oxetan-3-amine;hydrochloride

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

Procedure: Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 41 mg, 0.138 mmol), oxetan-3-amine hydrochloride (30.3 mg, 0.277 mmol, Frontier Scientific), and DIPEA (121 μl, 0.692 mmol), heating at 100° C. for 30 min. Purification by silica gel (100% DCM to 8% MeOH/DCM) provided 2-(2-methyl-3-(oxetan-3-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.60 (s, 3H) 2.92 (t, J=6.85 Hz, 2H) 3.45 (td, J=6.85, 2.35 Hz, 2H) 4.74 (t, J=6.16 Hz, 2H) 4.98 (t, J=6.16 Hz, 2H) 5.04-5.15 (m, 1H) 6.98 (br. s., 1H) 7.10 (d, J=2.15 Hz, 1H) 7.37 (t, J=7.73 Hz, 1H) 7.60 (dd, J=8.02, 1.17 Hz, 1H) 7.70 (d, J=4.69 Hz, 1H) 7.85 (dd, J=7.63, 1.17 Hz, 1H) 11.80 (br. s., 1H). MS (ESI, pos. ion) m/z: 350.1 (M+1). Prepared similarly to that Purification by silica gel (100% DCM to 8% MeOH/DCM)

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

Procedure: Prepared according to the procedure described in Example 111, by reacting 3-(2-chloropyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine with 3-aminooxetane hydrochloride for 70 minutes in Step 1 to give the title compound (13.3 mg, 19% over two steps). LC-MS (Method G): m/z=368.1 [M+H]+; 2.93 min. 1H-NMR (400 MHz, DMSO): δ 13.68 (s, 1H), 8.24 (d, J=7.1, 1H), 7.96-7.91 (m, 1H), 7.63 (s, 1H), 7.54 (d, J=7.1, 1H), 7.24 (d, J=5.4, 1H), 5.55-5.40 (m, 2H), 3.91-3.81 (m, 2H), 3.68-3.46 (m, 5H), 2.18-1.99 (m, 2H), 1.91-1.78 (m, 2H). Prepared for 70 minutes

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

Procedure: Similarly to as described in General Procedure D, 2-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylic acid was reacted with 3-aminooxetane hydrochloride to give 297 as a colorless solid after reverse phase HPLC (146 mg). LCMS: 496.1

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoic acid (Example 21, 90 mg, 0.25 mmol) in toluene (5 mL) was added N,N-diisopropylethylamine (33 mg, 0.25 mmol) and diphenylphosphoryl azide (77 mg, 0.28 mmol). The mixture was stirred at 80° C. for 30 minutes. The LCMS confirmed the disappearance of the starting acid. A solution of oxetan-3-amine hydrochloride (41.5 mg, 0.38 mmol), N,N-diisopropylethylamine (49 mg, 0.38 mmol) and DCM (2 mL) was added to the reaction mixture and stirred at room temperature for 2 h. The LCMS confirmed the presence of the product. All solvents were removed under reduced pressure. Purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound (50 mg, 46%). 1H NMR (400 MHz, CD3OD) δ 7.99 (d, J=2.3 Hz, 1H), 7.49 (d, J=2.3 Hz, 2H), 7.41-7.24 (m, 5H), 7.14 (d, J=8.6 Hz, 2H), 4.87 (br s, 3H), 4.55 (s, 2H), 3.91 (s, 3H), 3.90 (s, 2H). [M+H]=424.20. stirred at room temperature for 2 h All solvents were removed under reduced pressure Purification (FCC, SiO2, 0-5%, MeOH/DCM)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoic acid (Example 21, 90 mg, 0.25 mmol) in toluene (5 mL) was added N,N-diisopropylethylamine (33 mg, 0.25 mmol) and diphenylphosphoryl azide (77 mg, 0.28 mmol). The mixture was stirred at 80° C. for 30 minutes. The LCMS confirmed the disappearance of the starting acid. A solution of oxetan-3-amine hydrochloride (41.5 mg, 0.38 mmol), N,N-diisopropylethylamine (49 mg, 0.38 mmol) and DCM (2 mL) was added to the reaction mixture and stirred at room temperature for 2 h. The LCMS confirmed the presence of the product. All solvents were removed under reduced pressure. Purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound (50 mg, 46%). 1H NMR (400 MHz, CD3OD) δ 7.99 (d, J=2.3 Hz, 1H), 7.49 (d, J=2.3 Hz, 2H), 7.41-7.24 (m, 5H), 7.14 (d, J=8.6 Hz, 2H), 4.87 (br s, 3H), 4.55 (s, 2H), 3.91 (s, 3H), 3.90 (s, 2H). [M+H]=424.20. stirred at room temperature for 2 h All solvents were removed under reduced pressure Purification (FCC, SiO2, 0-5%, MeOH/DCM)

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

Procedure: According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with oxetan-3-amine hydrochloride, providing the title compound as yellow solid (58%).

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

Procedure: According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with oxetan-3-amine hydrochloride, providing the title compound as yellow solid (58%).

Conditions: temp:90.01; pressure:0.00; stir:

Procedure: 2-bromo-1-methyl-4-nitrobenzene (864 mg, 4mmol), oxetan-3-amine hydrochloride (438 mg, 4 mmol), CS2CO3 (3910 mg, 12.00 mmol), palladium(II) acetate (44.9 mg, 0.20 mmol), (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t- butylphosphine (224 mg, 0.40 mmol) in 1,4-doxane was degased, inflated with Ar and heated at 90 oC for 5h. LCMS showed some product peak. Silica gel 2g was added to the mixture, evaporated all solvents in GeneVac. The sample was dry loaded for purification by ISCO (Hexane/EtOAc=100/10-100/50) N-(2-methyl-5-nitrophenyl)oxetan-3-amine (240 mg, 28.8 %) 1H NMR (400 MHz, CD2Cl2) d: 7.47 (dd, 1H), 7.14 (d, 1H), 6.98 (s, 1H), 4.99 (t, 2H), 4.63 (m, 1H), 4.46 (t, 2H), 4.20(m, 1H), 2.18 (s, 3H). LCMS: 209 [M+H]+.

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

Procedure: Similarly to as described in General Procedure D, 2-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylic acid was reacted with 3-aminooxetane hydrochloride to give 297 as a colorless solid after reverse phase HPLC (146 mg). LCMS: 496.1

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

Procedure: According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with oxetan-3-amine hydrochloride, providing the title compound as yellow solid (58%).

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoic acid (Example 21, 90 mg, 0.25 mmol) in toluene (5 mL) was added N,N-diisopropylethylamine (33 mg, 0.25 mmol) and diphenylphosphoryl azide (77 mg, 0.28 mmol). The mixture was stirred at 80° C. for 30 minutes. The LCMS confirmed the disappearance of the starting acid. A solution of oxetan-3-amine hydrochloride (41.5 mg, 0.38 mmol), N,N-diisopropylethylamine (49 mg, 0.38 mmol) and DCM (2 mL) was added to the reaction mixture and stirred at room temperature for 2 h. The LCMS confirmed the presence of the product. All solvents were removed under reduced pressure. Purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound (50 mg, 46%). 1H NMR (400 MHz, CD3OD) δ 7.99 (d, J=2.3 Hz, 1H), 7.49 (d, J=2.3 Hz, 2H), 7.41-7.24 (m, 5H), 7.14 (d, J=8.6 Hz, 2H), 4.87 (br s, 3H), 4.55 (s, 2H), 3.91 (s, 3H), 3.90 (s, 2H). [M+H]=424.20. stirred at room temperature for 2 h All solvents were removed under reduced pressure Purification (FCC, SiO2, 0-5%, MeOH/DCM)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoic acid (Example 21, 90 mg, 0.25 mmol) in toluene (5 mL) was added N,N-diisopropylethylamine (33 mg, 0.25 mmol) and diphenylphosphoryl azide (77 mg, 0.28 mmol). The mixture was stirred at 80° C. for 30 minutes. The LCMS confirmed the disappearance of the starting acid. A solution of oxetan-3-amine hydrochloride (41.5 mg, 0.38 mmol), N,N-diisopropylethylamine (49 mg, 0.38 mmol) and DCM (2 mL) was added to the reaction mixture and stirred at room temperature for 2 h. The LCMS confirmed the presence of the product. All solvents were removed under reduced pressure. Purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound (50 mg, 46%). 1H NMR (400 MHz, CD3OD) δ 7.99 (d, J=2.3 Hz, 1H), 7.49 (d, J=2.3 Hz, 2H), 7.41-7.24 (m, 5H), 7.14 (d, J=8.6 Hz, 2H), 4.87 (br s, 3H), 4.55 (s, 2H), 3.91 (s, 3H), 3.90 (s, 2H). [M+H]=424.20. stirred at room temperature for 2 h All solvents were removed under reduced pressure Purification (FCC, SiO2, 0-5%, MeOH/DCM)