Thieno[3,2-b]pyridine-6-carbonitriles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 11 3897
to provide 1.10 g of 7 as a white solid: 1H NMR (DMSO-d6) δ
2.40 (br s, 4H), 2.84 (t, J ) 4 Hz, 4H), 3.17 (s, 1H), 3.51 (s,
2H), 3.84 (s, 3H), 7.23 (s, 1H), 7.41 (d, J ) 8 Hz, 2H), 7.67 (d,
J ) 8 Hz, 2H), 7.71 (s, 1H), 7.85 (s, 1H), 8.53 (s, 1H); MS 524.1
(M + H)+. Anal. (C26H23Cl2N5OS‚H2O) C, H, N.
Hz, 2H), 7.56 (s, 1H), 7.64 (s, 1H), 8.66 (s, 1H); MS 511.0 (M
+ H)+. Anal. (C26H24Cl2N4OS) C, H, N.
4-{6-Cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]-
thieno[3,2-b]pyridin-2-yl]benzoic Acid (14). A mixture of
13 (500 mg, 1.05 mmol), 4-carboxylphenylboronic acid (350 mg,
2.12 mmol), and 100 mg of tetrakis(triphenylphosphine)-
palladium(0) in 50 mL of ethylene glycol dimethyl ether and
35 mL of saturated aqueous sodium bicarbonate was heated
at reflux for 1 h. The reaction mixture was cooled to room
temperature and partitioned between water and ethyl acetate.
The organic layer was washed with saturated aqueous sodium
chloride, dried over sodium sulfate, filtered, and concentrated
in vacuo. The residue was purified by flash column chroma-
tography eluting with a gradient of chloroform to 10% metha-
nol in chloroform to provide 165 mg of 14 as yellow crystals:
mp >300 °C; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.40 (s, 1H),
7.78 (s, 1H), 7.86 (d, J ) 8 Hz, 2H), 8.03 (d, J ) 8 Hz, 2H),
8.03 (s, 1H), 8.08 (s, 1H), 8.64 (s, 1H), 9.80 (s, 1H), 13.14 (s,
1H); MS 470.2 (M + H)+.
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-[(4-me-
thylpiperazin-1-yl)carbonyl]phenyl}thieno[3,2-b]pyridine-
6-carbonitrile (15). A mixture of 14 (327 mg, 0.70 mmol) and
N,N-carbonyldiimidazole (260 mg, 1.60 mmol) in 25 mL of N,N-
dimethylformamide was heated at 60 °C for 2 h. To the
resulting solution was added 1-methylpiperazine (0.35 mL,
3.15 mmol) and the reaction mixture was heated at reflux for
20 min then concentrated in vacuo. The residue was purified
by flash column chromatography eluting with a gradient of
1:4 methanol: ethyl acetate to 1:3 methanol:ethyl acetate.
Further recrystallization from ethyl acetate provided 59 mg
of 15 as a bright yellow solid: mp 240-243 °C; 1H NMR
(CDCl3) δ 2.30-2.41 (br s, 2H), 2.33 (s, 3H), 2.43-2.58 (br s,
2H), 3.40-3.51 (br s, 2H), 3.76-3.90 (br s, 2H), 3.86 (s, 3H),
6.83 (s, 1H), 6.92 (s, 1H), 7.47 (d, J ) 8 Hz, 2H), 7.58 (s, 1H),
7.63 (d, J ) 8 Hz, 2H), 7.69 (s, 1H), 8.68 (s, 1H); MS 552.1,
554.1 (M + H)+. Anal. (C27H23Cl2N5O2S) C, H, N.
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-
hydroxyethyl)piperazin-1-yl]methyl}phenyl)thieno[3,2-
b]pyridine-6-carbonitrile (8). 1-(2-Hydroxyethyl)piperazine
(1.72 g, 13.20 mmol) was added to a suspension of 5 (2.0 g,
4.40 mmol) in 48 mL of dichloromethane and 3.5 mL of
1-methyl-2-pyrrolidinone. The reaction mixture was cooled to
0 °C and sodium triacetoxyborohydride (4.66 g, 22.0 mmol) was
added. After stirring at 0 °C for 5 min, 0.3 mL of acetic acid
was added and the reaction mixture warmed to room temper-
ature and stirred for 1.5 h. The reaction was quenched by the
addition of water and then partitioned between aqueous
sodium bicarbonate and dichloromethane. The organic layer
was washed with saturated aqueous sodium chloride, dried
over sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography eluting
with a gradient of 1% to 20% methanol in dichloromethane to
1
provide 1.4 g of 8 as a white solid: mp 204-206 °C; H NMR
(DMSO-d6) δ 2.38 (br s, 10H), 3.45-3.48 (m, 4H), 3.85 (s, 3H),
4.37 (br s, 1H), 7.37 (s, 1H), 7.40 (d, J ) 8 Hz, 2H), 7.67 (d, J
) 8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.74 (s,
1H); MS 568.0, 570.1 (M + H)+. Anal. (C28H27Cl2N5O2S‚H2O)
C, H, N.
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(piperi-
din-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carboni-
trile (9). Following the route used to prepare 7, 9 was obtained
as an off-white solid in 47% yield from 5: 1H NMR (DMSO-
d6, TFA) δ 1.34-1.37 (m, 1H), 1.55-1.66 (m, 3H), 1.79-1.83
(m, 2H), 2.84-2.92 (m, 2H), 3.30-3.48 (m, 2H), 3.86 (s, 1H),
4.33 (d, J ) 4 Hz, 2H), 7.51 (s, 1H), 7.63 (d, J ) 8 Hz, 2H),
7.80 (d, J ) 8 Hz, 2H), 7.84 (s, 1H), 8.00 (s, 1H), 8.74 (s, 1H),
9.62 (brs, 1H); MS 523.0 (M + H)+. Anal. (C27H24Cl2N4-
OS‚0.6H2O) C, H, N
4-{6-Cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]-
thieno[3,2-b]pyridin-2-yl}-N,N-dimethylbenzamide (16).
To a solution of 4-bromo-N,N-dimethylbenzamide (400 mg,
1.75 mmol) in 20 mL of tetrahydrofuran at -78 °C was added
triisopropyl borate (0.45 mL, 1.95 mol) followed by 1.1 mL of
2.6 M n-butyllithium in hexanes (2.86 mmol). The reaction
mixture was stirred at -78 °C for 2 h then at room temper-
ature overnight. The volatiles were removed by concentration
in vacuo, and the residue was added to a mixture of 13 (400
mg, 0.89 mmol) and 50 mg of tetrakis(triphenylphosphine)-
palladium(0) in 16 mL of N,N-dimethylformamide and 8 mL
of saturated aqueous sodium bicarbonate. The reaction mix-
ture was heated at reflux for 5 h and then cooled to room
temperature and partitioned between ethyl acetate and satu-
rated aqueous sodium bicarbonate. The organic layer was dried
over magnesium sulfate, filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography
eluting with a gradient of 1:1 hexane:ethyl acetate to 20%
methanol in ethyl acetate to provide 127 mg of 16 as an off-
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(thio-
morpholin-4-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-
carbonitrile (10). Following the route used to prepare 7, 10
was obtained as an off-white solid in 55% yield from 5: mp
198-201 °C; 1H NMR (DMSO-d6) δ 2.62 (br s, 8H), 3.53 (s,
2H), 3.85 (s, 3H), 7.37 (s, 1H), 7.41 (d, J ) 8 Hz, 2H), 7.65 (d,
J ) 8 Hz, 2H), 7.77 (s, 1H), 7.90 (s, 1H), 8.60 (s, 1H), 9.63 (s,
1H); MS 541.0 (M + H)+. Anal. (C26H22Cl2N4OS2‚H2O) C, H,
N.
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-{4-[(di-
methylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-
carbonitrile (11). A solution of 2 M dimethylamine in
tetrahydrofuran (1.73 mL, 3.45 mmol) was added to a suspen-
sion of 5 (312 mg, 0.69 mmol) in 7 mL of dichloromethane and
2 mL of N,N-dimethylformamide. The reaction mixture was
cooled to 0 °C and sodium triacetoxyborohydride (877 mg, 4.14
mmol) was added. After stirring at 0 °C for 5 min, 0.2 mL of
acetic acid was added and the reaction mixture was warmed
to room temperature and stirred overnight. The reaction was
quenched by the addition of water and then partitioned
between aqueous sodium bicarbonate and dichloromethane.
The organic layer was dried over sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by flash
column chromatography eluting with a gradient of 1%-10%
methanol in dichloromethane to provide 222 mg of 11 as a tan
solid: mp 224-225 °C; 1H NMR (DMSO-d6) δ 2.16 (s, 6H), 3.44
(s, 2H), 3.86 (s, 3H), 7.37 (s, 1H), 7.40 (d, J ) 8 Hz, 2H), 7.68
(d, J ) 8 Hz, 2H), 7.76 (s, 1H), 7.90 (s, 1H), 8.60 (s, 1H), 9.73
(s, 1H); MS 483.1, 485.1 (M + H)+. Anal. (C24H20Cl2N4-
OS‚0.5H2O) C, H, N.
1
white solid: mp 246-249 °C; H NMR (DMSO-d6) δ 2.89 (s,
3H), 2.99 (s, 3H), 3.86 (s, 3H), 7.41 (s, 1H), 7.52 (d, J ) 8 Hz,
2H), 7.77-7.80 (m, 3H), 8.02 (s, 1H), 8.64 (s, 1H), 9.79 (s, 1H);
MS 497.1, 499.0 (M + H)+. Anal. (C24H18Cl2N4O2S) C, H, N.
7-[(2,4-Dichloro-5-methoxyphenyl)amino]-2-[4-(dime-
thylamino)phenyl]thieno[3,2-b]pyridine-6-carbonitrile
(17). A mixture of 13 (200 mg, 0.42 mmol), 4-(dimethylamino)-
phenylboronic acid (104 mg, 0.63 mmol), and 24 mg (0.021
mmol) of tetrakis(triphenylphosphine)palladium(0) in 5.5 mL
of ethylene glycol dimethyl ether and 4.5 mL of saturated
aqueous sodium bicarbonate was heated at reflux for 22 h. The
reaction mixture was cooled to room temperature and parti-
tioned between water and dichloromethane. The organic layer
was washed with saturated aqueous sodium chloride, dried
over sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography eluting
with a gradient of hexane to 60% ethyl acetate in hexane,
followed by preparative thin-layer chromatography developing
with 20% ethyl acetate in dichloromethane to provide 23 mg
2-{4-[(Butylamino)methyl]phenyl}-7-[(2,4-dichloro-5-
methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carboni-
trile (12). Following the route used to prepare 7, 12 was
obtained as an off-white solid in 78% yield from 5: mp 167-
1
169 °C; H NMR (CDCl3) δ 0.91 (t, J ) 7 Hz, 3H), 1.19-1.53
(m, 4H), 2.63 (t, J ) 7 Hz, 2H), 3.83 (s, 2H), 3.85 (s, 3H), 6.81
(brs, 1H), 6.90 (s, 1H), 7.39 (d, J ) 8 Hz, 2H), 7.54 (d, J ) 8