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C. J. Aquino et al. / Bioorg. Med. Chem. 12 (2004) 2691–2708
filtered, and concentrated. The residue was purified by
flash chromatography on silica gel eluted with a gradient
from 0% to 3% CH3OH in EtOAc to give the desired
516.95 (Mꢂ1); Anal. Calcd for C29H29F3N6 0.79HI: C,
56.21; H, 4.85; N, 13.56. Found: C, 56.19; H, 4.98; N,
13.48.
1
product in 75% (295 mg) yield. H NMR (DMSO-d6,
5.3.3.15. N-(2-Furylmethyl)-N0-{4-methyl-6-[(2-phenyl-
ethyl)amino]-2-pyrimidinyl}-N00-[4-(trifluoromethyl)phenyl]-
guanidine (82). Desired product was obtained in 69%
300 MHz) d 8.30 (br s, 1H), 7.42–7.18 (m, 8H), 6.93–6.70
(m, 2H), 5.70 (s, 1H), 3.47–3.30 (m, 2H), 2.95 (s, 6H),
2.76 (t, 2H, J ¼ 7:1 Hz), 2.02 (s, 3H); MS (ESIþ) m=e
442.97 (MþH); Anal. Calcd for C23H25F3N6 0.30HI: C,
57.45; H, 5.30; N, 17.48. Found: C, 57.60; H, 5.41; N,
17.48.
1
(301 mg) yield as per general procedure C. H NMR
(DMSO-d6, 300 MHz) d 9.43 (br s, 1H), 7.63–7.50 (m,
4H), 7.30–6.93 (m, 8H), 6.39 (s, 1H), 6.33 (s, 1H), 5.91
(s, 1H), 4.51 (d, 2H, J ¼ 4:4 Hz), 3.35–3.25 (m, 2H),
2.80–2.70 (m, 2H), 2.07 (s, 3H); MS (ESIþ) m=e 494.89
(MþH); MS (ESIꢂ) m=e 492.88 (Mꢂ1); Anal. Calcd for
C26H25F3N6O: C, 63.15; H, 5.10; N, 16.99. Found: C,
63.21; H, 5.08; N, 16.91.
5.3.3.11. N-{4-Methyl-6-[(2-phenylethyl)amino]-2-pyri-
midinyl}-N0-[4-(trifluoromethyl)phenyl]-4-morpholine carbox-
imidamide (78). Desired product was obtained in 61%
1
(260 mg) yield as per general procedure C. H NMR
(DMSO-d6, 300 MHz) d 8.40 (br s, 1H), 7.39 (d, 2H, J ¼
8.0Hz), 7.36–7.03 (m, 5H), 6.91–6.81 (m, 2H), 5.70 (s,
1H), 3.63–3.58 (m, 4H), 3.44–3.36 (m, 4H), 3.40–3.30
(m, 2H), 2.78 (t, 2H, J ¼ 7:4 Hz), 2.01 (s, 3H); MS
(ESIþ) m=e 484.90 (MþH); MS (ESIꢂ) m=e 482.90
(Mꢂ1); Anal. Calcd for C25H27F3N6O 0.07HI: C, 60.85;
H, 5.53; N, 17.03. Found: C, 60.82; H, 5.65; N, 17.01.
5.3.3.16. N-{4-Methyl-6-[(2-phenylethyl)amino]-2-pyri-
midinyl}-N0-(4-pyridinylmethyl)-N00-[4-(trifluoromethyl)-
phenyl]guanidine (83). Desired product was obtained in
27% (60 mg) yield as per general procedure C. 1H NMR
(DMSO-d6, 300 MHz) d 9.62–9.43 (m, 1H), 8.46 (d, 2H,
J ¼ 5:8 Hz), 7.53 (d, 2H, J ¼ 7:9 Hz), 7.55–7.40 (m, 1H),
7.33 (d, 2H, J ¼ 5:5 Hz), 7.15–7.00 (m, 6H), 6.92–6.85
(m, 2H), 6.00–5.90 (m, 1H), 4.55 (d, 2H, J ¼ 5:3 Hz),
3.35–3.25 (m, 2H), 2.80–2.65 (m, 2H), 2.06 (s, 3H); MS
(ESIþ) m=e 506.02 (MþH); MS (ESIꢂ) m=e 503.96
(Mꢂ1); Anal. Calcd for C27H26F3N7: C, 64.15; H, 5.18;
N, 19.39. Found: C, 64.10; H, 5.37; N, 19.08.
5.3.3.12. N-{4-Methyl-6-[(2-phenylethyl)amino]-2-pyri-
midinyl}-N0-phenyl-N00-[4-(trifluoromethyl)phenyl]guani-
dine (79). Desired product was obtained as the HI salt in
99% (270 mg) yield as per general procedure C. 1H
NMR (DMSO-d6, 300 MHz) d 8.62 (br s, 1H), 7.63 (d,
2H, J ¼ 8:4 Hz), 7.48 (d, 2H, J ¼ 8:6 Hz), 7.40–7.23 (m,
5H), 7.21–7.08 (m, 4H), 6.98 (d, 2H, J ¼ 7:3 Hz), 5.87 (s,
1H), 3.43–3.37 (m, 2H), 2.66 (t, 2H, J ¼ 7:4 Hz), 2.14 (s,
3H); MS (ESIþ) m=e 491.24 (MþH); Anal. Calcd for
C27H25F3N6 1.0HI: C, 52.44; H, 4.24; N, 13.59. Found:
C, 52.61; H, 4.29; N, 13.54.
5.3.3.17. N-{4-Methyl-6-[(2-phenylethyl)amino]-2-pyr-
imidinyl}-N0-[2-(4-morpholinyl)ethyl]-N00-[4-(trifluoro-
methyl)phenyl]guanidine (84). Product oiled out upon
addition of water. Water was decanted off and residue
washed with water to give the desired product in 73%
1
(170 mg) yield. H NMR (DMSO-d6, 300 MHz) d 9.10
N-(4-Methoxybenzyl)-N0-{4-methyl-6-[(2-
(br s, 1H), 7.71–7.62 (m, 3H), 7.33–7.17 (m, 5H), 7.10–
6.92 (m, 2H), 5.93 (s, 1H), 3.60–3.35 (m, 8H), 2.87–2.75
(m, 2H), 2.40–2.30 (m, 2H), 2.17 (s, 3H); MS (ESIꢂ) m=e
526.00 (Mꢂ1); Anal. Calcd for C27H32F3N7O1 0.5HI: C,
54.82; H, 5.54; N, 16.57. Found: C, 54.92; H, 5.64; N,
16.48.
5.3.3.13.
phenylethyl)amino]-2-pyrimidinyl}-N00-[4-(trifluoromethyl)-
phenyl]guanidine (80). Desired product was obtained as
the HI salt in 81% (235 mg) yield as per general proce-
1
dure C. H NMR (DMSO-d6, 300 MHz, 100C) d 9.10
(br s, 1H), 7.59 (d, 2H, J ¼ 8:3 Hz), 7.31 (d, 2H,
J ¼ 8:6 Hz), 7.25–7.11 (m, 6H), 6.88 (d, 2H, J ¼ 8:7 Hz),
5.93 (s, 1H), 4.52 (s, 2H), 3.73 (s, 3H), 3.35 (m, 2H), 2.72
(t, 2H, J ¼ 7:1 Hz), 2.12 (s, 3H); MS (ESIþ) m=e 535.05
(MþH); MS (ESIꢂ) m=e 532.99 (Mꢂ1); Anal. Calcd for
C29H29F3N6O 0.43HI: C, 59.08; H, 5.03; N, 14.25.
Found: C, 59.12; H, 5.10; N, 14.39; HRMS calcd for
C29H29F3N6O (MþH) 535.2433, found 535.2424.
5.3.3.18. N-{4-Methyl-6-[(2-phenylethyl)amino]-2-pyri-
midinyl}-N0-(2,2,2-trifluoroethyl)-N00-[4-(trifluoromethyl)-
phenyl]guanidine (85). Reaction was performed in a
sealed tube with 2,2,2-trifluoroethylamine (9 equiv).
Desired product was obtained in 71% (313 mg) yield. 1H
NMR (DMSO-d6, 300 MHz) d 9.66 (t, 1H, J ¼ 5:8 Hz),
7.61 (d, 2H, J ¼ 8:3 Hz), 7.30–7.15 (m, 5H), 6.97 (d, 2H,
J ¼ 8:0 Hz), 5.96 (s, 1H), 4.21 (m, 2H), 3.42 (m, 2H),
2.78 (m, 2H), 2.11 (s, 3H); MS (ESIþ) m=e 496.85
(MþH); MS (ESIꢂ) m=e 494.87 (Mꢂ1); Anal. Calcd for
C23H22F6N6: C, 55.64; H, 4.47; N, 16.93. Found: C,
55.57; H, 4.44; N, 16.83.
5.3.3.14. N-{4-Methyl-6-[(2-phenylethyl)amino]-2-pyri-
midinyl}-N0-(2-phenylethyl)-N00-[4-(trifluoromethyl)phenyl]-
guanidine (81). The reaction mixture was concentrated,
partitioned between EtOAc/satd NaHCO3, organic
phase separated, dried over MgSO4, filtered, and con-
centrated. The residue was purified by flash chroma-
tography on silica gel eluted with EtOAc to give the
desired product in 67% (378 mg) yield. 1H NMR
(DMSO-d6, 300 MHz) d 9.08 (s, 1H), 7.58 (d, 2H,
J ¼ 8:4 Hz), 7.60–7.45 (m, 1H), 7.37–7.10 (m, 9H), 7.03–
6.90 (m, 2H), 5.90 (s, 1H), 3.63–3.52 (m, 2H), 3.35–3.25
(m, 2H), 2.97–2.83 (m, 2H), 2.83–2.70 (m, 2H), 2.02 (s,
3H); MS (ESIþ) m=e 518.99 (MþH); MS (ESIꢂ) m=e
5.3.4. General procedure D, for synthesis of compounds of
type 7 (86–88, Scheme 3). A stirring solution of 31
(1.0 equiv) in anhydrous DCM was treated with an
appropriate electrophile (1.0 equiv) and DIEA
(1.1 equiv) sequentially. The resulting solution was stir-
red at room temperature until the starting material was
consumed as judged by LCMS (2–8 h). The reaction