Thyroid hormone receptor beta agonist compounds
A technology of compounds and tautomers, applied in the direction of drug combination, organic chemistry, organic active ingredients, etc., can solve problems such as bone mineral density reduction
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[0168] It should be understood that the present disclosure is made by way of example only, and that those skilled in the art may make various changes in the combination and arrangement of parts without departing from the spirit and scope of the present disclosure.
[0169] The chemical reactions in the examples can be readily adapted to prepare a variety of other compounds disclosed herein, and alternative methods for preparing the disclosed compounds are considered to be within the scope of the disclosure. Modifications that are apparent to those skilled in the art are possible, for example, by suitably protecting interfering groups, by utilizing other suitable reagents other than those described in the art, or by routinely altering the reaction conditions , reagents and starting materials to successfully synthesize unexemplified compounds according to the present disclosure. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for p...
example S1
[0186] Example S1: Synthesis of N-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-5-oxo-4, 5-Dihydro-1,2,4-oxadiazole-3-carboxamide
[0187]
[0188] Synthesis of 3,5-dichloro-4-((4-chlorophthalazin-1-yl)oxy)aniline (1a). To 1,4-dichlorophthalazine (100g, 502.4mmol) and 4-amino- To a solution of 2,6-dichlorophenol (107.3 g, 602.9 mmol) in DMSO (1.0 L) was added Cs 2 CO 3 (196.4 g, 602.9 mmol). The mixture was then stirred at 80°C for 1 hour. TLC and LCMS showed the reaction was complete. The mixture was cooled to 20 °C and added to HCl solution (2M, 7.5 L). The mixture was then filtered to collect solids. H for solid 2 O (800 mL*3) was washed and dried in vacuo to afford 1a. For [M+1] + (C 14 h 8 Cl 3 N 3 O) Calculated MS mass requires m / z 340.0, LCMS experimental value m / z 340.0; 1 H NMR (400MHz, DMSO-d 6 )δ8.46-8.55 (m, 1H), 8.30-8.35 (m, 1H), 8.20-8.29 (m, 2H), 6.78 (s, 2H).
[0189] Synthesis of 4-(4-amino-2,6-dichloro-phenoxy)-2H-phthalaz...
example S2
[0191] Example S2: Synthesis of N-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-5- Oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide
[0192]
[0193]Synthesis of 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)isoindoline-1,3-dione (2a). To a solution of 4-(4-amino-2,6-dichloro-phenoxy)-2H-phthalazin-1-one (1b) (500 mg, 1.55 mmol) in AcOH (10 mL) was added Isobenzofuran-1,3-dione (252.88 mg, 1.71 mmol). The mixture was stirred at 120°C for 3 hours. TLC and LCMS showed the reaction was complete. The reaction mixture was diluted with water (30 mL) and filtered to give a cake pad. The cake pad was dried under reduced pressure to afford crude material 2a. The crude product was used directly in the next step. For [M+1] + (C 22 h 11 Cl 2 N 3 o 4 ) calculated MS mass requires m / z 452.0, LCMS experimental value m / z 452.0; 1 H NMR (400MHz, DMSO-d 6 )δ12.06-12.03(m,1H),8.36-8.25(m,3H),8.14-8.09(m,1H),8.07-8.02(m,3H),7.99-7.94(m,2H...
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