J. Qi et al. / European Journal of Medicinal Chemistry 46 (2011) 934e943
941
HRMS (ESI) calcd for C18H9Cl2F4N4O ([M þ H]þ), 443.0090; found
was obtained by the reaction of intermediate 5a (0.227 g, 1 mmol)
and ethyl 4,4-difluoro-3-oxobutanoate (0.166 g, 1 mmol) as a white
needle crystal. ESI-Ms (m/z) 330.3 [M þ H]þ; 1H NMR (500 MHz,
443.0085; IRvmax (KBr):1701 (C]O), 1629, 1558, cmꢂ1
.
4.1.4.2. 5-(Chloromethyl)-3-(naphthalen-1-yl)-2-(trifluoromethyl)py
razolo[1,5-a]pyrimidin-7(4H)-one (15). The compound 15 (0.245 g,
65%) was obtained by the reaction of intermediate 5d (0.277 g,
1 mmol) and 4-chloro-3-oxobutanoate (0.165 g, 1 mmol) as
a white solid. mp >300 ꢀC; ESI-Ms (m/z): 378.1 [M þ H]þ; 1H NMR
DMSO-d6) d: 7.53 (m, 3H, Ph-H), 7.46 (m, 2H, Ph-H), 6.96 (t, 1H,
J ¼ 53, CHF2), 6.22 (s, 1H, 6-CH]); 13C NMR (125 MHz, DMSO-d6)
d:
95.12 (6-C]H), 104.92 (3-C), 155.98 (7-C]O), 146.07, 141.08 (2-C),
130.80 (Ph-C), 129.06 (Ph-C), 128.83 (Ph-C), 128.13 (Ph-C), 122.86
(CF3), 110.57 (CHF2); HRMS (ESI) calcd for C14H9F5N3O ([M þ H]þ),
330.0666; found 330.0660.
(500 MHz, DMSO-d6)
d
: 12.58 (s, 1H, NH), 8.10 (d, 1H, J ¼ 8, NAPH-
H), 8.05 (d, 1H, J ¼ 8.5, NAPH-H), 7.63 (t, 1H, J ¼ 7, NAPH-H), 7.58
(m, 3H, NAPH-H), 7.49 (m, 1H, NAPH-H), 6.17 (s, 1H, 6-CH]), 4.57
4.1.4.8. 3-Phenyl-5-(2,3,4,5-tetrafluorophenyl)-2-(trifluoromethyl)
pyrazolo[1,5-a]pyrimidin-7(4H)-one (23). The compound 23
(0.178 g, 40%) was obtained by the reaction of intermediate 5a
(0.227 g, 1 mmol) and ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)
propanoate (0.264 g, 1 mmol) as a white powder. ESI-Ms (m/z)
(s, 2H, CH2Cl); 13C NMR (125 MHz, DMSO-d6)
d: 41.13 (CH2Cl),
97.98 (6-C]H), 101.49 (3-C), 156.22 (7-C]O), 150.71, 142.87 (5-C),
141.55 (2-C), 133.75, 133.17, 130.34, 129.76, 128.77, 127.28, 126.72,
126.00, 125.81, 125.62, 125.43, 122.83 (CF3), 41.13 (CH2Cl); HRMS
(ESI) calcd for C18H12ClF3N3O ([M þ H]þ), 378.0621; found
378.0609.
428.2 [M þ H]þ; 1H NMR (500 MHz, DMSO-d6)
d: 7.51 (m, 2H), 7.44
(m, 3H), 7.80 (m,1H),12.88 (brs,1H, NH), 6.16 (s,1H, 6-CH]); HRMS
(ESI) calcd for C19H9F7N3O ([M þ H]þ), 428.0634; found 428.06324.
4.1.4.3. 3-(Naphthalen-1-yl)-2,5-bis(trifluoromethyl)pyrazolo[1,5-a]
pyrimidin-7(4H)-one (16). The compound 16 (0.175 g, 44%) was
obtained by the reaction of intermediate 5d (0.277 g, 1 mmol) and
ethyl 4,4,4-trifluoro-3-oxobutanoate (0.18 g, 1 mmol) as a white
solid. mp >300 ꢀC; ESI-Ms (m/z): 398.2 [M þ H]þ; 1H NMR
4.1.4.9. 5-(3-Nitrophenyl)-3-phenyl-2-(trifluoromethyl)pyrazolo[1,5-
a]pyrimidin-7(4H)-one (24). The compound 24 (0.280 g, 70%) was
obtained by the reaction of intermediate 5a (0.227 g, 1 mmol) and
ethyl 3-(3-nitrophenyl)-3-oxopropanoate (0.237 g, 1 mmol) as
a white needle crystal. ESI-Ms (m/z) 401.3 [M þ H]þ; 1H NMR
(600 MHz, CD3OD)
d
: 8.03 (d, 1H, J ¼ 8.4, NAPH-H), 7.98 (d, 1H,
J ¼ 7.8, NAPH-H), 7.59 (t, 1H, J ¼ 6.6, NAPH-H), 7.51 (m, 3H, NAPH-
H), 7.45 (m, 1H, NAPH-H), 6.44 (s, 1H, 6-CH]); HRMS (ESI) calcd for
C18H10F6N3O ([M þ H]þ), 398.0728; found 398.0730.
(500 MHz, DMSO-d6) d: 7.50 (m, 3H, Ph-H), 7.46 (m, 2H, Ph-H), 8.55
(t,1H, J ¼ 2, Ph-H), 8.40 (m,1H, Ph-H), 8.18 (m,1H, Ph-H), 7.83 (t,1H,
J ¼ 8, Ph-H), 6.29 (s, 1H, 6-CH]), 12.81 (brs, 1H, NH); 13C NMR
(125 MHz, DMSO-d6) d: 96.86 (6-C]H), 104.19 (3-C), 155.43 (7-C]
4.1.4.4. 5-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-(naphthalen-1-yl)-
O),147.49,140.65 (2-C),130.37,128.51,128.18,127.93,122.47,123.29,
125.37, 130.16, 133.98, 134.99; HRMS (ESI) calcd for C19H12F3N4O3
([M þ H]þ), 401.0861; found 401.0868.
2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one
(18). The
compound 18 (0.271 g, 55%) was obtained by the reaction of
intermediate 5d (0.277 g, 1 mmol) and ethyl 3-(2,6-dichloro-5-
fluoropyridin-3-yl)-3-oxopropanoate (0.28 g, 1 mmol) as a white
solid. mp >300 ꢀC; ESI-Ms (m/z): 493.3 [M þ H]þ; 1H NMR
4.1.4.10. 5-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-(3,4-dimethoxyph
enyl)-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (25).
The compound 25 (0.186 g, 37%) was obtained by the reaction of
intermediate 5c (0.287 g, 1 mmol) and ethyl 3-(2,6-dichloro-5-
fluoropyridin-3-yl)-3-oxopropanoate (0.28 g, 1 mmol) as a white
solid. ESI-Ms (m/z) 503.1[M þ H]þ; 1H NMR (500 MHz, DMSO-d6)
(600 MHz, CD3OD)
d
: 8.01 (d, 1H, J ¼ 3.6, NAPH-H), 7.99 (d, 1H,
J ¼ 3.6, NAPH-H), 7.59 (t, 1H, J ¼ 6.6, NAPH-H), 7.51 (m, 3H, NAPH-
H), 7.45 (m, 1H, NAPH-H), 6.12 (s, 1H, 6-CH]), 7.96 (d, 1H, J ¼ 8.4,
pyridine 4-CH]); HRMS (ESI) calcd for C22H11Cl2F4N4O ([M þ H]þ),
493.0246; found 493.0252.
d
: 3.80 (s, 3H, CH3O), 3.76 (s, 3H, OCH3), 7.09 (d, 1H, J ¼ 8, Ph-H),
7.00 (m, 1H, Ph-H), 6.83 (m, 1H, Ph-H), 6.15 (s, 1H, 6-CH]), 8.40 (d,
1H, J ¼ 8, pyridine 4-CH]), 12.85 (brs, 1H, NH); HRMS (ESI) calcd
for C20H13Cl2F4N4O3 ([M þ H]þ), 503.0301; found 503.0307.
4.1.4.5. 5-(4-Methoxyphenyl)-3-phenyl-2-(trifluoromethyl)pyrazolo
[1,5-a]pyrimidin-7(4H)-one (20). The compound 20 (0.288 g, 75%)
was obtained by the reaction of intermediate 5a (0.227 g, 1 mmol)
and ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (0.222 g,
1 mmol) as a white solid. ESI-Ms (m/z) 386.4 [M þ H]þ; 1H NMR
4.1.4.11. 5-(3-Nitrophenyl)-3-(thiophen-2-yl)-2-(trifluoromethyl)pyr
azolo[1,5-a]pyrimidin-7(4H)-one (26). The compound 26 (0.172 g,
42%)wasobtainedbythereactionofintermediate5e(0.233g,1mmol)
and ethyl 3-(3-nitrophenyl)-3-oxopropanoate (0.237 g, 1 mmol) as
a violet solid. ESI-Ms (m/z) 407.1 [M þ H]þ; 1H NMR (500 MHz, DMSO-
(500 MHz, DMSO-d6) d: 3.83 (s, 3H, CH3O), 6.12 (s, 1H, 6-CH]),
12.49 (brs, 1H, NH), 7.08 (d, 2H, J ¼ 9, Ph-H), 7.71 (m, 2H, Ph-H),
7.42e7.51 (m, 5H, Ph-H); 13C NMR (125 MHz, DMSO-d6)
d
: 95.25 (6-
C]H), 104.44 (3-C), 156.07 (7-C]O), 152.93, 162.06, 141.00 (2-C),
130.84, 129.78, 128.93, 128.54, 123.02 (CF3), 130.35, 114.48, 55.96
(CH3O); HRMS (ESI) calcd for C20H15F3N3O2 ([M þ H]þ), 386.1116;
found 386.1110.
d6) d: 7.22 (m, 1H, thienyl-H), 7.30 (m, 1H, thienyl-H), 7.74 (m, 1H,
thienyl-H), 6.33 (s, 1H, 6-CH]), 7.84 (t, 1H, J ¼ 8, Ph-H), 8.20 (d, 1H,
J ¼ 8, Ph-H), 8.41 (m,1H, Ph-H), 8.57 (s,1H, Ph-H),12.87 (brs,1H, NH);
13C NMR (125 MHz, DMSO-d6)
d: 96.73, 97.08, 155.34, 147.52, 141.59,
123.22, 125.36, 127.18, 127.52, 127.96, 129.82, 130.19, 134.08, 134.88,
141.88, 122.27; HRMS (ESI) calcd for C17H10F3N4O3S ([M þ H]þ),
407.0426; found 407.0420.
4.1.4.6. 5-tert-Butyl-3-phenyl-2-(trifluoromethyl)pyrazolo[1,5-a]pyr-
imidin-7(4H)-one (21). The compound 21 (0.217 g, 65%) was
obtained by the reaction of intermediate 5a (0.227 g, 1 mmol) and
ethyl 4,4-dimethyl-3-oxopentanoate (0.172 g, 1 mmol) as a white
solid. ESI-Ms (m/z) 336.2 [M þ H]þ; 1H NMR (500 MHz, DMSO-d6)
4.1.4.12. 5-(2,3,4,5-Tetrafluorophenyl)-3-(thiophen-2-yl)-2-(trifluoro
methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (27). The compound 27
(0.217 g, 50%) was obtained by the reaction of intermediate 5e
(0.233 g, 1 mmol) and ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)
propanoate (0.264 g, 1 mmol) as a violet solid. ESI-Ms (m/z) 434.3
d
: 7.50 (m, 2H, Ph-H), 7.45 (m, 1H, Ph-H), 7.40 (d, 2H, J ¼ 7, Ph-H),
5.85 (d, 1H, J ¼ 1.5 6-CH]), 11.48 (brs, 1H, NH), 1.33 (s, 9H, CH3);
HRMS (ESI) calcd for C17H17F3N3O ([M þ H]þ), 336.1324; found
336.1322.
[M þ H]þ; 1H NMR (500 MHz, DMSO-d6)
: 7.18 (d, 1H, J ¼ 2.5,
d
thienyl-H), 7.25 (d, 1H, J ¼ 3.0, thienyl-H), 7.68 (m, 1H, thienyl-H),
7.86 (s, 1H, Ph-H), 6.17 (s, 1H, 6-CH]); HRMS (ESI) calcd for
C17H7F7N3OS ([M þ H]þ), 434.0198; found 434.0204.
4.1.4.7. 5-(Difluoromethyl)-3-phenyl-2-(trifluoromethyl)pyrazolo
[1,5-a]pyrimidin-7(4H)-one (22). The compound 22 (0.223 g, 68%)