Journal of Medicinal Chemistry
Article
N-(5-(3,4-Dimethoxyphenyl)isothiazolo[5,4-b]pyridin-3-yl)-
cyclobutanecarboxamide (10q). This compound was prepared
according to the general procedure D from 3-amino-5-(3,4-
dimethoxyphenyl)-isothiazolo[5,4-b]pyridine (8b, 0.20 mmol, 57
mg) and cyclobutanecarbonyl chloride (0.2 mmol). The crude residue
was purified by flash chromatography on silicagel using a mixture of
cyclohexane and ethyl acetate (in a ratio of 5:1) as mobile phase,
affording the pure title compound as a yellowish solid (60 mg, 81%).
1H NMR (300 MHz, DMSO-d6): δ = 1.96 (m, 2H, CH2), 2.7 (m, 4H,
CH2), 3.50 (m, 1H, CH), 3.83 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),
7.14 (d, J = 8.3 Hz, 1H, arom H), 7.32 (d, J = 8.3 Hz, 1H, arom H),
7.39 (s, 1H, arom H), 8.72 (d, J = 1.9 Hz, 1H, arom H), 9.16 (d, J =
1.9 Hz, 1H, arom H), 10.85 (s, 1H, NH) ppm. 13C NMR (150 MHz,
DMSO-d6): δ = 173.75, 169.14, 152.37, 150.22, 149.41, 149.36,
132.27, 130.72, 129.13, 122.01, 119.83, 112.55, 111.08, 55.85, 55.72,
38.94, 24.67, 17.79 ppm. HRMS: calcd for C19H19N3O3S1 370.1220,
found 370.1219.
mg) and 2-cyclohexylacetyl chloride (0.2 mmol). The crude residue
was purified by flash chromatography on silica gel using a mixture of
dichloromethane and ethyl acetate (in a ratio of 8:1) as mobile phase,
affording the pure title compound as a yellowish solid (60 mg, 73%).
1H NMR (300 MHz, DMSO-d6): δ = 1.20 (m, 5H, CH2) 1.7 (m, 6H,
CH2), 2.42 (d, J = 6.5 Hz, 2H, CH2), 3.83 (s, 3H, OCH3), 3.88 (s, 3H,
OCH3), 7.14 (d, J = 8.3 Hz, 1H, arom H), 7.32 (d, J = 8.3 Hz, 1H,
arom H), 7.36 (s, 1H, arom H), 10.96 (s, 1H, NH), 8.67 (d, J = 1.9
Hz, 1H, arom H), 9.16 (d, J = 1.9 Hz, 1H, arom H) ppm. 13C NMR
(150 MHz, DMSO-d6): δ = 171.27, 169.17, 152.46, 150.19, 149.43,
149.37, 132.21, 130.73, 129.08, 122.12, 119.75, 112.54, 110.96, 55.78,
55.73, 43.29, 34.66, 32.61, 25.90, 25.70 ppm. HRMS: calcd for
C22H25N3O3S1 412.1689, found 412.1681.
N-(5-(3,4-Dimethoxyphenyl)isothiazolo[5,4-b]pyridin-3-yl)-
3-noradamantanecarboxamide (10v). This compound was
prepared according to the general procedure D from 3-amino-5-
(3,4-dimethoxyphenyl)-isothiazolo[5,4-b]pyridine (8b, 0.20 mmol, 57
mg) and 3-noradamantanecarbonyl chloride (0.2 mmol). The crude
residue was purified by flash chromatography on silica gel using a
mixture of dichloromethane and ethyl acetate (in a ratio of 6:1) as
mobile phase, affording the pure title compound as a white solid (70
N-(5-(3,4-Dimethoxyphenyl)isothiazolo[5,4-b]pyridin-3-yl)-
cyclopentanecarboxamide (10r). This compound was prepared
according to the general procedure D from 3-amino-5-(3,4-
dimethoxyphenyl)-isothiazolo[5,4-b]pyridine (8b, 0.30 mmol, 86
mg) and cyclopentanecarbonyl chloride (0.30 mmol). The crude
residue was purified by flash chromatography on silica gel using a
mixture of cyclohexane and ethyl acetate (in a ratio of 10:1) as mobile
phase, affording the pure title compound as a white solid (90 mg,
1
mg, 80%). H NMR (300 MHz, DMSO-d6): δ = 1.60−2.30 (m, 13H,
CH and CH2), 3.83 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 7.14 (d, J =
8.3 Hz, 1H, arom H), 7.32 (d, J = 8.3 Hz, 1H, arom H), 7.37 (s, 1H,
arom H), 8.38 (d, J = 1.9 Hz, 1H, arom H), 9.16 (d, J = 1.9 Hz, 1H,
arom H), 10.41 (s, 1H, NH) ppm. 13C NMR (150 MHz, DMSO-d6):
δ = 176.20, 169.22, 153.32, 150.32, 149.40, 149.35, 132.36, 131.01,
129.14, 122.95, 119.87, 112.60, 111.14, 55.78, 55.72, 46.65, 43.25,
42.53, 37.15, 34.29 ppm. HRMS: calcd for C24H25N3O3S1 436.1689,
found 436.1686.
1
84%). H NMR (300 MHz, CDCl3): δ = 1.69−2.10 (m, 8H, CH2),
2.99 (m, 1H, CH), 3.97 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 7.02 (d, J
= 8.3 Hz), 7.15 (d, J = 2.1 Hz, 1H, arom H), 7.23 (dd, J = 8.3 Hz and J
= 2.1 Hz, 1H, arom H), 8.64 (br s, 1H, NH), 8.71 (d, J = 2.3 Hz, 1H,
arom H), 8.97 (d, J = 2.3 Hz, 1H, arom H) ppm. 13C NMR (150
MHz, DMSO-d6): δ = 175.14, 169.16, 152.50, 150.20, 149.41, 149.35,
132.24, 130.74, 129.13, 122.11, 119.79, 112.56, 111.05, 55.82, 55.72,
44.43, 30.12, 25.79 ppm. HRMS: calcd for C20H21N3O2S1 384.1376,
found 384.1374.
N-(5-(3,4-Dimethoxyphenyl)isothiazolo[5,4-b]pyridin-3-yl)-
1-adamantanecarboxamide (10w). This compound was prepared
according to the general procedure D from 3-amino-5-(3,4-
dimethoxyphenyl)-isothiazolo[5,4-b]pyridine (8b, 0.20 mmol, 57
mg) and adamantanecarbonyl chloride (0.2 mmol). The crude residue
was purified by flash chromatography on silica gel using a mixture of
dichloromethane and ethyl acetate (in a ratio of 6:1) as mobile phase,
N-(5-(3,4-Dimethoxyphenyl)isothiazolo[5,4-b]pyridin-3-yl)-
cycloheptanecarboxamide (10s). This compound was prepared
according to the general procedure F from 3-amino-5-(3,4-
dimethoxyphenyl)-isothiazolo[5,4-b]pyridine (8b, 0.20 mmol, 57
mg) and cycloheptanecarbonic acid (0.30 mmol). The crude residue
was purified by flash chromatography on silica gel using a mixture of
cyclohexane and ethyl acetate (in a ratio of 10:1) as mobile phase,
1
affording the pure title compound as a white solid (70 mg, 78%). H
NMR (300 MHz, DMSO-d6): δ = 2.02−1.73 (m, 15H, CH and CH2),
3.83 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 7.14 (d, J = 8.3 Hz, 1H,
arom H), 7.29 (d, J = 8.3 Hz, 1H, arom H), 7.36 (s, 1H, arom H), 8.32
(d, J = 2.0 Hz, 1H, arom H), 9.16 (d, J = 2.0 Hz, 1H, arom H), 10.42
(s, 1H, NH) ppm. 13C NMR (150 MHz, DMSO-d6): δ = 177.13,
169.20, 153.40, 150.32, 149.40, 149.35, 132.37, 130.87, 129.14, 122.91,
119.88, 112.63, 111.16, 55.80, 55.73, 40.97, 38.23, 36.03, 27.69 ppm.
HRMS: calcd for C25H27N3O3S1 450.1846, found 450.1841.
1
affording the pure title compound as a white solid (70 mg, 85%). H
NMR (300 MHz, DMSO-d6): δ = 1.40−2 (m, 12H, CH and CH2),
2.79 (m, 1H, CH), 10.88 (s, 1H, NH), 3.83 (s, 3H, OCH3), 3.88 (s,
3H, OCH3), 7.14 (d, J = 8.3 Hz, 1H, arom H), 7.29 (d, J = 8.3 Hz, 1H,
arom H), 7.38 (s, 1H, arom H), 8.63 (d, J = 2.0 Hz, 1H, arom H), 9.16
(d, J = 2.0 Hz, 1H, arom H) ppm. HRMS: calcd for C22H25N3O3S1
412.1689, found 412.1683.
trans-N-(5-(3,4-Dimethoxyphenyl)isothiazolo[5,4-b]pyridin-
3-yl)-4-methylcyclohexanecarboxamide (10x). This compound
was prepared according to the general procedure F from 3-amino-5-
(3,4-dimethoxyphenyl)-isothiazolo[5,4-b]pyridine (8b, 0.20 mmol, 57
mg) and trans-4-methylcyclohexanecarboxylic acid (0.3 mmol). The
crude residue was purified by flash chromatography on silica gel using
a mixture of dichloromethane and ethyl acetate (in a ratio of 7:1) as
mobile phase, affording the pure title compound as a white solid (70
N-(5-(3,4-Dimethoxyphenyl)isothiazolo[5,4-b]pyridin-3-yl)-
cyclohex-3-enecarboxamide (10t). This compound was prepared
according to the general procedure D from 3-amino-5-(3,4-
dimethoxyphenyl)-isothiazolo[5,4-b]pyridine (8b, 0.20 mmol, 57
mg) and cyclohex-3-enecarbonyl chloride (0.2 mmol). The crude
residue was purified by flash chromatography on silicagel using a
mixture of dichloromethane and ethyl acetate (in a ratio of 8:1) as
mobile phase, affording the pure title compound as a yellowish solid
1
mg, 85%). H NMR (300 MHz, DMSO-d6): δ = 0.90 (d, J = 6.5 Hz,
3H, CH3), 1.44−2.00 (m, 10H, CH and CH2), 3.83 (s, 3H, OCH3),
3.88 (s, 3H, OCH3), 7.14 (d, J = 8.3 Hz, 1H, arom H), 7.30 (d, J = 8.3
Hz, 1H, arom H), 7.38 (s, 1H, arom H), 8.64 (d, J = 2.0 Hz, 1H, arom
H), 9.16 (d, J = 2.0 Hz, 1H, arom H), 10.90 (s, 1H, NH) ppm. 13C
NMR (150 MHz, DMSO-d6): δ = 174.97, 169.13, 152.47, 150.21,
149.40, 149.36, 132.26, 130.65, 129.13, 122.12, 119.83, 112.57, 111.09,
55.85, 55.72, 43.77, 34.00, 31.64, 29.03, 22.60 ppm. HRMS: calcd for
C22H25N3O3S1 412.1689, found 412.1687.
N-(5-(3,4-Dimethoxyphenyl)isothiazolo[5,4-b]pyridin-3-yl)-
pivalamide (10aa). This compound was prepared according to the
general procedure E from 3-amino-5-(3,4-dimethoxyphenyl)-
isothiazolo[5,4-b]pyridine (8b, 72 mg, 0.25 mmol) and pivaloyl
chloride (0.3 mmol). The residue was purified by flash chromatog-
raphy on silica, the mobile phase being a mixture of ethyl acetate and
dichloromethane (in a ratio of 1/8), yielding the title compound (60
1
(70 mg, 89%). H NMR (300 MHz, DMSO-d6): δ = 1.60−2.50 (m,
6H, CH2), 2.83 (m, 1H, CH), 3.83 (s, 3H, OCH3), 3.88 (s, 3H,
OCH3), 5.67 (d, J = 11.8 Hz, 1H, CCH), 5.73 (s, 1H, CCH),
7.14 (d, J = 8.3 Hz, 1H, arom H), 7.32 (d, J = 8.3 Hz, 1H, arom H),
7.38 (s, 1H, arom H), 8.81 (d, J = 1.9 Hz, 1H, arom H), 9.16 (d, J =
1.9 Hz, 1H, arom H), 10.99 (s, 1H, NH) ppm. 13C NMR (150 MHz,
DMSO-d6): δ = 176.58, 169.15, 152.41, 150.23, 149.37, 132.27,
130.67, 129.12, 126.60, 125.61, 122.12, 119.83, 112.57, 111.08, 55.85,
55.73, 38.49, 27.52, 25.39, 24.32 ppm. HRMS: calcd for C21H21N3O3S1
396.1376, found 396.1371.
2-Cyclohexyl-N-(5-(3,4-dimethoxyphenyl)isothiazolo[5,4-b]-
pyridin-3-yl)acetamide (10u). This compound was prepared
according to the general procedure D from 3-amino-5-(3,4-
dimethoxyphenyl)-isothiazolo[5,4-b]pyridine (8b, 0.20 mmol, 57
M
dx.doi.org/10.1021/jm5007929 | J. Med. Chem. XXXX, XXX, XXX−XXX