2574 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8
Serby et al.
(10 mL). The organic phase was washed with water (1 × 20 mL)
and then brine (1 × 20 mL), dried over Na2SO4, and concentrated
in vacuo to give 3,5-difluoro-4-methanesulfonylbenzaldehyde (200
mg, 70%), which was used directly without any further purification.
1H NMR (300 MHz, CDCl3) δ 10.0 (t, J ) 1.7 Hz, 1H), 7.58 (s,
1H), 7.56 (s, 1H), 3.36 (s, 3H). MS (DCI) m/z ) 238 (M + NH4)+.
Title compound 7c was synthesized by the general procedure
described for 7a substituting 3,5-difluoro-4-methanesulfonyl-
benzaldehyde for 4-chlorobenzaldehyde. Yield, 65%. 1H NMR (300
MHz, DMSO-d6) δ 7.33 (d, J ) 10.2 Hz, 2H), 6.88 (d, J ) 8.5
Hz, 2H), 6.61 (d, J ) 8.5 Hz, 2H), 6.50 (t, J ) 6.3 Hz, 1H), 5.72
(s, 2H), 5.27 (s, 2H), 4.39 (d, J ) 6.1 Hz, 2H), 3.41 (s, 3H), 2.11
(q, J ) 7.6 Hz, 2H), 0.94 (t, J ) 7.6 Hz, 3H). MS (ESI) m/z ) 434
[M + H]+. Anal. (C20H21F2N5O2S‚1.0CF3CO2H) C, H, N. Calcd
for C, 48.26; H, 4.05; N, 12.79. Found: C, 47.96; H, 4.46; N, 12.36.
6-Ethyl-5-{4-[(4-nitrobenzyl)amino]phenyl}pyrimidine-2,4-di-
amine (7d). Title compound 7d was synthesized by the general
procedure described for 7a substituting 4-nitro-benzaldehyde for
4-chlorobenzaldehyde. Yield, 56%.1H NMR (300 MHz, DMSO-
d6) δ 8.22 (d, J ) 8.8 Hz, 2H), 7.67 (d, J ) 8.8 Hz, 2H), 6.86 (d,
J ) 8.5 Hz, 2H), 6.62 (d, J ) 8.5 Hz, 2H), 6.51 (t, J ) 6.1 Hz,
1H), 5.71 (s, 2H), 5.23 (bs, 2H), 4.44 (d, J ) 6.1 Hz, 2H), 2.10 (q,
J ) 7.5 Hz, 2H), 0.94 (t, J ) 7.5 Hz, 3H). MS (ESI) m/z ) 365
[M + H]+. Anal. (C19H20N6O2‚0.15CF3CO2H) C, H, N. Calcd for
C, 60.76; H, 5.32; N, 22.03. Found: C, 60.92; H, 5.49; N, 21.47.
1-(4-{[4-(2,4-Diamino-6-ethyl-pyrimidin-5-yl)-phenylamino]-
methyl}-phenyl)-ethanone (7e). Title compound 7e was synthe-
sized by the general procedure described for 7a substituting
pyridine-4-carboxaldehyde31 for 4-chlorobenzaldehyde. Yield, 78%.
1H NMR (300 MHz, DMSO-d6) δ 8.35 (d, J ) 5.1 Hz, 1H), 7.49
(s, 1H), 7.42 (d, J ) 5.1 Hz, 1H), 6.88 (d, J ) 8.5 Hz, 2H), 6.62
(d, J ) 8.5 Hz, 2H), 6.46 (t, J ) 6.1 Hz, 1H), 5.72 (s, 2H), 5.27
(bs, 2H), 4.36 (d, J ) 6.1 Hz, 2H), 2.11 (q, J ) 7.5 Hz, 2H), 0.94
(t, J ) 7.5 Hz, 3H). MS (ESI) m/z ) 455 [M + H]+. Anal.
(C18H19ClN6‚0.05CF3CO2H) C, H, N.
5-{4-[(5-Chloro-thiophen-3-ylmethyl)-amino]-phenyl}-6-
ethyl-pyrimidine-2,4-diamine (7j). Title compound 7j was
synthesized by the general procedure described for 7a substituting
5-chloro-2-thiophenecarboxaldehyde for 4-chlorobenzaldehyde. Yield,
30%. 1H NMR (500 MHz, DMSO-d6) δ 7.28 (d, J ) 1.6 Hz, 1H),
7.09 (d, J ) 1.9 Hz, 1H), 6.87 (d, J ) 8.7 Hz, 2H), 6.66 (d, J )
8.7 Hz, 2H), 6.16 (t, J ) 5.8 Hz, 1H), 5.28 (bs, 2H), 5.73 (s, 2H),
4.18 (d, J ) 5.6 Hz, 2H), 2.12 (q, J ) 7.5 Hz, 2H), 0.95 (t, J ) 7.5
Hz, 3H). MS (ESI) m/z ) 360 [M + H]+. HRMS calcd for
(C17H19ClN5S) 360.1050. Found: 360.1044.
6-[(Benzyloxy)methyl]-5-{4-[(4-nitrobenzyl)amino]phenyl}-
pyrimidine-2,4-diamine (8b). Title compound 8b was synthesized
by the general procedure described for 8a substituting 4-nitro-
benzaldehyde for 4-chlorobenzaldehyde. Yield, 27%. 1H NMR (300
MHz, DMSO-d6) δ 8.20 (ddd, J ) 9.1, 2.5, 2.3 Hz, 2H), 7.66 (d,
J ) 8.8 Hz, 2H), 7.25 (m, 3H), 7.16 (dd, J ) 7.5, 2.0 Hz, 2H),
6.90 (d, J ) 8.5 Hz, 2H), 6.60 (d, J ) 8.5 Hz, 2H), 6.55 (t, J ) 6.3
Hz, 1H), 5.97 (s, 2H), 5.61 (s, 2H), 4.44 (d, J ) 6.1 Hz, 2H), 4.32
(s, 2H), 3.95 (s, 2H). MS (ESI) m/z ) 457 [M + H]+, 455 [M -
H]-. HRMS calcd for (C25H25N6O3) 457.1988. Found: 457.1984.
6-[(Benzyloxy)methyl]-5-(4-{[4-(methylsulfonyl)benzyl]amino}-
phenyl)pyrimidine-2,4-diamine (8c). Title compound 8c was
synthesized by the general procedure described for 8a substituting
4-methanesulfonylbenzaldehyde for 4-chlorobenzaldehyde. Yield,
67%. 1H NMR (300 MHz, DMSO-d6) δ 7.89 (d, J ) 8.5 Hz, 2H),
7.65 (d, J ) 8.5 Hz, 2H), 7.31-7.15 (m, 5H), 6.90 (d, J ) 8.5 Hz,
2H), 6.61 (d, J ) 8.8 Hz, 2H), 6.52 (t, J ) 6.3 Hz, 1H), 6.01 (s,
2H), 5.64 (s, 2H), 4.41 (d, J ) 6.1 Hz, 2H), 4.33 (s, 2H), 3.96 (s,
2H), 3.18 (s, 3H). MS (ESI) m/z ) 490 [M + H]+. Anal.
(C26H27N5O3S‚0.53CF3CO2H) C, H, N. Calcd for C, 59.09; H, 5.04;
N, 12.73. Found: C, 59.23; H, 5.48; N, 12.29.
1
4-acetylbenzaldehyde for 4-chlorobenzaldehyde. Yield, 72%. H
NMR (300 MHz, DMSO-d6) δ 7.93 (d, J ) 8.5 Hz, 2H), 7.53 (d,
J ) 8.1 Hz, 2H), 6.85 (d, J ) 8.5 Hz, 2H), 6.62 (d, J ) 8.5 Hz,
2H), 6.43 (t, J ) 5.9 Hz, 1H), 5.73 (s, 2H), 5.27 (s, 2H), 4.36 (d,
J ) 6.1 Hz, 2H), 2.56 (s, 2H), 2.10 (q, J ) 7.5 Hz, 2H), 0.94 (t,
J ) 7.6 Hz, 3H). MS (ESI) m/z ) 362 [M + H]+. HRMS calcd for
(C21H24N5O) 362.1981. Found: 362.1977.
1-(4-{[4-(2,4-Diamino-6-ethyl-pyrimidin-5-yl)-phenylamino]-
methyl}-phenyl)-ethanol (7f). To a solution of 7e (76 mg, 0.21
mmol) in 3:1 MeOH/THF (1.5 mL) at room temperature was added
NaBH4 (32 mg, 0.84 mmol) slowly, then the reaction mixture was
stirred for 1 h. The reaction mixture was quenched with 1 M HCl,
filtered, and purified by preparative RP-HPLC to give 1-(4-{[4-
(2,4-diamino-6-ethyl-pyrimidin-5-yl)-phenylamino]-methyl}-phen-
yl)-ethanol (55 mg, 72%). 1H NMR (300 MHz, DMSO-d6) δ 7.36-
7.26 (m, 4H), 6.84 (d, J ) 8.5 Hz, 2H), 6.63 (d, J ) 8.8 Hz, 2H),
6.25 (t, J ) 5.9 Hz, 1H), 5.72 (s, 2H), 5.26 (s, 2H), 5.08 (s, 1H),
4.69 (q, J ) 6.3 Hz, 1H), 4.23 (d, J ) 5.8 Hz, 2H), 2.11 (q, J )
7.8 Hz, 2H), 1.30 (d, J ) 6.4 Hz, 2H), 0.94 (t, J ) 7.5 Hz, 3H).
MS (ESI) m/z ) 364 [M + H]+. Anal. (C21H25N5O‚ 0.15CF3CO2H)
C, H, N.
6-[(Benzyloxy)methyl]-5-[4-({4-[(trifluoromethyl)sulfonyl]-
benzyl}amino)phenyl]pyrimidine-2,4-diamine (8d). Title com-
pound 8d was synthesized by the general procedure described
for 8a substituting 4-trifluoromethanesulfonylbenzaldehyde for
1
4-chlorobenzaldehyde. Yield, 70%. H NMR (300 MHz, DMSO-
d6) δ 8.11 (d, J ) 8.5 Hz, 2H), 7.85 (d, J ) 8.5 Hz, 2H), 7.30-
7.15(m, 5H), 6.92 (d, J ) 8.5 Hz, 2H), 6.61 (d, J ) 8.5 Hz, 2H),
6.57 (t, J ) 6.1 Hz, 1H), 5.89 (s, 2H), 5.51 (bs, 2H), 4.51(d, J )
6.1 Hz, 2H), 4.31 (s, 2H), 3.94 (s, 2H). MS (ESI) m/z ) 544 [M
+ H]+, 542 [M - H]-. Anal. (C26H24F3N5O3S‚0.1CF3CO2H) C,
H, N.
1-(4-{[4-(2,4-Diamino-6-benzyloxymethyl-pyrimidin-5-yl)-
phenylamino]-methyl}-phenyl)-ethanone (8e). Title compound 8e
was synthesized by the general procedure described for 8a
substituting 4-acetylbenzaldehyde for 4-chlorobenzaldehyde. Yield,
73%. 1H NMR (300 MHz, DMSO-d6) δ 7.92 (d, J ) 8.5 Hz, 2H),
7.53 (d, J ) 8.5 Hz, 2H), 7.30-7.12 (m, 5H), 6.89 (d, J ) 8.5 Hz,
2H), 6.60 (d, J ) 8.5 Hz, 2H), 6.46 (t, J ) 6.1 Hz, 1H), 5.88 (s,
2H), 5.48 (s, 2H), 4.37 (d, J ) 5.8 Hz, 2H), 4.31 (s, 2H), 3.94 (s,
2H), 2.55 (s, 2H), 1.89 (s, 3H). MS [ESI] m/z ) 454 [M + H]+.
Anal. (C27H27N5O2‚0.2CF3CO2H) C, H, N.
6-[(Benzyloxy)methyl]-5-(4-{[(2-chloropyridin-4-yl)methyl]-
amino}phenyl)pyrimidine-2,4-diamine (8f). Title compound 8f
was synthesized by the general procedure described for 8a
substituting 2-chloro-pyridine-4-carboxaldehyde32 for 4-chloro-
benzaldehyde. Yield, 70%. 1H NMR (300 MHz, DMSO-d6) δ 8.34
(d, J ) 5.1 Hz, 1H), 7.49 (s, 1H), 7.42 (d, J ) 5.1 Hz, 1H), 7.30-
7.15 (m, 5H), 6.91 (d, J ) 8.5 Hz, 2H), 6.60 (d, J ) 8.5 Hz, 2H),
6.49 (t, J ) 6.5 Hz, 1H), 5.87 (s, 2H), 5.50 (bs, 2H), 4.36
(d, J ) 6.5 Hz, 2H), 4.31 (s, 2H), 3.93 (s, 2H). MS (ESI)
m/z ) 447 [M + H]+, 445 [M - H]-. Anal. (C24H23ClN6O‚
0.15CH3CO2NH4‚0.6CH3CN) C, H, N.
4-({[4-(2,4-Diamino-6-ethylpyrimidin-5-yl)phenyl]amino}-
methyl)benzonitrile (7g). Title compound 7g was synthesized by
the general procedure described for 7a substituting 4-cyano-
benzaldehyde for 4-chlorobenzaldehyde. Yield, 73%. 1H NMR (500
MHz, DMSO-d6) δ 7.80 (d, J ) 8.1 Hz, 2H), 7.58 (d, J ) 8.1 Hz,
2H), 6.85 (d, J ) 8.4 Hz, 2H), 6.61 (d, J ) 8.4 Hz, 2H), 6.44 (t,
J ) 5.9 Hz, 1H), 5.77 (s, 2H), 5.32 (s, 2H), 4.38 (d, J ) 5.9 Hz,
2H), 2.11 (q, J ) 7.6 Hz, 2H), 0.94 (t, J ) 7.5 Hz, 3H). MS (ESI)
m/z ) 345 [M + H]+. Anal. (C20H20N6‚0.05CF3CO2H) C, H, N.
6-Ethyl-5-[4-(4-trifluoromethanesulfonyl-benzylamino)-phen-
yl]-pyrimidine-2,4-diamine (7h). Title compound 7h was synthe-
sized by the general procedure described for 7a substituting (4-
trifluoromethanesulfonyl)-benzaldehyde30 for 4-chlorbenzaldehyde.
1
Yield, 71%. H NMR (300 MHz, DMSO-d6) δ 8.12 (d, J ) 8.5
Hz, 2H), 7.85 (d, J ) 8.5 Hz, 2H), 6.87 (d, J ) 8.5 Hz, 2H), 6.63
(d, J ) 8.5 Hz, 2H), 6.54 (t, J ) 6.1 Hz, 1H), 5.72 (s, 2H), 5.27
(bs, 2H), 4.50 (d, J ) 6.1 Hz, 2H), 2.11 (q, J ) 7.5 Hz, 2H), 0.94
(t, J ) 7.5 Hz, 3H). MS (ESI) m/z ) 452 [M + H]+, 450 [M -
H]-. Anal. (C20H20F3N5O2S‚0.1CF3CO2H) C, H, N.
5-{4-[(2-Chloro-pyridin-4-ylmethyl)-amino]-phenyl}-6-ethyl-
pyrimidine-2,4-diamine (7i). Title compound 7i was synthesized
by the general procedure described for 7a substituting 2-chloro-