X. Chen, G. Wang, A.M. Mohammed Alsayed et al.
European Journal of Medicinal Chemistry 214 (2021) 113203
4.2.9.6. 4-(5-Chloro-2-hydroxybenzamido)-N-(4-methoxyphenyl)-
J ¼ 7.9 Hz,1H), 7.07 (d, J ¼ 8.8 Hz,1H), 4.68 (t, J ¼ 6.3 Hz, 2H), 3.59 (s,
1H-indazole-1-carboxamide (11f). White powder, 74.5% yield, m.p:
3H), 3.07 (t, J ¼ 6.4 Hz, 2H). 13C NMR (126 MHz, DMSO‑d6)
d (ppm):
231.4e232.5 ꢀC. 1H NMR (500 MHz, DMSO‑d6)
d
(ppm): 11.78 (s,
171.01, 164.26,156.46, 148.88, 133.05,129.95, 128.84, 125.85, 123.04,
122.97, 119.77, 119.11, 116.26, 113.69, 112.18, 51.59, 48.47, 34.03. ESI-
MS m/z: 374.1 (M þ H)þ.
1H), 10.87 (s, 1H), 10.29 (s, 1H), 8.50 (s, 1H), 8.14 (d, J ¼ 8.4 Hz, 1H),
7.99 (d, J ¼ 2.5 Hz, 1H), 7.81 (d, J ¼ 7.6 Hz, 1H), 7.68 (d, J ¼ 8.9 Hz,
2H), 7.60 (t, J ¼ 8.0 Hz, 1H), 7.50 (dd, J ¼ 8.8, 2.6 Hz, 1H), 7.07 (d,
J ¼ 8.8 Hz, 1H), 6.95 (d, J ¼ 9.0 Hz, 2H), 3.76 (s, 3H). 13C NMR
4.2.10.6. 5-Chloro-2-hydroxy-N-[2-(2-hydroxyethyl)-2H-indazol-4-
(126 MHz, DMSO‑d6)
d
(ppm): 164.76,155.98,148.85,144.57,140.22,
yl]benzamide
(15b). White
powder,
78.2%
yield,
m.p:
139.47, 133.04, 131.40, 130.65, 128.90, 123.56, 122.23, 119.91, 119.44,
175.6e176.9 ꢀC. 1H NMR (500 MHz, DMSO‑d6)
d (ppm): 12.00 (s,
118.89, 116.81, 112.81, 111.04. ESI-MS m/z: 436.4 (M þ H)þ.
1H), 10.68 (s, 1H), 8.38 (s, 1H), 8.00 (d, J ¼ 2.6 Hz, 1H), 7.57 (d,
J ¼ 7.2 Hz, 1H), 7.49 (dd, J ¼ 8.8, 2.7 Hz, 1H), 7.42 (d, J ¼ 8.6 Hz, 1H),
7.28e7.20 (m, 1H), 7.07 (d, J ¼ 8.8 Hz, 1H), 5.00 (s, 1H), 4.47 (t,
4.2.10. General procedures for the synthesis of compounds 14a-14d
and 15a-15d
J ¼ 5.3 Hz, 2H), 3.88 (s, 2H). 13C NMR (126 MHz, DMSO‑d6)
d (ppm):
The key intermediates (12a-12d and its respective analogs 13a-
13d) were synthesized from compound 9 following a procedure
described in preparing compounds 10a-10f. The target compounds
14a-14d and its respective analogs 15a-15d were synthesized
following a procedure described in preparing compounds 11a-11f.
164.18, 156.46, 148.79,132.98, 129.92, 128.85, 125.61, 123.06,122.90,
119.81, 119.10, 116.24, 113.52, 111.82, 60.05, 55.75. ESI-MS m/z: 332.1
(M þ H)þ.
4.2.10.7. 5-Chloro-N-{2-[2-(dimethylamino)-2-oxoethyl]-2H-inda-
zol-4-yl}-2-hydroxybenzamide (15c). White powder, 67.4% yield,
4.2.10.1. Methyl 3-(4-(5-chloro-2-hydroxybenzamido)-1H-indazol-1-
m.p: 262.5e263.4 ꢀC. 1H NMR (500 MHz, DMSO‑d6)
d (ppm): 12.06
yl) propanoate (14a). Yellow powder, 78.2% yield, m.p:
(s, 1H), 10.70 (s, 1H), 8.34 (s, 1H), 8.01 (s, 1H), 7.57 (d, J ¼ 7.1 Hz, 1H),
170.6e172.3 ꢀC. 1H NMR (500 MHz, DMSO‑d6)
d (ppm): 12.02 (s,
7.50 (d, J ¼ 8.9 Hz, 1H), 7.41 (d, J ¼ 8.7 Hz, 1H), 7.25 (t, J ¼ 8.0 Hz,1H),
1H), 10.77 (s, 1H), 8.09 (s, 1H), 7.99 (d, J ¼ 2.5 Hz, 1H), 7.72 (d,
J ¼ 7.4 Hz, 1H), 7.51e7.47 (m, 2H), 7.40 (t, J ¼ 7.9 Hz, 1H), 7.08 (d,
J ¼ 8.8 Hz,1H), 4.64 (t, J ¼ 6.6 Hz, 2H), 3.55 (s, 3H), 2.95 (t, J ¼ 6.6 Hz,
7.07 (d, J ¼ 8.7 Hz, 1H), 5.48 (s, 2H), 3.09 (s, 3H), 2.87 (s, 3H). 13
C
NMR (126 MHz, DMSO‑d6)
d (ppm): 166.02, 164.21, 156.46, 148.61,
133.02, 129.95, 128.83, 125.76, 124.28, 122.97, 119.72, 119.11, 116.53,
2H). 13C NMR (126 MHz, DMSO‑d6)
d
(ppm): 171.17, 164.06, 156.14,
113.60, 111.98, 54.20, 36.07, 35.24. ESI-MS m/z: 373.1 (M þ H)þ.
140.21, 133.02, 130.90, 130.30, 129.02, 126.76, 123.07, 120.00, 119.07,
117.00, 111.89, 106.20, 51.45, 43.94, 33.67. ESI-MS m/z: 374.1
(M þ H)þ.
4.2.10.8. 4-(5-Chloro-2-hydroxybenzamido)-N,
indazole-2-carboxamide (15d). White powder, 74.9% yield, m.p:
112.7e113.4 ꢀC. 1H NMR (500 MHz, DMSO‑d6)
(ppm): 11.84 (s, 1H),
N-dimethyl-2H-
d
4.2.10.2. 5-Chloro-2-hydroxy-N-[1-(2-hydroxyethyl)-1H-indazol-4-
10.67 (s, 1H), 8.84 (s, 1H), 7.94 (d, J ¼ 2.5 Hz, 1H), 7.70 (d, J ¼ 7.1 Hz,
yl]benzamide
(14b). White
powder,
89.2%
yield,
m.p:
1H), 7.51e7.43 (m, 2H), 7.40e7.33 (m, 1H), 7.05 (d, J ¼ 8.8 Hz, 1H),
221.6e223.5 ꢀC. 1H NMR (500 MHz, DMSO‑d6)
d
(ppm): 12.04 (s,
3.17 (s, 6H). 13C NMR (126 MHz, DMSO‑d6)
d (ppm): 164.36, 156.11,
1H), 10.79 (s, 1H), 8.08 (s, 1H), 8.00 (d, J ¼ 2.6 Hz, 1H), 7.71 (d,
J ¼ 7.4 Hz, 1H), 7.50 (dd, J ¼ 8.8, 2.7 Hz, 1H), 7.46 (d, J ¼ 8.4 Hz, 1H),
7.37 (t, J ¼ 7.9 Hz, 1H), 7.08 (d, J ¼ 8.8 Hz, 1H), 4.86 (s, 1H), 4.45 (t,
151.84, 149.10, 132.91, 130.82, 128.93, 128.61, 124.28, 122.95, 120.39,
118.99, 115.78, 114.07, 112.61. ESI-MS m/z: 359.1 (M þ H)þ.
J ¼ 5.6 Hz, 2H), 3.82 (s, 2H). 13C NMR (126 MHz, CDCl3)
d
(ppm):
4.2.11. General procedures for the synthesis of compounds 16a and
17a
161.94, 155.27, 134.44, 133.12, 132.64, 131.10, 129.86, 129.52, 128.94,
127.80, 127.59, 123.20, 114.36,111.61, 105.05, 72.63, 61.81, 50.38. ESI-
MS m/z: 333.2 (M þ H)þ.
To a stirred solution of 14a and 15a (0.1 mmol) in MeOH (20 mL)
was added 10% NaOH (10 mL) slowly. The resulting solution was
stirred for 3 h and then quenched by water, the solution was
removed MeOH in vacuo, and the solution was acidated to
pH ¼ 2e3 with 6 N HCl. The precipitated product was collected by
vacuum filtration, and the remaining dissolved product was
extracted with EtOAc (2 ꢁ 20 mL). The precipitate was dissolved in
THF, and its solution was combined with organic layers from the
extractions. Dried over MgSO4, filtration, concentration in vacuo,
and crystallization with THF/EtOAc/hexane afforded desired com-
pounds 16a and 17a, respectively.
4.2.10.3. 5-Chloro-N-[1-(2-(dimethylamino)-2-oxoethyl)-1H-inda-
zol-4-yl]-2-hydroxybenzamide (14c). White powder, 78.2% yield,
m.p: 245.3e246.2 ꢀC. 1H NMR (500 MHz, DMSO‑d6)
d (ppm): 12.02
(s, 1H), 10.79 (s, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 7.70 (s, 1H), 7.50 (d,
J ¼ 8.4 Hz, 1H), 7.36 (s, 2H), 7.08 (d, J ¼ 8.4 Hz, 1H), 5.42 (s, 2H), 3.11
(s, 3H), 2.85 (s, 3H). 13C NMR (126 MHz, DMSO‑d6)
d (ppm): 166.46,
164.08, 156.21, 141.31, 133.03, 130.76, 130.21, 129.01, 126.53, 123.05,
119.98, 119.09, 117.17, 111.77, 106.58, 50.20, 35.96, 35.19. ESI-MS m/z:
373.1 (M þ H)þ.
4.2.11.1. 3-[4-(5-Chloro-2-hydroxybenzamido)-1H-indazol-1-yl]
4.2.10.4. 4-(5-Chloro-2-hydroxybenzamido)-N,N-dimethyl-1H-inda-
propanoic acid (16a). Yellow powder, 69.4% yield, m.p:
zole-1-carboxamide (14d). White powder, 45.3% yield, m.p:
196.3e198.2 ꢀC. 1H NMR (500 MHz, DMSO‑d6)
d (ppm): 12.26 (s,
248.4e249.3 ꢀC. 1H NMR (500 MHz, DMSO‑d6)
d
(ppm): 11.89 (s,
1H), 10.97 (s, 1H), 8.09 (s, 1H), 7.98 (d, J ¼ 2.6 Hz, 1H), 7.75 (d,
1H), 10.82 (s, 1H), 8.36 (s, 1H), 7.99 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H),
J ¼ 7.4 Hz, 1H), 7.51e7.45 (m, 2H), 7.39 (t, J ¼ 8.0 Hz, 1H), 7.07 (d,
7.51 (s, 2H), 7.07 (s, 1H), 3.15 (s, 6H). 13C NMR (126 MHz, DMSO‑d6)
J ¼ 8.8 Hz, 1H), 4.60 (t, J ¼ 6.7 Hz, 2H), 2.87 (t, J ¼ 6.7 Hz, 2H). 13
C
d
(ppm): 164.64, 156.41, 152.58, 140.91, 135.07, 133.10, 130.51,
NMR (126 MHz, DMSO‑d6) d (ppm): 167.52, 165.17, 156.85, 141.11,
128.87, 128.72, 122.93, 119.87, 119.07, 118.13, 114.86, 110.13. ESI-MS
136.30,135.04,133.09,132.93,132.22,130.68,128.40,127.95,126.35,
123.75, 122.77, 119.54, 119.10, 115.31, 112.59, 39.96. ESI-MS m/z:
360.1 (M þ H)þ.
m/z: 359.1 (M þ H)þ.
4.2.10.5. Methyl 3-[4-(5-chloro-2-hydroxybenzamido)-2H-indazol-
2-yl] propanoate (15a). Yellow powder, 65.4% yield, m.p:
4.2.11.2. 3-[4-(5-Chloro-2-hydroxybenzamido)-2H-indazol-2-yl]
99.8e101.2 ꢀC. 1H NMR (500 MHz, DMSO‑d6)
d
(ppm): 12.02 (s, 1H),
propanoic acid (17a). Yellow powder, 78.2% yield, m.p:
10.64 (s, 1H), 8.40 (s, 1H), 8.00 (d, J ¼ 2.2 Hz, 1H), 7.54 (d, J ¼ 7.1 Hz,
105.2e107.1 ꢀC. 1H NMR (500 MHz, DMSO‑d6)
d
(ppm): 10.73 (s,1H),
1H), 7.50 (dd, J ¼ 8.7, 2.4 Hz, 1H), 7.42 (d, J ¼ 8.5 Hz, 1H), 7.25 (t,
8.39 (s, 1H), 7.99 (d, J ¼ 2.7 Hz, 1H), 7.55 (d, J ¼ 7.3 Hz, 1H), 7.48 (dd,
16