S. Wang, R.-H. Zhang, H. Zhang et al.
European Journal of Medicinal Chemistry 222 (2021) 113573
4
.2.16. 4-((4-((2-chlorophenyl)amino)-5-(trifluoromethyl)
pyrimidin-2-yl)amino)-N-methylbenzamide (12b)
White solid; 28% yield; m. p. 264.2e265.9 C; 1H NMR
400 MHz, DMSO‑d 9.86 (s, 1H), 8.87 (s, 1H), 8.40 (s, 1H), 8.14 (d,
J ¼ 4.4 Hz, 1H), 7.64 (dd, J ¼ 6.8, 2.0 Hz, 1H), 7.54 (d, J ¼ 6.8 Hz, 1H),
.49e7.45 (m, 4H), 7.39 (d, J ¼ 8.4 Hz, 2H), 2.76 (d, J ¼ 4.4 Hz, 3H).
126.49, 123.81, 118.85, 118.32, 111.81, 111.55, 99.02, 55.66, 26.70.
-
HRMS (ESI) calcd for C20
416.1327. RT,HPLC ¼ 12.99 min, purity >99%.
H
18
F
3
N
5
O
2
[M ꢂ H] : 416.1334; found:
ꢀ
(
6
) d
4.2.22. 4-((4-((4-methoxyphenyl)amino)-5-(trifluoromethyl)
pyrimidin-2-yl)amino)-N-methylbenzamide (12h)
7
1
3
ꢀ
1
C NMR (100 MHz, DMSO‑d
6
)
d
166.76, 160.81, 158.53, 156.08,
White solid; 57% yield; m. p. 251.4e255.0 C; H NMR (400 MHz,
OD)
8.23 (s, 1H), 7.56e7.50 (s, 4H), 7.30 (d, J ¼ 8.8 Hz, 2H), 6.97
(d, J ¼ 8.8 Hz, 2H), 3.84 (s, 3H), 2.86 (s, 3H). C NMR (100 MHz,
CD OD) 169.09, 160.61, 158.00, 154.89, 154.84, 142.94, 130.71,
142.82, 136.42, 131.03, 131.01, 130.22, 128.92, 128.36, 127.84, 126.55,
CD
3
d
þ
13
123.87, 118.26, 26.68. HRMS (ESI) calcd for C19
H
15
F
3
N
6
O
3
[MþH] :
4
22.0989; found: 422.0974. RT,HPLC ¼ 6.55 min, purity >95%.
3
d
1
27.61, 127.52, 127.44, 127.16, 126.15, 123.48, 118.38, 113.78, 113.75,
þ
4.2.17. N-methyl-4-((4-((2-nitrophenyl)amino)-5-(trifluoromethyl)
54.71, 25.52. HRMS (ESI) calcd for C20
found: 418.1482. RT,HPLC ¼ 6.37 min, purity >96%.
H
18
F
3
N
5
O
2
[MþH] : 418.1485;
pyrimidin-2-yl)amino)benzamide (12c)
White solid; 43% yield; m. p. 251.0e253.1 C; H NMR (400 MHz,
DMSO‑d
10.08 (s, 1H), 9.56 (s,1H), 8.52 (s, 1H), 8.26 (d, J ¼ 4.4 Hz,
H), 8.17 (d, J ¼ 8.0 Hz, 1H), 8.02 (s, 1H), 7.85 (d, J ¼ 8.0 Hz, 1H),
ꢀ
1
6
)
d
4.2.23. 4-((3-((3-fluoro-4-methoxyphenyl)amino)-4-
(trifluoromethyl)phenyl)amino)-N-methylbenzamide(12i)
1
13
ꢀ
1
7
.61e7.53 (m, 5H), 2.76 (d, J ¼ 4.4 Hz, 3H). C NMR (100 MHz,
White solid; 48% yield; m. p. 234.2e237.0 C; H NMR (400 MHz,
CDCl
8.31 (s, 1H), 7.64 (d, J ¼ 8.0 Hz, 2H), 7.54e7.52 (m, 3H), 7.45
(d, J ¼ 12.0 Hz, 1H), 7.02 (d, J ¼ 8.4 Hz, 1H), 6.96 (t, J ¼ 8.8 Hz, 1H),
DMSO‑d 166.67, 160.79, 157.74, 157.44, 156.69, 142.43, 134.90,
6
)
d
3
) d
134.89, 133.36, 133.33, 128.45, 127.94, 125.82, 118.92, 118.76, 26.69.
þ
13
HRMS (ESI) calcd for C19
4
H
15
F
3
N
6
O
3
[MþH] : 433.1230; found:
6.82 (s, 1H), 6.09 (s, 1H), 3.93 (s, 3H), 2.99 (d, J ¼ 4.4 Hz, 3H).
C
33.1202. RT,HPLC ¼ 6.38 min, purity >96%.
NMR (100 MHz, CDCl 167.72, 160.35, 157.66, 153.17, 150.73,
3
) d
1
45.62, 145.51, 141.44, 130.20, 130.10, 129.06, 127.85, 119.23, 113.33,
þ
4.2.18. 4-((4-((4-aminophenyl)amino)-5-(trifluoromethyl)
113.30, 56.64, 26.95
436.1391; found: 436.1393. RT,HPLC ¼ 6.37 min, purity >96%.
.
HRMS (ESI) calcd for C20
H F
17 4
N
5
O
2
[MþH] :
pyrimidin-2-yl)amino)-N-methylbenzamide (12d)
White solid; 18% yield; m. p. 266.5e268.9 C; 1H NMR
400 MHz, DMSO‑d 9.71 (s, 1H), 8.45 (s, 1H), 8.29 (s, 1H), 8.09 (d,
J ¼ 4.8 Hz, 1H), 7.63e7.56 (m, 5H), 7.04 (d, J ¼ 8.4 Hz, 2H), 6.63 (d,
ꢀ
(
6
)
d
4.2.24. 4-((4-((3-chloro-4-methoxyphenyl)amino)-5-
(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzamide (12j)
13
ꢀ
1
J ¼ 8.4 Hz, 2H), 5.07 (s, 2H), 2.75 (d, J ¼ 4.4 Hz, 3H). C NMR
White solid; 57% yield; m. p. 230.2e232.5 C; H NMR
(400 MHz, DMSO‑d 9.93 (s, 1H), 8.83 (s, 1H), 8.39 (s, 1H), 8.22 (q,
(
100 MHz, DMSO‑d 166.96,160.99,158.59,155.69,147.29,143.02,
6
)
d
6
) d
1
28.01, 127.93, 126.94, 126.69, 124.00, 118.60, 114.23, 26.71. HRMS
J ¼ 4.4 Hz, 1H), 7.6e7.57 (m, 4H), 7.54 (d, J ¼ 2.8 Hz, 1H), 7.39 (dd,
þ
(
ESI) calcd for C19
H
17
F
3
N
6
O [MþH] : 403.1488; found: 403.1478.
J ¼ 8.8, 2.4 Hz, 1H), 7.19 (d, J ¼ 8.8 Hz, 1H), 3.928 (s, 3H), 2.75 (d,
13
R
T,HPLC ¼ 6.50 min, purity >96%.
J ¼ 4.4 Hz, 1H). C NMR (100 MHz, DMSO‑d
6
) d 166.77, 160.89,
158.12, 156.18, 156.13, 152.76, 142.76, 131.87, 128.24, 128.12, 128.03,
4
.2.19. 4-((4-((3-aminophenyl)amino)-5-(trifluoromethyl)
pyrimidin-2-yl)amino)-N-methylbenzamide (12e)
White solid; 33% yield; m. p. 256.2e258.7 C; 1H NMR
400 MHz, CD OD) 8.25 (s, 1H), 7.67e7.58 (m, 4H), 7.19e7.13 (m,
H), 6.84 (s, 1H), 6.74 (dd, J ¼ 8.0, 2.0 Hz, 1H), 6.67 (dd, J ¼ 8.0,
126.70, 120.90, 118.72, 112.83, 56.84, 26.69. HRMS (ESI) calcd for
þ
C
R
20
H
17ClF
3
N
5
O
2
[MþH] :
452.1095;
found:
452.1084.
ꢀ
T,HPLC ¼ 6.37 min, purity >95%.
(
1
2
3
d
4.2.25. 4-((4-((4-acetamidophenyl)amino)-5-(trifluoromethyl)
pyrimidin-2-yl)amino)-N-methylbenzamide (12k)
13
.0 Hz, 1H), 2.87 (s, 3H). C NMR (100 MHz, CD
3
OD) d 169.13,
160.56, 158.20, 154.94, 154.88, 147.90, 142.97, 138.72, 129.06, 127.53,
White solid; 46% yield; m. p. 278.2e279.5 C; 1H NMR
ꢀ
1
27.13, 126.13, 123.45, 118.37, 112.99, 100.00, 25.52. HRMS (ESI)
(400 MHz, DMSO‑d
6
) d 10.10 (s, 1H), 9.91 (s, 1H), 8.82 (s, 1H), 8.38 (s,
þ
calcd for
R
C
19
H
17
F
3
N
6
O
[MþH] : 403.1488; found: 403.1478.
1H), 8.18 (d, J ¼ 4.4 Hz, 1H), 7.63e7.60 (m, 6H), 7.38 (d, J ¼ 8.8 Hz,
13
T,HPLC ¼ 6.37 min, purity >98%.
2H), 2.76 (d, J ¼ 4.4 Hz, 3H), 2.10 (s, 3H). C NMR (100 MHz,
DMSO‑d 168.97, 166.78, 166.76, 160.88, 142.87, 137.21, 133.56,
6
) d
4
.2.20. 4-((4-((2-methoxyphenyl)amino)-5-(trifluoromethyl)
pyrimidin-2-yl)amino)-N-methylbenzamide (12f)
White solid; 65% yield; m. p. 262.4e265.2 C; 1H NMR
400 MHz, DMSO‑d 9.94 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 8.24 (d,
J ¼ 4.4 Hz, 1H), 7.83 (d, J ¼ 8.8 Hz, 1H), 7.68 (d, J ¼ 8.8 Hz, 1H),
127.97, 127.92, 119.72, 118.66, 100.00, 26.70, 24.55. HRMS (ESI) calcd
þ
for
C
21
H
19
F
3
N
6
O
2
[MþH] : 444.1590; found: 444.1589.
ꢀ
R
T,HPLC ¼ 11.39 min, purity >98%.
(
6
) d
4.2.26. N-methyl-4-((4-((4-((methylsulfinyl)amino)phenyl)amino)-
5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (12l)
White solid; 40% yield; m. p. 282.5e284.6 C; 1H NMR
7
.59e7.55 (m, 4H), 7.32 (t, J ¼ 8.0 Hz, 1H), 7.18 (d, J ¼ 8.0 Hz, 1H),
13
ꢀ
7.03 (td, J ¼ 7.6, 1.2 Hz, 1H), 3.78 (s, 3H), 2.76 (d, J ¼ 4.4 Hz, 3H).
C
NMR (100 MHz, DMSO‑d
6
)
d
167.35, 167.17, 160.92, 158.27, 157.94,
6
(400 MHz, DMSO‑d ) d 9.93 (s, 1H), 9.86 (s, 1H), 8.86 (s, 1H), 8.40 (s,
1
42.78, 140.57, 130.08, 128.46, 128.37, 127.99, 127.28, 126.58, 123.89,
1H), 8.16 (d, J ¼ 4.4 Hz, 1H), 7.59 (s, 4H), 7.43 (d, J ¼ 8.4 Hz, 2H), 7.27
13
120.88, 119.06, 118.97, 100.00, 56.33, 26.76. HRMS (ESI) calcd for
(d, J ¼ 8.8 Hz, 2H), 3.04 (s, 3H), 2.76 (d, J ¼ 4.4 Hz, 3H). C NMR
(100 MHz, DMSO‑d 172.49, 170.87, 166.94, 160.89, 158.11, 156.03,
142.76, 136.04, 134.80, 128.24, 127.90, 127.43, 126.49, 120.83, 120.77,
þ
C
R
20
H
18
F
3
N
5
O
2
[MþH] :
418.1485;
found:
418.1484.
6
) d
T,HPLC ¼ 6.55 min, purity >95%.
-
1
18.94, 60.27, 26.69. HRMS (ESI) calcd for C20
H
19
F
3
N
6
O
2
S [M ꢂ H] :
4.2.21. 4-((4-((3-methoxyphenyl)amino)-5-(trifluoromethyl)
479.1113; found: 479.1066. RT,HPLC ¼ 11.76 min, purity >99%.
pyrimidin-2-yl)amino)-N-methylbenzamide (12g)
ꢀ
1
White solid; 53% yield; m. p. 284.2e289.1 C; H NMR (400 MHz,
DMSO‑d
9.87 (s, 1H), 8.69 (s, 1H), 8.40 (s, 1H), 8.15 (d, J ¼ 4.4 Hz,
H), 7.61 (q, J ¼ 8.8 Hz, 4H), 7.33 (t, J ¼ 8.0 Hz,1H), 7.09 (d, J ¼ 8.0 Hz,
H), 7.07 (t, J ¼ 2.0 Hz, 1H), 6.85 (dd, J ¼ 8.4, 2.4 Hz, 1H), 3.75 (s, 3H),
4.3. Biochemistry
6
) d
1
1
2
4.3.1. Kinase assay
In vitro FAK, VEGFR2, PYK2, TRKA, TRKB, TRKC, JAK2, JAK3, and
TYK2 kinases inhibition potency were measured using radiometric
assay provided by Kinase Profiler service (ICE Bioscience Co. Ltd,
13
.76 (d, J ¼ 4.4 Hz, 3H). C NMR (100 MHz, DMSO‑d
6
) d 166.80,
160.94, 160.01, 157.97, 156.17, 142.76, 139.80, 129.63, 128.25, 127.95,
15