T. Nagata et al. / Bioorg. Med. Chem. 17 (2009) 1193–1206
1201
chloride, and then 1 N HCl in ethanol (171
l
L) was added. The
37Cl]. Anal. Calcd for C26H31ClN6O3SꢃHClꢃ1.5H2O: C, 51.48; H,
5.82; Cl, 11.69; N, 13.85; S, 5.29. Found: C, 51.37; H, 5.89; Cl,
12.11; N, 13.77; S, 5.45.
solvent was distilled away under reduced pressure, and methanol
and diethyl ether were added to the residue to collect the precip-
itate formed by filtration to give 4a (74 mg, 41%) as a colorless
powder.
5.13. N-{(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-
[ethyl(methyl)carbamoyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahy-
drothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride (4d)
1H NMR (DMSO-d6) d: 0.99 (3H, t, J = 7.2 Hz), 1.57ꢀ2.02 (6H,
m), 2.33ꢀ2.38 (1H, m), 2.92 (3H, s), 3.01ꢀ3.08 (2H, m),
3.17ꢀ3.20 (2H, s), 3.45ꢀ3.70 (2H, m), 4.10ꢀ4.17 (1H, m),
4.40ꢀ4.69 (3H, m), 7.04 (1H, d, J = 2.0 Hz), 7.17 (1H, dd, J = 8.8,
2.0 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.69 (1H, d, J = 2.0 Hz), 7.78ꢀ7.81
(1H, m), 8.08ꢀ8.12 (1H, m), 8.40 (1H, d, J = 8.1 Hz), 11.23 (1H, br
s), 11.79 (1H, br s); MS (FAB) m/z 543 [(M+H)+, 35Cl], 545
[(M+H)+, 37Cl]. Anal. Calcd for C26H31ClN6O3SꢃHClꢃ2.2H2O: C,
50.44; H, 5.93; Cl, 11.45; N, 13.57; S, 5.28. Found: C, 50.29; H,
5.89; Cl, 11.60; N, 13.56; S, 5.29.
Compound 4d was synthesized from 12 and ethylmethylamine
according to the same procedure described for 4a, as a pale yellow
solid (85 mg, 52%).
1H NMR (DMSO-d6) d: 0.93ꢀ1.13 (3H, m), 1.40ꢀ1.64 (1H, m),
1.64ꢀ1.88 (3H, m), 1.88ꢀ2.10 (2H, m), 2.76 (1/2 of 3H, s), 2.90
(3H, s), 2.93 (1/2 of 3H, s), 3.10ꢀ3.80 (7H, m), 4.05ꢀ4.17 (1H, m),
4.30ꢀ4.85 (3H, m), 7.04 (1H, s), 7.15 (1H, dd, J = 8.8, 1.7 Hz), 7.40
(1H, d, J = 8.8 Hz), 7.67 (1H, s), 8.30ꢀ8.50 (2H, m), 11.29 (1H, br
s), 11.77 (1H, s); MS (FAB) m/z 557 [(M+H)+, 35Cl], 559 [(M+H)+,
37Cl]. Anal. Calcd for C27H33ClN6O3SꢃHClꢃ1.5 H2O: C, 52.26; H,
6.01; Cl, 11.43; N, 13.54; S, 5.17. Found: C, 52.27; H, 5.85; Cl,
11.70; N, 13.41; S, 5.33.
5.11. N-[(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-
(isopropylcarbamoyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahy-
drothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride (4b)
Compound 4b was synthesized from 12 and isopropylamine
according the same procedure described for 4a, colorless powder
(125 mg, 77%).
5.14. N-[(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-
(diethylcarbamoyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydro-
thiazolo[5,4-c]pyridine-2-carboxamide hydrochloride (4e)
1HNMR(DMSO-d6)d:1.02(6H, dd, J = 6.5, 2.5 Hz), 1.50ꢀ2.10(6H,
m), 2.30 (1H, t, J = 12.0 Hz), 2.91 (3H, s), 3.10ꢀ3.75 (4H, m),
3.75ꢀ3.90 (1H, m), 4.07ꢀ4.20 (1H, m), 4.30ꢀ4.57 (2H, br s),
4.57ꢀ4.83 (1H, br s), 7.03 (1H, d, J = 1.5 Hz), 7.16 (1H, dd, J = 8.8,
2.1 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.60ꢀ7.75 (2H, m), 8.05 (1H, br s),
8.43 (1H, br d, J = 7.8 Hz), 11.63 (1H, br s), 11.79 (1H, s); MS (FAB)
m/z 557 [(M+H)+, 35Cl], 559 [(M+H)+, 37Cl]. Anal. Calcd for
C27H33ClN6O3SꢃHClꢃ2.5H2O: C, 50.78; H, 6.16; Cl, 11.10; N, 13.16; S,
5.02. Found: C, 50.78; H, 6.03; Cl, 11.24; N, 13.06; S, 5.21.
Compound 4e was synthesized from 12 and diethylamine
according to the same procedure described for 4a, as a colorless so-
lid (125 mg, 50%).
1H NMR (DMSO-d6) d: 0.99, 1.05 (6H, each t, J = 7.1 Hz),
1.53ꢀ1.61 (1H, m), 1.74ꢀ1.80 (3H, m), 1.96ꢀ2.05 (2H, m),
2.88ꢀ2.95 (4H, m), 3.17ꢀ3.67 (8H, m), 4.11ꢀ4.16 (1H, m), 4.45
(1H, br s), 4.55ꢀ4.58 (1H, m), 4.66 (1H, br s), 7.06 (1H, d,
J = 2.0 Hz), 7.16 (1H, dd, J = 8.9, 1.9 Hz), 7.42 (1H, d, J = 8.9 Hz),
7.69 (1H, d, J = 1.9 Hz), 8.41 (2H, d, J = 7.8 Hz), 11.65 (1H, br s),
11.81 (1H, br s); MS (FAB) m/z 571 [(M+H)+, 35Cl], 573 [(M+H)+,
37Cl]. Anal. Calcd for C28H35ClN6O3SꢃHClꢃH2O: C, 53.76; H, 6.12;
Cl, 11.33; N, 13.43; S, 5.13. Found: C, 53.45; H, 5.99; Cl, 11.59; N,
13.36; S, 5.29.
5.12. N-[(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-
(dimethylcarbamoyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahy-
drothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride (4c)
Compound 12 (900 mg, 1.74 mmol) was dissolved in N,N-
dimethylformamide (50 mL), and then dimethylamine hydrochlo-
ride (304 mg, 3.73 mmol), 1-hydroxybenzotriazole monohydrate
(262 mg, 1.71 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodi-
imide hydrochloride (369 mg, 1.93 mmol) and diisopropylethyl-
amine (1.83 mL, 10.5 mmol) were added, and the mixture was
stirred at room temperature for 12 h. The solvent was distilled
away under reduced pressure, and saturated aqueous sodium
hydrogencarbonate was added to the residue, followed by extrac-
tion with methylene chloride. The resultant organic layer was
dried over sodium sulfate anhydrate. The solvent was distilled
away under reduced pressure, and the resultant residue was puri-
fied by silica gel column chromatography (methylene chlo-
ride:methanol = 47:3). The thus-obtained white solids were
dissolved in methylene chloride, and then 1 N HCl in ethanol
(1.49 mL) was added. The solvent was distilled away under re-
duced pressure, and methanol and diethyl ether were added to
the residue to collect the precipitate formed by filtration to give
4c (777 mg, 74%) as a white solid.
5.15. N-[(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-
(dipropylcarbamoyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydro-
thiazolo[5,4-c]pyridine-2-carboxamide hydrochloride (4f)
Compound 4f was synthesized from 12 and dipropylamine
according to the same procedure described for 4a, as a colorless so-
lid (78 mg, 30%).
1HNMR(DMSO-d6)d:0.69(3H,t,J = 7.3 Hz),0.79(3H,t,J = 7.3 Hz),
1.38ꢀ1.47(4H, m), 1.57ꢀ1.78(4H, m), 1.98ꢀ2.01(2H, m), 2.80(1H, t,
J = 11.5 Hz),2.91(3H,s),3.01ꢀ3.39(6H,m),3.48(1H,brs),3.68(1H,br
s),4.13ꢀ4.16(1H,m),4.43(1H,brs),4.48ꢀ4.50(1H,m),4.68(1H,brs),
7.04 (1H, d, J = 2.0 Hz), 7.16 (1H, dd, J = 8.8, 2.2 Hz), 7.41 (1H, d,
J = 8.8 Hz), 7.70 (1H, d, J = 2.2 Hz), 8.33 (1H, d, J = 7.6 Hz), 8.41 (1H,
d, J = 8.0 Hz), 11.27ꢀ11.40 (1H, m), 11.80 (1H, br s); MS (FAB) m/z
599 [(M+H)+, 35Cl], 601 [(M+H)+, 37Cl]. Anal. Calcd for
C39H39ClN6O3SꢃHClꢃ1.5H2O: C, 54.37; H, 6.54; Cl, 10.70; N, 12.68; S,
4.84. Found: C, 54.21; H, 6.44; Cl, 10.88; N, 12.59; S, 4.97.
Mp 248–254 °C (dec); ½a D18
= ꢀ53.9 (c 0.505, methanol); enantio-
ꢂ
meric excess: >99% (column: CHIRALPAK AD-H, 0.46 ꢁ 25 cm, flow:
3.0 mL/min, eluent: hexane/isopropropanol/diethylamine = 65/35/
0.5); 1H NMR (DMSO-d6) d: 1.45ꢀ1.60 (1H, m), 1.70ꢀ1.85 (3H,
m), 1.90ꢀ2.05 (2H, m), 2.80 (3H, s), 2.91 (3H, s), 2.95ꢀ3.10 (1H,
m), 2.97 (3H, s), 3.10ꢀ3.75 (4H, m), 4.05ꢀ4.15 (1H, m),
4.35ꢀ4.75 (3H, m), 7.05 (1H, s), 7.16 (1H, dd, J = 8.7, 2.1 Hz), 7.41
(1H, d, J = 8.6 Hz), 7.67 (1H, s), 8.30ꢀ8.45 (2H, m), 11.63 (1H, br),
11.78 (1H, s); MS (FAB) m/z 543 [(M+H)+, 35Cl], 545 [(M+H)+,
5.16. N-[(1R,2S,5S)-2-{[(5-Chloroindol-2-yl)carbonyl]amino}-5-
(pyrrolidin-1-ylcarbonyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahy-
drothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride (4g)
Compound 4g was synthesized from 12 and pyrrolidine accord-
ing to the procedure described for 4a, as a pale yellow solid (67 mg,
40%).