S.D. Banister et al. / European Journal of Medicinal Chemistry 93 (2015) 392e400
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6.52 (1H, s, ArH), 4.69 (1H, quin., J ¼ 7.3 Hz, OCH), 3.99 (2H, s,
ArCH2), 3.51 (2H, q, J ¼ 7.3 Hz, NCH2), 3.41 (2H, q, J ¼ 7.3 Hz, NCH2),
2.77 (3H, s, ArCH3), 2.60 (3H, s, ArCH3), 2.50e2.44 (2H, m, CHCH2),
2.23e2.15 (2H, m, CHCH2), 1.91e1.84 (1H, m, CHCH2CH2), 1.75e1.67
(1H, m, CHCH2CH2), 1.22 (3H, t, J ¼ 7.3 Hz, CH2CH3), 1.12 (3H, t,
(Cquat.), 144.9 (Cquat.), 130.0 (2C, CH), 126.3 (Cquat.), 114.8 (2C, CH),
108.2 (CH), 100.9 (Cquat.), 72.3 (OCH2), 42.4 (NCH2), 40.7 (NCH2),
34.8 (CH), 29.8 (CH2), 28.3 (CH2), 25.0 (2C, CH2), 24.7 (CH3), 18.7
(CH2), 17.0 (CH3), 14.5 (CH3), 13.2 (CH3); LRMS (þESI) m/z 421.13
([MþH]þ, 100%); Anal. (C25H32N4O2): calcd, C 71.40, H 7.67, N 13.32;
found, C 71.46, H 7.62, N 13.27.
J ¼ 7.3 Hz, CH2CH3); 13C NMR (125 MHz, CDCl3)
d 170.0 (C]O),157.9
(Cquat.), 157.5 (Cquat.), 155.3 (Cquat.), 147.8 (Cquat.), 144.8 (Cquat.), 130.1
(2C, CH), 126.4 (Cquat.), 115.2 (2C, CH), 108.2 (CH), 100.9 (Cquat.), 71.6
(OCH), 42.4 (NCH2), 40.7 (NCH2), 30.8 (2C, CH2), 28.3 (CH2), 24.8
(CH3), 17.0 (CH3), 14.5 (CH3), 13.4 (CH2), 13.2 (CH3); LRMS (þESI) m/z
407.07 ([MþH]þ,100%); Anal. (C24H30N4O2): calcd, C 70.91, H 7.44, N
13.78; found, C 70.95, H 7.54, N 13.85.
5.2.6. 2-(2-(4-Cyclopentylmethoxyphenyl)-5,7-dimethylpyrazolo
[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (19)
Treating 13 with (iodomethyl)cyclopentane (100 mL, 0.75 mmol,
1.5 equiv.) at 50 ꢀC for 5 days according to the general procedure
gave 19 as a colorless crystalline solid (84 mg, 37%, 78% brsm). m.p.
107e108 ꢀC; Rf 0.45 (CHCl3eMeOH, 90:10); 1H NMR (500 MHz,
5.2.3. 2-(2-(4-Cyclopentyloxyphenyl)-5,7-dimethylpyrazolo[1,5-a]
pyrimidin-3-yl)-N,N-diethylacetamide (16)
CDCl3)
d
7.74 (2H, d, J ¼ 9.0 Hz, ArH), 6.97 (2H, d, J ¼ 9.0 Hz, ArH),
6.49 (1H, s, ArH), 3.91 (2H, s, ArCH2), 3.87 (2H, d, , J ¼ 7.0 Hz, OCH2),
3.49 (2H, q, J ¼ 7.2 Hz, NCH2), 3.41 (2H, q, J ¼ 7.2 Hz, NCH2), 2.73
(3H, s, ArCH3), 2.53 (3H, s, ArCH3), 2.42e2.33 (1H, m, OCH2CH),
1.88e1.82 (2H, m), 1.68e1.56 (4H, m), 1.41e1.34 (2H, m), 1.20 (3H, t,
J ¼ 7.0 Hz, CH2CH3), 1.11 (3H, t, J ¼ 7.0 Hz, CH2CH3); 13C NMR
Treating 13 with bromocyclopentane (80
mL, 0.75 mmol,
1.5 equiv.) for 5 days at 45 ꢀC according to the general procedure
gave 16 as a colorless crystalline solid (198 mg, 47%). m.p.
130e132 ꢀC; Rf 0.42 (CHCl3eMeOH, 90:10); 1H NMR (500 MHz,
CDCl3)
d
7.73 (2H, d, J ¼ 9.0 Hz, ArH), 6.94 (2H, d, J ¼ 9.0 Hz, ArH),
(125 MHz, CDCl3)
d 170.3 (C]O), 159.7 (Cquat.), 157.5 (Cquat.), 155.3
6.47 (1H, s, ArH), 4.80 (1H, sep., J ¼ 2.9 Hz, OCH), 3.90 (2H, s, ArCH2),
3.49 (2H, q, J ¼ 7.2 Hz, NCH2), 3.40 (2H, q, J ¼ 7.2 Hz, NCH2), 2.72
(3H, s, ArCH3), 2.52 (3H, s, ArCH3), 1.95e1.76 (6H, m), 1.65e1.57 (2H,
m), 1.19 (3H, t, J ¼ 7.2 Hz, CH2CH3), 1.10 (3H, t, J ¼ 7.2 Hz, CH2CH3);
(Cquat.), 147.8 (Cquat.), 144.9 (Cquat.), 130.0 (2C, CH), 126.2 (Cquat.),
114.8 (2C, CH), 108.2 (CH), 100.9 (Cquat.), 72.5 (OCH2), 42.4 (NCH2),
40.7 (NCH2), 39.2 (CH), 29.6 (2C, CH2), 28.3 (CH2), 25.6 (2C, CH2),
24.7 (CH3), 17.1 (CH3), 14.5 (CH3), 13.2 (CH3); LRMS (þESI) m/z
435.07 ([MþH]þ, 100%); Anal. (C26H34N4O2): calcd, C 71.86, H 7.89,
N 12.89; found, C 71.46, H 7.62, N 13.27.
13C NMR (125 MHz, CDCl3)
d 170.2 (C]O), 158.5 (Cquat.), 157.5
(Cquat.), 155.3 (Cquat.), 147.7 (Cquat.), 144.8 (Cquat.), 130.1 (2C, CH),
125.9 (Cquat.), 115.7 (2C, CH), 108.2 (CH), 100.8 (Cquat.), 79.3 (OCH),
42.4 (NCH2), 40.7 (NCH2), 32.9 (CH2), 28.3 (CH2), 24.7 (CH3), 24.1
(2C, OCHCH3), 17.0 (CH3), 14.4 (CH3), 13.2 (CH3); LRMS (þESI) m/z
421.13 ([MþH]þ, 100%); Anal. (C25H32N4O2): calcd, C 71.40, H 7.67, N
13.32; found, C 71.49, H 7.87, N 13.23.
5.2.7. 2-(2-(4-Cyclohexylmethoxyphenyl)-5,7-dimethylpyrazolo
[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (20)
Treating 13 with (bromomethyl)cyclohexane (105
mL,
0.75 mmol, 1.5 equiv.) according to the general procedure gave 20
as a colorless crystalline solid (193 mg, 86%). m.p. 141e143 ꢀC; Rf
5.2.4. 2-(2-(4-Cyclopropylmethoxyphenyl)-5,7-dimethylpyrazolo
[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (17)
0.42 (CHCl3eMeOH, 90:10); 1H NMR (500 MHz, CDCl3)
d 7.74 (2H, d,
J ¼ 8.5 Hz, ArH), 6.96 (2H, d, J ¼ 8.5 Hz, ArH), 6.49 (1H, s, ArH), 3.92
(2H, s, ArCH2), 3.79 (2H, d, J ¼ 6.5 Hz, OCH2), 3.49 (2H, q, J ¼ 7.0 Hz,
NCH2), 3.41 (2H, q, J ¼ 7.2 Hz, NCH2), 2.73 (3H, s, ArCH3), 2.54 (3H, s,
ArCH3), 1.89e1.69 (6H, m), 1.34e1.22 (3H, m), 1.20 (3H, t, J ¼ 7.0 Hz,
CH2CH3),1.11 (3H, t, J ¼ 7.0 Hz, CH2CH3), 1.10e1.02 (2H, m); 13C NMR
Treating 13 with (bromomethyl)cyclopropane (73
mL,
0.75 mmol, 1.5 equiv.) for 20 h according to the general procedure
gave 17 as a colorless crystalline solid (176 mg, 86%). m.p.
122e124 ꢀC; Rf 0.38 (CHCl3eMeOH, 90:10); 1H NMR (500 MHz,
CDCl3)
d
7.75 (2H, d, J ¼ 9.0 Hz, ArH), 6.97 (2H, d, J ¼ 9.0 Hz, ArH),
(125 MHz, CDCl3)
d 170.2 (C]O), 159.7 (Cquat.), 157.5 (Cquat.), 155.3
6.48 (1H, s, ArH), 3.90 (2H, s, ArCH2), 3.84 (2H, d, J ¼ 7.0 Hz, OCH2),
3.49 (2H, q, J ¼ 7.2 Hz, NCH2), 3.40 (2H, q, J ¼ 7.2 Hz, NCH2), 2.73
(3H, s, ArCH3), 2.53 (3H, s, ArCH3), 1.30e1.27 (1H, m, OCH2CH), 1.19
(3H, t, J ¼ 7.2 Hz, CH2CH3), 1.11 (3H, t, J ¼ 7.2 Hz, CH2CH3), 0.66e0.63
(2H, m, CHCH2), 0.38e0.35 (2H, m, CHCH2); 13C NMR (125 MHz,
(Cquat.), 147.6 (Cquat.), 145.0 (Cquat.), 130.0 (2C, CH), 126.1 (Cquat.),
114.7 (2C, CH), 108.2 (CH), 100.9 (Cquat.), 73.7 (OCH2), 42.4 (NCH2),
40.7 (NCH2), 37.8 (CH), 30.1 (2C, CH2), 28.3 (CH2), 26.7 (CH2), 26.0
(2C, CH2), 24.6 (CH3), 17.1 (CH3), 14.5 (CH3), 13.2 (CH3); LRMS (þESI)
m/z 449.13 ([MþH]þ, 100%); Anal. (C27H36N4O2): calcd, C 72.29, H
8.09, N 12.49; found, C 72.38, H 8.32, N 12.43.
CDCl3) d 170.2 (C]O), 159.4 (Cquat.), 157.5 (Cquat.), 155.2 (Cquat.), 147.8
(Cquat.), 144.8 (Cquat.), 130.1 (2C, CH), 126.4 (Cquat.), 114.8 (2C, CH),
108.2 (CH), 100.9 (Cquat.), 72.9 (OCH2), 42.4 (NCH2), 40.7 (NCH2),
28.3 (CH2), 24.7 (CH3), 17.0 (CH3), 14.5 (CH3), 13.2 (CH3), 10.4
(OCH2CH), 3.31 (2C, CHCH2); LRMS (þESI) m/z 407.07 ([MþH]þ,
100%); Anal. (C24H30N4O2): calcd, C 70.91, H 7.44, N 13.78; found, C
70.98, H 7.62, N 13.80.
5.2.8. 2-(2-(4-(Benzyl)oxyphenyl)-5,7-dimethylpyrazolo[1,5-a]
pyrimidin-3-yl)-N,N-diethylacetamide (21)
Treating 13 with benzyl bromide (90 mL, 0.75 mmol, 1.5 equiv.)
according to the general procedure gave 21 as a colorless crystalline
solid (191 mg, 86%). m.p.151e153 ꢀC; Rf 0.50 (CHCl3eMeOH, 90:10);
5.2.5. 2-(2-(4-Cyclobutylmethoxyphenyl)-5,7-dimethylpyrazolo
[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (18)
1H NMR (500 MHz, CDCl3)
d
7.78 (2H, d, J ¼ 8.5 Hz, ArH), 7.45 (2H, d,
J ¼ 7.5 Hz, ArH), 7.40e7.37 (2H, m, ArH), 7.34e7.31 (1H, m, ArH),
7.05 (2H, d, J ¼ 8.5 Hz, ArH), 6.50 (1H, s, ArH), 5.12 (2H, s, OCH2),
3.91 (2H, s, ArCH2), 3.50 (2H, q, J ¼ 7.2 Hz, NCH2), 3.40 (2H, q,
J ¼ 7.2 Hz, NCH2), 2.74 (3H, s, ArCH3), 2.54 (3H, s, ArCH3), 1.19 (3H, t,
J ¼ 7.2 Hz, CH2CH3), 1.11 (3H, t, J ¼ 7.2 Hz, CH2CH3); 13C NMR
Treating 13 with (bromomethyl)cyclobutane (85 mL, 0.75 mmol,
1.5 equiv.) according to the general procedure gave 18 as a colorless
crystalline solid (189 g, 90%). m.p. 107e109 ꢀC; Rf 0.47
(CHCl3eMeOH, 90:10); 1H NMR (500 MHz, CDCl3)
d 7.75 (2H, d,
J ¼ 9.0 Hz, ArH), 6.97 (2H, d, J ¼ 9.0 Hz, ArH), 6.49 (1H, s, ArH), 3.97
(2H, d, J ¼ 6.5 Hz, OCH2), 3.91 (2H, s, ArCH2), 3.49 (2H, q, J ¼ 7.2 Hz,
NCH2), 3.41 (2H, q, J ¼ 7.2 Hz, NCH2), 2.80e2.77 (1H, m, OCH2CH),
2.72 (3H, s, ArCH3), 2.53 (3H, s, ArCH3), 2.17e2.13 (2H, m, cyclo-
butane), 1.98e1.86 (2H, m, cyclobutane), 1.20 (3H, t, J ¼ 7.1 Hz,
CH2CH3), 1.11 (3H, t, J ¼ 7.1 Hz, CH2CH3); 13C NMR (125 MHz, CDCl3)
(125 MHz, CDCl3) d 170.3 (C]O), 159.2 (Cquat.), 157.6 (Cquat.), 155.2
(Cquat.), 147.9 (Cquat.), 144.8 (Cquat.), 137.1 (Cquat.), 130.2 (2C, CH),
128.7 (2C, CH), 128.1 (CH), 127.6 (2C, CH), 126.8 (Cquat.), 115.1 (2C,
CH),108.3 (CH),101.0 (Cquat.), 70.2 (OCH2), 42.5 (NCH2), 40.7 (NCH2),
28.3 (CH2), 24.8 (CH3), 17.1 (CH3), 14.5 (CH3), 13.2 (CH3); LRMS
(þESI) m/z 443.07 ([MþH]þ, 100%); Anal. (C27H30N4O2): calcd, C
73.28, H 6.83, N 12.66; found, C 73.28, H 6.82, N 12.61.
d
170.2 (C]O), 159.7 (Cquat.), 157.5 (Cquat.), 155.2 (Cquat.), 147.8