4716 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 12
Huang et al.
(dd, J = 1.7, 8.0 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 8.05 (s, 1H),
8.18 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 1.6 Hz, 1H), 8.65 (d, J =
6.7 Hz, 1H), 10.55 (s, 1H). MS: m/z 560.2 [M þ H]þ.
4-Methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoro-
methyl)phenyl}-3-[2-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxa-
zin-7-yl)ethynyl]benzamide (20d). 1H NMR (DMSO-d6): δ 2.16
(s, 3H), 2.34 (m, 4H), 2.39 (m, 4H), 2.55 (s, 3H), 3.57 (s, 2H), 4.70
(d, J = 6.3 Hz, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 1.8 Hz,
1H), 7.71 (d, J = 8.5 Hz, 1H), 7.92 (dd, J = 1.7, 8.0 Hz, 1H), 8.06
(dd, J = 1.7, 8.5 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 8.16 (d, J = 1.9
Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 10.52 (s, 1H), 11.51 (s, 1H). MS:
m/z 564.1 [M þ H]þ.
N-{4-[(4-(2-Hydroxyethyl)piperazin-1-yl)methyl]-3-(trifluoro-
methyl)phenyl}-3-[2-(imidazo[1,2-a]pyridin-3-yl)ethynyl]-4-me-
thylbenzamide (19j). 1H NMR (MeOH-d4): δ 2.41 (m, 6H), 2.55
(s, 3H), 2.80 (m, 4H), 3.62 (m, 2H), 3.83 (s, 2H), 7.20 (m, 1H),
7.41 (m, 2H), 7.65 (d, J = 9.1 Hz, 1H) 7.77 (d, J = 9.1 Hz, 1H),
7.81 (m, 3H), 8.05 (d, J = 1.9 Hz, 1H), 8.11 (d, J = 1.9 Hz, 1H),
8.55 (d, J = 6.7 Hz, 1H). MS: m/z 562.2 [M þ H]þ.
3-[2-(Imidazo[1,2-a]pyrimidin-3-yl)ethynyl]-4-methyl-N-{4-
[(4-Methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}ben-
zamide (20e). 1H NMR (DMSO-d6): δ 2.16 (s, 3H), 2.34 (m, 4H),
2.40 (m, 4H), 2.62 (s, 3H), 3.57 (s, 2H), 7.31 (dd, J = 4.2, 6.8 Hz,
1H), 7.57 (d, J =8.2 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.95 (dd, J=
1.9, 8.0 Hz, 1H), 8.07 (dd, J=2.0, 8.4 Hz, 1H), 8.22 (d, J=2.0 Hz,
1H), 8.23 (s, 1H), 8.28 (d, J=1.8 Hz, 1H), 8.67 (dd, J=2.0, 4.1
Hz, 1H), 9.06 (dd, J=2.0, 6.8 Hz, 1H), 10.54 (s, 1H). MS: m/z
533.2 [M þ H]þ.
N-{4-[(4-(2-Fluoroethyl)piperazin-1-yl)methyl]-3-(trifluoro-
methyl)phenyl}-3-[2-(imidazo[1,2-a]pyridin-3-yl)ethynyl]-4-me-
thylbenzamide (19k). This was made from coupling of 9c and 18k
in 81% yield. 1H NMR (DMSO-d6): δ 2.31 (m, 4H), 2.41 (s, 3H),
2.50 (m, 6H), 3.72 (s, 2H), 4.53 (m, 1H), 4.70 (m, 1H), 7.30 (m,
1H), 7.55 (m, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.81 (m, 2H), 8.10 (d,
J = 8.1 Hz, 1H), 8.22 (m, 2H), 8.31 (s, 1H), 8.35 (s, 1H), 8.70 (d,
J = 6.6 Hz, 1H), 10.3 (s, 1H). MS: m/z 564.2 [M þ H]þ.
3-[2-(Imidazo[1,2-a]pyridin-3-yl)ethynyl]-4-methyl-N-[4-(1-pipe-
razinylmethyl)-3-(trifluoromethyl)phenyl]benzamide (19l). This
was made from coupling of 9c and 18l followed by standard
de-Boc with TFA. 1H NMR (DMSO-d6): δ 2.33 (m, 4H), 2.62 (s,
3H), 2.72 (t, J = 4.5 Hz, 4H), 3.54 (s, 2H), 7.20 (t, J = 6.7 Hz, 1H),
7.47 (dd, J = 6.9, 8.9 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.73 (d,
J = 3.9 Hz, 1H), 7.76 (d, J = 4.6 Hz, 1H), 7.94 (d, J= 7.9 Hz, 1H),
8.07 (d, J= 5.1 Hz, 1H), 8.08 (s, 1H), 8.22 (s, 1H), 8.27 (s, 1H), 8.63
(d, J = 6.6 Hz, 1H), 10.54 (s, 1H). MS: m/z 518.1 [M þ H]þ.
3-[2-(Imidazo[1,2-a]pyridin-3-yl)ethynyl]-4-methyl-N-{4-[(3-
methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benza-
mide (19m). Substituted N-benzylpiperazine 16m was pre-
pared analogously to 16a using 2-methylpiperazine instead of
N-methylpiperazine as starting material. Coventional Boc pro-
tection (Boc2O, DMAP) of 16m gave 16m0 in 69% yield. This
was converted to 18m similarly to the synthesis of 18a from
16a except that the reduction of NO2 to NH2 was done via
hydrogenation on Pd/C in 66% yield. The coupling of 9c and
18m followed by standard de-Boc with TFA furnished desired
product, which was purified by reverse phase prep-HPLC
(MeCN/H2O, 0.1% TFA) as TFA salt. 1H NMR (DMSO-d6):
δ 1.19 (d, J = 6.9 Hz, 3H), 2.15 (t, J = 11.2 Hz, 1H), 2.34 (t,
J = 11.3 Hz, 1H), 2.62 (s, 3H), 2.84 (dd, J = 10.9, 11.7 Hz, 2H),
3.02 (d, J = 9.2 Hz, 1H), 3.28 (d, J = 10.4 Hz, 2H), 3.66 (s, 2H),
7.20 (dd, J = 6.5, 6.7 Hz, 1H), 7.48 (dd, J = 6.9, 8.1 Hz, 1H), 7.56
(d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 8.1 Hz,
1H), 7.94 (d, J=7.9Hz, 1H), 8.10(s, 1H), 8.12(d, J= 8.6 Hz, 1H),
8.25 (d, J = 9.1 Hz, 2H), 8.50 (br, 1H), 8.63 (d, J = 6.4 Hz, 1H),
8.93 (br, 1H), 10.59 (s, 1H). MS: m/z 532.2 [M þ H]þ.
3-[2-(Imidazo[1,2-a]pyrazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-
methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benza-
mide (20f). 1H NMR (DMSO-d6): δ 2.10 (m, 4H), 2.17 (s, 3H),
2.40 (m, 7H), 3.71 (s, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.65 (d,
J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz,
1H), 8.10 (s, 2H), 8.25 (d, J = 8.0 Hz, 1H), 8.31 (s, 1H), 8.55 (d,
J = 4.4 Hz, 1H), 9.10 (s, 1H), 10.50 (s, 1H). MS: m/z 533.1
[M þ H]þ.
3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-
[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}ben-
zamide (20g). 1H NMR (DMSO-d6): δ 2.15 (s, 3H), 2.33 (m, 4H),
2.39 (m, 4H), 2.61 (s, 3H), 3.56 (s, 2H), 7.39 (dd, J = 4.5, 9.2 Hz,
1H), 7.55 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.95 (dd,
J = 1.9, 8.0 Hz, 1H), 8.06 (dd, J = 1.9, 8.5 Hz, 1H), 8.21 (d, J =
1.7 Hz, 2H), 8.23 (s, 1H), 8.25 (dd, J = 1.5, 9.2 Hz, 1H), 8.72 (dd,
J = 1.5, 4.4 Hz, 1H), 10.54 (s, 1H). MS: m/z 533.3 [M þ H]þ.
N-{4-[(4-Ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phe-
nyl}-3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methylbenza-
mide (20h). Purified as HCl salts. 1H NMR (D2O): δ 1.32 (t, J =
7.2 Hz, 3H), 2.38 (s, 3H), 3.27 (q, J = 7.2 Hz, 2H), 3.28 (m, 4H),
3.48 (m, 4H), 4.15 (s, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.39 (dd, J =
4.2, 9.6 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.0 Hz,
1H), 7.70 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 9.2 Hz, 2H), 8.02 (s,
1H), 8.09 (d, J=9.6 Hz, 1H), 8.67 (d, J=4.4 Hz, 1H).
N-{4-[(4-(2-Hydroxyethyl)piperazin-1-yl)methyl]-3-(trifluoro-
methyl)phenyl}-3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-me-
thylbenzamide (20i). Purified as HCl salt. 1H NMR (D2O): δ 1.25
(s, 3H), 3.44 (s, 2H), 3.61 (m, 4H), 3.71 (m, 4H), 3.94 (s, 2H), 4.44
(s, 2H), 7.11 (d, J = 7.6 Hz, 1H), 7.54-7.59 (m, 3H), 7.70 (d, J =
8.0 Hz, 1H), 7.74 (s, 1H), 7.88 (s, 1H), 8.02 (s, 1H), 8.10 (d,
J = 9.2 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H).
4-Methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoro-
methyl)phenyl}-3-[2-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl]ben-
zamide (20a). 1H NMR (DMSO-d6): δ 2.17 (s, 3H), 2.33 (m, 4H),
2.40 (m, 4H), 2.58 (s, 3H), 3.57 (s, 2H), 6.52 (dd, J = 1.8, 3.4 Hz,
1H), 7.52 (d, J = 8.0 Hz, 1H), 7.57 (dd, J = 2.8, 3.2 Hz, 1H), 7.71
(d, J = 8.4 Hz, 1H), 7.90 (dd, J = 1.8, 7.8 Hz, 1H), 8.07 (dd, J =
1.8, 7.8 Hz, 1H), 8.17 (d, J= 1.8Hz, 1H), 8.22(m, 2H), 8.45(d, J=
2.0 Hz, 1H), 10.51 (s, 3H), 11.93 (s, 3H). MS: m/z 531.8 [M þ H]þ.
3-[2-(3H-Imidazo[4,5-b]pyridin-6-yl)ethynyl]-4-methyl-N-{4-
[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benza-
mide (20b). 1H NMR (CD2Cl2): δ 2.27 (s, 3H), 2.47 (m, 8H), 2.55
(s, 3H), 3.63 (s, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.61 (m, 1H), 7.75
(d, J = 8.5 Hz, 1H), 7.79 (m, 1H), 7.82 (dd, J = 1.8, 8.0 Hz, 1H),
7.94 (d, J = 8.8 Hz, 1H), 8.07 (dd, J = 1.8, 8.9 Hz, 1H), 8.09 (s,
1H), 8.30 (s, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.88 (br, 1H).
4-Methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoro-
methyl)phenyl}-3-[2-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyri-
din-6-yl)ethynyl]benzamide (20c). 1H NMR (DMSO-d6): δ 2.17
(s, 3H), 2.37 (m, 8H), 2.55 (s, 3H), 3.57 (s, 2H), 7.38 (d, J = 1.4
Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.90
(dd, J = 1.8, 8.0 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.14 (d, J =
1.7 Hz, 2H), 8.21 (d, J = 1.8 Hz, 1H), 10.50 (s, 1H), 11.03 (s, 1H),
11.61 (s, 1H). MS: m/z 549.2 [M þ H]þ.
3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-[4-(1-
piperazinylmethyl)-3-(trifluoromethyl)phenyl}benzamide (20j).
1H NMR (DMSO-d6): δ 2.38 (m, 4H), 2.66 (s, 3H), 2.75 (m,
4H), 3.61 (s, 2H), 7.40 (dd, J = 4.4, 9.2 Hz, 1H), 7.58 (d, J = 8.2
Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.97 (dd, J = 1.9, 8.0 Hz, 1H),
8.09 (dd, J = 2.0, 8.4 Hz, 1H), 8.15-8.31 (m, 4H), 8.77 (dd, J =
1.5, 4.4 Hz, 1H), 10.59 (s, 1H). MS: m/z 519.0 [M þ H]þ.
3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-N-{4-[(4-methyl-
piperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (20k).
1H NMR (DMSO-d6): δ 2.17 (s, 3H), 2.37 (m, 8H), 3.57 (s, 2H),
7.40 (dd, J = 4.5, 9.2 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.72 (d,
J = 8.6 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 8.04 (dd, J = 1.2, 9.4
Hz, 1H), 8.07 (d, J = 9.3 Hz, 1H), 8.22 (m, 1H), 8.23 (s, 1H), 8.25
(d, J = 1.6 Hz, 1H), 8.28 (d, J = 1.6 Hz, 1H), 8.73 (dd, J = 1.5,
4.4 Hz, 1H), 10.63 (s, 1H). MS: m/z 519.2 [M þ H]þ.
4-Chloro-3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-N-{4-[(4-
methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benza-
mide (20l). 1H NMR (DMSO-d6): δ 2.15 (s, 3H), 2.50 (m, 4H),
2.84 (m, 4H), 3.63 (s, 2H), 7.44 (dd, J = 4.5, 9.2 Hz, 1H), 7.73
(d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 8.03 (dd, J = 2.2,
8.5 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H),