Methods and compositions for modulating splicing
A compound, solvate technology for modulating splicing and composition to address oligonucleotide therapy potency and efficacy limitations
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[1186] These examples are provided for illustration purposes only, and do not limit the scope of the claims presented herein. Starting materials and reagents for the synthesis of the compounds described herein can be synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.
[1187] In some embodiments used in the Examples, G1 is H, PMB (p-methoxybenzyl), BOC (tert-butoxycarbonyl), or other protecting group. In some embodiments, G1 is H or BOC. In some embodiments, G2 is H, alkyl or bis(pinacolato) or other protecting group. In some embodiments, G2 is H or bis(pinacolato). In some embodiments, G3 is H, methyl, MOM (methoxymethyl), benzyl, or other protecting groups. In some embodiments, G3 is H, methyl, benzyl, PMB, or MOM.
[1188] Synthesis of amino alcohols (AA):
[1189] Scheme AA-1: Bicyclic Amino Alcohols
[1190]
[1191] The aminoalcohols shown in Scheme AA-1 were used in the synt...
Embodiment 1
[1401] Example 1: Synthesis of 2-(6-(((1S,2S,3R,5R)-2-fluoro-9-azabicyclo[3.3.1]non-3-yl)oxy)pyridazine-3- yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol and 2-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3 .1]Non-3-yl)oxy)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol (compounds 1-Ent1 and 1-Ent2)
[1402]
[1403] Step 1. Synthesis of rac-(1S,2S,3R,5R)-3-((6-chloropyridazin-3-yl)oxy)-2-fluoro-9-azabicyclo[3.3.1] Nonane-9-carboxylate tert-butyl ester (racemic 1-F1)
[1404] Racemic-(1S,2S,3R,5R)-2-fluoro-3-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester under nitrogen protection at 0°C (racemic PFDOD, 7.0 g, 27.1 mmol) and NaH (3.2 g, 81.1 mmol, 60% in mineral oil) to a stirred solution of 100 mL of THF was added 3,6-dichloropyridazine (4.8 g, 32.4 mmol). After the addition, the mixture was then stirred at 50°C for 3 hours. The mixture was cooled to room temperature with H 2 quenched with O (200 mL) and extracted with EtOAc (100 mL x 3). The combined ...
Embodiment 2
[1414] Example 2: Synthesis of 2-(6-(((1R,2R,3S,5S)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]oct-3-yl) Oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol and 2-(6-(((1S,2S,3R,5R)-2-fluoro-1,5- Dimethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol (2-Ent1,2 -Ent2)
[1415]
[1416] Step 1. Synthesis of Racemic-(1S,2S,3R,5R)-3-((6-chloropyridazin-3-yl)oxy)-2-fluoro-1,5-dimethyl-8- Azabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester.
[1417] 3,6-Dichloropyridazine (720 mg, 4.84 mmol) was added to rac-(1S,2S,3R,5R)-2-fluoro-3-hydroxy-9-nitrogen at 0°C under nitrogen Heterobicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (1.1 g, 4.03 mmol) and NaH (484 mg, 12.1 mmol, 60% in mineral oil) in a stirred solution of 15 mL of THF. After the addition, the mixture was then stirred at 50°C for 3 hours. The mixture was cooled to room temperature with H 2 quenched with O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic solvents ...
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