Journal of Medicinal Chemistry
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7.54 (2H, d), 7.62 (2H, d), 7.95 (2H, d), 8.77 (1H, d); m/z (ES+) (M
+ H)+ = 444.
temperature for 2 h and then concentrated. The crude product was
purified by ion exchange chromatography, using an SCX column (7 M
NH3/methanol) to afford 7 (64 mg, 98%) as a white solid: 1H NMR δ
1.58−1.72 (1H, m), 1.93−2.05 (1H, m), 2.06−2.19 (2H, m), 2.34−
2.45 (2H, m), 3.6 (2H,s), 6.89 (1H, td), 7.26−7.35 (1H, m), 7.38 (2H,
d), 7.47−7.70 (8H, m), 7.99 (1H, d); HRMS m/z (ES+) (M + H)+ =
340.180 69 (theoretical 340.180 82).
tert-Butyl 1-(4-(3-Phenylpyrazolo[1,5-a]pyridin-2-yl)phenyl)-
cyclobutylcarbamate (42). Phenylboronic acid (127 mg, 1 mmol),
aq Na2CO3 (2 M, 0.52 mL, 1 mmol), 41 (230 mg, 0.5 mmol) and
Pd(PPh3)2Cl2 (37 mg, 0.05 mmol) were suspended in 18%
dimethylformamide in 1,2-dimethoxyethane/water/ethanol (7:3:2)
(2 mL), heated at 150 °C for 15 min in a microwave reactor, and
then cooled to room temperature. The reaction mixture was diluted
with ethyl acetate (20 mL) and washed with water (2 × 20 mL) and
brine (20 mL). The organic layer was dried and concentrated and the
residue purified by flash silica chromatography (55−80% acetonitrile
in water +1% NH4OH) to afford 42 (138 mg, 60%) as a white solid:
1H NMR δ 1.06−1.41 (9H, m), 1.79 (1H, s), 1.99 (1H, s), 2.31−2.44
1 - ( 4 - ( 5 - A m i n o - 3 - c h l o r o p y r a z i n - 2 - y l ) p h e n y l ) -
cyclobutylcarbamate (47). A tube was charged with 5-bromo-6-
chloropyrazin-2-amine (100 mg, 0.5 mmol), tert-butyl 1-(4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutylcarbamate (179
mg, 0.5 mmol), and Pd(PPh3)4 (42 mg, 0.04 mmol) in dioxane (2
mL) and aq Na2CO3 (2 M, 0.48 mL, 1 mmol) and the reaction heated
at 100 °C under microwave irradiation for 2 h. The reaction was
filtered and evaporated and the crude product purified by silica
chromatography (0−6% methanol in dichloromethane) to afford 47
(4H, m), 6.97 (1H, td), 7.23−7.32 (1H, m), 7.35 (5H, d), 7.42 (2H,
d), 7.47 (2H, d), 7.53−7.64 (2H, m), 8.76 (1H, d); m/z (ES+) (M +
H)+ = 440.
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(162 mg, 90%) as a yellow solid: H NMR δ 1.17 and 1.35 (9H, 2 ×
bs), 1.82 (1H, s), 2.00 (1H, s), 2.41 (4H, s), 6.94 (2H, s), 7.43 (2H,
d), 7.59 (2H, d), 7.93 (1H, s); m/z (ES−) (M − H)− = 373.
tert-Butyl 1-(4-(5-Amino-3-phenylpyrazin-2-yl)phenyl)-
cyclobutylcarbamate (48). A tube was charged with 47 (160 mg,
0.4 mmol), phenylboronic acid (57 mg, 0.5 mmol), and Pd(PPh3)4 (49
mg, 0.04 mmol) in dioxane (2 mL) and aq Na2CO3, (2 M, 0.43 mL,
0.9 mmol) and then heated at 110 °C under microwave irradiation for
50 min. The reaction mixture was allowed to cool to room
temperature, filtered, and evaporated. The crude product was purified
by silica chromatography (20−60% ethyl acetate in isohexane) to
1-(4-(3-Phenylpyrazolo[1,5-a]pyridin-2-yl)phenyl)-
cyclobutanamine (6). A solution of TFA in dichloromethane (10%,
10 mL) was added to 42 (134 mg, 0.3 mmol), and the mixture was
stirred at room temperature for 2 h and then concentrated. The crude
product was purified by ion exchange chromatography, using an SCX
column (7 M NH3/methanol) to afford 6 (103 mg, 100%) as a white
solid: 1H NMR δ 1.60−1.72 (1H, m), 1.97−2.05 (1H, m), 2.06−2.15
(2H, m), 2.39 (2H, ddd), 2.72 (2H, bs), 6.97 (1H, td), 7.27 (1H,
ddd), 7.36 (3H, dt), 7.41−7.48 (4H, m), 7.53 (3H, dd), 8.76 (1H, d);
HRMS m/z (ES+) M+ = 340.180 57 (theoretical 340.180 82).
tert-Butyl 1-(4-(Imidazo[1,2-a]pyridin-2-yl)phenyl)-
cyclobutylcarbamate (44). tert-Butyl 1-(4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)phenyl)cyclobutylcarbamate (284 mg, 0.8
mmol), aq Na2CO3 (2 M, 0.31 mL, 0.6 mmol), 43 (100 mg, 0.5
mmol), and Pd(PPh3)2Cl2 (36 mg, 0.05 mmol) were suspended in
18% dimethylformamide in 1,2-dimethoxyethane/water/ethanol
(7:3:2) (2.0 mL), and the mixture was heated at 150 °C for 10 min
in a microwave reactor and then cooled to room temperature. The
reaction mixture was diluted with ethyl acetate (20 mL) and washed
with water (2 × 20 mL) and brine (20 mL). The organic layer was
dried and evaporated to afford crude product which was purified by
flash silica chromatography, with an elution gradient from 0 to 50%
ethyl acetate in isohexane, to afford 44 (140 mg, 76%) as a white solid:
1H NMR δ 1.32 (9H, d), 1.82 (1H, s), 1.97−2.07 (1H, m), 2.42 (4H,
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afford 48 (70 mg, 39%) as a white solid: H NMR δ 1.16 and 1.32
(9H, 2 × bs), 1.76 (1H, bm), 1.99 (1H, bm), 2.26−2.42 (4H, m), 6.52
(2H, s), 7.16−7.35 (9H, m), 7.46 (1H, bs), 7.95 (1H, s); m/z (ES+)
(M + H)+ = 417.
1-(4-(5-Phenylimidazo[1,2-a]pyrazin-6-yl)phenyl)-
cyclobutanamine Hydrochloride (11). A mixture of 48 (75 mg, 0.2
mmol) and aq 2-chloroacetaldehyde (55%, 0.21 mL, 1.8 mmol) in
dimethylformamide (2.5 mL) was heated at 70 °C for 1.5 h. The
solution was allowed to cool to room temperature, diluted with ethyl
acetate (25 mL), and washed with saturated aq NaHCO3 (2 × 15 mL).
The organic layer was dried, filtered, and evaporated and crude
product purified by silica chromatography (0−3% methanol in
dichloromethane) to afford a pale yellow glassy solid. The solid was
dissolved in dichloromethane (2.5 mL), and HCl in dioxane (4M, 2
mL) was added dropwise. The solution was stirred at room
temperature for 1 h and then evaporated to dryness to afford 11
t), 6.89 (1H, td), 7.18−7.29 (1H, m), 7.44 (2H, d), 7.57 (2H, d), 7.91
(2H, d), 8.36 (1H, s), 8.52 (1H, d); m/z (ES+) (M + H)+ = 364.
tert-Butyl 1-(4-(3-Iodoimidazo[1,2-a]pyridin-2-yl)phenyl)-
cyclobutylcarbamate (45). NIS (222 mg, 1 mmol) was added to
44 (342 mg, 0.9 mmol) in acetonitrile (10 mL). The resulting solution
was stirred at room temperature for 1 h and then evaporated, and the
residue was dissolved in ethyl acetate (25 mL) and washed with aq
NaOH (10% w/v, 25 mL), water (25 mL), and brine (25 mL). The
organic layer was dried and evaporated to afford 45 (460 mg, 100%) as
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(42 mg, 56%) as a pale orange solid: H NMR δ 1.77−1.89 (1H, m),
2.16−2.28 (1H, m), 2.54−2.63 (4H, m, partially obscured by DMSO
peak), 7.46−7.53 (4H, m), 7.58−7.66 (6H, m), 7.99 (1H, s), 8.72
(3H, bs), 9.36 (1H, s); HRMS m/z (ES+) (M + H)+ = 341.176 12
(theoretical 341.176 07).
tert-Butyl 1-(4-((3-Formylpyridin-4-yl)ethynyl)phenyl)-
cyclobutylcarbamate (49). A solution of 4-bromoisonicotinalde-
hyde hydrobromide (157 mg, 0.6 mmol) and 37 (160 mg, 0.6 mmol)
in acetonitrile (6 mL) was degassed with a stream of nitrogen.
Pd(PPh3)4 (34 mg, 0.03 mmol), CuI (2.2 mg, 0.01 mmol), and Et3N
(0.25 mL, 1.8 mmol) were added and the mixture was stirred under
nitrogen at room temperature for 4 days. The reaction mixture was
filtered and evaporated to dryness. The residue was purified by silica
chromatography (10−35% ethyl acetate in isohexane) to afford 49
(106 mg, 48%) as an orange solid: 1H NMR δ 1.18 and 1.29 (9H, 2 ×
bs), 1.73−1.88 (1H, m), 1.94−2.09 (1H, m), 2.35−2.46 (4H, m), 7.49
(2H, d), 7.63−7.76 (4H, m), 8.84 (1H, d), 9.03 (1H, s), 10.48 (1H, s);
m/z (ES+) (M + H)+ = 377.
tert-Butyl N-[1-[4-[2-[3-[(E)-Methoxyiminomethyl]pyridin-4-
yl]ethynyl]phenyl]cyclobutyl]carbamate (50). To a solution of
49 (105 mg, 0.3 mmol) in dichloromethane (4 mL) was added Et3N
(0.04 mL, 0.3 mmol) followed by O-methylhydroxylamine hydro-
chloride (26 mg, 0.3 mmol). The solution was stirred overnight,
diluted with dichloromethane (15 mL), and washed with water (15
mL). The aqueous phase was extracted with dichloromethane (2 × 15
mL). The combined extracts were washed with brine, dried, and
evaporated to afford 50 (109 mg, 96%) as a brown gum. UPLC shows
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a yellow oil: H NMR δ 1.29 (9H, d), 1.82 (1H, s), 1.95−2.06 (1H,
m), 2.43 (4H, t), 7.08 (1H, td), 7.31−7.41 (1H, m), 7.50 (2H, d),
7.58−7.66 (2H, m), 8.02 (2H, d), 8.42 (1H, d); m/z (ES+) M+ = 490.
tert-Butyl 1-(4-(3-Phenylimidazo[1,2-a]pyridin-2-yl)phenyl)-
cyclobutylcarbamate (46). Phenylboronic acid (168 mg, 1.4
mmol), aq Na2CO3 (2 M, 0.7 mL, 1.4 mmol), 45 (450 mg, 0.9
mmol), and Pd(PPh3)2Cl2 (65 mg, 0.1 mmol) were suspended in 18%
dimethylformamide in 1,2-dimethoxyethane/water/ethanol (7:3:2) (6
mL), heated at 150 °C for 15 min in a microwave reactor, and then
cooled to room temperature. The reaction mixture was diluted with
ethyl acetate (20 mL) and washed with water (2 × 20 mL) and brine
(20 mL). The organic layer was dried and concentrated and the crude
product purified by silica chromatography (0−70% ethyl acetate in
1
isohexane) to afford 46 (259 mg, 64%) as a white solid: H NMR δ
1.31 (9H, s), 1.66−1.84 (1H, m), 1.90−2.03 (1H, m), 2.25−2.45 (4H,
m), 6.88 (1H, t), 7.23−7.37 (3H, m), 7.42−7.70 (9H, m), 7.99 (1H,
d); m/z (ES+) (M + H)+ = 440.
1-(4-(3-Phenylimidazo[1,2-a]pyridin-2-yl)phenyl)-
cyclobutanamine (7). TFA in dichloromethane (10%, 5 mL) was
added to 46 (85 mg, 0.2 mmol) and the solution was stirred at room
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dx.doi.org/10.1021/jm201394e | J. Med. Chem. 2012, 55, 1261−1273