Journal of Medicinal Chemistry
Article
cartridge which was then washed with MeOH (3 mL). The wash was
evaporated under a stream of nitrogen, and the residue was dried in a
high-vacuum oven to give the title compound as an off-white solid (48
mg, 0.13 mmol, 53% yield). 1H NMR (400 MHz, CDCl3): δ 7.72 (d,
J = 2.5 Hz, 1 H), 7.52−7.48 (m, 1 H), 7.25 (d, J = 9.0 Hz, 1 H), 7.11
(d, J = 2.5 Hz, 1 H), 6.92 (dd, J = 9.0, 2.5 Hz, 1 H), 4.08 (d, J = 7.5
Hz, 2 H), 3.90 (dd, J = 11.5, 4.0 Hz, 2 H), 3.65 (s, 3 H), 3.24 (td, J =
11.5, 2.0 Hz, 2 H), 2.99 (s, 6 H), 2.25 (s, 3 H), 2.09 (ttt, J = 11.5, 7.5,
3.5 Hz, 1 H), 1.36 (ddd, J = 13.0, 3.5, 2.0 Hz, 2 H), 1.27 (dtd, J =
13.0, 11.5, 4.0 Hz, 2 H); LC−MS (method F) m/z: 381 [(M + H)+];
Rt: 0.48 min; 100% purity.
1.11 (m, 2 H). LC−MS (method F) m/z: 368 [(M + H)+]; Rt: 0.53
min; 96% purity.
1,3-Dimethyl-5-(5-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-
1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one (22g). 11 mg, 0.03
1
mmol, 7% yield. H NMR (600 MHz, DMSO-d6): δ 8.11 (s, 1 H),
7.72 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.40 (s, 1 H), 7.08 (d, J = 8.0
Hz, 1 H), 4.24 (d, J = 7.5 Hz, 2 H), 3.71 (dd, J = 11.5, 3.5 Hz, 2 H),
3.55 (s, 3 H), 3.10 (t, J = 11.5 Hz, 2 H), 2.41 (s, 3 H), 2.10 (s, 3 H),
1.94 (ttt, J = 11.5, 7.5, 3.5 Hz, 1 H), 1.19 (dd, J = 11.5 Hz, 2 H), 1.13
(qd, J = 11.5, 3.5 Hz, 2 H). LC−MS (method F) m/z: 352 [(M +
H)+]; Rt: 0.54 min; 100% purity.
1,3-Dimethyl-5-(6-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-
5-(6-(Dimethylamino)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-
benzo[d]imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one (22d). 5-(6-
Bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-
2-yl)-1,3-dimethylpyridin-2(1H)-one 22b (50 mg, 0.12 mmol),
JohnPhos (4.6 mg, 0.015 mmol), 2 M dimethylamine in THF (0.10
mL, 0.20 mmol), NaOtBu (23.1 mg, 0.24 mmol), and Pd2(dba)3 (4.5
mg, 0.05 mmol) were suspended in 1,4-dioxane (1 mL). The reaction
vessel was sealed and heated in a microwave at 90 °C for 20 min. The
reaction mixture was allowed to cool to rt, and JohnPhos (4.6 mg,
0.015 mmol), Pd2(dba)3 (4.5 mg, 0.005 mmol), and NaOtBu (23.1
mg, 0.24 mmol) were added to the reaction vessel. The reaction vessel
was sealed and heated in a microwave at 90 °C for 20 min. The
reaction was allowed to cool to rt, and the solution was loaded onto a
1 g C18 SPE cartridge (preconditioned with MeCN [3 mL]). The
column was flushed with MeCN (3 mL), and the filtrate was
evaporated under a stream of nitrogen. The sample was dissolved in
DMSO (1 mL) and purified by MDAP (method B). The appropriate
fractions were evaporated, and the sample was dissolved in DMSO (1
mL) and purified by MDAP (method A) to give the title compound
1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one (22h). 11 mg, 0.03
1
mmol, 6% yield. H NMR (600 MHz, DMSO-d6): δ 8.10 (s, 1 H),
7.72 (s, 1 H), 7.48 (d, J = 8.5 Hz, 1 H), 7.47 (s, 1 H), 7.03 (d, J = 8.5
Hz, 1 H), 4.23 (d, J = 7.5 Hz, 2 H), 3.71 (dd, J = 11.5, 3.5 Hz, 2 H),
3.55 (s, 3 H), 3.11 (t, J = 11.5 Hz, 2 H), 2.46 (s, 3 H), 2.10 (s, 3 H),
1.95 (ttt, J = 11.5, 7.5, 3.5, Hz, 1 H), 1.21 (dd, J = 11.5 Hz, 2 H), 1.14
(qd, J = 11.5, 3.5 Hz, 2 H). LC−MS (method F) m/z: 352 [(M +
H)+]; Rt: 0.55 min; 100% purity.
5-(5-Fluoro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]-
imidazole-2-yl)-1,3-dimethylpyridin-2(1H)-one (22i). 15 mg, 0.04
1
mmol, 9% yield. H NMR (600 MHz, DMSO-d6): δ 8.14 (s, 1 H),
7.74 (s, 1 H), 7.72 (dd, J = 8.5, 4.5 Hz, 1 H), 7.41 (dd, J = 9.5, 2.0 Hz,
1 H), 7.13 (ddd, J = 9.5, 8.5, 2.0 Hz, 1 H), 4.29 (d, J = 7.5 Hz, 2 H),
3.71 (dd, J = 11.5, 3.5 Hz, 2 H), 3.56 (s, 3 H), 3.11 (t, J = 11.5 Hz, 2
H), 2.10 (s, 3 H), 1.95 (ttt, J = 11.5, 7.5, 3.5 Hz, 1 H), 1.20 (dd, J =
11.5, Hz, 2 H), 1.15 (qd, J = 11.5, 3.5 Hz, 2 H). LC−MS (method F)
m/z: 356 [(M + H)+]; Rt: 0.65 min; 99% purity.
5-(5-Chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]-
imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one (22j). 41 mg, 0.11
1
(8.9 mg, 0.02 mmol, 19% yield). H NMR (400 MHz, DMSO-d6): δ
1
mmol, 23% yield. H NMR (600 MHz, DMSO-d6): δ 8.15 (s, 1 H),
8.05 (d, J = 2.5 Hz, 1 H), 7.72−7.68 (m, 1 H), 7.41 (d, J = 9.0 Hz, 1
H), 6.83 (d, J = 2.5 Hz, 1 H), 6.76 (dd, J = 9.0, 2.5 Hz, 1 H), 4.20 (d,
J = 7.5 Hz, 2 H), 3.72 (dd, J = 11.5, 4.0 Hz, 2 H), 3.55 (s, 3 H), 3.11
(td, J = 11.5, 2.5 Hz, 2 H), 2.95 (s, 6 H), 2.10 (s, 3 H), 1.94 (ddd, J =
11.5, 7.5, 3.5 Hz, 1 H), 1.28−1.10 (m, 4 H); LC−MS (method F) m/
z: 381 [(M + H)+]; Rt: 0.50 min; 99% purity.
7.77−7.71 (m, 2 H), 7.67 (s, 1 H), 7.29 (d, J = 8.5 Hz, 1 H), 4.29 (d,
J = 7.5 Hz, 2 H), 3.71 (d, J = 11.5 Hz, 2 H), 3.56 (s, 3 H), 3.10 (t, J =
11.5 Hz, 2 H), 2.10 (s, 3 H), 1.98−1.89 (m, 1 H), 1.22−1.09 (m, 4
H). LC−MS (method F) m/z: 372, 374 [(M + H)+]; Rt: 0.79 min;
99% purity.
5-(6-Chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]-
General SNAr-Cyclization Method. To a solution of the
appropriately substituted 1-fluoro-2-nitrobenzene (83 mg, 0.52
mmol) in 2-MeTHF (0.5 mL) were added (tetrahydro-2H-pyran-4-
yl)methanamine (50 mg, 0.43 mmol) and DIPEA (0.23 mL, 1.30
mmol). The reaction vessel was sealed and heated in a microwave at
110 °C for 20 min. The solvent was removed under a stream of
nitrogen. To the dried material were added 1,5-dimethyl-6-oxo-1,6-
dihydropyridine-3-carbaldehyde (72 mg, 0.48 mmol) and Na2S2O4
(227 mg, 1.30 mmol) as a solution in EtOH (1.0 mL), followed by
water (0.5 mL). The sealed vessels were heated at 100 °C for 18 h.
The solvent was removed under a stream of nitrogen. The reaction
mixture was partitioned between saturated aqueous NaHCO3 (3 mL)
and DCM (2 × 3 mL). The DCM extracts were evaporated under a
stream of nitrogen. The residue was dissolved in DMSO (1 mL) and
purified by MDAP (method B). The solvent was removed under a
stream of nitrogen to give the compounds 22e−22p.
imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one (22k). 19 mg, 0.05
1
mmol, 11% yield. H NMR (600 MHz, DMSO-d6): δ 8.15 (s, 1 H),
7.89 (s, 1 H), 7.74 (s, 1 H), 7.62 (d, J = 8.5 Hz, 1 H), 7.23 (d, J = 8.5
Hz, 1 H), 4.29 (d, J = 7.5 Hz, 2 H), 3.71 (dd, J = 11.5, 3.5 Hz, 2 H),
3.55 (s, 3 H), 3.11 (t, J = 11.5 Hz, 2 H), 2.10 (s, 3 H), 1.93 (ttt, J =
11.5, 7.5, 3.5 Hz, 1 H), 1.20 (dd, J = 11.5 Hz, 2 H), 1.14 (qd, J = 11.5,
3.5 Hz, 2 H). LC−MS (method F) m/z: 372, 374 [(M + H)+]; Rt:
0.78 min; 99% purity.
2-(1,5-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((tetrahydro-
2H-pyran-4-yl)methyl)-1H-benzo[d]imidazole-5-carboxamide
(22l). 30 mg, 0.08 mmol, 16% yield. 1H NMR (600 MHz, DMSO-d6):
δ 8.18 (s, 1 H), 8.16 (s, 1 H), 7.98 (br s, 1 H), 7.83 (d, J = 8.5 Hz, 1
H), 7.75 (s, 1 H), 7.73 (d, J = 8.5 Hz, 1 H), 7.26 (br s, 1 H), 4.30 (d, J
= 7.5 Hz, 2 H), 3.71 (dd, J = 11.5, 3.5 Hz, 2 H), 3.56 (s, 3 H), 3.11 (t,
J = 11.5 Hz, 2 H), 2.11 (s, 3 H), 1.95 (ttt, J = 11.5, 7.5, 3.5 Hz, 1 H),
1.23−1.12 (m, 4 H). LC−MS (method F) m/z: 381 [(M + H)+]; Rt:
0.49 min; 100% purity.
5-(5-Methoxy-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo-
[d]imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one (22e). 7 mg, 0.02
2-(1,5-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((tetrahydro-
1
mmol, 4% yield. H NMR (600 MHz, DMSO-d6): δ 8.09 (s, 1 H),
2H-pyran-4-yl)methyl)-1H-benzo[d]imidazole-6-carboxamide
1
7.72 (s, 1 H), 7.56 (d, J = 8.5 Hz, 1 H), 7.13 (d, J = 2.0 Hz, 1 H), 6.88
(dd, J = 8.5, 2.0 Hz, 1 H), 4.23 (d, J = 7.5 Hz, 2 H), 3.79 (s, 3 H),
3.71 (d, J = 11.5 Hz, 2 H), 3.55 (s, 3 H), 3.10 (t, J = 11.5 Hz, 2 H),
2.10 (s, 3 H), 1.94 (ttt, J = 11.5, 7.5, 3.5 Hz, 1 H), 1.20 (d, J = 11.5
Hz, 2 H), 1.13 (qd, J = 11.5, 3.5 Hz, 2 H). LC−MS (method F) m/z:
368 [(M + H)+]; Rt: 0.51 min; 96% purity.
(22m). 1 mg, 0.003 mmol, 1% yield. H NMR (600 MHz, DMSO-
d6): δ 8.22 (s, 1 H), 8.18 (s, 1 H), 8.00 (br s, 1 H), 7.79 (d, J = 8.5
Hz, 1 H), 7.77 (s, 1 H), 7.63 (d, J = 8.5 Hz, 1 H), 7.35 (br s, 1 H),
4.32 (d, J = 7.5 Hz, 2 H), 3.72 (dd, J = 11.5, 3.5 Hz, 2 H), 3.56 (s, 3
H), 3.12 (t, J = 11.5 Hz, 2 H), 2.11 (s, 3 H), 2.00 (ttt, J = 11.5, 7.5,
3.5 Hz, 1 H), 1.24−1.13 (m, 4 H). LC−MS (method F) m/z: 381
[(M + H)+]; Rt: 0.47 min; 100% purity.
5-(6-Methoxy-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo-
[d]imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one (22f). 8 mg, 0.02
2-(1,5-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((tetrahydro-
1
mmol, 4% yield. H NMR (600 MHz, DMSO-d6): δ 8.08 (s, 1 H),
2H-pyran-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (22n).
1
7.71 (s, 1 H), 7.48 (d, J = 8.5 Hz, 1 H), 7.22 (s, 1 H), 6.83 (dd, J =
8.5, 2.0 Hz, 1 H), 4.24 (d, J = 7.5 Hz, 2 H), 3.83 (s, 3 H), 3.71 (d, J =
11.5 Hz, 2 H), 3.55 (s, 3 H), 3.11 (t, J = 11.5 Hz, 2 H), 2.10 (s, 3 H),
1.93 (ttt, J = 11.5, 7.5, 3.5 Hz, 1 H), 1.20 (d, J = 11.5 Hz, 2 H), 1.19−
54 mg, 0.15 mmol, 31% yield. H NMR (600 MHz, DMSO-d6): δ
8.21 (s, 1 H), 8.16 (s, 1 H), 7.94 (d, J = 8.5 Hz, 1 H), 7.77 (s, 1 H),
7.67 (d, J = 8.5 Hz, 1 H), 4.36 (d, J = 7.5 Hz, 2 H), 3.71 (dd, J = 11.5,
3.5 Hz, 2 H), 3.56 (s, 3 H), 3.10 (td, J = 11.5, 3.5 Hz, 2 H), 2.11 (s, 3
W
J. Med. Chem. XXXX, XXX, XXX−XXX