Pyrazol-4-ylurea
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 2 387
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1-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimida-
zol-2-yl)-1H-pyrazol-4-yl]urea (16). A mixture of aminopyrazole
23 (10.96 g, 36.8 mmol) and CDI (11.7 g, 72.2 mmol) in THF
(200 mL) was heated at reflux for ∼16 h. The mixture was allowed
to cool, and the resulting precipitate was collected by filtration,
washed with THF, and dried in vacuo. The material was combined
with cyclopropylamine (17 mL) and DMF (50 mL) and then the
mixture heated at 100 °C for 16 h. The mixture was then allowed
to cool and concentrated in vacuo. The residue was purified by
SiO2 column chromatography, eluting with 2-20% MeOH in
EtOAc, to give a 16 as a pale-yellow solid (8.19 g, 87%). 1H NMR
(400 MHz, Me-d3-OD): 8.07 (s, 1H), 7.58 (s, 2H), 7.26 (d, J ) 8
Hz, 1H), 3.74-3.69 (m, 4H), 3.67 (s, 2H), 2.74-2.69 (m, 1H),
2.55-2.50 (m, 4H), 1.02-0.93 (m, 2H), 0.72-0.65 (m, 2H). LC/
MS: tR ) 1.08 min, m/z ) 382 [M + H]+.
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1-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimida-
zol-2-yl)-1H-pyrazol-4-yl]urea (16), Hydrochloride Salt. Com-
pound 16 (2.05 g, 5.37 mmol) was dissolved in MeOH/EtOAc (1:
10, 100 mL) and treated with 4 N HCl in dioxane (1.48 mL, 5.91
mmol). The resulting precipitate was collected by filtration and dried
1
to give 16 as the monohydrochloride salt (1.5 g, 67%). H NMR
(400 MHz, DMSO-d6): 13.26-13.07 (m, 2H), 11.05-10.80 (m,
1H), 9.64 (s, 1H), 8.08 (s, 1H), 7.98-7.19 (4H, m), 4.44 (s, 2H),
3.94 (d, J ) 12.4 Hz, 2H), 3.77 (t, J ) 12.3 Hz, 2H), 3.28-3.20
(m, 2H), 3.17-3.05 (m, 2H), 2.65-2.57 (m, 1H), 0.96-0.79 (m,
2H), 0.63-0.51 (m, 2H).
Acknowledgment. The authors thank Neil Thompson,
Chris Murray, Jeff Yon, Michelle Jones, Nicola Wallis, and
Miles Congreve for advice and useful discussion. We also
acknowledge Harren Jhoti and Robin Carr for their support
throughout this work. We are also grateful to Douglas Ross
for the measurement of plasma protein binding, Cesare
Granata for both analytical and preparative HPLC support,
Hayley Angove, Caroline Richardson, and Lisa Seavers for
biology support, Margaret Walker, Nick Davies, and Gary
Trewartha for synthetic chemistry support, and Martyn
Frederickson for proofreading.
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Supporting Information Available: Detailed descriptions of
HPLC methods; HPLC purity analysis of final compounds; synthetic
procedures and spectral data for compounds 9 and 11-15;
experimental details for other biological assays and DMPK studies.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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