X. Jiang, C. Liu, M. Zou et al.
European Journal of Medicinal Chemistry 223 (2021) 113663
7.13 (t, J ¼ 7.5 Hz, 2H), 7.06 (t, J ¼ 4.5 Hz, 1H), 3.51 (s, 2H), 3.18 (s,
2H), 2.84 (d, J ¼ 6.0 Hz, 2H), 2.05 (m, 2H), 1.94 (s, 1H), 1.68 (d,
J ¼ 9.0 Hz, 2H),1.58 (s, 1H), 1.23 (t, J ¼ 4.5 Hz, 2H), 0.85 (d, J ¼ 6.0 Hz,
found, 543.2716.
N-(1-benzylpiperidin-4-yl)-5-(2-(cyclopropanecarboxamido)iso-
nicotinamido) nicotinamide (10j). Compound 10j (63%) was syn-
thesized by a procedure similar to that used to prepare compound
4H). 13C NMR (125 MHz, DMSO‑d6)
d 173.37, 165.25, 165.13, 158.33
(d, 2JC-F ¼ 30.9 Hz), 153.26, 150.69 (d, 3JC-F ¼ 12.6 Hz), 149.12, 144.45,
9a as a light yellow solid. 1H NMR (500 MHz, DMSO‑d6)
d 11.02 (s,
2,3
143.90, 135.61, 130.73, 127.05, 125.85, 118.96, 117.85 (dd,
J
C-
1H), 10.90 (s, 1H), 9.02 (d, J ¼ 5.0 Hz, 1H), 8.76 (s, 1H), 8.71 (d,
J ¼ 7.3 Hz, 1H), 8.55 (s, 1H), 8.52 (s, 1H), 8.51 (d, J ¼ 5.1 Hz, 1H), 7.56
(d, J ¼ 5.1 Hz, 1H), 7.48e7.39 (m, 5H), 4.04 (s, 2H), 3.21 (d,
J ¼ 11.5 Hz, 2H), 3.14 (t, J ¼ 7.2 Hz, 1H), 2.82 (d, J ¼ 20.3 Hz, 2H), 2.02
(d, J ¼ 6.1 Hz, 1H), 2.00e1.94 (m, 2H), 1.78 (t, J ¼ 12.5 Hz, 2H), 0.85
3
¼ 21.7, 8.1 Hz), 117.54 (d, JC-F ¼ 16.9 Hz), 117.37, 116.57, 112.00,
F
61.23, 53.11, 45.20, 35.86, 29.99, 14.69, 8.28. HRMS (ESI): (M þ H)þ
calcd for C29H31F2N6O3, 549.2420; found, 549.2424.
N-((1-(3-chlorobenzyl)piperidin-4-yl)methyl)-5-(2-(cyclo-
propanecarboxamido) isonicotinamido)nicotinamide (10f). Com-
pound 10f (68%) was synthesized by a procedure similar to that
used to prepare compound 9a as a light yellow solid. 1H NMR
(d, J ¼ 5.5 Hz, 4H). 13C NMR (125 MHz, DMSO‑d6)
d 173.6, 165.4,
165.0, 153.1, 150.5, 149.2, 144.6, 144.0, 143.8, 135.5, 131.0, 130.6,
129.5, 129.1, 127.2, 117.4, 112.0, 56.5, 49.0, 46.3, 29.4, 14.7, 8.3. HRMS
(ESI): (M þ H)þ calcd for C28H31N6O3, 499.3452; found, 499.2460.
N-(1-(3-chlorobenzyl)piperidin-4-yl)-5-(2-(cyclo-
(500 MHz, DMSO‑d6)
d
11.05 (s, 1H), 10.86 (s, 1H), 9.04 (d, J ¼ 2.2 Hz,
1H), 8.77 (d, J ¼ 1.6 Hz, 1H), 8.74 (d, J ¼ 5.2 Hz, 1H), 8.56 (d,
J ¼ 3.2 Hz, 2H), 8.53 (d, J ¼ 5.1 Hz, 1H), 7.58 (dd, J ¼ 5.0, 1.2 Hz, 1H),
7.36 (dd, J ¼ 15.1, 7.6 Hz, 3H), 7.30 (s, 1H), 3.55 (s, 2H), 3.19 (t,
J ¼ 5.9 Hz, 2H), 2.86 (s, 2H), 2.11e2.00 (m, 2H), 1.99 (s, 1H), 1.70 (d,
J ¼ 11.3 Hz, 2H), 1.61 (s, 1H), 1.26 (d, J ¼ 4.4 Hz, 2H), 0.90e0.81 (m,
propanecarboxamido) isonicotinamido)nicotinamide (10k). Com-
pound 10k (67%) was synthesized by a procedure similar to that
used to prepare compound 9a as a light yellow solid. 1H NMR
(500 MHz, DMSO‑d6)
d
11.05 (s, 1H), 10.88 (s, 1H), 9.04 (d, J ¼ 2.4 Hz,
4H). 13C NMR (125 MHz, DMSO‑d6)
d
173.4, 165.3, 165.2, 153.3, 149.1,
1H), 8.78 (s, 1H), 8.57 (d, J ¼ 2.3 Hz, 1H), 8.56 (d, J ¼ 4.4 Hz, 1H), 8.53
(d, J ¼ 5.1 Hz, 1H), 7.63 (d, J ¼ 9.1 Hz, 1H), 7.60e7.57 (m, 1H), 7.54 (d,
J ¼ 7.6 Hz, 1H), 7.49 (s, 3H), 4.13 (s, 2H), 3.20 (t, J ¼ 7.2 Hz, 2H), 3.17
(s, 2H), 3.10 (d, J ¼ 7.5 Hz, 2H), 2.05 (m, 2H), 1.76 (s, 2H), 0.91e0.81
144.4, 143.9, 135.6, 134.2, 133.4, 130.7, 130.6, 129.3, 128.1, 127.0,
120.6, 118.0, 117.4, 112.0, 60.2, 53.1, 45.2, 21.2, 14.7, 14.5, 8.3. HRMS
(ESI): (M þ H)þ calcd for C29H32ClN6O3, 547.2219; found, 547.2224.
5-(2-(Cyclopropanecarboxamido)isonicotinamido)-N-((1-(2-
(m, 4H). 13C NMR (125 MHz, DMSO‑d6)
d 173.4, 165.3, 158.2, 153.2,
methylbenzyl)piperidin-4-yl)methyl)nicotinamide (10g). Compound
10g (56%) was synthesized by a procedure similar to that used to
prepare compound 9a as a light yellow solid. 1H NMR (500 MHz,
149.1, 144.6, 144.5, 144.0, 143.8,135.6, 133.6, 132.7, 131.8, 131.7, 131.0,
131.0, 130.6, 127.1, 117.3, 111.9, 49.0, 46.2, 14.7, 9.0, 7.9. HRMS (ESI):
(M þ H)þ calcd for C28H30ClN6O3, 533.2062; found, 533.2074.
N-(2-(1-(3-chlorobenzyl)piperidin-4-yl)ethyl)-5-(2-(cyclo-
propanecarboxamido) isonicotinamido)nicotinamide (10l). Com-
pound 10l (65%) was synthesized by a procedure similar to that
used to prepare compound 9a as a light yellow solid. 1H NMR
DMSO‑d6)
d
11.05 (s, 1H), 10.84 (s, 1H), 9.04 (d, J ¼ 2.4 Hz, 1H), 8.77
(d, J ¼ 1.8 Hz, 1H), 8.71 (t, J ¼ 5.6 Hz, 1H), 8.60e8.54 (m, 2H), 8.53 (d,
J ¼ 5.1 Hz, 1H), 7.58 (m, 1H), 7.23e7.18 (m, 1H), 7.14 (d, J ¼ 3.4 Hz,
2H), 7.12 (d, J ¼ 3.8 Hz, 1H), 3.19 (d, J ¼ 5.9 Hz, 2H), 3.17 (s, 2H), 2.79
(d, J ¼ 11.0 Hz, 2H), 2.30 (s, 3H), 2.05 (m,1H),1.94 (t, J ¼ 10.8 Hz, 2H),
1.67 (d, J ¼ 12.3 Hz, 2H), 1.62e1.55 (m, 1H), 1.18 (d, J ¼ 9.4 Hz, 2H),
(300 MHz, DMSO‑d6)
d
11.07 (s, 1H), 10.86 (s, 1H), 9.04 (d, J ¼ 2.4 Hz,
1H), 8.76 (d, J ¼ 1.6 Hz, 1H), 8.68 (t, J ¼ 5.3 Hz, 1H), 8.57 (s, 2H), 8.53
(d, J ¼ 5.1 Hz, 1H), 7.58 (d, J ¼ 5.1 Hz, 1H), 7.35 (t, J ¼ 7.6 Hz, 2H), 7.30
(d, J ¼ 8.0 Hz, 1H), 7.26 (d, J ¼ 7.2 Hz, 1H), 3.45 (s, 2H), 3.32 (d,
J ¼ 6.8 Hz, 2H), 3.17 (d, J ¼ 4.9 Hz, 2H), 2.78 (d, J ¼ 8.6 Hz, 2H),
2.10e2.02 (m, 1H), 1.92 (d, J ¼ 4.3 Hz, 1H), 1.69 (d, J ¼ 11.6 Hz, 2H),
1.52e1.44 (m, 2H), 1.17 (m, 2H), 0.88e0.82 (m, 4H); 13C NMR
0.85 (d, J ¼ 7.8 Hz, 4H). 13C NMR (125 MHz, DMSO‑d6)
d 173.4, 165.3,
165.1, 153.3, 149.1, 144.4, 143.9, 143.8, 137.4, 135.6, 130.8, 130.5,
129.8, 127.2, 127.0, 125.8, 117.4, 112.0, 60.9, 53.6, 49.1, 45.3, 36.2,
30.4, 19.3, 14.7, 8.3. HRMS (ESI): (M þ H)þ calcd for C30H35N6O3,
527.2765; found, 527.2774.
5-(2-(Cyclopropanecarboxamido)isonicotinamido)-N-((1-(3-
methylbenzyl)piperidin-4-yl)methyl)nicotinamide (10h). Compound
10h (59%) was synthesized by a procedure similar to that used to
prepare compound 9a as a light yellow solid. 1H NMR (500 MHz,
(75 MHz, DMSO‑d6) d 173.4, 165.3, 164.8, 153.3, 149.2, 144.4, 143.9,
143.8, 141.9, 135.6, 133.3,130.7, 130.5, 128.8, 127.8, 127.2, 127.0, 117.4,
112.0, 62.1, 53.7, 37.4, 36.2, 33.3, 32.3, 14.7, 8.3. HRMS (ESI):
(M þ H)þ calcd for C30H34ClN6O3, 561.2375; found, 561.2386.
DMSO‑d6)
d
11.06 (s, 1H), 10.88 (s, 1H), 9.02 (d, J ¼ 2.2 Hz, 1H), 8.82
(s, 1H), 8.78 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 8.53 (d, J ¼ 5.1 Hz, 1H),
7.61e7.54 (m, 1H), 7.38e7.33 (m, 1H), 7.32e7.23 (m, 3H), 4.22 (s,
2H), 3.51 (s, 2H), 3.21 (s, 2H), 2.91 (s, 2H), 2.34 (s, 3H), 2.05 (m, 1H),
1.88 (d, J ¼ 13.3 Hz, 2H), 1.84e1.75 (m, 1H), 1.43 (d, J ¼ 9.9 Hz, 2H),
4.3. General procedure for the synthesis of target compounds
11aꢀ11j
Tert-butyl
4-(((5-bromopyridin-3-yl)oxy)methyl)piperidine-1-
0.86 (d, J ¼ 6.2 Hz, 4H). 13C NMR (125 MHz, DMSO‑d6)
d
173.4, 165.3,
carboxylate (28a). To a solution of intermediate 26a (5.22 g,
30 mmol) in DMF (90 mL) was added of K2CO3 (10 g, 72 mmol) and
intermediate 27a (9.17 g, 33 mmol). The reaction mixture was
stirred at 60 ꢁC for 10 h. When TLC showed the completion of the
reaction, the reaction mixture was cooled to room temperature and
filtered off. The filtrate was evaporated off to dryness to give off-
white intermediate 28a, which could also be purified by recrys-
tallization with MeOH as a white powder (70%). 1H NMR (300 MHz,
158.6, 158.4, 153.3, 149.2, 144.5, 143.9, 138.6, 135.6, 132.2, 132.1,
130.6, 129.2, 127.0, 118.9, 117.3, 116.6, 112.0, 51.9, 46.2, 44.4, 21.4,
14.7, 9.0, 8.3, 7.9. HRMS (ESI): (M þ H)þ C30H35N6O3, 527.2765;
found, 527.2769.
5-(2-(Cyclopropanecarboxamido)isonicotinamido)-N-((1-(3-
methoxybenzyl) piperidin-4-yl)methyl)nicotinamide (10i). Com-
pound 10i (47%) was synthesized by a procedure similar to that
used to prepare compound 9a as a light yellow solid. 1H NMR
DMSO‑d6)
d
8.30e8.28 (m, 2H), 7.72 (t, J ¼ 2.1 Hz, 1H), 3.97 (m, 2H),
(300 MHz, DMSO‑d6)
d
11.06 (s, 1H), 10.88 (s, 1H), 9.02 (s, 1H), 8.82
3.94 (m, 2H), 2.74 (br s, 2H), 1.97e1.90 (m, 1H), 1.74 (d, J ¼ 12.0 Hz,
2H), 1.40 (s, 9H), 1.21e1.08 (m, 2H). MS (ESI) m/z: 370.1 [M ꢀ Hꢀ].
Tert-butyl 4-((5-bromopyridin-3-yl)oxy)piperidine-1-carboxylate
(28b). To a solution of intermediate 26a (1.73 g, 10 mmol) in DMF
(20 mL) was added of K2CO3 (4.14 g, 30 mmol) and intermediate
27a (3.96 g, 15 mmol). The reaction mixture was stirred at 60 ꢁC for
10 h. When TLC showed the completion of the reaction, the reaction
mixture was cooled to room temperature and filtered off. The
filtrate was evaporated off to dryness to give off-white intermediate
(s, 1H), 8.78 (s, 1H), 8.61 (s, 2H), 8.53 (d, J ¼ 3.0 Hz, 1H), 7.59 (d,
J ¼ 3.0 Hz, 1H), 7.35 (t, J ¼ 4.5 Hz, 1H), 7.28 (t, J ¼ 6.0 Hz, 3H), 3.19 (s,
2H), 3.18 (m, 2H), 2.80 (s, 2H), 2.30 (s, 3H), 2.05 (t, J ¼ 4.5 Hz, 1H),
1.93 (s, 2H), 1.67 (q, J ¼ 6.0 Hz, 2H), 1.59 (s, 1H), 1.19 (m, 2H), 0.86 (d,
J ¼ 3.0 Hz, 4H). 13C NMR (75 MHz, DMSO‑d6)
d 173.4, 165.3, 165.1,
159.7, 153.3, 149.2, 144.4, 144.0, 143.9, 135.6, 130.7, 129.6, 127.0,
121.4, 117.4, 114.6, 112.7, 112.1, 112.0, 62.7, 55.4, 53.4, 45.3, 36.0, 30.2,
14.7, 8.3. HRMS (ESI): (M þ H)þ calcd for C30H35N6O4, 543.2714;
14