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D. Kubota et al. / Bioorg. Med. Chem. 14 (2006) 4158–4181
C6H4), 7.20–7.25 (2H, m, C6H4), 7.33 (1H, ddd, C6H4);
C6H5), 7.53–7.59 (1H, m, C6H5), 7.85–7.90 (2H, m,
EIMS m/z 201 (M)+.
C6H5); FAB-HRMS (M+H)+ calcd for C25H32N6O5S:
25
D
529.2233. Found: 529.2239; ½aꢀ +66 (c 0.57, MeOH).
6.7.4.4.
3-{(3S)-(Pyrimidin-2-ylamino)piperidin-1-
yl}benzonitrile. The title compound was prepared from
3-{(3S)-aminopiperidin-1-yl}benzonitrile by the same
procedure as employed for compound 25. Yield:
6.7.5. Preparation of compound 35 (method A)
6.7.5.1. (3R)-Aminopiperidin-2-one. The title com-
pound was prepared from D-ornithine hydrochloride
by the same procedure as employed for (3S)-amin-
opiperidin-2-one. Yield: (1.7 g, 63%); 1H NMR
(400 MHz, CD3OD) d: 1.48 (1H, m, piperidine),
1.72 (2H, m, piperidine), 1.99 (1H, dddd, piperidine),
3.16 (2H, dd, piperidine), 3.24 (1H, dd, piperidine);
EIMS m/z 114 (M)+.
1
(144 mg, 75%); H NMR (400 MHz, CD3OD) d: 1.60–
1.81 (2H, m, piperidine), 1.83–1.93 (1H, m, piperidine),
1.96–2.04 (1H, m, piperidine), 2.95 (1H, dd, piperidine),
3.11 (1H, dd, piperidine), 3.41 (1H, ddd, piperidine),
3.75 (1H, dd, piperidine), 4.15 (1H, ddddd, piperidine),
6.58 (1H, t, pyrimidine), 7.06 (1H, d, C6H4), 7.15 (1H,
dd, C6H4), 7.24 (1H, br s, C6H4), 7.29 (1H, dd, C6H4),
8.32 (2H, d, pyrimidine); EIMS m/z 279 (M)+;
6.7.5.2. (3R)-Aminopiperidine. The title compound
was prepared from (3R)-aminopiperidin-2-one by the
same procedure as employed for (3S)-aminopiperidine.
25
D
½aꢀ +8.6 (c 0.67, CH2Cl2).
1
6.7.4.5.
3-{(3S)-(Pyrimidin-2-ylamino)piperidin-1-
Yield: (1.0 g, 60%); H NMR (400 MHz, CD3OD) d:
yl}benzoic acid. The title compound was prepared from
3-{(3S)-(pyrimidin-2-ylamino)piperidin-1-yl}benzonitri-
le by the same procedure as employed for compound 26
from compound 25. Yield: (79 mg, 60%); 1H NMR
(400 MHz, DMSO-d6) d: 1.46–1.67 (2H, m, piperidine),
1.74–1.84 (1H, m, piperidine), 1.91–1.99 (1H, m, piperi-
dine), 2.64 (1H, dd, piperidine), 2.77 (1H, br dd, piperi-
dine), 3.67 (1H, br d, piperidine), 3.83 (1H, br d,
piperidine), 3.86–3.97 (1H, m, piperidine), 6.58 (1H, t,
pyrimidine), 7.13 (1H, d, C6H4), 7.19 (1H, ddd, C6H4),
7.30 (1H, dd, C6H4), 7.53 (1H, br s, C6H4), 8.29 (2H,
d, pyrimidine); EIMS m/z 298 (M)+.
1.75 (1H, dddd, piperidine), 1.90 (1H, m, piperidine),
2.09 (1H, ddddd, piperidine), 2.23 (1H, br d, piperidine),
3.02 (1H, ddd, piperidine), 3.09 (1H, dd, piperidine),
3.41 (1H, br d, piperidine), 3.62 (2H, m, piperidine);
EIMS m/z 100 (M)+.
6.7.5.3.
3-{(3R)-(Pyrimidin-2-ylamino)piperidin-1-
yl}benzonitrile. The title compound was prepared from
(3R)-aminopiperidine by the same procedure as em-
ployed for compound 25. Yield: (59 mg, 10% (two
steps)); 1H NMR (400 MHz, CD3OD) d: 1.60–1.95
(3H, m, piperidine), 1.96–2.05 (1H, m, piperidine),
2.97 (1H, dd, piperidine), 3.11 (1H, ddd, piperidine),
3.37–3.45 (1H, m, piperidine), 3.74 (1H, dd, piperi-
dine), 4.12–4.21 (1H, m, piperidine), 6.60 (1H, t, pyrim-
idine), 7.06 (1H, ddd, C6H4), 7.15 (1H, ddd, C6H4),
6.7.4.6. tert-Butyl (2S)-benzenesulfonylamino-3-[3-
{(3S)-(pyrimidin-2-ylamino)piperidin-1-yl} benzoylami-
no]propionate. The title compound was prepared from
3-{(3S)-(pyrimidin-2-ylamino)piperidin-1-yl}benzoic acid
by the same procedure as employed for compound 30.
7.24 (1H, dd, C6H4), 7.29 (1H, dd, C6H4), 8.33 (2H,
25
d, pyrimidine); TSPMS m/z 280 (M+H)+; ½aꢀ ꢁ7.0 (c
D
1
Yield: (130 mg, 85%); H NMR (400 MHz, CDCl3) d:
0.65, CH2Cl2).
1.29 (9H, s, t-Bu), 1.62–1.71 (1H, m, piperidine), 1.71–
1.81 (1H, m, piperidine), 1.85–2.00 (2H, m, piperidine),
3.02 (1H, dd, piperidine), 3.10–3.20 (1H, m, piperidine),
3.32–3.39 (1H, m, piperidine), 3.60 (1H, ddd, CON-
HCH2), 3.67 (1H, dd, piperidine), 3.85–3.96 (2H, m,
CONHCH2CH), 4.16–4.25 (1H, m, piperidine), 6.53
(1H, t, pyrimidine), 7.10 (1H, dd, C6H4), 7.16 (1H, d,
C6H4), 7.29 (1H, dd, C6H4), 7.44 (1H, dd, C6H4), 7.46–
7.52 (2H, m, C6H5), 7.54–7.59 (1H, m, C6H5), 7.83–
6.7.5.4.
3-{(3R)-(Pyrimidin-2-ylamino)piperidin-1-
yl}benzoic acid. The title compound was prepared from
3-{(3R)-(pyrimidin-2-ylamino)piperidin-1-yl}benzonitri-
le by the same procedure as employed for compound 26
from compound 25. Yield: (44 mg, 71%); 1H NMR
(400 MHz, DMSO-d6) d: 1.45–1.66 (2H, m, piperidine),
1.74–1.82 (1H, m, piperidine), 1.95 (1H, br d, piperi-
dine), 2.63 (1H, dd, piperidine), 2.76 (1H, ddd, piperi-
dine), 3.65 (1H, br d, piperidine), 3.81 (1H, br d,
piperidine), 3.86–3.96 (1H, m, piperidine), 6.57 (1H, t,
pyrimidine), 7.11 (1H, d, C6H4), 7.18 (1H, ddd, C6H4),
7.28 (1H, dd, C6H4), 7.52 (1H, br s, C6H4), 8.29 (2H,
d, pyrimidine); TSPMS m/z 299 (M+H)+.
7.87 (2H, m, C6H5), 8.29 (2H, d, pyrimidine); TSPMS
25
m/z 581 (M+H)+; ½aꢀ +40 (c 0.54, CH2Cl2).
D
6.7.4.7. Compound 34. The title compound was pre-
pared from tert-butyl (2S)-benzenesulfonylamino-3-[3-
{(3S)-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-
propionate by the same procedure as employed for com-
6.7.5.5. tert-Butyl (2S)-benzenesulfonylamino-3-[3-
{(3R)-(pyrimidin-2-ylamino)piperidin-1-yl} benzoylami-
no]propionate. The title compound was prepared from
3-{(3R)-(pyrimidin-2-ylamino)piperidin-1-yl}benzoic acid
by the same procedure as employed for compound 30.
1
pound 22. Yield: (59 mg, 59%); H NMR (400 MHz,
CD3OD) d: 1.60 (1H, ddd, piperidine), 1.70–1.81 (1H,
m, piperidine), 1.85–1.93 (4H, m, piperidine and tetrahy-
dropyrimidine), 3.06 (1H, dd, piperidine), 3.10–3.15 (1H,
m, piperidine), 3.28 (1H, m, piperidine), 3.33 (4H, br t, tet-
rahydropyrimidine), 3.48 (1H, dd, piperidine), 3.52 (1H,
dd, CONHCH2), 3.65–3.72 (1H, m, piperidine), 3.71
(1H, dd, CONHCH2), 3.77 (1H, dd, CONHCH2CH),
7.13 (1H, ddd, C6H4), 7.26 (1H, ddd, C6H4), 7.31 (1H,
dd, C6H4), 7.46 (1H, dd, C6H4), 7.47–7.53 (2H, m,
1
Yield: (80 mg, 100%); H NMR (400 MHz, CDCl3) d:
1.29 (9H, s, t-Bu), 1.63–1.72 (1H, m, piperidine), 1.73–
1.82 (1H, m, piperidine), 1.86–2.00 (2H, m, piperidine),
3.03 (1H, dd, piperidine), 3.16 (1H, ddd, piperidine),
3.30–3.39 (1H, m, piperidine), 3.61 (1H, ddd, CON-
HCH2), 3.67 (1H, dd, piperidine), 3.88 (1H, m,