HIE-124 is the new member of ultra-short acting hypnotics drug family. In this research, thiadiazole can act as the bio-isosteric replacement of thiazole in synthesized compounds as HIE-124 derivatives. HIE-124 drug, in which the heterocyclic thiazole ring replaced to thiadiazole, will be presented. Thiadiazolodiazepines were synthesized by a two-step reaction starting from the amino thiadiazole resulted from-various derivatives of benzoic acid and thiosemi-carbazide. In the first step, the reaction of synthetic raw material 2-amino thiadiazole and 4-chlorobutyrilchloride in toluene give the 4-chloro-N-(5-(methyl/aryl)-1,3,4-thiadiazol-2-yl)butanamide intermediate. In the next step, from the cyclization reaction of this intermediate ring in the presence of base under reflux, the target products are synthesized. Structure of products were identified based on IR, 1HNMR and 13CNMR spectroscopy analysis. The docking study of ligands were performed on the active site of GABAA that the common residues involved in allosteric modulators such as benzodiazepines and HIE-124 include ASN82, ASN81, PHE79, MET1, TYR106, ALA38 and AlA168. In the compounds 7a, 7c, 7d and 7e there is no any hydrogen bonding interaction, any π-π interactions and any π-cation interactions. According to the results the Ki’s (inhibition-constant) of all compounds 7a-7e with amount 67.59, 21.45, 43.7, 83.83, and 82.85 can inhibit the enzyme more efficiently compare to HIE-124 in which has 693.3 inhibition-constant. Based on the Docking calculations the new compounds might show better interaction between receptor (GABAA) than the HIE-124.