Y. Zhou et al.
Bioorganic Chemistry xxx (xxxx) xxx
665.2757 [M+H]+, Calcd. for 665.2699.
3.02–3.08 (m, 2H), 2.76 (s, 6H), 2.04–2.06 (m, 2H), 1.66–1.71 (m, 2H);
13C NMR (100 MHz, DMSO‑d6) δ: 169.0, 164.3, 160.6, 154.3, 150.5,
150.4, 149.3, 149.0, 146.7, 137.1, 132.1, 132.0, 122.0 (2C), 120.6,
115.7 (2C), 115.3, 115.2, 112.9, 112.7, 110.9, 103.4, 100.1, 73.7, 56.2,
52.3, 44.2 (2C), 38.6 (2C), 30.6 (2C), 29.7. HRMS (ESI) m/z 715.2252
[M+Na]+, Calcd. for 715.2126.
5.1.8.10. (E)-4-((4-(4-(2-(2,6-difluorobenzylidene)hydrazine-1-carbox-
amido)-3-fluorophenoxy)-6-methoxyquinolin-7-yl)oxy)-N,N-diethylpiper-
idine-1-carboxamide (14j). White solid, yield: 82.4%. HRMS (ESI) m/z
665.2757 [M+H]+, Calcd. for 665.2699.
5.1.9. General procedure for the synthesis of target compounds 15a-j
To a solution of semicarbazides 14a-j (0.5 mmol) and mercapto-
acetic acid (0.5 mL) in dry CH2Cl2 (10 mL), SiCl4 (20 drops) were added
at room temperature. After the resulting mixture refluxed for 6 h, the
reaction mixture was allowed to cooled to room temperature before
quenched by ice water, and 10% NaOH aqueous solution was added
until pH reached to 9–10. The organic phase was separated and washed
with water (2 × 5 mL), concentrated under vacuum to afford yellow oil
which was purified by silica gel column chromatography (eluent,
CH2Cl2: MeOH: Et3N = 100:5:1 to 100:10:1) to afford target compounds
15a-j.
5.1.9.5. 4-((4-(4-(3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)ure-
ido)phenoxy)-6-methoxyquinolin-7-yl)oxy)-N,N-dimethylpiperidine-1-sul-
fonamide (15e). White solid, yield: 41.6%. 1H NMR (400 MHz,
DMSO‑d6) δ: 8.99 (s, 1H), 8.79 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H),
7.51–7.54 (m, 5H), 7.17–7.21 (m, 4H), 6.41 (d, J = 5.2 Hz, 1H), 6.16 (s,
1H), 4.82 (br, 1H), 3.94 (s, 3H), 3.84 (s, 2H), 3.46 (m, 2H), 3.22 (m, 2H),
2.78 (s, 6H), 2.17 (m, 2H), 1.77 (m, 2H); 13C NMR (100 MHz, DMSO‑d6)
δ: 169.0, 164.3, 160.6, 154.3, 150.5, 150.3, 149.4, 149.0, 146.7, 137.1,
132.0, 131.9, 122.0 (2C), 120.6, 115.8 (2C), 115.6, 115.3, 112.9, 112.7,
111.1, 103.4, 100.1, 72.6, 56.3, 52.3, 43.9 (2C), 38.4 (2C), 30.4 (2C),
29.8. HRMS (ESI) m/z 751.1925 [M+Na]+, Calcd. for 751.1796.
5.1.9.1. 1-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((7-((1-
(furan-2-carbonyl)piperidin-4-yl)oxy)-6-methoxyquinolin-4-yl)oxy)
phenyl)urea (15a). White solid, yield: 39.1%. 1H NMR (400 MHz,
DMSO‑d6) δ: 8.97 (s, 1H), 8.77 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.85 (m,
1H), 7.48–7.55 (m, 5H), 7.16–7.21 (m, 4H), 7.03 (m, 1H), 6.64 (m, 1H),
6.43 (d, J = 5.2 Hz, 1H), 6.17 (s, 1H), 4.93–4.97 (m, 1H), 4.02–4.07 (m,
2H), 3.94 (s, 3H), 3.85 (s, 2H), 3.58 (br, 2H), 2.12–2.15 (m, 2H),
1.71–1.78 (m, 2H); 13C NMR (100 MHz, DMSO‑d6) δ: 169.0, 164.3,
160.6, 154.3, 150.5, 150.4, 149.3, 149.0, 147.2, 146.7, 142.6, 137.1,
132.1, 132.0, 122.0 (2C), 120.6, 117.7, 115.7 (2C), 115.3, 115.2, 112.9,
112.7, 111.5, 110.9, 103.4, 100.1, 73.7, 56.2, 52.3, 44.2 (2C), 30.6 (2C),
29.7. HRMS (ESI) m/z 738.1949 [M+Na]+, Calcd. for 738.1810.
5.1.9.6. 1-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((6-
methoxy-7-((1-(morpholinosulfonyl)piperidin-4-yl)oxy)quinolin-4-yl)oxy)
phenyl)urea (15f). White solid, yield: 42.0%. 1H NMR (400 MHz,
DMSO‑d6) δ: 8.96 (s, 1H), 8.75 (s, 1H), 8.45 (d, J = 4.0 Hz, 1H),
7.48–7.54 (m, 5H), 7.17–7.20 (m, 4H), 6.42 (d, J = 4.0 Hz, 1H), 6.18 (s,
1H), 4.80–4.83 (m, 1H), 3.94 (s, 3H), 3.84 (s, 2H), 3.49–3.51 (m, 2H),
3.21–3.25 (m, 2H), 3.05–3.08 (m, 2H), 2.09 (br, 2H), 1.69–1.79 (m, 4H),
1.23–1.30 (m, 1H), 1.02 (m, 3H); 13C NMR (100 MHz, DMSO‑d6) δ:
169.0, 160.6, 154.4, 150.5, 150.3, 149.4, 149.0, 146.6, 137.1, 132.0,
131.9, 122.0 (2C), 120.6, 115.9, 115.6, 115.1 (2C), 112.9, 112.7, 111.1,
103.5, 100.2, 72.6, 56.3, 50.4, 43.1 (2C), 30.6 (2C), 29.8, 17.0 (2C),
13.3 (2C). HRMS (ESI) m/z 793.2042 [M+Na]+, Calcd. for 793.1902.
5.1.9.2. 1-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((6-
methoxy-7-((1-pivaloylpiperidin-4-yl)oxy)quinolin-4-yl)oxy)phenyl)urea
(15b). White solid, yield: 45.2%. 1H NMR (400 MHz, DMSO‑d6) δ: 8.97
(s, 1H), 8.77 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.49–7.55 (m, 5H),
7.17–7.21 (m, 4H), 6.41 (d, J = 5.2 Hz, 1H), 6.17 (s, 1H), 4.87–4.91 (m,
1H), 4.02–4.07 (m, 2H), 3.94–3.99 (m, 4H), 3.85 (m, 3H), 3.41–3.47 (m,
1H), 3.24–3.29 (m, 1H), 2.00–2.07 (m, 2H), 1.59–1.67 (m, 2H), 1.03 (s,
3H), 1.02 (s, 3H), 0.97 (s, 3H); 13C NMR (100 MHz, DMSO‑d6) δ: 169.0,
164.3, 160.6, 154.3, 150.5, 150.4, 149.3, 149.0, 146.7, 137.1, 132.1,
132.0, 122.0 (2C), 120.6, 115.7 (2C), 115.3, 115.2, 112.9, 112.7, 110.9,
103.4, 100.1, 73.7, 56.2, 52.3, 44.2 (2C), 38.7, 30.6 (2C), 29.7, 27.5
(3C). HRMS (ESI) m/z 728.2395 [M+Na]+, Calcd. for 728.2330.
5.1.9.7. 1-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((7-((1-
(ethylsulfonyl)piperidin-4-yl)oxy)-6-methoxyquinolin-4-yl)oxy)phenyl)
urea (15 g). 1H NMR (400 MHz, DMSO‑d6) δ: 8.99 (s, 1H), 8.78 (s, 1H),
8.45 (d, J = 5.2 Hz, 1H), 7.48–7.55 (m, 5H), 7.14–7.20 (m, 4H), 6.41 (d,
J = 5.2 Hz, 1H), 6.17 (s, 1H), 4.82 (s, 1H), 3.94 (s, 3H), 3.84 (s, 2H),
3.50–3.52 (m, 2H), 3.21–3.26 (m, 2H), 3.09–3.13 (q, J = 7.2 Hz, 2H),
2.09 (br, 2H), 1.75–1.80 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, DMSO‑d6) δ: 169.0, 160.8, 154.3, 150.5, 150.3, 149.4, 149.0,
146.7, 137.1, 132.1, 132.0, 131.9, 122.0 (2C), 120.6, 115.9 (2C), 115.6,
115.3, 112.9, 112.8, 111.2, 103.5, 72.6, 56.3, 52.3, 43.6, 43.1 (2C), 30.6
(2C), 29.8, 8.1. HRMS (ESI) m/z 736.1833 [M+Na]+, Calcd. for
736.1687.
5.1.9.3. 4-((4-(4-(3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)ure-
ido)phenoxy)-6-methoxyquinolin-7-yl)oxy)-N,N-diethylpiperidine-1-car-
boxamide (15c). White solid, yield: 42.6%. 1H NMR (400 MHz,
DMSO‑d6) δ: 8.96 (s, 1H), 8.76 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H),
7.50–7.55 (m, 5H), 7.17–7.21 (m, 4H), 6.41 (d, J = 5.2 Hz, 1H), 6.17 (s,
1H), 4.80–4.84 (m, 1H), 3.94 (s, 3H), 3.85 (s, 2H), 3.42–3.46 (m, 2H),
3.13 (q, J = 7.2 Hz, 4H), 3.02–3.08 (m, 2H), 2.03–2.07 (m, 2H),
1.64–1.72 (m, 2H), 1.06 (t. J = 7.2 Hz, 6H); 13C NMR (100 MHz,
DMSO‑d6) δ: 169.0, 164.0, 160.6, 154.3, 150.5, 150.4, 149.3, 149.0,
146.7, 137.1, 132.1, 131.9, 122.0 (2C), 120.6, 115.7 (2C), 115.4, 115.3,
112.9, 112.7, 110.9, 103.4, 100.1, 73.7, 56.2, 52.3, 44.5 (2C), 41.9 (2C),
30.6 (2C), 29.8, 13.6 (2C). HRMS (ESI) m/z 743.2554 [M+Na]+, Calcd.
for 743.2439.
5.1.9.8. 1-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((6-
methoxy-7-((1-(thiophen-2-ylsulfonyl)piperidin-4-yl)oxy)quinolin-4-yl)
oxy)phenyl)urea (15 h). White solid, yield: 43.5%. 1H NMR (400 MHz,
DMSO‑d6) δ: 8.97 (s, 1H), 8.77 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.10 (m,
1H), 7.68 (m, 1H), 7.48–7.51 (m, 5H), 7.33 (m, 1H), 7.13–7.20 (m, 4H),
6.40 (d, J = 5.2 Hz, 1H), 6.16 (s, 1H), 4.77 (m, 1H), 3.80–3.84 (m, 5H),
3.28 (m, 2H), 3.01 (m, 2H), 2.10 (m, 2H), 1.82 (m, 2H); 13C NMR (100
MHz, DMSO‑d6) δ: 169.0, 164.3, 160.6, 154.3, 150.5, 150.3, 149.4,
149.0, 146.7, 137.1, 132.0, 131.9, 127.4 (2C), 126.2, 125.3, 122.0 (2C),
120.6, 115.8 (2C), 115.6, 115.3, 112.9, 112.7, 111.1, 103.4, 100.1, 72.6,
56.3, 52.3, 43.9 (2C), 30.4 (2C), 22.6. HRMS (ESI) m/z 790.1399
[M+Na]+, Calcd. for 790.1251.
5.1.9.9. 4-((4-(4-(3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)ure-
ido)-2-fluorophenoxy)-6-methoxyquinolin-7-yl)oxy)-N,N-diethylpiperidine-
1-carboxamide (15i). White solid, yield: 38.9%, purity: 98.14%. 1H
NMR (400 MHz, DMSO‑d6) δ: 9.20 (s, 1H), 8.96 (s, 1H), 8.44 (d, J = 5.2
Hz, 1H), 7.63–7.66 (m, 1H), 7.47–7.52 (m, 2H), 7.35–7.40 (m, 2H), 7.29
(m, 1H), 7.16–7.21 (m, 2H), 6.41 (d, J = 5.2 Hz, 1H), 6.15 (s, 1H), 4.04
(m, 1H), 3.93 (s, 3H), 3.85 (s, 2H), 3.43–3.46 (m, 2H), 3.10 (m, 4H),
5.1.9.4. 4-((4-(4-(3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)ure-
ido)phenoxy)-6-methoxyquinolin-7-yl)oxy)-N,N-dimethylpiperidine-1-car-
boxamide (15d). White solid, yield: 39.8%. 1H NMR (400 MHz,
DMSO‑d6) δ:9.00 (s, 1H), 8.79 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H),
7.48–7.56 (m, 5H), 7.17–7.21 (m, 4H), 6.42 (d, J = 5.2 Hz, 1H), 6.19 (s,
1H), 4.79–4.83 (m, 1H), 3.94 (s, 3H), 3.85 (s, 2H), 3.45–3.48 (m, 2H),
12