Respiratory Syncytial Virus Fusion Inhibitor
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19 4581
°C); 1H NMR (DMSO-d6) δ 1.55 (qd, 2 H, J ) 10.2 Hz), 2.05 (d,
2 H, J ) 10.2 Hz), 2.18 (s, 6 H), 2.20-2.30 (m, 5 H), 2.20-2.30
(m, 7 H), 2.70-2.80 (m, 2 H), 3.70-3.85 (m, 2 H), 5.10 (s, 2 H),
6.70-6.80 (m, 3 H), 7.00-7.20 (m, 3 H); HRMS (ESI) calcd for
C25H37N6O2, 453.2973; found [MH]+, 453.2978.
21 (0.4 mmol) and Pd/C 10% (0.1 g) in CH3OH (20 mL) was
hydrogenated at 40 °C for 3 h under a 5 bar pressure, then cooled
down to rt, and filtered over celite. The filtrate was evaporated
until dryness, yielding 0.16 g (100%). This fraction was crystallized
from 2-propanone/DIPE. The precipitate was filtered off and dried
(0.07 g, 43%, melting point: 258 °C); 1H NMR (DMSO-d6) δ 1.55
(qd, 2 H, J ) 10.2 Hz), 2.05 (d, 2 H J ) 10.2 Hz), 2.20 (t, 2 H, J
) 10.2 Hz), 2.35 (s, 6 H), 2.45 (t, 2 H, J ) 6.4 Hz), 2.85 (d, 2 H,
J ) 10.2 Hz), 3.50 (t, 2 H, J ) 6.4 Hz), 3.70-3.82 (m, 1 H), 4.40
(br s, 1 H), 5.10 (s, 2 H), 6.65-6.82 (m, 3 H), 7.00-7.15 (m, 2
H), 10.3 (brs, 1 H); HRMS (ESI) calcd for C22H30N5O2, 396.2409;
found [MH]+, 396.2400; Anal. (C22H29N5O2‚0.3H2O) C, H, N.
Methanesulfonic Acid 2-{4-[1-(3-Benzyloxy-6-methyl-pyridin-
2-ylmethyl)-4-methyl-1H-benzoimidazol-2-ylamino]-piperidin-
1-yl}-ethyl Ester (23). Triethylamine (3.1 mmol) was added at 5
°C to a mixture of 21 (2 mmol) in CH2Cl2 (40 mL) under a N2
flow. Methanesulfonyl chloride (3.1 mmol) was added dropwise.
The mixture was stirred at 5 °C for 1 h and then at rt for 2 h and
poured into H2O. The organic layer was separated, dried (over
MgSO4), and filtered, and the solvent was evaporated until dryness
(1.2 g, 100%). The crude compound was used directly in the next
reaction step.
[1-(3-Benzyloxy-6-methyl-pyridin-2-ylmethyl)-4-methyl-1H-
benzoimidazol-2-yl]-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-
amine (24). A mixture of 23 (2 mmol), morpholine (2.5 mmol),
and K2CO3 (3.1 mmol) in CH3CN (50 mL) was stirred at 80 °C
for 2 h, then stirred at 60 °C for 12 h. The solvent was evaporated
until dryness. The residue was taken up in CH2Cl2/H2O. The organic
layer was separated, dried (over MgSO4), and filtered, and the
solvent was concentrated under reduced pressure. The residue (2
g) was purified by column chromatography over silica gel (eluent:
toluene/2-propanol/NH4OH 80/20/1). The pure fractions were
collected, and the solvent was evaporated. The residue (0.6 g, 53%)
was crystallized from CH3CN. The precipitate was filtered off and
dried (0.17 g, 15%, melting point: 183 °C); 1H NMR (DMSO-d6)
δ 1.47 (qd, 2 H, J ) 10.2 Hz), 2.00 (d, 2 H, J ) 10.2 Hz), 2.13 (t,
2 H, J ) 10.2 Hz), 2.35 (s, 3 H), 2.37-2.47 (m, 8 H), 2.85 (d, 2
H, J ) 10.2 Hz), 3.55 (t, 4 H, J ) 5.1 Hz), 3.70-3.80 (m, 1 H),
5.15 (s, 2 H), 5.19 (s, 2 H), 6.60 (t, 1 H, J ) 7.7 Hz), 6.65 (d, 1H,
J ) 7.7 Hz), 6.72 (d, 1 H, J ) 7.7 Hz), 6.80 (d, 1 H, J ) 7.7 Hz),
7.20 (d, 1 H, J ) 7.7 Hz), 7.35-7.52 (m, 6 H); MS (ESI+) found
for C33H43N6O2 [MH]+, 555.
4-[1-(3-Benzyloxy-6-methyl-pyridin-2-ylmethyl)-4-methyl-1H-
benzoimidazol-2-ylamino]-piperidine-1-carboxylic Acid Ethyl
Ester (18). A mixture of 17 (23.6 mmol), benzyl bromide (26
mmol), and K2CO3 (0.0354 mol) in a mixture of CH3CN (50 mL),
DMF (50 mL), and THF (100 mL) was stirred at 60 °C for 24 h.
The solvent was evaporated until dryness. The residue was taken
up in H2O. The precipitate was filtered on celite, the pad was
washed with H2O, and the filtrate was extracted with diethyl ether.
The organic layer was separated, dried (over MgSO4), and filtered,
and the solvent was evaporated until dryness. The residue (12 g)
was purified by column chromatography over silica gel (eluent:
CH2Cl2/CH3OH/NH4OH 98/2/0.1). Three fractions were collected
1
and the solvent was evaporated (5 g, 41%); H NMR (DMSO-d6)
δ 1.20 (t, 3 H, J ) 7.7 Hz), 1.40 (d, 2 H, J ) 10.2 Hz), 2.02 (d,
2 H, J ) 10.2 Hz), 2.37 (s, 6 H), 3.00-3.12 (m, 2 H), 3.88 (d, 2
H, J ) 10.2 Hz), 3.95-4.02 (m, 1 H), 4.06 (qd, 2 H, J ) 7.7 Hz),
5.17 (s, 4 H), 6.62 (t, 1 H, J ) 7.7 Hz), 6.68 (d, 1 H, J ) 7.7 Hz),
6.73 (d, 1 H, J ) 7.7 Hz), 6.82 (d, 1 H, J ) 7.7 Hz), 7.18 (d, 1 H,
J ) 7.7 Hz), 7.35-7.50 (m, 6 H).
[1-(3-Benzyloxy-6-methyl-pyridin-2-ylmethyl)-4-methyl-1H-
benzoimidazol-2-yl]-piperidin-4-yl-amine (19). A mixture of 18
(9.5 mmol) and KOH (9.5 mmol) in 2-propanol (60 mL) was stirred
and refluxed for 4 h. The solvent was evaporated until dryness.
The residue was taken up in CH2Cl2. The organic layer was washed
with H2O, dried (over MgSO4), and filtered, and the solvent was
evaporated until dryness (4.19 g, 100%, melting point: 182 °C);
1H NMR (DMSO-d6) δ 1.35 (qd, 2 H, J ) 10.2 Hz), 1.95 (d, 2 H,
J ) 10.2 Hz), 2.35 (s, 3 H), 2.40 (s, 3 H), 2.55 (t, 2 H, J ) 10.2
Hz), 2.95 (d, 2 H, J ) 10.2 Hz), 3.75-3.85 (m, 1 H), 5.15 (s, 2
H), 5.18 (s, 2 H), 6.60 (t, 1 H, J ) 7.7 Hz), 6.70 (d, 1 H, J ) 7.7
Hz), 6.80 (d, 1 H, J ) 7.7 Hz), 7.20 (d, 1 H, J ) 7.7 Hz), 7.38-
7.52 (m, 6 H).
{4-[1-(3-Benzyloxy-6-methyl-pyridin-2-ylmethyl)-4-methyl-
1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-acetic Acid Ethyl
Ester (20). A mixture of 19 (30.7 mmol), ethyl chloro-acetate (37
mmol), and K2CO3 (0.046 mol) in CH3CN (150 mL) was stirred at
60 °C for 12 h. The solvent was evaporated until dryness. The
residue was taken up in CH2Cl2. The organic layer was washed
with H2O, dried (over MgSO4), and filtered, and the solvent was
evaporated until dryness. The residue was crystallized from
2-propanone/CH3CN. The precipitate was filtered off and dried
(14.5 g, 90%, melting point: 116 °C); 1H NMR (DMSO-d6) δ 1.20
(t, 3 H, J ) 6.8 Hz), 1.52 (qd, 2 H, J ) 10.2 Hz), 2.00 (d, 2 H, J
) 10.2 Hz), 2.30-2.40 (m, 8 H), 2.85 (d, 2 H, J ) 10.2 Hz), 3.24
(s, 2 H), 3.70-3.80 (m, 1 H), 4.09 (qd, 2 H, J ) 6.8 Hz), 5.14 (s,
2 H), 5.18 (s, 2 H), 6.60 (t, 1 H, J ) 7.7 Hz), 6.68 (d, 1 H, J ) 7.7
Hz), 6.72 (d, 1 H, J ) 7.7 Hz), 6.79 (d, 1 H, J ) 7.7 Hz), 7.20 (d,
1 H, J ) 7.7 Hz), 7.35-7.50 (m, 6 H).
6-Methyl-2-{4-methyl-2-[1-(2-morpholin-4-yl-ethyl)-piperidin-
4-ylamino]-benzoimidazol-1-ylmethyl}-pyridin-3-ol (25). A mix-
ture of 24 (0.5 mmol) and Pd/C 10% (0.1 g) in MeOH (20 mL)
was hydrogenated at rt for 4 h under a 5 bar pressure. The mixture
was filtered over celite. The filtrate was evaporated. The residue
(0.2 g) was purified by column chromatography over kromasil
(eluent: CH2Cl2/CH3OH/NH4OH 90/10/1). The pure fractions were
collected and the solvent was evaporated. The residue (0.13 g, 54%)
was crystallized from CH3CN/DIPE. The precipitate was filtered
1
off and dried (0.122 g, 49%, melting point: 238 °C); H NMR
(DMSO-d6) δ 1.55 (qd, 2 H, J ) 10.2 Hz), 2.05 (d, 2 H, J ) 10.2
Hz), 2.15 (t, 2 H, J ) 10.2 Hz), 2.35 (s, 6 H), 2.35-2.45 (m, 8 H),
2.85 (d, 2 H, J ) 10.2 Hz), 3.55 (t, 4 H, J ) 5.1 Hz), 3.70-3.80
(m, 1 H), 5.10 (s, 2 H), 6.70-6.82 (m, 3 H), 7.00-7.10 (m, 2 H),
7.15 (d, 1H, J ) 7.7 Hz), 10.2 (brs,1 H); HRMS (ESI) calcd for
C26H37N6O2, 465.2980; found [MH]+, 465.2978; Anal. (C26H36N6O2‚
1.5H2O) C, H, N.
2-{2-[1-(2-Chloro-ethyl)-piperidin-4-ylamino]-4-methyl-ben-
zoimidazol-1-ylmethyl}-6-methyl-pyridin-3-ol (26). SOCl2 (21.4
mmol) was added dropwise to a solution of 22 in CH2Cl2 at 0 °C.
The reaction was stirred at rt for 5 h. The precipitate was filtered
off, rinsed with DIPE, and dried. The crude compound was used
directly in the next reaction step.
6-Methyl-2-{4-methyl-2-[1-(2-pyrrolidin-1-yl-ethyl)-piperidin-
4-ylamino]-benzoimidazol-1-ylmethyl}-pyridin-3-ol (27). A mix-
ture of 26 (1.1 mmol), K2CO3 (0.0038 mol), and pyrrolidine (1.3
mmol) in CH3CN (10 mL) was stirred at 70 °C for 12 h. H2O was
added. The mixture was extracted with CH2Cl2. The organic layer
was separated, dried (over MgSO4), and filtered, and the solvent
2-{4-[1-(3-Benzyloxy-6-methyl-pyridin-2-ylmethyl)-4-methyl-
1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-ethanol (21). Li-
AlH4 (47 mmol) was added portionwise at 5 °C to a mixture of 20
(23 mmol) in THF (250 mL) under a N2 flow. The mixture was
stirred at 5 °C for 2 h. H2O was added. The mixture was extracted
with EtOAc and filtered over celite. The organic layer was
separated, dried (over MgSO4), and filtered, and the solvent was
1
evaporated until dryness (8 g, 72%, melting point: 159 °C); H
NMR (DMSO-d6) δ 1.50 (qd, 2 H, J ) 10.2 Hz), 2.00 (d, 2 H, J
) 10.2 Hz), 2.15 (t, 2 H, J ) 10.2 Hz), 2.35 (s, 3 H), 2.40-2.48
(m, 5 H), 2.85 (d, 2 H, J ) 10.2 Hz), 3.50 (qd, 2 H, J ) 5.1 Hz),
3.70-3.80 (m, 1 H), 4.38 (t, 1 H, J ) 5.1 Hz), 5.15 (s, 2 H), 5.19
(s, 2 H), 6.60 (t, 1 H, J ) 7.7 Hz), 6.65 (d, 1 H, J ) 7.7 Hz), 6.72
(d, 1 H, J ) 7.7 Hz), 6.79 (d, 1 H, J ) 7.7 Hz), 7.20 (d, 1 H, J )
7.7 Hz), 7.35-7.50 (m, 6 H); MS (ESI+) found for C29H35N5O2
[MH]+, 486.
2-{2-[1-(2-Hydroxy-ethyl)-piperidin-4-ylamino]-4-methyl-ben-
zoimidazol-1-ylmethyl}-6-methyl-pyridin-3-ol (22). A mixture of