N. Teno et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
7
2H), 4.20 (m, 1H), 3.96 (s, 3H), 3.35 (s,3H), 3.00 (m, 2H), 1.99 (m,
2H), 1.46 (m,2H), 1.40 (m, 2H).
4.91 (m,1H), 4.88 (s, 2H), 4.44 (s, 2H), 3.78 (s, 3H), 3.61 (t, J =
6.0 Hz, 2H), 2.84 (t, J = 7.2 Hz, 2H), 1.93 (sext., J = 8.4 Hz, 2H), 1.58
(m, 2H), 1.43 (m, 2H), 0.72 (t, J = 7.2 Hz, 3H). HR-ESI-MS [M+H]+
576.25639 for C28H32N9O5 (calculated 574.25264).
5.1.15. 9H-Fluoren-9-ylmethyl N-{5-cyano-5-[(6-{[2,5-dioxo-3-
(2-oxo-3-propyl-2,3-dihydro-1,3-benzoxazol-5-yl)imidazolidin-
1-yl]methyl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)
formamido]pentyl}carbamate (7b)
Compound7b was prepared in a manner similar to that described
for 7a in 69% yield. Rf = 0.8 (EtOAc/MeOH = 9/1), 1H NMR (600 MHz,
DMSO-d6): d 9.59 (d, J = 8.4 Hz, 1H), 9.05 (s, 1H), 7.88 (d, J = 7.2 Hz,
2H), 7.67 (br d, J = 7.8 Hz, 2H), 7.64 (br s, 1H), 7.41 (m, 4H), 7.31
(m, 3H), 6.79 (s, 1H), 5.02 (s, 2H), 4.99 (q, J = 7.8 Hz, 1H), 4.66 (s,
2H), 4.29 (m, 2H), 4.19 (t, J = 7.2 Hz, 1H), 3.97 (s, 3H), 3.79 (t,
J = 7.2 Hz, 2H), 3.00 (m, 2H), 1.98 (m, 2H), 1.73 (sext., J = 7.2 Hz,
2H), 1.45 (m, 2H), 1.40 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).
5.1.20. N-(5-Amino-1-cyanopentyl)-7-methyl-6-({3-[3-(2-
methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-2,5-
dioxoimidazolidin-1-yl}methyl)-7H-pyrrolo[2,3-d]pyrimidine-
2-carboxamide (8c)
Compound 8c was prepared in a manner similar to that
described for 8a in 54% yield. 1H NMR (600 MHz, DMSO-d6): d
9.63 (d, J = 9.0 Hz, 1H), 9.09 (s, 1H), 7.64 (m, 3H), 7.41 (s, 2H),
6.80 (s, 1H), 5.03 (br s, 3H), 4.66 (s, 2H), 3.99 (s, 3H), 3.64 (d,
J = 6.0 Hz, 2H), 2.82 (m, 2H), 2.15 (m, 1H), 2.01 (m, 2H), 1.59 (m,
2H), 1.46 (m, 2H), 0.93 (d, J = 4.8 Hz, 6H). HR-ESI-MS [M+H]+
588.26829 for C29H34N9O5 (calculated 588.26829).
5.1.16. 9H-Fluoren-9-ylmethyl N-(5-cyano-5-{[7-methyl-6-({3-
[3-(2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-
2,5-dioxoimidazolidin-1-yl}methyl)-7H-pyrrolo[2,3-d]
pyrimidin-2-yl]formamido}pentyl)carbamate (7c)
Compound 7c was prepared in a manner similar to that
described for 7a in 40% yield, Rf = 0.8 (EtOAc), 1H NMR (600 MHz,
DMSO-d6): d 9.56 (br s, 1H), 9.02 (s, 1H), 7.85 (d, J = 7.2 Hz, 2H),
7.64 (d, J = 7.8 Hz, 2H), 7.61 (s, 1H), 7.38 (m, 4H), 7.29 (m, 3H),
6.75 (s, 1H), 4.99 (s, 2H), 4.96 (br s, 1H), 4.63 (s, 2H), 4.26 (br s,
2H), 4.17 (br s, 1H), 3.93 (s, 3H), 3.61 (d, J = 7.2 Hz, 2H), 2.97 (br
s, 2H), 2.12 (br s, 1H), 1.95 (m, 2H), 1.43 (m, 2H), 1.37 (m, 2H),
0.90 (d, J = 7.2 Hz, 6H).
5.1.21. N-(5-Amino-1-cyanopentyl)-6-({2,5-dioxo-3-[2-oxo-3-
(pyridin-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]
imidazolidin-1-yl}methyl)-7-methyl-7H-pyrrolo[2,3-d]
pyrimidine-2-carboxamide (8d)
Compound 8b was prepared in a manner similar to that
described for 8a in 61% yield. 1H NMR (600 MHz, D2O): d 8.85 (s,
1H), 8.57 (d, J = 6.6 Hz, 2H), 7.83 (d, J = 6.0 Hz, 2H), 7.21 (d,
J = 9.0 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 9.0, 1.8 Hz,
1H), 6.70 (s, 1H), 5.25 (s, 2H), 4.92 (t, J = 7.8 Hz, 1H), 4.86 (s, 2H),
4.39 (s, 2H), 3.78 (s, 3H), 2.84 (t, J = 7.2 Hz, 2H), 1.93 (m, 2H),
1.58 (m, 2H), 1.43 (m, 2H). HR-ESI-MS [M+H]+ 623.24705 for
C31H31N10O5 (calculated 623.24789).
5.1.17. 9H-Fluoren-9-ylmethyl N-(5-cyano-5-{[6-({2,5-dioxo-3-
[2-oxo-3-(pyridin-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-
yl]imidazolidin-1-yl}methyl)-7-methyl-7H-pyrrolo[2,3-d]
pyrimidin-2-yl]formamido}pentyl)carbamate (7d)
Compound 7d was prepared in a manner similar to that
described for 7a in 64% yield. Rf = 0.1 (EtOAc/MeOH = 9/1), 1H
NMR (600 MHz, DMSO-d6): d 9.58 (d, J = 7.8 Hz, 1H), 9.04 (s, 1H),
8.56 (d, J = 5.4 Hz, 2H), 7.88 (d, J = 7.2 Hz, 2H), 7.67 (d, J = 7.2 Hz,
2H), 7.59 (br s, 1H), 7.47 (br d, J = 9.0 Hz, 1H), 7.41 (m, 3H), 7.33
(m, 5H), 6.75 (s, 1H), 5.13 (s, 2H), 4.98 (m, 3H), 4.59 (s, 2H), 4.29
(m, 2H), 4.19 (m, 1H), 3.94 (s, 3H), 3.00 (m, 2H), 1.98 (m, 2H),
1.46 (m, 2H), 1.40 (m, 2H).
5.1.22. Methyl 2-(chloromethyl)-3-methyl-benzimidazole-5-
carboxylate (10)
To a solution of methyl 4-amino-3-(methylamino)benzoate
(89 mg, 0.5 mmol)20 in THF (3 ml) was successively added
triethylamine (77
ll, 0.55 mmol) and chloroacethyl chloride
(44 l, 0.55 mmol), and stirred for 1 h. Following, SOCl2 (91
l
l
l,
1.25 mmol) was added, stirred for 15 h at room temperature, and
quenched by addition of MeOH (1 ml). The solution was diluted
with EtOAc, and the organic layer was washed successively with
dil. NaHCO3, water, and brine, dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by sil-
ica gel column chromatography to give desired product (95 mg) as
pale yellow needles in 80% yield. Rf = 0.32 (n-hexane/EtOAc = 2/1),
1H NMR (600 MHz, CDCl3): d 8.14 (d, J = 0.8 Hz, 1 H), 8.00 (dd,
J = 8.5, 1.5 Hz, 1 H), 7.77 (d, J = 8.5 Hz, 1 H), 4.86 (s, 2 H), 3.97 (s,
3 H), 3.94 (s, 3 H).
5.1.18. N-(5-Amino-1-cyanopentyl)-7-methyl-6-{[3-(3-methyl-
2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,5-dioxoimidazolidin-
1-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamide (8a)
Compound 8a (32 mg, 0.041 mmol) was dissolved in 20% piper-
idine in DMF (400 ll) at room temperature. The reaction mixture
was stirred under the same conditions for 40 min. The mixture
was evaporated and pale yellow products were precipitated by
ether. The products were purified with HPLC system (column;
5.1.23. Methyl 2-(chloromethyl)-1-methyl-benzimidazole-5-
carboxylate (11)
Compound 11 was prepared in a matter similar to that described
for 10 in 95% yield. Rf = 0.48 (n-hexane/EtOAc = 1/1), 1H NMR
(600 MHz, CDCl3): d 8.47 (d, J = 1.1 Hz, 1 H), 8.07 (dd, J = 8.5,
1.5 Hz, 1 H), 7.39 (d, J = 8.5 Hz, 1 H), 4.86 (s, 2 H), 3.95 (s, 3 H),
3.91 (s, 3 H).
TSK gel ODS-120T,
U
21.5 Â 300 mm, eluent CH3CN containing
0.1% TFA/H2O containing 0.1% TFA) to give 8a in 35% yield, 1H
NMR (600 MHz, D2O): d 8.83 (br s, 1H), 7.11 (br s, 1H), 7.05 (br
d, J = 7.2 Hz, 1H), 6.97 (br d, J = 9.0 Hz, 1H), 6.69 (s, 1H), 4.90 (t,
J = 7.8 Hz, 1H), 4.85 (s, 2H), 4.40 (s, 2H), 3.77 (s, 3H), 3.14 (s, 3H),
2.84 (t, J = 7.2 Hz, 2H), 1.93 (m, 2H), 1.59 (quint., J = 6.6 Hz, 2H),
1.43 (quint., J = 7.2 Hz, 2H). HR-ESI-MS [M+H]+ 546.21708 for
5.1.24. Ethyl 2-[4-(4-pyridyloxy)anilino]acetate (12a)
To a solution of 4-(4-pyridyloxy)aniline22 (1.0 g, 3.86 mmol) in
DMF (20 ml), diisopropylethylamine (2.35 ml, 13.5 mmol) and
ethyl bromoacetate (0.97 g, 5.8 mmol) were added at ambient tem-
perature. The reaction mixture was stirred for 15 h at 100 °C. The
reaction solvent was evaporated. The residue was purified by silica
gel column chromatography to give 12a quantitatively. Rf = 0.50
(CH2Cl2/MeOH = 9/1), 1H NMR (600 MHz, DMSO-d6): d 7.85 (d,
J = 7.8 Hz, 2H), 7.25 (d, J = 9.0 Hz, 2H), 6.67 (d, J = 9.0 Hz, 2H),
6.20 (d, J = 7.8 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.96 (d, J = 6.6 Hz,
2H), 1.22 (t, J = 7.8 Hz, 3H).
C26H28N9O5 (calculated 546.22134).
5.1.19. N-(5-Amino-1-cyanopentyl)-6-{[2,5-dioxo-3-(2-oxo-3-
propyl-2,3-dihydro-1,3-benzoxazol-5-yl)imidazolidin-1-yl]
methyl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamide
(8b)
Compound8b was prepared in a manner similar to that described
for 8a in 54% yield. 1H NMR (600 MHz, D2O): d 8.81 (s, 1H), 7.23 (br s,
1H), 7.11 (d, J = 9.0 Hz, 1H), 7.01 (br d, J = 7.8 Hz, 1H), 6.65 (s, 1H),