2-(oxetan-3-yl)ethanol

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

Procedure: At 0° C., to a solution of 2-(3-oxetanyl)ethanol (according to the synthesis procedure in the reference: Journal of American Chemical Society, 2009, 131, 2786-2787.) (193 mg, 1.89 mmol) in CH2Cl2 (15 mL) was added DABCO (847 mg, 7.56 mmol) and TsCl (1.43 g, 7.56 mmol) was then added dropwise, the mixture was stirred for 15 minutes. After filtration, the filter cake was washed with CH2Cl2 and the filtrate was washed twice with water. The organic phase was dries over anhydrous sodium sulphate. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5:1) to afford the target compound. was then added dropwise After filtration the filter cake was washed with CH2Cl2 the filtrate was washed twice with water The solvent was evaporated under vacuum The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5:1) to afford the target compound

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

Procedure: At 0° C., to a solution of 2-(3-oxetanyl)ethanol (according to the synthesis procedure in the reference: Journal of American Chemical Society, 2009, 131, 2786-2787.) (193 mg, 1.89 mmol) in CH2Cl2 (15 mL) was added DABCO (847 mg, 7.56 mmol) and TsCl (1.43 g, 7.56 mmol) was then added dropwise, the mixture was stirred for 15 minutes. After filtration, the filter cake was washed with CH2Cl2 and the filtrate was washed twice with water. The organic phase was dries over anhydrous sodium sulphate. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5:1) to afford the target compound. was then added dropwise After filtration the filter cake was washed with CH2Cl2 the filtrate was washed twice with water The solvent was evaporated under vacuum The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5:1) to afford the target compound

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

Procedure: To a stirred suspension of 5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (i) (11 mg, 0.03 mmol) and 2-(oxetan-3-yl)ethanol (5.6 mg, 0.06 mmol) in THF (200 μL) was added triphenylphosphine (11 mg, 0.04 mmol) followed by DIAD (8 μL, 0.04 mmol). The suspension dissolved slowly upon stirring. LCMS analysis of the reaction after 2.5 hr showed the presence of starting material and further aliquots of triphenylphosphine (5.0 mg, 0.05 mmol) and DIAD (8 μL, 0.04 mmol) were added. After stirring for 2 h, the reaction was diluted with EtOAc (10 mL), the organics washed with water (10 mL), brine (10 mL) and dried (MgSO4). The organics were concentrated in vacuo and the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid: DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide followed by MeOH: DCM (gradient elution, 0% to 20%, 20 CV) to give Compound (5) (7.8 mg, 59%). ESI-MS m/z calculated for [M+H]+: 484.2. found: 484.2. 1H NMR (400 MHz, CDCl3) δ 8.47 (brs, 1H), 8.36 (s, 1H), 7.83-7.76 (m, 2H), 7.72 (s, 1H), 7.60 (s, 1H), 4.84-4.71 (m, 2H), 4.34 (q, J=6.0 Hz, 2H), 3.74-3.56 (m, 2H), 3.10-2.99 (m, 7H), 2.47 (s, 3H), 2.30 (ddd, J=13.6, 8.3, 5.4 Hz, 1H), 2.07-1.95 (m, 2H), 1.09-0.94 (m, 3H), 0.65-0.56 (m, 1H). The suspension dissolved slowly LCMS analysis of the reaction after 2.5 hr were added After stirring for 2 h the organics washed with water (10 mL), brine (10 mL) dried (MgSO4) The organics were concentrated in vacuo the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide

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

Procedure: To a stirred solution of 2-(oxetan-3-yl)ethyl methanesulfonate (11 mg, 0.06 mmol, prepared by treating 2-(oxetan-3-yl)ethanol with methanesulfonyl chloride in DCM in the presence of DIPEA) was added 5-cyclopropyl-6-(methanesulfonamido)-N-methyl-2-(p-tolyl)indazole-3-carboxamide (24 mg, 0.06 mmol) followed by potassium carbonate (68 mg, 0.49 mmol). The resultant suspension was heated at 60° C. for 18 h whereupon another portion of (oxetan-3-yl)ethyl methanesulfonate (81 mg, 0.45 mmol) in ACN (2 mL) was added and heating/stirring continued. After 24 h, the reaction mixture was diluted with EtOAc (15 mL) and the organics washed with water (20 mL). The aqueous layer was back-extracted into EtOAc (15 mL) and the combined organics were then washed with brine (10 mL), dried (MgSO4) and the volatiles removed in vacuo. The residue was purified by preparative HPLC eluting with ACN:0.1% formic acid in water (gradient elution, 5% to 30% to 40% to 100%) to give Compound (3) (4 mg, 14%). ESI-MS m/z calculated for [M+H]+: 483.2 found: 483.1. 1H NMR (400 MHz, CD3CN) δ 7.78 (s, 1H), 7.58 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.40 (d, J=7.94 Hz, 2H), 5.63 (brs, 1H), 4.86-4.78 (m, 2H), 4.40-4.33 (m, 2H), 3.70 (t, J=7.94 Hz, 2H), 3.18-3.05 (m, 4H), 2.98 (d, J=5.0 Hz, 3H), 2.51 (s, 3H), 2.47-2.38 (m, 1H), 2.17-1.97 (m, 2H), 1.19-1.03 (m, 3H), 0.72-0.63 (m, 1H). was added the organics washed with water (20 mL) The aqueous layer was back-extracted into EtOAc (15 mL) the combined organics were then washed with brine (10 mL) dried (MgSO4) the volatiles removed in vacuo The residue was purified by preparative HPLC eluting with ACN

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

Procedure: To a stirred suspension of 5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (i) (11 mg, 0.03 mmol) and 2-(oxetan-3-yl)ethanol (5.6 mg, 0.06 mmol) in THF (200 μL) was added triphenylphosphine (11 mg, 0.04 mmol) followed by DIAD (8 μL, 0.04 mmol). The suspension dissolved slowly upon stirring. LCMS analysis of the reaction after 2.5 hr showed the presence of starting material and further aliquots of triphenylphosphine (5.0 mg, 0.05 mmol) and DIAD (8 μL, 0.04 mmol) were added. After stirring for 2 h, the reaction was diluted with EtOAc (10 mL), the organics washed with water (10 mL), brine (10 mL) and dried (MgSO4). The organics were concentrated in vacuo and the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid: DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide followed by MeOH: DCM (gradient elution, 0% to 20%, 20 CV) to give Compound (5) (7.8 mg, 59%). ESI-MS m/z calculated for [M+H]+: 484.2. found: 484.2. 1H NMR (400 MHz, CDCl3) δ 8.47 (brs, 1H), 8.36 (s, 1H), 7.83-7.76 (m, 2H), 7.72 (s, 1H), 7.60 (s, 1H), 4.84-4.71 (m, 2H), 4.34 (q, J=6.0 Hz, 2H), 3.74-3.56 (m, 2H), 3.10-2.99 (m, 7H), 2.47 (s, 3H), 2.30 (ddd, J=13.6, 8.3, 5.4 Hz, 1H), 2.07-1.95 (m, 2H), 1.09-0.94 (m, 3H), 0.65-0.56 (m, 1H). The suspension dissolved slowly LCMS analysis of the reaction after 2.5 hr were added After stirring for 2 h the organics washed with water (10 mL), brine (10 mL) dried (MgSO4) The organics were concentrated in vacuo the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide

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

Procedure: To a stirred solution of 2-(oxetan-3-yl)ethyl methanesulfonate (11 mg, 0.06 mmol, prepared by treating 2-(oxetan-3-yl)ethanol with methanesulfonyl chloride in DCM in the presence of DIPEA) was added 5-cyclopropyl-6-(methanesulfonamido)-N-methyl-2-(p-tolyl)indazole-3-carboxamide (24 mg, 0.06 mmol) followed by potassium carbonate (68 mg, 0.49 mmol). The resultant suspension was heated at 60° C. for 18 h whereupon another portion of (oxetan-3-yl)ethyl methanesulfonate (81 mg, 0.45 mmol) in ACN (2 mL) was added and heating/stirring continued. After 24 h, the reaction mixture was diluted with EtOAc (15 mL) and the organics washed with water (20 mL). The aqueous layer was back-extracted into EtOAc (15 mL) and the combined organics were then washed with brine (10 mL), dried (MgSO4) and the volatiles removed in vacuo. The residue was purified by preparative HPLC eluting with ACN:0.1% formic acid in water (gradient elution, 5% to 30% to 40% to 100%) to give Compound (3) (4 mg, 14%). ESI-MS m/z calculated for [M+H]+: 483.2 found: 483.1. 1H NMR (400 MHz, CD3CN) δ 7.78 (s, 1H), 7.58 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.40 (d, J=7.94 Hz, 2H), 5.63 (brs, 1H), 4.86-4.78 (m, 2H), 4.40-4.33 (m, 2H), 3.70 (t, J=7.94 Hz, 2H), 3.18-3.05 (m, 4H), 2.98 (d, J=5.0 Hz, 3H), 2.51 (s, 3H), 2.47-2.38 (m, 1H), 2.17-1.97 (m, 2H), 1.19-1.03 (m, 3H), 0.72-0.63 (m, 1H). was added the organics washed with water (20 mL) The aqueous layer was back-extracted into EtOAc (15 mL) the combined organics were then washed with brine (10 mL) dried (MgSO4) the volatiles removed in vacuo The residue was purified by preparative HPLC eluting with ACN

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

Procedure: To a stirred solution of 2-(oxetan-3-yl)ethyl methanesulfonate (11 mg, 0.06 mmol, prepared by treating 2-(oxetan-3-yl)ethanol with methanesulfonyl chloride in DCM in the presence of DIPEA) was added 5-cyclopropyl-6-(methanesulfonamido)-N-methyl-2-(p-tolyl)indazole-3-carboxamide (24 mg, 0.06 mmol) followed by potassium carbonate (68 mg, 0.49 mmol). The resultant suspension was heated at 60° C. for 18 h whereupon another portion of (oxetan-3-yl)ethyl methanesulfonate (81 mg, 0.45 mmol) in ACN (2 mL) was added and heating/stirring continued. After 24 h, the reaction mixture was diluted with EtOAc (15 mL) and the organics washed with water (20 mL). The aqueous layer was back-extracted into EtOAc (15 mL) and the combined organics were then washed with brine (10 mL), dried (MgSO4) and the volatiles removed in vacuo. The residue was purified by preparative HPLC eluting with ACN:0.1% formic acid in water (gradient elution, 5% to 30% to 40% to 100%) to give Compound (3) (4 mg, 14%). ESI-MS m/z calculated for [M+H]+: 483.2 found: 483.1. 1H NMR (400 MHz, CD3CN) δ 7.78 (s, 1H), 7.58 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.40 (d, J=7.94 Hz, 2H), 5.63 (brs, 1H), 4.86-4.78 (m, 2H), 4.40-4.33 (m, 2H), 3.70 (t, J=7.94 Hz, 2H), 3.18-3.05 (m, 4H), 2.98 (d, J=5.0 Hz, 3H), 2.51 (s, 3H), 2.47-2.38 (m, 1H), 2.17-1.97 (m, 2H), 1.19-1.03 (m, 3H), 0.72-0.63 (m, 1H). was added the organics washed with water (20 mL) The aqueous layer was back-extracted into EtOAc (15 mL) the combined organics were then washed with brine (10 mL) dried (MgSO4) the volatiles removed in vacuo The residue was purified by preparative HPLC eluting with ACN

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

Procedure: To a stirred solution of 2-(oxetan-3-yl)ethyl methanesulfonate (11 mg, 0.06 mmol, prepared by treating 2-(oxetan-3-yl)ethanol with methanesulfonyl chloride in DCM in the presence of DIPEA) was added 5-cyclopropyl-6-(methanesulfonamido)-N-methyl-2-(p-tolyl)indazole-3-carboxamide (24 mg, 0.06 mmol) followed by potassium carbonate (68 mg, 0.49 mmol). The resultant suspension was heated at 60° C. for 18 h whereupon another portion of (oxetan-3-yl)ethyl methanesulfonate (81 mg, 0.45 mmol) in ACN (2 mL) was added and heating/stirring continued. After 24 h, the reaction mixture was diluted with EtOAc (15 mL) and the organics washed with water (20 mL). The aqueous layer was back-extracted into EtOAc (15 mL) and the combined organics were then washed with brine (10 mL), dried (MgSO4) and the volatiles removed in vacuo. The residue was purified by preparative HPLC eluting with ACN:0.1% formic acid in water (gradient elution, 5% to 30% to 40% to 100%) to give Compound (3) (4 mg, 14%). ESI-MS m/z calculated for [M+H]+: 483.2 found: 483.1. 1H NMR (400 MHz, CD3CN) δ 7.78 (s, 1H), 7.58 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.40 (d, J=7.94 Hz, 2H), 5.63 (brs, 1H), 4.86-4.78 (m, 2H), 4.40-4.33 (m, 2H), 3.70 (t, J=7.94 Hz, 2H), 3.18-3.05 (m, 4H), 2.98 (d, J=5.0 Hz, 3H), 2.51 (s, 3H), 2.47-2.38 (m, 1H), 2.17-1.97 (m, 2H), 1.19-1.03 (m, 3H), 0.72-0.63 (m, 1H). was added the organics washed with water (20 mL) The aqueous layer was back-extracted into EtOAc (15 mL) the combined organics were then washed with brine (10 mL) dried (MgSO4) the volatiles removed in vacuo The residue was purified by preparative HPLC eluting with ACN

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

Procedure: To a stirred solution of 2-(oxetan-3-yl)ethyl methanesulfonate (11 mg, 0.06 mmol, prepared by treating 2-(oxetan-3-yl)ethanol with methanesulfonyl chloride in DCM in the presence of DIPEA) was added 5-cyclopropyl-6-(methanesulfonamido)-N-methyl-2-(p-tolyl)indazole-3-carboxamide (24 mg, 0.06 mmol) followed by potassium carbonate (68 mg, 0.49 mmol). The resultant suspension was heated at 60° C. for 18 h whereupon another portion of (oxetan-3-yl)ethyl methanesulfonate (81 mg, 0.45 mmol) in ACN (2 mL) was added and heating/stirring continued. After 24 h, the reaction mixture was diluted with EtOAc (15 mL) and the organics washed with water (20 mL). The aqueous layer was back-extracted into EtOAc (15 mL) and the combined organics were then washed with brine (10 mL), dried (MgSO4) and the volatiles removed in vacuo. The residue was purified by preparative HPLC eluting with ACN:0.1% formic acid in water (gradient elution, 5% to 30% to 40% to 100%) to give Compound (3) (4 mg, 14%). ESI-MS m/z calculated for [M+H]+: 483.2 found: 483.1. 1H NMR (400 MHz, CD3CN) δ 7.78 (s, 1H), 7.58 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.40 (d, J=7.94 Hz, 2H), 5.63 (brs, 1H), 4.86-4.78 (m, 2H), 4.40-4.33 (m, 2H), 3.70 (t, J=7.94 Hz, 2H), 3.18-3.05 (m, 4H), 2.98 (d, J=5.0 Hz, 3H), 2.51 (s, 3H), 2.47-2.38 (m, 1H), 2.17-1.97 (m, 2H), 1.19-1.03 (m, 3H), 0.72-0.63 (m, 1H). was added the organics washed with water (20 mL) The aqueous layer was back-extracted into EtOAc (15 mL) the combined organics were then washed with brine (10 mL) dried (MgSO4) the volatiles removed in vacuo The residue was purified by preparative HPLC eluting with ACN

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

Procedure: To a stirred suspension of Compound 1 (11 mg, 0.03 mmol) and 2-(oxetan-3-yl)ethanol (5.6 mg, 0.06 mmol) in THF (200 μL) was added triphenylphosphine (11 mg, 0.04 mmol) followed by DIAD (8 μL, 0.04 mmol). The suspension dissolved slowly upon stirring. Analysis of the reaction mixture after 2.5 h by LCMS showed the presence of starting material and so further aliquots of triphenylphosphine (5.0 mg, 0.05 mmol) and DIAD (8 μL, 0.04 mmol) were added. After stirring for 2 h, the reaction was diluted with EtOAc (10 mL), the organics washed with water (10 mL), brine (10 mL) and dried (MgSO4). The organics were concentrated in vacuo and the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid: DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide followed by MeOH: DCM (gradient elution, 0% to 20%, 20 CV) to give Compound (4) (7.8 mg, 59%). ESI-MS m/z calculated for [M+H]+: 484.2; found: 484.2. 1H NMR (400 MHz, CDCl3) δ 8.47 (brs, 1H), 8.36 (s, 1H), 7.83-7.76 (m, 2H), 7.72 (s, 1H), 7.60 (s, 1H), 4.84-4.71 (m, 2H), 4.34 (q, J=6.0 Hz, 2H), 3.74-3.56 (m, 2H), 3.10-2.99 (m, 7H), 2.47 (s, 3H), 2.30 (ddd, J=13.6, 8.3, 5.4 Hz, 1H), 2.07-1.95 (m, 2H), 1.09-0.94 (m, 3H), 0.65-0.56 (m, 1H). The suspension dissolved slowly After stirring for 2 h the organics washed with water (10 mL), brine (10 mL) dried (MgSO4) The organics were concentrated in vacuo the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide

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

Procedure: To a stirred suspension of Compound 1 (11 mg, 0.03 mmol) and 2-(oxetan-3-yl)ethanol (5.6 mg, 0.06 mmol) in THF (200 μL) was added triphenylphosphine (11 mg, 0.04 mmol) followed by DIAD (8 μL, 0.04 mmol). The suspension dissolved slowly upon stirring. Analysis of the reaction mixture after 2.5 h by LCMS showed the presence of starting material and so further aliquots of triphenylphosphine (5.0 mg, 0.05 mmol) and DIAD (8 μL, 0.04 mmol) were added. After stirring for 2 h, the reaction was diluted with EtOAc (10 mL), the organics washed with water (10 mL), brine (10 mL) and dried (MgSO4). The organics were concentrated in vacuo and the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid: DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide followed by MeOH: DCM (gradient elution, 0% to 20%, 20 CV) to give Compound (4) (7.8 mg, 59%). ESI-MS m/z calculated for [M+H]+: 484.2. found: 484.2. 1H NMR (400 MHz, CDCl3) δ 8.47 (brs, 1H), 8.36 (s, 1H), 7.83-7.76 (m, 2H), 7.72 (s, 1H), 7.60 (s, 1H), 4.84-4.71 (m, 2H), 4.34 (q, J=6.0 Hz, 2H), 3.74-3.56 (m, 2H), 3.10-2.99 (m, 7H), 2.47 (s, 3H), 2.30 (ddd, J=13.6, 8.3, 5.4 Hz, 1H), 2.07-1.95 (m, 2H), 1.09-0.94 (m, 3H), 0.65-0.56 (m, 1H). The suspension dissolved slowly After stirring for 2 h the organics washed with water (10 mL), brine (10 mL) dried (MgSO4) The organics were concentrated in vacuo the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide

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

Procedure: Using the same reaction conditions and procedure as described for the preparation of Intermediate (I-16a), 2-(oxetan-3-yl)ethanol (1 g, 6.944 mmol) was reacted with p-Toluene sulfonyl chloride (1.9 g, 10.416 mmol) in dry pyridine (10 mL) to afford the crude product. The reaction mass was poured into ice-water and extracted using ethyl acetate. The organic layer was washed with 1N HCl, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 1 g of the product (40% yield). the same reaction conditions and procedure to afford the crude product extracted The organic layer was washed with 1N HCl, brine solution dried over anhydrous sodium sulfate concentrated under reduced pressure to afford the crude product Purification by column chromatography on silica gel (20% ethyl acetate in hexane)