PRODRUGS OF HUMAN DIHYDROOROTATE DEHYDROGENASE ( hDHODH) INHIBITORS

Abstract

The present disclosure refers to a pro-drug of formula (I) which allows not only to improve the solubility of a hydroxyazole scaffold-based hDHODH inhibitor but also its bioavailability. In particular, the prodrug of formula (I) is able to release in vivo the corresponding hydroxyazole scaffold-based hDHODH inhibitor of general Formula (Ia): The disclosure refers also to the use of the pro-drug for the treatment of cancer or viral infections.

Description

[0001] “Prodrugs of human dihydroorotate dehydrogenase (hDHODH) inhibitors” DESCRIPTION FIELD OF THE INVENTION This disclosure is in the field of prodrugs of human dihydroorotate dehydrogenase (hDHODH) inhibitors structurally based on hydroxyazole scaffolds and methods of making and using them. In particular, the present disclosure relates to the use of such prodrugs of hDHODH inhibitors in the treatment of cancer or viral infections. BACKGROUND OF THE INVENTION Human dihydroorotate dehydrogenase (hDHODH, EC 1.3.99.11), present in the inner mitochondrial membrane, is a flavin-dependent enzyme involved in de novo pyrimidine biosynthesis. It catalyses the rate-limiting step in de novo pyrimidine biosynthesis, which converts dihydroorotate (DHO) to orotate (ORO). hDHODH has already been validated as a therapeutic target for the treatment of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. Furthermore, hDHODH has also recently been identified as a relevant target in the treatment of triple-negative breast cancer,1PTEN-mutant tumors,2KRAS-driven tumors,3acute myelogenous leukemia (AML),4small cell lung cancer,5esophageal squamous cell carcinoma,6colorectal cancer,7viral infection8and ferroptosis-driven tumors.9While the connection with AML has paved the way for completely new perspectives in the treatment of such diseases as well as in the hDHODH field, COVID-19 pandemic showed the importance to invest on the design of new Broad Spectrum Antiviral Agents (BSAAs), such as hDHODH inhibitors.10It is believed that both the cancer malignancies and the viral infections converge on a similar pathway of metabolic reprogramming to drive their dependence on pyrimidine synthesis and sensitivity to hDHODH inhibition. The present inventors recently identified and characterized a novel class of hDHODH inhibitors11characterized by the presence of an acidic hydroxyazole moiety in the structure, which interacts with Arg136 at hDHODH subsite 2. The novel class includes, inter alia, compound MEDS433 (named as compound 4 in ref.11). Characterized by the presence of a 2- hydroxypyrazolo[1,5-a]pyridine moiety, MEDS433 shows particular high potency against hDHODH enzyme (hDHODH IC501.2 nM), excellent drug-like properties and in vivo hDHODH related activity in different animal models.12Designed to target a mitochondrial based enzyme, compound MEDS433 owes its high potency to a great lipophilicity profile which in turn determines reduced aqueous solubility, a behaviour which could create problems in the path towards human experimentation and treatment. The object of the present disclosure is to target and overcome the solubility problems of MEDS433 and its analogues. The solution to the solubility problem provided by the present disclosure is a water-soluble prodrug of compound MEDS433 and its analogues that can be administered intravenously / per os, thereby preventing any future formulation and administration issues. SUMMARY OF THE INVENTION The present disclosure refers to a pro-drug of formula (I) which allows not only to improve the solubility of a hydroxyazole scaffold-based hDHODH inhibitor but also its bioavailability. In particular, the prodrug of formula (I) is able to release in vivo the corresponding hydroxyazole scaffold-based hDHODH inhibitor of general Formula (Ia): The disclosure refers also to the use of the pro-drug for the treatment of cancer or viral infections. BRIEF DESCRIPTION OF THE FIGURES Figure 1 a), b), c) shows the stability behaviour of pro-drug 1 in different mouse homogenates and MEDS433 subsequent formation; d) Stability behaviour of 1 in human serum and MEDS433 subsequent formation. Figure 2 shows the plasma concentrations of MEDS433 in CD1 mice after intravenous (IV) and per os (PO) administration of 5 and 20 mg / Kg of MEDS433, respectively. Figure 3 shows pro-drug 2 and MEDS433 plasma concentration in mice after IV (panel a)) and PO (panel b)) administration of pro-drug 2 at doses of 6.85 and 27.38 mg / Kg equivalent to 5 and 20 mg / Kg of MEDS433. Figure 4 shows the comparison of the plasma pharmacokinetic profiles of MEDS433 and pro- drug 2, expressed as MEDS433 concentrations. Drugs were administered at the doses (MEDS433 equivalent) of 5 and 20 mg / Kg, given by IV (panel A) and PO (panel B) route, respectively. Figure 5 shows the plasma concentrations of compound 6 in Balb / C mice after intravenous (IV) and per os (PO) administration of 5 and 20 mg / Kg of 6, respectively. Figure 6 shows the plasma concentrations of compound 8 in CD1 mice after intravenous (IV) and per os (PO) administration of 5 and 20 mg / Kg of 8, respectively. Figure 7 A) and B) show OCI-AML3 cells treated with indicated concentrations of MEDS433 in combination with Dipyridamole and Fludarabine or Cladribine for 3 days. Cell apoptosis was analysed by annexin V staining. The percentage of annexin positive cells is shown in the graph. Figure 8 A) and B) show OCI-AML3 and THP1 cells treated with indicated concentration of MEDS433 in combination with increased concentrations of Draflazine for 3 days; C) and D) show OCI-AML3 and THP1 cells treated with indicated concentration of MEDS433 in combination with different concentrations of JNK-IN-8 for 3 days. Cell apoptosis was analysed by annexin V staining. The percentage of annexin positive cells is shown in the graph. Figure 9 show SF8628 cells treated with indicated concentration of compound 6 in combination with A) Panabinostat, B) Abemaciclib, C) ONC212 through serial doses in constant / variable ratios at 72 hours. Synergistic activity was analyzed using the CellTiter-Glo 2.0 and Cell Counting Kit-8 assays. Synergism and combination index are shown in the graph. DETAILED DESCRIPTION OF THE INVENTION A first aspect of the present disclosure is a prodrug of Formula (I) able to release in vivo the corresponding hydroxyazole scaffold-based hDHODH inhibitor of general Formula (Ia). Formula (I) Formula (Ia) In Formulas (I) and (Ia): R1, R2, R4 and R5 are independently selected from a hydrogen atom, a deuterium atom, a halogen atom, a linear and / or branched C1-8 alkyl group, an alkyloxy group, an alkylammino group, an alkylthio group, a halo C1-8 alkyl group, a halo C1-8 alkyloxy group, a halo C1-8 alkylamino group, a nitro group, a cyano group; R3 is: - an aromatic group selected from the group consisting of: phenyl group, heteroaryl group, preferably an azinyl group such as pyridinyl group, pyrimidinyl group; phenoxy group; azinyloxy group such as pyridinyloxy group, pyrimidinyloxy group; phenylthio group; azinylthio group such as pyridinylthio group, pyrimidinylthio group; phenylsulfinyl group; phenylsulfonyl group; phenylsulfonylamino group; N-phenylcarbamoyl group. The aromatic group is optionally substituted, one or two times; each substituent is independently selected from a deuterium atom, a halogen atom, a hydroxyl group, an amino group, an alkyl group, a trifluoromethyl group, a trifluoromethoxy group, an alkyloxy group, a deuterium-alkyloxy group, a halo-alkyloxy group, a nitro group, a cyano group, and an alkylamino group; - an aliphatic group selected from the group consisting of: C1-12alkyl group; C1-12alkyloxy group; C1-12alkylthio group; C1-12alkylsulfinyl group; C1-12alkylsulfonyl group; C1-12alkylsulfonylamino group; C1-12alkylamino group; C1-12alkylaminosulfonyl group; halo C1-12alkyl group; halo C1-12alkyloxy group; halo C1-12alkylthio group; halo C1-12alkylsulfinyl group; halo C1-12alkylsulfonyl group; halo C1-12alkylsulfonylamino group; halo C1-12alkylamino group; halo C1-12alkylaminosulfonyl group. The aliphatic group is optionally substituted, one or two times; each substituent is independently selected from a deuterium atom, a halogen atom, a hydroxyl group, an amino group, an alkyl group, a trifluoromethyl group, a trifluoromethoxy group, an alkyloxy group, a halo-alkyloxy group, a nitro group, a cyano group, and an alkylamino group; R7, R8 and R9 are independently selected from a hydrogen atom, a deuterium atom, a halogen atom, a nitro group, a cyano group, a C1-4 alkyl group, a halo C1-4 alkyl group, a mercapto C1-4 alkyl group, an amino C1-4 alkyl group, and a hydroxy C1-4 alkyl group; X, Y and Z are independently selected from a carbon atom, and a nitrogen atom, with the proviso that when one of X, Y or Z is nitrogen, the other two positions are carbon atoms and when Y or Z are nitrogen atoms, R8 and R9 are not present. According to an embodiment, at least one of R1, R2, R4 and R5 is or contains a halogen atom. A preferred halogen atom is a fluorine or a chlorine atom, more preferably a fluorine atom (F) According to an embodiment, the alkyl group of any of R1, R2, R4and R5is C1-4alkyl group, preferably C1-3 alkyl group. The alkyl group can be linear, branched or cyclic. According to an embodiment at least one of R1, R2, R4and R5is selected from hydrogen, deuterium, -OCD3, -OCF3, methyl, isopropyl, methyl, 1,1,1-trifluoro-2-propanoxy. According to an embodiment, the alkyl group of R3is C1-6alkyl group, preferably C1-4alkyl group. The alkyl group can be liner, branched or cyclic. According to an embodiment, R3is selected from phenyl, deuterophenyl, ortho- trifluoromethoxyphenyl, meta-trifluoromethoxyphenyl, meta-trideuteromethoxyphenyl, meta- (2,2-difluoropropyloxy)phenyl, 3-pyridinyl, phenyloxy, ortho-trifluoromethylphenyl, ortho- trideuteromethylphenyl meta-trifluoromethylphenyl, meta-trideuteromethylphenyl, meta- deuterophenyl, ortho-deuterophenyl, meta-chlorophenyl, ortho-chlorophenyl, meta- fluorophenyl, ortho-fluorophenyl, meta-hydroxyphenyl, meta-butoxyphenyl. According to an embodiment R7, R8and R9are independently selected from hydrogen, deuterium, methyl, chloro, methyloxy and hydroxymethyl. According to an embodiment, X, Y and Z are independently selected from a carbon atom and a nitrogen atom, with the proviso that when one of X, Y or Z is nitrogen, the other two positions are carbon atoms and when Y or Z are nitrogen atoms, R8 and R9 are not present. In one embodiment, X, Z are carbon atoms, Y is carbon or nitrogen, R7, R8, R9 are hydrogen, R1, R2, R4, R5 are fluorine, R3 is a phenyl or m-(2,2-difluoro(C1-C3)alkyloxy)phenyl or m- (trifluoro(C1-C3)alkyl)phenyl or m-(trifluoro(C1-C3)alkyloxy)phenyl or m-butoxyphenyl. In an embodiment, X, Y, Z are carbon atoms, R7, R8, R9 are hydrogen atoms, R1, R4 are hydrogen atoms, R2 is a methyl, R5 is iso-propyl, R3 is phenyloxy. In an embodiment of the disclosure, one or more atoms of the formulae (I) and (Ia) can be replaced by its isotopes. Isotopes that can be incorporated into a compound of the disclosure in a form that exceeds natural abundances and include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H (or chemical symbol D),3H (or chemical symbol T),11C,13C,14C,15N,18O,17O,31P,32P,35S,18F,36Cl, and125I, respectively. Such isotopically labelled compounds are useful in metabolic studies (for example based on14C), reaction kinetic studies (for example based on2H or3H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)), including drug or substrate tissue distribution assays, or in the case of radioactive treatment of patients. In particular, a18F or11C labelled compound may be preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. An isotopically labelled compound of this disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples of preparations described below by substituting a non-isotopically labelled reagent with an isotopically labelled reagent. In Formula (I), R6is selected from the group consisting of a linear or branched C1-6alkyl substituted with a group selected from a phosphate, a -COOH, a -CONHR10, wherein R10is selected from hydrogen and a C1-6 alkyl chain. In a preferred embodiment R6is a linear or branched C1-6alkyl substituted with a phosphate group. More preferably, R6 is a linear C1-3 alkyl substituted with a phosphate group. Even more preferably R6 is a phosphonoxymethyl group represented by formula (II): Formula (II) The phosphonoxymethyl group of Formula (II) can be in the free or salified form. The salt can be an alkali metal salt, for example lithium, sodium, potassium, and cesium salt; an alkaline earth metal salt, for example calcium, magnesium or strontium salt; aluminum or zinc salt; an ammonium salt a quaternary ammonium salt having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n- butyl)ammonium, N-benzyl-N,N,N-trimethylammonium; a choline salt; a benzalkonium salt. The ammonium salt is preferably derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane (tromethamine), procaine, dibenzylamine, N- methylmorpholine, arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methyl- glucamine, N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3- butanetriol. Preferred prodrugs falling within Formula (I) are compounds 1, 2, 2a, 2b, 2c, 3, 5 and 7 having the following structures (Scheme 1). In vivo, such pro-drugs yield the corresponding drugs MEDS433, compound 4, compound 6 and compound 8, according to Scheme 1 below:

[0002]  Scheme 1. Prodrugs 1, 2, 2a, 2b, 2c, 3, 5 and 7 and the correspondent drugs MEDS433, 4, 6 and 8. A second aspect of the present disclosure is a pharmaceutical composition comprising a hydroxyazole scaffold-based hDHODH prodrug of Formula (I) as defined above and a pharmaceutically accepted carrier, excipient and / or diluent. Another aspect of the disclosure is the use of a pro-drug of Formula (I) or a pharmaceutical composition comprising such pro-drug as an anticancer agent, preferably for the treatment of: a) hematologic malignancies, preferably selected from the group consisting of: acute myeloid leukemia, myelodysplastic syndromes, chronic myeloid leukemia and other myeloproliferative neoplasms, multiple myeloma, angioimmunoblastic T-cell lymphoma and acute lymphoblastic leukemia, Hodgkin’s and non-Hodgkin’s lymphomas, IDH mutated tumors, BRAF-mutated, RAS-mutated, PTEN-mutated and MYC / MYCN-driven hematologic neoplasms; b) solid tumors, preferably selected from the group consisting of: osteosarcoma; Ewing sarcoma; melanoma; BRAF mutated tumors; PTEN-mutant tumors; H3K27M-mutated diffuse midline glioma; diffuse intrinsic pontine glioma; atypical teratoid rhabdoid tumor, ependymomas; neuroendocrine tumors; multiple endocrine neoplasia type 1 (MEN1) tumors; mutated MEN1 tumors; mutated KRAS hepatic tumors; mutated KRAS lung tumors; mutated KRAS pancreatic tumors; mutated KRAS colon carcinoma; prostate tumors; bladder tumors; kidney tumors; ferroptosis sensitive tumors, preferably lung cancer, glioblastoma, breast cancer, preferably triple-negative breast cancer, pancreatic cancer, hepatocellular carcinoma and colorectal cancer; IDH mutated tumors, preferably low-grade gliomas, secondary glioblastoma, primary glioblastoma, cartilaginous and bone tumors, fibrosarcoma, sinonasal undifferentiated carcinoma, intrahepatic cholangiocarcinoma, MYC and MYCN driven tumors, preferably neuroblastoma, medulloblastoma, retinoblastoma, astrocytoma, glioblastoma multiforme, castration-resistant prostate cancer, neuroendocrine prostate cancer, rhabdomyosarcoma, Wilms tumors, small cell lung cancer, pancreatic tumors; AMPKα1low expressing tumors; GPX4low expressing tumors; p53 wild type and mutated cancers. In another aspect, the present disclosure refers to the use of a compound of Formula (Ia) as an anticancer agent for the treatment of a) hematologic malignancies, preferably selected from the group consisting of: myelodysplastic syndromes, chronic myeloid leukemia and other myeloproliferative neoplasms, multiple myeloma, angioimmunoblastic T-cell lymphoma and acute lymphoblastic leukemia, Hodgkin’s and non-Hodgkin’s lymphomas, IDH mutated tumors, BRAF-mutated, RAS-mutated, PTEN-mutated and MYC / MYCN-driven hematologic neoplasms; b) solid tumors, preferably selected from the group consisting of: osteosarcoma; Ewing sarcoma; melanoma; BRAF mutated tumors; H3K27M-mutated diffuse midline glioma; diffuse intrinsic pontine glioma; atypical teratoid rhabdoid tumor, ependymomas; neuroendocrine tumors; multiple endocrine neoplasia type 1 (MEN1) tumors; mutated MEN1 tumors; mutated KRAS hepatic tumors; mutated KRAS lung tumors; mutated KRAS pancreatic tumors; mutated KRAS colon carcinoma; prostate tumors; bladder tumors; kidney tumors; ferroptosis sensitive tumors, preferably lung cancer, glioblastoma, breast cancer, pancreatic cancer, hepatocellular carcinoma and colorectal cancer; IDH mutated tumors, preferably low-grade gliomas, secondary glioblastoma, primary glioblastoma, cartilaginous and bone tumors, fibrosarcoma, sinonasal undifferentiated carcinoma, intrahepatic cholangiocarcinoma,; MYC and MYCN driven tumors, preferably neuroblastoma, medulloblastoma, retinoblastoma, astrocytoma, glioblastoma multiforme, castration-resistant prostate cancer, neuroendocrine prostate cancer, , rhabdomyosarcoma, Wilms tumors, small cell lung cancer, pancreatic tumors; AMPKα1lowexpressing tumors; GPX4lowexpressing tumors; p53 wild type and mutated cancers. In one embodiment, the compound of formula (I) and / o (Ia) are used for the treatment of osteosarcoma, glioblastoma, Ewing sarcoma, breast cancer, melanoma, H3K27M-mutated diffuse midline glioma, neuroblastoma, mutated KRAS lung tumors, bladder cancer, IDH mutated tumors. Another aspect of the present disclosure is a hydroxyazole scaffold-based hDHODH inhibitor prodrug of Formula (I) or a pharmaceutical composition containing such prodrug for use as antiviral agent, preferably for the treatment of a viral infection. Preferably, the viral infection is caused by a DNA virus or an RNA virus. Preferably, the virus is selected from the group consisting of Herpesviridae, Orthomyxoviridae, Paramyxoviridae and Coronaviridae. More preferably, the virus is selected from the group consisting of Herpes simplex virus 1 to 8 (HSV-1-8), paramyxovirus, pneumovirus, morbillivirus, Influenza A virus, Influenza B virus, Respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) and Middle East respiratory syndrome-related coronavirus (MERS-CoV). Another aspect of the disclosure is the use of a compound of formula (Ia) for the treatment of a viral infection caused by Herpes simplex virus 3-8 (HSV-3-8). The pathologies caused by the above viruses are, for example: - HSV1: Gingivostomatitis, keratoconjunctivitis, cutaneous herpes, genital herpes, encephalitis, herpes labialis, viral meningitis, esophagitis, pneumonia, disseminated infection, hepatitis; - HSV2: Genital herpes, cutaneous herpes, gingivostomatitis, neonatal herpes, viral meningitis, disseminated infection, hepatitis; - HSV3: Chickenpox, herpes zoster, disseminated herpes zoster; - HSV4: Infectious mononucleosis, hepatitis, encephalitis, nasopharyngeal carcinoma, Hodgkin lymphoma, Burkitt lymphoma, lymphoproliferative syndromes*, oral hairy leukoplakia*, gastric cancer; - HSV5: Cytomegalovirus mononucleosis, hepatitis, congenital cytomegalic inclusion disease, hepatitis, retinitis, pneumonia, colitis; - HSV6: Roseola infantum, otitis media with fever, encephalitis; - HSV7: Roseola infantum; - HSV8: Kaposi sarcoma–associated herpesvirus; - Orthomyxoviridae: influenza and lower and upper respiratory tract infections such as pneumonia; - Paramyxoviridae (paramyxovirus, pneumovirus, morbillivirus): upper and lower respiratory tract infections, such as bronchiolitis and pneumonia, pancreatitis, meningitis, encephalitis; - Coronaviridae: severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome-related coronavirus (MERS-CoV). The compound of formula (I) and / or (Ia) can be used to treat any of the above listed pathologies. Another aspect of the present disclosure is a method for the treatment of a cancer disease or a viral infection or a pathology caused by a viral infection, as above defined, comprising a step of administering an effective amount of a compound of formula (I) and / or a drug of formula (Ia) or a pharmaceutical composition comprising the same, to a subject in need thereof. In another embodiment, the disclosure refers to a composition comprising a 2-hydroxyazole scaffold-based hDHODH pro-drug of Formulae (I) and / or a drug of Formula (Ia) and one or more anticancer agents, preferably selected from: Abemaciclib, Abiraterone, Acalabrutinib, Actimide, Adagrasib, Artemisinin, Artesunate Ado-Trastuzumab Emtansine, Afatinib, Alectinib, Alpelisib, Atezolizumab, Amivantamab, Amsacrine, Anastozole, Apalutamide, Ascitiminib, Asparaginase, Axitinib, Azacitidine, Azathioprine, 6-Azauridina, Belzutifan, Bevacizumab, Bicalutamide, Bleomycin, Bosutinib, Brentuximab vedotin, Brigatinib, Busulfan, Cabazitaxel, Cabozantinib, Capecitabine, Capmatinib, Cyclophosphamide, Carboplatin, Carglumic acid, Carmustine, Cedazuridine, Cemiplimab-rwlc, Ceritinib, Cetuximab, Cisplatin, Chlorambucil, Cytarabine, Cladribine, Clofarabine, CNX774, Cobimetininb, Curcumin, Dabrafenib, Dacarbaziine, Dacomitinib, Dactinomycin Darolutamide, Dasatinib, Daunorubicin, Decitabine, Degarelix, Dilazep, Dihydroartemisinin, Dinutuximab, Dinutuximab beta, Dipyridamole, Docetaxel, Dordaviprone, Doxifluridine, Doxorubicin, Draflazine, Durvalumab, Epcoritamab, Enasidenib, Encorafenib, Enfortumab vedotin-ejfv, Entrectinib, Enzalutamide, EOS984 Epirubicin, Erastin, Erdafitinib, Erlotinib, Etoposide, Everolimus, ExemestaneFam- trastuzumab deruxtecan-nxki, Fenalidomide, Feucovorin, Fludarabine, Fluorouracil, FPMINT, Flutamide, Gemcitabine, Gefitinib, Glofitamab, Hydroxyurea, , Ibrutinib, Idarubicin, Infigratinib, Ifosfamide, Imatinib, Ipilimumab, Irinotecan, Isotretinoin, Ivosidenib, JNK-IN 8, , Larotrectinib, Lenvatinib, Lenalidomide, Letrozole, Leucovorin, Lidoflazine, Lomustine, Loncastuximab tesirine-lpy, Lorlatinib, L-alanosine, 8MDP, Masitinib, Mechlorethamine, Melphalan, Mercaptopurine, Methotrexate, Mioflazine, Mitomycin-C, Mitoxantrone, Mizoribine, Mobocertinib, Mosunetuzumab-axgb, Mycophenolic acid, Nab-paclitaxel, Nanoliposomal irinotecan, Naxitamab, Neratinib, Nilotinib, Nilutamide, Niraparib, Nivolumab, Nitrobenzylmercaptopurine riboside (NBMPR), Obinutuzumab, Olaparib, ONC212, OR0642, Osimertinib, Oxaliplatin, Panobinostat, Paclitaxel, Pacritinib, Pazopanib, PBP 4883, Pembrolizumab, Pertuzumab, Pemetrexed, Pemigatinib, Pirtobutinib, Pyrazofurin, Pralsetinib, Ponatinib, Polatuzumab vedotin-piiq, Rapadocin, Ramucirumab, Regorafenib, Relugolix, Revlimid, Rituximab, RO7117997, Rucaparib, Sacituzumab govitecan, Selepercatinib, Selinexor, Sorafenib, Sotarasib, Sulfasalazine, Sunitinib, Talazoparib, Tamibarotene, Tamoxifen, Tazemetostat, Temozolomide, Teniposide, Tepotinib, Thioguanine, Thiotepa, Ticagrelor, Tivozanib, Tofacitinib, Topotecan, Tafasitamab-cxix, Temsirolimus, Trametinib, Trastuzumab, TRE 515, Tremelimumab, Trifluridine / Tipiracil, Treosulfan, Troglitazone, Valrubicin, Vandetanib Venetoclax, Vemurafenib, Vinblastine, Vincristine, Vindesine and Vinorelbine, Vorasenib, Zanubrutinib, Ziv-aflibercept. A preferred composition comprises a pro-drug of Formula (I), preferably one or more of the pro-drugs 1, 2, 2a, 2b, 2c, 3, 5 and 7, and one or more of Acalabrutinib, Adagrasib, Artemisinin, Artesunate, Afatinib, Atezolizumab, Amivantamab, Ascitiminib, Axitinib, Azacitidine, Bevacizumab, Bosutinib, Busulfan, Cabozantinib Capecitabine, Carboplatin, Cemiplimab-rwlc, Cetuximab, Cisplatin, Cyclopentenyl Uracil, Cyclophosphamide, Cytarabine, Cladribine, Clofarabine, CNX774, Cobimetininb, Curcumin, Dabrafenib, Dacarbazine, Dacomitinib, Dasatinib, Daunorubicin, Decitabine, Dihydroartemisinin, Dilazep, Dipyridamole, Dinutuximab, Docetaxel, Dordaviprone, Doxorubicin, Draflazine, Durvalumab, Enasidenib, Encorafenib, Entrectinib, Enzalutamide, EOS984, Epirubicin, Erdafitinib, Erlotinib, Etoposide, Everolimus, Fludarabine, Fluorouracil, FPMINT, Gefitinib, Gemcitabine Hydroxyurea, Ibrutinib, Idarubicin, Imatinib, Infigratinib, Ipilimumab, Irinotecan, Ivosidenib, JNK-IN 8, Lidoflazine, 8MDP ,Masitinib, Mitomycin-C, Melphalan, Mercaptopurine, Methotrexate, Mioflazine Mycophenolic acid, Mobocertinib, Sulfasalazine, Nab-paclitaxel, Nanoliposomal irinotecan, Niraparib, Nilotinib Nivolumab, ONC212, Olaparib, OR0642, Osimertinib, Oxaliplatin, Paclitaxel, Panobinostat, Pazopanib, PBP 4883, Pebrolizumab, Pemigatinib, Pralsetinib, Ponatinib, Rapadocin, Ramucirumab, Regorafenib, RO7117997, Rucaparib, Selepercatinib, Sorafenib, Sotarasib, Sunitinib, Temozolomide, Tepotinib, Thioguanine, Tivozanib, Tofacitinib, Topotecan, Temsirolimus, Trametinib, TRE 515, Tremelimumab, Troglitazone ,Vandetanib, Vemurafenib, Venetoclax Vinblastine, Vincristine, Vinorelbine, Vorasenib. In another embodiment the composition comprises a pro-drug of Formula (I), preferably one or more of the pro-drugs 1, 2, 2a, 2b, 2c, 3, 5 and 7, and one or more of Cetuximab, CNX774, Dabrafenib, Dihydroartemisinin, Dipyridamol, Dordaviprone, Doxorubicina, Draflazine, Enasidenib, EOS984, Erlotinib, Everolimus, FPMINT, Gemcitabine, Ibrutinib, Ivosidenib, JNK- IN-8, 8MD, Mioflazine, Nivolumab, ONC212, Panobinostat, PBP 4883, Pembrolizumab, Rapadocin, RO7117997, Sorafenib, Sulfasalazine, Tofacitinib, Temozolomide, Trametinib, Troglitazone, TRE515, Vemurafenib, Vorasenib. In another embodiment, the disclosure refers to a composition comprising a 2-hydroxyazole scaffold-based hDHODH pro-drug of Formulae (I) and / or a drug of Formula (Ia) and one or more antiviral agents, preferably selected from acyclovir, adefovir, amantadine, baloxavir marboxil, bamlanivimab / etesevimab, brivudine, casirivimab / imdevimab, cidofovir, famciclovir, favipiravir, fomivirsen, foscarnet, ganciclovir, N(4)-Hydroxycytidine, indinavir, idoxuridine, laninamivir, lopinavir, molnupiravir, nelfinavir, nirmatrelvir, oseltamivir, penciclovir, permivir, ribavirin, sotrovimab, tenofovir, tenofovir alafenamide, tenofovir diisoproxilfumarate, trifluridine, telbivudine, vidarabine, sofosbuvir, nevirapine, efavirenz, raltegravir, remdesvir, rimantadine, ritonavir, ritonavir – amlanivimab, saquinavir, tixagevimab / cilgavimab, trifluridine, valacyclovir, valganciclovir, vidarabine, zanamivir, zidovudine. A preferred composition comprises a pro-drug of Formula (I), preferably one or more of the pro-drugs 1, 2, 2a, 2b, 2c, 3, 5 and 7, and one or more of acyclovir, adefovir, cidofovir, famciclovir, favipiravir, foscarnet, ganciclovir, N(4)-Hydroxycytidine, idoxuridine, molnupiravir, nirmatrelvir, oseltamivir, penciclovir, ribavirin, tenofovir, sofosbuvir, remdesvir, ritonavir, valganciclovir, zidovudine. The composition is used to treat a cancer or tumor or viral pathology by administration to a patient in need thereof. Chemistry: synthesis of prodrugs 1, 2, 2a, 2b, 2c, 3, 5, 7 and drug 4. For the synthesis of prodrugs 1, 2, 2a, 2b, 2c, 3, 5, 7 and drug 4 a synthetic approach was designed, improving in some case, in terms of yield and reactivity, the synthetic pathway already described in the authors previous patents.13,14The starting materials are the carboxylic acids 14a-b; while 14a is a known compound,11for the synthesis of 14b an original scheme was designed (Scheme 2). The ethyl 3-ethoxypyrazol-4-carboxylate 10 was initially boulted up by the reaction of compound 9 and hydrazine hydrochloride. Compound 10 was regioselectively alkylated on the nitrogen in position 1 with 2-bromo-1,1-diethoxyethane to obtain compound 11, which undergoes a formylation step to afford 12. In the following a two- step deprotection−cyclization protocol was used to synthetize the target ethyl 2- ethoxypyrazolo[1,5-a]pyrazine-3-carboxylate 13, obtained in high yields. Firstly, acetal deprotection of intermediate 11 with aqueous TFA, followed by solvent evaporation and subsequent cyclization with ammonium acetate furnished the desired bicyclic product 13. In the last step the ethyl ester present in 13 was hydrolysed in basic environment to obtain the acid 14b. Scheme 2. Synthesis of compound 14b. i) NH2NH2 HCl, EtOH, reflux.; ii) Cs2CO3, 2-bromo- 1,1-diethoxyethane, dry DMF, reflux; iii) nBuLi, dry THF, -78 °C, dry DMF; iv) a) TFA, H2O, THF; b) NH4OAc, AcOH, EtOH; v) 5 M NaOH, 60 °C. The carboxylates 14a,b were then used for the preparation of the corresponding acyl chloride (15a-b) via treatment with oxalyl chloride, both used without any further purification in the reaction with the lithium salt of 2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-amine or 3’-(2, 2- difluoropropoxy)-2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-amine affording the desired amides 16a- d with a 70 - 90 % yield (Scheme 2A). Under these conditions, the benzylic or ethoxy protecting groups did not translate from the exocyclic oxygen to the endocyclic N1 nitrogen as occurred in previous synthetic scheme, thereby facilitating the following deprotection steps. At this stage, compound 16d was deprotected with BBr3 in dry DCM to afford compound 4 in good yields (Scheme 2B). In the following step (Scheme 2C), compounds 16a-d were then protected on the amide nitrogen with Boc to afford compounds 17a-d. To introduce a methyl phosphate group, in the following step the oxygen protection was removed using different strategies. For compounds 17a-c, the 4-methoxybenzyl group was removed via catalytic hydrogenation conditions, while for compound 17d the ethoxy group was removed using BBr3in dry DCM at 0°C. In the next step, compounds 18a-d were alkylated with dibenzyl(chloromethyl)phosphate to afford the corresponding protected prodrugs 19a-d. The latter were deprotected following a two steps reaction sequence: the two benzyl groups of the phosphate were removed via catalytic hydrogenation to yield compounds 20a-d. The final prodrugs 1, 3, 5 and 7 were then obtained by removing the Boc protection in mild acid conditions. In the following, compound 1 was then converted into the corresponding salts 2, 2a, 2b, 2c by using 1 equivalent of KOH, NaOH, tromethamine and lysine respectively.

[0003] Scheme 3A-C. Synthesis of pro-drugs 1, 2, 2a, 2b, 2c, 3, 5 and 7 and drug 4. i) Oxalyl chloride, dry DMF, dry THF, nitrogen atmosphere; ii) LiHMDS, dry THF, 2,3,5,6-tetrafluoro-[1,1'- biphenyl]-4-amine for 14a and 14c, 3’-(2, 2-difluoropropoxy)-2,3,5,6-tetrafluoro-[1,1'-biphenyl]- 4-amine for 14b; -10 °C; iii) NaH, Boc2O, THF; iv) a) Pd / C (9 % w / w) THF for 16a-b or b) BBr3, DCM, 0 °C for 16c; v) Cesium carbonate, dibenzyl(chloromethyl)phosphate, acetonitrile; vi) Pd / C (10 % w / w), THF; vii) TFA, DCM; viii) KOH, (or NaOH, or tromethamine, or lysine) water, lyophilization. Solubility and stability profile The determination of solubility in different vehicle was carried out (Table 1). Compounds solubility was evaluated initially in water and in phosphate buffered saline (PBS) at pH 7.4, after 24 hours stirring at 25 °C. While MEDS433 confirmed its low solubility, instead 1 and its different salts 2, 2a, 2b, 2c display a better solubility, reaching values closer to 1 mM in water. In analogy to prodrug 1, also prodrugs 5 and 7 improve the solubility of related compounds 6 (1 µM in PBS) and 8 (8 µM in PBS13). For compounds 1 and 2, the solubility in simulated gastric and intestinal fluids was also measured, to mimic the passage in the gastrointestinal tract and to observe the variation of solubility in these fluids. As expected, the solubility of the two compounds 1 and 2 became lower at acidic pH and while it is better at the intestinal pH of 6.5, still falling in the high µM range. However, their solubility remains always evaluable. Table 1. Solubility at 24 h in different vehicle of MEDS433, its prodrugs 1, 2, 2a, 2b, 2c and prodrugs 5 and 7. Vehicle MEDS433 µMµ12 2a 2b 2c 5 7 M µM µM µM µM µM µM Water 2 347 1053 1390 1521 1107 742 325 PBS (pH: 7.4)6 497 644 469 390 530 267 55SGFan.d. 10 49 n.d n.d. n.d. n.d. n.d. SIFbn.d. 306 338 n.d. n.d. n.d. n.d. n.d. a) Simulated gastric fluid 37 °C (pH 1.6); b) Simulated intestinal fluid 37 °C (pH 6.5); n.d. not detected. The analyses of the stability profile of 1 in different mouse organ homogenates and in human serum were performed to demonstrate the capacity to release active compound MEDS433. The results, showed in Figure 1, demonstrate that 1 is capable of releasing MEDS433 in liver, kidney, and intestine rapidly, while is stable in human serum until 24 hours. Like compound 1 also compounds 5 and 7 are able to release the related compounds 6 and 8 in mouse homogenates. In vivo pharmacokinetic studies and drug releasing The preclinical pharmacokinetic of MEDS433 and compound 2 in CD1 mice after both oral and intravenous administration was studied. All treatments were well tolerated, and no clinical signs of toxicity were observed. Collected biological samples were analysed by Mass Spectrometry. The concentration time data of MEDS433 and 2 were elaborated according to non- compartmental analysis to obtain the pharmacokinetic profile of the drugs and the main pharmacokinetic parameters. Table 2. MEDS433 main pharmacokinetic parameters after intravenous and oral administration Administration Cmax T max C0AUC0-lastAUC0-infHL Cl / F Vd route (dose)Tissue(ng / mL) (h) Plasma 15840 0.08 26616 14028 14051 3.6 0.36 1.84 Liver 4097 0.25 16433 IV Lung 1589 0.25 4401 Brain 142 0.25 519 Plasma 2539 0.25 - 30224 30275 3.4 0.66 3.11 54 PO Liver 2556 0.25 37552 (20 mg / kg) Lung 1630 0.25 9461 Brain 53 0.25 708 As shown in Figure 2, which pictures concentration vs time data obtained after IV and PO administration, MEDS433 rapidly distributes into the mouse body, within half an hour. From a visual inspection of the curves, early peak concentrations of 15840 and 2539 ng / mL can be seen, followed by a rebound of concentrations at 2 and 8 hours, suggesting that the drug undergoes enterohepatic recirculation. After this intermediate phase, characterized by slow concentration decay, MEDS433 disappears from plasma with a half-life of 3.6 and 3.4 hours after IV and PO (Table 2), respectively, and with a plasmatic clearance (Cl / F of 0.36 L / (h*kg). Drug levels were measurable up to 32 and 24 hours after PO and IV, respectively. Comparing the AUC0-inf obtained in the two routes of administration, the bioavailability (F) resulted 54%. MEDS433 was mainly excreted in feces. Looking at Table 2A, can be observed how about 80 % of the drug dose was recovered in feces after the two routes of administrations. In urine (Table 2B), the percentage of the dose recovered amounted to 13 % and 5 % after IV and PO, respectively. Table 2A. Faecal excretion (% of dose) of MEDS433 after intravenous and oral administration of MEDS433 and compound 2. )MEDS433 IV MEDS433 OSMEDS43MEDS433 Time (h3from 2 IV from 2 OS 24 81.7 % 80.2 % 86.5 % 55.5 % 48 1.3 % 3.3 % 2.7 % 2.0 % Table 2B. Urinary excretion (% of dose) of MEDS433 after intravenous and oral administration of MEDS433 and compound 2. MEDS433MEDS433 Time (h) MEDS433 IV MEDS433 OSfrom 2 IV from 2 OS 24 12.6 % 2.7 % 20.7 % -12.6 % 48 0.85 % 2.2 % 0.4 % -0.3 %

[0004] Table 3. Pro-drug 2 main pharmacokinetic parameters obtained after intravenous and oral administration at doses of 6.85 mg / Kg and 27.38 mg / Kg equivalent to 5 mg / Kg and 20 mg / Kg of MEDS433. Administration Cmax T max C0AUC0-last AUC0-inf HL Cl / F Vd route (dose)Tissue F%(ng / mL) (h) (ng / mL) (ng / mL*h) (ng / mL*h) (h) (L / (h*kg))(kg / L)Plasma 71999 0.08 131623 25295 25314 1.1 0.27 0.42 Liver 985 0.25 873 IV Lung 2556 0.25 3675 Brain 13 0.25 - Plasma 62 0.25 - 67 - - - - 0.07 Liver 46 0.25 - PO Lung 1237 0.25 670 Brain - - -Table 4. MEDS433 main pharmacokinetic parameters obtained after intravenous and oral administration of compound 2 at doses of 6.85 mg / Kg and 27.38 mg / Kg equivalent to 5 mg / Kg and 20 mg / Kg of MEDS433. Administration Cmax T max C0AUC0-lastAUC0-infHL Cl / F Vd route (dose)Tissue(ng / mL) (h) (ng(kg / L)F%(ng / mL) / mL*h) (ng / mL*h) (h) (L / (h*kg)) Plasma 18088 0.08 22929 20535 20581 3.8 0.24 1.35 Liver 11937 0.25 41066 IV Lung 6397 0.25 15325 Brain 249 0.25 324 Plasma 9440 0.25 - 105972 106257 3.6 0.19 0.97 130 Liver 13756 0.25 184697 P.O. Lung 7982 0.25 30482 Brain 81 0.25 960 As shown in Figure 3 (part A and B) which plots concentration vs time data of 2 obtained after IV and PO administrations, cpd 2 distributed rapidly in the body and disappears from plasma with a half-life of 1.1 h (Table 3), very rapid Cl / F of 0.27 L / (h*kg) and with measurable plasma levels up to 8 hours. Due to almost no absorption (F < 0.1%) and detectable levels only up to 2 hours, the half-life is not calculable after oral route. After intravenous administration, cpd 2 AUC in liver and lung were 30 and 7 times lower than in plasma, respectively. Interestingly after oral administration, cpd 2 AUC in lung was ten times higher than in plasma, but not measurable in liver. Cpd 2 was never detectable in brain (Table 3). From Figure 3A after IV administration of cpd 2, a prompt release of MEDS433 leading to a plasma C0 of 22929 ng / mL can be noticed. MEDS433 is promptly released also after PO leading to a Cmax of 9440 ng / mL at 15 min (Figure 3B and Table 4). This is expected because cpd 2 probably undergoes massive first-pass effect releasing high concentrations of MEDS433, then due to enterohepatic recirculation, a sustained concentration profile with bioavailability over than 100 % can be observed. Similarly, as shown after administration of MEDS433, even after the doses of cpd 2, MEDS433 disappears from plasma with a half-life of 3.8 and 3.6 hours, after IV and PO route respectively and with plasma clearance slightly lower 0.24 L / (h*kg), but with measurable plasma levels up to 32 hours after both routes. After intravenous administration of cpd 2, the experimental AUC of MEDS433 was two times higher in liver than in plasma, slightly lower in lung and 60 times lower in brain. After oral route, MEDS433 AUC resulted 1.7-fold higher in liver than in plasma, but three-fold lower in lung and 100-fold lower in brain. Cpd 2 was never detectable in feces and urine being, as mentioned before, the drug is converted into MEDS433 that was mainly excreted in feces. Looking at Table 2A, about 80 % and 50 % of MEDS433 dose was recovered in feces after IV and PO, respectively. In urine (Table 2B), the percentage of the MEDS433 recovered amounted to 20 % and 12 % after IV and PO, respectively. The comparison of the pharmacokinetics of MEDS433 after administration of the drug itself, and of MEDS433 obtained after administration of the pro-drug 2, shows that: • the pharmacokinetic profiles after IV administration are substantially superimposable (Figure 4, part A), even if there is evidence of more prolonged, up to 32 hours, exposure to MEDS433 after cpd 2. • important differences were observed in bioavailability. After oral administration of cpd 2 the concentration vs time curves of MEDS433 in plasma showed similar trend, but with higher levels compared to those observed after oral administration of MEDS433, leading to F > 100 % vs 54 % (see Figure 4, part B). • important differences were observed in the drug tissue distribution of MEDS433 in liver and lung in which AUC resulted two-five times higher after the treatment with cpd 2 than with MEDS433. Antitumoral activity. The in vitro activity profile of preferred compounds MEDS433 and 6 against the above- mentioned tumors are reported in Table 5. Both falling within Formulae (Ia), MEDS433 and 6 are released in vivo from the correspondent prodrug 1 and 5, these latter falling within Formulae (I). Table 5. The in vitro activity profile of preferred compounds MEDS433 and 6 against different tumors. MEDS433 6 Tumors Cell line IC50 (72h, nM) IC50 (72h, nM) Osteosarcoma SAOS-2 470.4 515.6 A673 59.85 50.90 Ewing sarcoma TC71 31.87 31.93 Bladder carcinoma T24 56.1 17.8 IDH mutated Fibrosarcoma HT1080 Not tested 4.9 Glioblastoma LN18 84.9 77.18 IDH mutated Glioblastoma U87 IDH mt Not tested 121.3 Breast cancer MDA MB 231 103.7* 91.9* Melanoma A375 105.1 97.9 H3K27M-mutated diffuse midline gliomaSF-7761 31.09 9.26SF-8628 Not tested 112*LAN-5 91.93 88.52 Neuroblastoma SHSY5Y Not tested 15.6 Mutated KRAS lung tumors A549 501.74 485.9 *IC505 days The obtained submicromolar IC50showed the high potency of the preferred compound MEDS433 and 6 to inhibit the tumour cellular proliferation. Notable the high potency of 6 to inhibit the proliferation of Ewing sarcoma, Neuroblastoma, Bladder carcinoma, IDH-mutated fibrosarcoma and glioblastoma and H3K27M-mutated diffuse midline glioma cell line with an IC50in the nanomolar range. In vivo pharmacokinetic studies of compounds 6 and 8 In preparation to in vivo efficacy assay the preliminary preclinical pharmacokinetic of compound 6 in Balb / c mice after both oral and intravenous administration was studied. All treatments were well tolerated, and no clinical signs of toxicity were observed. Collected biological samples were analysed by Mass Spectrometry. The concentration time data of 6 was elaborated according to non-compartmental analysis to obtain the pharmacokinetic profile of the drugs and the main pharmacokinetic parameters. Table 6. Compound 6 main pharmacokinetic parameters after intravenous and oral administration Admin Cmax T max C0AUC0-last AUC0-inf HL Cl Vd F route(ng / mL) (h) (ng / mL) (ng / mL*h) (ng / mL*h) (h) (L / h*kg) (L / kg) % Plasma 66300 0.25 74400 382600 435100 8.1 0.115 0.135 IV Brain 720 0.25 4636 PO Plasma 43130 0.25 - 473400 658300 >12.0 - - 37.8 Brain 670 0.25 7059 As shown in Figure 5, which pictures concentration vs time data obtained after IV and PO administration of compound 6, after IV route the drug appears distributed in the body within 2 hour and disappears from plasma with a half-life of 8 hour. After oral administration, there is slower absorption than IV route and enterohepatic recirculation at 2 and 4 hours, then drug disappears from plasma with a long half-life >12 hours. Drug levels were measurable up to 24 hours after both way of administrations. The main pharmacokinetic parameters are listed in Table 6. Comparing the compound 6 AUC0-inf, obtained after the two routes of administration the bioavailability (F) results 37.8 %. The plasmatic clearance (Cl) and the volume of distribution Vd, of 0.115 L / h / Kg and 0.135 L / Kg, indicate low drug distribution in the body fluid. Compound 6 was measurable in brain early at 15 min, and up to 24 hours after both PO and IV administration. The preliminary preclinical pharmacokinetic of compound 8 in CD1 mice after both oral and intravenous administration was also studied. All treatments were well tolerated, and no clinical signs of toxicity were observed. Collected biological samples were analysed by Mass Spectrometry. The concentration time data of 8 was elaborated according to non- compartmental analysis to obtain the pharmacokinetic profile of the drugs and the main pharmacokinetic parameters. Table 7. Compound 8 main pharmacokinetic parameters after intravenous and oral administration of 20 and 5 mg / kg of the drug Admin T Cmax T max C0AUC0-last AUC0-inf HL Cl Vd F routeissue(ng / mL) (h) (ng / mL) (ng / mL*h) (ng / mL*h) (h) (L / h*kg) (L / kg) % Plasma 21300 0.25 32110 48980 49090 3.7 0.102 0.54 IV Brain 430 0.25 696 PO Plasma 19430 0.25 - 127570 127820 3.4 - - 65.1 Brain 350 0.25 1643 As shown in Figure 6, which pictures concentration vs time data obtained after IV and PO administration of compound 8, the drug appears rapidly distributed in the body within 1 hour, then it is probably subjected to entero-hepatic re-circulation mainly after PO (notable a rebound of concentration at 2 h) rather than after IV route, and disappears from plasma with a half-life of 3.4 and 3.7 hours, respectively. From a visual inspection of the curves, plasma levels above the LOQ (10 ng / mL) were measurable up to 32 hours after both route of administration. The main pharmacokinetic parameters are listed in Table 7. Comparing the compound 8 AUC0- inf, obtained after the two routes of administration the bioavailability (F) result is 65.1 %. The plasmatic clearance (Cl) and the volume of distribution Vd, of 0.101 L / h / Kg and 0.54 L / Kg, indicate moderate drug distribution in the body fluid. Compound 8 was measurable in brain early at 15 min, and up to 8 hours after both PO and IV administration. Use in combination The in vitro activity profile on AML cells of preferred compound MEDS433 in combination with five drugs are reported in Figure 7 (panel A and B) and in Figure 8 (panel A-D) showing the % of apoptotic cells after three days of treatment. The anti-tumour activity of MEDS433 is potentiated by combination with registered and common drugs, able to enhance its pro- apoptotic activity. In addition, compound 6 shows a synergistic activity also with three different anticancer drugs (Figure 9). These data support the potential use of compound 6 in combination with panabinostat, abemaciclib and ONC212 in diffuse midline glioma and also in cancer where these medicinal products are clinical recommended. Conclusions This disclosure covers prodrugs of human dihydroorotate dehydrogenase (hDHODH) inhibitors structurally based on hydroxyazole scaffold and methods of making and using thereof. As representative compound, 2 was found able to effectively release the parent drug MEDS433 in in vitro as well as in vivo environments. The strategy was able to successfully increase the solubility, being solubility of 2 increased x 500 in water compared to the drug MEDS433, as well as the bioavailability. In fact, after oral administration of 2 the concentration vs time curves of MEDS433 in plasma showed higher levels compared to those observed after oral administration of MEDS433 itself, leading to F > 100 % vs 54 %. The improvement of PK parameters here demonstrated is crucial to optimize the in vivo treatment of aggressive solid tumors targeted by hDHODH inhibitors object of this disclosure. This improvement along with the potent anticancer profile demonstrated in in vitro cancer cell line models illustrated in Table 5 represent an innovative solution to efficiently target, in association with standard of care, cancers that are still unmet medical need in oncology. In particular the data described herein show that solid tumors that express low levels of GPX4 (A549 and MDA MB 231 reported in Table 5)9, 15can be effectively targeted by hDHODH inhibitors to reduce tumor burden, and that a combination of hDHODH inhibitors with known ferroptosis inducers, such as sulfasalazine, sorafenib and artemisinin derivatives (i.e. artesunate and dihydroartemisinin), can be used to treat GPX4highand ferroptosis sensitive tumors. Furthermore, our data reveal a promising antiproliferative activity of our compounds in IDH mutated cancer. This evidence indicates that IDH mutated cancer are probably hyper dependent on de novo pyrimidine nucleotide synthesis. This preferential pharmacological activity could represent a new therapeutic strategy to treat IDH mutated cancer, also in combination with IDH inhibitors. In addition, hDHODH inhibitors could be combined with other standard-of-cares in cancer therapy that can induce ferroptosis, such as chemotherapy, radiotherapy and immunotherapy. Looking for synergic combinations to boost apoptosis in AML cells, MEDS433 was combined with classical antileukemic drugs and / or drugs targeting pyrimidine salvage pathway. The combination of MEDS433 with selected drugs increased significantly the apoptotic rate, demonstrating synergistic effects. Materials and methods Chemistry General methods. All chemical reagents were obtained from commercial sources (Sigma Aldrich, Alfa Aesar, FluoroChem and BLD Pharma), and used without further purification. Thin-layer chromatography (TLC) was carried out to monitor reaction progress. Analytical grade solvents (acetonitrile, diisopropyl ether, diethyl ether, dichloromethane [DCM], dimethylformamide [DMF], ethanol 99.8 % v / v, ethyl acetate [EtOAc], hexane, methanol [MeOH], petroleum ether b.p. 40 – 60 °C [petroleum ether], toluene), were used without further purification. When needed, solvents were dried over 4 Å molecular sieves. Tetrahydrofuran (THF) was distilled from Na and benzophenone under N2immediately prior to use. Thin layer chromatography (TLC), on silica gel was carried out on 5 x 20 cm plates at 0.25 mm layer thickness. Anhydrous Na2SO4was used as a drying agent for the organic phases. Compound purification was either achieved using flash column chromatography on silica gel (Merck Kieselgel 60, 230-400 mesh ASTM), and the eluents indicated in the procedures for each compound, or using CombiFlash Rf 200 (Teledyne Isco), with 5–200 mL / min, 200 psi (with automatic injection valve), and RediSep Rf Silica columns (Teledyne Isco), with the eluents indicated in the procedures for each compound. Compounds synthesized in our laboratory generally varied between 90 % and 99 % purity. Biological experiments were performed on compounds with a purity of at least 95 %. Purity was checked using two analytical methods. HPLC analyses were performed on an UHPLC chromatographic system (Perkin Elmer, Flexar). The analytical column was an UHPLC Acquity CSH Fluoro-Phenyl (2.1x100 mm, 1.7 µm particle size, Waters). Compounds were dissolved in MeOH and injected through a 20 µl loop. The mobile phase consisted of MeOH / water with 0.1 % trifluoroacetic acid (ratio between 90 / 10 and 20 / 80, depending on the compound’s retention factor). UHPLC retention times were obtained at flow rates of 0.5 mL / min, and the column effluent was monitored at 215 and 254 nm, referenced against a 360 nm wavelength. Solubility assays, and stability assays were performed on UHPLC chromatographic system (Perkin Elmer, Flexar). Melting points (m.p.) were measured on a capillary apparatus (Büchi 540). Final m.p. determination was achieved by placing the sample at a temperature 10° C below the m.p. and applying a heating rate of 1° C min-1. All compounds were routinely checked by1H and13C NMR and mass spectrometry. MS spectra were performed on Waters Micromass ZQ equipped with an ESCi source for electrospray ionization mass spectra.1H and13C NMR spectra were either performed on a JEOL ECZR600. The following abbreviations are used for coupling patterns: br = broad, s = singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet. Chemical shifts (δ) are given in parts per million (ppm). In this work protons and carbons are labelled (a, b, c, d, e, f, g, h, l, m, n and o) according to Scheme 2. Values marked with an asterisk are interchangeable. Not for all the tetrafluorinated biphenyl compounds detailed13C spectra, have been entirely reported due to their especially complicated patterns (attributable to the multiple couplings between fluorine and carbon atoms). For some compounds, only the13C signals caused by the heterocyclic substructure and non-aromatic carbons are assigned; for other compounds only the MS spectra were reported. Compound 6a was prepared according to previously described procedures.11Ethyl 3-ethoxy-1H-pyrazole-4-carboxylate (10). Diethyl 2-(ethoxymethylene) malonate (3 g, 0.0139 mol) was added to a solution of hydrazine hydrochloride (950 mg, 13.9 mmol) in EtOH abs (30 mL). The resulting mixture was refluxed overnight, then saturated aqueous solution of NaHCO3(70 mL) was added. The mixture was extracted with EtOAc (2 x 50 mL) and the combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The resulting crude product was purified by flash chromatography (eluent: dichloromethane / MeOH 95 / 5 v / v) affording the title compound as a white solid. Yield 36%.1H NMR (600 MHz, chloroform-d), δ 1.32 (t, J = 7.1 Hz, 3H, -OCH2CH3), 1.41 (t, J = 7.1 Hz, 3H, - OCH2CH3), 4.27 (q, J = 7.1 Hz, 2H, -OCH2CH3), 4.33 (q, J = 7.0 Hz, 2H, -OCH2CH3), 7.87 (s, 1H, pyr-H), 10.45 (br s, 1H, -NH).13C NMR (151 MHz, chloroform-d), δ 14.5 (C-m, 14.8 (C-i), 60.2 (C-l), 65.4 (C-h), 99.7 (C-e), 134.0 (C-d), 162.5 (C-g), 163.2 (C-f). MS (ESI-): 183 (M-1). Ethyl 1-(2,2-diethoxyethyl)-3-ethoxy-1H-pyrazole-4-carboxylate (11). Ethyl 3-ethoxy-1H- pyrazole-4-carboxylate (10), 2-bromo-1,1-diethoxyethane and Cs2CO3 were solubilized in dry DMF. The obtained mixture was heated at 85 °C overnight, then the reaction was quenched in water (50 mL) and extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over Na2SO4and evaporated under reduced pressure. The resulting crude product was purified by flash chromatography (eluent: petroleum ether / EtOAc 80 / 20 v / v) affording the title compound as a colorless oil. Yield 68 %.1H NMR (600 MHz, chloroform-d), δ 1.14 (t, J = 7.0 Hz, 6H, -(OCH2CH3)2), 1.31 (t, J = 7.1 Hz, 3H, -OCH2CH3), 1.42 (t, J = 7.1 Hz, 3H, -OCH2CH3), 3.37 – 3.45 (m, 2H, -CH(OCH2CH3)2), 3.65 – 3.73 (m, 2H, -CH(OCH2CH3)2), 3.97 (d, J = 5.4 Hz, 2H, -CH2CH-), 4.25 (q, J = 7.1 Hz, 2H, -OCH2CH3), 4.29 (q, J = 7.0 Hz, 2H, -OCH2CH3), 4.74 (t, J = 5.4 Hz, -CH2CH-), 7.72 (s, 1H, pyr-H);13C NMR (151 MHz, chloroform-d), δ 14.5 (C-m), 14.8 (C-i), 15.4, 55.6, 59.9, 64.0, 65.3, 99.7, 100.9, 135.7, 162.2, 162.7. MS (ESI+): 301 (M+1). Ethyl 1-(2,2-diethoxyethyl)-3-ethoxy-5-formyl-1H-pyrazole-4-carboxylate (12). 2.5 M solution of butyl lithium in dry THF (650 µL, 1.612 mmol) was added to a -78°C cooled solution of 11 (440 mg, 1.466 mmol) in dry THF (15 mL). The resulting mixture was stirred at -78 °C for 15 minutes, then dry DMF (200 µL, 2.199 mmol) was added and the reaction mixture was stirred for 20 minutes. The reaction mixture was quenched in sat. aq. ammonium chloride solution (150 mL) and the resulting mixture was extracted with Et2O (2 x 50 mL) and the combined organic layers were dried over Na2SO4and evaporated under reduced pressure. The resulting crude product was purified by flash chromatography (eluent: petroleum ether / EtOAc 95 / 5 v / v) affording the title compound as a colorless oil. Yield 77 %.1H NMR (600 MHz, chloroform-d), δ 1.13 (t, J = 7.0 Hz, 6H, -CH(OCH2CH3)2), 1.37 (t, J = 7.1 Hz, 3H, -OCH2CH3), 1.44 (t, J = 7.0 Hz, 3H, -OCH2CH3), 3.42 – 3.49 (m, 2H, -CH(OCH2CH3)2), 3.65 – 3.72 (m, 2H, - CH(OCH2CH3)2), 4.32 – 4.38 (m, 4H, -OCH2CH3), 4.54 (d, J = 5.6 Hz, 2H, -CH2CH-), 4.81 (t, J = 5.6 Hz, 1H, -CH2CH-), 10.37 (s, 1H, -COH);13C NMR (151 MHz, chloroform-d), δ 14.4, 14.7, 15.3, 53.5, 60.9, 62.6, 65.8, 100.5, 103.0, 139.5, 161.3, 162.3, 183.4. MS (ESI+): 329 (M+1). Ethyl 2-ethoxypyrazolo[1,5-a]pyrazine-3-carboxylate (13). Compound 12 (300 mg, 0.914 mmol, 1.0 eq.) was solubilized in trifluoroacetic acid (2.3 mL), water (0.7 mL), and tetrahydrofuran (1.0 mL) at room temperature. The reaction mixture was stirred at 50 °C for 4 h, then was cooled to room temperature, and concentrated to give a residue, which was take up with toluene and concentrated three times (3 x 5 mL). The resultant residue was combined with ethanol (3 mL), acetic acid (1.3 mL), and ammonium acetate (211 mg, 2.742 mmol, 3.0 eq.), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated, and then water (40 mL) was added. The mixture was stirred at room temperature, and solid potassium carbonate was added portion-wise until the aqueous layer reached pH 8. Then, the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to give a crude which was purified by flash chromatography (eluent: DCM / EtOAc 9:1 v / v) to afford the title compound as a white solid. Yield 78 %.1H NMR (600 MHz, chloroform-d), δ 1.42 (t, J = 7.1 Hz, 3H, -OCH2CH3), 1.51 (t, J = 7.0 Hz, 3H, -OCH2CH3), 4.40 (q, J = 7.1 Hz, 2H, - OCH2CH3), 4.51 (q, J = 7.1 Hz, 2H, -OCH2CH3), 7.99 (d, J = 4.5 Hz, 1H, H-a), 8.20 (d, J = 4.3 Hz, 1H, H-b), 9.37 (s, 1H, H-d);13C NMR (151 MHz, chloroform-d), δ 14.6, 14.8, 60.4, 66.4, 89.4, 121.6, 130.5, 136.9, 144.1, 162.3, 165.3; MS (ESI+): 236 (M+1). 2-Ethoxypyrazolo[1,5-a]pyrazine-3-carboxylic acid (14b).5 M NaOH (5.0 eq.) was added to a solution of 13 (290 mg, 1.233 mmol) in EtOH (10 mL). The solution was stirred for 3 h at 60 °C, and then neutralized with 6 M HCl and concentrated under reduced pressure. Subsequent, a phosphate buffer solution pH 4 (40 mL) was added, and the aqueous layer was extracted with EtOAc (10 x 25 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to give a residue which was purified by titration with diisopropyl ether to afford the title compound as white solid. Yield 76 %.1H NMR (600 MHz, DMSO-d6), δ 1.40 (t, J = 7.0 Hz, 3H, -OCH2CH3), 4.43 (q, J = 7.1 Hz, 2H, -OCH2CH3), 8.06 (d, J = 4.5 Hz, 1H, H-a), 8.75 (dd, J = 4.5, 1.4 Hz, 1H, H-b), 9.24 (d, J = 1.4 Hz, 1H, H-d), 12.57 (s, 1H, -COOH);13C NMR (151 MHz, DMSO-d6), δ 14.6, 65.6, 88.6, 122.4, 130.8, 136.6, 142.8, 162.8, 164.2; MS (ESI-): 206 (M-1). General procedure for synthesis of amide 16a - 16d. Oxalyl chloride (2.2 eq.) and dry DMF (20 µL) were added to a cooled (0 °C) solution of corresponding acid (14a,b, 1.0 eq.) in dry THF kept under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature. In parallel, a 1 M THF solution of LiHMDS in (2.2 eq.) was added to a solution of appropriate aniline (2.0 eq.) in dry THF under a nitrogen atmosphere. The resulting suspension was stirred for 50 minutes at room temperature. The solution of corresponding acyl chloride (15a,b) was then concentrated under reduced pressure, and the residue was dissolved in dry THF (50 mL); this step was repeated three times to eliminate all gaseous residues. The corresponding acyl chloride was then dissolved in dry THF, and the solution was added to the described above solution via cannula. The reaction mixture was stirred at -10 °C for 30 minutes, then was quenched in ammonium saturated solution and the organic layer was separated. The aqueous solution was extracted with EtOAc (2 x 120 mL), and the combined organic layers were washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The crude material was purified using flash chromatography. 2-((4-Methoxybenzyl)oxy)-N-(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyridine-3- carboxamide (16a). The crude material was purified using flash chromatography (eluent: petroleum ether / EtOAc 8 / 2 v / v and then 7 / 3 v / v) to afford the title compound as a white solid. Yield 90 %.1H NMR (600 MHz, chloroform-d) δ: 3.83 (s, 3H, -OCH3), 5.52 (s, 2H, -OCH2Ar), 6.91 (td, 1H, J = 6.9, 1.0 Hz, H-b), 6.96 (d, 2H, J = 8.6 Hz, H-n), 7.40 – 7.51 (m, 8H, aromatic protons and H-c), 8.26 (d, 1H, J = 8.8 Hz, H-d), 8.31 (s, 1H, -NH), 8.34 (d, 1H, J = 6.8 Hz, H- a);13C NMR (151 MHz, chloroform-d) δ: 55.5 (-OCH3), 72.2 (-OCH2Ar), 90.0 (C-f), 113.3 (C- b), 114.3 (C-n), 115.8 (t, J = 15.8 Hz, C-s)*, 117.9 (t, J = 17.3 Hz, C-p)*, 118.8 (C-d), 127.5, 127.7, 128.3 (C-l), 128.7, 128.8 (C-m), 129.2, 130.3, 142.6 (dd, J = 248.1, 15.8 Hz, C-r)**, 143.2 (C-e), 144.1 (dd, J = 242.0, 15.3 Hz, C-q)**, 160.2 (C-o)***, 160.6 (C-h)***, 163.0 (C- NMR (564 MHz, chloroform-d) δ: -144.66 (d, J = 25.4 Hz), -145.81 (d, J = 27.9 Hz); : 522 (M + 1). N-(3'-(2,2-Difluoropropoxy)-2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)-2-((4- methoxybenzyl)oxy)pyrazolo[1,5a] pyridine-3-carboxamide (16b). The crude product was purified by flash chromatography (eluent: petroleum ether / EtOAc 8 / 2 then 7:3 v / v) to obtain the title compound as solid. The latter was then triturated with diisopropyl ether, and the title compound was obtained as a yellow solid (mp 114.6 - 117.0 °C). Yield 79 %.1H NMR (600 MHz, chloroform-d) δ: 1.79 (t, 3H, J= 18.8 Hz, -OCH2CF2CH3), 3.83 (s, 3H, -OCH3), 4.14 (t, 2H, J = 11.3 Hz, -OCH2CF2CH3), 5.52 (s, 2H, -CH2Ar), 6.92 (td, 1H, J = 6.9, 1.1 Hz, H-b), 6.95 (d, 2H, J = 8.6 Hz, H-n), 6.99 - 7.03 (m, 2H, aromatic protons), 7.09 (d, 1H, J = 7.5 Hz, aromatic proton), 7.40 – 7.45 (m, 2H, aromatic protons and H-c), 7.48 (d, 2H, J = 8.6 Hz, H-m), 8.25 (d, 1H, J = 8.8 Hz, H-d), 8.31 (s, 1H, -NH-), 8.34 (d, 1H, J =6.9 Hz, H-a).13C NMR (151 MHz, chloroform-d) δ: 21.1 (t, J = 25.6 Hz, -OCH2CF2CH3), 55.5 (-OCH3), 69.9 (t, J = 35.0 Hz, - OCH2CF2CH3), 72.3 (-CH2Ar), 90.0 (C-f), 113.3 (C-b), 114.3 (C-n), 115.5, 116.2 (t, J = 17.3 Hz, C-s)*, 116.7, 117.4 (t, J = 17.3 Hz, C-p)*, 118.8 (C-d), 121.5 (t, J= 239.6 Hz, - OCH2CF2CH3), 123.8, 127.7.128.3 (C-a), 128.8, 128.9, 129.9 (C-c), 130.3 (C-m), 140.9 (d, J = 255.9 Hz, C-r)**, 143.2 (C-e), 144.1 (d, J = 251.1 Hz, C-q)**, 158.1, 160.2, 160.5, 163.0; MS (ES+): 616 [M+1]. 2-((4-Methoxybenzyl)oxy)-N-(2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4- yl)pyrazolo[1,5-a]pyridine-3-carboxamide (16c). The crude product was purified by flash chromatography (eluent: petroleum ether / EtOAc 7:3 v / v) to obtain the title compound as yellow solid (3.0 g, 4.95 mmol). Yield 65%.1H NMR (600 MHz, chloroform-d) δ: 3.83 (s, 3H, - ArOCH3), 5.52 (s, 2H, -OCH2Ar), 6.92 (td, 1H, J = 6.9, 1.4 Hz, H-b), 6.96 (d, 2H, J = 8.7 Hz, H- v), 7.30 – 7.34 (m, 2H, H-c and H-n), 7.38 – 7.44 (m, 2H, H-r), 7.48 (d, 1H, J = 8.7 Hz, H-u), 7.52 (t, 1H, J = 8.1 Hz, H-p)*, 8.24 – 8.27 (m, 1H, H-q)*, 8.32 – 8.36 (m, 2H, H-a and -NH).13C NMR (151 MHz, chloroform-d) δ: 55.5 (-OCH3), 72.3 (-CH2Ar), 89.9 (C-f), 113.4 (C-b), 114.3 (C-v), 116.2 (t, J = 16.7 Hz), 116.7 (t, J = 17.5 Hz), 118.8, 120.6, (q, J = 257.8 Hz), 121.6 (C- p)***, 123.0 (C-r)***, 127.7 (C-a)**, 128.3 (C-c)**, 128.78 (C-t), 128.83 (C-d), 129.3 (C-m), 130.2 (C-q), 130.3 (C-u), 142.6 (d, J = 247.4 Hz), 143.2 (C-e), 144.1 (d, J = 246.7 Hz), 149.4 (d, J = 1.1 Hz, -OCF3), 160.2 (C-z), 160.5 (C-h)****, 163.0 (C-g)****.19F NMR (564 MHz, chloroform-d) δ: -145.14 (dd, 2F, J = 22.7, 9.9 Hz, F-k)*, -144.47 (dd, 2F, J = 21.7, 8.1 Hz, F- j)*, -57.75 (s, 3F, -OCF3). MS (ES+): 606 [M+1]. 2-Ethoxy-N-(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (16d). The crude material was purified by flash chromatography (eluent: from DCM / EtOAc 9 / 1 v / v to 7 / 3 v / v) to afford the title compound as a white solid. Yield 85 %.1H NMR (600 MHz, Chloroform-d), δ 1.59 (t, J = 7.1 Hz, 3H, -OCH2CH3), 4.68 (q, J = 7.1 Hz, 2H, -OCH2CH3), 7.43 – 7.54 (m, 5H, aromatic protons), 8.07 (d, J = 4.6 Hz, 1H, H-a), 8.24 (dd, J = 4.6, 1.4 Hz, 1H, H-b), 8.36 (s, 1H, -NH), 9.65 (d, J = 1.3 Hz, 1H, H-d);13C NMR (151 MHz, Chloroform-d), δ 14.9, 67.5, 91.3, 115.3 (t, J = 14.5 Hz), 118.5 (t, J = 17.1 Hz), 121.5, 127.3, 128.8, 129.3, 130.3, 131.4, 137.3, 142.6 (d, J = 248.6 Hz), 144.2 (d, J = 246.0 Hz), 144.8, 159.7, 162.6;19F NMR (564 MHz, DMSO-d6) δ: -145.69 (d, J = 21.6 Hz), -144.20 (d, J = 24.0 Hz); MS (ESI+): 431 (M+1). General procedure for synthesis of compounds 17a-d. NaH (1.1 eq.) was added to a solution of appropriate amide (16a-d) (1.0 eq.) in dry THF and the mixture was stirred for 1 h at room temperature. In the following, a solution of di-tert-butyl dicarbonate (1.1 eq.) in 4 mL of dry THF was added and the reaction mixture was heated to reflux. After 8 h additional NaH (0.5 eq.) and di-tert-butyldicarbonate (0.5 eq.) were added and the reaction mixture was stirred at reflux for 16 h. The reaction mixture was cooled at 0 °C with an ice bath and quenched in phosphate buffer pH = 7 (50 mL), the aqueous layer was extracted with EtOAc (4 x 40 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified via flash chromatography. Tert-butyl (2-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonyl)(2,3,5,6-tetrafluoro- [1,1'-biphenyl]-4-yl)carbamate (17a). The crude material was purified via flash chromatography (eluent petroleum ether / EtOAc 7 / 3 v / v) to afford the title compound as white solid. Yield 73 %.1H NMR (600 MHz, chloroform-d) δ: 1.26 (s, 9H, -CCH3), 3.80 (s, 3H, -OCH3), 5.45 (s, 2H, -OCH2Ar), 6.87 – 6.94 (m, 3H, aromatic protons and H-b), 7.39 – 7.54 (m, 8H, aromatic protons and H-c), 8.00 (d, 1H, J = 8.8 Hz, H-d), 8.33 (d, 1H, J = 6.8 Hz, H-a);13C NMR (151 MHz, DMSO-d6) δ: 27.0, 55.1, 70.8, 83.7, 91.9, 113.7, 114.4, 116.7, 118.1 (t, J = 15.2 Hz), 119.8 (t, J = 17.1 Hz), 126.2, 128.0, 128.9, 129.1, 129.7, 130.1, 130.14, 130.19, 142.6, 143.2 (d, J = 245.3 Hz), 150.5, 159.1, 162.3, 163.1. MS (ESI+): 622 (M+1). Tert-butyl (3'-(2,2-difluoropropoxy)-2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)(2-((4- methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonyl)carbamate (17b). The crude material was purified via flash chromatography (eluent petroleum ether / EtOAc 7 / 3 v / v) to afford the title compound as white vitreous solid (460 mg, 0.699 mmol). Yield: 92%.1H NMR (600 MHz, chloroform-d) δ: 1.27 (s, 9H, -C(CH3)3), 1.79 (t, 3H, J = 18.8 Hz, -OCH2CF2CH3), 3.80 (s, 3H, -OCH3), 4.16 (t, 2H, J = 11.3 Hz, -OCH2CF2CH3), 5.45 (s, 2H, -OCH2Ph), 6.87 – 6.91 (m, 3H, aromatic protons and H-b), 7.02 – 7.07 (m, 2H), 7.14 (d, 1H, J = 7.6 Hz, H-r), 7.40 – 7.46 (m, 4H, aromatic protons and H-c), 8.00 (ddd, 1H, J = 8.8, 1.4, 1.0 Hz, H-d), 8.33 (dt, J = 6.9, 1.1 Hz, H-a).13C NMR (151 MHz, chloroform-d) δ: 21.1 (t, J = 26.0 Hz, -OCH2CF2CH3), 27.7 (- C(CH3)3), 55.4 (-OCH3), 69.9 (t, J = 34.9 Hz, -OCH2CF2CH3), 71.3 (-OCH2Ph), 84.0 (C-f), 93.3 (-C(CH3)3), 113.5 (C-b), 113.9 (aromatic carbon), 115.8, 116.7, 118.2 (C-d), 118.8 (t, J = 19.0 Hz), 119.7 (t, J = 17.0 Hz), 121.6 (t, J = 239.4 Hz, -CH2CF2CH3), 123.9 (C-r), 128.4, 128.7, 128.8 (C-a)**, 129.1 (C-c)**, 129.3 (aromatic carbon), 130.0 (C-q), 143.8 (C-e), 144.0 (dd, 2C, J = 256.4, 10.0 Hz), 151.3 (-COOC(CH3)3), 158.1 (C-o), 159.6 (C-OCH3), 163.5 (C-h)*, 163.7 (C-g)*.19F NMR (564 MHz, chloroform-d) δ: -145.76 (s, 2F), -144.14 (dd, 2F, J = 21.8, 8.5 Hz) , -98.00 - -97.93(m, 2F). MS (ES+): 716 [M+1]. Tert-butyl (2-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonyl)(2,3,5,6-tetrafluoro-3'- (trifluoromethoxy)-[1,1'-biphenyl]-4-yl)carbamate (17c) The crude material was purified via flash chromatography (eluent petroleum ether / EtOAc 7 / 3 v / v) to afford the title compound as vitreous white solid (2.0 g, 2.83 mmol). Yield: 78%.1H NMR (600 MHz, chloroform-d) δ: 1.27 (s, 9H, -C(CH3)3), 3.80 (s, 3H, -OCH3), 5.45 (s, 2H, H-s), 6.88 – 6.93 (m, 3H, H-v and H-b), 7.32 – 7.35 (m, 1H, H-r), 7.38 (s, 1H, H-n), 7.40 – 7.46 (m, 4H, H-c, H-d, H-u), 7.55 (t, 1H, J = 8.0 Hz, H-p)*, 7.98 – 8.01 (m, 1H, H-q)*, 8.33 (dt, 1H, J = 6.8, 1.0 Hz, H-a).13C NMR (151 MHz, chloroform-d) δ: 27.6 (-C(CH3)3), 55.4 (-OCH3), 71.4 (C-s), 84.1 (C-f), 93.2 (C(CH3)3), 113.5 (C-b), 113.9 (C-u), 118.2 (C-d), 118.5 (t, J = 16.4 Hz), 119.3 (t, J = 18.4 Hz), 120.6 (q, J = 257.8 Hz), 121.9 (C-p), 123.1 (C-r), 128.4 (C-t), 128.8 (C-a)**, 128.9 (C-c)**, 129.1 (C-m)**, 129.3 (C-m)?, 129.3 (C-u), 130.2 (C-q), 143.7 (d, J = 244.2 Hz), 143.8 (C-e), 143.9 (d, J = 241.8 Hz), 149.4 (d, J = 1.9 Hz), 151.2 (-COOC(CH3)3), 159.6 (C-z), 163.4 (C-h)*, 163.6 (C- g)*.19F NMR (564 MHz, chloroform-d) δ: -145.29 (s, 2F, F-k)*, -144.36 (dd, 2F, J = 21.7, 8.5 Hz, F-j)*, -57.75 (s, 3F, -OCF3). MS (ESI) 728 [M+Na]+. Tert-butyl (2-ethoxypyrazolo[1,5-a]pyrazine-3-carbonyl)(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4- yl)carbamate (17d). The crude material was purified via flash chromatography (eluent petroleum ether / EtOAc 5 / 5 v / v) to afford the title compound as vitreous white solid.1H NMR (600 MHz, DMSO-d6) δ: 1.35 – 1.41 (m, 12H, -C(CH3)3 and -OCH2CH3), 4.50 (q, 2H, J = 7.0 Hz, -OCH2CH3), 7.51 – 7.63 (m, 5H, aromatic protons), 8.21 (d, 1H, J = 4.5 Hz, H-a), 8.89 (dd, 1H, J = 4.5, 1.4 Hz, H-b), 9.24 (d, 1H, J = 1.4 Hz, H-d)13C NMR (151 MHz, DMSO-d6) δ: 14.3 (-OCH2CH3), 27.1 (-C(CH3)3), 66.4 OCH2CH3), 84.4 (-C(CH3)3), 92.4 (C-f), 117.5 (t, J = 14.5 Hz), 120.2 (t, J = 17.1 Hz), 122.9, 126.1, 128.9, 129.7, 130.1, 132.1, 136.8, 142.1, 143.1 (d, J = 248.5 Hz), 143.4 (d, J = 248.6 Hz), 150.2, 162.0, 162.6.19F NMR (564 MHz, DMSO-d6) δ: - 146.73 (dd, 2F, J = 15.8 Hz), -144.11 (dd, 2F, J = 24.2, 7.7 Hz). MS (ESI+): 531 (M+1). Tert-butyl (2-hydroxypyrazolo[1,5-a]pyridine-3-carbonyl)(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4- yl)carbamate (18a). Palladium on carbon (Pd / C, 0.15 g, 9 % w / w) was added to a solution of compound 17a (1.7 g, 2.7 mmol) in dry THF (40 mL) under inert atmosphere of nitrogen. The resulting mixture was vigorously stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered on silica C18 and the product was eluted with MeOH to afford the title compound as white solid. Yield 81 %.1H NMR (600 MHz, DMSO-d6) δ: 1.36 (s, 9H, -CCH3), 7.09 (t, 1H, J = 6.8 Hz, H-b), 7.51 – 7.62 (m, 6H, H-c), 7.83 (d, 1H, J = 8.8 Hz, H-d), 8.67 (d, 1H, J = 6.8 Hz, H-a), 12.25 (s, 1H, -OH);13C NMR (151 MHz, DMSO-d6) δ: 27.1, 83.3, 91.1, 113.9, 116.3, 118.3 (t, J = 21.1 Hz), 119.3 (t, J = 24.2 Hz), 126.1, 128.8, 129.3, 129.4, 129.5, 130.0, 142.3, 144.0, 145.3, 150.5, 162.6, 163.4. Tert-butyl (3'-(2,2-difluoropropoxy)-2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)(2- hydroxypyrazolo[1,5-a]pyridine-3-carbonyl)carbamate (18b). Palladium on carbon (Pd / C, 30 mg, 9 % w / w) was added to a solution of compound 17b (340 mg, 0.48 mmol) in dry THF (20 mL) under inert atmosphere of nitrogen. The resulting mixture was vigorously stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered on silica C18and the product was eluted with MeOH to afford the title compound as white solid (380 mg, 638 mmol). Yield 99%.1H NMR (600 MHz, DMSO-d6) δ: 1.36 (s, 9H, -C(CH3)3), 1.75 (t, 3H, J = 19.2 Hz, -OCH2CF2CH3), 4.35 (t, 2H, J = 12.6 Hz, -OCH2CF2CH3), 7.09 (td, 1H, J = 6.9, 1.4 Hz, H-b), 7.17 – 7.22 (m, 2H, H-p and H-r), 7.29 (s, 1H, H-n), 7.51 (t, 1H, J = 8.0 Hz, H-c), 7.56 – 7.60 (m, 1H, H-q), 7.83 (d, 1H, J = 8.7 Hz, H-d), 8.66 (d, 1H, J = 6.8 Hz, H-a), 12.22 (v br s, -OH).13C NMR (151 MHz, DMSO-d6) δ: 20.7 (t, J = 25.1 Hz, -OCH2CF2CH3), 27.2 (-C(CH3)3), 68.9 (t, J = 31.5 Hz, -OCH2CF2CH3), 83.5 (C-f), 91.2 (-C(CH3)3), 114.0 (C-b), 116.2, 116.40, 116.43, 118.6 (t, J = 13.4 Hz), 119.1 (t, J = 17.7 Hz), 122.2 (t, J = 238.9 Hz, -OCH2CF2CH3), 123.2 (C-r), 127.5, 129.4, 129.5, 130.1, 142.4 (C-e), 143.2 (dd, 2C, J = 241.3, 8.9 Hz), 150.1 (-COOC(CH3)3), 157.8 (C-o), 162.7 (C-h)*, 163.5 (C-g)*.19F NMR (564 MHz, chloroform-d) δ: -146.59 (d, 2F, J = 14.4 Hz), -144.08 (d, 2F, J = 17.7 Hz), -97.05 - -96.81 (m, 2F). MS (ESI) 594 [M-1]-. MS (ES-): 594 [M-1]. Tert-butyl-(2-hydroxypyrazolo[1,5-a]pyridine-3-carbonyl)(2,3,5,6-tetrafluoro-3'- (trifluoromethoxy)-[1,1'-biphenyl]-4-yl)carbamate (18c). Palladium on carbon (Pd / C, 15 mg, 9 % w / w) was added to a solution of compound 17c (166 mg, 0.235 mmol) in dry THF (10 mL) under inert atmosphere of nitrogen. The resulting mixture was vigorously stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered on silica C18and the product was eluted with MeOH to afford the title compound as white solid (883 mg, 1.5mmol). Yield 56%.1H NMR (600 MHz, chloroform-d) δ: 1.44 (s, 9H, C(CH3)3), 7.01 (td, 1H, J = 7.0, 1.4 Hz, H-b), 7.33 – 7.36 (m, 1H, H-r), 7.37 (s, 1H, H-n), 7.44 (d, J = 7.9 Hz, 1H), 7.51 (ddd, J = 8.7, 7.1, 1.1 Hz, 1H, H-c)*, 7.55 (t, J = 8.0 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H, H-d), 8.33 (dt, 1H, J = 6.8, 1.0 Hz, H-a), 11.41 (v br s, 1H, -OH).13C NMR (151 MHz, chloroform-d) δ: 27.8 (-C(CH3)3), 84.9 (C-f), 92.4 (-C(CH3)3), 114.4 (C-b), 118.1 (C-d), 119.02 (t, J = 16.5 Hz), 119.74 (t, J = 16.2 Hz), 122.0 (C-p), 122.3 (q, J = 257.6 Hz), 123.0 (C-r), 128.8 (C-c)**, 128.88 (C-a)**, 128.90 (C-m), 129.5 (C-n), 130.3 (C-q)***, 141.7 (C-e), 143.9 (d, J = 247.0 Hz), 144.1 (d, J = 248.5 Hz), 149.4 (q, J = 1.4 Hz), 151.0 (-COOC(CH3)3), 164.9 (C-h)*, 165.7 (C-g)*.19F NMR (564 MHz, chloroform-d) δ: -144.98 (d, 2F, J = 8.5 Hz, F-k)*, -143.87 (dd, 2F, J = 22.6, 9.8 Hz, F-j)*, -57.77 (s, 3F, -OCF3). MS (ESI) 586 [M+H]+. Tert-butyl (2-hydroxypyrazolo[1,5-a]pyrazine-3-carbonyl)(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4- yl)carbamate (18d). 1M BBr3solution in DCM (1200 μL, 1.161 mmol) was dissolved in dry DCM (10 mL) under inert atmosphere. The solution was cooled at -10 °C and compound 17d (0.200 g, 0.46 mmol) was added, and the reaction mixture was stirred for 30 minutes at -10 °C. Then, additional BBr31M solution in DCM (600 μL, 0.5807 mmol) was added and the reaction was stirred overnight. The reaction was quenched in distilled water (50 mL) and extracted with DCM (3 x 60 mL). Organic layers were collected, washed with a saturated brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford a pale, yellow solid. The crude solid was triturated with diisopropyl ether to afford the title compound as a solid. MS (ESI-): 501 (M-1). General procedure for synthesis of compounds 19a-d. Cesium carbonate (1.1 eq.) was added to a suspension of appropriate compound (18a-d, 1 eq.) in acetonitrile (30 mL), and the reaction mixture was stirred at room temperature for 40 min. Then a solution of dibenzyl(chloromethyl)phosphate (1.1 eq.) in acetonitrile (5 mL) was added, and the reaction mixture was stirred at room temperature until complete consumption of the starting material. In the following, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography. Tert-butyl (2-(((bis(benzyloxy)phosphoryl)oxy)methoxy)pyrazolo[1,5-a]pyridine-3- carbonyl)(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)carbamate (19a). The crude material was purified by flash chromatography (eluent petroleum ether / EtOAc from 7:3 v / v to 5:5 v / v) to afford the title compound as white solid. Yield 56 %.1H NMR (600 MHz, chloroform-d) δ: 1.44 (s, 9H, -CCH3), 5.04 – 5.14 (m, 4H, -CH2OPh), 6.00 (d, 2H, J = 11.9 Hz, -OCH2OP-), 6.91 (t, 1H, J = 6.5 Hz, H-b), 7.22 – 7.33 (m, 10H, aromatic protons), 7.40 – 7.53 (m, 6H, aromatic protons and H-c), 8.00 (d, 1H, J = 8.8 Hz, H-d), 8.23 (d, 1H, J = 6.8 Hz, H-a);13C NMR (151 MHz, chloroform-d) δ: 27.8, 69.6 (d, J = 5.3 Hz), 84.4, 88.2 (d, J = 3.9 Hz), 93.2, 113.9, 118.2 (t, J = 15.0 Hz), 118.4, 120.2 (t, J = 16.8 Hz), 127.2, 127.9, 128.57, 128.59, 128.8, 129.0, 129.2, 129.4, 130.3, 135.6 (d, J = 7.5 Hz), 142.9, 143.5, 144.5, 151.2, 161.1, 163.0;31P NMR (243 MHz, chloroform-d) δ: -2.34. MS (ES+): 792 [M+1]. Tert-butyl (2-(((bis(benzyloxy)phosphoryl)oxy)methoxy)pyrazolo[1,5-a]pyridine-3-carbonyl)(3'- (2,2-difluoropropoxy)-2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)carbamate (19b). The crude material was purified by flash chromatography (eluent petroleum ether / EtOAc from 8:2 v / v to 6:4 v / v) to afford the title compound as white vitreous solid (240 mg, 0.272 mmol). Yield 45%.1H NMR (600 MHz, chloroform-d) δ: 1.44 (s, 9H, -C(CH3)3), 1.80 (t, 3H, J = 18.8 Hz, - OCH2CF2CH3), 4.15 (t, 2H, J = 11.4 Hz, -OCH2CF2CH3), 5.05 – 5.12 (m, 4H, -OCH2Ph), 5.99 (d, 2H, J = 12.0 Hz, -OCH2OP-), 6.90 (td, 1H, J = 7.0, 1.4 Hz, H-b), 7.01 (s, 1H, H-n), 7.03 (ddd, 1H, J = 8.3, 2.6, 0.8 Hz, H-q), 7.10 (d, 1H, J = 7.6 Hz, H-p), 7.24 - 7.31 (m, 10H, aromatic protons), 7.41 - 7.46 (m, 2H, H-c and H-r), 7.98 - 8.01 (m, 1H, H-d), 8.23 (dt, 1H, J = 6.9, 1.0 Hz, H-a).13C NMR (151 MHz, DMSO-d6) δ: 21.1 (t, J = 26.0 Hz, -OCH2CF2CH3), 27.8 (- C(CH3)3), 69.6 (d, J = 5.4 Hz, -OCH2OP-), 69.9 (t, J = 35.0 Hz, -OCH2CF2CH3), 84.4 (C-f), 88.2 (d, J = 3.7 Hz, -OCH2OP-), 93.2 (-C(CH3)3), 113.9 (C-b), 115.8, 116.7, 117.0, 118.4, 119.7, 121.5 (t, J = 239.3 Hz, -OCH2CF2CH3), 123.8, 127.9 (aromatic protons), 128.58, 128.60, 129.0, 129.2, 130.0, 135.6 (d, J = 7.3 Hz, C-u), 143.6 (C-e), 143.58 (dd, 2C, J = 244.7, 7.9 Hz), 151.2 (-COOC(CH3)3 ), 158.1 (C-o), 161.1 (C-h)*, 162.9 (C-g)*.19F NMR (564 MHz, chloroform-d) δ: -145.34 (dd, 2F, J = 22.7, 9.1 Hz), -143.92 (d, 2F, J = 14.1 Hz), -98.00 - -97.83 (m, 2- OCH2CF2CH3).31P NMR (243 MHz, chloroform-d) δ: -2.36 (s). MS (ES+): 886 [M+1]. Tert-butyl (2-(((bis(benzyloxy)phosphoryl)oxy)methoxy)pyrazolo[1,5-a]pyridine-3- carbonyl)(2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)carbamate (19c). The crude material was purified by flash chromatography (eluent petroleum ether / EtOAc from 8:2 v / v to 6:4 v / v) to afford the title compound as white vitreous solid (644 mg, 0,735 mmol). Yield 49%.1H NMR (600 MHz, chloroform-d) δ: 1.45 (s, 9H, -CCH3), 5.05 – 5.14 (m, 4H, -OCH2Ph), 5.99 (d, 2H, J = 12.0 Hz, -OCH2OP-), 6.91 (td, 1H, , J = 7.0, 1.4 Hz, H-b), 7.25 – 7.30 (m, 10H, aromatic protons), 7.32 – 7.35 (m, 2H, H-n and H-c), 7.40 (d, 1H, J = 7.8 Hz, H-r), 7.44 (ddd, 1H, J = 8.8, 7.0, 1.1 Hz, H-c), 7.53 (dd, 1H, J = 8.9, 7.8 Hz), 7.99 (dt, J = 8.9, 1.1 Hz, H-d), 8.23 (dt, 1H, J = 6.9, 1.0 Hz, H-a);13C NMR (151 MHz, chloroform-d) δ: 27.8 (-C(CH3)3), 69.6 (d, J = 5.5 Hz, -OCH2Ph) 84.6 (C-f), 88.2 (d, J = 4.1 Hz, -OCH2OP-), 93.2 (-C(CH3)3), 114.0 (C-b), 118.4 (C-d), 118.6 (t, J = 13.7 Hz), 119.0 (t, J = 15.1 Hz), 120.6 (q, J = 257.9 Hz, -OCF3), 121.9 (C-p)*, 123.0 (C-r)*, 127.9 (aromatic carbons), 128.58, 128.59, 128.8 (C-c)**, 128.9 (C- m), 129.1 (C-a)**, 129.2 (C-n)**, 130.2 (C-q)*, 135.6 (d, J = 7.4 Hz, C-u), 143.6 (C-e), 143.7 (d, J = 245.0 Hz), 143.8 (d, J = 246.2 Hz), 149.4 (q, J = 2.1 Hz), 151.1 (COOC(CH3)3), 161.1 (C-h)****, 162.9 (C-g)****.19F NMR (564 MHz, chloroform-d) δ: -144.82 (dd, 2F, J = 22.7, 9.5 Hz, F-k)*, -144.12 (d, 2F, J = 13.6 Hz, F-j)*, -57.75 (s, 3F, -OCF3)..31P NMR (243 MHz, chloroform-d) δ: -2.31 (s). MS (ESI) 898 [M+Na]+. Tert-butyl (2-(((bis(benzyloxy)phosphoryl)oxy)methoxy)pyrazolo[1,5-a]pyrazine-3- carbonyl)(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)carbamate (19d). The crude material was purified by flash chromatography (eluent DCM / EtOAc from 95:5 v / v to 90: 10 v / v) to afford the title compound as white solid. MS (ESI-): 791 (M-1). General procedure for synthesis of compounds 1, 3, 5 and 7 Palladium on carbon (Pd / C, 10 % w / w) was added to a solution of 19a-d (1 eq.) in dry THF (15 mL). The resulting mixture was vigorously stirred under a hydrogen atmosphere for 2 h. The reaction mixture was filtered on silica C18 and the product was eluted with MeOH, and concentrated under reduced pressure to afford the intermediate compounds 20a-d that were dissolved in dry DCM (10 mL). After cooling (0 °C), a solution of TFA (5 mL) in dry DCM (15 mL) was then added and the reaction mixture was stirred at the same temperature for 3 h. In the following, the solvent was evaporated, involving toluene to facilitate the evaporation of TFA, affording the title compound as white solids. ((3-((2,3,5,6-Tetrafluoro-[1,1'-biphenyl]-4-yl)carbamoyl)pyrazolo[1,5-a]pyridin-2-yl)oxy)methyl dihydrogen phosphate (1). Yield 90 %.1H NMR (600 MHz, DMSO-d6) δ: 5.94 (d, 2H, J = 14.9 Hz, -OCH2OP-), 7.14 (t, 1H, J = 6.8 Hz, H-b), 7.49 – 7.65 (m, 6H, aromatic protons and H -c), 8.04 (d, 1H, J = 8.8 Hz, H-d), 8.76 (t, 1H, J = 6.9 Hz, H-a), 9.25 (s, 1H, -NH);13C NMR (151 MHz, DMSO-d6) δ: 87.8 (d, J = 5.4 Hz), 89.8, 114.1, 116.6 (t, J = 16.5 Hz), 117.4, 117.7 (t, J = 17.3 Hz), 126.6, 128.9, 129.0, 129.5, 129.7, 130.2, 142.0, 142.9 (d, J = 246.6 Hz), 143.2 (d, J = 245.9 Hz), 159.9, 160.3;31P NMR (243 MHz, DMSO-d6) δ: -1.60. MS (ESI-): 510 (M-1). ((3-((3'-(2,2-Difluoropropoxy)-2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)carbamoyl)pyrazolo[1,5- a]pyridin-2-yl)oxy)methyl dihydrogen phosphate (5). White solids. It was then crystallized with acetone. The solid was take up with H2O (100 mL) and lyophilized. Yield 56 %.1H NMR (600 MHz, DMSO-d6) δ: 1.76 (t, 3H, J = 19.2 Hz, -OCH2CF2CH3), 4.36 (t, 2H, J = 12.5 Hz, - OCH2CF2CH3), 5.95 (d, 2H, J = 14.7 Hz, -OCH2OP-), 7.14 (t, 1H, J = 6.9 Hz, H-b), 7.19 (d, 2H, J = 7.8 Hz, H-p and H-c), 7.26 (s, 1H, H-n), 7.51 (t, 1H, J = 7.5 Hz, H-q), 7.60 (t, 1H, J = 7.8 Hz, H-r), 8.05 (d, 1H, J = 8.8 Hz, H-d), 8.76 (d, 1H, J = 6.8 Hz, H-a), 9.24 (s, 1H, -NH);13C NMR (151 MHz, DMSO-d6) δ: 20.7 (t, J = 25.2 Hz, -OCH2CF2CH3), 68.9 (t, J = 31.1 Hz, - OCH2CF2CH3), 87.7 (d, J = 5.4 Hz, -OCH2OP-), 89.8 (C-f), 114.1 (C-b), 115.8, 116.6 (C-d), 116.8 (t, J = 15.0 Hz), 117.3 (t, J = 16.2 Hz), 117.4, 122.2 (t, J = 238.9 Hz, - OCH2CF2CH3), 123.3, 127.9, 129.0, 129.7, 130.1, 142.0 (C-e), 157.8 (C-o), 159.8 (C-h)*, 160.3 (C-g)*.19F NMR (564 MHz, chloroform-d) δ: -144.92 (d, 2F, J = 22.1 Hz), -144.80 (d, 2F, J = 23.8 Hz), - 97.03 - -96.80 (m, 2-OCH2CF2CH3).31P NMR (243 MHz, chloroform-d) δ: -1.65 (s). MS (ESI-): 605 (M-1). ((3-((2,3,5,6-Tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)carbamoyl)pyrazolo[1,5- a]pyridin-2-yl)oxy)methyl dihydrogen phosphate (7). White solids. It was then crystallized with acetone (211 mg, 354 mmol). Yield 56 %. The obtained solid was take up with water (100 mL) and lyophilized.1H NMR (600 MHz, DMSO-d6) 5.94 (d, 2H, J = 14.9 Hz, -OCH2OP-), 7.14 (td, 1H, J = 7.0, 1.4 Hz, H-b), 7.49 – 7.69 (m, 4H, aromatic protons and H-c), 7.72 (t, J = 8.0 Hz), 8.04 (d, 1H, J = 8.8 Hz, H-d), 8.76 (t, 1H, J = 6.9 Hz, H-a), 9.30 (s, 1H, -NH);13C NMR (151 MHz, DMSO-d6) δ: 87.8 (d, J = 5.0 Hz, -OCH2OP-), 89.8 (C-f), 113.5, 114.1 (C-b), 116.0 (t, J = 15.9 Hz, C-i)*, 117.4 (C-d), 117.6 (t, J = 14.1 Hz, C-l)*, 122.1 (d, J = 2.1 Hz), 123.0, 123.6, 124.6, 128.7, 129.1, 129.5, 129.7, 130.1, 142.0 (C-e), 148.4, 159.8, 160.3;19F NMR (564 MHz, DMSO-d6) δ: -145.27 (dd, 2F, J = 24.2, 7.0 Hz, F-k)*, -144.5 (dd, 2F, J = 22.9, 7.7 Hz,, F-j)*, - 56.77 (s, 3F, -OCF3);31P NMR (243 MHz, DMSO-d6) δ: -1.61. MS (ESI-): 594 (M-1). ((3-((2,3,5,6-Tetrafluoro-[1,1'-biphenyl]-4-yl)carbamoyl)pyrazolo[1,5-a]pyrazin-2-yl)oxy)methyl dihydrogen phosphate (3). MS (ESI-): 511 (M-1). Potassium ((3-((2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)carbamoyl)pyrazolo[1,5-a]pyridin-2- yl)oxy)methyl hydrogen phosphate (2). Compound 1 (50.0 mg, 1.0 eq., 0.0978 mmol) was dissolved in ultrapure water (50 mL). The solution was stirred and cooled to 5° C, then 9.78 mL of 0.01 M KOH solution (1.0 eq., 0.0978 mmol) was slowly added. The solution was freeze- dried for 24 h, obtaining 2 as a white porous solid with a quantitative yield.1H NMR (600 MHz, DMSO-d6) δ: 5.73 (d, 2H, J = 15.7 Hz, -OCH2OP-), 7.05 (td, 1H, J = 6.9, 1.4 Hz, H-b), 7.48 – 7.59 (m, 6H, aromatic protons and H-c), 7.93 – 7.96 (m, 1H, H-d), 8.70 (dt, 1H, J = 6.9, 1.0 Hz, H-a), 11.20 (v br s, 1H, -OH);31P NMR (243 MHz, chloroform-d) δ: -1.10 (t, J = 15.6 Hz). Sodium ((3-((2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)carbamoyl)pyrazolo[1,5-a]pyridin-2- yl)oxy)methyl hydrogen phosphate. (2a). Compound 1 (48.6 mg, 1.0 eq., 0.095 mmol) was dissolved in ultrapure water (50 mL). The solution was stirred and cooled to 5° C, then 9.5 mL of 0.01 M NaOH solution (1.0 eq., 0.095 mmol) was slowly added. The solution was freeze- dried for 24 h, obtaining 2a as a white porous solid with a quantitative yield.1H NMR (600 MHz, DMSO-d6) δ: 5.73 (d, 2H, J = 15.7 Hz, -OCH2OP-), 7.05 (td, 1H, J = 6.9, 1.4 Hz, H-b), 7.46 – 7.61 (m, 6H, aromatic protons and H-c), 7.95 (d, 1H, J = 8.9 Hz, H-d), 8.69 (d, 1H, J = 6.9 Hz, H-a), 11.23 (v br s, 1H, -OH);31P NMR (243 MHz, chloroform-d) δ: -1.07 (t, J = 15.4 Hz). 1,3-Dihydroxy-2-(hydroxymethyl)propan-2-aminium ((3-((2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4- yl)carbamoyl)pyrazolo[1,5-a]pyridin-2-yl)oxy)methyl hydrogen phosphate (2b). Compound 1 (40.25 mg, 1.0 eq., 0.0787 mmol) was dissolved in EtOH (10 mL). The solution was stirred and then a solution of 2-amino-2-(hydroxymethyl)propane-1,3-diol (9.53 mg, 1.0 eq. , 0.0787 mmol) in EtOH (10 mL) was slowly added. The suspension was stirred in 40°C bath for 15 min and then the solvent was evaporated to obtain 2b as a white solid with a quantitative yield.1H NMR (600 MHz, DMSO-d6) δ: 3.45 (s, 6H, (HOCH2)3CNH2) 5.75 (d, 2H, J = 15.6 Hz, -OCH2OP-), 7.06 (td, 1H, J = 6.9, 1.4 Hz, H-b), 7.49 – 7.60 (m, 6H, aromatic protons and H-c), 7.96 (d, 1H, J = 8.8 Hz, H-d), 8.70 (dt, 1H, J = 6.9, 1.0 Hz, H-a), 10.96 (v br s, 1H, -OH);13C NMR (151 MHz, DMSO-d6) δ: 59.4 ((HOCH2)3CNH2), 60.8 ((HOCH2)3CNH2), 88.5 (d, J = 6.0 Hz, - OCH2OP-), 91.0 (C-f), 113.5 (C-b), 117.2 (C-d), 118.4, 119.2, 126.8, 128.3, 128.8, 129.3, 129.4, 130.1, 141.7 (C-e), 143.3 (dd, J = 245.3, 13.1 Hz, 2C), 160.6 (C-h)*, 161.2 (C-g)*.19F NMR (564 MHz, chloroform-d) δ: -146.05 (dd, J = 24.4, 6.8 Hz), -144.40 (dd, J = 24.7, 6.3 Hz).31P NMR (243 MHz, chloroform-d) δ: -0.67 (t, J = 15.4 Hz). (R)-5-amino-5-carboxypentan-1-aminium ((3-((2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4- yl)carbamoyl)pyrazolo[1,5-a]pyridin-2-yl)oxy)methyl hydrogen phosphate (2c). Compound 1 (45.05 mg, 1.0 eq., 0.0881 mmol) was dissolved in EtOH (10 mL). The solution was stirred and then a solution of 2-amino-2-(hydroxymethyl)propane-1,3-diol (12.88 mg, 1.0 eq. , 0.0881 mmol) in EtOH (10 mL) was slowly added. The suspension was stirred in 40°C bath for 15 min and then the solvent was evaporated to obtain 2c as a white solid.1H NMR (600 MHz, DMSO- d6) δ: 1.21 – 1.85 (m, 6H, -CH2CH2CH2-), 2.73 (t, 2H, J = 7.2 Hz, -CH2NH2), 3.36 – 3.42 (m, 1H, -CH-), 5.77 (d, 2H, J = 15.4 Hz, -OCH2OP-), 7.07 (td, 1H, J = 6.9, 1.3 Hz, H-b), 7.48 – 7.59 (m, 6H, aromatic protons and H-c), 7.97 (d, 1H, J = 8.8 Hz, H-d), 8.70 (d, 1H, J = 6.9, H-a), 10.59 (s, 1H, -NH). 2-Hydroxy-N-(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (4). BBr31M solution in DCM (600 μL, 0.5807 mmol) was dissolved in dry DCM (5 mL) under inert atmosphere. The solution was cooled at -10°C and compound 16d (0.100 g, 0.2323 mmol) was added and the reaction mixture was stirred for 30 minutes at -10°C. Then, additional BBr31M solution in DCM (600 μL, 0.5807 mmol) was added and the reaction was stirred overnight. The reaction was quenched in distilled water (50 mL) and extracted with DCM (3 x 60 mL). Organic layers were collected, washed with a saturated brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford a pale, yellow solid. The crude solid was triturated with diisopropyl ether to afford the title compound as pale, yellow solid. Yield 80%.1H NMR (600 MHz, DMSO-d6), δ 7.51 – 7.60 (m, 5H, aromatic protons), 8.10 (d, J = 4.5 Hz, 1H, H-a), 8.75 (dd, J = 4.5, 1.3 Hz, 1H, H-b), 9.12 (s, 1H, -NH), 9.31 (d, J = 1.3 Hz, 1H, H-c), 13.38 (br s, 1H, -OH);13C NMR (151 MHz, DMSO-d6), δ 89.4, 116.5 (t, J = 14.8 Hz), 117.6 (t, J = 17.5 Hz), 122.1, 126.5, 128.7, 129.3, 130.0, 131.0, 136.2, 142.1, 142.8 (dd, J = 244.8, 13.2 Hz), 143.2 (dd, J = 244.6, 12.3 Hz), 159.7, 162.4;19F NMR (564 MHz, DMSO-d6) δ: -145.66 (d, J = 24.8 Hz), -145.07 (d, J = 24.3 Hz); MS (ESI-): 401 (M-1). Solubility assay Solubility was performed in different vehicles: saline phosphate buffer (PBS; Na2HPO410 mM, KH2PO41.8 mM, NaCl 137 mM and KCl 2.7 mM, pH 7.4), ultrapure water, simulated gastric fluid (SGF, purchased from Biorelevant and prepared according the instructions), simulated intestine fluid (SIF, purchased from Biorelevant and prepared according the instructions). For each sample, the compound was weighted (1 mg), then 1 mL of vehicle was added, and the solution was stirred at 350 rpm for 24 hours at 25 °C (PBS and water) or 37 °C (SGF, SIF). Before the analysis, suspensions were filtered through a PTFE 0.22 µm filter and analyzed using UHPLC-UV system (Perkin Elmer, Flexar). The analytical column used was an UHPLC XBridge BEH C18 (3x75mm column XP, 2,5 µm particle size, Waters). Each analysis was performed at flow rates of 0.5 mL / min in elution gradient using water (eluent A) and Methanol (eluent B) with 0.1 % trifluoroacetic acid (TFA) as mobile phase. The analysis started with 50 % of eluent B and the profile used was: (time min, % B) 9.50, 100 %; 12.5, 100 %; 14.5, 50 %. Quantification of the compounds was achieved by interpolation with the respective calibration curve obtained by analyzing standard sample solutions in MeOH. Serum stability assay A DMSO solution of the compound was added to human serum (sterile-filtered from human male AB plasma, Sigma-Aldrich) to obtain a concentration of 100 µM resulting in 2 % of DMSO. The solution was incubated under stirring at 350 rpm at 37 °C for 24 h. At selected time (t0; t30min; t1h; t4h; t24h), an aliquot was denatured 1 : 2 with ice-cold acetonitrile with 0.1 % of trifluoroacetic acid. Then, the obtained solution was vortexed, sonicated for 3 min and then centrifuged at 3900rpm for 5 min. The supernatant was filtered through PTFE 0.22 µm filter and analyzed using UHPLC-UV system (PerkinElmer, Flexar). The analytical column used was an UHPLC XBridge BEH C18 (3x75 mm column XP, 2,5 µm particle size, Waters). The analysis was performed at flow rates of 0.5 mL / min in elution gradient using water (eluent A) and Methanol (eluent B) with 0.1 % trifluoroacetic acid (TFA) as mobile phase. The analysis started with 50 % of eluent B and the profile used was: (time min, % B) 9.50, 100 %; 12.5, 100%; 14.5, 50 %. Quantification of the compound was achieved by interpolation with the respective calibration curve obtained by analysing standard sample solutions in MeOH. Liver, intestine, kidney S9 Fraction homogenates preparation and stability assay S9 fraction of mouse tissue homogenates have been prepared by the homogenization of freshly isolated organs; Mouse liver, intestine and kidneys have been isolated, cut into smaller pieces and respectively mixed with ice-cold 50mM TRIS buffer (TRIS 50 mM, KCl 150 mM, pH 7.4) to obtain a 4 ml / g of organ suspension. Each organ suspension has been homogenized using Potter-Elvehjem mortar and pestle, followed by centrifugation at 9000 g for 30 minutes at 4 ° C to yield a supernatant fraction known as S9 fractions. Supernatants protein content was quantified using a protein Lowry assay. Aliquots of the S9 fraction were then stored at −80 °C until used. In the assay the reaction mixture was composed of mouse S9 fraction (0.5 mg protein / mL), 50 mM TRIS buffer (TRIS 50 mM, KCl 150 mM, pH 7.4), 100 µM compound resulting in 2 % of DMSO. The solution was incubated under stirring at 350 rpm at 37 °C for 24 h. At selected time (t0; t30min; t1h; t1h; t2h) an aliquot was denatured 1:1 with ice-cold acetonitrile. The obtained solution was vortexed and centrifuged at 3900rpm for 10 min. The supernatant was filtered through PTFE 0.22 µm filter and analyzed using UHPLC-UV system (Perkin Elmer, Flexar). The analytical column used was an UHPLC XBridge BEH C18 (3x75mm column XP, 2,5µm particle size, Waters). The analysis was performed at flow rates of 0.5 mL / min in elution gradient using water (eluent A) and Methanol (eluent B) with 0.1 % trifluoroacetic acid (TFA) as mobile phase. The analysis started with 50 % of eluent B and the profile used was: (time min, % B) 9.50, 100 %; 12.5, 100 %; 14.5, 50 %. Quantification of the compound was achieved by interpolation with the respective calibration curve obtained by analyzing standard sample solutions in MeOH. Compounds under pharmacokinetic studies: sample preparation MEDS433 (HPLC purity > 95 %) 2 (> 95 % containing traces of MEDS433 (around 4%)), 6 and 8 for analytical purpose, were dissolved in DMSO (1 mg / mL, stock solution), and diluted with acetonitrile for working solutions used for the analytical method set-up and the analysis of pharmacokinetic samples. For treating animal purpose, oral administration, all compounds were dissolved in 10 % DMSO 5 % Tween 10 % PEG400 75 % Methocell (0.5%). For intravenous treatment, they were dissolved in DMSO 10%, Cremophor 5% e 85% saline. The stability of 2 in the vehicle used for intravenous treatment, was assessed by HPLC-HRMS before the conduction of the pharmacokinetic study. The analytical result showed that 2 is stable at 4 hours at room temperature, in fact at that time the % of MEDS433 present is just slightly increased to 6.1 %. Test system: mice. Seven-week-old male mice were purchased from Charles River Italia (Calco, Italy). Animals were housed at the Mario Negri Istituto di Ricerche Farmacologiche and handled under specific pathogen-free conditions in the Institute's Animal Care Facilities, which meet international standards; procedures involving animals and their care were conducted in conformity with the following laws, regulations, and policies governing the care and use of laboratory animals: Italian Governing Law (D.lgs 26 / 2014; Authorization n.19 / 2008-A issued March 6, 2008 by Ministry of Health); Mario Negri Institutional Regulations and Policies providing internal authorization for persons conducting animal experiments (Quality Management System Certificate – UNI EN ISO 9001:2008 – Reg. N° 6121); the NIH Guide for the Care and Use of Laboratory Animals (2011 edition) and EU directives and guidelines (EEC Council Directive 2010 / 63 / UE). Experimental protocols have been reviewed and approved by the IRFMN Animal Care and Use Committee (IACUC), that includes members "ad hoc" for ethical issues, and by the Italian Ministry of Health (aut. Min n.779 / 2022). Pharmacokinetic of MEDS433, 2, 6 and 8. Mice were treated with MEDS433, 6 and 8 at the doses of 5 mg / kg given intravenously (IV) and 20 mg / kg given by oral gavage (PO), and with 2 at 6.85 mg / kg (IV) and 27.38 mg / kg (PO), corresponding to equivalent doses of MEDS433 of 5 mg / kg and of 20 mg / kg respectively. Blood was collected from the retro-orbital plexus under isoflurane anesthesia at the following time points: IV bolus: 5,15, 30 min and 1, 2, 4, 8, 24, 32 and 48 h, after treatment. Oral bolus: 15, 30, 45 min and 1, 2, 4, 8, 24, 32 and 48 h, after treatment. Four mice were used at each time point. Mice were sacrificed by cervical dislocation. Liver, heart, kidney, lung, brain and spleen were collected. To obtain plasma, blood was centrifuged at 4000 rpm for 10 min at 4 °C. To study drug excretion, urine and feces of four mice were collected in fraction of 24 h (0 - 24 h and 24 - 48 h). All the biological samples collected were immediately frozen in dry ice and then stored at -20 °C until analysis of MEDS433, 2, 6 and 8 by HPLC-MS / MS. Pharmacokinetic assay. MEDS433, 2, 6 and 8 were quantified according to the procedures of extraction and analysis below reported. Sample preparation Plasma. 20 µL of plasma were spiked with 10 ng of internal standard previously published (compound 5, in ref11) in 10 µL of acetonitrile, used as (final concentration 500 ng / mL), then 50 µL of acetonitrile were added for deproteinization. After mixing by vortex and subsequent centrifugation at 4 °C for 15 minutes at 13200 rpm, the supernatants were transferred for instrumental analysis. A set of calibration points were prepared using a control plasma sample, with separate additions of MEDS433 or 2 or 6 and 8 in the range from 0 to 30 µg / mL Liver.1 g of tissue was homogenized with 4 mL of methanol, after addition of 500 ng of internal standard (final concentration 500 ng / g). Tissue homogenization was carried out with a Precellys system, using 7 mL vials with a program consisting of 3x20s 6500rpm cycles separated by a 30 s pause. Finally, samples were centrifuged at 4 °C for 15 minutes at 13200 rpm, and 200 µL aliquots of the supernatants were transferred for instrumental analysis. A set of calibration points were prepared using a control liver sample, with separate additions of MEDS433 or 2 in the range from 0 to 30 µg / g. Lung.1 g of tissue was homogenized with 4 mL of methanol, after addition of 500 ng of internal standard (final concentration 500 ng / g). Tissue homogenization was carried out with a Precellys system, using 7 mL vials with a program consisting of 3x20s 6500rpm cycles separated by a 30s pause. Finally, samples were centrifuged at 4 °C for 15 minutes at 13200 rpm, and 200 µL aliquots of the supernatants were transferred to autosampler vials for instrumental analysis. A set of calibration points were prepared using a control lung sample, with separate additions of MEDS433 or 2 in the range from 0 to 3 µg / g. Brain. Whole samples were weighed and spiked with 1000 ng / g of internal standard, then homogenized with 3 volumes of methanol. Tissue homogenization was carried out with a Precellys system, using 2 mL vials with a program consisting of 3x15 s 8500rpm cycles separated by a 10 s pause. Finally, samples were centrifuged at 4 °C for 15 minutes at 13200 rpm, and 100 µL aliquots of the supernatants were transferred to autosampler vials for instrumental analysis. A set of calibration points were prepared using a control brain sample, with separate additions of MEDS433 or 2 or 6 and 8 in the range from 0 to 3 µg / g. Urine. 200 µL of urine were spiked with 100 ng of internal standard in 800 µL of methanol, (final concentration 500 ng / mL). After mixing by vortex and centrifugation at 4 °C for 15 minutes at 13200 rpm, 100 µL of the supernatants were transferred to autosampler vials for instrumental analysis. A set of calibration points were prepared using a control urine sample, with separate additions of MEDS433 or 2 in the range from 0 to 3 µg / mL. Feces. Whole samples were weighed and homogenized with 8 volumes of methanol. Tissue homogenization was carried out with a Precellys system, using 15 mL vials with a program consisting of 5x10s 4500rpm cycles separated by a 30 s pause. An aliquot of the homogenized suspension was withdrawn and spiked with 5000 ng / g of internal standard. Finally, after mixing, samples were centrifuged at 4 °C for 15 minutes at 13200 rpm, and 100 µL aliquots of the supernatants were transferred to autosampler vials for instrumental analysis. A set of calibration points were prepared using a control faeces sample, with separate additions of MEDS433 or 2 in the range from 0 to 300 µg / g. Instrumental analysis. The analyses by HPLC-HRMS were performed for all sample extracts with the following conditions: HPLC instrument: 1200 series pumps and autosampler (Agilent) HPLC column: XBridge C18, 3.5 µm, 100 x 2.1 mm (Waters) Solvent A: Ammonium formate 10 mM in water Solvent B: Acetonitrile Flow rate and inj. vol.: 200 µL / min; 2 µL injections Elution gradient: from 1 % to 99 % of B in 10 min, hold for 2 min MS instrument: Orbitrap Q Exactive (Thermo) MS source: HESI, with positive ionization Heated capillary temperature, 320 °C Auxiliary heating gas temperature, 240 °C Spray voltage, 3500 V MS acquisition: Full Scan MS, 150-800 Da, at 35000 resolution Data Dependent MS2 scans at 17500 resolution The detection of analytes was performed by extracting from the high resolution full scan data the chromatograms of the molecular ions ([M+H]+) with a 10 ppm window, using the values indicated in Table 8. When significant molecular adducts were present ([M+NH4]+), [M+Na]+, [M+C2H7N]+) they were included in the extracted data. Calibration curves were made using linear regression with 1 / x weighing. The limit of quantification (LOQ) for MEDS433 was 5 ng / mL or 5 ng / g for all biological samples, except for feces, for which it was 20 ng / g. Table 8. MEDS433 and cpd 2, with HPLC-MS retention times and measured molecular and adduct ions. Retention Time Substance (min.)Molecular ion Molecular AdductsMEDS433 7.95 402.0860 447.1439 2 7.35 512.0629 557.1208 (IS) 8.36 416.1017 461.1595 * source fragment Pharmacokinetic elaboration Pharmacokinetic parameters were calculated using PK Solver (a Microsoft Excel add). Cell Cultures Cell lines were grown as monolayer in different growth media: in Dulbecco’s Modified Eagle’s Medium (Capricorn) for Triple Negative Breast Cancer (MDA-MB-231), Human Osteosarcoma (SAOS2), Human Lung Adenocarcinoma (A549), Human Melanoma (A375) and Glioblastoma Tmz-Resistant (LN-18); in Eagle's Minimum Essential Medium for Human IDH mutated (U87mt) and Human IDH mutated fibrosarcoma (HT1080); in Iscove’s MDM for Ewing’s sarcoma (TC-71 and A673); in RPMI 1640 medium (Biowest) for Human Neuroblastoma (LAN- 5) and Eagle's Minimum Essential Medium and F12 Medium for (SH-SY5Y); in McCoy's 5a medium modified for (T24), in ReNcell NSC Maintenance Medium serum-free supplemented with 20 ng / mL EGF and 20 ng / mL FGF-2(Sigma–Aldrich) for Human Diffuse Intrinsic Pontine Glioma (SF-7761); in DMEM-High Glucose (Sigma -Aldrich) for Human Diffuse Intrinsic Pontine Glioma (SF8628). Culture media according to the manufacturer’s protocols, were supplemented with 5 % or 10 % heat-inactivated Fetal Bovine Serum, L-glutamine (2 mM), penicillin (100 IU / mL) and streptomycin (100 μg / mL) and cell cultures were maintained at 37 °C, in a humidified atmosphere of 5 % CO2. Cells were subcultured at ratio of 1 : 4 to 1 : 6 after being detached from culture flasks with 0.05 % trypsin and 0.002 % EDTA solution. All media supplements for cell cultures were purchased from Gibco BRL (Grand Island, NY). The human cell OCI-AML3 (acute monocytic leukemia) and human THP1 (acute monocytic leukemia) were cultured in complete RPMI 1640 (GIBCO BRL) supplemented with 10 % heat-inactivated fetal bovine serum (GIBCO, Invitrogen, Milan, Italy) and 1 % penicillin / streptomycin. MTT Assay Exponentially growing cells, MDA 231, SAOS2, A549, LAN-5 and A375 were seeded in triplicate in 96 well plates at density of 4x103 or 6x103 cells / well in 100 μL and were maintained in culture for 24 h prior to treatments in appropriate growth medium. Cells were treated with different concentration ranges of MEDS433 and 6 (from 1 to 10000 nM). After 72 h or 5 days of treatment (exclusively for MDA MB 231), a 10 μL of 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolim bromide (MTT) (5 mg / mL in PBS - Sigma Chemical, Saint Louis, CO) were added to each well and incubated for 4 hours. At the end of incubation cells were lysed with 200 µL of dimethyl sulfoxide (DMSO). Absorbance values (OD) were measured at 570 nm versus 630 nm using a microplate reader (Neobiotech). Trypan Blue Viability assay For the determination of viability, TC71, A673, LN18, SF-7716, SF8628, T24, HT1080, SHSY5Y, U87mt cells were seeded at a density of 150x103cells / well onto 6-well cell culture plates and allowed to adhere for 24 h. Thereafter, MEDS433 and / or 6 were added in fresh culture medium at different concentration ranges (from 1 to 10000 nM) and cells were allowed to grow for 24h, 48h, 72 h and 120 h (exclusively for SF8628). Cell viability was determined at the mentioned times, based on the Trypan blue dye exclusion method. Live and dead cell were evaluated through an automatic cell counter platform (CytoSMART – Corning). Statistical analysis All data are reported as the mean ± standard error of the mean (SD) with at least 3 experiments in cell lines. Statistical analyses were obtained using GraphPad Prism version 9 (GraphPad Software, San Diego, CA). For the determination of IC50, a nonlinear regression model was applied. Normality of the data set was determined by Shapiro–Wilk normality test. For multiple comparisons, one-way ANOVA tests were performed and combined with Tukey’s tests for post hoc analyses. Moreover, in this case, a p-value < 0.05 was considered significant. Annexin assay. 1x104OCI-AML3acute myeloid cell lines were plated in 96-well round-bottom plates and treated with MEDS433 at 0.1 µM, dipyridamole (Merck Life Science, Italy) at 0.1 µM and fludarabine at 2.5 µM or Cladribine (CliniSciences, France) at 25 nM in a volume of 200 μL of complete medium for three days. 1x104OCI-AML3 or THP1 acute myeloid cell lines were plated in 96-well round-bottom plates and treated with MEDS433 at 0.1 µM, and increased doses of Draflazine ((CliniSciences, France) range: 10 nM to 1 µM) or JNK-IN-8 ((Merck Life Science, Italy) range: 0.1 µM to 1 µM) in a volume of 200 μL of complete medium for three days. The apoptotic assay was assessed using the Annexin V-FITC Kit purchased from Miltenyi Biotec, Italy. Cells were washed with binding buffer and centrifugated at 300×g for 10 minutes. Then, cells were stained with 10 µL of Annexin V-FITC and incubated at dark for 15 minutes. After a wash, cells were resuspended in binding buffer and finally 5 μL propidium iodide (PI) solution was added. After the PI addition, samples were acquired on FACSVerse and analysed by Kaluza software version 2.1(Beckman Coulter Fullerton, CA). Synergism assay. The synergism of compound 6 with anticancer drugs (Panabinostat – ONC212 – Abemacilib) was evaluated in SF8628 cell line. Cytotoxicity experiments in combination with 6 were conducted with serial doses in constant / variable ratios at 72 hours using the CellTiter-Glo 2.0 and Cell Counting Kit-8 assays purchased, respectively, from Promega and Sigma Aldrich. Synergism and combination index theorem were assessed using CompuSyn software16. Bibliography (1) Brown, K. K.; Spinelli, J. B.; Asara, J. M.; Toker, A. Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer. Cancer Discovery 2017, 7 (4), 391-399. DOI: 10.1158 / 2159-8290.cd-16-0611. (2) Mathur, D.; Stratikopoulos, E.; Ozturk, S.; Steinbach, N.; Pegno, S.; Schoenfeld, S.; Yong, R.; Murty, V. V.; Asara, J. M.; Cantley, L. C.; et al. PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition. Cancer Discovery 2017, 7 (4), 380-390, 10.1158 / 2159-8290.CD-16-0612. DOI: 10.1158 / 2159- 8290.CD-16-0612. (3) Koundinya, M.; Sudhalter, J.; Courjaud, A.; Lionne, B.; Touyer, G.; Bonnet, L.; Menguy, I.; Schreiber, I.; Perrault, C.; Vougier, S.; et al. Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers. Cell Chemical Biology 2018, 25 (6), 705-717.e711. DOI: https: / / doi.org / 10.1016 / j.chembiol.2018.03.005. (4) Sykes, D. B. The Emergence of Dihydroorotate Dehydrogenase (DHODH) as a Therapeutic Target in Acute Myeloid Leukemia. Expert Opin Ther Targets 2018, 22 (11), 893-898, Article in Press. DOI: 10.1080 / 14728222.2018.1536748 Scopus. (5) Li, L.; Ng, S. R.; Colón, C. I.; Drapkin, B. J.; Hsu, P. P.; Li, Z.; Nabel, C. S.; Lewis, C. A.; Romero, R.; Mercer, K. L.; et al. Identification of DHODH as a therapeutic target in small cell lung cancer. Sci. Transl. Med.2019, 11 (517), Article. DOI: 10.1126 / scitranslmed.aaw7852 Scopus. (6) Qian, Y.; Liang, X.; Kong, P.; Cheng, Y.; Cui, H.; Yan, T.; Wang, J.; Zhang, L.; Liu, Y.; Guo, S.; et al. Elevated DHODH expression promotes cell proliferation via stabilizing β-catenin in esophageal squamous cell carcinoma. Cell Death Dis. 2020, 11 (10), Article. DOI: 10.1038 / s41419-020-03044-1 Scopus. (7) Yamaguchi, N.; Weinberg, E. M.; Nguyen, A.; Liberti, M. V.; Goodarzi, H.; Janjigian, Y. Y.; Paty, P. B.; Saltz, L. B.; Kingham, T. P.; Loo, J. M.; et al. 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Claims

CLAIMS 1. A compound of Formula (Ia):Formula (Ia) wherein R1, R2, R4and R5are independently selected from a hydrogen atom, deuterium atom, a halogen atom, a linear and / or branched C1-8alkyl group, an alkyloxy group, an alkylammino group, an alkylthio group, a halo C1-8alkyl group, a halo C1-8alkyloxy group, a halo C1-8alkylamino group, a nitro group, a cyano group; R3is: - an aromatic group selected from the group consisting of: phenyl group, heteroaryl group preferably an azinyl group such as pyridinyl group, pyrimidinyl group; phenoxy group; azinyloxy group such as pyridinyloxy group, pyrimidinyloxy group; phenylthio group; azinylthio group such as pyridinylthio group, pyrimidinylthio group; phenylsulfinyl group; phenylsulfonyl group; phenylsulfonylamino group; N-phenylcarbamoyl group. - an aliphatic group selected from the group consisting of: C1-12alkyl group; C1-12alkyloxy group; C1-12alkylthio group; C1-12alkylsulfinyl group; C1-12alkylsulfonyl group; C1-12alkylsulfonylamino group; C1-12alkylamino group; C1-12alkylaminosulfonyl group; halo C1-12alkyl group; halo C1-12alkyloxy group; halo C1-12alkylthio group; halo C1-12alkylsulfinyl group; halo C1-12alkylsulfonyl group; halo C1-12alkylsulfonylamino group; halo C1-12alkylamino group; halo C1-12alkylaminosulfonyl group.R7, R8 and R9 are independently selected from a hydrogen atom, deuterium atom, a halogen atom, a nitro group, a cyano group, a C1-4 alkyl group, a halo C1-4 alkyl group, a mercapto C1-4 alkyl group, an amino C1-4 alkyl group, and a hydroxy C1-4 alkyl group; X, Y and Z are independently selected from a carbon atom, a nitrogen atom, with the proviso that when one of X, Y or Z is nitrogen, the other two positions are carbon atoms and that when Y or Z are nitrogen atoms, R8 and R9 are not present; for use in the treatment of: a) hematologic malignancies selected from the group consisting of: myelodysplastic syndromes, chronic myeloid leukemia and other myeloproliferative neoplasms, multiple myeloma, angioimmunoblastic T-cell lymphoma and acute lymphoblastic leukemia, Hodgkin’s and non-Hodgkin’s lymphomas, IDH mutated tumors, BRAF-mutated, RAS- mutated, PTEN-mutated and MYC / MYCN-driven hematologic neoplasms; b) solid tumors selected from the group consisting of: osteosarcoma; Ewing sarcoma; melanoma; BRAF mutated tumors; H3K27M-mutated diffuse midline glioma; diffuse intrinsic pontine glioma; atypical teratoid rhabdoid tumor; ependymomas, neuroendocrine tumors; multiple endocrine neoplasia type 1 (MEN1) tumors; mutated MEN1 tumors; KRAS-driven tumorous, preferably mutated KRAS hepatic tumors, mutated KRAS lung tumors, mutated KRAS pancreatic tumors, mutated KRAS colon carcinoma; prostate tumors; bladder tumors; kidney tumors; ferroptosis sensitive tumors preferably, lung cancer, glioblastoma, breast cancer, pancreatic cancer, hepatocellular carcinoma and colorectal cancer; IDH mutated tumors, preferably low- grade gliomas, secondary glioblastoma, primary glioblastoma, cartilaginous and bone tumors, fibrosarcoma, sinonasal undifferentiated carcinoma, intrahepatic cholangiocarcinoma; MYC and MYCN driven tumors, preferably neuroblastoma, medulloblastoma, retinoblastoma, astrocytoma, glioblastoma multiforme, castration- resistant prostate cancer, neuroendocrine prostate cancer, , rhabdomyosarcoma, Wilms tumors, small cell lung cancer, pancreatic tumors; AMPKα1low expressing tumors; GPX4low expressing tumors; p53 wild type and mutated cancers.

2. A composition comprising a compound of Formula (Ia) as defined in claim 1 and one or more anticancer agents, preferably selected from: Abemaciclib, Abiraterone, Acalabrutinib, Actimide, Adagrasib, Artemisinin, Artesunate Ado-Trastuzumab Emtansine, Afatinib, Alectinib, Alpelisib, Atezolizumab, Amivantamab, Amsacrine, Anastozole, Apalutamide, Asparaginase, Axitinib, Azacitidine, Azathioprine, Belzutifan, Bevacizumab, Bicalutamide, Bleomycin, Brentuximab vedotin, Brigatinib, Busulfan, Cabazitaxel, Cabozantinib, Capecitabine, Capmatinib, Cyclophosphamide, Carboplatin, Carmustine, Cedazuridine, Cemiplimab-rwlc, Ceritinib, Cisplatin, Chlorambucil, Cytarabine, Cladribine, Clofarabine, CNX774,Cobimetininb, Dabrafenib, Dacarbaziine, Dacomitinib, Dactinomycin Darolutamide, Daunorubicin, Decitabine, Degarelix, Dilazep, Dihydroartemisinin, Dinutuximab, Dinutuximab beta, Dipyridamole, Docetaxel, Dordaviprone, Doxifluridine, Doxorubicin, Draflazine, Durvalumab, Epcoritamab, Enasidenib, Encorafenib, Enfortumab vedotin-ejfv, Entrectinib, Enzalutamide, EOS984, Epirubicin, Erastin, Erdafitinib, Erlotinib, Etoposide, Everolimus, Exemestane, , , Fam-trastuzumab deruxtecan-nxki, Fenalidomide, Feucovorin, Fludarabine, Fluorouracil, FPMINT, Flutamide, Gemcitabine, Gefitinib, Glofitamab, Hydroxyurea, , Ibrutinib, Idarubicin, Infigratinib, Ifosfamide, Ipilimumab, Irinotecan, Isotretinoin, Ivosidenib, JNK-IN-8, Larotrectinib, Lenvatinib, Lenalidomide, Letrozole, Leucovorin, Lomustine, Loncastuximab tesirine-lpy, Lorlatinib, L-alanosine, 8MDP, Mechlorethamine, Melphalan, Mercaptopurine, Methotrexate, Mioflazine, Mitomycin-C, Mitoxantrone, Mizoribine, Mobocertinib, Mosunetuzumab-axgb, Mycophenolic acid, Nab-paclitaxel, Nanoliposomal irinotecan, Naxitamab, Neratinib, Nilutamide, Niraparib, Nivolumab, Obinutuzumab, ONC212, Olaparib, Osimertinib, Oxaliplatin, Paclitaxel, Pacritinib, Panobinostat, Pazopanib, PBP 4883, Pebrolizumab, Pertuzumab, Pemetrexed, Pemigatinib, Pirtobutinib, Pralsetinib, Polatuzumab vedotin-piiq, Rapadocin, Ramucirumab, Regorafenib, Relugolix, Revlimid, Rituximab, RO7117997, Rucaparib, Sacituzumab govitecan, Selepercatinib, Selinexor, Sorafenib, Sotarasib, Sulfasalazine, Sunitinib, Talazoparib, Tamibarotene, Tamoxifen, Tazemetostat, Temozolomide, Teniposide, Tepotinib, Thioguanine, Thiotepa, Ticagrelor, Tivozanib, Tofacitinib, Topotecan, Tafasitamab- cxix, Temsirolimus, Trametinib, Trastuzumab, Tremelimumab, Trifluridine / Tipiracil, Treosulfan, Troglitazone, Valrubicin, Venetoclax, Vemurafenib, Vinblastine, Vincristine, Vindesine and Vinorelbine, Vorasenib, Zanubrutinib, Ziv-aflibercept.

3. A compound of Formula (Ia) as defined in claim 1 for use in the treatment of a viral infection caused by Herpes simplex virus 3-8 (HSV-3-8).

4. A compound of formula (I):Formula (I) wherein R1, R2, R4 and R5 are independently selected from a hydrogen atom, deuterium atom, a halogen atom, a linear and / or branched C1-8alkyl group, an alkyloxy group, an alkylammino group, an alkylthio group, a halo C1-8alkyl group, a halo C1-8alkyloxy group, a halo C1-8alkylamino group, a nitro group, a cyano group; R3is: - an aromatic group selected from the group consisting of: phenyl group, heteroaryl group preferably an azinyl group such as pyridinyl group, pyrimidinyl group; phenoxy group; azinyloxy group such as pyridinyloxy group, pyrimidinyloxy group; phenylthio group; azinylthio group such as pyridinylthio group, pyrimidinylthio group; phenylsulfinyl group; phenylsulfonyl group; phenylsulfonylamino group; N-phenylcarbamoyl group; - an aliphatic group selected from the group consisting of: C1-12alkyl group; C1-12alkyloxy group; C1-12alkylthio group; C1-12alkylsulfinyl group; C1-12alkylsulfonyl group; C1-12alkylsulfonylamino group; C1-12alkylamino group; C1-12alkylaminosulfonyl group; halo C1-12alkyl group; halo C1-12alkyloxy group; halo C1-12alkylthio group; halo C1-12alkylsulfinyl group; halo C1-12alkylsulfonyl group; halo C1-12alkylsulfonylamino group; halo C1-12alkylamino group; halo C1-12alkylaminosulfonyl group;R7, R8 and R9 are independently selected from a hydrogen atom, deuterium atom, a halogen atom, a nitro group, a cyano group, a C1-4 alkyl group, a halo C1-4 alkyl group, a mercapto C1-4 alkyl group, an amino C1-4 alkyl group, and a hydroxy C1-4 alkyl group; R6 is selected from the group consisting of a linear or branched C1-6 alkyl substituted with a group selected from a phosphate, a -COOH, a -CONHR10, wherein R10 is selected from hydrogen and C1-6 alkyl chain; X, Y and Z are independently selected from a carbon atom, a nitrogen atom, with the proviso that when one of X, Y or Z is nitrogen, the other two positions are carbon atoms and when Y or Z are nitrogen atoms, R8 and R9 are not present.

5. A compound according to claim 4, wherein at least one of R1, R2, R4and R5is or contains a halogen atom, preferably a fluorine or chlorine atom, more preferably a fluorine atom.

6. A compound according to claim 4, wherein at least one of R1, R2, R4and R5is selected from hydrogen, -OCF3, methyl, isopropyl, methyl, 1,1,1-trifluoro-2-propanoxy. 7 A compound according to any one of claims 4 to 6, wherein R3is selected from trifluoromethoxyphenyl, 2,2 difluoropropyloxyphenyl, 3-pyridinyl, phenyloxy, ortho- trifluoromethylphenyl, meta-trifluoromethylphenyl, meta-chlorophenyl, ortho-chlorophenyl, meta-fluorophenyl, ortho-fluorophenyl, meta-hydroxyphenyl, meta-butoxyphenyl.

8. A compound according to any one of claims 4 to 7, wherein R7, R8 and R9 are independently selected from hydrogen, methyl, chloro, methyloxy, and hydroxymethyl.

9. A compound according to any one of claims 4 to 8, wherein X, Z are carbon atoms, Y is carbon or nitrogen, R7, R8, R9 are hydrogen, R1, R2, R4, R5 are fluorine, R3 is a phenyl or 2,2- difluoro(C1-C3)alkyloxyphenyl or trifluoro(C1-C3)alkylphenyl or trifluoro(C1-C3)alkyloxyphenyl.

10. A compound according to any one of claims 4 to 9, wherein X, Y, Z are carbon atoms, R7, R8, R9 are hydrogen atoms, R1, R4 are hydrogen atoms, R2 is a methyl, R5 is iso-propyl, R3 is phenyloxy.

11. A compound according to any one of claims 4 to 10, wherein R6 is a phosphonoxymethyl group represented by formula (II):Formula (II) 12. A compound according to claim 11, wherein R6 is in salified form, wherein the salt is selected from an alkali metal salt, preferably lithium, sodium, potassium, and cesium salt; an alkaline earth metal salt, preferably calcium, magnesium or strontium salt; aluminum or zinc salt; an ammonium salt; a quaternary ammonium salt having 1 to 20 carbon atoms, preferably tris(hydroxymethyl)aminomethane (tromethamine), tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N- trimethylammonium; a lysine salt, a choline salt; a benzalkonium salt.

13. A compound according to any one of claims 4 to 12, wherein the compound is selected from the following formulas:

14. A pharmaceutical composition comprising a compound of Formula (I) according to any one of claims 4 to 13 and a pharmaceutically accepted carrier, excipient and / or diluent.

15. A composition comprising a compound of Formula (I) according to any one of claims 4 to 14 and one or more anticancer agents, preferably selected from: Abemaciclib, Abiraterone, Acalabrutinib, Actimide, Adagrasib, Artemisinin, Artesunate Ado-Trastuzumab Emtansine, Afatinib, Alectinib, Alpelisib, Atezolizumab, Amivantamab, Amsacrine, Anastozole, Apalutamide, Asparaginase, Axitinib, Azacitidine, Azathioprine, Belzutifan, Bevacizumab, Bicalutamide, Bleomycin, Brentuximab vedotin, Brigatinib, Busulfan, Cabazitaxel, Cabozantinib, Capecitabine, Capmatinib, Cyclophosphamide, Carboplatin, Carmustine, Cedazuridine, Cemiplimab-rwlc, Ceritinib, Cisplatin, Chlorambucil, Cytarabine, Cladribine,Clofarabine, CNX774,Cobimetininb, Dabrafenib, Dacarbaziine, Dacomitinib, Dactinomycin Darolutamide, Daunorubicin, Decitabine, Degarelix, Dilazep, Dihydroartemisinin, Dinutuximab, Dinutuximab beta, Dipyridamole, Docetaxel, Dordaviprone, Doxifluridine, Doxorubicin, Draflazine, Durvalumab, Epcoritamab, Enasidenib, Encorafenib, Enfortumab vedotin-ejfv, Entrectinib, Enzalutamide, EOS984 ,Epirubicin, Erastin, Erdafitinib, Erlotinib, Etoposide, Everolimus, Exemestane, Fam-trastuzumab deruxtecan-nxki, Fenalidomide, Feucovorin, Fludarabine, Fluorouracil, FPMINT, Flutamide, Gemcitabine, Gefitinib, Glofitamab, Hydroxyurea, , Ibrutinib, Idarubicin, Infigratinib, Ifosfamide, Ipilimumab, Irinotecan, Isotretinoin, Ivosidenib, JNK-IN-8, , Larotrectinib, Lenvatinib, Lenalidomide, Letrozole, Leucovorin, Lomustine, Loncastuximab tesirine-lpy, Lorlatinib, L-alanosine, 8MDP , Mechlorethamine, Melphalan, Mercaptopurine, Methotrexate, Mioflazine, Mitomycin-C, Mitoxantrone, Mizoribine, Mobocertinib, Mosunetuzumab-axgb, Mycophenolic acid, Nab-paclitaxel, Nanoliposomal irinotecan, Naxitamab, Neratinib, Nilutamide, Niraparib, Nivolumab, Obinutuzumab, Olaparib, ONC212, Osimertinib, Oxaliplatin, Paclitaxel, Pacritinib, Panobinostat, Pazopanib, PBP 4883, Pebrolizumab, Pertuzumab, Pemetrexed, Pemigatinib, Pirtobutinib, Pralsetinib, Polatuzumab vedotin-piiq, Rapadocin,, Ramucirumab, Regorafenib, Relugolix, Revlimid, Rituximab, RO7117997, Rucaparib, Sacituzumab govitecan, Selepercatinib, Selinexor, Sorafenib, Sotarasib, Sulfasalazine, Sunitinib, Talazoparib, Tamibarotene, Tamoxifen, Tazemetostat, Temozolomide, Teniposide, Tepotinib, Thioguanine, Thiotepa, Ticagrelor, Tivozanib, Tofacitinib, Topotecan, Tafasitamab-cxix, Temsirolimus, Trametinib, Trastuzumab, Tremelimumab, Trifluridine / Tipiracil, Treosulfan, Troglitazone, Valrubicin, Venetoclax, Vemurafenib, Vinblastine, Vincristine, Vindesine and Vinorelbine, Vorasenib, Zanubrutinib, Ziv-aflibercept.

16. A compound of Formula (I) according to any one of claims from 4 to 13 or a pharmaceutical composition according to claim 14 or a composition according to claim 15, for use as an anticancer agent, preferably for the treatment of a) hematologic malignancies, preferably selected from the group consisting of: acute myeloid leukemia, myelodysplastic syndromes, chronic myeloid leukemia and other myeloproliferative neoplasms, multiple myeloma, angioimmunoblastic T-cell lymphoma and acute lymphoblastic leukemia, Hodgkin’s and non-Hodgkin’s lymphomas, IDH mutated tumors,BRAF-mutated, RAS-mutated, PTEN-mutated and MYC / MYCN-driven hematologic neoplasms; b) solid tumors, preferably selected from the group consisting of: osteosarcoma; Ewing sarcoma; melanoma; BRAF mutated tumors; PTEN-mutant tumors; H3K27M-mutated diffuse midline glioma; diffuse intrinsic pontine glioma; atypical teratoid rhabdoid tumor; ependymomas, neuroendocrine tumors; multiple endocrine neoplasia type 1 (MEN1) tumors; mutated MEN1 tumors; KRAS-driven tumorous, preferably mutated KRAS hepatic tumors, mutated KRAS lung tumors, mutated KRAS pancreatic tumors, mutated KRAS colon carcinoma; prostate tumors; bladder tumors; kidney tumors; ferroptosis sensitive tumors preferably, lung cancer, glioblastoma, breast cancer, preferably triple-negative breast cancer, pancreatic cancer, hepatocellular carcinoma and colorectal cancer; IDH mutated tumors, preferably low-grade gliomas, secondary glioblastoma, primary glioblastoma, cartilaginous and bone tumors, fibrosarcoma, sinonasal undifferentiated carcinoma, intrahepatic cholangiocarcinoma; MYC and MYCN driven tumors, preferably neuroblastoma, medulloblastoma, retinoblastoma, astrocytoma, glioblastoma multiforme, castration-resistant prostate cancer, neuroendocrine prostate cancer, rhabdomyosarcoma, Wilms tumors, small cell lung cancer, pancreatic tumors; AMPKα1lowexpressing tumors; GPX4lowexpressing tumors; p53 wild type and mutated cancers.

17. A compound of Formula (I) according to any one of claims from 4 to 13 or a pharmaceutical composition according to claim 14, for use as antiviral agent, preferably for the treatment of a viral infection caused by a DNA virus or an RNA virus, wherein the virus is selected from the group consisting of Herpesviridae, Orthomyxoviridae, Paramyxoviridae and Coronaviridae.

18. A compound of Formula (I) or a pharmaceutical composition for use according to claim 17, wherein the virus is selected from the group consisting of Herpes simplex virus 1 to 8 (HSV- 1-8), paramyxovirus, pneumovirus, morbillivirus, Influenza A virus, Influenza B virus, Respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 1 (SARS- CoV-1), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome-related coronavirus (MERS-CoV).

19. A composition comprising a compound of Formula (I) as defined in claim 4 and / or a compound of formula (Ia) as defined in claim 1 and one or more antiviral agents, preferably selected from acyclovir, adefovir, amantadine, baloxavir marboxil, bamlanivimab / etesevimab, brivudine, casirivimab / imdevimab, cidofovir, famciclovir, favipiravir, fomivirsen, foscarnet, ganciclovir, N(4)-Hydroxycytidine, indinavir, idoxuridine, laninamivir, lopinavir, molnupiravir, nelfinavir, nirmatrelvir, oseltamivir, penciclovir, permivir, ribavirin, sotrovimab, tenofovir, tenofovir alafenamide, tenofovir diisoproxilfumarate, trifluridine, telbivudine, vidarabine, sofosbuvir, nevirapine, efavirenz, raltegravir, remdesvir, rimantadine, ritonavir, ritonavir – amlanivimab, saquinavir, tixagevimab / cilgavimab, trifluridine, valacyclovir, valganciclovir, vidarabine, zanamivir, zidovudine.

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