Butler et al.
130.8, 130.7, 126.6, 122.8, 120.7, 120.2, 120.0, 116.1, 108.4, 68.8,
21.4; ESI MS m/z 281 (M + H)+. Purity was determined to be
83% by HPLC analysis on the basis of absorption at 214 nm.
3-Chloro-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-9-carboxy-
lic Acid (7c). By using the general procedure for the synthesis of
indazolobenzoxazine carboxylic acids, the target was synthesized
yielding tan crystals (539 mg, 60%): mp 298-300 °C; IR (neat)
(d, J ) 8.8 Hz, 1H), 7.25 (d, J ) 8.8 Hz, 1H), 7.17 (d, J ) 8.4 Hz,
1H), 6.66 (t, J ) 5.6 Hz, 1H), 5.89 (m, 1H), 5.31 (s, 2H), 5.22 (d,
J ) 17.2 Hz, 1H), 5.12 (d, J ) 10.4 Hz, 1H), 4.05 (t, J ) 5.6 Hz,
2H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.1, 147.9,
143.6, 137.6, 134.5, 134.4, 131.1, 130.4, 125.4, 121.4, 119.9, 118.7,
116.9, 116.6, 116.1, 108.0, 68.6, 42.7, 21.4; ESI MS m/z 320 (M
+ H)+. Purity was determined to be 98% by HPLC analysis on the
basis of absorption at 214 nm.
ν
max 2839, 2632, 2539, 1686, 1520, 1500, 820, 745 cm-1; 1H NMR
(300 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.09 (s, 1H), 7.86 (d, J )
9.3 Hz, 1H), 7.61-7.55 (m, 3H), 7.38 (d, J ) 8.7 Hz, 1H), 5.62 (s,
2H); 13C NMR (75 MHz, DMSO-d6) δ 168.1, 147.9, 144.3, 132.3,
132.1, 131.2, 130.3, 126.3, 124.8, 120.7, 120.3, 120.2, 117.9, 108.3,
68.8; ESI MS m/z 300 (M + H)+. Purity was determined to be
93% by HPLC analysis on the basis of absorption at 214 nm.
General Procedure for the Synthesis of Indazolobenzoxazine
Carboxamides: Isopropyl-5H-indazolo[3,2-b]benzo[d]-1,3-ox-
azine-9-carboxamide (8a). Carboxylic acid 7a (100 mg, 0.3 mmol,
1 equiv), HOBt (40 mg, 0.36 mmol, 1.2 equiv), and EDC (69 mg,
0.36 mmol, 1.2 equiv) were dissolved in a 1:4 DMF/CH2Cl2 solution
(50 mL) and combined at 0 °C in a dry round-bottomed flask and
allowed to stir for 30 min. Isopropylamine was added (0.03 mL,
0.3 mmol, 1 equiv). The solution was allowed to stir under a
nitrogen atmosphere for 24 h while warming to 30 °C. The resulting
solution was concentrated and taken up in ethyl acetate (50 mL).
The solution was then extracted with sodium bicarbonate (100 mL),
1 N HCl (100 mL), water (100 mL), and brine (100 mL). The
organic layer was dried over sodium sulfate, concentrated, and
purified via flash chromatography (1:1 ethyl acetate/hexanes)
resulting in white crystals (70 mg, 76%): mp 219-220 °C; IR (neat)
N-(2-Methoxyethyl)-3-methyl-5H-indazolo[3,2-b]benzo[d]-1,3-
oxazine-9-carboxamide (9c). By using the general procedure for
the synthesis of indazolobenzoxazine carboxamides, the target was
synthesized yielding yellow crystals (64 mg, 63%): mp 187-
188 °C; IR (neat) νmax 3336, 2922, 2876, 1639, 1515, 1266, 1106,
1
749 cm-1; H NMR (600 MHz, CDCl3) δ 7.93 (s, 1H), 7.01 (d, J
) 7.8 Hz, 1H), 7.52 (d, J ) 9.0 Hz, 1H), 7.29 (d, J ) 8.4 Hz, 1H),
7.24 (d, J ) 8.4 Hz, 1H), 6.99 (s, 1H), 6.69 (s, 1H), 5.37 (s, 2H),
3.65 (m, 2H), 3.56 (m, 2H), 3.38 (s, 3H), 2.35 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 168.1, 148.0, 143.7, 137.7, 134.6, 131.2,
130.5, 125.5, 121.5, 119.9, 118.8, 116.9, 116.1, 108.0, 71.4, 68.7,
59.1, 39.9, 21.4; ESI MS m/z 338 (M + H)+. Purity was determined
to be 98% by HPLC analysis on the basis of absorption at 214 nm.
Piperidinyl-3-methyl-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-
9-carboxamide (9e). By using the general procedure for the
synthesis of indazolobenzoxazine carboxamides, the target was
synthesized yielding white crystals (59 mg, 57%): mp 188-
189 °C; IR (neat) νmax 2927, 2855, 1618, 1520, 1427, 1375, 827
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.81 (d, J ) 8.4 Hz, 1H),
7.53-7.51 (m, 2H), 7.23 (d, J ) 8.4 Hz, 1H), 6.99 (s, 1H), 6.91
(d, J ) 8.8 Hz, 1H), 5.36 (s, 2H), 3.69-3.38 (m, 4H), 2.34 (s,
3H), 1.64-1.52 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 170.6,
148.0, 143.8, 137.5, 136.2, 131.2, 130.4, 125.5, 121.4, 120.1, 119.4,
116.0, 115.7, 107.0, 68.6, 46.2, 26.4, 24.8, 21.4; ESI MS m/z 348
(M + H)+. Purity was determined to be 96% by HPLC analysis on
the basis of absorption at 214 nm.
νmax 3279, 2974, 1629, 1520, 759 cm-1 1H NMR (300 MHz,
;
DMSO-d6) δ 7.92 (d, J ) 7.9 Hz, 1H), 7.84 (s, 1H), 7.50 (d, J )
9.0 Hz, 1H), 7.43 (t, J ) 7.7 Hz, 1H), 7.16-7.28 (m, 3H), 5.92
(br s, 1H), 5.40 (s, 2H), 4.24 (m, 1H), 1.21 (d, J ) 7.5 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 167.2, 148.3, 135.2, 133.5, 130.1,
127.4, 124.9, 121.5, 120.0, 118.9, 116.6, 116.3, 107.8, 68.6, 42.1,
29.9, 23.0; ESI MS m/z 308 (M + H)+. Purity was determined to
be 94% by HPLC analysis on the basis of absorption at 214 nm.
N-(2-Methoxyethyl)-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-
9-carboxamide (8c). By using the general procedure for the
synthesis of indazolobenzoxazine carboxamides, the target was
synthesized yielding tan crystals (69 mg, 68%): mp 159-161 °C;
IR (neat) νmax 3352, 2927, 2855, 1629, 1536, 1096, 765 cm-1; 1H
NMR (600 MHz, DMSO-d6) δ 8.61 (t, J ) 5.4 Hz, 1H), 8.02 (s,
1H), 7.88 (m, 2H), 7.60 (m, 3H), 7.57 (d, J ) 9.6, 1H), 5.64 (s,
2H), 3.46-3.43 (m, 4H), 3.26 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 168.1, 148.3, 144.1, 134.8, 133.6, 130.1, 127.5, 125.0, 121.6,
120.1, 118.9, 116.9, 116.3, 107.9, 71.4, 68.6, 59.1, 39.9; ESI MS
m/z 324 (M + H)+. Purity was determined to be 97% by HPLC
analysis on the basis of absorption at 214 nm.
N-(Cyclopropylmethyl)-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-
9-carboxamide (8i). By using the general procedure for the
synthesis of indazolobenzoxazine carboxamides, the target was
synthesized yielding white crystals (78 mg, 82%): mp 186-
187 °C; IR (neat) νmax 3300, 3067, 2912, 1639, 1520, 1266, 754
cm-1; 1H NMR (600 MHz, CDCl3) δ 7.67-7.65 (m, 2H), 7.24 (d,
J ) 9.0 Hz, 1H), 7.18 (t, J ) 6.0 Hz, 1H), 7.04-6.99 (m, 2H),
6.94 (d, J ) 7.2 Hz, 1H), 6.33 (s, 1H), 5.14 (s, 2H), 3.50 (t, J )
6.0 Hz, 2H), 0.81 (m, 1H), 0.27 (d, J ) 7.8 Hz, 2H), 0.00 (d, J )
4.8 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 168.1, 148.3, 143.9,
134.9, 134.5, 129.9, 127.4, 124.9, 121.5, 119.9, 118.9, 116.8, 116.2,
107.8, 68.6, 45.2, 10.9, 3.7; ESI MS m/z 320 (M + H)+. Purity
was determined to be 90% by HPLC analysis on the basis of
absorption at 214 nm.
Morpholino-3-methyl-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-
9-carboxamide (9f). By using the general procedure for the
synthesis of indazolobenzoxazine carboxamides, the target was
synthesized yielding cream-colored crystals (54 mg, 52%): mp
212-214 °C; IR (neat) νmax 2974, 2922, 2855, 1629, 1520, 1427,
1
1246, 1116, 816 cm-1; H NMR (400 MHz, CDCl3) δ 7.83 (d, J
) 8.0 Hz, 1H), 7.57 (s, 1H), 7.55 (d, J ) 8.0 Hz, 1H), 7.26 (d, J
) 6.8 Hz, 1H), 7.02 (s, 1H), 6.93 (d, J ) 8.0 Hz, 1H), 5.39 (s,
2H), 3.69 (m, 8H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.8, 147.8, 143.9, 137.6, 134.9, 131.2, 130.6, 125.5, 121.4, 120.4,
119.3, 116.3, 116.0, 107.2, 68.7, 67.1, 45.6, 21.4; ESI MS m/z 350
(M + H)+. Purity was determined to be 94% by HPLC analysis on
the basis of absorption at 214 nm.
N-((S)-1-Hydroxy-3-methylbutan-2-yl)-3-methyl-5H-indazolo-
[3,2-b]benzo[d]-1,3-oxazine-9-carboxamide (9h). By using the
general procedure for the synthesis of indazolobenzoxazine car-
boxamides, the target was synthesized yielding tan crystals (82 mg,
75%): mp 202-203 °C; IR (neat) νmax 3435, 3290, 2964, 2876,
1608, 1515, 1360, 1075, 821 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.85 (s, 1H), 7.76 (d, J ) 8.4 Hz, 1H), 7.43 (d, J ) 8.8 Hz, 1H),
7.25-7.21 (m, 2H), 6.98 (s, 1H), 6.72 (d, J ) 8.8 Hz, 1H), 5.35
(s, 2H), 3.95 (m, 1H), 3.80 (m, 2H), 2.36 (s, 3H), 2.02 (m, 1H),
1.01 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 169.2, 147.9, 143.7,
137.6, 134.7, 131.1, 130.5, 125.4, 121.5, 119.9, 118.9, 116.6, 116.1,
108.0, 68.6, 63.9, 57.9, 29.5, 21.4, 19.5; ESI MS m/z 366 (M +
H)+. Purity was determined to be 93% by HPLC analysis on the
basis of absorption at 214 nm.
Isopropyl-3-chloro-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-
9-carboxamide (10a). By using the general procedure for the
synthesis of indazolobenzoxazine carboxamides, the target was
synthesized yielding white crystals (71 mg, 70%): mp 209-
210 °C; IR (neat) νmax 3269, 3062, 2974, 2922, 2860, 1639, 1510,
739 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.91-7.88 (m, 2H), 7.55
(d, J ) 9.0 Hz, 1H), 7.47 (dd, J ) 8.4, 1.8 Hz, 1H), 7.30 (dd, J )
7.8, 1.2 Hz, 1H), 7.25 (m, 1H), 6.09 (d, J ) 7.8 Hz, 1H), 5.43 (s,
N-Allyl-3-methyl-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-9-
carboxamide (9b). By using the general procedure for the synthesis
of indazolobenzoxazine carboxamides, the target was synthesized
yielding tan crystals (72 mg, 75%): mp 186-187 °C; IR (neat)
ν
max 2839, 2632, 2539, 1686, 1520, 1500, 820, 745 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.89 (s, 1H), 7.73 (d, J ) 8.0 Hz, 1H), 7.44
238 J. Org. Chem., Vol. 73, No. 1, 2008