2-(4-aminopiperidin-1-yl)ethanol

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

Procedure: The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 2-(4-aminopiperidin-1-yl)ethanol as described in the General procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.86 (m, 12H) 1.88-2.10 (m, 5H) 2.33-2.42 (m, 2H) 2.84 (d, J=11.4 Hz, 2H) 3.48 (q, J=6.2 Hz, 2H) 3.73 (d, J=4.6 Hz, 1H) 4.08 (t, J=14.0 Hz, 2H) 4.37 (t, J=5.4 Hz, 1H) 4.82 (t, J=8.2 Hz, 1H) 7.18 (d, J=6.6 Hz, 1H) 7.90 (dd, J=7.7, 3.4 Hz, 1H) 8.04 (s, 1H) 8.18-8.34 (m, 2H). [M+H] calc'd for C28H36F3N7O4, 592. found 592. as described in the General procedure for amide bond synthesis The final compound was purified by reverse phase HPLC to give the free base

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

Procedure: The title compound was synthesized from (R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 2-(4-aminopiperidin-1-yl)ethanol. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47-2.14 (m, 15H) 2.38 (t, J=6.32 Hz, 3H) 2.89 (d, J=11.62 Hz, 2H) 3.28 (s, 3H) 3.49 (q, J=6.23 Hz, 2H) 3.67-3.85 (m, 3H) 3.94 (s, 3H) 4.37 (t, J=5.43 Hz, 1H) 4.89 (d, J=8.34 Hz, 1H) 5.28-5.48 (m, 2H) 6.01 (ddd, J=17.56, 12.76, 10.86 Hz, 1H) 7.40-7.54 (m, 2H) 7.82 (s, 1H) 8.10 (d, J=7.58 Hz, 2H) 8.30 (d, J=8.34 Hz, 1H). [M+H] calc'd for C30H40FN7O4, 582. found 582. as described in the General procedure for amide bond synthesis

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

Procedure: The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 2-(4-aminopiperidin-1-yl)ethanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (m, 1H) 1.39 (m, 3H) 1.54-1.90 (m, 10H) 2.02 (t, J=10.99 Hz, 2H) 2.38 (t, J=6.32 Hz, 2H) 2.89 (d, J=10.86 Hz, 2H) 3.31 (s, 3H) 3.49 (br. s., 2H) 3.74 (m, 1H) 3.94 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.45 (m, 2H) 7.47 (d, J=8.0 Hz, 1H) 7.51 (s, 1H) 7.90 (s, 1H) 8.14 (d, J=8.0 Hz, 1H) 8.21 (s, 1H) 8.26 (d, J=8.0 Hz, 1H). [M+H] calculated for C29H39F2N7O4, 588. found 588. as described in the General procedure for amide bond synthesis The final compound was purified by reverse phase HPLC to give the free base

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

Procedure: The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 2-(4-aminopiperidin-1-yl)ethanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (m, 1H) 1.39 (m, 3H) 1.54-1.90 (m, 10H) 2.02 (t, J=10.99 Hz, 2H) 2.38 (t, J=6.32 Hz, 2H) 2.89 (d, J=10.86 Hz, 2H) 3.31 (s, 3H) 3.49 (br. s., 2H) 3.74 (m, 1H) 3.94 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.45 (m, 2H) 7.47 (d, J=8.0 Hz, 1H) 7.51 (s, 1H) 7.90 (s, 1H) 8.14 (d, J=8.0 Hz, 1H) 8.21 (s, 1H) 8.26 (d, J=8.0 Hz, 1H). [M+H] calculated for C29H39F2N7O4, 588. found 588. as described in the General procedure for amide bond synthesis The final compound was purified by reverse phase HPLC to give the free base

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

Procedure: The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino piperidine 1-ethanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-2.07 (m, 12H) 2.38 (t, J=6.32 Hz, 2H) 2.89 (d, J=11.37 Hz, 2H) 3.27-3.34 (s, 3H) 3.49 (q, J=6.06 Hz, 2H) 3.65-3.83 (m, 1H) 3.93 (s, 2H) 3.97-4.14 (m, 2H) 4.37 (t, J=5.31 Hz, 1H) 4.76 (t, J=7.83 Hz, 1H) 7.48 (d, J=8.0 Hz, 1H), 7.49 (br. s., 1H) 7.96 (s, 1H) 8.12 (d, J=7.83 Hz, 1H)), 8.26 (s, 1H) 8.27 (d, J=8.0 Hz, 1H). [M+H] calculated for C28H37F2N7O4, 574. found 574. as described in the General procedure for amide bond synthesis The final compound was purified by reverse phase HPLC to give the free base

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

Procedure: To a solution of 0.58 g of tert-butyl 1-(2-hydroxyethyl)piperidin-4-ylcarbamate obtained in step 1 in 10 ml of ethanol was added 1 ml of conc. HCl, followed by stirring for 2 hrs under reflux. The reaction mixture was cooled to room temperature, and concentrated in a reduced pressure to remove solvent. The residue was added with 10 ml of distilled water, neutralized with saturated sodium hydrogen carbonate aqueous solution, and extracted twice with 10 ml of methylene chloride. After being dried over a desiccant, the fraction was concentrated in a reduced pressure to afford 0.33 g of the title compound (Yield: 95%). 1H NMR (CDCl3) δ 3.68 (s, 2H), 3.60 (t, 2H), 2.86 (d, 2H), 2.69 (m, 1H), 2.53 (t, 2H), 2.11 (t, 2H), 1.82 (d, 2H), 1.42 (t, 2H) ppm. under reflux concentrated in a reduced pressure to remove solvent The residue was added with 10 ml of distilled water extracted twice with 10 ml of methylene chloride After being dried over a desiccant, the fraction was concentrated in a reduced pressure

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

Procedure: A solution of 0.5 g of tert-butyl 4-piperidinylcarbamate, 0.21 ml of 2-bromoethanol and 2.76 g of K2CO3 in 10 ml of acetonitrile was stirred for 5 hrs under reflux. The reaction mixture was cooled to a room temperature, filtered to remove solids, and concentrated. The concentrate was purified by silica gel column chromatography (mobile phase: 20 (v/v) % EA in hexane) to afford 0.58 g of the title compound (Yield: 94%). 1H NMR (CDCl3) δ 4.76 (d, 1H), 3.65 (t, 2H), 3.48 (m, 1H), 2.92 (m, 2H), 2.59 (t, 2H), 2.26 (m, 2H), 1.94 (m, 2H), 1.52 (m, 2H), 1.44 (s, 9H) ppm. under reflux filtered to remove solids concentrated The concentrate was purified by silica gel column chromatography (mobile phase: 20 (v/v) % EA in hexane)

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

Procedure: A solution of 0.5 g of tert-butyl 4-piperidinylcarbamate, 0.21 ml of 2-bromoethanol and 2.76 g of K2CO3 in 10 ml of acetonitrile was stirred for 5 hrs under reflux. The reaction mixture was cooled to a room temperature, filtered to remove solids, and concentrated. The concentrate was purified by silica gel column chromatography (mobile phase: 20 (v/v) % EA in hexane) to afford 0.58 g of the title compound (Yield: 94%). 1H NMR (CDCl3) δ 4.76 (d, 1H), 3.65 (t, 2H), 3.48 (m, 1H), 2.92 (m, 2H), 2.59 (t, 2H), 2.26 (m, 2H), 1.94 (m, 2H), 1.52 (m, 2H), 1.44 (s, 9H) ppm. under reflux filtered to remove solids concentrated The concentrate was purified by silica gel column chromatography (mobile phase: 20 (v/v) % EA in hexane)

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

Procedure: 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8, 1 g, 4.29 mmol) is suspended in 5 ml of DMF, cooled to 0° C. and treated with Hünig's Base (1.46 ml, 8.58 mmol). The mixture is stirred for 15 min at 0° C. In a separate reaction flask, compound 192 (931 mg, 4.29 mmol) in 10 ml of DMF is cooled to 0° C., treated with 10M aqueous sodium hydroxide solution (0.858 ml, 8.58 mmol) and stirred for 15 min at this temperature. This solution is added to the above mentioned mixture, followed by benzotriazol-1-yl-oxytripyrrolidinphosphonium hexafluorophosphate (PyBOP, 2.34 g, 4.5 mmol) and stirred for 4 h at room temperature. The reaction mixture is diluted with ethyl acetate and washed with 2N sodium hydroxide solution, water and brine. Evaporation gave a semisolid, yellow crude product, which is treated with ether, filtered of and washed with ether. is cooled to 0° C. stirred for 15 min at this temperature This solution is added to the stirred for 4 h at room temperature washed with 2N sodium hydroxide solution, water and brine Evaporation gave a semisolid, yellow crude product, which filtered of and washed with ether

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

Procedure: Compound 191 (4.02 g, 16.46 mmol) are treated with 4M HCl in dioxane (60 ml, 240 mmol) and the mixture is stirred at room temperature for 1 h. The white precipitate is filtered off, washed with ether and dried under high vacuum. The mother liquor is concentrated and treatred with ether. The white solid is filtered off and dried under high vacuum. The white precipitate is filtered off washed with ether dried under high vacuum The mother liquor is concentrated The white solid is filtered off dried under high vacuum

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

Procedure: Compound 191 (4.02 g, 16.46 mmol) are treated with 4M HCl in dioxane (60 ml, 240 mmol) and the mixture is stirred at room temperature for 1 h. The white precipitate is filtered off, washed with ether and dried under high vacuum. The mother liquor is concentrated and treatred with ether. The white solid is filtered off and dried under high vacuum. The white precipitate is filtered off washed with ether dried under high vacuum The mother liquor is concentrated The white solid is filtered off dried under high vacuum

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

Procedure: 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8, 1 g, 4.29 mmol) is suspended in 5 ml of DMF, cooled to 0° C. and treated with Hünig's Base (1.46 ml, 8.58 mmol). The mixture is stirred for 15 min at 0° C. In a separate reaction flask, compound 192 (931 mg, 4.29 mmol) in 10 ml of DMF is cooled to 0° C., treated with 10M aqueous sodium hydroxide solution (0.858 ml, 8.58 mmol) and stirred for 15 min at this temperature. This solution is added to the above mentioned mixture, followed by benzotriazol-1-yl-oxytripyrrolidinphosphonium hexafluorophosphate (PyBOP, 2.34 g, 4.5 mmol) and stirred for 4 h at room temperature. The reaction mixture is diluted with ethyl acetate and washed with 2N sodium hydroxide solution, water and brine. Evaporation gave a semisolid, yellow crude product, which is treated with ether, filtered of and washed with ether. is cooled to 0° C. stirred for 15 min at this temperature This solution is added to the stirred for 4 h at room temperature washed with 2N sodium hydroxide solution, water and brine Evaporation gave a semisolid, yellow crude product, which filtered of and washed with ether