H. Shan, X. Ma, G. Yan et al.
European Journal of Medicinal Chemistry 219 (2021) 113432
d
202.66, 172.15, 161.42, 158.09, 157.25, 155.55, 145.24, 143.26,
4.1.41. 2-(4-(6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazin-
1-yl)-N-(2-(2-(2-(cyanomethylamino)ethoxy) ethoxy)ethyl)
acetamide (B-11)
141.78, 136.52, 130.77, 126.00, 117.79, 113.62, 107.76, 54.07, 54.01,
52.41, 49.56, 48.40, 38.75, 37.31, 32.31, 31.53, 28.09, 27.27, 26.90,
25.77, 13.96. HRMS (DART-TOF) calculated for C34H44N10O4 [M þ
Na]þ m/z 679.3439, found 679.3431.
B-11 (13 mg, 35%) was synthesized with similar procedures as B-
1. 1H NMR (400 MHz, CDCl3)
d
8.83 (s, 1H), 8.18 (d, J ¼ 9.1 Hz, 1H),
4.1.37. 2-(4-(6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazin-
1-yl)-N-(6-(cyanomethylamino)hexyl)acetamide (B-7)
8.04 (d, J ¼ 2.8 Hz, 1H), 7.34 (dd, J ¼ 9.1, 3.0 Hz, 1H), 3.64e3.57 (m,
10H), 3.53e3.49 (m, 2H), 3.25e3.19 (m, 4H), 3.11 (s, 2H), 2.90e2.86
(m, 2H), 2.76e2.70 (m, 4H), 2.55 (s, 3H), 2.39e2.33 (m, 5H),
2.10e2.03 (m, 2H), 1.90e1.86 (m, 2H), 1.26 (s, 3H). 13C NMR
B-7 (7 mg, 22%) was synthesized with similar procedures as B-1.
1H NMR (400 MHz, CDCl3)
d
8.83 (s, 1H), 8.19 (d, J ¼ 9.1 Hz, 1H), 8.04
(101 MHz, CDCl3) d 202.65, 169.98, 161.42, 158.06, 157.21, 155.54,
(d, J ¼ 2.9 Hz, 1H), 7.34 (dd, J ¼ 9.1, 2.9 Hz, 1H), 3.59 (s, 2H),
3.30e3.21 (m, 6H), 3.11 (s, 2H), 2.77e2.71 (m, 6H), 2.55 (s, 3H),
2.39e2.33 (m, 5H), 2.10e2.03 (m, 2H), 1.92e1.86 (m, 2H), 1.58e1.50
(m, 4H), 1.42e1.34 (m, 4H), 1.26 (s, 3H). 13C NMR (101 MHz, CDCl3)
145.08, 143.39, 141.75, 136.43, 130.81, 126.07, 117.81, 113.65, 107.84,
70.36, 70.20, 70.15, 69.98, 61.57, 54.04, 53.25, 49.56, 48.09, 38.72,
37.41, 31.53, 28.10, 25.77, 13.96. HRMS (DART-TOF) calculated for
C
34H46N10O5 [M þ H]þ m/z 675.3727, found 675.3723.
d
202.63, 169.67, 161.42, 158.05, 157.20, 155.55, 145.14, 143.33,
141.75, 136.47, 130.83, 126.11, 117.83, 113.63, 107.84, 61.59, 54.05,
53.35, 49.58, 48.66, 38.80, 37.37, 31.53, 29.71, 29.31, 28.09, 26.63,
25.77, 13.96. HRMS (DART-TOF) calculated for C34H46N10O3 [M þ
H]þ m/z 643.3828 found 643.3820.
4.1.42. 3-(4-(6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyri midin-2-ylamino)pyridin-3-yl)piperazin-
1-yl)-N-(2-(2-(2-(cyanomethylamino)ethoxy) ethoxy)ethyl)
propanamide (B-12)
B-12 (14 mg, 40%) was synthesized with similar procedures as
4.1.38. 3-(4-(6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyri midin-2-ylamino)pyridin-3-yl)piperazin-
1-yl)-N-(6-(cyanomethylamino)hexyl)propan amide (B-8)
B-8 (11 mg, 32%) was synthesized with similar procedures as B-
B-1. 1H NMR (400 MHz, CDCl3)
d
8.84 (s, 1H), 8.19 (d, J ¼ 9.1 Hz, 1H),
8.06 (d, J ¼ 2.8 Hz, 1H), 7.34 (dd, J ¼ 9.1, 2.9 Hz, 1H), 3.68e3.41 (m,
14H), 3.25e3.20 (m, 4H), 2.76e2.69 (m, 6H), 2.55 (s, 3H), 2.47e2.44
(m, 2H), 2.40e2.33 (m, 5H), 2.09e2.04 (m, 2H), 1.92e1.85 (m, 2H),
1. 1H NMR (400 MHz, CDCl3)
d
8.82 (s, 1H), 8.19 (d, J ¼ 9.1 Hz, 1H),
1.26 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 202.68, 172.37, 161.41,
8.06 (d, J ¼ 2.8 Hz, 1H), 7.35 (dd, J ¼ 9.1, 3.0 Hz, 1H), 3.56 (s, 2H),
3.28e3.20 (m, 6H), 2.76e2.66 (m, 8H), 2.55 (s, 3H), 2.46e2.43 (m,
2H), 2.39e2.30 (m, 5H), 2.11e2.03 (m, 2H), 1.92e1.85 (m, 2H),
1.71e1.67 (m, 2H), 1.53e1.45 (m, 4H),1.37e1.35 (m, 2H),1.26 (s, 3H).
158.09, 157.51, 157.26, 155.55, 145.21, 143.35, 141.79, 136.32, 130.77,
126.14, 113.69, 107.76, 70.38, 70.12, 70.05, 68.70, 54.07, 53.83, 52.35,
49.49, 39.67, 38.80, 32.51, 31.53, 28.08, 25.75, 13.95. HRMS (DART-
TOF) calculated for C35H48N10O5 [M þ Na]þ m/z 711.3701, found
711.3698.
13C NMR (101 MHz, CDCl3)
d 202.64, 172.08, 161.41, 158.07, 157.22,
155.55, 145.20, 143.29, 141.75, 136.41, 130.82, 126.03, 117.84, 113.64,
107.84, 54.03, 52.38, 49.58, 48.67, 38.90, 37.35, 32.29, 31.53, 29.56,
29.40, 28.10, 26.82, 26.69, 25.77, 13.96. HRMS (DART-TOF) calcu-
lated for C35H48N10O3 [M þ H]þ m/z 657.3985, found 657.3983.
4.1.43. 2-(4-(6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyri midin-2-ylamino)pyridin-3-yl)piperazin-
1-yl)acetonitrile (B-13)
B-13 (11 mg, 40%) was synthesized with similar procedures as B-
4.1.39. 2-(4-(6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazin-
1-yl)-N-(2-(2-(cyanomethylamino)ethoxy)ethyl)acetamide (B-9)
B-9 (9 mg, 26%) was synthesized with similar procedures as B-1.
1. 1H NMR (400 MHz, CDCl3)
8.04 (d, J ¼ 2.8 Hz, 1H), 7.34 (dd, J ¼ 9.1, 2.9 Hz, 1H), 3.60 (s, 2H),
3.30e3.20 (m, 4H), 2.83e2.78 (m, 4H), 2.55 (s, 3H), 2.41e2.30 (m,
5H), 2.11e2.03 (m, 2H), 1.92e1.86 (m, 2H), 1.26 (s, 3H). 13C NMR
d
8.82 (s, 1H), 8.19 (d, J ¼ 9.1 Hz, 1H),
1H NMR (400 MHz, CDCl3)
d
8.83 (s, 1H), 8.18 (d, J ¼ 9.1 Hz, 1H), 8.05
(101 MHz, CDCl3) d 202.63, 161.42, 158.06, 157.20, 155.55, 145.25,
(d, J ¼ 2.8 Hz, 1H), 7.35 (dd, J ¼ 9.1, 2.9 Hz, 1H), 3.70e3.55 (m, 6H),
3.54e3.48 (m, 2H), 3.29e3.16 (m, 4H), 3.12 (s, 2H), 2.93e2.90 (m,
2H), 2.80e2.68 (m, 4H), 2.55 (s, 3H), 2.42e2.30 (m, 5H), 2.10e2.01
(m, 2H), 1.91e1.84 (m, 2H), 1.26 (s, 3H). 13C NMR (101 MHz, CDCl3)
143.25, 141.74, 136.71, 130.84, 126.35, 114.42, 113.64, 107.86, 54.07,
51.59, 49.23, 46.00, 31.53, 28.10, 25.77, 13.96. HRMS (DART-TOF)
calculated for C26H30N8O2 [M þ H]þ m/z 487.2566, found 487.2566.
d
202.66, 170.00, 161.43, 158.06, 157.22, 155.54, 146.51, 143.37,
4.1.44. 2-(4-(6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-
141.77, 136.59, 130.79, 126.10, 117.72, 113.61, 107.80, 69.97, 69.88,
61.57, 54.05, 53.32, 49.63, 48.25, 38.71, 37.46, 31.53, 29.69, 28.09,
25.77, 13.96. HRMS (DART-TOF) calculated for C32H42N10O4 [M þ
H]þ m/z 631.3464, found 631.3466.
dihydropyrido[2,3-d]pyrimid-in-2-ylamino)pyridin-3-yl)piperazin-
1-yl)-N-(2-(2-chloroacetamido)ethyl) aceta m-ide (C-1)
TFA (1 mL) was added to a solution of compound 8a (20 mg,
0.031 mmol) in DCM (3 mL), and stirred for 3 h at room tempera-
ture. The mixture was evaporated under reduced pressure, which
directly dissolved into THF (15 mL). The THF solution was added
triethylamine (0.013 mL, 0.093 mmol) which stirred at 0 ꢁC for
5min. Chloroacetyl chloride (0.006 mL, 0.062 mmol) was added
dropwise at 0 ꢁC under N2, the mixture was stirred at room tem-
perature for 5 h. The reaction was monitored by TLC. After
completion of the reaction, it was evaporated under reduced
pressure. Water (20 mL) was added and the mixture was extracted
with EtOAc (20 mL ꢂ 3) and organic layer washed twice with brine,
dried over anhydrous Na2SO4. The green organic layer was
concentrated in vacuo. The crude product was purified by flash
column chromatography to give C-1 as a green solid (9 mg, 46%). 1H
4.1.40. 3-(4-(6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazin-
1-yl)-N-(2-(2-(cyanomethylamino)ethoxy)ethyl)propanamide (B-
10)
B-10 (7 mg, 19%) was synthesized with similar procedures as B-
1. 1H NMR (400 MHz, CDCl3)
d
8.82 (s, 1H), 8.19 (d, J ¼ 8.3 Hz, 1H),
8.04 (d, J ¼ 2.9 Hz, 1H), 7.33 (dd, J ¼ 9.1, 2.9 Hz, 1H), 3.68e3.42 (m,
10H), 3.28e3.20 (m, 4H), 2.78e2.69 (m, 6H), 2.55 (s, 3H), 2.49e2.45
(m, 2H), 2.40e2.32 (m, 5H), 2.09e2.04 (m, 2H), 1.90e1.85 (m, 2H),
1.26 (s, 3H). 13C NMR (101 MHz, DMSO)
d 202.91, 171.66, 161.24,
159.03, 158.72, 156.72, 155.24, 144.74, 143.90, 142.56, 135.81, 129.69,
125.12, 115.60, 107.03, 69.38, 68.06, 54.42, 53.38, 52.69, 48.78,
38.81, 33.54, 31.77, 28.02, 25.57, 14.08. HRMS (DART-TOF) calculated
for C33H44N10O4 [M þ Na]þ m/z 667.3439, found 667.3435.
NMR (400 MHz, CDCl3)
d
8.85 (s, 1H), 8.18 (d, J ¼ 9.1 Hz, 1H), 8.05 (d,
J ¼ 2.8 Hz, 1H), 7.33 (dd, J ¼ 9.1, 2.9 Hz, 1H), 4.04 (s, 2H), 3.56e3.44
(m, 4H), 3.28e3.19 (m, 4H), 3.12 (s, 2H), 2.77e2.68 (m, 4H), 2.55 (s,
16