Inhibitors of heme oxygenase, compositions and uses thereof

Abstract

1, 4-disubstituted-l, 2, 3 triazoles compounds of formula ( I ) : (I) able to inhibit heme oxygenase activity, their use as a medicament in treating and / or preventing pathological conditions associated to alterations in heme oxygenase activity and pharmaceutical compositions containing the same.

Description

[0001] "Inhibitors of Heme Oxygenase, compositions and uses thereof"

[0002] ★ ★ ★

[0003] Field of the invention

[0004] This disclosure concerns compounds able to inhibit heme oxygenase. The disclosure also relates to the use of these compounds for treatment of pathological conditions in which over-expression of heme oxygenase-1 by myeloid cells is associated with disease progression.

[0005] Background of the invention

[0006] Although the pathological significance of tumor- associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. We showed that a distinct subset of TAMs (F4 / 80hiCD115hiC3aRhiCD88hi) , endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1) , plays a critical role in shaping a prometastatic tumor microenvironment, favoring immunosuppression, angiogenesis and epithelial-to- mesenchymal transition (Consonni F. et al. 2021, DOI: 10.1038 / s41590-021-00921-5) . This population originates from F4 / 80+HO-1+ bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-KBl-CSFlR-C3aR axis. Inhibition of F4 / 80+HO-1+ TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy, in models of sarcoma, lung and melanoma. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients . Substituted 1 , 2 , 3-triazole compounds have been disclosed in WO 2014 / 205414; WO 2018 / 067615; Khan Sadaf et al. Synthesis (2010) , 2010 ( 15 ) : 2609-2615 ; Vereshchagin L I et al. Russian Journal Of Organic Chemistry (2006) , 42 ( 6) : 912-917 ; Lv Mingxiu et al. Phosphorus , Sulfur, And Silicon And The Related Elements (2018) , 193 ( 4 ) : 206-210 ; Sahbi Azzeddine et al. lucrdata (2017) , 2 (4) ; Boutouil Aziz et al. Journal Of Adhesion Science And Technology (2019) , 34 ( 5 ) : 549-578 ; Narsimha Sirassu et al. Heterocyclic Letters (2015) , 5(4) : 653- 660.

[0007] Summary of the invention

[0008] The object of this disclosure is to provide new compounds which exhibit inhibitory activity against the heme oxygenase enzymes, these new compounds being a valuable therapeutic tool for the treatment and / or prevention of disease conditions characterized by an over-activity of these enzymes.

[0009] According to the invention, the above object is achieved thanks to the subject matter recalled specifically in the ensuing claims, which are understood as forming an integral part of this disclosure.

[0010] An embodiment of the present disclosure provides 1 , 4-disubstituted-l , 2 , 3 triazoles of formula (I) : wherein

[0011] A is selected from

[0012] B is selected from straight or branched, substituted or unsubstituted Ci-s alkyl, straight or branched, substituted or unsubstituted C2-8 alkenyl, straight or branched, substituted or unsubstituted Ci-s carbonyl, straight or branched, substituted or unsubstituted Ci-s alkoxy, C3-6 cycloalkyl, Ar1, and substituted or unsubstituted (CH2)n-Ar1; n is an integer 1 to 4;

[0013] Ar1is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl group.

[0014] In an embodiment, the disclosure also relates to the compounds of formula (I) for use in the treatment of disease conditions in which heme oxygenase is aberrantly over activated.

[0015] In an embodiment, the disclosure also provides a pharmaceutical composition comprising at least one compound of formula (I) and a pharmaceutically acceptable excipient.

[0016] Overall, the results disclosed herein identify heme oxygenase as a therapeutic target for the treatment of disease conditions characterized by an over-activity of this enzyme. Based on these results, the inventors of the present application were able to develop novel HO-1 inhibitors that can prevent metastatic activity of various human tumors .

[0017] Brief description of the drawings

[0018] The invention will now be described in detail, purely by way of illustrative and non-limiting example, with reference to the attached figures, wherein:

[0019] - Figure 1. (A) Experimental scheme for determining the activity of HO-1 inhibitors. (B) ELISA-based bilirubin quantification produced by hemin-treated PANC-

[0020] 1 cells after incubation with selected compounds of formula (I) . Data are mean ± SD of 2 independent experiments. *p<0.05, **p<0.01.

[0021] Figure 2: (A) HO-1 inhibition assay performed in saturation condition of purified HO-1, by adding a single concentration of the tested inhibitors and compound #A (40 pM) . Residual activity of the HO-1 enzyme in the tested conditions is shown. (B) ELISA-based bilirubin quantification produced by HeLa cells after treatment with the inhibitors #28 and #A derived from formula (I) , in comparison with the standard inhibitor OB24 and the heme oxygenase inducer hemin. The table shows the fold change of HO-1 activity upon 24h treatment with respect to untreated control. (C) A spectral analysis was carried out to assess the binding between the tested compounds (#28, #32, #A) and the substrate of HO-1 (hemin) ; shift in the absorption peak of the hemin (395 nm) in the presence of compounds of formula (I) #28 and #32 indicates a direct interaction of the tested compounds with the free hemin. #A does not show interaction with hemin .

[0022] - Figure 3: (A) Cell viability assay by crystal violet staining assay. HeLa cells were seeded at a low density (0.3*106cells / well in a 6 multiwell plates) and treated at different concentrations with the indicated compounds. After 48h cells were stained with crystal violet (0.1% w / v solution in 10% formalin) and the viable and stained cells were dissolved for OD reading using 100% MetOH. Absorbance was measured using Victor 3V (Perkin Elmer, Turku, Finland) at 595 nm and results are reported as optical density (OD) , which directly correlates with cell quantity. As internal controls, 0.2% DMSO (negative control) and lOpM cisplatin (reference anticancer cytotoxic drug) were used. (B) HeLa cells were treated with the indicated concentrations of test compounds (#28, #A) . As internal controls, 0.2% DMSO (negative control) and lOpM cisplatin (reference anticancer cytotoxic drug) were used. After 48h, cells were detached using trypsin, pelleted and incubated with Live / Dead Near IR (LD NIR) staining dye for 15 min, prior staining with Annexin conjugated with FITC (additional 15 min) . The percentage (% cells) of live cells (AnnexinV- / LD NIR-) , early apoptosis cells (AnnexinV+ / LD NIR-) , late apoptosis cells (AnnexinV+ / LD NIR + ) , and necrosis cells (Annexin V- / LD NIR+) was measured by flow cytometry.

[0023] Data are mean ± SD of 2 independent experiments, each including 3 technical replicates. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001

[0024] Figure 4: (A-C) WT mice were injected intramuscularly in their left hindlimb with MN / MCA1 fibrosarcoma cells (10*5 cells per mouse in 100 pl of PBS) and from day 7 post implantation were intraperitoneally injected or not with 30 mg / kg HO-1 inhibitor (ZnPPIX) (Consonni et al 2021, DOI: 10.1038 / s41590-021-00921-5) , three times per week until sacrifice. 24 days after tumor cells injection, mice were sacrificed and primary tumors and lungs were collected. (A) Area of metastatic burden was quantified from H&E-stained lung sections and expressed as percentage of total lung surface area; representative images are shown. Scale bars, 1 mm. (B) FACS quantification of epithelial (E-cadherin, EPCAM) and mesenchymal (Vimentin and N-cadherin) markers in primary tumor cells. (C) FACS quantification of CD31+ endothelial cells in primary tumors. Data are mean ± s.e.m. *P<0.05, **P<0.01, ***P< 0.001.

[0025] Figure 5: (A-C) WT mice were subcutaneously injected with 100 pl of PBS containing 5x10*5 murine melanoma B16 / F10 cells and from day 3 post implantation, were intraperitoneally injected or not with 30 mg / kg of HO-1 inhibitor ZnPPIX three times per week until sacrifice. Starting from 10 days after tumor cells injection, tumor growth was monitored three times per week with a caliper. 17 days after tumor cells injection, mice were sacrificed, and primary tumors estimated for size and volumes. (A) Mean ±- SEM tumor volume of Bl 6 implants in WT mice treated with vehicle or HO-1 inhibitor (ZnPPIX) . (B) FACS quantification of the Ml- (TNF) and M2- (CD206) macrophage polarization markers in F4 / 80hiand F4 / 8010TAMs subsets; (C) Quantification of IFNy expression by B16 tumor-infiltrating CD8+ T lymphocytes and CD8 / Treg ratio. Data are mean ± s.e.m. *P<0.05, **P<0.01, ***P< 0.001.

[0026] Figure 6: (A) WT mice were injected intramuscularly in their left hindlimb with MN / MCA1 fibrosarcoma cells (10*5 cells per mouse in 100 pl of PBS) and from day 7 post implantation were intraperitoneally injected or not with 30 mg / kg of compounds (#28, #32, #40, #43) , three times per week until sacrifice. 24 days after tumor cells injection, mice were sacrifice and lungs were collected. Macroscopic lung metastasis count is shown. (B) WT mice were injected orthotopically in the pancreas with K8484 pancreatic cancer cells (lxlOA5 cells per mouse in 20pl of PBS + 5pl of Matrigel lOmg / ml) and from day 7 post implantation were intraperitoneally injected or not with 30 mg / kg of compounds #28, #32, #40, #43, three times per week until sacrifice. 28 days after tumor cells injection, mice were sacrificed, pancreases were collected and the weights of tumor mass estimated. Data are mean ± s.e.m. *p<0.05, **p<0.01, ***p<0.001, ****p<0 .0001

[0027] Figure 7: (A-C) WT mice were injected intramuscularly in their left hindlimb with MN / MCA1 fibrosarcoma cells (10*5 cells per mouse in 100 pl of PBS) and from day 7 post implantation, were intraperitoneally injected or not with 30 mg / kg of HO-1 inhibitors or the comparison #A, three times per week. 24 days after tumor cells injection, mice were sacrificed, primary tumors and lungs were collected. (A) Macroscopic lung metastasis (left) and area of metastatic burden quantified from H&E-stained lung sections (right) are shown (3 slices / lungs were analyzed) . (B) ELISA quantification of serum COHb levels in different experimental groups. (C) FACS quantification of TNF expression in F4 / 80hiand F4 / 8010TAMs subsets and of IFNy expression in tumorinfiltrating CD8+ T lymphocyte. Data are mean ± s.e.m. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001

[0028] Figure 8: (A-C) WT mice were subcutaneously injected with 100 pl of PBS containing 10*6 murine pancreatic PANC-02 cells. From day 7 post implantation, mice were intraperitoneally injected or not with 30 mg / kg of HO-1 inhibitors or #A, three times per week. Starting from 13 days after tumor cell injection, tumor growth was monitored three times per week with a caliper. 22 days after tumor cells injection, mice were sacrifice and primary tumors were collected. (A) Mean ±- SEM tumor volume (left) and weight of primary tumors (right) of PANC-02 implants in WT mice treated with vehicle, #A or HO-1 inhibitors; representative images are shown. (B) ELISA quantification of serum carboxyhemoglobin (COHb) levels in the different experimental groups. COHb is a stable hemoglobin (Hb) complex acting as an indirect indicator of endogenous carbon monoxide CO production, via HO-1 enzymatic activity (J Pers Me. 2024 Jan 31; 14 (2) : 168. doi: 10.3390 / jpml4020168 ) . (C) FACS quantification of TNF expression in F4 / 80hiand F4 / 8010TAMs subsets and of GRZB in tumor-infiltrating CD8+ T lymphocytes. Data are mean ± s.e.m. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001

[0029] Figure 9: MTT ( 3- ( 4 , 5-dimethylthiazol-2-yl ) -2 , 5- diphenyltetrazolium bromide) viability assay on human pancreatic cancer cells PANC-1 treated or not with selected compounds of formula (I) for 24h was performed to evaluate non-toxic concentrations of tested compounds in our in vitro experimental settings.

[0030] Detailed description of the invention

[0031] In the following description, numerous specific details are given to provide a thorough understanding of embodiments. The embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the embodiments.

[0032] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments .

[0033] The headings provided herein are for convenience only and do not interpret the scope or meaning of the embodiments .

[0034] The disclosure relates to compounds of formula (I) with a specific HO-1 inhibitory activity on protumor myeloid cells (i.e. tumor-associated macrophages, myeloid-derived suppressor cells, circulating monocytes, as well as tumor cells) . In particular, inhibition of HO-1 in myeloid cells by means of compounds of formula (I) prevents their proangiogenic and immunosuppressive action, reactivating host-specific tumor immunity, while preventing epithelial-to-mesenchyme transition (first step of the metastasis process) in tumor cells.

[0035] An embodiment of the present disclosure provides 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) : wherein

[0036] A is selected from

[0037] B is selected from straight or branched, substituted or unsubstituted Ch-s alkyl, straight or branched, substituted or unsubstituted C2-8 alkenyl, straight or branched, substituted or unsubstituted Ci-s carbonyl, straight or branched, substituted or unsubstituted Ci-s alkoxy, C3-6 cycloalkyl, Ar1, and substituted or unsubstituted (CH2)n-Ar1; n is an integer 1 to 4;

[0038] Ar1is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0039] In one embodiment, when Ar1is a substituted aryl or a substituted heteroaryl, the one or more substituents are independently selected from halogen atom, substituted or unsubstituted C1-4 alkyl, IH-tetrazole, - COOH, -OH, -CH2-OH, -NH2, -NH-C (0) -NH-R1, -COOR1, -N02, - CF3, -ON, -OR1, -CONH2, -CONHR1, -CONR1R2, -NHR1, -NRW, -NHCOR1, -NHSO2R1, or -SO2NHR1;

[0040] R1and R2are identical or different from each other and independently selected from H, straight or branched, substituted or unsubstituted Ci-s alkyl, Ar2;

[0041] Ar2is selected from aryl and heteroaryl.

[0042] In one embodiment, when B is a substituted Ci-g alkyl, a substituted C2-8 alkenyl, a substituted Ci-s carbonyl, a substituted Ci-s alkoxy, or a substituted (CH2)nr1, the one or more substituents are independently selected from aryl and heteroaryl, preferably phenyl and naphthyl .

[0043] In one embodiment, B is selected from straight or branched, substituted or unsubstituted C1-4 alkyl, straight or branched, substituted or unsubstituted C2-4 alkenyl, straight or branched, substituted or unsubstituted C1-4 carbonyl, straight or branched, substituted or unsubstituted C1-4 alkoxy, Ar1, and substituted or unsubstituted (CH2)n-Ar1, wherein n is 1 to 4.

[0044] In one embodiment, B is selected from straight or branched, substituted or unsubstituted C1-3 alkyl, straight or branched, substituted or unsubstituted C2-3 alkenyl, substituted or unsubstituted C1-2 carbonyl, substituted or unsubstituted C1-2 alkoxy, Ar1, and substituted or unsubstituted (CH2)n-Ar1, wherein n is an integer 1 to 3.

[0045] In one embodiment, B is selected from substituted or unsubstituted (CH2)n-Ar1.

[0046] In one embodiment, n is an integer 1 to 2.

[0047] In one embodiment, when B is a substituted (CH2)n- Ar1, the one or more substituents are independently selected from aryl.

[0048] In one embodiment, the compound of formula (I) is not 4- [ ( IH-imidazol-l-yl ) methyl ] -1- ( 4 -nitrobenzyl )-lH- 1,2,3-triazole, 4 — [ 4 — ( IH-imidazol-l-yl ) methyl- 1H- 1 , 2,3- triazol-l-yl] methylbenzophenone, 4 - [4 - (1H-1, 2, 4triazol- 1-yl ) methyl- 1H- 1 , 2, 3-triazol-l-yl] methylbenzophenone .

[0049] In one embodiment, B is selected from substituted methyl, substituted ethyl, substituted methanone, substituted ethanone, substituted methoxy, substituted ethoxy, substituted ethylene, substituted or unsubstituted benzene, substituted or unsubstituted naphthalene, substituted or unsubstituted methyl-aryl, substituted or unsubstituted ethyl-aryl, substituted or unsubstituted propyl-aryl, wherein preferably aryl is selected from phenyl and naphthyl.

[0050] In one embodiment, when B is selected from substituted methyl, substituted ethyl, substituted methanone, substituted ethanone, substituted methoxy, substituted ethoxy, substituted ethylene, substituted benzene, substituted methyl-aryl, substituted ethylaryl, substituted propyl-aryl, the one or more substituents are independently selected from phenyl and naphthyl .

[0051] In one embodiment, B is selected from substituted or unsubstituted (CH2)n-Ar1, n is an integer 1 to 4, Ar1is selected from substituted or unsubstituted aryl and the compound of formula (I) is not 4- [ ( IH-imidazol-l- yl ) methyl ] -1- ( 4 -nitrobenzyl )-lH-l,2,3-triazole, 4- [ 4-

[0052] ( IH-imidazol-l-yl ) methyl- 1H- 1 , 2, 3-triazol-l- yl ] methylbenzophenone, 4- [4- (1H-1, 2, 4triazol-l- yl ) methyl- 1H- 1 , 2, 3-triazol-l-yl] methylbenzophenone .

[0053] In one embodiment, Ar1is selected from substituted or unsubstituted aryl.

[0054] In one embodiment, Ar1is selected from benzene, and naphthalene.

[0055] In one embodiment, when Ar1is a substituted aryl or a substituted heteroaryl group, the one or more substituents are independently selected from halogen atom, substituted or unsubstituted Ci-4 alkyl, -NH2, CF3, -COOH, -OH, -CH2-OH, -NO2, -ON, -OMe, -CONH2, -COOMe.

[0056] In one embodiment, when Ar1is a substituted aryl, the one or more substituents are independently selected from halogen atom, C1-4 alkyl, -NH2, -CF3.

[0057] In one embodiment, Ar2is selected from benzene, furan, thiophene, pyrrolidine, pyrrole, 1 , 2 , 3-triazole, pyrazole, imidazole, oxazole, isooxazole, thiazole, isothiazole, 1 , 2 , 3-oxadiazole, 1 , 2 , 4-oxadiazole, 1,2,5- oxadiazole, pyridine, pyrididazine, pyrimidine, pyrazine, naphthalene, indole, IH-indazole, 1H- benzo [d] imidazole, benzo [d] thiazol-2-amine, isoindole, indolizine, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, or carbazole.

[0058] In one embodiment, the 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) is selected from:

[0059] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1-benzyl-lH- 1,2,3-triazole (#1) ;

[0060] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1-phenethyl-lH- 1,2,3-triazole (#6) ;

[0061] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- chlorophenethyl ) -1H-1, 2, 3-triazole (#7) ;

[0062] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (3- phenylpropyl ) -1H-1, 2, 3-triazole (#8) ;

[0063] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (naphthalen-1- ylmethyl )-lH- 1,2, 3-triazole ( #9) ;

[0064] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 2 , 2- diphenylethyl ) -1H-1, 2, 3-triazole (#10) ;

[0065] - l- ( (l-benzyl-lH-l,2,3-triazol-4-yl) methyl ) - IH-tetrazole (#11) ;

[0066] - 1- ( ( 1 -phene thy 1 - 1H- 1 , 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#12) ;

[0067] - 1- ( ( 1- ( 4 -chlorophenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#13) ;

[0068] - 1- ( ( 1- ( 3 -phenylpropyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#14) ;

[0069] - 1- ( ( 1- (naphthalen-l-ylmethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#15) ;

[0070] - 1- ( ( 1- ( 2 , 2 -diphenyl ethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#16) ;

[0071] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1-benzyl- 1H-1, 2, 3-triazole (#17) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl )-l- phenethyl-lH-1 , 2 , 3-triazole (#18) ;

[0072] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (4- chlorophenethyl ) -1H-1, 2, 3-triazole (#19) ;

[0073] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (3- phenylpropyl ) -1H-1, 2, 3-triazole (#20) ;

[0074] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (naphthalen-l-ylmethyl ) -1H-1, 2, 3-triazole (#21) ;

[0075] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 2 , 2- diphenylethyl ) -1H-1, 2, 3-triazole (#22) ;

[0076] - 2 - ( 4 - ( ( IH-imidazol-l-yl ) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) -1-phenylethan-l-one (#23) ;

[0077] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (2- phenoxy ethyl )-lH- 1,2, 3-triazole (#24) ;

[0078] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- phenylbutyl) -1H-1, 2, 3-triazole (#25) ;

[0079] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 3 , 3- diphenylpropyl ) -1H-1, 2, 3-triazole (#26) ;

[0080] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1-cinnamyl-lH- 1,2, 3-triazole (#27) ;

[0081] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (2- (naphthalen-l-yl ) ethyl) -1H-1, 2, 3-triazole (#28) ;

[0082] - 4 - ( 2 - ( 4 - ( ( IH-imidazol-l-yl ) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) ethyl) aniline (#29) ;

[0083] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- methylphenethyl ) -1H-1, 2, 3-triazole (#30) ;

[0084] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4-

[0085] ( tri fluoromethyl) phenethyl) -1H-1, 2, 3-triazole (#31) ;

[0086] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 3 , 4- dichlorophenethyl ) -1H-1, 2, 3-triazole (#32) ;

[0087] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (3- (4- chlorophenyl ) propyl )-lH- 1,2, 3-triazole ( #33) ;

[0088] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- f luorophenethyl )-lH- 1,2, 3-triazole ( #34 ) ;

[0089] - 2- (4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1H- 1.2.3-triazol-l-yl) -1-phenylethan-l-one (#35) ;

[0090] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (2- phenoxyethyl ) -1H-1, 2, 3-triazole (#36) ;

[0091] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (4- phenylbutyl) -1H-1, 2, 3-triazole (#37) ;

[0092] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 3 , 3- diphenylpropyl ) -1H-1, 2, 3-triazole (#38) ;

[0093] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1-cinnamyl- 1H-1, 2, 3-triazole (#39;

[0094] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (2- (naphthalen-l-yl ) ethyl) -1H-1, 2, 3-triazole (#40) ;

[0095] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4-

[0096] ( tri fluoromethyl) phenethyl) -1H-1, 2, 3-triazole (#41) ;

[0097] - 4- (2 - (4 - ( (lH-l,2,4-triazol-l-yl) methyl )-lH-

[0098] 1.2.3-triazol-l-yl) ethyl ) aniline ( #42 ) ;

[0099] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- methylphenethyl ) -1H-1, 2, 3-triazole (#43) ;

[0100] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) — 1 — ( 3 , 4 — dichlorophenethyl )-lH- 1,2, 3-triazole (#44) ;

[0101] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (3- (4- chlorophenyl ) propyl) -1H-1, 2, 3-triazole (#45) ;

[0102] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- f luorophenethyl ) -1H-1, 2, 3-triazole (#46) ;

[0103] - 2- (4- ( (lH-tetrazol-l-yl) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) -1-phenylethan-l-one (#47) ;

[0104] - 1- ( ( 1- ( 2 -phenoxy ethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#48) ;

[0105] - 1- ( ( 1- ( 4 -phenylbutyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#49) ;

[0106] - 1- ( ( 1- ( 3 , 3 -diphenylpropyl ) -1H-1, 2, 3-triazol- 4-yl ) methyl ) -IH-tetrazole (#50) ;

[0107] - 1- ( ( 1-cinnamyl-lH-l , 2, 3-triazol-4-yl) methyl ) - IH-tetrazole (#51) ;

[0108] - 1- ( ( 1- ( 2- (naphthalen-l-yl ) ethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#52) ; - 4- (2- (4- ( (lH-tetrazol-l-yl) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) ethyl) aniline (#53) ;

[0109] - 1- ( ( 1- ( 4 -methylphenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#54) ;

[0110] - 1- ( ( 1- ( 3 , 4 -di chlorophenethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#55) ;

[0111] - 1- ( ( 1- ( 3- ( 4 -chlorophenyl ) propyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#56) ;

[0112] - 1- ( ( 1- ( 4- fluorophenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#57) .

[0113] In one embodiment, the 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) is selected from:

[0114] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1-benzyl-lH- 1,2,3-triazole (#1) ;

[0115] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1-phenethyl-lH- 1,2,3-triazole (#6) ;

[0116] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- chlorophenethyl ) -1H-1, 2, 3-triazole (#7) ;

[0117] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (3- phenylpropyl ) -1H-1, 2, 3-triazole (#8) ;

[0118] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (naphthalen-1- ylmethyl )-lH- 1,2, 3-triazole (#9) ;

[0119] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 2 , 2- diphenylethyl ) -1H-1, 2, 3-triazole (#10) ;

[0120] - l- ( (l-benzyl-lH-l,2,3-triazol-4-yl) methyl ) - IH-tetrazole (#11) ;

[0121] - 1- ( ( 1 -phene thy 1 - 1H- 1 , 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#12) ;

[0122] - 1- ( ( 1- ( 4 -chlorophenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#13) ;

[0123] - 1- ( ( 1- ( 3 -phenylpropyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#14) ;

[0124] - 1- ( ( 1- (naphthalen-l-ylmethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#15) ;

[0125] - 1- ( ( 1- ( 2 , 2 -diphenyl ethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#16) ;

[0126] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1-benzyl- 1H-1, 2, 3-triazole (#17) ;

[0127] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- phenethyl-lH-1 , 2 , 3-triazole (#18) ;

[0128] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (4- chlorophenethyl ) -1H-1, 2, 3-triazole (#19) ;

[0129] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 3- phenylpropyl ) -1H-1, 2, 3-triazole (#20) ;

[0130] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (naphthalen-l-ylmethyl ) -1H-1, 2, 3-triazole (#21) ;

[0131] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 2 , 2- diphenylethyl ) -1H-1, 2, 3-triazole (#22) ;

[0132] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- phenylbutyl) -1H-1, 2, 3-triazole (#25) ;

[0133] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 3 , 3- diphenylpropyl ) -1H-1, 2, 3-triazole (#26) ;

[0134] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1-cinnamyl-lH- 1,2, 3-triazole (#27) ;

[0135] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (2- (naphthalen-l-yl ) ethyl) -1H-1, 2, 3-triazole (#28) ;

[0136] - 4 - ( 2 - ( 4 - ( ( IH-imidazol-l-yl ) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) ethyl) aniline (#29) ;

[0137] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- methylphenethyl ) -1H-1, 2, 3-triazole (#30) ;

[0138] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4-

[0139] ( tri fluoromethyl) phenethyl) -1H-1, 2, 3-triazole (#31) ;

[0140] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 3 , 4- dichlorophenethyl ) -1H-1, 2, 3-triazole (#32) ;

[0141] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (3- (4- chlorophenyl ) propyl )-lH- 1,2, 3-triazole ( #33) ;

[0142] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- f luorophenethyl )-lH- 1,2, 3-triazole ( #34 ) ;

[0143] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- phenylbutyl) -1H-1, 2, 3-triazole (#37) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 3 , 3- diphenylpropyl ) -1H-1, 2, 3-triazole (#38) ;

[0144] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (2- (naphthalen-l-yl ) ethyl) -1H-1, 2, 3-triazole (#40) ;

[0145] - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4-

[0146] ( tri fluoromethyl) phenethyl) -1H-1, 2, 3-triazole (#41) ;

[0147] - 4- (2 - (4 - ( (lH-l,2,4-triazol-l-yl) methyl )-lH- 1,2,3-triazol-l-yl) ethyl ) aniline ( #42 ) ;

[0148] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- methylphenethyl ) -1H-1, 2, 3-triazole (#43) ;

[0149] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) - 1 - ( 3 , 4 - dichlorophenethyl )-lH- 1,2, 3-triazole (#44) ;

[0150] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (3- (4- chlorophenyl ) propyl) -1H-1, 2, 3-triazole (#45) ;

[0151] - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- f luorophenethyl ) -1H-1, 2, 3-triazole (#46) ;

[0152] - 1- ( ( 1- ( 4 -phenylbutyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#49) ;

[0153] - 1- ( ( 1- ( 3 , 3 -diphenylpropyl ) -1H-1, 2, 3-triazol- 4-yl ) methyl ) -IH-tetrazole (#50) ;

[0154] - 1- ( ( 1-cinnamyl-lH-l , 2, 3-triazol-4-yl) methyl ) - IH-tetrazole (#51) ;

[0155] - 1- ( ( 1- ( 2- (naphthalen-l-yl ) ethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#52) ;

[0156] - 4- (2- (4- ( (lH-tetrazol-l-yl) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) ethyl) aniline (#53) ;

[0157] - 1- ( ( 1- ( 4 -methylphenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#54) ;

[0158] - 1- ( ( 1- ( 3 , 4 -di chlorophenethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#55) ;

[0159] - 1- ( ( 1- ( 3- ( 4 -chlorophenyl ) propyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#56) ;

[0160] 1- ( (1- ( 4- fluorophenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#57) .

[0161] In one embodiment, the present disclosure concerns 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) as disclosed above for use in the treatment and / or prevention of a disease condition in which heme oxygenase, preferably heme oxygenase-1, is aberrantly over- activated .

[0162] In one embodiment, the disease condition in which heme oxygenase is aberrantly over-expressed is a neoplastic condition. Indeed, comprehensive bioinformatics analysis of HO-1 (HMOX1) gene expression in normal and tumor tissues in TCGA pan-cancer reports significantly elevated expression of HO-1 in tumor samples compared to normal tissues, across multiple tumor types, and associations analyses between this expression and patient outcomes corroborates the essential role of HO-1 in tumor progression (Wenrui Ye et al 2021, doi: 10.3389 / fcell .2021.760800) . Accordingly, TCGA pan-cancer analysis shows that HMOX1 expression is significantly associated with epithelial- mesenchymal transition (EMT) in most tumors and that tumors with lymph and distant metastasis have significantly higher HMOX1 expression than tumors without metastasis, supporting the prometastatic role of HO-1 (Chen Bo et al, / doi . org / 10.3389 / f one .2022.978006 ) . Thus, while HO-1 catabolism physiologically provides homeostatic signals, tumours co-opt HO-1 activities to promote immunosuppression, angiogenesis and epithelial- to-mesenchymal transition (EMT) , enhancing metastasis formation (Luu Hoang KN et al, doi: 10.3389 / fimmu.2021.658315) .

[0163] In one embodiment, the disease conditions in which the HO-1 pathway was found to be aberrantly overactivated include: i) solid tumors, among which it is possible to cite breast, ovary, prostate, thyroid, colon, colorectal, stomach, kidney, lung, non-small cell lung, urothelial, cervix, prostate and pancreas carcinomas, hepatoma, glioblastoma, neuroblastoma, lymphosarcoma, advanced metastatic sarcoma; as well as ii) hematological malignances, among which it is possible to cite Acute lymphoblastic leukemia (ALL) , Acute myeloid leukemia (AML) , Chronic lymphocytic leukemia (CLL) , Hodgkin's lymphomas, Non-Hodgkin ' s lymphomas (Nitti M. et al 2021, doi.org / 10.3390 / anti oxi 0050789 ) .

[0164] In one embodiment, the present invention concerns a pharmaceutical composition comprising at least one 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) as disclosed above. The pharmaceutical composition shows good metabolic stability in both rat (RLM) and human (HLM) liver microsomes.

[0165] The present inventors have reason to believe that compounds of formula (I) exert their antitumor activities by inhibiting pro-tumoral immune functions of HO-1, counteracting HO-l-mediated immunosuppressive skewing of tumor microenvironment. Distinctly from current monoclonal antibodies that target immunological checkpoints in anti-tumor immunotherapy (ICIs) , the compounds of formula (I) act on a distinct target (HO- 1) , thus offering an alternative route for the efficient reactivation of the specific anti-tumor response, exploitable even in patients who show resistance or toxicity towards current treatments with ICIs (Syn NL, Teng MWL, Mok TSK, Soo RA. De-novo and acquired resistance to immune checkpoint targeting. Lancet Oncol. 2017; 18 : e731-41) .

[0166] It is known to the authors that triazole derivatives of formula (I) , wherein different N-containing heterocycles are selected at position A, show in vitro anticancer activity against certain human cancer cell lines (Narsimha Sirassu et al. Heterocyclic Letters (2015) , 5 (4) : 653-660) . In particular, 2- ( (4- ( (lH- imidazol-l-yl ) methyl ) -1H-1, 2, 3-triazol-l-yl) methyl ) -5- phenyl-1, 3, 4-oxadiazole (corresponding to compound #A) represents an example of 1 , 2 , 3-triazole-derived 1,3,4- oxadiazole containing N-heterocyclic moieties with documented anticancer activity. Nonetheless, not every compound falling within this definition could be used for the specific inhibition of HO-1, as a target for anticancer treatment. In fact, although compound #A (Narsimha Sirassu et al. Heterocyclic Letters 2015, 5, 653-660) results extremely stable in both RLM and HLM incubations, spectral analysis of hemin (substrate of HO-1) in the presence of compound #A, as well as in vitro inhibitory assay on both purified HO-1 and intact cells, demonstrate that this compound has not inhibitory activity on HO-1 enzyme. Likewise, in vitro cytotoxicity assays demonstrate no direct cytotoxic effect of compound #A on tumor cells viability.

[0167] In one embodiment, the present invention concerns a pharmaceutical composition comprising at least one 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) as disclosed above and a pharmaceutically acceptable excipient .

[0168] In one embodiment, the present invention concerns a pharmaceutical composition comprising at least one 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) as disclosed above for use in the treatment and / or prevention of a disease condition in which heme oxygenase, preferably heme oxygenase-1, is aberrantly over- activated .

[0169] Compounds of formula (I) can be administered in various routes appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural) , transdermal, rectal, nasal, topical (including buccal and sublingual) , vaginal, intraperitoneal, intrapulmonary and intranasal . When the compound / s is / are administered orally, it / they may be formulated as pills, tables, capsules, ingested daily or less frequently for a specific period of time.

[0170] The dosage depends on a variety of factors including the age, weight and condition of the patient and the route of administration. Although daily dosage can vary from one individual to another, the compound / s will be administered to an adult human in a range of 0.0001-50 mg / kg of body weight as daily single dose or 0.01 to 1 mg / kg as daily repeated doses.

[0171] Compounds of formula (I) can be formulated as a pharmaceutical composition in the form of tablet, capsule, aqueous solution, granule, powder, suspension, cream, syrup, gel, emulsion, etc. in association with suitable pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients suitable to be used in the preparation of a pharmaceutical composition are known in the field and does not necessitate a detailed description herein.

[0172] The compounds of the present disclosure act by binding to heme-oxygenase I (HO-1) inhibiting heme catabolism, known to be involved in cytoprotection, immunosuppression, proangiogenic activities, epithelial-mesenchymal transition / EMT, as well as heme metabolism (Consonni et al. 2021, DOI: 10.1038 / s41590- 021-00921-5) .

[0173] The present inventors have reason to believe the inhibitors of formula (I) represent an effective new anticancer drug, with a distinct mechanism of action compared to current therapies. In brief, these molecules act by binding to the enzyme already complexed with heme, at the moment when it needs to be processed, thus blocking it. These molecules can coordinate the iron (II) of heme through an azole group, preventing the binding with oxygen and therefore the turnover of heme, effectively resulting in the inhibition of the enzyme.

[0174] The HO-1 inhibitors were evaluated by the competitive ELISA kit (Human Total Bilirubin ELISA kit, MyBioSource) for the HO-l-dependent production of bilirubin, a product of heme catabolism (Petteri Hirvonen 0 et al. 2022, doi: 10.3390 / antioxlll22319) , as depicted in Figure 1. Table 1 shows the inhibitory activity observed for some inhibitors, as well as for the standard inhibitor 1- [ [2- [2- ( 4-Bromophenyl ) ethyl] -1, 3-dioxolan-2 yl ] methyl ] -IH-imidazole hydrochloride (OB24) , on the production of bilirubin, in comparison with the production of bilirubin induced by hemin.

[0175] Table 1

[0176] Figure 2 reports the HO-1 enzymatic inhibitory activity of compounds of formula (I) , showing that they

[0177] (i) reduce residual activity of purified HO-1 (panel A) ;

[0178] (ii) reduce HO-1 derived bilirubin production by human cervical adenocarcinoma HeLa cells (panel B) ; (iii) induce spectral shift in the absorption peak of the hemin (395 nm) indicating a direct interaction of the tested compounds with the free hemin (panel c) . None of the aforementioned activities were shown with compound #A (panel a-c) .

[0179] To exclude cytotoxicity of test compounds, a crystal violet viability assay was performed (Fig. 3A) and in parallel apoptosis / necrosis were assessed by flow cytometry to confirm the results (Fig. 3B) . Panel A of Figure 3 shows that cervical cancer cells (HeLa) were able to survive at least 48h upon incubation both with compounds of formula (I) and compound #A, even in the presence of high doses of drug. As a control, cisplatin was used and it was shown to be highly cytotoxic, even at low concentration (10 pM) . Furthermore, flow cytometry apoptosis assay showed that neither compound #28 nor #A were triggering cell death or apoptosis after 48h of treatment (panel B) . These results showed that the compounds had no direct anticancer activity and were in contrast to what expected for compound #A (Narsimha Sirassu et al. Heterocyclic Letters (2015) , 5(4) : 653- 660) . Since we have previously shown that myeloid- specific deletion of the HO-l-encoding HMOX1 gene blocks metastasis formation and improves anti-tumor immunotherapy (Consonni F. et al. 2021, DOI: 10.1038 / s41590-021-00921-5) , we performed pilot testing experiments to evaluate the pharmacological targetability and antitumor activity of commercial HO-1 inhibitors. For this purpose, we used the commercially available HO-1 zinc inhibitor protoporphyrin-9 (Ref. : PMC9952556) . Figure 4 shows that the HO-1 enzymatic inhibitor zinc protoporphyrin IX (ZnPPIX) (i) strongly reduces the formation of lung metastases in a metastatic melanoma model (panel A) ; (ii) decreases the epithelial- to-mesenchymal transition (EMT) demonstrated by the increased expression of the epithelial markers E- cadherin and EpCAM and by the decreased expression of genes characterizing the mesenchymal phenotype (i.e. Vimentin and N-cadherin) (panel B) ; (iii) decreases tumor angiogenesis as demonstrated by reduction of the endothelial marker CD31 in the tumor lesion (panel C) .

[0180] Figure 5 shows that the HO-1 enzymatic inhibitor zinc protoporphyrin IX (ZnPPIX) (i) reduces the growth of primary melanoma, either alone or in combination with anti-PD-1 treatment (panel A) ; (ii) promotes and antitumor M2 to Ml reprogramming of F480+ tumor- associated macrophages (TAMs) by enhancing TNFa and decreasing CD206 expression (Sica et al 2012, doi: 10.1172 / JCI59643) (panel B) ; (iii) restores CD8+ T cells activation and decreases the frequency of T regulatory cells (panel C) .

[0181] Figure 6 shows that compounds of formula (I) (#28, #32, #40, #43) (i) reduce lung metastasis formation in preclinical model of fibrosarcoma (panel A) ; (ii) restrain primary tumor growth of orthotopic pancreatic ductal adenocarcinoma PDAC (panel B) .

[0182] Figure 7 shows in vivo antitumor activity of compounds of formula (I) compared to compound #A in metastatic fibrosarcoma model, demonstrating that HO-1 inhibition mediated by compounds of formula (I) (#28, #32) (i) reduces the formation of lung metastases (panel A) ; (ii) decreases serum level of carboxyhemoglobin (CoHb) , an indirect indicator of endogenous HO-1 mediated CO production, (panel b) ; (iii) induces antitumor reprogramming of tumor-associated macrophages (TAMs) restoring cytotoxic activity of CD8+ tumorinfiltrating T cells (panel c) .

[0183] Figure 8 shows that the HO-1 enzymatic inhibition mediated by compound of formula (I) (#28 and #32) (i) reduced primary tumor growth in pancreatic cancer model (panel A) ; (ii) decrease systemic COHb levels (panel B) ; (iii) promotes M2 to Ml phenotypic switch of tumor- associated macrophages (TAMs) and increases production of GRZB by CD8+ infiltrating T cells (panel 0) .

[0184] Figure 9 shows no cytotoxicity activity of compounds of formula (I) in our in vitro experimental settings; indeed, MTT ( 3- ( 4 , 5-dimethylthiazol-2-yl ) - 2 , 5-diphenyltetrazolium bromide) viability assay on human pancreatic cancer cells PANC-1 treated or not with selected compounds of formula (I) for 24h was performed to evaluate in vitro non-toxic concentrations of tested compounds .

[0185] The chemical structures of preferred compounds of formula (I) are shown in Table 2 below.

[0186] Table 2

[0187]

[0188]

[0189] The following schemes show general methods for preparing key intermediates as well as some preferred compounds of the present description . For a more detailed description of the individual reaction steps , see the Examples herein below . Those skilled in the art will appreciate that other synthetic routes may be used to synthesi ze the compounds of the invention . Although speci fic starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions . In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0190] Synthesis of compounds of formula (I)

[0191] All the compounds of formula (I) were synthesized starting from the intermediate azides and alkynes as outlined in the Scheme a below.

[0192] The azides are prepared applying synthetic methodology known in the art of organic chemistry starting from the corresponding halogen derivatives via SN2 reaction with sodium azide or starting from the corresponding aniline derivatives via diazotation- azidation protocol.

[0193] The alkyne derivatives propargyl imidazole, propargyl-1 , 2 , 4-triazole and proparyl-tetrazoles were prepared according to literature procedures.

[0194] The 1,4- disubstituted triazoles of formula (I) are prepared by a 1,3-dipolar cycloaddition between the corresponding azides and alkynes catalyzed by the active copper (I) species generated in situ by sodium ascorbate and copper (IT) sulfate (Angew. Chem. Int. Ed. 2002, 41, 2596) .

[0195] Preparation Schemes

[0196] Scheme a shows a method for the preparation of the alkynes intermediates:

[0197] Scheme a

[0198] Intermediate 2

[0199] Intermediate 3

[0200] Scheme b shows a method for the preparation of 1,4- disubstituted triazoles:

[0201] Scheme b

[0202] H2O / t-BuOH

[0203] 40 °C

[0204] Example 1 : Synthesis of Intermediate 1 To a solution of imidazole (2 g; 29 mmol;l eq) in

[0205] THF (60 mL) is slowly added NaH (1.29 g; 32 mmol, 1.1 eq) and the solution was stirred for 15 minutes. Then, propargyl bromide (5.17 mL; 58 mmol; 2 eq) was added and the reaction was under stirring for another 30 minutes. At the end of the reaction, NH4CI is added and, once the THF has evaporated in the rotavapor, worked up with H2O and EtOAc. The organic phase is dried with Brine and Na2SO4. After filtering, it is concentrated in a rotavapor obtaining 2.70 g of product as brown oil (87%) .

[0206] Analytical data:

[0207] 1H NMR (300 MHz, CDCI3) : 5 6.88 (br s; 1H) ; 6.34 (br s;

[0208] 1H) ; 6.22 (br s; 1H) ; 4.02 (s; 2H) ;2.21 (br s; 1H) ppm.

[0209] Example 2 : Synthesis of Intermediate 2

[0210] 1H-1 , 2 , 4-triazole (1.74 g; 29 mmol; 1 eq) is dissolved in EtOH (20 mL) . After cooling at 0°Cd, a solution of NaOH (1.01 g; 25 mmol; 1 eq) in H2O (2 mL) was added; a white precipitate immediately forms. Propargyl bromide (2.25 mL; 25 mmol; 1 eq) was added dropwise. The reaction is left under stirring at RT for 48 hours. Then, it is worked up by diluting with water and the resulting solution is extracted with DCM (x3) . The collected organic phases are washed again with H2O (x2) and subsequently dried with Brine and Na2SO4. The crude is purified by column chromatography using as eluents petrolether / ethyl acetate 5:5 and ethyl acetate; 0.90 g of product as yellow oil is obtained (34%) . Analytical data: 1H NMR (300 MHz, CDCI3) : 5 8.20 (s; 1H) ; 7.86 (s; 1H) ; 4.90 (br s; 2H) ; 2.54 (br s; 2H) ppm.

[0211] Example 3 : Synthesis of Intermediate 3

[0212] 1 eq of propargylamine (4 g; 73 mmol) , 1.5 eq of NaNs (7.08 g; 109 mmol) and 1.55 eq of triethylorthoformate (18.72 mL; 113 mmol) are dissolved in glacial acetic acid (20 mL) . The mixture is then heated to 90°C under reflux for 21 hours. The reaction was then cooled, diluted with H2O and NaOH is added 2 N until the pH becomes neutral. The resulting solution was extracted with EtOAc (x3) and the collected organic phases are dried with Brine and Na2SO4. After evaporating the solvent, the rotavapor produces an orange / yellow oil. The crude is purified by column chromatography using petroleum / ethyl as eluent acetate 2:8; 3.00 g of product are obtained as yellowish oil (39%) . Analytical data:

[0213] 1H NMR (300 MHz, CDCI3) : 5 8.85 (s; 1H) ; 5.22 (br s; 2H) ; 2.62 (br s; 1H) ppm.

[0214] Example 4 : General synthesis of compounds of formula (I)

[0215] The alkyne of interest (1 eq.) is dissolved in H20 / t-Bu0H in a 1:1 ratio. Under stirring, the azide of interest (1 eq.) , sodium ascorbate (0.1 eq.) and

[0216] CUSO4*5H2O (0.01 eq.) are added. The reaction proceeds at 40°C overnight. For reactions in which the final product precipitates, this is filtered through a sintered funnel and washed with H2O and Et2O without further processing; for those in which there is no precipitate, the chromatographic column is made to obtain the clean product after elimination of the solvent by rotavapor.

[0217] Example 5 : Synthesis of 4- ( (lH-imidazol-l-yl) methyl) -1- benzyl-lH-1 , 2 , 3-triazole (compound #1)

[0218] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 1 and the azide is phenylazide (synthetized as disclosed in Organic Letters (2022) , 24 (48) , 8920- 8924) . The product was obtained as a brownish solid (85%) .

[0219] Analytical data:

[0220] Melting point: 104-106 °C

[0221] 1H NMR (300 MHz, DMSO-d6) : 5 8.05 (br s; 1H) ; 7.69 (br s;2H) ; 7.55-7.25 (br s; 5H) ; 7.17 (br s; 1H) ; 6.92 (br s: 1H) ; 5.58 (s; 2H) ; 5.26 (s; 2H) ppm.

[0222] IR (Neat) : 1495, 1220, 1052, 736, 662 cm-1

[0223] MS (ESI) [M+H] + : 240 Example 6: Synthesis of 4- ( (lH-imidazol-l-yl) methyl) -1- phenethyl-lH-1 , 2 , 3-triazole (compound #6)

[0224] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 1 and the azide is ( 2-azidoethyl ) benzene (synthetized as disclosed in Molecular Diversity (2021) , 25(4) , 2201-2218) . The product was obtained as a off- white solid (74%) . Analytical data: Melting point: 100-102 °C 1H NMR (300 MHz, CDC13) : 5 7.23-7.10 (br s; 6H) ; 6.90 (br d; 3H) ; 5.02 (s; 2H) ; 4.41 (t;2H; J = 6.72 Hz) ; 3.02 (t; 2H; J = 6.72 Hz) ppm . IR (Neat) : 1504, 1226, 1051, 694, 660 cm-1MS (ESI) [M+H] + : 254

[0225] Example 7 ; Synthesis of 4- ( (lH-imidazol-l-yl) methyl) -1- (4 -chlorophenethyl ) -1H-1 ,2 , 3-triazole (compound #7)

[0226] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 1 and the azide is 1- (2-azidoethyl) -4- chlorobenzene (synthetized as disclosed in Journal of Medicinal Chemistry (2012) , 55(22) , 9562-9575) . The product was obtained as a off-white solid (92%) . Analytical data: Melting point: 140-142 °C 1H NMR (300 MHz, CDCI3) : 5 7.21-6.92 (m; 7H) ; 5.17 (br s; 2H) ; 4.51 (t; 2H; J = 6.72 Hz) ; 3.14 (t; 2H; J = 6.72 Hz) ppm. IR (Neat) : 1492, 1054, 816, 765, 512 cm-1MS (ESI) [M+H] + : 288

[0227] Example 8 : Synthesis of 4-((lH-imidazol-l-yl)methyl)-l- (3-phenylpropyl) -1H-1 ,2 , 3-triazole (compound #8)

[0228] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 1 and the azide is ( 3-azidopropyl ) benzene (synthetized as disclosed in Chemical Communications (Cambridge, United Kingdom) (2018) , 54 (7) , 763-766) . The product was obtained as a brownish solid (75%) . Analytical data: Melting point: 88-90 °C 1H NMR (300 MHz, CDC13) ; 5 7.38 (br s; 1H) ; 7.17-6.78 (m; 8H) ; 5.11 (s; 2H) ; 4.20 (t; 2H; J = 7.05 Hz) ; 2.52 (t; 2H; J = 7.35 Hz) ; 2.15-2.06 (m; 2H) ppm. IR (Neat) : 1494, 1221, 1057, 697, 663 cm-1MS (ESI) [M+H] + : 268

[0229] Example 9 : Synthesis of 4- ( (lH-imidazol-l-yl) methyl) -1- (naphthalen-l-ylmethyl) -1H-1 ,2 ,3-triazole (compound #9)

[0230] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 1 and the azide is 1- ( azidomethyl ) naphthalene (synthetized as disclosed in ChemMedChem (2011) , 6(5) , 840-847) . The product was obtained as a brownish solid (75%) . Analytical data: Melting point: 64-66 °C 1H NMR (300 MHz, CDCI3) : 5 7.85-7.83 (m, 4H) ; 7.46-7.33 (m; 5H) ; 7.25 (br s; 1H) ; 7.01 (br s; 1H) ; 5.86 (s; 2H) ; 5.04 ( s ; 2 H ) ppm . IR (Neat) : 1509, 1224, 1058, 792, 778 cm-1MS (ESI) [M+H] + : 290

[0231] Example 10: Synthesis of 4- ( (lH-imidazol-l-yl) methyl) - 1- (2 ,2 -diphenylethyl) -1H-1 ,2 ,3-triazole (compound #10)

[0232] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 1 and the azide is (2-azidoethane-l, 1- diyl ) dibenzene (synthetized as disclosed in W02010023946 Al 2010-03-04) . The product was obtained as a yellowish solid ( 42% ) .

[0233] Analytical data:

[0234] Melting point: 158-160 °C 1H NMR (400 MHz, CDC13) : 5 7.43 (s; 1H) ; 7.31-7.17 (m; 10H) ; 7.04 (br s; 1H) ; 6.86 (br s; 1H) ; 6.80 (br s; 1H) ; 5.10 (s; 2H) ; 4.94 (d; 2H; J = 8.04 Hz) ; 4.56 (t; 1H; J = 8.04 Hz ) ppm.

[0235] IR (Neat) : 1503, 1223, 822, 740, 699 cm-1MS (ESI) [M+H] + : 330

[0236] Example 11: Synthesis of l-((l-benzyl-lH-l,2,3-triazol- 4 -yl) methyl ) -lH-tetrazole (compound #11)

[0237] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 3 and the azide is phenylazide ( synthetized as disclosed in Organic Letters (2022) , 24 (48) , 8920- 8924) . The product was obtained as a white solid (42%) . Analytical data: Melting point: 143-145 °C 1H NMR (300 MHz, CDCI3) : 5 8.77 (s; 1H) ; 7.61 (s; 1H) ; 7.37-7.35 (br s; 3H) ; 7.27-25 (br s; 2H) ; 5.69 (s; 2H) ; 5.51 ( s ; 2 H ) ppm . IR (Neat) : 1433, 1103, 1057, 740, 693 cm-1MS (ESI) [M+H] + : 242

[0238] Example 12 : Synthesis of 1- ( (1 -phenethyl -1H-1 ,2 ,3- triazol -4 -yl) methyl) -lH-tetrazole (compound #12)

[0239] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 3 and the azide is ( 2-azidoethyl ) benzene (synthetized as disclosed in Molecular Diversity (2021) , 25(4) , 2201-2218) . The product was obtained as a white solid (76%) . Analytical data: Melting point: 105-107 °C 1H NMR (300 MHz, CDC13) : 5 8.67 (s; 1H) ; 7.35 (s; 1H) ; 7.24 (br d; 3H) ; 7.03 (br d; 2H) ; 5.65 (s; 2H) ; 4.59 (t; 2H; J = 7.05 Hz) ; 3.19 (t; 2H; J = 7.05 Hz) ppm. IR (Neat) : 1453, 1155, 1053, 742, 700 cm-1MS (ESI) [M+H] + : 256

[0240] Example 13 : Synthesis of 1- ( (1- (4 -chlorophenethyl ) -1H- 1 ,2 ,3-triazol -4 -yl) methyl) -lH-tetrazole (compound #13)

[0241] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 3 and the azide is 1- (2-azidoethyl) -4- chlorobenzene (synthetized as disclosed in Journal of Medicinal Chemistry (2012) , 55(22) , 9562-9575) . The product was obtained as a off-white solid (88%) . Analytical data: Melting point: 166-168 °C 1H NMR (300 MHz, DMSO-d6) : 5 9.31 (s; 1H) ; 8.06 (s; 1H) ; 7.28 (br d; AA' ; 2H) ; 7.16 (br d; BB' ; 2H) ; 5.77 (s; 2H) ; 4.62 (t; 2H; J = 7.05 Hz) ; 3.18 (br s, 2H) ppm. IR (Neat) : 1493, 1169, 1052, 790, 512 cm-1MS (ESI) [M+H] + : 290

[0242] Example 14 : Synthesis of 1- ( (1- (3-phenylpropyl) -1H- 1 ,2 ,3-triazol -4 -yl) methyl) -lH-tetrazole (compound #14)

[0243] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 3 and the azide is ( 3-azidopropyl ) benzene (synthetized as disclosed in Chemical Communications (Cambridge, United Kingdom) (2018) , 54 (7) , 763-766) . The product was obtained as a off-white solid (56%) . Analytical data: Melting point: 102-104 °C 1H NMR (300 MHz, CDCI3) : 5 8.80 (s; 1H) ; 7.70 (s; 1H) ; 7.25-7.09 (m; 5H) ; 5.70 (s; 2H) ;4.32 (t; 2H; J = 7.05 Hz) ; 2.61 (t; 2H; J = 7.35 Hz) ; 2.25-2.18 (m; 2H) ppm. IR (Neat) : 1473, 1159, 1101, 761, 699 cm-1MS (ESI) [M+H] + : 270

[0244] Example 15: Synthesis of 1- ( (1- (naphthalen-l-ylmethyl) - 1H-1 ,2 , 3-triazol -4 -yl) methyl) -lH-tetrazole (compound

[0245] #15)

[0246] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 3 and the azide is 1- ( azidomethyl ) naphthalene (synthetized as disclosed in ChemMedChem (2011) , 6(5) , 840-847) . The product was obtained as a off-white solid (45%) . Analytical data: Melting point: 124-126 °C 1H NMR (300 MHz, CDC13) : 5 8.68 (s; 1H) ; 7.88-7.79 (m; 3H) ; 7.50-7.43 (m; 5H) ; 5.94 (s; 2H) ; 6.57 (s; 2H) ppm IR (Neat) : 1468, 1104, 1050, 778, 762 cm-1MS (ESI) [M+H] + : 292

[0247] Example 16: Synthesis of 1- ( (1- (2 ,2-diphenylethyl) -1H- 1 ,2 ,3-triazol -4 -yl) methyl) -lH-tetrazole (compound #16)

[0248] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 3 and the azide is (2-azidoethane-l, 1- diyl ) dibenzene (synthetized as disclosed in W02010023946 Al 2010-03-04) . The product was obtained as a off-white solid ( 84% ) . Analytical data: Melting point: 178-180 °C 1H NMR (400 MHz, DMSO-d6) : 5 9.19 (s; 1H) ; 8.08 (s; 1H) ; 7-36-7.18 (m; 10H) ; 5.71 (s;2H) ; 5.08 (d; 2H; J = 8.0 Hz) ; 4.70 (d; 2H; J = 8.0 Hz) ppm . IR (Neat) : 1497, 1454, 1167, 749, 700 cm-1

[0249] MS (ESI) [M+H] + : 332 Example 17 : Synthesis of 4-((lH-l,2,4-triazol-l- yl)methyl) -1-benzyl-lH-l ,2 ,3-triazole (compound #17)

[0250] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 2 and the azide is phenylazide ( synthetized as disclosed in Organic Letters (2022) , 24 (48) , 8920- 8924) . The product was obtained as a off-white solid (56%) . Analytical data: Melting point: 110-112 °C 1H NMR (300 MHz, CDC13) : 5 8.15 (s; 1H) ; 7.85 (s; 1H) ; 7.49 (s; 1H) ; 7.29 (br s; 3H) ; 7.26-7.20 (br s; 2H) ; 5.44 (s; 2H) ; 5.39 (s; 2H) ppm . IR (Neat) : 1503, 1270, 1053, 741, 680 cm-1MS (ESI) [M+H] + : 241

[0251] Example 18: Synthesis of 4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1 -phenethyl -1H-1 ,2 ,3-triazole (compound #18)

[0252] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 2 and the azide is ( 2-azidoethyl ) benzene (synthetized as disclosed in Molecular Diversity (2021) , 25(4) , 2201-2218) . The product was obtained as a off- white solid (73%) . Analytical data: Melting point: 87-89 °C 1H NMR (300 MHz, CDCI3) : 5 8.05 (s; 1H) ; 7.80 (s; 1H) ; 7.27 (s; 1H) ; 7.12 (br d; 3H) ; 6.95 (br d; 2H) ; 5.31 (s; 2H) ; 4.46 (t; 2H; J = 7.32 Hz) ; 3.06 (t; 2H; J = 7.32 Hz) ppm. IR (Neat) : 1501, 1271, 1015, 751, 673 cm-1MS (ESI) [M+H] + : 255

[0253] Example 19: Synthesis of 4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1- (4 -chlorophenethyl) -1H-1 ,2 ,3-triazole ( compound #19)

[0254] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 2 and the azide is 1- (2-azidoethyl) -4- chlorobenzene (synthetized as disclosed in Journal of Medicinal Chemistry (2012) , 55(22) , 9562-9575) . The product was obtained as a off-white solid (81%) . Analytical data: Melting point: 119-122 °C 1H NMR (300 MHz, CDC13) : 5 8.15 (s; 1H) ; 7.91 (br s; 1H) ; 7.31 (br s; 1H) ; 7.22 (br s; AA' ;2H) ; 6.95 (br d; BB' ; 2H) ; 5.42 (s; 2H) ; 4.53 (t; 2H; J = 7.02 Hz) ; 3.16 (t; 2H; J = 7.02 Hz) ppm . IR (Neat) : 1492, 1015, 760, 678, 512 cm-1MS (ESI) [M+H] + : 289

[0255] Example 20: Synthesis of 4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1- (3-phenylpropyl) -1H-1 ,2 ,3-triazole (compound #20)

[0256] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 2 and the azide is ( 3-azidopropyl ) benzene (synthetized as disclosed in Chemical Communications (Cambridge, United Kingdom) (2018) , 54 (7) , 763-766) . The product was obtained as a off-white solid (68%) . Analytical data: Melting point: 67-69 °C 1H NMR (300 MHz, CDCI3) : 5 8.17 (s; 1H) ; 7.86 (s; 1H) ; 7.53 (s; 1H) ; 7.20-6.93 (m; 5H) ; 5.40 (s; 2H) ; 4.25 (t; 2H; J = 7.02 Hz) ; 2.56 (t; 2H; J = 7.02 Hz) ; 2.13 (m; 2H) ppm .

[0257] IR (Neat) : 1504, 1270, 1134, 781, 680 cm-1

[0258] MS (ESI) [M+H] + : 269 Example 21 : Synthesis of 4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1- (naphthalen-l-ylmethyl) -1H-1 ,2 ,3-triazole (compound #21)

[0259] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 2 and the azide is 1- ( azidomethyl ) naphthalene (synthetized as disclosed in ChemMedChem (2011) , 6(5) , 840-847) . The product was obtained as a brownish solid (71%) . Analytical data: Melting point: 73-75 °C 1H NMR (300 MHz, CDC13) : 5 8.18 (br s; 1H) ; 7.85-7.80 (m; 4H) ; 7.44-7.25 (m; 5H) ; 5.85 s; 2H) ; 5.28 (s; 2H) ppm. IR (Neat) : 1509, 1136, 1049, 778, 676 cm-1MS (ESI) [M+H] + : 291

[0260] Example 22 : Synthesis of 4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1- (2 ,2 -diphenylethyl) -1H-1 ,2 ,3-triazole (compound #22)

[0261] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 2 and the azide is (2-azidoethane-l, 1- diyl ) dibenzene (synthetized as disclosed in W02010023946 Al 2010-03-04) . The product was obtained as a white solid (84%) . Analytical data: Melting point: 133-135 °C 1H NMR (400 MHz, CDCI3) : 5 8.04 (s; 1H) ; 7.92 (s; 1H) ; 7.33-7.19 (m; 10H) ; 7.09 (br s; 1H) ; 5.36 (s; 2H) ; 4.97 (d; 2H; J = 8.0 Hz) ; 4.58 (t; 1H; J = 8.0 Hz) ppm. IR (Neat) : 1501, 1272, 1016, 786, 697 cm-1MS (ESI) [M+H] + : 331

[0262] Example 23 : Synthesis of 2- (4- ( (lH-imidazol-1- yl)methyl) -1H-1 ,2 , 3-triazol-l-yl) -1-phenylethan-l-one (compound #23)

[0263] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 1 and the azide is 2-azido-l-phenylethan- 1-one (synthetized as disclosed in Chemical Communications (Cambridge, United Kingdom) (2009) , (26) , 3907-3909) . The product was obtained as a brown solid (59%) .

[0264] Analytical data:

[0265] Melting point: 102 °C 1H NMR (400 MHz, CDCI3) : 5 8.00 (d, J = 7.3 Hz, 2H) , 7.70 (t, J = 1.4 Hz, 2H) , 7.57 (m, 3H) , 7.08 (d, J = 20.3 Hz, 2H) , 5.86 (s, 2H) , 5.31 (s, 2H) ppm.

[0266] IR (Neat) : 3099, 2939, 1676, 1577, 1589, 1223, 1053, 773, 625, 571 cm-1

[0267] MS (ESI) [M+H] + : 268

[0268] Example 24 : Synthesis of 4- ( (lH-imidazol-l-yl) methyl) - 1- (2-phenoxyethyl) -1H-1 ,2 ,3-triazole (compound #24)

[0269] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 1 and the azide is ( 2-azidoethoxy) benzene (synthetized as disclosed in Journal of Medicinal Chemistry (2008) , 51 (23) , 7417-7427) . The product was obtained as a yellowish solid (71%) . Analytical data: Melting point: 101 °C 1H NMR (400 MHz, CDC13) : 5 7.64 (br s, 1H) , 7.62 (s, 1H) , 7.43 - 7.27 (m, 2H) , 7.14 (br s, 1H) , 7.05 (br s, 1H) ,

[0270] 7.27 - 6.96 (m, 1H) , 6.85 (dd, J = 8.7, 0.9 Hz, 2H) ,

[0271] 5.27 (s, 2H) , 4.79 - 4.72 (m, 2H) , 4.39 - 4.32 (m, 2H) ppm.

[0272] IR (Neat) : 3130, 2918, 2870, 1587, 1598, 1495, 1225, 1072, 748, 662 cm-1 MS (ESI) [M+H] + : 270

[0273] Example 25 : Synthesis of 4-((lH-imidazol-l-yl)methyl)- 1- (4-phenylbutyl) -1H-1 ,2 ,3-triazole (compound #25)

[0274] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 1 and the azide is ( 4-azidobutyl ) benzene (synthetized as disclosed in Journal of Medicinal Chemistry (2010) , 53 (2) , 616-623) . The product was obtained as a brown solid (75%) . Analytical data: Melting point: 74 °C 1H NMR (400 MHz, CDC13) : 5 7.63 (br d, 1H) , 7.29-7.11 (m, 8H5.25 (s, 2H) , 4.33 (t, J = 7.2 Hz, 2H) , 2.65 (t, J = 7.5 Hz, 2H) , 1.92 (m, 2H) , 1.67 (m, 2H) ppm.

[0275] IR (Neat) : 2935, 2859, 1504, 1459, 1227, 1077, 744, 695 cnr1

[0276] MS (ESI) [M+H] + : 282

[0277] Example 26: Synthesis of 4-((lH-imidazol-l-yl)methyl)- 1- (3, 3-diphenylpropyl) -1H-1 ,2 ,3-triazole (compound #26)

[0278] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 1 and the azide is ( 3-azidopropane-l , 1- diyl ) dibenzene (synthetized as disclosed in Journal of Medicinal Chemistry (2011) , 54 (7) , 2069-2079) . The product was obtained as a brown oil (69%) . Analytical data: 1H NMR (400 MHz, CDCI3) : 5 7.63 (br s, 1H) , 7.30 (m, 4H) , 7.22 (s, 1H) (m, 6H) , 7.10 (s, 1H) , 7.03 (s, 1H) , 5.24 (s, 2H) , 4.28 (t, J = 7.2 Hz, 2H) , 3.89 (t, J = 7.9 Hz, 1H) , 2.67 (q, J = 7.6 Hz, 2H) ppm.

[0279] IR (Neat) : 3025, 2947, 1493, 1450, 1225, 701, 662 cm-1MS (ESI) [M+Na] + : 244 Example 27: Synthesis of 4- ( (lH-imidazol-l-yl) methyl) - 1-cinnamyl-lH-l , 2 , 3-triazole (compound #27)

[0280] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 1 and the azide is (E) - (3-azidoprop-l-en- 1-yl) benzene (synthetized as disclosed in Organic & Biomolecular Chemistry (2008) , 6(19) , 3461-3463) . The product was obtained as a white solid (42%) . Analytical data: Melting point: 121 °C 1H NMR (400 MHz, CDCI3) : 5 8.03 (s, 1H) , 7.77 (s, 1H) ,

[0281] 7.44 (br t, 1H) , 7.42 (br d, 1H) 7.37 - 7.30 (m, 2H) ,

[0282] 7.29-7.24 (m, 1H) , 7.19 (s, 1H) , 6.98 (s, 1H) , 6.71 (d,

[0283] J = 15.8 Hz, 1H) , 6.44 (m, 1H) , 5.34 (s, 2H) , 5.18 (br d, 2H) ppm.

[0284] IR (Neat) : 3423, 3312, 3205, 3122, 1613, 1515, 1218, 1051, 745, 525 cm-1

[0285] MS (ESI) [M+Na] + : 288

[0286] Example 28: Synthesis of 4- ( (lH-imidazol-l-yl) methyl) - 1- (2- (naphthalen-l-yl) ethyl) -1H-1 ,2 ,3-triazole (compound #28)

[0287] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 1 and the azide is 1- (2- azidoethyl ) naphthalene (synthetized as disclosed in Journal of the American Chemical Society (2003) , 125(32) , 9588-9589 ) . The product was obtained as a brownish solid (70%) . Analytical data: Melting point: 107 °C 1H NMR (400 MHz, CDC13) : 5 8.02 - 7.93 (m, 1H) , 7.90 - 7.83 (m, 1H) , 7.76 (d, J = 8.3 Hz, 1H) , 7.63 (br s, 1H) , 7.56 (s, 1H) , 7.53 - 7.45 (m, 2H) , 7.30 (br t, 1H) , 7.13 (br d, 1H) , 7.02 (br s, 1H) , 5.19 (s, 2H) , 4.76 (t, J = 6.9 Hz, 2H) , 3.66 (t, J = 6.9 Hz, 2H) , 3.33 (m, 1H) ppm. IR (Neat) : 3139, 3105, 1507, 1046, 804, 780, 639 cm-1MS (ESI) [M+Na] + : 326

[0288] Example 29: Synthesis of 4- (2- (4- ( (lH-imidazol-1- yl)methyl) -1H-1 ,2 , 3-triazol-l-yl) ethyl) aniline (compound #29)

[0289] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 1 and the azide is 4- ( 2-azidoethyl ) aniline (synthetized as disclosed in Advanced Functional Materials (2011) , 21 (3) , 494-500) . The product was obtained as a brownish solid (49%) . Analytical data: Melting point: 140 °C 1H NMR (400 MHz, CDCI3) : 5 7.55 (s, 1H) , 7.06 (s, 2H) , 6.95 (s, 1H) , 6.80 - 6.75 (m, 2H) , 6.58 - 6.53 (m, 2H) , 5.19 (s, 2H) , 4.49 (t, J = 7.0 Hz, 2H) , 3.86 (s, 2H) , 3.04 (t, J = 7.0 Hz, 2H) ppm.

[0290] IR (Neat) : 3423, 3312, 3205, 3122, 1613, 1515, 1218, 1051, 745, 525 cm-1

[0291] MS (ESI) [M+H] + : 269

[0292] Example 30: Synthesis of 4- ( (lH-imidazol-l-yl) methyl) - 1- (4 -methylphenethyl) -1H-1 ,2 ,3-triazole (compound #30)

[0293] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 1 and the azide is 1- (2-azidoethyl) -4- methylbenzene (synthetized as disclosed in Journal of Medicinal Chemistry (2012) , 55(22) , 9562-9575) . The product was obtained as a brownish solid (65%) . Analytical data: Melting point: 121 °C 1H NMR (400 MHz, CDC13) : 5 7.60 (s, 1H) , 7.15 - 7.00 (m, 4H) , 6.93 (d, J = 8.0 Hz, 3H) , 5.21 (s, 2H) , 4.55 (t, J = 7.1 Hz, 2H) , 3.14 (t, J = 7.1 Hz, 2H) , 2.33 (s, 3H) ppm.

[0294] IR (Neat) : 3118, 2923, 2858, 1504, 1454, 1221, 1049, 809, 753, 659, 522, 490 cm-1

[0295] MS (ESI) [M+H] + : 268

[0296] Example 31 : Synthesis of 4- ( (lH-imidazol-l-yl) methyl) - 1- (4- (tri fluoromethyl) phenethyl) -1H-1 ,2 ,3-triazole (compound #31)

[0297] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 1 and the azide is 1- (2-azidoethyl) -4- (trifluoromethyl) benzene (synthetized as disclosed in Journal of Medicinal Chemistry (2012) , 55(22) , 9562- 9575) . The product was obtained as a brownish amorphous solid (35%) . Analytical data: 1H NMR (400 MHz, CDC13) : 5 7.55 (d, J = 8.0 Hz, 2H) , 7.27 (d, J = 14.4 Hz, 2H) , 7.20 (d, J = 8.0 Hz, 2H) , 7.14 (d, J = 9.1 Hz, 1H) , 7.01 (d, J = 6.3 Hz, 1H) , 5.27 (s, 2H) , 4.61 (t, J = 7.2 Hz, 2H) , 3.30 (t, J = 7.2 Hz, 2H) ppm. MS (ESI) [M+H] + : 322

[0298] Example 32 : Synthesis of 4- ( (lH-imidazol-l-yl) methyl) - 1- (3 , 4 -dichlorophenethyl) -1H-1 ,2 ,3-triazole (compound #32)

[0299] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 1 and the azide is 4- (2-azidoethyl) -1, 2- dichlorobenzene (synthetized as disclosed in Nature (London, United Kingdom) (2019) , 574 (7776) , 86-89) . The product was obtained as a yellow solid (67%) . Analytical data: Melting point: 112 °C 1H NMR (400 MHz, CDCI3) : 5 7.52 (s, 1H) , 7.28 (d, J = 8.2 Hz, 1H) , 7.21 (s, 1H) , 7.12 (d, J = 2.0 Hz, 1H) , 7.01 (s, 1H) , 6.90 (s, 1H) , 6.83 (dd, J = 8.2, 2.1 Hz, 1H) , 5.18 (s, 2H) , 4.51 (t, J = 7.1 Hz, 2H) , 3.13 (t, J = 7.1 Hz, 2H) ppm.

[0300] IR (Neat) : 3121, 2984, 1508, 1458, 1028, 824, 723, 664 cur1

[0301] MS (ESI) [M+H] + : 322

[0302] Example 33 : Synthesis of 4- ( (lH-imidazol-l-yl) methyl) - 1- (3- (4 -chlorophenyl) propyl) -1H-1 ,2 ,3-triazole (compound #33)

[0303] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 1 and the azide is 1- ( 3-azidopropyl ) -4- chlorobenzene (synthetized as disclosed in JP2018027897 A 2018-02-22) . The product was obtained as a yellow solid (73%) .

[0304] Analytical data:

[0305] Melting point: 88 °C 1H NMR (400 MHz, CDC13) : 5 7.53 (s, 1H) , 7.38 (s, 1H) , 7.20 (d, sistema AB, 2H) , 7.03 (d, sistema AB, 2H) , 7.00 (s, 1H) , 6.95 (s, 1H) 5.19 (s, 2H) , 4.26 (t, J = 7.1 Hz, 2H) , 2.55 (t, J = 7.5 Hz, 2H) , 2.23 - 2.07 (m, 2H) ppm. IR (Neat) : 3108, 2947, 1505, 1490, 1222, 1080, 817, 742, 661, 530 cm-1

[0306] MS (ESI) [M+H] + : 302

[0307] Example 34 : Synthesis of 4- ( (lH-imidazol-l-yl) methyl) - 1- (4 -fluorophenethyl) -1H-1 ,2 ,3-triazole (compound #34)

[0308] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 1 and the azide is 1- (2-azidoethyl) -4- fluorobenzene ( synthetized as disclosed in Organic Letters (2020) , 22 (6) , 2376-2380) . The product was obtained as a yellow solid (53%) . Analytical data:

[0309] Melting point: 104 °C 1H NMR (400 MHz, CDC13) : 5 7.54 (s, 1H) , 7.14 (s, 1H) , 7.03 (s, 1H) , 7.00 - 6.89 (m, 5H) , 5.18 (s, 2H) , 4.52 (t, J = 7.1 Hz, 2H) , 3.14 (t, J = 7.1 Hz, 2H) ppm.

[0310] IR (Neat) : 3120, 2924, 1600, 1510, 1454, 1221, 1052, 820, 753, 663, 495 cm-1MS (ESI) [M+H] + : 272

[0311] Example 35 : Synthesis of 2- (4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1H-1 ,2 , 3-triazol-l-yl) -1-phenylethan-l-one (compound #35)

[0312] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 2 and the azide is 2-azido-l-phenylethan- 1-one (synthetized as disclosed in Chemical Communications (Cambridge, United Kingdom) (2009) , (26) , 3907-3909) . The product was obtained as a off-white solid (50%) .

[0313] Analytical data:

[0314] Melting point: 166 °C 1H NMR (400 MHz, CDCI3) : 5 8.29 (s, 1H) , 8.00 (m, 3H) , 7.82 (s, 1H) , 7.71 (t, J = Hz, 1H) , 7.57 (t, J = 7.8 Hz, 2H) , 5.88 (s, 2H) , 5.57 (s, 2H) ppm.

[0315] IR (Neat) : 3087, 2983, 1689, 1579, 1594, 1227, 1056, 769, 688, 573 cm-1MS (ESI) [M+H] + : 269

[0316] Example 36: Synthesis of 4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1- (2-phenoxyethyl) -1H-1 ,2 ,3-triazole (compound #36)

[0317] The title compound was synthesized following the procedure described in example 4. wherein the alkyne is intermediate 2 and the azide is ( 2-azidoethoxy) benzene (synthetized as disclosed in Journal of Medicinal Chemistry (2008) , 51 (23) , 7417-7427) . The product was obtained as a yellowish solid (44%) .

[0318] Analytical data: Melting point: 75 °C 1H NMR (400 MHz, CDC13) : 5 8.25 (s, 1H) , 7.97 (s, 1H) , 7.84 (s, 1H) , 7.29 (m, 2H) , 7.06 - 6.96 (m, 1H) , 6.86 (m, 2H) , 5.51 (s, 2H) , 4.83 - 4.73 (m, 2H) , 4.42 - 4.32 (m, 2H) ppm.

[0319] IR (Neat) : 3107, 2927, 1599, 1586, 1496, 1229, 749, 680 err1MS (ESI) [M+H] + : 271

[0320] Example 37: Synthesis of 4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1- (4-phenylbutyl) -1H-1 ,2 ,3-triazole (compound #37)

[0321] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 2 and the azide is ( 4-azidobutyl ) benzene (synthetized as disclosed in Journal of Medicinal Chemistry (2010) , 53 (2) , 616-623) . The product was obtained as a yellowish solid (86%) . Analytical data: Melting point: 70 °C 1H NMR (400 MHz, CDCI3) : 5 8.25 (s, 1H) , 7.97 (s, 1H) , 7.55 (s, 1H) , 7.32 - 7.26 (m, 2H) , 7.20 (m, 1H) , 7.18 -

[0322] 7.12 (m, 2H) , 5.50 (s, 2H) , 4.35 (t, J = 7.2 Hz, 2H) ,

[0323] 2.66 (t, J = 7.5 Hz, 2H) , 2.02 - 1.85 (m, 2H) , 1.74 -

[0324] 1.57 (m, 2H) ppm.

[0325] IR (Neat) : 3113, 2929, 1504, 1271, 1033, 1018, 744, 681 err1

[0326] MS (ESI) [M+H] + : 283

[0327] Example 38: Synthesis of 4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1- (3 , 3-diphenylpropyl) -1H-1 ,2 ,3-triazole (compound #38) The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 2 and the azide is ( 3-azidopropane-l , 1- diyl ) dibenzene (synthetized as disclosed in Journal of Medicinal Chemistry (2011) , 54 (7) , 2069-2079) . The product was obtained as a yellowish solid (87%) . Analytical data: Melting point: 50 °C 1H NMR (400 MHz, CDCI3) : 5 8.27 (s, 1H) , 7.98 (s, 1H) ,

[0328] 7.48 (s, 1H) , 7.35 - 7.26 (m, 4H) , 7.26 - 7.18 (m, 6H) ,

[0329] 5.48 (s, 2H) , 4.30 (t, J = 7.2 Hz, 2H) , 3.90 (t, J = 7.9 Hz, 1H) , 2.69 (m, 2H) ppm.

[0330] IR (Neat) : 3025, 2940, 1493, 1450, 1272, 728, 697, 676 enr1

[0331] MS (ESI) [M+Na] + : 367

[0332] Example 39: Synthesis of 4-((lH-l,2,4-triazol-l- yl)methyl) -1-cinnamyl-lH-l ,2 ,3-triazole (compound #39)

[0333] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 2 and the azide is (E) - (3-azidoprop-l-en- 1-yl) benzene (synthetized as disclosed in Organic & Biomolecular Chemistry (2008) , 6(19) , 3461-3463) . The product was obtained as a white solid (73%) . Analytical data: Melting point: 121 °C 1H NMR (400 MHz, CDC13) : 5 8.57 (s, 1H) , 8.08 (s, 1H) , 7.99 (s, 1H) , 7.43 (br t, 1H) , 7.40 (br d, 1H) , 7.36 -

[0334] 7.24 (m, 3H) , 6.71 (d, J = 15.8 Hz, 1H) , 6.44 (m, 1H) ,

[0335] 5.57 (s, 2H) , 5.18 (dd, J = 6.6, 1.3 Hz, 2H) ppm

[0336] IR (Neat) : 3109, 3072, 1655, 1503, 1272, 969, 767, 682 err1MS (ESI) [M+Na] + : 289

[0337] Example 40 : Synthesis of 4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1- (2- (naphthalen-l-yl) ethyl) -1H-1 ,2 ,3- triazole (compound #40)

[0338] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 2 and the azide is 1- (2- azidoethyl ) naphthalene (synthetized as disclosed inJournal of the American Chemical Society (2003) , 125(32) , 9588-9589. The product was obtained as a white solid (77%) . Analytical data: Melting point: 101 °C 1H NMR (400 MHz, CDCI3) : 5 8.08 (s, 1H) , 7.94 - 7.83 (m, 3H) , 7.77 (d, J = 8.3 Hz, 1H) , 7.57 - 7.44 (m, 2H) , 7.41 - 7.27 (m, 1H) , 7.18 - 7.09 (m, 2H) , 5.38 (s, 2H) , 4.70 (d, J = 7.3 Hz, 2H) , 3.65 (t, J = 7.2 Hz, 2H) ppm. IR (Neat) : 3099, 2966. 1509, 1137, 1020, 774, 667 cm-1MS (ESI) [M+Na] + : 327

[0339] Example 41: Synthesis of 4- ( (lH-imidazol-l-yl) methyl) - 1- (4- (tri fluoromethyl) phenethyl) -1H-1 ,2 ,3-triazole ( compound #41)

[0340] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 2 and the azide is 4- ( 2-azidoethyl ) aniline (synthetized as disclosed in Advanced Functional Materials (2011) , 21 (3) , 494-500) . The product was obtained as a white amorphous solid (49%) . Analytical data: 1H NMR (400 MHz, CDC13) : 5 8.26 (s, 1H) , 7.96 (s, 1H) , 7.55 (d, J = 8.0 Hz, 2H) , 7.38 (s, 1H) , 7.19 (d, J = 8.0 Hz, 2H) , 5.47 (s, 2H) , 4.62 (t, J = 7.2 Hz, 2H) , 3.30 (t, J = 7.2 Hz, 2H) ppm.

[0341] IR (Neat) : 3132, 3104, 1618, 1503, 1319, 1104, 1063, 831, 679 cm-1

[0342] MS (ESI) [M+H] + : 323 Example 42: Synthesis of 4- (2- (4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1H-1 ,2 , 3-triazol-l-yl) ethyl) aniline (compound #42)

[0343] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 2 and the azide is 1- (2-azidoethyl) -4- methylbenzene (synthetized as disclosed in Journal of Medicinal Chemistry (2012) , 55(22) , 9562-9575) . The product was obtained as a yellow solid (39%) Analytical data: Melting point: 154 °C 1H NMR (400 MHz, CDCI3) : 5 8.13 (s, 1H) , 7.95 (s, 1H) , 6.83 (d, J = 8.4 Hz, 2H) , 6.62 - 6.58 (m, 2H) , 5.45 (d, J = 4.1 Hz, 3H) , 4.54 (t, J = 7.1 Hz, 2H) , 3.09 (t, J = 7.1 Hz, 2H) , 2.87 (s, 2H) .

[0344] IR (Neat) : 3423, 3316, 3211, 3069, 1637, 1611, 1518, 1505, 1272, 1136, 679, 532 cm-1MS (ESI) [M+H] + : 270

[0345] Example 43: Synthesis of 4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1- (4 -methylphenethyl) -1H-1 ,2 ,3-triazole (compound #43)

[0346] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 2 and the azide is 1- (2-azidoethyl) -4- (trifluoromethyl) benzene (synthetized as disclosed in Journal of Medicinal Chemistry (2012) , 55(22) , 9562- 9575) . The product was obtained as a yellowish solid (84%) Analytical data: Melting point: 126 °C 1H NMR (400 MHz, CDC13) : 5 8.20 (br s, 1H) , 7.97 (br s, 1H) , 7.30 (s, 1H) , 7.09 (d AB, 2H) , 6.95 (d AB , 2H) , 5.46 (s, 2H) , 4.58 (t, J = 7.2 Hz, 2H) , 3.17 (t, J = 7.2 Hz, 2H) , 2.34 (s, 3H) ppm.

[0347] IR (Neat) : 3117, 2952, 1505, 1453, 1272, 1203, 1131, 1018, 775, 670, 521, 490 cm-1MS (ESI) [M+H] + : 269

[0348] Example 44: Synthesis of 4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1- (3 , 4 -dichlorophenethyl) -1H-1 ,2 ,3-triazole (compound #44)

[0349] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 2 and the azide is 4- (2-azidoethyl) -1, 2- dichlorobenzene (synthetized as disclosed in Nature (London, United Kingdom) (2019) , 574 (7776) , 86-89) . The product was obtained as a white solid (68%) Analytical data: Melting point: 123 °C 1H NMR (400 MHz, CDC13) : 5 8.19 (s, 1H) , 7.94 (s, 1H) , 7.39 (s, 1H) , 7.35 - 7.27 (m, 1H) , 7.17 (d, J = 2.0 Hz, 1H) , 6.86 (dd, J = 8.2, 2.0 Hz, 1H) , 5.46 (s, 2H) , 4.56 (t, J = 7.1 Hz, 2H) , 3.18 (t, J = 7.1 Hz, 2H) ppm. IR (Neat) : 3124, 2960, 1508, 1458, 1132, 1117, 787, 678 cm-1MS (ESI) [M+H] + : 323

[0350] Example 45: Synthesis of 4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1- (3- (4 -chlorophenyl) propyl) -1H-1 ,2 ,3- triazole (compound #45)

[0351] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 2 and the azide is 1- ( 3-azidopropyl ) -4- chlorobenzene (synthetized as disclosed in JP2018027897 A 2018-02-22) . The product was obtained as a white solid (63%) Analytical data:

[0352] Melting point: 49 °C 1H NMR (400 MHz, CDC13) : 5 8.21 (s, 1H) , 7.90 (s, 1H) , 7.56 (s, 1H) , 7.24 - 7.15 (m, 2H) , 7.03 (d, J = 8.4 Hz, 2H) , 5.44 (s, 2H) , 4.28 (t, J = 7.1 Hz, 2H) , 2.56 (t, J = 7.5 Hz, 2H) , 2.22 - 2.08 (m, 2H) ppm.

[0353] IR (Neat) : 3113, 2955, 1492, 1268, 1009, 810, 673, 521 cur1MS (ESI) [M+Na] + : 325

[0354] Example 46: Synthesis of 4- ( (1H-1 ,2 ,4-triazol-l- yl)methyl) -1- (4 -fluorophenethyl) -1H-1 ,2 ,3-triazole (compound #46)

[0355] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 2 and the azide is 1- (2-azidoethyl) -4- f luorobenzene ( synthetized as disclosed in Organic Letters (2020) , 22 (6) , 2376-2380) . The product was obtained as a yellowish solid (54%) Analytical data: Melting point: 89 °C 1H NMR (400 MHz, CDCI3) : 5 8.17 (s, 1H) , 7.90 (s, 1H) , 7.33 (s, 1H) , 7.02 - 6.86 (m, 4H) , 5.41 (s, 2H) , 4.52 (t, J = 7.2 Hz, 2H) , 3.14 (t, J = 7.1 Hz, 2H) ppm. IR (Neat) : 3133, 2922, 1598, 1508, 1460, 1215, 795, 678, 529 cur1MS (ESI) [M+Na] + : 295

[0356] Example 47 : Synthesis of 2- (4- ( (lH-tetrazol-1- yl)methyl) -1H-1 ,2 , 3-triazol-l-yl) -1-phenylethan-l-one (compound #47)

[0357] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 3 and the azide is 2-azido-l-phenylethan- 1-one (synthetized as disclosed in Chemical Communications (Cambridge, United Kingdom) (2009) , (26) , 3907-3909) . The product was obtained as a yellowish solid (48%)

[0358] Analytical data:

[0359] Melting point: 162 °C (dec) 1H NMR (400 MHz, CDC13) : 5 8.82 (s, 1H) , 8.02 (d, J = 7.6 Hz, 2H) , 7.89 (s, 1H) , 7.72 (t, J = 7.4 Hz, 1H) , 7.59 (t, J = 7.7 Hz, 2H) , 5.86 (d, J = 31.1 Hz, 4H) ppm. IR (Neat) : 3037, 2940, 1700, 1577, 1592, 1221, 1057, 785, 720,570 cm-1MS (ESI) [M+Na] + : 292

[0360] Example 48: Synthesis of 1- ( (1- (2-phenoxyethyl) -1H- 1 ,2 ,3-triazol -4 -yl) methyl) -lH-tetrazole (compound #48)

[0361] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 3 and the azide is ( 2-azidoethoxy) benzene (synthetized as disclosed in Journal of Medicinal Chemistry (2008) , 51 (23) , 7417-7427) . The product was obtained as a off-white solid (60%) Analytical data: Melting point: 118 °C 1H NMR (400 MHz, MeOD) : 5 9.20 (s, 1H) , 8.21 (s, 1H) , 7.25 (t, J = 8.0 Hz, 2H) , 7.01 - 6.83 (m, 3H) , 5.80 (d, J = 26.9 Hz, 2H) , 4.88 - 4.79 (m, 2H) , 4.44 - 4.39 (m, 2H) ppm.

[0362] IR (Neat) : 3115, 2967, 1600, 1586, 1495, 1231, 1047, 751, 689 cm-1MS (ESI) [M+Na] + : 294

[0363] Example 49: Synthesis of 1- ( (1- (4-phenylbutyl) -1H-1 ,2 ,3- triazol -4 -yl) methyl) -lH-tetrazole (compound #49)

[0364] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 3 and the azide is ( 4-azidobutyl ) benzene (synthetized as disclosed in Journal of Medicinal Chemistry (2010) , 53 (2) , 616-623) . The product was obtained as a off-white solid (57%)

[0365] Analytical data:

[0366] Melting point: 88 °C

[0367] 1H NMR (400 MHz, MeOD) : 5 9.23 (s, 1H) , 8.07 (s, 1H) , 7.25 (t, J = 7.5 Hz, 2H) , 7.15 (t, J = 6.8 Hz, 3H) , 5.82 (s, 2H) , 4.43 (t, J = 7.1 Hz, 2H) , 2.65 (t, J = 7.6 Hz, 2H) , 1.97 - 1.86 (m, 2H) , 1.62 (m, 2H) ppm.

[0368] IR (Neat) : 3116, 3073, 2941, 1434, 1171, 1106,764 cm-1MS (ESI) [M+H] + : 368

[0369] Example 50: Synthesis of 1- ( (1- (3 , 3-diphenylpropyl) -1H- 1 ,2 ,3-triazol -4 -yl) methyl) -lH-tetrazole (compound #50)

[0370] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 3 and the azide is ( 3-azidopropane-l , 1- diyl ) dibenzene (synthetized as disclosed in Journal of Medicinal Chemistry (2011) , 54 (7) , 2069-2079) . The product was obtained as a off-white solid (56%) Analytical data: Melting point: 119 °C 1H NMR (400 MHz, MeOD) : 5 9.22 (s, 1H) , 7.97 (s, 1H) , 7.28 (m, 10H) , 5.79 (s, 2H) , 4.37 (t, J = 7.1 Hz, 2H) , 3.94 (d, J = 7.9 Hz, 1H) , 2.71 (m, 2H) ppm.

[0371] IR (Neat) : 3015, 3024, 2952, 1434, 751, 1171, 698 cm-1MS (ESI) [M+Na] + : 368

[0372] Example 51 : Synthesis of 1- ( (1-cinnamyl-lH-l ,2 ,3- triazol -4 -yl) methyl) -lH-tetrazole (compound #51)

[0373] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 3 and the azide is (E) - (3-azidoprop-l-en- 1-yl) benzene (synthetized as disclosed in Organic & Biomolecular Chemistry (2008) , 6(19) , 3461-3463) . The product was obtained as a off-white solid (54%) Analytical data: Melting point: 167 °C

[0374] 1H NMR (400 MHz, MeOD) : 5 8.83 (s, 1H) , 7.79 (s, 1H) , 7.45 - 7.30 (m, 5H) , 6.73 (d, J = 15.7 Hz, 1H) , 6.34 (m, 1H) , 5.77 (s, 2H) , 5.17 (d, J = 6.7 Hz, 2H) ppm.

[0375] IR (Neat) : 3115, 2870, 1599, 1494, 1105, 751, 698 cm-1MS (ESI) [M+Na] + : 290

[0376] Example 52 : Synthesis of 1- ( (1- (2- (naphthalen-1- yl) ethyl) -1H-1 ,2 ,3-triazol -4 -yl) methyl) -lH-tetrazole (compound #52)

[0377] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 3 and the azide is 1- (2- azidoethyl ) naphthalene (synthetized as disclosed inJournal of the American Chemical Society (2003) , 125(32) , 9588-9589. The product was obtained as an off- white solid (69%) Analytical data: Melting point: 134 °C 1H NMR (400 MHz, MeOD) : 5 9.04 (s, 1H) , 8.11 - 7.60 (m, 4H) , 7.60 - 7.07 (m, 4H) , 5.71 (s, 2H) , 3.68 (t, J = 6.9 Hz, 2H) , 3.33 (s, 2H) ppm. IR (Neat) : 3115, 2959, 1508, 1103, 802, 780 cm-1MS (ESI) [M+Na] + : 328

[0378] Example 53 : Synthesis of 4- (2- (4- ( (lH-tetrazol-1- yl)methyl) -1H-1 ,2 , 3-triazol-l-yl) ethyl) aniline (compound #53)

[0379] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 3 and the azide is 4- ( 2-azidoethyl ) aniline (synthetized as disclosed in Advanced Functional Materials (2011) , 21 (3) , 494-500) . The product was obtained as a off-white solid (71%) Analytical data: Melting point: 168 °C 1H NMR (400 MHz, DMSO-d6) : 5 9.43 (s, 1H) , 8.12 (s, 1H) , 6.80 (s, 2H) , 6.46 (s, 2H) , 5.79 (s, 2H) , 4.90 (s, 2H) , 4.49 (t, J = 7.3 Hz, 2H) , 2.94 (t, J = 7.3 Hz, 2H) ppm. IR (Neat) : 3453, 3355, 3095, 3120, 1625, 1517, 1279, 1102, 768, 526 cm-1MS (ESI) [M+H] + : 271

[0380] Example 54 : Synthesis of 1- ( (1- (4 -methylphenethyl ) -1H- 1 ,2 ,3-triazol -4 -yl) methyl) -lH-tetrazole (compound #54)

[0381] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 3 and the azide is 1- (2-azidoethyl) -4- methylbenzene (synthetized as disclosed in Journal of Medicinal Chemistry (2012) , 55(22) , 9562-9575) . The product was obtained as a off-white solid (91%) Analytical data: Melting point: 138 °C 1H NMR (400 MHz, MeOD) : 5 9.15 (s, 1H) , 7.83 (s, 1H) , 7.04 (d sistema AB , 2H) , 6.95 (d sistema AB , 2H) , 5.77 (s, 2H) , 4.64 (t, J = 7.0 Hz, 2H) , 3.15 (t, J = 7.0 Hz, 2H) , 2.29 (s, 3H) ppm.

[0382] IR (Neat) : 3119, 2953, 1514, 1452, 1160, 1104, 1053, 808, 776, 520, 489 cm-1MS (ESI) [M+Na] + : 292

[0383] Example 55 : Synthesis of 1- ( (1- (3 , 4 -dichlorophenethyl) - 1H-1 ,2 ,3-triazol -4 -yl) methyl) -lH-tetrazole (compound

[0384] #55)

[0385] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 3 and the azide is 4- (2-azidoethyl) -1, 2- dichlorobenzene (synthetized as disclosed in Nature (London, United Kingdom) (2019) , 574 (7776) , 86-89) . The product was obtained as a off-white solid (70%) Analytical data:

[0386] Melting point: 127 °C 1H NMR (400 MHz, MeOD) : 5 9.22 (s, 1H) , 7.99 (s, 1H) , 7.45 - 7.26 (m, 2H) , 7.01 (d, J = 8.1 Hz, 1H) , 5.76 (s, 2H) , 4.69 (t, J = 6.9 Hz, 2H) , 3.22 (t, J = 6.9 Hz, 2H) ppm.

[0387] IR (Neat) : 3111, 2885, 1474, 1425, 1170, 1055, 828, 779, 658 cur1

[0388] MS (ESI) [M+Na] + : 346

[0389] Example 56: Synthesis of l-((l-(3-(4- chlorophenyl) propyl) -1H-1 ,2 , 3-triazol -4 -yl) methyl) -1H- tetrazole (compound #56)

[0390] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 3 and the azide is 1- ( 3-azidopropyl ) -4- chlorobenzene (synthetized as disclosed in JP2018027897 A 2018-02-22) . The product was obtained as a off-white solid (76%) Analytical data: Melting point: 110 °C 1H NMR (400 MHz, MeOD) : 5 9.47 (s, 1H) , 8.25 (s, 1H) , 7.34 (d, J = 8.3 Hz, 2H) , 7.23 (d, J = 8.3 Hz, 2H) , 5.82 (s, 2H) , 4.36 (t, J = 7.1 Hz, 2H) , 2.58 - 2.53 (m, 2H) , 2.17 - 2.06 (m, 2H) ppm.

[0391] IR (Neat) : 3111, 2951, 1490, 1460, 1107, 1051, 788, 532 err1

[0392] MS (ESI) [M+Na] + : 326

[0393] Example 57: Synthesis of 1- ( (1- (4 -fluorophenethyl ) -1H- 1 ,2 ,3-triazol -4 -yl) methyl) -lH-tetrazole (compound #57)

[0394] The title compound was synthesized following the procedure described in example 4, wherein the alkyne is intermediate 3 and the azide is 1- (2-azidoethyl) -4- fluorobenzene ( synthetized as disclosed in Organic Letters (2020) , 22 (6) , 2376-2380) . The product was obtained as a off-white solid (62%)

[0395] Analytical data:

[0396] Melting point: 132 °C 1H NMR (400 MHz, MeOD) : 5 9.44 (s, 1H) , 8.12 (s, 1H) , 7.19 (m, 2H) , 7.07 (br t, 2H) , 5.79 (s, 2H) , 4.60 (t, J = 7.3 Hz, 2H) , 3.14 (t, J = 7.2 Hz, 2H) ppm

[0397] IR (Neat) : 3107, 2963, 1006, 1510, 1461, 1217, 1052, 800, 528 cm-1

[0398] MS (ESI) [M+Na] + : 296

[0399] Example A : Synthesis of 2- ( (4- ( (lH-imidazol-l-yl) methyl) -1H-1 ,2 , 3-triazol-l-yl) methyl) -5-phenyl-l ,3,4- oxadiazole (compound #A)

[0400] The title compound was synthetized following the literature procedure in Heterocyclic Letters 2015, 5, 653-660. The spectroscopic data are consistent with the reported ones.

[0401] Activity evaluation of compounds of formula (I) on HO-1

[0402] Determination of the activity of some compounds of formula (I) on HO-1 was performed by a number of direct and indirect detection methods.

[0403] First, we evaluated the non-toxic concentrations of in vitro tested compounds in our experimental settings (Figure 9) . In particular, to determine the viability of cancer cells, MTT ( 3- ( 4 , 5-dimethylthiazol-2-yl ) -2 , 5- diphenyltetrazolium bromide) (Sigma-Aldrich) assay was used on human pancreatic cancer cells PANC-1 (ATCC) . In detail, 10.000 cells / well were seeded in 96-plate and after 24h treatment with HO-1 inhibitors at different concentrations (1|1M, 5 ,M, 10 ,M, 12, 5 p.M; DMSO concentration was kept constant at 0.2%) , cells were incubated with 1 mg / mL MTT in the culture medium for 2 h at 37 °C. As experimental controls, 0.2% DMSO (negative control) and 5% DMSO (positive control) were used. Formazan crystals were dissolved in 100 pL / well of lysis buffer consisting of 0 . IN HC1 and 10% NP40 in isopropanol, and absorbance at 570 nm was determined using a Synergy H4 (Bio-Tek instrument INC) . Blank values (untreated and unstained cells) were subtracted from all reads .

[0404] In the second approach, we examined the effect of non-toxic compounds on HO-1 activity. In order to evaluate the effectiveness of our new small-molecule inhibitors of HO-1 activity in tumor cells, a competitive ELISA (Human Total Bilirubin ELISA kit, catalog n° MBS756198, MyBioSource) was performed to determine the production of bilirubin, a well-known end-product of the degradation of heme. In detail, tumor cells were in vitro co-treated with hemin 50 pM (a HO-1 inducer) and tested compounds at different concentrations (IpM, 5 pM, 10 pM) . After 24h, HO-1 activity was determined in cell lysates, after three cycles of subsequent freezing and thawing, according to manufacturer's instructions. The concentration of extracted bilirubin was calculated as picomole of bilirubin formed per milligram of protein per hour. Protein concentration in cell lysates was measured using the BOA method, following the manufacturer's protocol (Sigma-Aldrich) . Specifically, PANC-1 cells were plated in T25 flasks at a concentration of 2xl06cells / flask and incubated at 37,0°C in a humidified atmosphere at 5% CO2. After 24h, we add 50pM of Hemin (Sigma-Aldrich) , in order to induce the activity of HO-1, and the cells were incubated at 37,0°C. After 2h, tested compounds and controls were added to the cells according to the experimental scheme (Figure 1, panel A) .

[0405] In detail, the inhibitors to be tested were diluted in PBS by serial dilutions to obtain the following final concentrations: 1 pM, 5 pM and 10 pM. DMSO concentration was kept constant at 0.2%. As experimental controls, 0.2% DMSO (negative control) and 50 pM hemin (positive control) was used. After 24h, the HO-1 activity was determined by quantifying the concentration of bilirubin in cell lysates, after three cycles of subsequent freezing and thawing, according to manufacturer' s instructions. In particular, once detached from the flask, the cells were frozen quickly through dry ice and 96% ethanol, and then placed for 5 minutes at 37 °C; this freeze-thaw cycle was repeated three times.

[0406] The ELISA kit (Human Total Bilirubin ELISA kit, catalog n° MBS756198, MyBioSource) uses polyclonal antibilirubin antibodies and a bilirubin-HRP conjugate (peroxidase) used as a tracer for the detection of successful antibody binding; it consists of a plate pretreated with polyclonal anti-antibodies bilirubin, attached to the bottom of the wells, able to recognize and bind the bilirubin present in the samples. The kit also contains 6 standard solutions at known serial concentrations of bilirubin. According to the manufacturer's instructions, lOOpl of each standard or lOOpl of sample to be tested were added to each well of the plate. Then in each well with the samples, lOpl of Balance Solution was added to stabilize the pH of the solution containing the cell lysate. Thereafter, 50pl of bilirubin-HRP conjugate was added to each sample, except for the blank. The plate was incubated for Ih at 37 °C. After the incubation time, the wells were washed three times with 250pl of Wash Solution in order to eliminate the conjugate and excess antigen not related to specific antibodies. To each well 50pl of Substrate A and 50pl of Substrate B were added consecutively and the plate was incubated for 15 minutes in the dark. Substrates A and B are reagents containing traces of buffered hydrogen peroxide and tetramethylbenzidine which react with the HRP peroxide of the conjugate. After 15 minutes of incubation, the reaction was blocked by the addition of 50pl per well of Stop Solution, present in the kit.

[0407] The absorbance at a wavelength of 450 nm was determined using a Synergy H4 spectrophotometer (Bio-Tek INC) . The concentration of extracted bilirubin was calculated as picomole of bilirubin formed per milligram of protein per hour (Figure 1, panel B) . Protein concentration in cell lysates was measured using the BCA method, following the manufacturer's protocol (Sigma- Aldrich) .

[0408] Figure 2 show data about inhibitory properties toward purified HO-1 enzyme and molecular modeling of some compounds of formula (I) and compound #A on the purified HO-1 enzyme. HO-1 has been recombinantly expressed in E. coli BL21 (DE3) cells and the purification process yielded homogeneous and pure preparation of the target protein that underwent the biochemical characterization. The open reading frame of an N- terminal truncated version of hHOl (Metl-Ala233 ) was subcloned into a pET-28a (GenScript) expression vector using Ndel / Xhol restriction sites. In detail, the vector allows the expression of an N-terminal His-tagged protein using E. coli BL21 (DE3) (Novagen) as the expression system. Using standard techniques, an aliquot of E. coli BL21 (DE3) was transformed with the target construct and grown on an agar plate at 37°C for 16 hours. The bacterial culture was then inoculated into 1 L of 2xYT medium [16 g Tryptone, 10 g yeast extract, 5 g NaCl (Sigma Aldrich) ] in the presence of kanamycin (50 pg / mL) (Sigma Aldrich) and grown at 37°C / 200 rpm to OD600 = 0.7. Expression of the recombinant protein was induced by the addition of 0.5 mM isopropyl-l-thio-D- galactopyranoside (Sigma Aldrich) , and cells were further incubated at 15°C / 200 rpm for 16 hours. Cells were harvested by centrifugation at 6000 rpm for 10 min at 4°C. 11 g of wet cells were resuspended in 70 mL lysis buffer [50 mM NaH2PO4+ Na2HPO4 (pH 7.6) , 500 mM NaCI, 5% (v / v) glycerol, 20 mM imidazole, Triton (v\v) 0.1%] supplemented with complete EDTA-free protease inhibitor cocktail (Merck) and DNAse. Cells were lysed using a Sonics Vibra-Cell VC 130 ultrasonic homogenizer (strokes: 10; pulse: 30"; stop: 1' ; amplitude: 45) . The lysate was centrifuged at 17,000 rpm for 45 min at 4°C (Beckman Coulter Avanti Centrifuge J-26 XP) , and the clarified cell lysate was applied to a 2 mL Qiagen Ni- NTA agarose column pre-equilibrated with lysis buffer. After washing the resin with 20 CV of wash buffer (lysis buffer supplemented with 50 mM imidazole) , protein was eluted with elution buffer (lysis buffer supplemented with 500 mM imidazole) . The eluted fractions were checked by SDS-PAGE, and all positive fractions were pooled and concentrated using a Vivaspin 20-10000 MWCO centrifugal concentrator (Sartorius) . The protein sample was dialyzed [50 mM Tris-HCl; 150 mM NaCI; 2.5 mM CaC12; pH=7.5] and His-tag removed with human plasma thrombin (Calbiochem) .

[0409] Thrombin protease and excess biliverdin were removed with HiTrap Benzamidine FF (Cytiva) . The concentrated protein was loaded on a Hiload Superdex 200 16 / 600 column (GE Healthcare) , pre-equilibrated with a size exclusion buffer [10 mM KH2PO4+K2HPO4 (pH 7.4) ] . Size exclusion chromatography resulted in a single well- defined peak at the elution volume, consistent with the monomeric structure in solution. Aliquots corresponding to the elution peak measured at 280 nm wavelengths were concentrated to 10 mg / ml using an Vivaspin 20-10000 MWCO. Protein quantification was performed using the Bradford assay in a calibrated system with a Savatec Onda UV-21 spectrophotometer. The hHOl aliquots were stocked at 80°C.

[0410] The catalytic parameters of the enzyme were evaluated by means of a biochemical assay that was optimized with respect the one described by Rahman MN et al. (Rahman MN Vlahakis JZ, Vukomanovic D, et al. A novel, "double-clamp" binding mode for human heme oxygenase-1 inhibition. PLoS One 2012;7 (l) : e29514. doi: 10.1371 / journal .pone .0029514. ) Briefly, the spectrophotometric analysis was performed by means of a multi-plate spectrophotometer (Sunrise, Tecan) following heme degradation at 404 nm of wavelength for 1 hour at 37°C (Soret Peak) ; the recombinant protein HOI at a concentration of 2.5 pM was incubated with 10 mM KH2PO4+K2HPO4 , 40 pM hemin porcine (thermo scientific; Cat : 345960010 ; Lot :A0459402 ) , 5% DMSO, 2.5 mM ascorbic acid and mmH20. The inhibition assay was performed in saturation condition of the substrate by adding a single concentration of the tested inhibitor (40 pM) . As reported in Figure 2, panel A, compounds #28 and #32 markedly inhibit HO-1 enzyme activity, while in contrast, compound #A has no inhibitory activity. Accordingly, in vitro bilirubin production quantification performed on intact human cervical adenocarcinoma (HeLa) cells (ATCC) treated for 24h with #28 (10 pM) and #A (lOpM) confirmed that only #28 reduced HO-1 activity in cell lysates behaving as a HO inhibitor (Figure 2, panel B) . No significant differences in terms of bilirubin production were noted in Hela cells treated with #A. Bilirubin production quantification was performed following the experimental procedure previously described in detail, using the competitive ELISA (Human Total Bilirubin ELISA kit, catalog n° MBS756198, MyBioSource) . The standard inhibitor OB24 and the heme oxygenase inducer hemin were used as internal controls. Table reported Figure 2, panel B shows the fold change of HOI activity upon 24h treatment with respect to untreated control.

[0411] In addition, a spectral analysis was also carried out to assess the binding between some compounds of formula (I) or compound #A with the substrate of HOI (hemin) . As showed in Figure 2, panel C, #28 and #32 tested compounds induced a significant shift in the absorption peak of hemin (395 nm) , that is indicative of a direct interaction of the tested compound with the free hemin also in absence of HO-1 enzyme. On the contrary, the compound #A did not induce any spectral shift. The reaction mixture included: the tested compounds at the concentration of 100 pM in 10 mM KH2PO4+K2HPO4 buffer at pH 7,5, 40 pM hemin porcine, 5% DMSO, 2.5 mM ascorbic acid and mmH20.

[0412] Determination of metabolic stability and metabolite profiling of some compounds of formula (I) (#28, #32, #40) was also evaluated. In detail, metabolic stability was evaluated in terms of residual substrate % after 60 min incubation (phase I) in rat (RLM) and human HLM) liver microsomes.

[0413] Briefly, the in vitro phase I metabolic stability was assessed in Male Sprague Dawley rat liver microsomes (RLM) , (XenoTech-BioIVT 098R1000 Pooled IGS Sprague- Dawley rat, protein concentration: 20 mg / mL, total CYP : 721 pmol / mg protein) , and human liver microsomes (HLM, (Corning 452161 Pooled mixed sex, twenty individual donors, protein concentration: 20 mg / mL, total CYP: 330 pmol / mg protein) . The standard incubation mixture (350 pL final volume) was carried out in a 0.1 M TRIS-HC1 buffer (pH 7.4) + 150 mM KC1, containing 2 pM of the test substrate, 1 mM 0NADPH, acetonitrile as cosolvent (1% of the total volume) . After pre-equilibration of the mixture, an appropriate volume of microsomal suspension is added to give a final protein concentration of 1.0 mg / mL. The mixture is shaken for 60 min at 37 °C in a thermomixer (700 rpm) . Aliquots (50 pL) were withdrawn at 0-5-10-20-40-60 minutes and quenched by the addition of 50 pL ice-cold acetonitrile, vortexed and centrifuged at 13,000 rpm for 5 min. The supernatants were analysed by LC-HRMS (method 1) .

[0414] Method 1

[0415] Instrumentation: Hybrid quadrupole-orbitrap, Thermo Scientific Q-exactive Plus, equipped with a Vanquish UHPLC system..

[0416] Column: Kinetex C18 (150 x 2 mm, 2.6 pm dP)

[0417] (Phenomenex) .

[0418] Mobile Phase Phase A: 0.1% formic acid in water UHPLC grade . Phase B: 0.1% formic acid in methanol

[0419] UHPLC grade.

[0420] Analysis mode: Gradient of concentration.

[0421] Flow rate: 0.250 mL / min

[0422] Column temperature: 40 °C

[0423] Sample temperature: 15 °C

[0424] Injected volume: 5 pL

[0425] The in vitro phase I metabolic profile was assessed also in human liver microsomes (HLM) , (Corning 452161 Pooled mixed sex, twenty individual donors, protein concentration: 20 mg / mL, total CYP : 330 pmol / mg protein) . The standard incubation mixture (200 pL final volume) was carried out in a 0.1 M TRIS-HC1 buffer (pH 7.4)+ 150 mM KC1, containing 50 pM of the test substrate

[0426] 1.3 mM NADPNa2, 3.3 mM glucose 6-phosphate, 0.4 units / mL glucose 6-phosphate dehydrogenase, acetonitrile as cosolvent (1% of total volume) . After pre-equilibration of the mixture, an appropriate volume of microsomal suspension is added to give a final protein concentration of 1.0 mg / mL. The mixture was shaken for 60 min at 37 °C and quenched by the addition of 200 pL ice-cold acetonitrile, vortexed and centrifuged at 13,000 rpm for 5 min. The supernatants were analysed by LC-HRMS (method 2) . Metabolite profile was determined by processing the raw files with both Xcalibur™ and Compound Discoverer™

[0427] 3.3 software (Thermo Scientific) and using a customized workflow for detection and identification of the expected and unknown metabolites based on the interpretation and comparison of the MS and MS2spectra of the parent compound and its related metabolites.

[0428] Method 2

[0429] Instrumentation: Hybrid quadrupole-orbitrap, Thermo Scientific Q-exactive Plus, equipped with a Vanquish UHPLC system.

[0430] Column: Kinetex C18 (150 x 2 mm, 2.6 pm dP)

[0431] (Phenomenex) .

[0432] Mobile Phase Phase A: 0.1% formic acid in water UHPLC grade . Phase B: 0.1% formic acid in methanol

[0433] UHPLC grade.

[0434] Analysis mode: Gradient of concentration.

[0435] Flow rate: 0.250 mL / min

[0436] Column temperature: 40 °C

[0437] Sample temperature: 15 °C

[0438] Injected volume: 5 pL

[0439] The operating conditions of the HESI were as follows :

[0440] Microsomal half-life (min) and the intrinsic hepatic clearance in vitro (pL / min / mg microsomes ) parameters were also calculated. Compounds have been categorized based on their clearance value. Table 3 - #28 stability in liver microsomes

[0441] #28 proposed metabolic scheme in human liver microsomes :

[0442] #28-M6

[0443] #28 underwent aromatic hydroxylation at different positions (M1-M5) suggesting that naphthalene represents the principal metabolic soft spot. Imidazole oxidation also occurred (M6) probably according to the following metabolic route reported in the relevant literature (Dalvie et al., Chem. Res. Tox., 15(3) , 2002) :

[0444] Table 4 - #32 stability in liver microsomes

[0445] #32 proposed metabolic scheme in human liver microsomes :

[0446] #32 underwent aromatic hydroxylation at the dichloro-substituted benzene ring, forming the metabolite Ml . Oxidation of the imidazole ring also occurred (M2 ) . The substitution of the naphthalene group likely contributed to improving the overall metabolic stability of this compound compared to #28 and #40 . Table 5 - #40 stability in liver microsomes

[0447] #40 proposed metabolic scheme in human liver microsomes :

[0448] #40 underwent aromatic hydroxylation at different positions (M1-M5) suggesting that naphthalene represents the principal metabolic soft spot. Further two metabolic routes were observed: hydroxylation of the methylene group linking the 1,2,3 and 1,2,4 triazoles leading to the formation of the metabolites M6 and M7 and the oxidation of the 1,2,4 triazole (M8-M9) .

[0449] The metabolic profile of compound #A was also performed to verify that its biological non-activity, observed in our experiments, is due to its putative metabolic instability.

[0450] Table 6 - #A stability in liver microsomes

[0451] - #A proposed metabolic scheme in human liver microsomes

[0452] Compound #A resulted extremely stable both in RLM and HLM incubations. Only traces of the metabolite Ml was revealed.

[0453] Figure 3 shows in vitro cytotoxicity analysis of compounds of formula (I) , as compared to #A, on human cervical cancer cells (HeLa) , demonstrating that, in contrast to what reported for compound #A (Narsimha Sirassu et al. Heterocyclic Letters (2015) , 5(4) : 653- 660) , both compounds have no direct anticancer activity. In particular, crystal violet viability assay was performed (Fig. 3A) and apoptosis / necrosis events were assessed by flow cytometry to confirm the results (Fig. 3B) . Panel A of Figure 3 shows that cervical cancer cells (HeLa) were able to survive at least 48h upon incubation both with either compounds of formula (I) or compound #A. As a control, the antineoplastic chemotherapy cisplatin was used, which demonstrated high cytotoxic activity even at low concentration (10 M) . In detail, HeLa cells were seeded at a low density (0.3*106 cells / well in a 6 multiwell plate) . 48h after treatment, cells were stained with crystal violet (0.1% w / v solution in 10% formalin, Sigma Aldrich) and the viable and stained cells were dissolved for OD reading using 100% MetOH (Sigma Aldrich) . Absorbance was measured using Victor 3V (Perkin Elmer, Turku, Finland) at 595 nm and results reported as optical density (OD) , which is directly correlated with cell quantity. As experimental controls, 0.2% DMSO (negative control) and lOpM cisplatin (Sigma Aldrich) (positive control) were used. Furthermore, determination of apoptosis by flow cytometry showed that neither compound #28 nor #A triggered apoptosis or cell death after 48h of treatment (panel B) . In detail, after 48h of treatment, cells were detached using trypsin / EDTA (Euroclone) , pelleted and incubated with Live / Dead Near IR (catalog n° L23105 Thermo Fisher Scientific, LD NIR) staining dye for 15 min, prior staining with Annexin conjugated with FITS (n° of catalog 640906, Biolegend) (additional 15 min) . The percentage (% cells) of live cells (AnnexinV- / LD NIR-) , early apoptosis cells (AnnexinV + / LD NIR-) , late apoptosis cells (AnnexinV + / LD NIR + ) , and necrosis cells (Annexin V- / LD NIR+) was measured by flow cytometry.

[0454] The data shown in Figures 4 show that HO-1 inhibition strongly reduces the formation of lung metastases in a metastatic fibrosarcoma model (Fig. 4, panel A) ; decreases the epithelial-to-mesenchymal transition (EMT) as assessed by the increase of the epithelial markers E-cadherin and EpCAM and by the decreased expression of genes characterizing the mesenchymal phenotype (i.e. Vimentin and N-cadherin) ; decreases tumor angiogenesis as demonstrated by reduction of the endothelial marker CD31 in the tumor lesion .

[0455] In particular, in Figure 4, as reported in detail in Consonni et al 2021, DOI: 10.1038 / s41590-021-00921- 5, WT mice were injected intramuscularly in their left hindlimb with MN / MCA1 fibrosarcoma cells (10*5 cells per mouse in 100 pl of PBS) , using insulin syringes (BD micro-fine 25 Gauge) , and from day 7 post implantation, were intraperitoneally injected or not with 30 mg / kg HO- 1 inhibitor (ZnPPIX, Frontier Scientific) three times per week until sacrifice. 24 days after tumor cells injection, mice were sacrifice, primary tumors and lungs were collected.

[0456] Panel A shows the area of metastatic burden, quantified from H&E-stained lung sections and is expressed as a percentage of total lung surface area; representative images are shown. Scale bars, 1 mm. In detail, lungs were collected and were formalin fixed for 24 h, dehydrated and paraffin embedded for histologic analysis. Histology was performed on longitudinal serial sections (100 m apart, width 8 m) from each lung, stained with hematoxylin and eosin (H&E) and scanned using a VS120 Dot-Slide BX61 virtual slide microscope (Olympus Optical) . The area of lung lesions was obtained by manual tracing of the perimeter of lesions using Image Pro-Premiere software 9.2 (Media Cybernetics) .

[0457] Panel B shows FACS quantification of E-cadherin, EPCAM, Vimentin and N-cadherin expression in primary tumor cells. Panel C shows FACS quantification of CD31+ cells in primary tumors. Data are mean ± s.e.m. *P<0.05, **P<0.01, ***P<0.001. In detail, primary tumors were cut into small pieces, disaggregated with 0.5 mg ml-1Collagenase IV (COL IV, C5138, Sigma Aldrich) and 150 U ml-1DNase I from bovine pancreas (70271500, Roche) in RPMI 1640 (Euroclone) for 30 min at 37 °C and filtered through Falcon strainers (70 pm) . Cells were resuspended in Hank's balanced salt solution (Lonza) supplemented with 0.5% bovine serum albumin (BSA) (Sigma-Aldrich) . Staining was performed at 4 °C for 20 min with the following mouse antibodies: CD45-PerCP (30-F11) (Biolegend catalog n° 103130) ; CD45-BUV563 (3O-F11) (BD Horizon catalog n° 565710) ; E-Cadherin-BV421 (DECMA-1 ) (Biolegend catalog n° 147319) ; CD31-PE (MEC 13.3) (BD Pharmingen catalog n° 553373) ; EpCAM-PE-Cy7 (Biolegend catalog n° 118215) ; unconjugated Vimentin rabbit monoclonal antibody (SP20) (ThermoFisher catalog n° MAS- 14564) and N-Cadherin rabbit monoclonal antibody (3B9) (ThermoFisher catalog n° 33-3990) followed by incubation with secondary goat anti-rabbit Alexa Fluor 488- conjugated antibodies (ThermoFisher catalog n° . A-11008) and goat anti-rabbit Alexa Fluor 647-conjugated antibodies (ThermoFisher catalog n° A27040) . Cell viability was determined by either Aqua LIVE / Dead-405- nm staining (Biolegend catalog n° 423102) or LIVE / DEAD Fixable Violet Dead Cell Stain Kit (ThermoFisher catalog n° L34960) ; negative cells were considered viable. Cells were detected using either BD LSRFortessa or BD FACSymphony A5 and analyzed with Flow Jo (9.9.6) software .

[0458] Figure 5 shows the in vivo inhibitory effect of HO- 1 inhibition on melanoma model (B16 / F10) , as well as the Ml-related anti-tumor reprogramming of tumor-associated macrophages (TAMs) (increased TNFa expression and decreased CD206) and CD8+ infiltrating T cells (increased IFNy expression and reduced ratio CD8+ T cells / Treg cells) . In particular, WT mice were subcutaneously injected with 100 pl of PBS containing 5x10*5 murine melanoma B16 / F10 cells (ATCC) and from day 3 post implantation, were intraperitoneally injected or not with 30 mg / kg HO-1 inhibitor (ZnPPIX, Frontier Scientific) three times per week until sacrifice. Starting from 10 days after tumor cell injection, tumor growth was monitored three times per week with a caliper. 17 days after tumor cell injection, mice were sacrificed and primary tumors estimated for size and volume. Panel A, Mean ± / - SEM tumor volume of Bl 6 implants in WT mice treated with vehicle or HO-1 inhibitor (ZnPPIX) (Consonni et al 2021, DOI: 10.1038 / s41590-021-00921-5) . Panel B, FACS quantification of TNFa and CD206 expression in F4 / 80hiand F4 / 8010TAMs subsets; Panel C, Quantification of IFNy expression in B16 tumorinfiltrating CD8+ T lymphocytes and CD8 / Treg ratio. Data are mean ± s.e.m. *P<0.05, **P<0.01, ***P<0.001. In detail, primary tumors were cut into small pieces, disaggregated with 0.5 mg ml-1Collagenase IV (COL IV, C5138, Sigma Aldrich) and 150 U ml-1DNase I from bovine pancreas (70271500, Roche) in RPMI 1640 (Euroclone) for 30 min at 37 °C and filtered through Falcon strainers (70 pm) . Cells were resuspended in Hank's balanced salt solution (Lonza) supplemented with 0.5% bovine serum albumin (BSA) (Sigma-Aldrich) and FACS staining was performed at 4 °C for 20 min with the following mouse antibodies: CD45-PerCP (30-F11) (Biolegend catalog n° 103130) ; CD45-BUV563 (3O-F11) (BD Horizon catalog n° 565710) ; CDllb-BV711 (MI / 70) (Biolegend catalog n° 101242) ; F4 / 80-APC (BM8) (Biolegend catalog n° 123116) ; F4 / 80-PE-Cy7 (BM8) (Biolegend catalog n° 123114) ; Ly6G- BV570 ( 1A8 ) (Biolegend catalog n° 127629) ; Ly6C-APC-Cy7 (HK1.4) (eBioscence catalog n° 47-5932-82) ; TNFa-Alexa Fluor 647 (MP6-XT22) (BD Pharmingen catalog n° 557730) ; CD206-APC (C068C2 ) (Biolegend catalog n° 141708) ; FoxP3- Alexa Fluor 488 (MF23) (BD Pharmingen catalog n° 560403) ; CD8-BUV805 (53-6.7) (1 / 200, BD Horizon catalog n° 564920) ; CD4-BUV496 (GK1.5) (BD Horizon catalog n° 564667) ; CD4-PE-Cy7 (GK1.5) (Biolegend catalog n° 100422) ; CD3-PerCP (145-2C11) (Biolegend catalog n° 100326) ; CD3-BV650 (145-2C11) (Biolegend catalog n° 100229) ; IFNy-FITC (XMG1.2) (Biolegend catalog n° 505806) ; IFNy-PE (XMG1.2) (BD Pharmingen catalog n° 554412) ; A Foxp3 / Transcription Factor Staining Buffer Set (eBioscience) was used for intracellular staining of TNF-a, IFN-y, Foxp3 and CD206. Expression of TNFa and IFNy was analyzed by flow cytometry following 4h of treatment with brefeldin A (5 pg ml-1, Sigma Aldrich) , PMA (50 ng ml-1, Sigma Aldrich) and ionomycin (1 pg ml-1, Sigma Aldrich) . Cell viability was determined by either Aqua LIVE / Dead-405-nm staining (Biolegend catalog no. 423102) or LIVE / DEAD Fixable Violet Dead Cell Stain Kit (ThermoFisher catalog no. L34960) ; negative cells were considered viable. Cells were detected using either BD LSRFortessa or BD FACSymphony A5 and analyzed with FlowJo (9.9.6) software .

[0459] The data shown in Figure 6 demonstrate the in vivo antitumor activity of some compounds of formula (I) (#28, #32, #40, #43) in preclinical model of metastatic fibrosarcoma and pancreatic ductal adenocarcinoma (PDAC) , respectively in terms of reduced lung metastasis formation and primary tumor growth. In particular, in panel A, WT mice were injected intramuscularly in their left hindlimb with MN / MCA1 fibrosarcoma cells (10*5 cells per mouse in 100 pl of PBS) and from day 7 post implantation, were intraperitoneally injected or not with 30 mg / kg of tested compounds three times per week until sacrifice. 24 days after tumor cells injection, mice were sacrifice and lungs were collected. Panel A shows macroscopic lung metastasis count. Panel B shows the antitumor activity of #28, #32, #40, #43 in the aggressive orthotopic PDA mouse model. In detail, to establish the orthotopic model, WT mice were anesthetized and, after left abdominal incision, pancreatic tails were exposed and injected with lxlOA5 K8484 tumor cells resuspended in cold PBS mixed at 1:5 dilution with Matrigel (Corning, catalog n° 354248) in a final volume of 25pL, using insulin syringes (BD microfine 25 Gauge) . The injection was considered successful by the development of bubbles without signs of leakage. The peritoneum was sutured with short-term absorbable suture (Vetsuture) , and the skin was closed with wound clips. K8484 cell lines were previously established from tumors arising in genetically engineered mouse models carrying the missense point R720H mutation in the Tpr53 gene KrasLSL G12D / +; Tpr53LSL R270H / +; PdxlCre / WT) (Curcio C. et al., doi 10.1186 / sl3046-024-03080-1 ) . From day 7 post implantation, were intraperitoneally injected or not with 30 mg / kg of tested compounds three times per week until sacrifice. 28 days after tumor cells injection, mice were sacrifice, pancreases were collected and the weight of the tumor mass was estimated.

[0460] The data shown in Figures 7 and 8, clearly demonstrate in vivo antitumor activity of compound of formula (I) compared to compound #A. In detail, Figure 7 shows that HO-1 inhibition mediated by some compounds of formula (I) (#28, #32) reduces the formation of lung metastases in a metastatic fibrosarcoma model (MN / MCA1) (Figure 7, panel A) , decreases serum level of carboxyhemoglobin (CoHb) , induces phenotypic switch of tumor-associated macrophages (TAMs) towards anti-tumor phenotype (higher TNFa) and restores higher expression of the antitumor cytokine IFNy by CD8+ tumor-infiltrating T cells. None of these aforementioned antitumor activities were observed in mice treated with #A. In particular, as previously described in detail, WT mice were injected intramuscularly in their left hindlimb with MN / MCA1 fibrosarcoma cells (10*5 cells per mouse in 100 pl of PBS) and from day 7 post implantation, were intraperitoneally injected or not with 30 mg / kg of HO-1 inhibitors (#28, #32) or #A three times per week until sacrifice. 24 days after tumor cells injection, mice were sacrifice, primary tumors and lungs were collected. Panel A shows macroscopic lung metastasis (left) and area of metastatic burden quantified from H&E-stained lung sections (right) (3 slices / lungs were analyzed) ; representative images are shown. In detail, lungs were collected and were formalin fixed for 24 h, dehydrated and paraffin embedded for histologic analysis. Histology was performed on longitudinal serial sections (100 pm apart, width 8 pm) from each lung, stained with hematoxylin and eosin (H&E) and scanned using a VS120 Dot-Slide BX61 virtual slide microscope (Olympus Optical) . The area of lung lesions was obtained by manual tracing of the perimeter of lesions using Image ProPremiere software 9.2 (Media Cybernetics) .

[0461] Panel B shows ELISA quantification of systemic serum COHb levels in mice of different experimental groups. In detail, mouse blood samples were collected at sacrifice by puncturing the facial vein into microcentrifuge tubes and kept on ice for 20 min. They were then centrifuged for 20 min at 13,000 rpm at 4°C to separate the serum. Mouse Carboxyhemoglobin (HBCO) ELISA Kit (MyBiosource, catalog n° MBS029653) was used following the manufacturer's protocol, to estimate circulating COHb concentration. According to the manufacturer's instructions, 50pl of each six standard or 50pl of sample to be tested were added to each well of the plate. Thereafter, lOOpl of HRP-conj ugate reagent was added to each sample, except for the blank. The plate was incubated for Ih at 37 °C. After the incubation time, the wells were washed three times with 250pl of Wash Solution in order to eliminate the conjugate and excess antigen not related to specific antibodies. To each well 50pl of Chromogen A and 50pl of Chromogen B were added consecutively and the plate was incubated for 15 minutes in the dark. After incubation, the reaction was blocked by the addition of 50pl per well of Stop Solution, present in the kit. The absorbance at a wavelength of 450 nm was determined using a Synergy H4 spectrophotometer (Bio-Tek INC) . Panel C shows FACS quantification of TNFa expression in F4 / 80hiand F4 / 8010TAMs subsets and of IFNy expression in tumorinfiltrating CD8+ T lymphocyte. Data are mean ± s.e.m. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. In detail, primary tumors were cut into small pieces, disaggregated with 0.5 mg ml-1Collagenase IV (COL IV, C5138, Sigma Aldrich) and 150 U ml-1DNase I from bovine pancreas (70271500, Roche) in RPMI 1640 (Euroclone) for 30 min at 37 °C and filtered through Falcon strainers (70 pm) . Then cells were resuspended in Hank' s balanced salt solution (Lonza) supplemented with 0.5% bovine serum albumin (BSA) (Sigma-Aldrich) and FACS staining was performed at 4 °C for 20 min with the following mouse antibodies: CD45-FITC (30-F11) (Biolegend catalog n° 103108) ; CDllb-BV711 (MI / 70) (Biolegend catalog n° 101242) ; F4 / 80-PE-Cy7 (BM8) (Biolegend catalog n° 123114) ; Ly6G-Pe-Cy5 ( 1A8 ) (Biolegend catalog n° 127671) ; Ly6C-FITC (HK1.4) (Biolegend, catalog n° 128005) ; TNFa- BV650 (MP6-XT22) (Biolegend catalog n° 506333) ; CD8-PE- Cy5 (53-6.7) (Biolegend catalog n° 100709) ; CD4-PE-Cy7 (RM4-5) (Biolegend catalog n° 100527) ; CD3-BV711 (145- 2C11) (Biolegend catalog n° 100349) ; IFNy-BV786 (XMG1.2) (BD Horizon catalog n° 563773) . A Foxp3 / Transcription Factor Staining Buffer Set (eBioscience) was used for intracellular staining of TNFa and IFNy. Expression of TNFa and IFNy was analyzed by flow cytometry following 4 h of treatment with brefeldin A (5 pg ml-1, Sigma Aldrich) , PMA (50 ng ml-1, Sigma Aldrich) and ionomycin (1 pg ml-1, Sigma Aldrich) . Cell viability was determined by either Aqua LIVE / Dead-405-nm staining (Biolegend catalog no. 423102) or LIVE / DEAD Fixable Violet Dead Cell Stain Kit (ThermoFisher catalog no. L34960) ; negative cells were considered viable. Cells were detected using BD FACSymphony A5 and analyzed with FlowJo (9.9.6) software .

[0462] Corroborating the results obtained in the metastatic fibrosarcoma model, Figure 8 presents the inhibitory effect of HO-1 inhibition mediated by #28 and #32 on pancreatic cancer model (PANC-02) , as well as the anti-tumor reprogramming of tumor-associated macrophages (TAMs) and CD8+ infiltrating T cells) . In particular, WT mice were subcutaneously injected with 100 pl of PBS containing 10*6 murine pancreatic PANC-02 cells (ATCC) and from day 7 post implantation, were intraperitoneally injected or not with 30 mg / kg of HO-1 inhibitors or #A three times per week until sacrifice. Starting from 13 days after tumor cell injection, tumor growth was monitored three times per week with a caliper. 22 days after tumor cells injection, mice were sacrifice and primary tumors were collected. Panel A shows mean ±- SEM tumor volume (left) and weights of primary tumors (right) of PANC-02 implants in WT mice treated with vehicle, #A or HO-1 inhibitors (#28, #32) ; representative images are shown. Panel B shows ELISA quantification of serum COHb levels in the different experimental groups. In detail, mouse blood samples were collected at sacrifice by puncturing the facial vein into microcentrifuge tubes and kept on ice for 20 min. They were then centrifuged for 20 min at 13,000 rpm at 4°C to separate the serum. Mouse Carboxyhemoglobin (HBCO) ELISA Kit (MyBiosource, catalog n° MBS029653) was used to estimate circulating COHb concentration. According to the manufacturer's instructions, 50pl of each six standard or 50pl of sample to be tested were added to each well of the plate. Thereafter, lOOpl of HRP-conj ugate reagent was added to each sample, except for the blank. The plate was incubated for Ih at 37 °C. After the incubation time, the wells were washed three times with 250pl of Wash Solution in order to eliminate the conjugate and excess antigen not related to specific antibodies. To each well 50pl of Chromogen A and 50pl of Chromogen B were added consecutively and the plate was incubated for 15 minutes in the dark. After incubation, the reaction was blocked by the addition of 50pl per well of Stop Solution, present in the kit. The absorbance at a wavelength of 450 nm was determined using a Synergy H4 spectrophotometer (Bio-Tek INC) . Panel C shows FACS quantification of TNFa expression in F4 / 80hiand F4 / 8010TAMs subsets and of GRZB in tumor-infiltrating CD8+ T lymphocytes. Data are mean ± s.e.m. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. In detail, primary tumors were cut into small pieces, disaggregated with 0.5 mg ml-1Collagenase IV (COL IV, C5138, Sigma Aldrich) and 150 U ml-1DNase I from bovine pancreas (70271500, Roche) in RPMI 1640 (Euroclone) for 30 min at 37 °C and filtered through Falcon strainers (70 pm) . Tumor cells were then resuspended in Hank's balanced salt solution (Lonza) supplemented with 0.5% bovine serum albumin (BSA) (Sigma-Aldrich) and FACS staining was performed at 4 °C for 20 min with the following mouse antibodies: CD45- APC-Cy7 (30-F11) (Biolegend catalog n° 103115) ; CDllb- BV711 (MI / 70) (Biolegend catalog n° 101242) ; F4 / 80-PE-Cy7 (BM8) (Biolegend catalog n° 123114) ; Ly6G-Pe-Cy5 ( 1A8 ) (Biolegend catalog n° 127671) ; Ly6C-FITC (HK1.4) (Biolegend, catalog n° 128005) ; TNFa-BV650 (MP6-XT22) (Biolegend catalog n° 506333) ; CD8-PE-Cy7 (53-6.7) (Biolegend catalog n° 100721) ; CD4-PE (RM4-5) (Biolegend catalog n° 564667) ; CD3-BV650 (145-2C11) (Biolegend catalog n° 100511) ; GRZB-Alexa Fluor 700 (QA16A02) (Biolegend catalog n° 37221) . A Foxp3 / Transcription Factor Staining Buffer Set (eBioscience) was used for intracellular staining of TNF-a and GRZB. Expression of TNF- a and GRZB was analyzed by flow cytometry following 4 h of treatment with brefeldin A (5 ,g ml-1, Sigma Aldrich) , PMA (50 ng ml-1, Sigma Aldrich) and ionomycin (1 ,g ml-1, Sigma Aldrich) . Cell viability was determined by either Aqua LIVE / Dead-405-nm staining (Biolegend catalog n° 423102) or LIVE / DEAD Fixable Violet Dead Cell Stain Kit (ThermoFisher catalog n° L34960) ; negative cells were considered viable. Cells were detected using either BD LSRFortessa or BD FACSymphony A5 and analyzed with FlowJo (9.9.6) software.

Claims

CLAIMS1. A 1 , 4-disubstituted-l , 2 , 3 triazole compound of formula ( I ) :B N >N A(I) whereinA is selected fromB is selected from straight or branched, substituted or unsubstituted Ch-s alkyl, straight or branched, substituted or unsubstituted C2-s alkenyl, straight or branched, substituted or unsubstituted Ci-s carbonyl, straight or branched, substituted or unsubstituted Ci-s alkoxy, C3-6 cycloalkyl, Ar1, and substituted or unsubstituted (CH2)n-Ar1; n is an integer 1 to 4;Ar1is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl group.

2. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to claim 1, wherein, when Ar1is a substituted aryl or a substituted heteroaryl, the one or more substituents are independently selected from halogen atom, substituted or unsubstituted Ci-4 alkyl, 1H- tetrazole, -COOH, -OH, -CH2-OH, -NH2, -NH-C (0) -NH-R1, - COOR1, -NO2, -CF3, -ON, -OR1, -CONH2, -CONHR1, -CONR1R2, - NHR1, -NR1R2, -NHCOR1, -NHSO2R1, or -SO2NHR1;R1and R2are identical or different from each other and independently selected from H, straight or branched, substituted or unsubstituted Ci-s alkyl, Ar2;Ar2is selected from aryl and heteroaryl.

3. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to claim 1 or claim 2, wherein, when B is a substituted Ci-s alkyl, a substituted C2-8 alkenyl, a substituted Ci-s carbonyl, a substituted Ci-s alkoxy, or a substituted (CH2)n-Ar1, the one or more substituents are independently selected from aryl and heteroaryl.

4. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein B is selected from straight or branched, substituted or unsubstituted C1-4 alkyl, straight or branched, substituted or unsubstituted C2-4 alkenyl, straight or branched, substituted or unsubstituted C1-4 carbonyl, straight or branched, substituted or unsubstituted C1-4 alkoxy, Ar1, and substituted or unsubstituted (CH2)n-Ar1, and wherein n is 1 to 4.

5. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein B is selected from straight or branched, substituted or unsubstituted C1-3 alkyl, straight or branched, substituted or unsubstituted C2-3 alkenyl, substituted or unsubstituted C1-2 carbonyl, substituted or unsubstituted C1-2 alkoxy, Ar1, and substituted or unsubstituted (CH2)n- Ar1, wherein n is an integer 1 to 3.

6. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein B is selected from substituted or unsubstituted (CH2)n-Ar1, and wherein n is an integer 1 to 4.

7. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein n is an integer 1 to 2.

8. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein Ar1is selected from substituted or unsubstituted aryl.

9. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein, when B is a substituted (CH2)n-Ar1, the one or more substituents are independently selected from aryl.

10. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein the compound of formula (I) is not 4- [ ( IH-imidazol-l- yl ) methyl ] -1- ( 4 -nitrobenzyl )-lH-l,2,3-triazole, 4- [ 4-( IH-imidazol-l-yl ) methyl- 1H- 1 , 2, 3-triazol-l- yl ] methylbenzophenone, 4- [4- (1H-1, 2, 4triazol-l- yl ) methyl- 1H- 1 , 2, 3-triazol-l-yl] methylbenzophenone .

11. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein Ar1is selected from substituted or unsubstituted benzene, and substituted or unsubstituted naphthalene.

12. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein, when Ar1is a substituted aryl or a substituted heteroaryl group, the one or more substituents are independently selected from halogen atom, substituted or unsubstituted Ci-4alkyl, -NH2, -CF3, -COOH, -OH, -CH2-OH, -NO2, -ON, -Ome, -CONH2, -COOMe.

13. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein, when Ar1is a substituted aryl, the one or more substituents are independently selected from halogen atom, substituted or unsubstituted Ci-4 alkyl, -NH2,CF3.

14. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein B is selected from substituted or unsubstituted (CH2)n-Ar1, n is an integer 1 to 4, Ar1is selected from substituted or unsubstituted aryl and wherein the compound of formula (I) is not 4- [ ( IH-imidazol-l-yl ) methyl ] -1- ( 4- nitrobenzyl )-lH- 1,2, 3-triazole, 4 — [ 4 — ( IH-imidazol-l- yl ) methyl- 1H- 1 , 2, 3-triazol-l-yl] methylbenzophenone, 4- [4 - (lH-l,2,4triazol-l-yl) methyl- 1H- 1 , 2, 3-triazol-l- yl ] methylbenzophenone .

15. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein Ar2is selected from benzene, furan, thiophene, pyrrolidine, pyrrole, 1 , 2 , 3-triazole, pyrazole, imidazole, oxazole, isooxazole, thiazole, isothiazole,1.2.3-oxadiazole, 1 , 2 , 4-oxadiazole, 1 , 2 , 5-oxadiazole, pyridine, pyrididazine, pyrimidine, pyrazine, naphthalene, indole, IH-indazole, IH-benzo [d] imidazole, benzo [d] thiazol-2-amine, isoindole, indolizine, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, or carbazole.

16. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein the 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) is selected from:- 4- ( ( IH-imidazol-l-yl ) methyl ) -1-benzyl-lH-1.2.3-triazole (#1) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1-phenethyl-lH-1,2, 3-triazole (#6) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- chlorophenethyl ) -1H-1, 2, 3-triazole (#7) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (3- phenylpropyl ) -1H-1, 2, 3-triazole (#8) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (naphthalen-1- ylmethyl )-lH- 1,2, 3-triazole ( #9) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 2 , 2- diphenylethyl ) -1H-1, 2, 3-triazole (#10) ;- l- ( (l-benzyl-lH-l,2,3-triazol-4-yl) methyl ) - IH-tetrazole (#11) ;- 1- ( ( 1 -phene thy 1 - 1H- 1 , 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#12) ;- 1- ( ( 1- ( 4 -chlorophenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#13) ;- 1- ( ( 1- ( 3 -phenylpropyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#14) ;- 1- ( ( 1- (naphthalen-l-ylmethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#15) ;- 1- ( ( 1- ( 2 , 2 -diphenyl ethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#16) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1-benzyl- 1H-1, 2, 3-triazole (#17) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- phenethyl-lH-1 , 2 , 3-triazole (#18) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- chlorophenethyl ) -1H-1, 2, 3-triazole (#19) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 3- phenylpropyl ) -1H-1, 2, 3-triazole (#20) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (naphthalen-l-ylmethyl ) -1H-1, 2, 3-triazole (#21) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 2 , 2- diphenylethyl ) -1H-1, 2, 3-triazole (#22) ;- 2 - ( 4 - ( ( IH-imidazol-l-yl ) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) -1-phenylethan-l-one (#23) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (2- phenoxy ethyl )-lH- 1,2, 3-triazole (#24) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4-phenylbutyl) -1H-1, 2, 3-triazole (#25) ;- 4 — ( ( IH-imidazol-l-yl ) methyl ) -1- ( 3 , 3- diphenylpropyl ) -1H-1, 2, 3-triazole (#26) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1-cinnamyl-lH-1.2.3-triazole (#27) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (2- (naphthalen-l-yl ) ethyl) -1H-1, 2, 3-triazole (#28) ;- 4 - ( 2 - ( 4 - ( ( IH-imidazol-l-yl ) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) ethyl) aniline (#29) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- methylphenethyl ) -1H-1, 2, 3-triazole (#30) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4-( tri fluoromethyl) phenethyl) -1H-1, 2, 3-triazole (#31) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 3 , 4- dichlorophenethyl ) -1H-1, 2, 3-triazole (#32) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (3- (4- chlorophenyl ) propyl )-lH- 1,2, 3-triazole ( #33) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- f luorophenethyl )-lH- 1,2, 3-triazole ( #34 ) ;- 2- (4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1H-1.2.3-triazol-l-yl ) -1-phenylethan-l-one (#35) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 2- phenoxyethyl ) -1H-1, 2, 3-triazole (#36) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- phenylbutyl) -1H-1, 2, 3-triazole (#37) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 3 , 3- diphenylpropyl ) -1H-1, 2, 3-triazole (#38) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1-cinnamyl- 1H-1, 2, 3-triazole (#39;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (2- (naphthalen-l-yl ) ethyl) -1H-1, 2, 3-triazole (#40) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4-( tri fluoromethyl) phenethyl) -1H-1, 2, 3-triazole (#41) ;- 4- (2 - (4- ( (lH-l,2,4-triazol-l-yl) methyl )-lH-1.2.3-triazol-l-yl) ethyl ) aniline ( #42 ) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (4- methylphenethyl ) -1H-1, 2, 3-triazole (#43) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) - 1 - ( 3 , 4 - dichlorophenethyl )-lH- 1,2, 3-triazole (#44) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (3- (4- chlorophenyl ) propyl) -1H-1, 2, 3-triazole (#45) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- f luorophenethyl ) -1H-1, 2, 3-triazole (#46) ;- 2- (4- ( (lH-tetrazol-l-yl) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) -1-phenylethan-l-one (#47) ;- 1- ( ( 1- ( 2 -phenoxy ethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#48) ;- 1- ( ( 1- ( 4 -phenylbutyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#49) ;- 1- ( ( 1- ( 3 , 3 -diphenylpropyl ) -1H-1, 2, 3-triazol- 4-yl ) methyl ) -IH-tetrazole (#50) ;- 1- ( ( 1-cinnamyl-lH-l , 2, 3-triazol-4-yl) methyl ) - IH-tetrazole (#51) ;- 1- ( ( 1- ( 2- (naphthalen-l-yl ) ethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#52) ;- 4- (2- (4- ( (lH-tetrazol-l-yl) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) ethyl) aniline (#53) ;- 1- ( ( 1- ( 4 -methylphenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#54) ;- 1- ( ( 1- ( 3 , 4 -di chlorophenethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#55) ;- 1- ( ( 1- ( 3- ( 4 -chlorophenyl ) propyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#56) ;- 1- ( ( 1- ( 4- fluorophenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#57) .

17. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein the 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) is selected from:- 4- ( ( IH-imidazol-l-yl ) methyl ) -1-benzyl-lH- 1,2,3-triazole (#1) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1-phenethyl-lH- 1,2,3-triazole (#6) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- chlorophenethyl ) -1H-1, 2, 3-triazole (#7) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (3- phenylpropyl ) -1H-1, 2, 3-triazole (#8) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (naphthalen-1- ylmethyl )-lH- 1,2, 3-triazole ( #9) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 2 , 2- diphenylethyl ) -1H-1, 2, 3-triazole (#10) ;- l- ( (l-benzyl-lH-l,2,3-triazol-4-yl) methyl ) - IH-tetrazole (#11) ;- 1- ( ( 1 -phene thy 1 - 1H- 1 , 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#12) ;- 1- ( ( 1- ( 4 -chlorophenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#13) ;- 1- ( ( 1- ( 3 -phenylpropyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#14) ;- 1- ( ( 1- (naphthalen-l-ylmethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#15) ;- 1- ( ( 1- ( 2 , 2 -diphenyl ethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#16) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1-benzyl- 1H-1, 2, 3-triazole (#17) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- phenethyl-lH-1 , 2 , 3-triazole (#18) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- chlorophenethyl ) -1H-1, 2, 3-triazole (#19) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 3- phenylpropyl ) -1H-1, 2, 3-triazole (#20) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (naphthalen-l-ylmethyl ) -1H-1, 2, 3-triazole (#21) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 2 , 2-diphenylethyl) -1H-1, 2, 3-triazole (#22) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- phenylbutyl) -1H-1, 2, 3-triazole (#25) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 3 , 3- diphenylpropyl ) -1H-1, 2, 3-triazole (#26) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1-cinnamyl-lH-1.2.3-triazole (#27) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (2- (naphthalen-l-yl ) ethyl) -1H-1, 2, 3-triazole (#28) ;- 4 - ( 2 - ( 4 - ( ( IH-imidazol-l-yl ) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) ethyl) aniline (#29) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- methylphenethyl ) -1H-1, 2, 3-triazole (#30) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4-( tri fluoromethyl) phenethyl) -1H-1, 2, 3-triazole (#31) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 3 , 4- dichlorophenethyl ) -1H-1, 2, 3-triazole (#32) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (3- (4- chlorophenyl ) propyl )-lH- 1,2, 3-triazole ( #33) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- f luorophenethyl )-lH- 1,2, 3-triazole ( #34 ) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- phenylbutyl) -1H-1, 2, 3-triazole (#37) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 3 , 3- diphenylpropyl ) -1H-1, 2, 3-triazole (#38) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (2- (naphthalen-l-yl ) ethyl) -1H-1, 2, 3-triazole (#40) ;- 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4-( tri fluoromethyl) phenethyl) -1H-1, 2, 3-triazole (#41) ;- 4- (2 - (4 - ( (lH-l,2,4-triazol-l-yl) methyl )-lH-1.2.3-triazol-l-yl) ethyl ) aniline ( #42 ) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- methylphenethyl ) -1H-1, 2, 3-triazole (#43) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) — 1 — ( 3 , 4 — dichlorophenethyl )-lH- 1,2, 3-triazole (#44) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (3- (4- chlorophenyl ) propyl) -lH-l,2,3-triazole (#45) ;- 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (4- f luorophenethyl ) -1H-1, 2, 3-triazole (#46) ;- 1- ( ( 1- ( 4 -phenylbutyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#49) ;- 1- ( ( 1- ( 3 , 3 -diphenylpropyl ) -1H-1, 2, 3-triazol- 4-yl ) methyl ) -IH-tetrazole (#50) ;- 1- ( ( 1-cinnamyl-lH-l , 2, 3-triazol-4-yl) methyl ) - IH-tetrazole (#51) ;- 1- ( ( 1- ( 2- (naphthalen-l-yl ) ethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#52) ;- 4- (2- (4- ( (lH-tetrazol-l-yl) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) ethyl) aniline (#53) ;- 1- ( ( 1- ( 4 -methylphenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#54) ;- 1- ( ( 1- ( 3 , 4 -di chlorophenethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#55) ;- 1- ( ( 1- ( 3- ( 4 -chlorophenyl ) propyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#56) ;- 1- ( ( 1- ( 4- fluorophenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#57) .

18. A 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) according to any one of claims 1 to 17 for use in the treatment and / or prevention of a disease condition in which heme oxygenase is aberrantly over-activated.

19. The 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) for use according to claim 18, wherein the disease condition in which heme oxygenase is aberrantly overactivated is a neoplastic condition.

20. A pharmaceutical composition comprising at least one 1 , 4-disubstituted-l , 2 , 3 triazole of formula(I) according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient.

21. A pharmaceutical composition comprising at least one 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) according to any one of claims 1 to 17 for use in the treatment and / or prevention of a disease condition in which heme oxygenase is aberrantly over-activated.

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