Xbridge c18

Example 24

A solution of cis-2-(3-(5′-chloro-2′-hydroxy-3′-(2-methylallyl)-[1,1′-biphenyl]-4-yl)cyclobutoxy)acetic acid (40 mg, 0.10 mmol) in formic acid (0.5 mL) and water (0.05 mL) was heated at 110° C. for 30 h. Volatiles were removed in vacuo and the residue was azeotroped with toluene. The crude product was purified by preparative LC/MS using the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN:H₂O with 0.1% TFA; Mobile Phase B: 95:5 MeCN:H₂O with 0.1% TFA; 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 to provide the title compound (14 mg, 0.04 mmol, 35% yield). LCMS, [M−H]⁺=385.1. ¹H NMR (500 M Hz, DMSO-d₆) δ 7.60 (d, J=7.7 Hz, 2H), 7.32-7.25 (m, 3H), 7.21 (s, 1H), 4.04 (quin, J=7.2 Hz, 1H), 3.92 (s, 2H), 3.06 (s, 2H), 2.98 (quin, J=8.8 Hz, 1H), 2.67-2.57 (m, 2H), 2.00-1.89 (m, 2H), 1.43 (s, 6H). HPLC-4: RT=1.76 min; HPLC-5: RT=2.30 min; purity=99%.

Example 46

To a solution of cis-1-diazo-3-(3-(2′-fluoro-5′-isopropoxy-[1,1′-biphenyl]-4-yl)cyclobutyl) propan-2-one (6 mg, 0.02 mmol) in THF (0.6 mL) and water (0.3 mL) was added AgNO₃ (3 mg, 0.02 mmol). The yellow/green solution was stirred overnight, then was concentrated in vacuo to remove the THF. The resulting slurry was partitioned between H₂O and CH₂Cl₂. The aqueous layer was extracted with CH₂Cl₂ (5×10 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO₄) and concentrated in vacuo. The residue was purified by preparative LC/MS using the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN:H₂O with 0.1% TFA; Mobile Phase B: 95:5 MeCN:H₂O with 0.1% TFA; 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 to provide the desired product (4 mg, 10.89 μmol, 67% yield). LCMS, [M−H]⁺=355.2. ¹H NMR (500M Hz, DMSO-d₆) δ 7.46 (d, J=7.2 Hz, 2H), 7.30 (d, J=7.4 Hz, 2H), 7.18 (t, J=9.6 Hz, 1H), 6.99-6.87 (m, 2H), 4.67-4.57 (m, 1H), 2.47-2.39 (m, 3H), 2.27-2.10 (m, 3H), 1.73-1.58 (m, 4H), 1.26 (d, J=5.8 Hz, 6H). HPLC-4: RT=2.08 min; HPLC-5: RT=2.34 min; purity=97%.

EXAMPLE 84

To the above crude reaction mixture was added MeOH (0.5 mL), water (0.5 mL) and LiOH.H₂O (17 mg, 0.7 mmol). The mixture was heated to 100° C. for 30 min in a microwave reactor, then was cooled to rt and concentrated in vacuo. The residue was acidified with 1N aq. HCl to pH=2-3, then was extracted with EtOAc (3×5 mL). The combined organic extracts were dried over MgSO₄ and concentrated in vacuo. The crude product was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×100 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-am particles; Mobile Phase A: 5:95 MeCN:water with 0.1% TFA; Mobile Phase B: 95:5 MeCN:water with 0.1% TFA; Gradient: 20-60% 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 afford the title compound (8 mg, 62% yield). LCMS, [M+H]⁺=363.2. ¹H NMR (500 MHz, DMSO-d₆) δ 7.93 (d, J=3.2 Hz, 1H), 7.37-7.25 (m, 7H), 6.94 (d, J=8.1 Hz, 2H), 5.22 (s, 2H), 3.99 (dt, J=9.8, 4.1 Hz, 1H), 3.88-3.77 (m, 1H), 2.25 (d, J=3.0 Hz, 3H), 1.70 (s, 1H), 1.60 (h, J=4.0 Hz, 1H), 1.08 (dq, J=8.3, 4.1 Hz, 1H), 0.96 (dt, J=8.7, 4.5 Hz, 1H). HPLC-4: RT=1.32 min, purity=99%; HPLC-5: RT=1.61 min, purity=99%.

Example 95

To a solution of tert-butyl 4-(3-isopropyl-2-(8-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin e-1-carboxylate (140 mg, 0.279 mmol) in DCM (10 mL) was added 4 M HCl in dioxane (5 mL) at ambient temperature. The mixture was stirred at the same temperature for 1 h. The solution was concentrated to afford crude product. The crude sample was purified by preparative LCMS with the following conditions: Waters Xbridge C18, 19×150 mm, 5 μm; Guard Column: Waters Xbridge C18, 19×10 mm, 5 μm; Mobile Phase A:5:95 Methanol:water with 10 mM NH₄OAc; Mobile Phase B: 95:5 Methanol:water with 10 mM NH₄OAc; Gradient: 15-65% B over 25 minutes, followed by a 10 minute hold at 65% B and 5 minute hold at 100% B; Flow: 15 mL/min. Fractions containing the product were combined and dried using a Genevac centrifugal evaporator to provide 8-isopropyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.5 mg, 1.3%) as a white solid. LC retention time=1.49 min [E]. MS (E⁻) m/z: 402 (M+H).

Example 39

A mixture of trans-2-(3-(4-bromophenyl)cyclobutoxy)acetic acid (15 mg, 0.05 mmol), (2-fluoro-5-phenoxyphenyl)boronic acid (18 mg, 0.08 mmol), (Ph₃P)₄Pd (6 mg, 5.26 μmol) and K₂CO₃ (22 mg, 0.16 mmol) in THF (2 mL) and water (0.7 mL) was heated in a microwave reactor at 130° C. for 20 min under Ar, then was cooled to rt. The reaction was acidified with 1N aq. HCl to pH=2-3, and extracted with EtOAc (4×10 mL). The combined organic extracts were dried (MgSO₄) and concentrated in vacuo. The residue was purified by preparative LC/MS using the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN:H₂O with 0.1% TFA; Mobile Phase B: 95:5 MeCN:H₂O with 0.1% TFA; 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 to provide the title compound (12 mg, 0.03 mmol, 54% yield). LCMS, [M−H]⁺=391.1. ¹H NMR (500 MHz, DMSO-d₆) δ 7.48 (d, J=7.7 Hz, 2H), 7.42-7.30 (m, 5H), 7.17-7.12 (m, 2H), 7.08-7.00 (m, 3H), 4.29-4.21 (m, 1H), 3.92 (s, 2H), 3.61-3.52 (m, 1H), 2.46-2.28 (m, 4H). HPLC-4: RT=1.74 min; HPLC-5: RT=2.26 min; purity=96%.