Journal of Medicinal Chemistry
ARTICLE
(100 MHz, CDCl3) δ 144.7, 144.2, 143.0, 138.8, 137.4, 133.4, 132.5,
yellow solid (90%) from phenol 23 following a similar procedure as
that for preparation of compounds 4aꢀc. 1H NMR (300 MHz, CDCl3)
δ 8.86 (d, J = 2.7 Hz, 1H), 8.46 (s, 1H), 8.24 (d, J = 9.3 Hz, 1H), 7.93 (s,
1H), 7.80 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 8.1
Hz, 1H), 6.97 (s, 1H), 5.36 (s, 2H), 3.41 (t, J = 4.8 Hz, 4H), 2.64 (t, J =
4.8 Hz, 4H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.1, 148.5,
145.5, 145.2, 141.8, 138.3, 133.0, 129.7, 127.2, 123.2, 123.0, 122.1,
120.0, 110.0, 101.7, 69.2, 54.6, 48.2, 46.1; MS (EI) m/z 446 (Mþ);
HRMS calcd for C22H21F3N4O3 (Mþ) 446.1566, found 446.1565.
General Procedure for Preparation of 3,5,7-Trisubstituted
Quinolines 27aꢀd. These compounds were prepared by reduction of
5-nitroquinolines 26aꢀd with Fe/NH4Cl followed by reductive amina-
tion viaaproceduresimilartothatofpreparationofquinolines11a and 11b.
3-(4-(Cyclopropylsulfonyl)piperazin-1-yl)-N-(3-nitroben-
zyl)-7-(trifluoromethyl)quinolin-5-amine (27a). Yellow solid
(60%); 1H NMR (300 MHz, CDCl3) δ 8.81 (d, J = 1.8 Hz, 1H), 8.30
(s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.70 (s, 1H),
7.55 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 1.5 Hz, 1H), 6.62 (s, 1H), 5.19
(t, J = 5.1 Hz, 1H), 4.67 (d, J = 5.1 Hz, 2H), 3.53 (t, J = 4.8 Hz, 4H), 3.39
(t, J = 4.8 Hz, 4H), 2.32 (s, 1H), 1.20 (m, 2H), 1.04 (m, 2H); 13C NMR
(100 MHz, CDCl3 þ CD3OD) δ 148.4, 145.0, 144.5, 143.0, 142.1,
140.6, 133.3, 129.6, 129.1 (q, J = 31.9 Hz), 124.1 (q, J = 270.6 Hz),
122.4, 121.9, 120.3, 115.2, 111.7, 100.5, 49.5, 47.0, 45.7, 25.3, 4.2; MS
(EI) m/z 535 (Mþ). Anal. (C24H24F3N5O4S) C, H, N.
128.5, 128.4, 128.0, 127.8, 127.6, 127.1, 126.3, 126.1, 125.8, 114.8, 54.6,
48.7, 46.0; MS (EI) m/z 353 (Mþ). Anal. (C24H23N3 0.25H2O) C, H, N.
3
General Procedure for Preparation of 3,5,7-Trisubstituted
Quinolines 21aꢀd,fꢀl. These compounds were prepared from
5-nitroquinoline 20aꢀf through Fe/NH4Cl reduction followed by
reductive amination with an appropriate aldehyde using a procedure
similar to the preparation of 3,5-disubstituted quinolines 11a and 11b.
3-(4-Methylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7-(tri-
1
fluoromethyl)quinoline (21a). Yellow powder (70%); H NMR
(300 MHz, CDCl3) δ 8.79 (d, J = 2.4 Hz, 1H), 8.21 (s, 1H), 8.08 (d, J =
8.1 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.66 (s, 1H), 7.48 (t, J = 8.1 Hz,
1H), 7.32 (d, J = 1.5 Hz, 1H), 6.59 (s, 1H), 5.07 (t, J = 5.4 Hz, 1H), 4.59
(d, J = 5.4 Hz, 2H), 3.32 (t, J = 4.8 Hz, 4H), 2.57 (t, J = 4.8 Hz, 4H), 2.33
(s, 3H); 13C NMR (100 MHz, CDCl3 þ CD3OD) δ 148.3, 144.9, 144.4,
142.8, 141.6, 140.6, 133.3, 129.5, 128.3 (q, J = 31.9 Hz), 124.2 (q, J =
3270.6 Hz), 122.2, 122.0, 120.6, 115.4, 110.3, 100.3, 54.4, 48.2, 47.1,
45.7; MS (EI) m/z 445 (Mþ). Anal. (C22H22F3N4O2 0.40H2O) C, H, N.
3
3-(4-Acetylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7-(tri-
fluoromethyl)quinoline (21b). Yellow powder (64%); 1H NMR
(300 MHz, CDCl3 þ CD3OD) δ 8.65 (s, 1H), 8.17 (s, 1H), 8.03 (d, J =
7.5 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.58 (s, 1H), 7.45 (m, 2H), 6.40
(s, 1H), 4.55 (s, 2H), 3.71 (s, 2H), 3.63 (s, 2H), 3.32 (s, 2H), 3.24 (s,
2H), 2.06 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 168.5, 147.9,
144.6, 143.8, 142.0, 141.3, 133.9, 130.0, 126.6 (q, J = 31.0 Hz), 124.6 (q,
J = 270.1 Hz), 121.9, 121.7, 120.3, 113.6, 110.4, 98.1, 48.1, 47.6, 45.5,
3-(4-(Methylsulfonyl)piperazin-1-yl)-N-(3-nitrobenzyl)-
7-(trifluoromethyl)quinolin-5-amine (27b). Yellow solid
1
45.2, 40.4, 21.2; MS (EI) m/z 473 (Mþ). Anal. (C23H22F3N5O3 1.0H2O)
(62%); H NMR (300 MHz, CDCl3 þ CD3OD) δ 8.70 (d, J = 2.4
3
Hz, 1H), 8.22 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 7.2 Hz,
1H), 7.58 (d, J = 2.7 Hz, 1H), 7.55 (s, 1H), 7.49 (t, J = 7.8 Hz, 1H),
6.48 (s, 1H), 4.59 (s, 2H), 3.40 (s, 8H), 2.82 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ 147.9, 144.5, 144.2, 143.9, 142.0, 141.4, 133.8,
130.0, 126.8 (q, J = 30.9 Hz), 124.6 (q, J = 270.5 Hz), 122.0, 121.7,
120.2, 113.5, 110.9, 98.1, 47.5, 45.4, 45.0, 33.9; MS (EI) m/z 509
(Mþ). Anal. (C22H22F3N5O4S) C, H, N.
C, H, N.
3-(4-Ethylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7-(trifl-
uoromethyl)quinoline (21c). Yellow powder (65%); 1H NMR
(300 MHz, CDCl3) δ 8.83 (s, 1H), 8.27 (s, 1H), 8.14 (d, J = 7.2 Hz,
1H), 7.76 (d, J = 7.8 Hz, 1H), 7.70 (s, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.27
(s, 1H), 6.61 (s, 1H), 4.85 (t, J = 5.4 Hz, 1H), 4.63 (d, J = 5.4 Hz, 2H),
3.37 (t, J = 4.8 Hz, 4H), 2.65 (t, J = 4.8 Hz, 4H), 2.49 (q, J = 7.2 Hz, 2H),
1.13 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 148.5, 145.1,
144.7, 142.3, 141.8, 140.4, 133.5, 129.7, 128.1 (q, J = 32.0 Hz), 124.3 (q,
J = 270.8 Hz), 122.7, 122.3, 120.6, 117.0, 108.7, 101.0, 52.3, 52.2, 48.5,
N-(3-Nitrobenzyl)-5-(trifluoromethyl)quinolin-7-amines
31a and 31b. These two compounds were prepared from anilines
30a and 30b following a procedure similar to that of preparation of
1
47.7, 11.9; MS (EI) m/z 459 (Mþ). Anal. (C23H24F3N5O2 0.10H2O)
quinolines 11a and 11b. For quinoline 31a: yellow solid (75%); H
3
NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 8.17 (s, 1H), 8.02 (d, J = 7.8
Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.41 (m, 2H), 7.32 (s, 1H), 6.99
(s, 1H), 4.94 (t, J = 5.1 Hz, 1H), 4.48 (d, J = 5.1 Hz, 2H), 3.23 (s, 4H),
2.58 (s, 4H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.4,
145.3, 144.7, 144.1, 143.0, 140.6, 133.0, 129.5, 125.6 (q, J = 30.0 Hz),
124.0 (q, J = 272.0 Hz), 122.3, 121.7, 118.2, 117.5, 114.0, 109.6, 54.6, 49.0,
C, H, N.
tert-Butyl 4-(5-(3-Nitrobenzylamino)-7-(trifluoromethyl)-
quinolin-3-yl)piperazine-1-carboxylate (21d). Yellow powder
(68%); 1H NMR (300 MHz, CDCl3) δ 8.82 (d, J = 2.7 Hz, 1H), 8.28 (s,
1H), 8.15 (d, J = 7.2 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.55
(t, J = 7.8 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 6.63 (s, 1H), 4.94 (t, J = 5.1
Hz, 1H), 4.64 (d, J = 5.1 Hz, 2H), 3.64 (t, J = 5.1 Hz, 4H), 3.28 (t, J = 5.1
Hz, 4H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 154.5, 148.3,
145.1, 145.0, 142.7, 142.2, 140.3, 133.7, 129.7, 128.5 (q, J = 31.9 Hz),
124.2 (q, J = 270.5 Hz), 122.5, 122.2, 120.4, 116.4, 110.1, 100.8, 80.2,
48.7, 47.6, 43.5, 28.3; MS (EI) m/z 531 (Mþ). Anal. (C26H28F3N5O4)
C, H, N.
N-(3-(4-Methylpiperazin-1-yl)-7-(trifluoromethyl)quino-
lin-5-yl)-3-nitrobenzenesulfonamide (22). This compound
was prepared as a yellow solid from 20a in 85% yield by following a
similar procedure as that for preparation of disubstituted quinoline 4f.
1H NMR (300 MHz, CDCl3) δ 8.62 (d, J = 2.7 Hz, 1H), 8.46 (s, 1H),
8.23 (d, J = 8.1 Hz, 1H), 7.92 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.49 (d,
J = 8.1 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.14 (s, 1H), 3.19 (d, J = 5.4
Hz, 4H), 2.51 (d, J = 5.4 Hz, 4H), 2.26 (s, 3H); 13C NMR (100 MHz,
CDCl3 þ CD3OD) δ 147.8, 145.4, 144.6, 141.1, 140.7, 132.4, 131.8,
130.1, 127.7, 126.8, 124.3, 121.8, 120.0, 111.0, 53.8, 47.0, 45.1; MS
(EI) m/z 495 (Mþ); HRMS calcd for C21H20F3N5O4S (Mþ)
495.1188, found 495.1193.
47.1, 45.9; MS (EI) m/z 445 (Mþ). Anal. (C22H22F3N5O2 0.2H2O) C, H,
3
N. For quinoline 31b: yellow solid (69%); 1H NMR (300 MHz,
CDCl3) δ 8.65 (d, J = 2.4 Hz, 1H), 8.20 (s, 1H), 8.07 (d, J = 8.4 Hz,
1H), 7.67 (d, J = 7.5 Hz, 1H), 7.45 (m, 2H), 7.33 (d, J = 2.1 Hz, 1H),
7.01 (s, 1H), 4.78 (t, J = 4.8 Hz, 1H), 4.52 (d, J = 5.7 Hz, 2H), 3.26
(t, J = 4.8 Hz, 4H), 2.64 (t, J = 4.8 Hz, 4H), 2.48 (q, J = 6.9 Hz, 2H),
1.12 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 148.4, 145.4,
144.7, 144.0, 143.2, 140.6, 133.1, 129.6, 125.6 (q, J = 30.1 Hz), 124.0
(q, J = 272.4 Hz), 122.4, 121.8, 118.2, 117.5, 114.1, 109.7, 52.4, 52.2,
49.1, 47.2, 11.8; MS (EI) m/z 459 (Mþ). Anal. (C23H24F3N5O2)
C, H, N.
ELISA Kinase Assay. The tyrosine kinase activities were evaluated
according to the reported protocol.44ꢀ48 Briefly, in an enzyme-linked-
immunosorbent assay (ELISA), 20 μg/mL poly(Glu,Tyr) 4:1 (Sigma)
was precoated as a substrate in 96-well plates. Then 50 μL of 10 μM ATP
solution diluted in kinase reaction buffer (50 mM HEPES, pH 7.4,
50 mM MgCl2, 0.5 mM MnCl2, 0.2 mM Na3VO4, 1 mM DTT) was added
to each well. Various concentrations of compounds diluted in 10 μL of
1% DMSO (v/v) were added to each reaction well, with 1% DMSO
(v/v) used as the negative control. The kinase reaction was initiated by
3-(4-Methylpiperazin-1-yl)-5-(3-nitrobenzyloxy)-7-(triflu-
oromethyl)quinoline (24). This compound was prepared as a
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dx.doi.org/10.1021/jm101340q |J. Med. Chem. 2011, 54, 2127–2142