H. Bu et al.
Bioorganic & Medicinal Chemistry 40 (2021) 116186
and Pd(PPh3)4 (24 mg, 0.02 mmol, 0.1 eq) provided I-4 (57 mg, 48%) as
white solid. m.p.: 207-218℃; 1H NMR (400 MHz, DMSO‑d6) δ (ppm):
9.39 (d, J = 7.7 Hz, 1H), 8.94 (d, J = 7.1 Hz, 1H), 8.57 (dd, J = 7.7, 5.8
Hz, 1H), 8.43 (d, J = 7.3 Hz, 1H), 8.30 (t, J = 8.1 Hz, 1H), 8.16–8.04 (m,
2H), 8.03–7.94 (m, 1H), 7.85 (dd, J = 10.1, 5.7 Hz, 3H), 7.76 (dd, J =
9.3, 7.9 Hz, 1H), 7.51 (t, J = 8.0 Hz, 2H), 4.48 (s, 1H), 3.47 (d, J = 90.0
Hz, 10H), 2.95 (d, J = 95.3 Hz, 2H), 1.82 (d, J = 39.6 Hz, 2H), 1.48 (d, J
= 5.4 Hz, 2H); MS: found m/z [M+H]+ 518.3, calcd. m/z [M] 517.3.
1.0 eq), quinolin-3-ylboronic acid (56 mg, 0.32 mmol, 1.5 eq),
K3PO4⋅3H2O (114 mg, 0.42 mmol, 2.0 eq) and Pd(PPh3)4 (24 mg, 0.02
mmol, 0.1 eq) provided I-8 (52 mg, 47%) as white solid. m.p.: 168-
172℃; 1H NMR (400 MHz, DMSO‑d6) δ (ppm): 9.27 (d, J = 2.1 Hz, 1H),
8.92 (s, 1H), 8.85 (s, 1H), 8.17–8.07 (m, 3H), 7.88–7.84 (m, 3H), 7.82
(d, J = 9.4 Hz, 1H), 7.78–7.74 (m, 1H), 7.70 (dd, J = 13.1, 5.7 Hz, 1H),
7.51 (t, J = 7.1 Hz, 2H), 4.54 (s, 1H), 3.70 (s, 1H), 3.04 (d, J = 19.7 Hz,
1H), 2.88–2.56 (m, 5H), 2.00 (s, 1H), 1.76 (s, 2H), 1.56 (s, 5H), 1.43 (s,
4H); MS: found m/z [M+H]+ 516.3, calcd. m/z [M] 515.3.
4.1.9. Synthesis of (4-morpholinopiperidin-1-yl)(4-(3-(quinolin-3-yl)
imidazo[1,2-a]pyridin-6-yl)phenyl)methanone (I-5)
4.1.14. Synthesis of [1,4′-bipiperidin]-1′-yl(4-(3-(quinolin-6-yl)imidazo
[1,2-a]pyridin-6-yl)phenyl)methanone (I-9)
Following general procedure A, compound 8b (100 mg, 0.21 mmol,
1.0 eq), quinolin-3-ylboronic acid (56 mg, 0.32 mmol, 1.5 eq),
K3PO4⋅3H2O (114 mg, 0.42 mmol, 2.0 eq) and Pd(PPh3)4 (24 mg, 0.02
mmol, 0.1 eq) provided I-5 (28 mg, 25%) as white solid. m.p.: 202-
207℃; 1H NMR (400 MHz, CDCl3) δ (ppm): 9.22 (t, J = 11.3 Hz, 1H),
8.56 (d, J = 21.7 Hz, 1H), 8.46–8.35 (m, 1H), 8.21 (d, J = 8.4 Hz, 1H),
7.95 (dd, J = 15.5, 7.2 Hz, 2H), 7.84 (t, J = 10.3 Hz, 2H), 7.73–7.63 (m,
2H), 7.62–7.56 (m, 2H), 7.50 (d, J = 8.1 Hz, 2H), 4.77 (s, 1H), 3.77 (d, J
= 3.6 Hz, 5H), 2.98 (d, J = 77.0 Hz, 2H), 2.61 (s, 6H), 1.90 (s, 4H); MS:
found m/z [M+H]+ 518.3, calcd. m/z [M] 517.3.
Following general procedure A, compound 8c (100 mg, 0.21 mmol,
1.0 eq), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (77
mg, 0.30 mmol, 1.5 eq), K3PO4⋅3H2O (114 mg, 0.42 mmol, 2.0 eq) and
Pd(PPh3)4 (24 mg, 0.02 mmol, 0.1 eq) provided I-9 (56 mg, 51%) as
white solid. m.p.: 147-156℃; 1H NMR (400 MHz, DMSO‑d6) δ (ppm):
8.96 (dd, J = 4.2, 1.7 Hz, 1H), 8.90 (s, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.44
(s, 1H), 8.22–8.12 (m, 2H), 8.01 (s, 1H), 7.84 (dd, J = 8.8, 4.5 Hz, 3H),
7.74 (dd, J = 9.4, 1.7 Hz, 1H), 7.62 (dd, J = 8.3, 4.2 Hz, 1H), 7.51 (t, J =
8.4 Hz, 2H), 4.51 (s, 1H), 3.66 (s, 1H), 3.01 (d, J = 25.2 Hz, 1H), 2.72 (d,
J = 27.6 Hz, 1H), 2.52 (d, J = 1.7 Hz, 5H), 1.76 (d, J = 51.4 Hz, 2H),
1.49 (s, 4H), 1.42–1.34 (m, 4H); MS: found m/z [M+H]+ 516.3, calcd.
m/z [M] 515.3.
4.1.10. Synthesis of (4-morpholinopiperidin-1-yl)(4-(3-(quinolin-6-yl)
imidazo[1,2-a]pyridin-6-yl)phenyl)methanone (I-6)
Following general procedure A, compound 8b (100 mg, 0.21 mmol,
1.0 eq), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (82
mg, 0.32 mmol, 1.5 eq), K3PO4⋅3H2O (114 mg, 0.42 mmol, 2.0 eq) and
Pd(PPh3)4 (24 mg, 0.02 mmol, 0.1 eq) provided I-6 (48 mg, 44%) as
white solid. m.p.: 176-178℃; 1H NMR (400 MHz, DMSO‑d6) δ (ppm):
8.96 (dd, J = 4.2, 1.7 Hz, 1H), 8.89 (s, 1H), 8.51 (dd, J = 8.3, 1.4 Hz,
1H), 8.43 (d, J = 1.7 Hz, 1H), 8.16 (dt, J = 8.7, 5.3 Hz, 2H), 7.99 (s, 1H),
7.84 (dd, J = 9.0, 3.1 Hz, 3H), 7.73 (dd, J = 9.4, 1.7 Hz, 1H), 7.61 (dd, J
= 8.3, 4.2 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 3.62 (s, 1H), 3.58 (s, 4H),
2.95 (d, J = 82.6 Hz, 2H), 2.50 (s, 6H), 1.80 (s, 2H), 1.36 (d, J = 8.3 Hz,
2H); MS: found m/z [M+H]+ 518.3, calcd. m/z [M] 517.3.
4.1.15. Synthesis of tert-butyl 4-(4-(3-bromoimidazo[1,2-a]pyridin-6-yl)
benzoyl)piperazine-1-carboxylate (8d)
Following general procedure B, compound 7 (500 mg, 1.58 mmol,
1.0 eq), tert-butyl piperazine-1-carboxylate (353 mg, 1.89 mmol, 1.2
eq), EDCI (322 mg, 1.89 mmol, 1.2 eq), HOBt (256 mg, 1.89 mmol, 1.2
eq), DMAP (20 mg, 0.16 mmol, 0.1 eq) and TEA (479 mg, 4.73 mmol,
3.0 eq) provided 8c (663 mg, 86.73%) as yellow solid.
Synthesis of Tert-butyl-4-(4-(3-(isoquinolin-6-yl)imidazo[1,2-a]pyr-
idine-6-yl)benzoyl)piperazine-1-carboxylate (9a)
Following general procedure A, compound 8d (100 mg, 0.21 mmol,
1.0 eq), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline
(79 mg, 0.31 mmol, 1.5 eq), K3PO4⋅3H2O (114 mg, 0.42 mmol, 2.0 eq)
and Pd(PPh3)4 (24 mg, 0.02 mmol, 0.1 eq) provided 9a (78 mg, 71%) as
white solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.36 (s, 1H), 8.64 (d, J
= 5.8 Hz, 2H), 8.20 (d, J = 8.5 Hz, 1H), 8.08 (s, 1H), 7.96–7.84 (m, 3H),
7.77 (d, J = 5.9 Hz, 1H), 7.64 (s, 1H), 7.60 (dd, J = 6.5, 4.7 Hz, 2H), 7.53
(d, J = 8.2 Hz, 2H), 3.84–3.38 (m, 9H), 1.49 (s, 9H).
4.1.11. Synthesis of [1,4′-bipiperidin]-1′-yl(4-(3-bromoimidazo[1,2-a]
pyridin-6-yl)phenyl)methanone (8c)
Following general procedure B, compound 7 (500 mg, 1.58 mmol,
1.0 eq), 1,4′-bipiperidine (319 mg, 1.89 mmol, 1.2 eq), EDCI (322 mg,
1.89 mmol, 1.2 eq), HOBt (256 mg, 1.89 mmol, 1.2 eq), DMAP (20 mg,
0.16 mmol, 0.1 eq) and TEA (479 mg, 4.73 mmol, 3.0 eq) provided 8c
(670 mg, 90.92%) as yellow solid. 1H NMR (400 MHz, DMSO‑d6) δ
(ppm): 8.53 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.77 (dt, J = 9.3, 5.0 Hz,
4H), 7.54 (d, J = 8.2 Hz, 2H), 4.56 (s, 1H), 3.71 (s, 1H), 3.05 (d, J = 22.6
Hz, 1H), 2.72 (d, J = 41.9 Hz, 6H), 1.87 (d, J = 44.9 Hz, 2H), 1.58 (s,
4H), 1.54–1.39 (m, 4H).
4.1.16. Synthesis of (4-(3-(isoquinolin-6-yl)imidazo[1,2-a]pyridin-6-yl)
phenyl)(piperazin-1-yl)methanone (I-10)
To a solution of compound 9a (78 mg, 0.15 mmol, 1.0 eq) in CH2Cl2
(3 mL) was added TFA (167 mg, 1.46 mmol, 10 eq) dropwise. The
mixture was stirred at room temperature for 4 h. The mixture was
concentrated in vacuo, and the residue was diluted with CH2Cl2 (3 mL).
To the mixture was then added TEA (18 mg, 0.18 mmol, 1.2 eq). After
stirred at room temperature for additional 30 min, the mixture was
concentrated in vacuo. The residue was purified by flash column chro-
matography (silica gel, CH2Cl2/ CH3OH = 20/1) to afford (4-(3-(iso-
quinolin-6-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)meth-
anone (I-10, 41 mg, 65%) as yellow solid. m.p.: 189-196℃; 1H NMR
(400 MHz, DMSO‑d6) δ (ppm): 9.38 (s, 1H), 8.93 (s, 1H), 8.57 (d, J = 5.7
Hz, 1H), 8.42 (s, 1H), 8.30 (d, J = 8.5 Hz, 1H), 8.09 (dd, J = 8.5, 1.4 Hz,
1H), 8.06 (s, 1H), 7.96 (d, J = 5.7 Hz, 1H), 7.91–7.83 (m, 3H), 7.75 (dd,
J = 9.4, 1.4 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H), 3.60 (d, J = 20.4 Hz, 4H),
2.99 (d, J = 24.9 Hz, 4H); MS: found m/z [M+H]+ 434.3, calcd. m/z [M]
433.2.
4.1.12. Synthesis of [1,4′-bipiperidin]-1′-yl(4-(3-(isoquinolin-6-yl)imidazo
[1,2-a]pyridin-6-yl)phenyl)methanone (I-7)
Following general procedure A, compound 8c (100 mg, 0.21 mmol,
1.0 eq), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline
(77 mg, 0.30 mmol, 1.5 eq), K3PO4⋅3H2O (114 mg, 0.42 mmol, 2.0 eq)
and Pd(PPh3)4 (24 mg, 0.02 mmol, 0.1 eq) provided I-7 (40 mg, 36%) as
white solid. m.p.: 158-165℃; 1H NMR (400 MHz, DMSO‑d6) δ (ppm):
9.39 (d, J = 5.9 Hz, 1H), 8.94 (d, J = 5.4 Hz, 1H), 8.57 (t, J = 5.9 Hz,
1H), 8.43 (d, J = 5.7 Hz, 1H), 8.36–8.26 (m, 1H), 8.09 (ddd, J = 16.6,
9.1, 3.9 Hz, 2H), 7.97 (t, J = 5.9 Hz, 1H), 7.90–7.83 (m, 3H), 7.77 (dd, J
= 7.8, 3.2 Hz, 1H), 7.51 (dd, J = 8.0, 6.2 Hz, 2H), 4.55 (s, 1H), 3.70 (s,
1H), 3.07 (s, 1H), 2.75 (s, 1H), 2.61 (s, 3H), 1.77 (s, 2H), 1.56 (s, 4H),
1.50–1.40 (m, 4H); MS: found m/z [M+H]+ 516.3, calcd. m/z [M]
515.3.
4.1.17. Synthesis of Tert-butyl-4-(4-(3-(quinolin-3-yl)imidazo[1,2-a]
pyridine-6-yl)benzoyl)piperazine-1-carboxylate (9b)
4.1.13. Synthesis of [1,4′-bipiperidin]-1′-yl(4-(3-(quinolin-3-yl)imidazo
[1,2-a]pyridin-6-yl)phenyl)methanone (I-8)
Following general procedure A, compound 8d (100 mg, 0.21 mmol,
1.0 eq), quinolin-3-ylboronic acid (53 mg, 0.31 mmol, 1.5 eq),
Following general procedure A, compound 8c (100 mg, 0.21 mmol,
8