3,5-Diaminotriazole Derivatives and Their Uses in the Treatment of Eye Diseases

Abstract

The present invention relates to 3,5-diaminotriazole derivatives of formula (I) and pharmaceutical or veterinary compositions comprising such derivatives. It further relates to the compounds of formula (I) for use for treating an ocular disease, preferably diabetic retinopathy, macular degeneration, neovascular glaucoma, macular oedema or Stargardt's disease.

Description

1 / 124 3,5-Diaminotriazole Derivatives and Their Uses in the Treatment of Eye Diseases FIELD OF THE INVENTION

[001] The present invention relates to the field of medicine, in particular to 3,5-diaminotriazole derivatives and their uses in the treatment of eye diseases. FUNDAMENTALS OF THE INVENTION

[002] Angiogenesis is a physiological process involving the formation of new capillary blood vessels from pre-existing microvessels. There are a large number of diseases distinguished by exacerbated or impaired angiogenesis and increased inflammation, such as eye diseases. Eye diseases (also referred to in this document as ocular diseases) associated with angiogenesis include, among others, corneal graft angiogenesis, neovascular glaucoma, diabetic retinopathy, corneal diseases induced by new blood vessels, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasia, granular conjunctivitis, Stargardt disease, and the like. Excessive development of blood vessels can often lead to serious damage to the patient. Macular degeneration, for example, impairs central vision and, in acute cases, can lead to blindness.Furthermore, 30% of patients suffering from neovascular glaucoma are forced to undergo enucleation to relieve pain. Petition 870250080754, dated 09 / 09 / 2025, p. 22 / 186 2 / 124

[003] In this context, there is an urgent need for the development of new therapeutic approaches to prevent and / or treat highly vascularized and inflammatory eye diseases. In 2012, document WO 2012 / 027289 described aminopyridine and aminopyrimidine carboxamide derivatives targeting CXCR2 receptors, which may be suitable for the treatment of inflammatory and neoplastic disorders such as angiogenic eye diseases, ocular inflammation, diabetic retinopathy, macular degeneration, and corneal neovascularization. A decade later, Wang et al. (Redox Biol., 2022, 56, 102438) reported that selective blockade of CXCL1-CXCL2 activation could be a potential treatment for hypertensive retinopathy. Monickaraj et al. (Investigative Ophthalmology & Visual Science, 2021, 62, 3032) reported the role of the chemokine CXCL1 in altering the blood-retinal barrier in diabetic retinopathy and, therefore, as a potential new therapeutic target.

[004] In previous studies, the inventors reported the use of urea derivatives as antagonists of CXCR1 and CXCR2 receptors for the treatment of macular degeneration (WO 2020 / 079184). They also reported in WO 2022 / 219123 that these urea derivatives are effective in the treatment of uveal melanoma by inhibiting the production of ROS, which is also known to modulate angiogenesis and Petition 870250080754, dated 09 / 09 / 2025, page 23 / 186 3 / 124 inflammation in neovascular glaucoma (Masuda et al.: Oxid. Med. Cell Longev., Volume 2017; Nita et al.: Oxid. Med. Cell Longev., Volume 2016).

[005] There is a variety of targets (ROS species, chemokine receptors...) and others still need to be investigated to develop new therapeutic approaches for the treatment of eye diseases. Therefore, there is a need for the development of new drugs or new compounds that have a therapeutic effect against eye diseases (or ocular diseases) and, at the same time, are safe for the patient. SUMMARY OF THE INVENTION

[006] In this context, the inventors synthesized and provided novel 3,5-diaminotriazole derivatives of formula (I). They demonstrated therapeutic interest, particularly for the treatment of ocular diseases, especially those associated with exacerbated angiogenesis. More specifically, the inventors demonstrated that the compounds of formula (I), according to the invention, possess inhibitory properties, such as an inhibitory effect on therapeutic targets associated with ocular diseases. The inventors further demonstrated that the compounds of formula (I), according to the invention, were able to inhibit ocular (retinal) neoangiogenesis in the zebrafish model. Petition 870250080754, dated 09 / 09 / 2025, page 24 / 186 4 / 124

[007] The present invention therefore relates to a compound of formula (I) or to a pharmaceutically acceptable salt thereof: (I), where: X is -(CH2)-, -(CH2)-CO-, or -(CH2)-(CH2)-; Ri is an aryl or heteroaryl group, said aryl or heteroaryl groups are optionally substituted by at least one radical selected from the group consisting of an (C1-C1)alkyl group optionally substituted by at least one halogen, an (C1-C6)alkyloxy group optionally substituted by at least one halogen, a halogen, a CO2R3 group with R3 being a hydrogen or an (C1-C1)alkyl group, and a -C(O)R4 group with R4 being a hydrogen group, an (C1-C1)alkyl group, or an -NRsRg group with R5 and Rg being independently a hydrogen group or an (C1-C1)alkyl group, a nitrile group, and a nitro group; n is an integer between 0 and 5; and each R2 is independently a radical selected from the group consisting of an (C1-C1)alkyl group optionally substituted with at least one halogen, an (C1-C6)alkyloxy group optionally substituted with at least one halogen Petition 870250080754, dated 09 / 09 / 2025, page 25 / 186 5 / 124 halogen, a halogen, a -CO2R3 with R3 being a hydrogen or a (C1-C1)alkyl, and a -C(O)R4 with R4 being a hydrogen, a (C1-C1)alkyl, or a -NR5R6 with R5 and Rg being independently a hydrogen or a (C1-C1)alkyl, a nitrile, and a nitro; provided that the compound in question is not a compound selected from a group consisting of: - 1-benzyl-N3-phenyl-1H-1,2,4-triazol-3,5-diamine; and - 1-phenethyl-N3-phenyl-1H-1,2,4-triazol-3,5-diamine.

[008] Specifically, n is an integer between 1 and 5.

[009] In a specific embodiment, the compound of the invention has the following formula (IA) or (IB): H (IA), or H (IB).

[0010] Preferably, the compounds of the invention with formulas (I), (IA) and (IB) are such that X is -(CH2)-.

[0011] In a specific embodiment, the compounds of the invention of formulas (I), (IA) and (IB) are such that Ri is a phenyl or pyridinyl group, preferably a phenyl, said phenyl or pyridinyl groups being optionally substituted by at least one radical selected from the group Petition 870250080754, dated 09 / 09 / 2025, p. 26 / 186 6 / 124 consisting of a (C1-C6)alkyloxy, preferably a methoxy, a (C1-C1)alkyl, preferably a methyl, a halogen, preferably a chlorine or a bromine, and a -CO2R3, with R3 being a (C1-C1)alkyl, preferably a methyl.

[0012] In another aspect, the compounds of the invention of formulas (I), (IA) and (IB) are such that n is an integer between 0 and 3, preferably n is 0, 1 or 2, more preferably 1.

[0013] In another aspect, the compounds of the invention of formulas (I), (IA) and (IB) are such that n is an integer between 1 and 3, preferably n is 1 or 2, more preferably 1.

[0014] More particularly, each R2 is independently a radical selected from the group consisting of an (C1-C6)alkyl group optionally substituted with at least one halogen, preferably a methyl, a trifluoromethyl or an isopropyl group, an (C1-C6)alkyloxy group, preferably a methoxy group, a halogen, preferably a fluorine group, a bromine group or a chlorine group, a nitro group and a nitrile group. In a preferred embodiment, each R2 is independently a radical selected from the group consisting of an isopropyl group and a bromine group, preferably a bromine group.

[0015] In a preferred embodiment, a compound of Petition 870250080754, dated 09 / 09 / 2025, p. 27 / 186 7 / 124 invention is a compound of formula (I), (IA) or (IB) wherein: X is - (CH2) -; Ri is a phenyl or pyridinyl group, preferably a phenyl, the phenyl or pyridinyl groups being optionally replaced by at least one radical selected from the group consisting of a methyl, a chlorine, a bromine and a -CO2R3, R3 being a methyl; n is 1; and R2 is a radical selected from the group consisting of an isopropyl and a bromine.

[0016] In a more preferred embodiment, the compound of formulas (I), (IA) and (IB) is selected from the group consisting of: - MCK248: 1-benzyl-N5-phenyl-1H-1,2,4-triazol-3,5diamine; - MCK250: 1-(2-methylbenzyl)-N3-phenyl-1H-1,2,4-triazol3,5-diamine; - MCK253: 1-benzyl-N3-(pyridin-2-yl)-1H-1,2,4-triazol3,5-diamine; - MCK254: 1-benzyl-N3-(pyridin-3-yl)-1H-1,2,4-triazol3,5-diamine; - MCK257: 1-(2,6-difluorobenzyl)-N5-phenyl-1H-1,2,4triazol-3,5-diamine; - MCK259: 1-(2,6-difluorobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; Petição 870250080754, de 09 / 09 / 2025, pág. 28 / 186 8 / 124 - MCK260: 1-(3-metoxibenzil)- N5-fenil-1H-1,2,4triazol-3,5-diamina; - MCK261: 1-(3-metoxibenzil)- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK262: 1-(4-isopropilbenzil)- N5-fenil-1H-1,2,4triazol-3,5-diamina; - MCK263: 1-(4-isopropilbenzil)- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK264: 1-(3-bromobenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK268: 1-(2, 6-diclorobenzil)- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK269: 1-(2-metilbenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK271: 1-(4-metilbenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK272: 1-(4-clorobenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK273: N3-fenil-1-(3-(trifluorometil)benzil)-1 H 1,2,4-triazol-3,5-diamina; - MCK274: 1-(3,5-difluorobenzil)- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK275: 1-(3-nitrobenzil))- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK276: 1-(3-bromobenzil)- N3-(piridin-2-il)-1H- Petição 870250080754, de 09 / 09 / 2025, pág. 29 / 186 9 / 124 1,2,4-triazol-3,5-diamina; - MCK278: 1-(2,6-diclorobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK279: 1-(4-metilbenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK280: 1-(4-clorobenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK281: 4-((5-amino-3-(piridin-2-ilamino)-1 H -1,2,4triazol-1-il)metil)benzonitrila; - MCK282: N3-(piridin-2-il)-1-(3- (trifluorometil)benzil)-1H-1,2,4-triazol-3,5-diamina; - MCK283: 1-(3,5-difluorobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK284: 1-(2,4-difluorobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK288: 1-(4-nitrobenzil))- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK289: 1-(2-nitrobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK290: 1-(4-nitrobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK292: 1-(3-nitrobenzil)- N3-(piridin-2-il)-1 H - 1,2,4-triazol-3,5-diamina; - MCK295: 2-(5-amino-3-(piridin-2-ilamino)-1H-1,2,4triazol-1-il)-1-(3-nitrofenil)etan-1-ona; Petição 870250080754, de 09 / 09 / 2025, pág. 30 / 186 10 / 124 - MCK297: 1-(2-nitrobenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK298: N3-fenil-1-(3,4,5-trimetoxibenzil)-1 H -1,2,4triazol-3,5-diamina; - MCK299: 2-(5-amino-3-(fenilamino)-1H-1,2,4-triazol1-il)-1-feniletan-1-ona; - MCK300: 1-fenetil-N5-fenil-1H-1,2,4-triazol-3,5diamina; - MCK338: N5-fenil-1-(3-(trifluorometil)benzil)-1H1,2,4-triazol-3,5-diamina; - MCK339: 1-(3-bromobenzil)- N5-fenil-1H-1,2,4-triazol3,5-diamina; - MCK340: 1-(3-bromobenzil)- N3-(4-metoxifenil)-1H1,2,4-triazol-3,5-diamina; - MCK341: 1-(3-bromobenzil)- N5-(4-metilfenil)-1H1,2,4-triazol-3,5-diamina; - MCK342: 1-(3-bromobenzil)- N3-(4-metilfenil)-1H1,2,4-triazol-3,5-diamina; - MCK343: 1-(3-bromobenzil)- N5-(4-clorofenil)-1H1,2,4-triazol-3,5-diamina; - MCK344: 1-(3-bromobenzil)- N3-(4-clorofenil)-1H1,2,4-triazol-3,5-diamina; - MCK345: 1-(3-bromobenzil)- N5-(4-bromofenil)-1H1,2,4-triazol-3,5-diamina; - MCK346: 1-(3-bromobenzil)- N3-(4-bromofenil)-1H- Petição 870250080754, de 09 / 09 / 2025, pág. 31 / 186 11 / 124 1,2,4-triazol-3,5-diamina; - MCK347: metil-4-((3-amino-1-(3-bromobenzil)-1H1,2,4-triazol-5-il)amino)benzoato; - MCK348: methyl-4-((5-amino-1-(3-bromobenzyl)-1H1,2,4-triazol-3-yl)amino)benzoate; - MCK349: 1-(3-bromobenzyl)-N3-(3,4-dichlorophenyl)-1H1,2,4-triazol-3,5-diamine; - MCK350: N3-(3,4-dichlorophenyl)-1-(4-isopropylbenzyl)1H-1,2,4-triazol-3,5-diamine; - MCK351: 1-(3-bromobenzyl)-N3-(pyridin-3-yl)-1H1,2,4-triazol-3,5-diamine; and - MCK352: 1-(3-bromobenzyl)-N4-(pyridin-3-yl)-1H1,2,4-triazol-3,5-diamine.

[0017] Another object of the invention is a compound according to the invention, as defined in this document, for use as a drug or medicine. Another object is a pharmaceutical or veterinary composition comprising a compound as defined in this document and a pharmaceutically acceptable excipient.

[0018] Another object is a pharmaceutical or veterinary compound or composition according to the invention for use in the treatment of an eye disease. In a specific embodiment, the eye disease is chosen from corneal graft angiogenesis, neovascular glaucoma, diabetic retinopathy, macular edema, corneal diseases induced by Petition 870250080754, dated 09 / 09 / 2025, page 32 / 186 12 / 124 new blood vessels, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasia, granular conjunctivitis, macular edema, or Stargardt disease. In a preferred embodiment, the eye disease is chosen from diabetic retinopathy, macular degeneration, neovascular glaucoma, macular edema, or Stargardt disease.

[0019] In a specific embodiment, the pharmaceutical or veterinary composition for use according to the invention is administered orally, parenterally or topically, preferably topically, and most preferably topically to the eyes. FIGURE CAPTIONS Figure 1: MCK349 inhibits oxidative stress in ARPE and angiogenesis.

[0020] A. ARPE-19 cells were treated with 1 μM of MCK349 followed by 200 μM of H2O2 for 2 h. ROS were analyzed by cytometry. B. ARPE-19 cells were treated with 2.5 μM of MCK349 for 48 h; CXCL1 mRNA level was evaluated by qPCR. C. TIME cells were pre-treated with 2.5 μM of MCK349 for 11 h, then stimulated with 100 ng / ml of CXCL8 for 15 min. p-ERK levels were analyzed by immunoblotting. HSP90 served as a charge control. D. Vessel formation by TIME cells cultured in Matrigel and treated with 5 or 10 μM of MCK349. E and F. TIME cells were incubated for 72 h with 100 ng / mL Petition 870250080754, dated 09 / 09 / 2025, page 33 / 186 13 / 124 of CXCL8 (E) or CXCL7 (F) and MCK349 (0.1, 0.2, or 0.5 μM). Cell proliferation is determined by the number of cells. Results are presented as the mean of three independent experiments ± SEM. For A and B, statistical significance (compared to the control condition) was determined using an unpaired Student's t-test: ***P < 0.001. For E and F, statistical significance (compared to the CXCL-8 or CXCL7 condition) was determined using one-way ANOVA with Bonferroni post-hoc test: ***P < 0.001. Figure 2: MCK349 and MCK342 inhibit pro-inflammatory cytokines in human blood stimulated with LPS.

[0021] Human whole blood will be incubated with MCK349 or MCK342 (5 or 10 μM) for 1 h before stimulation with 10 ng / ml LPS for 18 h. The cytokines IL1β, IL6, INFγ, IL4, IL5, and IL10 were analyzed by multiplex ELISA. All cytokines analyzed showed a significant increase in the LPS condition compared to the control condition. Statistical significance (compared to the LPS condition) was determined using one-way ANOVA with Bonferroni post-hoc test: *P < 0.05; **P < 0.01; ***P < 0.001. Figure 3: MCK349 inhibits pro-inflammatory, pro-angiogenic and / or pro-fibrotic mRNA markers in diabetic retinopathy in vitro.

[0022] ARPE-19 cells were cultured under hyperglycemic conditions (high blood glucose) and pre-treated with Petition 870250080754, dated 09 / 09 / 2025, page 34 / 186 14 / 124 MCK349 (5 or 10 μM) for 24 h, then stimulated with cytokines (10 ng / ml IL1β, 25 ng / ml VEGF, and 25 ng / ml TNF) for 24 h. The mRNAs of IL1β, VEGF, TNF, CXCL8, CXCL1, TGFβ, MMP9, IL6, and IL33 were analyzed by qPCR. All analyzed mRNA markers showed a significant increase in the high glucose + cytokine condition compared to the control condition. Statistical significance (compared to the high glucose + cytokine (CT) condition) was determined using one-way ANOVA with Bonferroni post-hoc test: *P < 0.05; **P < 0.01; ***P < 0.001. Figure 4: MCK349 inhibits pro-inflammatory, pro-angiogenic and / or pro-fibrotic cytokines in diabetic retinopathy in vitro.

[0023] ARPE-19 cells were cultured under hyperglycemic conditions (high blood glucose) and pre-treated with MCK349 (5, 10, or 25 μM) for 24 h, then stimulated with cytokines (10 ng / ml IL1β, 25 ng / ml VEGF, and 25 ng / ml TNF) for 24 h. Cytokines (IL1β, IFNγ, TNF, CXCL8, IL4, IL2, IL13, IL10, IL5, IL12p70, IL6, and IL33) were analyzed by multiplex ELISA in the supernatant. All cytokines analyzed showed a significant increase in the high glucose + cytokine condition compared to the control condition. Statistical significance (compared to the high glucose + cytokine (CT) condition) was determined. Petition 870250080754, dated 09 / 09 / 2025, page 35 / 186 15 / 124 using one-way ANOVA with Bonferroni post-hoc test: *P < 0.05; **P < 0.01; ***P < 0.001. Figure 5: MCK263, MC342, MCK344, and MCK349 inhibit ocular (retinal) neoangiogenesis in zebrafish.

[0024] A to E. Transgenic zebrafish (fli: EGFP, blood vessels labeled in GFP) were placed for 72 h in normoxia (Nx) or hypoxia with 5% oxygen (Hx), in the presence of MCK263 (B), MC342 (C), MCK344 (D) or MCK349 (E) (0.25, 0.5 or 1 μM). Neoangiogenesis in the retina was analyzed by confocal microscopy. A. Representative image is shown. In the image, GFP blood vessels appear white. B to E. Quantification of the area of ​​blood vessels in the retina. Statistical significance (compared to the Hx condition) was determined using one-way ANOVA with Bonferroni post hoc test: ***P < 0.001. Figure 6: Inhibition of ERK activation induced by CXCL8

[0025] TIME cells were pretreated with vehicle (CT) or 2.5 μM of compound MCK295, MCK299, or MCK300 for 1 hectare, then stimulated with 100 ng / ml of CXCL8 for 15 min. p-ERK levels were analyzed by immunoblotting. HSP90 served as a loading control. Figure 7: Inhibition of ROS activation by H2O2

[0026] ARPE-19 cells were treated with vehicle (CT) or 5 or 1 μM of MCK248 or MCK249; or with 1 μM of MCK263 or MCK264 followed by 200 μM of H2O2 for 2h. ROS were Petition 870250080754, dated 09 / 09 / 2025, page 36 / 186 16 / 124 analyzed by cytometry. Figure 8: Inhibition of CXCL1 mRNA

[0027] ARPE-19 cells were treated with vehicle (CT) or 2.5 μM of MCK301 or MCK340 for 48 hours; CXCL1 mRNA level was assessed by qPCR. Figure 9: MCK349 inhibits choroidal neovascularization (NVC) and vascular extravasation in mice.

[0028] Choroidal neovascularization (CNV) in mice was induced by laser photocoagulation of the retina. Vehicle (CT) and MCK349 (52 μg / ml) were administered by binocular intravitreal injection (2 μl) four times in total. Once on Day 1 (immediately after shaping), Day 4, Day 7, and Day 11.

[0029] A. Grade 2b lesions (bright hyperfluorescence and late extravasation beyond the treated areas) were quantified by Fundus Fluorescein Angiography (FFA) on Days 9 and 15.

[0030] B. The volume of the NVC of each lesion was measured on Days 9 and 15 by Optical Coherence Tomography (OCT).

[0031] C. Representative image of Fluorescein Angiography (FFA) on Day 15 is shown. DETAILED DESCRIPTION OF THE INVENTION

[0032] According to the present invention, the terms below have the following meanings: Petition 870250080754, dated 09 / 09 / 2025, p. 37 / 186 17 / 124 The terms mentioned in this document with prefixes such as, for example, C1-C3 or C1-C6 may also be used with smaller numbers of carbon atoms, such as C1-C2, or C1-C5. If, for example, the term C1-C3 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 3 carbon atoms, especially 1, 2 or 3 carbon atoms. If, for example, the term C1-C6 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 6 carbon atoms, especially 1, 2, 3, 4, 5 or 6 carbon atoms.

[0033] The term alkyl refers to a saturated, linear or branched aliphatic group. The term (C1-C5)alkyl more specifically means methyl, ethyl, propyl or isopropyl. The term (C1-C6)alkyl more specifically means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl. In a preferred embodiment, the alkyl is a methyl, an ethyl, a propyl, an isopropyl or a tert-butyl.

[0034] The term alkyloxy or alkoxy corresponds to the alkyl group, as defined above, linked to the molecule by an -O- (ether) bond. (C1-C3)alkyloxy includes methoxy, ethoxy, propyloxy, and isopropyloxy. (C1-C6)alkyloxy includes methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, pentyloxy, and hexyloxy.

[0035] The term halogen corresponds to an atom of Petition 870250080754, dated 09 / 09 / 2025, p. 38 / 186 18 / 124 fluorine, chlorine, bromine or iodine.

[0036] The term aryl corresponds to a mono-, bi-, tri- or tetracyclic aromatic hydrocarbon with 6 to 24 carbon atoms. For example, the term aryl includes phenyl, naphthalenyl, anthracenyl or pyrenyl. In a preferred embodiment, aryl is a phenyl.

[0037] The term heteroaryl, as used in this document, corresponds to an aromatic group, mono- or polycyclic, comprising between 5 and 24 atoms and comprising at least one heteroatom, such as nitrogen, oxygen, or sulfur. As used in this document, the term heteroaryl additionally includes fused aryl-heterocycloalkyl and fused heteroarylcycloalkyl. The terms fused aryl-heterocycloalkyl and fused heteroarylcycloalkyl correspond to a bicyclic group in which an aryl, as defined above, or a heteroaryl is linked, respectively, to the heterocycloalkyl or cycloalkyl, as defined above, by at least two carbons. In other words, the aryl or heteroaryl shares a carbon bond with the heterocycloalkyl or cycloalkyl.Examples of such mono- and polycyclic heteroaryl groups, fused arylheterocycloalkyl and fused arylcycloalkyl groups may include: pyridinyl, thiazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl. Petition 870250080754, dated 09 / 09 / 2025, p. 39 / 186 19 / 124 benzofuranyl, thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isocromanyl, cromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzoisoxazolyl, oxindolyl, benzoxazolyl, benzoxazolinyl, benzoxazinyl, benzothienyl, benzothiazolyl, benzodiazepine, benzazepinyl, benzoxazepinyl, isatinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl or thiofuranyl.In a preferred embodiment, heteroaryl is a pyridinyl.

[0038] The expression “replaced by at least one radical” means that the group or radical is replaced by one or more radicals from the list. The expression “optionally replaced” means that the group or radical is not replaced (i.e., not substituted) or is replaced by Petition 870250080754, dated 09 / 09 / 2025, p. 40 / 186 20 / 124 one or more radicals from the list.

[0039] As used in this document, the term “pharmaceutically acceptable salt” includes salts of inorganic and organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, maleic, methanesulfonic, and the like. Other examples of pharmaceutically acceptable addition salts of inorganic or organic acids include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, and in the Handbook of Pharmaceutical Salts: Properties, Selection, and Use edited by P. Heinrich Stahl and Camille G. Wermuth 2002. Compounds

[0040] The present invention relates to compounds of formula (I): (I), where: X is -(CH2)-, -(CH2)-CO-, or -(CH2)-(CH2)-; Ri is an aryl or heteroaryl group, as referred to Petition 870250080754, dated 09 / 09 / 2025, page 41 / 186 21 / 124 aryl or heteroaryl groups are optionally substituted by at least one radical selected from the group consisting of an (C1-C1g)alkyl group optionally substituted by at least one halogen, an (C1-C1g)alkyloxy group optionally substituted by at least one halogen, a halogen, a CO2R3 group with R3 being a hydrogen or an (C1-C1g)alkyl group, and a -C(O)R4 group with R4 being a hydrogen group, an (C1-C1g)alkyl group, or an -NRsRg group with R5 and Rg being independently a hydrogen group or an (C1-C1g)alkyl group, a nitrile group, and a nitro group; n is an integer between 0 and 5; each R2 is independently a radical selected from the group consisting of an (Ci-Cg)alkyl optionally substituted with at least one halogen, an (Ci-Cg)alkyloxy optionally substituted with at least one halogen, a halogen, a -CO2R3 with R3 being a hydrogen or an (Ci-Cg)alkyl, and a -C(O)R4 with R4 being a hydrogen, an (Ci-Cg)alkyl, or an -NR5R6 with R5 and Rg independently being a hydrogen or an (Ci-Cg)alkyl, a nitrile, and a nitro; or a pharmaceutically acceptable salt thereof.

[0041] In one embodiment, the present invention relates to a compound of formula (I): Petition 870250080754, dated 09 / 09 / 2025, page 42 / 186 22 / 124 (I), where: X is -(CH2)-, -(CH2)-CO-, or -(CH2)-(CH2)-; Ri is an aryl or heteroaryl group, said aryl or heteroaryl groups are optionally substituted by at least one radical selected from the group consisting of an (Ci-Cg)alkyl group optionally substituted by at least one halogen, an (Ci-Cg)alkyloxy group optionally substituted by at least one halogen, a halogen, a CO2R3 group with R3 being a hydrogen or an (Ci-Cg)alkyl group, and a -C(O)R4 group with R4 being a hydrogen group, an (Ci-Cg)alkyl group, or an -NRsRg group with R5 and Rg being independently a hydrogen group or an (Ci-Cg)alkyl group, a nitrile group, and a nitro group; n is an integer between 0 and 5; each R2 is independently a radical selected from the group consisting of an (Ci-Cg)alkyl optionally substituted with at least one halogen, an (Ci-Cg)alkyloxy optionally substituted with at least one halogen, a halogen, a -CO2R3 with R3 being a hydrogen or an (Ci-Cg)alkyl, and a -C(O)R4 with R4 being a hydrogen, an (Ci-Cg)alkyl, or an -NR5R6 with R5 and Rg independently being a hydrogen or an (Ci-Cg)alkyl, a nitrile, and a nitro; Petition 870250080754, dated 09 / 09 / 2025, page 43 / 186 23 / 124 on the condition that the said compound is not a compound selected from a group consisting of: - 1-benzyl-N3-phenyl-1H-1,2,4-triazol-3,5-diamine; and - 1-phenethyl-N3-phenyl-1H-1,2,4-triazol-3,5-diamine. or a pharmaceutically acceptable salt thereof.

[0042] According to this embodiment, 1-benzyl-N3-phenyl-1H-1,2,4-triazol-3,5-diamine and 1-phenethyl-N3-phenyl-1H1,2,4-triazol-3,5-diamine with the following formulas, II y NH2f η II / / —NH2n^n H H ~ 1 and are excluded.

[0043] In a specific embodiment, the compounds of the invention are of the following formula (IA): (IA), with X, Ri, n, and R2 being as defined in this document.

[0044] In another specific embodiment, the compounds of the invention are of the following formula (IB): Petition 870250080754, dated 09 / 09 / 2025, p. 44 / 186 24 / 124 H (IB), with X, Ri, n, and R2 being as defined in this document.

[0045] According to the invention, X is -(CH2)-, -(CH2)CO-, or -(CH2)-(CH2)-, preferably -(CH2)-.

[0046] According to the invention, Ri is an aryl or heteroaryl group, optionally substituted by at least one radical selected from the group consisting of an (C1-C1)alkyl optionally substituted by at least one halogen, an (C1-C6)alkyloxy optionally substituted by at least one halogen, a halogen, a -CO2R3 with R3 being a hydrogen or an (C1-C1)alkyl, and a -C(O)R4 with R4 being a hydrogen, an (C1-C1)alkyl, or an -NR5R6 with R5 and Rg independently being a hydrogen or an (C1-C1)alkyl, a nitrile, and a nitro.

[0047] In a specific embodiment, Ri is an aryl or heteroaryl group, preferably a phenyl or pyridinyl group, optionally substituted by at least one radical selected from the group consisting of an (C1-C1)alkyl group optionally substituted by at least one halogen, an (C1-C6)alkyloxy group optionally substituted by Petition 870250080754, dated 09 / 09 / 2025, p. 45 / 186 25 / 124 at least one halogen, one halogen and one -CO2R3, where R3 is either a hydrogen or an (C1-C1) alkyl group.

[0048] In a more specific embodiment, Ri is a phenyl or pyridinyl group, preferably a phenyl group, said phenyl or pyridinyl groups being optionally substituted by at least one radical selected from the group consisting of a (C1-C6)alkyloxy, a (C1-C6)alkyl, a halogen, and a -CO2R3, where R3 is a (C1-C6)alkyl. In a further specific embodiment, Ri is a phenyl or pyridinyl group, preferably a phenyl group, said phenyl or pyridinyl groups being optionally substituted by at least one radical selected from the group consisting of a methoxy, a methyl, a halogen, preferably a chlorine or a bromine, and a -CO2R3, where R3 is a methyl.

[0049] In a preferred embodiment, Ri is a phenyl group optionally substituted by at least one radical selected from the group consisting of a methoxy, a methyl, a chlorine, a bromine and a -CO2R3, where R3 is a methyl.

[0050] In another preferred embodiment, Ri is a pyridinyl group.

[0051] According to the invention, n is an integer between 0 and 5, that is, n is 0, 1, 2, 3, 4 and 5. In a specific embodiment, n is an integer between 0 and 3. Preferably, n is 0, 1 or 2. In another Petition 870250080754, dated 09 / 09 / 2025, p. 46 / 186 26 / 124 specific modality, n is an integer between 1 and 5, that is, n is 1, 2, 3, 4 and 5. Preferably, n is an integer between 1 and 3. More preferably, n is 1 or 2, and even more preferably 1.

[0052] According to the invention, each R2 is independently a radical selected from the group consisting of an (C1-C1)alkyl optionally substituted with at least one halogen, an (C1-C6)alkyloxy optionally substituted with at least one halogen, a halogen, CO2R3 with R3 being a hydrogen or an (C1-C1)alkyl, and a -C(O)R4 with R4 being a hydrogen, an (C1-C1)alkyl, or an -NRsRg with R5 and Rg independently being a hydrogen or an (C1-C1)alkyl, a nitrile, and a nitro.

[0053] In a specific embodiment, each R2 is independently a radical selected from the group consisting of an (C1-C6)alkyl group optionally substituted with at least one halogen, an (C1-C6)alkyloxy group optionally substituted with at least one halogen, a halogen group, a nitrile group, and a nitro group.

[0054] In a further specific embodiment, each R2 is independently a radical selected from the group consisting of an (C1-C1)alkyl group optionally substituted with at least one halogen, a (C1-C6)alkyloxy group, a halogen group, a nitro group, and a nitrile group. In a still more specific embodiment Petition 870250080754, dated 09 / 09 / 2025, p. 47 / 186 27 / 124 specifically, each R2 is independently a radical selected from the group consisting of a methyl, a trifluoromethyl, an isopropyl, a methoxy, a fluorine, a bromine or a chlorine, a nitro, and a nitrile.

[0055] In a preferred embodiment, n is 1 and R2 is a radical selected from the group consisting of an (C1-C6)alkyl group optionally substituted with at least one halogen, preferably a methyl, an isopropyl or an isopropyl group, an (C1-C6)alkyloxy group, preferably a methoxy group, a halogen group, preferably a bromine or a chlorine group, a nitrile and a nitro group.

[0056] In a further preferred embodiment, n is 2 and each R2 is independently a radical selected from the group consisting of a halogen, preferably a fluorine or a chlorine.

[0057] In a further preferred embodiment, n is 3 and each R2 is a methoxy.

[0058] In a particular embodiment, X is -(CH2)-, and Ri, ne R2 are as defined above.

[0059] According to this specific embodiment, Ri is a phenyl or pyridinyl group, preferably a phenyl, said phenyl or pyridinyl groups being optionally substituted by at least one radical selected from the group consisting of an (C1-C1e)alkyl group optionally substituted by at least one halogen, a Petition 870250080754, dated 09 / 09 / 2025, p. 48 / 186 28 / 124 (C1-C6)alkyloxy optionally substituted by at least one halogen, a halogen and a -CO2R3, with R3 being a hydrogen or a (C1-C6)alkyl. More particularly, Ri is a phenyl or pyridinyl group, preferably a phenyl group, said phenyl or pyridinyl groups being optionally substituted by at least one radical selected from the group consisting of a methoxy, a methyl, a halogen, preferably a chlorine or a bromine, and a -CO2R3, with R3 being a methyl.

[0060] According to this specific embodiment, n is an integer between 0 and 3. Preferably, n is 0, 1, or 2. More preferably, n is 1 or 2, and even more preferably, 1. Each R2 is independently a radical selected from the group consisting of an (C1-C6)alkyl group optionally substituted with at least one halogen, an (C1-C6)alkyloxy group optionally substituted with at least one halogen, a halogen, a nitrile, and a nitro group. Preferably, R2 is independently a radical selected from the group consisting of a methyl group, a trifluoromethyl group, an isopropyl group, a methoxy group, a fluorine group, a bromine group, or a chlorine group, a nitro group, and a nitrile group.

[0061] In a preferred embodiment of the invention, a compound of formula (I), (IA) or (IB) is such that: X is - (CH2) -; Petition 870250080754, dated 09 / 09 / 2025, p. 49 / 186 29 / 124 Ri is a phenyl or pyridinyl group, preferably a phenyl, the phenyl or pyridinyl groups being optionally replaced by at least one radical selected from the group consisting of a methyl, a chlorine, a bromine and a -CO2R3, R3 being a methyl; n is 1; and R2 is a radical selected from the group consisting of an isopropyl and a bromine.

[0062] In a further specific embodiment, X is (CH2)-CO-, and Ri, ne R2 are as defined above.

[0063] According to this specific embodiment, Ri is a phenyl or pyridinyl group, said phenyl or pyridinyl groups being optionally substituted by at least one radical selected from the group consisting of an (C1-C6)alkyl group optionally substituted by at least one halogen, an (C1-C6)alkyloxy group optionally substituted by at least one halogen, a halogen and a -CO2R3 group, with R3 being a hydrogen or an (C1-C6)alkyl group. Preferably, Ri is a phenyl or pyridinyl group.

[0064] According to this specific embodiment, n is an integer between 0 and 3. Preferably, n is 0, 1, or 2. More preferably, n is 0 or 1. Each R2 is independently a radical selected from the group consisting of an (C1-C1)alkyl group optionally substituted with at least one halogen, an (C1-C6)alkyloxy group, Petition 870250080754, dated 09 / 09 / 2025, p. 50 / 186 30 / 124 optionally replaced by at least one halogen, one halogen, one nitrile, and one nitro. Preferably, n is 0 or 1 and R2 is a nitro.

[0065] In a further specific embodiment, X is (CH2)-(CH2)-, and Ri, ne R2 are as defined above.

[0066] According to this specific embodiment, Ri is a phenyl or pyridinyl group, said phenyl or pyridinyl groups being optionally substituted by at least one radical selected from the group consisting of an (C1-C6)alkyl group optionally substituted by at least one halogen, an (C1-C6)alkyloxy group optionally substituted by at least one halogen, a halogen and a -CO2R3 group, with R3 being a hydrogen or an (C1-C6)alkyl group. Preferably, Ri is a phenyl group.

[0067] According to this specific embodiment, n is an integer between 0 and 3. Preferably, n is 0, 1, or 2. More preferably, n is 0. Each R2 is independently a radical selected from the group consisting of an (C1-C1)alkyl group optionally substituted with at least one halogen, an (C1-C6)alkyloxy group optionally substituted with at least one halogen, a halogen group, a nitrile group, and a nitro group.

[0068] In a preferred embodiment, a compound of formula (I), (IA) or (IB) as defined above is selected from the group consisting of: Petition 870250080754, dated 09 / 09 / 2025, page 51 / 186 31 / 124 - MCK248: 1-benzyl-N5-phenyl-1H-1,2,4-triazol-3,5diamine; - MCK249: 1-benzyl-N3-phenyl-1H-1,2,4-triazol-3,5diamine; - MCK250: 1-(2-methylbenzyl)-N3-phenyl-1H-1,2,4-triazol3,5-diamine; - MCK253: 1-benzyl-N3-(pyridin-2-yl)-1H-1,2,4-triazol3,5-diamine; - MCK254: 1-benzil-N3-(piridin-3-il)-1H-1,2,4-triazol3,5-diamina; - MCK257: 1-(2,6-difluorobenzil)- N5-fenil-1H-1,2,4triazol-3,5-diamina; - MCK259: 1-(2,6-difluorobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK260: 1-(3-metoxibenzil)- N5-fenil-1H-1,2,4triazol-3,5-diamina; - MCK261: 1-(3-metoxibenzil)- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK262: 1-(4-isopropilbenzil)- N5-fenil-1H-1,2,4triazol-3,5-diamina; - MCK263: 1-(4-isopropilbenzil)- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK264: 1-(3-bromobenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK268: 1-(2, 6-diclorobenzil)- N3-fenil-1H-1,2,4- Petição 870250080754, de 09 / 09 / 2025, pág. 52 / 186 32 / 124 triazol-3,5-diamina; - MCK269: 1-(2-metilbenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK271: 1-(4-metilbenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK272: 1-(4-clorobenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK273: N3-fenil-1-(3-(trifluorometil)benzil)-1 H 1,2,4-triazol-3,5-diamina; - MCK274: 1-(3,5-difluorobenzil)- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK275: 1-(3-nitrobenzil))- N3-fenil-1H-1,2,4- triazol-3,5-diamina; - MCK276: 1-(3-bromobenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK278: 1-(2, 6-diclorobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK279: 1-(4-metilbenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK280: 1-(4-clorobenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK281: 4-((5-amino-3-(piridin-2-ilamino)-1 H -1,2,4triazol-1-il)metil)benzonitrila; - MCK282: N3-(piridin-2-il)-1-(3- (trifluorometil)benzil)-1H-1,2,4-triazol-3,5-diamina; Petição 870250080754, de 09 / 09 / 2025, pág. 53 / 186 33 / 124 - MCK283: 1-(3,5-difluorobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK284: 1-(2,4-difluorobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK288: 1-(4-nitrobenzil))- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK289: 1-(2-nitrobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK290: 1-(4-nitrobenzil)- N3-(piridin-2-il)-1 H 1,2,4-triazol-3,5-diamina; - MCK292: 1-(3-nitrobenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK295: 2-(5-amino-3-(piridin-2-ilamino)-1H-1,2,4triazol-1-il)-1-(3-nitrofenil)etan-1-ona; - MCK297: 1-(2-nitrobenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK298: N3-fenil-1-(3,4,5-trimetoxibenzil)-1 H -1,2,4triazol-3,5-diamina; - MCK299: 2-(5-amino-3-(fenilamino)-1H-1,2,4-triazol1-il)-1-feniletan-1-ona; - MCK300: 1-fenetil-N5-fenil-1H-1,2,4-triazol-3,5diamina; - MCK301: 1-fenetil-N3-fenil-1H-1,2,4-triazol-3,5diamina; - MCK338: N5-fenil-1-(3-(trifluorometil)benzil)-1 H - Petição 870250080754, de 09 / 09 / 2025, pág. 54 / 186 34 / 124 1,2,4-triazol-3,5-diamina; - MCK339: 1-(3-bromobenzil)- N5-fenil-1H-1,2,4-triazol3,5-diamina; - MCK340: 1-(3-bromobenzil)- N3-(4-metoxifenil)-1H- 1,2,4-triazol-3,5-diamina; - MCK341: 1-(3-bromobenzil)- N5-(4-metilfenil)-1H- 1,2,4-triazol-3,5-diamina; - MCK342: 1-(3-bromobenzil)- N3-(4-metilfenil)-1 H - 1,2,4-triazol-3,5-diamina; - MCK343: 1-(3-bromobenzil)- N5-(4-clorofenil)-1H- 1,2,4-triazol-3,5-diamina; - MCK344: 1-(3-bromobenzil)- N3-(4-clorofenil)-1H- 1,2,4-triazol-3,5-diamina; - MCK345: 1-(3-bromobenzil)- N5-(4-bromofenil)-1H- 1,2,4-triazol-3,5-diamina; - MCK346: 1-(3-bromobenzyl)- N3-(4-bromophenyl)-1H- 1,2,4-triazol-3,5-diamine; - MCK347: methyl-4-((3-amino-1-(3-bromobenzyl)-1 H - 1,2,4-triazol-5-yl)amino)benzoate; - MCK348: methyl-4-((5-amino-1-(3-bromobenzyl)-1 H - 1,2,4-triazol-3-yl)amino)benzoate; - MCK349: 1-(3-bromobenzyl)-N3-(3,4-dichlorophenyl)-1H 1,2,4-triazol-3,5-diamine; - MCK350: N3-(3,4-dichlorophenyl)-1-(4-isopropylbenzyl)1H-1,2,4-triazol-3,5-diamine; Petition 870250080754, dated 09 / 09 / 2025, page 55 / 186 35 / 124 - MCK351: 1-(3-bromobenzyl)- N3-(pyridin-3-yl)-1H- 1,2,4-triazol-3,5-diamine; and - MCK352: 1-(3-bromobenzyl)- N4-(pyridin-3-yl)-1H- 1,2,4-triazol-3,5-diamine.

[0069] In a more preferred embodiment, a compound of formula (I), (IA) or (IB) as defined above is selected from the group consisting of: - MCK250: 1-(2-metilbenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK257: 1-(2,6-difluorobenzil)- N5-fenil-1H-1,2,4triazol-3,5-diamina; - MCK259: 1-(2,6-difluorobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK260: 1-(3-metoxibenzil)-N5-fenil-1H-1,2,4triazol-3,5-diamina; - MCK261: 1-(3-metoxibenzil)-N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK262: 1-(4-isopropilbenzil)- N5-fenil-1H-1,2,4triazol-3,5-diamina; - MCK263: 1-(4-isopropilbenzil)- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK264: 1-(3-bromobenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK268: 1-(2, 6-diclorobenzil)- N3-fenil-1H-1,2,4triazol-3,5-diamina; Petição 870250080754, de 09 / 09 / 2025, pág. 56 / 186 36 / 124 - MCK269: 1-(2-metilbenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK271: 1-(4-metilbenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK272: 1-(4-clorobenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK273: N3-fenil-1-(3-(trifluorometil)benzil)-1 H 1,2,4-triazol-3,5-diamina; - MCK274: 1-(3,5-difluorobenzil)- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK275: 1-(3-nitrobenzil))- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK276: 1-(3-bromobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK278: 1-(2, 6-diclorobenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK279: 1-(4-metilbenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK280: 1-(4-clorobenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK281: 4-((5-amino-3-(piridin-2-ilamino)-1 H -1,2,4triazol-1-il)metil)benzonitrila; - MCK282: N3-(piridin-2-il)-1-(3- (trifluorometil)benzil)-1H-1,2,4-triazol-3,5-diamina; - MCK283: 1-(3,5-difluorobenzil)- N3-(piridin-2-il)-1H Petição 870250080754, de 09 / 09 / 2025, pág. 57 / 186 37 / 124 1,2,4-triazol-3,5-diamina; - MCK284: 1-(2,4-difluorobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK288: 1-(4-nitrobenzil))- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK289: 1-(2-nitrobenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK290: 1-(4-nitrobenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK292: 1-(3-nitrobenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK295: 2-(5-amino-3-(piridin-2-ilamino)-1H-1,2,4triazol-1-il)-1-(3-nitrofenil)etan-1-ona; - MCK297: 1-(2-nitrobenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK298: N3-fenil-1-(3,4,5-trimetoxibenzil)-1 H -1,2,4triazol-3,5-diamina; - MCK338: N5-fenil-1-(3-(trifluorometil)benzil)-1 H - 1,2,4-triazol-3,5-diamina; - MCK339: 1-(3-bromobenzil)- N5-fenil-1H-1,2,4-triazol3,5-diamina; - MCK340: 1-(3-bromobenzil)- N3-(4-metoxifenil)-1H- 1,2,4-triazol-3,5-diamina; - MCK341: 1-(3-bromobenzil)- N5-(4-metilfenil)-1H- 1,2,4-triazol-3,5-diamina; Petição 870250080754, de 09 / 09 / 2025, pág. 58 / 186 38 / 124 - MCK342: 1-(3-bromobenzil)- N3-(4-metilfenil)-1H1,2,4-triazol-3,5-diamina; - MCK343: 1-(3-bromobenzil)- N5-(4-clorofenil)-1H1,2,4-triazol-3,5-diamina; - MCK344: 1-(3-bromobenzil)- N3-(4-clorofenil)-1H1,2,4-triazol-3,5-diamina; - MCK345: 1-(3-bromobenzil)- N5-(4-bromofenil)-1H1,2,4-triazol-3,5-diamina; - MCK346: 1-(3-bromobenzil)- N3-(4-bromofenil)-1H1,2,4-triazol-3,5-diamina; - MCK347: metil-4-((3-amino-1-(3-bromobenzil)-1 H 1,2,4-triazol-5-il)amino)benzoato; - MCK348: metil-4-((5-amino-1-(3-bromobenzil)-1 H 1,2,4-triazol-3-il)amino)benzoato; - MCK349: 1-(3-bromobenzyl)-N3-(3,4-dichlorophenyl)-1H1,2,4-triazol-3,5-diamine; - MCK350: N3-(3,4-dichlorophenyl)-1-(4-isopropylbenzyl)1H-1,2,4-triazol-3,5-diamine; - MCK351: 1-(3-bromobenzyl)- N3-(pyridin-3-yl)-1H- 1,2,4-triazol-3,5-diamine; and - MCK352: 1-(3-bromobenzyl)- N4-(pyridin-3-yl)-1H- 1,2,4-triazol-3,5-diamine.

[0070] In a still more preferred embodiment, a compound of formula (I), (IA) or (IB) as defined above is selected from the group consisting of: Petition 870250080754, dated 09 / 09 / 2025, page 59 / 186 39 / 124 - MCK263: 1-(4-isopropylbenzyl)-N3-phenyl-1H-1,2,4triazol-3,5-diamine; - MCK264: 1-(3-bromobenzyl)-N3-phenyl-1H-1,2,4-triazol3,5-diamine; - MCK342: 1-(3-bromobenzyl)-N3-(4-methylphenyl)-1H1,2,4-triazol-3,5-diamine; - MCK343: 1-(3-bromobenzyl)-N5-(4-chlorophenyl)-1H1,2,4-triazol-3,5-diamine; - MCK344: 1-(3-bromobenzyl)-N3-(4-chlorophenyl)-1H1,2,4-triazol-3,5-diamine; - MCK345: 1-(3-bromobenzyl)-N5-(4-bromophenyl)-1H1,2,4-triazol-3,5-diamine; - MCK348: methyl-4-((5-amino-1-(3-bromobenzyl)-1H1,2,4-triazol-3-yl)amino)benzoate; - MCK349: 1-(3-bromobenzyl)-N3-(3,4-dichlorophenyl)-1H 1,2,4-triazol-3,5-diamine; - MCK350: N3-(3,4-dichlorophenyl)-1-(4-isopropylbenzyl)- 1H-1,2,4-triazol-3,5-diamine; and - MCK352: 1-(3-bromobenzyl)-N4-(pyridin-3-yl)-1H1,2,4-triazol-3,5-diamine. Application

[0071] According to the present invention, the terms below have the following meanings: As used in this document, the terms treatment, to treat, or being treated refer to any Petition 870250080754, dated 09 / 09 / 2025, page 60 / 186 40 / 124 An act intended to improve the health status of patients, such as therapy, prevention, prophylaxis, and delay of a disease, particularly an eye or ocular disease. In certain modalities, such terms refer to the improvement or eradication of the disease or its associated symptoms. In other modalities, this term refers to minimizing the spread or worsening of the disease resulting from the administration of one or more therapeutic agents to an individual with such a disease.

[0072] As used in this document, the terms subject, individual or patient are interchangeable and refer to an animal, preferably a mammal, and even more preferably a human being.

[0073] The terms quantity, amount and dose are used interchangeably in this document and may refer to an absolute quantification of a molecule.

[0074] As used in this document, the terms active principle, active ingredient and active pharmaceutical ingredient are equivalent and refer to a component of a pharmaceutical composition with a therapeutic effect. In particular, such terms designate a compound of formula (I), (IA) or (IB).

[0075] As used in this document, the term therapeutic effect refers to an effect induced by an active ingredient, or a pharmaceutical composition according to Petition 870250080754, dated 09 / 09 / 2025, p. 61 / 186 41 / 124 with the invention, capable of preventing or delaying the onset or development of a disease or disorder, or of curing or mitigating the effects of a disease or disorder, particularly an eye or ocular disease.

[0076] As used in this document, the term “effective amount” refers to an amount of an active ingredient or pharmaceutical composition that prevents, eliminates, or reduces the deleterious effects of a disease, particularly an eye or ocular disease. Obviously, the amount to be administered can be adapted by the person skilled in the art according to the individual being treated, the nature of the disease, etc. In particular, the doses and administration regimen can be adapted to the nature, stage, and severity of the disease being treated, as well as to the weight, age, and general health status of the individual being treated, and to the physician's judgment.

[0077] As used in this document, the term “pharmaceutically acceptable excipient or carrier” refers to any ingredient, other than active ingredients, present in a pharmaceutical composition. Its addition may aim to impart a specific consistency or other physical or taste properties to the final product. A pharmaceutically acceptable excipient or carrier must be free from any interaction, particularly chemical, with the active ingredients. Petition 870250080754, dated 09 / 09 / 2025, page 62 / 186 42 / 124

[0078] As illustrated by examples, the inventors have demonstrated the therapeutic interest of the compounds of the invention.

[0079] Consequently, the present invention relates to a pharmaceutical or veterinary composition comprising a compound of formula (I), (IA) or (IB) according to the invention or a pharmaceutically acceptable salt thereof. Preferably, the pharmaceutical composition further comprises a pharmaceutically or veterinary acceptable carrier or excipient. The present invention relates to the use of a compound of formula (I), (IA) or (IB) according to the invention as a drug or medicine. The invention further relates to a method for treating a disease in an individual, wherein a therapeutically effective amount of a compound of formula (I), (IA) or (IB) according to the invention is administered to the individual in need thereof. The invention also relates to the use of a compound of formula (I), (IA) or (IB) according to the invention for the manufacture of a remedy, drug or medicine.The invention also relates to a pharmaceutical composition comprising a compound of formula (I), (IA) or (IB), according to the invention, for use as a drug.

[0080] The present invention also relates to a compound of formula (I), (IA) or (IB), as defined herein, or to a pharmaceutically acceptable salt or Petition 870250080754, dated 09 / 09 / 2025, p. 63 / 186 43 / 124 to a tautomer of the same, for use in the treatment of an eye disease.

[0081] The present invention further relates to a method for treating an eye disease, comprising administering to a needy individual an effective amount of a compound of formula (I), (IA) or (IB), as defined herein, or a pharmaceutically acceptable salt thereof.

[0082] The present invention also relates to the use of a compound of formula (I), (IA) or (IB), as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a drug, remedy or medicine for the treatment of an eye disease.

[0083] The present invention further relates to a pharmaceutical or veterinary composition comprising a compound of formula (I), (IA) or (IB), as defined herein, and a pharmaceutically acceptable salt thereof, for use in the treatment of an eye disease.

[0084] The present invention further relates to a method for treating an eye disease, comprising administering to a needy individual an effective amount of a pharmaceutical composition comprising a compound of formula (I), (IA) or (IB), as defined herein, or a pharmaceutically acceptable salt thereof. Petition 870250080754, dated 09 / 09 / 2025, p. 64 / 186 44 / 124

[0085] The present invention also relates to the use of a compound of formula (I), (IA) or (IB), as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a drug, medicine or pharmaceutical composition for the treatment of an eye disease.

[0086] In a specific modality, the eye disease is an angiogenesis-associated eye disease.

[0087] The present invention therefore relates to a compound of formula (I), (IA) or (IB), as defined herein, or to a pharmaceutically acceptable salt thereof, or to a pharmaceutical or veterinary composition comprising such compound, for use in the treatment of an ocular disease associated with angiogenesis.

[0088] The present invention further relates to a method for treating an ocular disease associated with angiogenesis, comprising administering to a needy individual an effective amount of a compound of formula (I), (IA) or (IB), as defined herein, or to a pharmaceutically acceptable salt thereof, or to a pharmaceutical or veterinary composition comprising such compound.

[0089] The present invention also relates to the use of a compound of formula (I), (IA) or (IB), as defined herein, or to a pharmaceutically acceptable salt of Petition 870250080754, dated 09 / 09 / 2025, p. 65 / 186 45 / 124 same, for the manufacture of a drug, medicine or pharmaceutical or veterinary composition for the treatment of an eye disease associated with angiogenesis.

[0090] In a specific embodiment, the ocular disease is chosen from corneal graft angiogenesis, neovascular glaucoma, diabetic retinopathy, corneal diseases induced by new blood vessels, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasia, granular conjunctivitis, macular edema, or Stargardt disease. Preferredly, the ocular disease is chosen from diabetic retinopathy, macular degeneration, neovascular glaucoma, macular edema, or Stargardt disease.

[0091] An object of the invention is also a compound of formula (I), (IA) or (IB), as defined in this document, or a pharmaceutically acceptable salt thereof, or a pharmaceutical or veterinary composition comprising such compound, for use in the treatment of an eye disease chosen from diabetic retinopathy, macular degeneration, neovascular glaucoma, macular edema or Stargardt disease.

[0092] The present invention further relates to a method for treating an eye disease chosen from diabetic retinopathy, macular degeneration, neovascular glaucoma, macular edema or Stargardt disease, comprising administering to a needy individual an effective amount of a compound of formula (I), (IA) Petition 870250080754, dated 09 / 09 / 2025, p. 66 / 186 46 / 124 or (IB), as defined in this document, or to a pharmaceutically acceptable salt thereof, or to a pharmaceutical or veterinary composition comprising such compound.

[0093] The present invention also relates to the use of a compound of formula (I), (IA) or (IB), as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a drug, medicine or pharmaceutical or veterinary composition for the treatment of an eye disease chosen from diabetic retinopathy, macular degeneration, neovascular glaucoma, macular edema or Stargardt disease.

[0094] The route of administration may be topical ocular (i.e., topical ophthalmic instillation), transdermal, oral, rectal, sublingual, intranasal, intrathecal, intraocular, or parenteral (including subcutaneous, intramuscular, intraperitoneal, intravenous, and / or intradermal). Preferably, the route of administration is topical, oral, or parenteral. Even more preferably, the route of administration is topical or oral. Even more preferably, the route of administration is topical. Advantageously, the route of administration is topical ocular. The pharmaceutical composition is suitable for one or more of the above routes.

[0095] The pharmaceutical or veterinary composition may be formulated as solutions in pharmaceutical solvents. Petition 870250080754, dated 09 / 09 / 2025, p. 67 / 186 47 / 124 acceptable either as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets or capsules containing solid vehicles in a form known in the art. The formulations of the present invention suitable for oral administration may be in the form of individual units, such as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of powder or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Formulations suitable for parenteral administration include, for example, a sterile oily or aqueous preparation of the active ingredient, preferably isotonic with the recipient's blood. Formulations for topical application may be in the form of a cream, lotion, ointment, solution, suspension, gel, oil-in-water emulsion or water-in-oil emulsion.Any such formulation may also contain other pharmaceutically compatible and non-toxic auxiliary agents, such as stabilizers, antioxidants, binders, colorants, emulsifiers, or flavorings. The formulations of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier and, optionally, other therapeutic ingredients. The carrier must be acceptable in the sense that... Petition 870250080754, dated 09 / 09 / 2025, page 68 / 186 48 / 124 which is compatible with the other ingredients in the formulations and not harmful to the recipient.

[0096] In a preferred embodiment, the pharmaceutical or veterinary compositions according to the invention are formulated for topical administration, preferably via ocular topical administration, typically by topical ophthalmic instillation. Preferably, the pharmaceutical or veterinary compositions according to the invention are in the form of a gel, a suspension, a solution, or a prolonged-release device.

[0097] In a specific embodiment, the pharmaceutical or veterinary composition, according to the invention, is coated onto an implant. Said implant dissolves naturally and slowly releases the pharmaceutical or veterinary composition over time, thus reducing the daily need for multiple eye drops. Advantageously, the implant does not need to be removed from the patient.

[0098] Other aspects and advantages of the present invention will be described in the following examples, which should be considered illustrative and not limiting. EXAMPLES Example A: Chemistry General information

[0099] All commercially available products from chemical suppliers were used without purification. The Petition 870250080754, dated 09 / 09 / 2025, page 69 / 186 49 / 124 solvents were purchased from Sigma Aldrich. All chemicals were purchased from Aldrich, Fisher, or Alfa Aesar. All chemical reactions were monitored simultaneously by LCMS, HPLC, and thin-layer chromatography (TLC, Merck 60 F254 silica gel plates) and visualized by both UV radiation (254 and 365 nm) and spraying with a relevant staining agent followed by heating with a hot air gun. Column chromatography was performed on a CombiFlash Rf+, TELEDYNE Isco, using a pre-packed column (CHROMABOND Flash, SiOH 40-63 μm, MACHEREY NAGEL or CHROMABOND Flash, Ci8ec 40-63 μm, MACHEREY NAGEL or POLYGOPREP 60-30 Ci8, MACHEREY NAGEL). All NMR spectra (1H,13C,19F) were recorded on Bruker Advance spectrometers (200 or 400 MHz).The 1H NMR (200 and 400 MHz), 13C{1H} NMR (50 and 101 MHz), and 19F{1H} NMR (188 and 377 MHz) spectra were obtained with samples dissolved in CDCl3 and DMSO-d6, with the residual solvent signals as internal references: CHCl3 (1H = 7.26 ppm, 13C = 77.16) and DMSO-d6 (1H = 2.50 ppm, 13C = 39.52). Chemical shifts (d) are expressed in ppm to the nearest 0.01 (1H) or 0.1 ppm (13C). Coupling constants (J) are expressed in Hertz (Hz). The signals are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of doublets, br s = wide singlet), coupling constants. Petition 870250080754, dated 09 / 09 / 2025, page 70 / 186 50 / 124 (J) and integration. Dye syntheses were performed in a Branson 5510 ultrasonic bath. Mass spectra (ESI-MS) were recorded on a ThermoFisher LCQ advantage ion-trap mass spectrometer, hyphenated with an Agilent 1100 HPLC, or on an Agilent iQ single quadrupole mass spectrometer, hyphenated with an Agilent 1260 Infinity HPLC. HRMS was performed on a Thermo Q-exactive Focus mass spectrometer hyphenated to the Thermo Vanquish UHPLC system, including degasser, binary pump, autosampler, and multiwavelength detector. Separation was performed on a Thermo Scientific Hypersil GOLD instrument (150 mm x 2.1 mm, 1.9 μm) at 0.2 ml / min. The gradient starts at 90 / 10 water (0.1% formic acid) / acetonitrile (0.1% formic acid) up to 98% acetonitrile (0.1% formic acid) in 15 minutes and is then maintained for two minutes.Mass spectrometry was used in electrospray ionization in switched mode (alternating positive / negative scanning) using the following parameters: spray voltage of 3.7 kV (positive mode) and 2.7 kV (negative mode); capillary temperature: 320 °C; coating gas: 30 ua; auxiliary gas: 15 ua; probe heater temperature: 350 °C. Melting points were obtained on a Kofler WME Heizbank No. 7563 system (44-266 °C). The purity of the compounds was subsequently analyzed by HPLC on a JASCO PU-2089 instrument with a column. Petition 870250080754, dated 09 / 09 / 2025, page 71 / 186 51 / 124 analytical Supelco Ascentis Express C18, 100 mm x 46 mm 5 μM. Eluent A: water with 1k formic acid, Eluent B: CH3CN with 1k formic acid. Foram used four different methods, described as follows: Method 1: 100% of A for 2 min, from 100% of A to 60% of A for 5 min, 60% of A for 3 min and, then, from 60% of A to 100% of A for 1 min (total of 11 min). Method 2: 100% of A for 2 min, from 100% of A to 60% of A for 8 min, 60% of A for 4 min, and then from 60% of A to 100% of A for 1 min (total of 15 min). Method 3: 95% of A for 2 min, from 95% of A to 50% of A for 8 min, 50% of A for 4 min, from 50% of A to 40% of A for 6.5 min, 40% of A for 6 min, from 40% of A to 95% of A for 2 min and 95% of A for 2.5 min (total of 30 min). Method 4: 95% of A for 2 min, from 95% of A to 50% of A for 8 min, 50% of A for 8 min, from 50% of A to 95% of A for 0.5 min and 95% of A for 0.5 min (total of 20 min). MCK248: 1-benzyl-N5-phenyl-1H-1,2,4-triazole-3,5-diamine

[00100] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (200 mg, 1.14 mmol) was dissolved in degassed DMF, and then Cs2CO3 (447 mg, 1.37 mmol) was added. Benzyl chloride (0.14 mL, 1.26 mmol) was added and the mixture Petition 870250080754, dated 09 / 09 / 2025, p. 72 / 186 The 52 / 124 reaction was stirred at room temperature overnight. CS2CO3 was filtered and DMF was evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / THF, 10 / 0 and then 5 / 5) yielded the title compound as a brown solid (20.9 mg, 0.0786 mmol, 7% yield) along with the N3-benzylated regioisomer. Brown solid, 20.9 mg, 0.0786 mmol, 7% yield. Rf (C&CE / THF, 1 / 1, v / v) = 0.69. MP = 166-168 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H, NH), 7.59 (d, d = 7.7 Hz, 2H, CHAr), 7.34 (t, J = 7.3 Hz, 2H, CHAr), 7.29 - 7.22 (m, 3H, CHAr), 7.22 - 7.17 (m, 2H, CHAr), 6.88 (t, J = 7.3 Hz, 1H, CHAr), 5.14 (s, 2H, NH2), 5.11 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d6) δ 160.7, 150.2, 141, 1, 137, 6, 128, 6 (2C), 128.4 (2C), 127.2, 127.2 (2C), 120.5, 116.9 (2C), 48.7. LCMS: tr = 9.56 min. [M+H]+= 266.07. HPLC (À254): purity 97.7%; HPLC (À28o): purity 96.8%; tr: 7.73 min (method 1). MCK249: 1-benzyl-N3-phenyl-1H-1,2,4-triazol-3,5-diamine H

[00101] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (150 mg, 0.857 mmol) was dissolved in degassed DMF (1 mL), then potassium tert-butoxide (96 mg, 0.857 mmol) was added. Benzyl chloride (0.12 mL, 0.857 mmol), Petition 870250080754, dated 09 / 09 / 2025, p. 73 / 186 53 / 124 dissolved in degassed DMF (1 mL) was added dropwise and the reaction mixture was stirred at 0 °C for 1 h, then at room temperature for a further 1 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 60 / 40) yielded the title compound as a white solid (119 mg, 0.449 mmol, 50% yield) along with the N5-benzylated regioisomer (15.9 mg, 0.06 mmol, 7%). White solid, 119 mg, 0.449 mmol, 50% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.54. PF = 136-138°C. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H, NH), 7.46 (d, J = 7.8 Hz, 2H, CHAr), 7.34 (t, J = 7.3 Hz, 2H, CHAr), 7.29 - 7.21 (m, 3H, CHAr), 7.14 (t, J = 7.9 Hz, 2H, CHAr), 6.70 (t, J = 7.3 Hz, 1H, CHAr), 6.29 (s, 2H, NH2), 5.03 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d6) δ 157.1, 154.1, 142.4, 137.6, 128.4 (2C), 128.4 (2C), 127.2 (2C), 127.2, 118.4, 115.5 (2C), 48.7. LCMS: tr = 9.65 min. [M+H]+ = 266.07. HPLC (À254): purity 99.4%; HPLC (À2so): purity 97.9%; tr: 8.25 min (method 1). Petition 870250080754, dated 09 / 09 / 2025, p. 74 / 186 54 / 124 MCK250: 1-(2-methylbenzyl)-N3-phenyl-1H-1,2,4-triazole 3,5-diamine

[00102] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (150 mg, 0.857 mmol) was dissolved in degassed DMF, then potassium tert-butoxide (96 mg, 0.857 mmol) was added. 2-Methylbenzyl chloride (150 mg, 1.07 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0 and then 60 / 40) yielded the title compound as a brown solid (111 mg, 0.398 mmol, 46% yield). Brown solid, 111 mg, 0.398 mmol, yield of 46%. Rf (CH2Cl2 / THF,1 / 1, v / v) = 0.51. MP = 156-158 °C.RMN de 1H (400 MHz, DMSO-d6) δ 8.67 (s, 1H, NH), 7.48 — 7.41 (m, 2H, CHAr), 7.14 (ddd, J = 15.8, 13.8, 7.6 Hz, 5H, CHAr), 6.82 (d, J = 6.8 Hz, 1H, CHAr), 6.68 (t, J = 7.3 Hz, 1H, CHAr), 6.23 (s, 2H, NH2), 4.99 (s, 2H, CH2), 2.33 (s, 3H, CH3). RMN de13C (101 MHz, DMSO-d6) δ 157.1, 154.3, 142.4, 135.8, 135.4, 129.9, 128.4 (2C), 126.9,. Petition: 870250080754, on September 9, 2025, page. 75 / 186 55 / 124 126, 6, 125, 8, 118,4, 115,5 (2C), 46,9, 18,7. LCMS: tr = 10,10 min. [M+H]+= 280,13. HPLC (À254): pure 99.5%; HPLC (À28o): pure 98,5%; tr: 8,78 min (meter 1). MCK253: 1-benzil-N3-(piridin-2-il)-1H-1,2,4-triazol 3,5-diamina

[00103] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. Benzyl chloride (0.16 mL, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture and it was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by silica gel flash chromatography (CH2Cl2 / MeOH, 10 / 0 and then 9 / 1) yielded the title compound as a yellow solid (140 mg, 0.526 mmol, 37% yield). Yellow solid, 16.4 mg, 0.062 mmol, 2% yield. Rf (CH2Cl2 / MeOH: 9 / 1, v / v) = 0.61. MP = 204 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H, NH), 8.16 — 8.11 (m, 1H, Petition 870250080754, dated 09 / 09 / 2025, page 76 / 186 56 / 124 CHpyr), 7,83 (d, J = 8,5 Hz, 1H, CHpyr), 7, 64 - 7,57 (m, 1H, CHpyr), 7,35 (t, J = 7,3 Hz, 2H, CHph), 7,30 - 7,20 (m, 3H, CHph), 6, 80 — 6, 72 (m, 1H, CHpyr), 6,47 (s, 2H, NH2), 5,06 (s, 2H, CH2). RMN de13C (101 MHz, DMSO-d6) δ 155, 8, 154,4, 154,3, 147, 6, 137, 6, 137,4, 128,4 (2C), 127,2, 127,2 (2C), 114,9, 109, 5, 48,7. LCMS: t r = 2,71; 6,42 min. [M+H]+= 267,13. HPLC (À254 ): pureza de 98,8%; HPLC (À28o): pureza de 95,6%; tr: 5,55 min (método 1). MCK254 : 1-benzil-N3- (piridin-3-il) -1H-1,2,4-triazol3,5-diamina I H JI <^NH2 Np / VN H

[00104] N3-(pyridin-3-yl)-1H-1,2,4-triazol-3,5diamine (50 mg, 0.284 mmol) was dissolved in degassed DMF, then Cs2CO3 (92 mg, 0.284 mmol) was added. Benzyl chloride (0.03 mL, 0.284 mmol) was added and the reaction mixture was stirred at room temperature overnight. Cs2CO3 was filtered and DMF was evaporated under reduced pressure. Purification by silica gel flash chromatography (CH2Cl2 / MeOH, 10 / 0 and then 9 / 1) yielded the title compound as a brown solid (12.5 mg, 0.047 mmol, 17% yield). Brown solid, 12.5 mg, 0.047 mmol, 17% yield. Rf (CH2Cl2 / MeOH, 9 / 1, v / v) = 0.12. PF = 140°C. 1H NMR (400 MHz, DMSO-d6) δ Petition 870250080754, dated 09 / 09 / 2025, page 77 / 186 57 / 124 8.97 (s, 1H, NH), 8.64 (d, J = 2.3 Hz, 1H, CHAr), 7.93 (dd, J = 12.0, 3.5 Hz, 2H, CHAr), 7.35 (t, J = 7.3 Hz, 2H, CHAr), 7.30 — 7.24 (m, 3H, CHAr), 7.18 (dd, J = 8.3, 4.6 Hz, 1H), CHAr, 6.37 (s, 2H, NH2), 5.04 (s, 2H, CH2). RMN de13C (101 MHz, DMSO-d 6) δ 156, 5, 154.1, 139, 2, 138.7, 137.7, 137.3, 128.2 (2C), 127.1 (2C), 127.0, 123.1, 121.3, 48.5. LCMS: tr = 2,69; 4.92 min. [M+H]+= 267,20. HPLC (À254): pure 97.6%; HPLC (À28o): pure 97.1%; tr: 5.21 min (método 1). MCK257: 1-(2,6-difluorobenzil)-N5-fenil-1H-1,2,4triazol-3,5-diamina

[00105] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (500 mg, 2.86 mmol) was dissolved in degassed DMF, and then Cs2CO3 (930 mg, 2.86 mmol) was added. 2,6-Difluorobenzyl chloride (463 mg, 2.86 mmol) was added and the reaction mixture was stirred at room temperature overnight. Cs2CO3 was filtered and DMF was evaporated under reduced pressure. Purification by silica gel flash chromatography (CH2Cl2 / THF, 10 / 0 and then 6 / 4) yielded the title compound as a white solid (46.9 mg, 0.155 mmol, 5% yield) along with the N3benzylated regioisomer (257 mg, 0.851 mmol, 30% yield). White solid, 46.9 mg, 0.155 mmol, 5% yield. Rf Petition 870250080754, dated 09 / 09 / 2025, page 78 / 186 58 / 124 (CH2Cl2 / THF,1 / 1, v / v) = 0,65. P.F. = 240-242 °C. RMN de 1H (400 MHz, DMSO-d6) δ 8,86 (s, 1H, NH), 7,59 (d, J = 7,7 Hz, 2H, CHAr), 7,42 (ddd, J = 15,0, 8,4, 6,7 Hz, 1H, CHAr), 7,29 - 7,22 (m, 2H, CHAr), 7,09 (t, J = 8,0 Hz, 2H, CHAr), 6,92 6,84 (m, 1H, CHAr), 5,18 (s, 2H, NH2), 5,11 (s, 2H, CH2). RMN de13C (101 MHz, DMSO-d6) δ 160,9 (dd, J = 248,3, 8, 0 Hz, 2C), 160,7, 150,0, 141,1, 130,48 (t, J = 10,3 Hz), 128,6 (2C), 120,4, 116,8 (2C), 112,64 (t, J = 19,1 Hz), 111,6 (dd, J = 18,8, 6,2 Hz, 2C), 37,21 (t, J = 3,4 Hz). RMN de19F (376 MHz, DMSO-d6) δ -114,99 (2F). LCMS: tr = 9,77 min. [M+H]+= 302,07. HPLC (À254 ): pureza de 95,3%; HPLC (À2so): pureza de 97,5%; t r: 7,68 min (método 1). MCK259: 1-(2,6-difluorobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina

[00106] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 2,6-difluorobenzyl chloride (230 mg, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at room temperature for 1 h 30. Petition 870250080754, dated 09 / 09 / 2025, page 79 / 186 59 / 124 Water was added to the reaction mixture and it was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the title compound as a white solid (87.8 mg, 0.291 mmol, 20% yield). White solid, 87.8 mg, 0.291 mmol, 20% yield. Rf (CH2Cl2 / MeOH: 9 / 1, v / v) = 0.56. MP > 260 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H, NH), 8.16 — 8.08 (m, 1H, CHAr), 7.73 (d, J = 8.4 Hz, 1H, CHAr), 7.57 (ddd, J = 8.8, 7.2, 2.0 Hz, 1H, CHAr), 7.43 (ddd, J = 15.0, 8.5, 6.6 Hz, 1H, CHAr), 7.12 (t, J = 7.9 Hz, 2H, CHAr), 6.74 (ddd, J = 7.2, 4.9, 1.0 Hz, 1H, CHAr), 6.56 (s, 2H, NH2), 5.10 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d6) δ 160.9 (dd, J = 248.9, 7.9 Hz, 2C), 155.7, 154.2, 154.2, 147.5, 137.5, 130.5 (t, J = 10.4 Hz), 114.8, 112.3 (t, J = 19.3 Hz), 111.6 (dd, J = 18.8, 6.1 Hz, 2C), 109.3, 37.44 - 37.1 (m).de19F NMR (376 MHz, DMSO-d6) δ-114.67(2F). LCMS: tr = 2.48; 3.80 min. [M+H]+= 303. 07. HPLC (À254 ): purity of 99.8%; HPLC (À28o): purity of 95.3%; tr: 5.53 min (method 1). Petition 870250080754, 09 / 09 / 2025, p. 80 / 1 60 / 1 MCK260: 1-(3-methoxybenzyl)- N5-phenyl-1H-1,2,4-triazol3,5-diamine

[00107] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.43 mmol) was added. 3-Methoxybenzyl chloride (0.22 mL, 1.43 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 4 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2CU / THF, 10 / 0 and then 40 / 60) yielded the title compound as a white solid (3 mg, 0.0102 mmol, yield 0.7%) along with the N3-benzylated regioisomer. White solid, 3 mg, 0.0102 mmol, yield 0.7%. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.74. MP = 130-132 °C.RMN de 1H (400 MHz, DMSO-d6) δ 8.78 (s, 1H, NH), 7.58 (d, J = 7.7 Hz, 2H, CHAr), 7.24 (t, J = 7.6 Hz, 3H, CHAr), 6.87 (t, J = 7.3 Hz, 1H, CHAr), 6.83 (dd, J = 8.2, 1.8 Hz, 1H, CHAr), 6.77. Petition: 870250080754, on September 9, 2025, page. 81 / 186 61 / 124 6.71 (m, 2H, CHAr), 5.11 (s, 2H, NH2), 5.09 (s, 2H, CH2), 3.70 (s, 3H, OCH3). RMN de13C (101 MHz, DMSO-d6) δ 160, 6, 159, 2, 150,2, 141, 1, 139, 1, 129, 5, 128, 6 (2C), 120,4, 119,2, 116,8 (2C), 113,0, 112.2, 55.0, 48.6. LCMS: tr = 9,82 min. [M+H]+= 296, 07. HPLC (À254): pure 90,7%; HPLC (À28o): pure 92.4%; tr: 7.75 minutes (metre 2). MCK261: 1-(3-metoxibenzil)-N3-fenil-1H-1,2,4-triazol3,5-diamina

[00108] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.43 mmol) was added. 3-Methoxybenzyl chloride (0.22 mL, 1.43 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 4 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / THF, 10 / 0 and then 40 / 60) yielded the title compound as a white solid (3 mg, 0.114 mmol, yield Petition 870250080754, dated 09 / 09 / 2025, page 82 / 186 62 / 124 de 8%) juntamente com o regioisômero N5-benzilado. Sólido branco, 33,7 mg, 0,114 mmol, rendimento de 8%. Rf (CH2Cl2 / THF,1 / 1, v / v) = 0.69. PF = 106-108 °C. RMN de 1H (400 MHz, DMSO-d6) δ 8, 69 — 8, 64 (m, 1H, NH), 7.46 (d, d = 7.7 Hz, 2H, CHAr), 7.25 (td, J = 7.5, 1.3 Hz, 1H, CHAr), 7.14 (t, J = 7.9 Hz, 2H, CHAr), 6, 86 — 6, 78 (m, 3H, CHAr), 6,70 (t, J = 7,3 Hz, 1H, CHAr), 6,27 (s, 2H, NH2), 5, 03 — 4, 94 (m, 2H, CH2), 3,72 (s, 3H, CH3). RMN de13C (101 MHz, DMSO-d6) δ 159.2, 157.1, 154.1, 142.3, 139.1, 129.4, 128.4 (2C), 119.4, 118.3, 115.5 (2C), 113.2, 112.3, 54,9, 48,5. LCMS: tr = 9,71 min. [M+H]+ = 296, 00. HPLC (À254): purity of 96,7%; tr: 8,18 min (método 2). MCK262: 1-(4-isopropylbenzil)-N5-fenil-1H-1,2,4triazol-3,5-diamina H

[00109] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (160 mg, 1.43 mmol) was added. 4-Isopropylbenzyl chloride (0.22 mL, 1.43 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. Water was added to Petition 870250080754, dated 09 / 09 / 2025, page 83 / 186 63 / 124 reaction mixture and solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as a white solid (51.8 mg, 0.169 mmol, 12% yield) along with the N3-benzylated regioisomer. White solid, 51.8 mg, 0.169 mmol, 12% yield). Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.81. MP = 146 °C. 1H NMR (400 MHz, DMSO-d 6) δ 8.78 (s, 1H, NH), 7.59 (d, J = 7.7 Hz, 2H, CHAr), 7.27 - 7.21 (m, 2H, CHAr), 7.19 (d, J = 8.1 Hz, 2H, CHAr), 7.11 (d, J = 8.1 Hz, 2H, CHAr), 6.87 (t, J = 7.3 Hz, 1H, CHAr), 5.09 (s, 2H, NH2), 5.07 (s, 2H, CH2), 2.84 (p, J = 6.9 Hz, 1H, CH), 1.16 (d, J = 6.9 Hz, 6H, CH3). 13C NMR (101 MHz, DMSO-d6) δ 160.6, 150.0, 147.4, 141.1, 134.9, 128.6 (2C), 127.2 (2C), 126.2 (2C), 120.4, 116.8 (2C), 48.4, 33.1, 23.8 (2C). LCMS: tr = 11.15 min. [M+H]+= 308.07. HPLC (À254): purity 91.1%; tr: 9.47 min (method 2). MCK263: 1-(4-isopropylbenzyl)-N3-phenyl-1H-1,2,4triazol-3,5-diamine

[00110] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in anhydrous DMF (1 mL), in Petition 870250080754, dated 09 / 09 / 2025, page 84 / 186 64 / 124 followed by potassium tert-butoxide (160 mg, 1.43 mmol) was added. 4-Isopropylbenzyl chloride (0.22 mL, 1.43 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. Water was added to the reaction mixture and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as a white solid (122 mg, 0.397 mmol, 28% yield) along with the N5-benzylated regioisomer. White solid, 122 mg, 0.397 mmol, 28% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.79. PF = 140-142°C. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H, NH), 7.47 (d, d = 7.8 Hz, 2H, CHAr), 7.17 (dq, J = 15.6, 8.2 Hz, 6H, CHAr), 6.70 (t, J = 7.3 Hz, 1H, CHAr), 6.27 (s, 2H, NH2), 4.98 (s, 2H, CH2), 2.84 (hept, J = 6.9 Hz, 1H, CH), 1.16 (s, 6H, CH3).13C NMR (101 MHz, DMSO-d6) δ 157.0, 154.0, 147.3, 142.3, 135, 0, 128.4 (2C), 127.3 (2C), 126.2 (2C), 118.3, 115.5 (2C), 48.4, 33.1, 23.9 (2C). LCMS: tr = 11.15 min. [M+H]+= 308.07. HPLC (À254): purity 97.3%; tr: 9.82 min (method 2). Petition 870250080754, dated 09 / 09 / 2025, page 85 / 186 65 / 124 MCK264: 1-(3-bromobenzyl)-N3-phenyl-1H-1,2,4-triazole 3,5-diamine Br H

[00111] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (150 mg, 0.857 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (96 mg, 0.857 mmol) was added. 3-Bromobenzyl bromide (225 mg, 0.857 mmol), dissolved in anhydrous CH2CU (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for a further 1 h. Water was added to the reaction mixture and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as a purple solid (89 mg, 0.259 mmol, 30% yield) along with the N5-benzylated regioisomer. Purple solid, 89 mg, 0.259 mmol, 30% yield. Rf (CH2Cl2 / THF,1 / 1, v / v) = 0.56. MP = 108-110 °C.NMR of 1H (400 MHz, DMSO-d6) δ 8.69 (s, 1H, NH), 7.46 (q, J = 6.2, 5.5 Hz, 4H, CHAr), 7.32 (t, J = 7.8 Hz, 1H, CHAr), d CHAr), 7.14 (t, J = 7.7 Hz, 2H, CHAr), 6.71 (t, J = 7.3 Hz, 1H, CHAr), 6.34 (s, 2H, NH2), 5.04 (s, 2H, CH2). de13C NMR (101 MHz, DMSO-d 6) δ 157.2, 154.2, 142.2, 140.3, 130, 6, 130.0,. Petition 870250080754, of 09 / 09 / 2025, p. 86 / 186 66 / 124 128.4 (2C), 126.3, 121.6, 118.4, 115.5 (2C), 48.0. LCMS: tr = 10.75 min. [M+H]+= 244.00; 246, 00. HPLC (À254 ): purity of 99.4%; HPLC (À2so): 96.7% purity; tr: 8.85 min (method 2). MCK268: 1-(2,6-dichlorobenzyl)- N3-phenyl-1H-1,2,4 triazole-3,5-diamine

[00112] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.43 mmol) was added. 2,6-Dichlorobenzyl chloride (276 mg, 1.43 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 3 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / THF, 10 / 0 and then 50 / 50) yielded the title compound as a brown solid (93.3 mg, 0.028 mmol, 20% yield). Brown solid, 93.3 mg, 0.028 mmol, 20% yield. Rf (CH2Cl2 / THF, 8 / 2, v / v) = 0.57. MP = 206-208 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H, NH), 7.51 (d, J = 8.0 Petition 870250080754, dated 09 / 09 / 2025, page 87 / 186 67 / 124 Hz, 2H, CHAr), 7,43 — 7,33 (m, 3H, CHAr), 7,07 (t, J = 7,9 Hz, 2H, CHAr), 6,66 (t, J = 7,3 Hz, 1H, CHAr), 6,37 (s, 2H, NH2), 5,16 (s, 2H, CH2). RMN de13C (101 MHz, DMSO-d6) δ 157,1, 154,0, 142,4, 135,6 (2C), 131,7, 130,4, 128,5 (2C), 128,2 (2C), 118,2, 115,4 (2C), 44,6. LCMS: tr = 10,31 min. [M+H]+= 334,00. HPLC (À254 ): pureza de 100%; HPLC (À28o): pureza de 96,9%; t r: 8,78 min (método 2). MCK269: 1-(2-metilbenzil)- N3-(piridin-2-il)-1 H -1,2,4triazol-3,5-diamina

[00113] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 2-Methylbenzyl chloride (0.19 mL, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at room temperature for 3 h. Water was added to the reaction mixture and it was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the compound of Petition 870250080754, dated 09 / 09 / 2025, page 88 / 186 68 / 124 titrated as a yellow solid (210.9 mg, 0.753 mmol, yield 53%). Yellow solid, 210.9 mg, 0.753 mmol, yield 53%. Rf(CH2Cl2 / MeOH:95 / 5, v / v) = 0.44. PF = 256-258°C. 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H, NH), 8.17 (d, J = 3.8 Hz, 1H, CHAr), 7.84 (d, J = 8.5 Hz, 1H, CHAr), 7.71 - 7.55 (m, 1H, CHAr), 7.16 (dq, J = 12.8, 7.0 Hz, 3H, CHAr), 6.90 — 6.75 (m, 2H, CHAr), 6.56 (s, 2H, NH2), 5.07 (s, 2H, CH2), 2.35 (s, 3H, CH3). de13C NMR (101 MHz, DMSOd6) δ 155, 6, 154.5, 154.2, 147, 6, 137.7, 135.5, 135.3, 129, 9, 127.0; 109, 5, 47, 0, 18, 6. LCMS: tr = 2.53; 3.64 min. [M+H]+= HPLC (λ254 ): purity of 99.9%; HPLC (À28º): purity of 97.4%; tr: 5.85 min (method 1). MCK271: 1-(4-methylbenzyl)- N3-phenyl-1H-1,2,4-triazole 3,5-diamine

[00114] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.43 mmol) was added. 4-Methylbenzyl chloride (0.19 mL, 1.43 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 30 min. Petition 870250080754, dated 09 / 09 / 2025, page 89 / 186 69 / 124 and then at room temperature for 2 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / THF, 10 / 0 and then 50 / 50) yielded the title compound as a purple solid (28 mg, 0.100 mmol, 7% yield). Purple solid, 28 mg, 0.100 mmol, 7% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.56. MP = 116-118 °C. 1H NMR (400MHz, DMSO-d6) δ 8.70 (s, 1H, NH), 7.45 (d, J = 7.7Hz, 2H, CHAr), 7.14 (s, 6H, CHAr), 6.72 (t, J = 7.3Hz, 1H, CHAr), 6.37 (s, 2H, NH2), 4.97 (s, 2H, CH2), 2.26 (s, 3H, CH3). 13C NMR (101 MHz, DMSO-d6) δ 156.3, 153.5, 142.1, 136.3, 134.4, 128.8 (2C), 128.4 (2C), 127.2 (2C), 118.5, 115.5 (2C), 48.5, 20.6. LCMS: tr = 9.82 min. [M+H]+= 280.00. HPLC (À254): purity 99.7%; HPLC (À28o): purity 95.0%; tr: 8.61 min (method 2). MCK272: 1-(4-chlorobenzyl)-N3-phenyl-1H-1,2,4-triazol3,5-diamine

[00115] N3-phenyl-1 H -1,2,4-triazol-3,5-diamine (250 Petition 870250080754, dated 09 / 09 / 2025, page 90 / 186 A compound (70 / 124 mg, 1.43 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.43 mmol) was added. 4-Chlorobenzyl chloride (230 mg, 1.43 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 2 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / THF, 10 / 0 and then 40 / 60) yielded the title compound as a purple solid (76.9 mg, 0.257 mmol, 18% yield).

[00116] Red solid, 76.9 mg, 0.257 mmol, 18% yield. Rf (CH2Cl2 / THF,1 / 1, v / v) = 0.47. PF = 156-158 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H, NH), 7.43 (dd, J = 14.6, 8.1 Hz, 4H, CHAr), 7.26 (d, J = 8.1 Hz, 2H, CHAr), 7.14 (t, J = 7.8 Hz, 2H, CHAr), 6.71 (t, J = 7.3 Hz, 1H, CHAr), 6.34 (s, 2H, NH2), 5.03 (s, 2H, CH2). NMR de13C (101 MHz, DMSO-d 6) δ 157.0, 154.0, 142.2, 136.5, 131.8, 129.1 (2C), 128.4 (2C), 128.3 (2C), 118.4, 115.5 (2C), 48.0. LCMS: tr = 10.63 min. [M+H]+= 30 0.07. HPLC (À254 ): 99.7% pure; HPLC (À28o): 98.5% pure; tr: 8.98 min (method 2). Petition 870250080754, 09 / 09 / 2025, pág. 91 / 186 71 / 124 MCK273: N3-phenyl-1-(3-(trifluoromethyl)benzyl)-1H1,2,4-triazol-3,5-diamine H

[00117] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (160 mg, 1.43 mmol) was added. 3-(trifluoromethyl)benzyl chloride (0.22 mL, 1.43 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. Water was added to the reaction mixture and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as a yellow solid (197.1 mg, 0.592 mmol, 41% yield) along with the N5-benzylated regioisomer. Yellow solid, 197.1 mg, 0.592 mmol, 41% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.71. MP = 118-120 °C.RMN de 1H (400 MHz, DMSO-d6) δ 8,69 (s, 1H, NH), 7, 68 - 7,57 (m, 3H, CHAr), 7,54 (d, J = 7,6 Hz, 1H, CHAr), 7,45 (d, J = 7,8 Hz, 2H, CHAr), 7,14 (t, J = 7,9 Hz, 2H, CHAr), 6,71 (t, J = 7,3 Hz, 1H, CHAr), 6,35 (s, 2H, NH2), 5,13 (s, 2H, CH2). RMN de13C (101 MHz, DMSO-d6) δ 157,3,. Petição 870250080754, de 09 / 09 / 2025, pág. 92 / 186 72 / 124 154,2, 142,2, 139,0, 131,4, 129,5 (2C), 129,2, 128,9, 128,4 (2C), 124,0-123, 8 (m), 118,5, 115,5 (2C), 48,1. RMN de19F (376 MHz, DMSO-d6) δ -61,11 (3F). LCMS: tr = 10,58 min. [M+H]+= 334,07. HPLC (À254 ): pureza de 98,1%; t r: 9,59 min (método 2). MCK274: 1-(3,5-difluorobenzil)- N3-fenil-1 H -1,2,4triazol-3,5-diamina

[00118] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.43 mmol) was added. 3,5-Difluorobenzyl chloride (230 mg, 1.43 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 3 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / THF, 10 / 0 and then 50 / 50) yielded the title compound as a purple solid (20.1 mg, 0.066 mmol, 5% yield). Petition 870250080754, dated 09 / 09 / 2025, page 93 / 186 73 / 124

[00119] Sólido roxo, 20,1 mg, 0,066 mmol, rendimento de 5%. Rf (CH2Cl2 / THF,1 / 1, v / v) = 0,61. P.F. = 146-148 °C. RMN de 1H (400 MHz, DMSO-d6) δ 8,82 (s, 1H, NH) , 7,46 (d, J = 8,0 Hz, 2H, CHAr), 7,16 (t, J = 7,9 Hz, 3H, CHAr), 6,94 (d, J = 6,5 Hz, 2H, CHAr), 6,74 (t, J = 7,3 Hz, 1H, CHAr), 6,54 (s, 2H, NH2), 5,09 (s, 2H, CH2). RMN de13C (101 MHz, DMSOd 6) δ 162,36 (dd, J = 246, 4, 13, 1 Hz, 2C), 156, 4, 153, 8, 142,0, 141,96 (t, J = 4,4 Hz), 128,5 (2C), 118,8, 115,7 (2C), 110,3 (dd, J = 18,7, 6,9 Hz, 2C), 102,79 (t, J = 25,7 Hz), 47,9. RMN de19F (376 MHz, DMSO-d 6) δ -109, 66 (2F). LCMS: t r = 10,13 min. [M+H]+= 302,07. HPLC (À254 ): pureza de 98,4%; t r: 8,88 min (método 2). MCK275: 1-(3-nitrobenzil))- N3-fenil-1H-1,2,4-triazol3,5-diamina H

[00120] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.43 mmol) was added. 3-Nitrobenzyl bromide (307 mg, 1.43 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 3 h. Water was Petition 870250080754, dated 09 / 09 / 2025, page 94 / 186 74 / 124 added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / THF, 10 / 0 and then 50 / 50) yielded the title compound as a yellow solid (37.3 mg, 0.120 mmol, 8% yield). Yellow solid, 37.3 mg, 0.120 mmol, 8% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.51. MP = 180-182 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H, NH), 8.24 - 8.12 (m, 2H, CHAr), 7.76 (d, J = 7.7 Hz, 1H, CHAr), 7.69 (t, J = 7.8 Hz, 1H, CHAr), 7.43 (d, J = 7.7 Hz, 2H, CHAr), 7.26 - 7.15 (m, 2H, CHAr), 6.82 (t, J = 7.3 Hz, 1H, CHAr), 5.25 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d6) δ 149.4, 148.9, 147.8, 139.7, 137.8, 134.3, 130.2, 128.9 (2C), 122.8, 122.5, 120.9, 116.6 (2C), 48.6. LCMS: tr = 9.77 min. [M+H]+= 311.07. HPLC (À254): purity 98.0%; HPLC (À28o): purity 95.3%; tr: 8.61 min (method 2). MCK276: 1-(3-bromobenzyl)- N3-(pyridin-2-yl)-1H -1,2,4triazol-3,5-diamine Br

[00121] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5 diamine (250 mg, 1.42 mmol) was dissolved in DMF Petition 870250080754, dated 09 / 09 / 2025, page 95 / 186 75 / 124 degassed (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 3-Bromobenzyl bromide (352 mg, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture and it was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the title compound as a yellow solid (121.9 mg, 0.352 mmol, 25% yield). Yellow solid, 121.9 mg, 0.352 mmol, 25% yield. Rf (CH2Cl2 / MeOH:9 / 1, v / v) = 0.50. PF = 232-234 °C.RMN de 1H (400 MHz, DMSO-d6) δ 9,97 (s, 1H, NH), 8,18 (ddd, J = 4,9, 2,0, 0,9 Hz, 1H, CHAr), 7,84 (dt, J = 8,6, 1,0 Hz, 1H, CHAr), 7,63 (ddd, J = 8,8, 7,2, 2,0 Hz, 1H, CHAr), 7,54 - 7,43 (m, 2H, CHAr), 7,33 (t, J = 7,8 Hz, 1H, CHAr), 7,25 (dt, J = 7,8, 1,3 Hz, 1H, CHAr), 6,79 (ddd, J = 7,2, 4,9, 1,1 Hz, 1H, CHAr), 6,62 (s, 2H, NH2), 5,10 (s, 2H, CH2). RMN de13C (101 MHz, DMSO-d6) δ 155, 8, 154,4, 154,1, 147,6, 140,1, 137,8, 130,7, 130,1, 129,9, 126,3, 121,6, 115,0, 109,5, 48,0. LCMS: tr = 7,40 min. [M+H]+= 345,07; 347,07. HPLC (À254 ): pureza de 99,4%; t r: 6,55 min (método 1). Petição 870250080754, de 09 / 09 / 2025, pág. 96 / 186 76 / 124 MCK278: 1-(2,6-diclorobenzil)- N3-(piridin-2-il)-1H 1,2,4-triazol-3,5-diamina

[00122] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 2,6-dichlorobenzyl chloride (274 mg, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at room temperature for 3 h. Water was added to the reaction mixture and it was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the title compound as a white solid (30.9 mg, 0.093 mmol, 7% yield). White solid, 30.9 mg, 0.093 mmol, 7% yield. Rf (CH2Cl2 / MeOH: 9 / 1, v / v) = 0.42. MP > 60 °C.RMN de 1H (400 MHz, DMSO-d6) δ 9,57 (s, 1H, NH), 8,11 (dd, J = 5,0, 1,8 Hz, 1H, CHAr), 7,72 - 7, 66 (m, 1H, CHAr), 7,52 (dq, J = 5,7, 2,9, 1,9 Hz, 3H, CHAr), 7,39 (dd, J = 8,7, 7,4 Hz, 1H, CHAr), 6,72 (ddd, J = 7,2, 4,8, 1,0 Hz, 1H, CHAr), 6,57 (s,. Petição 870250080754, de 09 / 09 / 2025, pág. 97 / 186 77 / 124 2H, NH2), 5,20 (s, 2H, CH2). RMN de13C (101 MHz, DMSO-d6) δ 155,6, 154,2, 154,2, 147,5, 137,4, 135,6 (2C), 131,5, 130,5, 128,6 (2C), 114, 8, 109, 3, 44,7. LCMS: t r = 2,57; 2,08min. [M+H]+= 335, 00. HPLC (À254 ): pureza de 97,2%; t r: 6,26 min (método 1). MCK279: 1-(4-metilbenzil)-N3- (piridin-2-il)-1H-1,2,4triazol-3,5-diamina

[00123] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 4-methylbenzyl chloride (0.19 mL, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture and it was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the title compound as a yellow solid (99.9 mg, 0.357 mmol, Petition 870250080754, dated 09 / 09 / 2025, page 98 / 186 78 / 124 yield of 25%). Yellow solid, 99.9 mg, 0.357 mmol, yield 25%. Rf(CH2Cl2 / MeOH:9 / 1, v / v) = 0.52. PF = 210-212°C. NMR of 1H (400 MHz, DMSO-d6) δ 10.03 (s, 1H, NH), 8.23 ​​— 8.13 (m, 1H, CHAr), 7.85 (d, J = 8.5 Hz, 1H, CHAr), 7.63 (td, J = 8.8, 8.1, 1.9 Hz, 1H, CHAr), 7.15 (s, 4H, CHAr), 6.78 (ddd, J = 7.2, 4.9, 1.1 Hz, 1H, CHAr), 6.56 (s, 2H, NH2), 5.03 (s, 2H, CH2), 2.27 (s, 3H, CH3). de13C NMR (101 MHz, DMSO-d6) δ 155.5, 154.2, 154.2, 147.5, 137.8, 136, 3, 134.3, 128.9 (2C), 127.2 (2C), 114.9, 109.5, 48.5. 20.6. LCMS: tr = 2.45; 3.95min. [M+H]+= HPLC (À254 ): purity of 99.5%; HPLC (À28c): purity of 97.1%; tr: 6.13 min (method 1). MCK280: 1-(4-chlorobenzyl)- N3-(pyridin-2-yl)-1H-1,2,4triazol-3,5-diamine

[00124] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 4-Chlorobenzyl chloride (229 mg, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at room temperature for 2 h. Water Petition 870250080754, dated 09 / 09 / 2025, page 99 / 186 79 / 124 was added to the reaction mixture and extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the title compound as a yellow solid (70.9 mg, 0.236 mmol, 17% yield). Yellow solid, 70.9 mg, 0.236 mmol, 17% yield. Rf (CH2Cl2 / MeOH, 9 / 1, v / v) = 0.47. MP = 230-232 °C. 1H NMR (400 MHz, DMSO-d) 2.0 Hz, 1H, CHAr), 7.49 — 7.36 (m, 2H, CHAr), 7.26 (d, J = 8.5 Hz, 2H, CHAr), 6.77 (ddd, J = 7.2, 4.9, 1.0 Hz, 1H, CHAr), 6.54 (s, 2H, NH2), 5.07 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d6) δ 155.8, 154.4, 154.1, 147.6, 137.7, 136.4, 131.8, 129.1 (2C), 128.4 (2C), 114.9, 109.5, 48.0. LCMS: tr = 2.50; 3.49 min. [M+H]+= 301.13.HPLC (À254 ): purity of 98.4%; tr: 6.47 min (method 1). MCK281: 4-((5-amino-3-(pyridin-2-ylamino)-1H-1,2,4triazol-1-yl)methyl)benzonitrile [0012 5] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5Application 870250080754, dated 09 / 09 / 2025, p. 100 / 1 80 / 124 diamine (250 mg, 1.42 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 4-(Chloromethyl)benzonitrile (220 mg, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture and it was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the title compound as a yellow solid (49.8 mg, 0.171 mmol, 12% yield). Yellow solid, 49.8 mg, 0.171 mmol, 12% yield. Rf (CH2Cl2 / MeOH:9 / 1, v / v) = 0.47. MP = 242 °C.RMN de 1H (400 MHz, DMSO-d6) δ 10,07 (s, 1H, NH), 8,20 — 8,15 (m, 1H, CHAr), 7,84 (d, J = 8,2 Hz, 3H, CHAr), 7,63 (ddd, J = 8,8, 7,2, 2,0 Hz, 1H, CHAr), 7,40 (d, J = 8,3 Hz, 2H, CHAr), 6,79 (ddd, J = 7,2, 4,9, 1,0 Hz, 1H, CHAr), 6,65 (s, 2H, NH2), 5,21 (s, 2H, CH2). RMN de13C (101 MHz, DMSO-d 6) δ 155, 9, 154, 6, 154,1, 147, 6, 143, 1, 137,8, 132,4 (2C), 127,9 (2C), 118,7, 115,0, 110,0, 109,5, 48,4. LCMS: tr = 2,68; 4,46 min. [M+H]+ = 292,07. HPLC (À254 ): pureza de 99,8%; t r: 5,26 min (método 1). Petição 870250080754, de 09 / 09 / 2025, pág. 101 / 186 81 / 124 MCK282: N3-(piridin-2-il)-1-(3(trifluorometil)benzil)-1H-1,2,4-triazol-3,5-diamina

[00126] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 3-(trifluoromethyl)benzyl chloride (0.22 mL, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture and it was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the title compound as a white solid (194.7 mg, 0.583 mmol, 41% yield). White solid, 194.7 mg, 0.583 mmol, 41% yield. Rf (CH2Cl2 / MeOH: 9 / 1, v / v) = 0.42. MP = 248-250 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H, NH), 8.23 ​​— 8.12 (m, 1H, CHAR), 7.84 (d, J = 8.5 Hz, 1H, CHAR). 7.69 — 7.58 (m, 4H, CHAr), 7.54 (d, J = 7.8 Hz, 1H, CHAr), 6.78 (ddd, J = 7.3, 4.9, 1.0 Hz, 1H, CHAr), 6.62 (s, 2H, Petition 870250080754, of 09 / 09 / 2025, p. 102 / 186 82 / 124 NH2), 5.19 (s, 2H, CH2). NMR de13C (101 MHz, DMSO-d 6) δ 155.9, 154.5, 154.1, 147, 6, 138.8, 137.7, 131.4, 129, 6, 129, 1 (q, J = 3, 15), (q, 1, 24 Hz = 1 272.2 Hz), 124.1 (q, J = 3.8 Hz), 123.8 (q, J = 3.9 Hz), 115, 0, 109, 5, 48.2. de19F NMR (376 MHz, DMSO-d6) δ -61.12 (3F). LCMS: tr = 4.00 min. [M+H]+= 335, 07. HPLC (À254 ): purity 99.7%; HPLC (À28º): 99.3% purity; tr: 6.75 min (method 1). MCK283: 1-(3,5-difluorobenzyl)- N3-(pyridin-2-yl)-1H 1,2,4-triazole-3,5-diamine [0012 7] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 3,5-difluorobenzyl chloride (232 mg, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture and it was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel was performed. Petition 870250080754, dated 09 / 09 / 2025, page 103 / 186 83 / 124 (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the title compound as a yellow solid (124.8 mg, 0.413 mmol, 29% yield). Yellow solid, 124.8 mg, 0.413 mmol, 29% yield. Rf (CH2Cl2 / MeOH: 9 / 1, v / v) = 0.45. MP = 258 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H, NH), 8.25 — 8.15 (m, 1H, CHAr), 7.85 (d, J = 8.5 Hz, 1H, CHAr), 7.64 (ddd, J = 8.8, 7.2, 2.0 Hz, 1H, CHAr), 7.17 (tt, J = 9.4, 2.4 Hz, 1H, CHAr), 6.97 - 6.89 (m, 2H, CHAr), 6.80 (ddd, J = 7.2, 4.9, 1.0 Hz, 1H, CHAr), 6.66 (s, 2H, NH2), 5.13 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d6) δ 162.3 (dd, J = 246.4, 13.1 Hz, 2C), 155.9, 154.5, 154.1, 147.6, 141.9 (t, J = 9.0 Hz), 137.88, 115.07, 110.2 (d, J = 6.8, 18.7 Hz, 2C), 109.5, 102.8 (t, J = 25.7 Hz), 47.9. 19F NMR (376 MHz, DMSO-d6) δ -109.58 (2F). LCMS: tr = 2.66; 4.80 min. [M+H]+ = 303.13. HPLC (À254): purity 98.7%; tr: 6.03 min (method 1). MCK284: 1-(2,4-difluorobenzyl)-N3-(pyridin-2-yl)-1H 1,2,4-triazol-3,5-diamine

[00128] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide. Petition 870250080754, dated 09 / 09 / 2025, page 104 / 186 84 / 124 (159 mg, 1.42 mmol) was added at 0 °C. 2,4-difluorobenzyl chloride (232 mg, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture and it was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the title compound as a yellow solid (199.3 mg, 0.660 mmol, 46% yield). Yellow solid, 199.3 mg, 0.660 mmol, 46% yield. Rf (CH2Cl2 / MeOH: 9 / 1, v / v) = 0.40. PF > 60°C. 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H, NH), 8.20 — 8.12 (m, 1H, CHAr), 7.82 (d, J = 8.5 Hz, 1H, CHAr), 7.62 (ddd, J = 8.8, 7.2, 2.0 Hz, 1H, CHAr), 7.27 (ddd, J = 10.5, 9.3, 2.5 Hz, 1H, CHAr), 7.17 (td, J = 8.6, 6.6 Hz, 1H, CHAr), 7.08 (td, J = 8.6, 2.6 Hz, 1H, CHAr), 6.78 (ddd, J = 7.2.10). 4.9, 1.0 Hz, 1H, CHAr, 6.60 (s, 2H, NH2), 5.12 (s, 2H, CH2). NMR of13C (101 MHz, DMSO-d6) δ 161.9 (dd, J = 182.2, 12.2 Hz), 159.5 (dd, J = 184.6, 12.3 Hz), 155.9, 154.5, 154.1, 147.0, 137.7, 130.4 (dd, J = 9.9, 5.9 Hz), 120.66 (dd, J = 15.1, 3.7 Hz), 114.9, 111.5 (dd, J = 21.3, 3.6 Hz), 109.5, 103.9 (t, J = 25.7 Hz), 42.7 (d, J = 2.8 Hz). de19F NMR (376 MHz, DMSO-d6) δ-111.33, -113.74. LCMS: tr = 2.73; 6.94 min. [M+H]+ = 303, 13. HPLC (À254 ): purity of 97.1%; tr: 5.60 min Petition 870250080754, 09 / 09 / 2025, p. 105 / 1 85 / 124 (method 1). MCK288: 1-(4-nitrobenzyl))- N3-phenyl-1H-1,2,4-triazole3,5-diamine

[00129] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.43 mmol) was added. 4-Nitrobenzyl bromide (307 mg, 1.43 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 3 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / THF, 10 / 0 and then 50 / 50) and a second purification by flash chromatography on silica gel (CH2Cl2 / THF, iso 50 / 50) yielded the title compound as a yellow solid (21.1 mg, 0.068 mmol, 5% yield). Yellow solid, 21.1 mg, 0.068 mmol, 5% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.32. MP = 168-170 °C.RMN de 1H (400 MHz, DMSO-d6) δ 8,72 (s, 1H, NH), 8,24 (d, J = 8,8 Hz, 2H, CHAr), 7,50 — 7,39 (m,. Petição 870250080754, de 09 / 09 / 2025, pág. 106 / 186 86 / 124 4H, CHAr), 7,21 - 7,08 (m, 2H, CHAr), 6,71 (t, J = 7,3 Hz, 1H, CHAr), 6,37 (s, 2H, NH2), 5,19 (s, 2H, CH2). RMN de13C (101 MHz, DMSO-d6) δ 157,4, 154,4, 146, 7, 145,4, 142,2, 128,4 (2C), 128,2 (2C), 123,6 (2C), 118,5, 115,5 (2C), 48,1. LCMS: t r = 10,18 min. [M+H]+ = 311,13. HPLC (À254 ): pureza de 97,2%; t r: 8,41 min (método 2). MCK289: 1-(2-nitrobenzil)- N3-(piridin-2-il)-1H -1,2,4 triazol-3,5-diamina

[00130] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 2-Nitrobenzyl bromide (305 mg, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h, then at room temperature for 4 h. Water was added to the reaction mixture and it was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the title compound as a yellow solid (94.1 mg, 0.303 Petition 870250080754, dated 09 / 09 / 2025, page 107 / 186 87 / 124 mmol, rendimento de 21%). Sólido amarelo, 94,1 mg, 0,303 mmol, rendimento de 21%. Rf (CH2Cl2 / MeOH:9 / 1, v / v) = 0,22. P.F. = 262 °C. RMN de 1H (400 MHz, DMSO-d6) δ 9,76 (s, 1H, NH), 8,20 — 8,10 (m, 2H, CHAr), 7,84 (d, J = 8,5 Hz, 1H, CHAr), 7,74 (t, J = 7,2 Hz, 1H, CHAr), 7,59 (ddd, J = 14,3, 10,4, 4,5 Hz, 2H, CHAr), 6,98 (d, J = 7,6 Hz, 1H, CHAr), 6,84 — 6,73 (m, 1H, CHAr), 6,56 (s, 2H, NH2), 5,46 (s, 2H, CH2). RMN de13C (101 MHz, DMSO-d6) δ 156, 2, 154, 9, 154,1, 147, 6, 147,3, 137,6, 134,2, 133,2, 128,5, 128,1, 124,9, 115,0, 109, 6, 46, 7. LCMS: t r = 2,68; 6,32 min. [M+H]+= 312,13. HPLC (À254 ): pureza de 98,6%; t r: 5,23 min (método 1). MCK290: 1-(4-nitrobenzil)- N3-(piridin-2-il)-1H -1,2,4triazol-3,5-diamina

[00131] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 4-Nitrobenzyl bromide (305 mg, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h, then at room temperature for 4 h. Water was added to the reaction mixture and Petition 870250080754, dated 09 / 09 / 2025, page 108 / 186 88 / 124 was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the title compound as a yellow solid (107.3 mg, 0.345 mmol, 24% yield). Yellow solid, 107.3 mg, 0.345 mmol, 24% yield. Rf (CH2Cl2 / MeOH: 9 / 1, v / v) = 0.28. MP = 246 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H, NH), 8.28 — 8.22 (m, 2H, CHAr), 8.22 - 8.17 (m, 1H, CHAr), 7.85 (d, J = 8.5 Hz, 1H, CHAr), 7.64 (ddd, J = 8.8, 7.2, 2.0 Hz, 1H, CHAr), 7.48 (d, J = 8.7 Hz, 2H, CHAr), 6.80 (ddd, J = 7.2, 4.9, 1.0 Hz, 1H, CHAr), 6.72 (s, 2H, NH2), 5.27 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d6) δ 156, 0, 154, 6, 154.0, 147.6, 146.7, 145.1, 137.9, 128.2 (2C), 123.7 (2C), 115.0, 109.6, 48.2. LCMS: tr = 2.69; 6.36 min. [M+H]+= 312.13. HPLC (À254): purity 98.8%; tr: 5.43 min (method 1). MCK292: 1-(3-nitrobenzyl)- N3-(pyridin-2-yl)-1H -1,2,4triazol-3,5-diamine

[00132] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in DMF Petition 870250080754, dated 09 / 09 / 2025, page 109 / 186 89 / 124 degassed (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 3-Nitrobenzyl chloride (305 mg, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at room temperature for 3 h. Water was added to the reaction mixture and it was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the title compound as a yellow solid (89 mg, 0.286 mmol, 20% yield). Yellow solid, 89 mg, 0.286 mmol, 20% yield. Rf (CH2Cl2 / MeOH:9 / 1, v / v) = 0.32. PF = 266 °C.RMN de 1H (400 MHz, DMSO-d6) δ 9.92 (s, 1H, NH), 8.21 - 8.12 (m, 3H, CHAr), 7.85 (dt, J = 8.5, 1.0 Hz, 1H, CHAr), 7.73 - 7, 67 (m, 2H, CHAr), 7, 66 - 7, 60 (m, 1H, CHAr), 6,79 (ddd, J = 7,2, 4,9, 1,0 Hz, 1H, CHAr), 6,66 (s, 2H, NH2), 5,24 (s, 2H, CH2). RMN de13C (101 MHz, DMSO-d6) δ 156, 0, 154.5, 154.1, 147, 8, 147, 6, 139.6, 137.7, 134.0, 130.1, 122.3, 121.9, 115.0, 109.5, 48,0. LCMS: tr = 6,86 min. [M+H]+ = 312.07. HPLC (À254): pure 99.5%; HPLC (À28o): pure 99.1%; tr: 5.80 min (método 1). Petition: 870250080754, on September 9, 2025, page. 110 / 186 90 / 124 MCK295: 2-(5-amino-3-(piridin-2-ilamino)-1H-1,2,4triazol-1-il)-1-(3-nitrofenil)etan-1-ona

[00133] N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 2-Bromo-1-(3-nitrophenyl)ethan-1-one (344 mg, 1.42 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h, then at room temperature for 4 h. Water was added to the reaction mixture and it was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 50 / 50) yielded the title compound as a yellow solid (56.4 mg, 0.166 mmol, 12% yield). Yellow solid, 56.4 mg, 0.166 mmol, 12% yield. Rf (CH2Cl2 / MeOH: 9 / 1, v / v) = 0.30. MP = 240 °C.RMN de 1H (400 MHz, DMSO-d6) δ 10,22 (s, 1H, NH), 8,74 (t, J = 1,9 Hz, 1H, CHAr), 8,57 - 8,50 (m, 1H, CHAr), 8,47 (d, J = 7,8 Hz, 1H, CHAr), 8,19 - 8,13 (m, 1H,. Petição 870250080754, de 09 / 09 / 2025, pág. 111 / 186 91 / 124 CHAr), 7, 94 - 7, 83 (m, 2H, CHAr), 7,62 (ddd, J = 8,8, 7,1, 2,0 Hz, 1H, CHAr), 6,79 (ddd, J = 7,2, 4,9, 1,0 Hz, 1H, CHAr), 6,55 (s, 2H, NH2), 5,66 (s, 2H, CH2). RMN de13C (101 MHz, DMSO-d6) δ 192,0, 155,7, 155,5, 154,1, 148,0, 147,5, 137,8, 135,8, 134,2, 130,7, 127,9, 122,4, 114,9, 109,6, 53,1. LCMS: t r = 2,76; 6,66 min. [M+H]+ = 340,07. HPLC (À254 ): pureza de 96,1%; t r: 5,71 min (método 1). MCK297: 1-(2-nitrobenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina ^çN°2nA I H JI ANH2 H

[00134] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.43 mmol) was added. 2-Nitrobenzyl bromide (307 mg, 1.43 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 3 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0 and then 60 / 40) yielded the title compound as a Petition 870250080754, dated 09 / 09 / 2025, page 112 / 186 92 / 124 yellow solid (60.9 mg, 0.196 mmol, yield of 14%). Yellow solid, 60.9 mg, 0.196 mmol, yield 14%. Rf(CH2Cl2 / THF,1 / 1, v / v) = 0.57. PF = 78-80°C. NMR of 1H (400 MHz, DMSO-d6) δ 8.76 (s, 1H, NH), 8.14 (dd, J = 8.2, 1.3 Hz, 1H, CHAr), 7.73 (td, J = 7.6, 1.3 Hz, 1H, CHAr), 7.62 - 7.52 (m. 1H, CHAr), 7.47 (dd, J = 8.7, 1.2 Hz, 2H, CHAr), 7.14 (dd, J = 8.6, 7.2 Hz, 2H, CHAr), 6.99 (dd, J = 7.9, 1.3 Hz, 1H, CHAr), 6.72 (tt, J = 7.3, 1.2). Hz, 1H, CHar), 6.34(s,2H,NH2), 5.41(s,2H,CH2). NMR of13C (101 MHz, DMSO-d6) δ 157.5, 154.6, 147.3, 142.2, 134.2, 133.5, 128.5, 128.4 (2C); 46.6. LCMS: tr = 10.47 min. [M+H]+= HPLC (À282 ): purity of 97.2%; tr: 8.21 min (method 2). MCK298: N3-phenyl-1-(3,4,5-trimethoxybenzyl)-1H-1,2,4triazol-3,5-diamine

[00135] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.43 mmol) was added. 5-(chloromethyl)-1,2,3-trimethoxybenzene (309 mg, 1.43 mmol), dissolved in degassed DMF (5 mL), was Petition 870250080754, dated 09 / 09 / 2025, page 113 / 186 93 / 124 added dropwise and the reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 3 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0 and then 60 / 40) yielded the title compound as a white solid (103.5 mg, 0.292 mmol, 20% yield). White solid, 103.5 mg, 0.292 mmol, 20% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.48. MP = 168-170 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H, NH), 7.49 (dd, J = 8.6, 1.2 Hz, 2H, CHAr), 7.21 - 7.07 (m,2H, CHAr), 6.71 (tt, J = 7.3, 1.2 Hz, 1H, CHAr), 6.66 (s,2H, CHAr), 6.27 (s, 2H, NH2), 4.92 (s, 2H, CH2), 3.74 (s,6H, CH3), 3.63 (s, 3H, CH3). NMR of13C (101 MHz, DMSO-d6) δ 157.0, 153.9, 152.7(2C), 142.4, 136.7, 133.0, 128.4(2C), 118.4, 115.4(2C), 105.0(2C), 59.9. 55.7 (2C), LCMS: tr = 9.36 min. [M+H]+= 355, 95. HPLC (À254 ): purity of 99.7%; HPLC (À282 ): purity of 98.8%; tr: 7.44 min (method 2). MCK299: 2-(5-amino-3-(phenylamino)-1H-1,2,4-triazol-1yl)-1-phenylethan-1-one H Petition 870250080754, 09 / 09 / 2025, p. 114 / 1 94 / 1

[00136] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.43 mmol) was added. 2-Bromo-1-phenylethan-1-one (283 mg, 1.43 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 2 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0 and then 60 / 40) yielded the title compound as a white solid (139.2 mg, 0.475 mmol, 33% yield). White solid, 139.2 mg, 0.475 mmol, 33% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.50. MP = 170-172 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H, NH), 8.09 - 7.99 (m, 2H, CHAR), 7.70 (t, J = 7.4 Hz, 1H, CHAR), 7.59 (t, J = 7.7 Hz, 2H, CHAr), 7.46 (d, J = 7.7 Hz, 2H, CHAr), 7.13 (t, J = 7.9 Hz, 2H, CHAr), 6.70 (t, J = 7.3 Hz, 1H, CHAr), 6.16 (s, 2H, NH2), 5.45 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d6) δ 193.2, 157.0, 155.2, 142.3, 134.6, 133.7, 128.8 (2C), 128.3 (2C), 128.0 (2C), 118.3, 115.5 (2C), 52.6. LCMS: tr = 9.80 min. [M+H]+= 294.07. HPLC (À254): purity 97.6%; HPLC (À28o): purity 94.2%; tr: 7.73 min (method 2). Petition 870250080754, dated 09 / 09 / 2025, pp. 115 / 186 95 / 124 MCK300: 1-phenethyl-N5-phenyl-1H-1,2,4-triazol-3,5diamine

[00137] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.43 mmol) was added. (2-chloroethyl)benzene (0.19 mL, 1.43 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C, then potassium iodide (1.19 g, 7.14 mmol) was added at room temperature for 24 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 60 / 40) yielded the title compound as a white solid (12.7 mg, 0.046 mmol, 3% yield) along with the N3-benzylated regioisomer. White solid, 12.7 mg, 0.046 mmol, 3% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.57. MP = 158-160 °C.RMN de 1H (400 MHz, DMSO-d6) δ 8.48 (s, 1H, NH), 7.50 — 7.44 (m, 2H, CHAr), 7.31 — 7.14 (m, 7H, CHAr), 6.88 — 6.81 (m, 1H, CHAr), 5.11 (s, 2H, NH2), 4.12 - 4.04 (m,. Petition: 870250080754, on September 9, 2025, page. 116 / 186 96 / 124 2H, CH2), 3, 03 — 2, 94 (m, 2H, CH2). RMN de13C (101 MHz, DMSOd 6) δ 160.4, 149, 6, 141, 1, 138.4, 128.7 (2C), 128.4 (2C), 128.2 (2C), 126.2, 120.2, 116.9 (2C), 46.4, 34,8. LCMS: tr = 9,51 min. [M+H]+ = 280.07. HPLC (À254): purity of 94.2%; tr: 6.47 min (método 2). MCK301: 1-fenetil-N3-fenil-1H-1,2,4-triazol-3,5diamina

[00138] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in degassed DMF (10 mL), then potassium tert-butoxide (159 mg, 1.43 mmol) was added. (2-chloroethyl)benzene (0.19 mL, 1.43 mmol), dissolved in degassed DMF (5 mL), was added dropwise and the reaction mixture was stirred at 0 °C, then potassium iodide (1.19 g, 7.14 mmol) was added at room temperature for 24 h. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 60 / 40) yielded the title compound as a white solid (37.6 mg, 0.135 mmol, 9% yield) along with the Petition 870250080754, dated 09 / 09 / 2025, pp. 117 / 186 97 / 124 regioisômero N5-benzilado. Sólido branco, 37.6 mg, 0.135 mmol, rendimento de 9%. Rf (CH2Cl2 / THF,1 / 1, v / v) = 0.56. PF = 160-162 °C. RMN de 1H (400 MHz, DMSO-d6) δ 8.61 (s,1H, NH), 7.53 — 7.43 (m, 2H, CHAr), 7.28 (h, J = 5.7 Hz,4H, CHAr), 7.21 (td, J = 6.0, 2.5 Hz, 1H, CHAr), 7.16 (ddd,J = 8.5, 5.7, 2.1 Hz, 2H, CHAr), 6.77 - 6.65 (m, 1H, CHAr), 6.06 (s, 2H, NH2), 4.06 — 3.91 (m, 2H, CH2), 3.04 - 2.92 (m, 2H, CH2). RMN de13C (101 MHz, DMSO-d6) δ 156, 7, 153.5, 142.4, 138.5, 128.8 (2C), 128.4 (2C), 128.2 (2C), 126.2, 118.3, 115,5 (2C), 46, 4, 34, 6. LCMS: tr = 9,58 min. [M+H]+= 280.07. HPLC (À254): pure 97.3%; tr: 7,00 min (método 2). MCK338: N5-fenil-1-(3-(trifluorometil)benzil)-1H1,2,4-triazol-3,5-diamina

[00139] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (250 mg, 1.43 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (160 mg, 1.43 mmol) was added at 0 °C. 3-(trifluoromethyl)benzyl chloride (0.23 mL, 1.50 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. The reaction mixture was rapidly cooled with water (1 mL) and the Petition 870250080754, dated 09 / 09 / 2025, pp. 118 / 186 98 / 124 solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as a white solid (51.3 mg, 0.154 mmol, 11% yield) along with the N3-benzylated regioisomer. White solid, 51.3 mg, 0.154 mmol, 11% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.83. MP = 128-130 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H, NH), 7.68 — 7.60 (m, 2H, CHAr), 7.60 — 7.55 (m, 3H, CHAr), 7.49 (d, J = 7.6 Hz, 1H, CHAr), 7.24 (t, J = 7.9 Hz, 2H, CHAr), 6.88 (t, J = 7.3 Hz, 1H, CHAr), 5.23 (s, 2H, NH2), 5.17 (d, J = 9.4 Hz, 2H, CH2). 13C NMR (101 MHz, DMSO-d6) 117.0 (2C), 48.2. LCMS: tr = 10.83 min. [M+H]+= 334.16. HPLC (À28o): purity 94.5%; tr: 10.7 min (method 2). MCK339: 1-(3-bromobenzyl)-N5-phenyl-1H-1,2,4-triazol3,5-diamine

[00140] N3-phenyl-1H-1,2,4-triazol-3,5-diamine (150 mg, 1.43 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (96 mg, 0.857 mmol) was added at 0 °C. 3-Bromobenzyl bromide (225 mg, 0.857 Petition 870250080754, dated 09 / 09 / 2025, pp. 119 / 186 A solution of 99 / 124 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for a further 1 h. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as a white solid (29.5 mg, 0.086 mmol, 10% yield) along with the N3-benzylated regioisomer. White solid, 29.5 mg, 0.086 mmol, 10% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.63. MP = 146-148 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H, NH), 7.62 - 7.55 (m, 2H, CHAr), 7.50 — 7.45 (m, 1H, CHAr), 7.39 (t, J = 1.8 Hz, 1H, CHAr), 7.31 (t, J = 7.8 Hz, 1H, CHAr), 7.27 - 7.18 (m, 3H, CHAr), 6.88 (tt, J = 7.4, 1.1 Hz, 1H, CHAr), 5.16 (s, 2H, NH2), 5.13 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d6) δ 160.8, 150.3, 140.9, 140.3, 130.6, 130.0, 129.9, 128.6 (2C), 126.2, 121.6, 120.5, 116.9 (2C), 48.0. LCMS: tr = 8.47 min. [M+H]+= 342.30; 343, 90. HPLC (À28o): purity 96.5%; tr: 10.5 min (method 3). MCK340: 1-(3-bromobenzyl)- N3-(4-methoxyphenyl)-1H -1,2,4triazol-3,5-diamine Petition 870250080754, dated 09 / 09 / 2025, pp. 120 / 186 100 / 124

[00141] N3-(4-methoxyphenyl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.22 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (137 mg, 1.22 mmol) was added at 0 °C. 3-Bromobenzyl bromide (320 mg, 1.28 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise, and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0 and then 45 / 55) yielded the title compound as a beige solid (88.4 mg, 0.237 mmol, 19% yield). Beige solid, 88.4 mg, 0.237 mmol, 19% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.35. MP = 96-98 °C. 1H NMR (400 MHz, DMSO-d 6) δ 8,43 (s, 1H, NH), 7,47 (ddd, J = 7,9, 2,0, 1,1 Hz, 1H, CHAr), 7,42 (t, J = 1,8 Hz, 1H, CHAr), 7,41 - 7,35 (m, 2H, CHAr), 7,32 (t, J = 7,8 Hz, 1H, CHAr), 7,24 (dt, J = 7,8, 1,4 Hz, 1H, CHAr), 6,82 - 6,70 (m, 2H, NH2), 6,28 (s, 2H, CH2), 5,01 (s, 2H), 3,66 (s, 3H, OCH3). RMN de13C (101 MHz, DMSO-d6) δ 157,6, 154,1, 152,1, 140,4, 136,0, 130,6, 130,0, 129,9, 126,3, 121,5, 116,7 (2C), 113,8 (2C), 55,1, 47,9. LCMS: t r = 8,63 min. [M+H]+= 374,30; 376, 40. HPLC (À254 ): pureza de 100%; HPLC (À28c): pureza de 98,8%; t r: 10,5 min (método 3). Petição 870250080754, de 09 / 09 / 2025, pág. 121 / 186 101 / 124 MCK341: 1-(3-bromobenzil)- N5-(4-metilfenil)-1H-1,2,4 triazol-3,5-diamina

[00142] N3-(4-methylphenyl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.32 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (148 mg, 1.32 mmol) was added at 0 °C. 3-Bromobenzyl bromide (347 mg, 1.39 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as a light pink solid (47.7 mg, 0.134 mmol, 10% yield) along with the N3-benzylated regioisomer. Light pink solid, 47.7 mg, 0.134 mmol, 10% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.54. MP = 162-164 °C.RMN de 1H (400 MHz, DMSO-d6) δ 8,70 (s, 1H, NH), 7,47 (dd, J = 8,8, 2,1 Hz, 3H, CHAr), 7,38 (t, J = 1,8 Hz, 1H, CHAr), 7,31 (t, J = 7,8 Hz, 1H, CHAr), 7,22 - 7,18 (m, 1H, CHAr), 7,08 — 7,02 (m, 2H, CHAr), 5,14 (s, 2H, NH2), 5,11 (s, 2H, CH2), 2,22 (s,. Petição 870250080754, de 09 / 09 / 2025, pág. 122 / 186 102 / 124 3H, CH3). RMN de13C (101 MHz, DMSO-d β)) δ 160, 8, 150,5, 140,3, 138,4, 130, 6, 130,0, 129, 9, 129, 2, 129, 0 (2C), 126,2, 121,6, 117,1 (2C), 47, 9, 20,2. LCMS: t r = 9,06 min. [M+H]+= 357, 9; 358, 9. HPLC (À254 ): pureza de 99,3%; HPLC (À28o): pureza de 99,7%; t r: 11,0 min (método 3). MCK342: 1-(3-bromobenzil)- N3-(4-metilfenil)-1H -1,2,4triazol-3,5-diamina Br

[00143] N3-(4-methylphenyl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.32 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (148 mg, 1.32 mmol) was added at 0 °C. 3-Bromobenzyl bromide (347 mg, 1.39 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under reduced pressure. Purification by reverse-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as a yellow solid (157.4 mg, 0.441 mmol, 33% yield) along with the N5-benzylated regioisomer. Yellow solid, Petition 870250080754, dated 09 / 09 / 2025, pp. 123 / 186 103 / 124 157,4 mg, 0,441 mmol, rendimento de 33%. Rf (CH2Cl2 / THF,1 / 1, v / v) = 0,46. P.F. = 86-88 °C. RMN de 1H (400 MHz, DMSO-d6) δ 8,54 (s, 1H, NH), 7,50 — 7,45 (m, 1H, CHAr), 7,43 (t, J = 1,8 Hz, 1H, CHAr), 7,37 - 7,29 (m, 3H, CHAr), 7,26 - 7,21 (m, 1H, CHAr), 7,02 - 6, 90 (m, 2H, CHAr), 6,30 (s, 2H, NH2), 5,02 (s, 2H, CH2), 2,18 (s, 3H, CH3). RMN de13C (101 MHz, DMSO-d6) δ 157,4, 154,1, 140,4, 139,8, 130,6, 130,0, 129,9, 128,8 (2C), 126, 8, 126, 3, 121,5, 115,5 (2C), 47, 9, 20,2. LCMS: t r = 9,57 min. [M+H]+= 357,40; 358,40. HPLC (À254 ): pureza de 96,6%; HPLC (À28o): pureza de 95,1%; t r: 11,5 min (método 3). MCK343: 1-(3-bromobenzil)- N5-(4-clorofenil)-1H-1,2,4triazol-3,5-diamina

[00144] N3-(4-chlorophenyl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.20 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (134 mg, 1.20 mmol) was added at 0 °C. 3-Bromobenzyl bromide (310 mg, 1.26 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under reduced pressure. A Petition 870250080754, dated 09 / 09 / 2025, pp. 124 / 186 104 / 124 purification by reverse-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as a light pink solid (22.4 mg, 0.059 mmol, 5% yield) along with the N3-benzylated regioisomer. Light pink solid, 22.4 mg, 0.059 mmol, 5% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.54. MP = 82-84 °C. 1H NMR (400 MHz, DMSO-d 6) δ 9.00 (s, 1H, NH), 7.68 — 7.57 (m, 2H, CHAr), 7.47 (ddd, d = 8.0, 2.1, 1.1 Hz, 1H, CHAr), 7.38 (t, J = 1.8 Hz, 1H, CHAr), 7.36 — 7.27 (m, 3H, CHAr), 7.19 (dt, J = 7.8, 1.3 Hz, 1H, CHAr), 5.20 (s, 2H, NH2), 5.12 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d 6) δ 160.8, 149.8, 140.1, 139.9, 130.6, 130.1, 129.9, 128.4 (2C), 126.2, 124.0, 121.6, 118.4 (2C), 48.0. LCMS: tr = 9.76 min. [M+H]+= 378.4; 380.3. HPLC (À254): purity 96.4%; HPLC (À28c): purity 98.7%; tr: 11.9 min (method 3). MCK344: 1-(3-bromobenzyl)-N3-(4-chlorophenyl)-1H-1,2,4triazol-3,5-diamine Br H

[00145] N3-(4-chlorophenyl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.20 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (134 mg, 1.20 mmol) was added. 3-Bromobenzyl bromide (310 mg, 1.26 Petition 870250080754, dated 09 / 09 / 2025, pages 125 / 186 A solution of 105 / 124 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as an orange solid (197.7 mg, 0.524 mmol, 44% yield) along with the N5-benzylated regioisomer. Orange solid, 197.7 mg, 0.524 mmol, 44% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.42. MP = 124-126 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H NH), 7.53 — 7.45 (m, 3H, CHAr), 7.43 (t, J = 1.8 Hz, 1H, CHAr), 7.32 (t, J = 7.8 Hz, 1H, CHAr), 7.27 - 7.22 (m, 1H, CHAr), 7.22 - 7.16 (m, 2H, CHAr), 6.38 (s, 2H, NH2), 5.04 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d6) δ 157.0, 154.3, 141.2, 140.2, 130.6, 130.1, 129.9, 128.2 (2C), 126.3, 121.8, 121.6, 116.9 (2C), 48.0. LCMS: tr = 10.52 min.[M+H]+= 378.4; 380.3. HPLC (À254 ): purity of 98.5%; HPLC (À28c): purity of 98.7%; tr: 12.6 min (method 3). MCK345: 1-(3-bromobenzyl)- N5-(4-bromophenyl)-1H-1,2,4triazol-3,5-diamine Petition 870250080754, 09 / 09 / 2025, p. 126 / 1 106 / 1

[00146] N3-(4-bromophenyl)-1H-1,2,4-triazol-3,5diamine (250 mg, 0.988 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (111 mg, 0.988 mmol) was added at 0 °C. 3-Bromobenzyl bromide (259 mg, 1.04 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as a pink solid (3.5 mg, 0.008 mmol, 1% yield) along with the N3-benzylated regioisomer. Pink solid, 3.5 mg, 0.008 mmol, 1% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.54. MP = 76-78 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H, NH), 7.59 — 7.55 (m, 2H, CHAr), 7.47 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H, CHAr), 7.44 - 7.37 (m, 3H, CHAr), 7.31 (t, J = 7.8 Hz, 1H, CHAr), 7.19 (dt, J = 7.8, 1.3 Hz, 1H, CHAr), 5.20 (d, J = 7.7 Hz, 2H, NH2), 5.12 (s, 2H, CH2). NMR de13C (101 MHz, DMSO-d 6) δ 160, 8, 149, 8, 140.3, 140, 1, 131.3 (2C), 130.6, 130.1, 129, 9, 126, 130.1, 18, 28, 111.8, 48.1. LCMS: tr = 10.01 min. [M+H]+ = 422.3; 424.4. HPLC (À28c): 95.1% purity; tr: 12.2 min (method 3). Petition 870250080754, of 09 / 09 / 2025, p. 127 / 186 107 / 124 MCK346: 1-(3-bromobenzyl)- N3-(4-bromophenyl)-1H -1,2,4triazole-3,5-diamine Br Br^^x N\ H IL - / NH2 H

[00147] N3-(4-bromophenyl)-1H-1,2,4-triazol-3,5diamine (250 mg, 0.988 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (111 mg, 0.988 mmol) was added at 0 °C. 3-Bromobenzyl bromide (259 mg, 1.04 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as a pink solid (132.4 mg, 0.314 mmol, 32% yield) along with the N5-benzylated regioisomer. Pink solid, 132.4 mg, 0.314 mmol, 32% yield. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.42. MP = 130-132 °C.1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H, NH), 7.50 — 7.45 (m, 1H, CHAr), 7.45 — 7.41 (m, 3H, CHAr), 7.35 — 7.28 (m, 3H, CHAr), 7.26 — 7.21 (m, 1H, CHar), 6.38(s, 2H, NH2), 5.04 (s, 2H, CH2). NMR of13C ( 101 . Petition 870250080754, 09 / 09 / 2025, p. 128 / 1 108 / 1 MHz, DMSO-d6) δ156.9.154.3.141.6.140.2.131.0(2C), 130, 6, 130.1, 129, 9, 126, 3, 121, 6, 117.5 (2C), 109, 5, 48.0. LCMS: tr = 10.64 min. [M+H]+= 422.3; 424.2. HPLC (À254 ): purity of 97.7%; HPLC (À28o): purity of 98.8%; tr: 13.0 min (method 3). MCK347: methyl-4-((3-amino-1-(3-bromobenzyl)-1H-1,2,4triazol-5-yl)amino)benzoate

[00148] Methyl-4-((5-amino-1H-1,2,4-triazol-3yl)amino)benzoate (250 mg, 1.07 mmol) was dissolved in anhydrous DMF (1 mL), and then potassium tert-butoxide (120 mg, 1.07 mmol) was added at 0 °C. 3-Bromobenzyl bromide (280 mg, 1.13 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise, and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 5 h and 30 min. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as a whitish solid (9.9 mg, 0.025 mmol, 2% yield) along with the N3-benzylated regioisomer. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.56. MP = 100 °C. 1H NMR (400 Petition 870250080754, dated 09 / 09 / 2025, pp. 129 / 186 109 / 124 MHz, DMSO-d 6) δ 9,33 (s, 1H, NH), 7, 90 — 7,82 (m, 2H, CHAr), 7,72 - 7, 64 (m, 2H, CHAr), 7,47 (ddd, J = 8,0, 2,1, 1,1 Hz, 1H, CHAr), 7,39 (t, J = 1,8 Hz, 1H, CHAr), 7,31 (t, J = 7,8 Hz, 1H, CHAr), 7,22 - 7,15 (m, 1H, CHAr), 5,28 (s, 2H, NH2), 5,16 (s, 2H, CH2), 3,80 (s, 3H, CH3). RMN de13C (101 MHz, DMSO-d6) δ 166, 0, 161, 0, 145,4, 140, 0, 130, 6 (2C) , 130,3 (2C), 130,1, 129,9 (2C), 126,2, 121,6, 115,9 (2C), 51,6, 48.2. LCMS: t r = 8,92 min. [M+H]+= 400,4; 401,8. HPLC (λ280 ): pureza de 96,7%; tr: 11,0 min (método 3). MCK348: metil-4-((5-amino-1-(3-bromobenzil)-1H -1,2,4triazol-3-il)amino)benzoato

[00149] Methyl-4-((5-amino-1H-1,2,4-triazol-3yl)amino)benzoate (250 mg, 1.07 mmol) was dissolved in anhydrous DMF (1 mL), and then potassium tert-butoxide (120 mg, 1.07 mmol) was added at 0 °C. 3-Bromobenzyl bromide (280 mg, 1.13 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise, and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 5 h and 30 min. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under pressure. Petition 870250080754, dated 09 / 09 / 2025, pp. 130 / 186 110 / 124 reduced. Purification by reverse-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as a whitish solid (83.7 mg, 0.209 mmol, 20% yield) along with the N5-benzylated regioisomer. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.39. MP = 182 °C. 1H NMR (400 MHz, DMSO-d 6) δ 9.37 (s, 1H, NH), 7.81 - 7.75 (m, 2H, CHAr), 7.56 - 7.51 (m, 2H, CHAr), 7.48 (ddd, J = 7.9, 2.1, 1.1 Hz, 1H, CHAr), 7.44 (t, J = 1.8 Hz, 1H, CHAr), 7.33 (t, J =7.8 Hz, 1H, CHAr), 7.25 (dt, J = 7.8, 1.3 Hz, 1H, CHAr), 6.45(s, 2H, NH2), 5.06 (s, 2H, CH2), 3.77 (s, 3H, CH3). NMR de (101 MHz, DMSO-d 6) δ 166, 1, 156, 5, 154.3, 146, 6, 140, 1, 130.7, 130.3, 130.1, 130.0 (2C), 126.4, 121.6, 119.0, 114.7 (2C), 51.4, 51.4, 48.0. LCMS: tr = 9.63 min. [M+H]+= 402.3; 404.3. HPLC (À28o): 96.0% purity; HPLC (À28o): 98.1% pure; tr: 11.6 min (method 3). MCK349: 1-(3-bromobenzyl)- N3-(3,4-dichlorophenyl)-1H 1,2,4-triazol-3,5-diamine

[00150] N3-(3,4-dichlorophenyl)-1H -1,2,4-triazol-3,5diamina (250 mg, 1.03 mmol) when dissolved in anhydrous DMF (1 mL), followed by potassium terc-butoxide (115 mg, 1.03 mmol) Petition 870250080754, 09 / 09 / 2025, pág. 131 / 186 111 / 124 was added at 0 °C. 3-Bromobenzyl bromide (270 mg, 1.08 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 16 h. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0 and then 45 / 55) yielded the title compound as a white solid (93.9 mg, 0.229 mmol, 22% yield). Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.39. MP = 150 °C. 1H NMR (400 MHz, DMSO-d 6) δ 9.18 (s, 1H, NH), 7.82 (d, J = 2.3 Hz, 1H, CHAr), 7.49 (ddd, J = 7.9, 2.2, 1.1 Hz, 1H, CHAr), 7.44 (t, J = 1.8 Hz, 1H, CHAr), 7.40 — 7.30 (m, 3H, CHAr), 7.24 (dt, J = 7.8, 1.3 Hz, 1H, CHAr), 6.45 (s, 2H, NH2), 5.05 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d 6) δ 156.6, 154.3, 142.3, 140.0, 130.7, 130.7, 130.2, 130.1, 130.0, 126.4, 121.6, 119.4 116.3, 115.8, 48.0. LCMS: tr = 11.64 min. [M+H]+= 412.3; 414.4. HPLC (À254): purity 97.7%; HPLC (À2so): purity of 96.4%; tr: 15.0 min (method 3). MCK350: N3-(3,4-dichlorophenyl)-1-(4-isopropylbenzyl)1H -1,2,4-triazol-3,5-diamine Petition 870250080754, dated 09 / 09 / 2025, pp. 132 / 186 112 / 124

[00151] N3-(3,4-dichlorophenyl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.03 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (115 mg, 1.03 mmol) was added at 0 °C. 4-Isopropylbenzyl chloride (0.18 mL, 1.08 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 6 h. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0, then 45 / 55) yielded the title compound as an orange solid (162 mg, 0.432 mmol, 42% yield) along with the N5-benzylated regioisomer. Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.53. MP = 138 °C. 1H NMR (400 MHz, DMSO-d 6) δ 9.14 (s, 1H, NH), 7.83 (dd, J = 1.8, 1.0 Hz, 1H, CHAr), 7.45 — 7.30 (m, 2H, CHAr), 7.26 − 7.11 (H2, CHA8), NH2), 4.99 (s, 2H, CH2), 2.84 (hept, J = 6.9 Hz, 1H, CH), 1.16 (d, J = 6.9 Hz, 6H, 2CH3). de13C NMR (101 MHz, DMSO-d 6) δ 156, 3, 154.1, 147.4, 142.4, 134.7, 130.7, 130.2, 127.3 (2C), 126.2 (2C), 119.3, 116.3, 115.8, 48.5, 33.1, 23.8 (2C). LCMS: tr = 12.49 min. [M+H]+= 376.4; 378.4. HPLC (À254 ): purity of 95.4%; tr: 17.1 min (method 3). Petition 870250080754, dated 09 / 09 / 2025, p. 133 / 186 113 / 124 MCK351: 1-(3-bromobenzyl)-N3- (pyridine-3-yl)-1H-1,2,4 triazol-3,5-diamine Br N\ Γ ü Ji / Xnh2 nYnan H

[00152] N3-(pyridin-3-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 0.988 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 3-Bromobenzyl bromide (373 mg, 1.42 mmol), dissolved in anhydrous CH2Cl2 (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 4 h. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH, 10 / 0 and then 9 / 1) yielded the title compound as a brown solid (141.3 mg, 0.411 mmol, 29% yield). Rf (CH2Cl2 / MeOH, 9 / 1, v / v) = 0.44. MP = 92-94 °C.1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.63 (dd, J = 2.7, 0.7 Hz, 1H), 7.94 (dd, J = 4.6, 1.5 Hz, 1H), 7.91 (ddd, J = 8.4, 2.7, 1.5 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.33 (t, J = 7.7 Hz, 1H), 7.25 (dt, J = 7.8, 1.4 Hz, 1H), 7.22 - 7.14 (m, 1H), 6.41 (s, 2H), 5.04 (s, 2H). NMR of13C. Petition 870250080754, 09 / 09 / 2025, p. 134 / 1 114 / 124 (101 MHz, DMSO-d6) δ156,8,154.4,140,1,139,5,138.8. 138.0, 130.6, 130.1, 130.0, 126.4, 123.2, 121.1, 121.4, 48.0. LCMS: tr = 6.91 min. [M+H]+= 345.5; 347.4. HPLC (À254 ): purity of 96.6%; HPLC (À28º): purity of 96.5%; tr: 7.39 min (method 4). MCK352: 1-(3-bromobenzyl)- N4-(pyridin-3-yl)-1H-1,2,4triazol-3,5-diamine

[00153] N4-(pyridin-3-yl)-1H-1,2,4-triazol-3,5diamine (250 mg, 1.42 mmol) was dissolved in anhydrous DMF (1 mL), then potassium tert-butoxide (159 mg, 1.42 mmol) was added at 0 °C. 3-Bromobenzyl bromide (373 mg, 1.49 mmol), dissolved in anhydrous DMF (1 mL), was added dropwise and the reaction mixture was stirred at 0 °C for 1 h and at room temperature for 1 h 30. The reaction mixture was rapidly cooled with water (1 mL) and the solvents were evaporated under reduced pressure. Purification by reversed-phase chromatography (H2O / CH3CN, 10 / 0 and then 45 / 55) yielded the title compound as an orange solid (68.7 mg, 0.200 mmol, 14% yield). Rf (CH2Cl2 / THF, 1 / 1, v / v) = 0.72. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H, NH), Petition 870250080754, dated 09 / 09 / 2025, pages 135 / 186 115 / 124 8.19 (d, J = 6.4 Hz, 2H, CHAr), 7.49 (ddd, J = 7.9, 2.1, 1.2 Hz, 1H, CHAr), 7.45 (t, J = 1.8 Hz, 1H, CHAr), 7.40 - 7.36 (m, 2H, CHAr), 7.33 (t, J = 7.8 Hz, 1H, CHAr), 7.25 (dt, J = 7.8, 1.3 Hz, 1H, CHAr), 6.47 (s, 2H, NH2), 5.07 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d6) δ 156.2, 154.4, 149.5 (2C), 148.0, 140.0, 130.7, 130.2, 130.0, 126.4, 121.6, 110.3 (2C), 48.1. LCMS: tr = 5.50 min. [M+H]+= 345.5; 347.4. HPLC (À254): purity 97.7%; HPLC (λ28θ): 100% purity; tr: 7.22 min (method 4). Example B: Biology I. Materials and methods. Cell culture.

[00154] ARPE-19 (ATCC CRL2302) and TIME (ATCC CRL-4025) endothelial cells were acquired from the American Tissue Culture Collection. ARPE-19 cells were cultured in DMEM:F12 medium and 10% FBS. TIME cells were cultured in Vascular Cell Basal Medium (ATCC® PCS-100-030) and 6% FBS. Cell viability (XTT assay)

[00155] ARPE-19 cells were incubated in a 96-well plate with different effectors for 48 hours. Fifty microliters of sodium 3'-[1-phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzenesulfonic acid hydrate (XTT) reagent were added to each well. The test is based on the cleavage of the yellow salt of Petition 870250080754, dated 09 / 09 / 2025, pp. 136 / 186 116 / 124 tetrazolium XTT to form an orange formazan dye by metabolically active cells. This bioreduction occurs only in viable cells and is associated with NAD(P)H production by glycolysis. Therefore, the amount of formazan dye measured at 490 nm correlates directly with the number of metabolically active cells, reflecting cell proliferation, viability, and cytotoxicity. Each assay was performed in quadruplicate. Marking with ROS

[00156] ARPE-19 cells were treated with MCK349 for 30 minutes and then with 200 μM H2O2 for 2 h. 10 μM DCF-DA (2',7'-dichlorofluorescine diacetate) was added to the cell medium for 30 minutes. The cells were washed, detached (trypsin), and resuspended in PBS 0.5% BSA and 2 mM EDTA. The cells were analyzed by cytometry (ROS labeled with DCFDA-FITC). Quantitative real-time PCR (qPCR) experiments

[00157] One microgram of total RNA was used for reverse transcription using the QuantiTect Reverse Transcription kit (QIAGEN, Hilden, Germany), with a mixture of oligonucleotides (dT) and random primers to initiate first-strand synthesis. SYBR master mix plus (Eurogentec) was used for qPCR. The mRNA level was normalized to 36B4 mRNA. Petition 870250080754, dated 09 / 09 / 2025, pp. 137 / 186 117 / 124 Immunoblotting

[00158] Cells were lysed in buffer containing 3% SDS, 10% glycerol, and 0.825 mM Na2HPO4. 30 to 50 μg of proteins were separated by 10% SDS-PAGE, transferred to a PVDF membrane, and then exposed to appropriate antibodies. Proteins were visualized with the ECL system using anti-rabbit or anti-mouse antibodies conjugated with horseradish peroxidase. Vessel formation assays

[00159] 300 μL of Matrigel Matrix were coated onto 24-well plates and incubated for 1 hour at 37 °C. Time cells were then plated (300,000 cells / well). The plates were then incubated at 37 °C, 5% CO2, for 24 hours. Representative images were obtained with the Evos XL Core Cell Imaging System at low magnification (4X). Endothelial cell proliferation

[00160] TIME cells were seeded in 12-well plates (25,000 cells / well) in 0.5% SVF medium and then stimulated with 100 ng / mL of CXCL8 or CXCL7 for 72 h. Cell proliferation is assessed by cell counting. Results are expressed as % of day 0 relative to the tested condition. LPS-stimulated whole blood

[00161] Human peripheral volunteers were obtained from healthy donors with informed consent, following Petition 870250080754, dated 09 / 09 / 2025, pp. 138 / 186 118 / 124 the Declaration of Helsinki, in accordance with the recommendations of an independent scientific review committee. The project was validated by the Établissement Français du Sang, the French national agency for blood collection (protocol 7952NQ). Blood samples were collected using tubes containing ethylenediaminetetraacetic acid.

[00162] Whole blood will be collected from a single donor (K3-EDTA) and diluted 1:5 with RPMI 1640. Within 30 minutes of collection, the blood will be incubated with 5 or 10 μM of MCK349 for 1 h, before stimulation with 10 ng / ml of LPS for 18 h. The blood is centrifuged to recover the plasma and the cytokines are analyzed by multiplex ELISA (Meso Scale Discovery). Stimulation with ARPE-19 to mimic diabetic retinopathy in vitro

[00163] ARPE-19 cells were cultured under hyperglycemic conditions (D-glucose, 25 mmol / L) for 16 days at 37°C under 5% CO2 in medium (DMEM / F12) supplemented with 10% FBS and 1% penicillin. On day 16, the cells were pre-treated with MCK349. On day 17, the cells were washed and treated with MCK349 and cytokines (10 ng / mL IL1B, 25 ng / mL VEGF, and 25 ng / mL TNF) for 24 h. Cytokines were analyzed by multiplex ELISA (Meso Scale Discovery) in the supernatant. Cells were recovered to analyze the mRNA level of different markers by qPCR. Petition 870250080754, dated 09 / 09 / 2025, pp. 139 / 186 119 / 124 ELISA Multiplex (Meso Scale Discovery)

[00164] Plasma (whole blood) or supernatant (ARPE-19 cells) cytokines were analyzed by multiplex ELISA. A multiplex ELISA was developed from the U-PLEX Biomarker Group 1 (hu) Assays (K15069L-1). The protocol performed follows the supplier's instructions. Metastatic tumor model in zebrafish

[00165] All animal experiments were approved by the Animal Experimentation Ethics Committee. Transgenic zebrafish embryos (fli: EGFP, blood vessels labeled in GFP) were reared at 28 °C under standard experimental conditions. Zebrafish embryos at 24 hpf were incubated in aquarium water containing 0.2 mmol / L of 1-phenyl-2-thiourea (PTU, Sigma). At 48 hpf, zebrafish embryos were placed for 72 h in normoxia (Nx) or hypoxia with 5% oxygen (Nx), in the presence of treatment. Retinal neoangiogenesis was analyzed by confocal fluorescence microscopy and quantified by ImageJ. Laser-induced choroidal neovascularization and vascular extravasation in mice

[00166] Laser photocoagulation (injecting a laser beam (50 pm, 0.1 se 250 to 300 mW or any other reasonable parameter) into the retina at 4 points, avoiding blood vessels) was performed binocularly in each animal on Day 1 in male C57 mice (8 mice per group). Petition 870250080754, dated 09 / 09 / 2025, pp. 140 / 186 120 / 124

[00167] The vehicle and MCK349 (52 μg / ml) were administered by binocular intravitreal injection (2 μl) four times in total. Once on Day 1 (immediately after shaping), Day 4, Day 7, and Day 11. Optical Coherence Tomography (OCT) was performed once on the day of shaping, immediately after laser photocoagulation, and once on Days 9 and 15. The volume of the CNV of each lesion will be measured. Fluorescein Angiography (FFA) was performed once on Days 9 and 15. The angiograms will be classified as follows: Grade 0, no bright hyperfluorescence; Grade 1, hyperfluorescence without extravasation; Grade 2a, hyperfluorescence and late extravasation; and Grade 2b, bright hyperfluorescence and late extravasation beyond the treated areas. Statistical analysis

[00168] All data are expressed as mean ± standard error (SD). Statistical significance and p-values ​​were determined using Prism 5.0b (GraphPad Software) by one-way ANOVA with Bonferroni post-hoc test or by two-tailed Student's t-test. Screening of the MCK compound (Table 1 below)

[00169] All compounds were evaluated in different experiments. The results are represented as the average of three independent experiments. A. ARPE-19 cells were treated with the dose-response compound by Petition 870250080754, dated 09 / 09 / 2025, pp. 141 / 186 121 / 124 h. Values ​​are reported as IC50 measured with the XTT assay. B and C. ARPE-19 cells were treated with 5 μM (B) or 1 μM (C) of the compound and then with 200 μM of H2O2 for 2 h. ROS were analyzed by cytometry. A score of 1 means that the compound inhibited ROS by at least 50% (significant inhibition). A score of 0 means that the compound inhibited ROS by less than 50% (non-significant inhibition). As illustrated in Figure 1A. D. ARPE-19 cells were treated with 2.5 μM of the compound for 48 h; CXCL1 mRNA level was assessed by qPCR. A score of 1 means that the compound inhibited CXCL1 mRNA by at least 50% (significant inhibition). A score of 0 means that the compound inhibited CXCL1 mRNA by less than 50% (non-significant inhibition). As illustrated in Figure IB. E. TIME cells were pre-treated with 2.5 μM of the compound per 100 ng / ml, then stimulated with 100 ng / ml of CXCL8 for 15 min.p-ERK levels were analyzed by immunoblotting. HSP90 served as a loading control. A score of 1 means that the compound inhibited ERK (p-ERK) activation by at least 50% (significant inhibition). A score of 0 means that the compound inhibited ERK (p-ERK) activation by less than 50% (non-significant inhibition). As illustrated in Figure 1C. Petition 870250080754, dated 09 / 09 / 2025, pages 142 / 186 122 / 124 II. Results Table 1: MCK compounds A. Security IC50 in ARPE-19 cells B. ROS inhibition 5 pM - ARPE-19 cells C. ROS inhibition 1 pM - ARPE-19 cells D. CXCL1B mRNA inhibition ARPE-19 cells E. p-ERK TIME inhibition Total score 248 > 25 µM 1 0 0 0 1 249 > 25 µM 1 0 0 0 1 250 > 25 µM 1 1 0 0 2 253 > 25 µM 0 0 1 0 1 254 > 25 µM 0 0 1 0 1 257 > 25 µM 1 1 1 1 4 259 > 25 µM 0 0 1 1 2 260 > 25 µM 1 1 0 1 3 261 > 25 μM 1 0 0 1 2 262 > 25 μM 1 1 0 1 3 263 > 25 μM 1 1 1 1 4 264 > 25 μM 1 1 1 1 4 268 > 25 μM 1 0 0 1 2 269 > 25 μM 1 1 0 1 3 271 > 25 μM 1 1 0 1 3 272 > 25 μM 1 0 1 1 3 273 > 25 μM 1 1 0 1 3 274 > 25 μM 1 1 0 0 2 275 > 25 μM 1 1 0 0 2 276 > 25 μM 0 0 0 1 1 278 > 25 μM 0 0 0 1 1 279 > 25 μM 0 0 0 1 1 280 > 25 μM 0 0 0 1 1 281 > 25 μM 0 0 0 1 1 282 > 25 μM 0 0 1 1 2 283 > 25 μM 0 0 1 1 2 284 > 25 μM 0 0 0 1 1 288 > 25 μM 1 1 0 0 2 289 > 25 μM 1 1 0 0 2 290 > 25 μM 1 1 0 1 3 292 > 25 μM 0 0 0 1 1 295 > 25 μM 0 0 0 1 1 297 > 25 μM 0 0 0 1 1 298 > 25 μM 0 0 1 1 2 299 > 25 μM 0 0 0 1 1 300 >25 μΜ 0 0 0 1 1 301 > 25 μΜ 0 0 1 0 1 338 > 25 μΜ 1 1 1 0 3 339 > 25 μΜ 1 0 1 0 2 340 > 25 μΜ 0 0 1 0 1 341 > 25 μΜ 1 1 1 0 3 342 > 25 μΜ 1 1 1 0 3 343 > 25 μΜ 1 0 1 1 3 344 > 25 μΜ 1 1 1 1 4 345 > 25 μΜ 1 1 1 1 4 346 > 25 μΜ 1 1 0 1 3 347 > 25 μΜ 0 0 1 1 2 348 > 25 μΜ 1 1 1 1 4 Petition 870250080754, dated 09 / 09 / 2025, pp. 143 / 186 123 / 124 349 > 25 μΜ 1 1 1 1 4 350 > 25 μΜ 1 1 1 1 4 351 > 25 μΜ 0 0 1 1 2 352 > 25 μΜ 1 0 1 1 3

[00170] The inventors evaluated the compounds by screening them for their ability to: i) to be non-toxic to retinal cells (IC50 > 25μM), Table 1. A), ii) to inhibit reactive oxygen species (ROS, Table 1. BC and Figure 1A), iii) to inhibit CXCR2 and its signaling: decreased transcription of CXCL1 (Table 1. D and Figure 1B) and inhibition of ERK (p-ERK) activation after stimulation by CXCL8 (Table 1. E and Figure 1C).

[00171] The inventors also demonstrated that the compound MCK349 is capable of inhibiting angiogenesis in vitro, inhibiting vessel formation in matrigel (Figure 1D) and endothelial cell proliferation induced by CXCL8 (Figure 1E) and CXCL7 (Figure 1F).

[00172] They also demonstrated that MCK342 and MCK349 were able to inhibit inflammation. More specifically, they demonstrated that MCK342 and MCK349 were able to inhibit pro-inflammatory cytokines (CXCL8, IL2, IL1b, IL4, IL6, IL5, IFNg, IL10) induced by LPS stimulation in whole blood (Figure 2) and to inhibit the expression (mRNA, Figure 3) and secretion (Figure 4) of pro-angiogenic and / or pro-inflammatory cytokines. Petition 870250080754, dated 09 / 09 / 2025, pages 144 / 186 124 / 124 inflammatory markers (IL1b, CXCL8, MMP9, VEGFC, CXCL1, IL6, TNFa, TGFb, IL33, IL13, IL12p70, INFg, IL4, IL10, IL6, IL5, IL33) in an in vitro diabetic retinopathy model.

[00173] The inventors further developed a model of retinal neoangiogenesis in zebrafish (fluorescent blood vessels, in white in Figure 5A) induced by hypoxia. They demonstrated that compounds MCK263, MCK342, MCK344 and MCK349 were able to inhibit ocular neoangiogenesis in this in vivo model (Figure 5).

[00174] They also demonstrated that substituted compounds comprising at least one R2 substituent, as defined in this document, exhibit enhanced efficacy compared with unsubstituted compounds (n = 0) in inhibiting CXCL8-induced p-ERK activation (Figure 6), in inhibiting ROS (Figure 7), and in inhibiting CXCL1 expression (Figure 8).

[00175] Furthermore, in a laser-induced choroidal neovascularization (CNV) model in mice, MCK349 (intravitreal treatment) inhibits vascular leakage (Figure 9A and B) and neovascularization (Figure 9C). Petition 870250080754, dated 09 / 09 / 2025, pages 145 / 186

Claims

1 / 10 CLAIMS 1. Compound, characterized in that it is of formula (I): H (I), wherein: O X is -(CH2)-, -(CH2)-CO-, or -(CH2)-(CH2)-; O Ri is an aryl or heteroaryl group, said aryl or heteroaryl groups are optionally substituted by at least one radical selected from the group consisting of an (C1-C1)alkyl optionally substituted by at least one halogen, an (C1-C6)alkyloxy optionally substituted by at least one halogen, a halogen, a CO2R3 with R3 being a hydrogen or an (C1-C1)alkyl, and a -C(O)R4 with R4 being a hydrogen, an (C1-C1)alkyl, or an -NRsRg with R5 and Rg independently being a hydrogen or an (C1-C1)alkyl, a nitrile, and a nitro; 0 n is an integer between 0 and 5;0 each R2 is independently a radical selected from the group consisting of an (Ci-Cg)alkyl optionally substituted with at least one halogen, an (Ci-C6)alkyloxy optionally substituted with at least one halogen, a Petition 870250080754, dated 09 / 09 / 2025, page 146 / 186 2 / 10 halogen, a -CO2R3 with R3 being a hydrogen or an (Ci-Cg)alkyl, and a -C(O)R4 with R4 being a hydrogen, an (Ci-Cg)alkyl, or an -NR5R6 with R5 and Rg being independently a hydrogen or an (Ci-Cg)alkyl, a nitrile, and a nitro; provided that said compound is not a compound selected from a group consisting of: - 1-benzyl-N3-phenyl-1H-1,2,4-triazol-3,5-diamine; and - 1-phenethyl-N3-phenyl-1H-1,2,4-triazol-3,5-diamine, or a pharmaceutically acceptable salt thereof.

2. A composite according to claim 1, characterized in that n is an integer between 1 and 5.

3. Compound according to claim 1 or 2, characterized in that said compound is of formula (IA): (IA).

4. Compound according to claim 1 or 2, characterized in that said compound is of formula (IB): Petition 870250080754, dated 09 / 09 / 2025, p. 147 / 186 3 / 10 H (IB).

5. Compound according to any one of claims 1 to 4, characterized in that X is (CH2)-.

6. Compound, according to any one of claims 1 to 5, characterized in that Ri is a phenyl or pyridinyl group, preferably a phenyl, said phenyl or pyridinyl groups being optionally substituted by at least one radical selected from the group consisting of a (C1-C6)alkyloxy, preferably a methoxy, a (C1-C1)alkyl, preferably a methyl, a halogen, preferably a chlorine or a bromine, and a -CO2R3, where R3 is a (C1-C1)alkyl, preferably a methyl.

7. A compound, according to any one of claims 1 to 6, characterized in that n is an integer between 1 and 3, preferably n is 1 or 2, more preferably 1.

8. Compound, according to any one of claims 1 to 7, characterized in that each R2 Petition 870250080754, dated 09 / 09 / 2025, p. 148 / 186 4 / 10 is independently a radical selected from the group consisting of, an (C1-C1)alkyl optionally substituted with at least one halogen, preferably a methyl, a trifluoromethyl or an isopropyl, an (C1-C6)alkyloxy, preferably a methoxy, a halogen, preferably a fluorine, a bromine or a chlorine, a nitro and a nitrile.

9. A compound according to any one of claims 1 to 8, characterized in that each R2 is independently a radical selected from the group consisting of an isopropyl and a bromine, preferably a bromine.

10. Compound according to any one of claims 1 to 9, characterized in that: 0 X is - (CH2) -; 0 Ri is a phenyl or pyridinyl group, preferably a phenyl, said phenyl or pyridinyl groups being optionally substituted by at least one radical selected from the group consisting of a methyl, a chlorine, a bromine and a -CO2R3, R3 being a methyl; 0 n is 1; and 0 R2 is a radical selected from the group consisting of an isopropyl and a bromine.

1. Compound according to claim 1, characterized in that said compound is selected from the group consisting of: - MCK248: 1-benzyl-N5-phenyl-1H-1,2,4-triazol-3,5-diamine; - MCK250: 1-(2-methylbenzyl)-N3-phenyl-1H-1,2,4-triazol-3,5-diamine; - MCK253: 1-benzyl-N3-(pyridin-2-yl)-1H-1,2,4-triazol-3,5-diamine; - MCK254: 1-benzyl-N3-(pyridin-3-yl)-1H-1,2,4-triazol-3,5-diamine; - MCK257: 1-(2,6-difluorobenzyl)-N5-phenyl-1H-1,2,4triazol-3,5-diamine; - MCK259: 1-(2,6-difluorobenzyl)-N3-(pyridin-2-yl)-1H1,2,4-triazol-3,5-diamine; - MCK260: 1-(3-methoxybenzyl)-N5-phenyl-1H-1,2,4triazol-3,5-diamine; - MCK261: 1-(3-methoxybenzyl)-N3-phenyl-1H-1,2,4triazol-3,5-diamine; - MCK262: 1-(4-isopropylbenzyl)-N5-phenyl-1H-1,2,4triazol-3,5-diamine; - MCK263: 1-(4-isopropylbenzyl)-N3-phenyl-1H-1,2,4triazol-3,5-diamine; - MCK264: 1-(3-bromobenzyl)-N3-phenyl-1H-1,2,4-triazol3,5-diamine;- MCK268: 1-(2, 6-diclorobenzil)- N3-fenil-1H-1,2,4triazol-3,5-diamina; Petição 870250080754, de 09 / 09 / 2025, pág. 150 / 186 6 / 10 - MCK269: 1-(2-metilbenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK271: 1-(4-metilbenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK272: 1-(4-clorobenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK273: N3-fenil-1-(3-(trifluorometil)benzil)-1 H 1,2,4-triazol-3,5-diamina; - MCK274: 1-(3,5-difluorobenzil)- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK275: 1-(3-nitrobenzil))- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK276: 1-(3-bromobenzil)- N3-(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK278: 1-(2, 6-diclorobenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK279: 1-(4-metilbenzil)- N3 -(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK280: 1-(4-clorobenzil)- N3 -(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK281: 4-((5-amino-3-(piridin-2-ilamino)-1 H -1,2,4triazol-1-il)metil)benzonitrila;- MCK282: N3-(piridin-2-il)-1-(3- (trifluorometil)benzil)-1H-1,2,4-triazol-3,5-diamina; - MCK283: 1-(3,5-difluorobenzil)- N3 -(piridin-2-il)-1H Petição 870250080754, de 09 / 09 / 2025, pág. 151 / 186 7 / 10 1,2,4-triazol-3,5-diamina; - MCK284: 1-(2,4-difluorobenzil)- N3 -(piridin-2-il)-1H1,2,4-triazol-3,5-diamina; - MCK288: 1-(4-nitrobenzil))- N3-fenil-1H-1,2,4triazol-3,5-diamina; - MCK289: 1-(2-nitrobenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK290: 1-(4-nitrobenzil)- N3-(piridin-2-il)-1 H - 1,2,4-triazol-3,5-diamina; - MCK292: 1-(3-nitrobenzil)- N3-(piridin-2-il)-1H- 1,2,4-triazol-3,5-diamina; - MCK295: 2-(5-amino-3-(piridin-2-ilamino)-1 H -1,2,4triazol-1-il)-1-(3-nitrofenil)etan-1-ona; - MCK297: 1-(2-nitrobenzil)- N3-fenil-1H-1,2,4-triazol3,5-diamina; - MCK298: N3-fenil-1-(3,4,5-trimetoxibenzil)-1 H -1,2,4triazol-3,5-diamina; - MCK299: 2-(5-amino-3-(fenilamino)-1H-1,2,4-triazol1-il)-1-feniletan-1-ona; - MCK300: 1-fenetil-N5-fenil-1H-1,2,4-triazol-3,5diamina;- MCK338: N5-fenil-1-(3-(trifluorometil)benzil)-1 H - 1,2,4-triazol-3,5-diamina; - MCK339: 1-(3-bromobenzil)- N5-fenil-1H-1,2,4-triazol- 3,5-diamina; Petição 870250080754, de 09 / 09 / 2025, pág. 152 / 186 8 / 10 - MCK340: 1-(3-bromobenzil)- N3-(4-metoxifenil)-1H- 1,2,4-triazol-3,5-diamina; - MCK341: 1-(3-bromobenzil)- N5-(4-metilfenil)-1H1,2,4-triazol-3,5-diamina; - MCK342: 1-(3-bromobenzil)- N3-(4-metilfenil)-1H- 1,2,4-triazol-3,5-diamina; - MCK343: 1-(3-bromobenzil)- N5-(4-clorofenil)-1H1,2,4-triazol-3,5-diamina; - MCK344: 1-(3-bromobenzil)- N3-(4-clorofenil)-1H- 1,2,4-triazol-3,5-diamina; - MCK345: 1-(3-bromobenzil)- N5-(4-bromofenil)-1H1,2,4-triazol-3,5-diamina; - MCK346: 1-(3-bromobenzil)- N3-(4-bromofenil)-1H1,2,4-triazol-3,5-diamina; - MCK347: metil-4-((3-amino-1-(3-bromobenzil)-1 H - 1,2,4-triazol-5-il)amino)benzoato; - MCK348: metil-4-((5-amino-1-(3-bromobenzil)-1 H - 1,2,4-triazol-3-il)amino)benzoato; - MCK349: 1-(3-bromobenzil)- N3-(3,4-diclorofenil)-1H1,2,4-triazol-3,5-diamina;- MCK350: N3-(3,4-dichlorophenyl)-1-(4-isopropylbenzyl)1H-1,2,4-triazol-3,5-diamine; - MCK351: 1-(3-bromobenzyl)- N3-(pyridin-3-yl)-1H- 1,2,4-triazol-3,5-diamine; and - MCK352: 1-(3-bromobenzyl)- N4-(pyridin-3-yl)-1H- Petition 870250080754, of 09 / 09 / 2025, p. 153 / 186 9 / 10 1,2,4-triazol-3,5-diamine.; 12. Compound, according to any one of claims 1 to 11, characterized in that it is for use as a drug.

13. Pharmaceutical or veterinary composition, characterized in that it comprises a compound, as defined in any one of claims 1 to 12, and a pharmaceutically acceptable excipient.

14. Compound according to any one of claims 1 to 11, or pharmaceutical or veterinary composition according to claim 13, characterized in that it is for use in the treatment of an eye disease.

15. Pharmaceutical or veterinary compound or composition for use according to claim 14, characterized in that the eye disease is chosen from corneal graft angiogenesis, neovascular glaucoma, diabetic retinopathy, corneal diseases induced by new blood vessels, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasia, granular conjunctivitis, macular edema or Stargardt disease, preferably diabetic retinopathy, macular degeneration, neovascular glaucoma, macular edema or Stargardt disease.

16. Pharmaceutical or veterinary composition for use, according to claim 14 or 15, characterized by the fact that said composition is administered orally, parenterally or topically, preferably topically, and more preferably topically to the eye. (Petition 870250080754, dated 09 / 09 / 2025, pp. 154 / 186 10 / 10)

Images