Journal of Medicinal Chemistry
Article
CDCl3): δ 175.9, 166.5, 149.7, 134.6, 133.0, 130.8, 130.0, 127.0,
126.7, 113.1, 60.5, 26.3, 24.3, 22.9, 22.8, 14.1. HRMS (ESI): calcd for
C18H19ClN2O2S2 (M + H)+ 395.0655, found 395.0658.
22.7. HRMS (ESI): calcd for C21H20N2O2S2 (M + H)+ 397.1044,
found 397.1048.
Ethyl 2-(3-(Naphthalen-1-yl)thioureido)-5,6-dihydro-4H-
1
cyclopenta[b]thiophene-3-carboxylate (31). Yield: 92%. H NMR
Ethyl 2-(3-(4-Fluorophenyl)thioureido)-5,6-dihydro-4H-
1
(400 MHz, CDCl3): δ 11.69 (s, 1H), 8.03−8.06 (m, 1H), 7.95−7.99
(m, 2H), 7.91 (s, 1H), 3.93 (q, 2H), 2.79−2.85 (m, 4H), 2.31−2.35
(m, 2H), 1.13 (t, J1 = 14.4 Hz, J2 = 7.2 Hz, 3H). 13C NMR (101
MHz, CDCl3): δ 177.0, 165.3, 153.3, 141.2, 134.7, 132.2, 131.4,
130.0, 129.3, 128.5, 127.4, 126.8, 125.7, 125.6, 122.1, 109.8, 60.3,
30.3, 28.8, 27.7, 14.0. HRMS (ESI): calcd for C21H20N2O2S2 (M +
H)+ 397.1044, found 397.1047.
Ethyl 2-(3-(Naphthalen-1-yl)thioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (32). Yield: 92%. 1H
NMR (400 MHz, CDCl3): δ 11.93 (s, 1H), 8.02−8.05 (m, 2H),
7.94−7.98 (m, 2H), 7.56−7.61 (m, 4H), 3.88 (q, 2H), 2.62−2.65 (m,
4H), 1.71−1.79 (m, 4H), 1.09 (t, J1 = 10 Hz, J2 = 7.2 Hz, 3H). 13C
NMR (101 MHz, CDCl3): δ 177.4, 165.7, 149.4, 134.7, 131.5, 130.8,
130.0, 129.2, 128.4, 127.4, 126.8, 126.7, 125.8, 125.7, 122.2, 113.1,
60.0, 26.1, 24.2, 22.9, 22.8, 14.0. HRMS (ESI): calcd for
C22H22N2O2S2 (M + H)+ 411.1201, found 411.1206.
cyclopenta[b]thiophene-3-carboxylate (23). Yield: 89%. H NMR
(400 MHz, CDCl3): δ 11.86 (s, 1H), 7.75 (s, 1H), 7.33−7.37 (m,
2H), 7.19 (t, J1 = 16.8 Hz, J2 = 8.4 Hz, 2H), 4.17 (q, 2H), 2.83−2.90
(m, 4H), 2.34−2.38 (m, 2H), 1.29 (t, J1 = 14.4 Hz, J2 = 7.2 Hz, 3H).
13C NMR (101 MHz, CDCl3): δ 176.0, 165.9, 163.0, 160.6, 153.5,
141.1, 132.5, 131.7, 128.2, 117.0, 109.7, 60.3, 30.4, 28.8, 27.7, 14.1.
HRMS (ESI): calcd for C17H17FN2O2S2 (M + H)+ 365.0794, found
365.0799.
Ethyl 2-(3-(4-Fluorophenyl)thioureido)-4,5,6,7-tetrahydrobenzo-
1
[b]thiophene-3-carboxylate (24). Yield: 90%. H NMR (400 MHz,
CDCl3): δ 12.18 (s, 1H), 7.80 (s, 1H), 7.33−7.36 (m, 2H), 7.18 (t,
2H), 4.17 (q, 2H), 2.64−2.75 (m, 4H), 1.76−1.81 (m, 4H), 1.29 (t, J1
= 14.4 Hz, J2 = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 176.5,
166.5, 149.8, 131.7, 130.8, 128.2, 128.1, 126.9, 117.0, 116.8, 113.1,
60.4, 26.3, 24.3, 22.9, 22.8, 14.1. HRMS (ESI): calcd for
C18H19FN2O2S2 (M + H)+ 379.0950, found 379.0954.
Methyl 2-(3-(3-(Methylthio)propyl)thioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (33). Yield: 87%. 1H
NMR (400 MHz, CDCl3): δ 12.13 (s, 1H), 6.36 (s, 1H), 3.89 (s,
3H), 3.66−3.67 (m, 2H), 2.76−2.78 (m, 2H), 2.62−2.67 (m, 4H),
2.15 (s, 3H), 2.00−2.05 (m, 2H), 1.79−1.82 (m, 4H). 13C NMR (101
MHz, CDCl3): δ 177.1, 168.0, 151.2, 130.4, 126.3, 111.8, 51.5, 43.2,
31.4, 27.6, 26.2, 24.3, 22.9, 22.8, 15.4. HRMS (ESI): calcd for
C15H22N2O2S3 (M + H)+ 359.0922, found 359.0925.
Methyl 2-(3-(4-(Trifluoromethyl)phenyl)thioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (25). Yield: 89%. 1H
NMR (400 MHz, CDCl3): δ 12.38 (s, 1H), 8.03 (s, 1H), 7.72 (d, J =
8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 3.76 (s, 3H), 2.67−2.75 (m,
4H), 1.79−1.81 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 175.5,
167.0, 149.6, 139.4, 130.9, 127.2, 127.0, 127.0, 127.0, 126.9, 124.5,
113.0, 51.4, 26.2, 24.3, 22.9, 22.7. HRMS (ESI): calcd for
C18H17F3N2O2S2 (M + H)+ 415.0762, found 415.0768.
Ethyl 2-(3-(3-(Methylthio)propyl)thioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (34). Yield: 85%. 1H
NMR (400 MHz, CDCl3): δ 12.18 (s, 1H), 6.36 (s, 1H), 4.34 (q,
2H), 3.65 (s, 2H), 2.77−2.80 (m, 2H), 2.62−2.67 (m, 4H), 2.15 (s,
3H), 1.98−2.05 (m, 2H), 1.80−1.82 (m, 4H), 1.40 (t, J1 = 14.4 Hz, J2
= 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 177.1, 167.5, 151.1,
130.5, 126.2, 112.0, 60.6, 43.2, 31.4, 27.6, 26.3, 24.3, 22.9, 22.8, 15.4,
14.2. HRMS (ESI): calcd for C16H24N2O2S3 (M + H)+ 373.1078,
found 373.1074.
Ethyl 2-(3-(4-(Trifluoromethyl)phenyl)thioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (26). Yield: 90%. 1H
NMR (400 MHz, CDCl3): δ 12.47 (s, 1H), 8.16 (s, 1H), 7.71 (d, J =
8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 4.21 (q, 2H), 2.75−2.77 (m,
2H), 2.65−2.66 (m, 2H) 1.77−1.82 (m, 4H), 1.31 (t, J1= 14 Hz, J2 =
7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 175.4, 166.7, 149.6,
139.5, 130.9, 127.2, 127.0, 126.9, 126.9, 126.9, 124.4, 113.2, 60.6,
26.2, 24.3, 22.9, 22.8, 14.1. HRMS (ESI): calcd for C19H19F3N2O2S2
(M + H)+ 429.0918, found 429.0923.
Ethyl 2-(3-(Naphthalen-1-yl)thioureido)-5,6,7,8-tetrahydro-4H-
Ethyl 2-(3-([1,1′-Biphenyl]-4-yl)thioureido)-5,6-dihydro-4H-
1
cyclohepta[b]thiophene-3-carboxylate (35). Yield: 88%. H NMR
1
cyclopenta[b]thiophene-3-carboxylate (27). Yield: 83%. H NMR
(400 MHz, CDCl3): δ 11.70 (s, 1H), 7.95−8.06 (m, 4H), 7.57−7.61
(m, 4H), 3.84 (q, 2H), 2.91−2.93 (m, 2H), 2.71−2.74 (m, 2H),
1.81−1.82 (m, 2H), 1.65−1.66 (m, 2H), 1.54−1.56 (m, 2H), 1.04 (t,
J1 = 13.6 Hz, J2 = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
177.2, 165.6, 146.9, 136.4, 134.7, 131.6, 130.9, 130.1, 129.2, 128.4,
127.4, 126.8, 125.8, 125.8, 122.4, 114.6, 60.2, 32.1, 28.5, 280, 27.7,
26.9, 13.9. HRMS (ESI): calcd for C23H24N2O2S2 (M + H)+
425.1357, found 425.1359.
(400 MHz, CDCl3): δ 11.99 (s, 1H), 7.96 (s, 1H), 7.71 (d, J = 8.4
Hz, 2H), 7.64 (d, J = 7.2 Hz, 2H), 7.41−7.52 (m, 5H), 4.16 (q, 2H),
2.85−2.91 (m, 4H), 2.33−2.41 (m, 2H), 1.28 (t, J1 = 14.4 Hz, J2 = 7.2
Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 175.6, 165.8, 153.6, 141.2,
140.4, 140.1, 135.0, 132.4, 128.8, 128.6, 127.6, 127.0, 125.5, 109.7,
60.3, 30.4, 28.9, 27.7, 14.1. HRMS (ESI): calcd for C23H22N2O2S2 (M
+ H)+ 423.1201, found 423.1206.
Methyl 2-(3-Phenethylthioureido)-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxylate (28). Yield: 86%. 1H NMR (400 MHz,
CDCl3): δ 12.13 (s, 1H), 7.35 (t, J1= 14.0 Hz, J2 = 7.0 Hz, 2H), 7.28−
7.30 (m, 3H), 6.21 (s, 1H), 3.88 (s, 3H), 3.80 (s, 2H), 3.01 (t, J1 =
14.4 Hz, J2 = 7.2 Hz, 2H), 2.64−2.78 (m, 4H), 1.79−1.81 (m, 4H).
13C NMR (101 MHz, DMSO-d6): δ 177.9, 166.4, 150.9, 139.5, 130.0,
Propyl 2-(3-(Naphthalen-1-yl)thioureido)-5,6-dihydro-4H-
1
cyclopenta[b]thiophene-3-carboxylate (36). Yield: 90%. H NMR
(400 MHz, CDCl3): δ 11.73 (s, 1H), 7.94−8.05 (m, 4H), 7.56−7.62
(m, 4H), 3.85 (t, J1 = 12.8 Hz, J2 = 6.4 Hz, 2H), 2.80−2.85 (m, 4H),
2.29−2.36 (m, 2H), 1.50−1.55 (m, 2H), 0.88 (t, J1 = 14.4 Hz, J2 = 7.2
Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 177.0, 165.5, 153.4, 141.1,
134.7, 132.2, 131.4, 129.9, 129.2, 128.5, 127.4, 126.8, 125.8, 125.6,
122.1, 109.8, 65.7, 30.3, 28.8, 27.7, 21.8, 10.5. HRMS (ESI): calcd for
C22H22N2O2S2 (M + H)+ 411.1201, found 411.1206.
129.0, 128.9, 126.6, 125.0, 111.0, 51.8, 45.9, 34.3, 26.2, 24.0, 23.0,
22.8. HRMS (ESI): calcd for C19H22N2O2S2 (M + H)+ 375.1201,
found 375.1205.
Methyl 2-(3-(Naphthalen-1-yl)thioureido)-5,6-dihydro-4H-
Propyl 2-(3-(Naphthalen-1-yl)thioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (37). Yield: 91%. 1H
NMR (400 MHz, CDCl3): δ 11.98 (s, 1H), 7.93−8.11 (m, 4H),
7.54−7.61 (m, 4H), 3.81 (t, J1 = 12.8 Hz, J2 = 6.4 Hz, 2H), 2.62−2.67
(m, 4H), 1.73−1.79 (m, 4H), 1.46−1.52 (m, 2H), 0.86 (t, J1 = 14.4
Hz, J2 = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 177.3, 165.9,
149.6, 134.7, 131.6, 130.7, 130.0, 129.2, 128.4, 127.3, 126.7, 126.6,
125.7, 122.3, 113.0, 65.8, 26.2, 24.2, 22.9, 22.8, 21.8, 10.5. HRMS
(ESI): calcd for C23H24N2O2S2 (M + H)+ 425.1357, found 425.1354.
Isopropyl 2-(3-(Naphthalen-1-yl)thioureido)-5,6-dihydro-4H-
1
cyclopenta[b]thiophene-3-carboxylate (29). Yield: 95%. H NMR
(400 MHz, CDCl3): δ 11.57 (s, 1H), 7.96−8.06 (m, 4H), 7.58−7.63
(m, 4H), 3.47 (s, 3H), 2.78−2.85 (m, 4H), 2.29−2.36 (m, 2H). 13C
NMR (101 MHz, CDCl3): δ 176.9, 165.5, 153.3, 141.2, 134.7, 132.3,
131.3, 130.0, 129.3, 128.5, 127.5, 126.9, 125.8, 125.7, 122.1, 109.5,
51.1, 30.2, 28.8, 27.7. HRMS (ESI): calcd for C20H18N2O2S2 (M +
H)+ 383.0888, found 383.0892.
Methyl 2-(3-(Naphthalen-1-yl)thioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (30). Yield: 93%. 1H
NMR (400 MHz, CDCl3): δ 11.73 (s, 1H), 8.15 (s, 1H), 8.03−8.05
(m, 1H), 7.95−7.99 (m, 2H), 7.56−7.62 (m, 4H), 3.38 (s, 3H),
2.62−2.64 (m, 4H), 1.70−1.78 (m, 4H). 13C NMR (101 MHz,
CDCl3): δ 177.3, 165.8, 149.3, 134.7, 131.5, 130.9, 130.0, 129.3,
128.5, 127.5, 126.9, 126.7, 125.8, 122.2, 112.9, 50.8, 26.0, 24.2, 22.9,
1
cyclopenta[b]thiophene-3-carboxylate (38). Yield: 92%. H NMR
(400 MHz, CDCl3): δ 11.79 (s, 1H), 7.94−8.08 (m, 4H), 7.55−7.61
(m, 4H), 4.75−4.81 (m, 1H), 2.78−2.84 (m, 4H), 2.28−2.35 (m,
2H), 1.10 (d, J = 6.4 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 176.9,
165.5, 153.3, 141.2, 134.7, 132.3, 131.4, 130.0, 129.3, 128.5, 127.5,
7383
J. Med. Chem. 2021, 64, 7371−7389