2-(oxan-2-yl)ethanamine;hydrochloride

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

Procedure: The title compound was prepared in a manner similar to Example 198 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.19 (m, 1 H) 1.31-1.43 (m, 3 H) 1.52 (d, J=12.9 Hz, 1 H) 1.58 (q, J=7.1 Hz, 2 H) 1.65-1.75 (m, 1H) 3.18-3.25 (m, 2 H) 3.29-3.38 (m, 2 H) 3.81 (m, J=2.0 Hz, 4 H) 7.34 (br. s., 1 H) 7.42 (d, J=5.1 Hz, 1 H) 7.98 (d, J=5.6 Hz, 1 H) 8.26-8.34 (m, 1 H) 8.37 (br. s., 1 H) 8.52 (br. s., 1 H) 8.59 (t, J=5.4 Hz, 1 H) 8.82 (s, 1 H) 13.45 (br. s., 1 H). MS m/z 424 [M+H]+.

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

Procedure: The title compound was prepared in a manner similar to Example 198 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.27 (m, 1 H) 1.38-1.50 (m, 3 H) 1.60 (d, J=12.9 Hz, 1 H) 1.62-1.70 (m, 2 H) 1.71-1.82 (m, 1 H) 2.44 (s, 3 H) 3.26-3.33 (m, 2 H) 3.35-3.45 (m, 2 H) 3.87 (dd, J=11.0, 1.9 Hz, 1 H) 7.66 (dd, J=8.0, 1.4 Hz, 1 H) 7.72 (s, 1 H) 7.80 (d, J=8.1 Hz, 1 H) 8.16 (s, 1 H) 8.40 (br. s., 2 H) 8.67 (t, J=5.6 Hz, 1 H) 8.90 (t, J=1.5 Hz, 1 H) 13.18 (br. s., 1 H). MS m/z 432 [M+H]+.

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

Procedure: The title compound was prepared in a manner similar to Example 198 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.27 (m, 1 H) 1.38-1.50 (m, 3 H) 1.60 (d, J=12.9 Hz, 1 H) 1.62-1.70 (m, 2 H) 1.71-1.82 (m, 1 H) 2.44 (s, 3 H) 3.26-3.33 (m, 2 H) 3.35-3.45 (m, 2 H) 3.87 (dd, J=11.0, 1.9 Hz, 1 H) 7.66 (dd, J=8.0, 1.4 Hz, 1 H) 7.72 (s, 1 H) 7.80 (d, J=8.1 Hz, 1 H) 8.16 (s, 1 H) 8.40 (br. s., 2 H) 8.67 (t, J=5.6 Hz, 1 H) 8.90 (t, J=1.5 Hz, 1 H) 13.18 (br. s., 1 H). MS m/z 432 [M+H]+.

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

Procedure: The title compound was prepared in a manner similar to Example 198 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.19 (m, 1H) 1.31-1.43 (m, 3H) 1.52 (d, J=12.9 Hz, 1H) 1.58 (q, J=7.1 Hz, 2H) 1.65-1.75 (m, 1H) 3.18-3.25 (m, 2H) 3.29-3.38 (m, 2H) 3.81 (m, J=2.0 Hz, 4H) 7.34 (br. s., 1H) 7.42 (d, J=5.1 Hz, 1H) 7.98 (d, J=5.6 Hz, 1H) 8.26-8.34 (m, 1H) 8.37 (br. s., 1H) 8.52 (br. s., 1H) 8.59 (t, J=5.4 Hz, 1H) 8.82 (s, 1H) 13.45 (br. s., 1H). MS m/z 424 [M+H]+.

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

Procedure: The title compound was prepared in a manner similar to Example 198 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.27 (m, 1H) 1.38-1.50 (m, 3H) 1.60 (d, J=12.9 Hz, 1H) 1.62-1.70 (m, 2H) 1.71-1.82 (m, 1H) 2.44 (s, 3H) 3.26-3.33 (m, 2H) 3.35-3.45 (m, 2H) 3.87 (dd, J=11.0, 1.9 Hz, 1H) 7.66 (dd, J=8.0, 1.4 Hz, 1H) 7.72 (s, 1H) 7.80 (d, J=8.1 Hz, 1H) 8.16 (s, 1H) 8.40 (br. s., 2H) 8.67 (t, J=5.6 Hz, 1H) 8.90 (t, J=1.5 Hz, 1H) 13.18 (br. s., 1H). MS m/z 432 [M+H]+.

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of chloride (R)-benzyl 4-(2-((2,6-dichloronicotinamido)methyl)pyrrolidin-1-yl)-4-oxobutylcarbamate (150 mg, 0.304 mmol), 2-(tetrahydro-2H-pyran-2-yl)ethanamine HCl salt (76 mg, 0.459 mmol), K2CO3 (125 mg, 0.905 mmol) and DMF (1 mL) was stirred at 100° C. for 10 hrs. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give benzyl 4-((R)-2-((6-chloro-2-(2-(tetrahydro-2H-pyran-2-yl)ethylamino)nicotinamido)methyl)pyrrolidin-1-yl)-4-oxobutylcarbamate (62 mg, 35%). LRMS (M+H+) m/z 586.3. The crude mixture was purified on RP-HPLC a mixture of acetonitrile and H2O

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

Procedure: The title compound was prepared in a manner similar to Example 198 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.19 (m, 1 H) 1.31-1.43 (m, 3 H) 1.52 (d, J=12.9 Hz, 1 H) 1.58 (q, J=7.1 Hz, 2 H) 1.65-1.75 (m, 1H) 3.18-3.25 (m, 2 H) 3.29-3.38 (m, 2 H) 3.81 (m, J=2.0 Hz, 4 H) 7.34 (br. s., 1 H) 7.42 (d, J=5.1 Hz, 1 H) 7.98 (d, J=5.6 Hz, 1 H) 8.26-8.34 (m, 1 H) 8.37 (br. s., 1 H) 8.52 (br. s., 1 H) 8.59 (t, J=5.4 Hz, 1 H) 8.82 (s, 1 H) 13.45 (br. s., 1 H). MS m/z 424 [M+H]+.

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

Procedure: The title compound was prepared in a manner similar to Example 198 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.27 (m, 1 H) 1.38-1.50 (m, 3 H) 1.60 (d, J=12.9 Hz, 1 H) 1.62-1.70 (m, 2 H) 1.71-1.82 (m, 1 H) 2.44 (s, 3 H) 3.26-3.33 (m, 2 H) 3.35-3.45 (m, 2 H) 3.87 (dd, J=11.0, 1.9 Hz, 1 H) 7.66 (dd, J=8.0, 1.4 Hz, 1 H) 7.72 (s, 1 H) 7.80 (d, J=8.1 Hz, 1 H) 8.16 (s, 1 H) 8.40 (br. s., 2 H) 8.67 (t, J=5.6 Hz, 1 H) 8.90 (t, J=1.5 Hz, 1 H) 13.18 (br. s., 1 H). MS m/z 432 [M+H]+.

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

Procedure: The title compound was prepared in a manner similar to Example 198 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.19 (m, 1H) 1.31-1.43 (m, 3H) 1.52 (d, J=12.9 Hz, 1H) 1.58 (q, J=7.1 Hz, 2H) 1.65-1.75 (m, 1H) 3.18-3.25 (m, 2H) 3.29-3.38 (m, 2H) 3.81 (m, J=2.0 Hz, 4H) 7.34 (br. s., 1H) 7.42 (d, J=5.1 Hz, 1H) 7.98 (d, J=5.6 Hz, 1H) 8.26-8.34 (m, 1H) 8.37 (br. s., 1H) 8.52 (br. s., 1H) 8.59 (t, J=5.4 Hz, 1H) 8.82 (s, 1H) 13.45 (br. s., 1H). MS m/z 424 [M+H]+.

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

Procedure: The title compound was prepared in a manner similar to Example 198 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.27 (m, 1H) 1.38-1.50 (m, 3H) 1.60 (d, J=12.9 Hz, 1H) 1.62-1.70 (m, 2H) 1.71-1.82 (m, 1H) 2.44 (s, 3H) 3.26-3.33 (m, 2H) 3.35-3.45 (m, 2H) 3.87 (dd, J=11.0, 1.9 Hz, 1H) 7.66 (dd, J=8.0, 1.4 Hz, 1H) 7.72 (s, 1H) 7.80 (d, J=8.1 Hz, 1H) 8.16 (s, 1H) 8.40 (br. s., 2H) 8.67 (t, J=5.6 Hz, 1H) 8.90 (t, J=1.5 Hz, 1H) 13.18 (br. s., 1H). MS m/z 432 [M+H]+.