A.K. El-Damasy et al. / European Journal of Medicinal Chemistry 207 (2020) 112710
13
4.10. General procedure for synthesis of compounds 9aeh and
10aeg
J ¼ 7.2 Hz, 1H), 4.96 (d, J ¼ 2.5 Hz, 2H); 13C NMR (100 MHz, Acetone-
d6)
d 163.75, 162.88, 161.28, 139.19, 129.26, 127.27, 126.37, 123.25,
123.07, 122.94, 122.85, 120.88, 120.78, 120.46, 120.42, 118.80, 118.57,
115.83 (q, J ¼ 4 Hz), 115.58 (q, J ¼ 4 Hz), 114.56, 110.84, 92.73, 87.17;
HRMS (FABþ) m/z calcd for C23H15F4N4O [MþH]þ: 439.1182, found:
439.1178.
To a stirred solution of compound 8 (75 mg, 0.29 mmol) and the
appropriate acetylene derivative 2aeh or 7aeg (0.29 mmol) in
DMF/Et3N, 1:1 (4 mL) was added PdCl2(PPh3)2 (4.2 mg,
0.006 mmol) and CuI (2.3 mg, 0.012 mmol). The solution was
purged with argon for 15 min, sealed, and heated at 85e90 ꢁC for
18 h. The solvents were evaporated under reduced pressure and to
the residue was added H2O and ethyl acetate (10 mL each). The
organic layer was separated, and the aqueous layer was repeatedly
extracted with ethyl acetate (3 ꢂ 10 mL). The combined organic
layers were washed with brine solution, dried over anhydrous
Na2SO4, and filtered. The solvent was evaporated under reduced
pressure, and the resulting residue was purified by flash column
chromatography on silica gel using the proper elution system to
yield compounds 9aeh and 10aeg in pure form.
4.10.5. N-(3-((3-Amino-1H-indazol-4-yl)ethynyl)phenyl)-3-
morpholino-5-(trifluoromethyl)benzamide (9e)
Flash column chromatography was carried out using (Ethyl
acetate-hexane, 2:1, v/v then switching to 100% ethyl acetate). Yield
58.6%; 1H NMR (400 MHz, DMSO‑d6)
d 11.82 (br.s, 1H), 10.50 (s, 1H),
8.04 (s, 1H), 7.87 (d, J ¼ 8.4 Hz, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 7.48 (t,
J ¼ 7.6 Hz, 1H), 7.41e7.39 (m, 2H), 7.35 (d, J ¼ 8.0 Hz, 1H), 7.28 (t,
J ¼ 8.4 Hz, 1H), 7.16 (d, J ¼ 7.2 Hz, 1H), 5.16 (s, 2H), 3.79 (t, J ¼ 4.8 Hz,
4H), 3.32e3.31 (m, 4H); 13C NMR (100 MHz, DMSO‑d6)
d 165.12,
151.95, 141.75, 139.68, 136.90, 130.83, 130.51, 129.79, 127.35, 126.85,
125.95, 123.43, 123.24, 122.78, 121.74, 120.48, 117.70, 114.40, 114.29,
113.98,111.53, 93.33, 87.59, 66.36, 48.16; HRMS (FABþ) m/z calcd for
4.10.1. N-(3-((3-Amino-1H-indazol-4-yl)ethynyl)phenyl)-3-
(trifluoromethyl)benzamide (9a)
C
27H23F3N5O2 [MþH]þ: 506.1804, found: 506.1806.
Flash column chromatography was carried out using (Ethyl
acetate-hexane, 1:1 then switching to 2:1, v/v). Yield 56%; 1H NMR
(400 MHz, Acetone-d6)
d
11.14 (br. s, 1H), 10.00 (s, 1H), 8.37e8.34
4.10.6. N-(3-((3-Amino-1H-indazol-4-yl)ethynyl)phenyl)-4-
methyl-3-(trifluoromethyl)benzamide (9f)
(m, 2H), 8.18 (s, 1H), 7.97e7.94 (m, 2H), 7.81 (t, J ¼ 7.7 Hz, 1H),
7.50e7.41 (m, 3H), 7.32 (t, J ¼ 8.2 Hz, 1H), 7.22 (d, J ¼ 7.0 Hz, 1H),
Flash column chromatography was carried out using (Ethyl
5.04 (d, J ¼ 7.3 Hz, 2H); 13C NMR (100 MHz, Acetone-d6)
d 164.29,
acetate-hexane, 1:1 then switching to 3:1, v/v). Yield 55.2%; 1H
139.40 (d, J ¼ 9 Hz), 136.07 (d, J ¼ 3 Hz), 131.45, 130.26 (q, J ¼ 32 Hz),
129.64, 129.20, 128.16 (q, J ¼ 4 Hz), 127.17, 127.05, 126.46, 126.34,
124.87, 124.31 (q, J ¼ 4 Hz), 124.15 (q, J ¼ 270 Hz), 123.17, 123.09,
122.94, 122.84, 120.89, 120.79, 92.91, 87.08; HRMS (FABþ) m/z calcd
for C23H16F3N4O [MþH]þ: 421.1276, found: 421.1277.
NMR (400 MHz, DMSO‑d6) d 11.83 (s, 1H), 10.55 (s, 1H), 8.28 (s, 1H),
8.19 (d, J ¼ 7.6 Hz, 1H), 8.07 (s, 1H), 7.87 (d, J ¼ 8.0 Hz, 1H), 7.64 (d,
J ¼ 7.6 Hz, 1H), 7.48 (t, J ¼ 8.0 Hz, 1H), 7.41e7.34 (m, 2H), 7.28 (t,
J ¼ 8.0 Hz, 1H), 7.16 (d, J ¼ 6.8 Hz, 1H), 5.17 (s, 2H), 2.54 (s, 3H); 13
C
NMR (100 MHz, DMSO‑d6)
d 164.65, 149.20, 141.77, 140.54, 139.75,
137.00, 133.06, 132.97, 132.06, 129.77, 128.00 (q, J ¼ 30 Hz), 127.29,
126.84, 125.45 (q, J ¼ 6 Hz), 124.67, 123.38, 123.27 (q, J ¼ 6 Hz),
122.74, 121.63, 114.31, 111.52, 93.38, 87.57, 19.27; HRMS (FABþ) m/z
calcd for C24H18F3N4O [MþH]þ: 435.1432, found: 435.1436.
4.10.2. N-(3-((3-Amino-1H-indazol-4-yl)ethynyl)phenyl)-3,5-
bis(trifluoromethyl)benzamide (9b)
Flash column chromatography was carried out using (Ethyl
acetate-hexane, 1:1 then switching to 2:1, v/v). Yield 62.3%; 1H
NMR (400 MHz, Acetone-d6) d 10.99 (br. s, 1H), 10.14 (s, 1H), 8.64 (s,
4.10.7. N-(3-((3-Amino-1H-indazol-4-yl)ethynyl)phenyl)-4-(4-
methylpiperazin-1-yl)-3-(trifluoromethyl)benzamide (9g)
2H), 8.29 (s, 1H), 8.11 (s, 1H), 7.89 (d, J ¼ 5.6 Hz, 1H), 7.43e7.33 (m,
4H), 7.20 (d, J ¼ 6.0 Hz, 1H), 5.35 (br.s, 2H); 13C NMR (100 MHz,
Flash column chromatography was carried out using (2e5%
Acetone-d6)
d 162.76, 139.04, 137.41, 131.95, 131.62, 131.29, 130.95,
Methanol, 1% NH4OH in dichloromethane). Yield 24.7%; 1H NMR
129.24, 128.34, 127.45,127.36, 125.07, 124.68, 123.65, 123.08,123.02,
(400 MHz, Acetone-d6) d 11.04 (br. s, 1H), 9.85 (s, 1H), 8.32e8.28 (m,
121.98, 120.98, 111.09, 93.25, 86.83; HRMS (FABþ) m/z calcd for
2H), 8.16 (s, 1H), 7.92 (d, J ¼ 8.0 Hz, 1H), 7.61 (d, J ¼ 8.4 Hz, 1H), 7.47
(t, J ¼ 7.9 Hz, 1H), 7.43e7.40 (m, 2H), 7.31 (t, J ¼ 8.4 Hz, 1H), 7.20 (d,
J ¼ 7.0 Hz, 1H), 4.98 (br. s, 2H), 3.06 (t, J ¼ 4.7 Hz, 4H), 2.57 (t,
J ¼ 4.6 Hz, 4H), 2.31 (s, 3H); 13C NMR (100 MHz, Acetone-d6)
C
24H15F6N4O [MþH]þ: 489.1150, found: 489.1153.
4.10.3. N-(3-((3-Amino-1H-indazol-4-yl)ethynyl)phenyl)-3-(4-
methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) benzamide (9c)
Flash column chromatography was carried out using (2e5%
Methanol in dichloromethane). Yield 33%; 1H NMR (400 MHz,
d
164.07, 155.48, 149.06, 139.64, 132.46, 130.63, 129.16, 127.13,
127.07, 127.03, 126.84, 126.36, 125.51, 125.10, 123.62, 123.13, 123.02,
122.80, 120.77, 114.61, 110.79, 92.91, 87.03, 55.07, 53.01, 45.37;
HRMS (ESI-TOF) m/z calcd for C28H26F3N6O [MþH]þ: 519.2120,
found: 519.2134.
Acetone-d6)
d 11.10 (br.s, 1H), 10.10 (s, 1H), 8.51 (s, 1H), 8.28 (s, 2H),
8.18 (s, 1H), 8.15 (s, 1H), 7.95 (d, J ¼ 8.0 Hz, 1H), 7.57 (s, 1H),
7.52e7.41 (m, 3H), 7.32 (t, J ¼ 7.6 Hz, 1H), 7.21 (d, J ¼ 6.8 Hz, 1H),
4.98 (br.s, 2H), 2.24 (s, 3H); 13C NMR (100 MHz, Acetone-d6)
d
163.39, 149.02, 141.97, 139.95, 139.27, 138.49, 137.96, 134.99,
4.10.8. N-(3-((3-Amino-1H-indazol-4-yl)ethynyl)phenyl)-4-
morpholino-3-(trifluoromethyl)benzamide (9h)
132.08, 131.76, 129.29, 127.29, 126.36, 124.97, 123.90, 123.24, 122.99,
120.85, 120.00, 115.17, 114.54, 114.12, 112.98, 110.83, 92.75, 87.19;
12.91; HRMS (ESI-TOF) m/z calcd for
Flash column chromatography was carried out using (Ethyl
acetate-hexane, 2:1, v/v then switching to 100% ethyl acetate). Yield
C
27H20F3N6O [MþH]þ:
501.1651, found: 501.1650.
67.7%; 1H NMR (400 MHz, Acetone-d6)
d 11.01 (br.s, 1H), 9.84 (s, 1H),
8.34e8.30 (m, 2H), 8.15 (s, 1H), 7.92 (d, J ¼ 7.5 Hz, 1H), 7.66 (d,
J ¼ 8.3 Hz, 1H), 7.49e7.40 (m, 3H), 7.31 (t, J ¼ 8.2 Hz, 1H), 7.21 (d,
J ¼ 7.0 Hz, 1H), 4.97 (br.s, 2H), 3.81 (t, J ¼ 4.4 Hz, 4H), 3.04 (t,
4.10.4. N-(3-((3-Amino-1H-indazol-4-yl)ethynyl)phenyl)-3-fluoro-
5-(trifluoromethyl)benzamide (9d)
Flash column chromatography was carried out using (Ethyl
acetate-hexane, 1:1, v/v then switching to 100% ethyl acetate). Yield
J ¼ 4.3 Hz, 4H); 13C NMR (100 MHz, DMSO‑d6)
d 164.50, 155.03,
149.05, 141.74, 139.80, 133.47, 130.80, 129.78, 127.50 (q, J ¼ 6 Hz),
127.24, 126.83, 124.91, 124.63, 124.33, 123.24, 123.02, 122.73, 121.59,
114.29, 112.72, 111.52, 93.37, 87.56, 66.89, 53.57; HRMS (ESI-TOF) m/
z calcd for C27H23F3N5O2 [MþH]þ: 506.1804, found: 506.1807.
11.3%; 1H NMR (400 MHz, Acetone-d6)
d 11.02 (br.s, 1H), 9.97 (s, 1H),
8.23 (s, 1H), 8.14e8.11 (m, 2H), 7.92 (d, J ¼ 8.0 Hz, 1H), 7.80 (d,
J ¼ 8.4 Hz, 1H), 7.51e7.40 (m, 3H), 7.31 (t, J ¼ 8.0 Hz, 1H), 7.21 (d,