S. Nikhar, I. Siokas, L. Schlicher et al.
European Journal of Medicinal Chemistry 215 (2021) 113252
N-(3-(Methylsulfonyl)phenyl)formamide (A13c). White solid
131.2, 131.1, 130.6, 114.8, 39.3, 29.4.
(80% yield): 1H NMR (400 MHz, DMSO‑d6)
d
10.64 (s, 1H), 8.40 (s,
6-(4-((Tert-butyldimethylsilyl)oxy)phenyl)-8-methyl-2-
1H), 8.28 (s, 1H), 7.89e7.86 (m, 1H), 7.67e7.63 (m, 2H), 3.24 (s, 3H).
(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (A11k). Light
13C NMR (100 MHz, DMSO‑d6)
d
160.7, 141.9, 139.4, 130.8, 124.1,
yellow solid (64% yield): 1H NMR (600 MHz, CDCl3)
d 8.96 (s, 1H),
122.5, 117.5, 44.1.
7.80 (s, 1H), 7.60 (d, J ¼ 8.4 Hz, 2H), 6.88 (d, J ¼ 8.4 Hz, 2H), 3.85 (s,
General Procedure for the preparation of 2-(methylsulfonyl)
pyrido[2,3-d]pyrimidin-7(8H)-ones (A11a-i) and (A11k-t).
Exemplified for 6-(2,4-dichlorophenyl)-8-methyl-2-(methyl-
sulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (A11a). m-CPBA
(85 mg, 55%) was added to the solution of A9a (38 mg, 0.108 mmol)
in DCM (2 mL). The solution was stirred for 3 h. The reaction
mixture was then partitioned between water and DCM and the
organic layer was washed with brine, filtered and concentrated. The
residue was purified by column chromatography using silica gel
(40% EtOAc/Hexane) to get A11a as a white solid (63% yield). 1H
3H), 3.39 (s, 3H), 0.98 (s, 9H), 0.21 (s, 6H). 13C NMR (150 MHz,
CDCl3)
d 163.6, 162.0, 157.2, 156.6, 154.3, 136.9, 130.4, 129.9, 127.5,
120.2, 115.7, 39.3, 29.2, 25.7, 18.3.
6-(4-Methoxyphenyl)-8-methyl-2-(methylsulfonyl)pyrido
[2,3-d]pyrimidin-7(8H)-one (A11l). Yellow solid (97% yield): 1H
NMR (400 MHz, CDCl3)
d
8.98 (s, 1H), 7.80 (s, 1H), 7.68 (d, J ¼ 8.8 Hz,
2H), 6.98 (d, J ¼ 8.8 Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.42 (s, 3H).
8-Ethyl-2-(methylsulfonyl)-6-phenylpyrido[2,3-d]pyr-
imidin-7(8H)-one (A11m). White solid (55% yield): 1H NMR
(400 MHz, CDCl3)
d 9.01 (s, 1H), 7.85 (s, 1H), 7.72e7.67 (m, 2H),
NMR (400 MHz, CDCl3)
1H), 7.36 (dd, J ¼ 8.2, 2.3 Hz,1H), 7.31 (d, J ¼ 8.2 Hz,1H), 3.89 (s, 3H),
3.43 (s, 3H). 13C NMR (100 MHz, CDCl3)
164.7, 161.0, 157.4, 155.2,
136.0, 135.4, 134.3, 134.0, 132.1, 132.0, 131.0, 127.4, 114.9, 39.3, 29.4.
6-(2-Chlorophenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-
d]pyrimidin-7(8H)-one (A11b). White solid (45% yield): 1H NMR
d
9.01 (s, 1H), 7.82 (s, 1H), 7.53 (d, J ¼ 1.8 Hz,
7.52e7.44 (m, 3H), 4.60 (q, J ¼ 7.0 Hz, 2H), 3.42 (s, 3H), 1.40 (t,
J ¼ 7.1 Hz, 3H).
d
8-(2-Hydroxyethyl)-2-(methylsulfonyl)-6-phenylpyrido[2,3-
d]pyrimidin-7(8H)-one (A11n). Light yellow solid (81% yield),
which was used without purification in next step.
6-(2,6-Dichlorophenyl)-8-(2-methoxyethyl)-2-(methyl-
sulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (A11o). White solid
(400 MHz, CDCl3)
7.42e7.32 (m, 3H), 3.87 (s, 3H), 3.42 (s, 3H). 13C NMR (100 MHz,
CDCl3) 164.5, 161.2, 157.3, 155.1, 136.5, 133.8, 133.7, 133.4, 131.2,
d
9.00 (s, 1H), 7.82 (s, 1H), 7.48 (d, J ¼ 7.2 Hz, 1H),
(58% yield): 1H NMR (400 MHz, CDCl3)
d 9.02 (s, 1H), 7.78 (s, 1H),
d
7.43 (d, J ¼ 8.2 Hz, 2H), 7.33 (dd, J ¼ 8.8, 7.2 Hz, 1H), 4.79 (t,
130.6, 130.0, 127.0, 115.0, 39.4, 29.3.
J ¼ 5.6 Hz, 2H), 3.80 (t, J ¼ 5.6 Hz, 2H), 3.41 (s, 3H), 3.36 (s, 3H). 13
C
8-Methyl-2-(methylsulfonyl)-6-phenylpyrido[2,3-d]pyr-
NMR (100 MHz, CDCl3) d 164.6, 160.2, 157.6, 155.4, 135.1, 134.6,
imidin-7(8H)-one (A11c). Light yellow solid (54% yield): 1H NMR
132.7, 130.9, 128.3, 114.9, 69.1, 59.0, 41.2, 39.4.
(400 MHz, CDCl3)
7.49e7.44 (m, 3H), 3.88 (s, 3H), 3.42 (s, 3H). 13C NMR (100 MHz,
CDCl3) 164.0, 161.9, 156.9, 154.6, 137.6, 134.5, 131.15, 129.7, 129.0,
d
9.00 (s, 1H), 7.85 (s, 1H), 7.70e7.66 (m, 2H),
8-Benzyl-6-(2,6-dichlorophenyl)-2-(methylsulfonyl)pyrido
[2,3-d]pyrimidin-7(8H)-one (A11p). White solid (61% yield): 1H
d
NMR (400 MHz, CDCl3)
2H), 7.45 (d, J ¼ 8 Hz, 2H), 7.39e7.24 (m, 4H), 5.73 (s, 2H), 3.33 (s,
3H). 13C NMR (100 MHz, CDCl3)
164.6, 160.4, 157.6, 154.9, 135.8,
d
9.01 (s, 1H), 7.78 (s, 1H), 7.59 (d, J ¼ 7.6 Hz,
128.6, 115.6, 39.3, 29.3.
6-(4-Chlorophenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-
d
d]pyrimidin-7(8H)-one (A11d). White solid (72% yield): 1H NMR
135.1, 134.9, 132.7, 130.9, 129.3, 128.7, 128.3, 128.2, 115.0, 45.5, 39.5.
6-(2,6-Dichlorophenyl)-8-isobutyl-2-(methylsulfonyl)pyrido
[2,3-d]pyrimidin-7(8H)-one (A11q). White solid (87% yield): 1H
(400 MHz, CDCl3)
d
9.01 (s, 1H), 7.86 (s, 1H), 7.652 (d, J ¼ 8.8 Hz, 2H),
7.445 (d, J ¼ 8.8 Hz, 2H), 3.89 (s, 3H), 3.43 (s, 3H). 13C NMR
(100 MHz, CDCl3)
d
164.2, 161.6, 157.0, 154.7, 136.4, 135.9, 132.9,
NMR (400 MHz, CDCl3)
d
9.03 (s, 1H), 7.77 (s, 1H), 7.43 (d, J ¼ 7.6 Hz,
131.2, 130.3, 128.9, 115.4, 39.3, 29.4.
2H), 7.33 (dd, J ¼ 9.0, 7.4 Hz,1H), 4.40 (d, J ¼ 7.3 Hz, 2H), 3.41 (s, 3H),
6-(4-(Tert-butyl)phenyl)-8-methyl-2-(methylsulfonyl)pyrido
2.37e2.27 (sep, J ¼ 6.8, 7.2 Hz, 1H), 0.98 (d, J ¼ 6.9 Hz, 6H). 13C NMR
[2,3-d]pyrimidin-7(8H)-one (A11e). White solid (81% yield): 1H
(100 MHz, CDCl3)
d 164.7, 160.4, 157.7, 155.2, 135.0, 134.8, 134.7,
NMR (400 MHz, CDCl3)
d
8.98 (s, 1H), 7.84 (s, 1H), 7.63 (d, J ¼ 8.8 Hz,
132.9, 130.8, 128.3, 114.8, 49.1, 39.3, 27.6, 20.3.
2H), 7.47 (d, J ¼ 8 Hz, 2H), 3.86 (s, 3H), 3.40 (s, 3H), 1.34 (s, 9H). 13
C
6-(4-Chlorophenyl)-8-isobutyl-2-(methylsulfonyl)pyrido
[2,3-d]pyrimidin-7(8H)-one (A11r). Light brown solid (66% yield),
which was used without purification in next step.
NMR (100 MHz, CDCl3)
131.7, 130.6, 128.7, 125.6, 115.7, 39.3, 34.9, 31.3, 29.3.
d 163.8, 162.0, 156.8, 154.5, 153.0, 137.4,
6-(2,6-Dichlorophenyl)-8-methyl-2-(methylsulfonyl)pyrido
6-(2,6-Dichlorophenyl)-2-(methylsulfonyl)-8-(3-(methyl-
[2,3-d]pyrimidin-7(8H)-one (A11f). White solid (93% yield): 1H
sulfonyl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one
(A11s).
9.03 (s, 1H),
NMR (600 MHz, CDCl3)
d
9.03 (s, 1H), 7.77 (s, 1H), 7.45 (d, J ¼ 7.8 Hz,
White powder (79% yield): 1H NMR (500 MHz, CDCl3)
d
2H), 7.35 (t, J ¼ 7.8, 9 Hz, 1H), 3.91 (s, 3H), 3.44 (s, 3H).
8.25 (s, 1H), 7.91 (d, J ¼ 8 Hz, 1H), 7.86 (d, J ¼ 8 Hz, 1H), 7.81 (s, 1H),
7.52 (t, J ¼ 7.5 Hz, 1H), 7.46 (d, J ¼ 7.5 Hz, 2H), 7.38e7.33 (m, 1H),
5.79 (s, 2H), 3.39 (s, 3H), 3.09 (s, 3H).
6-(2,3-Dichlorophenyl)-8-methyl-2-(methylsulfonyl)pyrido
[2,3-d]pyrimidin-7(8H)-one (A11g). Light yellow solid (65% yield):
1H NMR (400 MHz, CDCl3)
d
9.02 (s, 1H), 7.82 (s, 1H), 7.57 (dd, J ¼ 8,
2 Hz, 1H), 7.34e7.25 (m, 2H), 3.90 (s, 3H), 3.44 (s, 3H). 13C NMR
(100 MHz, CDCl3) 164.7, 160.9, 157.4, 155.2, 136.4, 135.8, 133.9,
6-(2,6-Dichlorophenyl)-2-(methylsulfonyl)-8-(4-(methyl-
sulfonyl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one (A11t). White
d
powder (72% yield): 1H NMR (500 MHz, CDCl3)
d 9.03 (s, 1H),
133.7, 132.1, 131.4, 129.2, 127.6, 114.9, 39.3, 29.4.
7.89e7.81 (m, 5H), 7.46 (d, J ¼ 8 Hz, 2H), 7.38e7.35 (m, 1H), 3.37 (s,
6-(2-Chloro-4-fluorophenyl)-8-methyl-2-(methylsulfonyl)
pyrido[2,3-d]pyrimidin-7(8H)-one (A11h). White solid (40%
3H), 3.01 (s, 3H).
General procedure for the preparation of 2,6-diphenyl-pyr-
ido[2,3-d]pyrimidin-7(8H)-ones (15e40). Exemplified for 6-(2,4-
dichlorophenyl)-2-((4-(2-(diethylamino)ethoxy)phenyl)
yield): 1H NMR (400 MHz, CDCl3)
d
9.02 (s,1H), 7.83 (s,1H), 7.37 (dd,
J ¼ 14, 6.6 Hz, 1H), 7.29e7.26 (m, 1H), 7.11 (td, J ¼ 8, 2.4 Hz, 1H), 3.90
(s, 3H), 3.44 (s, 3H). 13C NMR (150 MHz, CDCl3)
164.7, 163.7, 162.0,
d
amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (15). To a
161.2, 157.3, 155.1, 135.5, 134.6, 134.5, 134.0, 132.5, 132.4, 129.7, 117.7,
117.5, 114.9, 114.5, 114.4, 39.3, 29.4.
solution of A13a (30 mg, 0.13 mmol) in THF (0.5 mL) and DMF
(0.5 mL) was added 60% NaH (8 mg, 0.33 mmol) at 0 ꢀC. The mixture
was stirred for 30 min at rt under argon. The mixture was cooled to
6-(2,5-Dichlorophenyl)-8-methyl-2-(methylsulfonyl)pyrido
[2,3-d]pyrimidin-7(8H)-one (A11i). White solid (75% yield): 1H
0
ꢀC and then A11a (25 mg, 0.06 mmol) was added. The reaction
NMR (400 MHz, CDCl3)
7.39e7.36 (m, 2H), 3.89 (s, 3H), 3.44 (s, 3H). 13C NMR (100 MHz,
CDCl3) 164.8, 160.8, 157.4, 155.2, 135.3, 135.0, 134.1, 132.9, 131.9,
d
9.02 (s, 1H), 7.83 (s, 1H), 7.46e7.47 (m, 1H),
mixture was stirred at rt for 2 h. The reaction mixture was
quenched by addition of ice and NaOH (0.5 mL, 2N) solution and
then partitioned between water and EtOAc. The organic layer was
d
10