Triazolopyrimidine-Based Inhibitor
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1871
Biphenyl-4-yl(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-
yl)amine (26). Mp 114 °C. 1H NMR (300 MHz, DMSO-d6): δ 10.31
(brs, NH, exchangeable), 8.52 (s, 1H), 7.78-7.69 (m, 4H),
7.56-7.37 (m, 4H), 7.21 (m, 1H), 6.49 (s, 1H), 2.43 (s, 3H). MS
m/z 302.1 [M + H]+.
(4-Benzylphenyl)(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-
yl)amine (27). Mp 190 °C. 1H NMR (300 MHz, DMSO-d6): δ 10.11
(brs, NH, exchangeable), 8.48 (s, 1H), 7.35-7.21 (m, 9H), 6.34
(s, 1H), 3.97 (s, 2H), 2.40 (s, 3H). MS m/z 316.2 [M + H]+.
(2,3-Difluorophenyl)(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-
yl)amine (28). Mp 231 °C. 1H NMR (300 MHz, DMSO-d6): δ 8.76
(s, 1H), 7.57-7.48 (m, 1H), 7.41-7.33 (m, 2H), 6.33 (s, 1H), 2.46
(s, 3H). MS m/z 262.1 [M + H]+.
(2,5-Difluorophenyl)(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-
yl)amine (29). Mp 227 °C. 1H NMR (300 MHz, DMSO-d6): δ 10.21
(brs, NH, exchangeable), 8.53 (s, 1H), 7.54-7.44 (m, 2H),
7.35-7.28 (m, 1H), 6.12 (s, 1H), 2.43 (s, 3H). MS m/z 262.1 [M
+ H]+.
(4-Bromo-3-trifluoromethylphenyl)(5-methyl[1,2,4]triazolo[1,5-
a]pyrimidin-7-yl)amine (42). Mp 243 °C. H NMR (300 MHz,
DMSO-d6): δ 10.41 (brs, NH, exchangeable), 8.52 (s, 1H), 7.92
(s, 1H), 7.68 (m, 2H), 6.61 (s, 1H), 2.40 (s, 3H). MS m/z 373.9 [M
+ H]+.
1
(5-Methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)(4-methyl-3-trifluo-
romethylphenyl)amine (43). Mp 200 °C. 1H NMR (300 MHz,
DMSO-d6): δ 10.28 (brs, NH, exchangeable), 8.50 (s, 1H), 7.74
(s, 1H), 7.68 (d, J ) 8.1 Hz, 1H), 7.55 (d, J ) 8.4 Hz, 1H), 6.41
(s, 1H), 2.47 (s, 3H), 2.43 (s, 3H). MS m/z 308.2 [M + H]+.
(3,4-Dimethylphenyl)(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-
yl)amine (44). Mp 224 °C. 1H NMR (300 MHz, DMSO-d6): δ 10.01
(brs, NH, exchangeable), 8.44 (s, 1H), 7.46-7.06 (m, 3H), 6.20
(s, 1H), 2.37 (s, 3H), 2.23 (s, 6H). MS m/z 254.2 [M + H]+.
4-(5-Methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamino)-2-trifluo-
romethylbenzonitrile (45). Mp 264 °C. 1H NMR (300 MHz,
DMSO-d6): δ 8.55 (s, 1H), 8.20 (m, 1H), 8.05 (s, 1H), 7.95 (m,
1H), 6.90 (s, 1H), 2.48 (s, 3H). MS m/z 319.1 [M + H]+.
(3-Fluoro-4-methylphenyl)(5-methyl[1,2,4]triazolo[1,5-a]pyrimi-
din-7-yl)amine (46). Mp 251 °C. 1H NMR (300 MHz, DMSO-d6):
δ 10.20 (brs, NH, exchangeable), 8.48 (s, 1H), 7.36-7.23 (m, 3H),
6.43 (s, 1H), 2.41 (s, 3H), 2.25 (s, 3H). MS m/z 258.1 [M + H]+.
(3-Fluoro-4-trifluoromethylphenyl)(5-methyl[1,2,4]triazolo[1,5-
(2,6-Difluorophenyl)(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-
yl)amine (30). Mp 231 °C. 1H NMR (300 MHz, DMSO-d6): δ 8.76
(s, 1H), 7.62-7.53 (m, 1H), 7.39-7.34 (m, 2H), 6.17 (s, 1H), 2.45
(s, 3H). MS m/z 262 [M + H]+.
1
a]pyrimidin-7-yl)amine (47). Mp 247 °C. H NMR (300 MHz,
(5-Methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)(2,3,4-trifluorophe-
DMSO-d6): δ 10.65 (brs, NH, exchangeable), 8.56 (s, 1H),
7.85-7.78 (m, 1H), 7.68-7.60 (m, 1H), 7.55-7.45 (m, 1H), 6.88
(s, 1H), 2.50 (s, 3H). MS m/z 312.2 [M + H]+.
1
nyl)amine (31). Mp 246 °C. H NMR (300 MHz, DMSO-d6): δ
8.73 (s, 1H), 7.55-7.37 (m, 2H), 6.34 (s, 1H), 2.45 (s, 3H). MS
m/z 280.2 [M + H]+.
(5-Methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)(2,4,5-trifluorophe-
Acknowledgment. The authors thank David Floyd, Kip Guy,
David Matthews, and Carl Craft of the Medicines for Malaria
Venture (MMV) Expert Scientific Advisory Committee for
helpful discussions, and Rajan K. Paranji, Martin Sadilek, and
UW for analytical support. This work was supported by the
U.S. National Institutes of Health Grants U01AI075594 (to
M.A.P., P.K.R., and W.N.C.; Ian Bathurst (PI); Malaria
Medicines Venture), AI053680 (to M.A.P. and P.K.R.), and
AI60360 (to P.K.R.) and by a grant from Malaria Medicines
Venture (to M.A.P., P.K.R., and W.N.C.). M.A.P. also acknowl-
edges the support of the Welch Foundation (Grant I-1257), and
PKR also acknowledges support from a Senior Scholar Award
in Global Infectious Diseases from the Ellison Medical Founda-
tion and from the UW Keck Center for Microbial Pathogens.
1
nyl)amine (32). Mp 272 °C. H NMR (300 MHz, DMSO-d6): δ
8.67 (s, 1H), 7.89-7.72 (m, 2H), 6.25 (s, 1H), 2.44 (s, 3H). MS
m/z 280.1 [M + H]+.
(5-Methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)(2,4,6-trifluorophe-
1
nyl)amine (33). Mp 178 °C. H NMR (300 MHz, DMSO-d6): δ
10.02 (brs, NH, exchangeable), 8.54 (s, 1H), 7.51-7.46 (m, 2H),
6.08 (s, 1H), 2.41 (s, 3H). MS m/z 280.1 [M + H]+.
(5-Methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)(2,3,5,6-tetrafluo-
1
rophenyl)amine (34). Mp 211 °C. H NMR (300 MHz, DMSO-
d6): δ 13.25 (brs, NH, exchangeable), 8.53 (s, 1H), 8.18 (s, 1H),
5.83 (s, 1H), 2.32 (s, 3H). MS m/z 298.1 [M + H]+.
(5-Methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)(2,3,4,5,6-pentaflu-
1
orophenyl)amine (35). Mp 278 °C. H NMR (300 MHz, DMSO-
d6): δ 13.20 (brs, NH, exchangeable), 8.18 (s, 1H), 5.83 (s, 1H),
2.32 (s, 3H). MS m/z 316.2 [M + H]+.
Supporting Information Available: 1H NMR, MS, and HPLC
traces for compound 21. This material is available free of charge
(2-Fluoro-4-methylphenyl)(5-methyl[1,2,4]triazolo[1,5-a]pyrimi-
din-7-yl)amine (36). Mp 208 °C. 1H NMR (300 MHz, DMSO-d6):
δ 10.05 (brs, NH, exchangeable), 8.50 (s, 1H), 7.38-7.12 (m, 3H),
5.95 (s, 1H), 2.35 (s, 3H). MS m/z 258.1 [M + H]+.
(3,4-Difluorophenyl)(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-
yl)amine (37). Mp 265 °C. 1H NMR (300 MHz, DMSO-d6): δ 8.54
(s, 1H), 7.62-7.51 (m, 2H), 7.38-7.31 (m, 1H), 6.47 (s, 1H), 2.44
(s, 3H). MS m/z 262.1 [M + H]+.
(3,5-Difluorophenyl)(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-
yl)amine (38). Mp 256 °C. 1H NMR (300 MHz, DMSO-d6): δ 10.41
(brs, NH, exchangeable), 8.54 (s, 1H), 7.25 (m, 2H), 7.15 (m, 1H),
6.73 (s, 1H), 2.49 (s, 3H). MS m/z 262.1 [M + H]+.
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