Journal of Medicinal Chemistry
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249.4 Hz, 1C), 162.83, 160.31, 154.16, 153.44 (d, J = 248.8 Hz, 1C),
151.34, 150.53, 150.45, 146.37, 137.66, 130.29 (d, J = 3.3 Hz, 1C),
130.08 (d, J = 8.9 Hz, 2C), 129.20, 123.91 (d, J = 10.4 Hz, 1C), 123.29−
123.18 (m, 2C), 116.89 (d, J = 23.0 Hz, 2C), 116.48 (d, J = 3.6 Hz, 1C),
109.93, 108.47 (d, J = 21.8 Hz, 1C), 107.90, 105.73, 50.55, 39.26, 21.67
(s, 2C). HRMS: (M − H)− calcd for C29H23F2N6O4, 557.1754; found,
557.1757.
N-(3-Chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-
phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxamide (11d). The compound was prepared
from 20d and 17h by following a similar procedure as described for 13c.
White solid, 59% yield. 1H NMR (400 MHz, acetone-d6): δ 11.05 (s,
1H), 8.66 (s, 1H), 8.37 (d, J = 5.7 Hz, 1H), 8.23 (d, J = 2.5 Hz, 1H),
8.11 (s, 1H), 7.93 (d, J = 0.8 Hz, 1H), 7.66 (dd, J = 8.8, 2.6 Hz, 1H),
7.50−7.40 (m, 2H), 7.39−7.26 (m, 3H), 7.14 (d, J = 2.4 Hz, 1H), 6.59
(dd, J = 5.7, 2.4 Hz, 1H), 4.93 (p, J = 6.8 Hz, 1H), 3.90 (s, 3H), 1.50 (d,
J = 6.8 Hz, 6H). 13C NMR (126 MHz, CDCl3): δ 164.88, 163.13,
162.93 (d, J = 249.7 Hz, 1C), 160.25, 154.10, 151.31, 150.44, 146.54,
145.89, 137.72, 136.46, 130.26 (d, J = 3.7 Hz, 1C), 130.02 (d, J = 8.8
Hz, 2C), 129.20, 127.65, 123.44, 123.38, 122.63, 119.96, 117.00 (d, J =
23.3 Hz, 2C), 109.00, 107.08, 105.53, 50.67, 39.29, 21.73 (s, 2C).
HRMS: (M + H)+ calcd for C29H25ClFN6O4, 575.1604; found,
575.1603.
3-(4-Fluorophenyl)-1-isopropyl-N-(3-methyl-4-((2-(1-methyl-1H-
pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxamide (11e). The compound was prepared from
20e and 17h by following a similar procedure as described for 13c.
White solid, 70% yield. 1H NMR (400 MHz, DMSO-d6): δ 10.91 (s,
1H), 8.66 (s, 1H), 8.33 (d, J = 5.8 Hz, 1H), 8.24 (s, 1H), 7.95 (s, 1H),
7.71−7.62 (m, 2H), 7.47−7.32 (m, 4H), 7.18 (d, J = 2.5 Hz, 1H), 7.09
(d, J = 8.4 Hz, 1H), 6.51 (dd, J = 5.7, 2.4 Hz, 1H), 4.78 (p, J = 6.8 Hz,
1H), 3.85 (s, 3H), 2.10 (s, 3H), 1.42 (d, J = 6.8 Hz, 6H). 13C NMR (126
MHz, CDCl3): δ 165.53, 163.08, 162.86 (d, J = 249.5 Hz, 1C), 160.03,
153.91, 151.17, 150.50, 148.34, 146.23, 137.66, 135.57, 131.54, 130.36
(d, J = 3.4 Hz, 1C), 130.03 (d, J = 8.9 Hz, 2C), 129.16, 123.48, 123.39,
121.96, 119.40, 116.93 (d, J = 23.1 Hz, 2C), 108.97, 106.91, 105.86,
50.50, 39.25, 21.69 (s, 2C), 16.33. HRMS: (M + H)+ calcd for
C30H28FN6O4, 555.2151; found, 555.2155.
3-(4-Fluorophenyl)-1-isopropyl-N-(3-methoxy-4-((2-(1-methyl-
1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxamide (11f). The compound was prepared
from 20f and 17h by following a similar procedure as described for 13c.
White solid, 72% yield. 1H NMR (400 MHz, acetone-d6): δ 10.96 (s,
1H), 8.66 (s, 1H), 8.30 (d, J = 5.7 Hz, 1H), 8.08 (s, 1H), 7.90 (s, 1H),
7.70 (d, J = 2.4 Hz, 1H), 7.52−7.38 (m, 3H), 7.38−7.28 (m, 2H), 7.13
(d, J = 8.6 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.53 (dd, J = 5.7, 2.4 Hz,
1H), 4.94 (p, J = 6.8 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 1.51 (d, J = 6.8
Hz, 6H). 13C NMR (126 MHz, CDCl3): δ 165.69, 163.14, 162.91 (d, J
= 249.5 Hz, 1C), 160.11, 153.75, 151.94, 151.03, 150.50, 146.27,
138.40, 137.68, 136.76, 130.35 (d, J = 3.4 Hz, 1C), 130.03 (d, J = 8.8
Hz, 2C), 129.10, 123.58, 122.99, 117.00 (d, J = 23.2 Hz, 2C), 112.53,
108.79, 106.87, 105.79, 105.47, 56.02, 50.51, 39.26, 21.72 (s, 2C).
HRMS: (M + H)+ calcd for C30H28FN6O5, 571.2100; found, 571.2106.
N-(2,3-Difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-
oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxamide (11g). The compound was prepared
from 20g and 17h by following a similar procedure as described for 13c.
Off-white solid, 52% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.27 (s,
1H), 8.71 (s, 1H), 8.40 (d, J = 5.7 Hz, 1H), 8.31−8.19 (m, 2H), 7.99 (s,
1H), 7.48−7.32 (m, 4H), 7.32−7.22 (m, 2H), 6.77 (dd, J = 5.9, 2.4 Hz,
1H), 4.78 (p, J = 6.9 Hz, 1H), 3.86 (s, 3H), 1.43 (d, J = 6.7 Hz, 6H). 13C
NMR (126 MHz, CDCl3): δ 164.76, 162.88 (d, J = 249.3 Hz, 1C),
162.85, 160.56, 154.21, 151.38, 150.46, 146.60, 144.25 (dd, J = 99.4,
12.6 Hz, 1C), 142.25 (dd, J = 97.9, 12.5 Hz, 1C), 138.13 (d, J = 9.5 Hz
1C), 137.68, 130.19 (d, J = 3.3 Hz, 1C), 130.06 (d, J = 8.7 Hz, 2C),
129.25, 125.72 (d, J = 8.0 Hz, 1C), 123.26, 117.57 (d, J = 3.8 Hz, 2C),
116.93 (d, J = 23.2 Hz, 1C), 116.64 (d, J = 3.9 Hz, 1C), 108.85, 106.97,
105.45, 50.65, 39.26, 21.67 (s, 2C). HRMS: (M − H)− calcd for
C29H22F3N6O4, 575.1660; found, 575.1667.
hydropyrimidine-5-carboxamide (11h). The compound was prepared
from 24 and 17h by following a similar procedure as described for 13c.
Light brown solid, 56% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.34
(s, 1H), 8.72 (s, 1H), 8.48 (dd, J = 12.5, 7.2 Hz, 1H), 8.39 (d, J = 5.7 Hz,
1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.61 (dd, J = 11.1, 7.4 Hz, 1H), 7.47−
7.33 (m, 4H), 7.27 (d, J = 2.4 Hz, 1H), 6.74 (dd, J = 5.7, 2.5 Hz, 1H),
4.78 (p, J = 6.7 Hz, 1H), 3.86 (s, 3H), 1.43 (d, J = 6.7 Hz, 6H). 13C
NMR (126 MHz, CDCl3): δ 164.66, 162.86 (d, J = 249.4 Hz, 1C),
162.82, 160.40, 154.20, 151.36, 150.45, 149.56−147.46 (m, 2C),
146.61, 137.68, 136.10 (dd, J = 14.3, 10.2 Hz, 1C), 130.19 (d, J = 3.6
Hz, 1C), 130.05 (d, J = 8.8 Hz, 2C), 129.23, 124.82 (t, J = 11.2 Hz, 1C),
123.28, 116.91 (d, J = 23.2 Hz, 2C), 110.58 (d, J = 26.2 Hz, 1C), 110.17
(d, J = 23.3 Hz, 1C), 108.76, 106.86, 105.40, 50.68, 39.26, 21.67 (s, 2C).
HRMS: (M + H)+ calcd for C29H24F3N6O4, 577.1806; found, 577.1812.
N-(3,5-Difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-
oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxamide (11i). The compound was prepared
from 20h and 17h by following a similar procedure as described for 13c.
Off-white solid, 62% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s,
1H), 8.69 (s, 1H), 8.39 (d, J = 5.7 Hz, 1H), 8.29 (s, 1H), 8.00 (d, J = 0.7
Hz, 1H), 7.79 (d, J = 10.3 Hz, 2H), 7.48−7.28 (m, 5H), 6.74 (dd, J =
5.8, 2.5 Hz, 1H), 4.78 (p, J = 6.8 Hz, 1H), 3.86 (s, 3H), 1.43 (d, J = 6.8
Hz, 6H). 13C NMR (126 MHz, CDCl3): δ 164.60, 163.07, 162.89 (d, J
= 249.7 Hz, 1C), 160.39, 155.70 (dd, J = 249.7, 5.9 Hz, 2C), 154.13,
151.31, 150.34, 146.73, 137.69, 136.28 (t, J = 12.3 Hz, 1C), 130.15 (d, J
= 3.5 Hz, 1C), 129.96 (d, J = 8.7 Hz, 2C), 129.23, 125.69 (t, J = 15.6 Hz,
1C), 123.29, 116.96 (d, J = 23.2 Hz, 2C), 107.96, 106.23, 105.15,
104.73−104.45 (m, 2C), 50.74, 39.24, 21.65 (s, 2C). HRMS: (M + H)+
calcd for C29H24F3N6O4, 577.1806; found, 577.1809.
N-(4-((2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-3-fluo-
rophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxamide (12a). The compound was prepared
from 20i and 17h by following a similar procedure as described for 13c.
Off-white solid, 97% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.01 (s,
1H), 8.66 (s, 1H), 8.39 (d, J = 5.8 Hz, 1H), 8.12 (s, 1H), 7.97 (dd, J =
12.9, 2.5 Hz, 1H), 7.53−7.30 (m, 6H), 7.04 (d, J = 2.4 Hz, 1H), 6.67
(dd, J = 5.7, 2.5 Hz, 1H), 4.76 (p, J = 6.7 Hz, 1H), 3.75 (s, 3H), 2.35 (s,
3H), 1.41 (d, J = 6.8 Hz, 6H). 13C NMR (126 MHz, CDCl3): δ 164.88,
163.06, 162.84 (d, J = 249.7 Hz, 1C), 160.15, 155.02, 154.41 (d, J =
249.1 Hz, 1C), 151.12, 150.37, 146.66, 146.48, 137.00 (d, J = 12.6 Hz,
1C), 136.58 (d, J = 9.5 Hz, 1C), 130.87, 130.23 (d, J = 3.3 Hz, 1C),
129.97 (d, J = 8.7 Hz, 2C), 123.61, 120.54, 116.91 (d, J = 23.1 Hz, 2C),
116.30 (d, J = 3.4 Hz, 1C), 109.64 (d, J = 23.3 Hz, 1 C), 108.17, 107.80,
105.44, 50.61, 38.80, 21.63 (s, 2C), 14.03. HRMS: (M + H)+ calcd for
C30H27F2N6O4, 573.2056; found, 573.2062.
N-(4-((2-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-3-fluo-
rophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxamide (12b). The compound was prepared
from 20j and 17h by following a similar procedure as described for 13c.
Off-white solid, 73% yield. 1H NMR (400 MHz, CDCl3): δ 10.94 (s,
1H), 8.69 (s, 1H), 8.38 (d, J = 5.7 Hz, 1H), 7.97 (s, 1H), 7.89−7.81 (m,
2H), 7.26−7.23 (m, 5H), 7.13 (t, J = 8.7 Hz, 1H), 6.97 (d, J = 2.4 Hz,
1H), 6.62 (dd, J = 6.0, 2.3 Hz, 1H), 4.97 (p, J = 6.8 Hz, 1H), 3.70−3.57
(m, 1H), 1.50 (d, J = 6.8 Hz, 6H), 1.19−1.12 (m, 2H), 1.07−1.00 (m,
2H). 13C NMR (126 MHz, CDCl3): δ 165.13, 163.09, 162.89 (d, J =
249.5 Hz, 1C), 160.20, 154.43 (d, J = 249.1 Hz, 1C), 154.00, 151.26,
150.41, 146.52, 137.66, 137.04 (d, J = 12.5 Hz, 1C), 136.62 (d, J = 9.6
Hz, 1C), 130.25 (d, J = 3.6 Hz, 1C), 130.00 (d, J = 8.9 Hz, 2C), 128.62,
123.62, 122.85, 116.96 (d, J = 23.2 Hz, 1C), 116.38 (d, J = 3.4 Hz, 2C),
109.76 (d, J = 23.3 Hz, 1C), 108.79, 106.86, 105.50, 50.65, 33.08, 21.69
(s, 2C), 6.66 (s, 2C). HRMS: (M + H)+ calcd for C31H27F2N6O4,
585.2056; found, 585.2060.
N-(3-Fluoro-4-((2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-
yl)pyridin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-
dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (12c). The com-
pound was prepared from 20k and 17h by following a similar procedure
as described for 13c. Off-white solid, 89% yield. 1H NMR (400 MHz,
DMSO-d6): δ 11.03 (s, 1H), 8.68 (s, 1H), 8.37 (d, J = 5.7 Hz, 1H), 8.22
(s, 1H), 8.05−7.92 (m, 2H), 7.59−7.20 (m, 7H), 6.65 (dd, J = 5.8, 2.4
Hz, 1H), 4.78 (p, J = 6.6 Hz, 1H), 4.72 (s, 1H), 4.03 (s, 2H), 1.42 (d, J =
6.7 Hz, 6H), 1.07 (s, 6H). 13C NMR (126 MHz, CDCl3): δ 165.19,
N-(2,5-Difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-
oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetra-
3968
J. Med. Chem. 2021, 64, 3956−3975