Journal of Medicinal Chemistry
Article
°C. The reaction mixture was stirred at this temperature for an
additional 1 h and then heated at 40 °C for 4 h; the reaction
was quenched with water. The crude was extracted with
CH2Cl2 and then dried over MgSO4. Then the organic layer
was concentrated, and the resultant residue was chromato-
graphed over silica gel, eluting with petroleum ether to afford
the desired product 17a (1.1 g, 58% yield): MS (ESI, positive
ion), m/z 181.41 [M + H]+.
= 9.2 Hz, 2H), 7.38 (s, 1H), 7.16 (d, J = 9.2 Hz, 1H), 7.10−
7.08 (m, 1H), 6.93 (d, J = 9.2 Hz, 2H), 6.39 (s, 1H), 4.98−4.96
(m, 1H), 3.43 (m, 2H), 3.34 (m, 2H), 3.16 (m, 4H), 2.80 (s,
3H), 2.46 (m, 2H), 2.04 (m, 4H), 1.69 (m, 2H); MS (ESI,
positive ion), m/z 485.9 [M + H]+.
N8-(3-Chlorophenyl)-9-cyclopentyl-N2-(4-(4-methylpipera-
zin-1-yl)phenyl)-9H-purine-2,8-diamine (18e): yield, 0.7 g
1
(45%, 95% HPLC purity); H NMR (400 MHz, DMSO-d6),
Compounds 17b−j were prepared from 15b−j in a
manner identical to the preparation of 17a. 1-Alkynyl-3-
isothiocyanatobenzene (17b): yield, 70%; MS (ESI, positive
ion), m/z 160.10 [M + H]+.
δ 9.38 (s, 1H), 9.13 (s, 1H), 8. 44 (s, 1H), 8.11 (s, 1H), 7.75
(d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.35 (m, 1H),
7.02 (m, 1H), 6.94 (d, J = 8.8 Hz, 2H), 5.01 (m, 1H), 3.43 (m,
4H), 3.10 (m, 4H), 2.82 (s, 3H), 2.45 (m, 2H), 2.05 (m, 4H),
1.70 (m, 2H); MS (ESI, positive ion), m/z 505.1 [M + H]+.
N8-(4-Bromophenyl)-9-cyclopentyl-N2-(4-(4-methylpipera-
zin-1-yl)phenyl)-9H-purine-2,8-diamine (18f): yield, 0.7 g
1-Methyl-3-isothiocyanatobenzene (17c): yield, 61%; MS
(ESI, positive ion), m/z 150.30 [M + H]+.
1-Hydroxy-3-isothiocyanatobenzene (17d): yield, 56%; MS
(ESI, positive ion), m/z 152.3 [M + H]+.
1
(48%, 95% HPLC purity); H NMR (400 MHz, DMSO-d6),
1-Chloro-3-isothiocyanatobenzene (17e): yield, 58%; MS
δ 9.22 (s, 1H), 9.09 (s, 1H), 8.39 (s, 1H), 7.83 (d, J = 9.2 Hz,
2H), 7.66 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 6.93 (d,
J = 8.0 Hz, 2H), 4.98−4.94 (m, 1H), 3.15 (m, 4H), 2.75 (m,
4H), 2.46 (s, 3H), 2.05 (m, 4H), 1.68 (m, 2H), 1.23 (m, 2H);
MS (ESI, positive ion), m/z 548.6 [M + H]+.
(ESI, positive ion), m/z 170.8 [M + H]+.
1-Bromo-4-isothiocyanatobenzene (17f): yield, 50%; MS
(ESI, positive ion), m/z 215.3 [M + H]+.
1-Fluoro-3-bromo-6-isothiocyanatobenzene (17g): yield,
52%; MS (ESI, positive ion), m/z 233.1 [M + H]+.
1,4-Dichloro-2-isothiocyanatobenzene (17h): yield, 67%;
MS (ESI, positive ion), m/z 205.1 [M + H]+.
N-(4-Chlorophenyl)-3-isothiocyanatobenzamide (17i):
yield, 63%; MS (ESI, positive ion), m/z 289.9 [M + H]+.
N-(3-Isothiocyanatophenyl)benzamide (17j): yield, 60%;
MS (ESI, positive ion), m/z 255.6 [M + H]+.
N8-(4-Bromo-2-fluorophenyl)-9-cyclopentyl-N2-(4-(4-
methylpiperazin-1-yl)phenyl)-9H-purine-2,8-diamine (18g):
1
yield, 0.6 g (46%, 95% HPLC purity); H NMR (400 MHz,
DMSO-d6), δ 9.06 (s, 1H), 8.93 (s, 1H), 8.35 (s, 1H), 7.88−
7.83 (m, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.40 (d, J
= 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 2H), 4.90−4.86 (m, 1H),
3.10 (m, 4H), 2.62 (m, 4H), 2.43 (m, 2H), 2.34 (s, 3H), 2.03
(m, 4H), 1.68 (m, 2H); MS (ESI, positive ion), m/z 566.7 [M
+ H]+.
Compounds 18a−j were prepared by condensation
of 8e with various substituted phenyl isothiocyanates
(17a−j) using the procedure previously described for
compound 9e and were purified by column chroma-
tography. 9-Cyclopentyl-N2-(4-(4-methylpiperazin-1-yl)-
phenyl)-N8-(3-nitrophenyl)-9H-purine-2,8-diamine (18a):
9-Cyclopentyl-N8-(2,5-dichlorophenyl)-N2-(4-(4-methylpi-
perazin-1-yl)phenyl)-9H-purine-2,8-diamine (18h): yield, 0.9
1
g (47%, 95% HPLC purity); H NMR (400 MHz, DMSO-d6),
δ 9.02 (s, 1H), 8.62 (s, 1H), 8.37 (s, 1H), 7.91 (s, 1H), 7.59 (d,
J = 8.4 Hz, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.10 (m, 1H), 6.86
(d, J = 9.2 Hz, 2H), 4.91 (m, 1H), 3.04 (m, 4H), 2.45 (m, 4H),
2.31 (m, 2H), 2.22 (s, 3H), 2.00 (m, 4H), 1.67 (m, 2H); MS
(ESI, positive ion), m/z 623.5 [M + H]+.
1
yield, 1.1 g (46%, 95% HPLC purity); H NMR (400 MHz,
DMSO-d6), δ 9.54 (s, 1H), 9.05 (s, 1H), 8.82 (s, 1H), 8.45 (s,
1H), 8.32 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.63 (s,
1H), 7.61 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.98−
4.94 (m, 1H), 3.05 (s, 4H), 2.48 (s, 2H), 2.48 (s, 4H), 2.23 (s,
3H), 2.06 (s, 4H), 1.71 (s, 2H); MS (ESI, positive ion), m/z
514.7 [M + H]+.
N-(4-Chlorophenyl)-3-(9-cyclopentyl-2-(4-(4-methylpiper-
azin-1-yl)phenylamino)-9H-purin-8-ylamino)benzamide
1
9-Cyclopentyl-N8-(3-ethynylphenyl)-N2-(4-(4-methylpiper-
azin-1-yl)phenyl)-9H-purine-2,8-diamine (18b): yield, 1.3 g
(18i): yield, 0.8 g (49%, 95% HPLC purity); H NMR (400
MHz, DMSO-d6), δ 10.42 (s, 1H), 9.36 (s, 1H), 9.12 (s, 1H),
8.41 (s, 1H), 8.26 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.84 (d, J =
9.2 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 7.6 Hz, 1H),
7.49 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 6.94 (d, J =
8.8 Hz, 2H), 4.99 (m, 1H), 3.85−3.45 (br, 2H), 3.20−2.90 (br,
4H), 2.80 (s, 3H), 2.46−2.39 (br, 4H), 2.05 (m, 4H), 1.71 (m,
2H); MS (ESI, positive ion), m/z 623.2 [M + H]+.
1
(41%, 95% HPLC purity); H NMR (400 MHz, DMSO-d6), δ
9.26 (s, 1H), 9.13 (s, 1H), 8.43 (s, 1H), 8.09 (s, 1H), 7.85 (d, J
= 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 8.0 Hz,
1H), 7.09 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 2H), 5.02−
4.98 (m, 1H), 4.20 (s, 1H), 3.70 (br, 2H), 3.47 (br, 2H), 3.18
(br, 2H), 3.00 (br, 2H), 2.83 (s, 3H), 2.46 (br, 2H), 2.05 (br,
4H), 1.71 (br, 2H); MS (ESI, positive ion), m/z 493.9 [M +
H]+.
N-(3-(9-Cyclopentyl-2-(4-(4-methylpiperazin-1-yl)-
phenylamino)-9H-purin-8-ylamino)phenyl)benzamide (18j):
1
9-Cyclopentyl-N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-
m-tolyl-9H-purine-2,8-diamine (18c): yield, 1.3 g (42%, 95%
yield, 0.8 g (49%, 95% HPLC purity); H NMR (400 MHz,
DMSO-d6), δ 10.30 (s, 1H), 9.15 (s, 1H), 9.05 (s, 1H), 8.36 (s,
1H), 8.26 (s, 1H), 7.98 (d, J = 7.2 Hz, 2H), 7.67 (s, 1H), 7.64
(d, J = 8.8 Hz, 2H), 7.59 (d, J = 6.8 Hz, 1H), 7.55 (d, J = 6.8
Hz, 2H), 7.52 (s, 1H), 7.30 (d, J = 6.8 Hz, 1H), 6.90 (d, J = 8.8
Hz, 2H), 5.00 (m, 1H), 3.17−3.05 (br, 4H), 2.82 (s, 3H),
2.50−2.40 (br, 4H), 2.47 (m, 2H), 2.05 (m, 4H), 1.71−1.70
(br, 2H); MS (ESI, positive ion), m/z 588.9 [M + H]+.
Kinase Inhibition and Binding Affinity Assays. Kinase
inhibition profiles were obtained using KinaseProfiler services
provided by Millipore, and ATP concentrations used are the
ATP Km of corresponding kinases. Binding affinities were
1
HPLC purity); H NMR (400 MHz, DMSO-d6), δ 9.08 (s,
1H), 9.02 (s, 1H), 8.37 (s, 1H), 7.68−7.62 (m, 4H), 7.22 (m,
1H), 6.93 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 7.6 Hz, 1H), 4.99
(m, 1H), 3.67 (m, 2H), 3.44 (m, 2H), 3.03 (m, 4H), 2.81 (s,
3H), 2.45 (m, 2H), 2.31 (s, 3H), 2.04 (m, 4H), 1.69 (m, 2H);
MS (ESI, positive ion), m/z 483.9 [M + H]+.
3-(9-Cyclopentyl-2-(4-(4-methylpiperazin-1-yl)-
phenylamino)-9H-purin-8-ylamino)phenol (18d): yield, 0.5 g
1
(36%, 95% HPLC purity); H NMR (400 MHz, DMSO-d6), δ
9.36 (s, 1H), 9.07 (s, 1H), 8.93 (s, 1H), 8.35 (s, 1H), 7.67 (d, J
10696
dx.doi.org/10.1021/jm301365e | J. Med. Chem. 2012, 55, 10685−10699