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Casein Kinase 1 isoform δ (CK1δ) belongs to Protein Kinase (PK) superfamily and it is involved in several cellular processes and in neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS). The PhD thesis is focused on the development of ATP-competitive CK1δ inhibitors by exploring heteroaromatic systems applying three main strategies: metabolic-based design, new scaffold development and molecular simplification approach. The first investigated scaffold involves the benzo[d]thiazole nucleus; Riluzole, approved drug for Amyotrophic Lateral Sclerosis (ALS), has proved to interact with the glutamatergic transmission even if the real mechanism of action is still unclear. The research group has experimentally demonstrated an activity of the candidate on CK1δ (IC50 = 16.1 μM) and to corroborate the hypothesis, since Riluzole underwent a strong hepatic metabolism, the N-hydroxylamine derivative was developed and assayed on the target obtaining an activity in the same range. Moreover, the hydrazine analogue appears as another appealing precursor. Therefore, a series of functionalized hydroxylamine and hydrazine derivatives have been developed introducing several types of alkyl and arylalkyl moieties to outline the SAR profile with encouraging results; the benzyl- and isopentyl-hydrazine derivatives proved to be the best of the series with IC50s of 1.62 μM and 0.92 μM, respectively. Moving to another heterocyclic system, a screening of in-house derivative allowed to develop a series of pyrazines exploring a new scaffold. The four positions of the system have been investigated obtaining promising results with two lead compounds reporting IC50s of 69 nM and 200 nM. Finally, starting from derivative 5-(7-amino-5-(benzylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)benzen-1,3-diol that displayed activity of 180 nM, to simplify the synthetic approach and obtain a quicker and deepen SAR profile, a molecular simplification was applied. A series of 1,3,5-triazines was developed exploring several substituents even if the activities registered were in the high micromolar range. To obtain a hit compound, a molecular hybrid was achieved by combining the best derivative of the series (IC50 = 19.6 μM) and the 4-fluoro-1H-indazol-3-amine (IC50 = 24.9 μM) discovered in a fragment-based work. The hybrid displayed an activity of 3.86 μM confirming this strategy as challenging. For the most promising derivatives the CNS-prediction permeability was estimated as well as the ATP-competitive behavior. In conclusion, to validate the achieved results, a biological characterization was conducted exploring neuroprotective features as well as the decrease of phosphorylated TDP-43 (hallmark of ALS) via Western Blot analysis. Casein Kinase 1 isoform δ (CK1δ) belongs to Protein Kinase (PK) superfamily and it is involved in several cellular processes and in neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS). The PhD thesis is focused on the development of ATP-competitive CK1δ inhibitors by exploring heteroaromatic systems applying three main strategies: metabolic-based design, new scaffold development and molecular simplification approach. The first investigated scaffold involves the benzo[d]thiazole nucleus; Riluzole, approved drug for Amyotrophic Lateral Sclerosis (ALS), has proved to interact with the glutamatergic transmission even if the real mechanism of action is still unclear. The research group has experimentally demonstrated an activity of the candidate on CK1δ (IC50 = 16.1 μM) and to corroborate the hypothesis, since Riluzole underwent a strong hepatic metabolism, the N-hydroxylamine derivative was developed and assayed on the target obtaining an activity in the same range. Moreover, the hydrazine analogue appears as another appealing precursor. Therefore, a series of functionalized hydroxylamine and hydrazine derivatives have been developed introducing several types of alkyl and arylalkyl moieties to outline the SAR profile with encouraging results; the benzyl- and isopentyl-hydrazine derivatives proved to be the best of the series with IC50s of 1.62 μM and 0.92 μM, respectively. Moving to another heterocyclic system, a screening of in-house derivative allowed to develop a series of pyrazines exploring a new scaffold. The four positions of the system have been investigated obtaining promising results with two lead compounds reporting IC50s of 69 nM and 200 nM. Finally, starting from derivative 5-(7-amino-5-(benzylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)benzen-1,3-diol that displayed activity of 180 nM, to simplify the synthetic approach and obtain a quicker and deepen SAR profile, a molecular simplification was applied. A series of 1,3,5-triazines was developed exploring several substituents even if the activities registered were in the high micromolar range. To obtain a hit compound, a molecular hybrid was achieved by combining the best derivative of the series (IC50 = 19.6 μM) and the 4-fluoro-1H-indazol-3-amine (IC50 = 24.9 μM) discovered in a fragment-based work. The hybrid displayed an activity of 3.86 μM confirming this strategy as challenging. For the most promising derivatives the CNS-prediction permeability was estimated as well as the ATP-competitive behavior. In conclusion, to validate the achieved results, a biological characterization was conducted exploring neuroprotective features as well as the decrease of phosphorylated TDP-43 (hallmark of ALS) via Western Blot analysis.