7182 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 22
Jones et al.
pressure gave methyl 2-phenyl[1,2,4]triazolo[1,5-a]pyridine-8-
carboxylate (29) as a brown oil which was used in the next step
without further purification. H NMR (400 MHz, DMSO-d6,
300 K) δ 9.25 (1H, d, J = 6.4 Hz), 8.28 (1H, d, J = 7.2 Hz),
9.25 (2H, dd, J = 8.0 and 2.0 Hz), 7.94-7.89 (2H, m), 7.31 (2H,
d, J = 5.6 Hz), 3.97 (3H, s). MS (ES) C14H11N3O2 requires 253,
found 254 (M þ H)þ.
phenyl}-2H-indazole-7-carboxylate (33g) was prepared according
to general method E using methyl 2-(4-formylphenyl)-2H-indazole-
7-carboxylate (32) (80 mg, 0.28 mmol) and MeNH2 HCl (308 mg,
1
3
4.6 mmol) in a mixture DCE/MeOH (4:1, 5 mL), and AcOH was
used to adjust the pH to 6. The crude product was used in the next
step without further purification. MS (ES) C17H17N3O2 requires
295, found 296 (M þ H)þ. 2-{4-[(Methylamino)methyl]phenyl}-
2H-indazole-7-carboxamide was prepared according to general
method C using methyl 2-{4-[(methylamino)methyl]phenyl}-2H-
indazole-7-carboxylate (33g). The residue was purified by flash
column chromatography on silica using a gradient of 0-20%
DCM/MeOH (þ1% Et3N) to afford a yellow powder (62 mg,
78%). The free base (21 mg, 0.08 mmol) was then dissolved in a
solution of CH3CN/H2O (1:1, 0.025 M), concentrated HCl (81 μL,
0.08 mmol) was added and the solution was lyophilized, affording
43 (23 mg, quant) as a yellow powder. 1H NMR (400 MHz,
DMSO-d6, 300 K) δ 9.30 (1H, s), 9.26 (2H, br s), 8.47 (1H, br s),
8.19 (2H, d, J = 8.4 Hz), 8.00 (1H, d, J = 6.8 Hz), 7.96 (1H, d, J =
8.2 Hz), 7.81 (1H, br s), 7.71 (2H, d, J = 8.4 Hz), 7.21 (1H, app t,
J = 7.6 Hz), 4.14 (2H, s), 2.43 (3H, s). HRMS (ESI) m/z calcd for
C16H17N4O 281.1397, found 281.1403. MS (ES) C16H16N4O re-
quires 280, found 281 (M þ H)þ.
2-Phenyl[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (30).
Methyl 2-phenyl[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate
(29) (1 mmol) was converted according to method C to give
2-phenyl[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (30) (63 mg,
26% over two steps) as a white solid. 1H NMR (400 MHz, DMSO-
d6, 300 K) δ 9.20 (1H, d, J = 6.0 Hz), 8.96 (1H, br s), 8.33-8.28
(3H, m), 8.21 (1H, br s), 7.60-7.55 (3H, m), 7.38 (1H, t, J =
7.2 Hz). HRMS (ESI) m/z calcd for C13H11N4O 239.0927, found
239.0928. MS (ES) C13H10N4O requires 238, found 239 (M þ H)þ.
Methyl 2-(4-Formylphenyl)-2H-indazole-7-carboxylate (32).
32 was prepared according to general method D using methyl
2H-indazole-7-carboxylate (31) (0.3 g, 1.7 mmol) and 4-fluor-
obenzaldehyde (235 μL, 2.2 mmol) to give, after purification by
flash column chromatography on silica using a gradient of
30-40% EtOAc/petroleum ether, methyl 2-(4-formylphenyl)-
2H-indazole-7-carboxylate (32) (185 mg, 39%). 1H NMR (400
MHz, CDCl3, 300 K) δ 10.08 (1H, s), 8.64 (1H, s), 8.20 (2H, d,
J = 8.6 Hz), 8.16 (1H, d, J = 7.2 Hz), 8.05 (2H, d, J = 8.6 Hz),
7.96 (1H, d, J = 7.2 Hz), 7.21 (1H, t, J = 7.2 Hz), 4.06 (3H, s).
1-{4-[7-(Aminocarbonyl)-2H-indazol-2-yl]phenyl}-N-methyl-
ethanaminium Chloride (48). 48 was prepared according to
general method E using 2-(4-acetylphenyl)-2H-indazole-7-car-
boxamide (36) (0.1 g, 0.36 mmol) which, after purification by
IST ISOLUTE SPE column SCX, gave 2-{4-[1-(methyl-
amino)ethyl]phenyl}-2H-indazole-7-carboxamide (78 mg, 74%).
The free base (78 mg, 0.26 mmol) was then dissolved in a
solution of CH3CN/H2O (1:1) and 37% HCl(aq) (0.26 mmol)
and the solution was lyophilized, affording 1-{4-[7-(amino-
carbonyl)-2H-indazol-2-yl]phenyl}-N-methylethanaminium
chloride (48) as a yellow powder. 1H NMR (400 MHz,
DMSO-d6, 300 K) δ 9.79 (1H, br s), 9.43-9.38 (1H, m),
9.38-9.35 (1H, m), 8.55 (1H, s), 8.26 (1H, d, J = 8.4 Hz), 8.07
(1H, d, J = 6.8 Hz), 8.03 (2H, d, J = 8.2 Hz), 7.88 (1H, br s), 7.81
(2H, d, J = 8.2 Hz), 7.28 (1H, app. t, J = 7 Hz), 4.44-4.40 (1H,
m), 2.42 (3H, s), 1.62 (3H, d, J = 6.8 Hz). HRMS (ESI) m/z calcd
for C17H19N4O 295.1553, found 295.1556. MS (ESþ) C17H18N4O
requires 294, found 295 (M þ H)þ.
MS (ES) C16H12N2O3 requires 280, found 281 (M þ H) þ
.
2-(4-Formylphenyl)-2H-indazole-7-carboxamide (35). 35 was
prepared according to general method D using 2H-indazole-7-
carboxamide (34) (0.8 g, 5.0 mmol) and 4-fluorobenzaldehyde
(685 μL, 6.4 mmol) to yield, after purification by flash column
chromatography on silica with 10% MeOH/DCM, 2-(4-for-
mylphenyl)-2H-indazole-7-carboxamide (35) (0.59 g, 45%). 1H
NMR (400 MHz, DMSO-d6, 300 K) δ 10.10 (1H, s), 9.50 (1H, s),
8.52 (1H, br s), 8.45 (2H, d, J = 8.6 Hz), 8.15 (2H, d, J = 8.6 Hz),
8.08 (1H, d, J = 7.2 Hz), 8.04 (1H, d, J = 7.2 Hz), 7.92 (1H, br s),
7.30 (1H, t, J = 7.2 Hz). MS (ES) C15H11N3O2 requires 265,
found 266 (M þ H)þ.
2-(4-Acetylphenyl)-2H-indazole-7-carboxamide (36). 36 was
prepared following general method D using 2H-indazole-7-
carboxamide (34) (322 mg, 2 mmol) and 1-(4-fluorophe-
nyl)ethanone (0.19 mL, 2 mmol). The product (36) (540 mg,
97%) was obtained as a white solid by precipitation from the
reaction mixture by adding MeOH/EtOAc (5:1) and was used in
the next step without further purification. 1H NMR (400 MHz,
DMSO-d6, 300 K) δ 9.48 (1H, s), 8.53 (1H, br s), 8.36 (2H, d, J =
8.8 Hz), 8.20 (2H, d, J = 8.8 Hz), 8.09 (1H, dd, J = 7.0 and 0.8
Hz), 8.05 (1H, dd, J = 8.4 and 0.8 Hz), 7.92 (1H, br s), 7.30 (1H,
dd, J = 8.4 and 7.0 Hz), 2.66 (3H, s). MS (ESþ) C16H13N3O2
requires 279, found 280 (M þ H)þ.
2-[4-(1-Hydroxy-1-methylethyl)phenyl]-2H-indazole-7-carbox-
amide (49). To a solution of 2-(4-acetylphenyl)-2H-indazole-
7-carboxamide (36) (2.0 g, 7.2 mmol) in THF (150 mL) at 0 °C,
MeMgBr (3 M in THF, 3.6 mL, 10.7 mmol) was added dropwise.
The mixture was stirred overnight at room temperature, then
quenched with H2O and extracted with EtOAc. The combined
organic phase was dried over MgSO4. Evaporation of the solvent
under reduced pressure gave 2-[4-(1-hydroxy-1-methylethyl)-
phenyl]-2H-indazole-7-carboxamide (49) (1.6 g, 76%) as a yellow
solid. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 9.27 (1H, s), 8.57
(1H, br s), 8.07-8.00 (4H, m), 7.87 (1H, br s), 7.68 (2H, d, J =
8.6 Hz), 7.28-7.24 (1H, m), 1.48 (6H, s). MS (ESþ) C17H17N3O2
requires 295, found 296 (M þ H)þ.
2-{4-[(Dimethylamino)methyl]phenyl}-2H-indazole-7-carbox-
amide (37). 37 was prepared according to general method E, with
methyl 2-(4-formylphenyl)-2H-indazole-7-carboxylate (32)
(50 mg, 0.18 mmol) and 2.0 M Me2NH in MeOH (0.71 mL,
1.4 mmol) to give methyl 2-{4-[(dimethylamino)methyl]-
phenyl}-2H-indazole-7-carboxylate (33a) which was used in
the next step without further purification. MS (ES) C18H19-
N3O2 requires 309, found 310 (M þ H)þ. Methyl 2-{4-[-
(dimethylamino)methyl]phenyl}-2H-indazole-7-carboxylate (33a)
(55 mg, 0.18 mmol) was treated according to general method C to
give, after purification by flash column chromatography on silica
with 10% MeOH/DCM, 2-{4-[(dimethylamino)methyl]phenyl}-
2H-indazole-7-carboxamide (37) (40 mg, 76%). 1H NMR
(300 MHz, CD3CN, 300 K) δ 8.85 (1H, s), 8.78 (1H, br s), 8.17
(1H, d, J = 8.0 Hz), 8.05-8.00 (3H, m), 7.56 (2H, d, J = 8.4 Hz),
7.28 (1H, t, J = 8.0 Hz), 6.36 (1H, br s), 3.56 (2H, s), 2.28 (6H, s).
HRMS (ESI) m/z calcd for C17H19N4O 295.1553, found 295.1554.
MS (ES) C17H18N4O requires 294, found 295 (M þ H)þ.
2-{4-[7-(Aminocarbonyl)-2H-indazol-2-yl]phenyl}-N-methylpro-
pan-2-aminium Trifluoroacetate (50). In a well ventilated fume
hood, to a solution of 2-[4-(1-hydroxy-1-methylethyl)phenyl]-
2H-indazole-7-carboxamide (49) (0.5 g, 1.7 mmol) and NaCN
(0.41 g, 8.5 mmol) in DCM (10 mL) was added concentrated
H2SO4 (0.45 mL, 8.5 mmol), and the mixture was stirred for 24 h
at room temperature. The reaction mixture was quenched by
addition of saturated aqueous NaHCO3 solution, and the
mixture was extracted with EtOAc. The combined organic
phase was dried (MgSO4) and evaporation of the solvent under
reduced pressure gave a residue that was purified by flash
chromatography column using 0-10% MeOH/DCM to
afford 2-{4-[1-(formylamino)-1-methylethyl]phenyl}-2H-inda-
zole-7-carboxamide (120 mg, 22%) as a yellow solid. 1H
NMR (600 MHz, DMSO-d6, 300 K) δ 9.27 (1H, s), 8.57 (1H,
br s), 8.43 (1H, br s), 8.07-8.01 (4H, m), 7.99 (1H, d, J =
1.6 Hz), 7.88 (1H, br s), 7.57 (2H, d, J = 8.6 Hz), 7.26 (1H, dd,
{4-[7-(Aminocarbonyl)-2H-indazol-2-yl]phenyl}-N-methylmetha-
naminium Chloride (43). Methyl 2-{4-[(methylamino)methyl]-