Imidazopyridazine-substituted benzene ring system derivatives, preparation methods, pharmaceutical compositions and uses

Abstract

The present invention relates to imidazopyridazine derivatives, their preparation methods, pharmaceutical compositions and uses. The present invention provides a compound represented by formula (1), its stereoisomers, tautomers, prodrugs, pharma- ceutically acceptable salts, amorphous substances, isotopes, crystalline polymorphs or solvates. A Pharmaceutical compositions containing such compounds and uses of said compounds as receptor modulators. [Formula 1] JPEG2025515215000202.jpg36169

Description

[Technical Field]

[0001] Cross-Citation of Related Applications This application claims priority to a Chinese patent application filed with the China Patent Office on May 10, 2022, bearing application number 202210542611.3 and entitled "Imidazopyridazine-substituted benzene ring system derivatives, preparation methods, pharmaceutical compositions and uses," the entire contents of which are incorporated herein by reference.

[0002] The present invention is directed to the A The present invention relates to imidazopyridazine-substituted benzene ring derivatives having receptor modulatory functions, their preparation methods, pharmaceutical compositions and their use as medicines. [Background technology]

[0003] γ-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 discovered 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 receptor formation, and it interacts with benzodiazepines and 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 the α2 or α3 subunits are more potent than GABA receptors containing the α2 or α3 subunits. A receptors (α2 / 3-GABA A It has been suggested that certain receptors (termed 'allosteric receptors') 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 the 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 (Robert M. Owen, J. Med. Chem. 2019, 62, 5773-5796) describe the use of α2 / 3-GABA receptor antagonists for the treatment of various disorders, including pain. ADeveloped 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):255-260).

[0006] The mainstream view is that GABA receptors containing the α1 subunit A The modulatory activity of the receptor is currently A GABA is thought 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 α1-GABA receptors A Finding new compounds with fewer receptor-related side effects has enormous therapeutic potential. Summary of the Invention

[0007] Therefore, the technical problem to be solved by the present invention is to provide an imidazopyridazine-substituted benzene ring system compound represented by formula (1), its derivatives, stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, amorphous substances, crystalline polymorphs or solvates.

[0008] [ka]

[0009] however, R1 is a fused group formed from a substituted or unsubstituted benzene ring and a heterocycle, R2 is selected from H, halogen, OH, C1-C6 alkoxy, or CN; The R3 is selected from H, substituted or unsubstituted straight or branched chain C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

[0010] Unless otherwise stated, the following definitions are used to illustrate and define the meaning and scope of various terms used to describe this specification.

[0011] The following definitions of general terms apply whether they appear alone or in combination.

[0012] The nomenclature used in this application is based on AutoNom™ 2000, a Beilstein Institute computerized system used to generate names according to the IUPAC system. Any open valence bond on a carbon, oxygen, sulfur, or nitrogen atom in the structures depicted herein indicates the presence of a hydrogen atom.

[0013] 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 may have multiple substituents and multiple possible substituents are provided, the substituents are independently selected and do not have to be the same.

[0014] The term "unsubstituted" refers to the absence of substituents on a particular group.

[0015] The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from the possible substituents.

[0016] When specifying the number of substituents, the term "one or more" refers to the maximum number of substitutions possible with one substitution, i.e., replacing one hydrogen so that all hydrogens are replaced by substituents. Unless otherwise specified, preferably 1, 2, 3, 4, or 5 substituents.

[0017] Specifically, in the definitions of the R1 and R3 groups, "substituted" means that one or more hydrogen atoms of the group are substituted with one selected from C1-C4 alkyl, C1-C4 alkoxy, alkyl substituted with C1-C4 halogen, or halogen.

[0018] The term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine.

[0019] The compounds of the present invention may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropostereoisomers, as well as mixtures thereof, such as racemic mixtures, constitute part of the present invention. When the stereochemistry of a particular chiral atom is not determined herein, all stereoisomers are contemplated. Furthermore, the present invention relates to all geometric and positional isomers. The compounds of the present invention may exist in different tautomeric forms, and all such forms are included within the scope of the present invention. All stereoisomers of the compounds of the present invention are expected to exist in mixtures or in pure or substantially pure form. Resolution can be carried out by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.

[0020] The term "prodrug" refers to a functional derivative of the compound of formula (1) that is easily converted into the compound of formula (1) in the body. Suitable derivatives can be selected and prepared by conventional techniques known to those skilled in the art; see, for example, "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.

[0021] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention. 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 salts. 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.

[0022] When the compound of the present invention 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 the like, or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, salicylic acid, pyranosyl acid (e.g., glucuronic acid or galacturonic acid), α-hydroxy acid (e.g., citric acid or tartaric acid), amino acid (e.g., glutamic acid), aromatic acid (e.g., benzoic acid or cinnamic acid), sulfonic acid (e.g., methanesulfonic acid or p-toluenesulfonic acid), or the like.

[0023] When the compound of the present invention is an acid, the desired "pharmaceutically acceptable salt" can be prepared by a suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine, alkali metal hydroxide, or 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.

[0024] The compounds of the present invention can exist on 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 either a solid or a 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 possesses a regularly ordered internal structure at the molecular level and provides a unique X-ray diffraction pattern with distinct peaks. When such materials are heated sufficiently, they will exhibit liquid properties, but the change from solid to liquid is generally characterized by a first-order phase change ("melting point").

[0025] As used herein, the term "crystalline polymorphism" refers to different solid crystalline phases that result from the existence of two or more different molecular configurations of a particular compound of the present invention in the solid state. A particular compound of the present invention may exist in one or more crystalline forms, and the present invention is intended to encompass various crystalline forms and mixtures thereof.

[0026] The term "solvate" as used herein refers to a combination or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. The compound of the present invention may exist in a non-solvated form or in a solvated form with a pharmaceutically acceptable solvent such as water, ethanol, etc., and therefore the present invention includes both solvated and non-solvated forms.

[0027] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms that constitute the compounds. The term "isotope" refers to an isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. For example, the compounds can be labeled with radioactive isotopes such as deuterium (H), tritium (H), iodine-125 (I), or C-14 (C). All isotopically modified versions of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention. Isotopic variants can 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 of Formula (1) can be prepared without undue experimentation using 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.

[0028] [R2] In the compounds according to the present invention, R2 is selected from H, halogen, OH, C1-C6 alkoxy or CN, preferably R2 is H or halogen, more preferably H or F.

[0029] [R3] In the compounds described in the present invention, R3 is selected from H, substituted or unsubstituted linear or branched C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In R3, 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 more 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.

[0030] The term "cycloalkyl" refers to a monovalent saturated cyclic hydrocarbon group, and in R3, exemplary C3-C5 cycloalkyls include cyclopropyl, cyclobutyl, or cyclopentyl.

[0031] In R3, exemplary C3-C6 cycloalkyl include 1-methylcyclopropyl, 2-methylcyclopropyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 3-methylcyclobutyl, 1-methylcyclopentyl, 2-methylcyclopentyl, or 3-methylcyclopentyl. One to more 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.

[0032] The term "alkoxy" refers to alkyloxy, and in R3, exemplary C1-C6 alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, etc. One to more 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.

[0033] In one optional embodiment of the present invention, R3 is selected from straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, more preferably C2-C4 alkyl, more preferably ethyl or isopropyl.

[0034] [R1] In an embodiment of the present invention, R1 is a fused group of a benzene ring and a heterocycle, and the heterocycle refers to a saturated or partially unsaturated monocyclic or polycyclic group having a heteroatom, and the heteroatom is N, O, or S. Preferably, the two heterocycles are 3- to 7-membered saturated or partially unsaturated monocyclic or polycyclic groups containing 1 to 3 ring heteroatoms independently selected from N, O, or S, and S and O may exist as -SO or -SO2.

[0035] As a preferred structure, in the compound of the present invention, the heterocycle forming the fused group represented by R1 is a 5- to 7-membered saturated or unsaturated monocyclic or bicyclic group containing 1 to 3 ring heteroatoms selected from N, O, and S. Preferably, the heterocycle is a 5- to 6-membered saturated or unsaturated monocyclic group containing 1, 2, or 3 ring heteroatoms selected from N and / or O, and more preferably a heterocycle containing only N or simultaneously N and O as heteroatoms.

[0036] Preferably, R1 has a structure represented by the following formula (M):

[0037] [ka]

[0038] wherein m is 1, 2, or 3, and n is 1 or 2;

[0039] [ka]

[0040] represents the linking site, The ring A refers to a 5- to 7-membered saturated or partially unsaturated monocyclic or bicyclic ring containing at least one heteroatom selected from N, O, and S.

[0041] The ring A is a 5- to 7-membered saturated or partially unsaturated monocyclic ring containing at least one heteroatom selected from N, O, and S, m is 1, 2, or 3, and n is 1 or 2;

[0042] [ka]

[0043] represents the linking site.

[0044] R1 is

[0045] [ka]

[0046] is linked to the phenyl of the compound of formula (I) via

[0047] R4 or R5 is a substituent on the heterocycle and may be linked to a heteroatom or a carbon atom.

[0048] In a more preferred structure, the ring A is a 5- or 6-membered saturated or unsaturated monocyclic group containing 1 to 3 heteroatoms and at least one heteroatom selected from N, O, and S. Specifically, when R1 has a structure represented by formula (M), R1 has a structure represented by any of the following (a) to (e).

[0049] [ka]

[0050] More preferably, in the structure of the ring A, when R1 has a structure represented by formula (M), the ring A may be selected from the following structures.

[0051] [ka]

[0052] As an alternative structure, R1 has a structure represented by the following formula (N):

[0053] [ka]

[0054] As an optional structure, when R1 has a structure represented by formula (N), the A ring may be selected from the following structures.

[0055] [ka]

[0056] In the alternative structures of R1 above, R4 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy, and the groups are optionally unsubstituted or each independently substituted with at least one of 1 to 4 halogen, hydroxy, C1-C3 alkyl, haloC1-C3 alkyl, C1-C3 alkoxy, or haloC1-C3 alkoxy.

[0057] Preferably, R4 is selected from hydrogen, C1-C3 alkyl or C1-C3 alkoxy, which groups are optionally unsubstituted or each independently substituted with C1-C3 alkoxy or halogen.

[0058] More preferably, said R4 is selected from methoxy C1-C3 alkyl or C1-C3 alkoxy, more preferably methoxymethyl or methoxy.

[0059] In the alternative structures of R1 above, the heteroatoms in the R5 group are selected from N, O, or S.

[0060] R5 is selected from hydrogen, halogen, hydroxy, oxo, C1-C6 alkyl acyl, C1-C6 alkylamido, C1-C6 alkoxyimino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C6-C10 aryl, 5- to 7-membered heteroaryl containing 1 to 3 heteroatoms, or C3-C7 non-aromatic heterocycle containing 1 to 3 heteroatoms, and the groups are optionally unsubstituted or each independently substituted with at least one of 1 to 4 halogen, hydroxy, oxo, C1-C4 acyl, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, haloC1-C3 alkoxy, or sulfonyl.

[0061] In a preferred structure, R5 is selected from hydrogen, halogen, oxo, C1-C3 alkyl acyl, C1-C3 alkylamido, C1-C3 alkoxyimino, C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C6-C8 aryl, 5-6 heteroaryl containing 1-2 heteroatoms, or C4-C6 non-aromatic heterocycle containing 1-2 heteroatoms, and the groups are optionally unsubstituted or each independently substituted with at least one of 1-2 halogen, hydroxy, oxo, C1-C3 acyl, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, haloC1-C3 alkoxy, or sulfonyl.

[0062] In a more preferred structure, R5 is H, oxo, methyl, ethyl, isopropyl, acetyl, methylmethoxy, ethylmethoxy, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, methylamino, phenyl,

[0063] [ka]

[0064] is selected from.

[0065] In the compound according to the present invention, R1 is selected from any one of the following structures:

[0066] [ka]

[0067] and, wherein R4 is selected from H, C1-C3 alkoxy, or substituted or unsubstituted methoxy C1-C3 alkyl, preferably H, methylmethoxy, ethylmethoxy, methoxy, or difluoromethoxy; R5 is H, methyl, ethyl, acetyl, ethylmethoxy, methylmethoxy, methylcyclopropyl, phenyl,

[0068] [ka]

[0069] is selected from.

[0070] In the most preferred structures, the compound is selected from any one of the compounds in Table 1 below.

[0071] [Table 1] TIFF2025515215000015.tif241169TIFF2025515215000016.tif241169TIFF2025515215000017.tif240169TIFF20255152150 00018.tif232169TIFF2025515215000019.tif217169TIFF2025515215000020.tif244169TIFF2025515215000021.tif160169

[0072] 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, pharmaceutically acceptable salt, amorphous material, isotope, crystalline polymorph, or solvate thereof.

[0073] 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, pharmaceutically acceptable salt, amorphous material, isotope, crystalline polymorph, or solvate thereof, and optionally a pharmaceutically acceptable carrier and / or adjuvant.

[0074] GABA A Provided is the use of a compound according to any one of the present application or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, amorphous material, crystalline polymorph, solvate, pharmaceutical mixture, or pharmaceutical composition thereof in the manufacture of a medicament for treating or preventing a receptor-related disease.

[0075] Furthermore, the GABA A The receptor-associated disease is at least one selected from pain, Alzheimer's disease, multi-infarct dementia, and stroke.

[0076] Furthermore, the pain is neuropathic pain, inflammatory pain and cancer pain.

[0077] Further, the pain is selected from headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, lower back pain, lower back pain, leg 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.

[0078] The present application also provides a method for treating GABAergic disorders by administering to a patient an effective amount of a compound described in any one of the present application or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, amorphous material, crystalline polymorph, solvate thereof, said pharmaceutical mixture, or said pharmaceutical composition. A Methods for treating or preventing receptor-related diseases are provided.

[0079] 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 a compound described in any one of the claims herein, or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, amorphous material, crystalline polymorph, solvate thereof, said pharmaceutical mixture, or said pharmaceutical composition.

[0080] 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 from within the body.

[0081] Therefore, the present application also relates to a pharmaceutical composition comprising a compound as defined above or a pharmaceutically acceptable salt thereof or a prodrug thereof and a pharmaceutically acceptable carrier and / or adjuvant.

[0082] Similarly, the present application further provides 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.

[0083] Preferably, the treatment or prevention of pain.

[0084] Particularly preferred is the treatment or prevention of neuropathic pain, inflammatory pain and cancer pain.

[0085] As used herein, "cancer pain" refers to pain that occurs during the development of a malignant tumor, and cancer pain currently has three mechanisms: direct pain caused by the onset of cancer, pain caused by cancer treatment, and pain disorders that occur concomitantly in cancer patients.

[0086] As used herein, "neuropathic pain" is pain caused or resulting from primary damage and dysfunction of the nervous system.

[0087] As used herein, "inflammatory pain" is pain caused by localized acute or chronic inflammation that irritates nerves.

[0088] As used herein, "treatment" also includes prophylactic administration to reduce or eliminate the disease once the disease has developed.

[0089] 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, with the patient preferably being a human.

[0090] 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.

[0091] As used herein, "chronic pain" is defined as pain that persists beyond the typical course of an acute disease or injury, beyond a reasonable time for healing, or that is associated with a chronic pathological process that causes persistent pain, or that recurs at intervals of months or years, persists after the pain has healed, and persists beyond the typical course of treatment. The duration of pain depends on the nature of the pain and the associated treatment course, and pain is chronic when it exceeds the typical 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, leg 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 due to infectious diseases (such as AIDS and shingles), pain due to autoimmune diseases (rheumatoid arthritis), acute and chronic pain, post-operative pain, and post-burn pain.

[0092] The medicament disclosed in the present application can effectively treat chronic pain as defined above, and the medicament disclosed in the present application can treat 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.

[0093] As used herein, "headache" can be divided into primary headaches and secondary headaches, where primary headaches include tension headaches, migraines, and cluster headaches, and secondary headaches are 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, throat, etc., and are mainly the muscles and blood vessels of the head, and contain abundant nerve fibers that are sensitive to pain. Therefore, damage to these tissues can cause headaches.

[0094] As used herein, "facial pain" includes, but is not limited to, trigeminal neuralgia, atypical facial pain, facial paralysis, and hemifacial spasm.

[0095] As used herein, "trigeminal neuralgia," also known as painful spasms, is a unique chronic pain disorder characterized by short-term, paroxysmal, and repetitive severe pain resembling electric shocks in the area distributed by the trigeminal nerve, or by ipsilateral facial spasms. Trigeminal neuralgia is divided into two types: primary and secondary. Primary trigeminal neuralgia refers to a condition in which there are no clinical neurological signs and no underlying lesions on examination, while secondary trigeminal neuralgia refers to a condition in which there are clinical neurological signs and an organic lesion such as a tumor or inflammation is found on examination.

[0096] As used herein, "atypical facial pain" refers to pain caused by a variety of etiologies. It presents as a constant, burning pain that is not intermittent and is not associated with any specific behavior or provoking stimulus. The pain is mostly bilateral, and the pain often extends beyond the trigeminal nerve distribution to the skin of the neck. The 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.

[0097] As used herein, "neck pain, back pain, shoulder pain" refers to pain caused by acute and chronic muscle injuries, bone and joint degeneration, and trauma, etc. Common diseases that cause pain in the neck, shoulders, and upper limbs include cervical shoulder fasciitis, nuchal tendinitis, cervical spondylosis, thoracic outlet syndrome, lateral epicondylitis, etc., or pain due to autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, and rheumatoid arthritis. Other diseases that can cause neck pain, back pain, and shoulder pain include neck and shoulder tumors, neuritis, arteriovenous diseases, various infections, and referred pain due to lesions in the chest and abdominal organs.

[0098] As used herein, "chest, abdominal and back pain" refers to pain due to disorders of the thoracic and abdominal viscera, thoracic and abdominal wall tissues, including, but not limited to, intercostal neuralgia, intercostal chondritis, angina pectoris, abdominal pain (acute abdominal visceral pain), and lumbago myofascial syndrome.

[0099] As used herein, "lower back and lower limb pain" refers to pain in the lower back, lumbosacral region, sacroiliac joint, hip joint, buttocks, and lower limb. Lower back and lower limb pain is often not an independent disease, but rather a common feature of various diseases, with diverse clinical manifestations and highly complex causes, often degenerative and traumatic, including, but not limited to, pain associated with lumbar disc herniation, acute lumbar sprain, sciatica, osteoporosis, third lumbar transverse process syndrome, piriformis syndrome, osteoarthritis of the knee, tail pain, and heel pain.

[0100] As used herein, "musculoskeletal pain" includes, but is not limited to, myofascial pain, trauma-induced pain, and chronic regional pain syndromes.

[0101] 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 experience the disease first. Diabetic neuropathy pain can be divided into mononeuropathy, involving one or more focal sites, and generalized polyneuropathy, which may be diffuse and symmetric and generally associated primarily with sensory aspects (Merrit's Textbook of Neurology, 9th Edition, edited by L.P. Rowland, L.P.). Symptoms of diabetic neuropathy may include autonomic nervous system dysfunction, which can cause regulatory disorders involving the heart, smooth muscle, and glands, resulting in hypotension, diarrhea, constipation, and sexual dysfunction. Diabetic neuropathy often develops in stages, initially affecting 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 presenting. In later stages, the pain becomes more intense and frequent, and finally, painless neuropathy occurs when there is no pain sensation in a particular area, and the risk of serious tissue damage is greatly increased because there is no pain that is an indicator of damage.

[0102] 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.

[0103] As used herein, "vascular pain" refers to pain resulting from one or more of the following: first, inadequate perfusion of tissue, resulting in transient or persistent local 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 an aneurysm; fourth, aortic rupture, resulting in a flood of blood, which stimulates 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; and 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 disorders, Raynaud's disease, acrocyanosis, acute venous occlusion, thrombophlebitis, varicose veins, and lymphedema.

[0104] As used herein, "autonomic reflex pain" refers to pain caused by "reflex sympathetic atrophy," which is a severe, spontaneous pain, hypersensitivity to touch and pain after acute and chronic injuries to the body, and can be accompanied by edema and impaired blood circulation, followed by symptoms such as dermal and musculoskeletal dystrophies and atrophy.

[0105] As used herein, "postoperative pain" refers to the body's complex physiological response to tissue damage caused by the disease itself and surgery, which manifests as an unpleasant psychological and behavioral experience.

[0106] As used herein, "arthritic pain" includes, but is not limited to, pain from diseases such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthropathy, gout, pseudogout, infectious arthritis, tendonitis, bursitis, bone injuries, and joint soft tissue inflammation.

[0107] 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.

[0108] As used herein, "nociceptive pain" refers to pain caused by a tissue-damaging process that stimulates nociceptor afferents or pain caused by prolonged excitation of nociceptors. Pain resulting from prolonged excitation of nociceptors can 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.

[0109] This application relates to a therapeutically effective amount of α2 / 3-GABA A The present application provides a pharmaceutical compound comprising a positive allosteric modulator of α2 / 3-GABA for use in the treatment of A While the positive allosteric modulator may be administered in the form of the raw compound, preferably the active ingredient, optionally in the form of a physiologically acceptable salt, is mixed into a pharmaceutical composition along with one or more additives, excipients, carriers, buffers, diluents and / or other conventional pharmaceutical excipients.

[0110] In an optional embodiment, the present application provides 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 pharmaceutically acceptable carriers, and optionally other therapeutic and / or prophylactic ingredients known or used in the art. The carrier must be "acceptable," i.e., compatible with the other ingredients in the formulation and not deleterious to the recipient.

[0111] 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 tablets, filled capsules, powders, and pills), and liquids (especially aqueous or non-aqueous solutions, suspensions, emulsions, and elixirs), as well as 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 the active ingredient corresponding to the required daily dosage range.

[0112] 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 pharmaceutically acceptable salts as the active ingredient.

[0113] For preparing the compounds used in the present application as pharmaceutical compositions, pharmaceutically acceptable carriers can be solid or liquid.Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.Solid carriers can be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

[0114] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active ingredient.

[0115] 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.

[0116] Powders and tablets preferably contain 5% or 10% to about 70% of the active compound. Suitable carriers include 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 the carrier, is surrounded by and bound to the carrier. Similarly, formulations include cachets and lozenges. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0117] To prepare suppositories, a low melting wax such as a fatty acid glyceride or cocoa butter is first melted and stirred to disperse the active ingredient homogeneously, The molten mixture is then poured into suitable sized molds and allowed to cool and solidify.

[0118] 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.

[0119] Liquid preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions.For example, parenteral injection liquid preparations can be prepared as water-polyethylene glycol solutions.

[0120] Thus, the compounds used in this application can be prepared as formulations for parenteral administration (e.g., injection, such as bolus injection or continuous infusion), and may be presented in unit dosage form in ampoules, prefilled syringes, small infusion bags, or multi-dose containers with an added preservative. The compositions may be used in the form of suspensions, solutions, or emulsions in oily or aqueous carriers, and may contain formulation ingredients such as suspending agents, stabilizers, and / or dispersing agents. Furthermore, the active ingredient may be in powder form, obtained by sterilization isolation from sterile solids or by lyophilization of a solution, for reconstitution with a suitable carrier, such as sterile, pyrogen-free water, before use.

[0121] Aqueous solutions suitable for oral administration can be prepared by dissolving the active component in water and adding desired colorants, flavors, stabilizers, and thickening agents.

[0122] Aqueous suspensions suitable for oral administration can be prepared by dispersing the finely divided active ingredient in water containing a viscous substance such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other known suspending agent.

[0123] Also included are solid preparations designed to be converted immediately before 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, etc.

[0124] For topical administration to the epidermis, the compounds of the present application can be prepared into ointments, creams, 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 contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or colorants.

[0125] Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored matrix, typically sucrose and gum arabic or gum tragacanth; pastilles comprising the active ingredient in an inert matrix such as gelatin and glycerol or sucrose and gum arabic; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0126] 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.

[0127] Respiratory administration can also be achieved via an aerosol in which the active ingredient is contained in a pressurized pack with a suitable propellant containing a chlorofluorocarbon (CFC), such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol can also suitably contain a surfactant, such as lecithin. The dosage of the drug can be controlled by a metered valve.

[0128] 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 is capable of readily forming a gel in the nasal cavity. The powder composition may be presented in unit dosage form, for example, in capsules or cartridges (e.g., gelatin capsules or cartridges), or in blister packs from which the powder can be administered by an inhaler.

[0129] In compositions for respiratory administration (including compositions for intranasal use), the compound generally has a small particle size, for example of 5 microns or less. Such a particle size can be obtained using methods known in the art such as micronization.

[0130] When desired, compositions adapted for sustained release of the active ingredient may be employed.

[0131] Pharmaceutical preparations are optionally in unit dose form. In this form, the preparation is subdivided into appropriate unit doses of active ingredients. The unit dose form may be an encapsulated preparation containing an isolated large amount of preparation, such as a tablet, capsule, or 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 an appropriate amount of the capsule, tablet, etc., in any encapsulated form.

[0132] Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

[0133] 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).

[0134] The amount of active ingredient in a unit dosage formulation 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 a capsule of 0.01 to about 100 mg three times a day, and the composition may contain other compatible therapeutic agents as needed.

[0135] For therapeutic use, the compounds used in this application are used at a starting dosage of 0.001 mg / kg to 10 mg / kg of body weight per day. However, such dosages 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 at a dosage lower than the optimum dose of the compound, and this dosage is subsequently increased by small increments to reach the optimum effect, and the total daily dosage can be administered in divided doses throughout the day if necessary for convenience.

[0136] The pharmaceutical composition of the present application can also be used in combination with other drugs for simultaneously treating pain, epilepsy, anxiety, and depression, 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 that is highly safe for specific patient groups, such as the elderly, patients with impaired liver or kidney function, or patients suffering from cardiovascular disease.

[0137] The present application also provides a method for treating or preventing a disease, comprising administering to a patient an effective amount of the above-described compound or composition.

[0138] The present application also provides a method for treating GABA-deficiency by administering to a patient an effective amount of the compound or the composition. A Methods for treating or preventing receptor-related diseases are provided.

[0139] The present application also provides the use of the above compound or composition in the manufacture of a medicament for treating or preventing pain, Alzheimer's disease, multi-infarct dementia or stroke.

[0140] 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, lower back pain, lower back pain, leg 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.

[0141] The present application also provides a method for 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.

[0142] The present application also relates to a method for preparing the imidazopyridazine-substituted benzene ring system compound represented by formula (1) described above, including the following scheme:

[0143] [ka]

[0144] Note: R3 is ethyl or isopropyl, and the experimental procedure is the same.

[0145] Z-1a: 5-chloro-N3-ethylpyridazine-3,4-diamine 3,5-Dichloropyridazin-4-amine (80.5 g, 0.5 mol) and ethylamine ethanol solution (30%, 600 ml) were placed in an autoclave and reacted at 150 °C for 16 hours. After cooling the reaction solution to room temperature, a solid precipitated and was filtered. The cake was washed with dichloromethane (300 ml). The mother liquor was concentrated (without evaporation), and a solid precipitated and filtered again. This process was repeated three times, and all the cakes were collected to obtain the crude product (containing ethylamine hydrochloride). The crude product was added to water and stirred to form a slurry, filtered, and the cake was spin-dried to obtain 65 g (76.5% yield) 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. The crude product was dissolved in dichloromethane and 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 (20 g, 108 mmol), (3-chloro-4-fluorophenyl)boronic acid (19.08 g, 108 mmol), sodium carbonate (24 g, 216 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (9.2 g, 10.8 mmol) were added to 1,4-dioxane / water (160 ml / 40 ml) 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 give the title compound (26 g, 85.7% yield) 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), and 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 give the title compound (12 g, yield: 60%) as a pale yellow solid. 1H 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.

[0146] Beneficial Effects: The compounds of the present invention and pharmaceutically acceptable salts thereof or prodrugs thereof have important pharmacological properties and are effective in inhibiting α2 / 3-GABA receptor agonists. A The compounds of the present application are positive allosteric modulators of the α2 / 3-GABA receptor. A Therefore, the compounds of the present invention and pharmaceutically acceptable salts or prodrugs thereof have excellent affinity for α2 / 3-GABA receptors, positive modulatory activity, and excellent genotoxicity safety and potential for drug discovery. A It can be used alone or in combination with other drugs to treat or prevent diseases associated with DETAILED DESCRIPTION OF THE INVENTION

[0147] The technical solutions of the present application will be described clearly and completely below. Of course, the described examples are only some examples of the present invention, not all examples. Other examples obtained by those skilled in the art based on the examples of the present application without any creative effort are all included in the scope of protection of the present application. Here, the solvent ratios used in the purification steps (e.g., preparative thin-layer chromatography, column chromatography, etc.) in the following examples are volume ratios.

[0148] Example 1

[0149] [ka]

[0150] 1-1:4-Methoxy-2-(methylamino)benzoic acid 2-Amino-4-methoxybenzoic acid (2 g, 12 mmol, 1.0 eq) was dissolved in methanol (20 mL) at 25 °C, and 37% formaldehyde solution (1 mL, 13.2 mmol, 1.1 eq) was added. Sodium cyanoborohydride (791 mg, 12.6 mmol, 1.05 eq) was added in batches with stirring. The mixture was stirred for 2 h. After LCMS detection, the reaction solution was poured into 100 mL of water and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with water and brine, then dried, concentrated, and spin-dried to give the crude product 4-methoxy-2-(methylamino)benzoic acid (2.2 g, 100%). LC-MS: m / z [M+H] + =182.

[0151] 1-2: 5-Bromo-4-methoxy-2-(methylamino)benzoic acid 4-Methoxy-2-(methylamino)benzoic acid (1.5 g, 8.3 mmol, 1.0 eq) was dissolved in acetic acid (20 mL), and a 1.4 M bromoacetic acid solution (6.2 mL, 8.7 mmol, 1.05 eq) prepared in-house was added dropwise, and the mixture was reacted at 25 °C for 3 h. The mixture was poured into 100 mL of water, extracted with ethyl acetate, dried, and spun to give the crude product 5-bromo-4-methoxy-2-(methylamino)benzoic acid (2.05 g, 100%). LC-MS: m / z [M+H] + =261.

[0152] 1-3: (5-bromo-4-methoxy-2-(methylamino)phenyl)methanol 5-Bromo-4-methoxy-2-(methylamino)benzoic acid (2.05 g, 7.7 mmol, 1.0 eq) was dissolved in tetrahydrofuran (40 mL) at 25 °C, and 2 M borane dimethyl sulfide in tetrahydrofuran (20 mL) was added. The mixture was stirred at 65 °C for 16 h. It was poured into 150 mL of water and extracted with ethyl acetate (100 mL x 2). Approximately half of the solvent was removed using a rotary evaporator, and the remaining organic phase was dried over anhydrous sodium sulfate to prepare the product-containing organic phase (200 mL). Upon spin-drying, the product turned blue and was highly unstable. LC-MS: m / z [M+H] + =248.

[0153] 1-4: 5-Bromo-4-methoxy-2-(methylamino)benzaldehyde The crude product (5-bromo-4-methoxy-2-(methylamino)phenyl)methanol (50 mL) was added to dichloromethane (50 mL) at 25°C, followed by Dess-Martin oxidant (CAS: 87413-09-0, 3 g). The mixture was stirred at 25°C for 4 hours. The reaction mixture was filtered, and xylene (50 mL) was added to the filtrate. Low-boiling solvents such as ethyl acetate were removed using a rotary evaporator, followed by drying over anhydrous sodium sulfate. A dry xylene solution containing the product (50 mL, 500 mg crude product, 100%) was obtained. LC-MS: m / z [M+H] + =244.

[0154] 1-5: 3-acetyl-6-bromo-7-methoxy-1-methylquinolin-2(1H)-one The crude product 5-bromo-4-methoxy-2-(methylamino)benzaldehyde (20 mL, content: 200 mg) was added to 2,2,6-trimethyl-4H-1,3-dioxin-4-one (1.13 g, 8 mmol, 10.0 eq) at 25°C. The mixture was stirred at 120°C for 2 hours. After removing the bulk of the xylene by evaporation, the mixture was subjected to column chromatography (dichloromethane:methanol=10:1) to obtain the title crude product (150 mg, 60%). LC-MS: m / z [M+H] + =311.

[0155] 1: 3-acetyl-6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxy-1-methylquinolin-2(1H)-one 3-Acetyl-6-bromo-7-methoxy-1-methylquinolin-2(1H)-one (150 mg, 0.48 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (138 mg, 0.48 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (CAS: 95408-45-0, 32 mg, 0.05 mmol), and cesium carbonate (325 mg, 1.0 mmol) were added to 1,4-dioxane / water (3 mL / 0.3 mL). The reaction was carried out at 100 °C for 2 hours under argon gas protection. The reaction mixture was purified by HPLC and lyophilized to give the title compound (100 mg, 21%).

[0156] 1H NMR (400 MHz, DMSO-d6) 9.59 (s, 1H), 8.89 (s, 1H), 8.52 (dd, J = 9.2, 5.9 Hz, 2H), 8.47 (s, 1H), 8.00 (s, 1H), 7.54 (t, J = 9.0 Hz, 1H), 7.12 (s, 1H), 4.51 (q, J = 7.2 Hz, 2H), 4.00 (s, 3H), 3.77 (s, 3H), 2.63 (s, 3H), 1.56 (t, J = 7.3 Hz, 3H). LC-MS: m / z [M+H] + =474.

[0157] Example 2

[0158] [ka]

[0159] 2-1: (3-fluoro-2-nitrophenyl)methanol Methyl 3-fluoro-2-nitrobenzoate (1 g, 5.02 mmol) and sodium borohydride (570 mg, 15.06 mmol) were added to a tetrahydrofuran / methanol (10 / 10 mL) mixed solvent and stirred at room temperature for 1 hour. The reaction mixture was subjected to column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (800 mg, 93%).

[0160] 2-2: (3-(methylamino)-2-nitrophenyl)methanol (3-Fluoro-2-nitrophenyl)methanol (600 mg, 3.51 mmol) and an alcohol solution of methylamine (5 mL) were stirred in an autoclave at 100° C. overnight. The reaction mixture was subjected to column chromatography (dichloromethane / methanol=20 / 1) to obtain the title compound (500 mg, 78%).

[0161] 2-3: (6-bromo-3-(methylamino)-2-nitrophenyl)methanol (3-(Methylamino)-2-nitrophenyl)methanol (500 mg, 2.74 mmol) and N-bromosuccinimide (439 mg, 2.47 mmol) were added to acetonitrile (20 mL) and stirred at room temperature for 2 hours. The reaction mixture was added to water (150 mL), extracted with ethyl acetate (200 mL x 2), washed once with water, and once with saturated brine. The mixture was then concentrated to give the title compound (600 mg, 84%) as a red solid. LC-MS: m / z [M+H] + =243.

[0162] 2-4: (2-amino-6-bromo-3-(methylamino)phenyl)methanol (6-Bromo-3-(methylamino)-2-nitrophenyl)methanol (600 mg, 2.3 mmol) and Raney nickel (68 mg) were added to methanol (20 ml), and the reaction mixture was stirred at room temperature under a hydrogen gas atmosphere for 2 hours. The reaction mixture was filtered, and the cake was washed twice with methanol. The filtrate was concentrated to give the title compound (500 mg, 94%) as a yellow solid. LC-MS: m / z [M+H] + =231.

[0163] 2-5: (5-bromo-1-methyl-1H-benzo[d]imidazol-4-yl)methanol (2-Amino-6-bromo-3-(methylamino)phenyl)methanol (500 mg, 2.16 mmol) was added to trimethyl orthoformate (10 ml) and stirred at 90° C. overnight. The reaction mixture was directly subjected to thin layer chromatography (petroleum ether / ethyl acetate=1 / 1) to give the title compound (400 mg, 76%) as a yellow oil. LC-MS: m / z [M+H] + =241.

[0164] 2-6: 5-Bromo-4-(methoxymethyl)-1-methyl-1H-benzo[d]imidazole (5-Bromo-1-methyl-1H-benzo[d]imidazol-4-yl)methanol (400 mg, 1.65 mmol) was added to tetrahydrofuran (10 mL), followed by the addition of sodium hydride (119 mg, 4.95 mmol) to the reaction mixture. After stirring at room temperature for 10 minutes, methyl iodide (1171 mg, 8.25 mmol) was added and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (200 mL) was added to the reaction mixture, which was then washed with water (100 mL x 2) and once with saturated brine. The mixture was then dried over anhydrous sodium sulfate and concentrated to give the title compound (240 mg, 57%) as a yellow oil. LC-MS: m / z [M+H] + =255.

[0165] 2: 7-Ethyl-4-(4-fluoro-3-(4-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-4-(methoxymethyl)-1-methyl-1H-benzo[d]imidazole (100 mg, 0.39 mmol) and (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (112 mg, 0.39 mmol) were used as raw materials to obtain the title compound (14 mg, 9%) as a yellow solid.

[0166] 1 H NMR (400 MHz, CHLOROFORM-d) ppm 1.68 (t, J=7.34 Hz, 3 H) 3.33 (s, 3 H) 3.89 (s, 3 H) 4.57 (q, J=7.34 Hz, 2 H) 4.83 (br. s., 2 H) 7.33 - 7.41 (m, 2H) 7.43 - 7.49 (m, 1H) 7.97 (s, 1H) 8.27 (s, 1H) 8.31 (d, J=7.34 Hz, 1H) 8.37 - 8.44 (m, 1H) 9.40 (s, 1H). LC-MS: m / z [M+H] + =417.

[0167] Example 3

[0168] [ka]

[0169] 3-1: (2-nitro-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)methanol (3-Fluoro-2-nitrophenyl)methanol (500 mg, 2.92 mmol) and tetrahydro-2H-pyran-4-amine (570 mg, 5.84 mmol) were added to absolute ethanol (10 ml) and stirred overnight in an autoclave at 100°C. The reaction mixture was directly separated and purified using a preparative plate (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (680 mg, 92%). LC-MS: m / z [M+H] + =253.

[0170] 3-2: (6-bromo-2-nitro-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)methanol The experimental procedure was the same as the synthesis method of 2-3 in Example 2, and the title compound (300 mg, 38%) was obtained using (2-nitro-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)methanol (600 mg, 2.4 mmol) as the raw material. LC-MS: m / z [M+H] + =331, 333.

[0171] 3-3: (2-amino-6-bromo-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)methanol The experimental procedure was the same as the synthesis method of 2-4 in Example 2, and the title compound (220 mg, 82%) was obtained using (6-bromo-2-nitro-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)methanol (300 mg, 0.9 mmol) as the raw material. LC-MS: m / z [M+H] + =301, 303.

[0172] 3-4: (5-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d][1,2,3]triazol-4-yl)methanol (2-Amino-6-bromo-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)methanol (200 mg, 0.67 mol) and sodium nitrite (231 mg, 3.35 mmol) were added to a hydrochloric acid solution (1 M, 8 ml) and stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was separated and purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (150 mg, 72%). LC-MS: m / z [M+H] + =312, 314.

[0173] 3-5: 5-Bromo-4-(methoxymethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d][1,2,3]triazole The experimental procedure was the same as that of Example 2, 2-6, and (5-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d][1,2,3]triazol-4-yl)methanol (150 mg, 0.48 mmol) was used as the raw material to obtain the title compound (140 mg, 90%). LC-MS: m / z [M+H] + =326, 328.

[0174] 3:7-Ethyl-4-(4-fluoro-3-(4-(methoxymethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d][1,2,3]triazol-5)-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and the title compound (65 mg, 61%) was obtained using 5-bromo-4-(methoxymethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d][1,2,3]triazole (70 mg, 0.22 mmol) and (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (75 mg, 0.26 mmol) as raw materials.

[0175] 1 H NMR (400MHz, CHLOROFORM-d) 9.40 (s, 1 H), 8.42 (br. s., 1 H), 8.35 (d, J = 6.8 Hz, 1 H), 8.27 (s, 1 H), 7.65 (d, J = 8.3 Hz, 1 H), 7.55 (d, J = 8.3 Hz, 1 H), 7.40 (t, J = 8.8 Hz, 1 H), 5.06 - 4.89 (m, 3 H), 4.58 (q, J = 7.0 Hz, 2 H), 4.24 (d, J = 9.8 Hz, 2 H), 3.69 (t, J = 11.5 Hz, 2 H), 3.40 (s, 3 H), 2.63 - 2.50 (m, 2 H), 2.17 (d, J = 13.2 Hz, 2 H), 1.72 - 1.67 (m, 3 H). LC-MS: m / z[M+H] + =488.

[0176] Example 4

[0177] [ka]

[0178] 4-1: 3-(5-chloro-4-methoxy-2-nitrophenoxy)propan-1-ol 1-Chloro-5-fluoro-2-methoxy-4-nitrobenzene (1 g, 4.86 mmol), 1,3-propanediol (740 mg, 9.72 mmol), and cesium carbonate (3.17 g, 9.72 mmol) were added to N,N-dimethylformamide (5 mL) and reacted at 120° C. for 3 hours. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride (30 mL), concentrated, and the sample was stirred and subjected to column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the title compound (648 mg, 51%) as a white solid.

[0179] 1H NMR (400MHz, CHLOROFORM-d) d = 7.54 (s, 1 H), 7.20 (s, 1 H), 4.24 (t, J = 5.9 Hz, 2 H), 3.94 - 3.89 (m, 5 H), 2.11 (quin, J = 5.5 Hz, 2 H).

[0180] 4-2: 3-(5-chloro-4-methoxy-2-nitrophenoxy)propionic acid Jones reagent (2.5M, 2 ml) was added to acetone (4 ml), and 3-(5-chloro-4-methoxy-2-nitrophenoxy)propan-1-ol (200 mg, 0.76 mmol) dissolved in acetone (4 ml) was slowly added dropwise to the reaction mixture and stirred at room temperature for 30 minutes. The reaction mixture was poured into water (30 ml) and extracted with dichloromethane (30 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound (178 mg, 84.97%) as a pale yellow solid.

[0181] 1 H NMR (400MHz, CHLOROFORM-d) d = 7.49 (s, 1 H), 7.22 (s, 1 H), 4.36 (t, J = 6.1 Hz, 2 H), 3.93 (s, 3 H), 2.93 (t, J = 6.1 Hz, 2 H).

[0182] 4-3: 8-Chloro-7-methoxy-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 3-(5-Chloro-4-methoxy-2-nitrophenoxy)propionic acid (170 mg, 0.62 mmol) and iron powder (69 mg, 1.24 mmol) were added to acetic acid (3 ml) and stirred at 110°C overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (30 ml) and suction filtered to give the title compound (120 mg, 85%) as a white solid. LC-MS: m / z [M+H] + =228, 230. 4-4: 8-Chloro-7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 8-Chloro-7-methoxy-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (60 mg, 0.26 mmol) was added to tetrahydrofuran (2 ml), sodium hydride (12 mg, 0.40 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes. After that, methyl iodide (55 mg, 0.39 mmol) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was slowly poured into water (30 ml), extracted with dichloromethane (30 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give the title compound (40 mg, 64%) as a gray solid. LC-MS: m / z [M+H] + =242, 244.

[0183] 4: 8-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxy-5-methyl-2,3-dihydrobenzo[b][1.4]oxazepin-4(5H)-one 8-Chloro-7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (30 mg, 0.12 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (34 mg, 0.12 mmol), cesium carbonate (78 mg, 0.24 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (Xphos-Pd-G3, cas: 1445085-55-1, 10 mg, 0.01 mmol) were added to 1,4-dioxane (2 mL). The reaction was carried out under argon gas protection at 100° C. for 2 hours. The reaction solution was subjected to preparative thin-layer chromatography (dichloromethane / methanol=15 / 1) to obtain the title compound (11 mg, 20%) as a brown solid.

[0184] 1H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.28 (s, 3 H), 7.37 - 7.35 (m, 1 H), 7.16 (s, 1 H), 6.80 (s, 1 H), 4.58 (br. s., 2 H), 4.45 (br. s., 2 H), 3.83 (s, 3 H), 3.42 (s, 3 H), 2.73 (s, 2 H), 1.71 - 1.70 (m, 3 H). LC-MS: m / z [M+H] + =448.

[0185] Example 5

[0186] [ka]

[0187] 5-1: Ethyl 3-(3-bromo-4-methoxyphenoxy)propanoate 3-Bromo-4-methoxyphenol (10 g, 49 mmol) was added to ethyl acrylate (70 mL) at 25°C, and a catalytic amount of 4-dimethylaminopyridine (0.5 g) was added, and the solution was stirred at 100°C for 24 hours. After LCMS detection, the ethyl acrylate was removed by rotary evaporation, and then the sample was dissolved in ethyl acetate and stirred. The product was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give the product (7 g, 47%) as an off-white solid. LC-MS: m / z [M+H] + =303.

[0188] 5-2: 3-(3-bromo-4-methoxyphenoxy)propionic acid Ethyl 3-(3-bromo-4-methoxyphenoxy)propanoate (600 mg, 2 mmol) was added to concentrated hydrochloric acid (5 mL), and the mixture was heated to 100° C. and refluxed for 2 hours. The mixture was diluted with water and then extracted with ethyl acetate (2×100 mL). The combined organic phase was washed with water and brine. It was then dried over anhydrous sodium sulfate and concentrated in vacuo. It was then purified by column chromatography (petroleum ether:ethyl acetate=1:2) to give the product (400 mg, 72%) as an off-white solid. LC-MS: m / z [M+H] + =276.

[0189] 5-3: 7-Bromo-6-methoxychroman-4-one 3-(3-Bromo-4-methoxyphenoxy)propionic acid (400 mg, 1.45 mmol) was added to polyphosphoric acid (5 mL) at 25°C, and the mixture was stirred at 80°C for 2 hours. After pouring into 20 mL of water and stirring for 30 minutes, the mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product (500 mg, 100%) as a yellow solid. LC-MS: m / z [M+H] + =257.

[0190] 5-4: (Z)-7-Bromo-6-methoxychroman-4-one oxime 7-Bromo-6-methoxychroman-4-one (500 mg, 1.94 mmol) was dissolved in ethanol (7 mL) at 25°C, and hydroxylamine hydrochloride (404 mg, 5.82 mmol) was added, followed by dropwise addition of 2 M sodium hydroxide solution (5 mL). The mixture was stirred at 25°C for 16 hours. The mixture was poured into water, extracted with ethyl acetate, dried, and spin-dried to give the crude product (240 mg, 45%) as a yellow solid. LC-MS: m / z [M+H] + =273.

[0191] 5-5: 8-Bromo-7-methoxy-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (Z)-7-Bromo-6-methoxychroman-4-one oxime (240 mg, 0.22 mmol) was dissolved in polyphosphoric acid (5 mL) at 25°C, and the mixture was stirred at 100°C for 3 hours. The mixture was poured into water, extracted with ethyl acetate, dried, and spin-dried to obtain the crude product (180 mg, 75%). LC-MS: m / z [M+H] + =273.

[0192] 5-6: 8-Bromo-7-methoxy-4-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one 8-Bromo-7-methoxy-3,4-dihydrobenzo[f][1,4]oxazin-5(2H)-one (180 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (5 mL) at 25°C, and NaH (23 mg, 0.55 mmol) was added in batches. After stirring for 30 minutes, methyl iodide (142 mg, 1 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The mixture was poured into water, extracted with ethyl acetate, dried, and spin-dried to give the crude product (100 mg, 96%) as a yellow solid. LC-MS: m / z [M+H] + =287.

[0193] 5: 8-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxy-4-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one The experimental procedure was the same as in Example 1, and 8-bromo-7-methoxy-4-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (100 mg, 0.35 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (100 mg, 0.35 mmol) were used as raw materials to obtain the title compound (25 mg, 16%) as an off-white solid.

[0194] 1H NMR (400 MHz, DMSO-d6) 9.56 (s, 1H), 8.86 (s, 1H), 8.47 (tt, J = 7.3, 2.3 Hz, 2H), 7.57-7.45 (m, 1H), 7.31 (s, 1H), 7.07 (s, 1H), 4.51 (q, J = 7.3 Hz, 2H), 4.35 (t, J = 5.1 Hz, 2H), 3.78 (s, 3H), 3.59 (t, J = 5.2 Hz, 2H), 3.13 (s, 3H), 1.56 (t, J = 7.3 Hz, 3H). LC-MS: m / z [M+H] + =448.

[0195] Example 6

[0196] [ka]

[0197] 6-1: 2-amino-6-methoxyphenol 2-Nitro-6-methoxyphenol (CAS: 15969-08-1, 900 mg, 5.3 mmol) was dissolved in 10 mL of methanol, Raney nickel (1 g) was added, and the mixture was stirred at room temperature under hydrogen gas protection for 30 minutes. The mixture was filtered and concentrated to give the title compound (600 mg, 80%) as a yellow solid. LC-MS: m / z [M+H] + =140.

[0198] 6-2: 6-amino-3-bromo-2-methoxyphenol 2-Amino-6-methoxyphenol (600 mg, 4.3 mmol) was dissolved in 10 mL of dichloromethane, cooled to 0 °C, and N-bromosuccinimide (613 mg, 3.45 mmol) was added. The mixture was stirred for 30 minutes while maintaining the temperature at 0 °C, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the title compound (110 mg, 12%) as a yellow solid. LC-MS: m / z [M+H] + =218.

[0199] 6-3: 6-Bromo-7-methoxybenzo[d]oxazol-2(3H)-one 6-Amino-3-bromo-2-methoxyphenol (100 mg, 0.46 mmol) was dissolved in 10 mL of tetrahydrofuran, triphosgene (273 mg, 0.92 mmol) was added, the mixture was stirred at room temperature for 2 hours, concentrated, and purified by preparative plate (dichloromethane:methanol=20:1) to give the title compound (100 mg, 89%) as a white solid. LC-MS: m / z [M+H] + =244.

[0200] 6-4: 6-Bromo-7-methoxy-3-methylbenzo[d]oxazol-2(3H)-one 6-Bromo-7-methoxybenzo[d]oxazol-2(3H)-one (100 mg, 0.41 mmol) was added to 10 mL of acetonitrile, and methyl iodide (116 mg, 0.82 mmol) and cesium carbonate (270 mg, 0.82 mmol) were added. The mixture was stirred at room temperature for 2 hours, and the solid was filtered and concentrated to give the title compound (100 mg, 94%) as a yellow solid. LC-MS: m / z [M+H] + =258.

[0201] 6: 6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxy-3-methylbenzo[d]oxazol-2(3H)-one The experimental procedure was the same as in Example 4, 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 (100 mg, 0.35 mmol), 6-bromo-7-methoxy-3-methylbenzo[d]oxazol-2(3H)-one (90 mg, 0.35 mmol) were used as raw materials to obtain the title compound (10 mg, 7%) as a white solid.

[0202] 1H NMR (400 MHz, CHLOROFORM-d) δ9.39 (s, 1 H) 8.26 - 8.37 (m, 3 H) 7.40 (s, 1 H) 7.08 (d, J=8.31 ​​Hz, 1 H) 6.82 (d, J=8.80 Hz, 1 H) 4.60 (d, J=7.34 Hz, 2 H) 4.04 (s, 3 H) 3.16 (s, 3 H) 1.70 (t, J=7.58 Hz, 3 H). LC-MS: m / z [M+H] + =420.

[0203] Example 7

[0204] [ka]

[0205] 7-1: (2-amino-5-bromo-4-methoxyphenyl)methanol Methyl 2-amino-5-bromo-4-methoxybenzoate (500 mg, 1.92 mmol) was added to tetrahydrofuran (10 mL), followed by lithium aluminum hydride (291 mg, 7.68 mmol) and stirring at room temperature for 2 hours. The reaction mixture was directly subjected to thin-layer chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (380 mg, 85%) as a yellow oil. LC-MS: m / z [M+H] + =213.9.

[0206] 7-2: 6-Bromo-7-methoxy-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (2-Amino-5-bromo-4-methoxyphenyl)methanol (380 mg, 1.64 mmol) and bis(trichloromethyl)carbonate (1947 mg, 6.56 mmol) were added to tetrahydrofuran (10 ml) and stirred at room temperature for 2 hours. The reaction mixture was directly concentrated and then purified by thin layer chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (180 mg, 42%) as a yellow solid. LC-MS: m / z [M+H] + =258.

[0207] 7-3: 6-Bromo-7-methoxy-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one 6-Bromo-7-methoxy-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (150 mg, 0.58 mmol), potassium carbonate (80 mg, 0.58 mol), and methyl iodide (247 mg, 1.74 mmol) were added to methanol (5 ml) and stirred at 40° C. overnight. The reaction mixture was directly subjected to thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (150 mg, 95%) as a yellow solid. LC-MS: m / z [M+H] + =272.

[0208] 7: 6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxy-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one 6-Bromo-7-methoxy-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (90 mg, 0.33 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (122 mg, 0.33 mmol), bis(triphenylphosphine)palladium(II) dichloride (23 mg, 0.033 mmol), and sodium carbonate (70 mg, 0.66 mmol) were added to tetrahydrofuran / water (5 mL / 1 mL). The reaction was carried out overnight at 80°C under argon gas protection. The reaction mixture was directly purified by thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (28 mg, 19%) as a yellow solid.

[0209] 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.68 - 1.73 (m, 3 H) 3.47 (s, 3 H) 3.89 (s, 3 H) 4.54 - 4.63 (m, 2 H) 5.22 (s, 2 H) 7.15 (s, 1 H) 7.34 (t, J=9.29Hz, 1 H) 7.64 - 7.72 (m, 1 H) 8.19 (d, J=6.85 Hz, 1 H) 8.28 (s, 2 H) 9.39 (br. s., 1 H). LC-MS: m / z [M+H] + =434.

[0210] Examples 8 and 9

[0211] [ka]

[0212] 8-1: 2-Ethyl-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one Under nitrogen gas protection, 2-amino-4-methoxyphenol (1.9 g, 13.8 mmol) and ethyl 2-bromobutyrate (3 g, 15.2 mmol) were dissolved in 20 mL of N,N-dimethylformamide, followed by the addition of cesium carbonate (9 g, 27.6 mmol) and the reaction mixture was heated at 95°C for 16 hours. After the reaction was complete, the mixture was added to 50 mL of water, extracted with ethyl acetate (50 mL x 3), backwashed with water (30 mL x 3), and the organic phase was spin-dried and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the title compound (1 g, 35%) as a white solid. LC-MS: m / z [M+H] + =208.

[0213] 8-2: 7-Bromo-2-ethyl-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one 2-Ethyl-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (3.4 g, 16.4 mmol) was dissolved in dimethylformamide (40 mL) and N-bromosuccinimide (5.8 g, 32.8 mmol) was added in batches. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was poured into ice water, extracted with ethyl acetate (3 × 50 mL), dried over anhydrous sodium sulfate, and purified by prep-HPLC to give the title product, which was spin-dried to give 7-bromo-2-ethyl-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (2.1 g, 45%) as a yellow solid. LC-MS: m / z [M+1] + =208.

[0214] 8-3: 7-Bromo-2-ethyl-6-methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-2-ethyl-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one 1c (2.1 g, 7.4 mmol) was dissolved in tetrahydrofuran (30 ml) and stirred for 10 minutes. Sodium hydride (596 mg, 14.8 mmol) was added at 0°C, and the mixture was stirred for 20 minutes. After that, methyl iodide (2.1 g, 14.8 mmol) was added. The ice-water bath was removed, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was poured into ice-water (20 ml), extracted with ethyl acetate (3 x 50 ml), dried over anhydrous sodium sulfate, purified by HPLC, and spin-dried to give the title compound (2.0 g, oily liquid, 91% yield). LCMS: m / z [M+1] + =301.

[0215] 8: rel-(S)-2-ethyl-7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 9: rel-(R)-2-ethyl-7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 1. 7-Bromo-2-ethyl-6-methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (2.0 g, 6.7 mmol) and (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (1.9 g, 6.7 mmol) were used as raw materials to obtain the title compound (1.0 g, 33%) as an off-white solid. Further chiral separation gave Example 8 (first peak, 10 mg, white solid) and Example 9 (second peak, 10 mg, white solid).

[0216] Division method: Instrument: MG II preparative SFC (SFC-1); Column: ChiralPak AD, 250×30mm ID, 10 μm; Mobile phase: A for CO2 and B for Isopropanol; Gradient: B 55%; Flow rate: 80 mL / min; Back pressure: 100 bar; Column temperature: 38 °C; Wavelength: 220 nm.

[0217] Example 8: 1 H NMR (400 MHz, DMSO-d6) 9.55 (s, 1H), 8.86 (s, 1H), 8.44 (d, J = 6.0 Hz, 2H), 7.48 (t, J = 9.4 Hz, 1H), 7.05 (s, 1H), 6.92 (s, 1H), 4.51 (d, J = 7.2 Hz, 3H), 3.81 (s, 3H), 3.39 (s, 3H), 1.83 (ddd, J = 21.7, 14.2, 6.8 Hz, 2H), 1.56 (t, J = 7.3 Hz, 3H), 1.01 (s, 3H). LC-MS: m / z [M+1] + =462.

[0218] Example 9: 1 H NMR (400 MHz, DMSO-d6) 9.37 (s, 1H), 8.34-8.24 (m, 2H), 8.19 (dd, J = 6.9, 2.1 Hz, 1H), 7.33 (t, J = 9.0 Hz, 1H), 7.05 (s, 1H), 6.62 (s, 1H), 4.58 (q, J = 7.3 Hz, 2H), 4.48 (dd, J = 8.5, 4.4 Hz, 1H), 3.83 (s, 3H), 3.43 (s, 3H), 2.11-1.83 (m, 3H), 1.69 (t, J = 7.3 Hz, 4H), 1.09 (t, J = 7.4 Hz, 3H). LC-MS: m / z [M+1] + =462.

[0219] Example 10

[0220] [ka]

[0221] 10-1: Ethyl 5-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-1H-pyrazole-4-carboxylate The experimental procedure was the same as in Example 1, and the title compound (200 mg, yield: 47%) was obtained as a yellow solid using methyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate (300 mg, 1.37 mmol) and 4-chloro-2-fluoro-5-methoxyphenyl)boronic acid (279 mg, 1.37 mmol). LC-MS: m / z [M+1] + =313.

[0222] 10-2: (5-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)methanol Ethyl 5-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-1H-pyrazole-4-carboxylate (400 mg, 1.28 mmol) was dissolved in tetrahydrofuran (40 ml) and cooled to 0°C. Lithium borohydride (84 mg, 3.84 mmol) was added. The reaction mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water (20 ml), extracted with ethyl acetate (3 x 50 ml), dried over anhydrous sodium sulfate, purified by HPLC, and spin-dried to give the title compound (150 mg, 43%) as an oily liquid. LC-MS: m / z [M+1] + =272.

[0223] 10-3: 7-Chloro-8-methoxy-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole (5-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)methanol (200 mg, 0.74 mmol) was dissolved in dimethyl sulfoxide (10 ml), potassium carbonate (200 mg) was added, and the mixture was heated to 165°C and reacted for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water (20 ml), extracted with ethyl acetate (3 x 50 ml), dried over anhydrous sodium sulfate, purified by HPLC, and spin-dried to obtain the title compound (75 mg, oily liquid, yield: 40%). LC-MS: m / z [M+1] + =251.

[0224] 10:7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-8-methoxy-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole The experimental procedure was the same as in Example 1, and 7-chloro-8-methoxy-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole (20.0 mg, 0.08 mmol) and (5-(7-isopropyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (23 mg, 0.08 mmol) were used as raw materials to obtain the title compound (8 mg, 22%) as an off-white solid.

[0225] 1 H NMR (400 MHz, CDCl3) 9.39 (s, 1H), 8.29 (s, 2H), 8.24-8.17 (m, 1H), 7.35 (t, J = 9.0 Hz, 2H), 7.17 (s, 1H), 7.10 (s, 1H), 5.22 (s, 2H), 4.58 (q, J = 7.2 Hz, 2H), 4.22 (s, 3H), 3.86 (s, 3H), 1.69 (t, J = 7.3 Hz, 3H). LC-MS: m / z [M+1] + = 457.

[0226] Example 11

[0227] [ka]

[0228] 11-1: (3-(ethylamino)-2-nitrophenyl)methanol (3-Fluoro-2-nitrophenyl)methanol (1000 mg, 5.84 mmol) and aqueous ethylamine solution (50%, 4 ml) were added to ethanol (10 ml), and the tube was sealed and stirred overnight at 100°C. The reaction mixture was directly subjected to column chromatography (dichloromethane / methanol = 30 / 1) to give the title compound (1100 mg, 96%) as a red solid. LC-MS: m / z [M+H] + =197.

[0229] 11-2: (6-bromo-3-(ethylamino)-2-nitrophenyl)methanol The experimental procedure was the same as in Example 2, 2-3, and (3-(ethylamino)-2-nitrophenyl)methanol (1100 mg, 5.61 mmol) was used as the raw material to obtain the title compound (1500 mg, 97%) as a red solid. LC-MS: m / z [M+H] + =275.

[0230] 11-3: (2-amino-6-bromo-3-(ethylamino)phenyl)methanol The experimental procedure was the same as that of Example 2, 2-4, and the title compound (1300 mg, 97%) was obtained as a yellow solid using (6-bromo-3-(ethylamino)-2-nitrophenyl)methanol (1500 mg, 5.47 mmol). LC-MS: m / z [M+H] + =245.

[0231] 11-4: (5-bromo-1-ethyl-1H-benzo[d][1,2,3]triazol-4-yl)methanol The experimental procedure was the same as that of Example 3, 3-4, and (2-amino-6-bromo-3-(ethylamino)phenyl)methanol (1300 mg, 5.3 mmol) was used as the raw material to obtain the title compound (1100 mg, 81%) as a brown solid. LC-MS: m / z [M+H] + =256.

[0232] 11-5: 5-Bromo-1-ethyl-4-(methoxymethyl)-1H-benzo[d][1,2,3]triazole The experimental procedure was the same as that of Example 2, 2-6, and (5-bromo-1-ethyl-1H-benzo[d][1,2,3]triazol-4-yl)methanol (1100 mg, 4.3 mmol) was used as the raw material to obtain the title compound (1100 mg, 95%) as a yellow oil. LC-MS: m / z [M+H] + =270.

[0233] 11: 7-Ethyl-4-(3-(1-ethyl-4-(methoxymethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-1-ethyl-4-(methoxymethyl)-1H-benzo[d][1,2,3]triazole (1100 mg, 4.07 mmol) and (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (932 mg, 3.26 mmol) were used as raw materials to obtain the title compound (545 mg, 31%) as a white solid.

[0234] 1 H NMR (400 MHz, DMSO-d6) 1.54 (s, 6 H) 3.12 (s, 3 H) 4.46 - 4.54 (m, 2 H) 4.76 - 4.85 (m, 4 H) 7.55 - 7.62 (m, 2 H) 7.96 - 8.00 (m, 1 H) 8.52 -8.59 (m, 2 H) 8.83 - 8.86 (m, 1 H) 9.53 - 9.56 (m, 1 H). LC-MS: m / z [M+H] + =432.2.

[0235] Example 12

[0236] [ka]

[0237] 12-1: 6-Methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one 2-Amino-4-methoxyphenol (10,000 mg, 71.68 mmol), potassium carbonate (19,860 mg, 147.72 mmol), and chloroacetyl chloride (8,120 mg, 71.68 mmol) were added sequentially to acetonitrile (80 mL) and stirred at 90°C for 16 hours. The reaction mixture was added to water (200 mL), and the precipitated solid was filtered and then concentrated to give the title compound (12,000 mg, 93%) as a purple solid. LC-MS: m / z [M+H] + =259, 261.

[0238] 12-2: 7-Bromo-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one 6-Methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (12,000 mg, 66.98 mmol) and a hydrobromic acid-acetic acid solution (33 wt%) (24,633 mg, 100.47 mmol) were added sequentially to acetic acid (80 mL) and stirred at room temperature for 0.5 hours. Hydrogen peroxide (2,278 mg, 66.98 mmol) was then added and stirred at room temperature for 2 hours. Water (200 mL) was added to the reaction mixture, and the precipitated solid was filtered and concentrated to give the title compound (10,000 mg, 46%) as a purple solid. LC-MS: m / z [M+H] + =259,261.

[0239] 12-3: 7-Bromo-6-methoxy-2H-benzo[b][1,4]oxazine-3(4H)-thione Under nitrogen gas protection, phosphorus pentasulfide (947.3 mg, 4.26 mmol), potassium carbonate (802.9 mg, 5.81 mmol), and TEBA (44.1 mg, 0.19 mmol) were suspended in 1,2-dichloroethane (40 mL) and stirred at 100 °C for 2 hours. The mixture was cooled to approximately 40 °C, and 7-bromo-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (1.0 g, 3.87 mmol) was added to the reaction mixture and reacted at 100 °C for 15 minutes. The mixture was filtered at high temperature, and the cake was washed three times with dichloromethane. The filtrate was concentrated and purified by column chromatography (dichloromethane / ethyl acetate = 3 / 1) to give the title product (0.51 g, 48%) as a yellow solid. LC-MS: m / z [M+H] + =275.

[0240] 12-4: (Z)-7-Bromo-3-hydrazino-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine Under nitrogen gas protection, 7-bromo-6-methoxy-2H-benzo[b][1,4]oxazine-3(4H)-thione (470 mg, 1.7 mmol) was dissolved in 20 mL of ethanol, and hydrazine hydrate (103 mg, 2.1 mmol) was added. The mixture was allowed to react at room temperature for 2 hours. Water (100 mL) was added, and the mixture was stirred for 30 minutes. The mixture was then filtered. The cake was washed three times with water and dried under vacuum to obtain the title product (290 mg, brown solid) in a 62% yield. LC-MS: m / z [M+H] + =273.

[0241] 12-5: 7-Bromo-8-methoxy-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazine Under nitrogen gas protection, (Z)-7-bromo-3-hydrazino-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine (290 mg, 1.07 mmol) was suspended in 12 mL of trimethyl orthoformate and stirred at 125°C for 2 hours. The mixture was then purified by column chromatography (dichloromethane / ethyl acetate = 3 / 1) to give the title product (202 mg, 67%) as a white solid. LC-MS: m / z [M+H] + =283.

[0242] 12:7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-8-methoxy-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazine The experimental procedure was the same as in Example 1, and 7-bromo-8-methoxy-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazine (100.0 mg, 0.35 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 (100.1 mg, 0.35 mmol) were used as raw materials to obtain the title compound (23 mg, 15%) as an off-white solid.

[0243] 1H NMR (400 MHz, DMSO-d6) 9.57 (s, 1H), 9.47 (s, 1H), 8.87 (s, 1H), 8.47 (d, J = 6.7 Hz, 2H), 7.72 (s, 1H), 7.51 (t, J = 9.5 Hz, 1H), 7.27 (s, 1H), 5.50 (s, 2H), 4.51 (dd, J = 14.5, 7.3 Hz, 2H), 3.85 (s, 3H), 1.56 (t, J = 7.2 Hz, 3H). LC-MS: m / z [M+H] + =444.

[0244] Example 13

[0245] [ka]

[0246] 13-1: 5-Methoxybenzo[d]oxazol-2(3H)-one 2-Amino-4-methoxyphenol (5.01 g, 35.93 mmol) was dissolved in anhydrous dichloromethane (100 mL), N,N-carbonyldiimidazole (6.41 g, 39.53 mmol) was added in batches, and the mixture was stirred at room temperature for 16 hours. After quenching with water (100 mL), the layers were separated, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (100 mL x 3). After spin-drying, a crude product was obtained. After purification by column chromatography (dichloromethane:ethyl acetate), the title product (4.51 g, brown solid) was obtained in 76% yield. LC-MS: m / z [M+H] + =166.

[0247] 13-2: 6-Bromo-5-methoxybenzo[d]oxazol-2(3H)-one 5-Methoxybenzo[d]oxazol-2(3H)-one (1 g, 6.06 mmol) and a solution of hydrobromic acid in acetic acid (33%, 3.71 g, 15.1 mmol) were dissolved in acetic acid (8 mL), and hydrogen peroxide (30%, 0.895 g, 7.88 mmol) was added dropwise at 0°C, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, and a pink solid precipitated. The solid was filtered and concentrated to give the title compound (500 mg, 34%). 1 H NMR (400 MHz, DMSO-d6) 11.78 (s, 1H), 7.59 (s, 1H), 6.86 (s, 1H), 3.84 (s, 3H). LC-MS: m / z [M+H] + =244, 244.

[0248] 13-3: 6-Bromo-5-methoxy-3-(2-(pyrrolidin-1-yl)ethyl)benzo[d]oxazol-2(3H)-one 6-Bromo-5-methoxybenzo[d]oxazol-2(3H)-one (100 mg, 0.41 mmol), potassium carbonate (170 mg, 1.23 mmol), and 1-(2-chloroethyl)pyrrolidine hydrochloride (104.6 mmol, 0.61 mmol) were dissolved in dimethyl sulfoxide (4 mL) and stirred at 80 °C overnight. The reaction mixture was extracted three times with ethyl acetate and water, and the organic phase was concentrated and purified by thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (70 mg, 50%). LC-MS: m / z [M+H] + =341, 343.

[0249] 13: 6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxy-3-(2-(pyrrolidin-1-yl)ethyl)benzo[d]oxazol-2(3H)-one The experimental procedure was the same as in Example 1, and the title compound (30 mg, 33%) was obtained using 6-bromo-5-methoxy-3-(2-(pyrrolidin-1-yl)ethyl)benzo[d]oxazol-2(3H)-one (68 mg, 0.2 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 (75 mg, 0.2 mmol).

[0250] 1 H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.30 - 8.17 (m, 3 H), 7.34 (t, J = 9.0 Hz, 1 H), 7.23 (s, 1 H), 7.00 (br. s., 1 H), 4.58 (q, J = 7.2 Hz, 2 H), 4.17 (br. s., 2 H), 3.87 (s, 3 H), 3.08 (br. s., 2 H), 2.85 (br. s., 4 H), 1.92 (br. s., 4 H), 1.72 - 1.68 (m, 3 H). LC-MS: m / z[M+H] + =448.

[0251] Example 14

[0252] [ka]

[0253] 14-1: 5-((2-bromo-5-chloro-4-methoxyphenoxy)methyl)pyrrolidin-2-one 1-Bromo-4-chloro-2-fluoro-5-methoxybenzene (500 mg, 2.0 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (4 mL) at 25 °C, and 5-(hydroxymethyl)pyrrolidin-2-one (350 mg, 3.0 mmol, 1.5 eq) was added. Cesium carbonate (500 mg, 1.5 mmol, 0.77 eq) was then added. After purging the gas, the mixture was heated in a microwave oven at 100 °C for 2 hours. LCMS detection was performed, and the solution was filtered and purified by reverse-phase HPLC. Lyophilization afforded 5-((2-bromo-5-chloro-4-methoxyphenoxy)methyl)pyrrolidin-2-one (200 mg, 30%). LC-MS: m / z [M+H] + =334.

[0254] 14-2: 7-Chloro-8-methoxy-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-one 5-((2-Bromo-5-chloro-4-methoxyphenoxy)methyl)pyrrolidin-2-one (150 mg, 0.45 mmol, 1.0 eq) was dissolved in toluene (3 mL), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (150 mg, 0.24 mmol, 0.5 eq) was added, followed by cesium carbonate (300 mg, 0.92 mmol, 2.0 eq) and palladium acetate (60 mg, 0.2 mmol, 0.45 eq). After purging with nitrogen gas, the mixture was microwaved at 100°C for 1.5 hours. After LCMS detection, the reaction was filtered and then purified by reverse phase HPLC and lyophilized to give 7-chloro-8-methoxy-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-one (70 mg, 61%). LC-MS: m / z [M+H] + =254.

[0255] 14: 7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-8-methoxy-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-one The experimental procedure was the same as in Example 1, and the title compound (10 mg, 11%) was obtained using 7-chloro-8-methoxy-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-one (50 mg, 0.2 mmol) and (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (112 mg, 0.4 mmol).

[0256] 1 H NMR (400 MHz, DMSO-d6) 9.54 (s, 1H), 8.86 (s, 1H), 8.43 (t, J = 6.4 Hz, 2H), 8.29 (s, 1H), 7.47 (t, J = 9.3 Hz, 1H), 6.98 (s, 1H), 4.52 (dt, J = 14.7, 5.2 Hz, 3H), 4.06 (d, J = 9.5 Hz, 1H), 3.77 (t, J = 10.3 Hz, 1H), 3.70 (s, 3H), 2.77-2.57 (m, 1H), 2.44-2.31 (m, 1H), 2.24 (t, J = 13.7 Hz, 1H), 1.79-1.62 (m, 1H), 1.55 (t, J = 7.2 Hz, 3H). LC-MS: m / z [M+H] + =460.

[0257] Example 15

[0258] [ka]

[0259] 15-1: 6-Methoxy-4-(2-(2-oxopyrrolidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one 6-Methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 1.12 mmol), cesium carbonate (730 mg, 2.24 mmol), and 11-(2-chloroethyl)pyrrolidin-2-one (248 mg, 1.68 mmol) were added to acetonitrile (8 mL) and stirred overnight at 60 °C. The reaction mixture was concentrated and separated and purified using a preparative plate (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (220 mg, 38%).

[0260] 15-2: 7-Bromo-6-methoxy-4-(2-(2-oxopyrrolidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one 6-Methoxy-4-(2-(2-oxopyrrolidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.69 mmol), HBr (0.3 mL), and hydrogen peroxide (0.1 mL) were added to acetic acid (10 mL) and stirred at room temperature for 1 hour. A large amount of water was added to the reaction mixture, and the product precipitated from the reaction mixture. The reaction mixture was filtered and concentrated to give the title compound (140 mg, 55%).

[0261] 15: 7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-4-(2-(2-oxopyrrolidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 1, and 7-bromo-6-methoxy-4-(2-(2-oxopyrrolidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (130 mg, 0.17 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 (130 mg, 0.35 mmol) were used as raw materials to obtain the title compound (100 mg, 54%).

[0262] 1H NMR (CHLOROFORM-d, 400MHz) 9.36 (s, 1 H), 8.23 ​​- 8.29 (m, 2 H), 8.19 (d, J=5.9 Hz, 1 H), 7.33 (t, J=8.8 Hz, 1 H), 7.14 (s, 1 H), 7.04 (s, 1 H), 4.61 (s, 2 H), 4.55 - 4.60 (m, 2 H), 4.16 (t, J=7.1 Hz, 2 H), 3.92 (s, 3 H), 3.59 (t, J=7.1 Hz, 2 H), 3.50 (t, J=7.1 Hz, 2 H), 2.36 (t, J=8.1 Hz, 2 H), 1.99 - 2.06 (m, 2H), 1.68 - 1.72 ppm (m, 3H). LC-MS: m / z[M+H] + =531.

[0263] Example 16

[0264] [ka]

[0265] 16-1: (5-bromo-1-methyl-1H-benzo[d][1,2,3]triazol-4-yl)methanol The experimental procedure was the same as the synthesis method of 3-4 in Example 3, and the title compound (170 mg, 81%) was obtained using (2-amino-6-bromo-3-(methylamino)phenyl)methanol (200 mg, 0.87 mol) as the raw material.

[0266] 16-2: 5-Bromo-4-(methoxymethyl)-1-methyl-1H-benzo[d][1,2,3]triazole The experimental procedure was the same as the synthesis method of 2-6 in Example 2, and the title compound (140 mg, 88%) was obtained using (5-bromo-1-methyl-1H-benzo[d][1,2,3]triazol-4-yl)methanol (150 mg, 0.69 mmol) as the raw material.

[0267] 16:7-Ethyl-4-(4-fluoro-3-(4-(methoxymethyl)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-4-(methoxymethyl)-1-methyl-1H-benzo[d][1,2,3]triazole (101 mg, 0.4 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 (120 mg, 0.33 mmol) were used as raw materials to obtain the title compound (80 mg, 58%).

[0268] 1 H NMR (400MHz, CHLOROFORM-d) 9.41 (s, 1 H), 8.45 - 8.39 (m, 1 H), 8.35 (d, J = 5.9 Hz, 1 H), 8.28 (s, 1 H), 7.57 (s, 2 H), 7.40 (t, J = 9.0 Hz, 1 H), 4.95 (br. s., 2 H), 4.58 (q, J = 7.0 Hz, 2 H), 4.36 (s, 3 H), 3.38 (s, 3 H), 1.72 - 1.67 (m, 3 H). LC-MS: m / z[M+H] + =418.

[0269] Example 17

[0270] [ka]

[0271] 17-1: 7-Bromo-6-methoxy-4-(2-(pyrrolidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.77 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (262 mg, 1.54 mmol), and cesium carbonate (753 mg, 2.31 mmol) were added to acetonitrile (10 mL) and stirred at 80°C for 0.5 hours. 2-Bromo-N,N-dimethylethylamine hydrochloride (360 mg, 1.54 mmol) was then added and stirred at room temperature for 2 hours. The reaction mixture was filtered, concentrated, and separated by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give the title compound (110 mg, 40%). LC-MS: m / z [M+H] + =356, 358.

[0272] 17: 7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-4-(2-(pyrrolidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 1, and 7-bromo-6-methoxy-4-(2-(pyrrolidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.28 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 (100 mg, 0.28 mmol) was used as raw materials to obtain the title compound (46 mg, 32%).

[0273] 1H NMR (400MHz, CHLOROFORM-d) 9.35 (s, 1 H), 8.31 - 8.21 (m, 2 H), 8.19 (d, J = 6.4 Hz, 1 H), 7.32 (t, J = 8.8 Hz, 1 H), 7.05 (d, J = 6.4 Hz, 2 H), 4.62 - 4.53 (m, 4 H), 4.43 (br. s., 2 H), 3.93 (s, 3 H), 3.10 (br. s., 6 H), 2.03 (br. s., 4 H), 1.68 (t, J = 7.1 Hz, 3 H). LC-MS: m / z [M+H] + =517.

[0274] Example 18

[0275] [ka]

[0276] 18-1: 7-Bromo-6-methoxy-4-(2-morpholinethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.77 mmol), cesium carbonate (752.6 mg, 2.31 mmol), and 4-(2-chloroethyl)morpholine (172.8 mg, 1.16 mmol) were added to acetonitrile (6 mL) and stirred overnight at 60 °C. The reaction mixture was directly separated and purified using a preparative plate (dichloromethane / methanol = 20 / 1) to give the title compound (190 mg, 66%).

[0277] 18:7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-4-(2-morpholinethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 7, and 7-bromo-6-methoxy-4-(2-morpholinethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (80 mg, 0.22 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 (100 mg, 0.27 mmol) were used as raw materials to obtain the title compound (35 mg, 24%).

[0278] 1 HNMR (400MHz, CHLOROFORM-d) 9.36(s, 1H), 8.28(s, 2H), 8.19(d, J=6.8Hz, 1H), 7.34(t, J=8.8Hz, 1H), 7.05(s, 1H), 6.78(s, 1H), 4.61(s, 2H), 4.60-4.55(m, 2H), 4.13(t, J=6.8Hz, 2H), 3.82(s, 3H), 3.73(br.s., 4H), 2.68 (t, J=6.8Hz, 2H), 2.59(br.s., 4H), 1.69(s, 3H). LC-MS: m / z[M+H] + =533.

[0279] Example 19

[0280] [ka]

[0281] 19-1: 7-Bromo-4-(2,2-difluoroethyl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.39 mmol), cesium carbonate (381 mg, 1.17 mmol), and 2,2-difluoroethyl trifluoromethanesulfonate (36 mg, 0.09 mmol) were added to acetonitrile (6 mL) and stirred overnight at 60 °C. The reaction mixture was directly separated and purified using a preparative plate (dichloromethane / methanol = 20 / 1) to give the title compound (90 mg, 72%).

[0282] 19: 4-(2,2-difluoroethyl)-7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 1, and 7-bromo-4-(2,2-difluoroethyl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (92 mg, 0.29 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 (90 mg, 0.24 mmol) were used as raw materials to obtain the title compound (70 mg, 63%).

[0283] 1 H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.28 (s, 2 H), 8.19 (d, J = 6.8 Hz, 1 H), 7.34 (t, J = 9.0 Hz, 1 H), 7.08 (s, 1 H), 6.79 (s, 1 H), 6.31 - 5.98 (m, 1 H), 4.66 (s, 2 H), 4.58 (q, J = 7.3 Hz, 2 H), 4.37 - 4.27 (m, 2 H), 3.83 (s, 3 H), 1.69 (t, J = 7.3 Hz, 3 H). LC-MS: m / z[M+H] + =484.

[0284] Example 20

[0285] [ka]

[0286] 20-1: 4-((4-methoxybenzyl)oxy)-3-nitrobenzaldehyde 4-Hydroxy-3-nitrobenzaldehyde (5.0 g, 29.92 mmol), 1-(chloromethyl)-4-methoxybenzene (7.03 g, 44.88 mmol), and cesium carbonate (19.50 g, 59.84 mmol) were added to N,N-dimethylformamide (100 mL) and stirred at 65° C. for 16 hours. The reaction mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL × 3), washed with 5% lithium chloride and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (7.0 g, yellow oil, yield: 81%).

[0287] 1 H NMR (400 MHz, DMSO-d6) 9.94 (s, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.18 (dd, J = 8.7, 2.1 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.45-7.37 (m, 2H), 7.01-6.95 (m, 2H), 5.35 (s, 2H), 3.76 (s, 3H).

[0288] 20-2: (4-((4-methoxybenzyl)oxy)-3-nitrophenyl)methanol 4-((4-Methoxybenzyl)oxy)-3-nitrobenzaldehyde (7.0 g, 24.37 mmol) was dissolved in methanol (150 mL), and sodium borohydride (4.63 g, 121.84 mmol) was added slowly at room temperature. The mixture was stirred at room temperature for 16 hours, poured into water (200 mL), extracted with ethyl acetate (100 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (7.0 g, yellow oil, yield: 99%).

[0289] 1 H NMR (400 MHz, CDCl3) 7.84 (d, J = 2.1 Hz, 1H), 7.49 (dd, J = 8.6, 2.1 Hz, 1H), 7.37 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 8.6 Hz, 1H), 6.93-6.89 (m, 2H), 5.17 (s, 2H), 4.67 (s, 2H), 3.81 (s, 3H).

[0290] 20-3: 1-((4-methoxybenzyl)oxy)-4-(methoxymethyl)-2-nitrobenzene (4-((4-Methoxybenzyl)oxy)-3-nitrophenyl)methanol (6.7 g, 23.16 mmol) and methyl iodide (2.2 mL, 34.74 mmol) were dissolved in anhydrous N,N-dimethylformamide (134 mL), and 60% sodium hydride (1.39 g, 34.74 mmol) was slowly added under nitrogen gas. The mixture was stirred at room temperature for 16 hours, poured into saturated ammonium chloride (200 mL), extracted with ethyl acetate (100 mL × 3), washed with 5% lithium chloride and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (6.8 g, yellow oil, yield: 97.1%).

[0291] 1 H NMR (400 MHz, CDCl3) 7.82 (d, J = 2.1 Hz, 1H), 7.46 (dd, J = 8.6, 2.2 Hz, 1H), 7.37 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.6 Hz, 1H), 6.93-6.90 (m, 2H), 5.17 (s, 2H), 4.41 (s, 2H), 3.81 (s, 3H), 3.39 (s, 3H).

[0292] 20-4: 4-(methoxymethyl)-2-nitrophenol 1-((4-Methoxybenzyl)oxy)-4-(methoxymethyl)-2-nitrobenzene (7.0 g, 23.08 mmol) was dissolved in dichloromethane (100 mL), trifluoroacetic acid (10.0 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 mL), extracted with dichloromethane (100 mL × 3), washed with 10% potassium carbonate (50 mL × 5), and the aqueous phase was collected. The aqueous phase was washed with ethyl acetate (50 mL × 3), adjusted to pH = 1 with concentrated hydrochloric acid, extracted with ethyl acetate (100 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (3.4 g, yellow oil, yield: 81%).

[0293] 1 H NMR (400 MHz, CDCl3) 10.50 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.6, 2.1 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 4.36 (s, 2H), 3.34 (s, 3H).

[0294] 20-5: 2-amino-4-(methoxymethyl)phenol 4-(Methoxymethyl)-2-nitrophenol (3.5 g, 19.10 mmol) was dissolved in ethanol (70 mL), platinum dioxide (350 mg) was added, and the reaction was stirred at room temperature under a hydrogen gas atmosphere (1 atm) for 16 hours, filtered, and the filtrate was concentrated to give the title compound (2.1 g, brown solid, yield: 72%).

[0295] 20-6: 5-(Methoxymethyl)benzo[d]oxazol-2(3H)-one 2-Amino-4-(methoxymethyl)phenol (2.1 g, 13.71 mmol) was dissolved in anhydrous dichloromethane (100 mL), N,N'-carbonyldiimidazole (2.45 g, 15.08 mmol) was added in batches, and the mixture was stirred at room temperature for 16 hours. After quenching with water (100 mL), the layers were separated, the organic phase was collected, and the aqueous phase was further extracted with dichloromethane (100 mL x 3). After spin-drying, a crude product was obtained. After purification by normal phase (dichloromethane:ethyl acetate), the title product (1.7 g, brown solid) was obtained in 69% yield. 1 H NMR (400 MHz, DMSO-d6) 7.23 (d, 1H), 7.01 (m, 2H), 4.40 (s, 2H), 3.27 (s, 3H).LCMS: m / z[M+1] + = 180.0 . 20-7: 6-Bromo-5-(methoxymethyl)benzo[d]oxazol-2(3H)-one 5-(Methoxymethyl)benzo[d]oxazol-2(3H)-one (500 mg, 2.79 mmol) was dissolved in glacial acetic acid (12.5 mL), (33%) hydrobromic acid / acetic acid (1.72 g, 6.98 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 10°C, and (30%) hydrogen peroxide (284.6 mg, 2.51 mmol) was slowly added dropwise. The temperature was controlled below 10°C, and the mixture was reacted at 10°C to room temperature for 2 hours. The reaction mixture was poured into 100 mL of water, extracted with ethyl acetate (50 mL x 3), concentrated, and purified by prep-HPLC (0.5% HCOOH ~ acetonitrile) to give the title compound (415.0 mg, white solid, yield: 57.6%).

[0296] 1 H NMR (400 MHz, DMSO-d6) 11.82 (s, 1H), 7.63 (s, 1H), 7.15 (s, 1H), 4.43 (s, 2H), 3.36 (s, 3H).

[0297] 20-8: 6-Bromo-5-(methoxymethyl)-3-methylbenzo[d]oxazol-2(3H)-one 6-Bromo-5-(methoxymethyl)benzo[d]oxazol-2(3H)-one (431 mg, 1.67 mmol) was suspended in dimethyl sulfoxide (10.0 mL), methyl iodide (3.1 mL, 50.1 mmol) and potassium carbonate (461.1 mg, 3.34 mmol) were added at room temperature, and the mixture was allowed to react at room temperature for 16 hours. After quenching with water (100 mL), the mixture was extracted with ethyl acetate (50 mL x 3), washed once with saturated brine (50 mL), and spin-dried to obtain a crude product. After purification by HPLC, the title product (267.7 mg, white solid) was obtained in 59% yield.

[0298] 1 H NMR (400 MHz, DMSO-d6) 7.68 (s, 1H), 7.34 (s, 1H), 4.47 (s, 2H), 3.39 (s, 3H), 3.34 (s, 3H).

[0299] 20: 6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-(methoxymethyl)-3-methylbenzo[d]oxazol-2(3H)-one The experimental procedure was the same as in Example 1, and 6-bromo-5-(methoxymethyl)-3-methylbenzo[d]oxazol-2(3H)-one (100.0 mg, 0.37 mmol), (2-fluoro-5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)phenyl)boronic acid (105.1 mg, 0.37 mmol) were used as raw materials to obtain the title compound (82 mg, white solid), with a yield of 52%.

[0300] 1H NMR (400 MHz, DMSO-d6) 9.57 (s, 1H), 8.87 (s, 1H), 8.53 (m, 1H), 8.46 (m, 1H), 7.56 (t, 1H), 7.40 (m, 2H), 4.51 (q, J = 7.3 Hz, 2H), 4.33 (s, 2H), 3.41 (s, 3H), 3.19 (s, 3H), 1.56 (t, J = 7.3 Hz, 3H). LCMS: m / z [M+1] + =434.

[0301] Example 21

[0302] [ka]

[0303] 21-1: 7-Bromo-6-methoxy-4-(3-(4-methylpiperazin-1-yl)propyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one 7-Bromo-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.77 mmol), 1-(3-chloropropyl)-4-methylpiperazine hydrochloride (380 mg, 1.54 mmol), and cesium carbonate (750 mg, 2.31 mmol) were added sequentially to acetonitrile (5 mL) and stirred at 80°C for 2 hours. The reaction mixture was filtered, concentrated, and separated by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give the title compound (200 mg, 65%). LC-MS: m / z [M+H] + =399,401.

[0304] 21: 7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-4-(3-(4-methylpiperazin-1-yl)propyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one The experimental procedure was the same as in Example 7, and 7-bromo-4-(2-(dimethylamino)ethyl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (150 mg, 0.38 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 (140 mg, 0.38 mmol) was used as raw materials to obtain the title compound (120 mg, 56%).

[0305] 1 H NMR (400MHz ,CHLOROFORM-d) 9.36 (s, 1 H), 8.29 (s, 1 H), 8.28 - 8.22 (m, 1 H), 8.19 (d, J = 5.4 Hz, 1 H), 7.33 (t, J = 9.0 Hz, 1 H), 7.04 (s, 1 H), 6.70 (s, 1 H), 4.62 - 4.54 (m, 4 H), 4.06 (t, J = 7.1 Hz, 2 H), 3.81 (s, 3 H), 2.60 (br. s., 8 H), 2.51 (t, J = 6.8 Hz, 2 H), 2.38 (s, 3 H), 1.98 - 1.89 (m, 2 H), 1.69 (t, J = 7.3 Hz, 3H). LC-MS: m / z [M+H] + =560.

[0306] Example 22

[0307] [ka]

[0308] 22-1: 7-Bromo-4-(2-(dimethylamino)ethyl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.77 mmol) was added to tetrahydrofuran (10 mL), and sodium hydride (92 mg, 3.85 mmol) was added in an ice bath. The mixture was stirred at room temperature for 0.5 hours, and then 2-bromo-N,N-dimethylethylamine hydrochloride (360 mg, 1.54 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, concentrated, and separated by preparative thin-layer chromatography (ethyl acetate) to obtain the title compound (120 mg, 47%). LC-MS: m / z [M+H] + =330,332.

[0309] 22: 4-(2-(dimethylamino)ethyl)-7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 7, and 7-bromo-4-(2-(dimethylamino)ethyl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (120 mg, 0.36 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 (133 mg, 0.36 mmol) were used as raw materials to obtain the title compound (24 mg, 14%) as a white solid.

[0310] 1 H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.28 (s, 2 H), 8.20 (d, J = 6.4 Hz, 1 H), 7.34 (t, J = 8.8 Hz, 1 H), 7.05 (s, 1 H), 6.93 (br. s., 1 H), 4.62 - 4.56 (m, 4 H), 4.23 (br. s., 2 H), 3.87 (s, 3 H), 2.77 (br. s., 2 H), 2.50 (br. s., 6 H), 1.70 (t, J = 7.1 Hz, 3 H). LC-MS: m / z [M+H]+ =491.

[0311] Example 23

[0312] [ka]

[0313] 23-1: 7-Bromo-6-methoxy-4-(2-methoxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (300 mg, 1.16 mmol), 1-bromo-2-methoxyethane (322 mg, 2.32 mmol), and potassium carbonate (481 mg, 3.48 mmol) were added sequentially to methanol (5 mL) and stirred at 45°C for 16 hours. The reaction mixture was filtered, concentrated, and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (40 mg, 11%) as a yellow solid. LC-MS: m / z [M+H] + =317, 319.

[0314] 23:7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-4-(2-methoxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 7, and 7-bromo-6-methoxy-4-(2-methoxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (60 mg, 0.22 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 (81 mg, 0.22 mmol) were used as raw materials to obtain the title compound (10 mg, 10%) as a yellow solid.

[0315] 1H NMR (400MHz, CHLOROFORM-d) 9.40 (br. s., 1 H), 8.34 - 8.22 (m, 2 H), 8.18 (d, J = 6.4 Hz, 1 H), 7.33 (t, J = 8.8 Hz, 1 H), 7.05 (s, 1 H), 6.54 (s, 1 H), 4.62 - 4.52 (m, 3 H), 4.50 (s, 2 H), 3.80 (s, 3 H), 2.62 (br. s., 2 H), 2.55 - 2.42 (m, 2 H), 1.86 (d, J = 8.3 Hz, 2 H), 1.69 (t, J = 7.3 Hz, 3H). LC-MS: m / z [M+H] + =474.

[0316] Example 24

[0317] [ka]

[0318] 24:7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 7, and 7-bromo-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.39 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 (144 mg, 0.39 mmol) were used as raw materials to obtain the title compound (68 mg, 42%).

[0319] 1H NMR (400MHz, CHLOROFORM-d) 10.76 (s, 1 H), 9.50 (s, 1 H), 8.83 (s, 1 H), 8.41 - 8.35 (m, 2 H), 7.43 (s, 1 H), 6.95 (s, 1 H), 6.66 (s, 1 H), 4.54 (s, 2 H), 4.51 - 4.43 (m, 2 H), 3.67 (s, 3 H), 1.51 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H] + =420.

[0320] Example 25

[0321] [ka]

[0322] 25-1: Methyl 1-(4-methoxy-2-nitrophenoxy)cyclopropane-1-carboxylate 1-Fluoro-4-methoxy-2-nitrobenzene (1 g, 5.85 mmol), sodium hydrogen carbonate (420 mg, 17.52 mmol), and methyl 1-hydroxycyclopropane-1-carboxylate (1.06 g, 8.76 mmol) were added to tetrahydrofuran (10 ml) and stirred for 2 hours at 0° C. The reaction mixture was concentrated and separated and purified using a preparative plate (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (1.1 g, 71%).

[0323] 25-2:6-Methoxyspiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one Methyl 1-(4-methoxy-2-nitrophenoxy)cyclopropane-1-carboxylate (1 g, 3.74 mmol) and Fe (1.04 g, 18.7 mmol) were added to acetic acid (6 ml) and stirred at 80° C. for 1 hour. The reaction mixture was concentrated, an appropriate amount of methanol was added, and the residue was separated and purified using a preparative plate (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (550 mg, 71%).

[0324] 25-3: 6-Methoxy-4-methylspiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one 6-Methoxyspiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one (550 mg, 2.65 mmol), cesium carbonate (2.59 g, 7.95 mmol), and methyl iodide (2.59 mg, 7.95 mmol) were added to methanol (8 mL) and stirred overnight at room temperature. The reaction mixture was filtered and concentrated, and the mother liquor was separated and purified using a preparative plate (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (400 mg, 68.22%).

[0325] 25-4: 7-Bromo-6-methoxy-4-methylspiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one 6-Methoxy-4-methylspiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one (200 mg, 0.9 mmol), HBr (0.3 mL), and hydrogen peroxide (0.1 mL) were added to acetic acid (10 mL) and stirred at room temperature for 1 hour. A large amount of water was added to the reaction mixture, and the product precipitated from the reaction mixture. The reaction mixture was filtered and concentrated to give the title compound (110 mg, 41%).

[0326] 25:7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-4-methylspiro[phenyl[b][1,4]oxazine-2,1'-cyclopropan]-3(4H)-one The experimental procedure was the same as in Example 1, and 7-bromo-6-methoxy-4-methylspiro[benzo[b][1,4]oxazin-2,1'-cyclopropane]-3(4H)-one (97 mg, 0.32 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 (100 mg, 0.27 mmol) were used as raw materials to obtain the title compound (57 mg, 46%).

[0327] 1 H NMR (400MHz, CHLOROFORM-d) 9.36 (br. s., 1 H), 8.31 - 8.23 ​​(m, 2 H), 8.18 (d, J = 6.8 Hz, 1 H), 7.33 (t, J = 9.0 Hz, 1 H), 6.94 (s, 1 H), 6.64 (s, 1 H), 4.58 (q, J = 7.3 Hz, 2 H), 3.85 (s, 3 H), 3.49 - 3.41 (m, 3 H), 1.73 - 1.68 (m, 3 H), 1.45 - 1.38 (m, 2 H), 1.25 - 1.21 (m, 2 H). LCMS: m / z[M+H] + =460. Example 26

[0328] [ka]

[0329] 26-1: 6-Methoxy-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 2-Amino-4-methoxyphenol (500 mg, 3.59 mmol), cesium carbonate (2.34 g, 7.18 mmol), and ethyl 2-bromopropionate (650 mg, 3.59 mmol) were added to N,N-dimethylformamide (8 mL) and stirred overnight at 95°C. The reaction mixture was extracted three times with ethyl acetate and water, and the organic phase was concentrated and directly separated and purified using a preparative plate (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (500 mg, 72.09%).

[0330] 26-2: 6-Methoxy-2,4-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one 6-Methoxy-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (500 mg, 2.59 mmol), cesium carbonate (2.53 g, 7.77 mmol), and methyl iodide (1.85 mg, 12.95 mmol) were added to methanol (20 mL) and stirred overnight at room temperature. The reaction mixture was directly separated and purified using a preparative plate (dichloromethane / methanol = 30 / 1) to give the title compound (400 mg, 74.6%).

[0331] 26-3: 7-Bromo-6-methoxy-2,4-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one 6-Methoxy-2,4-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (400 mg, 1.93 mmol), HBr (0.5 mL), and hydrogen peroxide (0.2 mL) were added to acetic acid (20 mL) and stirred at room temperature for 1 hour. A large amount of water was added to the reaction mixture, and the product precipitated from the reaction mixture. The reaction mixture was filtered and concentrated to give the title compound (190 mg, 34%).

[0332] 26:7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2,4-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 1, and 2-(5-bromo-6-ethoxypyridin-2-yl)-5-methyl-1,3,4-oxadiazole (92 mg, 0.32 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 (100 mg, 0.27 mmol) were used as raw materials to obtain the title compound (60 mg, 50%).

[0333] 1H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.30 - 8.25 (m, 2 H), 8.19 (d, J = 6.8 Hz, 1 H), 7.34 (t, J = 9.0 Hz, 1 H), 7.05 (s, 1 H), 6.63 (s, 1 H), 4.67 - 4.62 (m, 1 H), 4.59 (d, J = 7.3 Hz, 2 H), 3.84 (s, 3 H), 3.44 (s, 3 H), 1.72 - 1.69 (m, 3 H), 1.60 (d, J = 6.8 Hz, 3 H). LC-MS: m / z[M+H] + =448.

[0334] Example 27

[0335] [ka]

[0336] 27-1: 7-Bromo-4-cyclobutyl-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (300 mg, 1.16 mmol), cyclobutyl bromide (235 mg, 1.74 mmol), and potassium carbonate (481 mg, 3.48 mmol) were added sequentially to N,N-dimethylformamide (5 mL) and stirred at 80°C for 2 hours. The reaction mixture was filtered, concentrated, and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (110 mg, 30%) as a white solid. LCMS: m / z [M+H] + =313, 315.

[0337] 27: 4-Cyclobutyl-7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 1, and 7-bromo-4-cyclobutyl-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.32 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 (117 mg, 0.32 mmol) were used as raw materials to obtain the title compound (17 mg, 11%) as a yellow solid.

[0338] 1 H NMR (400MHz, CHLOROFORM-d) δ = 9.40 (br. s., 1 H), 8.34 - 8.22 (m, 2 H), 8.18 (d, J = 6.4 Hz, 1 H), 7.33 (t, J = 8.8 Hz, 1 H), 7.05 (s, 1 H), 6.54 (s, 1 H), 4.62 - 4.52 (m, 3 H), 4.50 (s, 2 H), 3.80 (s, 3 H), 2.62 (br. s., 2 H), 2.55 - 2.42 (m, 2 H), 1.86 (d, J = 8.3 Hz, 2 H), 1.69 (t, J = 7.3 Hz, 3H). LCMS: m / z [M+H] + =474.

[0339] Example 28

[0340] [ka]

[0341] 28-1: 6-Bromo-5-methoxy-3-(2-methoxyethyl)benzo[d]oxazol-2(3H)-one 6-Bromo-5-methoxybenzo[d]oxazol-2(3H)-one (200 mg, 0.82 mmol) was added to N,N-dimethylformamide (10 mL), potassium carbonate (113 mg, 0.82 mmol), and 1-bromo-2-methoxyethane (0.77 mL, 0.82 mmol) were added, and the mixture was stirred at 80°C for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate (100 mL x 3), concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give the title compound (70 mg, yield: 57%) as a white solid. LCMS: m / z [M+H] + =302.

[0342] 28: 6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxy-3-(2-methoxyethyl)benzo[d]oxazol-2(3H)-one The experimental procedure was the same as in Example 1, and 6-bromo-5-methoxy-3-(2-methoxyethyl)benzo[d]oxazol-2(3H)-one (70 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 (66.28 mg, 0.23 mmol) was used as raw materials to obtain the title compound (43 mg, yield: 40%).

[0343] 1 H NMR (400 MHz, DMSO-d6) 9.56 (s, 1H), 8.86 (s, 1H), 8.45 (m, 2H), 7.47 (m, 1H), 7.37-7.32 (m, 1H), 7.24 (s, 1H), 4.52 (m, 2H), 4.08 (m, 2H), 3.81 (s, 3H), 3.71 (m, 2H), 1.56 (t, J = 7.1 Hz, 3H). LC-MS: m / z [M+H] + =464.2.

[0344] Example 29

[0345] [ka]

[0346] 29-1: 6-Bromo-3-cyclobutyl-5-methoxybenzo[d]oxazol-2(3H)-one 6-Bromo-5-methoxybenzo[d]oxazol-2(3H)-one (100 mg, 0.41 mmol) was added to N,N-dimethylformamide (10 mL), bromocyclobutane (1.11 g, 8.19 mmol), and potassium carbonate (113.27 mg, 0.82 mmol) were added, and the mixture was heated to 80°C and stirred for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate (50 mL x 3), concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give the title compound (130 mg) as a pink solid. LC-MS: m / z [M+H] + =298.

[0347] 29: 3-Cyclobutyl-6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxybenzo[d]oxazol-2(3H)-one The experimental procedure was the same as in Example 1, and the title compound (45 mg, yield: 22%) was obtained using 6-bromo-3-cyclobutyl-5-methoxybenzo[d]oxazol-2(3H)-one (130 mg, 0.44 mmol) and (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (124.74 mg, 0.44 mmol).

[0348] 1H NMR (400 MHz, DMSO-d6) 9.59 (s, 1H), 8.91 (s, 1H), 8.56-8.35 (m, 2H), 7.50 (t, 1H), 7.39 (s, 1H), 7.22 (s, 1H), 4.95-4.74 (m, 1H), 4.52 (q, J = 7.3 Hz, 2H), 3.84 (s, 3H), 2.84 (m, 2H), 2.42-2.30 (m, 2H), 1.99-1.75 (m, 2H), 1.56 (t, J = 7.2 Hz, 3H). LC-MS: m / z [M+H] + =460.

[0349] Example 30

[0350] [ka]

[0351] 30-1: 7-Bromo-4-cyclopropyl-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (500 mg, 1.94 mmol), copper acetate (352 mg, 1.94 mmol), cesium carbonate (316 mg, 0.97 mmol), cyclopropylboronic acid (330 mg, 3.88 mmol), and bipyridine (460 mg, 5.82 mmol) were added sequentially to toluene (10 mL) and stirred at 110 °C for 2 hours. The reaction mixture was filtered, concentrated, and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (190 mg, 33%). LC-MS: m / z [M+H]+ = 299, 231.

[0352] 30: 4-Cyclopropyl-7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 7, and 7-bromo-4-cyclopropyl-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (190 mg, 0.70 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 (258 mg, 0.70 mmol) were used as raw materials to obtain the title compound (99 mg, 33%) as a white solid.

[0353] 1 H NMR (400MHz, CHLOROFORM-d) 9.38 (s, 1 H), 8.31 - 8.22 (m, 2 H), 8.18 (d, J = 6.4 Hz, 1 H), 7.33 (t, J = 9.0 Hz, 1 H), 7.00 (br. s., 2 H), 4.63 - 4.51 (m, 4 H), 3.83 (s, 3 H), 2.80 (br. s., 1 H), 1.69 (t, J = 7.1 Hz, 3 H), 1.26 - 1.19 (m, 4 H). LC-MS: m / z [M+H] + =434.

[0354] Example 31

[0355] [ka]

[0356] 31-1: 7-Bromo-4-ethyl-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one 7-Bromo-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (500 mg, 1.94 mmol), ethyl iodide (454 mg, 2.91 mmol), and potassium carbonate (804 mg, 5.82 mmol) were added sequentially to methanol (5 mL) and stirred at 45°C for 16 hours. The reaction mixture was filtered, concentrated, and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (200 mg, 36%). LC-MS: m / z [M+H] + =287, 289.

[0357] 31: 4-Ethyl-7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 7, and 7-bromo-6-methoxy-4-(2-methoxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.70 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 (258 mg, 0.70 mmol) were used as raw materials to obtain the title compound (72 mg, 23%) as a yellow solid.

[0358] 1 H NMR (400MHz, CHLOROFORM-d) 9.34 (s, 1 H), 8.31 - 8.20 (m, 2 H), 8.17 (d, J = 6.8 Hz, 1 H), 7.31 (t, J = 8.8 Hz, 1 H), 7.02 (s, 1 H), 6.64 (s, 1 H), 4.61 - 4.50 (m, 4 H), 4.02 (q, J = 6.8 Hz, 2 H), 3.81 (s, 3 H), 1.66 (t, J = 7.3 Hz, 3 H), 1.33 (t, J = 6.8 Hz, 3 H). LC-MS: m / z [M+H] + =448.

[0359] Example 32

[0360] [ka]

[0361] 32-1: 3-Ethyl-5-methoxybenzo[d]thiazol-2(3H)-one 5-Methoxy-2,3-dihydro-1,3-benzothiazol-2-one (CAS: 15193-51-8, 300 mg, 1.7 mmol) was dissolved in 10 mL of methanol, and ethyl iodide (1.3 g, 8.3 mmol) and potassium carbonate (0.5 g, 3.3 mmol) were added. The mixture was heated to 40°C and stirred for 2 hours. The potassium carbonate was filtered off, concentrated, and purified by preparative plate (petroleum ether: ethyl acetate = 3:1) to give the title compound (200 mg, 57%) as a yellow solid. LC-MS: m / z [M+H] + =210.

[0362] 32-2: 6-Bromo-3-ethyl-5-methoxybenzo[d]thiazol-2(3H)-one 3-Ethyl-5-methoxybenzo[d]thiazol-2(3H)-one (200 mg, 0.96 mmol) was dissolved in 2 mL of acetic acid, and 33% hydrobromic acid-acetic acid solution (588 mg, 2.4 mmol) was added. The mixture was stirred at room temperature for 30 minutes, cooled to 0°C, and hydrogen peroxide (163 mg, 1.44 mmol) was added. The mixture was then warmed to room temperature and stirred for 2 hours. Water was added, and a large amount of solid precipitated. This solid was filtered, dried, and purified by preparative plate (petroleum ether:ethyl acetate = 3:1) to give the title compound (100 mg, 36%) as a white solid. LC-MS: m / z [M+H] + =288.

[0363] 32: 3-Ethyl-6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxybenzo[d]thiazol-2(3H)-one The experimental procedure was the same as in Example 1, 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 (120 mg, 0.33 mmol), 6-bromo-3-ethyl-5-methoxybenzo[d]thiazol-2(3H)-one (100 mg, 0.33 mmol) were used as raw materials to obtain the title compound (16 mg, 11%) as a white solid.

[0364] 1 H NMR (400 MHz, CHLOROFORM-d) 9.37 (br. s., 1 H) 8.18 - 8.34 (m, 3 H) 7.41 (s, 1 H) 7.34 (t, J=8.80 Hz, 1 H) 6.72 (s, 1 H) 4.59 (q, J=6.85 Hz,2 H) 4.03 - 4.12 (m, 2 H) 3.89 (s, 3 H) 1.67 - 1.70 (m, 3 H) 1.41 (t, J=6.85 Hz, 3 H). LC-MS: m / z [M+H] + =450.

[0365] Example 33

[0366] [ka]

[0367] 33-1: 5-Methoxy-3-(2-methoxyethyl)benzo[d]thiazol-2(3H)-one 5-Methoxy-2,3-dihydro-1,3-benzothiazol-2-one (CAS: 15193-51-8, 300 mg, 1.7 mmol) was dissolved in 10 mL of acetonitrile, 1-bromo-2-methoxyethane (346 mg, 2.5 mmol) and cesium carbonate (1.1 g, 0.33 mmol) were added, the mixture was heated to 60 °C and stirred overnight, filtered, the cesium carbonate was filtered, concentrated, and purified by preparative plate (petroleum ether: ethyl acetate = 3:1) to give the title compound (200 mg, 50%) as a yellow solid. LC-MS: m / z [M+H]+ =241.

[0368] 33-2: 6-Bromo-5-methoxy-3-(2-methoxyethyl)benzo[d]thiazol-2(3H)-one 5-Methoxy-3-(2-methoxyethyl)benzo[d]thiazol-2(3H)-one (200 mg, 0.96 mmol) was dissolved in 2 mL of acetic acid, and 33% hydrobromic acid-acetic acid solution (588 mg, 2.4 mmol) was added. The mixture was stirred at room temperature for 30 minutes, cooled to 0 °C, and hydrogen peroxide (163 mg, 1.44 mmol) was added. The mixture was then warmed to room temperature and stirred for 2 hours. Water was added, and a large amount of solid precipitated. The solid was filtered, dried, concentrated, and purified by preparative plate (petroleum ether: ethyl acetate = 2:1) to give the title compound (120 mg, 39%) as a white solid. LC-MS: m / z [M+H] + =318.

[0369] 33: 6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxy-3-(2-methoxyethyl)benzo[d]thiazol-2(3H)-one The experimental procedure was the same as in Example 1, 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 (129 mg, 0.35 mmol), 6-bromo-5-methoxy-3-(2-methoxyethyl)benzo[d]thiazol-2(3H)-one (110 mg, 0.35 mmol) were used as raw materials to obtain the title compound (125 mg, 74%) as a white solid.

[0370] 1H NMR (400 MHz, CHLOROFORM-d) 9.37 (s, 1 H) 8.20 - 8.32 (m, 3 H) 7.31 - 7.40 (m, 2 H) 6.95 (s, 1 H) 4.59 (q, J=7.34 Hz, 2 H) 4.19 (t, J=5.14 Hz, 2 H) 3.87 (s, 3 H) 3.74 (t, J=5.14 Hz, 2 H) 3.38 (s, 3 H) 1.69 (t, J=7.34 Hz, 3 H). LC-MS: m / z [M+H] + =480.

[0371] Example 34

[0372] [ka]

[0373] 34-1: 6-Bromo-3-(cyclopropylmethyl)-5-methoxybenzo[d]oxazol-2(3H)-one Under an inert nitrogen atmosphere, 6-bromo-5-methoxybenzo[d]oxazol-2(3H)-one (100 mg, 0.4 mmol) was dissolved in N-methylpyrrolidone (10 mL). Sodium cyanide (40 mg, 1.0 mmol) was added at 0°C. After the addition was complete, the mixture was stirred at room temperature for 15 minutes. (Bromomethyl)cyclopropane (108 mg, 0.8 mmol) was added and stirred for 2 hours. The reaction mixture was poured into ice water (50 mL), extracted with ethyl acetate (100 mL x 3), spin-dried, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give the title product (110 g, 90% yield) as a yellow solid. LC-MS: m / z [M+H] + =298.0.

[0374] 34: 3-(Cyclopropylmethyl)-6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxybenzo[d]oxazol-2(3H)-one The experimental procedure was the same as in Example 1, and the title compound (30 mg, yield: 26%) was obtained as a white solid using 6-bromo-3-(cyclopropylmethyl)-5-methoxybenzo[d]oxazol-2(3H)-one (75 mg, 0.25 mmol) and (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (86 mg, 0.3 mmol).

[0375] 1 H NMR (400 MHz, CDCl3) 9.40 (s, 1H), 8.35 (s, 1H), 8.31-8.22 (m, 2H), 7.35 (t, 1H), 7.24 (s, 1H), 6.73 (s, 1H), 4.59 (q, J = 7.3 Hz, 2H), 3.86 (s, 3H), 3.77 (d, J = 7.0 Hz, 2H), 1.70 (t, J = 7.3 Hz, 3H), 1.28 (m, 1H), 0.70-0.60 (m, 2H), 0.49 (m, 2H). LC-MS: m / z [M+H] + =460.

[0376] Example 35

[0377] [ka]

[0378] 35-1: 6-Bromo-5-methoxy-3-methylbenzo[d]oxazol-2(3H)-one 6-Bromo-5-methoxybenzo[d]oxazol-2(3H)-one (200 mg, 0.82 mmol) was added to dimethyl sulfoxide (20 mL), methyl iodide (1.53 mL, 24.59 mmol), and cesium carbonate (534 mg, 1.64 mmol) were added, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate (40 mL × 3), concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give the title compound (130 mg, yield: 49%) as a purple solid.

[0379] 1 H NMR (400 MHz, DMSO-d6) 7.64 (s, 1H), 7.19 (s, 1H), 3.88 (s, 3H), 3.35 (s, 3H). LC-MS: m / z [M+H] + =258.

[0380] 35: 6-(2-Fluoro-5-(7-isopropyl-7H-imidazo[4,5-c]pyridazin-4-yl)phenyl)-5-methoxy-3-methylbenzo[d]oxazol-2(3H)-one The experimental procedure was the same as in Example 1, and the title compound (40 mg, yield: 77%) was obtained using 6-bromo-5-methoxy-3-methylbenzo[d]oxazol-2(3H)-one (30 mg, 0.12 mmol) and (2-fluoro-5-(7-isopropyl-7H-imidazo[4,5-c]pyridazin-4-yl)phenyl)boronic acid (44 mg, 0.12 mmol). LC-MS: m / z [M+H] + =434.2.

[0381] 1 H NMR (400 MHz, DMSO-d6) 9.60 (s, 1H), 8.99 (s, 1H), 8.70-8.40 (m, 2H), 7.61-7.45 (m, 1H), 7.38 (s, 1H), 7.21 (s, 1H), 5.11 (m, 1H), 3.82 (s, 3H), 3.42 (s, 3H), 1.68 (m, 6H).

[0382] Example 36

[0383] [ka]

[0384] 36-1: 6-Methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 6-Methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (500 mg, 2.8 mmol), cesium carbonate (2.8 g, 8.4 mmol), and methyl iodide (800 mg, 5.6 mmol) were added sequentially to 20 mL of methanol, heated to 35°C, and stirred for 2 hours. The cesium carbonate was filtered off, concentrated, and purified by preparative plate (dichloromethane:methanol = 30:1) to give the title compound (400 mg, 74%) as a brown solid. LC-MS: m / z [M+H] + =194.

[0385] 36-2: 7-Bromo-6-methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 6-Methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (400 mg, 2 mmol) was dissolved in 5 mL of acetic acid, 2 mL of 3M hydrogen bromide-acetic acid solution was added, and the mixture was stirred at room temperature for 30 minutes. After cooling to 0°C, 1 mL of hydrogen peroxide was added, and the mixture was warmed to room temperature and stirred for 2 hours. Water was added, and a large amount of solid precipitated. The mixture was extracted with dichloromethane, dried, concentrated, and purified using a preparative plate (dichloromethane:methanol = 30:1) to give the title compound (180 mg, 32%) as a white solid. LC-MS: m / z [M+H] + =272.

[0386] 36: 7-(2-Fluoro-5-(7-isopropyl-7H-imidazo[4,5-c]pyridazin-4-yl)phenyl)-6-methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 1, and the title compound (140 mg, 85%) was obtained using 7-bromo-6-methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (151 mg, 0.55 mmol) and 4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7-isopropyl-7H-imidazo[4,5-c]pyridazine (141 mg, 0.37 mmol).

[0387] 1 H NMR (400MHz ,DMSO-d6) 9.53 (s, 1 H), 8.92 (s, 1 H), 8.42 (d, J = 7.3 Hz, 2 H), 7.47 (t, J = 9.0 Hz, 1 H), 7.03 (s, 1 H), 6.92 (s, 1 H), 5.13 - 5.08 (m, 1 H), 4.67 - 4.62 (m, 2 H), 3.80 (s, 3 H), 3.37 (s, 3 H), 1.66 (d, J = 6.8 Hz, 6 H). LC-MS: m / z[M+H] + =448.

[0388] Example 37

[0389] [ka]

[0390] 37-1: 4-Bromo-3-methoxy-2-methylaniline 3-Methoxy-2-methylaniline (5.48 g, 40.0 mmol) was added to N,N-dimethylformamide (50 mL). Next, N-bromosuccinimide (7.2 g, 40.0 mmol) was added in batches, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was spin-dried and then separated by column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (3.5 g, yield: 41%) as a gray solid. LCMS: m / z [M+H] + = 216.1.

[0391] 37-2: 4-Bromo-3-methoxy-2-methylbenzenesulfonyl chloride 4-Bromo-3-methoxy-2-methylaniline (2.0 g, 9.3 mmol) was dissolved in a mixture of hydrochloric acid (8 mL), acetic acid (4 mL), and acetonitrile (30 mL). After stirring for 10 minutes, the mixture was cooled to 0°C and sodium nitrite (5N, 2 mL) was added dropwise. The mixture was then reacted for 30 minutes. Saturated sulfur dioxide-acetic acid solution (5 mL) was added dropwise and the temperature was controlled below 50°C for 10 minutes. An aqueous solution of copper chloride (2.4 g, 2 mL / g) was then added dropwise. The mixture was allowed to warm to room temperature and react for 16 hours. The mixture was then poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine, then with saturated sodium bicarbonate until it became slightly acidic, dried, and concentrated to give 1.5 g of the crude product of the title compound. LCMS: m / z [M+H] + = 298.9.

[0392] 37-3: 4-Bromo-3-methoxy-N,2-dimethylbenzenesulfonamide 4-Bromo-3-methoxy-2-methylbenzenesulfonyl chloride (200 mg, 0.67 mmol) and methylamine hydrochloride (90 mg, 1.33 mmol) were added sequentially to dichloromethane (10 mL). Next, triethylamine (203 mg, 2.01 mmol) was added dropwise, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), and spin-dried to give the title compound (200 mg) as a gray solid. 1 H NMR (400 MHz, CDCl3) 7.64 (d, J = 8.5 Hz, 1H), 7.58-7.50 (m, 1H), 3.83 (s, 3H), 2.66 (d, J = 4.5 Hz, 3H), 2.61 (s, 3H). LCMS: m / z [M+H] + = 294.

[0393] 37-4: 4-Bromo-2-(bromomethyl)-3-methoxy-N-methylbenzenesulfonamide The starting materials, 4-bromo-3-methoxy-N,2-dimethylbenzenesulfonamide (200 mg, 0.67 mmol) and dibenzoyl peroxide (100 mg, 0.41 mmol), were added to a mixture of carbon tetrachloride (10 mL) and dichloromethane (4 mL). The starting material, N-bromosuccinimide (145 mg, 0.81 mmol), was added to the reaction mixture in batches. The reaction mixture was allowed to react overnight at 90°C. The reaction mixture was added to water (100 mL), extracted with ethyl acetate (50 mL x 3), concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 20% to 30%) to obtain the title compound (110 mg, yield: 44%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) 7.94-7.84 (m, 2H), 7.55 (t, J = 12.4 Hz, 1H), 4.96 (s, 2H), 4.04-3.97 (m, 3H), 2.49 (s, 3H). LCMS: m / z [M+H] + = 373.

[0394] 37-5: 5-Bromo-4-methoxy-2-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide 4-Bromo-2-(bromomethyl)-3-methoxy-N-methylbenzenesulfonamide (110 mg, 0.29 mmol) was added to N,N-dimethylformamide (10 mL). Sodium hydride (14 mg, 0.35 mmol) was added at room temperature and the mixture was allowed to react for 1 hour. The mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), spin-dried, and purified by TLC plate (petroleum ether / ethyl acetate = 4:1) to give the title compound (10 mg, yield: 11.8%) as a white solid. 1 H NMR (400 MHz, CDCl3) 7.65 (m, 1H), 7.49-7.30 (m, 1H), 4.29 (s, 2H), 3.86 (s, 3H), 2.89 (s, 3H). LCMS: m / z [M+H] + = 292.

[0395] 37: 5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-4-methoxy-2-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide The experimental procedure was the same as in Example 1, and 5-bromo-4-methoxy-2-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (10 mg, 0.034 mmol) and (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (10 mg, 0.035 mmol) were used as raw materials to obtain the title compound (2.7 mg, yield: 18%) as a white solid.

[0396] 1 H NMR (400 MHz, DMSO-d6) 9.59 (s, 1H), 8.88 (s, 1H), 8.57 (t, 2H), 7.74 (d, 1H), 7.68 (d, 1H), 7.60 (t, 1H), 4.63 (s, 2H), 4.52 (q, J = 7.2 Hz, 2H), 3.72 (s, 3H), 2.89 (s, 3H), 1.56 (t, J = 7.3 Hz, 3H). LCMS: m / z[M+1] + = 454.

[0397] Example 38

[0398] [ka]

[0399] 38-1: 6,7-Dihydrobenzo[b]thiophen-4-(5H)-one 4-(Thiophen-2-yl)butanoic acid (5000 mg, 29.37 mmol) and trifluoroacetic anhydride (18510 mg, 88.11 mmol) were added sequentially to trifluoroacetic acid (40 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated, water (40 mL) was added, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (5400 mg, crude product) as a brown liquid. 1 H NMR (400MHz, CHLOROFORM-d) δ =7.39 (d, J = 5.4 Hz, 1 H), 7.07 (d, J = 5.4 Hz, 1 H), 3.04 (t, J = 5.9 Hz, 2 H), 2.59 (t, J = 6.4 Hz, 2 H), 2.22 (q, J = 6.2Hz, 2H).

[0400] 38-2: 5,5-Dibromo-6,7-dihydrobenzo[b]thiophen-4-(5H)-one Ethyl acetate (20 mL), 6,7-dihydrobenzo[b]thiophen-4-(5H)-one (5000 mg, 32.85 mmol), and copper bromide (14670 mg, 65.7 mmol) were added sequentially to chloroform (20 mL), and the mixture was stirred open at 80° C. for 16 hours. The reaction mixture was filtered, and the filtered solid was subjected to silica gel column chromatography (petroleum ether:ethyl acetate=100:1) to afford the title compound (1500 mg, 15%) as a brown solid. 1 H NMR (400MHz, CHLOROFORM-d) δ =7.47 (d, J = 4.9 Hz, 1H), 7.16 (d, J = 4.9 Hz, 1H), 3.15 (s, 4H).

[0401] 38-3:5-Bromobenzo[b]thiophen-4-ol 5,5-Dibromo-6,7-dihydrobenzo[b]thiophen-4-(5H)-one (1400 mg, 4.52 mmol) and lithium carbonate (1000 mg, 13.56 mmol) were added sequentially to N,N-dimethylformamide (20 mL), and the mixture was stirred at 100° C. for 3 hours. Water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1000 mg, 94%) as a white solid. 1 H NMR (400MHz, CHLOROFORM-d) δ =7.52 (d, J = 5.4 Hz, 1 H), 7.40 - 7.35 (m, 2 H), 7.34 - 7.30 (m, 1 H), 6.32 (br. s., 1 H).

[0402] 38-4: 5-Bromo-4-methoxybenzo[b]thiophene 5-Bromobenzo[b]thiophen-4-ol (1000 mg, 4.37 mmol), dimethyl sulfate (1650 mg, 13.11 mmol), and potassium carbonate (1810 mg, 13.11 mmol) were added sequentially to acetone (40 mL) and stirred at 50°C for 16 hours. The reaction mixture was filtered, and the residue was washed with acetone (5 mL x 3). The filtrate was concentrated under reduced pressure, followed by dissolution in methanol (20 mL). Sodium hydroxide (600 mg) was added, and the mixture was stirred at room temperature for 0.5 hours to quench the excess dimethyl sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (1000 mg, 97%) as a brown solid. 1 H NMR (400MHz, CHLOROFORM-d) δ =7.52 - 7.42 (m, 4H), 4.00 (s, 3H).

[0403] 38-5: 5-Bromo-4-methoxybenzo[b]thiophene 1,1-dioxide 5-Bromo-4-methoxybenzo[b]thiophene (600 mg, 2.47 mmol) and potassium hydrogen peroxide (4555 mg, 7.41 mmol) were added sequentially to a mixture of methanol (5 mL), tetrahydrofuran (5 mL), and water (5 mL) and stirred at 40°C for 16 hours. The reaction mixture was diluted with water (100 mL), filtered, and dried to give the title compound (500 mg, 74%) as a white solid. LC-MS: m / z [M+H]+ = 276, 278.

[0404] 38-6: 5-Bromo-4-methoxy-2,3-dihydrobenzo[b]thiophene 1,1-dioxide 5-Bromo-4-methoxybenzo[b]thiophene 1,1-dioxide (200 mg, 0.73 mmol) and sodium cyanoborohydride (55 mg, 1.46 mmol) were added sequentially to ethanol (10 mL) and stirred at room temperature for 2 hours. The reaction mixture was adjusted to a weakly acidic state with aqueous hydrochloric acid (1 M), diluted with water (20 mL), separated, and the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding the title compound (150 mg, 74%) as a white solid. LC-MS: m / z [M+H] + =278, 280. 38: 5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-4-methoxy-2,3-dihydrobenzo[b]thiophene-1,1-dioxide The experimental procedure was the same as in Example 1, and 5-bromo-4-methoxy-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (120 mg, 0.43 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 (158 mg, 0.43 mmol) were used as raw materials to obtain the title compound (40 mg, 21%) as a white solid.

[0405] 1H NMR (400MHz, CHLOROFORM-d) δ = 9.40 (br. s., 1 H), 8.38 - 8.28 (m, 3 H), 7.64 - 7.52 (m, 2 H), 7.41 (t, J = 8.8 Hz, 1 H), 4.59 (q, J = 7.3 Hz, 2 LC-MS: m / z [M+H]+ =439. Example 39

[0406] [ka]

[0407] 39: 5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-2-(trifluoromethyl)quinoline The experimental procedure was the same as in Example 1, and 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, 0.27 mmol) and 5-bromo-2-(trifluoromethyl)quinoline (74 mg, 0.27 mmol) were used as raw materials to obtain the title compound (68 mg, 55.31%) as a white solid.

[0408] 1 H NMR (400MHz, CHLOROFORM-d) d = 9.41 (s, 1 H), 8.42 - 8.22 (m, 5 H), 7.94 (t, J = 7.8 Hz, 1 H), 7.81 - 7.70 (m, 2 H), 7.49 (t, J = 8.8 Hz, 1 H), 4.60 (q, J = 7.0 Hz, 2 H), 1.70 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H]+ =438. Example 40 and Example 41

[0409] [ka]

[0410] 40-1: 1-(5-bromo-4-methoxy-2-nitrophenyl)-N-(1-methylpiperidin-4-yl)methanamine 5-Bromo-4-methoxy-2-nitrobenzaldehyde (780 mg, 3.0 mmol) and 1-methylpiperidin-4-amine (342 mg, 3.0 mmol) were added to toluene (50 mL) and stirred at 110° C. for 16 hours. The reaction mixture was concentrated to give the title compound (1.0 g, yield: 94%) as a yellowish-brown oil. LC-MS: m / z [M+H] + =356 40-2: 5-Bromo-6-methoxy-2-(1-methylpiperidin-4-yl)-2H-indazole 1-(5-Bromo-4-methoxy-2-nitrophenyl)-N-(1-methylpiperidin-4-yl)methanamine (1.0 g, 2.8 mmol) was dissolved in triethyl phosphate (20 mL) and reacted at 150° C. for 2 hours. The reaction mixture was directly purified by column chromatography (dichloromethane:methanol=12:1) to give the title compound (650 mg, yield: 71%) as a yellow solid. LC-MS: m / z [M+H] + =324 40-3: 7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-(1-methylpiperidin-4-yl)-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1. 5-Bromo-6-methoxy-2-(1-methylpiperidin-4-yl)-2H-indazole (324 mg, 1.0 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 (286 g, 1.0 mmol) were used as raw materials to obtain a yellow-brown solid (200 mg, yield: 37%). LC-MS: m / z [M+H] + =486.

[0411] Example 40: rel-(R)-4-(5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2H-indazol-2-yl)-1-methylpiperidin-2-one Example 41: rel-(S)-4-(5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2H-indazol-2-yl)-1-methylpiperidin-2-one 7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-(1-methylpiperidin-4-yl)-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine (175 mg, 0.36 mmol) was dissolved in tetrahydrofuran (20 mL), sodium bicarbonate (303 mg, 3.6 mmol), iodine (916 mg, 3.6 mmol), and water (8 mL) were added, and the mixture was stirred at 30°C for 24 hours. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), dried, concentrated, and separated by column chromatography (dichloromethane:methanol = 10:1) to give a yellow solid (120 mg), which was then purified by HPLC to give a white solid (60 mg). Subsequently, SFC chiral resolution was performed to give Examples 40 and 41. Dividing method: Instrument: MG II preparative SFC (SFC-1); Column: ChiralPak AD, 250 × 30 mm ID, 10 μm; Mobile phase: A for CO2 and B for Isopropanol; Gradient: B 55%; Flow rate: 80 mL / min; Back pressure: 100 bar; Column temperature: 38 °C; Wavelength: 220 nm.

[0412] Example 40: The title product was obtained (7.2 mg, white solid, second peak). 1H NMR (400 MHz, CDCl3) 9.43 (brs, 1H), 8.35 (m, 2H), 8.23 ​​(d, 1H), 7.92 (s, 1H), 7.62 (s, 1H), 7.35 (t, 1H), 7.11 (s, 1H), 4.91 (m, 1H), 4.59 (d, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.43 (m, 1H), 3.35 (m, 1H), 3.09 (m, 2H), 3.02 (s, 3H), 2.56 (m, 1H), 2.49 (m, 1H), 1.70 (t, J = 7.0 Hz, 3H). LC-MS: m / z [M+H] + = 500.

[0413] Example 41: The title product (6.2 mg, white solid, No. 1 product) was obtained. 1 H NMR (400 MHz, CDCl3) 9.41 (brs, 1H), 8.31 (m, 2H), 8.21 (d, 1H), 7.91 (s, 1H), 7.62 (s, 1H), 7.34 (t, 1H), 7.11 (s, 1H), 4.89 (m, 1H), 4.59 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.53-3.39 (m, 1H), 3.39-3.28 (m, 1H), 3.19-3.05 (m, 2H), 3.02 (s, 3H), 2.67-2.52 (m, 1H), 2.48 (s, 1H), 1.69 (t, J = 7.1 Hz, 3H). LC-MS: m / z [M+H] + = 500.

[0414] Example 42

[0415]

change

[0416] 42: 7-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one The experimental procedure was the same as in Example 1, 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 (220 mg, 0.6 mmol), 7-bromo-6-methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (160 mg, 0.6 mmol) were used as raw materials to obtain the title compound (97 mg, 37%) as a brown solid.

[0417] 1 H NMR (400 MHz, CHLOROFORM-d) 9.54 (s, 1 H) 8.86 (s, 1 H) 8.37 - 8.46 (m, 2 H) 7.43 - 7.51 (m, 1 H) 7.04 (s, 1 H) 6.93 (s, 1 H) 4.65 (s, 2 H) 4.50 (d, J=7.34 Hz, 2 H) 3.81 (s, 3 H) 3.38 (s, 3 H) 1.55 (t, J=7.09 Hz, 3 H). LC-MS: m / z [M+H] + =434.

[0418] Example 43

[0419] [ka]

[0420] 43-1: 5-Methoxy-2,3-dimethylbenzo[b]thiophene 4-Methoxybenzenethiol (501 mg, 3.57 mmol) was added to the reaction vial and stirred at 0°C for 15 minutes. Sodium hydroxide (285 mg, 7.14 mmol) was dissolved in water (3 mL) and slowly added to the reaction mixture. After the addition was complete, the mixture was stirred at 0°C for 30 minutes. 3-Bromo-2-butanone (1 g, 6.62 mmol) was slowly added to the reaction mixture. After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (30 mL), extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude intermediate. Polyphosphoric acid (3.24 g, 39.5 mmol), the crude product from the previous step, was slowly added to the reaction vial and stirred at 150°C for 1 hour. The reaction mixture was cooled to room temperature, poured into water (30 mL), extracted with dichloromethane, and the organic phase was concentrated. Column chromatography (petroleum ether / ethyl acetate=50 / 1) gave the title compound (480 mg, 57%) as a yellow oily liquid. 1 H NMR(400MHz, CHLOROFORM-d) 7.61(d, J=8.8Hz, 1H), 7.05 (d, J=2.0 Hz, 1 H), 6.93(dd, J=2.0,8.8 Hz, 1 H), 3.89 (s, 3 H), 2.48 (s, 3 H ), 2.27 (s, 3H).

[0421] 43-2: 6-Bromo-5-methoxy-2,3-dimethylbenzo[b]thiophene 5-Methoxy-2,3-dimethylbenzo[b]thiophene (480 mg, 2.5 mmol) was added to diethyl ether (3 mL) and stirred at 0°C for 10 minutes. Liquid bromine (400 mg, 2.5 mmol) was dissolved in diethyl ether (2 mL) and slowly added dropwise to the reaction mixture at 0°C. After the addition was complete, the mixture was slowly warmed to room temperature and then stirred for 1 hour. The reaction mixture was poured into saturated aqueous sodium bicarbonate (30 mL), stirred at room temperature for 10 minutes, extracted with ethyl acetate, and the organic phase was dried, concentrated, and purified by HPLC to yield the title compound and 4-bromo-5-methoxy-2,3-dimethylbenzo[b]thiophene (240 mg) as a brown solid. 1H NMR (400MHz, CHLOROFORM-d) 7.87 (s, 1H), 7.00 (s, 1H), 3.97 (s, 3H), 2.46 (s, 3H), 2.26 (s, 3H).

[0422] 43: 7-Ethyl-4-(4-fluoro-3-(5-methoxy-2,3-dimethylbenzo[b]thiophen-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, 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 (70 mg, 0.19 mmol), 6-bromo-5-methoxy-2,3-dimethylbenzo[b]thiophene (103 mg, 0.19 mmol) were used as raw materials to obtain the title compound (11 mg, 13%) as a white solid.

[0423] 1 H NMR (400MHz, CHLOROFORM-d) d = 9.37 (s, 1 H), 8.32 - 8.19 (m, 3 H), 7.69 (s, 1 H), 7.33 (t, J = 8.8 Hz, 1 H), 7.13 (s, 1 H), 4.57 (q, J = 7.3 Hz, 2 H), 3.90 (s, 3 H), 2.50 (s, 3 H), 2.32 (s, 3 H), 1.68 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H] + =433.

[0424] Example 44

[0425] [ka]

[0426] 44-1: 2-chloro-1-methoxy-3-(2-methoxyvinyl)benzene Potassium tert-butoxide (855 mg, 7.62 mmol) was added to (methoxymethyl)triphenyl chloride (2.61 g, 7.62 mmol) in tetrahydrofuran (20 mL) at 0°C, and the mixture was stirred for 1 hour. 2-Chloro-3-methoxybenzaldehyde (1 g, 5.86 mmol) was then added dropwise, and the solution was stirred for 1 hour at 0°C. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with diethyl ether (3 x 40 mL). The combined organic phases were washed with water and brine, then dried over anhydrous sodium sulfate, and concentrated in vacuo to give 2-chloro-1-methoxy-3-(2-methoxyvinyl)benzene (1 g, yield: 85%), which was used without further purification.

[0427] 44-2: 2-(2-chloro-3-methoxyphenyl)acetaldehyde 6N HCl (20 mL) was added to a solution of 2-chloro-1-methoxy-3-(2-methoxyvinyl)benzene (1 g) in tetrahydrofuran (20 mL), and the mixture was heated to reflux for 4 hours. Water was added, followed by extraction with diethyl ether (3 × 40 mL). The combined organic phase was washed with water and brine. It was then dried over anhydrous sodium sulfate and concentrated in vacuo. It was then purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to give 2-(2-chloro-3-methoxyphenyl)acetaldehyde (500 mg, yield: 45%) as a colorless oil.

[0428] 44-3: 2-(2-chloro-3-methoxyphenyl)ethan-1-ol Sodium borohydride (0.61 g, 15 mmol) was added to a methanolic solution of 2-(2-chloro-3-methoxyphenyl)acetaldehyde (1 g, 15 mmol) at 0°C. The mixture was stirred at 0°C for 2 hours. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted with diethyl ether (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo, and then purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to give 2-(2-chloro-3-methoxyphenyl)ethan-1-ol (0.3 g, yield: 29%) as a colorless oil.1 H NMR (400 MHz, CDCl3) 7.15 (dd, 1H), 6.88 (dd, 1H), 6.81(dd, 1H), 3.86 (m, 5H), 3.01 (t, 2H), 1.85 (s,1H).

[0429] 44-4: 4-chloro-5-methoxy-2,3-dihydrobenzofuran Under an argon atmosphere at 0°C, (bis(trifluoroacetoxy)iodo)p-toluene (720 mg, 1.76 mmol) and triethylamine (40 mg, 0.4 mmol) were added to 2-(2-chloro-3-methoxyphenyl)ethan-1-ol (300 mg, 1.6 mmol) in trifluoroethanol (30 mL). The mixture was stirred at 50°C for 36 hours. Triethylamine (640 mg, 6.4 mmol) was added at 50°C, followed immediately by hexacupor(II) hexafluoroacetylacetonate (760 mg, 1.6 mmol). The mixture was heated to 50°C and stirred until the iodonium salt intermediate was consumed. Saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with diethyl ether (3 × 10 mL). The combined organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and then purified by column chromatography (petroleum ether: ethyl acetate = 100:1 to 10:1) to give 4-chloro-5-methoxy-2,3-dihydrobenzofuran (40 mg, yield: 14%) as a white solid. 1 H NMR (400 MHz, CDCl3) 6.69 (d, 1H), 6.61 (d, H), 4.59 (t, 2H), 3.84 (s, 3H), 3.24 (t, 2H).

[0430] 44: 7-Ethyl-4-(4-fluoro-3-(5-methoxy-2,3-dihydrobenzofuran-4-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and the title compound (14 mg, yield: 16%) was obtained using 4-chloro-5-methoxy-2,3-dihydrobenzofuran (30 mg, 0.16 mmol) and (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (45 mg, 0.16 mmol) as raw materials.

[0431] 1 H NMR (400 MHz, DMSO-d6) 9.39 (s, 1H), 8.43-8.10 (m, 3H), 7.36 (t, 1H), 6.85-6.73 (m, 2H), 4.57 (t, 4H), 3.74 (s, 3H), 3.10 (m, 2H), 1.70 (m, 3H). LC-MS: m / z [M+H] + =391.

[0432] Example 45

[0433] [ka]

[0434] 45-A1: 6-Bromo-5-methoxy-1-methyl-1H-indazole 45-A2: 6-Bromo-5-methoxy-2-methyl-2H-indazole 6-Bromo-5-methoxy-1H-indazole (200 mg, 0.88 mmol), cesium carbonate (287 mg, 0.88 mmol), and methyl iodide (125 mg, 0.88 mmol) were added sequentially to tetrahydrofuran (5 ml). The mixture was stirred at 35°C overnight. The reaction mixture was directly subjected to thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound A1 (76 mg, 36%, Rf = 0.4) and compound A2 (70 mg, 33%, Rf = 0.3). LC-MS: m / z [M+H] + =241.

[0435] 45: 7-Ethyl-4-(4-fluoro-3-(5-methoxy-2-methyl-2H-indazol-6-yl)phenyl)-7H-imidazo4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 6-bromo-5-methoxy-2-methyl-2H-indazole (70 mg, 0.29 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 (107 mg, 0.29 mmol) were used as raw materials to obtain the title compound (20 mg, 16%). LC-MS: m / z [M+H] + =403.

[0436] 1 H NMR (400 MHz, DMSO-d6) d ppm 1.51 (br. s., 3 H) 3.72 (br. s., 3 H) 4.12 (br. s., 3 H) 4.47 (br. s., 2 H) 7.14 (br. s., 1 H) 7.35 - 7.63 (m, 2 H) 8.21 (br. s.,1 H) 8.45 (br. s., 2 H) 8.81 (br. s., 1 H) 9.53 (br. s., 1 H).

[0437] Example 46 and Example 47

[0438] [ka]

[0439] 46-1: tert-butyl (E)-4-((5-bromo-4-methoxy-2-nitrobenzylidene)amino)-3,3-difluoropiperidine-1-carboxylate The experimental procedure was the same as that of Example 40, 40-1, and 5-bromo-4-methoxy-2-nitrobenzaldehyde (780 mg, 3.0 mmol) and tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate (1.06 g, 4.5 mmol) were used as raw materials to obtain the title compound (950 mg, 66% yield) as a yellow oil. LC-MS: m / z [M+H-56] + =422.

[0440] 46-2: tert-butyl 4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3,3-difluoropiperidine-1-carboxylate The experimental procedure was the same as that of Example 40, 40-1, and tert-butyl (E)-4-((5-bromo-4-methoxy-2-nitrobenzylidene)amino)-3,3-difluoropiperidine-1-carboxylate (950 mg, 2.0 mmol) was used as the raw material to obtain the title compound (500 mg, yield: 56%) as a bluish-brown solid. LC-MS: m / z [M+H] + =446.

[0441] 46-3: 5-Bromo-2-(3,3-difluoropiperidin-4-yl)-6-methoxy-2H-indazole hydrochloride tert-Butyl 4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3,3-difluoropiperidine-1-carboxylate (500 mg, 1.1 mmol) was dissolved in methanol (25 mL), and then a 1,4-dioxane solution of hydrochloric acid (4 mol / L, 25 mL) was added. The mixture was allowed to react at room temperature for 2 hours, and the reaction mixture was then directly concentrated to give the title compound (420 mg, 98% yield) as a white solid. LC-MS: m / z [M+H] + =346.

[0442] 46-4: 5-Bromo-2-(3,3-difluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole 5-Bromo-2-(3,3-difluoropiperidin-4-yl)-6-methoxy-2H-indazole hydrochloride (420 mg, 1.1 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of formaldehyde (37% aqueous solution, 1 mL) and acetic acid (0.5 mL). After stirring for 30 minutes, sodium triacetoxyborohydride (467 mg, 2.2 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was directly concentrated and purified by column chromatography (dichloromethane:methanol = 10:1) to give the title compound (396 mg, yield: 99.5%) as an off-white solid. LC-MS: m / z [M+H] + =360.

[0443] Example 46: rel-(S)-4-(3-(2-(3,3-difluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine Example 47: rel-(R)-4-(3-(2-(3,3-difluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1. 5-Bromo-2-(3,3-difluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole (396 mg, 1.1 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 (315 g, 1.1 mmol) were used as raw materials to obtain a yellow solid (570 mg). Further chiral separation was performed. Separation method: Instrument: MG II preparative SFC (SFC-1); Column: ChiralPak AD, 250 × 30 mm ID, 10 μm; Mobile phase: A for CO2 and B for isopropanol; Gradient: B 55%; Flow rate: 80 mL / min; Back pressure: 100 bar; Column Temperature: 38℃; Wavelength: 220nm.

[0444] Example 46: The title compound was obtained (275 mg, first peak). 1 H NMR (400 MHz, CDCl3) 9.38 (s, 1H), 8.35 - 8.25 (m, 2H), 8.22 (m, 1H), 8.07 (s, 1H), 7.65 (s, 1H), 7.33 (t, 1H), 7.09 (s, 1H), 4.81 LC-MS: m / z [M+H] + = 522.

[0445] Example 47: The title compound was obtained (273 mg, second peak). 1H NMR (400 MHz, DMSO-d6) 9.56 (s, 1H), 8.85 (s, 1H), 8.55-8.36 (m, 3H), 7.71 (s, 1H), 7.48 (t, J = 9.1 Hz, 1H), 7.14 (s, 1H), 5.06 (m, 1H), 4.51 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 3.22 (m, 1H), 2.99 (m, 1H), 2.64-2.53 (m, 1H), 2.35 (m, 4H), 2.16 (m, 1H), 1.55 (t, J = 7.3 Hz, 3H), 1.26 (m, 1H). LC-MS: m / z [M+H] + = 522.

[0446] Example 48

[0447] [ka]

[0448] 48:7-Ethyl-4-(4-fluoro-3-(5-methoxy-1-methyl-1H-indazol-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 6-bromo-5-methoxy-1-methyl-1H-indazole (70 mg, 0.29 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 (107 mg, 0.29 mmol) were used as raw materials to obtain the title compound (33 mg, 28%).

[0449] 1H NMR (400MHz, CHLOROFORM-d) 9.38 (br. s., 1 H), 8.41 - 8.17 (m, 3 H), 7.93 (br. s., 1 H), 7.45 - 7.32 (m, 2 H), 7.19 (br. s., 1 H), 4.66 - 4.46 (m, 2H), 4.07 (s, 3H), 3.85 (s, 3H), 1.68 (t, J = 6.8 Hz, 3H). LC-MS: m / z [M+H] + =403.

[0450] Example 49

[0451] [ka]

[0452] 49-A1: 5-Bromo-6-methoxy-1-methyl-1H-indazole 49-A2: 5-Bromo-6-methoxy-2-methyl-2H-indazole 5-Bromo-6-methoxy-1H-indazole (200 mg, 0.88 mmol) was added to anhydrous N,N-dimethylformamide (5 mL), sodium hydride (43 mg, 1.06 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. Methyl iodide (151 mg, 1.06 mmol) was added, and the mixture was stirred at room temperature for another 0.5 h. The reaction mixture was added dropwise to saturated aqueous ammonium chloride (20 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine (30 mL). The organic phase was concentrated and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 5-bromo-6-methoxy-1-methyl-1H-indazole (150 mg, 70%) as a yellow solid and 5-bromo-6-methoxy-2-methyl-2H-indazole (60 mg, 28%) as a white solid.

[0453] A1: 5-bromo-6-methoxy-1-methyl-1H-indazole (developer: petroleum ether: ethyl acetate = 3:1, Rf = 0.5). 1H NMR (400MHz, CHLOROFORM-d) 7.89 (s, 1 H), 7.83 (s, 1 H), 6.74 (s, 1 H), 4.03 (s, 3 H), 3.98 (s, 3 H).LC-MS: m / z [M+H] + =241, 243.

[0454] A2: 5-bromo-6-methoxy-2-methyl-2H-indazole (developer: petroleum ether: ethyl acetate = 3:1, Rf = 0.3). 1 H NMR (400MHz, CHLOROFORM-d) 7.85 (s, 1 H), 7.76 (s, 1H), 7.02 (s, 1 H), 4.16 (s, 26 H), 3.94 (s, 3 H) .LC-MS: m / z [M+H] + =241, 243.

[0455] 49: 4-(4-Fluoro-3-(6-methoxy-2-methyl-2H-indazol-5-yl)phenyl)-7-isopropyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and the title compound (45 mg, 60%) was obtained using 5-bromo-6-methoxy-2-methyl-2H-indazole (52 mg, 0.22 mmol) and 4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7-isopropyl-7H-imidazo[4,5-c]pyridazine (68.8 mg, 0.18 mmol) as raw materials.

[0456] 1H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.34 - 8.24 (m, 2 H), 8.19 (d, J = 4.9 Hz, 1 H), 7.85 (s, 1 H), 7.60 (s, 1 H), 7.32 (t, J = 9.0 Hz, 1 H), 7.08 (s, 1 H), 5.18 (br. s., 1 H), 4.19 (s, 3 H), 3.86 (s, 3 H), 1.75 (d, J = 6.8 Hz, 6 H). LC-MS: m / z[M+H] + =417.

[0457] Example 50

[0458] [ka]

[0459] 50-1:1-Bromo-2,4-difluoro-3-nitrobenzene 1,3-Difluoro-2-nitrobenzene (5.0 g, 31.4 mmol) was dissolved in a mixture of concentrated sulfuric acid (10 mL) and trifluoroacetic acid (50 mL), followed by the addition of N-bromosuccinimide (6.7 g, 37.7 mmol) and stirring at room temperature for 16 hours. The reaction mixture was poured into ice water (300 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with 2 mol / L sodium hydroxide solution (200 mL x 2), saturated sodium bicarbonate solution (200 mL), and saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to give a red oily liquid (5.0 g, 65% yield).

[0460] 50-2: 1-Bromo-4-fluoro-2-methoxy-3-nitrobenzene 1-Bromo-2,4-difluoro-3-nitrobenzene (4.5 g, 18.9 mmol) was dissolved in methanol (50 mL), and a solution of sodium methoxide in methanol (4.0 mL, 5 mol / L) was added dropwise. The mixture was stirred at room temperature for 2 hours, then poured into ice water (200 mL), extracted with ethyl acetate (150 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give a white solid (1.0 g, yield: 21%). 1 H NMR (400 MHz, DMSO-d6) 8.04 (dd, J = 9.2Hz, 5.9Hz,1H), 7.44 (t, J = 9.3Hz 1H), 3.95(s, 3H).

[0461] 50-3: 4-Bromo-N-cyclopropyl-3-methoxy-2-nitroaniline 1-Bromo-4-fluoro-2-methoxy-3-nitrobenzene (500 mg, 2.0 mmol), cyclopropylamine (1.14 g, 20 mmol), and dimethyl sulfoxide (5 mL) were added to a microwave tube, and the reaction system was microwaved at 80 °C for 2 hours. The reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 15:1) to give a yellow solid (300 mg, yield: 85%). LC-MS: m / z [M+H] + =287.

[0462] 50-4: 4-Bromo-N1-cyclopropyl-3-methoxybenzene-1,2-diamine 4-Bromo-N-cyclopropyl-3-methoxy-2-nitroaniline (300.0 mg, 1.04 mmol) was dissolved in methanol (20 mL), Raney nickel (100 mg) was added, and the mixture was stirred at room temperature under a hydrogen gas balloon for 2 hours. The reaction was completed after filtration and the filtrate was concentrated to give a brown solid (256 mg, 94% yield). LC-MS: m / z [M+H] + =257.

[0463] 50-5: 5-Bromo-1-cyclopropyl-4-methoxy-1H-benzo[d][1,2,3]triazole 4-Bromo-N1-cyclopropyl-3-methoxybenzene-1,2-diamine (256 mg, 1.0 mmol) was dissolved in acetic acid (5 mL) and added to a reaction vial. An aqueous solution (1 mL) of sodium nitrite (173 mg, 2.5 mmol) was added dropwise to the reaction vial at 0°C. After stirring at room temperature for 30 minutes, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (50 mL x 5), concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give a yellow solid (150 mg, yield: 56%). LC-MS: m / z [M+H] + =268.

[0464] 50: 4-(3-(1-cyclopropyl-4-methoxy-1H-benzo[d][1,2,3]triazol-5-yl)-4-fluorophenyl)-7-isopropyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-1-cyclopropyl-4-methoxy-1H-benzo[d][1,2,3]triazole (58 mg, 0.22 mmol) and 4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7-isopropyl-7H-imidazo[4,5-c]pyridazine (68.8 mg, 0.18 mmol) were used as raw materials to obtain the title compound (45 mg, 60%).

[0465] 1H NMR (400MHz, CHLOROFORM-d) 9.38 (s, 1 H), 8.32 (s, 1 H), 8.29 - 8.20 (m, 2 H), 7.49 (d, J = 8.3 Hz, 1 H), 7.41 - 7.31 (m, 2 H), 5.32 - 5.15 (m, 1 H), 4.60 (s, 3 H), 3.78 (d, J = 3.9 Hz, 1 H), 1.77 (d, J = 6.4 Hz, 6 H), 1.41 (br. s., 2 H), 1.33 (d, J = 5.9 Hz, 2 H). LC-MS: m / z[M+H] + =444.

[0466] Example 51

[0467] [ka]

[0468] 51-1: 6-Bromo-3-cyclopropyl-5-methoxybenzo[d]oxazol-2(3H)-one 6-Bromo-5-methoxybenzo[d]oxazol-2(3H)-one (500 mg, 2.05 mmol), copper acetate (102 mg, 0.51 mmol), 1,10-phenanthroline (56 mg, 0.15 mmol), and potassium carbonate (566 mg, 4.10 mmol) were suspended in toluene (10 mL) and water (2.5 mL) and heated to 70 °C under an oxygen atmosphere (1 atm) for 16 h. The reaction mixture was quenched by pouring into saturated ammonium chloride (100 mL). The mixture was extracted with ethyl acetate (50 mL x 3) and spin-dried to give a crude product. The product was purified by HPLC to give the title product (144 mg, white solid) in 21% yield. LCMS: m / z [M+H] + =284.1.

[0469] 51: 3-Cyclopropyl-6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxybenzo[d]oxazol-2(3H)-one The experimental procedure was the same as in Example 1, and 6-bromo-3-cyclopropyl-5-methoxybenzo[d]oxazol-2(3H)-one (144.0 mg, 0.51 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (144.9 mg, 0.51 mmol) were used as raw materials to obtain the title product (25.1 mg, white solid), with a yield of 11%.

[0470] 1 H NMR (400 MHz, DMSO-d6)δ9.55 (s, 1H), 8.85 (s, 1H), 8.44 (m, 2H), 7.48 (t, 1H), 7.36 (s, 1H), 7.04 (s, 1H), 4.51 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.05 (m, 1H), 1.56 (t, J = 7.2 Hz, 3H), 1.21-0.96 (m, 4H). LCMS: m / z [M+H] + =446.1.

[0471] Example 52

[0472] [ka]

[0473] 52-1: 6-Bromo-3-ethyl-5-methoxybenzo[d]oxazol-2(3H)-one 6-Bromo-5-methoxybenzo[d]oxazol-2(3H)-one (200 mg, 0.82 mmol) was added to dimethyl sulfoxide (20 mL), and ethyl iodide (1.97 mL, 0.82 mmol) and cesium carbonate (534.43 mg, 1.64 mmol) were added, followed by stirring at 80°C for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate (40 mL x 3), concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give the title compound (175 mg, yield: 78%) as a pink solid. LC-MS: m / z [M+H] + =272.

[0474] 52: 3-Ethyl-6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxybenzo[d]oxazol-2(3H)-one The experimental procedure was the same as in Example 1, and the title compound (100 mg, yield: 36%) was obtained using 6-bromo-3-ethyl-5-methoxybenzo[d]oxazol-2(3H)-one (175 mg, 0.64 mmol) and (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (184.01 mg, 0.64 mmol).

[0475] 1 H NMR (400 MHz, DMSO-d6) 9.55 (s, 1H), 8.85 (s, 1H), 8.50 - 8.38 (m, 2H), 7.48 (t, J = 9.3 Hz, 1H), 7.39 (s, 1H), 7.25 (s, 1H), 4.51 (q, J = 7.3 Hz, 2H), 3.94 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 1.56 (t, J = 7.3 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H). LC-MS: m / z [M+H] + =434.2.

[0476] Example 53

[0477] [ka]

[0478] 53-1: 6-Bromo-5-methoxy-3-methylbenzo[d]thiazol-2(3H)-one 5-Methoxy-3-methylbenzo[d]thiazol-2(3H)-one (230 mg, 1.2 mmol) was dissolved in 5 mL of acetic acid, 2 mL of 3M hydrogen bromide-acetic acid solution was added, and the mixture was stirred at room temperature for 30 minutes. After cooling to 0°C, 1 mL of hydrogen peroxide was added, and the mixture was warmed to room temperature and stirred for 2 hours. Water was added, and a large amount of solid precipitated. The mixture was extracted with dichloromethane, dried, and concentrated to give the title compound (170 mg, 52%) as a white solid. LC-MS: m / z [M+H] + =272.

[0479] 53: 6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxy-3-methylbenzo[d]thiazol-2(3H)-one The experimental procedure was the same as in Example 1, 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 (220 mg, 0.6 mmol), 6-bromo-5-methoxy-3-methylbenzo[d]thiazol-2(3H)-one (160 mg, 0.6 mmol) were used as raw materials to obtain the title compound (118 mg, 45%) as a white solid.

[0480] 1 H NMR (400 MHz, CHLOROFORM-d) 9.28 - 9.41 (m, 1 H) 8.23 ​​- 8.31 (m, 2 H) 8.21 (d, J=6.85 Hz, 1 H) 7.41 (s, 1 H) 7.35 (t, J=8.80 Hz, 1 H) 6.71(s, 1 H) 4.59 (q, J=7.17 Hz, 2 H) 3.90 (s, 3 H) 3.52 (s, 3 H) 1.68 - 1.73 (m, 3 H). LC-MS: m / z [M+H]+ =436.

[0481] Example 54

[0482] [ka]

[0483] 54-1: 1-(2-amino-5-bromo-4-methoxyphenyl)-2-chloroethan-1-one 4-Bromo-3-methoxyaniline (CAS: 19056-40-7, 100 mg, 0.5 mmol) was added to 5 mL of 1,2-dichloroethane, 1 M boron trichloride (1.5 mL, 1.5 mmol) was added, and the mixture was stirred for 10 minutes. After that, chloroacetonitrile (112 mg, 1.5 mmol) and zinc chloride (204 mg, 1.5 mmol) were added, and the mixture was then reacted at 40 °C overnight. After cooling to room temperature, the mixture was neutralized with 1 M hydrochloric acid and further heated to reflux for 1 hour. The mixture was extracted with dichloromethane, dried, and concentrated to give the title compound (100 mg, 90%) as a yellow solid. LC-MS: m / z [M+H] + =278.

[0484] 54-2: 5-Bromo-6-methoxy-1H-indole 1-(2-amino-5-bromo-4-methoxyphenyl)-2-chloroethan-1-one (500 mg, 1.8 mmol) and sodium borohydride (62 mg, 1.6 mmol) were added sequentially to 20 mL of dioxane and 2 mL of water, and then reacted overnight at 100° C. Water was added, and the mixture was extracted with ethyl acetate, concentrated, and purified by preparative plate (petroleum ether:ethyl acetate=5:1) to give the title compound (170 mg, 42%) as a yellow solid. LC-MS: m / z [M+H] + =226.

[0485] 54-3: 5-Bromo-6-methoxyindoline 5-Bromo-6-methoxy-1H-indole (100 mg, 0.45 mmol) was added to dichloromethane (1 mL) and methanol (0.5 mL). Sodium cyanoborohydride (56 mg, 0.89 mmol) was then added to the reaction mixture. Acetic acid (1 mL) was then added dropwise to the reaction mixture and stirred at room temperature for 2 hours. 10 mL of saturated aqueous sodium hydroxide was added to the reaction mixture to adjust the pH to basic. Ethyl acetate (3 x 50 mL) was then added for extraction. The ethyl acetate was washed three times with water, then once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (80 mg, 79%). LC-MS: m / z [M+H] + =228.

[0486] 54-4: (5-Bromo-6-methoxyindol-1-yl)(pyrrolidin-1-yl)methanone 5-Bromo-6-methoxyindoline (80 mg, 0.35 mmol), 1-pyrrolidinecarbonyl chloride (93.5 mg, 0.7 mmol), and triethylamine (106 mg, 1.05 mmol) were added to dichloromethane (4 ml) and stirred overnight at 30° C. The reaction mixture was directly purified by thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (20 mg, 18%). LC-MS: m / z [M+H] + =325.

[0487] 54: (5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxyindol-1-yl)(pyrrolidin-1-yl)methanone The experimental procedure was the same as in Example 1, and the title compound (9 mg, 27%) was obtained using (5-bromo-6-methoxyindol-1-yl)(pyrrolidin-1-yl)methanone (20 mg, 0.062 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 (23 mg, 0.06 mmol). LC-MS: m / z [M+H] + =487.

[0488] 1 H NMR (400 MHz, CHLOROFORM-d) 1.69 (br. s., 3 H) 1.94 (br. s., 4 H) 3.11 (t, J=8.07 Hz, 2 H) 3.52 (br. s., 4 H) 3.82 (s, 3 H) 4.04 (t, J=8.31 ​​Hz, 2H) 4.54 - 4.62 (m, 2 H) 7.13 (s, 2 H) 7.30 - 7.36 (m, 1 H) 8.16 (d, J=6.85 Hz, 1 H) 8.21 - 8.30 (m, 2 H) 9.37 (s, 1 H).

[0489] Example 55

[0490] [ka]

[0491] 55: 6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxy-1-methylquinolin-2(1H)-one The experimental procedure was the same as in Example 1, 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 (136 mg, 0.37 mmol), 6-bromo-7-methoxy-1-methylquinolin-2(1H)-one (99 mg, 0.37 mmol) were used as raw materials to obtain the title compound (90 mg, 57%) as a white solid.

[0492] 1H NMR (400 MHz, CHLOROFORM-d) 9.38 (s, 1 H) 8.26 - 8.34 (m, 2 H) 8.24 (dd, J=6.85, 1.96 Hz, 1 H) 7.67 (d, J=9.29 Hz, 1 H) 7.57 (s, 1 H) 7.36 (t, LC-MS: m / z [M+H] + =430.

[0493] Example 56

[0494] [ka]

[0495] 56-1: 5-Bromo-4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole 5-Bromo-4-methoxy-1H-indazole (CAS: 850363-67-6, 250 mg, 1.1 mmol) was dissolved in 10 mL of N,N-dimethylformamide, tetrahydro-2H-pyran-4-ylmethanesulfonic acid (400 mg, 2.2 mmol) and cesium carbonate (1 g, 3.3 mmol) were added, and the mixture was heated to 70 °C and stirred for 3 hours. The mixture was diluted with water, extracted with ethyl acetate, concentrated, and purified by preparative plate (petroleum ether: ethyl acetate = 3:1) to give the title compound (240 mg, 70%) as a white solid. LC-MS: m / z [M+H] + =311.

[0496] 56:7-Ethyl-4-(4-fluoro-3-(4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, 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 (129 mg, 0.35 mmol), 5-bromo-4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (110 mg, 0.35 mmol) were used as raw materials to obtain the title compound (50 mg, 30%) as a white solid.

[0497] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.39 (s, 1 H) 8.19 - 8.32 (m, 4 H) 7.33 - 7.45 (m, 2 H) 7.22 (d, J=8.31 ​​Hz, 1 H) 4.63 - 4.73 (m, 1 H) 4.59 (q, J=7.34 Hz, 2 H) 4.13 - 4.27 (m, 5 H) 3.66 (t, J=11.49 Hz, 2 H) 2.45 (qd, J=12.23, 4.40 Hz, 2 H) 2.04 (d, J=12.72 Hz, 2 H) 1.70 (t, J=7.34 Hz, 3H). LC-MS: m / z [M+H] + =473.

[0498] Example 57

[0499] [ka]

[0500] 57-1: N-(3-methoxy-2-nitrophenyl)tetrahydro-2H-pyran-4-amine 1-Fluoro-3-methoxy-2-nitrobenzene (500 mg, 2.9 mmol), tetrahydro-2H-pyran-4-amine (590 mg, 5.8 mmol), and potassium carbonate (1200 mg, 8.8 mmol) were added to dimethyl sulfoxide (20 ml). The mixture was stirred at 90°C overnight. Ethyl acetate (300 ml) was added to the reaction mixture, which was then washed with water (200 ml x 3), dried with ethyl acetate, and concentrated to give the title compound (730 mg, 99%). LC-MS: m / z [M+H] + =253.

[0501] 57-2: N-(4-bromo-3-methoxy-2-nitrophenyl)tetrahydro-2H-pyran-4-amine N-(3-Methoxy-2-nitrophenyl)tetrahydro-2H-pyran-4-amine (730 mg, 2.9 mmol) and N-bromosuccinimide (620 mg, 3.48 mmol) were added to acetonitrile (20 ml). The mixture was stirred at room temperature overnight. Ethyl acetate (300 ml) was added to the reaction mixture, which was then washed with water (200 ml x 3), dried with ethyl acetate, and concentrated to give the title compound (750 mg, 75%). LC-MS: m / z [M+H] + =331.

[0502] 57-3: 4-Bromo-3-methoxy-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine N-(4-Bromo-3-methoxy-2-nitrophenyl)tetrahydro-2H-pyran-4-amine (750 mg, 2.3 mmol) and Raney nickel (100 mg, 1.7 mmol) were added to methanol (20 ml). The mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated to give the title compound (600 mg, 88%). LC-MS: m / z [M+H] + =301.

[0503] 57-4: 5-Bromo-4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole 4-Bromo-3-methoxy-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine (500 mg, 1.66 mmol) was added to triethyl orthoformate (20 ml). The mixture was stirred at 90° C. overnight. The reaction mixture was directly subjected to thin layer chromatography (dichloromethane / methanol=30 / 1) to obtain the title compound (400 mg, 70%). LC-MS: m / z [M+H] + =311.

[0504] 57:7-Ethyl-4-(4-fluoro-3-(4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole (100 mg, 0.32 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 (118 mg, 0.32 mmol) were used as raw materials to obtain the title compound (35 mg, 22%).

[0505] 1 H NMR (400 MHz, CHLOROFORM-d) d ppm 1.68 (t, J=7.09 Hz, 3 H) 2.13 - 2.28 (m, 4 H) 3.64 (t, J=11.00 Hz, 2 H) 4.20 (d, J=10.27 Hz, 2 H) 4.38 (s, 3 H)4.44 (d, J=11.25 Hz, 1 H) 4.57 (d, J=7.34 Hz, 2 H) 7.19 (d, J=7.83 Hz, 1 H) 7.25 - 7.40 (m, 2 H) 7.98 (br. s., 1 H) 8.14 - 8.34 (m, 3 H) 9.37 (s, 1H). LC-MS: m / z [M+H] + =473.

[0506] Example 58

[0507] [ka]

[0508] 58-1: Ethyl 5-methoxy-3-methylbenzofuran-2-carboxylate Under an argon gas atmosphere, 1-(2-hydroxy-5-methoxyphenyl)ethan-1-one (CAS: 705-15-7, 1 g, 6 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and ethyl bromoacetate (1.3 g, 7.8 mmol) and potassium carbonate (1.7 g, 4.5 mmol) were heated to 100 °C and stirred overnight. The mixture was diluted with water, extracted with ethyl acetate, and concentrated to give the title compound (1 g, 71%) as a red solid. LC-MS: m / z [M+H] + =235.

[0509] 58-2: 5-Methoxy-3-methylbenzofuran-2-carboxylic acid Ethyl 5-methoxy-3-methylbenzofuran-2-carboxylate (1 g, 4.2 mmol) was dissolved in 10 mL of ethanol, 4 M aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with water and neutralized with 1 M hydrochloric acid. The solid was filtered and dried to give the title compound (600 mg, 70%) as a red solid. LC-MS: m / z [M+H] + =207.

[0510] 58-3: (5-Methoxy-3-methylbenzofuran-2-yl)(pyrrolidin-1-yl)methanone 5-Methoxy-3-methylbenzofuran-2-carboxylic acid (600 mg, 2.9 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.2 g, 5.8 mmol), pyrrolidine (310 mg, 4.3 mmol), and N,N-diisopropylethylamine (2 mL) were added sequentially to 10 mL of dichloromethane and stirred at room temperature for 3 hours. The mixture was washed with saturated aqueous ammonium chloride, dried, and concentrated to give the crude title compound (1 g, 100%) as a red solid. LC-MS: m / z [M+H] + =260.

[0511] 58-4: (6-Bromo-5-methoxy-3-methylbenzofuran-2-yl)(pyrrolidin-1-yl)methanone (5-Methoxy-3-methylbenzofuran-2-yl)(pyrrolidin-1-yl)methanone (300 mg, 1 mmol) was dissolved in 10 mL of acetonitrile, and N-bromosuccinimide (150 mg, 1 mmol) was added. The mixture was heated to 40°C and stirred for 2 hours. Purification by preparative plate (petroleum ether: ethyl acetate = 3:1) afforded the title compound (60 mg, 18%) as a white solid. LC-MS: m / z [M+H] + =338.

[0512] 58: (6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxy-3-methylbenzofuran-2-yl)(pyrrolidin-1-yl)methanone The experimental procedure was the same as in Example 1, 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 (77 mg, 0.21 mmol), (6-bromo-5-methoxy-3-methylbenzofuran-2-yl)(pyrrolidin-1-yl)methanone (70 mg, 0.21 mmol) were used as raw materials to obtain the title compound (15 mg, 14%) as a white solid.

[0513] 1H NMR (400 MHz, CHLOROFORM-d) 9.38 (s, 1 H) 8.28 (s, 2 H) 8.19 - 8.26 (m, 1 H) 7.47 (s, 1 H) 7.32 - 7.40 (m, 1 H) 7.11 (s, 1 H) 4.54 - 4.62 (m, 2 H) 3.87 - 3.95 (m, 5 H) 3.65 - 3.72 (m, 2 H) 2.60 (s, 3 H) 1.92 - 2.02 (m, 4 H) 1.66 - 1.73 (m, 3 H). LC-MS: m / z [M+H] + =500.

[0514] Example 59

[0515] [ka]

[0516] 59-1: 6-Bromo-3-isopropyl-5-methoxybenzo[d]oxazol-2(3H)-one 6-Bromo-5-methoxybenzo[d]oxazol-2(3H)-one (1.0 g, 4.10 mmol), 2-iodopropane (17.4 mL, 122.95 mmol), and cesium carbonate (2.67 g, 8.20 mmol) were dissolved in dimethyl sulfoxide (20 mL) and heated to 80 °C in an autoclave for 16 hours. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to give the crude product (344 mg, white solid) in 29% yield. This product was purified by HPLC. 1 H NMR (400 MHz, DMSO-d6) 7.64 (s, 1H), 7.19 (s, 1H), 4.52 (m, 1H), 3.89 (s, 3H), 1.47 (d, J = 6.9 Hz, 6H). LCMS: m / z [M+H] + = 286.1.

[0517] 59: 6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-3-isopropyl-5-methoxybenzo[d]oxazol-2(3H)-one The experimental procedure was the same as in Example 1, and 6-bromo-3-isopropyl-5-methoxybenzo[d]oxazol-2(3H)-one (244 mg, 0.85 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (244 mg, 0.85 mmol), and cesium carbonate (277.9 mg, 0.85 mmol) were used as raw materials to obtain the title product (144.1 mg, white solid), with a yield of 38%.

[0518] 1 H NMR (400 MHz, DMSO-d6) 9.55 (s, 1H), 8.86 (s, 1H), 8.45 (m, 2H), 7.50 (m, 1H), 7.39 (s, 1H), 7.22 (s, 1H), 4.53 (m, 3H), 3.84 (s, 3H), 1.55 (m, 9H). LCMS: m / z [M+H] + =448.

[0519] Example 60

[0520] [ka]

[0521] 60-1: 5-Bromo-1-(ethylsulfonyl)-6-methoxyindoline 5-Bromo-6-methoxyindoline (70 mg, 0.31 mmol), (chloromethyl)sulfonyluethane (79 mg, 0.62 mmol), and triethylamine (0.5 ml) were added to dichloromethane (3 ml). The mixture was stirred at room temperature for 3 hours. The reaction mixture was directly subjected to thin layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (40 mg, 40.1%). LC-MS: m / z [M+H] + =320.

[0522] 60:7-Ethyl-4-(3-(1-(ethylsulfonyl)-6-methoxyindol-5-yl)-4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-1-(ethylsulfonyl)-6-methoxyindoline (40 mg, 0.125 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 (46 mg, 0.125 mmol) were used as raw materials to obtain the title compound (20 mg, 33%).

[0523] 1 H NMR (400 MHz, CHLOROFORM-d) 1.45 (t, J=7.58 Hz, 3 H) 1.69 (t, J=7.34 Hz, 3 H) 3.10 - 3.24 (m, 4 H) 3.83 (s, 3 H) 4.12 (t, J=8.56 Hz, 2 H)4.58 LC-MS: m / z [M+H] + =482.

[0524] Example 61

[0525] [ka]

[0526] 61-1: 6-Bromo-7-methoxyisoquinoline Sodium methoxide (1 g, 18 mmol) was dissolved in 10 mL of methanol, 6-bromo-7-fluoroisoquinoline (CAS: 1258833-80-5, 1 g, 4.2 mmol) was added, and the mixture was heated to reflux for 2 hours. The mixture was diluted with water, extracted with ethyl acetate, dried, and concentrated to give the title compound (800 mg, 80%) as a white solid. LC-MS: m / z [M+H] + =238.

[0527] 61-2: 6-Bromo-7-methoxyisoquinoline 2-oxide 6-Bromo-7-methoxyisoquinoline (800 mg, 3.9 mmol) was dissolved in 10 mL of dichloromethane, metachloroperbenzoic acid (1.3 g, 8 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and purified using a preparative plate (dichloromethane:methanol = 40:1) to give the title compound (700 mg, 80%) as a white solid. LC-MS: m / z [M+H] + =254.

[0528] 61-3: 6-Bromo-7-methoxyisoquinolin-1(2H)-one 6-Bromo-7-methoxyisoquinoline 2-oxide (700 mg, 2.7 mmol) was dissolved in 10 mL of acetic anhydride, heated to reflux for 2 hours, cooled, and then 20 mL of water was added. The mixture was further heated to reflux for 2 hours. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified using a preparative plate (dichloromethane:methanol = 20:1) to give the title compound (400 mg, 55%) as a reddish-brown solid. LC-MS: m / z [M+H] + =254.

[0529] 61-4: 6-Bromo-2-ethyl-7-methoxyisoquinolin-1(2H)-one 6-Bromo-7-methoxyisoquinolin-1(2H)-one (100 mg, 0.39 mmol) was dissolved in 5 mL of methanol, potassium carbonate (170 mg, 1.2 mmol) and ethyl iodide (0.2 mL) were added, and the mixture was stirred at room temperature for 3 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by preparative plate chromatography (dichloromethane:methanol=20:1) to give the title compound (60 mg, 55%) as a yellow solid. LC-MS: m / z [M+H] + =282.

[0530] 61: 2-Ethyl-6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxyisoquinolin-1(2H)-one The experimental procedure was the same as in Example 1, 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 (78 mg, 0.21 mmol) and 6-bromo-2-ethyl-7-methoxyisoquinolin-1(2H)-one (60 mg, 0.21 mmol) were used as raw materials to obtain the title compound (50 mg, 54%) as a white solid.

[0531] 1 H NMR (400 MHz, CHLOROFORM-d) 9.38 (s, 1 H) 8.20 - 8.38 (m, 3 H) 7.98 (s, 1 H) 7.55 (s, 1 H) 7.36 (t, J=9.05 Hz, 1 H) 7.03 (d, J=7.34 Hz, 1H) 6.53 (d, J=7.34 Hz, 1 H) 4.58 (q, J=7.17 Hz, 2 H) 4.11 (q, J=7.34 Hz, 2 H) 3.95 (s, 3 H) 1.69 (t, J=7.34 Hz, 3 H) 1.41 (t, J=7.09 Hz, 3 H). LC-MS: m / z [M+H] + =444.

[0532] Example 62

[0533] [ka]

[0534] 62-1: tert-butyl (3S,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-fluoropiperidine-1-carboxylate The experimental procedure was the same as that for synthesizing 40-1 and 40-2 in Example 40. 5-Bromo-4-methoxy-2-nitrobenzaldehyde (300 mg, 1.15 mmol) and tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (500 mg, 2.29 mmol) were used as raw materials to obtain the title compound (250 mg, 51%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =428, 430.

[0535] 62-2: 5-Bromo-2-((3S,4R)-3-fluoropiperidin-4-yl)-6-methoxy-2H-indazole hydrochloride The experimental procedure was the same as that of Example 46, 46-3, and tert-butyl (3S,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-fluoropiperidine-1-carboxylate (250 mg, 0.58 mmol) was used as the raw material to obtain the title compound (203 mg, crude product) as a yellow solid. LC-MS: m / z [M+H] + =328, 330.

[0536] 62-3: 5-Bromo-2-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole The experimental procedure was the same as that of Example 46, 46-4, and 5-bromo-2-((3S,4R)-3-fluoropiperidin-4-yl)-6-methoxy-2H-indazole hydrochloride (203 mg, 0.58 mmol) was used as the raw material to obtain the title compound (150 mg, 76%) as a yellow oily liquid. LC-MS: m / z [M+H] + =342, 344.

[0537] 62: 7-Ethyl-4-(4-fluoro-3-(2-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-2-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole (150 mg, 0.439 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 (162 mg, 0.439 mmol) was used as raw materials to obtain the title compound (18 mg, 8%) as a brown solid.

[0538] 1 H NMR (400MHz, CHLOROFORM-d) δ 9.38 (s, 1 H), 8.27 (s, 2 H), 8.22 (d, J = 5.4 Hz, 1 H), 8.07 (s, 1 H), 7.65 (s, 1 H), 7.33 (t, J = 8.8 Hz, 1 H), 7.07 (s, 1 H), 5.37 - 5.02 (m, 1 H), 4.69 - 4.52 (m, 3 H), 3.87 (s, 3 H), 3.35 (br. s., 1 H), 3.16 (br. s., 1 H), 2.71 - 2.57 (m, 1 H), 2.49 - 2.27 (m, 5 H), 2.22 (br. s., 1 H), 1.69 (s., 3 H). LC-MS: m / z [M+H] + =504.

[0539] Example 63

[0540] [ka]

[0541] 63-1: tert-butyl (3S,4S)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-fluoropiperidine-1-carboxylate The experimental procedure was the same as that for synthesizing 40-1 and 40-2 in Example 40. 5-Bromo-4-methoxy-2-nitrobenzaldehyde (300 mg, 1.15 mmol) and tert-butyl (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate (500 mg, 2.29 mmol) were used as raw materials to obtain the title compound (280 mg, 57%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =428, 430.

[0542] 63-2: 5-Bromo-2-((3S,4S)-3-fluoropiperidin-4-yl)-6-methoxy-2H-indazole hydrochloride The experimental procedure was the same as that of Example 46, 46-3, and tert-butyl (3S,4S)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-fluoropiperidine-1-carboxylate (280 mg, 0.65 mmol) was used as the raw material to obtain the title compound (227 mg, crude product) as a yellow solid. LC-MS: m / z [M+H] + =328, 330.

[0543] 63-3: 5-Bromo-2-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole The experimental procedure was the same as that of Example 46, 46-4, and 5-bromo-2-((3S,4S)-3-fluoropiperidin-4-yl)-6-methoxy-2H-indazole hydrochloride (227 mg, 0.65 mmol) was used as the raw material to obtain the title compound (180 mg, 81%) as a white solid. LC-MS: m / z [M+H] + =342, 344.

[0544] 63: 7-Ethyl-4-(4-fluoro-3-(2-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-2-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole (170 mg, 0.497 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 (183 mg, 0.497 mmol) was used as raw materials to obtain the title compound (89 mg, 36%) as a gray-white solid.

[0545] 1 H NMR (400MHz, CHLOROFORM-d) δ 9.38 (s, 1 H), 8.27 (s, 2 H), 8.21 (d, J = 6.8 Hz, 1 H), 7.99 (s, 1 H), 7.63 (s, 1 H), 7.33 (t, J = 9.0 Hz, 1 H), 7.13 (s, 1 H), 5.32 - 4.97 (m, 1 H), 4.57 (q, J = 7.0 Hz, 2 H), 4.35 (d, J = 11.7 Hz, 1 H), 3.87 (s, 3 H), 3.40 - 3.29 (m, 1 H), 2.99 (d, J = 10.8Hz, 1H), 2.57 - 2.35 (m, 3 H), 2.30 - 2.16 (m, 3 H), 1.68 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H] + =504.

[0546] Example 64

[0547] [ka]

[0548] 64-1: tert-butyl (3S,4R)-3-(5-bromo-6-methoxy-2H-indazol-2-yl)-4-fluoropyrrolidine-1-carboxylate The experimental procedure was the same as that of Example 40, 40-1 and 40-2, and 5-bromo-4-methoxy-2-nitrobenzaldehyde (500 mg, 1.92 mmol) and tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (783 mg, 3.84 mmol) were used as raw materials to obtain the title compound (760 mg, 95%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =414, 416.

[0549] 64-2: 5-Bromo-2-((3S,4R)-4-fluoropyrrolidin-3-yl)-6-methoxy-2H-indazole hydrochloride The experimental procedure was the same as that of Example 46, 46-3, and tert-butyl (3S,4R)-3-(5-bromo-6-methoxy-2H-indazol-2-yl)-4-fluoropyrrolidine-1-carboxylate (760 mg, 1.84 mmol) was used as the raw material to obtain the title compound (720 mg, crude product) as a yellow solid. LC-MS: m / z [M+H] + =314, 316.

[0550] 64-3: 5-Bromo-2-((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)-6-methoxy-2H-indazole The experimental procedure was the same as the synthesis method of 46-4 in Example 46, and 5-bromo-2-((3S,4R)-4-fluoropyrrolidin-3-yl)-6-methoxy-2H-indazole hydrochloride (720 mg, 2.06 mmol) was used as the raw material to obtain the title compound (150 mg, 22%) as a yellow oily liquid. LC-MS: m / z [M+H] + =414, 416.

[0551] 64:7-Ethyl-4-(4-fluoro-3-(2-((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)-6-methoxy-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-2-((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)-6-methoxy-2H-indazole (150 mg, 0.46 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 (169 mg, 0.46 mmol) was used as raw materials to obtain the title compound (60 mg, 27%) as a brown solid.

[0552] 1 H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.30 - 8.24 (m, 2 H), 8.23 ​​- 8.18 (m, 1 H), 8.12 (s, 1 H), 7.62 (s, 1 H), 7.32 (t, J = 8.8 Hz, 1 H), 7.08 (s, 1 H), 5.42 - 5.19 (m, 2 H), 4.56 (q, J = 7.3 Hz, 2 H), 3.86 (s, 3 H), 3.37 - 3.30 (m, 1 H), 3.27 - 3.12 (m, 2 H), 3.11 - 2.96 (m, 1 H), 2.52 (s, 3 H), 1.67 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H] + =490.

[0553] Example 65

[0554] [ka]

[0555] 65-1: 2-(azetidin-1-yl)-5-methoxybenzo[d]oxazole 5-Methoxybenzo[d]oxazole (400 mg, 2.7 mmol) was dissolved in 10 mL of acetonitrile, and azetidine (300 mg, 5.3 mmol), NIS (30 mg, 0.13 mmol), acetic acid (0.5 mL), and 30% hydrogen peroxide (0.6 mL) were added and stirred overnight at room temperature. The mixture was diluted with water, extracted with dichloromethane, concentrated, and purified by preparative plate (petroleum ether:ethyl acetate = 2:1) to give the title compound (70 mg, 4%) as a brown solid. LC-MS: m / z [M+H] + =205.

[0556] 65-2: 2-(azetidin-1-yl)-6-bromo-5-methoxybenzo[d]oxazole 2-(Azetidin-1-yl)-5-methoxybenzo[d]oxazole (70 mg, 0.34 mmol) was dissolved in 10 mL of acetonitrile, N-bromosuccinimide (30 mg, 0.17 mmol) was added, the mixture was heated to 40 °C and stirred overnight, and purified by preparative plate (dichloromethane:methanol = 20:1) to give the title compound (55 mg, 57%) as a brown solid. LC-MS: m / z [M+H] + =283.

[0557] 65: 2-(azetidin-1-yl)-6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxybenzo[d]oxazole The experimental procedure was the same as in Example 1, 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), 2-(azetidin-1-yl)-6-bromo-5-methoxybenzo[d]oxazole (55 mg, 0.19 mmol) were used as raw materials to obtain the title compound (40 mg, 48%) as a white solid.

[0558] 1H NMR (400 MHz, CHLOROFORM-d) 9.38 (s, 1 H) 8.23 ​​- 8.32 (m, 2 H) 8.21 (dd, J=7.09, 2.20 Hz, 1 H) 7.33 (t, J=9.05 Hz, 1 H) 7.26 (s, 1 H) 7.06 (s, 1 H) 4.58 (q, J=7.34 Hz, 2 H) 4.32 (t, J=7.58 Hz, 4 H) 3.83 (s, 3 H) 2.53 (quin, J=7.58 Hz, 2 H) 1.69 (t, J=7.34 Hz, 3 H). LC-MS: m / z [M+H] + =445.

[0559] Example 66

[0560] [ka]

[0561] 66-1: 5-Bromo-2-(3,3-difluorocyclobutyl)-6-methoxy-2H-indazole The experimental procedure was the same as that for synthesizing 40-1 and 40-2 in Example 40. 5-Bromo-4-methoxy-2-nitrobenzaldehyde (200 mg, 0.77 mmol) and 3,3-difluorocyclobutan-1-amine (165 mg, 1.54 mmol) were used as raw materials to obtain the title compound (150 mg, 62%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =317, 319.

[0562] 66: 4-(3-(2-(3,3-difluorocyclobutyl)-6-methoxy-2H-indazol-5-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-2-(3,3-difluorocyclobutyl)-6-methoxy-2H-indazole (150 mg, 0.475 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 (175 mg, 0.475 mmol) were used as raw materials to obtain the title compound (120 mg, 53%) as a white solid.

[0563] 1 H NMR (400MHz, CHLOROFORM-d) δ = 9.38 (s, 1 H), 8.27 (br. s., 2 H), 8.20 (d, J = 6.8 Hz, 1 H), 7.95 (s, 1 H), 7.60 (s, 1 H), 7.33 (t, J = 8.8 Hz, 1 H), 7.13 (s, 1 H), 4.95 (d, J = 5.9 Hz, 1 H), 4.58 (q, J = 7.3 Hz, 2 H), 3.87 (s, 3 H), 3.52 - 3.37 (m, 2 H), 3.23 (d, J = 8.3 Hz, 2 H), 1.69 (t, J = 7.3 Hz, 3H). LC-MS: m / z [M+H] + =479.

[0564] Example 67

[0565] [ka]

[0566] 67-1: 5-Bromo-6-methoxy-2-(1-methyl-1H-pyrazol-5-yl)-2H-indazole The experimental procedure was the same as that for synthesizing 40-1 and 40-2 in Example 40. 5-Bromo-4-methoxy-2-nitrobenzaldehyde (200 mg, 0.77 mmol) and 1-methyl-1H-pyrazol-5-amine (224 mg, 2.31 mmol) were used as raw materials to obtain the title compound (50 mg, 21%) as a white solid. LC-MS: m / z [M+H] + =307, 309.

[0567] 67:7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-(1-methyl-1H-pyrazol-5-yl)-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-2-(1-methyl-1H-pyrazol-5-yl)-2H-indazole (50 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 raw materials to obtain the title compound (12 mg, 16%) as a yellow solid.

[0568] 1 H NMR (400MHz, CHLOROFORM-d) δ = 9.39 (s, 1 H), 8.33 - 8.26 (m, 2 H), 8.25 - 8.21 (m, 1 H), 8.14 (s, 1 H), 7.69 (s, 1 H), 7.57 (d, J = 2.0 Hz, 1 H), 7.35 (t, J = 8.8 Hz, 1 H), 7.12 (s, 1 H), 6.43 (d, J = 2.0 Hz, 1 H), 4.58 (q, J = 7.3 Hz, 2 H), 3.99 (s, 3 H), 3.90 (s, 3 H), 1.69 (t, J = 7.3Hz, 3H). LC-MS: m / z [M+H] + =469.

[0569] Example 68

[0570] [ka]

[0571] 68-1:8-Bromo-N-methylquinoline-3-carboxamide 8-Bromoquinoline-3-carboxylic acid (80 mg, 0.32 mmol), methylamine hydrochloride (65 mg, 0.96 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (360 mg, 0.96 mmol), and triethylamine (97 mg, 0.96 mmol) were added to dichloromethane (5 mL). The mixture was stirred at 40°C overnight. The reaction mixture was directly subjected to thin-layer chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (20 mg, 24%). LC-MS: m / z [M+H] + =265.

[0572] 68:8-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-N-methylquinoline-3-carboxamide The experimental procedure was the same as in Example 1, and the title compound (10 mg, 31%) was obtained using 8-bromo-N-methylquinoline-3-carboxamide (20 mg, 0.076 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 (28 mg, 0.076 mmol).

[0573] 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.69 - 1.78 (m, 3 H) 3.10 (br. s., 3 H) 4.57 (d, J=6.85 Hz, 2 H) 6.52 (br. s., 1 H) 7.43 (br. s., 1 H) 7.71 (br. s.,1 H) 7.85 - 8.06 (m, 2 H) 8.20 - 8.45 (m, 3 H) 8.70 (br. s., 1 H) 9.23 (br. s., 1 H) 9.40 (br. s., 1 H). LC-MS: m / z [M+H] + =427.

[0574] Example 69

[0575] [ka]

[0576] 69-1: 3-Methoxy-N-methyl-2-nitroaniline The experimental procedure was the same as that of Example 57-1. 1-Fluoro-3-methoxy-2-nitrobenzene (800 mg, 4.7 mmol) and methylamine hydrochloride (635 mg, 9.4 mmol) were used as raw materials to obtain the title compound (700 mg, yield: 53%) as a red oily liquid. LC-MS: m / z [M+H] + =183.

[0577] 69-2: 4-Bromo-3-methoxy-N-methyl-2-nitroaniline The experimental procedure was the same as that of Example 57-2. 3-Methoxy-N-methyl-2-nitroaniline (700 mg, 3.8 mmol) was used as the starting material to obtain the title compound (914 mg, yield: 91%) as a yellow oily liquid. LC-MS: m / z [M+H] + =261.

[0578] 69-3: 4-Bromo-3-methoxy-N1-methylbenzene-1,2-diamine The experimental procedure was the same as that of Example 57-3, and 4-bromo-3-methoxy-N-methyl-2-nitroaniline (914 mg, 3.5 mmol) was used as the raw material to obtain the title compound (0.116 g, yield: 55%) as a yellow solid. LC-MS: m / z [M+H] + =231.

[0579] 69-4: 5-Bromo-4-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole 4-Bromo-3-methoxy-N1-methylbenzene-1,2-diamine (696 mg, 3.0 mmol) was dissolved in acetic acid (7 mL), and an aqueous solution (5 mL) of sodium nitrite (414 mg, 6.0 mmol) was added dropwise to the reaction mixture at 0°C. After stirring for 30 minutes at 0°C, the reaction was completed. The reaction mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain the title compound (365 mg, yield: 50%) as a yellow solid. LC-MS: m / z [M+H] + =242.

[0580] 69: 4-(4-Fluoro-3-(4-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)phenyl)-7-isopropyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and the title compound (157 mg, yield: 38%) was obtained using 5-bromo-4-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole (242 mg, 1.0 mmol), (2-fluoro-5-(7-isopropyl-7H-imidazo[4,5-c]pyridazin-4-yl)phenyl)boronic acid (314 mg, 1.1 mmol) as raw materials.

[0581] 1H NMR (400 MHz, CDCl3) 9.41 (s, 1H), 8.38 (s, 1H), 8.34-8.22 (m, 2H), 7.48 (d, 1H), 7.38 (t, 1H), 7.18 (d, 1H), 5.32-5.07 (m, 1H), 4.61 (s, 3H), 4.31 (s, 3H), 1.77 (d, J = 6.7 Hz, 6H). LC-MS: m / z [M+H] + =418.

[0582] Example 70

[0583] [ka]

[0584] 70: 4-(3-(1-cyclopropyl-4-methoxy-1H-benzo[d][1,2,3]triazol-5-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-1-cyclopropyl-4-methoxy-1H-benzo[d][1,2,3]triazole (100 mg, 0.37 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (126 mg, 0.45 mmol) were used as raw materials to obtain the title compound (83 mg, white solid), with a yield of 41%.

[0585] 1 H NMR (400 MHz, CDCl3) 9.41 (s, 1H), 8.38-8.21 (m, 3H), 7.48 (d, 1H), 7.38 (t, 1H), 7.33 (d, 1H), 4.65-4.49 (m, 5H), 3.84-3.72 (m, 1H), 1.70 (t, J = 7.3 Hz, 3H), 1.46-1.38 (m, 2H), 1.37-1.30 (m, 2H). LC-MS: m / z [M+H] + =430.

[0586] Example 71

[0587] [ka]

[0588] 71-1: 2-Bromo-3-(dimethoxymethyl)phenol 2-Bromo-3-hydroxybenzaldehyde (4 g, 20 mmol) and trimethyl orthoformate (4.1 g, 40 mmol) were added to methanol (10 ml), and concentrated hydrochloric acid (0.02 ml) was added dropwise, followed by reaction at 60° C. overnight. The reaction solution was evaporated to dryness to obtain the title compound (5338 mg) as a crude product.

[0589] 71-2: 2,4-Dibromo-3-hydroxybenzaldehyde 2-Bromo-3-(dimethoxymethyl)phenol (5338 mg, 20 mmol) was added to chloroform (10 ml) and stirred at 0°C for 10 minutes. Liquid bromine (1.8 g, 12 mmol) was dissolved in chloroform (10 ml) and slowly added dropwise to the reaction mixture at 0°C. After the addition was complete, the reaction mixture was allowed to react at 0°C for 1 hour. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate solution (50 ml), extracted with dichloromethane, and concentrated. The resulting intermediate was dissolved in dichloromethane (20 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred at 25°C for 30 minutes. The reaction mixture was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain the title compound (570 mg, 10%) as a yellow solid. LC-MS: m / z [M+H] + =279, 281, 283.

[0590] 71-3: 2,4-Dibromo-3-methoxybenzaldehyde 2,4-Dibromo-3-hydroxybenzaldehyde (570 mg, 2.036 mmol), potassium carbonate (2484 mg, 18 mmol), and methyl iodide (1406 mg, 9.9 mmol) were added to acetonitrile (5 ml) and reacted at 50°C overnight. The reaction mixture was added to water (50 ml), extracted with ethyl acetate, and concentrated to give the title compound (688 mg) as a crude yellow solid. LC-MS: m / z [M+H] + =293, 295, 297.

[0591] 71-4: N'-(2,4-dibromo-3-methoxybenzylidene)-4-methylbenzenesulfonohydrazide 2,4-Dibromo-3-methoxybenzaldehyde (688 mg, 2.340 mmol) and p-toluenesulfonyl hydrazide (1637 mg, 8.8 mmol) were added to ethanol (5 mL) and reacted at 80°C overnight. The reaction mixture was concentrated and subjected to column chromatography (dichloromethane / methanol = 30 / 1) to give the title compound (717 mg, 66%) as a yellow solid. LC-MS: m / z [M+H]+ = 461,463,465.

[0592] 71-5: 6-Bromo-7-methoxy-1-tosyl-1H-indazole N'-(2,4-Dibromo-3-methoxybenzylidene)-4-methylbenzenesulfonohydrazide (717 mg, 1.552 mmol) and cuprous oxide (343 mg, 2.4 mmol) were added to isopropanol (10 ml) and reacted at 100°C overnight. The reaction mixture was suction filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 30 / 1) to give the title compound (327 mg, 55%) as a brown oily liquid. LC-MS: m / z [M+H] + =381,383.

[0593] 71-6: 6-Bromo-7-methoxy-1H-indazole 6-Bromo-7-methoxy-1-tosyl-1H-indazole (327 mg, 0.858 mmol) was added to methanol (6 ml), magnesium chips (42 mg, 1.716 mmol) were added, and the mixture was reacted at 0°C for 3 hours under argon gas protection. The reaction mixture was suction filtered, concentrated, and subjected to preparative thin-layer chromatography (petroleum ether / dichloromethane / methanol = 10 / 30 / 1) to obtain the title compound (141 mg, 72%) as a yellow solid. LC-MS: m / z [M+H] + =227,229.

[0594] 71-A1: 6-Bromo-7-methoxy-1-methyl-1H-indazole 71-A2: 6-Bromo-7-methoxy-2-methyl-2H-indazole 6-Bromo-7-methoxy-1H-indazole (135 mg, 0.595 mmol), methyl iodide (85 mg, 0.595 mmol), and cesium carbonate (395 mg, 1.190 mmol) were added to N,N-dimethylformamide (2 mL) and reacted at 25°C for 15 minutes. The reaction mixture was filtered under suction and subjected to preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compounds A1 (49 mg, 34.17%, Rf = 0.6) and A2 (51 mg, 34.23%, Rf = 0.4) as white solids. LC-MS: m / z [M+H] + =241,243.

[0595] 71:7-Ethyl-4-(4-fluoro-3-(7-methoxy-2-methyl-2H-indazol-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, 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 (61 mg, 0.166 mmol), 6-bromo-7-methoxy-2-methyl-indazole (40 mg, 0.166 mmol) were used as raw materials to obtain the title compound (25 mg, 37%) as a pale yellow solid.

[0596] 1H NMR (400MHz, CHLOROFORM-d) 9.39 (s, 1 H), 8.32 - 8.25 (m, 3 H), 7.95 (s, 1 H), 7.42 - 7.34 (m, 2 H), 7.07 (d, J = 8.8 Hz, 1 H), 4.58 (q, J = 7.3 Hz, 2 H), 4.27 (s, 3 H), 4.24 (s, 3 H), 1.69 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H] + =403.

[0597] Example 72

[0598] [ka]

[0599] 72:7-Ethyl-4-(4-fluoro-3-(7-methoxy-1-methyl-1H-indazol-6-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, 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 (61 mg, 0.166 mmol) and 6-bromo-7-methoxy-1-methyl-1H-indazole (40 mg, 0.166 mmol) were used as raw materials to obtain the title compound (14 mg, 21%) as a pale yellow solid.

[0600] 1H NMR (400MHz, CHLOROFORM-d) 9.40 (br. s., 1 H), 8.39 - 8.32 (m, 2 H), 8.29 (s, 1 H), 8.00 (s, 1 H), 7.53 (d, J = 8.3 Hz, 1 H), 7.41 (t, J = 8.8 Hz, 1 H), 7.14 (d, J = 7.8 Hz, 1 H), 4.58 (q, J = 7.3 Hz, 2 H), 4.33 (s, 3 H), 3.60 (s, 3 H), 1.69 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H] + =403.

[0601] Example 73

[0602] [ka]

[0603] 73-1: 5-Methoxybenzo[d]oxazole 2-Amino-4-methoxyphenol (CAS: 20734-76-3, 1 g, 7.2 mmol) was dissolved in 10 mL of toluene, 3A molecular sieves (1 g) was added, and triethyl orthoformate (1.5 g, 10 mmol) was heated to 100 °C and stirred overnight. The mixture was diluted with saturated aqueous ammonium chloride, extracted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 30:1) to give the title compound (900 mg, 83%) as a yellow solid. LC-MS: m / z [M+H] + =150.

[0604] 73-2: 5-Methoxy-2-morpholinobenzo[d]oxazole 5-Methoxybenzo[d]oxazole (40 mg, 2.7 mmol) was dissolved in 10 mL of acetonitrile, and morpholine (464 mg, 5.3 mmol), N-iodosuccinimide (30 mg, 0.13 mmol), 0.5 mL of acetic acid, and 30% hydrogen peroxide (0.6 mL) were added. The mixture was stirred overnight at room temperature, diluted with water, extracted with dichloromethane, concentrated, and purified by preparative plate (petroleum ether:ethyl acetate = 5:1) to give the title compound (120 mg, 20%) as a white solid. LC-MS: m / z [M+H] + =235.

[0605] 73-3: 6-Bromo-5-methoxy-2-morpholinobenzo[d]oxazole 5-Methoxy-2-morpholinobenzo[d]oxazole (120 mg, 0.5 mmol) was dissolved in 10 mL of acetonitrile, N-bromosuccinimide (108 mg, 0.6 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was purified by preparative plate (dichloromethane) to give the title compound (200 mg, 100%) as a white solid. LC-MS: m / z [M+H] + =313.

[0606] 73: 6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxy-2-morpholinobenzo[d]oxazole The experimental procedure was the same as in Example 1, 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 (100 mg, 0.27 mmol) and 6-bromo-5-methoxy-2-morpholinobenzo[d]oxazole (100 mg, 0.27 mmol) were used as raw materials to obtain the title compound (42 mg, 33%) as a brown solid.

[0607] 1H NMR (400 MHz, CHLOROFORM-d) 9.38 (br. s., 1 H) 8.24 - 8.34 (m, 2 H) 8.11 - 8.22 (m, 1 H) 7.34 (t, J=9.05 Hz, 1 H) 7.25 (s, 1 H) 7.06 (s, 1 H) 4.58 (q, J=7.34 Hz, 2 H) 3.78 - 3.89 (m, 7 H) 3.67 - 3.75 (m, 4 H) 1.69 (t, J=7.34 Hz, 3 H). LC-MS: m / z [M+H] + =475.

[0608] Example 74

[0609] [ka]

[0610] 74-1: tert-Butyl 4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3,3-difluoropiperidine-1-carboxylate The experimental procedure was the same as that for synthesizing 40-1 and 40-2 in Example 40. 5-Bromo-4-methoxy-2-nitrobenzaldehyde (275 mg, 1.06 mmol) and tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate (250 mg, 1.06 mmol) were used as raw materials to obtain the title compound (330 mg, 70%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =446, 448.

[0611] 74-2: 5-Bromo-2-(3,3-difluoropiperidin-4-yl)-6-methoxy-2H-indazole hydrochloride The experimental procedure was the same as that of Example 46, 46-3, and tert-butyl 4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3,3-difluoropiperidine-1-carboxylate (330 mg, 0.74 mmol) was used as the raw material to obtain the title compound (190 mg, 67%) as a yellow solid. LC-MS: m / z [M+H] + =346, 348.

[0612] 74-3: 5-Bromo-2-(3,3-difluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole The experimental procedure was the same as that of Example 46, 46-4, and 5-bromo-2-(3,3-difluoropiperidin-4-yl)-6-methoxy-2H-indazole hydrochloride (190 mg, 0.50 mmol) was used as the raw material to obtain the title compound (160 mg, 90%) as a colorless oily liquid. LC-MS: m / z [M+H] + =360, 362.

[0613] 74: 4-(3-(2-(3,3-difluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-2-(3,3-difluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole (150 mg, 0.42 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 (155 mg, 0.42 mmol) were used as raw materials to obtain the title compound (37 mg, 17%) as a gray-white solid.

[0614] 1H NMR (400MHz ,CHLOROFORM-d) 9.38 (s, 1 H), 8.28 (s, 2 H), 8.22 (d, J = 6.4 Hz, 1 H), 8.08 (s, 1 H), 7.65 (s, 1 H), 7.33 (t, J = 8.8 Hz, 1 H), 7.10 (s, 1 H), 4.84 - 4.71 (m, 1 H), 4.58 (q, J = 7.3 Hz, 2 H), 3.87 (s, 3 H), 3.29 (br. s., 1 H), 3.13 (d, J = 11.7 Hz, 1 H), 2.60 - 2.52 (m, 1 H), 2.46 (s, 3 H), 2.40 - 2.30 (m, 3H), 1.69 (t, J = 7.3Hz, 3H). LC-MS: m / z [M+H] + =522.

[0615] Example 75

[0616] [ka]

[0617] 75-1: 2-(difluoromethyl)-5-methoxybenzo[d]oxazole 2-Amino-4-methoxyphenol (500 mg, 3.59 mmol), triethylamine (725 mg, 7.18 mmol), triphenylphosphine (941 mg, 3.59 mmol), and difluoroacetic acid (344.7 mg, 3.59 mmol) were added to carbon tetrachloride (8 mL) and stirred overnight in an autoclave at 100 °C. The reaction mixture was filtered, and the mother liquor was separated and purified using a preparative plate (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (110 mg, 15%).

[0618] 75-2: 4-Bromo-2-(difluoromethyl)-5-methoxybenzo[d]oxazole 2-(Difluoromethyl)-5-methoxybenzo[d]oxazole (100 mg, 0.5 mmol) and N-bromosuccinimide (90 mg, 0.5 mmol) were added to acetic acid (4 mL) and stirred at 90°C for 2 hours. The reaction mixture was concentrated, an appropriate amount of methanol was added, and the mixture was separated and purified using a preparative plate (petroleum ether / ethyl acetate = 6 / 1) to obtain the title compound (68 mg, 49%). 1 H NMR (400 MHz, CDCl3) 7.55 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 9.3 Hz, 1H), 6.91 - 6.69 (m, 1 H), 3.99 (s, 3 H).

[0619] 75: 2-(Difluoromethyl)-4-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxybenzo[d]oxazole The experimental procedure was the same as in Example 1, and 4-bromo-2-(difluoromethyl)-5-methoxybenzo[d]oxazole (60 mg, 0.215 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 (67 mg, 0.17 mmol) were used as raw materials to obtain the title compound (40 mg, 54%).

[0620] 1 H NMR (400MHz, CHLOROFORM-d) 9.39 (s, 1 H), 8.39 (br. s., 1 H), 8.32 - 8.20 (m, 3 H), 7.72 - 7.62 (m, 1 H), 7.45 - 7.37 (m, 1 H), 7.24 (d, J = 9.8 Hz, 1 H), 6.90 - 6.62 (m, 1 H), 4.63 - 4.56 (m, 1 H), 3.90 (s, 3 H), 1.71 - 1.68 (m, 3 H). LC-MS: m / z[M+H] + =440.

[0621] Example 76

[0622] [ka]

[0623] 76-1: tert-butyl 4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-fluoropiperidine-1-carboxylate The experimental procedure was the same as that for synthesizing 40-1 and 40-2 in Example 40. 5-Bromo-4-methoxy-2-nitrobenzaldehyde (300 mg, 1.15 mmol) and tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (377 mg, 1.73 mmol) were used as raw materials to obtain the title compound (400 mg, 81%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =428, 430.

[0624] 76-2: 5-Bromo-2-(3-fluoropiperidin-4-yl)-6-methoxy-2H-indazole hydrochloride The experimental procedure was the same as that of Example 46, 46-3, and tert-butyl 4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-fluoropiperidine-1-carboxylate (400 mg, 0.93 mmol) was used as the raw material to obtain the title compound (290 mg, 86%) as a yellow solid. LC-MS: m / z [M+H] + =328, 330.

[0625] 76-3: 5-Bromo-2-(3-fluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole The experimental procedure was the same as that of Example 46, 46-4, and 5-bromo-2-(3-fluoropiperidin-4-yl)-6-methoxy-2H-indazole hydrochloride (290 mg, 0.80 mmol) was used as the raw material to obtain the title compound (100 mg, 37%) as a colorless oily liquid. LC-MS: m / z [M+H] + =342, 346.

[0626] 76: 7-Ethyl-4-(4-fluoro-3-(2-(3-fluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-2-(3-fluoro-1-methylpiperidin-4-yl)-6-methoxy-2H-indazole (100 mg, 0.29 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 (95 mg, 0.29 mmol) were used as raw materials to obtain the title compound (68 mg, 46%) as a yellow solid.

[0627] 1 H NMR (400MHz ,CHLOROFORM-d) 9.38 (s, 1 H), 8.26 (br. s., 2 H), 8.22 (d, J = 6.4 Hz, 1 H), 7.99 (s, 1 H), 7.63 (s, 1 H), 7.32 (t, J = 9.0 Hz, 1 H), 7.13 (s, 1 H), 5.18 - 4.98 (m, 1 H), 4.57 (q, J = 6.8 Hz, 2 H), 4.35 (d, J = 9.3 Hz, 1 H), 3.87 (s, 3 H), 3.40 - 3.30 (m, 1 H), 2.98 (d, J = 10.3 Hz, 1 H), 2.56 - 2.38 (m, 4 H), 2.30 - 2.16 (m, 3 H), 1.68 (t, J = 7.1 Hz, 3 H). LC-MS: m / z [M+H] + =504.

[0628] Example 77

[0629] [ka]

[0630] 77-1: tert-Butyl 4-(5-bromo-6-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate The experimental procedure was the same as that for synthesizing 40-1 and 40-2 in Example 40. 5-Bromo-4-methoxy-2-nitrobenzaldehyde (300 mg, 1.15 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (345 mg, 1.73 mmol) were used as raw materials to obtain the title compound (300 mg, 64%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =410,412.

[0631] 77-2: 5-Bromo-6-methoxy-2-(piperidin-4-yl)-2H-indazole hydrochloride The experimental procedure was the same as that of Example 46, 46-3, and tert-butyl 4-(5-bromo-6-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate (300 mg, 0.73 mmol) was used as the raw material to obtain the title compound (251 mg, 100%) as a white solid. LC-MS: m / z [M+H] + =310, 312.

[0632] 77-3: 5-Bromo-6-methoxy-2-(1-(oxetan-3-yl)piperidin-4-yl)-2H-indazole The experimental procedure was the same as that of Example 46, 46-4, and 5-bromo-6-methoxy-2-(piperidin-4-yl)-2H-indazole hydrochloride (280 mg, 0.81 mmol) and oxetan-3-one (62 mg, 1.62 mmol) were used as raw materials to obtain the title compound (170 mg, 58%) as a yellow solid. LC-MS: m / z [M+H] + =366, 368.

[0633] 77: 7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-(1-(oxetan-3-yl)piperidin-4-yl)-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-2-(1-(oxetan-3-yl)piperidin-4-yl)-2H-indazole (70 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 raw materials to obtain the title compound (28 mg, 28%) as a white solid.

[0634] 1 H NMR (400MHz ,CHLOROFORM-d) 9.37 (s, 1 H), 8.31 - 8.24 (m, 2 H), 8.20 (d, J = 5.4 Hz, 1 H), 7.93 (s, 1 H), 7.62 (s, 1 H), 7.32 (t, J = 8.8 Hz, 1 H), 7.10 (s, 1 H), 4.67 (td, J = 6.4, 18.1 Hz, 4 H), 4.56 (q, J = 7.3 Hz, 2 H), 4.46 - 4.37 (m, 1 H), 3.86 (s, 3 H), 3.56 (quin, J = 6.4 Hz, 1 H), 2.93 (d, J = 11.2 Hz, 2 H), 2.36 - 2.28 (m, 2 H), 2.28 - 2.16 (m, 2 H), 2.13 - 2.04 (m, 2 H), 1.68 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H] + =528.

[0635] Example 78

[0636] [ka]

[0637] 78-1: 5-Bromo-6-methoxy-2-(1-methyl-1H-imidazol-2-yl)-2H-indazole The experimental procedure was the same as that for synthesizing 40-1 and 40-2 in Example 40. 5-Bromo-4-methoxy-2-nitrobenzaldehyde (200 mg, 0.77 mmol) and 1-methyl-1H-imidazol-2-amine (112 mg, 3.45 mmol) were used as raw materials to obtain the title compound (50 mg, 54%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =307, 309.

[0638] 78:7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-(1-methyl-1H-imidazol-2-yl)-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-2-(1-methyl-1H-imidazol-2-yl)-2H-indazole (50 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 raw materials to obtain the title compound (6 mg, 8%) as a yellow solid.

[0639] 1 H NMR (400MHz, CHLOROFORM-d) 9.39 (s, 1 H), 8.58 (s, 1 H), 8.30 - 8.24 (m, 3 H), 7.70 (s, 1 H), 7.34 (t, J = 8.8 Hz, 1 H), 7.09 (s, 1 H), 7.03 (s, 1 H), 6.94 (s, 1 H), 4.58 (q, J = 7.3 Hz, 2 H), 4.00 (s, 3 H), 3.90 (s, 3 H), 1.69 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H] + =469.

[0640] Example 79

[0641] [ka]

[0642] 79-1: 4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3,5-dimethylisoxazole The experimental procedure was the same as that for synthesizing 40-1 and 40-2 in Example 40. 5-Bromo-4-methoxy-2-nitrobenzaldehyde (300 mg, 1.15 mmol) and 3,5-dimethylisoxazol-4-amine (386 mg, 3.45 mmol) were used as raw materials to obtain the title compound (200 mg, 54%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =322, 324.

[0643] 79: 4-(5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2H-indazol-2-yl)-3,5-dimethylisoxazole The experimental procedure was the same as in Example 1, and 4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3,5-dimethylisoxazole (200 mg, 0.62 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 (228 mg, 0.62 mmol) were used as raw materials to obtain the title compound (28 mg, 9%) as a white solid.

[0644] 1 H NMR (400MHz, CHLOROFORM-d) 9.38 (s, 1 H), 8.33 - 8.26 (m, 2 H), 8.22 (d, J = 6.4 Hz, 1 H), 8.00 (s, 1 H), 7.68 (s, 1 H), 7.34 (t, J = 8.8 Hz, 1 H), 7.12 (s, 1 H), 4.57 (q, J = 7.3 Hz, 2 H), 3.89 (s, 3 H), 2.51 (s, 3 H), 2.34 (s, 3 H), 1.68 (t, J = 7.1 Hz, 3 H). LC-MS: m / z [M+H] +=484.

[0645] Example 80

[0646] [ka]

[0647] 80-1: 5-Bromo-2-(difluoromethyl)-4-methoxy-1-methyl-1H-benzo[d]imidazole 4-Bromo-3-methoxy-N1-methylbenzene-1,2-diamine (200 mg, 0.87 mmol), pyrogallol (20 mg, 0.159 mmol), and 2,2-difluoroethyl-1-amine (211 mg, 2.61 mmol) were added sequentially to methanol (5 mL) and stirred at 80°C for 16 hours. The reaction mixture was concentrated and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (30 mg, 49%) as a brown solid. LC-MS: m / z [M+H] + =291, 293.

[0648] 80: 4-(3-(2-(difluoromethyl)-4-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-2-(difluoromethyl)-4-methoxy-1-methyl-1H-benzo[d]imidazole (30 mg, 0.1 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 (37 mg, 0.1 mmol) were used as raw materials to obtain the title compound (2 mg, 4%) as a yellow solid.

[0649] 1H NMR (400MHz, CHLOROFORM-d) 9.40 (br. s., 1 H), 8.28 (s, 2 H), 8.23 ​​(d, J = 6.8 Hz, 1 H), 7.42 - 7.35 (m, 2 H), 7.18 (d, J = 8.3 Hz, 1 H), 7.08 - 6.80 (m, 1 H), 4.58 (q, J = 7.3 Hz, 2 H), 4.37 (s, 3 H), 3.99 (s, 3 H), 1.71 - 1.67 (m, 3 H). LC-MS: m / z [M+H] + =453.

[0650] Example 81

[0651] [ka]

[0652] 81:7-Ethyl-4-(4-fluoro-3-(4-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, 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 (90 mg, 0.24 mmol), 5-bromo-4-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole (60 mg, 0.24 mmol) were used as raw materials to obtain the title compound (48 mg, 48%) as a brown solid.

[0653] 1H NMR (400MHz ,CHLOROFORM-d) 9.39 (s, 1 H), 8.34 - 8.19 (m, 3 H), 7.49 (d, J = 8.3 Hz, 1 H), 7.37 (t, J = 9.0 Hz, 1 H), 7.17 (d, J = 8.8 Hz, 1 H), 4.64 - 4.52 (m, 5 H), 4.34 - 4.28 (m, 3 H), 1.70 - 1.66 (m, 3 H). LC-MS: m / z [M+H] + =404.

[0654] Example 82

[0655] [ka]

[0656] 82-1: 5-Bromo-2-methyl-2H-indazol-6-ol 5-Bromo-6-methoxy-2-methyl-2H-indazole (500 mg, 2 mmol) was dissolved in 10 mL of dichloromethane, and 1 M boron tribromide dichloromethane solution (5 mL) was added. The mixture was then stirred overnight at room temperature, concentrated, and purified by preparative plate (dichloromethane:methanol=20:1) to give the title compound (800 mg, 100%) as a yellow solid. LC-MS: m / z [M+H] + =227.

[0657] 82-2: 5-Bromo-6-(difluoromethoxy)-2-methyl-2H-indazole 5-Bromo-2-methyl-2H-indazol-6-ol (500 mg, 2 mmol) was dissolved in 10 mL of acetonitrile, and aqueous potassium hydroxide solution (200 mg dissolved in 5 mL) was added. The mixture was cooled to 0°C, and sodium chlorodifluoroacetate (600 mg, 4 mmol) was added. The mixture was stirred for 1 hour, separated, concentrated, and purified by preparative plate (petroleum ether: ethyl acetate = 1:1) to give the title compound (160 mg, 29%) as a yellow solid. LC-MS: m / z [M+H] + =277.

[0658] 82: 4-(3-(6-(difluoromethoxy)-2-methyl-2H-indazol-5-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, 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 (90 mg, 0.24 mmol), 5-bromo-6-(difluoromethoxy)-2-methyl-2H-indazole (66 mg, 0.24 mmol) were used as raw materials to obtain the title compound (47 mg, 49%) as a brown solid.

[0659] 1 H NMR (400MHz ,CHLOROFORM-d) 9.39 (s, 1 H), 8.36 - 8.20 (m, 3 H), 7.96 (s, 1 H), 7.74 (s, 1 H), 7.50 (s, 1 H), 7.36 (t, J = 9.0 Hz, 1 H), 6.75 - 6.31 (m, 1 H), 4.58 (q, J = 7.3 Hz, 2 H), 4.25 (s, 3 H), 1.69 (s, 3 H). LC-MS: m / z [M+H] + =439.

[0660] Example 83, Example 84

[0661] [ka]

[0662] 83-A1: 2-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-(pyrrolidin-1-yl)ethan-1-one 83-A2: 2-(5-bromo-6-methoxy-1H-indazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one 5-Bromo-6-(methoxy)-1H-benzo[d]imidazole (CAS: 1008361-65-6, 300 mg, 1.3 mmol) was dissolved in 10 mL of acetonitrile, and cesium carbonate (1 g, 2.6 mmol) and 2-chloro-1-(pyrrolidin-1-yl)ethyl-1-one (200 mg, 1.3 mmol) were added. The mixture was stirred at 80 °C for 1 hour, and the solid was filtered and diluted with water to precipitate. The solid was purified by preparative plate (dichloromethane:methanol = 10:1) to give the title compound A1 (70 mg, 16%, Rf = 0.3) as a white solid and the title compound A2 (270 mg, 60%, Rf = 0.4) as a white solid. LC-MS: m / z [M+H] + =338.

[0663] 83: 2-(5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2H-indazol-2-yl)-1-(pyrrolidin-1-yl)ethan-1-one The experimental procedure was the same as in Example 1, 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 (80 mg, 0.22 mmol), 2-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-(pyrrolidin-1-yl)ethan-1-one (70 mg, 0.22 mmol) were used as raw materials to obtain the title compound (70 mg, 64%) as a brown solid.

[0664] 1H NMR (400 MHz, CHLOROFORM-d) 9.38 (s, 1 H) 8.25 - 8.30 (m, 2 H) 8.23 ​​(dd, J=6.85, 2.45 Hz, 1 H) 8.07 (s, 1 H) 7.63 (s, 1 H) 7.32 (t, J=9.05 Hz, 1 H) 7.07 (s, 1 H) 5.16 (s, 2 H) 4.51 - 4.61 (m, 2 H) 3.85 (s, 3 H) 3.54 (dt, J=14.06, 6.91 Hz, 4 H) 1.97 - 2.05 (m, 2 H) 1.86 - 1.93 (m, 2 H) 1.68 (t, J=7.09 Hz, 3H). LC-MS: m / z [M+H] + =500.

[0665] 84: 2-(5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-1H-indazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one The experimental procedure was the same as in Example 1, 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 (80 mg, 0.22 mmol), 2-(5-bromo-6-methoxy-1H-indazol-1-yl)-1-(pyrrolidin-1-yl)ethyl-1-one (70 mg, 0.22 mmol) were used as raw materials to obtain the title compound (46 mg, 42%) as a brown solid.

[0666] 1H NMR (400 MHz, CHLOROFORM-d) 9.38 (s, 1 H) 8.19 - 8.29 (m, 3 H) 7.98 (s, 1 H) 7.68 (s, 1 H) 7.34 (t, J=9.05 Hz, 1 H) 6.99 (s, 1 H) 5.17 (s, 2 H) 4.54 - 4.63 (m, 2 H) 3.90 (s, 3 H) 3.53 (q, J=6.85 Hz, 4 H) 1.99 (quin, J=6.73 Hz, 2 H) 1.84 - 1.92 (m, 2 H) 1.69 (t, J=7.09 Hz, 3 H). LC-MS: m / z [M+H] + =500.

[0667] Example 85, Example 86

[0668] [ka]

[0669] 85-A1: 3-((5-bromo-6-methoxy-2H-indazol-2-yl)methyl)-5-methylisoxazole 85-A2: 3-((5-bromo-6-methoxy-1H-indazol-1-yl)methyl)-5-methylisoxazole 5-Bromo-6-(methoxy)-1H-benzo[d]imidazole (CAS: 1008361-65-6, 300 mg, 1.3 mmol) was dissolved in 10 mL of acetonitrile, and cesium carbonate (845 mg, 2.6 mmol) and 3-(chloromethyl)-5-methylisoxazole (180 mg, 1.3 mmol) were added. The mixture was heated to 80 °C and stirred for 2 hours. The solid was filtered and purified by preparative plate (petroleum ether: ethyl acetate = 10:1) to give the title compound A1 (110 mg, 26%, Rf = 0.3) as a yellow solid and the title compound A2 (260 mg, 61%, Rf = 0.5) as a yellow solid. LC-MS: m / z [M+H] + =322.

[0670] 85:3-((5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2H-indazol-2-yl)methyl)-5-methylisoxazole The experimental procedure was the same as in Example 1, 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 (80 mg, 0.22 mmol), 3-((5-bromo-6-methoxy-2H-indazol-2-yl)methyl)-5-methylisoxazole (70 mg, 0.22 mmol) were used as raw materials to obtain the title compound (29 mg, 27%) as a white solid.

[0671] 1 H NMR (400 MHz, CHLOROFORM-d) 9.37 (s, 1 H) 8.27 (br. s., 2 H) 8.20 (d, J=5.38 Hz, 1 H) 7.96 (s, 1 H) 7.61 (s, 1 H) 7.33 (t, J=8.80 Hz, 1 H) 7.10 (s, 1 H) 5.98 (s, 1 H) 5.60 (s, 2 H) 4.58 (q, J=6.85 Hz, 2 H) 3.87 (s, 3 H) 2.39 (s, 3 H) 1.69 (t, J=7.09 Hz, 3 H). LC-MS: m / z [M+H] + =484.

[0672] 86:3-((5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-1H-indazol-1-yl)methyl)-5-methylisoxazole The experimental procedure was the same as in Example 1, 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 (80 mg, 0.22 mmol), 3-((5-bromo-6-methoxy-1H-indazol-1-yl)methyl)-5-methylisoxazole (70 mg, 0.22 mmol) were used as raw materials to obtain the title compound (38 mg, 35%) as a brown solid.

[0673] 1 H NMR (400 MHz, CHLOROFORM-d) 9.28 - 9.43 (m, 1 H) 8.24 - 8.31 (m, 2 H) 8.21 (d, J=6.85 Hz, 1 H) 7.98 (s, 1 H) 7.68 (s, 1 H) 7.33 (t, J=9.05 Hz, 1 H) 6.92 (s, 1 H) 5.87 (s, 1 H) 5.61 (s, 2 H) 4.58 (q, J=7.34 Hz, 2 H) 3.87 (s, 3 H) 2.37 (s, 3 H) 1.69 (t, J=7.34 Hz, 3 H). LC-MS: m / z [M+H] + =484.

[0674] Example 87

[0675] [ka]

[0676] 87:6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxy-3-methylbenzo[d]oxazol-2(3H)-one The experimental procedure was the same as in Example 1, and 6-bromo-5-methoxy-3-methylbenzo[d]oxazol-2(3H)-one (500.0 mg, 1.94 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (554 mg, 1.94 mmol) were used as raw materials to obtain the title product (310 mg, white solid), with a yield of 38%.

[0677] 1 H NMR (400 MHz, DMSO-d6) 9.55 (s, 1H), 8.86 (s, 1H), 8.45 (dd, 2H), 7.48 (t, 1H), 7.38 (s, 1H), 7.21 (s, 1H), 4.51 (q, 2H), 3.82 (s, 3H), 3.42 (s, 3H), 1.56 (t, 3H). LC-MS: m / z [M+H] + =420.

[0678] Example 88

[0679] [ka]

[0680] 88-1: 5-Bromo-2-cyclopropyl-4-methoxy-1-methyl-1H-benzo[d]imidazole 4-Bromo-3-methoxy-N1-methylbenzene-1,2-diamine (200 mg, 0.87 mmol), pyrogallol (20 mg, 0.159 mmol), and aminomethylcyclopropane (93 mg, 1.31 mmol) were added sequentially to methanol (5 mL) and stirred at 60°C for 16 hours. The reaction mixture was concentrated and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (120 mg, 49%) as a brown oily liquid. LC-MS: m / z [M+H] + =281, 283.

[0681] 88: 4-(3-(2-cyclopropyl-4-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-2-cyclopropyl-4-methoxy-1-methyl-1H-benzo[d]imidazole (120 mg, 0.43 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 (158 mg, 0.43 mmol) were used as raw materials to obtain the title compound (17 mg, 9%) as a white solid.

[0682] 1 H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.30 - 8.24 (m, 2 H), 8.21 (dd, J = 2.0, 6.8 Hz, 1 H), 7.34 (t, J = 8.8 Hz, 1 H), 7.21 (d, J = 8.3 Hz, 1 H), 7.04 (d, J = 8.3 Hz, 1 H), 4.57 (q, J = 7.0 Hz, 2 H), 4.29 (s, 3 H), 3.85 (s, 3 H), 2.05 - 1.97 (m, 1 H), 1.68 (t, J = 7.3 Hz, 3 H), 1.25 (br. s., 2 H), 1.14 - 1.07 (m, 2H). LC-MS: m / z [M+H] + =443.

[0683] Example 89

[0684] [ka]

[0685] 89-1:8-Bromoquinoline-5-carbohydrazide Methyl 8-bromoquinoline-5-carboxylate (500 mg, 1.88 g) and hydrazine hydrate (280 mg, 5.6 mmol) were added to absolute ethanol (10 mL) and stirred overnight at 50° C. The reaction mixture was directly separated and purified using a preparative plate (dichloromethane / methanol = 15 / 1) to obtain the title compound (260 mg, 52%).

[0686] 89-2: 8-Bromo-N'-(cyclopropanecarbonyl)quinoline-5-carbohydrazide 8-Bromoquinoline-5-carbohydrazide (230 mg, 0.86 mmol), N,N-diisopropylethylamine (223 mg, 1.73 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (162 mg, 1.73 mmol), and cyclopropanecarboxylic acid (150 mg, 1.73 mmol) were added to dichloromethane (6 mL) and stirred overnight at room temperature. The reaction mixture was directly separated and purified using a preparative plate (dichloromethane / methanol = 20 / ) to give the title compound (150 mg, 52%).

[0687] 89-3: 2-(8-bromoquinolin-5-yl)-5-cyclopropyl-1,3,4-oxadiazole 8-Bromo-N'-(cyclopropanecarbonyl)quinoline-5-carbohydrazide (150 mg, 0.45 mmol), N,N-diisopropylethylamine (174 mg, 1.35 mmol), and p-toluenesulfonyl chloride (256 mg, 1.35 mmol) were added to dichloromethane (6 mL) and stirred overnight at room temperature. The reaction mixture was directly separated and purified using a preparative plate (petroleum ether / ethyl acetate = 11) to give the title compound (20 mg, 14.1%).

[0688] 89: 2-Cyclopropyl-5-(8-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)quinolin-5-yl)-1,3,4-oxadiazole The experimental procedure was the same as in Example 1, and 2-(8-bromoquinolin-5-yl)-5-cyclopropyl-1,3,4-oxadiazole (23 mg, 0.06 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 (23 mg, 0.06 mmol) were used as raw materials to obtain the title compound (13 mg, 45%).

[0689] 1 H NMR (400MHz, CHLOROFORM-d) 9.77 (d, J = 8.8 Hz, 1 H), 9.42 (s, 1 H), 9.00 (br. s., 1 H), 8.40 (d, J = 6.4 Hz, 2 H), 8.30 - 8.22 (m, 2 H), 7.92 (d, J = 7.8 Hz, 1 H), 7.60 (br. s., 1 H), 7.45 (s, 1 H), 4.58 (d, J = 6.8 Hz, 2 H), 2.33 (br. s., 1 H), 1.71 - 1.67 (m, 3 H), 1.32 - 1.30 (m, 4H).

[0690] Example 90

[0691] [ka]

[0692] 90-1: Methyl 5-methoxybenzo[d]oxazole-2-carboxylate 2-Amino-4-methoxyphenol (1.0 g, 7.19 mmol) and methyl 2,2,2-trimethoxyacetate (11.8 g, 72 mmol) were heated to 110°C in a microwave reactor and reacted for 3 hours. The reaction mixture was concentrated and separated by column chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to obtain the title compound (0.46 g, yield: 31%) as a reddish-brown solid. LC-MS: m / z [M+H] + = 208.

[0693] 90-2: Methyl 6-bromo-5-methoxybenzo[d]oxazole-2-carboxylate Methyl 5-methoxybenzo[d]oxazole-2-carboxylate (0.4 g, 1.93 mmol) and N-bromosuccinimide (0.376 g, 2.1 mmol) were added sequentially to acetonitrile (20 mL). The mixture was then reacted at 50°C for 4 hours. The mixture was concentrated and purified to obtain the crude title compound (0.4 g, yield: 72%). LC-MS: m / z [M+H] + = 286.

[0694] 90-3: 6-Bromo-5-methoxybenzo[d]oxazole-2-carboxylic acid Methyl 6-bromo-5-methoxybenzo[d]oxazole-2-carboxylate (0.4 g, 1.4 mmol) and lithium hydroxide (0.117 g, 2.8 mmol) were added sequentially to tetrahydrofuran:water (10:1) (5 mL). The mixture was then allowed to react at room temperature for 4 hours. The pH was adjusted to 3-4 with 1N hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phase was concentrated and purified to give the title compound (300 mg, 79% yield). LC-MS: m / z [M+H] + = 272.

[0695] 90-4: (6-Bromo-5-methoxybenzo[d]oxazol-2-yl)(pyrrolidin-1-yl)methanone The raw materials, 6-bromo-5-methoxybenzo[d]oxazole-2-carboxylic acid (300 mg, 1.1 mmol), tetrahydropyrrole (90 mg, 1.2 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (630 mg, 1.6 mmol), and N,N-diisopropylethylamine (280 mg, 2.2 mmol) were added to N,N-dimethylformamide (10 mL). The reaction was carried out overnight at room temperature under nitrogen gas. Water was added to the reaction mixture to quench the reaction, and the mixture was concentrated. The product was then purified by column chromatography (dichloromethane / methanol = 30:1 to 10:1) to obtain the title compound (200 mg, 56% yield) as a brown solid. LC-MS: m / z [M+H] + = 325.

[0696] 90: (6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxybenzo[d]oxazol-2-yl)(pyrrolidin-1-yl)methanone The experimental procedure was the same as in Example 1, and (6-bromo-5-methoxybenzo[d]oxazol-2-yl)(pyrrolidin-1-yl)methanone (100 mg, 0.3 mmol), (5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)boronic acid (124 mg, 0.33 mmol) were used as raw materials to obtain the title compound (80 mg, yield: 54%) as an off-white solid.

[0697] 1 H NMR (400 MHz, CDCl3): δ 9.38 (s, 1H), 8.28 (t, 3H), 7.65 (s, 1H), 7.42-7.32 (m, 2H), 4.58 (q, 2H), 4.15 (t, 2H), 3.89 (s, 3H), 3.77 (t, 2H), 2.03 (m, 4H), 1.69 (t, 3H).

[0698] Example 91

[0699] [ka]

[0700] 91-1: 5-Bromo-1-methyl-1H-indazol-6-ol 5-Bromo-6-methoxy-1-methyl-1H-indazole (500 mg, 2 mmol) was dissolved in 10 mL of dichloromethane, and 1 M boron tribromide dichloromethane solution (5 mL) was added. The mixture was stirred at room temperature for 2 hours, concentrated, and purified by preparative plate (petroleum ether: ethyl acetate = 1:1) to give the title compound (300 mg, 65%) as a yellow liquid. LC-MS: m / z [M+H] + =227.

[0701] 91-2: 5-Bromo-6-(difluoromethoxy)-1-methyl-1H-indazole 5-Bromo-1-methyl-1H-indazol-6-ol (300 mg, 1 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and cesium carbonate (700 mg, 1 mmol) and sodium chlorodifluoroacetate (230 mg, 1.5 mmol) were added. The mixture was heated to 100°C and stirred for 2 hours. The mixture was diluted with water, extracted with ethyl acetate, concentrated, and purified by preparative plate (petroleum ether:ethyl acetate = 3:1) to give the title compound (150 mg, 50%) as a white solid. LC-MS: m / z [M+H] + =277.

[0702] 91: 4-(3-(6-(difluoromethoxy)-1-methyl-1H-indazol-5-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, 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 (80 mg, 0.22 mmol), 5-bromo-6-(difluoromethoxy)-1-methyl-1H-indazole (75 mg, 0.22 mmol) were used as raw materials to obtain the title compound (25 mg, 27%) as a brown solid.

[0703] 1 H NMR (400 MHz, CHLOROFORM-d) 9.41 (s, 1 H) 8.30 (s, 3 H) 8.04 (s, 1 H) 7.82 (s, 1 H) 7.34 - 7.42 (m, 1 H) 7.27 (s, 1 H) 6.32 - 6.78 (m, 1 H) 4.59 (d, J=7.34 Hz, 2 H) 4.12 (s, 3 H) 1.70 (t, J=7.34 Hz, 3 H). LC-MS: m / z [M+H] + =439.

[0704] Example 92

[0705] [ka]

[0706] 92-1: 8-Bromo-4-(methylamino)-N-propylcinnoline-3-carboxamide 4-Amino-8-bromo-N-propylcinnoline-3-carboxamide (400 mg, 1.3 mmol), cesium carbonate (1300 mg, 3.9 mmol), and methyl iodide (553 mg, 3.9 mmol) were added to tetrahydrofuran (10 ml). The mixture was stirred at 40°C for 72 hours. The reaction mixture was directly purified by thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give the title compound (200 mg, 48%). LC-MS: m / z [M+H] + =323.

[0707] 92:8-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-4-(methylamino)-N-propylcinnoline-3-carboxamide The experimental procedure was the same as in Example 1, and the title compound (26 mg, 40%) was obtained using 8-bromo-4-(methylamino)-N-propylcinnoline-3-carboxamide (53 mg, 0.16 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).

[0708] 1 H NMR (400 MHz, CHLOROFORM-d) 0.97 (t,J=6.36 Hz, 3 H) 1.63 (br. s., 5 H) 3.40 (d,J=5.38 Hz, 2 H) 3.55 (d,J=4.40 Hz, 3 H) 4.57 (d,J=6.85Hz, 2 H) 7.41 (t,J=8.56 Hz, 1 H) 7.64 (br. s., 1 H) 7.84 (d,J=5.87 Hz, 1 H) 8.26 (br. s., 1 H) 8.34 (br. s., 2 H) 8.48 (d,J=7.83 Hz, 1 H) 8.60 (br. s., 1 H) 9.39 (br. s., 1 H) 10.54 (br. s., 1 H). LC-MS: m / z [M+H] + =485.

[0709] Example 93

[0710] [ka]

[0711] 93-1: N-(2,4-dibromo-5-methoxyphenyl)tetrahydro-2H-pyran-4-carboxamide 2,4-Dibromo-5-methoxyaniline (500 mg, 1.8 mmol), methyl tetrahydro-2H-pyran-4-carboxylate (308 mg, 2.1 mmol), and potassium tert-butoxide (400 mg, 3.6 mmol) were added to tetrahydrofuran (20 ml). The mixture was stirred at room temperature in air for 5 hours. The reaction mixture was directly added to ethyl acetate (200 ml) and washed three times with water (100 ml). The ethyl acetate was then dried over anhydrous sodium sulfate and concentrated to give the title compound (600 mg, 85.8%). LC-MS: m / z [M+H] + =394.

[0712] 93-2: 6-Bromo-5-methoxy-2-(tetrahydro-2H-pyran-4-yl)benzo[d]oxazole N-(2,4-Dibromo-5-methoxyphenyl)tetrahydro-2H-pyran-4-carboxamide (300 mg, 0.76 mmol), potassium carbonate (316 mg, 2.3 mmol), copper powder (147 mg, 2.3 mmol), and aluminum oxide (233 mg, 2.3 mmol) were added to N,N-dimethylformamide (10 ml). The mixture was stirred at 110°C for 4 hours. The reaction mixture was directly subjected to column chromatography to obtain the title compound (170 mg, 71.7%). LC-MS: m / z [M+H] + =312.

[0713] 93:6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxy-2-(tetrahydro-2H-pyran-4-yl)benzo[d]oxazole The experimental procedure was the same as in Example 1, and 6-bromo-5-methoxy-2-(tetrahydro-2H-pyran-4-yl)benzo[d]oxazole (50 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 (50 mg, 0.13 mmol) were used as raw materials to obtain the title compound (12 mg, 19%).

[0714] 1 H NMR (400 MHz, CHLOROFORM-d) 1.66 - 1.70 (m, 3 H) 2.03 - 2.16 (m, 4 H) 3.23 (br. s., 1 H) 3.59 (t, J=10.76 Hz, 2 H) 3.85 (s, 3 H) 4.08 (d, J=11.25 Hz, 2 H) 4.57 (q, J=7.34 Hz, 2 H) 7.28 - 7.40 (m, 2 H) 7.49 (s, 1 H) 8.22 (d, J=6.85 Hz, 1 H) 8.27 (br. s., 2 H) 9.38 (br. s., 1 H). LC-MS: m / z [M+H] + =474.

[0715] Example 94, Example 95

[0716] [ka]

[0717] 94-A1: tert-Butyl 3-(5-bromo-6-methoxy-1H-indazol-1-yl)azetidine-1-carboxylate 94-A2: tert-Butyl 3-(5-bromo-6-methoxy-2H-indazol-2-yl)azetidine-1-carboxylate 5-Bromo-6-methoxy-1H-indazole (2 g, 8.81 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL), and sodium hydride (705 mg, 17.62 mmol) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours, and then tert-butyl 3-iodoazetidine-1-carboxylate (4.19 g, 17.62 mmol) was added, followed by further stirring at room temperature for 16 hours. Sodium sulfate decahydrate (500 mg) was added to the reaction mixture, which was then filtered, concentrated, and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl 3-(5-bromo-6-methoxy-2H-indazol-1-yl)azetidine-1-carboxylate (340 mg, 10%, Rf = 0.3) and tert-butyl 3-(5-bromo-6-methoxy-1H-indazol-1-yl)azetidine-1-carboxylate (900 mg, 27%, Rf = 0.5). LC-MS: m / z [M+H] + =382, 384.

[0718] 94-2: 1-(azetidin-3-yl)-5-bromo-6-methoxy-1H-indazole hydrochloride tert-Butyl 3-(5-bromo-6-methoxy-1H-indazol-1-yl)azetidine-1-carboxylate (900 mg, 2.36 mmol) was added to dichloromethane (5 mL), and then a hydrochloric acid-ethyl acetate solution (2 mL, 6 M) was added and stirred at room temperature for 10 minutes. The precipitated solid was filtered to give the title compound (663 mg, 100%) as a white solid. LC-MS: m / z [M+H] + =282, 284.

[0719] 94-3: 5-Bromo-6-methoxy-1-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-1H-indazole 1-(Azetidin-3-yl)-5-bromo-6-methoxy-1H-indazole hydrochloride (80 mg, 0.25 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (116 mg, 0.50 mmol), and triethylamine (126 mg, 1.25 mmol) were added sequentially to dichloromethane (2 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (60 mg, 66%) as a white solid. LC-MS: m / z [M+H] + =364, 366.

[0720] 94:7-Ethyl-4-(4-fluoro-3-(6-methoxy-1-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-1H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-1-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-1H-indazole (60 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 raw materials to obtain the title compound (35 mg, 42%) as a yellow solid.

[0721] 1H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.26 (s, 2 H), 8.20 (d, J = 6.8 Hz, 1 H), 7.99 (s, 1 H), 7.67 (s, 1 H), 7.33 (t, J = 9.0 Hz, 1 H), 7.08 (s, 1 H), 5.39 - 5.30 (m, 1 H), 4.57 (q, J = 7.2 Hz, 2 H), 4.14 - 4.06 (m, 2 H), 3.99 (t, J = 7.1 Hz, 2 H), 3.90 (s, 3 H), 3.24 (q, J = 9.1 Hz, 2 H), 1.68 (t, J = 7.1 Hz, 3H). LC-MS: m / z [M+H] + =526.

[0722] 95-2: 2-(azetidin-3-yl)-5-bromo-6-methoxy-2H-indazole hydrochloride The procedure was the same as in 94-2, and tert-butyl 3-(5-bromo-6-methoxy-2H-indazol-1-yl)azetidine-1-carboxylate (900 mg, 2.36 mmol) was used as the raw material to obtain the title compound (660 mg, 100%) as a white solid. LC-MS: m / z [M+H] + =282, 284.

[0723] 95-3: 5-Bromo-6-methoxy-2-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-2H-indazole The procedure was the same as for 94-2, and 2-(azetidin-3-yl)-5-bromo-6-methoxy-2H-indazole hydrochloride (80 mg, 0.25 mmol) was used as the raw material to obtain the title compound (50 mg, 55%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =364, 366.

[0724] 95:7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-2-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-2H-indazole (50 mg, 0.14 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 (52 mg, 0.14 mmol) were used as raw materials to obtain the title compound (35 mg, 48%) as a yellow solid.

[0725] 1 H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.26 (s, 2 H), 8.20 (d, J = 6.4 Hz, 1 H), 8.01 (s, 1 H), 7.60 (s, 1 H), 7.32 (t, J = 8.6 Hz, 1 H), 7.11 (s, 1 H), 5.24 (t, J = 6.4 Hz, 1 H), 4.61 - 4.53 (m, 2 H), 4.13 - 4.06 (m, 2 H), 3.96 (t, J = 6.6 Hz, 2 H), 3.87 (s, 3 H), 3.23 (q, J = 9.1 Hz, 2 H), 1.68 (t, J = 7.1 Hz, 3H). LC-MS: m / z [M+H] + =526.

[0726] Example 96

[0727] [ka]

[0728] 96-1: 4-((5-bromo-6-methoxy-2H-indazol-2-yl)methyl)tetrahydro-2H-pyran-4-ol The experimental procedure was the same as that for synthesizing 40-1 and 40-2 in Example 40. 5-Bromo-4-methoxy-2-nitrobenzaldehyde (150 mg, 0.58 mmol) and 4-(aminomethyl)tetrahydro-2H-pyran-4-ol (152 mg, 1.16 mmol) were used as raw materials to obtain the title compound (50 mg, 25%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =341, 343.

[0729] 96:4-((5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2H-indazol-2-yl)methyl)tetrahydro-2H-pyran-4-ol The experimental procedure was the same as in Example 1, and 4-((5-bromo-6-methoxy-2H-indazol-2-yl)methyl)tetrahydro-2H-pyran-4-ol (50 mg, 0.15 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 (55 mg, 0.15 mmol) were used as raw materials to obtain the title compound (8 mg, 11%) as a yellow solid.

[0730] 1 H NMR (400MHz, CHLOROFORM-d) 9.38 (s, 1 H), 8.28 (s, 2 H), 8.20 (d, J = 6.8 Hz, 1 H), 7.90 (s, 1 H), 7.63 (s, 1 H), 7.36 - 7.30 (m, 1 H), 7.08 (s, 1 H), 4.57 (q, J = 7.3 Hz, 2 H), 4.34 (s, 2 H), 3.87 (s, 3 H), 3.83 - 3.73 (m, 4 H), 2.23 - 2.11 (m, 4 H), 1.70 - 1.67 (m, 3 H). LC-MS: m / z [M+H] + =503.

[0731] Example 97

[0732] [ka]

[0733] 97-1: 1-(3-(5-bromo-6-methoxy-1H-indazol-1-yl)azetidin-1-yl)ethan-1-one 1-(Azetidin-3-yl)-5-bromo-6-methoxy-1H-indazole hydrochloride (100 mg, 0.31 mmol), acetic anhydride (63 mg, 0.62 mmol), and triethylamine (116 mg, 1.15 mmol) were added sequentially to dichloromethane (5 mL) and stirred at room temperature for 2 hours. The reaction mixture was added dropwise to saturated aqueous ammonium chloride (10 mL). The separated organic phase was purified by preparative thin-layer chromatography (ethyl acetate) to give the title compound (100 mg, 100%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =324,326.

[0734] 97:1-(3-(5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-1H-indazol-1-yl)azetidin-1-yl)ethan-1-one The experimental procedure was the same as in Example 1, and 1-(3-(5-bromo-6-methoxy-1H-indazol-1-yl)azetidin-1-yl)ethan-1-one (60 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 raw materials to obtain the title compound (30 mg, 33%) as a yellow solid.

[0735] 1H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.28 (s, 2 H), 8.20 (d, J = 6.8 Hz, 1 H), 8.04 (s, 1 H), 7.70 (s, 1 H), 7.33 (t, J = 8.8 Hz, 1 H), 6.84 (s, 1 H), 5.42 (d, J = 6.4 Hz, 1 H), 4.86 - 4.79 (m, 1 H), 4.66 (t, J = 8.3 Hz, 1 H), 4.60 - 4.54 (m, 4 H), 3.89 (s, 3 H), 1.99 (s, 3 H), 1.68 (t, J = 7.1 Hz, 3 H). LC-MS: m / z [M+H] + =486.

[0736] Example 98

[0737] [ka]

[0738] 98-1: 1-(3-(5-bromo-6-methoxy-2H-indazol-2-yl)azetidin-1-yl)ethan-1-one 2-(Azetidin-3-yl)-5-bromo-6-methoxy-2H-indazole hydrochloride (100 mg, 0.31 mmol), acetic anhydride (63 mg, 0.62 mmol), and triethylamine (116 mg, 1.15 mmol) were added sequentially to dichloromethane (5 mL) and stirred at room temperature for 2 hours. The reaction mixture was added dropwise to saturated aqueous ammonium chloride (10 mL). The separated organic phase was purified by preparative thin-layer chromatography (ethyl acetate) to afford the title compound (50 mg, 50%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =324,326.

[0739] 98:1-(3-(5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxy-2H-indazol-2-yl)azetidin-1-yl)ethan-1-one The experimental procedure was the same as in Example 1, and 1-(3-(5-bromo-6-methoxy-2H-indazol-2-yl)azetidin-1-yl)ethan-1-one (50 mg, 0.15 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 (55 mg, 0.15 mmol) were used as raw materials to obtain the title compound (20 mg, 27%) as a yellow solid.

[0740] 1 H NMR (400MHz, CHLOROFORM-d) 9.36 (s, 1 H), 8.26 (s, 2 H), 8.19 (d, J = 6.4 Hz, 1 H), 7.98 (s, 1 H), 7.59 (s, 1 H), 7.31 (t, J = 9.0 Hz, 1 H), 7.11 (s, 1 H), 5.36 - 5.27 (m, 1 H), 4.80 - 4.73 (m, 1 H), 4.65 (t, J = 8.3 Hz, 1 H), 4.59 - 4.52 (m, 4 H), 3.86 (s, 3 H), 1.96 (s, 3 H), 1.66 (t, J = 7.3 Hz, 3H). LC-MS: m / z [M+H] + =486.

[0741] Example 99

[0742] [ka]

[0743] 99:7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-(1-methylpiperidin-4-yl)-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-2-(1-methylpiperidin-4-yl)-2H-indazole (200 mg, 0.62 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 (228 mg, 0.62 mmol) were used as raw materials to obtain the title compound (160 mg, 53%) as a white solid.

[0744] 1 H NMR (400MHz, CHLOROFORM-d) 9.38 (s, 1 H), 8.27 (br. s., 2 H), 8.20 (d, J = 5.9 Hz, 1 H), 7.95 (s, 1 H), 7.62 (s, 1 H), 7.33 (t, J = 8.8 Hz, 1 H), 7.10 (s, 1 H), 4.63 - 4.53 (m, 2 H), 4.47 (br. s., 1 H), 3.87 (s, 3 H), 3.17 (br. s., 2 H), 2.52 - 2.26 (m, 9 H), 1.69 (t, J = 7.1 Hz, 3 H). LC-MS: m / z [M+H] + =486.

[0745] Example 100

[0746] [ka]

[0747] 100-1: 5-Bromo-6-methoxy-2-(4-methyltetrahydro-2H-pyran-4-yl)-2H-indazole The experimental procedure was the same as that for synthesizing 40-1 and 40-2 in Example 40. 5-Bromo-4-methoxy-2-nitrobenzaldehyde (150 mg, 0.58 mmol) and tetrahydro-4-methyl-2H-pyran-4-amine (132 mg, 1.16 mmol) were used as raw materials to obtain the title compound (80 mg, 43%) as a pale yellow oily liquid. LC-MS: m / z [M+H]+ =325, 327.

[0748] 100:7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-(4-methyltetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-2-(4-methyltetrahydro-2H-pyran-4-yl)-2H-indazole (80 mg, 0.25 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, 0.25 mmol) were used as raw materials to obtain the title compound (25 mg, 21%) as a yellow solid.

[0749] 1 H NMR (400MHz, CHLOROFORM-d) 9.37 (s, 1 H), 8.31 - 8.24 (m, 2 H), 8.20 (dd, J = 2.0, 6.8 Hz, 1 H), 8.01 (s, 1 H), 7.62 (s, 1 H), 7.32 (t, J = 9.0 Hz, 1 H), 7.14 (s, 1 H), 4.56 (q, J = 7.3 Hz, 2 H), 3.90 - 3.79 (m, 5 H), 3.74 - 3.66 (m, 2 H), 2.65 - 2.56 (m, 2 H), 2.17 - 2.08 (m, 2 H), 1.71 - 1.61 (m, 6 H). LC-MS: m / z [M+H] + =487.

[0750] Example 101, Example 102

[0751] [ka]

[0752] 101-A1: 5-Bromo-6-methoxy-2-phenyl-2H-indazole 101-A2: 5-Bromo-6-methoxy-1-phenyl-1H-indazole 5-Bromo-6-methoxy-1H-indazole (200 mg, 0.88 mmol) was dissolved in N,N-dimethylformamide (4 mL), and iodobenzene (359 mg, 1.76 mmol), copper iodide (17 mg, 0.088 mmol), N,N-dimethylethylenediamine (8 mg, 0.088 mmol), and potassium phosphate (560 mg, 2.64 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. The reaction mixture was separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 5-bromo-6-methoxy-2-phenyl-2H-indazole (20 mg, 8%, Rf = 0.3) and 5-bromo-6-methoxy-1-phenyl-1H-indazole (120 mg, 45%, Rf = 0.5). LC-MS: m / z [M+H]+ =303, 305.

[0753] Example 101: 7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-phenyl-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-2-phenyl-2H-indazole (20 mg, 0.07 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 (37 mg, 0.07 mmol) were used as raw materials to obtain the title compound (8 mg, 25%) as a yellow solid.

[0754] 1H NMR (400MHz, CHLOROFORM-d) 9.43 (s, 1 H), 8.39 (s, 1 H), 8.34 - 8.23 ​​(m, 3 H), 7.91 (S, 1 H), 7.89 (S, 1 H), 7.69 (s, 1 H), 7.56 - 7.51 (m, 2 H), 7.42 - 7.34 (m, 2 H), 7.17 (s, 1 H), 4.62-4.55 (m, 2 H), 3.90 (s, 3 H), 1.70 (d, J = 6.4 Hz, 3 H). LC-MS: m / z [M+H] + =465.

[0755] Example 102: 7-Ethyl-4-(4-fluoro-3-(6-methoxy-1-phenyl-3a,7a-dihydro-1H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-1-phenyl-1H-indazole (60 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 raw materials to obtain the title compound (35 mg, 38%) as a yellow solid.

[0756] 1 H NMR (400MHz, CHLOROFORM-d) 9.40 (s, 1 H), 8.32 - 8.23 ​​(m, 3 H), 8.16 (s, 1 H), 7.79 - 7.74 (m, 3 H), 7.59 (t, J = 7.8 Hz, 2 H), 7.44 - 7.32 (m, 2H), 7.20 (s, 1H), 4.62-4.55 (m, 2H), 3.88 (s, 3H), 1.72 - 1.66 (m, 3H). LC-MS: m / z [M+H] + =465.

[0757] Example 103

[0758] [ka]

[0759] 103-1: 5-Bromo-4-methoxy-1,2-dimethyl-1H-benzo[d]imidazole 4-Bromo-3-methoxy-N1-methylbenzene-1,2-diamine (200 mg, 0.87 mmol) was added to triethyl orthophthalate (5 ml). The mixture was stirred at 90°C overnight. The reaction mixture was directly subjected to thin layer chromatography (dichloromethane / methanol = 40 / 1) to obtain the title compound (200 mg, 90%). LC-MS: m / z [M+H] + =255.

[0760] 103:7-Ethyl-4-(4-fluoro-3-(4-methoxy-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-4-methoxy-1,2-dimethyl-1H-benzo[d]imidazole (42 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 (50 mg, 0.13 mmol) were used as raw materials to obtain the title compound (25 mg, 44%).

[0761] 1 H NMR (400 MHz, CHLOROFORM-d) 1.63 - 1.72 (m, 3 H) 2.63 (br. s., 3 H) 3.73 (br. s., 3 H) 4.29 (br. s., 3 H) 4.56 (d, J=7.34 Hz, 2 H) 7.05 (d, J=7.83 Hz, 1 H) 7.22 (br. s., 1 H) 7.34 (t, J=8.07 Hz, 1 H) 8.16 - 8.32 (m, 3 H) 9.37 (br. s., 1 H). LC-MS: m / z [M+H] + =417.

[0762] Example 104

[0763] [ka]

[0764] 104-1: N-(3-methoxy-2-nitrophenyl)tetrahydrofuran-3-amine The experimental procedure was the same as that of Example 57-1, and the title compound (700 mg, 100%) was obtained using 1-fluoro-3-methoxy-2-nitrobenzene (500 mg, 2.9 mmol) and tetrahydrofuran-3-amine (508 mg, 5.8 mmol) as raw materials. LC-MS: m / z [M+H] + =239.

[0765] 104-2: N-(4-bromo-3-methoxy-2-nitrophenyl)tetrahydrofuran-3-amine The experimental procedure was the same as that of Example 57-2, and N-(3-methoxy-2-nitrophenyl)tetrahydrofuran-3-amine (700 mg, 2.94 mmol) was used as the raw material to obtain the title compound (1000 mg, 100%). LC-MS: m / z [M+H] + =317.

[0766] 104-3: 4-Bromo-3-methoxy-N1-(tetrahydrofuran-3-yl)benzene-1,2-diamine The experimental procedure was the same as that of Example 57, 57-3, and N-(4-bromo-3-methoxy-2-nitrophenyl)tetrahydrofuran-3-amine (1000 mg, 3.2 mmol) was used as the raw material to obtain the title compound (700 mg, 77%). LC-MS: m / z [M+H] + =287.

[0767] 104-4: 5-Bromo-4-methoxy-1-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole 4-Bromo-3-methoxy-N1-(tetrahydrofuran-3-yl)benzene-1,2-diamine (200 mg, 1.75 mmol) was added to triethyl orthoformate (10 ml). The mixture was stirred at 90° C. overnight. The reaction mixture was directly subjected to thin layer chromatography (dichloromethane / methanol=30 / 1) to obtain the title compound (140 mg, 68%). LC-MS: m / z [M+H] + =297.

[0768] 104:7-Ethyl-4-(4-fluoro-3-(4-methoxy-1-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-4-methoxy-1-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole (85 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 (50 mg, 0.13 mmol) were used as raw materials to obtain the title compound (14 mg, 23%).

[0769] 1 H NMR (400 MHz, CHLOROFORM-d) 1.68 (br. s., 3 H) 2.32 (br. s., 1 H) 2.60 (dd,J=13.69, 6.36 Hz, 1 H) 3.95 - 4.04 (m, 1 H) 4.11 (dd,J=10.03,6.11 Hz, 1 H) 4.21 - 4.28 (m, 2 H) 4.37 (br. s., 3 H) 4.55 - 4.60 (m, 2 H) 5.07 (br. s., 1 H) 7.22 (br. s., 1 H) 7.29 - 7.39 (m, 2 H) 8.01 (br. s., 1 H) 8.22 (d,J=5.87 Hz, 1 H) 8.26 (s, 2 H) 9.37 (s, 1 H). LC-MS: m / z [M+H] + =459.

[0770] Example 105

[0771] [ka]

[0772] 105-1: Tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonic acid Tetrahydro-4-pyranol (CAS: 2081-44-9, 500 mg, 5 mmol) was dissolved in 10 mL of dichloromethane, and p-toluenesulfonyl chloride (1 g, 5.3 mmol) and N,N-diisopropylethylamine (2 mL) were added. The mixture was then stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous ammonium chloride, concentrated, and purified using a preparative plate (petroleum ether: ethyl acetate = 20:1) to give the title compound (400 mg, 30%) as a white solid. LC-MS: m / z [M+H] + =257.

[0773] 105-2: 5-Bromo-6-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole 5-Bromo-6-(methoxy)-1H-benzo[d]imidazole (CAS: 1008361-65-6, 354 mg, 1.5 mmol) was dissolved in 10 mL of acetonitrile, and cesium carbonate (1 g, 3 mmol) and tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonic acid (400 mg, 1.5 mmol) were added. The mixture was then heated to 60° C. and stirred for 3 hours. The solid was filtered, concentrated, and purified by preparative plate (petroleum ether:ethyl acetate=5:1) to give the title compound (300 mg, 62%) as a white solid. LC-MS: m / z [M+H] + =311.

[0774] 105:7-Ethyl-4-(4-fluoro-3-(6-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, 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 (60 mg, 0.16 mmol), 5-bromo-6-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (50 mg, 0.16 mmol) were used as raw materials to obtain the title compound (36 mg, 48%) as a white solid.

[0775] 1 H NMR (400 MHz, CHLOROFORM-d) 9.40 (s, 1 H) 8.28 (s, 2 H) 8.23 ​​(d, J=6.36 Hz, 1 H) 7.98 (s, 1 H) 7.70 (s, 1 H) 7.35 (t, J=9.05 Hz, 1 H) 6.89 (s, 1 H) 4.54 - 4.68 (m, 3 H) 4.22 (d, J=11.74 Hz, 2 H) 3.93 (s, 3 H) 3.68 (t, J=11.74 Hz, 2 H) 2.40 - 2.54 (m, 2 H) 2.04 (d, J=11.74 Hz, 2 H) 1.68 - 1.71 (m, 3H). LC-MS: m / z [M+H] + =473.

[0776] Example 106

[0777] [ka]

[0778] 106: 4-Amino-8-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-N-propylcinnoline-3-carboxamide 4-Amino-8-iodo-N-propylcinnoline-3-carboxamide (40 mg, 0.11 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 (40 mg, 0.11 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (9 mg, 0.011 mmol), cesium carbonate (108 mg, 0.33 mmol), and water (0.4 mL) were added to 1,4-dioxane (4 mL). The mixture was purged with nitrogen gas and stirred at 100°C for 2 hours. The reaction mixture was filtered, concentrated, and separated by preparative thin-layer chromatography (dichloromethane / methanol=20 / 1) to give the title compound (30 mg, 58%) as a brown solid.

[0779] 1 H NMR (400MHz, CHLOROFORM-d) 9.39 (s, 1 H), 8.52 (br. s., 1 H), 8.42 - 8.30 (m, 2 H), 8.26 (s, 1 H), 7.99 (d, J = 7.8 Hz, 1 H), 7.86 (d, J = 6.8 Hz, 1 H), 7.72 (t, J = 7.6 Hz, 1 H), 7.62 - 7.53 (m, 1 H), 7.48 - 7.36 (m, 2 H), 4.56 (q, J = 7.3 Hz, 2 H), 3.43 (q, J = 6.4 Hz, 2 H), 1.69 - 1.59 (m, 5 H), 0.97 (t, J = 7.3Hz, 3H). LC-MS: m / z [M+H] + =471.

[0780] Example 107

[0781] [ka]

[0782] 107-1: 5-Bromo-6-methoxy-1-(tetrahydrofuran-3-yl)-1H-indazole 5-Bromo-6-methoxy-1H-indazole (200 mg, 0.88 mmol) was dissolved in N,N-dimethylformamide (4 mL), sodium hydride (70 mg, 1.76 mmol) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hours. 3-Iodotetrahydrofuran (349 mg, 1.76 mmol) was added, and the mixture was stirred at room temperature for an additional 16 hours. Sodium sulfate decahydrate (100 mg) was added to the reaction mixture, which was then filtered, concentrated, and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (90 mg, 35%) as a pale yellow solid. LC-MS: m / z [M+H] + =297, 299.

[0783] 107:7-Ethyl-4-(4-fluoro-3-(6-methoxy-1-(tetrahydrofuran-3-yl)-3a,7a-dihydro-1H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-1-(tetrahydrofuran-3-yl)-1H-indazole (55 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 raw materials to obtain the title compound (40 mg, 46%) as a yellow solid.

[0784] 1H NMR (400MHz, CHLOROFORM-d) δ = 9.38 (br. s., 1 H), 8.35 - 8.14 (m, 3 H), 7.96 (s, 1 H), 7.68 (s, 1 H), 7.33 (t, J = 8.8 Hz, 1 H), 6.97 (s, 1 H), 5.29 (br. s., 1 H), 4.57 (q, J = 7.0 Hz, 2 H), 4.34 - 4.17 (m, 3 H), 4.06 - 3.99 (m, 1 H), 3.90 (s, 3 H), 2.53 (d, J = 6.8 Hz, 2 H), 1.68 (t, J = 7.1 Hz, 3H). LC-MS: m / z [M+H] + =461.

[0785] Example 108

[0786] [ka]

[0787] 108-1: 5-Bromo-6-methoxy-1-(oxetan-3-yl)-1H-indazole 5-Bromo-6-methoxy-1H-indazole (1000 mg, 4.40 mmol) was dissolved in N,N-dimethylformamide (8 mL), sodium hydride (176 mg, 4.40 mmol) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hours. 3-Iodooxetane (1619 mg, 8.80 mmol) was added, and the mixture was stirred at room temperature for an additional 16 hours. Sodium sulfate decahydrate (500 mg) was added to the reaction mixture, which was then filtered, concentrated, and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (310 mg, 25%) as a pale yellow solid. LC-MS: m / z [M+H] + =283, 285.

[0788] 108:7-Ethyl-4-(4-fluoro-3-(6-methoxy-1-(oxetan-3-yl)-3a,7a-dihydro-1H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-1-(oxetan-3-yl)-1H-indazole (50 mg, 0.18 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 (66 mg, 0.18 mmol) were used as raw materials to obtain the title compound (40 mg, 50%) as a yellow solid.

[0789] 1 H NMR (400MHz, CHLOROFORM-d) 9.38 (br. s., 1 H), 8.27 (s, 2 H), 8.21 (d, J = 6.8 Hz, 1 H), 8.04 (s, 1 H), 7.70 (s, 1 H), 7.34 (t, J = 9.0 Hz, 1 H), 7.00 (s, 1 H), 5.79 (quin, J = 6.8 Hz, 1 H), 5.34 (t, J = 6.4 Hz, 2 H), 5.18 (t, J = 7.1 Hz, 2 H), 4.57 (q, J = 7.3 Hz, 2 H), 3.91 (s, 3 H), 1.68 (t, J = 7.1 Hz, 3H). LC-MS: m / z [M+H] + =447.

[0790] Example 109

[0791] [ka]

[0792] 109-1: 5-Bromo-4-methoxy-1-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole 4-Bromo-3-methoxy-N1-methylbenzene-1,2-diamine (200 mg, 0.87 mmol), tetrahydropyran-4-carbaldehyde (100 mg, 0.87 mmol) were added to tetrahydrofuran (10 ml) and acetic acid (0.5 ml). The mixture was stirred overnight at 65°C under argon gas protection. The reaction mixture was directly subjected to thin layer chromatography to obtain the title compound (100 mg, 36%). LC-MS: m / z [M+H] + =325.

[0793] 109:7-Ethyl-4-(4-fluoro-3-(4-methoxy-1-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-4-methoxy-1-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole (85 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) was used as raw materials to obtain the title compound (24 mg, 36.3%).

[0794] 1 H NMR (400 MHz, CHLOROFORM-d) 1.70 (br. s., 3 H) 1.92 (d, J=11.74 Hz, 2 H) 2.21 (br. s., 2 H) 3.15 (br. s., 1 H) 3.62 (t, J=10.03 Hz, 2 H) 3.78(br. s., 3 H) 4.15 (d, J=10.76 Hz, 2 H) 4.37 (s, 3 H) 4.57 (d, J=6.85 Hz, 2 H) 7.05 (d, J=6.85 Hz, 1 H) 7.20 - 7.23 (m, 1 H) 7.31 - 7.38 (m, 1 H) 8.19 - 8.29 (m,3 H) 9.37 (br. s., 1 H). LC-MS: m / z [M+H] + =487.

[0795] Example 110, Example 111

[0796] [ka]

[0797] 110-A1: 5-Bromo-1-(difluoromethyl)-6-methoxy-1H-indazole 110-A2: 5-Bromo-2-(difluoromethyl)-6-methoxy-2H-indazole 5-Bromo-6-(methoxy)-1H-benzo[d]imidazole (CAS: 1008361-65-6, 440 mg, 1.9 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and cesium carbonate (2 g, 5.8 mmol), potassium fluoride (1 g, 5.8 mmol), and sodium chlorodifluoroacetate (589 mg, 3.8 mmol) were added. The mixture was heated to 100 °C and stirred overnight. The solid was filtered and purified by preparative plate (petroleum ether:ethyl acetate = 3:1) to give the title compound A1 (80 mg, 15%, eluent:petroleum ether:ethyl acetate = 3:1, Rf = 0.7) as a less polar white solid and the title compound A2 (200 mg, 38%, eluent:petroleum ether:ethyl acetate = 3:1, Rf = 0.5) as a more polar yellow solid. LC-MS: m / z [M+H] + =277.

[0798] 110: 4-(3-(1-(difluoromethyl)-6-methoxy-1H-indazol-5-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, 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 (60 mg, 0.16 mmol), 5-bromo-1-(difluoromethyl)-6-methoxy-1H-indazole (50 mg, 0.16 mmol) were used as raw materials to obtain the title compound (36 mg, 51%) as a white solid.

[0799] 1 H NMR (400 MHz, CHLOROFORM-d) δ 9.38 (s, 1 H) 8.28 (s, 2 H) 8.23 ​​(d, J=6.85 Hz, 1 H) 8.04 (s, 1 H) 7.72 (s, 1 H) 7.33 - 7.65 (m, 2 H) 7.27 (s, 1 H) 4.58 (q, J=7.34 Hz, 2 H) 3.93 (s, 3 H) 1.69 (t, J=7.34 Hz, 3 H). LC-MS: m / z [M+H] + =439.

[0800] 111:4-(3-(2-(difluoromethyl)-6-methoxy-2H-indazol-5-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, 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 (60 mg, 0.16 mmol), 5-bromo-2-(difluoromethyl)-6-methoxy-2H-indazole (50 mg, 0.16 mmol) were used as raw materials to obtain the title compound (32 mg, 46%) as a yellow solid.

[0801] 1 H NMR (400 MHz, CHLOROFORM-d) 9.40 (s, 1 H) 8.30 (d, J=5.87 Hz, 3 H) 8.23 ​​(d, J=6.85 Hz, 1 H) 7.67 (s, 1 H) 7.28 - 7.61 (m, 2 H) 7.06 (s, 1H) 4.59 (q, J=7.17 Hz, 2 H) 3.89 (s, 3 H) 1.70 (s, 3 H). LC-MS: m / z [M+H] + =439.

[0802] Example 112

[0803] [ka]

[0804] 112-1: 2,5-Dibromo-4-methoxybenzaldehyde 2-Bromo-4-methoxybenzaldehyde (5000 mg, 23.26 mmol) and pyridinium tribromide (14886 mg, 46.52 mmol) were added to methanol (50 mL) and stirred at 35° C. for 16 hours. The reaction mixture was added dropwise to saturated aqueous ammonium chloride solution (100 mL) and filtered to give the title compound (6000 mg, 88%) as a white solid. LC-MS: m / z [M+H] + =293, 295.

[0805] 112-2: (Z)-1,4-Dibromo-2-(2-bromovinyl)-5-methoxybenzene (Bromomethyl)triphenylphosphonium bromide (8000 mg, 18.35 mmol) was dissolved in tetrahydrofuran (50 mL). Potassium tert-butoxide (3394 mg, 30.30 mmol) dissolved in tetrahydrofuran (20 mL) was added dropwise to the reaction solution at -78°C. After stirring at -78°C for 2 hours, 2,5-dibromo-4-methoxybenzaldehyde (4000 mg, 15.15 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and then separated by column chromatography (ethyl acetate) to obtain the title compound (1500 mg, 27%) as a white solid. LC-MS: m / z [M+H] + =369, 371.

[0806] 112-3: Diethyl 6-bromo-7-methoxycinnoline-1,2-dicarboxylate (Z)-1,4-Dibromo-2-(2-bromovinyl)-5-methoxybenzene (1500 mg, 4.05 mmol), diethyl hydrazine-1,2-dicarboxylate (1426 mg, 8.10 mmol), potassium carbonate (1397 mg, 10.13 mmol), cuprous iodide (77 mg, 0.405 mmol), and N,N-dimethylethylenediamine (179 mg, 2.03 mmol) were added to 1,4-dioxane (10 mL), purged with nitrogen gas, and stirred at 90°C for 16 hours. Water (40 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL x 3). The organic phase was separated by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (950 mg, 61%) as a yellow oil. LC-MS: m / z [M+H] + =385, 387.

[0807] 112-4: 6-Bromo-7-methoxycinnoline Diethyl 6-bromo-7-methoxycinnoline-1,2-dicarboxylate (950 mg, 2.47 mmol) and sodium hydroxide (99 mg, 2.47 mmol) were added to ethanol (20 mL) and stirred at room temperature for 16 hours. The ethanol was concentrated to dryness, and the mixture was separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (300 mg, 51%) as a yellow solid. LC-MS: m / z [M+H] + =239, 241.

[0808] 112:6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxycinnoline The experimental procedure was the same as in Example 1, and 6-bromo-7-methoxycinnoline (200 mg, 0.84 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 (309 mg, 0.84 mmol) were used as raw materials to obtain the title compound (135 mg, 27%) as a white solid.

[0809] 1H NMR (400 MHz, CHLOROFORM-d) 9.39 (s, 1 H), 9.27 (d, J = 5.4 Hz, 1 H), 8.39 - 8.26 (m, 3 H), 7.92 (s, 1 H), 7.88 - 7.80 (m, 2 H), 7.45 - 7.36 (m, 1 H), 4.59 (q, J = 7.0 Hz, 2 H), 4.05 (s, 3 H), 1.69 (t, J = 7.1 Hz, 3 H). LC-MS: m / z [M+H] + =401.

[0810] Example 113

[0811] [ka]

[0812] 113-1: 5-Bromo-6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole The experimental procedure was the same as that for synthesizing 40-1 and 40-2 in Example 40. 5-Bromo-4-methoxy-2-nitrobenzaldehyde (500 mg, 1.92 mmol) and tetrahydro-2H-pyran-4-amine (388 mg, 3.84 mmol) were used as raw materials to obtain the title compound (500 mg, 84%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =311, 313.

[0813] 113:7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole (200 mg, 0.64 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 (236 mg, 0.64 mmol) were used as raw materials to obtain the title compound (140 mg, 46%) as a yellow solid.

[0814] 1 H NMR (400MHz, CHLOROFORM-d) 9.36 (s, 1 H), 8.25 (s, 2 H), 8.19 (d, J = 6.8 Hz, 1 H), 7.92 (s, 1 H), 7.61 (s, 1 H), 7.31 (t, J = 9.0 Hz, 1 H), 7.10 (s, 1 H), 4.56 (td, J = 7.5, 14.8 Hz, 3 H), 4.15 (d, J = 11.2 Hz, 2 H), 3.85 (s, 3 H), 3.64 - 3.54 (m, 2 H), 2.23 (br. s., 4 H), 1.66 (t, J = 7.1 Hz, 3H). LC-MS: m / z [M+H] + =473.

[0815] Example 114

[0816] [ka]

[0817] 114-1: 5-Bromo-2-cyclopropyl-6-methoxy-2H-indazole The experimental procedure was the same as that for synthesizing 40-1 and 40-2 in Example 40. 5-Bromo-4-methoxy-2-nitrobenzaldehyde (100 mg, 0.38 mmol) and cyclopropylamine (43 mg, 0.76 mmol) were used as raw materials to obtain the title compound (70 mg, 69%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =267, 269.

[0818] 114: 4-(3-(2-cyclopropyl-6-methoxy-2H-indazol-5-yl)-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-2-cyclopropyl-6-methoxy-2H-indazole (70 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 (96 mg, 0.26 mmol) were used as raw materials to obtain the title compound (15 mg, 13%) as a yellow solid.

[0819] 1 H NMR (400MHz ,CHLOROFORM-d) δ = 9.35 (br. s., 1 H), 8.24 (br. s., 2 H), 8.17 (d, J = 5.9 Hz, 1 H), 7.93 (s, 1 H), 7.56 (s, 1 H), 7.30 (t, J = 8.8 Hz, 1 H), 7.05 (br. s., 1 H), 4.55 (d, J = 7.3 Hz, 2 H), 3.89 (br. s., 1 H), 3.83 (s, 3 H), 1.66 (t, J = 7.1 Hz, 3 H), 1.31 (br. s., 2 H), 1.14 (d, J = 6.4 Hz, 2H). LC-MS: m / z [M+H] + =429.

[0820] Example 115

[0821] [ka]

[0822] 115-1: N-(3-methoxy-2-nitrophenyl)oxetan-3-amine The experimental procedure was the same as that of Example 57-1, and 1-fluoro-3-methoxy-2-nitrobenzene (500 mg, 2.9 mmol) was used as the raw material to obtain the title compound (400 mg, 62%) as a yellow oil. LC-MS: m / z [M+H] + =225.

[0823] 115-2: N-(4-bromo-3-methoxy-2-nitrophenyl)oxetan-3-amine The experimental procedure was the same as that of Example 57-2, and N-(3-methoxy-2-nitrophenyl)oxetan-3-amine (400 mg, 1.79 mmol) was used as the starting material to obtain the title compound (400 mg, 74%) as a yellow oil. LC-MS: m / z [M+H] + =303.

[0824] 115-3: 4-Bromo-3-methoxy-N1-(oxetan-3-yl)benzene-1,2-diamine The experimental procedure was the same as that of Example 57-3, and N-(4-bromo-3-methoxy-2-nitrophenyl)oxetan-3-amine (400 mg, 1.32 mmol) was used as the starting material to obtain the title compound (300 mg, 84%) as a red oil. LC-MS: m / z [M+H] + =273.

[0825] 115-4: 5-Bromo-4-methoxy-1-(oxetan-3-yl)-1H-benzo[d]imidazole The experimental procedure was the same as that of Example 57-4, and 4-bromo-3-methoxy-N1-(oxetan-3-yl)benzene-1,2-diamine (300 mg, 1.1 mmol) was used as the raw material to obtain the title compound (140 mg, 45%) as a red oil. LC-MS: m / z [M+H] + =283.

[0826] 115:7-Ethyl-4-(4-fluoro-3-(4-methoxy-1-(oxetan-3-yl)-1H-benzo[d]imidazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, 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, 0.136 mmol), 5-bromo-4-methoxy-1-(oxetan-3-yl)-1H-benzo[d]imidazole (60 mg, 0.21 mmol) were used as raw materials to obtain the title compound (13 mg, 22%).

[0827] 1 H NMR (400 MHz, CHLOROFORM-d) 9.37 (br.s., 1 H) 8.19 - 8.32 (m, 3 H) 8.03 (br. s., 1 H) 7.45 (d, J=7.83 Hz, 1 H) 7.31 -7.39 (m, 2 H) 5.56 (br. s., 1 H) 5.14 - 5.27 (m, 4 H) 4.56 (d, J=7.34 Hz, 2 H) 4.36 (br. s., 3 H) 1.66 - 1.69 (m, 3 H). LC-MS: m / z [M+H] + =445.

[0828] Example 116

[0829] [ka]

[0830] 116-1: N-(2,4-dibromo-5-methoxyphenyl)-2-methoxyacetamide 2,4-Dibromo-5-methoxyaniline (200 mg, 0.71 mmol), triethylamine (36 mg, 0.35 mmol), and 2-methoxyacetyl chloride (154 mg, 1.42 mmol) were added to dichloromethane (4 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated and directly separated and purified on a preparative plate (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (300 mg, 80%). LC-MS: m / z [M+H] + =354.

[0831] 116-2: 6-Bromo-5-methoxy-2-(methoxymethyl)benzo[d]oxazole N-(2,4-Dibromo-5-methoxyphenyl)-2-methoxyacetamide (300 mg, 0.85 mmol), potassium carbonate (293 mg, 2.12 mmol), cuprous iodide (16 mg, 0.09 mmol), and N,N-dimethylethylenediamine (37.4 mg, 0.43 mmol) were added to toluene (6 mL) and stirred at 110°C for 16 hours. The reaction mixture was concentrated and directly separated and purified using a preparative plate (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (60 mg, 26%). LC-MS: m / z [M+H] + =272,274.

[0832] 116:6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-5-methoxy-2-(methoxymethyl)benzo[d]oxazole The experimental procedure was the same as in Example 1, and 6-bromo-5-methoxy-2-(methoxymethyl)benzoxazole (60 mg, 0.22 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 (68 mg, 0.17 mmol) were used as raw materials to obtain the title compound (10 mg, 11%).

[0833] 1 H NMR (400MHz, CDCl3) δ 9.38 (br. s., 1 H), 8.32 - 8.20 (m, 3 H), 7.54 (s, 1 H), 7.38 - 7.34 (m, 1 H), 7.32 (s, 1 H), 4.72 (s, 2 H), 4.57 (q, J = 7.0 Hz, 2 H), 3.92 - 3.83 (m, 3 H), 3.54 (s, 3 H), 1.72 - 1.67 (m, 3 H). LC-MS: m / z [M+H] + =434.

[0834] Example 117

[0835] [ka]

[0836] 117-1: 5-Bromo-6-methoxy-2-(1-methylazetidin-3-yl)-2H-indazole 2-(azetidin-3-yl)-5-bromo-6-methoxy-2H-indazole (150 mg, 0.5 mmol) was dissolved in 20 mL of methanol, and 37% aqueous formaldehyde (1 mL) and sodium cyanoborohydride (620 mg, 10 mmol) were added. The mixture was then stirred overnight at room temperature. The mixture was concentrated, dissolved in dichloromethane, filtered, concentrated, and purified by preparative plate (dichloromethane:methanol=10:1) to give the title compound (100 mg, 64%) as a white solid. LC-MS: m / z [M+H] + =296.

[0837] 117:7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-(1-methylazetidin-3-yl)-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, 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 (60 mg, 0.16 mmol), 5-bromo-6-methoxy-2-(1-methylazetidin-3-yl)-2H-indazole (50 mg, 0.16 mmol) were used as raw materials to obtain the title compound (20 mg, 27%) as a yellow solid.

[0838] 1H NMR (400MHz, CHLOROFORM-d) δ9.38 (s, 1 H), 8.27 (s, 2 H), 8.21 (d, J = 6.4 Hz, 1 H), 8.03 (s, 1 H), 7.62 (s, 1 H), 7.34 (t, J = 9.0 Hz, 1 H), 7.12 (s, 1 H), 5.28 (d, J = 17.1 Hz, 1 H), 4.58 (q, J = 7.2 Hz, 2 H), 4.17 (br. s., 2 H), 3.88 (br. s., 5 H), 2.67 (br. s., 3 H), 1.71 - 1.68 (m, 3H). LC-MS: m / z [M+H] + =458.

[0839] Example 118

[0840] [ka]

[0841] 118-1: 5-Bromo-6-methoxy-1-(1-methylazetidin-3-yl)-1H-indazole 1-(azetidin-3-yl)-5-bromo-6-methoxy-1H-indazole (150 mg, 0.5 mmol) was dissolved in 20 mL of methanol, and 37% aqueous formaldehyde (1 mL) and sodium cyanoborohydride (620 mg, 10 mmol) were added, followed by stirring at room temperature overnight. The mixture was concentrated, dissolved in dichloromethane, filtered, concentrated, and purified by preparative plate (dichloromethane:methanol=10:1) to give the title compound (100 mg, 64%) as a white solid. LC-MS: m / z [M+H] + =296.

[0842] 118:7-Ethyl-4-(4-fluoro-3-(6-methoxy-1-(1-methylazetidin-3-yl)-1H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, 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 (60 mg, 0.16 mmol), 5-bromo-6-methoxy-1-(1-methylazetidin-3-yl)-1H-indazole (50 mg, 0.16 mmol) were used as raw materials to obtain the title compound (20 mg, 27%) as a yellow solid.

[0843] 1 H NMR (400 MHz, CHLOROFORM-d) δ 9.38 (s, 1 H) 8.28 (s, 2 H) 8.20 (d, J=5.87 Hz, 1 H) 8.05 (s, 1 H) 7.68 (s, 1 H) 7.34 (t, J=8.80 Hz, 1 H) 6.93(s, 1 H) 5.50 (br. s., 1 H) 4.58 (q, J=7.34 Hz, 2 H) 4.51 (t, J=7.58 Hz, 2 H) 4.13 (t, J=7.83 Hz, 2 H) 3.92 (s, 3 H) 2.85 (s, 3 H) 1.69 (t, J=7.34 Hz, 3H). LC-MS: m / z [M+H] + =458.

[0844] Example 119

[0845] [ka]

[0846] 119-1: N-ethyl-3-methoxy-2-nitroaniline The experimental procedure was the same as that of Example 57-1, and 1-fluoro-3-methoxy-2-nitrobenzene (500 mg, 2.9 mmol) was used as the raw material to obtain the title compound (450 mg, 79%) as a yellow oil. LC-MS: m / z [M+H] + =197.

[0847] 119-2: 4-Bromo-N-ethyl-3-methoxy-2-nitroaniline The experimental procedure was the same as that of Example 57-2, and N-ethyl-3-methoxy-2-nitroaniline (400 mg, 2.04 mmol) was used as the raw material to obtain the title compound (350 mg, 62.6%) as a yellow oil. LC-MS: m / z [M+H] + =275.

[0848] 119-3: 4-Bromo-N1-ethyl-3-methoxybenzene-1,2-diamine The experimental procedure was the same as that of Example 57, 57-3, and 4-bromo-N-ethyl-3-methoxy-2-nitroaniline (350 mg, 1.28 mmol) was used as the raw material to obtain the yellow title compound (300 mg, 96%). LC-MS: m / z [M+H] + =245.

[0849] 119-4: 5-Bromo-1-ethyl-4-methoxy-1H-benzo[d]imidazole The experimental procedure was the same as that of Example 57-4, and 4-bromo-N1-ethyl-3-methoxybenzene-1,2-diamine (300 mg, 1.2 mmol) was used as the raw material to obtain the title compound (200 mg, 66%) as a yellow solid. LC-MS: m / z [M+H] + =255.

[0850] 119:7-Ethyl-4-(3-(1-ethyl-4-methoxy-1H-benzo[d]imidazol-5-yl)-4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and the title compound (48 mg, 85%) was obtained using 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, 0.136 mmol) and 5-bromo-1-ethyl-4-methoxy-1H-benzo[d]imidazole (69 mg, 0.27 mmol).

[0851] 1 H NMR (400 MHz, CHLOROFORM-d) 9.37 (s, 1 H) 8.26 (s, 2 H) 8.22 (d, J=5.87 Hz, 1 H),7.93 (br. s., 1 H) 7.28 - 7.39 (m, 2 H) 7.16 (d, J=8.31 ​​Hz, 1 H) 4.57 (q, J=7.01Hz, 2 H) 4.37 (br. s., 3 H) 4.26 (q, J=7.01 Hz, 2 H) 1.68 (t, J=7.34 Hz, 3 H) 1.58 (t, J=7.09 Hz, 3 H). LC-MS: m / z [M+H] + =417.

[0852] Example 120

[0853] [ka]

[0854] 120-1: 5-Bromo-6-methoxy-2-(2-methoxyethyl)-2H-indazole 5-Bromo-6-methoxy-1H-indazole (200 mg, 0.9 mmol), sodium bicarbonate (108 mg, 4.5 mmol), and 1-bromo-2-methoxyethane (187 mg, 1.4 mmol) were dissolved in anhydrous N,N-dimethylformamide (8 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated, diluted with water, extracted with ethyl acetate, and the organic phase was concentrated and separated and purified (ethyl acetate) using a preparative plate to give the title compound (80 mg, 31.3%). LC-MS: m / z [M+H] + =285,287.

[0855] 120:7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-(2-methoxyethyl)-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-2-(2-methoxyethyl)-2H-indazole (80 mg, 0.28 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 (87 mg, 0.28 mmol) were used as raw materials to obtain the title compound (60 mg, 61%).

[0856] 1 H NMR (400MHz, CDCl3) δ 9.37 (s, 1 H), 8.30 - 8.24 (m, 2 H), 8.23 ​​- 8.18 (m, 1 H), 7.97 (s, 1 H), 7.61 (s, 1 H), 7.32 (t, J = 9.0 Hz, 1 H), 7.09 (s, 1 H), 4.59 - 4.52 (m, 4 H), 3.90 - 3.86 (m, 2 H), 3.85 (s, 3 H), 3.34 (s, 3 H), 1.71 - 1.66 (m, 3 H). LC-MS: m / z [M+H] + =447.

[0857] Example 121

[0858] [ka]

[0859] 121-1: 6-Bromo-7-methoxyisoquinoline 6-Bromo-7-fluoroisoquinoline (CAS: 1258833-80-5, 130 mg, 0.5 mmol) and 4 M sodium methoxide in methanol (2 mL) were dissolved in 10 mL of methanol, followed by heating to reflux for 2 hours. Water was added and the mixture was neutralized with 1 M hydrochloric acid. Extraction with dichloromethane, drying, and concentration afforded the title compound (800 mg, 76%) as a white solid. LC-MS: m / z [M+H] + =238.

[0860] 121-2: 6-Bromo-7-methoxyisoquinoline 2-oxide 6-Bromo-7-methoxyisoquinoline (700 mg, 3.4 mmol) was dissolved in 10 mL of dichloromethane, metachloroperbenzoic acid (1.1 g, 6.8 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was concentrated and purified by preparative plate chromatography (dichloromethane:methanol = 20:1) to give the title compound (600 mg, 80%) as a white solid. LC-MS: m / z [M+H]+ = 254.

[0861] 121-3: 6-Bromo-7-methoxyisoquinolin-1(2H)-one 6-Bromo-7-methoxyisoquinoline 2-oxide (600 mg, 2.3 mmol) was dissolved in acetic anhydride (50 mL) and then heated to reflux for 2 hours. After cooling to 100°C, 50 mL of water was added and the mixture was heated to reflux overnight. Extraction with ethyl acetate, concentration, and purification by preparative plate (dichloromethane:methanol=20:1) afforded the title compound (200 mg, 33%) as a yellow solid. LC-MS: m / z [M+H] + =254.

[0862] 121-4: 6-Bromo-7-methoxy-2-methylisoquinolin-1(2H)-one 6-Bromo-7-methoxyisoquinolin-1(2H)-one (200 mg, 0.78 mmol), potassium carbonate (500 mg, 1.6 mmol), and methyl iodide (0.5 mL) were dissolved in 10 mL of methanol, followed by stirring overnight at room temperature. The mixture was concentrated and purified by preparative plate chromatography (dichloromethane:methanol=20:1). The title compound (110 mg, 52%) was obtained as a white solid. LC-MS: m / z [M+H] + =268.

[0863] 121:6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxy-2-methylisoquinolin-1(2H)-one The experimental procedure was the same as in Example 1, 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 (70 mg, 0.2 mmol), 6-bromo-7-methoxy-2-methylisoquinolin-1(2H)-one (60 mg, 0.2 mmol) were used as raw materials to obtain the title compound (48 mg, 58%) as a white solid.

[0864] 1 H NMR (400 MHz, CHLOROFORM-d) δ 9.39 (s, 1 H) 8.22 - 8.37 (m, 3 H) 7.97 (s, 1 H) 7.55 (s, 1 H) 7.37 (t, J=9.05 Hz, 1 H) 7.03 (d, J=6.85 Hz, 1H) 6.51 (d, J=7.34 Hz, 1 H) 4.59 (q, J=7.34 Hz, 2 H) 3.96 (s, 3 H) 3.66 (s, 3 H) 1.70 (t, J=7.09 Hz, 3 H). LC-MS: m / z [M+H] + =430.

[0865] Example 122

[0866] [ka]

[0867] 122-1: 5-Bromo-6-methoxy-2-(tetrahydrofuran-3-yl)-2H-indazole 5-Bromo-6-methoxy-1H-indazole (200 mg, 0.88 mmol) was added to anhydrous N,N-dimethylformamide (4 mL), and sodium hydride (35 mg, 0.88 mmol) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. 3-Iodotetrahydrofuran (523 mg, 2.64 mmol) was added, and the mixture was stirred at room temperature for an additional 16 hours. Sodium sulfate decahydrate (100 mg) was added to the reaction mixture, which was then filtered, concentrated, and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (40 mg, 15%). LC-MS: m / z [M+H] + =297, 299.

[0868] 122:7-Ethyl-4-(4-fluoro-3-(6-methoxy-2-(tetrahydrofuran-3-yl)-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-2-(tetrahydrofuran-3-yl)-2H-indazole (40 mg, 0.14 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 (52 mg, 0.14 mmol) were used as raw materials to obtain the title compound (27 mg, 42%) as a yellow solid.

[0869] 1H NMR (400MHz ,CHLOROFORM-d) 9.37 (s, 1 H), 8.31 - 8.24 (m, 2 H), 8.22 - 8.17 (m, 1 H), 7.98 (s, 1 H), 7.60 (s, 1 H), 7.32 (t, J = 9.0 Hz, 1 H), 7.10 (s, 1 H), 5.23 (br. s., 1 H), 4.56 (q, J = 7.3 Hz, 2 H), 4.26 - 4.13 (m, 3 H), 4.03 - 3.96 (m, 1 H), 3.85 (s, 3 H), 2.64 - 2.53 (m, 1 H), 2.51 - 2.42 (m, 1 H), 1.67 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H] + =459.

[0870] Example 123

[0871] [ka]

[0872] 123:6-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-7-methoxyisoquinoline The experimental procedure was the same as in Example 1, 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, 0.14 mmol) and 6-bromo-7-methoxyisoquinoline (30 mg, 0.16 mmol) were used as raw materials to obtain the title compound (19 mg, 35%) as a white solid.

[0873] 1H NMR (400 MHz, CHLOROFORM-d) δ 9.40 (s, 1 H) 9.25 (s, 1 H) 8.48 (d, J=5.38 Hz, 1 H) 8.25 - 8.37 (m, 3 H) 7.85 (s, 1 H) 7.65 (d, J=5.38 Hz, 1H) 7.33 - 7.44 (m, 2 H) 4.59 (q, J=7.01 Hz, 2 H) 3.98 (s, 3 H) 1.70 (t, J=7.09 Hz, 3 H). LC-MS: m / z [M+H] + =400.

[0874] Example 124

[0875] [ka]

[0876] 124-1: 5'-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2'-fluoro-4-hydroxy-6-methoxy-[1,1'-biphenyl]-3-carbaldehyde The experimental procedure was the same as in Example 1, and 5-bromo-2-hydroxy-4-methoxybenzaldehyde (70 mg, 0.299 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 (100 mg, 0.272 mmol) were used as raw materials to obtain the title compound (66 mg, 62%). LC-MS: m / z [M+H] + =393.

[0877] 124-2: 5'-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2'-fluoro-4-hydroxy-6-methoxy-[1,1'-biphenyl]-3-carbaldehyde oxime 5'-(7-Ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2'-fluoro-4-hydroxy-6-methoxy-[1,1'-biphenyl]-3-carbaldehyde (66 mg, 0.168 mmol), hydroxylamine hydrochloride (35 mg, 0.505 mmol), sodium carbonate (53 mg, 0.505 mmol) were added to ethanol (2 ml) and water (0.2 ml) and stirred at room temperature overnight. The reaction mixture was suction filtered and concentrated, and the crude product (48 mg) was directly used in the next step.

[0878] 124:5-(5-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2-fluorophenyl)-6-methoxybenzo[d]isoxazole 5'-(7-Ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2'-fluoro-4-hydroxy-6-methoxy-[1,1'-biphenyl]-3-carbaldehyde oxime (48 mg, 0.118 mmol), triphenylphosphine (31 mg, 0.120 mmol) was added to acetonitrile (1 ml) and stirred at room temperature for 5 minutes. Then, diisopropyl azodicarboxylate (24 mg, 0.12 mmol) was dissolved in acetonitrile (0.5 ml) and added dropwise to the reaction mixture under Ar protection. After the addition was completed, the mixture was stirred at room temperature overnight. The reaction mixture was suction filtered, concentrated, and subjected to preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 3) to obtain the title compound (1 mg, 2%).

[0879] 1 H NMR (400MHz, CHLOROFORM-d) d = 9.20 (s, 1 H), 8.31 (s, 1 H), 8.12 - 7.99 (m, 2 H), 7.38 (s, 1 H), 7.26-7.23 (m, 2 H), 6.50 (s, 1 H), 4.48 (d, J = 7.8 Hz, 2 H), 3.73 (s, 3 H), 1.59 (t, J = 7.3 Hz, 3 H). LC-MS: m / z [M+H] + =390.

[0880] Example 125

[0881] [ka]

[0882] 125-1:7-Bromo-4-(oxetan-3-yloxy)benzofuran 7-Bromo-4-fluorobenzofuran (200 mg, 0.9 mmol), oxetan-3-ol (133 mg, 1.8 mmol), and cesium carbonate (472 mg, 1.45 mmol) were added to N,N-dimethylformamide (1 ml) and reacted at 80°C for 6 hours. The reaction mixture was suction filtered, concentrated, and subjected to preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (188 mg, 77%). LC-MS: m / z [M+H] + =269, 271.

[0883] 125:7-Ethyl-4-(4-fluoro-3-(4-(oxetan-3-yloxy)benzofuran-7-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 7-bromo-4-(oxetan-3-yloxy)benzofuran (46 mg, 0.163 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 (60 mg, 0.163 mmol) were used as raw materials to obtain the title compound (33 mg, 47%).

[0884] 1H NMR (400MHz, CHLOROFORM-d) 9.40 (s, 1 H), 8.45 (d, J = 6.8 Hz, 1 H), 8.32 - 8.25 (m, 2 H), 7.62 (s, 1 H), 7.44 - 7.35 (m, 2 H), 6.98 (s, 1 H), 6.35 (d, J = 7.8 Hz, 1 H), 5.41 (t, J = 5.4 Hz, 1 H), 5.07 (t, J = 6.6 Hz, 2 H), 4.89 (t, J = 5.9 Hz, 2 H), 4.58 (q, J = 7.3 Hz, 2 H), 1.71 - 1.67 (m, 3 H). LC-MS: m / z [M+H] + =431.

[0885] Example 126

[0886] [ka]

[0887] 126-1: 5-Bromo-4-methoxy-1-methyl-1H-benzo[d]imidazole 4-Bromo-3-methoxy-N1-methylbenzene-1,2-diamine (200 mg, 0.87 mmol) was added to triethyl orthoformate (5 mL) and stirred at 80°C for 1 hour. The reaction mixture was concentrated and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (100 mg, 47%) as a pale yellow oily liquid. LC-MS: m / z [M+H] + =241, 243. 126:7-Ethyl-4-(4-fluoro-3-(4-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 106, and 5-bromo-4-methoxy-1-methyl-1H-benzo[d]imidazole (50 mg, 0.21 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 (77 mg, 0.21 mmol) were used as raw materials to obtain the title compound (26 mg, 30%) as a white solid.

[0888] 1 H NMR (400MHz, CHLOROFORM-d) 9.38 (s, 1 H), 8.34 - 8.19 (m, 3 H), 7.89 (br. s., 1 H), 7.40 - 7.29 (m, 2 H), 7.14 (d, J = 7.8 Hz, 1 H), 4.57 (q, J = 6.8 Hz, 2 H), 4.39 (s, 3 H), 3.87 (s, 3 H), 1.68 (t, J = 7.1 Hz, 3 H). LC-MS: m / z [M+H] + =403.

[0889] Example 127

[0890] [ka]

[0891] 127-1:6-Methoxy-2,3-dihydrobenzofuran 6-Methoxybenzofuran (500 mg, 3.38 mmol) and palladium carbon (20 mg) were added to ethanol (5 ml) and reacted at room temperature under H protection for 4 hours. The reaction mixture was suction filtered and concentrated to obtain the crude product (321 mg), which was directly used in the next step. LC-MS: m / z [M+H] + =151.

[0892] 127-2: 5-Bromo-6-methoxy-2,3-dihydrobenzofuran 6-Methoxy-2,3-dihydrobenzofuran (200 mg, 1.333 mmol) was added to acetic acid (1 ml), and liquid bromine (229 mg, 1.466 mmol) was dissolved in acetic acid (1 ml) and slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was allowed to react at room temperature for 30 minutes. The reaction mixture was poured into saturated sodium carbonate solution (20 ml), extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and subjected to preparative thin-layer chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (126 mg, 41%). LC-MS: m / z [M+H] + =228, 230.

[0893] 127:7-Ethyl-4-(4-fluoro-3-(6-methoxy-2,3-dihydrobenzofuran-5-yl)phenyl)-7H-imidazo[4,5-c]pyridazine The experimental procedure was the same as in Example 1, and 5-bromo-6-methoxy-2,3-dihydrobenzofuran (20 mg, 0.088 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 (32 mg, 0.088 mmol) were used as raw materials to obtain the title compound (6 mg, 18%).

[0894] 1 H NMR (400MHz, CHLOROFORM-d) 9.39 - 9.33 (m, 1 H), 8.28 - 8.20 (m, 2 H), 8.14 (dd, J = 2.2, 7.1 Hz, 1 H), 7.33 - 7.28 (m, 1 H), 7.16 (s, 1 H), 6.53 (s, 1 H), 4.64 (t, J = 8.6 Hz, 2 H), 4.59 - 4.55 (m, 2 H), 3.78 (s, 3 H), 3.21 (t, J = 8.6 Hz, 2 H), 1.70 - 1.67 (m, 3 H). LC-MS: m / z [M+H] + =391.

[0895] Example 128

[0896] [ka]

[0897] 128-1: 5-Bromo-2-isopropyl-6-methoxy-2H-indazole 5-Bromo-6-methoxy-1H-indazole (200 mg, 0.88 mmol) was added to anhydrous N,N-dimethylformamide (5 mL), and sodium hydride (35 mg, 0.88 mmol) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. 2-Iodopropane (300 mg, 1.76 mmol) was added and the mixture was stirred at room temperature for an additional 1 hour. Sodium sulfate decahydrate (100 mg) was added to the reaction mixture, which was then filtered, concentrated, and separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (50 mg, 19%). LC-MS: m / z [M+H] + =269, 271.

[0898] 128:7-Ethyl-4-(4-fluoro-3-(2-isopropyl-6-methoxy-2H-indazol-5-yl)phenyl)-7H-imidazo[4,5-c]pyri...

Claims

1. Imidazopyridazine-substituted benzene ring system compounds represented by formula (I) and derivatives, stereoisomers, tautomers, prodrugs, pharma- ceutically acceptable salts, amorphous substances, isotopes, crystal polymorphs or solvates thereof. 【Chemistry 1】 (however, The R １ is a condensed group formed from a substituted or unsubstituted benzene ring and a heterocycle, The R ２ is selected from H, halogen, OH, C1-C6 alkoxy or CN; The R ３ is selected from H, substituted or unsubstituted straight or branched chain C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

2. The R １ The compound according to claim 1, wherein the heterocycle forming the fused group represented by the formula (I) is a 5- to 7-membered saturated or unsaturated monocyclic or bicyclic group containing 1 to 3 heteroatoms selected from N, O, or S.

3. The R １ The compound according to claim 1 or 2, characterized in that it has a structure represented by the following formula (M): 【Chemistry 2】 (wherein m is 1, 2, or 3, and n is 1 or 2; 【Chemistry 3】 represents the linkage site, The A ring is a 5- to 7-membered saturated or partially unsaturated monocyclic or bicyclic ring containing at least one heteroatom selected from N, O, or S.

4. The R １ has a structure represented by formula (M), １ The compound according to claim 3, characterized in that it has a structure represented by the following (a) to (e). 【Chemistry 4】

5. The R １ The compound according to claim 3 or 4, wherein when the compound has a structure represented by formula (M), the A ring may be selected from the following structures: 【Chemistry 5】

6. The R ４ is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy, said groups being optionally unsubstituted or each independently substituted with at least one of 1 to 4 each selected from halogen, hydroxy, C1-C3 alkyl, haloC1-C3 alkyl, C1-C3 alkoxy or haloC1-C3 alkoxy.

7. The R ４ is selected from hydrogen, C1-C3 alkyl or C1-C3 alkoxy, said groups being optionally unsubstituted or each independently substituted with C1-C3 alkoxy or halogen.

8. The R ５ is selected from hydrogen, halogen, hydroxy, oxo, C1-C6 alkyl acyl, C1-C6 alkyl amido, C1-C6 alkoxyimino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C6-C10 aryl, 5-7 membered heteroaryl containing 1-3 heteroatoms, or C3-C7 non-aromatic heterocycle containing 1-3 heteroatoms, optionally unsubstituted or each independently substituted with at least one of 1-4 halogen, hydroxy, oxo, C1-C4 acyl, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, haloC1-C3 alkoxy, or sulfonyl, respectively.

9. The R ５ is selected from hydrogen, halogen, oxo, C1-C3 alkyl acyl, C1-C3 alkyl amido, C1-C3 alkoxyimino, C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C6-C8 aryl, 5-6 heteroaryl containing 1-2 heteroatoms, or C4-C6 non-aromatic heterocycle containing 1-2 heteroatoms, each of which is optionally unsubstituted or substituted by at least one of each independently selected from 1-2 halogen, hydroxy, oxo, C1-C3 acyl, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, haloC1-C3 alkoxy, or sulfonyl.

10. The R ５ is H, oxo, methyl, ethyl, isopropyl, acetyl, methylmethoxy, ethylmethoxy, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, methylamino, phenyl, 【Chemistry 6】 10. The compound according to claim 8 or 9, characterized in that it is selected from:

11. The R １ is selected from any one of the following structures: 【Chemistry 7】 Also, The R ４ is selected from H, C1-C3 alkoxy, or substituted or unsubstituted methoxy C1-C3 alkyl, preferably H, methylmethoxy, ethylmethoxy, methoxy or difluoromethoxy; The R ５ is H, methyl, ethyl, acetyl, ethylmethoxy, methylmethoxy, methylcyclopropyl, phenyl, 【Chemistry 8】 The compound according to any one of claims 3 to 10, characterized in that it is selected from:

12. The R ２ is selected from H or F, preferably F; The R ３ Compounds according to any one of claims 1 to 11, characterized in that is selected from H or linear or branched C1-C6 alkyl, preferably ethyl or isopropyl.

13. The compound according to any one of claims 1 to 3, characterized in that the compound is selected from the following compounds: 【Table 1】

14. A pharmaceutical composition comprising at least one of the imidazopyridazine-substituted benzene ring compound according to any one of claims 1 to 13 or a derivative, stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous substance, isotope, crystal polymorph or solvate thereof, optionally containing a pharma- ceutical acceptable carrier and / or auxiliary.

15. GABA Ａ Use of an imidazopyridazine-substituted benzene ring system compound or a derivative, stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous substance, isotope, crystalline polymorph or solvate thereof according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14, in the preparation of a medicament for treating or preventing a receptor-related disease.

16. The GABA Ａ 16. The use according to claim 15, characterized in that the receptor-related disease is selected from at least one of the following: pain, Alzheimer's disease, multi-infarct dementia, epilepsy, pruritus or stroke.

17. 17. The use according to claim 16, characterized in that the pain comprises neuropathic pain, inflammatory pain and cancer pain.

18. 18. Use according to claim 16 or 17, 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 deficiencies, viral or bacterial infection or pain associated with osteoarthritis.

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