Journal of Medicinal Chemistry
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intermediate 31. The final compound was obtained as a white solid in
61% yield. M.p.: 124−126 °C. H NMR (400 MHz, DMSO-d6) δ
(dd, J = 4.0, 8.0 Hz 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 4.0 Hz,
1H), 5.86 (s, 1H), 5.41 (s, 2H), 2.23 (s, 3H), 2.11 (s, 3H). 13C NMR
(101 MHz, DMSO-d6) δ 160.38, 147.39, 139.33, 139.17, 138.94,
131.36, 131.09, 130.04, 127.03, 125.64, 121.82, 120.62, 113.46,
105.79, 47.36, 13.81, 11.07. HRMS (ESI): calcd for C17H16Cl2N3OS
[M + H]+ m/z 380.0391, found 380.0385; purity: ≥97% by HPLC
analysis.
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9.88 (s, 1H), 7.80 (d, J = 3.3 Hz, 1H), 7.34−7.23 (m, 1H), 7.19−7.10
(m, 1H), 7.11−6.98 (m, 2H), 5.85 (s, 1H), 5.40 (s, 2H), 2.24 (s, 3H),
2.21 (s, 3H), 2.11 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.53
(d), 160.35, 147.03, 146.35, 139.37, 139.10, 137.28 (d, J = 8.4 Hz),
132.54 (d, J = 2.7 Hz), 129.26, 129.11 (d, J = 8.9 Hz), 126.91, 117.09
(d, J = 22.1 Hz), 113.11 (d, J = 22.1 Hz), 105.75, 47.36, 18.32, 13.80,
11.06. HRMS (ESI): calcd for C18H19FN3OS [M + H]+ m/z
344.1233, found 344.1230; purity: ≥97% by HPLC analysis.
5-((3,5-Dimethyl-1H-pyrazol-1-yl)methyl)-N-(3-methyl-[1,1′-bi-
phenyl]-4-yl)thiophene-2-carboxamide (32d). Compound 32d was
prepared with general procedure C using 3-methyl-[1,1′-biphenyl]-4-
amine and intermediate 31. The final compound was obtained as a
white solid in 59% yield. M.p.: 70−72 °C.1H NMR (400 MHz,
DMSO-d6) δ 9.92 (s, 3H), 7.84 (d, J = 4.0 Hz, 1H), 7.67 (d, J = 8.0
Hz, 1H), 7.58 (s, 1H), 7.52−7.45 (m, 2H), 7.39−7.36 (m, 2H), 7.09
(d, J = 4.0 Hz, 1H), 5.86 (s, 1H), 5.40 (s, 2H), 2.29 (s, 3H), 2.25 (s,
3H), 2.11 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.25,
147.04, 146.38, 140.17, 139.56, 139.13, 138.35, 135.75, 134.65,
129.37, 129.31, 129.10, 127.79, 127.50, 127.03, 126.95, 124.77,
105.77, 47.37, 18.50, 13.82, 11.09. HRMS (ESI): calcd for
C24H24N3OS [M + H]+ m/z 402.1640, found 402.1633; purity:
≥97% by HPLC analysis.
N-(3-Fluoro-4-chlorophenyl)-5-((3,5-dimethyl-1H-pyrazol-1-yl)-
methyl)thiophene-2-carboxamide (32i). Compound 32i was pre-
pared with general procedure C using 3-fluoro-4-chloroaniline and
intermediate 31. The final compound was obtained as a white solid in
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54% yield. M.p.: 246 ∼ 248 °C. H NMR (400 MHz, DMSO-d6) δ
10.42 (bs, 1H), 7.86 (d, J = 4.0 Hz, 1H) 7.82 (d, J = 2.0 Hz, 1H),
7.32−7.15 (m, 1H), 7.09 (d, J = 4.0 Hz, 1H), 5.86 (s, 1H), 5.41 (s,
2H), 2.23 (s, 3H), 2.11 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ
160.51, 147.63, 147.10, 141.57, 139.18, 138.70, 134.46, 130.23,
127.07, 123.31, 118.65, 105.80, 47.36, 13.81, 11.06. HRMS (ESI):
calcd for C17H16Cl2N3OS [M + H]+ m/z 380.0391, found 380.0385;
purity: ≥98% by HPLC analysis.
N-(3,4-Diethyoxylphenyl)-5-((3,5-dimethyl-1H-pyrazol-1-yl)-
methyl)thiophene-2-carboxamide (32j). Compound 32j was pre-
pared with general procedure C using 3,4-diethyoxylaniline and
intermediate 31. The final compound was obtained as a white solid in
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44% yield. M.p.: 223−225 °C. H NMR (400 MHz, DMSO-d6) δ
10.47 (s, 1H), 7.86 (d, J = 4.0 Hz, 1H), 7.50−7.44 (m, 2H), 7.09 (d, J
= 4.0 Hz, 1H), 6.99−6.93 (m, 1H), 5.86 (s, 1H), 5.41 (s, 2H), 2.23
(s, 3H), 2.11 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.52,
147.57, 147.10, 141.75, 139.18, 138.78, 130.17, 127.03, 105.80,
103.50, 103.21, 101.07, 47.36, 13.81, 11.06. HRMS (ESI): calcd for
C17H16F2N3OS [M + H]+ m/z 348.0982, found 347.0977; purity:
≥99% by HPLC analysis.
5-((3,5-Dimethyl-1H-pyrazol-1-yl)methyl)-N-(2-methyl-4-(pyri-
din-3-yl)phenyl)thiophene-2-carboxamide (32e). Compound 32e
was prepared with general procedure C using 2-methyl-4-(pyridin-3-
yl)aniline and intermediate 31. The final compound was obtained as a
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white solid in 58% yield. M.p.: 74−76 °C. H NMR (400 MHz,
DMSO-d6) δ 9.94 (s, 1H), 8.92 (d, J = 2.0 Hz, 1H), 8.57 (dd, J = 2.0,
4.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 4.0 Hz, 1H), 7.66
(s, 1H), 7.58 (d, J = 12.0 Hz, 1H), 7.50−7.47 (m 1H), 7.42 (d, J =
12.0 Hz, 1H), 7.10 (d, J = 4.0 Hz, 1H), 5.86 (s, 1H), 5.41 (s, 2H),
2.30 (s, 3H), 2.24 (s, 3H), 2.11 (s, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 160.25, 148.83, 148.02, 147.05, 146.47, 139.47, 139.14,
136.44, 135.57, 135.14, 134.87, 134.41, 129.40, 129.31, 127.60,
126.96, 124.97, 124.31, 105.77, 47.37, 18.47, 13.82, 11.09. HRMS
(ESI): calcd for C23H23N4OS [M + H]+ m/z 403.1593, found
403.1586; purity: ≥98% by HPLC analysis.
N-(3,5-Dichlorophenyl)-5-((3,5-dimethyl-1H-pyrazol-1-yl)-
methyl)thiophene-2-carboxamide (32k). Compound 32k was
prepared with general procedure C using 3,5-dichloroaniline and
intermediate 31. The final compound was obtained as a white solid in
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39% yield. M.p.: 239−241 °C. H NMR (400 MHz, DMSO-d6) δ
10.44 (s, 1H), 7.87−7.84 (m, 2H), 7.58−7.51 (m, 2H), 7.09 (d, J =
4.0 Hz, 1H), 5.85 (s, 1H), 5.41 (s, 2H), 2.23 (s, 3H), 2.11 (s, 3H).
13C NMR (101 MHz, DMSO-d6) δ 160.41, 147.38, 147.09, 139.17,
5-((3,5-Dimethyl-1H-pyrazol-1-yl)methyl)-N-(4-fluoro-3-
methylphenyl)thiophene-2-carboxamide (32f). Compound 32f was
prepared with general procedure C using 4-fluoro-3-methyl aniline
and intermediate 31. The final compound was obtained as a white
solid in 57% yield. M.p.: 154−156 °C.1H NMR (400 MHz, CDCl3) δ
7.74 (s, 1H), 7.45 (m, 2H), 7.44, 7.32 (m, 1H), 6.98 (d, J = 4.0 Hz,
1H), 6.88 (d, J = 4.0 Hz, 1H), 5.88 (s, 1H), 5.35 (s, 2H), 2.28 (s,
6H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.72, 148.43,
145.54, 139.08, 138.60, 133.22, 128.63, 126.01, 125.56, 125.37,
123.64, 119.43, 115.36, 106.08, 47.68, 14.69, 14.65, 13.52, 11.09.
HRMS (ESI): calcd for C18H19FN3OS [M + H]+ m/z 344.1233,
found 344.1226; purity: ≥98% by HPLC analysis.
N-(3-Chloro-4-fluorophenyl)-5-((3,5-dimethyl-1H-pyrazol-1-yl)-
methyl)thiophene-2-carboxamide (32g). Compound 32g was
prepared with general procedure C using 3-chloro-4-fluoroaniline
and intermediate 31. The final compound was obtained as a white
solid in 74% yield. M.p.: 163−165 °C.1H NMR (400 MHz, DMSO-
d6) δ 10.34 (s, 1H), 7.98 (dd, J = 4.0, 8.0 Hz 1H), 7.84 (d, J = 4.0 Hz,
1H), 7.65 (m, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 4.0 Hz, 1H),
5.85 (s, 1H), 5.41(s, 2H), 2.23 (s, 3H), 2.11 (s, 3H). 13C NMR (101
MHz, DMSO-d6) δ 160.26, 152.66, 147.07 (d, J = 28 Hz), 139.16 (d,
J = 36 Hz), 136.42, 129.82, 126.99, 122.18, 121.00 (d, J = 28 Hz),
119.62, 119.43, 117.45, 117.23, 105.79, 47.37, 13.81, 11.06. HRMS
(ESI): calcd for C17H16ClFN3OS [M + H]+ m/z 363.0687. found
363.0680; purity: ≥96% by HPLC analysis.
138.95, 130.94, 130.03, 127.00, 117.48, 113.94, 108.83, 108.58,
105.80, 101.81, 47.37, 13.81, 11.06. HRMS (ESI): calcd for
C17H16ClFN3OS [M + H]+ m/z 364.0687, found 364.0686; purity:
≥97% by HPLC analysis.
N-(3,5-Difluorophenyl)-5-((3,5-dimethyl-1H-pyrazol-1-yl)-
methyl)thiophene-2-carboxamide (32l). Compound 32l was pre-
pared with general procedure C using 3,5-difluoroaniline and
intermediate 31. The final compound was obtained as a white solid
in 67% yield. M.p.: 194−196 °C. 1H NMR (400 MHz, CDCl3) δ 7.76
(s, 1H), 7.45 (d, J = 4.0 Hz, 1H), 6.88 (d, J = 4.0 Hz, 1H), 6.86 (d, J =
2.0 Hz, 2H), 6.28 (t, J = 2.0 Hz, 1H), 5.88 (s, 1H), 5.36 (s, 2H), 3.80
(s, 6H), 2.28 (s, 3H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
161.05 (2C), 159.80, 148.43, 145.69, 139.52, 139.12, 138.90, 128.53,
126.01, 106.08, 98.29 (2C), 97.14, 55.38 (2C), 47.67, 13.52, 11.08.
HRMS (ESI): calcd for C19H22N3O3S [M + H]+ m/z 372.1382, found
372.1375; purity: ≥96% by HPLC analysis.
N-(3,5-Dimethoxyphenyl)-5-((3,5-Dimethyl-1H-pyrazol-1-yl)-
methyl)thiophene-2-carboxamide (32m). Compound 32m was
prepared with general procedure C using 3,5-dimethoxyaniline and
intermediate 31. The final compound was obtained as a white solid in
77% yield. M.p.: 146−148 °C.1H NMR (400 MHz, CDCl3) δ 7.77
(bs, 2H), 7.43 (dd, J = 2.0, 12.0 Hz, 1H), 6.93 (dd, J = 4.0, 8.0 Hz,
1H), 6.87−6.83 (m, 2H), 5.88 (s, 1H), 5.35 (s, 2H), 4.15−4.06 (m,
4H), 2.28 (s, 3H), 2.26 (s, 3H), 1.47−1.43 (m, 6H). 13C NMR (101
MHz, CDCl3) δ 159.69, 148.92, 148.38, 145.58, 145.29, 139.11,
139.03, 131.44, 128.35, 125.99, 113.90, 112.33, 106.86, 106.05, 64.95,
64.45, 47.68, 14.86, 14.71, 13.51, 11.08. HRMS (ESI): calcd for
C21H26N3O3S [M + H]+ m/z 400.1695, found 400.1691; purity:
≥96% by HPLC analysis.
N-(3,4-Dichlorophenyl)-5-((3,5-dimethyl-1H-pyrazol-1-yl)-
methyl)thiophene-2-carboxamide (32h). Compound 32h was
prepared with general procedure C using 3,4-dichloroaniline and
intermediate 31. The final compound was obtained as a white solid in
70% yield. M.p.: 162−164 °C.1H NMR (400 MHz, DMSO-d6) δ
10.41 (s, 1H), 8.06 (d, J = 3.2 Hz, 1H), 7.86 (d, J = 4.0 Hz, 1H), 7.70
N-([1,1′-Biphenyl]-4-yl)-5-((3,5-dimethyl-1H-pyrazol-1-yl)-
methyl)thiophene-2-carboxamide (32n). Compound 32n was
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J. Med. Chem. 2021, 64, 5551−5576