Substituted 2-(phenylamino))pyrido[2,3-d]pyrimidin-7-one compounds for use in the treatment of pancreatic cancer

Abstract

The present invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of pancreatic cancer in a mammal. It also refers to compounds of formula (I1) and to pharmaceutical compositions comprising these compounds.

Description

[0001] for use in the treatment of cancerThis application claims the priority of the European Patent Application 24383132.8 filed onOctober 15th, 2024, and the European Patent Application 25382543.4 filed on May 28th,2025. Technical Field The invention refers to compounds for use in the treatment of pancreatic cancer, in particular compounds that show inhibitory activity against tyrosine kinase receptorsinvolved in pancreatic cancer. It also relates to new compounds per se and theirpharmaceutical compositions as well as processes for their preparation. Background Art Under the name of silent cancer, pancreatic cancer is one of the most aggressive known, being difficult to treat and having a very low life expectancy, since only 10-15% of patients survive 5 years after diagnosis. One of the most aggressive types of solid tumors develops in the exocrine part of the pancreas, the pancreatic ductal adenocarcinoma (PDAC), which represents more than 85% of pancreatic cancer cases known today. PDAC usually originates in the head of the pancreas from a precursor lesion that causes gradual mutations from normal tissue to an invasive malignancy to neighboring tissues such as lymph nodes, spleen, the liver, or the lungs. One of the main particularities of PDAC is the presence of high quantities of collagen I-rich extracellular matrix (ECM). Pancreatic cancer cells have been shown to stimulate collagen synthesis in adjacent fibroblast populations, causing the apparition of malignant phenotype which increases proliferation and resistance to chemically induced apoptosis. It has also been demonstrated that collagen fibers can act as highways for migration, facilitating metastasis. Currently used treatments include prodrugs, namely gemcitabine, that targets DNA incancer cells, arresting tumor growth and causing apoptosis of the cell. This may also becombined with erlotinib in severe cases, which is a tyrosine kinase inhibitor (TKI) inhibiting EGFR (epidermal growth factor receptor). Several receptor tyrosine kinases (RTKs) have been identified as important drivers in PDAC, namely EGFR, FGFR (fibroblast growth factor receptors), IGF1R (insulin-like growth factor 1 receptor), PDGFR (platelet-derived GFR), VEGFR (vascular endothelial GFRs), and, more recently, RON (recepteur d’origine Nantais). Most treatments currently under study or recently approved, such as erlotinib,target a single kinase and are combined with gemcitabine, since inhibition of multiplekinases was considered undesirable, and pan-inhibition was believed to cause severesecondary effects. However, today, multitarget kinase inhibitors are used for the treatmentof several cancers because, by targeting multiple signaling pathways, they lead toimportant results in terms of survival although, sometimes, side effects appear.In the past years, several straightforward strategies for synthesizing TKIs have beendescribed. For instance, our group developed compound 4-amino-6-(2,6-dichlorophenyl)- 8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one, having the following structure: which has been described in the patent application WO2017013160 as well as its use forthe treatment of solid tumors, in particular, lung cancer. However, the major drawback of this compound was the poor in vivo pharmacokinetic properties. Other pyrido[2,3-d]pyrimidin-7(8H)-one and 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one derivatives have also been described as TKIs (Balsas et al.2017 and Galve et al.2020), for use in the treatment of hepatitis C virus (Camarasa et al 2016), infections caused by viruses of the Flaviviridae family (EP2905024A1), non-Hodgkin’s Iymphomas (NHLs) (Puig de la Bellacasa et al 2014 and EP2813504A1) or without any particular therapeutic use (Galve et al.2012).There is thus a need for the development of drugs for use in the treatment of pancreaticcancer that may constitute an advancement and opportunity for these patients.Summary of Invention The inventors have surprisingly found that when in the unsubstituted phenyl ring of the compound 4-amino-6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3d- ]pyrimidin-7(8H)-one of formula (X) described above at least one substituent is placed, such for example in compound (Ia) of the present invention, not only an improved metabolism is obtained but also a change in the inhibition profile of the compounds can be observed. As illustrated in the examples below, it was found that compound (Ia) remained stable, above 85% when incubated with rat-liver microsomes for 60 min (FIG.1), contrary to compound (X), which in the same period of time is reduced to 40%. No metabolites of compound (Ia) were identified due to its low metabolism. Further, the compounds of the present invention showed inhibitory activity against intracellular tyrosine kinase (TK) receptors, and, apparently, also the KRAS proto- oncogene which are only inhibited to a much lesser extent by the compound of formula (X) or the standard erlotinib. In particular, when compounds (Ia), (If), and (Ig) were tested against the panel of membrane and cytosolic TKs (ERK1, ERK2, JNK1, JNK2, p38alpha, and p38beta) they showed good inhibitory profile. It is remarkable that compound (Ia) showed inhibitory activity against p38alpha, and p38beta with residual activities below 15% both at 5 and 10 µM (Table 1). On the contrary, erlotinib (E) was found to be virtually inactive against this group of kinases. The same happened with compound (X) previously described. Further, it was found that the compound (Ia) showed IC50 for the inhibition of KRAS wild-type and some of the mutants in the range 17 to 42 μM, thus revealing a certain degree of interaction with such group of proteins (Table 2). This inhibitory activity against intracellular TK receptors was also accompanied by IC50 values in the low µM range when tested against the human pancreatic ductal adenocarcinomas (PDAC) cell lines in classical culture dishes (2D, MTT, 72 h). Surprisingly, the IC50 obtained were in the low µM range: 0.70 µM for PANC-1 (FIG.2a), 1.31 µM for MiaPaCa-2 (FIG.2b), and 0.30 µM for BxPC-3 (FIG.2c). These results represent an improvement and thus an advantage when compared to benchmark erlotinib which gave IC50 values of 45, 40, and 10 µM for PANC-1, MiaPaCa-2, and BxPC-3, respectively when tested under the same conditions. In 3D cell cultures of PANC-1, MiaPaCa-2, BxPC-3, and primary human normal dermal fibroblasts (hNDF) in RAD16-I prepared at 0.3% peptide concentration, the IC50 obtained for compound (Ia) was around 4 µM for PANC-1 (FIG.3a), MiaPaCa-2 (FIG.3b), and BxPC-3 (FIG.3c). In the same conditions the IC50 for erlotinib was >100 µM. Interestingly, in contrast to the compound of formula (X), the compounds of formula (I), particularly compound (Ia), are multitarget. This has the advantage that the compounds show a more reduced toxicity while showing sustained efficacy in comparison tocompounds that have activity only against a specific receptor. Additionally, this multitargetapproach helps avoid activation of the cancer cells of compensatory pathways or mutations, resulting thus in an overall improved activity against cancer (Yesilkanal 2021). Moreover, the inventors have advantageously found that the compounds of the invention, in particular compound (Ia), is safe even at high concentrations, that is, above its IC50 value, as shown in the examples. In particular, when the safety profile of compound (Ia) was tested using ChickChorioallantoic Membrane (CAM) assay as a preclinical in vivo model, the results collectively and advantageously suggested that compound (Ia), even at higher doses, did not exhibit significant toxicity or adverse effects on the overall development and organogenesis of the chicken embryos.Finally, the in vivo studies using subcutaneous xenografts derived from MiaPaca-2 cells(FIG.6), PANC-1 cells (FIG. 7), BxPC-3 cells (FIG. 8), and a PDOX model (FIG.9)emphasize the potential of the compounds of formula (I), particularly compound (Ia), bothas a monotherapy for pancreatic cancer, showing efficacy similar to that of existing treatments, and, more importantly, they highlight its ability to enhance the effects of other therapies with different mechanisms of action. This is especially noteworthy given the low toxicity observed in mice when compound (Ia) is used in combination treatments.Therefore, these compounds are advantageous because they represent a new treatment opportunity for pancreatic cancer, showing greater inhibitory activity against pancreatic cell lines. Accordingly, a first aspect of the present invention relates to a compound of formula (I) ora pharmaceutically acceptable salt thereof, for use in the treatment of pancreatic cancer ina mammal, wherein: each of R1-R5 is a radical independently selected from the group consisting of H, halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, piperazin-1-yl, 4-(C1-C6)alkylpiperazin-1-yl, -NH(C1-C6)alkyl, and -N[(C1-C6)alkyl]2;R6 is H or -(C1-C6)alkyl;R7 is H or -(C1-C6)alkyl;each of R8 or R10 is a radical independently selected from the group consisting of H;-(C1-C6)alkyl optionally substituted with a 5- to 6-membered aromatic carbocyclic orheterocyclic ring; and a 3- to 7-membered aromatic, unsaturated, partially unsaturated, orsaturated carbocyclic or heterocyclic ring;R9 is a radical selected from the group consisting of H, -(C1-C6)alkyl, -(C1-C6)alkyl(C3-C6)aryl, -(C3-C6)aryl and -(CH2)nO(C1-C6)alkyl;R11 is H;Cy is a known ring system selected from the group consisting of: 3- to 7-memberedaromatic, unsaturated or partially unsaturated carbocyclic or heterocyclic ring, wherein the selected ring may be fused, bridged-fused or spiro fused to any other ring selected from the same group forming a bicyclic ring, and wherein any of the rings are optionally substituted with one or more radicals independently selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl; and is a single or a double bond; n is an integer from 2 to 6;(C3-C6)aryl is a known 3- to 6-membered aromatic carbocyclic or heterocyclic ringoptionally substituted with one or more radicals independently selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl; with the proviso that: at least one of R1-R5 is other than H; at least one of R8 or R10 is H;and when is a double bond, one of R10 or R8 is absent R11 is H, and R11 is absent.A second aspect of the invention relates to a pharmaceutical composition comprising atherapeutically effective amount of the compound of formula (I) as defined herein, togetherwith one or more pharmaceutically acceptable excipients, for use in the treatment ofpancreatic cancer in a mammal.A third aspect of the present invention relates to a compound of formula (I1) or apharmaceutically acceptable salt thereof, wherein: each of R1-R5 is a radical independently selected from the group consisting of H, halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, piperazin-1-yl, 4-(C1-C6)alkylpiperazin-1-yl, -NH(C1-C6)alkyl, and -N[(C1-C6)alkyl]2;R6 is H or -(C1-C6)alkyl;R7 is H or -(C1-C6)alkyl;R8 is a radical selected from the group consisting of H; -(C1-C6)alkyl optionally substitutedwith a 5- to 6-membered aromatic carbocyclic or heterocyclic ring; and a 3- to 7- membered aromatic, unsaturated, partially unsaturated, or saturated carbocyclic or heterocyclic ring; R9 is a radical selected from the group consisting of H, -(C1-C6)alkyl, -(C1-C6)alkyl(C3- C6)aryl, -(C3-C6)aryl and -(CH2)nO(C1-C6)alkyl;Cy is a known ring system selected from the group consisting of: 3- to 7-memberedaromatic, unsaturated or partially unsaturated carbocyclic or heterocyclic ring, wherein the selected ring may be fused, bridged-fused or spiro fused to any other ring selected from the same group forming a bicyclic ring, and wherein any of the rings are optionally substituted with one or more radicals independently selected from the group consisting of H, halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl; n is an integer from 2 to 6;(C3-C6)aryl is a known 3- to 6-membered aromatic carbocyclic or heterocyclic ringoptionally substituted with one or more radicals independently selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl; with the proviso that: at least two of R1-R5 are other than H. A fourth aspect of the present invention relates to a combination comprising a compound offormula (I1) as defined above and one or more chemotherapeutic agents.A fifth aspect of the present invention relates to a pharmaceutical composition comprising atherapeutically effective amount of the compound of formula (I1) as above, or apharmaceutically acceptable salt thereof, together with one or more pharmaceuticalexcipients. Brief Description of Drawings FIG.1 shows metabolic stability of compound (Ia) compared to compound (X), known in the art, during 60 min of incubation with liver rat microsomes (n=2).FIG.2 shows MTT test for cell viability assessment after treatment with compound (Ia) ofa PDAC cell line in classical culture dishes (2D, 72 h), where the y-axis represents the cellviability (%) and the x-axis compound (Ia) concentration (µM): a) cell line PANC-1, b) cell line MiaPaCa-2, and c) cell line BxPC-3.FIG.3 shows MTT test for cell viability assessment after treatment with compound (Ia) ofcell line PANC-1 in 3D cultures in RAD16-I prepared at 0.3% peptide concentration (72 h), where the y-axis represents the cell viability (%) and the x-axis compound (Ia) concentration (µM): a) cell line PANC-1, b) cell line MiaPaCa-2, and c) cell line BxPC-3.FIG.4 shows egg weight (g) at 4 different days (D2, D3, D4, and D5) after initiation of thetreatment with compound (Ia), at different concentrations (0.5 µM, 1 µM, 2.5 µM, 5 µM,and 10 µM), and where control represents the embryo that received no treatment. Acomparison of the different embryo weights (g) at D5 is also included.FIG.5 shows the weight (mg) of the three organs (where H is heart, L is liver, and B isbrain) of the embryos on the last day (D5) of the experiment, at different concentrations of compound (Ia) and control (no treatment). FIG.6 shows the evolution of tumor growth in volume (mm3) and over the course of 7 administrations (d) of different treatments (A) and tumor weight at sacrifice (B) in an in vivo experiment using subcutaneous xenografts derived from MiaPaca-2 cells. FIG.7 shows the evolution of tumor growth in volume (mm3) and over the course of 7 administrations (d) of different treatments (A) and tumor weight at sacrifice (B) in an in vivo experiment using subcutaneous xenografts derived from PANC-1 cells. FIG.8 shows the evolution of tumor growth in volume (mm3) and over the course of 7 administrations (d) of different treatments (A) and tumor weight at sacrifice (B) in an in vivo experiment using subcutaneous xenografts derived from BxPC-3 cells. FIG.9 shows tumor weight at sacrifice after administration of different treatments in a PDOX model. Detailed description of the invention All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply throughout the description and claims. As used herein, the indefinite articles “a” and “an” are synonymous with “at least one” or “one or more.” Unless indicated otherwise, definite articles used herein, such as “the,” also include the plural of the noun. The term “treatment” is meant to include alleviating or eradicating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease or condition, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. For the purposes of the invention, the expression “room temperature” means a temperature from 20 to 25 ºC. The term “halogen” is meant to include the chemically related elements fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). The term “(C1-Cn)alkyl” refers to a linear or branched saturated hydrocarbon group having from 1 to n carbon atoms. By way of example, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl groups. As used herein, the term "chemotherapy or chemotherapeutic agent" refers to cytotoxic, cytostatic, and antineoplastic agents that preferentially kill, inhibit the growth of, or inhibit the metastasis of neoplastic cells or disrupt the cell cycle of rapidly proliferating cells. As used herein, “tyrosine kinase inhibitors” refers to compounds that totally or partially reduce, inhibit, interfere with or modulate the action of one or more protein kinases.The term "simultaneously" as used herein means administering the compound of theinvention and the anticancer agent or agents at or about the same time. The term"separately" means administering the compound of the invention on the one hand, and theanticancer agent or agents on the other hand, at different times. The term "sequentially"means administering in a specific order, where one first drug (either the compound of theinvention or the anticancer agent or agents) is administered first, and then, the secondone is administered after an interval of predetermined time. The term “therapeutically effective amount” as used herein, refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease to be treated. The particular dose of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and the similar considerations. The term “pharmaceutical composition” refers to a mixture of a compound disclosed herein with other excipients, such as diluents. The pharmaceutical composition facilitatesthe administration of the compound to an organism.The term "single pharmaceutical composition" as used herein refers to a dosage form that contains both a) and b) in the same composition. The term “pharmaceutically acceptable excipient” refers to pharmaceutically acceptable material, composition or vehicle, such as liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit / risk ratio. The term “administering” means providing a compound of the invention of formula (I) or (I1) or a prodrug thereof to the individual in need. As mentioned above, a first aspect of the present invention relates to compounds of formula (I) as defined above, or their pharmaceutically acceptable salts, for use in the treatment of pancreatic cancer in a mammal. This aspect can also be formulated as the use of compounds of formula (I) as defined above for the preparation of a medicament for the treatment of pancreatic cancer in a mammal. The invention also relates to a method of treatment of a mammal suffering from or being susceptible of suffering from pancreatic cancer, said method comprising the administration to said mammal of a therapeutically effective amount of a compound of formula (I) as defined above, together with one or more pharmaceutically acceptable excipients. In a second aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) as defined herein, together with one or more pharmaceutically acceptable excipients, for use in the treatment ofpancreatic cancer in a mammal.There is no limitation on the type of salt of the compound of formula (I) or (I1) that can beused, provided that these are pharmaceutically acceptable when they are used fortherapeutic purposes. The term "pharmaceutically acceptable salts", embraces non-toxicsalts commonly used. The preparation of pharmaceutically acceptable salts of thecompound of formula (I) or (I1) can be carried out by methods known in the art. The preparation of pharmaceutically acceptable salts of the compounds of formula (I) or (I1) can be carried out by methods known in the art. For instance, they can be prepared from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate pharmaceutically acceptable base in water or in an organic solvent or in a mixture of them. The pharmaceutically acceptable salts of the compounds of formula (I) or (I1) include acid addition salts such as the hydrochloride, but also any other pharmaceutically acceptable salts of other acids such as hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, citric, fumaric, gluconic, lactic, maleic, succinic or tartaric acid. The compound of formula (I) or (I1) or its salts may be in crystalline form either as free solvation compounds or as solvates (e.g. hydrates). All these forms are within the scope of the present invention. Methods of solvation are generally known within the art. In general, the solvated forms withpharmaceutically acceptable solvents such as water, ethanol and the like are equivalent tothe unsolvated form for the purposes of the invention. The compounds of formula (I) or (I1) or their salts can exist in solvated, as well as unsolvated forms, including hydrated forms. Thus, they can contain in its structure stoichiometric amounts of solvent in the case of solvates, or of water in the case of hydrates. It is to be understood that the invention encompasses all such solvated, as well as unsolvated forms. Some compounds of formula (I) or (I1) or their salts can have chiral centers that can give rise to various stereoisomers. As used herein, the term "stereoisomer" refers to all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis / trans or syn / anti or E / Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers). The present invention relates to each of these stereoisomers and also mixtures thereof. Racemates and diastereomer mixtures obtained can be separated into the pure isomers or racemates in a known manner on the basis of the physicochemical differences of the components, for example by fractional crystallization. Racemates obtained may furthermore be resolved into the optical enantiomers by known methods, for example by recrystallization from an optically active solvent, chromatography on chiral adsorbents, with the aid of suitable microorganisms, by cleavage with specific immobilized enzymes, via the formation of inclusion compounds or by conversion into diastereomeric salts. Thus, for example, a racemic compound of formula (I) or (I1) can be separated into its enantiomers by reaction of the racemate with an optically active acid or bases and separation of the diastereomer mixture obtained. Examples of appropriate optically active acids are carboxylic acids such as tartaric or malic acid; sulfonic acids such as camphorsulfonic acid. Examples of appropriate optically active bases are naturally occurring alkaloids such as quinine or brucine, or basic amino acids such as lysine. The separation of the diastereomer mixture obtained in this manner, can be done on the basis of its differing solubilities. Then, the desired enantiomer can be liberated by the action ofsuitable agents. The most active enantiomer is advantageously isolated. In allembodiments of the invention referring to the compound of formula (I) or (I1), itspharmaceutically acceptable salts thereof as well as its solvated form, are alwayscontemplated even if they are not specifically mentioned. Human pancreatic ductal adenocarcinomas (PDAC) cell lines BxPC-3, PANC-1, and MiaPaCa-2 were used to study the activity of the tyrosine kinase inhibitors (TKIs) of the present invention. These three PDAC cell lines represent different stages in the epithelial- to-mesenchymal transition (EMT) spectrum, being epithelial phenotype (BxPC-3),an intermediate phenotype (PANC-1), and a mesenchymal phenotype (MiaPaCa-2).Moreover, these cell lines present differences regarding erlotinib sensitivity, with BxPC-3 being considered an erlotinib-sensitive line and PANC-1 and MiaPaCa-2 insensitive ones.They furthermore present different KRAS genetic signatures, the latter being an importantgene involved in PDAC progression. BxPC-3 cells have wild-type KRAS, while PANC-1 cells and MiaPaCa-2 present key mutations that keep them in constitutive activation state (G12D and G12C, respectively). This is of vital importance since 95% of primary pancreatic tumors show mutations in the KRAS gene. In one embodiment of the first or the second aspect, in combination with any of the embodiments above or below, the treatment of pancreatic cancer comprises inhibition of intracellular tyrosine kinase receptors. In a particular embodiment of the compound of formula (I) for use according to the invention, in combination with any of the embodiments above or below, the intracellular tyrosine kinase receptors involved in pancreatic cancer are selected from the list consisting of ERK1, ERK2, JNK1, JNK2, p38alpha, and p38beta. In another particular embodiment of the first or the second aspect, in combination with any of the embodiments above or below, the treatment of pancreatic cancer comprises the inhibition of KRAS oncogene. In a particular embodiment of the first or the second aspect, in combination with any of theembodiments above or below, in the compound of formula (I), is a single bond.In a particular embodiment of the first or the second aspect, in combination with any of the embodiments above or below, in the compound of formula (I), is a double bond. In a particular embodiment of the first or the second aspect, in combination with any of theembodiments above or below, in the compound of formula (I), Cy is a phenyl ring,optionally substituted with at least one substituent selected from the group consisting of:halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl. In a particular embodiment of the first or the second aspect, in combination with any of theembodiments above or below, in the compound of formula (I), Cy is a 3- to 7-memberedaromatic heterocyclic ring, wherein the selected ring may be fused, bridged-fused or spiro fused to any other ring selected from the same group forming a bicyclic ring, particularly a3- to 7-membered aromatic heterocyclic monocyclic ring optionally substituted with at least one selected from the group consisting of: halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl. In a particular embodiment of the first or the second aspect, in combination with any of theembodiments above or below, in the compound of formula (I), Cy is a phenyl ringsubstituted with at least one selected from the group consisting of: halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl, more particularly Cy is a phenyl ring substituted with at least one substituent selected from the group consisting of: halogen and -O(C1-C6)alkyl. In a particular embodiment of the first or the second aspect, in combination with any of theembodiments above or below, in the compound of formula (I), Cy is a phenyl ringsubstituted with one substituent selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and-NH(C1-C6)alkyl placed in the p position; more particularly Cy is a phenyl ring substitutedwith one substituent selected from the group consisting of: halogen and -O(C1-C6)alkylplaced in the p position.In a particular embodiment of the first or the second aspect, in combination with any of theembodiments above or below, in the compound of formula (I), Cy is a phenyl ringsubstituted with two substituents selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and-NH(C1-C6)alkyl placed in the o and o’ positions; more particularly Cy is a phenyl ringsubstituted with two substituents selected from the group consisting of: halogen and-O(C1-C6)alkyl placed in the o and o’ positions; even more particularly, Cy is a phenyl ringsubstituted with two halogens placed in the o and o’ positions; and even more particularly,Cy is a phenyl ring substituted with two chlorine atoms placed in the o and o’ positions.In a particular embodiment of the first or the second aspect, in combination with any of theembodiments above or below, in the compound of formula (I), Cy is a phenyl ringsubstituted with three substituents selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and-NH(C1-C6)alkyl placed in the o, o’ and p positions; more particularly Cy is a phenyl ringsubstituted with three substituents selected from the group consisting of: halogen and-O(C1-C6)alkyl placed in the o, o’ and p positions.In a particular embodiment of the first or the second aspect, in combination with any of theembodiments above or below, in the compound of formula (I), Cy is a phenyl ringsubstituted with three substituents selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and-NH(C1-C6)alkyl placed in the o, o’ and m positions; more particularly Cy is a phenyl ring substituted with three substituents selected from the group consisting of: halogen and-O(C1-C6)alkyl placed in the o, o’ and m positions.In a particular embodiment of the first or the second aspect, in combination with any of theembodiments above or below, in the compound of formula (I), Cy is a phenyl ringsubstituted with four substituents selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and-NH(C1-C6)alkyl placed in the o, o’, m and m’ positions; more particularly Cy is a phenylring substituted with four substituents selected from the group consisting of: halogen and-O(C1-C6)alkyl placed in the o, o’, m and m’ positions.In a particular embodiment of the first or the second aspect, in combination with any of the embodiments above or below, in the compound of formula (I), R6-R8 are H. In a particular embodiment of the first or the second aspect, in combination with any of theembodiments above or below, in the compound of formula (I), is a double bond andR10 and R11 are absent.In a particular embodiment of the first or the second aspect, in combination with any of the embodiments above or below, in the compound of formula (I), R9 is a radical selected from the group consisting of H, -(C1-C6)alkyl, -(C1-C6)alkylphenyl, phenyl and -(CH2)nO(C1-C6)alkyl; wherein n is an integer from 2 to 4; and phenyl is optionally substituted with one or more radicals independently selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl,-NH2, and -NH(C1-C6)alkyl. More particularly, R9 is H or -(C1-C6)alkyl, and even moreparticularly R9 is H or methyl. In a particular embodiment of the first or the second aspect, in combination with any of the embodiments above or below, in the compound of formula (I), at least one of R1-R5 is selected from the group consisting of H, halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, piperazin-1-yl, and 4-(C1-C6)alkylpiperazin-1-yl. In a particular embodiment of the first or the second aspect, in combination with any of the embodiments above or below, in the compound of formula (I), at least two of R1-R5 are independently selected from the group consisting of H, halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, piperazin-1-yl, and 4-(C1-C6)alkylpiperazin-1-yl. In a particular embodiment of the first or the second aspect, in combination with any of the embodiments above or below, in the compound of formula (I), R2, R4, and R5 are H. In a particular embodiment of the first or the second aspect, in combination with any of the embodiments above or below, in the compound of formula (I), R1 is a radical selected fromthe group consisting of halogen, -OH, and -O(C1-C6)alkyl. In a more particularembodiment, the halogen is fluorine and the -O(C1-C6)alkyl is methoxy.In a particular embodiment of the first or the second aspect, in combination with any of the embodiments above or below, in the compound of formula (I), R1 is a halogen, moreparticularly, fluorine or bromine.In a particular embodiment of the first or the second aspect, in combination with any of the embodiments above or below, in the compound of formula (I), R3 is a radical selected from the group consisting of H, halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, piperazin-1-yl, and 4-(C1-C6)alkylpiperazin-1-yl, more particularly selected from the group consisting ofmethyl-piperazin-1-yl, halogen, methoxy, and hydroxy. In a more particular embodiment,R3 is a halogen, more particularly selected from fluorine and bromine.In a particular embodiment of the first or the second aspect, in combination with any of the embodiments above or below, in the compound of formula (I), R2, R4, and R5 are H; R1 is a radical selected from the group consisting of halogen, -OH, and -O(C1-C6)alkyl, more particularly R1 is halogen, and even more particularly R1 is fluorine; and R3 is a radical selected from the group consisting of H, halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, piperazin-1-yl, and 4-(C1-C6)alkylpiperazin-1-yl, more particularly R3 is halogen, and even more particularly R3 is fluorine. In a particular embodiment of the first or the second aspect, in combination with any of theembodiments above or below, the compound of formula (I) is selected from the groupconsisting of: Formula IUPAC Name4-amino-6-(2,6-dichlorophenyl)-2- (Ia) ((2,4-difluorophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)- one 4-amino-6-(2,6-dichlorophenyl)-2-((4- (Ib) fluoro-2-methoxyphenyl)amino)- pyrido[2,3-d]pyrimidin-7(8H)oneFormula IUPAC Name4-amino-6-(2,6-dichlorophenyl)-2-((4- (Ic) fluoro-2-hydroxyphenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)- one 4-amino-6-(2,6-dichlorophenyl)-2- (Id) ((2,4-difluorophenyl)amino)pyrido[2,3- d]pyrimidin-7(8H)-one 4-amino-6-(2,6-dichlorophenyl)-2-((4- (Ie) fluoro-2-methoxyphenyl)amino)- pyrido[2,3d]pyrimidin-7(8H)-one 4-amino-6-(2,6-dichlorophenyl)-8- (If) methyl-2-((4-(4-methylpiperazin-1- yl)phenyl)amino)pyrido[2,3- d]pyrimidin-7(8H)-one 4-amino-6-(2,6-dichlorophenyl)-2-((4- (Ig) fluorophenyl)amino)-8-methylpyrido- [2,3-d]pyrimidin-7(8H)-one 4-amino-6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-methyl-2-((4-(4- (Ih) methylpiperazin-1-yl)phenyl)- amino)pyrido[2,3-d]pyrimidin-7(8H)- one 4-amino-6-(2,6-dichlorophenyl)-2- (Ii) ((2,4-difluorophenyl)amino)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)- oneFormula IUPAC Name4-amino-6-(2,6-dichlorophenyl)-2-((4- (Ij) fluoro-2-methoxyphenyl)amino)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)- one 4-amino-6-(2,6-dichlorophenyl)-2-((2- (Ik) methoxyphenyl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7(8H)one 4-amino-6-(2,6-dichlorophenyl)-2-((2- (IL) hydroxyphenyl)amino)-8-methyl- pyrido[2,3-d]pyrimidin-7(8H)-one 4-amino-6-(2,6-dichlorophenyl)-2-((4- (Im) methoxyphenyl)amino)-8-methyl- pyrido[2,3-d]pyrimidin-7(8H)-one 4-amino-6-(2,6-dichlorophenyl)-2-((4- (In) hydroxyphenyl)amino)-8-methyl- pyrido[2,3-d]pyrimidin-7(8H)-one 4-amino-6-(2,6-dichlorophenyl)-2-((2- (Io) methoxyphenyl)amino)pyrido[2,3- d]pyrimidin-7(8H)-one 4-amino-6-(2,6-dichlorophenyl)-2-((4- (Ip) methoxyphenyl)amino)pyrido[2,3-d]- pyrimidin-7(8H)-oneFormula IUPAC Name4-amino-6-(2,6-dichlorophenyl)-2-((2- (Iq) methoxyphenyl)amino)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)- one 4-amino-6-(2,6-dichlorophenyl)-2-((4- (Ir) methoxyphenyl)amino)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)- one H O N N N 4-amino-2-((4-bromophenyl)amino)-6- (Is) MeO N (3,5-dimethoxyphenyl)-8- Br methylpyrido[2,3-d]pyrimidin-7(8H)- NH2one OMe 4-amino-2-((4-bromophenyl)amino)-6- (It) (2,6-dichloro-3,5-dimethoxyphenyl)-8- methylpyrido[2,3-d]pyrimidin-7(8H)- one The compounds of the present invention can be used in the same manner as other known chemotherapeutic agents, i.e., in combination with other treatments, either simultaneously or sequentially, depending on the condition to be treated. In another particular embodiment, the compounds of formula (I) for use in the treatment of pancreatic cancer as defined above, are administered in combination with a chemotherapeutic agent. This isespecially advantageous because of the fact that heterogeneous cancers (more than asingle population of cancer cells) tend to be resistant to certain treatments or develop mechanisms that enable cancer cells to keep proliferating, and by combining more than one strategy, it can be targeted different aspects of cancer. Non-limiting examples of chemotherapeutic agents include antimetabolites such as cytarabine, 5-fluorouracil (5-FU), capecitabine, and gemcitabine; alkylating agents such as cisplatin, carboplatin, and oxaliplatin; topoisomerase inhibitors such as irinotecan and topotecan; mitotic inhibitors such as docetaxel, and paclitaxel; protein kinase inhibitorssuch as erlotinib, imatinib, and dasatinib; proteasome inhibitors such as bortezomib and carfilzomib; PARP inhibitors such as Olaparib; and histone deacetylase inhibitors such as vorinostat and romidepsin. In a more particular embodiment, the chemotherapeutic agent is selected from the groupconsisting of MEK inhibitors (such as trametinib, selumetinib and the like), RAS inhibitors(such as sotorasib), ALK inhibitors (such as crizotinib), EGFR inhibitors (such as gefitinib) and other inhibitors of DNA repair proteins. In another particular embodiment, in combination with any of the embodiments above or below, the compound of formula (I) is administered in combination with a chemotherapeutic agent which selected from the group consisting of a Kirsten rat sarcoma viral oncogene (KRAS) inhibitor, a Mitogen-activated extracellular signal- regulated kinase (MEK) inhibitor, a Src Homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2(PTPN11)) inhibitor, a Phosphoinositide 3-kinase (PI3K) inhibitor, a poly-ADP ribose polymerase (PARP) inhibitor, a Son of Sevenless homolog 1 (SOS1) inhibitor, an Anaplastic Lymphoma Kinase (ALK) inhibidor, an Epidermal Growth FactorReceptor (EGFR) inhibitor, a platinum compound, 5-fluorouracil (5-FU), irinotecan,leucovorin, gemcitabine, nab-Paclitaxel, and combinations thereof.In another particular embodiment, in combination with any of the embodiments above orbelow, the compound of formula (I) is administered in combination with achemotherapeutic agent which is a Kirsten rat sarcoma viral oncogene (KRAS) inhibitorsuch as sotorasib, adagrasib, opnurasib, 4-[4-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2- [[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]- 5-ethynyl-6-fluoro-2-naphthalenol (MRTX1133), daraxonrasib, or zoldonrasib. More particularly, the KRAS inhibitor is selected from the group consisting of adagrasib, sotorasib, and MRTX1133.In another particular embodiment, in combination with any of the embodiments above orbelow, the compound of formula (I) is administered in combination with achemotherapeutic agent which is a Mitogen-activated extracellular signal-regulated kinase(MEK) inhibitor such as trametinib, selumetinib, binimetinib, cobimetinib, or avutometinib.More particularly, the MEK inhibitor is selected from the group consisting of selumetinib and trametinib.In another particular embodiment, in combination with any of the embodiments above orbelow, the compound of formula (I) is administered in combination with achemotherapeutic agent which is a Src Homology 2 domain-containing protein tyrosinephosphatase 2 (SHP2(PTPN11)) inhibitor such as batoprotafib, vociprotafib, 1-[4-[3-Amino-5-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazin-2-yl]sulfanyl-3,3-difluoro- 2H-indol-1-yl]ethanone (JAB-3068), 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6- yl]-4-methylpiperidin-4-amine (BBP-398) or 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP-099). More particularly, the SHP2(PTPN11)inhibitor is selected from the group consisting of batoprotafib and vociprotafibIn another particular embodiment, in combination with any of the embodiments above orbelow, the compound of formula (I) is administered in combination with achemotherapeutic agent which is a Phosphoinositide 3-kinase (PI3K) inhibitor such asidealisib, copanilisib or apelisib. More particularly, the PI3K inhibitor is idealisibIn another particular embodiment, in combination with any of the embodiments above orbelow, the compound of formula (I) is administered in combination with achemotherapeutic agent which is a poly-ADP ribose polymerase (PARP) inhibitor such asolaparib, niraparib, rucaparib, talazoparib or pamiparib. More particularly, the PARPinhibitor is selected from the group consisting of olaparib and niraparib.In another particular embodiment, in combination with any of the embodiments above orbelow, the compound of formula (I) is administered in combination with achemotherapeutic agent which is a Son of Sevenless homolog 1 (SOS1) inhibitor such as(R)-6,7-Dimethoxy-2-methyl-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2- yl)ethyl)quinazolin-4-amine (BAY-293), N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)- 7-methoxy-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine (BI-3406), (R)-2- Methyl-3-(1-((4-methyl-7-morpholinopyrido(3,4-d)pyridazin-1-yl)amino)ethyl)benzonitrile(MRTX0902). More particularly, the SOS1 inhibitor is selected from the group consistingof BI-3406, and BAY-293.In another particular embodiment, in combination with any of the embodiments above orbelow, the compound of formula (I) is administered in combination with achemotherapeutic agent which is a platinum compound such as oxaliplatin, cisplatin orcarboplatin. More particularly, the platinum compound is oxaliplatin.In another particular embodiment, in combination with any of the embodiments above orbelow, the compound of formula (I) is administered in combination with achemotherapeutic agent selected from the group consisting of 5-fluorouracil (5-FU),oxaliplatin, irinotecan, leucovorin, gemcitabine, nab-Paclitaxel (Abraxane), andcombinations thereof. More particularly, the chemotherapeutic agent selected from thegroup consisting of FOLFOX (5-Fluorouracil+Oxaliplatin+ leucovorin), FOLFIRI (5-Fluorouracil+Irinotecan+ leucovorin), FOLFIRINOX (5-Fluorouracil+Irinotecan+Oxaliplatin+ leucovorin), Gemcitabine, and Gemcitabine+nab-Paclitaxel. Thus, in a particular embodiment of a compound of formula (I) for use as defined above, in combination with any of the embodiments above or below, the compound is administered in combination with a chemotherapeutic agent. In a more particular embodiment, the compounds of the invention are administered simultaneously with the chemotherapeutic agent. In another more particular embodiment, the compounds of the invention and the chemotherapeutic agent are administered separately, in any order, within a therapeutically effective interval. In another particular embodiment, the compounds of the invention and the chemotherapeutic agent are administeredsimultaneously or sequentially.It also forms part of the invention those compounds of formula (I) which are selected fromthe group consisting of: -4-amino-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Ih); -4-amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (Ii); -4-amino-6-(2,6-dichlorophenyl)-2-((4-fluoro-2-methoxyphenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (Ij); -4-amino-6-(2,6-dichlorophenyl)-2-((2-methoxyphenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)one (Ik); -4-amino-6-(2,6-dichlorophenyl)-2-((2-hydroxyphenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (IL); -4-amino-6-(2,6-dichlorophenyl)-2-((4-methoxyphenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Im); -4-amino-6-(2,6-dichlorophenyl)-2-((4-hydroxyphenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (In); -4-amino-6-(2,6-dichlorophenyl)-2-((2-methoxyphenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Io); -4-amino-6-(2,6-dichlorophenyl)-2-((4-methoxyphenyl)amino)pyrido[2,3-d]-pyrimidin-7(8H)-one (Ip); -4-amino-6-(2,6-dichlorophenyl)-2-((2-methoxyphenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (Iq); -4-amino-6-(2,6-dichlorophenyl)-2-((4-methoxyphenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (Ir), -4-amino-2-((4-bromophenyl)amino)-6-(3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Is), and -4-amino-2-((4-bromophenyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (It).As mentioned above, in a third aspect the invention relates to a compound of formula (I1)or a pharmaceutically acceptable salt thereof.In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), Cy is a phenyl ring, optionally substituted with at least one substituent selected from the group consisting of: halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl. In a particular embodiment of the third aspect, in combination with any of theembodiments above or below, in the compound of formula (I1), Cy is a 3- to 7-memberedaromatic heterocyclic ring, wherein the selected ring may be fused, bridged-fused or spiro fused to any other ring selected from the same group forming a bicyclic ring, particularly a3- to 7-membered aromatic heterocyclic monocyclic ring optionally substituted with atleast one selected from the group consisting of: halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl. In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), Cy is a phenyl ring substituted with at least one selected from the group consisting of: halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl, more particularly Cy is a phenyl ring substituted with at least one substituent selected from the group consisting of: halogen and -O(C1-C6)alkyl. In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), Cy is a phenyl ring substituted with one substituent selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and-NH(C1-C6)alkyl placed in the p position; more particularly Cy is a phenyl ring substitutedwith one substituent selected from the group consisting of: halogen and -O(C1-C6)alkylplaced in the p position.In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), Cy is a phenyl ring substituted with two substituents selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and-NH(C1-C6)alkyl placed in the o and o’ positions; more particularly Cy is a phenyl ringsubstituted with two substituents selected from the group consisting of: halogen and-O(C1-C6)alkyl placed in the o and o’ positions; even more particularly, Cy is a phenyl ringsubstituted with two halogens placed in the o and o’ positions; and even more particularly,Cy is a phenyl ring substituted with two chlorine atoms placed in the o and o’ positions. In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), Cy is a phenyl ring substituted with three substituents selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and-NH(C1-C6)alkyl placed in the o, o’ and p positions; more particularly Cy is a phenyl ringsubstituted with three substituents selected from the group consisting of: halogen and-O(C1-C6)alkyl placed in the o, o’ and p positions.In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), Cy is a phenyl ring substituted with three substituents selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and-NH(C1-C6)alkyl placed in the o, o’ and m positions; more particularly Cy is a phenyl ringsubstituted with three substituents selected from the group consisting of: halogen and-O(C1-C6)alkyl placed in the o, o’ and m positions.In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), Cy is a phenyl ring substituted with four substituents selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and-NH(C1-C6)alkyl placed in the o, o’, m and m’ positions; more particularly Cy is a phenylring substituted with four substituents selected from the group consisting of: halogen and-O(C1-C6)alkyl placed in the o, o’, m and m’ positions.In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), R6-R8 are H. In a more particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), R9 is a radical selected from the group consisting of H, -(C1-C6)alkyl, -(C1-C6)alkylphenyl, phenyl and -(CH2)nO(C1-C6)alkyl; wherein n is an integer from 2 to 4; and phenyl is optionally substituted with one or more radicals independently selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl. More particularly, R9 is H or -(C1-C6)alkyl, and even more particularly R9 is H or methyl. In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), at least two of R1-R5 are independently selected from the group consisting of H, halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, piperazin-1-yl, and 4-(C1-C6)alkylpiperazin-1-yl. In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), R1 is a radical selected from halogen, -OH, and -O(C1-C6)alkyl. In a more particular embodiment, the halogen is fluorine and the -O(C1-C6)alkyl is methoxy. In a particular embodiment of the third aspect, in combination with any of theembodiments above or below, in the compound of formula (I1), R2, R4, and R5 are H.In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), R1 is a radical selected from the group consisting of halogen, -OH, and -O(C1-C6)alkyl. In a more particular embodiment, the halogen is fluorine and the -O(C1-C6)alkyl is methoxy. In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), R1 is a halogen, more particularly, fluorine or bromine. In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), R3 is a radical selected from the group consisting of H, halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, piperazin-1-yl, and 4-(C1-C6)alkylpiperazin-1-yl, more particularly selected from the group consisting of methyl-piperazin-1-yl, halogen, methoxy, and hydroxy. In a more particular embodiment, R3 is a halogen, more particularly selected from fluorine and bromine. In a particular embodiment of the third aspect, in combination with any of the embodiments above or below, in the compound of formula (I1), R2, R4, and R5 are H; R1 is a radical selected from the group consisting of halogen, -OH, and -O(C1-C6)alkyl, more particularly R1 is halogen, and even more particularly R1 is fluorine; and R3 is a radical selected from the group consisting of H, halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, piperazin-1-yl, and 4-(C1-C6)alkylpiperazin-1-yl, more particularly R3 is halogen, and even more particularly R3 is fluorine or bromine. In another particular embodiment, in combination with any of the embodiments above or below, the compounds of formula (I1) as defined above are those selected from the following list: -4-amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Ia), -4-amino-6-(2,6-dichlorophenyl)-2-((4-fluoro-2-methoxyphenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)one (Ib),- 4-amino-6-(2,6-dichlorophenyl)-2-((4-fluoro-2-hydroxyphenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Ic),- 4-amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Id), and- 4-amino-6-(2,6-dichlorophenyl)-2-((4-fluoro-2-methoxyphenyl)amino)pyrido[2,3d]pyrimidin-7(8H)-one (Ie).In another particular embodiment of a compound of formula (I1) as defined above, incombination with any of the embodiments above or below, the compound is that where: R1 and R3 are fluorine; R2, and R4-R8 are H; R9 is methyl, and Cy is a phenyl ring substituted with two chlorine atoms, i.e., the compound of formula (I1) is a compound of formula (Ia).Its IUPAC name is 4-amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one. The preparation of the compounds of the invention can be carried out by methods well- known in the art. For instance, the compounds of formulas (I) and (I1) of the present invention may be prepared by the process illustrated in Scheme I. All radicals in theformula of Scheme I have the same meaning as the corresponding radicals in formulas (I)and (I1), as defined above. Cy in Scheme I has the same meaning as the correspondingCy in formulas (I) and (I1), as defined above.Scheme I

[0002] Compounds of formula (I1) wherein R7 is H, can be prepared by reacting a compound offormula (VI), where R12 is a radical selected from -O(C1-C6)alkyl, and paraformaldehyde(p-CHO with R8=R10=H) or an aldehyde (R8CHO with R10=H) or a ketone (R8COR10) instep (A), in the presence of a base, such as K2CO3 and a solvent, such as DMF,particularly heating, to form a compound of formula (V). This compound is then submittedto step (B), in which malononitrile is added to the solution in the presence of a solvent, such as methanol, and optionally in the presence of a base, such as NaOMe, particularly at reflux, giving a compound of formula (IV) as a result. This compound then reacts with the corresponding compound of formula (III) in step (C),in the presence of a base such as NaOMe and a solvent, such as 1,4-dioxane, particularlyheating and optionally using microwave (MW) irradiation, producing a further cyclization togive a compound of formula (II) that can be optionally isolated. A subsequent Dimrothtransposition is performed in step (D), in the presence of NaOMe and a solvent, such as MeOH, particularly heating and optionally using microwave (MW) irradiation, to give a compound of formula (IA). Compounds of formula (IA) are compounds of formula (I) of the present invention, where is a single bond. The resulting compound of formula (IA) is then treated in step (E)with a dehydrogenating agent, such as NaH in the presence of a solvent, such as DMSOor DMF, and air at room temperature or heating, or in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) / acetic acid in 1,4-dioxane at 100ºC or sodium selenitein DMSO or 10% Pd / C in decalin at high temperature to give a compound of formula (IB).Compounds of formula (IB) are compounds of formula (I) of the present invention, where is a double bond, and R9 and R11 are H. Subsequently, in step (F) or (F’), anelectrophilic compound, that is R9X, where R9 is a radical, such as methyl, and X is ahalogen, such as iodide, is added to the solution together with a base such as NaH in asolvent, such as DMSO or DMF, particularly at room temperature, to finally givecompounds of formula (I1A) or (IC), respectively.In an additional step, after step (F), and when R1 is H and R3 is -O(C1-C6)alkyl, or whereR1 is -O(C1-C6)alkyl and R3 is H, and R2, R4-R5 are H in both cases, HX, where X is ahalogen, and propanoic acid was added in an inert atmosphere, and reflux was performedovernight to obtain other compounds of formula (I1) where R1 is H and R3 is -OH, or whereR1 is -OH and R3 is H, and R2, R4-R5 are H in both cases. Compound (III) may be obtained by dissolving a compound of formula (VII) in a solvent, such as ethanol, and in the presence of an acid such as HNO3 or HCl in step (H), followed by the addition of cyanamide to give a compound of formula (III). Alternatively, compound of formula (VII) can be reacted with AIMSOA (aminoiminomethanesulfonic acid) obtained by reaction of the commercially available formamidinesulfinic acid with 39% peracetic acid solution in acetic acid at room temperature to afford compound (III) after treatment with HNO3. The compounds of formula (I1) of the present invention may be industrially prepared by the process illustrated in Scheme II. All radicals in the formula of Scheme II have the same meaning as the corresponding radicals in formulas (I) and (I1), as defined above. Cy in Scheme I has the same meaning as the corresponding Cy in formulas (I) and (I1), as defined above. Scheme II Compounds of formula (I1) can be prepared by reacting a compound of formula (IV) instep (c) with NH2CN and NaOMe, in the presence of a solvent, such as 1,4-dioxane, and particularly left under an inert atmosphere, to finally give a compound of formula (IIIA).This compound then reacts in step (d) with a hydrogen halide, particularly hydrogen bromide, in the presence of a solvent, such as 1,4-dioxane, to give a compound of formula (IIA). This compound then reacts in step (e) with a base, such as NaH, in the presence of a solvent, such as DMSO, in particular under an inert atmosphere, giving a compound of formula (IIB). This compound reacts in step (f) with a dehydrogenating agent, such as NaH in the presence of a solvent, such as DMSO or DMF, in the presence of air at room temperature or heating, or in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) / acetic acid in 1,4-dioxane at 100ºC or sodium selenite in DMSO or 10% Pd / C in decalin at high temperature to give a compound of formula (IIC).This compound thenreacts in step (g) with a phenylamine compound, substituted with one or more radicals, in asolvent, such as ethylene glycol, particularly under an inert atmosphere and at hightemperatures, such as 180 ºC, to give a compound of formula (I1B), which are compounds of formula (I1) of the present invention. As mentioned above, in a fourth aspect, the present invention relates to a combinationcomprising a compound of formula (I1) as defined above and a chemotherapeutic agent. As mentioned above, in a fifth aspect, the invention relates to a pharmaceutical compositioncomprising a therapeutically effective amount of the compound of (I1) as defined above, ora pharmaceutically acceptable salt thereof, or the combination as defined above of thecompound of formula (I1) with a chemotherapeutic agent, together with one or morepharmaceutical excipients.It is also part of the invention a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of formula (I) selected from the group consisting of (Ig),(Ih), (Ii), (Ij), (Ik), (IL), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is) and (It), or a pharmaceuticallyacceptable salt thereof, or the combination as defined above of the compound of formula(I1) with a chemotherapeutic agent, together with one or more pharmaceutical excipients. In a particular embodiment, in combination with any of the embodiments above or below, the compound of formula (I1) or a salt thereof is the only active ingredient of thepharmaceutical composition.In another particular embodiment, in combination with any of the embodiments above orbelow, the pharmaceutical composition is a single pharmaceutical composition whichcomprises: a) a therapeutically effective amount of a compound of formula (I1), or a saltthereof; b) a therapeutically effective amount of one or more of chemotherapeutic agents;and one or more pharmaceutically acceptable excipients.Suitable pharmaceutical compositions to be used in the present invention are well-knownin the art. The election of the pharmaceutical formulation will be determined by the skilled person depending upon the nature of the active compounds present in the composition, and its route of administration. Any route of administration may be used, for example oral, parenteral and topical administration.The pharmaceutical composition may be formulated for oral administration and maycontain one or more physiologically compatible excipients, in solid or liquid form. For example, formulations suitable for oral administration may include liquid solutions, suspensions, capsules, sachets or tablets, emulsions or dry powdered forms suitable for reconstitution with water.The pharmaceutical composition may also be formulated for parenteral administration incombination with conventional injectable liquid carriers, such as water or suitable alcohols. Conventional pharmaceutical excipients for injection, such as stabilizing agents, solubilizing agents, and buffers, may be included in such compositions. Thesepharmaceutical compositions may be injected intramuscularly, intraperitoneally, orintravenously. Parenteral forms suitable for injection of the composition may include intravenous bolus injections, intravenous infusion, implantation into the body, oral, intrathecal, or intranasal.The pharmaceutical composition may also be formulated for topical administration.Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients. These preparations may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents. Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word “comprise” encompasses the case of “consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein. Examples 1. Chemical SynthesisAbbreviations: Ar (argon), RT (room temperature), diethyl ether (EtOEt), iodomethane(MeI), (HBr), sodium hydride (NaH), cycle (Cy), nitric acid (HNO3), sodium nitrate (NaNO3), ammonium nitrate (NH4NO3), methanol (MeOH), dimethyl sulfoxide (DMSO),sodium methoxide (NaOMe), microwave (MW), equivalents (equiv.), N,N-dimethylformamide (DMF), melting point (MP), hydrogen (1H-NMR) and carbon (13C-NMR)nuclear magnetic resonance, infrared spectra (IR), mass spectrometry (MS), andcompound (X) for 4-amino-6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3- d]pyrimidin-7(8H)-one.1H-NMR and13C-NMR positions: Compounds (Ia), (Id), and (Ii): where between positions 5 and 6 is a double or a single bond. Compounds (Ib), (Ic), (Ie), (Ij), (Ik), (IL), (Io), and (Iq): where between positions 5 and 6 is a double or a single bond, and R is a radical selected from -OH (to form compounds (Ic) and (IL) of the present invention), or OMe (to form compounds (Ib), (Ie), (Ij), (Ik), and (Io) of the present invention). Compounds (Im), (In), (Ip), and (Ir): where between positions 5 and 6 is a double or a single bond, and where R is a radical selected from -OH (to form compound (In) of the present invention), or OMe (to form compounds (Ir), (Ip), and (Im) of the present invention). Materials and methods: General Methods: All the reagents and solvents were obtained at the highest commercial quality from sources such as Sigma-Aldrich, Fisher Scientific, TCI International, Acros organics, and Alfa Aesar and were used without further purification. Unless otherwisementioned, all the reactions were carried out with dry solvents. Melting points (mp) weredetermined with a SMP3 melting point apparatus (Stuart Scientific). Infrared spectra (IR) were recorded in a Nicolet iS10 FTIR spectrometer with Smart iTr (Thermo Scientific).Values are reported in wave numbers (cm-1). NMR spectra (1H NMR and 13C NMR) wererecorded in a Varian 400-MR spectrometer (1H NMR at 400 MHz and13C NMR at 100.6MHz). Chemical shifts are reported in parts per million (ppm) on the ^ scale and arereferenced to the residual signal of the solvent (DMSO-d6: 2.5 ppm in1H NMR and 39.52 ppm in13C NMR). Coupling constants (J) are reposted in Hertz (Hz). Standard and peak multiplicities are designated as follows: s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet), qn (quintet), m (multiplet) and br (broad signal). Mass Spectrometry (MS) was conducted on an Agilent Technologies 5975 mass spectrometer operating inelectron ionization (EI) mode at 70 eV and at 4kV accelerating potential. High-ResolutionMass Spectrometry (HRMS) was conducted on a high-resolution mass spectrometer X500B QTOF system operating in ESI positive mode at the IQS Sciex Demo Lab. Automatic flash chromatography was performed in a Combiflash®Rf (Teledyne Isco) withRediStep® silica gel columns or Büchi Pure C-815 Flash with Ecoflex Büchi silica gelcolumn. Organic elemental analysis (OEA) were obtained on a Euro EA 3000 ElementalAnalyzer (EuroVector). Microwave irradiation experiments were carried out in anInitiatorTM(Biotage) microwave apparatus, operating at a frequency of 2.45 GHz with continuous irradiation power from 0 to 400 W. Reactions were performed in 2.5, 5, and 20 mL glass tubes, sealed with aluminium / Teflon crimp tops, which can be exposed up to250ºC and 20 bar internal pressure. Temperature was measured with an IR sensor on theouter surface of the process vial. After the irradiation period, the reaction vessel was cooled rapidly to 50ºC by air jet cooling.Intermediate 1: Synthesis of methyl 2-(2,6-dichlorophenyl)acrylate, compound (V1)First, 15.22 g (69.5 mmol) of methyl 2-(2,6-dichlorophenyl)acetate were placed in a 500 round-flask and dissolved in 225 mL of anhydrous DMF. Then, 2.29 g (76.4 mmol) of paraformaldehyde (PFA) were added together with 9.60 g (69.5 mmol) of K2CO3. The mixture was couped to a reflux system and heated at 100 ºC for 2.5 h, protected from moisture with a tube of anhydrous CaCl2. After the reaction was completely cooled down to room temperature, water was added (enough quantity to dissolve the K2CO3). Once added, the product was extracted with diethyl ether (EtOEt, 3 x 20 mL) and the combined extracts were washed with saturated LiCl solution (2 x 8 mL) to remove any traces of DMF that may be present. The combined organic phases were dried over anhydrous MgSO4, filtered and, the solvent (EtOEt) removed under reduced pressure to afford 14.88 g (64.4 mmol, 93%) of the desired compound as a pale yellowish oil. The product was kept protected from light covered in aluminum foil. Intermediate 2: Synthesis of 5-(2,6-dichlorophenyl)-2-methoxy-6-oxo-1,4,5,6- tetrahydropyridine-3-carbonitrile, compound (IV1) First, 1.13 g (20.91 mmol) of NaOMe were dissolved in 27 mL of anhydrous MeOH. Then, 1.90 (15.7 mmol) g of malononitrile and 3.02 g (13.1 mmol) of compound (V1) were successively added and the mixture was heated at reflux for 5 hours under argon atmosphere. After this time, the solvent was removed under reduce pressure until a sponge-like solid was obtained. Finally, a minimum volume of water was added dropwise, and the solution was neutralized to pH 7 with a 2M HCl solution. The solid was then filtered and left to dry under vacuum for three days affording 3.84 g (12.9 mmol, 99%) of the desired compound as a beige fine solid. Intermediate 3: Synthesis of 1-(4-methoxyphenyl)guanidine nitrate, compound (III1) 6.16 g (50.0 mmol) of 4-methoxyaniline were dissolved in EtOH (20 mL) and cooled with an ice bath before 3.85 mL (60.0 mmol) of 65% HNO3 were added dropwise. Then, 8 mL (105.0 mmol) of cyanamide in 50% H2O solution were added afterwards just before leaving the reaction at reflux for 21 h under argon atmosphere. The reaction was then left to cool at room temperature, and the solvent (EtOH) was removed under reduced pressure. The lilac solid obtained through this operation was resuspended in the minimum amount of absolute ethanol and filtered and dried under vacuum. A total of 9.21 g (40.3 mmol, 84%) of the desired compound were afforded as a dark lilac solid. Intermediate 4: Synthesis of 1-(2-methoxyphenyl)guanidine nitrate, compound (III2) 5.6 mL (46.5 mmol) of 2-methoxyaniline were dissolved in EtOH (20 mL) and cooled with an ice bath before 3.85 mL (60.0 mmol) of 65% HNO3 were added dropwise. Then, 8 mL (105.0 mmol) of cyanamide in 50% H2O solution were added afterwards just before leaving the reaction at reflux for 21 h under argon atmosphere. The reaction was then left to cool at room temperature, and the solvent (EtOH) was removed under reduced pressure. The lilac solid obtained through this operation was resuspended in the minimum amount of absolute ethanol and filtered and dried under vacuum. A total of 6.96 g (32.4 mmol, 67%) of the desired compound was afforded as a light pink solid.Intermediate 5: Synthesis of 1-(4-fluoro-2-methoxy)guanidine nitrate, compound (III3)4.00 g (28.3 mmol) of 4-fluoro-2-methoxyaniline were dissolved in EtOH (7 mL) and cooled with an ice bath before 0.91 mL of 37% HCl were added dropwise. Then, 2.5 mL (60.0 mmol) of cyanamide in 50% H2O solution were added afterwards just before leaving the reaction at reflux for 6 h under argon atmosphere and protected from light. The reaction was then left to cool at room temperature, and the solvent (EtOH) was removed under reduce pressure. The remaining oil mixture was completely dissolved in deionized water and two successive additions of 2.4 g (30.0 mmol) of NH4NO3 were made. Finally, the pale lilac solid obtained through this operation was filtered and dried under vacuum overnight, affording a total of 5.50 g (22.4 mmol, 79%) of the desired compound. Intermediate 6: Synthesis of 1-(2,4-difluorophenyl)guanidine nitrate, compound (III4) 3.8131 mg (29.6 mmol) of 2,4-difluoroaniline were dissolved in EtOH (7 mL).3.84 mL of 37% HCl were added dropwise with the solution immersed in an ice bath. Then, 4.8 mL (62.5 mmol) of cyanamide in 50% H2O solution were added afterwards just before leaving the reaction at reflux for 6 h under argon atmosphere and protected from light. The reaction was then left to cool at room temperature, and the solvent (EtOH) was removedunder reduced pressure. The remaining oil mixture was completely dissolved in deionizedwater and two successive additions of 2.4 g (30.0 mmol) of NH4NO3 were made. Finally, the lilac crystals obtained was filtered and dried under vacuum overnight, affording a total of 4.92 g (21.0 mmol, 71%) of the desired compound. Intermediate 7: Synthesis of 2-amino-6-(2,6-dichlorophenyl)-4-imino-3-(4-methoxyphenyl)- 4,5,6,8-tetrahydropyrido[2,3-d]pyrimidin-7(3H)-one, compound (II1) 881.4 mg (3.9 mmol) of compound (III1) were suspended in 15 mL of anhydrous 1,4- dioxane in a 20 mL microwave vial, then 230.7 mg (4.3 mmol) of NaOMe were afterwards added. The reaction mixture was then set to an oil bath at 65°C during 15 min and after cooling down the mixture to room temperature the white solid was filtered and washed with 5 mL of anhydrous 1,4-dioxane. The filtrated liquid was transferred into a second 20 mL microwave vial containing 302.6 mg (1.0 mmol) of compound (IV1), the vial was sealed and set to an oil bath at 140°C for 40 min. This procedure was repeated four times, and the resulting dark brown solutions were emptied into a 100 mL round-bottomed flask in order to remove the solvent under reduced pressure. The solid obtained was then resuspended in a minimum amount of acetone and diethyl ether, filtered, and dried under vacuum overnight, affording 1.368 g (3.4 mmol, 84%) of the desired compound as a beige powder. Intermediate 8: Synthesis of 2-amino-6-(2,6-dichlorophenyl)-4-imino-3-(2-methoxyphenyl)- 4,5,6,8-tetrahydropyrido[2,3-d]pyrimidin7(3H)-one, compound (II2) 883.41 mg (3.9 mmol) of compound (III2) were suspended in 15 mL of anhydrous 1,4- dioxane in a 20 mL microwave vial, then 230.7 mg (4.3 mmol) of NaOMe were afterwards added. The reaction mixture was then set to an oil bath at 65°C during 15 min and after cooling down the mixture to room temperature the white solid was filtered and washed with 5 mL of anhydrous 1,4-dioxane. The filtrated liquid was transferred into a second 20 mL microwave vial containing 302.6 mg (1.0 mmol) of compound (IV1), the vial was sealed and set to an oil bath at 140°C for 40 min. This procedure was repeated four times, and the resulting dark brown solutions were emptied into a 100 mL round-bottomed flask in order to remove the solvent under reduced pressure. The solid obtained was then resuspended in a minimum amount of acetone and diethyl ether, filtered, and dried under vacuum overnight. A total of 1.592 g (3.7 mmol, 91%) of the desired compound was afforded as a brown powder. Intermediate 9: Synthesis of 2-amino-6-(2,6-dichlorophenyl)-3-(4-fluoro-2-methoxyphenyl)-4-imino-4,5,6,8-tetrahydropyrido[2,3-d]pyrimidin7(3H)-one, compound (II3)1280 mg (5.2 mmol) of compound (III3) were suspended in 15 mL of anhydrous 1,4-dioxane in a 20 mL microwave vial, then 230.7 mg (4.3 mmol) of NaOMe were afterwards added. The reaction mixture was then set to an oil bath at 65°C during 15 min and after cooling down the mixture to room temperature the white solid was filtered and washed with 5 mL of anhydrous 1,4-dioxane. The filtrated liquid was transferred into a second 20 mL microwave vial containing 302.6 mg (1.0 mmol) of compound (IV1), the vial was sealed and set to an oil bath at 140°C for 40 min. This procedure was repeated four times, and the resulting dark brown solutions were emptied into a 100 mL round-bottomed flask in order to remove the solvent under reduced pressure. The solid obtained was then resuspended in a minimum amount of acetone and diethyl ether, filtered, and dried under vacuum overnight. The process was repeated three times, and the reaction crude was pooled for the next purification step. After removing the solvent under reduced pressure, the brownish solid was dissolved in the minimum amount of acetone. EtOEt was added dropwise until no more precipitation of solid was observed. It was important to allow the solid to settle completely before filtering and drying. A total of 1.2098 g (2.7 mmol, 89%) of the desired compound was afforded as a fine brown solid. Example 1: Synthesis of 4-Amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)amino)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one, compound (Ii) 717.9 mg (3.066 mmol, 3 equiv.) of the compound of formula (III4) as previously prepared were suspended in 15 mL of anhydrous methanol in a 20 mL microwave vial, then 232.5mg (4.304 mmol, 4.2 equiv.) of NaOMe were added. The reaction mixture was thenheated at 65 °C for 15 min assisted with microwaves and after cooling down the mixture toroom temperature, 302.6 mg (1.018 mmol) of a compound (IV1) were added and the vialwas sealed and heated at 140 °C for 40 min. The mixture was allowed to cool while observing the appearance of a solid which was filtered and washed with water and finallydried under vacuum affording 171.8 mg (0.394 mmol, 39%) of the desired compound as afine grey powder.1H NMR (400 MHz, DMSO-d6) δ: 10.30 (s, 1H, N8-H), 8.03 – 7.92 (m, 2H, C15-H, N9-H),7.58 – 7.49 (m, 2H, C19-H), 7.38 (t, J = 8.1 Hz, 1H, C20-H), 7.22 (ddd, J = 11.0, 9.0, 2.9 Hz,1H, C12-H), 7.01 – 6.94 (m, 1H, C14-H), 6.38 (br s, 2H, N16-H2), 4.65 (dd, J = 13.1, 8.8 Hz,1H, C6-H), 2.92 (dd, J = 15.8, 8.9 Hz, 1H, C5-H), 2.78 (dd, J = 15.8, 13.2 Hz, 1H, C5-H).13C NMR (100.5 MHz, DMSO-d6) δ: 169.3 (C7), 161.6 (C4), 158.6 (C2), 157.4 (dd, J =241.6, 11.5 Hz, C13), 155.9 (C8a), 154.31 (dd, J = 247.2, 12.4 Hz, C11), 135.6 (C17), 135.2(C18), 134.8 (C19), 129.8 (C20, C19), 128.3 (C19), 125.5 (dd, J = 9.0, 2.9 Hz, C15), 125.1 (dd,J = 11.1, 3.4 Hz, C10), 110.6 (dd, J = 21.3, 3.7 Hz, C14), 103.7 (dd, J = 26.6, 24.3 Hz, C12),84.6 (C4a), 43.2 (C6), 23.4 (C5). MP: >300ºC.Example 2: Synthesis of 4-Amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)amino)- pyrido[2,3-d]pyrimidin-7(8H)-one, compound (Id) 218.2 mg (0.5 mmol) of compound (Ii) as previously prepared in Example 1 were dissolved in 5 mL of anhydrous DMSO in a 10 mL round-bottom flask and then, 60 mg (1.5 mmol, 60% in mineral oil, 3 equiv.) of NaH were added. An anhydrous CaCl2 tube was added on top of the round-bottomed flask in order to protect the content from moisture. The reaction mixture was stirred at room temperature for 10 min, and then heated at 100 °C for 4h. After the heating time, the mixture cooled down to room temperature and was diluted with 100 mL of water, forming a dark brown suspension. AcOH was added dropwise to the suspension until neutral pH was reached: a heavier flocculation and a change of colour was observed from dark brown to orange. The suspension was filtered, successively washed with water, cold EtOH and EtOEt and dried under vacuum overnight, affording 190.5 mg (0.44 mmol, 88%) of the desired compound as a brownish solid.1H-NMR (400 MHz, DMSO- d6) δ: 11.76 (s, 1H, N8-H), 8.65 (s, 1H, N9-H), 8.02 (s, 1H, C5-H), 7.83 – 7.73 (m, 1H, C15-H), 7.63 – 7.42 (m, 2H, C19-H), 7.45 – 7.41 (dd, 1H, C20-H),7.33 – 7.19 (m, 3H, C14-H, N16-H2), 7.11 – 6.99 (m, 1H,C12-H).13C-NMR (100.5 MHz,DMSO- d6) δ: 161.4 (C7), 161.2 (C2), 160.3 (C8a), 156.4 (C4), 135.5 (C5), 135.4 (C10),135.3 (C17), 130.3 (C20), 128.5 (C19), 128.1 (C15), 128.0 (C18).124.1 (C11), 123.9 (C6), 121.6 (C13), 110.7 (C12), 104.1 (C14),91.3 (C4a). MP: >300ºC. Example 3: Synthesis of 4-amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one, compound (Ia) 1.56 g (3.595 mmol, 1 equiv.) of compound (Id) as previously prepared in Example 2 were dissolved in 51 mL of anhydrous DMSO in a 100 mL round-bottom flask, under argon atmosphere and then, 143.8 mg (3.595 mmol, 60% in mineral oil, 1 equiv.) of NaH were added. The reaction mixture was stirred at room temperature for 1 hour before theaddition of 225.1 µL (3.595 mmol) of MeI. The reaction was left overnight. After thereaction time, the mixture was diluted with 250 mL of water and a dark green suspension was formed. AcOH was added dropwise to the suspension until neutral pH was reached: a heavy flocculation and a change of colour was observed. The suspension was filtered, washed with cold EtOH and EtOEt and dried under vacuum overnight, affording 1.60 g (3.57 mmol, 99%) of the desired compound as a brownish solid. The compound could be purified with an automated flash chromatography (silica gel, 100% cyclohexane to 60:40% of cyclohexane:ethyl acetate).1H NMR (400 MHz, DMSO-d6) δ: 8.92 (s, 1H, N9-H), 8.08 (s, 1H, C5-H), 7.74 (td, J = 9.1,6.2 Hz, 1H, C15-H), 7.59 – 7.54 (m, 2H, C19-H), 7.46 – 7.40 (m, 1H, C20-H), 7,39 (br s, 2H,N16-H2), 7.30 (ddd, J = 10.8, 9.0, 2.9 Hz, 1H, C14-H), 7.11 – 7.03 (m, 1H, C12-H), 3.48 (s,3H, C -H ). 1321 3 C NMR (100.5 MHz, DMSO-d6) δ: 161.9 (C2), 160.5 (C7), 159.8 (C4), 158.1(dd, J = 243,2, 12.6 Hz, C11), 156.1 (C8a), 155,6 (dd, J = 248.7, 12.6 Hz, C13), 135.4 (C18),135.3 (C6), 134.0 (C5), 130.3 (C20), 128.0 (C19), 127.5 (dd, J = 9.5, 2.8 Hz, C15), 123.9 (dd,J = 11.7, 3.6 Hz, C10), 120.1 (C17), 110.8 (dd, J = 21.8, 3.6 Hz, C14), 104.0 (dd, J = 26.6,24,5 Hz, C12), 91.6 (C4a), 28.0 (C21). MP: 250,2 °C (DSC).Example 4: Synthesis of 4-Amino-6-(2,6-dichlorophenyl)-2-((2-methoxyphenyl)amino)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one, compound (Iq) 903.2 mg (2.1 mmol) of compound (II2) were mixed with 5.6 mL of anhydrous MeOH in a 5 mL microwave vial, and 109.4 mg (2.0 mmol) of NaOMe were added afterwards. The reaction mixture was then set to an oil bath and heated at 140°C during 40 min. Then, the product was filtered under reduced pressure, washed with water and diethyl ether, and dried overnight. A total of 740.10 mg (1.72 mmol, 82%) of the desired compound was afforded as a very little grey powder.1H-NMR (400 MHz, DMSO- d6) δ: 10.44 (s, 1H, N8-H), 8.59 (m, 1H, C12-H), 7.54 (m, J =8.1 Hz 2H, C20-H), 7.38 (t, J = 8.1 Hz, 1H, C21-H), 7.23 (s, 1H, N9-H), 6.98 (m, 1H, C15-H), 6.89 (m, 2H, C13 / C14-H), 6.53 (s, 2H, N17-H2), 4.68 (dd, J = 13.1, 8.9 Hz, 1H, C6-H), 3.88 (s, 3H, C16-H3), 2.95 (dd, J = 15.8, 8.9 Hz, 1H, C5-H), 2.79 (dd, J = 15.8, 13.2 Hz, 1H, C5-H).13C-NMR (100.5 MHz, DMSO- d6) δ: 169.7 (C7), 162.0 (C4), 158.3 (C2), 147.4 (C11),136.1 (C18), 135.7 (C19), 135.3 (C8a) 130.8 (C20), 130.5 (C21), 121.6 (C13-C14), 118.3 (C12), 110.6 (C ), 85.1 (C ), 56.2 (C ), 43.6 (C), 23.8 (C). IR v (cm-115 4a 16 6 5 max): 3495, 3373, 3276,3082, 2960, 1677, 1630, 1596, 1543, 1497, 1429, 1381, 1294, 1252, 1227, 1175, 1108, 1025, 827, 776, 743. MP: >300ºC. MS (70 eV, EI) m / z: 430.0830. Example 5: Synthesis of 4-Amino-6-(2,6-dichlorophenyl)-2-((2-methoxyphenyl)amino)-pyrido[2,3-d]pyrimidin-7(8H)-one, compound (Io)112.7 g (0.3 mmol) of compound (Iq), prepared as described above in Example 4, were dissolved in 5 mL of anhydrous DMSO in a 10 mL round-bottom flask and then, 0.06 g (1.5 mmol, 60% in mineral oil) of NaH were added. An anhydrous CaCl2 tube was added on top of the round-bottomed flask in order to protect the content from moisture. The reaction mixture was stirred at room temperature for 10 min, and then heated at 100°C for 4h. After the heating time, the mixture cooled down to room temperature and was diluted with 100 mL of water, forming a dark brown suspension. AcOH was added dropwise to the suspension until neutral pH was reached: a heavier flocculation and a change of color was observed from dark brown to dark green. The suspension was filtered, washed with EtOH and EtOEt and dried under vacuum overnight, giving a total of 97.50 mg (0.3 mmol, 87%) of the desired compound as a dark brown solid.1H-NMR (400 MHz, DMSO- d) δ: 11.91 (s, 1H, N-H), 8.51 (dd, J = 7.9, 1.7 Hz, 1H, C -6 8 12H), 8.04 (s, 1H, C-H), 7.64 (s, 1H, N-H), 7.57 (d, J = 8.0 Hz, 2H, C -H), 7.50 – 7.39 (m,5 9 20133H, C -H, N -H), 7.07 – 6.87 (m, 3H, C -C -C ), 3.88 (s, 3H, C -H). C-NMR (100.521 17 2 13 14 15 16 3MHz, DMSO- d) δ: 161.7 (C), 161.6 (C), 159.7 (C ), 156.6 (C), 148.7 (C ), 135.9 (C),6 7 2 8a 4 11 5135.8 (C ), 135.4 (C), 130.8 (C ), 129.1 (C ), 128.5 (C ), 122.7 (C ), 122.4-121.019 6 21 20 18 10 -1 (C -C ), 120.3 (C ), 111.0 (C ), 91.8 (C ), 56.3 (C ). IR v (cm ): 3336, 3204, 2924,13 14 12 15 4a 16 max1637, 1614, 1558, 1528, 1448, 1427, 1291, 1255, 1220, 1189, 1109, 1023, 892, 789, 745.MP: >300ºC. MS (70 eV, EI) m / z: 428.0681. -8- 130.1 mg (0.3 mmol) of compound (Io), prepared as described above in Example 5, was dissolved in 4 mL of anhydrous DMSO in a 10 mL round-bottom flask and then, 16.4 mg (0.4 mmol, 60% in mineral oil) of NaH were added. An anhydrous CaCl2 tube was added on top of the round-bottom flask in order to protect the content from moisture. The reaction mixture was stirred at room temperature for 1 hour before the addition of 25 μL (0.4 mmol) of MeI. The reaction was left overnight. After the reaction time, the mixture was diluted with 100 mL of water and a dark green suspension was formed. AcOH was added dropwise to the suspension until neutral pH was reached: a heavier flocculation and a change of color was observed. The suspension was filtered, washed with EtOH and EtOEt and dried under vacuum overnight, giving a total of 106.4 mg (0.2 mmol, 79%) of the desired compound as a brown solid.1H-NMR (400 MHz, DMSO- d6) δ: 8.33 (dt, J = 7.8, 1.5 Hz, 1H, C12-H), 8.10 (d, J = 1.2 Hz,1H, C5-H), 7.85 (s, 1H, N9-H), 7.62 – 7.54 (m, 2H, C20-H), 7.50 (s, 2H, N17-H2), 7.44 (ddd,J = 8.7, 7.4, 1.3 Hz, 1H, C21-H), 7.10 – 6.94 (m, 3H, C13-C14-C15), 3.89 (d, J = 1.2 Hz, 3H,C16-H3), 3.59 (d, J = 1.2 Hz, 3H, C22-H ).133C-NMR (100.5 MHz, DMSO- d6) δ: 162.24 (C7),160.9 (C4), 159.3 (C2), 156.5 (C8a), 149.2 (C11), 135.8 (C18), 135.7 (C6), 134.4 (C5), 130.8 (C21), 128.9 (C19), 128.5 (C20), 123.2 (C13), 120.9 (C14), 120.8 (C12), 120.7 (C10), 111.2 (C15), 92.1 (C4a), 56.3 (C16), 28.8 (C22). IR vmax (cm-1): 3408, 3322, 3191, 1627, 1529, 1456, 1430, 1349, 1288, 1242, 1198, 1103, 1026, 918, 825, 799, 740. MP: >300ºC. MS(70 eV, EI) m / z: 442.08374-Amino-6-(2,6- -8- 7(8H)-one, (IL) of formula (I1)136.1 mg (0.3 mmol) of compound (Ik) as previously prepared in Example 6 weredissolved in 0.8 mL of 48% HBr and 1.7 mL of propanoic acid and the mixture was heated at reflux overnight under argon atmosphere. Then, after cooling the reaction to room temperature, a saturated solution of NaHCO3 was added dropwise to the suspension until a neutral pH was reached. Finally, the solid appeared was filtered and dried under vacuum overnight affording 59.7 mg (0.1 mmol, 45%) of the desired compound as a grey solid.1H NMR (400 MHz, DMSO-d6) δ: 10.01 (s, 1H, OH), 8.13 (d, J = 7.8 Hz, 1H, C12-H), 8.09(s, 1H, C5-H), 8.00 (s, 1H, N9-H), 7.60 – 7.55 (m, 2H, C19-H), 7.52 (s, 2H, N17-H2), 7.46 –7.41 (m, 1H, C21-H), 6.89 (dd, J = 3.9, 0.9 Hz, 2H, C13-H, C14-H), 6.86 – 6.80 (m, 1H, C15-H), 3.58 (s, 3H, C22-H3). 13C NMR (100.5 MHz, DMSO-d6) δ: 172.9 (C7), 172.4(C4) , 158.9(C2), 156.1 (C8a), 135.3 (C18), 135.3 (C6), 133.9 (C5), 128.0 (C19-C20), 127.6 (C13), 92.4 (C4a), 28.3 (C22). IR vmax (cm-1): 3342, 3213, 1644, 1618, 1551, 1497, 1452, 1301, 1191,1011, 801, 778, 759. MP: >300ºC. MS (70 eV, EI) m / z: 428.07 [M+1]+. Anal. calculated forC20H15Cl2N5O2: C, 56.09; H, 3.53; N, 16.35. Found: C, 56.68; H, 3.30; N 16.54. Example 8: Synthesis of 4-Amino-6-(2,6-dichlorophenyl)-2-((4-methoxyphenyl)amino)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one, compound (Ir) 817.3 mg (2.0 mmol) of the compound of formula (II1) as previously prepared were mixed with 5.6 mL of anhydrous MeOH in a 5 mL microwave vial, and 109.4 mg (2.0 mmol) of NaOMe were added. The reaction mixture was then set to an oil bath and heated at 140°C for 40 min. Then, the product was filtered under reduced pressure, washed with water and diethyl ether, and dried in vacuo, affording 775.9 mg (1.8 mmol, 89%) of the desired compound as a light grey solid.1H-NMR (400 MHz, DMSO-d6) δ: 10.29 (s, 1H, N8-H), 8.57 (s, 1H, N9-H), 7.71 (m, 2H,C11-H), 7.54 (ddd, J = 8.1 Hz, 2H, C18-H), 7.38 (t, J = 8.1 Hz, 1H, C19-H), 6.8 (m, 2H, C12- H), 6.31 (s, 2H, N15-H2), 4.66 (dd, J = 13.1, 8.9 Hz, 1H, C6H), 3.70 (s, 3H, C14-H3), 2.94 (dd, J = 15.8, 8.9 Hz, 1H, C5-H), 2.79 (dd, J = 15.7, 13.2 Hz, 1H, C5-H).13C-NMR (100.5MHz, DMSO- d6) δ: 169.9 (C7), 161.9 (C4), 158.9 (C2), 154.0 (C13), 136.2 (C17), 135.7(C16), 135.2 (C8a), 130.2 (C10-C19), 128.7 (C18), 120.4 (C11), 113.9 (C12), 84.3 (C4a), 55.6(C -14), 43.8 (C6), 23.8 (C5). IR vmax (cm1): 3462, 3184, 2931, 2835, 1684, 1640, 1570,1541, 1510, 1434, 1376, 1293, 1241, 1162, 1033, 851, 802, 741. Elemental analysis for C20H17Cl2N5O2: Calc: C, 55.83; H, 3.98; N, 16.28. Found: C, 55.83; H, 4.02; N 16.08. MP:>300ºC. MS (70 eV, EI) m / z: 430.0834.Example 9: Synthesis of 4-Amino-6-(2,6-dichlorophenyl)-2-((4-methoxyphenyl)amino)-pyrido[2,3-d]pyrimidin-7(8H)-one, compound (Ip)213.6 g (0.5 mmol) of compound (Ir), prepared as described above in Example 8, were dissolved in 5 mL of anhydrous DMSO in a 10 mL round-bottom flask and then, 0.06 g (1.5 mmol, 60% in mineral oil) of NaH were added. An anhydrous CaCl2 tube was added on top of the round-bottomed flask in order to protect the content from moisture. The reaction mixture was stirred at room temperature for 10 min, and then heated at 100°C for 4h. After the heating time, the mixture cooled down to room temperature and was diluted with 100 mL of water, forming a dark brown suspension. AcOH was added dropwise to the suspension until neutral pH was reached: a heavier flocculation and a change of color was observed from dark brown to dark green. The suspension was filtered, washed with EtOH and EtOEt and dried under vacuum overnight, affording 201.7 mg (0.5 mmol, 95%) of the desired compound as a dark brown solid.1H-NMR (400 MHz, DMSO- d6) δ: 11.76 (s, 1H, N8-H), 9.10 (s, 1H, N9-H), 8.02 (s, 1H, C5-H), 7.75 (m, 2H, C11-H), 7.57 (dd, J = 8.1, 0.6 Hz, 2H, C18-H), 7.42 (m, 1H, C19-H), 7.25 (br s, 2H, N15-H2), 6.83 (m, 2H, C12-H), 3.72 (s, 3H, C14-H3).13C-NMR (100.5 MHz, DMSO- d6)δ: 161.3 (C7), 161.3 (C4), 159.7 (C2), 156.2 (C8a), 154.3 (C13), 135.6 (C5), 135.4 (C17),135.1 (C16), 133.6 (C6), 130.2 (C19), 128.1 (C18), 121.2 (C11), 113.6 (C12), 91.1 (C4a), 56.2 (C14). IR vmax (cm-1): 2926, 1601, 1558, 1529, 1508, 1428, 1233, 1175, 1029, 800, 775.MP: >300ºC. MS (70 eV, EI) m / z: 428.0685. d]pyrimidin-7(8H)-one, compound (Im)175.4 mg (0.4 mmol) of compound (Ip), prepared as described above in Example 9, was dissolved in 4 mL of anhydrous DMSO in a 10 mL round-bottom flask and then, 16.4 mg (0.4 mmol, 60% in mineral oil) of NaH were added. An anhydrous CaCl2 tube was added on top of the round-bottom flask in order to protect the content from moisture. The reaction mixture was stirred at room temperature for 1 hour before the addition of 25 μL (0.4 mmol) of MeI. The reaction was left overnight. After the reaction time, the mixture was diluted with 100 mL of water and a dark green suspension was formed. AcOH was added dropwise to the suspension until neutral pH was reached: a heavier flocculation and a change of color was observed. The suspension was filtered, washed with EtOH and EtOEt and dried under vacuum overnight, affording 104.1 mg (0.2 mmol, 57%) of the desired compound as a dark brown solid.1H-NMR (400 MHz, DMSO- d6) δ: 9.27 (s, 1H, N9-H), 8.07 (s, 1H, C5-H), 7.75 – 7.67 (m,2H, C11-H), 7.61 – 7.54 (m, 2H, C18-H), 7.43 (dd, J = 8.6, 7.5 Hz, 1H, C19-H), 7.33 (s, 2H,N1 -H ), 6.92 – 6.85 (m, 2H, C -H), 3.73 (s, 3H, C -H ), 3.58 (s, 3H, C -H ). 135 2 12 14 3 20 3 C-NMR(100.5 MHz, DMSO- d6) δ: 161.7 (C7), 160.59 (C2), 159.16 (C4), 156.2 (C8a), 154.5 (C13),135.5 (C6), 135.4 (C16), 134.0 (C5), 133.5 (C17), 130.3 (C19), 128.1 (C18), 121.4 (C11), 119.7 (C10), 113.7 (C12), 91.5 (C4a), 55.2 (C14), 28.3 (C20). IR vmax (cm-1): 3316, 3179, 2952, 1615, 1556, 1508, 1461, 1429, 1297, 1244, 1177, 1030, 827, 798, 779. MP: >300ºC. MS(70 eV, EI) m / z: 442.4836.-8- 110.0 mg (0.3 mmol) of compound (Im) as previously prepared in Example 10 were dissolved in 0.8 mL of 48% HBr and 1.7 mL of propanoic acid and the mixture was heated at reflux overnight under argon atmosphere. Then, after cooling the reaction to room temperature, a saturated solution of NaHCO3 was added dropwise to the suspension until a neutral pH was reached. Finally, the solid appeared was filtered and dried under vacuum overnight affording 30.4 mg (0.071 mmol, 29%) of the desired compound as a grey solid.1H NMR (400 MHz, DMSO-d6) δ: 9.14 (s, 1H, N9-H), 9.06 (s, 1H, OH), 8.06 (s, 1H, C5-H),7.59 – 7.53 (m, 4H, C11-H, C18-H), 7.43 (dd, J = 8.7, 7.5 Hz, 1H, C19-H), 7.29 (s, 2H, N15-H2), 6.75 – 6.65 (m, 2H, C12-H), 3.56 (s, 3H, C20-H3).13C NMR (100.5 MHz, DMSO-d6) δ: 173.6 (C ), 173.3 (C ), 172.9 (C ), 160.9 (C ), 159.6 (C ), 135.9 (C ), 134.4 (C ), 132.37 2 4 8a 13 6 5 (C ), 130.6 (C ), 128.5 (C ), 122.2 (C ), 115.3 (C ), 28.8(C ). IR v (cm-117 19 18 11 10 20 max): 3208,1616, 1556, 1524, 1465, 1428, 1277, 1192, 1011, 828, 798, 779. MP: >300ºC. MS (70 eV,+ EI) m / z: 428.06 [M+1] . Anal. calculated for C H Cl N O: C, 56.09; H, 3.53; N, 16.35.20 15 2 5 2 Found: C, 56.81; H, 3.11; N 16.16. Example 12: Industrial synthesis of 4-amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)- amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one, compound (Ia) In a round bottom flask containing 6.10 g (44.17 mmol, 1.01 eq) of K CO in 80 mL of2 3 DMF, 7.2 mL (43.72 mmol) of a compound of formula (VI), namely methyl 2-(2-chloro-6- methylphenyl)acetate, were added followed by 1.71 g (56.90 mmol, 1.30 eq) of p-CH O. In2 this step (a), the mixture was stirred at 100°C during 3h. The reaction crude was then cooled down to room temperature and two-thirds of the solvent were evaporated at reduced pressure.80 mL of water were then added, and the solution was stirred at room temperature until the K CO was completely dissolved. The solution was then extracted2 3 with 3 x 55 mL of AcOEt and the combined organic phases were washed with 2 x 55 mL of water and 2 x 55 mL of LiCl solution. The organic phase was then dried with anhydrous MgSO and evaporated under reduced pressure. The final product, a compound of4 formula (V), namely methyl 2-(2-chloro-6-methylphenyl)acrylate, was obtained as an amber-coloured liquid (8.95 g, 38.71 mmol, 89% yield). To a round bottom flask containing 8.95 g (38.71 mmol) of a compound of formula (V),namely methyl 2-(2-chloro-6-methylphenyl)acrylate, in 103 mL of anhydrous MeOH underAr atmosphere, 2.58 g (39.11 mmol, 1.01 eq.) of malononitrile and 3.98 g (73.65 mmol, 1.90 eq) of NaOMe were added. In this step (b), the solution was then left at reflux for 2h and 30 min. After that time the solution was cooled to room temperature and half of the solvent was removed under reduced pressure.150 mL of water were then added and neutralized with 55 mL of HCl 1M. The solid that appeared was then filtered and washed with 2 x 120 mL of water. The product, a compound of formula (IV), namely 5-(2,6- dichlorophenyl)-2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitrile, was obtained as a beige solid (10.84 g, 36.47 mmol, 94%). In a round bottom flask containing 10.75 g (36.19 mmol) of compound of formula (IV), namely 5-(2,6-dichlorophenyl)-2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitrile, in 168 mL of anhydrous 1,4-dioxane under Ar atmosphere, 1.67 g (39.83 mmol, 1.10 eq.) of NH CN and 2.16 g (39.90 mmol, 1.10 eq) of NaOMe were added. In this step (c), the2 reaction was stirred at reflux temperature for 4h and 30 min. After this time, the solution was cooled down at room temperature. The product of this reaction, a compound of formula (IIIA), namely (Sodium N-(3-cyano-5-(2,6-dichlorophenyl)-6-oxo-1,4,5,6- tetrahydropyridin-2-yl)cyanamide), was not isolated, and the obtained solution was used directly to the following step (d). To a solution of 36.19 mmol of a compound of formula (IIIA), namely (Sodium N-(3-cyano- 5-(2,6-dichlorophenyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)cyanamide, in 168 mL of dioxane, 181 mL of 48% HBr (aq) were added (5 mL / mmol of Sodium N-(3-cyano-5-(2,6- dichlorophenyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)cyanamide). In this step (d), the mixture was then stirred at room temperature under normal atmosphere during 3h. After that time, the solution was cooled down at 0°C and 140 mL of 30% NH3(aq) were added to neutralize the solution, taking into account that the pH could not be above 8. The solid formed was then filtered and washed with 2x120mL of water. Once the solid was dry, it was suspended in acetone and filtered to eliminate the impurities. The product, a compound of formula (IIA), namely (4-amino-2-bromo-6-(2,6-dichlorophenyl)-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one), was obtained as a white solid (10.95 g, 28.21 mmol, 78% yield).1H NMR (400 MHz, DMSO-d6) δ: 10.80 (s, 1H, H6), 7.52 (ddd, J = 12.1, 8.1, 1.3 Hz, 2H,H9, 9’), 7.37 (t, J = 8.1 Hz, 1H, H10), 7.11 (s, 2H, H14), 4.75 (dd, J = 13.1, 9.0 Hz, 1H, H2),2.92 (dd, J = 16.5, 9.0 Hz, 1H, H3), 2.74 (dd, J = 16.5, 13.1 Hz, 1H, H3’) ppm.13C NMR (100.5 MHz, DMSO-d6) δ: 169.37 (C1), 162.49 (C5, 11), 156.80 (C5, 11), 149.28 (C13), 135.70 (C7, 8, 8’), 135.66 (C7, 8, 8’), 135.22 (C7, 8, 8’), 130.41 (C10), 130.25 (C9), 128.82 (C9’), 91.69 (C4), 42.81 (C2), 23.68 (C3) ppm. In a double neck round bottom flask containing 3.00 g (7.74 mmol) of a compound of formula (IIA), namely 4-amino-2-bromo-6-(2,6-dichlorophenyl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one, in 43 mL of anhydrous DMSO in Ar atmosphere with no light, 0.34 g (8.50 mmol, 1.1 eq) of NaH were added. In this step (e), the solution was stirred during 1 to 2 h at room temperature and 0.53 mL (8.51 mmol, 1.1 eq.) of CH3I were then added. Finally, the mixture was stirred at room temperature overnight without light. The product, a compound of formula (IIB), namely (4-amino-2-bromo-6-(2,6-dichlorophenyl)-8-methyl-5,8- dihydropyrido[2,3-d]pyrimidin-7(6H)-one), was not isolated, and the solution was used directly in the next step (f). In step (f), to one of the entries of the double neck round bottom flask a tube with air flow was connected, leaving the other for an outlet, and the solution was left to stir at RT for 30 minutes. To the solution of 7.74 mmol of a compound of formula (IIB), namely 4-amino-2- bromo-6-(2,6-dichlorophenyl)-8-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one, in 43 mL of DMSO, 0.93 g (23.2 mmol, 3.00 eq.) of 60% NaH were added and the resulting solution was stirred with the air flow at room temperature for 4h. After this time, once the reaction was completed (monitoring with TLC) 100 mL of brine were added to the solution, and the formed solid was then filtered and washed 2x100 mL of water. The product, a compound of formula (IIC), namely (4-amino-2-bromo-6-(2,6-dichlorophenyl)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one), was suspended in DCM and filtered to eliminate the grease. The solid was obtained as a yellow solid (2.11 g, 5.26 mmol, 68% yield.)1H NMR (400 MHz, DMSO-d6) δ: 8.21 (s, 1H, H6), 8.33 – 7.99 (m, 2H, NH2), 7.61 – 7.56(m, 2H, H11), 7.46 (dd, J = 8.8, 7.4 Hz, 1H, H12), 3.55 (s, 3H, H1) ppm.13C NMR (100.5MHz, DMSO-d6) δ: 162.10 (C4), 160.28 (C2, 8), 155.28 (C2, 8), 152.25 (C3), 135.24 (C10),134.69 (C9), 134.09 (C6), 131.31 (C12), 128.61(C11), 126.35 (C7), 95.40 (C5), 29.18 (C1) ppm. In step (g), in a round bottom flask containing 1.50 g (3.75 mmol) of a compound of formula (IIC), namely 4-amino-2-bromo-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3- d]pyrimidin-7(8H)-one, in 38 mL of ethylene glycol, 0.80 mL (7.88 mmol, 2.10 eq) of 2,4- difluoroaniline were added under argon atmosphere. The suspension was then stirred at 180°C with no light during 2h. After this time, the brown solution was cooled down to room temperature and poured over 100 mL of brine. The obtained beige solid was then filtered and washed with 2x100mL of water. The desired 4-amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)-amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one, compound (Ia) wasobtained as a beige solid (1.64 g, 3.66 mmol, 98% yield).1H NMR (400 MHz, DMSO-d6) δ: 8.92 (s, 1H, N9-H), 8.08 (s, 1H, C5-H), 7.74 (td, J = 9.1,6.2 Hz, 1H, C15-H), 7.59 – 7.54 (m, 2H, C19-H), 7.46 – 7.40 (m, 1H, C20-H), 7,39 (br s, 2H,N16-H2), 7.30 (ddd, J = 10.8, 9.0, 2.9 Hz, 1H, C14-H), 7.11 – 7.03 (m, 1H, C12-H), 3.48 (s,3H, C -H ). 1321 3 C NMR (100.5 MHz, DMSO-d6) δ: 161.9 (C2), 160.5 (C7), 159.8 (C4), 158.1(dd, J = 243,2, 12.6 Hz, C11), 156.1 (C8a), 155,6 (dd, J = 248.7, 12.6 Hz, C13), 135.4 (C18),135.3 (C6), 134.0 (C5), 130.3 (C20), 128.0 (C19), 127.5 (dd, J = 9.5, 2.8 Hz, C15), 123.9 (dd,J = 11.7, 3.6 Hz, C10), 120.1 (C17), 110.8 (dd, J = 21.8, 3.6 Hz, C14), 104.0 (dd, J = 26.6,24,5 Hz, C12), 91.6 (C4a), 28.0 (C21). -2-((4-fluoro-2- 1.1086 g (2.5 mmol) of compound (II3) were mixed with 5.6 mL of anhydrous MeOH in a 5 mL microwave vial, and 109.4 mg (2.0 mmol) of NaOMe were added afterwards. The reaction mixture was then set to an oil bath and heated at 140°C during 40 min. Then, the product was filtered under reduced pressure, washed with water and diethyl ether, and dried overnight. A total of 798.3 mg (1.8 mmol, 72%) of the desired compound was afforded as a fine white powder.1H-NMR (400 MHz, DMSO- d6) δ: 10.41 (s, 1H, N8-H), 8.49 (dd, J = 9.0, 6.4 Hz, 1H, C15-H), 7.53 (ddd, J = 13.7, 8.1, 1.3 Hz, 2H, C20-H), 7.38 (t, J = 8.1 Hz, 1H, C21-H), 7.14 (s, 1H, N9-H), 6.93 (dd, J = 10.7, 2.8 Hz, 1H, C12-H), 6.67 (td, J = 8.7, 2.8 Hz, 1H, C14-H), 6.51 (s, 2H, N17-H2), 4.67 (dd, J = 13.1, 8.9 Hz, 1H, C6-H), 3.88 (d, J = 1.6 Hz, 3H, C16-H3), 2.94 (dd, J = 15.8, 8.9 Hz, 1H, C5-H), 2.78 (dd, J = 15.8, 13.1 Hz, 1H, C5-H).13C-NMR(100.5 MHz, DMSO- d6) δ: 169.3 (C7), 161.6 (C2), 158.2 (C13), 157.9 (C8a), 155.8 (C4),148.5 (C11), 135.6 (C18), 135.2 (C21), 134.8 (C18), 129.8 (C20), 128.3 (C19), 126.0 (C10), 119.0 (C2), 118.94 (C15), 105.7 (C14), 99.2 (C12), 84.6 (C4a), 56.3 (C16), 43.2 (C6), 23.4 (C5). IR vmax (cm-1): 3496, 3373, 3277, 3082, 2933, 1679, 1630, 1573, 1544, 153, 1433, 1412,1380, 1324, 1264, 1228, 1150, 1033, 948, 839, 774, 742. Elemental analysis for C20H16N5OFCl2: Calc: C, 53.59; H, 3.60; N, 15.62. Found: C, 53.58; H, 3.60; N, 15.51. MP:>300ºC. MS (70 eV, EI) m / z: 448.7391.Example 14: Synthesis of 4-amino-6-(2,6-dichlorophenyl)-2-((2- methoxyphenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, compound (Ie) 441 g (1.0 mmol) of compound (Ij), prepared as described above in Example 13, were dissolved in 5 mL of anhydrous DMSO in a 10 mL round-bottom flask and then, 0.06 g (1.5 mmol, 60% in mineral oil) of NaH were added. An anhydrous CaCl2 tube was added on top of the round-bottomed flask in order to protect the content from moisture. The reaction mixture was stirred at room temperature for 10 min, and then heated at 100°C for 4h. After the heating time, the mixture cooled down to room temperature and was dilutedwith 100 mL of water, forming a dark brown suspension. AcOH was added dropwise to thesuspension until neutral pH was reached: a heavier flocculation and a change of color was observed from dark brown to dark green. The suspension was filtered, washed with EtOH and EtOEt and dried under vacuum overnight, giving a total of 390.90 mg (0.88 mmol, 89%) of the desired compound as a brownish solid.1H-NMR (400 MHz, DMSO- d6) δ: 11.87 (s, 1H, N8-H), 8.32 (dd, J = 8.9, 6.4 Hz, 1H, C15-H), 8.03 (s, 1H, C5-H), 7.66 (s, 1H, N9-H), 7.59 – 7.54 (m, 2H, C20-H), 7.47 – 7.36 (m, 3H,C21-H, N17-H2), 6.98 (dd, J = 10.7, 2.8 Hz, 1H, C12-H), 6.73 (td, J = 8.7, 2.8 Hz, 1H, C14-H),3.88 (s, 3H, C 116-H3). 3C-NMR (100.5 MHz, DMSO- d6) δ: 161.5 (C7), 161.4 (C2), 159.7(C8a), 156.6 (C4), 148.7 (C11), 135.7 (C5), 135.6 (C18), 135.2 (C21), 130.5 (C20), 128.2 (C19), 125.2 (C6), 122.0 (C15), 106.3 (C10), 106.1 (C14), 99.5 (C12), 91.5 (C4a), 56.3 (C16). IR vmax(cm-1): 3208, 2931, 2217, 1693, 1592, 1564, 1528, 1436, 1342, 1298, 1261, 1210, 949,780. MP: >300ºC. MS (70 eV, EI) m / z: 446.0564. Example 15: Synthesis of 4-amino-6-(2,6-dichlorophenyl)-2-((4-fluoro-2- methoxyphenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one, compound (Ib) First of all, a CaCl2 tube was prepared just before starting the reaction to minimize the presence of moisture. Then, 276.1 mg (0.6 mmol) of compound (Ie), prepared as described above in Example 14, was dissolved in 4 mL of anhydrous DMSO in a 10 mL round-bottom flask and then, 16.4 mg (0.4 mmol, 60% in mineral oil) of NaH were added. An anhydrous CaCl2 tube was added on top of the round-bottom flask in order to protect the content from moisture. The reaction mixture was stirred at room temperature for 1 hour before the addition of 38.5 μL (0.6 mmol) of MeI. The reaction was left to react overnight. The suspension was filtered, washed with EtOH and EtOEt and dried under vacuum overnight, giving the desired compound as a result. After the work-up, a total of 196.3 mg (0.4 mmol, 69%) of the desired compound was afforded as a brownish solid.1H-NMR (400 MHz, DMSO- d6) δ: 8.15 – 8.06 (m, 2H, C15-H, N9-H), 7.92 (d, J = 1.9 Hz,1H, C5-H), 7.57 (dd, J = 8.1, 2.4 Hz, 2H, C20-H), 7.50 – 7.40 (m, 3H, C21-H, N17-H2), 7.04 –6.96 (m, 1H, C12-H), 6.79 (t, J = 8.8 Hz, 1H, C14-H), 3.87 (d, J = 2.4 Hz, 3H, C16-H3), 3.54 (d, J = 2.4 Hz, 3H, C22-H3).13C-NMR (100.5 MHz, DMSO- d6) δ: 161.8 (C7), 160.5 (C2),157.3 (C8a), 156.1 (C4), 151.0 (C11), 135.4 (C6), 134.0 (C19), 130.3 (C5), 128.0 (C21), 124.8 (C20), 124.7 (C10), 122.4 (C15), 120.2 (C7), 106.09, 105.9 (C14), 99.73 (C12) 91.6 (C4a), 56.3 (C16), 28.3 (C ). IR v (cm-122 max): 3331, 3202, 2928, 1629, 1522, 1451, 1415, 1271, 1187,1148, 1038, 948, 837, 799. MP: >300ºC. MS (70 eV, EI) m / z: 460.0723.Example 16: Synthesis of 4-amino-6-(2,6-dichlorophenyl)-2-((4-fluoro-2- hydroxyphenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one, compound (Ic) In an additional step, 136.2 mg (0.3 mmol) of compound (Ib), prepared as describedabove in Example 15, were dissolved in 0.8 mL of HBr 48% and 1.7 mL of propanoic acidand the mixture was heated at reflux overnight under argon atmosphere Then, after cooling the reaction to room temperature, a saturated solution of NaHCO3 was added dropwise to the suspension until neutral pH was reached. Finally, the solid appeared was filtered and dried under vacuum overnight, giving a total of 59.7 mg (0.13 mmol, 45%) of the desired compound as a pale brown solid.1H-NMR (400 MHz, DMSO- d6) δ: 10.43 (s, 1H, OH), 8.08 (s, 1H, C5-H), 8.04 (s, 1H, N9-H), 7.96 (dd, J = 8.8, 6.5 Hz, 1H, C15-H), 7.57 (dd, J = 8.1, 0.6 Hz, 2H, C20-H), 7.49 (s, 2H,N17-H2), 7.43 (dd, J = 8.7, 7.5 Hz, 1H, C21-H), 6.72 – 6.62 (m, 2H, C12-H, C14-H), 3.55 (s,3H, C2 -H ). 132 3 C-NMR (100.5 MHz, DMSO- d6) δ: 160.5 (C7), 160.3 (C13), 156.3 (C8a),149.2 (C11), 135.4 (C18), 135.3 (C19), 134.0 (C5), 130.3 (C21), 128.1 (C20), 124.0 (C10),105.1 (C14), 100.6 (C12), 91.4 (C4a), 28.3 (C22). IR vmax (cm-1): 3339, 3193, 2939, 1616,1555, 1521, 1464, 1428, 1277, 1188, 1150, 1092, 1012, 970, 843, 798, 779. MP: >300ºC.MS (70 eV, EI) m / z: 446.0564.Example 17: Synthesis of 4-amino-2-((4-bromophenyl)amino)-6-(3,5-dimethoxyphenyl)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one, compound (Is) 4-amino-2-((4-bromophenyl)amino)-6-iodo-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one(Galve et al.2020) (400 mg, 0.847 mmol), 3,5-dimethoxyboronic acid (215.9 mg, 1.19mmol, 1.4 equiv.), caesium carbonate (0.969 g, 2.97 mmol, 3.5 equiv.) andtetrakis(triphenylphosphine)palladium(0) (19.6 mg, 2 mol %) with deoxygenated 1,4-dioxane / water (40 mL) mixture was heated at 90 °C for 2h. 238 mg (0.493 mmol, 58%) ofthe desired compound (spectroscopically pure) as a yellowish solid were obtained after the work up and an automatic flash chromatography (silica, from 100:0 to 30:70 ofcyclohexane / AcOEt as eluent in 50 min.; retention time of: 25 - 35 min.)1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.52 (s, 1H, H-N10), 8.3 (s, 1H, H-C5), 7.84 – 7.82(m, 2H, H-C12), 7.65 – 7.30 (m, 4H, H-N9, H-C13), 6.95 – 6.93 (m, 2H, H-C17), 6.48 – 6.47(m, 1H, H-C19), 3.78 (s, 3H, H-C20), 3.57 (s, 3H, H-C15);13C NMR (100.5 MHz, DMSO-d6) δ (ppm): 161.7 (C7*), 161.6 (C4*), 159.9 (C18), 158.5 (C2), 155.21 (C8a*) 139.9 (C11), 138.8 (C16), 131.5 (C5), 131.1 (C13), 122.9 (C6), 121.23 (C12), 112.9 (C14), 106.8 (C17), 99.0 (C19), 92.3 (C4a), 55.2 (C20), 28.5 (C15); IR (KBr) νmax (cm-1): 3404, 3296, 1625, 1606, 1560,1517, 1451, 1403, 1204, 1152, 1070, 817, 796; mp (°C): 267 – 269; HRMS (ESI) (m / z):calcd [M+H]+: 482.0750; found [M+H]+: 482.0815. Example 18: Synthesis of 4-amino-2-((4-bromophenyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one, compound (It) Compound (Is) (200mg, 0.415 mmol) was added with 10 mL of acetonitrile anhydrous in a50mL round bottom flask. Then, sulphuryl chloride (0.080mL, 1.00 mmol) was added slowly and the mixture is stirred overnight at room temperature. The mixture was filtered under vacuum and the solid was washed with acetonitrile.155 mg (0.281 mmol, 68%) of the desired compound (spectroscopically pure) as a yellowish solid were obtained after automatic flash chromatography (silica, from 100:0 to 0:100 of cyclohexane / AcOEt aseluent in 40 min.; retention time of: 25 - 35 min.),1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.56 (s, 1H, H-N10), 8.02 (s, 1H, H-C5), 7.83 –7.81 (m, 1H, H-C12), 7.46 – 7.44 (m, 4H, H-C13+H-N9), 6.98 (s, 1H, H-C19), 3.96 (s, 8H,H-C20), 3.59 (s, 3H, H-C15). 13C NMR (100.6 MHz, DMSO-d6) δ (ppm): 161.6 (C4),160.4 (C7*), 158.8 (C2), 155.9 (C8a*), 154.2 (C18), 139.9 (C11), 136.5 (C16), 133.6 (C5), 131.1 (C13), 121.4 (C12), 121.0 (C6), 114.1 (C17), 113.0 (C14), 98.0 (C19), 91.7 (C4a),6.74 (C20), 28.4 (C15). IR (ATR) νmax (cm-1): 3453, 3035, 1627, 1572, 1515, 1346, 1211,1178, 1015, 822, 798, 742. MP (°C): >300. HRMS (APCI-FIA-QTOF) (m / z): calculated for[M]+: 548.9970 ; found [M+H]+: 550.0040. Example 19: Synthesis of 4-amino-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, compound (Ih) Compound (It) (190 mg, 0.345 mmol), L-proline (79.4 mg, 0.689 mmol), copper (I) iodide (65.7 mg, 0.345 mmol), sodium carbonate (42.0 mg, 0.396 mmol) and 1-methylpiperazine(0.77mL, 6.89mmol) in 5 mL of anhydrous DMSO was heated under microwave irradiationfor 16h at 80 °C. The resulting solution was cooled and water was added (200mL). The resulting precipitate was filtered, washed with water, and dried. After an automatic flash chromatography (silica, from 100:0 to 85:15 of dichloromethane / MeOH as eluent in 45 min.; retention time: 25 min.), 97.0 mg (0.170 mmol, 49%) spectroscopically pure 4- amino-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-2-((4-(4-methylpiperazin-1- yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Ih) as a yellowish solid.1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.18 (s, 1H, H-N10), 7.98 (s, 1H, H-C5), 7.67 –7.61 (m, 2H, H-C12), 7.26 (br s, 2H, H-N9), 6.98 (s, 1H, H-C19), 6.90 – 6.87 (m, 2H, H-C13), 3.95 (s, 8H, H-C20), 3.56 (s, 3H, H-C15), 3.07 (t, J = 5.0 Hz, 4H, H-C22), 2.46 (t, J= 4.9 Hz, 4H, H-C23), 2.22 (s, 3H, H-C25).13C NMR (100.5 MHz, DMSO-d6) δ (ppm):161.5 (C4), 160.4 (C7*), 159.0 (C2), 156.1 (C8a*), 154.2 (C18), 146.3 (C14), 136.7 (C16), 133.6 (C5), 132.3 (C11), 120.9 (C12), 120.0 (C6), 115.7 (C13), 114.2 (C17), 97.9 (C19),91.4 (C4a), 56.7 (C20), 54.7 (C23), 48.8 (C22), 45.8 (C25), 28.7 (C15). FTIR (ATR) νmax(cm-1): 3292, 3186, 2938, 1631, 1574, 1511, 1453, 1343, 1235, 1213, 1005, 816, 797.mp (°C): 274 – 276 (decomp.) HRMS (ESI) (m / z): calcd for [M+H]+: 570.1709; found[M+H]+: 570.1741. 2. Study of metabolism of compounds of the inventionIn-vitro Liver Microsomal Stability: A stock solution of the given compound at 10 mM inDMSO (HPLC / MS grade, Sigma Aldrich) is prepared by weighing 1-2 mg of the compoundunder study in an Eppendorf tube using a high precision analytical balance (M5000P, Sartorius). For each incubation trial, place 713 µL of deionized water, 200 µL ofphosphate buffer saline (PBS, pH = 7.4), 50 µL of NADPH solution A (Corning®Gentest™ NADPH Regenerating System Solution A, ref. 451220), 10 µL of NADPH ofsolution B (Corning® Gentest™ NADPH Regenerating System Solution B, ref.451200),and 2 µL of drug stock solution into a 1.5 mL Eppendorf (each compound is prepared in duplicate). Incubate each sample at 37 ºC for 5 minutes in an Eppendorf ThermoMixer.The reaction is initiated by the addition of 25 µL of pooled male rat liver microsomes(Corning® Gentest™ Rat Liver Microsomes Pooled Male (Sprague-Dawley), 20mg / mL,452501). At desired time point (0, 5, 15, 30 and 60 min), transferred 100 µL of the sample into a vial containing 100 µL of acetonitrile (HPLC / MS grade, VWR) in ice. Centrifuge each quenched sample at 3000 rpm for 5 minutes or until there is a contained pellet at the bottom of each tube. Transfer the supernatant to HPLC vial. Analyze the metabolic profile using HPLC-MS / MS equipment. Monitor the parent compound at the different time points:0, 5-, 15-, 30- and 60-min. Convert data to % of remaining compound by dividing by thetime zero concentration value. Establish the mass of the potential metabolites for identification. Chromatographic Method: Equipment: Exion 1.0 AD coupled to a X500B QTOF System, SCIEX. Column: Phenomenex Luna Omega 1.6 mm Polar C18 (100 x 2.1 mm). Injection volume: 3 µL. Flow rate: 0.4 mL / min. Tcolumn: 40ºC. Tsampler: 15 ºC. Gradient: Time %A %B (min) (ACN[H+]) (H2O[H+]) 0.00 90.0 10.01.00 90.0 10.09.00 1.0 99.011.00 1.0 99.011.10 90.0 10.015.00 90.0 10.0Detection: Mode: SWATH scan with a combination of a full-scan TOF spectrum (100 – 1000 Da). Ion source: Turbo Electro Spray (+). Curtain gas: 35 psi. CAD gas: 9. Ion source gas 1: 60 psi. Ion source gas 2: 60 psi. Temperature: 500 ºC. Spray voltage: 5500 V. Declustering potential: 80 V. Collision energy: 10 V. CID parameters: Collision energy: 45 V, Collision energy spread: 25 V. Metabolic stability of compound (Ia) Compound (Ia) was incubated with rat-liver microsomes for 60 min. The metabolic stability profile is included in FIG.1, clearly showing how compound (Ia) remains stable, above 85%, during this period, in particular when compared to compound (X), known in the state of the art, which in the same period of time is reduced to 40%. It is not possible to identify metabolites of compound (Ia) due to its low metabolism. 3. Kinase Inhibition Profile The kinase inhibition profile of compounds was evaluated at Reaction Biology (https: / / www.reactionbiology.com / ) by measuring residual activity values at a concentration of 10 µM of the test compound in singlicate in front of the kinases: studiedherein using the following protocol:The compounds were dissolved to 1 x 10-3M stock solutions in 100% DMSO. Subsequently, 100 μL of each stock solution were transferred into wells A3-F12 of a microtiter plate (“master plate”). Wells A1-F2 were filled with 100 μL 100% DMSO as controls.5 x 10 μL of the master plate were aliquoted into 5 copy plates, which were stored at -20° Celsius until use. For the testing of each group of up to 8 kinases, one copy plate was used. In the process, 90 μL H2O were added to each well of a copy plate. To minimize precipitation, the H2O was added to each well only a few minutes before the transfer of the compound solutions into the assay plates. The plate was shaken thoroughly, resulting in a "compound dilution plate" with a compound concentration of 1 x 10-04M / 10 % DMSO. This plate was used for the transfer of 5 μL compound solution into the assay plates. The final volume of the assay was 50 μL. All compounds were tested at 1 x 10-05M in singlicate. The final DMSO concentration in the reaction cocktails was 1 % in all cases. The compound dilution plates were disposed at the end of each working day. A radiometric protein kinase assay (33PanQinase® Activity Assay) was used for measuring the kinase activity of the corresponding protein kinases. All kinase assays were performed in 96-well FlashPlatesTM from Perkin Elmer (Boston, MA, USA) in a 50 μL reaction volume. The reaction cocktail was pipetted in 4 steps in the following order: 10 μL of non-radioactive ATP solution (in H2O); 25 μL of assay buffer / [^-33P]-ATP mixture; 5 μL of test sample in 10% DMSO; 10 μL of enzyme / substrate mixture. The assay for all protein kinases contained 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3 mM MnCl2, 3 μM Na-orthovanadate, 1.2 mM DTT, ATP (variable amounts, corresponding to the apparent ATP-Km of the respective kinase), [^-33P]-ATP (approx.8 x 1005cpm per well), protein kinase (variable amounts), and substrate (variable amounts). The protein kinase reaction cocktails were incubated at 30°C for 60 minutes. The reaction was stopped with 50 μL of 2 % (v / v) H3PO4, plates were aspirated and washed two times with 200 μL 0.9 % (w / v) NaCl. All assays were performed with a BeckmanCoulter Biomek 2000 / SL robotic system. Incorporation of33Pi (counting of “cpm”) was determined with a microplate scintillation counter (Microbeta, Wallac). All protein kinase assays were performed with a BeckmanCoulter Core robotic system. For each kinase, the median value of the cpm of six wells of column 1 of each assay plate was defined as "low control" (n=6). This value reflects unspecific binding of radioactivity tothe plate in the absence of a protein kinase but in the presence of the substrate.Additionally, for each kinase the median value of the cpm of six wells of column 2 of each assay plate was taken as the "high control", i.e. full activity in the absence of any inhibitor(n=6). The difference between high and low control of each enzyme was taken as 100 %activity. As part of the data evaluation the low control of each kinase was subtracted from the high control value as well as from their corresponding "compound values". The residual activity (in %) for each compound well was calculated by using the following formula:Res. Activity (%) = 100 X [(signal of compound – low control) / (high control – low control)]As a parameter for assay quality, the Z´-factor for the low and high controls of each assayplate (n = 8) was used (Zhang, et al. 1999). Reaction Biology´s criterion for repetition of anassay plate is a Z´-factor below 0.4. Z´-factors did not drop below 0.51, indicating an excellent assay quality. Inhibitory activity of compound (Ia) against intracellular TK receptors Compounds (Ia), (If), and (Ig) were submitted to Reaction Biology to be tested against the panel of membrane and cytosolic TKs and showed good inhibitory profile against the cytosolic TKs (ERK1, ERK2, JNK1, JNK2, p38alpha, and p38beta), in particular compound (Ia)’s inhibitory activity against p38alpha, and p38beta with residual activitiesbelow 15% both at 5 and 10 µM (Table 1). On the contrary, erlotinib (E) was found to bevirtually inactive against this group of kinases. The same happened with compound (X) previously described. Table 1: Compounds of the invention were evaluated at two concentrations, 5 and 10 µM, against a group of selected intracellular TK receptors obtained at Reaction Biology, showing good tyrosine kinase inhibitory activity results (lower than 50%).Compound (Ia) (If) (Ig) E (X)Concentration 5 µM 10 µM 5 µM 10 µM 5 µM 10 µM 5 µM 10 µM 5 µM 10 µMERK1 54 21 52 31 49 28 103 101 83 37ERK2 33 13 46 26 34 16 95 74 71 25JNK1 107 63 48 2 95 72 91 69 100 54JNK2 64 49 17 13 42 43 68 70 79 36p38alpha 11 5 7 5 39 22 74 77 64 22p38beta 14 5 26 16 48 27 87 103 64 33E = Erlotinib, X = 4-amino-6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)- one 4.2D and 3D In-vitro Biological Testing of TKIs2D Cell Culture: The human pancreatic ductal adenocarcinoma (PDAC) cell lines BxPC-3(EP-CL-0042, Elabscience, Houston, TX, USA) , PANC-1 (CRL-1469, ATCC, Manassas, VA, USA), and MiaPaCa-2 (85062806, ECAAC), and primary human normal dermal fibroblasts (hNDF) (C-12302, Promocell, Heidelberg, Germany), were cultured at 10,000 cells / cm2 for no more than 15 passages in DMEM (DMEM-HXA, Capricorn, Ebsdorfergrund, Germany) or RPMI (RPMI-XA, Capricorn) in the case of BxPC-3, supplemented with 10% Fetal Bovine Serum (FBS) (S1810; Biowest, Nuaillé, France), L- glutamine (X055, Biowest) and Penicillin / Streptomycin (P / S) (L0022, Biowest). Cultures were maintained at 37 °C and 5% CO2 in a humidified atmosphere.3D Cell Culture in the Self-Assembling Peptide Scaffold RAD16-I: The peptide RAD16-I(commercially available at 1% in water, PuraMatrixTM, 354250, Corning, New York, NY, USA) was diluted to a final concentration of 0.6% (v / v) in 10% (w / v) sucrose (S0389, Merck, St Louis, MO, USA). Meanwhile, cells were harvested by trypsinization and resuspended to 4·106cells / mL in 10% (w / v) sucrose, which is an isotonic and non-ionic medium that avoids peptide spontaneous assembly during the encapsulation process. The cell suspension was then mixed with an equal volume of 0.6% RAD16-I peptide solution to obtain a mixture of 2·106cells / mL and 0.3% RAD16-I. Next, 40 µL of cell / peptide suspension (80,000 cells) was loaded into wells of a 48-well plate previously filled with 500 µL of culture medium, which induced the peptide spontaneous self- assembly. The plate was left in the flow cabinet for 20 min to let the peptide gel and then placed in the incubator for 1 h. Medium was changed twice to favor the leaching of sucrose.3D cultures were maintained in DMEM or RPMI supplemented with 10% FBS, L- glutamine, P / S at 37 ºC and 5% CO2 in a humidified atmosphere, and medium was changed three times per week. Cells were cultured for 6 days to ensure adaptation to the 3D environment before being incubated with drugs and / or processed for protein extraction or MTT assay.MTT Assay for Cell Viability: MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide] (M5655, Merck) was used to assess cell viability in 2D and 3D cultures. To determine IC50, cells in 2D cultures were seeded at 10,000 cells / cm2and the drug was added the following day. For 3D cultures, cells were cultured for 6 days before adding the drug. In both cases (2D and 3D cultures), IC50 was calculated at 72 h from drug addition using MTT assay. For that, cell culture medium was aspirated and 200 μL (for 2D cultures) or 500 μL (for 3D cultures) of MTT reagent were added to a final concentration of 0.5 mg / mL in culture medium. Samples were incubated for 2 h (2D cultures) or 3 h (3D cultures) at 37 ºC and 5% CO2 in a humidified atmosphere. MTT solution was then removed, and cells were lysed with 200 µL of DMSO (D8418, Merck). Absorbance was read at 570 nm using a microplate reader (BiotekEpochTM, Biotek, Winooski, VT, USA). Activity of compound (Ia) against cancer cell viability and proliferationFor the in vitro evaluation, erlotinib was included in the assay for comparison purposesand as the control, respectively. In vitro evaluation of compound (Ia) against the PDAC cell lines PANC-1, MiaPaCa-2, and BxPC-3 was carried out in classical culture dishes (2D, MTT, 72 h). Surprisingly, the IC50 obtained were in the low µM range: 0.70 µM for PANC-1 (FIG.2a), 1.31 µM for MiaPaCa- 2 (FIG.2b), and 0.30 µM for BxPC-3 (FIG.2c). In our hands, erlotinib gave IC50 of 45, 40, and 10 µM for PANC-1, MiaPaCa-2, and BxPC-3, respectively (the values reported inIoannou, N., et al., 2011 are >20, >20, and 1.26 µM, respectively).Compound (Ia) was also tested in 3D cell cultures of PANC-1, MiaPaCa-2, BxPC-3, andprimary human normal dermal fibroblasts (hNDF) in RAD16-I prepared at 0.3% peptide concentration. The IC50 obtained were around 4 µM for PANC-1 (FIG.3a), MiaPaCa-2 (FIG.3b), and BxPC-3 (FIG.3c). In the same conditions the IC50 for erlotinib was >100 µM. 5. NanoBRET Target Engagement Assay To test if the good activity reports of the compounds of the invention were also influenced by targeting KRAS receptors, Surface Plasmon Resonance (SPR) protocol was used to establish the possible inhibition of KRAS (mutated Q61H) at the GTP binding site, determining a dissociation constant (Kd) of 29.6 μM, better than a described reference (4- (2-benzothiazolylthio)-3-chlorobenzenamine, compound BI-2852 (CAS no.2375482-51-0) that inhibits KRAS downstream signaling pathway RAF / MEK / ERK and RAF / PI3K / AKT (Kd = 702 μM). HEK293 cells were transfected with 1 µg LgBiT®-KRAS G12D vector, 1 µg SmBiT®- KRAS G12D vector, and 8 µg transfection carrier DNA; or 1 µg LgBiT®-KRAS G12C vector, 1 µg SmBiT®-KRAS G12C vector, and 8 µg transfection carrier DNA. HEK293 cells were transfected with 1 µg LgBiT®-KRAS G12V vector, 1 µg SmBiT®-KRAS G12V vector, and 8 µg transfection carrier DNA; or 1 µg LgBiT®-KRAS WT vector, 1 µg SmBiT®-KRAS WT vector, and 8 µg transfection carrier DNA. The transfected cells weretreated with test compound (starting at 100 µM, 10-dose with 3-fold dilution) and referencecompound BI-2852 (starting at 10 µM, 10-dose with 3-fold dilution). Target engagement was measured by NanoBRET assay. Curve fits were performed only when % NanoBret signal at the highest concentration of compounds was less than 55%. Cells: HEK293 cells from ATCC. Compound treatment time: 2 h. Assay format: 384-well format, 4000 cells / well. Inhibitory activity of compound (Ia) against KRAS receptors A sample of compound (Ia) was sent to Reaction Biology to carry out the NanoBRET Target Engagement Assay in HEK293 cells transiently transfected with KRAS WT, KRASG12C, and KRAS G12V-NanoLuc Fusion Vector. The results obtained (Table 2) showed IC50 for the inhibition of KRAS wild-type and some of the mutants in the range 17 to 42 μM, thus revealing a certain degree of interaction with such group of proteins. Table 2: NanoBRET Target Engagement Assay of compound (Ia) in HEK293 cells transiently transfected with KRAS WT, KRASG12C, KRASG12D and KRAS G12V- NanoLuc Fusion Vector IC50value (M) Compound \Target KRAS WT KRAS G12C KRAS G12VCompound (Ia) 4.19E-05 2.40E-05 1.70E-05BI-2852a 3.98E-07 6.10E-07 3.28E-07a: Compound BI-2852 (CAS no.2375482-51-0) is a KRAS inhibitor for the switch I / II pocket (SI / II-pocket) with nanomolar affinity. 6. Evaluation of compound (Ia) safety profile using Chick Chorioallantoic Membrane(CAM) assay as a preclinical in vivo model.IC50 value of compound (Ia) ranges from 1 to 4 µM in vitro, demonstrating significantly higher potency compared to the approved pancreatic cancer inhibitor erlotinib, whichexhibits an IC50 value between 45 and 100 µM. The safety profile of compound (Ia) wastested using the CAM assay as a preclinical in vivo model.Fertilized chicken eggs (Granja Santa Isabel, Spain) were incubated at 37.5 °C and 55% humidity for 12 days. On the 12thday of embryonic development, the eggshells were carefully opened, and treatment with increasing doses of compound (Ia) (that is, with 0.5,1, 2.5, and 5 µM) was administered daily for 4 consecutive days (days D1, D2, D3, D4).The eggs were weighed daily to monitor development. At the end of the experiment, on the 16thday, the embryos were sacrificed and weighted, together with 3 relevant organs (heart, liver, and brain). A visual evaluation of the embryos and their organs was also conducted to assess any macroscopic signs of toxicity. Experimental data recorded on the 16thday (day D5) indicate that there were no observable changes in the weight of the eggs over the different days of treatment, and no significant differences in embryo weight between the treatment arms (FIG.4). Of note, a decrease in egg weight was consistently observed across all groups, which can be attributed to the natural evaporation of water from the eggs. This decrease was expected and fell within the normal range, as observed in the control group. In parallel, we did observe an increase in the weights of the organs in the 2.5 µM and 5 µM treatment arms, albeit these changes were not statistically significant when comparedto the control group (FIG.5). This indicates that, despite some variation, there were nomajor differences in organ weight upon drug exposure. Thus, the treatment with thecompound (Ia) at the tested concentrations did not result in any substantial alteration ofembryonic development, including at the highest dose tested, suggesting a good safety profile of the compound. The results collectively and advantageously suggest that compound (Ia), even at higher doses, does not exhibit significant toxicity or adverse effects on the overall development and organogenesis of the chicken embryos. The consistency of the findings across different doses further supports the compound's safety. 7. In vivo biological activity of compound (Ia) by intraperitoneal route of administration using advanced preclinical models In vivo experiments with compound (Ia) were carried out with subcutaneous xenograftsderived from PANC-1, MiaPaCa-2, BxPC-3 cell lines, and a Patient-Derived OrthotopicXenograft (PDOX) model.7.1. Animal model and housing conditions For MiaPaCa-2, BxPC-3 and PDOX: Male athymic Nude-Fox1nu aged 6-8 weeks (Envigo) were housed in individually ventilated cages (IVCs) under specific pathogen-free (SPF) conditions. For PANC-1: Female athymic Nude-Fox1nu aged 6-8 weeks (Envigo) were housed in individually ventilated cages (IVCs) under specific pathogen-free (SPF) conditions.For all experiments: Each cage contained a maximum of 5 mice, with a controlledenvironment maintained at 22 ± 2°C, 40–60% relative humidity, and a 12-hour light / dark cycle. Standard autoclaved bedding and nesting material was provided, and animals had ad libitum access to irradiated chow and filtered water. Cage cleaning and bedding replacement were performed weekly. All procedures involving animals were approved by the Ethical Committee of Animal Experimentation of the Parc Científic de Barcelona (PCB) and Catalan Government (23-049-P4) and complied with the relevant ethical guidelines for the care and use of laboratory animals.7.2 Cell injection and randomization (PANC-1, MiaPaCa-2, BxPC-3)For PANC-1: Mycoplasma- and C. bovis -free Panc-1 cells (3x106 cells in 100 µl of PBS+100ul Matrigel) were injected into one or two flanks of athymic mice to generate subcutaneous tumors. When mean tumor size reached approximately 400 mm3, mice were randomized into six different groups to start treatments.For MiaPaCa-2: Mycoplasma- and C. bovis -free MIA PaCa cells (3x106 cells in 100 µl ofPBS+ 100ul Matrigel) were injected into one or two flanks of athymic mice to generate subcutaneous tumors. When mean tumor size reached approximately 600 mm3, mice were randomized into eight different groups to start treatments.For BxPC-3: Mycoplasma- and C. bovis -free BxPC-3 cells (3x106 cells in 100 µl of PBS+100ul Matrigel) were injected into two flanks of athymic mice to generate subcutaneous tumors. When mean tumor size reached approximately 400-500 mm3, mice were randomized into six different groups to start treatments. 7.3 Tumor implantation and randomization (PDOX) PDX tumors (XP0150008) were de-cryopreserved in athymic mice. Once tumors reached the desired volume, they were excised and cut into small fragments (approx.20 mm3). PDX tumor fragments were orthotopically implanted into the pancreas of 32 mice togenerate orthoxenografts / PDOX of pancreatic cancer. Approximately 3 weeks afterimplantation, 27 mice with well stablished orthotopic tumors were randomized and assigned to different groups in order to receive the different treatments. Randomization was based on tumor size assessed by an internal palpation scoring and performed at the level of individual animals. While mice remained housed in the same cages, each mouse within a cage was assigned to a different treatment group, ensuring that the experimental unit was the individual mouse. This approach enhances statistical robustness by aligning the experimental design with the statistical analysis, preventing pseudoreplication, minimizing cage effects, and ensuring the individual mouse remains the true experimental unit, thereby strengthening statistical validity and overall study rigor. 7.4 Tumor measurement and ethical endpoints Tumor dimensions were measured twice weekly using digital calipers, and tumor volume were calculated using the formula V=L×W2 / 2 where L represents the long axis and W the short axis of the tumor. Body weight and general behavior were monitored twice weekly. Mice were euthanized upon reaching any of the following humane endpoint criteria: weight loss greater than 20% of total body weight, tumor volume exceeding 3000 mm³, tumor ulceration, or any signs of distress. 7.5 Drugs and drug preparation -Vehicle: 10% DMSO + 10% Cremophor ® EL + 80% H20.- Compound (Ia): Each day before injection, it was weighted in glass vials andsuspended in 10% DMSO, followed by 10% Cremophor® EL, and 80% H20 toreach a concentration of 5 mg / ml (Dose: 50 mg / kg, Vol: 10 ml / kg). -5- Fluoracil (5Fu): The stock solution (50 mg / ml) was diluted 1:50 in saline to reacha concentration of 1 mg / ml (Dose: 50 mg / kg, Vol: 5 ml / kg). -Oxaliplatin (Oxa): The stock solution (5 mg / ml) was diluted 1:3.125 in H2O to reacha concentration of 1.6 mg / ml (Dose: 8 mg / kg, Vol: 5 ml / kg). -Selumetinib: It was suspended in DMSO at 50 mg / ml, aliquoted and kept at-20ºC. Each day, before injection, an aliquot was thawed and diluted 1:10 by adding 30% PEG300, 5% Tween® 80, and H2O to reach a concentration of 5 mg / ml (Dose: 50 mg / kg, Vol: 10 ml / kg). -Adagrasib: It was suspended in DMSO at 25 mg / ml, aliquoted and kept at-20ºC. Each day, before injection, an aliquot was thawed and diluted 1:10 by adding corn oil to reach a concentration of 2.5 mg / ml (Dose: 25 mg / kg, Vol: 10 ml / kg). -Crizotinib: It was suspended in DMSO at 25 mg / ml, aliquoted and kept at -20ºC.Each day, before injection, an aliquot was thawed and diluted 1:10 by adding 40% PEG300, 10% Tween® 80, and H2O to reach a concentration of 2.5 mg / ml (Dose: 25 mg / kg, Vol: 10 ml / kg). -Gefitinib: Each day, before injection, gefitinib was weighted and dissolved in 0.05%Tween® 80 and H2O to reach a concentration of 5 mg / ml (Dose: 50 mg / kg, Vol: 10 ml / kg). 7.6 Treatment groupsFor PANC-1 xenografts:- Group A: Vehicle. IP.5 days / week. 3 weeks (n=3- Group B: compound (Ia).50 mg / kg. IP.5 days / week. 3 weeks (n=5)- Group C: Selumetinib. 50 mg / kg. Oral. 5 days / week.3 weeks (n=4)- Group D: 5Fu + Oxa.50 +8 mg / kg. lP. Day 0 and 14 (5Fu)+ Day 0 (Oxa).3 week(n=3) -Group E: compound (Ia) + Selumetinib.50 +50 mg / kg. IP + Oral.5 days / week. 3weeks (n=5) -Group F: compound (Ia) + 5Fu + Oxa.50+50 +8 mg / kg. lP.5 days / week(compound (Ia) + Day 0 and 14 (5Fu) + Day 0 (Oxa). 3 weeks (n=4)For MiaPaCa-2 xenografts:- Group A: Vehicle. IP.5 days / week. 3 weeks (n=3)- Group B: compound (Ia).50 mg / kg. IP.5 days / week. 3 weeks (n=4)- Group C: Adagrasib. 25 mg / kg. Oral. 5 days / week.3 weeks (n=3)- Group D: Selumetinib. 50 mg / kg. Oral. 5 days / week.3 weeks (n=3)- Group E: 5Fu + Oxa.50 +8 mg / kg. lP. Day 0 and 14 (5Fu) + Day 0 (Oxa). 3 weeks(n=3) -Group F: compound (Ia) + Adagrasib. 50 + 25 mg / kg. IP + Oral.5 days / week. 3weeks (n=4) -Group G: compound (Ia) + Selumetinib.50 +50 mg / kg. IP + Oral.5 days / week. 3weeks (n=4) -Group H: compound (Ia) + 5Fu + Oxa.50+50+8 mg / kg. lP.5 days / week(compound (Ia) + Day 0 and 14 (5Fu) + Day 0 (Oxa).3 weeks (n=4)For BxPC-3 xenografts:- Group A: Vehicle IP.5 days / week. 3 weeks (n=3).- Group B: 5Fu + Oxa.50 +8 mg / kg. lP.. Day 0 and 14 (5Fu) + Day 0 (Oxa). 3 (n=3)- Group C: compound (Ia).50 mg / kg. IP.5 days / week. 3 weeks (n=3)- Group D: Selumetinib. 50 mg / kg. Oral. 5 days / week.3 weeks (n=3)- Group E: compound (Ia) + 5Fu + Oxa.50+50 + 8 mg / kg. lP.5 days / week(compound (Ia) + Day 0 and 14 (5Fu) + Day 0 (Oxa) (n=4) -Group F: compound (Ia) + Selumetinib. 50 +50 mg / kg. IP + Oral.5 days / week. 3weeks (n=3) For orthoxenograft / PDOX: -Group A: Vehicle. IP. 5 days / week.3 weeks (n=4).- Group B: compound (Ia). 50 mg / kg. IP. 5 days / week.3 weeks (n=5).- Group C: compound (Ia)+ 5Fu + Oxa.50+50 + 8 mg / kg. IP.5 days / week(compound (Ia) + Day 0 and 14 (5Fu) + Day 0 (Oxa).3 weeks (n=4) -Group D: compound (Ia)+ Selumetinib.50 + 50 mg / kg. IP + Oral.5 days / week. 3weeks (n=5). -Group E: compound (Ia)+ Crizotinib.50+ 25 mg / kg. IP + Oral.5 days / week.3weeks (n=4). -Group F: compound (Ia)+ Gefitinib. 50 + 50 mg / kg. IP + Oral. 5 days / week. 3weeks (n=5).7.7 Statistical analysesOne-way ANOVA t-test followed by Bonferroni post-hoc test was conducted to determine differences between groups in initial tumor volume and final tumor weight. Two-way repeated-measures ANOVA (RMANOVA) with Bonferroni’s multiple comparisons post-hoc test was used to determine differences in tumor volume and body weight over time between the different treatments. Statistical calculations were performed using Prism 5 software (version 5.03, GraphPad Software, Inc., La Jolla, USA).7.8 ResultsAn in vivo experiment using subcutaneous xenografts derived from MiaPaCa-2 cells (FIG. 6) shows that treatment with compound (Ia) as monotherapy leads to a statistically significant reduction in tumor volume compared to the control group (Vehicle). Notably, the antitumor effect of compound (Ia) is comparable to that achieved with the standard-of- care combination therapy of 5-fluorouracil and oxaliplatin (5Fu + Oxa). Among the monotherapies tested, selumetinib, a MEK inhibitor, and adagrasib, a specific inhibitor of the KRAS G12C mutation present in the MiaPaCa-2 cell line, produced a greater reduction in tumor volume, indicating a stronger therapeutic effect than either compound (Ia) or 5Fu+Oxa. Adagrasib, in particular, elicited a more robust antitumor response. However, complete tumor regression was not achieved with either targeted agent administered as monotherapy, highlighting the rationale for pursuing combination approaches to optimize therapeutic outcomes. In this context, combination studies involving compound (Ia) are supported by its favorable toxicity profile when administered as monotherapy, as well as by the complementary mechanisms of action of the various agents. The combinations of compound (Ia) with either adagrasib or selumetinib both resulted in a significant and marked reduction in tumor volume, with the compound (Ia) + adagrasib combination being notably more effective. Interestingly, the addition of compound (Ia) to the standard chemotherapyregimen (5Fu + Oxa) also led to tumor growth inhibition, although to a lesser extent thanthe combinations with the targeted agents. Final tumor weight measurements at the time of mouse sacrifice confirmed the superior efficacy of the combination treatments. Importantly, none of the three combination regimens showed increased toxicity, further supporting the feasibility of combining compound (Ia) with other therapeutic agents. These results suggest that compound (Ia), when used alone, shows antitumor activity similar to the standard treatment and to other therapies currently being tested in clinical trials for PDAC. However, its effect is much stronger when used in combination with othertreatments, suggesting it may be more effective as part of a combination therapy than onits own. In the case of PANC-1 xenografts (FIG.7), monotherapy with compound (Ia) demonstrated an antitumor effect comparable to that of the standard-of-care treatment(5Fu + oxaliplatin) and selumetinib. All three treatments resulted in similar levels of tumorcontrol, with no statistically significant differences observed among them. However, each treatment achieved a significant tumor regression compared to the control group (Vehicle). The combination of compound (Ia) with selumetinib or with 5Fu+oxaliplatin resulted in a further reduction in tumor size; however, these improvements were not statistically significant compared to the respective monotherapies. This is likely attributable more to numerical factors than to true biological differences and may be explained by the limited sample size of treated mice, combined with the variability in tumor sizes observed during the experiment. This observation is further supported by the analysis of tumor growth curves, which shows that the addition of compound (Ia) toselumetinib or to 5Fu + oxaliplatin leads to an earlier onset of statistically significant tumorgrowth inhibition. Specifically, significant differences compared to the control group(Vehicle) were observed on day 15 for compound (Ia) alone, on day 19 for the 5Fu +oxaliplatin combination, and on day 21 for selumetinib. In contrast, the combinations ofcompound (Ia) with 5Fu + oxaliplatin and with selumetinib showed significant antitumoreffects as early as day 5 and day 15, respectively. It is also important to note that, asobserved in the previous experiment, no increase in toxicity was detected in any of the combination regimens. In the case of BxPC-3 xenografts (FIG.8), the results, consistent with previous experiments, demonstrate that compound (Ia) administered as monotherapy exhibits therapeutic potency comparable to that of the standard chemotherapy treatment for PDAC(5Fu + oxaliplatin) and to selumetinib, which is currently under clinical investigation. Mostnotably, the data continue to reinforce the potential of compound (Ia) when used as part ofcombination therapy strategies. Specifically, analysis of the tumor growth curves showsthat significant tumor growth inhibition compared to the vehicle control occurs by day 7 forcompound (Ia) alone, day 7 for selumetinib, and day 9 for 5Fu + oxaliplatin. Furthermore,the combination treatments demonstrate an even earlier onset of significant inhibition, withcompound (Ia) combined with 5Fu + oxaliplatin showing significance at day 7, andcompound (Ia) combined with selumetinib achieving significance as early as day 5. At the time of sacrifice, tumor weight measurements revealed that the addition of compound (Ia)to selumetinib or to 5Fu + oxaliplatin lead to a significantly greater reduction in final tumorweight than Selumetinib alone. Moreover, the combination of compound (Ia) withselumetinib outperformed the current standard 5Fu + oxaliplatin regimen, demonstratingsuperior antitumor efficacy. To further extend the analysis using a more clinically relevant tumor model, compound (Ia) was evaluated both as a single agent and in combination in a Patient-Derived Orthotopic Xenograft (PDOX) or orthoxenogrfat model (FIG.9). This model was generated by implanting a liver metastasis biopsy from a pancreatic cancer patient into the pancreas of mice. Tumors treated with compound (Ia) alone showed a significant reduction in tumorweight compared to the control group (Vehicle). When selumetinib or 5Fu + oxaliplatinwere combined with compound (Ia), a further reduction in tumor volume was observed compared to compound (Ia) monotherapy. In contrast, no additional benefit was seen when compound (Ia) was combined with gefitinib or crizotinib—two drugs previously proposed for PDAC treatment. These findings suggest that the adjuvant effect of compound (Ia) may depend on the specific mechanism of action of the agents with which it is combined. Altogether, the four in vivo studies underscore the potential of compound (Ia) as a monotherapy for the preclinical treatment of pancreatic cancer, demonstrating antitumor efficacy comparable to that of existing therapeutic options. More importantly, they highlight its ability to potentiate the therapeutical effects of other agents with distinct mechanisms of action. This is especially noteworthy given the low toxicity observed in mice when compound (Ia) is administered in combination regimens, further supporting its value as a promising component of combination therapy strategies. Citation List -WO2017013160- Balsas et al., “Activity of the novel BCR kinase inhibitor IQS019 in preclinicalmodels of B-cell non-Hodgkin lymphoma", Journal of Hematology & Oncology 2017, vol.10, no.1 -Galve et al., “A captured room temperature stable Wheland intermediate as a keystructure for the orthogonal decoration of 4-amino-pyrido[2,3-d]pyrimidin-7(8H)- ones”, Org. Biomol. Chem.2020, 18, 9810 -Camarasa et al, "Design, synthesis and biological evaluation of pyrido[2,3-d]pyrimidin-7-(8H)-ones as HCV inhibitors", European Journal of Medicinal Chemistry 2016, vol.115, pages 463-483 -EP2905024A1- Puig de la Bellacasa et al, "4-Amino-2-arylamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7-(8H)-ones as BCR kinase inhibitors for B lymphoid malignancies", European Journal Of Medicinal Chemistry 2014, vol.86, pages 664-675 -EP2813504A1- Galve et al, "Synthesis of 2-arylamino substituted 5,6-dihydropyrido[2,3-d]pyrimidine-7(8H)-ones from arylguanidines", Molecular Diversity 2012, vol.16no.4, pages 639-649 -Yesilkanal, A. E. et al., “New strategies for targeting kinase networks in cancer”,Journal of Biological Chemistry 2021, Volume 297, Issue 4, 101128 -Ioannou, N., et al., ”Anti-Tumour Activity of Afatinib, an Irreversible ErbB FamilyBlocker, in Human Pancreatic Tumour Cells”, Br J Cancer, 2011, 105 (10), 1554–1562 -Zhang, et al., “A Simple Statistical Parameter for Use in Evaluation and Validationof High Throughput Screening Assays”, J Biomol Screen 1999, 4 (2), 67–73.

Claims

Claims1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in thetreatment of pancreatic cancer in a mammal,wherein:each of R1-R5 is a radical independently selected from the group consisting of H, halogen,-OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, piperazin-1-yl, 4-(C1-C6)alkylpiperazin-1-yl, -NH(C1- C6)alkyl, and -N[(C1-C6)alkyl]2;R6 is H or -(C1-C6)alkyl;R7 is H or -(C1-C6)alkyl;each of R8 or R10 is a radical independently selected from the group consisting of H;-(C1-C6)alkyl optionally substituted with a 5- to 6-membered aromatic carbocyclic orheterocyclic ring; and a 3- to 7-membered aromatic, unsaturated, partially unsaturated, orsaturated carbocyclic or heterocyclic ring; R9 is a radical selected from the group consisting of H, -(C1-C6)alkyl, -(C1-C6)alkyl(C3- C6)aryl, -(C3-C6)aryl and -(CH2)nO(C1-C6)alkyl; R11 is H;Cy is a known ring system selected from the group consisting of: 3- to 7-memberedaromatic, unsaturated or partially unsaturated carbocyclic or heterocyclic ring, wherein the selected ring may be fused, bridged-fused or spiro fused to any other ring selected from the same group forming a bicyclic ring, and wherein any of the rings are optionally substituted with one or more radicals independently selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl; and is a single or a double bond; n is an integer from 2 to 6;(C3-C6)aryl is a known 3- to 6-membered aromatic carbocyclic or heterocyclic ringoptionally substituted with one or more radicals independently selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl;with the proviso that: at least one of R1-R5 is other than H;at least one of R8 or R10 is H; andwhen is a double bond, one of R10 or R8 is absent, and R11 is absent.

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) as defined in claim 1, together with one or more pharmaceuticallyacceptable excipients, for use in the treatment of pancreatic cancer in a mammal.

3. The compound or the composition for use according to any of the claims 1-2, whereinthe treatment of the pancreatic cancer comprises inhibition of intracellular tyrosine kinase receptors.

4. The compound or the composition for use according to any of the claims 1-3, whereinCy is a phenyl ring substituted with at least one halogen.

5. The compound or the composition for use according to any of the claims 1-4, whereinis a double bond and R10 and R11 are absent.

6. The compound or the composition for use according to any of the claims 1-5, which isadministered in combination therapy with one or more chemotherapeutic agents, whereinthe compound or the composition as defined in any of the claims 1-5 is to be administered simultaneously, concurrently, separately or sequentially with the one or more chemotherapeutic agents.

7. The compound or the composition for use according to any of the claims 1-6, which is selected from the group consisting of: -4-amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Ia); -4-amino-6-(2,6-dichlorophenyl)-2-((4-fluoro-2-methoxyphenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)one (Ib) ;- 4-amino-6-(2,6-dichlorophenyl)-2-((4-fluoro-2-hydroxyphenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Ic) ;- 4-amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Id) ;- 4-amino-6-(2,6-dichlorophenyl)-2-((4-fluoro-2-methoxyphenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Ie);- 4-amino-6-(2,6-dichlorophenyl)-8-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (If);- 4-amino-6-(2,6-dichlorophenyl)-2-((4-fluorophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Ig);- 4-amino-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Ih); -4-amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (Ii); -4-amino-6-(2,6-dichlorophenyl)-2-((4-fluoro-2-methoxyphenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (Ij); -4-amino-6-(2,6-dichlorophenyl)-2-((2-methoxyphenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)one (Ik); -4-amino-6-(2,6-dichlorophenyl)-2-((2-hydroxyphenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (IL); -4-amino-6-(2,6-dichlorophenyl)-2-((4-methoxyphenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Im); -4-amino-6-(2,6-dichlorophenyl)-2-((4-hydroxyphenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (In); -4-amino-6-(2,6-dichlorophenyl)-2-((2-methoxyphenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Io); -4-amino-6-(2,6-dichlorophenyl)-2-((4-methoxyphenyl)amino)pyrido[2,3-d]-pyrimidin-7(8H)-one (Ip); -4-amino-6-(2,6-dichlorophenyl)-2-((2-methoxyphenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (Iq); -4-amino-6-(2,6-dichlorophenyl)-2-((4-methoxyphenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (Ir), -4-amino-2-((4-bromophenyl)amino)-6-(3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Is), and- 4-amino-2-((4-bromophenyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (It).

8. A compound of formula (I1) or a pharmaceutically acceptable salt thereof,wherein: each of R1-R5 is a radical independently selected from the group consisting of H, halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, piperazin-1-yl, 4-(C1-C6)alkylpiperazin-1-yl,-NH(C1-C6)alkyl, and -N[(C1-C6)alkyl]2;R6 is H or -(C1-C6)alkyl;R7 is H or -(C1-C6)alkyl;R8 is a radical selected from the group consisting of H; -(C1-C6)alkyl optionally substitutedwith a 5- to 6-membered aromatic carbocyclic or heterocyclic ring; and a 3- to 7-membered aromatic, unsaturated, partially unsaturated, or saturated carbocyclic or heterocyclic ring; saturated carbocyclic or heterocyclic ring; R9 is a radical selected from the group consisting of H, -(C1-C6)alkyl, -(C1-C6)alkyl(C3- C6)aryl, -(C3-C6)aryl and -(CH2)nO(C1-C6)alkyl;Cy is a known ring system selected from the group consisting of: 3- to 7-memberedaromatic, unsaturated or partially unsaturated carbocyclic or heterocyclic ring, wherein the selected ring may be fused, bridged-fused or spiro fused to any other ring selected from the same group forming a bicyclic ring, and wherein any of the rings are optionally substituted with one or more radicals independently selected from the group consisting of H, halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl; n is an integer from 2 to 6;(C3-C6)aryl is a known 3- to 6-membered aromatic carbocyclic or heterocyclic ringoptionally substituted with one or more radicals independently selected from the group consisting of halogen, -OH, -(C1-C6)alkyl, -O(C1-C6)alkyl, -O-CO(C1-C6)alkyl, -O-CO-NH(C1-C6)alkyl, -NH2, and -NH(C1-C6)alkyl; with the proviso that: at least two of R1-R5 are other than H.

9. The compound according to claim 8, wherein at least two of R1-R5 are independentlyselected from the group consisting of halogen, OH, and -O(C1-C6)alkyl.

10. The compound according to any of the claims 8-9, wherein R6-R8 are H.

11. The compound according to any of the claims 8-10, wherein Cy is a phenyl ring substituted with at least one halogen.

12. The compound according to any of the claims 8-11, which is selected from thefollowing list: -4-amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Ia); -4-amino-6-(2,6-dichlorophenyl)-2-((4-fluoro-2-methoxyphenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)one (Ib);- 4-amino-6-(2,6-dichlorophenyl)-2-((4-fluoro-2-hydroxyphenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Ic);- 4-amino-6-(2,6-dichlorophenyl)-2-((2,4-difluorophenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Id), and- 4-amino-6-(2,6-dichlorophenyl)-2-((4-fluoro-2-methoxyphenyl)amino)-pyrido[2,3-d]pyrimidin-7(8H)-one (Ie).

13. The compound according to any of the claims 8-12, which is 4-amino-6-(2,6- dichlorophenyl)-2-((2,4-difluorophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one.

14. A combination comprising a compound of formula (I1) as defined in claims 8-13 andone or more chemotherapeutic agents.

15. The combination as defined in claim 14, wherein the one or more chemotherapeuticagents are selected from the group consisting of a Kirsten rat sarcoma viral oncogene (KRAS) inhibitor, a Mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, a Src Homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2(PTPN11)) inhibitor, a Phosphoinositide 3-kinase (PI3K) inhibitor, a poly-ADP ribose polymerase (PARP) inhibitor, a Son of Sevenless homolog 1 (SOS1) inhibitor, an Anaplastic Lymphoma Kinase (ALK) inhibitor, an Epidermal Growth Factor Receptor (EGFR) inhibitor, a platinum compound, 5-fluorouracil (5-FU), irinotecan, leucovorin, gemcitabine, nab-Paclitaxel, and combinations thereof.

16. A pharmaceutical composition comprising a therapeutically effective amount of thecompound of formula (I1) as defined in any of the claims 8-13, or the combination asdefined in claim 14, together with one or more pharmaceutical excipients.

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