General procedure for the synthesis of sulfonyl chloride (2a and 2b)

Step (a) Thionyl chloride (4.2 mmol) was added dropwise, over 10 min, to 2-mL water, and cooled to 0 °C. The solution was then allowed to warm to 15 °C, over 16 h. Copper (I) chloride (0.01 mmol) was added to the mixture, and the resultant yellow-green solution was cooled to −3 °C. Step (b) Concentrated HCl (1 mL) was added, with stirring, to an appropriate aniline (1 mmol), using ice to maintain the temperature of the mixture below 30 °C. The reaction mixture was then cooled to −5 °C, and a solution of sodium nitrite (1.1 mmol) in water (0.3 mL) was added drop-wise, over 10 min, maintaining the temperature at −5 to 0 °C. The resultant slurry was cooled to −2 °C, and stirred for 10 min. Step (c) The slurry from step (b) was cooled to −5 °C, and added to the solution obtained from step (a), over 30 min. As the reaction proceeded, a solid began to precipitate. When the addition was complete, the reaction mixture was stirred at 0°C for 70 min, and the suspended solid collected by vacuum filtration, washed with water, and dried under vacuum, to give the corresponding sulfonyl chlorides, in 52–62% yields. The sulfonyl chloride products 2a and 2b were used for the next step, without further purification (Fig. 1b).

Binding modes and synthesis of BI6015 derivates. a The proposed binding modes of BI6015-ortho (3a), BI6015-meta (3b), and BI6015-para (3c) forms in the binding pocket of human HNF4α (PDB code 3FS1), with key amino acid residues shown. Hydrogen bonds are denoted as black dotted lines. (1) Each part of the ligand-binding pocket for the ortho-nitro-substituted BI6015 3a is represented as a lipophilic potential surface. (2) Each part of the ligand-binding pocket for the meta-nitro-substituted 3b is represented as a lipophilic potential surface. (3) Each part of the HNF4α ligand-binding pocket for para-nitro-substituted 3c is represented as a lipophilic potential surface. (4) The binding site for para-nitro-substituted 3c, as an HNF4α ligand, is in ribbon cartoon. Amino acid residues interacting via hydrogen bonds are labeled. b Reagents and conditions: (a) (i) HCl, H₂O, NaNO₂, (ii) SOCl₂, H₂O, CuCl; (b) 2-methyl-1H-benzo[d]imidazole, CH₃CN