Imidazopyridazine derivatives, their preparation, pharmaceutical compositions and uses

Abstract

The present invention provides imidazopyridazine derivatives, their preparation methods, pharmaceutical compositions and uses. Specifically, the present invention relates to a compound represented by formula (1), its stereoisomers, tautomers, prodrugs, pharma- ceutically acceptable salts, amorphous substances, isotopes, crystalline polymorphs or solvates, pharmaceutical compositions containing the compound, and GABA A Use of the compound as a receptor modulator is provided. [Formula 1] JPEG2025506747000101.jpg43169

Description

Detailed Description of the Invention

[0001] Cross-citation of related applications This application claims priority to a Chinese patent application filed on February 25, 2022 with the China Patent Office, bearing application number 202210178772.9, and entitled "Imidazopyridazine derivatives, their preparation methods, pharmaceutical compositions and uses," the entire contents of which are incorporated herein by reference.

[0002] [Technical field] This application relates to GABA A The present invention relates to imidazopyridazine derivatives having receptor-regulating function, their preparation methods, pharmaceutical compositions and their use as medicines.

[0003] [Background technology] Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the mammalian central nervous system. Substances that modulate GABA neurotransmission are widely used to treat various disorders, such as epilepsy, anxiety, and depression. There are two types of GABA receptors in nature. One is the GABA receptor, which belongs to the superfamily of ligand-gated ion channels. A Receptor (GABA A R), and the other is GABA receptors, which belong to the G protein-coupled receptor superfamily. B Receptor (GABA B R) GABA in mammals A The receptor subunits found include α1-6, β1-4, γ1-3, δ, ε, θ, and ρ1-2, among which α, β, and γ subunits are fully functional GABA receptors. A The α subunit is essential for the formation of the receptor, and is involved in the binding of benzodiazepines to GABA A Important for receptor binding.

[0004] Drugs that bind to the allosteric binding site may be positive allosteric modulators (or positive allosteric modulators) that increase receptor activity, negative allosteric modulators (or negative allosteric modulators) that decrease receptor activity, or neutral allosteric modulators (compounds that bind to the allosteric binding site but do not modulate receptor activity) that do not alter receptor activity. Recent evidence suggests that GABA receptors containing α2 or α3 subunits A Receptor (α2 / 3-GABA A It has been suggested that certain neuropathic pain receptors (receptors termed agonists and antagonists) are involved in certain pain states and that positive allosteric modulators of such receptors may be effective analgesics (Mirza, N. R. and Munro, G., Drug News and Perspectives, 2010, 23(6), 351-360).

[0005] International patent applications PCT / GB01 / 04948 (disclosed in WO2002 / 038568) and PCT / GB02 / 03114 (disclosed in WO2003 / 008418) describe 7-phenylimidazo[1,2-b][1,2,4]triazine derivatives with affinity for α2, α3 and / or α5 subunits. International patent application PCT / US99 / 14935 (disclosed in WO2000 / 001697) discloses 4-phenyl-7H-imidazo[4,5-c]pyridazine derivatives that are inter alia corticotropin releasing factor antagonists. International patent applications PCT / IB2013 / 060631 (disclosed in WO2014 / 091368) and PCT / IB2015 / 054200 (disclosed in WO2015 / 189744) and an article by Robert M. Owen (J. Med. Chem. 2019, 62, 5773-5796 by Robert M. Owen) describe the use of α2 / 3-GABA receptor antagonists for treating various disorders, including pain. ADescribed are 4-(biphenyl-3-yl)-7H-imidazo[4,5-c]pyridazine derivatives that interact with the receptor. Compounds of this type are also used to treat pruritus (International Patent Application PCT / US2019 / 033598, Publication No. WO2019 / 26820A1) and epilepsy (Duveau, V., CNS Neurosci Ther. 2019.25(2):p.255-260.).

[0006] The mainstream view is that GABA receptors containing the α1 subunit A The modulatory activity of the receptor is currently A It is believed to be the main cause of side effects (e.g., sedation, addiction, drowsiness, amnesia) of GABA modulators (e.g., benzodiazepines) (Uwe Rudolph and Frederic Knoflach, Nature Reviews: Drug Discovery, 2011, 10(9), 685-697). A Interacts with the receptor, α1-GABA A Finding new compounds with fewer receptor-related side effects has enormous therapeutic potential.

[0007] [Summary of the Invention] In one aspect of the present application, there is provided a compound of formula (1), a stereoisomer, a tautomer, a prodrug, a pharma- ceutically acceptable salt, an amorphous material, a crystalline polymorph, or a solvate thereof.

[0008] [ka] however, R 1 is a fused group formed from a substituted or unsubstituted heterocycle and a heterocycle, R 2 is selected from H, halogen, OH, C1-C6 alkoxy or CN; R 3 is H, substituted or unsubstituted straight or branched chain C1-C6 alkyl or substituted or unsubstituted C Selected from 3 to C6 cycloalkyl.

[0009] Unless otherwise stated, the following definitions are used to illustrate and define the meaning and scope of various terms to describe this application.

[0010] The following definitions of general terms apply whether they appear alone or in combination.

[0011] The naming conventions used in this application are based on the IUPAC rules.

[0012] Unless otherwise specified, the term "substituted" means that a particular group or moiety may have 1, 2, 3, 4, 5 or 6 substituents. When a group contains multiple substituents providing for multiple possible substituents, the substituents are independently selected and do not have to be the same.

[0013] The term "unsubstituted" refers to the absence of substituents on a particular group.

[0014] The term "optionally substituted" means that the particular group is unsubstituted or substituted with one or more substituents independently selected from possible substituents.

[0015] When specifying the number of substituents, the term "one or more" refers to the maximum number of substitutions possible with one substitution, i.e., by replacing one hydrogen, all hydrogens are replaced by a substituent. Unless otherwise stated, preferably 1, 2, 3, 4 or 5 substituents.

[0016] Specifically, R 1 and R 3 In the definition of the group, "substituted" refers to one or more hydrogens of the group being replaced by one selected from C1-C4 alkyl, C1-C4 alkoxy, alkyl substituted with C1-C4 halogen, or halogen.

[0017] The term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine.

[0018] The compounds of the present application may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present application, including but not limited to diastereomers, enantiomers and atropstereoisomers, as well as mixtures thereof, such as racemic mixtures, form part of the present application. In the present specification, all stereoisomers are contemplated, unless the stereochemistry of a particular chiral atom is determined. Furthermore, the present application relates to all geometric and positional isomers. The compounds of the present application may exist in different tautomeric forms, and all such forms are included within the scope of the present application. All stereoisomers of the compounds of the present application are expected to include mixtures or pure or substantially pure forms. Resolution can be carried out by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.

[0019] The term "prodrug" refers to a functional derivative of the compound of formula (1) that is easily converted to the compound of formula (1) in the body. A person skilled in the art can select and prepare a suitable derivative by conventional techniques known to those skilled in the art, see, for example, Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

[0020] The term "pharmaceutically acceptable salt" as used herein refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present application. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, acid sulfate, isonicotinate, lactate, salicylate, acid citrate, succinate, maleate, fumarate, gluconate, formate, mesylate, and pamoate. A "pharmaceutically acceptable salt" may involve the inclusion of another molecule, such as maleate or other counterion. The counterion stabilizes the charge of the parent compound. A "pharmaceutically acceptable salt" may have one or more charged atoms, and multiple charged atoms may have multiple counterions.

[0021] If the compound of the present application is a base, the desired "pharmaceutically acceptable salt" can be prepared by a suitable method, for example, by treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, salicylic acid, pyranosyl acids (e.g., glucuronic acid or galacturonic acid), α-hydroxy acids (e.g., citric acid or tartaric acid), amino acids (e.g., glutamic acid), aromatic acids (e.g., benzoic acid or cinnamic acid), sulfonic acids (e.g., methanesulfonic acid or p-toluenesulfonic acid), or the like.

[0022] If the compound of the present application is an acid, the desired "pharmaceutically acceptable salt" can be prepared by a suitable method, for example, treating the free acid with an inorganic or organic base, such as an amine, an alkali metal hydroxide or an alkaline earth metal hydroxide. Examples of suitable salts include, but are not limited to, organic salts derived from amino acids, primary, secondary, and tertiary amine salts, and salts of cyclic amines, such as piperidine, morpholine, and piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0023] The compounds of the present application can exist in a continuum of solid states ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or liquid depending on temperature. Typically, such materials do not exhibit a distinct X-ray diffraction pattern and are more formally described as liquids while exhibiting solid properties. Upon heating, a change from solid to liquid properties occurs, generally characterized by a second order state change ("glass transition"). The term "crystalline" refers to a solid phase in which the material has a regularly ordered internal structure at the molecular level and provides a unique X-ray diffraction pattern with well-defined peaks. Such materials, when heated sufficiently, exhibit liquid properties, but the change from solid to liquid is generally characterized by a first order phase change ("melting point").

[0024] As used herein, the term "crystalline polymorphism" refers to different solid crystalline phases that a particular compound of the present application may have due to the existence of two or more different molecular configurations in the solid state. A particular compound of the present application may exist in one or more crystal forms, and the present application is intended to include various crystal forms and mixtures thereof.

[0025] The term "solvate" as used herein refers to an association or complex of one or more solvent molecules with the compounds of the present application. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and ethanolamine. The compounds of the present application may exist in unsolvated form or in solvated form with pharma- ceutically acceptable solvents such as water, ethanol, etc., and therefore the present application includes solvated and unsolvated forms.

[0026] The compounds of the present application may contain unnatural ratios of atomic isotopes on one or more atoms constituting said compounds, the term "isotopes" referring to compounds having the same atomic number but whose atomic mass or mass number is different from that predominantly found in nature. For example, the compounds may be labeled with radioactive isotopes such as deuterium (2H), tritium (3H), iodine-125 (125I) or C-14 (14C). All isotopically composed variations of the compounds of the present application, whether radioactive or not, are all within the scope of the present application. Isotopic variants may enhance certain therapeutic benefits, such as deuterium enrichment, which can increase in vivo half-life or reduce dosage requirements, or provide standard compounds that can be used to characterize biological samples. Isotopically enriched compounds in formula (1) can be produced without undue experimentation using the appropriate isotopically enriched reagents and / or intermediates by conventional techniques known to those skilled in the art or by methods similar to those described in the pathways and examples herein.

[0027] [R 2 ] In the compounds described in the present application, R 2 is selected from H, halogen, OH, C1-C6 alkoxy or CN, preferably, 2 is preferably H or a halogen, more preferably H or F.

[0028] [R 3 ] In the compounds described in the present application, R 3 is selected from H, substituted or unsubstituted linear or branched C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl. 3In the above, the C1-C6 alkyl may be linear or branched, and exemplary C1-C6 alkyls include methyl, ethyl, n-propyl (1-propyl), isopropyl (2-propyl, 1-methylethyl), n-butyl (1-butyl), sec-butyl (2-butyl, 1-methylpropyl), isobutyl (2-methylpropyl) or Fe / F-butyl (1,1-dimethylethyl). One to multiple hydrogen atoms on the alkyl may be substituted with a substituent such as methyl, ethyl, n-propyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, fluorine, chlorine, or bromine.

[0029] The term "cycloalkyl" refers to a monovalent saturated cyclic hydrocarbon radical, R 3 In the above, exemplary C3-C5 cycloalkyl include cyclopropyl, cyclobutyl, or cyclopentyl.

[0030] R 3 In the above, exemplary C3-C6 cycloalkyl include 1-methylcyclopropyl, 2-methylcyclopropyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 3-methylcyclobutyl, 1-methylcyclopentyl, 2-methylcyclopentyl, or 3-methylcyclopentyl. One to several hydrogen atoms on the cycloalkyl may be substituted with a substituent such as methyl, ethyl, n-propyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, fluorine, chlorine, or bromine.

[0031] The term "alkoxy" refers to alkyloxy, R 3 In the above, exemplary C1-C6 alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, etc. One to multiple hydrogen atoms on the alkoxy may be substituted with a substituent such as methyl, ethyl, n-propyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, fluorine, chlorine, bromine, etc.

[0032] In one optional embodiment of the present application, R 3is selected from straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, more preferably C2-C4 alkyl, more preferably ethyl or isopropyl.

[0033] [R 1 ] In the present application, the R 1 is a fused heterocycle, wherein the two heterocycles are independently a saturated or partially unsaturated monocyclic or polycyclic group having a heteroatom, optionally N, O or S. Optionally, the two heterocycles are 3-7 membered saturated or partially unsaturated monocyclic or polycyclic groups containing 1-3 ring heteroatoms independently selected from N, O or S. Optionally, S and O are -SO or SO 2 It can exist as.

[0034] Optionally, the two heterocycles are 5-7 membered saturated or unsaturated monocyclic groups containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S. Optionally, the two heterocycles are 5-6 membered saturated or unsaturated monocyclic groups containing 1, 2 or 3 ring heteroatoms independently selected from N or O.

[0035] Optionally, R 1 has a structure represented by formula (2), (3), (4), (5), (6) or (7).

[0036] [ka] in particular, R 4is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio or C1-C6 alkylsulfonyl, the above groups (including the associated alkyl, cycloalkyl, alkoxy, alkylthio or alkylsulfonyl) are optionally unsubstituted or substituted with at least one of each independently selected from 1 to 4 halogen, hydroxyl, C1-C3 alkyl, haloC1-C3 alkyl, C1-C3 alkoxy or haloC1-C3 alkoxy; R 5 is selected from hydrogen, halogen, hydroxyl, oxo, C1-C6 alkyl acyl, C1-C6 alkyl amido, C1-C6 alkoxyimino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms, C1-C6 non-aromatic heterocycle containing 1-3 heteroatoms, and the above groups (related to the above alkyl acyl, alkyl amido, alkoxy imino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms, C1-C6 non-aromatic heterocycle containing 1-3 heteroatoms) , methoxyimino, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryl, heteroaryl, non-aromatic heterocycloalkyl) are optionally unsubstituted or substituted, independently of one another, by at least one selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkyl substituted with halogen, C1-C3 alkoxy, or C1-C6 3- to 7-membered heterocycloalkyl containing 1-3 N or O heteroatoms; The ring A is a 5- to 7-membered saturated or partially unsaturated monocyclic group containing N, m is 1, 2 or 3, and n is 1 or 2, preferably m is 1 and n is 1; [ka] represents the linking site.

[0037] R 1 teeth, [ka] is linked to the phenyl of the compound of formula (1) via

[0038] R 4 or R 5 is a substituent on a heterocycle and may be linked to a heteroatom or to a carbon atom.

[0039] R 5 In the group, the heteroatoms are selected from N, O or S.

[0040] In certain optional embodiments, R 4 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, n-propoxy, -CH 2 -O-CH 3 , methylsulfonyl or ethylsulfonyl, which are optionally unsubstituted or substituted, independently of each other, by C1-C3 alkoxy or halogen. 4 is selected from H, C1-C3 alkyl, C1-C3 alkyl substituted with C1-C3 alkoxy or C1-C3 alkoxy, most preferably methoxymethyl or methoxy.

[0041] In certain optional embodiments, R 5 is hydrogen, F, Cl, Br, hydroxyl, formyl, acetyl, formamido, acetamido, methoxyimino, ethoxyimino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, phenyl, benzyl, tetrahydrofuranyl, Tetrahydropyranyl , hexahydropyridyl, oxetane, azetidine, which are optionally unsubstituted or independently of one to four of F, Cl, Br, hydroxyl, methoxy, methyl, tetrahydropyrrole, morpholinyl or -CH 2 -CF 3 is replaced by at least one selected from:

[0042] In an alternative embodiment, R 5 is H, methyl, ethyl, isopropyl, [ka] Cyclopropyl, fluorocyclopropyl, [ka] is selected from.

[0043] Optionally, the A ring refers to a 5-6 membered saturated or unsaturated monocyclic group containing 1, 2 or 3 N ring heteroatoms.

[0044] In certain optional embodiments, R 1 has a structure represented by formula (2) or (7), ring A has the following structure: [ka]

[0045] [ka] represents a linking site, 5 is as defined in any one of the preceding paragraphs of this application.

[0046] In certain optional embodiments, R 1 has a structure represented by formula (3), (4), (5) or (6), the A ring has the following structure: [ka]

[0047] [ka] represents a linking site,5 is as defined in any one of the preceding paragraphs of this application.

[0048] In the present application, optionally, the R 1 is a substituted or unsubstituted pyridine fused heterocycle, and more preferably, 1 is a substituted or unsubstituted pyridotriazole or a substituted or unsubstituted pyridoimidazole.

[0049] In a more preferred embodiment, the R 1 is selected from any one of the following compounds:

[0050] [ka] however, [ka] represents the linking site.

[0051] R 4 and R 5 is as defined in any one of the paragraphs of this application.

[0052] In alternative structures, R 1 is any one selected from the following structures:

[0053] [ka] Furthermore, R 4 is selected from methoxy C1-C3 alkyl or C1-C3 alkoxy, more preferably methoxymethyl or methoxy; R 5 is H, methyl, ethyl, isopropyl, [ka] Cyclopropyl, fluorocyclopropyl, [ka] is selected from.

[0054] More preferably, the compounds described in the present application have the structures shown in Table 1 below.

[0055] [Table 1] JPEG0007688954000017.jpg217169 JPEG0007688954000018.jpg232169 JPEG0007688954000019.jpg243169 JPEG0007688954000020.jpg243169 JPEG0007688954000021.jpg245169 The present application also provides a pharmaceutical mixture comprising two or more compounds selected from the group consisting of a compound described in any one of the present application or a stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous material, isotope, crystalline polymorph, or solvate thereof.

[0056] The present application also provides pharmaceutical compositions comprising at least one of the compounds described in any one of the claims herein or a stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous material, isotope, crystalline polymorph, or solvate thereof, optionally comprising a pharma- ceutically acceptable carrier and / or adjuvant.

[0057] GABA A The present invention provides the use of a compound according to any one of the present applications or a stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous material, crystalline polymorph, solvate, said pharmaceutical mixture, or said pharmaceutical composition in the manufacture of a medicament for treating or preventing a disease associated with a receptor.

[0058] Furthermore, the GABA A The receptor-associated disease is at least one selected from pain, Alzheimer's disease, multi-infarct dementia, and stroke.

[0059] Further, said pain is neuropathic pain, inflammatory pain and cancer pain.

[0060] Further, the pain is selected from headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, lower back pain, lower limb pain, musculoskeletal pain, vascular pain, gout, arthritis pain, visceral pain, pain due to infection, bone pain, pain associated with sickle cell disease, autoimmune disease, multiple sclerosis or inflammation, chronic pain due to injury or surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, lumbar or cervical radiculopathy pain, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, pain associated with cancer, chemical injury, toxins, nutritional deficiency, viral or bacterial infection or osteoarthritis.

[0061] The present application also provides a method for treating GABAergic syndrome by administering to a patient an effective amount of a compound described in any one of the present application or a stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous material, crystalline polymorph, solvate, pharmaceutical mixture, or pharmaceutical composition thereof. A Methods for treating or preventing receptor-related diseases are provided.

[0062] The present application also provides a method of treating or preventing pain, Alzheimer's disease, multi-infarct dementia or stroke by administering to a patient an effective amount of a compound described in any one of the present application or a stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous material, crystalline polymorph, solvate thereof, pharmaceutical mixture, or pharmaceutical composition.

[0063] The present application also relates to a method for preparing the compound of formula (1) above, comprising the following scheme:

[0064] [ka] Note: R 3 is ethyl or isopropyl, and the experimental procedures are the same.

[0065] Z-1a: 5-chloro-N3-ethylpyridazine-3,4-diamine 3,5-Dichloropyridazin-4-amine (80.5g, 0.5mol) and ethylamine ethanol solution (30%, 600ml) were placed in an autoclave and reacted at 150°C for 16 hours. After the reaction solution was cooled to room temperature, a solid precipitated, filtered, the cake was washed with dichloromethane (300ml), the mother liquor (not evaporated to dryness) was concentrated, a solid precipitated, filtered again, and repeated three times to collect all the cakes to obtain a crude product (containing ethylamine hydrochloride). The crude product was added with water and stirred to form a slurry, filtered, and the cake was spin-dried to obtain 65g (yield: 76.5%) of the target product as a pale yellow solid. LC-MS: m / z [M+H] + =173. Z-2a: 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine 5-Chloro-N3-ethylpyridazine-3,4-diamine (30 g, 0.17 mol) was added to trimethyl orthoformate (600 ml). The reaction was carried out at 120° C. for 4 hours. The reaction solution was directly spin-dried to obtain a crude product, which was dissolved in dichloromethane / methanol. The sample was stirred and passed through a column (dichloromethane, dichloromethane / methanol=50 / 1, V / V) to obtain 20 g (yield: 63%) of the target product as a yellow solid. LC-MS: m / z [M+H] + =183. Z-3a: 4-(3-chloro-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine 4-Chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine (20g, 108mmol), (3-chloro-4-fluorophenyl)boronic acid (19.08g, 108mmol), sodium carbonate (24g, 216mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (9.2g, 10.8mmol) were added to 1,4-dioxane / water (160ml / 40ml) and reacted at 90°C for 2 hours. The reaction solution was directly purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1, 5 / 1, 1 / 1, ethyl acetate, V / V.) to obtain the title compound (26g, yield: 85.7%) as a yellow solid. LC-MS: m / z [M+H] + =277. Z-4a-1: 7-Ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine 4-(3-chloro-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine (15 g, 54 mmol), bis(pinacolato)diboron (27.6 g, 108 mmol), sodium acetate (13 g, 163 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (2.7 g, 5.4 mmol), tris(dibenzylideneacetone)dipalladium (5 g, 5.4 mmol) were added to anhydrous 1,4-dioxane (150 ml) and stirred overnight at 110° C. The reaction solution was directly purified by column chromatography (dichloromethane / anhydrous methanol=50 / 1) to obtain the title compound (12 g, yield: 60%) as a pale yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) ppm 1.40 (s, 12 H) 1.69 (t, J=7.09 Hz, 3 H) 4.58 (q, J=7.34 Hz, 2 H) 7.26 (d, J=6.36 Hz, 1 H) 8.29 (s, 1 H) 8.45 (d, J=1.96 Hz, 2 H) 9.39 (s, 1 H). LC-MS: m / z [M+H] + =287,369. Z-4a-2: (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid 7-Ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (12 g, 32.5 mmol) was dissolved in 200 mL of aqueous hydrochloric acid (2 M), stirred at room temperature for 2 hours, and lyophilized to give the title compound (9.3 g, crude), which appeared as a white solid.

[0066] The compound of the present invention represented by formula (1) and its pharma- ceutically acceptable salts can be prepared by the above-mentioned method.

[0067] If no preparation method is described in the examples, the compounds of formula (1) and intermediate products thereof can be prepared by similar methods or according to the methods described above. Raw materials known in the art are commercially available or can be prepared according to methods known in the art or methods analogous to known methods.

[0068] It is understood that the compounds of formula (1) of the present invention can be derivatized at functional groups to provide derivatives which may be converted back to the parent compound within the body.

[0069] The present application therefore also relates to a pharmaceutical composition comprising a compound as defined above or a pharma- ceutically acceptable salt or a prodrug thereof and a pharma- ceutically acceptable carrier and / or adjuvant.

[0070] Similarly, the present application further relates to α2 / 3-GABA A This includes the use of a compound or composition as described above in the manufacture of a medicament for treating or preventing a disease associated with the receptor, in particular for treating or preventing pain, epilepsy, anxiety, pruritus and depression.

[0071] Preferably, the treatment or prevention of pain.

[0072] Particularly preferred is the treatment or prevention of neuropathic pain, inflammatory pain and cancer pain.

[0073] As used herein, "cancer pain" refers to pain that occurs during the course of the development of malignant tumors, and there are currently three mechanisms of cancer pain: direct pain caused by the onset of cancer, pain caused by cancer treatment, and pain disorders that occur concomitantly in cancer patients.

[0074] As used herein, "neuropathic pain" is pain caused or resulting from primary injury and dysfunction of the nervous system.

[0075] As used herein, "inflammatory pain" is pain caused by localized acute or chronic inflammation that irritates nerves.

[0076] As used herein, "treatment" also includes prophylactic administration to reduce or eliminate the disease once the disease has developed.

[0077] As used herein, a "patient" is defined as any warm-blooded animal, such as, but not limited to, a mouse, guinea pig, dog, horse, or human, and preferably, the patient is a human.

[0078] As used herein, "acute pain" is defined as pain due to noxious stimuli resulting from injury and / or disease of the skin, body structures or internal organs, or pain due to abnormal functioning of muscles or internal organs without causing actual tissue damage.

[0079] As used herein, "chronic pain" is defined as pain that persists beyond the normal course of acute disease or injury that can heal for a reasonable time, or is associated with a chronic pathological process that causes persistent pain, or pain that recurs at intervals of months or years, persists after the pain has healed, and persists beyond the normal course of treatment. The duration of pain depends on the nature of the pain and the treatment course associated with the pain, and pain is chronic when it exceeds the normal course of treatment. Chronic pain includes, but is not limited to, headache, facial pain, neck pain, shoulder pain, chest pain, abdominal pain, back pain, lower back pain, lower limb pain, musculoskeletal pain, pain associated with somatoform psychiatric disorders, visceral pain, painful diabetic neuropathy, vascular pain, gout, arthritis pain, cancer pain, autonomic reflex pain, pain from infectious diseases (such as AIDS and shingles), pain from autoimmune diseases (rheumatism), acute and chronic pain, postoperative pain, and post-burn pain.

[0080] The medicaments disclosed in the present application are capable of effectively treating chronic pain as defined above, and the medicaments presented in the present application are capable of treating hyperalgesia associated with other symptoms including hyperalgesia, allodynia, increased pain perception and enhanced pain memory, and the present application improves the treatment of said pain.

[0081] As used herein, "headache" can be divided into primary headache and secondary headache, primary headache includes tension headache, migraine and cluster headache, secondary headache is caused by other diseases. Lesions or irritation of pain-sensitive tissues in the head and face can cause various headaches, these pain-sensitive tissues are distributed in the scalp, face, mouth and throat, etc., which are mainly head muscles and blood vessels, contain rich nerve fibers, and are sensitive to pain, so damage to these tissues can cause headaches.

[0082] As used herein, "facial pain" includes, but is not limited to, trigeminal neuralgia, atypical facial pain, facial paralysis, and hemifacial spasm.

[0083] As used herein, "trigeminal neuralgia" is a unique chronic pain disease, also known as painful spasm, which refers to short-term, paroxysmal, and repetitive electric shock-like severe pain in the distribution area of ​​the trigeminal nerve, or ipsilateral facial spasm.Trigeminal neuralgia is divided into two types: primary and secondary.Primary trigeminal neuralgia refers to the absence of clinical neurological signs and the absence of substrate lesions on examination, while secondary trigeminal neuralgia refers to the presence of clinical neurological signs and the discovery of organic lesions such as tumors and inflammation on examination.

[0084] As used herein, "atypical facial pain" refers to pain caused by a variety of etiologies. It presents as a constant, burning pain, is not intermittent, is not associated with a specific behavior or provoking stimulus, is mostly bilateral, and often extends beyond the trigeminal nerve distribution to the skin of the neck. Etiology may include pain induced by irritation or damage to the trigeminal nerve due to sinusitis, malignant tumors, infections of the jaw and base of the skull, etc.

[0085] As used herein, "neck pain, back pain, shoulder pain" refers to pain caused by acute and chronic muscle injuries, degeneration and trauma of bones and joints, etc. Common diseases that cause pain in the neck, shoulder and upper limbs include cervical shoulder fasciitis, nuchal ligamentitis, cervical spondylosis, 50-dog, thoracic outlet syndrome, lateral epicondylitis of the humerus, etc., or pain due to autoimmune diseases is common in diseases such as rheumatoid arthritis, ankylosing spondylitis and rheumatoid arthritis, and other diseases that may cause neck pain, back pain, shoulder pain include tumors of the neck, shoulder, neuritis, arteriovenous diseases and various infections and referred pain due to chest and abdominal organ lesions.

[0086] As used herein, "chest, abdominal and back pain" refers to pain due to disorders of the chest and abdominal viscera, chest and abdominal wall tissues, including, but not limited to, intercostal neuralgia, intercostal chondritis, angina pectoris, abdominal pain (acute abdominal visceral pain) and lumbar myofascial syndrome.

[0087] As used herein, "lower back, lower limb pain" refers to pain in the lower back, lumbosacral, sacroiliac joints, hip joints, buttocks and lower limbs. Lower back and lower limb pain is often not an independent disease, but a common feature of various diseases, with diverse clinical expressions, and the causes are often very complex and degenerative and traumatic, including but not limited to pain related to lumbar disc herniation, acute lumbar sprain, sciatica, osteoporosis, third lumbar transverse process syndrome, piriformis syndrome, osteoarthritis of the knee, tail pain and heel pain.

[0088] As used herein, "musculoskeletal pain" includes, but is not limited to, myofascial pain, trauma-induced pain, and chronic regional pain syndromes.

[0089] As used herein, "painful diabetes" refers to pain due to nerve damage associated with diabetes, which is at least partially due to reduced blood flow and hyperglycemia. Some diabetic patients do not develop neuropathy, while others develop the disease first, and diabetic neuropathy pain can be divided into mononeuropathy involving one or more localized sites and generalized polyneuropathy, which may be diffuse and symmetrical, and generally related mainly to sensory aspects (Merrit's Textbook of Neurology, 9th Edition, edited by LPRowland LP). Symptoms of diabetic neuropathy may include autonomic nervous system dysfunction, which causes dysregulation involving the heart, smooth muscles and glands, leading to low blood pressure, diarrhea, constipation and sexual dysfunction. Diabetic neuropathy often develops in stages, initially at the nerve endings, in the feet in the case of autonomic or sensory neuropathy, or in the face and around the eyes in the case of cranial neuropathy, with intermittent pain and numbness appearing, with the pain becoming more intense and frequent in later stages, and finally with a loss of sensation of pain in a particular area known as painless neuropathy, and with the absence of pain as an indicator of damage, the risk of serious tissue damage is greatly increased.

[0090] As used herein, "visceral pain" includes, but is not limited to, pain with or without associated irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), inflammatory bowel disease (IBD), and interstitial cystitis.

[0091] As used herein, "vascular pain" is pain due to one or more of the following causes: first, inadequate perfusion of tissues, resulting in temporary or persistent localized ischemia, such as that occurring in limb muscles during exercise; second, delayed changes, such as ulcers or gangrene of the skin or abdominal viscera; third, sudden or accelerated changes in the caliber of large blood vessels, such as the development of aneurysms; fourth, aortic rupture, resulting in a flood of blood, stimulating nociceptive fibers in the parietal layers of the peritoneum or pleura; fifth, intense spasm due to intense stimulation of the arterial endothelium by intra-arterial injection; sixth, impaired venous return, resulting in massive edema that rapidly expands the fascial compartment (Bonica et al., The Management of Pain, Vol. 1(Second Edition), Philadelphia; Lea&Feboger, 1990). Examples include, but are not limited to, arteriosclerosis obliterans, thromboangiitis obliterans, acute arterial occlusion, embolism, congenital arteriovenous aneurysms, vasospastic disease, Raynaud's disease, acrocyanosis, acute venous occlusion, thrombophlebitis, varicose veins, and lymphedema.

[0092] As used herein, "autonomic reflex pain" refers to pain caused by "reflex sympathetic atrophy". Reflex sympathetic atrophy is a severe spontaneous pain, hypersensitivity to touch and pain after acute and chronic injury of the body, which can be accompanied by edema and blood circulation disorders, followed by symptoms such as nutritional disorders and atrophy of the skin and musculoskeletal system.

[0093] As used herein, "post-surgical pain" refers to the body's complex physiological response to the tissue damage caused by disease itself and surgery, which manifests as an unpleasant psychological and behavioral experience.

[0094] As used herein, "arthritic pain" includes, but is not limited to, pain due to diseases such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthropathy, gout, pseudogout, infectious arthritis, tendonitis, bursitis, bone injuries and joint soft tissue inflammation.

[0095] As used herein, "postherpetic neuralgia" refers to severe pain that persists under the skin at the site of the original herpetic rash after the rash has healed.

[0096] "Nociceptive pain" as used herein is pain caused by tissue injury processes that stimulate the afferents of nociceptors or pain caused by prolonged excitation of nociceptors. Pain resulting from prolonged excitation of nociceptors may be caused by persistent noxious stimulation of nociceptors or their sensitization, or a combination of the two, and may be prolonged due to its persistence, various reflex mechanisms, and other factors.

[0097] The present application relates to a therapeutically effective amount of α2 / 3-GABA A The present application provides a pharmaceutical compound comprising a positive allosteric modulator for use in the treatment of α2 / 3-GABA A While the positive allosteric modulators may be administered in the form of raw compounds, preferably the active ingredient, optionally in the form of a physiologically acceptable salt, is mixed into a pharmaceutical composition together with one or more additives, excipients, carriers, buffers, diluents and / or other conventional pharmaceutical excipients.

[0098] In an optional embodiment, the present application relates to α2 / 3-GABA A A pharmaceutical composition comprising a positive allosteric modulator, wherein the α2 / 3-GABA A The positive allosteric modulators are mixed with one or more pharma- ceutically acceptable carriers, and optionally other therapeutic and / or prophylactic ingredients known or used in the art, said carriers must be "acceptable", i.e., compatible with other ingredients in the formulation and not deleterious to the recipient.

[0099] Thus, the compounds used in this application can be prepared into pharmaceutical compositions and unit dosage forms thereof together with conventional additives or diluents. Such forms include solids (especially in the form of tablets, filled capsules, powders and pills), and liquids (especially aqueous or non-aqueous solutions, suspensions, emulsions, elixirs), and capsules filled in the above forms, all oral administration forms, suppositories for rectal administration, and sterile injection solutions for parenteral administration. Such pharmaceutical compositions and unit dosage forms thereof can contain conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and such unit dosage forms can contain any suitable effective amount of active ingredient corresponding to the required daily dose range.

[0100] The compounds used in the present application can be administered in a variety of oral and parenteral formulations. Those skilled in the art will recognize that the following formulations may contain the compounds of the present application or their pharma- ceutically acceptable salts as the active ingredient.

[0101] For preparing the compound used in the present application as a pharmaceutical composition, the pharma- ceutically acceptable carrier may be solid or liquid.The solid form preparation includes powder, tablet, pill, capsule, cachet, suppository, and dispersible granule.The solid carrier may be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

[0102] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active ingredient.

[0103] In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0104] Powders and tablets preferably contain 5% or 10% to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. The term "formulation" includes the active compound prepared with an encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without a carrier, is surrounded by and bound to the carrier. Similarly, the formulation includes cachets and lozenges. Tablets, powders, capsules, pills, cachets, and lozenges can be used in solid forms suitable for oral administration.

[0105] To prepare suppositories, a low melting wax, such as fatty acid glycerides or cocoa butter, is first melted and stirred to disperse the active ingredient homogeneously. The molten homogeneous mixture is then poured into suitable sized molds and allowed to cool and solidify.

[0106] Compositions suitable for vaginal administration may be in the form of pessaries, tampons, creams, gels, pastes, foams or sprays, and will further comprise, in addition to the active ingredient, suitable carriers known in the art.

[0107] Liquid preparations include solutions, suspensions and emulsions, for example, water solutions or water-propylene glycol solutions.For example, parenteral injection liquid preparations can be prepared as water-polyethylene glycol solutions.

[0108] Thus, the compounds used in this application can be prepared as formulations for parenteral administration (e.g., injection, such as bolus injection or continuous injection), and may be present in unit dose form in ampoules, prefilled syringes, small injection bags, or multi-dose containers with added preservatives. The compositions can be used in the form of suspensions, solutions, or emulsions in oily or aqueous carriers, and can contain formulation ingredients such as suspending agents, stabilizers, and / or dispersing agents. In addition, the active ingredient is in powder form, which can be obtained by sterilization separation with sterile solids or by lyophilization of the solution, for reconstitution with a suitable carrier, such as sterile, pyrogen-free water, before use.

[0109] Aqueous solutions suitable for oral administration can be prepared by dissolving the active component in water and adding desired colorants, flavors, stabilizing, and thickening agents.

[0110] Aqueous suspensions suitable for oral administration may be prepared by dispersing the finely divided active ingredient in water containing viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other known suspending agents.

[0111] Also included are solid preparations designed to be converted immediately prior to use into liquid preparations for oral administration. Such liquid preparations include solutions, suspensions, and emulsions. In addition to the active ingredient, such preparations may contain colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0112] For topical administration to the epidermis, the compounds of the present application can be prepared into ointments, creams or detergents or transdermal patches.For example, ointments and creams can be prepared by adding suitable thickening and / or gelling agents to an aqueous or oily matrix.Detergents can be prepared using an aqueous or oily matrix, and generally further include one or more emulsifiers, stabilizers, dispersants, suspending agents, thickening agents or colorants.

[0113] Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored matrix, typically sucrose and arabic gum or tragacanth gum, pastilles comprising the active ingredient in an inert matrix such as gelatin and glycerol or sucrose and arabic gum, and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0114] Solutions or suspensions may be applied directly to the nasal cavity using conventional means such as a dropper, pipette or spray. The compositions may be in single or multidose form.

[0115] Respiratory administration may also be accomplished via an aerosol in which the active ingredient is contained in a pressurized package with a suitable propellant containing a chlorofluorocarbon (CFC), such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may also suitably contain a surfactant, such as lecithin. The dosage of drug may be controlled by a metered valve.

[0116] Furthermore, the active ingredient may be in the form of a dry powder, for example a powder mixture of the compound and a suitable powder matrix, such as lactose, starch, hydroxypropylmethylcellulose and starch derivatives, such as polyvinylpyrrolidone (PVP). The powder carrier can easily form a gel in the nasal cavity. The powder composition can be presented in unit dosage form, for example in capsules or cartridges, such as gelatin capsules or cartridges, or in blister packs, from which the powder can be administered by an inhaler.

[0117] In compositions for respiratory administration (including compositions for intranasal use), the compound generally has a small particle size, for example a particle size of 5 microns or less. Such a particle size can be obtained using methods known in the art, such as micronization.

[0118] Where appropriate, compositions adapted for sustained release of the active ingredient may be employed.

[0119] Pharmaceutical preparations are optionally in unit dose form. In this form, the preparation is subdivided into appropriate amounts of unit doses of active ingredient. The unit dose form may be an encapsulated preparation, which contains an isolated bulk of the preparation, such as a tablet, capsule, and powder in a vial or ampoule, sealed in a sealed package. Furthermore, the unit dose form may be a capsule, tablet, casette, or lozenge itself, or the appropriate amount of said capsule, tablet, etc., in any encapsulated form.

[0120] Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

[0121] More detailed information on formulation and administration techniques can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

[0122] The amount of active ingredient in a unit dose preparation can vary depending on the particular use and the potency of the active ingredient, and can be adjusted from 0.01 mg to about 0.1 g. For example, in pharmaceutical use, the medicament can be administered in capsules of 0.01 to about 100 mg three times a day, and the composition may contain other compatible therapeutic agents as needed.

[0123] Treatment method In therapeutic use, the compounds used in this application are used at starting doses of 0.001 mg / kg to 10 mg / kg of body weight per day. However, such doses may vary depending on the needs of the patient, the severity of the disease being treated and the compound being used, and generally, treatment is initiated with a dose that is less than the optimum dose of the compound, and this dose is then increased by small amounts to reach optimal effect, and the total daily dose can be administered in divided doses throughout the day if necessary for convenience.

[0124] The pharmaceutical composition of the present application can also be used in combination with other drugs for treating pain, epilepsy, anxiety and depression at the same time, including but not limited to morphine, gabapentin, etc. Therefore, the present application provides a drug for treating pain, epilepsy, anxiety and depression, which is not only effective but also has no significant side effects, and another object of the present application is to provide a drug with high safety for specific patient groups, such as elderly people, patients with reduced liver or kidney function, or patients suffering from cardiovascular disease.

[0125] The present application also provides a method of treating or preventing a disease, comprising administering to a patient an effective amount of the above-described compound or composition.

[0126] The present application also provides a method for administering to a patient an effective amount of the compound or the composition described above, comprising administering to the patient a GABA A Methods for treating or preventing receptor-related diseases are provided.

[0127] The application also provides the use of a compound or composition as described above in the manufacture of a medicament for treating or preventing pain, Alzheimer's disease, multi-infarct dementia or stroke.

[0128] The pain is neuropathic pain, inflammatory pain and cancer pain. Optionally, the pain is selected from headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, lower back pain, lower limb pain, musculoskeletal pain, vascular pain, gout, arthritis pain, visceral pain, pain due to infection, bone pain, pain associated with sickle cell disease, autoimmune disease, multiple sclerosis or inflammation, chronic pain due to injury or surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, pain from lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, cancer, chemical injury, toxins, nutritional deficiency, viral or bacterial infection or pain associated with osteoarthritis.

[0129] The present application also provides a method of treating or preventing pain, Alzheimer's disease, multi-infarct dementia or stroke, comprising administering to a patient an effective amount of the compound or the composition described above.

[0130] Beneficial Effects: The compounds of the present application and their pharma- ceutically acceptable salts or prodrugs thereof have important pharmacological properties and are capable of inhibiting α2 / 3-GABA A The compounds of the present application are positive allosteric modulators of the α2 / 3-GABA receptor. A The compounds of the present application and their pharma- ceutical acceptable salts or prodrugs thereof have excellent affinity activity and positive regulatory activity for the α2 / 3-GABA receptor, and have excellent genotoxicity safety and drug development potential. A They can be used alone or in combination with other drugs to treat or prevent diseases associated with.

[0131] [Mode for carrying out the invention] The technical solutions of the present application are described below clearly and completely. Of course, the described embodiments are only some of the embodiments of the present invention, and are not all of the embodiments. Based on the embodiments of the present application, other embodiments obtained by those skilled in the art without paying creative labor are all included in the scope of protection of the present application. Here, the solvent ratios used in the purification steps (such as preparative thin layer chromatography, column chromatography, etc.) in the following examples are volume ratios.

[0132] Example 1 [ka] 1-1: (4-bromo-2-fluoropyridin-3-yl)methanol 4-Bromo-2-fluoronicotinaldehyde (565 mg, 2.77 mmol) was added to tetrahydrofuran (3 ml), sodium borohydride (63 mg, 1.67 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was poured into methanol (10 ml) to quench the reaction, poured into water (30 ml), extracted with dichloromethane (30 ml x 3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product (508 mg, 89%) as a colorless oily liquid. LC-MS: m / z [M+H]+ =206, 208.

[0133] 1-2: (4-bromo-2-hydrazinylpyridin-3-yl)methanol (4-Bromo-2-fluoropyridin-3-yl)methanol (505 mg, 2.45 mmol) and hydrazine hydrate (246 mg, 4.9 mmol) were added to ethanol (4 ml) and reacted at 95° C. for 2 hours. The reaction solution was stirred directly and subjected to column chromatography (dichloromethane / methanol=10 / 1) to obtain the title compound (388 mg, 51%) as a white solid. LC-MS: m / z [M+H] + =218, 220.

[0134] 1-3: (7-bromo-3-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methanol (4-Bromo-2-hydrazinylpyridin-3-yl)methanol (150 mg, 0.48 mmol) and cyclopropylcarboxaldehyde (50 mg, 0.72 mmol) were added to ethanol (2 ml) and reacted at 90° C. for 1 hour. Potassium carbonate (66 mg, 0.66 mmol) and iodine (12 mg, 0.05 mmol) were added to the reaction solution and stirred at room temperature for 4 hours. The reaction solution was subjected to preparative thin layer chromatography (dichloromethane / methanol=25 / 1) to obtain the title compound (65 mg, 51%) as a brown solid. LC-MS: m / z [M+H] + =268, 270.

[0135] 1-4: 7-Bromo-3-cyclopropyl-8-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (7-Bromo-3-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methanol (60 mg, 0.22 mmol) was added to tetrahydrofuran (2 ml), sodium hydride (8 mg, 0.26 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. Iodomethane (47 mg, 0.33 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was subjected to preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain the title compound (55 mg, 89%) as a brown solid. LC-MS: m / z [M+H] + =282, 284.

[0136] Compound 1: 4-(3-(3-cyclopropyl-8-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine 7-Bromo-3-cyclopropyl-8-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (30 mg, 0.11 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (31 mg, 0.11 mmol), sodium carbonate (23 mg, 0.22 mmol), bis(triphenylphosphino)palladium dichloride (8 mg, 0.01 mmol) were added to tetrahydrofuran (2 ml) and water (0.1 ml), and the mixture was reacted at 80° C. for 16 hours under the protection of argon gas. The reaction solution was subjected to preparative thin layer chromatography (dichloromethane / methanol = 15 / 1) to obtain the title compound (8 mg, 16%) as a brown solid.

[0137] 1H NMR (400MHz, CHLOROFORM-d) 9.40 (s, 1 H), 8.42 (d, J = 6.8 Hz, 2 H), 8.28 (s, 1 H), 8.16 - 8.10 (m, 1 H), 7.46 - 7.38 (m, 1 H), 6.93 (br. s., 1 LC-MS: m / z [M+H] + =444.

[0138] Example 2 [ka] 2-1: 5-Bromo-4-methoxypyridin-2-amine 2-Amino-4-methoxypyridine (5 g, 40 mmol) was dissolved in anhydrous acetonitrile (80.0 ml), N-bromosuccinimide (NBS, 7 g, 40 mmol) was added in batches, stirred at 0°C for 2 hours, quenched with saturated aqueous sodium bicarbonate (100 ml), separated, the organic layer was collected, and the aqueous phase was further extracted with dichloromethane (100 ml x 3). After spin drying, the crude product was obtained, which was purified by normal phase silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 2: 1) to obtain the title product (4 g, 58%) as a white solid. LC-MS: m / z [M+1] + =203 2-2: 6-Bromo-2-(1-fluorocyclopropyl)-7-methoxyimidazo[1,2-a]pyridine 5-Bromo-4-methoxypyridin-2-amine (500 mg, 2.5 mmol), 2-chloro-1-(1-fluorocyclopropyl)ethan-1-one (670 mg, 5 mmol), cesium carbonate (1.6 g, 5 mmol) were dissolved in a solution of ethanol (10.0 ml), heated to 100° C. in a microwave reactor and reacted for 1 hour, and the reaction solution was purified by preparative HPLC to obtain the title product (100 mg, 27%) as a white solid. LC-MS: m / z [M+1] + = 285 Compound 2: 7-isopropyl-4-(4-fluoro-3-(2-(1-fluorocyclopropyl)-7-methoxyimidazo[1,2-a]pyridin-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine 6-Bromo-2-(1-fluorocyclopropyl)-7-methoxyimidazo[1,2-a]pyridine (100.0 mg, 0.36 mmol), (5-(7-isopropyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (105 mg, 0.36 mmol), cesium carbonate (210 mg, 0.54 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (16.5 mg, 0.036 mmol) were suspended in a solution of 1,4-dioxane / water (5.5 mL, v / v=10 / 1) and heated to 100° C. for 2 hours. The reaction solution was diluted with ethyl acetate (50 ml), washed with saturated aqueous sodium chloride solution (50 ml x 3), and the organic phase was dried, concentrated, and further purified by preparative HPLC to give the title product (30 mg, 17%) as a white solid.

[0139] 1H NMR (400 MHz, CDCl3) 9.64 (s, 1H), 9.06 (s, 1H), 8.98 (s, 1H), 8.70-8.62 (m, 1H), 8.58 (dd, J = 7.0, 2.2 Hz, 1H), 8.25 (s, 1H), 7.65 LC-MS: m / z [M+1] + = 461

[0140] Examples 3 and 4 [ka] 3-1: 2-Fluoro-4-iodo-3-methoxypyridine 2-Fluoro-3-methoxypyridine (5 g, 39.3 mmol) was dissolved in anhydrous tetrahydrofuran (150 ml), and the reaction solution was cooled to -60°C under nitrogen gas protection, and N-butyllithium (2.5 M) (23.6 ml, 59 mmol) was slowly added dropwise, and the temperature was controlled at -60 to -65°C for 10 minutes, followed by stirring at -60°C for 1 hour. A solution of iodine (11 g, 43 mmol) in anhydrous tetrahydrofuran (100 ml) was slowly added, and the temperature was maintained at about -60°C for 2 hours. Then, the reaction was allowed to proceed at -60°C for 2 hours. A saturated aqueous solution of ammonium chloride (200 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 ml x 3), washed with saturated saline (100 ml), dried over anhydrous sodium sulfate, concentrated, and then purified by normal phase chromatography (petroleum ether:ethyl acetate=3:1) to obtain the title product (6.8 g, white solid) with a yield of 68%. 1 H NMR (400 MHz, CDCl3) 7.56 (m, 2H), 3.99 (s, 3H). 3-2: 2-hydrazinyl-4-iodo-3-methoxypyridine 2-Fluoro-4-iodo-3-methoxypyridine (6.8g, 26.88mmol) was dissolved in ethanol (68.0ml), hydrazine hydrate (2.7g, 53.8mmol) was added, and the mixture was reacted at 90°C for 16 hours. After concentration, water (100ml) was added, stirred for 30 minutes, filtered, and the cake was collected and dried in vacuum to obtain the title product (5.5g, white solid) with a yield of 78%. LCMS: m / z [M+1] + =266 3-3: N'-(4-iodo-3-methoxypyridin-2-yl)-3-methoxycyclobutane-1-carbohydrazide 2-Hydrazinyl-4-iodo-3-methoxypyridine (300mg, 1.13mmol), 3-methoxycyclobutane-1-carboxylic acid (147mg, 1.13mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (472.6mg, 1.24mmol) were dissolved in anhydrous dichloromethane (12ml), diisopropylethylamine (366mg, 2.83mmol) was slowly added dropwise under the protection of nitrogen gas, and the mixture was stirred at 30°C for 2 hours. The reaction solution was poured into ice water, extracted with dichloromethane (100ml x 3), concentrated, and purified by reverse phase to obtain the title product (270mg, yellow oil) with a yield of 71%. LCMS: m / z [M+1] + =378 3-4: 7-Iodo-8-methoxy-3-(3-methoxycyclobutyl)-[1,2,4]triazolo[4,3-a]pyridine N'-(4-iodo-3-methoxypyridin-2-yl)-3-methoxycyclobutane-1-carbohydrazide (270 mg, 0.72 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), Burgess reagent (N-(triethylammonium sulfonyl)carbamate, 512 mg, 2.15 mmol) was added, and the reaction system was reacted at 60°C for 3 hours under the protection of nitrogen gas. The reaction solution was poured into water (50 ml). The crude product was obtained after extraction with ethyl acetate (50 ml x 3) and concentration, and purified by preparative HPLC to obtain the title product (170 mg, white solid) with a yield of 66%. LCMS: m / z [M+1] +=360 Compound 3: rel-4-(4-fluoro-3-(8-methoxy-3-((1s,3s)-3-methoxycyclobutyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7-isopropyl-7H-imidazo[4,5-c]pyridazine Compound 4: rel-4-(4-fluoro-3-(8-methoxy-3-((1r,3r)-3-methoxycyclobutyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7-isopropyl-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-iodo-8-methoxy-3-(3-methoxycyclobutyl)-[1,2,4]triazolo[4,3-a]pyridine (100.0 mg, 0.278 mmol), (2-fluoro-5-(7-isopropyl-7H-imidazo[4,5-c]pyridazin-4-yl)phenyl)boronic acid (100.3 mg, 0.334 mmol) were used as raw materials to obtain the two title mixtures, which appeared as white solids. Further chiral separation was carried out to obtain Examples 3 and 4. Separation method: Instrument: MG II preparative SFC (supercritical fluid preparative chromatography, SFC-1); Chromatography column: ChiralPak AD, 250×30 mm ID, 10 μm; Mobile phase: A is CO 2 where B is isopropanol, B is 55vt%, flow rate: 80ml / min; back pressure: 100bar; column temperature: 38°C; wavelength: 220nm.

[0141] Example 3: First peak, 14 mg, white solid, 10% yield. 1H NMR (400 MHz, DMSO-d6) 9.58 (s, 1H), 8.95 (s, 1H), 8.64-8.44 (m, 2H), 8.13 (d, 1H), 7.67-7.46 (m, 1H), 7.03 (d, 1H), 5.24-4.92 (m, 1H), 4.33 (d, J = 3.2 Hz, 3H), 4.22-3.88 (m, 2H), 3.21 (s, 3H), 2.72 (m, 2H), 2.59-2.49 (m, 2H), 1.68 (d, J = 6.8 Hz, 6H). LCMS: m / z[M+H] + =488

[0142] Example 4: Second のピーク, 38 mg, white solid, yield 28%. 1 H NMR (400 MHz, DMSO-d6) 9.58 (s, 1H), 8.95 (s, 1H), 8.65-8.43 (m, 2H), 8.19 (d, 1H), 7.70-7.44 (m, 1H), 7.04 (d, 1H), 5.22-5.00 (m, 1H), 4.33 (s, 3H), 4.02 (t, J = 6.9 Hz, 1H), 3.60 (d, J = 7.9 Hz, 1H), 3.21 (s, 3H), 2.97-2.75 (m, 2H), 2.32 (dd, J = 10.5, 8.8 Hz, 2H), 1.68 (d, J = 6.8 Hz, 6H).LCMS: m / z [M+H] + =488.

[0143] Example 5

change

[0144] 1 H NMR (400 MHz, DMSO-d6) 9.58 (s, 1H), 8.88 (s, 1H), 8.68-8.49 (m, 2H), 8.44 (d, 1H), 7.66-7.53 (m, 1H), 7.04 (d, 1H), 4.52 (q, LCMS: m / z [M+H] + =488

[0145] Example 6 [ka] Compound 6: 7-Ethyl-4-(4-fluoro-3-(8-methoxy-3-(3-methoxycyclobutyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-iodo-8-methoxy-3-(3-methoxycyclobutyl)-[1,2,4]triazolo[4,3-a]pyridine (85 mg, 0.24 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (66 mg, 0.24 mmol) were used as raw materials to obtain the title compound (41.0 mg, white solid) with a yield of 36.2%.

[0146] 1H NMR (400 MHz, DMSO-d6) 9.58 (s, 1H), 8.88 (s, 1H), 8.63-8.46 (m, 2H), 8.18 (d, J = 7.0 Hz, 1H), 7.59 (t, J = 9.2 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 4.32 (s, 3H), 4.02 (m, 1H), 3.61 (m, 1H), 3.21 (s, 3H), 2.87 (m, 2H), 2.31 (m, 2H), 1.56 (t, J = 7.3 Hz, 3H). LCMS: m / z [M+1] + =474

[0147] Example 7 [ka] 7-1: 4-Chloro-2-(chloromethyl)-3-methoxypyridine 4-Chloro-3-methoxy-2-methylpyridine 1-oxide (4.9g, 28.31mmol) was dissolved in anhydrous dichloromethane (250ml), and under the protection of nitrogen gas, phosphorus oxychloride (6.5g, 42.47mmol) dissolved in dichloromethane (40ml) and triethylamine (5.7g, 56.62mmol) dissolved in dichloromethane (40ml) were slowly added dropwise at the same rate, and after the addition was completed, the mixture was stirred at 30°C for 3 hours. The reaction solution was poured into 300ml of saturated sodium bicarbonate solution, extracted with dichloromethane (200ml x 3), washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain the title product (4.9g, yellow solid) with a yield of 89%. LCMS: m / z [M+1] + =192 7-2: 2-((4-chloro-3-methoxypyridin-2-yl)methyl)isoindoline-1,3-dione 4-Chloro-2-(chloromethyl)-3-methoxypyridine (5.4 g, 28.31 mmol) and potassium phthalimide salt (5.2 g, 28.31 mmol) were dissolved in N,N-dimethylformamide (100.0 ml), and the reaction system was reacted at 60° C. for 16 hours under nitrogen gas protection. The reaction solution was poured into water (100 ml). The crude product obtained by extracting with ethyl acetate (100 mL x 3), washing with 5% lithium chloride and saturated saline, drying with anhydrous sodium sulfate, and concentrating was purified by normal phase (CH 2 Cl 2 ~ ethyl acetate) to give the title product (3.7 g, white solid) in 48% yield. 1 H NMR (400 MHz, CDCl3) 8.09 (d, J = 5.2 Hz, 1H), 7.91- 7.85 (m, 2H), 7.78-7.71 (m, 2H), 7.21 (d, J = 5.2 Hz, 1H), 5.08 (s, 2H), 4.03 (s, 3H).LCMS: m / z [M+1] + =303 7-3: (4-chloro-3-methoxypyridin-2-yl)methanamine 2-((4-chloro-3-methoxypyridin-2-yl)methyl)isoindoline-1,3-dione (3.8g, 12.53mmol) was dissolved in ethanol (38ml), hydrazine hydrate (7.6ml) was added, and the reaction system was reacted at 80℃ for 16 hours. The reaction solution was spun to remove ethanol, 50ml water was added, and the pH was adjusted to 1 with concentrated hydrochloric acid. A large amount of solid precipitated, filtered, and the filtrate was collected and adjusted to PH=9~10 with NaOH, and then extracted with ethyl acetate (100mL×3), washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain the title product (1.35g, yellow oil) with a yield of 62%. LCMS: m / z [M+1] + =173 7-4: N-((4-chloro-3-methoxypyridin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide (4-Chloro-3-methoxypyridin-2-yl)methanamine (300mg, 1.74mmol) was dissolved in dichloromethane (6ml), diisopropylethylamine (562mg, 4.35mmol) was added, and then 4-hydropyran-4-carbonyl chloride (258.5mg, 1.74mmol) was slowly added dropwise to the reaction solution, and the reaction system was reacted at 30°C for 3 hours. The reaction solution was poured into 50ml of water, extracted with dichloromethane (50ml x 3), washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain the title product (497mg, yellow oil).

[0148] 7-5: 7-Chloro-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyridine N-((4-chloro-3-methoxypyridin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide (200 mg, 0.7 mmol) was dissolved in anhydrous tetrahydrofuran (4 ml), Burgess reagent (502 mg, 2.1 mmol) was added, and the reaction system was heated to 100° C. 2 The reaction was carried out at 60°C for 3 hours under the protection of . The reaction solution was poured into water (50 ml). The crude product obtained after extraction with ethyl acetate (50 ml x 3) and concentration was purified by reverse phase (0.5% HCOOH-CH 3 CN) to give the title product (102 mg, white solid) in 54% yield. LCMS: m / z [M+1] + =267 7: 7-Ethyl-4-(4-fluoro-3-(8-methoxy-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-chloro-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyridine (102.1 mg, 0.38 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (109.5 mg, 0.38 mmol) were used as starting materials to obtain the title compound (22 mg, white solid) with a yield of 12%.

[0149] 1 H NMR (400 MHz, DMSO-d6) 9.57 (s, 1H), 8.87 (s, 1H), 8.56 (d, 1H), 8.52-8.38 (m, 1H), 8.19 (d, 1H), 7.61 (s, 1H), 7.55 (t, 1H), 6.71 (d, 1H), 4.52 (q, J = 7.2 Hz, 2H), 4.04-3.88 (m, 5H), 3.53 (m, 3H), 1.96-1.75 (m, 4H), 1.56 (t, J = 7.2 Hz, 3H). LCMS: m / z [M+1] + =473

[0150] Example 8 [ka] 8-1: 5-Amino-1-methyl-1H-pyrazole-4-carbaldehyde 5-Amino-1-methyl-1H-pyrazole-4-carbonitrile (5g, 128mmol) was added to tetrahydrofuran (20ml), cooled to -20°C under argon gas protection, diisobutylaluminum hydride (40ml, 40mmol) was added dropwise, and after completion of the addition, the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into ice water (50ml), filtered, and the filtrate was extracted with ethyl acetate (50mL x 3), concentrated, and purified by column chromatography (dichloromethane:methanol = 15:1) to obtain a white solid compound (420mg, yield: 20%). LC-MS: m / z [M+H] + =126.0 8-2: Methyl 3-(5-amino-1-methyl-1H-pyrazol-4-yl)acrylate 18-crown-6 (2.9g, 11.0mmol) was dissolved in tetrahydrofuran (20ml) and cooled to -40℃, and methyl 2-(dimethoxyphosphoryl)acetate (420mg, 2.2mmol) and lithium bis(trimethylsilyl)amide (2.2ml, 2.2mmol) were added. 5-amino-1-methyl-1H-pyrazole-4-carbaldehyde (275mg, 2.2mmol) was dissolved in tetrahydrofuran (10ml) and then added dropwise to the reaction system. The mixture was stirred at room temperature for 16 hours, and the reaction solution was poured into water (50ml), extracted with ethyl acetate (50mL x 3), concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a white solid compound (200mg, yield: 50%). LC-MS: m / z [M+H] + =182 8-3: 1-Methyl-1H-pyrazolo[3,4-b]pyridin-6-ol Methyl 3-(5-amino-1-methyl-1H-pyrazol-4-yl)acrylate (200 mg, 1.1 mmol) was dissolved in dilute hydrochloric acid (3 mol / L, 20 ml) and stirred at 100° C. for 4 hours. It was then directly spin-dried, dissolved in distilled water (5 ml) by heating, and cooled on the top layer of a refrigerator. A large amount of white flocculent precipitate was precipitated, which was filtered to obtain a white solid (150 mg, yield: 91%). LC-MS: m / z [M+H] + =150 8-4: 5-Bromo-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-ol 1-Methyl-1H-pyrazolo[3,4-b]pyridin-6-ol (150 mg, 1.0 mmol) was added to acetic acid (15 ml), liquid bromine (480 mg, 3.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was directly spin-dried, and deionized water (20 ml) was added. A large amount of white solid precipitated. The solid was filtered to obtain a white solid (100 mg, yield: 44%). LC-MS: m / z [M+H] + =228 8-5: 5-Bromo-6-methoxy-1-methyl-1H-pyrazolo[3,4-b]pyridine 5-Bromo-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-ol (114 mg, 0.5 mmol) was added to N,N-dimethylformamide (20 ml), cesium carbonate (326 mg, 1.0 mmol) and iodomethane (142 mg, 1.0 mmol) were added, and the mixture was reacted at 60°C for 2 hours. The reaction solution was poured into ice water (50 ml), extracted with ethyl acetate (50 mL x 3), concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain a white solid compound (120 mg, yield: 99%). LC-MS: m / z [M+H] + =242 8: 7-Ethyl-4-(4-fluoro-3-(6-methoxy-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 5-bromo-6-methoxy-1-methyl-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.40 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-7H-imidazo[4,5-c]pyridazine (125 mg, 0.44 mmol) were used as raw materials to obtain a white solid (30 mg, yield: 20%).

[0151] 1 H NMR (400 MHz, CDCl3) 9.42 (s, 1H), 8.36 (s, 1H), 8.30 (s, 2H), 7.96 (s, 1H), 7.92 (s, 1H), 7.37 (t, 1H), 4.59 (d, J = 6.8 Hz, 2H), 4.11 (s, 3H), 4.06 (s, 3H), 1.70 (t, J = 6.4 Hz, 3H). LC-MS: m / z [M+H] + =404

[0152] Example 9 [ka] 9-1: 6-Bromo-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate 5-Bromo-4-methoxypyridin-2-amine (1g, 3.5mmol) and methyl 3-bromo-2-oxopropanoate (762mg, 4.2mmol) were added to anhydrous ethanol (10ml) and stirred overnight at 90℃ in a sealed vessel. The reaction solution was directly separated and purified using a separation plate (petroleum ether / ethyl acetate=3 / 1) to obtain the title compound (600mg, 60%).

[0153] 9-2: 6-Bromo-7-methoxyimidazo[1,2-a]pyridine-2-carboxylic acid Methyl 6-bromo-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate (400 mg, 1.4 mmol) and (2M) aqueous sodium hydroxide solution (2 ml) were added to tetrahydrofuran (4 ml) and stirred at room temperature overnight. The reaction solution was concentrated, and the aqueous phase was extracted three times with ethyl acetate. The organic phase was concentrated, and then separated and purified using a separation plate (dichloromethane / methanol = 20 / 1) to obtain the title compound (300 mg, 79%).

[0154] 9-3: (6-bromo-7-methoxyimidazo[1,2-a]pyridin-2-yl)(pyrrolidin-1-yl)methanone 6-Bromo-7-methoxyimidazo[1,2-a]pyridine-2-carboxylic acid (300 mg, 1.1 mmol), 1-hydroxybenzotriazole (234 mg, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95 mg, 0.5 mmol), N,N-diisopropylethylamine (425 mg, 3.3 mmol) and pyrrolidine (213 mg, 3.3 mmol) were added to N,N-dimethylformamide (6 ml) and stirred overnight at 35° C. The reaction mixture was directly separated and purified using a fractionation plate (dichloromethane / methanol=20 / 1) to obtain the title compound (60 mg, 17%).

[0155] 9: (6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxyimidazo[1,2-a]pyridin-2-yl)(pyrrolidin-1-yl)methanone Following the same experimental steps as in Example 2, (6-bromo-7-methoxyimidazo[1,2-a]pyridin-2-yl)(pyrrolidin-1-yl)methanone (60 mg, 0.19 mmol) and 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (72 mg, 0.19 mmol) were used as starting materials to obtain the title compound (50 mg, 54%).

[0156] 1 H NMR (400MHz, CHLOROFORM-d) 9.38 (s, 1 H), 8.30 (br. s., 1 H), 8.15 - 8.04 (m, 1 H), 7.79 - 7.67 (m, 1 H), 7.53 (br. s., 1 H), 7.38 (br. s., 1 H), 4.59 (d, J = 6.8 Hz, 1 H), 4.13 (br. s., 1 H), 3.90 (br. s., 3 H), 3.75 (br. s., 1 H), 2.03 - 1.93 (m, 4 H), 1.70 (d, J = 7.3 Hz, 1 H). LC-MS: m / z[M+H] + =486.

[0157] Example 10 [ka] 10-1: 1-(Ethylsulfonyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine 1,2,3,4-Tetrahydropyrido[2,3-b]pyrazine (500mg, 3.7mmol) was dissolved in tetrahydrofuran (10ml), triethylamine (1.12g, 11.1mmol) was added, and ethanesulfonyl chloride (480mg, 3.7mmol) was further added. The mixture was stirred at room temperature for 12 hours, diluted with ethyl acetate (200ml), washed with water (150mL x 2), dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a yellow solid (300mg, yield: 35.7%). LC-MS: m / z [M+H] + =228.0 10: 4-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-1-(ethylsulfonyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine 1-(ethylsulfonyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (200 mg, 0.88 mmol), 4-(3-chloro-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine (364 mg, 1.32 mmol), potassium phosphate (374 mg, 1.76 mmol), tris(dibenzylideneacetone)dipalladium (80 mg, 0.09 mmol) and toluene (20 ml) were added to the reaction flask in sequence, and the mixture was heated to 90° C. and reacted for 16 hours. The reaction solution was directly concentrated and analyzed by prep-HPLC (0.5% NH 3 .H 2 0 to acetonitrile) to give a white solid (30 mg, yield: 15%).

[0158] 1H NMR (400 MHz, CDCl3) 9.39 (s, 1H), 8.32 (m, , 2H), 8.28-8.19 (m, 1H), 7.91 (d, J = 4.8 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.43-7.33 (m, 1H), 6.74 (m, 1H), 4.58 (q, J = 7.3 Hz, 2H), 4.14-4.00 (m, 2H), 4.00-3.90 (m, 2H), 3.18 (q, J = 7.4 Hz, 2H), 1.70 (t, J = 7.3 Hz, 3H), 1.44 (t, J = 7.4 Hz, 3H). LC-MS: m / z [M+H] + =468

[0159] Example 11 [ka] 11-1: 4-Bromo-2-nitropyridin-3-ol Under an inert atmosphere of nitrogen gas, 4-bromopyridin-3-ol (3 g, 17.3 mmol) was added to 8 ml of concentrated sulfuric acid and stirred for 15 minutes. Fuming nitric acid (1.64 g, 26 mmol) was added dropwise at 0°C and stirred overnight. The reaction solution was added to 10 g of ice, extracted with ethyl acetate (10 mL x 3), spin-dried, and the resulting crude product was purified by normal phase silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 1: 1) to obtain the title product (2.19 g, yield: 56%) as a yellow solid. LC-MS: m / z [M+H] + =219 11-2: 4-Bromo-3-methoxy-2-nitropyridine 4-Bromo-2-nitropyridin-3-ol (2.19 g, 10 mmol) and potassium carbonate (1.39 g, 20 mmol) were dissolved in N,N-dimethylformamide (17.0 ml), iodomethane (1.43 g, 20 mmol) was added dropwise, and the mixture was stirred at room temperature for 17 hours. The mixture was quenched with water (20 ml), and then extracted with ethyl acetate (20 mL x 2). The crude product obtained by spin drying was purified by normal phase silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 2: 1) to obtain the title product (0.65 g, yield: 28%) as a white solid. LC-MS: m / z [M+H] + =233 11-3: 4-Bromo-3-methoxypyridin-2-amine 4-Bromo-3-methoxy-2-nitropyridine (550 mg, 2.37 mmol) and ammonium chloride (628 mg, 11.85 mmol) were dissolved in ethanol:water=1:1 (16.6 ml) and heated to 60°C. Iron powder (664 mg, 11.85 mmol) was added in batches, the reaction was stirred at 60°C for 2 hours, filtered, the cake was rinsed with methanol (10 mL x 3), the combined washings were spun dry. Diluted with 5 ml water, the aqueous phase was further extracted with ethyl acetate (10 mL x 3), and the title product (514 mg, 100%) was obtained as a brown solid after spun dry. LC-MS: m / z [M+H] + =203 11-4: 7-Bromo-8-methoxyimidazo[1,2-a]pyridine 4-Bromo-3-methoxypyridin-2-amine (200 mg, 0.99 mmol), chloroacetaldehyde (295 mg, 40 Wt%, 1.5 mmol), sodium bicarbonate (159 mg, 1.5 mmol) were dissolved in a solution of ethanol (10.0 ml), heated to 90° C. in a microwave reactor, and reacted for 1 hour. The reaction solution was concentrated, diluted with 2 ml of water, the aqueous phase was extracted with dichloromethane (2 mL×3), the organic phases were combined, dried, and spun to give the title product (290 mg, 100%) as a brown solid. LC-MS: m / z [M+H] + =227 11-5: 7-Bromo-3-iodo-8-methoxyimidazo[1,2-a]pyridine 7-Bromo-8-methoxyimidazo[1,2-a]pyridine (400 mg, 1.28 mmol) was dissolved in N,N-dimethylformamide (7.5 ml), N-iodosuccinimide (375 mg, 1.67 mmol) was added and the reaction was stirred at 100° C. for 1 h. It was cooled to room temperature and diluted with 10 ml of water, and the aqueous phase was further extracted with methyl tert-butyl ether (10 mL×3) and spun to dryness to give the title product (220 mg, 100%) as a brown solid. LC-MS: m / z [M+H] + =353 11-6: 7-Bromo-3-cyclopropyl-8-methoxyimidazo[1,2-a]pyridine 7-Bromo-3-iodo-8-methoxyimidazo[1,2-a]pyridine (400 mg, 1.13 mmol), cyclopropylboronic acid (97 mg, 1.13 mmol), tetrakis(triphenylphosphine)palladium (131 mg, 0.113 mmol), and potassium phosphate (481 mg, 2.27 mmol) were dissolved in dioxane:H 2 The mixture was dissolved in 11 ml of 10:1 O, purged with argon gas three times, and stirred at 95°C for 17 hours. The mixture was cooled to room temperature and purified by normal phase silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 1:1) to give the title product (100 mg, 33%) as a yellow solid. LC-MS: m / z [M+H] + =267 11: 4-(3-(3-cyclopropyl-8-methoxyimidazo[1,2-a]pyridin-7-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, starting from 7-bromo-3-cyclopropyl-8-methoxyimidazo[1,2-a]pyridine (100 mg, 0.37 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (107 mg, 0.37 mmol), the title compound (60 mg, 37%) was obtained as an off-white solid.

[0160] 1 H NMR (400 MHz, CDCl3) 9.37 (s, 1H), 8.38-8.30 (m, 1H), 8.29-8.20 (m, 2H), 7.85 (d, 1H), 7.36 (dd, 2H), 6.78 (d, 1H), 4.58 (q, 2H), 4.24 (s, 3H), 2.12 (s, 1H), 1.69 (t, 3H), 0.97 (m, 4H). LC-MS: m / z [M+H] + =429 Example 12

[0161] [ka] 12: 7-Ethyl-4-(4-fluoro-3-(2-(1-fluorocyclopropyl)-7-methoxyimidazo[1,2-a]pyridin-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 6-bromo-2-(1-fluorocyclopropyl)-7-methoxyimidazo[1,2-a]pyridine (100.0 mg, 0.36 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (100 mg, 0.36 mmol) were used as raw materials to obtain the title product (30 mg, yield: 17%) as a white solid.

[0162] 1 H NMR (400 MHz, DMSO-d6) 9.38 (s, 1H), 8.29 (m, 3H), 8.05 (s, 1H), 7.55 (s, 1H), 7.37 (t, 1H), 6.99 (s, 1H), 4.59 (q, 2H), 3.85 (s, 3H), 1.70 (t, 3H), 1.56-1.33 (m, 4H). LC-MS: m / z [M+H] + =447

[0163] Example 13 [ka] 13-1: Methyl 3-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-carboxylate Methyl 3-bromo-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (102 mg, 0.4 mmol) was dissolved in N,N-dimethylformamide (5 ml), sodium cyanide (32 mg, 0.8 mmol) was added at 0°C, and the mixture was stirred for 30 minutes, followed by addition of iodomethane (65 mg, 0.6 mmol) and stirring at room temperature for 16 hours. The reaction solution was poured into ice water (30 ml), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid (100 mg, yield: 92.9%). LC-MS: m / z [M+H] + =269 13-2: 3-Bromo-N,1-dimethyl-1H-pyrrolo[3,2-b]pyridine-6-carboxamide 3-Bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (110 mg, 0.41 mmol) was dissolved in ethanolic methylamine (5 ml), stirred at 80° C. for 16 h, and directly concentrated to give a white solid (80 mg, yield: 73.1%). LC-MS: m / z [M+H] + =268 13: 3-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-N,1-dimethyl-1H-pyrrolo[3,2-b]pyridine-6-carboxamide Following the same experimental steps as in Example 2, 3-bromo-N,1-dimethyl-1H-pyrrolo[3,2-b]pyridine-6-carboxamide (80 mg, 0.30 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (101 mg, 0.36 mmol) was used as starting materials to obtain the title compound (45.0 mg, white solid) with a yield of 35%.

[0164] 1H NMR (400 MHz, CDCl3) 9.59-9.42 (m, 1H), 9.41-9.25 (m, 1H), 8.99-8.88 (m, 1H), 8.30-8.18 (m, 2H), 8.13-8.03 (m, 1H), 8.00-7.92 (m, LC-MS: m / z [M+H] + =430

[0165] Example 14 [ka] 14-1: 7-Iodo-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[4,3-a]pyridine The synthesis method was the same as that of 5-3 in Example 5. The title compound (100 mg, 74%) was obtained as a white solid using 2-hydrazinyl-4-iodo-3-methoxypyridine (100 mg, 0.38 mmol) and tetrahydro-2H-pyran-4-carbaldehyde (50 mg, 0.38 mmol). LC-MS: m / z [M+H] + =360. 14: 4-(4-fluoro-3-(8-methoxy-3-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7-isopropyl-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7-isopropyl-7H-imidazo[4,5-c]pyridazine (45 mg, 0.11 mmol) and 7-iodo-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.14 mmol) were used as starting materials to obtain the title compound (40 mg, 74.5%).

[0166] 1 H NMR (400MHz ,CHLOROFORM-d) 9.37 (s, 1 H), 8.37 - 8.31 (m, 2 H), 8.27 (dd, J = 3.2, 5.6 Hz, 1 H), 7.74 (d, J = 6.8 Hz, 1 H), 7.40 (t, J = 9.0 Hz, 1 H), 6.90 (d, J = 6.8 Hz, 1 H), 5.30 - 5.17 (m, 1 H), 4.50 (s, 3 H), 4.19 (d, J = 11.7 Hz, 2 H), 3.67 (t, J = 10.5 Hz, 2 H), 3.43 - 3.31 (m, 1 H), 2.33 - 2.22 (m, 2 H), 2.07 (d, J = 13.7 Hz, 2 H), 1.77 (d, J = 6.8 Hz, 6 H). LC-MS: m / z[M+H] + =488.

[0167] Example 15 [ka] 15: 4,4'-(4-fluoro-1,3-phenylene)bis(7-ethyl-7H-imidazo[4,5-c]pyridazine) Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (100 mg, 0.3 mmol) and 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine (5 mg, 0.3 mmol) were used as starting materials to obtain the title compound (17 mg, 16%) as a white solid.

[0168] 1H NMR (400 MHz, CHLOROFORM-d) 9.45 (br. s., 2 H) 8.84 - 9.02 (m, 1 H) 8.37 - 8.49 (m, 1 H) 8.30 (br. s., 2 H) 7.50 (br. s., 1 H) 4.49 - 4.69 (m, 4 H) 1.71 (q, J=7.01 Hz, 6 H).LC-MS: m / z [M+H] + =389.

[0169] Example 16 [ka] 16-1: 3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine The synthesis method was the same as that of 5-3 in Example 5. 2-hydrazinyl-4-iodo-3-methoxypyridine (300 mg, 1.132 mmol) and 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde (161 mg, 1.132 mmol) were used as raw materials to obtain the title compound (259 mg, 59%) as a brown solid. LC-MS: m / z [M+H] + =388. 16: 4-(3-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-8-methoxy-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (50 mg, 0.13 mmol), 3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine (59 mg, 0.15 mmol) were used as starting materials to obtain the title compound (34 mg, 53%) as a yellow solid.

[0170] 1 H NMR (400MHz ,CHLOROFORM-d) 9.35 (s, 1 H), 8.32 (dd, J = 2.2, 7.1 Hz, 1 H), 8.29 - 8.23 ​​(m, 2 H), 7.74 (d, J = 7.3 Hz, 1 H), 7.37 (t, J = 9.0 Hz, 1 H), 6.89 (d, J = 7.3 Hz, 1 H), 4.57 (q, J = 7.3 Hz, 2 H), 4.46 (s, 3 H), 3.97 - 3.84 (m, 2 H), 3.53 - 3.43 (m, 1 H), 2.16 - 2.07 (m, 2 H), 1.99 - 1.92 (m, 2 H), 1.67 (t, J = 7.3 Hz, 3 H), 1.39 (s, 3 H), 1.32 (s, 3 H). LC-MS: m / z [M+H] + =502.

[0171] Example 17 [ka] 17-1: 3-Cyclobutyl-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine The synthesis was carried out in the same manner as in Example 5-3, and the title compound (262 mg, 70%) was obtained as a brown solid using 2-hydrazinyl-4-iodo-3-methoxypyridine (300 mg, 1.132 mmol) and cyclobutanecarbaldehyde (95 mg, 1.132 mmol). LC-MS: m / z [M+H] + =330. 17: 4-(3-(3-cyclobutyl-8-methoxy-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4],5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (60 mg, 0.152 mmol), 3-cyclobutyl-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.152 mmol) were used as starting materials to obtain the title compound (34 mg, 50%) as a yellow solid.

[0172] 1 H NMR (400MHz, CHLOROFORM-d) d = 9.37 (s, 1 H), 8.35 - 8.31 (m, 1 H), 8.30 - 8.23 ​​(m, 2 H), 7.58 (d, J = 6.8 Hz, 1 H), 7.38 (t, J = 9.0 Hz, 1 H), 6.85 (d, J = 7.3 Hz, 1 H), 4.62 - 4.55 (m, 2 H), 4.48 (s, 3 H), 3.88 (quin, J = 8.4 Hz, 1 H), 2.76 - 2.54 (m, 4 H), 2.29 - 2.09 (m, 2 H), 1.68 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H] + =444.

[0173] Example 18 [ka] 18-1: 7-Iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 2-Hydrazinyl-4-iodo-3-methoxypyridine (450 mg, 1.698 mmol) and carbonyldiimidazole (550 mg, 3.400 mmol) were added to acetonitrile (4 ml) and reacted at 85° C. for 2 hours. The reaction solution was filtered with suction, and the filtered solid was washed with water and filtered with suction to obtain the title compound (370 mg, 75%). LC-MS: m / z [M+H] + =292. 18-2: 7-Iodo-8-methoxy-2-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 7-Iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (60 mg, 0.206 mmol), iodomethane (32 mg, 0.227 mmol), cesium carbonate (134 mg, 0.412 mmol) were added to acetonitrile (1 ml) and stirred at room temperature for 30 minutes. The reaction solution was suction filtered, concentrated, and subjected to preparative thin layer chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain the title compound (39 mg, 62%) as a white solid. LC-MS: m / z [M+H] + =306. 18: 7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-8-methoxy-2-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (42 mg, 0.115 mmol), 3-(4-fluoro-1-methylpiperidin-4-yl)-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine (35 mg, 0.115 mmol) were used as starting materials to obtain the title compound (13 mg, 27%) as a yellow solid.

[0174] 1 H NMR (400MHz, CHLOROFORM-d) 9.36 (s, 1 H), 8.32 - 8.25 (m, 3 H), 7.62 (d, J = 6.8 Hz, 1 H), 7.38 (t, J = 9.0 Hz, 1 H), 6.56 (d, J = 6.8 Hz, 1 H), 4.59 (q, J = 7.2 Hz, 2 H), 4.14 (s, 3 H), 3.73 (s, 3 H), 1.69 (t, J = 7.1 Hz, 3 H). LC-MS: m / z [M+H] + =420.

[0175] Example 19 [ka] 19: (7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxyimidazo[1,5-a]pyridin-3-yl)(morpholino)methanone 7-Ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (60 mg, 0.15 mmol), (7-bromo-6-methoxyimidazo[1,5-a]pyridin-3-yl)(morpholino)methanone (50 mg, 0.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (CAS: 95464-05-4, 12 mg, 0.02 mmol) and cesium carbonate (200 mg, 0.3 mmol) were added successively to 5 ml of dioxane and 0.5 ml of water, and then stirred at 95°C for 2 hours. The reaction solution was filtered, concentrated, and purified by preparative plate (dichloromethane:methanol=20:1) to give the title compound (24 mg, 33%) as a white solid.

[0176] 1 H NMR (400 MHz, CHLOROFORM-d) 9.38 (s, 1 H) 9.06 (s, 1 H) 8.29 (s, 3 H) 7.51 - 7.65 (m, 2 H) 7.37 (t, J=8.80 Hz, 1 H) 4.59 (q, J=7.34 Hz, 4H) 3.89 (s, 3 H) 3.84 (br. s., 6 H) 1.70 (t, J=7.34 Hz, 3 H). LC-MS: m / z [M+H] + =502.

[0177] Example 20 [ka] 20-1: N-((4-chloro-3-methoxypyridin-2-yl)methyl)cyclopropanecarboxamide (4-Chloro-3-methoxypyridin-2-yl)methanamine (900mg, 5.2mmol) and potassium carbonate (2.2g, 15.7mmol) were dissolved in acetonitrile (20ml), and then cyclopropyl chloride (816mg, 7.8mmol) was added in an ice-water bath and stirred at room temperature for 2 hours. The reaction solution was directly spin-dried and separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid (300mg, yield: 24%). LC-MS: m / z [M+H] + =241 20-2: 7-Chloro-3-cyclopropyl-8-methoxyimidazo[1,5-a]pyridine N-((4-chloro-3-methoxypyridin-2-yl)methyl)cyclopropanecarboxamide (200 mg, 0.83 mmol), Burgess reagent (500 mg, 2.1 mmol) and dichloromethane (5 ml) were added to the reaction flask, stirred at room temperature for 2 hours, and then spun to dryness directly and purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain a yellow oily liquid (110 mg, yield: 60%). LC-MS: m / z [M+H] + =223 20: 4-(3-(3-cyclopropyl-8-methoxyimidazo[1,5-a]pyridin-7-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine 7-Chloro-3-cyclopropyl-8-methoxyimidazo[1,5-a]pyridine (50 mg, 0.23 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-7H-imidazo[4,5-c]pyridazine (97 mg, 0.34 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.023 mmol), cesium carbonate (150 mg, 0.46 mmol) were added to 1,4-dioxane / water (5 ml / 1 ml). The reaction was carried out in a microwave oven at 100° C. for 2 hours under the protection of argon gas. After filtration, the filtrate was spun dry, subjected to preparative HPLC, and lyophilized to give the title product (26 mg, yield: 27%).

[0178] 1 H NMR (400 MHz, DMSO-d6) 9.57 (s, 1H), 8.87 (s, 1H), 8.57 (dd, J = 7.2, 2.3 Hz, 1H), 8.52-8.36 (m, 1H), 8.20 (d, J = 7.2 Hz, 1H), 7.62-7.45 (m, 2H), 6.74 (d, J = 7.2 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 2.41-2.30 (m, 1H), 1.56 (t, J = 7.3 Hz, 3H), 1.15-1.03 (m, 2H), 1.00-0.84 (m, 2H). LC-MS: m / z [M+H] + =429

[0179] Example 21 [ka] 7-Chloro-6-methoxy-2-methylimidazo[1,2-a]pyridine 4-Chloro-5-methoxypyridin-2-amine (20 mg, 0.13 mmol) was added to ethanol (2 ml), chloroacetone (35 mg, 0.38 mmol) and sodium carbonate (40 mg, 0.38 mmol) were added, and the mixture was heated to 100° C. in a microwave oven for 1 hour, filtered, concentrated, and purified by column chromatography to obtain the title product (5 mg, yield: 20%). LC-MS: m / z [M+H] + =197 7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-methylimidazo[1,2-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine 7-Chloro-6-methoxy-2-methylimidazo[1,2-a]pyridine (72 mg, 0.367 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (105 mg, 0.367 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24 mg, 0.0367 mmol), and cesium carbonate (239 mg, 0.735 mmol) were added to 1,4-dioxane / water (7.2 ml / 0.8 ml). The reaction was carried out at 95°C for 2 hours under the protection of argon gas. 10 ml of water was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and analyzed by prep-HPLC (0.5% NH 3 .H 2 0 to acetonitrile) to give a white solid (40 mg, yield: 31%).

[0180] 1 H NMR (400 MHz, CDCl 3 ) 9.38 (s, 1H), 8.40-8.16 (m, 3H), 7.71 (s, 2H), 7.43-7.29 (m, 2H), 4.58 (q, J = 7.3 Hz, 2H), 3.84 (s, 3H), 2.51 (s, 3H), 1.69 (t, J = 7.3 Hz, 3H). LC-MS: m / z [M+H] + =403.

[0181] Example 22 [ka] 22-1: 3-(4-fluoropiperidin-4-yl)-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine 2-Hydrazinyl-4-iodo-3-methoxypyridine (300 mg, 0.822 mmol), 4-fluoro-4-formylpiperidine-1-carboxylate (285 mg, 1.233 mmol) were added to ethanol (2 ml) and stirred at 25° C. for 2 hours. Copper bromide (37 mg, 0.164 mmol), potassium peroxymonosulfate (606 mg, 0.986 mmol) were added to the reaction solution and stirred at 25° C. for 1.5 hours. The reaction solution was suction filtered, concentrated, and dissolved in dichloromethane (5 ml), and hydrochloric acid-ethyl acetate solution (4 mol / L, 2 ml) was added to the reaction solution and stirred at 25° C. for 1 hour. The reaction solution was concentrated, evaporated to dryness, and the title compound (179 mg, 61%) was obtained as a yellow solid by preparative thin layer chromatography (dichloromethane / methanol=15 / 1). LC-MS: m / z [M+H] + =377. 22-2: 3-(4-fluoro-1-methylpiperidin-4-yl)-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine 3-(4-fluoropiperidin-4-yl)-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine (179 mg, 0.500 mmol) and aqueous formaldehyde solution (60 mg, 1 mmol) were added to tetrahydrofuran (1 ml) and stirred at 25° C. for 5 minutes. Sodium cyanoborohydride (63 mg, 1 mmol) was added to the reaction solution and stirred at 25° C. for 1 hour. The reaction solution was suction filtered, concentrated, and subjected to preparative thin layer chromatography (dichloromethane / methanol=20 / 1) to obtain the title compound (79 mg, 42%) as a brown solid. LC-MS: m / z [M+H] + =391. 22: 7-Ethyl-4-(4-fluoro-3-(3-(4-fluoro-1-methylpiperidin-4-yl)-8-methoxy-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (71 mg, 0.195 mmol), 3-(4-fluoro-1-methylpiperidin-4-yl)-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine (76 mg, 0.195 mmol) were used as starting materials to obtain the title compound (6 mg, 6%) as a pale yellow solid.

[0182] 1 H NMR (400MHz, CHLOROFORM-d) 9.38 (s, 1 H), 8.36 (d, J = 6.8 Hz, 1 H), 8.28 (s, 2 H), 8.15 (d, J = 6.8 Hz, 1 H), 7.41 (t, J = 9.0 Hz, 1 H), 6.93 (d, J = 7.3 Hz, 1 H), 4.59 (q, J = 7.3 Hz, 2 H), 4.48 (s, 3 H), 3.04 (br. s., 2 H), 2.88 - 2.57 (m, 6 H), 2.53 (s, 3 H), 1.70 (br. s., 3 H). LC-MS: m / z [M+H] + =505.

[0183] Example 23 [ka] 23-1: 3-(azetidin-3-yl)-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine The synthesis method was the same as that of 22-1 in Example 22. 2-hydrazinyl-4-iodo-3-methoxypyridine (250 mg, 0.94 mmol) and 3-formylazetidine-1-carboxylate (349 mg, 1.89 mmol) were used as raw materials to obtain the title compound (136 mg, 44%) as a brown solid. LC-MS: m / z [M+H] + =331. 23-2: 7-Iodo-8-methoxy-3-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine 3-(azetidin-3-yl)-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine (136 mg, 0.41 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (113 mg, 0.50 mmol), potassium carbonate (114 mg, 0.82 mmol) were added to acetonitrile (3 ml) and reacted at 50° C. for 2 hours. The reaction solution was suction filtered, concentrated, and subjected to preparative thin layer chromatography (dichloromethane / methanol=30 / 1) to obtain the title compound (70 mg, 41%) as a yellow gelatinous solid. LC-MS: m / z [M+H] + =413. 23: 7-Ethyl-4-(4-fluoro-3-(8-methoxy-3-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (62 mg, 0.17 mmol), 7-iodo-8-methoxy-3-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 0.17 mmol) were used as starting materials to obtain the title compound (22 mg, 25%) as a pale yellow solid.

[0184] 1H NMR (400MHz ,CHLOROFORM-d) 9.36 (s, 1 H), 8.34 (d, J = 5.9 Hz, 1 H), 8.28 (s, 2 H), 7.98 (d, J = 6.8 Hz, 1 H), 7.39 (t, J = 9.0 Hz, 1 H), 6.93 (d, J = 6.8 Hz, 1 H), 4.58 (q, J = 7.3 Hz, 2 H), 4.46 (s, 3 H), 4.27 (quin, J = 7.5 Hz, 1 H), 4.09 (t, J = 7.6 Hz, 2 H), 3.88 (t, J = 7.1 Hz, 2 H), 3.17 (q, J = 9.3 Hz, 2 H), 1.68 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H] + =527.

[0185] Example 24 [ka] 24-1: 7-Iodo-8-methoxy-3-(4-methyltetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[4,3-a]pyridine The synthesis method was the same as that of 5-3 in Example 5. 2-hydrazinyl-4-iodo-3-methoxypyridine (100 mg, 0.38 mmol) and 4-methyltetrahydro-2H-pyran-4-carbaldehyde (96 mg, 0.75 mmol) were used as raw materials to obtain the title compound (113 mg, 80%) as a tea-colored solid. LC-MS: m / z [M+H] + =374. 24: 7-Ethyl-4-(4-fluoro-3-(8-methoxy-3-(4-methyltetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (54 mg, 0.15 mmol), 7-iodo-8-methoxy-3-(4-methyltetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (55 mg, 0.15 mmol) were used as starting materials to obtain the title compound (19 mg, 27%) as a yellow solid.

[0186] 1 H NMR (400MHz ,CHLOROFORM-d) 9.38 (s, 1 H), 8.35 (d, J = 5.9 Hz, 1 H), 8.28 (s, 2 H), 7.94 (d, J = 7.3 Hz, 1 H), 7.40 (t, J = 9.0 Hz, 1 H), 6.87 (d, J = 6.8 Hz, 1 H), 4.59 (q, J = 7.3 Hz, 2 H), 4.49 (s, 3 H), 3.93 - 3.85 (m, 2 H), 3.83 - 3.73 (m, 2 H), 2.60 (d, J = 14.2 Hz, 2 H), 2.00 - 1.91 (m, 2 H), 1.69 (br. s., 3 H), 1.59 (s, 3 H). LC-MS: m / z [M+H] + =488.

[0187] Example 25 [ka] 25-1: 3-(4,4-difluorocyclohexyl)-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine The synthesis method was the same as that of 5-3 in Example 5. 2-hydrazinyl-4-iodo-3-methoxypyridine (100 mg, 0.38 mmol) and 4,4-difluorocyclohexane-1-carbaldehyde (112 mg, 0.75 mmol) were used as raw materials to obtain the title compound (100 mg, 67%) as a black tea-colored solid. LC-MS: m / z [M+H]+ =394. 25: 4-(3-(3-(4,4-difluorocyclohexyl)-8-methoxy-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (52 mg, 0.14 mmol), 3-(4,4-difluorocyclohexyl)-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine (55 mg, 0.14 mmol) were used as starting materials to obtain the title compound (13 mg, 20%) as a pale yellow solid.

[0188] 1 H NMR (400MHz ,CHLOROFORM-d) 9.38 (br. s., 1 H), 8.34 (dd, J = 2.0, 6.8 Hz, 1 H), 8.30 - 8.25 (m, 2 H), 7.71 (d, J = 6.8 Hz, 1 H), 7.39 (t, J = 9.0 Hz, 1 H), 6.92 (d, J = 7.3 Hz, 1 H), 4.61 - 4.56 (m, 2 H), 4.49 (s, 3 H), 3.25 (br. s., 1 H), 2.39 (d, J = 9.3 Hz, 2 H), 2.29 - 2.20 (m, 4 H), 1.88 - 1.78 (m, 2 H), 1.69 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H] + =508.

[0189] Example 26 [ka] 26-1: 6-Bromo-7-methoxy-2-methylimidazo[1,2-a]pyridine 5-Bromo-4-methoxypyridin-2-amine (200 mg, 1 mmol) and bromoacetone (274 mg, 2 mmol) were added to anhydrous EtOH (5 ml) and stirred at 90°C overnight. The reaction solution was concentrated and then separated and purified using a separation plate (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (120 mg, 50%).

[0190] 26: 4-(4-fluoro-3-(7-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)phenyl)-7-isopropyl-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 6-bromo-7-methoxy-2-methylimidazo[1,2-a]pyridine (24.2 mg, 0.1 mmol) and 7-isopropyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (40 mg, 0.1 mmol) were used as starting materials to obtain the title compound (17 mg, 42%).

[0191] 1 H NMR (400MHz, DMSO-d6) 9.55 - 9.51(s, 1 H), 8.93 - 8.89 (s, 1 H), 8.64 - 8.41 (m, 4 H), 7.60 - 7.49 (m, 2 H), 5.12 - 5.06 (m, 1 H), 3.87 - 3.78 (m, 3 H), 2.39 - 2.24 (m, 3 H), 1.66 (d, J = 6.8 Hz, 6 H). LC-MS: m / z[M+H] + =417.

[0192] Example 27 [ka] 27-1: N'-(4-iodo-3-methoxypyridin-2-yl)cyclopropanecarbohydrazide The synthesis method was the same as that of 3-3 in Example 3. 2-hydrazinyl-4-iodo-3-methoxypyridine (200 mg, 0.76 mmol) and cyclopropanecarboxylic acid (65 mg, 0.76 mmol) were used as raw materials to obtain the title product (190.1 mg, white solid) in 76% yield. LC-MS: m / z [M+H] + =334 27-2: 3-Cyclopropyl-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine The synthesis method was the same as that of 3-4 in Example 3. N'-(4-iodo-3-methoxypyridin-2-yl)cyclopropanecarbohydrazide (150.0 mg, 0.45 mmol) was used as the raw material to obtain the title product (60.1 mg, white solid), with a yield of 32%. LC-MS: m / z [M+H] + =316 27: 4-(3-(3-cyclopropyl-8-methoxy-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-fluorophenyl)-7-isopropyl-7H-imidazo[4],5-c]pyridazine Following the same experimental steps as in Example 2, 3-cyclopropyl-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine (100.0 mg, 0.32 mmol), (2-fluoro-5-(7-isopropyl-7H-imidazo[4,5-c]pyridazin-4-yl)phenyl)boronic acid (142.8 mg, 0.48 mmol) were used as raw materials to obtain the title compound (62.1 mg, white solid), with a yield of 37%.

[0193] 1H NMR (400 MHz, DMSO-d6) 9.57 (s, 1H), 8.94 (s, 1H), 8.65-8.48 (m, 2H), 8.40 (d, J = 7.0 Hz, 1H), 7.59 (t, J = 9.2 Hz, 1H), 7.07 (d, J = LC-MS: m / z [M+H] + =444

[0194] Example 28 [ka] 28-1: 7-Iodo-8-methoxy-3-(oxetan-3-yl)-[1,2,4]triazolo[4,3-a]pyridine The synthesis method was the same as that of 5-3 in Example 5. 2-hydrazinyl-4-iodo-3-methoxypyridine (200 mg, 0.754 mmol) and oxetane-3-carbaldehyde (207 mg, 3.77 mmol) were used as raw materials to obtain the title compound (151 mg, 61%) as a brown solid. LC-MS: m / z [M+H] + =332. 28: 7-Ethyl-4-(4-fluoro-3-(8-methoxy-3-(oxetan-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (56 mg, 0.151 mmol), 7-iodo-8-methoxy-3-(oxetan-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.151 mmol) were used as starting materials to obtain the title compound (26 mg, 39%) as a yellow solid.

[0195] 1 H NMR (400MHz, CHLOROFORM-d) d = 9.38 (br. s., 1 H), 8.39 - 8.24 (m, 3 H), 7.92 - 7.85 (m, 1 H), 7.40 (t, J = 9.3 Hz, 1 H), 6.96 (d, J = 4.9 Hz, 1 LC-MS: m / z [M+H] + =446.

[0196] Example 29 [ka] 29-1: 7-Iodo-8-methoxy-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine The synthesis was carried out in the same manner as in Example 5-3, and the title compound (109 mg, 46%) was obtained as a brown solid using 2-hydrazinyl-4-iodo-3-methoxypyridine (200 mg, 0.754 mmol) and isobutyraldehyde (271 mg, 3.77 mmol) as raw materials. LC-MS: m / z [M+H] + =318. 29: 7-Ethyl-4-(4-fluoro-3-(8-methoxy-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (58 mg, 0.158 mmol), 7-iodo-8-methoxy-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.158 mmol) were used as starting materials to obtain the title compound (17 mg, 25%) as a yellow solid.

[0197] 1 H NMR (400MHz, CHLOROFORM-d) 9.38 (br. s., 1 H), 8.37 - 8.23 ​​(m, 3 H), 7.72 (d, J = 6.4 Hz, 1 H), 7.43 - 7.35 (m, 1 H), 6.89 (d, J = 6.8 Hz, 1 H), 4.59 (d, J = 7.3 Hz, 2 H), 4.48 (br. s., 3 H), 3.39 (d, J = 5.9 Hz, 1 H), 1.70 (d, J = 7.8 Hz, 3 H), 1.57 (d, J = 5.9 Hz, 6 H). LC-MS: m / z [M+H] + =432.

[0198] Example 30 [ka] 30-1: 6-Bromo-2-ethyl-7-methoxyimidazo[1,2-a]pyridine 5-Bromo-4-methoxypyridin-2-amine (200 mg, 0.99 mmol) and bromobutanone (747 mg, 4.95 mmol) were added successively to absolute ethanol (5 ml) and stirred at 90° C. for 16 hours. The reaction solution was concentrated and separated by preparative thin layer chromatography (petroleum ether / acetone=4 / 1) to obtain the title compound (150 mg, 60%) as an oily liquid. LC-MS: m / z [M+H] + =255, 257.

[0199] 30: 7-Ethyl-4-(3-(2-ethyl-7-methoxyimidazo[1,2-a]pyridin-6-yl)-4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 6-bromo-2-ethyl-7-methoxyimidazo[1,2-a]pyridine (50 mg, 0.20 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (74 mg, 0.20 mmol) were used as starting materials to obtain the title compound (10 mg, 12%) as a brown solid.

[0200] 1 H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.28 (br. s., 3 H), 8.02 (br. s., 1 H), 7.36 (t, J = 8.8 Hz, 1 H), 7.21 (br. s., 1 H), 7.05 (br. s., 1 LC-MS: m / z [M+H] + =417.

[0201] Example 31 [ka] 31-1: 7-Iodo-8-methoxy-3-ethyl-[1,2,4]triazolo[4,3-a]pyridine The synthesis was carried out in the same manner as in Example 5-3, and the title compound was obtained as a brown solid (147 mg, 64%) using 2-hydrazinyl-4-iodo-3-methoxypyridine (200 mg, 0.75 mmol) and propionaldehyde (219 mg, 3.77 mmol) as raw materials. LC-MS: m / z [M+H] + =304. 31: 7-Ethyl-4-(4-fluoro-3-(8-methoxy-3-ethyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (60 mg, 0.165 mmol), 7-iodo-8-methoxy-3-ethyl-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.165 mmol) were used as starting materials to obtain the title compound (23 mg, 33%) as a yellow solid.

[0202] 1 H NMR (400MHz, CHLOROFORM-d) 9.37 (br. s., 1 H), 8.38 - 8.22 (m, 3 H), 7.68 (d, J = 4.4 Hz, 1 H), 7.38 (t, J = 9.0 Hz, 1 H), 6.89 (d, J = 5.9 Hz, 1 LC-MS: m / z [M+H] + =418.

[0203] Example 32 [ka] 32-1: 7-Iodo-8-methoxy-3-methyl-[1,2,4]triazolo[4,3-a]pyridine The synthesis was carried out in the same manner as in Example 5-3, and the title compound (140 mg, 64%) was obtained as a brown solid using 2-hydrazinyl-4-iodo-3-methoxypyridine (200 mg, 0.75 mmol) and acetaldehyde-tetrahydrofuran solution (0.75 ml, 3.77 mmol). LC-MS: m / z [M+H] + =290. 32: 7-Ethyl-4-(4-fluoro-3-(8-methoxy-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (67 mg, 0.182 mmol), 7-iodo-8-methoxy-3-methyl-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.182 mmol) were used as starting materials to obtain the title compound (27 mg, 37%) as a yellow solid.

[0204] 1 H NMR (400MHz, CHLOROFORM-d) 9.38 (s, 1 H), 8.34 (d, J = 6.4 Hz, 1 H), 8.28 (s, 2 H), 7.66 (d, J = 6.8 Hz, 1 H), 7.39 (t, J = 9.0 Hz, 1 H), 6.91 (d, LC-MS: m / z [M+H] + =404.

[0205] Example 33 [ka] 33-1: 7-Iodo-8-methoxy-3-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[4,3-a]pyridine The synthesis method was the same as that of 5-3 in Example 5. The title compound was obtained as a white solid (140 mg, 100%) using 2-hydrazinyl-4-iodo-3-methoxypyridine (100 mg, 0.38 mmol) and tetrahydrofuran-3-carbaldehyde (50 mg, 0.38 mmol). LC-MS: m / z [M+H] + =346. 33: 7-Ethyl-4-(4-fluoro-3-(8-methoxy-3-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (60 mg, 0.17 mmol), 7-iodo-8-methoxy-3-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.17 mmol) were used as starting materials to obtain the title compound (47 mg, 60%) as a yellow solid.

[0206] 1 H NMR (400 MHz, CHLOROFORM-d) 9.39 (s, 1 H) 8.35 (d, J=6.36 Hz, 1 H) 8.29 (s, 2 H) 7.83 (d, J=6.85 Hz, 1 H) 7.38 - 7.43 (m, 1 H) 6.93 (d,J=6.85 Hz, 1 H) 4.59 (q, J=6.85 Hz, 2 H) 4.49 (s, 3 H) 4.30 (d, J=8.31 ​​Hz, 1 H) 4.23 (dd, J=15.41, 7.09 Hz, 2 H) 3.91 - 4.08 (m, 2 H) 2.53 (d, J=6.85Hz, 2H) 1.69 - 1.72 (m, 3 H).LC-MS: m / z [M+H] + =460.

[0207] Example 34 [ka] 34: 7-Ethyl-4-(4-fluoro-3-(8-methoxy-3-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (70 mg, 0.2 mmol), 7-iodo-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.2 mmol) were used as starting materials to obtain the title compound (47 mg, 50%) as a brown solid.

[0208] 1 H NMR (400 MHz, CHLOROFORM-d) 9.39 (s, 1 H) 8.35 (d, J=5.87 Hz, 1 H) 8.29 (s, 2 H) 7.75 (d, J=6.85 Hz, 1 H) 7.40 (t, J=9.05 Hz, 1 H) 6.91(d, J=6.85 Hz, 1 H) 4.59 (q, J=7.34 Hz, 2 H) 4.50 (s, 3 H) 4.19 (d, J=11.25 Hz, 2 H) 3.67 (t, J=11.00 Hz, 2 H) 3.37 (t, J=11.00 Hz, 1 H) 2.20 - 2.35 (m, 2H)2.08 (d, J=13.21 Hz, 2 H) 1.68 (br. s., 3 H).LC-MS: m / z [M+H] + =474.

[0209] Example 35 [ka] 35-1: 3-(Difluoromethyl)-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine 2-Hydrazinyl-4-iodo-3-methoxypyridine (160 mg, 0.57 mmol) was dissolved in 2 mL of difluoroacetic anhydride and heated to reflux overnight. It was diluted with water, neutralized with sodium bicarbonate solution, extracted with dichloromethane, concentrated, and purified by preparative plate (petroleum ether:ethyl acetate=1:1) to give the title compound (150 mg, 82%) as a white solid. LC-MS: m / z [M+H] + =326. 35: 4-(3-(3-(difluoromethyl)-8-methoxy-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (80 mg, 0.22 mmol), 3-(difluoromethyl)-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine (75 mg, 0.22 mmol) were used as raw materials to obtain the title compound (39 mg, 41%) as a white solid.

[0210] 1 H NMR (400 MHz, CHLOROFORM-d) 9.38 (s, 1 H) 8.38 (d, J=6.85 Hz, 1 H) 8.29 (s, 2 H) 8.18 (d, J=6.85 Hz, 1 H) 7.42 (t, J=9.05 Hz, 1 H) 7.30(br. s., 1 H) 7.08 (d, J=6.85 Hz, 1 H) 4.59 (q, J=7.17 Hz, 2 H) 4.50 (s, 3 H) 1.67 - 1.70 (m, 3 H).LC-MS: m / z [M+H] + =440.

[0211] Example 36 [ka] 36-1: 2-Bromo-1-(tetrahydro-2H-pyran-4-yl)ethanone 1-(tetrahydro-2H-pyran-4-yl)ethanone (1000mg, 7.8mmol) was added to methanol (5ml) and cooled to 0℃, then liquid bromine (0.4ml, 7.8mmol) was added, stirred at 0℃ for 45 minutes, stirred at room temperature for 45 minutes, then sulfuric acid (2.7ml, 30mmol) was added, and stirred at room temperature overnight. The reaction solution was quenched by adding aqueous sodium hydrogen sulfite, then ethyl acetate (300ml) was added, and the ethyl acetate was washed with water (200ml×3), dried, and concentrated to give the title compound (600mg, 37%).

[0212] 36-2: 6-Bromo-7-methoxy-2-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine 5-Bromo-4-methoxypyridin-2-amine (200 mg, 1 mmol), 2-bromo-1-(tetrahydro-2H-pyran-4-yl)ethanone (600 mg, 3 mmol) were added to absolute ethanol (10 ml). The mixture was stirred at 80° C. overnight. The reaction solution was directly subjected to thin layer chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain the title compound (300 mg, 98%). LC-MS: m / z [M+H] + =311 36: 7-Ethyl-4-(4-fluoro-3-(7-methoxy-2-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyridin-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 6-bromo-7-methoxy-2-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine (80 mg, 0.26 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (50 mg, 0.13 mmol) were used as starting materials to obtain the title compound (16 mg, 25%).

[0213] 1H NMR (400 MHz, CHLOROFORM-d) 1.70 (d,J=7.34 Hz, 3 H) 2.07 (br. s., 4 H) 3.08 (br. s., 1 H) 3.59 (br. s., 2 H) 3.89 (br. s., 3 H) 4.07 (br. s., 2 H) 4.58 (d,J=6.85 Hz, 2 H) 7.12 (br. s., 1 H) 7.22 (br. s., 1 H) 7.35 - 7.41 (m, 1 H) 8.06 (br. s., 1 H) 8.28 (br. s., 3 H) 9.37 (s, 1 H). LC-MS: m / z [M+H] + =473

[0214] Example 37 [ka] 37-1: 6-Bromo-2-cyclopropyl-7-methoxyimidazo[1,2-a]pyridine 5-Bromo-4-methoxypyridin-2-amine (2000 mg, 9.85 mmol), 2-bromo-1-cyclopropylethanone (3211 mg, 19.7 mmol) were added to absolute ethanol (20 ml). The tube was sealed and stirred at 90° C. overnight. The reaction solution was directly subjected to column chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain the title compound (1900 mg, 72%). LC-MS: m / z [M+H] + =267 37: 4-(3-(2-cyclopropyl-7-methoxyimidazo[1,2-a]pyridin-6-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 6-bromo-2-cyclopropyl-7-methoxyimidazo[1,2-a]pyridine (150 mg, 0.56 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (249 mg, 0.67 mmol) were used as starting materials to obtain the title compound (83 mg, 34%).

[0215] 1 H NMR (400 MHz, DMSO-d6) 0.78 - 0.91 (m, 4 H) 1.54 (s, 3 H) 1.94 - 2.00 (m, 1 H) 3.79 (s, 3 H) 4.46 - 4.54 (m, 2 H) 6.96 (s, 1 H) 7.54 (s, 2 LC-MS: m / z [M+H] + =429

[0216] Example 38 [ka] 38-1: 3-Cyclopropyl-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine The synthesis method was the same as that of 5-3 in Example 5. The title compound was obtained as a white solid (160 mg, 67%) using 2-hydrazinyl-4-iodo-3-methoxypyridine (200 mg, 0.76 mmol) and cyclopropanecarboxaldehyde (53 mg, 0.76 mmol) as raw materials. LC-MS: m / z [M+H] + =316. 38: 4-(3-(3-cyclopropyl-8-methoxy-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4],5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (70 mg, 0.2 mmol), 3-cyclopropyl-7-iodo-8-methoxy-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.2 mmol) were used as starting materials to obtain the title compound (43 mg, 50%) as a yellow solid.

[0217] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.38 (s, 1 H) 8.34 (d, J=5.87 Hz, 1 H) 8.29 (br. s., 2 H) 7.91 (d, J=6.85 Hz, 1 H) 7.39 (t, J=9.05 Hz, 1 H) 6.92 (d, J=6.85 Hz, 1 H) 4.59 (q, J=6.85 Hz, 2 H) 4.38 - 4.52 (m, 3 H) 2.08 (br. s., 1 H) 1.70 (t, J=6.85 Hz, 3 H) 1.21 (d, J=7.83 Hz, 2 H) 0.88 (br. s, 2 H).LC-MS: m / z [M+H] + =430.

[0218] Example 39 [ka] 39-1: 6-Bromo-2-(bromomethyl)-7-methoxyimidazo[1,2-a]pyridine 5-Bromo-4-methoxypyridin-2-amine (300 mg, 1.48 mmol) and dibromoacetone (635 mg, 2.95 mmol) were added to anhydrous ethanol (4 ml) and stirred at 90°C for 2 hours. The reaction solution was concentrated and directly separated and purified using a fractionation plate (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (210 mg, 45%). LC-MS: m / z [M+H] + =321 39-2: 6-Bromo-7-methoxy-2-(methoxymethyl)imidazo[1,2-a]pyridine 6-Bromo-2-(bromomethyl)-7-methoxyimidazo[1,2-a]pyridine (200mg, 0.63mmol) and sodium methoxide (0.5ml, 4mmol) were added to methanol (4ml) and stirred at room temperature for 2 hours. The reaction solution was concentrated and directly separated and purified using a separation plate (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (35mg, 21%). LC-MS: m / z [M+H] + =271,273. 39: 7-Ethyl-4-(4-fluoro-3-(7-methoxy-2-(methoxymethyl)imidazo[1,2-a]pyridin-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 6-bromo-7-methoxy-2-(methoxymethyl)imidazo[1,2-a]pyridine (35 mg, 0.13 mmol) and 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (50 mg, 0.13 mmol) were used as starting materials to obtain the title compound (21 mg, 38%).

[0219] 1 H NMR (400MHz, CDCl3) δ 9.37 (s, 1 H), 8.31 - 8.22 (m, 3 H), 8.05 (s, 1 H), 7.45 (s, 1 H), 7.40 - 7.33 (m, 1 H), 7.00 (br. s., 1 H), 4.65 - 4.54 (m, 4 H), 3.87 (s, 3 H), 3.48 (br. s., 3 H), 1.69 - 1.67 (m, 3 H). LC-MS: m / z [M+H] + =433.

[0220] Example 40 [ka] 40-1: 5-Bromo-6-methoxy-2-methylimidazo[1,2-a]pyridine 6-Bromo-5-methoxypyridin-2-amine (90 mg, 0.45 mmol) and bromoacetone (120 mg, 0.88 mmol) were added to absolute ethanol (10 mL), reacted at 90° C. for 16 hours, concentrated, and purified by preparative plate (petroleum ether:ethyl acetate=1:2) to obtain a yellow oil (35 mg, yield: 32%). LC-MS: m / z [M+H] + =241, 243. 40: 7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-methylimidazo[1,2-a]pyridin-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (54 mg, 0.15 mmol), 5-bromo-6-methoxy-2-methylimidazo[1,2-a]pyridine (35 mg, 0.15 mmol) were used as raw materials to obtain a brown solid (25 mg, yield: 41%).

[0221] 1 H NMR (400MHz, CHLOROFORM-d) 9.38 (s, 1 H), 8.43 (br. s., 2 H), 8.28 (s, 2 H), 7.50 (t, J = 9.0 Hz, 1 H), 7.36 - 7.28 (m, 1 H), 7.11 (br. s., 1 LC-MS: m / z [M+H] + =403.

[0222] Example 41 [ka] 41-1: 6-Bromo-7-methoxyimidazo[1,2-a]pyridine-2-carbaldehyde 5-Bromo-4-methoxypyridin-2-amine (610 mg, 3.0 mmol) and 1,1,3-trichloroacetone (720 mg, 4.5 mmol) were added to 1,2-dimethoxyethane (2 ml), stirred at room temperature for 24 hours, the reaction solution was filtered by suction, the resulting white solid was dissolved in ethanol (4 ml), reacted at 95°C for 24 hours, the reaction solution was concentrated, added to dichloromethane (5 ml) and trifluoroacetic acid (0.5 ml), stirred at room temperature for 1 hour, the reaction solution was concentrated, and the title compound (60 mg, 7.8%) was obtained by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1). LC-MS: m / z [M+H] + =255, 257 41-2: 6-Bromo-2-(difluoromethyl)-7-methoxyimidazo[1,2-a]pyridine 6-Bromo-7-methoxyimidazo[1,2-a]pyridine-2-carbaldehyde (60 mg, 0.235 mmol) was added to dichloromethane (2 ml), (diethylamino)sulfur trifluoride (0.05 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with 0.5 ml, concentrated, and the title compound (17 mg, 26%) was obtained by preparative thin layer chromatography (petroleum ether / ethyl acetate / dichloromethane=3 / 1 / 0.1). LC-MS: m / z [M+H] + =277, 279. 41: 4-(3-(2-(difluoromethyl)-7-methoxyimidazo[1,2-a]pyridin-6-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 19, 6-bromo-2-(difluoromethyl)-7-methoxyimidazo[12-a]pyridine (9 mg, 0.032 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (12 mg, 0.032 mmol) were used as starting materials to obtain the title compound (7 mg, 50%).

[0223] 1 H NMR (400MHz, CHLOROFORM-d) d = 9.38 (s, 1 H), 8.29 (br. s., 3 H), 8.10 (s, 1 H), 7.69 (s, 1 H), 7.38 (s, 1 H), 7.05 - 6.67 (m, 2 H), 4.59 (q, J = 7.0 Hz, 2 H), 3.88 (s, 3 H), 1.70 (br. s., 3 H). LC-MS: m / z [M+H] + =439.

[0224] Example 42 [ka] 42-1: 5-Bromo-2-(methoxycarbonyl)-3-methylpyridine 1-oxide 5-Bromo-3-methylpicolinate (1.2 g, 5.22 mmol) and m-chloroperbenzoic acid (3 g, 17.44 mmol) were added to dichloromethane (100 mL), stirred at room temperature for 16 hours, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate=5:1) to give the title compound (1.06 g, yield: 83%) as a white solid. LC-MS: m / z [M+H] + =246, 248. 42-2: 5-Bromo-6-chloro-3-methylpicolinate 5-Bromo-2-(methoxycarbonyl)-3-methylpyridine 1-oxide (1.05 g, 4.30 mmol) and triethylamine (5 g, 49.5 mmol) were added to dichloromethane (100 mL), and oxalyl chloride (2.5 g, 20.5 mmol) was added dropwise under ice bath, stirred at room temperature for 1 hour, filtered, and the mother liquor was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the title compound (0.52 g, yield: 44%) as a pale yellow solid. LC-MS: m / z [M+H] + =264, 266. 42-3: 5-Bromo-3-(bromomethyl)-6-chloropicolinate 5-Bromo-6-chloro-3-methylpicolinate (0.52 g, 1.90 mmol), NBS (0.48 g, 2.7 mmol) and AIBN (30 mg) were added to carbon tetrachloride (10 mL), stirred at 65° C. for 16 hours, concentrated and purified by separation plate (petroleum ether: ethyl acetate = 5:1) to obtain a mixture containing the title compound and the starting material (0.5 g, 1:1 crude product). LC-MS: m / z [M+H] + =342, 344, 346. 42-4: 3-Bromo-2-chloro-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 5-Bromo-3-(bromomethyl)-6-chloropicolinate (0.5 g, crude product), methylamine hydrochloride (200 mg, 3 mmol) and triethylamine (0.5 g, 4.95 mmol) were added to acetonitrile (10 mL), stirred at room temperature for 2 hours, added with 100 ml of saturated ammonium chloride solution, extracted with ethyl acetate (3×100 mL), concentrated the mother liquor and purified by preparative plate to give the title compound (200 mg) as a white solid. LC-MS: m / z [M+H] + =261, 263. 42-5: 3-Bromo-2-methoxy-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 3-Bromo-2-chloro-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (120 mg, 0.46 mmol), sodium phosphate (250 mg, 1.52 mmol) were added to methanol (5 mL), stirred at 60° C. for 16 hours, filtered, and the mother liquor was concentrated and purified by preparative plate to give the title compound (17 mg, 14%) as a white solid. LC-MS: m / z [M+H] + =257, 259. 42: 3-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-2-methoxy-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (25 mg, 0.07 mmol), 3-bromo-2-methoxy-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (15 mg, 0.06 mmol) were used as raw materials to obtain a brown solid (12 mg, yield: 48%).

[0225] 1 H NMR (400MHz ,CHLOROFORM-d) 9.37 (s, 1 H), 8.28 (s, 3 H), 7.78 (s, 1 H), 7.37 (t, J = 9.3 Hz, 1 H), 4.67 - 4.52 (m, 2 H), 4.38 (s, 2 H), 4.10 (s, 3 H), 3.28 (s, 3 H), 1.71 - 1.68 (m, 3 H).LC-MS: m / z [M+H] + =419.

[0226] Example 43 [ka] 43-1: 6-Bromo-7-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridine 5-Bromo-4-methoxypyridin-2-amine (202 mg, 1.0 mmol) was added to a mixed solvent of ethanol (1.5 ml) and 1,4-dioxane (0.5 ml), 3-chloro-1,1,1-trifluoroacetone (161 mg, 1.1 mmol) was slowly added to the reaction solution, and the mixture was stirred at room temperature for 6 hours. Triethylamine (202 mg, 2.0 mmol) was added to the reaction solution, and the mixture was reacted at 95° C. overnight. The reaction solution was suction filtered and concentrated, and the title compound (50 mg, 16.9%) was obtained by preparative thin layer chromatography (petroleum ether / ethyl acetate=20 / 1). LC-MS: m / z [M+H] + =295, 297. 43: 7-Ethyl-4-(4-fluoro-3-(7-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 19, 6-bromo-7-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridine (50 mg, 0.170 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (58 mg, 0.155 mmol) was used as starting material to obtain the title compound (32 mg, 45%).

[0227] 1 H NMR (400MHz, CHLOROFORM-d) 9.36 (br. s., 1 H), 8.27 (br. s., 3 H), 8.09 (s, 1 H), 7.76 (s, 1 H), 7.36 (t, J = 8.6 Hz, 1 H), 7.01 (s, 1 H), 4.57 (d, J = 7.3 Hz, 2 H), 3.86 (s, 3 H), 1.68 (br. s., 3 H). LC-MS: m / z [M+H] + =457.

[0228] Example 44 [ka] 44-1: 4-Bromo-2-hydrazinyl-5-methoxypyridine 4-Bromo-2-fluoro-5-methoxypyridine (560 mg, 2.72 mmol) and hydrazine hydrate (1360 mg, 27.20 mmol) were added to ethanol (10 ml) and stirred at 80° C. for 16 hours. The reaction solution was concentrated and separated by preparative thin layer chromatography (ethyl acetate) to obtain the title compound (110 mg, 20%) as a yellow oily liquid. LC-MS: m / z [M+H] + =218, 220. 44-2: 7-Bromo-6-methoxy-[1,2,4]triazolo[4,3-a]pyridine 4-Bromo-2-hydrazinyl-5-methoxypyridine (110 mg, 0.50 mmol) was added to formic acid (5 ml) and stirred at 110° C. for 16 hours. The reaction solution was filtered, concentrated, and separated by preparative thin-layer chromatography (dichloromethane / methanol=20 / 1) to give the title compound (30 mg, 26%) as a white solid. LC-MS: m / z [M+H] + =228, 230. 44: 7-Ethyl-4-(4-fluoro-3-(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-bromo-6-methoxy-[1,2,4]triazolo[4,3-a]pyridine (30 mg, 0.13 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (48 mg, 0.13 mmol) were used as starting materials to obtain the title compound (3 mg, 6%) as a yellow solid.

[0229] 1 H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.83 (s, 1 H), 8.34 (d, J = 6.4 Hz, 1 H), 8.28 (s, 2 H), 7.82 (s, 1 H), 7.71 (s, 1 H), 7.37 (t, J = 9.0 Hz, 1 H), 4.58 (q, J = 7.3 Hz, 2 H), 3.86 (s, 3 H), 1.69 (t, J = 7.3 Hz, 3 H).LC-MS: m / z [M+H] + =390.

[0230] Example 45 [ka] 45-1: (6-bromo-7-methoxyimidazo[1,2-a]pyridin-2-yl)methanol 6-Bromo-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate (800 mg, 2.81 mmol) was added to dichloromethane (4 ml), and a solution of diisobutylaluminum hydride in n-hexane (1 M, 4 ml) was added and stirred at room temperature for 16 hours. The reaction solution was filtered and then concentrated, and separated by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (190 mg, 26%) as a yellow solid. LC-MS: m / z [M+H] + =257, 259. 45: (6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxyimidazo[1,2-a]pyridin-2-yl)methanol Following the same experimental steps as in Example 2, (6-bromo-7-methoxyimidazo[1,2-a]pyridin-2-yl)methanol (50 mg, 0.19 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (70 mg, 0.19 mmol) were used as starting materials to obtain the title compound (15 mg, 18%) as a brown solid.

[0231] 1 H NMR (400MHz, CHLOROFORM-d) 9.23 (s, 1 H), 8.32 (s, 1 H), 8.20 - 8.10 (m, 3 H), 7.45 (s, 1 H), 7.30 (t, J = 9.3 Hz, 1 H), 7.20 - 6.98 (m, 1 H), 4.67 (s, 2 H), 4.50 (q, J = 7.2 Hz, 2 H), 3.80 (s, 3 H), 1.60 (t, J = 7.3 Hz, 3 H).LC-MS: m / z [M+H] + =419.

[0232] Example 46 [ka] 46-1: 6-Bromo-7-methoxyimidazo[1,2-a]pyridine-3-carbaldehyde 5-Bromo-4-methoxypyridin-2-amine (300 mg, 1.48 mmol) and 2-bromomalonaldehyde (335 mg, 2.22 mmol) were added to ethanol (10 ml) and stirred at 80° C. for 0.5 hours, after which sodium bicarbonate (249 mg, 2.96 mmol) was added and stirred at 80° C. for 16 hours. The reaction solution was filtered and then concentrated, and separated by preparative thin layer chromatography (ethyl acetate) to obtain the title compound (120 mg, 25%) as a yellow solid. LC-MS: m / z [M+H] + =255,257. 46-2: 6-Bromo-7-methoxyimidazo[1,2-a]pyridine-3-methanol 6-Bromo-7-methoxyimidazo[1,2-a]pyridine-3-carbaldehyde (120 mg, 0.47 mmol) was added to dichloromethane (4 ml), and a solution of diisobutylaluminum hydride in n-hexane (1 M, 4 ml) was added and stirred at room temperature for 16 hours. The reaction solution was filtered and then concentrated, and separated by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (40 mg, 33%) as a white solid. LC-MS: m / z [M+H] + =257, 259. 46: (6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)methanol Following the same experimental steps as in Example 2, 6-bromo-7-methoxyimidazo[1,2-a]pyridine-3-methanol (40 mg, 0.16 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (59 mg, 0.16 mmol) were used as starting materials to obtain the title compound (6 mg, 8%) as a brown solid.

[0233] 1 H NMR (400MHz, DMSO-d6) 9.57 - 9.54 (m, 1 H), 8.87 - 8.84 (m, 1 H), 8.59 - 8.53 (m, 1 H), 8.53 - 8.47 (m, 2 H), 7.58 - 7.53 (m, 1 H), 7.52 - 7.49 (m, 1 H), 7.26 - 7.15 (m, 1 H), 5.33 - 5.26 (m, 1 H), 4.79 - 4.75 (m, 2 H), 4.53 - 4.47 (m, 2 H), 3.86 (s, 3 H), 1.54 (s, 3 H).LC-MS: m / z [M+H] + =419.

[0234] Example 47 [ka] 47-1: 3-Bromo-1,8-naphthyridin-2(1H)-one 2-Oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid (490 mg, 2.58 mmol) was added to N,N-dimethylformamide (10 ml), liquid bromine (2 g, 12.9 mmol) and pyridine (5 ml) were added, and the mixture was stirred at 100° C. for 1 hour. 5 ml of saturated aqueous sodium hydrogen sulfite solution was added dropwise to the reaction solution, and then ethyl acetate (3×200 ml) was added for extraction. The ethyl acetate was washed three times with water and once with saturated saline, and then dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin layer chromatography (petroleum ether / ethyl acetate=4 / 1) to obtain the title compound (140 mg, 21%). LC-MS: m / z [M+H] + =225 47-2: 3-Bromo-2-methoxy-1,8-naphthyridine 3-Bromo-1,8-naphthyridin-2(1H)-one (140 mg, 0.63 mmol) was added to dichloromethane / methanol (5 ml / 2 ml), followed by (trimethylsilyl)diazomethane (2 ml) and stirred at room temperature overnight. The reaction solution was directly concentrated and then purified by thin layer chromatography (petroleum ether / ethyl acetate=4 / 1) to give the title compound (40 mg, 27%). LC-MS: m / z [M+H] + =239 47: 3-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-2-methoxy-1,8-naphthyridine Following the same experimental steps as in Example 19, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (74 mg, 0.2 mmol), 3-bromo-2-methoxy-1,8-naphthyridine (40 mg, 0.17 mmol) were used as starting materials to obtain the title compound (38 mg, 48%).

[0235] 1 H NMR (400 MHz, CHLOROFORM-d) 9.39 (s, 1 H) 8.66 (d, J=3.42 Hz, 1 H) 8.43 (d, J=4.89 Hz, 1 H) 8.29 (br. s., 1 H) 8.27 (s, 1 H) 7.95 (d, J=6.36 Hz, 1 H) 7.90 (s, 1 H) 7.39 (t, J=9.05 Hz, 1H) 7.23 (d, J=7.83 Hz, 1 H) 4.58 (q, J=7.34 Hz, 2 H) 3.94 (s, 3 H) 1.69 (t, J=7.34 Hz, 3 H). LC-MS: m / z [M+H] + =401.

[0236] Example 48 [ka] 48-1: 6-Bromo-7-methoxyimidazo[1,2-a]pyrimidine 5-Bromo-4-methoxypyrimidin-2-amine (203 mg, 1.0 mmol) and chloroacetaldehyde (94 mg, 1.2 mmol) were added to ethanol (2 ml) and stirred at room temperature overnight. Sodium hydrogen carbonate (168 mg, 2.0 mmol) was added to the reaction solution and reacted at 60° C. for 2 hours. The reaction solution was suction filtered, concentrated, and subjected to preparative thin layer chromatography (dichloromethane / methanol=20 / 1) to obtain the title compound (57 mg, 25%). LC-MS: m / z [M+H] + =228, 230. 48: 7-Ethyl-4-(4-fluoro-3-(7-methoxyimidazo[1,2-a]pyrimidin-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 19, 6-bromo-7-methoxyimidazo[1,2-a]pyrimidine (57 mg, 0.251 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (92 mg, 0.251 mmol) were used as starting materials to obtain the title compound (50 mg, 52%).

[0237] 1 H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.31 (d, J = 16.6 Hz, 4 H), 7.57 (br. s., 1 H), 7.44 - 7.34 (m, 2 H), 4.59 (q, J = 7.3 Hz, 2 H), 4.08 (s, 3 H), 1.72 - 1.68 (m, 3 H). LC-MS: m / z [M+H] + =390.

[0238] Example 49 [ka] 49-1: 5-Bromo-6-methoxyimidazo[1,2-a]pyridine 6-Bromo-5-methoxypyridin-2-amine (200 mg, 0.99 mmol) and chloroacetaldehyde (40%, 290 mg, 1.49 mmol) were added to anhydrous methanol (10 mL), stirred at room temperature for 1 hour, sodium bicarbonate (200 mg, 2.38 mmol) was added, reacted at 60°C for 16 hours, concentrated, and purified using a separation plate (petroleum ether: ethyl acetate = 3:1) to obtain a pale yellow solid (130 mg, yield: 58%). LC-MS: m / z [M+H] + =227, 229. 49: 7-Ethyl-4-(4-fluoro-3-(6-methoxyimidazo[1,2-a]pyridin-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (36 mg, 0.1 mmol), 5-bromo-6-methoxyimidazo[1,2-a]pyridine (23 mg, 0.1 mmol) were used as raw materials to obtain a brown solid (7 mg, yield: 18%).

[0239] 1 H NMR (400MHz, CHLOROFORM-d) 9.38 (s, 1 H), 8.47 - 8.39 (m, 2 H), 8.28 (s, 1 H), 7.84 - 7.59 (m, 1 H), 7.50 (t, J = 8.8 Hz, 1 H), 7.41 - 7.26 (m, 2 H), 7.25 - 6.97 (m, 1 H), 4.58 (q, J = 7.3 Hz, 2 H), 3.85 (s, 3 H), 1.70 - 1.65 (m, 3 H). LC-MS: m / z [M+H] + =389.

[0240] Example 50 [ka] 50: 7-Ethyl-4-(4-fluoro-3-(7-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 6-bromo-7-methoxy-2-methylimidazo[1,2-a]pyridine (30 mg, 0.12 mmol), 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (44 mg, 0.12 mmol) were used as starting materials to obtain the title compound (13 mg, 27%) as a white solid.

[0241] 1 H NMR (400MHz, CHLOROFORM-d) 9.35 (s, 1 H), 8.32 - 8.16 (m, 3 H), 7.98 (s, 1 H), 7.34 (t, J = 8.8 Hz, 1 H), 7.20 (s, 1 H), 6.90 (br. s., 1 H), 4.57 (q, J = 7.3 Hz, 2 H), 3.93 - 3.74 (m, 3 H), 2.47 - 2.33 (m, 3 H), 1.68 (t, J = 7.1 Hz, 3 H). LC-MS: m / z [M+H] + =403.

[0242] Example 51 [ka] 51-1: 6-Bromo-5-methoxyimidazo[1,2-a]pyridine 5-Bromo-6-methoxypyridin-2-amine (200 mg, 0.99 mmol) and chloroacetaldehyde (40%, 290 mg, 1.49 mmol) were added to anhydrous methanol (10 mL), stirred at room temperature for 1 hour, sodium bicarbonate (200 mg, 2.38 mmol) was added, reacted at 70°C for 16 hours, concentrated, and purified using a separation plate (petroleum ether: ethyl acetate = 3:1) to obtain a pale yellow solid (70 mg, yield: 31%). LC-MS: m / z [M+H]+ =227, 229. 51: 7-Ethyl-4-(4-fluoro-3-(5-methoxyimidazo[1,2-a]pyridin-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (36 mg, 0.1 mmol), 6-bromo-5-methoxyimidazo[1,2-a]pyridine (23 mg, 0.1 mmol) were used as raw materials to obtain a brown solid (4 mg, yield: 10%).

[0243] 1 H NMR (400MHz, CHLOROFORM-d) 9.39 (s, 1 H), 8.41 (d, J = 4.9 Hz, 1 H), 8.29 (br. s., 2 H), 7.76 (br. s., 2 H), 7.49 - 7.27 (m, 3 H), 4.68 - 4.50 (m, 2 H), 3.84 (s, 3 H), 1.69 (br. s., 3 H). LC-MS: m / z [M+H] + =389.

[0244] Example 52 [ka] 52: 7-Ethyl-4-(4-fluoro-3-(7-methoxyimidazo[1,2-a]pyridin-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (50 mg, 0.14 mmol), 6-bromo-7-methoxyimidazo[1,2-a]pyridine (30 mg, 0.14 mmol) were used as starting materials to obtain the title compound (8 mg, 15%) as a yellow solid.

[0245] 1 H NMR (400 MHz, DMSO-d6)δ 9.57 (s, 1 H) 8.87 (s, 1 H) 8.67 (s, 1 H) 8.48 - 8.61 (m, 2 H) 7.82 (br. s., 1 H) 7.46 - 7.65 (m, 2 H) 7.17 (br. s., 1 H)4.51 (q, J=6.85 Hz, 2 H) 3.84 (s, 3 H) 1.55 (t, J=7.09 Hz, 3 H). LC-MS: m / z [M+H] + =389.

[0246] Example 53 [ka] 53-1: N-(4-(methoxymethyl)pyridin-2-yl)-1,1-diphenylmethanimine 2-Chloro-4-(methoxymethyl)pyridine (2.87g, 18.28mmol), benzhydrylamine (3.3g, 18.28mmol), R-(+)-1.1-binaphthyl-2,2-diphenylphosphine (1.10g, 1.82mmol), cesium carbonate (8.30g, 25.59mmol) were added to a solution of 1,4-dioxane (50ml), purged with argon gas three times, heated to 80°C and reacted for 15 hours. After cooling to room temperature, the reaction solution was poured into ice water (40ml), extracted with ethyl acetate (50ml x 3), washed with saturated aqueous sodium chloride (50ml x 3), the organic phase was dried, concentrated and purified by prep-preparative HPLC (3.4g, 61.8%) to obtain a yellow oily liquid. LC-MS: m / z [M+1] + : 303 53-2: 4-(Methoxymethyl)pyridin-2-amine N-(4-(methoxymethyl)pyridin-2-yl)-1,1-diphenylmethanimine (3.3g, 11mmol) was dissolved in tetrahydrofuran (50ml) solution, and hydrochloric acid in 1,4-dioxane (17ml) was added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate (30ml) was added to the reaction solution to adjust the pH to about 7, and the mixture was extracted with ethyl acetate (50mL x 3), washed with saturated aqueous sodium chloride solution (50mL x 3), and the organic phase was dried, concentrated, and purified by prep-preparative HPLC (800mg, 53.3%) to obtain a white solid. LC-MS: m / z [M+1] + : 139 53-3: 5-Bromo-4-(methoxymethyl)pyridin-2-amine 5-Bromo-4-(methoxymethyl)pyridin-2-amine (260 mg, 1.88 mmol) and ammonium acetate (14.5 mg, 0.188 mmol) were added to an acetonitrile (25 ml) solution, and NBS (167.7 mg, 0.94 mmol) was added in batches at 0° C., the ice-water bath was removed, and the mixture was reacted at room temperature for 40 minutes. Dichloromethane (20 ml) was added to dissolve the mixture, and the pH was adjusted to about 7 with saturated sodium bicarbonate (40 ml), and the mixture was extracted with dichloromethane (50 mL×4). The organic phase was dried, concentrated, and purified by prep-preparative HPLC (220 mg, 40%) to obtain a white solid. LC-MS: m / z [M+1] + : 219 53-4: 6-Bromo-2-(1-fluorocyclopropyl)-7-(methoxymethyl)imidazo[1,2-a]pyridine 5-Bromo-4-(methoxymethyl)pyridin-2-amine (524 mg, 2.5 mmol), 2-chloro-1-(1-fluorocyclopropyl)ethan-1-one (670 mg, 5 mmol), and cesium carbonate (1.6 g, 5 mmol) were dissolved in a solution of ethanol (10.0 ml), heated to 100° C. in a microwave reactor, and reacted for 1 hour. The reaction solution was purified by preparative HPLC (100 mg, 26%) to obtain a white solid. LC-MS: m / z [M+1] + = 300 53: 7-Ethyl-4-(4-fluoro-3-(2-(1-fluorocyclopropyl)-7-(methoxymethyl)imidazo[1,2-a]pyridin-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The title compound (20 mg, 26%) was obtained as an off-white solid starting from 6-bromo-2-(1-fluorocyclopropyl)-7-(methoxymethyl)imidazo[1,2-a]pyridine (50.0 mg, 0.17 mmol) and (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (105 mg, 0.36 mmol).

[0247] 1 H NMR (400MHz, CHLOROFORM-d) d = 9.39 (s, 1 H), 8.30 (d, J = 10.8 Hz, 3 H), 8.13 (br. s., 1 H), 7.81 (br. s., 1 H), 7.70 (s, 1 H), 7.40 (t, J = 8.6 Hz, 1 H), 4.59 (q, J = 7.0 Hz, 2 H), 4.38 (s, 2 H), 3.31 (s, 3 H), 1.70 (t, J = 7.1 Hz, 3H), 1.54 (d, J = 19.6 Hz, 2 H), 1.26 (d, J = 14.5 Hz, 2 H). LC-MS: m / z [M+1] + = 461

[0248] Example 54 [ka] 54-1: (2,4-dichloropyridin-3-yl)methanol Under the protection of nitrogen gas, 2,4-dichloronicotinaldehyde (5g, 28.6mmol) was dissolved in 50ml of ethanol, the solution was cooled to 0℃, and at that temperature, sodium borohydride (1.4g, 37.2mmol) was slowly added, and the mixture was allowed to warm to room temperature and react for 16 hours, and then added to a cold aqueous ammonium chloride solution, extracted with dichloromethane (100ml×3), and the organic phase was concentrated to obtain a yellow solid (2,4-dichloropyridin-3-yl)methanol (4.8g, 94.1%). LC-MS: m / z [M+H] + =178.

[0249] 54-2: 2,4-Dichloro-3-(methoxymethyl)pyridine Under the protection of nitrogen gas, (2,4-dichloropyridin-3-yl)methanol (4.8g, 27mmol) was dissolved in 50ml of N,N-dimethylformamide, the solution was cooled to 0°C, and NaH (2.2g, 54mmol) was slowly added at that temperature. The reaction was carried out in an ice bath for 30 minutes, iodomethane (4.6g, 32.4mmol) was further added, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction solution was added to 100ml of ice water, extracted with ethyl acetate (100ml x 3), backwashed with water (50mL x 2), and the organic phase was spin-dried to obtain a pale yellow liquid 2,4-dichloro-3-(methoxymethyl)pyridine (2.3g, 44.5%). 1H NMR (400 MHz, CDCl3) 8.16 (d, J = 5.1 Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H), 4.64 (s, 2H), 3.38 (s, 3H). LC-MS: m / z [M+H] + =192 54-3: N-(4-chloro-3-(methoxymethyl)pyridin-2-yl)-1,1-diphenylmethanimine Under the protection of nitrogen gas, 2,4-dichloro-3-(methoxymethyl)pyridine (1g, 5.8mmol) and benzhydrylamine (1.1g, 5.8mmol) were dissolved in 15ml, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (361mg, 0.58mmol), cesium carbonate (2.83g, 8.7mmol) were further added, and finally palladium acetate (130mg, 0.58mmol) was added, and the reaction was carried out at 90°C for 16 hours. After the reaction was completed, the reaction solution was added to 60ml of water, extracted with ethyl acetate (50mL x 3), the organic phase was spin-dried, and subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1), and the organic phase was spin-dried to obtain a yellow oily liquid N-(4-chloro-3-(methoxymethyl)pyridin-2-yl)-1,1-diphenylmethanimine (700mg, 40%). LC-MS: m / z [M+H] + =337 54-4: 4-Chloro-3-(methoxymethyl)pyridin-2-amine Under the protection of nitrogen gas, N-(4-chloro-3-(methoxymethyl)pyridin-2-yl)-1,1-diphenylmethanimine (0.7g, 2.1mmol) was added to 10ml of tetrahydrofuran, and 8ml of hydrochloric acid dioxane solution was added. After reacting for 16 hours at room temperature, the reaction solution was added to 20ml of sodium bicarbonate solution, extracted with ethyl acetate (30ml x 3), the organic phase was spin-dried, and subjected to column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 4-chloro-3-(methoxymethyl)pyridin-2-amine (220mg, 20%) as a white solid.

[0250] 1 HNMR (400 MHz, CDCl3) 7.85 (d, J = 5.7 Hz, 1H), 6.71 (d, J = 5.8 Hz, 1H), 5.72 (s, 2H), 4.69 (s, 2H), 3.37 (s, 3H). LC-MS: m / z [M+H] + =173 54-5: 7-Chloro-8-(methoxymethyl)-3-methylimidazo[1,2-a]pyridine Under the protection of nitrogen gas, 4-chloro-3-(methoxymethyl)pyridin-2-amine (50 mg, 0.29 mmol) and 1,1-dimethoxy-2-bromopropane (265 mg, 1.45 mmol) were dissolved in 2 mL of ethanol, and then 0.2 ml of hydrochloric acid in methanol was added and reacted for 2 hours in a microwave at 120°C. The mixture was directly spin-dried and used in the next step to obtain a white solid 7-chloro-8-(methoxymethyl)-3-methylimidazo[1,2-a]pyridine (70 mg, 100%). LC-MS: m / z [M+H] + =211 54: 7-Ethyl-4-(4-fluoro-3-(8-(methoxymethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 2, 7-chloro-8-(methoxymethyl)-3-methylimidazo[1,2-a]pyridine (70 mg, 0.33 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (95 mg, 0.33 mmol) were used as starting materials to obtain the title compound (16.1 mg, 11.6%) as a white solid.

[0251] 1 HNMR (400 MHz, DMSO-d6) 9.54 (s, 1H), 8.87 (s, 1H), 8.61-8.53 (m, 2H), 8.35 (d, J = 7.1 Hz, 1H), 7.59 (t, J = 9.3 Hz, 1H), 7.46 (d, J = 0.7 Hz, 1H), 7.00 (d, J = 7.0 Hz, 1H), 4.72 (s, 2H), 4.52 (q, J = 7.3 Hz, 2H), 3.11 (d, J = 3.8 Hz, 3H), 2.53 (s, 3H), 1.64-1.47 (m, 3H). LC-MS: m / z [M+H] + =417

[0252] Example 55 and Example 56 [ka] 55-1: 1-(6-bromo-7-methoxyimidazo[1,2-a]pyridin-2-yl)ethan-1-one 5-Bromo-4-methoxypyridin-2-amine (500 mg, 2.46 mmol) and 1-bromobutane-2,3-dione (406 mg, 2.46 mmol) were added to ethanol (10 ml) and stirred at 90° C. overnight. The reaction solution was directly subjected to thin layer chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain the title compound (150 mg, 22.66%) as a yellow solid. LC-MS: m / z [M+H]+=269 55-2: 1-(6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxyimidazo[1,2-a]pyridin-2-yl)ethan-1-one Following the same experimental steps as in Example 2, 1-(6-bromo-7-methoxyimidazo[1,2-a]pyridin-2-yl)ethane-1-1 (150 mg, 0.56 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (161 mg, 0.56 mmol) were used as starting materials to obtain the title compound (100 mg, 41.29%) as a yellow solid. LC-MS: m / z [M+H] + =431 55: (Z)-1-(6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxyimidazo[1,2-a]pyridin-2-yl)ethan-1-one O-methyloxime 56: (E)-1-(6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxyimidazo[1,2-a]pyridin-2-yl)ethan-1-one O-methyloxime 1-(6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxyimidazo[1,2-a]pyridin-2-yl)ethan-1-one (100 mg, 0.23 mmol), methoxylamine hydrochloride (58 mg, 0.69 mmol) were added to ethanol (10 ml). The mixture was stirred at room temperature for 1 hour. The reaction solution was directly purified by thin layer chromatography (dichloromethane / methanol=20 / 1) to obtain Example 55 (6 mg, 5%) and Example 56 (15 mg, 13%) as yellow solids.

[0253] Example 55: 1 H NMR (400 MHz, DMSO-d6) ppm 1.50 - 1.57 (m, 3 H) 2.26 - 2.32 (m, 3 H) 3.80 - 3.85 (m, 3 H) 3.89 - 3.97 (m, 3 H) 4.47 - 4.54 (m, 2 H) 7.12 - 7.17 (m,1H) 7.52 - 7.58 (m, 1 H) 8.44 - 8.59 (m, 3 H) 8.65 - 8.71 (m, 1 H) 8.83 - 8.89 (m, 1 H) 9.52 - 9.60 (m, 1 H). LC-MS: m / z [M+H] + =460

[0254] Example 56: 1 H NMR (400 MHz, DMSO-d6) ppm 1.54 (t, J=7.34 Hz, 3H) 2.21 - 2.29 (m, 3H) 3.83 (s, 3H) 3.89 (s, 3H) 4.49 - 4.53 (m, 2H) 7.11 (s, 1H) 7.54 (t, J=8.80 Hz, 1H) 8.02 (s, 1H) 8.48 - 8.60 (m, 3H) 8.86 (s, 1H) 9.56 (s, 1H).LC-MS: m / z [M+H] + =460

[0255] Example 57 [ka] 57-1: 2-(6-bromo-7-methoxy[1,2-a]pyridin-2-yl)propan-2-ol Methylmagnesium chloride (620mg, 8.35mmol) and 6-bromo-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate (500mg, 1.67mmol) were added to tetrahydrofuran (20ml) and stirred at room temperature for 1 hour. The reaction solution was acidified with aqueous hydrochloric acid (1N), concentrated, adjusted to alkaline with saturated aqueous sodium bicarbonate, extracted with dichloromethane (50ml x 3), the organic phase was washed with saturated saline (50ml), further dried over sodium sulfate, concentrated, and separated by preparative thin layer chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (130mg, 27%). LC-MS: m / z [M+H]+ =285, 287. 57: 2-(6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxyimidazo[1,2-a]pyridin-2-yl)propan-2-ol Following the same experimental steps as in Example 2, 2-(6-bromo-7-methoxy[1,2-a]pyridin-2-yl)propan-2-ol (120 mg, 0.42 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (120 mg, 0.42 mmol) were used as starting materials to obtain the title compound (25 mg, 13%).

[0256] 1 H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.31 - 8.23 ​​(m, 3 H), 8.03 (s, 1 H), 7.40 - 7.33 (m, 2 H), 6.97 (s, 1 H), 4.59 (q, J = 7.3 Hz, 2 H), 3.86 (s, 3 H), 1.71 - 1.67 (m, 9 H). LC-MS: m / z [M+H] + =447.

[0257] Example 58 [ka] 58-1: 4-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoropyridine (4-Bromo-2-fluoropyridin-3-yl)methanol (2.0 g, 9.71 mmol), tert-butylchlorodimethylsilane (2.93 g, 19.42 mmol), and imidazole (1.32 g, 19.42 mmol) were added to dichloromethane (15 ml) and stirred at room temperature for 30 minutes. The reaction solution was stirred and subjected to column chromatography (petroleum ether / ethyl acetate=20 / 1) to obtain the title compound (3.8 g, crude product) as a colorless oily liquid. LC-MS: m / z [M+H] + =320, 322. 58-2: 4-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-hydrazinylpyridine 4-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoropyridine (3.8 g, 11.86 mmol) and hydrazine hydrate (5.94 g, 118.6 mmol) were added to 1,4-dioxane (20 ml) and reacted at 80° C. for 2 hours. The reaction solution was stirred and subjected to column chromatography (petroleum ether / ethyl acetate / aqueous ammonia=20 / 1 / 0.05) to obtain the title compound (2.1 g, 53%) as a gray solid. LC-MS: m / z [M+H] + =332, 334. 58-3: 7-Bromo-8-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-hydrazinylpyridine (1.03 g, 3.01 mmol) and 5M acetaldehyde-tetrahydrofuran solution (1.6 ml) were added to 1,4-dioxane (6 ml) and reacted at 80° C. for 1 hour. Copper bromide (280 mg, 1.24 mmol) and potassium peroxymonosulfate (2.29 g, 3.72 mmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction solution was suction filtered, stirred, and subjected to column chromatography (dichloromethane / methanol=30 / 1) to obtain the title compound (262 mg, 23.54%) as a white solid. LC-MS: m / z [M+H] + =356, 358. 58-4: (7-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methanol 7-Bromo-8-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-[1,2,4]triazolo[4,3-a]pyridine (260 mg, 0.61 mmol) was added to dichloromethane (10 ml), and 4M hydrochloric acid in dioxane (2 ml) was added and stirred at room temperature for 20 minutes. The reaction solution was concentrated, stirred, and subjected to column chromatography (dichloromethane / methanol=20 / 1) to obtain the title compound (160 mg, 96%) as a brown solid. LC-MS: m / z [M+H] + =242,244. 58-5: 7-Bromo-8-(methoxymethyl)-3-methyl-[1,2,4]triazolo[4,3-a]pyridine (7-Bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methanol (160 mg, 0.66 mmol) was added to N,N-dimethylformamide (2 ml), sodium hydride (52 mg, 1.32 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes. Iodomethane (190 mg, 1.31 mmol) was added to the reaction solution, and the mixture was reacted at room temperature for 30 minutes. The reaction solution was subjected to preparative thin layer chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (143 mg, 85%). LC-MS: m / z [M+H] + =256, 258. 58: 7-Ethyl-4-(4-fluoro-3-(8-(methoxymethyl)-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine Following the same experimental steps as in Example 1, 7-bromo-3-methyl-8-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (143 mg, 0.56 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (159 mg, 0.56 mmol) were used as starting materials to obtain the title compound (82 mg, 35%) as a brown solid.

[0258] 1 H NMR (400MHz, CHLOROFORM-d) 9.40 (s, 1 H), 8.43 (d, J = 5.9 Hz, 2 H), 8.28 (s, 1 H), 7.89 (d, J = 7.3 Hz, 1 H), 7.42 (t, J = 9.3 Hz, 1 H), 6.95 (d, LC-MS: m / z [M+H] + =418.

[0259] Example 59 [ka] 59-1: 3-Methoxybenzo[b]thiophene 3-Bromobenzo[b]thiophene (500mg, 2.35mmol), sodium methoxide (1267mg, 23.5mmol), copper oxide (93mg, 1.18mmol), cuprous iodide (22mg, 0.12mmol), potassium iodide (19mg, 0.12mmol) were added to N,N-dimethylformamide (5ml) and methanol (5ml) and reacted at 120°C overnight in a sealed tube. Water (30ml) was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (pure petroleum ether) to obtain the title compound (308mg, 80%) as a colorless oily liquid. LC-MS: m / z [M+H] + =165. 59-2: 2-Bromo-3-methoxybenzo[b]thiophene 3-Methoxybenzo[b]thiophene (308 mg, 1.88 mmol) and N-bromosuccinimide (368 mg, 2.07 mmol) were added to dichloromethane (5 ml) and stirred for 30 minutes at 25° C. The reaction solution was suction filtered, concentrated, and subjected to preparative thin-layer chromatography (pure petroleum ether) to obtain the title compound (311 mg, 68%) as a light-colored oily liquid. 1 H NMR (400MHz, CHLOROFORM-d) d = 7.72 (d, J = 7.3 Hz, 1 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.39 - 7.31 (m, 2 H), 4.05 (s, 3 H). 59: 7-Ethyl-4-(4-fluoro-3-(3-methoxybenzo[b]thiophen-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine 7-Ethyl-4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (59mg, 0.16mmol), 2-bromo-3-methoxybenzo[b]thiophene (97mg, 0.4mmol), cesium carbonate (104mg, 0.32mmol), tetrakis(triphenylphosphine)palladium(0) (9mg, 0.008mmol) were added to 1,4-dioxane (2ml) and water (0.2ml), and the mixture was reacted at 100°C for 4 hours under the protection of argon gas. The reaction solution was suction filtered, concentrated, and the title compound (6mg, 9%) was obtained as a pale yellow solid by preparative thin layer chromatography (petroleum ether / dichloromethane / methanol=20 / 30 / 1).

[0260] 1 H NMR (400MHz, CHLOROFORM-d) 9.43 (br. s., 1 H), 8.68 (d, J = 5.4 Hz, 1 H), 8.31 (br. s., 2 H), 7.90 - 7.76 (m, 2 H), 7.41 (br. s., 3 H), 4.60 (d, LC-MS: m / z [M+H] + =405. Cell line construction and subculture The α, β and γ subunits are fully functional GABA receptors. A In this example, the present application uses the liposome transfection method (Felgner, PL, et al. Proceedings of the National Academy of Sciences, 1987, 84:) to construct and express human α1-GABA receptors. A Receptor (α1-GABA A R) and α2-GABA A Receptor (α2-GABA A We screened HEK293 cells stably expressing α1-GABA.A The R-HEK293 cell model simultaneously expresses the α1 subunit (protein sequence see GenBank accession no. NM_000806.5), the β3 subunit (protein sequence see GenBank accession no. NM_000814.5), and the γ2 subunit (protein sequence see GenBank accession no. NM_000816.3). A The R-HEK293 cell model simultaneously expresses the α2 subunit (protein sequence see GenBank accession no. NM_000807.4), the β3 subunit (protein sequence see GenBank accession no. NM_000814.5), and the γ2 subunit (protein sequence see GenBank accession no. NM_000816.3).

[0261] The above cell lines were subcultured. A R-HEK293 cells were expanded to express GABA A Used to test the affinity of compounds to the benzodiazepine site of the receptor (BZD). A R-HEK293 cells and α2-GABA A During the subculture of R-HEK293 cells, some suspension cells were plated onto glass slides pretreated with Poly-D-Lysine and used for electrophysiological testing (see paragraph 0586 of Patent CN107344936A for the method).

[0262] α2-GABA A Affinity activity of the compounds of the present application for receptors Human derived α2-GABA A R-HEK293 cells stably expressing membrane protein BZD site 3 H-Flunitrazepam ( 3 H-flunitrazepam) (isotope 3 Competition for the binding of 3H-labeled flunitrazepam to α2-GABA A The affinity of the compounds for the receptor was measured.

[0263] Membrane preparation: Cells were suspended in 50 mM Tris-HCl buffer (pH = 7.4), homogenized 10 times for 20 seconds with a homogenizer on ice, and centrifuged at 1000 g for 10 minutes at 4 °C. The supernatant was taken and the above steps were repeated. The supernatant was centrifuged at 4 °C (33800 g; Thermo (Thermo Fisher Scientific), rotor: A27-8 × 50) for 60 minutes, and the precipitate was resuspended in Tris buffer (50 mM Tris-HCl, 10 mM MgCl 2 The cells were resuspended in 0.5 mM EDTA and 10% glycerol. Protein content was measured (BCA (bicinchoninic acid) protein quantification assay based on copper ion reduction method, BCA reagent kit was purchased from Pierce (Annoron Biotechnology)) and 1 mL aliquots were prepared and stored at -80°C.

[0264] Radioligand competitive binding experiments: The experiments were carried out in 200 μL reactions (96-well plates) containing 100 μL of cell membranes. 3 The concentration of H-flunitrazepam was 1 nM and the concentration of the test compound was 1 × 10 -5 ~10 -6The concentrations ranged from 0.1 to 100 μM. Flumazenil was used as a control. 1 μL of 2 mM flumazenil (final concentration 10 μM) was added to the low signal control wells (LC) and 1 μL of dimethyl sulfoxide was added to the high signal control wells (HC). The final concentration of the target membrane protein was 5 μg / well. Sample stock solutions of all test compounds were 10 mM dimethyl sulfoxide solutions. Sample working concentrations were determined by diluting all samples to 0.2 mM with dimethyl sulfoxide, followed by 4-fold serial gradient dilutions with a total of eight concentration gradients. The 96-well plate was sealed with sealing film and then incubated in a shaker at room temperature for 1 h. At the same time, the soaking buffer (0.3% PEI (polyethyleneimine, purchased from sigmaaldrich, model: P314), stored at 4 °C) was used to soak the GF / C filtration plate for at least 0.5 h. After the binding culture was completed, the cells were collected into GF / C filtration plates using a cell collector, and the plates were washed four times with washing buffer (50 mM Tris-HCl, pH 7.4, stored at 4°C). After drying in an oven at 50°C for 1 hour, the bottom of the dried GF / C filtration plate was sealed with film, and the residual radioactivity of the filtration membrane was detected using liquid scintillation counting method, 50 μL of scintillation liquid was added to each well, sealed, and counted with Microbeta. 2 The plates were read using a microplate counter (purchased from PerkinElmer, model CNLL0153). 3 H-Flunitrazepam and GABA A The inhibitory activity of the test samples against the binding of receptor membrane proteins was calculated, and the IC of each test sample was calculated by dose-response curve fitting (GraphPad Prism 5 software). 50 Calculate IC 50 The Ki of the sample was calculated based on the compound and α2-GABA A The binding ability to the BZD site of the receptor was evaluated.

[0265] The above human-derived α2-GABA ARepresentative detection results obtained by the method for measuring the binding affinity of a compound to the BZD site of a membrane protein in R-expressing HEK293 cells are shown in Table 1 below.

[0266] Different subtypes of GABA A Functional activity of the compounds of the present application on receptors Electrophysiological methods have demonstrated that α1-GABA A Receptors and α2-GABA A The positive regulatory activity of the test drugs on the receptor was detected by the specific method as follows:

[0267] Compound concentration setting: The final concentration of the compounds used in compound screening was 100 nM. A For cell lines expressing the receptor, GABA concentrations ranged from 0.05 to .07 μM (approximately EC 2-4 ) and α2-GABA A For cell lines expressing the receptor, GABA concentrations were 0.10–0.11 μM (approximately EC 7-8 ) The electrophysiological experiments were performed using the whole-cell patch clamp technique, and the method can be referred to the method reported in the literature (Nickolls, SA, et al. British Journal of Pharmacology, 2018, 175:). The components of the extracellular solution (ECS) for electrophysiology were 150 mM NaCl, 5 mM KCl, 2.5 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES, and 10 mM glucose (pH 7.4), and the composition of the electrophysiology electrode internal solution (ICS) was 140 mM CsCl, 11 mM EGTA, 10 mM HEPES, 2 mM CaCl 2 , 1 mM MgCl 2 , 4 mM MgATP, 2 mM TEA (pH 7.3). GABA (γ-aminobutyric acid) powder was prepared in pure water and diluted with ECS, and compounds were first prepared in 4 mM mother solution using dimethyl sulfoxide and then gradually diluted with the corresponding concentration of GABA-ECS. Solutions were freshly prepared before electrophysiological testing.

[0268] Electrophysiological signals were acquired using an EPC10 amplifier and PatchMaster software (HEKA) or an Axon700B amplifier and Clampex software (AXON). Recording electrodes were drawn with borosilicate glass, and electrode resistance was 4–6 MΩ. Extracellular administration was performed with ALA-VC-8PG. TM The system was used. An independently growing single cell was selected, and after a good seal was made between the glass electrode and the cell, the membrane was ruptured to form a whole-cell mode. The cell membrane potential was clamped at -60 mV and recorded in gap-free mode. During the experiment, extracellular solution was first applied to the outside of the cell for about 20 seconds. The baseline (I prebaseline After the GABA-induced current (I) was stabilized, the extracellular fluid was converted to GABA-ECS. gaba After the current stabilized for about 10 to 20 seconds, the current induced by the compound and GABA together (I treatment The extracellular solution was then replaced with a mixed solution of the compound and GABA-ECS until the baseline was stable and the control current size (I gaba -I prebaseline ) was greater than 40 pA and the current was relatively stable within 10-20 seconds. Only cells with such a current were used for compound testing.

[0269] α1-GABA A R and α2-GABA A The experimental results of the forward allosteric regulatory activity of R were analyzed using PatchMaster v2x90.1 or PatchMaster v2x90.3 software (EPC 10 amplifier) ​​and Clampex 10.6 software (Axon 700B amplifier). The current value of each step was calculated according to the average value of the current after stabilization at the relevant conditions. The control current was I gaba -I prebaseline and the current after compound treatment is I treatment -I prebaseline The allosteric modulatory activity of the compound was expressed as a percentage and calculated according to the following formula: Functional activity = [(Itreatment -I gaba ) / (I gaba -I prebaseline )]×100%. If the value is negative, it indicates that the modulatory effect of the test compound on the GABA receptor is reverse allosteric modulation. If the value is positive, it indicates that the modulatory effect of the test compound on the GABA receptor is forward allosteric modulation. To facilitate comparison, the positive compound CVL-865 was taken as the reference and normalization was performed, i.e., forward allosteric modulatory activity=[compound functional activity / positive compound functional activity]×100%. α1-GABA A Receptors and α2-GABA A The test results of the forward allosteric modulatory activity of the compounds against the receptor are shown in Table 1.

[0270] In vitro micronucleus test 1. Guidelines for genotoxicity studies The experimental design follows the principles of experimental design guidelines based on the experimental objectives.

[0271] (1) OECD Chemicals Testing Guideline 487, revised in 2016, In Vitro Mammalian Cell Micronucleus Test, (2) ICH S2(R1), which came into effect in November 2011: Guidelines for genotoxicity testing of human drugs and analysis of the results.

[0272] 2. Materials and methods Experimental system and reasons for selection: This experiment used Chinese hamster ovary cells (CHO-WBL cells) as the experimental system, the karyotype of the cell line contains 21 chromosomes, and the growth cycle is 12-13 hours. CHO-WBL cells were originally derived from Dr. S. Wolff at the University of California, San Francisco, USA, cloned in the laboratory of Dr. A. Bloom at Columbia University, New York, and then recloned by Dr. S. Galloway at the Litton Bionetics laboratory in Maryland. The cell stock solution was stored in liquid nitrogen. All cell stock solutions of each batch were identified for cell karyotype and demonstrated to be free of mycoplasma contamination by detection. The number of passages of the cells after cloning did not exceed 15. The reason for selecting Chinese hamster ovary cells is that the cell line is a cell line recommended by OECD Chemicals Testing Guideline 487 and has been proven to be sensitive to some chromosomal clastogens / aneugen (Marilyn J. et al., 2006).

[0273] Culture medium and cell growth conditions: Chinese hamster ovary cells were cultured in McCoy's 5A complete medium (supplemented with 10vt% fetal bovine serum, 2mM GlutaMAXTM medium, 100 units / mL penicillin, and 100μg / mL streptomycin in McCoy's 5A complete medium) and grown in a standard environment (temperature 37°C, CO 2 The day before administration, CHO-WBL cells in the exponential growth phase were cultured at 8 × 10 3 Cells were seeded into 8-well cell culture slides with 400 μL McCoy's 5A complete medium / well.

[0274] Metabolic activation system: The in vitro metabolic activation system (Maron and Ames, 1983) contains rat liver microsomal homogenate induced by β-naphthoflavone and phenobarbital (abbreviated as S9) and one NADPH generating system (i.e., disodium NADP and trisodium isocitrate). S9 was purchased from CHI Scientific, Inc. and stored in a refrigerator at -75°C before use. Method for preparing S9 homogenate: The material was prepared after a single dose of β-naphthoflavone and phenobarbital was administered to male Sprague Dawley rats.

[0275] Preparation of S9 metabolic activation system: First, NADP disodium salt and isocitrate trisodium salt were dissolved in serum-free medium to prepare a core solution, which was then filtered through a 0.22 μm filter and sterilized. Before use, the S9 homogenate was dissolved and each component of the S9 metabolic activation system was mixed uniformly according to the ratios shown in Table 2 below.

[0276] [Table 2] Dose Finding Experiment: In the dose finding experiment, eight dose concentrations were set for each dosing treatment series. One well of cells was set for each concentration of the test substance. In the ICH Guidance Principle S2(R1), the maximum concentration recommended is 1 mM or 0.5 mg / mL if not limited by the solubility of the test substance in the solvent / medium or the cytotoxicity of the test substance, and the lower concentration was taken. However, if limited by solubility, the highest concentration tested is the lowest concentration that shows a small amount of precipitation in the medium under the microscope. To ensure that the upper limit of solubility in the medium is reached, up to four concentrations including visible precipitation can be tested.

[0277] Treatment: S9 metabolic activation For the 3-hour treatment series, the medium in each well was aspirated and serum-free McCoy's 5A / S9 mixed medium was added containing the appropriate concentrations of test / control articles in reference to ICH S2(R1) guiding principles.

[0278] In the non-metabolically activated 3 hour dose series, the medium in each well was aspirated and McCoy's 5A complete medium containing the appropriate concentration of test / control article was added.

[0279] Cells were cultured for 3 hours under standard conditions. After 3 hours, the existing medium in each well was aspirated and washed twice with McCoy's 5A complete medium. McCoy's 5A complete medium containing cytochalasin B (final concentration in the medium was approximately 3 μg / mL) was added to each well and cultured for 21 hours before harvesting.

[0280] For the non-metabolically activated 24-h dosing system, the treatment method was similar to that for the non-metabolically activated 3-h dosing system, with the exception that cells were cultured with the test / control substances for 24 hours (± 30 minutes) in complete medium containing cytochalasin B (final concentration in the medium was approximately 3 μg / mL).

[0281] Slide preparation: At harvest, the medium of the 8-well slides was discarded and wiped with absorbent paper, after which 75 mM KCl stock solution was added to each well, cells were fixed in two successive changes of fixative solution (anhydrous methanol:glacial acetic acid, 3:1 v / v) for 5 min, then air-dried, stained with acridine orange in the dark, and then air-dried.

[0282] Cytotoxicity index: The staining conditions shown at low magnification were examined to assess the feasibility (sufficient number of cells) of analyzing all wells of each slide. At least 500 cells per well were analyzed under a fluorescent microscope and the number of mononuclear, binuclear and multinuclear cells contained was counted to calculate the cytokinesis-blocking proliferation index (CBPI).

[0283] The cytotoxicity of the test substance was evaluated using CBPI. The formula for calculating CBPI is as follows:

[0284]

number

[0285] A CBPI of 1 corresponds to 100% cytotoxicity.

[0286] Micronucleus main experiment: In the micronucleus main experiment, CHO-WBL cells were exposed to 3 to 8 concentrations of the test substance, and at the same time, a positive control group (cyclophosphamide monohydrate) and a solvent control group (dimethyl sulfoxide) were set up, which were treated in the same way as the solvent group, and 2 wells of cells were set up for each dosage group. In the inactivation test system, the administration time was 3 and 24 hours, and the exposure time of the test substance in the S9 activation test system was 3 hours. The upper limit of the test substance test depends on the solubility of the medium, but generally does not exceed the maximum concentration of 1 mM or 0.5 mg / mL, and a lower concentration is taken. When selecting the highest dose for micronucleus frequency analysis, the test substance dose group should not have a cytotoxicity that greatly exceeds 50% compared to the corresponding solvent control group. If the highest concentration is not limited by cytotoxicity, multiple doses containing visible precipitation can be tested to reach the upper limit of solubility in the medium, and a small amount of discernible precipitation could be seen in the medium of the highest dose group.

[0287] Dose selection for micronucleus assay: Dose selection for CHO-WBL cell micronucleus assay depends on the cytotoxicity of the test substance. The highest dose selected for evaluation causes cytotoxicity not significantly exceeding 50%. At least two lower dose groups (from moderately cytotoxic to non-cytotoxic range, if applicable) were further analyzed. If the test substance was not cytotoxic, the dose at which a precipitation was visible microscopically at the end of dosing was selected, or the highest concentration tested (1 mM or 0.5 mg / mL, whichever was lower) was taken as the highest concentration used for the micronucleus assay.

[0288] Micronucleus frequency coefficients: All slides selected for micronucleus analysis were labeled with a randomly generated blind code to reduce subjectivity in reading the slides, and the blind code was created by personnel who did not participate in reading the slides. Slide labels labeled with the blind code included information such as the experiment number, treatment series, and random number.

[0289] For each dose group, 2000 binucleated cells (1000 per well) were analyzed to count the frequency of binucleated cells containing micronuclei.

[0290] Binucleated cells must meet the following criteria before being counted:

[0291] a) It has an intact cell membrane. b) The two daughter nuclei are the same size.

[0292] The criteria for determining micronuclei are as follows:

[0293] a. Micronuclei have similar fluorescence intensity as the main nucleus. b. Micronuclei must be free in the cytoplasm. c. Micronuclei have smooth edges and a diameter less than one-third the diameter of the main nucleus.

[0294] The slides were discarded before the lab report was signed.

[0295] data Data reporting: Cytotoxicity of treatment groups was determined and presented according to cytotoxicity compared to the corresponding solvent control group. For micronucleus main experiments, the frequency of micronuclei for each well and each dose was also presented.

[0296] Statistical analysis: Fisher's exact probability test was used to compare the significance of differences in the frequency of micronucleated binucleated cells between treatment groups and the corresponding vehicle control group. P values ​​were corrected with Bonferroni when multiple comparisons were performed. Cochran-Armitage test was used to detect dose-response relationships when comparing data from multiple groups.

[0297] Differences can be considered significant if P≦0.05.

[0298] Test Validity Criteria: An acceptable genotoxicity test must meet the following criteria: The frequency of vehicle / negative control micronucleated cells must be comparable to historical negative control data. At least three concentrations should be available for analysis. The positive control micronucleated cell ratio should be statistically significantly increased (p ≤ 0.05) compared to the parallel vehicle / negative control.

[0299] Judgment criteria for experimental results: Under the premise that the experiment is valid, according to the guiding principle ICH S2 (R1), the judgment of the test results should be based on the combination of the results of the micronucleus rate at different concentrations of the test substance under different administration conditions (3 hours administration with S9, 3 hours administration without S9, 24 hours administration without S9), and referring to the evaluation criteria of the test results, the in vitro micronucleus results of the test substance are negative, positive or suspected positive, and the result is preferably negative. The specific standard evaluation experimental results are as follows:

[0300] Positive: A test substance can be considered positive if it simultaneously meets the following criteria: A significant increase in the frequency of micronucleated cells is observed in one or more dose groups compared to parallel vehicle controls. The increase in micronucleus frequency has a dose-response relationship. A frequency of micronucleated cells outside the range of laboratory negative historical data is observed in one or more dose groups.

[0301] Negative: If any of the above three conditions are not met, the test substance can be considered negative.

[0302] False positive: If a test substance meets only some of the above three criteria, scientific judgement is required. Evidence of a concentration-related effect is deemed useful but not necessary when assessing a positive result. Biological relevance is considered, such as consistency of response within and between concentrations, and (if applicable) between experiments, or effects occurring only at high or highly cytotoxic concentrations.

[0303] α2-GABAA The affinity activity of each compound of the present application for the α1,α2-GABA receptor A The results of the forward allosteric regulatory activity against the receptor are shown in Table 3 below, and the results of the in vitro micronucleus test are shown in Table 4.

[0304] It should be noted that the advantage of the compounds according to the present application is not only the absolute activity of the drug but also the high selectivity of the receptor; at the same time, the absolute value of the functional activity of the compounds may have a certain difference in different detection systems, making comparison impossible. In order to facilitate comparison, in the experiments of the present application, the control group and related compounds were simultaneously detected in the same detection system, and the positive compound CVL-865 was used as the reference, and standardization was performed, that is, forward allosteric regulatory activity = [functional activity of the compound / functional activity of the positive compound] × 100%, and the specific results are shown in Table 3 below.

[0305] [Table 3] The example compounds of the present application have superior selectivity to the reference compound CVL-865 and are suitable for α2-GABA A α1-GABA receptor antagonists, while maintaining receptor affinity and electrophysiological activity A It was found that the receptor electrophysiological activity was maintained at less than 70% of that of CVL-865, thereby maintaining the drug's efficacy in the body while at the same time resulting in fewer side effects.

[0306] [Table 4] The in vitro micronucleus results showed that the compounds of the present application have better genotoxicity safety and better druggability.

[0307] Obviously, the above embodiments are illustrative and not limiting. Those skilled in the art can make other modifications or alterations based on the above description. It is not necessary or possible to describe all the embodiments here. Any obvious modifications or alterations derived therefrom are still within the scope of protection of the present invention.

Claims

1. A compound of formula (1) and its stereoisomers, tautomers, pharma- ceutically acceptable salts, amorphous substances, isotopes or solvates. 【Chemistry 1】 (however, R １ is selected from any one of the following structures: 【Chemistry 2】 R ２ is F, R ３ is a straight or branched C1-C6 alkyl; R 4 is selected from C1-C6 alkyl or C1-C6 alkoxy, which are optionally unsubstituted or substituted, independently of each other, by 1 to 4 C1-C3 alkoxy; R 5 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 non-aromatic heterocycle containing 1-3 heteroatoms, which are optionally unsubstituted or substituted with at least one of each independently selected from 1-4 halogen, C1-C3 alkyl, or C1-C3 alkoxy.

2. The R ４ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy or -CH ２ The compound according to claim 1, characterized in that it is selected from: —O—CH3.

3. The R ５ is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, hexahydropyridyl, oxetane, azetidine, said groups being optionally unsubstituted or substituted by at least one of each independently selected from 1 to 4 F, Cl, Br, methoxy or methyl.

4. The R ５ is H, methyl, ethyl, isopropyl, 【Chemistry 3】 Cyclopropyl, fluorocyclopropyl, 【Chemistry 4】 The compound according to claim 3, characterized in that it is selected from:

5. The R １ is selected from any one of the following structures: 【Chemistry 5】 Furthermore, The R ４ is selected from methoxy C1-C3 alkyl or C1-C3 alkoxy; The R ５ is H, methyl, ethyl, isopropyl, 【Chemistry 6】 Cyclopropyl, fluorocyclopropyl, 【Chemistry 7】 The compound according to claim 1, characterized in that it is selected from:

6. The R ４ 2. The compound according to claim 1, characterized in that is selected from methoxymethyl or methoxy.

7. A compound selected from any one of the following compounds, and its stereoisomers, tautomers, pharma- ceutically acceptable salts, amorphous substances, isotopes, or solvates: 【Chemistry 8】 【change】 【change】 【change】

8. 10. A pharmaceutical composition comprising at least one of the compounds of claim 1 or 7 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, amorphous material, isotope or solvate thereof, optionally comprising a pharma- ceutically acceptable carrier and / or adjuvant.

9. GABA Ａ 13. Use of a compound according to claim 1 or 7 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, amorphous material, isotope or solvate thereof in the manufacture of a medicament for treating or preventing a receptor-related disease.

10. The GABA Ａ 10. The use according to claim 9, characterized in that the receptor-related disease is selected from at least one of pain, Alzheimer's disease, multi-infarct dementia, epilepsy, pruritus or stroke.

11. The use according to claim 10, characterized in that the pain comprises neuropathic pain, inflammatory pain and cancer pain.

12. 11. The use according to claim 10, characterized in that the pain is selected from headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, lower back pain, lower limb pain, musculoskeletal pain, vascular pain, gout, arthritis pain, visceral pain, pain due to infection, bone pain, pain associated with sickle cell disease, autoimmune diseases, multiple sclerosis or inflammation, chronic pain due to injury or surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, pain from lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, cancer, chemical injury, toxins, nutritional deficiency, viral or bacterial infection or pain associated with osteoarthritis.

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