Journal of Medicinal Chemistry
Article
1-(3-Methoxyphenyl)-4-methyl-N-{4-[(methylsulfonyl)-
amino]phenyl}-1,4-dihydropyrazolo[4,3-c][1,2]benzothiazine-
3-carboxamide 5,5-Dioxide (2j). Following the general procedure
method C, compound 2j was obtained, from 8j, in 30% yield as a white
and H-6′), 8.10−8.15 (m, 1H, H-6), 9.70 (s, 1H, SO2NH), 10.50 (s,
1H, CONH). 13C NMR (DMSO-d6): δ 39.33, 39.37, 121.21, 122.31,
123.05 (q, JC−F = 270 Hz, CF3), 123.28, 123.68, 125.26, 126.03, 126.68
(q, JC−F = 30 Hz, C-2′), 128.63−128.68 (m, C-6′), 130.84, 130.98,
131.28, 132.54, 132.57, 133.62, 134.69, 134.96, 135.24, 136.62, 139.63,
158.61. Anal. Calcd for C25H20F3N5O5S2: C, 50.76; H, 3.41; N, 11.84.
Found: C, 50.67; H, 3.36; N, 12.00.
1-(3,4-Difluorophenyl)-4-methyl-N-{4-[(methylsulfonyl)-
amino]phenyl}-1,4-dihydropyrazolo[4,3-c][1,2]benzothiazine-
3-carboxamide 5,5-Dioxide (2o). Following the general procedure
method C, compound 2o was obtained, from 8o, in 70% yield as a
white solid: mp 290−292 °C. 1H NMR (400 MHz, DMSO-d6): δ 2.95
(s, 3H, SO2CH3), 3.30 (s, 3H, NCH3), 7.10 (d, J = 7.5 Hz, 1H, H-9),
7.15−7.25 (m, 2H, H-3″ and H-5″), 7.50−7.55 (m, 1H, H-6′), 7.65−
7.85 (m, 5H, H-7, H-8, H-2′, H-2″, and H-6″), 7.95−8.05 (m, 2H, H-6
and H-5′), 9.65 (s, 1H, SO2NH), 10.50 (s, 1H, CONH). 13C NMR
(DMSO-d6): δ 39.20, 39.30, 116.62 (d, JC−F = 20 Hz, C-2′), 119.27 (d,
JC−F = 18.6 Hz, C-5′), 121.26, 122.13, 123.23, 123.65−123.80 (m, C-
6′), 125.00, 125.18, 126.62, 130.77, 130.83, 130.85, 133.62, 134.69,
135.02, 135.75 (dd, JC−F = 3.4 and 8.3 Hz, C-1′), 139.69, 150.10 (dd,
JC−F = 13.1 and 247.5 Hz, C-4′), 150.80 (dd, JC−F = 12.2 and 248 Hz,
C-3′), 158.67. Anal. Calcd for C24H19F2N5O5S2: C, 51.51; H, 3.42; N,
12.52. Found: C, 51.76; H, 3.67; N, 12.22.
1-(3,4-Dichlorophenyl)-4-methyl-N-{4-[(methylsulfonyl)-
amino]phenyl}-1,4-dihydropyrazolo[4,3-c][1,2]benzothiazine-
3-carboxamide 5,5-Dioxide (2p). Following the general procedure
method C, compound 2p was obtained, from 8p, in 40% yield as a
white solid: mp 259−261 °C. 1H NMR (400 MHz, DMSO-d6): δ 3.00
(s, 3H, SO2CH3), 3.25 (s, 3H, NCH3), 7.20−7.25 (m, 3H, H-9, H-3″,
and H-5″), 7.60 (dd, J = 2.3 and 8.6 Hz, 1H, H-6′), 7.70−7.80 (m, 4H,
H-7, H-8, H-2″, and H-6″), 7.85 (d, J = 8.6 Hz, 1H, H-5′), 8.00 (dd, J
= 1.1 and 7.2 Hz, 1H, H-6), 8.10 (d, J = 2.3 Hz, 1H, H-2′), 9.60 (s,
1H, SO2NH), 10.45 (s, 1H, CONH). 13C NMR (DMSO-d6): δ 39.09,
39.33, 121.25, 122.15, 123.20, 125.15, 125.21, 126.14, 126.95, 128.07,
130.61, 130.82, 130.83, 132.21, 132.93, 133.09, 133.63, 134.74, 134.97,
138.80, 139.90, 158.61. Anal. Calcd for C24H19Cl2N5O5S2: C, 48.65; H,
3.23; N, 11.82. Found: C, 48.33; H, 2.29; N, 12.06.
1-(3,4-Dimethylphenyl)-4-methyl-N-{4-[(methylsulfonyl)-
amino]phenyl}-1,4-dihydropyrazolo[4,3-c][1,2]benzothiazine-
3-carboxamide 5,5-Dioxide (2q). Following the general procedure
method C, compound 2q was obtained, from 8q, in 40% yield as a
white solid: mp 301−303 °C. 1H NMR (400 MHz, DMSO-d6): δ 2.25
and 2.30 (s, each 3H, CH3), 2.95 (s, 3H, SO2CH3), 3.20 (s, 3H,
NCH3), 7.00 (d, J = 8.0 Hz, 1H, H-9), 7.15−7.20 (m, 2H, H-3″ and
H-5″), 7.30 (dd, J = 2.0 and 8.0 Hz, 1H, H-6′), 7.40 (d, J = 8.0 Hz, 1H,
H-5′), 7.45 (d, J = 2.0 Hz, 1H, H-2′), 7.65−7.75 (m, 2H, H-7 and H-
8), 7.75−7.80 (m, 2H, H-2″ and H-6″), 8.00 (dd, J = 1.3 and 7.8 Hz,
1H, H-6), 9.50 (s, 1H, SO2NH), 10.35 (s, 1H, CONH). 13C NMR
(DMSO-d6): δ 19.66, 19.70, 39.21, 39.36, 121.29, 122.11, 123.46,
123.70, 124.66, 125.11, 126.40, 126.89, 130.39, 130.51, 130.81, 131.12,
133.36, 134.61, 135.12, 137.11, 138.99, 139.08, 139.18, 158.89. Anal.
Calcd for C26H25N5O5S2: C, 56.61; H, 4.57; N, 12.70. Found: C,
56.59; H, 4.53; N, 12.75.
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solid: mp 286−288 °C. H NMR (400 MHz, DMSO-d6): δ 3.00 (s,
3H, SO2CH3), 3.25 (s, 3H, NCH3), 3.80 (s, 3H, OCH3), 7.05 (dd, J =
1.1 and 7.0 Hz, 1H, H-9), 7.15 (dd, J = 2.0 and 8.0 Hz, 1H, H-4′),
7.15−7.20 (m, 2H, H-3″ and H-5″), 7.25 (dd, J = 2.0 and 8.2 Hz, 1H,
H-6′), 7.30 (t, J = 2.0 Hz, 1H, H-2′), 7.55 (t, J = 8.2 Hz, 1H, H-5′),
7.65−7.75 (m, 2H, H-7 and H-8), 7.75−7.80 (m, 2H, H-2″ and H-6″),
8.05 (dd, J = 1.4 and 7.5 Hz, 1H, H-6), 9.60 (s, 1H, SO2NH), 10.50 (s,
1H, CONH). 13C NMR (DMSO-d6): δ 39.22, 39.35, 56.21, 111.87,
116.50, 118.35, 121.28, 122.14, 123.53, 124.81, 125.12, 126.52, 130.52,
130.61, 130.81, 131.32, 133.38, 134.65, 135.09, 139.35, 140.33, 158.84,
160.70. Anal. Calcd for C25H23N5O6S2: C, 54.24; H, 4.19; N, 12.65.
Found: C, 54.48; H, 4.32; N, 12.38.
1-(4-Methoxyphenyl)-4-methyl-N-{4-[(methylsulfonyl)-
amino]phenyl}-1,4-dihydropyrazolo[4,3-c][1,2]benzothiazine-
3-carboxamide 5,5-Dioxide (2k). Following the general procedure
method C, compound 2k was obtained, from 8k, in 40% yield as a
white solid: mp 269−271 °C. 1H NMR (400 MHz, DMSO-d6): δ 3.00
(s, 3H, SO2CH3), 3.25 (s, 3H, NCH3), 3.90 (s, 3H, OCH3), 6.95 (dd,
J = 1.2 and 7.5 Hz, 1H, H-9), 7.15−7.25 (m, 4H, H-3′, H-5′, H-3″, and
H-5″), 7.55−7.60 (m, 2H, H-2′ and H-6′), 7.65−7.75 (m, 2H, H-7
and H-8), 7.75−7.80 (m, 2H, H-2″ and H-6″), 8.00 (dd, J = 1.4 and
7.6 Hz, 1H, H-6), 9.60 (s, 1H, SO2NH), 10.40 (s, 1H, CONH). 13C
NMR (DMSO-d6): δ 39.23, 39.34, 56.13, 115.53, 121.29, 122.12,
123.69, 124.58, 125.15, 126.24, 127.90, 130.49, 130.64, 130.88, 132.21,
133.40, 134.60, 135.15, 139.14, 158.91, 160.65. Anal. Calcd for
C25H23N5O6S2: C, 54.24; H, 4.19; N, 12.65. Found: C, 53.04; H, 4.06;
N, 12.78.
4-Methyl-N-{4-[(methylsulfonyl)amino]phenyl}-1-[3-
(trifluoromethyl)phenyl]-1,4-dihydropyrazolo[4,3-c][1,2]-
benzothiazine-3-carboxamide 5,5-Dioxide (2l). Following the
general procedure method C, compound 2l was obtained, from 8l,19 in
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60% yield as a white solid: mp 200−202 °C. H NMR (400 MHz,
DMSO-d6): δ 3.00 (s, 3H, SO2CH3), 3.30 (s, 3H, NCH3), 7.00 (d, J =
7.6 Hz, 1H, H-9), 7.15−7.20 (m, 2H, H-3″ and H-5″), 7.65−7.75 (m,
4H, H-7, H-8, H-2″, and H-6″), 7.80−7.90 (m, 2H, H-5′ and H-6′),
7.95−8.00 (m, 2H, H-6 and H-4′), 8.15−8.20 (bs, 1H, H-2′), 9.70 (s,
1H, SO2NH), 10.60 (s, 1H, CONH). 13C NMR (DMSO-d6): δ 39.15,
39.33, 121.27, 122.19, 123.09−123.13 (m, C-2′), 123.28, 123.90 (q,
JC−F = 270 Hz, CF3), 124.92, 125.22, 126.96, 127.07−127.11 (m, C-
4′), 130.20, 130.68, 130.82, 131.14 (q, JC−F = 32 Hz, C-3′), 131.82,
133.45, 134.73, 134.99, 139.81, 140.00, 158.69. Anal. Calcd for
C25H20F3N5O5S2: C, 50.76; H, 3.41; N, 11.84. Found: C, 50.80; H,
3.46; N, 11.74.
4-Methyl-N-{4-[(methylsulfonyl)amino]phenyl}-1-[4-
(trifluoromethyl)phenyl]-1,4-dihydropyrazolo[4,3-c][1,2]-
benzothiazine-3-carboxamide 5,5-Dioxide (2m). Following the
general procedure method C, compound 2m was obtained, from 8m,
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in 60% yield as a white solid: mp 285−286 °C. H NMR (400 MHz,
DMSO-d6): δ 2.95 (s, 3H, SO2CH3), 3.25 (s, 3H, NCH3), 7.10 (d, J =
7.4 Hz, 1H, H-9), 7.15−7.25 (m, 2H, H-3″ and H-5″), 7.70−7.80 (m,
4H, H-7, H-8, H-2″, and H-6″), 7.90−7.95 (m, 2H, H-2′ and H-6′),
8.00−8.10 (m, 3H, H-6, H-3′, and H-5′), 9.60 (s, 1H, SO2NH), 10.50
(s, 1H, CONH). 13C NMR (DMSO-d6): δ 39.00, 39.11, 121.27,
1 - ( 3 - C h l o r o - 4 - m e t h y l p h e n y l ) - 4 - m e t h y l - N - { 4 -
[(methylsulfonyl)amino]phenyl}-1,4-dihydropyrazolo[4,3-c]-
[1,2]benzothiazine-3-carboxamide 5,5-Dioxide (2r). Following
the general procedure method C, compound 2r was obtained, from 8r,
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122.09, 123.29, 125.17−125.22 (m, C-2′ and C-6′), 126.10 (q, JC−F
=
in 40% yield as a white solid: mp 287−289 °C. H NMR (400 MHz,
300 Hz, CF3), 126.69, 127.16, 127.70−127.75 (m, C-3′ and C-5′),
130.49 (q, J = 32 Hz, C-4′), 130.57, 130.80, 130.83, 133.59, 134.75,
134.98, 140.24, 142.36, 158.67. Anal. Calcd for C25H20F3N5O5S2: C,
50.76; H, 3.41; N, 11.84. Found: C, 50.96; H, 3.58; N, 11.66.
4-Methyl-N-{4-[(methylsulfonyl)amino]phenyl}-1-[2-
(trifluoromethyl)phenyl]-1,4-dihydropyrazolo[4,3-c][1,2]-
benzothiazine-3-carboxamide 5,5-Dioxide (2n). Following the
general procedure method C, compound 2n was obtained, from 8n, in
DMSO-d6): δ 2.45 (s, 3H, CH3), 2.95 (s, 3H, SO2CH3), 3.20 (s, 3H,
NCH3), 7.10 (dd, J = 1.4 and 7.5 Hz, 1H, H-9), 7.15−7.20 (m, 2H, H-
3″ and H-5″), 7.50 (dd, J = 2.1 and 8.0 Hz, 1H, H-6′), 7.60 (d, J = 8.0
Hz, 1H, H-5′), 7.65−7.80 (m, 4H, H-7, H-8, H-2″, and H-6″), 7.85 (d,
J = 2.1 Hz, 1H, H-2′), 8.05 (dd, J = 1.6 and 7.3 Hz, 1H, H-6), 9.60 (s,
1H, SO2NH), 10.40 (s, 1H, CONH). 13C NMR (DMSO-d6): δ 19.92,
39.12, 39.33, 121.26, 122.14, 123.41, 124.72, 124.90, 125.14, 126.41,
126.69, 130.49, 130.70, 130.82, 132.68, 133.48, 134.63, 134.68, 135.03,
138.10, 138.14, 139.55, 158.72. Anal. Calcd for C25H22ClN5O5S2: C,
52.49; H, 3.88; N, 12.24. Found: C, 52.89; H, 4.93; N, 12.15.
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30% yield as a white solid: mp 255−257 °C. H NMR (400 MHz,
DMSO-d6): δ 3.00 (s, 3H, SO2CH3), 3.30 (s, 3H, NCH3), 6.70 (d, J =
8.0 Hz, 1H, H-9), 7.15−7.20 (m, 2H, H-3″ and H-5″), 7.65 (dt, J = 1.2
and 7.9 Hz, 1H, H-8), 7.70 (dt, J = 1.2 and 7.9 Hz, 1H, H-7), 7.75−
7.80 (m, 2H, H-2″, and H-6″), 7.95−8.05 (m, 4H, H-3′, H-4′, H-5′,
1-[4-Chloro-3-(trifluoromethyl)phenyl]-4-methyl-N-{4-
[(methylsulfonyl)amino]phenyl}-1,4-dihydropyrazolo[4,3-c]-
[1,2]benzothiazine-3-carboxamide 5,5-Dioxide (2s). Following
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dx.doi.org/10.1021/jm401688h | J. Med. Chem. 2014, 57, 3247−3262