Quinolinecarbonitriles as Inhibitors of Src Kinase
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23 3975
heated at 95 °C for 20 h. The reaction mixture was concen-
trated in vacuo and partitioned between ethyl acetate and
saturated aqueous sodium bicarbonate. The organic layer was
washed with saturated aqueous sodium bicarbonate, followed
by brine, dried over sodium sulfate, filtered, and concentrated
in vacuo. Diethyl ether was added to the residue, and the white
solid was collected by filtration to provide 1.80 g (44%) of
31b: mp 102-104 °C; 1H NMR (DMSO-d6) δ 0.98 (t, J ) 7
Hz, 3H), 1.88-2.02 (m, 2H), 2.25-2.52 (m, 12 H), 3.86 (s, 3H),
3.94 (s, 3H), 4.19 (t, J ) 6 Hz, 2H), 7.30 (br s, 2H), 7.72 (s,
1H), 7.82 (s, 1H), 8.39 (s, 1H), 9.60 (s, 1H); MS (ES) m/z 544.3,
546.4 (M + 1).
4-[(2,4-Dich lor o-5-m eth oxyp h en yl)a m in o]-6-m eth oxy-
7-[3-(4-p ip er id in -1-yl )p r op oxy]-3-qu in olin eca r bon itr ile
(31h ). According to the procedure used to prepare 31b,
reaction of 30 with piperidine provided, after preparative thin-
layer chromatography, eluting with 20% methanol in dichloro-
methane, 31h in 61% yield as a white solid: mp 157-161 °C;
1H NMR (DMSO-d6) δ 1.34-1.45 (m, 2H), 1.45-1.57 (m, 4H),
1.88-2.02 (m, 2H), 2.32-2.49 (m, 6H), 3.86 (s, 3H), 3.94 (s,
3H), 4.19 (t, J ) 6 Hz, 2H), 7.31 (br s, 2H), 7.73 (s, 1H), 7.83
(s, 1H), 8.40 (s, 1H), 9.62 (s, 1H); MS (ES) m/z 515.2, 517.2 (M
+ 1).
Anal. (C26H28Cl2N4O3‚2.7H2O) C, H, N.
Anal. (C27H31Cl2N5O3 ‚ 2.0 H2O) C, H, N.
4-[(2,4-Dich lor o-5-m et h oxyp h en yl)a m in o]-7-[3-(4-h y-
d r oxyp ip er id in -1-yl)p r op oxy]-6-m et h oxy-3-q u in olin e-
ca r bon itr ile (31i). According to the procedure used to prepare
31b, reaction of 30 with 4-hydroxypiperidine provided 31i as
a white solid in 75% yield: mp 122-125 °C; 1H NMR (DMSO-
d6) δ 1.30-1.46 (m, 2H), 1.65-1.78 (m, 2H), 1.88-2.09 (m, 4H),
2.43 (t, J ) 6 Hz, 2H), 2.67-2.78 (m, 2H), 3.39-3.50 (m, 1H),
3.86 (s, 3H), 3.94 (s, 3H), 4.18 (t, J ) 6 Hz, 2H), 4.53 (d, J )
3 Hz, 1H), 7.31 (br s, 2H), 7.74 (s, 1H), 7.83 (s, 1H), 8.40 (s,
1H), 9.62 (s, 1H); MS (ES) m/z 531.0, 533.1 (M + 1).
4-[(2,4-Dich lor o-5-m e t h oxyp h e n yl)a m in o]-6-m e t h -
oxy-7-[3-(cis-3,4,5-t r im e t h ylp ip e r a zin yl)p r op oxy]-3-
qu in olin eca r bon itr ile (31c). According to the procedure
used to prepare 31b, reaction of 30 and cis-1,2,6-trimethyl-
piperazine33 provided, after flash column chromatography,
eluting with 25% methanol in dichloromethane, 31c in 39%
1
yield as a white solid: mp 98-101 °C; H NMR (DMSO-d6) δ
0.96 (s, 3H), 0.98 (s, 3H), 1.65-1.77 (m, 2H), 1.90-1.98 (m,
2H), 2.07-2.18 (m, 5H), 2.34-2.41 (m, 2H), 2.69-2.78 (m, 2H),
3.86 (s, 3H), 3.94 (s, 3H), 4.19 (t, J ) 6 Hz, 2H), 7.32 (br s,
2H), 7.74 (s, 1H), 7.83 (s, 1H), 8.41 (s, 1H), 9.60 (s, 1H); MS
(ES) m/z 558.3, 560.3 (M + 1).
Anal. (C26H28Cl2N4O4‚2.0H2O) C, H, N.
4-[(2,4-Dich lor o-5-m e t h oxyp h e n yl)a m in o]-6-m e t h -
oxy-7-[3-(2H-1,2,3-tr iazol-2-yl)pr opoxy]-3-qu in olin ecar bo-
n it r ile (31j) a n d 4-[(2,4-Dich lor o-5-m et h oxyp h en yl)-
a m in o]-6-m eth oxy-7-[3-(1H-1,2,3-tr ia zol-1-yl)p r op oxy]-3-
qu in olin eca r bon itr ile (31k ). According to the procedure
used to prepare 31b, reaction of 30 with 1,2,3-triazole provided
a mixture of 31j and 31k . The mixture was separated by
preparative thin-layer chromatography, eluting with 5% metha-
nol in dichloromethane. 31j was obtained as an off-white solid
Anal. (C28H33Cl2N5O3‚2.0H2O) C, H.
4-[(2,4-Dich lor o-5-m eth oxyp h en yl)a m in o]-6-m eth oxy-
7-[3-(4-p r op yl-1-p ip er a zin yl)p r op oxy]-3-qu in olin eca r bo-
n itr ile (31d ). According to the procedure used to prepare 31b,
reaction of 30 and N-propylpiperazine provided, after prepara-
tive thin-layer chromatography, eluting with 20% methanol
in dichloromethane, and subsequent recrystallization from
diethyl ether and hexane, 31d in 15% yield as a white solid:
1
in 30% yield: mp 190-191 °C; H NMR (DMSO-d6) δ 2.35-
1
mp 97-101 °C; H NMR (DMSO-d6) δ 0.84 (t, J ) 7 Hz, 3H),
2.46 (m, 2H), 3.86 (s, 3H), 3.94 (s, 3H), 4.18 (t, J ) 6 Hz, 2H),
4.64 (d, J ) 7 Hz, 2H), 7.29 (s, 1H), 7.34 (s, 1H), 7.75 (s, 1H),
7.80 (s, 2H), 7.85 (s, 1H), 8.42 (s, 1H), 9.63 (s, 1H); MS (ES)
m/z 499.4, 501.3 (M + 1).
1.32-1.47 (m, 2H), 1.89-2.03 (m, 2H), 2.15-2.27 (m, 2H),
2.25-2.52 (m, 10 H), 3.86 (s, 3H), 3.94 (s, 3H), 4.19 (t, J ) 6
Hz, 2H), 7.32 (br s, 2H), 7.74 (s, 1H), 7.83 (s, 1H), 8.41 (s, 1H),
9.61 (s, 1H); MS (ES) m/z 558.2, 560.2 (M + 1). Anal.
(C28H33Cl2N5O3‚2.2H2O) C, H.
Anal. (C23H20Cl2N6O3) C, H, N.
31k was obtained as an off-white solid in 39% yield: mp
4-[(2,4-Dich lor o-5-m eth oxyp h en yl)a m in o]-6-m eth oxy-
7-(3-piper azin -1-ylpr opoxy)-3-qu in olin ecar bon itr ile (31e).
According to the procedure used to prepare 31b, reaction of
30 with piperazine provided, after preparative thin-layer
chromatography, eluting with 25% methanol in dichloro-
methane, 31e in 48% yield as a white solid: mp 123-125 °C;
1H NMR (DMSO-d6) δ 1.89-2.02 (m, 2H), 2.27-2.37 (m, 4 H),
2.42 (t, J ) 7 Hz, 2H), 2.72 (t, J ) 5 Hz, 4H), 3.85 (s, 3H), 3.93
(s, 3H), 4.19 (t, J ) 6 Hz, 2H), 7.28 (s, 1H), 7.30 (s, 1H), 7.72
(s, 1H), 7.82 (s, 1H), 8.38 (s, 1H), 9.61 (s, 1H); MS (ES) m/z
516.2, 518.1 (M + 1).
1
188-190 °C; H NMR (DMSO-d6) δ 2.33-2.45 (m, 2H), 3.86
(s, 3H), 3.96 (s, 3H), 4.17 (t, J ) 6 Hz, 2H), 4.60 (d, J ) 7 Hz,
2H), 7.32 (s, 1H), 7.33 (s, 1H), 7.75 (s, 2H), 7.85 (s, 1H), 8.20
(s, 1H), 8.41 (s, 1H), 9.63 (s, 1H); MS (ES) m/z 499.4, 501.3 (M
+ 1).
Anal. (C23H20Cl2N6O3‚0.3H2O) C, H, N.
4-[(2,4-Dich lor o-5-m e t h oxyp h e n yl)a m in o]-7-[3-(1H -
im id a zol-1-yl)p r op oxy]-6-m e t h oxy-3-q u in olin e ca r b o-
n itr ile (31l). A mixture of 30 (200 mg, 0.43 mmol), imidazole
(300 mg, 4.3 mmol), sodium hydroxide powder (80 mg, 2.0
mmol), and sodium iodide (30 mg, 0.2 mmol) in 3 mL of N,N-
dimethylformamide was heated at 80 °C for 2 h. The reaction
mixture was cooled, poured into water, and stirred. The
resultant solid was collected by filtration, washing with water
and diethyl ether. The solid was purified by silica gel chro-
matography, eluting with a gradient of 3% methanol in
dichloromethane to 6% methanol in dichloromethane, to
provide 180 mg (84%) of 31l as a yellow solid: mp 155-170°
C; 1H NMR (DMSO-d6) δ 2.27-2.44 (m, 2H), 3.87 (s, 3H), 3.95
(s, 3H), 4.26 (t, J ) 6 Hz, 2H), 4.42 (t, J ) 7 Hz, 2H), 7.36 (s,
1H), 7.39 (s, 1H), 7.71 (s, 1H), 7.76 (s, 1H), 7.84 (s, 1H), 7.96
(s, 1H), 8.14 (s, 1H), 8.55 (s, 1H), 9.18 (s, 1H); MS (ES) m/z
498.0, 500.1 (M + 1).
Anal. (C25H27Cl2N5O3) C, H.
4-[(2,4-Dich lor o-5-m e t h oxyp h e n yl)a m in o]-6-m e t h -
oxy-7-{3-[4-(2-h yd r oxyet h yl)p ip er a zin -1-yl]p r op oxy}-3-
qu in olin eca r bon itr ile (31f). According to the procedure used
to prepare 31b, reaction of 30 with 4-(2-hydroxyethyl)piper-
azine provided 31f in 75% yield as a white solid: mp 133-
1
137 °C; H NMR (DMSO-d6) δ 1.90-2.01 (m, 2H), 2.31-2.50
(m, 10H), 3.47 (q, J ) 6 Hz, 2H), 3.86 (s, 3H), 3.94 (s, 3H),
4.18 (t, J ) 6 Hz, 2H), 4.37 (t, J ) 5 Hz, 1H), 7.31 (br s, 2H),
7.74 (s, 1H), 7.82 (s, 1H), 8.41 (s, 1H), 9.62 (s, 1H); MS (ES)
m/z 560.1, 562.1 (M + 1).
Anal. (C27H31Cl2N5O4‚1.2H2O) C, H, N.
4-[(2,4-Dich lor o-5-m eth oxyp h en yl)a m in o]-6-m eth oxy-
7-[3-(4-m eth yl-[1,4]d ia zep a n -1-yl)p r op oxy]-3-qu in olin e-
ca r bon itr ile (31g). According to the procedure used to
prepare 31b, reaction of 30 with 1-methylhomopiperazine
provided, after preparative thin-layer chromatography, eluting
with 20% methanol in dichloromethane, 31g in 43% yield as
Anal. (C24H21Cl2N5O3‚1.05CH2Cl2) C, H, N.
4-[(2,4-Dich lor o-5-m eth oxyp h en yl)a m in o]-6-m eth oxy-
7-{3-[(2-(4-m or ph olin yl)eth yl)am in o]pr opoxy}-6-m eth oxy-
3-qu in olin eca r bon itr ile (31m ). According to the procedure
used to prepare 31b, reaction of 30 with 4-(2-aminoethyl)-
morpholine provided, after preparative thin-layer chromatog-
raphy, eluting with 20% methanol in dichloromethane, 31m
as an orange solid in 31% yield: mp 75-80 °C; 1H NMR
(DMSO-d6) δ 1.95-2.06 (m, 2H), 2.31-2.44 (m, 6H), 2.72 (t, J
) 6.5 Hz, 2H), 2.79 (t, J ) 7 Hz, 2H), 3.86 (s, 3H), 3.94 (s,
3H), 4.23 (t, J ) 6 Hz, 2H), 4.53 (d, J ) 3 Hz, 1H), 7.30 (s,
1
a light yellow solid: mp 134-137 °C; H NMR (DMSO-d6) δ
1.65-1.77 (m, 2H), 1.86-1.97 (m, 2H), 2.25 (s, 3H), 2.50-2.69
(m, 10H), 3.86 (s, 3H), 3.94 (s, 3H), 4.19 (t, J ) 6 Hz, 2H),
7.30 (br s, 2H), 7.73 (s, 1H), 7.82 (s, 1H), 8.40 (s, 1H), 9.61 (s,
1H); MS (ES) m/z 544.2, 546.2 (M + 1). Anal.
(C27H31Cl2N5O3‚1.7 H2O) C, H, N.