Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15 4753
byproduct; the latter is slightly less polar (TLC) but difficult
to separate by column chromatography. The product mixture
was then dissolved in THF (30 mL) and stirred with 4 N aq
NaOH (30 mL) at 50 °C for 15 min. Extraction with EtOAc
followed by concentration of combined organic layers gave
the desired product, which was pure by NMR and used in
next step without purification. Yield: 95%. 1H NMR (DMSO-
d6): δ 2.45 (s, 3H), 7.48 (d, J = 8.1 Hz, 1H), 7.54 (dd, J = 5.1, 1.9
Hz, 1H), 7.97 (dd, J =7.9, 1.8 Hz, 1H), 8.49 (d, J =1.8 Hz,
1H), 8.51 (m, 1H), 8.68 (d, J =5.1 Hz, 1H), 11.33 (s, 1H). MS
[M þ H]þ 407.0.
(E)-3-(2-(6-(Cyclopropylamino)-9H-purin-9-yl)vinyl)-4-meth-
yl-N-(3-(iso-propyl)phenyl)benzamide (9e). Method B; purified
by reverse phase prep-HPLC (MeCN/H2O, 0.1% TFA) as TFA
salt. 1H NMR (DMSO-d6): δ 0.71 (m, 2H), 0.80 (m, 2H), 1.23 (d,
J = 6.9 Hz, 6H), 2.51 (s, 3H), 2.89 (septet, J = 6.9 Hz, 1H), 3.06
(m, 1H), 7.00 (d, J = 7.6 Hz, 1H), 7.28 (dt, J = 2.5, 7.8 Hz, 1H),
7.42 (d, J = 8.0 Hz, 1H), 7.65 (m, 2H), 7.83 (dd, J = 2.0, 1.7 Hz,
1H), 7.90(s, 1H), 7.92 (s, 1H), 8.24 (d, J = 1.5 Hz, 1H), 8.45 (s,
1H), 8.75 (s, 1H), 10.21 (s, 1H). MS [M þ H]þ 452.7.
(E)-3-(2-(6-(Cyclopropylamino)-9H-purin-9-yl)vinyl)-4-meth-
yl-N-(5-(tert-butyl)thiazo-2-yl)benzamide (9f). Method B. 1H
NMR (CDCl3): δ 0.70 (m, 2H), 0.89 (m, 2H), 1.31 (s, 9H),
2.53 (s, 3H), 3.09 (m, 1H), 6.01 (s, 1H), 6.61 (s, 1H), 7.38 (d, J =
8.0 Hz, 1H), 7.61 (d, J = 14.6 Hz, 1H), 7.78 (d, J = 14.9 Hz, 1H),
7.82 (dd, J = 8.0, 1.9 Hz, 1H), 8.06 (s, 1H), 8.17 (d, J = 1.6 Hz,
1H), 8.56 (s, 1H). Anal. calcd for (C25H27N7OS): C, H, N.
(E)-3-(2-(6-(Cyclopropylamino)-9H-purin-9-yl)vinyl)-4-meth-
yl-N-(5-(tert-butyl)oxazo-3-yl)benzamide (9g). Method B. 1H
NMR (CDCl3): δ 0.75 (m, 2H), 0.98 (m, 2H), 1.39 (s, 9H),
2.52 (s, 3H), 3.15 (m, 1H), 6.62 (br, 1H), 6.88 (s, 1H), 7.27-7.52
(m, 2H), 7.66 (m, 1H), 8.00 (m, 1H), 8.05 (d, J = 18.8 Hz, 1H),
8.49 (s, 1H), 9.31 (s, 1H).
N-(3-(tert-Butyl)phenyl)-3-iodo-4-methylbenzamide (8d). Meth-
od D. 1H NMR (DMSO-d6): δ1.29 (s, 9H), 2.45 (s, 3H), 7.14 (dtt, J
= 7.9, 1.8, 1.0 Hz, 1H), 7.09 (dd, J = 7.9, 7.9 Hz, 1H), 7.48 (d, J =
8.1 Hz, 1H), 7.66 (dtt, J = 8.0, 1.9, 1.0 Hz, 1H), 7.75 (dd, J = 1.9,
1.8 Hz, 1H), 7.91 (dd, J = 7.9, 1.8 Hz, 1H), 8.41 (d, J = 1.8 Hz,
1H), 10.16 (s, 1H).
N-(3-(iso-Propyl)phenyl)-3-iodo-4-methylbenzamide (8e). Meth-
od D. 1H NMR (DMSO-d6): δ 1.22 (d, J = 6.9 Hz, 6H), 2.44 (s,
3H), 2.88 (septet, J = 6.9 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 7.26
(dd, J = 7.8, 7.7 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.61 - 7.63 (m,
2H), 7.91 (dd, J = 7.9, 1.8 Hz, 1H), 8.41 (d, J = 1.8 Hz, 1H), 10.16
(s, 1H).
N-(5-(tert-Butyl)-1H-oxazo-3-yl)-3-iodo-4-methylbenzamide
(8g). Method D. 1H NMR (CDCl3): δ 1.39 (s, 9H), 2.52 (s, 3H),
6.84 (s, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.84 (dd, J = 7.9, 1.7 Hz,
1H), 8.40 (d, J = 1.7 Hz, 1H), 9.36 (s, 1H).
(E)-3-(2-(6-(Cyclopropylamino)-9H-purin-9-yl)vinyl)-4-meth-
yl-N-(1-methyl-3-(tert-butyl)pyrazo-5-yl)benzamide (9h). Meth-
od B; purified by reverse phase prep-HPLC (MeCN/H2O, 0.1%
TFA) as TFA salt. 1H NMR (DMSO-d6): δ 0.71 (m, 2H), 0.80
(m, 2H), 1.27 (s, 9H), 2.51 (s, 3H), 3.06 (m, 1H), 3.64 (s, 3H), 6.11
(s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.82 (dd, J = 8.0, 1.6 Hz, 1H),
7.84 (d, J = 14.8 Hz, 1H), 7.89 (d, J = 10.4 Hz, 1H), 7.93 (d, J =
14.7 Hz, 1H), 8.26 (s, 1H), 8.44 (s, 1H), 8.78 (s, 1H), 10.29 (s,
N-(1-Methyl-3-(tert-butyl)-1H-pyrazo-5-yl)-3-iodo-4-methyl-
1
benzamide (8h). Method D. H NMR (DMSO-d6): δ 1.23 (s,
9H), 2.45 (s, 3H), 3.61 (s, 3H), 6.09 (s, 1H), 7.49 (d, J = 8.1 Hz,
1H), 7.89 (dd, J = 7.9, 1.7 Hz, 1H), 8.39 (d, J = 1.7 Hz, 1H),
10.24 (s, 1H).
(E)-3-(2-(6-(Cyclopropylamino)-9H-purin-9-yl)vinyl)-4-methyl-
N-(3-(trifluoromethyl)phenyl)benzamide (9a). Method B. 1H
NMR (CDCl3): δ 0.71 (m, 2H), 0.97 (m, 2H), 2.50 (s, 3H), 3.13
(m, 1H), 7.34 (d, J = 7.9Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.48 (d,
J = 8.0 Hz, 1H), 7.55 (d, J = 16.0 Hz, 1H), 7.62 (s, 1H), 7.66 (s,
1H), 7.73 (dd, J = 7.9, 1.8 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 8.01
(s, 1H), 8.07 (m, 2H), 8.23 (s, 1H), 8.50 (s, 1H). Anal. calcd for
1H). MS [M þ H]þ 470.7. Anal. calcd for (C26H30N8O 2
3
CF3CO2H): C, H, N.
(E)-3-(2-(6-(Cyclopropylamino)-9H-purin-9-yl)vinyl)-4-meth-
yl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (9i). Method B;
1
82% yield, white solid, mp 232 °C. H NMR (DMSO-d6, 300
MHz): δ 11.44 (s, 1H), 8.72 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.38
(m, 2H), 8.05 (m, 1H), 8.03 (d, 1H, J=14.7 Hz), 7.87 (d, 1H, J=7.9
Hz), 7.81 (d, 1H, J=14.7 Hz), 7.55 (d, 1H, J=4.1 Hz), 7.42 (d, 1H,
J=8.0 Hz), 3.09 (m, 1H), 2.43 (s, 3H), 0.74 (m, 2H), 0.66 (m, 2H).
MS [MþH]þ 480.0 Anal. calcd for (C24H20F3N7O): C, H, N.
N-(3-Iodo-4-methylphenyl)-N0-(3-(trifluoromethyl)phenyl)urea
(10). A mixture of 3-(trifluoromethyl)phenylisocyanate (1.03 g,
5.5 mmol) and 3-iodo-4-methylaniline (1.17 g, 5 mmol) in
CH2Cl2 (20 mL) was stirred at rt for 4 h. Filtration gave pure
product as white solid, 98% yield. 1H NMR (DMSO-d6): δ 2.31
(s, 3H), 7.22-7.33 (m, 3H), 7.48-7.59 (m, 2H), 8.00 (s, 1H), 8.09
(d, J = 2.0 Hz, 1H), 8.80 (s, 1H), 9.03 (s, 1H).
(C25H21F3N6O 0.02CH2Cl2): C, H, N.
3
(E)-3-(2-(6-(Cyclopropylamino)-9H-purin-9-yl)vinyl)-4-meth-
yl-N-(2-fluoro-5-(trifluoromethyl)phenyl)benzamide (9b). Meth-
od B; purified by reverse phase prep-HPLC (MeCN/H2O, 0.1%
TFA)as TFA salt. 1H NMR(DMSO-d6):δ 0.72(m, 2H), 0.82 (m,
2H), 2.51 (s, 3H), 2.98 (m, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.58 (dd,
J = 9.6, 9.2 Hz, 1H), 7.68 (m, 1H), 7.85 (dd, J = 7.9, 1.8 Hz, 1H),
7.90 (d, J = 10.0 Hz, 1H), 7.94(d, J = 14.7 Hz, 1H), 7.85 (dd, J =
7.9, 1.8 Hz, 1H), 8.11 (dd, J = 6.7, 1.9 Hz, 1H), 8.29 (d, J = 1.5
Hz, 1H), 8.46 (s, 1H), 8.80 (s, 1H), 10.43 (s, 1H). MS [M þ H]þ
(E)-1-(3-(2-(6-(Cyclopropylamino)-9H-purin-9-yl)vinyl)-4-methyl-
phenyl)-3-(3-(trifluoromethyl)phenyl)urea (11). Method B. 1H NMR
(CD3OD): δ 0.67 (m, 2H), 0.89 (m, 2H), 2.39 (s, 3H), 2.98 (m, 1H),
7.12-7.33 (m, 3H), 7.46 (m, 1H), 7.58-7.80 (m, 4H), 7.93 (s, 1H),
8.37 (s, 1H), 8.44 (s, 1H).
496.7. Anal. calcd for (C25H20F4N6O 1.7CF3CO2H): C, H, N.
3
(E)-3-(2-(6-(Cyclopropylamino)-9H-purin-9-yl)vinyl)-4-meth-
yl-N-(4-chloro-3-(trifluoromethyl)phenyl)benzamide (9c). Meth-
od B; purified by reverse phase prep-HPLC (MeCN/H2O, 0.1%
TFA) as TFA salt. 1H NMR (DMSO-d6): δ 0.71 (m, 2H), 0.81
(m, 2H), 2.51 (s, 3H), 3.04 (m, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.45
(d, J = 8.1 Hz, 1H), 7.85 (dd, J = 7.9, 1.8 Hz, 1H), 7.90 (d, J =
3.2 Hz, 2H), 8.15 (dd, J = 8.6, 2.4 Hz, 1H), 8.25 (d, J = 1.6 Hz,
1H), 8.38 (d, J = 2.5 Hz, 1H), 8.46 (s, 1H), 8.76 (s, 1H), 10.67 (s,
(E)-3-(2-(6-(Cyclopropylamino)-9H-purin-9-yl)vinyl)-4-methyl-N-
(3-(4-methyl-1-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide
(14a). Method B. 1H NMR (DMSO-d6): δ 0.66 (m, 2H), 0.74 (m,
2H), 2.19 (s, 3H), 2.50 (s, 3H), 3.29 (m, 1H), 7.45 (d, J = 8.1 Hz,
1H), 7.50 (s, 1H), 7.74 (s, 1H), 7.86 (dd, J = 7.9, 1.6 Hz, 1H), 7.90
(d, J = 1.3 Hz, 2H), 8.16-8.21 (m, 2H), 8.27 (d, J = 1.3 Hz, 1H),
8.33-8.39(m, 2H),8.67(s, 1H),10.71(s,1H).MS[M þ H]þ 558.8.
1H). MS [M þ H]þ 512.7. Anal. calcd for (C25H20ClF3N6O 1.4
3
CF3CO2H): C, H, N.
Anal. calcd for (C29H25F3N8O 0.09CH2Cl2): C, H, N.
(E)-3-(2-(6-(Cyclopropylamino)-9H-purin-9-yl)vinyl)-4-meth-
yl-N-(3-(tert-butyl)phenyl)benzamide (9d). Method B; purified
by reverse phase prep-HPLC (MeCN/H2O, 0.1% TFA) as TFA
3
3-Iodo-4-methyl-N-[3-(imidazol-1-yl)-5-(trifluoromethyl)phenyl]-
benzamide (13b). Prepared via our previously reported procedure
for the synthesis of 13a.29 1H NMR (DMSO-d6): 2.47 (s, 3H), 7.28
(s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.84 (s, 2H), 7.95 (d, J = 7.9 Hz,
1H), 8.22 (s, 1H), 8.33 (s, 1H), 8.36 (s, 1H), 8.50 (s, 1H), 10.71 (s, 1H).
(E)-3-(2-(6-(Cyclopropylamino)-9H-purin-9-yl)vinyl)-4-meth-
yl-N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide
(14b). Method B. 1H NMR (DMSO-d6): 0.67 (m, 2H), 0.76
(m, 2H), 2.50 (s, 3H), 3.67 (m, 1H), 7.44 (d, J = 8.0 Hz, 2H),
1
salt. H NMR (DMSO-d6): δ 0.71 (m, 2H), 0.81 (m, 2H), 1.31
(s, 9H), 2.51 (s, 3H), 3.06 (m, 1H), 7.15 (m, 1H), 7.29 (dd, J =
7.9, 7.9 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.69 (m, 1H), 7.79
(dd, J = 1.9, 1.9 Hz, 1H), 7.84 (dd, J = 7.6, 1.7 Hz, 1H), 7.91 (d,
J = 3.8 Hz, 2H), 8.24 (d, J = 1.4 Hz, 1H), 8.45 (s, 1H), 8.75 (s,
1H), 10.21 (s, 1H). MS [M þ H]þ 466.7. Anal. calcd for
(C28H30N6O 1.2CF3CO2H): C, H, N.
3