New rhoj / cdc42 inhibitors developed for the treatment of cancer, benign tumors, retinal disorders, vascular disorders, and cardiomyopathies

Abstract

The present invention discloses new compounds having Rho / Cdc42 inhibitory activity, a good selectivity and a robust antiproliferative activity.

Description

[0001] “New RHOJ / CDC42 inhibitors developed for the treatment of cancer, benign tumors, retinal disorders, vascular disorders, and cardiomyopathies” DESCRIPTION The incidence of melanoma, a type of cancer that develops from the malignant transformation of melanocytes, is increasing while, unfortunately, traditional therapies such as dacarbazine and high-dose of interleukin-2 (IL-2), and new therapies such as BRAF inhibitors and immunotherapies, have efficacy in only a small fraction of patients. Moreover, these therapies have significant toxicities, some of which can be life threatening. In addition, there are many different inherited vascular disorders that can cause significant morbidity and mortality with limited treatments available. Benign tumors can also grow uncontrolled in the body and cause significant morbidity through impingement / destruction of nearby structures. A drug therapy that would inhibit vasculogenesis around tumors (benign and malignant) and in the context of genetic vascular disorders could have a profound impact on improving the health of patients with these conditions with limited effect on normal tissue. Intriguingly, some of the therapies described herein also target tumor growth itself, providing a two-pronged strategy to inhibit the growth of tumors. CDC42 family GTPases (including RhoJ) is currently presented as a validated target in a combined treatment strategy since its expression modulates the development of melanoma, other cancers, benign tumors (neurofibromas, etc) and vasculature. RhoJ is a member of the Rho-family of small GTPases, known to bind and activate PAK kinases. Functional validation studies revealed that RhoJ activates PAK1, which then inhibits p53 signaling and apoptosis pathways in melanoma cells in vitro. Additional studies showed that CDC42 and PAK1 also modulate melanoma cell migration and invasion in vitro, as well as tumor growth and invasion in melanoma xenograft model. While RhoJ and CDC42 was known to have a role in endothelial cell biology and angiogenesis, it was not known whether RhoJ had cell autonomous effects on the growth of melanocytic tumors. Recent studies have determined that RhoJ modulates the growth and development of melanoma tumors in autochthonous mouse models and is expressed at a higher level in stage III as compared to stage IV melanomas. We also showed that targeting RhoJ and CDC42 could inhibit tumor growth by blocking key signaling in tumor cells and preventing tumors from recruiting vasculature to feed them. As the vasculature is critical for the growth of benign and malignant tumors, and also activated in vascular disorders, this work provides a rationale for the indications that we cover here. The publication “Pyrimidine: a review on anticancer activity with key emphasis on SAR.” Mahapatra et al. Future Journal of Pharmaceutical Sciences (2021) 7:123 discloses 2,4,6-trisubstituted pyrimidine compounds as anticancer agents. The prior-art document WO 2021 / 159993 discloses inhibitors of interleukin-1 receptor associated kinase (IRAK) enzyme / FMS-like receptor tyrosine kinase (FLT3). The prior-art document WO 2022 / 214606 discloses 2,4,6-trisubstituted pyrimidine compounds bearing a pyrazine substituent in position 4 and a 2-methylpiperidin-1-yl)ethan-1-one in position 2. The prior-art document WO 2018 / 03256 A1 discloses compounds having a RhoJ / Cdc42 inhibitory activity characterized by a different structure; no data are reported on the activity on the inhibitory activity on cell lines A375, WM3248, SKMEL3, SKMEL28 nor SW480. The publication “Structure-based design of CDC42 effector interaction inhibitors for the treatment of cancer” Jahid et al. Cell Reports (2022) 110641; and “Design, Synthesis, In Vitro and In Vivo Characterization of CDC42 GTPase Interaction Inhibitors for the Treatment of Cancer”, Journal of Medicinal Chemistry (2023), 66, 8, 5981-6001 reported several 2,4,6-trisubstituted pyrimidine compounds bearing either piperidine nitrogen masked with different groups or different heterocycles (cyclohexyl, tetrahydropyranyl) on position 2. These compounds resulted with a decreased activity compared to those with free piperidine, suggesting a critical role of free piperidine nitrogen for the activity. Indeed, the activity could be restored with specific substituents on piperidine nitrogen, which can establish supplementary interaction with CDC42 (e.g. methoxyethyl group in compound 22 of Journal of Medicinal Chemistry, Brindani et al.). Abstract of the invention The inventors of the present patent application have surprisingly found new compounds having activity as RhoJ / CDC42 inhibitors, that can be used in the treatment of pathologies. The compounds disclosed are endowed with high specificity. Object of the invention In a first object there are disclosed new compounds. In a second object there are disclosed new compound for use as a medicament. In a first preferred embodiment, the compounds are disclosed for use as a medicament in the treatment of cancers and, a further preferred embodiment, for the treatment of melanoma. In a second preferred embodiment, the compounds are disclosed for use as a medicament in the treatment of cardiomyopathies, retinal disorders and vascular disorders. In a further object, there are disclosed pharmaceutical compositions comprising the compounds of the invention and their medical use. Brief description of the figures Figure 1 shows the general procedure for the synthesis of compounds 7a-j of the invention. Figure 2 shows the general procedure for the synthesis of compounds 8a-b of the invention. Figure 3 shows the general procedure for the synthesis of compounds of type 13 of the invention. Figure 4 the general procedure for the synthesis of compounds 18a, 18k and 18l of the invention. Figure 5 shows: (A) the in vivo mouse PK profile of 7e (ARN25375) and 7i (ARN25499) following intravenous (I.V.) and oral (P.O.) administration at 3 and 10 mg / Kg, respectively, and (B) the corresponding observed and calculated PK parameters. Figure 6 shows the results of the in vivo efficacy assay. ARN25499 slows the growth of melanoma PDX tumors in NSG mice. (A) Line plot showing the growth curves of vehicle and ARN24599 treated tumors in mean+SEM. (B) Scatterplot showing the vehicle and ARN25499 dots representing tumor volume in millimeter cube at the end of the 2-week treatment. GraphPad Prism 9 was used to generate plot and statistical analysis using 2 way ANOVA (A) and unpaired two tail T-test (B), ***,**p-value < 0.0001, 0.0047, respectively. (C) Line plot (mean+SD) shows no significant difference in weights between vehicle and ARN25499 treated mice for the 2-week treatment. Figure 7 shows the Western Blot analysis after in vitro treatment of WM3248 cells were treated with 10 μM of ARN22089 (reference compound), ARN25375, and ARN25499 for 6 hours to verify the accumulation of pS6 and pERK by immunoblotting. Relative densitometry of pERK and pS6 as compared to unphosphorylated forms of the protein were determined and are reported below each lane. A representative blot of three independent biologic replicates is shown. Detailed description of the invention According to a first embodiment, the present invention discloses new compounds having RhoJ / Cdc42 inhibitory activity. In particular, said compounds are characterized by the following general structure (I): wherein Y is -N- or -CH-, A is selected from pyrrolidine, phenyl and heteroaromatic rings such as: pyrazole, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N- R2indazole, B is selected from a six membered saturated or partially unsaturated (hetero)cycles and differently substituted aniline, C is selected from a six membered saturated or partially unsaturated (hetero)cycles and differently substituted aniline. For the purposes of the present patent application, pharmaceutically acceptable salt of the compounds of general structure (I), stereoisomeric forms thereof, individual geometrical isomers, enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof are within the scope of the present invention. In a first preferred embodiment, the compounds disclosed are characterized by the following general structure (II): wherein dashed bond may be a single or a double bond, Y is -N- or -CH-, A is selected from pyrrolidine, phenyl and heteroaromatic rings such as:, pyrazole, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, with the proviso that when Y is N, A is different from phenyl including heteroaryl groups, A’ is selected from aromatic and heteroaromatic rings such as: pyrazole, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole substituted by one or more substituents R2, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, each one of X1 and X2 may be independently -N(H)-, -N(R2)- or -O-, R1may be H, (C1-C6)alkyl, halo(C1-C6)alkyl, amino(C1-C6)alkyl, cycloalkyl, hydroxy(C1-C6)alkyl, alkoxy-(C1-C6)-alkyl , C1-C6 acyloxy, R2 may be a H, (C1-C6)alkyl, halo(C1-C6)alkyl, amino, amino(C1- C6)alkyl, hydroxyl, hydroxy(C1-C6)alkyl, alkoxy-(C1-C6)-alkyl, carboxyl, ester, C1-C6-acyloxy. For the purposes of the present patent application, pharmaceutically acceptable salt of the compounds of general structure (II), stereoisomeric forms thereof, individual geometrical isomers, enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof are within the scope of the present invention. In a second preferred embodiment, the compounds disclosed are characterized by the following general structure (III): wherein each one of R1and R2may be independently H, C1-C4 alkyl, cycloalkyl each one of X1 and X2 may be independently -N(H), -N(R2)- or -O-, dashed bond may be single or double, ring D may not be present and –N(R2)- is -N(R2)(H)-, or when ring D is present,–N(R2) is embedded in five- or six-membered (hetero)aromatic or not aromatic ring, introducing an indole, indoline, quinoxaline, tetrahydroquinoxaline, quinoline, or tetrahydroquinoline, as depicted below with the proviso that when D is absent then the dashed bond is a double bond. In a preferred embodiment, within the general structures (I), (II) and (III) the dashed bond is a single bond and X1is –N(H)-. In a third preferred embodiment, the compounds disclosed are characterized by the following general structure (IV): wherein Y1 and Y2 may independently be: -CH- or -N- and at least one of Y1 and Y2 is -N-, the dashed bond may be a single or a double bond, each R1may be: H, C1-C4 alkyl, cycloalkyl, A is a non-substituted or a R3-substituted ring A selected from: phenyl, pyrrolidine, N-dimethylaminoaniline, and heteroaromatic rings such as: pyrazole, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, with the proviso that when Y2 is N A is different from non- substituted phenyl, wherein R2is H, C1-C4 alkyl, cycloalkyl, and wherein R3is selected from C1-C4 alkyl, C1-C4 haloalkyl (and preferably -CF3), cycloalkyl, A’ is a non-substituted or a R4mono- or di-substituted ring A’ selected from aromatic and heteroaromatic rings such as: phenyl, pyrazole, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole substituted by one or more substituents R2, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, wherein R2may be: H, C1- C4 alkyl, cycloalkyl and wherein R4is independently selected from –OH, -COOH, -COOR2, C1-C4 alkyl, C1-C4 haloalkyl (and preferably -CF3), C1-C4- haloalkyloxy (and preferably -OCF3or -OCHF2), C1-C4-alkoxy (and preferably -OCH3), cycloalkyl, -NR2or -N(R2)2. In the above formula, when Y1 is -N- and Y2 is -C-, R1is H and A’ is phenyl, then the dashed bond of piperidine is present as a double bond. In particular, in the above formula (IV), when Y1 is -N- and Y2 is -C-, R1is H and A’ is phenyl, R4is –N(R2)2wherein both R2are C1-C4 alkyl (preferably -CH3) then the dashed bond of piperidine is a double bond. In a fourth preferred embodiment, the compounds disclosed are characterized by the following general structure (V): wherein any of Y1 and Y2 may be: -CH- or -N- and only one of Y1 and Y2 being -N-, the dashed bond is a single or a double bond, R1may be: H, C1-C4 alkyl, cycloalkyl, A’ is a non-substituted or a R4mono- or di-substituted ring A’ selected from aromatic and heteroaromatic rings such as: phenyl, pyrazole, N-dimethylaminoaniline, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole substituted by one or more substituents R2, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, wherein R2may be: H, C1-C4 alkyl, cycloalkyl and wherein each R4is independently selected from –OH, -COOH, -COOR2, C1-C4 alkyl, C1-C4 haloalkyl (and preferably -CF3), C1-C4-haloalkyloxy (and preferably -OCF3 or -OCHF2), C1-C4-alkoxy (and preferably -OCH3), cycloalkyl, -NR2or -N(R2)2. In a preferred embodiment, the compounds of formula (V) are those wherein: R1is H, R2is H o -CH3, and wherein A’ is a non-substituted or a R4mono- or di-substituted ring A’ selected from aromatic and heteroaromatic rings such as: phenyl, pyridine, NH-indole, N-R2indole, N-dimethylaminoaniline, and wherein each R4is independently selected from –OH, -COOH, -COOR2, CH3, -CF3, -OCF3, -OCHF2, -OCH3, -NR2or -N(R2)2. In a more preferred embodiment, the compounds of formula (V) above are those wherein: any of Y1 and Y2 may be: -CH- or -N- and only one of Y1 and Y2 is -N-, the dashed bond is a single or a double bond, R1is H, A’ is a non-substituted or a R4mono- or di-substituted ring A’ selected from: phenyl, pyridine, N-dimethylaminoaniline, NH-indole, N-R2indole, wherein R2is CH3: and wherein each R4is independently selected from –OH, -COOH, -COOR2, CH3, -CF3, -OCF3, -OCHF2, -OCH3, -NR2or -N(R2)2. In particular, in the above formula (V), when Y1 is -C- and Y2 is -N-, R1is H and A’ is phenyl then the dashed bond of piperidine is a double bond. In particular, in the above formula (V), when Y1 is -C- and Y2 is -N-, R1is H and A’ is phenyl and R4is –N(R2)2wherein both R2are C1-C4 alkyl (preferably -CH3) then the dashed bond of piperidine is a double bond. In a fifth preferred embodiment, the compounds disclosed are characterized by the following general structure (VI): wherein R1may be: H, C1-C4 alkyl, cycloalkyl, A’ is a non-substituted or a R4mono- or di-substituted ring A’ selected from aromatic and heteroaromatic rings such as: phenyl, pyrazole, N-dimethylaminoaniline, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole substituted by one or more substituents R2, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, wherein R2may be: H, C1-C4 alkyl, cycloalkyl and wherein each R4is independently selected from –OH, -COOH, -COOR2, C1-C4 alkyl, C1-C4 haloalkyl (and preferably -CF3), C1-C4-haloalkyloxy (and preferably - OCHF2), C1-C4-alkoxy (and preferably -OCH3), cycloalkyl, -NR2or -N(R2)2. In a preferred embodiment, the compounds of formula (VI) above are those wherein: R1may be: H, C1-C4 alkyl, cycloalkyl, and A’ is a non-substituted or a R4mono- or di-substituted ring A’ selected from: phenyl, pyridine, N-dimethylaminoaniline, wherein each R4is independently selected from –OH, -COOH, -COOR2, -CH3, -CF3, -OCF3, -OCHF2, -OCH3, -NR2or -N(R2)2, wherein R2is -CH3. In a sixth embodiment, the compounds disclosed are characterized by the following general structure (VII): wherein R5is selected from H, C1-C4 alkyl (preferably -CH3), R6is selected from H, C1-C4-alkyl (preferably -CH3), or R6is -CH=CH- and together with the nitrogen atom to which it is bound and the phenyl ring forms a 6-indolyl ring of general formula: ; the dashed C-C bond may be present or absent, with the proviso that when R6is a -CH=CH- group and forms a 6-indolyl radical, then the dashed bond is present as a double bond in the piperidine ring. In a seventh embodiment, the compounds disclosed are characterized by the following general structure (VIII): wherein the dashed bond is a single or a double bond, ring A is a R3-substituted phenyl or a non-substituted or a R3- substituted ring A selected from: pyrrolidine, and heteroaromatic rings such as: pyrazole, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, wherein R3is selected from C1-C4 alkyl, C1-C4 haloalkyl (and preferably -CF3), cycloalkyl, wherein R2is H, C1-C4 alkyl, cycloalkyl, wherein R4is selected from C1-C4 alkyl, C1-C4 haloalkyl (and preferably -CF3), cycloalkyl. In a preferred embodiment, the compounds of formula (VIII) above are those wherein A is a R3-substituted phenyl or a non-substituted or a R3- substituted ring A selected from: benzofuran, NH-indole, N-R2indole, pyrazole, pyrrolidine, isoquinoline, quinoline, pyrimidine, pyrrole, indazole, N-R2indazole, imidazole, N-R2imidazole, thiophene, R3is H or -CH3, wherein R2is H or -CH3, wherein R4is selected from C1-C4 alkyl (and preferably -CH3), C1-C4 haloalkyl (and preferably -CF3), cycloalkyl. For the purposes of the present patent application, pharmaceutically acceptable salt of the compounds of general structure (III), stereoisomeric forms thereof, individual geometrical isomers, enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof are within the scope of the present invention. According to an even preferred embodiment, the present invention discloses the following compounds: Table 1 Structure Compounds 7 7 7 7 7 7 7 7 According to a second object of the invention, there are disclosed the compounds of the invention for the medical use. The compounds of the invention are intended those of the general structures (I) to (VIII) above and each of the compounds of Table 1 above. Preferred compounds for the medical use are those of the following Table 2:

[0002] 18l (ARN25092) In a first preferred embodiment, the compounds are disclosed for use as a medicament in the treatment of cancers. In a more preferred embodiment, the compounds of the invention are disclosed for the medical use in the treatment of melanoma. In a second preferred embodiment, the compounds are disclosed for use as a medicament in the treatment of cardiomyopathies, retinal disorders and vascular disorders. For the purposes of the present invention, vascular disorders are selected from the group comprising: aneurysm, carotid artery disease, deep vein thrombosis, peripheral artery disease, renal artery disease, vascular malformations (involving small capillaries, to mid and larger size vessels), varicose and spider veins, carotid body tumors, chronic venous insufficiency, thoracic outlet syndrome. They also consist of disorders wherein the vasculature is induced by other factors such as: rosacea, flushing, venous insufficiency and stasis dermatitis. In addition, as skin ages, the vasculature becomes more prominent due to sun exposure. The compounds of the invention may also find cosmetic application for use in improving the skin quality and remove the signs of aging by reducing visually apparent vascularity. For the purposes of the present invention, the compounds are disclosed for the medical use and for specific medical uses alone or in combination with one or more other therapeutic agent having the same mechanism or a different therapeutic mechanism. As a combination therapy it is intended that the administration of the compounds of the invention may be together with one or more other agents or within the same therapeutic protocol. In a further object, the present invention discloses pharmaceutical compositions comprising the compounds of the invention together with suitable pharmaceutically acceptable excipients. In a still further embodiment, said pharmaceutical compositions are disclosed for the medical use. In a preferred embodiment, the pharmaceutical compositions of the invention are disclosed for the medical use in the treatment of melanoma. In another preferred embodiment, the pharmaceutical compositions are disclosed for use as a medicament in the treatment of cardiomyopathies, retinal disorders and vascular disorders. The invention will be further disclosed in the following experimental section. Synthesis General considerations: All the commercially available reagents and solvents were used as purchased from vendors without further purification. Intermediates 1a and 1b could be synthesized according to the procedure reported on European Journal of Medicinal Chemistry 180 (2019) 350-366. Intermediate 1c could be synthesized according to the procedure reported in the international patent application WO 2017 / 132928 A1. Dry solvents were purchased from Sigma-Aldrich. Automated column chromatography purifications were done using a Teledyne ISCO apparatus (CombiFlash®Rf) with pre-packed silica gel columns of different sizes (from 4 g up to 120 g) and mixtures of increasing polarity of cyclohexane and ethyl acetate (EtOAc) or dicloromethane (DCM) and methanol (MeOH). NMR experiments were run on a Bruker Avance III 400 system (400.13 MHz for 1H, and 100.62 MHz for 13C), equipped with a BBI probe and Z-gradients. Spectra were acquired at 300 K, using deuterated dimethylsulfoxide (DMSO–d6) or deuterated chloroform (CDCl3) as solvents. For1H-NMR, data are reported as follows: chemical shift, multiplicity (s= singlet, d= doublet, dd= double of doublets, ddd= doublet of doublet of doublets, t= triplet, td= triplet of doublets, q= quartet,p= quintet, m= multiplet), coupling constants (Hz) and integration. UPLC / MS analyses were run on a Waters ACQUITY UPLC / MS system consisting of a SQD (single quadrupole detector) mass spectrometer equipped with an electrospray ionization interface and a photodiode array detector. The PDA range was 210–400 nm. Analyses were performed on an ACQUITY UPLC BEH C18 column (100x2.1 mmID, particle size 1.7 µm) with a VanGuard BEH C18 pre-column (5x2.1 mmID, particle size 1.7 µm). Mobile phase was 10 mM NH4OAc in H2O at pH 5 adjusted with CH3COOH (A) and 10 mM NH4OAc in CH3CN–H2O (95:5) at pH 5.0. Three types of gradients were applied depending on the analysis, gradient 1 (5 % to 100 % mobile phase B in 3 min); gradient 2 (50 % to 100 % mobile phase B in 3 min); gradient 3 (70 % to 100 % mobile phase B in 3 min). The analysis with the gradient 4 (0 % to 100 % mobile phase B in 3 min) were performed using a different system on Waters ACQUITY UPLC HSS T3 C18 column (50x2.1 mmID particle size 1.8μm) with VanGuard HSS T3 C18 pre-column (5x2.1 mmID, particle size 1.8μm). Electrospray ionization in positive and negative mode was applied. ESI was applied in positive and negative mode. All tested compounds showed ≥ 95% purity by UPLC / MS analysis. General procedure 1 (Scheme 1). Buchwald reaction for the obtainment of compounds 5a-j. A mixture of Compound 3 (1 equiv), proper aniline 4a-j (1.2 equiv), Pd(OAc)2 (5mol%), (±)-BINAP (5mol%), Cs2CO3 (1.5 equiv) in 1,4-dioxane dry (0.15M) stirred at 120°C until complete consumption of starting material 3. After that, water and brine were added, aqueous layer was extracted with EtOAc, and collected organic layers were dried over Na2SO4, filtered and concentrated under vacuum. Intermediate 5a-j were purified by silica. General procedure 2 (Scheme 1, 3-4). Double C-C reduction. Method A- Under N2 atmosphere, a suspension of intermediate of type 5, 11, 16 (1 equiv), ammonium formate (6 equiv), Pd(OH)2 / C (20 % of starting material weight) in MeOH dry (0.04 M solution) was stirred at reflux temperature until reaction completion. Catalyst was filtered off through a celite coarse patch and resulting filtrate concentrated to dryness at low pressure. Final chromatographic normal phase purification (cyclohexane / EtOAc) afforded pure desired compound of type 6, 12, 18. Method B- Reduction with Et3SiH. Under N2 atmosphere, Et3SiH (10 equiv.) was dropwise added to a mixture of starting material 6d or 11d (1.0 equiv.) and Pd / C (20% w / w of starting material weight) in EtOH (0.5 M). When no intermediate was detected by UPLC or TLC, catalyst was filtered off through a celite coarse patch and resulting filtrate concentrated to dryness at low pressure. Resulting crude was purified by silica gel chromatography. General procedure 3 (Scheme 1, 3-4). Boc removal for the obtainment of compounds 7a-j, 18. Under N2 atmosphere, HCl (4 M in dioxane) (10 equiv) was added to a solution of intermediate of type 6, 16, 17 (1 equiv) in 1,4-dioxane dry (0.06 M). After completion of reaction NaOH (2 M) aq was added until pH = 7, aqueous layer was extracted with EtOAc, collected organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. Final purification by alumina (DCM / MeOH or DCM / MeOH•NH3) afforded pure desired compound of type 7, and 18. General procedure 4 (Scheme 2). Methyl and Boc removal for the obtainment of compounds 8a, 8b. Under N2 atmosphere, BBr3 (1 M in DCM) (6 equiv) was added to a solution of intermediate of type 6 (1 equiv) in CHCl3 dry (0.06 M). After completion of reaction, MeOH was added, the mixture was concentrated under vacuum. The crude was purified by trituration with EtOAc, obtaining pure product of type 8. General procedure 5. SNAr (Scheme 3). To a DCM solution (0.5M) of cyanuric chloride (1.3 equiv.), corresponding aniline (1.0 equiv.) was dropwise added at 0°C, followed by DIPEA (1.1 equiv.). After 10 minutes H2O was slowly added at the same temperature to quench the excess of reagent and the resulting mixture was left to stir 10-15 minutes. Organic layer was separated and dried with Na2SO4, the solvent was evaporated and resulting crude was purified by silica gel chromatography. General procedure 6 (Scheme 3-4). Suzuki cross coupling. To a degassed 1,4-dioxane solution (0.13 M) of starting material (4,6- dichloro-N-(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine) (1.0 equiv.), suitable boronic acid (1.2 equiv.), Pd(dppf)Cl2•DCM (0.05 equiv.) and K2CO3 (2 M)aq (2.0 equiv.) were added. Resulting mixture was sparged with Argon for further 10 minutes and heated at 80°C (for 4,6- dichloro-N-(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine, Scheme 3), 100°C (for substrate of type 10 and 14, Scheme 3, 4) or 120°C (for substrate of type 15) in dependence of substrate. Then, H2O and EtOAc were added and separated; aqueous layers were extracted two times with EtOAc and collected organic layers were dried over Na2SO4. The solvent was evaporated and resulting crude was purified by silica gel chromatography. General procedure 7 (Scheme 4). A solution (0.15 M) of 6-phenyl-2,4- dichloropyrimidine 23 (1.00 equiv) with a suitable aniline of type 4 (1.00 mmol) in THF was cooled to -60 °C. To this solution was added dropwise LiHMDS (1.0 M in THF, 2.5 equiv). After complete conversion of starting material, water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. Final normal phase chromatographic purification (Cyclohexane / EtOAc) provided desired product of type 15. Figure 1 reports Scheme 1 showing the synthesis of compounds 7a-j. Example 1. N1,N1-dimethyl-N3-(4-phenyl-6-(piperidin-4-yl)pyrimidin-2- yl)benzene-1,3-diamine (compounds 7a, Scheme 1) Step 1. tert-butyl 4-(2-chloro-6-phenylpyrimidin-4-yl)-3,6- dihydropyridine-1(2H)-carboxylate (compound 3, Scheme 1). K2CO3(2 M) aq (2 mL), phenyl boronic acid (256 mg, 2.1 mmol) and PdCl2(dppf)•DCM (163 mg, 0.2 mmol) were added to a solution of trichloropyrimidine 1 (366 mg, 2 mmol) in 1,4-dioxane dry (4 mL) under argon. Reaction mixture stirred at 65°C for 2 hours until complete consumption of starting material 1 (UPLC / MS of not isolated intermediate 2,4-dichloro-6-phenylpyrimidine: Rt = 1.50 min (gradient 2), MS (ESI) m / z: 224.9 [M+H]+.[M+H]+Calculated for C10H7Cl2N2: 226.1). After that, boronic ester 2 (618 mg, 2 mmol) and a second addition of PdCl2(dppf)•DCM (82 mg, 0.1 mmol) was added and reaction mixture stirred at 90°C for other 2h at 90°C under argon until complete conversion of 2,4-dichloro-6- phenylpyrimidine intermediate. Then water (3 mL) was added and aqueous layer was extracted with EtOAc (5 mL x 2). Collected organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The desired product 3 was purified by silica eluting by gradient from 100% cyclohexane to 85 / 15 cyclohexane / EtOAc, obtaining pure compound 3 (410 mg, 55%). UPLC / MS Rt: 2.20 min (gradient 2), MS (ESI) m / z: 372.1 [M+H]+.[M+H]+Calculated for C20H23ClN3O2: 372.9.1H NMR (400 MHz, CDCl3) δ 8.12 – 8.02 (m, 2H), 7.59 (s, 1H), 7.56 – 7.47 (m, 3H), 7.05 (m, 1H), 4.20 (q, J = 3.0 Hz, 2H), 3.66 (t, J = 5.7 Hz, 2H), 2.64 (m, 2H), 1.49 (s, 9H).13C NMR (101 MHz, CDCl3) δ 167.7 (Cq), 167.2 (Cq), 161.7 (Cq), 154.8 (Cq), 135.8 (Cq), 133.2 (Cq), 131.8 (CH), 130.7 (CH), 129.2 (CH, 2C), 127.5 (CH, 2C), 109.7 (CH), 80.2 (Cq), 44.1 (CH2), 40.0 (CH2), 28.6 (CH2), 25.4 (CH3). Step 2. tert-butyl 4-(2-((3-(dimethylamino)phenyl)amino)-6- phenylpyrimidin-4-yl)-3,6- dihydropyridine-1(2H)-carboxylate (compound 5a, Scheme 1). Title compound was synthesized following the general procedure 1 previously described using intermediate 3 (100 mg, 0.27 mmol), aniline 4a (44 mg, 0.32 mmol) in 1,4 dioxane (1.8 mL). Purification by silica (elution by gradient from 95 / 5 to 80 / 20 cyclohexane / EtOAc) afforded pure intermediate 5a (89 mg, 70% yield). UPLC / MS Rt: 2.42 min (gradient 2), MS (ESI) m / z: 472.4 [M+H]+.[M+H]+Calculated for C28H34N5O2: 472.6.1H NMR (400 MHz, CDCl3) δ 8.12 – 8.02 (m, 2H), 7.55 – 7.46 (m, 3H), 7.44 (s, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.19 (s, 1H), 6.96 (s, 1H), 6.93 (s, 1H), 6.48 (d, J = 8.2 Hz, 1H), 4.18 (q, J = 3.0 Hz, 2H), 3.66 (t, J = 5.6 Hz, 2H), 2.69 (m, 2H), 1.51 (s, 9H). Step 3. tert-butyl 4-(2-((3-(dimethylamino)phenyl)amino)-6- phenylpyrimidin-4-yl)piperidine-1-carboxylate. (compound 6a, Scheme 1). Titled compound was synthesized following the general procedure 2-Method A previously described using intermediate 5a (60 mg, 0.1274 mmol), Pd(OH)2 / C (12 mg), NH4CO2H (48 mg, 0.76 mmol) in MeOH (3.2 mL). Purification by silica (elution by gradient from 100 / 0 to 80 / 20 cyclohexane / EtOAc) afforded pure intermediate 6a (59 mg, 98% yield). UPLC / MS Rt: 2.30 min (gradient 2), MS (ESI) m / z: 474.3 [M+H]+.[M+H]+Calculated for C28H36N5O2: 474.6.1H NMR (400 MHz, CDCl3) δ 8.12 – 8.02 (m, 2H), 7.52 (s, 1H), 7.51 – 7.43 (m, 3H), 7.20 (t, J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 8.3 Hz, 1H), 4.27 (bs, 2H), 2.93 – 2.70 (m, 3H), 1.97 (d, J = 13.0 Hz, 2H), 1.90 – 1.74 (qd, J = 12.8, 4.2 Hz, 2H), 1.49 (s, 9H). Step 4. N1,N1-dimethyl-N3-(4-phenyl-6-(piperidin-4-yl)pyrimidin-2- yl)benzene-1,3-diamine (compound 7a, Scheme 1). Titled compound was synthesized following the general procedure 3 previously described using intermediate 6a (58 mg, 0.12 mmol), HCl (4 M in dioxane) (0.32 mL) in 1,4-dioxane dry (2.1 mL). Purification by alumina (elution by gradient from 100 / 0 to 98 / 2 DCM / MeOH•NH31N) afforded pure intermediate 7a (15.5 mg, 33% yield). UPLC / MS Rt: 1.08 min (gradient 1), MS (ESI) m / z: 374.3 [M+H]+.[M+H]+Calculated for C23H28N5: 374.5.1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.23 – 8.10 (m, 2H), 7.58 (s, 1H), 7.55 – 7.49 (m, 3H), 7.26 (s, 1H), 7.08 (t, J = 7.9 Hz, 1H), 7.06 (s, 1H), 6.35 (dt, J = 7.2, 2.3 Hz, 1H), 3.10 – 3.00 (m, 3H), 2.92 (s, 6H), 2.69 (tt, J = 11.8, 3.8 Hz, 1H), 2.59 (td, J = 12.0, 2.5 Hz, 2H), 1.83 (d, J = 12.1 Hz, 2H), 1.68 (qd, J = 12.2, 4.0 Hz, 2H). Example 2. 4-phenyl-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)pyrimidin-2-amine (compounds 7b, Scheme 1) Step 1 of Example 1 was carried out followed by the further steps listed below. Step 2. tert-butyl 4-(6-phenyl-2-((3- (trifluoromethyl)phenyl)amino)pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)- carboxylate (compound 5b, Scheme 1). Title compound was synthesized following the general procedure 1 previously described using intermediate 3 (100 mg, 0.27 mmol), aniline 4b (0.04 mL, 0.32 mmol) in 1,4 dioxane (1.8 mL), Pd(OAc)2 (3.0 mg, 0.013 mmol), (±)- BINAP (8.4 mg, 0.013 mmol), Cs2CO3(132.0 mg, 0.40 mmol). Purification by silica (elution by gradient from 95 / 5 to 80 / 20 cyclohexane / EtOAc) afforded pure intermediate 5b (83 mg, 62% combined yield of the two isomers: an isomerization of the double bond occurred during the reaction). UPLC / MS Rt: 1.53 min (gradient 3), MS (ESI) m / z: 497.2 [M+H]+.[M+H]+Calculated for C27H28F3N4O2: 497.5. The mixture was used as such in the step 3 Step 3. tert-butyl 4-(6-phenyl-2-((3- (trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperidine-1-carboxylate (compound 6b, Scheme 1) Titled compound was synthesized following the general procedure 2-Method A previously described using intermediate 5b as isomeric mixture (70 mg, 0.14 mmol), Pd(OH)2 / C (14 mg), NH4CO2H (53 mg, 0.84 mmol) in MeOH (3.5 mL). Purification by silica (elution by gradient from 100 / 0 to 85 / 15 cyclohexane / EtOAc) afforded pure intermediate 6b (59.3 mg, 85% yield). UPLC / MS Rt: 1.49 min (gradient 3), MS (ESI) m / z: 499.2 [M+H]+.[M+H]+Calculated for C27H30F3N4O2: 499.6. 1H NMR (400 MHz, CDCl3) δ 8.39 (t, J = 2.0 Hz, 1H), 8.10 – 8.03 (m, 2H), 7.68 (dd, J = 8.2, 2.0 Hz, 1H), 7.54 – 7.47 (m, 3H), 7.44 (t, J = 8.0 Hz, 1H), 7.30 – 7.26 (m, 1H), 7.11 (s, 1H), 4.30 (bs, 2H), 2.90 – 2.84 (m, 2H), 2.80 (tt, J = 11.9, 3.8 Hz, 1H), 1.98 (d, J = 13.1 Hz, 2H), 1.80 (qd, J = 12.3, 4.4 Hz,2H), 1.49 (s, 9H). Step . 4-phenyl-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)pyrimidin-2-amine (compound 7b, Scheme 1). Titled compound was synthesized following the general procedure 3 previously described using intermediate 6b (45 mg, 0.09 mmol), HCl (4 M in dioxane) (0.22 mL) in 1,4-dioxane dry (1.5 mL). Purification by alumina (elution by gradient from 100 / 0 to 90 / 10 DCM / MeOH) afforded pure intermediate 7b (16.2 mg, 45% yield). UPLC / MS Rt: 1.49 min (gradient 3), MS (ESI) m / z: 499.2 [M+H]+.[M+H]+Calculated for C27H30F3N4O2: 499.6. 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.60 (bs, 1H), 8.18 (m, 2H), 7.96 (dd, J = 8.3, 1.4 Hz, 1H), 7.30 – 7.26 (m, 4H), 7.40 (s, 1H), 7.27 (d, J = 7.7 Hz, 1H), 3.06 (dt, J = 12.2, 3.2 Hz, 2H), 2.74 (tt, J = 11.9, 3.2 Hz, 1H), 2.60 (td, J = 12.0, 2.5 Hz, 2H), 1.85 (d, J = 12.5 Hz, 2H), 1.70 (qd, J = 12.2, 4.0 Hz, 2H). Example 3. 4-phenyl-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)pyrimidin-2-amine (compounds 7c, Scheme 1) Step 1 of Example 1 was carried out followed by the further steps listed below. Step . tert-butyl 4-(6-phenyl-2-((3- (trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-dihydropyridine-1(2H)- carboxylate (compound 5c as two isomeric mixture, Scheme 1). Title compound was synthesized following the general procedure 1 previously described using intermediate 3 (100 mg, 0.27 mmol), aniline 4c (0.04 mL, 0.32 mmol) in 1,4 dioxane (1.8 mL), Pd(OAc)2(2.7 mg, 0.012 mmol), (±)- BINAP (7.4 mg, 0.012 mmol), Cs2CO3(131.0 mg, 0.40 mmol). Purification by silica (elution by gradient from 95 / 5 to 85 / 15 cyclohexane / EtOAc) afforded pure intermediate 5c (109 mg, 79% combined yield of the two isomers: an isomerization of the double bond occurred during the reaction). UPLC / MS: there are two main picks related to the isomers α and β of 5c with double C-C bond shifted Rt: 1.53 min, 1.68 min (gradient 3), MS (ESI) m / z: 513.1 [M+H]+.[M+H]+Calculated for C27H28F3N4O3: 513.5. The mixture was used as such in the step 3. Step 3. tert-butyl 4-(6-phenyl-2-((3- (trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)piperidine-1-carboxylate (compound 6c, Scheme 1) Titled compound was synthesized following the general procedure 2-Method A previously described using intermediate 5c as isomeric mixture (110 mg, 0.21 mmol), Pd(OH)2 / C (22 mg), NH4CO2H (79 mg, 1.26 mmol) in MeOH (5.2 mL). Purification by silica (elution by gradient from 90 / 10 to 85 / 15 cyclohexane / EtOAc) afforded pure intermediate 6c (79.5 mg, 72% yield). UPLC / MS Rt: 1.50 min (gradient 3), MS (ESI) m / z: 515.1 [M+H]+.[M+H]+Calculated for C27H30F3N4O3: 515.6.1H NMR (400 MHz, CDCl3) δ 8.11 – 8.01 (m, 3H), 7.58 – 7.44 (m, 3H), 7.37 (dt, J = 8.2, 1.5 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.09 (s, 1H), 6.86 (d, J = 7.9 Hz, 1H), 4.29 (bs, 2H), 2.91 – 2.83 (m, 2H), (tt, J = 11.9, 3.5 Hz, 1H), 1.98 (d, J = 13.1 Hz, 2H), 1.79 (qd, J = 12.5, 4.3 Hz, 2H), 1.49 (s, 9H). Step 4. 4-phenyl-6-(piperidin-4-yl)-N-(3- (trifluoromethoxy)phenyl)pyrimidin-2-amine (compound 7c, Scheme 1). Titled compound was synthesized following the general procedure 3 previously described using intermediate 6c (70 mg, 0.14 mmol), HCl (4 M in dioxane) (0.34 mL) in 1,4-dioxane dry (2.3 mL). Purification by alumina (elution by gradient from 100 / 0 to 95 / 5 DCM / MeOH) afforded pure intermediate 7c (23.1 mg, 41% yield). UPLC / MS Rt: 2.41 min (gradient 1), MS (ESI) m / z: 415.0 [M+H]+.[M+H]+Calculated for C22H22F3N4O: 415.4.1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.22 (s, 1H), 8.17 (m, 2H), 7.70 (dd, J = 8.4, 2.0 Hz, 1H), 7.57 – 7.51 (m, 3H), 7.41 (t, J = 8.2 Hz, 1H), 7.38 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 3.05 (dt, J = 12.0, 2.7 Hz, 2H), 2.72 (tt, J = 11.7, 3.7 Hz, 1H), 2.60 (td, J = 12.1, 2.5 Hz, 2H), 1.84 (d, J = 12.4 Hz, 2H), 1.69 (qd, J = 12.2, 3.9 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 175.6 (Cq), 164.0 (Cq), 159.7 (Cq), 148.7 (Cq), 142.7 (Cq), 136.9 (Cq), 130.8 (CH), 130.0 (CH), 128.8 (CH, 2C), 127.0 (CH, 2C), 120.6 (Cq, q,1JCF= 255.6 Hz), 119.4 (Cq), 116.4 (CH), 112.9 (CH), 110.4 (CH), 106.2 (CH), 46.2 (CH2, 2C), 44.3 (CH), 31.7 (CH2, 2C). Example 4. 4-phenyl-6-(piperidin-4-yl)-N-(pyridin-4-yl)pyrimidin-2- amine (compounds 7d, Scheme 1) Step 1 of Example 1 was carried out followed by the further steps listed below. Step 2. tert-butyl 4-(6-phenyl-2-(pyridin-4-ylamino)pyrimidin-4-yl) - dihydropyridine-1(2H)- carboxylate (compound 5d as two isomeric mixture α + β, scheme 1). Title compound was synthesized following the general procedure 1 previously described using intermediate 3 (100 mg, 0.27 mmol), aniline 4d (30.4 mg, 0.32 mmol) in 1,4 dioxane (1.8 mL), Pd(OAc)2(2.7 mg, 0.012 mmol), Xantphos (6.9 mg, 0.012 mmol), Cs2CO3(131.0 mg, 0.40 mmol). Purification by silica (elution by gradient from 100 / 0 to 95 / 5 DCM / EtOH) afforded pure intermediate 5d (97.8 mg, 85% combined yield of the two isomers: an isomerization of the double bond occurred during the reaction). UPLC / MS: Rt: 1.68 min (gradient 2), MS (ESI) m / z: 430.1 [M+H]+.[M+H]+Calculated for C25H28N5O2: 430.5. The mixture was used as such in the step 3. Step 3. tert-butyl 4-(6-phenyl-2-(pyridin-4-ylamino)pyrimidin-4- yl)piperidine-1-carboxylate (compound 6d, scheme 1). Titled compound was synthesized following the general procedure 2-Method B previously described using intermediate 5d as isomeric mixture (100 mg, 0.23 mmol), Et3SiH (0.37 mL, 2.33 mmol), Pd / C (20 mg) in EtOH (3.8 mL). Purification by silica (elution by gradient from 90 / 10 to 85 / 15 cyclohexane / EtOAc) afforded pure intermediate 6d (79.3 mg, 79% yield). UPLC / MS Rt: 1.34 min (gradient 2), MS (ESI) m / z: 432.1 [M+H]+.[M+H]+Calculated for C25H30N5O2: 432.5.1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 6.4 Hz, 2H), 8.07 – 8.00 (m, 2H), 7.96 (d, J = 6.1 Hz, 2H), 7.51-7-50 (m, 3H), 7.22 (s, 1H), 4.26 (bs, 2H), 2.96 – 2.76 (m, 3H), 1.97 (d, J = 12.6 Hz, 2H), 1.79 (qd, J = 12.7, 4.4 Hz, 2H), 1.49 (s, 9H). Step 4. 4-phenyl-6-(piperidin-4-yl)-N-(pyridin-4-yl)pyrimidin-2-amine (compound 7d, Scheme 1). Titled compound was synthesized following the general procedure 3 previously described using intermediate 6d (70 mg, 0.16 mmol), HCl (4 M in dioxane) (0.40 mL) in 1,4-dioxane dry (2.5 mL). Purification by alumina (elution by gradient from 100 / 0 to 90 / 5 DCM / MeOH) afforded pure intermediate 7d (18.5 mg, 35% yield). UPLC / MS Rt: 1.88 min (gradient 1), MS (ESI) m / z: 332.1 [M+H]+.[M+H]+Calculated for C20H22N5: 332.4.1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.42 – 8.32 (m, 2H), 8.23 – 8.15 (m, 2H), 7.89 – 7.82 (m, 2H), 7.63 – 7.50 (m, 3H), 7.44 (s, 1H), 3.06 (dt, J = 11.9, 3.2 Hz, 2H), 2.77 (tt, J = 11.7, 3.7 Hz, 1H), 2.61 (td, J = 12.1, 2.5 Hz, 2H), 1.84 (d, J = 12.4 Hz, 2H), 1.71 (qd, J = 11.0, 2.8 Hz, 2H). Example 5. 4-phenyl-6-(piperidin-4-yl)-N-(2-(trifluoromethyl)pyridin-4- yl)pyrimidin-2-amine (compound 7e, Scheme 1) Step 1 of Example 1 was carried out followed by the further steps listed below. Step 2. tert-butyl 4-(6-phenyl-2-((2-(trifluoromethyl)pyridin-4- yl)amino)pyrimidin-4-yl)- dihydropyridine-1(2H)-carboxylate (compound 5e as two isomeric mixture α + β, Scheme 1). Title compound was synthesized following the general procedure 1 previously described using intermediate 3 (100 mg, 0.27 mmol), aniline 4e (52.3 mg, 0.32 mmol) in 1,4 dioxane (1.8 mL), Pd(OAc)2 (2.7 mg, 0.012 mmol), (±)- BINAP(7.4 mg, 0.012 mmol), Cs2CO3 (131.0 mg, 0.40 mmol). Purification by silica (elution by gradient from 100 / 0 to 75 / 25 cyclohexane / EtOAc) afforded pure intermediate 5e (85.6 mg, 80% combined yield of the two isomers: an isomerization of the double bond occurred during the reaction). UPLC / MS: Rt: 2.30 min (gradient 2), MS (ESI) m / z: 498.1 [M+H]+.[M+H]+Calculated for C26H27F3N5O2: 498.5. The mixture was used as such in the step 3. Step 3. tert-butyl 4-(6-phenyl-2-((2-(trifluoromethyl)pyridin-4- yl)amino)pyrimidin-4-yl)piperidine-1-carboxylate (compound 6e, Scheme 1). Titled compound was synthesized following the general procedure 2-Method A previously described using intermediate 5e as isomeric mixture (100 mg, 0.20 mmol), Pd(OH)2 / C (20 mg), NH4CO2H (79 mg, 1.26 mmol) in MeOH (5.2 mL). Purification by silica (elution by gradient from 100 / 0 to 85 / 15 cyclohexane / EtOAc) afforded pure intermediate 6e (64.9 mg, 65% yield). UPLC / MS Rt: 2.25 min (gradient 2), MS (ESI) m / z: 500.1 [M+H]+.[M+H]+Calculated for C26H29F3N5O2: 500.5.1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 5.6 Hz, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.12 – 8.01 (m, 2H), 7.69 (dd, J = 5.6, 2.2 Hz, 2H), 7.57 – 7.48 (m, 3H), 7.21 (s, 1H), 4.30 (bs, 2H), 3.00 – 2.85 (m, 2H), 2.82 (tt, J = 11.9, 3.6 Hz, 1H), 1.98 (d, J = 12.9 Hz, 2H), 1.81 (qd, J = 12.5, 4.3 Hz, 3H), 1.50 (s, 9H). Step 4. 4-phenyl-6-(piperidin-4-yl)-N-(2-(trifluoromethyl)pyridin-4- yl)pyrimidin-2-amine (compound 7e, scheme 1). Titled compound was synthesized following the general procedure 3 previously described using intermediate 6e (70 mg, 0.14 mmol), HCl (4 M in dioxane) (0.35 mL) in 1,4-dioxane dry (2.3 mL). Purification by alumina (elution by gradient from 100 / 0 to 96 / 4 DCM / MeOH) afforded pure compound 7e (25.1 mg, 45% yield). UPLC / MS Rt: 2.05 min (gradient 1), MS (ESI) m / z: 400.0 [M+H]+.[M+H]+Calculated for C21H21F3N5: 400.4.1H NMR (400 MHz, DMSO- d6) δ 10.51 (s, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.54 (d, J = 5.6 Hz, 1H), 8.20 (dd, J = 6.7, 2.9 Hz, 2H), 7.98 (dd, J = 5.7, 2.1 Hz, 1H), 7.61 – 7.55 (m, 3H), 7.54 (s, 1H), 3.06 (dt, J = 12.1, 3.2 Hz, 2H), 2.79 (tt, J = 11.8, 3.7 Hz, 1H), 2.61 (td, J = 12.1, 2.5 Hz, 2H), 1.86 (d, J = 11.9 Hz, 2H), 1.71 (qd, J = 12.2, 4.0 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 175.9 (Cq), 164.2 (Cq), 159.3 (Cq), 150.5 (Cq), 149.0 (Cq), 147.2 (q,2JF = 32.9 Hz, Cq), 136.5 (Cq), 131.1 (CH), 128.9 (CH, 2C), 127.1 (CH, 2C), 121.9 (q,1JF = 273.4 Hz, Cq), 114.7 (CH), 109.1 (q,3JF = 3.4 Hz, CH), 107.8 (CH), 46.2 (CH2), 44.2 (CH), 31.8 (CH2). Example 6. N-(2-(difluoromethoxy)pyridin-4-yl)-4-phenyl-6-(piperidin-4- yl)pyrimidin-2-amine (compound 7f, Scheme 1). Step 1 of Example 1 was carried out followed by the further steps listed below. Step 2. tert-butyl 4-(2-((2-(difluoromethoxy)pyridin-4-yl)amino)-6- phenylpyrimidin-4-yl) -dihydropyridine-1(2H)-carboxylate (compound 5f as two isomeric mixture α + β, scheme 1). Title compound was synthesized following the general procedure 1 previously described using intermediate 3 (100 mg, 0.27 mmol), aniline 4f (51.7 mg, 0.32 mmol) in 1,4 dioxane (1.8 mL), Pd(OAc)2 (2.7 mg, 0.012 mmol), (±)- BINAP (7.4 mg, 0.012 mmol), Cs2CO3 (131.0 mg, 0.40 mmol). Purification by silica (elution by gradient from 100 / 0 to 80 / 20 cyclohexane / EtOAc) afforded pure intermediate 5f (85.6 mg, 80% combined yield of the two isomers: an isomerization of the double bond occurred during the reaction). UPLC / MS: Rt: 2.30 min (gradient 2), MS (ESI) m / z: 496.1 [M+H]+.[M+H]+Calculated for C26H28F2N5O3: 496.5. The mixture was used as such in the step 3. Step 3. tert-butyl 4-(6-phenyl-2-((2-(trifluoromethyl)pyridin-4- yl)amino)pyrimidin-4-yl)piperidine-1-carboxylate (compound 6f, Scheme 1). Titled compound was synthesized following the general procedure 2-Method A previously described using intermediate 5f as isomeric mixture (75 mg, 0.15 mmol), Pd(OH)2 / C (15 mg), NH4CO2H (76.3 mg, 1.21 mmol) in MeOH (5.2 mL). Purification by silica (elution by gradient from 100 / 0 to 80 / 20 cyclohexane / EtOAc) afforded pure intermediate 6f (63.4 mg, 85% yield). UPLC / MS Rt: 2.21 min (gradient 2), MS (ESI) m / z: 498.1 [M+H]+.[M+H]+Calculated for C26H30F2N5O3: 498.61H NMR (400 MHz, CDCl3) δ 8.11 – 8.02 (m, 3H), 7.61 – 7.52 (m, 4H), 7.48 (t, J = 73.3 Hz, 1H), 7.33 (dd, J = 5.8, 1.9 Hz, 1H), 7.20 (s, 1H), 4.30 (bs, 2H), 2.93 – 2.87 (m, 3H), 2.02 (d, J = 12.6 Hz, 2H), 1.81 (qd, J = 12.4, 4.4 Hz, 3H), 1.49 (s, 9H). Step 4. 4-phenyl-6-(piperidin-4-yl)-N-(2-(trifluoromethyl)pyridin-4- yl)pyrimidin-2-amine (compound 7f, Scheme 1). Titled compound was synthesized following the general procedure 3 previously described using intermediate 6f (70 mg, 0.14 mmol), HCl (4 M in dioxane) (0.35 mL) in 1,4-dioxane dry (2.3 mL). Purification by alumina (elution by gradient from 100 / 0 to 96 / 4 DCM / MeOH) afforded pure compound 7f (25.1 mg, 45% yield). UPLC / MS Rt: 2.05 min (gradient 1), MS (ESI) m / z: 400.0 [M+H]+.[M+H]+Calculated for C21H21F3N5: 400.4.1H NMR (400 MHz, DMSO- d6) δ 10.51 (s, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.54 (d, J = 5.6 Hz, 1H), 8.20 (dd, J = 6.7, 2.9 Hz, 2H), 7.98 (dd, J = 5.7, 2.1 Hz, 1H), 7.61 – 7.55 (m, 3H), 7.54 (s, 1H), 3.06 (dt, J = 12.1, 3.2 Hz, 2H), 2.79 (tt, J = 11.8, 3.7 Hz, 1H), 2.61 (td, J = 12.1, 2.5 Hz, 2H), 1.86 (d, J = 11.9 Hz, 2H), 1.71 (qd, J = 12.2, 4.0 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 175.9 (Cq), 164.2 (Cq), 159.3 (Cq), 150.5 (Cq), 149.0 (Cq), 147.2 (q,2JF = 32.9 Hz, Cq), 136.5 (Cq), 131.1 (CH), 128.9 (CH, 2C), 127.1 (CH, 2C), 121.9 (q,1JF = 273.4 Hz, Cq), 114.7 (CH), 109.1 (q,3JF = 3.4 Hz, CH), 107.8 (CH), 46.2 (CH2), 44.2 (CH), 31.8 (CH2). Example 7. N-(2-methoxypyridin-4-yl)-4-phenyl-6-(piperidin-4- yl)pyrimidin-2-amine (compound 7g, Scheme 1) Step 1 of Example 1 was carried out followed by the further steps listed below. Step 2. tert-butyl 4-(2-((2-methoxypyridin-4-yl)amino)-6-phenylpyrimidin- 4-yl)- dihydropyridine-1(2H)-carboxylate (compound 5g as two isomeric mixture α + β, scheme 1). Title compound was synthesized following the general procedure 1 previously described using intermediate 3 (100 mg, 0.27 mmol), aniline 4g (40.0 mg, 0.32 mmol) in 1,4 dioxane (1.8 mL), Pd(OAc)2 (2.7 mg, 0.012 mmol), Xantphos (6.9 mg, 0.012 mmol), Cs2CO3 (131.0 mg, 0.40 mmol). Purification by silica (elution by gradient from 80 / 20 to 75 / 25 cyclohexane / EtOAc) afforded pure intermediate 5g (74.1 mg, 60% combined yield of the two isomers: an isomerization of the double bond occurred during the reaction). UPLC / MS. There are two main picks related to the isomers. Rt1: 1.95 min; Rt2 = 2.05 min (gradient 2), MS (ESI) m / z: 460.1 [M+H]+.[M+H]+Calculated for C26H30N5O3: 460.6. The mixture was used as such in the step 3. Step 3. tert-butyl 4-(2-((2-methoxypyridin-4-yl)amino)-6-phenylpyrimidin- 4-yl)piperidine-1-carboxylate (compound 6g, Scheme 1). Titled compound was synthesized following the general procedure 2-Method A previously described using intermediate 5f as isomeric mixture (80 mg, 0.17 mmol), Pd(OH)2 / C (16 mg), NH4CO2H (64.4 mg, 1.02 mmol) in MeOH (5.5 mL). Purification by silica (elution by gradient from 85 / 15 to 75 / 25 cyclohexane / EtOAc) afforded pure intermediate 6f (64.2 mg, 80% yield). UPLC / MS Rt: 1.95 min (gradient 2), MS (ESI) m / z: 462.1 [M+H]+.[M+H]+Calculated for C26H32N5O3: 462.6.1H NMR (400 MHz, CDCl3) δ 8.04 (m, 3H), 7.64 (s, 1H), 7.55 – 7.49 (m, 3H), 7.47 (bs, 1H), 7.19 (dd, J = 6.0, 2.0 Hz, 1H), 7.15 (s, 1H), 4.29 (bs, 2H), 3.99 (s, 3H), 2.97 – 2.83 (m, 2H), 2.88 (tt, J = 11.8, 3.6 Hz, 1H), 1.97 (d, J = 12.5 Hz, 2H), 1.81 (qd, J = 12.5, 4.3 Hz, 2H), 1.49 (s, 9H). Step 4. N-(2-methoxypyridin-4-yl)-4-phenyl-6-(piperidin-4-yl)pyrimidin-2- amine (compound 7f, Scheme 1). Titled compound was synthesized following the general procedure 3 previously described using intermediate 6f (70 mg, 0.15 mmol), HCl (4 M in dioxane) (0.37 mL) in 1,4-dioxane dry (2.5 mL). Purification by alumina (elution by gradient from 100 / 0 to 95 / 5 CHCl3 / MeOH) afforded pure compound 7f (21.1 mg, 39% yield). UPLC / MS Rt: 1.70 min (gradient 1), MS (ESI) m / z: 362.1 [M+H]+.[M+H]+Calculated for C21H24N5O: 362.5.1H NMR (400 MHz, DMSO- d6) δ 10.01 (s, 1H), 8.17 (dd, J = 6.7, 2.8 Hz, 2H), 7.97 (d, J = 5.8 Hz, 1H), 7.58 – 7.54 (m, 3H), 7.50 (d, J = 1.8 Hz, 1H), 7.44 (s, 1H), 7.37 (dd, J = 5.8, 1.9 Hz, 1H), 3.83 (s, 3H), 3.08 (dt, J = 11.8, 2.8 Hz, 2H), 2.75 (tt, J = 11.8, 3.7 Hz, 1H), 2.60 (td, J = 12.1, 2.5 Hz, 2H), 1.84 (d, J = 12.4 Hz, 2H), 1.70 (qd, J = 12.2, 4.0 Hz, 2H).13C NMR (101 MHz, DMSO- d6) δ 175.7 (Cq), 164.7 (Cq), 164.1 (Cq), 159.7 (Cq), 149.7 (Cq), 146.7 (CH), 136.8 (Cq), 130.9 (CH), 128.9 (CH, 2C), 127.0 (CH, 2C), 108.0 (CH), 106.9 (CH), 97.0 (CH), 53.0 (CH3), 46.2 (CH2), 44.4 (CH), 31.8 (CH2). Example 8. N-(6-methoxypyridin-3-yl)-4-phenyl-6-(piperidin-4- yl)pyrimidin-2-amine (compound 7h, Scheme 1) Step 1 of Example 1 was carried out followed by the further steps listed below. Step 2. tert-butyl 4-(2-((6-methoxypyridin-3-yl)amino)-6-phenylpyrimidin- 4-yl)- dihydropyridine-1(2H)-carboxylate (compound 5h as two isomeric mixture α + β, Scheme 1). Title compound was synthesized following the general procedure 1 previously described using intermediate 3 (100 mg, 0.27 mmol), aniline 4h (40.0 mg, 0.32 mmol) in 1,4 dioxane (1.8 mL), Pd(OAc)2(2.7 mg, 0.012 mmol), Xantphos (6.9 mg, 0.012 mmol), Cs2CO3(131.0 mg, 0.40 mmol). Purification by silica (elution by gradient from 80 / 20 to 75 / 25 cyclohexane / EtOAc) afforded pure intermediate 5h (82.3 mg, 66% combined yield of the two isomers: an isomerization of the double bond occurred during the reaction). UPLC / MS. There are two main picks related to the isomers. Rt1: 2.01 min; Rt2= 2.05 min (gradient 2), MS (ESI) m / z: 460.1 [M+H]+.[M+H]+Calculated for C26H30N5O3: 460.6. The mixture was used as such in the step 3. Step 3. tert-butyl 4-(2-((6-methoxypyridin-3-yl)amino)-6-phenylpyrimidin- 4-yl)piperidine-1-carboxylate (compound 6h, Scheme 1). Titled compound was synthesized following the general procedure 2-Method A previously described using intermediate 5h as isomeric mixture (80 mg, 0.17 mmol), Pd(OH)2 / C (16 mg), NH4CO2H (64.4 mg, 1.02 mmol) in MeOH (5.5 mL). Purification by silica (elution by gradient from 85 / 15 to 75 / 25 cyclohexane / EtOAc) afforded pure intermediate 6h (44.9 mg, 56% yield). UPLC / MS Rt: 1.91 min (gradient 2), MS (ESI) m / z: 462.1 [M+H]+.[M+H]+Calculated for C26H32N5O3: 462.61H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 2.7 Hz, 1H), 8.06 – 8.00 (m, 2H), 7.98 (dd, J = 8.9, 2.8 Hz, 1H), 7.50 (dd, J = 5.1, 1.9 Hz, 3H), 7.03 (s, 1H), 6.78 (d, J = 9.0 Hz, 1H), 4.27 (s, 2H), 3.95 (s, 3H), 2.93 – 2.79 (m, 2H), 2.76 (tt, J = 11.9, 3.6 Hz, 1H), 1.97 (d, J = 13.0 Hz, 2H), 1.78 (qd, J = 12.5, 4.2 Hz, 2H), 1.49 (s, 9H). Step 4. N-(6-methoxypyridin-3-yl)-4-phenyl-6-(piperidin-4-yl)pyrimidin-2- amine (compound 7h, Scheme 1). Titled compound was synthesized following the general procedure 3 previously described using intermediate 6h (44 mg, 0.09 mmol), HCl (4 M in dioxane) (0.24 mL) in 1,4-dioxane dry (1.5 mL). Purification by alumina (elution by gradient from 100 / 0 to 93 / 7 DCM / MeOH) afforded pure compound 7h (12.4 mg, 38% yield). UPLC / MS Rt: 1.79 min (gradient 1), MS (ESI) m / z: 362.0 [M+H]+.[M+H]+Calculated for C21H24N5O: 362.5.1H NMR (400 MHz, DMSO- d6) δ 9.48 (s, 1H), 8.68 (d, J = 2.7 Hz, 1H), 8.13 (dd, J = 6.7, 3.0 Hz, 2H), 8.07 (dd, J = 8.9, 2.8 Hz, 1H), 7.57 – 7.48 (m, 3H), 7.28 (s, 1H), 6.81 (d, J = 8.9 Hz, 1H), 3.83 (s, 3H), 3.07 (d, J = 11.8 Hz, 2H), 2.73 (tt, J = 11.9, 3.6 Hz, 1H), 2.62 (td, J = 12.2, 1.7 Hz, 2H), 1.83 (d, J = 12.0 Hz, 2H), 1.69 (qd, J = 12.3, 4.0 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 174.9 (Cq), 164.6 (Cq), 160.6 (Cq), 159.0 (Cq), 137.5 (CH), 137.4 (Cq), 132.2 (Cq), 131.8 (CH), 131.2 (CH), 129.3 (CH, 2C), 127.4 (CH, 2C), 110.2 (CH), 105.9 (CH), 53.5 (CH3), 45.1 (CH2), 30.1 (CH2). Example 9. N-(3,4-dimethoxyphenyl)-4-phenyl-6-(piperidin-4-yl)pyrimidin- 2-amine (compound 7i, Scheme 1) Step 1 of Example 1 was carried out followed by the further steps listed below. Step 2. tert-butyl 4-(2-((3,4-dimethoxyphenyl)amino)-6-phenylpyrimidin-4- yl)- dihydropyridine-1(2H)-carboxylate (compound 5i as two isomeric mixture α + β, Scheme 1). Title compound was synthesized following the general procedure 1 previously described using intermediate 3 (200 mg, 0.54 mmol), aniline 4i (99.0 mg, 0.64 mmol) in 1,4 dioxane (3.6 mL), Pd(OAc)2(6.0 mg, 0.025 mmol), Xantphos (15.5 mg, 0.025 mmol), Cs2CO3(263.0 mg, 0.81 mmol). Purification by silica (elution by gradient from 80 / 20 to 75 / 25 cyclohexane / EtOAc) afforded pure intermediate 5i (197.9 mg, 75% combined yield of the two isomers: an isomerization of the double bond occurred during the reaction). UPLC / MS. Rt: 1.97 min (gradient 2), MS (ESI) m / z: 489.1 [M+H]+.[M+H]+Calculated for C28H33N4O4: 489.6. The mixture was used as such in the step 3. Step 3. tert-butyl 4-(2-((3,4-dimethoxyphenyl)amino)-6-phenylpyrimidin-4- yl)piperidine-1-carboxylate (compound 6i, Scheme 1). Titled compound was synthesized following the general procedure 2-Method A previously described using intermediate 5i as isomeric mixture (197 mg, 0.40 mmol), Pd(OH)2 / C (39.4 mg), NH4CO2H (151.4 mg, 2.5 mmol) in MeOH (10.0 mL). Purification by silica (elution by gradient from 100 / 0 to 75 / 25 cyclohexane / EtOAc) afforded pure intermediate 6i (174.6 mg, 89% yield). UPLC / MS Rt: 1.91 min (gradient 2), MS (ESI) m / z: 491.1 [M+H]+.[M+H]+Calculated for C28H35N4O4: 491.61H NMR (400 MHz, CDCl3) δ 8.10 – 8.00 (m, 2H), 7.85 (s, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.53 – 7.45 (m, 3H), 7.04 (dd, J = 8.5, 2.4 Hz, 1H), 7.01 (s, 1H), 6.86 (d, J = 8.7 Hz, 1H), 4.27 (bs, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 2.89 – 2.81 (m, 2H), 2.79 (tt, J = 11.8, 3.9 Hz, 1H), 1.99 (d, J = 13.1 Hz, 2H), 1.80 (qd, J = 12.5, 4.4 Hz, 2H), 1.48 (s, 9H). Step 4. N-(3,4-dimethoxyphenyl)-4-phenyl-6-(piperidin-4-yl)pyrimidin-2- amine (compound 7i, Scheme 1). Titled compound was synthesized following the general procedure 3 previously described using intermediate 6i (30 mg, 0.06 mmol), HCl (4 M in dioxane) (0.15 mL) in 1,4-dioxane dry (1.0 mL). Purification by alumina (elution by gradient from 100 / 0 to 95 / 5 DCM / MeOH) afforded pure compound 7i (12.4 mg, 38% yield). UPLC / MS Rt: 1.79 min (gradient 1), MS (ESI) m / z: 391.0 [M+H]+.[M+H]+Calculated for C23H27N4O2: 391.5.1H NMR (400 MHz, DMSO- d6) δ 9.35 (s, 1H), 8.21 – 8.11 (m, 2H), 7.78 (d, J = 2.4 Hz, 1H), 7.57 – 7.49 (m, 3H), 7.26 (dd, J = 8.6, 2.4 Hz, 1H), 7.25 (s, 1H), 6.90 (d, J = 8.7 Hz, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 3.05 (d, J = 12.0 Hz, 2H), 2.70 (tt, J = 11.9, 4.4 Hz, 1H), 2.59 (td, J = 12.0, 2.5 Hz, 2H), 1.82 (d, J = 12.4 Hz, 2H), 1.70 (qd, J = 12.2, 4.0 Hz, 2H). Example 10. methyl 2-methoxy-5-((4-phenyl-6-(piperidin-4-yl)pyrimidin-2- yl)amino)benzoate (compound 7j, Scheme 1) Step 1 of Example 1 was carried out followed by the further steps listed below. Step 2. tert-butyl 4-(2-((4-methoxy-3-(methoxycarbonyl)phenyl)amino)-6- phenylpyrimidin-4-yl)- dihydropyridine-1(2H)-carboxylate (compound 5j as two isomeric mixture α + β, Scheme 1). Title compound was synthesized following the general procedure 1 previously described using intermediate 3 (200 mg, 0.54 mmol), aniline 4j (117.0 mg, 0.64 mmol) in 1,4 dioxane (3.6 mL), Pd(OAc)2(6.0 mg, 0.025 mmol), Xantphos (15.5 mg, 0.025 mmol), Cs2CO3(263.0 mg, 0.81 mmol). Purification by silica (elution by gradient from 100 / 0 to 75 / 25 cyclohexane / EtOAc) afforded pure intermediate 5j (236.4 mg, 85% combined yield of the two isomers: an isomerization of the double bond occurred during the reaction). UPLC / MS. Rt: 1.92 min (gradient 2), MS (ESI) m / z: 517.1 [M+H]+.[M+H]+Calculated for C29H33N4O5: 517.6. The mixture was used as such in the step 3. Step 3. tert-butyl 4-(2-((4-methoxy-3-(methoxycarbonyl)phenyl)amino)-6- phenylpyrimidin-4-yl)piperidine-1-carboxylate (compound 6j, Scheme 1). Titled compound was synthesized following the general procedure 2-Method A previously described using intermediate 5j as isomeric mixture (270 mg, 0.52 mmol), Pd(OH)2 / C (54.0 mg), NH4CO2H (196.8 mg, 3.1 mmol) in MeOH (13.0 mL). Purification by silica (elution by gradient from 100 / 0 to 75 / 25 DCM / EtOAc) afforded pure intermediate 6j (371.3 mg, 73% yield). UPLC / MS Rt: 1.88 min (gradient 2), MS (ESI) m / z: 519.1 [M+H]+.[M+H]+Calculated for C29H35N4O5: 519.61H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 2.9 Hz, 1H), 8.10 – 8.05 (m, 2H), 7.75 (dd, J = 8.9, 2.9 Hz, 1H), 7.53 – 7.48 (m, 3H), 7.05 (s, 1H), 7.00 (d, J = 9.0 Hz, 1H), 4.28 (s, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 2.84 (m, 3H), 2.00 (d, J = 13.0 Hz, 2H), 1.80 (qd, J = 12.5, 4.3 Hz, 2H), 1.49 (s, 9H). Step 4. methyl 2-methoxy-5-((4-phenyl-6-(piperidin-4-yl)pyrimidin-2- yl)amino)benzoate (compound 7j, Scheme 1). Titled compound was synthesized following the general procedure 3 previously described using intermediate 6j (51.8 mg, 0.1 mmol), HCl (4 M in dioxane) (0.200 mL) in 1,4-dioxane dry (2.5 mL). Purification by alumina (elution by gradient from 100 / 0 to 95 / 5 DCM / MeOH) afforded pure compound 7j (17.6 mg, 42% yield). UPLC / MS Rt: 1.79 min (gradient 1), MS (ESI) m / z: 319.1 [M+H]+.[M+H]+Calculated for C24H27N4O3: 319.5.1H NMR (400 MHz, DMSO- d6) δ 9.56 (s, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.18 (m, 2H), 7.85 (dd, J = 9.0, 2.8 Hz, 1H), 7.58 – 7.48 (m, 3H), 7.29 (s, 1H), 7.13 (d, J = 9.1 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.05 (dt, J = 12.1, 3.2 Hz, 2H), 2.70 (tt, J = 11.8, 3.7 Hz, 1H), 2.59 (td, J = 12.1, 2.5 Hz, 2H), 1.83 (d, J = 12.8 Hz, 2H), 1.69 (qd, J = 12.2, 4.0 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 175.5 (Cq), 166.0 (Cq), 163.7 (Cq), 160.0 (Cq), 153.0 (Cq), 137.0 (Cq), 133.8 (Cq), 130.7 (CH), 128.8 (CH, 2C), 126.9 (CH, 2C), 123.9 (CH, 2C), 121.1 (CH), 119.4 (Cq), 113.2 (CH), 105.3 (CH), 56.1 (CH3), 51.8 (CH3), 46.2 (CH2), 44.3 (CH), 31.8 (CH2). Figure 2 reports the Scheme 2 showing the synthesis of compounds 8a, 8b. Example 11. 4-((4-phenyl-6-(piperidin-4-yl)pyrimidin-2-yl)amino)benzene- 1,2-diol (compound 8a, Scheme 2) Title compound was synthesized following the general procedure 4 previously described using intermediate 6i (66 mg, 0.13 mmol) and BBr3 (1 M in DCM) (0.78 mL, 0.78 mmol) in CHCl3 dry (2.2 mL). Purification by trituration with EtOAc (1.5 mL) afforded pure compound 8a (16.6 mg, 34% yield). UPLC / MS Rt: 2.48 min (gradient 4), MS (ESI) m / z: 363.0 [M+H]+.[M+H]+Calculated for C21H23N4O2: 363.4.1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.64 (d, J = 10.4 Hz, 1H), 8.37 (q, J = 10.5 Hz, 1H), 8.19 – 8.06 (m, 2H), 7.61 – 7.48 (m, 3H), 7.22 (d, J = 2.5 Hz, 1H), 7.21 (s, 1H), 7.08 (dd, J = 8.5, 2.5 Hz, 1H), 6.67 (d, J = 8.5 Hz, 1H), 3.41 (d, J = 12.9 Hz, 2H), 3.12 – 3.03 (m, 2H), 2.96 (tt, J = 11.4, 3.2 Hz, 1H), 2.13 (dd, J = 14.6, 3.7 Hz, 2H), 2.03 – 1.87 (m, 2H). Example 12. 2-hydroxy-5-((4-phenyl-6-(piperidin-4-yl)pyrimidin-2- yl)amino)benzoic acid (compound 8b, Scheme 2) Title compound was synthesized following the general procedure 4 previously described using intermediate 6i (31.1 mg, 0.06 mmol) and BBr3(1 M in DCM) (0.36 mL, 0.36 mmol) in CHCl3 dry (1.0 mL). Purification by trituration with EtOAc (1.0 mL) afforded pure compound 8b (9.6 mg, 41% yield). UPLC / MS Rt: 2.37 min (gradient 4), MS (ESI) m / z: 391.0 [M+H]+.[M+H]+Calculated for C22H23N4O3: 391.4.1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.57 (s, 1H), 8.74 (d, J = 11.2 Hz, 1H), 8.63 (s), 8.45 (q, J = 10.9 Hz, 1H), 8.22 – 8.20 (m, 2H), 7.81 (dd, J = 8.9, 2.8 Hz, 1H), 7.54 – 7.50 (m, 3H), 7.33 (s, 1H), 6.94 (d, J = 9.0 Hz, 1H), 3.40 (d, J = 12.4 Hz, 2H), 3.14 – 3.09 (m, 2H), 2.94 (tt, J = 11.4, 3.3 Hz, 1H), 2.18 (d, J = 13.8 Hz, 2H), 1.95 (qd, 12.4, 2.6 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 172.0 (Cq), 163.9 (Cq), 160.0 (Cq), 157.8 (Cq), 156.0 (Cq), 136.8 (Cq), 132.4 (Cq), 130.8 (CH), 128.8 (CH, 2C), 127.6 (CH), 127.0 (CH, 2C), 120.1 (CH), 116.9 (CH), 112.2 (Cq), 105.2 (CH), 43.0 (CH2), 40.2 (CH), 27.0 (CH2). Figure 3 reports Scheme 3 showing the synthesis of compound of type 13. Example 13. 4-(benzofuran-3-yl)-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine Step 1. 4,6-dichloro-N-(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 9, Scheme 3) Compound 9 was synthesized following general procedure 5 using: 3- trifluoromethyl aniline (320 µL, 2.17 mmol), 2,4,6-trichloro-1,3,5- triazine (520 mg, 2.82 mmol), DIPEA (416 µL, 2.39 mmol) and DCM (10 mL). After standard workup, the crude product was purified by CombiFlash automatic system (elution by gradient from 100 / 0 to 80 / 20 cyclohexane / EtOAc) giving pure product as white solid (600 mg, 89% yield). UPLC / MS: Rt = 1.47 min (gradient 2), [M + H]+= 309.0; [M + H]+calculated for C10H5Cl2F3N4: 308.0.1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.55 (t, J = 7.9 Hz, 2H), 7.48 (d, J = 7.7 Hz, 1H). Step 2. tert-butyl 4-(4-(benzofuran-3-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (compound 11a, Scheme 3) To a degassed 1,4-dioxane solution (0.13 M, 5.0 mL) of compound 10 (4,6- dichloro-N-(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine) (240 mg, 0.777 mmol), (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4- yl)boronic acid (211 mg, 0.932 mmol), Pd(dppf)Cl2*DCM (31.7 mg, 0.0388 mmol) and K2CO3(aq) 2 M (0.78 mL, 1.55 mmol) were added. Resulting mixture was sparged with Argon for further 10 minutes and heated up to 80°C until consumption of starting material was detected by UPLC (5 hours) Then, Pd(dppf)Cl2*DCM (31.7 mg, 0.0388 mmol) and new boronic acid benzofuran-3- ylboronic acid (151 mg, 0.932 mmol) were added and reaction mixture was heated up to 120°C until no intermediate was detected by UPLC. Then, H2O and EtOAc were added and separated; aqueous layers were extracted two times with AcOEt and collected organic layers were dried over Na2SO4. The solvent was evaporated and resulting crude was purified by silica (elution by gradient 100 / 0 to 70 / 30 cyclohexane / EtOAc) giving pure product 11a as white solid (189 mg, 45% yield for two steps). UPLC / MS: Rt = 1.73 min (gradient 3), [M + H]+= 538.0; [M + H]+calculated for C28H27F3N5O3: 538.4.1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.49 – 8.41 (m, 1H), 8.33 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.60 – 7.55 (m, 1H), 7.54 – 7.46 (m, 2H), 7.43 – 7.37 (m, 3H), 4.28 – 4.23 (m, 2H), 3.72 – 3.64 (m, 2H), 2.77 (s, 2H), 1.52 (s, 9H). Step 3. tert-butyl 4-(4-(benzofuran-3-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)piperidine-1- carboxylate (compound 12a, Scheme 3) Compound 12a was synthesized following general procedure 2-Method A using: compound 11a (170 mg, 0.316 mmol), ammonium formate (100 mg, 1.90 mmol), Pd(OH)2 / C (34 mg) and MeOH dry (3.2 mL). After 1.5 hours, standard workup has been performed and the crude product was purified by silica (elution by gradient 90 / 10 to 85 / 15 cyclohexane / EtOAc) giving pure product as white foaming solid (108 mg, 63% yield). UPLC / MS: Rt = 1.63 min (gradient 3), [M + H]+= 540.0; [M + H]+Calculated for C28H29F3N5O3: 540.4.1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.47 – 8.41 (m, 1H), 8.28 (s, 1H), 7.73 – 7.67 (m, 1H), 7.61 – 7.54 (m, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.43 – 7.33 (m, 4H), 4.24 (s, 2H), 3.01 – 2.83 (m, 3H), 2.20 – 2.04 (m, 2H), 1.89 (dd, J = 12.1, 4.3 Hz, 2H), 1.50 (s, 9H). Step . 4-(benzofuran-3-yl)-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (Compound 13a, Scheme 3) Compound 13a was synthesized following general procedure 3 using: 12a (102 mg, 0.19 mmol), HCl 4 M 1,4-dioxane solution (0.48 mL, 1.90 mmol), 1,4- dioxane (1.0 mL). After 7 hours, HCl 4 M (0.24 mL) has been added again and reaction mixture was stirred overnight. Further, HCl 4 M (0.24 mL) has been added and after 16 hours standard workup has been performed. The crude product was purified by neutral alumina (elution by gradient DCM / EtOH 100:0 to 90:10) giving pure product as white solid (3.5 mg, 4% yield). UPLC / MS: Rt = 1.27 min (gradient 2), [M + H]+= 440.0; [M + H]+Calculated for C23H21F3N5O: 440.5.1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.85 (s, 1H), 8.34 (d, J = 54.9 Hz, 2H), 8.03 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.51 – 7.32 (m, 3H), 3.10 – 3.02 (m, 2H), 2.84 – 2.73 (m, 1H), 2.68 – 2.56 (m, 2H), 2.05 – 1.91 (m, 2H), 1.81 – 1.67 (m, 2H).19F NMR (565 MHz, DMSO-d6) δ -60.20 Example 14. 4-(1-methyl-1H-indol-5-yl)-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13b, Scheme 3) Step 1 of Example 13 was carried out followed by the further steps listed below. Step 2. tert-butyl 4-(4-chloro-6-((3-(trifluoromethyl)phenyl)amino)- 1,3,5-triazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (compound 10, Scheme 3) Compound 10 was synthesized following general procedure 6 using: intermediate 9 (1.0 g, 3.247 mmol), (1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)boronic acid (885 mg, 3.9 mmol), Pd(dppf)Cl2•DCM (132 mg, 0.162 mmol), K2CO3(aq) 2 M (3.3 mL, 6.49 mmol) and 1,4-dioxane dry (20 mL). After 5 hours, standard workup has been performed. Purification by gradient (elution by gradient 100 / 0 to 70 / 30 cyclohexane / EtOAc) giving pure product as white solid (816 mg, 55% yield). UPLC / MS: Rt = 2.26 min (gradient 2), [M + H]+= 456.0; [M + H]+Calculated for C20H21ClF3N5O2: 456.4. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.30 (s, 1H), 7.90 (s, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.33 (s, 1H), 4.14 (s, 2H), 3.51 (t, J = 5.8 Hz, 2H), 2.56 – 2.51 (m, 2H), 1.42 (s, 9H). Step 3. tert-butyl 4-(4-(1-methyl-1H-indol-5-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (compound 11b, Scheme 3).

[0003] Compound 11b was synthesized following general procedure 6 using: compound 10 (200 mg, 0.438 mmol), (1-methyl-1H-indol-5-yl)boronic acid (92 mg, 0.526 mmol), Pd(dppf)Cl2•DCM (17.9 mg, 0.022 mmol), K2CO3(aq) 2 M (0.44 mL, 0.876 mmol) in 1,4 dioxane dry (3.4 mL). Purification by silica (elution by gradient from 100 / 0 to 70 / 30 cyclohexane / EtOAc) afforded pure product as yellowish solid (180 mg, 74% yield). UPLC / MS: Rt = 1.50 min (gradient 3), [M + H]+= 551.0; [M + H]+Calculated for C29H30F3N6O2: 552.6.1H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 1.6 Hz, 1H), 8.48 – 8.38 (m, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.58 – 7.46 (m, 2H), 7.43 – 7.35 (m, 2H), 7.12 (d, J = 3.2 Hz, 1H), 6.63 (d, J = 3.3 Hz, 1H), 4.28 – 4.23 (m, 2H), 3.85 (s, 3H), 3.73 – 3.60 (m, 2H), 2.86 – 2.74 (m, 2H), 1.51 (s, 9H). Step . tert-butyl 4-(4-(1-methyl-1H-indol-5-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)piperidine-1- carboxylate (compound 12b, Scheme 3)

[0004] Compound 12b was synthesized following general procedure 2-Method A using: compound 11b (155 mg, 0.282 mmol), ammonium formate (106.8 mg, 1.69 mmol), Pd(OH)2 / C (31 mg) and dry EtOH (4.0 mL) and THF (3.0 mL). Purification by silica (elution by gradient 95 / 5 to 70 / 30 cyclohexane / EtOAc) giving pure product 12b as white foaming solid (105.0 mg, 67% yield). UPLC / MS: Rt = 1.42 min (gradient 3), [M + H]+ = 553.0; [M + H]+ Calculated for C29H32F3N6O2: 553.6.1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.75 (d, J = 1.6 Hz, 1H), 8.61 (s, 1H), 8.28 (dd, J = 8.7, 1.7 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.65 – 7.54 (m, 2H), 7.47 – 7.37 (m, 2H), 6.60 (d, J = 3.1 Hz, 1H), 4.12 – 3.98 (m, 2H), 3.85 (s, 3H), 3.05 – 2.81 (m, 3H), 2.10 – 1.97 (m, 2H), 1.81 – 1.66 (m, 2H), 1.43 (s, 9H). Step 5. 4-(1-methyl-1H-indol-5-yl)-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13b, Scheme 3).

[0005] Compound 13b was synthesized following general procedure 3 using: compound 12b (100 mg, 0.18 mmol), HCl 4 M 1,4-dioxane solution (0.45 mL, 1.8 mmol), 1,4-dioxane (3.0 mL). After 3.5 hours, standard workup has been performed. Purification by silica (elution by gradient from 95 / 5 to 80 / 20 DCM / MeOH (1N NH3)) afforded not pure compound, that have been subjected to trituration with petroleum ether giving pure product as white solid (40 mg, 49% yield). UPLC / MS: Rt = 1.18 min (gradient 2), [M + H]+= 453.0; Calculated for [M + H]+C24H24F3N6: 452.2.1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.75 (d, J = 1.6 Hz, 1H), 8.61 (s, 1H), 8.28 (dd, J = 8.8, 1.7 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.66 – 7.54 (m, 2H), 7.43 (d, J = 3.1 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 6.60 (d, J = 3.1 Hz, 1H), 3.85 (s, 3H), 3.14 – 3.02 (m, 2H), 2.78 (t, J = 11.6 Hz, 1H), 2.72 – 2.57 (m, 2H), 2.06 – 1.89 (m, 2H), 1.85 – 1.68 (m, 2H).19F NMR (565 MHz, DMSO-d6) δ -61.26. Example 15. 4-(1-methyl-1H-pyrazol-4-yl)-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13c, Scheme 3) Step 1 and step 2 of examples 13 and 14 were carried out followed by the further steps listed below. Step 3. tert-butyl 4-(4-(1-methyl-1H-pyrazol-4-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (compound 11c, Scheme 3).

[0006] Compound 11c was synthesized following general procedure 6 using: compound 10 (200 mg, 0.44 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (66.5 mg, 0.528 mmol), Pd(dppf)Cl2DCM (18.0 mg, 0.022 mmol), K2CO3 (2 M)aq (0.44 mL, 0.876 mmol) in 1,4-dioxane dry (3.4 mL). After 1.5 hours, standard workup has been performed. Purification by silica (elution by gradient from 90 / 10 to 40 / 60 cyclohexane / EtOAc) afforded pure product as white solid (143 mg, 65% yield). UPLC / MS: Rt = 0.67 min (gradient 3), [M + H]+= 502.0; [M + H]+Calculated for C24H27F3N7O2: 502.5.1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.51 – 7.32 (m, 3H), 4.25 – 4.17 (m, 2H), 3.98 (s, 3H), 3.67 – 3.59 (m, 2H), 2.77 – 2.63 (m, 2H), 1.50 (s, 9H). Step 4. tert-butyl 4-(4-(1-methyl-1H-pyrazol-4-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)piperidine-1- carboxylate (compound 12c, Scheme 3).

[0007] Compound 12c was synthesized following general procedure 2-Method A using: compound 11c (132 mg, 0.263 mmol), ammonium formate (99.6 mg, 1.58 mmol), Pd(OH)2 / C (26.4 mg) in EtOH dry (4.4 mL) and THF dry (2.2 mL). After 1 hour, standard workup has been performed. Purification by silica (elution by gradient from 80 / 20 to 50 / 50 cyclohexane / EtOAc) afforded pure product as white solid (78 mg, 59% yield). UPLC / MS: Rt = 1.68 mins, [M + H]+= 504.0; [M + H]+Calculated for C24H29F3N7O2: 504.5.1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.48 – 8.37 (m, 2H), 8.04 (s, 1H), 8.04 (d, J = 0.7 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 7.4 Hz, 1H), 4.06 – 3.98 (m, 2H), 3.93 (s, 3H), 3.02 – 2.75 (m, 3H), 2.06 – 1.88 (m, 2H), 1.74 – 1.59 (m, 2H), 1.42 (s, 9H). Step 5. 4-(1-methyl-1H-pyrazol-4-yl)-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13c, Scheme 3). Compound 13c was synthesized following general procedure 3 using: compound 12c (75 mg, 0.14 mmol), HCl 4 M 1,4-dioxane solution (0.35 mL, 1.4 mmol), 1,4-dioxane (1.0 mL). After 16 hours, standard workup has been performed. Purification by silica (elution by gradient from 100 / 0 to 90 / 10 DCM / MeOH(1N NH3)) afforded pure product as white solid (43 mg, 76% yield). UPLC / MS: Rt = 1.76 min (gradient 1), [M + H]+= 404.0; [M + H]+Calculated for C19H21F3N7: 403.4.1H NMR (600 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.42 (s, 1H), 8.41 (s, 1H), 8.07 – 7.96 (m, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 6.0 Hz, 1H), 3.93 (s, 3H), 3.04 (dt, J = 12.3, 3.4 Hz, 2H), 2.72 – 2.67 (m, 1H), 2.60 (td, J = 12.1, 2.5 Hz, 2H), 1.97 – 1.85 (m, 2H), 1.69 (qd, J = 12.1, 3.9 Hz, 2H).19F NMR (565 MHz, DMSO-d6) δ -60.31 Example 16. 4-(piperidin-4-yl)-6-(pyrrolidin-2-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13d, Scheme 3) Step 1 and step 2 of examples 13 and 14 were carried out followed by the further steps listed below. Step 3. tert-butyl 4-(4-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (11d, Scheme 3) Compound 11d was synthesized following general procedure 6 using: compound 10 (200 mg, 0.44 mmol), (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (111 mg, 0.528 mmol), Pd(dppf)Cl2•DCM (18.0 mg, 0.022 mmol), K2CO3(2 M)aq (0.44 mL, 0.876 mmol) 1,4-dioxane dry (3.4 mL). After 3 hours, standard workup has been performed. Purification by silica (elution by gradient 100 / 0 to 80 / 20 cyclohexane / EtOAc) afforded pure product as white solid (170 mg, 65% yield). UPLC / MS: Rt = 1.68 min (gradient 2), [M + H]+= 587.3; [M + H]+Calculated for C29H34F3N6O4: 587.6.1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.71 (s, 1H), 7.54 – 7.31 (m, 5H), 6.96 (t, J = 3.6, 1.7 Hz, 1H), 6.28 (t, J = 3.3 Hz, 1H), 4.18 (s, 2H), 3.68 – 3.56 (m, 2H), 2.69 (s, 2H), 1.50 (s, 9H), 1.47 (s, 9H). Step 4. tert-butyl 4-(4-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)piperidine-1- carboxylate (compound 12d, Scheme 3) Compound 12d was synthesized following general procedure 2-Method A using: compound 11d (145 mg, 0.247 mmol), ammonium formate (93.4 mg, 1.48 mmol), Pd(OH)2 / C (29 mg) and dry EtOH (6.0 mL). After 1 hour, standard workup has been performed. Purification by silica (elution by gradient 90 / 10 to 60 / 40 cyclohexane / EtOAc) afforded pure product as white foaming solid (127 mg, 86% yield). UPLC / MS: Rt = 2.25 min (gradient 2), [M + H]+= 593.0; [M + H]+Calculated for C29H40F3N6O4: 592.7.1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.36 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.59 – 7.50 (m, 1H), 7.42 – 7.34 (m, 1H), 4.64 – 4.50 (m, 1H), 4.07 – 3.90 (m, 2H), 3.62 – 3.38 (m, 2H), 2.99 – 2.76 (m, 3H), 2.42 – 2.26 (m, 1H), 2.06 – 1.76 (m, 5H), 1.72 – 1.52 (m, 2H), 1.40 (s, 9H), 1.10 (s, 9H).NMR Step 5. 4-(piperidin-4-yl)-6-(pyrrolidin-2-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13d, Scheme 3) Compound 13d was synthesized following general procedure 3 using: compound 12d (123 mg, 0.21 mmol), HCl 4 M 1,4-dioxane solution (0.53 mL, 2.1 mmol), 1,4-dioxane (1.2 mL). After 16 hours, no conversion occurred; thus, HCl 4 M (3.5 mL) was added and reaction mixture was stirred over weekend. Then, standard workup has been performed. Purification by silica (elution by gradient 100 / 0 to 90 / 10 DCM / MeOH (1 N NH3)) afforded yellowish unclean solid that was subjected to trituration with pentane. Pure product was collected as white solid after filtration (16 mg, 20% yield). UPLC / MS: Rt = 1.68 min (gradient 1), [M + H]+= 393.0; [M + H]+ Calculated for C19H24F3N6: 393.4.1H NMR (600 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.40 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 3.99 (s, 1H), 3.10 – 3.04 (m, 1H), 3.00 (dt, J = 12.3, 3.5 Hz, 2H), 2.86 – 2.79 (m, 1H), 2.72 – 2.63 (m, 1H), 2.56 (td, J = 12.1, 2.5 Hz, 2H), 2.16 – 2.09 (m, 1H), 1.90 – 1.78 (m, 2H), 1.76 – 1.69 (m, 2H), 1.63 (qd, J = 12.2, 4.0 Hz, 2H).19F NMR (565 MHz, DMSO-d6) δ -60.34. Example 17. 4-(isoquinolin-5-yl)-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13e, Scheme 3) Step 1 and step 2 of examples 13 and 14 were carried out followed by the further steps listed below. Step 3. tert-butyl 4-(4-(isoquinolin-5-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (compound 11e, Scheme 3). Compound 11e was synthesized following general procedure 6 using: compound 10 (200 mg, 0.44 mmol), isoquinolin-5-yl boronic acid (91 mg, 0.528 mmol), Pd(dppf)Cl2•DCM (18.0 mg, 0.022 mmol), K2CO3(2 M) aq (0.44 mL, 0.876 mmol) and 1,4-dioxane dry (3.4 mL). After 3 hours, standard workup has been performed. Purification by silica (elution by gradient from 70 / 30 to 40 / 60 cyclohexane / EtOAc) afforded pure product as yellowish solid (175 mg, 73% yield). UPLC / MS: Rt = 2.21 min (gradient 2), [M + H]+ = 549.0; [M + H]+ Calculated for C29H28F3N6O2: 549.6.1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.43 (d, J = 1.0 Hz, 1H), 8.90 (s, 1H), 8.65 – 8.57 (m, 2H), 8.46 (s, 1H), 8.37 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.89 – 7.82 (m, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.49 – 7.39 (m, 2H), 4.23 – 4.14 (m, 2H), 3.62 – 3.54 (m, 2H), 2.72 – 2.65 (m, 2H), 1.44 (s, 9H). Step 4. tert-butyl 4-(4-(isoquinolin-5-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)piperidine-1- carboxylate (compound 12e, Scheme 3). Compound 12e was synthesized following general procedure 2-Method A using: compound 11e (147 mg, 0.26 mmol), ammonium formate (98.4 mg, 1.56 mmol), Pd(OH)2 / C (30 mg) and dry EtOH (4.2 mL) and THF (2.1 mL). After 3.5 hour, standard workup has been performed. Purification by silica (elution by gradient from 80 / 20 to 50 / 50 cyclohexane / EtOAc) afforded pure product as white foaming solid (63 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.43 (s, 1H), 8.88 (s, 1H), 8.70 – 8.28 (m, 4H), 7.98 (d, J = 7.8 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 4.12 – 3.98 (m, 2H), 3.06 – 2.87 (m, 3H), 2.13 – 2.03 (m, 2H), 1.83 – 1.67 (m, 2H), 1.42 (s, 9H). UPLC / MS: Rt = 2.01 min (gradient 2), [M − H]−= 549.0; [M − H]−Calculated for C29H28F3N6O2: 549.6. Step . 4-(isoquinolin-5-yl)-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13e, Scheme 3).

[0008] Compound 13e was synthesized following general procedure 3 using: compound 12e (68 mg, 0.123 mmol), HCl 4 M 1,4-dioxane solution (0.31 mL, 1.23 mmol), 1,4-dioxane (2.0 mL). After 16 hours, standard workup has been performed. Purification by silica (elution by gradient from 100 / 0 to 90 / 10 DCM / MeOH(NH31N)) afforded yellowish unclean solid that was subjected to trituration with petroleum ether / AcOEt / MeOH 85:13:2. Pure white solid was collected by trituration (27 mg, 49% yield). UPLC / MS: Rt = 1.91 min (gradient 1), [M + H]+= 451.0; [M + H]+Calculated for C24H22F3N6: 451.5.1H NMR (600 MHz, DMSO-d6) δ 10.68 (bs, 1H), 9.43 (s, 1H), 8.89 (bs, 1H), 8.58 (d, J = 6.7 Hz, 2H), 8.52 – 8.34 (m, 2H), 8.02 (bs, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 3.09 (dd, J = 12.2, 3.4 Hz, 2H), 2.87 (t, J = 12.2 Hz, 1H), 2.67 (td, J = 12.1, 2.5 Hz, 2H), 2.12 – 1.95 (m, 2H), 1.80 (dd, J = 12.1, 4.0 Hz, 2H).19F NMR (565 MHz, DMSO-d6) δ -60.28. Example 18. 4-(piperidin-4-yl)-6-(pyrimidin-5-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13f, Scheme 3). Step 1 and step 2 of examples 13 and 14 were carried out followed by the further steps listed below. Step 3. tert-butyl 4-(4-(pyrimidin-5-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (compound 11f, Scheme 3) Compound 11f was synthesized following general procedure 6 using: compound 10 (200 mg, 0.44 mmol), pyrimidin-5-yl boronic acid (65.3 mg, 0.528 mmol), Pd(dppf)Cl2•DCM (18.0 mg, 0.022 mmol), K2CO3(2 M) aq (0.44 mL, 0.876 mmol) in 1, 4-dioxane dry (3.4 mL). After 1 hour, standard workup has been performed. Purification by silica (elution by gradient 90 / 10 to 60 / 40 cyclohexane / EtOAc) afforded pure product as white solid (174 mg, 79% yield). UPLC / MS: Rt = 1.87 min (gradient 2), [M - H]- = 498.0; [M - H]- Calculated for C24H23F3N7O2: 498.5.1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.64 (s, 2H), 9.42 (s, 1H), 8.43 (s, 1H), 8.00 (s, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 4.22 – 4.15 (m, 2H), 3.61 – 3.54 (m, 2H), 2.68 – 2.62 (m, 2H), 1.44 (s, 9H). Step 4. tert-butyl 4-(4-(pyrimidin-5-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)piperidine-1- carboxylate (compound 12f, Scheme 3).

[0009] Compound 12f was synthesized following general procedure 2-Method A using: compound 11f (153 mg, 0.306 mmol), ammonium formate (113.6 mg, 1.8 mmol), Pd(OH)2 / C (30.6 mg) and dry EtOH (5.0 mL) and THF (2.5 mL). After 1 hour, standard workup has been performed. Purification by silica (elution by gradient 80 / 20 to 50 / 50 cyclohexane / EtOAc) afforded pure product as white solid (51 mg, 32% yield). UPLC / MS: Rt = 1.75 min (gradient 2), [M + H]+= 502.1; [M + H]+Calculated for C24H27F3N7O2: 502.5.1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.58 (s, 2H), 9.41 (s, 1H), 8.50 – 8.30 (m, 1H), 8.08 – 7.88 (m, 1H), 7.69 – 7.58 (m, 1H), 7.45 (d, J = 7.8 Hz, 1H), 4.03 (d, J = 13.0 Hz, 2H), 3.05 – 2.84 (m, 3H), 2.11 – 1.95 (m, 2H), 1.80 – 1.63 (m, 2H), 1.42 (s, 9H). Step . 4-(piperidin-4-yl)-6-(pyrimidin-5-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13f, Scheme 3). Compound 13f was synthesized following general procedure 3 using: compound 12f (50 mg, 0.10 mmol), HCl 4 M 1,4-dioxane solution (0.25 mL, 1.0 mmol), 1,4-dioxane (2.5 mL). After 24 hours, no conversion occurred; thus, HCl 4 M (0.28 mL) was added and reaction mixture was stirred overnight. After further 24 hours, HCl 4 M (0.28 mL) was again added and standard workup has been performed after 24 hours. Purification by silica (elution by gradient from 100 / 0 to 90 / 10 DCM / MeOH(NH31N)) afforded white solid as product (25 mg, 62% yield). UPLC / MS: Rt = 0.52 min (gradient 2), [M + H]+= 402.0; [M + H]+Calculated for C19H19F3N7: 402.4.1H NMR (600 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.58 (s, 2H), 9.41 (s, 1H), 8.57 – 8.29 (m, 1H), 8.00 (s, 1H), 7.63 (s, 1H), 7.44 (d, J = 7.7 Hz, 1H), 3.04 (dt, J = 12.3, 3.4 Hz, 2H), 2.81 (s, 1H), 2.61 (td, J = 12.0, 2.5 Hz, 2H), 2.06 – 1.86 (m, 2H), 1.79 – 1.65 (m, 2H).19F NMR (565 MHz, DMSO-d6) δ -60.32. Example 19. 4-(piperidin-4-yl)-6-(pyrimidin-5-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13g, Scheme 3). Step 1, step 2, step 3 of examples 13, 14 and 16 respectively were carried out followed by the further steps listed below. Step . tert-butyl 4-(4-(pyrimidin-5-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)piperidine-1- carboxylate (compound 12g, Scheme 3).

[0010] Compound 12g was synthesized following general procedure 2-Method B using: compound 11d (100 mg, 0.17 mmol), Et3SiH (0.27 mL, 1.7 mmol), Pd / C (20 mg) and dry EtOH (3.4 mL). After 3 hours, further Et3SiH (0.27 mL, 1.7 mmol) was added at 0°C and reaction mixture was left to stir overnight. After the addition of further 5 equivalents of reducing agent, standard workup has been performed. Purification by silica (elution by gradient 95 / 5 to 80 / 20 cyclohexane / EtOAc) afforded pure product as white solid (60 mg, 60% yield). UPLC / MS: Rt = 1.18 min (gradient 3), [M + H]+= 589.0; [M + H]+Calculated for C29H36F3N6O4: 588.3.1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.38 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.46 (t, J = 3.1, 1.7 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 6.90 – 6.85 (m, 1H), 6.35 (t, J = 3.3 Hz, 1H), 4.07 – 3.93 (m, 2H), 3.01 – 2.77 (m, 3H), 2.00 – 1.87 (m, 2H), 1.72 – 1.57 (m, 2H), 1.41 (s, 18H). Step . 4-(piperidin-4-yl)-6-(1H-pyrrol-2-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13g, Scheme 3).

[0011] Compound 13g was synthesized following general procedure 3 using: compound 12g (60 mg, 0.102 mmol), HCl 4 M 1,4-dioxane solution (0.38 mL, 1.53 mmol), 1,4-dioxane (1.7 mL). After 2 days, standard workup has been performed. Purification by silica (elution by gradient from 99:1 to 90:10 DCM / MeOH(NH31N)) afforded white solid as product (15 mg, 38% yield). UPLC / MS: Rt = 1.91 min (gradient 2), [M + H]+= 389.0; [M + H]+Calculated for C19H20F3N6: 389.4.1H NMR (600 MHz, DMSO-d6) δ 11.66 (s, 1H), 10.26 (s, 1H), 8.47 (s, 1H), 8.11 – 7.92 (m, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.08 – 7.02 (m, 2H), 6.29 – 6.24 (m, 1H), 3.05 (dd, J = 12.1, 3.4 Hz, 2H), 2.74 – 2.67 (m, 1H), 2.62 (dd, J = 12.0, 2.5 Hz, 2H), 1.99 – 1.87 (m, 2H), 1.74 (dd, J = 12.2, 3.8 Hz, 2H).19F NMR (565 MHz, DMSO-d6) δ -60.3. Example 20. 4-(1H-indazol-5-yl)-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13h, Scheme 3). Step 1 and step 2 of examples 13 and 14 were carried out followed by the further steps listed below. Step . tert-butyl 4-(4-(1H-indazol-4-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (compound 11h, Scheme 3)

[0012] Compound 11h was synthesized following general procedure 6 using: compound 10 (200 mg, 0.44 mmol), (1H-indazol-6-yl)boronic acid (85.3 mg, 0.528 mmol), Pd(dppf)Cl2•DCM (18.0 mg, 0.022 mmol), K2CO3(2 M)aq (0.66 mL, 1.32 mmol) in 1,4-dioxane dry (3.4 mL). After 1.5 hours, standard workup has been performed. Purification by silica (elution by gradient from 90 / 10 to 30 / 70 cyclohexane / EtOAc) afforded pure product that was washed with acetone. Filtration of solid furnished pure product as as white solid (55 mg, 23% yield). UPLC / MS: Rt = 1.97 min (gradient 2), [M - H]-= 536.0; [M - H]- Calculated for C27H25F3N7O2: 536.6.1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 10.51 (s, 1H), 8.98 (s, 1H), 8.54 – 8.43 (m, 2H), 8.27 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.71 – 7.59 (m, 2H), 7.51 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 4.27 – 4.15 (m, 2H), 3.63 – 3.55 (m, 2H), 2.74 – 2.64 (m, 2H), 1.45 (s, 9H). Step 4. tert-butyl 4-(4-(1H-indazol-4-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)piperidine-1- carboxylate (compound 12h, Scheme 3)

[0013] Compound 12h was synthesized following general procedure 2-Method A using: compound 11h (110 mg, 0.205 mmol), ammonium formate (77.6 mg, 1.23 mmol), Pd(OH)2 / C (22 mg), dry MeOH (3.4 mL) and THF (1.7 mL). After 2 hours, standard workup has been performed. Purification by silica (elution by gradient from 95 / 5 to 50 / 50 cyclohexane / EtOAc) afforded pure product as white solid (28 mg, 25% yield). UPLC / MS: Rt = 1.80 min (gradient 2), [M + H]+= 540.1 [M + H]+; [M + H]+Calculated for C27H29F3N7O2: 540.5.1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 10.51 (s, 1H), 8.93 (s, 1H), 8.51 (s, 1H), 8.43 (d, J = 9.0 Hz, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.71 – 7.56 (m, 2H), 7.42 (d, J = 7.8 Hz, 1H), 4.12 – 4.00 (m, 2H), 3.04 – 2.85 (m, 2H), 2.12 – 1.93 (m, 3H), 1.80 – 1.66 (m, 2H), 1.43 (s, 9H). Step . 4-(1H-indazol-5-yl)-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13h, Scheme 3).

[0014] Compound 13h was synthesized following general procedure 3 using: compound 12h (27 mg, 0.05 mmol), HCl 4 M 1,4-dioxane solution (0.125 mL, 0.5 mmol), 1,4-dioxane dry (0.08 mL). After 6 hours, standard workup has been performed. Purification by silica (elution by gradient from 99 / 1 to 85 / 15 DCM / MeOH(NH31N)) afforded white solid as product (11 mg, 50% yield). UPLC / MS: Rt = 0.76 min (gradient 2), [M + H]+= 440.0; [M + H]+Calculated for C22H21F3N7: 439.5.1H NMR (400 MHz, DMSO-d6) δ 13.37 (s, 1H), 10.49 (s, 1H), 8.93 (s, 1H), 8.50 (s, 1H), 8.43 (dd, J = 8.8, 1.6 Hz, 1H), 8.28 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 8.03 (dd, J = 8.1, 2.2 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.62 (t, J = 8.1 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 3.15 – 3.06 (m, 2H), 2.88 – 2.78 (m, 1H), 2.74 – 2.63 (m, 2H), 2.05 – 1.97 (m, 2H), 1.79 (dd, J = 12.0, 3.9 Hz, 2H).19F NMR (565 MHz, DMSO-d6) δ -60.28. Example 21. 4-(1-methyl-1H-imidazol-5-yl)-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13i, Scheme 3) Step 1 and step 2 of examples 13 and 14 were carried out followed by the further steps listed below. Step 3. tert-butyl 4-(4-(1-methyl-1H-imidazol-5-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (compound 11i, Scheme 3). Compound 11i was synthesized following general procedure 6 using: compound 10 (100 mg, 0.22 mmol), (1-methyl-1H-imidazol-5-yl)boronic acid (54.8 mg, 0.26 mmol), Pd(dppf)Cl2•DCM (9.0 mg, 0.011 mmol), K2CO3(2 M)aq (0.22 mL, 0.44 mmol) in 1,4-dioxane dry (2.0 mL). After 1.5 hours, the addition of H2O promotes the precipitation of solid that has been filtered and washed with AcOEt, furnishing desired product as white solid (65 mg, 60% yield). UPLC / MS: Rt = 1.61 min (gradient 2), [M + H]+= 502.0; [M + H]+Calculated for C24H27F3N7O2: 502.5.1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.41 (s, 1H), 8.01 – 7.84 (m, 3H), 7.60 (t, J = 8.0 Hz, 1H), 7.44 – 7.35 (m, 2H), 4.21 – 4.10 (m, 2H), 4.06 (s, 3H), 3.61 – 3.52 (m, 2H), 2.64 – 2.58 (m, 2H), 1.44 (s, 9H). Step 4. tert-butyl 4-(4-(1-methyl-1H-imidazol-5-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)piperidine-1- carboxylate (compound 12i, Scheme 3).

[0015] Compound 12i was synthesized following general procedure 2-Method A using: compound 11i (90 mg, 0.180 mmol), ammonium formate (68.1 mg, 1.08 mmol), Pd(OH)2 / C (18 mg) in dry MeOH (3.0 mL) and THF (1.5 mL). After 5 hours, standard workup has been performed giving pure product without any purification as white solid (83 mg, 92% yield). UPLC / MS: Rt = 1.47 min (gradient 2), [M + H]+= 504.0; [M + H]+Calculated for C24H29F3N7O2: 504.5.1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.39 (s, 1H), 7.93 – 7.89 (m, 2H), 7.86 (d, J = 1.1 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 4.09 – 3.95 (m, 5H), 3.02 – 2.78 (m, 3H), 2.04 – 1.93 (m, 2H), 1.74 – 1.59 (m, 2H), 1.41 (s, 9H). Step 5. 4-(1-methyl-1H-imidazol-5-yl)-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)- 1,3,5-triazin-2-amine (compound 13i, Scheme 3). Compound 13i was synthesized following general procedure 3 using: compound 12i (83 mg, 0.165 mmol), HCl 4 M 1,4-dioxane solution (0.41 mL, 1.65 mmol) in 1,4-dioxane (4.1 mL). After 2 days, standard workup has been performed. Purification by silica (elution by gradient from 98 / 2 to 90 / 10 DCM / MeOH(NH3 1N)) afforded unclean compound, that was subjected to trituration with pentane / AcOEt 9 / 1 furnishing a white solid as product (48 mg, 72% yield). UPLC / MS: Rt = 1.65 min (gradient 2), [M + H]+= 404 [M + H]+; Calculated for C19H21F3N7: 404.4.1H NMR (600 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.38 (s, 1H), 7.93 (s, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 4.04 (s, 3H), 3.14 – 2.97 (m, 2H), 2.73 (t, J = 11.4 Hz, 1H), 2.63 (t, J = 12.1 Hz, 2H), 2.01 – 1.89 (m, 2H), 1.70 (qd, J = 12.2, 3.9 Hz, 2H).19F NMR (565 MHz, DMSO-d6) δ -60.28. Example 22. 4-(1-methyl-1H-imidazol-5-yl)-6-(piperidin-4-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13, Scheme 3) Step 1 and step 2 of examples 13 and 14 were carried out followed by the further steps listed below. Step . tert-butyl 4-(4-(thiophen-3-yl)-6-((3- (trifluoromethyl)phenyl)amino)-1,3,5-triazin-2-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (compound 11j, Scheme 3)

[0016] Compound 11j was synthesized following general procedure 6 using: compound 10 (120 mg, 0.263 mmol), thiophen-3-ylboronic acid (40 mg, 0.316 mmol), Pd(dppf)Cl2•DCM (10.6 mg, 0.013 mmol), K2CO3 (2 M) aq (0.26 mL, 0.526 mmol) in 1,4-dioxane dry (2.0 mL). After 1.5 hours, standard workup has been performed. Purification by silica (elution by gradient from 95 / 5 to 80 / 20 cyclohexane / EtOAc) afforded not pure product that was washed with acetone. Filtration of solid furnished pure product as a white solid (99 mg, 70% yield). UPLC / MS: Rt = 1.15 mins (gradient 3), [M + H]+= 504.0; [M + H]+Calculated for C24H25F3N5O2S: 504.5.1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.54 (d, J = 3.1 Hz, 1H), 8.46 (s, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 5.0 Hz, 1H), 7.72 (t, J = 5.0, 3.1 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 4.19 – 4.14 (m, 2H), 3.60 – 3.52 (m, 2H), 2.66 – 2.62 (m, 2H), 1.44 (s, 9H). Step 4. 4-(1,2,3,6-tetrahydropyridin-4-yl)-6-(thiophen-3-yl)-N-(3- (trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (compound 13j, Scheme 3).

[0017] Compound 13j was synthesized following general procedure 3 using: compound 11j (48 mg, 0.095 mmol), HCl 4 M 1,4-dioxane solution (0.24 mL, 0.95 mmol), 1,4-dioxane (2.3 mL). After 16 hours, no conversion occurred; thus, HCl 4 M (0.78 mL) was added and reaction mixture was stirred over weekend. Then, standard workup has been. Purification by silica (elution by gradient from 99 / 1 to 96 / 4 DCM / MeOH(NH31N)) afforded unclean compound, that was subjected to trituration with pentane / AcOEt 1 / 1 furnishing a white solid as product (15 mg, 39% yield).1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.53 (dd, J = 3.0, 1.2 Hz, 1H), 8.50 (s, 1H), 7.98 (s, 1H), 7.83 (dd, J = 5.0, 1.2 Hz, 1H), 7.72 (t, J = 5.0, 3.1 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.53 – 7.46 (m, 1H), 7.40 (d, J = 7.7 Hz, 1H), 3.62 – 3.54 (m, 2H), 2.99 (t, J = 5.6 Hz, 2H), 2.60 – 2.53 (m, 2H).19F NMR (565 MHz, DMSO-d6) δ - 60.29.UPLC / MS: Rt = 0.90 min (gradient 2), [M + H]+= 404.0; [M + H]+Calculated for C19H17F3N5S: 404.4. Figure 4 reports Scheme 4 showing the synthesis of compounds 18a, 18k, 18l. Example 23. N1,N1-dimethyl-N3-(6-phenyl-2-(1,2,3,6-tetrahydropyridin-4- yl)pyrimidin-4-yl)benzene-1,3-diamine (compound 18a, Scheme 4). Step 1, 2 from compound 14 to compound 16a were made as previously described in patent application WO 20182 / 03256. Example 18a was carried out followed by the further step described below. Step 3. N1,N1-dimethyl-N3-(6-phenyl-2-(1,2,3,6-tetrahydropyridin-4- yl)pyrimidin-4- yl)benzene-1,3-diamine (Compound 18a, Scheme 4). Titled compound was synthesized following the general procedure 3 previously described using intermediate 16a (60 mg, 0.13 mmol), HCl (4 M in dioxane) (0.33 mL) in 1,4-dioxane dry (4.4 mL). Purification by alumina (elution by gradient from 100 / 0 to 90 / 10 DCM / MeOH) afforded pure compound 18a (26.5 mg, 56% yield). UPLC / MS Rt: 2.06 min (gradient 1), MS (ESI) m / z: 372.3 [M+H]+.[M+H]+Calculated for C23H26N5: 372.5.1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.11 – 8.01 (m, 2H), 7.57 – 7.45 (m, 3H), 7.40 (t, J = 2.3 Hz, 1H), 7.30 – 7.24 (m, 1H), 7.13 (t, J = 8.1 Hz, 1H), 7.09 (s, 1H), 6.95 (dd, J = 7.8, 1.9 Hz, 1H), 6.40 (dd, J = 8.2, 2.4 Hz, 1H), 3.46 (q, J = 3.2 Hz, 2H), 2.90 (bs, 1H), 2.58 (bs, 2H). Example 24. N1,N1-dimethyl-N3-(6-phenyl-2-(1,2,3,6-tetrahydropyridin-4- yl)pyrimidin-4-yl)benzene-1,3-diamine (compound 18k, Scheme 4). Step 1. N-(2-chloro-6-phenylpyrimidin-4-yl)-1-methyl-1H-indol-6-amine (compound 15k, Scheme 4). Titled compound was synthesized following the general procedure 7 previously described using compound 14 (184 mg, 0.82 mmol), aniline 4k (120 mg, 0.82 mmol) in THF dry (5.5 mL). Purification by silica (elution by gradient from 100 / 0 to 95 / 5 cyclohexane / EtOAc) afforded pure compound 15k (150.0 mg, 55%). UPLC / MS Rt: 2.52 min (gradient 1), MS (ESI) m / z: 335.2 [M+H]+.[M+H]+Calculated for C19H16ClN4: 335.8. 1H NMR (400 MHz, CDCl3) δ 7.91 – 7.83 (m, 2H), 7.67 (d, J = 8.3 Hz, 1H), 7.47 – 7.36 (m, 3H), 7.34 (d, J = 11.3 Hz, 2H), 7.13 (d, J = 3.1 Hz, 1H), 7.04 (dd, J = 8.3, 1.9 Hz, 1H), 6.88 (s, 1H), 6.54 (d, J = 3.1 Hz, 1H), 3.80 (s, 3H). Step 2. tert-butyl 4-(4-((1-methyl-1H-indol-6-yl)amino)-6- phenylpyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (compound 16k, Scheme 4). Title compound was synthesized following the general procedure 6 previously described using intermediate 15k (140.0 mg, 0.42 mmol) boronic ester 2 (155.8 mg, 0.50 mmol), Pd(Cl2)(dppf)•DCM (34.0 mg, 0.04 mmol), K2CO3 (2 M)aq (0.46 mL) in 1,4 dioxane dry (4 mL). Purification by silica (elution by gradient from 100 / 0 to 75 / 25 cyclohexane / EtOAc) afforded pure intermediate 16k (175.0 mg, 86%). UPLC / MS. Rt: 2.31 min (gradient 2), [M − H]−= 480.6. [M − H]−Calculated for C29H32N5O2: 480.6.1H NMR (400 MHz, CDCl3) δ 8.02 – 7.93 (m, 2H), 7.63 (d, J = 8.3 Hz, 1H), 7.53 (s, 1H), 7.46 – 7.40 (m, 3H), 7.23 (bs, 1H), 7.09 (d, J = 3.1 Hz, 1H), 7.04 (dd, J = 8.3, 1.9 Hz, 1H), 6.99 (s, 1H), 6.90 (s, 1H), 6.51 (dd, J = 3.1, 0.8 Hz, 1H), 4.20 (bs, 2H), 3.78 (s, 3H), 3.66 (bs, 2H), 2.84 (bs, 2H). Step 3. tert-butyl 4-(4-((1-methyl-1H-indol-6-yl)amino)-6- phenylpyrimidin-2-yl)piperidine-1-carboxylate. (compound 17k, Scheme 4). Titled compound was synthesized following the general procedure 2-Method A previously described using intermediate 16k (85 mg, 0.18 mmol), Pd(OH)2 / C (17.0 mg), NH4CO2H (68.1 mg, 1.1 mmol) in MeOH (4.5 mL). Purification by silica (elution by gradient from 100 / 0 to 70 / 30 cyclohexane / EtOAc) afforded pure intermediate 17k (60.0 mg, 69% yield). UPLC / MS Rt: 2.23 min (gradient 2), MS (ESI) m / z: 484.5 [M+H]+.[M+H]+Calculated for C29H34N5O2: 484.61H NMR (400 MHz, CDCl3) δ 7.97 – 7.87 (m, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.45 – 7.36 (m, 3H), 7.09 (dd, J = 3.1, 1.3 Hz, 1H), 7.03 (dd, J = 8.3, 1.9 Hz, 1H), 6.87 (d, J = 1.2 Hz, 1H), 6.51 (dd, J = 3.1, 0.9 Hz, 1H), 4.23 (bs, 2H), 3.78 (s, 3H), 2.96 - 2.90 (m, 3H), 2.08 (bs, 2H), 1.93 (qd, J = 12.2, 3.9 Hz, 2H), 1.49 (s, 9H). Step 4. 1-methyl-N-(6-phenyl-2-(piperidin-4-yl)pyrimidin-4-yl)-1H-indol- 6-amine (compound 18k, Scheme 4). Titled compound was synthesized following the general procedure 3 previously described using intermediate 17k (50.0 mg, 0.10 mmol), HCl (4 M in dioxane) (0.25 mL) in 1,4-dioxane dry (1.7 mL). Purification by alumina (elution by gradient from 100 / 0 to 95 / 5 DCM / MeOH) afforded pure compound 18k (229.9 mg, 60% yield). UPLC / MS Rt: 1.94 min (gradient 1), MS (ESI) m / z: 384.3 [M+H]+.[M+H]+ Calculated for C24H26N5: 384.5.1H NMR 1H NMR (400 MHz, MeOD) δ 8.01 (s, 1H), 7.96-7.90 (m, 2H), 7.50 (d, J = 8.3 Hz, 1H), 7.52-7.40 (m, 3H), 7.13 – 7.07 (m, 2H), 6.92 (s, 1H), 6.40 (dd, J = 3.2, 0.9 Hz, 1H), 3.81 (s, 3H), 3.19 (dt, J = 12.6, 3.1 Hz, 2H), 2.95 (tt, J = 11.4, 3.8 Hz, 1H), 2.79 (td, J = 12.3, 2.8 Hz, 2H), 2.11 (dd, J = 12.9, 2.6 Hz, 2H), 1.99 (qd, J = 12.3, 4.0 Hz, 2H). Example 25. N1,N1-dimethyl-N3-(6-phenyl-2-(1,2,3,6-tetrahydropyridin-4- yl)pyrimidin-4-yl)benzene-1,3-diamine (compound 18l, Scheme 4). Step 1. tert-butyl 6-((2-chloro-6-phenylpyrimidin-4-yl)amino)-1H-indole- 1-carboxylate (compound 15l, Scheme 4). Titled compound was synthesized following the general procedure 7 previously described using compound 14 (100 mg, 0.82 mmol), aniline 4l (112.0 mg, 0.50 mmol) in THF dry (3.3 mL). Purification by silica (elution by gradient from 100 / 0 to 95 / 5 cyclohexane / EtOAc) afforded pure compound 15l (202.0 mg, 96%). UPLC / MS Rt: 2.17 min (gradient 2), MS (ESI) m / z: 419.3 [M−H]−. [M−H]−Calculated for C23H20ClN4O2: 419.9.1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.94 – 7.88 (m, 2H), 7.64 (d, J = 3.7 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.48 – 7.37 (m, 3H), 7.27 (s, 1H), 7.18 (dd, J = 8.3, 2.0 Hz, 1H), 7.04 (s, 1H), 6.60 (dd, J = 3.7, 0.8 Hz, 1H), 1.64 (s, 9H). Step 2. tert-butyl 6-((2-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-6-phenylpyrimidin-4-yl)amino)-1H-indole-1- carboxylate (compound 16l, Scheme 4). Title compound was synthesized following the general procedure 6 previously described using intermediate 15l (190.0 mg, 0.45 mmol) boronic ester 2 (209.4 mg, 0.67 mmol), Pd(Cl2)(dppf)•DCM (36.8 mg, 0.05 mmol), K2CO3 (2 M)aq (0.68 mL) in 1,4 dioxane dry (5 mL). Purification by silica (elution by gradient from 100 / 0 to 85 / 15 cyclohexane / EtOAc) afforded pure intermediate 16l (217.0 mg, 85%). UPLC / MS. Rt: 2.31 min (gradient 2), [M − H]−= 566.4. [M − H]−Calculated for C33H36N5O4: 566.7.1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.06 – 8.0 (m, 2H), 7.58 (d, J = 3.7 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.49 – 7.40 (m, 3H), 7.34 (s, 1H), 7.18 (dd, J = 8.3, 2.0 Hz, 1H), 7.02 (s, 1H), 6.90 (s, 1H), 6.57 (d, J = 3.7 Hz, 1H), 4.22 (bs, 2H), 3.67 (t, J = 5.2 Hz, 2H), 2.85 (bs, 2H), 1.64 (s, 9H), 1.50 (s, 9H). Step 3. tert-butyl 6-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6- phenylpyrimidin-4-yl)amino)-1H-indole-1-carboxylate (compound 17l, Scheme 4). Titled compound was synthesized following the general procedure 2-Method B previously described using intermediate 16l (220.0 mg, 0.39 mmol), Pd(OH)2 / C (44.0 mg), NH4CO2H (147.7 mg, 2.3 mmol) in MeOH (5.0 mL). Purification by silica (elution by gradient from 100 / 0 to 75 / 25 cyclohexane / EtOAc) afforded pure intermediate 17l (69.2 mg, 32% yield). UPLC / MS Rt: 1.56 min (gradient 3), MS (ESI) m / z: 570.4 [M+H]+.[M+H]+ Calculated for C33H40N5O4: 570.71H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.01 – 7.93 (m, 2H), 7.59 (d, J = 3.7 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.46 – 7.39 (m, 3H), 7.22 (dd, J = 8.3, 2.0 Hz, 1H), 7.03 (s, 1H), 6.57 (d, J = 3.7 Hz, 1H), 4.23 (bs, 2H), 3.03 – 2.82 (m, 3H), 2.09 (d, J = 13.3 Hz, 2H), 1.92 (qd, J = 12.5, 3.9 Hz, 2H), 1.63 (s, 9H), 1.49 (s, 9H). Step 4. N-(6-phenyl-2-(piperidin-4-yl)pyrimidin-4-yl)-1H-indol-6-amine (compound 18l, Scheme 4). Titled compound was synthesized following the general procedure 3 previously described using intermediate 17l (69.0 mg, 0.12 mmol), HCl (4 M in dioxane) (0.30 mL) in 1,4-dioxane dry (2.0 mL). Purification by alumina (elution by gradient from 100 / 0 to 95 / 5 DCM / MeOH) afforded pure compound 18l (14.6 mg, 33% yield). UPLC / MS Rt: 1.79 min (gradient 1), MS (ESI) m / z: 370.2 [M+H]+.[M+H]+ Calculated for C24H26N5: 384.5.1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.43 (s, 1H), 8.01 (dd, J = 7.8, 2.0 Hz, 3H), 7.58 – 7.46 (m, 5H), 7.26 (t, J = 2.7 Hz, 1H), 7.13 (dd, J = 8.5, 1.9 Hz, 1H), 7.03 (s, 1H), 6.37 (t, J = 2.5 Hz, 1H), 3.07 (d, J = 12.0 Hz, 2H), 2.79 (t, J = 11.7 Hz, 1H), 2.68 – 2.58 (m, 2H), 1.94 (d, J = 12.7 Hz, 2H), 1.78 (qd, J = 12.2, 4.0 Hz, 2H). Cell Viability Assay Cells were seeded at 2857 cells / well in 96-well plates and incubated for 24 h at 37°C with 5% CO2. After an overnight incubation, cells were treated with inhibitor (1.25-50 μM) for 24 hours. The cell viability was determined using the Cell Titer-Glo luminescent cell viability assay kit (Promega, Madison, WI), according to the manufacturer’s instructions. Luminescence was measured using a DTX 800 microplate reader (Coulter). The half-maximal inhibitory concentration (IC50) values were calculated using the GraphPad Prism software. The assay was done by conducting at least 2-3 independent experiments. The results are illustrated in Table 3 (below). Table 3. Antiproliferative activity in 5 cell lines. NR = not responsive

[0018] As shown in the Table 4, the compounds of the present invention show a good antiproliferative activity in five cancer cell lines and importantly excellent plasma (> 120 minutes) and microsomal stability (> 60 minutes), kinetic and thermodynamic solubility. Table 4: kinetic solubility, thermodynamic solubility, mouse microsomal and plasma stability of selected compounds.

[0019] aCompound initially reported by Brindani et al., Med Chem 2023 ND = not detected Remarkably, while 7e (ARN25375) exhibited a favorable pharmacokinetic profile only I.V., with a bioavailability of 8% in accordance to its pH dependent thermodynamic solubility (Table above), 7i (ARN25499) possesses a favorable pharmacokinetic profile both I.V. and P.O. with an increased bioavailability in mouse of 22% compared to the previous leads ARN22089 and ARN25062, which showed a bioavailability of 13% and 18%, respectively (see Figure 5A). Next, it has been tested the efficacy of 7i (ARN25499) since it has a favorable PK profile, overall. It has been used a NOD scid gamma (NSG) model and inoculated melanoma patient-derived xenograft (PDX) tumor cells on either side of the mouse. When the tumors reached a measurable size range of about 150-200 mm3, the mice have been treated with 10 mg / kg ARN25499 via I.V. daily for two weeks. Tumors and weight of the mouse were measured every other day with a caliper and weight scale. As shown in the growth curve, the drug-treated tumor grown less than the vehicle-treated tumor (Figure 6A). After two weeks of treatment, ARN25499-treated tumor had a smaller volume as compared to the vehicle-treated tumor (Figure 6B). Two-week treatment with the compound showed no adverse effect on the animals and no change in body weight (Figure 6C). Furthermore, it has been investigated the pathway engagement of new compounds. Notably, following a 6-hour incubation period, 7i -ARN25499 inhibited the accumulation of pERK and pS6 to a greater extent than previous ARN22089 (Figure 7). After in vitro treatment ofWM3248 cells were treated with 10 μM of ARN22089, ARN25375, and ARN25499 for 6 hours to verify the accumulation of pS6 and pERK by Western immunoblotting. Relative densitometry of pERK and pS6 as compared to unphosphorylated forms of the protein were determined and are reported below each lane. A representative blot of three independent biologic replicates is shown. In vitro metabolic stability 10 mM DMSO stock solution of test compound was pre-incubated at 37˚C for 15 min with mouse liver microsomes in 0.1 M Tris-HCl buffer (pH 7.4) with 10% DMSO. The final concentration was 4.6 µM. After pre-incubation, the co-factors (NADPH, G6P, G6PDH and MgCl2 pre-dissolved in 0.1 M Tris- HCl) were added to the incubation mixture and the incubation was continued at 37˚C for 1h. At each time point (0, 5, 15, 30, 60 min), 30 µL of incubation mixture was diluted with 200 µL cold CH3CN spiked with 200 nM of an appropriate internal standard, followed by centrifugation at 3.270 x g for 15 min. The supernatant was further diluted with H2O (1:1) for analysis. A reference incubation mixture (microsomes without cofactors) was prepared for each test compound and analyzed at t=0 and 60 min in order to verify the compounds stability in the matrix. The two time points were diluted as for the time points of the incubation mixture above. The concentration of test compound was quantified by LC-MS / MS on a Waters ACQUITY UPLC-MS system consisting of a Triple Quadrupole Detector (TQD) Mass Spectrometer equipped with an Electrospray Ionization interface and a Photodiode Array Detector from Waters Inc. (Milford, MA, USA). The analyses were run on an ACQUITY UPLC BEH C18 (50x2.1 mmID, particle size 1.7 µm) with a VanGuard BEH C18 pre-column (5x2.1 mmID, particle size 1.7 µm) at 40°C, using 0.1% HCOOH in H2O (A) and 0.1% HCOOH in CH3CN (B) as mobile phase. Electrospray ionization was applied in positive mode. Compound-dependent parameters as MRM transitions and collision energy were developed for each compound. The percentage of test compound remaining at each time point relative to t=0 was calculated by the response factor on the basis of the internal standard peak area. The percentage of test compound versus time was plotted and fitted by GraphPad Prism (GraphPad Software, Version 5 for Windows, CA, USA, www.graphpad.com) to estimate the compounds half-life (t½) which was reported as mean value along with the standard deviation (n = 3). In vitro plasma stability 10 mM DMSO stock solution of test compound was diluted 50-fold with DMSO-H2O (1:1) and incubated at 37˚C for 2 h with mouse plasma added 5% DMSO (pre-heated at 37˚C for 10 min). The final concentration was 2 µM. At each time point (0, 5, 15, 30, 60, 120 min), 50 µL of incubation mixture was diluted with 200 µL cold CH3CN spiked with 200 nM of internal standard, followed by centrifugation at 3500g for 2 0 min. The supernatant was further diluted with H2O (1:1) for analysis. The concentration of test compound was quantified by LC / MS-MS on a Waters ACQUITY UPLC / MS TQD system consisting of a TQD (Triple Quadrupole Detector) Mass Spectrometer equipped with an Electrospray Ionization interface. The analyses were run on an ACQUITY UPLC BEH C18 (50x2.1 mmID, particle size 1.7 µm) with a VanGuard BEH C18 precolumn (5x2.1 mmID, particle size 1.7 µm) at 40°C, using 0.1% HCOOH in H2O (A) and 0.1% HCOOH in CH3CN (B) as mobile phase. Electrospray ionization (ESI) was applied in positive mode. The response factors, calculated on the basis of the internal standard peak area, were plotted over time. When possible, response vs. time profiles were fitted with Prism (GraphPad Software, Inc., USA) to estimate compounds half-life in plasma. Thermodynamic solubility The thermodynamic solubility was determined by addition of Phosphate Buffered Saline (PBS) at pH 7.4 to an excess of solid test compound. The study was performed by incubation of an aliquot of 2.5 mg of test compound in 500 µL of PBS at pH 7.4. The suspension was shaken at 300 rpm for 24 hours at 25°C. At the end of the incubation, the saturated solution was filtered. The filtrate was further diluted with MeCN and then analyzed by LC-MS for the quantification of dissolved compound (in µM) by UV at a specific wavelength (λmax of the test compound). The analyses were performed on a Waters ACQUITY UPLC-MS system consisting of a single quadrupole detector (SQD) mass spectrometer equipped with an electrospray ionization interface (ESI) and a photodiode array detector (PDA) from Waters Inc. (Milford, MA, USA). Electrospray ionization in positive mode was used in the mass scan range 100-500 Da. The PDA range was 210-400 nm. The analyses were run on an ACQUITY UPLC BEH C18 column (50x2.1 mmID, particle size 1.7 µm) with a VanGuard BEH C18 pre-column (5x2.1 mmID, particle size 1.7 µm), using 10 mM NH4OAc in H2O at pH 5 adjusted with AcOH (A) and 10 mM NH4OAc in MeCN-H2O (95:5) at pH 5 (B) as mobile phase. The test compound was quantified towards a calibration curve in MeCN-H2O (1:1). In vitro treatment and Western Blot analysis (Figure 7) Melanoma cells (WM3248) were cultured as described in Sohail et al (Cell Reports, 2022), were seeded at 1.5 x 106cells per 60.8 cm2plate. 16 hrs. later, WM3248 cells were treated with 10 μM of ARN22089, ARN25375, or ARN25499 for 6 hrs. and lysed in Lysis buffer (Cytoskeleton, Inc.) containing a protease inhibitors cocktail. Lysates were then subjected to SDS-PAGE and transferred to PVDF membranes. The expression or phosphorylation of proteins was detected by western blotting using the following primary Abs: pERK at 1:500, ERK at 1:6000, pS6 at 1:6000, S6 at 1:1000 for 16 h and appropriate HRP-secondary antibody for 2 h (all from Cell Signaling). ImageJ was used to perform densitometry. The experiments were performed in triplicate and representative results are shown in Figure 7. From the above disclosure there are evident the advantages offered by the present invention. In particular, there has been disclosed a new class of CDC42 inhibitors that are structurally distinct from those already reported. The symmetrization of the system and the one-pot production using advanced and versatile intermediate (Zins K, Gunawardhana S, Lucas T, Abraham D, Aharinejad S. Targeting Cdc42 with the small molecule drug AZA197 suppresses primary colon cancer growth and prolongs survival in a preclinical mouse xenograft model by downregulation of PAK1 activity. J Transl Med. 2013 Nov 27;11:295. doi: 10.1186 / 1479-5876-11-295) improve their synthetic feasibility and accessibility. The disclosed compounds are promising agents in several conditions involving wherein CDC42 / RHOJ signaling is critical in the development of the pathology, such as cancer, retinal disorders, vascular disorders, inherited cancer predisposition syndromes, benign tumors, and cardiomyopathies. In addition to this, the disclosed compounds may find a repurposing application as RhoA inhibitors. For instance, such compounds may find application in the development of treatments for injuries to the Central Nervous System and spinal muscular atrophy. * * *

Claims

CLAIMS:

1. A compound having the general structure (I):wherein Y is -N- or -CH-, A is selected from pyrrolidine, phenyl and heteroaromatic rings such as: pyrazole, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N- R2indazole, B is selected from a six membered saturated or partially unsaturated (hetero)cycles and differently substituted aniline C is selected from a six membered saturated or partially unsaturated (hetero)cycles and differently substituted aniline, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 having the general structure (II):wherein dashed bond may be a single or a double bond, Y is -N- or -CH-, A is selected from pyrrolidine, phenyl and heteroaromatic rings such as: pyrazole, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, with the proviso that when Y is N A is different from phenyl including heteroaryl groups, A’ is selected from aromatic and heteroaromatic rings such as: pyrazole, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole substituted by one or more substituents R2, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, each one of X1and X2may be independently -N(H)-, -N(R2)- or -O-, R1may be H, (C1-C6)alkyl, halo(C1-C6)alkyl, amino(C1-C6)alkyl, cycloalkyl, hydroxy(C1-C6)alkyl, alkoxy-(C1-C6)-alkyl , C1-C6 acyloxy,R2 may be a H, (C1-C6)alkyl, halo(C1-C6)alkyl, amino, amino(C1- C6)alkyl, hydroxyl, hydroxy(C1-C6)alkyl, alkoxy-(C1-C6)-alkyl, carboxyl, ester, C1-C6-acyloxy, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2 having the general structure (III):wherein each one of R1and R2may be independently H, C1-C4 alkyl, cycloalkyl each one of X1 and X2 may be independently -N(H), -N(R2)- or -O-, dashed bond may be single or double, ring D may not be present and –N(R2)- is -N(R2)(H)-, or when ring D is present –N(R2) is embedded in five- or six-membered (hetero)aromatic or not aromatic ring, introducing an indole, indoline, quinoxaline, tetrahydroquinoxaline, quinoline, or tetrahydroquinoline, as depicted belowwith the proviso that when D is absent then the dashed bond is a double bond.

4. The compound according to any one of the preceding claims 1 to 3, having the general structure (IV):wherein Y1 and Y2 may independently be: -CH- or -N- and at least one of Y1 and Y2 is -N-, the dashed bond may be a single or a double bond, each R1may be: H, C1-C4 alkyl, cycloalkyl, A is a non-substituted or a R3-substituted ring A selected from: phenyl, pyrrolidine, N-dimethylaminoaniline, and heteroaromatic rings such as: pyrazole, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, with the proviso that when Y2 is N A is different from phenyl, wherein R2is H, C1-C4 alkyl, cycloalkyl, and wherein R3is selected from C1-C4 alkyl, C1-C4 haloalkyl (and preferably -CF3), cycloalkyl. A’ is a non-substituted or a R4mono- or di-substituted ring A’ selected from aromatic and heteroaromatic rings such as: phenyl, pyrazole, N-R2pyrazole pyrrole N-R2pyrrole pyridine pyrimidine pyrazinepyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole substituted by one or more substituents R2, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, wherein R2may be: H, C1- C4 alkyl, cycloalkyl and wherein R4is independently selected from –OH, -COOH, -COOR2, C1-C4 alkyl, C1-C4 haloalkyl (and preferably -CF3), C1-C4- haloalkyloxy (and preferably -OCF3or -OCHF2), C1-C4-alkoxy (and preferably -OCH3), cycloalkyl, -NR2or -N(R2)2, wherein when Y1 is -N- and Y2 is -C-, R1is H and A’ is phenyl, then the dashed bond of piperidine is present as a double bond.

5. The compound according to any one of the preceding claims 1 to 4, having the general structure (V):wherein any of Y1 and Y2 may be: -CH- or -N- and only one of Y1 and Y2 being -N-, the dashed bond is a single or a double bond, R1may be: H, C1-C4 alkyl, cycloalkyl, A’ is a non-substituted or a R4mono- or di-substituted ring A’ selected from aromatic and heteroaromatic rings such as: phenyl, pyrazole, N-dimethylaminoaniline, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole substituted by one or moresubstituents R2, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, wherein R2may be: H, C1-C4 alkyl, cycloalkyl and wherein each R4is independently selected from –OH, -COOH, -COOR2, C1-C4 alkyl, C1-C4 haloalkyl (and preferably -CF3), C1-C4-haloalkyloxy (and preferably -OCF3 or -OCHF2), C1-C4-alkoxy (and preferably -OCH3), cycloalkyl, -NR2or -N(R2)2, wherein when Y1 is -C- and Y2 is -N-, R1 is H and A’ in phenyl, then the dashed bond of piperidine is present as a double bond.

6. The compound according to the preceding claim, wherein R1is hydrogen, R2is H o -CH3, and wherein A’ is a non-substituted or a R4mono- or di-substituted ring A’ selected from aromatic and heteroaromatic rings such as: phenyl, pyridine, NH-indole, N-R2indole, N-dimethylaminoaniline, and wherein each R4is independently selected from –OH, -COOH, -COOR2, CH3, -CF3, -OCF3, -OCHF2, -OCH3, -NR2or -N(R2)2.

7. The compound according to preceding claim 5 or 6, wherein any of Y1 and Y2 may be: -CH or -N- and only one of Y1 and Y2 is -N-, the dashed bond is a single or a double bond, R1is H, A’ is a non-substituted or a R4mono- or di-substituted ring A’ selected from: phenyl, pyridine, N-dimethylaminoaniline, NH-indole, N-R2indole, wherein R2is CH3: and wherein each R4is independently selected from –OH, -COOH, -COOR2, CH3, -CF3, -OCF3, -OCHF2, -OCH3, -NR2or -N(R2)2.

8. The compound according to any one of the preceding claims, having the general structure (VI):whereinR1may be: H, C1-C4 alkyl, cycloalkyl,A' is a non-substituted or a R4mono- or di-substituted ring A' selected from aromatic and heteroaromatic rings such as: phenyl, pyrazole, N-dimethylaminoaniline, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole substituted by one or more substituents R2, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, wherein R2may be: H, C1-C4 alkyl, cycloalkyl and wherein each R4is independently selected from -OH, -COOH, -COOR2, C1-C4 alkyl, C1-C4 haloalkyl (and preferably -CF3), Cl-C4-haloalkyloxy (and preferably - OCHF2), Cl-C4-alkoxy (and preferably -OCH3), cycloalkyl, -NR2or -N(R2)2-9. The compound according to the preceding claim, whereinR1may be: H, C1-C4 alkyl, cycloalkyl,A' is a non-substituted or a R4mono- or di-substituted ring A' selected from: phenyl, pyridine, N-dimethylaminoaniline, wherein each R4is independently selected from -OH, -COOH, -COOR2, -CH3, -CF3, -OCF3, -OCHF2, -OCH3, -NR2or -N(R2)2, wherein R2is -CH3.

10. The compound according to any one of the preceding claims, having the general structure (VII):whereinR5is selected from H, C1-C4 alkyl (preferably -CH3),R6is selected from H, Cl-C4-alkyl (preferably -CH3) or R6is -CH=CH- and together with the nitrogen atom to which it is bound and the phenyl ring forms a 6-indolyl radical of general formula:the dashed C-C bond may be present or absent, with the proviso that when R6is a -CH=CH- group and forms a 6-indolyl radical, then the dashed bond is present as a double bond in the piperidine ring.

11. The compound according to the preceding claim, wherein each of R5and R6may independently be -H or -CH3.

12. The compound according to any one of the preceding claims, having the general structure (VIII):whthe dashed bond is a single or a double bond, ring A is a R3-substituted phenyl or a non-substituted or a R3- substituted ring A selected from: pyrrolidine, and heteroaromatic rings such as: pyrazole, N-R2pyrazole, pyrrole, N-R2pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, imidazole, N-R2imidazole, thiophene, thiazole, isothiazole, oxazole, isoxazole, and bicyclic-heteroaromatic rings such as: benzofuran, NH-indole, N-R2indole, isoquinoline, quinoline, indazole, N-R2indazole, wherein R3is selected from C1-C4 alkyl, C1-C4 haloalkyl (and preferably -CF3), cycloalkyl, wherein R2is H, C1-C4 alkyl, cycloalkyl, wherein R4is selected from C1-C4 alkyl, C1-C4 haloalkyl (and preferably -CF3), cycloalkyl.

13. The compound according to the preceding claim, wherein A is a R3- substituted phenyl or a non-substituted or a R3-substituted ring A selected from: benzofuran, NH-indole, N-R2indole, pyrazole, pyrrolidine, isoquinoline, quinoline, pyrimidine, pyrrole, indazole, N-R2indazole, imidazole, N-R2imidazole, thiophene, R3is H or -CH3, wherein R2is H or - CH3, wherein R4is selected from C1-C4 alkyl (and preferably -CH3), C1-C4 haloalkyl (and preferably -CF3), cycloalkyl.

14. The compound according to any one of the preceding claims having a structure selected from:

15. A compound according to any one of the preceding claims for the medical use.

16. The compound according to any one of the preceding claims 1 to 15 for the medical use in the treatment of cancer.

17. The compound for the medical use according to the preceding claim, wherein said cancer is melanoma.

18. The compound according to any one of the preceding claims 1 to 15 for the medical use in the treatment of cardiomyopathies, retinal disorders and vascular disorders.

19. The compound according to the preceding claim, wherein said vascular disorders are selected from the group comprising: aneurysm, carotid artery disease, deep vein thrombosis, peripheral artery disease, renal artery disease, vascular malformations, varicose and spider veins, carotid body tumors, chronic venous insufficiency, thoracic outlet syndrome.

20. The compound for the medical use according to claim 15, which is selected from:

21. A compound for the medical use according to any one of the preceding claims 15 to 20, which is used alone or in combination with one or more other therapeutic agent.

22. A pharmaceutical composition comprising a compound according to any one of the preceding claims from 1 to 14 with suitable pharmaceutically acceptable excipients.

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