Discovery of functionalized bisimidazoles bearing cyclic aliphatic-phenyl motifs as HCV NS5A inhibitors

Improving Nonspecific Binding and Solubility: Bicycloalkyl Groups and Cubanes as para‐Phenyl Bioisosteres

“…Ph‐BCPs 1 b and 2 b can be prepared by three main methods: 1) by Grignard addition to propellane (tricyclo[1.1.1.0 1,3 ] pentane, 5 ); 2) decarboxylation of the BCP‐ tert ‐butyl per ester followed by arylation of the bridgehead carbon by heating in benzene; and more recently, 3) by iron‐catalyzed coupling of redox‐active esters with arylzinc reagents . The corresponding Ph‐BCO derivatives 1 c and 2 c can be prepared by two main methods: 1) HgO‐mediated decarboxylation of the BCO‐acid and bromination followed by AlCl 3 ‐catalyzed Friedel–Crafts reaction with benzene or 2) Diels–Alder reaction between 2‐oxo‐6‐phenyl‐2 H ‐pyran‐3‐carboxylates and ethene followed by hydrogenation . To allow a full comparison of the three p ‐Ph bioisosteres shown in Figure , the BCP, BCO, and cubane derivatives of their analogues were prepared according to published procedures, or purchased from commercial sources.…”

“…General methods : All chemicals, reagents, and solvents were analytical grade, purchased from commercial sources and used without purification, unless otherwise specified. Compounds 1 a and 2 a were purchased from commercial suppliers; 1 b and 2 b were prepared according to published methods, as well as 1 c and 2 c . Compounds 1 d and 2 d were supplied by SpiroChem.…”

Sulfur(vi) fluoride exchange as a key reaction for synthesizing biaryl sulfate core derivatives as potent hepatitis C virus NS5A inhibitors and their structure–activity relationship studies

“…83,84 The imidazole-linked monomers 7a-c were prepared from the acetophenone derivatives following an established procedure. 64,85 a-Bromination of acetophenone 4 was carried out in the presence of copper(II) bromide to provide a-bromoacetophenone 5 in an 81% yield. 85,86 Then, the resulting product 5 was treated with N-Boc-L-proline in the presence of DIPEA to yield ester 6a.…”

“…64,85 a-Bromination of acetophenone 4 was carried out in the presence of copper(II) bromide to provide a-bromoacetophenone 5 in an 81% yield. 85,86 Then, the resulting product 5 was treated with N-Boc-L-proline in the presence of DIPEA to yield ester 6a. 85 Likewise, commercially available a-bromoacetophenone derivatives 5b and 5c were converted to the corresponding esters 6b and 6c, respectively.…”

“…85,86 Then, the resulting product 5 was treated with N-Boc-L-proline in the presence of DIPEA to yield ester 6a. 85 Likewise, commercially available a-bromoacetophenone derivatives 5b and 5c were converted to the corresponding esters 6b and 6c, respectively. Synthesis of the imidazole derivatives 7a-c was accomplished by the reaction of 6a-c with ammonium acetate.…”