5676 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 18
Heerding et al.
1
piperidinecarboxylate. H NMR (400 MHz, DMSO-d6) δ 8.02 (s,
Na2CO3 (0.16 mL, 0.32 mmol), 3-furylboronic acid (25 mg, 0.23
mmol), and 1,4-dioxane (3 mL). The flask was flushed with argon,
sealed, and heated with stirring for 10 min at 160 °C in a microwave
apparatus. The resulting mixture was then diluted with 1,4-dioxane,
filtered, and concentrated under reduced pressure to afford 34b as
a brownish-red residue. This material was used in the next step
without further purification. MS m/z 470.4 [M + H]+.
1 H), 6.94 (s, 2 H), 4.85 (q, J ) 7.2 Hz, 2 H), 3.93-4.26 (m, 3 H),
3.72-3.89 (m, 1 H), 2.66-3.02 (m, 2 H), 1.95-2.13 (m, 1 H),
1.82-1.95 (m, 1 H), 1.64-1.76 (m, 1 H), 1.49 (t, J ) 7.1 Hz, 3
H), 1.27-1.45 (m, 11 H). MS m/z 478 [M + H]+.
4-(4-Chloro-1-ethyl-7-{[(3R)-3-piperidinylmethyl]oxy}-1H-imi-
dazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine. A solution of 32h
(200 mg, 0.42 mmol) in CH2Cl2 (3.2 mL) with TFA (0.8 mL, 10.4
mmol) was stirred at room temperature for 45 min. The solvent
was removed at reduced pressure to give 220 mg (87%) the title
4-[7-[(3-Aminopropyl)oxy]-1-ethyl-4-(3-furanyl)-1H-imidazo[4,5-
c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine, Bis-trifluoroacetate (11b).
Trifluoroacetic acid (2 mL) was added to a solution of crude 34b
in CH2Cl2 (6 mL) at ambient temperature. After 30 min, the solvent
was removed under reduced pressure and the residue was subjected
to reverse phase preparative HPLC to give 35 mg (49% over two
1
compound as a TFA salt. H NMR (400 MHz, DMSO-d6) δ 7.95
(s, 1 H), 6.95 (s, 2 H), 4.81 (q, J ) 7.2 Hz, 2 H), 4.13-4.27 (m,
2 H), 3.41 (dd, J ) 12.0, 3.4 Hz, 1 H), 3.15-3.31 (m, 2 H),
2.77-2.89 (m, 2 H), 2.27-2.39 (m, 1 H), 1.83-1.95 (m, 2 H),
1.63-1.72 (m, 1 H), 1.39-1.49 (m, 4 H). MS m/z 378 [M + H]+.
4-(2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3R)-3-piperidi-
nylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-
2-ol, Bis-trifluoroacetate (3h). In a thick wall pressure tube, a mixture
consisting of 4-(4-chloro-1-ethyl-7-{[(3R)-3-piperidinylmethyl]oxy}-
1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine (125 mg, 0.33
mmol), 2-methyl-3-butyn-2-ol (83 mg, 0.99 mmol), tetrakis(triph-
enylphosphine)palladium(0) (15.3 mg, 0.013 mmol), zinc (3.8 mg,
0.058 mmol), sodium iodide (8.7 mg, 0.058 mmol), DBU (0.075 mL,
0.495 mmol), and TEA (0.069 mL, 0.495 mmol) in DMSO (3 mL)
was purged with argon, sealed, and then heated with stirring at 80 °C
for 3 h. The product mixture was subjected to reverse phase HPLC to
afford 79 mg (36%) of 3h. [R]2D3 +6.7° (c 0.75, methanol). 1H NMR
(400 MHz, DMSO-d6 + D2O) δ 8.15 (s, 1 H), 4.83 (q, J ) 7.2 Hz,
2 H), 4.19-4.33 (m, 2 H), 3.38-3.47 (m, 1 H), 3.29 (d, J ) 12.9 Hz,
1 H), 2.84 (t, J ) 12.1 Hz, 2 H), 2.27-2.40 (m, 1 H), 1.85-1.97 (m,
2 H), 1.60-1.75 (m, 1 H), 1.53 (s, 6 H), 1.45 (t, J ) 7.1 Hz, 3 H),
1
steps) of 11b. H NMR (400 MHz, CH3OH-d4) δ 8.82 (s, 1 H),
8.17 (s, 1 H), 7.84 (t, J ) 1.77 Hz, 1 H), 7.35 (dd, J ) 1.77, 0.76
Hz, 1 H), 5.09 (q, J ) 7.07 Hz, 2 H), 4.53 (t, J ) 5.94 Hz, 2 H),
3.28 (t, J ) 7.71 Hz, 2 H), 2.23-2.51 (m, 2 H), 1.62 (t, J ) 7.07
Hz, 3 H). Anal. (C17H19N7O3 ·2C2HF3O2 ·H2O) calcd: C, 40.98; H,
3.77; N, 15.93. Found: C, 40.89; H, 3.48; N, 15.68.
1,1-Dimethylethyl {3-[(2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-
4-{1-[tris(1-methylethyl)silyl]-1H-pyrrol-3-yl}-1H-imidazo[4,5-c]py-
ridin-7-yl)oxy]propyl}carbamate (34c). A mixture of 30 (135 mg,
0.31 mmol), {1-[tris(1-methylethyl)silyl]-1H-pyrrol-3-yl}boronic
acid (165 mg, 0.62 mmol), tetrakis(triphenylphosphine)palladium(0)
(71 mg, 0.062 mmol), and 2 N Na2CO3 (0.48 mL, 0.95 mmol) in
1,4-dioxane (5 mL) was heated in a sealed tube at 105 °C for 2 h.
The mixture was cooled to ambient temperature, diluted with ethyl
acetate, dried over MgSO4, filtered, and concentrated under reduced
pressure to provide 34c. This material was used in the next step
without further purification. MS m/z 625.4 [M + H]+.
4-[7-[(3-Aminopropyl)oxy]-1-ethyl-4-(1H-pyrrol-3-yl)-1H-imi-
dazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine, Bis-trifluoroac-
etate (11c). A solution of crude 34c in CH2Cl2 (5 mL) was treated
with trifluoroacetic acid (1 mL), and the resultant mixture was
stirred at 30 °C for 1 h. The reaction mixture was diluted with
methanol (5 mL) and concentrated under reduced pressure to yield
4-(7-[(3-aminopropyl)oxy]-1-ethyl-4-{1-[tris(1-methylethyl)silyl]-
1H-pyrrol-3-yl}-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-
amine. This material was used in the next step without further
purification. MS m/z 525.4 [M + H]+.
1.41-1.50 (m,
1 H). MS m/z 426 [M +
H]+. Anal.
(C21H27N7O3 ·2TFA·H2O) calcd: C, 44.71; H, 4.65; N, 14.60. Found:
C, 44.87; H, 4.48; N, 14.23.
1,1-Dimethylethyl 2-(2-(4-Amino-1,2,5-oxadiazol-3-yl)-7-{[3-
({[(1,1-dimethylethyl)oxy]-carbonyl}amino)propyl]oxy}-1-ethyl-1H-
imidazo[4,5-c]pyridin-4-yl)-1H-pyrrole-1-carboxylate (34a). A mix-
ture of 30 (317 mg, 0.720 mmol), (1-{[(1,1-dimethylethyl)oxy]-
carbonyl}-1H-pyrrol-2-yl)boronic acid (382 mg, 1.81 mmol),
tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.110 mmol),
and 2 M aqueous potassium carbonate (1.09 mL, 2.17 mmol) in
1,2-dimethoxyethane (11 mL) was heated in a sealed tube at 90 °C
for 5 h. The mixture was cooled to ambient temperature, diluted
with ethyl acetate (15 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (silica gel, 50% ethyl acetate in hexanes) to
A solution of crude 4-(7-[(3-aminopropyl)oxy]-1-ethyl-4-{1-
[tris(1-methylethyl)silyl]-1H-pyrrol-3-yl}-1H-imidazo[4,5-c]pyridin-
2-yl)-1,2,5-oxadiazol-3-amine in THF (5 mL) was treated with
tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran,
1 mL, 1.0 mmol), and the resultant mixture was stirred for 15 min.
Concentration under reduced pressure followed by reverse phase
1
1
furnish 334 mg (69%) of 34a as a pale-yellow foamy solid. H
HPLC afforded 127 mg (61%) of 11c as an off-white solid. H
NMR (400 MHz, CDCl3) δ 8.11 (s, 1 H), 7.43 (dd, J ) 3.16, 1.64
Hz, 1 H), 6.61-6.71 (m, 1 H), 6.35 (t, J ) 3.28 Hz, 1 H), 5.74 (br
s, 2 H), 5.03 (q, J ) 6.91 Hz, 2 H), 4.64-4.77 (m, 1 H), 4.35 (t,
J ) 6.06 Hz, 2 H), 3.42 (q, J ) 5.98 Hz, 2 H), 2.09-2.21 (m, 2
H), 1.54 (t, J ) 6.95 Hz, 3 H), 1.46 (s, 9 H), 1.22 (s, 9 H).
4-[7-[(3-Aminopropyl)oxy]-1-ethyl-4-(1H-pyrrol-2-yl)-1H-imi-
dazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine, Bis-trifluoro-
acetate (11a). A solution of 34a (334 mg, 0.59 mmol) in CH2Cl2
(3 mL) was treated with trifluoroacetic acid (0.75 mL). The mixture
was stirred at 30 °C for 2 h and then concentrated under reduced
pressure. The crude residue was redissolved in a mixture of
methanol (5 mL) and dimethyl sulfoxide (1.5 mL) and subjected
to purification by reverse phase HPLC to give 209 mg (57%) of
11a as a flaky light-yellow solid. 1H NMR (400 MHz, DMSO-d6)
δ 11.60 (br s, 1 H), 8.09 (s, 1 H), 7.90 (br s, 3 H), 7.20-7.29 (m,
1 H), 7.07 (d, J ) 1.01 Hz, 1 H), 6.98 (br s, 2 H), 6.26-6.34 (m,
1 H), 4.86 (q, J ) 6.99 Hz, 2 H), 4.40 (t, J ) 5.94 Hz, 2 H),
3.00-3.14 (m, 2 H), 2.10-2.24 (m, 2 H), 1.49 (t, J ) 7.07 Hz, 3
H). Anal. (C17H20N8O2 ·2C2HF3O2 ·0.5H2O) calcd: C, 41.66; H,
3.83; N, 18.51. Found: C, 41.85; H, 3.51; N, 18.49.
NMR (400 MHz, DMSO-d6) δ 11.83 (br s, 1 H), 8.18 (br s, 1 H),
8.07 (s, 1 H), 7.99-8.06 (m, 3 H), 7.10-7.16 (m, 1 H), 7.05-7.10
(m, 1 H), 6.87 (br s, 2 H), 4.87 (q, J ) 6.74 Hz, 2 H), 4.41 (t, J )
5.56 Hz, 2 H), 3.01-3.14 (m, 2 H), 2.12-2.26 (m, 2 H), 1.50 (t,
J ) 7.07 Hz, 3 H). Anal. (C17H20N8O2 ·2C2HF3O2) calcd: C, 42.29;
H, 3.72; N, 18.79. Found: C, 42.07; H, 3.55; N, 18.48.
1,1-Dimethylethyl (3-{[2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-
4-(1H-pyrazol-4-yl)-1H-imidazo[4,5-c]pyridin-7-yl]oxy}propyl)-
carbamate (34d). A mixture of 30 (163 mg, 0.37 mmol), 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (145 mg, 0.74 mmol),
tetrakis(triphenylphosphine)palladium(0) (79 mg, 0.074 mmol), and
2 N Na2CO3 (0.58 mL, 1.16 mmol) in 1,4-dioxane (5 mL) was heated
in a sealed tube at 105 °C for 3 h. The mixture was cooled to ambient
temperature, diluted with ethyl acetate, dried over MgSO4, filtered,
and concentrated under reduced pressure to furnish 34d that was used
1
in the next step without further purification. H NMR (400 MHz,
DMSO-d6) δ 8.41 (br s, 2 H), 8.11 (s, 1 H), 7.01 (t, J ) 5.56 Hz, 1
H), 6.91 (br s, 2 H), 4.85 (q, J ) 6.82 Hz, 2 H), 4.28 (t, J ) 5.81 Hz,
2 H), 3.19 (q, J ) 6.57 Hz, 2 H), 1.91-2.02 (m, 2 H), 1.47 (t, J )
6.95 Hz, 3 H), 1.36 (s, 9 H).
1,1-Dimethylethyl (3-{[2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-
4-(3-furanyl)-1H-imidazo[4,5-c]pyridin-7-yl]oxy}propyl)-
carbamate (34b). Tetrakis(triphenylphosphine)palladium(0) (20 mg,
0.017 mmol) was added to a mixture of 30 (50 mg, 0.11 mol), 2 N
4-[7-[(3-Aminopropyl)oxy]-1-ethyl-4-(1H-pyrazol-3-yl)-1H-imi-
dazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine, Bis-trifluoro-
acetate (11d). A solution of crude 34d in CH2Cl2 (5 mL) was treated
with trifluoroacetic acid (2 mL), and the resultant mixture was