Substituted 2-amino-9-(3,3-difluoropiperidin-4-yl)-7,9-dihydro-8H-purin-8-one compounds and their use in cancer treatment

Claims

1. A compound having a structure of formula (I) where R1 is selected independently from hydrogen, methyl, ethyl, isopropyl, deuterated methyl, oxetane; R2 is selected independently from methyl or deuterated methyl; R3 is selected independently from fluoride, methyl or OCH₃; X is selected independently from CH or nitrogen.

2. A pharmaceutical composition comprising a compound according to claim 1, its salt, its solvate, its hydrate or its polycrystal, as well as pharmaceutically acceptable excipients or additional ingredients.

3. A DNA-PK inhibitor, characterized in that the inhibitor is an active ingredient according to the compound according to claim 1; the inhibitor is capable of crossing the blood-brain barrier.

4. The compound of claim 1, or the pharmaceutical composition of claim 2, or the inhibitor of claim 3, used in the manufacture of a medicinal product for the treatment or prevention of DNA-PK protein activation mediated by DNA-PK when using medicinal products.

5. The use according to claim 4, characterized in that said protein is a DNA-dependent protein kinase.

6. The use according to claim 4, characterized in that the disease is a metastatic lesion of the central nervous system by cancer, brain cancer, proliferative disease, cancer, in which the compound of formula (I) is administered simultaneously, separately or sequentially with radiation therapy.

7. The use according to claim 4 for use in the treatment of cancer according to claim 6, wherein the compound of formula (I) is administered simultaneously, separately or sequentially with at least one additional antineoplastic agent that can cause DNA double-strand breaks, selected from the group consisting of cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, rucaparib, niraparib, talazoparib, pamiparib, pembrolizumab, nivolumab, cemiplimab, spartalizumab, sintilimab, tislelizumab, dostarlimab. atezolizumab, avelumab, durvalumab, osimertinib and WSD0922.

8. The use according to paragraph 6, characterized in that the disease is a glioblastoma, diffuse intrapontine glioma, astrocytoma, oligodendroglioma, ependymoma, meningioma, pituitary adenoma, vestibular schwannoma, and medulloblastoma.

9. A method for treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially with other methods of treatment.