[1, 2, 4]-triazolo [4, 3-b] pyridazine derivatives for use as medicaments

Abstract

The present invention relates to a compound of formula (I) or any pharmaceutically acceptable salt thereof. The invention also relates to a synthetic process for the preparation of a compound of formula (I) or any pharmaceutically acceptable salt thereof, comprising at least the step of reacting a compound of formula (II) with an amine NHR5R6 of formula (IV) in a molar ratio of 1 to 20 equivalents, for example relative to the compound of formula (II), in an aprotic solvent or in solvent-free conditions or in a protic solvent.

Description

Invention Field

[0001] This invention relates to [1,2,4]-triazolo[4,3-b]pyridazine derivatives, which can be used to treat pathologies mediated by adenosine A3 receptor (A3AR). The invention also relates to methods of their preparation and pharmaceutical compositions comprising them.

[0002] background

[0003] Adenosine interacts with four types of G protein-coupled receptors (GPCRs), namely adenosine receptors (ARs): A1AR, A... 2A AR, A 2B AR, A3AR, such as IJzerman, AP et al., International Union of Basic and Clinical Pharmacology, CXII: Adenosine Receptors: A Further Update, Pharmacol Rev 2022, 74(2), 340-372. Regarding A... 2A AR is the most extensively studied, while A3AR is the least studied AR.

[0004] Over the past few decades, numerous subtype-specific AR agonists and antagonists have been developed and tested in clinical trials for various indications, as described in IJzerman, AP et al., International Union of Basic and Clinical Pharmacology, CXII: Adenosine Receptors: A Further Update, Pharmacol Rev 2022, 74(2), 340-372; and Jacobson, KA et al., Medicinal Chemistry of P2 and Adenosine Receptors: Common Scaffolds Adapted for Multiple Targets, BiochemPharmacol 2021, 187, 114311. Approved AR drugs include the A1AR agonist adenosine (for paroxysmal supraventricular tachycardia), A... 2AAR agonist Regadenoson (used for myocardial perfusion imaging), A1AR antagonist chamophylline (for asthma), and A 2A AR antagonist isodefylline (Parkinson's disease).

[0005] A3AR (P0DMS8) (a gene located on human chromosome 1 (1p13.2), human-derived, containing 318 amino acids) was discovered in the early 1990s, as described by Borea, PA et al. in *The A3 Adenosine Receptor: History and Perspectives*, *Pharmacol Rev* 2015, 67, 74-102. A3AR couples with Gi protein, thereby inhibiting adenylate cyclase, and with Go protein, thereby activating phospholipase C and Ca2+. ++ The release of A3AR. A3AR is also coupled with the PI3K / Akt, MAPK, and NF-κB signaling pathways. The biodistribution of A3AR is closely related to species. In humans, A3AR is expressed in lung, liver, kidney, pancreas, brain, testis, and immune system cells. To investigate the function of A3AR, A3AR knockout mice were created. - / - The mice were alive, fertile, and morphologically indistinguishable from wild-type mice, suggesting that inhibiting this receptor is unlikely to lead to severe toxicity.

[0006] Despite A1AR, A 2A AR and A 2B The A3AR sequence is well conserved during evolution, but there are significant differences between rodent and human A3AR sequences (72% and 73% sequence identity between human A3AR and rat or mouse A3AR, respectively). Many human A3AR antagonists exhibit very poor or even no activity against their rat and mouse orthologs. This complicates translational studies of the roles of A3AR agonists and antagonists in rodent models of human diseases. Humanized A3AR (A3AR...) has been constructed... h / h ) and human / mouse chimeric A3AR (A3AR c / c Mice that are sensitive to agonists developed for human A3AR.

[0007] In cerebral ischemia, A3AR may interact with A 1AA3AR agonists exert a protective effect by synergistically inhibiting excitatory synaptic transmission, but may also exert detrimental effects by promoting excitotoxicity. A3AR agonists can modulate pain signals, particularly in the case of drug-induced neuropathic pain. A3AR is overexpressed in several tumors and exhibits both anti-proliferative and pro-proliferative effects. Both A3AR agonists and antagonists have shown antitumor activity. A3AR appears to play a key role in adenosine-mediated inflammation. Therefore, A3AR agonists have been evaluated in clinical trials for the treatment of various inflammatory diseases, such as knee osteoarthritis, asthma, and pulmonary fibrosis. A3AR agonists have been investigated for inducing hypothermia and potential cardioprotective activity, but A3AR deficiency appears to provide some resistance to myocardial ischemia-related injury.

[0008] Several potent and highly selective A3AR agonists have been described, among which, picrinoson (IB-MECA, N... 6 2-Iodobenzyl-substituted methylcarboxamide adenosine (CF101, Can-Fite BioPharma) and namodenoson (2-Cl-IB-MECA, CF102) are the most advanced drug candidates. Picotinoxon is undergoing clinical trials for rheumatoid arthritis and psoriasis, while namodenoson is undergoing clinical trials for hepatocellular carcinoma and non-alcoholic steatohepatitis (NASH).

[0009] like Figure 1 As shown, several A3AR antagonists are also described, such as KF2677, PSB-10, DPTN (N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazolyl-2-yl]nicotinamide), MRS1523, SSR161421, LJ-1888, pyrazolo-triazolo-pyrimidine, ISVY-130 analogue, 2-chloro-N6-phenylethyl adenosine (mentioned previously in Borea, PA et al.), 7-amino-pyrazolo[3,4-d]pyridazine 10a (a bis-A1 / A3AR antagonist, as described in Gao, ZG. et al., Species Dependence of A3 Adenosine Receptor Pharmacology and Function, Purinergic Signal 2, 2022, 1-28).

[0010] In the 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 have been evaluated for the treatment of glaucoma due to their ability to reduce intraocular pressure (IOP) in animal models of glaucoma. A3AR antagonists have been evaluated for the treatment of asthma, ulcerative colitis, liver fibrosis, kidney disease, particularly renal fibrosis, nephropathy, nephrotoxicity, atherosclerosis, and hypercholesterolemia. Under hypoxic conditions, adenosine stimulation of A3AR contributes to the migration, invasion, and chemotherapy resistance of glioblastoma stem-like cells, and may also be present in other cancer types under hypoxic conditions. A3AR antagonists inhibit the proliferation of glioblastoma cell lines.

[0011] Hearing loss (HL) results from exposure to ototoxic drugs (such as platinum-based anticancer drugs or aminoglycoside antibiotics—more than 600 ototoxic drugs have been described, with over 200 marketed), noise, acoustic trauma (high-intensity noise), or aging. These attacks trigger the irreversible death of hair cells located in the organ of Curtis (cochlea). These cells function to capture sound vibrations and transduce them into neural signals that are sent to the auditory structures in the brain. There is considerable interest in the development of otoprotective compounds.

[0012] 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. The incidence of elevated hearing thresholds can be as high as 100% in cancer patients treated with cisplatin. Ear protection allows the use of these highly effective drugs to treat life-threatening diseases while reducing the risk of HL, thus addressing a significant unmet clinical need. Similarly, addressing cisplatin-induced nephrotoxicity would also be beneficial. This also applies to potent but HL-inducing antibiotics, particularly those treated with gentamicin, where ototoxicity has been observed in up to 47% of patients, as well as 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 are frequently exposed to noise include agriculture, mining, construction, manufacturing and utilities, transportation, and the military. Globally, approximately 1.1 billion adolescents and young adults are at risk of HL due to unsafe use of personal audio devices and exposure to damaging levels of sound in noisy entertainment venues. In all these cases, external earplugs are either insufficient or unsuitable. Furthermore, A3R is present in the rat cochlea, primarily expressed in the organ of Corti (inner and outer hair cells, D. Deutsche cells, Claudius cells, and column cells). Additionally, adenosine plays a protective role against drug-induced nephrotoxicity.In particular, data in the literature suggest that A2AR and A3AR antagonism may have some protective effects on the kidneys exposed to nephrotoxic drugs. For example, Dewaeles et al. found that istradefyline protects against cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving the antitumor effect of cisplatin (J. Clin. Invest.), 2022, 132, e152924; Lee et al. found that A3 adenosine receptor knockout mice protected against ischemia- and myoglobinuria-induced renal failure (Am. J. Physiol. Renal). Physiol., 2003, 284, 267-273; Min et al., Renopprotective effects of a highly selective A3 adenosine receptor antagonist in a mouse model of adriamycin-induced ncphropathy, J. Korean Med. Sci., 2016, 31, 1403-1412.

[0013] Therefore, it is necessary to find therapeutic agents that specifically target A3R inhibition. Invention Summary

[0014] It has now been found that compounds defined in formula (I) below can be used to treat and / or prevent diseases mediated by A3R.

[0015] Attached Figure

[0016] Figure 1 Two A3AR agonists and some reported antagonists are described.

[0017] Figure 2The results of the evaluation of the potential agonist or antagonist activity of compound (175) against 168 GPCRs are described and illustrated in Example 10.2.

[0018] Figure 3 The results of a study evaluating the selectivity of compound (175) for various ARs are described, as illustrated in Example 10.3.

[0019] Figure 4 The results of the A3AR function measurement described in Example 10.3 are described.

[0020] Figure 5 The effects of compound (175) on ciliated cells in mouse organelles cultured in vitro and exposed to cisplatin (5A), gentamicin (5B), or neomycin (5C) are described and illustrated in Example 10.4.

[0021] Figure 6 The effects of compound (175) on the antiproliferative activity of cisplatin were evaluated in various cancer cell lines: A549 (human lung cancer) Figure 6 -A), PANC-1 (human pancreatic cancer) Figure 6 -B) and MDA-435 (human breast cancer) Figure 6 -C), and is described in Example 10.5.

[0022] Figure 7 The results of antimicrobial spectrum determinations obtained by Pseudomonas aeruginosa PA-19660 after incubation without pre-incubation (A), after incubation with a carrier (DMSO) (B), or after incubation with compound (175) are described, wherein G: gentamicin; K: kanamycin; N: neomycin; S: streptomycin; T: tobramycin; and W: water, as illustrated in Example 10.6.

[0023] Figure 8 The text describes the use of Pseudomonas aeruginosa PA-19660 (…) prior to exposure to paper plates containing gentamicin, kanamycin, neomycin, streptomycin, or tobramycin. Figure 8 (left) and Staphylococcus aureus Newman strain ( Figure 8 The diameter of the inhibition zone (right) was determined by pre-incubation with a carrier (0.1% DMSO), compound (175), or compound (147), as illustrated in Example 10.6.

[0024] definition

[0025] As used herein, the term “patient” means an animal that has or may have one or more of the diseases and conditions described herein, such as valuable animals used for breeding, companionship or protection purposes, or preferably a human or human child.

[0026] 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.

[0027] Identifying patients who require treatment for the diseases and conditions described herein is entirely within the competence and knowledge of those skilled in the art. Veterinarians or physicians proficient in this field can readily identify patients requiring such treatment using clinical trials, physical examinations, medical / family history, or biological and diagnostic tests.

[0028] In the context of this invention, the term “cured” or “treatment” as used herein means prevention, reversal, mitigation, or inhibition of the progression of a disease, or prevention of the disease described in the “Pathology” section below.

[0029] Therefore, in this invention, the term "treated" or "cured" includes improving the medical condition of a patient suffering from an A3AR receptor-mediated disease as described in the "Pathology" section below.

[0030] As used herein, an "A3AR inhibitor" or "A3AR antagonist" is a compound capable of inhibiting A3AR in the assay shown in Example 10.1 of the bioactivity section described below. In one embodiment, the IC50 of the compound of formula (I) of the present invention... 50 The value can be less than or equal to 1000 nM, particularly less than or equal to 100 nM, more particularly less than or equal to 10 nM, and even more particularly less than or equal to 1 nM, the IC 50 The values ​​all demonstrate the inhibitory activity of the compound.

[0031] As used herein, "effective amount" means the amount of the compound of the present invention that is effective in preventing, reducing, eliminating, treating or controlling the diseases and symptoms described herein. "Effective amount" also means the amount of the compound of the present invention that is capable of effectively inhibiting A3AR.

[0032] The term “control” is intended to refer to all processes that may slow, interrupt, prevent or stop the progression of the diseases and conditions described herein, but does not necessarily mean the complete elimination of all symptoms of the diseases and conditions, and is intended to include preventative treatment.

[0033] The term "effective dose" includes "preventive effective dose" and "therapeutic effective dose".

[0034] As used herein, the term “prevention” refers to reducing the risk of developing or slowing the occurrence of a particular phenomenon, which in this invention refers to diseases mediated by ADORA3.

[0035] As used in this article, “prevention” also includes “reducing the likelihood of occurrence” or “reducing the likelihood of recurrence”.

[0036] The term "preventive effective dose" refers to the concentration of the compound of the present invention that is capable of effectively inhibiting, preventing, or reducing the likelihood of any of the diseases described herein.

[0037] Similarly, the term "therapeutic effective dose" refers to the concentration of a compound that can effectively treat the aforementioned diseases.

[0038] As used herein, the term “pharmaceutically acceptable” means that, within reasonable medical judgment, compounds, materials, excipients, compositions or dosage forms are suitable for contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0039] Detailed Description of the Invention

[0040] The inventors were surprised to discover that the compound of formula (I) disclosed below has inhibitory activity against A3AR.

[0041] This claim is based on data as described in the following examples and detailed below.

[0042] This article further describes compounds of formula (I) or any pharmaceutically acceptable salt thereof.

[0043]

[0044] in

[0045] R 1 Indicates a hydrogen atom or a (C1-C6) alkyl group;

[0046] R 2 Represents a hydrogen atom;

[0047] R 3 represent

[0048] - Straight-chain or branched (C1-C6) alkyl groups, optionally substituted with the following:

[0049] • A phenyl group, which is optionally composed of at least one component selected from OR 7 Substitution with -NH2, halogens, phenyl, and (C5-C6) heteroaryl groups.

[0050] • One (C6-C 10 ) heteroaryl, or

[0051] • One OR 7 ,

[0052] -Phenyl, or phenyl fused with (C4-C6)cycloalkyl groups; or

[0053] -(C5-C6) heteroaryl, which is optionally substituted by 1 to 3 substituents selected from (C1-C4) alkyl, deuterated (C1-C4) alkyl, (C1-C4) alkoxy, deuterated (C1-C4) alkoxy, and halogen (especially fluorine or chlorine atoms);

[0054] L represents a bond, -CO-, or -C(O)O-;

[0055] Alternatively, L is the key, and R... 2 and R 3 Together with the nitrogen atom attached thereto, it forms a (C5-C6) heterocyclic alkyl group fused with the phenyl group and containing at least one nitrogen atom;

[0056] R 4 It represents a hydrogen atom, a straight-chain or branched (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C4) alkoxy, (C5-C6) heterocycloalkyl, phenyl, (C5-C6) heteroaryl, or -CF3;

[0057] R 5 Represents a hydrogen atom, or a (C1-C4) alkyl group;

[0058] R 6 represent

[0059] - A straight-chain or branched (C1-C6) alkyl group, optionally interrupted by one or two oxygen atoms, and optionally substituted with the following groups:

[0060] • A phenyl group, optionally substituted with one or two substituents selected from (C1-C4) alkyl and (C1-C4) alkoxy groups,

[0061] • A (C3-C8) cycloalkyl group, optionally composed of one or two groups selected from halogens, (C1-C4) alkyl groups, and -OR 7 Substituents of the substituents

[0062] • One (C5-C6) heterocyclic alkyl group,

[0063] • One (C5-C6) heteroaryl group, optionally substituted with one or two (C1-C6) alkyl groups,

[0064] One or two - OR 7 ,

[0065] • One SR 7 ,

[0066] • One -C(O)NR 8 R 9 ,

[0067] • One -C(O)OR 10 ,or

[0068] • One - NHR 11 ,

[0069] -(C3-C7)cycloalkyl, optionally composed of one or two radicals selected from halogens, (C1-C4)alkyl groups, and -OR 7 Substituents of the substituents

[0070] - A bridged (C6-C) 10 )cycloalkyl,

[0071] - One screw (C5-C) 11 Double ring,

[0072] - A (C5-C6) heteroaryl group,

[0073] - A (C5-C6) heterocyclic alkyl group, or

[0074] -Phenyl fused with (C4-C6)cycloalkyl groups;

[0075] Or, R 5 and R 6 Together with the nitrogen atoms they are linked to, they form (C5-C6) heterocyclic alkyl groups;

[0076] R 7 It represents a hydrogen atom, a (C1-C4)alkyl group, or a deuterated (C1-C4)alkyl group;

[0077] R 8 and R 9 Independently represents a hydrogen atom, or a (C1-C6) alkyl group;

[0078] R 10 Indicates (C1-C4) alkyl; and

[0079] R 11 Represents a hydrogen atom, or a -CO-(C1-C6) alkyl group;

[0080] The condition is that when NR 2 LR 3 When representing benzylamino, R 4 It is not a hydrogen atom.

[0081] According to the first aspect, the subject matter of the present invention relates to compounds of formula (I) or any pharmaceutically acceptable salt thereof.

[0082]

[0083] in

[0084] R 1 Indicates a hydrogen atom or a (C1-C6) alkyl group;

[0085] R 2 Represents a hydrogen atom;

[0086] R 3 represent

[0087] - Straight-chain or branched (C1-C6) alkyl groups, wherein the following groups are substituted:

[0088] • A phenyl group, which is optionally composed of at least one component selected from -OR 7 -NH2, halogens, phenyl, and (C5-

[0089] C6) Substitution of heteroaryl groups

[0090] • One (C6-C 10 ) heteroaryl, or

[0091] • One OR 7 ,

[0092] -Phenyl, or phenyl fused with (C4-C6)cycloalkyl groups; or

[0093] -(C5-C6) heteroaryl, which is optionally substituted by 1 to 3 substituents selected from (C1-C4) alkyl, deuterated (C1-C4) alkyl, (C1-C4) alkoxy, deuterated (C1-C4) alkoxy, and halogen (especially fluorine or chlorine atoms);

[0094] L represents a bond, or a -CO- group;

[0095] Alternatively, L is the key, and R... 2 and R 3 Together with the nitrogen atom attached thereto, it forms a (C5-C6) heterocyclic alkyl group fused with the phenyl group and containing at least one nitrogen atom;

[0096] R 4 It represents a hydrogen atom, a straight-chain or branched (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C4) alkoxy, (C5-C6) heterocycloalkyl, phenyl, (C5-C6) heteroaryl, or -CF3;

[0097] R 5 Represents a hydrogen atom, or a (C1-C4) alkyl group;

[0098] R 6 represent

[0099] - A straight-chain or branched (C1-C8) alkyl group, optionally interrupted by one or two oxygen atoms, and optionally substituted with the following groups:

[0100] • A phenyl group, optionally substituted with one or two substituents selected from (C1-C4) alkyl and (C1-C4) alkoxy groups,

[0101] • A (C3-C8) cycloalkyl group, optionally composed of one or two groups selected from halogens, (C1-C4) alkyl groups, and -OR 7 Substituents of the substituents

[0102] • One (C5-C6) heterocyclic alkyl group,

[0103] • One (C5-C6) heteroaryl group, optionally substituted with one or two (C1-C6) alkyl groups,

[0104] One or two - OR 7 ,

[0105] ·One -SR 7 ,

[0106] • One -C(O)NR 8 R 9 ,

[0107] • One -C(O)OR 10 ,or

[0108] • One - NHR 11 ,

[0109] -(C3-C7)cycloalkyl, optionally composed of one or two radicals selected from halogens, (C1-C4)alkyl groups, and -OR 7 Substituents of the substituents

[0110] - A bridged (C6-C) 10 )cycloalkyl,

[0111] - One screw (C5-C) 11 Double ring,

[0112] - A (C5-C6) heteroaryl group,

[0113] - A (C5-C6) heterocyclic alkyl group, or

[0114] -Phenyl fused with (C4-C6)cycloalkyl groups;

[0115] Or, R 5 and R 6 Together with the nitrogen atoms they are linked to, they form (C5-C6) heterocyclic alkyl groups;

[0116] R 7 It represents a hydrogen atom, a (C1-C4)alkyl group, or a deuterated (C1-C4)alkyl group;

[0117] R 8 and R 9 Independently represents a hydrogen atom, or a (C1-C6) alkyl group;

[0118] R 10 Indicates (C1-C4) alkyl; and

[0119] R 11 Represents a hydrogen atom, or a -CO-(C1-C6) alkyl group;

[0120] The condition is that when NR 2 LR 3 When representing benzylamino, R 4 It is not a hydrogen atom.

[0121] The inventors were surprised to discover that compounds of formula (I) have specific inhibitory activity against adenosine receptor A3 (A3AR), some of which even have strong inhibitory activity.

[0122] According to another specific embodiment, this document further provides a compound of formula (I) as described above, wherein R 1 It represents a hydrogen atom or a methyl group.

[0123] According to another specific embodiment, this document further provides a compound of formula (I) as defined above, wherein

[0124] R 2 Represents a hydrogen atom;

[0125] R 3 represent

[0126] - Straight-chain or branched (C1-C6) alkyl groups, which are substituted with the following groups,

[0127] • A phenyl group, optionally substituted with a substituent selected from hydroxyl, methoxy, amino, halogen, phenyl, and pyridyl groups.

[0128] • A pyridyl group, a pyrazinyl group, a pyrimidinyl group, or a pyridazinyl group, especially a pyridyl group, a pyrimidinyl group, or a pyrimidinyl group, or an indoleyl group, or an isoindoleyl group, especially an indoleyl group.

[0129] One hydroxyl group,

[0130] • One methoxy group, one deuterated methoxy group, or

[0131] Halogens, especially fluorine or chlorine atoms,

[0132] -Phenyl or indene; or

[0133] -pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl (especially pyridinyl), which is optionally substituted with a methoxy or deuterated methoxy group;

[0134] L represents a bond, or -CO-;

[0135] Alternatively, L is the key, and R... 2 and R 3 Together with the nitrogen atom it is connected to, it forms an indole group, isoindole group, tetrahydroquinolino group, or tetrahydroisoquinolino group, especially isoindole group or tetrahydroisoquinolino group.

[0136] According to another specific embodiment, this document further provides a compound of formula (I) as described above, wherein R 4 It represents a hydrogen atom, a straight-chain or branched (C1-C5) alkyl group, a (C3-C6) cycloalkyl group, a phenyl group, a pyridyl group, or -CF3.

[0137] According to another specific embodiment, this document further provides a compound of formula (I) as defined above, wherein

[0138] R 5 Represents a hydrogen atom, or a (C1-C4) alkyl group, especially a methyl group;

[0139] R 6 represent

[0140] - A straight-chain or branched (C1-C8) alkyl group, optionally interrupted by one or two oxygen atoms, and optionally substituted with the following groups:

[0141] • A phenyl group, optionally substituted with one or two substituents selected from methyl and methoxy groups.

[0142] • A (C3-C6) cycloalkyl group, optionally substituted with a methyl group,

[0143] • One tetrahydropyranyl group, or one tetrahydrofuranyl group,

[0144] • One pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridyl, furanyl, or thiophene group, which may optionally be substituted with one or two methyl groups.

[0145] • One or two hydroxyl or methoxy groups,

[0146] • One methylthio group,

[0147] • One -CONH2, one -CONHCH3, or one -CON(CH3)2,

[0148] • One -COOCH3, or one -COOCH2CH3, or

[0149] • One -NH2, or one -NCOCH3,

[0150] -(C3-C7)cycloalkyl, optionally substituted with one or two substituents selected from halogen, hydroxyl, or methoxy.

[0151] -adamantyl,

[0152] -spiro[3.3]heptyl,

[0153] -imidazolium group, which may optionally be substituted with one or two methyl groups,

[0154] -morpholino, tetrahydropyrano, or tetrahydrofurano, or

[0155] -Indene;

[0156] Or, R 5 and R 6 Together with the nitrogen atom it is attached to, they form a morpholino or piperidinyl group.

[0157] The present invention further provides a pharmaceutical composition comprising a compound of formula (I) as defined below, or at least any one of compounds (1) to (234) as defined below, or any pharmaceutically acceptable salt thereof.

[0158] As shown in Example 10.1, the compound of formula (I) has been tested as an A3AR antagonist. The inhibitory activity of the compound of formula (I) against A3AR has been observed, and therefore it can be used to treat A3AR-mediated pathologies.

[0159] As shown 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 them.

[0160] As shown in Example 10.3, the compound of formula (I) has been shown to target other adenosine receptors A1AR, A 2A AR and A 2B Additional tests were conducted on A3AR for selective studies. Surprisingly, compound (I) was observed to be active only against A3AR. Furthermore, compound (I) was additionally tested in A3AR function assays. It has been observed that compound (I) is an antagonistic inhibitor of A3AR.

[0161] The unusual and unexpected specificity and functional requirements highlighted in Examples 10.2 and 10.3 necessitate the development of potent and selective A3AR antagonists for clinical application.

[0162] In other words, as shown in Examples 10.1, 10.2 and 10.3, the compound of formula (I) is a potent and selective A3AR antagonist.

[0163] Furthermore, the inventors have surprisingly discovered that compounds of formula (I) have a protective effect on hair cells in the inner ear of the organ of Corti exposed to ototoxic substances, particularly platinum-based anticancer drugs such as cisplatin, or aminoglycoside antibiotics such as gentamicin or neomycin. Typically, as shown in Example 10.4, the inventors have demonstrated that the compounds of the present invention exhibit otoprotective activity in in vitro models of ototoxicity (cultured organs of the organ of Corti) induced by ototoxic drugs, particularly platinum-based anticancer drugs such as cisplatin, or aminoglycoside antibiotics such as gentamicin or neomycin.

[0164] Finally, as shown in Example 10.5, it has been demonstrated that compounds of formula (I), particularly compound (175), have only a slight effect on the sensitivity of the three cancer cell lines to cisplatin; and as shown in Example 10.6, compounds of formula (I) do not alter the sensitivity of bacterial strains (particularly Pseudomonas aeruginosa and Staphylococcus aureus) to antibiotics (particularly aminoglycosides, and even more particularly gentamicin, kanamycin, neomycin, streptomycin and tobramycin).

[0165] In the context of this invention, the terminology is:

[0166] - "Halogen" is understood to refer to chlorine, fluorine, bromine, or iodine, especially chlorine, fluorine, or bromine.

[0167] -As used in this article, "(C1-C x "alkyl" refers to C1-C1 alkyl groups respectively. x Monovalent saturated hydrocarbon groups, such as (C1-C8) alkyl groups. 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.

[0168] -As used in this article, "(C1-C x "Alkoxy" refers to -O-(C1-C6) alkyl or -O-(C3-C6) alkyl group. x The cycloalkyl moiety, wherein the alkyl and cycloalkyl groups are as defined above, such as (C1-C6)alkoxy groups. Examples include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy and cyclopropoxy, butoxy, tert-butoxy and pentoxy.

[0169] -(C1-C4)alkylthio, also known as (C1-C4)alkylthioalkyl: -S-alkyl, wherein the alkyl group is as described above. Examples, but not limited to: methylthio, ethylthio, propylthio, isopropylthio, straight-chain, secondary or tert-butylthio, isobutylthio, etc., may be mentioned.

[0170] As used herein, “(C3-C8)cycloalkyl” refers to a monocyclic saturated hydrocarbon containing 3 to 8 carbon atoms that is saturated or partially unsaturated and unsubstituted or substituted. Examples of monocyclic hydrocarbons include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0171] -As used in this article, "bridging (C6-C)" 10 "Cycloalkyl" refers to a bicyclic or tricyclic compound in which the rings are cycloalkyl groups and the rings share three or more atoms, and the bridge contains at least one atom, such as 1, 2, or 3 atoms. Such a bridged cycloalkyl group may be substituted with one or more C1-C3 alkyl groups. Examples include, but are not limited to: 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.

[0172] -“Screw (C5-C) 11 "Bicyclic" refers to two rings linked by a common atom. Such spirocyclic bicyclic alkyl groups typically contain 5 to 11 carbon atoms, referring to "spiro(C5-C6)". 11 "Bicycloalkyl". This spirobicyclo may be unsubstituted or substituted, particularly substituted with at least one (C1-C3) alkyl group such as methyl. Examples include, but are not limited to, spiro[3.3]heptyl, spiro[2.5]octyl, and especially spiro[3.3]heptyl.

[0173] As used herein, “(C5-C6)heteroalkyl” means a (C5-C6)cycloalkyl group in which one or two carbon atoms are substituted by a heteroatom such as oxygen, nitrogen, or sulfur, and more particularly by at least one nitrogen atom. Such heteroalkyl groups may be saturated or partially saturated, and may be unsubstituted or substituted. Examples include, but are not limited to, piperazinyl, piperidinyl, pyrrolyl, aziridinyl, oxalyl, oxacyclobutyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxazolyl, oxacycloheptyl, diazacycloheptyl, dioxahexacycloyl, and tetrahydrothiopyranyl, and more particularly pyrrolylyl, piperidinyl, morpholinyl, tetrahydropyranyl, or a tetrahydrofuran group.

[0174] -As used in this article, (C5-C 10A heteroaryl group refers to a monocyclic aromatic or bicyclic group in which one to three carbon atoms are substituted by heteroatoms such as nitrogen, oxygen, or sulfur. Examples of monocyclic aromatic rings of heteroaryl groups, more particularly (C5-C6) heteroaryl groups, include, but are not limited to: oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl, pyrazinyl, oxadiazolyl, furanyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazoleyl, triazolyl, etc. In this invention, preferred heteroaryl groups are pyridinyl, imidazoleyl, pyrazinyl, furanyl, thiazolyl, pyrazolyl, thiadiazolyl, pyridazinyl, and pyrimidinyl, especially pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. Examples of bicyclic aromatic rings of heteroaryl groups include indolyl, isoyindolyl, indololinyl, isoyindololinyl, quinolinyl, or isoquinolinyl.

[0175] According to Hückel's rule, an aromatic ring means that a molecule has 4n+2 π electrons.

[0176] - "Deuterated" refers to a group in which at least one hydrogen atom is replaced by a deuterium atom, such as a fully deuterated group in which all hydrogen atoms are replaced by deuterium atoms. In other words, a deuterated group can be partially or fully deuterated. As examples of deuterated groups, more particularly deuterated (C1-C4)alkyl groups, including but not limited to: -CH2D, -CHD2, or -CD3. As other examples of deuterated groups, more particularly deuterated (C1-C4)alkoxy groups, including but not limited to: deuterated methoxy groups, such as OCH2D, OCHD2, or OCD3.

[0177] In the context of this invention, the terms "aromatic ring" and "heteroaryl" include all positional isomers.

[0178] The following compounds (1) to (234) are named according to the principles of the International Union of Pure and Applied Chemistry, using Generated by Professional v22.0.022. To avoid any confusion, the “(±)” symbol is added to indicate racemic mixtures; the “cis” and “trans” prefixes are also used to specify the relative stereochemistry of two adjacent chiral centers.

[0179] The specific compounds of this invention are as follows:

[0180] (1)(2R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1-ol,

[0181] (2)(2S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1-ol,

[0182] (3) 2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propane-1,3-diol,

[0183] (4) (2R,3R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1,3-diol,

[0184] (5) (2S,3S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1,3-diol,

[0185] (6) N-Benzyl-3-isopropyl-6-morpholino-[1,2,4]triazolo[4,3-b]pyridazine-8-amine

[0186] (7)(2S)-3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propane-1,2-diol,

[0187] (8) N6-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N8-benzyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0188] (9) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]prop-1-ol,

[0189] (10) N8-benzyl-3-isopropyl-N6-(3-methoxypropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0190] (11) 2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]ethanol,

[0191] (12) N8-benzyl-3-isopropyl-N6-(2-methoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0192] (13) 4-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1-ol,

[0193] (14) N8-benzyl-3-isopropyl-N6-(4-methoxybutyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0194] (15) 5-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]pentan-1-ol,

[0195] (16) N8-benzyl-3-isopropyl-N6-(5-methoxypentyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0196] (17) N8-benzyl-3-isopropyl-N6-(3-methylthiopropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0197] (18) N8-benzyl-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0198] (19) N8-benzyl-3-isopropyl-N6-[(3R)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0199] (20)N8-benzyl-3-cyclopentyl-N6-[(3R)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0200] (21) N8-benzyl-3-isopropyl-N6-[(3R)-tetrahydropyran-3-yl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0201] (22) N8-benzyl-3-isopropyl-N6-[(3S)-tetrahydropyran-3-yl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0202] (23) N8-benzyl-3-isopropyl-N6-tetrahydropyran-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0203] (24) N-[3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]propyl]acetamide,

[0204] (25) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]propionamide,

[0205] (26) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]-N-methylpropionamide,

[0206] (27) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]-N,N-dimethylpropionamide,

[0207] (28) Methyl 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]propionate,

[0208] (29) Ethyl 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]propionate,

[0209] (30)(2R)-2-[[8-(benzylamino)-3-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1-ol,

[0210] (31) N8-benzyl-3-cyclopropyl-N6-(3-methoxypropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0211] (32) N8-benzyl-N6-(3-methoxypropyl)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0212] (33)(2R)-2-[[8-(benzylamino)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1-ol,

[0213] (34) N8-benzyl-N6-(3-methoxypropyl)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0214] (35)(2R)-2-[[8-(benzylamino)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1-ol,

[0215] (36) N8-benzyl-N6-(3-methoxypropyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0216] (37)(2R)-2-[[8-(benzylamino)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1-ol,

[0217] (38)2-[[[6-[[(1R)-1-(hydroxymethyl)propyl]amino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]amino]methyl]phenol,

[0218] (39) 2-[[[3-Isopropyl-6-(3-methoxypropylamino)-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol,

[0219] (40) 2-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]amino]methyl]phenol,

[0220] (41) 3-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]amino]methyl]phenol,

[0221] (42) 4-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]amino]methyl]phenol,

[0222] (43) 2-[[[3-Isopropyl-6-[[(3R)-tetrahydropyran-3-yl]amino]-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]amino]methyl]phenol,

[0223] (44) 2-[[[3-Isopropyl-6-(tetrahydropyran-4-ylamino)-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]amino]methyl]phenol,

[0224] (45) N6-(1-ethylpropyl)-3-isopropyl-N8-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0225] (46)N6-(1-ethylpropyl)-3-isopropyl-N8-(2-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0226] (47) N6-(1-ethylpropyl)-3-isopropyl-N8-(3-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0227] (48) N6-(1-ethylpropyl)-3-isopropyl-N8-(4-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0228] (49) N6-(1-ethylpropyl)-3-isopropyl-N8-(4-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0229] (50)N6-(1-ethylpropyl)-3-isopropyl-N8-(3-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0230] (51)N6-(1-ethylpropyl)-3-isopropyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0231] (52) N6-tert-butyl-3-isopropyl-N8-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0232] (53) 3-Isopropyl-N8-(2-pyridylmethyl)-N6-spiro[3.3]hept-2-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0233] (54)N6-(3,3-difluorocyclobutyl)-3-isopropyl-N8-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0234] (55)N6-(4,4-difluorocyclohexyl)-3-isopropyl-N8-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0235] (56) N6-benzyl-3-isopropyl-N8-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0236] (57)N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0237] (58) N6-(1-ethylpropyl)-3-methyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0238] (59) 3-Ethyl-N6-(1-Ethylpropyl)-N8-(2-Pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0239] (60)N6-(1-ethylpropyl)-3-propyl-N8-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0240] (61) 3-tert-butyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0241] (62) 3-Cyclopropyl-N6-(1-Ethylpropyl)-N8-(2-Pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0242] (63) 3-Cyclobutyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0243] (64) 3-Cyclopentyl-N6-(1-Ethylpropyl)-N8-(2-Pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0244] (65) 3-Cyclohexyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0245] (66)N6-(1-ethylpropyl)-3-phenyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0246] (67)N6-(1-ethylpropyl)-N8-(2-pyridinylmethyl)-3-sec-butyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0247] (68) N6,3-bis(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0248] (69) N6-(1-ethylpropyl)-3-isobutyl-N8-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0249] (70)N6-(1-ethylpropyl)-3-(2-pyridine)-N8-(2-pyridinemethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0250] (71)N6-(1-ethylpropyl)-3-(3-pyridine)-N8-(2-pyridinemethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0251] (72)N6-(1-ethylpropyl)-3-(4-pyridine)-N8-(2-pyridinemethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0252] (73)N6-(1-ethylpropyl)-3-isopropyl-N8-[(2-methoxyphenyl)methyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0253] (74)(2R)-2-[[8-[(4-aminophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1-ol,

[0254] (75)N8-[(4-aminophenyl)methyl]-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0255] (76)N8-[(3-aminophenyl)methyl]-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0256] (77)N8-[(2-aminophenyl)methyl]-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0257] (78) N6-(1-ethylpropyl)-N8-(1H-indol-2-ylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0258] (79) N-(1-ethylpropyl)-8-isoindoline-2-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-amine,

[0259] (80)8-(3,4-dihydro-1H-isoquinolinyl-2-yl)-N-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-amine,

[0260] (81)N6-(1-ethylpropyl)-N8-indan-1-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0261] (82)N6-(1-ethylpropyl)-3-isopropyl-N8-(2-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0262] (83)N6-(1-ethylpropyl)-3-isopropyl-N8-[2-(2-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0263] (84)N6-(1-ethylpropyl)-3-isopropyl-N8-[2-(3-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0264] (85)N6-(1-ethylpropyl)-3-isopropyl-N8-[2-(4-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0265] (86) 3-Cyclopropyl-N6-(1-Ethylpropyl)-N8-[2-(2-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0266] (87) 3-Cyclopropyl-N6-(1-Ethylpropyl)-N8-[2-(3-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0267] (88) 3-Cyclopropyl-N6-(1-Ethylpropyl)-N8-[2-(4-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0268] (89) N6-(1-ethylpropyl)-3-isopropyl-N8-[3-(2-pyridinyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0269] (90)N6-(1-ethylpropyl)-3-isopropyl-N8-[3-(3-pyridinyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0270] (91)N6-(1-ethylpropyl)-3-isopropyl-N8-[3-(4-pyridinyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine

[0271] (92)N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrimidin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0272] (93)N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrimidin-5-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0273] (94)N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrazin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0274] (95)N6-(1-ethylpropyl)-3-isopropyl-N8-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0275] (96)N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]benzamide,

[0276] (97) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]pyridine-2-carboxylic acid amide,

[0277] (98)N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2-phenylacetamide,

[0278] (99) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]carbamate,

[0279] (100)N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]carbamate,

[0280] (101)(2S)-2-[[8-[(4-bromophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1-ol,

[0281] (102)(2S)-2-[[3-isopropyl-8-[(4-phenylphenyl)methylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol,

[0282] (103)(2S)-2-[[3-isopropyl-8-[[4-(4-pyridine)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol,

[0283] (104)(2S)-2-[[3-isopropyl-8-[[4-(3-pyridine)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol,

[0284] (105)(2S)-2-[[3-isopropyl-8-[[4-(2-pyridine)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol,

[0285] (106)(2R,3R)-2-[[8-[(4-bromophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1,3-diol,

[0286] (107)(2R,3R)-2-[[3-isopropyl-8-[[4-(2-pyridine)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1,3-diol,

[0287] (108)(2R,3R)-2-[[3-isopropyl-8-[[4-(4-pyridine)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1,3-diol,

[0288] (109)N6,N8-bis(3-methoxypropyl)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0289] (110) 3-Cyclopropyl-N6,N8-bis(3-methoxypropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0290] (111)N6,N8-bis(3-methoxypropyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0291] (112) 3-Isopropyl-N6,N8-bis(2-methoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0292] (113)(2R)-2-[[6-[[(1R)-1-(hydroxymethyl)propyl]amino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]but-1-ol,

[0293] (114)N6,N8-Bis(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0294] (115)(2R)-2-[[8-(benzylamino)-3-isopropyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1-ol,

[0295] (116)N8-[(4-bromophenyl)methyl]-3-isopropyl-N6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0296] (117)N8-benzyl-N6-cyclobutyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0297] (118)N8-Benzyl-N6-Cyclopentyl-3-Isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0298] (119) N8-benzyl-N6-cyclohexyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0299] (120)N8-benzyl-3-isopropyl-N6-(4-methoxycyclohexyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0300] (121)N8-benzyl-N6-cycloheptyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0301] (122)N8-benzyl-N6-(cyclopropylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0302] (123)N8-benzyl-N6-(cyclobutylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0303] (124)N8-benzyl-N6-(cyclohexylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0304] (125)N8-benzyl-3-isopropyl-N6-(tetrahydropyran-4-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0305] (126)N8-benzyl-N6-(2-ethylbutyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0306] (127)N8-benzyl-3-isopropyl-N6-(2-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0307] (128)N8-Benzyl-3-isopropyl-N6-(2-phenoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0308] (129)N8-benzyl-3-isopropyl-N6-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0309] (130)N6,N8-Dibenzyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0310] (131)N8-benzyl-3-isopropyl-N6-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0311] (132)N8-benzyl-3-isopropyl-N6-(3-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0312] (133)N8-benzyl-3-isopropyl-N6-(4-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0313] (134) Racemic trans-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]cyclohexanol,

[0314] (135) Racemic trans-4-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]cyclohexanol,

[0315] (136)N8-benzyl-3-isopropyl-N6-[(1-methylcyclohexyl)methyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0316] (137)N6-(1-adamantyl)-N8-benzyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0317] (138)N8-benzyl-N6-indan-2-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0318] (139)N8-Benzyl-3-isopropyl-N6-[(5-methylpyrazin-2-yl)methyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0319] (140)N8-benzyl-3-isopropyl-N6-[(1-methylpyrazol-4-yl)methyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0320] (141)N8-benzyl-N6-[(3,5-dimethylphenyl)methyl]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0321] (142) N8-benzyl-3-isopropyl-N6-(tetrahydrofuran-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0322] (143)N8-benzyl-3-isopropyl-N6-(2-methylthioethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0323] (144)N8-benzyl-3-isopropyl-N6-(1-methylimidazol-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0324] (145)N8-benzyl-N6-[(4,6-dimethylpyrimidin-2-yl)methyl]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0325] (146) N8-benzyl-N6-indan-1-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0326] (147)N6-(2-ethylbutyl)-3-isopropyl-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0327] (148) 3-Isopropyl-N6-(pent-3-yl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0328] (149) 3-Isopropyl-N6-(pent-3-yl)-N8-(pyridazin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0329] (150)3-Isopropyl-N6-(pent-3-yl)-N8-(pyrimidin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0330] (151) 3-Isopropyl-N6-(pent-3-yl)-N8-(pyrimidin-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0331] (152) 3-Isopropyl-N6-(pent-3-yl)-N8-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0332] (153) 3-Isopropyl-N6-(pent-3-yl)-N8-(pyrazin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0333] (154) 3-Isopropyl-N8-(6-methoxypyridin-2-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0334] (155) 3-Isopropyl-N8-(5-methoxypyridin-2-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0335] (156) 3-Isopropyl-N8-(4-methoxypyridin-2-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0336] (157) 3-Isopropyl-N8-(3-methoxypyridin-2-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0337] (158) 3-Isopropyl-N8-(2-methoxypyridin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0338] (159) 3-Isopropyl-N8-(6-methoxypyridin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0339] (160)isopropyl-N8-(5-methoxypyridin-3-yl)-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0340] (161) 3-Isopropyl-N8-(4-methoxypyridin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0341] (162) 3-Isopropyl-N8-(5-methoxypyridazin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0342] (163)(2R)-2-[[3-isopropyl-8-(2-pyridinamino)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol,

[0343] (164)N6-(2-ethylbutyl)-3-isopropyl-N8-[2-(2-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0344] (165)N6-Cyclopentyl-3-isopropyl-N8-[2-(2-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0345] (166)N6-(2-ethylbutyl)-3-isopropyl-N8-[2-(3-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0346] (167)N6,N8-Bis(2-ethylbutyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine

[0347] (168)N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2-(3-pyridine)acetamide,

[0348] (169)(2R)-2-[[3-isopropyl-8-(2-pyridinemethylamino)imidazo[1,2-b]pyridazin-6-yl]amino]but-1-ol,

[0349] (170)N6-(1-ethylpropyl)-3-isopropyl-N8-(3-phenylpropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0350] (171) 3-Cyclopropyl-N6-(1-Ethylpropyl)-N8-Phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0351] (172) 3-Cyclopropyl-N6-(1-Ethylpropyl)-N8-(2-Pyridine)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0352] (173) 3-Cyclopropyl-N6-(1-Ethylpropyl)-N8-(3-Pyridine)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0353] (174) 3-Cyclopropyl-N6-(1-Ethylpropyl)-N8-(4-Pyridine)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0354] (175) 3-Cyclopropyl-N6-(pent-3-yl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0355] (176) 3-Cyclopropyl-N6-(pent-3-yl)-N8-(pyridazin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0356] (177) 3-Cyclopropyl-N6-(pent-3-yl)-N8-(pyrimidin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0357] (178) 3-Cyclopropyl-N6-(1-Ethylpropyl)-N8-Pyrimidin-5-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0358] (179) 3-Cyclopropyl-N6-(pent-3-yl)-N8-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0359] (180)3-Cyclopropyl-N6-(pent-3-yl)-N8-(pyrazin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0360] (181)(R)-2-((3-Cyclopropyl-8-(pyridazin-3-ylamino)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino)but-1-ol,

[0361] (182)(S)-2-((3-Cyclopropyl-8-(pyridazin-3-ylamino)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino)but-1-ol,

[0362] (183) 3-Cyclopropyl-N8-(6-methoxypyridin-2-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0363] (184) 3-Cyclopropyl-N8-(2-methoxypyridin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0364] (185)(2R)-2-[[3-Cyclopropyl-8-[2-(2-pyridine)ethylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol,

[0365] (186)N6-Benzyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0366] (187) 3-Cyclopropyl-N6-(4-Methoxybenzyl)-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0367] (188) 3-Cyclopropyl-N6-(4-Methoxybenzyl)-N6-methyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0368] (189) 3-Cyclopropyl-N6-ethyl-N8-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0369] (190)3-Cyclopropyl-N6-propyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0370] (191)N6-Butyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0371] (192) 3-Cyclopropyl-N6-Isopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0372] (193)N6-(sec-butyl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0373] (194) 3-Cyclopropyl-N6-isobutyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0374] (195)N6-(tert-butyl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0375] (196) 3-Cyclopropyl-N6-(2-Ethylbutyl)-N8-(Pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0376] (197)N6,3-Dicyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0377] (198)N6-Cyclobutyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0378] (199)N6-Cyclopentyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0379] (200)N6-cyclohexyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0380] (201)N6-Cycloheptyl-3-Cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0381] (202)N6-((3s,5s,7s)-adamantyl-1-yl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0382] (203)3-Cyclopropyl-N6-(Cyclopropylmethyl)-N8-(Pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0383] (204)N6-(cyclobutylmethyl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0384] (205)3-Cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(spiro[3.3]hept-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0385] (206)3-Cyclopropyl-N6-((1-methylcyclobutyl)methyl)-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0386] (207)3-Cyclopropyl-6-(1-piperidinyl)-N-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine,

[0387] (208)3-Cyclopropyl-N6-(furan-2-ylmethyl)-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0388] (209)3-Cyclopropyl-N6-(furan-3-ylmethyl)-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0389] (210) 3-Cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(thiophen-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0390] (211)(R)-2-((3-Cyclopropyl-8-((pyridin-2-ylmethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino)but-1-ol,

[0391] (212)(S)-2-((3-Cyclopropyl-8-((pyridin-2-ylmethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino)but-1-ol,

[0392] (213)(R)-3-Cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0393] (214)(R)-3-Cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(tetrahydro-2H-pyran-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0394] (215) 3-Cyclopropyl-N8-(6-methoxypyridazin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0395] (216) 3-Cyclopropyl-N6-(pent-3-yl)-N8-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0396] (217) 3-Cyclopropyl-N6-(pent-3-yl)-N8-phenethyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0397] (218) 3-Cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(thiophen-3-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0398] (219) 3-Cyclopropyl-N6-methyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0399] (220)3-Cyclopropyl-N-(pyridin-2-ylmethyl)-6-(pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine,

[0400] (221) 3-Isopropyl-N8-(2-methoxypyrimidin-4-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0401] (222)3-Isopropyl-N8-(5-methoxypyrimidin-4-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0402] (223) 3-Isopropyl-N8-(6-methoxypyrimidin-4-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0403] (224) 3-Isopropyl-N8-(6-methoxypyridazin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0404] (225) 3-Cyclopropyl-N6-(2-Ethylbutyl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0405] (226) 3-Cyclopropyl-N6-(2-Ethylbutyl)-N8-(6-Methoxypyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0406] (227)N8-(6-chloropyridazin-3-yl)-3-isopropyl-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0407] (228)N8-(2-chloropyrimidin-4-yl)-3-isopropyl-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine,

[0408] (229)N6-(2-ethylbutyl)-3-isopropyl-N8-(6-methoxypyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0409] (230)N6-(3-ethylpentyl)-3-isopropyl-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0410] (231) 3-Isopropyl-N8-(6-(methoxy-d3)pyridazin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0411] (232)N8-(6-chloropyridazin-3-yl)-N6-(2-ethylbutyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine,

[0412] (233)N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2-(2-pyridine)acetamide,

[0413] (234)N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2-(4-pyridine)acetamide

[0414] And its pharmaceutically acceptable salts.

[0415] Therefore, this document provides any one of the compounds (1) to (234) as defined above, or any pharmaceutically acceptable salt thereof.

[0416] According to a more preferred embodiment of the invention, the compound is selected from the group consisting of compounds (1), (2), (10), (13), (14), (17) to (19), (21) to (23), (26), (28), (29), (31), (35) to (56), (58) to (64), (66) to (69), (71) to (78), (80) to (105), (107), (110), (111), (114). (117) to (119), (121) to (124), (126), (127), (130) to (132), (134), (136), (138), (140), (143), (146) to (160), (162) to (187), (189) to (206), (208) to (212), (215) to (218), (221) and (223) to (234), and their pharmaceutically acceptable salts.

[0417] According to a more preferred embodiment of the invention, the compound is selected from the group consisting of compounds (18), (38), (40) to (42), (45) to (53), (56), (59), (62), (63), (67), (68), (73), (75), (76), (80), (82) to (88), (90), (91), (93) to (95), (98) to (100), (114), (118), (126), (130), (147) to (1... 51), (153) to (156), (158) to (160), (162), (164) to (168), (170) to (178), (180) to (183), (186), (187), (191) to (193), (195), (196), (198) to (202), (204) to (206), (208) to (210), (215) to (218), (221) and (223) to (234), and their pharmaceutically acceptable salts.

[0418] According to a more particularly preferred embodiment of the 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), and pharmaceutically acceptable salts thereof.

[0419] According to another aspect, the subject matter of the present invention relates to compounds of formula (I) as defined above, or any pharmaceutically acceptable salt thereof, used as medicines, or at least any one of compounds (1) to (234) or any pharmaceutically acceptable salt thereof.

[0420] "Pharmaceutically acceptable salts" refer to salts formed by acid addition, including salts formed with inorganic acids (such as hydrochloric acid and hydrobromic acid) and salts formed with organic acids such as acetic acid, tartaric acid, and succinic acid.

[0421] Physiologically acceptable acid addition salts of suitable compounds of formula (I) include hydrobromide, tartrate, hydrochloride, methanesulfonate, succinate, and acetate.

[0422] Compounds 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 includes all such solvates and hydrates.

[0423] The terms "hydrate" and "solvent" simply mean that the compound (I) of the present invention can be in the form of a hydrate or a solvate, i.e., combined or associated with one or more water or solvent molecules. This is only one chemical characteristic of such compounds and applies to all such organic compounds.

[0424] Compounds of formula (I) may contain one or more asymmetric carbon atoms. Therefore, they may exist in enantiomeric or diastereomeric forms. These enantiomers, diastereomeric forms, and mixtures thereof, including racemic mixtures, are all included within the scope of this invention.

[0425] The compounds of this 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 that can be used to prepare the compounds of this invention and are not intended to limit their scope or applicability.

[0426] List of abbreviations:

[0427]

[0428]

[0429] Compounds of general formula (I) can be prepared according to route 1 as described in scheme 1 below.

[0430] Option 1

[0431]

[0432] According to route 1, the synthesis of the compounds of the present invention is based on the amine represented by formula (IV) (wherein, R...). 5 and R 6As defined above, for compounds of formula (II) (where L, R) 2 R 3 and R 4 Functionalization (as defined above). In step 3a, the compound of formula (II) may be placed in an aprotic solvent (such as Et3N, THF, 2-MeTHF, dioxane, eucalyptol, or NMP, or a mixture thereof), or in the absence of a solvent, or in a protic solvent (such as ethylene glycol). The amine represented by formula (IV) may be added, for example, at a molar ratio of 1 to 20 eq (especially 10 eq) relative to the compound of formula (II). The reaction mixture may be heated at a temperature of 150 to 180 °C. After the reaction is complete, the mixture may be restored to room temperature.

[0433] In step 3b, the compound of formula (II) may be placed in an aprotic solvent (such as Et3N, THF, 2-MeTHF, dioxane, eucalyptol, or NMP, or a mixture thereof), or in the absence of a solvent, or in a protic solvent (such as ethylene glycol). The amine represented by formula (IV') (wherein R') 6 The compound containing -COOH can be added, for example, at a molar ratio of 1 to 20 eq (especially 10 eq) relative to the compound of formula (II). The reaction mixture can be heated at a temperature of 150 to 180 °C. After the reaction is complete, the mixture can be brought back to room temperature.

[0434] Step 3c can be carried out according to known methods for obtaining the amide or ester compound represented by the corresponding formula (I).

[0435] The compound of formula (II) as defined above can be obtained in step 2 by the compound of formula (III) (where L, R) 2 and R 3 As defined above, it is obtained by reaction in an aprotic solvent (such as dioxane). The hydrazide shown in formula (V) can be added, for example, at a molar ratio of 1 to 3 eq (especially 1.2 eq) relative to the compound of formula (III). The resulting mixture can then be heated at a temperature of 100°C to 115°C by reflux or by stirring in a sealed tube, for example, for 1 to 36 hours, especially 16 hours.

[0436] The compound of formula (III) as defined above can be obtained in step 1 by reacting the compound of formula (a) with the compound of formula (VI) (where L, R) 2 and R 3 As defined above, it is obtained by reacting in an aprotic solvent (such as DCM, THF, 2-MeTHF, dioxane, or mixtures thereof). The reaction mixture may be stirred at room temperature or reflux temperature, or stirred with DCM in a sealed tube at 50°C for 1 to 24 hours, for example 16 hours.

[0437] Alternatively, compounds of general formula (I) can be formulated according to the following scheme 2. Route 2 preparation.

[0438] Option 2

[0439]

[0440] According to route 2, the synthesis of the compounds of the present invention is based on compounds of formula (II) (wherein L, R) 2 R 3 R 4 and R 5 As described above) and the amine represented by formula (IV) (where R 5 and R 6 The functionalization reaction is as described above. In step 3, the compound of formula (II) can be placed in an aprotic solvent (such as Et3N, THF, 2-MeTHF, dioxane, eucalyptol, or NMP, or a mixture thereof), or in the absence of a solvent, or in a protic solvent (such as ethylene glycol). The amine represented by formula (IV) can be added, for example, at a molar ratio of 1 to 20 eq (especially 10 eq) relative to the compound of formula (II). The reaction mixture can be heated at a temperature of 150 to 180 °C. After the reaction is complete, the mixture can be restored to room temperature. The compound of formula (II) as defined above can be reacted in step 2 with the compound of formula (VII) (wherein R 4 As defined above) and amines of formula (VI) (where L, R) 2 and R 3 As defined above, the amine is obtained by reaction in an aprotic solvent (such as DCM, THF, or 2Me-THF). The amine represented by formula (VI) can be added, for example, at a molar ratio of 1 to 5 eq (especially 1.2 eq) relative to the compound of formula (VII). The resulting mixture can then be stirred at room temperature to reflux temperature for, for example, 1 to 24 hours, especially 3 hours.

[0441] The compound of formula (VII) as defined above can be obtained in step 1 by reacting the compound of formula (b) with the compound of formula (VIII) (where R... 4 The reaction mixture (as defined above) is obtained by reacting in a nonprotic solvent (such as THF, 2-MeTHF, or dioxane). The reaction mixture can be stirred at room temperature for 1 to 24 hours, for example, 16 hours.

[0442] Alternatively, compounds of general formula (I) can be formulated according to the following scheme 3. Route 3 preparation.

[0443] Option 3

[0444]

[0445] According to route 3, the synthesis of the compounds of the present invention is based on compounds of formula (IX) (where R... 4 R 5 and R 6 As described above) and the amine shown in formula (VI) (where L, R) 2 and R 3 Functionalization as described above. In step 5, the compound of formula (IX) can be placed in an aprotic solvent (such as dioxane). The amine represented by formula (VI) can be added, for example, at a molar ratio of 1 to 10 eq (especially 6 eq) relative to the compound of formula (IX). The reaction mixture is heated in a sealed tube at a temperature of 100 to 130°C (especially 110°C). After the reaction is complete, the mixture can be returned to room temperature.

[0446] The compound of formula (IX) as described above can be oxidized in step 4 by oxidizing the compound of formula (X) (where R) in a mixture of THF and water. 4 R 5 and R 6 The oxidizing agent can be added, for example, at a molar ratio of 2 to 5 eq (especially 3.3 eq) relative to the compound of formula (IX). The resulting mixture can then be stirred at room temperature for, for example, 1 to 24 hours, such as 18 hours.

[0447] The compound of formula (X) as defined above can be obtained in step 3 by the amine of formula (V), wherein R 1 and R 2 As defined above. In step 3, the compound of formula (X) may be placed in an aprotic solvent (such as Et3N, DIPEA, THF, 2-MeTHF, dioxane, eucalyptol, or NMP, or a mixture thereof) or without a solvent. The amine reagent may be added, for example, at a molar ratio of 2 to 20 eq (especially 15 eq) relative to the compound of formula (IX). The resulting mixture may then be stirred in a sealed tube at a temperature of 100 to 150 °C (especially 120 °C) for, for example, 0.5 to 24 hours, especially 18 hours.

[0448] The compound of formula (XI) as defined above can be obtained in step 2 by reacting the compound of formula (d) with the compound of formula (V) (where R... 4 As defined above, the reaction mixture is obtained by reacting it in an aprotic solvent (such as THF, 2-MeTHF, or dioxane). The reaction mixture can be stirred in a sealed tube at a temperature of 100 to 150°C, particularly 110°C, for 1 to 24 hours, for example, 16 hours.

[0449] The compound of formula (d) as defined above can be obtained in step 2 by reacting the compound of formula (a) with sodium methylthiosulfate in an aprotic solvent (such as THF or 2-MeTH). The reaction mixture can be stirred at room temperature or under solvent reflux for 1 to 6 hours, for example 3 hours.

[0450] Alternatively, compounds of general formula (I) can be formulated according to the following scheme 4. Route 4 preparation.

[0451] Option 4

[0452]

[0453] According to route 4, the synthesis of the compounds of the present invention is based on compounds of formula (XII) (wherein R...). 4 R 5 and R 6 As described above) and reagents of formula (XIV) (where L and R) 3 As defined above, X represents the functionalization of a hydroxyl group, chlorine atom, bromine atom, (C1-C3) alkyl sulfonate group, or phenyl sulfonate group. The compound of formula (XII) can be placed in an aprotic solvent such as THF, 2-MeTHF, dioxane, DMSO, or DMF in step 3. The reagent of formula (XIV) can be added, for example, at a molar ratio of 1 to 10 eq (especially 2 eq) relative to the compound of formula (XII). The reaction mixture can be stirred at room temperature or under solvent reflux for 1 to 24 hours, for example, 3 hours.

[0454] The compound of formula (XII) as defined above can be obtained in step 2 by the compound of formula (XIII) (where R... 4 As defined above) and the amine shown in formula (IV) (where R) 5 and R 6 The reaction is as defined above. The compound of formula (XIII) can be placed in an aprotic solvent (such as Et3N, DIPEA, THF, 2-MeTHF, dioxane, eucalyptol, or NMP, or a mixture thereof) in step 2, or without a solvent. The amine reagent can be added, for example, at a molar ratio of 2 to 20 eq (especially 10 eq) relative to the compound of formula (XIII). The resulting mixture can then be stirred in a sealed tube or under microwave irradiation at a temperature of 150 to 220 °C, especially 180 °C, for example, for 0.5 to 72 hours, especially 24 hours.

[0455] The compound of formula (XIII) as defined above can be obtained in step 1 by reacting compound (e) with compound (V) (where R) 4As defined above, the reaction mixture is obtained by reacting in a nonprotic solvent (such as THF, 2-MeTHF, or dioxane) or a protic solvent (such as iPrOH, nPrOH, 2-MeOH, or nBuOH). The reaction mixture can be stirred in a sealed tube at a temperature of 100 to 150°C, particularly 110°C, or under solvent reflux for 1 to 24 hours, for example, 18 hours.

[0456] Therefore, this document further provides a method for preparing a compound of formula (I) as defined above, or any pharmaceutically acceptable salt thereof, or at least any one of compounds (1) to (234) as defined above, or any pharmaceutically acceptable salt thereof, comprising at least the following steps: in an aprotic solvent or under solvent-free conditions, or in a protic solvent, causing a compound of formula (II) to...

[0457]

[0458] Among them, L and R 2 R 3 and R 4 As defined above,

[0459] Reacts with, for example, amines of formula (IV) in molar ratios of 1 to 20 equivalents relative to compounds of formula (II),

[0460] NHR 5 R 6 (IV)

[0461] Where R 5 and R 6 As defined above.

[0462] This article further provides a method for preparing a compound of formula (I) above or any pharmaceutically acceptable salt thereof, or at least any one of compounds (1) to (234) above or any medically acceptable salt thereof, comprising at least the following steps: in an aprotic solvent, causing a compound of formula (IX) to...

[0463]

[0464] Among them, R 4 R 5 and R 6 As defined above,

[0465] Reacts with, for example, 1 to 10 equivalents of compound (VI) relative to compound (IX).

[0466]

[0467] Among them, R 2 and R 3 As defined above, compound (VI) is a compound.

[0468] This article further provides a method for preparing a compound of formula (I) above or any pharmaceutically acceptable salt thereof, or at least any one of compounds (1) to (234) above or any medically acceptable salt thereof, comprising at least the following steps: in an aprotic solvent, causing a compound of formula (XII),

[0469]

[0470] Where R 5 and R 6 As defined above

[0471] Reacts with, for example, 1 to 10 equivalents of compound (XIV) relative to compound (XII).

[0472]

[0473] Where 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.

[0474] This document further provides compounds represented by formulas (II), (X), (XI) or (VII), particularly compounds represented by formulas (II), (X), (XI) or (VII) as intermediate compounds.

[0475]

[0476] Among them, R 4 R 5 and R 6 As defined above, the condition is that R in equation (XI) 4 It is not methyl.

[0477] The intermediate products (a), (b) and (e) are commercially available or obtained using methods known to those skilled in the art.

[0478] The chemical structures, analytical and spectroscopic data of some of the compounds of formula (I) of this invention are shown in Tables 1 and 2 below.

[0479] The reaction was carried out under an inert or non-inert atmosphere of argon, using glassware or oven-dried glassware. Unless otherwise specified, all reagent-grade chemicals and solvents were obtained from commercial suppliers and used as is. The reaction was monitored by thin-layer chromatography using pre-coated aluminum plates (0.25 mm) with silica gel 60F254. Color development was performed under UV light at 254 or 365 nm, or using appropriate TLC staining, including but not limited to: phosphomolybdic acid, KMnO4, ninhydrin, CAM, vanillin, and p-anisaldehyde.

[0480] Chromatographic purification of the compounds was performed on an automated Interchim Puriflash XS420 equipped with either a 30 μm spherical silica pre-packed column as the stationary phase (normal phase) or a C18 silica pre-packed column as the stationary phase (reversed phase). However, a second purification could be achieved using preparative thin-layer chromatography with standard silica. The purification process employed various solvents, either pure or mixed, such as normal-phase solvents like ethyl acetate, cyclohexane, methanol, methanol with 7N ammonia, dichloromethane, triethylamine, and tetrahydrofuran, followed by reversed-phase solvents like ACN, MeOH, H₂O, and NH₄OH.

[0481] Mixture possibilities: Cyclohexane / EtOAc, Cyclohexane / DCM, Cyclohexane / DCM / EtOAc, DCM / EtOA, DCM / MeOH, DCM / MeOHNH3 7N, DCM / MeOH / Et3N, DCM / MeOH / THF, EtOAc / MeOH, EtOAc / MeOHNH3 7N, EtOAc / THF, ACN / H2O, ACN / NH4OH, MeOH / H2O, MeOH / NH4OH.

[0482] Table 1 below describes some of the compounds and their structures of the present invention. This is merely illustrative and does not limit the scope of the invention.

[0483] Table 1: Structures of compounds (1) through (234). Using Perkin-Elmer's... Professional v22.0.022 generates molecular formulas and molecular weights.

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510] Table 2 below describes the analytical and spectroscopic data of the compounds described in Table 1.

[0511] Record using a Bruker ULTRASHIELD 500 or 400 spectrometer. 1 HNMR analysis (400 or 500 MHz) and 13 CNMR spectra (101 MHz). Spectra were processed and analyzed using MestReNova. Data are presented in the following order: chemical shift (ppm, reference to internal solvent signal), multiplicity, proton number, and coupling constant J (Hz).

[0512] Synthetic intermediates: Reversed-phase UPLC / MS analysis was performed using UPLC Acquity (Waters) with a UV-DAD detector and a mass detector (SQD2). The compound (0.2 to 0.6 mg) was dissolved in a mixture of DMSO / H2O (1 / 1) and filtered through a 0.2 μm syringe filter.

[0513] - Acidic conditions:

[0514] Acquity BEH C18 column, 2.1 x 50 mm, 1.7 μm. Flow rate: 0.65 mL / min. Gradient: (H2O + 0.1% HCOOH v / v) / (CAN + 0.1% HCOOH v / v) decreased from 95 / 5 to 5 / 95 in 4.0 min.

[0515] Final compounds: Reversed-phase HPLC / MS analysis was performed using an HPLC Ultimate 3000 (ThermoScience) with a UV-DAD detector. Quality control was performed using a direct injection UPLC Acquity (Waters) mass detector (SQD2). Compounds (0.2 to 0.6 mg) were dissolved in a DMSO / H₂O (1 / 1) mixture and filtered through a 0.2 μm syringe filter.

[0516] - Acidic conditions:

[0517] Thermo Scientific Syncronis C18 column, 150 x 4.6 mm, 5 μm. Flow rate: 1 mL / min. Gradient: (H2O + 0.1% HCOOH v / v) / (ACN + 0.1% HCOOH v / v) decreased from 95 / 5 to 5 / 95 in 19.0 min.

[0518] -Alkaline conditions:

[0519] Thermo Scientific Syncronis C18 column, 150 x 4.6 mm, 5 μm or XTE RRARP18, 150 x 4.6 mm, 3.5 μm. Flow rate: 1 mL / min. Gradient: (HCOONH4 10 mM + NH4OH 25% aqueous solution, adjusted to pH = 10) / ACN decreased from 95 / 5 to 5 / 95 in 19.0 min.

[0520] Table 2: Spectroscopic and analytical characterization of compounds (1) to (234)

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629] a acidic conditions b alkaline conditions

[0630] Pathology

[0631] Examples of diseases mediated by A3AR include, but are not limited to: ulcerative colitis, atopic dermatitis, glaucoma, asthma, liver fibrosis, kidney disease (especially renal fibrosis), nephropathy, acute kidney injury (AKI), chronic kidney disease (CKD) (especially that caused by ischemia and / or reperfusion injury), toxic nephropathy or myoglobinuria, diabetic nephropathy, kidney disease caused by nephrotoxicity of therapeutic drugs, atherosclerosis, hypercholesterolemia, partial or complete hearing loss caused by noise, acoustic trauma or ototoxic substances or conditions, and cancers that occur under hypoxic conditions (especially glioblastoma).

[0632] Compounds of formula (I) or any pharmaceutically acceptable salt thereof may be used specifically for the treatment and / or prevention of hearing loss, particularly hearing loss caused by ototoxic drugs, and for the treatment and / or prevention of kidney disease, particularly kidney disease caused by nephrotoxicity.

[0633] Compounds of formula (I) or any pharmaceutically acceptable salt thereof may be used specifically for the treatment and / or prevention of partial or complete hearing loss, particularly hearing loss caused by noise, acoustic trauma or ototoxic substances or conditions, and even more particularly hearing loss caused by ototoxic substances and conditions.

[0634] Compounds of formula (I) or any pharmaceutically acceptable salt thereof may be used specifically to treat and / or prevent partial or complete hearing loss caused by ototoxic drugs or conditions described below.

[0635] As an ototoxic substance, meaning it causes hearing loss, the following can be cited:

[0636] - Solvents, such as polyethylene glycol, propylene glycol, or benzalkonium chloride;

[0637] - Antibiotics, especially local and / or systemic antibiotics, and more particularly aminoglycosides, macrolides or amyloids, such as gentamicin, neomycin, tobramycin, kanamycin, nystatin, polymyxin B, amphotericin B, bacitracin or chloramphenicol.

[0638] - Anticancer drugs, especially platinum-based anticancer drugs, such as cisplatin or carboplatin.

[0639] - Bactericides, especially acetic acid, alcohols (such as ethanol), chlorhexidine, cresol salts, gentian violet or povidone-iodine;

[0640] - Nonsteroidal anti-inflammatory drugs (NSAIDs), especially salicylates, cyclodextrins, indomethacin, ibuprofen, phenylbutazone, or acetaminophen;

[0641] - Topical combinations, especially polymyxin / neomycin / hydrocortisone, or ticarcillin / clavulanic acid;

[0642] - COVID-19 medications, specifically lopinavir or ritonavir;

[0643] - Antimalarial drugs, especially quinine or chloroquine;

[0644] - Cardiovascular medications, especially loop diuretics; or

[0645] - Anti-erectile dysfunction drugs, especially phosphodiesterase type 5 (PDE-5) inhibitors.

[0646] Compounds of formula (I) or any pharmaceutically acceptable salt thereof may be used specifically to treat and / or prevent partial or complete hearing loss, particularly hearing loss caused by noise, acoustic trauma, or ototoxic substances or conditions, and more specifically hearing loss caused by platinum-based anticancer drugs (such as cisplatin or carboplatin), antibiotics (especially macrolides or aminoglycosides such as gentamicin or neomycin), Covid-19 drugs (such as lopinavir or ritonavir), antimalarial drugs (such as quinine or chloroquine), cardiovascular drugs (such as loop diuretics), nonsteroidal anti-inflammatory drugs (such as salicylates or cyclodextrin), and anti-erectile drugs (such as phosphodiesterase type 5 (PDE-5) inhibitors).

[0647] Compounds of formula (I) or any pharmaceutically acceptable salt thereof may be used specifically for the treatment and / or prevention of kidney diseases, particularly those selected from nephropathy, acute kidney injury (AKI), chronic kidney disease (CKD) (especially caused by ischemia and / or reperfusion injury), toxic nephropathy or myoglobinuria, diabetic nephropathy, or nephropathy caused by nephrotoxicity of therapeutic drugs.

[0648] Compounds of formula (I) or any pharmaceutically acceptable salt thereof may be used specifically for the treatment and / or prevention of kidney disease caused by nephrotoxicity of the therapeutic drugs described below.

[0649] The following drugs can be used as treatments for nephrotoxicity: acyclovir, ambisome, amikacin, aminoglycosides, antibiotics, amphotericin B, captopril, carboplatin, cefotaxime, ceftazidime, cefuroxime, cephalosporins, cidofovir, ciprofloxacin, cisplatin, colistimethate, cyclosporine, dapsone, enalaprilat, enalapril, foscarnet, and gadopentetate. Dimeglumine, Gadoxetate, Ganciclovir, Gentamicin, Ibuprofen, Ifosfamide, Iodixanol, Iohexol, Iopamidol, Ioversol, Ketorolac, Lisinopril, Lithium, Mesalamine, Methotrexate, Nafcillin Disodium, penicillins, piperacillin / tazobactam, piperacillin, rifampin, sirolimus, sulfasalazine, tacrolimus, ticarcillin / clavulanicacid, tobramycin, topiramate, valacyclovir, valganciclovir, vancomycin, or zonisamide.

[0650] The following examples illustrate in detail the preparation of some compounds of the present invention. The structures of the obtained products have been confirmed by NMR analysis and mass spectrometry. The following examples further illustrate some of the biological activities of some compounds of the present invention.

[0651] Example 1: The synthesis of 3,6-dichloro-pyridazine-4-amine derivatives is as described in step 1 of scheme 1.

[0652]

[0653] Example 1.1: Synthesis of N-benzyl-3,6-dichloro-pyridazine-4-amine (1.1)

[0654] Triethylamine (8.93 mL, 63.46 mmol, 1.2 eq.) and benzylamine (6.48 mL, 58.17 mmol, 1.1 eq.) were added to a solution of 3,4,6-trichloropyridazine (a) (10.000 g, 52.88 mmol, 1.0 eq.) in THF (100.0 mL), and the mixture was refluxed for 3 hours. After cooling, the solid was filtered off, washed with THF, and then the filtrate was concentrated under vacuum. The resulting solid was ground in Et2O, filtered, washed with a small amount of Et2O, and dried under vacuum to give a beige solid (1.1) (13.000 g, 97%).

[0655] 1 HNMR(400MHz,DMSO-d6)δ:4.52(d,J=6.3Hz,2H,CH2),6.82(s,1H,H 芳基 ),7.26(td,J=5.9,2.8Hz,1H,H 芳基 ), 7.34(d, J = 5.4 Hz, 4H, 4xH 芳基 ), 7.97 (t, J = 6.3 Hz, 1H, NH).

[0656] 13 CNMR(101MHz,DMSO-d6)δ:44.7(CH2),105.5(CH 芳基 ),127.0(2xCH 芳基 ),127.2(CH 芳基 ),128.6(2xCH 芳基 ),137.0(C q ),143.8(C q ),144.4(C q ),154.5(C q ).

[0657] MS(ESI+): m / z calculated value C 11H9Cl2N3: 254.0 [M+H]+, measured value 254.0.

[0658] Example 1.2: Synthesis of 3,6-dichloro-N-(2-pyridylmethyl)pyridazine-4-amine (1.2)

[0659] Triethylamine (19.36 mL, 137.50 mmol, 1.3 eq.) was added to a solution of 3,4,6-trichloropyridazine (a) (20.000 g, 105.77 mmol, 1.0 eq.) in THF (210.0 mL), followed by the addition of the corresponding amine (12.67 mL, 121.63 mmol, 1.15 eq.), 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 and then ground in MeOH in another vacuum flask, washed with Et2O, and dried under vacuum to give the first part (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, washed with Et2O, and dried under vacuum to give the second part (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 dried under vacuum to obtain the third part (1.000 g) of (1.2). Total (1.2): 23.600 g, 87% white solid.

[0660] 1 HNMR(400MHz,DMSO-d6)δ:4.60(d,J=6.1Hz,2H,CH 2苄基 ),6.90(s,1H,H 芳基 ),7.31(ddd,J=7.5,4.8,1.1Hz,1H,H 芳基 ), 7.35(dt, J = 7.8, 1.1 Hz, 1H, H 芳基 ),7.79(td,J=7.7,1.8Hz,1H,H 芳基 ), 7.87(t, J = 6.0 Hz, 1H, NH 苄基 ),8.54(ddd,J=4.9,1.9,0.9Hz,1H).

[0661] 13 CNMR(101MHz,DMSO-d6)δ:46.6(CH 2苄基 ),105.9(CH 芳基 ),121.6(CH 芳基 ),122.7(CH 芳基 ),137.1(CH 芳基 ),143.8(C q),144.7(C q ),149.2(CH 芳基 ),154.6(C q ),156.3(C q ).

[0662] MS(ESI+): m / z calculated value C 10 H8Cl2N4: 255.0 [M+H]+, measured value 255.1.

[0663] Example 1.3: Synthesis of 3,6-dichloro-N-(3-pyridylmethyl)pyridazine-4-amine (1.3)

[0664] Triethylamine (3.00 mL, 21.31 mmol, 1.0 eq.) was added to a THF (33.0 mL) solution of 3,4,6-trichloropyridazine (a) (3.100 g, 16.39 mmol, 1.0 eq.), followed by the addition of the corresponding amine (2.04 mL, 19.67 mmol, 1.2 eq.), 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, ground with a small amount of MeOH, and dried under vacuum to give a pale orange solid (1.3) (2.320 g, 55%).

[0665] Rf(DCM / MeOH, 94 / 6): 0.55

[0666] 1 HNMR(400MHz,DMSO-d6)δ:4.56(d,J=6.3Hz,2H,CH 2苄基 ),6.96(s,1H,H 芳基 ), 7.37(dd, J = 7.8, 4.7 Hz, 1H, H 芳基 ), 7.73(dt, J = 7.8, 2.0 Hz, 1H, H 芳基 ), 7.96(t, J = 6.3 Hz, 1H, NH 苄基 ), 8.48(dd, J = 4.8, 1.7 Hz, 1H, H 芳基 ), 8.59 (d, J = 2.3 Hz, 1H, H 芳基 ).

[0667] 13 CNMR(101MHz,DMSO-d6)δ:42.4(CH 2苄基 ),105.5(CH 芳基 ),123.6(CH 芳基 ),132.7(C q ),134.9(CH 芳基),143.9(C q ),144.3(C q ),148.5(CH 芳基 ),148.8(CH 芳基 ),154.7(C q ).

[0668] MS(ESI+): m / z calculated value C 10 H8Cl2N4: 255.0 [M+H]+, measured value 255.1.

[0669] Example 1.4: Synthesis of 3,6-dichloro-N-(4-pyridinylmethyl)pyridazine-4-amine (1.4)

[0670] Triethylamine (11.13 mL, 79.06 mmol, 1.3 eq.) was added to a THF (120.0 mL) solution of 3,4,6-trichloropyridazine (a) (11.500 g, 60.82 mmol, 1.0 eq.), followed by the addition of the corresponding amine (7.640 g, 69.94 mmol, 1.15 eq.), 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, ground with a small amount of MeOH, and dried under vacuum to give a pale orange solid (1.4) (2.320 g, 55%).

[0671] 1 HNMR(400MHz,DMSO-d6)δ:4.57(d,J=6.4Hz,2H,CH 2苄基 ), 6.84(s, 1H, H-aryl), 7.27–7.36(m, 2H, 2xH-aryl), 7.98(t, J = 6.4 Hz, 1H, NH 苄基 ), 8.45–8.58 (m,2H,2xH aryl).

[0672] 13 CNMR(101MHz,DMSO-d6)δ:43.7(CH 2苄基 ),105.6(CH 芳基 ),122.0(2xCH 芳基 ),143.9(C q ),144.5(C q ),146.3(C q ),149.8(2xCH 芳基 ),154.7(C q ).

[0673] MS(ESI+): m / z calculated value C 10H8Cl2N4: 255.0 [M+H]+, measured value 255.1.

[0674] Example 1.5: Synthesis of 4-[[(3,6-dichloropyridazine-4-yl)amino]methyl]phenol (1.5)

[0675] 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 equivalent), and the corresponding amine (1.172 g, 9.52 mmol, 1.2 equivalent) were packed into 2–5 mL sealed vials equipped with stirrers. The vials were sealed and placed on a heating block, and heated at 50 °C for 15 hours. After cooling, the mixture was concentrated with SiO2 to form a solid precipitate, which was then directly purified by rapid chromatography using DCM / MeOH (98 / 2 to 96 / 4) as the eluent to give a white solid (1.5 g) (0.515 g, 24%).

[0676] 1 HNMR(400MHz,DMSO-d6)δ:4.38(d,J=6.2Hz,2H,CH 2苄基 ), 6.68–6.76 (m, 2H, 2xH aryl), 6.80 (s, 1H, H 芳基 ), 7.08–7.21(m,2H,2xH) 芳基 ), 7.87(t, J = 6.2 Hz, 1H, NH 苄基 ),9.36(s,1H,OH).

[0677] 13 CNMR(101MHz,DMSO-d6)δ:44.3(CH 2苄基 ),105.4(CH 芳基 ),115.3(2xCH 芳基 ),126.9(C q ),128.3(2xCH 芳基 ),143.8(C q ),144.3(C q ),154.5(C q ),156.6(C q ).

[0678] MS(ESI+): m / z calculated value C 11 H9Cl2N3O: 270.0 [M+H]+, measured value 270.1.

[0679] Example 1.6: Synthesis of 3-[[(3,6-dichloropyridazine-4-yl)amino]methyl]phenol (1.6)

[0680] 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 equivalent), and the corresponding amine (1.172 g, 9.52 mmol, 1.2 equivalent) were packed into 2–5 mL sealed vials equipped with stirrers. The vials were sealed and placed on a heating block, and heated at 50 °C for 15 hours. After cooling, the mixture was concentrated with SiO2 to form a solid precipitate, which was then directly purified by rapid chromatography using DCM / MeOH (98 / 2 to 96 / 4) as the eluent to give a white solid (1.6 g) (0.670 g, 31%).

[0681] 1 HNMR(400MHz,DMSO-d6)δ:4.43(d,J=6.3Hz,2H,CH 2苄基 ), 6.64(dd, J = 8.0, 2.4 Hz, 1H, H 芳基 ), 6.69(t, J = 2.0 Hz, 1H, H 芳基 ), 6.74 (d, J = 7.6 Hz, 1H, H 芳基 ),6.77(s,1H,H 芳基 ), 7.13(t, J = 7.8 Hz, 1H, H 芳基 ), 7.94(t, J = 6.3 Hz, 1H, NH 苄基 ),9.39(s,1H,OH).

[0682] 13 CNMR(101MHz,DMSO-d6)δ:44.6(CH 2苄基 ),105.5(CH 芳基 ),113.4(CH 芳基 ),114.2(CH 芳基 ),117.4(CH 芳基 ),129.6(CH 芳基 ),138.4(C q ),143.7(C q ),144.4(C q ),154.5(C q ),157.6(C q ).

[0683] MS(ESI+): m / z calculated value C 11H9Cl2N3O: 270.0 [M+H]+, measured value 270.1.

[0684] Example 1.7: Synthesis of 2-[[(3,6-dichloropyridazine-4-yl)amino]methyl]phenol (1.7)

[0685] Triethylamine (3.41 mL, 24.2 mmol, 1.2 eq.) was added to a THF (50 mL) solution of 3,4,6-trichloropyridazine (a) (3.700 g, 20.2 mmol, 1.0 eq.), followed by the addition of the corresponding amount of benzylamine (3.700 g, 24.2 mmol, 1.2 eq.), and the mixture was refluxed for 3 hours. After cooling, the mixture was filtered, washed with THF, and the filtrate was concentrated. After filtration, the crude residue was ground in DCM / MeOH (94 / 4), and filtered to obtain the first fraction (1.450 g) of (1.7). The filtrate was concentrated, and the residue was ground in DCM / MeOH (98 / 2), and filtered to obtain the second fraction (0.950 g) of (1.7). The filtrate was concentrated and purified by rapid chromatography (96 / 4) to obtain the third fraction (0.900 g) of (1.7). Total (1.7): 3.400g, 62%, yellow solid.

[0686] 1 HNMR(400MHz,DMSO-d6)δ:4.39(d,J=6.2Hz,2H,CH 2苄基 ), 6.76(td, J = 7.4, 1.2 Hz, 1H, H 芳基 ),6.81(s,1H,H 芳基 ), 6.85(dd, J = 8.0, 1.2 Hz, 1H, H 芳基 ), 7.06–7.14(m,2H,2xH) 芳基 ), 7.75(t, J = 6.2 Hz, 1H, NH 苄基 ),9.84(s,1H,OH).

[0687] 13 CNMR(101MHz,DMSO-d6)δ:40.1(CH 2苄基 ),105.3(CH 芳基 ),115.1(CH 芳基 ),119.2(CH 芳基 ),122.4(C q ),128.2(CH 芳基 ),128.4(CH 芳基 ),143.7(C q ),144.4(C q ),154.6(Cq ),154.9(C q ).

[0688] MS(ESI+): m / z calculated value C 11 H9Cl2N3O: 270.0 [M+H]+, measured value 270.1.

[0689] Example 1.8: Synthesis of 3,6-dichloro-N-[(2-methoxyphenyl)methyl]pyridazine-4-amine (1.8)

[0690] Triethylamine (3.87 mL, 27.50 mmol, 2.0 eq.) and the corresponding amine (2.887 g, 20.63 mmol, 1.5 eq.) were added to a solution of 3,4,6-trichloropyridazine(a) (2.600 g, 13.75 mmol, 1.0 eq.) in DCM (70.0 mL), and the mixture was refluxed for 19 hours. After cooling, 1 M HCl (50.0 mL) was added, and the mixture was stirred vigorously for 5 minutes to separate the layers. The aqueous layer was extracted twice with DCM (2 x 20.0 mL), and the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (100 / 0 to 98 / 2) as eluent to give a white solid (1.8 g) (3.200 g, 82%).

[0691] 1 HNMR(400MHz,DMSO-d6)δ:3.85(s,3H,OCH3),4.44(s,2H,CH 2苄基 ),6.75(s,1H,H 芳基 ), 6.87–6.95 (m, 1H, H) 芳基 ), 7.00–7.06(m, 1H, H 芳基 ),7.13(dd,J=7.5,1.8Hz,1H,H 芳基 ),7.27(td,J=7.8,1.8Hz,1H,H 芳基 ),7.73(s,1H,NH 苄基 ).

[0692] 13 CNMR(101MHz,DMSO-d6)δ:40.2(CH 2苄基 ),55.4(CH3),105.4(CH 芳基 ),110.9(CH 芳基 ),120.5(CH 芳基 ),124.1(C q ),127.5(CH 芳基 ),128.7(CH芳基 ),143.7(C q ),144.5(C q ),154.6(C q ),156.8(C q ).

[0693] MS(ESI+): m / z calculated value C 12 H 11 Cl2N3O: 284.0 [M+H]+, measured value 284.1.

[0694] Example 1.9: Synthesis of 3,6-dichloro-N-(1H-indol-3-ylmethyl)pyridazine-4-amine (1.9)

[0695] In 10–20 mL vials, a stir bar was added to 3,4,6-trichloropyridazine(a) (1.750 g, 9.25 mmol, 1.0 eq.), DCM (18 mL), 1H-indol-2-ylmethylamine hydrochloride (2.135 g, 11.11 mmol, 1.2 eq.), and triethylamine (2.87 mL, 20.36 mmol, 2.2 eq.). The vials were sealed and placed on a heating block, and heated 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 EtOAc (30 mL) was added. The heterogeneous mixture was stirred vigorously, and the precipitate was filtered, washed with water (pH up to 7), then washed with EtOAc, and dried under vacuum to give the first part (1.465 g) of (1.9) as a white solid. The aqueous layer was extracted with EtOAc (30 mL), the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5) as eluent to obtain the second part (1.9) (0.430 g), a white solid. Total (1.9): 1.895 g, 70%.

[0696] 1 HNMR(400MHz,DMSO-d6)δ:4.63(d,J=5.9Hz,2H,CH 2苄基 ), 7.01(d, J = 7.4 Hz, 2H, 2xH 芳 (Base), 7.08 (t, J = 7.5 Hz, 1H, H) 芳基 ), 7.35 (d, J = 8.1 Hz, 1H, H 芳基 ), 7.44(d, J = 2.4 Hz, 1H, H 芳基 ), 7.73 (d, J = 7.9 Hz, 1H, H 芳基 ), 7.85(t, J = 5.9 Hz, 1H, NH 苄基),10.97(s,1H,NH 吲哚 ).

[0697] 13 CNMR(101MHz,DMSO-d6)δ:37.7(CH 2苄基 ),105.4(CH 芳基 ),109.1(C q ),111.6(CH 芳基 ),118.7(CH 芳基 ),118.8(CH 芳基 ),121.3(CH 芳基 ),124.7(CH 芳基 ),126.2(C q ),136.5(C q ),143.8(C q ),144.2(C q ),154.3(C q ).

[0698] MS(ESI+): m / z calculated value C 13 H 10 Cl2N4: 293.0 [M+H]+, measured value 293.1.

[0699] Example 1.10: Synthesis of 3,6-dichloro-N-(1H-indol-2-ylmethyl)pyridazine-4-amine (1.10)

[0700] In 10–20 mL vials, a stir bar was added to 3,4,6-trichloropyridazine(a) (1.750 g, 9.25 mmol, 1.0 eq.), DCM (18 mL), 1H-indol-2-ylmethylamine hydrochloride (2.135 g, 11.11 mmol, 1.2 eq.), and triethylamine (2.87 mL, 20.36 mmol, 2.2 eq.). The vials were sealed and placed on a heating block, and heated 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 EtOAc (30 mL) was added. The heterogeneous mixture was stirred vigorously, and the precipitate was filtered, washed with water (pH up to 7), then washed with EtOAc, and dried under vacuum to give the first fraction (2.040 g) of (1.10) as a white solid. The aqueous layer was extracted with EtOAc (30 mL), the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5) as eluent to give the second part (1.10) (0.300 g), a white solid. Total (1.10): 2.340 g, 86%.

[0701] 1 HNMR(400MHz,DMSO-d6)δ:4.66(d,J=6.1Hz,2H,CH 2苄基 ), 6.33(d, J = 2.0 Hz, 1H, H 芳基 ), 6.95(t, J = 7.4 Hz, 1H, H 芳基 ),6.98(s,1H,H 芳基 ), 7.04(t, J = 7.4 Hz, 1H, H 芳基 ), 7.33 (d, J = 8.0 Hz, 1H, H 芳 (base), 7.45 (d, J = 8.0 Hz, 1H, H) 芳基 ), 7.79 (t, J = 6.1 Hz, 1H, NH benzyl), 10.96 (s, 1H, H indole).

[0702] 13 CNMR(101MHz,DMSO-d6)δ:39.3(CH 2苄基 ),99.7(CH 芳基 ),105.7(CH 芳基 ),111.2(CH 芳基 ),119.0(CH 芳基 ),119.7(CH 芳基 ),120.9(CH 芳基 ),127.8(C q ),134.6(C q ),136.2(C q ),143.9(C q ),144.5(C q ),154.6(C q ).

[0703] MS(ESI+): m / z calculated value C 13 H 10 Cl2N4: 293.0 [M+H]+, measured value 293.1.

[0704] Example 1.11: Synthesis of N-[(4-aminophenyl)methyl]-3,6-dichloro-pyridazine-4-amine (1.11)

[0705] Triethylamine (20.33 mL, 144.69 mmol, 1.5 eq.) and 4-(aminomethyl)aniline (12.000 g, 96.26 mmol, 1.0 eq.) were added to a THF (200.0 mL) solution of 3,4,6-trichloropyridazine (a) (22.953 g, 125.14 mmol, 1.3 eq.), and the mixture was refluxed for 18 h. N-[(4-aminophenyl)methyl]-6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine was filtered after cooling, 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 give a yellow solid (1.11) (23.950 g, 92%).

[0706] 1 HNMR(400MHz,DMSO-d6)δ:4.30(d,J=6.1Hz,2H,CH2),5.09(s,2H,NH2),6.41–6.69(m,2H,2xH 芳基 ),6.77(s,1H,H 芳基 ), 6.89–7.12(m,2H,2xH) 芳基 ), 7.80 (t, J = 6.1 Hz, 1H, NH).

[0707] 13 CNMR(101MHz,DMSO-d6)δ:44.6(CH2),105.4(CH 芳基 ),113.9(2xCH 芳基 ),123.4(C q ),128.0(2xCH 芳基 ),143.7(C q ),144.3(C q ),147.8(C q ),154.4(C q ).

[0708] MS(ESI+): m / z calculated value C 11 H 10 Cl2N4: 269.0 [M+H]+, measured value 269.1.

[0709] Example 1.12: Synthesis of N-[(2-aminophenyl)methyl]-3,6-dichloro-pyridazine-4-amine (1.12)

[0710] Triethylamine (4.22 mL, 30.0 mmol, 1.1 eq.) was added to a solution of 3,4,6-trichloropyridazine (a) (5.000 g, 27.3 mmol, 1.0 eq.) in 52 mL of THF, followed by the addition of 2-(aminomethyl)aniline (3.228 g, 25.9 mmol, 0.95 eq.). The mixture was refluxed for 3.5 h. After cooling, the mixture was filtered, the solid was washed with THF, and the filtrate was concentrated. The solid was then purified directly by rapid chromatography using DCM / MeOH (98 / 2 to 96 / 4) as the eluent to give a white solid (1.12 g) (5.280 g, 76%).

[0711] 1 HNMR(400MHz,DMSO-d6)δ:4.30(d,J=6.0Hz,2H,CH 2苄基 ),5.15(s,2H,NH2),6.52(td,J=7.4,1.3Hz,1H,H 芳基 ), 6.65(dd, J = 8.0, 1.3 Hz, 1H, H 芳基 ),6.74(s,1H,H 芳基 ), 6.97(td, J = 7.6, 1.6 Hz, 1H, H 芳基 ),7.02(dd,J=7.5,1.6Hz,1H,H 芳基 ), 7.74(t, J = 6.0 Hz, 1H, NH 苄基 ).

[0712] 13 CNMR(101MHz,DMSO-d6)δ:42.0(CH 2苄基 ),105.6(CH 芳基 ),115.2(CH 芳基 ),116.1(CH 芳基 ),118.8(C q ),127.9(CH 芳基 ),128.1(CH 芳基 ),143.8(C q ),144.4(C q ),146.3(C q ),154.5(C q ).

[0713] MS(ESI+): m / z calculated value C 11 H 10 Cl2N4: 269.0 [M+H]+, measured value 269.1.

[0714] Example 1.13: Synthesis of N-[(4-bromophenyl)methyl]-3,6-dichloro-pyridazine-4-amine (1.13)

[0715] Triethylamine (3.68 mL, 26.17 mmol, 1.2 eq.) and the corresponding amine (3.03 mL, 23.99 mmol, 1.1 eq.) were added to a solution of 3,4,6-trichloropyridazine(a) (4.000 g, 24.81 mmol, 1.0 eq.) in THF (87.0 mL), and the mixture was refluxed for 3.5 h. 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 dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (100 / 0 to 98 / 2) as eluent to give a pale yellow solid (1.13 g) (6.500 g, 90%).

[0716] 1 HNMR(400MHz,DMSO-d6)δ:4.49(d,J=6.3Hz,2H,CH 2苄基 ),6.84(s,1H,H 芳基 ), 7.25–7.35(m,2H,2xH) 芳基 ), 7.50–7.58 (m, 2H, 2xH) 芳基 ), 7.97(t, J = 6.4 Hz, 1H, NH 苄基 ).

[0717] 13 CNMR(101MHz,DMSO-d6)δ:44.0(CH 2苄基 ),105.5(CH 芳基 ),120.3(C q ),129.3(2xCH 芳基 ),131.4(2xCH 芳基 ),136.6(C q ),143.8(C q ),144.3(C q ),154.6(C q ).

[0718] MS(ESI+): m / z calculated value C 11 H8BrCl2N3: 331.9 [M+H]+, measured value 331.9.

[0719] Example 1.14: Synthesis of 3,6-dichloro-N-[[4-(2-pyridine)phenyl]methyl]pyridazine-4-amine (1.14)

[0720] Triethylamine (1.15 mL, 8.18 mmol, 3.0 eq.) was added to a solution of 3,4,6-trichloropyridazine (a) (0.500 g, 2.73 mmol, 1.0 eq.) in THF (13.5 mL), followed by the addition of [4-(2-pyridyl)phenyl]methylamine (0.603 g, 3.27 mmol, 1.2 eq.), and the mixture was refluxed for 3 hours. After cooling, the mixture was filtered, the solid was washed with THF, the filtrate was concentrated, and the solid was directly purified by rapid chromatography using DCM / MeOH (99 / 1 to 95 / 5) as eluent to give a yellow solid (1.14 g) (0.360 g, 40%).

[0721] 1 HNMR(400MHz,DMSO-d6)δ:4.59(d,J=6.3Hz,2H,CH 2苄基 ),6.86(s,1H,H 芳基 ),7.33(ddd,J=7.5,4.8,1.2Hz,1H,H 芳基 ), 7.45(d, J = 8.1 Hz, 2H, 2xH 芳基 ), 7.86(td, J = 7.7, 1.9 Hz, 1H, H 芳基 ), 7.93 (d, J = 8.0 Hz, 1H, H 芳基 ),8.02(t,J=6.0Hz,1H,NH 苄基 ), 8.04–8.10(m,2H,2xH) 芳基 ),8.62–8.67(m,1H,H 芳基 ).

[0722] 13 CNMR(101MHz,DMSO-d6)δ:44.5(CH 2苄基 ),105.6(CH 芳基 ),120.1(CH 芳基 ),122.6(CH 芳基 ),126.7(2xCH 芳基 ),127.4(2xCH 芳基 ),137.2(CH 芳基 ),137.7(C q ),138.0(C q ),143.9(C q ),144.4(C q ),149.5(CH 芳基 ),154.6(C q ),155.7(Cq ).

[0723] MS(ESI+): m / z calculated value C 16 H 12 Cl2N4: 331.1[M+H]+, measured value 331.1.

[0724] Example 1.15: Synthesis of 2-(3,6-dichloropyridazine-4-yl)-3,4-dihydro-1H-isoquinoline (1.15)

[0725] Triethylamine (4.41 mL, 31.3 mmol, 1.1 eq.) was added to a solution of 3,4,6-trichloropyridazine(a) (5.000 g, 27.3 mmol, 1.0 eq.) in THF (54.0 mL), followed by 2-(aminomethyl)aniline (3.228 g, 25.9 mmol, 0.95 eq.), and the mixture was refluxed for 3.5 h. After cooling, the mixture was filtered, the solid was washed with THF, the filtrate was concentrated, and the solid was directly purified by rapid chromatography using DCM / EtOAc (100 / 0 to 92 / 8) as eluent to give (1.15) (6.800 g, 89%) as a white crystalline solid.

[0726] Rf(DCM, 100%): 0.42.

[0727] 1 HNMR(400MHz,DMSO-d6)δ:2.99(t,J=5.8Hz,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) 芳基 ),7.42(s,1H,H 芳基 ).

[0728] 13 CNMR(101MHz,DMSO-d6)δ:28.2(CH 2-CH2-N ),47.5( N- CH 2-CH2 ),50.4(CH 2-N ),115.4(CH aryl),126.1(CH 芳基 ),126.4(CH 芳基 ),126.7(CH 芳基 ),128.7(CH 芳基 ),132.8(C q ),133.9(C q),147.9(C q ),148.9(C q ),154.9(C q ).

[0729] MS(ESI+): m / z calculated value C 13 H 11 Cl2N3: 280.0[M+H]+, measured value 280.1.

[0730] Example 1.16: Synthesis of 3,6-dichloro-N-(2-phenylethyl)pyridazine-4-amine (1.16)

[0731] Et3N (6.45 mL, 45.8 mmol, 2.1 eq.) was added to a solution of 3,4,6-trichloropyridazine(a) (4.000 g, 21.8 mmol, 1.0 eq.) in THF (42 mL), followed by the addition of the corresponding amine hydrochloride (3.438 g, 21.8 mmol, 1.0 eq.), and the mixture was refluxed for 3 hours. After cooling, the mixture was filtered, 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 neutral pH, and dissolved in EtOAc. The organic filtrate was dried over MgSO4, filtered, and concentrated to give a beige solid (1.16 g) (5.515 g, 88%).

[0732] 1 HNMR(400MHz,DMSO-d6)δ:2.86(t,J=7.4Hz,2H,CH 2-CH2-NH ), 3.43–3.56 (m, 2H, CH) 2-NH ), 6.95(s, 1H, H 芳基 ),7.20(ddd,J=8.6,5.6,2.4Hz,1H,H 芳基 ),7.27(q,J=4.2Hz,5H,NH&5xH 芳基 ).

[0733] 13 CNMR(101MHz,DMSO-d6)δ:33.8(CH 2-CH2-NH ),43.1(CH 2-NH ),105.2(CH 芳基 ),126.3(CH aryl),128.3(2xCH 芳基 ),128.9(2xCH 芳基 ),138.8(C q ),143.5(C q ),144.3(C q),154.7(C q ).

[0734] MS(ESI+): m / z calculated value C 12 H 11 Cl2N3: 268.0 [M+H]+, measured value 268.1.

[0735] Example 2: The synthesis of 6,8-dichloro-[1,2,4]triazolo[4,3-b]pyridazine derivatives was performed as described in step 1 of scheme 2.

[0736]

[0737] Example 2.1: Synthesis of 6,8-dichloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (2.1)

[0738] To a THF (21.0 mL) solution of 4-methylbenzenesulfonyl hydrazine (3.895 g, 20.91 mmol, 1.0 eq.), the corresponding aldehyde (1.97 mL, 21.33 mmol, 1.02 eq.) was added, and the mixture was stirred at 50 °C for 5 min. 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 eq.) was added, followed by the sequential addition of I2 (1.056 g, 4.16 mmol, 0.2 eq.) and fractionally added PIDA (10.257 g, 31.21 mmol, 1.5 eq.). The reaction was slightly exothermic and stirred at room temperature for 22 h. Saturated Na2S2O3 (30.0 mL) and water (15.0 mL) were added, and the mixture was stirred vigorously for 5 min. The layers were separated, and the aqueous layer was extracted twice with EtOAc (2 x 20.0 mL). The organic layers were then combined, washed with brine, dried with MgSO4, filtered, concentrated, and purified by rapid chromatography using EtOAc / cyclohexane as the eluent to obtain a pale yellow solid (2.1) (2.100 g, 44%).

[0739] 1 HNMR(400MHz,DMSO-d6)δ:1.41(d,J=7.0Hz,6H,2xCH 3异丙基 ), 3.50 (hept, J = 6.9 Hz, 1H, H 异丙基 ),7.93(s,1H,H 芳基 ).

[0740] 13 CNMR(101MHz,DMSO-d6)δ:19.7(2xCH 3异丙基 ),24.6(CH异丙基 ),121.2(CH 芳基 ),133.2(C q ),142.1(C q ),147.5(C q ),154.8(C q ).

[0741] MS(ESI+): m / z calculated value C8H8Cl2N4: 231.0[M+H]+, measured value 230.9.

[0742] Example 2.2: Synthesis of 6,8-dichloro-3-sec-butyl-[1,2,4]triazolo[4,3-b]pyridazine (2.2)

[0743] To a solution of 4-methylbenzenesulfonyl hydrazine (1.900 g, 9.90 mmol, 1.0 eq.) in THF (25.0 mL), 2-methylbutyraldehyde (1.12 mL, 9.90 mmol, 1.0 eq.) was added, and the mixture was stirred at room temperature for 25 minutes. After this, 3,5-dichloropyridazine(b) (1.552 g, 9.90 mmol, 1.0 eq.) was added, followed by a one-time addition of PIDA (6.505 g, 19.79 mmol, 2.0 eq.) and I2 (0.502 g, 1.98 mmol, 0.2 eq.). The mixture was stirred at room temperature for 17 hours, and then saturated Na2S2O3 (10.0 mL) and saturated NaHCO3 (10.0 mL) were added, followed by vigorous stirring of the mixture for 5 minutes. The layers were separated, and the aqueous layer was extracted twice with EtOAc (2 x 10.0 mL). The organic layers were combined, dried with MgSO4, filtered, and purified by rapid chromatography with EtOAc / cyclohexane (30 / 70) as the eluent to give a white solid (2.2) (0.670 g, 28%).

[0744] 1 HNMR(400MHz,DMSO-d6)δ:0.86(t,J=7.4Hz,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 芳基 ).

[0745] 13 CNMR(101MHz,DMSO-d6)δ:11.4(CH 3-CH2 ),17.4(CH 3-CH ),26.7(CH2-CH3 ),31.1(CH -CH3 ),121.3(CH 芳基 ),133.3(C q ),142.1(C q ),147.6(C q ),154.0(C q ).

[0746] MS(ESI+): m / z calculated value C9H 10 Cl2N4: 245.0 [M+H]+, measured value 245.1.

[0747] Example 2.3: Synthesis of 6,8-dichloro-3-(1-ethylpropyl)-[1,2,4]triazolo[4,3-b]pyridazine (2.3)

[0748] To a THF (20.0 mL) solution of 4-methylbenzenesulfonyl hydrazine (1.600 g, 8.59 mmol, 1.0 eq.), 2-ethylbutyraldehyde (1.14 mL, 8.59 mmol, 1.0 eq.) was added, and the mixture was stirred at room temperature for 25 minutes. After this, 3,5-dichloropyridazine(b) (1.307 g, 8.59 mmol, 1.0 eq.) was added, followed by a one-time addition of PIDA (5.478 g, 16.67 mmol, 2.0 eq.) and I2 (0.423 g, 1.67 mmol, 0.2 eq.). 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, followed by vigorous stirring for 5 minutes. The layers were separated, and the aqueous layer was extracted twice with EtOAc (2 x 10.0 mL). The organic layers were combined, dried with MgSO4, filtered, and purified by rapid chromatography with EtOAc / cyclohexane (30 / 70) as the eluent to give a white solid (2.3) (0.570 g, 26%).

[0749] 1 HNMR(400MHz,DMSO-d6)δ:0.80(t,J=7.4Hz,6H,2xCH 3-CH2 ), 1.75–1.97 (m, 4H, 2xCH) 2-CH3 ),3.23(tt,J=8.3,5.7Hz,1H,H 异戊 ),7.94(s,1H,H 芳基 ).

[0750] 13 CNMR(101MHz,DMSO-d6)δ:11.4(2xCH 3-CH2 ),24.8(2xCH2-CH3 ),38.3(CH 异戊基 ),121.3(CH 芳基 ),133.3(C q ),142.1(C q ),147.7(C q ),

[0751] MS(ESI+): m / z calculated value C 10 H 12 Cl2N4: 259.1 [M+H]+, measured value 259.1.

[0752] Example 2.4: Synthesis of 6,8-dichloro-3-isobutyl-[1,2,4]triazolo[4,3-b]pyridazine (2.4)

[0753] Add 3-methylbutyraldehyde (0.58 mL, 5.37 mmol, 1.0 eq.) to a THF (20.0 mL) solution of 4-methylbenzenesulfonyl hydrazine (1.000 g, 5.37 mmol, 1.0 eq.), and then stir the mixture at room temperature for 20 minutes. After this, add 3,5-dichloropyridazine(b) (0.927 g, 5.91 mmol, 1.1 eq.), followed by a one-time addition of PIDA (3.530 g, 10.74 mmol, 2.0 eq.) and I2 (0.273 g, 1.07 mmol, 0.2 eq.). Stir the mixture at room temperature for 2 hours, then add saturated Na2S2O3 (20.0 mL) and H2O (10.0 mL), and stir the mixture vigorously for 5 minutes. The layers were separated, the aqueous layer was extracted twice with EtOAc (2 x 20.0 mL), the organic layers were combined, dried with MgSO4, filtered, concentrated, and purified by rapid chromatography with EtOAc / cyclohexane (85 / 15 to 50 / 50) as eluent to obtain a beige solid (2.4) (0.452 g, 34%).

[0754] 1 HNMR(400MHz,DMSO-d6)δ:0.96(d,J=6.7Hz,6H,2xCH 3异丙基 ),2.23(dp,J=13.6,6.8Hz,1H,H 异丙基 ),2.97(d,J=7.1Hz,2H,CH 2-CH ),7.93(s,1H,H 芳基 ).

[0755] 13 CNMR(101MHz,DMSO-d6)δ:22.2(2xCH 3异丙基 ),26.3(CH -CH2),32.2(CH 2-CH ),121.2(CH 芳 Base), 133.2(C q ),141.9(C q ),147.7(C q ),150.1(C q ).

[0756] MS(ESI+): m / z calculated value C9H 12 Cl2N4: 245.0 [M+H]+, measured value 245.1.

[0757] Example 2.5: Synthesis of 6,8-dichloro-3-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazine (2.5)

[0758] To a THF (95.0 mL) solution of 3,5-dichloropyridazine (b) (2.000 g, 12.7 mmol, 1.0 eq.) and N-(cyclopropylmethyleneamino)-4-methylbenzenesulfonamide (4.559 g, 19.1 mmol, 1.5 eq.), PIDA (6.288 g, 19.1 mmol, 1.5 eq.) and I2 (0.647 g, 2.5 mmol, 0.2 eq.) were added in a single addition, and the mixture was stirred at room temperature for 2 hours. After stirring, a mixture of saturated Na2S2O3 (20.0 mL) and water (10.0 mL) was added, and the two phases were stirred vigorously for 5 minutes. The layers were then separated. The aqueous layer was extracted twice with EtOAc (2 x 15.0 mL), the organic layers were combined, dried over MgSO4, filtered, and rapidly purified by chromatography with EtOAc / cyclohexane (75 / 25, then 70 / 30) as eluent to give a white solid (2.5 g) (0.400 g, 14%).

[0759] 1 HNMR(400MHz,DMSO-d6)δ:1.07–1.27(m,4H,2xCH 2环丙基 ),2.40(tt,J=8.3,5.0Hz,1H,H 环丙基 ),7.91(s,1H,H 芳基 ).

[0760] 13 CNMR (101MHz, DMSO-d6) δ: 4.9 (CH 环丙基 ),7.5(2xCH 2环丙基 ),121.1(CH 芳基 ),133.1(C q ),142.1(C q ),147.7(Cq ),152.3(C q ).

[0761] MS(ESI+): m / z calculated value C8H6Cl2N4: 229.0 [M+H]+, measured value 228.9.

[0762] Example 2.6: Synthesis of 6,8-dichloro-3-cyclopentyl-[1,2,4]triazolo[4,3-b]pyridazine (2.6)

[0763] To a solution of 4-methylbenzenesulfonyl hydrazine (1.800 g, 9.38 mmol, 1.0 eq.) in THF (140.0 mL), cyclopentaneformaldehyde (0.995 g, 9.84 mmol, 1.05 eq.) was added, and the mixture was stirred at room temperature for 20 minutes. After stirring, 3,5-dichloropyridazine(b) (1.470 g, 9.38 mmol, 1.0 eq.) was added, followed by a one-time addition of PIDA (4.622 g, 14.06 mmol, 1.5 eq.) and I2 (0.476 g, 1.88 mmol, 0.2 eq.). The mixture was stirred at room temperature for 1.3 hours, then partially concentrated, and the residue was diluted in EtOAc (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 EtOAc (2 x 30.0 mL), the organic layers were combined, dried with MgSO4, filtered, and rapidly purified by chromatography with EtOAc / cyclohexane (15 / 85 to 50 / 50) as eluent to obtain white flakes (2.6) (0.260 g, 11%).

[0764] 1 HNMR(400MHz,DMSO-d6)δ:1.63–1.86(m,4H,2xCH 2环戊 ), 1.90–2.03(m,2H,CH) 2环戊 ),2.11(dq,J=12.3,7.0,6.0Hz,2H,CH 2环戊 ), 3.61 (p, J = 7.9 Hz, 1H, H 环戊 ),7.92(s,1H,H 芳基 ).

[0765] 13 CNMR(101MHz,DMSO-d6)δ:25.1(2xCH 2环戊基 ),30.1(2xCH 2环戊基 ),34.3(CH 环戊基 ),121.2(CH 芳基 ),133.2(Cq ),142.2(C q ),147.5(C q ),154.0(C q ).

[0766] MS(ESI+): m / z calculated value C 10 H 10 Cl2N4: 257.0 [M+H]+, measured value 257.1.

[0767] Example 2.7: Synthesis of 6,8-dichloro-3-sec-butyl-[1,2,4]triazolo[4,3-b]pyridazine (2.7)

[0768] Butyraldehyde (0.52 mL, 5.74 mmol, 1.2 eq.) was added to a THF (15.0 mL) solution of 4-methylbenzenesulfonyl hydrazine (1.102 g, 5.74 mmol, 1.2 eq.), and the mixture was stirred at room temperature for 10 minutes. After this, 3,5-dichloropyridazine(b) (0.750 g, 4.78 mmol, 1.0 eq.) was added, followed by a one-time addition of PIDA (6.505 g, 19.79 mmol, 2.0 eq.) and I2 (0.502 g, 1.98 mmol, 0.2 eq.). The mixture was stirred 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 stirred vigorously for 5 minutes. The layers were separated, and the aqueous layer was extracted twice with EtOAc (2 x 10.0 mL). The organic layers were combined, dried over MgSO4, filtered, and purified by rapid chromatography using EtOAc / cyclohexane (30 / 70) as the eluent to give a white solid (2.7 g) (0.957 g, containing impurities (RMN purity 70%), calculated = 0.670 g, 28%).

[0769] 1 HNMR(400MHz,DMSO-d6)δ:0.86(t,J=7.4Hz,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 芳基 ).

[0770] 13 CNMR(101MHz,DMSO-d6)δ:11.4(CH 3-CH2 ),17.4(CH 3-CH ),26.7(CH2-CH3 ),31.1(CH -CH3 ),121.3(CH 芳基 ),133.3(C q ),142.1(C q ),147.6(C q ),154.0(C q ).

[0771] MS(ESI+): m / z calculated value C9H 10 Cl2N4: 245.0 [M+H]+, measured value 245.1.

[0772] Example 3: The synthesis of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-8-amine derivatives is as described in step 1 of scheme 1 or step 2 of scheme 2.

[0773]

[0774] Example 3.1: Synthesis of N-benzyl-6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.1)

[0775] In a 10–20 mL sealed vial equipped with a stir bar, (1.1) (0.250 g, 0.98 mmol, 1.0 equivalent), dioxane (3.5 mL), isobutyric acid hydrazide (0.121 g, 1.18 mmol, 1.2 equivalent), and AcOH (0.05 mL, 0.79 mmol, 0.8 equivalent) were loaded. The vial was sealed and placed on a heating block, and heated at 100 °C for 4 hours. The reaction mixture was cooled, and a saturated solution of NaHCO3 (8.0 mL) was added, followed by dilution with water (8.0 mL). The precipitate was filtered off, washed with water to neutral pH, ground in Et2O, and dried under vacuum to give the target compound (3.1) (0.220 g, 74%) as a white solid.

[0776] Rf(DCM / EtOAc, 75 / 25): 0.30.

[0777] 1 ¹H NMR (400 MHz, DMSO-d⁶) δ: 1.38 (d, J = 6.9 Hz, 6H, 2xCH₃), 3.43 (hept, J = 7.1 Hz, 1H, Halkyl), 4.60 (d, J = 4.2 Hz, 2H, CH₂), 6.14 (s, 1H, H) 芳基 ), 7.22–7.31(m,1H,H 芳基 ), 7.32–7.44(m,4H,4xH) 芳基 ),9.13(s,1H,NH).

[0778] 13 CNMR(101MHz,DMSO-d6)δ:20.3(CH3),24.9(CH 烷基 ), 45.6(CH2), 92.0(CH 芳基 ),127.6(CH 芳基 ),127.7(CH 芳基 ),129.0(CH 芳基 ),137.9(C q ),139.9(C q ),142.8(C q ),149.9(C q ),154.4(C q ).

[0779] MS(ESI+): m / z calculated value C 15 H 16 ClN5: 302.12[M+H]+, measured value 302.33.

[0780] Example 3.2: Synthesis of N-benzyl-6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.2)

[0781] In a 2–5 mL sealed tube equipped with a stir 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 loaded. The mixture was refluxed for 36 hours, cooled, and then MeOH (2 mL) was added, followed by DCM (2 mL). The mixture was concentrated and purified by rapid chromatography using DCM / EtOAc (8 / 2) as eluent to give the target compound (3.2) (0.250 g, 29%) as a white solid.

[0782] Rf(DCM / EtOAc, 75 / 25): 0.21.

[0783] 1 HNMR(400MHz,DMSO-d6)δ:4.60(d,J=6.4Hz,2H,CH 2苄基 ),6.17(s,1H,H 芳基 ), 7.26(t, J = 7.4 Hz, 1H, H 芳基 ), 7.35(t, J = 7.4 Hz, 2H, 2xH 芳基 ), 7.40(d, J=7.6Hz, 2H, 2xH 芳基), 9.17(s, 1H, NH), 9.41(s, 1H, H 芳基 ).

[0784] 13 CNMR(101MHz,DMSO-d6)δ:45.2(CH2),92.1(CH 芳基 ),127.2(2xCH 芳基 ),127.2(CH 芳基 ),128.5(2xCH 芳基 ),137.4(C q ),139.1(C q ),139.6(CH 芳基 ),142.1(C q ),150.0(C q ).

[0785] MS(ESI+): m / z calculated value C 12 H 10 ClN5: 260.07[M+H]+, measured value 260.1.

[0786] Example 3.3: Synthesis of N-benzyl-6-chloro-3-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.3)

[0787] In a 2–5 mL sealed tube equipped with a stir 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 loaded. The vial was sealed and placed on a heating block and heated 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 rapid chromatography using DCM / EtOAc (7 / 3) as eluent to give the target compound (3.3) (0.184 g, 52%) as a white solid.

[0788] Rf(DCM / EtOAc, 7 / 3): 0.44

[0789] 1 HNMR(400MHz,DMSO-d6)δ:1.06–1.15(m,4H,2xCH 2烷基 ),2.31(ddd,J=13.3,8.0,5.4Hz,1H,H 烷基 ),4.58(d,J=6.5Hz,2H,CH2),6.12(s,1H,H芳基 ), 7.26(t, J = 7.1 Hz, 1H, H 芳基 ), 7.32–7.41(m,4H,4xH) 芳基 ),9.08(s,1H,NH).

[0790] 13 CNMR (101MHz, DMSO-d6) δ: 4.8 (CH 烷基 ),7.1(2xCH 2烷基 ),45.1(CH2),91.5(CH),127.2(2xCH 芳基 ),127.2(CH 芳基 ),128.5(2xCH 芳基 ),137.4(C q ),139.4(C q ),142.3(C q ),149.6(C q ),151.4(C q ).

[0791] MS(ESI+): m / z calculated value C 15 H 14 ClN5: 300.1 [M+H]+, measured value 300.1.

[0792] Example 3.4: Synthesis of N-benzyl-6-chloro-3-cyclopentyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.4)

[0793] To a solution of (2.6) (0.200 g, 0.75 mmol, 1.0 eq.) in THF (15.0 mL), the corresponding amine (0.17 mL, 1.51 mmol, 2.0 eq.) and Et3N (0.21 mL, 1.51 mmol, 2.0 eq.) 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 washed with Et2O, and dried under vacuum to give a white solid (3.4) (0.220 g, 89%).

[0794] 1 HNMR(400MHz,DMSO-d6)δ:1.61–1.84(m,4H,2xCH 2环戊 ),1.92(dq,J=12.0,7.4Hz,2H,CH 2环戊 ),2.02–2.18(m,2H,CH 2环戊 ), 3.52 (p, J = 8.0 Hz, 1H, H 环戊),4.58(s,2H,CH 2苄基 ),6.13(s,1H,H 芳基 ), 7.26(t, J = 7.1 Hz, 1H, H 芳基 ), 7.34(t, J = 7.5 Hz, 2H, 2xH 芳基 ), 7.39(d, J = 7.5 Hz, 2H, 2xH 芳基 ),9.09(s,1H,NH 苄基 ).

[0795] 13 CNMR(101MHz,DMSO-d6)δ:25.0(2xCH 2环戊基 ),30.2(2xCH 2环戊基 ),34.3(CH 环戊基 ),45.1(CH 2苄基 ),91.5(CH 芳基 ),127.2(2xCH 芳基 ),127.2(CH 芳基 ),128.5(2xCH 芳基 ),137.4(C q ),139.5(C q ),142.28(C q ),149.4(C q ),153.1(C q ).

[0796] MS(ESI+): m / z calculated value C 17 H 18 ClN5: 328.1 [M+H]+, measured value 328.2.

[0797] Example 3.5: Synthesis of N-benzyl-6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.5)

[0798] In a 2–5 mL sealed vial equipped with a stir bar, (1.1) (0.300 g, 1.18 mmol, 1.0 equivalent), dioxane (3.9 mL), trifluoroacetylhydrazine (0.166 g, 1.30 mmol, 1.1 equivalent), and PTSA·H₂O (0.023 g, 0.12 mmol, 0.1 equivalent) were loaded. The vial was sealed and placed on a heating block, and heated 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 rapid chromatography using DCM / EtOAc (9 / 1) as eluent to give the target compound (3.5) (0.070 g, 18%) as a white solid.

[0799] Rf(DCM / EtOAc, 9 / 1): 0.63

[0800] 1 HNMR(400MHz,DMSO-d6)δ:4.65(d,J=6.2Hz,2H,CH2),6.43(s,1H,H 芳基 ),7.28(dq,J=7.2,4.9,3.3Hz,1H,H 芳基 ),7.35(dd,J=8.3,6.6Hz,2H,2xH 芳基 ), 7.41(d, J = 7.2 Hz, 2H, 2xH 芳基 ),9.52(s,1H,NH).

[0801] 13 CNMR(101MHz,DMSO-d6)δ:45.19(CH2),93.80(CH 芳基 ),118.24(q,J=269.9Hz,CF3),127.26(2xCH 芳基 ),127.32(CH 芳基 ),128.53(2xCH 芳基 ),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 ).

[0802] MS(ESI+): m / z calculated value C 13 H9ClF3N5: 328.1 [M+H]+, measured value 328.1.

[0803] Example 3.6: Synthesis of N-benzyl-6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.6)

[0804] Acetylhydrazine (0.228 g, 3.25 mmol, 1.1 eq.) and PTSA·H₂O (0.281 g, 1.48 mmol, 0.5 eq.) were added to a solution of (1.1) (0.750 g, 2.95 mmol, 1.0 eq.) in dioxane (15.0 mL), and the mixture was refluxed for 24 hours. The reaction mixture was cooled and MeOH (10.0 mL) was added. The mixture was concentrated with SiO₂ to form a solid precipitate, and purified directly by rapid chromatography using DCM / EtOAc / MeOH (60 / 40 / 0 to 60 / 30 / 10) as eluent to give the target compound (3.6) (0.350 g, 43%) as a white solid.

[0805] Rf(DCM / EtOAc, 75 / 25): 0.24

[0806] 1 HNMR(400MHz,DMSO-d6)δ:2.58(s,3H,CH3),4.60(s,2H,CH2),6.14(s,1H,H 芳基 ), 7.22–7.42(m,5H,5xH) 芳基 ),9.09(s,1H,NH).

[0807] 13 CNMR(101MHz,DMSO-d6)δ:9.4(CH3),45.1(CH2),91.4(CH 芳基 ),127.1(2xCH 芳基 ),127.2(CH 芳基 ),128.5(2xCH 芳基 ),137.4(C q ),139.2(C q ),142.3(C q ),146.8(C q ),149.6(C q ).

[0808] MS(ESI+): m / z calculated value C 13 H 12 ClN5: 274.1 [M+H]+, measured value 274.1.

[0809] Example 3.7: Synthesis of N-benzyl-6-chloro-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.7)

[0810] Benzoylhydrazine (0.442 g, 3.25 mmol, 1.1 eq.) and PTSA·H₂O (0.281 g, 1.48 mmol, 0.5 eq.) were added to a solution of dioxane (15.0 mL) of (1.1) (0.750 g, 2.95 mmol, 1.0 eq.), and the mixture was refluxed for 22.5 h. The reaction mixture was cooled and MeOH (5.0 mL) was added. The mixture was concentrated with SiO₂ to form a solid precipitate, which was purified directly by rapid chromatography using DCM / MeOH (94 / 6) as eluent to give the target compound (3.7) (0.425 g, 46%) as a white solid.

[0811] Rf(DCM / MeOH,94 / 6):0.46

[0812] 1 HNMR(400MHz,DMSO-d6)δ:4.64(d,J=6.4Hz,2H,CH 2苄基 ),6.27(s,1H,H 芳基 ), 7.27(t, J = 7.2 Hz, 1H, H 芳基 ), 7.36(t, J = 7.5 Hz, 2H, 2xH 芳基 ), 7.43(d, J=7.6Hz, 2H, 2xH 芳基 ),7.58(dt,J=13.3,7.2Hz,3H,3xH 芳基 ),8.31(d,J=7.5Hz,2H,2xH 芳基 ),9.25(s,1H,NH 苄基 ).

[0813] 13 CNMR (101MHz, DMSO-d6)δ:ND

[0814] MS(ESI+): m / z calculated value C 18 H 14 ClN5: 336.1 [M+H]+, measured value 336.1.

[0815] Example 3.8: Synthesis of 2-[[(6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)amino]methyl]phenol (3.8)

[0816] Isobutyric acid hydrazide (1.150 g, 11.25 mmol, 1.6 eq.) was added to a suspension of (1.7) (1.900 g, 7.03 mmol, 1.0 eq.) in dioxane (40.0 mL), followed by the addition of AcOH (0.45 mL, 7.74 mmol, 1.1 eq.). The mixture was refluxed for 16 hours, cooled, and then MeOH (5.0 mL) was added, followed by the addition of SiO2 to directly form a solid precipitate. The mixture was concentrated and purified by rapid chromatography using DCM / MeOH (97 / 3 to 93 / 7) as eluent to give a white solid (3.8) (1.000 g, 45%).

[0817] Rf(DCM / MeOH,92 / 8):0.15

[0818] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.42 (p, J = 6.9 Hz, 1H, CH) 异丙基 ), 4.37–4.61(m,2H,CH) 2苄基 ),6.12(s,1H,CH 芳基 ), 6.76(t, J = 7.4 Hz, 1H, CH 芳基 ), 6.85 (d, J = 8.0 Hz, 1H, CH) 芳基 ),7.10(t,J=7.7Hz,1H,CH 芳基 ), 7.18 (d, J = 7.6 Hz, 1H, CH) 芳基 ),8.90(s,1H,NH 苄基 ),9.82(s,1H,OH).

[0819] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基 ),40.2(CH 2苄基 ),91.3(CH 芳基 ),115.1(CH 芳基 ),119.1(CH 芳基 ),122.9(C q ),128.4(2xCH 芳基 ),139.4(C q ),142.3(C q ),149.4(C q ),154.0(C q ),154.8(C q).

[0820] MS(ESI+): m / z calculated value C 15 H 16 ClN5O: 318.1 [M+H]+, measured value 318.2.

[0821] Example 3.9: Synthesis of 3-[[(6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)amino]methyl]phenol (3.9)

[0822] In a 10–20 mL sealed vial equipped with a stir bar, (1.6) (0.460 g, 1.70 mmol, 1.0 eq.) dioxane (10.0 mL), isobutyric acid hydrazide (0.211 g, 2.04 mmol, 1.2 eq.), and PTSA·H₂O (0.197 g, 1.02 mmol, 0.6 equivalent) were added. The vial was sealed and placed on a heating block, and heated at 100 °C for 17 hours. After cooling, MeOH (3.0 mL) was added, and the mixture was then concentrated with SiO₂ to form a solid precipitate, which was directly purified by rapid chromatography using DCM / MeOH (97 / 3 to 94 / 6) as the eluent to give a white solid (3.9) (0.250 g, 46%).

[0823] Rf(DCM / MeOH,92 / 8):0.23

[0824] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.42 (p, J = 7.0 Hz, 1H, H 异丙基 ), 4.50 (d, J = 6.2 Hz, 2H, CH 2苄基 ),6.09(s,1H,H 芳基 ), 6.64(dd, J = 8.0, 1.8 Hz, 1H, H 芳基 ), 6.75(t, J = 2.0 Hz, 1H, H 芳基 ), 6.79 (d, J = 7.6 Hz, 1H, H 芳基 ),7.12(t,J=7.8Hz,1H,H 芳基 ),9.09(s,1H,NH 苄基 ),9.37(s,1H,OH).

[0825] 13 CNMR(101MHz,DMSO-d6)δ:19.9(2xCH 3异丙基 ),24.4(CH 异丙基),45.0(CH 2苄基 ),91.5(CH 芳基 ),113.7(CH 芳基 ),114.2(CH 芳基 ),117.7(CH 芳基 ),129.5(CH 芳基 ),138.8(Cq),139.4(Cq),142.3(Cq),149.4(Cq),154.0(Cq),157.5(Cq).

[0826] MS(ESI+): m / z calculated value C 15 H 16 ClN5O: 318.1 [M+H]+, measured value 318.3.

[0827] Example 3.10: Synthesis of 4-[[(6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)amino]methyl]phenol (3.10)

[0828] In a 10–20 mL sealed vial equipped with a stir bar, 10.0 mL of dioxane (1.5 g) (0.520 g, 1.93 mmol, 1.0 eq.), isobutyric acid hydrazide (0.238 g, 2.31 mmol, 1.2 eq.), and PTSA·H₂O (0.223 g, 1.16 mmol, 0.6 equivalence) were added. The vial was sealed and placed on a heating block, and heated at 100 °C for 17 hours. After cooling, 3.0 mL of MeOH was added, and the mixture was then concentrated with SiO₂ to form a solid precipitate, which was directly purified by rapid chromatography using DCM / MeOH (97 / 3 to 94 / 6) as the eluent to give a white solid (3.10 g) (0.115 g, 19%).

[0829] Rf(DCM / MeOH,92 / 8):0.25.

[0830] 1 HNMR(400MHz,DMSO-d6)δ:1.37(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.41(hept, J = 7.0 Hz, 1H, H 异丙基 ), 4.44(d, J = 6.2 Hz, 2H, CH 2苄基 ),6.12(s,1H,H 芳基 ), 6.71(d, J = 8.5 Hz, 2H, 2xH 芳基 ), 7.20(d, J = 8.5 Hz, 2H, 2xH 芳基 ),9.02(s,1H,NH苄基 ),9.34(s,1H,OH).

[0831] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基 ),44.7(CH 2苄基 ),91.4(CH 芳基 ),115.2(2xCH 芳基 ),127.5(C q ),128.6(2xCH 芳基 ),139.5(C q ),142.2(C q ),149.4(C q ),153.9(C q ),156.6(C q ).

[0832] MS(ESI+): m / z calculated value C 15 H 16 ClN5O: 318.1 [M+H]+, measured value 318.3.

[0833] 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)

[0834] Isobutyric acid hydrazide (1.307 g, 12.67 mmol, 1.2 eq.) was added to a suspension of (1.8) (3.000 g, 10.56 mmol, 1.0 eq.) in dioxane (40.0 mL), followed by the addition of AcOH (0.67 mL, 11.61 mmol, 1.1 eq.), and the mixture was refluxed for 16 hours. After cooling, MeOH (10.0 mL) was added, and the mixture was stirred vigorously for 5 minutes, followed by the addition of SiO2 to form a solid precipitate. The mixture was concentrated and purified by rapid chromatography using DCM / MeOH (99 / 1 to 97 / 3) as eluent to give a white solid (3.11) (1.490 g, 43%).

[0835] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.43 (hept, J = 7.1 Hz, 1H, H 异丙基 ),3.87(s,3H,OCH3),4.51(d,J=6.3Hz,2H,CH 2苄基),6.06(s,1H,H 芳基 ), 6.91(t, J = 7.4 Hz, 1H, H 芳基 ), 7.05 (d, J = 8.1 Hz, 1H, H 芳基 ), 7.22(d, J = 7.5 Hz, 1H, H 芳基 ), 7.28(td, J = 7.9, 1.8 Hz, 1H, H 芳基 ),8.90(s,1H,NH 苄基 ).

[0836] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基 ),40.2(CH 2苄基 ),55.4(OCH3),91.3(CH 芳基 ),110.8(CH 芳基 ),120.4(CH 芳基 ),124.4(C q ),127.7(CH 芳基 ),128.6(CH 芳基 ),139.4(C q ),142.4(C q ),149.4(C q ),154.0(C q ),156.7(C q ).

[0837] MS(ESI+): m / z calculated value C 16 H 18 ClN5O: 332.1 [M+H]+, measured value 332.3.

[0838] Example 3.12: Synthesis of 6-chloro-3-isopropyl-N-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.12)

[0839] To a solution of (2.1) (0.150 g, 0.65 mmol, 1.0 eq.) in anhydrous THF (5.0 mL), aniline (0.12 mL, 1.30 mmol, 2.0 eq.) was added, followed by a solution of 1 M tBuOK in THF (1.30 mL, 1.3 mmol, 2.0 eq.), and the mixture was stirred at room temperature for 1 hour. After this, saturated NH4Cl (5.0 mL) and water (1.5 mL) were added, and the two phases were stirred vigorously for 5 minutes. The layers were separated, the aqueous layer was extracted with EtOAc (2 x 5.0 mL), and the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1 to 98 / 2) as eluent to give a white solid (3.12) (0.175 g, 94%).

[0840] Rf(DCM / MeOH, 96 / 4): 0.40

[0841] 1 HNMR(400MHz,DMSO-d6)δ:1.41(d,J=7.0Hz,6H,2xCH 3异丙基 ), 3.48 (hept, J = 6.9 Hz, 1H, H 异丙基 ), 6.35(s, 1H, H 芳基 ),7.27(tt,J=5.7,2.4Hz,1H,H 芳基 ), 7.40–7.58(m,4H,4xH) 芳基 ),10.46(s,1H,NH).

[0842] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.5(CH 异丙基 ),92.9(CH 芳基 ),123.6(2xCH 芳基 ),125.7(CH 芳基 ),129.5(2xCH 芳基 ),137.7(C q ),139.5(C q ),140.2(C q ),149.6(C q ),154.2(C q ).

[0843] MS(ESI+): m / z calculated value C 14 H 14 ClN5: 288.1 [M+H]+, measured value 288.1.

[0844] Example 3.13: Synthesis of 6-chloro-3-isopropyl-N-(2-pyridine)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.13)

[0845] To a solution of (2.1) (0.100 g, 0.43 mmol, 1.0 eq.) in anhydrous THF (5.0 mL), 2-aminopyridine (0.082, 0.87 mmol, 2.0 eq.) was added, followed by a solution of 1 M tBuOK in THF (0.87 mL, 0.87 mmol, 2.0 eq.). The mixture was stirred at room temperature for 1 hour. After this, saturated NH4Cl (3.5 mL) and water (1.5 mL) were added, and the biphasic mixture was stirred vigorously for 5 minutes. The layers were separated, the aqueous layer was extracted with EtOAc (2 x 5.0 mL), and the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2) as eluent to give a white solid (3.13) (0.120 g, 96%).

[0846] Rf(DCM / MeOH, 96 / 4): 0.27

[0847] 1 HNMR(400MHz,DMSO-d6)δ:1.42(d,J=6.9Hz,6H,2xCH 3异丙基 ),3.50(hept,J=7.1,6.5Hz,1H,H 异丙基 ),7.13(ddd,J=7.4,5.0,1.0Hz,1H,H 芳基 ), 7.61(d, J = 8.3 Hz, 1H, H 芳基 ),7.82(ddd,J=9.0,7.3,2.0Hz,1H,H 芳基 ),8.32(s,1H,H 芳基 ), 8.46 (d, J = 1.9 Hz, 1H, H 芳基 ),10.90(s,1H,NH).

[0848] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.5(CH 异丙基 ),99.5(CH 芳基 ),114.7(CH 芳基 ),118.6(CH 芳基 ),136.6(C q ),138.3(CH 芳基 ),139.3(Cq ),147.3(CH 芳基 ),149.7(C q ),153.9(C q ),154.3(C q ).

[0849] MS(ESI+): m / z calculated value C 13 H 13 ClN6: 289.1 [M+H]+, measured value 289.2.

[0850] Example 3.14: Synthesis of 6-chloro-3-isopropyl-N-(3-pyridine)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.14)

[0851] To a solution of (2.1) (0.100 g, 0.43 mmol, 1.0 eq.) in anhydrous THF (5.0 mL), 3-aminopyridine (0.082, 0.87 mmol, 2.0 eq.) was added, followed by a 1 Mt solution of Buok THF (0.87 mL, 0.87 mmol, 2.0 eq.). The mixture was stirred at room temperature for 1 hour. After this, saturated NH4Cl (3.5 mL) and water (1.5 mL) were added, and the two phases were stirred vigorously for 5 minutes. The layers were separated, the aqueous layer was extracted with EtOAc (2 x 5.0 mL), and the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 96 / 4) as eluent to give a white solid (3.14) (0.115 g, 92%).

[0852] Rf(DCM / MeOH,96 / 4):0.17

[0853] 1 HNMR(400MHz,DMSO-d6)δ:1.41(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.48 (hept, J = 6.9 Hz, 1H, H 异丙基 ), 6.43(s, 1H, H 芳基 ), 7.50(dd, J = 8.2, 4.7 Hz, 1H, H 芳基 ), 7.91(dt, J = 8.3, 1.9 Hz, 1H, H 芳基 ), 8.46(dd, J = 4.8, 1.5 Hz, 1H, H 芳基 ), 8.69 (d, J = 2.6 Hz, 1H, H 芳基 ),10.55(s,1H,NH).

[0854] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.5(CH 异丙基 ),93.8(CH 芳基 ),124.1(CH 芳基 ),130.8(CH 芳基 ),134.6(C q ),139.4(C q ),140.0(C q ),145.1(CH 芳基 ),146.4(CH 芳基 ),149.6(C q ),154.2(C q ).

[0855] MS(ESI+): m / z calculated value C 13 H 13 ClN6: 289.1 [M+H]+, measured value 289.1.

[0856] Example 3.15: Synthesis of 6-chloro-3-isopropyl-N-(4-pyridine)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.15)

[0857] To a solution of (2.1) (0.150 g, 0.65 mmol, 1.0 eq.) in anhydrous THF (5.0 mL), 4-aminopyridine (0.123 g, 1.30 mmol, 2.0 eq.) was added, followed by a solution of 1 M 1000 oz THF (1.30 mL, 1.30 mmol, 2.0 eq.). The mixture was stirred at room temperature for 1 hour. After this, saturated NH4Cl (5.0 mL) and water (1.5 mL) were added, and the two phases were stirred vigorously for 5 minutes. The layers were separated, the aqueous layer was extracted with EtOAc (2 x 5.0 mL), and the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1 to 96 / 4) as eluent to give a white solid (3.15) (0.180 g, 96%).

[0858] Rf(DCM / MeOH, 96 / 4): 0.10

[0859] 1 HNMR(400MHz,DMSO-d6)δ:1.42(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.50 (hept, J = 6.9 Hz, 1H, H 异丙基 ),6.88(s,1H,H芳基 ), 7.34–7.70(m,2H,2xH) 芳基 ), 8.39–8.68(m,2H,2xH) 芳基 ), 10.69(s, 1H, NH).

[0860] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ), 24.5(CH isopropyl), 96.7(CH 芳基 ),115.5(CH 芳基 ),138.1(C q ),139.5(C q ),145.7(C q ),149.6(C q ),150.8(CH 芳基 ),154.3(C q ).

[0861] MS(ESI+): m / z calculated value C 13 H 13 ClN6: 289.1 [M+H]+, measured value 289.1.

[0862] Example 3.16: Synthesis of 6-chloro-3-isopropyl-N-(4-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.16)

[0863] Isobutyric acid hydrazide (0.189 g, 1.89 mmol, 1.2 eq.) was added to a suspension of dioxane (25.0 mL) containing (1.4) (0.390 g, 1.53 mmol, 1.0 eq.), followed by APTS·H₂O (0.177 g, 0.92 mmol, 0.6 eq.), 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 stirred vigorously for 5 minutes. SiO₂ was added to form a solid precipitate, the mixture was concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5 to 93 / 7) as the eluent to obtain a beige solid (3.16) (0.175 g, 38%).

[0864] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.43 (p, J = 7.0 Hz, 1H, H 异丙基 ),4.64(s,2H,CH 2苄基),6.15(s,1H,H 芳基 ), 7.31–7.43(m,2H,2xH) 芳基 ), 8.44–8.60(m,2H,2xH) 芳基 ),9.12(s,1H,NH 苄基 ).

[0865] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基 ),44.1(CH 2苄基 ),91.7(CH 芳基 ),122.1(2xCH 芳基 ),139.4(Cq),142.4(Cq),146.5(C q ),149.5(Cq),149.7(2xCH 芳基 ), 154.0 (Cq).

[0866] MS(ESI+): m / z calculated value C 14 H 15 ClN6: 303.1 [M+H]+, measured value 303.2.

[0867] Example 3.17: Synthesis of 6-chloro-3-isopropyl-N-(3-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.17)

[0868] Isobutyric acid hydrazide (0.667 g, 6.47 mmol, 1.1 eq.) was added to a suspension of (1.3) (1.500 g, 5.88 mmol, 1.0 eq.) in dioxane (20.0 mL), followed by the addition of AcOH (0.37 mL, 6.47 mmol, 1.1 eq.), and the mixture was refluxed for 16 hours. After cooling, MeOH (10.0 mL) and NaHCO3 (1.000 g) were added, and the mixture was stirred vigorously for 5 minutes, followed by the addition of SiO2 to form a solid precipitate. The mixture was concentrated and purified by rapid chromatography using DCM / MeOH (98 / 2 to 93 / 7) as eluent to give a white solid (3.17) (0.700 g, 39%).

[0869] 1 HNMR(400MHz,DMSO-d6)δ:1.37(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.42(hept, J = 7.1 Hz, 1H, H 异丙基 ),4.63(s,2H,CH2苄基 ),6.26(s,1H,H 芳基 ), 7.37(dd, J = 7.9, 4.8 Hz, 1H, H 芳基 ), 7.79(dt, J = 7.9, 2.0 Hz, 1H, H 芳基 ), 8.48(dd, J = 4.9, 1.6 Hz, 1H, H 芳基 ), 8.64 (d, J = 2.3 Hz, 1H, H 芳基 ),9.10(s,1H,NH 苄基 ).

[0870] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基 ),42.8(CH 2苄基 ),91.6(CH 芳基 ),123.6(CH 芳基 ),133.1(C q ),135.1(CH 芳基 ),139.4(C q ),142.2(C q ),148.5(CH 芳基 ),148.9(CH 芳基 ),149.5(C q ),154.0(C q ).

[0871] MS(ESI+): m / z calculated value C 14 H 15 ClN6: 303.1 [M+H]+, measured value 303.3.

[0872] Example 3.18: Synthesis of 6-chloro-3-isopropyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.18)

[0873] To a solution of (1.2) (5.000 g, 19.60 mmol, 1.0 eq.) in dioxane (80.0 mL), isobutyric acid hydrazide (2.224 g, 21.560 mmol, 1.1 eq.) was added, followed by the addition of AcOH (1.25 mL, 21.56 mmol, 1.1 equivalents), 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 off, washed with water to neutral pH, washed with ethanol and Et2O, and then dried under vacuum to give the first fraction (1.880 g) of (3.18). The aqueous layer was extracted twice with EtOAc (2 x 50.0 mL), and the organic layers were combined, washed with saturated NaHCO3, dried with MgSO4, filtered, and concentrated to give the second fraction (3.18) (0.500 g). (3.18) Amount: 2.380g, white solid.

[0874] Rf(DCM / MeOH,94 / 6):0.30

[0875] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.43 (hept, J = 7.0 Hz, 1H, H 异丙基 ), 4.46–4.78 (m, 2H, CH) 2苄基 ),6.15(s,1H,H 芳基 ), 7.30(dd, J = 7.6, 4.8 Hz, 1H, H 芳基 ), 7.38 (d, J = 7.8 Hz, 1H, H) 芳基 ),7.78(td,J=7.7,1.9Hz,1H,H 芳基 ), 8.55 (d, J = 4.9 Hz, 1H, H 芳基 ),8.98(s,1H,NH 苄基 ).

[0876] 13 CNMR (101MHz, DMSO-d6)δ:ND

[0877] MS(ESI+): m / z calculated value C 14 H 15 ClN6: 303.1 [M+H]+, measured value 303.2.

[0878] Example 3.19: Synthesis of 6-chloro-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.19)

[0879] To a solution of (1.2) (4.000 g, 15.68 mmol, 1.0 eq.) in dioxane (52.0 mL), the corresponding acid hydrazide (1.130 g, 18.82 mmol, 1.2 eq.) and APTS·H₂O (3.028 g, 15.68 mmol, 1.0 eq.) were added. The mixture was refluxed for 1 hour, then cooled, and MeOH (20.0 mL) and Na₂CO₃ (1.000 g) were added and stirred for 5 minutes. SiO₂ was added to form a solid precipitate, which was then concentrated and purified directly by rapid chromatography using DCM / MeOH (98 / 2 to 95 / 5) as the eluent to give a light brown solid (3.19) (0.580 g, 14%).

[0880] 1 HNMR(400MHz,DMSO-d6)δ:4.69(d,J=5.9Hz,2H,CH 2苄基 ),6.20(s,1H,H 芳基 ),7.31(dd,J=7.5,5.0Hz,1H,H 芳基 ), 7.39 (d, J = 7.8 Hz, 1H, H 芳基 ),7.78(tt,J=7.7,1.6Hz,1H,H 芳基 ), 8.55 (d, J = 4.8 Hz, 1H, H 芳基 ),9.02(s,1H,NH 苄基 ), 9.42(d, J = 1.3 Hz, 1H, H 芳基 ).

[0881] 13 CNMR(101MHz,DMSO-d6)δ:47.2(CH 2苄基 ),92.4(CH 芳基 ),121.5(CH 芳基 ),122.6(CH 芳基 ),137.1(CH 芳基 ),139.0(C q ),139.6(CH 芳基 ),142.2(C q ),149.1(CH 芳基 ),150.0(C q ),156.6(C q ).

[0882] MS(ESI+): m / z calculated value C 11 H9ClN6: 261.1 [M+H]+, measured value 261.2.

[0883] Example 3.20: Synthesis of 6-chloro-3-methyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.20)

[0884] To a solution of (1.2) (4.000 g, 15.68 mmol, 1.0 eq.) of dioxane (52.0 mL), the corresponding acid hydrazide (1.467 g, 18.82 mmol, 1.2 eq.) and APTS·H₂O (3.028 g, 15.68 mmol, 1.0 eq.) were added. The mixture was refluxed for 1 hour, then cooled, and MeOH (10.0 mL) and a MeOH (6.0 mL) solution of 7N NH₃ were added, and the mixture was stirred for 10 minutes. SiO₂ was added to form a solid precipitate, which was then concentrated and purified directly by rapid chromatography using DCM / MeOH (98 / 2 to 95 / 5) as the eluent to give a gray solid (3.20) (1.150 g, 27%).

[0885] 1 HNMR(400MHz,DMSO-d6)δ:2.59(s,3H,CH3),4.56–4.86(m,2H,CH 2苄基 ),6.16(s,1H,H 芳基 ), 7.30(dd, J = 7.5, 4.9 Hz, 1H, H 芳基 ), 7.38 (d, J = 7.9 Hz, 1H, H) 芳基 ),7.78(td,J=7.7,1.8Hz,1H,H 芳基 ), 8.48–8.60 (m, 1H, H) 芳基 ),8.93(s,1H,NH 苄基 ).

[0886] 13 CNMR(101MHz,DMSO-d6)δ:9.4(CH3),47.2(CH 2苄基 ),91.7(CH 芳基 ),121.4(CH 芳基 ),122.6(CH 芳基 ),137.0(CH 芳基 ),139.2(C q ),142.4(C q ),146.8(C q ),149.1(CH 芳基 ),149.6(C q ),156.6(C q ).

[0887] MS(ESI+): m / z calculated value C 12 H 11 ClN6: 275.1 [M+H]+, measured value 275.2.

[0888] Example 3.21: Synthesis of 6-chloro-3-ethyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.21)

[0889] In a 10–20 mL sealed tube equipped with a stirrer, (1.2) (2.000 g, 7.84 mmol, 1.0 eq.), dioxane (15.6 mL), the corresponding hydrazide (0.768 g, 8.62 mmol, 1.1 eq.), and AcOH (0.50 mL, 8.62 mmol, 1.1 eq.) were loaded. The vial was sealed and placed on a heating block and heated at 115 °C for 23 hours. After cooling, the mixture was poured into saturated NaHCO3 (20.0 mL), followed by the addition of water (40.0 mL). The aqueous layer mixture was extracted three times with EtOAc (3 x 30 mL), and the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (96 / 4 to 94 / 6) as eluent to give a white solid (3.21) (0.550 g, 24%).

[0890] 1 HNMR(400MHz,DMSO-d6)δ:1.34(t,J=7.5Hz,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苄基 ),6.16(s,1H,H 芳基 ), 7.30(dd, J = 7.5, 4.8 Hz, 1H, H 芳基 ), 7.38 (d, J = 7.8 Hz, 1H, H) 芳基 ),7.78(td,J=7.7,1.8Hz,1H,H 芳基 ), 8.55 (d, J = 5.3 Hz, 1H, H 芳基 ),8.96(s,1H,NH 苄基 ).

[0891] 13 CNMR(101MHz,DMSO-d6)δ:10.8(CH 3-CH2 ),17.3(CH 2-CH3 ),47.2(CH 2苄基 ),91.8(CH 芳基 ),121.4(CH芳基 ),122.6(CH 芳基 ),137.1(CH 芳基 ),139.3(C q ),142.5(C q ),149.1(CH 芳基 ),149.6(C q ),150.9(C q ),156.6(C q ).

[0892] MS(ESI+): m / z calculated value C 13 H 13 ClN6: 289.1 [M+H]+, measured value 289.2.

[0893] Example 3.22: Synthesis of 6-chloro-3-propyl-N-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.22)

[0894] To a solution of (2.7) (approximately 70% purity, 0.800 g, 2.42 mmol, 1.0 eq.) in THF (11.0 mL), Et3N (0.48 mL, 3.39 mmol, 1.4 eq.) and the corresponding amine (0.367 g, 3.39 mmol, 1.4 eq.) were added, and the mixture was refluxed for 1.5 h. After cooling, the solid was filtered off, washed with THF, and the filtrate was concentrated and purified by rapid chromatography using DCM / EtOAc (98 / 2 to 96 / 4) as eluent to give a white solid (3.22) (0.480 g, 65%).

[0895] 1 HNMR(400MHz,DMSO-d6)δ:0.96(t,J=7.4Hz,3H,CH3),1.80(h,J=7.4Hz,2H,CH2),2.97(t,J=7.5Hz,2H,CH2),4.58–4.81(m,2H,CH 2苄基 ),6.16(s,1H,H 芳基 ),7.31(dd,J=7.5,4.9Hz,1H,H 芳基 ), 7.38 (d, J = 7.9 Hz, 1H, H) 芳基 ),7.78(td,J=7.7,1.8Hz,1H,H 芳基 ),8.55(dd,J=5.2,1.8Hz,1H,H 芳基 ),8.96(s,1H,NH 苄基 ).

[0896] 13 CNMR(101MHz,DMSO-d6)δ:13.6(CH3),19.4(CH2),25.4(CH2),47.2(CH 2苄基 ),91.8(CH 芳基 ),121.4(CH 芳基 ),122.6(CH 芳基 ),137.0(CH 芳基 ),139.2(C q ),142.5(C q ),149.1(CH 芳基 ),149.5(C q ),149.8(C q ),156.6(C q ).

[0897] MS(ESI+): m / z calculated value C 14 H 15 ClN6: 303.1 [M+H]+, measured value 303.3.

[0898] Example 3.23: Synthesis of 3-tert-butyl-6-chloro-N-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.23)

[0899] To a solution of (1.2) (2.000 g, 7.84 mmol, 1.0 eq.) in anhydrous dioxane (31.0 mL), the corresponding hydrazide (1.033 g, 8.62 mmol, 1.1 eq.) and AcOH (0.50 mL, 8.62 mmol, 1.1 eq.) were added, and the mixture was refluxed for 17 hours. After cooling, the reaction mixture was poured into saturated NaHCO3 (100.0 mL) and EtOAc (60.0 mL). The two-phase mixture was stirred vigorously for 10 minutes, and then the layers were separated. The aqueous layer was extracted twice with EtOAc (2 x 50.0 mL), and the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (97 / 3 to 93 / 7) as eluent to give a white solid (3.23) (0.880 g, 35%).

[0900] 1 HNMR(400MHz,DMSO-d6)δ:1.50(s,9H,3xCH 3叔丁基 ), 4.67 (d, J = 6.9 Hz, 2H, CH 2苄基 ),6.15(s,1H,H 芳基 ), 7.30(dd, J = 7.5, 4.9 Hz, 1H, H 芳基), 7.38 (d, J = 7.8 Hz, 1H, H) 芳基 ),7.78(td,J=7.7,1.8Hz,1H,H 芳基 ), 8.49–8.63(m,1H,H) 芳基 ),8.96(s,1H,NH 苄基 ).

[0901] 13 CNMR(101MHz,DMSO-d6)δ:27.0(3xCH 3叔丁基 ),32.4(C q叔丁基 ),47.2(CH 2苄基 ),91.5(CH 芳基 ),121.4(CH 芳基 ),122.6(CH 芳基 ),137.1(CH 芳基 ),140.2(CH 芳基 ),142.5(C q ),148.7(C q ),149.1(C q ),155.2(C q ),156.7(C q ).

[0902] MS(ESI+): m / z calculated value C 15 H 17 ClN6: 317.13 [M+H]+, measured value 317.3.

[0903] Example 3.24: Synthesis of 6-chloro-3-cyclopropyl-N-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.24)

[0904] To a solution of (1.2) (4.000 g, 15.68 mmol, 1.0 eq.) in dioxane (52.0 mL), the corresponding hydrazide (1.884 g, 18.82 mmol, 1.2 eq.) and AcOH (1.00 mL, 17.25 mmol, 1.1 eq.) 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 form a solid precipitate, which was then concentrated and purified directly by rapid chromatography using DCM / MeOH (98 / 2 to 95 / 5) as the eluent to give a light rose-colored solid (3.24) (1.620 g, 34%).

[0905] Rf(DCM / MeOH,94 / 6):0.28

[0906] 1 HNMR(400MHz,DMSO-d6)δ:1.02–1.23(m,4H,2xCH 2环丙基 ),2.32(td,J=8.2,4.3Hz,1H,H 环丙基 ), 4.67 (d, J = 6.0 Hz, 2H, CH) 2苄基 ),6.15(s,1H,H 芳基 ), 7.30(dd, J = 7.4, 4.9 Hz, 1H, H 芳基 ), 7.37 (d, J = 7.8 Hz, 1H, H 芳基 ), 7.78(t, J = 7.7 Hz, 1H, H 芳基 ), 8.55 (d, J = 4.9 Hz, 1H, H 芳基 ),8.94(s,1H,NH 苄基 ).

[0907] 13 CNMR (101MHz, DMSO-d6) δ: 4.8 (CH 环戊基 ),7.1(2xCH 2环戊基 ),47.2(CH 2苄基 ),91.8(CH 芳基 ),121.4(CH 芳基 ),122.6C(H 芳基 ),137.0(CH 芳基 ),139.3(C q ),142.4(C q ),149.1(CH 芳基 ),149.6(C q ),151.4(C q ),156.6(C q ).

[0908] MS(ESI+): m / z calculated value C 14 H 13 ClN6: 301.1 [M+H]+, measured value 301.2.

[0909] Example 3.25: Synthesis of 6-chloro-3-cyclobutyl-N-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.25)

[0910] In a 10–20 mL sealed tube equipped with a stir bar, (1.2) (1.900 g, 7.45 mmol, 1.0 eq.), dioxane (15.0 mL), the corresponding hydrazide (0.984 g, 8.19 mmol, 1.1 eq.), and AcOH (0.47 mL, 8.19 mmol, 1.1 eq.) were loaded. The vial was sealed and placed on a heating block, and heated at 115 °C for 23 hours. After cooling, the mixture was poured into saturated NaHCO3 (20.0 mL), followed by the addition of water (40.0 mL). The aqueous layer mixture was extracted three times with EtOAc (3 x 30 mL), and the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using EtOAc (100%) as the eluent to give a white solid (3.25) (0.550 g, 23%).

[0911] Rf(EtOAc,100%):0.14

[0912] 1 HNMR(400MHz,DMSO-d6)δ:1.91–2.03(m,1H,H (CH2环丁) ),2.12(dq,J=10.8,8.6Hz,1H,H (CH2环丁) ),2.43(ddd,J=12.2,6.2,2.9Hz,4H,2xCH 2环丁 ), 3.95 (p, J = 8.4 Hz, 1H, H 环丁 ),4.68(s,2H,CH 2苄基 ),6.14(s,1H,H 芳基 ), 7.30(dd, J = 7.5, 4.9 Hz, 1H, H 芳基 ), 7.38 (d, J = 7.9 Hz, 1H, H) 芳基 ),7.78(td,J=7.7,1.8Hz,1H,H 芳基 ), 8.55 (d, J = 5.4 Hz, 1H, H 芳基 ),8.97(s,1H,NH 苄基 ).

[0913] 13 CNMR (101MHz, DMSO-d6)δ:ND

[0914] MS(ESI+): m / z calculated value C 15 H 15 ClN6: 315.1 [M+H]+, measured value 315.3.

[0915] Example 3.26: Synthesis of 6-chloro-3-cyclopentyl-N-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.26)

[0916] To a solution of (1.2) (4.000 g, 15.68 mmol, 1.0 eq.) in dioxane (52 mL), the corresponding hydrazide (1.884 g, 18.82 mmol, 1.2 eq.) and AcOH (1.00 mL, 17.25 mmol, 0.1 eq.) 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 form a solid precipitate, which was then concentrated and purified directly by rapid chromatography using DCM / MeOH (94 / 6) as the eluent to give a light rose-colored solid (3.26) (1.620 g, 34%).

[0917] 1 HNMR(400MHz,DMSO-d6)δ:1.64–1.85(m,4H,2xCH 2环戊 ),1.93(dq,J=11.9,7.2Hz,2H,CH 2环戊 ),2.10(qd,J=11.8,9.6,6.5Hz,2H,CH 2环戊 ), 3.53 (p, J = 8.0 Hz, 1H, CH) 环戊 ), 4.60–4.76 (s, 2H, CH) 2苄基 ),6.15(s,1H,H 芳基 ), 7.30(dd, J = 7.5, 4.8 Hz, 1H, H 芳基 ), 7.38 (d, J = 7.8 Hz, 1H, H) 芳基 ),7.78(td,J=7.7,1.8Hz,1H,H 芳基 ),8.51–8.61(m,1H,H 芳基 ),8.95(s,1H,NH 苄基 ).

[0918] 13 CNMR (101MHz, DMSO-d6)δ:ND

[0919] MS(ESI+): m / z calculated value C 16 H 17 ClN6: 329.1 [M+H]+, measured value 329.3.

[0920] Example 3.27: Synthesis of 6-chloro-3-cyclohexyl-N-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.27)

[0921] In a 10–20 mL sealed tube equipped with a stir bar, (1.2) (1.500 g, 5.88 mmol, 1.0 eq.), dioxane (17.8 mL), the corresponding acid hydrazide (0.939 g, 6.47 mmol, 1.1 eq.), and AcOH (0.37 mL, 6.47 mmol, 1.1 eq.) were loaded. The vial was sealed and placed on a heating block and heated at 110 °C for 21 hours. The reaction mixture was cooled and MeOH (3.0 mL) was added. The mixture was concentrated with SiO2 to form a solid deposit and purified by rapid chromatography using DCM / MeOH (97 / 3 to 93 / 7) as eluent to give a white solid (3.27) (0.800 g, 40%).

[0922] 1 HNMR(400MHz,DMSO-d6)δ:1.39(dt,J=36.4,12.5Hz,3H,H (CH2)环己基 &CH 2环己基 ),1.67(dt,J=24.1,12.5Hz,3H,H (CH2)环己基 &CH 2环己基 ), 1.81(d, J = 12.3 Hz, 2H, CH 2环己基 ), 2.01(d, J = 12.6 Hz, 2H, CH 2环己基 ), 3.15(t, J = 11.5 Hz, 1H, H 环己基 ),4.68(s,2H,CH 2苄基 ),6.14(s,1H,H 芳基 ), 7.30(dd, J = 7.5, 4.9 Hz, 1H, H 芳基 ), 7.38 (d, J = 7.7 Hz, 1H, H) 芳基 ),7.78(td,J=7.7,3.7Hz,1H,H 芳基 ), 8.51–8.63(m,1H,H) 芳基 ),8.97(s,1H,NH 苄基 ).

[0923] 13 CNMR(101MHz,DMSO-d6)δ:25.3(2xCH 2环己基 ),25.5(CH 2环己基 ),29.8(2xCH 2环己基 ),33.3(CH 环己基),47.2(CH 2苄基 ),91.8(CH 芳基 ),121.4(CH 芳基 ),122.6(CH 芳基 ),129.5(C q ),137.1(CH 芳基 ),139.2(C q ),142.5(C q ),149.1(CH 芳基 ),149.4(C q ),153.2(C q ).

[0924] MS(ESI+): m / z calculated value C 17 H 19 ClN6: 343.1 [M+H]+, measured value 343.3.

[0925] Example 3.28: Synthesis of 6-chloro-3-phenyl-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.28)

[0926] In a 10–20 mL sealed tube equipped with a stir bar, (1.2) (1.500 g, 5.88 mmol, 1.0 eq.), dioxane (17.8 mL), the corresponding acid hydrazide (0.899 g, 6.47 mmol, 1.1 eq.), and AcOH (0.37 mL, 6.47 mmol, 1.1 eq.) were loaded. The vial was sealed and placed on a heating block and heated at 110 °C for 21 hours. The reaction mixture was cooled and MeOH (3.0 mL) was added. The mixture was concentrated with SiO2 to form a solid deposit and purified by rapid chromatography using DCM / MeOH (97 / 3 to 93 / 7) as eluent to give a beige solid (3.28) (0.750 g, 38%).

[0927] 1 HNMR(400MHz,DMSO-d6)δ:4.73(d,J=5.9Hz,2H,CH 2苄基 ),7.32(dd,J=7.5,4.9Hz,1H,H 芳基 ), 7.42 (d, J = 7.8 Hz, 1H, H 芳基 ),7.59(dt,J=13.6,7.1Hz,3H,3xH 芳基 ), 7.80(t, J = 7.7 Hz, 1H, H 芳基 ),8.32(d,J=7.6Hz,2H,H 芳基), 8.57 (d, J = 4.9 Hz, 1H, H 芳基 ),9.11(s,1H,NH 苄基 ).

[0928] 13 CNMR (101MHz, DMSO-d6)δ:ND

[0929] MS(ESI+): m / z calculated value C 17 H 13 ClN6: 337.1 [M+H]+, measured value 337.3.

[0930] Example 3.29: Synthesis of 6-chloro-N-(2-pyridinylmethyl)-3-sec-butyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.29)

[0931] To a solution of (2.2) (0.565 g, 2.31 mmol, 1.0 eq.) in THF (23.0 mL), the corresponding amine (0.44 mL, 3.00 mmol, 1.3 eq.) and DIPEA (0.61 mL, 3.46 mmol, 1.5 eq.) 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 neutral pH, then washed with Et2O, and dried under vacuum to give a white solid (3.29) (0.600 g, 82%).

[0932] 1 HNMR(400MHz,DMSO-d6)δ:0.84(t,J=7.4Hz,3H,CH 3-CH2 ), 1.35(d, J = 7.0 Hz, 3H, CH 3-CH ),1.82(ddq,J=68.8,13.8,7.1Hz,2H,CH 2-CH3 ), 3.24–3.31(m,1H,H C-CH3 ), 4.67 (d, J = 5.7 Hz, 2H, CH 2苄基 ),6.15(s,1H,H 芳基 ),7.31(dd,J=7.5,4.9Hz,1H,H 芳基 ), 7.39 (d, J = 7.9 Hz, 1H, H 芳基 ),7.78(td,J=7.7,1.8Hz,1H,H 芳基 ), 8.55 (d, J = 4.9 Hz, 1H, H 芳基 ),8.98(s,1H,NH 苄基 ).

[0933] 13 CNMR(101MHz,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苄基 ),91.8(CH 芳基 ),121.5(CH 芳基 ),122.6(CH 芳基 ),137.1(CH 芳基 ),139.3(C q ),142.5(C q ),149.1(CH 芳基 ),149.4(C q ),153.2(C q ),156.6(C q ).

[0934] MS(ESI+): m / z calculated value C 15 H 17 ClN6: 317.8 [M+H]+, measured value 317.2.

[0935] 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)

[0936] To a solution of (2.3) (0.510 g, 1.97 mmol, 1.0 eq.) in THF (20.0 mL), the corresponding amine (0.38 mL, 2.56 mmol, 1.3 eq.) and DIPEA (0.52 mL, 2.95 mmol, 1.5 eq.) 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 neutral pH, then washed with Et2O, and dried under vacuum to give a white solid (3.30) (0.580 g, 89%).

[0937] 1 HNMR(400MHz,DMSO-d6)δ:0.77(t,J=7.4Hz,6H,2xCH 3-CH2 ),1.83(ddt,J=37.0,13.5,6.9Hz,4H,2xCH 2-CH3 ), 3.10–3.24(m,1H,H) 异戊), 4.67 (d, J = 5.8 Hz, 2H, CH) 2苄基 ),6.15(s,1H,H 芳基 ),7.31(dd,J=7.4,4.9Hz,1H,H 芳基 ), 7.40 (d, J = 7.9 Hz, 1H, H 芳基 ),7.79(td,J=7.7,1.7Hz,1H,H 芳基 ), 8.55 (d, J = 4.9 Hz, 1H, H 芳基 ),8.98(s,1H,NH 苄基 ).

[0938] 13 CNMR (101MHz, DMSO-d6)δ:ND

[0939] MS(ESI+): m / z calculated value C 16 H 19 ClN6: 331.1 [M+H]+, measured value 331.2.

[0940] Example 3.31: Synthesis of 6-chloro-3-isobutyl-N-(2-pyridinylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.31)

[0941] To a solution of (2.4) (0.290 g, 1.18 mmol, 1.0 eq.) in THF (11.0 mL), the corresponding amine (0.23 mL, 1.54 mmol, 1.3 eq.) and DIPEA (0.31 mL, 1.78 mmol, 1.5 eq.) were added, and the mixture was refluxed for 1 hour. After cooling, the precipitate was filtered through Et2O (30.0 mL), washed with water, ground in Et2O, and then dried under vacuum to give a white solid (3.31) (0.285 g, 76%).

[0942] 1 HNMR(400MHz,DMSO-d6)δ:0.94(d,J=6.6Hz,6H,2xCH 3异丙基 ),2.21(hept,J=6.8Hz,1H,H 异丙基 ),2.89(d,J=7.2Hz,2H,CH 2-CH ),4.68(s,2H,CH 2苄基 ),6.16(s,1H,H 芳基 ),7.31(dd,J=7.5,4.9Hz,1H,H 芳基 ), 7.39 (d, J = 7.8 Hz, 1H, H 芳基),7.79(td,J=7.7,1.8Hz,1H,H 芳基 ), 8.55 (d, J = 4.7 Hz, 1H, H 芳基 ),8.95(s,1H,NH 苄基 ).

[0943] 13 CNMR (101MHz, DMSO-d6)δ:ND

[0944] MS(ESI+): m / z calculated value C 15 H 17 ClN6: 317.8 [M+H]+, measured value 317.2.

[0945] Example 3.32: Synthesis of 6-chloro-3-(2-pyridine)-N-(2-pyridinemethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.32)

[0946] In a 10–20 mL sealed tube equipped with a stir 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 loaded. The vial was sealed and placed on a heating block and heated at 110 °C for 19 hours. After cooling, MeOH (5.0 mL) and a 7 M NH₃ solution of MeOH (3.0 mL) were added. The mixture was then concentrated with SiO₂ to form a solid precipitate, which was directly purified by rapid chromatography using DCM / MeOH (98 / 2 to 90 / 10) as the eluent to give a yellow solid (3.32) (0.300 g, 18%).

[0947] Rf(DCM / MeOH,94 / 6):0.10

[0948] 1 HNMR(400MHz,DMSO-d6)δ:4.74(s,2H,CH 2苄基 ),6.32(s,1H,H 芳基 ), 7.32(dd, J = 7.5, 5.0 Hz, 1H, H 芳基 ), 7.43 (d, J = 7.9 Hz, 1H, H 芳基 ), 7.53–7.65 (m, 1H, H) 芳基 ),7.80(td,J=7.7,1.8Hz,1H,H 芳基 ),8.05(td,J=7.8,1.8Hz,1H,H 芳基), 8.23 ​​(d, J = 7.9 Hz, 1H, H 芳基 ), 8.57 (d, J = 4.9 Hz, 1H, H 芳基 ), 8.81(d, J = 4.9 Hz, 1H, H 芳基 ),9.13(s,1H,NH 苄基 ).

[0949] 13 CNMR (101MHz, DMSO-d6)δ:ND

[0950] MS(ESI+): m / z calculated value C 16 H 12 ClN7: 338.1 [M+H]+, measured value 338.2.

[0951] Example 3.33: Synthesis of 6-chloro-3-(3-pyridine)-N-(2-pyridinemethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.33)

[0952] In a 10–20 mL sealed tube equipped with a stir bar, (1.2) (1.250 g, 4.90 mmol, 1.0 eq.), dioxane (10.0 mL), the corresponding hydrazide (0.754 g, 5.39 mmol, 1.1 eq.), and PTSA·H₂O (0.946 g, 4.90 mmol, 1.0 eq.) were loaded. The vial was sealed and placed on a heating block and heated at 110 °C for 19 hours. After cooling, a MeOH solution of NH₃ 7N (2.80 mL, 19.6 mmol, 4.0 eq.) was added, and the mixture was concentrated with silica. Then, it was directly purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as the eluent to give a white solid (3.33) (0.275 g, 17%).

[0953] Rf(DCM / MeOH,94 / 6):0.25

[0954] 1 HNMR(400MHz,DMSO-d6)δ:4.74(s,2H,CH 2苄基 ), 6.34(s, 1H, H 芳基 ), 7.24–7.39(m,1H,H) 芳基 ), 7.42 (d, J = 7.9 Hz, 1H, H 芳基 ), 7.65(dd, J = 8.1, 4.9 Hz, 1H, H 芳基 ), 7.75–7.90 (m, 1H, H) 芳基 ), 8.57 (d, J = 4.8 Hz, 1H, H芳基 ), 8.64(dt, J = 8.1, 2.0 Hz, 1H, H 芳基 ), 8.74(dd, J = 4.8, 1.7 Hz, 1H, H 芳基 ),9.19(s,1H,NH 苄基 ), 9.44(d, J = 2.2 Hz, 1H, H 芳基 ).

[0955] 13 CNMR (101MHz, DMSO-d6)δ:ND

[0956] MS(ESI+): m / z calculated value C 16 H 12 ClN7: 338.1 [M+H]+, measured value 338.2.

[0957] Example 3.34: Synthesis of 6-chloro-3-(4-pyridine)-N-(2-pyridinemethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.34)

[0958] In a 10–20 mL sealed tube equipped with a stir bar, (1.2) (1.250 g, 4.90 mmol, 1.0 eq.), dioxane (10.0 mL), the corresponding hydrazide (0.778 g, 5.39 mmol, 1.1 eq.), and PTSA·H₂O (0.946 g, 4.90 mmol, 1.0 eq.) were loaded. The vial was sealed and placed on a heating block and heated at 110 °C for 19 hours. After cooling, a MeOH solution of NH₃ 7N (2.80 mL, 19.6 mmol, 4.0 eq.) was added, and the mixture was concentrated with silica. Then, it was directly purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as the eluent to give a white solid (3.34) (0.310 g, 19%).

[0959] Rf(DCM / MeOH,94 / 6):0.29

[0960] 1 HNMR(400MHz,DMSO-d6)δ:4.74(d,J=6.1Hz,2H,CH 2苄基 ),6.37(s,1H,H 芳基 ),7.32(dd,J=7.3,5.1Hz,1H,H 芳基 ), 7.42 (d, J = 7.8 Hz, 1H, H 芳基 ), 7.80 (dd, J = 8.2, 6.5 Hz, 1H, H 芳基 ), 8.23–8.38(m,2H,2xH)芳基 ), 8.56 (d, J = 4.9 Hz, 1H, H 芳基 ),8.72–8.92(m,2H,2xH 芳基 ),9.21(s,1H,NH 苄基 ).

[0961] 13 CNMR (101MHz, DMSO-d6)δ:ND

[0962] MS(ESI+): m / z calculated value C 16 H 12 ClN7: 338.1 [M+H]+, measured value 338.2.

[0963] 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)

[0964] To a solution of (2.1) (0.300 g, 1.30 mmol, 1.0 eq.) in THF (18.0 mL), 4-(aminomethyl)aniline dihydrochloride (0.512 g, 2.60 mmol, 2.0 eq.) and Et3N (1.28 mL, 9.09 mmol, 7.0 eq.) were added, and the mixture was refluxed for 2 hours. After cooling, the solid was filtered off, washed with THF, and the filtrate was concentrated. The solid was then purified directly by rapid chromatography using DCM / MeOH (98 / 2 to 96 / 4) as the eluent to give a pale yellow solid (3.35) (0.245 g, 60%).

[0965] Rf(DCM / MeOH,94 / 6):0.24

[0966] 1 HNMR(400MHz,DMSO-d6)δ:1.37(d,J=7.0Hz,6H,2xCH 3异丙基 ), 3.42(h, J = 6.9 Hz, 1H, H 异丙基 ), 4.37 (d, J = 6.3 Hz, 2H, CH 2苄基 ), 5.01(s, 2H, NH2), 6.10(s, 1H, H 芳基 ), 6.51(d, J = 8.4 Hz, 2H, 2xH 芳基 ), 7.05(d, J = 8.3 Hz, 2H, 2xH 芳基 ), 8.95(t, J = 6.2 Hz, 1H, NH 苄基 ).

[0967] 13CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基 ),45.0(CH 2苄基 ),91.3(CH 芳基 ),113.8(2xCH 芳基 ),124.0(C q ),128.2(2xCH 芳基 ),139.5(C q ),142.1(C q ),147.9(C q ),149.4(C q ),153.9(C q ).

[0968] MS(ESI+): m / z calculated value C 15 H 17 ClN6: 317.1 [M+H]+, measured value 317.2.

[0969] 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)

[0970] To a solution of (2.1) (0.300 g, 1.30 mmol, 1.0 eq.) in THF (18.0 mL), 3-(aminomethyl)aniline (0.320 g, 2.60 mmol, 2.0 eq.) and Et3N (0.37 mL, 2.60 mmol, 2.0 eq.) were added, and the mixture was refluxed for 2 hours. After cooling, the solid was filtered off, washed with THF, and the filtrate was concentrated. The solid was then purified directly by rapid chromatography using DCM / MeOH (98 / 2 to 96 / 4) as the eluent to give a yellow solid (3.36) (0.280 g, 68%).

[0971] Rf(DCM / MeOH, 96 / 4): 0.27

[0972] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.42 (hept, J = 6.9 Hz, 1H, H 异丙基 ), 4.43 (d, J = 6.4 Hz, 2H, CH 2苄基 ), 5.06(s, 2H, NH2), 6.02(s, 1H, H 芳基 ), 6.40–6.56(m,3H,3xH)芳基 ), 6.96(t, J = 7.7 Hz, 1H, H 芳基 ),9.03(s,1H,NH 苄基 ).

[0973] 13 CNMR (101MHz, DMSO-d6)δ:ND

[0974] MS(ESI+): m / z calculated value C 15 H 17 ClN6: 317.13 [M+H]+, measured value 317.3.

[0975] 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)

[0976] To a solution of (1.12) (4.000 g, 14.86 mmol, 1.0 eq.) in anhydrous dioxane (60.0 mL), isobutyric acid hydrazide (1.840 g, 17.84 mmol, 1.2 eq.) and AcOH (0.86 mL, 14.86 mmol, 1.0 eq.) were added, and the mixture was refluxed for 18 hours. After cooling, the reaction mixture was concentrated, and the residue was ground in water, filtered, and washed with water to neutral pH. The solid was dissolved in DCM and MeOH, the filtrate was concentrated, and purified by rapid chromatography using DCM / MeOH (97 / 3 to 95 / 5) as eluent to give (3.37) (0.600 g, 13%) as a pale yellow solid.

[0977] Rf(DCM / MeOH,94 / 6):0.41

[0978] 1 HNMR(400MHz,DMSO-d6)δ:1.37(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.42 (p, J = 6.9 Hz, 1H, H 异丙基 ),4.39(s,2H,CH 2苄基 ), 5.17(s, 2H, NH2), 6.07(s, 1H, H 芳基 ), 6.51(t, J = 7.4 Hz, 1H, H 芳基 ), 6.65 (d, J = 7.9 Hz, 1H, H 芳基 ), 6.97(td, J = 7.6, 1.6 Hz, 1H, H 芳基 ), 7.09(dd, J = 7.6, 1.6 Hz, 1H, H 芳基),8.92(s,1H,NH 苄基 ).

[0979] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基 ),42.4(CH 2苄基 ),91.6(CH 芳基 ),115.1(CH 芳基 ),115.9(CH 芳基 ),119.3(C q ),128.1(CH 芳基 ),128.2(CH 芳基 ),139.5(C q ),142.3(C q ),146.3(C q ),149.4(C q ),154.0(C q ).

[0980] MS(ESI+): m / z calculated value C 15 H 17 ClN6: 317.1 [M+H]+, measured value 317.3.

[0981] 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)

[0982] Isobutyric acid hydrazide (1.863 g, 18.06 mmol, 1.1 eq.) and AcOH (1.04 mL, 18.06 mmol, 1.1 eq.) were added to a suspension of (1.15) (4.600 g, 16.42 mmol, 1.0 eq.) in anhydrous dioxane (66 mL), and the mixture was refluxed for 22 hours. After cooling, MeOH (10.0 mL) was added, and the mixture was concentrated with SiO2 to form a solid precipitate. The precipitate was then purified directly by rapid chromatography using DCM / EtOAc (98 / 2 to 96 / 4) as the eluent to give a white solid (3.38) (1.390 g, 26%).

[0983] Rf(DCM / EtOAc, 98 / 2): 0.23

[0984] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=7.0Hz,6H,2xCH 3异丙基), 3.02(t, J = 5.9 Hz, 2H, CH 2-CH2-N ), 3.44 (hept, J = 6.9 Hz, 1H, H 异丙基 ),4.42(s,2H, N -CH 2-CH2 ),5.18(s,2H,CH 2-N ), 6.40(s, 1H, H 芳基 ),7.24(td,J=4.9,4.5,2.6Hz,4H,4xH 芳基 ).

[0985] 13 CNMR(101MHz,DMSO-d6)δ:19.7(2xCH 3异丙基 ),24.4(CH 异丙基 ),28.0(CH 2-CH2-N ),45.9( N- CH 2-CH2 ),49.3(CH 2-N ),94.0(CH 芳基 ),126.3(CH 芳基 ),126.3(CH 芳基 ),126.8(CH 芳基 ),128.3(CH 芳基 ),134.5(C q ),140.4(C q ),142.7(C q ),149.4(C q ),153.6(C q ).

[0986] MS(EI-MS): m / z calculated value C 17 H 18 ClN5: 328.1 [M+H]+, measured value 328.2.

[0987] Example 3.39: Synthesis of 6-chloro-8-isoindoline-2-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (3.39)

[0988] To a solution of (2.1) (0.350 g, 1.52 mmol, 1.0 eq.) in THF (15.0 mL), the corresponding amine hydrochloride (0.340 g, 2.12 mmol, 1.4 eq.) and Et3N (0.64 mL, 4.54 mmol, 3.0 eq.) were added, and the mixture was refluxed for 1.5 h. After cooling, the precipitate was filtered, washed with THF, and the filtrate was concentrated and purified by rapid chromatography using DCM / MeOH (100 / 0 to 98 / 2) as the eluent. The impurity fraction was concentrated, and the residue was then ground in Et2O, filtered, washed with a small amount of Et2O, and dried under vacuum to give a white solid (3.39) (0.280 g, 59%).

[0989] 1 HNMR(400MHz,DMSO-d6)δ:1.40(d,J=7.0Hz,6H,2xCH 3异丙基 ), 3.46 (hept, J = 6.9 Hz, 1H, H 异丙基 ),4.87(s,2H,CH2),5.61(s,2H,CH2),6.10(s,1H,H 芳基 ),7.37(dd,J=5.6,3.2Hz,2H,2xH 芳基 ), 7.44(s, 1H, H 芳基 ),7.50(s,1H,H 芳基 ).

[0990] 13 CNMR(101MHz,DMSO-d6)δ:19.7(2xCH 3异丙基 ),24.4(CH 异丙基 ), 54.9(CH2), 57.4(CH2), 93.4(CH 芳基 ),122.5(CH 芳基 ),122.8(CH 芳基 ),127.6(2xCH 芳基 ),134.8(C q ),136.7(C q ),140.2(C q ),141.5(C q ),149.3(C q ),153.6(C q ).

[0991] MS(EI-MS): m / z calculated value C 16 H 16 ClN5: 314.1 [M+H]+, measured value 314.3.

[0992] 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)

[0993] To a solution of (2.1) (0.250 g, 1.05 mmol, 1.0 eq.) in 13.0 mL of THF, the corresponding amine hydrochloride (0.273 g, 1.57 mmol, 1.5 eq.) and Et3N (0.44 mL, 3.15 mmol, 3.0 eq.) 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 neutral pH, and the solid was dissolved in EtOAc. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1 to 95 / 5) as eluent to give a beige solid (3.40) (0.300 g, 87%).

[0994] 1 HNMR(400MHz,DMSO-d6)δ:1.39(d,J=6.9Hz,6H,2xCH 3异丙基 ),2.19(dt,J=17.4,8.0Hz,1H,H (CH2)茚满基 ),2.55(s,1H,H (CH2)茚满基 ), 2.85(dt, J = 16.2, 8.3 Hz, 1H, H (CH2)茚满基 ),3.03(ddd,J=15.9,8.9,3.1Hz,1H,H (CH2)茚满基 ),3.45(hept,J=7.7,7.2Hz,1H,H 异丙基 ),5.41(s,1H,H 茚满基 ), 6.48(s, 1H, H 芳基 ), 7.14–7.34(m,4H,4xH) 芳基 ),8.75(s,1H,NH 茚满基 ).

[0995] 13 CNMR(101MHz,DMSO-d6)δ:19.9(2xCH 3异丙基 ),24.4(CH 异丙基 ),29.8(CH 2茚满 ),31.6(CH 2茚满 ),57.3(CH 茚满 ),91.4(CH 芳基 ),123.8(CH 芳基 ),124.8(CH 芳基 ),126.4(CH芳基 ),127.8(CH 芳基 ),139.4(C q ),142.3(C q ),142.7(C q ),143.1(C q ),149.8(C q ),154.0(C q ).

[0996] MS(ESI+): m / z calculated value C 17 H 18 ClN5: 328.1 [M+H]+, measured value 328.3.

[0997] Example 3.41: Synthesis of 6-chloro-N-(1H-indol-2-ylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.41)

[0998] In a 10–20 mL sealed tube equipped with a stir bar, (1.10) (1.100 g, 3.57 mmol, 1.0 eq.), dioxane (15.0 mL), isobutyric acid hydrazide (0.441 g, 4.28 mmol, 1.2 eq.), and AcOH (0.23 mL, 3.92 mmol, 1.1 eq.) were loaded. The vial was sealed and placed on a heating block and heated at 100 °C for 17 hours. After cooling, MeOH (10.0 mL) was added, and the mixture was stirred vigorously for 5 minutes. The mixture was then concentrated with SiO2 to form a solid precipitate, which was directly purified by rapid chromatography using DCM / MeOH (97 / 3 to 94 / 6) as the eluent to give a beige solid (3.41) (0.270 g, 22%).

[0999] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.43 (hept, J = 7.1 Hz, 1H, H 异丙基 ),4.74(s,2H,CH 2苄基 ),6.29(s,1H,H 芳基 ), 6.36 (d, J = 2.0 Hz, 1H, H 芳基 ), 6.94(t, J = 7.4 Hz, 1H, H 芳基 ), 7.00–7.08 (m, 1H, H) 芳基 ), 7.33 (d, J = 8.0 Hz, 1H, H 芳基 ), 7.45 (d, J = 7.8 Hz, 1H, H 芳基), 8.89(s, 1H, NH), 10.99(s, 1H, NH) 吲哚 ).

[1000] 13 CNMR (101MHz, DMSO-d6)δ:ND

[1001] MS(ESI+): m / z calculated value C 17 H 17 ClN6: 341.1 [M+H]+, measured value 341.3.

[1002] 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)

[1003] To a solution of dioxane (50.0 mL) containing (1.13 g) (4.100 g, 12.32 mmol, 1.0 eq.), isobutyric acid hydrazide (1.524 g, 14.77 mmol, 1.2 eq.) and AcOH (0.78 mL, 13.54 mmol, 1.1 eq.) was added, and the mixture was refluxed for 18 hours. After cooling, the mixture was poured into water (200.0 mL), and the precipitate was ground, filtered, and washed with water to a neutral pH. The solid was ground in EtOAc, filtered, and vacuum dried to give a pale yellow solid (3.42 g) (2.400 g, 51%).

[1004] 1 HNMR(400MHz,DMSO-d6)δ:1.37(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.42 (hept, J = 7.0 Hz, 1H, H 异丙基 ), 4.40–4.73 (m, 2H, CH) 2苄基 ),6.15(s,1H,H 芳基 ), 7.35(d, J=8.2Hz, 2H, 2xH 芳基 ), 7.54(d, J = 8.4 Hz, 2H, 2xH 芳基 ),9.11(s,1H,NH 苄基 ).

[1005] 13 CNMR (101MHz, DMSO-d6)δ:ND

[1006] MS(ESI+): m / z calculated value C 15 H 15 BrClN5: 380.0 [M+H]+, measured value 380.2.

[1007] Example 3.43: Synthesis of 6-chloro-3-isopropyl-N-(2-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.43)

[1008] To a solution of (1.16) (4.000 g, 14.92 mmol, 1.0 eq.) in anhydrous dioxane (60 mL), isobutyric acid hydrazide (1.847 g, 17.90 mmol, 1.2 eq.) was added, followed by AcOH (0.95 mL, 16.41 mmol, 1.1 eq.), and the mixture was refluxed for 4 hours. After cooling, the mixture was concentrated, and the residue was then suspended in water (120 mL) and ground. The solid was filtered off, washed with water to neutral pH, dissolved in ethanol, concentrated under vacuum, and dried to give the target compound (3.43) (2.350 g, 50%) as a white solid.

[1009] 1 HNMR(400MHz,DMSO-d6)δ:1.37(d,J=7.0Hz,6H,2xCH 3异丙基 ),2.94(t,J=7.3Hz,2H,CH 2-CH2-NH ), 3.42 (p, J = 6.9 Hz, 1H, H 异丙基 ), 3.52–3.68 (m, 2H, CH) 2-NH ),6.21(s,1H,H 芳基 ),7.20(tt,J=5.6,2.9Hz,1H,H 芳基 ), 7.25–7.38(m, 4H, 4xH) 芳基 ),8.51(s,1H,NH).

[1010] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基 ),33.8(CH 2-CH2-NH ),43.5(CH 2-NH ),91.0(CH 芳基 ),126.2(CH 芳基 ),128.3(2xCH 芳基 ),128.9(2xCH 芳基 ),138.9(C q ),139.4(C q ),142.2(C q ),149.7(C q ),153.9(C q ).

[1011] MS(ESI+): m / z calculated value C 16 H 18 ClN5: 316.1 [M+H]+, measured value 316.2.

[1012] Example 3.44: Synthesis of 6-chloro-3-isopropyl-N-[2-(2-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.44)

[1013] To a solution of (2.1) (0.300 g, 1.30 mmol, 1.0 eq.) in THF (3.9 mL), the corresponding amine (0.190 g, 1.56 mmol, 1.2 eq.) and DIPEA (0.27 mL, 1.56 mmol, 1.2 eq.) 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 and purified by rapid chromatography using DCM / MeOH (98 / 2 to 95 / 5) as eluent to give a beige solid (3.44) (0.270 g, 66%).

[1014] 1 HNMR(400MHz,DMSO-d6)δ:1.37(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.09(t, J = 7.1 Hz, 2H, CH 2-CH2-NH ), 3.42(h, J = 7.0 Hz, 1H, H 异丙基 ), 3.71(d, J = 6.9 Hz, 2H, CH 2-NH ),6.18(s,1H,H 芳基 ), 7.23(dd, J = 7.5, 4.9 Hz, 1H, H 芳基 ), 7.34 (d, J = 7.8 Hz, 1H, H 芳基 ), 7.70(t, J = 7.7 Hz, 1H, H 芳基 ), 8.51(d, J = 4.9 Hz, 1H, H 芳基 ),8.56(s,1H,NH -CH2 ).

[1015] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基 ),35.9(CH 2-CH2-NH ),41.8(CH 2-NH ),91.0(CH 芳基 ),121.7(CH 芳基 ),123.5(CH芳基 ),136.5(CH 芳基 ),139.4(C q ),142.2(C q ),149.1(CH 芳基 ),149.6(C q ),153.9(C q ),158.6(C q ).

[1016] MS(ESI+): m / z calculated value C 15 H 17 ClN6: 317.13[M+H]+, measured value 317.2.

[1017] Example 3.45: Synthesis of 6-chloro-3-isopropyl-N-[2-(3-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.45)

[1018] To a solution of (2.1) (0.250 g, 1.08 mmol, 1.0 eq.) in THF (10.0 mL), the corresponding amine (0.181 g, 1.41 mmol, 1.3 eq.) and DIPEA (0.28 mL, 1.62 mmol, 1.5 eq.) were added, and the mixture was refluxed for 3 hours. After cooling, Et2O (30.0 mL) was added, the precipitate was filtered, washed with water, ground in Et2O, and then dried under vacuum to give a white solid (3.45) (0.260 g, 76%).

[1019] Rf(DCM / MeOH,94 / 6):0.24

[1020] 1 HNMR(400MHz,DMSO-d6)δ:1.37(d,J=6.9Hz,6H,2xCH 3异丙基 ),2.96(t,J=7.1Hz,2H,CH 2-CH2-NH ), 3.41(hept, J = 7.0 Hz, 1H, H 异丙基 ), 3.62 (d, J = 7.1 Hz, 2H, CH 2-NH ),6.26(s,1H,H 芳基 ),7.31(dd,J=7.9,4.8Hz,1H,H 芳基 ), 7.72 (d, J = 7.7 Hz, 1H, H 芳基 ), 8.41(d, J = 4.8 Hz, 1H, H 芳基 ), 8.49(d, J = 2.2 Hz, 1H, H 芳基),8.55(s,1H,NH -CH2 ).

[1021] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基 ),30.9(CH 2-CH2-NH ),42.9(CH 2-NH ),91.1(CH 芳基 ),123.3(CH 芳基 ),134.4(C q ),136.4(CH 芳基 ),139.4(C q ),142.2(C q ),147.5(CH 芳基 ),149.7(C q ),150.0(CH 芳基 ),153.9(C q ).

[1022] MS(ESI+): m / z calculated value C 15 H 17 ClN6: 317.13[M+H]+, measured value 317.2.

[1023] Example 3.46: Synthesis of 6-chloro-3-isopropyl-N-[2-(4-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.46)

[1024] To a solution of (2.1) (0.250 g, 1.08 mmol, 1.0 eq.) in THF (10.0 mL), the corresponding amine (0.181 g, 1.41 mmol, 1.3 eq.) and DIPEA (0.28 mL, 1.62 mmol, 1.5 eq.) were added, and the mixture was refluxed for 3 hours. After cooling, Et2O (30.0 mL) was added, the precipitate was filtered, washed with water, ground in Et2O, and then dried under vacuum to give a white solid (3.46) (0.285 g, 82%).

[1025] Rf(DCM / MeOH,94 / 6):0.27

[1026] 1 HNMR(400MHz,DMSO-d6)δ:1.37(d,J=6.9Hz,6H,2xCH 3异丙基 ),2.97(t,J=7.1Hz,2H,CH 2-CH2-NH), 3.42 (p, J = 7.0 Hz, 1H, H 异丙基 ), 3.56–3.75 (m, 2H, CH) 2-NH ),6.29(s,1H,H 芳基 ), 7.33(d, J=5.1Hz, 2H, 2xH 芳基 ),8.44–8.51(m,2H,2xH 芳基 ),8.54(s,1H,NH -CH2 ).

[1027] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基 ),32.9(CH 2-CH2-NH ),42.2(CH 2-NH ),91.2(CH 芳基 ),124.4(2xCH 芳基 ),139.3(C q ),142.2(C q ),147.9(C q ),149.4(2xCH 芳基 ),149.7(C q ),153.9(C q ).

[1028] MS(ESI+): m / z calculated value C 15 H 17 ClN6: 317.13[M+H]+, measured value 317.2.

[1029] Example 3.47: Synthesis of 6-chloro-3-cyclopropyl-N-[2-(2-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.47)

[1030] To a solution of (2.5) (0.125 g, 0.51 mmol, 1.0 eq.) in THF (2.5 mL), the corresponding amine (0.080 g, 0.62 mmol, 1.2 eq.) and Et3N (0.15 mL, 1.04 mmol, 2.0 eq.) were added, and the mixture was refluxed for 1.5 h. 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, washed with water, then ground in Et2O, filtered, washed with Et2O, and dried under vacuum to give a beige solid (3.47) (0.130 g, 80%).

[1031] Rf(DCM / MeOH, 96 / 4): 0.14

[1032] 1 HNMR(400MHz,DMSO-d6)δ:1.03–1.18(m,4H,2xCH 2环丙基 ),2.31(tt,J=8.2,5.2Hz,1H,H 环丙基 ),3.09(t,J=7.1Hz,2H,CH2),3.64–3.81(m,2H,CH2),6.16(s,1H,H 芳基 ),7.23(dd,J=7.6,4.8Hz,1H,H 芳基 ), 7.33 (d, J = 7.8 Hz, 1H, H 芳基 ),7.70(td,J=7.7,1.9Hz,1H,H 芳基 ), 8.46–8.61(m,2H,NH&H) 芳基 ).

[1033] 13 CNMR (101MHz, DMSO-d6) δ: 4.8 (CH 环丙基 ),7.2(2xCH 2环丙基 ),35.9(CH2),41.9(CH2),91.0(CH 芳基 ),121.7(CH 芳基 ),123.5(CH 芳基 ),136.5(CH 芳基 ),139.3(C q ),142.2(C q ),149.1(CH 芳基 ),149.8(C q ),151.3(C q ),158.6(C q ).

[1034] MS(ESI+): m / z calculated value C 15 H 15 ClN6: 315.1 [M+H]+, measured value 315.1.

[1035] Example 3.48: Synthesis of 6-chloro-3-cyclopropyl-N-[2-(3-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.48)

[1036] To a solution of (2.5) (0.125 g, 0.51 mmol, 1.0 eq.) in THF (2.5 mL), the corresponding amine (0.080 g, 0.62 mmol, 1.2 eq.) and Et3N (0.15 mL, 1.04 mmol, 2.0 eq.) were added, and the mixture was refluxed for 1.5 h. 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, washed with water, then ground in Et2O, filtered, washed with Et2O, and dried under vacuum to give a beige solid (3.48) (0.127 g, 80%).

[1037] Rf(DCM / MeOH,94 / 6):0.20

[1038] 1 HNMR(400MHz,DMSO-d6)δ:1.00–1.20(m,4H,2xCH 2环丙基 ),2.31(tt,J=8.1,5.3Hz,1H,H 环丙基 ),2.96(t,J=7.1Hz,2H,CH2),3.49–3.76(m,2H,CH2),6.24(s,1H,H 芳基 ),7.31(dd,J=7.8,4.8Hz,1H,H 芳基 ),7.71(dt,J=7.8,2.0Hz,1H,H 芳基 ),8.41(dd,J=4.8,1.7Hz,1H,H 芳基 ), 8.49(d, J = 2.3 Hz, 1H, H 芳基 ),8.52(s,1H,NH).

[1039] 13 CNMR(101MHz,DMSO-d6)δ:4.8(CH),7.1(2xCH2),30.9(CH2),42.9(CH2),91.1(CH 芳基 ),123.3(CH 芳基 ),134.4(C q ),136.4(CH 芳基 ),139.3(C q ),142.2(C q ),147.5(CH 芳基 ),149.9(C q ),150.0(CH 芳基 ),151.3(C q ).

[1040] MS(ESI+): m / z calculated value C 15 H 15 ClN6: 315.1 [M+H]+, measured value 315.2.

[1041] Example 3.49: Synthesis of 6-chloro-3-cyclopropyl-N-[2-(4-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.49)

[1042] To a solution of (2.5) (0.125 g, 0.51 mmol, 1.0 eq.) in THF (2.5 mL), the corresponding amine (0.080 g, 0.62 mmol, 1.2 eq.) and Et3N (0.15 mL, 1.04 mmol, 2.0 eq.) were added, and the mixture was refluxed for 1.5 h. 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, washed with water, then ground in Et2O, filtered, washed with Et2O, and dried under vacuum to give an orange solid (3.4 g) (0.134 g, 82%).

[1043] 1 HNMR(400MHz,DMSO-d6)δ:1.05–1.17(m,4H,2xCH 2环丙基 ),2.31(ddt,J=10.9,8.1,5.2Hz,1H,H 环丙基 ),2.96(t,J=7.1Hz,2H,CH2),3.63(d,J=7.9Hz,2H,CH2),6.28(s,1H,H 芳基 ), 7.27–7.39(m,2H,2xH) 芳基 ),8.42–8.48(m,2H,2xH 芳基 ),8.51(s,1H,NH).

[1044] 13 CNMR (101MHz, DMSO-d6) δ: 4.8 (CH 环丙基 ),7.2(2xCH 2环丙基 ),32.9(CH2),42.3(CH2),91.2(CH 芳基 ),124.4(CH 芳基 ),139.3(C q ),142.2(C q ),147.9(C q ),149.4(CH 芳基 ),149.9(C q ),151.3(Cq ).

[1045] MS(ESI+): m / z calculated value C 15 H 15 ClN6: 315.1 [M+H]+, measured value 315.2.

[1046] Example 3.50: Synthesis of 6-chloro-3-isopropyl-N-[3-(2-pyridinyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.50)

[1047] To a solution of (2.1) (0.200 g, 0.87 mmol, 1.0 eq.) in THF (8.7 mL), the corresponding amine (0.161 g, 1.13 mmol, 1.3 eq.) and Et3N (0.24 mL, 1.73 mmol, 2.0 eq.) 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 neutral pH, and then dissolved in EtOAc. The organic filtrate was dried over MgSO4, filtered, and concentrated to give a pale yellow solid (3.50) (0.250 g, 87%).

[1048] Rf(DCM / MeOH,94 / 6):0.42

[1049] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=6.9Hz,6H,2xCH 3异丙基 ),2.03(p,J=7.3Hz,2H,CH2),2.83(t,J=7.5Hz,2H,CH2),3.41(td,J=13.7,6.8Hz,3H,H 异丙基 &CH2), 6.20(s,1H,H 芳基 ), 7.20(dd, J = 7.6, 4.9 Hz, 1H, H 芳基 ), 7.28 (d, J = 7.8 Hz, 1H, H) 芳基 ),7.69(td,J=7.6,1.9Hz,1H,H 芳基 ), 8.45–8.54 (m, 1H, H) 芳基 ),8.70(s,1H,NH).

[1050] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基),27.2(CH2),34.5(CH2),41.8(CH2),90.8(CH 芳基 ),121.3(CH 芳基 ),122.9(CH 芳基 ),136.5(CH 芳基 ),139.5(C q ),142.4(C q ),148.9(CH 芳基 ),153.9(C q ),160.8(C q ).

[1051] MS(ESI+): m / z calculated value C 16 H 19 ClN6: 331.1 [M+H]+, measured value 331.2.

[1052] Example 3.51: Synthesis of 6-chloro-3-isopropyl-N-[3-(3-pyridinyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.51)

[1053] To a solution of (2.1) (0.200 g, 0.87 mmol, 1.0 eq.) in THF (8.7 mL), the corresponding amine dihydrochloride (0.248 g, 1.13 mmol, 1.3 eq.) and Et3N (0.73 mL, 5.19 mmol, 6.0 eq.) 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, EtOAc (15.0 mL) was added, the mixture was dried with MgSO4, filtered, and concentrated. The residue was ground in water (20.0 mL), the solid was filtered off, dissolved in EtOAc, and the organic filtrate was dried with MgSO4, filtered, and concentrated to give a beige solid (3.51) (0.240 g, 84%).

[1054] Rf(DCM / MeOH, 94 / 6): 0.35

[1055] 1 HNMR(400MHz,DMSO-d6)δ:1.39(d,J=7.0Hz,6H,2xCH 3异丙基 ), 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 异丙基 ),6.18(s,1H,H芳基 ),7.31(dd,J=7.8,4.8Hz,1H,H 芳基 ), 7.68(dt, J = 7.9, 2.0 Hz, 1H, H 芳基 ), 8.40(dd, J = 4.8, 1.7 Hz, 1H, H 芳基 ), 8.47 (d, J = 2.3 Hz, 1H, H 芳基 ),8.61(s,1H,NH -CH2 ).

[1056] 13 CNMR (101MHz, DMSO-d6)δ:ND

[1057] MS(ESI+): m / z calculated value C 16 H 19 ClN6: 331.1 [M+H]+, measured value 331.2.

[1058] Example 3.52: Synthesis of 6-chloro-3-isopropyl-N-[3-(4-pyridinyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.52)

[1059] To a solution of (2.1) (0.200 g, 0.87 mmol, 1.0 eq.) in THF (8.7 mL), the corresponding amine (0.161 g, 1.13 mmol, 1.3 eq.) and Et3N (0.24 mL, 1.73 mmol, 2.0 eq.) 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 neutral pH, and then dissolved in EtOAc. The organic filtrate was dried over MgSO4, filtered, and concentrated to give an orange solid (3.52) (0.260 g, 91%).

[1060] Rf(DCM / MeOH,94 / 6):0.33

[1061] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=6.9Hz,6H,2xCH 3异丙基 ),1.94(p,J=7.2Hz,2H,CH2),2.65–2.72(m,2H,CH2),3.33–3.38(m,2H,CH2),3.42(p,J=7.0Hz,1H,H 异丙基 ),6.18(s,1H,H 芳基 ), 7.19–7.37(m,2H,2xH) 芳基), 8.31–8.48(m,2H,2xH) 芳基 ), 8.60(s, 1H, NH).

[1062] 13 CNMR (101MHz, DMSO-d6)δ:ND

[1063] MS(ESI+): m / z calculated value C 16 H 19 ClN6: 331.1 [M+H]+, measured value 331.2.

[1064] Example 3.53: Synthesis of 6-chloro-3-cyclopropyl-N-[3-(2-pyridinyl)propyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.53)

[1065] To a solution of (2.5) (0.170 g, 0.74 mmol, 1.0 eq.) in THF / H₂O (15.0 / 0.5 mL), the corresponding amine dihydrochloride (0.229 g, 1.04 mmol, 1.3 eq.) and Et₃N (0.63 mL, 4.45 mmol, 6.0 eq.) were added, and the mixture was refluxed for 16 hours. After cooling, THF (10.0 mL) was added, the precipitate was filtered, washed with THF, and the filtrate was concentrated. The filtrate was then purified by rapid chromatography using DCM / MeOH (98 / 2 to 95 / 5) as the eluent to give a beige solid (3.53) (0.080 g, 33%).

[1066] 1 HNMR(400MHz,DMSO-d6)δ:1.11(tt,J=8.0,2.7Hz,4H,2xCH 2环丙基 ),1.85–2.02(m,2H,CH2),2.32(tt,J=8.2,5.2Hz,1H,H 环丙基 ),2.64–2.76(m,2H,CH2),3.32–3.42(m,2H,CH2),6.16(s,1H,H 芳基 ), 7.30(dd, J = 7.8, 4.7 Hz, 1H, H 芳基 ), 7.66(dt, J = 7.9, 2.0 Hz, 1H, H 芳基 ), 8.39(dd, J = 4.8, 1.6 Hz, 1H, H 芳基 ), 8.46 (d, J = 2.3 Hz, 1H, H 芳基 ), 8.57 (t, J = 5.6 Hz, 1H, NH).

[1067] 13CNMR (101MHz, DMSO-d6) δ: 4.8 (CH 环丙基 ),7.1(2xCH 2环丙基 ),29.1(CH2),29.4(CH2),41.7(CH2),90.8(CH 芳基 ),123.4(CH 芳基 ),135.8(CH 芳基 ),136.9(C q ),139.4(C q ),142.3(C q ),147.2(CH 芳基 ),149.6(CH 芳基 ),149.8(C q ),151.3(C q ).

[1068] MS(ESI+): m / z calculated value C 16 H 17 ClN6: 329.1 [M+H]+, measured value 329.2.

[1069] Example 3.54: Synthesis of 6-chloro-3-isopropyl-N-(pyrimidin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.54)

[1070] To a solution of (2.1) (0.190 g, 0.82 mmol, 1.0 eq.) in THF (9.0 mL), the corresponding amine hydrochloride (0.164 g, 1.07 mmol, 1.3 eq.) and DIPEA (0.36 mL, 2.06 mmol, 2.5 eq.) 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, washed with water, and then washed with EtOAc to give the first fraction (0.072 g) of (3.54). The two-phase filtrates were separated, and the aqueous layer was extracted twice with EtOAc (2 x 10.0 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as eluent to give the second fraction (0.020 g) of (3.54). Total (3.54): 0.092 g, 37% yield, white solid.

[1071] Rf(DCM / MeOH,94 / 6):0.40

[1072] 1 HNMR(400MHz,DMSO-d6)δ:1.39(d,J=6.9Hz,6H,2xCH3异丙基 ), 3.44 (p, J = 7.0 Hz, 1H, H 异丙基 ),4.80(s,2H,CH 2苄基 ),6.22(s,1H,H 芳基 ), 7.45(t, J = 4.9 Hz, 1H, NH 苄基 ), 8.74–8.89(m,3H,3xH) 芳基 ).

[1073] 13 CNMR (101MHz, DMSO-d6)δ:ND

[1074] MS(ESI+): m / z calculated value C 13 H 14 ClN7: 304.1 [M+H]+, measured value 304.2.

[1075] Example 3.55: Synthesis of 6-chloro-3-isopropyl-N-(pyrazin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.55)

[1076] To a solution of (2.1) (0.290 g, 1.26 mmol, 1.0 eq.) in 10.0 mL of THF, the corresponding amine (0.187 g, 1.63 mmol, 1.3 eq.) and DIPEA (0.33 mL, 1.88 mmol, 1.5 eq.) were added, and the mixture was refluxed for 1 hour. After cooling, the precipitate was filtered and washed with THF. The solid was washed with water and then with Et2O, and dried under vacuum to give the first fraction (0.103 g) of (3.55). The THF filtrate was concentrated and purified by rapid chromatography using DCM / MeOH (98 / 2 to 95 / 5) as eluent to give the second fraction (0.015 g) of (3.55). Total (3.55): 0.118 g, 31% yield, white solid.

[1077] Rf (ethyl acetate / cyclohexane, 7 / 3): 0.37

[1078] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.43 (p, J = 7.0 Hz, 1H, H 异丙基 ),4.77(s,2H,CH 2苄基 ),6.29(s,1H,H 芳基 ), 8.57 (d, J = 2.6 Hz, 1H, H 芳基 ), 8.60–8.63(m,1H,H)芳基 ), 8.69 (d, J = 1.5 Hz, 1H, H 芳基 ),8.98(s,1H,NH 苄基 ).

[1079] 13 CNMR (101MHz, DMSO-d6)δ:ND

[1080] MS(ESI+): m / z calculated value C 13 H 14 ClN7: 304.1 [M+H]+, measured value 304.2.

[1081] Example 3.56: Synthesis of 6-chloro-3-isopropyl-N-(pyrimidin-5-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.56)

[1082] To a solution of (2.1) (0.190 g, 0.82 mmol, 1.0 eq.) in THF (9.0 mL), the corresponding amine hydrochloride (0.164 g, 1.07 mmol, 1.3 eq.) and DIPEA (0.36 mL, 2.06 mmol, 2.5 eq.) 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, washed with water, and then washed with EtOAc to give the first fraction (0.055 g) of (3.56). The two-phase filtrates were separated, and the aqueous layer was extracted twice with EtOAc (2 x 10.0 mL). The organic layers were combined, dried with MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as eluent to give the second part (0.055 g) of (3.56), total (3.56): 0.110 g, 44% yield, white solid.

[1083] Rf(DCM / MeOH,94 / 6):0.30

[1084] 1 HNMR(400MHz,DMSO-d6)δ:1.37(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.42 (hept, J = 6.6 Hz, 1H, H 异丙基 ),4.66(s,2H,CH 2苄基 ),6.37(s,1H,H 芳基 ),8.85(s,2H,2xH 芳基 ),9.05(s,1H,NH 苄基 ),9.10(s,1H,H 芳基 ).

[1085] 13 CNMR (101MHz, DMSO-d6)δ:ND

[1086] MS(ESI+): m / z calculated value C 13 H 14 ClN7: 304.1 [M+H]+, measured value 304.2.

[1087] 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)

[1088] To a solution of (2.1) (0.300 g, 1.30 mmol, 1.0 eq.) in THF (9.0 mL), the corresponding amine dihydrochloride (0.323 g, 1.69 mmol, 1.3 eq.) and DIPEA (0.75 mL, 4.28 mmol, 3.3 eq.) 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 off, washed with water to neutral pH, ground in Et2O, filtered, and dried to give a white solid (3.57) (0.286 g, 73%).

[1089] Rf(DCM / MeOH,94 / 6):0.38

[1090] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.43 (p, J = 6.9 Hz, 1H, H 异丙基 ),4.89(s,2H,CH 2苄基 ),6.27(s,1H,H 芳基 ), 7.69(d, J = 3.3 Hz, 2H, 2xH 芳基 ),9.08(s,1H,NH 苄基 ),9.17(t,J=3.4Hz,1H,H 芳基 ).

[1091] 13 CNMR(101MHz,DMSO-d6)δ:19.8(CH 3异丙基 ),24.4(CH 异丙基 ),45.7(CH 2苄基 ),92.0(CH 芳基 ),125.7(CH 芳基 ),127.5(CH芳基 ),139.4(C q ),142.5(C q ),149.4(C q ),151.0(CH 芳基 ),154.0(C q ),159.3(C q ).

[1092] MS(ESI+): m / z calculated value C 13 H 14 ClN7: 304.1 [M+H]+, measured value 304.1.

[1093] Example 3.58: Synthesis of 6-chloro-3-isopropyl-N-[[4-(2-pyridinyl)phenyl]methyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.58)

[1094] To a 10–20 mL vial equipped with a stir bar, add (1.14) (0.300 g, 0.91 mmol, 1.0 eq.), dioxane (4.9 mL), isobutyric acid hydrazide (0.112 g, 1.09 mmol, 1.2 eq.), and AcOH (0.06 mL, 1.00 mmol, 1.1 eq.). Seal the vial and place it on a heating block. Heat at 110 °C for 22 hours. After cooling, pour the reaction mixture into saturated NaHCO3 (20.0 mL) and stir vigorously for 5 minutes. Filter out the resulting precipitate, wash with water, and then dissolve in DCM (10.0 mL). The aqueous filtrate was extracted twice with EtOAc (2 x 10.0 mL) and combined with the DCM solution. All of the solution was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 95 / 5) as the eluent to obtain the target compound (3.58) (0.140 g, 41%) as a white solid.

[1095] Rf(DCM / MeOH,94 / 6):0.47

[1096] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.42(hept, J = 7.1 Hz, 1H, H 异丙基 ), 4.65 (d, J = 3.9 Hz, 2H, CH 2苄基 ),6.18(s,1H,H 芳基 ),7.33(dd,J=7.4,4.9Hz,1H,H 芳基),7.51(d,J=8.1Hz,2H,2xH 芳基 ), 7.86(td, J = 7.7, 1.9 Hz, 1H, H 芳基 ), 7.93 (d, J = 8.0 Hz, 1H, H 芳基 ), 8.06(d, J = 8.1 Hz, 2H, 2xH 芳基 ), 8.65 (d, J = 3.8 Hz, 1H, H 芳基 ),9.17(s,1H,NH 苄基 ).

[1097] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基 ),44.9(CH 2苄基 ),91.6(CH 芳基 ),120.1(CH 芳基 ),122.5(CH 芳基 ),126.7(2xCH 芳基 ),127.5(2xCH 芳基 ),137.2(CH 芳基 ),137.7(C q ),138.3(C q ),139.4(C q ),142.3(C q ),149.4(C q ),149.5(CH 芳基 ),154.0(C q ),155.7(C q ).

[1098] MS(ESI+): m / z calculated value C 20 H 19 ClN6: 379.1 [M+H]+, measured value 379.3.

[1099] Example 3.59: Synthesis of 6-chloro-3-isopropyl-N-[[4-(4-pyridine)phenyl]methyl]-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.59)

[1100] LiAlH4 (0.066 g, 1.73 mmol, 1.6 eq.) was added in portions to a solution of 4-(4-pyridyl)benzonitrile (0.224 g, 1.24 mmol, 1.15 eq.) in anhydrous THF (12.0 mL), and the mixture was stirred for 45 minutes. After stirring, saturated NH4Cl (10.0 mL), water (5.0 mL), and EtOAc (10.0 mL) were added, and the mixture was stirred vigorously for 5 minutes. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10.0 mL). The organic layers were then combined, dried over MgSO4, filtered, and concentrated. The residue was dissolved directly in THF (18.0 mL) with (2.1) (0.250 g, 1.08 mmol, 1.0 eq.) and Et3N (0.46 mL, 3.25 mmol, 3.0 eq.), and the mixture was refluxed for 3 hours. After cooling, the solid was filtered, washed with THF, and then the filtrate was concentrated and purified directly by rapid chromatography using DCM / MeOH (98 / 2 to 93 / 7) as eluent to give a white solid (3.5g) (0.110g, 27%).

[1101] Rf(DCM / MeOH,94 / 6):0.25

[1102] 1 HNMR(400MHz,DMSO-d6)δ:1.38(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.42 (p, J = 6.9 Hz, 1H, H 异丙基 ), 4.66 (d, J = 6.2 Hz, 2H, CH 2苄基 ),6.19(s,1H,H 芳基 ), 7.54(d, J = 8.1 Hz, 2H, 2xH 芳基 ), 7.66–7.75(m,2H,2xH) 芳基 ),7.76–7.87(m,2H,2xH 芳基 ), 8.56–8.70(m,2H,2xH) 芳基 ),9.18(s,1H,NH).

[1103] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.4(CH 异丙基 ),44.7(CH2),91.6(CH 芳基 ),121.1(2xCH 芳基 ),127.0(2xCH 芳基 ),128.0(2xCH 芳基 ),136.0(Cq ),138.8(C q ),139.4(C q ),142.3(C q ),146.6(C q ),149.4(C q ),150.2(2xCH 芳基 ),154.0(C q ).

[1104] MS(ESI+): m / z calculated value C 20 H 19 ClN6: 379.1 [M+H]+, measured value 379.2.

[1105] 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)

[1106] To a solution of (2.1) (0.100 g, 0.433 mmol, 1.0 eq.) in anhydrous THF (3.33 mL), 3-aminopyridazine (0.084 g, 0.866 mmol, 2.0 eq.) was added, followed by a solution of 1.65 MtBuOK of THF (0.52 mL, 0.866 mmol, 2.0 eq.), and the mixture was stirred at room temperature for 0.8 h. After this was complete, saturated NH4Cl (3.33 mL) and water (1 mL) were added, and the two-phase mixture was stirred vigorously for 5 min. The precipitate formed was filtered off and washed with H2O and Et2O to give a white solid (3.60) (0.023 g, 18%). The filtrate layer was separated, the aqueous layer was extracted with EtOAc (2 x 10.0 mL), the organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was ground in Et2O, filtered, washed with Et2O and vacuum dried to give a beige solid (3.60) (0.063 g, 51%). (3.60) was obtained in a yield of 69% (0.086 g).

[1107] Rf(DCM / MeOH,96 / 4):0.28

[1108] 1 HNMR(400MHz,DMSO-d6)δ:1.43(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.53(h, J = 6.9 Hz, 1H, H 异丙基 ), 7.73(dd, J = 9.0, 4.6 Hz, 1H, H 芳基 ), 7.89(dd, J = 9.0, 1.4 Hz, 1H, H 芳基),8.39(s,1H,H 芳基 ),9.00(dd,J=4.6,1.4Hz,1H,H 芳基 ),11.13(s,1H,NH).

[1109] 13 CNMR(101MHz,DMSO-d6)δ:19.83(2xCH 3异丙基 ),24.50(CH 异丙基 ),101.29(CH 芳基 ),119.50(CH 芳基 ),128.69(CH 芳基 ),136.05(C q ),139.24(C q ),147.89(CH 芳基 ),149.82(C q ),154.39(C q ),157.23(C q ).

[1110] MS(ESI+): m / z calculated value C 12 H 12 ClN7: 290.1 ​​[M+H]+, measured value 290.2.

[1111] 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)

[1112] To a solution of (2.1) (0.350 g, 1.515 mmol, 1.0 eq.) in anhydrous THF (11.5 mL), 4-aminopyridazine (0.294 g, 3.029 mmol, 2.0 eq.) was added, followed by a solution of 1 M tBuOK THF (1.84 mL, 3.029 mmol, 2.0 eq.), and the mixture was stirred at room temperature for 1.25 h. After this, saturated NH4Cl (11.5 mL) and water (5.23 mL) were added, and the two-phase mixture was stirred vigorously for 5 min. The layers were separated, the aqueous layer was extracted with EtOAc (2 x 10.0 mL), the organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by rapid chromatography using DCM / MeOH (99 / 1 to 94 / 6) as eluent to give a yellow solid (3.61) (0.256 g, 58%).

[1113] Rf(DCM / MeOH,94 / 6):0.28

[1114] 1 HNMR(400MHz,DMSO-d6)δ:1.42(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.50 (hept, J = 6.9 Hz, 1H, H 异丙基 ),7.06(s,1H,H 芳基 ),7.77(dd,J=6.2,2.9Hz,1H,H 芳基 ),9.09(d,J=5.9Hz,1H,H 芳基 ), 9.38 (d, J = 2.7 Hz, 1H, H 芳基 ), 10.88(s, 1H, NH).

[1115] 13 CNMR(101MHz,DMSO-d6)δ:19.80(2xCH 3异丙基 ),24.50(CH 异丙基 ),98.77(CH 芳基 ),115.13(CH 芳基 ),137.58(C q ),138.40(C q ),139.48(C q ),145.30(CH 芳基 ),149.54(C q ),151.27(CH 芳基 ),154.37(C q ).

[1116] MS(ESI+): m / z calculated value C 12 H 12 ClN7: 290.1 ​​[M+H]+, measured value 290.1.

[1117] Example 3.62: Synthesis of 6-chloro-3-isopropyl-N-(pyrimidin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.62)

[1118] To a solution of (2.1) (0.40 g, 1.731 mmol, 1.0 eq.) in anhydrous THF (13.14 mL), 4-aminopyrimidine (0.281 g, 2.891 mmol, 2.0 eq.) was added, followed by a 1.65 M tBuOK THF solution (1.75 mL, 2.891 mmol, 2.0 eq.), and the mixture was stirred at room temperature for 1 hour. After this, 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 were separated, the aqueous layer was extracted with EtOAc (2 x 10.0 mL), the organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was ground in DCM, filtered, washed with MeOH and Et2O, and dried under vacuum to give (3.62), a pale yellow / beige solid (0.171 g, 34%). The filtrate was purified by rapid chromatography using DCM / MeOH (99 / 1 to 94 / 6) as eluent to give the second part of (3.62) (0.150 g, 30%) as a beige solid. Total (3.62): 0.321 g, 64%.

[1119] Rf(DCM / MeOH, 94 / 6): 0.35

[1120] 1 HNMR(400MHz,DMSO-d6)δ:1.42(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.50 (hept, J = 7.0 Hz, 1H, H 异丙基 ), 7.60(dd, J = 5.8, 1.3 Hz, 1H, H 芳基 ),8.37(s,1H,H 芳基 ), 8.62 (d, J = 5.8 Hz, 1H, H 芳基 ), 8.99 (d, J = 1.2 Hz, 1H, H 芳基 ), 11.28(s, 1H, NH).

[1121] 13 CNMR(101MHz,DMSO-d6)δ:19.81(2xCH 3异丙基 ),24.48(CH 异丙基 ),102.67(CH 芳基 ),110.88(CH 芳基 ),135.84(C q ),139.11(C q ),149.48(C q ),154.39(C q ),157.07(CH 芳基),157.72(CH 芳基 ),159.68(C q ).

[1122] MS(ESI+): m / z calculated value C 12 H 10 ClN7: 290.1 ​​[M+H]+, measured value 290.1.

[1123] Example 3.63: Synthesis of 6-chloro-3-isopropyl-N-(pyrimidin-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.63)

[1124] Add 5-aminopyrimidine (0.166 g, 1.731 mmol, 2.0 eq.) to anhydrous THF (6.63 mL) solution of (2.1) (0.200 g, 0.866 mmol, 1.0 eq.), then add a 1.65 M tBuOK THF solution (1.05 mL, 1.731 mmol, 2.0 eq.), and stir the mixture at room temperature for 1.5 h. After this, add saturated NH4Cl (6.63 mL) and water (1.77 mL), and then stir the two-phase mixture vigorously for 5 min. Filter out the precipitate formed, wash with H2O and Et2O to give a white solid (3.63) (0.150 g, 60%). Separate the filtrate layers, extract the aqueous layer with EtOAc (2 x 10.0 mL), then combine the organic layers, dry with MgSO4, filter and concentrate. The residue was purified by rapid chromatography using DCM / MeOH (99 / 1 to 94 / 6) as eluent to give a second part of a white solid (3.63). The total was (3.63) obtained in a yield of 79% (0.198 g).

[1125] Rf(DCM / MeOH,94 / 6):0.25

[1126] 1 HNMR(400MHz,DMSO-d6)δ:1.42(d,J=7.0Hz,6H,2xCH 3异丙基 ), 3.49 (p, J = 6.9 Hz, 1H, H 异丙基 ), 6.65(s, 1H, H 芳基 ),8.95(s,2H,2xH 芳基 ),9.06(s,1H,H 芳基 ),10.57(s,1H,NH).

[1127] 13 CNMR(101MHz,DMSO)δ:19.81(2xCH 3异丙基 ),24.49(CH异丙基 ),95.16(CH 芳基 ),133.98(C q ),139.40(C q ),139.60(C q ),149.66(C q ),151.64(2xCH 芳基 ),154.23(C q ),154.71(CH 芳基 ).

[1128] MS(ESI+): m / z calculated value C 12 H 10 ClN7: 290.1 ​​[M+H]+, measured value 290.2.

[1129] Example 3.64: Synthesis of 6-chloro-3-isopropyl-N-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.64)

[1130] To a solution of (2.1) (0.152 g, 0.664 mmol, 1.0 eq.) in anhydrous THF (5.04 mL), 2-aminopyrimidine (0.126 g, 1.316 mmol, 2.0 eq.) was added, followed by a solution of 1.65 M tBuOK in THF (0.80 mL, 1.316 mmol, 2.0 eq.), and the mixture was stirred at room temperature for 2.25 h. After this, saturated NH4Cl (5.04 mL) and water (2.3 mL) were added, and the two-phase mixture was stirred vigorously for 5 min. The layers were separated, the aqueous layer was extracted with EtOAc (2 x 10.0 mL), the organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was ground in Et2O, filtered, washed with Et2O, and dried under vacuum to give a beige solid (3.64) (0.124 g, 65%).

[1131] Rf(DCM / MeOH,94 / 6):0.48

[1132] 1 HNMR(400MHz,DMSO-d6)δ:1.42(d,J=6.9,2.0Hz,6H,2xCH 3异丙基 ), 3.45–3.56 (m, 1H, H) 异丙基 ), 7.26(dt, J = 4.9, 3.1 Hz, 1H, H 芳基 ),8.16(s,1H,H 芳基 ),8.80(dd,J=4.9,1.9Hz,2H,2xH 芳基),10.31(s,1H,NH).

[1133] 13 CNMR(101MHz,DMSO-d6)δ:19.81(2xCH 3异丙基 ),24.49(CH 异丙基 ),101.32(CH 芳基 ),116.40(CH 芳基 ),136.11(C q ),139.01(C q ),149.61(C q ),154.38(C q ),158.56(C q ),158.64(2xCH 芳基 ).

[1134] MS(ESI+): m / z calculated value C 12 H 12 ClN7: 290.1 ​​[M+H]+, measured value: 290.2.

[1135] Example 3.65: Synthesis of 6-chloro-3-isopropyl-N-(pyrazin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.65)

[1136] To a solution of (2.1) (0.100 g, 0.433 mmol, 1.0 eq.) in anhydrous THF (3.33 mL), 2-aminopyrazine (0.082 g, 0.866 mmol, 2.0 eq.) was added, followed by a solution of 1.65 M tBuOK in THF (0.52 mL, 0.866 mmol, 2.0 eq.), and the mixture was stirred at room temperature for 0.8 h. After this, saturated NH4Cl (3.33 mL) and water (1 mL) were added, and the two-phase mixture was stirred vigorously for 5 min. The layers were separated, the aqueous layer was extracted with EtOAc (2 x 10.0 mL), the organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was ground in Et2O, filtered, washed with Et2O, and dried under vacuum to give a beige solid (3.65) (0.093 g, 74%).

[1137] Rf(DCM / MeOH, 96 / 4): 0.31

[1138] 1 HNMR(400MHz,DMSO-d6)δ:1.43(d,J=7.0Hz,6H,2xCH 3异丙基 ), 3.51(hept, J = 6.8 Hz, 1H, H 异丙基),8.19(s,1H,H 芳基 ), 8.33 (d, J = 2.7 Hz, 1H, H 芳基 ),8.47(dd,J=2.7,1.4Hz,1H,H 芳基 ), 8.93 (d, J = 1.5 Hz, 1H, H 芳基 ),11.32(s,1H,NH).

[1139] 13 CNMR(101MHz,DMSO-d6)δ:19.83(2xCH 3异丙基 ),24.48(CH 异丙基 ),100.32(CH 芳基 ),136.30(C q ),137.69(CH 芳基 ),138.02(CH 芳基 ),139.21(C q ),141.16(CH 芳基 ),149.60(C q ),150.64(C q ),154.37(C q ).

[1140] MS(ESI+): m / z calculated value C 12 H 12 ClN7: 290.1 ​​[M+H]+, measured value 290.2

[1141] Example 3.66: Synthesis of 6-chloro-3-isopropyl-N-(6-methoxypyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.66)

[1142] Under an inert atmosphere, a solution of 1 M tBuOK in THF (0.81 mL, 0.81 mmol, 1.5 eq.) was added dropwise to a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) and the corresponding aminopyridine derivative (0.102 g, 0.81 mmol, 1.5 eq.) in anhydrous THF (7.5 mL). The mixture was stirred at room temperature for 3.5 h, and then saturated NH4Cl (3.0 mL), water (1.0 mL), and EtOAc (3.0 mL) were added. The mixture was stirred vigorously for 5 min, and then the layers were separated. The aqueous layer was extracted twice with EtOAc (2 x 5.0 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1 to 98 / 2) as eluent to give (3.66) (0.128 g, 74%) as a light orange solid.

[1143] Rf(DCM / MeOH, 98 / 2): 0.30

[1144] 1 HNMR(400MHz,DMSO-d6)δ:1.42(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.50 (hept, J = 6.9 Hz, 1H, H 异丙基 ), 3.95(s, 3H, CH 3-O ), 6.55 (d, J = 8.0 Hz, 1H, H 芳基 ), 7.18(d, J = 7.8 Hz, 1H, H 芳基 ), 7.73(t, J = 8.0 Hz, 1H, H 芳基 ),8.26(s,1H,H 芳基 ),10.91(s,1H,NH).

[1145] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.5(CH 异丙基 ),53.6(CH 3-O ),99.7(CH 芳基 ),103.7(CH 芳基 ),106.3(CH 芳基 ),136.4(C q ),139.3(C q ),141.0(CH 芳基 ),149.6(C q ),152.0(C q ),154.3(C q ),162.4(C q ).

[1146] Example 3.67: Synthesis of 6-chloro-3-isopropyl-N-(5-methoxypyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.67)

[1147] Under an inert atmosphere, a solution of 1 M tBuOK in THF (0.81 mL, 0.81 mmol, 1.5 eq.) was added dropwise to a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) and the corresponding aminopyridine derivative (0.102 g, 0.81 mmol, 1.5 eq.) in anhydrous THF (7.5 mL). The mixture was stirred at room temperature for 3.5 h, and then saturated NH4Cl (3.0 mL), water (1.0 mL), and EtOAc (3.0 mL) were added. The mixture was stirred vigorously for 5 min, and then the layers were separated. The aqueous layer was extracted twice with EtOAc (2 x 5.0 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1 to 98 / 2) as eluent to give an orange solid (3.67) (0.112 g, 65%).

[1148] Rf(DCM / MeOH,98 / 2):0.24

[1149] 1 HNMR(400MHz,DMSO-d6)δ:1.42(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.48 (hept, J = 6.9 Hz, 1H, H 异丙基 ),3.83(s,3H,CH 3-O ), 7.50(dd, J = 9.0, 3.0 Hz, 1H, H 芳基 ), 7.56 (d, J = 9.0 Hz, 1H, H 芳基 ),8.15(s,1H,H 芳基 ), 8.18(d, J = 3.0 Hz, 1H, H 芳基 ), 10.82(s, 1H, NH).

[1150] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.5(CH 异丙基 ),55.9(CH 3-O ),97.8(CH 芳基 ),115.6(CH 芳基 ),124.9(CH 芳基 ),132.7(CH 芳基 ),136.7(C q ),139.3(C q ),147.3(C q ),149.8(C q ),151.8(C q),154.2(C q ).

[1151] MS(ESI+): m / z calculated value C 14 H 15 ClN6O: 319.1 [M+H]+, measured value 319.2.

[1152] Example 3.68: Synthesis of 6-chloro-3-isopropyl-N-(4-methoxypyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.68)

[1153] Under an inert atmosphere, a solution of 1 M tBuOK in THF (0.81 mL, 0.81 mmol, 1.5 eq.) was added dropwise to a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) and the corresponding aminopyridine derivative (0.102 g, 0.81 mmol, 1.5 eq.) in anhydrous THF (7.5 mL). The mixture was stirred at room temperature for 3.5 h, and then saturated NH4Cl (3.0 mL), water (1.0 mL), and EtOAc (3.0 mL) were added. The mixture was stirred vigorously for 5 min, and then the layers were separated. The aqueous layer was extracted twice with EtOAc (2 x 5.0 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1 to 98 / 2) as eluent to give (3.68) (0.125 g, 72%) as a light orange solid.

[1154] Rf(DCM / MeOH,98 / 2):0.25

[1155] 1 HNMR(400MHz,DMSO-d6)δ:1.42(d,J=7.0Hz,6H,2xCH 3异丙基 ), 3.49 (hept, J = 6.9 Hz, 1H, H 异丙基 ),3.83(s,3H,CH 3-O ), 6.76(dd, J = 5.9, 2.3 Hz, 1H, H 芳基 ), 7.25 (d, J = 2.3 Hz, 1H, H 芳基 ), 8.26 (d, J = 5.9 Hz, 1H, H 芳基 ),8.32(s,1H,H 芳基 ),10.74(s,1H,NH).

[1156] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基),24.5(CH 异丙基 ),55.3(CH 3-O ),99.1(CH 芳基 ),99.7(CH 芳基 ),106.6(CH 芳基 ),136.7(C q ),139.3(C q ),148.5(CH 芳基 ),149.7(C q ),154.3(C q ),155.6(C q ),166.5(C q ).

[1157] Example 3.69: Synthesis of 6-chloro-3-isopropyl-N-(3-methoxypyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.69)

[1158] Under inert gas, a solution of 1 M tBuOK in THF (0.81 mL, 0.81 mmol, 1.5 eq.) was added dropwise to a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) and the corresponding aminopyridine derivative (0.102 g, 0.81 mmol, 1.5 eq.) in anhydrous THF (7.5 mL). The mixture was stirred at room temperature for 3.5 h, and then saturated NH4Cl (3.0 mL), water (1.0 mL), and EtOAc (3.0 mL) were added. The mixture was stirred vigorously for 5 min, and then the layers were separated. The aqueous layer was extracted twice with EtOAc (2 x 5.0 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1 to 98 / 2) as eluent to give a white solid (3.6 g) (0.120 g, 70%).

[1159] Rf(DCM / MeOH,98 / 2):0.38

[1160] 1 HNMR(400MHz,DMSO-d6)δ:1.42(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.49 (hept, J = 7.0 Hz, 1H, H 异丙基 ),4.01(s,3H,CH 3-O ), 7.10–7.29(m,1H,H) 芳基 ), 7.55 (d, J = 8.1 Hz, 1H, H 芳基 ), 8.04 (d, J = 4.9 Hz, 1H, H芳基 ),8.14(s,1H,H 芳基 ),8.78(s,1H,NH).

[1161] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.5(CH 异丙基 ),56.4(CH 3-O ),99.3(CH 芳基 ),118.1(CH 芳基 ),119.4(CH 芳基 ),135.2(C q ),138.3(CH 芳基 ),139.1(C q ),142.7(C q ),144.0(C q ),149.7(C q ),154.5(C q ).

[1162] MS(ESI+): m / z calculated value C 14 H 15 ClN6O: 319.1 [M+H]+, measured value 319.2.

[1163] Example 3.70: Synthesis of 6-chloro-3-isopropyl-N-(3-phenylpropyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.70)

[1164] To a solution of (2.1) (0.130 g, 0.56 mmol, 1.0 eq.) in THF (6.0 mL), the corresponding amine (0.16 mL, 1.12 mmol, 2.0 eq.) and Et3N (0.16 mL, 1.12 mmol, 2.0 eq.) were added, and the mixture was refluxed for 2 hours. After cooling, the precipitate was filtered, washed with THF, and the filtrate was concentrated. The residue was purified by rapid chromatography using DCM / MeOH (98 / 2) as eluent to give a white solid (3.70) (0.177 g, 95%).

[1165] 1 HNMR(400MHz,DMSO-d6)δ:1.39(d,J=6.9Hz,6H,2xCH 3异丙基 ), 1.84–2.02(m,2H,CH) 2-CH2-NH ),2.68(dd,J=8.8,6.7Hz,2H,CH 2-苯基 ), 3.33-3.39(m,2H,CH)2-NH ), 3.44(h, J = 7.0 Hz, 1H, H 异丙基 ),6.13(s,1H,H 芳基 ), 7.14–7.23(m,1H,H) 芳基 ), 7.21–7.33(m,4H,4xH) 芳基 ),8.61(s,1H,NH).

[1166] 13 CNMR(101MHz,DMSO-d6)δ:20.3(2xCH 3异丙基 ),24.9(CH 异丙基 ),29.9(CH 2-CH2-NH ),32.9(CH 2-苯基 ),42.2(CH 2-NH ),91.2(CH 芳基 ),126.3(CH 芳基 ),128.8(2xCH 芳基 ),128.8(CH 芳基 ),139.9(C q ),142.0(C q ),142.9(C q ),150.1(C q ),154.4(C q ).

[1167] Example 3.71: Synthesis of 6-chloro-3-cyclopropyl-N-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.71)

[1168] Under inert gas, aniline (0.12 mL, 1.31 mmol, 2.0 eq.) was added to a solution of (2.5) (0.150 g, 0.65 mmol, 1.0 eq.) in anhydrous THF (5.0 mL), followed by a solution of 1 M tBuOK THF (1.31 mL, 1.31 mmol, 2.0 eq.). 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 EtOAc (2 x 5.0 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and the residue was purified by rapid chromatography using DCM / MeOH (99 / 1 to 98 / 2) as eluent to give (3.71) (0.175 g, 94%) as a white solid.

[1169] 1HNMR(400MHz,DMSO-d6)δ:1.10–1.26(m,4H,2xCH 2环丙基 ),2.37(tt,J=8.1,5.3Hz,1H,H 环丙基 ), 6.34(s, 1H, H 芳基 ),7.27(ddd,J=8.5,5.9,2.2Hz,1H,H 芳基 ), 7.38–7.55(m, 4H, 4xH) 芳基 ),10.43(s,1H,NH).

[1170] 13 CNMR (101MHz, DMSO-d6) δ: 4.9 (CH 环丙基 ),7.2(2xCH 2环丙基 ),92.9(CH 芳基 ),123.5(2xCH 芳基 ),125.7(CH 芳基 ),129.5(2xCH 芳基 ),137.7(C q ),139.5(C q ),140.2(C q ),149.8(C q ),151.6(C q ).

[1171] MS(ESI+): m / z calculated value C 14 H 12 ClN5: 286.1 [M+H]+, measured value 286.2.

[1172] Example 3.72: Synthesis of 6-chloro-3-cyclopropyl-N-(2-pyridine)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.72)

[1173] Under inert gas, the corresponding aminopyridine (0.125 g, 1.31 mmol, 2.0 eq.) was added to a solution of (2.5) (0.150 g, 0.65 mmol, 1.0 eq.) in anhydrous THF (5.0 mL), followed by a solution of 1 M tBuOK THF (1.31 mL, 1.31 mmol, 2.0 eq.). The mixture was stirred at room temperature for 1 hour, and then saturated NH4Cl (5.0 mL) and water (1.5 mL) were added, followed by vigorous stirring for 5 minutes. The layers were separated, and the aqueous layer was extracted twice with EtOAc (2 x 5.0 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and the residue was purified by rapid chromatography using DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (3.72) (0.085 g, 45%) as a white solid.

[1174] 1 HNMR(400MHz,DMSO-d6)δ:1.11–1.21(m,4H,2xCH 2环丙基 ),2.39(tt,J=8.0,5.4Hz,1H,CH 环丙基 ),7.13(ddd,J=7.3,5.0,1.0Hz,1H,H 芳基 ), 7.48–7.66 (m, 1H, H) 芳基 ),7.82(ddd,J=8.4,7.3,2.0Hz,1H,H 芳基 ),8.31(s,1H,H 芳基 ), 8.45(dd, J = 5.3, 1.9 Hz, 1H, H 芳基 ), 10.87(s, 1H, NH).

[1175] 13 CNMR (101MHz, DMSO-d6) δ: 4.9 (CH 环丙基 ),7.2(2xCH 2环丙基 ),99.5(CH 芳基 ),114.6(CH 芳基 ),118.6(CH 芳基 ),136.6(C q ),138.3(CH 芳基 ),139.2(C q ),147.3(CH 芳基 ),150.0(C q ),151.7(C q ),153.9(C q ).

[1176] MS(ESI+): m / z calculated value C13 H 11 ClN6: 287.1 [M+H]+, measured value 287.2.

[1177] Example 3.73: Synthesis of 6-chloro-3-cyclopropyl-N-(3-pyridine)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.73)

[1178] Under inert gas, the corresponding aminopyridine (0.125 g, 1.31 mmol, 2.0 eq.) was added to a solution of (2.5) (0.150 g, 0.65 mmol, 1.0 eq.) in anhydrous THF (5.0 mL), followed by a solution of 1 M tBuOK THF (1.31 mL, 1.31 mmol, 2.0 eq.). The mixture was stirred at room temperature for 1 hour, and then saturated NH4Cl (5.0 mL) and water (1.5 mL) were added, followed by vigorous stirring for 5 minutes. The layers were separated, and the aqueous layer was extracted twice with EtOAc (2 x 5.0 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and the residue was purified by rapid chromatography using DCM / MeOH (99 / 1 to 96 / 4) as eluent to give a white solid (3.73) (0.080 g, 43%).

[1179] 1 HNMR(400MHz,DMSO-d6)δ:1.15(tt,J=7.7,2.6Hz,4H,2xCH 2环丙基 ),2.38(tt,J=8.1,5.3Hz,1H,H 环丙基 ),6.42(s,1H,H 芳基 ), 7.50(dd, J = 8.2, 4.7 Hz, 1H, H 芳基 ),7.91(ddd,J=8.3,2.7,1.5Hz,1H,H 芳基 ), 8.46(dd, J = 4.8, 1.5 Hz, 1H, H 芳基 ), 8.69 (d, J = 2.6 Hz, 1H, H 芳基 ),10.51(s,1H,NH).

[1180] 13 CNMR (101MHz, DMSO-d6)δ:ND

[1181] MS(ESI+): m / z calculated value C 13 H 11 ClN6: 287.1 [M+H]+, measured value 287.2.

[1182] Example 3.74: Synthesis of 6-chloro-3-cyclopropyl-N-(4-pyridine)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.74)

[1183] Under an inert atmosphere, the corresponding aminopyridine (0.125 g, 1.31 mmol, 2.0 eq.) was added to a solution of (2.5) (0.150 g, 0.65 mmol, 1.0 eq.) in anhydrous THF (5.0 mL), followed by a solution of 1 M tBuOK THF (1.31 mL, 1.31 mmol, 2.0 eq.). The mixture was stirred at room temperature for 1 hour, and then saturated NH4Cl (5.0 mL) and water (1.5 mL) were added, followed by vigorous stirring for 5 minutes. The layers were separated, and the aqueous layer was extracted twice with EtOAc (2 x 5.0 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and the residue was purified by rapid chromatography using DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (3.74) (0.090 g, 48%) as a white solid.

[1184] 1 HNMR(400MHz,DMSO-d6)δ:1.16(tt,J=8.0,2.8Hz,4H,2xCH 2环丙基 ),2.38(ddd,J=10.5,8.3,5.2Hz,1H,H 环丙基 ),6.87(s,1H,H 芳基 ), 7.42–7.58(m,2H,2xH) 芳基 ), 8.54(d, J = 5.4 Hz, 2H, 2xH 芳基 ), 10.66(s, 1H, NH).

[1185] 13 CNMR (101MHz, DMSO-d6) δ: 4.9 (CH 环丙基 ),7.3(2xCH 2环丙基 ),96.8(CH 芳基 ),115.5(CH 芳基 ),138.0(C q ),139.4(C q ),145.7(C q ),149.8(C q ),150.7(CH 芳基 ),151.8(C q ).

[1186] MS(ESI+): m / z calculated value C 13 H 11ClN6: 287.1 [M+H]+, measured value 287.2.

[1187] 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)

[1188] To a solution of (2.5%) (0.250 g, 1.091 mmol, 1.0 eq.) in anhydrous THF (8.38 mL), 3-aminopyridazine (0.212 g, 2.183 mmol, 2.0 eq.) was added, followed by a 1 M tBuOK THF solution (1.32 mL, 2.183 mmol, 2.0 eq.), and the mixture was stirred at room temperature for 2 hours. After this, saturated NH4Cl (8.38 mL) and water (2.53 mL) were added, and the two-phase mixture was stirred vigorously for 5 minutes. The precipitate formed was filtered off and washed with H2O and Et2O to give a beige solid (3.75%) (0.286 g, 91%).

[1189] Rf(DCM / MeOH, 96 / 4): 0.38

[1190] 1 HNMR(400MHz,DMSO-d6)δ:1.12–1.22(m,4H,2xCH 2环丙基 ),2.40(td,J=8.1,4.0Hz,1H,H 环丙基 ),7.72(dd,J=9.0,4.6Hz,1H,H 芳基 ),7.87(d,1H,H 芳基 ),8.37(s,1H,H 芳基 ),9.00(d,J=4.6Hz,1H,H 芳基 ),11.10(s,1H,NH).

[1191] 13 CNMR(101MHz,DMSO-d6)δ:4.87(CH 环丙基 ),7.28(2xCH 2环丙基 ),101.25(CH 芳基 ),119.51(CH 芳基 ),128.67(CH 芳基 ),136.07(C q ),139.23(C q ),147.86(CH 芳基 ),150.02(C q ),151.82(C q ),157.27(Cq ).

[1192] MS(ESI+): m / z calculated value C 12 H 10 ClN7: 288.1 [M+H]+, measured value 288.1.

[1193] 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)

[1194] To a solution of (2.5) (0.087 g, 0.380 mmol, 1.0 eq.) in anhydrous THF (2.94 mL), 4-aminopyridazine (0.074 g, 0.760 mmol, 2.0 eq.) was added, followed by a solution of 1 M tBuOK THF (0.76 mL, 0.760 mmol, 2.0 eq.), and the mixture was stirred at room temperature for 1.2 h. After this, saturated NH4Cl (2.94 mL) and water (0.871 mL) were added, and the two phases were stirred vigorously for 5 min. The layers were separated; the aqueous layer was extracted with EtOAc (2 x 10 mL), and the organic layers were combined, dried over 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 dried under vacuum to give a white solid (3.76) (0.094 g, 86%).

[1195] Rf(DCM / MeOH, 96 / 4): 0.35

[1196] 1 HNMR(400MHz,DMSO-d6)δ:1.10–1.23(m,4H,2xCH 2环丙基 ),2.35–2.44(m,1H,H 环丙基 ),7.05(s,1H,H 芳基 ),7.76(dd,J=6.2,2.9Hz,1H,H 芳基 ), 9.08 (d, J = 5.9 Hz, 1H, H 芳基 ),9.37(s,1H,H 芳基 ), 10.87(s, 1H, NH).

[1197] 13 CNMR(101MHz,DMSO-d6)δ:4.85(CH 环丙基 ),7.30(2xCH 2环丙基 ),98.78(CH 芳基 ),115.07(CH芳基 ),137.63(C q ),138.57(C q ),139.43(C q ),145.29(CH 芳基 ),149.72(C q ),151.17(CH 芳基 ),151.82(C q ).

[1198] MS(ESI+): m / z calculated value C 12 H 10 ClN7: 288.1 [M+H]+, measured value 288.2.

[1199] Example 3.77: Synthesis of 6-chloro-3-cyclopropyl-N-pyrimidin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.77)

[1200] To a solution of (2.5) (0.500 g, 2.183 mmol, 1.0 eq.) in anhydrous THF (16.77 mL), 4-aminopyrimidine (0.416 g, 4.366 mmol, 2.0 eq.) was added, followed by a solution of 1.65 M tBuOK in THF (2.65 mL, 4.366 mmol, 2.0 eq.), and the mixture was stirred at room temperature for 1.3 h. After this was complete, saturated NH4Cl (16.77 mL) and water (5.06 mL) were added, and the two-phase mixture was stirred vigorously for 5 min. The precipitate formed was filtered off, washed with H2O, Et2O, and pentane, and dried under vacuum to give a yellow solid (3.77) (0.463 g, 74%).

[1201] Rf(DCM / MeOH, 96 / 4): 0.31

[1202] 1 HNMR(400MHz,DMSO-d6)δ:1.11–1.23(m,4H,2xCH 2环丙基 ), 2.35–2.44 (m, 1H, CH) 环丙基 ), 7.58 (d, J = 5.8 Hz, 1H, H 芳基 ),8.36(s,1H,H 芳基 ), 8.62 (d, J = 5.8 Hz, 1H, H 芳基 ),9.00(s,1H,H 芳基 ),11.25(s,1H,NH).

[1203] 13CNMR(101MHz,DMSO-d6)δ:4.84(CH 环丙基 ),7.30(2xCH 2环丙基 ),102.66(CH 芳基 ),110.86(CH 芳基 ),135.79(C q ),139.05(C q ),149.69(C q ),151.85(C q ),157.08(CH 芳基 ),157.73(CH 芳基 ),159.67(C q ).

[1204] MS(ESI+): m / z calculated value C 12 H 10 ClN7: 288.1 [M+H]+, measured value 288.2.

[1205] Example 3.78: Synthesis of 6-chloro-3-cyclopropyl-N-(pyrimidin-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.78)

[1206] Add 5-aminopyrimidine (0.113 g, 1.179 mmol, 2.0 eq.) to anhydrous THF (4.53 mL) solution of (2.5 g) (0.135 g, 0.589 mmol, 1.0 eq.), then add a 1 M tBuOK THF solution (1.18 mL, 1.179 mmol, 2.0 eq.), and stir the mixture at room temperature for 1 hour. After completion, add saturated NH4Cl (4.53 mL) and water (1.35 mL), and then stir the two-phase mixture vigorously for 5 minutes. Separate the layers, extract the aqueous layer with EtOAc (2 x 10.0 mL), then combine the organic layers, dry with MgSO4, filter, and concentrate. Grind the residue in Et2O, filter, wash with Et2O, dissolve in DCM, and concentrate under vacuum to give a beige solid (3.78 g) (0.153 g, 90%).

[1207] Rf(DCM / MeOH, 92 / 8): 0.54

[1208] 1 HNMR(400MHz,DMSO-d6)δ:1.09–1.20(m,4H,2xCH 2环丙基 ),2.34–2.42(m,1H,H 环丙基 ),6.63(s,1H,H 芳基), 8.94(d, J = 1.4 Hz, 2H, 2xH 芳基 ), 9.05(d, J = 1.4 Hz, 1H, H 芳基 ),10.54(s,1H,NH).

[1209] 13 CNMR(101MHz,DMSO-d6)δ:4.86(CH 环丙基 ),7.26(2xCH 2环丙基 ),95.16(CH 芳基 ),133.99(C q ),139.34(C q ),139.54(C q ),149.85(C q ),151.58(2xCH 芳基 ),151.68(C q ),154.67(CH 芳基 ).

[1210] MS(ESI+): m / z calculated value C 12 H 10 ClN7: 288.1 [M+H]+, measured value 288.2.

[1211] Example 3.79: Synthesis of 6-chloro-3-cyclopropyl-N-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.79)

[1212] To a solution of (2.5) (0.100 g, 0.437 mmol, 1.0 eq.) in anhydrous THF (3.36 mL), 2-aminopyrimidine (0.084 g, 0.873 mmol, 2.0 eq.) was added, followed by a solution of 1 M tBuOK THF (0.87 mL, 0.873 mmol, 2.0 eq.), and the mixture was stirred at room temperature for 1.4 h. After this, saturated NH4Cl (3.36 mL) and water (1.0 mL) were added, and the two-phase mixture was stirred vigorously for 5 min. The layers were separated, the aqueous layer was extracted with EtOAc (2 x 5.0 mL), and the organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was ground in Et2O, filtered, washed with Et2O, and dried under vacuum to give a white solid (3.79) (0.100 g, 80%).

[1213] Rf(DCM / MeOH, 96 / 4): 0.57

[1214] 1HNMR(400MHz,DMSO-d6)δ:1.12–1.22(m,4H,2xCH 2环丙基 ),2.39(td,J=8.2,4.1Hz,1H,H 环丙基 ), 7.26(t, J = 4.8 Hz, 1H, H 芳基 ),8.15(s,1H,H 芳基 ), 8.79(d, J = 4.8 Hz, 2H, 2xH 芳基 ),10.28(s,1H,NH).

[1215] 13 CNMR(101MHz,DMSO-d6)δ:4.84(CH 环丙基 ),7.28(2xCH 2环丙基 ),99.52(C q ),101.30(CH 芳基 ),116.39(CH 芳基 ),136.08(C q ),138.96(C q ),149.82(C q ),151.82(C q ),158.64(2xCH 芳基 ).

[1216] MS(ESI+): m / z calculated value C 12 H 10 ClN7: 288.1 [M+H]+, measured value 288.2.

[1217] Example 3.80: Synthesis of 6-chloro-3-cyclopropyl-N-(pyrazin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (3.80)

[1218] To a solution of (2.5) (0.080 g, 0.349 mmol, 1.0 eq.) in anhydrous THF (2.68 mL), 2-aminopyrazine (0.066 g, 0.699 mmol, 2.0 eq.) was added, followed by 1 M tBuOK of THF (0.70 mL, 0.699 mmol, 2.0 eq.), and the mixture was stirred at room temperature for 1.2 h. After this, saturated NH4Cl (2.68 mL) and water (0.81 mL) were added, and the two-phase mixture was stirred vigorously for 5 min. The precipitate formed was filtered off and washed with H2O and Et2O to give a white solid (3.80) (0.072 g, 72%). The filtrate layers were separated, the aqueous layer was extracted with EtOAc (2 x 5.0 mL), and the organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was ground in Et₂O, filtered, washed with Et₂O, and vacuum dried to give a second portion (0.012 g, 12%) of (3.80), as a white solid. Total (3.80): 0.084 g, 84%.

[1219] Rf(DCM / MeOH,96 / 4):0.11

[1220] 1 HNMR(400MHz,DMSO-d6)δ:1.12–1.21(m,4H,2xCH 2环丙基 ),2.39(tt,J=8.0,5.3Hz,1H,H 环丙基 ),8.18(s,1H,H 芳基 ), 8.32(d, J = 2.8 Hz, 1H, H 芳基 ), 8.44–8.50 (m, 1H, H) 芳基 ),8.91(s,1H,H 芳基 ),11.29(s,1H,NH).

[1221] 13 CNMR(101MHz,DMSO-d6)δ:4.84(CH 环丙基 ),7.28(2xCH 2环丙基 ),100.30(CH 芳基 ),136.25(C q ),137.68(CH 芳基 ),138.02(CH 芳基 ),139.14(C q ),141.16(CH 芳基 ),149.80(C q ),150.63(C q ),151.81(C q ).

[1222] MS(ESI+): m / z calculated value C 12 H 10 ClN7: 288.1 [M+H]+, measured value 288.1.

[1223] Example 3.81: Synthesis of 6-chloro-3-cyclopropyl-N-(6-methoxypyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.81)

[1224] Under an inert atmosphere, 6-methoxypyridine-2-amine (0.103 g, 0.82 mmol, 1.5 eq.) was added to a solution of (2.5) (0.125 g, 0.55 mmol, 1.0 eq.) in anhydrous THF (7.5 mL), followed by a solution of 1 M tBuOK THF (0.82 mL, 0.82 mmol, 1.5 eq.). 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 EtOAc (2 x 5.0 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and the residue was purified by rapid chromatography using DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (3.81) (0.115 g, 67%) as a white solid.

[1225] Rf(DCM / MeOH,98 / 2):0.28

[1226] 1 HNMR(400MHz,DMSO-d6)δ:1.12–1.20(m,4H,2xCH 2环丙基 ),2.38(tt,J=8.0,5.4Hz,1H,H 环丙基 ),3.95(s,3H,OCH3),6.54(d,J=8.0Hz,1H,H 芳基 ), 7.16(d, J = 7.8 Hz, 1H, H 芳基 ), 7.72(t, J = 7.9 Hz, 1H, H 芳基 ),8.25(s,1H,H 芳基 ), 10.87(s, 1H, NH).

[1227] 13 CNMR (101MHz, DMSO-d6) δ: 4.9 (C q ),7.3(2xCH 2环丙基 ), 53.6(OCH3), 99.6(CH 芳基 ),103.7(CH芳基 ),106.3(CH 芳基 ),136.4(C q ),139.2(C q ),140.9(CH 芳基 ),149.8(C q ),151.7(C q ),152.0(C q ),162.4(C q ).

[1228] MS(ESI+): m / z calculated value C 14 H 13 ClN6O: 317.1 [M+H]+, measured value 317.3.

[1229] Example 3.82: Synthesis of 6-chloro-3-cyclopropyl-N-(2-methoxypyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.82)

[1230] Under an inert atmosphere, 2-methoxypyridine-3-amine (0.103 g, 0.82 mmol, 1.5 eq.) was added to a solution of (2.5) (0.125 g, 0.55 mmol, 1.0 eq.) in anhydrous THF (7.5 mL), followed by a solution of 1 M tBuOK THF (0.82 mL, 0.82 mmol, 1.5 eq.). 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 EtOAc (2 x 5.0 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and the residue was purified by rapid chromatography using DCM / MeOH (99 / 1 to 96 / 4) as eluent to give (3.82) (0.113 g, 65%) as a white solid.

[1231] Rf(DCM / MeOH,98 / 2):0.28

[1232] 1 HNMR(400MHz,DMSO-d6)δ:1.08–1.21(m,4H,2xCH 2环丙基 ),2.36(tt,J=7.6,5.1Hz,1H,H 环丙基 ), 3.90(s, 3H, OCH3), 5.85(s, 1H, H 芳基 ),7.11(dd,J=7.5,4.9Hz,1H,H 芳基 ), 7.78(dd, J = 7.6, 1.7 Hz, 1H, H 芳基),8.18(dd,J=4.9,1.8Hz,1H,H 芳基 ),9.99(s,1H,NH).

[1233] 13 CNMR (101MHz, DMSO-d6) δ: 4.9 (CH 环丙基 ),7.2(2xCH 2环丙基 ), 53.5(OCH3), 94.2(CH 芳基 ),117.5(CH 芳基 ),120.7(C q ),135.7(CH 芳基 ),139.3(C q ),140.5(C q ),145.0(CH 芳基 ),149.5(C q ),151.5(C q ),157.9(C q ).

[1234] MS(ESI+): m / z calculated value C 14 H 13 ClN6O: 317.1 [M+H]+, measured value 317.3.

[1235] Example 3.83: Synthesis of 6-chloro-3-cyclopropyl-N-(2-methoxypyrimidin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.83)

[1236] Under an inert atmosphere, a 0.5 M KHMDS toluene solution (1.83 mL, 0.92 mmol, 1.4 eq.) was added to an anhydrous THF (6.5 mL) solution of 2-methoxypyrimidin-4-amine (0.112 g, 0.85 mmol, 1.3 eq.). The mixture was stirred at room temperature for 10 minutes, and then (2.5) (0.150 g, 0.65 mmol, 1.0 eq.) 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 stirred vigorously for 5 minutes. The mixture was then concentrated with SiO2 to form a solid precipitate, which was purified by rapid chromatography using DCM / MeOH (99 / 1 to 95 / 5) as eluent to give a white solid (3.83) (0.097 g, 47%).

[1237] Rf(DCM / MeOH,96 / 4):0.22

[1238] 1HNMR(400MHz,DMSO-d6)δ:1.11–1.23(m,4H,2xCH 2环丙基 ),2.39(tt,J=8.1,5.3Hz,1H,H 环丙基 ), 3.95(s, 3H, CH 3-O ), 7.20(d, J = 5.6 Hz, 1H, H 芳基 ),8.30(s,1H,H 芳基 ), 8.39 (d, J = 5.6 Hz, 1H, H 芳基 ),11.21(s,1H,NH).

[1239] 13 CNMR (101MHz, DMSO-d6) δ: 4.8 (CH 环丙基 ),7.3(2xCH 环丙基 ),54.5(CH 3-O ),103.0(CH 芳基 ),104.4(CH 芳基 ),135.7(C q ),139.0(C q ),149.6(C q ),151.8(C q ),158.9(CH 芳基 ),161.7(C q ),164.4(C q ).

[1240] 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)

[1241] Under an inert atmosphere, a solution of 0.5 M KHMDS in toluene (1.83 mL, 0.92 mmol, 1.4 eq.) was added to an anhydrous THF (6.5 mL) solution of 6-methoxypyridazine-3-amine (0.112 g, 0.85 mmol, 1.3 eq.). The mixture was stirred at room temperature for 10 minutes, and then (2.5) (0.150 g, 0.65 mmol, 1.0 eq.) 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 form a solid precipitate, which was purified by rapid chromatography using DCM / MeOH (99 / 1 to 95 / 5) as the eluent to give a white solid (3.84) (0.110 g, 53%).

[1242] Rf(DCM / MeOH, 96 / 4): 0.34

[1243] 1 HNMR(400MHz,DMSO-d6)δ:1.17(dd,J=7.8,5.4Hz,4H,2xCH 2环丙基 ),2.39(tt,J=8.0,5.3Hz,1H,H 环丙基 ),4.02(s,3H,CH 3-O ), 7.32 (d, J = 9.4 Hz, 1H, H 芳基 ), 7.85 (d, J = 9.5 Hz, 1H, H 芳基 ),8.26(s,1H,H 芳基 ), 10.98 (s, 1H, NH).

[1244] 13 CNMR (101MHz, DMSO-d6) δ: 4.9 (CH 环丙基 ),7.3(2xCH 环丙基 ),54.4(CH 3-O ),100.3(CH 芳基 ),120.1(CH 芳基 ),124.0(CH 芳基 ),136.0(C q ),139.1(C q ),150.1(C q ),151.8(C q ),153.7(C q ),161.6(C q ).

[1245] 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)

[1246] To a solution of (2.5) (0.100 g, 0.44 mmol, 1.0 eq.) in THF / H₂O (6.0 / 0.1 mL), the corresponding amine dihydrochloride (0.103 g, 0.57 mmol, 1.3 eq.) and DIPEA (0.33 mL, 1.88 mmol, 4.3 eq.) were added, and the mixture was refluxed for 2 hours. After cooling, the precipitate was filtered and washed with THF. The solid was washed with water in another vacuum flask, and then washed again with THF in the first flask. The solid was dried under vacuum to give the first fraction (0.063 g) of (3.85). The organic filtrates were combined, dried over MgSO₄, concentrated, and the residue was purified by rapid chromatography using DCM / MeOH (98 / 2) as eluent to give the second fraction (0.018 g) of (3.85). Total (3.85): 0.081 g, 61%, as a white solid.

[1247] Rf(DCM / MeOH, 96 / 4): 0.18

[1248] 1 HNMR(400MHz,DMSO-d6)δ:1.06–1.16(m,4H,2xCH 2环丙基 ),2.32(tt,J=8.1,5.3Hz,1H,H 环丙基 ),4.89(s,2H,CH 2苄基 ),6.26(s,1H,H 芳基 ), 7.63–7.75(m,2H,2xH) 芳基 ),9.04(s,1H,NH 苄基 ),9.17(dd,J=4.0,2.6Hz,1H,H 芳基 ).

[1249] 13 CNMR (101MHz, DMSO-d6) δ: 4.8 (CH 环丙基 ),7.1(2xCH 2环丙基 ),45.7(CH 2苄基 ),92.0(CH 芳基 ),125.7(CH 芳基 ),127.5(CH 芳基 ),139.3(C q ),142.5(C q ),149.7(C q ),151.0(CH 芳基 ),151.4(C q ),159.3(C q ).

[1250] Example 3.86: Synthesis of 6-chloro-3-cyclopropyl-N-phenethyl-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.86)

[1251] To a solution of (2.5) (0.100 g, 0.44 mmol, 1.0 eq.) in THF / H₂O (6.0 / 0.1 mL), the corresponding amine hydrochloride (0.089 g, 0.57 mmol, 1.3 eq.) and DIPEA (0.23 mL, 1.31 mmol, 3.0 eq.) were added, and the mixture was refluxed for 1.5 hours. After cooling, the solvent was removed, and the residue was ground in water. The solid was filtered, washed with water, then washed with Et₂O, and dried under vacuum to give a white solid (3.86) (0.115 g, 84%).

[1252] Rf(DCM / MeOH, 96 / 4): 0.66

[1253] 1 HNMR(400MHz,DMSO-d6)δ:1.10(ddt,J=8.7,7.5,2.6Hz,4H,2xCH 2环丙基 ),2.31(tt,J=8.1,5.3Hz,1H,H 环丙基 ),2.94(dd,J=8.0,6.6Hz,2H,CH 2-CH2-NH ), 3.58 (d, J = 7.2 Hz, 2H, CH) 2-NH ),6.19(s,1H,H 芳基 ), 7.12–7.35(m,5H,5xH) 芳基 ), 8.48(s, 1H, NH).

[1254] 13 CNMR (101MHz, DMSO-d6) δ: 4.8 (CH 环丙基 ),7.2(2xCH 2环丙基 ),33.8(CH 2-CH2-NH ),43.5(CH 2-NH ),91.0(CH 芳基 ),126.2(CH 芳基 ),128.3(2xCH 芳基 ),128.9(CH 芳基 ),138.9(C q ),139.3(C q ),142.2(C q ),149.9(C q ),151.3(C q ).

[1255] MS(ESI+): m / z calculated value C 16 H 16 ClN5: 314.1 [M+H]+, measured value 314.2.

[1256] Example 3.87: Synthesis of 6-chloro-3-isopropyl-N-(6-methoxypyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.87)

[1257] The reaction was carried out in a solution of (2.1) (0.180 g, 0.78 mmol, 1 eq), an aminopyridine derivative (0.145 g, 1.17 mmol, 1.5 eq), and 1 MtBuOK of THF (1.17 mL, 1.17 mmol, 1.5 eq.) in anhydrous THF (10.8 mL), and stirred in a round flask at room temperature for 4 hours. After completion, saturated NH4Cl, water, and EtOAc were added. The reaction mixture was extracted twice with AcOEt, filtered with MgSO4, concentrated, and purified by rapid chromatography with DCM / MeOH (99 / 1 to 98 / 2) as eluent to give a pale orange solid (3.87 g) (0.175 g, 71%).

[1258] 1 HNMR(400MHz,DMSO)δ:10.04(s,1H),8.18(dd,J=4.9,1.8Hz,1H),7.78(dd,J=7.6,1.8Hz,1H),7.12 (dd,J=7.6,4.9Hz,1H),5.84(s,1H),3.91(s,3H),3.48(hept,J=6.9Hz,1H),1.41(d,J=7.0Hz,6H).

[1259] 13 CNMR(101MHz,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.

[1260] Example 3.88: Synthesis of 6-chloro-3-isopropyl-N-(6-methoxypyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.88)

[1261] The reaction was carried out in a solution of (2.1) (0.180 g, 0.78 mmol, 1 eq), aminopyridine derivative (0.145 g, 1.17 mmol, 1.5 eq), and 1 MtBuOK of THF solution (1.17 mL, 1.17 mmol, 1.5 eq.) in anhydrous THF (10.8 mL), and stirred in a round flask at room temperature for 4 hours. After completion, saturated NH4Cl, water, and EtOAc were added. The reaction mixture was extracted twice with AcOEt, filtered with MgSO4, concentrated, and purified by rapid chromatography with DCM / MeOH (99 / 1 to 98 / 2) as eluent to give a pale orange solid (3.88 g) (0.106 g, 43%).

[1262] 1 HNMR (400MHz, DMSO) δ: 10.32 (s, 1H), 8.24 (d, J = 2.7Hz, 1H), 7.80 (dd, J = 8.8, 2.7Hz, 1H), 6.93 (d,J=8.8Hz,1H),6.15(s,1H),3.88(s,3H),3.47(hept,J=6.9Hz,1H),1.41(d,J=6.9Hz,6H).

[1263] 13 CNMR(101MHz,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.

[1264] Example 3.89: Synthesis of 6-chloro-3-isopropyl-N-(5-methoxypyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.89)

[1265] The reaction was carried out in a solution of (2.1) (0.180 g, 0.78 mmol, 1 eq), aminopyridine derivative (0.145 g, 1.17 mmol, 1.5 eq), and 1 MtBuOK of THF solution (1.17 mL, 1.17 mmol, 1.5 eq.) in anhydrous THF (10.8 mL), and stirred in a round flask at room temperature for 4 hours. After completion, saturated NH4Cl, water, and EtOAc were added. The reaction mixture was extracted twice with AcOEt, filtered with MgSO4, concentrated, and purified by rapid chromatography with DCM / AcOEt (8 / 2 to 35 / 65) as the eluent to give a pale orange solid (3.8 g) (0.162 g, 65%).

[1266] 1HNMR (400MHz, DMSO) δ: 10.50 (s, 1H), 8.31 (d, J = 2.0Hz, 1H), 8.20 (d, J = 2.6Hz, 1H), 7. 49(s,1H),6.49(s,1H),3.86(s,3H),3.49(hept,J=6.9Hz,1H),1.41(d,J=6.9Hz,6H).

[1267] 13 CNMR(101MHz,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.

[1268] Example 3.90: Synthesis of 6-chloro-3-isopropyl-N-(4-methoxypyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.90)

[1269] The reaction was carried out in a solution of (2.1) (0.400 g, 1.73 mmol, 1 eq), aminopyridine derivative (0.322 g, 2.60 mmol, 1.5 eq), and 1 MtBuOK of THF solution (2.6 mL, 2.60 mmol, 1.5 eq) in anhydrous THF (20.0 mL), and stirred in a round flask at room temperature for 4 hours. After completion, saturated NH4Cl, water, and EtOAc were added. The reaction mixture was extracted twice with AcOEt, filtered with MgSO4, concentrated, and purified by rapid chromatography with DCM / AcOEt (8 / 2 to 35 / 65) eluent to give a brown solid (3.90 g) (0.261 g, 47%).

[1270] 1 HNMR (400MHz, DMSO) δ: 10.15 (s, 1H), 8.48 (d, J = 5.7Hz, 1H), 8.40 (s, 1H), 7.26 (d, J=5.7Hz,1H),5.74(s,1H),3.89(s,3H),3.53–3.41(m,1H),1.41(d,J=7.0Hz,6H).

[1271] 13 CNMR(101MHz,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.

[1272] Example 3.91: Synthesis of 6-chloro-3-isopropyl-N-(3-phenylpropyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.91)

[1273] To a solution of (2.1) (0.130 g, 0.56 mmol, 1.0 eq.) in THF (6.0 mL), the corresponding amine (0.152 g, 1.12 mmol, 2.0 eq.) and Et3N (0.16 mL, 1.12 mmol, 2.0 eq.) 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 rapid chromatography using DCM / MeOH (98 / 2) as eluent to give a white solid (3.91) (0.177 g, 95%).

[1274] Rf(DCM / MeOH,94 / 6):0.20

[1275] 1 HNMR(400MHz,DMSO-d6)δ:1.00–1.20(m,4H,2xCH 2环丙基 ),2.31(tt,J=8.1,5.3Hz,1H,H 环丙基 ),2.96(t,J=7.1Hz,2H,CH2),3.49–3.76(m,2H,CH2),6.24(s,1H,H 芳基 ),7.31(dd,J=7.8,4.8Hz,1H,H 芳基 ),7.71(dt,J=7.8,2.0Hz,1H,H 芳基 ),8.41(dd,J=4.8,1.7Hz,1H,H 芳基 ), 8.49(d, J = 2.3 Hz, 1H, H 芳基 ),8.52(s,1H,NH).

[1276] 13 CNMR(101MHz,DMSO-d6)δ:4.8(CH),7.1(2xCH2),30.9(CH2),42.9(CH2),91.1(CH 芳基 ),123.3(CH 芳基 ),134.4(C q ),136.4(CH 芳基 ),139.3(C q ),142.2(C q ),147.5(CH 芳基 ),149.9(C q ),150.0(CH aryl),151.3(Cq ).

[1277] Example 3.92: Synthesis of 6-chloro-3-isopropyl-N-(2-methoxypyrimidin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.92)

[1278] To a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) in anhydrous THF (5.4 mL), 2-methoxypyrimidine-4-amine (0.107 g, 0.81 mmol, 1.5 eq.) was added, followed by a solution of 1 M tBuOK THF (1.00 mL, 0.81 mmol, 1.5 eq.), and the mixture was stirred at room temperature for 4 hours. After this was completed, water (0.5 mL) and SiO2 were added to form a solid precipitate. The solvent was removed, and the crude product was purified by rapid chromatography using DCM / MeOH (99 / 1 to 96 / 4) as eluent to give a white solid (3.92) (0.113 g, 65%).

[1279] Rf(DCM / MeOH,95 / 5):0.32.

[1280] 1 HNMR(400MHz,DMSO-d6)δ:1.42(d,J=7.0Hz,6H,2xCH 3异丙基 ), 3.51(hept, J = 6.9 Hz, 1H, H 异丙基 ),3.96(s,3H,CH 3-O ), 7.24 (d, J = 5.6 Hz, 1H, H 芳基 ),8.34(s,1H,H 芳基 ), 8.42 (d, J = 5.6 Hz, 1H, H 芳基 ),11.30(s,1H,NH).

[1281] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.5(CH 异丙基 ),54.5(CH 3-O ),103.1(CH 芳基 ),104.4(CH 芳基 ),135.7(C q ),139.1(C q ),149.4(C q ),154.4(C q ),158.9(CH 芳基 ),161.7(C q),164.4(C q ).

[1282] MS(ESI+): m / z calculated value C 13 H 14 ClN7O: 320.1 [M+H]+, measured value 320.3.

[1283] Example 3.93: Synthesis of 6-chloro-3-isopropyl-N-(5-methoxypyrimidin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.93)

[1284] To a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) in anhydrous THF (5.4 mL), 5-methoxypyrimidine-4-amine (0.107 g, 0.81 mmol, 1.5 eq.) was added, followed by a solution of 1 M tBuOK THF (1.00 mL, 0.81 mmol, 1.5 eq.), and the mixture was stirred at room temperature for 4 hours. After completion, water (0.5 mL) and SiO2 were added to form a solid precipitate. The solvent was removed, and the crude product was purified by rapid chromatography using DCM / MeOH (99 / 1 to 98 / 2) as eluent to give a white solid (3.93) (0.130 g, 75%).

[1285] Rf(DCM / MeOH,95 / 5):0.39.

[1286] 1 HNMR(400MHz,DMSO-d6)δ:1.42(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.52 (p, J = 7.0 Hz, 1H, H 异丙基 ),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).

[1287] 13 CNMR (101MHz, DMSO-d6)δ:ND

[1288] MS(ESI+): m / z calculated value C 13 H 14 ClN7O: 320.1 [M+H]+, measured value 320.3.

[1289] Example 3.94: Synthesis of 6-chloro-3-isopropyl-N-(6-methoxypyrimidin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.94)

[1290] To a solution of (2.1) (0.125 g, 0.54 mmol, 1.0 eq.) in anhydrous THF (5.4 mL), 6-methoxypyrimidine-4-amine (0.107 g, 0.81 mmol, 1.5 eq.) was added, followed by a solution of 1 M tBuOK THF (1.00 mL, 0.81 mmol, 1.5 eq.), and the mixture was stirred at room temperature for 4 hours. Afterward, water (0.5 mL) and SiO2 were added to form a solid precipitate. The solvent was removed, and the crude product was purified by rapid chromatography using DCM / MeOH (99 / 1 to 96 / 4) as eluent to give a white solid (3.94) (0.105 g, 61%).

[1291] Rf(DCM / MeOH,95 / 5):0.59.

[1292] 1 HNMR(400MHz,DMSO-d6)δ:1.42(d,J=7.0Hz,6H,2xCH 3异丙基 ), 3.50 (hept, J = 6.9 Hz, 1H, H 异丙基 ),3.92(s,3H,CH 3-O ), 6.98 (d, J = 1.0 Hz, 1H, H) 芳基 ),8.30(s,1H,H 芳基 ), 8.70 (d, J = 0.9 Hz, 1H, H 芳基 ), 11.09(s, 1H, NH).

[1293] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.5(CH 异丙基 ),53.9(CH 3-O ),93.8(CH 芳基 ),102.0(CH 芳基 ),136.1(C q ),139.1(C q ),149.5(C q ),154.4(C q ),157.7(CH 芳基 ),161.0(C q ),169.8(C q ).

[1294] MS(ESI+): m / z calculated value C 13 H 14ClN7O: 320.1 [M+H]+, measured value 320.3.

[1295] 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)

[1296] To a solution of (2.1) (0.200 g, 0.87 mmol, 1.0 eq.) in anhydrous THF (8.7 mL), a solution of 0.5 M KHMDS in toluene (2.42 mL, 1.21 mmol, 1.4 eq.) was added, and the mixture was stirred at room temperature for 10 minutes. Then, 6-methoxypyridazine-3-amine (0.160 g, 1.21 mmol, 1.4 eq.) was added, and the mixture was stirred at room temperature for 5 hours. After this, saturated NH4Cl (0.5 mL) and water (0.5 mL) were added, and the solvent was removed. The crude product was purified by rapid chromatography using DCM / MeOH (99 / 1 to 95 / 5) as eluent to give a green solid (3.95) (0.075 g, 27%).

[1297] 1 HNMR(400MHz,DMSO-d6)δ:1.43(d,J=6.9Hz,6H,2xCH 3异丙基 ), 3.50 (hept, J = 7.0 Hz, 1H, H 异丙基 ),4.02(s,3H,CH 3-O ), 7.32 (d, J = 9.4 Hz, 1H, H 芳基 ), 7.86 (d, J = 9.4 Hz, 1H, H 芳基 ),8.27(s,1H,H 芳基 ), 11.03(s, 1H, NH).

[1298] 13 CNMR(101MHz,DMSO-d6)δ:19.8(2xCH 3异丙基 ),24.5(CH 异丙基 ),54.4(CH 3-O ),100.3(CH 芳基 ),120.1(CH 芳基 ),124.1(CH 芳基 ),136.1(C q ),139.2(C q ),149.9(C q ),153.7(C q ),154.3(C q ),161.7(C q).

[1299] MS(ESI+): m / z calculated value C 13 H 14 ClN7O: 320.1 [M+H]+, measured value 320.2.

[1300] Example 4: Synthesis of [1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine derivatives, as described in step 1 of scheme 1 or step 3 of scheme 2.

[1301]

[1302] Example 4.1: Synthesis of (2R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol (1)

[1303] (3.1) (0.100 g, 0.33 mmol, 1.0 eq.), NMP (1.0 mL), and the corresponding amine (0.42 mL, 5.30 mmol, 16.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 20 hours. After cooling, the mixture was poured into EtOAc (10 mL), and the organic layer was washed twice with water and brine. The organic layer was dried with Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (94 / 6) as eluent to give a pale yellow solid (1) (0.070 g, 61%).

[1304] Example 4.2: Synthesis of (2S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol (2)

[1305] In a 2–5 mL sealed tube equipped with a stir bar, (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (2.0 mL), and the corresponding amine (0.32 mL, 3.98 mmol, 6.0 eq.) were loaded. The vial was sealed and placed on a heating block and heated 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 washed with water. The residue was dissolved in EtOAc / MeOH (7 / 3), the organic filtrate was dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5, then 94 / 6) as the eluent to give a white solid (2) (0.094 g, 40%).

[1306] 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)

[1307] (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (2.0 mL), and serine alcohol (0.362 g, 3.98 mmol, 6.0 eq.) were loaded into a 2-5 mL sealed tube equipped with a stir bar. The tube was sealed and placed on a heating block and heated at 180 °C for 18 hours. After cooling, the mixture was poured into water (10 mL), the precipitate was filtered off, and the precipitate was washed with water. A new precipitate formed in the filtrate, which was filtered off and washed with water. The residue was dissolved in EtOAc / MeOH (7 / 3), the organic filtrate was dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5, then 94 / 6) as the eluent to give a white solid (3) (0.092 g, 39%).

[1308] Example 4.4: Synthesis of (2R,3R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1,3-diol (4)

[1309] (3.1) (0.175 g, 0.58 mmol, 1.0 eq.), NMP (1.75 mL), and D-threonine (0.754 g, 6.96 mmol, 12.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated 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 EtOAc (2 x 20 mL). The combined organic layers were washed with 0.1 M HCl (20 mL), then with brine, dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5, then 94 / 6) as eluent to give a white solid (4) (0.137 g, 64%).

[1310] Example 4.5: (2R,3R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1,3-diol (5)

[1311] (3.1) (0.175 g, 0.58 mmol, 1.0 eq.), NMP (1.75 mL), and D-threonine (0.754 g, 6.96 mmol, 12.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated 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 EtOAc (2 x 20 mL). The combined organic layers were washed with 0.1 M HCl (20 mL), then with brine, dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5, then 94 / 6) as eluent to give a white solid (5) (0.137 g, 64%).

[1312] Example 4.6: Synthesis of N-benzyl-3-isopropyl-6-morpholine-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (6)

[1313] (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (1.5 mL), and morpholine (0.82 mL, 9.28 mmol, 14.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated 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 EtOAc (2 x 25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (97 / 3 then 96 / 4) as eluent to give a white solid (6) (0.116 g, 50%).

[1314] 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)

[1315] (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 equivalent) were packed into a 2-5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated 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 EtOAc (2 x 15 mL), the combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5) as eluent to give a white solid (7) (0.087 g, 42%).

[1316] 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)

[1317] In a 2–5 mL vial equipped with a stir bar, (3.1) (0.250 g, 0.83 mmol, 1.0 equivalent), NMP (1.25 mL), and 2-[2-(2-aminoethoxy)ethoxy]ethylamine (0.97 mL, 6.63 mmol, 8.0 equivalent) were placed. The vial was sealed and heated under microwave irradiation at 180 °C for 4 hours. After cooling, the mixture was diluted in EtOAc (20 mL), and the organic layer was washed with water (40 mL). The aqueous layer was extracted with EtOAc (20 mL), the organic layers were combined, dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (97 / 3, then 86 / 14) as eluent to give a white crystalline solid (8) (0.125 g, 36%).

[1318] Example 4.9: Synthesis of 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]prop-1-ol (9)

[1319] (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (0.3 mL), and the corresponding amine (0.72 mL, 9.28 mmol, 14.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 17 hours. After cooling, the mixture was diluted in EtOAc (20.0 mL), and the organic layer was washed with a brine / water mixture (2 / 1, 3 x 20.0 mL). The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (96 / 4) as the eluent to give a white solid (9) (0.072 g, 32%).

[1320] Example 4.10: Synthesis of N8-benzyl-3-isopropyl-N6-(3-methoxypropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (10)

[1321] (3.1) (0.500 g, 1.66 mmol, 1.0 eq.), NMP (1.3 mL), and 3-methoxypropylamine (2.40 mL, 23.20 mmol, 14.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The tube was sealed and placed on a heating block and heated at 180 °C for 4 hours. After cooling, the mixture was diluted in EtOAc (40 mL) and the organic layer was washed three times with a brine / water (2 / 1, 3 x 50 mL) mixture. The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (97 / 3) as eluent to give a white solid (10) (0.460 g, 78%).

[1322] Example 4.11: Synthesis of 2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]ethanol (11)

[1323] (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (0.6 mL), and ethanolamine (0.57 mL, 9.28 mmol, 14.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 16 hours. After cooling, the mixture was diluted in EtOAc (20 mL) and the organic layer was washed three times with a brine / water (2 / 1, 3 x 20 mL) mixture. The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (96 / 4) as the eluent to give a white solid (11) (0.082 g, 38%).

[1324] Example 4.12: Synthesis of N8-benzyl-3-isopropyl-N6-(2-methoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (12)

[1325] (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (0.6 mL), and 2-methoxyethylamine (0.81 mL, 9.28 mmol, 14.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 16 hours. After cooling, the mixture was diluted in EtOAc (20 mL) and the organic layer was washed three times with a brine / water (2 / 1, 3 x 20 mL) mixture. The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5) as the eluent to give a white crystalline solid (12) (0.152 g, 67%).

[1326] Example 4.13: Synthesis of 3-isopropyl-N6,N8-bis(2-methoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (112)

[1327] (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (0.6 mL), and 2-methoxyethylamine (0.81 mL, 9.28 mmol, 14.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The tube was sealed and then placed on a heating block and heated at 180 °C for 16 hours. After cooling, the mixture was diluted in EtOAc (20 mL) and the organic layer was washed three times with a brine / water (2 / 1, 3 x 20 mL) mixture. The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5) as the eluent to give a beige solid secondary compound (112) (0.052 g, 25%).

[1328] Example 4.14: Synthesis of 4-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol (13)

[1329] (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 equivalent) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 16 hours. After cooling, the mixture was diluted in EtOAc (40.0 mL), and the organic layer was washed with a brine / water (2 / 1, 3 x 50 mL) mixture. The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (96 / 4) as the eluent to give a white solid (13) (0.220 g, 47%).

[1330] Example 4.15: Synthesis of N8-benzyl-3-isopropyl-N6-(4-methoxybutyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (14)

[1331] (3.1) (0.100 g, 0.33 mmol, 1.0 eq.), NMP (1.0 mL), and the corresponding amine (0.249 g, 2.65 mmol, 8.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was then sealed, placed on a heating block, and heated at 170 °C for 17 hours. After cooling, the mixture was diluted in EtOAc (20.0 mL), the organic layer was washed three times with a brine / water (3 / 1, 3 x 10 mL) mixture, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1 to 95 / 5) as the eluent to give a white crystalline solid (14) (0.096 g, 79%).

[1332] Example 4.16: Synthesis of 5-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]pentan-1-ol (15)

[1333] (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 equivalent) were loaded into a 2-5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 16 hours. After cooling, the mixture was diluted in EtOAc (40.0 mL), and the organic layer was washed with a brine / 0.05 M HCl mixture (2 / 1, 3 x 40 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5) as eluent to give a white solid (15) (0.250 g, 51%).

[1334] Example 4.17: Synthesis of N8-benzyl-3-isopropyl-N6-(5-methoxypentyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (16)

[1335] (3.1) (0.100 g, 0.33 mmol, 1.0 eq.), NMP (1.0 mL), and the corresponding amine (0.327 g, 2.65 mmol, 8.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was then sealed, placed on a heating block, and heated at 170 °C for 17 hours. After cooling, the mixture was diluted in EtOAc (20.0 mL), the organic layer was washed three times with a brine / water (3 / 1, 3 x 10 mL) mixture, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1 to 95 / 5) as the eluent to give a pale yellow solid (16) (0.100 g, 79%).

[1336] Example 4.18: Synthesis of N8-benzyl-3-isopropyl-N6-(3-methylthiopropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (17)

[1337] (3.1) (0.250 g, 1.30 mmol, 1.0 eq.), NMP (0.75 mL), and 3-methylthiopropyl-1-amine (1.46 mL, 13.02 mmol, 10.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The tube was sealed and placed on a heating block and heated at 180 °C for 2 hours. After cooling, the mixture was diluted in EtOAc (30 mL) and the organic layer was washed three times with a brine / water (2 / 1, 3 x 30 mL) mixture. The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (96 / 4) as the eluent to give a beige solid (17) (0.270 g, 88%).

[1338] Example 4.19: Synthesis of N8-benzyl-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (18)

[1339] In a 2–5 mL vial equipped with a stir bar, (3.1) (0.250 g, 0.83 mmol, 1.0 equivalent), NMP (0.8 mL), and pentyl-3-amine (0.88 mL, 7.46 mmol, 9.0 equivalent) were placed. The vial was sealed and placed on a heating block and heated at 180 °C for 24 hours. After cooling, the mixture was diluted in EtOAc (20 mL) and the organic layer was washed three times with a brine / water mixture (2 / 1, 3 x 20 mL). The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (97 / 3) as the eluent. The fraction containing trace amounts of NMP was concentrated, diluted in EtOAc (20 mL), washed three times with water (3 x 25 mL), and the organic layer was dried over Na₂SO₄, filtered, and concentrated to give a white crystalline solid (18) (0.096 g, 33%).

[1340] 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)

[1341] In 2–5 mL vials equipped with a stir bar, (3.1) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (0.6 mL), and the corresponding amine (0.84 mL, 9.28 mmol, 14.0 eq.) were placed. The vials were sealed and placed on a heating block and heated at 180 °C for 24 hours. After cooling, the mixture was diluted in EtOAc (30.0 mL), and the organic layer was washed with a brine / water (2 / 1, 3 x 20 mL) mixture. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (96 / 4) as the eluent to give a white solid (19) (0.149 g, 64%).

[1342] 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)

[1343] (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 equivalent) were loaded into a 2-5 mL sealed tube equipped with a stir bar. The tube was sealed and placed on a heating block and heated at 170 °C for 23 hours. After cooling, water (7.0 mL) was added and stirred for 5 minutes. The resulting dough ball was filtered, washed with water, and then dissolved in DCM. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as eluent to give a white solid (20) (0.071 g, 38%).

[1344] 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)

[1345] (3.1) (0.420 g, 1.24 mmol, 1.0 eq.), dioxane (1.2 mL), and benzylamine (0.83 mL, 7.42 mmol, 6.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The tube was sealed and placed on a heating block and heated 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 x 10 mL), the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (97 / 3 to 95 / 5) as the eluent to give a white solid (21) (0.175 g, 39%).

[1346] 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)

[1347] (3.1) (0.250 g, 0.83 mmol, 1.0 equivalent) and NMP (3.5 mL) were loaded into a 2–5 mL sealed tube equipped with a stir bar, followed by (3S)-tetrahydropyran-3-amine hydrochloride (1.080 g, 7.46 mmol, 9.0 equivalent) and K2CO3 (0.555 g, 3.98 mmol, 4.8 equivalent). The vial was sealed and placed on a heating block and heated at 180 °C for 15 hours. After cooling, the mixture was poured into water (50 mL), stirred vigorously for 5 min, and the resulting precipitate was filtered off. The precipitate was washed with water (to neutral pH) and then with EtOAc. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (97 / 3 to 95 / 5) as eluent to give a white crystalline solid (22) (0.040 g, 13%).

[1348] 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)

[1349] (3.1) (0.250 g, 0.83 mmol, 1.0 eq.) and the corresponding amine (1.29 mL, 12.43 mmol, 15.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The tube was then sealed and placed on a heating block and heated at 180 °C for 5.5 h. After cooling, the mixture was diluted in EtOAc (3.0 mL), and water (3.0 mL) was added. The two phases were stirred for 5 min. The layers were separated, and the aqueous layer was extracted twice with EtOAc (2 x 3.0 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (94 / 6) as the eluent to give a beige solid (23) (0.085 g, 28%).

[1350] Example 4.25: Synthesis of N-[3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propyl]acetyl (24)

[1351] In a 2–5 mL sealed tube equipped with a stir 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 equivalent) were added. The vial was sealed and placed on a heating block and heated at 180 °C for 15 hours. After cooling, the mixture was diluted in EtOAc (20.0 mL), and the organic layer was washed with brine / water (2 / 1, 3 x 20.0 mL), dried with Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (96 / 4) as the eluent to give a white solid (24) (0.118 g, 94%).

[1352] Example 4.26: 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propionic acid (4.26)

[1353] In a 10–20 mL sealed tube equipped with a stir bar, (3.1) (0.800 g, 2.65 mmol, 1.0 eq.) and DMSO (6.5 mL) were added, followed by β-alanine (1.431 g, 15.91 mmol, 6.0 eq.) and K3PO4 (3.376 g, 15.91 mmol, 6.0 eq.). The vial was sealed and placed on a heating block and heated at 180 °C for 4 hours. After cooling, the mixture was poured into an ice bath with 1 M HCl (150 mL) and water (40 mL). After 20 minutes, the precipitate was filtered, washed with water (to pH 7), and the solid was dissolved in ethanol and acetone, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 92 / 8, then 92 / 8) as the eluent to give a beige solid (4.26) (0.505 g, 54%).

[1354] Rf(DCM / MeOH, 92 / 8): 0.30

[1355] 1 HNMR(400MHz,DMSO-d6)δ:1.36(d,J=7.0Hz,6H,2xCH 3异丙基 ),2.51(m,2H,CH 2-CO ), 3.34(d, J = 9.7 Hz, 3H, H 异丙基 &CH 2-NH ), 4.42(d, J = 6.2 Hz, 2H, CH 2苄基 ),5.39(s,1H,H 芳基 ),6.64(t,J=5.4Hz,1H,NH),7.17–7.43(m,5H,5xH 芳基), 7.93(t, J = 6.4 Hz, 1H, NH 苄基 ),12.16(s,1H,COOH).

[1356] 13 CNMR(101MHz,DMSO-d6)δ:19.6(2xCH 3异丙基 ),24.7(CH 异丙基 ),33.3(CH 2-CO ),36.9(CH 2-NH ),45.2(CH 2苄基 ),84.1(CH 芳基 ),126.8(2xCH 芳基 ),126.9(CH 芳基 ),128.4(2xCH 芳基 ),138.3(C q ),139.7(C q ),139.9(C q ),152.9(C q ),155.7(C q ),173.2(C q ).

[1357] MS(ESI+): m / z calculated value C 18 H 22 N6O2: 355.19 [M+H]+, measured value 355.27.

[1358] Example 4.27: Synthesis of 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propionamide (25)

[1359] To a THF (3.1 mL) solution of (4.26) (0.110 g, 0.31 mmol, 1.0 eq.), HOBt·H2O (0.062 g, 0.40 mmol, 1.3 eq.), EDCI (0.058 g, 0.37 mmol, 1.2 eq.), and a THF solution of 0.5 M ammonia (0.81 mL, 0.40 mmol, 1.3 eq.) was added. The mixture was stirred at room temperature for 4 hours. After stirring, the mixture was directly concentrated and purified by rapid chromatography using DCM / MeOH (94 / 6) as the eluent to obtain a white solid (25) (0.090 g, 82%).

[1360] Example 4.28: Synthesis of 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]-N-methylpropionamide (26)

[1361] To a THF (3 mL) solution of (4.26) (0.120 g, 0.34 mmol, 1.0 eq.), HOBt·H2O (0.069 g, 0.44 mmol, 1.3 eq.), a THF solution of 2 M methylamine (0.24 mL, 0.47 mmol, 1.4 eq.), and EDCi (0.065 g, 0.41 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature for 3 hours. After stirring, the mixture was directly concentrated and purified by rapid chromatography using DCM / MeOH (95 / 5) as the eluent to obtain a white solid (26) (0.121 g, 97%).

[1362] Example 4.29: Synthesis of 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]-N,N-dimethylpropionamide (27)

[1363] To a THF (3 mL) solution of (4.26) (0.120 g, 0.34 mmol, 1.0 equivalent), HOBt·H2O (0.069 g, 0.44 mmol, 1.3 equivalent), a 2 M dimethylamine THF solution (0.24 mL, 0.47 mmol, 1.4 equivalent), and EDCi (0.065 g, 0.41 mmol, 1.2 equivalent) were added. The mixture was stirred at room temperature for 3 hours. After stirring, the mixture was directly concentrated and purified by rapid chromatography using DCM / MeOH (95 / 5) as eluent to obtain a white solid (27) (0.124 g, 96%).

[1364] Example 4.30: Synthesis of methyl 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propionate (28)

[1365] A solution of (4.26) (0.110 g, 2.65 mmol, 1.0 eq.) in 10 mL of MeOH was refluxed with two drops of H₂SO₄ 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 rapid chromatography using DCM / MeOH (95 / 5) as the eluent to give a white solid (28) (0.100 g, 87%).

[1366] Example 4.31: Synthesis of ethyl 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propionate (29)

[1367] A solution of (4.26) (0.110 g, 2.65 mmol, 1.0 eq.) in ethanol (10 mL) was refluxed with two drops of H2SO4 for 30 minutes. After cooling, Na2CO3 (0.075 g) was added and stirred at room temperature for 5 minutes. The mixture was directly concentrated and purified by rapid chromatography using DCM / MeOH (94 / 6) as eluent to give a white solid (29) (0.082 g, 69%).

[1368] Example 4.32: Synthesis of (2R)-2-[[8-(benzylamino)-3-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol (30)

[1369] (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 equivalent) were loaded into a 2-5 mL sealed tube equipped with a stir bar. The tube was sealed and placed on a heating block and heated at 180 °C for 18 hours. After cooling, the mixture was poured into EtOAc (20 mL), and the organic layer was washed three times with brine (20 mL). The organic layer was dried with Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (96 / 4) as eluent to give a beige solid (30) (0.112 g, 71%).

[1370] Example 4.33: Synthesis of N8-benzyl-3-cyclopropyl-N6-(3-methoxypropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (31)

[1371] (3.3) (0.250 g, 0.83 mmol, 1.0 eq.), NMP (0.8 mL), and 3-methoxypropylamine (1.21 mL, 11.68 mmol, 14.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The tube was sealed and placed on a heating block and heated at 180 °C for 18 hours. After cooling, the mixture was diluted in EtOAc (30 mL) and the organic layer was washed three times with a brine / water (2 / 1, 3 x 20 mL) mixture. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (97 / 3) as the eluent to give a white solid (31) (0.145 g, 49%).

[1372] Example 4.34: Synthesis of 3-cyclopropyl-N6,N8-bis(3-methoxypropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (110)

[1373] (3.3) (0.250 g, 0.83 mmol, 1.0 eq.), NMP (0.8 mL), and 3-methoxypropylamine (1.21 mL, 11.68 mmol, 14.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 18 hours. After cooling, the mixture was diluted in EtOAc (30 mL) and the organic layer was washed three times with a brine / water (2 / 1, 3 x 20 mL) mixture. The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (97 / 3) as eluent to give a white solid compound (110) (0.120 g, 43%).

[1374] Example 4.35: Synthesis of N8-benzyl-N6-(3-methoxypropyl)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (32)

[1375] (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 equivalent) were loaded into a 2-5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 16 hours. After cooling, the mixture was diluted in EtOAc (20.0 mL), the organic layer was washed with brine (3 x 10.0 mL), dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5) as eluent to give a white solid (32) (0.086 g, 58%).

[1376] Example 4.36: Synthesis of (2R)-2-[[8-(benzylamino)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol (33)

[1377] (3.6) (0.125 g, 0.46 mmol, 1.0 equivalence), NMP (0.4 mL), and (R)-(-)-2-amino-1-butanol (0.51 mL, 5.48 mmol, 12.0 equivalence) were packed into a 2-5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 16 hours. After cooling, the mixture was diluted in EtOAc (20.0 mL), the organic layer was washed with brine (3 x 10.0 mL), dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5) as eluent to give a white solid (33) (0.086 g, 58%).

[1378] Example 4.37: Synthesis of N8-benzyl-N6-(3-methoxypropyl)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (34)

[1379] (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 equivalent) were loaded into a 2-5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 18 hours. After cooling, the mixture was diluted in EtOAc (25.0 mL), the organic layer was washed with brine / water (2 / 1, 3 x 20.0 mL), washed with Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5) as eluent to give a white solid (34) (0.086 g, 58%).

[1380] Example 4.38: Synthesis of N6,N8-bis(3-methoxypropyl)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (109)

[1381] (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 equivalent) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 18 hours. After cooling, the mixture was diluted in EtOAc (25.0 mL), the organic layer was washed with brine / water (2 / 1, 3 x 20.0 mL), washed with Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5) as eluent to give a white solid secondary compound (109) (0.055 g, 39%).

[1382] Example 4.39: Synthesis of (2R)-2-[[8-(benzylamino)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol (35)

[1383] (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 equivalent) were packed into a 2-5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 18 hours. After cooling, the mixture was diluted in EtOAc (25.0 mL), the organic layer was washed with brine / water (2 / 1, 3 x 20.0 mL), dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (95 / 5) as eluent to give a white solid (35) (0.115 g, 65%).

[1384] Example 4.40: Synthesis of N8-benzyl-N6-(3-methoxypropyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (36)

[1385] (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 equivalent) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 18 hours. After cooling, the mixture was diluted in EtOAc (20.0 mL) and the organic layer was washed three times with a brine / water (2 / 1, 3 x 20 mL) mixture. The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1) as eluent to give a white solid (36) (0.110 g, 76%).

[1386] Example 4.41: Synthesis of N6,N8-bis(3-methoxypropyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (111)

[1387] (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 equivalent) were loaded into a 2–5 mL sealed vial equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 18 hours. After cooling, the mixture was diluted in EtOAc (20.0 mL) and the organic layer was washed three times with a brine / water (2 / 1, 3 x 20 mL) mixture. The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1) as eluent to give a white solid secondary compound (111) (0.010 g, 7%).

[1388] Example 4.42: Synthesis of (2R)-2-[[8-(benzylamino)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol (37)

[1389] (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 equivalent) were loaded into a 2-5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 18 hours. After cooling, the mixture was diluted in EtOAc (20.0 mL) and the organic layer was washed three times with a brine / water (2 / 1, 3 x 20 mL) mixture. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (97 / 3) as eluent to give a white solid (37) (0.070 g, 55%).

[1390] Example 4.43: Synthesis of (2R)-2-[[8-(benzylamino)-3-isopropyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol (115)

[1391] Under an inert atmosphere, 60% NaH (0.119 g, 2.98 mmol, 1.0 eq.) was added in portions to a solution of (1) (0.880 g, 2.48 mmol, 1.0 eq.) and anhydrous THF (48.0 mL), and the mixture was stirred at room temperature for 10 minutes. The solution was cooled at 0 °C, and MeI (0.17 mL, 2.73 mmol, 1.1 eq.) was added dropwise, followed by stirring at room temperature for 2 hours. To complete the reaction, MeI (0.03 mL, 0.50 mmol, 0.2 eq.) was added, and the mixture was stirred for 1 hour. After completion, MeOH (9.0 mL) was slowly added, and the mixture was directly concentrated with SiO2 to form a solid deposit. The deposit was purified by rapid chromatography using DCM / MeOH (98 / 2 to 96 / 4) as the eluent to give a beige solid secondary compound (115) (0.092 g, 10%).

[1392] Example 4.44: Synthesis of 2-[[[6-[[(1R)-1-(hydroxymethyl)propyl]amino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (38)

[1393] (3.8) (0.150 g, 0.47 mmol, 1.0 eq.) and (R)-(-)-2-amino-1-butanol (0.91 mL, 9.44 mmol, 20.0 eq.) were loaded into a 2–5 mL sealed vial equipped with a stir bar. The vial was then sealed and placed on a heating block and heated at 160 °C for 15 hours. After cooling, the mixture was diluted in EtOAc (25.0 mL), the organic layer was washed twice with a water / salt mixture (1 / 3, 2 x 30.0 mL), dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (96 / 4 to 92 / 8) as eluent to give the target compound (38) (0.010 g, 6%) as a beige solid.

[1394] Example 4.45: Synthesis of 2-[[[3-isopropyl-6-(3-methoxypropylamino)-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (39)

[1395] (3.8) (0.150 g, 0.47 mmol, 1.0 eq.) and 3-methoxypropylamine (1.07 mL, 9.44 mmol, 20.0 eq.) were loaded into a 2–5 mL sealed vial equipped with a stir bar. The vial was then sealed and placed on a heating block and heated at 150 °C for 19 hours. After cooling, the mixture was diluted in EtOAc (25.0 mL), the organic layer was washed twice with a water / salt mixture (1 / 3, 2 x 30.0 mL), dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (93 / 7 to 92 / 8) as eluent to give the target compound (39) (0.070 g, 40%) as a white solid.

[1396] Example 4.46: Synthesis of 2-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (40)

[1397] (3.8) (0.140 g, 0.44 mmol, 1.0 eq.), NMP (1.0 mL), and 3-aminopentane (0.52 mL, 4.41 mmol, 10.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The tube was sealed and placed on a heating block and heated at 170 °C for 16 hours. After cooling, the mixture was diluted in EtOAc (20.0 mL) and the organic layer was washed three times with a brine / water (2 / 1, 3 x 20 mL) mixture. The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 95 / 5) as eluent to give a white crystalline solid (40) (0.021 g, 13%).

[1398] Example 4.47: Synthesis of 3-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (41)

[1399] In a 2–5 mL sealed tube equipped with a stir 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 equivalent) were loaded. The tube was sealed and placed on a heating block and heated at 170 °C for 16 hours. After cooling, the mixture was poured into saturated NaHCO3 (20.0 mL), followed by the addition of water (30.0 mL), and the mixture was stirred for 5 minutes. The resulting solid was filtered off, washed with water to neutral pH, and then dissolved in DCM. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as eluent to give a white solid (41) (0.080 g, 15%).

[1400] Example 4.48: Synthesis of 4-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (42)

[1401] (3.10) (0.085 g, 0.27 mmol, 1.0 eq.), NMP (1.0 mL), and 3-aminopentane (0.31 mL, 2.68 mmol, 10.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The tube was sealed and placed on a heating block and heated at 170 °C for 16 hours. After cooling, the mixture was diluted in EtOAc (20.0 mL) and the organic layer was washed three times with a brine / water mixture (2 / 1, 3 x 10.0 mL). The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 95 / 5) as eluent to give a white crystalline solid (42) (0.015 g, 15%).

[1402] Example 4.49: Synthesis of 2-[[[3-isopropyl-6-[[(3R)-tetrahydropyran-3-yl]amino]-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (43)

[1403] (3.8) (0.200 g, 0.63 mmol, 1.0 eq.), the corresponding amine hydrochloride (0.912 g, 6.29 mmol, 10.0 eq.), and DIPEA (1.54 mL, 8.81 mmol, 14.0 eq.) were loaded into a 2–5 mL sealed vial equipped with a stir bar. The vial was then sealed and placed on a heating block and heated 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 neutral pH, and dissolved in EtOAc. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (96 / 4 to 94 / 6) as eluent to give a white solid (43) (0.018 g, 7%).

[1404] Example 4.50: Synthesis of 2-[[[3-isopropyl-6-(tetrahydropyran-4-ylamino)-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol (44)

[1405] (3.8) (0.250 g, 0.79 mmol, 1.0 eq.) and the corresponding amine (0.98 mL, 9.44 mmol, 12.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was then sealed and placed on a heating block and heated at 160 °C for 15 hours. After cooling, EtOAc (4.0 mL) and water (4.0 mL) were added, and the mixture was stirred for 5 minutes. The layers were then separated. The aqueous layer was extracted twice with EtOAc (2 x 3.0 mL), and the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (96 / 4 to 93 / 7) as the eluent to give a white solid (44) (0.030 g, 10%).

[1406] Example 4.51: Synthesis of (2S)-2-[[8-[(4-bromophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol (101)

[1407] (3.42) (1.800 g, 4.73 mmol, 1.0 eq.), NMP (5.0 mL), and (2S)-2-aminobut-1-ol (8.12 mL, 85.11 mmol, 18.0 eq.) were loaded into a 10–20 mL sealed tube equipped with a stir bar. The vial was then sealed and placed on a heating block and heated at 180 °C for 24 hours. After cooling, the reaction mixture was poured into water (100.0 mL), stirred vigorously for 5 minutes, and the aqueous mixture was extracted with EtOAc (3 x 30.0 mL). The organic layers were combined, washed with brine (20.0 mL), dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 93 / 7) as eluent to give a beige solid (101) (1.290 g, 63%).

[1408] 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)

[1409] (3.42) (1.800 g, 4.73 mmol, 1.0 eq.), NMP (5.0 mL), and (2S)-2-aminobut-1-ol (8.12 mL, 85.11 mmol, 18.0 eq.) were loaded into a 10–20 mL sealed tube equipped with a stir bar. The vial was then sealed and placed on a heating block and heated at 180 °C for 24 hours. After cooling, the reaction mixture was poured into water (100.0 mL), stirred vigorously for 5 minutes, and the aqueous mixture was extracted with EtOAc (3 x 30.0 mL). The organic layers were combined, washed with brine (20.0 mL), dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 93 / 7) as eluent to give a white solid secondary compound (116) (0.300 g, 17%).

[1410] Example 4.53: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (45)

[1411] (3.12) (0.090 g, 0.31 mmol, 1.0 eq.), eucalyptol (0.7 mL), and 3-aminopentane (0.55 mL, 4.69 mmol, 15.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 170 °C for 40 hours. After cooling, the mixture was concentrated with SiO2 to form a solid precipitate, and then directly purified by rapid chromatography using DCM / MeOH (99 / 1 to 97 / 3) as the eluent to give a white solid (45) (0.010 g, 9%).

[1412] Example 4.54: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-(2-pyridine)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (46)

[1413] (3.13) (0.090 g, 0.31 mmol, 1.0 eq.), eucalyptol (0.7 mL), and 3-aminopentane (0.55 mL, 4.68 mmol, 15.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 170 °C for 40 hours. After cooling, the mixture was concentrated with SiO2 to form a solid deposit, which was then directly purified by rapid chromatography using DCM / MeOH (99 / 1 to 97 / 3) as the eluent to give a beige solid (46) (0.021 g, 20%).

[1414] Example 4.55: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-(3-pyridine)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (47)

[1415] (3.14) (0.090 g, 0.31 mmol, 1.0 eq.), eucalyptol (0.7 mL), and 3-aminopentane (0.55 mL, 4.68 mmol, 15.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 170 °C for 40 hours. After cooling, the mixture was concentrated with SiO2 to form a solid deposit, which was then directly purified by rapid chromatography using DCM / MeOH (99 / 1 to 96 / 4) as the eluent to give a beige solid (47) (0.025 g, 24%).

[1416] Example 4.56: Synthesis of N6-(1-ethylpropyl)-3-isopropyl-N8-(4-pyridine)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (48)

[1417] (3.15) (0.090 g, 0.31 mmol, 1.0 eq.), eucalyptol (0.7 mL), and 3-aminopentane (0.55 mL, 4.68 mmol, 15.0 eq.) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 170 °C for 40 hours. After cooling, the mixture was concentrated with SiO2 to form a solid precipitate, and then directly purified by rapid chromatography using DCM / MeOH (99 / 1 to 95 / 5) as the eluent to give a white solid (48) (0.060 g, 57%).

[1418] 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)

[1419] (3.16) (0.100 g, 0.33 mmol, 1.0 eq.), NMP (0.17 mL), and 3-aminopentane (0.58 mL, 4.95 mmol, 15.0 eq.) were loaded into a 2–5 mL sealed vial equipped with a stir bar. The vial was then sealed and placed on a heating block, and heated at 160 °C for 15 hours. To complete the reaction, NMP (0.34 mL) was added, the vial was sealed, and placed on a heating block, and heated at 180 °C for 23 hours. After cooling, the mixture was diluted in EtOAc (10.0 mL), and the organic layer was washed three times with a brine / water mixture (2 / 1, 3 x 10.0 mL). The organic layer was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1 to 95 / 5) as eluent to give a white solid (49) (0.054 g, 46%).

[1420] 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)

[1421] In a 10–20 mL sealed tube equipped with a stir bar, (3.17) (0.580 g, 1.92 mmol, 1.0 eq.), NMP (4.1 mL), and 3-aminopentane (4.06 mL, 34.48 mmol, 18.0 eq.) were loaded. The tube was then sealed and placed on a heating block and heated at 180 °C for 20 hours. After cooling, the mixture was poured into saturated NaHCO3 (20.0 mL), the tube was rinsed, and the volume was adjusted to 80.0 mL with water. The mixture was then stirred for 10 minutes. The resulting precipitate was filtered off, washed with water to neutral pH, and the solid was washed with EtOAc in a separate flask. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as eluent to give a pale pink solid (50) (0.160 g, 24%).

[1422] 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)

[1423] (3.18) (0.750 g, 2.48 mmol, 1.0 eq.), NMP (5.0 mL), and 3-aminopentane (4.96 mL, 42.11 mmol, 17.0 eq.) were loaded into a 10–20 mL sealed tube equipped with a stir bar. The tube was then sealed and placed on a heating block and heated at 180 °C for 69 hours. After cooling, the mixture was poured into saturated NaHCO3 (20.0 mL), the tube was rinsed, and the volume was adjusted to 80.0 mL with water. The mixture was then stirred for 10 minutes. The resulting precipitate was filtered off, washed with water to neutral pH, and the solid was washed with DCM in a separate flask. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as eluent to give a white solid (51) (0.420 g, 48%).

[1424] 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)

[1425] (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 equivalent) were loaded into a 2–5 mL sealed vial equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 170 °C for 65 hours. After cooling, the reaction mixture was poured into brine / water (1 / 1, 30 mL) and stirred vigorously for 5 minutes. The resulting precipitate was filtered, washed with water, dissolved in DCM, and the organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1 to 93 / 7) as eluent to give a white solid (52) (0.020 g, 7%).

[1426] Example 4.61: Synthesis of 3-isopropyl-N8-(2-pyridylmethyl)-N6-spiro[3.3]hept-2-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (53)

[1427] In a 2–5 mL sealed tube equipped with a stir bar, (3.18) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (1.0 mL), the corresponding amine hydrochloride (0.399 g, 2.64 mmol, 4.0 eq.), and DIPEA (0.69 mL, 3.96 mmol, 6.0 eq.) were loaded. The vial was sealed and placed on a heating block and heated 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 EtOAc, filtered, and the organic filtrate was dried with MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 93 / 7) as eluent to give a gray solid (53) (0.035 g, 14%).

[1428] 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)

[1429] In a 2–5 mL sealed tube equipped with a stir bar, (3.18) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (1.0 mL), the corresponding amine hydrochloride (0.399 g, 2.64 mmol, 4.0 eq.), and DIPEA (0.69 mL, 3.96 mmol, 6.0 eq.) were loaded. The vial was sealed and placed on a heating block and heated 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 EtOAc, filtered, and the organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 93 / 7) as eluent to give a beige solid (54) (0.035 g, 14%).

[1430] 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)

[1431] In a 2–5 mL sealed tube equipped with a stir bar, (3.18) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (1.0 mL), the corresponding amine hydrochloride (0.399 g, 2.64 mmol, 4.0 eq.), and DIPEA (0.69 mL, 3.96 mmol, 6.0 eq.) were loaded. The vial was sealed and placed on a heating block and heated 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 EtOAc, filtered, and the organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 93 / 7) as eluent to give a white solid (55) (0.010 g, 14%).

[1432] Example 4.64: Synthesis of N6-benzyl-3-isopropyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (56)

[1433] (3.18) (0.150 g, 0.50 mmol, 1.0 equivalent), NMP (1.0 mL), and benzylamine (0.33 mL, 2.97 mmol, 6.0 equivalent) were loaded into a 2–5 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 17 hours. After cooling, the mixture was diluted in brine (30.0 mL) and water (10.0 mL), and the aqueous layer was extracted twice with EtOAc (2 x 20.0 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (99 / 1 to 84 / 6) as eluent to give a white solid (56) (0.070 g, 38%).

[1434] Example 4.65: Synthesis of N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (57)

[1435] In a 10–20 mL sealed tube equipped with a stir bar, (3.19) (0.500 g, 1.92 mmol, 1.0 equivalent), NMP (4.5 mL), and the corresponding amine (4.51 mL, 38.36 mmol, 20.0 equivalent) were loaded. The vial was sealed and placed on a heating block, and heated at 180 °C for 18 hours. After cooling, the mixture was poured into saturated NaHCO3 (50.0 mL), the vial was rinsed, and the volume was adjusted to 100.0 mL with water. The mixture was then stirred for 10 minutes. The resulting precipitate was filtered off, washed with water to neutral pH, and the solid was washed with EtOAc in a separate flask. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 93 / 7) as eluent to give a white solid (57) (0.180 g, 30%).

[1436] Example 4.66: Synthesis of N6-(1-ethylpropyl)-3-methyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (58)

[1437] (3.20)(0.550 g, 2.00 mmol, 1.0 eq.) NMP (4.7 mL) and the corresponding amine (4.71 mL, 40.04 mmol, 20.0 eq.) were loaded into a 10–20 mL sealed tube equipped with a stir bar. The vial was sealed and placed on a heating block and heated at 180 °C for 18 hours. After cooling, the mixture was poured into saturated NaHCO3 (50.0 mL), the vial was rinsed, and the volume was adjusted to 100.0 mL with water. The mixture was then stirred for 10 minutes. The resulting precipitate was filtered off, washed with water to neutral pH, and the solid was washed with EtOAc in a separate flask. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 93 / 7) as eluent to give a white solid (58)(0.100 g, 15%).

[1438] Example 4.67: Synthesis of 3-ethyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (59)

[1439] In a 10–20 mL sealed tube equipped with a stir bar, (3.21) (0.350 g, 1.21 mmol, 1.0 eq.), NMP (2.85 mL), and the corresponding amine (2.85 mL, 24.24 mmol, 20.0 eq.) were loaded. The vial was sealed and placed on a heating block and heated at 180 °C for 21 hours. After cooling, the mixture was poured into saturated NaHCO3 (20.0 mL), the vial was rinsed, and the volume was adjusted to 40.0 mL with water. The mixture was then stirred for 10 minutes. The aqueous mixture was extracted three times with EtOAc (3 x 15.0 mL), the organic layers were combined, washed with brine (15.0 mL), dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as eluent to give a white solid (59) (0.074 g, 18%).

[1440] Example 4.68: Synthesis of N6-(1-ethylpropyl)-3-propyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (60)

[1441] (3.22) (0.200 g, 0.66 mmol, 1.0 eq.), NMP (0.7 mL), and the corresponding amine (0.78 mL, 6.61 mmol, 10.0 eq.) were loaded into a 2–5 mL sealed vial equipped with a stir bar. The vial was then sealed and placed on a heating block and heated at 180 °C for 22 hours. After cooling, the mixture was diluted in brine (30.0 mL) and water (30.0 mL) and stirred for 10 minutes. The resulting precipitate was filtered off, washed with water to neutral pH, and then dissolved in EtOAc. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 95 / 5) as eluent to give a beige solid (60) (0.065 g, 28%).

[1442] Example 4.69: Synthesis of 3-tert-butyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (61)

[1443] In a 10–20 mL sealed tube equipped with a stir bar, (3.23) (0.500 g, 1.58 mmol, 1.0 equivalent), NMP (3.7 mL), and the corresponding amine (3.72 mL, 31.57 mmol, 20.0 equivalent) were loaded. The vial was sealed and placed on a heating block and heated at 180 °C for 21 hours. After cooling, the mixture was poured into saturated NaHCO3 (20.0 mL), the vial was rinsed, and the volume was adjusted to 40.0 mL with water. The mixture was then stirred for 10 minutes. The aqueous mixture was extracted three times with EtOAc (3 x 15.0 mL), the organic layers were combined, washed with brine (15.0 mL), dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as eluent to give a white solid (61) (0.105 g, 18%).

[1444] Example 4.70: Synthesis of 3-cyclopropyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (62)

[1445] In a 10–20 mL sealed tube equipped with a stir bar, (3.24) (1.000 g, 3.32 mmol, 1.0 eq.), NMP (5.9 mL), and the corresponding amine (5.87 mL, 49.88 mmol, 15.0 eq.) were loaded. The vial was sealed and placed on a heating block and heated at 180 °C for 18 hours. After cooling, the mixture was poured into saturated NaHCO3 (50.0 mL), the vial was rinsed, and the volume was adjusted to 100.0 mL with water. The mixture was then stirred for 10 minutes. The resulting precipitate was filtered off, washed with water to neutral pH, and the solid was washed with EtOAc in a separate flask. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 93 / 7) as eluent to give a gray solid (62) (0.160 g, 14%).

[1446] Example 4.71: Synthesis of 3-cyclobutyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (63)

[1447] In a 10–20 mL sealed tube equipped with a stir bar, (3.25) (0.320 g, 1.02 mmol, 1.0 eq.), NMP (2.4 mL), and the corresponding amine (2.39 mL, 20.33 mmol, 20.0 eq.) were loaded. The vial was sealed and placed on a heating block and heated at 180 °C for 21 hours. After cooling, the mixture was poured into saturated NaHCO3 (20.0 mL), the vial was rinsed, and the volume was adjusted to 60.0 mL with water. The mixture was then stirred for 10 minutes. The aqueous mixture was extracted three times with EtOAc (3 x 15.0 mL), the organic layers were combined, washed with brine (15.0 mL), dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as eluent to give a white solid (63) (0.093 g, 25%).

[1448] Example 4.72: Synthesis of 3-cyclopentyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (64)

[1449] In a 10–20 mL sealed tube equipped with a stir bar, (3.26) (0.500 g, 1.52 mmol, 1.0 equivalent), NMP (3.6 mL), and the corresponding amine (3.58 mL, 30.41 mmol, 20.0 equivalent) were loaded. The vial was sealed and placed on a heating block and heated at 180 °C for 21 hours. After cooling, the mixture was poured into saturated NaHCO3 (20.0 mL), the vial was rinsed, and the volume was adjusted to 60.0 mL with water. The mixture was then stirred for 10 minutes. The resulting precipitate was filtered off, washed with water to neutral pH, and the solid was then dissolved in DCM. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as eluent to give a white solid (64) (0.124 g, 21%).

[1450] Example 4.73: Synthesis of 3-cyclohexyl-N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (65)

[1451] In a 10–20 mL sealed tube equipped with a stir bar, (3.27) (0.600 g, 1.75 mmol, 1.0 equivalent), NMP (3.9 mL), and the corresponding amine (3.91 mL, 33.25 mmol, 19.0 equivalent) were loaded. The vial was sealed and placed on a heating block and heated at 180 °C for 16 hours. After cooling, the mixture was poured into saturated NaHCO3 (20.0 mL), the vial was rinsed, and the volume was adjusted to 80.0 mL with water. The mixture was then stirred for 10 minutes. The resulting precipitate was filtered off, washed with water to neutral pH, and the vacuum flask was replaced. The solid was then ground and washed with EtOAc. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 97 / 7) as eluent to give a white solid (65) (0.110 g, 16%).

[1452] Example 4.74: Synthesis of N6-(1-ethylpropyl)-3-phenyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (66)

[1453] In a 10–20 mL sealed tube equipped with a stir bar, (3.28) (0.550 g, 1.63 mmol, 1.0 equivalent), NMP (4.0 mL), and the corresponding amine (4.04 mL, 34.30 mmol, 21.0 equivalent) were loaded. The vial was sealed and placed on a heating block and heated at 180 °C for 20 hours. After cooling, the mixture was poured into saturated NaHCO3 (20.0 mL), the vial was rinsed, and the volume was adjusted to 80.0 mL with water. The mixture was then stirred for 10 minutes. The resulting precipitate was filtered off, washed with water to neutral pH, and the vacuum flask was replaced. The solid was then ground and washed with a DCM / MeOH (98 / 2) mixture. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as the eluent to give a white solid (66) (0.265 g, 42%).

[1454] Example 4.75: Synthesis of N6-(1-ethylpropyl)-N8-(2-pyridylmethyl)-3-sec-butyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (67)

[1455] In a 2–5 mL sealed tube equipped with a stir bar, (3.29 g) (0.100 g, 0.39 mmol, 1.0 eq.), monoethylene glycol (1.0 mL), and 3-aminopentane (0.98 mL g, 8.29 mmol, 15.0 eq.) were loaded. The tube was sealed and placed on a heating block and heated at 180 °C for 16 hours. After cooling, the reaction mixture was poured into saturated NaHCO3 (10.0 mL), the precipitate was ground, filtered, washed with water to neutral pH, and dissolved in EtOAc. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as eluent to give a white solid (67 g) (0.047 g, 23%).

[1456] Example 4.76: Synthesis of N6,3-bis(1-ethylpropyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (68)

[1457] In a 2–5 mL sealed tube equipped with a stir bar, (3.30) (0.200 g, 0.61 mmol, 1.0 eq.), monoethylene glycol (1.0 mL), and 3-aminopentane (1.07 mL, 9.07 mmol, 15.0 eq.) were loaded. The tube was sealed and placed on a heating block and heated at 180 °C for 19 hours. After cooling, the reaction mixture was poured into cold water (30.0 mL), stirred for 5 minutes, and the resulting precipitate was filtered off, washed with cold water to neutral pH, and dissolved in DCM. The organic filtrate was dried over MgSO4, filtered, concentrated, and purified by rapid chromatography using DCM / MeOH (98 / 2 to 94 / 6) as eluent to give a white solid (68) (0.085 g, 37%).

[1458] Example 4.77: Synthesis of N6-(1-ethylpropyl)-3-isobutyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (69)

[1459] (3.31) (0.250 g, 0.79 mmol, 1.0 equivalent), NMP (1.9 mL), and 3-aminopentane (1.86 mL g, 15.78 mmol, 20.0 equivalent) were loaded into a 2–5 mL se...

Claims

1. A compound of formula (I) or any pharmaceutically acceptable salt thereof in R 1 Indicates a hydrogen atom or a (C1-C6) alkyl group; R 2 Represents a hydrogen atom; R 3 represent - Straight-chain or branched (C1-C6) alkyl groups, which are replaced by the following groups: • A phenyl group, which is optionally selected from at least one of -OR 7 Substituents include -NH2, halogens, phenyl groups, and (C5-C6) heteroaryl groups. • One (C6-C 10 ) heteroaryl, or ·One-OR 7 , -Phenyl, or phenyl fused with (C4-C6)cycloalkyl groups; or -(C5-C6) heteroaryl, which is optionally substituted by 1 to 3 substituents selected from (C1-C4) alkyl, deuterated (C1-C4) alkyl, (C1-C4) alkoxy, deuterated (C1-C4) alkoxy, and halogen (especially fluorine or chlorine atoms); L represents a bond, or -CO-; Alternatively, L is a bond, and R 2 and R 3 And together with their nitrogen atoms, they form (C5-C6) heterocyclic alkyl groups fused with phenyl groups containing at least one nitrogen atom; R 4 It represents a hydrogen atom, a straight-chain or branched (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C4) alkoxy, (C5-C6) heterocycloalkyl, phenyl, (C5-C6) heteroaryl, or -CF3; R 5 Represents a hydrogen atom, or a (C1-C4) alkyl group; R 6 represent - A straight-chain or branched (C1-C8) alkyl group, which is optionally interrupted by one or two oxygen atoms and optionally substituted with the following groups; • A phenyl group, optionally substituted with one or two substituents selected from (C1-C4) alkyl and (C1-C4) alkoxy groups, • A (C3-C8) cycloalkyl group, optionally composed of one or two groups selected from halogens, (C1-C4) alkyl groups, and -OR 7 The substituents are replaced by the substituents. • One (C5-C6) heterocyclic alkyl group, • One (C5-C6) heteroaryl group, optionally substituted with one or two (C1-C6) alkyl groups, One or two - OR 7 , ·One -SR 7 , • One -C(O)NR 8 R 9 , • One -C(O)OR 10 ,or • One - NHR 11 , -(C3-C7)cycloalkyl, optionally composed of one or two radicals selected from halogens, (C1-C4)alkyl groups, and -OR 7 The substituents are replaced by the substituents. - A bridged (C6-C) 10 )cycloalkyl, - One screw (C5-C) 11 Double ring, - A (C5-C6) heteroaryl group, - A (C5-C6) heterocyclic alkyl group, or -Phenyl fused with (C4-C6)cycloalkyl groups; Or, R 5 and R 6 Together with the nitrogen atoms containing them, they form (C5-C6) heterocyclic alkyl groups; R 7 It 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 Indicates (C1-C4) alkyl; and R 11 Represents a hydrogen atom, or a -CO-(C1-C6) alkyl group; The condition is that when NR 2 LR 3 When representing benzylamino, R 4 It is not a hydrogen atom.

2. The compound of formula (I) as claimed in claim 1, or any pharmaceutically acceptable salt thereof, characterized in that, R 1 It represents a hydrogen atom or a methyl group.

3. The compound of formula (I) as described in claim 1 or 2, or any pharmaceutically acceptable salt thereof, characterized in that, R 2 Represents a hydrogen atom; R 3 represent - Straight-chain or branched (C1-C6) alkyl groups, substituted with the following groups, • A phenyl group, optionally substituted with a substituent selected from hydroxyl, methoxy, amino, halogen, phenyl, and pyridyl groups. • A pyridyl group, a pyrazinyl group, a pyrimidinyl group, or a pyridazinyl group, especially a pyridyl, pyridazinyl, or pyrimidinyl group, or an indole or isoindole group, especially an indole group. One hydroxyl group, • One methoxy group, one deuterated methoxy group, or Halogens, especially fluorine or chlorine atoms, -Phenyl or indanyl, or -pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, which may optionally be substituted with a methoxy or deuterated methoxy group; Specifically, pyridinyl; L represents a bond, or -CO-; Alternatively, L is a bond, and R 2 and R 3 Together with their nitrogen atoms, they form indole, isoyindo, tetrahydroquinolino, or tetrahydroisoquinolino, especially isoyindo or tetrahydroisoquinolino.

4. The compound of formula (I) as claimed in any one of claims 1 to 3, or any pharmaceutically acceptable salt thereof, characterized in that, R 4 It represents a hydrogen atom, a straight-chain or branched (C1-C5) alkyl group, a (C3-C6) cycloalkyl group, a phenyl group, a pyridyl group, or -CF3.

5. The compound of formula (I) as claimed in any one of claims 1 to 4, or any pharmaceutically acceptable salt thereof, characterized in that, R 5 Represents a hydrogen atom, or a (C1-C4) alkyl group, especially a methyl group; R 6 represent - A straight-chain or branched (C1-C8) alkyl group, optionally interrupted by one or two oxygen atoms and optionally substituted with the following groups: • A phenyl group, optionally substituted with one or two substituents selected from methyl and methoxy groups. • A (C3-C6) cycloalkyl group, optionally substituted with a methyl group, • One tetrahydropyranyl group or one tetrahydrofuranyl group, • One pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridinyl, furanyl, or thiophene group. It can be optionally replaced by one or two methyl groups. • One or two hydroxyl or methoxy groups, • One methylthio group, • One -CONH2, one -CONHCH3, or one -CON(CH3)2, • One -COOCH3 or one -COOCH2CH3, or • One -NH2 or one -NCOCH3, -(C3-C7)cycloalkyl, optionally substituted with one or two substituents selected from halogen, hydroxyl, or methoxy. -adamantyl, -spiro[3.3]heptyl, -Imidazolyl group, which may optionally be replaced by one or two methyl groups, -morpholino, tetrahydropyrano or tetrahydrofurano, or -Indaminozide; Or, R 5 and R 6 Together with their nitrogen atoms, they form morpholino or piperidinyl groups.

6. A compound or any pharmaceutically acceptable salt thereof, characterized in that, Selected from the following group: (1)(2R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1-ol, (2)(2S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-1-ol, (3) 2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]propyl-1,3-diol, (4) (2R,3R)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butane-1,3-diol, (5) (2S,3S)-2-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]butane-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]pyridazin-6-yl]amino]propyl-1,2-diol, (8) N6-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N8-benzyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (9) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]prop-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]amino]ethanol, (12) N8-benzyl-3-isopropyl-N6-(2-methoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (13) 4-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-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-methylthiopropyl)-[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]amino]propyl]acetamide, (25) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]propionamide, (26) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]-N-methylpropionamide, (27) 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]-N,N-dimethylpropionamide, (28) Methyl 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]propionate, (29) Ethyl 3-[[8-(benzylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]propionate, (30)(2R)-2-[[8-(benzylamino)-3-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]amino]but-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]but-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]amino]but-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]but-1-ol, (38)2-[[[6-[[(1R)-1-(hydroxymethyl)propyl]amino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]amino]methyl]phenol, (39) 2-[[[3-Isopropyl-6-(3-methoxypropylamino)-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]methyl]phenol, (40) 2-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]amino]methyl]phenol, (41) 3-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]amino]methyl]phenol, (42) 4-[[[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]amino]methyl]phenol, (43) 2-[[[3-Isopropyl-6-[[(3R)-tetrahydropyran-3-yl]amino]-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]amino]methyl]phenol, (44) 2-[[[3-Isopropyl-6-(tetrahydropyran-4-ylamino)-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]amino]methyl]phenol, (45) N6-(1-ethylpropyl)-3-isopropyl-N8-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (46)N6-(1-ethylpropyl)-3-isopropyl-N8-(2-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (47) N6-(1-ethylpropyl)-3-isopropyl-N8-(3-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (48) N6-(1-ethylpropyl)-3-isopropyl-N8-(4-pyridyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (49) N6-(1-ethylpropyl)-3-isopropyl-N8-(4-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (50)N6-(1-ethylpropyl)-3-isopropyl-N8-(3-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (51)N6-(1-ethylpropyl)-3-isopropyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (52) N6-tert-butyl-3-isopropyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (53) 3-Isopropyl-N8-(2-pyridylmethyl)-N6-spiro[3.3]hept-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-pyridinyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (71)N6-(1-ethylpropyl)-3-(3-pyridinyl)-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (72)N6-(1-ethylpropyl)-3-(4-pyridinyl)-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]but-1-ol, (75)N8-[(4-aminophenyl)methyl]-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (76)N8-[(3-aminophenyl)methyl]-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (77)N8-[(2-aminophenyl)methyl]-N6-(1-ethylpropyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (78) N6-(1-ethylpropyl)-N8-(1H-indol-2-ylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (79) N-(1-ethylpropyl)-8-isoindoline-2-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-amine, (80)8-(3,4-dihydro-1H-isoquinolin-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-(pyrimidin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (93)N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrimidin-5-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (94)N6-(1-ethylpropyl)-3-isopropyl-N8-(pyrazin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (95)N6-(1-ethylpropyl)-3-isopropyl-N8-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-b]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]pyridazin-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) N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-8-yl]carbamate, (100)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]but-1-ol, (102)(2S)-2-[[3-isopropyl-8-[(4-phenylphenyl)methylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol, (103)(2S)-2-[[3-isopropyl-8-[[4-(4-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol, (104)(2S)-2-[[3-isopropyl-8-[[4-(3-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol, (105)(2S)-2-[[3-isopropyl-8-[[4-(2-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol, (106)(2R,3R)-2-[[8-[(4-bromophenyl)methylamino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butane-1,3-diol, (107)(2R,3R)-2-[[3-isopropyl-8-[[4-(2-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butane-1,3-diol, (108)(2R,3R)-2-[[3-isopropyl-8-[[4-(4-pyridyl)phenyl]methylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]butane-1,3-diol, (109)N6,N8-bis(3-methoxypropyl)-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (110) 3-Cyclopropyl-N6,N8-bis(3-methoxypropyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (111)N6,N8-bis(3-methoxypropyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (112) 3-Isopropyl-N6,N8-bis(2-methoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (113)(2R)-2-[[6-[[(1R)-1-(hydroxymethyl)propyl]amino]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]amino]but-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]but-1-ol, (116)N8-[(4-bromophenyl)methyl]-3-isopropyl-N6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (117)N8-benzyl-N6-cyclobutyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (118)N8-Benzyl-N6-Cyclopentyl-3-Isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (119) N8-benzyl-N6-cyclohexyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (120)N8-benzyl-3-isopropyl-N6-(4-methoxycyclohexyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (121)N8-benzyl-N6-cycloheptyl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (122)N8-benzyl-N6-(cyclopropylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (123)N8-benzyl-N6-(cyclobutylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (124)N8-benzyl-N6-(cyclohexylmethyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (125)N8-benzyl-3-isopropyl-N6-(tetrahydropyran-4-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (126)N8-benzyl-N6-(2-ethylbutyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (127)N8-benzyl-3-isopropyl-N6-(2-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (128)N8-Benzyl-3-isopropyl-N6-(2-phenoxyethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (129) N8-benzyl-3-isopropyl-N6-[(1-methylimidazol-1-2-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-methylpyrazin-2-yl)methyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (140)N8-benzyl-3-isopropyl-N6-[(1-methylpyrazol-4-yl)methyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (141)N8-benzyl-N6-[(3,5-dimethylphenyl)methyl]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (142) N8-benzyl-3-isopropyl-N6-(tetrahydrofuran-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (143)N8-benzyl-3-isopropyl-N6-(2-methylthioethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (144)N8-benzyl-3-isopropyl-N6-(1-methylimidazol-1-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (145)N8-benzyl-N6-[(4,6-dimethylpyrimidin-2-yl)methyl]-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (146) N8-benzyl-N6-indan-1-yl-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (147)N6-(2-ethylbutyl)-3-isopropyl-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3-b]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-(pent-3-yl)-N8-(pyridazin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (150)3-Isopropyl-N6-(pent-3-yl)-N8-(pyrimidin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (151) 3-Isopropyl-N6-(pent-3-yl)-N8-(pyrimidin-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (152) 3-Isopropyl-N6-(pent-3-yl)-N8-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (153) 3-Isopropyl-N6-(pent-3-yl)-N8-(pyrazin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (154) 3-Isopropyl-N8-(6-methoxypyridin-2-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (155) 3-Isopropyl-N8-(5-methoxypyridin-2-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (156) 3-Isopropyl-N8-(4-methoxypyridin-2-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (157) 3-Isopropyl-N8-(3-methoxypyridin-2-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (158) 3-Isopropyl-N8-(2-methoxypyridin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (159) 3-Isopropyl-N8-(6-methoxypyridin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (160) Isopropyl-N8-(5-methoxypyridin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (161) 3-Isopropyl-N8-(4-methoxypyridin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (162) 3-Isopropyl-N8-(5-methoxypyridazin-3-yl)-N6-(pent-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]pyridazin-6-yl]amino]but-1-ol, (164)N6-(2-ethylbutyl)-3-isopropyl-N8-[2-(2-pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (165)N6-Cyclopentyl-3-isopropyl-N8-[2-(2-pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (166)N6-(2-ethylbutyl)-3-isopropyl-N8-[2-(3-pyridyl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (167)N6,N8-Bis(2-ethylbutyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (168)N-[6-(1-ethylpropylamino)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-2-(3-pyridyl)acetamide, (169)(2R)-2-[[3-isopropyl-8-(2-pyridylmethylamino)imidazol[1,2-b]pyridazin-6-yl]amino]but-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-(pent-3-yl)-N8-(pyridazin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (176) 3-Cyclopropyl-N6-(pent-3-yl)-N8-(pyridazin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (177) 3-Cyclopropyl-N6-(pent-3-yl)-N8-(pyrimidin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (178) 3-Cyclopropyl-N6-(1-Ethylpropyl)-N8-Pyrimidin-5-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (179) 3-Cyclopropyl-N6-(pent-3-yl)-N8-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (180)3-Cyclopropyl-N6-(pent-3-yl)-N8-(pyrazin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (181)(R)-2-((3-Cyclopropyl-8-(pyridazin-3-ylamino)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino)but-1-ol, (182)(S)-2-((3-Cyclopropyl-8-(pyridazin-3-ylamino)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino)but-1-ol, (183) 3-Cyclopropyl-N8-(6-methoxypyridin-2-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (184) 3-Cyclopropyl-N8-(2-methoxypyridin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (185)(2R)-2-[[3-Cyclopropyl-8-[2-(2-pyridyl)ethylamino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino]but-1-ol, (186)N6-Benzyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (187) 3-Cyclopropyl-N6-(4-Methoxybenzyl)-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (188) 3-Cyclopropyl-N6-(4-Methoxybenzyl)-N6-methyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (189) 3-Cyclopropyl-N6-ethyl-N8-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (190)3-Cyclopropyl-N6-propyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (191)N6-Butyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (192) 3-Cyclopropyl-N6-Isopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (193)N6-(sec-butyl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (194) 3-Cyclopropyl-N6-isobutyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (195)N6-(tert-butyl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (196) 3-Cyclopropyl-N6-(2-Ethylbutyl)-N8-(Pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (197)N6,3-Dicyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (198)N6-Cyclobutyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (199)N6-Cyclopentyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (200)N6-cyclohexyl-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (201)N6-Cycloheptyl-3-Cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (202)N6-((3s,5s,7s)-adamantyl-1-yl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (203)3-Cyclopropyl-N6-(Cyclopropylmethyl)-N8-(Pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (204)N6-(cyclobutylmethyl)-3-cyclopropyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (205)3-Cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(spiro[3.3]hept-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (206)3-Cyclopropyl-N6-((1-methylcyclobutyl)methyl)-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (207)3-Cyclopropyl-6-(1-piperidin)-N-(2-pyridylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine, (208)3-Cyclopropyl-N6-(furan-2-ylmethyl)-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (209)3-Cyclopropyl-N6-(furan-3-ylmethyl)-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (210) 3-Cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(thiophen-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (211)(R)-2-((3-Cyclopropyl-8-((pyridin-2-ylmethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino)but-1-ol, (212)(S)-2-((3-Cyclopropyl-8-((pyridin-2-ylmethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino)but-1-ol, (213)(R)-3-Cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (214)(R)-3-Cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(tetrahydro-2H-pyran-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (215) 3-Cyclopropyl-N8-(6-methoxypyridazin-3-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (216) 3-Cyclopropyl-N6-(pent-3-yl)-N8-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (217) 3-Cyclopropyl-N6-(pent-3-yl)-N8-phenethyl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (218) 3-Cyclopropyl-N8-(pyridin-2-ylmethyl)-N6-(thiophen-3-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (219) 3-Cyclopropyl-N6-methyl-N8-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (220)3-Cyclopropyl-N-(pyridin-2-ylmethyl)-6-(pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine, (221) 3-Isopropyl-N8-(2-methoxypyrimidin-4-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (222)3-Isopropyl-N8-(5-methoxypyrimidin-4-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (223) 3-Isopropyl-N8-(6-methoxypyrimidin-4-yl)-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (224) 3-Isopropyl-N8-(6-methoxypyridazin-3-yl)-N6-(pent-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-chloropyrazin-3-yl)-3-isopropyl-N6-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (228)N8-(2-chloropyrimidin-4-yl)-3-isopropyl-N6-(pentan-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine, (229)N6-(2-ethylbutyl)-3-isopropyl-N8-(6-methoxypyridazin-3-yl)-[1,2,4]triazolo[4,3-b]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-(pent-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6,8-diamine, (232)N8-(6-chloropyrazin-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, Specifically selected from compounds (1), (2), (10), (13), (14), (17) to (19), (21) to (23), (26), (28), (29), (31), (35) to (56), (58) to (64), (66) to (69), (71) to (78), (80) to (105), (107), (110), (111), (114), (117) to (119), (121) to (124), (126), (127), (130) to (132), (134), (136), (1 38), (140), (143), (146) to (160), (162) to (187), (189) to (206), (208) to (212), (215) to (218), (221) and (223) to (234), and their pharmaceutically acceptable salts; more particularly, selected from compounds (18), (38), (40) to (42), (45) to (53), (56), (59), (62), (63), (67), (68), (73), (75), (76), (80), (82) to (88), (90) ), (91), (93) to (95), (98) to (100), (114), (118), (126), (130), (147) to (151), (153) to (156), (158) to (160), (162), (164) to (168), (170) to (178), (180) to (183), (186), (187), (191) to (193), (195), (196), (198) to (202), (204) to (206), (208) to (210), (215) to (218), (221) and (223) to (234), and their pharmaceutically acceptable salts; more particularly, selected from compounds (46), (47), (83), (86), (87), (98), (147), (148), (150), (151), (153) to (155), (158), (159), (162), (164), (168), (171) to (175), (177), (178), (180) to (183), (215), (221), (223) to (232) and (234), and Its pharmaceutically acceptable salt.

7. A method for preparing a compound of formula (I) as defined in any one of claims 1 to 5, or any pharmaceutically acceptable salt thereof, or at least any one of compounds (1) to (234) as defined in claim 6, or any pharmaceutically acceptable salt thereof, comprising at least the following steps: in an aprotic solvent or under solvent-free conditions or in a protic solvent, causing a compound of formula (II): in, L, R 2 R 3 and R 4 As defined in any one of claims 1, 3 or 4, Reacting with, for example, amines of formula (IV) in molar ratios of 1 to 20 equivalents relative to compounds of formula (II), NHR 5 R 6 (IV) R5 and R6 are as defined in claim 1 or 5.

8. A method for preparing a compound of formula (I) as defined in any one of claims 1 to 5, or any pharmaceutically acceptable salt thereof, or at least any one of compounds (1) to (234) as defined in claim 6, or any pharmaceutically acceptable salt thereof, comprising at least the following steps: in an aprotic solvent, causing a compound of formula (IX): Where R 4 R 5 and R 6 As defined in claims 1, 4 and 5, React with, for example, compounds of formula (VI) in molar ratios of 1 to 10 equivalents relative to compounds of formula (IX); Where R 2 and R 3 As defined in claim 1 or 3.

9. A method for preparing a compound of formula (I) as defined in any one of claims 1 to 5, or any pharmaceutically acceptable salt thereof, or at least any one of compounds (1) to (234) as defined in claim 6, or any pharmaceutically acceptable salt thereof, comprising at least the following steps: in an aprotic solvent, causing a compound of formula (XII): Where R 5 and R 6 As defined in claim 1 or 5; It reacts with, for example, a compound of formula (XIV) in a molar amount equal to 1 to 10 equivalents of a compound of formula (XII) to a compound of formula (XIV). Where L and R 3 As defined in claim 1 or 3, X represents a hydroxyl group, a chlorine atom, a bromine atom, a (C1-C3) alkyl sulfonic acid group, or a phenyl sulfonic acid group.

10. Compounds of formula (II), (X), (XI) or (VII), especially compounds of formula (II), (X), (XI) or (VII) as intermediate compounds, in, L, R 2 R 3 R 4 R 5 and R 6 As defined in claim 1, 3, 4 or 5, the condition is R in equation (XI). 4 It is not methyl.

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

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

13. The compound for use as described in claim 12, characterized in that, The hearing loss mentioned is partial or complete hearing loss, particularly caused by noise, acoustic trauma, or ototoxic drugs or conditions, and more particularly by platinum-based anticancer drugs (such as cisplatin or carboplatin), antibiotics (even more specifically, macrolides or aminoglycosides, such as gentamicin or neomycin), COVID-19 drugs (such as lopinavir or ritonavir), antimalarial drugs (such as quinine or chloroquine), cardiovascular drugs (such as loop diuretics), nonsteroidal anti-inflammatory drugs (such as salicylates or cyclodextrin), and anti-erectile dysfunction drugs (such as phosphodiesterase type 5 inhibitors).

14. A compound for use as described in claim 12, characterized in that, The kidney disease is selected from the group consisting of: renal fibrosis, nephropathy, acute kidney injury, chronic kidney disease (especially chronic kidney disease caused by ischemia and / or reperfusion injury), toxic nephropathy or myoglobinuria, and diabetic nephropathy, or the kidney disease caused by nephrotoxicity of therapeutic drugs (more particularly cytotoxic drugs, such as platinum-based anticancer drugs, such as cisplatin or carboplatin).

15. A pharmaceutical composition, characterized in that, It comprises at least one compound of formula (I) as defined in any one of claims 1 to 5 or any pharmaceutically acceptable salt thereof, or at least any one of compounds (1) to (234) as defined in claims 6 or any pharmaceutically acceptable salt thereof.

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