O. Rabal et al. / European Journal of Medicinal Chemistry 150 (2018) 506e524
519
4.2.22. 4-[4-Ethoxy-3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo[4,3-
d]pyrimidin-5-yl)phenyl]cyclohex-3-ene-1-carbohydroxamic acid
(52a)
CH2-CH2-CH3), 2.70 (m, 1H, cyclohexene), 2.45 (m, 1H, cyclo-
hexene), 2.04e2.02 (m, 4H, cyclohexene), 1.83e1.71 (m, 6H, cyclo-
hexene and CH2-CH2-CH3), 1.44 (m, 3H O-CH2-CH3), 1.01 (t,
J ¼ 7.2 Hz, 3H, CH2-CH2-CH3).
A solution of compound 51a (90 mg, 0.168 mmol) in HCl/EtOAc
(4.0 M, 5 mL) was stirred at room temperature for 1 h. Then, the
mixture was concentrated to give the crude compound which was
purified by preparative HPLC (Method 1 described in supporting
information) to obtain pure compound 52a (14.5 mg, 19%) as a
white solid; m.p.: 235e236 ꢀC. ESI-MS m/z 452.2 [MþH]þ calc. for
4.2.25. 1-[4-Ethoxy-3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo[4,3-
d]pyrimidin-5-yl)phenyl]piperidine-4-carbohydroxamic acid (59)
A solution of compound 58 (40 mg, 0.074 mmol) in HCl/EtOAc
(2.0 M, 10 mL) was stirred at room temperature for 1 h. Then, the
mixture was concentrated to give the crude product which was
purified by preparative HPLC (Method 1 described in supporting
information) to obtain pure compound 59 (6 mg, 18%) þas a white
solid; m.p.: 186.5e187.5 ꢀC. ESI-MS m/z 455.2 [MþH] calc. for
C
24H29N5O4. 1H NMR (DMSO-d6, 400 MHz):
d 10.49 (s, 1H, CO-NH-
OH), 8.72 (s, 1H, CO-NH-OH), 7.62 (s, 1H, Harom), 7.52e7.50 (d,
J ¼ 8.4 Hz, 1H, Harom), 7.10e7.08 (d, J ¼ 8.4 Hz, 1H, Harom), 6.10 (s, 1H,
CH2-CH¼C), 4.15 (s, 3H, N-CH3), 4.12e4.08 (m, 2H, O-CH2-CH3),
2.79e2.75 (m, 2H, CH2-CH2-CH3), 2.47e2.23 (m, 5H, cyclohexene),
1.76e1.71 (m, 4H, cyclohexene and CH2-CH2-CH3), 1.33e1.29 (m,
3H, O-CH2-CH3), 0.95e0.92 (m, 3H, CH2-CH2-CH3).
C
23H30N6O4. 1H NMR (MeOD, 400 MHz):
d
8.07e8.05 (d, J ¼ 8 Hz,
1H, Harom), 7.70e7.60 (m, 1H, Harom), 7.33e7.31 (d, J ¼ 8 Hz, 1H,
arom), 4.30e4.15 (m, 5H, N-CH3 and O-CH2-CH3), 3.85e3.70 (m,
H
2H, piperidine), 3.55e3.45 (m, 2H, piperidine), 2.90e2.80 (m, 2H,
CH2-CH2-CH3), 2.53e2.49 (m, 1H, piperidine), 2.25e2.00 (m, 4H,
piperidine), 1.90e1.70 (m, 2H, CH2-CH2-CH3), 1.50e1.40 (m, 3H, O-
CH2-CH3), 1.00e0.90 (m, 3H, CH2-CH2-CH3).
4.2.23. 2-[4-[4-Ethoxy-3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo
[4,3-d]pyrimidin-5-yl)phenyl]cyclohex-3-en-1-yl]
ethanehydroxamic acid (52b)
A solution of compound 51b (102 mg, 0.186 mmol) in HCl/EtOAc
(4.0 M, 5 mL) was stirred at room temperature for 1 h. Then, the
mixture was concentrated to give the crude compound which was
purified by preparative HPLC (Method 1 described in supporting
information) to obtain pure compound 52b (15.3 mg, 18%) as a
white solid; m.p.: 172e173 ꢀC. ESI-MS m/z 466.3 [MþH]þ calc. for
4.2.26. 4-[[4-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3H-imidazo[5,1-
f][1,2,4]triazin-2-yl)phenyl]methyl]benzenecarbohydroxamic acid
(66a)
A solution of compound 65a (50 mg, 0.09 mmol) in HCl/EtOAc
(2.0 M, 10 mL) was stirred at room temperature for 1 h. Then, the
solution was concentrated to give the crude product which was
purified by preparative HPLC (Method 1 described in supporting
information) to obtain pure compound 66a (2.1 mg, 5%) as a white
solid. m.p.: 123e124 ꢀC. ESI-MS m/z 462.1 [MþH]þ calc. for
C
25H31N5O4. 1H NMR (DMSO-d6, 400 MHz):
d 11.99 (s, 1H, CO-NH-
C), 10.39 (s, 1H, CO-NH-OH), 7.62 (s, 1H, Harom), 7.52e7.50 (d,
J ¼ 8.4 Hz, 1H, Harom), 7.10e7.08 (d, J ¼ 8.8 Hz, 1H, Harom), 6.07 (s, 1H,
CH2-CH¼C), 4.15 (s, 3H, N-CH3), 4.13e4.08 (m, 2H, O-CH2-CH3),
2.79e2.75 (m, 2H, CH2-CH2-CH3), 2.42e2.25 (m, 4H, cyclohexene),
1.99 (s, 2H, CO-CH2-cyclohexene), 1.87e1.84 (m, 2H, cyclohexene),
1.79e1.70 (m, 2H, CH2-CH2-CH3), 1.43e1.36 (m, 1H, cyclohexene),
1.33e1.30 (m, 3H, O-CH2-CH3), 0.96e0.92 (m, 3H, CH2-CH2-CH3).
C
25H27N5O4. 1H NMR (MeOD, 400 MHz):
d
7.70e7.68 (d, J ¼ 8 Hz,
2H, Harom), 7.55 (s, 1H, Harom), 7.41e7.39 (d, J ¼ 8 Hz, 1H, Harom),
7.34e7.32 (d, J ¼ 8 Hz, 2H, H arom), 7.12e7.10 (d, J ¼ 8 Hz, 1H, H
arom), 4.21e4.15 (m, 2H, O-CH2-CH3), 4.05 (s, 2H, Carom-CH2-
Carom), 3.00e2.90 (m, 2H, CH2-CH2-CH3), 2.60 (s, 3H, C-CH3),
1.84e1.79 (m, 2H, CH2-CH2-CH3), 1.44e1.41 (m, 3H, O-CH2-CH3),
1.00e0.96 (m, 3H, CH2-CH2-CH3).
4.2.24. 4-[4-Ethoxy-3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo[4,3-
d]pyrimidin-5-yl)phenyl]cyclohexanecarbohydroxamic acid (55), cis
4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo[4,3-d]
pyrimidin-5-yl)phenyl]cyclohexanecarbohydroxamic acid (55a) and
trans 4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo[4,3-d]
pyrimidin-5-yl)phenyl]cyclohexanecarbohydroxamic acid (55b)
A solution of compound 54 (98 mg, 0.182 mmol) in HCl/EtOAc
(1.0 M, 15 mL) was stirred at room temperature for 1 h. Then, the
mixture was concentrated to give the crude product which was
purified by preparative HPLC (Method 1 described in supporting
information) to obtain pure compounds 55 (14.5 mg, 18%), 55a
(5.8 mg, 7%) and 55b (10 mg, 12%) as white solids. 55: m.p.:
103.5e104.5 ꢀC. ESI-MS m/z 454.2 [MþH]þ calc. for C24H31N5O4. 1H
4.2.27. 5-[[4-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3H-imidazo[5,1-
f][1,2,4]triazin-2-yl)phenyl]methyl]thiophene-2-carbohydroxamic
acid (66b)
A solution of compound 65b (40 mg, 0.07 mmol) in HCl/EtOAc
(4.0 M, 10 mL) was stirred at room temperature for 1 h. Then, the
mixture was concentrated to give the crude compound which was
purified by preparative HPLC (Method 1 described in supporting
information) to obtain pure compound 66b (10.5 mg, 32%) as a
yellow solid; m.p.: 131e132 ꢀC. ESI-MS m/z 468.1 [MþH]þ calc. for
C
23H25N5O4S. 1H NMR (MeOD, 400 MHz):
d 7.61 (s, 1H, Harom),
NMR (MeOD, 400 MHz):
d
7.78 (s, 1H, Harom), 7.42e7.36 (m, 1H,
7.47e7.42 (m, 2H, Harom), 7.14e7.12 (d, J ¼ 8 Hz, 1H, Harom), 6.89 (s,
1H, Harom), 4.20e4.28 (m, 4H, O-CH2-CH3 and Carom-CH2-Carom),
3.03e2.99 (m, 2H, CH2-CH2-CH3), 2.61 (s, 3H, C-CH3), 1.84e1.80 (m,
2H, CH2-CH2-CH3),1.44e1.41 (m, 3H, O-CH2-CH3),1.01e0.97 (m, 3H,
CH2-CH2-CH3).
Harom), 7.10e7.08 (m, 1H, Harom), 4.23e4.19 (m, 5H, N-CH3 and O-
CH2-CH3), 2.90e2.87 (m, 2H, CH2-CH2-CH3), 2.70e2.45 (m, 2H,
cyclohexene), 2.04e1.74 (m, 10H, cyclohexene and CH2-CH2-CH3),
1.44 (m, 3H, O-CH2-CH3), 1.01 (t, J ¼ 7.2 Hz, 3H, CH2-CH2-CH3). 55a:
m.p.: 204e205 ꢀC. ESI-MS m/z 454.2 [MþH]þ calc. for C24H31N5O4.
1H NMR (MeOD, 400 MHz):
d
7.77 (d, J ¼ 2.4 Hz, 1H, Harom),
4.2.28. 4-[4-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3H-imidazo[5,1-
f][1,2,4]triazin-2-yl)phenyl]benzenecarbohydroxamic acid (66c)
A solution of compound 65c (60 mg, 0.11 mmol) in HCl/EtOAc
(4.0 M, 10 mL) was stirred at room temperature for 1 h. Then, the
mixture was concentrated to give the crude compound which was
purified by preparative HPLC (Method 1 described in supporting
information) to obtain pure compound 66c (22 mg, 45%) as a yellow
solid; m.p.: 224.5e225.5 ꢀC. ESI-MS m/z 448.1 [MþH]þ calc. for
7.39e7.37 (m, 1H, Harom), 7.10 (d, J ¼ 8.4 Hz, 1H, Harom), 4.24e4.18
(m, 5H, N-CH3 and O-CH2-CH3), 2.92e2.88 (m, 2H, CH2-CH2-CH3),
2.63e2.60 (m, 1H, cyclohexene), 2.15 (m, 1H, cyclohexene),
2.00e1.96 (m, 2H, cyclohexene), 1.89e1.84 (m, 2H, cyclohexene),
1.82e1.80 (m, 2H, CH2-CH2-CH3), 1.73e1.71 (m, 2H, cyclohexene),
1.56 (m, 2H, cyclohexene),1.45 (t, J ¼ 6.8 Hz, 3H, O-CH2-CH3),1.02 (t,
J ¼ 6.8 Hz, 3H, CH2-CH2-CH3). 55b: m.p.: 184e185 ꢀC. ESI-MS m/z
454.2 [MþH]þ calc. for C24H31N5O4. 1H NMR (MeOD, 400 MHz):
C
24H25N5O4. 1H NMR (MeOD, 400 MHz):
d 7.97 (s, 1H, Harom),
d
7.78 (s, 1H, Harom), 7.41 (d, J ¼ 6.8 Hz, 1H, Harom), 7.10 (d, J ¼ 7.6 Hz,
7.90e7.88 (m, 1H, Harom), 7.85e7.83 (d, J ¼ 4 Hz, 2H, Harom),
1H, Harom), 4.23 (m, 5H, N-CH3 and O-CH2-CH3), 2.91e2.87 (m, 2H,
7.75e7.73 (d, J ¼ 4 Hz, 2H, Harom), 7.31e7.29 (d, J ¼ 4 Hz, 1H, Harom),