(3S,4R)-pyrrolidine-3,4-diol

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (3R,4S)-pyrrolidine-3,4-diol and isolated as light-yellow gum (10.3 mg, 54%). MS (m/e): 403.4 (MH+).

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

Procedure: The title compound was prepared in an analogous fashion to that described in Stage 71.1 using 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 169.2) and cis-pyrrolidine-3,4-diol (Stage 249.2). After purification by flash chromatography on Silica gel, the oily residue was taken-up in a toluene/MeOH mixture then evaporated to dryness under reduced pressure and dried to yield the title product as a white amorphous solid. UPLC-MS (Condition 3) tR=1.0 min, m/z=477.8-479.9 [M+H], m/z=475.8-477.9 [M−H]. The title compound was prepared in an analogous fashion to After purification by flash chromatography on Silica gel then evaporated to dryness under reduced pressure dried

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

Procedure: A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 1 g, 2.53 mmol) and (3R,4S)-pyrrolidine-3,4-diol (313 mg, 3.03 mmol) in a mixture of DIPEA (0.883 mL, 5.06 mmol) and iPrOH (2.53 mL) was subjected to MW irradiation at 140° C. for 30 min. The RM was treated with 0.5 M aq. HCl (30 mL) and extracted with EtOAc. The combined extracts were washed with sat. NaHCO3, brine and dried over Na2SO4. The crude product was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 50% to 100% EtOAc) to yield the title compound as a white amorphous solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=462.1-464.0 [M+H]+, m/z=460.1-462.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.61 (dd, J=11.13, 4.28 Hz, 2H) 3.84 (dd, J=10.76, 4.89 Hz, 2H) 4.10 (d, J=3.42 Hz, 2H) 4.96 (d, J=3.91 Hz, 2H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=8.80 Hz, 2H) 8.34 (s, 1H) 8.67 (s, 1H) 10.21 (s, 1H). was subjected to MW irradiation at 140° C. for 30 min extracted with EtOAc The combined extracts were washed with sat. NaHCO3, brine dried over Na2SO4 The crude product was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 50% to 100% EtOAc)

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

Procedure: A solution of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 500 mg, 1.32 mmol), (3S,4R)-pyrrolidine-3,4-diol (170 mg, 1.65 mmol) and TEA (369 μL, 2.64 mmol) in DMSO (1322 μL) was stirred at 90° C. for 20 h. The RM was treated with 0.5 M HCl (15 mL) and extracted with EtOAc (30 mL). The aq. phase was back-extracted with EtOAc (2×20 mL) and the combined organic layers were washed with sat. NaHCO3 and brine, and dried over Na2SO4. The crude product was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 50% to 100% EtOAc) to yield the title compound as a white amorphous solid. UPLC-MS (Condition 3) tR=1.02 min, m/z=461.2-463.1 [M+H]+, m/z=459.1-461.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.40 (dd, J=9.90, 4.52 Hz, 2H) 3.67 (dd, J=9.66, 5.26 Hz, 2H) 4.06-4.16 (m, 2H) 4.94 (d, J=4.65 Hz, 2H) 6.86 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.80-7.91 (m, 3H) 8.13 (d, J=2.20 Hz, 1H) 10.17 (s, 1H). extracted with EtOAc (30 mL) The aq. phase was back-extracted with EtOAc (2×20 mL) the combined organic layers were washed with sat. NaHCO3 and brine dried over Na2SO4 The crude product was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 50% to 100% EtOAc)

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

Procedure: A solution of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 500 mg, 1.32 mmol), (3S,4R)-pyrrolidine-3,4-diol (170 mg, 1.65 mmol) and TEA (369 μL, 2.64 mmol) in DMSO (1322 μL) was stirred at 90° C. for 20 h. The RM was treated with 0.5 M HCl (15 mL) and extracted with EtOAc (30 mL). The aq. phase was back-extracted with EtOAc (2×20 mL) and the combined organic layers were washed with sat. NaHCO3 and brine, and dried over Na2SO4. The crude product was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 50% to 100% EtOAc) to yield the title compound as a white amorphous solid. UPLC-MS (Condition 3) tR=1.02 min, m/z=461.2-463.1 [M+H]+, m/z=459.1-461.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.40 (dd, J=9.90, 4.52 Hz, 2H) 3.67 (dd, J=9.66, 5.26 Hz, 2H) 4.06-4.16 (m, 2H) 4.94 (d, J=4.65 Hz, 2H) 6.86 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.80-7.91 (m, 3H) 8.13 (d, J=2.20 Hz, 1H) 10.17 (s, 1H). extracted with EtOAc (30 mL) The aq. phase was back-extracted with EtOAc (2×20 mL) the combined organic layers were washed with sat. NaHCO3 and brine dried over Na2SO4 The crude product was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 50% to 100% EtOAc)

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

Procedure: cis-3,4-Dihydroxypyrrolidine (Preparation 23, 9 mg, 0.087 mmol) was added to a solution of 3-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(S)-hydroxy-4-phenylbutyric acid (EXAMPLE 124, 30 mg, 0.080 mmol), HOBt (14 mg, 0.091 mmol), DIPEA (31 μL, 0.18 mmol) and EDCI (18 mg, 0.094 mmol) in DMF (3 mL). After stirring for 12 h the mixture was added to diluted brine (100 mL, water/brine: 1/1). Extraction with ethyl acetate (4×25 mL), washing of the combined extracts with brine (50 mL) and drying (MgSO4) gave, after concentration, a residue which was purified by preparative LCMS to give the title compound as a colourless solid. m/z (ES+)=459.29 [M+H]+; RT=2.87 min. Extraction with ethyl acetate (4×25 mL) washing of the combined extracts with brine (50 mL) drying (MgSO4) gave after concentration a residue which was purified by preparative LCMS

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

Procedure: To a solution of (S)-3-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(R)-hydroxy-4-phenylbutyric acid (EXAMPLE 44, 50 mg, 0.13 mmol), cis-3,4-dihydroxypyrrolidine (Preparation 23, 15 mg, 0.15 mmol) and HOBt (27 mg, 0.20 mmol) in DMF (5 mL), was added DIPEA (47 μL, 0.27 mmol). After stirring for 5 min, EDCI (28 mg, 0.15 mmol) was added and the reaction stirred at rt for 72 h. The solvent was removed in vacuo and the residue partitioned between water (30 mL) and ethyl acetate (3×30 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with methanol/dichloromethane (1:9) to give the title compound as a white solid. m/z (ES+)=459 [M+H]+. RT=3.07 min. the reaction stirred at rt for 72 h The solvent was removed in vacuo the residue partitioned between water (30 mL) and ethyl acetate (3×30 mL) The combined organic fractions were dried (MgSO4) concentrated in vacuo the residue purified by chromatography on silica gel eluting with methanol/dichloromethane (1:9)

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (3R,4S)-pyrrolidine-3,4-diol and isolated as light-yellow gum (10.3 mg, 54%). MS (m/e): 403.4 (MH+).

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (3R,4S)-pyrrolidine-3,4-diol and isolated as light-yellow gum (10.3 mg, 54%). MS (m/e): 403.4 (MH+).

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (3R,4S)-pyrrolidine-3,4-diol and isolated as light-yellow gum (10.3 mg, 54%). MS(m/e): 403.4 (MH+).

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

Procedure: cis-3,4-Dihydroxypyrrolidine (Preparation 23, 9 mg, 0.087 mmol) was added to a solution of 3-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(S)-hydroxy-4-phenylbutyric acid (EXAMPLE 124, 30 mg, 0.080 mmol), HOBt (14 mg, 0.091 mmol), DIPEA (31 μL, 0.18 mmol) and EDCI (18 mg, 0.094 mmol) in DMF (3 mL). After stirring for 12 h the mixture was added to diluted brine (100 mL, water/brine: 1/1). Extraction with ethyl acetate (4×25 mL), washing of the combined extracts with brine (50 mL) and drying (MgSO4) gave, after concentration, a residue which was purified by preparative LCMS to give the title compound as a colourless solid. m/z (ES+)=459.29 [M+H]+; RT=2.87 min. Extraction with ethyl acetate (4×25 mL) washing of the combined extracts with brine (50 mL) drying (MgSO4) gave after concentration a residue which was purified by preparative LCMS

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

Procedure: To a solution of (S)-3-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(R)-hydroxy-4-phenylbutyric acid (EXAMPLE 44, 50 mg, 0.13 mmol), cis-3,4-dihydroxypyrrolidine (Preparation 23, 15 mg, 0.15 mmol) and HOBt (27 mg, 0.20 mmol) in DMF (5 mL), was added DIPEA (47 μL, 0.27 mmol). After stirring for 5 min, EDCI (28 mg, 0.15 mmol) was added and the reaction stirred at rt for 72 h. The solvent was removed in vacuo and the residue partitioned between water (30 mL) and ethyl acetate (3×30 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with methanol/dichloromethane (1:9) to give the title compound as a white solid. m/z (ES+)=459 [M+H]+. RT=3.07 min. the reaction stirred at rt for 72 h The solvent was removed in vacuo the residue partitioned between water (30 mL) and ethyl acetate (3×30 mL) The combined organic fractions were dried (MgSO4) concentrated in vacuo the residue purified by chromatography on silica gel eluting with methanol/dichloromethane (1:9)