1,4-diMethyl-1H-1,2,3-triazole

The compound 1G (1.02 g, 1.9 mmol), A vessel containing (S)-6-(5-bromo-1-(trans-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)- 1 -(3 , 4-difluorophenyl)piperidin-2-one (intermediate 17, 50 mg, 0.10 mmol), 1, 4-Dimethyl-1H-1, 2, 3-triazole (0.057 g, 0.588 mmol), potassium acetate (0.192 g, 1.960 mmol), PdOAc2 (8.80 mg, 0.039 mmol) and di((3S, 5S, 7S)-adamantan-1-yl)(butyl)phosphine (cataCXium A) (0.028 g, 0.078 mmol) were suspended in 2- methylbutan-2-ol (2.57 ml, 23.51 mmol) under nitrogen. The reaction mixture was purged with nitrogen for 5 mm and then ()-5-(5-bromo-1-(4, 4-difluorocyclohexyl)-1H- benzo[d]imidazol-2-yl)-1-(3, 4-difluoro phenyl)pyrrolidin-2-one (0.2 g, 0.392 mmol) was added. The green suspension was heated to 100C for 24h. The reaction was cooledto RT and partitioned between EtOAc (40 mL) and water (30 ml). The organic phase was separated, washed with brine (25 ml) and then dried over MgSO4, filtered and concentrated in vacuo to afford a yellow oil.The crude product was purified by chromatography on silica gel (24 g column, 0-5% MeOH/DCM) to afford (S)-5-(1-(4, 4- difluorocyclohexyl)-5 -(1 , 4-dimethyl- 1 H- 1, 2, 3 -triazol-5 -yl)- 1 H-benzo[d] imidazol-2-yl)-1-(3, 4-difluorophenyl)pyrrolidin-2-one (69.5 mg, 33%) as beige solid; Rt 2.02 mm(method 1), mlz 527 (M+H)+ (ES+); 1H NIVIR (d6-DMSO) : 7.86 (ddd, J = 13.3, 7.4, 2.7 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.38 (q, J = 10.6, 9.2 Hz, 1H), 7.32 (dd, J = 8.5, 1.7 Hz, 1H), 7.22 - 7.14 (m, 1H), 6.12 - 6.06 (m, 1H), 4.88 - 4.77(m, 1H), 3.90 (s, 3H), 2.81 -2.61 (m, 2H), 2.61 -2.42 (m, 3H), 2.31 -2.21 (m, 3H), 2.19 (s, 3H), 2.17- 1.93 (m, 4H).1, 4-Dimethyl-1H-1, 2, 3-triazole (27.4 mg, 0.282 mmol), potassium acetate (92 mg, 0.939 mmol), PdOAc2 (4.22 mg, 0.019 mmol), (1S, 4r)-4-(5-bromo-2-((5)-1-(3, 4- difluorophenyl)-5 -oxopyrrolidin-2-yl)- 1H-benzo[d] imidazol- 1 -yl)cyclohexyl acetate (100 mg, 0.188 mmol) and cataCXium A (13.47 mg, 0.038 mmol) were suspended in 2-methylbutan-2-ol (1234 pi, 11.27 mmol) under nitrogen. The reaction mixture was purged with nitrogen for 5 mm and then heated to 100C for 18 h. The reaction was cooled to RT and partitioned between EtOAc (40 mL) and water (30 mL). The organicphase was separated, washed with brine (25 mL) and then dried over MgSO4, filtered and concentrated in vacuo to afford a yellow oil, which was purified by chromatography on silica gel (24 g column, 0-5% MeOHIDCM) to afford (1S, 4r)-4-(2-((5)-1-(3, 4- difluorophenyl)-5 -oxopyrrolidin-2-yl)-5 -(1 , 4-dimethyl- 1 H- 1, 2, 3 -triazol-5 -yl)- 1H- benzo[d]imidazol-1-yl)cyclohexyl acetate (38 mg, 36%) as a colourless solid; Rt 1.93mm (method 1), m/z 549; 1H NMR (d6-DMSO) : 8.06 (1H, d, J=8.6 Hz), 7.84 (1H, ddd, J13.3, 7.4, 2.7 Hz), 7.73 (1H, d, J1.6 Hz), 7.38 (1H, dt, J=10.6, 9.2 Hz), 7.24(1H, dd, J=8.5, 1.7 Hz), 7.16 (OH, d, J=9.3 Hz), 6.13 (1H, d, J7.4 Hz), 5.06-4.94 (1H, m), 4.60 (1H, t, J=12.5 Hz), 3.90 (3H, s), 2.81 - 2.53 (3H, m), 2.48 - 2.39 (2H, m), 2.19(3H, s), 2.15 -2.05 (4H, m), 2.04 (3H, s), 1.98 - 1.88 (1H, m), 1.88 - 1.79 (1H, m), 1.79- 1.63 (2H, m).(R)-l-(7-Chloro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrrolo[2, 3- b:4, 5-b']dipyridin-3-yl)ethanone (30.0 mg, 0.071 mmol), l, 4-dimethyl-lH-l, 2, 3-triazole (10.4 mg, 0.107 mmol), tetramethylammonium acetate (11.4 mg, 0.086 mmol), and PdCl2(PPh3)2 (5.0 mg, 7.1 muetaiotaomicron) were weighed into a 20 mL scintillation vial. DMF (2 mL) was added and the air replaced with nitrogen. The reaction mixture was stirred at 100 C ovemight. The reaction was cooled to room temperature, diluted with EtOAc, and washed twice with brine. The organic layer was dried over MgSC>4 and concentrated. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-mupiiota particles; Mobile Phase A: 5:95 methanol: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 10- mM ammonium acetate; Gradient: 50-90% B over 20 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 84%. LC/MS [M+H]+ = 481 NMR (500MHz, DMSO-de) delta 9.13 (s, 1H), 8.84 (d, J=8.1 Hz, 2H), 7.72 (d, J=8.1 Hz, 3H), 7.33 - 7.28 (m, 2H), 7.25 - 7.21 (m, 1H), 6.04 (br. s., 1H), 4.34 (s, 3H), 3.89 (d, J=10.3 Hz, 1H), 3.72 (d, J=9.2 Hz, 1H), 3.58 (br. s., 1H), 3.51 (s, 3H), 3.46 - 3.39 (m, 1H), 3.25 - 3.15 (m, 1H), 2.78 (s, 3H), 1.59 (br. s., 1H), 1.51 (d, J=8.8 Hz, 1H), 1.31 (d, J=10.3 Hz, 1H), 1.07 (d, J=14.3 Hz, 1H).In a pressure vessel equipped with a magnetic stirring bar was added 3-bromo-7- chloro-5-((4, 4-difluorocyclohexyl)(phenyl)methyl)-5H-pyrrolo[2, 3-b:4, 5-b']dipyridine (240 mg, 0.489 mmol), l , 4-dimethyl-lH-l , 2, 3-triazole (52.2 mg, 0.538 mmol) and DMF (5 mL). Tetramethylammonium acetate (98 mg, 0.734 mmol) and PdCl2(dppf)-CH2Cl2 adduct (28.0 mg, 0.034 mmol) was added. Argon was bubbled into the mixture with sonication for 5 min, then the vessel was capped, placed into a preheated aluminum block set at 100C and was stirred for 16 h. Solids were filtered, and the filtrate was purified by preparative HPLC (20-100% B; B solvent 90% MeCN/0.1% TFA water, Phenomenex LUNA C18 30xl00mm, 10 micron, 30 mL/min flow rate, 254nm UV; Rt = 1 1.6 min.). Like fractions were concentrated and re-purified by preparative HPLC: Column: Waters XBridge C 18, 19 x 200 mm, 5-mupiiota particles; Mobile Phase A: 5 :95 methanol: water with lOmM NH40Ac; Mobile Phase B: 95:5 methanol: water with lOmM NFLtOAc; Gradient: 40-80% B over 15 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give 18 mg of a mixture of enantiomers. This material was subject to a chiral purification: Chiral SFC conditions: Chiralcel OJ-H preparative column, 30 x 250mm, 5muiotaeta; Mobile Phase: 15% methanol in CO2, 150 bar; Temp: 35C; Flow rate: 70.0 mL/min. for 25 min. ; UV monitored at 254nm; Injection: 0.25ml of ~9 mg/mL solution in MeOH (18 mg purified by stacked injection); Rt = isomer A: 13.8 min. ; isomer B: 18.3 min. Fractions containing the desired products were combined and dried via evaporation to give 6.9 mg (2%) of the isomer A with an average purity by LC/MS analysis was >99%. Fractions containing the desired products were combined and dried via evaporation to give 7.5 mg (3%) of the isomer B with an average purity by LC/MS analysis was >99%. Isomer A: Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7muetaiota particles; Mobile Phase A: 5:95 ACN:water with 10 mM NlrUOAc; Mobile Phase B: 95:5 ACN:water with 10 mM NH4OAc; Temperature: 50C; Gradient: 0%B, 0-100% B over 3 min, then a 0.5-min hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm. Rt = 1.76 min.; LC/MS (M+H) = 568.7. Injection 2 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7-muetaiota particles; Mobile Phase A: 5:95 methanol: water with 10 mM NFL Ac; Mobile Phase B: 95:5 methanol: water with 10 mM NFL Ac; Temperature: 50C; Gradient: 0%B, 0-100% B over 3 min, then a 0.5-min hold at 100% B; Flow: 0.5 mL/min; Detection: UV at 220 nm. Rt= 2.77 min.; LC/MS (M+H) = 568.7. Isomer B: Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7mupiiota particles; Mobile Phase A: 5:95 ACN:water with 10 mM NH4OAc; Mobile Phase B: 95:5 ACN:water with 10 mM MLtOAc; Temperature: 50C; Gradient: 0%B, 0-100% B over 3 min, then a 0.5-min hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm. Rt= 1.86 min.; LC/MS (M+H) = 568.7. Injection 2 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7-mupiiota particles; Mobile Phase A: 5:95 methanol: water with 10 mM MLtOAc; Mobile Phase B: 95:5 methanol: water with 10 mM MLtOAc; Temperature: 50C; Gradient: 0%B, 0-100% B over 3 min, then a 0.5-min hold at 100% B; Flow: 0.5 mL/min; Detection: UV at 220 nm. Rt= 2.73 min.; LC/MS (M+H) = 568.7. NMR (500MHz, DMSO-c e) delta 8.82 (d, J=8.1 Hz, 1H), 8.67 (s, 1H), 8.54 (br. s., 1H), 7.73 (d, J=8.1 Hz, 3H), 7.32 (t, J=7.5 Hz, 2H), 7.25 (t, J=7.3 Hz, 1H), 6.09 (br. s., 1H), 4.36 (s, 3H), 4.02 (s, 3H), 3.52 (br. s., 1H), 2.30 (s, 3H), 2.07 (br. s., 1H), 1.92 (d, J=7.3 Hz, 1H), 1.82 (br. s., 1H), 1.73 (br. s., 1H), 1.66 (br. s., 1H), 1.45 (d, J=12.1 Hz, 1H), 1.37 (br. s., 1H), 1.30 (d, J=11.7 Hz, 1H). LC/MS (M+H) = 568.2; HPLC conditions: Rt= 0.93 min. (Column: Waters Aquity BEH C18 2.1 X 50 mm 1.7u; Mobile Phase A: water with 0.05% TFA; Mobile Phase B: ACN with 0.05% TFA; Temperature: 40C; Gradient: 2-98% B over 1.5 min; Flow: 0.8 mL/min).In a 75 mL pressure vessel equipped with a magnetic stirring bar, was added (5)- 3-bromo-7-chloro-5-((2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrrolo[2, 3- b:4, 5-b']dipyridine (650 mg, 1.37 mmol), l, 4-dimethyl-lH-l, 2, 3-triazole (199 mg, 2.05 mmol) and NMP (10 mL). Tetramethyl NH4OAC (274 mg, 2.05 mmol) and bis(triphenylphosphine) palladium(II) chloride (67.3 mg, 0.096 mmol) was added. Argon was bubbled into the mixture with sonication for 5 min, then the vessel was capped and placed into a preheated oil bath at 100C. The reaction mixture was stirred overnight. Most of the solvent was removed under a stream of nitrogen while heating for several hours in an oil bath set at 100C. The remaining mixture was taken up in 2 mL of DMF then filtered for purification by preparative HPLC: Column: Waters XBridge CI 8, 19 x 200 mm, 5-muiotatauiota particles; Mobile Phase A: 5:95 methanol: water with lOmM NLUOAc; Mobile Phase B: 95:5 methanol: water with lOmM NHtOAc; Gradient: 10-80% B over 30 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give 4.7 mg (0.6%) of the title compound with an average purity by LC/MS analysis was >99%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7um particles; Mobile Phase A: 5:95 ACN:water with 10 mM NH4OAc; Mobile Phase B: 95:5 ACN:water with 10 mM NH4OAc; Temperature: 50C; Gradient: 0%B, 0-100% B over 3 min, then a 0.5-min hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm. Rt= 1.50 min; LC/MS (M+H) = 552.5. Injection 2 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7-mupiiota particles; Mobile Phase A: 5:95 methanol: water with 10 mM NFL Ac; Mobile Phase B: 95:5 methanol: water with 10 mM NH4OAc; Temperature: 50C; Gradient: 0%B, 0-100% B over 3 min, then a 0.5-min hold at 100% B; Flow: 0.5 mL/min; Detection: UV at 220 nm. Rt= 2.51 min; LC/MS (M+H) = 552.5. NMR (500MHz, DMSO-c e) delta 8.81 (d, J=8.1 Hz, 1H), 8.68 (s, 1H), 8.46 (br. s., 1H), 8.20 (br. s., 1H), 7.71 (d, J=8.1 Hz, 1H), 7.34 (d, J=5.5 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.17 - 7.04 (m, 1H), 6.36 (br. s., 1H), 4.34 (br. s., 3H), 4.00 (br. s., 3H), 3.93 - 3.83 (m, 1H), 3.72 (d, J=9.5 Hz, 1H), 3.47 - 3.38 (m, 4H), 3.27 - 3.15 (m, 1H), 2.29 (br. s., 3H), 1.72 (d, J=11.7 Hz, 1H), 1.58 - 1.42 (m, 1H), 1.33 (d, J=12.1 Hz, 1H), 0.98 (d, J=13.2 Hz, 1H). LC/MS (M+H) = 552.5; HPLC conditions: Rt= 2.57 min (Phenomenex LUNA C18 2 x 50 mm (4 min grad) eluting with 5-95% aq ACN containing lOmM NH4OAC, 0.8 mL/min, monitoring at 254 nm); Temperature: 40C).In a 75 mL pressure vessel equipped with a magnetic stirring bar was added (

Molecular Weight:97.12
XLogP3:0.1
Hydrogen Bond Acceptor Count:2
Exact Mass:97.063997236
Monoisotopic Mass:97.063997236
Topological Polar Surface Area:30.7
Heavy Atom Count:7
Complexity:64
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes