Journal of Medicinal Chemistry
Article
(ESI): m/z [M + H]+ calcd for C22H26N3O6S, 460.1537; found,
460.1533.
59−60 °C. 1H NMR (400 MHz, DMSO-d6) δ: 12.12 (brs, 1H), 10.74
(brs, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 6.0 Hz, 1H), 7.58 (d, J =
1.2 Hz, 1H), 7.46 (dd, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 7.09 (d, J = 6.0 Hz,
1H), 4.17−4.11 (m, 2H), 3.55 (brs, 2H), 3.23 (brs, 2H), 1.58−1.52 (m,
4H), 1.44 (br, 2H), 1.22 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6) δ: 166.4, 163.5, 162.5, 151.3, 147.8, 140.8, 133.8, 130.7,
130.3, 128.4, 125.8, 123.5, 117.2, 116.0, 61.3, 48.1, 42.4, 25.9, 25.2,
24.0, 14.3. HRMS (ESI): m/z [M + H]+ calcd for C21H23ClN3O5S,
464.1042; found, 464.0981.
Ethyl (2-(4-(4,4-Difluoropiperidine-1-carbonyl)benzamido)-
thiophene-3-carbonyl)carbamate (23n). White solid; yield 57%;
mp 177−178 °C. 1H NMR (400 MHz, DMSO-d6) δ: 12.65 (brs, 1H),
10.82 (brs, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.74−7.70 (m, 3H), 7.10 (d, J
= 5.6 Hz, 1H), 4.24−4.19 (m, 2H), 3.87−3.76 (m, 2H), 3.48−3.40 (m,
2H), 2.06 (brs, 4H), 1.29 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6) δ: 168.2, 164.2, 162.5, 151.2, 149.1, 139.9, 132.8, 127.7,
127.6, 123.4, 122.8 (J = 240 Hz), 116.9, 115.3, 61.4, 44.0, 38.5, 33.7,
14.3. HRMS (ESI): m/z [M + H]+ calcd for C21H22F2N3O5S,
466.1243; found, 466.1220.
Ethyl (2-(2-Bromo-4-(piperidine-1-carbonyl)benzamido)-
thiophene-3-carbonyl)carbamate (24d). White solid; yield 9%; mp
1
144−145 °C. H NMR (400 MHz, DMSO-d6) δ: 12.04 (brs, 1H),
Ethyl (2-(4-(Morpholine-4-carbonyl)benzamido)thiophene-3-
10.79 (brs, 1H), 7.78−7.76 (m, 2H), 7.69 (d, J = 6.0 Hz, 1H), 7.54 (d, J
= 8.0 Hz, 1H), 7.14 (d, J = 6.0 Hz, 1H), 4.21−4.16 (m, 2H), 3.59 (brs,
2H), 3.28 (brs, 2H), 1.61 (brs, 4H), 1.49 (brs, 2H), 1.26 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, DMSO-d6) δ: 166.4, 163.6, 151.3, 147.8,
140.6, 136.3, 131.4, 129.8, 126.2, 123.5, 119.4, 117.2, 116.0, 61.4, 48.1,
42.4, 25.9, 25.2, 24.0, 14.3. HRMS (ESI): m/z [M + H]+ calcd for
C21H23BrN3O5S, 508.0536; found, 508.0471.
carbonyl)carbamate (23o). White solid; yield 79%; mp 159−160
1
°C. H NMR (400 MHz, DMSO-d6) δ: 12.65 (brs, 1H), 10.82 (brs,
1H), 8.01 (d, J = 7.6 Hz, 2H), 7.74 (d, J = 5.6 Hz, 1H), 7.67 (d, J = 7.6
Hz, 2H), 7.10 (d, J = 5.6 Hz, 1H), 4.22−4.21 (m, 2H), 3.66−3.57 (m,
6H), 3.33 (brs, 2H), 1.29 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6) δ: 168.0, 164.1, 162.4, 151.2, 149.0, 139.7, 132.6, 127.8,
127.5, 123.3, 116.8, 115.2, 66.0, 61.3, 47.6, 42.0, 14.2. HRMS (ESI): m/
z [M + H]+ calcd for C20H22N3O6S, 432.1224; found, 432.1207.
Ethyl (2-(4-(Thiomorpholine-4-carbonyl)benzamido)thiophene-
3-carbonyl)carbamate (23p). White solid; yield 17%; mp 178−179
Ethyl (2-(2-Nitro-4-(piperidine-1-carbonyl)benzamido)-
thiophene-3-carbonyl)carbamate (24e). White solid; yield 27%;
mp 113−114 °C. 1H NMR (400 MHz, DMSO-d6) δ: 12.05 (brs, 1H),
10.79 (brs, 1H), 8.15 (m, 1H), 7.91−7.90 (m, 2H), 7.65 (d, J = 6.0 Hz,
1H), 7.15 (d, J = 6.0 Hz, 1H), 4.20−4.15 (m, 2H), 3.62 (brs, 2H), 3.32
(brs, 2H), 1.61 (brs, 4H), 1.49 (brs, 2H), 1.26 (t, J = 7.2 Hz, 3H). 13C
NMR (100 MHz, DMSO-d6) δ: 165.9, 163.2, 162.5, 151.3, 147.4,
146.9, 139.9, 132.0, 130.6, 129.4, 123.6, 122.9, 117.3, 116.6, 61.3, 48.1,
42.6, 25.9, 25.2, 24.0, 14.3. HRMS (ESI): m/z [M + H]+ calcd for
C21H23N4O7S, 475.1282; found, 475.1288.
Ethyl (2-(3-Fluoro-4-(piperidine-1-carbonyl)benzamido)-
thiophene-3-carbonyl)carbamate (24f). Off white solid; yield 48%;
mp 186−187 °C. 1H NMR (400 MHz, DMSO-d6) δ: 12.59 (brs, 1H),
10.84 (brs, 1H), 7.83−7.79 (m, 2H), 7.73 (d, J = 6.0 Hz, 1H), 7.69−
7.65 (m, 1H), 7.12 (d, J = 6.0 Hz, 1H), 4.22−4.19 (m, 2H), 3.65−3.62
(m, 2H), 3.21−3.18 (m, 2H), 1.63−1.57 (m, 4H), 1.46 (brs, 2H), 1.28
(t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 164.0, 162.8,
161.5, 157.6 (q, J = 246 Hz), 151.2, 148.7, 134.8 (q, J = 13 Hz), 129.7,
128.7 (J = 9 Hz), 123.7, 123.5, 117.1, 115.7, 115.1 (q, J = 24 Hz), 61.4,
47.6, 42.1, 26.1, 25.3, 23.9, 14.3. HRMS (ESI): m/z [M + H]+ calcd for
C21H23FN3O5S, 448.1337; found, 448.1338.
1
°C. H NMR (400 MHz, DMSO-d6) δ: 12.64 (brs, 1H), 10.82 (brs,
1H), 8.01 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 6.0 Hz, 1H), 7.66 (d, J = 8.4
Hz, 2H), 7.10 (d, J = 6.0 Hz, 1H), 4.24−4.19 (m, 2H), 3.90−3.89 (m,
2H), 3.52 (brs, 2H), 2.70−2.50 (m, 4H), 1.29 (t, J = 7.6 Hz, 3H). 13C
NMR (100 MHz, DMSO-d6) δ: 168.4, 164.2, 162.5, 151.2, 149.1,
140.3, 132.5, 127.6, 127.5, 123.4, 116.9, 115.3, 61.4, 49.7, 44.0, 27.0,
26.7, 14.3. HRMS (ESI): m/z [M + H]+ calcd for C20H22N3O5S2,
448.0995; found, 448.0971.
General Procedure for the Synthesis of Target Compounds 24a,
24c, 24d, 24f, and 24h−l. The target compounds were prepared from
16a and corresponding aryl carboxylic acids 7 in the same manner as
described for 23a−p.
General Procedure for the Synthesis of Target Compounds 24b,
24e, and 24g. To a magnetically stirred solution of the benzoic acids
7b, 7e or 7g (1 equiv) in CH2Cl2 were added thionyl chloride (2 equiv)
and a drop of DMF. The reaction mixture was heated to reflux for 3 h
under an argon atmosphere. The solvent was evaporated under reduced
pressure. The residue was dissolved in anhydrous THF. To a solution of
2-aminothiophene 16a (0.7 equiv), DMAP (0.07 equiv), and Et3N (3.5
equiv) in anhydrous THF was slowly added the above THF solution
cooled with an ice bath. The reaction mixture was stirred for additional
3 h at room temperature and then concentrated. The residue was
purified by silica gel column chromatography (CH2Cl2/MeOH = 100/
1) to give target compounds 24b, 24e, and 24g, respectively.
Ethyl (2-(3-(Piperidine-1-carbonyl)benzamido)thiophene-3-
carbonyl)carbamate (24a). White solid; yield 18%; mp 175−176
Ethyl (2-(3-Methyl-4-(piperidine-1-carbonyl)benzamido)-
thiophene-3-carbonyl)carbamate (24g). White solid; yield 9%; mp
1
103−104 °C. H NMR (150 MHz, DMSO-d6) δ: 12.58 (brs, 1H),
10.80 (brs, 1H), 7.84 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 6.0
Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 6.0 Hz, 1H), 4.23−4.21
(m, 2H), 3.68−3.59 (m, 2H), 3.10−3.09 (m, 2H), 2.32 (s, 3H), 1.60−
1.56 (m, 4H), 1.43−1.39 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H). 13C NMR
(150 MHz, DMSO-d6) δ: 167.3, 164.1, 162.7, 151.2, 149.2, 141.2,
134.9, 131.9, 129.2, 126.5, 124.8, 123.4, 116.8, 115.2, 61.4, 47.2, 41.7,
26.1, 25.4, 24.0, 18.7, 14.3. HRMS (ESI): m/z [M + H]+ calcd for
C22H26N3O5S, 444.1588; found, 444.1575.
1
°C. H NMR (500 MHz, DMSO-d6) δ: 12.63 (brs, 1H), 10.81 (brs,
1H), 8.00 (brs, 1H), 7.89 (brs, 1H), 7.79−7.72 (m, 3H), 7.10 (s, 1H),
4.22−4.21 (m, 2H), 3.62 (brs, 2H), 3.30 (brs, 2H), 1.62 (brs, 4H), 1.50
(brs, 2H), 1.28 (brs, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 167.8,
164.1, 162.5, 151.3, 149.1, 137.4, 132.2, 131.0, 129.6, 128.0, 125.6,
123.4, 116.9, 115.3, 61.4, 48.2, 42.5, 26.0, 25.3, 24.1, 14.3. HRMS
(ESI): m/z [M + H]+ calcd for C21H24N3O5S, 430.1431; found,
430.1434.
Ethyl (2-(6-(Piperidine-1-carbonyl)-2-naphthamido)thiophene-
3-carbonyl)carbamate (24h). White solid; yield 22%; mp 177−178
1
°C. H NMR (500 MHz, DMSO-d6) δ: 12.75 (brs, 1H), 10.86 (brs,
1H), 8,63 (s, 1H), 8.24 (d, J = 8.5 Hz, 2H), 8.08 (s, 1H), 8.02 (d, J = 8.5
Hz, 1H), 7.75 (d, J = 5.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.12 (d, J =
5.5 Hz, 1H), 4.25−4.21 (m, 2H), 3.65 (brs, 2H), 3.35 (brs, 2H), 1.63
(brs, 4H), 1.49 (brs, 2H), 1.30 (t, J = 9.0 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6) δ: 168.4, 164.2, 163.1, 151.3, 149.3, 136.5, 134.3, 132.2,
130.0, 129.7, 129.6, 128.3, 125.9, 125.6, 123.8, 123.4, 116.9, 115.3, 61.4,
48.2, 42.5, 26.1, 25.4, 24.1, 14.3. HRMS (ESI): m/z [M + H]+ calcd for
C25H26N3O5S, 480.1588; found, 480.1594.
Ethyl (2-(2-Fluoro-4-(piperidine-1-carbonyl)benzamido)-
thiophene-3-carbonyl)carbamate (24b). White solid; yield 38%;
mp 163−164 °C. 1H NMR (400 MHz, DMSO-d6) δ: 12.71 (d, J = 9.6
Hz, 1H), 10.77 (brs, 1H), 8.10 (t, J = 7.6 Hz, 1H), 7.73 (d, J = 6.0 Hz,
1H), 7.53 (d, J = 7.6 Hz, 1H), 7.41 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H),
7.12 (d, J = 6.0 Hz, 1H), 4.24−4.18 (m, 2H), 3.60 (brs, 2H), 3.25 (brs,
2H), 1.61−1.60 (m, 4H), 1.47 (brs, 2H), 1.28 (t, J = 7.6 Hz, 3H). 13C
NMR (100 MHz, DMSO-d6) δ: 166.4, 163.6, 159.8 (q, J = 250 Hz),
159.2 (q, J = 2 Hz), 151.3, 148.3, 143.0 (q, J = 8 Hz), 139.2, 132.1,
123.5, 119.8 (J = 11 Hz), 117.3, 115.7, 115.1 (q, J = 25 Hz), 61.4, 48.0,
42.4, 25.9, 25.2, 24.0, 14.3. HRMS (ESI): m/z [M + H]+ calcd for
C21H23FN3O5S, 448.1337; found, 448.1342.
Ethyl (2-(4′-(Piperidine-1-carbonyl)-[1,1′-biphenyl]-4-
carboxamido)thiophene-3-carbonyl)carbamate (24i). Light yellow
solid; yield 83%; mp 187−188 °C. 1H NMR (400 MHz, DMSO-d6) δ:
12.70 (brs, 1H), 10.83 (brs, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.99 (d, J =
8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 6.0 Hz, 1H), 7.51 (d, J
= 8.0 Hz, 2H), 7.10 (d, J = 6.0 Hz, 1H), 4.25−4.20 (m, 2H), 3.60 (brs,
2H), 3.32 (brs, 2H), 1.63 (brs, 2H), 1.52 (brs, 4H), 1.29 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, DMSO-d6) δ: 168.5, 164.2, 162.7, 151.3,
Ethyl (2-(2-Chloro-4-(piperidine-1-carbonyl)benzamido)-
thiophene-3-carbonyl)carbamate (24c). White solid; yield 16%; mp
6256
J. Med. Chem. 2021, 64, 6241−6261