4-[2-(4-methylpiperazin-1-yl)ethyl]aniline

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the crude of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-7-methyl-3H-benzoimidazole-5-carboxylic acid (estimated 0.4 mmol), 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamine (88 mg, 0.4 mmol) and HATU (167 mg, 0.44 mmol) in DMF (5 mL) was added DIEA (0.5 mL, 371 mg, 2.87 mmol). The reaction mixture was stirred at room temperature for 2 h and heated at 60° C. for 15 h, and then evaporated to dry under reduced pressure. The residue was diluted with DMSO (1.5 mL), filtered and then purified with using HPLC (TFA/H2O/CH3CN) to afford the title compound (34.5 mg, 11% from two steps from 3,4-diamino-5-methyl-benzoic acid). 1H NMR (MeOH-d4) δ 2.77 (s, 3H), 2.90 (s, 3H), 2.97-3.43 (12H), 3.97 (s, 3H), 7.09 (m, 1H), 7.22 (d, J=9 Hz, 1H), 7.31 (d, J=9 Hz, 2H), 7.70 (d, J=9 Hz, 2H), 7.82-7.84 (2H), 7.91 (s, 1H), 8.17 (m, 1H), 8.20 (s, 1H), 8.31 (s, 1H). ESI-MS m/z 577.5 (MH+). heated at 60° C. for 15 h evaporated to dry under reduced pressure The residue was diluted with DMSO (1.5 mL) filtered purified with using HPLC (TFA/H2O/CH3CN)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-amino-3-nitro-benzoic acid sodium salt (205 mg, 1.0 mmol), 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamine (219 mg, 1.0 mmol) and HATU (400 mg, 1.05 mmol) in DMF (2 mL) was added DIEA (0.52 mL, 388 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 1 h and heated at 70° C. for 1 h, and then evaporated under reduced pressure. The residue was purified by chromatography (50:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (300 mg, 78%). 1H NMR (MeOH-d4) δ 2.44 (s, 3H), 2.50-2.85 (12H), 6.74 (dd, J=9 Hz and 9 Hz, 1H), 7.23 (d, J=9 Hz, 2H), 7.58 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 1H), 8.29 (d, J=9 Hz, 1H). ESI-MS m/z 384.5 (MH+). heated at 70° C. for 1 h evaporated under reduced pressure The residue was purified by chromatography (50:10:1 CH2Cl2/MeOH/28% aqueous NH4OH)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-Amino-1-(8-methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (40 mg, 0.118 mM), diisopropylethylamine (70 ul, 0.402 mM), 4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenylamine (30 mg, 0.1369 mM) in DMF (1 ml) to which was added HBTU (60 mg, 0.1583 mM) and the stirred 16 hr at room temperature. The resulting suspension was filtered and the solid washed with water (1×1 ml) and dried in vacuo to afford 5-Amino-1-(7-methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid {4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-amide (12 mg, 19% yield) as a white solid. ES-MS MH+ 539. The filtrate may be purified via RP-HPLC 0.1% TFA to afford additional material. the stirred 16 hr at room temperature The resulting suspension was filtered the solid washed with water (1×1 ml) dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-Amino-1-(8-methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (40 mg, 0.118 mM), diisopropylethylamine (70 ul, 0.402 mM), 4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenylamine (30 mg, 0.1369 mM) in DMF (1 ml) to which was added HBTU (60 mg, 0.1583 mM) and the stirred 16 hr at room temperature. The resulting suspension was filtered and the solid washed with water (1×1 ml) and dried in vacuo to afford 5-Amino-1-(7-methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid {4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-amide (12 mg, 19% yield) as a white solid. ES-MS MH+ 539. The filtrate may be purified via RP-HPLC 0.1% TFA to afford additional material. the stirred 16 hr at room temperature The resulting suspension was filtered the solid washed with water (1×1 ml) dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (35 mg, 0.108 mM) diisopropylethylamine (70 ul, 0.402 mM), 4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenylamine (30 mg, 0.1369 mM) in DMF (1 ml) to which was added HBTU (60 mg, 0.1583 mM) and the stirred 16 hr at room temperature. The resulting suspension was filtered and the solid washed with water (1×1 ml) and dried in vacuo to afford 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid {4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-amide (13 mg, 21% yield). ES-MS MH+526.7. The filtrate may be purified via RP-HPLC 0.1% TFA to afford additional material. the stirred 16 hr at room temperature The resulting suspension was filtered the solid washed with water (1×1 ml) dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (35 mg, 0.108 mM) diisopropylethylamine (70 ul, 0.402 mM), 4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenylamine (30 mg, 0.1369 mM) in DMF (1 ml) to which was added HBTU (60 mg, 0.1583 mM) and the stirred 16 hr at room temperature. The resulting suspension was filtered and the solid washed with water (1×1 ml) and dried in vacuo to afford 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid {4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-amide (13 mg, 21% yield). ES-MS MH+526.7. The filtrate may be purified via RP-HPLC 0.1% TFA to afford additional material. the stirred 16 hr at room temperature The resulting suspension was filtered the solid washed with water (1×1 ml) dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[2-(N-methylpiperazino)-ethyl]-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[2-(N-methylpiperazino)-ethyl]-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.

Conditions: temp:0.00; pressure:0.00; stir: