998 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6
Stewart et al.
7.89 (br s, 1H), 8.26 (s, 1H), 8.35 (s, 1H), 8.54 (br s, 1H) 9.16
(s, 1H); MS (DCI/NH3) m/z 301 (M + H)+. Anal. (C15H12N2-
OS2) C, H, N.
Compounds 38, 57, and 58 were prepared from acid 54 in
analogy to the procedure for compound 7.
N-Meth oxy-N-m eth yl-4-[(4-m eth ylp h en yl)th io]th ien o-
[2,3-c]p yr id in e-2-ca r boxa m id e (38): mp 103-107 °C; 1H
NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 3.34 (s, 3H), 3.74
(s, 3H), 7.19 (m, 2H), 7.27 (m, 2H), 8.02 (s, 1H), 8.46 (s, 1H);
MS (DCI/NH3) m/z 345 (M + H)+. Anal. (C17H16N2O2S2) C, H,
N.
N-Meth oxy-4-[(4-m eth ylp h en yl)th io]th ien o[2,3-c]p yr i-
d in e-2-ca r boxa m id e (57): mp 200-203 °C; 1H NMR (300
MHz, DMSO-d6) δ 2.29 (s, 3H), 3.76 (s, 3H), 7.20 (m, 2H), 7.30
(m, 2H), 7.89 (br s, 1H), 8.15 (s, 1H), 8.4 (s, 1H), 9.3 (s, 1H);
MS (DCI/NH3) m/z 331 (M + H)+. Anal. (C16H14N2O2S2‚
0.25H2O) C, H, N.
9.15 (s, 1H); MS (APCI) m/z 315 (M + H)+. Anal. (C16H14N2-
OS2‚0.25H2O) C, H, N.
4-[(3,5-Dim et h ylp h en yl)t h io]t h ien o[2,3-c]p yr id in e-2-
ca r boxa m id e (71): mp 177-179 °C; 1H NMR (300 MHz,
DMSO-d6) δ 2.13 (s, 6H), 6.83 (s, 1H), 6.92 (s, 1H), 7.81 (br s,
1H), 8.21 (s, 1H), 8.30 (s, 1H), 8.50 (br s, 1H), 9.19 (s, 1H); MS
(DCI/NH3) m/z 315 (M + H)+. Anal. (C16H14N2OS2) C, H, N.
4-[(2,4-Dim et h ylp h en yl)t h io]t h ien o[2,3-c]p yr id in e-2-
ca r boxa m id e (72): mp 193-195 °C; 1H NMR (300 MHz,
DMSO-d6) δ 2.28 (s, 3H), 2.38 (s, 3H), 7.02 (d, J ) 6 Hz, 1H),
7.13 (d, J ) 6 Hz, 1H), 7.20 (s, 1H), 7.91 (br s, 1H), 8.05 (s,
1H), 8.58 (br s, 1H), 9.22 (s, 1H); MS (APCI) m/z 315 (M +
H)+. Anal. (C16H14N2OS2‚0.25H2O) C, H, N.
4-[[4-(Tr iflu or om eth yl)p h en yl]th io]th ien o[2,3-c]p yr i-
d in e-2-ca r boxa m id e (73): 1H NMR (300 MHz, DMSO-d6) δ
7.31 (d, J ) 8 Hz, 2H), 7.65 (d, J ) 8 Hz, 2H), 7.85 (br s, 1H),
8.19 (s, 1H), 8.50 (br s, 1H), 8.68 (s, 1H), 9.44 (s 1H); MS (DCI/
NH3) m/z 355 (M + H)+. Anal. (C15H9F3N2OS2) C, H, N.
N-(4-Ch lor op h en yl)-4-[(4-m et h ylp h en yl)t h io]t h ien o-
[2,3-c]p yr id in e-2-ca r boxa m id e (58): mp 208-211 °C; 1H
NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 7.23 (m, 2H), 7.33
(m, 2H), 7.47 (m, 2H), 7.81 (m, 2H), 8.34 (s, 1H), 8.57 (s, 1H),
9.31 (s, 1H), 10.90 (br s, 1H); MS (DCI/NH3) m/z 411 (M +
H)+. Anal. (C12H15ClN2OS2) C, H, N.
4-[(4-Ch lor op h en yl)t h io]t h ien o[2,3-c]p yr id in e-2-ca r -
boxa m id e (74): mp 239-241 °C; 1H NMR (300 MHz, DMSO-
d6) δ 7.31 (m, 2H), 7.43 (m, 2H), 7.89 (br s, 1H), 8.24 (s, 1H),
8.54 (br s, 1H), 8.56 (s, 1H), 9.38 (s, 1H); MS (DCI/NH3) m/z
321 (M + H)+. Anal. (C14H9ClN2OS2) C, H, N.
4-[(3,4-Dich lor op h en yl)t h io]t h ien o[2,3-c]p yr id in e-2-
ca r boxa m id e (75): 1H NMR (300 MHz, DMSO-d6) δ 7.10 (dd,
J ) 2, 8 Hz, 1H), 7.55 (d, J ) 8 Hz, 1H), 7.59 (d, J ) 8 Hz,
1H), 7.91 (br s, 1H), 8.21 (s, 1H), 8.53 (br s, 1H), 8.62 (s, 1H),
9.41 (s, 1H); MS (ESI) m/z 355 (M + H)+. Anal. (C14H8Cl2N2-
OS2) C, H, N.
4-Ch lor oth ien o[2,3-c]p yr id in e-2-ca r boxa m id e (20). Al-
dehyde 14 was treated with 1 equiv of methyl thioglycollate
as described for ester 55 to provide 4-chlorothienopyridine
20: 1H NMR (300 MHz, DMSO-d6) δ 7.93 (br s, 1H, NH), 8.28
(s, 1H), 8.55 (br s, 1H, NH), 8.58 (s, 1H), 9.28 (s, 1H); MS (DCI/
NH3) m/z 213 (M + H)+. Anal. (C8H5ClN2OS) C, H, N.
4-[(4-Br om op h en yl)t h io]t h ien o[2,3-c]p yr id in e-2-ca r -
boxa m id e (76): 1H NMR (300 MHz, DMSO-d6) δ 7.20 (dt,
J ) 2, 8 Hz, 2H), 7.53 (dt, J ) 2, 8 Hz, 2H), 7.87 (br s, 1H),
8.21 (s, 1H), 8.51 (br s, 1H), 8.54 (s, 1H), 9.36 (s, 1H); MS (DCI/
NH3) m/z 365 (M + H)+. Anal. (C14H9BrN2OS2) C, H, N.
4-[(4-Meth oxyp h en yl)th io]th ien o[2,3-c]p yr id in e-2-ca r -
boxa m id e (77): mp 219-221 °C; 1H NMR (300 MHz, DMSO-
d6) δ 3.76 (s, 3H), 6.99 (d, J ) 8 Hz, 2H), 7.46 (d, J ) 8 Hz,
2H), 7.89 (br s, 1H), 8.17 (s, 1H), 8.30 (s, 1H), 8.54 (br s, 1H),
9.18 (s, 1H); MS (ESI) m/z 317 (M + H)+. Anal. (C15H12N2O2S2)
C, H, N.
4-(4-Bip h en ylylt h io)t h ien o[2,3-c]p yr id in e-2-ca r b oxa -
m id e (78): 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.42 (m,
2H), 7.46 (td, J ) 1.5, 7 Hz, 2H), 7.5-7.7 (br m, 4H), 7.91 (s,
1H), 8.30 (d, J ) 0.8 Hz, 1H), 8.54 (s, 1H), 8.57 (s, 1H), 9.37
(s, 1H); MS (DCI/NH3) m/z 363 (M + H)+. Anal. (C20H14N2-
OS2) C, H, N.
4-(2-P yr id in ylt h io)t h ie n o[2,3-c]p yr id in e -2-ca r b ox-
a m id e (79): mp 239-242 °C; 1H NMR (300 MHz, DMSO-
d6) δ 6.99 (d, 1H), 7.17 (dd, 1H), 7.65 (dt, 1H), 7.85 (br s, 1H),
8.18 (s, 1H), 8.36 (m, 1H), 8.49 (br s, 1H), 8.69 (s, 1H), 9.23 (s,
1H); MS (DCI/NH3) m/z 305 (M + NH4)+. Anal. (C13H9N3OS2)
C, H, N.
4-[(2-Am in o-2-oxoet h yl)t h io]t h ien o[2,3-c]p yr id in e-2-
ca r boxa m id e (21). Reaction of 14 with an excess of methyl
thioglycollate, in analogy to that described for compound 55,
provided methyl 4-[(2-methoxy-2-oxoethyl)thio]thieno[2,3-c]-
pyridine-2-carboxylate: 1H NMR (500 MHz, DMSO-d6) δ 3.59
(s, 3H), 3.94 (s, 3H), 4.04 (s, 2H), 8.14 (s, 1H), 8.55 (s, 1H),
9.27 (s, 1H); MS (DCI/NH3) m/z 298 (M + H)+. The derived
ester was dissolved in 2 M methanolic ammonia and warmed
to 45 °C in a sealed tube for 18 h. The precipitate was filtered,
washed with methanol-diethyl ether (1:1) and dried under
vacuum to provide a 36% yield of diamide 21: 1H NMR (400
MHz, DMSO-d6) δ 3.81 (s, 2H), 7.17 (br s, 1H), 7.59 (br s, 1H),
7.82 (br s, 1H), 8.29 (br s, 1H), 8.46 (s, 1H), 8.52 (br s, 1H),
9.14 (s, 1H); 13C NMR (100 MHz, DMSO) δ 36.5 (S-CH2), 122.5
(CH), 127.7 (3-C), 136.2 (7a-C), 142.5 (5-CH), 143.2 (7-CH),
144.0 (Ar-C), 146.5 (Ar-C), 162.6 (CONH2), 169.4 (CONH2); MS
(APCI) m/z 268 (M + H)+; HRMS calcd for C10H9N3O2S2 (M+),
267.0138; found, 267.0136. Anal. (C10H9N3O2S2‚H2O) C, H; N:
calcd, 14.73; found, 13.93.
Compounds 67-83 were prepared from dichloropyridine-
carboxaldehyde 14 in analogy to that described for compound
7, using the appropriate aryl- or alkylthiol.
4-(P h en ylth io)th ien o[2,3-c]pyr idin e-2-car boxam ide (67):
1H NMR (300 MHz, DMSO-d6) δ 7.29-7.40 (m, 5H), 7.86 (br
s, 1H), 8.25 (s, 1H), 8.46 (s, 1H), 8.52 (br s, 1H), 9.31 (s, 1H);
MS (DCI/NH3) m/z 287 (M + H)+. Anal. (C14H10N2OS2) C, H,
N.
4-[(2-Met h ylp h en yl)t h io]t h ien o[2,3-c]p yr id in e-2-ca r -
boxa m id e (68): mp 170-172 °C; 1H NMR (300 MHz, DMSO-
d6) δ 2.41 (s, 3H), 7.04 (dd, J ) 1, 8 Hz, 1H), 7.15 (dt, J ) 1.5,
7 Hz, 1H), 7.27 (dt, J ) 1.5, 7.5 Hz, 1H), 7.38 (br d, J ) 7.5
Hz, 1H), 7.86 (br s, 1H), 8.20 (s, 1H), 8.23 (s, 1H), 8.53 (br s,
1H), 9.28 (s, 1H); MS (DCI/NH3) m/z 301 (M + H)+. Anal.
(C15H12N2OS2) C, H, N.
4-[(3-Met h ylp h en yl)t h io]t h ien o[2,3-c]p yr id in e-2-ca r -
boxa m id e (69): mp 171-173 °C; 1H NMR (300 MHz, DMSO-
d6) δ 2.27 (s, 3H), 7.06-713 (m, 2H), 7.21-7.27 (m, 2H), 7.89
(br s, 1H), 8.26 (s, 1H), 8.42 (s, 1H), 8.55 (br s, 1H), 9.30 (s,
1H); MS (DCI/NH3) m/z 301 (M + H)+. Anal. (C15H12N2OS2‚
0.25H2O) C, H, N.
4-[(5-Meth yl-1,3,4-th ia d ia zol-2-yl)th io]th ien o[2,3-c]p yr -
1
id in e-2-ca r boxa m id e (80): mp 240-243 °C; H NMR (300
MHz, DMSO-d6) δ 2.60 (s, 3H), 7.92 (br s, 1H), 8.32 (s, 1H),
8.56 (br s, 1H), 8.82 (s, 1H), 9.50 (s, 1H); MS (DCI/NH3) m/z
309 (M + H)+, 326 (M + NH4)+. Anal. (C11H8N4OS3) H; C:
calcd, 42.84; found, 43.43; N: calcd, 18.17; found, 17.27.
4-[(2-Met h yl-3-fu r a n yl)t h io]t h ien o[2,3-c]p yr id in e-2-
ca r boxa m id e (81): mp 236-239 °C dec; 1H NMR (300 MHz,
DMSO-d6) δ 2.41 (s, 3H), 6.68 (d, J ) 1.5 Hz, 1H), 7.74 (d,
J ) 1.5 Hz, 1H), 7.93 (br s, 1H), 8.19 (s, 1H), 8.38 (s, 1H), 8.60
(br s, 1H), 9.15 (s, 1H); MS (ESI) m/z 291 (M + H)+. Anal.
(C13H10N2O2S2‚0.25H2O) C, H, N.
4-(Cycloh e xylt h io)t h ie n o[2,3-c]p yr id in e -2-ca r b ox-
a m id e (82): mp 205-207 °C; 1H NMR (300 MHz, DMSO-
d6) δ 1.14-1.43 (br m, 6H), 1.51-1.61 (br m, 1H), 1.66-1.78
(br m, 2H), 1.83-1.98 (br m, 2H), 7.90 (br s, 1H), 8.33 (s, 1H),
8.52 (s, 1H), 8.57 (br s, 1H), 9.22 (s, 1H); MS (ESI) m/z 293
(M + H)+. Anal. (C14H16N2OS2) C, H, N.
4-[(3,4-Dim et h ylp h en yl)t h io]t h ien o[2,3-c]p yr id in e-2-
ca r boxa m id e (70): mp 192-194 °C; 1H NMR (300 MHz,
DMSO-d6) δ 2.09 (s, 3H), 2.11 (s, 3H), 7.05 (m, 2H), 7.19 (s,
1H) 7.81 (br s, 1H), 8.12 (d, J ) 6 Hz, 2H), 8.49 (br s, 1H),
4-[[(4-Ch lor oph en yl)m eth yl]th io]th ien o[2,3-c]pyr idin e-
1
2-ca r boxa m id e (83): mp 198-199 °C; H NMR (300 MHz,
DMSO-d6) δ 4.40 (s, 2H), 7.31 (s, 4H), 7.86 (br s, 1H), 8.26 (s,