NoVel Tyrosine Kinase ActiVity Inhibitor ABT-869
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 7 1593
Method B: A mixture of 8 (60 mg, 0.24 mmol), urea boronate
(0.29 mmol), Na2CO3 (64 mg, 0.60 mmol), and Pd(dppf)Cl2‚CH2-
Cl2 (10 mg, 0.012 mmol) in DME (3 mL) and water (1 mL) in a
microwave vial was degassed by bubbling through nitrogen for 1-2
min. The reaction vial was then capped and heated at 140-160 °C
under stirring for 15-20 min in a Smith Synthesizer microwave
oven (300 W). The reaction mixture was worked up and purified
as in Method A.
N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-phenylurea (17a).
1H NMR (DMSO-d6) δ 4.33 (s, 2H), 6.78 (dd, J ) 5.42, 2.37 Hz,
1H), 6.98 (t, J ) 7.29 Hz, 1H), 7.28 (m, 4H), 7.39 (d, J ) 8.81
Hz, 2H), 7.48 (d, J ) 7.46 Hz, 2H), 7.59 (d, J ) 8.82 Hz, 2H),
8.72 (s, 1H), 8.81 (s, 1H), 11.70 (s, 1H); MS (ESI) m/z 344 (M +
H)+. Anal. (C20H17N5O‚0.5EtOAc) C, H, N.
1H), 8.75 (s, 1H), 11.69 (s, 1H); MS (ESI) m/z 358 (M + H)+.
Anal. (C21H19N5O‚0.4H2O) C, H, N.
N-(4-(3-Amino-1H-indazol-4-yl)phenyl)-N′-(3-ethylphenyl)-
1
urea (17k). H NMR (DMSO-d6) δ 1.19 (t, J ) 7.63 Hz, 3H),
2.58 (q, J ) 7.68 Hz, 2H), 6.80-6.89 (m, 2H), 7.19 (t, J ) 7.80
Hz, 1H), 7.25-7.45 (m, 6H), 7.60 (d, J ) 8.81 Hz, 2H), 8.70 (s,
1H), 8.85 (s, 1H); MS (ESI) m/z 372 (M + H)+. Anal.
(C22H21N5O‚0.8CF3CO2H‚0.2H2O) C, H, N.
N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)-
1
urea (17l). H NMR (DMSO-d6) δ 6.89 (dd, J ) 6.44, 1.70 Hz,
1H), 7.03 (m, 1H), 7.28-7.38 (m, 4H), 7.42 (d, J ) 8.81 Hz, 2H),
7.61 (d, J ) 8.82 Hz, 2H), 7.74 (m, 1H), 9.00 (s, 1H), 9.03 (s,
1H); MS (ESI) m/z 378 (M + H)+. Anal. (C20H16ClN5O‚1.0CF3-
CO2H‚0.5H2O) C, H, N.
N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)-
N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)-
1
1
urea (17m). H NMR (DMSO-d6) δ 6.87 (dd, J ) 6.10, 1.70 Hz,
urea (17b). H NMR (DMSO-d6) δ 2.29 (s, 3H), 4.33 (s, 2H),
1H), 7.13-7.18 (m, 1H), 7.25 (t, J ) 7.97 Hz, 1H), 7.31-7.26
(m, 3H), 7.42 (d, J ) 8.82 Hz, 2H), 7.61 (d, J ) 8.48 Hz, 2H),
7.88 (t, J ) 1.86 Hz, 1H), 8.99 (s, 1H); MS (ESI) m/z 420, 422 (M
- H)-. Anal. (C20H16BrN5O‚0.1C6H14‚0.1CH2Cl2) C, H, N.
N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-[3-(trifluorometh-
yl)phenyl]urea (17n). 1H NMR (DMSO-d6) δ 6.86 (dd, J ) 6.10,
2.03 Hz, 1H), 7.29-7.35 (m, 3H), 7.42 (d, J ) 8.81 Hz, 2H), 7.53
(t, J ) 7.97 Hz, 1H), 7.58-7.65 (m, 3H), 8.05 (s, 1H), 9.01 (s,
1H), 9.16 (s, 1H). MS (ESI) m/z 412 (M + H)+. Anal.
(C21H16F3N5O‚0.7CF3CO2H) C, H, N.
6.76-6.83 (m, 2H), 7.17 (t, J ) 7.80 Hz, 1H), 7.23-7.28 (m, 3H),
7.32 (s, 1H), 7.39 (d, J ) 8.48 Hz, 2H), 7.59 (d, J ) 8.48 Hz, 2H),
8.64 (s, 1H), 8.79 (s, 1H), 11.70 (s, 1H); MS (ESI) m/z 358 (M +
H)+. Anal. (C21H19N5O‚0.8H2O) C, H, N.
N-[4-(3-Amino-1H-indazol-4-yl)-phenyl]-N′-thiophen-3-yl-
1
urea (17c). H NMR (DMSO-d6) δ 4.33 (s, 2H), 6.78 (dd, J )
5.59, 2.20 Hz, 1H), 7.07 (dd, J ) 5.09, 1.36 Hz, 1H), 7.24-7.28
(m, 2H), 7.29-7.33 (m, 1H), 7.39 (d, J ) 8.48 Hz, 2H), 7.45 (dd,
J ) 5.09, 3.39 Hz, 1H), 7.59 (d, J ) 8.48 Hz, 2H), 8.78 (s, 1H),
8.99 (s, 1H), 11.70 (s, 1H); MS (ESI) m/z 350 (M + H)+. Anal.
(C18H15N5OS‚0.1C6H14•0.3H2O) C, H, N.
N-(4-(3-Amino-1H-indazol-4-yl)phenyl)-N′-(3-hydroxypheny-
1
l)urea (17o). H NMR (DMSO-d6) δ 5.33 (s, 2H), 6.38 (dd, J )
N-[4-(3-Amino-1H-indazol-4-yl)-phenyl]-N′-cyclopentylurea
(17d). 1H NMR (DMSO-d6) δ 1.31-1.45 (m, 2 H), 1.47-1.71 (m,
4H), 1.77-1.93 (m, 2H), 3.89-4.00 (m, 1H), 4.31 (s, 2H), 6.21
(d, J ) 7.12 Hz, 1H), 6.75 (dd, J ) 5.59, 2.20 Hz, 1H), 7.22-7.27
(m, 2H), 7.32 (d, J ) 8.48 Hz, 2H), 7.50 (d, J ) 8.48 Hz, 2H),
8.39 (s, 1H), 11.68 (s, 1H); MS (ESI) m/z 336 (M + H)+.
N-[4-(3-Amino-1H-indazol-4-yl)-phenyl]-N′-cyclohexylurea
(17e). 1H NMR (DMSO-d6) δ 1.09-1.41 (m, 5H), 1.48-1.60 (m,
1H), 1.60-1.73 (m, 2H), 1.77-1.89 (m, 2H), 3.42-3.56 (m, 1H),
4.30 (s, 2H), 6.12 (d, J ) 7.80 Hz, 1H), 6.75 (dd, J ) 5.59, 2.20
Hz, 1H), 7.19-7.26 (m, 2H), 7.32 (d, J ) 8.82 Hz, 2H), 7.50 (d,
J ) 8.82 Hz, 2H), 8.43 (s, 1H), 11.67 (s, 1H); MS (ESI) m/z 350
(M + H)+. Anal. (C20H23N5O‚0.2H2O‚0.3EtOAc) C, H, N.
N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluorophenyl)-
7.63, 1.86 Hz, 1H), 6.76-6.92 (m, 2H), 6.99-7.14 (m, 2 H), 7.26-
7.45 (m, 4 H), 7.59 (d, J ) 8.81 Hz, 2H), 8.65 (s, 1H), 8.80 (s,
1H), 9.31 (s, 1H), 12.11 (s, 1H); MS (ESI) m/z 360 (M + H). Anal.
(C20H17N5O2‚0.85CF3CO3H) C, H, N.
N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-meth-
ylphenyl)urea (17p). 1H NMR (DMSO-d6) δ 2.28 (s, 3H), 6.78-
6.85 (m, 1H), 6.87 (dd, J ) 6.10, 1.70 Hz, 1H), 7.12 (dd, J )
11.53, 8.48 Hz, 1H), 7.30-7.39 (m, 2H), 7.42 (d, J ) 8.81 Hz,
2H), 7.60 (d, J ) 8.48 Hz, 2H), 8.01 (dd, J ) 7.80, 2.37 Hz, 1H),
8.54 (d, J ) 2.71 Hz, 1H), 9.23 (s, 1H); MS (ESI) m/z 376 (M +
H)+. Anal. (C21H18FN5O‚0.8CF3CO2H) C, H, N.
N-(4-(3-Amino-1H-indazol-4-yl)phenyl)-N′-(4-fluoro-3-meth-
1
ylphenyl)urea (17q). H NMR (DMSO-d6) δ 2.22 (d, J ) 1.70
Hz, 3H), 6.84 (dd, J ) 6.10, 1.70 Hz, 1H), 7.06 (t, J ) 9.16 Hz,
1H), 7.24-7.45 (m, 6 H), 7.59 (d, J ) 8.48 Hz, 2H), 8.69 (s, 1H),
8.84 (s, 1H); MS (ESI) m/z 376 (M + H)+. Anal. (C21H18-
FN5O‚0.8CF3CO3H) C, H, N.
1
urea (17f). H NMR (DMSO-d6) δ 4.33 (s, 2H), 6.79 (dd, J )
5.42, 2.71 Hz, 1H), 6.97-7.06 (m, 1H), 7.16 (t, J ) 7.63 Hz, 1H),
7.22-7.30 (m, 3H), 7.41 (d, J ) 8.48 Hz, 2H), 7.60 (d, J ) 8.48
Hz, 2H), 8.18 (m, 1H), 8.61 (d, J ) 2.37 Hz, 1H), 9.22 (s, 1H),
11.71 (s, 1H); MS (ESI) m/z 362 (M + H)+. Anal. (C20H16-
FN5O‚0.7CH2Cl2‚0.1EtOAc) C, H, N.
N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(3-fluoro-4-meth-
ylphenyl)urea (17r). 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 4.33 (s,
2H), 6.78 (dd, J ) 5.42, 2.71 Hz, 1H), 7.05 (dd, J ) 8.14, 2.03
Hz, 1H), 7.17 (t, J ) 8.65 Hz, 1H), 7.23-7.30 (m, 2H), 7.39 (d, J
) 8.48 Hz, 2H), 7.45 (dd, J ) 12.54, 2.03 Hz, 1H), 7.58 (d, J )
8.81 Hz, 2H), 8.84 (s, 2H), 11.70 (s, 1H); MS (ESI) m/z 376 (M +
H)+. Anal. (C21H18FN5O‚0.6CF3CO3H) C, H, N.
N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(3-fluorophenyl)-
1
urea (17g). H NMR (DMSO-d6) δ 4.33 (s, 2H), 6.75-6.83 (m,
2H), 7.15 (m, 1H), 7.23-7.36 (m, 3H), 7.40 (d, J ) 8.48 Hz, 2H),
7.52 (m, 1H), 7.59 (d, J ) 8.48 Hz, 2H), 8.89 (s, 1H), 8.97 (s,
1H), 11.71 (s, 1H); MS (ESI) m/z 362 (M + H)+. Anal. (C20H16-
FN5O‚0.2C6H14‚0.2EtOAc) C, H, N.
N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(trif-
1
luoromethyl)phenyl]urea (17s). H NMR (DMSO-d6) δ 4.33 (s,
N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(4-fluorophenyl)-
2H), 6.79 (dd, J ) 5.26, 2.54 Hz, 1H), 7.24-7.31 (m, 2H), 7.42
(m, 3H), 7.52 (m, 1H), 7.61 (d, J ) 8.48 Hz, 2H), 8.65 (dd, J )
7.29, 2.20 Hz, 1H), 8.96 (d, J ) 3.05 Hz, 1H), 9.32 (s, 1H), 11.72
(s, 1H); MS (ESI) m/z 430 (M + H)+.
1
urea (17h). H NMR (DMSO-d6) δ 4.33 (s, 2H), 6.78 (dd, J )
5.43, 2.37 Hz, 1H), 7.13 (t, J ) 8.99 Hz, 2H), 7.22-7.29 (m, 2H),
7.39 (d, J ) 8.48 Hz, 2H), 7.49 (m, 2H), 7.59 (d, J ) 8.82 Hz,
2H), 8.80 (d, J ) 15.60 Hz, 2H), 11.70 (s, 1H); MS (ESI) m/z 362
(M + H)+. Anal. (C20H16FN5O‚0.7H2O) C, H, N.
4-Iodo-1-methyl-1H-indazol-3-amine (20a). A mixture of
2-fluoro-6-iodobenzonitrile (7; 2.6 g, 10.5 mmol) and methyl
hydrazine (5.7 mL, 105 mmol) in n-butanol (60 mL) was stirred at
100-110 °C for 3 h and then cooled to room temperature and
concentrated. The residue was partitioned between water and ethyl
acetate. The aqueous layer was extracted twice with ethyl acetate.
The combined extracts were washed with water and brine, dried
(MgSO4), filtered, and concentrated to provide the title compound
N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N′-(2-methylphenyl)-
1
urea (17i). H NMR (DMSO-d6) δ 2.21-2.33 (m, 3H), 4.33 (s,
2H), 6.78 (dd, J ) 5.76, 2.37 Hz, 1H), 6.96 (t, J ) 7.46 Hz, 1H),
7.12-7.21 (m, 2H), 7.22-7.32 (m, 2H), 7.39 (d, J ) 8.82 Hz,
2H), 7.60 (d, J ) 8.82 Hz, 2H), 7.84 (d, J ) 7.12 Hz, 1H), 7.97 (s,
1H), 9.15 (s, 1H), 11.69 (s, 1H); MS (ESI) m/z 358 (M + H)+.
Anal. (C21H19N5O‚0.6H2O) C, H, N.
1
(2.5 g, 87%). H NMR (DMSO-d6) δ 3.74 (s, 3H), 5.11 (s, 2H),
6.97 (dd, J ) 8.48, 7.46 Hz, 1H), 7.35 (d, J ) 7.46 Hz, 1H), 7.40
N-[4-(3-Amino-1H-indazol-4-yl)-phenyl]-N′-(4-methylphenyl)-
urea (17j). 1H NMR (DMSO-d6) δ 2.25 (s, 3H), 4.32 (s, 2H), 6.78
(dd, J ) 5.43, 2.37 Hz, 1H), 7.10 (d, J ) 8.14 Hz, 2H), 7.21-7.31
(m, 2H), 7.33-7.43 (m, 4H), 7.58 (d, J ) 8.82 Hz, 2H), 8.60 (s,
(d, J ) 8.48 Hz, 1H); MS (ESI) m/z 274 (M + H)+.
2-(4-Iodo-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione (18). A
mixture of 8 (1.09 g, 4.21 mmol) and phthalic anhydride (0.75 g,