1H), 8.93 (m, 2H).
19F NMR (DMSO-d6): δ -128.2 (s). HPLC: tR 7.07 min, 99.2%
purity (method 1); tR 10.88 min, 99.7% purity (method 2). Anal.
(C17H11FN4O2S‚HCl‚0.4H2O) C, H, N.
5.0 Hz, 1H). 19F NMR (DMSO-d6): δ -119.0 (s). HPLC: tR 7.58
min, 99.5% purity (method 1); tR 10.82 min, 99.8% purity (method
2). Anal. (C20H16FN3O3S‚HCl‚1.1H2O) C, H, N.
9-Cyclopropyl-7-(2,6-dimethylpyridin-4-yl)-6-fluoro-8-meth-
oxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione Hydrochloride (7h).
Yield: 45%. 1H NMR (DMSO-d6): δ 1.05 (m, 2H), 1.14 (m, 2H),
2.77 (s, 6H), 3.45 (s, 3H), 3.77 (m, 1H), 7.77 (d, JH-F ) 9.5 Hz,
1H), 7.88 (br s, 2H). 19F NMR (DMSO-d6): δ -118.9 (s). HPLC:
tR 7.82 min, 98.7% purity (method 1); tR 13.08 min, 98.7% purity
(method 2). Anal. (C21H18FN3O3S‚HCl‚1.8H2O) C, H, N.
9-Cyclopropyl-7-(2,3-dihydro-1H-isoindol-5-yl)-8-methoxy-
9H-isothiazolo[5,4-b]quinoline-3,4-dione Hydrochloride (8a).
9-Cyclopropyl-6-fluoro-7-(2-methylpyridin-4-yl)-9H-1-thia-
2,8,9-triazacyclopenta[b]naphthalene-3,4-dione Hydrochloride
(6g). Yield: 42%. 1H NMR (DMSO-d6): δ 1.21 (m, 2H), 1.30 (m,
2H), 2.75 (s, 3H), 3.48 (m, 1H), 8.25 (m, 1H), 8.29 (m, 1H), 8.51
(d, J ) 10.5 Hz, 1H), 8.85 (d, J ) 6.0 Hz, 1H). 19F NMR (DMSO-
d6): δ -127.4 (s). HPLC: tR 7.20 min, 95.9% purity (method 1);
tR 10.84 min, 98.2% purity (method 2). Anal. (C18H13FN4O2S‚HCl‚
1.3H2O) C, H, N.
9-Cyclopropyl-7-(2,6-dimethylpyridin-4-yl)-6-fluoro-9H-1-
thia-2,8,9-triazacyclopenta[b]naphthalene-3,4-dione Hydrochlo-
1
Yield: 5%. H NMR (DMSO-d6): δ 1.06 (m, 2H), 1.22 (m, 2H),
3.35 (s, 3H), 3.85 (m, 1H), 4.59 (m, 4H), 7.40 (d, J ) 8.5 Hz, 1H),
7.55 (m, 1H), 7.65 (m, 2H), 8.06 (d, J ) 8.5 Hz, 1H). HPLC: tR
8.42 min, 99.5% purity (method 1); tR 12.29 min, 96.0% purity
(method 2).
1
ride (6h). Yield: 41%. H NMR (DMSO-d6): δ 1.21 (m, 2H),
1.31 (m, 2H), 2.73 (s, 6H), 3.47 (m, 1H), 8.15 (m, 2H), 8.52 (d, J
) 10.5 Hz, 1H). 19F NMR (DMSO-d6): δ -127.1 (br). HPLC: tR
7.45 min, 96.1% purity (method 1); tR 11.41 min, 95.2% purity
(method 2).
9-Cyclopropyl-8-methoxy-7-((R)-1-methyl-2,3-dihydro-1H-
isoindol-5-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione Hydro-
chloride (8b). Yield: 12%. 1H NMR (DMSO-d6): δ 1.06 (m, 2H),
1.22 (m, 2H), 1.64 (d, J ) 6.5 Hz, 3H), 3.36 (s, 3H), 3.85 (m, 1H),
4.58 (m, 2H), 5.00 (m, 1H), 7.40 (d, J ) 8.0 Hz, 1H), 7.53 (d, J )
8.0 Hz, 1H), 7.66 (m, 2H), 8.07 (d, J ) 8.0 Hz, 1H). HPLC: tR
8.75 min, 97.9% purity (method 1); tR 12.88 min, 95.6% purity
(method 2).
9-Cyclopropyl-7-(2,3-dihydro-1H-isoindol-5-yl)-6-fluoro-8-
methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione Hydrochlo-
1
ride (7a). Yield: 25%. H NMR (DMSO-d6): δ 1.06 (m, 2H),
1.18 (m, 2H), 3.39 (s, 3H), 3.82 (m, 1H), 4.59 (m, 4H), 7.49-7.60
(m, 3H), 7.79 (d, J ) 9.5 Hz, 1H). 19F NMR (DMSO-d6): δ -118.7
(s). HPLC: tR 8.51 min, 99.7% purity (method 1); tR 12.25 min,
99.9% purity (method 2). Anal. (C22H18FN3O3S‚HCl‚2.0H2O) C,
H, N.
9-Cyclopropyl-8-methoxy-7-(1,2,3,4-tetrahydroisoquinolin-6-
yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione Hydrochloride (8c).
Yield: 10%. 1H NMR (DMSO-d6): δ 1.06 (m, 2H), 1.22 (m, 2H),
3.10 (m, 2H), 3.36 (s, 3H), 3.43 (m, 2H), 3.85 (m, 1H), 4.35 (m,
2H), 7.36 (d, J ) 8.0 Hz, 1H), 7.40 (d, J ) 8.5 Hz, 1H), 7.50 (m,
1H), 7.56 (m, 1H), 8.05 (d, J ) 8.5 Hz, 1H). HPLC: tR 8.63 min,
99.3% purity (method 1); tR 12.52 min, 98.0% purity (method 2).
9-Cyclopropyl-8-methoxy-7-(2-methyl-1,2,3,4-tetrahydroiso-
quinolin-6-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione Hydro-
9-Cyclopropyl-6-fluoro-8-methoxy-7-((R)-1-methyl-2,3-dihy-
dro-1H-isoindol-5-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione
1
Hydrochloride (7b). Yield: 58%. H NMR (DMSO-d6): δ 1.06
(m, 2H), 1.18 (m, 2H), 1.65 (d, J ) 7.0 Hz, 3H), 3.39 (s, 3H), 3.81
(m, 1H), 4.48-4.67 (m, 2H), 5.00 (m, 1H), 7.55 (m, 3H), 7.79 (d,
J ) 9.5 Hz, 1H). 19F NMR (DMSO-d6): δ -118.7 (s). HPLC: tR
8.84 min, 99.3% purity (method 1); tR 13.08 min, 98.7% purity
(method 2). Anal. (C23H20FN3O3S‚HCl‚2.0H2O) C, H, N.
1
chloride (8d). Yield: 38%. H NMR (DMSO-d6, 80 °C): δ 1.07
9-Cyclopropyl-6-fluoro-8-methoxy-7-(1,2,3,4-tetrahydroiso-
quinolin-6-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione Hydro-
chloride (7c). Yield: 44%. 1H NMR (DMSO-d6): δ 1.06 (m, 2H),
1.18 (m, 2H), 3.09 (m, 2H), 3.40 (s, 3H), 3.43 (m, 2H), 3.81 (m,
1H), 4.35 (m, 2H), 7.38 (m, 3H), 7.78 (d, J ) 9.5 Hz, 1H). 19F
NMR (DMSO-d6): δ -118.7 (s). HPLC: tR 8.71 min, 97.2% purity
(method 1); tR 12.83 min, 98.6% purity (method 2).
(m, 2H), 1.25 (m, 2H), 2.97 (s, 3H), 3.21 (m, 2H), 3.42 (s, 3H),
3.54 (m, 2H), 3.89 (m, 1H), 4.44 (m, 2H), 7.33 (m, 1H), 7.41 (m,
1H), 7.49-7.60 (m, 2H), 8.09 (m, 1H). HPLC: tR 9.25 min, 99.0%
purity (method 1); tR 12.20 min, 99.5% purity (method 2).
9-Cyclopropyl-7-isoquinolin-6-yl-8-methoxy-9H-isothiazolo-
1
[5,4-b]quinoline-3,4-dione Hydrochloride (8e). Yield: 22%. H
NMR (DMSO-d6): δ 1.13 (m, 2H), 1.26 (m, 2H), 3.37 (s, 3H),
3.88 (m, 1H), 7.60 (d, J ) 8.5 Hz, 1H), 8.15 (d, J ) 8.5 Hz, 1H),
8.24 (dd, J ) 8.5 Hz, 2.0 Hz, 1H), 8.46 (d, J ) 6.5 Hz, 1H), 8.52
(m, 1H), 8.58 (d, J ) 8.5 Hz, 1H), 8.71 (d, J ) 6.5 Hz, 1H), 9.86
(s, 1H). HPLC: tR 8.51 min, 95.7% purity (method 1); tR 12.20
min, 96.3% purity (method 2).
9-Cyclopropyl-8-methoxy-7-pyridin-4-yl-9H-isothiazolo[5,4-
b]quinoline-3,4-dione Hydrochloride (8f). Yield: 55%. 1H NMR
(DMSO-d6): δ 1.10 (m, 2H), 1.22 (m, 2H), 3.42 (s, 3H), 3.86 (m,
1H), 7.54 (d, J ) 8.5 Hz, 1H), 7.99 (d, J ) 6.0 Hz, 2H), 8.13 (d,
J ) 8.5 Hz, 1H), 8.88 (d, J ) 6.0 Hz, 2H). HPLC: tR 7.12 min,
99.4% purity (method 1); tR 10.08 min, 99.4% purity (method 2).
Anal. (C19H15N3O3S‚HCl‚1.5H2O) C, H, N.
9-Cyclopropyl-6-fluoro-8-methoxy-7-(2-methyl-1,2,3,4-tet-
rahydroisoquinolin-6-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-di-
1
one Hydrochloride (7d). Yield: 50%. H NMR (DMSO-d6, 80
°C): δ 1.08 (m, 2H), 1.22 (m, 2H), 2.98 (s, 3H), 3.20 (m, 2H),
3.45 (s, 3H), 3.55 (m, 2H), 3.85 (m, 1H), 4.46 (m, 2H), 7.34-7.45
(m, 3H), 7.81 (d, JH-F ) 9.5 Hz, 1H). 19F NMR (DMSO-d6, 80
°C): δ -117.8 (s). HPLC: tR 8.75 min, 99.2% purity (method 1);
tR 12.55 min, 98.7% purity (method 2).
9-Cyclopropyl-6-fluoro-7-isoquinolin-6-yl-8-methoxy-9H-isothi-
azolo[5,4-b]quinoline-3,4-dione Hydrochloride (7e). Yield: 21%.
1H NMR (DMSO-d6): δ 1.12 (m, 2H), 1.21 (m, 2H), 3.39 (s, 3H),
3.84 (m, 1H), 7.89 (d, J ) 9.5 Hz, 1H), 8.04 (d, J ) 8.5 Hz, 1H),
8.34 (d, J ) 6.5 Hz, 1H), 8.39 (s, 1H), 8.53 (d, J ) 8.5 Hz, 1H),
8.69 (d, J ) 6.5 Hz, 1H), 9.76 (s, 1H). 19F NMR (DMSO-d6): δ
-119.1 (s). HPLC: tR 8.90 min, 99.9% purity (method 1); tR 12.37
min, 92.3% purity (method 2).
9-Cyclopropyl-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothi-
azolo[5,4-b]quinoline-3,4-dione Hydrochloride (8g). Yield: 50%.
1H NMR (DMSO-d6): δ 1.09 (m, 2H), 1.22 (m, 2H), 2.74 (s, 3H),
3.44 (s, 3H), 3.86 (m, 1H), 7.54 (d, J ) 8.5 Hz, 1H), 7.96 (m, 1H),