Clozapine-like compound without agranulocytosis risk is need to cure the treatment resistant schizophrenia (TRS). We discovered (S)-3 as Clozapine-like dopamine D/D receptor selectivity and improved reactive metabolites formation profile by the modification of piperazine moiety in Clozapine. The optimization of (S)-3 gave compound 5 to be best compound (approximately 10-fold stronger affinity for D/D receptor and similar D/D selectivity ratio with Clozapine). Clozapine-like D/D receptor occupancy profile was proved by in vivo evaluation. In addition, the reactive metabolites derived agranulocytosis risk of compound 5 was considered to be lower than Clozapine. The pharmacology detail of compound 5 is being investigated to develop it for TRS treatment.