B.C. Huddle, E. Grimley, M. Chtcherbinine et al.
European Journal of Medicinal Chemistry 211 (2021) 113060
150.84, 142.33, 139.55, 135.10, 134.70, 130.19, 130.12, 128.96, 128.06,
127.94, 102.77, 46.86, 39.92, 34.34, 33.16, 21.95. HPLC Purity: 98%.
7.28e7.22 (m, 2H), 7.15 (dd, J ¼ 8.2, 2.2 Hz, 1H), 5.02 (q, J ¼ 7.1 Hz,
1H), 4.00 (s, 3H), 3.17 (s, 1H), 1.71 (d, J ¼ 7.0 Hz, 3H).13C NMR
(126 MHz, CDCl3)
d 161.08, 157.62, 150.99, 141.93, 135.83, 135.39,
4.8.55. 1-methyl-5-(4-(2-(methylamino)ethyl)phenyl)-6-((1-
phenylethyl)thio)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
hydrochloride (62)
133.42 (d, J ¼ 9.6 Hz), 129.51 (d, J ¼ 2.9 Hz), 128.57, 127.64, 127.46,
124.07, 102.77, 82.53, 79.01, 47.01, 34.09, 21.97. HPLC Purity: 98%
60 (120 mg, 0.231 mmol) was dissolved in 1 mL DCM and 1 mL
TFA. The mixture was stirred for 2 h, at which point the starting
material was consumed by TLC. The reaction was concentrated and
the residue taken up in sat. aq. sodium bicarbonate and extracted
3ꢄ into EtOAc. The combined organics were washed with brine,
and dried over sodium sulfate. A few drops of 4 N HCl in dioxane
were added and the mixture was concentrated to yield the titled
compound as a white solid (105 mg, 0.230 mmol, 100% yield). (ESI):
4.8.59. 2-(oxetan-3-ylmethyl)-5-phenyl-6-((1-phenylethyl)thio)-
2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (67)
66 [22] (100 mg, 0.409 mmol), K2CO3 (141 mg, 1.023 mmol), and
(1-bromoethyl)benzene (55.9 ml, 0.409 mmol) were stirred in 2 mL
DMF at room temperature for 1 h. Oxetan-3-ylmethyl meth-
anesulfonate (prepared as previously described [80], 68.0 mg,
0.409 mmol) was added by syringe and the mixture was heated to
60 ꢀC overnight. The next morning the mixture was diluted with
water and extracted 2ꢄ with EtOAc. The combined organic portions
were washed 3ꢄ with brine, dried over sodium sulfate, and
concentrated. The crude residue was purified by flash (Eluting at
60% EtOAc in Hex) yielding the titled compound as a colorless oil
(26 mg, 0.062 mmol, 15.18% yield). MS (ESI): m/z 419.1537 [MþH]þ
m/z 420.1853 [MþH]þ 1H NMR (500 MHz, DMSO‑d6)
d 9.09 (s, 2H),
8.01 (s, 1H), 7.45e7.40 (m, 3H), 7.37 (dd, J ¼ 8.1, 2.0 Hz, 1H),
7.35e7.27 (m, 3H), 7.26e7.20 (m, 2H), 5.02 (q, J ¼ 7.1 Hz,1H), 3.95 (s,
3H), 3.17 (dq, J ¼ 10.9, 6.3, 5.9 Hz, 2H), 3.02 (dd, J ¼ 10.0, 6.5 Hz, 2H),
2.56 (t, J ¼ 5.3 Hz, 3H), 1.65 (d, J ¼ 7.1 Hz, 3H).13C NMR (126 MHz,
DMSO‑d6)
d
161.27, 157.32, 150.84, 142.37, 139.50, 135.09, 134.67,
1H NMR (500 MHz, CDCl3) d 8.06 (s, 1H), 7.56e7.40 (m, 3H), 7.35 (d,
130.20 (d, J ¼ 6.5 Hz), 130.15, 128.95, 128.06, 127.92, 102.77, 49.02,
J ¼ 7.6 Hz, 2H), 7.31e7.25 (m, 3H), 7.24e7.14 (m, 2H), 5.18 (q,
46.86, 34.35, 32.76, 31.48, 21.97. HPLC Purity: 98%.
J ¼ 7.0 Hz,1H), 4.87 (t, J ¼ 7.2 Hz, 2H), 4.57 (d, J ¼ 7.5 Hz, 2H), 4.54 (q,
J ¼ 5.7 Hz, 2H), 3.66 (h, J ¼ 6.9 Hz, 1H), 1.75 (d, J ¼ 7.0 Hz, 3H). 13
C
4.8.56. 5-(4-(2-(dimethylamino)ethyl)phenyl)-1-methyl-6-((1-
phenylethyl)thio)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (63)
61 (62 mg, 0.140 mmol) was dissolved in 2 mL DCE and treated
with DIPEA (0.025 mL, 0.140 mmol), stirred for 5 min, then 37% aq.
formaldehyde (0.031 mL, 0.421 mmol) and acetic acid (0.024 mL,
0.421 mmol) were added sequentially. The mixture was stirred for
10 min at which point sodium triacetoxyborohydride (89 mg,
0.421 mmol) was added and the mixture was stirred overnight. The
next day the mixture was diluted with 10% aq. Na2CO3 and
extracted with EtOAc. The organic portion was washed with brine,
dried over sodium sulfate, and concentrated to yield the pure
product as an off white foam (59 mg, 0.136 mmol, 97% yield). (ESI):
NMR (126 MHz, CDCl3) d 160.53, 158.69, 158.62, 141.62, 135.57,
129.82, 129.62, 129.59, 129.56, 129.51, 128.62, 128.54, 127.70,127.48,
105.00, 74.46, 55.80, 46.52, 35.38, 22.10. HPLC Purity: 99%
4.8.60. 2-(oxetan-3-yl)-5-phenyl-6-((1-phenylethyl)thio)-2H-
pyrazolo[3,4-d]pyrimidin-4(5H)-one (68)
Prepared in a similar manner to 67 employing 3-bromooxetane.
White Solid. (14 mg, 0.035 mmol, 8.45% yield) MS (ESI): m/z
405.1381 [MþH]þ 1H NMR (500 MHz, CDCl3)
d 8.19 (s, 1H),
7.55e7.42 (m, 3H), 7.36 (d, J ¼ 7.6 Hz, 2H), 7.31e7.26 (m, 3H),
7.25e7.16 (m, 2H), 5.57 (p, J ¼ 6.9 Hz,1H), 5.26e5.18 (m, 3H), 5.09 (t,
J ¼ 7.3 Hz, 2H), 1.77 (d, J ¼ 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3)
m/z 434.2009 [MþH]þ 1H NMR (500 MHz, CDCl3)
d
7.99 (s, 1H), 7.37
d 160.97, 158.63, 141.50, 135.49, 129.87, 129.61, 129.54, 129.53,
(ddd, J ¼ 15.8, 8.3, 1.8 Hz, 3H), 7.33e7.28 (m, 3H), 7.25 (d, J ¼ 8.9 Hz,
1H), 7.16 (dd, J ¼ 8.1, 2.3 Hz,1H), 7.08 (dd, J ¼ 8.1, 2.3 Hz,1H), 5.01 (q,
J ¼ 7.1 Hz, 1H), 3.99 (s, 3H), 2.89e2.80 (m, 2H), 2.65e2.52 (m, 2H),
2.32 (s, 6H), 1.71 (d, J ¼ 7.2 Hz, 3H).13C NMR (126 MHz, CDCl3)
128.57, 127.96, 127.70, 127.52, 105.33, 76.86, 76.82, 56.78, 46.58,
22.15. HPLC Purity: 98%
4.8.61. 2-(oxetan-3-yl)-5-phenyl-6-((1-(pyridin-2-yl)ethyl)thio)-
2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (69)
d
161.69, 157.86, 151.04, 142.47, 142.14, 135.35, 133.42, 129.98,
129.90, 129.18, 129.15, 128.50, 127.53, 127.52, 102.87, 61.08, 46.86,
45.47, 34.17, 34.03, 21.93. HPLC Purity: 98%
A dry flask was charged with 66 [22] (250 mg, 1.023 mmol),
K2CO3 (424 mg, 3.07 mmol), 2-(1-bromoethyl)pyridine (190 mg,
1.023 mmol), and 3 mL DMF. The mixture was stirred for 1 h at RT at
which point 3-bromooxetane (0.127 mL, 1.535 mmol) was added
before heating the mixture to 80 ꢀC. After 48 h the mixture was
diluted with water and extracted 2ꢄ with EtOAc, The combined
organic portion was washed 3ꢄ with brine and dried over sodium
sulfate. The mixture was purified by flash (60% EtOAc in Hex)
yielding the mostly pure product as the later peak. The product was
recrystallized from ethanol to obtain the titled compound as a
white solid (45 mg, 0.111 mmol, 10.84% yield). MS (ESI): m/z
4.8.57. 4-(1-methyl-4-oxo-6-((1-phenylethyl)thio)-1H-pyrazolo
[3,4-d]pyrimidin-5(4H)-yl)benzonitrile (64)
Prepared from 4-aminobenzonitrile and 50 in a similar manner
to 59 affording the titled compound as a white solid (50 mg,
0.129 mmol, 15.76% yield). (ESI): m/z 388.1225 [MþH]þ 1H NMR
(400 MHz, CDCl3)
d
7.99 (s, 1H), 7.83 (dd, J ¼ 8.2, 2.0, 0.6 Hz, 1H),
7.79 (dd, J ¼ 8.1, 2.0, 0.6 Hz, 1H), 7.42 (dd, J ¼ 8.1, 2.2, 0.6 Hz, 1H),
7.39e7.35 (m, 2H), 7.35e7.29 (m, 3H), 7.27 (d, J ¼ 7.7 Hz, 1H), 5.04
(q, J ¼ 7.2 Hz, 1H), 4.01 (s, 3H), 1.73 (d, J ¼ 7.2 Hz, 3H). 13C NMR
406.1340 [MþH]þ 1H NMR (500 MHz, CDCl3)
d
8.51 (d, J ¼ 4.3 Hz,
(101 MHz, CDCl3)
d
160.20, 157.34, 150.88, 141.55, 139.74, 135.44 (d,
1H), 8.19 (s, 1H), 7.60 (td, J ¼ 7.7, 1.9 Hz, 1H), 7.54e7.42 (m, 3H), 7.40
(d, J ¼ 7.8 Hz, 1H), 7.28 (dt, J ¼ 7.7, 1.8 Hz, 1H), 7.19 (dt, J ¼ 7.2, 2.0 Hz,
1H), 7.12 (dd, J ¼ 7.6, 4.9, 1.2 Hz, 1H), 5.65e5.47 (m, 1H), 5.33 (q,
J ¼ 6.9 Hz, 1H), 5.21 (q, J ¼ 6.2 Hz, 2H), 5.08 (td, J ¼ 7.4, 1.5 Hz, 2H),
J ¼ 2.8 Hz), 133.55 (d, J ¼ 6.9 Hz), 130.69, 128.65, 127.83, 127.44,
117.81, 114.08, 102.61, 47.28 (d, J ¼ 8.1 Hz), 34.22, 21.94. HPLC Purity:
99%
1.78 (d, J ¼ 7.0 Hz, 3H).13C NMR (126 MHz, CDCl3)
d 161.14, 160.59,
4.8.58. 5-(4-ethynylphenyl)-1-methyl-6-((1-phenylethyl)thio)-1H-
pyrazolo[3,4-d]pyrimidin-4(5H)-one (65)
158.64, 158.58, 149.59, 136.65, 135.36, 129.89, 129.67, 129.64,
129.60, 129.54, 128.00, 122.44, 122.31, 105.30, 76.87, 76.83, 56.77,
48.08, 21.49. HPLC Purity 97%
Prepared from 4-ethynylaniline and 50 in a similar manner to 59
affording the titled compound as
a yellow solid. (117 mg,
0.303 mmol, 32.0% yield) (ESI): m/z 387.1276 [MþH]þ 1H NMR
4.8.62. 2-(oxetan-3-yl)-5-phenyl-6-((1-(pyridin-3-yl)ethyl)thio)-
2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (70)
(500 MHz, CDCl3)
d
7.99 (s, 1H), 7.64 (dd, J ¼ 8.2, 1.8 Hz, 1H), 7.60
(dd, J ¼ 8.2,1.9 Hz,1H), 7.38 (d, J ¼ 7.1 Hz, 2H), 7.31 (t, J ¼ 7.5 Hz, 2H),
Prepared in a similar manner to 69. White solid. (100 mg,
23