ACS Chemical Neuroscience
Research Article
3H). 13C NMR (151 MHz, CDCl3) δ 148.3, 142.6, 142.1, 140.5, 131.9,
130.9, 127.43, 127.36, 123.2, 122.3, 120.3, 120.1, 112.36, 112.35, 111.7,
111.5, 108.5, 17.7. MS (ESI+) m/z: 368.1 [M + H, 79Br]+, 370.1 [M +
H, 81Br]+.
(dd, J = 8.2, 6.2 Hz, 1H), 4.41 (t, J = 8.6 Hz, 1H), 4.33−4.27 (m, 2H),
4.10−4.02 (m, 1H), 2.68 (s, 3H), 2.39 (s, 3H), 1.77 (s, 3H). 13C NMR
(151 MHz, CDCl3) δ 170.8, 142.8, 142.1, 139.5, 131.1, 127.4, 127.1,
125.2, 122.3, 120.6, 120.0, 119.4, 113.1, 111.4, 55.7, 53.4, 26.1, 18.7,
17.6, 16.8. MS (ESI+) m/z: 335.2 [M + H]+.
7-Bromo-2-(furan-2-yl)-N-(o-tolyl)imidazo[1,2-a]pyridin-3-
amine (3f). Prepared from commercially available 2-amino-4-
bromopyridine (86 mg, 0.5 mmol), furfural (12a, 42 μL, 0.5 mmol),
and freshly synthesized 2-methylphenyl isocyanide (13a, 62 μL, 0.5
mmol) according to General Procedure A. Purification by flash column
chromatography eluting with heptane and ethyl acetate (v/v, 4/1) gave
the target compound 3f as a yellow solid (102 mg, 56%). Rf = 0.33
(silica gel, heptane/ethyl acetate, 3/1). 1H NMR (600 MHz, CDCl3) δ
7.80 (dd, J = 1.8, 0.8 Hz, 1H), 7.63 (dd, J = 7.2, 0.8 Hz, 1H), 7.45 (dd, J
= 1.8, 0.8 Hz, 1H), 7.21 (d, J = 7.4 Hz, 2H), 6.99−6.93 (m, 1H), 6.88
(dd, J = 7.2, 1.9 Hz, 1H), 6.82 (td, J = 7.4, 1.2 Hz, 1H), 6.73 (dd, J = 3.4,
0.8 Hz, 1H), 6.45 (dd, J = 3.4, 1.8 Hz, 1H), 6.05 (d, J = 8.0 Hz, 1H), 5.66
(s, 1H), 2.45 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 148.3, 142.7,
142.7, 142.1, 131.4, 131.0, 127.5, 123.2, 123.2, 120.4, 119.7, 119.1,
119.0, 116.4, 112.3, 111.6, 108.2, 17.7. MS (ESI+) m/z: 368.1 [M + H,
79Br]+, 370.1 [M + H, 81Br]+.
1
For 4i: H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 6.8 Hz, 1H),
7.23−7.04 (m, 3H), 6.94 (t, J = 7.4 Hz, 1H), 6.87−6.70 (m, 2H), 6.13−
5.93 (m, 2H), 4.01 (ddd, J = 14.6, 8.6, 7.3 Hz, 1H), 3.84 (qd, J = 11.0,
6.9 Hz, 2H), 3.57 (dq, J = 8.4, 4.4 Hz, 2H), 2.66 (s, 3H), 2.43 (s, 3H),
1.89 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 170.9, 142.7, 141.9,
137.3, 131.1, 127.3, 126.7, 125.4, 122.7, 121.2, 121.1, 119.8, 113.1,
111.4, 46.1, 41.1, 40.4, 23.3, 17.6, 16.7. MS (ESI+) m/z: 371.2 [M +
H]+.
(2-Fluorophenyl)(3-(8-methyl-3-(o-tolylamino)imidazo[1,2-a]-
pyridin-2-yl)azetidin-1-yl)methanone (4j) and N-(3-Chloro-2-(8-
methyl-3-(o-tolylamino)imidazo[1,2-a]pyridin-2-yl)propyl)-2-fluo-
robenzamide (4k). Prepared from tert-butyl 3-(8-methyl-3-(o-
tolylamino)imidazo[1,2-a]pyridin-2-yl)azetidine-1-carboxylate (4g,
24 mg, 0.06 mmol) and 2-fluorobenzoyl chloride (7.2 μL, 0.06
mmol) according to the procedure described for the synthesis of
compounds 4h and 4i. Purification by flash column chromatography
eluting with heptane and ethyl acetate (v/v, 7/3) gave the target
compound 4k as a yellow solid (8 mg, 29%), and switching the eluting
system to heptane and ethyl acetate (v/v, 1/9) gave the target
compound 4j as a yellow solid (12 mg, 48%). For 4j: 1H NMR (600
MHz, CDCl3) δ 7.67 (d, J = 6.8 Hz, 1H), 7.45 (td, J = 7.3, 1.8 Hz, 1H),
7.41−7.34 (m, 1H), 7.19−7.12 (m, 2H), 7.10−7.02 (m, 2H), 6.93 (t, J
= 7.6 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 6.75 (s, 1H), 5.99 (d, J = 8.1 Hz,
1H), 5.32 (s, 1H), 4.51 (d, J = 7.8 Hz, 2H), 4.49−4.44 (m, 1H), 4.38 (t,
J = 8.8 Hz, 1H), 4.15 (s, 1H), 2.67 (s, 3H), 2.39 (s, 3H). 13C NMR (151
MHz, CDCl3) δ 166.5, 159.0 (d, 1JCF = 250.3 Hz), 142.7, 142.0, 139.2,
132.1 (d, 3JCF = 8.2 Hz), 131.1, 130.1 (d, 4JCF = 3.4 Hz), 127.5, 127.3,
125.1, 124.5 (d, 3JCF = 3.4 Hz), 122.3, 122.2 (d, 2JCF = 16.4 Hz), 120.6,
120.0, 119.3, 116.0 (d, 2JCF = 22.1 Hz), 112.9, 111.4, 56.4, 53.8, 27.0,
17.5, 16.8. MS (ESI+) m/z: 415.2 [M + H]+.
8-Bromo-2-(furan-2-yl)-7-methyl-N-(o-tolyl)imidazo[1,2-a]-
pyridin-3-amine (3m). Prepared from commercially available 2-amino-
3-bromo-4-methylpyridine (94 mg, 0.5 mmol), furfural (12a, 42 μL, 0.5
mmol), and freshly synthesized 2-methylphenyl isocyanide (13a, 62 μL,
0.5 mmol) according to General Procedure A. Purification by flash
column chromatography eluting with heptane and ethyl acetate (v/v, 3/
1) gave the target compound 3m as a yellow solid (102 mg, 56%). Rf =
1
0.33 (silica gel, heptane/ethyl acetate, 3/1). H NMR (600 MHz,
CDCl3) δ 7.63 (d, J = 6.8 Hz, 1H), 7.44 (dd, J = 1.8, 0.8 Hz, 1H), 7.20
(d, J = 7.5 Hz, 1H), 6.97−6.91 (m, 1H), 6.81 (td, J = 7.4, 1.2 Hz, 1H),
6.74 (d, J = 3.4 Hz, 1H), 6.63 (d, J = 6.8 Hz, 1H), 6.42 (dd, J = 3.4, 1.8
Hz, 1H), 6.07 (d, J = 8.1 Hz, 1H), 5.64 (s, 1H), 2.50 (s, 3H), 2.45 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 148.5, 142.4, 142.4, 141.2, 135.2,
131.7, 130.9, 127.4, 123.0, 121.0, 120.1, 119.6, 115.0, 112.3, 112.2,
111.4, 108.1, 22.1, 17.6. MS (ESI+) m/z: 382.0 [M + H, 79Br]+, 384.1
[M + H, 81Br]+.
tert-Butyl 3-(8-methyl-3-(o-tolylamino)imidazo[1,2-a]pyridin-2-
yl)azetidine-1-carboxylate (4g). Prepared from commercially avail-
able 2-amino-3-methylpyridine (11a, 50 μL, 0.5 mmol), N-Boc-
azetidine-3-carbaldehyde (12b, 93 mg, 0.5 mmol) and freshly
synthesized 2-methylphenyl isocyanide (13a, 62 μL, 0.5 mmol)
according to General Procedure A. Purification by flash column
chromatography eluting with heptane and ethyl acetate (v/v, 1/2) gave
the target compound 4g as a light yellow solid (132 mg, 67%). Rf = 0.27
(silica gel, heptane/ethyl acetate, 2/5). 1H NMR (400 MHz, CDCl3) δ
7.71 (d, J = 6.8 Hz, 1H), 7.22−7.13 (m, 1H), 7.08−7.02 (m, 1H),
6.99−6.90 (m, 1H), 6.83−6.70 (m, 2H), 6.00 (dd, J = 8.1, 1.2 Hz, 1H),
5.30 (s, 1H), 4.23 (dd, J = 7.6, 1.9 Hz, 4H), 3.99 (s, 1H), 2.67 (s, 3H),
2.38 (s, 3H), 1.41 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 156.4, 142.5,
141.4, 138.9, 131.1, 127.5, 126.8, 122.5, 120.7, 120.1, 119.6, 113.5,
111.5, 79.6, 54.5, 28.4, 26.4, 17.6, 16.9. MS (ESI+) m/z: 293.0 [M + H,
-Boc]+.
1-(3-(8-Methyl-3-(o-tolylamino)imidazo[1,2-a]pyridin-2-yl)-
azetidin-1-yl)ethan-1-one (4h) and N-(3-Chloro-2-(8-methyl-3-(o-
tolylamino)imidazo[1,2-a]pyridin-2-yl)propyl)acetamide (4i). tert-
Butyl 3-(8-methyl-3-(o-tolylamino)imidazo[1,2-a]pyridin-2-yl)-
azetidine-1-carboxylate (4g, 24 mg, 0.06 mmol) was dissolved in HCl
solution (4.0 M in dioxane, 0.6 mL). After stirring the reaction mixture
at room temperature for 30 min, the solvent was evaporated under
vacuum to give a solid residue, which was suspended in CH2Cl2 (0.6
mL), and Et3N (22 μL, 0.16 mmol) and acetyl chloride (4.3 μL, 0.06
mmol) were added. The resulting mixture was stirred at room
temperature for 1 h before evaporation under vacuum to give an oil
residue. Purification by flash column chromatography eluting with
heptane and iPrOH (v/v, 9/1) gave the target compound 4i as a white
solid (7 mg, 31%), and switching the eluting system to heptane and
iPrOH (v/v, 3/2) gave the target compound 4h as a white solid (8 mg,
40%). For 4h: 1H NMR (600 MHz, CDCl3) δ 7.70 (d, J = 6.7 Hz, 1H),
7.17 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 6.9 Hz, 1H), 6.95 (t, J = 7.6 Hz,
1H), 6.83−6.74 (m, 2H), 6.00 (d, J = 8.1 Hz, 1H), 5.40 (s, 1H), 4.48
For 4k: 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.98 (td, J = 7.8,
1.9 Hz, 1H), 7.67 (d, J = 6.8 Hz, 1H), 7.49−7.37 (m, 1H), 7.21 (td, J =
7.6, 1.1 Hz, 1H), 7.19−7.11 (m, 2H), 7.08 (ddd, J = 11.9, 8.3, 1.1 Hz,
1H), 6.91−6.72 (m, 3H), 6.00 (d, J = 8.0 Hz, 1H), 5.89 (s, 1H), 4.35−
4.23 (m, 1H), 4.07−3.90 (m, 2H), 3.83 (dt, J = 13.4, 4.4 Hz, 1H), 3.77
(s, 1H), 2.71 (s, 3H), 2.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
164.1, 160.6 (d, 1JCF = 249.1 Hz), 142.4, 141.7, 136.9, 133.2 (d, 3JCF
=
9.2 Hz), 131.8 (d, 4JCF = 1.9 Hz), 131.0, 127.4, 126.9, 126.2, 124.6 (d,
2
3JCF = 3.4 Hz), 122.8, 121.5 (d, JCF = 13.7 Hz), 121.4, 121.1, 120.0,
116.1 (d, 2JCF = 24.2 Hz), 113.5, 111.7, 46.0, 41.8, 39.7, 17.5, 16.7. MS
(ESI+) m/z: 451.2 [M + H]+.
tert-Butyl 3-(8-bromo-7-methyl-3-(o-tolylamino)imidazo[1,2-a]-
pyridin-2-yl)azetidine-1-carboxylate (7b). Prepared from commer-
cially available 2-amino-3-bromo-4-methylpyridine (12m, 94 mg, 0.5
mmol), N-Boc-azetidine-3-carbaldehyde (12b, 93 mg, 0.5 mmol), and
freshly synthesized 2-methylphenyl isocyanide (13a, 62 μL, 0.5 mmol)
according to General Procedure A. Purification by flash column
chromatography eluting with heptane and ethyl acetate (v/v, 1/3) gave
the target compound 7b as an off-white solid (119 mg, 51%). Rf = 0.31
(silica gel, heptane/ethyl acetate, 2/5). 1H NMR (600 MHz, CDCl3) δ
7.63 (d, J = 6.8 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.94 (t, J = 8.0 Hz,
1H), 6.78 (t, J = 7.4 Hz, 1H), 6.64 (d, J = 6.8 Hz, 1H), 5.98 (d, J = 8.0
Hz, 1H), 5.33 (s, 1H), 4.26−4.17 (m, 4H), 3.99−3.91 (m, 1H), 2.50 (s,
3H), 2.37 (s, 3H), 1.40 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 156.4,
142.8, 142.0, 140.8, 135.0, 131.0, 127.5, 122.2, 120.7, 119.9, 114.9,
112.2, 111.5, 79.3, 54.5, 28.4, 27.3, 22.0, 17.5. MS (ESI+) m/z: 471.2
[M + H, 79Br]+, 473.1 [M + H, 81Br]+.
Pharmacology. Materials. Culture media, serum, antibiotics and
buffers for cell culture and assays were obtained from Invitrogen
(Paisley, UK). The FLIPR Membrane Potential Blue assay dye was
purchased from Molecular Devices (Crawley, UK), and [3H]-D-Asp
was obtained from PerkinElmer (Boston, MA). (S)-Glu was purchased
from Sigma (St. Louis, MO). If not otherwise stated, all chemicals for
the screening were purchased from Sigma (St. Louis, MO). The
compound libraries included in the screening (ChemDiv6, Biomol 4,
M
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX