1-(3-aminoazetidin-1-yl)ethanone

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 1-(3-aminoazetidin-1-yl)ethanone. 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 (t, J=12.4 Hz, 1H) 1.34-1.45 (bq, 2H) 1.57-1.68 (m, 3H) 1.78 (s, 3H) 1.84 (m, 3H) 3.32 (s, 3H) 3.88 (m, 1H) 3.95 (s, 3H) 4.03-4.12 (m, 4H) 4.42 (t, J=8.2 Hz, 1H) 4.45-4.51 (m, 1H) 4.68 (q, J=6.8 Hz, 3H) 7.51 (dd, J=8.3, 1.8 Hz, 1H) 7.54 (d, J=1.5 Hz, 1H) 7.93 (s, 1H) 8.22 (s, 1H) 8.30 (d, J=8.3 Hz, 1H) 8.89 (d, J=6.8 Hz, 1H). [M+H] calc'd for C27H33F2N7O4 558. found 558. 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:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (240 g, 0.69 mol) in i-PrOH (2.5 L) was added 1-(3-amino azetidin-1-yl)ethanone (120 g) and TEA (100 g). After addition, the solution was heated at 60° C. for 16 h, at which time LCMS showed completion of the reaction. The mixture was concentrated and the residue was purified by flash chromatography to give the crude product. Four batches were run in parallel and produced a combined crude product weight of 420 g, 90% purity. This crude was further purified on preparative HPLC to give the title compound (330 g, >98% purity, free base form). 1H NMR (400 MHz, MeOD-d4) 8.27 (s, 1H), 7.12-6.98 (m, 5H), 4.71 (s, 1H), 4.54 (m, 1H), 4.32 (m, 1H), 4.06 (m, 2H), 3.88 (m, 1H), 3.70 (s, 2H), 3.53-3.50 (m, 2H), 2.91-2.83 (m, 4H), 2.65 (m, 2H), 1.88 (s, 3H); LCMS (m/z): 425.2 [M+H]+ After addition completion of the reaction The mixture was concentrated the residue was purified by flash chromatography to give the crude product produced a combined crude product weight of 420 g, 90% purity This crude was further purified on preparative HPLC

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) pyrimi dine-4-carboxamide (240 g, 0.69 mol) in i-PrOH (2.5 L) was added 1-(3-amino azetidin-1-yl)ethanone (120 g) and TEA (100 g). After addition, the solution was heated at 60° C. for 16 h, at which time LCMS showed completion of the reaction. The mixture was concentrated and the residue was purified by flash chromatography to give the crude product. Four batches were run in parallel and produced a combined crude product weight of 420 g, 90% purity. This crude was further purified on preparative HPLC to give the title compound (330 g, >98% purity, free base form). 1H NMR (400 MHz, MeOD-d4) 8.27 (s, 1H), 7.12-6.98 (m, 5H), 4.71 (s, 1H), 4.54 (m, 1H), 4.32 (m, 1H), 4.06 (m, 2H), 3.88 (m, 1H), 3.70 (s, 2H), 3.53-3.50 (m, 2H), 2.91-2.83 (m, 4H), 2.65 (m, 2H), 1.88 (s, 3H); LCMS (m/z): 425.2 [M+H]+ After addition completion of the reaction The mixture was concentrated the residue was purified by flash chromatography to give the crude product produced a combined crude product weight of 420 g, 90% purity This crude was further purified on preparative HPLC

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 1-(3-aminoazetidin-1-yl)ethanone. 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 (t, J=12.4 Hz, 1 H) 1.34-1.45 (bq, 2 H) 1.57-1.68 (m, 3 H) 1.78 (s, 3 H) 1.84 (m, 3 H) 3.32 (s, 3 H) 3.88 (m, 1 H) 3.95 (s, 3 H) 4.03-4.12 (m, 4 H) 4.42 (t, J=8.2 Hz, 1 H) 4.45-4.51 (m, 1 H) 4.68 (q, J=6.8 Hz, 3 H) 7.51 (dd, J=8.3, 1.8 Hz, 1 H) 7.54 (d, J=1.5 Hz, 1 H) 7.93 (s, 1 H) 8.22 (s, 1 H) 8.30 (d, J=8.3 Hz, 1 H) 8.89 (d, J=6.8 Hz, 1 H). [M+H] calc'd for C27H33F2N7O4 558; found 558. 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 1-(3-aminoazetidin-1-yl)ethanone. 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 (t, J=12.4 Hz, 1H) 1.34-1.45 (bq, 2H) 1.57-1.68 (m, 3H) 1.78 (s, 3H) 1.84 (m, 3H) 3.32 (s, 3H) 3.88 (m, 1H) 3.95 (s, 3H) 4.03-4.12 (m, 4H) 4.42 (t, J=8.2 Hz, 1H) 4.45-4.51 (m, 1H) 4.68 (q, J=6.8 Hz, 3H) 7.51 (dd, J=8.3, 1.8 Hz, 1H) 7.54 (d, J=1.5 Hz, 1H) 7.93 (s, 1H) 8.22 (s, 1H) 8.30 (d, J=8.3 Hz, 1H) 8.89 (d, J=6.8 Hz, 1H). [M+H] calc'd for C27H33F2N7O4 558. found 558. 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:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (240 g, 0.69 mol) in i-PrOH (2.5 L) was added 1-(3-amino azetidin-1-yl)ethanone (120 g) and TEA (100 g). After addition, the solution was heated at 60° C. for 16 h, at which time LCMS showed completion of the reaction. The mixture was concentrated and the residue was purified by flash chromatography to give the crude product. Four batches were run in parallel and produced a combined crude product weight of 420 g, 90% purity. This crude was further purified on preparative HPLC to give the title compound (330 g, >98% purity, free base form). 1H NMR (400 MHz, MeOD-d4) 8.27 (s, 1H), 7.12-6.98 (m, 5H), 4.71 (s, 1H), 4.54 (m, 1H), 4.32 (m, 1H), 4.06 (m, 2H), 3.88 (m, 1H), 3.70 (s, 2H), 3.53-3.50 (m, 2H), 2.91-2.83 (m, 4H), 2.65 (m, 2H), 1.88 (s, 3H); LCMS (m/z): 425.2 [M+H]+ After addition completion of the reaction The mixture was concentrated the residue was purified by flash chromatography to give the crude product produced a combined crude product weight of 420 g, 90% purity This crude was further purified on preparative HPLC