Dihydropyranoimidazopyridines as P-CABs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6261
(3-Hydroxyazetidin-1-yl)(2,3-dimethyl-9-phenyl-7H-8,9-dihy-
dropyrano[2,3-c]imidazo[1,2-a]pyridin-6-yl)methanone (91). Com-
pound 91 was obtained in 36% yield from carboxylic acid 84 by
applying a procedure similar to that described for the preparation
of 86, using 3-hydroxyazetidine instead of methylamine (for further
details, see Supporting Information): colorless solid; mp 306-
308 °C; 1H NMR (DMSO-d6, 200 MHz) δ ) 2.10 (mc, 1 H), 2.26
(s, mc, 4 H), 2.37 (s, 3 H), 2.66 (mc, 1 H), 2.92 (mc, 1 H), 3.85
(mc, 2 H), 4.23 (mc, 2 H), 4.50 (mc, 1 H), 5.26 (dd, 1 H), 5.75 (mc,
1 H), 7.42 (mc, 5 H), 7.85 (s, 1 H); HRMS calcd for C22H24N3O3
m/z (MH+) 378.1812, found 378.1798.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid Cyclopropylamide (92). Com-
pound 92 was obtained in 45% yield from carboxylic acid 84 by
applying a procedure similar to that described for the preparation
of 86, using cyclopropylamine instead of methylamine (for further
details, see Supporting Information): colorless solid; mp 260 °C;
1H NMR (DMSO-d6, 200 MHz) δ ) 0.57 (mc, 2 H), 0.70 (mc, 2
H), 2.06 (mc, 1 H), 2.26 (s, mc, 4 H), 2.37 (s, 3 H), 2.66-3.08 (m,
3 H), 3.17 (d, MeOH), 4.07 (q, MeOH), 5.23 (dd, 1 H), 7.42 (mc,
5 H), 7.86 (s, 1 H), 8.42 (d, 1 H); HRMS calcd for C22H24N3O2
m/z (MH+) 362.1863, found 362.1853. Anal. (C22H23N3O2·0.5H2O)
C, H, N.
5 H), 5.28 (dd, 1 H), 7.44 (mc, 5 H), 8.14 (s, 1 H); HRMS calcd
for C20H21N3O4S m/z (MH+) 400.1326, found 400.1318.
(2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridin-6-yl)piperazin-1-ylmethanone (97). Compound 97
was obtained in 13% yield from carboxylic acid 84 by applying a
procedure similar to that described for the preparation of 96, using
piperazine instead of methanesulfonamide (for further details, see
1
Supporting Information): H NMR (DMSO-d6, 200 MHz) δ ) 2.16,
2.25, 2.35 (mc, 2 s, 8 H), 2.73 (bs, overlay with DMSO signal),
3.20 (bs, overlay with water signal), 3.58 (bs, 2 H), 5.27 (dd, 1 H),
7.43 (mc, 6 H), 7.76 (s, 1 H); HRMS calcd for C23H27N4O2 m/z
(MH+) 391.2129, found 391.2121. Anal. (C23H26N4O2·0.5H2O) C,
H, N.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid Methoxymethylamide (98).
Compound 98 was obtained in 33% yield from carboxylic acid 84
by applying a procedure similar to that described for the preparation
of 86, using N,O-dimethylhydroxylamine instead of methylamine
(for further details, see Supporting Information): colorless solid;
mp 192-193 °C (enantiomers 98a and 98b, mp 215-216 °C); 1H
NMR (DMSO-d6, 200 MHz) δ ) 2.12 (mc, 1 H), 2.26 (mc, s, 4
H), 2.36 (s, 3 H), 2.54 (mc), 2.81 (mc, 1 H), 3.26 (s, 3 H), 3.57 (s,
3 H), 5.26 (dd, 1 H), 7.42 (mc, 5 H), 7.92 (s, 1 H); HRMS calcd
for C21H24N3O3 m/z (MH+) 366.1812, found 366.1820.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid Cyclobutylamide (93). Com-
pound 93 was obtained in 47% yield from carboxylic acid 84 by
applying a procedure similar to that described for the preparation
of 86, using cyclobutylamine instead of methylamine (for further
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid (2-Hydroxyethyl)amide (99).
A mixture of carboxylic acid 84 (0.50 g, 1.6 mmol) and thionyl
chloride (0.34 mL, 0.55 g, 4.6 mmol) was diluted with dry
dichloromethane (7 mL). The suspension was treated with DBU
(0.24 mL, 0.24 g, 1.6 mmol) and stirred for 24 h at room
temperature. The light-brown reaction mixture was evaporated to
dryness and the residue was dissolved in dry dichloromethane (15
mL). The resulting suspension was cooled to 0 °C and a solution
of 2-aminoethanol (0.17 mL, 0.17 g, 2.8 mmol) in dichloromethane
(5 mL) was added. The reaction mixture was stirred for 2.5 h at
room temperature. The precipitate was removed by filtration. The
filtrate was concentrated in vacuo and the brown residue (0.9 g)
was purified by column chromatography [36 g of silica gel; eluant,
ethyl acetate/methanol ) 10:1 (v/v)]. Evaporation of the corre-
sponding fractions yielded the pure title compound (0.25 g of a
1
details, see Supporting Information): mp 257-258 °C; H NMR
(CDCl3, 200 MHz) δ ) 1.79 (mc), 1.90-2.50, 2.33, 2.40 (m, 2 s,
12 H), 2.84 (mc, 1 H), 3.01 (mc, 1 H), 4.55 (mc, 1 H), 5.22 (dd, 1
H), 6.50 (d, 1 H), 7.39 (mc, 6 H); HRMS calcd for C23H26N3O2
m/z (MH+) 376.2020, found 376.2025.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid Phenylamide (94). Compound
94 was obtained in 39% yield from carboxylic acid 84 by applying
a procedure similar to that described for the preparation of 86, using
aniline instead of methylamine (for further details, see Supporting
Information): colorless solid; mp 285-287 °C; 1H NMR (DMSO-
d6, 200 MHz) δ ) 2.09 (mc, 1 H), 2.29 (mc, s, 4 H), 2.41 (s, 3 H),
2.77 (mc, 1 H), 3.06 (mc, 1 H), 5.28 (dd, 1 H), 7.11 (t, 1 H), 7.42
(mc, 7 H), 7.73 (d, 2 H), 8.14 (s, 1 H), 10.37 (s, 1 H); HRMS calcd
for C25H24N3O2 m/z (MH+) 398.1863, found 398.1851.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid (4-Ethoxyphenyl)amide (95).
Compound 95 was obtained in 49% yield from carboxylic acid 84
by applying a procedure similar to that described for the preparation
of 86, using 4-ethoxyaniline instead of methylamine (for further
details, see Supporting Information): mp 223 °C; 1H NMR (CDCl3,
200 MHz) δ ) 1.42 (t, 3 H), 2.11 (mc, 1 H), 2.27, 2.33, 2.39 (s,
mc, s, 7 H), 2.89 (mc, 1 H), 3.10 (mc, 1 H), 4.04 (q, 2 H), 5.14 (dd,
1 H), 6.87 (d, 2 H), 7.25 (mc), 7.38 (mc, 2 H), 7.44 (s, 1 H), 7.64
(d, 2 H), 8.71 (bs, 1 H). Anal. (C27H27N3O3) H, N. C: calcd, 73.45;
found, 73.00.
1
colorless solid, 44% yield): mp 209-210 °C; H NMR (CDCl3,
200 MHz) δ ) 1.92 (mc), 2.27 (mc, s, 4 H), 2.41 (s, 3 H), 2.68
(mc, 2 H), 3.46 (mc, 2 H), 3.71 (mc, 2 H), 4.97 (dd, 1 H), 7.14 (bt,
1 H), 7.27 (s), 7.42 (mc, 5 H).
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid (2-Chloroethyl)amide (100).
A solution of (2-hydroxyethyl)carboxamide 99 (0.30 g, 0.8 mmol)
in thionyl chloride (0.40 mL, 0.65 g, 5.5 mmol) was stirred for 1
h at room temperature. It was then diluted with dichloromethane
(30 mL) and water (5 mL) and a neutral pH value was adjusted by
addition of saturated sodium bicarbonate solution. The phases were
separated, and the aqueous phase was extracted with dichlo-
romethane (20 mL). The combined organic phases were dried over
sodium sulfate, concentrated under reduced pressure, and dried in
vacuo. The title compound was obtained in 70% yield (0.22 g of a
colorless solid): 1H NMR (CDCl3, 200 MHz) δ ) 2.14 (mc), 2.32,
2.38 (2 s, mc, 7 H), 2.85 (mc, 1 H), 3.08 (mc, 1 H), 3.75 (s, 4 H),
5.21 (dd, 1 H), 6.90 (bs, 1 H), 7.36 (mc, 5 H), 7.60 (s, 1 H).
6-(4,5-Dihydrooxazol-2-yl)-2,3-dimethyl-9-phenyl-7H-8,9-di-
hydropyrano[2,3-c]imidazo[1,2-a]pyridine (101). Three samples
of (2-chloroethyl)carboxamide 100 (3 × 70 mg, 0.55 mmol) were
transferred into microwave tubes and dissolved in dry DMF (3 ×
3 mL). The yellow solution was heated to 150 °C for 20 min and
to 170 °C for another 20 min. The reaction mixtures were combined
and evaporated to dryness. The residue was purified by column
chromatography [22 g of silica gel; eluant, ethyl acetate/methanol
) 100:3 (v/v)]. Evaporation of the corresponding fractions furnished
a red solid (106 mg, mixture of title compound with untransformed
starting material as indicated by TLC analysis), which was further
purified by preparative HPLC. The title compound was isolated in
14% yield (27 mg of a colorless solid): 1H NMR (CDCl3, 200
N-(2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carbonyl)methanesulfonamide (96). A suspen-
sion of carboxylic acid 84 (0.80 g, 2.5 mmol) in dry THF (30 mL)
was treated with N,N′-carbonyldiimidazole (0.80 g, 4.9 mmol). After
a reaction time of 2 h at 40 °C a brown solution was obtained.
DBU (0.75 g, 4.9 mmol) and methanesulfonamide (0.47 g, 4.9
mmol) was added and stirring was continued for 1 h at room
temperature. The reaction mixture was poured onto water (30 mL)
and dichloromethane (50 mL), the phases were separated, and the
aqueous phase was extracted with dichloromethane (30 mL). The
combined organic phases were dried over sodium sulfate and
concentrated in vacuo. The residue (1.5 g of a brown foamy solid)
was purified by column chromatography [45 g of silica gel; eluant,
dichloromethane/methanol ) 100:3 (v/v)]. The corresponding
fractions were evaporated and the title compound was isolated (0.70
1
g, 71% yield): mp 210 °C; H NMR (DMSO-d6, 200 MHz) δ )
2.09 (mc, 1 H), 2.30 (s, mc, 4 H), 2.41 (s, 3 H), 3.00, 3.10 (s, mc,