Journal of Medicinal Chemistry
Article
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CH2Cl2) gave the title compound as an off-white powder (78.3 mg,
0.25 mmol, 56%). 1H NMR (500 MHz, DMSO-d6): δ 11.49 (s,
1H), 10.12 (s, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 8.8, 2.4
Hz, 1H), 7.31 (m, 4H), 7.25 (m, 1H), 7.16 (d, J = 8.8 Hz, 1H),
5.09 (s, 2H), 2.05 (s, 3H). LC−MS m/z: 310 [M + H]+, tR = 3.3
min.
31%). H NMR (500 MHz, DMSO-d6): δ 11.35 (s, 1H), 10.10 (s,
1H), 8.23 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 8.8, 2.4 Hz, 1H), 7.12
(d, J = 8.8 Hz, 1H), 3.87 (t, J = 7.5 Hz, 2H), 2.05 (s, 3H), 1.56 (m,
2H), 1.28 (m, 6H), 0.87 (t, J = 7.8 Hz, 3H). LC−MS m/z: 304 [M
+ H]+, tR = 3.9 min.
N-(3-Cyclopentyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-
acetamide (16). The compound was prepared following General
Procedure B, using cyclopentylamine (57.48 mg). Purification by
flash chromatography (0−80% EtOAc/hexane) gave the title
compound as a white powder (127 mg, 0.442 mmol, 65%). 1H
NMR (500 MHz, DMSO-d6): δ 11.28 (s, 1H), 10.09 (s, 1H), 8.22
(d, J = 2.4 Hz, 1H), 7.77 (dd, J = 8.8, 2.4 Hz, 1H), 7.11 (d, J = 8.8,
1H), 5.30 (quintet, J = 8.7 Hz, 1H), 2.10−2.05 (m, 5H), 1.94−1.86
(m, 2H), 1.80−1.73 (m, 2H), 1.60−1.52 (m, 2H). 13C NMR (125
MHz, DMSO-d6): δ 168.2, 162.0, 149.8, 134.8, 134.1, 126.4, 116.5,
115.2, 114.0, 51.9, 28.0, 25.3, 23.8. LC−MS m/z: 288 [M + H]+,
305 [M + NH4]+, 575 [2M + H]+, tR = 4.3 min. HRMS (ES+):
N-(2,4-Dioxo-3-phenethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-
acetamide (10). The compound was prepared following General
Procedure B, using 2-phenylethylamine (85 μL). Purification by
flash chromatography (0−5% MeOH/CH2Cl2 + 0.1% NH3) gave
the title compound as an off-white powder (90 mg, 0.278 mmol,
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41%). H NMR (500 MHz, DMSO-d6): δ 11.39 (s, 1H), 10.11 (s,
1H), 8.24 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 8.8, 2.4 Hz, 1H), 7.32−
7.20 (m, 5H), 7.13 (d, J = 8.8 Hz, 1H), 4.12−4.09 (m, 2H), 2.89−
2.86 (m, 2H), 2.15 (s, 3H). 13C NMR (125 MHz, DMSO-d6): δ
168.2, 161.6, 149.7, 138.6, 134.9, 134.3, 128.5, 128.4, 126.5, 126.3,
114.6, 115.5, 113.7, 41.2, 33.3, 23.8. LC−MS m/z: 324 [M + H]+,
tR = 3.6 min.
found 288.1337 [M + H]+; C15H18N3O3 [M + H]+, requires
+
N-(2,4-Dioxo-3-(3-phenylpropyl)-1,2,3,4-tetrahydroquinazolin-
6-yl)acetamide (11). The compound was prepared following
General Procedure B, using N-(2,4-dioxo-2,4-dihydro-1H-benzo[d]-
[1,3]oxazin-6-yl)acetamide (100 mg, 0.45 mmol), benzenepropan-
amine (0.065 mL, 0.46 mmol), THF (4 mL), and carbon-
yldiimidazole (105 mg, 0.65 mmol) to give the title compound as
a white solid (110.2 mg, 0.33 mmol, 72%), which needed no further
purification. 1H NMR (500 MHz, DMSO-d6): δ 11.35 (s, 1H),
10.10 (s, 1H), 8.23 (d, J = 1.8 Hz, 1H), 7.79 (dd, J = 8.7, 1.9 Hz,
1H), 7.27 (t, J = 7.4 Hz, 2H), 7.23 (d, J = 7.1 Hz, 2H), 7.17 (d, J =
7.5 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 3.93 (t, J = 7.3 Hz, 2H),
2.64 (t, J = 7.6 Hz, 2H), 2.05 (s, 3H), 1.88 (m, 2H). LC−MS m/z:
338 [M + H]+, tR = 3.8 min.
N-(3-(Cyclohexylmethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazo-
lin-6-yl)acetamide (12). The compound was prepared following
General Procedure B, using cyclohexylmethylamine (76.41 mg).
Purification by flash chromatography (0−100% EtOAc/hexane) gave
the title compound as a pale pink off-white powder (167 mg, 0.530
mmol, 78%). 1H NMR (500 MHz, DMSO-d6): δ 11.33 (s, 1H),
10.08 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 8.8, 2.4 Hz,
1H), 7.12 (d, J = 8.8 Hz, 1H), 3.77 (d, J = 7.3 Hz, 2H), 2.05 (s,
3H), 1.76−1.73 (m, 1H), 1.67−1.65 (m, 2H), 1.59−1.56 (m, 3H),
1.19−1.10 (m, 3H), 1.02−0.96 (m, 2H). 13C NMR (125 MHz,
DMSO-d6): δ 168.2, 162.0, 150.1, 134.9, 134.2, 126.5, 116.6, 115.4,
113.6, 45.5, 35.8, 30.2, 25.8, 25.2, 23.8. LC−MS m/z: 316 [M +
H]+, 631 [2M + H]+, tR = 3.8 min.
288.1343.
N-(3-Cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-
acetamide (17). The compound was prepared by following General
Procedure B, using cyclohexylamine (66.95 mg). Purification by
flash chromatography (0−60% EtOAc/hexane) gave the title
compound as a white powder (101 mg, 0.335 mmol, 49%). 1H
NMR (500 MHz, DMSO-d6): δ 11.25 (s, 1H), 10.09 (s, 1H),
8.19(d, J = 2.4 Hz, 1H), 7.79 (dd, J = 8.8, 2.4 Hz, 1H), 7.09 (d, J =
8.8 Hz, 1H), 4.76−4.71 (m, 1H), 2.43−2.35 (dq, J = 15.8, 3.3 Hz,
2H), 2.04 (s, 3H), 1.80 (d, J = 12.9 Hz, 2H), 1.64 (d, J = 12.6 Hz,
1H), 1.58 (d, J = 10.5 Hz, 2H), 1.35−1.27 (m, 2H), 1.19−1.14 (m,
1H). 13C NMR (125 MHz, DMSO-d6): δ 168.2, 162.1, 150.0, 135.0,
134.1, 126.4, 116.6, 115.1, 114.1, 52.7, 28.3, 25.9, 25.0, 23.8. LC−
MS m/z: 302 [M + H]+, 319 [M + NH4]+, tR = 4.5 min. HRMS
+
(ES+): found 302.1499 [M + H]+; C16H20N3O3 [M + H]+, requires
302.1499.
N-(3-Cycloheptyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-
acetamide (18). The compound was prepared by following General
Procedure B, using cycloheptylamine (76.41 mg). Purification by
flash chromatography (0−60% EtOAc/hexane) gave the title
compound as a beige powder (137 mg, 0.434 mmol, 64%). 1H
NMR (500 MHz, DMSO-d6): δ 11.25 (s, 1H), 10.08 (s, 1H),
8.20(d, J = 2.4 Hz, 1H), 7.78 (dd, J = 8.8, 2.3 Hz, 1H), 7.09 (d, J =
8.8, 1H), 4.89 (bs, 1H), 2.35−2.27(m, 2H), 2.04 (s, 3H), 1.76−1.66
(m, 4H), 1.61−1.54 (m, 4H), 1.52−1.41 (m, 2H). 13C NMR (125
MHz, DMSO-d6): δ 168.2, 161.7, 149.8, 135.0, 134.1, 126.4, 116.7,
115.1, 54.0, 31.3, 27.5, 25.9, 23.8. LC−MS m/z: 316 [M + H]+, 648
[M + NH3]+, tR = 3.8 min.
N-(3-(tert-Butyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-
acetamide (13). The compound was prepared following General
Procedure B, using tert-butylamine (49.37 mg). Purification by flash
chromatography (0−60% EtOAc/hexane) gave the title compound
N-(3-(trans-4-tert-Butyl)cyclohexyl)-2,4-dioxo-1,2,3,4-tetrahy-
droquinazolin-6-yl)acetamide (19). The compound was prepared
following General Procedure B, using N-(2,4-dioxo-2,4-dihydro-1H-
benzo[d][1,3]oxazin-6-yl)acetamide (110 mg, 0.50 mmol), trans-4-
(tert-butyl)cyclohexanamine (78 mg, 0.50 mmol), THF (5 mL), and
carbonyldiimidazole (122 mg, 0.75 mmol). Purification by flash
chromatography (0−10% MeOH/CH2Cl2) gave the title compound
1
as an off-white powder (36 mg, 0.131 mmol, 19%). H NMR (500
MHz, DMSO-d6): δ 10.15 (s, 1H), 8.29 (d, J = 2.5 Hz, 1H), 7.82
(dd, J = 8.8, 2.6 Hz, 1H), 7.68 (s, 1H), 7.23 (d, J = 8.8, 1H), 2.06
(s, 3H), 1.47 (s, 9H). 13C NMR (125 MHz, DMSO-d6): δ 168.2,
159.7, 145.9, 134.6, 128.2, 124.4, 116.4, 112.5, 50.8, 28.3, 23.8. LC−
MS m/z: 276 [M + H]+, 551 [2M + H]+, tR = 4.8 min. HRMS
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as a white powder (60 mg, 0.17 mmol, 33%). H NMR (500 MHz,
+
(ES+): found 276.1335 [M + H]+; C14H18N3O3 [M + H]+, requires
DMSO-d6): δ 11.23 (s, 1H), 10.06 (s, 1H), 8.18 (d, J = 2.4 Hz,
1H), 7.79 (dd, J = 8.8, 2.4 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 4.71
(m, 1H), 2.42 (m, 2H), 2.04 (s, 3H), 1.84 (d, J = 10.6 Hz, 1H),
1.64 (d, J = 9.9 Hz, 2H), 1.14−1.04 (m, 3H), 0.88 (s, 9H). LC−MS
276.1343.
N-(3-(4-Methylpentyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-
yl)acetamide (14). The compound was prepared following General
Procedure B, using 4-methylpentan-1-amine (69 mg, 0.68 mmol),
and gave the title compound as a tan-colored powder (132.3 mg,
0.44 mmol, 64%). 1H NMR (500 MHz, DMSO-d6): δ 11.35 (s,
1H), 10.10 (s, 1H), 8.23 (d, J = 2.3 Hz, 1H), 7.79 (dd, J = 8.8, 2.3
Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 3.86 (t, J = 7.5 Hz, 2H), 2.05 (s,
3H), 1.54 (m, 3H), 1.18 (m, 2H), 0.86 (d, J = 6.6 Hz, 6H). LC−
MS m/z: 304 [M + H]+, tR = 3.9 min.
m/z: 356 [M
+ = 4.4 min. trans-4-(tert-Butyl)-
H]+, tR
cyclohexanamine was prepared from 4-(tert-butyl)cyclohexanone
following General Procedure C and used without purification. 1H
NMR (500 MHz, CDCl3): δ 2.58 (m, 1H), 1.91 (m, 2H), 1.77 (m,
2H), 1.61 (s, 2H), 1.11−0.94 (m, 5H), 0.86 (s, 9H).
N-(2,4-Dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-acet-
amide (20). See General Procedure A.
N-(3-Hexyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-
acetamide (15). The compound was prepared following General
Procedure B, using 1-hexylamine (0.090 mL, 0.68 mmol).
Purification by flash chromatography (0−10% MeOH/CH2Cl2)
gave the title compound as a white powder (58.3 mg, 0.21 mmol,
6-Amino-3-(2-cyclohexylethyl)quinazoline-2,4(1H,3H)-dione
(30). 5-Acetylamino-2-amino-N-(2-cyclohexyl-ethyl)-benzamide (0.1
g, 0.33 mmol), was taken in ethyl chloroformate (0.4 mL) and
heated to 90 °C for 1.5 h. The solvent was removed under reduced
pressure, and the crude was dissolved in EtOH (2 mL), followed by
M
J. Med. Chem. XXXX, XXX, XXX−XXX