[1,2,4]-Triazolo[4,3-b]pyridazine derivatives useful as pharmaceuticals

Abstract

The present invention relates to either the compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention further relates to a synthesis method for producing either the compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising, at least, the compound of formula (II) in a non-protic solvent, without a solvent, or in a protic solvent, and the amine of formula (IV) in a molar ratio of 1 to 20 equivalents relative to the compound of formula (II), for example, NHR 5 R 6 This invention relates to a synthesis method that includes a step of reacting with [a specific substance]. JPEG2026521175000180.jpg44170

Description

[Technical Field]

[0001] The present invention relates to [1,2,4]-triazolo[4,3-b]pyridazine derivatives useful for treating adenosine A3 receptor (A3AR)-mediated pathologies. The present invention further relates to methods for producing them and pharmaceutical compositions containing them. [Background technology]

[0002] Adenosine is a G protein-coupled receptor (GPCR) of four types, as described by IJzerman, AP et al., International Union of Basic and Clinical Pharmacology, CXII: Adenosine Receptors: A Further Update, Pharmacol Rev 2022, 74(2), 340-372: adenosine receptor (AR): A1AR, A 2A AR, A 2B AR interacts with A3AR. 2A While augmented reality (AR) is the most extensively studied, A3AR is the least studied form of AR.

[0003] As described in IJzerman, AP et al., International Union of Basic and Clinical Pharmacology, CXII: Adenosine Receptors: A Further Update, Pharmacol Rev 2022, 74, 340-372, and Jacobson, KA et al., Medicinal Chemistry of P2 and Adenosine Receptors: Common Scaffolds Adapted for Multiple Targets, Biochem Pharmacol 2021, 187, 114311, numerous subtype-specific AR agonists and antagonists have been developed over the past few decades and evaluated in clinical trials for numerous indications. Approved AR drugs include the A1 AR agonist adenosine (paroxysmal supraventricular tachycardia), A 2A Legadenoson (used for myocardial blood flow imaging), an AR agonist, and vamifilin (asthma), an A1AR antagonist. 2A Istradefylline (Parkinson's disease) is an AR antagonist.

[0004] A3AR (P0DMS8) (a gene located on human chromosome 1 (1p13.2); consisting of 318 amino acids in humans) was discovered in the early 1990s, as described by Borea, PA et al., The A3 Adenosine Receptor: History and Perspectives, Pharmacol Rev 2015, 67, 74-102. A3AR, coupled with the Gi protein, inhibits adenylyl cyclase, and, when bound with the Go protein, activates phospholipase C and Ca ++ It leads to release. A3AR is also coupled with the PI3K / Akt, MAPK, and NF-κB signaling pathways. The biodistribution of A3AR is quite species-dependent. In humans, A3AR is expressed in cells of the lungs, liver, kidneys, pancreas, brain, testes, and immune system. A3AR knockout mice have been created to investigate the function of A3AR. - / -The mice are viable, fertile, and morphologically indistinguishable from wild-type mice, suggesting that inhibition of this receptor is unlikely to result in significant toxicity.

[0005] A1AR, A 2A AR and A 2B ARs are well conserved through evolution, but there are significant differences between rodent and human A3AR sequences (sequence identity between human A3AR and rat or mouse A3AR is 72% and 73%, respectively). Many human A3AR antagonists are very low or even inactive against rat and mouse orthologs. This complicates bridging studies on the actions of A3AR agonists and antagonists in rodent models of human diseases. A3AR-humanized (A3AR h / h ) and human / mouse chimeric A3AR (A3AR c / c ) mice have been constructed.

[0006] In cerebral ischemia, A3AR can play both a protective role by inhibiting excitatory synaptic transmission in synergy with A 1A R and a harmful effect by supporting excitotoxicity. A3AR agonists can control pain signaling, especially in the case of anticancer drug-induced neuropathic pain. A3AR is overexpressed in some tumors and has anti-proliferative and pro-proliferative effects. A3AR agonists and antagonists exhibit antitumor activity. A3AR appears to play an important role in the regulation of inflammation by adenosine. Therefore, A3AR agonists have been evaluated in clinical trials for treating various inflammatory diseases such as knee osteoarthritis, asthma, and pulmonary fibrosis. A3AR agonists have been investigated for the induction of hypothermia and potential cardioprotective activity, but deletion of A3AR appears to confer some resistance to myocardial ischemic injury.

[0007] Several potent and selective A3AR agonists have been described, including piclidensone (IB-MECA, N 6Piclidenosine (CF101, Can-Fite BioPharma) and namodenosone (2-Cl-IB-MECA, CF102) are leading drug candidates. Piclidenosone is in clinical trials for rheumatoid arthritis and psoriasis, and namodenosone is in clinical trials for hepatocellular carcinoma and non-alcoholic steatohepatitis (NASH).

[0008] Several A3AR antagonists are also listed, such as KF2677, PSB-10, DPTN (N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazole-2-yl]nicotinamide), MRS1523, SSR161421, LJ-1888, pyrazolo-triazolo-pyrimidine, ISVY-130 analogues, 2-chloro-N6-phenylethyladenosine as described by Borea, PA et al., and 7-amino-pyrazolo[3,4-d]pyridazine 10a (dual A1 / A3AR antagonist) as described by Gao, Z.-G. et al. in Species Dependence of A3 Adenosine Receptor Pharmacology and function, Purinergic Signal 2022, 1-28.

[0009] In prior art, only compounds PBF-677 and PBF-1650 (structure not disclosed) have entered clinical trials for ulcerative colitis (Phase 2) and atopic dermatitis (Phase 1), respectively (https: / / www.palobiofarma.com / pipeline-2 / ). A3AR antagonists are being evaluated for the treatment of glaucoma because they reduce intraocular pressure (IOP) in animal models of glaucoma. A3AR antagonists are being evaluated for the treatment of asthma, ulcerative colitis, hepatic fibrosis, renal diseases, particularly renal fibrosis, nephropathy, nephrotoxicity, atherosclerosis, and hypercholesterolemia. Adenosine-induced stimulation of A3AR contributes to the migration, invasiveness, and chemotherapy resistance of glioblastoma stem cell-like cells under hypoxic conditions, and possibly also contributes to other cancer types under hypoxic conditions. A3AR antagonists inhibit the proliferation of glioblastoma cell lines.

[0010] Hearing loss (HL) can result from exposure to ototoxic agents (e.g., platinum-based anticancer drugs or aminoglycoside antibiotics—more than 600 ototoxic agents have been listed, of which more than 200 are commercially available), noise, acoustic trauma (high-intensity noise), or aging. These attacks cause irreversible death of the hair cells in the ear located in the organ of Corti (cochlea). The function of these cells is to capture sound vibrations and convert them into nerve signals that are sent to the auditory structures in the brain. There is considerable interest in the development of otoprotective compounds.

[0011] Cisplatin is a highly effective anticancer drug widely used to treat cancer. Side effects of cisplatin include nephrotoxicity and ototoxicity. Cisplatin-induced ototoxicity occurs in 23–50% of adults and up to 60% of children. Elevated hearing threshold can occur in up to 100% of cancer patients treated with cisplatin. Hearing protection would allow the use of these highly effective drugs for life-threatening diseases with a reduced HL risk, thereby addressing a significantly unmet clinical need. Similarly, addressing cisplatin-induced nephrotoxicity would also be beneficial. The same applies to potent but HL-inducing antibiotics; ototoxicity has been observed in up to 47% of patients treated with gentamicin, and other products such as neomycin, tobramycin, and kanamycin. Noise-induced HL occurs when the ear is exposed to unsafe levels of sound. Industries where workers often experience noise exposure include agriculture, mining, construction, manufacturing and public works, transportation, and the military. Globally, approximately 1.1 billion teenagers and young adults are at risk of HL (Hypertoxicostomy) due to unsafe use of personal audio devices and exposure to harmful levels of sound in noisy entertainment venues. In all of these situations, external protective ear coverings are insufficient or unsuitable. Furthermore, A3R is present particularly in the rat cochlea and is primarily expressed in the organ of Corti (internal and external hair cells, Deiterus cells, Claudius cells, and columnar cells). In addition, adenosine plays a protective role in nephrotoxicity induced by various drug-active substances.In particular, Dewaeles et al., Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects, J. Clin. Invest. 2022, 132, e152924; 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. As described in 2016, 31, 1403-1412, there is available literature suggesting that A2AR and A3AR antagonists may have some protective effect in kidneys exposed to nephrotoxic agents. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] IJzerman, AP et al., International Union of Basic and Clinical Pharmacology, CXII: Adenosine Receptors: A Further Update, Pharmacol Rev 2022, 74(2), 340~372 [Non-Patent Document 2] Jacobson, KA et al. Medicinal Chemistry of P2 and Adenosine Receptors: Common Scaffolds Adapted for Multiple Targets, Biochem Pharmacol 2021, 187, 114311 [Non-Patent Document 3] Borea, PA et al., The A3 Adenosine Receptor: History and Perspectives, Pharmacol Rev 2015, 67, 74~102 [Non-Patent Document 4] Gao, Z.-G. et al. Species Dependence of A3 Adenosine Receptor Pharmacology and function, Purinegic Signal 2022, 1~28 [Non-Patent Document 5] Dewaeles et al., Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects, J. Clin. Invest. 2022, 132, e152924 [Non-Patent Document 6] 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 [Non-Patent Document 7] 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 [Non-Patent Document 8] "Ullmann's Encyclopedia of Industrial Chemistry, 6th edition" (Various editors, 1989-1998, Marcel Dekker) [Non-Patent Document 9] "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994, WILLIAMS & WILKINS) [Overview of the Initiative] [Problems that the invention aims to solve]

[0013] Therefore, there is a need to find therapeutic drugs that specifically target the inhibition of A3R. [Means for solving the problem]

[0014] Herein, it was found that the compound defined by formula (I) below is useful in the treatment and / or prevention of diseases mediated by A3R. [Brief explanation of the drawing]

[0015] [Figure 1] This figure shows two agonists and several reported antagonists of A3AR. [Figure 2] This figure shows the results of evaluating the potential agonist or antagonist activity of compound (175) against 168 GPCRs, as illustrated in Example 10.2. [Figure 3]This figure shows the results of a test evaluating the selectivity of compound (175) for various ARs, as illustrated in Example 10.3. [Figure 4] This figure shows the results of the A3AR functional assay illustrated in Example 10.3. [Figure 5] This figure shows the effect of compound (175) on ciliated cells of the organ of Corti in ex vivo cultured mice exposed to cisplatin (5A), gentamicin (5B), or neomycin (5C), as illustrated in Example 10.4. [Figure 6] This figure shows the effect of compound (175) on the antiproliferative activity of cisplatin, evaluated for various cancer cell lines exemplified in Example 10.5: A549 (human lung cancer) (Figure 6-A), PANC-1 (human pancreatic cancer) (Figure 6-B), and MDA-435 (human breast cancer) (Figure 6-C). [Figure 7] This figure shows the results of an antibiogram assay obtained with Pseudomonas aeruginosa PA-19660 without pre-incubation (A) or after incubation with vehicle (DMSO) (B) or compound (175) (C), as illustrated in Example 10.6 (G: gentamicin; K: kanamycin; N: neomycin; S: streptomycin; T: tobramycin and W: water). [Figure 8] This figure shows the diameter of the zone of inhibition determined for Pseudomonas aeruginosa PA-19660 (Figure 8 left) and Staphylococcus aureus Newman strain (Figure 8 right) that were pre-incubated with vehicle (0.1% DMSO), compound (175), or compound (147) before exposure to paper discs containing gentamicin, kanamycin, neomycin, streptomycin, or tobramycin, as illustrated in Example 10.6. [Modes for carrying out the invention]

[0016] definition As used herein, the term “patient” means either an animal, for example, an animal beneficial for breeding, companionship, or protection purposes, or preferably a human or human child, that is suffering from or may suffer from one or more of the diseases and conditions described herein.

[0017] In particular, as used in this application, the term “patient” refers to a mammal, such as a rodent, cat, dog, primate, or human, and preferably the subject is a human.

[0018] Identifying patients requiring treatment for the diseases and conditions described herein is well within the capabilities and knowledge of those skilled in the art. Veterinarians or physicians skilled in the art can easily identify patients requiring such treatment by using clinical trials, physical examinations, medical / family history, or biological and diagnostic tests.

[0019] In the context of the present invention, the terms “to treat” or “treatment” as used herein mean to prevent, improve, alleviate, inhibit, or prevent the progression of any of the diseases described below in the “Pathology” paragraph.

[0020] Therefore, within the framework of the present invention, the terms “to treat” or “treatment” encompass the improvement of the medical condition of a patient suffering from a disease mediated by the A3AR receptor, as described below in the “pathology” paragraph.

[0021] As used herein, “A3AR inhibitor” or “A3AR antagonist” refers to a compound capable of inhibiting A3AR in the assay shown in Example 10.1 of the bioactivity section described below. In one embodiment, IC from a compound of formula (I) according to the present invention 50 The value may be 1000nM or less, particularly 100nM or less, even more particularly 10nM or less, and even more particularly 1nM or less, the IC 50 All values ​​demonstrate the inhibitory activity of the compound.

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

[0023] The term “control” is intended to refer to all processes in which there may be a slowing, interruption, inhibition, or cessation of the progression of the diseases and conditions described herein, but not necessarily the complete elimination of the symptoms of all diseases and conditions, and is intended to include preventive measures.

[0024] The term "effective dose" includes "preventive effective dose" and "treatment effective dose."

[0025] When used herein, the term "prevent" means reducing the risk of onset of a given phenomenon, i.e., in the present invention, a disease mediated by ADORA3, or delaying its onset.

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

[0027] The term "preventive effective dose" refers to the concentration of the compound of the present invention that is effective in inhibiting, preventing, or reducing the likelihood of any one of the above-mentioned diseases.

[0028] Similarly, the term "effective dose" refers to the concentration of a compound that is effective in treating the aforementioned diseases.

[0029] As used herein, the term “pharmaceutically acceptable” means a compound, material, excipient, composition or dosage form that is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problematic complications, within the bounds of sound medical judgment, commensurate with a reasonable benefit-risk ratio.

[0030] Detailed description of the invention To our surprise, the inventors have found that the compound of formula (I), disclosed below, provides inhibitory activity against A3AR.

[0031] This claim is based on the data illustrated in the following examples and further detailed below.

[0032] Either the compound of formula (I) or one of its pharmaceutically acceptable salts.

[0033] [ka]

[0034] (In the formula, R 1 represents a hydrogen atom or an (C1-C6) alkyl group; R 2 represents a hydrogen atom; R 3 teeth, - Linear or branched (C1-C6) alkyl groups ·-OR 7 One phenyl group, optionally substituted with at least one substituent selected from a group, an -NH2 group, a halogen atom, a phenyl group, and a (C5-C6) heteroaryl group. · One (C6~C 10 ) Heteroaryl group, or · One-OR 7 base Linear or branched (C1-C6) alkyl groups optionally substituted; - A phenyl group or a phenyl group condensed with a (C4-C6) cycloalkyl group; or - (C5-C6) heteroaryl groups optionally substituted with 1 to 3 substituents selected from (C1-C4) alkyl groups, deuterated (C1-C4) alkyl groups, (C1-C4) alkoxy groups, deuterated (C1-C4) alkoxy groups, and halogen atoms, particularly fluorine or chlorine atoms. It represents; L represents a bond, a -CO- group, or a -C(O)O- group; Alternatively, L is conjugation, and R2 and R 3 These, together with the nitrogen atoms having them, form a (C5-C6) heterocycloalkyl group containing at least one nitrogen atom, condensed with a phenyl group; R 4 represents a hydrogen atom, a linear or branched (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, a (C1-C4) alkoxy group, a (C5-C6) heterocycloalkyl group, a phenyl group, a (C5-C6) heteroaryl group, or a -CF3 group; R 5 represents a hydrogen atom or a (C1-C4) alkyl group; R 6 teeth, - A linear or branched (C1-C6) alkyl group optionally interrupted by one or two oxygen atoms, • One phenyl group optionally substituted with one or two substituents selected from (C1-C4) alkyl groups and (C1-C4) alkoxy groups. • Halogen atoms, (C1-C4) alkyl groups and -OR 7 A single (C3-C8) cycloalkyl group, optionally substituted with one or two substituents selected from the group. • One (C5-C6) heterocycloalkyl group, • One (C5-C6) heteroaryl group optionally substituted with one or two (C1-C6) alkyl groups, - One or two - OR 7 basis, · 1-SR 7 basis, • One -C(O)NR 8 R 9 basis, • One -C(O)OR 10 base, or • One-NHR 11 base Linear or branched (C1-C6) alkyl groups that are optionally substituted, - Halogen atoms, (C1~C4) alkyl groups and -OR 7(C3-C7) cycloalkyl groups optionally substituted with one or two substituents selected from the group. - One bridge (C6~C 10 ) Cycloalkyl groups, - One spiro (C5~C 11 ) bicyclic ring, - (C5~C6) heteroaryl group, - (C5~C6) heterocycloalkyl groups, or - Phenyl group condensed with (C4~C6) cycloalkyl group It represents; or R 5 and R 6 These, together with the nitrogen atoms containing them, form (C5-C6) heterocycloalkyl groups; R 7 represents a hydrogen atom, a (C1-C4) alkyl group, or a deuterated (C1-C4) alkyl group; R 8 and R 9 '' independently represents a hydrogen atom or a (C1-C6) alkyl group; R 10 represents an (C1-C4) alkyl group; R 11 represents a hydrogen atom or a -CO-(C1~C6) alkyl group; However, NR 2 LR 3 When R represents a benzylamino group, 4 (This does not represent a hydrogen atom.) Further details are provided herein.

[0035] According to the first aspect, the subject of the present invention is any of the compounds of formula (I) or any pharmaceutically acceptable salt thereof.

[0036] [ka]

[0037] (In the formula, R 1 represents a hydrogen atom or an (C1-C6) alkyl group; R2 represents a hydrogen atom; R 3 teeth, - A linear or branched (C1-C6) alkyl group, ·-OR 7 One phenyl group, optionally substituted with at least one substituent selected from a group, an -NH2 group, a halogen atom, a phenyl group, and a (C5-C6) heteroaryl group. · One (C6~C 10 ) Heteroaryl group, or · One-OR 7 base Linear or branched (C1-C6) alkyl groups substituted with; - A phenyl group or a phenyl group condensed with a (C4-C6) cycloalkyl group; or - (C5-C6) heteroaryl groups optionally substituted with 1 to 3 substituents selected from (C1-C4) alkyl groups, deuterated (C1-C4) alkyl groups, (C1-C4) alkoxy groups, deuterated (C1-C4) alkoxy groups, and halogen atoms, particularly fluorine or chlorine atoms. It represents; L represents a bond or a -CO- group; Alternatively, L is conjugation, and R 2 and R 3 These, together with the nitrogen atoms having them, form a (C5-C6) heterocycloalkyl group containing at least one nitrogen atom, condensed with a phenyl group; R 4 represents a hydrogen atom, a linear or branched (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, a (C1-C4) alkoxy group, a (C5-C6) heterocycloalkyl group, a phenyl group, a (C5-C6) heteroaryl group, or a -CF3 group; R 5 represents a hydrogen atom or a (C1-C4) alkyl group; R 6 teeth, - A linear or branched (C1-C8) alkyl group optionally interrupted by one or two oxygen atoms, • One phenyl group optionally substituted with one or two substituents selected from (C1-C4) alkyl groups and (C1-C4) alkoxy groups. • Halogen atoms, (C1-C4) alkyl groups and -OR 7 A single (C3-C8) cycloalkyl group, optionally substituted with one or two substituents selected from the group. • One (C5-C6) heterocycloalkyl group, • One (C5-C6) heteroaryl group optionally substituted with one or two (C1-C6) alkyl groups, - One or two - OR 7 basis, · 1-SR 7 basis, • One -C(O)NR 8 R 9 basis, • One -C(O)OR 10 base, or • One-NHR 11 base Linear or branched (C1-C8) alkyl groups that are optionally substituted, - Halogen atoms, (C1~C4) alkyl groups and -OR 7 (C3-C7) cycloalkyl groups optionally substituted with one or two substituents selected from the group. - One bridge (C6~C 10 ) Cycloalkyl groups, - One spiro (C5~C 11 ) bicyclic ring, - (C5~C6) heteroaryl group, - (C5~C6) heterocycloalkyl groups, or - Phenyl group condensed with (C4~C6) cycloalkyl group It represents; or R 5 and R 6 These, together with the nitrogen atoms containing them, form (C5-C6) heterocycloalkyl groups; R 7 represents a hydrogen atom, a (C1-C4) alkyl group, or a deuterated (C1-C4) alkyl group; R 8 and R 9 '' independently represents a hydrogen atom or a (C1-C6) alkyl group; R 10 represents an (C1-C4) alkyl group; R 11 represents a hydrogen atom or a -CO-(C1~C6) alkyl group; However, NR 2 LR 3 When R represents a benzylamino group, 4 (This does not represent a hydrogen atom.) Regarding.

[0038] The inventors have surprisingly discovered that compounds of formula (I) provide specific inhibitory activity against adenosine receptor A3 (A3AR), and that some of them provide even more potent inhibitory activity.

[0039] According to another specific embodiment, R 1 Compounds of formula (I) as defined above are further provided herein, wherein is a hydrogen atom or a methyl group.

[0040] According to another specific embodiment, R 2 This represents a hydrogen atom; R 3 but, - A linear or branched (C1-C6) alkyl group, • One phenyl group optionally substituted with one substituent selected from a hydroxyl group, methoxy group, amino group, halogen atom, phenyl group, and pyridyl group. • One pyridyl, one pyrazinyl, one pyrimidinyl, or one pyridazinyl group, particularly one pyridyl, pyridazinyl, or pyrimidinyl group, or one indolyl or isoindolyl group, particularly an indolyl group, • One hydroxyl group, · One methoxy group, one deuterated methoxy group, or • Halogen atoms, especially fluorine atoms or chlorine atoms Linear or branched (C1-C6) alkyl groups substituted with; - Phenyl group or indanyl group; or - Pyridyl, pyrazinyl, pyrimidinyl, or pyridadinyl groups, particularly pyridyl groups, optionally substituted with one methoxy group or deuterated methoxy group. It represents; L represents a bond or a -CO- group; Alternatively, L is a bond, and R 2 and R 3 However, together with nitrogen atoms having them, they form indolinyl, isoindolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl groups, particularly isoindolinyl or tetrahydroisoquinolinyl groups. Compounds of formula (I) as defined above are further provided herein.

[0041] According to another specific embodiment, R 4 Compounds of formula (I) as defined above, which represent a hydrogen atom, a linear or branched (C1-C5) alkyl group, a (C3-C6) cycloalkyl group, a phenyl group, a pyridyl group, or a -CF3 group, are further provided herein.

[0042] According to another specific embodiment, R 5 However, it represents a hydrogen atom or a (C1-C4) alkyl group, especially a methyl group; R 6 but, - A linear or branched (C1-C8) alkyl group optionally interrupted by one or two oxygen atoms, • One phenyl group optionally substituted with one or two substituents selected from methyl and methoxy groups. • A single (C3-C6) cycloalkyl group optionally substituted with a methyl group. • One tetrahydropyranyl or one tetrahydrofuranyl group, • One pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridyl, furanyl, or thienyl group, optionally substituted with one or two methyl groups. • One or two hydroxyl or methoxy groups, • One methylthio group, • One -CONH2 group, one -CONHCH3 group, or one -CON(CH3)2 group, · One -COOCH3 or one -COOCH2CH3 group, • One -NH2 group or one -NCOCH3 group Linear or branched (C1-C8) alkyl groups that are optionally substituted, - (C3-C7) cycloalkyl groups optionally substituted with one or two substituents selected from halogen atoms, hydroxyl groups, or methoxy groups. - Adamantyl group, - Spiro[3.3]heptanyl group, - Imidazolyl groups optionally substituted with one or two methyl groups, - Morpholinyl group, tetrahydropyranyl or tetrahydrofuranyl group, - indanyl group It represents; or R 5 and R 6 However, together with nitrogen atoms that have them, they form a morpholinyl group or a piperidinyl group. Compounds of formula (I) as defined above are further provided herein.

[0043] Pharmaceutical compositions comprising a compound of formula (I) as defined below, or at least one of the compounds (1) to (234) as defined below, or any pharmaceutically acceptable salt thereof are further provided herein.

[0044] As illustrated in Example 10.1, the compound of formula (I) was tested as an A3AR antagonist. It was observed that the compound of formula (I) exerts inhibitory activity against A3AR and therefore may be useful in treating A3AR-mediated pathologies.

[0045] As illustrated in Example 10.2, the compound of formula (I) was tested against 168 GPCR receptors. Surprisingly, it was observed that the compound of formula (I) was active against only one of these receptors.

[0046] As illustrated in Example 10.3, the compound of formula (I) was used for selectivity testing against other adenosine receptors A1AR, A 2A AR and A 2B Further testing was conducted against AR. Surprisingly, it was observed that the compound of formula (I) was active only against A3AR. Furthermore, the compound of formula (I) was further tested in an A3AR functional assay. It was observed that the compound of formula (I) is an antagonist inhibitor of A3AR.

[0047] The exceptional and unexpected specificity and functionality highlighted in Examples 10.2 and 10.3 necessitate the development of potent and selective A3AR antagonists with clinical applications.

[0048] In other words, as illustrated in Examples 10.1, 10.2, and 10.3, the compounds of formula (I) are potent and selective A3AR antagonists.

[0049] Furthermore, the inventors have surprisingly found that the compounds of formula (I) exhibit protective activity against the inner ear hair cells of the organ of Corti exposed to ototoxic agents, particularly platinum-based anticancer drugs such as cisplatin, or antibiotic aminoglycosides such as gentamicin or neomycin. Typically, as exemplified in Example 10.4, the inventors have shown that the compounds of the present invention exhibit auditory protective activity against an ex vivo model (cultured organ of Corti) of auditory toxicity induced by ototoxic agents, particularly platinum-based anticancer drugs such as cisplatin, or antibiotic aminoglycosides such as gentamicin or neomycin.

[0050] Finally, as exemplified in Example 10.5, the compounds of formula (I), particularly compound (175), have a modest effect on the sensitivity of three cancer cell lines to cisplatin, and as exemplified in Example 10.6, it has been demonstrated that the compounds of formula (I) do not modify the sensitivity of bacterial strains, particularly Pseudomonas aeruginosa and Staphylococcus aureus, to antibiotics, particularly aminoglycosides, more particularly gentamicin, kanamycin, neomycin, streptomycin and tobramycin.

[0051] In the context of the present invention, - The term "halogen" is understood to mean chlorine, fluorine, bromine, or iodine, particularly denoting chlorine, fluorine or bromine.

[0052] - The term "(C1-C x )alkyl", as used herein, refers to a normal, secondary or tertiary monovalent saturated hydrocarbon group of C1-C x , for example, (C1-C8)alkyl. Examples include, 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.

[0053] - The term "(C1-C xThe term "alkoxy" as used herein means -O-(C1~C x )alkyl or -O-(C3~C x ) refers to the cycloalkyl portion (wherein alkyl and cycloalkyl are as defined above), for example, (C1-C6) alkoxy. Examples, but not limited to, include methoxy, ethoxy, 1-propoxy, 2-propoxy, cyclopropoxy, butoxy, tert-butoxy, and pentoxy.

[0054] - The term (C1-C4) alkylthio group, also called (C1-C4) alkylsulfanyl group: -S-alkyl group (wherein the alkyl group is as previously defined). Examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, linear, secondary or tertiary butylthio, isobutylthio, etc.

[0055] - The term "(C3-C8) cycloalkyl," as used herein, refers to a saturated or partially unsaturated, unsubstituted or substituted monocyclic saturated hydrocarbon having 3 to 8 carbon atoms. Examples of monocyclic rings, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0056] - “Cross-linked (C6~C 10 The term "cycloalkyl" group, as used herein, refers to a bicyclic or tricyclic compound in which the ring is cycloalkyl, the ring shares three or more atoms, and the crosslink contains at least one atom, e.g., 1, 2, or 3 atoms. Such a crosslinked cycloalkyl group may be substituted with one or more C1-C3 alkyl groups. Examples, but not limited to, include adamantyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, 6,6-dimethylbicyclo[3.1.1]heptyl, bicyclo[3.1.1]heptyl, and 1,6,6-trimethylbicyclo[3.1.1]heptyl.

[0057] - "Spiro (C5~C11 ) The term "bicyclic ring" refers to two rings connected through a definitive single common atom. Such spirobicyclic alkyls generally contain 5 to 11 carbon atoms and refer to a "spiro(C5-C 11 ) bicyclic alkyl group". Such spirobicyclic rings may be unsubstituted or substituted, particularly with at least one (C1-C3) alkyl group, such as methyl. Examples include, but are not limited to, spiro[3.3]heptanyl, spiro[2.5]octanyl, particularly spiro[3.3]heptanyl.

[0058] - The term "(C5-C6) heterocycloalkyl group" as used herein refers to a (C5-C6) cycloalkyl group in which one or two carbon atoms are replaced by a heteroatom, such as oxygen, nitrogen or sulfur, more particularly at least one nitrogen atom. Such heterocycloalkyl groups can be saturated or partially saturated and may be unsubstituted or substituted. Examples include, but are not limited to, piperazinyl, piperidinyl, pyrrolidinyl, aziridinyl, oxanyl, oxetanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxazolidinyl, oxepanyl, diazepanyl, dioxanyl and tetrahydrothiopyranyl, more particularly pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl or one tetrahydrofuranyl group.

[0059] - (C5-C 10The term heteroaryl group, as used herein, refers to a monocyclic aromatic or bicyclic group in which one to three carbon atoms are replaced by heteroatoms, such as nitrogen, oxygen, or sulfur. Examples of monocyclic aromatic rings of heteroaryl groups include, but are not limited to, (C5-C6) heteroaryl groups such as oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl, pyrazinyl, oxadiazolyl, furanil, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, and triazolyl. In the framework of the present invention, heteroaryls are preferably pyridyl, imidazolyl, pyrazinyl, furanil, thiazolyl, pyrazolyl, thiadiazolyl, pyridazinyl, and pyrimidinyl, particularly pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl. Examples of bicyclic aromatic rings of heteroaryl groups include indolyl, isoindolyl, indolinyl, isoindolinyl, quinolinyl, or isoquinolinyl.

[0060] - The term aromatic ring means that, according to Hückel's rule, the molecule has 4n+2 π electrons.

[0061] - The term "deuterated" refers to a group in which at least one hydrogen atom is replaced by a deuterium atom, for example, a hyperdeuterated group in which all hydrogen atoms are replaced by deuterium atoms. In other words, a deuterated group may be partially deuterated or completely deuterated. Examples of deuterated groups include, but are not limited to, deuterated (C1-C4) alkyl groups such as -CH2D, -CHD2, or -CD3. Other examples of deuterated groups include, but are not limited to, deuterated (C1-C4) alkoxy groups such as deuterated methoxy groups, for example, -OCH2D, -OCHD2, or -OCD3.

[0062] In the context of this invention, the terms "aromatic ring" and "heteroaryl" include all positional isomers.

[0063] The nomenclature of the following compounds (1) to (234) was created using ChemDraw® Professional v22.0.022, in accordance with the principles of the International Union of Pure and Applied Chemistry. To avoid confusion, the symbol "(±)" was added to indicate racemic mixtures; the prefixes "cis" and "trans" were also used to assign the relative stereochemistry of two adjacent chiral centers.

[0064] The following are specific compounds of the present invention: (1) (2R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]aminobutan-1-ol, (2) (2S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butan-1-ol, (3) 2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]propane-1,3-diol, (4) (2R,3R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butan-1,3-diol, (5) (2S,3S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butan-1,3-diol, (6) N-benzyl-3-isopropyl-6-morpholino-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (7) (2S)-3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-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]pyridazine-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]pyridazine-6-yl]aminoethanol, (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]pyridazine-6-yl]aminobutan-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]pyridazine-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]pyridazine-6-yl]aminopropyl]acetamide, (25) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]aminoamide, (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-dimethylpropanamide, (28) Methyl 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-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]pyridazine-6-yl]aminobutan-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]pyridazine-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]pyridazine-6-yl]aminobutan-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]pyridazine-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]aminomethyl]phenol, (39) 2-[[[3-isopropyl-6-(3-methoxypropylamino)-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]phenol, (40) 2-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]phenol, (41) 3-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]phenol, (42) 4-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]phenol, (43) 2-[[[3-isopropyl-6-[[(3R)-tetrahydropyran-3-yl]amino]-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]phenol, (44) 2-[[[3-isopropyl-6-(tetrahydropyran-4-ylamino)-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]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]pyridazine-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-indole-2-ylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (79) N-(1-ethylpropyl)-8-isoindorin-2-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-amine, (80) 8-(3,4-dihydro-1H-isoquinoline-2-yl)-N-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-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-(pyrimidine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (93) N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrimidine-5-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (94) N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrazine-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]pyridazin-6,8-diamine, (96) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]benzamide, (97) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]pyridine-2-carboxamide, (98) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2-phenylacetamide, (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]pyridazine-8-yl]carbamate, (101) (2S)-2-[[8-[(4-bromophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butan-1-ol, (102) (2S)-2-[[3-isopropyl-8-[(4-phenylphenyl)methylamino]-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]amino-1-ol, (103) (2S)-2-[[3-isopropyl-8-[[4-(4-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]amino-1-ol, (104) (2S)-2-[[3-isopropyl-8-[[4-(3-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]amino-1-ol, (105) (2S)-2-[[3-isopropyl-8-[[4-(2-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]amino-1-ol, (106) (2R,3R)-2-[[8-[(4-bromophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butan-1,3-diol, (107) (2R,3R)-2-[[3-isopropyl-8-[[4-(2-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butan-1,3-diol, (108) (2R,3R)-2-[[3-isopropyl-8-[[4-(4-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butan-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]pyridazine-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-methylimidazole-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]pyridazine-6-yl]amino]cyclohexanol, (135) Racemic trans-4-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-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-methylpyrazine-2-yl)methyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (140) N8-benzyl-3-isopropyl-N6-[(1-methylpyrazole-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-methylimidazole-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (145) N8-benzyl-N6-[(4,6-dimethylpyrimidine-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]pyridazin-6,8-diamine, (148) 3-Isopropyl-N6-(pentan-3-yl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (149) 3-Isopropyl-N6-(pentan-3-yl)-N8-(pyridazin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (150) 3-Isopropyl-N6-(pentan-3-yl)-N8-(pyrimidine-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (151) 3-Isopropyl-N6-(pentan-3-yl)-N8-(pyrimidine-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (152) 3-Isopropyl-N6-(pentan-3-yl)-N8-(pyrimidine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (153) 3-Isopropyl-N6-(pentan-3-yl)-N8-(pyrazine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (154) 3-Isopropyl-N8-(6-methoxypyridine-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (155) 3-Isopropyl-N8-(5-methoxypyridine-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (156) 3-Isopropyl-N8-(4-methoxypyridine-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (157) 3-Isopropyl-N8-(3-methoxypyridine-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (158) 3-Isopropyl-N8-(2-methoxypyridine-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (159) 3-Isopropyl-N8-(6-methoxypyridine-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (160) Isopropyl-N8-(5-methoxypyridine-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (161) 3-Isopropyl-N8-(4-methoxypyridine-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]pyridazin-6,8-diamine, (163) (2R)-2-[[3-isopropyl-8-(2-pyridylamino)-[1,2,4]triazolo[4,3-b]pyridazine-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]pyridazine-8-yl]-2-(3-pyridyl)acetamide, (169) (2R)-2-[[3-isopropyl-8-(2-pyridylmethylamino)imidazo[1,2-b]pyridazine-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]pyridazin-6,8-diamine, (176) 3-Cyclopropyl-N6-(pentan-3-yl)-N8-(pyridazin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (177) 3-Cyclopropyl-N6-(pentan-3-yl)-N8-(pyrimidine-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (178) 3-Cyclopropyl-N6-(1-ethylpropyl)-N8-pyrimidine-5-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (179) 3-Cyclopropyl-N6-(pentan-3-yl)-N8-(pyrimidine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (180) 3-Cyclopropyl-N6-(pentan-3-yl)-N8-(pyrazine-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-methoxypyridine-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (184) 3-Cyclopropyl-N8-(2-methoxypyridine-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]pyridazine-6-yl]amino]butan-1-ol, (186) N6-benzyl-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (187) 3-Cyclopropyl-N6-(4-Methoxybenzyl)-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]pyridazine-6,8-diamine, (188) 3-Cyclopropyl-N6-(4-Methoxybenzyl)-N6-methyl-N8-(Pyridine-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-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (191) N6-butyl-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (192) 3-Cyclopropyl-N6-Isopropyl-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]Pyridazine-6,8-diamine, (193) N6-(sec-butyl)-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (194) 3-Cyclopropyl-N6-Isobutyl-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]pyridazine-6,8-diamine, (195) N6-(tert-butyl)-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (196) 3-Cyclopropyl-N6-(2-ethylbutyl)-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (197) N6,3-dicyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (198) N6-Cyclobutyl-3-Cyclopropyl-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]Pyridazine-6,8-diamine, (199) N6-Cyclopentyl-3-Cyclopropyl-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]Pyridazine-6,8-diamine, (200) N6-Cyclohexyl-3-Cyclopropyl-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]Pyridazine-6,8-diamine, (201) N6-cycloheptyl-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (202) N6-((3s,5s,7s)-adamantan-1-yl)-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (203) 3-Cyclopropyl-N6-(Cyclopropylmethyl)-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]pyridazine-6,8-diamine, (204) N6-(cyclobutylmethyl)-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (205) 3-Cyclopropyl-N8-(pyridine-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-(pyridine-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]pyridazine-8-amine, (208) 3-Cyclopropyl-N6-(furan-2-ylmethyl)-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (209) 3-Cyclopropyl-N6-(furan-3-ylmethyl)-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (210) 3-Cyclopropyl-N8-(pyridine-2-ylmethyl)-N6-(thiophen-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (211) (R)-2-((3-cyclopropyl-8-((pyridine-2-ylmethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-6-yl)amino)butan-1-ol, (212) (S)-2-((3-cyclopropyl-8-((pyridine-2-ylmethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-6-yl)amino)butan-1-ol, (213) (R)-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-N6-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (214) (R)-3-cyclopropyl-N8-(pyridine-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]pyridazin-6,8-diamine, (216) 3-Cyclopropyl-N6-(pentan-3-yl)-N8-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-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-(pyridine-2-ylmethyl)-N6-(thiophene-3-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (219) 3-Cyclopropyl-N6-methyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (220) 3-Cyclopropyl-N-(pyridine-2-ylmethyl)-6-(pyrrolidine-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine, (221) 3-Isopropyl-N8-(2-methoxypyrimidine-4-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (222) 3-Isopropyl-N8-(5-methoxypyrimidine-4-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (223) 3-Isopropyl-N8-(6-methoxypyrimidine-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]pyridazin-6,8-diamine, (225) 3-Cyclopropyl-N6-(2-ethylbutyl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (226) 3-Cyclopropyl-N6-(2-ethylbutyl)-N8-(6-methoxypyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (227) N8-(6-chloropyridazine-3-yl)-3-isopropyl-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (228) N8-(2-chloropyrimidine-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]pyridazin-6,8-diamine, (230) N6-(3-ethylpentyl)-3-isopropyl-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (231) 3-Isopropyl-N8-(6-(methoxy-d3)pyridazin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (232) N8-(6-chloropyridazine-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.

[0065] Therefore, any one of the compounds (1) to (234) defined above, or any pharmaceutically acceptable salt thereof, is provided herein.

[0066] According to a more preferred embodiment of the present invention, the compound is compound (1), (2), (10), (13), (14), (17)~(19), (21)~(23), (26), (28), (29), (31), (35)~(56), (58)~(64), (66)~(69), (71)~(78), (80)~(105), (107), (110), (111), (114), (117)~(11 9) Selected from the group consisting of (121)-(124), (126), (127), (130)-(132), (134), (136), (138), (140), (143), (146)-(160), (162)-(187), (189)-(206), (208)-(212), (215)-(218), (221), and (223)-(234), as well as pharmaceutically acceptable salts thereof.

[0067] According to a more preferred embodiment of the present invention, the compound is compound (18), (38), (40)~(42), (45)~(53), (56), (59), (62), (63), (67), (68), (73), (75), (76), (80), (82)~(88), (90), (91), (93)~(95), (98)~(100), (114), (118), (126), (130), (147)~(151), (153)~ Selected from the group consisting of (156), (158)-(160), (162), (164)-(168), (170)-(178), (180)-(183), (186), (187), (191)-(193), (195), (196), (198)-(202), (204)-(206), (208)-(210), (215)-(218), (221), and (223)-(234), as well as pharmaceutically acceptable salts thereof.

[0068] In a more particularly preferred embodiment of the present invention, the compound is selected 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), as well as pharmaceutically acceptable salts thereof.

[0069] In another aspect, the subject matter of the present invention relates to any compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, or to at least one of compounds (1) to (234) or any pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0070] "The pharmaceutically acceptable salt" refers to salts formed from acid addition salts formed by inorganic acids (e.g., hydrochloric acid, hydrobromic acid), and salts formed from salts formed by organic acids (e.g., acetic acid, tartaric acid, succinic acid).

[0071] Suitable physiologically acceptable acid addition salts of the compound of formula (I) include hydrobromide, tartrate, hydrochloride, mesylate, succinate, and acetate.

[0072] The compound of formula (I), and any of compounds (1) to (234) or any pharmaceutically acceptable salt thereof, can form solvates or hydrates, and the present invention encompasses all such solvates and hydrates.

[0073] The terms "hydrate" and "solvate" simply mean that compound (I) according to the present invention may be in the form of a hydrate or solvate, that is, it may be bound or associated with one or more water or solvent molecules. This is simply a chemical characteristic of such compounds that can be applied to all organic compounds of this kind.

[0074] Compounds of formula (I) may contain one or more chiral carbon atoms. Therefore, they can exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and mixtures thereof, including racemic mixtures, are included within the scope of the present invention.

[0075] The compounds of the present invention can be prepared by conventional organic synthesis methods practiced by those skilled in the art. The general reaction sequences outlined below represent general methods useful for preparing the compounds of the present invention and are not intended to limit their scope or usefulness.

[0076] [Table 1A]

[0077] [Table 1B]

[0078] Compounds of general formula (I) can be prepared according to route 1 shown in scheme 1 below.

[0079] [ka]

[0080] According to Route 1, the synthesis of the compound according to the present invention is carried out by the amine of formula (IV) (wherein R 5 and R 6 Compounds of formula (II) (wherein L, R are defined above) 2 , R 3 and R 4The functionalization is based on the formula (as defined above). The compound of formula (II) can be placed in step 3a in an aprotic solvent such as Et3N, THF, 2-MeTHF, dioxane, cineole, or NMP, or a mixture thereof, or without a solvent, or in a protic solvent such as ethylene glycol. The amine of formula (IV) can be added, for example, in an amount of 1 to 20 equivalents, particularly in a molar ratio of 10 equivalents, relative to the compound of formula (II). The reaction mixture can be heated at a temperature between 150 and 180°C. Once the reaction is complete, the mixture can be returned to room temperature.

[0081] The compound of formula (II) can be placed in step 3b in an aprotic solvent such as Et3N, THF, 2-MeTHF, dioxane, cineole, or NMP, or a mixture thereof, or without a solvent, or in a protic solvent such as ethylene glycol. The amine of formula (IV') (wherein R' 6 A compound containing a -COOH group can be added, for example, in an amount of 1 to 20 equivalents, particularly in a molar ratio of 10 equivalents, relative to the compound of formula (II). The reaction mixture can be heated at a temperature between 150 and 180°C. Once the reaction is complete, the mixture can be returned to room temperature.

[0082] Step 3c can be carried out according to known procedures for obtaining the corresponding amide or ester compound of formula (I).

[0083] Compound (III) of formula (wherein L, R) in aprotic solvents such as dioxane 2 and R 3 The reaction (as defined above) yields the compound of formula (II) as defined above in step 2. A hydrazide of formula (V) can be added, for example, to the compound of formula (III) in an amount of 1 to 3 equivalents, particularly in a molar ratio of 1.2 equivalents. The resulting mixture can then be stirred under reflux or in a sealed tube at a temperature between 100°C and 115°C for, for example, 1 to 36 hours, particularly 16 hours.

[0084] In a non-protic solvent such as DCM, THF, 2-MeTHF, or dioxane, or mixtures thereof, the compound of formula (a) and the compound of formula (VI) (wherein L, R 2 and R 3 The reaction (as defined above) can be used in step 1 to obtain the compound of formula (III) as defined above. The reaction mixture can be stirred at room temperature or reflux temperature or in a sealed tube with DCM at 50°C for a period ranging from 1 to 24 hours, for example, 16 hours.

[0085] Alternatively, the compound of general formula (I) can be prepared according to route 2, as shown in scheme 2 below.

[0086] [ka]

[0087] According to Route 2, the synthesis of the compound according to the present invention is carried out by the amine of formula (IV) (wherein R 5 and R 6 Compounds of formula (II) (wherein L, R are defined above) 2 , R 3 , R 4 and R 5 The process is based on the functionalization of (as defined above). The compound of formula (II) can be placed in step 3 in an aprotic solvent such as Et3N, THF, 2-MeTHF, dioxane, cineole, or NMP, or a mixture thereof, or without a solvent, or in a protic solvent such as ethylene glycol. The amine of formula (IV) can be added, for example, in an amount of 1 to 20 equivalents, particularly in a molar ratio of 10 equivalents, relative to the compound of formula (II). The reaction mixture can be heated at a temperature between 150 and 180°C. Once the reaction is complete, the mixture can be returned to room temperature. The compound of formula (VII) (wherein R is used in the formula) can be placed in an aprotic solvent such as DCM, THF, or 2Me-THF. 4 The amine of formula (VI) (wherein L, R is defined above) 2 and R 3The reaction (as defined above) yields the compound of formula (II) as defined above in step 2. The amine of formula (VI) can be added, for example, to the compound of formula (VII) in an amount of 1 to 5 equivalents, particularly in a molar ratio of 1.2 equivalents. The resulting mixture can then be stirred at a temperature between room temperature and reflux for, for example, 1 to 24 hours, particularly 3 hours.

[0088] The compound of formula (b) and the compound of formula (VIII) (wherein R) in an aprotic solvent such as THF, 2-MeTHF, or dioxane. 4 The reaction (as defined above) yields the compound of formula (VII) as defined above in step 1. The reaction mixture can be stirred at room temperature for a period ranging from 1 to 24 hours, for example, 16 hours.

[0089] Alternatively, the compound of general formula (I) can be prepared according to route 3, as shown in scheme 3 below.

[0090] [ka]

[0091] According to Route 3, the synthesis of the compound according to the present invention is carried out by the amine of formula (VI) (wherein L, R 2 and R 3 Compounds of formula (IX) by the formula (wherein R is defined above) 4 , R 5 and R 6 The reaction is based on the functionalization of (as defined above). The compound of formula (IX) can be placed in step 5 in an aprotic solvent such as dioxane. The amine of formula (VI) can be added, for example, in an amount of 1 to 10 equivalents, particularly in a molar ratio of 6 equivalents, relative to the compound of formula (IX). The reaction mixture can be heated in a sealed tube at a temperature between 100 and 130°C, particularly at 110°C. Once the reaction is complete, the mixture can be returned to room temperature.

[0092] Compound (X) of formula (wherein R) in a mixture of THF and water4 , R 5 and R 6 By oxidation of (as defined above), the compound of formula (IX) as defined above can be obtained in step 4. The oxidizing agent can be added, for example, in an amount of 2 to 5 equivalents, particularly in a molar ratio of 3.3 equivalents, relative to the compound of formula (IX). The resulting mixture can then be stirred at room temperature for, for example, 1 to 24 hours, particularly 18 hours.

[0093] The amine of formula (V) (wherein R 1 and R 2 As defined above, a compound of formula (X) as defined above can be obtained in step 3. The compound of formula (X) can be placed in step 3 in an aprotic solvent such as Et3N, DIPEA, THF, 2-MeTHF, dioxane, cineole, or NMP or a mixture thereof, or without a solvent. An amine reagent can be added, for example, in an amount of 2 to 20 equivalents, particularly in a molar ratio of 15 equivalents, relative to the compound of formula (IX). The resulting mixture can then be stirred in a sealed tube at a temperature between 100 and 150°C, particularly at 120°C, for, for, for 0.5 to 24 hours, particularly 18 hours.

[0094] Compound (d) and compound (V) (wherein R) in an aprotic solvent such as THF, 2-MeTHF, or dioxane. 4 The reaction (as defined above) can be used in step 2 to obtain the compound of formula (XI) as defined above. The reaction mixture can be stirred in a sealed tube at a temperature in the range of 100 to 150°C, particularly at 110°C, for a period of 1 to 24 hours, for example, 16 hours.

[0095] In step 2, the compound of formula (d) as defined above can be obtained by the reaction of the compound of formula (a) with sodium methylsulfanyl in an aprotic solvent such as THF or 2-MeTH. The reaction mixture can be stirred at room temperature or under reflux for a period of 1 to 6 hours, for example, 3 hours.

[0096] Alternatively, the compound of general formula (I) can be prepared according to route 4, as shown in scheme 4 below.

[0097] [ka]

[0098] According to Route 4, the synthesis of the compound according to the present invention is carried out using the reagent of formula (XIV) (wherein L and R 3 As defined above, X represents a hydroxyl group, a chlorine atom, a bromine atom, a (C1-C3) alkyl sulfonate group, or a phenyl sulfonate group) and a compound of formula (XII) (wherein R, 4 , R 5 and R 6 The functionalization is based on the formula (as defined above). The compound of formula (XII) can be placed in step 3 in an aprotic solvent such as THF, 2-MeTHF, dioxane, DMSO, or DMF. The reagent of formula (XIV) can be added, for example, in an amount of 1 to 10 equivalents, particularly in a molar ratio of 2 equivalents, relative to the compound of formula (XII). The reaction mixture can be stirred at room temperature or under reflux for a period of 1 to 24 hours, for example, 3 hours.

[0099] Compound of formula (XIII) (wherein R 4 (As defined above) the amine of formula (IV) (wherein R 5 and R 6 By reacting with (as defined above), the compound of formula (XII) as defined above can be obtained in step 2. The compound of formula (XIII) can be placed in step 2 in an aprotic solvent such as Et3N, DIPEA, THF, 2-MeTHF, dioxane, cineole, or NMP or a mixture thereof, or without a solvent. The amine reagent can be added, for example, in an amount of 2 to 20 equivalents, particularly in a molar ratio of 10 equivalents, relative to the compound of formula (XIII). The resulting mixture can then be stirred in a sealed tube or under a microwave irradiation system at a temperature between 150 and 220°C, particularly 180°C, for, for, for 0.5 to 72 hours, particularly 24 hours.

[0100] Compound (e) and compound (V) (wherein R) in a non-protic solvent such as THF, 2-MeTHF, or dioxane, or in a protic solvent such as iPrOH, nPrOH, 2-MePrOH, or nBuOH. 4 The reaction (as defined above) can be used in step 1 to obtain the compound of formula (XIII) as defined above. The reaction mixture can be stirred in a sealed tube or under reflux of the solvent at a temperature in the range of 100 to 150°C, particularly at 110°C, for a period of 1 to 24 hours, for example, 18 hours.

[0101] Therefore, a synthesis method for producing any of the compounds of formula (I) as defined above or any pharmaceutically acceptable salt thereof, or at least one of the compounds (1) to (234) as defined above or any pharmaceutically acceptable salt thereof, wherein at least the compound of formula (II)

[0102] [ka]

[0103] (In the formula, L, R 2 , R 3 and R 4 (As defined above) The amine of formula (IV) is then added in a non-protic solvent, or without a solvent, or in a protic solvent, for example, in a molar ratio of 1 to 20 equivalents to the compound of formula (II). NHR 5 R 6 (IV) (In the formula, R 5 and R 6 (As defined above) A synthesis method including a step of reacting with is further provided herein.

[0104] A synthesis method for producing any of the compounds of formula (I) as defined above or any pharmaceutically acceptable salt thereof, or at least one of the compounds (1) to (234) as defined above or any pharmaceutically acceptable salt thereof, wherein at least the compound of formula (IX)

[0105] [ka]

[0106] (In the formula, R 4 , R 5 and R 6 (As defined above) For example, the compound of formula (VI) in an aprotic solvent in a molar ratio of 1 to 10 equivalents relative to the compound of formula (IX)

[0107] [ka]

[0108] (In the formula, R 2 and R 3 (As defined above) A synthesis method including a step of reacting with is further provided herein.

[0109] A synthesis method for producing either the compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, or at least one of the compounds (1) to (234) as defined above or any pharmaceutically acceptable salt thereof, wherein at least the compound of formula (XII)

[0110] [ka]

[0111] (In the formula, R 5 and R 6 (As defined above) For example, the compound of formula (XIV) in an aprotic solvent in a molar ratio of 1 to 10 equivalents relative to the compound of formula (XII)

[0112] [ka]

[0113] (In the formula, L and R 3 (As defined above, X represents a hydroxyl group, a chlorine atom, a bromine atom, a (C1-C3) alkyl sulfonate group, or a phenyl sulfonate group.) A synthesis method including a step of reacting with is further provided herein.

[0114] In particular, compounds of formula (II), (X), (XI), or (VII) as intermediate compounds.

[0115] [ka]

[0116] (In the formula, R 4 , R 5 and R 6 As defined above, however, in equation (XI), R 4 (This is not a methyl group.) The following is further provided herein.

[0117] Intermediate products (a), (b), and (e) can be obtained commercially or by methods known to those skilled in the art.

[0118] The chemical structures, analysis, and spectroscopic data of some of the compounds of formula (I) of the present invention are shown in Table 1 (Table 2) and Table 2 (Table 3) below, respectively.

[0119] The reactions were carried out under an argon or other inert atmosphere using glassware or oven-dried glassware. Unless otherwise noted, all reagent-grade chemicals and solvents were obtained from commercial suppliers and used as is. The reactions were monitored by thin-layer chromatography using silica gel 60 F254 pre-coated aluminum plates (0.25 mm). Visualization was performed under UV light and at 254 or 365 nm, or using appropriate TLC chromogenic agents including, but not limited to, phosphomolybdic acid, KMnO4, ninhydrin, CAM, vanillin, and p-anisaldehyde.

[0120] Chromatographic purification of the compounds was performed using an automated Interchim Puriflash XS420 equipped with a 30 μm spherical silica-packed prepack column as the stationary phase (normal phase) or a C18 silica prepack column as the stationary phase (reverse phase). However, a second purification could be performed by preparative thin-layer chromatography using standard silica. Purification was carried out in various pure or mixed solvents, such as ethyl acetate, cyclohexane, methanol, methanol and ammonia 7N, dichloromethane, triethylamine, and tetrahydrofuran in the normal phase, and then in the reverse phase with ACN, MeOH, H2O, and NH4OH. Mixture options: cHex / Ã, cHex / DCM, cHex / DCM / Ã, DCM / Ã, DCM / MeOH, DCM / MeOH NH37N, DCM / MeOH / Et3N, DCM / MeOH / THF, Ã / MeOH, Ã / MeOH NH37N, Ã / THF, ACN / H2O, ACN / NH4OH, MeOH / H2O, MeOH / NH4OH.

[0121] Some of the compounds of the present invention are described in Table 1 (Table 2) below along with their structures, but these are merely illustrative examples and do not limit the scope of the present invention.

[0122] [Table 2-1]

[0123] Table 2-2

[0124] Table 2-3

[0125] Table 2-4

[0126] Table 2-5

[0127] Table 2-6

[0128] Table 2-7

[0129] Table 2-8

[0130] Table 2-9

[0131] Table 2-10

[0132] Table 2-11

[0133] Table 2-12

[0134] Table 2-13

[0135] Table 2-14

[0136] Table 2-15

[0137] Table 2-16

[0138] Table 2-17

[0139] Table 2-18

[0140] Table 2-19

[0141] Table 2-20

[0142] Table 2-21

[0143] [Table 2-22]

[0144] [Table 2-23]

[0145] [Table 2-24]

[0146] [Table 2-25]

[0147] [Table 2-26]

[0148] [Table 2-27]

[0149] [Table 2-28]

[0150] [Table 2-29]

[0151] [Table 2-30]

[0152] Table 2 (Table 3) below describes the analysis and spectroscopic data of the compounds introduced in Table 1 (Table 2).

[0153] 11H NMR analysis (400 or 500 MHz) and 13 ¹³C NMR spectra (10¹ MHz) were recorded using a Bruker ULTRASHIELD 500 or 400 spectrometer. Spectrum processing and analysis were performed using MestReNova. The data appear in the following order: chemical shift (ppm) referenced to the internal solvent signal, multiplicity, proton number, and coupling constant J (Hertz).

[0154] Synthetic intermediates: Reverse-phase ULC / MS analysis was performed using a ULC Acquity (Waters) equipped with a UV-DAD detector and a mass detector (SQD2). The compound (0.2-0.6 mg) was solubilized in a DMSO / H2O (1 / 1) mixture and filtered through a 0.2 μm syringe filter.

[0155] - Acidic conditions: Acquity BEH C18 column, 2.1 x 50mm, 1.7μm. Flow rate: 0.65mL / min. Gradient: (H2O+0.1% HCOOH v / v) / (CAN+0.1% HCOOH v / v) from 95 / 5 to 5 / 95 in 4.0 min.

[0156] Final compound analysis was performed using reverse-phase HPLC / MS on an HPLC Ultimate 3000 (Thermo Scientific) equipped with a UV-DAD detector. Mass detection was performed by direct injection into a mass detector (SQD2) of a UPLC Acquity (Waters). The compound (0.2-0.6 mg) was solubilized in a DMSO / H2O (1 / 1) mixture and filtered through a 0.2 μm syringe filter.

[0157] - Acidic conditions: Thermo Scientific Syncronis C18 column, 150 × 4.6 mm, 5 μm. Flow rate: 1 mL / min. Gradient: 19.0 min, 95 / 5 to 5 / 95 (H2O + 0.1% HCOOH v / v) / (ACN + 0.1% HCOOH v / v).

[0158] - Alkaline conditions: Thermo Scientific Syncronis C18 column, 150 × 4.6 mm, 5 μm or XTERRA RP18, 150 × 4.6 mm, 3.5 μm. Flow rate: 1 mL / min. Gradient: 95 / 5 to 5 / 95 (HCOONH4 10 mM + NH4OH 25% aqueous solution to adjust pH to 10) / ACN over 19.0 mins.

[0159] [Table 3-1]

[0160] [Table 3-2]

[0161] [Table 3-3]

[0162] [Table 3-4]

[0163] [Table 3-5]

[0164] [Table 3-6]

[0165] [Table 3-7]

[0166] [Table 3-8]

[0167] [Table 3-9]

[0168] Table 3-10

[0169] Table 3-11

[0170] Table 3-12

[0171] Table 3-13

[0172] Table 3-14

[0173] Table 3-15

[0174] Table 3-16

[0175] Table 3-17

[0176] Table 3-18

[0177] Table 3-19

[0178] Table 3-20

[0179] Table 3-21

[0180] Table 3-22

[0181] Table 3-23

[0182] Table 3-24

[0183] Table 3-25

[0184] Table 3-26

[0185] Table 3-27

[0186] Table 3-28

[0187] Table 3-29

[0188] Table 3-30

[0189] Table 3-31

[0190] Table 3-32

[0191] Table 3-33

[0192] Table 3-34

[0193] Table 3-35

[0194] Table 3-36

[0195] Table 3-37

[0196] Table 3-38

[0197] Table 3-39

[0198] Table 3-40

[0199] Table 3-41

[0200] Table 3-42

[0201] Table 3-43

[0202] Table 3-44

[0203] Table 3-45

[0204] Table 3-46

[0205] Table 3-47

[0206] Table 3-48

[0207] Table 3-49

[0208] Table 3-50

[0209] Table 3-51

[0210] Table 3-52

[0211] Table 3-53

[0212] Table 3-54

[0213] Table 3-55

[0214] Table 3-56

[0215] Table 3-57

[0216] Table 3-58

[0217] Table 3-59

[0218] Table 3-60

[0219] Table 3-61

[0220] Table 3-62

[0221] Table 3-63

[0222] Table 3-64

[0223] Table 3-65

[0224] Table 3-66

[0225] Table 3-67

[0226] Table 3-68

[0227] Table 3-69

[0228] Table 3-70

[0229] Table 3-71

[0230] Table 3-72

[0231] Table 3-73

[0232] Table 3-74

[0233] Table 3-75

[0234] Table 3-76

[0235] Table 3-77

[0236] Table 3-78

[0237] Table 3-79

[0238] Table 3-80

[0239] Table 3-81

[0240] Table 3-82

[0241] Table 3-83

[0242] Table 3-84

[0243] Table 3-85

[0244] Table 3-86

[0245] Table 3-87

[0246] Table 3-88

[0247] Table 3-89

[0248] Table 3-90

[0249] Table 3-91

[0250] Table 3-92

[0251] Table 3-93

[0252] Table 3-94

[0253] Table 3-95

[0254] Table 3-96

[0255] Table 3-97

[0256] Table 3-98

[0257] Table 3-99

[0258] Table 3-100

[0259] Table 3-101

[0260] Table 3-102

[0261] Table 3-103

[0262] Table 3-104

[0263] Table 3-105

[0264] Table 3-106

[0265] Table 3-107

[0266] Table 3-108

[0267] Table 3-109

[0268] Table 3-110

[0269] [Table 3-111]

[0270] [Table 3-112]

[0271] [Table 3-113]

[0272] [Table 3-114]

[0273] a acidic conditions, b Alkaline conditions

[0274] pathology Examples of diseases mediated by A3AR include, but are not limited to, ulcerative colitis, atopic dermatitis, glaucoma, asthma, hepatic fibrosis, kidney disease, particularly renal fibrosis, nephropathy, acute kidney injury (AKI), chronic kidney disease (CKD), and especially renal fibrosis, nephropathy, acute kidney injury (AKI), impaired chronic kidney disease (CKD), toxic nephropathy or myoglobinuria induced by ischemia and / or reperfusion injury, diabetes-related kidney disease, kidney disease induced by nephrotoxicity caused by therapeutic drugs, atherosclerosis, hypercholesterolemia, partial or complete hearing loss induced by noise, acoustic trauma or ototoxic agents or conditions, and cancers that develop under hypoxic conditions, particularly glioblastoma.

[0275] Any compound of formula (I) or any pharmaceutically acceptable salt thereof may be particularly useful in the treatment and / or prevention of hearing loss induced in particular by ototoxic agents, and in the treatment and / or prevention of renal disease induced in particular by nephrotoxicity.

[0276] Any compound of formula (I) or any pharmaceutically acceptable salt thereof may be particularly useful in the treatment and / or prevention of partial or complete hearing loss, particularly induced by noise, acoustic trauma, or ototoxic agents or conditions.

[0277] Any compound of formula (I) or any pharmaceutically acceptable salt thereof may be particularly useful in the treatment and / or prevention of partial or complete hearing loss induced by the ototoxic agents or conditions described below.

[0278] The following can be listed as ototoxic agents, that is, drugs that cause hearing loss: - Solvents, such as polyethylene glycol, propylene glycol, or benzalkonium chloride; - Antibiotics, especially topical and / or systemic antibiotics, and more particularly aminoglycosides, macrolides, or phenicol antibiotics, such as gentamicin, neomycin, tobramycin, kanamycin, nystatin, polymyxin B, amphotericin B, bacitracin, or chloramphenicol; - Anticancer drugs, especially platinum-based anticancer drugs, such as cisplatin or carboplatin; - Disinfectants, especially acetic acid, alcohol, such as ethanol, chlorhexidine, cresylate, gentian violet, or povidone-iodine; - Nonsteroidal anti-inflammatory drugs (NSAIDs), especially salicylic acids, cyclodextrins, indomethacin, ibuprofen, phenylbutazone, or paracetamol; - Local combinations, especially polymyxin / neomycin / hydrocortisone or ticarcillin / clavulanate; - Drugs for COVID-19, especially lopinavir or ritonavir; - Antimalarial drugs, especially quinine or chloroquine; - Cardiovascular drugs, especially loop diuretics; or - Erectile dysfunction medications, especially phosphodiesterase type 5 (PDE-5) inhibitors.

[0279] Any compound of formula (I) or any pharmaceutically acceptable salt thereof may be particularly useful in treating and / or preventing hearing loss, whether partial or complete, induced by noise, acoustic trauma, or ototoxic agents or conditions, especially platin-based anticancer drugs such as cisplatin or carboplatin, antibiotics, especially macrolides or aminoglycosides such as gentamicin or neomycin, drugs for COVID-19 such as lopinavir or ritonavir, antimalarial drugs such as quinine or chloroquine, cardiovascular drugs such as loop diuretics, nonsteroidal anti-inflammatory drugs such as salicylic acid or cyclodextrin, or erectile dysfunction drugs such as phosphodiesterase type 5 inhibitors.

[0280] Any compound of formula (I) or any pharmaceutically acceptable salt thereof may be particularly useful in the treatment and / or prevention of kidney diseases selected from nephropathy, acute kidney injury (AKI), chronic kidney disease (CKD), and more particularly ischemic and / or reperfusion injury-induced nephropathy, acute kidney injury (AKI), chronic kidney disease (CKD), toxic nephropathy or myoglobinuria, and diabetes-related kidney disease, or kidney diseases induced by nephrotoxicity caused by therapeutic agents.

[0281] Any compound of formula (I) or any pharmaceutically acceptable salt thereof may be particularly useful for treating and / or preventing renal disease induced by nephrotoxicity caused by the therapeutic agents described below.

[0282] The following are examples of drugs that can cause nephrotoxicity: acyclovir, ambisome, amikacin, aminoglycosides, antibiotics, amphotericin B, captopril, carboplatin, cefotaxime, ceftazidime, cefuroxime, cephalosporins, cidofovir, ciprofloxacin, cisplatin, colistin methanesulfonate, cyclosporine, dapsone, enalaprilat, enalapril, foscarnet, gadopentetate dimeglumine, gadoxetate, gancyclovir Viru, gentamicin, ibuprofen, ifosfamide, iodixanol, iohexol, iopamidol, ioversol, ketorolac, lisinopril, lithium, mesalamine, methotrexate, naphcillin disodium, penicillin, piperacillin / tazobactam, piperacillin, rifampin, sirolimus, sulfasalazine, tacrolimus, ticalcillin / clavulanate, tobramycin, topiramate, valacyclovir, valganciclovir, vancomycin, or zonisamide.

[0283] The following examples illustrate in detail the preparation of some compounds according to the present invention. The structures of the obtained products were confirmed by NMR analysis and mass spectrometry. The following examples further illustrate some of the biological activities of some compounds according to the present invention. [Examples]

[0284] (Example 1) Synthesis of 3,6-dichloropyridazine-4-amine derivatives as shown in Step 1 of Scheme 1.

[0285] [ka]

[0286] (Example 1.1) Synthesis of N-benzyl-3,6-dichloropyridazine-4-amine (1.1) To a solution of 3,4,6-trichloropyridazine(a) (10.000 g, 52.88 mmol, 1.0 equivalent) in THF (100.0 mL), triethylamine (8.93 mL, 63.46 mmol, 1.2 equivalents) and then benzylamine (6.48 mL, 58.17 mmol, 1.1 equivalents) were added, and the mixture was refluxed for 3 hours. After cooling, the solid was filtered off, washed with THF, and the filtrate was concentrated under vacuum. The obtained solid was ground in Et2O, filtered off, washed with a small amount of Et2O, and dried under vacuum to obtain (1.1) (13.000 g, 97%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6) δ: 4.52 (d, J = 6.3 Hz, 2H, CH2), 6.82 (s, 1H, H Ar ), 7.26 (td, J = 5.9, 2.8 Hz, 1H, H Ar ), 7.34 (d, J = 5.4 Hz, 4H, 4xH Ar ), 7.97 (t, J = 6.3 Hz, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 44.7 (CH2), 105.5 (CH Ar ), 127.0 (2xCH Ar ), 127.2 (CH Ar ), 128.6 (2xCH Ar ), 137.0 (C q ), 143.8 (C q ), 144.4 (C q ), 154.5 (C q ). MS (ESI+): m / z C 11 Calculated value of H9Cl2N3: 254.0 [M+H]+, Measured value: 254.0.

[0287] (Example 1.2) Synthesis of 3,6-dichloro-N-(2-pyridylmethyl)pyridazine-4-amine (1,2) To a solution of 3,4,6-trichloropyridazine (a) (20.000 g, 105.77 mmol, 1.0 equivalent) in THF (210.0 mL), triethylamine (19.36 mL, 137.50 mmol, 1.3 equivalents) was added, followed by the corresponding amine (12.67 mL, 121.63 mmol, 1.15 equivalents), and the mixture was refluxed for 4 hours. After cooling, the solid was filtered off and washed with THF. The solid was washed with water, then ground in MeOH in another vacuum flask, washed with Et2O, and dried under vacuum to obtain the first portion (12.500 g) of (1.2). The THF and MeOH / Et2O filtrates were combined and concentrated under vacuum. The resulting solid was ground in MeOH, filtered off, washed with Et2O, and dried under vacuum to obtain the second portion (10.100 g) of (1.2). The filtrate was concentrated, the resulting solid was ground in a small amount of MeOH, filtered, washed with Et2O, and vacuum dried to obtain the third portion (1.000 g) of (1.2). Total of (1.2): 23.600 g, 87% as white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 4.60 (d, J = 6.1 Hz, 2H, CH 2 Bn ), 6.90 (s, 1H, H Ar ), 7.31 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H, H Ar ), 7.35 (dt, J = 7.8, 1.1 Hz, 1H, H Ar ), 7.79 (td, J = 7.7, 1.8 Hz, 1H, H Ar ), 7.87 (t, J = 6.0 Hz, 1H, NH Bn ), 8.54 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ: 46.6 (CH 2 Bn ), 105.9 (CH Ar ), 121.6 (CH Ar ), 122.7 (CH Ar ), 137.1 (CH Ar ), 143.8 (C q), 144.7 (C q ), 149.2 (CH Ar ), 154.6 (C q ), 156.3 (C q ). MS (ESI+): m / z C 10 Calculated value of H8Cl2N4: 255.0 [M+H]+, Measured value: 255.1.

[0288] (Example 1.3) Synthesis of 3,6-dichloro-N-(3-pyridylmethyl)pyridazine-4-amine (1,3) To a solution of 3,4,6-trichloropyridazine (a) (3.100 g, 16.39 mmol, 1.0 equivalent) in THF (33.0 mL), triethylamine (3.00 mL, 21.31 mmol, 1.3 equivalents) was added, followed by the corresponding amine (2.04 mL, 19.67 mmol, 1.2 equivalents), and the mixture was refluxed for 2 hours. After cooling, the solid was filtered off and washed with THF. The filtrate was concentrated, the resulting solid was washed with water, then ground with a small amount of MeOH, and vacuum dried to obtain (1.3) (2.320 g, 55%) as a pale orange solid. Rf(DCM / MeOH, 94 / 6): 0.55 1 H NMR (400 MHz, DMSO-d6) δ: 4.56 (d, J = 6.3 Hz, 2H, CH 2 Bn ), 6.96 (s, 1H, H Ar ), 7.37 (dd, J = 7.8, 4.7 Hz, 1H, H Ar ), 7.73 (dt, J = 7.8, 2.0 Hz, 1H, H Ar ), 7.96 (t, J = 6.3 Hz, 1H, NH Bn ), 8.48 (dd, J = 4.8, 1.7 Hz, 1H, H Ar ), 8.59 (d, J = 2.3 Hz, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ: 42.4 (CH 2 Bn), 105.5 (CH Ar ), 123.6 (CH Ar ), 132.7 (C q ), 134.9 (CH Ar ), 143.9 (C q ), 144.3 (C q ), 148.5 (CH Ar ), 148.8 (CH Ar ), 154.7 (C q ). MS (ESI+): m / z C 10 Calculated value of H8Cl2N4: 255.0 [M+H]+, Measured value: 255.1.

[0289] (Example 1.4) Synthesis of 3,6-dichloro-N-(4-pyridylmethyl)pyridazine-4-amine (1,4) To a solution of 3,4,6-trichloropyridazine (a) (11.500 g, 60.82 mmol, 1.0 equivalent) in THF (120.0 mL), triethylamine (11.13 mL, 79.06 mmol, 1.3 equivalents) was added, followed by the corresponding amine (7.640 g, 69.94 mmol, 1.15 equivalents), and the mixture was refluxed for 2 hours. After cooling, the solid was filtered off and washed with THF. The filtrate was concentrated, the resulting solid was washed with water, then ground with a small amount of MeOH, and dried under vacuum to obtain (1.4) (2.320 g, 55%) as a pale orange solid. 1 H NMR (400 MHz, DMSO-d6) δ: 4.57 (d, J = 6.4 Hz, 2H, CH 2 Bn ), 6.84 (s, 1H, HAr), 7.27 - 7.36 (m, 2H, 2xHAr), 7.98 (t, J = 6.4 Hz, 1H, NH Bn ), 8.45 - 8.58 (m, 2H, 2xHAr). 13 C NMR (101 MHz, DMSO-d6) δ: 43.7 (CH 2 Bn ), 105.6 (CH Ar ), 122.0 (2xCHAr ), 143.9 (C q ), 144.5 (C q ), 146.3 (C q ), 149.8 (2xCH Ar ), 154.7 (C q ). MS (ESI+): m / z C 10 Calculated value of H8Cl2N4: 255.0 [M+H]+, Measured value: 255.1.

[0290] (Example 1.5) Synthesis of 4-[[(3,6-dichloropyridazine-4-yl)aminomethyl]phenol (1.5) 3,4,6-trichloropyridazine(a) (1.500 g, 7.93 mmol, 1.0 equivalent), DCM (19.0 mL), triethylamine (1.68 mL, 11.90 mmol, 1.5 equivalents), and the corresponding amine (1.172 g, 9.52 mmol, 1.2 equivalents) were placed in a sealed vial of 2-5 mL equipped with a stirring bar. The vial was sealed and placed on a heating block at 50°C for 15 hours. After cooling, the mixture was concentrated with SiO2 to obtain a solid precipitate, which was then directly purified by flash chromatography using DCM / MeOH (98 / 2 to 96 / 4) as the eluate to obtain (1.5) (0.515 g, 24%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 4.38 (d, J = 6.2 Hz, 2H, CH 2 Bn ), 6.68 - 6.76 (m, 2H, 2xHAr), 6.80 (s, 1H, H Ar ), 7.08 - 7.21 (m, 2H, 2xH Ar ), 7.87 (t, J = 6.2 Hz, 1H, NH Bn ), 9.36 (s, 1H, OH). 13 C NMR (101 MHz, DMSO-d6) δ: 44.3 (CH 2 Bn ), 105.4 (CH Ar ), 115.3 (2xCHAr ), 126.9 (C q ), 128.3 (2xCH Ar ), 143.8 (C q ), 144.3 (C q ), 154.5 (C q ), 156.6 (C q ). MS (ESI+): m / z C 11 Calculated value of H9Cl2N3O: 270.0 [M+H]+, Measured value: 270.1.

[0291] (Example 1.6) Synthesis of 3-[[(3,6-dichloropyridazine-4-yl)aminomethyl]phenol (1,6) 3,4,6-trichloropyridazine(a) (1.500 g, 7.93 mmol, 1.0 equivalent), DCM (19.0 mL), triethylamine (1.68 mL, 11.90 mmol, 1.5 equivalents), and the corresponding amine (1.172 g, 9.52 mmol, 1.2 equivalents) were placed in a sealed vial of 2-5 mL equipped with a stirring bar. The vial was sealed and placed on a heating block at 50°C for 15 hours. After cooling, the mixture was concentrated with SiO2 to obtain a solid precipitate, which was then directly purified by flash chromatography using DCM / MeOH (98 / 2 to 96 / 4) as the eluate to obtain (1.6) (0.670 g, 31%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 4.43 (d, J = 6.3 Hz, 2H, CH 2 Bn ), 6.64 (dd, J = 8.0, 2.4 Hz, 1H, H Ar ), 6.69 (t, J = 2.0 Hz, 1H, H Ar ), 6.74 (d, J = 7.6 Hz, 1H, H Ar ), 6.77 (s, 1H, H Ar ), 7.13 (t, J = 7.8 Hz, 1H, H Ar ), 7.94 (t, J = 6.3 Hz, 1H, NH Bn), 9.39 (s, 1H, OH). 13 C NMR (101 MHz, DMSO-d6) δ: 44.6 (CH 2 Bn ), 105.5 (CH Ar ), 113.4 (CH Ar ), 114.2 (CH Ar ), 117.4 (CH Ar ), 129.6 (CH Ar ), 138.4 (C q ), 143.7 (C q ), 144.4 (C q ), 154.5 (C q ), 157.6 (C q ). MS (ESI+): m / z C 11 Calculated value of H9Cl2N3O: 270.0 [M+H]+, Measured value: 270.1.

[0292] (Example 1.7) Synthesis of 2-[[(3,6-dichloropyridazine-4-yl)aminomethyl]phenol (1.7) To a solution of 3,4,6-trichloropyridazine (a) (3.700 g, 20.2 mmol, 1.0 equivalent) in THF (50 mL), triethylamine (3.41 mL, 24.2 mmol, 1.2 equivalents) was added, followed by the corresponding benzylamine (3.700 g, 24.2 mmol, 1.2 equivalents), and the mixture was refluxed for 3 hours. After cooling, the mixture was filtered, washed with THF, and the filtrate was concentrated. The crude residue was ground in DCM / MeOH (94 / 4), filtered, and obtained the first portion (1.7) (1.450 g). The filtrate was concentrated, the residue was ground in DCM / MeOH (98 / 2), filtered, and obtained the second portion (0.950 g) of (1.7). The filtrate was concentrated and purified by flash chromatography (96 / 4) to obtain the third portion (0.900 g) of (1.7). Total of (1.7): 3,400 g, 62%, as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 4.39 (d, J = 6.2 Hz, 2H, CH 2 Bn ), 6.76 (td, J = 7.4, 1.2 Hz, 1H, H Ar ), 6.81 (s, 1H, H Ar ), 6.85 (dd, J = 8.0, 1.2 Hz, 1H, H Ar ), 7.06 - 7.14 (m, 2H, 2xH Ar ), 7.75 (t, J = 6.2 Hz, 1H, NH Bn ), 9.84 (s, 1H, OH). 13 C NMR (101 MHz, DMSO-d6) δ: 40.1 (CH 2 Bn ), 105.3 (CH Ar ), 115.1 (CH Ar ), 119.2 (CH Ar ), 122.4 (C q ), 128.2 (CH Ar ), 128.4 (CH Ar ), 143.7 (C q ), 144.4 (C q ), 154.6 (C q ), 154.9 (C q ). MS (ESI+): m / z C 11 Calculated value of H9Cl2N3O: 270.0 [M+H]+, Measured value: 270.1.

[0293] (Example 1.8) Synthesis of 3,6-dichloro-N-[(2-methoxyphenyl)methyl]pyridazine-4-amine (1.8) To a solution of 3,4,6-trichloropyridazine (a) (2.600 g, 13.75 mmol, 1.0 equivalent) in DCM (70.0 mL), triethylamine (3.87 mL, 27.50 mmol, 2.0 equivalent) and the corresponding amine (2.887 g, 20.63 mmol, 1.5 equivalent) were added, and the mixture was refluxed for 19 hours. After cooling, 1 M HCl (50.0 mL) was added, and the mixture was vigorously stirred for 5 minutes to separate the layers. The aqueous layer was extracted twice with DCM (2 × 20.0 mL), and the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (100 / 0 to 98 / 2) as the eluate to obtain (1.8) (3.200 g, 82%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 3.85 (s, 3H, OCH3), 4.44 (s, 2H, CH 2 Bn ), 6.75 (s, 1H, H Ar ), 6.87 - 6.95 (m, 1H, H Ar ), 7.00 - 7.06 (m, 1H, H Ar ), 7.13 (dd, J = 7.5, 1.8 Hz, 1H, H Ar ), 7.27 (td, J = 7.8, 1.8 Hz, 1H, H Ar ), 7.73 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ: 40.2 (CH 2 Bn ), 55.4 (CH3), 105.4 (CH Ar ), 110.9 (CH Ar ), 120.5 (CH Ar ), 124.1 (C q ), 127.5 (CH Ar ), 128.7 (CH Ar ), 143.7 (C q ), 144.5 (C q ), 154.6 (C q ), 156.8 (C q ). MS (ESI+): m / z C 12 H 11 Calculated value of Cl2N3O: 284.0 [M+H]+, Measured value: 284.1.

[0294] (Example 1.9) Synthesis of 3,6-dichloro-N-(1H-indole-3-ylmethyl)pyridazine-4-amine (1.9) In 10-20 mL vials, a stirring bar, 3,4,6-trichloropyridazine(a) (1.750 g, 9.25 mmol, 1.0 equivalent), DCM (18 mL), 1H-indole-2-ylmethaneamine hydrochloride (2.135 g, 11.11 mmol, 1.2 equivalents), and triethylamine (2.87 mL, 20.36 mmol, 2.2 equivalents) were introduced. The vials were sealed and placed on a heating block at 50°C for 17 hours. After cooling, the mixture was concentrated and then ground in 0.5 M HCl (60 mL, pH < 5), and siRNA (30 mL) was added. The heterogeneous mixture was vigorously stirred, then the precipitate was filtered off, washed with water (to pH 7), then siRNA, and vacuum dried to obtain the first portion (1.465 g) of (1.9) as a white solid. The aqueous layer was extracted with toluene (30 mL), the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain the second portion (0.430 g) of (1.9) as a white solid. Total of (1.9): 1.895 g, 70%. 1 H NMR (400 MHz, DMSO-d6) δ: 4.63 (d, J = 5.9 Hz, 2H, CH 2 Bn ), 7.01 (d, J = 7.4 Hz, 2H, 2xH Ar ), 7.08 (t, J = 7.5 Hz, 1H, H Ar ), 7.35 (d, J = 8.1 Hz, 1H, H Ar ), 7.44 (d, J = 2.4 Hz, 1H, H Ar ), 7.73 (d, J = 7.9 Hz, 1H, H Ar), 7.85 (t, J = 5.9 Hz, 1H, NH Bn ), 10.97 (s, 1H, NH インドール ). 13 C NMR (101 MHz, DMSO-d6) δ: 37.7 (CH 2 Bn ), 105.4 (CH Ar ), 109.1 (C q ), 111.6 (CH Ar ), 118.7 (CH Ar ), 118.8 (CH Ar ), 121.3 (CH Ar ), 124.7 (CH Ar ), 126.2 (C q ), 136.5 (C q ), 143.8 (C q ), 144.2 (C q ), 154.3 (C q ). MS (ESI+): m / z C 13 H 10 Calculated value of Cl2N4: 293.0 [M+H]+, Measured value: 293.1.

[0295] (Example 1.10) Synthesis of 3,6-dichloro-N-(1H-indole-2-ylmethyl)pyridazine-4-amine (1.10) In 10-20 mL vials, a stirring bar, 3,4,6-trichloropyridazine(a) (1.750 g, 9.25 mmol, 1.0 equivalent), DCM (18 mL), 1H-indole-2-ylmethaneamine hydrochloride (2.135 g, 11.11 mmol, 1.2 equivalents), and triethylamine (2.87 mL, 20.36 mmol, 2.2 equivalents) were introduced. The vials were sealed and placed on a heating block at 50°C for 17 hours. After cooling, the mixture was concentrated and then ground in 0.5 M HCl (60 mL, pH < 5), and siRNA (30 mL) was added. The heterogeneous mixture was vigorously stirred, then the precipitate was filtered off, washed with water (to pH 7), then with siRNA, and vacuum dried to obtain the first portion (2.040 g) of (1.10) as a white solid. The aqueous layer was extracted with ELISA (30 mL), the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain the second portion (0.300 g) of (1.10) as a white solid. Total of (1.10): 2.340 g, 86%. 1 H NMR (400 MHz, DMSO-d6) δ: 4.66 (d, J = 6.1 Hz, 2H, CH 2 Bn ), 6.33 (d, J = 2.0 Hz, 1H, H Ar ), 6.95 (t, J = 7.4 Hz, 1H, H Ar ), 6.98 (s, 1H, H Ar ), 7.04 (t, J = 7.4 Hz, 1H, H Ar ), 7.33 (d, J = 8.0 Hz, 1H, H Ar ), 7.45 (d, J = 8.0 Hz, 1H, H Ar ), 7.79 (t, J = 6.1 Hz, 1H, NH Bn ), 10.96 (s, 1H, H インドール ). 13 C NMR (101 MHz, DMSO-d6) δ: 39.3 (CH 2 Bn ), 99.7 (CH Ar ), 105.7 (CHAr ), 111.2 (CH Ar ), 119.0 (CH Ar ), 119.7 (CH Ar ), 120.9 (CH Ar ), 127.8 (C q ), 134.6 (C q ), 136.2 (C q ), 143.9 (C q ), 144.5 (C q ), 154.6 (C q ). MS (ESI+): m / z C 13 H 10 Calculated value of Cl2N4: 293.0 [M+H]+, Measured value: 293.1.

[0296] (Example 1.11) Synthesis of N-[(4-aminophenyl)methyl]-3,6-dichloropyridazine-4-amine (1.11) To a solution of 3,4,6-trichloropyridazine (a) (22.953 g, 125.14 mmol, 1.3 equivalents) in THF (200.0 mL), triethylamine (20.33 mL, 144.69 mmol, 1.5 equivalents) and 4-(aminomethyl)aniline (12.000 g, 96.26 mmol, 1.0 equivalent) were added, and the mixture was refluxed for 18 hours. After cooling, the mixture was filtered off, the solid was washed with THF, and the filtrate was concentrated. The residue was ground in DCM, the solid was filtered off, washed with DCM, and dried under vacuum to obtain (1.11) (23.950 g, 92%) as a yellow solid. 1 H 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, 2xH Ar ), 6.77 (s, 1H, H Ar ), 6.89 - 7.12 (m, 2H, 2xH Ar ), 7.80 (t, J = 6.1 Hz, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δ: 44.6 (CH2), 105.4 (CH Ar ), 113.9 (2xCH Ar ), 123.4 (C q ), 128.0 (2xCH Ar ), 143.7 (C q ), 144.3 (C q ), 147.8 (C q ), 154.4 (C q ). MS (ESI+): m / z C 11 H 10 Calculated value of Cl2N4: 269.0 [M+H]+, Measured value: 269.1.

[0297] (Example 1.12) Synthesis of N-[(2-aminophenyl)methyl]-3,6-dichloropyridazine-4-amine (1.12) To a solution of 3,4,6-trichloropyridazine (a) (5.000 g, 27.3 mmol, 1.0 equivalent) in THF (52 mL), triethylamine (4.22 mL, 30.0 mmol, 1.1 equivalent), followed by 2-(aminomethyl)aniline (3.228 g, 25.9 mmol, 0.95 equivalent), was added, and the mixture was refluxed for 3.5 hours. After cooling, the mixture was filtered off, the solid was washed with THF, and the filtrate was concentrated. The eluate was directly purified by flash chromatography using DCM / MeOH (98 / 2 to 96 / 4) to obtain (1.12) (5.280 g, 76%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ : 4.30 (d, J = 6.0 Hz, 2H, CH 2 Bn ), 5.15 (s, 2H, NH2), 6.52 (td, J = 7.4, 1.3 Hz, 1H, H Ar ), 6.65 (dd, J = 8.0, 1.3 Hz, 1H, H Ar ), 6.74 (s, 1H, H Ar ), 6.97 (td, J = 7.6, 1.6 Hz, 1H, HAr ), 7.02 (dd, J = 7.5, 1.6 Hz, 1H, H Ar ), 7.74 (t, J = 6.0 Hz, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ: 42.0 (CH 2 Bn ), 105.6 (CH Ar ), 115.2 (CH Ar ), 116.1 (CH Ar ), 118.8 (C q ), 127.9 (CH Ar ), 128.1 (CH Ar ), 143.8 (C q ), 144.4 (C q ), 146.3 (C q ), 154.5 (C q ). MS (ESI+): m / z C 11 H 10 Calculated value of Cl2N4: 269.0 [M+H]+, Measured value: 269.1.

[0298] (Example 1.13) Synthesis of N-[(4-bromophenyl)methyl]-3,6-dichloropyridazine-4-amine (1.13) To a solution of 3,4,6-trichloropyridazine (a) (4.000 g, 24.81 mmol, 1.0 equivalent) in THF (87.0 mL), triethylamine (3.68 mL, 26.17 mmol, 1.2 equivalents) and the corresponding amine (3.03 mL, 23.99 mmol, 1.1 equivalents) were added, and the mixture was refluxed for 3.5 hours. After cooling, the solid was filtered off, washed with THF, and the filtrate was concentrated. The residue was dissolved in DCM (100.0 mL), washed with 1 M HCl (40.0 mL), and the organic layer was dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (100 / 0 to 98 / 2) as the eluate to obtain (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, CH 2 Bn ), 6.84 (s, 1H, H Ar ), 7.25 - 7.35 (m, 2H, 2xH Ar ), 7.50 - 7.58 (m, 2H, 2xH Ar ), 7.97 (t, J = 6.4 Hz, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ: 44.0 (CH 2 Bn ), 105.5 (CH Ar ), 120.3 (C q ), 129.3 (2xCH Ar ), 131.4 (2xCH Ar ), 136.6 (C q ), 143.8 (C q ), 144.3 (C q ), 154.6 (C q ). MS (ESI+): m / z C 11 Calculated value of H8BrCl2N3: 331.9 [M+H]+, Measured value: 331.9.

[0299] (Example 1.14) Synthesis of 3,6-dichloro-N-[[4-(2-pyridyl)phenyl]methyl]pyridazine-4-amine (1.14) To a solution of 3,4,6-trichloropyridazine (a) (0.500 g, 2.73 mmol, 1.0 equivalent) in THF (13.5 mL), triethylamine (1.15 mL, 8.18 mmol, 3.0 equivalents) was added, followed by [4-(2-pyridyl)phenyl]methaneamine (0.603 g, 3.27 mmol, 1.2 equivalents), and the mixture was refluxed for 3 hours. After cooling, the mixture was filtered off, the solid was washed with THF, and the filtrate was concentrated. The eluate was directly purified by flash chromatography using DCM / MeOH (99 / 1 to 95 / 5) to obtain (1.14) (0.360 g, 40%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ : 4.59 (d, J = 6.3 Hz, 2H, CH 2 Bn ), 6.86 (s, 1H, H Ar ), 7.33 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H, H Ar ), 7.45 (d, J = 8.1 Hz, 2H, 2xH Ar ), 7.86 (td, J = 7.7, 1.9 Hz, 1H, H Ar ), 7.93 (d, J = 8.0 Hz, 1H, H Ar ), 8.02 (t, J = 6.0 Hz, 1H, NH Bn ), 8.04 - 8.10 (m, 2H, 2xH Ar ), 8.62 - 8.67 (m, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ : 44.5 (CH 2 Bn ), 105.6 (CH Ar ), 120.1 (CH Ar ), 122.6 (CH Ar ), 126.7 (2xCH Ar ), 127.4 (2xCH Ar ), 137.2 (CH Ar ), 137.7 (C q ), 138.0 (C q ), 143.9 (C q ), 144.4 (C q ), 149.5 (CH Ar ), 154.6 (C q ), 155.7 (C q ). MS (ESI+): m / z C 16 H 12 Calculated value of Cl2N4: 331.1 [M+H]+, measured value: 331.1.

[0300] (Example 1.15) Synthesis of 2-(3,6-dichloropyridazine-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 equivalent) in THF (54.0 mL), triethylamine (4.41 mL, 31.3 mmol, 1.1 equivalent), followed by 2-(aminomethyl)aniline (3.228 g, 25.9 mmol, 0.95 equivalent), was added, and the mixture was refluxed for 3.5 hours. After cooling, the mixture was filtered off, the solid was washed with THF, and the filtrate was concentrated. The eluate was directly purified by flash chromatography using DCM / siRNA (100 / 0 to 92 / 8) to obtain (1.15) (6.800 g, 89%) as a white crystalline solid. Rf(DCM, 100%): 0.42. 1 H NMR (400 MHz, DMSO-d6) δ : 2.99 (t, J = 5.8 Hz, 2H, CH 2-CH2-N ), 3.69 (t, J = 5.8 Hz, 2H, N- CH 2-CH2 ), 4.50 (s, 2H, CH 2-N ), 7.13 - 7.29 (m, 4H, 4xH Ar ), 7.42 (s, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ: 28.2 (CH 2-CH2-N ), 47.5 ( N- CH 2-CH2 ), 50.4 (CH 2-N ), 115.4 (CH Ar ), 126.1 (CH Ar ), 126.4 (CH Ar ), 126.7 (CH Ar ), 128.7 (CH Ar ), 132.8 (C q ), 133.9 (C q ), 147.9 (C q ), 148.9 (C q ), 154.9 (Cq ). MS (ESI+): m / z C 13 H 11 Calculated value of Cl2N3: 280.0 [M+H]+, Measured value: 280.1.

[0301] (Example 1.16) Synthesis of 3,6-dichloro-N-(2-phenylethyl)pyridazine-4-amine (1.16) To a solution of 3,4,6-trichloropyridazine(a) (4.000 g, 21.8 mmol, 1.0 equivalent) in THF (42 mL), Et3N (6.45 mL, 45.80 mmol, 2.1 equivalents) was added, followed by the corresponding amine hydrochloride (3.438 g, 21.8 mmol, 1.0 equivalent), and the mixture was refluxed for 3 hours. After cooling, the mixture was filtered off, the solid was washed with THF, and the filtrate was concentrated. The residue was ground in 1 M HCl (25.0 mL), the resulting solid was filtered, washed with water to a neutral pH, and dissolved in SiO2. The organic filtrate was dehydrated with MgSO4, filtered, and concentrated to obtain (1.16) (5.515 g, 88%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6) δ : 2.86 (t, J = 7.4 Hz, 2H, CH 2-CH2-NH ), 3.43 - 3.56 (m, 2H, CH 2-NH ), 6.95 (s, 1H, H Ar ), 7.20 (ddd, J = 8.6, 5.6, 2.4 Hz, 1H, H Ar ), 7.27 (q, J = 4.2 Hz, 5H, NH & 5xH Ar ). 13 C NMR (101 MHz, DMSO-d6) δ: 33.8 (CH 2-CH2-NH ), 43.1 (CH 2-NH ), 105.2 (CH Ar ), 126.3 (CH Ar ), 128.3 (2xCH Ar ), 128.9 (2xCH Ar), 138.8 (C q ), 143.5 (C q ), 144.3 (C q ), 154.7 (C q ). MS (ESI+): m / z C 12 H 11 Calculated value of Cl2N3: 268.0 [M+H]+, Measured value: 268.1.

[0302] (Example 2) Synthesis of 6,8-dichloro-[1,2,4]triazolo[4,3-b]pyridazine derivatives as shown in Step 1 of Scheme 2.

[0303] [ka]

[0304] (Example 2.1) Synthesis of 6,8-dichloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (2.1) To a solution of 4-methylbenzenesulfonohydrazide (3.895 g, 20.91 mmol, 1.0 equivalent) in THF (21.0 mL), the corresponding aldehyde (1.97 mL, 21.33 mmol, 1.02 equivalents) was added, and the mixture was stirred at 50°C for 5 minutes. The solvent was completely removed by evaporation, and the crude residue was then dissolved in THF (63.0 mL). 3,5-dichloropyridazine (b) (3.915 g, 24.97 mmol, 1.2 equivalents) was added, followed by I2 (1.056 g, 4.16 mmol, 0.2 equivalents), and then PIDA (10.257 g, 31.21 mmol, 1.5 equivalents) in small increments. The reaction was slightly exothermic, and the mixture was stirred at room temperature for 22 hours. Saturated Na2S2O3 (30.0 mL) and water (15.0 mL) were added and the mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted twice with HCl (2 × 20.0 mL), then the organic layers were combined, washed with brine, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using HCl / cyclohexane as the eluate to obtain (2.1) (2.100 g, 44%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ: 1.41 (d, J = 7.0 Hz, 6H, 2xCH 3 iPr ), 3.50 (septet, J = 6.9 Hz, 1H, H iPr ), 7.93 (s, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ : 19.7 (2xCH 3 iPr ), 24.6 (CH iPr ), 121.2 (CH Ar ), 133.2 (C q ), 142.1 (C q ), 147.5 (C q ), 154.8 (C q ). MS (ESI+): m / z Calculated value for C8H8Cl2N4: 231.0 [M+H]+, Measured value: 230.9.

[0305] (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 equivalent) in THF (25.0 mL), 2-methylbutanal (1.12 mL, 9.90 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature for 25 minutes. After completion, 3,5-dichloropyridazine (b) (1.552 g, 9.90 mmol, 1.0 equivalent) was added, followed by the addition of PIDA (6.505 g, 19.79 mmol, 2.0 equivalents) and I2 (0.502 g, 1.98 mmol, 0.2 equivalents) all at once. The mixture was stirred at room temperature for 17 hours, followed by the addition of saturated Na2S2O3 (10.0 mL) and saturated NaHCO3 (10.0 mL), and the mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted twice with siRNA (2 × 10.0 mL), the organic layers were combined, dehydrated with MgSO4, filtered, and purified by flash chromatography using siRNA / cyclohexane (30 / 70) as the eluate to obtain (2.2) (0.670 g, 28%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 0.86 (t, J = 7.4 Hz, 3H, CH 3-CH2 ), 1.38 (d, J = 7.0 Hz, 3H, CH 3-CH ), 1.69 - 2.00 (m, 2H, CH 2-CH3 ), 3.33 - 3.41 (m, 1H, H C-CH3 ), 7.93 (s, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ: 11.4 (CH 3-CH2 ), 17.4 (CH 3-CH ), 26.7 (CH 2-CH3 ), 31.1 (CH -CH3 ), 121.3 (CH Ar ), 133.3 (C q ), 142.1 (C q ), 147.6 (C q), 154.0 (C q ). MS (ESI+): m / z C9H 10 Calculated value of Cl2N4: 245.0 [M+H]+, Measured value: 245.1.

[0306] (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-methylbenzenesulfonhydrazide (1.600 g, 8.59 mmol, 1.0 equivalent) in THF (20.0 mL), 2-ethylbutanal (1.14 mL, 8.59 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature for 25 minutes. After completion, 3,5-dichloropyridazine (b) (1.307 g, 8.59 mmol, 1.0 equivalent) was added, followed by PIDA (5.478 g, 16.67 mmol, 2.0 equivalents) and I2 (0.423 g, 1.67 mmol, 0.2 equivalents) in a single addition. The mixture was stirred at room temperature for 17 hours, and then saturated Na2S2O3 (10.0 mL) and saturated NaHCO3 (10.0 mL) were added, and the mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted twice with HCl (2 × 10.0 mL), the organic layers were combined, dehydrated with MgSO4, filtered, and purified by flash chromatography using HCl / cyclohexane (30 / 70) as the eluate to obtain (2.3) (0.570 g, 26%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 0.80 (t, J = 7.4 Hz, 6H, 2xCH 3-CH2 ), 1.75 - 1.97 (m, 4H, 2xCH 2-CH3 ), 3.23 (tt, J = 8.3, 5.7 Hz, 1H, H iPent ), 7.94 (s, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ : 11.4 (2xCH 3-CH2 ), 24.8 (2xCH 2-CH3 ), 38.3 (CHiPent ), 121.3 (CH Ar ), 133.3 (C q ), 142.1 (C q ), 147.7 (C q ), MS (ESI+): m / z C 10 H 12 Calculated value of Cl2N4: 259.1 [M+H]+, Measured value: 259.1.

[0307] (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 equivalent) in THF (20.0 mL), 3-methylbutanal (0.58 mL, 5.37 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature for 20 minutes. After completion, 3,5-dichloropyridazine (b) (0.927 g, 5.91 mmol, 1.1 equivalent) was added, followed by the addition of PIDA (3.530 g, 10.74 mmol, 2.0 equivalent) and I2 (0.273 g, 1.07 mmol, 0.2 equivalent) all at once. The mixture was stirred at room temperature for 2 hours, followed by the addition of saturated Na2S2O3 (20.0 mL) and H2O (10.0 mL), and the mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted twice with toluene (2 × 20.0 mL), the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using toluene / cyclohexane (85 / 15 to 50 / 50) as the eluate to obtain (2.4) (0.452 g, 34%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6) δ: 0.96 (d, J = 6.7 Hz, 6H, 2xCH 3 iPr ), 2.23 (dp, J = 13.6, 6.8 Hz, 1H, H iPr ), 2.97 (d, J = 7.1 Hz, 2H, CH 2-CH ), 7.93 (s, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ: 22.2 (2xCH 3 iPr ), 26.3 (CH -CH2 ), 32.2 (CH 2-CH ), 121.2 (CH Ar ), 133.2 (C q ), 141.9 (C q ), 147.7 (C q ), 150.1 (C q ). MS (ESI+): m / z C9H 12 Calculated value of Cl2N4: 245.0 [M+H]+, Measured value: 245.1.

[0308] (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 equivalent) and N-(cyclopropylmethyleneamino)-4-methylbenzenesulfonamide (4.559 g, 19.1 mmol, 1.5 equivalent) in THF (95.0 mL), PIDA (6.288 g, 19.1 mmol, 1.5 equivalent) and I2 (0.647 g, 2.5 mmol, 0.2 equivalent) were added in one step, and the mixture was stirred at room temperature for 2 hours. After completion, a mixture of saturated Na2S2O3 (20.0 mL) and water (10.0 mL) was added, and the two-phase mixture was vigorously stirred for 5 minutes, after which the layers were separated. The aqueous layer was extracted twice with siRNA (2 × 15.0 mL), the organic layers were combined, dehydrated with MgSO4, filtered, and purified by flash chromatography using siRNA / cyclohexane (75 / 25, then 70 / 30) as the eluate to obtain (2.5) (0.400 g, 14%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 1.07 - 1.27 (m, 4H, 2xCH 2 cPr ), 2.40 (tt, J = 8.3, 5.0 Hz, 1H, H cPr ), 7.91 (s, 1H, HAr ). 13 C NMR (101 MHz, DMSO-d6) δ: 4.9 (CH cPr ), 7.5 (2xCH 2 cPr ), 121.1 (CH Ar ), 133.1 (C q ), 142.1 (C q ), 147.7 (C q ), 152.3 (C q ). MS (ESI+): m / z Calculated value for C8H6Cl2N4: 229.0 [M+H]+, Measured value: 228.9.

[0309] (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-methylbenzenesulfonhydrazide (1.800 g, 9.38 mmol, 1.0 equivalent) in THF (140.0 mL), cyclopentanecarbaldehyde (0.995 g, 9.84 mmol, 1.05 equivalent) was added, and the mixture was stirred at room temperature for 20 minutes. After completion, 3,5-dichloropyridazine (b) (1.470 g, 9.38 mmol, 1.0 equivalent) was added, followed by the addition of PIDA (4.622 g, 14.06 mmol, 1.5 equivalent) and I2 (0.476 g, 1.88 mmol, 0.2 equivalent) in a single addition. The mixture was stirred at room temperature for 1.3 hours, then partially concentrated, and the residue was diluted in SiO2 (50.0 mL). The organic layer was washed with a mixture of saturated Na2S2O3 (40.0 mL) and water (80.0 mL). The aqueous layer was extracted twice with toluene (2 × 30.0 mL), the organic layers were combined, dehydrated with MgSO4, filtered, and purified by flash chromatography using toluene / cyclohexane (15 / 85 to 50 / 50) as the eluate to obtain (2.6) (0.260 g, 11%) as a white flake. 1 H NMR (400 MHz, DMSO-d6) δ: 1.63 - 1.86 (m, 4H, 2xCH 2シクロペンチル), 1.90 - 2.03 (m, 2H, CH 2シクロペンチル ), 2.11 (dq, J = 12.3, 7.0, 6.0 Hz, 2H, CH 2シクロペンチル ), 3.61 (p, J = 7.9 Hz, 1H, H シクロペンチル ), 7.92 (s, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ : 25.1 (2xCH 2シクロペンチル ), 30.1 (2xCH 2シクロペンチル ), 34.3 (CH シクロペンチル ), 121.2 (CH Ar ), 133.2 (C q ), 142.2 (C q ), 147.5 (C q ), 154.0 (C q ). MS (ESI+): m / z C 10 H 10 Calculated value of Cl2N4: 257.0 [M+H]+, Measured value: 257.1.

[0310] (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-methylbenzenesulfonhydrazide (1.102 g, 5.74 mmol, 1.2 equivalents) in THF (15.0 mL), butanal (0.52 mL, 5.74 mmol, 1.2 equivalents) was added, and the mixture was stirred at room temperature for 10 minutes. After completion, 3,5-dichloropyridazine (b) (0.750 g, 4.78 mmol, 1.0 equivalent) was added, followed by the addition of PIDA (6.505 g, 19.79 mmol, 2.0 equivalents) and I2 (0.502 g, 1.98 mmol, 0.2 equivalents) all at once. The mixture was stirred at room temperature for 17 hours, followed by the addition of saturated Na2S2O3 (10.0 mL) and saturated NaHCO3 (10.0 mL), and the mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted twice with siRNA (2 × 10.0 mL), the organic layers were combined, dehydrated with MgSO4, filtered, and purified by flash chromatography using siRNA / cyclohexane (30 / 70) as the eluate to obtain (2.7) (0.957 g (RMN purity 70%) including impurities, calculated value = 0.670 g, 28%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 0.86 (t, J = 7.4 Hz, 3H, CH 3-CH2 ), 1.38 (d, J = 7.0 Hz, 3H, CH 3-CH ), 1.69 - 2.00 (m, 2H, CH 2-CH3 ), 3.33 - 3.41 (m, 1H, H C-CH3 ), 7.93 (s, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ: 11.4 (CH 3-CH2 ), 17.4 (CH 3-CH ), 26.7 (CH 2-CH3 ), 31.1 (CH -CH3 ), 121.3 (CH Ar ), 133.3 (C q ), 142.1 (C q ), 147.6 (C q ), 154.0 (C q ). MS (ESI+): m / z C9H 10 Calculated value of Cl2N4: 245.0 [M+H]+, Measured value: 245.1.

[0311] (Example 3) Synthesis of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-8-amine derivatives as shown in step 2 of Scheme 1 or step 2 of Scheme 2.

[0312] [ka]

[0313] (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 10-20 mL sealed tube equipped with a stirring bar, (1.1) (0.250 g, 0.98 mmol, 1.0 equivalent), dioxane (3.5 mL), isobutyrate hydrazide (0.121 g, 1.18 mmol, 1.2 equivalents), and AcOH (0.05 mL, 0.79 mmol, 0.8 equivalents) were placed. The vial was sealed and then placed on a heating block at 100°C for 4 hours. The reaction mixture was cooled, saturated NaHCO3 (8.0 mL) was added, and then diluted with water (8.0 mL). The precipitate was filtered off, washed with water to a neutral pH, then ground in Et2O, and vacuum dried to obtain the title compound (3.1) (0.220 g, 74%) as a white solid. Rf(DCM / ا, 75 / 25): 0.30. 1 H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH3), 3.43 (septet, J = 7.1 Hz, 1H, H Alk ), 4.60 (d, J = 4.2 Hz, 2H, CH2), 6.14 (s, 1H, H Ar ), 7.22 - 7.31 (m, 1H, H Ar), 7.32 - 7.44 (m, 4H, 4xH Ar ), 9.13 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 20.3 (CH3), 24.9 (CH Alk ), 45.6 (CH2), 92.0 (CH Ar ), 127.6 (CH Ar ), 127.7 (CH Ar ), 129.0 (CH Ar ), 137.9 (C q ), 139.9 (C q ), 142.8 (C q ), 149.9 (C q ), 154.4 (C q ). MS (ESI+): m / z C 15 H 16 Calculated value of ClN5: 302.12 [M+H]+, Measured value: 302.33.

[0314] (Example 3.2) Synthesis of N-benzyl-6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.2) In a 2-5 mL sealed tube equipped with a stirring bar, (1.1) (0.850 g, 3.34 mmol, 1.0 equivalent), dioxane (17.0 mL), formate hydrazide (0.221 g, 3.68 mmol, 1.1 equivalent), and PTSA·H2O (0.318 g, 1.67 mmol, 0.5 equivalent) were placed. The mixture was refluxed for 36 hours, cooled, and then MeOH (2 mL) and then DCM (2 mL) were added. The mixture was concentrated and purified by flash chromatography using DCM / siRNA (8 / 2) as the eluate to obtain the title compound (3.2) (0.250 g, 29%) as a white solid. Rf(DCM / ا, 75 / 25): 0.21. 1 H NMR (400 MHz, DMSO-d6) δ : 4.60 (d, J = 6.4 Hz, 2H, CH 2 Bn), 6.17 (s, 1H, H Ar ), 7.26 (t, J = 7.4 Hz, 1H, H Ar ), 7.35 (t, J = 7.4 Hz, 2H, 2xH Ar ), 7.40 (d, J = 7.6 Hz, 2H, 2xH Ar ), 9.17 (s, 1H, NH), 9.41 (s, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ: 45.2 (CH2), 92.1 (CH Ar ), 127.2 (2xCH Ar ), 127.2 (CH Ar ), 128.5 (2xCH Ar ), 137.4 (C q ), 139.1 (C q ), 139.6 (CH Ar ), 142.1 (C q ), 150.0 (C q ). MS (ESI+): m / z C 12 H 10 Calculated value of ClN5: 260.07 [M+H]+, Measured value: 260.1.

[0315] (Example 3.3) Synthesis of N-benzyl-6-chloro-3-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.3) In a 2-5 mL sealed tube equipped with a stirring bar, (1.1) (0.300 g, 1.18 mmol, 1.0 equivalent), dioxane (3.9 mL), cyclopropanecarboxylic acid hydrazide (0.130 g, 1.30 mmol, 1.1 equivalent), and PTSA·H2O (0.023 g, 0.12 mmol, 0.1 equivalent) were placed. The vial was sealed and then placed on a heating block at 100°C for 20 hours. The reaction mixture was cooled and MeOH (2 mL) was added, followed by DCM (2 mL). The mixture was concentrated and purified by flash chromatography using DCM / siRNA (7 / 3) as the eluate to obtain the title compound (3.3) (0.184 g, 52%) as a white solid. Rf(DCM / Axial, 7 / 3): 0.44 1 H NMR (400 MHz, DMSO-d6) δ : 1.06 - 1.15 (m, 4H, 2xCH 2 Alk ), 2.31 (ddd, J = 13.3, 8.0, 5.4 Hz, 1H, H Alk ), 4.58 (d, J = 6.5 Hz, 2H, CH2), 6.12 (s, 1H, H Ar ), 7.26 (t, J = 7.1 Hz, 1H, H Ar ), 7.32 - 7.41 (m, 4H, 4xH Ar ), 9.08 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.8 (CH Alk ), 7.1 (2xCH 2 Alk ), 45.1 (CH2), 91.5 (CH), 127.2 (2xCH Ar ), 127.2 (CH Ar ), 128.5 (2xCH Ar ), 137.4 (C q ), 139.4 (C q ), 142.3 (C q ), 149.6 (C q ), 151.4 (C q ). MS (ESI+): m / z C15 H 14 Calculated value of ClN5: 300.1 [M+H]+, Measured value: 300.1.

[0316] (Example 3.4) Synthesis of N-benzyl-6-chloro-3-cyclopentyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.4) (2.6) To a solution of (0.200 g, 0.75 mmol, 1.0 equivalent) in THF (15.0 mL), the corresponding amine (0.17 mL, 1.51 mmol, 2.0 equivalents) and Et3N (0.21 mL, 1.51 mmol, 2.0 equivalents) were added, and the mixture was refluxed for 3 hours. After cooling, the mixture was concentrated, the residue was ground in water, the solid was filtered off, washed with water, then Et2O, and vacuum dried to obtain (3.4) (0.220 g, 89%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.61 - 1.84 (m, 4H, 2xCH 2シクロペンチル ), 1.92 (dq, J = 12.0, 7.4 Hz, 2H, CH 2シクロペンチル ), 2.02 - 2.18 (m, 2H, CH 2シクロペンチル ), 3.52 (p, J = 8.0 Hz, 1H, H シクロペンチル ), 4.58 (s, 2H, CH 2 Bn ), 6.13 (s, 1H, H Ar ), 7.26 (t, J = 7.1 Hz, 1H, H Ar ), 7.34 (t, J = 7.5 Hz, 2H, 2xH Ar ), 7.39 (d, J = 7.5 Hz, 2H, 2xH Ar ), 9.09 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : 25.0 (2xCH 2シクロペンチル ), 30.2 (2xCH 2シクロペンチル ), 34.3 (CH シクロペンチル ), 45.1 (CH 2 Bn), 91.5 (CH Ar ), 127.2 (2xCH Ar ), 127.2 (CH Ar ), 128.5 (2xCH Ar ), 137.4 (C q ), 139.5 (C q ), 142.28 (C q ), 149.4 (C q ), 153.1 (C q ). MS (ESI+): m / z C 17 H 18 Calculated value of ClN5: 328.1 [M+H]+, Measured value: 328.2.

[0317] (Example 3.5) Synthesis of N-benzyl-6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.5) In a 2-5 mL sealed tube equipped with a stirring bar, (1.1) (0.300 g, 1.18 mmol, 1.0 equivalent), dioxane (3.9 mL), trifluoroacetic acid hydrazide (0.166 g, 1.30 mmol, 1.1 equivalent), and PTSA·H2O (0.023 g, 0.12 mmol, 0.1 equivalent) were placed. The vial was sealed and then placed on a heating block at 100°C for 20 hours. The reaction mixture was cooled, and MeOH (2 mL) and then DCM (2 mL) were added. The mixture was concentrated and purified by flash chromatography using DCM / siRNA (9 / 1) as the eluate to obtain the title compound (3.5) (0.070 g, 18%) as a white solid. Rf(DCM / .'', 9 / 1): 0.63 1 H NMR (400 MHz, DMSO-d6) δ : 4.65 (d, J = 6.2 Hz, 2H, CH2), 6.43 (s, 1H, H Ar ), 7.28 (dq, J = 7.2, 4.9, 3.3 Hz, 1H, H Ar ), 7.35 (dd, J = 8.3, 6.6 Hz, 2H, 2xH Ar), 7.41 (d, J = 7.2 Hz, 2H, 2xH Ar ), 9.52 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 45.19 (CH2), 93.80 (CH Ar ), 118.24 (q, J = 269.9 Hz, CF3), 127.26 (2xCH Ar ), 127.32 (CH Ar ), 128.53 (2xCH Ar ), 136.98 (C q ), 138.45 (q, J = 41.0, 40.3 Hz, C q-CF3 ), 141.85 (C q ), 142.29 (C q ), 151.64 (C q ). MS (ESI+): m / z C 13 Calculated value of H9ClF3N5: 328.1 [M+H]+, Measured value: 328.1.

[0318] (Example 3.6) Synthesis of N-benzyl-6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.6) (1.1) To a solution of (0.750 g, 2.95 mmol, 1.0 equivalent) of dioxane (15.0 mL), acetohydrazide (0.228 g, 3.25 mmol, 1.1 equivalent) and PTSA·H2O (0.281 g, 1.48 mmol, 0.5 equivalent) were added and refluxed for 24 hours. The reaction mixture was cooled and MeOH (10.0 mL) was added. The mixture was directly concentrated using SiO2 to obtain a solid precipitate, and the eluate was directly purified by flash chromatography using DCM / siRNA / MeOH (60 / 40 / 0 to 60 / 30 / 10) to obtain the title compound (3.6) (0.350 g, 43%) as a white solid. Rf(DCM / ا, 75 / 25): 0.24 1H NMR (400 MHz, DMSO-d6) δ : 2.58 (s, 3H, CH3), 4.60 (s, 2H, CH2), 6.14 (s, 1H, H Ar ), 7.22 - 7.42 (m, 5H, 5xH Ar ), 9.09 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 9.4 (CH3), 45.1 (CH2), 91.4 (CH Ar ), 127.1 (2xCH Ar ), 127.2 (CH Ar ), 128.5 (2xCH Ar ), 137.4 (C q ), 139.2 (C q ), 142.3 (C q ), 146.8 (C q ), 149.6 (C q ). MS (ESI+): m / z C 13 H 12 Calculated value of ClN5: 274.1 [M+H]+, Measured value: 274.1.

[0319] (Example 3.7) Synthesis of N-benzyl-6-chloro-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.7) (1.1) To a solution of (0.750 g, 2.95 mmol, 1.0 equivalent) of dioxane (15.0 mL), benzohydrazide (0.442 g, 3.25 mmol, 1.1 equivalent) and PTSA·H2O (0.281 g, 1.48 mmol, 0.5 equivalent) were added and refluxed for 22.5 hours. The reaction mixture was cooled and MeOH (5.0 mL) was added. The mixture was concentrated with SiO2 to obtain a solid precipitate, which was directly purified by flash chromatography using DCM / MeOH (94 / 6) as the eluate to obtain the title compound (3.7) (0.425 g, 46%) as a white solid. Rf(DCM / MeOH, 94 / 6): 0.46 1H NMR (400 MHz, DMSO-d6) δ : 4.64 (d, J = 6.4 Hz, 2H, CH 2 Bn ), 6.27 (s, 1H, H Ar ), 7.27 (t, J = 7.2 Hz, 1H, H Ar ), 7.36 (t, J = 7.5 Hz, 2H, 2xH Ar ), 7.43 (d, J = 7.6 Hz, 2H, 2xH Ar ), 7.58 (dt, J = 13.3, 7.2 Hz, 3H, 3xH Ar ), 8.31 (d, J = 7.5 Hz, 2H, 2xH Ar ), 9.25 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 18 H 14 Calculated value of ClN5: 336.1 [M+H]+, Measured value: 336.1.

[0320] (Example 3.8) Synthesis of 2-[[(6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)aminomethyl]phenol (3.8) (1.7) A suspension of dioxane (1.900 g, 7.03 mmol, 1.0 equivalent) in 40.0 mL was mixed with isobutyric acid hydrazide (1.150 g, 11.25 mmol, 1.6 equivalents), followed by AcOH (0.45 mL, 7.74 mmol, 1.1 equivalents). The mixture was refluxed for 16 hours, cooled, and then MeOH (5.0 mL) and then SiO2 were added to directly obtain a solid precipitate. The mixture was concentrated and purified by flash chromatography using DCM / MeOH (97 / 3 to 93 / 7) as the eluate to obtain (3.8) (1.000 g, 45%) as a white solid. Rf(DCM / MeOH, 92 / 8): 0.15 1H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.42 (p, J = 6.9 Hz, 1H, CH iPr ), 4.37 - 4.61 (m, 2H, CH 2 Bn ), 6.12 (s, 1H, CH Ar ), 6.76 (t, J = 7.4 Hz, 1H, CH Ar ), 6.85 (d, J = 8.0 Hz, 1H, CH Ar ), 7.10 (t, J = 7.7 Hz, 1H, CH Ar ), 7.18 (d, J = 7.6 Hz, 1H, CH Ar ), 8.90 (s, 1H, NH Bn ), 9.82 (s, 1H, OH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 40.2 (CH 2 Bn ), 91.3 (CH Ar ), 115.1 (CH Ar ), 119.1 (CH Ar ), 122.9 (C q ), 128.4 (2xCH Ar ), 139.4 (C q ), 142.3 (C q ), 149.4 (C q ), 154.0 (C q ), 154.8 (C q ). MS (ESI+): m / z C 15 H 16 Calculated value of ClN5O: 318.1 [M+H]+, measured value: 318.2.

[0321] (Example 3.9) Synthesis of 3-[[(6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)aminomethyl]phenol (3.9) In a sealed vial of 10-20 mL equipped with a stirring bar, (1.6) (0.460 g, 1.70 mmol, 1.0 equivalent) was added to dioxane (10.0 mL), and isobutyric acid hydrazide (0.211 g, 2.04 mmol, 1.2 equivalents) and PTSA·H2O (0.197 g, 1.02 mmol, 0.6 equivalents) were added. The vial was sealed and placed on a heating block at 100°C for 17 hours. After cooling, MeOH (3.0 mL) was added, and the mixture was then concentrated with SiO2 to obtain a solid precipitate. The precipitate was directly purified by flash chromatography using DCM / MeOH (97 / 3 to 94 / 6) as the eluate to obtain (3.9) (0.250 g, 46%) as a white solid. Rf(DCM / MeOH, 92 / 8): 0.23 1 H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.42 (p, J = 7.0 Hz, 1H, H iPr ), 4.50 (d, J = 6.2 Hz, 2H, CH 2 Bn ), 6.09 (s, 1H, H Ar ), 6.64 (dd, J = 8.0, 1.8 Hz, 1H, H Ar ), 6.75 (t, J = 2.0 Hz, 1H, H Ar ), 6.79 (d, J = 7.6 Hz, 1H, H Ar ), 7.12 (t, J = 7.8 Hz, 1H, H Ar ), 9.09 (s, 1H, NH Bn ), 9.37 (s, 1H, OH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.9 (2xCH 3 iPr ), 24.4 (CH iPr ), 45.0 (CH 2 Bn ), 91.5 (CHAr ), 113.7 (CH Ar ), 114.2 (CH Ar ), 117.7 (CH Ar ), 129.5 (CH Ar ), 138.8 (Cq), 139.4 (Cq), 142.3 (Cq), 149.4 (Cq), 154.0 (Cq), 157.5 (Cq). MS (ESI+): m / z C 15 H 16 Calculated value of ClN5O: 318.1 [M+H]+, Measured value: 318.3.

[0322] (Example 3.10) Synthesis of 4-[[(6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)aminomethyl]phenol (3.10) In a sealed vial of 10-20 mL equipped with a stirring bar, (1.5) (0.520 g, 1.93 mmol, 1.0 equivalent) was added to dioxane (10.0 mL), and isobutyric acid hydrazide (0.238 g, 2.31 mmol, 1.2 equivalents) and PTSA·H2O (0.223 g, 1.16 mmol, 0.6 equivalents) were added. The vial was sealed and placed on a heating block at 100°C for 17 hours. After cooling, MeOH (3.0 mL) was added, and the mixture was then concentrated with SiO2 to obtain a solid precipitate. The precipitate was directly purified by flash chromatography using DCM / MeOH (97 / 3 to 94 / 6) as the eluate to obtain (3.10) (0.115 g, 19%) as a white solid. Rf(DCM / MeOH, 92 / 8): 0.25. 1 H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.41 (septet, J = 7.0 Hz, 1H, H iPr ), 4.44 (d, J = 6.2 Hz, 2H, CH 2 Bn ), 6.12 (s, 1H, H Ar), 6.71 (d, J = 8.5 Hz, 2H, 2xH Ar ), 7.20 (d, J = 8.5 Hz, 2H, 2xH Ar ), 9.02 (s, 1H, NH Bn ), 9.34 (s, 1H, OH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 44.7 (CH 2 Bn ), 91.4 (CH Ar ), 115.2 (2xCH Ar ), 127.5 (C q ), 128.6 (2xCH Ar ), 139.5 (C q ), 142.2 (C q ), 149.4 (C q ), 153.9 (C q ), 156.6 (C q ). MS (ESI+): m / z C 15 H 16 Calculated value of ClN5O: 318.1 [M+H]+, Measured value: 318.3.

[0323] (Example 3.11) Synthesis of 6-chloro-3-isopropyl-N-[(2-methoxyphenyl)methyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.11) (1.8) To a suspension of (3.000 g, 10.56 mmol, 1.0 equivalent) of dioxane (40.0 mL), isobutyrate hydrazide (1.307 g, 12.67 mmol, 1.2 equivalents) was added, followed by AcOH (0.67 mL, 11.61 mmol, 1.1 equivalents), and the mixture was refluxed for 16 hours. After cooling, MeOH (10.0 mL) was added while vigorously stirring for 5 minutes, followed by SiO2, to directly obtain a solid precipitate. The mixture was concentrated and purified by flash chromatography using DCM / MeOH (99 / 1 to 97 / 3) as the eluate to obtain (3.11) (1.490 g, 43%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.43 (septet, J = 7.1 Hz, 1H, H iPr ), 3.87 (s, 3H, OCH3), 4.51 (d, J = 6.3 Hz, 2H, CH 2 Bn ), 6.06 (s, 1H, H Ar ), 6.91 (t, J = 7.4 Hz, 1H, H Ar ), 7.05 (d, J = 8.1 Hz, 1H, H Ar ), 7.22 (d, J = 7.5 Hz, 1H, H Ar ), 7.28 (td, J = 7.9, 1.8 Hz, 1H, H Ar ), 8.90 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 40.2 (CH 2 Bn ), 55.4 (OCH3), 91.3 (CH Ar ), 110.8 (CH Ar ), 120.4 (CH Ar ), 124.4 (C q ), 127.7 (CH Ar ), 128.6 (CHAr ), 139.4 (C q ), 142.4 (C q ), 149.4 (C q ), 154.0 (C q ), 156.7 (C q ). MS (ESI+): m / z C 16 H 18 Calculated value of ClN5O: 332.1 [M+H]+, Measured value: 332.3.

[0324] (Example 3.12) Synthesis of 6-chloro-3-isopropyl-N-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.12) (2.1) To a solution of (0.150 g, 0.65 mmol, 1.0 equivalent) in dry THF (5.0 mL), aniline (0.12 mL, 1.30 mmol, 2.0 equivalents) was added, followed by 1 M tBuOK in THF (1.30 mL, 1.30 mmol, 2.0 equivalents), and the mixture was stirred at room temperature for 1 hour. After completion, saturated NH4Cl (5.0 mL) and water (1.5 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted with siRNA (2 × 5.0 mL), and then the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1 to 98 / 2) to obtain (3.12) (0.175 g, 94%) as a white solid. Rf(DCM / MeOH, 96 / 4): 0.40 1 H NMR (400 MHz, DMSO-d6) δ : 1.41 (d, J = 7.0 Hz, 6H, 2xCH 3 iPr ), 3.48 (septet, J = 6.9 Hz, 1H, H iPr ), 6.35 (s, 1H, H Ar ), 7.27 (tt, J = 5.7, 2.4 Hz, 1H, H Ar ), 7.40 - 7.58 (m, 4H, 4xH Ar ), 10.46 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.5 (CH iPr ), 92.9 (CH Ar ), 123.6 (2xCH Ar ), 125.7 (CH Ar ), 129.5 (2xCH Ar ), 137.7 (C q ), 139.5 (C q ), 140.2 (C q ), 149.6 (C q ), 154.2 (C q ). MS (ESI+): m / z C 14 H 14 Calculated value of ClN5: 288.1 [M+H]+, Measured value: 288.1.

[0325] (Example 3.13) Synthesis of 6-chloro-3-isopropyl-N-(2-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.13) (2.1) To a solution of (0.100 g, 0.43 mmol, 1.0 equivalent) in dry THF (5.0 mL), 2-aminopyridine (0.082, 0.87 mmol, 2.0 equivalents) was added, followed by 1 M tBuOK in THF (0.87 mL, 0.87 mmol, 2.0 equivalents), and the mixture was stirred at room temperature for 1 hour. After completion, saturated NH4Cl (3.5 mL) and water (1.5 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted with siRNA (2 × 5.0 mL), and then the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2) as the eluate to obtain (3.13) (0.120 g, 96%) as a white solid. Rf(DCM / MeOH, 96 / 4): 0.27 1 H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9 Hz, 6H, 2xCH3 iPr ), 3.50 (septet, J = 7.1, 6.5 Hz, 1H, H iPr ), 7.13 (ddd, J = 7.4, 5.0, 1.0 Hz, 1H, H Ar ), 7.61 (d, J = 8.3 Hz, 1H, H Ar ), 7.82 (ddd, J = 9.0, 7.3, 2.0 Hz, 1H, H Ar ), 8.32 (s, 1H, H Ar ), 8.46 (d, J = 1.9 Hz, 1H, H Ar ), 10.90 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.5 (CH iPr ), 99.5 (CH Ar ), 114.7 (CH Ar ), 118.6 (CH Ar ), 136.6 (C q ), 138.3 (CH Ar ), 139.3 (C q ), 147.3 (CH Ar ), 149.7 (C q ), 153.9 (C q ), 154.3 (C q ). MS (ESI+): m / z C 13 H 13 Calculated value of ClN6: 289.1 [M+H]+, Measured value: 289.2.

[0326] (Example 3.14) Synthesis of 6-chloro-3-isopropyl-N-(3-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.14) (2.1) To a solution of (0.100 g, 0.43 mmol, 1.0 equivalent) in dry THF (5.0 mL), 3-aminopyridine (0.082, 0.87 mmol, 2.0 equivalents) was added, followed by 1 M tBuOK in THF (0.87 mL, 0.87 mmol, 2.0 equivalents), and the mixture was stirred at room temperature for 1 hour. After completion, saturated NH4Cl (3.5 mL) and water (1.5 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted with SiO2 (2 × 5.0 mL), and then the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 96 / 4) to obtain (3.14) (0.115 g, 92%) as a white solid. Rf(DCM / MeOH, 96 / 4): 0.17 1 H NMR (400 MHz, DMSO-d6) δ : 1.41 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.48 (septet, J = 6.9 Hz, 1H, H iPr ), 6.43 (s, 1H, H Ar ), 7.50 (dd, J = 8.2, 4.7 Hz, 1H, H Ar ), 7.91 (dt, J = 8.3, 1.9 Hz, 1H, H Ar ), 8.46 (dd, J = 4.8, 1.5 Hz, 1H, H Ar ), 8.69 (d, J = 2.6 Hz, 1H, H Ar ), 10.55 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.5 (CH iPr ), 93.8 (CH Ar ), 124.1 (CH Ar ), 130.8 (CH Ar ), 134.6 (C q ), 139.4 (C q ), 140.0 (C q), 145.1 (CH Ar ), 146.4 (CH Ar ), 149.6 (C q ), 154.2 (C q ). MS (ESI+): m / z C 13 H 13 Calculated value of ClN6: 289.1 [M+H]+, Measured value: 289.1.

[0327] (Example 3.15) Synthesis of 6-chloro-3-isopropyl-N-(4-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.15) (2.1) To a solution of (0.150 g, 0.65 mmol, 1.0 equivalent) of (2.1) in dry THF (5.0 mL), 4-aminopyridine (0.123 g, 1.30 mmol, 2.0 equivalents) was added, followed by 1 M tBuOK in THF (1.30 mL, 1.30 mmol, 2.0 equivalents), and the mixture was stirred at room temperature for 1 hour. After completion, saturated NH4Cl (5.0 mL) and water (1.5 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted with ELISA (2 × 5.0 mL), and then the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1 to 96 / 4) to obtain (3.15) (0.180 g, 96%) as a white solid. Rf(DCM / MeOH, 96 / 4): 0.10 1 H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.50 (septet, J = 6.9 Hz, 1H, H iPr ), 6.88 (s, 1H, H Ar ), 7.34 - 7.70 (m, 2H, 2xH Ar ), 8.39 - 8.68 (m, 2H, 2xH Ar ), 10.69 (s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.5 (CHi Pr ), 96.7 (CH Ar ), 115.5 (CH Ar ), 138.1 (C q ), 139.5 (C q ), 145.7 (C q ), 149.6 (C q ), 150.8 (CH Ar ), 154.3 (C q ). MS (ESI+): m / z C 13 H 13 Calculated value of ClN6: 289.1 [M+H]+, Measured value: 289.1.

[0328] (Example 3.16) Synthesis of 6-chloro-3-isopropyl-N-(4-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.16) (1.4) To a suspension of (0.390 g, 1.53 mmol, 1.0 equivalent) of dioxane (25.0 mL), isobutyrate hydrazide (0.189 g, 1.89 mmol, 1.2 equivalents) was added, followed by APTS.H2O (0.177 g, 0.92 mmol, 0.6 equivalents), and the mixture was refluxed for 20 hours. After cooling, DCM (5.0 mL), MeOH (5.0 mL), and NaHCO3 (0.100 g) were added, and the mixture was vigorously stirred for 5 minutes. SiO2 was added to obtain a solid precipitate, and the mixture was concentrated and purified by flash chromatography using DCM / MeOH (95 / 5 to 93 / 7) as the eluate to obtain (3.16) (0.175 g, 38%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.43 (p, J = 7.0 Hz, 1H, H iPr ), 4.64 (s, 2H, CH 2 Bn ), 6.15 (s, 1H, HAr ), 7.31 - 7.43 (m, 2H, 2xH Ar ), 8.44 - 8.60 (m, 2H, 2xH Ar ), 9.12 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ: 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 44.1 (CH 2 Bn ), 91.7 (CH Ar ), 122.1 (2xCH Ar ), 139.4 (Cq), 142.4 (Cq), 146.5 (C q ), 149.5 (Cq), 149.7 (2xCH Ar ), 154.0 (Cq). MS (ESI+): m / z C 14 H 15 The calculated value of ClN6 for H is: 303.1 [M+H]+, the measured value: 303.2.

[0329] (Example 3.17) Synthesis of 6-chloro-3-isopropyl-N-(3-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.17) (1.3) (1.500 g, 5.88 mmol, 1.0 equivalent) was suspended in dioxane (20.0 mL), hydrazide isobutyrate (0.667 g, 6.47 mmol, 1.1 equivalent) was added, followed by AcOH (0.37 mL, 6.47 mmol, 1.1 equivalent), and the mixture was refluxed for 16 h. After cooling, MeOH (10.0 mL) and NaHCO3 (1.000 g) were added, and the mixture was stirred vigorously for 5 min, then SiO2 was added to directly obtain the solid precipitate. The mixture was concentrated and purified by flash chromatography using DCM / MeOH (from 98 / 2 to 93 / 7) as the eluent to obtain (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, 2xCH 3 iPr ), 3.42 (septet, J = 7.1 Hz, 1H, H iPr ), 4.63 (s, 2H, CH 2 Bn ), 6.26 (s, 1H, H Ar ), 7.37 (dd, J = 7.9, 4.8 Hz, 1H, H Ar ), 7.79 (dt, J = 7.9, 2.0 Hz, 1H, H Ar ), 8.48 (dd, J = 4.9, 1.6 Hz, 1H, H Ar ), 8.64 (d, J = 2.3 Hz, 1H, H Ar ), 9.10 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 42.8 (CH 2 Bn ), 91.6 (CH Ar ), 123.6 (CH Ar ), 133.1 (C q ), 135.1 (CH Ar ), 139.4 (C q ), 142.2 (C q ), 148.5 (CH Ar ), 148.9 (CH Ar ), 149.5 (C q ), 154.0 (C q ). MS (ESI+): m / z C 14 H 15 Calculated value of ClN6: 303.1 [M+H]+, Measured value: 303.3.

[0330] (Example 3.18) Synthesis of 6-chloro-3-isopropyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.18) (1.2) To a solution of (5.000 g, 19.60 mmol, 1.0 equivalent) of dioxane (80.0 mL), isobutyric acid hydrazide (2.224 g, 21.560 mmol, 1.1 equivalent) and then AcOH (1.25 mL, 21.56 mmol, 1.1 equivalent) were added, and the mixture was refluxed for 15 hours. After cooling, the solvent was removed, and the crude product was ground in water (150.0 mL). The resulting solid was filtered, washed with water to a neutral pH, washed with EtOH and Et2O, and then vacuum dried to obtain the first portion (1.880 g) of (3.18). The aqueous layer was extracted twice with SiO2 (2 × 50.0 mL), then the organic layers were combined, washed with saturated NaHCO3, dehydrated with MgSO4, filtered, and concentrated to obtain the second portion (0.500 g) of (3.18). Amount of (3.18): 2.380 g, as a white solid. Rf(DCM / MeOH, 94 / 6): 0.30 1 H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.43 (septet, J = 7.0 Hz, 1H, H iPr ), 4.46 - 4.78 (m, 2H, CH 2 Bn ), 6.15 (s, 1H, H Ar ), 7.30 (dd, J = 7.6, 4.8 Hz, 1H, H Ar ), 7.38 (d, J = 7.8 Hz, 1H, H Ar ), 7.78 (td, J = 7.7, 1.9 Hz, 1H, H Ar ), 8.55 (d, J = 4.9 Hz, 1H, H Ar ), 8.98 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 14 H 15 Calculated value of ClN6: 303.1 [M+H]+, Measured value: 303.2.

[0331] (Example 3.19) Synthesis of 6-chloro-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.19) (1.2) To a solution of (4.000 g, 15.68 mmol, 1.0 equivalent) of dioxane (52.0 mL), the corresponding acid hydrazide (1.130 g, 18.82 mmol, 1.2 equivalents) and APTS.H2O (3.028 g, 15.68 mmol, 1.0 equivalent) were added. The mixture was refluxed for 1 hour, then cooled, and MeOH (20.0 mL) and Na2CO3 (1.000 g) were added, and the mixture was stirred for 5 minutes. SiO2 was added to obtain a solid precipitate, which was concentrated and then directly purified using flash chromatography with DCM / MeOH (98 / 2 to 95 / 5) as the eluate to obtain (3.19) (0.580 g, 14%) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ : 4.69 (d, J = 5.9 Hz, 2H, CH 2 Bn ), 6.20 (s, 1H, H Ar ), 7.31 (dd, J = 7.5, 5.0 Hz, 1H, H Ar ), 7.39 (d, J = 7.8 Hz, 1H, H Ar ), 7.78 (tt, J = 7.7, 1.6 Hz, 1H, H Ar ), 8.55 (d, J = 4.8 Hz, 1H, H Ar ), 9.02 (s, 1H, NH Bn ), 9.42 (d, J = 1.3 Hz, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ: 47.2 (CH 2 Bn ), 92.4 (CH Ar ), 121.5 (CH Ar ), 122.6 (CH Ar ), 137.1 (CH Ar ), 139.0 (C q ), 139.6 (CH Ar), 142.2 (C q ), 149.1 (CH Ar ), 150.0 (C q ), 156.6 (C q ). MS (ESI+): m / z Calculated value for C 11 H9ClN6: 261.1 [M+H]+, Observed value: 261.2.

[0332] (Example 3.20) Synthesis of 6-chloro-3-methyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.20) (1.2) A solution of (4.000 g, 15.68 mmol, 1.0 equivalent) in dioxane (52.0 mL) was added to the corresponding acid hydrazide (1.467 g, 18.82 mmol, 1.2 equivalents) and APTS.H2O (3.028 g, 15.68 mmol, 1.0 equivalent). The mixture was refluxed for 1 hour and then cooled. After that, MeOH (10.0 mL) and 7N NH3 in MeOH (6.0 mL) were added and stirred for 10 minutes. SiO2 was added to obtain a solid precipitate, which was concentrated and then directly purified by flash chromatography using DCM / MeOH (from 98 / 2 to 95 / 5) as the eluent to obtain (3.20) (1.150 g, 27%) as a gray solid. 1 1H NMR (400 MHz, DMSO-d6) δ: 2.59 (s, 3H, CH3), 4.56 - 4.86 (m, 2H, CH 2 Bn ), 6.16 (s, 1H, H Ar ), 7.30 (dd, J = 7.5, 4.9 Hz, 1H, H Ar ), 7.38 (d, J = 7.9 Hz, 1H, H Ar ), 7.78 (td, J = 7.7, 1.8 Hz, 1H, H Ar ), 8.48 - 8.60 (m, 1H, H Ar ), 8.93 (s, 1H, NH Bn ). 13C NMR (101 MHz, DMSO-d6) δ: 9.4 (CH3), 47.2 (CH 2 Bn ), 91.7 (CH Ar ), 121.4 (CH Ar ), 122.6 (CH Ar ), 137.0 (CH Ar ), 139.2 (C q ), 142.4 (C q ), 146.8 (C q ), 149.1 (CH Ar ), 149.6 (C q ), 156.6 (C q ). MS (ESI+): m / z C 12 H 11 Calculated value of ClN6: 275.1 [M+H]+, Measured value: 275.2.

[0333] (Example 3.21) Synthesis of 6-chloro-3-ethyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.21) In a 10-20 mL sealed tube equipped with a stirring bar, (1.2) (2.000 g, 7.84 mmol, 1.0 equivalent), dioxane (15.6 mL), the corresponding hydrazide (0.768 g, 8.62 mmol, 1.1 equivalent), and AcOH (0.50 mL, 8.62 mmol, 1.1 equivalent) were placed. The vial was sealed and then placed on a heating block at 115°C for 23 hours. After cooling, the mixture was poured onto saturated NaHCO3 (20.0 mL) and then water (40.0 mL) was added. The aqueous mixture was extracted three times with siRNA (3 × 30 mL), then the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (96 / 4 to 94 / 6) as the eluate to obtain (3.21) (0.550 g, 24%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.34 (t, J = 7.5 Hz, 3H, CH 3-CH2), 3.00 (q, J = 7.6 Hz, 2H, CH 2-CH3 ), 4.68 (d, J = 6.2 Hz, 2H, CH 2 Bn ), 6.16 (s, 1H, H Ar ), 7.30 (dd, J = 7.5, 4.8 Hz, 1H, H Ar ), 7.38 (d, J = 7.8 Hz, 1H, H Ar ), 7.78 (td, J = 7.7, 1.8 Hz, 1H, H Ar ), 8.55 (d, J = 5.3 Hz, 1H, H Ar ), 8.96 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ: 10.8 (CH 3-CH2 ), 17.3 (CH 2-CH3 ), 47.2 (CH 2 Bn ), 91.8 (CH Ar ), 121.4 (CH Ar ), 122.6 (CH Ar ), 137.1 (CH Ar ), 139.3 (C q ), 142.5 (C q ), 149.1 (CH Ar ), 149.6 (C q ), 150.9 (C q ), 156.6 (C q ). MS (ESI+): m / z C 13 H 13 Calculated value of ClN6: 289.1 [M+H]+, Measured value: 289.2.

[0334] (Example 3.22) Synthesis of 6-chloro-3-propyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.22) (2.7) To a solution of (approximately 70% purity, 0.800 g, 2.42 mmol, 1.0 equivalent) in THF (11.0 mL), Et3N (0.48 mL, 3.39 mmol, 1.4 equivalents) and the corresponding amine (0.367 g, 3.39 mmol, 1.4 equivalents) were added, and the mixture was refluxed for 1.5 hours. After cooling, the solid was filtered off, washed with THF, and the filtrate was concentrated. The eluate was purified by flash chromatography using DCM / siRNA (98 / 2 to 96 / 4) to obtain (3.22) (0.480 g, 65%) as a white solid. 1 H 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, CH 2 Bn ), 6.16 (s, 1H, H Ar ), 7.31 (dd, J = 7.5, 4.9 Hz, 1H, H Ar ), 7.38 (d, J = 7.9 Hz, 1H, H Ar ), 7.78 (td, J = 7.7, 1.8 Hz, 1H, H Ar ), 8.55 (dd, J = 5.2, 1.8 Hz, 1H, H Ar ), 8.96 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ: 13.6 (CH3), 19.4 (CH2), 25.4 (CH2), 47.2 (CH 2 Bn ), 91.8 (CH Ar ), 121.4 (CH Ar ), 122.6 (CH Ar ), 137.0 (CH Ar ), 139.2 (C q ), 142.5 (C q ), 149.1 (CH Ar ), 149.5 (C q ), 149.8 (Cq ), 156.6 (C q ). MS (ESI+): m / z C 14 H 15 Calculated value of ClN6: 303.1 [M+H]+, Measured value: 303.3.

[0335] (Example 3.23) Synthesis of 3-tert-butyl-6-chloro-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.23) (1.2) To a solution of (2.000 g, 7.84 mmol, 1.0 equivalent) of dry dioxane (31.0 mL), the corresponding hydrazide (1.033 g, 8.62 mmol, 1.1 equivalent) and AcOH (0.50 mL, 8.62 mmol, 1.1 equivalent) were added, and the mixture was refluxed for 17 hours. After cooling, the reaction mixture was poured onto saturated NaHCO3 (100.0 mL) and siRNA (60.0 mL). The two-phase mixture was vigorously stirred for 10 minutes, and the layers were separated. The aqueous layer was extracted twice with siRNA (2 × 50.0 mL), and the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (97 / 3 to 93 / 7) to obtain (3.23) (0.880 g, 35%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.50 (s, 9H, 3xCH 3 tBu ), 4.67 (d, J = 6.9 Hz, 2H, CH 2 Bn ), 6.15 (s, 1H, H Ar ), 7.30 (dd, J = 7.5, 4.9 Hz, 1H, H Ar ), 7.38 (d, J = 7.8 Hz, 1H, H Ar ), 7.78 (td, J = 7.7, 1.8 Hz, 1H, H Ar ), 8.49 - 8.63 (m, 1H, H Ar ), 8.96 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : 27.0 (3xCH 3 tBu ), 32.4 (C q tBu ), 47.2 (CH 2 Bn ), 91.5 (CH Ar ), 121.4 (CH Ar ), 122.6 (CH Ar ), 137.1 (CH Ar ), 140.2 (CH Ar ), 142.5 (C q ), 148.7 (C q ), 149.1 (C q ), 155.2 (C q ), 156.7 (C q ). MS (ESI+): m / z C 15 H 17 Calculated value of ClN6: 317.13 [M+H]+, Measured value: 317.3.

[0336] (Example 3.24) Synthesis of 6-chloro-3-cyclopropyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.24) (1.2) To a solution of (4.000 g, 15.68 mmol, 1.0 equivalent) of dioxane (52.0 mL), the corresponding hydrazide (1.884 g, 18.82 mmol, 1.2 equivalents) and AcOH (1.00 mL, 17.25 mmol, 1.1 equivalents) were added. The mixture was refluxed for 15 hours, cooled, and then MeOH (20 mL) and DCM (20 mL) were added to dissolve the reaction mixture. SiO2 was added to obtain a solid precipitate, which was concentrated and then directly purified using flash chromatography with DCM / MeOH (98 / 2 to 95 / 5) as the eluate to obtain (3.24) (1.620 g, 34%) as a pale pink solid. Rf(DCM / MeOH, 94 / 6): 0.28 1 H NMR (400 MHz, DMSO-d6) δ : 1.02 - 1.23 (m, 4H, 2xCH 2 cPr), 2.32 (td, J = 8.2, 4.3 Hz, 1H, H cPr ), 4.67 (d, J = 6.0 Hz, 2H, CH 2 Bn ), 6.15 (s, 1H, H Ar ), 7.30 (dd, J = 7.4, 4.9 Hz, 1H, H Ar ), 7.37 (d, J = 7.8 Hz, 1H, H Ar ), 7.78 (t, J = 7.7 Hz, 1H, H Ar ), 8.55 (d, J = 4.9 Hz, 1H, H Ar ), 8.94 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ: 4.8 (CH cPr ), 7.1 (2xCH 2 cPr ), 47.2 (CH 2 Bn ), 91.8 (CH Ar ), 121.4 (CH Ar ), 122.6 C(H Ar ), 137.0 (CH Ar ), 139.3 (C q ), 142.4 (C q ), 149.1 (CH Ar ), 149.6 (C q ), 151.4 (C q ), 156.6 (C q ). MS (ESI+): m / z C 14 H 13 Calculated value of ClN6: 301.1 [M+H]+, Measured value: 301.2.

[0337] (Example 3.25) Synthesis of 6-chloro-3-cyclobutyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.25) In a 10-20 mL sealed tube equipped with a stirring bar, (1.2) (1.900 g, 7.45 mmol, 1.0 equivalent), dioxane (15.0 mL), the corresponding hydrazide (0.984 g, 8.19 mmol, 1.1 equivalent), and AcOH (0.47 mL, 8.19 mmol, 1.1 equivalent) were placed. The vial was sealed and then placed on a heating block at 115°C for 23 hours. After cooling, the mixture was poured onto saturated NaHCO3 (20.0 mL), and then water (40.0 mL) was added. The aqueous mixture was extracted three times with HCl (3 × 30 mL), then the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using HCl (100%) as the eluate to obtain (3.25) (0.550 g, 23%) as a white solid. Rf(æ,100%):0.14 1 H 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, 2xCH 2 cBut ), 3.95 (p, J = 8.4 Hz, 1H, H cBut ), 4.68 (s, 2H, CH 2 Bn ), 6.14 (s, 1H, H Ar ), 7.30 (dd, J = 7.5, 4.9 Hz, 1H, H Ar ), 7.38 (d, J = 7.9 Hz, 1H, H Ar ), 7.78 (td, J = 7.7, 1.8 Hz, 1H, H Ar ), 8.55 (d, J = 5.4 Hz, 1H, H Ar ), 8.97 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 15 H 15Calculated value of ClN6: 315.1 [M+H]+, Measured value: 315.3.

[0338] (Example 3.26) Synthesis of 6-chloro-3-cyclopentyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.26) (1.2) To a solution of (4.000 g, 15.68 mmol, 1.0 equivalent) of dioxane (52 mL), the corresponding hydrazide (1.884 g, 18.82 mmol, 1.2 equivalents) and AcOH (1.00 mL, 17.25 mmol, 0.1 equivalent) were added. The mixture was refluxed for 15 hours, cooled, and then MeOH (20 mL) and DCM (20 mL) were added to dissolve the reaction mixture. SiO2 was added to obtain a solid precipitate, which was concentrated and then directly purified using flash chromatography with DCM / MeOH (94 / 6) as the eluate to obtain (3.26) (1.620 g, 34%) as a pale pink solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.64 - 1.85 (m, 4H, 2xCH 2シクロペンチル ), 1.93 (dq, J = 11.9, 7.2 Hz, 2H, CH 2シクロペンチル ), 2.10 (qd, J = 11.8, 9.6, 6.5 Hz, 2H, CH 2シクロペンチル ), 3.53 (p, J = 8.0 Hz, 1H, CH シクロペンチル ), 4.60 - 4.76 (s, 2H, CH 2 Bn ), 6.15 (s, 1H, H Ar ), 7.30 (dd, J = 7.5, 4.8 Hz, 1H, H Ar ), 7.38 (d, J = 7.8 Hz, 1H, H Ar ), 7.78 (td, J = 7.7, 1.8 Hz, 1H, H Ar ), 8.51 - 8.61 (m, 1H, H Ar ), 8.95 (s, 1H, NH Bn ). 13C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 16 H 17 Calculated value of ClN6: 329.1 [M+H]+, Measured value: 329.3.

[0339] (Example 3.27) Synthesis of 6-chloro-3-cyclohexyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.27) In a 10-20 mL sealed tube equipped with a stirring bar, (1.2) (1.500 g, 5.88 mmol, 1.0 equivalent), dioxane (17.8 mL), the corresponding acid hydrazide (0.939 g, 6.47 mmol, 1.1 equivalent), and AcOH (0.37 mL, 6.47 mmol, 1.1 equivalent) were placed. The vial was sealed and then placed on a heating block at 110°C for 21 hours. The reaction mixture was cooled and MeOH (3.0 mL) was added. The mixture was concentrated using SiO2 to obtain a solid precipitate, which was purified by flash chromatography using DCM / MeOH (97 / 3 to 93 / 7) as the eluate to obtain (3.27) (0.800 g, 40%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.39 (dt, J = 36.4, 12.5 Hz, 3H, H (CH2) cHex & CH 2 cHex ), 1.67 (dt, J = 24.1, 12.5 Hz, 3H, H (CH2) cHex & CH 2 cHex ), 1.81 (d, J = 12.3 Hz, 2H, CH 2 cHex ), 2.01 (d, J = 12.6 Hz, 2H, CH 2 cHex ), 3.15 (t, J = 11.5 Hz, 1H, H cHex ), 4.68 (s, 2H, CH 2 Bn ), 6.14 (s, 1H, H Ar ), 7.30 (dd, J = 7.5, 4.9 Hz, 1H, H Ar), 7.38 (d, J = 7.7 Hz, 1H, H Ar ), 7.78 (td, J = 7.7, 3.7 Hz, 1H, H Ar ), 8.51 - 8.63 (m, 1H, H Ar ), 8.97 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : 25.3 (2xCH 2 cHex ), 25.5 (CH 2 cHex ), 29.8 (2xCH 2 cHex ), 33.3 (CH cHex ), 47.2 (CH 2 Bn ), 91.8 (CH Ar ), 121.4 (CH Ar ), 122.6 (CH Ar ), 129.5 (C q ), 137.1 (CH Ar ), 139.2 (C q ), 142.5 (C q ), 149.1 (CH Ar ), 149.4 (C q ), 153.2 (C q ). MS (ESI+): m / z C 17 H 19 Calculated value of ClN6: 343.1 [M+H]+, Measured value: 343.3.

[0340] (Example 3.28) Synthesis of 6-chloro-3-phenyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.28) In a 10-20 mL sealed tube equipped with a stirring bar, (1.2) (1.500 g, 5.88 mmol, 1.0 equivalent), dioxane (17.8 mL), the corresponding acid hydrazide (0.899 g, 6.47 mmol, 1.1 equivalent), and AcOH (0.37 mL, 6.47 mmol, 1.1 equivalent) were placed. The vial was sealed and then placed on a heating block at 110°C for 21 hours. The reaction mixture was cooled and MeOH (3.0 mL) was added. The mixture was concentrated using SiO2 to obtain a solid precipitate, which was purified by flash chromatography using DCM / MeOH (97 / 3 to 93 / 7) as the eluate to obtain (3.28) (0.750 g, 38%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6) δ : 4.73 (d, J = 5.9 Hz, 2H, CH 2 Bn ), 7.32 (dd, J = 7.5, 4.9 Hz, 1H, H Ar ), 7.42 (d, J = 7.8 Hz, 1H, H Ar ), 7.59 (dt, J = 13.6, 7.1 Hz, 3H, 3xH Ar ), 7.80 (t, J = 7.7 Hz, 1H, H Ar ), 8.32 (d, J = 7.6 Hz, 2H, H Ar ), 8.57 (d, J = 4.9 Hz, 1H, H Ar ), 9.11 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 17 H 13 Calculated value of ClN6: 337.1 [M+H]+, Measured value: 337.3.

[0341] (Example 3.29) Synthesis of 6-chloro-N-(2-pyridylmethyl)-3-sec-butyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.29) (2.2) To a solution of (0.565 g, 2.31 mmol, 1.0 equivalent) in THF (23.0 mL), the corresponding amine (0.44 mL, 3.00 mmol, 1.3 equivalents) and DIPEA (0.61 mL, 3.46 mmol, 1.5 equivalents) were added, and the mixture was refluxed for 5 hours. After cooling, the solvent was removed, and the crude product was ground in H2O (10.0 mL) and saturated NaHCO3 (10.0 mL). The resulting solid was filtered, washed with water to a neutral pH, then with Et2O, and dried under vacuum to obtain (3.29) (0.600 g, 82%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ : 0.84 (t, J = 7.4 Hz, 3H, CH 3-CH2 ), 1.35 (d, J = 7.0 Hz, 3H, CH 3-CH ), 1.82 (ddq, J = 68.8, 13.8, 7.1 Hz, 2H, CH 2-CH3 ), 3.24 - 3.31 (m, 1H, H C-CH3 ), 4.67 (d, J = 5.7 Hz, 2H, CH 2 Bn ), 6.15 (s, 1H, H Ar ), 7.31 (dd, J = 7.5, 4.9 Hz, 1H, H Ar ), 7.39 (d, J = 7.9 Hz, 1H, H Ar ), 7.78 (td, J = 7.7, 1.8 Hz, 1H, H Ar ), 8.55 (d, J = 4.9 Hz, 1H, H Ar ), 8.98 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ: 11.4 (CH 3-CH2 ), 17.6 (CH 3-CH ), 26.8 (CH 2-CH3 ), 30.9 (CH -CH3 ), 47.2 (CH 2 Bn ), 91.8 (CH Ar ), 121.5 (CH Ar ), 122.6 (CHAr ), 137.1 (CH Ar ), 139.3 (C q ), 142.5 (C q ), 149.1 (CH Ar ), 149.4 (C q ), 153.2 (C q ), 156.6 (C q ). MS (ESI+): m / z C 15 H 17 Calculated value of ClN6: 317.8 [M+H]+, Measured value: 317.2.

[0342] (Example 3.30) Synthesis of 6-chloro-3-(1-ethylpropyl)-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.30) (2.3) To a solution of (0.510 g, 1.97 mmol, 1.0 equivalent) in THF (20.0 mL), the corresponding amine (0.38 mL, 2.56 mmol, 1.3 equivalents) and DIPEA (0.52 mL, 2.95 mmol, 1.5 equivalents) were added, and the mixture was refluxed for 5 hours. After cooling, the solvent was removed, and the crude product was ground in H2O (10.0 mL) and saturated NaHCO3 (10.0 mL). The resulting solid was filtered, washed with water to a neutral pH, then with Et2O, and dried under vacuum to obtain (3.30) (0.580 g, 89%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ : 0.77 (t, J = 7.4 Hz, 6H, 2xCH 3-CH2 ), 1.83 (ddt, J = 37.0, 13.5, 6.9 Hz, 4H, 2xCH 2-CH3 ), 3.10 - 3.24 (m, 1H, H iPent ), 4.67 (d, J = 5.8 Hz, 2H, CH 2 Bn ), 6.15 (s, 1H, H Ar ), 7.31 (dd, J = 7.4, 4.9 Hz, 1H, H Ar), 7.40 (d, J = 7.9 Hz, 1H, H Ar ), 7.79 (td, J = 7.7, 1.7 Hz, 1H, H Ar ), 8.55 (d, J = 4.9 Hz, 1H, H Ar ), 8.98 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 16 H 19 Calculated value of ClN6: 331.1 [M+H]+, Measured value: 331.2.

[0343] (Example 3.31) Synthesis of 6-chloro-3-isobutyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.31) (2.4) (0.290 g, 1.18 mmol, 1.0 equivalent) in a solution of THF (11.0 mL) was mixed with the corresponding amine (0.23 mL, 1.54 mmol, 1.3 equivalent) and DIPEA (0.31 mL, 1.78 mmol, 1.5 equivalent), and the mixture was refluxed for 1 hour. After cooling, Et2O (30.0 mL) was added, the precipitate was filtered off, washed with water, ground in Et2O, and then vacuum dried to obtain (3.31) (0.285 g, 76%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ : 0.94 (d, J = 6.6 Hz, 6H, 2xCH 3 iPr ), 2.21 (septet, J = 6.8 Hz, 1H, H iPr ), 2.89 (d, J = 7.2 Hz, 2H, CH 2-CH ), 4.68 (s, 2H, CH 2 Bn ), 6.16 (s, 1H, H Ar ), 7.31 (dd, J = 7.5, 4.9 Hz, 1H, H Ar ), 7.39 (d, J = 7.8 Hz, 1H, HAr ), 7.79 (td, J = 7.7, 1.8 Hz, 1H, H Ar ), 8.55 (d, J = 4.7 Hz, 1H, H Ar ), 8.95 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 15 H 17 Calculated value of ClN6: 317.8 [M+H]+, Measured value: 317.2.

[0344] (Example 3.32) Synthesis of 6-chloro-3-(2-pyridyl)-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.32) In a 10-20 mL sealed tube equipped with a stirring bar, (1.2) (1.250 g, 4.90 mmol, 1.0 equivalent), dioxane (10.0 mL), the corresponding acid hydrazide (0.778 g, 5.39 mmol, 1.1 equivalent), and PTSA·H2O (0.946 g, 4.90 mmol, 1.0 equivalent) were placed. The vial was sealed and then placed on a heating block at 110°C for 19 hours. After cooling, MeOH (5.0 mL) and 7M NH3 in MeOH (3.0 mL) were added, and the mixture was concentrated with SiO2 to obtain a solid precipitate. This precipitate was directly purified by flash chromatography using DCM / MeOH (98 / 2 to 90 / 10) as the eluate to obtain (3.32) (0.300 g, 18%) as a yellow solid. Rf(DCM / MeOH, 94 / 6): 0.10 1 H NMR (400 MHz, DMSO-d6) δ : 4.74 (s, 2H, CH 2 Bn ), 6.32 (s, 1H, H Ar ), 7.32 (dd, J = 7.5, 5.0 Hz, 1H, H Ar ), 7.43 (d, J = 7.9 Hz, 1H, H Ar), 7.53 - 7.65 (m, 1H, H Ar ), 7.80 (td, J = 7.7, 1.8 Hz, 1H, H Ar ), 8.05 (td, J = 7.8, 1.8 Hz, 1H, H Ar ), 8.23 ​​(d, J = 7.9 Hz, 1H, H Ar ), 8.57 (d, J = 4.9 Hz, 1H, H Ar ), 8.81 (d, J = 4.9 Hz, 1H, H Ar ), 9.13 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 16 H 12 Calculated value of ClN7: 338.1 [M+H]+, Measured value: 338.2.

[0345] (Example 3.33) Synthesis of 6-chloro-3-(3-pyridyl)-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.33) In a 10-20 mL sealed tube equipped with a stirring bar, (1.2) (1.250 g, 4.90 mmol, 1.0 equivalent), dioxane (10.0 mL), the corresponding hydrazide (0.754 g, 5.39 mmol, 1.1 equivalent), and PTSA·H2O (0.946 g, 4.90 mmol, 1.0 equivalent) were placed. The vial was sealed and then placed on a heating block at 110°C for 19 hours. After cooling, 7N NH3 in MeOH (2.80 mL, 19.6 mmol, 4.0 equivalent) was added, the mixture was concentrated using silica, and then directly purified by flash chromatography using DCM / MeOH (98 / 2 to 94 / 6) as the eluate to obtain (3.33) (0.275 g, 17%) as a white solid. Rf(DCM / MeOH, 94 / 6): 0.25 1H NMR (400 MHz, DMSO-d6) δ : 4.74 (s, 2H, CH 2 Bn ), 6.34 (s, 1H, H Ar ), 7.24 - 7.39 (m, 1H, H Ar ), 7.42 (d, J = 7.9 Hz, 1H, H Ar ), 7.65 (dd, J = 8.1, 4.9 Hz, 1H, H Ar ), 7.75 - 7.90 (m, 1H, H Ar ), 8.57 (d, J = 4.8 Hz, 1H, H Ar ), 8.64 (dt, J = 8.1, 2.0 Hz, 1H, H Ar ), 8.74 (dd, J = 4.8, 1.7 Hz, 1H, H Ar ), 9.19 (s, 1H, NH Bn ), 9.44 (d, J = 2.2 Hz, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 16 H 12 Calculated value of ClN7: 338.1 [M+H]+, Measured value: 338.2.

[0346] (Example 3.34) Synthesis of 6-chloro-3-(4-pyridyl)-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.34) In a 10-20 mL sealed tube equipped with a stirring bar, (1.2) (1.250 g, 4.90 mmol, 1.0 equivalent), dioxane (10.0 mL), the corresponding hydrazide (0.778 g, 5.39 mmol, 1.1 equivalent), and PTSA·H2O (0.946 g, 4.90 mmol, 1.0 equivalent) were placed. The vial was sealed and then placed on a heating block at 110°C for 19 hours. After cooling, 7N NH3 in MeOH (2.80 mL, 19.6 mmol, 4.0 equivalent) was added, the mixture was concentrated using silica, and then directly purified by flash chromatography using DCM / MeOH (98 / 2 to 94 / 6) as the eluate to obtain (3.34) (0.310 g, 19%) as a white solid. Rf(DCM / MeOH, 94 / 6): 0.29 1 H NMR (400 MHz, DMSO-d6) δ : 4.74 (d, J = 6.1 Hz, 2H, CH 2 Bn ), 6.37 (s, 1H, H Ar ), 7.32 (dd, J = 7.3, 5.1 Hz, 1H, H Ar ), 7.42 (d, J = 7.8 Hz, 1H, H Ar ), 7.80 (dd, J = 8.2, 6.5 Hz, 1H, H Ar ), 8.23 ​​- 8.38 (m, 2H, 2xH Ar ), 8.56 (d, J = 4.9 Hz, 1H, H Ar ), 8.72 - 8.92 (m, 2H, 2xH Ar ), 9.21 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 16 H 12 Calculated value of ClN7: 338.1 [M+H]+, Measured value: 338.2.

[0347] (Example 3.35) Synthesis of N-[(4-aminophenyl)methyl]-6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.35) (2.1) To a solution of (0.300 g, 1.30 mmol, 1.0 equivalent) in THF (18.0 mL), 4-(aminomethyl)aniline dihydrochloride (0.512 g, 2.60 mmol, 2.0 equivalent) and Et3N (1.28 mL, 9.09 mmol, 7.0 equivalent) were added, and the mixture was refluxed for 2 hours. After cooling, the solid was filtered off, washed with THF, and the filtrate was concentrated and directly purified by flash chromatography using DCM / MeOH (98 / 2 to 96 / 4) as the eluate to obtain (3.35) (0.245 g, 60%) as a pale yellow solid. Rf(DCM / MeOH, 94 / 6): 0.24 1 H NMR (400 MHz, DMSO-d6) δ: 1.37 (d, J = 7.0 Hz, 6H, 2xCH 3 iPr ), 3.42 (h, J = 6.9 Hz, 1H, H iPr ), 4.37 (d, J = 6.3 Hz, 2H, CH 2 Bn ), 5.01 (s, 2H, NH2), 6.10 (s, 1H, H Ar ), 6.51 (d, J = 8.4 Hz, 2H, 2xH Ar ), 7.05 (d, J = 8.3 Hz, 2H, 2xH Ar ), 8.95 (t, J = 6.2 Hz, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 45.0 (CH 2 Bn ), 91.3 (CH Ar ), 113.8 (2xCH Ar ), 124.0 (C q ), 128.2 (2xCH Ar ), 139.5 (C q ), 142.1 (Cq ), 147.9 (C q ), 149.4 (C q ), 153.9 (C q ). MS (ESI+): m / z C 15 H 17 Calculated value of ClN6: 317.1 [M+H]+, Measured value: 317.2.

[0348] (Example 3.36) Synthesis of N-[(3-aminophenyl)methyl]-6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.36) (2.1) To a solution of (0.300 g, 1.30 mmol, 1.0 equivalent) in THF (18.0 mL), 3-(aminomethyl)aniline (0.320 g, 2.60 mmol, 2.0 equivalent) and Et3N (0.37 mL, 2.60 mmol, 2.0 equivalent) were added, and the mixture was refluxed for 2 hours. After cooling, the solid was filtered off, washed with THF, and the filtrate was concentrated and directly purified by flash chromatography using DCM / MeOH (98 / 2 to 96 / 4) as the eluate to obtain (3.36) (0.280 g, 68%) as a yellow solid. Rf(DCM / MeOH, 96 / 4): 0.27 1 H NMR (400 MHz, DMSO-d6) δ: 1.38 (d, J = 6.9 Hz, 6H, 2xCH 3 iP r), 3.42 (septet, J = 6.9 Hz, 1H, H iPr ), 4.43 (d, J = 6.4 Hz, 2H, CH 2 Bn ), 5.06 (s, 2H, NH2), 6.02 (s, 1H, H Ar ), 6.40 - 6.56 (m, 3H, 3xH Ar ), 6.96 (t, J = 7.7 Hz, 1H, H Ar ), 9.03 (s, 1H, NH Bn ). 13C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 15 H 17 Calculated value of ClN6: 317.13 [M+H]+, Measured value: 317.3.

[0349] (Example 3.37) Synthesis of N-[(2-aminophenyl)methyl]-6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.37) (1.12) To a solution of (4.000 g, 14.86 mmol, 1.0 equivalent) of dry dioxane (60.0 mL), isobutyric acid hydrazide (1.840 g, 17.84 mmol, 1.2 equivalents) and AcOH (0.86 mL, 14.86 mmol, 1.0 equivalent) were added, and the mixture was refluxed for 18 hours. After cooling, the reaction mixture was concentrated, the residue was ground in water, filtered, and washed with water until the pH was neutral. The solid was dissolved in DCM and MeOH, the filtrate was concentrated, and the eluate was purified by flash chromatography using DCM / MeOH (97 / 3 to 95 / 5) to obtain (3.37) (0.600 g, 13%) as a pale yellow solid. Rf(DCM / MeOH, 94 / 6): 0.41 1 H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.42 (p, J = 6.9 Hz, 1H, H iPr ), 4.39 (s, 2H, CH 2 Bn ), 5.17 (s, 2H, NH2), 6.07 (s, 1H, H Ar ), 6.51 (t, J = 7.4 Hz, 1H, H Ar ), 6.65 (d, J = 7.9 Hz, 1H, H Ar ), 6.97 (td, J = 7.6, 1.6 Hz, 1H, H Ar ), 7.09 (dd, J = 7.6, 1.6 Hz, 1H, H Ar), 8.92 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 42.4 (CH 2 Bn ), 91.6 (CH Ar ), 115.1 (CH Ar ), 115.9 (CH Ar ), 119.3 (C q ), 128.1 (CH Ar ), 128.2 (CH Ar ), 139.5 (C q ), 142.3 (C q ), 146.3 (C q ), 149.4 (C q ), 154.0 (C q ). MS (ESI+): m / z C 15 H 17 Calculated value of ClN6: 317.1 [M+H]+, Measured value: 317.3.

[0350] (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) (1.15) A suspension of (4.600 g, 16.42 mmol, 1.0 equivalent) of dry dioxane (66 mL) was mixed with isobutyric acid hydrazide (1.863 g, 18.06 mmol, 1.1 equivalent) and AcOH (1.04 mL, 18.06 mmol, 1.1 equivalent), and the mixture was refluxed for 22 hours. After cooling, MeOH (10.0 mL) was added, and the mixture was concentrated with SiO2 to obtain a solid precipitate. The eluate was directly purified by flash chromatography using DCM / siRNA (98 / 2 to 96 / 4) to obtain (3.38) (1.390 g, 26%) as a white solid. Rf(DCM / .'', 98 / 2): 0.23 1H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 7.0 Hz, 6H, 2xCH 3 iPr ), 3.02 (t, J = 5.9 Hz, 2H, CH 2-CH2-N ), 3.44 (septet, J = 6.9 Hz, 1H, H iPr ), 4.42 (s, 2H, N- CH 2-CH2 ), 5.18 (s, 2H, CH 2-N ), 6.40 (s, 1H, H Ar ), 7.24 (td, J = 4.9, 4.5, 2.6 Hz, 4H, 4xH Ar ). 13 C NMR (101 MHz, DMSO-d6) δ : 19.7 (2xCH 3 iPr ), 24.4 (CH iPr ), 28.0 (CH 2-CH2-N ), 45.9 ( N- CH 2-CH2 ), 49.3 (CH 2-N ), 94.0 (CH Ar ), 126.3 (CH Ar ), 126.3 (CH Ar ), 126.8 (CH Ar ), 128.3 (CH Ar ), 134.5 (C q ), 140.4 (C q ), 142.7 (C q ), 149.4 (C q ), 153.6 (C q ). MS (EI-MS): m / z C 17 H 18 Calculated value of ClN5: 328.1 [M+H]+, Measured value: 328.2.

[0351] (Example 3.39) Synthesis of 6-chloro-8-isoindorin-2-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (3.39) (2.1) To a solution of (0.350 g, 1.52 mmol, 1.0 equivalent) in THF (15.0 mL), the corresponding amine hydrochloride (0.340 g, 2.12 mmol, 1.4 equivalents) and Et3N (0.64 mL, 4.54 mmol, 3.0 equivalents) were added, and the mixture was refluxed for 1.5 hours. After cooling, the precipitate was filtered and washed with THF, and the filtrate was concentrated and purified by flash chromatography using DCM / MeOH (100 / 0 to 98 / 2) as the eluate. The fraction containing impurities was concentrated, and the residue was ground in Et2O, filtered, washed with a small amount of Et2O, and vacuum dried to obtain (3.39) (0.280 g, 59%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.40 (d, J = 7.0 Hz, 6H, 2xCH 3 iPr ), 3.46 (septet, J = 6.9 Hz, 1H, H iPr ), 4.87 (s, 2H, CH2), 5.61 (s, 2H, CH2), 6.10 (s, 1H, H Ar ), 7.37 (dd, J = 5.6, 3.2 Hz, 2H, 2xH Ar ), 7.44 (s, 1H, H Ar ), 7.50 (s, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ : 19.7 (2xCH 3 iPr ), 24.4 (CH iPr ), 54.9 (CH2), 57.4 (CH2), 93.4 (CH Ar ), 122.5 (CH Ar ), 122.8 (CH Ar ), 127.6 (2xCH Ar ), 134.8 (C q ), 136.7 (C q ), 140.2 (C q ), 141.5 (C q ), 149.3 (C q ), 153.6 (C q ). MS (EI-MS): m / z C 16 H 16 Calculated value of ClN5: 314.1 [M+H]+, Measured value: 314.3.

[0352] (Example 3.40) Synthesis of 6-chloro-N-indan-1-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.40) (2.1) To a solution of (0.250 g, 1.05 mmol, 1.0 equivalent) in THF (13.0 mL), the corresponding amine hydrochloride (0.273 g, 1.57 mmol, 1.5 equivalent) and Et3N (0.44 mL, 3.15 mmol, 3.0 equivalent) were added, and the mixture was refluxed for 4 hours. After cooling, the solvent was removed, the residue was ground in water, filtered, washed with water to a neutral pH, and the solid was dissolved in SiO2. The organic filtrate was dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1 to 95 / 5) as the eluate to obtain (3.40) (0.300 g, 87%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.39 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 2.19 (dt, J = 17.4, 8.0 Hz, 1H, H (CH2)インダン ), 2.55 (s, 1H, H (CH2)インダン ), 2.85 (dt, J = 16.2, 8.3 Hz, 1H, H (CH2)インダン ), 3.03 (ddd, J = 15.9, 8.9, 3.1 Hz, 1H, H (CH2)インダン ), 3.45 (septet, J = 7.7, 7.2 Hz, 1H, H iPr ), 5.41 (s, 1H, H インダン ), 6.48 (s, 1H, H Ar ), 7.14 - 7.34 (m, 4H, 4xH Ar ), 8.75 (s, 1H, NH インダン ). 13 C NMR (101 MHz, DMSO-d6) δ : 19.9 (2xCH 3 iPr ), 24.4 (CH iPr ), 29.8 (CH 2 インダン ), 31.6 (CH 2 インダン ), 57.3 (CH インダン ), 91.4 (CH Ar ), 123.8 (CH Ar ), 124.8 (CH Ar ), 126.4 (CH Ar ), 127.8 (CH Ar ), 139.4 (C q ), 142.3 (C q ), 142.7 (C q ), 143.1 (C q ), 149.8 (C q ), 154.0 (C q ). MS (ESI+): m / z C 17 H 18 Calculated value of ClN5: 328.1 [M+H]+, Measured value: 328.3.

[0353] (Example 3.41) Synthesis of 6-chloro-N-(1H-indole-2-ylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.41) In a 10-20 mL sealed tube equipped with a stirring bar, (1.10) (1.100 g, 3.57 mmol, 1.0 equivalent), dioxane (15.0 mL), isobutyrate hydrazide (0.441 g, 4.28 mmol, 1.2 equivalents), and AcOH (0.23 mL, 3.92 mmol, 1.1 equivalents) were placed. The vial was sealed and then placed on a heating block at 100°C for 17 hours. After cooling, MeOH (10.0 mL) was added and the mixture was vigorously stirred for 5 minutes. The mixture was then concentrated with SiO2 to obtain a solid precipitate, which was directly purified by flash chromatography using DCM / MeOH (97 / 3 to 94 / 6) as the eluate to obtain (3.41) (0.270 g, 22%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.43 (septet, J = 7.1 Hz, 1H, H iPr ), 4.74 (s, 2H, CH 2 Bn ), 6.29 (s, 1H, H Ar ), 6.36 (d, J = 2.0 Hz, 1H, H Ar ), 6.94 (t, J = 7.4 Hz, 1H, H Ar ), 7.00 - 7.08 (m, 1H, H Ar ), 7.33 (d, J = 8.0 Hz, 1H, H Ar ), 7.45 (d, J = 7.8 Hz, 1H, H Ar ), 8.89 (s, 1H, NH), 10.99 (s, 1H, NH インドール ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 17 H 17 Calculated value of ClN6: 341.1 [M+H]+, Measured value: 341.3.

[0354] (Example 3.42) Synthesis of N-[(4-bromophenyl)methyl]-6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.42) (1.13) To a solution of (4.100 g, 12.32 mmol, 1.0 equivalent) of dioxane (50.0 mL), isobutyric acid hydrazide (1.524 g, 14.77 mmol, 1.2 equivalents) and AcOH (0.78 mL, 13.54 mmol, 1.1 equivalents) were added, and the mixture was refluxed for 18 hours. After cooling, the mixture was poured onto water (200.0 mL), and the precipitate was then ground, filtered, and washed with water until the pH was neutral. The solid was ground in SiO2, filtered, and dried under vacuum to obtain (3.42) (2.400 g, 51%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.42 (septet, J = 7.0 Hz, 1H, H iPr ), 4.40 - 4.73 (m, 2H, CH 2 Bn ), 6.15 (s, 1H, H Ar ), 7.35 (d, J = 8.2 Hz, 2H, 2xH Ar ), 7.54 (d, J = 8.4 Hz, 2H, 2xH Ar ), 9.11 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 15 H 15 Calculated value of BrClN5: 380.0 [M+H]+, Measured value: 380.2.

[0355] (Example 3.43) Synthesis of 6-chloro-3-isopropyl-N-(2-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.43) (1.16) To a solution of (4.000 g, 14.92 mmol, 1.0 equivalent) of dry dioxane (60 mL), isobutyric acid hydrazide (1.847 g, 17.90 mmol, 1.2 equivalents) was added, followed by AcOH (0.95 mL, 16.41 mmol, 1.1 equivalents), and the mixture was refluxed for 4 hours. After cooling, the mixture was concentrated, the residue was suspended, and ground in water (120 mL). The solid was filtered off, washed with water to a neutral pH, then dissolved in EtOH, concentrated, and dried under vacuum to obtain the title compound (3.43) (2.350 g, 50%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 7.0 Hz, 6H, 2xCH 3 iPr), 2.94 (t, J = 7.3 Hz, 2H, CH 2-CH2-NH ), 3.42 (p, J = 6.9 Hz, 1H, H iPr ), 3.52 - 3.68 (m, 2H, CH 2-NH ), 6.21 (s, 1H, H Ar ), 7.20 (tt, J = 5.6, 2.9 Hz, 1H, H Ar ), 7.25 - 7.38 (m, 4H, 4xH Ar ), 8.51 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 33.8 (CH 2-CH2-NH ), 43.5 (CH 2-NH ), 91.0 (CH Ar ), 126.2 (CH Ar ), 128.3 (2xCH Ar ), 128.9 (2xCH Ar ), 138.9 (C q ), 139.4 (C q ), 142.2 (C q ), 149.7 (C q ), 153.9 (C q ). MS (ESI+): m / z C 16 H 18 Calculated value of ClN5: 316.1 [M+H]+, Measured value: 316.2.

[0356] (Example 3.44) Synthesis of 6-chloro-3-isopropyl-N-[2-(2-pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.44) (2.1) To a solution of (0.300 g, 1.30 mmol, 1.0 equivalent) in THF (3.9 mL), the corresponding amine (0.190 g, 1.56 mmol, 1.2 equivalents) and DIPEA (0.27 mL, 1.56 mmol, 1.2 equivalents) were added, and the mixture was stirred at room temperature for 16 hours. The precipitate was filtered off, washed with THF, and the filtrate was concentrated. The eluate was purified by flash chromatography using DCM / MeOH (98 / 2 to 95 / 5) to obtain (3.44) (0.270 g, 66%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.09 (t, J = 7.1 Hz, 2H, CH 2-CH2-NH ), 3.42 (h, J = 7.0 Hz, 1H, H iPr ), 3.71 (d, J = 6.9 Hz, 2H, CH 2-NH ), 6.18 (s, 1H, H Ar ), 7.23 (dd, J = 7.5, 4.9 Hz, 1H, H Ar ), 7.34 (d, J = 7.8 Hz, 1H, H Ar ), 7.70 (t, J = 7.7 Hz, 1H, H Ar ), 8.51 (d, J = 4.9 Hz, 1H, H Ar ), 8.56 (s, 1H, NH -CH2 ). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 35.9 (CH 2-CH2-NH ), 41.8 (CH 2-NH ), 91.0 (CH Ar ), 121.7 (CH Ar ), 123.5 (CH Ar ), 136.5 (CH Ar ), 139.4 (C q ), 142.2 (C q), 149.1 (CH Ar ), 149.6 (C q ), 153.9 (C q ), 158.6 (C q ). MS (ESI+): m / z C 15 H 17 Calculated value of ClN6: 317.13 [M+H]+, Measured value: 317.2.

[0357] (Example 3.45) Synthesis of 6-chloro-3-isopropyl-N-[2-(3-pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.45) (2.1) To a solution of (0.250 g, 1.08 mmol, 1.0 equivalent) of (0.250 g, 1.08 mmol, 1.0 equivalent) and THF (10.0 mL), the corresponding amine (0.181 g, 1.41 mmol, 1.3 equivalents) and DIPEA (0.28 mL, 1.62 mmol, 1.5 equivalents) were added, and the mixture was refluxed for 3 hours. After cooling, Et2O (30.0 mL) was added, the precipitate was filtered off, washed with water, ground in Et2O, and then vacuum dried to obtain (3.45) (0.260 g, 76%) as a white solid. Rf(DCM / MeOH, 94 / 6): 0.24 1 H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 2.96 (t, J = 7.1 Hz, 2H, CH 2-CH2-NH ), 3.41 (septet, J = 7.0 Hz, 1H, H iPr ), 3.62 (d, J = 7.1 Hz, 2H, CH 2-NH ), 6.26 (s, 1H, H Ar ), 7.31 (dd, J = 7.9, 4.8 Hz, 1H, H Ar ), 7.72 (d, J = 7.7 Hz, 1H, H Ar ), 8.41 (d, J = 4.8 Hz, 1H, H Ar), 8.49 (d, J = 2.2 Hz, 1H, H Ar ), 8.55 (s, 1H, NH -CH2 ). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 30.9 (CH 2-CH2-NH ), 42.9 (CH 2-NH ), 91.1 (CH Ar ), 123.3 (CH Ar ), 134.4 (C q ), 136.4 (CH Ar ), 139.4 (C q ), 142.2 (C q ), 147.5 (CH Ar ), 149.7 (C q ), 150.0 (CH Ar ), 153.9 (C q ). MS (ESI+): m / z C 15 H 17 Calculated value of ClN6: 317.13 [M+H]+, Measured value: 317.2.

[0358] (Example 3.46) Synthesis of 6-chloro-3-isopropyl-N-[2-(4-pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.46) (2.1) To a solution of (0.250 g, 1.08 mmol, 1.0 equivalent) of (2.1) in THF (10.0 mL), the corresponding amine (0.181 g, 1.41 mmol, 1.3 equivalents) and DIPEA (0.28 mL, 1.62 mmol, 1.5 equivalents) were added, and the mixture was refluxed for 3 hours. After cooling, Et2O (30.0 mL) was added, the precipitate was filtered off, washed with water, ground in Et2O, and then vacuum dried to obtain (3.46) (0.285 g, 82%) as a white solid. Rf(DCM / MeOH, 94 / 6): 0.27 1H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 2.97 (t, J = 7.1 Hz, 2H, CH 2-CH2-NH ), 3.42 (p, J = 7.0 Hz, 1H, H iPr ), 3.56 - 3.75 (m, 2H, CH 2-NH ), 6.29 (s, 1H, H Ar ), 7.33 (d, J = 5.1 Hz, 2H, 2xH Ar ), 8.44 - 8.51 (m, 2H, 2xH Ar ), 8.54 (s, 1H, NH -CH2 ). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 32.9 (CH 2-CH2-NH ), 42.2 (CH 2-NH ), 91.2 (CH Ar ), 124.4 (2xCH Ar ), 139.3 (C q ), 142.2 (C q ), 147.9 (C q ), 149.4 (2xCH Ar ), 149.7 (C q ), 153.9 (C q ). MS (ESI+): m / z C 15 H 17 Calculated value of ClN6: 317.13 [M+H]+, Measured value: 317.2.

[0359] (Example 3.47) Synthesis of 6-chloro-3-cyclopropyl-N-[2-(2-pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.47) (2.5) To a solution of (0.125 g, 0.51 mmol, 1.0 equivalent) in THF (2.5 mL), the corresponding amine (0.080 g, 0.62 mmol, 1.2 equivalents) and Et3N (0.15 mL, 1.04 mmol, 2.0 equivalents) were added, and the mixture was refluxed for 1.5 hours. After cooling, THF (10.0 mL) was added, the precipitate was filtered off, washed with THF, and the filtrate was concentrated. The residue was ground in water, filtered off, washed with water, then ground in Et2O, filtered, washed with Et2O, and vacuum dried to obtain (3.47) (0.130 g, 80%) as a beige solid. Rf(DCM / MeOH, 96 / 4): 0.14 1 H NMR (400 MHz, DMSO-d6) δ : 1.03 - 1.18 (m, 4H, 2xCH 2 cPr ), 2.31 (tt, J = 8.2, 5.2 Hz, 1H, H cPr ), 3.09 (t, J = 7.1 Hz, 2H, CH2), 3.64 - 3.81 (m, 2H, CH2), 6.16 (s, 1H, H Ar ), 7.23 (dd, J = 7.6, 4.8 Hz, 1H, H Ar ), 7.33 (d, J = 7.8 Hz, 1H, H Ar ), 7.70 (td, J = 7.7, 1.9 Hz, 1H, H Ar ), 8.46 - 8.61 (m, 2H, NH & H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ: 4.8 (CH cPr ), 7.2 (2xCH 2 cPr ), 35.9 (CH2), 41.9 (CH2), 91.0 (CH Ar ), 121.7 (CH Ar ), 123.5 (CH Ar ), 136.5 (CH Ar ), 139.3 (C q ), 142.2 (C q ), 149.1 (CH Ar), 149.8 (C q ), 151.3 (C q ), 158.6 (C q ). MS (ESI+): m / z C 15 H 15 Calculated value of ClN6: 315.1 [M+H]+, Measured value: 315.1.

[0360] (Example 3.48) Synthesis of 6-chloro-3-cyclopropyl-N-[2-(3-pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.48) (2.5) To a solution of (0.125 g, 0.51 mmol, 1.0 equivalent) in THF (2.5 mL), the corresponding amine (0.080 g, 0.62 mmol, 1.2 equivalents) and Et3N (0.15 mL, 1.04 mmol, 2.0 equivalents) were added, and the mixture was refluxed for 1.5 hours. After cooling, THF (10.0 mL) was added, the precipitate was filtered off, washed with THF, and the filtrate was concentrated. The residue was ground in water, filtered off, washed with water, then ground in Et2O, filtered, washed with Et2O, and vacuum dried to obtain (3.48) (0.127 g, 80%) as a beige solid. Rf(DCM / MeOH, 94 / 6): 0.20 1 H NMR (400 MHz, DMSO-d6) δ : 1.00 - 1.20 (m, 4H, 2xCH 2 cPr ), 2.31 (tt, J = 8.1, 5.3 Hz, 1H, H cPr ), 2.96 (t, J = 7.1 Hz, 2H, CH2), 3.49 - 3.76 (m, 2H, CH2), 6.24 (s, 1H, H Ar ), 7.31 (dd, J = 7.8, 4.8 Hz, 1H, H Ar ), 7.71 (dt, J = 7.8, 2.0 Hz, 1H, H Ar ), 8.41 (dd, J = 4.8, 1.7 Hz, 1H, H Ar), 8.49 (d, J = 2.3 Hz, 1H, H Ar ), 8.52 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 4.8 (CH), 7.1 (2xCH2), 30.9 (CH2), 42.9 (CH2), 91.1 (CH Ar ), 123.3 (CH Ar ), 134.4 (C q ), 136.4 (CH Ar ), 139.3 (C q ), 142.2 (C q ), 147.5 (CH Ar ), 149.9 (C q ), 150.0 (CH Ar ), 151.3 (C q ). MS (ESI+): m / z C 15 H 15 Calculated value of ClN6: 315.1 [M+H]+, Measured value: 315.2.

[0361] (Example 3.49) Synthesis of 6-chloro-3-cyclopropyl-N-[2-(4-pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.49) (2.5) To a solution of (0.125 g, 0.51 mmol, 1.0 equivalent) in THF (2.5 mL), the corresponding amine (0.080 g, 0.62 mmol, 1.2 equivalents) and Et3N (0.15 mL, 1.04 mmol, 2.0 equivalents) were added, and the mixture was refluxed for 1.5 hours. After cooling, THF (10.0 mL) was added, the precipitate was filtered off, washed with THF, and the filtrate was concentrated. The residue was ground in water, filtered off, washed with water, then ground in Et2O, filtered, washed with Et2O, and vacuum dried to obtain (3.49) (0.134 g, 82%) as an orange solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.05 - 1.17 (m, 4H, 2xCH 2 cPr), 2.31 (ddt, J = 10.9, 8.1, 5.2 Hz, 1H, H cPr ), 2.96 (t, J = 7.1 Hz, 2H, CH2), 3.63 (d, J = 7.9 Hz, 2H, CH2), 6.28 (s, 1H, H Ar ), 7.27 - 7.39 (m, 2H, 2xH Ar ), 8.42 - 8.48 (m, 2H, 2xH Ar ), 8.51 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.8 (CH cPr ), 7.2 (2xCH 2 cPr ), 32.9 (CH2), 42.3 (CH2), 91.2 (CH Ar ), 124.4 (CH Ar ), 139.3 (C q ), 142.2 (C q ), 147.9 (C q ), 149.4 (CH Ar ), 149.9 (C q ), 151.3 (C q ). MS (ESI+): m / z C 15 H 15 Calculated value of ClN6: 315.1 [M+H]+, Measured value: 315.2.

[0362] (Example 3.50) Synthesis of 6-chloro-3-isopropyl-N-[3-(2-pyridyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.50) (2.1) To a solution of (0.200 g, 0.87 mmol, 1.0 equivalent) in THF (8.7 mL), the corresponding amine (0.161 g, 1.13 mmol, 1.3 equivalents) and Et3N (0.24 mL, 1.73 mmol, 2.0 equivalents) were added, and the mixture was refluxed for 3 hours. After cooling, the solvent was removed, and the residue was ground in water (20.0 mL) and saturated NaHCO3 (10.0 mL). The solid was filtered off, washed with water to a neutral pH, and then dissolved in SiO2. The organic filtrate was dehydrated with MgSO4, filtered, and concentrated to obtain (3.50) (0.250 g, 87%) as a pale yellow solid. Rf(DCM / MeOH, 94 / 6): 0.42 1 H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH 3 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, H iPr & CH2), 6.20 (s, 1H, H Ar ), 7.20 (dd, J = 7.6, 4.9 Hz, 1H, H Ar ), 7.28 (d, J = 7.8 Hz, 1H, H Ar ), 7.69 (td, J = 7.6, 1.9 Hz, 1H, H Ar ), 8.45 - 8.54 (m, 1H, H Ar ), 8.70 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 27.2 (CH2), 34.5 (CH2), 41.8 (CH2), 90.8 (CH Ar ), 121.3 (CH Ar ), 122.9 (CH Ar ), 136.5 (CH Ar ), 139.5 (C q), 142.4 (C q ), 148.9 (CH Ar ), 153.9 (C q ), 160.8 (C q ). MS (ESI+): m / z C 16 H 19 Calculated value of ClN6: 331.1 [M+H]+, Measured value: 331.2.

[0363] (Example 3.51) Synthesis of 6-chloro-3-isopropyl-N-[3-(3-pyridyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.51) (2.1) To a solution of (0.200 g, 0.87 mmol, 1.0 equivalent) in THF (8.7 mL), the corresponding amine dihydrochloride (0.248 g, 1.13 mmol, 1.3 equivalents) and Et3N (0.73 mL, 5.19 mmol, 6.0 equivalents) were added, and the mixture was refluxed for 3 hours. Water (0.43 mL) was added, and the mixture was refluxed for 3 hours to complete the reaction. After cooling, SiO (15.0 mL) was added, the mixture was dehydrated with MgSO4, filtered, and concentrated. The residue was ground in water (20.0 mL), the solid was filtered off and dissolved in SiO, and the organic filtrate was then dehydrated with MgSO4, filtered, and concentrated to obtain (3.51) (0.240 g, 84%) as a beige solid. Rf(DCM / MeOH, 94 / 6): 0.35 1 H NMR (400 MHz, DMSO-d6) δ : 1.39 (d, J = 7.0 Hz, 6H, 2xCH 3 iPr ), 1.89 - 1.98 (m, 2H, CH 2-CH2-NH ), 2.66 - 2.75 (m, 2H, CH 2-CH2-CH2-NH ), 3.36 (s, 2H, CH 2-NH ), 3.43 (p, J = 6.9 Hz, 1H, H iPr ), 6.18 (s, 1H, H Ar ), 7.31 (dd, J = 7.8, 4.8 Hz, 1H, H Ar), 7.68 (dt, J = 7.9, 2.0 Hz, 1H, H Ar ), 8.40 (dd, J = 4.8, 1.7 Hz, 1H, H Ar ), 8.47 (d, J = 2.3 Hz, 1H, H Ar ), 8.61 (s, 1H, NH -CH2 ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 16 H 19 Calculated value of ClN6: 331.1 [M+H]+, Measured value: 331.2.

[0364] (Example 3.52) Synthesis of 6-chloro-3-isopropyl-N-[3-(4-pyridyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.52) (2.1) To a solution of (0.200 g, 0.87 mmol, 1.0 equivalent) in THF (8.7 mL), the corresponding amine (0.161 g, 1.13 mmol, 1.3 equivalents) and Et3N (0.24 mL, 1.73 mmol, 2.0 equivalents) were added, and the mixture was refluxed for 3 hours. After cooling, the solvent was removed, and the residue was ground in water (20.0 mL) and saturated NaHCO3 (10.0 mL). The solid was filtered off, washed with water to a neutral pH, and then dissolved in SiO2. The organic filtrate was dehydrated with MgSO4, filtered, and concentrated to obtain (3.52) (0.260 g, 91%) as an orange solid. Rf(DCM / MeOH, 94 / 6): 0.33 1 H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH 3 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, H iPr), 6.18 (s, 1H, H Ar ), 7.19 - 7.37 (m, 2H, 2xH Ar ), 8.31 - 8.48 (m, 2H, 2xH Ar ), 8.60 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 16 H 19 Calculated value of ClN6: 331.1 [M+H]+, Measured value: 331.2.

[0365] (Example 3.53) Synthesis of 6-chloro-3-cyclopropyl-N-[3-(2-pyridyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.53) (2.5) To a solution of (0.170 g, 0.74 mmol, 1.0 equivalent) in THF / H2O (15.0 / 0.5 mL), the corresponding amine dihydrochloride (0.229 g, 1.04 mmol, 1.3 equivalents) and Et3N (0.63 mL, 4.45 mmol, 6.0 equivalents) were added, and the mixture was refluxed for 16 hours. After cooling, THF (10.0 mL) was added, the precipitate was filtered off, washed with THF, and the filtrate was concentrated and purified by flash chromatography using DCM / MeOH (98 / 2 to 95 / 5) as the eluate to obtain (3.53) (0.080 g, 33%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6) δ : 1.11 (tt, J = 8.0, 2.7 Hz, 4H, 2xCH 2 cPr ), 1.85 - 2.02 (m, 2H, CH2), 2.32 (tt, J = 8.2, 5.2 Hz, 1H, H cPr ), 2.64 - 2.76 (m, 2H, CH2), 3.32 - 3.42 (m, 2H, CH2), 6.16 (s, 1H, H Ar ), 7.30 (dd, J = 7.8, 4.7 Hz, 1H, H Ar), 7.66 (dt, J = 7.9, 2.0 Hz, 1H, H Ar ), 8.39 (dd, J = 4.8, 1.6 Hz, 1H, H Ar ), 8.46 (d, J = 2.3 Hz, 1H, H Ar ), 8.57 (t, J = 5.6 Hz, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.8 (CH cPr ), 7.1 (2xCH 2 cPr ), 29.1 (CH2), 29.4 (CH2), 41.7 (CH2), 90.8 (CH Ar ), 123.4 (CH Ar ), 135.8 (CH Ar ), 136.9 (C q ), 139.4 (C q ), 142.3 (C q ), 147.2 (CH Ar ), 149.6 (CH Ar ), 149.8 (C q ), 151.3 (C q ). MS (ESI+): m / z C 16 H 17 Calculated value of ClN6: 329.1 [M+H]+, Measured value: 329.2.

[0366] (Example 3.54) Synthesis of 6-chloro-3-isopropyl-N-(pyrimidine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.54) (2.1) To a solution of (0.190 g, 0.82 mmol, 1.0 equivalent) in THF (9.0 mL), the corresponding amine hydrochloride (0.164 g, 1.07 mmol, 1.3 equivalents) and DIPEA (0.36 mL, 2.06 mmol, 2.5 equivalents) were added, and the mixture was refluxed for 3 hours. After cooling, the solvent was removed, and the residue was ground in saturated NaHCO3 (10.0 mL). The solid was filtered off and washed with water and then SiO to obtain the first portion (0.072 g) of (3.54). The two phases of filtrate were separated, and the aqueous layer was extracted twice with SiO2 (2 × 10.0 mL). The organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 94 / 6) as the eluate to obtain the second portion (0.020 g) of (3.54). Total of (3.54): 0.092 g, yield 37%, as a white solid. Rf(DCM / MeOH, 94 / 6): 0.40 1 H NMR (400 MHz, DMSO-d6) δ : 1.39 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.44 (p, J = 7.0 Hz, 1H, H iPr ), 4.80 (s, 2H, CH 2 Bn ), 6.22 (s, 1H, H Ar ), 7.45 (t, J = 4.9 Hz, 1H, NH Bn ), 8.74 - 8.89 (m, 3H, 3xH Ar ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 13 H 14 Calculated value of ClN7: 304.1 [M+H]+, Measured value: 304.2.

[0367] (Example 3.55) Synthesis of 6-chloro-3-isopropyl-N-(pyrazine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.55) (2.1) To a solution of (0.290 g, 1.26 mmol, 1.0 equivalent) in THF (10.0 mL), the corresponding amine (0.187 g, 1.63 mmol, 1.3 equivalents) and DIPEA (0.33 mL, 1.88 mmol, 1.5 equivalents) were added, and the mixture was refluxed for 1 hour. After cooling, the precipitate was filtered off and washed with THF. The solid was washed with water, then with Et2O, and vacuum dried to obtain the first portion (0.103 g) of (3.55). The THF filtrate was concentrated and purified by flash chromatography using DCM / MeOH (98 / 2 to 95 / 5) as the eluate to obtain the second portion (0.015 g) of (3.55). Total of (3.55): 0.118 g, yield 31%, as a white solid. Rf(ammonium cyclohexane, 7 / 3): 0.37 1 H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.43 (p, J = 7.0 Hz, 1H, H iPr ), 4.77 (s, 2H, CH 2 Bn ), 6.29 (s, 1H, H Ar ), 8.57 (d, J = 2.6 Hz, 1H, H Ar ), 8.60 - 8.63 (m, 1H, H Ar ), 8.69 (d, J = 1.5 Hz, 1H, H Ar ), 8.98 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 13 H 14 Calculated value of ClN7: 304.1 [M+H]+, Measured value: 304.2.

[0368] (Example 3.56) Synthesis of 6-chloro-3-isopropyl-N-(pyrimidine-5-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.56) (2.1) To a solution of (0.190 g, 0.82 mmol, 1.0 equivalent) in THF (9.0 mL), the corresponding amine hydrochloride (0.164 g, 1.07 mmol, 1.3 equivalents) and DIPEA (0.36 mL, 2.06 mmol, 2.5 equivalents) were added, and the mixture was refluxed for 3 hours. After cooling, the solvent was removed, and the residue was ground in saturated NaHCO3 (10.0 mL). The solid was filtered off and washed with water and then SiO to obtain the first portion (0.055 g) of (3.56). The two phases of filtrate were separated, and the aqueous layer was extracted twice with SiO (2 × 10.0 mL). The organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 94 / 6) as the eluate to obtain the second portion (0.055 g) of (3.56). Total of (3.56): 0.110 g, yield 44%, as a white solid. Rf(DCM / MeOH, 94 / 6): 0.30 1 H NMR (400 MHz, DMSO-d6) δ : 1.37 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.42 (septet, J = 6.6 Hz, 1H, H iPr ), 4.66 (s, 2H, CH 2 Bn ), 6.37 (s, 1H, H Ar ), 8.85 (s, 2H, 2xH Ar ), 9.05 (s, 1H, NH Bn ), 9.10 (s, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 13 H 14 Calculated value of ClN7: 304.1 [M+H]+, Measured value: 304.2.

[0369] (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) (2.1) To a solution of (0.300 g, 1.30 mmol, 1.0 equivalent) in THF (9.0 mL), the corresponding amine dihydrochloride (0.323 g, 1.69 mmol, 1.3 equivalents) and DIPEA (0.75 mL, 4.28 mmol, 3.3 equivalents) were added, and the mixture was stirred at room temperature for 16 hours, then refluxed for 2 hours to complete the reaction. After cooling, the solvent was removed, the crude product was ground in water, the resulting solid was filtered, washed with water to a neutral pH, ground in Et2O, filtered, and dried to obtain (3.57) (0.286 g, 73%) as a white solid. Rf(DCM / MeOH, 94 / 6): 0.38 1 H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.43 (p, J = 6.9 Hz, 1H, H iPr ), 4.89 (s, 2H, CH 2 Bn ), 6.27 (s, 1H, H Ar ), 7.69 (d, J = 3.3 Hz, 2H, 2xH Ar ), 9.08 (s, 1H, NH Bn ), 9.17 (t, J = 3.4 Hz, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ: 19.8 (CH 3 iPr ), 24.4 (CH iPr ), 45.7 (CH 2 Bn ), 92.0 (CH Ar ), 125.7 (CH Ar ), 127.5 (CH Ar ), 139.4 (C q ), 142.5 (C q ), 149.4 (C q ), 151.0 (CH Ar ), 154.0 (Cq ), 159.3 (C q ). MS (ESI+): m / z C 13 H 14 Calculated value of ClN7: 304.1 [M+H]+, Measured value: 304.1.

[0370] (Example 3.58) Synthesis of 6-chloro-3-isopropyl-N-[[4-(2-pyridyl)phenyl]methyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.58) In a 10-20 mL vial equipped with a stirring bar, (1.14) (0.300 g, 0.91 mmol, 1.0 equivalent), dioxane (4.9 mL), isobutyrate hydrazide (0.112 g, 1.09 mmol, 1.2 equivalents), and AcOH (0.06 mL, 1.00 mmol, 1.1 equivalents) were added. The vial was sealed and then placed on a heating block at 110°C for 22 hours. After cooling, the reaction mixture was poured onto saturated NaHCO3 (20.0 mL) and vigorously stirred for 5 minutes. The resulting precipitate was filtered, washed with water, and then dissolved in DCM (10.0 mL). The aqueous filtrate was extracted twice with ELISA (2 × 10.0 mL), combined with DCM solution, and the entire mixture was dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 95 / 5) as the eluate to obtain the title compound (3.58) (0.140 g, 41%) as a white solid. Rf(DCM / MeOH, 94 / 6): 0.47 1 H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.42 (septet, J = 7.1 Hz, 1H, H iPr ), 4.65 (d, J = 3.9 Hz, 2H, CH 2 Bn ), 6.18 (s, 1H, H Ar ), 7.33 (dd, J = 7.4, 4.9 Hz, 1H, H Ar ), 7.51 (d, J = 8.1 Hz, 2H, 2xHAr ), 7.86 (td, J = 7.7, 1.9 Hz, 1H, H Ar ), 7.93 (d, J = 8.0 Hz, 1H, H Ar ), 8.06 (d, J = 8.1 Hz, 2H, 2xH Ar ), 8.65 (d, J = 3.8 Hz, 1H, H Ar ), 9.17 (s, 1H, NH Bn ). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 44.9 (CH 2 Bn ), 91.6 (CH Ar ), 120.1 (CH Ar ), 122.5 (CH Ar ), 126.7 (2xCH Ar ), 127.5 (2xCH Ar ), 137.2 (CH Ar ), 137.7 (C q ), 138.3 (C q ), 139.4 (C q ), 142.3 (C q ), 149.4 (C q ), 149.5 (CH Ar ), 154.0 (C q ), 155.7 (C q ). MS (ESI+): m / z C 20 H 19 Calculated value of ClN6: 379.1 [M+H]+, Measured value: 379.3.

[0371] (Example 3.59) Synthesis of 6-chloro-3-isopropyl-N-[[4-(4-pyridyl)phenyl]methyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.59) To a solution of 4-(4-pyridyl)benzonitrile (0.224 g, 1.24 mmol, 1.15 equivalents) in dry THF (12.0 mL), LiAlH4 (0.066 g, 1.73 mmol, 1.6 equivalents) was gradually added, and the mixture was stirred for 45 minutes. After completion, saturated NH4Cl (10.0 mL), water (5.0 mL), and HCl (10.0 mL) were added, and the mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted with HCl (2 × 10.0 mL), and the organic layers were combined, dehydrated with MgSO4, filtered, and concentrated. The residue was used directly in THF (18.0 mL) containing (2.1) (0.250 g, 1.08 mmol, 1.0 equivalent) and Et3N (0.46 mL, 3.25 mmol, 3.0 equivalents), and the mixture was refluxed for 3 hours. After cooling, the solid was filtered, washed with THF, and then the filtrate was concentrated and directly purified by flash chromatography using DCM / MeOH (98 / 2 to 93 / 7) as the eluate to obtain (3.59) (0.110 g, 27%) as a white solid. Rf(DCM / MeOH, 94 / 6): 0.25 1 H NMR (400 MHz, DMSO-d6) δ : 1.38 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.42 (p, J = 6.9 Hz, 1H, H iPr ), 4.66 (d, J = 6.2 Hz, 2H, CH 2 Bn ), 6.19 (s, 1H, H Ar ), 7.54 (d, J = 8.1 Hz, 2H, 2xH Ar ), 7.66 - 7.75 (m, 2H, 2xH Ar ), 7.76 - 7.87 (m, 2H, 2xH Ar ), 8.56 - 8.70 (m, 2H, 2xH Ar ), 9.18 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.4 (CH iPr ), 44.7 (CH2), 91.6 (CHAr ), 121.1 (2xCH Ar ), 127.0 (2xCH Ar ), 128.0 (2xCH Ar ), 136.0 (C q ), 138.8 (C q ), 139.4 (C q ), 142.3 (C q ), 146.6 (C q ), 149.4 (C q ), 150.2 (2xCH Ar ), 154.0 (C q ). MS (ESI+): m / z C 20 H 19 Calculated value of ClN6: 379.1 [M+H]+, Measured value: 379.2.

[0372] (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) (2.1) To a solution of (0.100 g, 0.433 mmol, 1.0 equivalent) of (3.60) in dry THF (3.33 mL), 3-aminopyridazine (0.084 g, 0.866 mmol, 2.0 equivalents) was added, followed by 1.65 M tBuOK in THF (0.52 mL, 0.866 mmol, 2.0 equivalents), and the mixture was stirred at room temperature for 0.8 hours. After completion, saturated NH4Cl (3.33 mL) and water (1 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The resulting precipitate was filtered off and washed with H2O and Et2O to obtain (3.60) (0.023 g, 18%) as a white solid. The filtrate layers were separated, the aqueous layer was extracted with SiO2 (2 × 10.0 mL), and then the organic layers were combined, dehydrated with MgSO4, filtered, and concentrated. The residue was ground in Et2O, filtered, washed with Et2O, and vacuum dried to obtain (3.60) as a beige solid (0.063 g, 51%). (3.60) was obtained in 69% yield (0.086 g). Rf(DCM / MeOH, 96 / 4): 0.28 1H NMR (400 MHz, DMSO-d6) δ : 1.43 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.53 (h, J = 6.9 Hz, 1H, H iPr ), 7.73 (dd, J = 9.0, 4.6 Hz, 1H, H Ar ), 7.89 (dd, J = 9.0, 1.4 Hz, 1H, H Ar ), 8.39 (s, 1H, H Ar ), 9.00 (dd, J = 4.6, 1.4 Hz, 1H, H Ar ), 11.13 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.83 (2xCH 3 iPr ), 24.50 (CH iPr ), 101.29 (CH Ar ), 119.50 (CH Ar ), 128.69 (CH Ar ), 136.05 (C q ), 139.24 (C q ), 147.89 (CH Ar ), 149.82 (C q ), 154.39 (C q ), 157.23 (C q ). MS (ESI+): m / z C 12 H 12 Calculated value of ClN7: 290.1 ​​[M+H]+, Measured value: 290.2.

[0373] (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) (2.1) To a solution of (0.350 g, 1.515 mmol, 1.0 equivalent) in dry THF (11.5 mL), 4-aminopyridazine (0.294 g, 3.029 mmol, 2.0 equivalent), followed by 1 M tBuOK in THF (1.84 mL, 3.029 mmol, 2.0 equivalent), was added, and the mixture was stirred at room temperature for 1.25 hours. After completion, saturated NH4Cl (11.5 mL) and water (5.23 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The layers of the mixture were separated, the aqueous layer was extracted with SiO2 (2 × 10.0 mL), and then the organic layers were combined, dehydrated with MgSO4, filtered, and concentrated. The residue was purified by flash chromatography using DCM / MeOH (99 / 1 to 94 / 6) as the eluate to obtain (3.61) (0.256 g, 58%) as a yellow solid. Rf(DCM / MeOH, 94 / 6): 0.28 1 H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.50 (septet, J = 6.9 Hz, 1H, H iPr ), 7.06 (s, 1H, H Ar ), 7.77 (dd, J = 6.2, 2.9 Hz, 1H, H Ar ), 9.09 (d, J = 5.9 Hz, 1H, H Ar ), 9.38 (d, J = 2.7 Hz, 1H, H Ar ), 10.88 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.80 (2xCH 3iPr ), 24.50 (CH iPr ), 98.77 (CH Ar ), 115.13 (CH Ar ), 137.58 (C q ), 138.40 (C q ), 139.48 (C q ), 145.30 (CH Ar ), 149.54 (C q), 151.27 (CH Ar ), 154.37 (C q ). MS (ESI+): m / z C 12 H 12 Calculated value of ClN7: 290.1 ​​[M+H]+, Measured value: 290.1.

[0374] (Example 3.62) Synthesis of 6-chloro-3-isopropyl-N-(pyrimidine-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.62) (2.1) To a solution of (0.40 g, 1.731 mmol, 1.0 equivalent) of 4-aminopyrimidine (0.281 g, 2.891 mmol, 2.0 equivalent) in dry THF (13.14 mL), then 1.65 M tBuOK (1.75 mL, 2.891 mmol, 2.0 equivalent) in THF was added, and the mixture was stirred at room temperature for 1 hour. After completion, saturated NH4Cl (13.14 mL) and water (5.97 mL) were added, and the two-phase mixture was stirred vigorously for 5 minutes. The layers of the mixture were separated, the aqueous layer was extracted with SiO2 (2 × 10.0 mL), then the organic layers were combined, dehydrated with MgSO4, filtered, and concentrated. The residue was ground in DCM, filtered, washed with MeOH and Et2O, and dried under vacuum to obtain (3.62) as a pale yellow / beige solid (0.171 g, 34%). The filtrate was purified by flash chromatography using DCM / MeOH (99 / 1 to 94 / 6) as the eluent to obtain the second portion of (3.62) (0.150 g, 30%) as a beige solid. Total of (3.62): 0.321 g, 64%. Rf(DCM / MeOH, 94 / 6): 0.35 1 H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.50 (septet, J = 7.0 Hz, 1H, H iPr ), 7.60 (dd, J = 5.8, 1.3 Hz, 1H, H Ar ), 8.37 (s, 1H, H Ar), 8.62 (d, J = 5.8 Hz, 1H, H Ar ), 8.99 (d, J = 1.2 Hz, 1H, H Ar ), 11.28 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.81 (2xCH 3 iPr ), 24.48 (CH iPr ), 102.67 (CH Ar ), 110.88 (CH Ar ), 135.84 (C q ), 139.11 (C q ), 149.48 (C q ), 154.39 (C q ), 157.07 (CH Ar ), 157.72 (CH Ar ), 159.68 (C q ). MS (ESI+): m / z C 12 H 10 Calculated value of ClN7: 290.1 ​​[M+H]+, Measured value: 290.1.

[0375] (Example 3.63) Synthesis of 6-chloro-3-isopropyl-N-(pyrimidine-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.63) (2.1) To a solution of (0.200 g, 0.866 mmol, 1.0 equivalent) of (2.1) in dry THF (6.63 mL), 5-aminopyrimidine (0.166 g, 1.731 mmol, 2.0 equivalents) was added, followed by 1.05 mL of 1.65 M tBuOK in THF (1.05 mL, 1.731 mmol, 2.0 equivalents), and the mixture was stirred at room temperature for 1.5 hours. After completion, saturated NH4Cl (6.63 mL) and water (1.77 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The resulting precipitate was filtered off and washed with H2O and Et2O to obtain (3.63) (0.150 g, 60%) as a white solid. The filtrate layers were separated, the aqueous layer was extracted with SiO2 (2 × 10.0 mL), and then the organic layers were combined, dehydrated with MgSO4, filtered, and concentrated. The residue was purified by flash chromatography using DCM / MeOH (99 / 1 to 94 / 6) as the eluent, and the second portion of (3.63) (0.048 g, 19%) was obtained as a white solid. The total of (3.63) was obtained in 79% yield (0.198 g). Rf(DCM / MeOH, 94 / 6): 0.25 1 H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 7.0 Hz, 6H, 2xCH 3 iPr ), 3.49 (p, J = 6.9 Hz, 1H, H iPr ), 6.65 (s, 1H, H Ar ), 8.95 (s, 2H, 2xH Ar ), 9.06 (s, 1H, H Ar ), 10.57 (s, 1H, NH). 13 C NMR (101 MHz, DMSO) δ : 19.81 (2xCH 3 iPr ), 24.49 (CH iPr ), 95.16 (CH Ar ), 133.98 (C q ), 139.40 (C q ), 139.60 (C q ), 149.66 (C q ), 151.64(2xCH Ar ), 154.23 (Cq ), 154.71 (CH Ar ). MS (ESI+): m / z C 12 H 10 Calculated value of ClN7: 290.1 ​​[M+H]+, Measured value: 290.2.

[0376] (Example 3.64) Synthesis of 6-chloro-3-isopropyl-N-(pyrimidine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.64) (2.1) To a solution of (0.152 g, 0.664 mmol, 1.0 equivalent) of (2.1) in dry THF (5.04 mL), 2-aminopyrimidine (0.126 g, 1.316 mmol, 2.0 equivalent), followed by 1.65 M tBuOK in THF (0.80 mL, 1.316 mmol, 2.0 equivalent), the mixture was stirred at room temperature for 2.25 hours. After completion, saturated NH4Cl (5.04 mL) and water (2.3 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted with SiO2 (2 × 10.0 mL), then the organic layers were combined, dehydrated with MgSO4, filtered, and concentrated. The residue was ground in Et2O, filtered, washed with Et2O, and vacuum dried to obtain (3.64) (0.124 g, 65%) as a beige solid. Rf(DCM / MeOH, 94 / 6): 0.48 1 H NMR (400 MHz, DMSO-d6) δ : 1.42 (d, J = 6.9, 2.0 Hz, 6H, 2xCH 3 iPr ), 3.45 - 3.56 (m, 1H, H iPr ), 7.26 (dt, J = 4.9, 3.1 Hz, 1H, H Ar ), 8.16 (s, 1H, H Ar ), 8.80 (dd, J = 4.9, 1.9 Hz, 2H, 2xH Ar ), 10.31 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.81 (2xCH3 iPr ), 24.49 (CH iPr ), 101.32 (CH Ar ), 116.40 (CH Ar ), 136.11 (C q ), 139.01 (C q ), 149.61 (C q ), 154.38 (C q ), 158.56 (C q ), 158.64 (2xCH Ar ). MS (ESI+): m / z C 12 H 12 Calculated value of ClN7: 290.1 ​​[M+H]+, Measured value: 290.2.

[0377] (Example 3.65) Synthesis of 6-chloro-3-isopropyl-N-(pyrazine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.65) (2.1) To a solution of (0.100 g, 0.433 mmol, 1.0 equivalent) of (3.33 mL) dry THF, 2-aminopyrazine (0.082 g, 0.866 mmol, 2.0 equivalents) was added, followed by 1.65 M tBuOK (0.52 mL, 0.866 mmol, 2.0 equivalents) in THF, and the mixture was stirred at room temperature for 0.8 hours. After completion, saturated NH4Cl (3.33 mL) and water (1 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted with SiO2 (2 × 10.0 mL), and then the organic layers were combined, dehydrated with MgSO4, filtered, and concentrated. The residue was ground in Et2O, filtered, washed with Et2O, and vacuum dried to obtain (3.65) (0.093 g, 74%) as a beige solid. Rf(DCM / MeOH, 96 / 4): 0.31 1 H NMR (400 MHz, DMSO-d6) δ : 1.43 (d, J = 7.0 Hz, 6H, 2xCH 3 iPr ), 3.51 (septet, J = 6.8 Hz, 1H, H iPr ), 8.19 (s, 1H, HAr ), 8.33 (d, J = 2.7 Hz, 1H, H Ar ), 8.47 (dd, J = 2.7, 1.4 Hz, 1H, H Ar ), 8.93 (d, J = 1.5 Hz, 1H, H Ar ), 11.32 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.83 (2xCH 3 iPr ), 24.48 (CH iPr ), 100.32 (CH Ar ), 136.30 (C q ), 137.69 (CH Ar ), 138.02 (CH Ar ), 139.21 (C q ), 141.16 (CH Ar ), 149.60 (C q ), 150.64 (C q ), 154.37 (C q ). MS (ESI+): m / z C 12 H 12 Calculated value of ClN7: 290.1 ​​[M+H]+, Measured value: 290.2

[0378] (Example 3.66) Synthesis of 6-chloro-3-isopropyl-N-(6-methoxypyridine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.66) Under inert gas conditions, 1 M tBuOK (0.81 mL, 0.81 mmol, 1.5 equivalents) in THF was added dropwise to a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 equivalent) and the corresponding aminopyridine derivative (0.102 g, 0.81 mmol, 1.5 equivalents) in dry THF (7.5 mL). The mixture was stirred at room temperature for 3.5 hours, then saturated NH4Cl (3.0 mL), water (1.0 mL), and HCl (3.0 mL) were added. The mixture was stirred vigorously for 5 minutes, then the layers were separated, and the aqueous layer was extracted twice with HCl (2 × 5.0 mL). The organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1 to 98 / 2) as the eluate to obtain (3.66) (0.128 g, 74%) as a pale orange solid. Rf(DCM / MeOH, 98 / 2): 0.30 1 H NMR (400 MHz, DMSO-d6) δ: 1.42 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.50 (septet, J = 6.9 Hz, 1H, H iPr ), 3.95 (s, 3H, CH 3-O ), 6.55 (d, J = 8.0 Hz, 1H, H Ar ), 7.18 (d, J = 7.8 Hz, 1H, H Ar ), 7.73 (t, J = 8.0 Hz, 1H, H Ar ), 8.26 (s, 1H, H Ar ), 10.91 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.5 (CH iPr ), 53.6 (CH 3-O ), 99.7 (CH Ar ), 103.7 (CH Ar ), 106.3 (CH Ar ), 136.4 (C q ), 139.3 (C q ), 141.0 (CHAr ), 149.6 (C q ), 152.0 (C q ), 154.3 (C q ), 162.4 (C q ).

[0379] (Example 3.67) Synthesis of 6-chloro-3-isopropyl-N-(5-methoxypyridine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.67) Under inert gas conditions, 1 M tBuOK (0.81 mL, 0.81 mmol, 1.5 equivalents) in THF was added dropwise to a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 equivalent) and the corresponding aminopyridine derivative (0.102 g, 0.81 mmol, 1.5 equivalents) in dry THF (7.5 mL). The mixture was stirred at room temperature for 3.5 hours, then saturated NH4Cl (3.0 mL), water (1.0 mL), and HCl (3.0 mL) were added. The mixture was stirred vigorously for 5 minutes, then the layers were separated, and the aqueous layer was extracted twice with HCl (2 × 5.0 mL). The organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1 to 98 / 2) as the eluate to obtain (3.67) (0.112 g, 65%) as an orange solid. Rf(DCM / MeOH, 98 / 2): 0.24 1 H NMR (400 MHz, DMSO-d6) δ: 1.42 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.48 (septet, J = 6.9 Hz, 1H, H iPr ), 3.83 (s, 3H, CH 3-O ), 7.50 (dd, J = 9.0, 3.0 Hz, 1H, H Ar ), 7.56 (d, J = 9.0 Hz, 1H, H Ar ), 8.15 (s, 1H, H Ar ), 8.18 (d, J = 3.0 Hz, 1H, H Ar), 10.82 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.5 (CH iPr ), 55.9 (CH 3-O ), 97.8 (CH Ar ), 115.6 (CH Ar ), 124.9 (CH Ar ), 132.7 (CH Ar ), 136.7 (C q ), 139.3 (C q ), 147.3 (C q ), 149.8 (C q ), 151.8 (C q ), 154.2 (C q ). MS (ESI+): m / z C 14 H 15 Calculated value of ClN6O: 319.1 [M+H]+, Measured value: 319.2.

[0380] (Example 3.68) Synthesis of 6-chloro-3-isopropyl-N-(4-methoxypyridine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.68) Under inert gas conditions, 1 M tBuOK (0.81 mL, 0.81 mmol, 1.5 equivalents) in THF was added dropwise to a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 equivalent) and the corresponding aminopyridine derivative (0.102 g, 0.81 mmol, 1.5 equivalents) in dry THF (7.5 mL). The mixture was stirred at room temperature for 3.5 hours, then saturated NH4Cl (3.0 mL), water (1.0 mL), and HCl (3.0 mL) were added. The mixture was stirred vigorously for 5 minutes, then the layers were separated, and the aqueous layer was extracted twice with HCl (2 × 5.0 mL). The organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1 to 98 / 2) as the eluate to obtain (3.68) (0.125 g, 72%) as a pale orange solid. Rf(DCM / MeOH, 98 / 2): 0.25 1 H NMR (400 MHz, DMSO-d6) δ: 1.42 (d, J = 7.0 Hz, 6H, 2xCH 3 iPr ), 3.49 (septet, J = 6.9 Hz, 1H, H iPr ), 3.83 (s, 3H, CH 3-O ), 6.76 (dd, J = 5.9, 2.3 Hz, 1H, H Ar ), 7.25 (d, J = 2.3 Hz, 1H, H Ar ), 8.26 (d, J = 5.9 Hz, 1H, H Ar ), 8.32 (s, 1H, H Ar ), 10.74 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.5 (CH iPr ), 55.3 (CH 3-O ), 99.1 (CH Ar ), 99.7 (CH Ar ), 106.6 (CH Ar ), 136.7 (C q ), 139.3 (C q ), 148.5 (CH Ar ), 149.7 (C q ), 154.3 (C q ), 155.6 (C q ), 166.5 (C q ).

[0381] (Example 3.69) Synthesis of 6-chloro-3-isopropyl-N-(3-methoxypyridine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.69) Under inert gas conditions, 1 M tBuOK (0.81 mL, 0.81 mmol, 1.5 equivalents) in THF was added dropwise to a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 equivalent) and the corresponding aminopyridine derivative (0.102 g, 0.81 mmol, 1.5 equivalents) in dry THF (7.5 mL). The mixture was stirred at room temperature for 3.5 hours, then saturated NH4Cl (3.0 mL), water (1.0 mL), and HCl (3.0 mL) were added. The mixture was stirred vigorously for 5 minutes, then the layers were separated, and the aqueous layer was extracted twice with HCl (2 × 5.0 mL). The organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1 to 98 / 2) as the eluate to obtain (3.69) (0.120 g, 70%) as a white solid. Rf(DCM / MeOH, 98 / 2): 0.38 1 H NMR (400 MHz, DMSO-d6) δ: 1.42 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.49 (septet, J = 7.0 Hz, 1H, H iPr ), 4.01 (s, 3H, CH 3-O ), 7.10 - 7.29 (m, 1H, H Ar ), 7.55 (d, J = 8.1 Hz, 1H, H Ar ), 8.04 (d, J = 4.9 Hz, 1H, H Ar ), 8.14 (s, 1H, H Ar ), 8.78 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.5 (CH iPr ), 56.4 (CH 3-O ), 99.3 (CH Ar ), 118.1 (CH Ar ), 119.4 (CH Ar ), 135.2 (C q ), 138.3 (CH Ar ), 139.1 (C q), 142.7 (C q ), 144.0 (C q ), 149.7 (C q ), 154.5 (C q ). MS (ESI+): m / z C 14 H 15 Calculated value of ClN6O: 319.1 [M+H]+, Measured value: 319.2.

[0382] (Example 3.70) Synthesis of 6-chloro-3-isopropyl-N-(3-phenylpropyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.70) (2.1) To a solution of (0.130 g, 0.56 mmol, 1.0 equivalent) in THF (6.0 mL), the corresponding amine (0.16 mL, 1.12 mmol, 2.0 equivalent) and Et3N (0.16 mL, 1.12 mmol, 2.0 equivalent) were added, and the mixture was refluxed for 2 hours. After cooling, the precipitate was filtered off, washed with THF, and the filtrate was concentrated. The residue was purified by flash chromatography using DCM / MeOH (98 / 2) as the eluent to obtain (3.70) (0.177 g, 95%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 1.39 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 1.84 - 2.02 (m, 2H, CH 2-CH2-NH ), 2.68 (dd, J = 8.8, 6.7 Hz, 2H, CH 2-Ph ), 3.33 - 3.39 (m, 2H, CH 2-NH ), 3.44 (h, J = 7.0 Hz, 1H, H iPr ), 6.13 (s, 1H, H Ar ), 7.14 - 7.23 (m, 1H, H Ar ), 7.21 - 7.33 (m, 4H, 4xH Ar ), 8.61 (s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δ : 20.3 (2xCH 3 iPr ), 24.9 (CH iPr ), 29.9 (CH 2-CH2-NH ), 32.9 (CH 2-Ph ), 42.2 (CH 2-NH ), 91.2 (CH Ar ), 126.3 (CH Ar ), 128.8 (2xCH Ar ), 128.8 (CH Ar ), 139.9 (C q ), 142.0 (C q ), 142.9 (C q ), 150.1 (C q ), 154.4 (C q ).

[0383] (Example 3.71) Synthesis of 6-chloro-3-cyclopropyl-N-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.71) Under inert gas, (2.5) (0.150 g, 0.65 mmol, 1.0 equivalent) was dissolved in dry THF (5.0 mL), to which aniline (0.12 mL, 1.31 mmol, 2.0 equivalents) was added, followed by 1 M tBuOK (1.31 mL, 1.31 mmol, 2.0 equivalents) in THF. The mixture was stirred at room temperature for 1 hour, then saturated NH4Cl (5.0 mL) and water (1.5 mL) were added, and the mixture was stirred vigorously for 5 minutes. The layers were separated, and the aqueous layer was extracted twice with SiO2 (2 × 5.0 mL). The organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and the residue was purified by flash chromatography using DCM / MeOH (99 / 1 to 98 / 2) to obtain (3.71) (0.175 g, 94%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 1.10 - 1.26 (m, 4H, 2xCH 2 cPr ), 2.37 (tt, J = 8.1, 5.3 Hz, 1H, H cPr ), 6.34 (s, 1H, H Ar), 7.27 (ddd, J = 8.5, 5.9, 2.2 Hz, 1H, H Ar ), 7.38 - 7.55 (m, 4H, 4xH Ar ), 10.43 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.9 (CH cPr ), 7.2 (2xCH 2 cPr ), 92.9 (CH Ar ), 123.5 (2xCH Ar ), 125.7 (CH Ar ), 129.5 (2xCH Ar ), 137.7 (C q ), 139.5 (C q ), 140.2 (C q ), 149.8 (C q ), 151.6 (C q ). MS (ESI+): m / z C 14 H 12 Calculated value of ClN5: 286.1 [M+H]+, Measured value: 286.2.

[0384] (Example 3.72) Synthesis of 6-chloro-3-cyclopropyl-N-(2-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.72) Under inert gas conditions, (2.5) (0.150 g, 0.65 mmol, 1.0 equivalent) was dissolved in dry THF (5.0 mL) to which the corresponding aminopyridine (0.125 g, 1.31 mmol, 2.0 equivalents) was added, followed by 1 M tBuOK (1.31 mL, 1.31 mmol, 2.0 equivalents) in THF. The mixture was stirred at room temperature for 1 hour, then saturated NH4Cl (5.0 mL) and water (1.5 mL) were added, and the mixture was stirred vigorously for 5 minutes. The layers were separated, and the aqueous layer was extracted twice with SiO2 (2 × 5.0 mL). The organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and the residue was purified by flash chromatography using DCM / MeOH (99 / 1 to 96 / 4) to obtain (3.72) (0.085 g, 45%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 1.11 - 1.21 (m, 4H, 2xCH 2 cPr ), 2.39 (tt, J = 8.0, 5.4 Hz, 1H, CH cPr ), 7.13 (ddd, J = 7.3, 5.0, 1.0 Hz, 1H, H Ar ), 7.48 - 7.66 (m, 1H, H Ar ), 7.82 (ddd, J = 8.4, 7.3, 2.0 Hz, 1H, H Ar ), 8.31 (s, 1H, H Ar ), 8.45 (dd, J = 5.3, 1.9 Hz, 1H, H Ar ), 10.87 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.9 (CH cPr ), 7.2 (2xCH 2 cPr ), 99.5 (CH Ar ), 114.6 (CH Ar ), 118.6 (CH Ar ), 136.6 (C q ), 138.3 (CH Ar ), 139.2 (C q ), 147.3 (CH Ar ), 150.0 (Cq ), 151.7 (C q ), 153.9 (C q ). MS (ESI+): m / z C 13 H 11 Calculated value of ClN6: 287.1 [M+H]+, Measured value: 287.2.

[0385] (Example 3.73) Synthesis of 6-chloro-3-cyclopropyl-N-(3-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.73) Under inert gas, (2.5) (0.150 g, 0.65 mmol, 1.0 equivalent) was dissolved in dry THF (5.0 mL) to which the corresponding aminopyridine (0.125 g, 1.31 mmol, 2.0 equivalents) was added, followed by 1 M tBuOK (1.31 mL, 1.31 mmol, 2.0 equivalents) in THF. The mixture was stirred at room temperature for 1 hour, then saturated NH4Cl (5.0 mL) and water (1.5 mL) were added, and the mixture was stirred vigorously for 5 minutes. The layers were separated, and the aqueous layer was extracted twice with SiO2 (2 × 5.0 mL). The organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and the residue was purified by flash chromatography using DCM / MeOH (99 / 1 to 96 / 4) to obtain (3.73) (0.080 g, 43%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 1.15 (tt, J = 7.7, 2.6 Hz, 4H, 2xCH 2 cPr ), 2.38 (tt, J = 8.1, 5.3 Hz, 1H, H cPr ), 6.42 (s, 1H, H Ar ), 7.50 (dd, J = 8.2, 4.7 Hz, 1H, H Ar ), 7.91 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H, H Ar ), 8.46 (dd, J = 4.8, 1.5 Hz, 1H, H Ar ), 8.69 (d, J = 2.6 Hz, 1H, H Ar), 10.51 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : ND MS (ESI+): m / z C 13 H 11 Calculated value of ClN6: 287.1 [M+H]+, Measured value: 287.2.

[0386] (Example 3.74) Synthesis of 6-chloro-3-cyclopropyl-N-(4-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.74) Under inert gas, (2.5) (0.150 g, 0.65 mmol, 1.0 equivalent) was dissolved in dry THF (5.0 mL) to which the corresponding aminopyridine (0.125 g, 1.31 mmol, 2.0 equivalents) was added, followed by 1 M tBuOK (1.31 mL, 1.31 mmol, 2.0 equivalents) in THF. The mixture was stirred at room temperature for 1 hour, then saturated NH4Cl (5.0 mL) and water (1.5 mL) were added, and the mixture was stirred vigorously for 5 minutes. The layers were separated, and the aqueous layer was extracted twice with SiO2 (2 × 5.0 mL). The organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and the residue was purified by flash chromatography using DCM / MeOH (99 / 1 to 96 / 4) to obtain (3.74) (0.090 g, 48%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 1.16 (tt, J = 8.0, 2.8 Hz, 4H, 2xCH 2 cPr ), 2.38 (ddd, J = 10.5, 8.3, 5.2 Hz, 1H, H cPr ), 6.87 (s, 1H, H Ar ), 7.42 - 7.58 (m, 2H, 2xH Ar ), 8.54 (d, J = 5.4 Hz, 2H, 2xH Ar ), 10.66 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.9 (CHcPr ), 7.3 (2xCH 2 cPr ), 96.8 (CH Ar ), 115.5 (CH Ar ), 138.0 (C q ), 139.4 (C q ), 145.7 (C q ), 149.8 (C q ), 150.7 (CH Ar ), 151.8 (C q ). MS (ESI+): m / z C 13 H 11 Calculated value of ClN6: 287.1 [M+H]+, Measured value: 287.2.

[0387] (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) (2.5) To a solution of (0.250 g, 1.091 mmol, 1.0 equivalent) of (2.5) in dry THF (8.38 mL), 3-aminopyridazine (0.212 g, 2.183 mmol, 2.0 equivalent), followed by 1 M tBuOK in THF (1.32 mL, 2.183 mmol, 2.0 equivalent), the mixture was stirred at room temperature for 2 hours. After completion, saturated NH4Cl (8.38 mL) and water (2.53 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The resulting precipitate was filtered off and washed with H2O and Et2O to obtain (3.75) (0.286 g, 91%) as a beige solid. Rf(DCM / MeOH, 96 / 4): 0.38 1 H NMR (400 MHz, DMSO-d6) δ: 1.12 - 1.22 (m, 4H, 2xCH 2 cPr ), 2.40 (td, J = 8.1, 4.0 Hz, 1H, H cPr ), 7.72 (dd, J = 9.0, 4.6 Hz, 1H, H Ar ), 7.87 (d, 1H, H Ar ), 8.37 (s, 1H, HAr ), 9.00 (d, J = 4.6 Hz, 1H, H Ar ), 11.10 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.87 (CH cPr ), 7.28 (2xCH 2 cPr ), 101.25 (CH Ar ), 119.51 (CH Ar ), 128.67 (CH Ar ), 136.07 (C q ), 139.23 (C q ), 147.86 (CH Ar ), 150.02 (C q ), 151.82 (C q ), 157.27 (C q ). MS (ESI+): m / z C 12 H 10 Calculated value of ClN7: 288.1 [M+H]+, Measured value: 288.1.

[0388] (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) (2.5) To a solution of (0.087 g, 0.380 mmol, 1.0 equivalent) of 4-aminopyridazine (0.074 g, 0.760 mmol, 2.0 equivalents) in dry THF (2.94 mL), then 1 M tBuOK in THF (0.76 mL, 0.760 mmol, 2.0 equivalents) was added, and the mixture was stirred at room temperature for 1.2 hours. After completion, saturated NH4Cl (2.94 mL) and water (0.871 mL) were added, and the two-phase mixture was stirred vigorously for 5 minutes. The layers were separated, the aqueous layer was extracted with SiO2 (2 × 10 mL), then the organic layers were combined, dehydrated with MgSO4, filtered, and concentrated. The residue was ground in Et2O, filtered, washed with Et2O, and dried under vacuum. The residue was then ground in DCM, filtered, washed with DCM, and vacuum dried to obtain (3.76) (0.094 g, 86%) as a white solid. Rf(DCM / MeOH, 96 / 4): 0.35 1 H NMR (400 MHz, DMSO-d6) δ: 1.10 - 1.23 (m, 4H, 2xCH 2 cPr ), 2.35 - 2.44 (m, 1H, H cPr ), 7.05 (s, 1H, H Ar ), 7.76 (dd, J = 6.2, 2.9 Hz, 1H, H Ar ), 9.08 (d, J = 5.9 Hz, 1H, H Ar ), 9.37 (s, 1H, H Ar ), 10.87 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.85 (CH cPr ), 7.30 (2xCH 2 cPr ), 98.78 (CH Ar ), 115.07 (CH Ar ), 137.63 (C q ), 138.57 (C q ), 139.43 (C q ), 145.29 (CH Ar ), 149.72 (C q ), 151.17 (CH Ar ), 151.82 (C q ). MS (ESI+): m / z C 12 H 10 Calculated value of ClN7: 288.1 [M+H]+, Measured value: 288.2.

[0389] (Example 3.77) Synthesis of 6-chloro-3-cyclopropyl-N-pyrimidine-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.77) (2.5) To a solution of (0.500 g, 2.183 mmol, 1.0 equivalent) in dry THF (16.77 mL), 4-aminopyrimidine (0.416 g, 4.366 mmol, 2.0 equivalent), followed by 1.65 M tBuOK in THF (2.65 mL, 4.366 mmol, 2.0 equivalent), the mixture was stirred at room temperature for 1.3 hours. After completion, saturated NH4Cl (16.77 mL) and water (5.06 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The resulting precipitate was filtered off, washed with H2O, Et2O and pentane, and dried under vacuum to obtain (3.77) (0.463 g, 74%) as a yellow solid. Rf(DCM / MeOH, 96 / 4): 0.31 1 H NMR (400 MHz, DMSO-d6) δ : 1.11 - 1.23 (m, 4H, 2xCH 2 cPr ), 2.35 - 2.44 (m, 1H, CH cPr ), 7.58 (d, J = 5.8 Hz, 1H, H Ar ), 8.36 (s, 1H, H Ar ), 8.62 (d, J = 5.8 Hz, 1H, H Ar ), 9.00 (s, 1H, H Ar ), 11.25 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.84 (CH cPr ), 7.30 (2xCH 2 cPr ), 102.66 (CH Ar ), 110.86 (CH Ar ), 135.79 (C q ), 139.05 (C q ), 149.69 (C q ), 151.85 (C q ), 157.08 (CH Ar ), 157.73 (CH Ar ), 159.67 (C q ). MS (ESI+): m / z C 12 H 10Calculated value of ClN7: 288.1 [M+H]+, Measured value: 288.2.

[0390] (Example 3.78) Synthesis of 6-chloro-3-cyclopropyl-N-(pyrimidine-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.78) (2.5) To a solution of (0.135 g, 0.589 mmol, 1.0 equivalent) in dry THF (4.53 mL), 5-aminopyrimidine (0.113 g, 1.179 mmol, 2.0 equivalent), followed by 1 M tBuOK in THF (1.18 mL, 1.179 mmol, 2.0 equivalent), the mixture was stirred at room temperature for 1 hour. After completion, saturated NH4Cl (4.53 mL) and water (1.35 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted with SiO2 (2 × 10.0 mL), then the organic layers were combined, dehydrated with MgSO4, filtered, and concentrated. The residue was ground in Et2O, filtered, washed with Et2O, dissolved in DCM, and concentrated under vacuum to obtain (3.78) (0.153 g, 90%) as a beige solid. Rf(DCM / MeOH, 92 / 8): 0.54 1 H NMR (400 MHz, DMSO-d6) δ: 1.09 - 1.20 (m, 4H, 2xCH 2 cPr ), 2.34 - 2.42 (m, 1H, H cPr ), 6.63 (s, 1H, H Ar ), 8.94 (d, J = 1.4 Hz, 2H, 2xH Ar ), 9.05 (d, J = 1.4 Hz, 1H, H Ar ), 10.54 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.86 (CH cPr ), 7.26 (2xCH 2 cPr ), 95.16 (CH Ar ), 133.99 (C q ), 139.34 (C q ), 139.54 (Cq ), 149.85 (C q ), 151.58 (2xCH Ar ), 151.68 (C q ), 154.67 (CH Ar ). MS (ESI+): m / z C 12 H 10 Calculated value of ClN7: 288.1 [M+H]+, Measured value: 288.2.

[0391] (Example 3.79) Synthesis of 6-chloro-3-cyclopropyl-N-(pyrimidine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.79) (2.5) To a solution of (0.100 g, 0.437 mmol, 1.0 equivalent) of (2.5) in dry THF (3.36 mL), 2-aminopyrimidine (0.084 g, 0.873 mmol, 2.0 equivalent) was added, followed by 1 M tBuOK (0.87 mL, 0.873 mmol, 2.0 equivalent) in THF, and the mixture was stirred at room temperature for 1.4 hours. After completion, saturated NH4Cl (3.36 mL) and water (1.0 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The layers were separated, the aqueous layer was extracted with SiO2 (2 × 5.0 mL), and then the organic layers were combined, dehydrated with MgSO4, filtered, and concentrated. The residue was ground in Et2O, filtered, washed with Et2O, and vacuum dried to obtain (3.79) (0.100 g, 80%) as a white solid. Rf(DCM / MeOH, 96 / 4): 0.57 1 H NMR (400 MHz, DMSO-d6) δ: 1.12 - 1.22 (m, 4H, 2xCH 2 cPr ), 2.39 (td, J = 8.2, 4.1 Hz, 1H, H cPr ), 7.26 (t, J = 4.8 Hz, 1H, H Ar ), 8.15 (s, 1H, H Ar ), 8.79 (d, J = 4.8 Hz, 2H, 2xH Ar ), 10.28 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.84 (CH cPr ), 7.28 (2xCH 2 cPr ), 99.52 (C q ), 101.30 (CH Ar ), 116.39 (CH Ar ), 136.08 (C q ), 138.96 (C q ), 149.82 (C q ), 151.82 (C q ), 158.64 (2xCH Ar ). MS (ESI+): m / z C 12 H 10 Calculated value of ClN7: 288.1 [M+H]+, Measured value: 288.2.

[0392] (Example 3.80) Synthesis of 6-chloro-3-cyclopropyl-N-(pyrazine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.80) (2.5) To a solution of (0.080 g, 0.349 mmol, 1.0 equivalent) in dry THF (2.68 mL), 2-aminopyrazine (0.066 g, 0.699 mmol, 2.0 equivalent), followed by 1 M tBuOK in THF (0.70 mL, 0.699 mmol, 2.0 equivalent), the mixture was stirred at room temperature for 1.2 hours. After completion, saturated NH4Cl (2.68 mL) and water (0.81 mL) were added, and the two-phase mixture was vigorously stirred for 5 minutes. The resulting precipitate was filtered off and washed with H2O and Et2O to obtain (3.80) (0.072 g, 72%) as a white solid. The filtrate layers were separated, the aqueous layer was extracted with siRNA (2 × 5.0 mL), and then the organic layers were combined, dehydrated with MgSO4, filtered, and concentrated. The residue was ground in Et2O, filtered, washed with Et2O, and vacuum dried to obtain the second portion of (3.80) (0.012 g, 12%) as a white solid. Total of (3.80): 0.084 g, 84%. Rf(DCM / MeOH, 96 / 4): 0.11 1H NMR (400 MHz, DMSO-d6) δ : 1.12 - 1.21 (m, 4H, 2xCH 2 cPr ), 2.39 (tt, J = 8.0, 5.3 Hz, 1H, H cPr ), 8.18 (s, 1H, H Ar ), 8.32 (d, J = 2.8 Hz, 1H, H Ar ), 8.44 - 8.50 (m, 1H, H Ar ), 8.91 (s, 1H, H Ar ), 11.29 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.84 (CH cPr ), 7.28 (2xCH 2 cPr ), 100.30 (CH Ar ), 136.25 (C q ), 137.68 (CH Ar ), 138.02 (CH Ar ), 139.14 (C q ), 141.16 (CH Ar ), 149.80 (C q ), 150.63 (C q ), 151.81 (C q ). MS (ESI+): m / z C 12 H 10 Calculated value of ClN7: 288.1 [M+H]+, Measured value: 288.1.

[0393] (Example 3.81) Synthesis of 6-chloro-3-cyclopropyl-N-(6-methoxypyridine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.81) Under inert gas, 6-methoxypyridine-2-amine (0.103 g, 0.82 mmol, 1.5 equivalents) was added to a solution of (2.5) (0.125 g, 0.55 mmol, 1.0 equivalent) in dry THF (7.5 mL), followed by 1 M tBuOK (0.82 mL, 0.82 mmol, 1.5 equivalents) in THF. The mixture was stirred at room temperature for 3 hours, then saturated NH4Cl (6.0 mL) and water (1.5 mL) were added, and the mixture was stirred vigorously for 5 minutes. The layers were separated, and the aqueous layer was extracted twice with RINKAN (2 × 5.0 mL). The organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and the residue was purified by flash chromatography using DCM / MeOH (99 / 1 to 96 / 4) to obtain (3.81) (0.115 g, 67%) as a white solid. Rf(DCM / MeOH, 98 / 2): 0.28 1 H NMR (400 MHz, DMSO-d6) δ: 1.12 - 1.20 (m, 4H, 2xCH 2 cPr ), 2.38 (tt, J = 8.0, 5.4 Hz, 1H, H cPr ), 3.95 (s, 3H, OCH3), 6.54 (d, J = 8.0 Hz, 1H, H Ar ), 7.16 (d, J = 7.8 Hz, 1H, H Ar ), 7.72 (t, J = 7.9 Hz, 1H, H Ar ), 8.25 (s, 1H, H Ar ), 10.87 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 4.9 (C q ), 7.3 (2xCH 2 cPr ), 53.6 (OCH3), 99.6 (CH Ar ), 103.7 (CH Ar ), 106.3 (CH Ar ), 136.4 (C q ), 139.2 (C q ), 140.9 (CH Ar ), 149.8 (C q ), 151.7 (Cq ), 152.0 (C q ), 162.4 (C q ). MS (ESI+): m / z C 14 H 13 Calculated value of ClN6O: 317.1 [M+H]+, Measured value: 317.3.

[0394] (Example 3.82) Synthesis of 6-chloro-3-cyclopropyl-N-(2-methoxypyridine-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.82) Under inert gas, 2-methoxypyridine-3-amine (0.103 g, 0.82 mmol, 1.5 equivalents) was added to a solution of (2.5) (0.125 g, 0.55 mmol, 1.0 equivalent) in dry THF (7.5 mL), followed by 1 M tBuOK (0.82 mL, 0.82 mmol, 1.5 equivalents) in THF. The mixture was stirred at room temperature for 3 hours, then saturated NH4Cl (6.0 mL) and water (1.5 mL) were added, and the mixture was stirred vigorously for 5 minutes. The layers were separated, and the aqueous layer was extracted twice with RINKAN (2 × 5.0 mL). The organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and the residue was purified by flash chromatography using DCM / MeOH (99 / 1 to 96 / 4) to obtain (3.82) (0.113 g, 65%) as a white solid. Rf(DCM / MeOH, 98 / 2): 0.28 1 H NMR (400 MHz, DMSO-d6) δ: 1.08 - 1.21 (m, 4H, 2xCH 2 cPr ), 2.36 (tt, J = 7.6, 5.1 Hz, 1H, H cPr ), 3.90 (s, 3H, OCH3), 5.85 (s, 1H, H Ar ), 7.11 (dd, J = 7.5, 4.9 Hz, 1H, H Ar ), 7.78 (dd, J = 7.6, 1.7 Hz, 1H, H Ar ), 8.18 (dd, J = 4.9, 1.8 Hz, 1H, HAr ), 9.99 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.9 (CH cPr ), 7.2 (2xCH 2 cPr ), 53.5 (OCH3), 94.2 (CH Ar ), 117.5 (CH Ar ), 120.7 (C q ), 135.7 (CH Ar ), 139.3 (C q ), 140.5 (C q ), 145.0 (CH Ar ), 149.5 (C q ), 151.5 (C q ), 157.9 (C q ). MS (ESI+): m / z C 14 H 13 Calculated value of ClN6O: 317.1 [M+H]+, Measured value: 317.3.

[0395] (Example 3.83) Synthesis of 6-chloro-3-cyclopropyl-N-(2-methoxypyrimidine-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.83) Under inert gas conditions, 0.112 g, 0.85 mmol, 1.3 equivalents of 2-methoxypyrimidine-4-amine were dissolved in 6.5 mL of dry THF, to which 1.83 mL, 0.92 mmol, 1.4 equivalents of 0.5 M KHMDS in toluene were added. The mixture was stirred at room temperature for 10 minutes, then (2.5) (0.150 g, 0.65 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature for 2.5 hours. After completion, 0.5 mL of NH4Cl and 0.5 mL of water were added, and the mixture was vigorously stirred for 5 minutes. The mixture was then concentrated using SiO2 to obtain a solid precipitate, which was purified by flash chromatography using DCM / MeOH (99 / 1 to 95 / 5) to obtain (3.83) (0.097 g, 47%) as a white solid. Rf(DCM / MeOH, 96 / 4): 0.22 1 H NMR (400 MHz, DMSO-d6) δ: 1.11 - 1.23 (m, 4H, 2xCH 2 cPr ), 2.39 (tt, J = 8.1, 5.3 Hz, 1H, H cPr ), 3.95 (s, 3H, CH 3-O ), 7.20 (d, J = 5.6 Hz, 1H, H Ar ), 8.30 (s, 1H, H Ar ), 8.39 (d, J = 5.6 Hz, 1H, H Ar ), 11.21 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.8 (CH cPr ), 7.3 (2xCH cPr ), 54.5 (CH 3-O ), 103.0 (CH Ar ), 104.4 (CH Ar ), 135.7 (C q ), 139.0 (C q ), 149.6 (C q ), 151.8 (C q ), 158.9 (CH Ar ), 161.7 (C q ), 164.4 (C q ).

[0396] (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 conditions, 6-methoxypyridazine-3-amine (0.112 g, 0.85 mmol, 1.3 equivalents) was dissolved in dry THF (6.5 mL) and 0.5 M KHMDS (1.83 mL, 0.92 mmol, 1.4 equivalents) in toluene was added. The mixture was stirred at room temperature for 10 minutes, then (2.5) (0.150 g, 0.65 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature for 2.5 hours. After completion, NH4Cl (0.5 mL) and water (0.5 mL) were added, and the mixture was stirred vigorously for 5 minutes. The mixture was then concentrated with SiO2 to obtain a solid precipitate, which was purified by flash chromatography using DCM / MeOH (99 / 1 to 95 / 5) to obtain (3.84) (0.110 g, 53%) as a white solid. Rf(DCM / MeOH, 96 / 4): 0.34 1 H NMR (400 MHz, DMSO-d6) δ: 1.17 (dd, J = 7.8, 5.4 Hz, 4H, 2xCH 2 cPr ), 2.39 (tt, J = 8.0, 5.3 Hz, 1H, H cPr ), 4.02 (s, 3H, CH 3-O ), 7.32 (d, J = 9.4 Hz, 1H, H Ar ), 7.85 (d, J = 9.5 Hz, 1H, H Ar ), 8.26 (s, 1H, H Ar ), 10.98 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ: 4.9 (CH cPr ), 7.3 (2xCH cPr ), 54.4 (CH 3-O ), 100.3 (CH Ar ), 120.1 (CH Ar ), 124.0 (CH Ar ), 136.0 (C q ), 139.1 (C q ), 150.1 (C q ), 151.8 (C q ), 153.7 (C q), 161.6 (C q ).

[0397] (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) (2.5) To a solution of (0.100 g, 0.44 mmol, 1.0 equivalent) in THF / H2O (6.0 / 0.1 mL), the corresponding amine dihydrochloride (0.103 g, 0.57 mmol, 1.3 equivalents) and DIPEA (0.33 mL, 1.88 mmol, 4.3 equivalents) were added, and the mixture was refluxed for 2 hours. After cooling, the precipitate was filtered off and washed with THF. In a separate vacuum flask, the solid was washed with water, and then washed again with THF in the first flask. The solid was dried under vacuum to obtain the first portion (0.063 g) of (3.85). The organic filtrates were combined, dehydrated with MgSO4, concentrated, and the residue was purified by flash chromatography using DCM / MeOH (98 / 2) as the eluent to obtain the second portion (0.018 g) of (3.85). Total of (3.85): 0.081g, 61%, as a white solid. Rf(DCM / MeOH, 96 / 4): 0.18 1 H NMR (400 MHz, DMSO-d6) δ: 1.06 - 1.16 (m, 4H, 2xCH 2 cPr ), 2.32 (tt, J = 8.1, 5.3 Hz, 1H, H cPr ), 4.89 (s, 2H, CH 2 Bn ), 6.26 (s, 1H, H Ar ), 7.63 - 7.75 (m, 2H, 2xH Ar ), 9.04 (s, 1H, NH Bn ), 9.17 (dd, J = 4.0, 2.6 Hz, 1H, H Ar ). 13 C NMR (101 MHz, DMSO-d6) δ: 4.8 (CH cPr ), 7.1 (2xCH 2 cPr ), 45.7 (CH2 Bn ), 92.0 (CH Ar ), 125.7 (CH Ar ), 127.5 (CH Ar ), 139.3 (C q ), 142.5 (C q ), 149.7 (C q ), 151.0 (CH Ar ), 151.4 (C q ), 159.3 (C q ).

[0398] (Example 3.86) Synthesis of 6-chloro-3-cyclopropyl-N-phenethyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.86) (2.5) To a solution of (0.100 g, 0.44 mmol, 1.0 equivalent) in THF / H2O (6.0 / 0.1 mL), the corresponding amine hydrochloride (0.089 g, 0.57 mmol, 1.3 equivalents) and DIPEA (0.23 mL, 1.31 mmol, 3.0 equivalents) were added, and the mixture was refluxed for 1.5 hours. After cooling, the solvent was removed, the residue was ground in water, the solid was filtered off, washed with water, then Et2O, and vacuum dried to obtain (3.86) (0.115 g, 84%) as a white solid. Rf(DCM / MeOH, 96 / 4): 0.66 1 H NMR (400 MHz, DMSO-d6) δ: 1.10 (ddt, J = 8.7, 7.5, 2.6 Hz, 4H, 2xCH 2 cPr ), 2.31 (tt, J = 8.1, 5.3 Hz, 1H, H cPr ), 2.94 (dd, J = 8.0, 6.6 Hz, 2H, CH 2-CH2-NH ), 3.58 (d, J = 7.2 Hz, 2H, CH 2-NH ), 6.19 (s, 1H, H Ar ), 7.12 - 7.35 (m, 5H, 5xH Ar ), 8.48 (s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δ: 4.8 (CH cPr ), 7.2 (2xCH 2 cPr ), 33.8 (CH 2-CH2-NH ), 43.5 (CH 2-NH ), 91.0 (CH Ar ), 126.2 (CH Ar ), 128.3 (2xCH Ar ), 128.9 (CH Ar ), 138.9 (C q ), 139.3 (C q ), 142.2 (C q ), 149.9 (C q ), 151.3 (C q ). MS (ESI+): m / z C 16 H 16 Calculated value of ClN5: 314.1 [M+H]+, Measured value: 314.2.

[0399] (Example 3.87) Synthesis of 6-chloro-3-isopropyl-N-(6-methoxypyridine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.87) The reaction was carried out with (2.1) (0.180 g, 0.78 mmol, 1 equivalent), an aminopyridine derivative (0.145 g, 1.17 mmol, 1.5 equivalents) in dry THF (10.8 mL), and 1 M tBuOK (1.17 mL, 1.17 mmol, 1.5 equivalents) in THF, and stirred in a round-bottom flask at room temperature for 4 hours. After completion, saturated NH4Cl, water, and SiO were added. The reaction mixture was extracted twice with AcOEt, filtered over MgSO4, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1 to 98 / 2) to obtain (3.87) (0.175 g, 71%) as a pale orange solid. 1 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 (septet, J = 6.9 Hz, 1H), 1.41 (d, J = 7.0 Hz, 6H). 13 C 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.

[0400] (Example 3.88) Synthesis of 6-chloro-3-isopropyl-N-(6-methoxypyridine-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.88) The reaction was carried out with (2.1) (0.180 g, 0.78 mmol, 1 equivalent), an aminopyridine derivative (0.145 g, 1.17 mmol, 1.5 equivalents) in dry THF (10.8 mL), and 1 M tBuOK (1.17 mL, 1.17 mmol, 1.5 equivalents) in THF, and stirred in a round-bottom flask at room temperature for 4 hours. After completion, saturated NH4Cl, water, and SiO2 were added. The reaction mixture was extracted twice with AcOEt, filtered over MgSO4, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1 to 98 / 2) to obtain (3.88) (0.106 g, 43%) as a pale orange solid. 1 H 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 (septet, J = 6.9 Hz, 1H), 1.41 (d, J = 6.9 Hz, 6H). 13 C 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.

[0401] (Example 3.89) Synthesis of 6-chloro-3-isopropyl-N-(5-methoxypyridine-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.89) The reaction was carried out with (2.1) (0.180 g, 0.78 mmol, 1 equivalent), an aminopyridine derivative (0.145 g, 1.17 mmol, 1.5 equivalents) in dry THF (10.8 mL), and 1 M tBuOK (1.17 mL, 1.17 mmol, 1.5 equivalents) in THF, and stirred in a round-bottom flask at room temperature for 4 hours. After completion, saturated NH4Cl, water, and SiO were added. The reaction mixture was extracted twice with AcOEt, filtered over MgSO4, concentrated, and purified by flash chromatography using DCM / AcOEt (8 / 2 to 35 / 65) to obtain (3.89) (0.162 g, 65%) as a pale orange solid. 1 H 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 (septet, J = 6.9 Hz, 1H), 1.41 (d, J = 6.9 Hz, 6H). 13 C 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.

[0402] (Example 3.90) Synthesis of 6-chloro-3-isopropyl-N-(4-methoxypyridine-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.90) The reaction was carried out with (2.1) (0.400 g, 1.73 mmol, 1 equivalent), an aminopyridine derivative (0.322 g, 2.60 mmol, 1.5 equivalents) in dry THF (20.0 mL), and 1 M tBuOK (2.6 mL, 2.60 mmol, 1.5 equivalents) in THF, and stirred in a round-bottom flask at room temperature for 4 hours. After completion, saturated NH4Cl, water, and siRNA were added. The reaction mixture was extracted twice with AcOEt, filtered over MgSO4, concentrated, and purified by flash chromatography using DCM / AcOEt (8 / 2 to 35 / 65) to obtain (3.90) (0.261 g, 47%) as a brown solid. 1 H 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). 13 C 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.

[0403] (Example 3.91) Synthesis of 6-chloro-3-isopropyl-N-(3-phenylpropyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.91) (2.1) To a solution of (0.130 g, 0.56 mmol, 1.0 equivalent) in THF (6.0 mL), the corresponding amine (0.152 g, 1.12 mmol, 2.0 equivalent) and Et3N (0.16 mL, 1.12 mmol, 2.0 equivalent) were added, and the mixture was refluxed for 2 hours. After cooling, the precipitate was filtered off, washed with THF, and the filtrate was concentrated. The residue was purified by flash chromatography using DCM / MeOH (98 / 2) as the eluent to obtain (3.91) (0.177 g, 95%) as a white solid. Rf(DCM / MeOH, 94 / 6): 0.20 1 H NMR (400 MHz, DMSO-d6) δ : 1.00 - 1.20 (m, 4H, 2xCH 2 cPr ), 2.31 (tt, J = 8.1, 5.3 Hz, 1H, H cPr ), 2.96 (t, J = 7.1 Hz, 2H, CH2), 3.49 - 3.76 (m, 2H, CH2), 6.24 (s, 1H, H Ar ), 7.31 (dd, J = 7.8, 4.8 Hz, 1H, H Ar ), 7.71 (dt, J = 7.8, 2.0 Hz, 1H, H Ar ), 8.41 (dd, J = 4.8, 1.7 Hz, 1H, H Ar ), 8.49 (d, J = 2.3 Hz, 1H, H Ar ), 8.52 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 4.8 (CH), 7.1 (2xCH2), 30.9 (CH2), 42.9 (CH2), 91.1 (CH Ar ), 123.3 (CH Ar ), 134.4 (C q ), 136.4 (CH Ar ), 139.3 (C q ), 142.2 (C q ), 147.5 (CH Ar ), 149.9 (C q), 150.0 (CH Ar ), 151.3 (C q ).

[0404] (Example 3.92) Synthesis of 6-chloro-3-isopropyl-N-(2-methoxypyrimidine-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.92) (2.1) To a solution of (0.125 g, 0.54 mmol, 1.0 equivalent) of (2.1) in dry THF (5.4 mL), 2-methoxypyrimidine-4-amine (0.107 g, 0.81 mmol, 1.5 equivalents) was added, followed by 1.00 mL, 0.81 mmol, 1.5 equivalents of 1 M tBuOK in THF, and the mixture was stirred at room temperature for 4 hours. After completion, water (0.5 mL) and SiO2 were added to obtain a solid precipitate. The solvent was removed, and the crude product was purified by flash chromatography using DCM / MeOH (99 / 1 to 96 / 4) as the eluent to obtain (3.92) (0.113 g, 65%) as a white solid. Rf(DCM / MeOH, 95 / 5): 0.32. 1 H NMR (400 MHz, DMSO-d6) δ: 1.42 (d, J = 7.0 Hz, 6H, 2xCH 3 iPr ), 3.51 (septet, J = 6.9 Hz, 1H, H iPr ), 3.96 (s, 3H, CH 3-O ), 7.24 (d, J = 5.6 Hz, 1H, H Ar ), 8.34 (s, 1H, H Ar ), 8.42 (d, J = 5.6 Hz, 1H, H Ar ), 11.30 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.5 (CH iPr ), 54.5 (CH 3-O ), 103.1 (CH Ar ), 104.4 (CH Ar ), 135.7 (Cq ), 139.1 (C q ), 149.4 (C q ), 154.4 (C q ), 158.9 (CH Ar ), 161.7 (C q ), 164.4 (C q ). MS (ESI+): m / z C 13 H 14 Calculated value of ClN7O: 320.1 [M+H]+, Measured value: 320.3.

[0405] (Example 3.93) Synthesis of 6-chloro-3-isopropyl-N-(5-methoxypyrimidine-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.93) (2.1) To a solution of (0.125 g, 0.54 mmol, 1.0 equivalent) of (5-methoxypyrimidine-4-amine) in dry THF (5.4 mL), 0.107 g, 0.81 mmol, 1.5 equivalents were added, followed by 1.00 mL, 0.81 mmol, 1.5 equivalents of 1 M tBuOK in THF, and the mixture was stirred at room temperature for 4 hours. After completion, water (0.5 mL) and SiO2 were added to obtain a solid precipitate. The solvent was removed, and the crude product was purified by flash chromatography using DCM / MeOH (99 / 1 to 98 / 2) as the eluent to obtain (3.93) (0.130 g, 75%) as a white solid. Rf(DCM / MeOH, 95 / 5): 0.39. 1 H NMR (400 MHz, DMSO-d6) δ: 1.42 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.52 (p, J = 7.0 Hz, 1H, H iPr ), 4.10 (s, 3H, CH 3-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 : ND MS (ESI+): m / z C 13 H 14 Calculated value of ClN7O: 320.1 [M+H]+, Measured value: 320.3.

[0406] (Example 3.94) Synthesis of 6-chloro-3-isopropyl-N-(6-methoxypyrimidine-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.94) (2.1) To a solution of (0.125 g, 0.54 mmol, 1.0 equivalent) of (6-methoxypyrimidine-4-amine) in dry THF (5.4 mL), then 1.00 mL of 1 M tBuOK in THF (0.81 mmol, 1.5 equivalent) was added, and the mixture was stirred at room temperature for 4 hours. After completion, water (0.5 mL) and SiO2 were added to obtain a solid precipitate. The solvent was removed, and the crude product was purified by flash chromatography using DCM / MeOH (99 / 1 to 96 / 4) as the eluent to obtain (3.94) (0.105 g, 61%) as a white solid. Rf(DCM / MeOH, 95 / 5): 0.59. 1 H NMR (400 MHz, DMSO-d6) δ: 1.42 (d, J = 7.0 Hz, 6H, 2xCH 3 iPr ), 3.50 (septet, J = 6.9 Hz, 1H, H iPr ), 3.92 (s, 3H, CH 3-O ), 6.98 (d, J = 1.0 Hz, 1H, H Ar ), 8.30 (s, 1H, H Ar ), 8.70 (d, J = 0.9 Hz, 1H, H Ar ), 11.09 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.5 (CH iPr), 53.9 (CH 3-O ), 93.8 (CH Ar ), 102.0 (CH Ar ), 136.1 (C q ), 139.1 (C q ), 149.5 (C q ), 154.4 (C q ), 157.7 (CH Ar ), 161.0 (C q ), 169.8 (C q ). MS (ESI+): m / z C 13 H 14 Calculated value of ClN7O: 320.1 [M+H]+, Measured value: 320.3.

[0407] (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) (2.1) To a solution of (0.200 g, 0.87 mmol, 1.0 equivalent) of (6-methoxypyridazine-3-amine) in dry THF (8.7 mL), 0.5 M KHMDS (2.42 mL, 1.21 mmol, 1.4 equivalent) in toluene was added, and the mixture was stirred at room temperature for 10 minutes. 6-methoxypyridazine-3-amine (0.160 g, 1.21 mmol, 1.4 equivalent) was added, and the mixture was stirred at room temperature for 5 hours. After completion, saturated NH4Cl (0.5 mL) and water (0.5 mL) were added, then the solvent was removed, and the crude product was purified by flash chromatography using DCM / MeOH (99 / 1 to 95 / 5) as the eluate to obtain (3.95) (0.075 g, 27%) as a green solid. 1 H NMR (400 MHz, DMSO-d6) δ: 1.43 (d, J = 6.9 Hz, 6H, 2xCH 3 iPr ), 3.50 (septet, J = 7.0 Hz, 1H, H iPr ), 4.02 (s, 3H, CH 3-O ), 7.32 (d, J = 9.4 Hz, 1H, H Ar), 7.86 (d, J = 9.4 Hz, 1H, H Ar ), 8.27 (s, 1H, H Ar ), 11.03 (s, 1H, NH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.8 (2xCH 3 iPr ), 24.5 (CH iPr ), 54.4 (CH 3-O ), 100.3 (CH Ar ), 120.1 (CH Ar ), 124.1 (CH Ar ), 136.1 (C q ), 139.2 (C q ), 149.9 (C q ), 153.7 (C q ), 154.3 (C q ), 161.7 (C q ). MS (ESI+): m / z C 13 H 14 Calculated value of ClN7O: 320.1 [M+H]+, measured value: 320.2.

[0408] (Example 4) Synthesis of [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine derivatives as shown in Scheme 1 or step 3 of Scheme 2

[0409] [ka]

[0410] (Example 4.1) Synthesis of (2R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]aminobutan-1-ol (1) In a 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.100 g, 0.33 mmol, 1.0 equivalent), NMP (1.0 mL), and the corresponding amine (0.42 mL, 5.30 mmol, 16.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 20 hours. After cooling, the mixture was poured into siRNA (10 mL), and the organic layer was washed twice with water and brine. The organic layer was dehydrated with Na2SO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (94 / 6) as the eluate to obtain (1) (0.070 g, 61%) as a pale yellow solid.

[0411] (Example 4.2) Synthesis of (2S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]aminobutan-1-ol (2) In a 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.200 g, 0.66 mmol, 1.0 equivalent), NMP (2.0 mL), and the corresponding amine (0.32 mL, 3.98 mmol, 6.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was poured into water (10 mL), the resulting precipitate was filtered off and then washed with water. A new precipitate formed in the filtrate, which was filtered off and then washed with water. The residue was dissolved in siRNA / MeOH (7 / 3), the organic filtrate was dehydrated with Na2SO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5, then 94 / 6) as the eluate to obtain (2) (0.094 g, 40%) as a white solid.

[0412] (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 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.200 g, 0.66 mmol, 1.0 equivalent), NMP (2.0 mL), and selinol (0.362 g, 3.98 mmol, 6.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was poured into water (10 mL), the precipitate was filtered off, and washed with water. A new precipitate formed in the filtrate, which was filtered off and washed with water. The residue was dissolved in siRNA / MeOH (7 / 3), the organic filtrate was dehydrated with Na2SO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5, then 94 / 6) as the eluate to obtain (3) (0.092 g, 39%) as a white solid.

[0413] (Example 4.4) Synthesis of (2R,3R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butane-1,3-diol (4) In a 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.175 g, 0.58 mmol, 1.0 equivalent), NMP (1.75 mL), and D-threoninol (0.754 g, 6.96 mmol, 12.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was poured into a funnel containing water (30 mL), the aqueous layer was extracted twice with siRNA (2 × 20 mL), the combined organic layer was washed with 0.1 M HCl (20 mL), then brine, dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5, then 94 / 6) as the eluate to obtain (4) (0.137 g, 64%) as a white solid.

[0414] (Example 4.5) (2R,3R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butane-1,3-diol(5) In a 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.175 g, 0.58 mmol, 1.0 equivalent), NMP (1.75 mL), and D-threoninol (0.754 g, 6.96 mmol, 12.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was poured into a funnel containing water (30 mL), the aqueous layer was extracted twice with siRNA (2 × 20 mL), the combined organic layer was washed with 0.1 M HCl (20 mL), then brine, dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5, then 94 / 6) as the eluate to obtain (5) (0.137 g, 64%) as a white solid.

[0415] (Example 4.6) Synthesis of N-benzyl-3-isopropyl-6-morpholino-[1,2,4]triazolo[4,3-b]pyridazine-8-amine(6) In a 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.200 g, 0.66 mmol, 1.0 equivalent), NMP (1.5 mL), and morpholine (0.82 mL, 9.28 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was poured into a funnel containing water (30 mL), the aqueous layer was extracted twice with siRNA (2 × 25 mL), the combined organic layers were washed with brine, dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (97 / 3, then 96 / 4) as the eluate to obtain (6) (0.116 g, 50%) as a white solid.

[0416] (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 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.175 g, 0.58 mmol, 1.0 equivalent), NMP (1.25 mL), and (S)-(-)-3-amino-1,2-propanediol (0.755 g, 8.12 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was poured into a funnel containing saturated NaHCO3 (15 mL), the aqueous layer was extracted twice with SiO2 (2 × 15 mL), the combined organic layers were washed with brine, dehydrated with Na2SO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain (7) (0.087 g, 42%) as a white solid.

[0417] (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 2-5 mL vial equipped with a stirring bar, (3.1) (0.250 g, 0.83 mmol, 1.0 equivalent), NMP (1.25 mL), and 2-[2-(2-aminoethoxy)ethoxy]ethanamine (0.97 mL, 6.63 mmol, 8.0 equivalents) were placed. The vial was sealed and incubated at 180°C under microwave irradiation for 4 hours. After cooling, the mixture was diluted in Depositphotos (20 mL), and the organic layer was washed with water (40 mL). The aqueous layer was extracted with Depositphotos (20 mL), the organic layers were combined, dehydrated with Na2SO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (97 / 3 then 86 / 14) as the eluate to obtain (8) (0.125 g, 36%) as a white crystalline solid.

[0418] (Example 4.9) Synthesis of 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]propan-1-ol (9) In a 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.200 g, 0.66 mmol, 1.0 equivalent), NMP (0.3 mL), and the corresponding amine (0.72 mL, 9.28 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 17 hours. After cooling, the mixture was diluted in siRNA (20.0 mL), and the organic layer was washed with a brine / water mixture (1 / 2, 3 × 20.0 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (96 / 4) as the eluate to obtain (9) (0.072 g, 32%) as a white solid.

[0419] (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 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.500 g, 1.66 mmol, 1.0 equivalent), NMP (1.3 mL), and 3-methoxypropylamine (2.40 mL, 23.20 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 4 hours. After cooling, the mixture was diluted in siRNA (40 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 50 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (97 / 3) as the eluate to obtain (10) (0.460 g, 78%) as a white solid.

[0420] (Example 4.11) Synthesis of 2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]aminoethanol (11) In a 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.200 g, 0.66 mmol, 1.0 equivalent), NMP (0.6 mL), and ethanolamine (0.57 mL, 9.28 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 16 hours. After cooling, the mixture was diluted in siRNA (20 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 20 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (96 / 4) as the eluate to obtain (11) (0.082 g, 38%) as a white solid.

[0421] (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 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.200 g, 0.66 mmol, 1.0 equivalent), NMP (0.6 mL), and 2-methoxyethaneamine (0.81 mL, 9.28 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 16 hours. After cooling, the mixture was diluted in Depositphotos (20 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 20 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain (12) (0.152 g, 67%) as a white crystalline solid.

[0422] (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 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.200 g, 0.66 mmol, 1.0 equivalent), NMP (0.6 mL), and 2-methoxyethaneamine (0.81 mL, 9.28 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 16 hours. After cooling, the mixture was diluted in siRNA (20 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 20 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain the secondary compound (112) (0.052 g, 25%) as a beige solid.

[0423] (Example 4.14) Synthesis of 4-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]aminobutan-1-ol (13) In a 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.400 g, 1.33 mmol, 1.0 equivalent), NMP (1.2 mL), and the corresponding amine (1.76 mL, 18.56 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 16 hours. After cooling, the mixture was diluted in toluene (40.0 mL), and the organic layer was washed with a brine / water mixture (1 / 2, 3 × 50 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (96 / 4) as the eluate to obtain (13) (0.220 g, 47%) as a white solid.

[0424] (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 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.100 g, 0.33 mmol, 1.0 equivalent), NMP (1.0 mL), and the corresponding amine (0.249 g, 2.65 mmol, 8.0 equivalents) were placed, the vial was then sealed, and the mixture was placed on a heating block at 170°C for 17 hours. After cooling, the mixture was diluted in ELISA (20.0 mL), the organic layer was washed three times with a brine / water mixture (3 / 1, 3 × 10 mL), dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1 to 95 / 5) as the eluate to obtain (14) (0.096 g, 79%) as a white crystalline solid.

[0425] (Example 4.16) Synthesis of 5-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]aminopentan-1-ol (15) In a 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.400 g, 1.33 mmol, 1.0 equivalent), NMP (1.0 mL), and the corresponding amine (2.24 mL, 18.56 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 16 hours. After cooling, the mixture was diluted in Depositphotos (40.0 mL), and the organic layer was washed with a brine / 0.05 M HCl mixture (2 / 1, 3 × 40 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain (15) (0.250 g, 51%) as a white solid.

[0426] (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 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.100 g, 0.33 mmol, 1.0 equivalent), NMP (1.0 mL), and the corresponding amine (0.327 g, 2.65 mmol, 8.0 equivalents) were placed, the vial was then sealed, and the mixture was placed on a heating block at 170°C for 17 hours. After cooling, the mixture was diluted in toluene (20.0 mL), the organic layer was washed three times with a brine / water mixture (3 / 1, 3 × 10 mL), dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1 to 95 / 5) as the eluate to obtain (16) (0.100 g, 79%) as a pale yellow solid.

[0427] (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 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.250 g, 1.30 mmol, 1.0 equivalent), NMP (0.75 mL), and 3-methylsulfanylpropan-1-amine (1.46 mL, 13.02 mmol, 10.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 2 hours. After cooling, the mixture was diluted in toluene (30 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 30 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (96 / 4) as the eluate to obtain (17) (0.270 g, 88%) as a beige solid.

[0428] (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 2-5 mL vials equipped with a stirring bar, (3.1) (0.250 g, 0.83 mmol, 1.0 equivalent), NMP (0.8 mL), and pentane-3-amine (0.88 mL, 7.46 mmol, 9.0 equivalents) were placed. The vials were sealed and then placed on a heating block at 180°C for 24 hours. After cooling, the mixture was diluted in toluene (20 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 20 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (97 / 3) as the eluate. The fraction containing trace amounts of NMP was concentrated, diluted in toluene (20 mL), washed three times with water (3 × 25 mL), the organic layer was dehydrated with Na₂SO₄, filtered, and concentrated to obtain (18) (0.096 g, 33%) as a white crystalline solid.

[0429] (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 equipped with a stirring bar, (3.1) (0.200 g, 0.66 mmol, 1.0 equivalent), NMP (0.6 mL), and the corresponding amine (0.84 mL, 9.28 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 24 hours. After cooling, the mixture was diluted in Depositphotos (30.0 mL), and the organic layer was washed with a brine / water mixture (1 / 2, 3 × 20 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (96 / 4) as the eluate to obtain (19) (0.149 g, 64%) as a white solid.

[0430] (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 2-5 mL sealed tube equipped with a stirring bar, (3.4) (0.160 g, 0.49 mmol, 1.0 equivalent), NMP (0.8 mL), and the corresponding amine (0.358 g, 3.91 mmol, 8.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 170°C for 23 hours. After cooling, water (7.0 mL) was added and stirred for 5 minutes. The resulting mass was filtered, washed with water, and then dissolved in DCM. The organic filtrate was dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 94 / 6) as the eluate to obtain (20) (0.071 g, 38%) as a white solid.

[0431] (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 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.420 g, 1.24 mmol, 1.0 equivalent), dioxane (1.2 mL), and then benzylamine (0.83 mL, 7.42 mmol, 6.0 equivalents) were added. The vial was sealed and then placed on a heating block at 110°C for 4 hours. After cooling, the mixture was diluted in DCM (20 mL), and the resulting organic layer was washed with 0.5 M HCl (20 mL). The aqueous layer was extracted twice with DCM (2 × 10 mL), the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (97 / 3 to 95 / 5) as the eluate to obtain (21) (0.175 g, 39%) as a white solid.

[0432] (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 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.250 g, 0.83 mmol, 1.0 equivalent) and NMP (3.5 mL) were added, followed by (3S)-tetrahydropyran-3-amine hydrochloride (1.080 g, 7.46 mmol, 9.0 equivalents) and K2CO3 (0.555 g, 3.98 mmol, 4.8 equivalents). The vial was sealed and then placed on a heating block at 180°C for 15 hours. After cooling, the mixture was poured over water (50 mL), stirred vigorously for 5 minutes, filtered off the precipitate, washed with water (to neutral pH), then with ethyl acetate, dehydrated the organic filtrate with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (97 / 3 to 95 / 5) to obtain (22) (0.040 g, 13%) as a white crystalline solid.

[0433] (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 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.250 g, 0.83 mmol, 1.0 equivalent) and the corresponding amine (1.29 mL, 12.43 mmol, 15.0 equivalents) were placed, the vial was then sealed, and the vial was placed on a heating block at 180°C for 5.5 hours. After cooling, the mixture was diluted with toluene (3.0 mL), water (3.0 mL) was added, and the two-phase mixture was stirred for 5 minutes. The layers were separated, the aqueous layer was extracted twice with toluene (2 × 3.0 mL), the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (94 / 6) as the eluate to obtain (23) (0.085 g, 28%) as a beige solid.

[0434] (Example 4.25) Synthesis of N-[3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]aminopropyl]acetamide (24) In a 2-5 mL sealed tube equipped with a stirring bar, (3.1) (0.100 g, 0.33 mmol, 1.0 equivalent), NMP (0.2 mL), and then the corresponding amine (0.405 g, 3.31 mmol, 10.0 equivalents) were added. The vial was sealed and then placed on a heating block at 180°C for 15 hours. After cooling, the mixture was diluted in siRNA (20.0 mL), the organic layer was washed with brine / water (1 / 2, 3 × 20.0 mL), dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (96 / 4) as the eluate to obtain (24) (0.118 g, 94%) as a white solid.

[0435] (Example 4.26) Synthesis of 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]propanoic acid (4.26) In a 10-20 mL sealed tube equipped with a stirring bar, (3.1) (0.800 g, 2.65 mmol, 1.0 equivalent) and DMSO (6.5 mL) were added, followed by β-alanine (1.431 g, 15.91 mmol, 6.0 equivalents) and K3PO4 (3.376 g, 15.91 mmol, 6.0 equivalents). The vial was sealed and then placed on a heating block at 180°C for 4 hours. After cooling, the mixture was poured into 1 M HCl (150 mL) and then into water (40 mL) in an ice bath. After 20 minutes, the precipitate was filtered and washed with water (to pH 7), then the solid was isolated using EtOH, concentrated with acetone, and purified by flash chromatography using DCM / MeOH (98 / 2 to 92 / 8, then 92 / 8) as the eluate to obtain (4.26) (0.505 g, 54%) as a beige solid. Rf(DCM / MeOH, 92 / 8): 0.30 1 H NMR (400 MHz, DMSO-d6) δ : 1.36 (d, J = 7.0 Hz, 6H, 2xCH 3 iPr ), 2.51 (m, 2H, CH 2-CO ), 3.34 (d, J = 9.7 Hz, 3H, H iPr & CH2-NH ), 4.42 (d, J = 6.2 Hz, 2H, CH 2 Bn ), 5.39 (s, 1H, H Ar ), 6.64 (t, J = 5.4 Hz, 1H, NH), 7.17 - 7.43 (m, 5H, 5xH Ar ), 7.93 (t, J = 6.4 Hz, 1H, NH Bn ), 12.16 (s, 1H, COOH). 13 C NMR (101 MHz, DMSO-d6) δ : 19.6 (2xCH 3 iPr ), 24.7 (CH iPr ), 33.3 (CH 2-CO ), 36.9 (CH 2-NH ), 45.2 (CH 2 Bn ), 84.1 (CH Ar ), 126.8 (2xCH Ar ), 126.9 (CH Ar ), 128.4 (2xCH Ar ), 138.3 (C q ), 139.7 (C q ), 139.9 (C q ), 152.9 (C q ), 155.7 (C q ), 173.2 (C q ). MS (ESI+): m / z C 18 H 22 Calculated value of N6O2: 355.19 [M+H]+, Measured value: 355.27.

[0436] (Example 4.27) Synthesis of 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]propanamide (25) (4.26) To a solution of (0.110 g, 0.31 mmol, 1.0 equivalent) in THF (3.1 mL), HOBt.H2O (0.062 g, 0.40 mmol, 1.3 equivalent), EDCi (0.058 g, 0.37 mmol, 1.2 equivalent), and 0.5 M ammonia in THF (0.81 mL, 0.40 mmol, 1.3 equivalent) were added. The mixture was stirred at room temperature for 4 hours until complete. After completion, the mixture was concentrated directly and purified on the solid precipitate by flash chromatography using DCM / MeOH (94 / 6) as the eluate to obtain (25) (0.090 g, 82%) as a white solid.

[0437] (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) (4.26) To a solution of (0.120 g, 0.34 mmol, 1.0 equivalent) in THF (3 mL), HOBt.H2O (0.069 g, 0.44 mmol, 1.3 equivalents), 2M methylamine in THF (0.24 mL, 0.47 mmol, 1.4 equivalents), and EDCi (0.065 g, 0.41 mmol, 1.2 equivalents) were added. The mixture was stirred at room temperature for 3 hours until complete. After completion, the mixture was directly concentrated and purified on the solid precipitate by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain (26) (0.121 g, 97%) as a white solid.

[0438] (Example 4.29) Synthesis of 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]-N,N-dimethylpropanamide (27) (4.26) To a solution of (0.120 g, 0.34 mmol, 1.0 equivalent) in THF (3 mL), HOBt.H2O (0.069 g, 0.44 mmol, 1.3 equivalents), 2M dimethylamine in THF (0.24 mL, 0.47 mmol, 1.4 equivalents), and EDCi (0.065 g, 0.41 mmol, 1.2 equivalents) were added. The mixture was stirred at room temperature for 3 hours until complete. After completion, the mixture was concentrated directly and purified on the solid precipitate by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain (27) (0.124 g, 96%) as a white solid.

[0439] (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 equivalent) containing 2 drops of H2SO4 in MeOH (10 mL) was refluxed for 30 minutes. After cooling, Na2CO3 (0.075 g) was added and the mixture was stirred at room temperature for 5 minutes. The mixture was directly concentrated and purified by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain (28) (0.100 g, 87%) as a white solid.

[0440] (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 equivalent) containing 2 drops of H2SO4 in EtOH (10 mL) was refluxed for 30 minutes. After cooling, Na2CO3 (0.075 g) was added and the mixture was stirred at room temperature for 5 minutes. The mixture was directly concentrated and purified by flash chromatography using DCM / MeOH (94 / 6) as the eluate to obtain (29) (0.082 g, 69%) as a white solid.

[0441] (Example 4.32) Synthesis of (2R)-2-[[8-(benzylamino)-3-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]aminobutan-1-ol (30) In a 2-5 mL sealed tube equipped with a stirring bar, (3.3) (0.135 g, 0.45 mmol, 1.0 equivalent), NMP (1.0 mL), and (R)-(-)-2-amino-1-butanol (0.57 mL, 7.21 mmol, 16.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was poured into ELISA (20 mL), and the organic layer was washed three times with brine (20 mL). The organic layer was dehydrated with Na2SO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (96 / 4) as the eluate to obtain (30) (0.112 g, 71%) as a beige solid.

[0442] (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 2-5 mL sealed tube equipped with a stirring bar, (3.3) (0.250 g, 0.83 mmol, 1.0 equivalent), NMP (0.8 mL), and 3-methoxypropylamine (1.21 mL, 11.68 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was diluted in toluene (30 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 20 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (97 / 3) as the eluate to obtain (31) (0.145 g, 49%) as a white solid.

[0443] (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 2-5 mL sealed tube equipped with a stirring bar, (3.3) (0.250 g, 0.83 mmol, 1.0 equivalent), NMP (0.8 mL), and 3-methoxypropylamine (1.21 mL, 11.68 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was diluted in toluene (30 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 20 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (97 / 3) as the eluate to obtain compound (110) (0.120 g, 43%) as a white solid.

[0444] (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 2-5 mL sealed tube equipped with a stirring bar, (3.6) (0.125 g, 0.46 mmol, 1.0 equivalent), NMP (0.4 mL), and 3-methoxypropylamine (0.65 mL, 6.39 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 16 hours. After cooling, the mixture was diluted in Depositphotos (20.0 mL), the organic layer was washed with brine (3 × 10.0 mL), dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain (32) (0.086 g, 58%) as a white solid.

[0445] (Example 4.36) Synthesis of (2R)-2-[[8-(benzylamino)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]aminobutan-1-ol (33) In a 2-5 mL sealed tube equipped with a stirring bar, (3.6) (0.125 g, 0.46 mmol, 1.0 equivalent), NMP (0.4 mL), and (R)-(-)-2-amino-1-butanol (0.51 mL, 5.48 mmol, 12.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 16 hours. After cooling, the mixture was diluted in ELISA (20.0 mL), the organic layer was washed with brine (3 × 10.0 mL), dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain (33) (0.086 g, 58%) as a white solid.

[0446] (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 2-5 mL sealed tube equipped with a stirring bar, (3.7) (0.125 g, 0.38 mmol, 1.0 equivalent), NMP (0.35 mL), and 3-methoxypropylamine (0.55 mL, 5.34 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was diluted in ₹ (25.0 mL), the organic layer was washed with brine / water (1 / 2, 3 × 20.0 mL), dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain (34) (0.086 g, 58%) as a white solid.

[0447] (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 2-5 mL sealed tube equipped with a stirring bar, (3.7) (0.125 g, 0.38 mmol, 1.0 equivalent), NMP (0.35 mL), and 3-methoxypropylamine (0.55 mL, 5.34 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was diluted in Depositphotos (25.0 mL), the organic layer was washed with brine / water (1 / 2, 3 × 20.0 mL), dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain the secondary compound (109) (0.055 g, 39%) as a white solid.

[0448] (Example 4.39) Synthesis of (2R)-2-[[8-(benzylamino)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]aminobutan-1-ol (35) In a 2-5 mL sealed tube equipped with a stirring bar, (3.7) (0.150 g, 0.46 mmol, 1.0 equivalent), NMP (1.0 mL), and (R)-(-)-2-amino-1-butanol (0.59 mL, 6.41 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was diluted in ELISA (25.0 mL), the organic layer was washed with brine / water (1 / 2, 3 × 20.0 mL), dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (95 / 5) as the eluate to obtain (35) (0.115 g, 65%) as a white solid.

[0449] (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 2-5 mL sealed tube equipped with a stirring bar, (3.5) (0.125 g, 0.38 mmol, 1.0 equivalent), NMP (0.4 mL), and 3-methoxypropylamine (0.55 mL, 5.34 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was diluted in Depositphotos (20.0 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 20 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1) as the eluate to obtain (36) (0.110 g, 76%) as a white solid.

[0450] (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 2-5 mL sealed tube equipped with a stirring bar, (3.5) (0.125 g, 0.38 mmol, 1.0 equivalent), NMP (0.4 mL), and 3-methoxypropylamine (0.55 mL, 5.34 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was diluted in ELISA (20.0 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 20 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1) as the eluate to obtain the secondary compound (111) (0.010 g, 7%) as a white solid.

[0451] (Example 4.42) Synthesis of (2R)-2-[[8-(benzylamino)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]aminobutan-1-ol (37) In a 2-5 mL sealed tube equipped with a stirring bar, (3.5) (0.110 g, 0.34 mmol, 1.0 equivalent), NMP (0.3 mL), and (R)-(-)-2-amino-1-butanol (0.44 mL, 4.70 mmol, 14.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 180°C for 18 hours. After cooling, the mixture was diluted in ELISA (20.0 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 20 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (97 / 3) as the eluate to obtain (37) (0.070 g, 55%) as a white solid.

[0452] (Example 4.43) Synthesis of (2R)-2-[[8-(benzylamino)-3-isopropyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]aminobutan-1-ol (115) Under inert gas, 60% NaH (0.119 g, 2.98 mmol, 1.2 equivalents) was gradually added to a solution of (1) (0.880 g, 2.48 mmol, 1.0 equivalent) and dry THF (48.0 mL), and the mixture was stirred at room temperature for 10 minutes. The solution was cooled to 0°C, and MeI (0.17 mL, 2.73 mmol, 1.1 equivalents) was added dropwise, and the mixture was stirred at room temperature for 2 hours. To complete the reaction, MeI (0.03 mL, 0.50 mmol, 0.2 equivalents) was added, and the mixture was stirred for 1 hour. After completion, MeOH (9.0 mL) was slowly added, and the mixture was concentrated directly using SiO2 to obtain a solid precipitate. The precipitate was purified by flash chromatography using DCM / MeOH (98 / 2 to 96 / 4) as the eluate to obtain the secondary compound (115) (0.092 g, 10%) as a beige solid.

[0453] (Example 4.44) Synthesis of 2-[[[6-[[(1R)-1-(hydroxymethyl)propyl]amino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]aminomethyl]phenol (38) In a 2-5 mL sealed tube equipped with a stirring bar, (3.8) (0.150 g, 0.47 mmol, 1.0 equivalent) and (R)-(-)-2-amino-1-butanol (0.91 mL, 9.44 mmol, 20.0 equivalents) were placed, the vial was then sealed, and the mixture was placed on a heating block at 160°C for 15 hours. After cooling, the mixture was diluted in siRNA (25.0 mL), the organic layer was washed twice with a water / brine mixture (1 / 3, 2 × 30.0 mL), then dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (96 / 4 to 92 / 8) as the eluate to obtain the title compound (38) (0.010 g, 6%) as a beige solid.

[0454] (Example 4.45) Synthesis of 2-[[[3-isopropyl-6-(3-methoxypropylamino)-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]aminomethyl]phenol (39) In a 2-5 mL sealed tube equipped with a stirring bar, (3.8) (0.150 g, 0.47 mmol, 1.0 equivalent) and 3-methoxypropylamine (1.07 mL, 9.44 mmol, 20.0 equivalents) were placed, the vial was then sealed, and the mixture was placed on a heating block at 150°C for 19 hours. After cooling, the mixture was diluted in siRNA (25.0 mL), the organic layer was washed twice with a water / brine mixture (1 / 3, 2 × 30.0 mL), then dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (93 / 7 to 92 / 8) as the eluate to obtain the title compound (39) (0.070 g, 40%) as a white solid.

[0455] (Example 4.46) Synthesis of 2-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]aminomethyl]phenol (40) In a 2-5 mL sealed tube equipped with a stirring bar, (3.8) (0.140 g, 0.44 mmol, 1.0 equivalent), NMP (1.0 mL), and 3-aminopentane (0.52 mL, 4.41 mmol, 10.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 170°C for 16 hours. After cooling, the mixture was diluted in ELISA (20.0 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 20 mL). The organic layer was dehydrated with Na₂SO₄, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 95 / 5) as the eluate to obtain (40) (0.021 g, 13%) as a white crystalline solid.

[0456] (Example 4.47) Synthesis of 3-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]aminomethyl]phenol (41) In a 2-5 mL sealed tube equipped with a stirring bar, (3.9) (0.450 g, 1.42 mmol, 1.0 equivalent), NMP (3.3 mL), and 3-aminopentane (3.33 mL, 28.32 mmol, 20.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 170°C for 16 hours. After cooling, the mixture was poured onto saturated NaHCO3 (20.0 mL), then water (30.0 mL) was added, and the mixture was stirred for 5 minutes. The resulting solid was filtered off, washed with water to a neutral pH, then dissolved in DCM, the organic filtrate was dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 94 / 6) to obtain (41) (0.080 g, 15%) as a white solid.

[0457] (Example 4.48) Synthesis of 4-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]aminomethyl]phenol (42) In a 2-5 mL sealed tube equipped with a stirring bar, (3.10) (0.085 g, 0.27 mmol, 1.0 equivalent), NMP (1.0 mL), and 3-aminopentane (0.31 mL, 2.68 mmol, 10.0 equivalent) were placed. The vial was sealed and then placed on a heating block at 170°C for 16 hours. After cooling, the mixture was diluted in Depositphotos (20.0 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 10.0 mL). The organic layer was dehydrated with Na2SO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 95 / 5) as the eluate to obtain (42) (0.015 g, 15%) as a white crystalline solid.

[0458] (Example 4.49) Synthesis of 2-[[[3-isopropyl-6-[[(3R)-tetrahydropyran-3-yl]amino]-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]phenol (43) In a 2-5 mL sealed tube equipped with a stirring bar, (3.8) (0.200 g, 0.63 mmol, 1.0 equivalent), the corresponding amine hydrochloride (0.912 g, 6.29 mmol, 10.0 equivalent), and DIPEA (1.54 mL, 8.81 mmol, 14.0 equivalent) were placed, the vial was then sealed, and the mixture was placed on a heating block at 150°C for 24 hours. After cooling, water (5.0 mL) was added, the precipitate was ground, and the mixture was then poured into water (15.0 mL), stirred for 5 minutes, the precipitate was filtered off, washed with water to a neutral pH, and dissolved in siRNA. The organic filtrate was dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (96 / 4 to 94 / 6) as the eluate to obtain (43) (0.018 g, 7%) as a white solid.

[0459] (Example 4.50) Synthesis of 2-[[[3-isopropyl-6-(tetrahydropyran-4-ylamino)-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]phenol (44) In a 2-5 mL sealed tube equipped with a stirring bar, (3.8) (0.250 g, 0.79 mmol, 1.0 equivalent) and the corresponding amine (0.98 mL, 9.44 mmol, 12.0 equivalents) were placed, the vial was then sealed, and the vial was placed on a heating block at 160°C for 15 hours. After cooling, siRNA (4.0 mL) and water (4.0 mL) were added, the mixture was stirred for 5 minutes, and the layers were separated. The aqueous layer was extracted twice with siRNA (2 × 3.0 mL), the organic layers were combined, dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (96 / 4 to 93 / 7) to obtain (44) (0.030 g, 10%) as a white solid.

[0460] (Example 4.51) Synthesis of (2S)-2-[[8-[(4-bromophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]aminobutan-1-ol (101) In a 10-20 mL sealed tube equipped with a stirring bar, (3.42) (1.800 g, 4.73 mmol, 1.0 equivalent), NMP (5.0 mL), and (2S)-2-aminobutan-1-ol (8.12 mL, 85.11 mmol, 18.0 equivalents) were placed, the vial was then sealed, and the mixture was placed on a heating block at 180°C for 24 hours. After cooling, the reaction mixture was poured onto water (100.0 mL), stirred vigorously for 5 minutes, and the aqueous mixture was extracted with siRNA (3 × 30.0 mL). The organic layers were combined, washed with brine (20.0 mL), dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 93 / 7) as the eluate to obtain (101) (1.290 g, 63%) as a beige solid.

[0461] (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 10-20 mL sealed tube equipped with a stirring bar, (3.42) (1.800 g, 4.73 mmol, 1.0 equivalent), NMP (5.0 mL), and (2S)-2-aminobutan-1-ol (8.12 mL, 85.11 mmol, 18.0 equivalents) were placed, the vial was then sealed, and the vial was placed on a heating block at 180°C for 24 hours. After cooling, the reaction mixture was poured onto water (100.0 mL), stirred vigorously for 5 minutes, and the aqueous mixture was extracted with toluene (3 × 30.0 mL). The organic layers were combined, washed with brine (20.0 mL), dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 93 / 7) as the eluate to obtain the secondary compound (116) (0.300 g, 17%) as a white solid.

[0462] (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 2-5 mL sealed tube equipped with a stirring bar, (3.12) (0.090 g, 0.31 mmol, 1.0 equivalent), cineole (0.7 mL), and 3-aminopentane (0.55 mL, 4.69 mmol, 15.0 equivalents) were placed. The vial was sealed and placed on a heating block at 170°C for 40 hours. After cooling, the mixture was concentrated with SiO2 to obtain a solid precipitate, which was then directly purified by flash chromatography using DCM / MeOH (99 / 1 to 97 / 3) as the eluate to obtain (45) (0.010 g, 9%) as a white solid.

[0463] (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 2-5 mL sealed tube equipped with a stirring bar, (3.13) (0.090 g, 0.31 mmol, 1.0 equivalent), cineole (0.7 mL), and 3-aminopentane (0.55 mL, 4.68 mmol, 15.0 equivalents) were placed. The vial was sealed and placed on a heating block at 170°C for 40 hours. After cooling, the mixture was concentrated with SiO2 to obtain a solid precipitate, which was then directly purified by flash chromatography using DCM / MeOH (99 / 1 to 97 / 3) as the eluate to obtain (46) (0.021 g, 20%) as a beige solid.

[0464] (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 2-5 mL sealed tube equipped with a stirring bar, (3.14) (0.090 g, 0.31 mmol, 1.0 equivalent), cineole (0.7 mL), and 3-aminopentane (0.55 mL, 4.68 mmol, 15.0 equivalents) were placed. The vial was sealed and placed on a heating block at 170°C for 40 hours. After cooling, the mixture was concentrated with SiO2 to obtain a solid precipitate, which was then directly purified by flash chromatography using DCM / MeOH (99 / 1 to 96 / 4) as the eluate to obtain (47) (0.025 g, 24%) as a beige solid.

[0465] (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) (3.15) (0.090 g, 0.31 mmol, 1.0 equivalent), cineole (0.7 mL), and 3-aminopentane (0.55 mL, 4.68 mmol, 15.0 equivalents) were placed in a 2-5 mL sealed tube equipped with a stirring bar. The vial was sealed and placed on a heating block at 170°C for 40 hours. After cooling, the mixture was concentrated with SiO2 to obtain a solid precipitate, which was then directly purified by flash chromatography using DCM / MeOH (99 / 1 to 95 / 5) as the eluate to obtain (48) (0.060 g, 57%) as a white solid.

[0466] (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 2-5 mL sealed tube equipped with a stirring bar, (3.16) (0.100 g, 0.33 mmol, 1.0 equivalent), NMP (0.17 mL), and 3-aminopentane (0.58 mL, 4.95 mmol, 15.0 equivalents) were placed, the vial was then sealed, and the container was placed on a heating block at 160°C for 15 hours. To complete the reaction, NMP (0.34 mL) was added, the vial was sealed, and the container was placed on a heating block at 180°C for 23 hours. After cooling, the mixture was diluted in Depositphotos (10.0 mL), and the organic layer was washed three times with a brine / water mixture (1 / 2, 3 × 10.0 mL). The organic layer was dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1 to 95 / 5) as the eluate to obtain (49) (0.054 g, 46%) as a white solid.

[0467] (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 10-20 mL sealed tube equipped with a stirring bar, (3.17) (0.580 g, 1.92 mmol, 1.0 equivalent), NMP (4.1 mL), and 3-aminopentane (4.06 mL, 34.48 mmol, 18.0 equivalents) were placed, the vial was then sealed, and the vial was placed on a heating block at 180°C for 20 hours. After cooling, the mixture was poured onto saturated NaHCO3 (20.0 mL), the vial was rinsed, and the volume was adjusted to 80.0 mL with water, and the mixture was then stirred for 10 minutes. The resulting precipitate was filtered off, washed with water to a neutral pH, the flask was changed, and the solid was washed with siRNA. The organic filtrate was dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 94 / 6) as the eluate to obtain (50) (0.160 g, 24%) as a pale pink solid.

[0468] (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 10-20 mL sealed tube equipped with a stirring bar, (3.18) (0.750 g, 2.48 mmol, 1.0 equivalent), NMP (5.0 mL), and 3-aminopentane (4.96 mL, 42.11 mmol, 17.0 equivalents) were placed, the vial was then sealed, and the vial was placed on a heating block at 180°C for 69 hours. After cooling, the mixture was poured onto saturated NaHCO3 (20.0 mL), the vial was rinsed, and the volume was adjusted to 80.0 mL with water, and the mixture was then stirred for 10 minutes. The resulting precipitate was filtered off, washed with water to a neutral pH, the flask was changed, and the solid was washed with DCM. The organic filtrate was dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 94 / 6) as the eluate to obtain (51) (0.420 g, 48%) as a white solid.

[0469] (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 2-5 mL sealed tube equipped with a stirring bar, (3.18) (0.250 g, 0.83 mmol, 1.0 equivalent), NMP (2.0 mL), and the corresponding amine (0.45 mL, 4.13 mmol, 5.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 170°C for 65 hours. After cooling, the reaction mixture was poured onto brine / water (1 / 1, 30 mL) and vigorously stirred for 5 minutes. The resulting precipitate was filtered, washed with water, dissolved in DCM, the organic filtrate was dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (99 / 1 to 93 / 7) as the eluate to obtain (52) (0.020 g, 7%) as a white solid.

[0470] (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 2-5 mL sealed tube equipped with a stirring bar, (3.18) (0.200 g, 0.66 mmol, 1.0 equivalent), NMP (1.0 mL), the corresponding amine hydrochloride (0.399 g, 2.64 mmol, 4.0 equivalents), and DIPEA (0.69 mL, 3.96 mmol, 6.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 170°C for 23 hours. After cooling, the mixture was diluted in water (10.0 mL), the resulting precipitate was ground in water, filtered, and washed with a small amount of water. The solid was ground with siRNA, filtered, the organic filtrate was dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 93 / 7) to obtain (53) (0.035 g, 14%) as a gray solid.

[0471] (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 2-5 mL sealed tube equipped with a stirring bar, (3.18) (0.200 g, 0.66 mmol, 1.0 equivalent), NMP (1.0 mL), the corresponding amine hydrochloride (0.399 g, 2.64 mmol, 4.0 equivalents), and DIPEA (0.69 mL, 3.96 mmol, 6.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 170°C for 23 hours. After cooling, the mixture was diluted in water (10.0 mL), the resulting precipitate was ground in water, filtered, and washed with a small amount of water. The solid was ground with siRNA, filtered, the organic filtrate was dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 93 / 7) as the eluate to obtain (54) (0.035 g, 14%) as a beige solid.

[0472] (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 2-5 mL sealed tube equipped with a stirring bar, (3.18) (0.200 g, 0.66 mmol, 1.0 equivalent), NMP (1.0 mL), the corresponding amine hydrochloride (0.399 g, 2.64 mmol, 4.0 equivalents), and DIPEA (0.69 mL, 3.96 mmol, 6.0 equivalents) were placed. The vial was sealed and then placed on a heating block at 170°C for 23 hours. After cooling, the mixture was diluted in water (10.0 mL), the resulting precipitate was ground in water, filtered, and washed with a small amount of water. The solid was ground with siRNA, filtered, the organic filtrate was dehydrated with MgSO4, filtered, concentrated, and purified by flash chromatography using DCM / MeOH (98 / 2 to 93 / ...

Claims

1. Compound of formula (I) or its pharmaceutically acceptable salt 【Chemistry 1】 (In the formula, R 1 is a hydrogen atom or (C 1 ~C 6 ) Represents an alkyl group; R 2 represents a hydrogen atom; R 3 teeth, - Linear or branched (C 1 ~C 6 ) an alkyl group, ・ - OR 7 group, - NH 2 group, halogen atom, phenyl group and (C 5 ~C 6 ) heteroaryl group, optionally substituted with at least one substituent selected from, one phenyl group, ・One (C 6 ~C 10 ) Heteroaryl group, or - One -OR 7 base Linear or branched (C) replaced by 1 ~C 6 ) Alkyl group; - Phenyl group or (C 4 ~C 6 ) A phenyl group condensed with a cycloalkyl group; or - (C 1 ~C 4 ) Alkyl alkyl, deuterated (C 1 ~C 4 ) alkyl group, (C 1 ~C 4 )alkoxy group, deuterated (C 1 ~C 4 )Optionally substituted with 1 to 3 substituents selected from alkoxy groups and halogen atoms, particularly fluorine atoms or chlorine atoms (C 5 ~C 6 ) heteroaryl group It represents; L represents a bond or a -CO- group; Alternatively, L is conjugation, and R 2 and R 3 It contains at least one nitrogen atom that is condensed with a phenyl group, along with the nitrogen atoms that have them (C 5 ~C 6 ) form heterocycloalkyl groups; R 4 is a hydrogen atom, linear or branched (C 1 ~C 6 ) alkyl group, (C 3 ~C 6 )Cycloalkyl group, (C 1 ~C 4 )alkoxy group, (C 5 ~C 6 ) Heterocycloalkyl group, phenyl group, (C 5 ~C 6 ) Heteroaryl group or -CF 3 Represents the base; R 5 is a hydrogen atom or (C 1 ~C 4 ) Represents an alkyl group; R 6 teeth, - A linear or branched chain (C) that is optionally interrupted by one or two oxygen atoms. 1 ~C 8 ) an alkyl group, ・(C 1 ~C 4 ) alkyl groups and (C 1 ~C 4 ) One phenyl group optionally substituted with one or two substituents selected from alkoxy groups, • Halogen atoms, (C 1 ~C 4 ) alkyl groups and -OR 7 One (C) which is optionally substituted with one or two substituents selected from the group. 3 ~C 8 ) Cycloalkyl groups, ・One (C 5 ~C 6 ) Heterocycloalkyl, ・One or two (C 1 ~C 6 ) One (C) optionally substituted with an alkyl group 5 ~C 6 ) Heteroaryl group, - One or two -OR 7 base, ・1-SR 7 base, ・One -C(O)NR 8 R 9 base, - One -C(O)OR 10 base, or ・One-NHR 11 base Linear or branched (C) are optionally replaced. 1 ~C 8 ) alkyl group, - Halogen atom, (C 1 ~C 4 ) alkyl groups and -OR 7 (C) is optionally substituted with one or two substituents selected from the group. 3 ~C 7 ) Cycloalkyl groups, - One bridge (C 6 ~C 10 ) Cycloalkyl groups, - One spiro (C 5 ~C 11 ) bicyclic ring, - (C 5 ~C 6 ) Heteroaryl group, - (C 5 ~C 6 ) Heterocycloalkyl groups, or - (C 4 ~C 6 ) Phenyl group condensed with a cycloalkyl group It represents; or R 5 and R 6 together with the nitrogen atom bearing them form a (C 5 -C 6 ) heterocycloalkyl group; R 7 represents a hydrogen atom, a (C 1 to C 4 ) alkyl group or a deuterated (C 1 to C 4 ) alkyl group; R 8 and R 9 These are independently hydrogen atoms or (C 1 ~C 6 ) Represents an alkyl group; R 10 is (C 1 ~C 4 ) Represents an alkyl group; R 11 is a hydrogen atom or -CO-(C 1 ~C 6 ) Represents an alkyl group; However, NR 2 LR 3 When R represents a benzylamino group, 4 (This does not represent a hydrogen atom.)

2. R 1 A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein represents a hydrogen atom or a methyl group.

3. R 2 This represents a hydrogen atom; R 3 but, - Linear or branched (C 1 ~C 6 ) an alkyl group, - One phenyl group, optionally substituted with one substituent selected from a hydroxyl group, methoxy group, amino group, halogen atom, phenyl group, and 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 hydroxyl group, - One methoxy group, one deuterated methoxy group, or Halogen atoms, especially fluorine atoms or chlorine atoms Linear or branched (C) replaced by 1 ~C 6 ) alkyl group, - Phenyl group or indanyl group, - Pyridyl, pyrazinyl, pyrimidinyl, or pyridadinyl groups, particularly pyridyl groups, optionally substituted with one methoxy group or deuterated methoxy group. It represents; L represents a bond or a -CO- group; Alternatively, L is a conjunction, and R 2 and R 3 However, together with nitrogen atoms having them, they form indolinyl, isoindolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl groups, particularly isoindolinyl or tetrahydroisoquinolinyl groups. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R 4 However, hydrogen atoms, linear or branched (C 1 ~C 5 ) alkyl group, (C 3 ~C 6 ) Cycloalkyl group, phenyl group, pyridyl group or -CF 3 A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, representing a group.

5. R 5 However, a hydrogen atom or (C 1 ~C 4 ) Represents an alkyl group, especially a methyl group; R 6 but, - A linear or branched chain (C) that is optionally interrupted by one or two oxygen atoms. 1 ~C 8 ) an alkyl group, - One phenyl group optionally substituted with one or two substituents selected from methyl and methoxy groups, - One (C) group optionally substituted with a methyl group 3 ~C 6 ) Cycloalkyl groups, - One tetrahydropyranyl or one tetrahydrofuranyl group, - One pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridyl, furanyl, or thienyl group, optionally substituted with one or two methyl groups. - One or two hydroxyl or methoxy groups, • One methylthio group, ・1-CONH 2 Base, one - CONHCH 3 Base or one -CON(CH 3 ) 2 base, ・1-COOCH 3 Or one-COOCH 2 CH 3 base, or ・1 -NH 2 base or one -NCOCH 3 base Linear or branched (C) are optionally replaced. 1 ~C 8 ) alkyl group, - Optionally substituted with one or two substituents selected from halogen atoms, hydroxyl groups, or methoxy groups (C 3 ~C 7 ) Cycloalkyl groups, - Adamantyl group, - Spiro[3.3]heptanyl group, - Imidazolyl groups optionally substituted with one or two methyl groups, - Morpholinyl group, tetrahydropyranyl or tetrahydrofuranyl group, - Indanyl group It represents; or R 5 and R 6 However, together with nitrogen atoms that have them, they form a morpholinyl group or a piperidinyl group. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4.

6. (1) (2R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butan-1-ol, (2) (2S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butan-1-ol, (3) 2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]propane-1,3-diol, (4) (2R,3R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butan-1,3-diol, (5) (2S,3S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butan-1,3-diol, (6) N-benzyl-3-isopropyl-6-morpholino-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (7) (2S)-3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-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]pyridazine-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]pyridazine-6-yl]aminoethanol, (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]pyridazine-6-yl]aminobutan-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]pyridazine-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]pyridazine-6-yl]aminopropyl]acetamide, (25) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]aminoamide, (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-dimethylpropanamide, (28) Methyl 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-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]pyridazine-6-yl]aminobutan-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]pyridazine-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]pyridazine-6-yl]aminobutan-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]pyridazine-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]aminomethyl]phenol, (39) 2-[[[3-isopropyl-6-(3-methoxypropylamino)-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]phenol, (40) 2-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]phenol, (41) 3-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]phenol, (42) 4-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]phenol, (43) 2-[[[3-isopropyl-6-[[(3R)-tetrahydropyran-3-yl ]amino]-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]phenol, (44) 2-[[[3-isopropyl-6-(tetrahydropyran-4-ylamino)-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]aminomethyl]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]pyridazine-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-indole-2-ylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (79) N-(1-ethylpropyl)-8-isoindorin-2-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-amine, (80) 8-(3,4-dihydro-1H-isoquinoline-2-yl)-N-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-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-(pyrimidine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (93) N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrimidine-5-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (94) N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrazine-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]pyridazin-6,8-diamine, (96) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]benzamide, (97) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]pyridine-2-carboxamide, (98) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2-phenylacetamide, (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]pyridazine-8-yl]carbamate, (101) (2S)-2-[[8-[(4-bromophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butan-1-ol, (102) (2S)-2-[[3-isopropyl-8-[(4-phenylphenyl)methylamino]-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]amino-1-ol, (103) (2S)-2-[[3-isopropyl-8-[[4-(4-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]amino-1-ol, (104) (2S)-2-[[3-isopropyl-8-[[4-(3-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]amino-1-ol, (105) (2S)-2-[[3-isopropyl-8-[[4-(2-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]amino-1-ol, (106) (2R,3R)-2-[[8-[(4-bromophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butan-1,3-diol, (107) (2R,3R)-2-[[3-isopropyl-8-[[4-(2-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butan-1,3-diol, (108) (2R,3R)-2-[[3-isopropyl-8-[[4-(4-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butan-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]pyridazine-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-methylimidazole-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]pyridazine-6-yl]amino]cyclohexanol, (135) Racemic trans-4-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-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-methylpyrazine-2-yl)methyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (140) N8-benzyl-3-isopropyl-N6-[(1-methylpyrazole-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-methylimidazole-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (145) N8-benzyl-N6-[(4,6-dimethylpyrimidine-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]pyridazin-6,8-diamine, (148) 3-Isopropyl-N6-(pentan-3-yl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (149) 3-Isopropyl-N6-(pentan-3-yl)-N8-(pyridazin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (150) 3-Isopropyl-N6-(pentan-3-yl)-N8-(pyrimidine-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (151) 3-Isopropyl-N6-(pentan-3-yl)-N8-(pyrimidine-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (152) 3-Isopropyl-N6-(pentan-3-yl)-N8-(pyrimidine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (153) 3-Isopropyl-N6-(pentan-3-yl)-N8-(pyrazine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (154) 3-Isopropyl-N8-(6-methoxypyridine-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (155) 3-Isopropyl-N8-(5-methoxypyridine-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (156) 3-Isopropyl-N8-(4-methoxypyridine-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (157) 3-Isopropyl-N8-(3-methoxypyridine-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (158) 3-Isopropyl-N8-(2-methoxypyridine-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (159) 3-Isopropyl-N8-(6-methoxypyridine-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (160) Isopropyl-N8-(5-methoxypyridine-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (161) 3-Isopropyl-N8-(4-methoxypyridine-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]pyridazin-6,8-diamine, (163) (2R)-2-[[3-isopropyl-8-(2-pyridylamino)-[1,2,4]triazolo[4,3-b]pyridazine-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]pyridazine-8-yl]-2-(3-pyridyl)acetamide, (169) (2R)-2-[[3-isopropyl-8-(2-pyridylmethylamino)imidazo[1,2-b]pyridazine-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]pyridazin-6,8-diamine, (176) 3-Cyclopropyl-N6-(pentan-3-yl)-N8-(pyridazin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (177) 3-Cyclopropyl-N6-(pentan-3-yl)-N8-(pyrimidine-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (178) 3-Cyclopropyl-N6-(1-ethylpropyl)-N8-pyrimidine-5-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (179) 3-Cyclopropyl-N6-(pentan-3-yl)-N8-(pyrimidine-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (180) 3-Cyclopropyl-N6-(pentan-3-yl)-N8-(pyrazine-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-methoxypyridine-2-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (184) 3-Cyclopropyl-N8-(2-methoxypyridine-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]pyridazine-6-yl]amino]butan-1-ol, (186) N6-benzyl-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (187) 3-Cyclopropyl-N6-(4-Methoxybenzyl)-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]pyridazine-6,8-diamine, (188) 3-Cyclopropyl-N6-(4-Methoxybenzyl)-N6-methyl-N8-(Pyridine-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-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (191) N6-butyl-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (192) 3-Cyclopropyl-N6-Isopropyl-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]Pyridazine-6,8-diamine, (193) N6-(sec-butyl)-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (194) 3-Cyclopropyl-N6-Isobutyl-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]pyridazine-6,8-diamine, (195) N6-(tert-butyl)-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (196) 3-Cyclopropyl-N6-(2-ethylbutyl)-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (197) N6,3-dicyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (198) N6-Cyclobutyl-3-Cyclopropyl-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]Pyridazine-6,8-diamine, (199) N6-Cyclopentyl-3-Cyclopropyl-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]Pyridazine-6,8-diamine, (200) N6-Cyclohexyl-3-Cyclopropyl-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]Pyridazine-6,8-diamine, (201) N6-cycloheptyl-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (202) N6-((3s,5s,7s)-adamantan-1-yl)-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (203) 3-Cyclopropyl-N6-(Cyclopropylmethyl)-N8-(Pyridine-2-ylmethyl)-[1,2,4]Triazolo[4,3-b]pyridazine-6,8-diamine, (204) N6-(cyclobutylmethyl)-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (205) 3-Cyclopropyl-N8-(pyridine-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-(pyridine-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]pyridazine-8-amine, (208) 3-Cyclopropyl-N6-(furan-2-ylmethyl)-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (209) 3-Cyclopropyl-N6-(furan-3-ylmethyl)-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (210) 3-Cyclopropyl-N8-(pyridine-2-ylmethyl)-N6-(thiophen-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (211) (R)-2-((3-cyclopropyl-8-((pyridine-2-ylmethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-6-yl)amino)butan-1-ol, (212) (S)-2-((3-cyclopropyl-8-((pyridine-2-ylmethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-6-yl)amino)butan-1-ol, (213) (R)-3-cyclopropyl-N8-(pyridine-2-ylmethyl)-N6-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (214) (R)-3-cyclopropyl-N8-(pyridine-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]pyridazin-6,8-diamine, (216) 3-Cyclopropyl-N6-(pentan-3-yl)-N8-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-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-(pyridine-2-ylmethyl)-N6-(thiophene-3-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (219) 3-Cyclopropyl-N6-methyl-N8-(pyridine-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (220) 3-Cyclopropyl-N-(pyridine-2-ylmethyl)-6-(pyrrolidine-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine, (221) 3-Isopropyl-N8-(2-methoxypyrimidine-4-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (222) 3-Isopropyl-N8-(5-methoxypyrimidine-4-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (223) 3-Isopropyl-N8-(6-methoxypyrimidine-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]pyridazin-6,8-diamine, (225) 3-Cyclopropyl-N6-(2-ethylbutyl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (226) 3-Cyclopropyl-N6-(2-ethylbutyl)-N8-(6-methoxypyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (227) N8-(6-chloropyridazine-3-yl)-3-isopropyl-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (228) N8-(2-chloropyrimidine-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]pyridazin-6,8-diamine, (230) N6-(3-ethylpentyl)-3-isopropyl-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (231) 3-Isopropyl-N8-(6-(methoxy-d3)pyridazin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (232) N8-(6-chloropyridazine-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 Selected from, in particular, 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), as well as their pharmaceutically acceptable salts, and especially 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), (9 8) (100), (114), (118), (126), (130), (147) (151), (153) (156), (158) (160), (162), (164) (168), (170) (178), (180) (183), (186), (187), (191) (193), (195), (196), (198) (202), (204) (206), (208) (210), (215) (218), (221), and (223) (234), as well as their pharmaceuticals Compounds selected from pharmaceutically acceptable salts thereof, and 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), as well as pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof.

7. A synthesis method for producing a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, or at least one of compounds (1) to (234) as described in claim 6, or a pharmaceutically acceptable salt thereof, comprising at least a compound of formula (II) 【Chemistry 2】 (In the formula, L, R 2 , R 3 and R 4 (This is as set forth in any one of claims 1, 3, or 4.) The amine of formula (IV) is then added in a non-protic solvent, or without a solvent, or in a protic solvent, for example, in a molar ratio of 1 to 20 equivalents to the compound of formula (II). NHR 5 R 6 (IV) (In the formula, R 5 and R 6 (This is as set forth in claim 1 or 5.) A synthesis method that includes a step of reacting with [a certain substance].

8. A synthesis method for producing a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, or at least one of compounds (1) to (234) as described in claim 6, or a pharmaceutically acceptable salt thereof, comprising at least a compound of formula (IX) 【Transformation 3】 (In the formula, R 4 , R 5 and R 6 (As set forth in claims 1, 4, and 5) For example, the compound of formula (VI) in an aprotic solvent in a molar ratio of 1 to 10 equivalents relative to the compound of formula (IX) 【Chemistry 4】 (In the formula, R 2 and R 3 (This is as set forth in claim 1 or 3.) A synthesis method that includes a step of reacting with [a certain substance].

9. A synthesis method for producing a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, or at least one of compounds (1) to (234) as described in claim 6, or a pharmaceutically acceptable salt thereof, comprising at least a compound of formula (XII) 【Transformation 5】 (In the formula, R 5 and R 6 (This is as set forth in claim 1 or 5.) For example, the compound of formula (XIV) in an aprotic solvent in a molar ratio of 1 to 10 equivalents relative to the compound of formula (XII) 【Transformation 6】 (In the formula, L and R 3 is as defined in claim 1 or 3, where X is a hydroxyl group, a chlorine atom, a bromine atom, (C 1 ~C 3 (Represents an alkyl sulfonate group or a phenyl sulfonate group) A synthesis method that includes a step of reacting with [a certain substance].

10. In particular, compounds of formula (II), (X), (XI), or (VII) as intermediate compounds. 【Transformation 7】 (In the formula, L, R 2 , R 3 , R 4 , R 5 and R 6 The formula is as set forth in claim 1, 3, 4, or 5, provided that in formula (XI), R 4 (This is not a methyl group.)

11. A compound of formula (I) as described in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical, or at least one of compounds (1) to (234) as described in claim 6, or a pharmaceutically acceptable salt thereof.

12. A compound of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of ulcerative colitis, atopic dermatitis, glaucoma, asthma, hepatic fibrosis, kidney disease, atherosclerosis, hypercholesterolemia, hearing loss, and cancers that develop under hypoxic conditions, particularly glioblastoma, or at least one of compounds (1) to (234) according to claim 6 or a pharmaceutically acceptable salt thereof.

13. The compound for use according to claim 12, wherein the hearing loss is partial or complete hearing loss induced in particular by noise, acoustic trauma or ototoxic agents or conditions, more particularly by platinum-based anticancer drugs, e.g., cisplatin or carboplatin, antibiotics, more particularly macrolides or aminoglycosides, e.g., gentamicin or neomycin, drugs for COVID-19, e.g., lopinavir or ritonavir, antimalarial drugs, e.g., quinine or chloroquine, cardiovascular drugs, e.g., loop diuretics, nonsteroidal anti-inflammatory drugs, e.g., salicylic acid or cyclodextrin, erectile dysfunction drugs, e.g., phosphodiesterase type 5 inhibitors.

14. The compound for use according to claim 12, wherein the kidney disease is selected from renal fibrosis, nephropathy, acute kidney injury, chronic kidney disease, particularly renal fibrosis, nephropathy, acute kidney injury, chronic kidney disease, toxic nephropathy or myoglobinuria induced by ischemia and / or reperfusion injury, and diabetes-related kidney disease, or the kidney disease is induced by nephrotoxicity caused by a therapeutic agent, more particularly a cytotoxic agent, such as a platin-based anticancer drug, such as cisplatin or carboplatin.

15. A pharmaceutical composition comprising at least one compound of formula (I) described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or at least one of the compounds (1) to (234) described in claim 6 or a pharmaceutically acceptable salt thereof.

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