4058 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 16
Hunt et al.
layer was separated and extracted twice with methylene
chloride. The combined organic layers were washed with sat
NaHCO3 until neutral, and dried, and the solvent was removed
to yield a dark oily solid which was purified by flash chroma-
tography (10% EtOAc:hexane) to afford 3.6 g (89%) of a 4:1
mixture of 2-formyl-3-methylpyrrole and 2-formyl-4-meth-
ylpyrrole (isomers of 4, R1 ) Me) as a pale yellow solid. The
isomeric mixture was aminated as previously described to form
a 2:1 mixture of 1-amino-2-cyano-3-methylpyrrole and 1-amino-
2-cyano-4-methylpyrrole (isomers of 5, R1 ) Me) in 50% yield.13
The mixture of nitriles was hydrolyzed as described to form
1-amino-2-aminocarbonyl-4-methyl-pyrrole (6, R1 ) 4-Me) as
well as unreacted 1-amino-2-cyano-3-methylpyrrole, which
were separated by flash chromatography (10% EtOAc:hexane).
The conversion of 1-amino-2-cyano-3-methylpyrrole to 1-amino-
2-aminocarbonyl-3-methyl-pyrrole (6, R1 ) 3-Me) was ac-
complished by performing the hydrolysis in aqueous ethanol
at reflux for 2 h. Conversion of 1-amino-2-aminocarbonyl-4-
methyl-pyrrole to 6-methyl-pyrrolo[2,1-f][1,2,4]triazin-4(3H)-
one (8, R1 ) 6-Me) in 71% overall yield was performed as
described.13 A mixture of 23 mg (0.15 mmol) of 6-methyl-
pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one and 0.1 g of phosphorus
oxybromide was heated at 60 °C for 20 min under argon. A
melt was initially obtained which solidified on continued
heating. Ice was added to the solid with vigorous stirring. The
mixture was extracted twice with ethyl acetate. The combined
extracts were washed with sat NaHCO3 and brine and dried,
and the solvent was removed to afford 25 mg of crude 4-bromo-
6-methyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid. A solu-
tion of this material and 20 mg (0.165 mmol) of 3-hydroxy-4-
methylaniline in 0.5 mL of acetonitrile was stirred overnight
at room temperature under argon. The mixture was evapo-
rated to dryness, and the residue was diluted with EtOAc.
Sufficient sat NaHCO3 was added to generate the free base.
The organic layer was separated and washed with brine and
dried and the solvent removed. The residual solid was sub-
jected to flash chromatography (25% EtOAc:hexanes) to yield
11 mg (0.04 mmol, 29%) of 15 as a tan solid. 1H NMR (400
MHz, DMSO-d6) δ 9.56 (s, 1H), 9.38 (s, 1H), 7.91 (s, 1H), 7.55
(s, 1H), 7.39 (d, 1H, J ) 1.3 Hz), 7.12 (dd, 1H, J ) 1.8, 8.1
Hz), 7.02 (d, 1H, J ) 8.1 Hz), 6.97 (s, 1H), 2.26 (s, 3H), 2.10 (s,
3H). HRMS for C14H13N4O (M - H), Calcd: 253.1090, Found:
253.1094.
134.6, 128.4, 124.1, 121.6 (d, J ) 5.1 Hz), 121.1 (d, J ) 17.8
Hz), 116.5 (d, J ) 20.4 Hz), 113.6, 110.8, 99.4, 10.8. HRMS
for C13H11N4FCl (M + H), Calcd: 277.0659, Found: 277.0657.
2-Meth yl-5-(pyr r olo[2,1-f][1,2,4]tr iazin -4-ylam in o)ph en -
1
ol (13). H NMR (400 MHz, CD3OD) δ 7.83 (s, 1H), 7.57 (dd,
1H, J ) 1.6, 2.3 Hz), 7.31 (d, 1H, J ) 1.6 Hz), 7.06 (d, 1H, J
) 8.06 Hz), 6.96 (m, 2H), 6.69 (dd, 1H, J ) 2.6, 4.3 Hz), 2.18
(s, 3H). 13C NMR (125 MHz, CD3OD) δ 156.8, 154.2, 148.1,
138.1, 131.6, 122.7, 119.9, 116.1, 115.1, 111.9, 110.9, 102.5,
15.8. HRMS for C13H12N4O, Calcd: 240.1011, Found: 240.1014.
2-Meth yl-5-[(5-m eth ylp yr r olo[2,1-f][1,2,4]tr ia zin -4-yl)-
a m in o]p h en ol (14). 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s,
1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.61 (d, 1H, J ) 2.5 Hz), 7.24
(d, 1H, J ) 2.0 Hz), 7.02 (d, 1H, J ) 8.1 Hz), 6.96 (dd, 1H, J
) 2.0, 8.1 Hz), 6.63 (d, 1H, J ) 2.4 Hz), 2.60 (s, 3H), 2.10 (s,
3H). HRMS for C14H13N4O (M - H), Calcd: 253.1090, Found:
253.1084.
2-Meth yl-5-[(7-m eth ylp yr r olo[2,1-f][1,2,4]tr ia zin -4-yl)-
a m in o]p h en ol (16). 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s,
1H), 9.36 (s, 1H), 8.00 (s, 1H), 7.43 (d, 1H, J ) 1.9 Hz), 7.12
(dd, 1H, J ) 1.9, 8.1 Hz), 7.10 (d, 1H, J ) 4.3 Hz), 7.02 (d, 1H,
J ) 8.1 Hz), 6.53 (d, 1H, J ) 4.3 Hz), 2.44 (s, 3H), 2.10 (s,
3H). HRMS for C14H13N4O (M - H), Calcd: 253.1090, Found:
253.1094.
5-[(5,6-Dim eth ylpyr r olo[2,1-f][1,2,4]tr iazin -4-yl)am in o]-
1
2-m eth ylp h en ol (17). H NMR (CDCl3, 400 MHz) δ 7.74 (s,
1H), 7.34 (s, 1H), 7.06 (d, 1 H, J ) 8 Hz), 6.96 (d, 1H, J ) 2
Hz), 6.65 (dd, 1H, J ) 2, 8 Hz), 2.48 (s, 3H), 2.17 (s, 3H), 2.05
(s,3H).HRMS for C15H16N4O,Calcd: 268.1324,Found: 268.1330.
Ack n ow led gm en t. This manuscript is dedicated to
the memory of Toomas (Tom) Mitt, whose exceptional
experimental skills allowed the discovery of this novel
kinase inhibitor template. We also thank the Depart-
ment of Discovery Analytical Sciences for the mass
spectral data, and Veeraswamy Manne for technical
assistance.
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4-(2-Ch lor o-4-flu or op h en yla m in o)-p yr r olo[2,1-f][1,2,4]-
1
tr ia zin e (9). H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.91
(dd, 1H, J ) 2.8, 6.6 Hz), 7.65 (s, 1H), 7.50 (ddd, 1H, J ) 3.3,
7.1, 9.3 Hz), 7.16 (t, 1H, J ) 8.8 Hz), 6.92 (br s, 1H), 6.73 (dd,
1H, J ) 2.8, 4.4 Hz), 6.61 (d, 1H, J ) 4.4 Hz). 13C NMR (125
MHz, acetone-d6) δ 154.2 (d, J ) 244.2 Hz), 152.2, 146.6, 136.3,
123.2, 121.5 (d, J ) 7.6 Hz), 119.9 (d, J ) 20.4 Hz), 119.4,
116.6 (d, J ) 22.9 Hz), 114.5, 111.2, 101.0. HRMS for C12H9N4-
FCl (M + H), Calcd: 263.0510, Found: 263.0500.
4-(2-Ch lor o-4-flu or op h en yla m in o)-5-m et h yl-p yr r olo-
[2,1-f][1,2,4]tr ia zin e (10). 1H NMR (125 MHz, CDCl3/CD3-
OD) δ 7.70 (s, 2H), 7.42 (s, 1H), 7.36-7.34 (m, 1H), 7.29-7.06
(m, 1H), 6.43 (s, 1H), 2.53 (s, 3H). 13C NMR (125 MHz, CDCl3/
CD3OD) δ 156.3, 154.3, 152.8, 145.0, 133.6, 125.0, 122.6, 121.0,
118.6, 116.6, 116.4, 113.6, 113.3, 111.3, 13.3. HRMS for
C
13H11N4FCl (M + H), Calcd: 276.0578, Found: 276.0599.
4-(2-Ch lor o-4-flu or op h en yla m in o)-6-m et h yl-p yr r olo-
[2,1-f][1,2,4]tr ia zin e (11). 1H NMR (400 MHz, CDCl3) δ 8.00
(s, 1H), 7.91 (dd, 1H, J ) 2.8, 6.6 Hz), 7.50 (m, 2H), 7.16 (t,
1H, J ) 8.8 Hz), 6.76 (br s, 2H), 6.42 (s, 1H), 2.33 (s, 3H). 13C
NMR (125 MHz, acetone-d6) δ 154.4 (d, J ) 244.2 Hz), 151.4,
145.9, 136.4, 123.0, 122.4, 121.3 (d, J ) 7.6 Hz), 119.8 (d, J )
20.4 Hz), 118.4, 116.5 (d, J ) 22.9 Hz), 114.4, 101.3, 11.5.
HRMS for C13H11N4FCl (M + H), Calcd: 277.0656, Found:
277.0657.
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Structure-Activity Relationships for 4-[(Phenylmethyl)amino]-
4-(2-Ch lor o-4-flu or op h en yla m in o)-7-m et h yl-p yr r olo-
[2,1-f][1,2,4]tr ia zin e (12). 1H NMR (400 MHz, CDCl3) δ 8.10
(s, 1H), 7.93 (dd, 1H, J ) 2.5, 6.1 Hz), 7.50 (ddd, 1H, J ) 3.1,
4.0, 7.1 Hz), 7.16 (t, 1H, J ) 8.7 Hz), 6.84 (br s, 1H), 6.58 (d,
1H, J ) 4.6 Hz), 6.53 (d, 1H, J ) 4.1 Hz), 2.55 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 154.9 (d, J ) 246.7 Hz), 151.9, 146.4,