Thiazolo-[4,5-d]-thiazo-frame (tztz) compounds are important heteroaromatic organic systems, which recently became a subject of several studies in the field of organic electronics and organic photovoltaics. The most important physical nature of these systems is reported to be an equilibrium between enol and keto forms following excited-state proton transfer. This process originates from a flat trend of the S-1 PE (potential energy) profile along the proton transfer coordinate. In the present work, we determined and interpreted the excited-state proton transfer and photophysical nature of these systems extensively by means of the MP2/CC2 and CASSCF theoretical approaches. Also, the effects of amine (-NH2) and cyano (-CN) substitutions were taken into account comprehensively by considering the transition energies and proton transfer pathways of the resulting tztz derivatives. It has been predicted that the physical nature of the excited-state intramolecular proton transfer, as the main character of these systems, is being affected significantly by substitutions. For all of the considered tztz derivatives, a conical intersection (CI) between ground and the S-1 excited state was predicted. This CI makes the considered species capable to be responsible for photochromism and photoswitching as well.