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T. Kondo et al. / Bioorg. Med. Chem. 16 (2008) 1613–1631
4.1.23. tert-Butyl (2S,4S)-2-(1-pyrrolidinylcarbonyl)-4-
({4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]-1-piperazi-
nyl}carbonyl)-1-pyrrolidinecarboxylate (35h). Yield 99%.
A brown powder. TLC Rf = 0.35 (CH2Cl2/MeOH, 9:1);
1H NMR (300 MHz, CDCl3) d 1.40 and 1.45 (s, 9H),
1.78–2.06 (m, 4H), 2.30–2.59 (m, 2H), 3.07–4.02 (m,
15H), 4.34–4.58 (m, 1H).
Rf = 0.52 (CHCl3/MeOH/AcOH, 75:20:5); MS (FAB,
pos.) m/z 379 (M+H)+; IR (KBr) 3400, 3053, 1647,
1553, 1466, 1434, 1354, 1298, 1236, 1170 cmꢀ1 1H
;
NMR (300 MHz, DMSO-d6) d 1.72–1.96 (m, 5H), 2.29
(s, 3H), 2.62–2.84 (m, 1H), 3.14–3.77 (m, 15H), 4.33–
4.56 (m, 1H), 8.66 (s, 1H), 10.38 (s, 1H); HRMS
(FAB) calcd for C17H26N6O2S: 379.1916. Found:
379.1917.
4.1.24. tert-Butyl (2S,4S)-4-{[4-(3-phenyl-1,2,4-thia-
diazol-5-yl)-1-piperazinyl]carbonyl}-2-(1-pyrrolidinyl-
carbonyl)-1-pyrrolidinecarboxylate (35i). To a stirred
solution of 29a (200 mg, 0.32 mmol) in CH2Cl2 (1 mL)
were added 3-phenyl-5-piperazino-1,2,4-thiadiazole in
1,2-dichloroethane (0.5 M, 1.4 mL), 1-hydroxybenzotri-
azole (95 mg, 0.70 mmol), and 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (134 mg,
0.70 mmol) at room temperature. After being stirred
for 19 h, the reaction mixture was poured into water
and extracted with CH2Cl2. The organic layer was
washed with 10% aqueous citric acid, aqueous NaH-
CO3, brine, then dried over MgSO4, and evaporated to
give 35i (255 mg, 74%) as a white powder. TLC
Rf = 0.75 (EtOAc/MeOH, 5:1); 1H NMR (300 MHz,
DMSO-d6) d 1.30 and 1.38 (s, 9H), 1.71–2.00 (m, 4H),
2.40–2.55 (m, 2H), 3.20–3.84 (m, 15H), 4.30–4.42 (m,
1H), 7.42–7.50 (m, 3H), 8.05–8.14 (m, 2H).
4.1.28. 1-(3-Methyl-1,2,4-thiadiazol-5-yl)-4-{[(3S,5S)-5-
(1-pyrrolidinylcarbonyl)-3-pyrrolidinyl]carbonyl}-1,4-dia-
zepane hydrochloride (10). Yield 90%. A white powder.
TLC Rf = 0.25 (CH2Cl2/MeOH/AcOH, 8:1:1); MS
(APCI, pos.) m/z 393 (M+H)+; IR (KBr) 3378, 2925,
2878, 2711, 1645, 1455, 1361, 1254, 1153, 1040 cmꢀ1
;
1H NMR (300 MHz, DMSO-d6) d 1.70–2.03 (m, 7H),
2.28 (s, 3H), 2.58–2.75 (m, 1H), 3.20–3.94 (m, 15H),
4.36–4.56 (m, 1H), 7.85–9.00 (m, 1H), 10.17–11.25 (m,
1H); HRMS (FAB) calcd for C18H28N6O2S: 393.2073.
Found: 393.2079.
4.1.29. 1-{[(3S,5S)-5-(1-Pyrrolidinylcarbonyl)-3-pyrrolid-
inyl]carbonyl}-4-(1,2,4-thiadiazol-5-yl)piperazine hydro-
chloride (18). Yield 100%. A white powder. TLC
Rf = 0.17 (CHCl3/MeOH, 9:1); MS (ESI, pos.) m/z 365
(M+H)+; IR (KBr) 3410, 2973, 2881, 1646, 1553, 1448,
1375, 1349, 1284, 1239 cmꢀ1 1H NMR (300 MHz,
;
According to the same procedures as described for the
preparation of 35a from 33a and 29a, compounds 35j
were prepared from 33a and 29b.
DMSO-d6) d 1.74–1.96 (m, 5H), 2.66–2.82 (m, 1H),
3.25–3.77 (m, 15H), 4.32–4.53 (m, 1H), 8.06 (s, 1H),
8.53–8.80 (m, 1H), 10.25–10.48 (m, 1H); HRMS
(FAB) calcd for C16H24N6O2S: 365.176. Found:
365.175.
4.1.25. tert-Butyl (2S,4S)-4-{[4-(3-methyl-1,2,4-thiadiazol-
5-yl)-1-piperazinyl]carbonyl}-2-(1,3-thiazolidin-3-ylcarbon-
yl)-1-pyrrolidinecarboxylate (35j). Yield 91%. A colorless
oil. TLC Rf = 0.40 (EtOAc/MeOH, 5:1); MS (ESI, pos.)
m/z 497 (M+H)+; 1H NMR (300 MHz, DMSO-d6) d
1.30 and 1.38 (s, 9H), 1.71–2.09 (m, 2H), 2.29 (s, 3H),
2.89–3.18 (m, 2H), 3.33–3.84 (m, 13H), 4.30–4.70 (m,
3H).
4.1.30. 1-(3-Ethyl-1,2,4-thiadiazol-5-yl)-4-{[(3S,5S)-5-(1-
pyrrolidinylcarbonyl)-3-pyrrolidinyl]carbonyl}piperazine
hydrochloride (19). Yield 69%. A white powder. TLC
Rf = 0.31 (CHCl3/MeOH, 9:1); MS (APCI, pos.) m/z
393 (M+H)+; IR (KBr) 3409, 1648, 1552, 1452, 1376,
1354, 1240, 1033, 1008 cmꢀ1 1H NMR (300 MHz,
;
DMSO-d6) d 1.19 (t, 3H), 1.71–2.00 (m, 5H), 2.62 (q,
J = 7.6 Hz, 2H), 2.68–2.82 (m, 1H), 3.25–3.62 (m,
15H), 4.34–4.54 (m, 1H), 8.56–8.78 (m, 1H), 10.06–
10.29 (m, 1H); HRMS (FAB) calcd for C18H28N6O2S:
393.2073. Found: 393.2076.
4.1.26. 1-(3-Phenyl-1,2,4-thiadiazol-5-yl)-4-{[(3S,5S)-5-
(1-pyrrolidinylcarbonyl)-3-pyrrolidinyl]carbonyl}piperazine
hydrochloride (8). To a stirred solution of 35i (255 mg,
0.47 mmol) in EtOH (10 mL) was added 4 N hydrogen
chloride in EtOAc (1 mL). The resulting suspension
was stirred at room temperature for 16 h. The reaction
mixture was concentrated in vacuo. The resulting solid
was washed with EtOAc to yield 8 (234 mg, 100%) as
an ivory powder. TLC Rf = 0.30 (CHCl3/MeOH, 9:1);
MS (FAB, pos.) m/z 441 (M+H)+; IR (KBr) 3400,
3053, 1647, 1553, 1466, 1434, 1354, 1298, 1236,
4.1.31. 1-(3-Propyl-1,2,4-thiadiazol-5-yl)-4-{[(3S,5S)-5-
(1-pyrrolidinylcarbonyl)-3-pyrrolidinyl]carbonyl}piperazine
hydrochloride (20). Yield 100%. A white powder. TLC
Rf = 0.58 (CHCl3/MeOH, 5:1); MS (FAB, pos.) m/z
407 (M+H)+; IR (KBr) 3410, 2966, 2877, 1645, 1555,
1451, 1371, 1285, 1239 cmꢀ1 1H NMR (300 MHz,
;
1170 cmꢀ1
;
1H NMR (300 MHz, DMSO-d6) d 1.71–
DMSO-d6) d 0.89 (t, J = 7.4 Hz, 3H), 1.58–1.75 (m,
2H), 1.75–1.97 (m, 5H), 2.58 (t, J = 7.4 Hz, 2H), 2.67–
2.83 (m, 1H), 3.16–3.85 (m, 15H), 4.30–4.58 (m, 1H),
8.67 (s, 1H), 10.32 (s, 1H); HRMS (FAB) calcd for
C19H30N6O2S: 407.2229. Found: 407.2232.
1.98 (m, 5H), 2.65–2.87 (m, 1H), 3.22–3.82 (m, 15H),
4.35–4.55 (m, 1H), 7.40–7.52 (m, 3H), 8.03–8.17 (m,
2H), 8.69 (s, 1H), 9.97 (s, 1H).
According to the same procedures as described for the
preparation of 8 from 35i, compounds 9–10, 18–24 were
prepared from 35a–h, 35j, respectively.
4.1.32. 1-(3-Isopropyl-1,2,4-thiadiazol-5-yl)-4-{[(3S,5S)-
5-(1-pyrrolidinylcarbonyl)-3-pyrrolidinyl]carbonyl}pipera-
zine hydrochloride (21). Yield 86%. A white powder.
TLC Rf = 0.58 (CHCl3/MeOH, 5:1); MS (FAB, pos.)
m/z 407 (M+H)+; IR (KBr) 3409, 2974, 2879, 2735,
4.1.27. 1-(3-Methyl-1,2,4-thiadiazol-5-yl)-4-{[(3S,5S)-5-
(1-pyrrolidinylcarbonyl)-3-pyrrolidinyl]carbonyl}piperazine
hydrochloride (9). Yield 87%. A white powder. TLC
1644, 1555, 1451, 1385, 1349, 1284 cmꢀ1 1H NMR
;