[1,2,4]-triazolo[4,3-b]pyridazine derivatives useful as a medicament

Abstract

The present invention relates to a compound of formula (I) or any of its pharmaceutically acceptable salt. The present invention further relates to a synthesis process for manufacturing compound of formula (I) or any of its pharmaceutically acceptable salts, comprising at least a step of reacting a compound of formula (II) with an amine of formula (IV) NHR5R6 for example in a molar ratio ranging from 1 to 20 eq, with respect to the compound of formula (II), in an aprotic solvent or without solvent or else in a protic solvent.

Description

[0001] [1,2,4]-TRIAZOLO[4,3-B]PYRIDAZINE DERIVATIVES USEFUL AS A MEDICAMENT FIELD OF THE INVENTION The present invention relates to [1,2,4]-triazolo[4,3-b]pyridazine derivatives useful in treating pathologies mediated by adenosine A3 receptor (A3AR). It further relates to their manufacturing process and to pharmaceutical compositions containing them. BACKGROUND Adenosine interacts with four types of G-protein-coupled receptors (GPCRs), the adenosine receptors (AR): A1AR, A2AAR, A2BAR, A3AR as described in IJzerman, A. P. et al., International Union of Basic and Clinical Pharmacology, CXII: Adenosine Receptors: A Further Update, Pharmacol Rev 2022, 74 (2), 340–372. A2AAR has been most extensively studied while A3AR is the least studied AR. A large number of sub-type specific AR agonists and antagonists have been developed in the last few decades and evaluated in clinical trials for numerous indications as described in IJzerman, A. P. et al., International Union of Basic and Clinical Pharmacology, CXII: Adenosine Receptors: A Further Update, Pharmacol Rev 2022, 74, 340–372; and described in Jacobson, K. A. et al. Medicinal Chemistry of P2 and Adenosine Receptors: Common Scaffolds Adapted for Multiple Targets, Biochem Pharmacol 2021, 187, 114311. The approved AR drugs are the A1AR agonist adenosine (paroxysmal supraventricular tachycardia), the A2AAR agonist Regadenoson (used for myocardial perfusion imaging), the A1AR antagonist Bamifylline (asthma) and the A2AAR antagonist Istradefylline (Parkinson’s disease). A3AR (P0DMS8) (gene located on human chromosome 1 (1p13.2); 318 amino acids in human) was discovered in the early nineties as described in Borea, P. A. et al., The A3 Adenosine Receptor: History and Perspectives, Pharmacol Rev 2015, 67, 74–102. A3AR is coupled to Gi proteins, leading to inhibition of adenylate cyclase, and to Go proteins, leading to activation of phospholipase C and Ca++release. A3AR is also coupled to PI3K / Akt, MAPKs and NF-κB signaling pathways. The biodistribution of A3AR is rather species-dependent. In man, A3AR is expressed in lung, liver, kidney, pancreas, brain, testis and cells of the immune system. A3AR knock-out mice have been generated to investigate the functions of A3AR. A3AR- / -mice are viable, fertile and apparently morphologically indistinguishable from wild-type mice, suggesting that inhibition of this receptor is unlikely to lead to gross toxicity. Although A1AR, A2AAR and A2BAR are well conserved throughout evolution, there are rather important differences in the A3AR sequences of rodents and man (72% and 73% sequence identity between human A3AR and rat or mouse A3AR, respectively). Many human A3AR antagonists are very poorly active or even inactive on rat and mouse orthologs. This complicates translational investigations on the action of A3AR agonists and antagonists in rodent models of human diseases. A3AR-humanized (A3ARh / h) and human / mouse chimeric A3AR (A3ARc / c) mice have been constructed which are sensitive to the agonists developed against human A3AR. In cerebral ischemia A3AR may play both a protective role, by inhibiting excitatory synaptic transmission in synergy with A1AR, and a deleterious effect, by favoring excitotoxicity. A3AR agonists may regulate pain signaling, in particular in the case of anticancer drugs-induced neuropathic pain. A3AR is overexpressed in several tumors and has anti-proliferative and pro-proliferative effects. A3AR agonists and antagonists display antitumor activity. A3AR appears to play a key role in the modulation of inflammation by adenosine. A3AR agonists have therefore been evaluated in clinical trials to treat various inflammatory diseases such as osteoarthritis of the knee, asthma, lung fibrosis. A3AR agonists have been investigated for induction of hypothermia as well as for potential cardioprotective activity, yet the deletion of A3AR appears to confer some resistance to myocardial ischemic injury. Several potent and selective A3AR agonists have been described, Piclidenoson (IB-MECA, N6-iodobenzyl-substituted methylcarboxamidoadenosine, CF101, Can-Fite BioPharma) and Namodenoson (2-Cl-IB-MECA, CF102) being the most advanced drug candidates. Piclidenoson is in clinical trials against in rheumatoid arthritis and psoriasis, while Namodenoson is in clinical trials against hepatocellular carcinoma and non-alcoholic steatohepatitis (NASH). Several A3AR antagonists have also been described, such as KF2677, PSB-10, DPTN (N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide), MRS1523, SSR161421, LJ-1888, pyrazolo-triazolo-pyrimidines, ISVY-130 analogs, 2- chloro-N6-phenylethyladenosine as described in Borea, P. A. et al. previously mentioned, 7-Amino-pyrazolo[3,4-d]pyridazine 10a (dual A1 / A3AR antagonist), as described in Gao, Z.-G. el al. Species Dependence of A3 Adenosine Receptor Pharmacology and Function, Purinergic Signal 2022, 1-28, as illustrated in figure 1.

[0002] In prior art, only the compounds PBF-677 and PBF-1650, (undisclosed structures) have entered clinical trials, for ulcerative colitis (phase 2) and atopic dermatitis (phase 1), respectively (https: / / www.palobiofarma.com / pipeline-2 / ). A3AR antagonists are evaluated for the treatment of glaucoma as they lower intraocular pressure (IOP) in animal models of glaucoma. A3AR antagonists have been evaluated as treatment of asthma, ulcerative colitis, liver fibrosis, kidney diseases in particular kidney fibrosis, nephropathy, nephrotoxicity, atherosclerosis and hypercholestemia. Stimulation of A3AR by adenosine, under hypoxia, contributes to the migration, invasiveness and chemoresistance of glioblastoma stem-like cells and probably in other cancer types under hypoxic conditions. A3 AR antagonists inhibit the proliferation of glioblastoma cell lines.

[0003] Hearing loss (HL) originates from exposure to ototoxic agents (such as platinum-based anticancer drugs or aminoglycoside antibiotics - there are over 600 ototoxic agents described, among which over 200 marketed drugs), from noise, from acoustic trauma (high intensity noise) or from aging. These aggressions trigger irreversible death of ear hair cells located in the organ of Corti (cochlea). The function of these cells is to capture sound vibrations and transduce them as neuronal signals sent to the brain auditory structures. There is considerable interest in the development of otoprotective compounds.

[0004] Cisplatin is a highly effective anticancer drug widely used for the treatment of cancers. Cisplatin’s side effects include nephrotoxicity and ototoxicity. Cisplatin-induced ototoxicity occurs in 23-50% of adults and up to 60% in children. Elevated hearing thresholds may occur in up to 100% of cisplatin-treated cancer patients. Otoprotection would allow the use of these highly effective drugs for life threatening diseases at reduced risk of HL, thereby addressing a significant unmet clinical need. Similarly addressing cisplatin-induced nephrotoxicity would be beneficial. The same applies for the potent but HL-inducing antibiotics, in particular ototoxicity is observed in up to 47% of patients treated with gentamycin, and other products such as neomycin, tobramycin, kanamycin. Noise-induced HL occurs when the ear is exposed to unsafe levels of sounds. The industries where workers often experience noise exposure include agriculture, mining, construction, manufacturing and utilities, transportation, and the military. Globally, some 1.1 billion teenagers and young adults are at risk of HL due to the unsafe use of personal audio devices and exposure to damaging levels of sound at noisy entertainment venues. In all these situations, external protective ear coverings are either insufficient or inappropriate. Moreover, A3R is in particular present in the rat cochlea and is predominantly expressed in the organ of Corti (inner and outer hair cells, Deiter’s cells, Claudius cells, pillar cells). Furthermore, adenosine plays a protective role in nephrotoxicity induced by various drug agents. In particular, there is data available in the litterature suggesting that A2AR and A3AR antagonism may have some protective effects in kidneys exposed to nephrotoxic agents as described in Dewaeles et al. Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects, J. Clin. Invest. 2022, 132, el52924; Lee et al. A3 adenosine receptor knockout mice are protected against ischemia- and myoglobinuria-induced renal failure, Am. J. Physiol. Renal Physiol. 2003, 284, 267-273; and Min et al. Renopprotective effects of a highly selective A3 adenosine receptor antagonist in a mouse model of adriamycin-induced nephropathy, J. Korean Med. Sci. 2016, 31, 1403-1412.

[0005] There is a thus a need to find therapeutic agents to target specific inhibition of A3R.

[0006] SUMMARY OF THE INVENTION

[0007] It has now been found that the compounds as defined in formula (I) hereinafter are useful in the treatment and / or prevention of diseases mediated by A3R.

[0008] FIGURES

[0009] Figure 1 depicts two agonists and a few reported antagonists of A3 AR.

[0010] Figure 2 depicts the results of an evaluation of the potential agonist or antagonist activity of compound (175) on 168 GPCRs and being illustrated in example 10.2.

[0011] Figure 3 depicts the results of a study evaluating the selectivity of compound (175) towards various ARs being illustrated in example 10.3.

[0012] Figure 4 depicts the results of an A3AR functional assay being illustrated in exemple 10.3. Figure 5 depicts the effects of compound (175) on ciliated cells in ex vivo cultured mice organs of Corti exposed to either cisplatin (5A), gentamycin (5B) or neomycin (5C), and being illustrated in example 10.4.

[0013] Figure 6 depicts the effects of compound (175) on the antiproliferative activity of cisplatin evaluated for various cancer cell lines: A549 (human lung carcinoma) (figure 6-A), PANC- 1 (human pancreatic cancer) (figure 6-B), and MDA-435 (human breast cancer) (figure 6- C), being illustrated in example 10.5.

[0014] Figure 7 depicts the results of antibiogram assays obtained with Pseudomonas aeruginosa PA- 19660 without preincubation (A) or after an incubation with vehicle (DMSO) (B) or compound (175) (C), wherein G: Gentamicin; K: Kanamycin; N: Neomycin; S: Streptomycin; T: Tobramycin and W: Water, being illustrated in example 10.6.

[0015] Figure 8 depicts diameters of the inhibition zones determined with Pseudomonas aeruginosa PA- 19660 (figure 8 left) and Staphylococcus aureus Newman strains (figure 8 right) preincubated with vehicle (0.1% DMSO), compound (175) or compound (147) prior to exposure to paper disks containing Gentamicin, Kanamycin, Neomycin, Streptomycin or Tobramycin, being illustrated in example 10.6.

[0016] DEFINITIONS

[0017] As used herein, the term "patient” refers to either an animal, such as a valuable animal for breeding, company or preservation purposes, or preferably a human or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and conditions described herein.

[0018] In particular, as used in the present application, the term 'patient" refers to a mammal such as a rodent, cat, dog, primate or human, preferably said subject is a human.

[0019] The identification of those patients who are in need of treatment of herein- described diseases and conditions is well within the ability and knowledge of one skilled in the art. A veterinarian or a physician skilled in the art can readily identify, by the use of clinical tests, physical examination, medical / family history or biological and diagnostic tests, those patients who are in need of such treatment.

[0020] In the context of the invention, the term "treating" or " treatment" , as used herein, means preventing, reversing, alleviating, inhibiting the progress of, or preventing the diseases as described herein after in the paragraph “PATHOLOGIES”. Therefore, the term “treating” or “treatment” encompasses within the framework of the present invention the improvement of medical conditions of patients suffering from the diseases as described herein after in the paragraph “PATHOLOGIES”, mediated by the A3AR receptor.

[0021] As used herein, an “A3AR inhibitor” or “A3AR antagonist” is a compound able to inhibit A3AR in the assays displayed in example 10.1 in biological activity part described hereafter. In one embodiment, the IC50 value from the compounds of formula (I) according to the invention may be less than or equal to 1000 nM, in particular less than or equal to 100 nM, and more particularly less than or equal to 10 nM, and even more particularly less than or equal to 1 nM, said IC50 values all attesting the inhibitory activity of the compounds.

[0022] As used herein, an “effective amount” refers to an amount of a compound of the present invention which is effective in preventing, reducing, eliminating, treating or controlling the symptoms of the herein-described diseases and conditions. An “effective amount” also refers to an amount of a compound of the present invention which is effective in inhibiting A3AR.

[0023] The term “controlling” is intended to refer to all processes wherein there may be a slowing, interrupting, arresting, or stopping of the progression of the diseases and conditions described herein, but does not necessarily indicate a total elimination of all disease and condition symptoms, and is intended to include prophylactic treatment.

[0024] The term “effective amount” includes “prophylaxis-effective amount” as well as “treatment-effective amount”.

[0025] The term “preventing” , as used herein, means reducing the risk of onset or slowing the occurrence of a given phenomenon, namely in the present invention, a disease mediated by ADORA3.

[0026] As used herein, “preventing” also encompasses “reducing the likelihood of occurrence” or “reducing the likelihood of reoccurrence” .

[0027] The term “prophylaxis-effective amount” refers to a concentration of compound of this invention that is effective in inhibiting, preventing, decreasing the likelihood of anyone of the hereabove described diseases.

[0028] Likewise, the term “treatment-effective amount” refers to a concentration of compound that is effective in treating the hereabove described diseases. As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, excipients, compositions or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem complications commensurate with a reasonable benefit / risk ratio. DETAILED DESCRIPTION OF THE INVENTION The inventors have surprisingly found that the compounds of formula (I) as disclosed herein after, present inhibition activity of A3AR. This assertion is based on data as illustrated in the following examples and more detailed herein after. Herein is further describes a compound of formula (I) or any of its pharmaceutically acceptable salt wherein R1represents a hydrogen atom or a (C1-C6)alkyl group; R2represents a hydrogen atom; R3represents - a linear or branched (C1-C6)alkyl group, optionally substituted by • one phenyl group, optionally substituted by at least one substituent selected from a -OR7group, a -NH2group, a halogen atom, a phenyl group and a (C5-C6)heteroaryl group, • one (C6-C10)heteroaryl group, or • one -OR7group, - a phenyl group or a phenyl group fused with a (C4-C6)cycloalkyl group; or - a (C5-C6)heteroaryl group, optionally substituted by one to three substituents selected from a (C1-C4)alkyl group, a deuterated (C1-C4)alkyl group, a (C1-C4)alkoxy group, a deuterated (C1-C4)alkoxy group and a halogen atom, in particular a fluorine atom or a chlorine atom; L represents a bond, a -CO- group or a -C(O)O- group; or alternately L is a bond and R2and R3form together with the nitrogen atom bearing them a (C5-C6)heterocycloalkyl group containing at least a nitrogen atom fused with a phenyl group; R4represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, a (C3- C6)cycloalkyl group, a (C1-C4)alkoxy group, a (C5-C6)heterocyclocalkyl group, a phenyl group, a (C5-C6)heteroaryl group or a -CF3 group; R5represents a hydrogen atom or a (C1-C4)alkyl group; R6represents - a linear or branched (C1-C6)alkyl group, optionally interrupted by one or two oxygen atoms and optionally substituted by • one phenyl group, optionally substituted by one or two substituents selected from a (C1-C4)alkyl group and a (C1-C4)alkoxy group, • one (C3-C8)cycloalkyl group, optionally substituted by one or two substituents selected from a halogen atom, a (C1-C4)alkyl group and a -OR7group, • one (C5-C6)heterocycloalkyl, • one (C5-C6)heteroaryl group, optionally substituted by one or two (C1-C6)alkyl group, • one or two -OR7groups, • one -SR7group, • one -C(O)NR8R9group, • one -C(O)OR10group, or • one -NHR11group, - a (C3-C7)cycloalkyl group, optionally substituted by one or two substituents selected from a halogen atom, a (C1-C4)alkyl group and a -OR7group, - one bridged (C6-C10)cycloalkyl group, - one spiro(C5-C11)bicyclic ring, - a (C5-C6)heteroaryl group, - a (C5-C6)heterocycloalkyl group, or - a phenyl group fused with a (C4-C6)cycloalkyl group; or R5and R6form together with the nitrogen atom bearing them a (C5-C6)heterocycloalkyl group; R7represents a hydrogen atom, a (C1-C4)alkyl group or a deuterated (C1-C4)alkyl group; R8and R9independently represent a hydrogen atom or a (C1-C6)alkyl group; R10represents a (C1-C4)alkyl group; and R11represents a hydrogen atom or a -CO-(C1-C6)alkyl group; provided that when NR2LR3represents a benzylamino group, then R4does not represent a hydrogen atom. According to a first aspect, a subject-matter of the present invention relates to a compound of formula (I) or any of its pharmaceutically acceptable salt wherein R1represents a hydrogen atom or a (C1-C6)alkyl group; R2represents a hydrogen atom; R3represents - a linear or branched (C1-C6)alkyl group, substituted by • one phenyl group, optionally substituted by at least one substituent selected from a -OR7group, a -NH2group, a halogen atom, a phenyl group and a (C5-C6)heteroaryl group, • one (C6-C10)heteroaryl group, or • one -OR7group, - a phenyl group or a phenyl group fused with a (C4-C6)cycloalkyl group; or - a (C5-C6)heteroaryl group, optionally substituted by one to three substituents selected from a (C1-C4)alkyl group, a deuterated (C1-C4)alkyl group, a (C1-C4)alkoxy group, a deuterated (C1-C4)alkoxy group and a halogen atom, in particular a fluorine atom or a chlorine atom; L represents a bond or a -CO- group; or alternately L is a bond and R2and R3form together with the nitrogen atom bearing them a (C5-C6)heterocycloalkyl group containing at least a nitrogen atom fused with a phenyl group; R4represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, a (C3- C6)cycloalkyl group, a (C1-C4)alkoxy group, a (C5-C6)heterocyclocalkyl group, a phenyl group, a (C5-C6)heteroaryl group or a -CF3 group; R5represents a hydrogen atom or a (C1-C4)alkyl group; R6represents - a linear or branched (C1-C8)alkyl group, optionally interrupted by one or two oxygen atoms and optionally substituted by • one phenyl group, optionally substituted by one or two substituents selected from a (C1-C4)alkyl group and a (C1-C4)alkoxy group, • one (C3-C8)cycloalkyl group, optionally substituted by one or two substituents selected from a halogen atom, a (C1-C4)alkyl group and a -OR7group, • one (C5-C6)heterocycloalkyl, • one (C5-C6)heteroaryl group, optionally substituted by one or two (C1-C6)alkyl group, • one or two -OR7groups, • one -SR7group, • one -C(O)NR8R9group, • one -C(O)OR10group, or • one -NHR11group, - a (C3-C7)cycloalkyl group, optionally substituted by one or two substituents selected from a halogen atom, a (C1-C4)alkyl group and a -OR7group, - one bridged (C6-C10)cycloalkyl group, - one spiro(C5-C11)bicyclic ring, - a (C5-C6)heteroaryl group, - a (C5-C6)heterocycloalkyl group, or - a phenyl group fused with a (C4-C6)cycloalkyl group; or R5and R6form together with the nitrogen atom bearing them a (C5-C6)heterocycloalkyl group; R7represents a hydrogen atom, a (C1-C4)alkyl group or a deuterated (C1-C4)alkyl group; R8and R9independently represent a hydrogen atom or a (C1-C6)alkyl group; R10represents a (C1-C4)alkyl group; and R11represents a hydrogen atom or a -CO-(C1-C6)alkyl group; provided that when NR2LR3represents a benzylamino group, then R4does not represent a hydrogen atom. The inventors have surprisingly discovered that compounds of formula (I) present an inhibitory activity specific to the Adenosine receptor A3 (A3AR) and that some of them even present a powerful inhibitory activity. According to another particular embodiment, herein is further provided a compound of formula (I) as defined herein above, wherein R1represents a hydrogen atom or a methyl group. According to another particular embodiment, herein is further provided a compound of formula (I) as defined herein above, wherein R2represents a hydrogen atom; R3represents - a linear or branched (C1-C6)alkyl group, substituted by • one phenyl group, optionally substituted by one substituent selected from a hydroxy group, a methoxy group, an amino group, a halogen atom, a phenyl group and a pyridyl group, • one pyridyl, one pyrazinyl, one pyrimidinyl or one pyridazinyl group, in particular one pyridyl, pyridazinyl or pyrimidinyl group, or one indolyl or isoindolyl group, in particular an indolyl group, • one hydroxy group, • one methoxy group, one deuterated methoxy group, or • a halogen atom, in particular a fluorine atom or a chlorine atom, - a phenyl group or an indanyl group; or - a pyridyl, a pyrazinyl, a pyrimidinyl or a pyridazinyl group, optionally substituted by one methoxy group or deuterated methoxy group, in particular a pyridyl group; L represents a bond or a -CO- group; or alternately L is a bond and R2and R3form together with the nitrogen atom bearing them an indolinyl, an isoindolinyl, a tetrahydroquinolinyl or a tetrahydroisoquinolinyl group, in particular an isoindolinyl or a tetrahydroisoquinolinyl group. According to another particular embodiment, herein is further provided a compound of formula (I) as defined herein above, wherein R4represents a hydrogen atom, a linear or branched (C1-C5)alkyl group, a (C3-C6)cycloalkyl group, a phenyl group, a pyridyl group or a -CF3group. According to another particular embodiment, herein is further provided a compound of formula (I) as defined herein above, wherein R5represents a hydrogen atom or a (C1-C4) alkyl group, in particular a methyl group; R6represents - a linear or branched (C1-C8)alkyl group, optionally interrupted by one or two oxygen atoms and optionally substituted by • one phenyl group, optionally substituted by one or two substituents selected from a methyl group and a methoxy group, • one (C3-C6)cycloalkyl group, optionally substituted by a methyl group, • one tetrahydropyranyl or one tetrahydrofuranyl group, • one pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridyl, furanyl or thienyl group, optionally substituted by one or two methyl group, • one or two hydroxy group or methoxy group, • one methylthio group, • one -CONH2group, one –CONHCH3group or one -CON(CH3)2group, • one -COOCH3or one -COOCH2CH3group, or • one -NH2 group or one -NCOCH3 group, - a (C3-C7)cycloalkyl group, optionally substituted by one or two substituents selected from a halogen atom, a hydroxy group or a methoxy group, - an adamantyl group, - a spiro[3.3]heptanyl group,

[0029] - an imidazolyl group, optionally substituted by one or two methyl group,

[0030] - a morpholinyl group, a tetrahydropyranyl or a tetrahydrofuranyl group, or

[0031] - an indanyl group; or R5and R6form together with the nitrogen atom bearing them a morpholinyl group or a piperidinyl group.

[0032] Herein is further provided a pharmaceutical composition comprising a compound of formula (I) as defined herein after, or at least any of compounds (1) to (234) as defined hereinafter or any of their pharmaceutically acceptable salts.

[0033] As illustrated in example 10.1, the compounds of formula (I) have been tested as A3AR antagonists. It has been observed that the compounds of formula (I) exert an inhibitory activity on A3AR and thus may be useful in the treatment of pathologies mediated by A3AR.

[0034] As illustrated in example 10.2, a compound of formula (I) has been tested with respect to 168 GPCR receptors. It has been surprisingly observed that this compound of formula (I) is only active on one of them.

[0035] As illustrated in example 10.3, a compound of formula (I) has been additionnaly tested with respect to other adenosine receptors AiAR, AOAAR and AOBAR for selectivity study. It has been surprisingly observed that this compound of formula (I) is only active on A3AR. Moreover, a compound of formula (I) has been additionnaly tested in A3AR functional assay. It has been observed that this compound of formula (I) is an antagonist inhibitor of A3AR.

[0036] The unusal and unexpected specificity and functionality highligted in examples 10.2 and 10.3 calls for the development of potent and selective A3AR antagonists with clinical applications.

[0037] In other terms, as illustrated in examples 10.1, 10.2 and 10.3 the compounds of formula (I) are potent and selective A3 AR antagonists.

[0038] Additionaly, the inventors have suprisingly found that compounds of formula (I) display protective activity towards inner ear hair cells of the organ of Corti exposed to ototoxic agents, in particular platin-based anticancer drugs such as cisplatin, or antibiotics aminoglycosides such as gentamicin or neomycin. Typically, as illustrated in example 10.4, the inventors have shown that the compounds of the present invention display otoprotective activity on ex vivo models of ototoxicity (cultured organs of Corti) induced by ototoxic agents, in particular platin-based anticancer drugs such as cisplatin, or antibiotics aminoglycosides such as gentamicin or neomycin. At last, as illustrated in example 10.5, it has been demonstrated that compounds of formula (I), in particular compound (175), have modest effects on the sensitivity of three cancer cell lines to cisplatin and as illustrated in example 10.6, compounds of formula (I) do not modify the susceptibility of bacterial strains, in particular Pseudomonas aeruginosa and Staphylococcus aureus, to antibiotics, in particular aminoglycosides and more particularly Gentamicin, Kanamycin, Neomycin, Streptomycin and Tobramycin. In the context of the present invention, the term: - “halogen” is understood to mean chlorine, fluorine, bromine, or iodine, and in particular denotes chlorine, fluorine or bromine, - “(C1-Cx)alkyl”, as used herein, respectively refers to a C1-Cx normal, secondary or tertiary monovalent saturated hydrocarbon radical, for example (C1-C8)alkyl. Examples are, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl,ethylbutyl, isohexyl, heptyl, ethylpentyl and octyl groups, and the like. - “(C1-Cx)alkoxy”, as used herein, refers to a -O-(C1-Cx)alkyl or -O-(C3-Cx)cycloalkyl moiety, wherein alkyl and cycloalkyl are as defined above, for example (C1-C6)alkoxy. Examples are, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, cyclopropoxy, butoxy, tert-butoxy and pentoxy. - a (C1-C4)alkylthio group also named a (C1-C4)alkylsulfanyl group: a -S-alkyl group where the alkyl group is as previously defined. By way of examples, mention may be made of, but not limited to: methylthio, ethylthio, propylthio, isopropylthio, linear, secondary or tertiary butylthio, isobutylthio, and the like; - “(C3-C8)cycloalkyl”, as used herein, refers to a monocyclic saturated hydrocarbon, from 3 to 8 carbon atoms, saturated or partially unsaturated and unsubstituted or substituted. Examples of monocyclic rings are, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. - a “bridged (C6-C10)cycloalkyl” group, as used herein, refers to a bi- or tricyclic compound where the cycles are cycloalkyls, the rings share three or more atoms and the bridge contains at least one atom, for example 1, 2 or 3 atoms. Such bridged cycloalkyl groups may be substituted by one or more C1-C3alkyl. Examples are, but not limited to adamantyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, 6,6- dimethylbicyclo[3.1.1]heptyl, bicyclo[3.1.1]heptyl, 1,6,6-trimethylbicyclo[3.1.1]heptyl. - “spiro(C5-C11)bicyclic ring” refers to two rings connected through a defining single common atom. Such spiro bicyclic alkyl generally comprises 5 to 11 carbon atoms referring to a “spiro(C5-C11)bicyclic alkyl group”. Such spirobicyclic ring may be unsubstituted or substituted, in particular by at least one (C1-C3)alkyl group such as methyl. Examples are, but are not limited to spiro[3.3]heptanyl, spiro[2.5]octanyl, in particular a spiro[3.3]heptanyl. - “(C5-C6)heterocycloalkyl group”, as used herein, refers to a (C5-C6)cycloalkyl group wherein one or two of the carbon atoms are replaced with a heteroatom such as oxygen, nitrogen or sulphur, and more particularly with at least one nitrogen atom. Such heterocycloalkyl group may be saturated or partially saturated and unsubstituted or substituted. Examples are, but are not limited to piperazinyl, piperidinyl, pyrrolidinyl, aziridinyl, oxanyl, oxetanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxazolidinyl, oxepanyl, diazepanyl, dioxanyl and tetrahydrothiopyranyl, and more particularly pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl or one tetrahydrofuranyl group. - a (C5-C10)heteroaryl group, as used herein, refers to a monocyclic aromatic or a bicyclic group wherein one to three carbon atom is replaced by a heteroatom, such as nitrogen, oxygen or sulphur. By way of examples of monocyclic aromatic ring of heteroaryl groups, more particulary as a (C5-C6)heteroaryl group, mention may be made of, but not limited to: oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl, pyrazinyl, oxadiazolyl, furanyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, triazolyl and the like. In the framework of the present invention, the heteroaryl is advantageously pyridyl, imidazolyl, pyrazinyl, furanyl, thiazolyl, pyrazolyl, thiadiazolyl, pyridazinyl and pyrimidinyl, and in particular pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. By way of examples of bicyclic aromatic ring of heteroaryl groups, mention may be made of indolyl, isoindolyl, indolinyl, isoindolinyl, quinolinyl or isoquinolinyl. - an aromatic ring means, according to Hückel's rule, that a molecule has 4n + 2 π-electrons. - “deuterated” refers to a group wherein at least one hydrogen atom is replaced by a deuterium atom, such as perdeuterated group wherein all hydrogen atoms are replaced by deuterium atoms. In other terms, a deuterated group may be partially or totally deuterated. By way of examples of deuterated group, more particularly as deuterated (C1- C4)alkyl group, mention may be made of, but not limited to: -CH2D group, -CHD2group or -CD3group. By way of other examples of deuterated group, more particularly as deuterated (C1-C4)alkoxy group, mention may be made of, but not limited to: deuterated methoxy group such as -OCH2D group, -OCHD2group or -OCD3group. In the context of the present invention, the terms “aromatic ring”, and “heteroaryl” include all the positional isomers. The nomenclature of the following compounds (1) to (234) was generated according to the principles of the International Union of Pure and Applied Chemistry, using ChemDraw®Professional v22.0.022. To avoid any confusion, the “(±)” symbol added to designate a racemic mixture; “cis” and “trans” prefixes were also used to assign the relative stereochemistry of two adjacent chiral centers. Specific compounds of the present invention are listed herein after: (1) (2R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (2) (2S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (3) 2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propane-1,3-diol, (4) (2R,3R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butane-1,3-diol, (5) (2S,3S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butane-1,3-diol, (6) N-benzyl-3-isopropyl-6-morpholino-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (7) (2S)-3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propane-1,2-diol, (8) N6-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N8-benzyl-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (9) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propan-1-ol, (10) N8-benzyl-3-isopropyl-N6-(3-methoxypropyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (11) 2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]ethanol, (12) N8-benzyl-3-isopropyl-N6-(2-methoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (13) 4-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (14) N8-benzyl-3-isopropyl-N6-(4-methoxybutyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (15) 5-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]pentan-1-ol, (16) N8-benzyl-3-isopropyl-N6-(5-methoxypentyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (17) N8-benzyl-3-isopropyl-N6-(3-methylsulfanylpropyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (18) N8-benzyl-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (19) N8-benzyl-3-isopropyl-N6-[(3R)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (20) N8-benzyl-3-cyclopentyl-N6-[(3R)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (21) N8-benzyl-3-isopropyl-N6-[(3R)-tetrahydropyran-3-yl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (22) N8-benzyl-3-isopropyl-N6-[(3S)-tetrahydropyran-3-yl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (23) N8-benzyl-3-isopropyl-N6-tetrahydropyran-4-yl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (24) N-[3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propyl]acetamide, (25) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propanamide, (26) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]-N- methyl-propanamide, (27) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]- N,N-dimethyl-propanamide, (28) Methyl 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propanoate, (29) ethyl 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propanoate, (30) (2R)-2-[[8-(benzylamino)-3-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (31) N8-benzyl-3-cyclopropyl-N6-(3-methoxypropyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (32) N8-benzyl-N6-(3-methoxypropyl)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (33) (2R)-2-[[8-(benzylamino)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (34) N8-benzyl-N6-(3-methoxypropyl)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (35) (2R)-2-[[8-(benzylamino)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (36) N8-benzyl-N6-(3-methoxypropyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (37) (2R)-2-[[8-(benzylamino)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (38) 2-[[[6-[[(1R)-1-(hydroxymethyl)propyl]amino]-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazin-8-yl]amino]methyl]phenol, (39) 2-[[[3-isopropyl-6-(3-methoxypropylamino)-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]amino]methyl]phenol, (40) 2-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]amino]methyl]phenol, (41) 3-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]amino]methyl]phenol, (42) 4-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]amino]methyl]phenol, (43) 2-[[[3-isopropyl-6-[[(3R)-tetrahydropyran-3-yl]amino]-[1,2,4]triazolo[4,3- b]pyridazin-8-yl]amino]methyl]phenol, (44) 2-[[[3-isopropyl-6-(tetrahydropyran-4-ylamino)-[1,2,4]triazolo[4,3-b]pyridazin- 8-yl]amino]methyl]phenol, (45) N6-(1-ethylpropyl)-3-isopropyl-N8-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (46) N6-(1-ethylpropyl)-3-isopropyl-N8-(2-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (47) N6-(1-ethylpropyl)-3-isopropyl-N8-(3-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (48) N6-(1-ethylpropyl)-3-isopropyl-N8-(4-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (49) N6-(1-ethylpropyl)-3-isopropyl-N8-(4-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (50) N6-(1-ethylpropyl)-3-isopropyl-N8-(3-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (51) N6-(1-ethylpropyl)-3-isopropyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (52) N6-tert-butyl-3-isopropyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (53) 3-isopropyl-N8-(2-pyridylmethyl)-N6-spiro[3.3]heptan-2-yl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (54) N6-(3,3-difluorocyclobutyl)-3-isopropyl-N8-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (55) N6-(4,4-difluorocyclohexyl)-3-isopropyl-N8-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (56) N6-benzyl-3-isopropyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (57) N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (58) N6-(1-ethylpropyl)-3-methyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (59) 3-ethyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (60) N6-(1-ethylpropyl)-3-propyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (61) 3-tert-butyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (62) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (63) 3-cyclobutyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (64) 3-cyclopentyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (65) 3-cyclohexyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (66) N6-(1-ethylpropyl)-3-phenyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (67) N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-3-sec-butyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (68) N6,3-bis(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (69) N6-(1-ethylpropyl)-3-isobutyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (70) N6-(1-ethylpropyl)-3-(2-pyridyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (71) N6-(1-ethylpropyl)-3-(3-pyridyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (72) N6-(1-ethylpropyl)-3-(4-pyridyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (73) N6-(1-ethylpropyl)-3-isopropyl-N8-[(2-methoxyphenyl)methyl]- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (74) (2R)-2-[[8-[(4-aminophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (75) N8-[(4-aminophenyl)methyl]-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (76) N8-[(3-aminophenyl)methyl]-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (77) N8-[(2-aminophenyl)methyl]-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (78) N6-(1-ethylpropyl)-N8-(1H-indol-2-ylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (79) N-(1-ethylpropyl)-8-isoindolin-2-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin- 6-amine, (80) 8-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(1-ethylpropyl)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-amine, (81) N6-(1-ethylpropyl)-N8-indan-1-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (82) N6-(1-ethylpropyl)-3-isopropyl-N8-(2-phenylethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (83) N6-(1-ethylpropyl)-3-isopropyl-N8-[2-(2-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (84) N6-(1-ethylpropyl)-3-isopropyl-N8-[2-(3-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (85) N6-(1-ethylpropyl)-3-isopropyl-N8-[2-(4-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (86) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-[2-(2-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (87) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-[2-(3-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (88) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-[2-(4-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (89) N6-(1-ethylpropyl)-3-isopropyl-N8-[3-(2-pyridyl)propyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (90) N6-(1-ethylpropyl)-3-isopropyl-N8-[3-(3-pyridyl)propyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (91) N6-(1-ethylpropyl)-3-isopropyl-N8-[3-(4-pyridyl)propyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine (92) N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrimidin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (93) N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrimidin-5-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (94) N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrazin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (95) N6-(1-ethylpropyl)-3-isopropyl-N8-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (96) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]benzamide, (97) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]pyridine-2-carboxamide, (98) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2- phenyl-acetamide, (99) ethyl N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]carbamate, (100) phenyl N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]carbamate, (101) (2S)-2-[[8-[(4-bromophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (102) (2S)-2-[[3-isopropyl-8-[(4-phenylphenyl)methylamino]-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (103) (2S)-2-[[3-isopropyl-8-[[4-(4-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (104) (2S)-2-[[3-isopropyl-8-[[4-(3-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (105) (2S)-2-[[3-isopropyl-8-[[4-(2-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (106) (2R,3R)-2-[[8-[(4-bromophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butane-1,3-diol, (107) (2R,3R)-2-[[3-isopropyl-8-[[4-(2-pyridyl)phenyl]methylamino]- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butane-1,3-diol, (108) (2R,3R)-2-[[3-isopropyl-8-[[4-(4-pyridyl)phenyl]methylamino]- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butane-1,3-diol, (109) N6,N8-bis(3-methoxypropyl)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (110) 3-cyclopropyl-N6,N8-bis(3-methoxypropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (111) N6,N8-bis(3-methoxypropyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (112) 3-isopropyl-N6,N8-bis(2-methoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (113) (2R)-2-[[6-[[(1R)-1-(hydroxymethyl)propyl]amino]-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]butan-1-ol, (114) N6,N8-bis(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (115) (2R)-2-[[8-(benzylamino)-3-isopropyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazin- 6-yl]amino]butan-1-ol, (116) N8-[(4-bromophenyl)methyl]-3-isopropyl-N6-methyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (117) N8-benzyl-N6-cyclobutyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (118) N8-benzyl-N6-cyclopentyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (119) N8-benzyl-N6-cyclohexyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (120) N8-benzyl-3-isopropyl-N6-(4-methoxycyclohexyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (121) N8-benzyl-N6-cycloheptyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (122) N8-benzyl-N6-(cyclopropylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (123) N8-benzyl-N6-(cyclobutylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (124) N8-benzyl-N6-(cyclohexylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (125) N8-benzyl-3-isopropyl-N6-(tetrahydropyran-4-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (126) N8-benzyl-N6-(2-ethylbutyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (127) N8-benzyl-3-isopropyl-N6-(2-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (128) N8-benzyl-3-isopropyl-N6-(2-phenoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (129) N8-benzyl-3-isopropyl-N6-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (130) N6,N8-dibenzyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (131) N8-benzyl-3-isopropyl-N6-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (132) N8-benzyl-3-isopropyl-N6-(3-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (133) N8-benzyl-3-isopropyl-N6-(4-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (134) racemic trans-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]cyclohexanol, (135) racemic trans-4-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]cyclohexanol, (136) N8-benzyl-3-isopropyl-N6-[(1-methylcyclohexyl)methyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (137) N6-(1-adamantyl)-N8-benzyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (138) N8-benzyl-N6-indan-2-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (139) N8-benzyl-3-isopropyl-N6-[(5-methylpyrazin-2-yl)methyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (140) N8-benzyl-3-isopropyl-N6-[(1-methylpyrazol-4-yl)methyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (141) N8-benzyl-N6-[(3,5-dimethylphenyl)methyl]-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (142) N8-benzyl-3-isopropyl-N6-(tetrahydrofuran-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (143) N8-benzyl-3-isopropyl-N6-(2-methylsulfanylethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (144) N8-benzyl-3-isopropyl-N6-(1-methylimidazol-2-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (145) N8-benzyl-N6-[(4,6-dimethylpyrimidin-2-yl)methyl]-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (146) N8-benzyl-N6-indan-1-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (147) N6-(2-ethylbutyl)-3-isopropyl-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (148) 3-isopropyl-N6-(pentan-3-yl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (149) 3-isopropyl-N6-(pentan-3-yl)-N8-(pyridazin-4-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (150) 3-isopropyl-N6-(pentan-3-yl)-N8-(pyrimidin-4-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (151) 3-isopropyl-N6-(pentan-3-yl)-N8-(pyrimidin-5-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (152) 3-isopropyl-N6-(pentan-3-yl)-N8-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (153) 3-isopropyl-N6-(pentan-3-yl)-N8-(pyrazin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (154) 3-isopropyl-N8-(6-methoxypyridin-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (155) 3-isopropyl-N8-(5-methoxypyridin-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (156) 3-isopropyl-N8-(4-methoxypyridin-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (157) 3-isopropyl-N8-(3-methoxypyridin-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (158) 3-isopropyl-N8-(2-methoxypyridin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (159) 3-isopropyl-N8-(6-methoxypyridin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (160) isopropyl-N8-(5-methoxypyridin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (161) 3-isopropyl-N8-(4-methoxypyridin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (162) 3-isopropyl-N8-(5-methoxypyridazin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (163) (2R)-2-[[3-isopropyl-8-(2-pyridylamino)-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (164) N6-(2-ethylbutyl)-3-isopropyl-N8-[2-(2-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (165) N6-cyclopentyl-3-isopropyl-N8-[2-(2-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (166) N6-(2-ethylbutyl)-3-isopropyl-N8-[2-(3-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (167) N6,N8-bis(2-ethylbutyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (168) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2- (3-pyridyl)acetamide, (169) (2R)-2-[[3-isopropyl-8-(2-pyridylmethylamino)imidazo[1,2-b]pyridazin-6- yl]amino]butan-1-ol, (170) N6-(1-ethylpropyl)-3-isopropyl-N8-(3-phenylpropyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (171) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-phenyl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (172) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-(2-pyridyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (173) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-(3-pyridyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (174) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-(4-pyridyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (175) 3-cyclopropyl-N6-(pentan-3-yl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (176) 3-cyclopropyl-N6-(pentan-3-yl)-N8-(pyridazin-4-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (177) 3-cyclopropyl-N6-(pentan-3-yl)-N8-(pyrimidin-4-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (178) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-pyrimidin-5-yl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (179) 3-cyclopropyl-N6-(pentan-3-yl)-N8-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (180) 3-cyclopropyl-N6-(pentan-3-yl)-N8-(pyrazin-2-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (181) (R)-2-((3-cyclopropyl-8-(pyridazin-3-ylamino)-[1,2,4]triazolo[4,3-b]pyridazin-6- yl)amino)butan-1-ol, (182) (S)-2-((3-cyclopropyl-8-(pyridazin-3-ylamino)-[1,2,4]triazolo[4,3-b]pyridazin-6- yl)amino)butan-1-ol, (183) 3-cyclopropyl-N8-(6-methoxypyridin-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (184) 3-cyclopropyl-N8-(2-methoxypyridin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (185) (2R)-2-[[3-cyclopropyl-8-[2-(2-pyridyl)ethylamino]-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (186) N6-benzyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (187) 3-cyclopropyl-N6-(4-methoxybenzyl)-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (188) 3-cyclopropyl-N6-(4-methoxybenzyl)-N6-methyl-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (189) 3-cyclopropyl-N6-ethyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (190) 3-cyclopropyl-N6-propyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (191) N6-butyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (192) 3-cyclopropyl-N6-isopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (193) N6-(sec-butyl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (194) 3-cyclopropyl-N6-isobutyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (195) N6-(tert-butyl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (196) 3-cyclopropyl-N6-(2-ethylbutyl)-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (197) N6,3-dicyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (198) N6-cyclobutyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (199) N6-cyclopentyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (200) N6-cyclohexyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (201) N6-cycloheptyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (202) N6-((3s,5s,7s)-adamantan-1-yl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (203) 3-cyclopropyl-N6-(cyclopropylmethyl)-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (204) N6-(cyclobutylmethyl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (205) 3-cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(spiro[3.3]heptan-2-yl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (206) 3-cyclopropyl-N6-((1-methylcyclobutyl)methyl)-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (207) 3-cyclopropyl-6-(1-piperidyl)-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazin-8-amine, (208) 3-cyclopropyl-N6-(furan-2-ylmethyl)-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (209) 3-cyclopropyl-N6-(furan-3-ylmethyl)-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (210) 3-cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(thiophen-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (211) (R)-2-((3-cyclopropyl-8-((pyridin-2-ylmethyl)amino)-[1,2,4]triazolo[4,3- b]pyridazin-6-yl)amino)butan-1-ol, (212) (S)-2-((3-cyclopropyl-8-((pyridin-2-ylmethyl)amino)-[1,2,4]triazolo[4,3- b]pyridazin-6-yl)amino)butan-1-ol, (213) (R)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(tetrahydrofuran -3-yl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (214) (R)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(tetrahydro-2H-pyran-3-yl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (215) 3-cyclopropyl-N8-(6-methoxypyridazin-3-yl)-N6-(pentan-3-yl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (216) 3-cyclopropyl-N6-(pentan-3-yl)-N8-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (217) 3-cyclopropyl-N6-(pentan-3-yl)-N8-phenethyl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (218) 3-cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(thiophen-3-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (219) 3-cyclopropyl-N6-methyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (220) 3-cyclopropyl-N-(pyridin-2-ylmethyl)-6-(pyrrolidin-1-yl)-[1,2,4]triazolo[4,3- b]pyridazin-8-amine, (221) 3-isopropyl-N8-(2-methoxypyrimidin-4-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (222) 3-isopropyl-N8-(5-methoxypyrimidin-4-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (223) 3-isopropyl-N8-(6-methoxypyrimidin-4-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (224) 3-isopropyl-N8-(6-methoxypyridazin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (225) 3-cyclopropyl-N6-(2-ethylbutyl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (226) 3-cyclopropyl-N6-(2-ethylbutyl)-N8-(6-methoxypyridazin-3-yl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (227) N8-(6-chloropyridazin-3-yl)-3-isopropyl-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (228) N8-(2-chloropyrimidin-4-yl)-3-isopropyl-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (229) N6-(2-ethylbutyl)-3-isopropyl-N8-(6-methoxypyridazin-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (230) N6-(3-ethylpentyl)-3-isopropyl-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (231) 3-isopropyl-N8-(6-(methoxy-d3)pyridazin-3-yl)-N6-(pentan-3-yl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (232) N8-(6-chloropyridazin-3-yl)-N6-(2-ethylbutyl)-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (233) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2- (2-pyridyl)acetamide, (234) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2- (4-pyridyl)acetamide and their pharmaceutically acceptable salts. Thus, herein is provided anyone of the compounds (1) to (234) as defined above or any of their pharmaceutically acceptable salts. According to an even more preferred embodiment of the present invention, the compound is chosen from the group consisting of compounds (1), (2), (10), (13), (14), (17) to (19), (21) to (23), (26), (28), (29), (31), (35) to (56), (58) to (64), (66) to (69), (71) to (78), (80) to (105), (107), (110), (111), (114), (117) to (119), (121) to (124), (126), (127), (130) to (132), (134), (136), (138), (140), (143), (146) to (160), (162) to (187), (189) to (206), (208) to (212), (215) to (218), (221) and (223) to (234) and their pharmaceutically acceptable salts. According to an even more preferred embodiment of the present invention, the compound is chosen from the group consisting of compounds (18), (38), (40) to (42), (45) to (53), (56), (59), (62), (63), (67), (68), (73), (75), (76), (80), (82) to (88), (90), (91), (93) to (95), (98) to (100), (114), (118), (126), (130), (147) to (151), (153) to (156), (158) to (160), (162), (164) to (168), (170) to (178), (180) to (183), (186), (187), (191) to (193), (195), (196), (198) to (202), (204) to (206), (208) to (210), (215) to (218), (221) and (223) to (234) and their pharmaceutically acceptable salts. According to an even more particularly preferred embodiment of the present invention, the compound is chosen from the group consisting of compounds (46), (47), (83), (86), (87), (98), (147), (148), (150), (151), (153) to (155), (158), (159), (162), (164), (168), (171) to (175), (177), (178), (180) to (183), (215), (221), (223) to (232) and (234) and their pharmaceutically acceptable salts. According to another aspect, a subject-matter of the present invention relates to a compound of formula (I) as defined above or any of its pharmaceutically acceptable salts, or at least any of compounds (1) to (234) or any of their pharmaceutically acceptable salts, for use as a medicament. “Pharmaceutically acceptable salt thereof” refers to salts which are formed from acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid,), as well as salts formed with organic acids such as acetic acid, tartaric acid, succinic acid. Suitable physiologically acceptable acid addition salts of compounds of formula (I) include hydrobromide, tartrate, hydrochloride, mesylate, succinate and acetate. The compounds of formula (I), and any of compounds (1) to (234) or any of their pharmaceutically acceptable salts may form solvates or hydrates and the invention includes all such solvates and hydrates. The terms “hydrates” and “solvates” simply mean that the compounds (I) according to the invention can be in the form of a hydrate or solvate, i.e. combined or associated with one or more water or solvent molecules. This is only a chemical characteristic of such compounds, which can be applied for all organic compounds of this type. The compounds of formula (I) can comprise one or more asymmetric carbon atoms. They can thus exist in the form of enantiomers or of diastereoisomers. These enantiomers, diastereoisomers and their mixtures, including the racemic mixtures, are encompassed within the scope of the present invention. The compounds of the present invention can be prepared by conventional methods of organic synthesis practiced by those skilled in the art. The general reaction sequences outlined below represent a general method useful for preparing the compounds of the present invention and are not meant to be limiting in scope or utility. List of abbreviations: Abbreviation / acronym Name A1AR Adenosine receptor A1A2AAR Adenosine receptor A2AA2BAR Adenosine receptor A2B A3AR Adenosine receptor A3 ACN Acetonitrile AcOH Acetic acid Alk Alkyl ATP Adenosine triphosphate br s Broad singlet Abbreviation / acronym Name nBuOH Butan-1-ol C Molar concentration cHex Cyclohexane Cpd N° Compound number d Doublet DCM Methylene chloride dd Doublet of doublets DIPEA N,N-Diisopropylethylamine DMF Dimethylformamide DMSO Dimethylsulfoxide eq Equivalent ESI Electrospray ionization Et Ethyl EtOAc Ethyl Acetate GP General protocol Hal Halogen HPLC High pressure liquid chromatography IC50 Half maximal inhibitory concentration iPr isopropyl iPrOH Isopropanol KHMDS Potassium bis(trimethylsilyl)amide m Multiplet M Molarity Me Methyl 2MePrOH 2-Methylpropan-1-ol MS Mass spectroscopy MW Molecular weight NBS N-Bromosuccinimide NMP N-Methyl-2-pyrrolidone NMR Nuclear magnetic resonance N / A Not applicable n.t. Not tested Phe phenyl PIDA phenyliodine(III) diacetate nPrOH Propan-1-ol Abbreviation / acronym Name PTLC Preparative thin layer chromatography PTSA.H2O or APTS.H2O p-Toluenesulfonic acid monohydrate Rac Racemic r.t. Room temperature s Singlet t Triplet TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography Ts Tosyl T °C Temperature in degrees Celsius UV Ultraviolet v / v Volume per volume w / v Weight per volume Δ chemical shift µw Microwave irradiation The compounds of general formula (I) can be prepared according to Route 1 depicted in scheme 1 below.

[0039] Scheme 1 According to Route 1, the synthesis of compounds according to the invention is based on a functionalization of a compound of formula (II) wherein L, R2, R3and R4are as defined above by an amine of formula (IV) wherein R5and R6are as defined above. The compound of formula (II) may be placed in STEP 3a in an aprotic solvent such as Et3N, THF, 2-MeTHF, dioxane, cineol or NMP or a mixture of both or without solvent or else in a protic solvent such as ethylene glycol. The amine of formula (IV) may be added, for example in a molar ratio ranging from 1 to 20 eq, in particular of 10 eq, with respect to the compound of formula (II). The reaction mixture may be heated at a temperature between 150 to 180°C. Upon completion of the reaction, the mixture may be brought back to room temperature. The compound of formula (II) may be placed in STEP 3b in an aprotic solvent such as Et3N, THF, 2-MeTHF, dioxane, cineol or NMP or a mixture of both or without solvent or else in a protic solvent such as ethylene glycol. The amine of formula (IV’), wherein R’6comprises a -COOH group, may be added, for example in a molar ratio ranging from 1 to 20 eq, in particular of 10 eq, with respect to the compound of formula (II). The reaction mixture may be heated at a temperature between 150 to 180°C. Upon completion of the reaction, the mixture may be brought back to room temperature. STEP 3c may be implemented according to known procedures for obtaining the corresponding amide or ester compound of formula (I). A compound of formula (II) as defined above may be obtained in STEP 2 by reaction of a compound of formula (III) wherein L, R2and R3are as defined above, in an aprotic solvent such as dioxane. The hydrazide of formula (V) may be added, for example in a molar ratio ranging from 1 to 3 eq, in particular of 1.2 eq, with respect to the compound of formula (III). The resulting mixture may then be stirred, for example from 1 to 36 hours, in particular for 16 hours at a temperature between 100 °C to 115 °C by refluxing or in a sealed tube. A compound of formula (III) as defined above may be obtained in STEP 1 by reaction of a compound of formula (a) with a compound of formula (VI) wherein L, R2and R3are as defined above, in an aprotic solvent such as DCM, THF, 2-MeTHF or dioxane, or a mixture thereof. The reaction mixture may be stirred at room temperature or reflux temperature or in sealed tube with DCM at 50 °C for a duration ranging from 1 to 24 hours, for example for 16 hours. The compounds of general formula (I) can alternatively be prepared according to Route 2, depicted in scheme 2 below. Scheme 2 According to Route 2, the synthesis of compounds according to the invention is based on a functionalization of a compound of formula (II) wherein L, R2, R3, R4and R5are as defined above by an amine of formula (IV) wherein R5and R6are as defined above. The compound of formula (II) may be placed in STEP 3 in an aprotic solvent such as Et3N, THF, 2-MeTHF, dioxane, cineol or NMP or a mixture of both or without solvent or else in a protic solvent such as ethylene glycol. The amine of formula (IV) may be added, for example in a molar ratio ranging from 1 to 20 eq, in particular of 10 eq, with respect to the compound of formula (II). The reaction mixture may be heated at a temperature between 150 to 180°C. Upon completion of the reaction, the mixture may be brought back to room temperature.A compound of formula (II) as defined above may be obtained in STEP 2 by reaction of a compound of formula (VII) wherein R4is as defined above by an amine of formula (VI) wherein L, R2and R3are as defined above, in an aprotic solvent such as DCM, THF or 2Me-THF. The amine of formula (VI) may be added, for example in a molar ratio ranging from 1 to 5 eq, in particular of 1.2 eq, with respect to the compound of formula (VII). The resulting mixture may then be stirred, for example from 1 to 24 hours, in particular for 3 hours at a temperature between room temperature to solvent refluxing. A compound of formula (VII) as defined above may be obtained in STEP 1 by reaction of a compound of formula (b) with a compound of formula (VIII) wherein R4is as defined above, in an aprotic solvent such as THF, 2-MeTHF or dioxane. The reaction mixture may be stirred at room temperature for a duration ranging from 1 to 24 hours, for example for 16 hours. The compounds of general formula (I) can alternatively be prepared according to Routes 3, depicted in scheme 3 below. Scheme 3 According to Route 3, the synthesis of compounds according to the invention is based on a functionalization of a compound of formula (IX) wherein R4, R5and R6are as defined above by an amine of formula (VI) wherein L, R2and R3are as defined above. The compound of formula (IX) may be placed in STEP 5 in an aprotic solvent such as dioxane. The amine of formula (VI) may be added, for example in a molar ratio ranging from 1 to 10 eq, in particular of 6 eq, with respect to the compound of formula (IX). The reaction mixture may be heated at a temperature between 100 to 130°C, in particular 110°C in a sealed tube. Upon completion of the reaction, the mixture may be brought back to room temperature. A compound of formula (IX) as defined above may be obtained in STEP 4 by oxydation of a compound of formula (X) wherein R4, R5and R6are as defined above, in a mixture of THF and water. The oxidazing reagent may be added, for example in a molar ratio ranging from 2 to 5 eq, in particular of 3.3 eq, with respect to the compound of formula (IX). The resulting mixture may then be stirred, for example from 1 to 24 hours, in particular for 18 hours at room temperature. A compound of formula (X) as defined above may be obtained in STEP 3 by an amine of formula (V) wherein R1and R2are as defined above. The compound of formula (X) may be placed in STEP 3 in an aprotic solvent such as Et3N, DIPEA, THF, 2- MeTHF, dioxane, cineol or NMP or a mixture of both or without solvent. The amine reagent may be added, for example in a molar ratio ranging from 2 to 20 eq, in particular of 15 eq, with respect to the compound of formula (IX). The resulting mixture may then be stirred, for example from 0.5 to 24 hours, in particular for 18 hours at a temperature between 100 to 150°C, in particular 120°C in a sealed tube. A compound of formula (XI) as defined above may be obtained in STEP 2 by reaction of a compound of formula (d) with a compound of formula (V) wherein R4is as defined above, in an aprotic solvent such as THF, 2-MeTHF or dioxane. The reaction mixture may be stirred for a duration ranging from 1 to 24 hours, for example for 16 hours at a temperature ranging between 100 to 150°C, in particular 110°C in a sealed tube. A compound of formula (d) as defined above may be obtained in STEP 2 by reaction of a compound of formula (a) with methylsulfanylsodium in an aprotic solvent such as THF or 2-MeTH. The reaction mixture may be stirred for a duration ranging from 1 to 6 hours, for example for 3 hours at room temperature or solvent refluxing. The compounds of general formula (I) can alternatively be prepared according to Routes 4, depicted in scheme 4 below. Scheme 4 According to Route 4, the synthesis of compounds according to the invention is based on a functionalization of a compound of formula (XII) wherein R4, R5and R6are as defined above by a reagent of formula (XIV) wherein L and R3are as defined above and X represents a hydroxy group, a chlorine atom, a bromine atom, an (C1-C3)alkyl sulfonate group or a phenyl sulfonate group . The compound of formula (XII) may be placed in STEP 3 in an aprotic solvent such as THF, 2-MeTHF, dioxane, DMSO or DMF. The reagent of formula (XIV) may be added, for example in a molar ratio ranging from 1 to 10 eq, in particular of 2 eq, with respect to the compound of formula (XII). The reaction mixture may be stirred for a duration ranging from 1 to 24 hours, for example for 3 hours at room temperature or solvent refluxing. A compound of formula (XII) as defined above may be obtained in STEP 2 by reacting a compound of formula (XIII) wherein R4is as defined above with an amine of formula (IV) wherein R5and R6are as defined above. The compound of formula (XIII) may be placed in STEP 2 in an aprotic solvent such as Et3N, DIPEA, THF, 2-MeTHF, dioxane, cineol or NMP or a mixture of both or without solvent. The amine reagent may be added, for example in a molar ratio ranging from 2 to 20 eq, in particular of 10 eq, with respect to the compound of formula (XIII). The resulting mixture may then be stirred, for example from 0.5 to 72 hours, in particular for 24 hours at a temperature between 150 to 220 °C, in particular 180°C in a sealed tube or under microwave irradiation system. A compound of formula (XIII) as defined above may be obtained in STEP 1 by reaction of a compound (e) with a compound of formula (V) wherein R4is as defined above, in an aprotic solvent such as THF, 2-MeTHF or dioxane or an protic solvent such as iPrOH, nPrOH, 2-MePrOH or nBuOH. The reaction mixture may be stirred for a duration ranging from 1 to 24 hours, for example for 18 hours at a temperature ranging between 100 to 150°C, in particular 110°C in a sealed tube or solvent refluxing. Accordingly, herein is further provided a synthesis process for manufacturing a compound of formula (I) as defined above or any of its pharmaceutically acceptable salts, or at least any of compounds (1) to (234) as defined above or any of their pharmaceutically acceptable salts, comprising at least a step of reacting a compound of formula (II) wherein L, R2, R3and R4are as defined above, with an amine of formula (IV) NHR5R6(IV) wherein R5and R6are as defined above, for example in a molar ratio ranging from 1 to 20 eq, with respect to the compound of formula (II), in an aprotic solvent or without solvent or else in a protic solvent. Herein is further provided a synthesis process for manufacturing a compound of formula (I) as defined above or any of its pharmaceutically acceptable salts, or at least any of compounds (1) to (234) as defined above or any of their pharmaceutically acceptable salts, comprising at least a step of reacting a compound of formula (IX) wherein R4, R5and R6are as defined above, with a compound of formula (VI) (VI) wherein R2and R3are as defined above, in an aprotic solvent, for example in a molar ratio ranging from 1 to 10 eq, with respect to the compound of formula (IX). Herein is further provided a synthesis process for manufacturing a compound of formula (I) as defined above or any of its pharmaceutically acceptable salts, or at least any of compounds (1) to (234) as defined above or any of their pharmaceutically acceptable salts, comprising at least a step of reacting a compound of formula (XII) wherein R5and R6are as defined above, with a compound of formula (XIV) (XIV) wherein L and R3are as defined above and X represents a hydroxy group, a chlorine atom, a bromine atom, an (C1-C3)alkyl sulfonate group or a phenyl sulfonate group, in an aprotic solvent for example in a molar ratio ranging from 1 to 10 eq, with respect to the compound of formula (XII). Herein is further provided a compound of formula (II), (X), (XI) or (VII), in particular as an intermediate compound wherein R4, R5and R6are as defined above, provided that R4is not a methyl group in formula (XI). The intermediate products (a), (b) and (e) may be obtained commercially or according to methods known to the man skilled in the art. The chemical structures, the analytical and spectroscopic data of some compounds of formula (I) of the invention are illustrated respectively in the following Table 1 and Table 2. Reactions were performed using glassware or oven-dried glassware under inert atmosphere of argon or not. Unless otherwise noted, all reagent-grade chemicals and solvents were obtained from commercial suppliers and were used as received. Reactions were monitored by thin-layer chromatography with silica gel 60 F254 pre-coated aluminum plates (0.25 mm). Visualization was performed under UV light and 254 or 365 nm, or with appropriate TLC stains including, but not limited to: phosphomolybdic acid, KMnO4, ninhydrin, CAM, vanillin, p-anisaldehyde. Chromatographic purifications of compounds were achieved on an automated Interchim Puriflash XS420 equipped with 30 µm spherical silica-filled prepacked columns as stationary phase (normal phase) or with C18 silica prepacked columns as stationary phase (reversed phase). Nevertheless, a second purification could be achieved with preparative thin layer chromatography with standard silica. Purifications work with various solvent as pur or mixed such as ethyl acetate, cyclohexane, methanol, methanol with ammonia 7N, dichloromethane, triethylamine and tetrahydrofuran on a normal phase then ACN, MeOH, H2O and NH4OH on a reversed phase. Mixtures possibilities: cHex / EtOAc, cHex / DCM, cHex / DCM / EtOAc, DCM / EtOAc, DCM / MeOH, DCM / MeOH NH37N, DCM / MeOH / Et3N, DCM / MeOH / THF, EtOAc / MeOH, EtOAc / MeOH NH37N, EtOAc / THF, ACN / H2O, ACN / NH4OH, MeOH / H2O, MeOH / NH4OH. Some compounds of the invention are described with their structure in the below Table 1, which is merely illustrative and does not limit the scope of the present invention.

[0040] Table 1: Structure of compounds (1) to (234). Formulas and molecular weights were

[0041] 32) C17H22N6O 326.40 - (33) C17H22N6O 326.40 (R) (34) C22H24N6O 388.48 - (35) C22H24N6O 388.48 (R) (36) C17H19F3N6O 380.38 - (37) C17H19F3N6O 380.38 (R) (38) C19H26N6O2370.46 (R) (39) C19H26N6O2370.46 -

[0042] (103) C24H29N7O 431.54 (S) (104) C24H29N7O 431.54 (S) (105) C24H29N7O 431.54 (S) (106) C19H25BrN6O2449.35 (S) (107) C24H29N7O2 447.54 (2R,3R)

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050] The below Table 2 describes the analytical and spectroscopic data of the compounds introduced in Table 1.

[0051] ’ H NMR analyses (400 or 500 MHz) and13C NMR spectra (101 MHz) were recorded with a Bruker ULTRASHIELD 500 or 400 spectrometer. Processing and analyses of the spectra were performed with MestReNova. Data appear in the following order: chemical shifts in ppm which were referenced to the internal solvent signal, multiplicity, number of protons, and coupling constant J in Hertz.

[0052] Synthetic intermediates: re versed-phase UPLC / MS analyses were carried out with a UPLC Acquity (Waters) with an UV-DAD detector and a mass detector (SQD2). Compounds (0.2 to 0.6 mg) were solubilized in a mixture of DMSO / H2O (1 / 1) and filtered on syringe filter 0.2 pm. - Acidic conditions: Acquity BEH C18 column, 2.1 x 50 mm, 1.7 µm. Flow rate: 0.65 mL / min. Gradient: (H2O + 0.1% HCOOH v / v) / (CAN + 0.1% HCOOH v / v) from 95 / 5 to 5 / 95 in 4.0 min. Final compounds: Reversed-phase HPLC / MS analyses were carried out with a HPLC Ultimate 3000 (ThermoScientific) with an UV-DAD detector. Mass detection processing with direct infusion in mass detector (SQD2) from UPLC Acquity (Waters). Compounds (0.2 to 0.6 mg) were solubilized in a mixture of DMSO / H2O (1 / 1) and filtered on syringe filter 0.2 µm. - Acidic conditions: Thermo Scientific Syncronis C18 column, 150 x 4.6 mm, 5 µm. Flow rate: 1 mL / min. Gradient: (H2O + 0.1% HCOOH v / v) / (ACN + 0.1% HCOOH v / v) from 95 / 5 to 5 / 95 in 19.0 min. - Alkaline conditions: Thermo Scientific Syncronis C18 column, 150 x 4.6 mm, 5 µm or XTERRA RP18, 150x4.6mm, 3.5μm. Flow rate: 1 mL / min. Gradient: (HCOONH4 10mM + NH4OH 25% aq. to ajust pH = 10) / ACN from 95 / 5 to 5 / 95 in 19.0 min.

[0053] Table 2: Spectroscopic and analytical characterization of compounds (1) to (234) aAcidic conditions,bAlkaline conditions PATHOLOGIES Examples of diseases mediated A3AR include, but are not limited to, ulcerative colitis, atopic dermatitis, glaucoma, asthma, liver fibrosis, kidney diseases in particular kidney fibrosis, nephropathy, acute kidney injury (AKI), chronic kidney disease (CKD) more particularly induced by ischemia and / or reperfusion injury, toxic nephropathy or myoglobinuria, diabetic kidney disease, kidney diseases induced by nephrotoxicity caused by therapeutic drugs, atherosclerosis, hypercholestemia, partial or a complete hearing loss induced by noise, acoustic trauma or ototoxic agents or conditions, and cancers developing under hypoxic conditions, in particular glioblastoma. The compounds of formula (I) or any of its pharmaceutically acceptable salts, may in particular be useful in the treatment and / or in the prevention of hearing loss, in particular induced by ototoxic agents, as well as in the treatment and / or in the prevention of kidney diseases, in particular induced by nephrotoxicity. The compounds of formula (I) or any of its pharmaceutically acceptable salts may in particular be useful in the treatment and / or in the prevention of partial or a complete hearing loss, in particular induced by noise, acoustic trauma or ototoxic agents or conditions, more particularly induced by ototoxic agents or conditions. The compounds of formula (I) or any of its pharmaceutically acceptable salts may in particular be useful in the treatment and / or in the prevention of partial or a complete hearing loss induced by ototoxic agents or conditions as described hereinafter. As ototoxic agents, i.e. causing hear loss, the following may be cited: - solvents, such as polyethylene glycol, propylene glycol or benzalkonium chloride; - antibiotics, in particular topical and / or systemic antibiotics, more particularly aminoglycosides, macrolides or phenicol antibiotics, such as gentamycin, neomycin, tobramycin, kanamycin, nystatin, polymyxin B, amphotericin B, bacitracin or chloramphenicol; - anticancer drugs, in particular platinum-based anticancer drugs, such as cisplatin or carboplatin, - antiseptics, in particular acetic acid, alcohols such as ethanol, chlorhexidine, cresylate, gentian violet or povidone iodine; - nonsteroidal anti-inflammatory drugs (NSAIDs), in particular salicylates, cyclodextrins, indomethacin, ibuprofen, phenylbutazone or paracetamol; - topical combinations, in particular polymyxin / neomycin / hydrocortisone or ticarcilline / clavulanate; - drugs for COVID-19, in particular lopinavir or ritonavir; - antimalarial drugs, in particular quinine or chloroquine; - cardiovascular drugs, in particular loop diuretics; or - erectile dysfunction drugs, in particular phosphodiesterase type 5 (PDE-5) inhibitors. The compounds of formula (I) or any of its pharmaceutically acceptable salts may in particular be useful in the treatment and / or in the prevention of hearing loss being a partial or a complete hearing loss, in particular being induced by noise, acoustic trauma or ototoxic agents or conditions, more particularly platin-based anticancer drugs such as cisplatin or carboplatin, antibiotics, even more particularly macrolides or aminoglycosides such as gentamycin or neomycin, drugs for COVID-19 such as lopinavir or ritonavir, antimalarial drugs such as quinine or chloroquine, cardiovascular drugs such as loop diuretics, non-steroidal anti-inflammatory drugs such as salicylate or cyclodextrins, erectile dysfunction drugs such as phosphodiesterase type 5 inhibitors. The compounds of formula (I) or any of its pharmaceutically acceptable salts may in particular be useful in the treatment and / or in the prevention of kidney diseases, in particular selected from nephropathy, acute kidney injury (AKI), chronic kidney disease (CKD) more particularly induced by ischemia and / or reperfusion injury, toxic nephropathy or myoglobinuria, and diabetic kidney disease, or kidney diseases induced by nephrotoxicity caused by therapeutic drugs. The compounds of formula (I) or any of its pharmaceutically acceptable salts may in particular be useful in the treatment and / or in the prevention of kidney diseases induced by nephrotoxicity caused by therapeutic drugs as described hereinafter. As therapeutic drugs causing nephrotoxicity, the following may be cited: acyclovir, ambisome, amikacin, aminoglycosides, antibiotics, amphotericin B, captopril, carboplatin, cefotaxime, ceftazidime, cefuroxime, cephalosporins, cidofovir, ciprofloxacin, cisplatin, colistimethate, cyclosporine, dapsone, enalaprilat, enalapril, Foscarnet, gadopentetate dimeglumine, gadoxetate, ganciclovir gentamicin, ibuprofen, ifosfamide, iodixanol, iohexol, iopamidol, ioversol, ketorolac, lisinopril, lithium, mesalamine, methotrexate, nafcillin disodium, penicillins, piperacillin / tazobactam, piperacillin, rifampin, sirolimus, sulfasalazine, tacrolimus, ticarcillin / clavulanic acid, tobramycin, topiramate, valacyclovir, valganciclovir, vancomycin or zonisamide. The following examples illustrate in detail the preparation of some compounds according to the invention. The structures of the products obtained have been confirmed by NMR analyses and mass spectroscopy. The following examples further illustrate some biological activities of some compounds according to the invention. Example 1: Synthesis of 3,6-dichloro-pyridazin-4-amine derivatives, as illustrated in step 1 of scheme 1 Example 1.1: Synthesis of N-benzyl-3,6-dichloro-pyridazin-4-amine (1.1) To a solution of 3,4,6-trichloropyridazine (a) (10.000 g, 52.88 mmol, 1.0 eq.) in THF (100.0 mL), triethylamine (8.93 mL, 63.46 mmol, 1.2 eq.) then benzylamine (6.48 mL, 58.17 mmol, 1.1 eq.) was added and the mixture was refluxed on 3 h. After cooling, the solid was filtered off, washed with THF then the filtrate was concentrated under vacuum. The resulting solid was triturated in Et2O, filtered off, washed with a little amount of Et2O and dried under vacuum to give (1.1) (13.000 g, 97 %) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ : 4.52 (d, J = 6.3 Hz, 2H, CH2), 6.82 (s, 1H, HAr), 7.26 (td, J = 5.9, 2.8 Hz, 1H, HAr), 7.34 (d, J = 5.4 Hz, 4H, 4xHAr), 7.97 (t, J = 6.3 Hz, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 44.7 (CH2), 105.5 (CHAr), 127.0 (2xCHAr), 127.2 (CHAr), 128.6 (2xCHAr), 137.0 (Cq), 143.8 (Cq), 144.4 (Cq), 154.5 (Cq). MS (ESI+) : m / z calcd for C11H9Cl2N3 : 254.0 [M+H]+, found : 254.0. Example 1.2: Synthesis of 3,6-dichloro-N-(2-pyridylmethyl)pyridazin-4- amine (1.2) To a solution of 3,4,6-trichloropyridazine (a) (20.000 g, 105.77 mmol, 1.0 eq.) in THF (210.0 mL), triethylamine (19.36 mL, 137.50 mmol, 1.3 eq.) then corresponding amine (12.67 mL, 121.63 mmol, 1.15 eq.) was added and the mixture was refluxed on 4 h. After cooling, the solid was filtered off and washed with THF. The solid was washed with water then, in another vacuum flask, triturated in MeOH, washed with Et2O and dried under vacuum to give first part of (1.2) (12.500 g). THF and MeOH / Et2O filtrates were combined and concentrated under vacuum. The resulting solid was triturated in MeOH, filtered off, washed with Et2O and dried under vacuum to give a second part of (1.2) (10.100 g). The filtrate was concentrated and the resulting solid triturated in a little amount of MeOH, filtered off, washed with Et2O and dried under vacuum to give a third part of (1.2) (1.000 g). Total of (1.2): 23.600 g, 87 % as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 4.60 (d, J = 6.1 Hz, 2H, CH2 Bn), 6.90 (s, 1H, HAr), 7.31 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H, HAr), 7.35 (dt, J = 7.8, 1.1 Hz, 1H, HAr), 7.79 (td, J = 7.7, 1.8 Hz, 1H, HAr), 7.87 (t, J = 6.0 Hz, 1H, NHBn), 8.54 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H).13C NMR (101 MHz, DMSO-d6) δ : 46.6 (CH2 Bn), 105.9 (CHAr), 121.6 (CHAr), 122.7 (CHAr), 137.1 (CHAr), 143.8 (Cq), 144.7 (Cq), 149.2 (CHAr), 154.6 (Cq), 156.3 (Cq). MS (ESI+) : m / z calcd for C10H8Cl2N4 : 255.0 [M+H]+, found : 255.1. Example 1.3: Synthesis of 3,6-dichloro-N-(3-pyridylmethyl)pyridazin-4- amine (1.3) To a solution of 3,4,6-trichloropyridazine (a) (3.100 g, 16.39 mmol, 1.0 eq.) in THF (33.0 mL), triethylamine (3.00 mL, 21.31 mmol, 1.3 eq.) then corresponding amine (2.04 mL, 19.67 mmol, 1.2 eq.) was added and the mixture was refluxed on 2 h. After cooling, the solid was filtered off and washed with THF. The filtrate was concentrated and the resulting solid was washed with water, then triturated with a little amount of MeOH and dried under vacuum to give (1.3) (2.320 g, 55 %) as a pale orange solid. Rf (DCM / MeOH, 94 / 6) : 0.551H NMR (400 MHz, DMSO-d6) δ : 4.56 (d, J = 6.3 Hz, 2H, CH2 Bn), 6.96 (s, 1H, HAr), 7.37 (dd, J = 7.8, 4.7 Hz, 1H, HAr), 7.73 (dt, J = 7.8, 2.0 Hz, 1H, HAr), 7.96 (t, J = 6.3 Hz, 1H, NHBn), 8.48 (dd, J = 4.8, 1.7 Hz, 1H, HAr), 8.59 (d, J = 2.3 Hz, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 42.4 (CH2 Bn), 105.5 (CHAr), 123.6 (CHAr), 132.7 (Cq), 134.9 (CHAr), 143.9 (Cq), 144.3 (Cq), 148.5 (CHAr), 148.8 (CHAr), 154.7 (Cq). MS (ESI+) : m / z calcd for C10H8Cl2N4 : 255.0 [M+H]+, found : 255.1. Example 1.4: Synthesis of 3,6-dichloro-N-(4-pyridylmethyl)pyridazin-4- amine (1.4) To a solution of 3,4,6-trichloropyridazine (a) (11.500 g, 60.82 mmol, 1.0 eq.) in THF (120.0 mL), triethylamine (11.13 mL, 79.06 mmol, 1.3 eq.) then corresponding amine (7.640 g, 69.94 mmol, 1.15 eq.) was added and the mixture was refluxed on 2 h. After cooling, the solid was filtered off and washed with THF. The filtrate was concentrated and the resulting solid was washed with water, then triturated with a little amount of MeOH and dried under vacuum to give (1.4) (2.320 g, 55 %) as a pale orange solid.1H NMR (400 MHz, DMSO-d6) δ : 4.57 (d, J = 6.4 Hz, 2H, CH2 Bn), 6.84 (s, 1H, HAr), 7.27 – 7.36 (m, 2H, 2xHAr), 7.98 (t, J = 6.4 Hz, 1H, NHBn), 8.45 – 8.58 (m, 2H, 2xHAr).13C NMR (101 MHz, DMSO-d6) δ : 43.7 (CH2 Bn), 105.6 (CHAr), 122.0 (2xCHAr), 143.9 (Cq), 144.5 (Cq), 146.3 (Cq), 149.8 (2xCHAr), 154.7 (Cq). MS (ESI+) : m / z calcd for C10H8Cl2N4 : 255.0 [M+H]+, found : 255.1. Example 1.5: Synthesis of 4-[[(3,6-dichloropyridazin-4- yl)amino]methyl]phenol (1.5) In a sealed vial 2 - 5 mL with a stir bar was charged 3,4,6-trichloropyridazine (a) (1.500 g, 7.93 mmol, 1.0 eq.), DCM (19.0 mL), triethylamine (1.68 mL, 11.90 mmol, 1.5 eq.) and corresponding amine (1.172 g, 9.52 mmol, 1.2 eq.). The vial was sealed and put in heating bloc 15 h at 50 °C. After cooling, the mixture was concentrated with SiO2 to make solid deposit then directly purified by flash chromatography with DCM / MeOH (98 / 2 to 96 / 4) as eluent to give (1.5) (0.515 g, 24 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 4.38 (d, J = 6.2 Hz, 2H, CH2 Bn), 6.68 – 6.76 (m, 2H, 2xHAr), 6.80 (s, 1H, HAr), 7.08 – 7.21 (m, 2H, 2xHAr), 7.87 (t, J = 6.2 Hz, 1H, NHBn), 9.36 (s, 1H, OH).13C NMR (101 MHz, DMSO-d6) δ : 44.3 (CH2 Bn), 105.4 (CHAr), 115.3 (2xCHAr), 126.9 (Cq), 128.3 (2xCHAr), 143.8 (Cq), 144.3 (Cq), 154.5 (Cq), 156.6 (Cq). MS (ESI+) : m / z calcd for C11H9Cl2N3O : 270.0 [M+H]+, found : 270.1. Example 1.6: Synthesis of 3-[[(3,6-dichloropyridazin-4- yl)amino]methyl]phenol (1.6) In a sealed vial 2 - 5 mL with a stir bar was charged 3,4,6-trichloropyridazine (a) (1.500 g, 7.93 mmol, 1.0 eq.), DCM (19.0 mL), triethylamine (1.68 mL, 11.90 mmol, 1.5 eq.) and corresponding amine (1.172 g, 9.52 mmol, 1.2 eq.). The vial was sealed and put in heating bloc 15 h at 50 °C. After cooling, the mixture was concentrated with SiO2to make solid deposit then directly purified by flash chromatography with DCM / MeOH (98 / 2 to 96 / 4) as eluent to give (1.6) (0.670 g, 31 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 4.43 (d, J = 6.3 Hz, 2H, CH2 Bn), 6.64 (dd, J = 8.0, 2.4 Hz, 1H, HAr), 6.69 (t, J = 2.0 Hz, 1H, HAr), 6.74 (d, J = 7.6 Hz, 1H, HAr), 6.77 (s, 1H, HAr), 7.13 (t, J = 7.8 Hz, 1H, HAr), 7.94 (t, J = 6.3 Hz, 1H, NHBn), 9.39 (s, 1H, OH).13C NMR (101 MHz, DMSO-d6) δ : 44.6 (CH2 Bn), 105.5 (CHAr), 113.4 (CHAr), 114.2 (CHAr), 117.4 (CHAr), 129.6 (CHAr), 138.4 (Cq), 143.7 (Cq), 144.4 (Cq), 154.5 (Cq), 157.6 (Cq). MS (ESI+) : m / z calcd for C11H9Cl2N3O : 270.0 [M+H]+, found : 270.1. Example 1.7: Synthesis of 2-[[(3,6-dichloropyridazin-4- yl)amino]methyl]phenol (1.7) To a solution of 3,4,6-trichloropyridazine (a) (3.700 g, 20.2 mmol, 1.0 eq.) in THF (50 mL), triethylamine (3.41 mL, 24.2 mmol, 1.2 eq.) then corresponding benzylamine (3.700 g, 24.2 mmol, 1.2 eq.) was added and the mixture was refluxed 3 h. After cooling, the mixture was filtered, washed with THF then the filtrate was concentrated, the crude residue was triturated in DCM / MeOH (94 / 4) to give a first part of (1.7) (1.450 g) after filtration. The filtrate was concentrated and the residue triturated in DCM / MeOH (98 / 2) to give a second part of (1.7) (0.950 g) after filtration. The filtrate was concentrated and purified by flash chromatography (96 / 4) to give a third part of (1.7) (0.900 g). Total of (1.7): 3.400g, 62 %, as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ : 4.39 (d, J = 6.2 Hz, 2H, CH2 Bn), 6.76 (td, J = 7.4, 1.2 Hz, 1H, HAr), 6.81 (s, 1H, HAr), 6.85 (dd, J = 8.0, 1.2 Hz, 1H, HAr), 7.06 – 7.14 (m, 2H, 2xHAr), 7.75 (t, J = 6.2 Hz, 1H, NHBn), 9.84 (s, 1H, OH).13C NMR (101 MHz, DMSO-d6) δ : 40.1 (CH2 Bn), 105.3 (CHAr), 115.1 (CHAr), 119.2 (CHAr), 122.4 (Cq), 128.2 (CHAr), 128.4 (CHAr), 143.7 (Cq), 144.4 (Cq), 154.6 (Cq), 154.9 (Cq). MS (ESI+) : m / z calcd for C11H9Cl2N3O : 270.0 [M+H]+, found : 270.1. Example 1.8: Synthesis of 3,6-dichloro-N-[(2- methoxyphenyl)methyl]pyridazin-4-amine (1.8) To a solution of 3,4,6-trichloropyridazine (a) (2.600 g, 13.75 mmol, 1.0 eq.) in DCM (70.0 mL), triethylamine (3.87 mL, 27.50 mmol, 2.0 eq.) and corresponding amine (2.887 g, 20.63 mmol, 1.5 eq.) was added and the mixture was refluxed 19 h. After cooling, HCl 1M (50.0 mL) was added then the mixture was vigorously stirred 5 min and layers were separated. Aqueous layer was extracted twice with DCM (2x20.0 mL) then organics layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (100 / 0 to 98 / 2) as eluent to give (1.8) (3.200 g, 82 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 3.85 (s, 3H, OCH3), 4.44 (s, 2H, CH2 Bn), 6.75 (s, 1H, HAr), 6.87 – 6.95 (m, 1H, HAr), 7.00 – 7.06 (m, 1H, HAr), 7.13 (dd, J = 7.5, 1.8 Hz, 1H, HAr), 7.27 (td, J = 7.8, 1.8 Hz, 1H, HAr), 7.73 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 40.2 (CH2 Bn), 55.4 (CH3), 105.4 (CHAr), 110.9 (CHAr), 120.5 (CHAr), 124.1 (Cq), 127.5 (CHAr), 128.7 (CHAr), 143.7 (Cq), 144.5 (Cq), 154.6 (Cq), 156.8 (Cq). MS (ESI+) : m / z calcd for C12H11Cl2N3O : 284.0 [M+H]+, found : 284.1. Example 1.9: Synthesis of 3,6-dichloro-N-(1H-indol-3-ylmethyl)pyridazin- 4-amine (1.9) In a 10 - 20 mL vial was introduced a stir bar, 3,4,6-trichloropyridazine (a) (1.750 g, 9.25 mmol, 1.0 eq.), DCM (18 mL), 1H-indol-2-ylmethanamine hydrochloride (2.135 g, 11.11 mmol, 1.2 eq.) and triethylamine (2.87 mL, 20.36 mmol, 2.2 eq.). The vial was sealed and put in heating bloc 17 h at 50 °C. After cooling, the mixture was concentrated then triturated in HCl 0.5M (60 mL, pH < 5) and EtOAc was added (30 mL). Heterogenous mixture was vigorously stirred then the precipitate was filtered off, washed with water (up to pH 7) then EtOAc and dried under vacuum to give the first part of (1.9) (1.465 g) as a white solid. Aqueous layer was extracted EtOAc (30mL) and organics layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5) as eluent to give the second part of (1.9) (0.430 g) as a white solid. Total of (1.9) : 1.895 g, 70 %.1H NMR (400 MHz, DMSO-d6) δ : 4.63 (d, J = 5.9 Hz, 2H, CH2 Bn), 7.01 (d, J = 7.4 Hz, 2H, 2xHAr), 7.08 (t, J = 7.5 Hz, 1H, HAr), 7.35 (d, J = 8.1 Hz, 1H, HAr), 7.44 (d, J = 2.4 Hz, 1H, HAr), 7.73 (d, J = 7.9 Hz, 1H, HAr), 7.85 (t, J = 5.9 Hz, 1H, NHBn), 10.97 (s, 1H, NHIndole).13C NMR (101 MHz, DMSO-d6) δ : 37.7 (CH2 Bn), 105.4 (CHAr), 109.1 (Cq), 111.6 (CHAr), 118.7 (CHAr), 118.8 (CHAr), 121.3 (CHAr), 124.7 (CHAr), 126.2 (Cq), 136.5 (Cq), 143.8 (Cq), 144.2 (Cq), 154.3 (Cq). MS (ESI+) : m / z calcd for C13H10Cl2N4 : 293.0 [M+H]+, found : 293.1. Example 1.10: Synthesis of 3,6-dichloro-N-(1H-indol-2- ylmethyl)pyridazin-4-amine (1.10) In a 10 - 20 mL vial was introduced a stir bar, 3,4,6-trichloropyridazine (a) (1.750 g, 9.25 mmol, 1.0 eq.), DCM (18 mL), 1H-indol-2-ylmethanamine hydrochloride (2.135 g, 11.11 mmol, 1.2 eq.) and triethylamine (2.87 mL, 20.36 mmol, 2.2 eq.). The vial was sealed and put in heating bloc 17 h at 50 °C. After cooling, the mixture was concentrated then triturated in HCl 0.5M (60 mL, pH < 5) and EtOAc was added (30 mL). Heterogenous mixture was vigorously stirred then the precipitate was filtered off, washed with water (up to pH 7) then EtOAc and dried under vacuum to give the first part of (1.10) (2.040 g) as a white solid. Aqueous layer was extracted EtOAc (30mL) and organics layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5) as eluent to give the second part of (1.10) (0.300 g) as a white solid. Total of (1.10): 2.340 g, 86 %.1H NMR (400 MHz, DMSO-d6) δ : 4.66 (d, J = 6.1 Hz, 2H, CH2 Bn), 6.33 (d, J = 2.0 Hz, 1H, HAr), 6.95 (t, J = 7.4 Hz, 1H, HAr), 6.98 (s, 1H, HAr), 7.04 (t, J = 7.4 Hz, 1H, HAr), 7.33 (d, J = 8.0 Hz, 1H, HAr), 7.45 (d, J = 8.0 Hz, 1H, HAr), 7.79 (t, J = 6.1 Hz, 1H, NHBn), 10.96 (s, 1H, HIndole).13C NMR (101 MHz, DMSO-d6) δ : 39.3 (CH2 Bn), 99.7 (CHAr), 105.7 (CHAr), 111.2 (CHAr), 119.0 (CHAr), 119.7 (CHAr), 120.9 (CHAr), 127.8 (Cq), 134.6 (Cq), 136.2 (Cq), 143.9 (Cq), 144.5 (Cq), 154.6 (Cq). MS (ESI+) : m / z calcd for C13H10Cl2N4 : 293.0 [M+H]+, found : 293.1. Example 1.11: Synthesis of N-[(4-aminophenyl)methyl]-3,6-dichloro- pyridazin-4-amine (1.11) To a solution of 3,4,6-trichloropyridazine (a) (22.953 g, 125.14 mmol, 1.3 eq.) in THF (200.0 mL), triethylamine (20.33 mL, 144.69 mmol, 1.5 eq.) and 4-(aminomethyl)aniline (12.000 g, 96.26 mmol, 1.0 eq.) was added then the mixture was refluxed 18 N-[(4- aminophenyl)methyl]-6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-amine h. After cooling, the mixture was filtered off, the solid was washed with THF then the filtrate was concentrated. The residue was triturated in DCM and the solid was filtered off, washed with DCM and dried under vacuum to give (1.11) (23.950 g, 92 %) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ : 4.30 (d, J = 6.1 Hz, 2H, CH2), 5.09 (s, 2H, NH2), 6.41 – 6.69 (m, 2H, 2xHAr), 6.77 (s, 1H, HAr), 6.89 – 7.12 (m, 2H, 2xHAr), 7.80 (t, J = 6.1 Hz, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 44.6 (CH2), 105.4 (CHAr), 113.9 (2xCHAr), 123.4 (Cq), 128.0 (2xCHAr), 143.7 (Cq), 144.3 (Cq), 147.8 (Cq), 154.4 (Cq). MS (ESI+) : m / z calcd for C11H10Cl2N4 : 269.0 [M+H]+, found : 269.1. Example 1.12: Synthesis of N-[(2-aminophenyl)methyl]-3,6-dichloro- pyridazin-4-amine (1.12) To a solution of 3,4,6-trichloropyridazine (a) (5.000 g, 27.3 mmol, 1.0 eq.) in THF (52 mL), triethylamine (4.22 mL, 30.0 mmol, 1.1 eq.) then 2-(aminomethyl)aniline (3.228 g, 25.9 mmol, 0.95 eq.) was added and the mixture was refluxed 3.5 h. After cooling, the mixture was filtered off, the solid was washed with THF then the filtrate was concentrated and directly purified by flash chromatography with DCM / MeOH (98 / 2 to 96 / 4) as eluent to give (1.12) (5.280 g, 76 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 4.30 (d, J = 6.0 Hz, 2H, CH2 Bn), 5.15 (s, 2H, NH2), 6.52 (td, J = 7.4, 1.3 Hz, 1H, HAr), 6.65 (dd, J = 8.0, 1.3 Hz, 1H, HAr), 6.74 (s, 1H, HAr), 6.97 (td, J = 7.6, 1.6 Hz, 1H, HAr), 7.02 (dd, J = 7.5, 1.6 Hz, 1H, HAr), 7.74 (t, J = 6.0 Hz, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 42.0 (CH2 Bn), 105.6 (CHAr), 115.2 (CHAr), 116.1 (CHAr), 118.8 (Cq), 127.9 (CHAr), 128.1 (CHAr), 143.8 (Cq), 144.4 (Cq), 146.3 (Cq), 154.5 (Cq). MS (ESI+) : m / z calcd for C11H10Cl2N4 : 269.0 [M+H]+, found : 269.1. Example 1.13: Synthesis of N-[(4-bromophenyl)methyl]-3,6-dichloro- pyridazin-4-amine (1.13) To a solution of 3,4,6-trichloropyridazine (a) (4.000 g, 24.81 mmol, 1.0 eq.) in THF (87.0 mL), triethylamine (3.68 mL, 26.17 mmol, 1.2 eq.) and corresponding amine (3.03 mL, 23.99 mmol, 1.1 eq.) was added and the mixture was refluxed 3.5 h. After cooling, the solid was filtered off, washed with THF then the filtrate was concentrated. The residue was taken up in DCM (100.0 mL), washed with HCl 1M (40.0 mL) then organic layer was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (100 / 0 to 98 / 2) as eluent to give (1.13) (6.500 g, 90 %) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ : 4.49 (d, J = 6.3 Hz, 2H, CH2 Bn), 6.84 (s, 1H, HAr), 7.25 – 7.35 (m, 2H, 2xHAr), 7.50 – 7.58 (m, 2H, 2xHAr), 7.97 (t, J = 6.4 Hz, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 44.0 (CH2 Bn), 105.5 (CHAr), 120.3 (Cq), 129.3 (2xCHAr), 131.4 (2xCHAr), 136.6 (Cq), 143.8 (Cq), 144.3 (Cq), 154.6 (Cq). MS (ESI+) : m / z calcd for C11H8BrCl2N3 : 331.9 [M+H]+, found : 331.9. Example 1.14: Synthesis of 3,6-dichloro-N-[[4-(2- pyridyl)phenyl]methyl]pyridazin-4-amine (1.14) To a solution of 3,4,6-trichloropyridazine (a) (0.500 g, 2.73 mmol, 1.0 eq.) in THF (13.5 mL), triethylamine (1.15 mL, 8.18 mmol, 3.0 eq.) then [4-(2-pyridyl)phenyl]methanamine (0.603 g, 3.27 mmol, 1.2 eq.) was added and the mixture was refluxed 3 h. After cooling, the mixture was filtered off, the solid was washed with THF then the filtrate was concentrated and directly purified by flash chromatography with DCM / MeOH (99 / 1 to 95 / 5) as eluent to give (1.14) (0.360 g, 40 %) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ : 4.59 (d, J = 6.3 Hz, 2H, CH2 Bn), 6.86 (s, 1H, HAr), 7.33 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H, HAr), 7.45 (d, J = 8.1 Hz, 2H, 2xHAr), 7.86 (td, J = 7.7, 1.9 Hz, 1H, HAr), 7.93 (d, J = 8.0 Hz, 1H, HAr), 8.02 (t, J = 6.0 Hz, 1H, NHBn), 8.04 – 8.10 (m, 2H, 2xHAr), 8.62 – 8.67 (m, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 44.5 (CH2 Bn), 105.6 (CHAr), 120.1 (CHAr), 122.6 (CHAr), 126.7 (2xCHAr), 127.4 (2xCHAr), 137.2 (CHAr), 137.7 (Cq), 138.0 (Cq), 143.9 (Cq), 144.4 (Cq), 149.5 (CHAr), 154.6 (Cq), 155.7 (Cq). MS (ESI+) : m / z calcd for C16H12Cl2N4 : 331.1 [M+H]+, found : 331.1. Example 1.15: Synthesis of 2-(3,6-dichloropyridazin-4-yl)-3,4-dihydro-1H- isoquinoline (1.15) To a solution of 3,4,6-trichloropyridazine (a) (5.000 g, 27.3 mmol, 1.0 eq.) in THF (54.0 mL), triethylamine (4.41 mL, 31.3 mmol, 1.1 eq.) then 2-(aminomethyl)aniline (3.228 g, 25.9 mmol, 0.95 eq.) was added and the mixture was refluxed 3.5 h. After cooling, the mixture was filtered off, the solid was washed with THF then the filtrate was concentrated and directly purified by flash chromatography with DCM / EtOAc (100 / 0 to 92 / 8) as eluent to give (1.15) (6.800 g, 89 %) as a white crystalline solid. Rf (DCM, 100%) : 0.42.1H NMR (400 MHz, DMSO-d6) δ : 2.99 (t, J = 5.8 Hz, 2H, CH2-CH2-N), 3.69 (t, J = 5.8 Hz, 2H,N-CH2-CH2), 4.50 (s, 2H, CH2-N), 7.13 – 7.29 (m, 4H, 4xHAr), 7.42 (s, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 28.2 (CH2-CH2-N), 47.5 (N-CH2-CH2), 50.4 (CH2-N), 115.4 (CHAr), 126.1 (CHAr), 126.4 (CHAr), 126.7 (CHAr), 128.7 (CHAr), 132.8 (Cq), 133.9 (Cq), 147.9 (Cq), 148.9 (Cq), 154.9 (Cq). MS (ESI+) : m / z calcd for C13H11Cl2N3 : 280.0 [M+H]+, found : 280.1. Example 1.16: Synthesis of 3,6-dichloro-N-(2-phenylethyl)pyridazin-4- amine (1.16) To a solution of 3,4,6-trichloropyridazine (a) (4.000 g, 21.8 mmol, 1.0 eq.) in THF (42 mL), Et3N (6.45 mL, 45.8.0 mmol, 2.1 eq.) then corresponding amine hydrochloride (3.438 g, 21.8 mmol, 1.0 eq.) was added and the mixture was refluxed 3 h. After cooling, the mixture was filtered off, the solid was washed with THF then the filtrate was concentrated. The residue was triturated in HCl 1M (25.0 mL) then the resulting solid was filtered, washed with water up to neutral pH and taken up in EtOAc. Organic filtrate was dried over MgSO4, filtered, concentrated to give (1.16) (5.515 g, 88 %) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ : 2.86 (t, J = 7.4 Hz, 2H, CH2-CH2-NH), 3.43 – 3.56 (m, 2H, CH2-NH), 6.95 (s, 1H, HAr), 7.20 (ddd, J = 8.6, 5.6, 2.4 Hz, 1H, HAr), 7.27 (q, J = 4.2 Hz, 5H, NH & 5xHAr).13C NMR (101 MHz, DMSO-d6) δ : 33.8 (CH2-CH2-NH), 43.1 (CH2-NH), 105.2 (CHAr), 126.3 (CHAr), 128.3 (2xCHAr), 128.9 (2xCHAr), 138.8 (Cq), 143.5 (Cq), 144.3 (Cq), 154.7 (Cq). MS (ESI+) : m / z calcd for C12H11Cl2N3 : 268.0 [M+H]+, found : 268.1. Example 2: Synthesis of 6,8-dichloro-[1,2,4]triazolo[4,3-b]pyridazine derivatives, as illustrated in step 1 of scheme 2 Example 2.1: Synthesis of 6,8-dichloro-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazine (2.1) A solution of 4-methylbenzenesulfonohydrazide (3.895 g, 20.91 mmol, 1.0 eq.) in THF (21.0 mL), corresponding aldehyde (1.97 mL, 21.33 mmol, 1.02 eq.) was added and the mixture was stirred 5 min at 50°C. The solvent was completely removed by evaporation then the crude residue was solubilised in THF (63.0 mL), 3,5-dichloropyridazine (b) (3.915 g, 24.97 mmol, 1.2 eq.) was added then successively I2 (1.056 g, 4.16 mmol, 0.2 eq.) and portion wise PIDA (10.257g, 31.21 mmol, 1.5 eq.). The reaction was slightly exothermic and it was stirred 22 h at room temperature. Saturated Na2S2O3(30.0 mL) and water (15.0 mL) was added and vigorously stirred during 5 min. Layers were separated, aqueous layer was extracted twice with EtOAc (2x 20.0 mL) then organics layers were combined, washed with brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography with EtOAc / Cyclohexane as eluent to give (2.1) (2.100 g, 44 %) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ : 1.41 (d, J = 7.0 Hz, 6H, 2xCH3 iPr), 3.50 (hept, J = 6.9 Hz, 1H, HiPr), 7.93 (s, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 19.7 (2xCH3 iPr), 24.6 (CHiPr), 121.2 (CHAr), 133.2 (Cq), 142.1 (Cq), 147.5 (Cq), 154.8 (Cq). MS (ESI+) : m / z calcd for C8H8Cl2N4 : 231.0 [M+H]+, found : 230.9. Example 2.2: Synthesis of 6,8-dichloro-3-sec-butyl-[1,2,4]triazolo[4,3- b]pyridazine (2.2) To a solution of 4-methylbenzenesulfonohydrazide (1.900 g, 9.90 mmol, 1.0 eq.) in THF (25.0 mL), 2-methylbutanal (1.12 mL, 9.90 mmol, 1.0 eq.) was added then the mixture was stirred 25 min at room temperature. After completion, 3,5-dichloropyridazine (b) (1.552 g, 9.90 mmol, 1.0 eq.) was added then, in one portion, PIDA (6.505 g, 19.79 mmol, 2.0 eq.) and I2 (0.502 g, 1.98 mmol, 0.2 eq.). The mixture was stirred 17 h at room temperature then saturated Na2S2O3(10.0 mL) and saturated NaHCO3(10.0 mL) was added, the mixture was stirred vigorously 5 min. Layers were separated and aqueous layer was extracted twice with EtOAc (2 x 10.0 mL), organics layers were combined, dried over MgSO4, filtered and purified by flash chromatography with EtOAc / Cyclohexane (30 / 70) as eluent to give (2.2) (0.670 g, 28 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 0.86 (t, J = 7.4 Hz, 3H, CH3-CH2), 1.38 (d, J = 7.0 Hz, 3H, CH3-CH), 1.69 – 2.00 (m, 2H, CH2-CH3), 3.33 – 3.41 (m, 1H, HC-CH3), 7.93 (s, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 11.4 (CH3-CH2), 17.4 (CH3-CH), 26.7 (CH2-CH3), 31.1 (CH-CH3), 121.3 (CHAr), 133.3 (Cq), 142.1 (Cq), 147.6 (Cq), 154.0 (Cq). MS (ESI+) : m / z calcd for C9H10Cl2N4 : 245.0 [M+H]+, found : 245.1. Example 2.3: Synthesis of 6,8-dichloro-3-(1-ethylpropyl)- [1,2,4]triazolo[4,3-b]pyridazine (2.3) To a solution of 4-methylbenzenesulfonohydrazide (1.600 g, 8.59 mmol, 1.0 eq.) in THF (20.0 mL), 2-ethylbutanal (1.14 mL, 8.59 mmol, 1.0 eq.) was added then the mixture was stirred 25 min at room temperature. After completion, 3,5-dichloropyridazine (b) (1.307 g, 8.59 mmol, 1.0 eq.) was added then PIDA (5.478 g, 16.67 mmol, 2.0 eq.) and I2(0.423 g, 1.67 mmol, 0.2 eq.) in one portion. The mixture was stirred 17 h at room temperature then saturated Na2S2O3 (10.0 mL) and saturated NaHCO3 (10.0 mL) was added, the mixture was stirred vigorously 5 min. Layers were separated and aqueous layer was extracted twice with EtOAc (2 x 10.0 mL), organics layers were combined, dried over MgSO4, filtered and purified by flash chromatography with EtOAc / Cyclohexane (30 / 70) as eluent to give (2.3) (0.570 g, 26 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 0.80 (t, J = 7.4 Hz, 6H, 2xCH3-CH2), 1.75 – 1.97 (m, 4H, 2xCH2-CH3), 3.23 (tt, J = 8.3, 5.7 Hz, 1H, HiPent), 7.94 (s, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 11.4 (2xCH3-CH2), 24.8 (2xCH2-CH3), 38.3 (CHiPent), 121.3 (CHAr), 133.3 (Cq), 142.1 (Cq), 147.7 (Cq), MS (ESI+) : m / z calcd for C10H12Cl2N4 : 259.1 [M+H]+, found : 259.1. Example 2.4: Synthesis of 6,8-dichloro-3-isobutyl-[1,2,4]triazolo[4,3- b]pyridazine (2.4) To a solution of 4-methylbenzenesulfonohydrazide (1.000 g, 5.37 mmol, 1.0 eq.) in THF (20.0 mL), 3-methylbutanal (0.58 mL, 5.37 mmol, 1.0 eq.) was added then the mixture was stirred 20 min at room temperature. After completion, 3,5-dichloropyridazine (b) (0.927 g, 5.91 mmol, 1.1 eq.) was added then, in one portion, PIDA (3.530 g, 10.74 mmol, 2.0 eq.) and I2(0.273 g, 1.07 mmol, 0.2 eq.). The mixture was stirred 2 h at room temperature then saturated Na2S2O3(20.0 mL) and H2O (10.0 mL) was added, the mixture was stirred vigorously 5 min. Layers were separated and aqueous layer was extracted twice with EtOAc (2 x 20.0 mL), organics layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with EtOAc / Cyclohexane (85 / 15 to 50 / 50) as eluent to give (2.4) (0.452 g, 34 %) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ : 0.96 (d, J = 6.7 Hz, 6H, 2xCH3 iPr), 2.23 (dp, J = 13.6, 6.8 Hz, 1H, HiPr), 2.97 (d, J = 7.1 Hz, 2H, CH2-CH), 7.93 (s, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 22.2 (2xCH3 iPr), 26.3 (CH-CH2), 32.2 (CH2-CH), 121.2 (CHAr), 133.2 (Cq), 141.9 (Cq), 147.7 (Cq), 150.1 (Cq). MS (ESI+) : m / z calcd for C9H12Cl2N4 : 245.0 [M+H]+, found : 245.1. Example 2.5: Synthesis of 6,8-dichloro-3-cyclopropyl-[1,2,4]triazolo[4,3- b]pyridazine (2.5) To a solution of 3,5-dichloropyridazine (b) (2.000 g, 12.7 mmol, 1.0 eq.) and N- (cyclopropylmethyleneamino)-4-methyl-benzenesulfonamide (4.559 g, 19.1 mmol, 1.5 eq.) in THF (95.0 mL), PIDA (6.288 g, 19.1mmol, 1.5 eq.) and I2 (0.647 g, 2.5 mmol, 0.2 eq.) was added in one portion and the mixture was stirred 2 h at room temperature. After completion, a mixture of saturated Na2S2O3 (20.0 mL) and water (10.0 mL) was added, the biphasique mixture was vigorously stirred 5 min then layers were separated. Aqueous layer was extracted twice with EtOAc (2 x 15.0 mL) and organics layers were combined, dried over MgSO4, filtered and purified by flash chromatography with EtOAc / Cyclohexane (75 / 25 then 70 / 30) as eluent to give (2.5) (0.400 g, 14 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.07 – 1.27 (m, 4H, 2xCH2 cPr), 2.40 (tt, J = 8.3, 5.0 Hz, 1H, HcPr), 7.91 (s, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 4.9 (CHcPr), 7.5 (2xCH2 cPr), 121.1 (CHAr), 133.1 (Cq), 142.1 (Cq), 147.7 (Cq), 152.3 (Cq). MS (ESI+) : m / z calcd for C8H6Cl2N4 : 229.0 [M+H]+, found : 228.9. Example 2.6: Synthesis of 6,8-dichloro-3-cyclopentyl-[1,2,4]triazolo[4,3- b]pyridazine (2.6) To a solution of 4-methylbenzenesulfonohydrazide (1.800 g, 9.38 mmol, 1.0 eq.) in THF (140.0 mL), cyclopentanecarbaldehyde (0.995 g, 9.84 mmol, 1.05 eq.) was added then the mixture was stirred 20 min at room temperature. After completion, 3,5-dichloropyridazine (b) (1.470 g, 9.38 mmol, 1.0 eq.) was added then, in one portion, PIDA (4.622 g, 14.06 mmol, 1.5 eq.) and I2(0.476 g, 1.88 mmol, 0.2 eq.). The mixture was stirred 1.3 h at room temperature then partially concentrated, the residue was diluted in EtOAc (50.0 mL). Organic layer was washed with a mixture of saturated Na2S2O3 (40.0 mL) and water (80.0 mL). Aqueous layer was extracted twice with EtOAc (2 x 30.0 mL) and organics layers were combined, dried over MgSO4, filtered and purified by flash chromatography with EtOAc / Cyclohexane (15 / 85 to 50 / 50) as eluent to give (2.6) (0.260 g, 11 %) as a white flakes.1H NMR (400 MHz, DMSO-d6) δ : 1.63 – 1.86 (m, 4H, 2xCH2 cPent), 1.90 – 2.03 (m, 2H, CH2 cPent), 2.11 (dq, J = 12.3, 7.0, 6.0 Hz, 2H, CH2 cPent), 3.61 (p, J = 7.9 Hz, 1H, HcPent), 7.92 (s, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 25.1 (2xCH2 cPent), 30.1 (2xCH2 cPent), 34.3 (CHcPent), 121.2 (CHAr), 133.2 (Cq), 142.2 (Cq), 147.5 (Cq), 154.0 (Cq). MS (ESI+) : m / z calcd for C10H10Cl2N4 : 257.0 [M+H]+, found : 257.1. Example 2.7: Synthesis of 6,8-dichloro-3-sec-butyl-[1,2,4]triazolo[4,3- b]pyridazine (2.7) To a solution of 4-methylbenzenesulfonohydrazide (1.102 g, 5.74 mmol, 1.2 eq.) in THF (15.0 mL), butanal (0.52 mL, 5.74 mmol, 1.2 eq.) was added then the mixture was stirred 10 min at room temperature. After completion, 3,5-dichloropyridazine (b) (0.750 g, 4.78 mmol, 1.0 eq.) was added then, in one portion, PIDA (6.505 g, 19.79 mmol, 2.0 eq.) and I2 (0.502 g, 1.98 mmol, 0.2 eq.). The mixture was stirred 17 h at room temperature then saturated Na2S2O3(10.0 mL) and saturated NaHCO3(10.0 mL) was added, the mixture was stirred vigorously 5 min. Layers were separated and aqueous layer was extracted twice with EtOAc (2 x 10.0 mL), organics layers were combined, dried over MgSO4, filtered and purified by flash chromatography with EtOAc / Cyclohexane (30 / 70) as eluent to give (2.7) (0.957g with impurities (RMN purity 70%), calculated = 0.670 g, 28 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 0.86 (t, J = 7.4 Hz, 3H, CH3-CH2), 1.38 (d, J = 7.0 Hz, 3H, CH3-CH), 1.69 – 2.00 (m, 2H, CH2-CH3), 3.33 – 3.41 (m, 1H, HC-CH3), 7.93 (s, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 11.4 (CH3-CH2), 17.4 (CH3-CH), 26.7 (CH2-CH3), 31.1 (CH-CH3), 121.3 (CHAr), 133.3 (Cq), 142.1 (Cq), 147.6 (Cq), 154.0 (Cq). MS (ESI+) : m / z calcd for C9H10Cl2N4 : 245.0 [M+H]+, found : 245.1. Example 3: Synthesis of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-8-amine derivatives, as illustrated in step 2 of scheme 1 or in step 2 of scheme 2 Example 3.1: Synthesis of N-benzyl-6-chloro-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.1) In a sealed tube 10 – 20 mL with a stir bar was charged, (1.1) (0.250 g, 0.98 mmol, 1.0 eq.), dioxane (3.5 mL), isobutyric acid hydrazide (0.121 g, 1.18 mmol, 1.2 eq.) and AcOH (0.05 mL, 0.79 mmol, 0.8 eq.). The vial was sealed and then put on heating block, 4 h at 100 °C. The reaction mixture was cooled and NaHCO3 sat. (8.0 mL) was added then diluted with water (8.0 mL). The precipitate was filtered off, washed with water up to neutral pH then triturated in Et2O and dried under vacuum to give the title compound (3.1) (0.220 g, 74 %) as a white solid. Rf (DCM / EtOAc, 75 / 25) : 0.30.1H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3), 3.43 (hept, J = 7.1 Hz, 1H, HAlk), 4.60 (d, J = 4.2 Hz, 2H, CH2), 6.14 (s, 1H, HAr), 7.22 – 7.31 (m, 1H, HAr), 7.32 – 7.44 (m, 4H, 4xHAr), 9.13 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 20.3 (CH3), 24.9 (CHAlk), 45.6 (CH2), 92.0 (CHAr), 127.6 (CHAr), 127.7 (CHAr), 129.0 (CHAr), 137.9 (Cq), 139.9 (Cq), 142.8 (Cq), 149.9 (Cq), 154.4 (Cq). MS (ESI+) : m / z calcd for C15H16ClN5 : 302.12 [M+H]+, found : 302.33. Example 3.2: Synthesis of N-benzyl-6-chloro-[1,2,4]triazolo[4,3- b]pyridazin-8-amine (3.2) In a sealed tube 2 - 5 mL with a stir bar was charged, (1.1) (0.850 g, 3.34 mmol, 1.0 eq.), dioxane (17.0 mL), formic hydrazide (0.221 g, 3.68 mmol, 1.1 eq.) and PTSA.H2O (0.318 g, 1.67 mmol, 0.5 eq.). The mixture was refluxed for 36 h and after cooling, MeOH (2mL) then DCM (2mL) was added. The mixture was concentrated and purified by flash chromatography with DCM / EtOAc (8 / 2) as eluent to give the title compound (3.2) (0.250 g, 29 %) as a white solid. Rf (DCM / EtOAc, 75 / 25) : 0.21.1H NMR (400 MHz, DMSO-d6) δ : 4.60 (d, J = 6.4 Hz, 2H, CH2 Bn), 6.17 (s, 1H, HAr), 7.26 (t, J = 7.4 Hz, 1H, HAr), 7.35 (t, J = 7.4 Hz, 2H, 2xHAr), 7.40 (d, J = 7.6 Hz, 2H, 2xHAr), 9.17 (s, 1H, NH), 9.41 (s, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 45.2 (CH2), 92.1 (CHAr), 127.2 (2xCHAr), 127.2 (CHAr), 128.5 (2xCHAr), 137.4 (Cq), 139.1 (Cq), 139.6 (CHAr), 142.1 (Cq), 150.0 (Cq). MS (ESI+) : m / z calcd for C12H10ClN5 : 260.07 [M+H]+, found : 260.1. Example 3.3: Synthesis of N-benzyl-6-chloro-3-cyclopropyl- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.3) In a sealed tube 2 - 5 mL with a stir bar was charged, (1.1) (0.300 g, 1.18 mmol, 1.0 eq.), dioxane (3.9 mL), cyclopropanecarboxylic acid hydrazide (0.130 g, 1.30 mmol, 1.1 eq.) and PTSA.H2O (0.023 g, 0.12 mmol, 0.1 eq.). The vial was sealed and then put on heating block, 20 h at 100 °C. The reaction mixture was cooled and MeOH (2mL) then DCM (2mL) was added. The mixture was concentrated and purified by flash chromatography with DCM / EtOAc (7 / 3) as eluent to give the title compound (3.3) (0.184 g, 52 %) as a white solid. Rf (DCM / EtOAc, 7 / 3) : 0.441H NMR (400 MHz, DMSO-d6) δ : 1.06 – 1.15 (m, 4H, 2xCH2 Alk), 2.31 (ddd, J = 13.3, 8.0, 5.4 Hz, 1H, HAlk), 4.58 (d, J = 6.5 Hz, 2H, CH2), 6.12 (s, 1H, HAr), 7.26 (t, J = 7.1 Hz, 1H, HAr), 7.32 – 7.41 (m, 4H, 4xHAr), 9.08 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.8 (CHAlk), 7.1 (2xCH2 Alk), 45.1 (CH2), 91.5 (CH), 127.2 (2xCHAr), 127.2 (CHAr), 128.5 (2xCHAr), 137.4 (Cq), 139.4 (Cq), 142.3 (Cq), 149.6 (Cq), 151.4 (Cq). MS (ESI+) : m / z calcd for C15H14ClN5 : 300.1 [M+H]+, found : 300.1. Example 3.4: Synthesis of N-benzyl-6-chloro-3-cyclopentyl- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.4) To a solution of (2.6) (0.200 g, 0.75 mmol, 1.0 eq.) in THF (15.0 mL), corresponding amine (0.17 mL, 1.51 mmol, 2.0 eq.) and Et3N (0.21 mL, 1.51 mmol, 2.0 eq.) was added then the mixture was refluxed in 3 h. After cooling, the mixture was concentrated and the residue was triturated in water, solid was filtered off, washed wih water, then Et2O and dried under vacuum to give (3.4) (0.220 g, 89 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.61 – 1.84 (m, 4H, 2xCH2 cPent), 1.92 (dq, J = 12.0, 7.4 Hz, 2H, CH2 cPent), 2.02 – 2.18 (m, 2H, CH2 cPent), 3.52 (p, J = 8.0 Hz, 1H, HcPent), 4.58 (s, 2H, CH2 Bn), 6.13 (s, 1H, HAr), 7.26 (t, J = 7.1 Hz, 1H, HAr), 7.34 (t, J = 7.5 Hz, 2H, 2xHAr), 7.39 (d, J = 7.5 Hz, 2H, 2xHAr), 9.09 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 25.0 (2xCH2 cPent), 30.2 (2xCH2 cPent), 34.3 (CHcPent), 45.1 (CH2 Bn), 91.5 (CHAr), 127.2 (2xCHAr), 127.2 (CHAr), 128.5 (2xCHAr), 137.4 (Cq), 139.5 (Cq), 142.28 (Cq), 149.4 (Cq), 153.1 (Cq). MS (ESI+) : m / z calcd for C17H18ClN5 : 328.1 [M+H]+, found : 328.2. Example 3.5: Synthesis of N-benzyl-6-chloro-3-(trifluoromethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.5) In a sealed tube 2 - 5 mL with a stir bar was charged, (1.1) (0.300 g, 1.18 mmol, 1.0 eq.), dioxane (3.9 mL), trifluoroacetic acid hydrazide (0.166 g, 1.30 mmol, 1.1 eq.) and PTSA.H2O (0.023 g, 0.12 mmol, 0.1 eq.). The vial was sealed and then put on heating block, 20 h at 100 °C. The reaction mixture was cooled and MeOH (2mL) then DCM (2mL) was added. The mixture was concentrated and purified by flash chromatography with DCM / EtOAc (9 / 1) as eluent to give the title compound (3.5) (0.070 g, 18 %) as a white solid. Rf (DCM / EtOAc, 9 / 1) : 0.631H NMR (400 MHz, DMSO-d6) δ : 4.65 (d, J = 6.2 Hz, 2H, CH2), 6.43 (s, 1H, HAr), 7.28 (dq, J = 7.2, 4.9, 3.3 Hz, 1H, HAr), 7.35 (dd, J = 8.3, 6.6 Hz, 2H, 2xHAr), 7.41 (d, J = 7.2 Hz, 2H, 2xHAr), 9.52 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 45.19 (CH2), 93.80 (CHAr), 118.24 (q, J = 269.9 Hz, CF3), 127.26 (2xCHAr), 127.32 (CHAr), 128.53 (2xCHAr), 136.98 (Cq), 138.45 (q, J = 41.0, 40.3 Hz, Cq-CF3), 141.85 (Cq), 142.29 (Cq), 151.64 (Cq). MS (ESI+) : m / z calcd for C13H9ClF3N5 : 328.1 [M+H]+, found : 328.1. Example 3.6: Synthesis of N-benzyl-6-chloro-3-methyl-[1,2,4]triazolo[4,3- b]pyridazin-8-amine (3.6) To a solution of (1.1) (0.750 g, 2.95 mmol, 1.0 eq.) in dioxane (15.0 mL), acetohydrazide (0.228 g, 3.25 mmol, 1.1 eq.) and PTSA.H2O (0.281 g, 1.48 mmol, 0.5 eq.) was added and refluxed during 24 h. The reaction mixture was cooled and MeOH (10.0 mL) was added. The mixture was concentrated with SiO2 to make solid deposit and directly purified by flash chromatography with DCM / EtOAc / MeOH (60 / 40 / 0 to 60 / 30 / 10) as eluent to give the title compound (3.6) (0.350 g, 43 %) as a white solid. Rf (DCM / EtOAc, 75 / 25) : 0.241H NMR (400 MHz, DMSO-d6) δ : 2.58 (s, 3H, CH3), 4.60 (s, 2H, CH2), 6.14 (s, 1H, HAr), 7.22 – 7.42 (m, 5H, 5xHAr), 9.09 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 9.4 (CH3), 45.1 (CH2), 91.4 (CHAr), 127.1 (2xCHAr), 127.2 (CHAr), 128.5 (2xCHAr), 137.4 (Cq), 139.2 (Cq), 142.3 (Cq), 146.8 (Cq), 149.6 (Cq). MS (ESI+) : m / z calcd for C13H12ClN5 : 274.1 [M+H]+, found : 274.1. Example 3.7: Synthesis of N-benzyl-6-chloro-3-phenyl-[1,2,4]triazolo[4,3- b]pyridazin-8-amine (3.7) To a solution of (1.1) (0.750 g, 2.95 mmol, 1.0 eq.) in dioxane (15.0 mL), benzohydrazide (0.442 g, 3.25 mmol, 1.1 eq.) and PTSA.H2O (0.281 g, 1.48 mmol, 0.5 eq.) was added and refluxed during 22.5 h. The reaction mixture was cooled and MeOH (5.0 mL) was added. The mixture was concentrated with SiO2 to make solid deposit and directly purified by flash chromatography with DCM / MeOH (94 / 6) as eluent to give the title compound (3.7) (0.425 g, 46 %) as a white solid. Rf (DCM / MeOH, 94 / 6) : 0.461H NMR (400 MHz, DMSO-d6) δ : 4.64 (d, J = 6.4 Hz, 2H, CH2 Bn), 6.27 (s, 1H, HAr), 7.27 (t, J = 7.2 Hz, 1H, HAr), 7.36 (t, J = 7.5 Hz, 2H, 2xHAr), 7.43 (d, J = 7.6 Hz, 2H, 2xHAr), 7.58 (dt, J = 13.3, 7.2 Hz, 3H, 3xHAr), 8.31 (d, J = 7.5 Hz, 2H, 2xHAr), 9.25 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C18H14ClN5 : 336.1 [M+H]+, found : 336.1. Example 3.8: Synthesis of 2-[[(6-chloro-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazin-8-yl)amino]methyl]phenol (3.8) To a suspension of (1.7) (1.900 g, 7.03 mmol, 1.0 eq.) in dioxane (40.0 mL), isobutyric acid hydrazide (1.150 g, 11.25 mmol, 1.6 eq.) then AcOH (0.45 mL, 7.74 mmol, 1.1 eq.) was added. The mixture was refluxed 16 h and after cooling, MeOH (5.0 mL) was added then SiO2 to make solid deposit directly. The mixture was concentrated and purified by flash chromatography with DCM / MeOH (97 / 3 to 93 / 7) as eluent to give (3.8) (1.000 g, 45 %) as a white solid. Rf (DCM / MeOH, 92 / 8) : 0.151H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.42 (p, J = 6.9 Hz, 1H, CHiPr), 4.37 – 4.61 (m, 2H, CH2 Bn), 6.12 (s, 1H, CHAr), 6.76 (t, J = 7.4 Hz, 1H, CHAr), 6.85 (d, J = 8.0 Hz, 1H, CHAr), 7.10 (t, J = 7.7 Hz, 1H, CHAr), 7.18 (d, J = 7.6 Hz, 1H, CHAr), 8.90 (s, 1H, NHBn), 9.82 (s, 1H, OH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 40.2 (CH2 Bn), 91.3 (CHAr), 115.1 (CHAr), 119.1 (CHAr), 122.9 (Cq), 128.4 (2xCHAr), 139.4 (Cq), 142.3 (Cq), 149.4 (Cq), 154.0 (Cq), 154.8 (Cq). MS (ESI+) : m / z calcd for C15H16ClN5O : 318.1 [M+H]+, found : 318.2. Example 3.9: Synthesis of 3-[[(6-chloro-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazin-8-yl)amino]methyl]phenol (3.9) In a sealed vial 10 - 20 mL with a stir bar was charged (1.6) (0.460 g, 1.70 mmol, 1.0 eq.) in dioxane (10.0 mL), isobutyric acid hydrazide (0.211 g, 2.04 mmol, 1.2 eq.) and PTSA.H2O (0.197 g, 1.02 mmol, 0.6 eq.) was added. The vial was sealed and put on heating bloc 17 h at 100°C. After cooling, MeOH (3.0 mL) was added then the mixture was concentrated with SiO2 to make solid deposit and directly purified by flash chromatography with DCM / MeOH (97 / 3 to 94 / 6) as eluent to give (3.9) (0.250 g, 46 %) as a white solid. Rf (DCM / MeOH, 92 / 8) : 0.231H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.42 (p, J = 7.0 Hz, 1H, HiPr), 4.50 (d, J = 6.2 Hz, 2H, CH2 Bn), 6.09 (s, 1H, HAr), 6.64 (dd, J = 8.0, 1.8 Hz, 1H, HAr), 6.75 (t, J = 2.0 Hz, 1H, HAr), 6.79 (d, J = 7.6 Hz, 1H, HAr), 7.12 (t, J = 7.8 Hz, 1H, HAr), 9.09 (s, 1H, NHBn), 9.37 (s, 1H, OH).13C NMR (101 MHz, DMSO-d6) δ : 19.9 (2xCH3 iPr), 24.4 (CHiPr), 45.0 (CH2 Bn), 91.5 (CHAr), 113.7 (CHAr), 114.2 (CHAr), 117.7 (CHAr), 129.5 (CHAr), 138.8 (Cq), 139.4 (Cq), 142.3 (Cq), 149.4 (Cq), 154.0 (Cq), 157.5 (Cq). MS (ESI+) : m / z calcd for C15H16ClN5O : 318.1 [M+H]+, found : 318.3. Example 3.10: Synthesis of 4-[[(6-chloro-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazin-8-yl)amino]methyl]phenol (3.10) In a sealed vial 10 - 20 mL with a stir bar was charged (1.5) (0.520 g, 1.93 mmol, 1.0 eq.) in dioxane (10.0 mL), isobutyric acid hydrazide (0.238 g, 2.31 mmol, 1.2 eq.) and PTSA.H2O (0.223 g, 1.16 mmol, 0.6 eq.) was added. The vial was sealed and put on heating bloc 17 h at 100°C. After cooling, MeOH (3.0 mL) was added then the mixture was concentrated with SiO2to make solid deposit and directly purified by flash chromatography with DCM / MeOH (97 / 3 to 94 / 6) as eluent to give (3.10) (0.115 g, 19 %) as a white solid. Rf (DCM / MeOH, 92 / 8) : 0.25.1H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.41 (hept, J = 7.0 Hz, 1H, HiPr), 4.44 (d, J = 6.2 Hz, 2H, CH2 Bn), 6.12 (s, 1H, HAr), 6.71 (d, J = 8.5 Hz, 2H, 2xHAr), 7.20 (d, J = 8.5 Hz, 2H, 2xHAr), 9.02 (s, 1H, NHBn), 9.34 (s, 1H, OH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 44.7 (CH2 Bn), 91.4 (CHAr), 115.2 (2xCHAr), 127.5 (Cq), 128.6 (2xCHAr), 139.5 (Cq), 142.2 (Cq), 149.4 (Cq), 153.9 (Cq), 156.6 (Cq). MS (ESI+) : m / z calcd for C15H16ClN5O : 318.1 [M+H]+, found : 318.3. Example 3.11: Synthesis of 6-chloro-3-isopropyl-N-[(2- methoxyphenyl)methyl]-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.11) To a suspension of (1.8) (3.000 g, 10.56 mmol, 1.0 eq.) in dioxane (40.0 mL), isobutyric acid hydrazide (1.307 g, 12.67 mmol, 1.2 eq.) then AcOH (0.67 mL, 11.61 mmol, 1.1 eq.) was added and the mixture was refluxed 16 h. After cooling, MeOH (10.0 mL) was added, stirred vigorously 5 min then SiO2to make solid deposit directly. The mixture was concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 97 / 3) as eluent to give (3.11) (1.490 g, 43 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.43 (hept, J = 7.1 Hz, 1H, HiPr), 3.87 (s, 3H, OCH3), 4.51 (d, J = 6.3 Hz, 2H, CH2 Bn), 6.06 (s, 1H, HAr), 6.91 (t, J = 7.4 Hz, 1H, HAr), 7.05 (d, J = 8.1 Hz, 1H, HAr), 7.22 (d, J = 7.5 Hz, 1H, HAr), 7.28 (td, J = 7.9, 1.8 Hz, 1H, HAr), 8.90 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 40.2 (CH2 Bn), 55.4 (OCH3), 91.3 (CHAr), 110.8 (CHAr), 120.4 (CHAr), 124.4 (Cq), 127.7 (CHAr), 128.6 (CHAr), 139.4 (Cq), 142.4 (Cq), 149.4 (Cq), 154.0 (Cq), 156.7 (Cq). MS (ESI+) : m / z calcd for C16H18ClN5O : 332.1 [M+H]+, found : 332.3. Example 3.12: Synthesis of 6-chloro-3-isopropyl-N-phenyl- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.12) To a solution of (2.1) (0.150 g, 0.65 mmol, 1.0 eq.) in dry THF (5.0 mL), aniline (0.12 mL, 1.30 mmol, 2.0 eq.) then tBuOK 1M in THF (1.30 mL, 1.30 mmol, 2.0 eq.) was added and the mixture was stirred 1 h at room temperature. After completion, saturated NH4Cl (5.0 mL) and water (1.5 mL) was added then biphasic mixture was vigorously stirred 5 min. Layers were separated, aqueous layer was extracted with EtOAc (2x5.0 mL) then organic layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 98 / 2) as eluent to give (3.12) (0.175 g, 94 %) as a white solid. Rf (DCM / MeOH, 96 / 4) : 0.401H NMR (400 MHz, DMSO-d6) δ : 1.41 (d, J = 7.0 Hz, 6H, 2xCH3 iPr), 3.48 (hept, J = 6.9 Hz, 1H, HiPr), 6.35 (s, 1H, HAr), 7.27 (tt, J = 5.7, 2.4 Hz, 1H, HAr), 7.40 – 7.58 (m, 4H, 4xHAr), 10.46 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.5 (CHiPr), 92.9 (CHAr), 123.6 (2xCHAr), 125.7 (CHAr), 129.5 (2xCHAr), 137.7 (Cq), 139.5 (Cq), 140.2 (Cq), 149.6 (Cq), 154.2 (Cq). MS (ESI+) : m / z calcd for C14H14ClN5 : 288.1 [M+H]+, found : 288.1. Example 3.13: Synthesis of 6-chloro-3-isopropyl-N-(2-pyridyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.13) To a solution of (2.1) (0.100 g, 0.43 mmol, 1.0 eq.) in dry THF (5.0 mL), 2-aminopyridine (0.082, 0.87 mmol, 2.0 eq.) then tBuOK 1M in THF (0.87 mL, 0.87 mmol, 2.0 eq.) was added and the mixture was stirred 1 h at room temperature. After completion, saturated NH4Cl (3.5 mL) and water (1.5 mL) was added then biphasic mixture was vigorously stirred 5 min. Layers were separated, aqueous layer was extracted with EtOAc (2x5.0 mL) then organic layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2) as eluent to give (3.13) (0.120 g, 96 %) as a white solid. Rf (DCM / MeOH, 96 / 4) : 0.271H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.50 (hept, J = 7.1, 6.5 Hz, 1H, HiPr), 7.13 (ddd, J = 7.4, 5.0, 1.0 Hz, 1H, HAr), 7.61 (d, J = 8.3 Hz, 1H, HAr), 7.82 (ddd, J = 9.0, 7.3, 2.0 Hz, 1H, HAr), 8.32 (s, 1H, HAr), 8.46 (d, J = 1.9 Hz, 1H, HAr), 10.90 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.5 (CHiPr), 99.5 (CHAr), 114.7 (CHAr), 118.6 (CHAr), 136.6 (Cq), 138.3 (CHAr), 139.3 (Cq), 147.3 (CHAr), 149.7 (Cq), 153.9 (Cq), 154.3 (Cq). MS (ESI+) : m / z calcd for C13H13ClN6 : 289.1 [M+H]+, found : 289.2. Example 3.14: Synthesis of 6-chloro-3-isopropyl-N-(3-pyridyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.14) To a solution of (2.1) (0.100 g, 0.43 mmol, 1.0 eq.) in dry THF (5.0 mL), 3-aminopyridine (0.082, 0.87 mmol, 2.0 eq.) then tBuOK 1M in THF (0.87 mL, 0.87 mmol, 2.0 eq.) was added and the mixture was stirred 1 h at room temperature. After completion, saturated NH4Cl (3.5 mL) and water (1.5 mL) was added then biphasic mixture was vigorously stirred 5 min. Layers were separated, aqueous layer was extracted with EtOAc (2x5.0 mL) then organic layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 96 / 4) as eluent to give (3.14) (0.115 g, 92 %) as a white solid. Rf (DCM / MeOH, 96 / 4) : 0.171H NMR (400 MHz, DMSO-d6) δ : 1.41 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.48 (hept, J = 6.9 Hz, 1H, HiPr), 6.43 (s, 1H, HAr), 7.50 (dd, J = 8.2, 4.7 Hz, 1H, HAr), 7.91 (dt, J = 8.3, 1.9 Hz, 1H, HAr), 8.46 (dd, J = 4.8, 1.5 Hz, 1H, HAr), 8.69 (d, J = 2.6 Hz, 1H, HAr), 10.55 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.5 (CHiPr), 93.8 (CHAr), 124.1 (CHAr), 130.8 (CHAr), 134.6 (Cq), 139.4 (Cq), 140.0 (Cq), 145.1 (CHAr), 146.4 (CHAr), 149.6 (Cq), 154.2 (Cq). MS (ESI+) : m / z calcd for C13H13ClN6 : 289.1 [M+H]+, found : 289.1. Example 3.15: Synthesis of 6-chloro-3-isopropyl-N-(4-pyridyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.15) To a solution of (2.1) (0.150 g, 0.65 mmol, 1.0 eq.) in dry THF (5.0 mL), 4-aminopyridine (0.123 g, 1.30 mmol, 2.0 eq.) then tBuOK 1M in THF (1.30 mL, 1.30 mmol, 2.0 eq.) was added and the mixture was stirred 1 h at room temperature. After completion, saturated NH4Cl (5.0 mL) and water (1.5 mL) was added then biphasic mixture was vigorously stirred 5 min. Layers were separated, aqueous layer was extracted with EtOAc (2x5.0 mL) then organic layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (3.15) (0.180 g, 96 %) as a white solid. Rf (DCM / MeOH, 96 / 4) : 0.101H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.50 (hept, J = 6.9 Hz, 1H, HiPr), 6.88 (s, 1H, HAr), 7.34 – 7.70 (m, 2H, 2xHAr), 8.39 – 8.68 (m, 2H, 2xHAr), 10.69 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.5 (CHiPr), 96.7 (CHAr), 115.5 (CHAr), 138.1 (Cq), 139.5 (Cq), 145.7 (Cq), 149.6 (Cq), 150.8 (CHAr), 154.3 (Cq). MS (ESI+) : m / z calcd for C13H13ClN6 : 289.1 [M+H]+, found : 289.1. Example 3.16: Synthesis of 6-chloro-3-isopropyl-N-(4-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.16) To a suspension of (1.4) (0.390 g, 1.53 mmol, 1.0 eq.) in dioxane (25.0 mL), isobutyric acid hydrazide (0.189 g, 1.89 mmol, 1.2 eq.) then APTS.H2O (0.177 g, 0.92 mmol, 0.6 eq.) was added and the mixture was refluxed 20 h. After cooling, DCM (5.0 mL), MeOH (5.0 mL) and NaHCO3 (0.100 g) was added and the mixture was stirred vigorously 5 min. SiO2 was added to make solid deposit, the mixture was concentrated and purified by flash chromatography with DCM / MeOH (95 / 5 to 93 / 7) as eluent to give (3.16) (0.175 g, 38 %) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.43 (p, J = 7.0 Hz, 1H, HiPr), 4.64 (s, 2H, CH2 Bn), 6.15 (s, 1H, HAr), 7.31 – 7.43 (m, 2H, 2xHAr), 8.44 – 8.60 (m, 2H, 2xHAr), 9.12 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 44.1 (CH2 Bn), 91.7 (CHAr), 122.1 (2xCHAr), 139.4 (Cq), 142.4 (Cq), 146.5 (Cq), 149.5 (Cq), 149.7 (2xCHAr), 154.0 (Cq). MS (ESI+) : m / z calcd for C14H15ClN6 : 303.1 [M+H]+, found : 303.2. Example 3.17: Synthesis of 6-chloro-3-isopropyl-N-(3-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.17) To a suspension of (1.3) (1.500 g, 5.88 mmol, 1.0 eq.) in dioxane (20.0 mL), isobutyric acid hydrazide (0.667 g, 6.47 mmol, 1.1 eq.) then AcOH (0.37 mL, 6.47 mmol, 1.1 eq.) was added and the mixture was refluxed 16 h. After cooling, MeOH (10.0 mL) and NaHCO3(1.000 g) was added, stirred vigorously 5 min then SiO2to make solid deposit directly. The mixture was concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (3.17) (0.700 g, 39 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.42 (hept, J = 7.1 Hz, 1H, HiPr), 4.63 (s, 2H, CH2 Bn), 6.26 (s, 1H, HAr), 7.37 (dd, J = 7.9, 4.8 Hz, 1H, HAr), 7.79 (dt, J = 7.9, 2.0 Hz, 1H, HAr), 8.48 (dd, J = 4.9, 1.6 Hz, 1H, HAr), 8.64 (d, J = 2.3 Hz, 1H, HAr), 9.10 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 42.8 (CH2 Bn), 91.6 (CHAr), 123.6 (CHAr), 133.1 (Cq), 135.1 (CHAr), 139.4 (Cq), 142.2 (Cq), 148.5 (CHAr), 148.9 (CHAr), 149.5 (Cq), 154.0 (Cq). MS (ESI+) : m / z calcd for C14H15ClN6 : 303.1 [M+H]+, found : 303.3. Example 3.18: Synthesis of 6-chloro-3-isopropyl-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.18) To a solution of (1.2) (5.000 g, 19.60 mmol, 1.0 eq.) in dioxane (80.0 mL), isobutyric acid hydrazide (2.224 g, 21.560 mmol, 1.1 eq.) then AcOH (1.25 mL, 21.56 mmol, 1.1 eq.) was added and the mixture was refluxed 15 h. After cooling, the solvent was removed and the crude was triturated in water (150.0 ml). The resulting solid was filtered off, washed with water up to neutral pH, EtOH and Et2O then dried under vacuum to give a first part of (3.18) (1.880 g). The aqueous layer was extracted twice with EtOAc (2x 50.0 mL) then organics layers were combined, washed with saturated NaHCO3, dried over MgSO4, filtrered and concentrated to give second part of (3.18) (0.500 g). Quantity of (3.18): 2.380 g, as a white solid. Rf (DCM / MeOH, 94 / 6) : 0.301H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.43 (hept, J = 7.0 Hz, 1H, HiPr), 4.46 – 4.78 (m, 2H, CH2 Bn), 6.15 (s, 1H, HAr), 7.30 (dd, J = 7.6, 4.8 Hz, 1H, HAr), 7.38 (d, J = 7.8 Hz, 1H, HAr), 7.78 (td, J = 7.7, 1.9 Hz, 1H, HAr), 8.55 (d, J = 4.9 Hz, 1H, HAr), 8.98 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C14H15ClN6 : 303.1 [M+H]+, found : 303.2. Example 3.19: Synthesis of 6-chloro-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.19) To a solution of (1.2) (4.000 g, 15.68 mmol, 1.0 eq.) in dioxane (52.0 mL), corresponding acid hydrazide (1.130 g, 18.82 mmol, 1.2 eq.) and APTS.H2O (3.028 g, 15.68 mmol, 1.0 eq.) was added. The mixture was refluxed during 1 h then after cooling, MeOH (20.0 mL) and Na2CO3 (1.000 g) was added and stirred 5 min. SiO2 was added to make solid deposit and after concentration it was directly purified by flash chromatography with DCM / MeOH (98 / 2 to 95 / 5) as eluent to give (3.19) (0.580 g, 14 %) as a light brown solid.1H NMR (400 MHz, DMSO-d6) δ : 4.69 (d, J = 5.9 Hz, 2H, CH2 Bn), 6.20 (s, 1H, HAr), 7.31 (dd, J = 7.5, 5.0 Hz, 1H, HAr), 7.39 (d, J = 7.8 Hz, 1H, HAr), 7.78 (tt, J = 7.7, 1.6 Hz, 1H, HAr), 8.55 (d, J = 4.8 Hz, 1H, HAr), 9.02 (s, 1H, NHBn), 9.42 (d, J = 1.3 Hz, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 47.2 (CH2 Bn), 92.4 (CHAr), 121.5 (CHAr), 122.6 (CHAr), 137.1 (CHAr), 139.0 (Cq), 139.6 (CHAr), 142.2 (Cq), 149.1 (CHAr), 150.0 (Cq), 156.6 (Cq). MS (ESI+) : m / z calcd for C11H9ClN6 : 261.1 [M+H]+, found : 261.2. Example 3.20: Synthesis of 6-chloro-3-methyl-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.20) To a solution of (1.2) (4.000 g, 15.68 mmol, 1.0 eq.) in dioxane (52.0 mL), corresponding acid hydrazide (1.467 g, 18.82 mmol, 1.2 eq.) and APTS.H2O (3.028 g, 15.68 mmol, 1.0 eq.) was added. The mixture was refluxed during 1 h then after cooling, MeOH (10.0 mL) and NH37N in MeOH (6.0 mL) was added and stirred 10 min. SiO2was added to make solid deposit and after concentration it was directly purified by flash chromatography with DCM / MeOH (98 / 2 to 95 / 5) as eluent to give (3.20) (1.150 g, 27 %) as a grey solid.1H NMR (400 MHz, DMSO-d6) δ : 2.59 (s, 3H, CH3), 4.56 – 4.86 (m, 2H, CH2 Bn), 6.16 (s, 1H, HAr), 7.30 (dd, J = 7.5, 4.9 Hz, 1H, HAr), 7.38 (d, J = 7.9 Hz, 1H, HAr), 7.78 (td, J = 7.7, 1.8 Hz, 1H, HAr), 8.48 – 8.60 (m, 1H, HAr), 8.93 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 9.4 (CH3), 47.2 (CH2 Bn), 91.7 (CHAr), 121.4 (CHAr), 122.6 (CHAr), 137.0 (CHAr), 139.2 (Cq), 142.4 (Cq), 146.8 (Cq), 149.1 (CHAr), 149.6 (Cq), 156.6 (Cq). MS (ESI+) : m / z calcd for C12H11ClN6 : 275.1 [M+H]+, found : 275.2. Example 3.21: Synthesis of 6-chloro-3-ethyl-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.21) In a sealed tube 10 - 20 mL with a stir bar was charged (1.2) (2.000 g, 7.84 mmol, 1.0 eq.), dioxane sec (15.6 mL), corresponding hydrazide (0.768 g, 8.62 mmol, 1.1 eq.) and AcOH (0.50 mL, 8.62 mmol, 1.1 eq.). The vial was sealed and then put on heating block, 23h h at 115°C. After cooling, the mixture was poured onto saturated NaHCO3 (20.0 mL) then water (40.0 mL) was added. Aqueous mixture was extracted three times with EtOAc (3x30 mL) then organics layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (96 / 4 to 94 / 6) as eluent to give (3.21) (0.550 g, 24 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.34 (t, J = 7.5 Hz, 3H, CH3-CH2), 3.00 (q, J = 7.6 Hz, 2H, CH2-CH3), 4.68 (d, J = 6.2 Hz, 2H, CH2 Bn), 6.16 (s, 1H, HAr), 7.30 (dd, J = 7.5, 4.8 Hz, 1H, HAr), 7.38 (d, J = 7.8 Hz, 1H, HAr), 7.78 (td, J = 7.7, 1.8 Hz, 1H, HAr), 8.55 (d, J = 5.3 Hz, 1H, HAr), 8.96 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 10.8 (CH3-CH2), 17.3 (CH2-CH3), 47.2 (CH2 Bn), 91.8 (CHAr), 121.4 (CHAr), 122.6 (CHAr), 137.1 (CHAr), 139.3 (Cq), 142.5 (Cq), 149.1 (CHAr), 149.6 (Cq), 150.9 (Cq), 156.6 (Cq). MS (ESI+) : m / z calcd for C13H13ClN6 : 289.1 [M+H]+, found : 289.2. Example 3.22: Synthesis of 6-chloro-3-propyl-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.22) To a solution of (2.7) (~70 % purity, 0.800 g, 2.42 mmol, 1.0 eq.) in THF (11.0 mL), Et3N (0.48 mL, 3.39 mmol, 1.4 eq.) and corresponding amine (0.367 g, 3.39 mmol, 1.4 eq.) was added and the mixture was refluxed during 1.5 h. After cooling, the solid was filtered off, washed with THF then the filtrate was concentrated and purified by flash chromatography with DCM / EtOAc (98 / 2 to 96 / 4) as eluent to give (3.22) (0.480 g, 65 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 0.96 (t, J = 7.4 Hz, 3H, CH3), 1.80 (h, J = 7.4 Hz, 2H, CH2), 2.97 (t, J = 7.5 Hz, 2H, CH2), 4.58 – 4.81 (m, 2H, CH2 Bn), 6.16 (s, 1H, HAr), 7.31 (dd, J = 7.5, 4.9 Hz, 1H, HAr), 7.38 (d, J = 7.9 Hz, 1H, HAr), 7.78 (td, J = 7.7, 1.8 Hz, 1H, HAr), 8.55 (dd, J = 5.2, 1.8 Hz, 1H, HAr), 8.96 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 13.6 (CH3), 19.4 (CH2), 25.4 (CH2), 47.2 (CH2 Bn), 91.8 (CHAr), 121.4 (CHAr), 122.6 (CHAr), 137.0 (CHAr), 139.2 (Cq), 142.5 (Cq), 149.1 (CHAr), 149.5 (Cq), 149.8 (Cq), 156.6 (Cq). MS (ESI+) : m / z calcd for C14H15ClN6 : 303.1 [M+H]+, found : 303.3. Example 3.23: Synthesis of 3-tert-butyl-6-chloro-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.23) To a solution of (1.2) (2.000 g, 7.84 mmol, 1.0 eq.) in dry dioxane (31.0 mL), corresponding hydrazide (1.033 g, 8.62 mmol, 1.1 eq.) and AcOH (0.50 mL, 8.62 mmol, 1.1 eq.) was added then the mixture was refluxed 17 h. After cooling, the reaction mixture was poured onto saturated NaHCO3 (100.0 mL) and EtOAc (60.0 mL). The biphasique mixture was vigorously stirred 10 min then layers were separated. Aqueous layer was extracted twice with EtOAc (2x 50.0 mL) then organics layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3 to 93 / 7) as eluent to give (3.23) (0.880 g, 35 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.50 (s, 9H, 3xCH3 tBu), 4.67 (d, J = 6.9 Hz, 2H, CH2Bn), 6.15 (s, 1H, HAr), 7.30 (dd, J = 7.5, 4.9 Hz, 1H, HAr), 7.38 (d, J = 7.8 Hz, 1H, HAr), 7.78 (td, J = 7.7, 1.8 Hz, 1H, HAr), 8.49 – 8.63 (m, 1H, HAr), 8.96 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 27.0 (3xCH3 tBu), 32.4 (Cq tBu), 47.2 (CH2 Bn), 91.5 (CHAr), 121.4 (CHAr), 122.6 (CHAr), 137.1 (CHAr), 140.2 (CHAr), 142.5 (Cq), 148.7 (Cq), 149.1 (Cq), 155.2 (Cq), 156.7 (Cq). MS (ESI+) : m / z calcd for C15H17ClN6 : 317.13 [M+H]+, found : 317.3. Example 3.24: Synthesis of 6-chloro-3-cyclopropyl-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.24) To a solution of (1.2) (4.000 g, 15.68 mmol, 1.0 eq.) in dioxane (52.0 mL), corresponding hydrazide (1.884 g, 18.82 mmol, 1.2 eq.) and AcOH (1.00 mL, 17.25 mmol, 1.1 eq.) was added. The mixture was refluxed 15h and after cooling, MeOH (20 mL) and DCM (20 mL) was added to solubilize reaction mixture. SiO2was added to make solid deposit and after concentration it was directly purified by flash chromatography with DCM / MeOH (98 / 2 to 95 / 5) as eluent to give (3.24) (1.620 g, 34 %) as a rose pale solid. Rf (DCM / MeOH, 94 / 6) : 0.281H NMR (400 MHz, DMSO-d6) δ : 1.02 – 1.23 (m, 4H, 2xCH2 cPr), 2.32 (td, J = 8.2, 4.3 Hz, 1H, HcPr), 4.67 (d, J = 6.0 Hz, 2H, CH2 Bn), 6.15 (s, 1H, HAr), 7.30 (dd, J = 7.4, 4.9 Hz, 1H, HAr), 7.37 (d, J = 7.8 Hz, 1H, HAr), 7.78 (t, J = 7.7 Hz, 1H, HAr), 8.55 (d, J = 4.9 Hz, 1H, HAr), 8.94 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 4.8 (CHcPr), 7.1 (2xCH2 cPr), 47.2 (CH2 Bn), 91.8 (CHAr), 121.4 (CHAr), 122.6 C(HAr), 137.0 (CHAr), 139.3 (Cq), 142.4 (Cq), 149.1 (CHAr), 149.6 (Cq), 151.4 (Cq), 156.6 (Cq). MS (ESI+) : m / z calcd for C14H13ClN6 : 301.1 [M+H]+, found : 301.2. Example 3.25: Synthesis of 6-chloro-3-cyclobutyl-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.25) In a sealed tube 10 - 20 mL with a stir bar was charged (1.2) (1.900 g, 7.45 mmol, 1.0 eq.), dioxane sec (15.0 mL), corresponding hydrazide (0.984 g, 8.19 mmol, 1.1 eq.) and AcOH (0.47 mL, 8.19 mmol, 1.1 eq.). The vial was sealed and then put on heating block, 23h h at 115°C. After cooling, the mixture was poured onto saturated NaHCO3(20.0 mL) then water (40.0 mL) was added. Aqueous mixture was extracted three times with EtOAc (3x30 mL) then organics layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with EtOAc (100 %) as eluent to give (3.25) (0.550 g, 23 %) as a white solid. Rf (EtOAc,100 %) : 0.141H NMR (400 MHz, DMSO-d6) δ : 1.91 – 2.03 (m, 1H, H(CH2 cBut)), 2.12 (dq, J = 10.8, 8.6 Hz, 1H, H(CH2 cBut)), 2.43 (ddd, J = 12.2, 6.2, 2.9 Hz, 4H, 2xCH2 cBut), 3.95 (p, J = 8.4 Hz, 1H, HcBut), 4.68 (s, 2H, CH2 Bn), 6.14 (s, 1H, HAr), 7.30 (dd, J = 7.5, 4.9 Hz, 1H, HAr), 7.38 (d, J = 7.9 Hz, 1H, HAr), 7.78 (td, J = 7.7, 1.8 Hz, 1H, HAr), 8.55 (d, J = 5.4 Hz, 1H, HAr), 8.97 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C15H15ClN6 : 315.1 [M+H]+, found : 315.3. Example 3.26: Synthesis of 6-chloro-3-cyclopentyl-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.26) To a solution of (1.2) (4.000 g, 15.68 mmol, 1.0 eq.) in dioxane (52 mL), corresponding hydrazide (1.884 g, 18.82 mmol, 1.2 eq.) and AcOH (1.00 mL, 17.25 mmol, 0.1 eq.) was added. The mixture was refluxed 15h and after cooling, MeOH (20 mL) and DCM (20 mL) was added to solubilize reaction mixture. SiO2was added to make solid deposit and after concentration it was directly purified by flash chromatography with DCM / MeOH (94 / 6) as eluent to give (3.26) (1.620 g, 34 %) as a rose pale solid.1H NMR (400 MHz, DMSO-d6) δ : 1.64 – 1.85 (m, 4H, 2xCH2 cPent), 1.93 (dq, J = 11.9, 7.2 Hz, 2H, CH2 cPent), 2.10 (qd, J = 11.8, 9.6, 6.5 Hz, 2H, CH2 cPent), 3.53 (p, J = 8.0 Hz, 1H, CHcPent), 4.60 – 4.76 (s, 2H, CH2 Bn), 6.15 (s, 1H, HAr), 7.30 (dd, J = 7.5, 4.8 Hz, 1H, HAr), 7.38 (d, J = 7.8 Hz, 1H, HAr), 7.78 (td, J = 7.7, 1.8 Hz, 1H, HAr), 8.51 – 8.61 (m, 1H, HAr), 8.95 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C16H17ClN6 : 329.1 [M+H]+, found : 329.3. Example 3.27: Synthesis of 6-chloro-3-cyclohexyl-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.27) In a sealed tube 10 - 20 mL with a stir bar was charged (1.2) (1.500 g, 5.88 mmol, 1.0 eq.), dioxane (17.8 mL), corresponding acid hydrazide (0.939 g, 6.47 mmol, 1.1 eq.) and AcOH (0.37 mL, 6.47 mmol, 1.1 eq.). The vial was sealed and then put on heating block, 21 h at 110 °C. The reaction mixture was cooled and MeOH (3.0 mL) was added. The mixture was concentrated with SiO2to make solid deposit and purified by flash chromatography with DCM / MeOH (97 / 3 to 93 / 7) as eluent to give (3.27) (0.800 g, 40 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.39 (dt, J = 36.4, 12.5 Hz, 3H, H(CH2) cHex& CH2cHex), 1.67 (dt, J = 24.1, 12.5 Hz, 3H, H(CH2) cHex& CH2 cHex), 1.81 (d, J = 12.3 Hz, 2H, CH2cHex), 2.01 (d, J = 12.6 Hz, 2H, CH2 cHex), 3.15 (t, J = 11.5 Hz, 1H, HcHex), 4.68 (s, 2H, CH2Bn), 6.14 (s, 1H, HAr), 7.30 (dd, J = 7.5, 4.9 Hz, 1H, HAr), 7.38 (d, J = 7.7 Hz, 1H, HAr), 7.78 (td, J = 7.7, 3.7 Hz, 1H, HAr), 8.51 – 8.63 (m, 1H, HAr), 8.97 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 25.3 (2xCH2 cHex), 25.5 (CH2 cHex), 29.8 (2xCH2 cHex), 33.3 (CHcHex), 47.2 (CH2 Bn), 91.8 (CHAr), 121.4 (CHAr), 122.6 (CHAr), 129.5 (Cq), 137.1 (CHAr), 139.2 (Cq), 142.5 (Cq), 149.1 (CHAr), 149.4 (Cq), 153.2 (Cq). MS (ESI+) : m / z calcd for C17H19ClN6 : 343.1 [M+H]+, found : 343.3. Example 3.28: Synthesis of 6-chloro-3-phenyl-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.28) In a sealed tube 10 - 20 mL with a stir bar was charged (1.2) (1.500 g, 5.88 mmol, 1.0 eq.), dioxane (17.8 mL), corresponding acid hydrazide (0.899 g, 6.47 mmol, 1.1 eq.) and AcOH (0.37 mL, 6.47 mmol, 1.1 eq.). The vial was sealed and then put on heating block, 21 h at 110 °C. The reaction mixture was cooled and MeOH (3.0 mL) was added. The mixture was concentrated with SiO2to make solid deposit and purified by flash chromatography with DCM / MeOH (97 / 3 to 93 / 7) as eluent to give (3.28) (0.750 g, 38 %) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ : 4.73 (d, J = 5.9 Hz, 2H, CH2 Bn), 7.32 (dd, J = 7.5, 4.9 Hz, 1H, HAr), 7.42 (d, J = 7.8 Hz, 1H, HAr), 7.59 (dt, J = 13.6, 7.1 Hz, 3H, 3xHAr), 7.80 (t, J = 7.7 Hz, 1H, HAr), 8.32 (d, J = 7.6 Hz, 2H, HAr), 8.57 (d, J = 4.9 Hz, 1H, HAr), 9.11 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C17H13ClN6 : 337.1 [M+H]+, found : 337.3. Example 3.29: Synthesis of 6-chloro-N-(2-pyridylmethyl)-3-sec-butyl- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.29) To a solution of (2.2) (0.565 g, 2.31 mmol, 1.0 eq.) in THF (23.0 mL), corresponding amine (0.44 mL, 3.00 mmol, 1.3 eq.) and DIPEA (0.61 mL, 3.46 mmol, 1.5 eq.) was added and the mixture was refluxed during 5 h. After cooling, the solvent was removed, the crude was triturated in H2O (10.0 mL) and saturated NaHCO3(10.0 mL) and the resulting solid was filtered off, washed with water up to neutral pH then Et2O and dried under vacuum to give (3.29) (0.600 g, 82 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 0.84 (t, J = 7.4 Hz, 3H, CH3-CH2), 1.35 (d, J = 7.0 Hz, 3H, CH3-CH), 1.82 (ddq, J = 68.8, 13.8, 7.1 Hz, 2H, CH2-CH3), 3.24 – 3.31 (m, 1H, HC-CH3), 4.67 (d, J = 5.7 Hz, 2H, CH2 Bn), 6.15 (s, 1H, HAr), 7.31 (dd, J = 7.5, 4.9 Hz, 1H, HAr), 7.39 (d, J = 7.9 Hz, 1H, HAr), 7.78 (td, J = 7.7, 1.8 Hz, 1H, HAr), 8.55 (d, J = 4.9 Hz, 1H, HAr), 8.98 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 11.4 (CH3-CH2), 17.6 (CH3-CH), 26.8 (CH2-CH3), 30.9 (CH-CH3), 47.2 (CH2 Bn), 91.8 (CHAr), 121.5 (CHAr), 122.6 (CHAr), 137.1 (CHAr), 139.3 (Cq), 142.5 (Cq), 149.1 (CHAr), 149.4 (Cq), 153.2 (Cq), 156.6 (Cq). MS (ESI+) : m / z calcd for C15H17ClN6 : 317.8 [M+H]+, found : 317.2. Example 3.30: Synthesis of 6-chloro-3-(1-ethylpropyl)-N-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.30) To a solution of (2.3) (0.510 g, 1.97 mmol, 1.0 eq.) in THF (20.0 mL), corresponding amine (0.38 mL, 2.56 mmol, 1.3 eq.) and DIPEA (0.52 mL, 2.95 mmol, 1.5 eq.) was added and the mixture was refluxed during 5 h. After cooling, the solvent was removed, the crude was triturated in H2O (10.0 mL) and saturated NaHCO3(10.0 mL) and the resulting solid was filtered off, washed with water up to neutral pH then Et2O and dried under vacuum to give (3.30) (0.580 g, 89 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 0.77 (t, J = 7.4 Hz, 6H, 2xCH3-CH2), 1.83 (ddt, J = 37.0, 13.5, 6.9 Hz, 4H, 2xCH2-CH3), 3.10 – 3.24 (m, 1H, HiPent), 4.67 (d, J = 5.8 Hz, 2H, CH2 Bn), 6.15 (s, 1H, HAr), 7.31 (dd, J = 7.4, 4.9 Hz, 1H, HAr), 7.40 (d, J = 7.9 Hz, 1H, HAr), 7.79 (td, J = 7.7, 1.7 Hz, 1H, HAr), 8.55 (d, J = 4.9 Hz, 1H, HAr), 8.98 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C16H19ClN6 : 331.1 [M+H]+, found : 331.2. Example 3.31: Synthesis of 6-chloro-3-isobutyl-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.31) To a solution of (2.4) (0.290 g, 1.18 mmol, 1.0 eq.), THF (11.0 mL), corresponding amine (0.23 mL, 1.54 mmol, 1.3 eq.) and DIPEA (0.31 mL, 1.78 mmol, 1.5 eq.) was added then the mixture was refluxed 1 h. After cooling, Et2O (30.0 mL), the precipitate was filtered off, washed with water, triturated in Et2O then dried under vacuum to give (3.31) (0.285 g, 76 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 0.94 (d, J = 6.6 Hz, 6H, 2xCH3 iPr), 2.21 (hept, J = 6.8 Hz, 1H, HiPr), 2.89 (d, J = 7.2 Hz, 2H, CH2-CH), 4.68 (s, 2H, CH2 Bn), 6.16 (s, 1H, HAr), 7.31 (dd, J = 7.5, 4.9 Hz, 1H, HAr), 7.39 (d, J = 7.8 Hz, 1H, HAr), 7.79 (td, J = 7.7, 1.8 Hz, 1H, HAr), 8.55 (d, J = 4.7 Hz, 1H, HAr), 8.95 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C15H17ClN6 : 317.8 [M+H]+, found : 317.2. Example 3.32: Synthesis of 6-chloro-3-(2-pyridyl)-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.32) In a sealed tube 10 - 20 mL with a stir bar was charged (1.2) (1.250 g, 4.90 mmol, 1.0 eq.), dioxane (10.0 mL), corresponding acid hydrazide (0.778 g, 5.39 mmol, 1.1 eq.) and PTSA.H2O (0.946 g, 4.90 mmol, 1.0 eq.). The vial was sealed and then put on heating block, 19 h at 110 °C. After cooling, MeOH (5.0 mL) and NH37M in MeOH (3.0 mL) was added then the mixture was concentrated with SiO2to make solid deposit and directly purified by flash chromatography with DCM / MeOH (98 / 2 to 90 / 10) as eluent to give (3.32) (0.300 g, 18 %) as a yellow solid. Rf (DCM / MeOH, 94 / 6) : 0.101H NMR (400 MHz, DMSO-d6) δ : 4.74 (s, 2H, CH2 Bn), 6.32 (s, 1H, HAr), 7.32 (dd, J = 7.5, 5.0 Hz, 1H, HAr), 7.43 (d, J = 7.9 Hz, 1H, HAr), 7.53 – 7.65 (m, 1H, HAr), 7.80 (td, J = 7.7, 1.8 Hz, 1H, HAr), 8.05 (td, J = 7.8, 1.8 Hz, 1H, HAr), 8.23 (d, J = 7.9 Hz, 1H, HAr), 8.57 (d, J = 4.9 Hz, 1H, HAr), 8.81 (d, J = 4.9 Hz, 1H, HAr), 9.13 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C16H12ClN7 : 338.1 [M+H]+, found : 338.2. Example 3.33: Synthesis of 6-chloro-3-(3-pyridyl)-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.33) In a sealed tube 10 - 20 mL with a stir bar was charged (1.2) (1.250 g, 4.90 mmol, 1.0 eq.), dioxane (10.0 mL), corresponding hydrazide (0.754 g, 5.39 mmol, 1.1 eq.) and PTSA.H2O (0.946 g, 4.90 mmol, 1.0 eq.). The vial was sealed and then put on heating block, 19h h at 110 °C. After cooling, NH37N in MeOH (2.80 mL, 19.6 mmol, 4.0 eq.) was added and the mixture was concentrated with silica then directly purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to give (3.33) (0.275 g, 17 %) as a white solid. Rf (DCM / MeOH, 94 / 6) : 0.251H NMR (400 MHz, DMSO-d6) δ : 4.74 (s, 2H, CH2 Bn), 6.34 (s, 1H, HAr), 7.24 – 7.39 (m, 1H, HAr), 7.42 (d, J = 7.9 Hz, 1H, HAr), 7.65 (dd, J = 8.1, 4.9 Hz, 1H, HAr), 7.75 – 7.90 (m, 1H, HAr), 8.57 (d, J = 4.8 Hz, 1H, HAr), 8.64 (dt, J = 8.1, 2.0 Hz, 1H, HAr), 8.74 (dd, J = 4.8, 1.7 Hz, 1H, HAr), 9.19 (s, 1H, NHBn), 9.44 (d, J = 2.2 Hz, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C16H12ClN7 : 338.1 [M+H]+, found : 338.2. Example 3.34: Synthesis of 6-chloro-3-(4-pyridyl)-N-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.34) In a sealed tube 10 - 20 mL with a stir bar was charged (1.2) (1.250 g, 4.90 mmol, 1.0 eq.), dioxane (10.0 mL), corresponding hydrazide (0.778 g, 5.39 mmol, 1.1 eq.) and PTSA.H2O (0.946 g, 4.90 mmol, 1.0 eq.). The vial was sealed and then put on heating block, 19h h at 110 °C. After cooling, NH37N in MeOH (2.80 mL, 19.6 mmol, 4.0 eq.) was added and the mixture was concentrated with silica then directly purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to give (3.34) (0.310 g, 19 %) as a white solid. Rf (DCM / MeOH, 94 / 6) : 0.291H NMR (400 MHz, DMSO-d6) δ : 4.74 (d, J = 6.1 Hz, 2H, CH2 Bn), 6.37 (s, 1H, HAr), 7.32 (dd, J = 7.3, 5.1 Hz, 1H, HAr), 7.42 (d, J = 7.8 Hz, 1H, HAr), 7.80 (dd, J = 8.2, 6.5 Hz, 1H, HAr), 8.23 – 8.38 (m, 2H, 2xHAr), 8.56 (d, J = 4.9 Hz, 1H, HAr), 8.72 – 8.92 (m, 2H, 2xHAr), 9.21 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C16H12ClN7 : 338.1 [M+H]+, found : 338.2. Example 3.35: Synthesis of N-[(4-aminophenyl)methyl]-6-chloro-3- isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.35) To a solution of (2.1) (0.300 g, 1.30 mmol, 1.0 eq.) in THF (18.0 mL), 4- (aminomethyl)aniline dihydrochloride (0.512 g, 2.60 mmol, 2.0 eq.) and Et3N (1.28 mL, 9.09 mmol, 7.0 eq.) were added then the mixture was refluxed 2 h. After cooling, the solid was filtered off, washed with THF then the filtrate was concentrated and directly purified by flash chromatography with DCM / MeOH (98 / 2 to 96 / 4) as eluent to give (3.35) (0.245 g, 60 %) as a pale yellow solid. Rf (DCM / MeOH, 94 / 6) : 0.241H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 7.0 Hz, 6H, 2xCH3 iPr), 3.42 (h, J = 6.9 Hz, 1H, HiPr), 4.37 (d, J = 6.3 Hz, 2H, CH2 Bn), 5.01 (s, 2H, NH2), 6.10 (s, 1H, HAr), 6.51 (d, J = 8.4 Hz, 2H, 2xHAr), 7.05 (d, J = 8.3 Hz, 2H, 2xHAr), 8.95 (t, J = 6.2 Hz, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 45.0 (CH2 Bn), 91.3 (CHAr), 113.8 (2xCHAr), 124.0 (Cq), 128.2 (2xCHAr), 139.5 (Cq), 142.1 (Cq), 147.9 (Cq), 149.4 (Cq), 153.9 (Cq). MS (ESI+) : m / z calcd for C15H17ClN6 : 317.1 [M+H]+, found : 317.2. Example 3.36: Synthesis of N-[(3-aminophenyl)methyl]-6-chloro-3- isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.36) To a solution of (2.1) (0.300 g, 1.30 mmol, 1.0 eq.) in THF (18.0 mL), 3- (aminomethyl)aniline (0.320 g, 2.60 mmol, 2.0 eq.) and Et3N (0.37 mL, 2.60 mmol, 2.0 eq.) were added then the mixture was refluxed 2 h. After cooling, the solid was filtered off, washed with THF then the filtrate was concentrated and directly purified by flash chromatography with DCM / MeOH (98 / 2 to 96 / 4) as eluent to give (3.36) (0.280 g, 68 %) as a yellow solid. Rf (DCM / MeOH, 96 / 4) : 0.271H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.42 (hept, J = 6.9 Hz, 1H, HiPr), 4.43 (d, J = 6.4 Hz, 2H, CH2 Bn), 5.06 (s, 2H, NH2), 6.02 (s, 1H, HAr), 6.40 – 6.56 (m, 3H, 3xHAr), 6.96 (t, J = 7.7 Hz, 1H, HAr), 9.03 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C15H17ClN6 : 317.13 [M+H]+, found : 317.3. Example 3.37: Synthesis of N-[(2-aminophenyl)methyl]-6-chloro-3- isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.37) To a solution of (1.12) (4.000 g, 14.86 mmol, 1.0 eq.) in dry dioxane (60.0 mL), isobutyric acid hydrazide (1.840 g, 17.84 mmol, 1.2 eq.) and AcOH (0.86 mL, 14.86 mmol, 1.0 eq.) was added then the mixture was refluxed 18 h. After cooling, the reaction mixture was concentrated, the residue was triturated in water, filtered off, washed with water up to neutral pH. The solid was taken up with DCM and MeOH, the filtrate was concentrated and purified by flash chromatography with DCM / MeOH (97 / 3 to 95 / 5) as eluent to give (3.37) (0.600 g, 13 %) as a pale yellow solid. Rf (DCM / MeOH, 94 / 6) : 0.411H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.42 (p, J = 6.9 Hz, 1H, HiPr), 4.39 (s, 2H, CH2 Bn), 5.17 (s, 2H, NH2), 6.07 (s, 1H, HAr), 6.51 (t, J = 7.4 Hz, 1H, HAr), 6.65 (d, J = 7.9 Hz, 1H, HAr), 6.97 (td, J = 7.6, 1.6 Hz, 1H, HAr), 7.09 (dd, J = 7.6, 1.6 Hz, 1H, HAr), 8.92 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 42.4 (CH2 Bn), 91.6 (CHAr), 115.1 (CHAr), 115.9 (CHAr), 119.3 (Cq), 128.1 (CHAr), 128.2 (CHAr), 139.5 (Cq), 142.3 (Cq), 146.3 (Cq), 149.4 (Cq), 154.0 (Cq). MS (ESI+) : m / z calcd for C15H17ClN6 : 317.1 [M+H]+, found : 317.3. Example 3.38: Synthesis of 2-(6-chloro-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazin-8-yl)-3,4-dihydro-1H-isoquinoline (3.38) To a suspension of (1.15) (4.600 g, 16.42 mmol, 1.0 eq.) in dry dioxane (66 mL), isobutyric acid hydrazide (1.863 g, 18.06 mmol, 1.1 eq.) and AcOH (1.04 mL, 18.06 mmol, 1.1 eq.) was added then the mixture was refluxed 22 h. After cooling, MeOH (10.0 mL) was added, the mixture was concentrated with SiO2to make solid deposit and directly purified by flash chromatography with DCM / EtOAc (98 / 2 to 96 / 4) as eluent to give (3.38) (1.390 g, 26 %) as a white solid. Rf (DCM / EtOAc, 98 / 2) : 0.231H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 7.0 Hz, 6H, 2xCH3 iPr), 3.02 (t, J = 5.9 Hz, 2H, CH2-CH2-N), 3.44 (hept, J = 6.9 Hz, 1H, HiPr), 4.42 (s, 2H, N-CH2-CH2), 5.18 (s, 2H, CH2-N), 6.40 (s, 1H, HAr), 7.24 (td, J = 4.9, 4.5, 2.6 Hz, 4H, 4xHAr).13C NMR (101 MHz, DMSO-d6) δ : 19.7 (2xCH3 iPr), 24.4 (CHiPr), 28.0 (CH2-CH2-N), 45.9 (N-CH2-CH2), 49.3 (CH2-N), 94.0 (CHAr), 126.3 (CHAr), 126.3 (CHAr), 126.8 (CHAr), 128.3 (CHAr), 134.5 (Cq), 140.4 (Cq), 142.7 (Cq), 149.4 (Cq), 153.6 (Cq). MS (EI-MS) : m / z calcd for C17H18ClN5 : 328.1 [M+H]+, found : 328.2. Example 3.39: Synthesis of 6-chloro-8-isoindolin-2-yl-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazine (3.39) To a solution of (2.1) (0.350 g, 1.52 mmol, 1.0 eq.) in THF (15.0 mL), corresponding amine hydrochloride (0.340 g, 2.12 mmol, 1.4 eq.) and Et3N (0.64 mL, 4.54 mmol, 3.0 eq.) was added then the mixture was refluxed 1.5 h. After cooling, the precipitate was filtered, washed with THF then the filtrate was concentrated and purified by flash chromatography with DCM / MeOH (100 / 0 to 98 / 2) as eluent. The impur fraction was concentrated then the residu was triturated in Et2O, filtered, washed with a little amount of Et2O and dried under vacuum to give (3.39) (0.280 g, 59 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.40 (d, J = 7.0 Hz, 6H, 2xCH3 iPr), 3.46 (hept, J = 6.9 Hz, 1H, HiPr), 4.87 (s, 2H, CH2), 5.61 (s, 2H, CH2), 6.10 (s, 1H, HAr), 7.37 (dd, J = 5.6, 3.2 Hz, 2H, 2xHAr), 7.44 (s, 1H, HAr), 7.50 (s, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 19.7 (2xCH3 iPr), 24.4 (CHiPr), 54.9 (CH2), 57.4 (CH2), 93.4 (CHAr), 122.5 (CHAr), 122.8 (CHAr), 127.6 (2xCHAr), 134.8 (Cq), 136.7 (Cq), 140.2 (Cq), 141.5 (Cq), 149.3 (Cq), 153.6 (Cq). MS (EI-MS) : m / z calcd for C16H16ClN5 : 314.1 [M+H]+, found : 314.3. Example 3.40: Synthesis of 6-chloro-N-indan-1-yl-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.40) To a solution of (2.1) (0.250 g, 1.05 mmol, 1.0 eq.) in THF (13.0 mL), corresponding amine hydrochloride (0.273 g, 1.57 mmol, 1.5 eq.) and Et3N (0.44 mL, 3.15 mmol, 3.0 eq.) was added then the mixture was refluxed 4 h. After cooling, the solvent was removed, the residue was triturated in water, filtered off, washed with water up to neutral pH and the solid was taken up in EtOAc. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 95 / 5) as eluent to give (3.40) (0.300 g, 87 %) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ : 1.39 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 2.19 (dt, J = 17.4, 8.0 Hz, 1H, H(CH2)indane), 2.55 (s, 1H, H(CH2)indane), 2.85 (dt, J = 16.2, 8.3 Hz, 1H, H(CH2)indane), 3.03 (ddd, J = 15.9, 8.9, 3.1 Hz, 1H, H(CH2)indane), 3.45 (hept, J = 7.7, 7.2 Hz, 1H, HiPr), 5.41 (s, 1H, Hindane), 6.48 (s, 1H, HAr), 7.14 – 7.34 (m, 4H, 4xHAr), 8.75 (s, 1H, NHindane).13C NMR (101 MHz, DMSO-d6) δ : 19.9 (2xCH3 iPr), 24.4 (CHiPr), 29.8 (CH2 indane), 31.6 (CH2 indane), 57.3 (CHindane), 91.4 (CHAr), 123.8 (CHAr), 124.8 (CHAr), 126.4 (CHAr), 127.8 (CHAr), 139.4 (Cq), 142.3 (Cq), 142.7 (Cq), 143.1 (Cq), 149.8 (Cq), 154.0 (Cq). MS (ESI+) : m / z calcd for C17H18ClN5 : 328.1 [M+H]+, found : 328.3. Example 3.41: Synthesis of 6-chloro-N-(1H-indol-2-ylmethyl)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.41) In a sealed tube 10 - 20 mL with a stir bar was charged (1.10) (1.100 g, 3.57 mmol, 1.0 eq.), dioxane (15.0 mL), isobutyric acid hydrazide (0.441 g, 4.28 mmol, 1.2 eq.) and AcOH (0.23 mL, 3.92 mmol, 1.1 eq.). The vial was sealed and then put on heating block, 17 h at 100 °C. After cooling, MeOH (10.0 mL) was added, stirred vigorously 5 min then the mixture was concentrated with SiO2 to make solid deposit and directly purified by flash chromatography with DCM / MeOH (97 / 3 to 94 / 6) as eluent to give (3.41) (0.270 g, 22 %) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.43 (hept, J = 7.1 Hz, 1H, HiPr), 4.74 (s, 2H, CH2 Bn), 6.29 (s, 1H, HAr), 6.36 (d, J = 2.0 Hz, 1H, HAr), 6.94 (t, J = 7.4 Hz, 1H, HAr), 7.00 – 7.08 (m, 1H, HAr), 7.33 (d, J = 8.0 Hz, 1H, HAr), 7.45 (d, J = 7.8 Hz, 1H, HAr), 8.89 (s, 1H, NH), 10.99 (s, 1H, NHindol).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C17H17ClN6 : 341.1 [M+H]+, found : 341.3. Example 3.42: Synthesis of N-[(4-bromophenyl)methyl]-6-chloro-3- isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.42) To a solution of (1.13) (4.100 g, 12.32 mmol, 1.0 eq.) in dioxane (50.0 mL), isobutyric acid hydrazide (1.524 g, 14.77 mmol, 1.2 eq.) and AcOH (0.78 mL, 13.54 mmol, 1.1 eq.) was added then the miture was refluxed 18 h. After cooling, the mixture was poured onto water (200.0 mL) then the precipitate was triturated, filtered off, washed with water up to neutral pH. The solid was triturated in EtOAc, filtered and dried under vacuum to give (3.42) (2.400 g, 51 %) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.42 (hept, J = 7.0 Hz, 1H, HiPr), 4.40 – 4.73 (m, 2H, CH2 Bn), 6.15 (s, 1H, HAr), 7.35 (d, J = 8.2 Hz, 2H, 2xHAr), 7.54 (d, J = 8.4 Hz, 2H, 2xHAr), 9.11 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C15H15BrClN5 : 380.0 [M+H]+, found : 380.2. Example 3.43: Synthesis of 6-chloro-3-isopropyl-N-(2-phenylethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.43) To a solution of (1.16) (4.000 g, 14.92 mmol, 1.0 eq.) in dry dioxane (60 mL), isobutyric acid hydrazide (1.847 g, 17.90 mmol, 1.2 eq.) then AcOH (0.95 mL, 16.41 mmol, 1.1 eq.) was added and the mixture was refluxed 4 h. After cooling, the mixture was concentrated then the residue was suspended and triturated into water (120 mL). The solid was filtered off, washed with water up to neutral pH then taken up with EtOH, concentrated en dried under vacuum to give the title compound (3.43) (2.350 g, 50 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 7.0 Hz, 6H, 2xCH3 iPr), 2.94 (t, J = 7.3 Hz, 2H, CH2-CH2-NH), 3.42 (p, J = 6.9 Hz, 1H, HiPr), 3.52 – 3.68 (m, 2H, CH2-NH), 6.21 (s, 1H, HAr), 7.20 (tt, J = 5.6, 2.9 Hz, 1H, HAr), 7.25 – 7.38 (m, 4H, 4xHAr), 8.51 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 33.8 (CH2-CH2-NH), 43.5 (CH2-NH), 91.0 (CHAr), 126.2 (CHAr), 128.3 (2xCHAr), 128.9 (2xCHAr), 138.9 (Cq), 139.4 (Cq), 142.2 (Cq), 149.7 (Cq), 153.9 (Cq). MS (ESI+) : m / z calcd for C16H18ClN5 : 316.1 [M+H]+, found : 316.2. Example 3.44: Synthesis of 6-chloro-3-isopropyl-N-[2-(2-pyridyl)ethyl]- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.44) To a solution of (2.1) (0.300 g, 1.30 mmol, 1.0 eq.) in THF (3.9 mL), corresponding amine (0.190 g, 1.56 mmol, 1.2 eq.) and DIPEA (0.27 mL, 1.56 mmol, 1.2 eq.) was added and the mixture was stirred 16 h at room temperature. The precitpitate was filtered off, washed with THF then the filtrate was concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 95 / 5) as eluent to give (3.44) (0.270 g, 66 %) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.09 (t, J = 7.1 Hz, 2H, CH2-CH2-NH), 3.42 (h, J = 7.0 Hz, 1H, HiPr), 3.71 (d, J = 6.9 Hz, 2H, CH2-NH), 6.18 (s, 1H, HAr), 7.23 (dd, J = 7.5, 4.9 Hz, 1H, HAr), 7.34 (d, J = 7.8 Hz, 1H, HAr), 7.70 (t, J = 7.7 Hz, 1H, HAr), 8.51 (d, J = 4.9 Hz, 1H, HAr), 8.56 (s, 1H, NH-CH2).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 35.9 (CH2-CH2-NH), 41.8 (CH2-NH), 91.0 (CHAr), 121.7 (CHAr), 123.5 (CHAr), 136.5 (CHAr), 139.4 (Cq), 142.2 (Cq), 149.1 (CHAr), 149.6 (Cq), 153.9 (Cq), 158.6 (Cq). MS (ESI+) : m / z calcd C15H17ClN6 : 317.13 [M+H]+, found : 317.2. Example 3.45: Synthesis of 6-chloro-3-isopropyl-N-[2-(3-pyridyl)ethyl]- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.45) To a solution of (2.1) (0.250 g, 1.08 mmol, 1.0 eq.), THF (10.0 mL), corresponding amine (0.181 g, 1.41 mmol, 1.3 eq.) and DIPEA (0.28 mL, 1.62 mmol, 1.5 eq.) was added then the mixture was refluxed 3 h. After cooling, Et2O (30.0 mL) was added, the precipitate was filtered off, washed with water, triturated in Et2O then dried under vacuum to give (3.45) (0.260 g, 76 %) as a white solid. Rf (DCM / MeOH, 94 / 6) : 0.241H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 2.96 (t, J = 7.1 Hz, 2H, CH2-CH2-NH), 3.41 (hept, J = 7.0 Hz, 1H, HiPr), 3.62 (d, J = 7.1 Hz, 2H, CH2-NH), 6.26 (s, 1H, HAr), 7.31 (dd, J = 7.9, 4.8 Hz, 1H, HAr), 7.72 (d, J = 7.7 Hz, 1H, HAr), 8.41 (d, J = 4.8 Hz, 1H, HAr), 8.49 (d, J = 2.2 Hz, 1H, HAr), 8.55 (s, 1H, NH-CH2).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 30.9 (CH2-CH2-NH), 42.9 (CH2-NH), 91.1 (CHAr), 123.3 (CHAr), 134.4 (Cq), 136.4 (CHAr), 139.4 (Cq), 142.2 (Cq), 147.5 (CHAr), 149.7 (Cq), 150.0 (CHAr), 153.9 (Cq). MS (ESI+) : m / z calcd for C15H17ClN6 : 317.13 [M+H]+, found : 317.2. Example 3.46: Synthesis of 6-chloro-3-isopropyl-N-[2-(4-pyridyl)ethyl]- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.46) To a solution of (2.1) (0.250 g, 1.08 mmol, 1.0 eq.), THF (10.0 mL), corresponding amine (0.181 g, 1.41 mmol, 1.3 eq.) and DIPEA (0.28 mL, 1.62 mmol, 1.5 eq.) was added then the mixture was refluxed 3 h. After cooling, Et2O (30.0 mL) was added, the precipitate was filtered off, washed with water, triturated in Et2O then dried under vacuum to give (3.46) (0.285 g, 82 %) as a white solid. Rf (DCM / MeOH, 94 / 6) : 0.271H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 2.97 (t, J = 7.1 Hz, 2H, CH2-CH2-NH), 3.42 (p, J = 7.0 Hz, 1H, HiPr), 3.56 – 3.75 (m, 2H, CH2-NH), 6.29 (s, 1H, HAr), 7.33 (d, J = 5.1 Hz, 2H, 2xHAr), 8.44 – 8.51 (m, 2H, 2xHAr), 8.54 (s, 1H, NH-CH2).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 32.9 (CH2-CH2-NH), 42.2 (CH2-NH), 91.2 (CHAr), 124.4 (2xCHAr), 139.3 (Cq), 142.2 (Cq), 147.9 (Cq), 149.4 (2xCHAr), 149.7 (Cq), 153.9 (Cq). MS (ESI+) : m / z calcd for C15H17ClN6 : 317.13 [M+H]+, found : 317.2. Example 3.47: Synthesis of 6-chloro-3-cyclopropyl-N-[2-(2-pyridyl)ethyl]- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.47) To a solution of (2.5) (0.125 g, 0.51 mmol, 1.0 eq.) in THF (2.5 mL), corresponding amine (0.080 g, 0.62 mmol, 1.2 eq.) and Et3N (0.15 mL, 1.04 mmol, 2.0 eq.) was added and the mixture was refluxed 1.5 h. After cooling, THF (10.0 mL) wad added, the precipitate was filtered off, washed with THF then the filtrate was concentrated. The residue was triturated in water, filtered off, washed with water then triturated in Et2O, filtered, washed with Et2O and dried under vacuum to give (3.47) (0.130 g, 80 %) as a beige solid. Rf (DCM / MeOH, 96 / 4) : 0.141H NMR (400 MHz, DMSO-d6) δ : 1.03 – 1.18 (m, 4H, 2xCH2 cPr), 2.31 (tt, J = 8.2, 5.2 Hz, 1H, HcPr), 3.09 (t, J = 7.1 Hz, 2H, CH2), 3.64 – 3.81 (m, 2H, CH2), 6.16 (s, 1H, HAr), 7.23 (dd, J = 7.6, 4.8 Hz, 1H, HAr), 7.33 (d, J = 7.8 Hz, 1H, HAr), 7.70 (td, J = 7.7, 1.9 Hz, 1H, HAr), 8.46 – 8.61 (m, 2H, NH & HAr).13C NMR (101 MHz, DMSO-d6) δ : 4.8 (CHcPr), 7.2 (2xCH2 cPr), 35.9 (CH2), 41.9 (CH2), 91.0 (CHAr), 121.7 (CHAr), 123.5 (CHAr), 136.5 (CHAr), 139.3 (Cq), 142.2 (Cq), 149.1 (CHAr), 149.8 (Cq), 151.3 (Cq), 158.6 (Cq). MS (ESI+) : m / z calcd for C15H15ClN6 : 315.1 [M+H]+, found : 315.1. Example 3.48: Synthesis of 6-chloro-3-cyclopropyl-N-[2-(3-pyridyl)ethyl]- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.48) To a solution of (2.5) (0.125 g, 0.51 mmol, 1.0 eq.) in THF (2.5 mL), corresponding amine (0.080 g, 0.62 mmol, 1.2 eq.) and Et3N (0.15 mL, 1.04 mmol, 2.0 eq.) was added and the mixture was refluxed 1.5 h. After cooling, THF (10.0 mL) wad added, the precitpitate was filtered off, washed with THF then the filtrate was concentrated. The residue was triturated in water, filtered off, washed with water then triturated in Et2O, filtered, washed with Et2O and dried under vacuum to give (3.48) (0.127 g, 80 %) as a beige solid. Rf (DCM / MeOH, 94 / 6) : 0.201H NMR (400 MHz, DMSO-d6) δ : 1.00 – 1.20 (m, 4H, 2xCH2 cPr), 2.31 (tt, J = 8.1, 5.3 Hz, 1H, HcPr), 2.96 (t, J = 7.1 Hz, 2H, CH2), 3.49 – 3.76 (m, 2H, CH2), 6.24 (s, 1H, HAr), 7.31 (dd, J = 7.8, 4.8 Hz, 1H, HAr), 7.71 (dt, J = 7.8, 2.0 Hz, 1H, HAr), 8.41 (dd, J = 4.8, 1.7 Hz, 1H, HAr), 8.49 (d, J = 2.3 Hz, 1H, HAr), 8.52 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.8 (CH), 7.1 (2xCH2), 30.9 (CH2), 42.9 (CH2), 91.1 (CHAr), 123.3 (CHAr), 134.4 (Cq), 136.4 (CHAr), 139.3 (Cq), 142.2 (Cq), 147.5 (CHAr), 149.9 (Cq), 150.0 (CHAr), 151.3 (Cq). MS (ESI+) : m / z calcd for C15H15ClN6 : 315.1 [M+H]+, found : 315.2. Example 3.49: Synthesis of 6-chloro-3-cyclopropyl-N-[2-(4-pyridyl)ethyl]- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.49) To a solution of (2.5) (0.125 g, 0.51 mmol, 1.0 eq.) in THF (2.5 mL), corresponding amine (0.080 g, 0.62 mmol, 1.2 eq.) and Et3N (0.15 mL, 1.04 mmol, 2.0 eq.) was added and the mixture was refluxed 1.5 h. After cooling, THF (10.0 mL) wad added, the precitpitate was filtered off, washed with THF then the filtrate was concentrated. The residue was triturated in water, filtered off, washed with water then triturated in Et2O, filtered, washed with Et2O and dried under vacuum to give (3.49) (0.134 g, 82 %) as an orange solid.1H NMR (400 MHz, DMSO-d6) δ : 1.05 – 1.17 (m, 4H, 2xCH2 cPr), 2.31 (ddt, J = 10.9, 8.1, 5.2 Hz, 1H, HcPr), 2.96 (t, J = 7.1 Hz, 2H, CH2), 3.63 (d, J = 7.9 Hz, 2H, CH2), 6.28 (s, 1H, HAr), 7.27 – 7.39 (m, 2H, 2xHAr), 8.42 – 8.48 (m, 2H, 2xHAr), 8.51 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.8 (CHcPr), 7.2 (2xCH2 cPr), 32.9 (CH2), 42.3 (CH2), 91.2 (CHAr), 124.4 (CHAr), 139.3 (Cq), 142.2 (Cq), 147.9 (Cq), 149.4 (CHAr), 149.9 (Cq), 151.3 (Cq). MS (ESI+) : m / z calcd for C15H15ClN6 : 315.1 [M+H]+, found : 315.2. Example 3.50: Synthesis of 6-chloro-3-isopropyl-N-[3-(2-pyridyl)propyl]- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.50) To a solution of (2.1) (0.200 g, 0.87 mmol, 1.0 eq.) in THF (8.7 mL), corresponding amine (0.161 g, 1.13 mmol, 1.3 eq.) and Et3N (0.24 mL, 1.73 mmol, 2.0 eq.) was added and the mixture was refluxed 3 h. After cooling, the solvent was removed, the residue was triturated in water (20.0 mL) and saturated NaHCO3(10.0 mL), the solid was filtered off, washed with water up to neutral pH then taken up in EtOAc. Organic filtrate was dried over MgSO4, filtered and concentrated to give (3.50) (0.250 g, 87 %) as a pale yellow solid. Rf (DCM / MeOH, 94 / 6) : 0.421H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 2.03 (p, J = 7.3 Hz, 2H, CH2), 2.83 (t, J = 7.5 Hz, 2H, CH2), 3.41 (td, J = 13.7, 6.8 Hz, 3H, HiPr& CH2), 6.20 (s, 1H, HAr), 7.20 (dd, J = 7.6, 4.9 Hz, 1H, HAr), 7.28 (d, J = 7.8 Hz, 1H, HAr), 7.69 (td, J = 7.6, 1.9 Hz, 1H, HAr), 8.45 – 8.54 (m, 1H, HAr), 8.70 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 27.2 (CH2), 34.5 (CH2), 41.8 (CH2), 90.8 (CHAr), 121.3 (CHAr), 122.9 (CHAr), 136.5 (CHAr), 139.5 (Cq), 142.4 (Cq), 148.9 (CHAr), 153.9 (Cq), 160.8 (Cq). MS (ESI+) : m / z calcd for C16H19ClN6 : 331.1 [M+H]+, found : 331.2. Example 3.51: Synthesis of 6-chloro-3-isopropyl-N-[3-(3-pyridyl)propyl]- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.51) To a solution of (2.1) (0.200 g, 0.87 mmol, 1.0 eq.) in THF (8.7 mL), corresponding amine dihydrochloride (0.248 g, 1.13 mmol, 1.3 eq.) and Et3N (0.73 mL, 5.19 mmol, 6.0 eq.) was added and the mixture was refluxed 3 h. Water (0.43 mL) was added and the mixture was refluxed 3 h to complete the reaction. After cooling, EtOAc (15.0 mL) was added, the mixture was dried over MgSO4, filtered and concentrated. The residue was triturated in water (20.0 mL), the solid was filtered off, taken up in EtOAc then organic filtrate was dried over MgSO4, filtered and concentrated to give (3.51) (0.240 g, 84 %) as a beige solid. Rf (DCM / MeOH, 94 / 6) : 0.351H NMR (400 MHz, DMSO-d6) δ : 1.39 (d, J = 7.0 Hz, 6H, 2xCH3 iPr), 1.89 – 1.98 (m, 2H, CH2-CH2-NH), 2.66 – 2.75 (m, 2H, CH2-CH2-CH2-NH), 3.36 (s, 2H, CH2-NH), 3.43 (p, J = 6.9 Hz, 1H, HiPr), 6.18 (s, 1H, HAr), 7.31 (dd, J = 7.8, 4.8 Hz, 1H, HAr), 7.68 (dt, J = 7.9, 2.0 Hz, 1H, HAr), 8.40 (dd, J = 4.8, 1.7 Hz, 1H, HAr), 8.47 (d, J = 2.3 Hz, 1H, HAr), 8.61 (s, 1H, NH-CH2).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C16H19ClN6 : 331.1 [M+H]+, found : 331.2. Example 3.52: Synthesis of 6-chloro-3-isopropyl-N-[3-(4-pyridyl)propyl]- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.52) To a solution of (2.1) (0.200 g, 0.87 mmol, 1.0 eq.) in THF (8.7 mL), corresponding amine (0.161 g, 1.13 mmol, 1.3 eq.) and Et3N (0.24 mL, 1.73 mmol, 2.0 eq.) was added and the mixture was refluxed 3 h. After cooling, the solvent was removed, the residue was triturated in water (20.0 mL) and saturated NaHCO3 (10.0 mL), the solid was filtered off, washed with water up to neutral pH then taken up in EtOAc. Organic filtrate was dried over MgSO4, filtered and concentrated to give (3.52) (0.260 g, 91 %) as an orange solid. Rf (DCM / MeOH, 94 / 6) : 0.331H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 1.94 (p, J = 7.2 Hz, 2H, CH2), 2.65 – 2.72 (m, 2H, CH2), 3.33 – 3.38 (m, 2H, CH2), 3.42 (p, J = 7.0 Hz, 1H, HiPr), 6.18 (s, 1H, HAr), 7.19 – 7.37 (m, 2H, 2xHAr), 8.31 – 8.48 (m, 2H, 2xHAr), 8.60 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C16H19ClN6 : 331.1 [M+H]+, found : 331.2. Example 3.53: Synthesis of 6-chloro-3-cyclopropyl-N-[3-(2- pyridyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.53) To a solution of (2.5) (0.170 g, 0.74 mmol, 1.0 eq.) in THF / H2O (15.0 / 0.5 mL), corresponding amine dihydrochloride (0.229 g, 1.04 mmol, 1.3 eq.) and Et3N (0.63 mL, 4.45 mmol, 6.0 eq.) was added and the mixture was refluxed 16 h. After cooling, THF (10.0 mL) was added, the precipitate was filtered off, washed with THF then the filtrate was concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 95 / 5) as eluent to give (3.53) (0.080 g, 33 %) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ : 1.11 (tt, J = 8.0, 2.7 Hz, 4H, 2xCH2 cPr), 1.85 – 2.02 (m, 2H, CH2), 2.32 (tt, J = 8.2, 5.2 Hz, 1H, HcPr), 2.64 – 2.76 (m, 2H, CH2), 3.32 – 3.42 (m, 2H, CH2), 6.16 (s, 1H, HAr), 7.30 (dd, J = 7.8, 4.7 Hz, 1H, HAr), 7.66 (dt, J = 7.9, 2.0 Hz, 1H, HAr), 8.39 (dd, J = 4.8, 1.6 Hz, 1H, HAr), 8.46 (d, J = 2.3 Hz, 1H, HAr), 8.57 (t, J = 5.6 Hz, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.8 (CHcPr), 7.1 (2xCH2 cPr), 29.1 (CH2), 29.4 (CH2), 41.7 (CH2), 90.8 (CHAr), 123.4 (CHAr), 135.8 (CHAr), 136.9 (Cq), 139.4 (Cq), 142.3 (Cq), 147.2 (CHAr), 149.6 (CHAr), 149.8 (Cq), 151.3 (Cq). MS (ESI+) : m / z calcd for C16H17ClN6 : 329.1 [M+H]+, found : 329.2. Example 3.54: Synthesis of 6-chloro-3-isopropyl-N-(pyrimidin-2- ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.54) To a solution of (2.1) (0.190 g, 0.82 mmol, 1.0 eq.) in THF (9.0 mL), corresponding amine hydrochloride (0.164 g, 1.07 mmol, 1.3 eq.) and DIPEA (0.36 mL, 2.06 mmol, 2.5 eq.) was added then the mixture was refluxed 3 h. After cooling, the solvent was removed, the residue was triturated in saturated NaHCO3 (10.0 mL), the solid was filtered off, washed with water then EtOAc to give a first part of (3.54) (0.072 g). The biphasique filtrate was separated, aqueous layer was extracted twice with EtOAc (2x10.0 mL). Organic layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to give the second part of (3.54) (0.020 g). Total of (3.54): 0.092 g, 37 % yield, as a white solid. Rf (DCM / MeOH, 94 / 6) : 0.401H NMR (400 MHz, DMSO-d6) δ : 1.39 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.44 (p, J = 7.0 Hz, 1H, HiPr), 4.80 (s, 2H, CH2 Bn), 6.22 (s, 1H, HAr), 7.45 (t, J = 4.9 Hz, 1H, NHBn), 8.74 – 8.89 (m, 3H, 3xHAr).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C13H14ClN7 : 304.1 [M+H]+, found : 304.2. Example 3.55: Synthesis of 6-chloro-3-isopropyl-N-(pyrazin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.55) To a solution of (2.1) (0.290 g, 1.26 mmol, 1.0 eq.) in THF (10.0 mL), corresponding amine (0.187 g, 1.63 mmol, 1.3 eq.) and DIPEA (0.33 mL, 1.88 mmol, 1.5 eq.) was added then the mixture was refluxed 1 h. After cooling, the precipitate was filtered off and washed with THF. The solid was washed with water then Et2O and dried under vacuum to give a first part of (3.55) (0.103 g). THF filtrate was concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 95 / 5) as eluent to give the second part of (3.55) (0.015 g). Total of (3.55): 0.118 g, 31 % yield, as a white solid. Rf (EtOAc / Cyclohexane, 7 / 3) : 0.371H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.43 (p, J = 7.0 Hz, 1H, HiPr), 4.77 (s, 2H, CH2 Bn), 6.29 (s, 1H, HAr), 8.57 (d, J = 2.6 Hz, 1H, HAr), 8.60 – 8.63 (m, 1H, HAr), 8.69 (d, J = 1.5 Hz, 1H, HAr), 8.98 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C13H14ClN7 : 304.1 [M+H]+, found : 304.2. Example 3.56: Synthesis of 6-chloro-3-isopropyl-N-(pyrimidin-5- ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.56) To a solution of (2.1) (0.190 g, 0.82 mmol, 1.0 eq.) in THF (9.0 mL), corresponding amine hydrochloride (0.164 g, 1.07 mmol, 1.3 eq.) and DIPEA (0.36 mL, 2.06 mmol, 2.5 eq.) was added then the mixture was refluxed 3 h. After cooling, the solvent was removed, the residue was triturated in saturated NaHCO3(10.0 mL), the solid was filtered off, washed with water then EtOAc to give a first part of (3.56) (0.055 g). The biphasique filtrate was separated, aqueous layer was extracted twice with EtOAc (2x10.0 mL). Orgnics layers were combined, dired over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to give the second part of (3.56) (0.055 g), total of (3.56): 0.110 g, 44 % yield, as a white solid. Rf (DCM / MeOH, 94 / 6) : 0.301H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.42 (hept, J = 6.6 Hz, 1H, HiPr), 4.66 (s, 2H, CH2 Bn), 6.37 (s, 1H, HAr), 8.85 (s, 2H, 2xHAr), 9.05 (s, 1H, NHBn), 9.10 (s, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C13H14ClN7 : 304.1 [M+H]+, found : 304.2. Example 3.57: Synthesis of 6-chloro-3-isopropyl-N-(pyridazin-3-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.57) To a solution of (2.1) (0.300 g, 1.30 mmol, 1.0 eq.) in THF (9.0 mL), corresponding amine dihydrochloride (0.323 g, 1.69 mmol, 1.3 eq.) and DIPEA (0.75 mL, 4.28 mmol, 3.3 eq.) was added and the mixture was stirred 16 h at room temperature then refluxed 2 h to complete the reaction. After cooling, the solvent was removed, the crude was triturated in water and the resulting solid was filtered off, washed with water up to neutral pH, triturated in Et2O, filtered and dried to give (3.57) (0.286 g, 73 %) as a white solid. Rf (DCM / MeOH, 94 / 6) : 0.381H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.43 (p, J = 6.9 Hz, 1H, HiPr), 4.89 (s, 2H, CH2 Bn), 6.27 (s, 1H, HAr), 7.69 (d, J = 3.3 Hz, 2H, 2xHAr), 9.08 (s, 1H, NHBn), 9.17 (t, J = 3.4 Hz, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (CH3 iPr), 24.4 (CHiPr), 45.7 (CH2 Bn), 92.0 (CHAr), 125.7 (CHAr), 127.5 (CHAr), 139.4 (Cq), 142.5 (Cq), 149.4 (Cq), 151.0 (CHAr), 154.0 (Cq), 159.3 (Cq). MS (ESI+) : m / z calcd for C13H14ClN7 : 304.1 [M+H]+, found : 304.1. Example 3.58: Synthesis of 6-chloro-3-isopropyl-N-[[4-(2- pyridyl)phenyl]methyl]-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.58) A 10 - 20 mL vial with a stir bar was charged (1.14) (0.300 g, 0.91 mmol, 1.0 eq.), dioxane (4.9 mL), isobutyric acid hydrazide (0.112 g, 1.09 mmol, 1.2 eq.) and AcOH (0.06 mL, 1.00 mmol, 1.1 eq.). The vial was sealed and then put on heating block, 22 h at 110 °C. After cooling, reaction mixture was poured onto saturated NaHCO3 (20.0 mL) and vigorously stirred 5 min. The resulting precipitate was filtered off, washed with water then solubilized in DCM (10.0 mL). Aqueous filtrate was extracted twice with EtOAc (2 x 10.0 mL) and combined with DCM solution, all was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 95 / 5) as eluent to give the title compound (3.58) (0.140 g, 41 %) as a white solid. Rf (DCM / MeOH, 94 / 6) : 0.471H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.42 (hept, J = 7.1 Hz, 1H, HiPr), 4.65 (d, J = 3.9 Hz, 2H, CH2 Bn), 6.18 (s, 1H, HAr), 7.33 (dd, J = 7.4, 4.9 Hz, 1H, HAr), 7.51 (d, J = 8.1 Hz, 2H, 2xHAr), 7.86 (td, J = 7.7, 1.9 Hz, 1H, HAr), 7.93 (d, J = 8.0 Hz, 1H, HAr), 8.06 (d, J = 8.1 Hz, 2H, 2xHAr), 8.65 (d, J = 3.8 Hz, 1H, HAr), 9.17 (s, 1H, NHBn).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 44.9 (CH2 Bn), 91.6 (CHAr), 120.1 (CHAr), 122.5 (CHAr), 126.7 (2xCHAr), 127.5 (2xCHAr), 137.2 (CHAr), 137.7 (Cq), 138.3 (Cq), 139.4 (Cq), 142.3 (Cq), 149.4 (Cq), 149.5 (CHAr), 154.0 (Cq), 155.7 (Cq). MS (ESI+) : m / z calcd for C20H19ClN6 : 379.1 [M+H]+, found : 379.3. Example 3.59: Synthesis of 6-chloro-3-isopropyl-N-[[4-(4- pyridyl)phenyl]methyl]-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.59) To a solution of 4-(4-pyridyl)benzonitrile (0.224 g, 1.24 mmol, 1.15 eq.) in dry THF (12.0 mL), LiAlH4(0.066 g, 1.73 mmol, 1.6 eq.) was added portionwise then the mixture was stirred 45 min. After completion, saturated NH4Cl (10.0 mL), water (5.0 mL) and EtOAc (10.0 mL) was added and the mixture was vigorously stirred 5 min. Layers were separated, aqueous layer was extracted with EtOAc (2x10.0 mL) then organic layers were combined, dried over MgSO4,filtered and concentrated. The residu was directly used in THF (18.0 mL) with (2.1) (0.250 g, 1.08 mmol, 1.0 eq.) and Et3N (0.46 mL, 3.25 mmol, 3.0 eq.) and the mixture was refluxed 3 h. After cooling, the solid was filtered, washed with THF then the filtrate was concentrated and directly purified by flash chromatography with DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (3.59) (0.110 g, 27 %) as a white solid. Rf (DCM / MeOH, 94 / 6) : 0.251H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.42 (p, J = 6.9 Hz, 1H, HiPr), 4.66 (d, J = 6.2 Hz, 2H, CH2 Bn), 6.19 (s, 1H, HAr), 7.54 (d, J = 8.1 Hz, 2H, 2xHAr), 7.66 – 7.75 (m, 2H, 2xHAr), 7.76 – 7.87 (m, 2H, 2xHAr), 8.56 – 8.70 (m, 2H, 2xHAr), 9.18 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.4 (CHiPr), 44.7 (CH2), 91.6 (CHAr), 121.1 (2xCHAr), 127.0 (2xCHAr), 128.0 (2xCHAr), 136.0 (Cq), 138.8 (Cq), 139.4 (Cq), 142.3 (Cq), 146.6 (Cq), 149.4 (Cq), 150.2 (2xCHAr), 154.0 (Cq). MS (ESI+) : m / z calcd for C20H19ClN6 : 379.1 [M+H]+, found : 379.2. Example 3.60: Synthesis of 6-chloro-3-isopropyl-N-(pyridazin-3-yl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.60) To a solution of (2.1) (0.100 g, 0.433 mmol, 1.0 eq.) in dry THF (3.33 mL), 3- aminopyridazine (0.084 g, 0.866 mmol, 2.0 eq.) then tBuOK 1.65M in THF (0.52 mL, 0.866 mmol, 2.0 eq.) were added and the mixture was stirred 0.8h at room temperature. After completion, saturated NH4Cl (3.33 mL) and water (1 mL) were added then biphasic mixture was vigorously stirred 5 min. The precipitate formed was filtered off, washed with H2O and Et2O to give (3.60) (0.023 g, 18%) as a white solid. Layers of filtrate were separated, aqueous layer was extracted with EtOAc (2x10.0 mL) then organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was triturated in Et2O, filtered off, washed with Et2O and dried under vacuum to give (3.60) as a beige solid (0.063 g, 51%). (3.60) was obtained with a yield of 69% (0.086 g). Rf (DCM / MeOH, 96 / 4) : 0.281H NMR (400 MHz, DMSO-d6) δ : 1.43 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.53 (h, J = 6.9 Hz, 1H, HiPr), 7.73 (dd, J = 9.0, 4.6 Hz, 1H, HAr), 7.89 (dd, J = 9.0, 1.4 Hz, 1H, HAr), 8.39 (s, 1H, HAr), 9.00 (dd, J = 4.6, 1.4 Hz, 1H, HAr), 11.13 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.83 (2xCH3 iPr), 24.50 (CHiPr), 101.29 (CHAr), 119.50 (CHAr), 128.69 (CHAr), 136.05 (Cq), 139.24 (Cq), 147.89 (CHAr), 149.82 (Cq), 154.39 (Cq), 157.23 (Cq). MS (ESI+) : m / z calcd for C12H12ClN7 : 290.1 [M+H]+, found : 290.2. Example 3.61: Synthesis of 6-chloro-3-isopropyl-N-(pyridazin-4-yl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.61) To a solution of (2.1) (0.350 g, 1.515 mmol, 1.0 eq.) in dry THF (11.5 mL), 4- aminopyridazine (0.294 g, 3.029 mmol, 2.0 eq.) then tBuOK 1M in THF (1.84 mL, 3.029 mmol, 2.0 eq.) were added and the mixture was stirred 1.25h at room temperature. After completion, saturated NH4Cl (11.5 mL) and water (5.23 mL) were added then biphasic mixture was vigorously stirred 5 min. Layers of mixture were separated, aqueous layer was extracted with EtOAc (2x10.0 mL) then organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography with DCM / MeOH (99 / 1 to 94 / 6) as eluent to give (3.61) (0.256 g, 58%) as a yellow solid. Rf (DCM / MeOH, 94 / 6) : 0.281H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.50 (hept, J = 6.9 Hz, 1H, HiPr), 7.06 (s, 1H, HAr), 7.77 (dd, J = 6.2, 2.9 Hz, 1H, HAr), 9.09 (d, J = 5.9 Hz, 1H, HAr), 9.38 (d, J = 2.7 Hz, 1H, HAr), 10.88 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.80 (2xCH3iPr), 24.50 (CHiPr), 98.77 (CHAr), 115.13 (CHAr), 137.58 (Cq), 138.40 (Cq), 139.48 (Cq), 145.30 (CHAr), 149.54 (Cq), 151.27 (CHAr), 154.37 (Cq). MS (ESI+) : m / z calcd for C12H12ClN7 : 290.1 [M+H]+, found : 290.1. Example 3.62: Synthesis of 6-chloro-3-isopropyl-N-(pyrimidin-4-yl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.62) To a solution of (2.1) (0.40 g, 1.731 mmol, 1.0 eq.) in dry THF (13.14 mL), 4- aminopyrimidine (0.281 g, 2.891 mmol, 2.0 eq.) then tBuOK 1.65M in THF (1.75 mL, 2.891 mmol, 2.0 eq.) were added and the mixture was stirred 1 h at room temperature. After completion, saturated NH4Cl (13.14 mL) and water (5.97 mL) were added then biphasic mixture was vigorously stirred 5 min. Layers of mixture were separated, aqueous layer was extracted with EtOAc (2x10.0 mL) then organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was triturated in DCM, filtered off, washed with MeOH and Et2O and dried under vacuum to give (3.62) as a pale yellow / beige solid (0.171 g, 34%). The filtrate was purified by flash chromatography with DCM / MeOH (99 / 1 to 94 / 6) as eluent to give the second part of (3.62) (0.150 g, 30%) as a beige solid. Total of (3.62): 0.321 g, 64%. Rf (DCM / MeOH, 94 / 6) : 0.351H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.50 (hept, J = 7.0 Hz, 1H, HiPr), 7.60 (dd, J = 5.8, 1.3 Hz, 1H, HAr), 8.37 (s, 1H, HAr), 8.62 (d, J = 5.8 Hz, 1H, HAr), 8.99 (d, J = 1.2 Hz, 1H, HAr), 11.28 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.81 (2xCH3 iPr), 24.48 (CHiPr), 102.67 (CHAr), 110.88 (CHAr), 135.84 (Cq), 139.11 (Cq), 149.48 (Cq), 154.39 (Cq), 157.07 (CHAr), 157.72 (CHAr), 159.68 (Cq). MS (ESI+) : m / z calcd for C12H10ClN7 : 290.1 [M+H]+, found : 290.1. Example 3.63: Synthesis of 6-chloro-3-isopropyl-N-(pyrimidin-5-yl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.63) To a solution of (2.1) (0.200 g, 0.866 mmol, 1.0 eq.) in dry THF (6.63 mL), 5- aminopyrimidine (0.166 g, 1.731 mmol, 2.0 eq.) then tBuOK 1.65M in THF (1.05 mL, 1.731 mmol, 2.0 eq.) were added and the mixture was stirred 1.5h at room temperature. After completion, saturated NH4Cl (6.63 mL) and water (1.77 mL) were added then biphasic mixture was vigorously stirred 5 min. The precipitate formed was filtered off, washed with H2O and Et2O to give (3.63) (0.150 g, 60%) as a white solid. Layers of filtrate were separated, aqueous layer was extracted with EtOAc (2x10.0 mL) then organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography with DCM / MeOH (99 / 1 to 94 / 6) as eluent to give the second part of (3.63) (0.048 g, 19%) as a white solid. Total of (3.63) was obtained with a yield of 79% (0.198 g). Rf (DCM / MeOH, 94 / 6) : 0.251H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 7.0 Hz, 6H, 2xCH3 iPr), 3.49 (p, J = 6.9 Hz, 1H, HiPr), 6.65 (s, 1H, HAr), 8.95 (s, 2H, 2xHAr), 9.06 (s, 1H, HAr), 10.57 (s, 1H, NH).13C NMR (101 MHz, DMSO) δ : 19.81 (2xCH3 iPr), 24.49 (CHiPr), 95.16 (CHAr), 133.98 (Cq), 139.40 (Cq), 139.60 (Cq), 149.66 (Cq), 151.64(2xCHAr), 154.23 (Cq), 154.71 (CHAr). MS (ESI+) : m / z calcd for C12H10ClN7 : 290.1 [M+H]+, found : 290.2. Example 3.64: Synthesis of 6-chloro-3-isopropyl-N-(pyrimidin-2-yl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.64) To a solution of (2.1) (0.152 g, 0.664 mmol, 1.0 eq.) in dry THF (5.04 mL), 2- aminopyrimidine (0.126 g, 1.316 mmol, 2.0 eq.) then tBuOK 1.65M in THF (0.80 mL, 1.316 mmol, 2.0 eq.) were added and the mixture was stirred 2.25h at room temperature. After completion, saturated NH4Cl (5.04 mL) and water (2.3 mL) were added then biphasic mixture was vigorously stirred 5 min. Layers were separated, aqueous layer was extracted with EtOAc (2x10.0 mL) then organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was triturated in Et2O, filtered off, washed with Et2O and dried under vacuum to give (3.64) (0.124 g, 65%) as a beige solid. Rf (DCM / MeOH, 94 / 6) : 0.481H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9, 2.0 Hz, 6H, 2xCH3 iPr), 3.45 – 3.56 (m, 1H, HiPr), 7.26 (dt, J = 4.9, 3.1 Hz, 1H, HAr), 8.16 (s, 1H, HAr), 8.80 (dd, J = 4.9, 1.9 Hz, 2H, 2xHAr), 10.31 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.81 (2xCH3 iPr), 24.49 (CHiPr), 101.32 (CHAr), 116.40 (CHAr), 136.11 (Cq), 139.01 (Cq), 149.61 (Cq), 154.38 (Cq), 158.56 (Cq), 158.64 (2xCHAr). MS (ESI+) : m / z calcd for C12H12ClN7 : 290.1 [M+H]+, found : 290.2. Example 3.65: Synthesis of 6-chloro-3-isopropyl-N-(pyrazin-2-yl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.65) To a solution of (2.1) (0.100 g, 0.433 mmol, 1.0 eq.) in dry THF (3.33 mL), 2- aminopyrazine (0.082 g, 0.866 mmol, 2.0 eq.) then tBuOK 1.65M in THF (0.52 mL, 0.866 mmol, 2.0 eq.) were added and the mixture was stirred 0.8h at room temperature. After completion, saturated NH4Cl (3.33 mL) and water (1 mL) were added then biphasic mixture was vigorously stirred 5 min. Layers were separated, aqueous layer was extracted with EtOAc (2x10.0 mL) then organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was triturated in Et2O, filtered off, washed with Et2O and dried under vacuum to give (3.65) (0.093 g, 74%) as a beige solid. Rf (DCM / MeOH, 96 / 4) : 0.311H NMR (400 MHz, DMSO-d6) δ : 1.43 (d, J = 7.0 Hz, 6H, 2xCH3 iPr), 3.51 (hept, J = 6.8 Hz, 1H, HiPr), 8.19 (s, 1H, HAr), 8.33 (d, J = 2.7 Hz, 1H, HAr), 8.47 (dd, J = 2.7, 1.4 Hz, 1H, HAr), 8.93 (d, J = 1.5 Hz, 1H, HAr), 11.32 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.83 (2xCH3 iPr), 24.48 (CHiPr), 100.32 (CHAr), 136.30 (Cq), 137.69 (CHAr), 138.02 (CHAr), 139.21 (Cq), 141.16 (CHAr), 149.60 (Cq), 150.64 (Cq), 154.37 (Cq). MS (ESI+) : m / z calcd for C12H12ClN7 : 290.1 [M+H]+, found : 290.2 Example 3.66: Synthesis of 6-chloro-3-isopropyl-N-(6-methoxypyridin-2- yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.66) Under inert gas, to a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) and corresponding aminopyridine derivative (0.102 g, 0.81 mmol, 1.5 eq.) in dry THF (7.5 mL), tBuOK 1M in THF (0.81 mL, 0.81 mmol, 1.5 eq.) was added dropwise. The mixture was stirred 3.5 h at room temperature then saturated NH4Cl (3.0 mL), water (1.0 mL) and EtOAc (3.0 mL) were added. The mixture was vigorously stirred 5 min then layers were separated and aqueous layer was extracted twice with EtOAc (2x5.0 mL). Organic layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 98 / 2) as eluent to give (3.66) (0.128 g, 74 %) as a light orange solid. Rf (DCM / MeOH, 98 / 2) : 0.301H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.50 (hept, J = 6.9 Hz, 1H, HiPr), 3.95 (s, 3H, CH3-O), 6.55 (d, J = 8.0 Hz, 1H, HAr), 7.18 (d, J = 7.8 Hz, 1H, HAr), 7.73 (t, J = 8.0 Hz, 1H, HAr), 8.26 (s, 1H, HAr), 10.91 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.5 (CHiPr), 53.6 (CH3-O), 99.7 (CHAr), 103.7 (CHAr), 106.3 (CHAr), 136.4 (Cq), 139.3 (Cq), 141.0 (CHAr), 149.6 (Cq), 152.0 (Cq), 154.3 (Cq), 162.4 (Cq). Example 3.67: Synthesis of 6-chloro-3-isopropyl-N-(5-methoxypyridin-2- yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.67) Under inert gas, to a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) and corresponding aminopyridine derivative (0.102 g, 0.81 mmol, 1.5 eq.) in dry THF (7.5 mL), tBuOK 1M in THF (0.81 mL, 0.81 mmol, 1.5 eq.) was added dropwise. The mixture was stirred 3.5 h at room temperature then saturated NH4Cl (3.0 mL), water (1.0 mL) and EtOAc (3.0 mL) were added. The mixture was vigorously stirred 5 min then layers were separated and aqueous layer was extracted twice with EtOAc (2x5.0 mL). Organic layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 98 / 2) as eluent to give (3.67) (0.112 g, 65 %) as an orange solid. Rf (DCM / MeOH, 98 / 2) : 0.241H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.48 (hept, J = 6.9 Hz, 1H, HiPr), 3.83 (s, 3H, CH3-O), 7.50 (dd, J = 9.0, 3.0 Hz, 1H, HAr), 7.56 (d, J = 9.0 Hz, 1H, HAr), 8.15 (s, 1H, HAr), 8.18 (d, J = 3.0 Hz, 1H, HAr), 10.82 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.5 (CHiPr), 55.9 (CH3-O), 97.8 (CHAr), 115.6 (CHAr), 124.9 (CHAr), 132.7 (CHAr), 136.7 (Cq), 139.3 (Cq), 147.3 (Cq), 149.8 (Cq), 151.8 (Cq), 154.2 (Cq). MS (ESI+) : m / z calcd for C14H15ClN6O : 319.1 [M+H]+, found : 319.2. Example 3.68: Synthesis of 6-chloro-3-isopropyl-N-(4-methoxypyridin-2- yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.68) Under inert gas, to a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) and corresponding aminopyridine derivative (0.102 g, 0.81 mmol, 1.5 eq.) in dry THF (7.5 mL), tBuOK 1M in THF (0.81 mL, 0.81 mmol, 1.5 eq.) was added dropwise. The mixture was stirred 3.5 h at room temperature then saturated NH4Cl (3.0 mL), water (1.0 mL) and EtOAc (3.0 mL) were added. The mixture was vigorously stirred 5 min then layers were separated and aqueous layer was extracted twice with EtOAc (2x5.0 mL). Organic layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 98 / 2) as eluent to give (3.68) (0.125 g, 72 %) as a light orange solid. Rf (DCM / MeOH, 98 / 2) : 0.251H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 7.0 Hz, 6H, 2xCH3 iPr), 3.49 (hept, J = 6.9 Hz, 1H, HiPr), 3.83 (s, 3H, CH3-O), 6.76 (dd, J = 5.9, 2.3 Hz, 1H, HAr), 7.25 (d, J = 2.3 Hz, 1H, HAr), 8.26 (d, J = 5.9 Hz, 1H, HAr), 8.32 (s, 1H, HAr), 10.74 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.5 (CHiPr), 55.3 (CH3-O), 99.1 (CHAr), 99.7 (CHAr), 106.6 (CHAr), 136.7 (Cq), 139.3 (Cq), 148.5 (CHAr), 149.7 (Cq), 154.3 (Cq), 155.6 (Cq), 166.5 (Cq). Example 3.69: Synthesis of 6-chloro-3-isopropyl-N-(3-methoxypyridin-2- yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.69) Under inert gas, to a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) and corresponding aminopyridine derivative (0.102 g, 0.81 mmol, 1.5 eq.) in dry THF (7.5 mL), tBuOK 1M in THF (0.81 mL, 0.81 mmol, 1.5 eq.) was added dropwise. The mixture was stirred 3.5 h at room temperature then saturated NH4Cl (3.0 mL), water (1.0 mL) and EtOAc (3.0 mL) were added. The mixture was vigorously stirred 5 min then layers were separated and aqueous layer was extracted twice with EtOAc (2x5.0 mL). Organic layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 98 / 2) as eluent to give (3.69) (0.120 g, 70 %) as a white solid. Rf (DCM / MeOH, 98 / 2) : 0.381H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.49 (hept, J = 7.0 Hz, 1H, HiPr), 4.01 (s, 3H, CH3-O), 7.10 – 7.29 (m, 1H, HAr), 7.55 (d, J = 8.1 Hz, 1H, HAr), 8.04 (d, J = 4.9 Hz, 1H, HAr), 8.14 (s, 1H, HAr), 8.78 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.5 (CHiPr), 56.4 (CH3-O), 99.3 (CHAr), 118.1 (CHAr), 119.4 (CHAr), 135.2 (Cq), 138.3 (CHAr), 139.1 (Cq), 142.7 (Cq), 144.0 (Cq), 149.7 (Cq), 154.5 (Cq). MS (ESI+) : m / z calcd for C14H15ClN6O : 319.1 [M+H]+, found : 319.2. Example 3.70: Synthesis of 6-chloro-3-isopropyl-N-(3-phenylpropyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.70) To a solution of (2.1) (0.130 g, 0.56 mmol, 1.0 eq.) in THF (6.0 mL), corresponding amine (0.16 mL, 1.12 mmol, 2.0 eq.) and Et3N (0.16 mL, 1.12 mmol, 2.0 eq.) were added and the mixture was refluxed 2 h. After cooling, the precipitate was filtered off, washed with THF then the filtrate was concentrated and the residu was purified by flash chromatography with DCM / MeOH (98 / 2) as eluent to give (3.70) (0.177 g, 95 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.39 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 1.84 – 2.02 (m, 2H, CH2-CH2-NH), 2.68 (dd, J = 8.8, 6.7 Hz, 2H, CH2-Ph), 3.33 - 3.39 (m, 2H, CH2-NH), 3.44 (h, J = 7.0 Hz, 1H, HiPr), 6.13 (s, 1H, HAr), 7.14 – 7.23 (m, 1H, HAr), 7.21 – 7.33 (m, 4H, 4xHAr), 8.61 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 20.3 (2xCH3 iPr), 24.9 (CHiPr), 29.9 (CH2-CH2-NH), 32.9 (CH2-Ph), 42.2 (CH2-NH), 91.2 (CHAr), 126.3 (CHAr), 128.8 (2xCHAr), 128.8 (CHAr), 139.9 (Cq), 142.0 (Cq), 142.9 (Cq), 150.1 (Cq), 154.4 (Cq). Example 3.71: Synthesis of 6-chloro-3-cyclopropyl-N-phenyl- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.71) Under inert gas, to a solution of (2.5) (0.150 g, 0.65 mmol, 1.0 eq.) in dry THF (5.0 mL), aniline (0.12 mL, 1.31 mmol, 2.0 eq.) was added then tBuOK 1M in THF (1.31 mL, 1.31 mmol, 2.0 eq.). The mixture was stirred 1 h at room temperature then saturated NH4Cl (5.0 mL) and water (1.5 mL) were added and stirred vigorously 5 min. Layers were separated and aqueous layer was extracted twice with EtOAc (2x5.0 mL). Orgnics layers were combined, dried over MgSO4, filtered, concentrated and the residu was purified by flash chromatography with DCM / MeOH (99 / 1 to 98 / 2) as eluent to give (3.71) (0.175 g, 94 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.10 – 1.26 (m, 4H, 2xCH2 cPr), 2.37 (tt, J = 8.1, 5.3 Hz, 1H, HcPr), 6.34 (s, 1H, HAr), 7.27 (ddd, J = 8.5, 5.9, 2.2 Hz, 1H, HAr), 7.38 – 7.55 (m, 4H, 4xHAr), 10.43 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.9 (CHcPr), 7.2 (2xCH2 cPr), 92.9 (CHAr), 123.5 (2xCHAr), 125.7 (CHAr), 129.5 (2xCHAr), 137.7 (Cq), 139.5 (Cq), 140.2 (Cq), 149.8 (Cq), 151.6 (Cq). MS (ESI+) : m / z calcd for C14H12ClN5 : 286.1 [M+H]+, found : 286.2. Example 3.72: Synthesis of 6-chloro-3-cyclopropyl-N-(2-pyridyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.72) Under inert gas, to a solution of (2.5) (0.150 g, 0.65 mmol, 1.0 eq.) in dry THF (5.0 mL), corresponding aminopyridine (0.125 g, 1.31 mmol, 2.0 eq.) was added then tBuOK 1M in THF (1.31 mL, 1.31 mmol, 2.0 eq.). The mixture was stirred 1 h at room temperature then saturated NH4Cl (5.0 mL) and water (1.5 mL) were added and stirred vigorously 5 min. Layers were separated and aqueous layer was extracted twice with EtOAc (2x5.0 mL). Orgnics layers were combined, dried over MgSO4, filtered, concentrated and the residu was purified by flash chromatography with DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (3.72) (0.085 g, 45 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.11 – 1.21 (m, 4H, 2xCH2 cPr), 2.39 (tt, J = 8.0, 5.4 Hz, 1H, CHcPr), 7.13 (ddd, J = 7.3, 5.0, 1.0 Hz, 1H, HAr), 7.48 – 7.66 (m, 1H, HAr), 7.82 (ddd, J = 8.4, 7.3, 2.0 Hz, 1H, HAr), 8.31 (s, 1H, HAr), 8.45 (dd, J = 5.3, 1.9 Hz, 1H, HAr), 10.87 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.9 (CHcPr), 7.2 (2xCH2 cPr), 99.5 (CHAr), 114.6 (CHAr), 118.6 (CHAr), 136.6 (Cq), 138.3 (CHAr), 139.2 (Cq), 147.3 (CHAr), 150.0 (Cq), 151.7 (Cq), 153.9 (Cq). MS (ESI+) : m / z calcd for C13H11ClN6 : 287.1 [M+H]+, found : 287.2. Example 3.73: Synthesis of 6-chloro-3-cyclopropyl-N-(3-pyridyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.73) Under inert gas, to a solution of (2.5) (0.150 g, 0.65 mmol, 1.0 eq.) in dry THF (5.0 mL), corresponding aminopyridine (0.125 g, 1.31 mmol, 2.0 eq.) was added then tBuOK 1M in THF (1.31 mL, 1.31 mmol, 2.0 eq.). The mixture was stirred 1 h at room temperature then saturated NH4Cl (5.0 mL) and water (1.5 mL) were added and stirred vigorously 5 min. Layers were separated and aqueous layer was extracted twice with EtOAc (2x5.0 mL). Organic layers were combined, dried over MgSO4, filtered, concentrated and the residue was purified by flash chromatography with DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (3.73) (0.080 g, 43 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.15 (tt, J = 7.7, 2.6 Hz, 4H, 2xCH2 cPr), 2.38 (tt, J = 8.1, 5.3 Hz, 1H, HcPr), 6.42 (s, 1H, HAr), 7.50 (dd, J = 8.2, 4.7 Hz, 1H, HAr), 7.91 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H, HAr), 8.46 (dd, J = 4.8, 1.5 Hz, 1H, HAr), 8.69 (d, J = 2.6 Hz, 1H, HAr), 10.51 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C13H11ClN6 : 287.1 [M+H]+, found : 287.2. Example 3.74: Synthesis of 6-chloro-3-cyclopropyl-N-(4-pyridyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.74) Under inert gas, to a solution of (2.5) (0.150 g, 0.65 mmol, 1.0 eq.) in dry THF (5.0 mL), corresponding aminopyridine (0.125 g, 1.31 mmol, 2.0 eq.) was added then tBuOK 1M in THF (1.31 mL, 1.31 mmol, 2.0 eq.). The mixture was stirred 1 h at room temperature then saturated NH4Cl (5.0 mL) and water (1.5 mL) were added and stirred vigorously 5 min. Layers were separated and aqueous layer was extracted twice with EtOAc (2x5.0 mL). Orgnics layers were combined, dried over MgSO4, filtered, concentrated and the residu was purified by flash chromatography with DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (3.74) (0.090 g, 48 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ : 1.16 (tt, J = 8.0, 2.8 Hz, 4H, 2xCH2 cPr), 2.38 (ddd, J = 10.5, 8.3, 5.2 Hz, 1H, HcPr), 6.87 (s, 1H, HAr), 7.42 – 7.58 (m, 2H, 2xHAr), 8.54 (d, J = 5.4 Hz, 2H, 2xHAr), 10.66 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.9 (CHcPr), 7.3 (2xCH2 cPr), 96.8 (CHAr), 115.5 (CHAr), 138.0 (Cq), 139.4 (Cq), 145.7 (Cq), 149.8 (Cq), 150.7 (CHAr), 151.8 (Cq). MS (ESI+) : m / z calcd for C13H11ClN6 : 287.1 [M+H]+, found : 287.2. Example 3.75: Synthesis of 6-chloro-3-cyclopropyl-N-(pyridazin-3-yl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.75) To a solution of (2.5) (0.250 g, 1.091 mmol, 1.0 eq.) in dry THF (8.38 mL), 3- aminopyridazine (0.212 g, 2.183 mmol, 2.0 eq.) then tBuOK 1M in THF (1.32 mL, 2.183 mmol, 2.0 eq.) were added and the mixture was stirred 2h at room temperature. After completion, saturated NH4Cl (8.38 mL) and water (2.53 mL) were added then biphasic mixture was vigorously stirred 5 min. The precipitate formed was filtered off, washed with H2O and Et2O to give (3.75) (0.286 g, 91%) as a beige solid. Rf (DCM / MeOH, 96 / 4) : 0.381H NMR (400 MHz, DMSO-d6) δ : 1.12 – 1.22 (m, 4H, 2xCH2 cPr), 2.40 (td, J = 8.1, 4.0 Hz, 1H, HcPr), 7.72 (dd, J = 9.0, 4.6 Hz, 1H, HAr), 7.87 (d, 1H, HAr), 8.37 (s, 1H, HAr), 9.00 (d, J = 4.6 Hz, 1H, HAr), 11.10 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.87 (CHcPr),7.28 (2xCH2 cPr), 101.25 (CHAr), 119.51 (CHAr), 128.67 (CHAr), 136.07 (Cq), 139.23 (Cq), 147.86 (CHAr), 150.02 (Cq), 151.82 (Cq), 157.27 (Cq). MS (ESI+) : m / z calcd for C12H10ClN7 : 288.1 [M+H]+, found : 288.1. Example 3.76: Synthesis of 6-chloro-3-cyclopropyl-N-(pyridazin-4-yl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.76) To a solution of (2.5) (0.087 g, 0.380 mmol, 1.0 eq.) in dry THF (2.94 mL), 4- aminopyridazine (0.074 g, 0.760 mmol, 2.0 eq.) then tBuOK 1M in THF (0.76 mL, 0.760 mmol, 2.0 eq.) were added and the mixture was stirred 1.2h at room temperature. After completion, saturated NH4Cl (2.94 mL) and water (0.871 mL) were added then biphasic mixture was vigorously stirred 5 min. Layers were separated, aqueous layer was extracted with EtOAc (2x10 mL) then organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was triturated in Et2O, filtered off, washed with Et2O and dried under vacuum. The residue was then triturated in DCM, filtered off, washed with DCM and dried under vacuum to give (3.76) (0.094 g, 86%) as a white solid. Rf (DCM / MeOH, 96 / 4) : 0.351H NMR (400 MHz, DMSO-d6) δ : 1.10 – 1.23 (m, 4H, 2xCH2 cPr), 2.35 – 2.44 (m, 1H, HcPr), 7.05 (s, 1H, HAr), 7.76 (dd, J = 6.2, 2.9 Hz, 1H, HAr), 9.08 (d, J = 5.9 Hz, 1H, HAr), 9.37 (s, 1H, HAr), 10.87 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.85 (CHcPr), 7.30 (2xCH2 cPr), 98.78 (CHAr), 115.07 (CHAr), 137.63 (Cq), 138.57 (Cq), 139.43 (Cq), 145.29 (CHAr), 149.72 (Cq), 151.17 (CHAr), 151.82 (Cq). MS (ESI+) : m / z calcd for C12H10ClN7 : 288.1 [M+H]+, found : 288.2. Example 3.77: Synthesis of 6-chloro-3-cyclopropyl-N-pyrimidin-4-yl- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.77) To a solution of (2.5) (0.500 g, 2.183 mmol, 1.0 eq.) in dry THF (16.77 mL), 4- aminopyrimidine (0.416 g, 4.366 mmol, 2.0 eq.) then tBuOK 1.65M in THF (2.65 mL, 4.366 mmol, 2.0 eq.) were added and the mixture was stirred 1.3h at room temperature. After completion, saturated NH4Cl (16.77 mL) and water (5.06 mL) were added then biphasic mixture was vigorously stirred 5 min. The precipitate formed was filtered off, washed with H2O, Et2O and pentane and dried under vacuum to give (3.77) (0.463 g, 74%) as a yellow solid. Rf (DCM / MeOH, 96 / 4) : 0.311H NMR (400 MHz, DMSO-d6) δ : 1.11 – 1.23 (m, 4H, 2xCH2 cPr), 2.35 – 2.44 (m, 1H, CHcPr), 7.58 (d, J = 5.8 Hz, 1H, HAr), 8.36 (s, 1H, HAr), 8.62 (d, J = 5.8 Hz, 1H, HAr), 9.00 (s, 1H, HAr), 11.25 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.84 (CHcPr), 7.30 (2xCH2 cPr), 102.66 (CHAr), 110.86 (CHAr), 135.79 (Cq), 139.05 (Cq), 149.69 (Cq), 151.85 (Cq), 157.08 (CHAr), 157.73 (CHAr), 159.67 (Cq). MS (ESI+) : m / z calcd for C12H10ClN7 : 288.1 [M+H]+, found : 288.2. Example 3.78: Synthesis of 6-chloro-3-cyclopropyl-N-(pyrimidin-5-yl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.78) To a solution of (2.5) (0.135 g, 0.589 mmol, 1.0 eq.) in dry THF (4.53 mL), 5- aminopyrimidine (0.113 g, 1.179 mmol, 2.0 eq.) then tBuOK 1M in THF (1.18 mL, 1.179 mmol, 2.0 eq.) were added and the mixture was stirred 1h at room temperature. After completion, saturated NH4Cl (4.53 mL) and water (1.35 mL) were added then biphasic mixture was vigorously stirred 5 min. Layers were separated, aqueous layer was extracted with EtOAc (2x10.0 mL) then organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was triturated in Et2O, filtered off, washed with Et2O, solubilised in DCM and concentrated under vacuum to give (3.78) (0.153 g, 90%) as a beige solid. Rf (DCM / MeOH, 92 / 8) : 0.541H NMR (400 MHz, DMSO-d6) δ : 1.09 – 1.20 (m, 4H, 2xCH2 cPr), 2.34 – 2.42 (m, 1H, HcPr), 6.63 (s, 1H, HAr), 8.94 (d, J = 1.4 Hz, 2H, 2xHAr), 9.05 (d, J = 1.4 Hz, 1H, HAr), 10.54 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.86 (CHcPr), 7.26 (2xCH2 cPr), 95.16 (CHAr), 133.99 (Cq), 139.34 (Cq), 139.54 (Cq), 149.85 (Cq), 151.58 (2xCHAr), 151.68 (Cq), 154.67 (CHAr). MS (ESI+) : m / z calcd for C12H10ClN7 : 288.1 [M+H]+, found : 288.2. Example 3.79: Synthesis of 6-chloro-3-cyclopropyl-N-(pyrimidin-2-yl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.79) To a solution of (2.5) (0.100 g, 0.437 mmol, 1.0 eq.) in dry THF (3.36 mL), 2- aminopyrimidine (0.084 g, 0.873 mmol, 2.0 eq.) then tBuOK 1M in THF (0.87 mL, 0.873 mmol, 2.0 eq.) were added and the mixture was stirred 1.4h at room temperature. After completion, saturated NH4Cl (3.36 mL) and water (1.0 mL) were added then biphasic mixture was vigorously stirred 5 min. Layers were separated, aqueous layer was extracted with EtOAc (2x5.0 mL) then organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was triturated in Et2O, filtered off, washed with Et2O and dried under vacuum to give (3.79) (0.100 g, 80%) as a white solid. Rf (DCM / MeOH, 96 / 4) : 0.571H NMR (400 MHz, DMSO-d6) δ : 1.12 – 1.22 (m, 4H, 2xCH2 cPr), 2.39 (td, J = 8.2, 4.1 Hz, 1H, HcPr), 7.26 (t, J = 4.8 Hz, 1H, HAr), 8.15 (s, 1H, HAr), 8.79 (d, J = 4.8 Hz, 2H, 2xHAr), 10.28 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.84 (CHcPr), 7.28 (2xCH2 cPr), 99.52 (Cq), 101.30 (CHAr), 116.39 (CHAr), 136.08 (Cq), 138.96 (Cq), 149.82 (Cq), 151.82 (Cq), 158.64 (2xCHAr). MS (ESI+) : m / z calcd for C12H10ClN7 : 288.1 [M+H]+, found : 288.2. Example 3.80: Synthesis of 6-chloro-3-cyclopropyl-N-(pyrazin-2-yl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.80) To a solution of (2.5) (0.080 g, 0.349 mmol, 1.0 eq.) in dry THF (2.68 mL), 2- aminopyrazine (0.066 g, 0.699 mmol, 2.0 eq.) then tBuOK 1M in THF (0.70 mL, 0.699 mmol, 2.0 eq.) were added and the mixture was stirred 1.2h at room temperature. After completion, saturated NH4Cl (2.68 mL) and water (0.81 mL) were added then biphasic mixture was vigorously stirred 5 min. The precipitate formed was filtered off, washed with H2O and Et2O to give (3.80) (0.072 g, 72%) as a white solid. Layers of filtrate were separated, aqueous layer was extracted with EtOAc (2x5.0 mL) then organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was triturated in Et2O, filtered off, washed with Et2O and dried under vacuum to give the second part of (3.80) (0.012 g, 12%) as a white solid. Total of (3.80) : 0.084 g, 84%. Rf (DCM / MeOH, 96 / 4) : 0.111H NMR (400 MHz, DMSO-d6) δ : 1.12 – 1.21 (m, 4H, 2xCH2 cPr), 2.39 (tt, J = 8.0, 5.3 Hz, 1H, HcPr), 8.18 (s, 1H, HAr), 8.32 (d, J = 2.8 Hz, 1H, HAr), 8.44 – 8.50 (m, 1H, HAr), 8.91 (s, 1H, HAr), 11.29 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.84 (CHcPr), 7.28 (2xCH2 cPr), 100.30 (CHAr), 136.25 (Cq), 137.68 (CHAr), 138.02 (CHAr), 139.14 (Cq), 141.16 (CHAr), 149.80 (Cq), 150.63 (Cq), 151.81 (Cq). MS (ESI+) : m / z calcd for C12H10ClN7 : 288.1 [M+H]+, found : 288.1. Example 3.81: Synthesis of 6-chloro-3-cyclopropyl-N-(6-methoxypyridin- 2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.81) Under inert gas, to a solution of (2.5) (0.125 g, 0.55 mmol, 1.0 eq.) in dry THF (7.5 mL), 6-methoxypyridin-2-amine (0.103 g, 0.82 mmol, 1.5 eq.) was added then tBuOK 1M in THF (0.82 mL, 0.82 mmol, 1.5 eq.). The mixture was stirred 3 h at room temperature then saturated NH4Cl (6.0 mL) and water (1.5 mL) were added and stirred vigorously 5 min. Layers were separated and aqueous layer was extracted twice with EtOAc (2x5.0 mL). Orgnics layers were combined, dried over MgSO4, filtered, concentrated and the residu was purified by flash chromatography with DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (3.81) (0.115 g, 67 %) as a white solid. Rf (DCM / MeOH, 98 / 2) : 0.281H NMR (400 MHz, DMSO-d6) δ : 1.12 – 1.20 (m, 4H, 2xCH2 cPr), 2.38 (tt, J = 8.0, 5.4 Hz, 1H, HcPr), 3.95 (s, 3H, OCH3), 6.54 (d, J = 8.0 Hz, 1H, HAr), 7.16 (d, J = 7.8 Hz, 1H, HAr), 7.72 (t, J = 7.9 Hz, 1H, HAr), 8.25 (s, 1H, HAr), 10.87 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.9 (Cq), 7.3 (2xCH2 cPr), 53.6 (OCH3), 99.6 (CHAr), 103.7 (CHAr), 106.3 (CHAr), 136.4 (Cq), 139.2 (Cq), 140.9 (CHAr), 149.8 (Cq), 151.7 (Cq), 152.0 (Cq), 162.4 (Cq). MS (ESI+) : m / z calcd for C14H13ClN6O : 317.1 [M+H]+, found : 317.3. Example 3.82: Synthesis of 6-chloro-3-cyclopropyl-N-(2-methoxypyridin- 3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.82) Under inert gas, to a solution of (2.5) (0.125 g, 0.55 mmol, 1.0 eq.) in dry THF (7.5 mL), 2-methoxypyridin-3-amine (0.103 g, 0.82 mmol, 1.5 eq.) was added then tBuOK 1M in THF (0.82 mL, 0.82 mmol, 1.5 eq.). The mixture was stirred 3 h at room temperature then saturated NH4Cl (6.0 mL) and water (1.5 mL) were added and stirred vigorously 5 min. Layers were separated and aqueous layer was extracted twice with EtOAc (2x5.0 mL). Orgnics layers were combined, dried over MgSO4, filtered, concentrated and the residu was purified by flash chromatography with DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (3.82) (0.113 g, 65 %) as a white solid. Rf (DCM / MeOH, 98 / 2) : 0.281H NMR (400 MHz, DMSO-d6) δ : 1.08 – 1.21 (m, 4H, 2xCH2 cPr), 2.36 (tt, J = 7.6, 5.1 Hz, 1H, HcPr), 3.90 (s, 3H, OCH3), 5.85 (s, 1H, HAr), 7.11 (dd, J = 7.5, 4.9 Hz, 1H, HAr), 7.78 (dd, J = 7.6, 1.7 Hz, 1H, HAr), 8.18 (dd, J = 4.9, 1.8 Hz, 1H, HAr), 9.99 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.9 (CHcPr), 7.2 (2xCH2 cPr), 53.5 (OCH3), 94.2 (CHAr), 117.5 (CHAr), 120.7 (Cq), 135.7 (CHAr), 139.3 (Cq), 140.5 (Cq), 145.0 (CHAr), 149.5 (Cq), 151.5 (Cq), 157.9 (Cq). MS (ESI+) : m / z calcd for C14H13ClN6O : 317.1 [M+H]+, found : 317.3. Example 3.83: Synthesis of 6-chloro-3-cyclopropyl-N-(2- methoxypyrimidin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.83) Under inert gas, to a solution of 2-methoxypyrimidin-4-amine (0.112 g, 0.85 mmol, 1.3 eq.) in dry THF (6.5 mL), KHMDS 0.5M in toluene (1.83 mL, 0.92 mmol, 1.4 eq.) was added. The mixture was stirred 10 min at room temperature then (2.5) (0.150 g, 0.65 mmol, 1.0 eq.) was added and the mixture was stirred 2.5 h at room temperature. After completion, NH4Cl (0.5 mL) and water (0.5 mL) were added and stirred vigorously 5 min then the mixture was concentrated with SiO2 to make solid deposit and purified by flash chromatography with DCM / MeOH (99 / 1 to 95 / 5) as eluent to give (3.83) (0.097 g, 47 %) as a white solid. Rf (DCM / MeOH, 96 / 4) : 0.221H NMR (400 MHz, DMSO-d6) δ : 1.11 – 1.23 (m, 4H, 2xCH2 cPr), 2.39 (tt, J = 8.1, 5.3 Hz, 1H, HcPr), 3.95 (s, 3H, CH3-O), 7.20 (d, J = 5.6 Hz, 1H, HAr), 8.30 (s, 1H, HAr), 8.39 (d, J = 5.6 Hz, 1H, HAr), 11.21 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.8 (CHcPr), 7.3 (2xCHcPr), 54.5 (CH3-O), 103.0 (CHAr), 104.4 (CHAr), 135.7 (Cq), 139.0 (Cq), 149.6 (Cq), 151.8 (Cq), 158.9 (CHAr), 161.7 (Cq), 164.4 (Cq). Example 3.84: Synthesis of 6-chloro-3-cyclopropyl-N-(6- methoxypyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.84) Under inert gas, to a solution of 6-methoxypyridazin-3-amine (0.112 g, 0.85 mmol, 1.3 eq.) in dry THF (6.5 mL), KHMDS 0.5M in toluene (1.83 mL, 0.92 mmol, 1.4 eq.) was added. The mixture was stirred 10 min at room temperature then (2.5) (0.150 g, 0.65 mmol, 1.0 eq.) was added and the mixture was stirred 2.5 h at room temperature. After completion, NH4Cl (0.5 mL) and water (0.5 mL) were added and stirred vigorously 5 min then the mixture was concentrated with SiO2to make solid deposit and purified by flash chromatography with DCM / MeOH (99 / 1 to 95 / 5) as eluent to give (3.84) (0.110 g, 53 %) as a white solid. Rf (DCM / MeOH, 96 / 4) : 0.341H NMR (400 MHz, DMSO-d6) δ : 1.17 (dd, J = 7.8, 5.4 Hz, 4H, 2xCH2 cPr), 2.39 (tt, J = 8.0, 5.3 Hz, 1H, HcPr), 4.02 (s, 3H, CH3-O), 7.32 (d, J = 9.4 Hz, 1H, HAr), 7.85 (d, J = 9.5 Hz, 1H, HAr), 8.26 (s, 1H, HAr), 10.98 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.9 (CHcPr), 7.3 (2xCHcPr), 54.4 (CH3-O), 100.3 (CHAr), 120.1 (CHAr), 124.0 (CHAr), 136.0 (Cq), 139.1 (Cq), 150.1 (Cq), 151.8 (Cq), 153.7 (Cq), 161.6 (Cq). Example 3.85: Synthesis of 6-chloro-3-cyclopropyl-N-(pyridazin-3- ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.85) To a solution of (2.5) (0.100 g, 0.44 mmol, 1.0 eq.) in THF / H2O (6.0 / 0.1 mL), corresponding amine dihydrochloride (0.103 g, 0.57 mmol, 1.3 eq.) and DIPEA (0.33 mL, 1.88 mmol, 4.3 eq.) were added and the mixture was refluxed 2 h. After cooling, the precipitate was filtered off and washed with THF. In another vacuum flask, washed the solid with water then washed again with THF in the first flask. The solid was dried under vacuum to give the first part of (3.85) (0.063 g). Organics filtrates were combined, dried ver MgSO4, concentrated and the residu was purified by flash chromatography with DCM / MeOH (98 / 2) as eluent to give the second part of (3.85) (0.018 g). Total of (3.85): 0.081 g, 61 %, as a white solid. Rf (DCM / MeOH, 96 / 4) : 0.181H NMR (400 MHz, DMSO-d6) δ : 1.06 – 1.16 (m, 4H, 2xCH2 cPr), 2.32 (tt, J = 8.1, 5.3 Hz, 1H, HcPr), 4.89 (s, 2H, CH2 Bn), 6.26 (s, 1H, HAr), 7.63 – 7.75 (m, 2H, 2xHAr), 9.04 (s, 1H, NHBn), 9.17 (dd, J = 4.0, 2.6 Hz, 1H, HAr).13C NMR (101 MHz, DMSO-d6) δ : 4.8 (CHcPr), 7.1 (2xCH2 cPr), 45.7 (CH2 Bn), 92.0 (CHAr), 125.7 (CHAr), 127.5 (CHAr), 139.3 (Cq), 142.5 (Cq), 149.7 (Cq), 151.0 (CHAr), 151.4 (Cq), 159.3 (Cq). Example 3.86: Synthesis of 6-chloro-3-cyclopropyl-N-phenethyl- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.86) To a solution of (2.5) (0.100 g, 0.44 mmol, 1.0 eq.) in THF / H2O (6.0 / 0.1 mL), corresponding amine hydrochloride (0.089 g, 0.57 mmol, 1.3 eq.) and DIPEA (0.23 mL, 1.31 mmol, 3.0 eq.) were added and the mixture was refluxed 1.5 h. After cooling, the solvent was removed then the residu was triturated in water, the solid was filtered off, washed with water then Et2O and dried under vacuum to give (3.86) (0.115 g, 84 %) as a white solid. Rf (DCM / MeOH, 96 / 4) : 0.661H NMR (400 MHz, DMSO-d6) δ : 1.10 (ddt, J = 8.7, 7.5, 2.6 Hz, 4H, 2xCH2 cPr), 2.31 (tt, J = 8.1, 5.3 Hz, 1H, HcPr), 2.94 (dd, J = 8.0, 6.6 Hz, 2H, CH2-CH2-NH), 3.58 (d, J = 7.2 Hz, 2H, CH2-NH), 6.19 (s, 1H, HAr), 7.12 – 7.35 (m, 5H, 5xHAr), 8.48 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.8 (CHcPr), 7.2 (2xCH2 cPr), 33.8 (CH2-CH2-NH), 43.5 (CH2-NH), 91.0 (CHAr), 126.2 (CHAr), 128.3 (2xCHAr), 128.9 (CHAr), 138.9 (Cq), 139.3 (Cq), 142.2 (Cq), 149.9 (Cq), 151.3 (Cq). MS (ESI+) : m / z calcd for C16H16ClN5 : 314.1 [M+H]+, found : 314.2. Example 3.87: Synthesis of 6-chloro-3-isopropyl-N-(6-methoxypyridin-2- yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.87) Reaction was carried out on (2.1) (0.180 g, 0.78 mmol, 1 eq), aminopyridine derivative (0.145 g, 1.17 mmol, 1.5 eq), and tBuOK 1M in THF (1.17 mL, 1.17 mmol, 1.5 eq) in dry THF (10.8 mL) and stirred in a round flask at r.t for 4h. After completion, saturated NH4Cl , water and EtOAc were added. The reaction mixture was extracted twice with AcOEt, filtered over MgSO4, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 98 / 2) has eluent to give (3.87) (0.175 g, 71%) as a light orange solid.1H NMR (400 MHz, DMSO) δ : 10.04 (s, 1H), 8.18 (dd, J = 4.9, 1.8 Hz, 1H), 7.78 (dd, J = 7.6, 1.8 Hz, 1H), 7.12 (dd, J = 7.6, 4.9 Hz, 1H), 5.84 (s, 1H), 3.91 (s, 3H), 3.48 (hept, J = 6.9 Hz, 1H), 1.41 (d, J = 7.0 Hz, 6H).13C NMR (101 MHz, DMSO) δ : 158.0, 154.1, 149.3, 145.1, 140.5, 139.3, 135.7, 120.6, 117.5, 94.2, 53.5, 24.5, 19.8. Example 3.88: Synthesis of 6-chloro-3-isopropyl-N-(6-methoxypyridin-3- yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.88) Reaction was carried out on (2.1) (0.180 g, 0.78 mmol, 1 eq), aminopyridine derivative (0.145 g, 1.17 mmol, 1.5 eq), and tBuOK 1M in THF (1.17 mL, 1.17 mmol, 1.5 eq) in dry THF (10.8 mL) and stirred in a round flask at r.t for 4h. After completion, saturated NH4Cl , water and EtOAc were added. The reaction mixture was extracted twice with AcOEt, filtered over MgSO4, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 98 / 2) has eluent to give (3.88) (0.106 g, 43%) as a light orange solid.1H NMR (400 MHz, DMSO) δ : 10.32 (s, 1H), 8.24 (d, J = 2.7 Hz, 1H), 7.80 (dd, J = 8.8, 2.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.15 (s, 1H), 3.88 (s, 3H), 3.47 (hept, J = 6.9 Hz, 1H), 1.41 (d, J = 6.9 Hz, 6H).13C NMR (101 MHz, DMSO) δ : 161.6, 154.2, 149.6, 143.0, 141.2, 139.4, 136.1, 128.3, 111.1, 92.9, 53.5, 24.9, 19.8. Example 3.89: Synthesis of 6-chloro-3-isopropyl-N-(5-methoxypyridin-3- yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.89) Reaction was carried out on (2.1) (0.180 g, 0.78 mmol, 1 eq), aminopyridine derivative (0.145 g, 1.17 mmol, 1.5 eq), and tBuOK 1M in THF (1.17 mL, 1.17 mmol, 1.5 eq) in dry THF (10.8 mL) and stirred in a round flask at r.t for 4h. After completion, saturated NH4Cl , water and EtOAc were added. The reaction mixture was extracted twice with AcOEt, filtered over MgSO4, concentrated and purified by flash chromatography with DCM / AcOEt (8 / 2 to 35 / 65) has eluent to give (3.89) (0.162 g, 65%) as a light orange solid.1H NMR (400 MHz, DMSO) δ : 10.50 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.6 Hz, 1H), 7.49 (s, 1H), 6.49 (s, 1H), 3.86 (s, 3H), 3.49 (hept, J = 6.9 Hz, 1H), 1.41 (d, J = 6.9 Hz, 6H).13C NMR (101 MHz, DMSO) δ : 155.7, 154.2, 149.7, 140.0, 139.5, 136.9, 135.3, 134.2, 115.7, 94.3, 55.8, 24.5, 19.8. Example 3.90: Synthesis of 6-chloro-3-isopropyl-N-(4-methoxypyridin-3- yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.90) Reaction was carried out on (2.1) (0.400 g, 1.73 mmol, 1 eq), aminopyridine derivative (0.322 g, 2.60 mmol, 1.5 eq), and tBuOK 1M in THF (2.6 mL, 2.60 mmol, 1.5 eq) in dry THF (20.0 mL) and stirred in a round flask at r.t for 4h. After completion, saturated NH4Cl , water and EtOAc were added. The reaction mixture was extracted twice with AcOEt, filtered over MgSO4, concentrated and purified by flash chromatography with DCM / AcOEt (8 / 2 to 35 / 65) has eluent to give (3.90) (0.261 g, 47%) as a brown solid.1H NMR (400 MHz, DMSO) δ : 10.15 (s, 1H), 8.48 (d, J = 5.7 Hz, 1H), 8.40 (s, 1H), 7.26 (d, J = 5.7 Hz, 1H), 5.74 (s, 1H), 3.89 (s, 3H), 3.53 – 3.41 (m, 1H), 1.41 (d, J = 7.0 Hz, 6H).13C NMR (101 MHz, DMSO) δ : 160.6, 154.6, 150.7, 149.8, 148.8, 141.7, 139.8, 123.0, 108.8, 94.5, 56.4, 23.0, 20.3. Example 3.91: Synthesis of 6-chloro-3-isopropyl-N-(3-phenylpropyl)- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.91) To a solution of (2.1) (0.130 g, 0.56 mmol, 1.0 eq.) in THF (6.0 mL), corresponding amine (0.152 g, 1.12 mmol, 2.0 eq.) and Et3N (0.16 mL, 1.12 mmol, 2.0 eq.) was added and the mixture was refluxed 2 h. After cooling, the precitpitate was filtered off, washed with THF then the filtrate was concentrated and the residu was purified by flash chromatography with DCM / MeOH (98 / 2) as eluent to give (3.91) (0.177 g, 95 %) as a white solid. Rf (DCM / MeOH, 94 / 6) : 0.201H NMR (400 MHz, DMSO-d6) δ : 1.00 – 1.20 (m, 4H, 2xCH2 cPr), 2.31 (tt, J = 8.1, 5.3 Hz, 1H, HcPr), 2.96 (t, J = 7.1 Hz, 2H, CH2), 3.49 – 3.76 (m, 2H, CH2), 6.24 (s, 1H, HAr), 7.31 (dd, J = 7.8, 4.8 Hz, 1H, HAr), 7.71 (dt, J = 7.8, 2.0 Hz, 1H, HAr), 8.41 (dd, J = 4.8, 1.7 Hz, 1H, HAr), 8.49 (d, J = 2.3 Hz, 1H, HAr), 8.52 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 4.8 (CH), 7.1 (2xCH2), 30.9 (CH2), 42.9 (CH2), 91.1 (CHAr), 123.3 (CHAr), 134.4 (Cq), 136.4 (CHAr), 139.3 (Cq), 142.2 (Cq), 147.5 (CHAr), 149.9 (Cq), 150.0 (CHAr), 151.3 (Cq). Example 3.92: Synthesis of 6-chloro-3-isopropyl-N-(2-methoxypyrimidin- 4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.92) To a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) in dry THF (5.4 mL), 2- methoxypyrimidin-4-amine (0.107 g, 0.81 mmol, 1.5 eq.) then tBuOK 1M in THF (1.00 mL, 0.81 mmol, 1.5 eq.) was added and the mixture was stirred 4 h at room temperature. After completion, water (0.5 mL) was added and SiO2to make solid deposit. The solvent was removed and the crude was purified by flash chromatography with DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (3.92) (0.113 g, 65 %) as a white solid. Rf (DCM / MeOH, 95 / 5) : 0.32.1H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 7.0 Hz, 6H, 2xCH3 iPr), 3.51 (hept, J = 6.9 Hz, 1H, HiPr), 3.96 (s, 3H, CH3-O), 7.24 (d, J = 5.6 Hz, 1H, HAr), 8.34 (s, 1H, HAr), 8.42 (d, J = 5.6 Hz, 1H, HAr), 11.30 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.5 (CHiPr), 54.5 (CH3-O), 103.1 (CHAr), 104.4 (CHAr), 135.7 (Cq), 139.1 (Cq), 149.4 (Cq), 154.4 (Cq), 158.9 (CHAr), 161.7 (Cq), 164.4 (Cq). MS (ESI+) : m / z calcd for C13H14ClN7O : 320.1 [M+H]+, found : 320.3. Example 3.93: Synthesis of 6-chloro-3-isopropyl-N-(5-methoxypyrimidin- 4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.93) To a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) in dry THF (5.4 mL), 5- methoxypyrimidin-4-amine (0.107 g, 0.81 mmol, 1.5 eq.) then tBuOK 1M in THF (1.00 mL, 0.81 mmol, 1.5 eq.) was added and the mixture was stirred 4 h at room temperature. After completion, water (0.5 mL) was added and SiO2to make solid deposit. The solvent was removed and the crude was purified by flash chromatography with DCM / MeOH (99 / 1 to 98 / 2) as eluent to give (3.93) (0.130 g, 75 %) as a white solid. Rf (DCM / MeOH, 95 / 5) : 0.39.1H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.52 (p, J = 7.0 Hz, 1H, HiPr), 4.10 (s, 3H, CH3-O), 8.22 (s, 1H, H3), 8.51 (s, 1H, H3), 8.68 (s, 1H, H3), 8.84 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : N.D. MS (ESI+) : m / z calcd for C13H14ClN7O : 320.1 [M+H]+, found : 320.3. Example 3.94: Synthesis of 6-chloro-3-isopropyl-N-(6-methoxypyrimidin- 4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.94) To a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) in dry THF (5.4 mL), 6- methoxypyrimidin-4-amine (0.107 g, 0.81 mmol, 1.5 eq.) then tBuOK 1M in THF (1.00 mL, 0.81 mmol, 1.5 eq.) was added and the mixture was stirred 4 h at room temperature. After completion, water (0.5 mL) was added and SiO2 to make solid deposit. The solvent was removed and the crude was purified by flash chromatography with DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (3.94) (0.105 g, 61 %) as a white solid. Rf (DCM / MeOH, 95 / 5) : 0.59.1H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 7.0 Hz, 6H, 2xCH3 iPr), 3.50 (hept, J = 6.9 Hz, 1H, HiPr), 3.92 (s, 3H, CH3-O), 6.98 (d, J = 1.0 Hz, 1H, HAr), 8.30 (s, 1H, HAr), 8.70 (d, J = 0.9 Hz, 1H, HAr), 11.09 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.5 (CHiPr), 53.9 (CH3-O), 93.8 (CHAr), 102.0 (CHAr), 136.1 (Cq), 139.1 (Cq), 149.5 (Cq), 154.4 (Cq), 157.7 (CHAr), 161.0 (Cq), 169.8 (Cq). MS (ESI+) : m / z calcd for C13H14ClN7O : 320.1 [M+H]+, found : 320.3. Example 3.95: Synthesis of 6-chloro-3-isopropyl-N-(6-methoxypyridazin- 3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.95) To a solution of (2.1) (0.200 g, 0.87 mmol, 1.0 eq.) in dry THF (8.7 mL), KHMDS 0.5M in toluene (2.42 mL, 1.21 mmol, 1.4 eq.) was added and the mixture was stirred 10 min at room temperature. 6-methoxypyridazin-3-amine (0.160 g, 1.21 mmol, 1.4 eq.) was added and the mixture was stirred 5 h at room temperature. After completion, saturated NH4Cl (0.5 mL) and water (0.5 mL) were added then the solvent was removed and the crude was purified by flash chromatography with DCM / MeOH (99 / 1 to 95 / 5) as eluent to give (3.95) (0.075 g, 27 %) as a green solid.1H NMR (400 MHz, DMSO-d6) δ : 1.43 (d, J = 6.9 Hz, 6H, 2xCH3 iPr), 3.50 (hept, J = 7.0 Hz, 1H, HiPr), 4.02 (s, 3H, CH3-O), 7.32 (d, J = 9.4 Hz, 1H, HAr), 7.86 (d, J = 9.4 Hz, 1H, HAr), 8.27 (s, 1H, HAr), 11.03 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH3 iPr), 24.5 (CHiPr), 54.4 (CH3-O), 100.3 (CHAr), 120.1 (CHAr), 124.1 (CHAr), 136.1 (Cq), 139.2 (Cq), 149.9 (Cq), 153.7 (Cq), 154.3 (Cq), 161.7 (Cq). MS (ESI+) : m / z calcd for C13H14ClN7O : 320.1 [M+H]+, found : 320.2. Example 4: Synthesis of [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine derivatives, as illustrated in scheme 1 or in step 3 of scheme 2 Example 4.1: Synthesis of (2R)-2-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butan-1-ol (1) In a sealed tube 2 - 5 mL with a stir bar was charged (3.1) (0.100 g, 0.33 mmol, 1.0 eq.), NMP (1.0 mL) and corresponding amine (0.42 mL, 5.30 mmol, 16.0 eq.). The vial was sealed and then put on heating block, 20 h at 180 °C. After cooling, the mixture was poured in EtOAc (10 mL) then organic layer was washed twice with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (94 / 6) as eluent to give (1) (0.070 g, 61 %) as a pale yellow solid. Example 4.2: Synthesis of (2S)-2-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butan-1-ol (2) In a sealed tube 2 - 5 mL with a stir bar was charged (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (2.0 mL) and corresponding amine (0.32 mL, 3.98 mmol, 6.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was poured in water (10 mL), the resulting precipitate was filtered off then washed with water. A new precipitate was formed in the filtrate and it was filtered off then washed with water. The residue was taken up in EtOAc / MeOH (7 / 3), the organic filtrate was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5 then 94 / 6) as eluent to give (2) (0.094 g, 40 %) as a white solid. Example 4.3: Synthesis of 2-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propane-1,3-diol (3) In a sealed tube 2 - 5 mL with a stir bar was charged (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (2.0 mL) and serinol (0.362 g, 3.98 mmol, 6.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was poured in water (10 mL), the precipitate was filtered off, washed with water. A new precipitate was formed in filtrate, it was filtered off and washed with water. The residue was taken up in EtOAc / MeOH (7 / 3), the organic filtrate was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5 then 94 / 6) as eluent to give (3) (0.092 g, 39 %) as a white solid. Example 4.4: Synthesis of (2R,3R)-2-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]245yridazine-6-yl]amino]butane-1,3-diol (4) In a sealed tube 2 – 5 mL with a stir bar was charged (3.1) (0.175 g, 0.58 mmol, 1.0 eq.), NMP (1.75 mL) and D-threoninol (0.754 g, 6.96 mmol, 12.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was poured in a funnel with water (30 mL), aqueous layer was extracted twice with EtOAc (2x20 mL) and combined organics layers were washed with HCl 0.1M (20 mL) then brine and dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5 then 94 / 6) as eluent to give (4) (0.137 g, 64 %) as a white solid. Example 4.5: (2R,3R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butane-1,3-diol (5) In a sealed tube 2 - 5 mL with a stir bar was charged (3.1) (0.175 g, 0.58 mmol, 1.0 eq.), NMP (1.75 mL) and D-threoninol (0.754 g, 6.96 mmol, 12.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was poured in a funnel with water (30 mL), aqueous layer was extracted twice with EtOAc (2x20 mL) and combined organics layers were washed with HCl 0.1M (20 mL) then brine and dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5 then 94 / 6) as eluent to give (5) (0.137 g, 64 %) as a white solid. Example 4.6: Synthesis of N-benzyl-3-isopropyl-6-morpholino- [1,2,4]triazolo[4,3-b]pyridazin-8-amine (6) In a sealed tube 2 - 5 mL with a stir bar was charged (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (1.5 mL) and morpholine (0.82 mL, 9.28 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was poured in a funnel with water (30 mL), aqueous layer was extracted twice with EtOAc (2x25 mL) and combined organics layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3 then 96 / 4) as eluent to give (6) (0.116 g, 50 %) as a white solid. Example 4.7: Synthesis of (2S)-3-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propane-1,2-diol (7) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.1) (0.175 g, 0.58 mmol, 1.0 eq.), NMP (1.25 mL) and (S)-(-)-3-amino-1,2-propanediol (0.755 g, 8.12 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was poured in a funnel with NaHCO3 sat. (15 mL), aqueous layer was extracted twice with EtOAc (2x15 mL) and combined organics layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5) as eluent to give (7) (0.087 g, 42 %) as a white solid. Example 4.8: Synthesis of N6-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N8- benzyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (8) In a vial 2 - 5 mL with a stir bar was charged (3.1) (0.250 g, 0.83 mmol, 1.0 eq.), NMP (1.25 mL) and 2-[2-(2-aminoethoxy)ethoxy]ethanamine (0.97 mL, 6.63 mmol, 8.0 eq.). The vial was closed and put under microwave irradiation 4h at 180 °C. After cooling, the mixture was diluted in EtOAc (20 mL), organic layer was washed with water (40 mL). Aqueous Layer was extracted with EtOAc (20 mL) and organics layer were combined, dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3 then 86 / 14) as eluent to give (8) (0.125 g, 36 %) as a white crystalline solid. Example 4.9: Synthesis of 3-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propan-1-ol (9) In a sealed tube 2 - 5 mL with a stir bar was charged (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (0.3 mL) and corresponding amine (0.72 mL, 9.28 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 17 h at 180 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL) and organic layer was washed with a mixture brine / water (2 / 1, 3x20.0 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (96 / 4) as eluent to give (9) (0.072 g, 32 %) as a white solid. Example 4.10: Synthesis of N8-benzyl-3-isopropyl-N6-(3-methoxypropyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (10) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.1) (0.500 g, 1.66 mmol, 1.0 eq.), NMP (1.3 mL) and 3-methoxypropylamine (2.40 mL, 23.20 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 4 h at 180 °C. After cooling, the mixture was diluted in EtOAc (40 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x50 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3) as eluent to give (10) (0.460 g, 78 %) as a white solid. Example 4.11: Synthesis of 2-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]ethanol (11) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (0.6 mL) and ethanolamine (0.57 mL, 9.28 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 16 h at 180 °C. After cooling, the mixture was diluted in EtOAc (20 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x20 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (96 / 4) as eluent to give (11) (0.082 g, 38 %) as a white solid. Example 4.12: Synthesis of N8-benzyl-3-isopropyl-N6-(2-methoxyethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (12) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (0.6 mL) and 2-methoxyethanamine (0.81 mL, 9.28 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 16 h at 180 °C. After cooling, the mixture was diluted in EtOAc (20 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x20 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5) as eluent to give (12) (0.152 g, 67 %) as a white crystalline solid. Example 4.13: Synthesis of 3-isopropyl-N6,N8-bis(2-methoxyethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (112) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (0.6 mL) and 2-methoxyethanamine (0.81 mL, 9.28 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 16 h at 180 °C. After cooling, the mixture was diluted in EtOAc (20 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x20 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5) as eluent to give the secondary compound (112) (0.052 g, 25 %) as a beige solid. Example 4.14: Synthesis of 4-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butan-1-ol (13) In a sealed tube 2 - 5 mL with a stir bar was charged (3.1) (0.400 g, 1.33 mmol, 1.0 eq.), NMP (1.2 mL) and corresponding amine (1.76 mL, 18.56 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 16 h at 180 °C. After cooling, the mixture was diluted in EtOAc (40.0 mL) and organic layer was washed with a mixture brine / water (2 / 1, 3x50 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (96 / 4) as eluent to give (13) (0.220 g, 47 %) as a white solid. Example 4.15: Synthesis of N8-benzyl-3-isopropyl-N6-(4-methoxybutyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (14) In a sealed tube 2 - 5 mL with a stir bar was charged (3.1) (0.100 g, 0.33 mmol, 1.0 eq.), NMP (1.0 mL) and corresponding amine (0.249 g, 2.65 mmol, 8.0 eq.) then the vial was sealed and put on heating block 17 h at 170 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL) and organic layer was washed three times with a mixture brine / water (3 / 1, 3x10 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 95 / 5) as eluent to give (14) (0.096 g, 79 %) as a white crystalline solid. Example 4.16: Synthesis of 5-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]pentan-1-ol (15) In a sealed tube 2 - 5 mL with a stir bar was charged (3.1) (0.400 g, 1.33 mmol, 1.0 eq.), NMP (1.0 mL) and corresponding amine (2.24 mL, 18.56 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 16 h at 180 °C. After cooling, the mixture was diluted in EtOAc (40.0 mL) and organic layer was washed with a mixture brine / HCl 0.05M (2 / 1, 3x40 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5) as eluent to give (15) (0.250 g, 51 %) as a white solid. Example 4.17: Synthesis of N8-benzyl-3-isopropyl-N6-(5-methoxypentyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (16) In a sealed tube 2 - 5 mL with a stir bar was charged (3.1) (0.100 g, 0.33 mmol, 1.0 eq.), NMP (1.0 mL) and corresponding amine (0.327 g, 2.65 mmol, 8.0 eq.) then the vial was sealed and put on heating block 17 h at 170 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL) and organic layer was washed three times with a mixture brine / water (3 / 1, 3x10 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 95 / 5) as eluent to give (16) (0.100 g, 79 %) as a light yellow solid. Example 4.18: Synthesis of N8-benzyl-3-isopropyl-N6-(3- methylsulfanylpropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (17) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.1) (0.250 g, 1.30 mmol, 1.0 eq.), NMP (0.75 mL) and 3-methylsulfanylpropan-1-amine (1.46 mL, 13.02 mmol, 10.0 eq.). The vial was sealed and then put on heating block, 2 h at 180 °C. After cooling, the mixture was diluted in EtOAc (30 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x30 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (96 / 4) as eluent to give (17) (0.270 g, 88 %) as a beige solid. Example 4.19: Synthesis of N8-benzyl-N6-(1-ethylpropyl)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (18) In a 2 - 5 mL vial with a stir bar was charged, (3.1) (0.250 g, 0.83 mmol, 1.0 eq.), NMP (0.8 mL) and pentan-3-amine (0.88 mL, 7.46 mmol, 9.0 eq.). The vial was sealed and then put on heating block, 24 h at 180 °C. After cooling, the mixture was diluted in EtOAc (20 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x20 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3) as eluent. Fractions containing NMP traces were concentrated, diluted in EtOAc (20 mL), washed three times with water (3x25 mL) and organic layer was dried over Na2SO4, filtered, concentrated to give (18) (0.096 g, 33 %) as a white crystalline solid. Example 4.20: Synthesis of N8-benzyl-3-isopropyl-N6-[(3R)- tetrahydrofuran-3-yl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (19) In a 2 - 5 mL vial with a stir bar was charged, (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (0.6 mL) and corresponding amine (0.84 mL, 9.28 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 24 h at 180 °C. After cooling, the mixture was diluted in EtOAc (30.0 mL) and organic layer was washed with a mixture brine / water (2 / 1, 3x20 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (96 / 4) as eluent to give (19) (0.149 g, 64 %) as a white solid. Example 4.21: Synthesis of N8-benzyl-3-cyclopentyl-N6-[(3R)- tetrahydrofuran-3-yl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (20) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.4) (0.160 g, 0.49 mmol, 1.0 eq.), NMP (0.8 mL) and corresponding amine (0.358 g, 3.91 mmol, 8.0 eq.). The vial was sealed and then put on heating block 23 h at 170 °C. After cooling, water (7.0 mL) is added and stirred 5 min, the resulting dough ball was filtered, washed with water then solubilise with DCM. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to give (20) (0.071 g, 38 %) as a white solid. Example 4.22: Synthesis of N8-benzyl-3-isopropyl-N6-[(3R)- tetrahydropyran-3-yl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (21) In a sealed tube 2 - 5 mL with a stir bar was charged (3.1) (0.420 g, 1.24 mmol, 1.0 eq.), dioxane (1.2 mL) then benzylamine (0.83 mL, 7.42 mmol, 6.0 eq.). The vial was sealed and then put on heating block, 4h at 110 °C. After cooling, the mixture was diluted in DCM (20 mL) and the resulting organic layer was washed with HCl 0.5 M (20 mL). Aqueous layer was extracted twice with DCM (2x10 mL) and organic layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3 to 95 / 5) as eluent to give (21) (0.175 g, 39 %) as a white solid. Example 4.23: Synthesis of N8-benzyl-3-isopropyl-N6-[(3S)- tetrahydropyran-3-yl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (22) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.1) (0.250 g, 0.83 mmol, 1.0 eq.) and NMP (3.5 mL) then (3S)-tetrahydropyran-3-amine hydrochloride (1.080 g, 7.46 mmol, 9.0 eq.) and K2CO3 (0.555 g, 3.98 mmol, 4.8 eq.). The vial was sealed and then put on heating block, 15 h at 180 °C. After cooling, the mixture was poured onto water (50 mL), stirring 5min vigorously and the resulting precipitate was filtered off, washed with water (up to neutral pH) then EtOAc and the organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3 to 95 / 5) as eluent to give (22) (0.040 g, 13 %) as a white crystalline solid. Example 4.24: Synthesis of N8-benzyl-3-isopropyl-N6-tetrahydropyran-4- yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (23) In a sealed tube 2 - 5 mL with a stir bar was charged (3.1) (0.250 g, 0.83 mmol, 1.0 eq.) and corresponding amine (1.29 mL, 12.43 mmol, 15.0 eq.) then the vial was sealed and then put on heating block, 5.5 h at 180 °C. After cooling, the mixture was diluted in EtOAc (3.0 mL), water (3.0 mL) was added and the biphasique mixture was stirred 5 min. Layers were separated, aqueous layer was extracted twice with EtOAc (2x3.0 mL), organics layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (94 / 6) as eluent to give (23) (0.085 g, 28 %) as a beige solid. Example 4.25: Synthesis of N-[3-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propyl]acetamide (24) In a sealed tube 2 - 5 mL with a stir bar was charged (3.1) (0.100 g, 0.33 mmol, 1.0 eq.), NMP (0.2 mL) then corresponding amine (0.405 g, 3.31 mmol, 10.0 eq.). The vial was sealed and then put on heating block, 15 h at 180 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL) then organic layer was washed with brine / water (2 / 1, 3x20.0 mL), dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (96 / 4) as eluent to give (24) (0.118g, 94 %) as a white solid. Example 4.26: Synthesis of 3-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propanoic acid (4.26) In a sealed tube 10 - 20 mL with a stir bar was charged, (3.1) (0.800 g, 2.65 mmol, 1.0 eq.) and DMSO (6.5 mL) then β-alanine (1.431 g, 15.91 mmol, 6.0 eq.) and K3PO4(3.376 g, 15.91 mmol, 6.0 eq.). The vial was sealed and then put on heating block, 4 h at 180 °C. After cooling, the mixture was poured into HCl 1M (150 mL) in ice bath, and water (40 mL). After 20 min, the precipitate was filtered, washed with water (to pH 7) then the solid was taken off with EtOH and acetone, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 92 / 8 then 92 / 8) as eluent to give (4.26) (0.505 g, 54 %) as a beige solid. Rf (DCM / MeOH, 92 / 8) : 0.301H NMR (400 MHz, DMSO-d6) δ : 1.36 (d, J = 7.0 Hz, 6H, 2xCH3 iPr), 2.51 (m, 2H, CH2-CO), 3.34 (d, J = 9.7 Hz, 3H, HiPr & CH2-NH), 4.42 (d, J = 6.2 Hz, 2H, CH2 Bn), 5.39 (s, 1H, HAr), 6.64 (t, J = 5.4 Hz, 1H, NH), 7.17 – 7.43 (m, 5H, 5xHAr), 7.93 (t, J = 6.4 Hz, 1H, NHBn), 12.16 (s, 1H, COOH).13C NMR (101 MHz, DMSO-d6) δ : 19.6 (2xCH3 iPr), 24.7 (CHiPr), 33.3 (CH2-CO), 36.9 (CH2-NH), 45.2 (CH2 Bn), 84.1 (CHAr), 126.8 (2xCHAr), 126.9 (CHAr), 128.4 (2xCHAr), 138.3 (Cq), 139.7 (Cq), 139.9 (Cq), 152.9 (Cq), 155.7 (Cq), 173.2 (Cq). MS (ESI+) : m / z calcd for C18H22N6O2 : 355.19 [M+H]+, found : 355.27. Example 4.27: Synthesis of 3-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propanamide (25) To a solution of (4.26) (0.110 g, 0.31 mmol, 1.0 eq.) in THF (3.1 mL) was added HOBt.H2O (0.062 g, 0.40 mmol, 1.3 eq.), EDCi (0.058 g, 0.37 mmol, 1.2 eq.) and ammonia 0.5M in THF (0.81 mL, 0.40 mmol, 1.3 eq.). The mixture was stirred 4 h at room temperature and after completion the mixture was directly concentrated and purified on solid deposit by flash chromatography with DCM / MeOH (94 / 6) as eluent to give (25) (0.090 g, 82 %) as a white solid. Example 4.28: Synthesis of 3-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]-N-methyl-propanamide (26) To a solution of (4.26) (0.120 g, 0.34 mmol, 1.0 eq.) in THF (3 mL) was added HOBt.H2O (0.069 g, 0.44 mmol, 1.3 eq.), methylamine 2M in THF (0.24 mL, 0.47 mmol, 1.4 eq.) and EDCi (0.065 g, 0.41 mmol, 1.2 eq.). The mixture was stirred 3 h at room temperature and after completion the mixture was directly concentrated and purified on solid deposit by flash chromatography with DCM / MeOH (95 / 5) as eluent to give (26) (0.121 g, 97 %) as a white solid. Example 4.29: Synthesis of 3-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]-N,N-dimethyl-propanamide (27) To a solution of (4.26) (0.120 g, 0.34 mmol, 1.0 eq.) in THF (3 mL) was added HOBt.H2O (0.069 g, 0.44 mmol, 1.3 eq.), dimethylamine 2M in THF (0.24 mL, 0.47 mmol, 1.4 eq.) and EDCi (0.065 g, 0.41 mmol, 1.2 eq.). The mixture was stirred 3 h at room temperature and after completion the mixture was directly concentrated and purified on solid deposit by flash chromatography with DCM / MeOH (95 / 5) as eluent to give (27) (0.124 g, 96 %) as a white solid. Example 4.30: Synthesis of methyl 3-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propanoate (28) A solution of (4.26) (0.110 g, 2.65 mmol, 1.0 eq.) in MeOH (10 mL) with two drops of H2SO4 was refluxed 30 min. After cooling, Na2CO3 (0.075 g) was added and stirred 5 min at room temperature. The mixture was directly concentrated and purified by flash chromatography with DCM / MeOH (95 / 5) as eluent to give (28) (0.100 g, 87 %) as a white solid. Example 4.31: Synthesis of ethyl 3-[[8-(benzylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propanoate (29) A solution of (4.26) (0.110 g, 2.65 mmol, 1.0 eq.) in EtOH (10 mL) with two drops of H2SO4was refluxed 30 min. After cooling, Na2CO3(0.075 g) was added and stirred 5 min at room temperature. The mixture was directly concentrated and purified by flash chromatography with DCM / MeOH (94 / 6) as eluent to give (29) (0.082 g, 69 %) as a white solid. Example 4.32: Synthesis of (2R)-2-[[8-(benzylamino)-3-cyclopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butan-1-ol (30) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.3) (0.135 g, 0.45 mmol, 1.0 eq.), NMP (1.0 mL) and (R)-(-)-2-amino-1-butanol (0.57 mL, 7.21 mmol, 16.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was poured in EtOAc (20 mL) then organic layer was washed three times with brine (20 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (96 / 4) as eluent to give (30) (0.112 g, 71 %) as a beige solid. Example 4.33: Synthesis of N8-benzyl-3-cyclopropyl-N6-(3- methoxypropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (31) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.3) (0.250 g, 0.83 mmol, 1.0 eq.), NMP (0.8 mL) and 3-methoxypropylamine (1.21 mL, 11.68 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was diluted in EtOAc (30 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x20 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3) as eluent to give (31) (0.145 g, 49 %) as a white solid. Example 4.34: Synthesis of 3-cyclopropyl-N6,N8-bis(3-methoxypropyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (110) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.3) (0.250 g, 0.83 mmol, 1.0 eq.), NMP (0.8 mL) and 3-methoxypropylamine (1.21 mL, 11.68 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was diluted in EtOAc (30 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x20 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3) as eluent to give the compound (110) (0.120 g, 43 %) as a white solid. Example 4.35: Synthesis of N8-benzyl-N6-(3-methoxypropyl)-3-methyl- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (32) In a sealed tube 2 - 5 mL with a stir bar was charged (3.6) (0.125 g, 0.46 mmol, 1.0 eq.), NMP (0.4 mL) and 3-methoxypropylamine (0.65 mL, 6.39 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 16 h at 180 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL), organic layer was washed with brine (3x10.0 mL), dired over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5) as eluent to give (32) (0.086 g, 58 %) as a white solid. Example 4.36: Synthesis of (2R)-2-[[8-(benzylamino)-3-methyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butan-1-ol (33) In a sealed tube 2 - 5 mL with a stir bar was charged (3.6) (0.125 g, 0.46 mmol, 1.0 eq.), NMP (0.4 mL) and (R)-(-)-2-amino-1-butanol (0.51 mL, 5.48 mmol, 12.0 eq.). The vial was sealed and then put on heating block, 16 h at 180 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL), organic layer was washed with brine (3x10.0 mL), dired over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5) as eluent to give (33) (0.086 g, 58 %) as a white solid. Example 4.37: Synthesis of N8-benzyl-N6-(3-methoxypropyl)-3-phenyl- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (34) In a sealed tube 2 - 5 mL with a stir bar was charged (3.7) (0.125 g, 0.38 mmol, 1.0 eq.), NMP (0.35 mL) and 3-methoxypropylamine (0.55 mL, 5.34 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was diluted in EtOAc (25.0 mL), organic layer was washed with brine / water (2 / 1, 3x20.0 mL), dired over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5) as eluent to give (34) (0.086 g, 58 %) as a white solid. Example 4.38: Synthesis of N6,N8-bis(3-methoxypropyl)-3-phenyl- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (109) In a sealed tube 2 - 5 mL with a stir bar was charged (3.7) (0.125 g, 0.38 mmol, 1.0 eq.), NMP (0.35 mL) and 3-methoxypropylamine (0.55 mL, 5.34 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was diluted in EtOAc (25.0 mL), organic layer was washed with brine / water (2 / 1, 3x20.0 mL), dired over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5) as eluent to give the secondary compound (109) (0.055 g, 39 %) as a white solid. Example 4.39: Synthesis of (2R)-2-[[8-(benzylamino)-3-phenyl- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butan-1-ol (35) In a sealed tube 2 - 5 mL with a stir bar was charged (3.7) (0.150 g, 0.46 mmol, 1.0 eq.), NMP (1.0 mL) and (R)-(-)-2-amino-1-butanol (0.59 mL, 6.41 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was diluted in EtOAc (25.0 mL), organic layer was washed with brine / water (2 / 1, 3x20.0 mL), dired over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (95 / 5) as eluent to give (35) (0.115 g, 65 %) as a white solid. Example 4.40: Synthesis of N8-benzyl-N6-(3-methoxypropyl)-3- (trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (36) In a sealed tube 2 - 5 mL with a stir bar was charged (3.5) (0.125 g, 0.38 mmol, 1.0 eq.), NMP (0.4 mL) and 3-methoxypropylamine (0.55 mL, 5.34 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x20 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1) as eluent to give (36) (0.110 g, 76 %) as a white solid. Example 4.41: Synthesis of N6,N8-bis(3-methoxypropyl)-3- (trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (111) In a sealed tube 2 - 5 mL with a stir bar was charged (3.5) (0.125 g, 0.38 mmol, 1.0 eq.), NMP (0.4 mL) and 3-methoxypropylamine (0.55 mL, 5.34 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x20 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1) as eluent to give the secondary compound (111) (0.010 g, 7 %) as a white solid. Example 4.42: Synthesis of (2R)-2-[[8-(benzylamino)-3-(trifluoromethyl)- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butan-1-ol (37) In a sealed tube 2 - 5 mL with a stir bar was charged (3.5) (0.110 g, 0.34 mmol, 1.0 eq.), NMP (0.3 mL) and (R)-(-)-2-amino-1-butanol (0.44 mL, 4.70 mmol, 14.0 eq.). The vial was sealed and then put on heating block, 18 h at 180 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x20 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3) as eluent to give (37) (0.070 g, 55 %) as a white solid. Example 4.43: Synthesis of (2R)-2-[[8-(benzylamino)-3-isopropyl-7- methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butan-1-ol (115) Under inert gas, in a solution of (1) (0.880 g, 2.48 mmol, 1.0 eq.) and dry THF (48.0 mL), NaH 60% (0.119 g, 2.98 mmol, 1.2 eq.) was added portionwise then the mixture was stirred 10 min at room temperature. The solution was cooled at 0 °C and MeI (0.17 mL, 2.73 mmol, 1.1 eq.) was added dropwise then stirred 2 h at room temperature. To complete the reaction, MeI (0.03 mL, 0.50 mmol, 0.2 eq.) was added and the mixture was stirred 1 h. After completion, MeOH (9.0 mL) was added slowly and the mixture was directly concentrated with SiO2 to make solid deposit and purified by flash chromatography with DCM / MeOH (98 / 2 to 96 / 4) as eluent to give the secondary compound (115) (0.092 g, 10 %) as a beige solid. Example 4.44: Synthesis of 2-[[[6-[[(1R)-1-(hydroxymethyl)propyl]amino]- 3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (38) In a sealed tube 2 - 5 mL with a stir bar was charged with (3.8) (0.150 g, 0.47 mmol, 1.0 eq.) and (R)-(-)-2-amino-1-butanol (0.91 mL, 9.44 mmol, 20.0 eq.) then the vial was sealed and put on heating block, 15 h at 160 °C. After cooling, the mixture was diluted in EtOAc (25.0 mL) and organic layer was washed twice with water / brine mixture (1 / 3, 2x30.0 mL) then dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (96 / 4 to 92 / 8) as eluent to give the title compound (38) (0.010 g, 6 %) as a beige solid. Example 4.45: Synthesis of 2-[[[3-isopropyl-6-(3-methoxypropylamino)- [1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (39) In a sealed tube 2 - 5 mL with a stir bar was charged with (3.8) (0.150 g, 0.47 mmol, 1.0 eq.) and 3-methoxypropylamine (1.07 mL, 9.44 mmol, 20.0 eq.) then the vial was sealed and put on heating block, 19 h at 150 °C. After cooling, the mixture was diluted in EtOAc (25.0 mL) and organic layer was washed twice with water / brine mixture (1 / 3, 2x30.0 mL) then dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (93 / 7 to 92 / 8) as eluent to give the title compound (39) (0.070 g, 40 %) as a white solid. Example 4.46: Synthesis of 2-[[[6-(1-ethylpropylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (40) In a sealed tube 2 - 5 mL with a stir bar was charged (3.8) (0.140 g, 0.44 mmol, 1.0 eq.), NMP (1.0 mL) and 3-aminopentane (0.52 mL, 4.41 mmol, 10.0 eq.). The vial was sealed and then put on heating block, 16 h at 170 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x20 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 95 / 5) as eluent to give (40) (0.021 g, 13 %) as a white crystalline solid. Example 4.47: Synthesis of 3-[[[6-(1-ethylpropylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (41) In a sealed tube 2 - 5 mL with a stir bar was charged (3.9) (0.450 g, 1.42 mmol, 1.0 eq.), NMP (3.3 mL) and 3-aminopentane (3.33 mL, 28.32 mmol, 20.0 eq.). The vial was sealed and then put on heating block, 16 h at 170 °C. After cooling, the mixture was poured onto saturated NaHCO3 (20.0 mL) then water (30.0 mL) was added and the mixture was stirred 5 min. The resulting solid was filtered off, washed wih water up to neutral pH then the solid was taken up in DCM, organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to give (41) (0.080 g, 15 %) as a white solid. Example 4.48: Synthesis of 4-[[[6-(1-ethylpropylamino)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (42) In a sealed tube 2 - 5 mL with a stir bar was charged (3.10) (0.085 g, 0.27 mmol, 1.0 eq.), NMP (1.0 mL) and 3-aminopentane (0.31 mL, 2.68 mmol, 10.0 eq.). The vial was sealed and then put on heating block, 16 h at 170 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x10.0 mL). Organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 95 / 5) as eluent to give (42) (0.015 g, 15 %) as a white crystalline solid. Example 4.49: Synthesis of 2-[[[3-isopropyl-6-[[(3R)-tetrahydropyran-3- yl]amino]-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (43) In a sealed tube 2 - 5 mL with a stir bar was charged (3.8) (0.200 g, 0.63 mmol, 1.0 eq.), corresponding amine hydrochloride (0.912 g, 6.29 mmol, 10.0 eq.) and DIPEA (1.54 mL, 8.81 mmol, 14.0 eq.) then the vial was sealed and put on heating block 24 h at 150 °C. After cooling, water (5.0 mL) was added, the precipitate was triturated then the mixture was poured in water (15.0 mL), stirred 5 min and the precipitate was filtered off, washed with water up to neutral pH and taken up in EtOAc. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (96 / 4 to 94 / 6) as eluent to give (43) (0.018 g, 7 %) as a white solid. Example 4.50: Synthesis of 2-[[[3-isopropyl-6-(tetrahydropyran-4- ylamino)-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (44) In a sealed tube 2 - 5 mL with a stir bar was charged (3.8) (0.250 g, 0.79 mmol, 1.0 eq.) and corresponding amine (0.98 mL, 9.44 mmol, 12.0 eq.) then the vial was sealed and put on heating block 15 h at 160 °C. After cooling, EtOAc (4.0 mL) and water (4.0 mL) was added, stirred 5 min then layers were separated. Aqueous layer was extracted twice with EtOAc (2x3.0 mL) then organics layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (96 / 4 to 93 / 7) as eluent to give (44) (0.030 g, 10 %) as a white solid. Example 4.51: Synthesis of (2S)-2-[[8-[(4-bromophenyl)methylamino]-3- isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butan-1-ol (101) In a sealed tube 10 - 20 mL with a stir bar was charged (3.42) (1.800 g, 4.73 mmol, 1.0 eq.), NMP (5.0 mL) and (2S)-2-aminobutan-1-ol (8.12 mL, 85.11 mmol, 18.0 eq.) then the vial was sealed and put on heating block 24 h at 180 °C. After cooling, the reaction mixture was poured onto water (100.0 mL), vigorously stirred 5 min and the aqueous mixture was extracted with EtOAc (3x30.0 mL). Organic layers were combined, washed with brine (20.0 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (101) (1.290 g, 63 %) as a beige solid. Example 4.52: Synthesis of N8-[(4-bromophenyl)methyl]-3-isopropyl-N6- methyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (116) In a sealed tube 10 - 20 mL with a stir bar was charged (3.42) (1.800 g, 4.73 mmol, 1.0 eq.), NMP (5.0 mL) and (2S)-2-aminobutan-1-ol (8.12 mL, 85.11 mmol, 18.0 eq.) then the vial was sealed and put on heating block 24 h at 180 °C. After cooling, the reaction mixture was poured onto water (100.0 mL), vigorously stirred 5 min and the aqueous mixture was extracted with EtOAc (3x30.0 mL). Organic layers were combined, washed with brine (20.0 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 93 / 7) as eluent to give the secondary compound (116) (0.300 g, 17 %) as a white solid. Example 4.53: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-phenyl- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (45) In a sealed tube 2 - 5 mL with a stir bar was charged (3.12) (0.090 g, 0.31 mmol, 1.0 eq.), cineol (0.7 mL) and 3-aminopentane (0.55 mL, 4.69 mmol, 15.0 eq.). The vial was sealed and put on heating block 40 h at 170 °C. After cooling, the mixture was concentrated with SiO2to make solid deposit then directly purified by flash chromatography with DCM / MeOH (99 / 1 to 97 / 3) as eluent to give (45) (0.010 g, 9 %) as a white solid. Example 4.54: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-(2-pyridyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (46) In a sealed tube 2 - 5 mL with a stir bar was charged (3.13) (0.090 g, 0.31 mmol, 1.0 eq.), cineol (0.7 mL) and 3-aminopentane (0.55 mL, 4.68 mmol, 15.0 eq.). The vial was sealed and put on heating block 40 h at 170 °C. After cooling, the mixture was concentrated with SiO2to make solid deposit then directly purified by flash chromatography with DCM / MeOH (99 / 1 to 97 / 3) as eluent to give (46) (0.021 g, 20 %) as a beige solid. Example 4.55: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-(3-pyridyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (47) In a sealed tube 2 - 5 mL with a stir bar was charged (3.14) (0.090 g, 0.31 mmol, 1.0 eq.), cineol (0.7 mL) and 3-aminopentane (0.55 mL, 4.68 mmol, 15.0 eq.). The vial was sealed and put on heating block 40 h at 170 °C. After cooling, the mixture was concentrated with SiO2to make solid deposit then directly purified by flash chromatography with DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (47) (0.025 g, 24 %) as a beige solid. Example 4.56: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-(4-pyridyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (48) In a sealed tube 2 - 5 mL with a stir bar was charged (3.15) (0.090 g, 0.31 mmol, 1.0 eq.), cineol (0.7 mL) and 3-aminopentane (0.55 mL, 4.68 mmol, 15.0 eq.). The vial was sealed and put on heating block 40 h at 170 °C. After cooling, the mixture was concentrated with SiO2 to make solid deposit then directly purified by flash chromatography with DCM / MeOH (99 / 1 to 95 / 5) as eluent to give (48) (0.060 g, 57 %) as a white solid. Example 4.57: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-(4- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (49) In a sealed tube 2 - 5 mL with a stir bar was charged (3.16) (0.100 g, 0.33 mmol, 1.0 eq.), NMP (0.17 mL) and 3-aminopentane (0.58 mL, 4.95 mmol, 15.0 eq.) then the vial was sealed and put on heating block 15 h at 160 °C. To complete the reaction, NMP (0.34 mL) was added the the vial was sealed and put on heating block 23 h at 180 °C. After cooling, the mixture was diluted in EtOAc (10.0 mL) and organic layer was washed three times with a mixture brine / water (2 / 1, 3x10.0 mL). Organic layer was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 95 / 5) as eluent to give (49) (0.054 g, 46 %) as a white solid. Example 4.58: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-(3- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (50) In a sealed tube 10 - 20 mL with a stir bar was charged (3.17) (0.580 g, 1.92 mmol, 1.0 eq.), NMP (4.1 mL) and 3-aminopentane (4.06 mL, 34.48 mmol, 18.0 eq.) then the vial was sealed and put on heating block 20 h at 180 °C. After cooling, the mixture was poured onto saturated NaHCO3(20.0 mL), rinse the vial and adjust with water up to 80.0 mL then the mixture was stirred 10 min. The resulting precipitate was filtered off, washed with water up to neutral pH, change the flask and washed the solid with EtOAc. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to give (50) (0.160 g, 24 %) as a light pink solid. Example 4.59: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (51) In a sealed tube 10 - 20 mL with a stir bar was charged (3.18) (0.750 g, 2.48 mmol, 1.0 eq.), NMP (5.0 mL) and 3-aminopentane (4.96 mL, 42.11 mmol, 17.0 eq.) then the vial was sealed and put on heating block 69 h at 180 °C. After cooling, the mixture was poured onto saturated NaHCO3(20.0 mL), rinse the vial and adjust with water up to 80.0 mL then the mixture was stirred 10 min. The resulting precipitate was filtered off, washed with water up to neutral pH, change the flask and washed the solid with DCM. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to give (51) (0.420 g, 48 %) as a white solid. Example 4.60: Synthesis of N6-tert-butyl-3-isopropyl-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (52) In a sealed tube 2 - 5 mL with a stir bar was charged (3.18) (0.250 g, 0.83 mmol, 1.0 eq.), NMP (2.0 mL) and corresponding amine (0.45 mL, 4.13 mmol, 5.0 eq.). The vial was sealed and then put on heating block, 65 h at 170 °C. After cooling, the reaction mixture was poured onto brine / water (1 / 1, 30 mL) and stirred vigorously 5 min. The resulting precipitate was filtered, washed with water, taken up in DCM and organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 93 / 7) as eluent to give (52) (0.020 g, 7 %) as a white solid. Example 4.61: Synthesis of 3-isopropyl-N8-(2-pyridylmethyl)-N6- spiro[3.3]heptan-2-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (53) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.18) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (1.0 mL), corresponding amine hydrochloride (0.399 g, 2.64 mmol, 4.0 eq.) and DIPEA (0.69 mL, 3.96 mmol, 6.0 eq.). The vial was sealed and then put on heating block 23 h at 170 °C. After cooling, the mixture was diluted in water (10.0 mL), the resulting precipitate was triturated in water, filtered off and washed with a little amount of water. The solid was triturated with EtOAc, filtered and organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (53) (0.035 g, 14 %) as a grey solid. Example 4.62: Synthesis of N6-(3,3-difluorocyclobutyl)-3-isopropyl-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (54) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.18) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (1.0 mL), corresponding amine hydrochloride (0.399 g, 2.64 mmol, 4.0 eq.) and DIPEA (0.69 mL, 3.96 mmol, 6.0 eq.). The vial was sealed and then put on heating block 23 h at 170 °C. After cooling, the mixture was diluted in water (10.0 mL), the resulting precipitate was triturated in water, filtered off and washed with a little amount of water. The solid was triturated with EtOAc, filtered and organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (54) (0.035 g, 14 %) as a beige solid. Example 4.63: Synthesis of N6-(4,4-difluorocyclohexyl)-3-isopropyl-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (55) In a sealed tube 2 - 5 mL with a stir bar was charged, (3.18) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (1.0 mL), corresponding amine hydrochloride (0.399 g, 2.64 mmol, 4.0 eq.) and DIPEA (0.69 mL, 3.96 mmol, 6.0 eq.). The vial was sealed and then put on heating block 23 h at 170 °C. After cooling, the mixture was diluted in water (10.0 mL), the resulting precipitate was triturated in water, filtered off and washed with a little amount of water. The solid was triturated with EtOAc, filtered and organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (55) (0.010 g, 14 %) as a white solid. Example 4.64: Synthesis of N6-benzyl-3-isopropyl-N8-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (56) In a sealed tube 2 - 5 mL with a stir bar was charged (3.18) (0.150 g, 0.50 mmol, 1.0 eq.), NMP (1.0 mL) and benzylamine (0.33 mL, 2.97 mmol, 6.0 eq.). The vial was sealed and then put on heating block 17 h at 180 °C. After cooling, the mixture was diluted in brine (30.0 mL) and water (10.0 mL) then aqueous layer was extracted twice with EtOAc (2x20.0 mL). Organics layers were combined, washed with brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 84 / 6) as eluent to give (56) (0.070 g, 38 %) as a white solid. Example 4.65: Synthesis of N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (57) In a sealed tube 10 - 20 mL with a stir bar was charged (3.19) (0.500 g, 1.92 mmol, 1.0 eq.), NMP (4.5 mL) and corresponding amine (4.51 mL, 38.36 mmol, 20.0 eq.). The vial was sealed and then put on heating block 18 h at 180 °C. After cooling, the mixture was poured onto saturated NaHCO3(50.0 mL), rinse the vial and adjust with water up to 100.0 mL then the mixture was stirred 10 min. The resulting precipitate was filtered off, washed with water up to neutral pH, change the flask and washed the solid with EtOAc. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (57) (0.180 g, 30 %) as a white solid. Example 4.66: Synthesis of N6-(1-ethylpropyl)-3-methyl-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (58) In a sealed tube 10 - 20 mL with a stir bar was charged (3.20) (0.550 g, 2.00 mmol, 1.0 eq.), NMP (4.7 mL) and corresponding amine (4.71 mL, 40.04 mmol, 20.0 eq.). The vial was sealed and then put on heating block 18 h at 180 °C. After cooling, the mixture was poured onto saturated NaHCO3 (50.0 mL), rinse the vial and adjust with water up to 100.0 mL then the mixture was stirred 10 min. The resulting precipitate was filtered off, washed with water up to neutral pH, change the flask and washed the solid with EtOAc. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (58) (0.100 g, 15 %) as a white solid. Example 4.67: Synthesis of 3-ethyl-N6-(1-ethylpropyl)-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (59) In a sealed tube 10 - 20 mL with a stir bar was charged (3.21) (0.350 g, 1.21 mmol, 1.0 eq.), NMP (2.85 mL) and corresponding amine (2.85 mL, 24.24 mmol, 20.0 eq.). The vial was sealed and then put on heating block 21 h at 180 °C. After cooling, the mixture was poured onto saturated NaHCO3(20.0 mL), rinse the vial and adjust with water up to 40.0 mL then the mixture was stirred 10 min. Aqueous mixture was extracted three times with EtOAc (3x15.0 mL) then organics layers were combined, washed with brine (15.0 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to give (59) (0.074 g, 18 %) as a white solid. Example 4.68: Synthesis of N6-(1-ethylpropyl)-3-propyl-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (60) In a sealed tube 2 - 5 mL with a stir bar was charged (3.22) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (0.7 mL) and corresponding amine (0.78 mL, 6.61 mmol, 10.0 eq.) then the vial was sealed and put on heating block 22 h at 180 °C. After cooling, the mixture was diluted in brine (30.0 mL) and water (30.0 mL) and the mixture was stirred 10 min. The resulting precipitate was filtered off, washed with water up to neutral pH then taken up in EtOAc. Organic filtrate was dried over MgSO4,filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 95 / 5) as eluent to give (60) (0.065 g, 28 %) as a beige solid. Example 4.69: Synthesis of 3-tert-butyl-N6-(1-ethylpropyl)-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (61) In a sealed tube 10 - 20 mL with a stir bar was charged (3.23) (0.500g, 1.58 mmol, 1.0 eq.), NMP (3.7mL) and corresponding amine (3.72 mL, 31.57 mmol, 20.0 eq.). The vial was sealed and then put on heating block 21 h at 180 °C. After cooling, the mixture was poured onto saturated NaHCO3(20.0 mL), rinse the vial and adjust with water up to 40.0 mL then the mixture was stirred 10 min. Aqueous mixture was extracted three times with EtOAc (3x15.0 mL) then organics layers were combined, washed with brine (15.0 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to give (61) (0.105 g, 18 %) as a white solid. Example 4.70: Synthesis of 3-cyclopropyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (62) In a sealed tube 10 - 20 mL with a stir bar was charged (3.24) (1.000 g, 3.32 mmol, 1.0 eq.), NMP (5.9 mL) and corresponding amine (5.87 mL, 49.88 mmol, 15.0 eq.). The vial was sealed and then put on heating block 18 h at 180 °C. After cooling, the mixture was poured onto saturated NaHCO3 (50.0 mL), rinse the vial and adjust with water up to 100.0 mL then the mixture was stirred 10 min. The resulting precipitate was filtered off, washed with water up to neutral pH, change the flask and washed the solid with EtOAc. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (62) (0.160 g, 14 %) as a grey solid. Example 4.71: Synthesis of 3-cyclobutyl-N6-(1-ethylpropyl)-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (63) In a sealed tube 10 - 20 mL with a stir bar was charged (3.25) (0.320 g, 1.02 mmol, 1.0 eq.), NMP (2.4 mL) and corresponding amine (2.39 mL, 20.33 mmol, 20.0 eq.). The vial was sealed and then put on heating block 21 h at 180 °C. After cooling, the mixture was poured onto saturated NaHCO3 (20.0 mL), rinse the vial and adjust with water up to 60.0 mL then the mixture was stirred 10 min. Aqueous mixture was extracted three times with EtOAc (3x15.0 mL) then organics layers were combined, washed with brine (15.0 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to give (63) (0.093 g, 25 %) as a white solid. Example 4.72: Synthesis of 3-cyclopentyl-N6-(1-ethylpropyl)-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (64) In a sealed tube 10 - 20 mL with a stir bar was charged (3.26) (0.500 g, 1.52 mmol, 1.0 eq.), NMP (3.6 mL) and corresponding amine (3.58 mL, 30.41 mmol, 20.0 eq.). The vial was sealed and then put on heating block 21 h at 180 °C. After cooling, the mixture was poured onto saturated NaHCO3 (20.0 mL), rinse the vial and adjust with water up to 60.0 mL then the mixture was stirred 10 min. The resulting precipitate was filtered off, washed with water up to neutral pH then the solid was taken up in DCM. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to give (64) (0.124 g, 21 %) as a white solid. Example 4.73: Synthesis of 3-cyclohexyl-N6-(1-ethylpropyl)-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (65) In a sealed tube 10 - 20 mL with a stir bar was charged (3.27) (0.600 g, 1.75 mmol, 1.0 eq.), NMP (3.9 mL), corresponding amine (3.91 mL, 33.25 mmol, 19.0 eq.). The vial was sealed and then put on heating block, 16 h at 180 °C. After cooling, the mixture was poured onto saturated NaHCO3 (20.0 mL), rinse the vial and adjust with water up to 80.0 mL then the mixture was stirred 10 min. The resulting precipitate was filtered off, washed with water up to neutral pH, the vacuum flask was changed then the solid was triturated and washed with EtOAc. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 97 / 7) as eluent to give (65) (0.110 g, 16 %) as a white solid. Example 4.74: Synthesis of N6-(1-ethylpropyl)-3-phenyl-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (66) In a sealed tube 10 - 20 mL with a stir bar was charged (3.28) (0.550 g, 1.63 mmol, 1.0 eq.), NMP (4.0 mL), corresponding amine (4.04 mL, 34.30 mmol, 21.0 eq.). The vial was sealed and then put on heating block, 20 h at 180 °C. After cooling, the mixture was poured onto saturated NaHCO3 (20.0 mL), rinse the vial and adjust with water up to 80.0 mL then the mixture was stirred 10 min. The resulting precipitate was filtered off, washed with water up to neutral pH, the vacuum flask was changed then the solid was triturated and washed with a mixture of DCM / MeOH (98 / 2). Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to give (66) (0.265 g, 42 %) as a white solid. Example 4.75: Synthesis of N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-3- sec-butyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (67) In a sealed tube 2 - 5 mL with a stir bar was charged (3.29) (0.100 g, 0.39 mmol, 1.0 eq.), mono ethylene glycol (1.0 mL) and 3-aminopentane (0.98 mL g, 8.29 mmol, 15.0 eq.) then the vial was sealed and put on heating block 16 h at 180 °C. After cooling, the reaction mixture was poured onto saturated NaHCO3 (10.0 mL), the resulting precipitate was triturated, filtered, washed with water up to neutral pH and taken up in EtOAc. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to (67) (0.047 g, 23 %) as a white solid. Example 4.76: Synthesis of N6,3-bis(1-ethylpropyl)-N8-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (68) In a sealed tube 2 - 5 mL with a stir bar was charged (3.30) (0.200 g, 0.61 mmol, 1.0 eq.), mono ethylene glycol (1.0 mL) and 3-aminopentane (1.07 mL, 9.07 mmol, 15.0 eq.) then the vial was sealed and put on heating block 19 h at 180 °C. After cooling, the reaction mixture was poured onto cold water (30.0 mL), stirred 5 min then the resulting precipitate was filtered off, washed with cold water up to neutral pH and taken up in DCM. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 94 / 6) as eluent to (68) (0.085 g, 37 %) as a white solid. Example 4.77: Synthesis of N6-(1-ethylpropyl)-3-isobutyl-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (69) In a sealed tube 2 - 5 mL with a stir bar was charged (3.31) (0.250 g, 0.79 mmol, 1.0 eq.), NMP (1.9 mL) and 3-aminopentane (1.86 mL g, 15.78 mmol, 20.0 eq.) then the vial was sealed and put on heating block 15 h at 180 °C. After cooling, the reaction mixture was poured onto saturated NaHCO3 (30.0 mL) then aqueous mixture was extracted with EtOAc (3x20.0 mL). Organics layers were combined, washed with brine (40.0 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 94 / 6) as eluent to (69) (0.065 g, 22 %) as a white solid. Example 4.78: Synthesis of N6-(1-ethylpropyl)-3-(2-pyridyl)-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (70) In a sealed tube 2 - 5 mL with a stir bar was charged (3.32) (0.200 g, 0.59 mmol, 1.0 eq.), mono ethylene glycol (1.0 mL) and 3-aminopentane (1.05 mL, 8.88 mmol, 15.0 eq.) then the vial was sealed and put on heating block 19 h at 180 °C. After cooling, the reaction mixture was poured onto cold water (30.0 mL) then aqueous mixture was extracted with 2- MeTHF (3x15.0 mL). Orgnics layers were combined, washed with brine (20.0 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3 to 90 / 10) as eluent to (70) (0.070 g, 30 %) as a white solid. Example 4.79: Synthesis of N6-(1-ethylpropyl)-3-(3-pyridyl)-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (71) In a sealed tube 2 - 5 mL with a stir bar was charged (3.33) (0.200 g, 0.59 mmol, 1.0 eq.), mono ethylene glycol (1.0 mL) and 3-aminopentane (1.05 mL, 8.88 mmol, 15.0 eq.) then the vial was sealed and put on heating block 19 h at 180 °C. After cooling, the reaction mixture was poured onto cold water (30.0 mL), stirred 5 min then the resulting precipitate was filtered off, washed with cold water up to neutral pH and taken up in DCM. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3 to 93 / 7) as eluent to (71) (0.086 g, 37 %) as a grey solid. Example 4.80: Synthesis of N6-(1-ethylpropyl)-3-(4-pyridyl)-N8-(2- pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (72) In a sealed tube 2 - 5 mL with a stir bar was charged (3.34) (0.200 g, 0.59 mmol, 1.0 eq.), mono ethylene glycol (1.0 mL) and 3-aminopentane (1.05 mL, 8.88 mmol, 15.0 eq.) then the vial was sealed and put on heating block 19 h at 180 °C. After cooling, the reaction mixture was poured onto cold water (30.0 mL), stirred 5 min then the resulting precipitate was filtered off, washed with cold water up to neutral pH and taken up in DCM. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3 to 93 / 7) as eluent to (72) (0.160 g, 70 %) as a beige solid. Example 4.81: Synthesis of (2R)-2-[[8-[(4-aminophenyl)methylamino]-3- isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butan-1-ol (74) In a sealed tube 10-20 mL with a stir bar was charged (3.35) (0.400 g, 1.26 mmol, 1.0 eq.), NMP (3.0 mL) and corresponding amine (3.04 mL, 31.57 mmol, 25.0 eq.). The vial was sealed and then put on heating block 17.5 h at 180 °C. After cooling, the mixture was poured onto water (100.0 mL), aqueous layer was extracted with EtOAc (3 x 30.0 mL) then organic layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3 to 90 / 10) as eluent to give (74) (0.100 g, 21 %) as a white solid. Example 4.82: Synthesis of N8-[(4-aminophenyl)methyl]-N6-(1- ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (75) In a sealed tube 2 - 5 mL with a stir bar was charged (3.35) (0.100 g, 0.32 mmol, 1.0 eq.), NMP (0.3 mL) and corresponding amine (0.55 mL, 4.74 mmol, 15.0 eq.) then the vial was sealed and put on heating block 22 h at 180 °C. After cooling, the mixture was diluted in DCM (5.0 mL), Si2O was added to make solid deposit then purfied by flash chromatography with DCM / MeOH (99 / 1 to 95 / 5) as eluent to give (75) (0.020 g, 17 %) as a white solid. Example 4.83: Synthesis of N8-[(3-aminophenyl)methyl]-N6-(1- ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (76) In a sealed tube 2 - 5 mL with a stir bar was charged (3.36) (0.190 g, 0.60 mmol, 1.0 eq.), NMP (1.0 mL) and corresponding amine (0.71 mL, 6.00 mmol, 10.0 eq.) then the vial was sealed and put on heating block 22 h at 170 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL) and organic layer was washed three times with a mixture brine / water (3 / 1, 3x10 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 95 / 5) as eluent to give (76) (0.020 g, 9 %) as a light brown solid. Example 4.84: Synthesis of N8-[(2-aminophenyl)methyl]-N6-(1- ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (77) In a sealed tube 2 - 5 mL with a stir bar was charged (3.37) (0.200 g, 0.63 mmol, 1.0 eq.), NMP (1.4 mL) and corresponding amine (0.74 mL, 6.31 mmol, 10.0 eq.) then the vial was sealed and put on heating block 19 h at 170 °C. After cooling, the mixture was diluted in EtOAc (25.0 mL) and organic layer was washed three times with a mixture brine / water (3 / 1, 3 x 20.0 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3 to 92 / 8) as eluent to give (77) (0.021 g, 14 %) as a light brown solid. Example 4.85: Synthesis of N6-(1-ethylpropyl)-N8-(1H-indol-2-ylmethyl)- 3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (78) In a sealed tube 2 - 5 mL with a stir bar was charged (3.41) (0.150 g, 0.42 mmol, 1.0 eq.) and pentan-3-amine (1.48 mL, 12.54 mmol, 30.0 eq.). The vial was sealed and then put on heating block 21 h at 160 °C. After cooling, the mixture was poured into cold water (10 mL), the precipitate was filtered off, washed with water, dried under vacuum. The solid was taken up in EtOAc, the organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (97 / 3) as eluent to give (78) (0.015 g, 9 %) as a beige solid. Example 4.86: Synthesis of N-(1-ethylpropyl)-8-isoindolin-2-yl-3- isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (79) In a sealed tube 2 - 5 mL with a stir bar was charged (3.39) (0.150 g, 0.48 mmol, 1.0 eq.), NMP (1.5 mL) and corresponding amine (0.45 mL, 3.82 mmol, 8.0 eq.) then the vial was sealed and put on heating block 65 h at 170 °C. After cooling, the mixture was diluted in EtOAc then organic layer was washed three times with a mixture of brine / water (3 / 1, 3x10.0 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 96 / 4) as eluent to give the title compound (79) (0.065 g, 37 %) as a beige solid. Example 4.87: Synthesis of 8-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(1- ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (80) In a sealed tube 2 - 5 mL with a stir bar was charged (3.38) (0.150 g, 0.46 mmol, 1.0 eq.), NMP (1.0 mL), corresponding amine (0.54 mL, 4.58 mmol, 10.0 eq.). The vial was sealed and then put on heating block 17 h at 170 °C. The reaction mixture was diluted in EtOAc (20.0 mL) then the organic layer was washed with a mixture of brine / saturated NaHCO3 (3 / 1, 3 x 10.0 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (80) (0.033 g, 33 %) as light brown oil. Example 4.88: Synthesis of N6-(1-ethylpropyl)-N8-indan-1-yl-3- isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (81) In a sealed tube 2 - 5 mL with a stir bar was charged (3.40) (0.200 g, 0.61 mmol, 1.0 eq.), NMP (1.0 mL), corresponding amine (0.72 mL, 6.10 mmol, 10.0 eq.). The vial was sealed and then put on heating block, 16 h at 170 °C. The reaction mixture was poured onto cold water (30.0 mL), the mixture was stirred 5 min then the precipitate was filtered off, washed with water and taken up in EtOAc. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 92 / 8) as eluent to give (81) (0.025 g, 11 %) as a beige solid. Example 4.89: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-(2- phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (82) In a sealed tube 2 - 5 mL with a stir bar was charged (3.43) (0.240 g, 0.76 mmol, 1.0 eq.) in ethylene glycol (0.9 mL), corresponding amine (0.89 mL, 7.60 mmol, 10.0 eq.) was added then the tube was sealed and put on heating block 21 h at 180 °C. After cooling, the mixture was solublized in a mixture of DCM / MeOH (9 / 1) then concentrated with silica and directly purified by flash chromatography with DCM / MeOH (99 / 1 to 94 / 6) to give (82) (0.060 g, 22 %) as a white amorphous solid. Example 4.90: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-[2-(2- pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (83) In a sealed tube 2 - 5 mL with a stir bar was charged (3.44) (0.250 g, 0.79 mmol, 1.0 eq.), ethylene glycol (1.5 mL) and 3-aminopentane (1.39 mL, 11.84 mmol, 15.0 eq.). The vial was sealed and put on heating bloc 18 h at 170 °C. After cooling, the mixture was poured onto cold water (30.0 mL), stirred 5 min then the precipitate was filtered off and washed with cold water. On an other flask, the solid was washed with EtOAc, organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (83) (0.045 g, 16 %) as a white solid. Example 4.91: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-[2-(3- pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (84) In a sealed tube 2 - 5 mL with a stir bar was charged (3.45) (0.235 g, 0.74 mmol, 1.0 eq.), ethylene glycol (1.5 mL) and 3-aminopentane (1.31 mL, 11.13 mmol, 15.0 eq.). The vial was sealed and put on heating bloc 16 h at 170 °C. After cooling, the mixture was poured onto cold water (15.0 mL), stirred 5 min then the precipitate was filtered off, washed with cold water and taken up in DCM. Aqueous filtrate was extracted with DCM (10.0 mL) then organics layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (84) (0.063 g, 23 %) as a white solid. Example 4.92: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-[2-(4- pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (85) In a sealed tube 2 - 5 mL with a stir bar was charged (3.46) (0.255 g, 0.81 mmol, 1.0 eq.), ethylene glycol (1.5 mL) and 3-aminopentane (1.42 mL, 12.07 mmol, 15.0 eq.). The vial was sealed and put on heating bloc 16 h at 170 °C. After cooling, the mixture was poured onto cold water (15.0 mL), stirred 5 min then the precipitate was filtered off, washed with cold water and taken up in DCM. Aqueous filtrate was extracted with DCM (10.0 mL) then organics layers were combined, dried over MgSO4, filtered, concentrated and purified by flash chromatography with DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (85) (0.048 g, 16 %) as a white solid. Example 4.93: Synthesis of 3-cyclopropyl-N6-(1-ethylpropyl)-N8-[2-(2- pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (86) In a sealed tube 2 - 5 mL with a stir bar was charged (3.47) (0.110 g, 0.35 mmol, 1.0 eq.), NMP (1.0 mL) and 3-aminopentane (0.41 mL, 3.50 mmol, 10.0 eq.) was added then the vial was sealed and put on heating bloc 17 h at 180 °C. After cooling, the mixture was poured onto cold water (20.0 mL) and brine (30.0 mL) then the resulting precipitate was filtered off, washed with water and taken up in EtOAc. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography wth DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (86) (0.020 g, 16 %) as a white solid. Example 4.94: Synthesis of 3-cyclopropyl-N6-(1-ethylpropyl)-N8-[2-(3- pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (87) In a sealed tube 2 - 5 mL with a stir bar was charged (3.48) (0.110 g, 0.35 mmol, 1.0 eq.), NMP (1.0 mL) and 3-aminopentane (0.41 mL, 3.50 mmol, 10.0 eq.) was added then the vial was sealed and put on heating bloc 17 h at 180 °C. After cooling, the mixture was poured onto cold water (20.0 mL) and brine (30.0 mL) then the resulting precipitate was filtered off, washed with water and taken up in EtOAc. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography wth DCM / MeOH (97 / 3 to 92 / 8) as eluent to give (87) (0.030 g, 23 %) as a beige solid. Example 4.95: Synthesis of 3-cyclopropyl-N6-(1-ethylpropyl)-N8-[2-(4- pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (88) In a sealed tube 2 - 5 mL with a stir bar was charged (3.49) (0.110 g, 0.35 mmol, 1.0 eq.), NMP (1.0 mL) and 3-aminopentane (0.41 mL, 3.50 mmol, 10.0 eq.) was added then the vial was sealed and put on heating bloc 17 h at 180 °C. After cooling, the mixture was poured onto cold water (20.0 mL) and brine (30.0 mL) then the resulting precipitate was filtered off, washed with water and taken up in EtOAc. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography wth DCM / MeOH (97 / 3 to 92 / 8) as eluent to give (88) (0.039 g, 31 %) as a white solid. Example 4.96: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-[3-(2- pyridyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (89) In a sealed tube 2 - 5 mL with a stir bar was charged (3.50) (0.100 g, 0.30 mmol, 1.0 eq.), NMP (0.9 mL) and 3-aminopentane (0.36 mL, 3.02 mmol, 10.0 eq.) was added then the vial was sealed and put on heating bloc 64 h at 170 °C. After cooling, the mixture was poured onto cold water (30.0 mL) then aqueous layer was extracted with EtOAc (3x 15.0 mL). Oganic layers were combined, washed with brine (10.0 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography wth DCM / MeOH (98 / 2 to 92 / 8) as eluent to give (89) (0.040 g, 35 %) as a beige solid. Example 4.97: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-[3-(3- pyridyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (90) In a sealed tube 2 - 5 mL with a stir bar was charged (3.51) (0.180 g, 0.54 mmol, 1.0 eq.), NMP (0.5 mL) and 3-aminopentane (0.64 mL, 5.44 mmol, 10.0 eq.) was added then the vial was sealed and put on heating bloc 17 h at 170 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL), organic layer was washed with a mixture brine / water (3 / 1, 3x10.0 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography wth DCM / MeOH (98 / 2 to 92 / 8) as eluent to give (90) (0.018 g, 9 %) as a white solid. Example 4.98: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-[3-(4- pyridyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (91) In a sealed tube 2 - 5 mL with a stir bar was charged (3.52) (0.200 g, 0.61 mmol, 1.0 eq.), NMP (0.6 mL) and 3-aminopentane (0.71 mL, 6.05 mmol, 10.0 eq.) was added then the vial was sealed and put on heating bloc 17 h at 170 °C. After cooling, the mixture was diluted in EtOAc (20.0 mL), organic layer was washed with a mixture brine / water (3 / 1, 3x10.0 mL), dried over MgSO4, filtered, concentrated and purified by flash chromatography wth DCM / MeOH (98 / 2 to 92 / 8) as eluent to give (91) (0.030 g, 13 %) as a beige solid. Example 4.99: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrimidin- 2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (92) In a sealed tube 2 - 5 mL with a stir bar was charged (3.54) (0.070 g, 0.23 mmol, 1.0 eq.), ethylene glycol (0.5 mL) and 3-aminopentane (0.41 mL, 3.46 mmol, 15.0 eq.) was added then the vial was sealed and put on heating bloc 17 h at 180 °C. After cooling, the mixture was diluted in DCM, concentrated then the crude was triturated in saturated NaHCO3 (10.0 mL). The solid was filtered off, washed with water up to neutral pH, taken up in EtOAc then organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography wth DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (92) (0.022 g, 27 %) as a white solid. Example 4.100: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8- (pyrimidin-5-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (93) In a sealed tube 2 - 5 mL with a stir bar was charged (3.56) (0.080 g, 0.26 mmol, 1.0 eq.), ethylene glycol (0.5 mL) and 3-aminopentane (0.46 mL, 3.95 mmol, 15.0 eq.) was added then the vial was sealed and put on heating bloc 17 h at 180 °C. After cooling, the mixture was diluted in DCM, concentrated then the crude was triturated in saturated NaHCO3(10.0 mL). The solid was filtered off, washed with water up to neutral pH, taken up in EtOAc then organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography wth DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (93) (0.010 g, 11 %) as a white solid. Example 4.101: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrazin- 2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (94) In a sealed tube 2 - 5 mL with a stir bar was charged (3.55) (0.080 g, 0.26 mmol, 1.0 eq.), ethylene glycol (0.8 mL) and 3-aminopentane (0.62 mL, 5.27 mmol, 20.0 eq.) was added then the vial was sealed and put on heating bloc 18 h at 180 °C. After cooling, saturated NaHCO3 (5.0 mL) was added and the mixture was vigorously stirred 5 min, the precipitate was filtered off, washed with water up to neutral pH and taken up in DCM. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography wth DCM / MeOH (98 / 2 to 94 / 6) as eluent to give (94) (0.032 g, 34 %) as a white solid. Example 4.102: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8- (pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (95) In a sealed tube 2 - 5 mL with a stir bar was charged (3.57) (0.270 g, 0.89 mmol, 1.0 eq.), ethylene glycol (2.0 mL) and 3-aminopentane (1.57 mL, 13.33 mmol, 15.0 eq.) was added then the vial was sealed and put on heating bloc 18 h at 170 °C. After cooling, the mixture was poured onto cold water (20.0 mL) and brine (30.0 mL) then the resulting precipitate was filtered off, washed with water and taken up in DCM. Organic filtrate was dried over MgSO4, filtered, concentrated and purified by flash chromatography wth DCM / MeOH (98 / 2 to 93 / 7) as eluent to give (95) (0.045 g, 14 %) as a white solid. Example 4.103: Synthesis of N8-benzyl-N6-cyclobutyl-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (117) Reaction carried out in NMP (0.2M) on a 232 µmol scale of (3.1), with 5.0 eq. cyclobutylamine at 180 °C for 6h. Purification by TLC Prep (DCM / MeOH gradient) gives (117) with 6 % yield as a beige solid. Example 4.104: Synthesis of N8-benzyl-N6-cyclopentyl-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (118) Reaction carried out in NMP (0.2M) on a 232 µmol scale of (3.1), with 5.0 eq. of cyclopentylamine at 180 °C for 6h15. Purification by flash chromatography (DCM / MeOH gradient) gives (118) with 40 % yield as a beige solid. Example 4.105: Synthesis of N8-benzyl-N6-cyclohexyl-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (119) Reaction carried out in NMP (0.2M) on a 232 µmol scale of (3.1), with 5.0 eq. of cyclohexylamine at 180 °C for 45h. Purification by flash chromatography (DCM / MeOH gradient) gives (119) with 45 % yield as a beige solid. Example 4.106: Synthesis of N8-benzyl-3-isopropyl-N6-(4- methoxycyclohexyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (120) Reaction carried out in NMP (0.2M) on a 232 µmol scale of (3.1), with 5.0 eq. of 4- methoxycyclohexanamine at 200 °C for 16h. Purification by flash chromatography (DCM / MeOH gradient) gives (120) with 37 % yield as a beige solid. Example 4.107: Synthesis of N8-benzyl-N6-cycloheptyl-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (121) Reaction carried out in NMP (0.2M) on a 232 µmol scale of (3.1), with 5.0 eq. of cycloheptylamine at 200 °C for 45h. Purification by flash chromatography (DCM / MeOH gradient) gives (121) with 22 % yield as a white solid. Example 4.108: Synthesis of N8-benzyl-N6-(cyclopropylmethyl)-3- isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (122) Reaction carried out in NMP (0.2M) on a 232 µmol scale of (3.1), with 5.0 eq. aminomethylcyclopropane at 180 °C for 16h. Purification by TLC Prep (DCM / MeOH gradient) gives (122) with 22 % yield as a beige solid. Example 4.109: Synthesis of N8-benzyl-N6-(cyclopropylmethyl)-3- isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (123) Reaction carried out in NMP (0.2M) on a 232 µmol scale of (3.1), with 5.0 e...

Claims

CLAIMS 1. A compound of formula (I) or any of its pharmaceutically acceptable saltwherein R1represents a hydrogen atom or a (C1-C6)alkyl group; R2represents a hydrogen atom; R3represents - a linear or branched (C1-C6)alkyl group, substituted by • one phenyl group, optionally substituted by at least one substituent selected from a -OR7group, a -NH2group, a halogen atom, a phenyl group and a (C5-C6)heteroaryl group, • one (C6-C10)heteroaryl group, or • one -OR7group, - a phenyl group or a phenyl group fused with a (C4-C6)cycloalkyl group; or - a (C5-C6)heteroaryl group, optionally substituted by one to three substituents selected from a (C1-C4)alkyl group, a deuterated (C1-C4)alkyl group, a (C1-C4)alkoxy group, a deuterated (C1-C4)alkoxy group and a halogen atom, in particular a fluorine atom or a chlorine atom; L represents a bond or a -CO- group; or alternately L is a bond and R2and R3form together with the nitrogen atom bearing them a (C5-C6)heterocycloalkyl group containing at least a nitrogen atom fused with a phenyl group; R4represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, a (C3- C6)cycloalkyl group, a (C1-C4)alkoxy group, a (C5-C6)heterocyclocalkyl group, a phenyl group, a (C5-C6)heteroaryl group or a -CF3 group; R5represents a hydrogen atom or a (C1-C4)alkyl group; R6represents- a linear or branched (C1-C8)alkyl group, optionally interrupted by one or two oxygen atoms and optionally substituted by • one phenyl group, optionally substituted by one or two substituents selected from a (C1-C4)alkyl group and a (C1-C4)alkoxy group, • one (C3-C8)cycloalkyl group, optionally substituted by one or two substituents selected from a halogen atom, a (C1-C4)alkyl group and a -OR7group, • one (C5-C6)heterocycloalkyl, • one (C5-C6)heteroaryl group, optionally substituted by one or two (C1-C6)alkyl group, • one or two -OR7groups, • one -SR7group, • one -C(O)NR8R9group, • one -C(O)OR10group, or • one -NHR11group, - a (C3-C7)cycloalkyl group, optionally substituted by one or two substituents selected from a halogen atom, a (C1-C4)alkyl group and a -OR7group, - one bridged (C6-C10)cycloalkyl group, - one spiro(C5-C11)bicyclic ring, - a (C5-C6)heteroaryl group, - a (C5-C6)heterocycloalkyl group, or - a phenyl group fused with a (C4-C6)cycloalkyl group; or R5and R6form together with the nitrogen atom bearing them a (C5-C6)heterocycloalkyl group; R7represents a hydrogen atom, a (C1-C4)alkyl group or a deuterated (C1-C4)alkyl group; R8and R9independently represent a hydrogen atom or a (C1-C6)alkyl group; R10represents a (C1-C4)alkyl group; and R11represents a hydrogen atom or a -CO-(C1-C6)alkyl group; provided that when NR2LR3represents a benzylamino group, then R4does not represent a hydrogen atom.

2. The compound of formula (I) or any of its pharmaceutically acceptable salt as defined in claim 1, wherein R1represents a hydrogen atom or a methyl group.

3. The compound of formula (I) or any of its pharmaceutically acceptable salt, as defined in claim 1 or 2, wherein R2represents a hydrogen atom; R3represents - a linear or branched (C1-C6)alkyl group, substituted by • one phenyl group, optionally substituted by one substituent selected from a hydroxy group, a methoxy group, an amino group, a halogen atom, a phenyl group and a pyridyl group, • one pyridyl, one pyrazinyl, one pyrimidinyl or one pyridazinyl group, in particular one pyridyl, pyridazinyl or pyrimidinyl group, or one indolyl or isoindolyl group, in particular an indolyl group, • one hydroxy group, • one methoxy group, one deuterated methoxy group, or • a halogen atom, in particular a fluorine atom or a chlorine atom, - a phenyl group or an indanyl group, or - a pyridyl, a pyrazinyl, a pyrimidinyl or a pyridazinyl group, optionally substituted by one methoxy group or deuterated methoxy group, in particular a pyridyl group; L represents a bond or a -CO- group; or alternately L is a bond and R2and R3form together with the nitrogen atom bearing them an indolinyl, an isoindolinyl, a tetrahydroquinolinyl or a tetrahydroisoquinolinyl group, in particular an isoindolinyl or a tetrahydroisoquinolinyl group.

4. The compound of formula (I) or any of its pharmaceutically acceptable salt, as defined in any claim 1 to 3, wherein R4represents a hydrogen atom, a linear or branched (C1-C5)alkyl group, a (C3-C6)cycloalkyl group, a phenyl group, a pyridyl group or a -CF3group.

5. The compound of formula (I) or any of its pharmaceutically acceptable salt, as defined in any claim 1 to 4, whereinR5represents a hydrogen atom or a (C1-C4) alkyl group, in particular a methyl group; R6represents - a linear or branched (C1-C8)alkyl group, optionally interrupted by one or two oxygen atoms and optionally substituted by • one phenyl group, optionally substituted by one or two substituents selected from a methyl group and a methoxy group, • one (C3-C6)cycloalkyl group, optionally substituted by a methyl group, • one tetrahydropyranyl or one tetrahydrofuranyl group, • one pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridyl, furanyl or thienyl group, optionally substituted by one or two methyl group, • one or two hydroxy group or methoxy group, • one methylthio group, • one -CONH2 group, one –CONHCH3 group or one -CON(CH3)2 group, • one -COOCH3or one -COOCH2CH3group, or • one -NH2 group or one -NCOCH3 group, - a (C3-C7)cycloalkyl group, optionally substituted by one or two substituents selected from a halogen atom, a hydroxy group or a methoxy group, - an adamantyl group, - a spiro[3.3]heptanyl group, - an imidazolyl group, optionally substituted by one or two methyl group, - a morpholinyl group, a tetrahydropyranyl or a tetrahydrofuranyl group, or - an indanyl group; or R5and R6form together with the nitrogen atom bearing them a morpholinyl group or a piperidinyl group.

6. A compound, or any of its pharmaceutically acceptable salt, selected from (1) (2R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (2) (2S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (3) 2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propane-1,3-diol,(4) (2R,3R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butane-1,3-diol, (5) (2S,3S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butane-1,3-diol, (6) N-benzyl-3-isopropyl-6-morpholino-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (7) (2S)-3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propane-1,2-diol, (8) N6-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N8-benzyl-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (9) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propan-1-ol, (10) N8-benzyl-3-isopropyl-N6-(3-methoxypropyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (11) 2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]ethanol, (12) N8-benzyl-3-isopropyl-N6-(2-methoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (13) 4-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (14) N8-benzyl-3-isopropyl-N6-(4-methoxybutyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (15) 5-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]pentan-1-ol, (16) N8-benzyl-3-isopropyl-N6-(5-methoxypentyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (17) N8-benzyl-3-isopropyl-N6-(3-methylsulfanylpropyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (18) N8-benzyl-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (19) N8-benzyl-3-isopropyl-N6-[(3R)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (20) N8-benzyl-3-cyclopentyl-N6-[(3R)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (21) N8-benzyl-3-isopropyl-N6-[(3R)-tetrahydropyran-3-yl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (22) N8-benzyl-3-isopropyl-N6-[(3S)-tetrahydropyran-3-yl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (23) N8-benzyl-3-isopropyl-N6-tetrahydropyran-4-yl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (24) N-[3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propyl]acetamide, (25) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propanamide, (26) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]-N- methyl-propanamide, (27) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]- N,N-dimethyl-propanamide, (28) Methyl 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propanoate, (29) ethyl 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]propanoate, (30) (2R)-2-[[8-(benzylamino)-3-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (31) N8-benzyl-3-cyclopropyl-N6-(3-methoxypropyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (32) N8-benzyl-N6-(3-methoxypropyl)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (33) (2R)-2-[[8-(benzylamino)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (34) N8-benzyl-N6-(3-methoxypropyl)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (35) (2R)-2-[[8-(benzylamino)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (36) N8-benzyl-N6-(3-methoxypropyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (37) (2R)-2-[[8-(benzylamino)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (38) 2-[[[6-[[(1R)-1-(hydroxymethyl)propyl]amino]-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazin-8-yl]amino]methyl]phenol, (39) 2-[[[3-isopropyl-6-(3-methoxypropylamino)-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]amino]methyl]phenol, (40) 2-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]amino]methyl]phenol, (41) 3-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]amino]methyl]phenol, (42) 4-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]amino]methyl]phenol, (43) 2-[[[3-isopropyl-6-[[(3R)-tetrahydropyran-3-yl]amino]-[1,2,4]triazolo[4,3- b]pyridazin-8-yl]amino]methyl]phenol, (44) 2-[[[3-isopropyl-6-(tetrahydropyran-4-ylamino)-[1,2,4]triazolo[4,3-b]pyridazin- 8-yl]amino]methyl]phenol, (45) N6-(1-ethylpropyl)-3-isopropyl-N8-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (46) N6-(1-ethylpropyl)-3-isopropyl-N8-(2-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (47) N6-(1-ethylpropyl)-3-isopropyl-N8-(3-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (48) N6-(1-ethylpropyl)-3-isopropyl-N8-(4-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (49) N6-(1-ethylpropyl)-3-isopropyl-N8-(4-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (50) N6-(1-ethylpropyl)-3-isopropyl-N8-(3-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (51) N6-(1-ethylpropyl)-3-isopropyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (52) N6-tert-butyl-3-isopropyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (53) 3-isopropyl-N8-(2-pyridylmethyl)-N6-spiro[3.3]heptan-2-yl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (54) N6-(3,3-difluorocyclobutyl)-3-isopropyl-N8-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (55) N6-(4,4-difluorocyclohexyl)-3-isopropyl-N8-(2-pyridylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (56) N6-benzyl-3-isopropyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (57) N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (58) N6-(1-ethylpropyl)-3-methyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (59) 3-ethyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (60) N6-(1-ethylpropyl)-3-propyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (61) 3-tert-butyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (62) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (63) 3-cyclobutyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (64) 3-cyclopentyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (65) 3-cyclohexyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (66) N6-(1-ethylpropyl)-3-phenyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (67) N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-3-sec-butyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (68) N6,3-bis(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (69) N6-(1-ethylpropyl)-3-isobutyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (70) N6-(1-ethylpropyl)-3-(2-pyridyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (71) N6-(1-ethylpropyl)-3-(3-pyridyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (72) N6-(1-ethylpropyl)-3-(4-pyridyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (73) N6-(1-ethylpropyl)-3-isopropyl-N8-[(2-methoxyphenyl)methyl]- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (74) (2R)-2-[[8-[(4-aminophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (75) N8-[(4-aminophenyl)methyl]-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (76) N8-[(3-aminophenyl)methyl]-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (77) N8-[(2-aminophenyl)methyl]-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (78) N6-(1-ethylpropyl)-N8-(1H-indol-2-ylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (79) N-(1-ethylpropyl)-8-isoindolin-2-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin- 6-amine, (80) 8-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(1-ethylpropyl)-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-6-amine, (81) N6-(1-ethylpropyl)-N8-indan-1-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (82) N6-(1-ethylpropyl)-3-isopropyl-N8-(2-phenylethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (83) N6-(1-ethylpropyl)-3-isopropyl-N8-[2-(2-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (84) N6-(1-ethylpropyl)-3-isopropyl-N8-[2-(3-pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (85) N6-(1-ethylpropyl)-3-isopropyl-N8-[2-(4-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (86) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-[2-(2-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (87) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-[2-(3-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (88) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-[2-(4-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (89) N6-(1-ethylpropyl)-3-isopropyl-N8-[3-(2-pyridyl)propyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (90) N6-(1-ethylpropyl)-3-isopropyl-N8-[3-(3-pyridyl)propyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (91) N6-(1-ethylpropyl)-3-isopropyl-N8-[3-(4-pyridyl)propyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine (92) N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrimidin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (93) N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrimidin-5-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (94) N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrazin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (95) N6-(1-ethylpropyl)-3-isopropyl-N8-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (96) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]benzamide, (97) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]pyridine-2-carboxamide, (98) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2- phenyl-acetamide, (99) ethyl N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8- yl]carbamate, (100) phenyl N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]carbamate, (101) (2S)-2-[[8-[(4-bromophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (102) (2S)-2-[[3-isopropyl-8-[(4-phenylphenyl)methylamino]-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (103) (2S)-2-[[3-isopropyl-8-[[4-(4-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (104) (2S)-2-[[3-isopropyl-8-[[4-(3-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (105) (2S)-2-[[3-isopropyl-8-[[4-(2-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (106) (2R,3R)-2-[[8-[(4-bromophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butane-1,3-diol, (107) (2R,3R)-2-[[3-isopropyl-8-[[4-(2-pyridyl)phenyl]methylamino]- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butane-1,3-diol, (108) (2R,3R)-2-[[3-isopropyl-8-[[4-(4-pyridyl)phenyl]methylamino]- [1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butane-1,3-diol, (109) N6,N8-bis(3-methoxypropyl)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (110) 3-cyclopropyl-N6,N8-bis(3-methoxypropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (111) N6,N8-bis(3-methoxypropyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (112) 3-isopropyl-N6,N8-bis(2-methoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (113) (2R)-2-[[6-[[(1R)-1-(hydroxymethyl)propyl]amino]-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]butan-1-ol, (114) N6,N8-bis(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (115) (2R)-2-[[8-(benzylamino)-3-isopropyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazin- 6-yl]amino]butan-1-ol, (116) N8-[(4-bromophenyl)methyl]-3-isopropyl-N6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (117) N8-benzyl-N6-cyclobutyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (118) N8-benzyl-N6-cyclopentyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (119) N8-benzyl-N6-cyclohexyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (120) N8-benzyl-3-isopropyl-N6-(4-methoxycyclohexyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (121) N8-benzyl-N6-cycloheptyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (122) N8-benzyl-N6-(cyclopropylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (123) N8-benzyl-N6-(cyclobutylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (124) N8-benzyl-N6-(cyclohexylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (125) N8-benzyl-3-isopropyl-N6-(tetrahydropyran-4-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (126) N8-benzyl-N6-(2-ethylbutyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (127) N8-benzyl-3-isopropyl-N6-(2-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (128) N8-benzyl-3-isopropyl-N6-(2-phenoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (129) N8-benzyl-3-isopropyl-N6-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (130) N6,N8-dibenzyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (131) N8-benzyl-3-isopropyl-N6-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (132) N8-benzyl-3-isopropyl-N6-(3-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine,(133) N8-benzyl-3-isopropyl-N6-(4-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (134) racemic trans-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]cyclohexanol, (135) racemic trans-4-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]cyclohexanol, (136) N8-benzyl-3-isopropyl-N6-[(1-methylcyclohexyl)methyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (137) N6-(1-adamantyl)-N8-benzyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (138) N8-benzyl-N6-indan-2-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (139) N8-benzyl-3-isopropyl-N6-[(5-methylpyrazin-2-yl)methyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (140) N8-benzyl-3-isopropyl-N6-[(1-methylpyrazol-4-yl)methyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (141) N8-benzyl-N6-[(3,5-dimethylphenyl)methyl]-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (142) N8-benzyl-3-isopropyl-N6-(tetrahydrofuran-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (143) N8-benzyl-3-isopropyl-N6-(2-methylsulfanylethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (144) N8-benzyl-3-isopropyl-N6-(1-methylimidazol-2-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (145) N8-benzyl-N6-[(4,6-dimethylpyrimidin-2-yl)methyl]-3-isopropyl- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (146) N8-benzyl-N6-indan-1-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8- diamine, (147) N6-(2-ethylbutyl)-3-isopropyl-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (148) 3-isopropyl-N6-(pentan-3-yl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine,(149) 3-isopropyl-N6-(pentan-3-yl)-N8-(pyridazin-4-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (150) 3-isopropyl-N6-(pentan-3-yl)-N8-(pyrimidin-4-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (151) 3-isopropyl-N6-(pentan-3-yl)-N8-(pyrimidin-5-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (152) 3-isopropyl-N6-(pentan-3-yl)-N8-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (153) 3-isopropyl-N6-(pentan-3-yl)-N8-(pyrazin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (154) 3-isopropyl-N8-(6-methoxypyridin-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (155) 3-isopropyl-N8-(5-methoxypyridin-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (156) 3-isopropyl-N8-(4-methoxypyridin-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (157) 3-isopropyl-N8-(3-methoxypyridin-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (158) 3-isopropyl-N8-(2-methoxypyridin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (159) 3-isopropyl-N8-(6-methoxypyridin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (160) isopropyl-N8-(5-methoxypyridin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (161) 3-isopropyl-N8-(4-methoxypyridin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (162) 3-isopropyl-N8-(5-methoxypyridazin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (163) (2R)-2-[[3-isopropyl-8-(2-pyridylamino)-[1,2,4]triazolo[4,3-b]pyridazin-6- yl]amino]butan-1-ol, (164) N6-(2-ethylbutyl)-3-isopropyl-N8-[2-(2-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine,(165) N6-cyclopentyl-3-isopropyl-N8-[2-(2-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (166) N6-(2-ethylbutyl)-3-isopropyl-N8-[2-(3-pyridyl)ethyl]-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (167) N6,N8-bis(2-ethylbutyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (168) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2- (3-pyridyl)acetamide, (169) (2R)-2-[[3-isopropyl-8-(2-pyridylmethylamino)imidazo[1,2-b]pyridazin-6- yl]amino]butan-1-ol, (170) N6-(1-ethylpropyl)-3-isopropyl-N8-(3-phenylpropyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (171) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-phenyl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (172) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-(2-pyridyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (173) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-(3-pyridyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (174) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-(4-pyridyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (175) 3-cyclopropyl-N6-(pentan-3-yl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (176) 3-cyclopropyl-N6-(pentan-3-yl)-N8-(pyridazin-4-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (177) 3-cyclopropyl-N6-(pentan-3-yl)-N8-(pyrimidin-4-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (178) 3-cyclopropyl-N6-(1-ethylpropyl)-N8-pyrimidin-5-yl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (179) 3-cyclopropyl-N6-(pentan-3-yl)-N8-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (180) 3-cyclopropyl-N6-(pentan-3-yl)-N8-(pyrazin-2-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (181) (R)-2-((3-cyclopropyl-8-(pyridazin-3-ylamino)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino)butan-1-ol, (182) (S)-2-((3-cyclopropyl-8-(pyridazin-3-ylamino)-[1,2,4]triazolo[4,3-b]pyridazin-6- yl)amino)butan-1-ol, (183) 3-cyclopropyl-N8-(6-methoxypyridin-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (184) 3-cyclopropyl-N8-(2-methoxypyridin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (185) (2R)-2-[[3-cyclopropyl-8-[2-(2-pyridyl)ethylamino]-[1,2,4]triazolo[4,3- b]pyridazin-6-yl]amino]butan-1-ol, (186) N6-benzyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (187) 3-cyclopropyl-N6-(4-methoxybenzyl)-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (188) 3-cyclopropyl-N6-(4-methoxybenzyl)-N6-methyl-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (189) 3-cyclopropyl-N6-ethyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (190) 3-cyclopropyl-N6-propyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (191) N6-butyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (192) 3-cyclopropyl-N6-isopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (193) N6-(sec-butyl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (194) 3-cyclopropyl-N6-isobutyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (195) N6-(tert-butyl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (196) 3-cyclopropyl-N6-(2-ethylbutyl)-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (197) N6,3-dicyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (198) N6-cyclobutyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (199) N6-cyclopentyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (200) N6-cyclohexyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (201) N6-cycloheptyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (202) N6-((3s,5s,7s)-adamantan-1-yl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (203) 3-cyclopropyl-N6-(cyclopropylmethyl)-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (204) N6-(cyclobutylmethyl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (205) 3-cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(spiro[3.3]heptan-2-yl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (206) 3-cyclopropyl-N6-((1-methylcyclobutyl)methyl)-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (207) 3-cyclopropyl-6-(1-piperidyl)-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3- b]pyridazin-8-amine, (208) 3-cyclopropyl-N6-(furan-2-ylmethyl)-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (209) 3-cyclopropyl-N6-(furan-3-ylmethyl)-N8-(pyridin-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (210) 3-cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(thiophen-2-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (211) (R)-2-((3-cyclopropyl-8-((pyridin-2-ylmethyl)amino)-[1,2,4]triazolo[4,3- b]pyridazin-6-yl)amino)butan-1-ol, (212) (S)-2-((3-cyclopropyl-8-((pyridin-2-ylmethyl)amino)-[1,2,4]triazolo[4,3- b]pyridazin-6-yl)amino)butan-1-ol, (213) (R)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(tetrahydrofuran -3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (214) (R)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(tetrahydro-2H-pyran-3-yl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (215) 3-cyclopropyl-N8-(6-methoxypyridazin-3-yl)-N6-(pentan-3-yl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (216) 3-cyclopropyl-N6-(pentan-3-yl)-N8-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (217) 3-cyclopropyl-N6-(pentan-3-yl)-N8-phenethyl-[1,2,4]triazolo[4,3-b]pyridazine- 6,8-diamine, (218) 3-cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(thiophen-3-ylmethyl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (219) 3-cyclopropyl-N6-methyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (220) 3-cyclopropyl-N-(pyridin-2-ylmethyl)-6-(pyrrolidin-1-yl)-[1,2,4]triazolo[4,3- b]pyridazin-8-amine, (221) 3-isopropyl-N8-(2-methoxypyrimidin-4-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (222) 3-isopropyl-N8-(5-methoxypyrimidin-4-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (223) 3-isopropyl-N8-(6-methoxypyrimidin-4-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (224) 3-isopropyl-N8-(6-methoxypyridazin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (225) 3-cyclopropyl-N6-(2-ethylbutyl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (226) 3-cyclopropyl-N6-(2-ethylbutyl)-N8-(6-methoxypyridazin-3-yl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (227) N8-(6-chloropyridazin-3-yl)-3-isopropyl-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (228) N8-(2-chloropyrimidin-4-yl)-3-isopropyl-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (229) N6-(2-ethylbutyl)-3-isopropyl-N8-(6-methoxypyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (230) N6-(3-ethylpentyl)-3-isopropyl-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (231) 3-isopropyl-N8-(6-(methoxy-d3)pyridazin-3-yl)-N6-(pentan-3-yl)- [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (232) N8-(6-chloropyridazin-3-yl)-N6-(2-ethylbutyl)-3-isopropyl-[1,2,4]triazolo[4,3- b]pyridazine-6,8-diamine, (233) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2- (2-pyridyl)acetamide, (234) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2- (4-pyridyl)acetamide, in particular selected from compounds (1), (2), (10), (13), (14), (17) to (19), (21) to (23), (26), (28), (29), (31), (35) to (56), (58) to (64), (66) to (69), (71) to (78), (80) to (105), (107), (110), (111), (114), (117) to (119), (121) to (124), (126), (127), (130) to (132), (134), (136), (138), (140), (143), (146) to (160), (162) to (187), (189) to (206), (208) to (212), (215) to (218), (221) and (223) to (234) and their pharmaceutically acceptable salts, more particularly from compounds (18), (38), (40) to (42), (45) to (53), (56), (59), (62), (63), (67), (68), (73), (75), (76), (80), (82) to (88), (90), (91), (93) to (95), (98) to (100), (114), (118), (126), (130), (147) to (151), (153) to (156), (158) to (160), (162), (164) to (168), (170) to (178), (180) to (183), (186), (187), (191) to (193), (195), (196), (198) to (202), (204) to (206), (208) to (210), (215) to (218), (221) and (223) to (234) and their pharmaceutically acceptable salts, and even more particularly from compounds (46), (47), (83), (86), (87), (98), (147), (148), (150), (151), (153) to (155), (158), (159), (162), (164), (168), (171) to (175), (177), (178), (180) to (183), (215), (221), (223) to (232) and (234) and their pharmaceutically acceptable salts.

7. Synthesis process for manufacturing a compound of formula (I) as defined in anyone of claim 1 to 5 or any of its pharmaceutically acceptable salts, or at least any of compounds (1) to (234) as defined in claim 6 or any of their pharmaceutically acceptable salts, comprising at least a step of reacting a compound of formula (II)wherein L, R2, R3and R4are as defined in anyone of claim 1, 3 or 4, with an amine of formula (IV) NHR5R6(IV) wherein R5and R6are as defined in claim 1 or 5, for example in a molar ratio ranging from 1 to 20 eq, with respect to the compound of formula (II), in an aprotic solvent or without solvent or else in a protic solvent.

8. Synthesis process for manufacturing a compound of formula (I) as defined in anyone of claim 1 to 5 or any of its pharmaceutically acceptable salts, or at least any of compounds (1) to (234) as defined in claim 6 or any of their pharmaceutically acceptable salts, comprising at least a step of reacting a compound of formula (IX)wherein R4, R5and R6are as defined in claim 1, 4 and 5, with a compound of formula (VI) (VI) wherein R2and R3are as defined in claim 1 or 3, in an aprotic solvent, for example in a molar ratio ranging from 1 to 10 eq, with respect to the compound of formula (IX).

9. Synthesis process for manufacturing a compound of formula (I) as defined in anyone of claim 1 to 5 or any of its pharmaceutically acceptable salts, or at least any of compounds (1) to (234) as defined in claim 6 or any of their pharmaceutically acceptable salts, comprising at least a step of reacting a compound of formula (XII)e as defined in claim 1 or 5, with a compound of formula (XIV)wherein L and R3are as defined in claim 1 or 3 and X represents a hydroxy group, a chlorine atom, a bromine atom, an (C1-C3)alkyl sulfonate group or a phenyl sulfonate group, in an aprotic solvent for example in a molar ratio ranging from 1 to 10 eq, with respect to the compound of formula (XII).

10. A compound of formula (II), (X), (XI) or (VII), in particular as an intermediate compoundwherein L, R2, R3, R4, R5and R6are as defined in claims 1, 3, 4 or 5, provided that R4is not a methyl group in formula (XI).

11. A compound of formula (I) as defined in anyone of claim 1 to 5 or any of its pharmaceutically acceptable salts, or at least any of compounds (1) to (234) as defined in claim 6 or any of their pharmaceutically acceptable salts, for use as a medicament.

12. A compound of formula (I) as defined in anyone of claim 1 to 5 or any of its pharmaceutically acceptable salts, or at least any of compounds (1) to (234) as defined in claim 6 or any of their pharmaceutically acceptable salts, for use in the prevention and / or the treatment of ulcerative colitis, atopic dermatitis, glaucoma, asthma, liver fibrosis, kidney diseases, atherosclerosis, hypercholestemia, hearing loss and cancers developing under hypoxic conditions, in particular glioblastoma.

13. A compound for use as defined in claim 12, wherein the hearing loss is a partial or a complete hearing loss, in particular being induced by noise, acoustic trauma or ototoxic agents or conditions, more particularly platin-based anticancer drugs such as cisplatin or carboplatin, antibiotics, even more particularly macrolides or aminoglycosides such as gentamycin or neomycin, drugs for COVID-19 such as lopinavir or ritonavir, antimalarial drugs such as quinine or chloroquine, cardiovascular drugs such as loop diuretics, non- steroidal anti-inflammatory drugs such as salicylate or cyclodextrins, erectile dysfunction drugs such as phosphodiesterase type 5 inhibitors.

14. A compound for use as defined in claim 12, wherein the kidney disease is selected from kidney fibrosis, nephropathy, acute kidney injury, chronic kidney disease in particular induced by ischemia and / or reperfusion injury, toxic nephropathy or myoglobinuria, and diabetic kidney disease, or the kidney disease is induced by nephrotoxicity caused by therapeutic drugs, more particularly cytotoxic agents, such as platin-based anticancer drugs for example cisplatin or carboplatin.

15. A pharmaceutical composition comprising at least one compound of formula (I) as defined in anyone of claim 1 to 5 or any of its pharmaceutically acceptable salt, or at least any of compounds (1) to (234) as defined in claim 6 or any of their pharmaceutically acceptable salts.

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