Y. Yin, et al.
BioorganicChemistry98(2020)103720
4.1.43. N-(3-((6-((1-(2-Hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-
pyrazolo[3,4-d] pyrimidin-1-yl)methyl)phenyl)cyanamide (13o)
8.93 (s, 1H), 8.06 (s, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.49–7.47 (m, 1H),
7.42 (s, 1H), 7.30 (t, J = 9 Hz, 1H), 7.05–7.02 (m, 1H), 6.93 (s, 1H),
6.90 (s, 1H), 5.46 (s, 2H), 3.85 (s, 2H), 3.74 (brs, 4H), 3.05 (brs, 4H);
13C NMR (75 MHz, DMSO-d6) δ 161.00, 158.21, 153.94, 153.77,
138.65, 137.98, 133.69, 132.69, 129.11, 123.05, 120.10, 118.34,
118.01, 115.78, 115.59, 108.13, 66.18, 59.74, 54.85, 49.23; MS (ESI)
Compound 12 g (0.7 g, 2.0 mmol) was reacted using the general
procedure to the synthesis of 13o as a white solid, yield 52%, (0.4 g,
1.0 mmol); mp: 240–242 °C. 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s,
1H), 8.06 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.36 (t,
J = 9 Hz, 1H), 7.13 (s, 1H), 7.04–7.02 (m, 1H), 5.54 (s, 2H), 4.15 (t,
J = 6 Hz, 2H), 3.74 (t, J = 6 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ
157.50, 154.20, 153.92, 139.18, 137.44, 133.16, 130.05, 129.55,
128.71, 125.04, 122.67, 120.33, 117.08, 113.96, 107.67, 60.38, 54.32,
m/z:469.2 [M+H]+
.
4.1.48. 2-Cyano-N-(3-((6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-
1H-pyrazolo [3,4-d]pyrimidin-1-yl)methyl)phenyl)acetamide (13j)
Compound 12c (0.8 g, 2.0 mmol) was reacted using the general
procedure to the synthesis of 13j as a pale yellow solid, yield 64%,
(0.6 g, 1.3 mmol); mp: 208–210 °C. 1H NMR (300 MHz, CDCl3) δ 8.74
(s, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 7.44 (m,
2H), 7.27 (s, 1H), 7.14–7.11 (m, 1H), 6.96–6.93 (m, 1H), 5.45 (s, 2H),
3.46 (s, 2H), 3.19 (s, 4H), 2.62 (s, 4H), 2.38 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 161.75, 157.14, 154.47, 153.72, 139.13, 137.29, 136.03,
133.81, 129.73, 125.09, 121.13, 120.68, 119.98, 117.04, 113.28,
108.97, 55.21, 50.97, 49.74, 29.83, 26.93; MS (ESI) m/z: 482.2 [M
49.39; MS (ESI) m/z: 376.2 [M+H]+
.
4.1.44. N-(3-((6-((1-(2-Methoxyethyl)-1H-pyrazol-4-yl)amino)-1H-
pyrazolo[3,4-d] pyrimidin-1-yl)methyl)phenyl)cyanamide (13r)
Compound 12 h (0.7 g, 2.0 mmol) was reacted using the general
procedure to the synthesis of 13r as a white solid, yield 79%, (0.6 g,
1.6 mmol); mp: 275–276 °C. 1H NMR (300 MHz, DMSO-d6) δ 8.92 (s,
1H), 8.09 (s, 1H), 8.07 (s, 1H), 7.57 (s, 1H), 7.49 (t, J = 9 Hz, 1H), 7.36
(s, 1H), 7.30 (t, J = 9 Hz, 1H), 7.08–7.06 (m, 1H), 5.52 (s, 2H), 4.24 (t,
J = 6 Hz, 3H), 3.84 (s, 3H), 3.66 (t, J = 6 Hz, 3H), 3.20 (s, 3H); 13C
NMR (75 MHz, DMSO-d6) δ 161.05, 157.73, 154.14, 153.12, 138.67,
138.18, 133.83, 131.60, 129.50, 129.14, 123.02, 122.82, 120.24,
118.35, 115.87, 107.60, 70.80, 57.95, 51.25, 49.43, 26.71; MS (ESI) m/
+H]+
.
4.1.49. 2-Cyano-N-(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-
pyrazolo[3,4-d] pyrimidin-1-yl)methyl)phenyl)acetamide (13 m)
z: 390.2 [M+H]+
.
Compound 12f (0.6 g, 2.0 mmol) was reacted using the general
procedure to the synthesis of 13 m as a pale yellow solid, yield 56%,
(0.4 g, 1.1 mmol); mp: 162–164 °C. 1H NMR (300 MHz, DMSO-d6) δ
8.92 (s, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.54 (s, 1H), 7.50–7.48 (m, 1H),
7.39 (s, 1H), 7.31 (t, J = 9 Hz, 1H), 7.10–7.08 (m, 1H), 5.54 (s, 2H),
3.83 (s, 3H) , 3.39 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 161.14,
157.72, 154.18, 152.41, 138.71, 138.27, 133.86, 129.21, 123.21,
123.03, 120.55, 118.39, 118.06, 115.95,107.62, 49.58, 38.80, 26.77;
HRMS (ESI): m/z 388.1633 [M+H]+ (Calcd for C19H17N9O, 387.1556).
4.1.45. N-(4-((6-((4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]
pyrimidin-1-yl) methyl)phenyl)cyanamide (14a)
Compound 12d (0.8 g, 2.0 mmol) was reacted using the general
procedure to the synthesis of 14a as a white solid, yield 70%, (0.6 g,
1.4 mmol); mp: 208–210 °C. 1H NMR (300 MHz, DMSO-d6) δ 8.93 (s,
1H), 8.04 (s, 1H), 7.71–7.69 (m, 2H), 7.30–7.27 (m, 2H), 6.94–6.92 (m,
3H), 5.42 (s, 2H), 3.74 (brs, 4H), 3.05 (brs, 4H); 13C NMR (75 MHz,
DMSO-d6) δ 158.19, 153.99, 153.62, 141.94, 138.10, 133.60, 132.67,
131.31, 129.30, 120.13, 115.57, 115.09, 111.96, 108.20, 66.17, 54.44,
4.1.50. 2-Cyano-N-(3-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-
1H-pyrazolo [3,4-d]pyrimidin-1-yl)methyl)phenyl)acetamide (13p)
Compound 12 g (0.7 g, 2.0 mmol) was reacted using the general
procedure to the synthesis of 13p as a pale yellow solid, yield 43%,
(0.4 g, 0.9 mmol); mp: 220–221 °C. 1H NMR (300 MHz, DMSO-d6) δ
8.91 (s, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.57 (s, 1H), 7.55–7.52 (m, 1H),
7.49 (s, 1H), 7.28 (t, J = 9 Hz, 1H), 7.06 (m, 1H), 5.50 (s, 2H), 4.12 (t,
J = 6 Hz, 2H), 3.96 (s, 3H), 3.72 (t, J = 6 Hz, 2H); 13C NMR (75 MHz,
DMSO-d6) δ 161.13, 157.70, 154.15, 152.26, 138.81, 138.08, 133.80,
129.77, 129.10, 128.49, 123.10, 122.70, 120.37, 118.14, 116.03,
49.20; MS (ESI) m/z: 427.2 [M+H]+
.
4.1.46. N-(4-((6-((1-Methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]
pyrimidin-1- yl)methyl)phenyl)cyanamide (14e)
Compound 12i (0.6 g, 2.0 mmol) was reacted using the general
procedure to the synthesis of 14e as a white solid, yield 77%, (0.5 g,
1.5 mmol); mp: 169–171 °C. 1H NMR (300 MHz, DMSO-d6) δ 9.01 (s,
1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.68–7.63 (m, 2H), 7.39 (s, 2H),
7.27–7.25 (m, 1H), 6.56–6.47 (m, 1H), 6.24–6.19 (m, 1H), 5.71–5.68
(m, 1H), 5.59 (s, 2H), 3.85 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ
163.20, 157.24, 154.11, 152.61, 138.64, 137.08, 134.86, 131.97,
131.23, 129.72, 128.91, 128.22, 126.68, 123.70, 122.28, 119.46,
107.54, 60.37, 54.20, 49.52, 26.56; MS (ESI) m/z: 418.2 [M+H]+
.
4.1.51. 2-Cyano-N-(3-((6-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)-
1H-pyrazolo [3,4-d]pyrimidin-1-yl)methyl)phenyl)acetamide (13s)
Compound 12 h (0.7 g, 2.0 mmol) was reacted using the general
procedure to the synthesis of 13s as a pale yellow solid, yield 66%,
(0.6 g, 1.3 mmol); mp: 243–245 °C. 1H NMR (300 MHz, DMSO-d6) δ
8.92 (s, 1H), 8.09 (s, 1H), 8.07 (s, 1H), 7.57 (s, 1H), 7.51–7.45 (m, 1H),
7.36 (s, 1H), 7.30 (t, J = 9 Hz, 1H), 7.08–7.06 (m, 1H), 5.52 (s, 2H),
4.24 (t, J = 6 Hz, 2H), 3.84 (s, 2H), 3.66 (t, J = 6 Hz, 2H), 3.20 (s, 3H);
13C NMR (75 MHz, DMSO-d6) δ 161.05, 157.73, 154.14, 153.12,
138.67, 138.18, 133.83, 131.60, 129.50, 129.14, 123.02, 122.82,
120.24, 118.35, 115.87, 107.60, 70.80, 57.95, 51.25, 49.43, 26.71; MS
107.79, 49.52, 38.78; MS (ESI) m/z: 346.2 [M+H]+
.
General procedure for the synthesis of 13d, 13j, 13 m, 13p, 13s and
14b
To a stirred solution of 12 (2.0 mmol) in DMF (10 mL) was added
DIPEA (10.4 mg, 2.0 mmol), HATU (5.0 mmol), and 2-cyanoacetic acid
(2.5 mmol) at 0 °C. The reaction mixture was stirred at room tem-
perature for 16 h. It was quenched with water and extracted with ethyl
acetate (3 × 50 mL). The organic layer was washed with water
(2 × 30 mL) followed by brine (1 × 30 mL), dried over anhydrous
sodium sulfate, and was evaporated to dryness. The crude mass was
purified by silica gel column chromatography (0–10% MeOH in DCM)
to afford the title compounds.
(ESI) m/z: 432.2 [M+H]+
.
4.1.52. 2-Cyano-N-(4-((6-((4-morpholinophenyl)amino)-1H-pyrazolo
[3,4-d]pyrimidin −1-yl)methyl)phenyl)acetamide (14b)
Compound 12d (0.8 g, 2.0 mmol) was reacted using the general
procedure to the synthesis of 14b as a pale yellow solid, yield 70%,
(0.7 g, 1.4 mmol); mp: 197–199 °C. 1H NMR (300 MHz, DMSO-d6) δ
8.93 (s, 1H), 8.05 (s, 1H), 7.71–7.68 (m, 2H), 7.52–7.49 (m, 2H),
7.27–7.24 (m, 2H), 6.93–6.90 (m, 2H), 5.43 (s, 2H), 3.87 (brs, 2H), 3.74
(brs, 4H), 3.05 (s, 4H); 13C NMR (75 MHz, DMSO-d6) δ 161.00, 158.17,
4.1.47. 2-Cyano-N-(3-((6-((4-morpholinophenyl)amino)-1H-pyrazolo
[3,4-d]pyrimidin −1-yl)methyl)phenyl)acetamide (13d)
Compound 12b (0.8 g, 2.0 mmol) was reacted using the general
procedure to the synthesis of 13d as a pale yellow solid, yield 67%,
(0.6 g, 1.3 mmol); mp: 175–177 °C. 1H NMR (300 MHz, DMSO-d6) δ
13