N-ethyl-1H-pyrrole-3-carboxamide

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

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

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

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

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Ethyl-1H-pyrrole-3-carboxamide (50 mg, 0.36 mmol) was dissolved in THF (3 mL) and the solution was cooled down to 0° C. NaH (72 mg, 60%, 1.8 mmol) was then added and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour at room temperature. The reaction mixture was cooled down to 0° C. again and 2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (114 mg, 0.30 mmol) was added slowly, allowing the reaction to warm to room temperature and stirred for 3 hours. The reaction mixture was slowly added to a stirring mixture of EtOAc and NH4Cl at −20° C., which was extracted with EtOAc, washed with NH4Cl, water then brine. Concentrated under vacuum and purified by LCMS using high pH column 40-70% acetonitrile gradient to afford the title compound as a white solid. Yield: 25 mg (17%). 1H NMR (400 MHz, METHANOL-D4) δ 1.14 (t, J=7.23 Hz, 3 H), 1.32-1.41 (m, 2 H), 1.40-1.43 (m, 3 H), 1.43-1.53 (m, 2 H), 2.25 (t, J=19.53 Hz, 5H), 3.89 (dd, J=11.52, 2.54 Hz, 2 H), 4.37 (d, J=7.62 Hz, 2 H), 6.65 (s, 1 H), 7.31 (t, J=2.34 Hz, 1 H), 7.82 (s, 1 H), 7.88-7.94 (m, 1 H), 7.95-8.01 (m, 1 H), 8.40 (s, 1 H); MS (APPI) (M+H)+=481.2; Anal. Calc. for C22H26F2N4O4S+0.4 TFA: C, 52.05; H, 5.06; N, 10.65. Found: C, 52.41; H, 3.78; N, 10.41. to warm to room temperature The reaction mixture was cooled down to 0° C. again the reaction to warm to room temperature stirred for 3 hours which was extracted with EtOAc washed with NH4Cl, water Concentrated under vacuum purified by LCMS

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

Procedure: Following the same procedure in Example 29, using N-ethyl-1H-pyrrole-3-carboxamide (166 mg, 1.2 mmol) (see the step B in example 31 for preparation), sodium hydride (240 mg, 60%, 6.0 mmol) and 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (385 mg, 1.0 mmol) in THF (20 mL). The crude product was purified by MPLC using EtOAc on silica gel to give 195 mg (40%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.78 (t, J=7.42 Hz, 3 H), 1.13 (t, J=7.23 Hz, 3 H), 1.41-1.56 (m, 4 H), 1.59 (s, 6 H), 1.95 (q, J=7.49 Hz, 2 H), 2.21-2.35 (m, 1 H), 3.24-3.34 (m, 4 H), 3.85-3.94 (m, 2 H), 4.42 (d, J=7.62 Hz, 2 H), 6.65 (dd, J=3.32, 1.76 Hz, 1 H), 7.29 (dd, J=3.32, 2.34 Hz, 1 H), 7.78-7.82 (m, 1 H), 7.92 (d, J=8.8 Hz, 1 H), 7.96 (dd, J=8.8, 1.8 Hz, 1 H), 8.27 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=487.0; Anal. Calcd for C25H34N4O4S+110 TFA+0.1H2O (602.46): C, 53.83; H, 5.89; N, 9.30. Found: C, 53.79; H, 6.00; N, 9.19. The crude product was purified by MPLC

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

Procedure: DIPEA (10.4 mL, 7.8 g, 60 mmol) was added to a solution of 1H-pyrrole-3-carboxylic acid (2.2 g, 20 mmol) and ethylamine hydrochloride (2.5 g, 30 mmol) in DMF (50 mL) at 0° C. Stirring for 20 min, HATU (9.9 g, 26 mmol) was added at 0° C. The reaction mixture was stirred overnight at room temperature, diluted with EtOAc (300 mL), washed with H2O (3×30 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc on silica gel to give 4.0 mL of a solution of the desired product in DMF. Small amount of the desired product was purified again by MPLC using EtOAc on silica gel for NMR. 1H NMR (400 MHz, CHLOROFORM-D) δ 1.22 (t, J=7.23 Hz, 3 H), 3.39-3.51 (m, 2 H), 5.84 (s, 1 H), 6.37-6.42 (m, 1 H), 6.77 (dd, J=4.98, 2.44 Hz, 1 H), 7.30-7.39 (m, 1 H), 8.85 (t, 1 H). The reaction mixture was stirred overnight at room temperature washed with H2O (3×30 mL) dried over Na2SO4 The crude product was purified by MPLC

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

Procedure: Following the same procedure in Example 29, using N-ethyl-1H-pyrrole-3-carboxamide (2.7 g, 20 mmol) (see following step B for preparation), sodium hydride (4.0 g, 60%, 100 mmol) and 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (6.1 g, 16 mmol) in THF (250 mL). The crude product was purified by MPLC using Hex/EtOAc (1:4) on silica gel to give 4.0 g (53%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.13 (t, J=7.23 Hz, 3 H), 1.41-1.58 (m, 4 H), 1.61 (s, 9 H), 2.24-2.38 (m, 1 H), 3.24-3.35 (m, 4 H), 3.85-3.94 (m, 2 H), 4.44 (d, J=7.42 Hz, 2 H), 6.65 (dd, J=3.32, 1.56 Hz, 1 H), 7.29 (dd, J=3.32, 2.34 Hz, 1 H), 7.77-7.82 (m, 1 H), 7.95-7.98 (m, 2 H), 8.24-8.30 (m, 1 H); MS (ESI) (M+H)+=472.8; Anal. Calcd for C24H32N4O4S+1.20 TFA+0.10 EtOAc+0.30H2O (624.86): C, 51.71; H, 5.58; N, 8.97. Found: C, 51.73; H, 5.66; N, 8.91. The crude product was purified by MPLC