Journal of Medicinal Chemistry
Article
4-((trans-1-(3-Methoxybenzyl)-2-methylpiperidin-4-yl)amino)-N-
methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31d). 31d was
synthesized in 56% yield according to the same procedure as 20d
using 27a and 3-methoxybenzaldehyde; 1H NMR (400 MHz,
chloroform-d) δ 9.98 (s, 1H), 9.47 (d, J = 7.8 Hz, 1H), 8.23 (s,
1H), 7.23 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 3.7 Hz, 1H), 6.99−6.92 (m,
2H), 6.81−6.77 (m, 1H), 6.53 (d, J = 3.7 Hz, 1H), 6.34 (s, 1H), 4.33
(s, 1H), 3.99 (d, J = 13.4 Hz, 1H), 3.82 (s, 3H), 3.35 (d, J = 13.4 Hz,
1H) 3.00 (d, J = 4.7 Hz, 3H), 2.97−2.91 (m, 1H), 2.76−2.69 (m,
1H), 2.52−2.44 (m, 1H), 2.05−2.00 (m, 1H), 1.95 (t, J = 5.3 Hz,
2H), 1.84−1.75 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H); 13C NMR (100
MHz, methanol-d4) δ 171.6, 160.1, 150.1, 149.4, 143.9, 138.9, 129.7,
122.4, 121.9, 115.4, 113.5, 105.9, 104.0, 102.9, 58.7, 55.5, 53.3, 49.9,
46.7, 46.6, 39.1, 31.1, 17.6; HRMS calcd for C23H30N5O2 [M + H]+
408.2394, found 408.2399.
4-((trans-1-(4-Methoxybenzyl)-2-methylpiperidin-4-yl)amino)-N-
methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31e). 31e was
synthesized in 49% yield according to the same procedure as 20d
using 27a and 4-methoxybenzaldehyde; 1H NMR (400 MHz,
chloroform-d) δ 10.20 (s, 1H), 9.54 (d, J = 7.8 Hz, 1H), 8.23 (s,
1H), 7.31 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 3.6 Hz, 1H), 6.89−6.85
(m, 2H), 6.50 (d, J = 3.7 Hz, 2H), 4.34 (s, 1H), 4.06 (d, J = 13.1 Hz,
1H), 3.81 (s, 3H), 3.36 (d, J = 13.1 Hz, 1H), 3.02−2.95 (m, 3H),
2.77 (d, J = 12.3 Hz, 1H), 2.49 (t, J = 10.9 Hz, 1H), 2.00 (dd, J =
28.9, 10.6 Hz, 3H), 1.83 (d, J = 13.3 Hz, 2H), 1.29 (d, J = 6.3 Hz,
3H); 13C NMR (100 MHz, methanol-d4) δ 171.5, 159.9, 150.0, 149.4,
143.8, 131.8, 127.1, 122.2, 114.4, 105.9, 104.0, 102.7, 57.6, 55.5, 53.7,
49.9, 46.3, 38.5, 30.3, 26.6, 17.6; HRMS calcd for C23H30N5O2 [M +
H]+ 408.2394, found 408.2401.
4-((cis-1-(4-Methoxybenzyl)-2-methylpiperidin-4-yl)amino)-N-
methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31i). 31i was
synthesized in 63% yield according to the same procedure as 20d
using 27b and 4-methoxybenzaldehyde; 1H NMR (400 MHz,
chloroform-d) δ 9.66 (s, 1H), 9.07 (d, J = 7.9 Hz, 1H), 8.20 (s,
1H), 7.26−7.22 (m, 2H), 7.03 (d, J = 3.6 Hz, 1H), 6.88−6.84 (m,
2H), 6.52 (d, J = 3.7 Hz, 1H), 6.06 (s, 1H), 4.07 (d, J = 13.3 Hz, 1H),
3.97−3.86 (m, 1H), 3.81 (s, 3H), 3.15 (d, J = 13.3 Hz, 1H), 2.97 (d, J
= 4.8 Hz, 3H), 2.94−2.88 (m, 1H), 2.47−2.35 (m, 1H), 2.20−2.13
(m, 1H), 2.11−2.02 (m, 2H), 1.63−1.46 (m, 2H), 1.26 (d, J = 6.1 Hz,
3H); 13C NMR (100 MHz, chloroform-d) δ 170.9, 158.8, 149.8,
149.4, 143.6, 130.7, 129.8, 121.3, 113.7, 105.2, 103.7, 102.7, 57.5,
55.9, 55.2, 51.4, 51.0, 42.0, 33.2, 26.3, 20.9; HRMS calcd for
C23H30N5O2 [M + H]+ 408.2394, found 408.2394.
4-((cis-1-(4-Cyanobenzyl)-2-methylpiperidin-4-yl)amino)-N-
methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31j). 31j was
synthesized in 91% yield according to the same procedure as 20d
1
using 27b and 4-formylbenzonitrile; H NMR (400 MHz, chloro-
form-d) δ 9.67 (s, 1H), 9.12 (d, J = 7.9 Hz, 1H), 8.21 (s, 1H), 7.63−
7.44 (m, 4H), 7.04 (d, J = 3.7 Hz, 1H), 6.53 (d, J = 3.7 Hz, 1H), 6.09
(s, 1H), 4.16 (d, J = 14.4 Hz, 1H), 4.01−3.91 (m, 1H), 3.32 (d, J =
14.4 Hz, 1H), 2.98 (d, J = 4.8 Hz, 3H), 2.89−2.77 (m, 1H), 2.51−
2.42 (m, 1H), 2.24−2.04 (m, 3H), 1.62−1.55 (m, 1H), 1.55−1.46
(m, 1H), 1.20 (d, J = 6.1 Hz, 3H); 13C NMR (100 MHz, chloroform-
d) δ 170.8, 149.8, 149.3, 145.5, 143.5, 132.1, 129.4, 121.3, 119.0,
110.5, 105.2, 103.6, 102.5, 57.3, 56.2, 51.9, 51.0, 42.1, 33.3, 26.4, 21.1;
HRMS calcd for C23H27N6O [M + H]+ 403.2241, found 403.2247.
4-((cis-1-(3-Chlorobenzyl)-2-methylpiperidin-4-yl)amino)-1H-
pyrrolo[2,3-b]pyridine-5-carboxamide (31k). 31k was synthesized in
56% yield according to the same procedure as 20d using 27c and 3-
4-((cis-1-(3-Chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-
methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31f). 31f was
synthesized in 65% yield according to the same procedure as 20d
1
chlorobenzaldehyde; H NMR (400 MHz, chloroform-d) δ 9.86−
9.68 (m, 1H), 9.32 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 7.23 (d, J = 8.0
Hz, 1H), 7.04 (d, J = 3.6 Hz, 1H), 6.93 (d, J = 2.2 Hz, 2H), 6.80 (dd,
J = 7.9, 2.2 Hz, 1H), 6.55 (d, J = 3.7 Hz, 1H), 5.65 (s, 2H), 4.12 (d, J
= 13.5 Hz, 1H), 4.02−3.90 (m, 1H), 3.82 (s, 3H), 3.14 (d, J = 13.5
Hz, 1H), 2.97−2.90 (m, 1H), 2.50−2.38 (m, 1H), 2.17 (d, J = 13.0
Hz, 1H), 2.11−2.05 (m, 2H), 1.67−1.47 (m, 2H), 1.26 (d, J = 6.0 Hz,
3H); 13C NMR (100 MHz, DMSO-d6) δ 172.1, 150.4, 149.4, 145.6,
142.5, 132.9, 130.0, 128.1, 127.2, 126.6, 121.7, 104.4, 101.7, 99.0,
56.1, 55.2, 51.1, 50.2, 42.4, 33.4, 21.0; HRMS calcd for C21H25ClN5O
[M + H]+ 398.1742, found 398.1746.
1
using 27b and 3-clorobenzaldehyde; H NMR (400 MHz, chloro-
form-d) δ 9.08 (d, J = 7.9 Hz, 1H), 8.18 (s, 1H), 7.33 (s, 1H), 7.22−
7.14 (m, 3H), 7.02 (d, J = 3.7 Hz, 1H), 6.52 (d, J = 3.7 Hz, 1H), 6.05
(s, 1H), 4.08 (d, J = 13.7 Hz, 1H), 4.00−3.87 (m, 1H), 3.10 (d, J =
13.7 Hz, 1H), 2.96 (d, J = 4.8 Hz, 3H), 2.90−2.82 (m, 1H), 2.46−
2.36 (m, 1H), 2.15 (dd, J = 12.8, 2.4 Hz, 1H), 2.12−2.04 (m, 2H),
1.58 (dd, J = 11.5, 3.8 Hz, 2H), 1.21 (d, J = 6.1 Hz, 3H); 13C NMR
(100 MHz, methanol-d4) δ 170.9, 149.8, 149.3, 143.6, 140.9, 134.2,
129.5, 129.1, 127.3, 127.2, 121.3, 105.2, 103.6, 102.6, 57.8, 57.7, 57.1,
56.0, 51.5, 51.0, 42.0, 33.2, 26.3, 20.9; HRMS calcd for C22H27ClN5O
[M + H]+ 412.1899, found 412.1904.
4-((cis-1-(3-Methoxybenzyl)-2-methylpiperidin-4-yl)amino)-1H-
pyrrolo[2,3-b]pyridine-5-carboxamide (31l). 31l was synthesized in
36% yield according to the same procedure as 20d using 27c and 4-
methoxybenzaldehyde; 1H NMR (400 MHz, chloroform-d) δ 9.74 (d,
J = 2.6 Hz, 1H), 9.32 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 7.23 (d, J =
8.0 Hz, 1H), 7.04 (d, J = 3.6 Hz, 1H), 6.93 (d, J = 2.2 Hz, 2H), 6.80
(dd, J = 7.9, 2.2 Hz, 1H), 6.55 (d, J = 3.7 Hz, 1H), 5.65 (s, 2H), 4.12
(d, J = 13.5 Hz, 1H), 4.01−3.89 (m, 1H), 3.82 (s, 3H), 3.14 (d, J =
13.5 Hz, 1H), 2.97−2.90 (m, 1H), 2.50−2.39 (m, 1H), 2.17 (d, J =
13.0 Hz, 1H), 2.13−2.06 (m, 2H), 1.66−1.46 (m, 2H), 1.26 (d, J =
6.0 Hz, 3H); 13C NMR (100 MHz, chloroform-d) δ 173.0, 159.6,
150.4, 149.2, 144.6, 139.8, 129.2, 121.8, 121.2, 115.0, 112.4, 105.1,
102.8, 101.8, 57.5, 55.9, 55.2, 51.3, 51.0, 41.9, 33.1, 20.8; HRMS calcd
for C22H28N5O2 [M + H]+ 394.2238, found 394.2239.
4-((trans-1-(3-Chlorobenzyl)-3-fluoropiperidin-4-yl)amino)-N-
methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (32a). 32a was
synthesized in 25% yield according to the same procedure as 20d
using 28a and 3-chlorobenzaldehyde; 1H NMR (400 MHz,
chloroform-d) δ 9.38 (d, J = 8.2 Hz, 1H), 8.24 (s, 1H), 7.34 (s,
1H), 7.26−7.18 (m, 3H), 7.06 (d, J = 3.7 Hz, 1H), 6.59 (t, J = 3.3 Hz,
1H), 6.28 (s, 1H), 4.77−4.57 (m, 1H), 4.31−4.19 (m, 1H), 3.57 (s,
2H), 3.09−3.00 (m, 1H), 2.98 (d, J = 4.8 Hz, 3H), 2.78−2.67 (m,
1H), 2.51 (dt, J = 11.2, 7.2 Hz, 1H), 2.38 (t, J = 9.4 Hz, 1H), 2.28
(dd, J = 8.8, 3.5 Hz, 1H), 1.82−1.68 (m, 1H); 13C NMR (100 MHz,
chloroform-d) δ 170.8, 150.2, 149.3, 143.3, 139.8, 134.3, 129.7, 129.0,
127.5, 127.1, 121.6, 105.5, 104.0, 102.3, 90.2 (d, JC−F = 182.0 Hz),
61.8, 55.1 (d, JC−F = 23.9 Hz), 53.5 (d, JC−F = 23.7 Hz), 50.2, 29.8,
26.4; HRMS calcd for C21H24ClFN5O [M + H]+ 416.1648, found
416.1648.
4-((cis-1-(4-Chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-
methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31g). 31g was
synthesized in 63% yield according to the same procedure as 20d
1
using 27b and 4-clorobenzaldehyde; H NMR (400 MHz, chloro-
form-d) δ 9.38 (s, 1H), 9.09 (d, J = 7.9 Hz, 1H), 8.20 (s, 1H), 7.31−
7.27 (m, 4H), 7.03 (d, J = 3.7 Hz, 1H), 6.53 (d, J = 3.7 Hz, 1H),
6.11−5.99 (m, 1H), 4.08 (d, J = 13.7 Hz, 1H), 4.00−3.86 (m, 1H),
3.12 (d, J = 13.7 Hz, 1H), 2.98 (d, J = 4.8 Hz, 3H), 2.91−2.82 (m,
1H), 2.48−2.36 (m, 1H), 2.19−2.12 (m, 1H), 2.12−2.04 (m, 2H),
1.59−1.45 (m, 2H), 1.23 (d, J = 6.1 Hz, 3H); 13C NMR (100 MHz,
methanol-d4) δ 171.7, 150.1, 149.9, 144.3, 137.1, 133.3, 131.2, 128.8,
122.0, 105.8, 104.1, 102.8, 57.3, 56.5, 51.8, 51.4, 42.5, 33.7, 26.5, 21.1;
HRMS calcd for C22H27ClN5O [M + H]+ 412.1903, found 412.1899.
4-((cis-1-(3-Methoxybenzyl)-2-methylpiperidin-4-yl)amino)-N-
methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31h). 31h was
synthesized in 66% yield according to the same procedure as 20d
using 27b and 3-methoxybenzaldehyde; 1H NMR (400 MHz,
chloroform-d) δ 9.66 (s, 1H), 9.09 (d, J = 7.9 Hz, 1H), 8.20 (s,
1H), 7.22 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.93−6.90
(m, 2H), 6.82−6.77 (m, 1H), 6.53 (d, J = 3.7 Hz, 1H), 6.09 (s, 1H),
4.11 (d, J = 13.6 Hz, 1H), 3.99−3.88 (m, 1H), 3.82 (s, 3H), 3.36 (d, J
= 13.6 Hz, 1H), 2.98 (d, J = 4.8 Hz, 3H), 2.95−2.84 (m, 1H), 2.49−
2.39 (m, 1H), 2.20−2.04 (m, 3H), 1.66−1.46 (m, 2H), 1.24 (d, J =
6.1 Hz, 3H); 13C NMR (100 MHz, chloroform-d) δ 170.9, 158.7,
149.7, 149.3, 143.5, 130.7, 129.7, 121.2, 113.6, 105.2, 103.6, 102.6,
56.7, 55.7, 55.2, 51.1, 51.0, 41.9, 33.1, 26.3, 20.8; HRMS calcd for
C23H30N5O2 [M + H]+ 408.2394, found 408.2403.
975
J. Med. Chem. 2021, 64, 958−979