NoVel Pyridinylimidazoles as p38 MAP Kinase Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 18 5639
C2-/C6-H 4-F-Phe), 7.79 (d, J ) 6.1 Hz, 1H, C6-H Pyr). HRMS-
ESI, m/z (C22H27FN4O2S): calcd, 431.1912 [M + H]+; found,
431.1909.
Diethyl (4-(4-Fluorophenyl)-5-(2-(1-phenylethylamino)pyridin-
4-yl)-1H-imidazol-2-ylthio)methylphosphonate (3r). Compound 3r
was prepared according to general procedure K from 19a (200 mg,
0.51 mmol), t-BuOK (63 mg, 0.56 mmol), diethyl iodomethylphos-
phonate (157 mg, 0.56 mol) and MeOH (15 mL). The reaction
mixture was stirred at 55 °C for 3.5 h and purified by flash
chromatography (SiO2, from n-hexane/EtOAc 3:7 to n-hexane/
(2S)-3-(4-(4-Fluorophenyl)-5-(2-(3-methylbutan-2-ylamino)py-
ridin-4-yl)-1H-imidazol-2-ylthio)propane-1,2-diol (3m). Compound
3m was prepared according to general procedure H from 19f (300
mg, 0.84 mmol), t-BuOK (104 mg, 0.93 mmol), (S)-(+)-3-
chloropropane-1,2-diol (103 mg, 0.93 mol), and MeOH (20 mL).
The reaction mixture was heated to reflux temperature for 1.25 h
and purified by flash chromatography (SiO2, from DCM/EtOH 95:5
to DCM/MeOH 8:2). Yield: 210 mg (58%). 1H NMR (CD3OD) δ
0.90 and 0.91 (2d, J ) 6.8 Hz and J ) 6.8 Hz, 6H, 2 × CH3), 1.07
(d, J ) 6.6 Hz, 3H, CH3), 1.65-1.82 (m, 1H, CH), 3.14-3.35 (m,
CH2, solvent peak), 3.47-3.55 (m, 1H, CH), 3.64 (d, J ) 5.4 Hz,
CH2), 3.83-3.94 (m, 1H, CH), 6.50-6.53 (m, 2H, C3-/C5-H Pyr),
7.10-7.19 (m, 2H, C3-/C5-H 4-F-Phe), 7.44-7.51 (m, 2H, C2-/
C6-H 4-F-Phe), 7.81 (d, J ) 6.4 Hz, 1H, C6-H Pyr). HRMS-ESI,
m/z (C22H27FN4O2S): calcd, 431.1912 [M + H]+; found, 431.1910.
1
EtOAc 0:1). Yield: 129 mg (47%). H NMR (CD3OD) δ 1.22 (t,
J ) 7.0 Hz, 6H, 2 × CH3), 1.45 (d, J ) 6.8 Hz, 3H, CH3), 3.50 (d,
J ) 12.4 Hz, 2H, CH2), 4.02-4.16 (m, 4H, 2 × CH2), 4.60-4.70
(m, 1H, CH), 6.47 (s, 1H, C3-H Pyr), 6.58 (d, J ) 5.3 Hz, 1H,
C5-H Pyr), 7.06-7.24 (m, 7H, 5 × Ph, C3-/C5-H 4-F-Phe),
7.36-7.43 (m, 2H, C2-/C6-H 4-F-Phe), 7.82 (d, J ) 5.5 Hz, 1H,
C6-H Pyr). HRMS-ESI, m/z (C27H30FN4O3PS): calcd, 541.1833 [M
+ H]+; found, 541.1833.
Methyl 2-(4-(4-Fluorophenyl)-5-(2-(3-methylbutan-2-ylamino)py-
ridin-4-yl)-1H-imidazol-2-ylthio)acetate (3s). Compound 3s was
prepared according to general procedure H from 19f (300 mg, 0.84
mmol), t-BuOK (104 mg, 0.93 mmol), methyl 2-bromoacetate (142
mg, 0.93 mmol), and MeOH (20 mL). The reaction mixture was
heated to reflux temperature for 1 h and purified by flash
chromatography (SiO2, from petroleum ether/EtOAc 3:7 to EtOAc
100%). Yield: 140 mg (42%). 1H NMR (CD3OD) δ 0.85-0.94
(m, 6H, 2 × CH3), 1.08 (d, J ) 6.6 Hz, 3H, CH3), 1.65-1.82 (m,
1H, CH), 3.45-3.58 (m, 1H, CH), 3.72 (s, 3H, CH3), 3.89 (s, 2H,
CH2), 6.52-6.56 (m, 2H, C3-/C5-H Pyr), 7.11-7.20 (m, 2H, C3-/
C5-H 4-F-Phe), 7.44-7.51 (m, 2H, C2-/C6-H 4-F-Phe), 7.80 (d, J
) 5.5 Hz, 1H, C6-H Pyr). HRMS-ESI, m/z (C22H25FN4O2S): calcd,
429.1755 [M + H]+; found, 429.1753.
Methyl 2-(4-(4-Fluorophenyl)-5-(2-(isopropylamino)pyridin-4-
yl)-1H-imidazol-2-ylthio)acetate (3t). Compound 3t was prepared
according to general procedure H from 19h (200 mg, 0.61 mmol),
t-BuOK (75 mg, 0.67 mmol), methyl 2-bromoacetate (102 mg, 0.67
mmol), and MeOH (15 mL). The reaction mixture was heated to
reflux temperature for 1 h and purified by flash chromatography
(SiO2, from petroleum ether/EtOAc 3:7 to EtOAc 100%). Yield:
108 mg (44%). 1H NMR (CD3OD) δ 1.17 (d, J ) 6.4 Hz, 6H, 2 ×
CH3), 3.72 (s, 3H, CH3), 3.74-3.84 (m, 1H, CH), 3.89 (s, 2H, CH2),
6.53-6.55 (m, 2H, C3-/C5-H Pyr), 7.11-7.20 (m, 2H, C3-/C5-H
4-F-Phe), 7.44-7.51 (m, 2H, C2-/C6-H 4-F-Phe), 7.82 (d, J ) 5.0
Hz, 1H, C6-H Pyr). HRMS-ESI, m/z (C20H21FN4O2S): calcd,
401.1442 [M + H]+; found, 401.1443.
2-(4-(4-Fluorophenyl)-5-(2-(isopropylamino)pyridin-4-yl)-1H-
imidazol-2-ylthio)ethanol (3u). Compound 3u was prepared according
to general procedure H from 19h (150 mg, 0.46 mmol), t-BuOK (56
mg, 0.50 mmol), 2-bromoethanol (63 mg, 0.50 mol), and MeOH (10
mL). The reaction mixture was stirred at 55 °C for 3.5 h and purified
by flash chromatography (SiO2, from DCM/EtOH 95:5 to DCM/EtOH
75:25). Yield: 67 mg (39%). 1H NMR (CD3OD) δ 1.16 (d, J ) 6.4
Hz, 6H, 2 × CH3), 3.19 (t, J ) 6.3 Hz, 2H, CH2), 3.74-3.87 (m, 3H,
CH, CH2), 6.52-6.54 (m, 2H, C3-/C5-H Pyr), 7.07-7.19 (m, 2H, C3-/
C5-H 4-F-Phe), 7.43-7.51 (m, 2H, C2-/C6-H 4-F-Phe), 7.82 (d, J )
5.8 Hz, 1H, C6-H Pyr). HRMS-ESI, m/z (C19H21FN4OS): calcd,
373.1493 [M + H]+; found, 373.1494.
(2R)-3-(4-(4-Fluorophenyl)-5-(2-(isopropylamino)pyridin-4-yl)-
1H-imidazol-2-ylthio)propane-1,2-diol (3n). Compound 3n was
prepared according to general procedure H from 19h (200 mg, 0.61
mmol), t-BuOK (75 mg, 0.67 mmol), (R)-(-)-3-chloropropane-1,2-
diol (74 mg, 0.67 mol), and MeOH (15 mL). The reaction mixture
was heated to reflux temperature for 1 h and crystallized from
1
MeOH/Et2O/n-hexane. Yield: 113 mg (46%). H NMR (DMSO-
d6) 1.08 (d, J ) 6.4 Hz, 6H, 2 × CH3), 3.13-3.42 (m, 2 × CH2,
H2O in DMSO-d6), 3.67-3.92 (m, 2H, 2 × CH), 6.29 (d, J ) 7.3
Hz, 1H), 6.37 (dd, J1 ) 5.4 Hz, J2 ) 1.3 Hz, 1H, C5-H Pyr), 6.47
(s, 1H, C3-H Pyr), 7.17-7.26 (m, 2H, C3/C5-H 4-F-Phe), 7.43-7.50
(m, 2H, C2-/C6-H 4-F-Phe), 7.84 (d, J ) 4.7 Hz, 1H, C6-H Pyr).
Anal. (C20H23FN4O2S) C, H, N.
(2S)-3-(4-(4-Fluorophenyl)-5-(2-(isopropylamino)pyridin-4-yl)-
1H-imidazol-2-ylthio)propane-1,2-diol (3o). Compound 3o was
prepared according to general procedure H from 19h (200 mg, 0.61
mmol), t-BuOK (75 mg, 0.67 mmol), (S)-(+)-3-chloropropane-1,2-
diol (74 mg, 0.67 mol), and MeOH (15 mL). The reaction mixture
was heated to reflux temperature for 1 h and crystallized from
1
MeOH/Et2O/n-hexane. Yield: 119 mg (49%). H NMR (DMSO-
d6) δ 1.08 (d, J ) 6.4 Hz, 6H, 2 × CH3), 3.08-3.43 (m, 2 × CH2,
H2O in DMSO-d6), 3.69-3.93 (m, 2H, 2 × CH), 6.30 (d, J ) 7.6
Hz, 1H), 6.39 (d, J ) 5.3 Hz, 1H, C5-H Pyr), 6.49 (s, 1H, C3-H
Pyr), 7.17-7.26 (m, 2H, C3-/C5-H 4-F-Phe), 7.44-7.51 (m, 2H,
C2-/C6-H 4-F-Phe), 7.85 (d, J ) 5.2 Hz, 1H, C6-H Pyr). Anal.
(C20H23FN4O2S) C, H, N.
Methyl 2-(4-(4-Fluorophenyl)-5-(2-(1-phenylethylamino)pyridin-
4-yl)-1H-imidazol-2-ylthio)acetate (3p). Compound 3p was prepared
according to general procedure H from 19a (200 mg, 0.51 mmol),
t-BuOK (63 mg, 0.56 mmol), methyl bromoacetate (86 mg, 0.56
mol), and MeOH (5 mL). The reaction mixture was stirred at 55
°C for 1 h and purified by flash chromatography (SiO2, from DCM/
1
EtOAc 1:1 to DCM/EtOAc 1:2). Yield: 109 mg (46%). H NMR
(CD3OD) δ 1.45 (d, J ) 6.8 Hz, 3H, CH3), 3.69 (s, 3H, CH3), 3.86
(s, 2H, CH2), 6.48 (s, 1H, C3-H Pyr), 6.58 (d, J ) 5.3 Hz, 1H,
C5-H Pyr), 7.11-7.26 (m, 7H, 5 × Phe, C3-/C5-H 4-F-Phe),
7.36-7.43 (m, 2H, C2-/C6-H 4-F-Phe), 7.82 (d, J ) 5.4 Hz, 1H,
C6-H Pyr). Anal. (C25H23FN4O2S) C, H, N.
2-(4-(4-Fluorophenyl)-5-(2-(tetrahydro-2H-pyran-4-ylamino)py-
ridin-4-yl)-1H-imidazol-2-ylthio)ethanol (3v). Compound 3v was
prepared according to general procedure H from 19i (150 mg, 0.40
mmol), t-BuOK (50 mg, 0.45 mmol), 2-bromoethanol (56 mg, 0.45
mol), and MeOH (10 mL). The reaction mixture was stirred at 55
°C for 3.5 h and purified by flash chromatography (SiO2, from
2-(4-(4-Fluorophenyl)-5-(2-(1-phenylethylamino)pyridin-4-yl)-
1H-imidazol-2-ylthio)acetic Acid (3q). To a solution of 19a (100
mg, 0.25 mmol) and NaOEt (20 mg, 0.30 mmol) in dry MeOH (15
mL) was added under argon atmosphere 2-bromoacetic acid (41
mg, 0.30 mmol). The solution was stirred at 50 °C for 5 h and
cooled to room temperature. The solvent evaporated under reduced
pressure and the crude product was purified by flash chromatog-
raphy (SiO2, from EtOAc/MeOH 85:15 to 100% MeOH) to yield
23 mg (21%) of compound 3q. 1H NMR (CD3OD) δ 1.45 (d, J )
6.0 Hz, 3H, CH3), 3.67 (s, 2H, CH2), 6.50 (s, 1H, C3-H Pyr), 6.57
(d, J ) 5.3 Hz, 1H, C5-H Pyr), 7.05-7.25 (m, 7H, 5 × Ph, C3-/
C5-H 4-F-Phe), 7.38-7.44 (m, 2H, C2-/C6-H 4-F-Phe), 7.80 (d, J
) 5.5 Hz, 1H, C6-H Pyr). HRMS-ESI, m/z (C24H21FN4O2S): calcd,
449.1442 [M + H]+; found, 449.1443.
1
DCM/EtOH 95:5 to DCM/EtOH 75:25). Yield: 82 mg (50%). H
NMR (CD3OD) δ 1.39-1.56 (m, 2H, C3-/C5-H thp), 1.86-1.92
(m, 2H, C3-/C5-H thp), 3.20 (t, J ) 6.2 Hz, 2H, CH2), 3.42-3.52
(m, 2H, C2-/C6-H thp), 3.66-3.84 (m, 3H, CH, CH2), 3.91-3.97
(m, 2H, C2-/C6-H thp), 6.52-6.57 (m, 2H, C3-/C5-H Pyr),
7.11-7.20 (m, 2H, C3-/C5-H 4-F-Phe), 7.43-7.50 (m, 2H, C2-/
C6-H 4-F-Phe), 7.83 (d, J ) 4.8 Hz, 1H, C6-H Pyr). HRMS-ESI,
m/z (C19H21FN4OS): calcd, 415.1599 [M + H]+; found, 415.1600.
(1R,4R)-4-(4-(4-(4-Fluorophenyl)-2-(2-hydroxyethylthio)-1H-imi-
dazol-5-yl)pyridin-2-ylamino)cyclohexanol (3w). Compound 3w was
prepared by irradiating 21 (160 mg, 0.48 mmol) and trans-4-