TRIAZOLOPYRIDAZINE DERIVATIVE, METHOD OF PREPARATION THEREOF, PHARMACEUTICAL COMPOSITION THEREOF AND USE THEREOF

Abstract

A triazolopyridazine derivative, a method for its preparation, its pharmaceutical composition, and an application thereof are provided. The triazolopyridazine derivative is represented by Formula I. The triazolopyridazine derivative has excellent inverse agonist activity, thermodynamic solubility, bioavailability, and pharmacokinetic properties; therefore, its application prospects are promising. (See Formula).

Description

TRIAZOLOPYRIDAZINE DERIVATIVE, METHOD OF PREPARATION THEREOF, PHARMACEUTICAL COMPOSITION OF THE SAME AND USE OF THE SAME The present application claims priority of Chinese patent application 201911296884.9 filed on December 16, 2019. This application refers to the full text of the previous Chinese patent application. Field of Invention The present disclosure refers to triazolopyridazine derivatives with a regulatory function on an α5-GABAA receptor, to a method of preparation thereof, to a pharmaceutical composition containing the triazolopyridazine derivatives, and to a use thereof as a medicine. Background of the Invention γ-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the mammalian central nervous system. There are two classes of GABA receptors in nature. One is the GABAA receptor, which is a member of the ligand-gated ion channel superfamily, and the other is the GABAB receptor, which is a member of the G protein-coupled receptor superfamily. Several subunits have been found to exist in the mammalian GABAA receptor, including cd-6, β1-4, γ1-3, δ, ε, Θ and pl-2, among which, the a subunit, the β subunit and the γ subunit are essential to form a complete and functional GABAA receptor, and the oí subunit is crucial for the combination between the benzodiazepine and the GABAA receptor. The percentage of the GABAA receptor containing the «5 subunit («5GABAA receptor) in the GABAA receptors of the mammalian brain is less than 5%. The expression level of the c<5-GABAA receptor in the cerebral cortex is very low, while the percentage of GABAA receptors in the hippocampal tissue is more than 20%. There is virtually no expression in other brain regions. Taking into consideration the specific distribution and functional research of the α5-GABAA receptor in hippocampal tissue, a large number of pharmaceutical companies, including Roche, are working on the α5-GABAA receptor. Many compounds have gradually been synthesized, particularly inverse agonists of the «5GABAA receptor in the hippocampal tissue, and among them «5IA and MRK-016 showed good therapeutic effects in the treatment of diseases related to - 2 intellectual functions in animal models. It is believed that inverse agonists of the 5-GABAA receptor can be used for the treatment of diseases related to intellectual functions, especially Alzheimer's disease. Patent application US 20110224278 Al discloses "5GABAA" receptor inverse agonists that can be used for the treatment of diseases related to multi-infarct dementia and stroke. In the last decade, studies have shown that the blood-brain barrier is damaged in some pathological states, especially in neurodegenerative diseases such as Alzheimer's disease and stroke (Zlokovic et al. Nat Rev Neuroso!.; 12 (12): 723 -738). As a result, even those substances that cannot enter the brain can also exert the corresponding pharmacological effect. Therefore, inverse agonists of α5-GABAA receptors that cannot cross the blood-brain barrier can also be used to treat Alzheimer's disease and stroke. In 2002, Xu Zhang's laboratory reported that the 5-GABAA receptor was mainly expressed in small neurons, and its expression level was increased in the neurotomy model (Xiao HS et al., Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc Nati Acad Sel USA. June II, 2002; 99 (12)). Patent application CN103239720A discloses that the 5-GABAA receptor is also expressed in the peripheral nervous system, and that its expression increases dramatically in the partial nerve injury model. 5-GABAA receptor inverse agonists act to inhibit various pains by selectively binding to the 5-GABAA receptor in the peripheral nervous system. Animal model data show that the stronger the inverse agonism of the inverse agonist, the better the pain inhibitory effect. There is much research into detecting whether a compound is an inverse agonist or antagonist of the 5-GABAA receptors. For example, in international patent applications WO 92 / 22652 and WO 94 / 13799, the combination of α5, β3 and γ2 of the GABAA receptor was used to detect the binding of the compounds and the receptor. In the drug screening process, the method developed by Goeders et al is widely used. (Goeders N E and Kuhar M J (1985) Benzodiazepine binding in vivo with[3H]RO15-1788. Life Sci 37: 345-355). There is also much research on -3the detection of whether a ligand that can bind to the α5-GABAA receptor is an agonist, an antagonist or an inverse antagonist of the α5-GABAA receptors, which can refer to the method described by Wafford et al (Wafford K A, Whiting P J and Kemp J A (1993) Differences in affinity and efficacy of benzodiazepine receptor ligands on recombinant GABA.sub.A receptor subtypes. Mol. Pharmacol 43: 240-244). The method for detecting whether drugs cross the blood-brain barrier is relatively broad. It has been reported that the compound's inhibition of the binding of (3H)RO-15-1788 (a specific inverse agonist marked with the «5-GABAA receptor) can be detected in the brain. MRK016 can effectively inhibit the binding of (3H)RO-15-1788 in the central nervous system, while MRK016-M3 can barely inhibit the binding of (3H)RO-15-1788 in the central nervous system. It can also be detected by detecting drugs in different tissues, for example, to determine whether drugs can indeed cross the blood-brain barrier by detecting the distribution relationship of drugs in the brain and plasma. Previous studies have shown that inhibiting or decreasing 5-GABAA receptor-mediated extrasynaptic inhibition by drugs or genetic methods could improve cognitive and learning ability, but also cause mild anxiety-like behavior. (Brickley, S.G. and Mody, I. Extrasynaptic GABAA receptors: their function in the CNS and implications for disease. Neuron 73, 23-34 (2012); Harris, D. et al. Selective influence on contextual memory: physiochemical properties associated with selectivity of benzodiazepine ligands at GABAA receptors containing the alpha5 subunit. J. Med. Chem. 51, 3788-3803 (2008).; Savic', M.M. et al. PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing "5 subunits, improves passive, but not active, avoidance learning in rats. Brain Res. 1208, 150159 (2008); Clément, Y. et al. Gabra5-gene haplotype block associated with behavioral properties of the full agonist benzodiazepine chlordiazepoxide. Behav. Brain Res. 233, 474-482 (2012)). There are also studies showing that fear and anxiety traits are correlated with decreased Gabra5 mRNA. (Heldt, S.A. & Ressler, K.J. Training-induced changes in the expression of GABAAassociated genes in the amygdala after the acquisition and extinction of Pavlovian fear. Eur. J. Neurosci. 26, 3631-3644 (2007); Tasan, R.O. et al Altered GABA transmission in a mouse model of increased trait anxiety. Neuroscience 183, -471-80 (2011). Paolo Botta et al. have reported that 5-GABAA receptors are involved in the mechanism of fear and anxiety. Selective inactivation of α5-GABAA receptor expression in some brain regions could induce fear and anxiety behaviors in animals. Therefore, the above-disclosed 5-GABAA inverse agonist may cause side effects of fear and anxiety when it enters the brain, which is not suitable for application in the pharmaceutical field, and must be modified. Summary of the Invention The present disclosure provides a triazolopyridazine derivative, a method of preparation thereof, a pharmaceutical composition thereof, and a use thereof. This class of compounds has good inverse agonist activity, thermodynamic solubility, bioavailability and pharmacokinetic properties against α5-GABAA. The present disclosure provides a compound represented by formula I, a cis-trans isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a solvate thereof, a hydrate thereof, a pharmaceutically acceptable salt of the same or a prodrug thereof, EITHER R2 I wherein, Z is a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaromatic ring is optionally substituted with one or more R3; R3 is independently halogen, cyano, Cl-6 alkyl, Cl-6 alkoxy (Cl-6 alkyl), C3-6 cycloalkyl alkoxy (Cl-6), C3-6 cycloalkyl alkoxy (Cl-6) alkyl (Cl-6) , C3-7 heterocycloalkyl or C3-7 heterocycloalkyl (Cl-6), and each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, alkyl Cl-6 and alkylamino Cl-6; R1 is H, Cl-6 alkyl, C3-6 cycloalkyl, C3-7 heterocycloalkyl, cycloalkyl -5C3-6 alkyl (Cl-6) or alkoxy Cl-6 alkyl (Cl-6), and each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, alkyl Cl-6, alkoxy Cl-6 and alkylamino Cl-6; R2 is heterocyclyl, phenyl or heteroaryl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR , C3-6 cycloalguenyl, -NR4R5, -C(O)NR4R5, -COOH, -S02-Cl-6 alkyl and -SO2NR6R7; R is independently H, Cl-6 alkyl, Cl-6 alkenyl, C3-6 cycloalkyl, C3-6 cycloalguenyl, heterocyclyl, aryl or heteroaryl, and each of which is optionally substituted with 1-3 R'; R' is independently halogen, cyano, hydroxyl, C3-6 cycloalkyl, Cl-6 alkylamino, Cl-6 alkyl, alkoxy (Cl-6), Cl-3 alkyl substituted with cyano or halogen, Cl-6 alkylsulfuryl, heterocyclyl, heteroaryl , 5 to 10 membered heteroaryl substituted with 1-3 R'-l, -(C=O)NR8R9, C3-6 cycloalkyl substituted with 13 cyano, -(C=O)R'-2, C6-18 aryl or 3 to 9 membered heterocyclyl substituted with 1-3 R'-3, -SO2R10; R'-l is independently Cl-6 alkyl; R8 and R9 are independently H or Cl-6 alkyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl, and the heteroatom is selected from one or more of N, S and O , and the number of heteroatoms is 1, 2 or 3; R'-2 is C3-6 cycloalkyl or Cl-6 alkyl; R'-3 is independently Cl-6 alkyl; RIO is Cl-6 alkyl; R4 and R5 are independently H, Cl-6 alkyl or C3-6 cycloalkyl, or R4 and R5 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl, and the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; each of R4 and R5 is optionally substituted with 1-5 substituents independently selected from: amino, halogen, hydroxyl, Cl-6 alkyl and Cl-6 alkoxy; R6 and R7 are independently Cl-6 alkyl. In one embodiment, in compound I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate -6 thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof, some groups may be defined as follows (non-notated definitions are as described in any one of the above embodiments, hereinafter referred to as document as in an embodiment): formula I may be additionally represented by formula II, where, X is N or CH; III where, Y is C or N; A is a 5- to 6-membered heterocyclic ring, a 5- to 6-membered heteroaromatic ring or is absent, and the heteroatoms of the 5- to 6-membered heterocyclic ring and the 5- to 6-membered heteroaromatic ring are independently N, and the number of heteroatoms is 1 or 2; n is any integer from 0 to 4. In one embodiment, when the Z is a 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from oxygen , nitrogen and sulfur is, for example, a 5-membered heteroaromatic ring containing 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, for example, N-O λ isoxazole, as another example, 4-Ίa, as another example, NA >tii / Fi- b el - 7end b of it is connected to R3. In one embodiment, when the R3 is multiple, the R3 is the same or different. In one embodiment, the number of R3 is, for example, 1 or 2. In one embodiment, when R3 is Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-3 alkyl, as another example, methyl, ethyl, n-propyl or isopropyl, and as yet another example, methyl. In one embodiment, when R3 is Cl-6 alkoxy Cl-6 alkyl, an alkyl end thereof may be connected to Z. In one embodiment, when R3 is Cl-6 alkoxy or Cl-6 alkyl, the Cl-6 alkoxy is, for example, Cl-4 alkoxy (such as methoxy, ethoxy, n-propoxy, isopropoxy, nbutoxy, isobutoxy, sec- butoxy or tert-butoxy), as another example, Cl-3 alkoxy (such as methoxy, ethoxy, n-propoxy, isopropoxy), and as yet another example, methoxy. In one embodiment, when R3 is Cl-6 alkoxy Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-4 alkyl (methyl), ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl or tere-butyl), as another example, Cl-3 alkyl (methyl), ethyl, n-propyl, isopropyl), and as another example, methyl. In one embodiment, when R3 is Cl-6 alkoxy Cl-6 alkyl, the Cl-6 alkoxy Cl-6 alkyl is, for example, Cl-3 alkoxy Cl-3 alkyl, and as another example, In one embodiment, when R3 is substituted with 1-4 substituents, the number of substituents is, for example, 1, 2, 3 or 4, and as another example, 1 or 2. In one embodiment, when R3 is Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl), as another example, Cl-3 alkyl (such as methyl, ethyl, n-propyl, isopropyl), and as yet another example, methyl. In one embodiment, when R3 is Cl-6 alkyl substituted with hydroxyl, the R3 is, for example, In one embodiment, when R1 is Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-4 alkyl, as another example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl. In one embodiment, when R1 is substituted with halogen, the halogen is, for example, fluorine, chlorine, bromine or iodine, and as another example, fluorine. In one embodiment, when R1 is substituted with 1-4 substituents, the -8number of substituents is, for example, 1, 2, 3 or 4, and as another example, 1 or 2. In one embodiment, when R1 is Cl-6 alkyl and the Cl-6 alkyl is substituted with 1-4 substituents, R1 is, for example, methyl substituted with two halogens, and as another example, difluoromethyl. In one embodiment, when R1 is C3-6 cycloalkyl (Cl-6) alkyl, the Cl-6 alkyl is, for example, Cl-4 alkyl, as another example, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl or tere-butyl, and as another example, methyl. In one embodiment, when R1 is C3-6 cycloalkyl (Cl-6), the C3-6 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and as another example, cyclopropyl or cyclobutyl. In one embodiment, when R1 is C3-6 cycloalkyl alkyl (Cl-6), the C3-6 cycloalkyl alkyl (Cl-6) is, for example, C3 cycloalkyl alkyl (Cl-3), and as another example, In one embodiment, when the R2 is substituted with 1-4 substituents, and a carbon atom connecting the substituent and the R2 is a chiral carbon atom, and the chiral carbon atom is, for example, a carbon atom of R configuration or an S configuration carbon atom. In one embodiment, when R2 is heteroaryl, the heteroaryl is, for example, a 5- to 10-membered heteroaryl, where the heteroatoms are nitrogen and / or oxygen, and the number of heteroatoms is 1 or 4; as another example, a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl (the 9- to 10-membered bicyclic heteroaryl is, for example, a bicyclic heteroaryl of a 5- to 6-membered heteroaryl fused with a heteroaryl 5 to 6 membered heteroaryl, or, a bicyclic heteroaryl of a 5 to 6 membered heteroaryl fused with a 5 to 6 membered heterocyclyl), as another example, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolopyridyl, pyrrolopyridyl, pyridopyrrolonyl , naphthyridinyl, quinolyl, imidazopyridyl, dioxinopyridyl, pyridoxazinyl, pyrazolopyrimidinyl, pyridopyrazolyl, pyridopyrrolyl, pyridopyrazolyl, pyridonyl, pyridoimidazolyl, pyridotriazolyl, pyridinyl, pyridotriazolyl, pyridazinonyl, heteronaphthyl, naphthyridinonyl, imidazopyridazinyl , indolyl, diazanaphthyl, tetrahydronaphthyridinyl or naphthyridinyl, as another example, -910 In one embodiment, when R2 is a 9- to 10-membered bicyclic heteroaryl formed by a 5- to 6-membered heteroaryl fused to a 5- to 6-membered heterocyclyl, the substitution position of the substituent is on the heteroatom of the 5- to 6-membered heterocyclyl. 6 members. In one embodiment, when R2 is substituted with 1-4 substituents, the number of substituents is, for example, 1, 2, 3 or 4, and as another example, 1 or 2. In one embodiment, when R2 is substituted with 2, 3 or 4 substituents, the substituents are, for example, the same or different. -10 In one embodiment, when R2 is substituted with halogen, the halogen is, for example, fluorine, chlorine, bromine or iodine, and as another example, fluorine or chlorine. In one embodiment, when R2 is substituted with C3-6 cycloalkenyl, the C3-6 cycloalkenyl is, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl In one embodiment, when R2 is substituted with -SO2-Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tere-butyl), as another example, Cl-3 alkyl (such as methyl, ethyl, n-propyl, isopropyl), and as another example, methyl and ethyl. In one embodiment, when the R is independently Cl-6 alkyl, the alkyl Cl-6 is, for example, alkyl Cl-4, as another example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl, as another example, methyl, ethyl, n-propyl, isopropyl or tere-butyl. In one embodiment, when R is independently Cl-6 alkenyl, the Cl-6 alkenyl is, for example, C2-3 alkenyl, and as another example, ethenyl, In one embodiment, when R is independently C3-6 cycloalkyl, the C3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclobutyl or cyclopropyl. In one embodiment, when R is independently heterocyclyl, the heterocyclyl is, for example, a 3- to 10-membered heterocyclyl, wherein the heteroatoms are nitrogen and / or oxygen, and the number of heteroatoms is 1, 2, or 3, as another For example, a 5- to 6-membered monoheterocyclyl or a 7- to 8-membered heterospirocyclyl, wherein the heteroatoms are nitrogen and / or oxygen, and the number of heteroatoms is 1 or 2, and as yet another example, morpholinyl, pyrrolidinyl, azetidinyl , oxetanyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl or 2oxo-[3,3]heptyl, as another example, In one embodiment, when the R is C3-6 cycloalkenyl, the C36 cycloalkenyl is, for example, cyclohexenyl, cyclopropenyl or cyclobutenyl, as another example, In one embodiment, when R is aryl, the aryl is, for example, C614 aryl, as another example, phenyl, naphthyl, phenanthryl or anthranyl, and as yet another example, phenyl. In one embodiment, when the R is heteroaryl, the heteroaryl is, for example, a 5- to 10-membered heteroaryl, where the heteroatom is nitrogen and / or oxygen, and the number of heteroatoms is 1, 2 or 3, as another For example, 5-membered monocyclic heteroaryl, where the heteroatom is nitrogen and / or oxygen, and the number of heteroatoms is 2 or 3, as another example, pyrimidinyl, oxadiazolyl or In one embodiment, when R' is independently halogen, the halogen is, for example, fluorine, chlorine, bromine or iodine, and as another example, fluorine. In one embodiment, when R' is C3-6 cycloalkyl, the C3-6 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl. In one embodiment, when R' is independently Cl-6 alkylamino, the Cl-6 alkylamino is, for example, Cl-3 alkylamino, as another example, ethylamino, as yet another example, -NHEt. In one embodiment, when R' is independently Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl or tere-butyl), as another example, Cl-3 alkyl (methyl), ethyl, n-propyl, isopropyl), and as another example, methyl. In one embodiment, when R' is independently Cl-6 alkoxy, the alkoxy Cl-6 is, for example, Cl-4 alkoxy (methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), as another example, Cl-3 alkoxy (methoxy, ethoxy , n-propoxy, isopropoxy), and as another example, methoxy. - 12 In one embodiment, when R' is independently Cl-3 alkyl substituted with cyano or halogen, the Cl-3 alkyl is, for example, methyl, ethyl, n-propyl or isopropyl, as another example, methyl. In one embodiment, when the R' is independently Cl-3 alkyl substituted with cyano or halogen, the R' is, for example, 5í^CN. In one embodiment, when R' is independently Cl-6 alkylsulfuryl, the Cl-6 alkyl is, for example, Cl-4 alkyl (methyl), ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl), as another example, Cl-3 alkyl (methyl), ethyl, n-propyl, isopropyl), and as another example, methyl. In one embodiment, when R' is independently alkylsulfuryl Cl-6, the alkylsulfuryl Cl-6 is, for example, -SO2Me, -CH2CH2SO2Me, and as another example, -SO2Me. iviA / a / ¿u¿¿ / uu 14¿o In one embodiment, when R' is independently heterocyclyl, the heterocyclyl is, for example, a 3- to 6-membered monocyclic heterocyclyl, wherein the heteroatom is nitrogen and / or oxygen, and the number of heteroatoms is 1 or 2, as another example, tetrahydrofuranyl, oxetanyl, azetidinyl, morpholinyl or ^o.—. > Í~~O INH' i s / % U— / J I J P 4-N NH piperazinyl, as another example, , Tír'— / or \ / , as another Γ~° more example, In one embodiment, when R' is heteroaryl, the heteroaryl is, for example, a 5- to 10-membered heteroaryl, where the heteroatom is nitrogen and / or oxygen, and the number of heteroatoms is 1, 2 or 3, as another example, 5-membered monocyclic heteroaryl, where the heteroatom is nitrogen and / or oxygen, and the number of heteroatoms is 2 or 3, as another example, pyrimidinyl, oxadiazolyl or isoxazolyl, as another example, In one embodiment, when the R' is independently a 5- to 10-membered heteroaryl substituted with 1-3 R'-l, the heteroaryl is, for example, a 5- to 6-membered heteroaryl, wherein the heteroatoms are nitrogen and / or or oxygen, and the number of heteroatoms is 1, 2 or 3, for example, oxadiazolyl or oxadiazolyl, as another example, EITHER In one embodiment, when the R'-l is independently Cl-6 alkyl, the alkyl Cl-6 is, for example, Cl-4 alkyl (such as methyl, ethyl, n-propyl, tu N C N N isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl), as another example, Cl-3 alkyl (such as methyl, ethyl, n-propyl, isopropyl), and as yet another example, methyl. In one embodiment, when R' is independently a 5-membered heteroaryl substituted with R'-l, the 5- to 10-membered heteroaryl substituted with R'-l is, for example, EITHER NO In one embodiment, when R' is independently C3-6 cycloalkyl substituted with 1-3 cyano, the C3-6 cycloalkyl is, for example, a bridged 5-membered bicyclic cycloalkyl, as another example, In one embodiment, when R' is independently C6-14 aryl, the aryl C6-14 is, for example, phenyl, naphthyl, phenanthryl or anthranyl, as another example, phenyl. In one embodiment, when R' is independently a 1-3 membered heterocyclyl substituted with 1-3 R'-3, the 3- to 6-membered heterocyclyl is, for example, a 4- to 6-membered monoheterocyclyl, wherein the heteroatoms are nitrogen. and / or oxygen, and the number of heteroatoms is 1 or 2, as another example, piperazinyl or oxetanyl, as another example, -|-N NH In one embodiment, when the R'-3 is independently Cl-6 alkyl, Cl-6 alkyl is, for example, Cl-4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere- butyl), as another example, Cl-3 alkyl (such as methyl, ethyl, n-propyl, isopropyl), plus, methyl. In one embodiment, when the R' is independently a and as another example 3-membered heterocyclyl substituted with 1-3 R'-3, the 3- to 6-membered heterocyclyl substituted - 14. r~o . / \ j-N n— with 1-3 R'-3 is, for example, or %— / In one embodiment, when R8 and R9 are independently Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. -butyl or tere-butyl), as another example, Cl-3 alkyl (such as methyl, ethyl, n-propyl or isopropyl), and as yet another example, methyl. In one embodiment, when R8 and R9 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl, the 6-membered heterocyclyl is, for example, In one embodiment, when the RIO is alkyl Cl-6, Cl-6 alkyl is, for example, Cl-4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl), as another example, Cl-3 alkyl (such as methyl, ethyl, n-propyl, isopropyl), and as yet another example, methyl. In one embodiment, when R4 and R5 are independently Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-4 alkyl, as another example, methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, sec -butyl or tere-butyl, as another example, methyl, ethyl and n-propyl. In one embodiment, when R4 and R5 are independently C36 cycloalkyl, the C3-6 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and as another example, cyclohexyl. In one embodiment, when R4 and R5 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl, the 5- or 6-membered heterocycloalkyl is, for example, In one embodiment, when R4 and R5 are substituted with 1-5 substituents, and the substituents are independently halogen, the halogen is, for example, fluorine, chlorine, bromine or iodine, and as another example, fluorine. In one embodiment, when R4 and R5 are substituted with 1-5 substituents, the number of substituents is, for example, 1, 2, 3, 4 or 5, and as another example, 1 or 2 or 3. In one embodiment, when R4 and R5 are independently replaced with - 15 1-5 substituents, R4 and R5 are independently, for example,3o '^CF2 In one embodiment, when R6 and R7 are independently Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. -butyl or tere-butyl), as another example, Cl-3 alkyl (such as methyl, ethyl, n-propyl, isopropyl), and as yet another example, methyl. In one embodiment, when R2 is substituted with 1-4 substituents and the substituents are -R, the -R is -Cl-6 alkyl, -Cl-6 alkenyl, -C3-6 cycloalkyl, -heterocyclyl, -aryl or - heteroaryl. In one embodiment, when R2 is substituted with 1-4 substituents and the substituents are -OR, the -OR is -0-Cl-6 alkyl or -O-heterocyclyl. In one embodiment, when R2 is substituted with 1-4 substituents and the substituents are -C(O)R, the -C(O)R is -C(O)-Cl-6 alkyl, -C(O)- Cl-6 alkenyl, C(O)-C3-6 cycloalkyl or -C(O)-aryl. In one embodiment, R3 is independently Cl-6 alkyl or Cl-6 alkoxy alkyl (Cl-6); R3 is optionally substituted with 1-4 hydroxyl. —O H In one embodiment, R3 is methyl, or In one embodiment, -Z is a 5-membered heteroaromatic ring containing 2 heteroatoms independently selected from oxygen and nitrogen. In one embodiment, -Z is ' , ' or ' In one embodiment, R1 is Cl-6 alkyl or C3-6 cycloalkyl (Cl-6) alkyl, and R1 is optionally substituted with 1-4 halogens. F ^f In one embodiment, R1 is methyl, ethyl,τov. In one embodiment, R2 is phenyl or heteroaryl; heteroaryl is a 5- to 10-membered heteroaryl, where the heteroatoms are nitrogen and / or oxygen, and the number of heteroatoms is 1-4; preferably a 5- to 6-membered monocyclic heteroaryl - 16 or a 9- to 10-membered bicyclic heteroaryl. In one embodiment, R2 is phenyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolopyridyl, pyrrolopyridyl, pyridopyrrolonyl, naphthyridinyl, quinolyl, imidazopyridyl, dioxinopyridyl, pyridooxazinyl, pyrazolopyrimidinyl, pyridopyrazolyl, pyridopyrrolyl, pyridopyrazolyl. , pyridonyl, pyridoimidazolyl, pyridotriazolyl, pyridinyl, pyridotriazolyl, pyridazinonyl, heteronaphthyl, naphthyridinonyl, imidazopyridazinyl, indolyl or diazanaphthyl, In one embodiment, R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, R, -OR, -NHR, C3-6 cycloalkenyl, -NR4R5, -SO2-Cl-6 alkyl and -SO2NR6R7, preferably cyano, -R and -OR. In one embodiment, R2 is substituted with 1-4 substituents independently selected from the group consisting of Me, -Et, -iPr, -CF3, -OCF3, -OCHF2, Cl, -F, -CN, -OMe, -OEt , -NMe2, -CH2CF3, -(CH2)2CN, -(CH2)3CN, -CH2NHEt, -OCHF2, OCH(CH3)2, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -SO2Me, - CH2CH2SO2Me, -COOH, Η Ν . 1 J / f F f ^O ^o, V°Ov, ^ΧΟ,Χ, vx^O >C^^N \ ' > zN\ 1 X Ό X r r F / \ >CCN E 5 f , , y 0 ^N >AL· L V N >íxx 1 f f X^N- ^CN 3OCH3, x χχ ^n^j3 r r r r~c X' J.__ / i H fx7n y Α°Χ, ' , Ο. , r t r f ooo ? oS xA Aa Μ V γ-d । Xof3 r f ti / H XX YF x ΧΊ jg / X jXÜ F , -OEt, - -(CH2)3CN, -CH2NHEt, -0CHF2, -OCH(CH3)2, -CH2OCH3, - -S02Me, -CH2CH2SO2Me, -COOH, V° / 'o / , °' , / V° ^o- An^o^ O A , v , । , H , ' , x , Η H ϊ N \ hitX 1 > FU / rX'-nh ¿Lj r r r r f r t H XO rX ' Χ / Ό ' Ν more preferably, Me, -CN, In one embodiment, R3 is Cl-6 alkyl or Cl-6 alkoxy (Cl-6) alkyl, and R3 is optionally substituted with 1-4 hydroxyl; R1 is Cl-6 alkyl or C3-6 cycloalkyl (Cl-6) alkyl, and R1 is optionally substituted with 1-4 halogens; R2 is phenyl or heteroaryl; R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, C3-6 cycloalkenyl, -NR4R5, -C(O)NR4R5, -COOH, -S0215 alkyl Cl-6 and -SO2NR6R7; -R is -Cl-6 alkyl, -Cl-6 alkenyl, -C3-6 cycloalkyl, -heterocyclyl, -aryl or -heteroaryl; the -OR is -0-Cl-6 alkyl or -0heterocyclyl; -C(0)R is -C(0)-Cl-6 alkyl, -C(0)-Cl-6 alkenyl, -C(0)C3-6 cycloalkyl or -C(0)-aryl. In one embodiment, R1 is methyl, ethyl, - 19 R3 is methyl, or; R2 is phenyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolopyridyl, pyrrolopyridyl, pyridopyrrolonyl, naphthyridinyl, quinolyl, imidazopyridyl, dioxinopyridyl, pyridooxazinyl, pyrazolopyrimidinyl, pyridopyrazolyl, pyridopyrrolyl, pyridopyrazolyl, pyridonyl, pydoimidazolyl, pyridotriazolyl, pyridonyl, pyridotriazolyl, pyridazinonyl , heteronaphthyl, naphthyridinonyl, imidazopyridazinyl, indolyl or diazanaphthyl, and R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of Me, -Et, -iPr, -CF3, -OCF3, -OCHF2, -Cl, -F , -CN, -OMe, -OEt, 10 -NMe2, -CH2CF3, -(CH2)2CN, -(CH2)3CN, -CH2NHEt, -OCHF2, -OCH(CH3)2, -CH2OCH3, (CH2)2OCH3, -(CH2)3OCH3, -SO2Me, -CH2CH2SO2Me, -COOH, In one embodiment, R3 is Cl-6 alkyl or Cl-6 alkoxy (Cl-6) alkyl, and R3 is optionally substituted with 1-4 hydroxyl; R1 is Cl-6 alkyl or C3-6 cycloalkyl (Cl-6) alkyl, and R1 is optionally substituted with 1-4 halogens; R2 is phenyl or heteroaryl; R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -0R, C3-6 cycloalkenyl, -NR4R5, -S02-Cl-6 alkyl and -SO2NR6R7; -R is -Cl-6 alkyl, -Cl-6 alguenyl, -C3-6 cycloalkyl, -heterocyclyl, -aryl or -heteroaryl; -0R is -0-Cl-6 alkyl or -heterocyclyl; -C(O)R is -C(0)-Cl-6 alkyl, -C(O)-Cl-6 alguenyl, -C(O)-C3-6 cycloalkyl or -C(0)-aryl. In one embodiment, R3 is Cl-6 alkyl or Cl-6 alkoxy (Cl-6) alkyl, and R3 is optionally substituted with 1-4 hydroxyl; R1 is Cl-6 alkyl or C3-6 cycloalkyl (Cl-6) alkyl, and R1 is optionally substituted with 1-4 halogens; R2 is phenyl or heteroaryl, and the heteroaryl is a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl, and the 9- to 10-membered bicyclic heteroaryl is a 5- to 6-membered heteroaryl fused with a 5- to 6-membered heteroaryl. 5 to 6 members; R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -0R, C3-6 cycloalkenyl, -NR4R5, -SO2-Cl-6 alkyl and -SO2NR6R7; -R is -Cl6 alkyl, -Cl-6 alguenyl, -C3-6 cycloalkyl, -heterocyclyl, -aryl or -heteroaryl; -0R is -0-alkyl Cl-6 or -heterocyclyl; -C(O)R is -C(0)-Cl-6 alkyl, -C(0)Cl-6 alkenyl, -C(0)-C3-6 cycloalkyl or -C(0)-aryl. In one embodiment, R3 is Cl-6 alkyl; R1 is Cl-6 alkyl; - 21 R2 is heteroaryl, and heteroaryl is a 9- to 10-membered bicyclic heteroaryl of a 5- to 6-membered heteroaryl fused to a 5- to 6-membered heterocyclyl; R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halokene, cyano, oxo, -R, -OR, C3-6 cycloalkenyl, -NR4R5, -SO2-Cl-6 alkyl and -SO2NR6R7; -R is -Cl6alkyl, -Cl-6alkenyl, -C3-6cycloalkyl, -heterocyclyl, -aryl or -heteroaryl; the -OR is -O-Cl-6 alkyl or -heterocyclyl; -C(O)R is -C(O)-Cl-6alkyl, -C(O)Cl-6alkenyl, -C(O)-C3-6cycloalkyl or -C(O)-aryl. In one embodiment, R1 is Cl-6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl); R3 is Cl-6 alkyl (such as methyl, ethyl, n-propyl or isopropyl, as another example, methyl); R2 is a heteroaryl; heteroaryl is a 5- to 10-membered heteroaryl, the heteroatom is N, and the number of heteroatoms is 1, 2, or 3 (for example, a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl; as another example, pyridyl, pyrazolopyridyl, tetrahydronaphthyridinyl, pyrrolopyridyl, pyridazinyl or imidazopyridazinyl; and as another example R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of cyano, -R or -OR; R is independently Cl-6 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or ere-butyl, as another example, methyl, ethyl, n-propyl, isopropyl or ere -butyl) or heterocyclyl R (as another example, a 3- to 10-membered heterocyclyl, where the heteroatom is nitrogen and / or oxygen, and the number of heteroatoms is 1, 2 or 3, as another example, a 5-membered monoheterocyclyl 6-membered or a 7- to 8-membered heterospirocyclyl, wherein the heteroatoms are nitrogen and / or oxygen, and the number of heteroatoms is 1 or 2, and as yet another example, morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetrahydropyranyl , tetrahydrofuranyl or 2-oxo-[3,3]heptyl, as - 22 another example, ), R is optionally substituted with 1-3 R'; R' is independently halogen, hydroxyl, 3- to 9-membered heterocyclyl substituted with 1-3 R'-3 (e.g., 4- to 6-membered monoheterocyclyl, wherein the heteroatoms are nitrogen and / or oxygen, and the number of heteroatoms is 1 or 2, as another example, piperazinyl or oxetanyl, as another example, N / 5- to 10-membered heteroaryl substituted with R'-l (e.g., O) or alkoxy (Cl-6) (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, as another example, methoxy, ethoxy, n-propoxy or isopropoxy, and as another example, methoxy). In one embodiment, R1 is Cl-6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl); R3 is Cl-6 alkyl (such as methyl, ethyl, n-propyl or isopropyl, as another example, methyl); R2 is ; Y is C or N; A is a 5- to 6-membered heterocyclic ring, and the heteroatom of the 5- to 6-membered heterocyclic ring is N, and the number of NH heteroatoms is 1 or 2 (e.g. R2 is optionally substituted with 1-4 substituents selected from Cl-6 alkyl or heterocyclyl (heterocyclyl is, for example, a 3 to 10 membered heterocyclyl, where the heteroatom is nitrogen and / or oxygen, and the number of heteroatoms is 1, 2 or 3, as another example, a 5- to 6-membered monoheterocyclyl or a 7- to 8-membered heterospirocyclyl, wherein the heteroatoms are nitrogen and / or oxygen, and the number of heteroatoms is 1 or 2, and as another as a further example, morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl or 2-oxo-[3,3]heptyl, as another example, -23R' is independently hydroxyl or a 5- to 10-membered heteroaryl substituted with 1-3 R'-l (e.g., °. In one embodiment, R1 is Cl-6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl); R3 is Cl-6 alkyl (such as methyl, ethyl, n-propyl or isopropyl, as another example, methyl); R2 is N; Y is C or N; A is a 5- to 6-membered heterocyclic ring, and the heteroatom of the 5- to 6-membered heterocyclic ring is N, and the number of NH heteroatoms is 1 or 2 (e.g. R2 is optionally substituted with 1-4 substituents selected from Cl-6 alkyl or heterocyclyl (heterocyclyl is, for example, a 3 to 10 membered heterocyclyl, where the heteroatom is nitrogen and / or oxygen, and the number of heteroatoms is 1, 2 or 3, as another example, a 5- to 6-membered monoheterocyclyl or a 7- to 8-membered heterospirocyclyl, wherein the heteroatoms are nitrogen and / or oxygen, and the number of heteroatoms is 1 or 2, and as another as a further example, morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl or 2-oxo-[3,3]heptyl, as another example, R' is independently hydroxyl or a 5- to 10-membered heteroaryl substituted with 1-3 R'-l (eg, NO). When R2 is optionally substituted with 1-4 Cl-6 alkyl or heterocyclyl, the position of the substitution is on a heteroatom of an A ring. In one embodiment, in compound I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof or the - 24 prodrug thereof, some groups may be defined as follows (non-annotated definitions are described in any one of the above embodiments): N-N í 'Rr..0AfNO. ib (i) wherein, Z is a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and the heteroaromatic ring is optionally substituted with one or more R3; R3 is selected from halogen, cyano, Cl-6 alkyl, Cl-6 alkoxy (Cl-6 alkyl 6), C3-6 cycloalkyl alkoxy (Cl-6), C3-6 cycloalkyl alkoxy (Cl-6) alkyl (Cl6), C3-7 heterocycloalkyl, C3-7 heterocycloalkyl (Cl-6), and each of the which is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, Cl-6 alkyl and Cl-6 alkylamino; R1 is selected from H, Cl-6 alkyl, C3-6 cycloalkyl, C3-7 heterocycloalkyl, C3-6 cycloalkyl (Cl-6), Cl-6 alkoxy (Cl-6), and each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, Cl-6 alkyl, Cl-6 alkoxy and Cl-6 alkylamino; R2 is heterocyclyl, phenyl or heteroaryl; R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, C3-6 cycloalkenyl, -NR4R5, -C(O )NR4R5, -COOH, -S02-alkyl Cl-6; R is selected from H, Cl-6 alkyl, Cl-6 alkenyl, 3-6 C cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with 1-3 R'; R' is selected from halogen, cyano, hydroxyl, C3-6 cycloalkyl, Cl-6 alkylamino, Cl-6 alkyl, alkoxy (Cl-6), cyano or halogen-substituted Cl-3 alkyl, Cl-6 alkylsulfuryl, heterocyclyl, heteroaryl; R4 or R5 is independently H or Cl-6 alkyl, and each of which is optionally substituted with 1-5 substituents, the substituents are selected -25independently between amino, halogen, hydroxyl, Cl-6 alkyl and Cl-6 alkoxy. In one embodiment, in compound I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, a hydrate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof, some groups may be defined as follows (non-annotated definitions are described in any one of the above embodiments): formula I may be additionally represented by formula II, EITHER. r2(II) In one embodiment, when the Z is a 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from oxygen , nitrogen and sulfur is, for example, a 5-membered heteroaromatic ring containing 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, for example, N-°aWbaX^-bisoxazole, as another example, N O , as yet another example, , the b end thereof is connected to R3. In one embodiment, when R3 is Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-3 alkyl, as another example, methyl, ethyl, n-propyl or isopropyl, and as yet another example, methyl. In one embodiment, when R3 is Cl-6 alkoxy Cl-6 alkyl, an alkyl end thereof may be connected to the Z. In one embodiment, when R3 is Cl-6 alkoxy or Cl-6 alkyl, the Cl-6 alkoxy is, for example, Cl-3 alkoxy, as another example, methoxy, ethoxy, n-propoxy, isopropoxy, and as another example plus, methoxy. In one embodiment, when R3 is Cl-6 alkoxy Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-3 alkyl, as another example, methyl, ethyl, n-propyl or isopropyl, and as another example more, methyl. -26In one embodiment, when R3 is Cl-6 alkyl substituted with hydroxyl, the Cl-6 alkyl is Cl-3 alkyl, as another example, methyl, ethyl, n-propyl or isopropyl, and as another example, methyl. In one embodiment, when R3 is substituted with one or more substituents, the number of substituents is, for example, 1, 2, 3, 4 or 5, and as another example, 1 or 2. In one embodiment, when the Z is substituted with one or more R3, the number of substituents is, for example, 1, 2, 3, 4 or 5, and as another example, 1 or 2. In one embodiment, when R1 is Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-3 alkyl, as another example, methyl, ethyl, n-propyl or isopropyl, and as another example, methyl or ethyl. In one embodiment, when R1 is C3-6 cycloalkyl (Cl-6) alkyl, the Cl-6 alkyl is, for example, Cl-3 alkyl, as another example, methyl, ethyl, n-propyl or isopropyl, and as another example, methyl. In one embodiment, when R1 is C3-6 cycloalkyl (Cl-6), the C3-6 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and as another example, cyclopropyl or cyclobutyl. In one embodiment, when R1 is substituted with halogen, the halogen is, for example, fluorine, chlorine, bromine or iodine, and as another example, fluorine. In one embodiment, when R1 is substituted with 1-4 groups, the number of substituents is, for example, 1, 2, 3, 4 or 5, and as another example, 1 or 2. In one embodiment, when R2 is heteroaryl, the heteroaryl is, for example, triazolyl, pyridyl, pyridopyrrolonyl, pyridopyrrolyl, pyridopyrazolyl, pyridonyl, pyridoimidazolyl, pyridotriazolyl, pyridooxazinyl, dioxinopyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridazinonyl, pyrazolopyrimidinyl, heteronaphth yl, naphthyridinonyl , imidazopyridazinyl, naphthyridinyl, quinolyl, such as 1,2,4-triazolyl, diazanaphthyl, for example, In one embodiment, when R2 is substituted with 1-4 substituents, the number of substituents is, for example, 1, 2, 3, 4 or 5, and as another example, 1 or 2. In one embodiment, when R2 is substituted with halogen, the halogen is, for example, fluorine, chlorine, bromine or iodine, and as another example, fluorine or chlorine. In one embodiment, when R2 is substituted with -SO2-Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-3 alkyl, as another example, methyl and ethyl. In one embodiment, when R is Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-3 alkyl, as another example, methyl, ethyl, n-propyl or isopropyl. In one embodiment, when R is Cl-6 alkoxy, the Cl-6 alkoxy is, for example, Cl-3 alkoxy, as another example, methoxy, ethoxy, n-propoxy, isopropoxy, and as yet another example, methoxy. In one embodiment, when R is Cl-6 alkenyl, the Cl-6 alkenyl is, for example, Cl-3 alkenyl, and as another example, ethenyl or propenyl. -28In one embodiment, when the R is heterocyclyl, the heterocyclyl is, for example, morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, spiro ring, as another example, h In one embodiment, when R is C3-6 cycloalkyl, the C3-6 cycloalkyl is, for example, cyclohexenyl, cyclopropyl, cyclobutenyl, as another example, In one embodiment, when R is heteroaryl, the heteroaryl is, for example, pyrimidinyl, oxadiazolyl, and as another example, In one embodiment, when the is substituted with 1-3 R', the number of substituents is, for example, 1, 2, 3, or 5, and as another example, 1, 2 or 3. In one embodiment, when R' is Cl-6 alkoxy, the Cl-6 alkoxy is, for example, Cl-3 alkoxy, as another example, methoxy, ethoxy, n-propoxy, isopropoxy, and as yet another example, methoxy . In one embodiment, when R' is Cl-6 alkylamino, the Cl-6 alkylamino is, for example, alkylamino Cl-3, as another example, ethylamino, as another example, NHEt. In one embodiment, when R' is halogen, the halogen is, for example, fluorine, chlorine, bromine or iodine, and as another example, fluorine. In one embodiment, when R' is C3-6 cycloalkyl, the C3-6 cycloalkyl is, for example, cyclopropyl. In one embodiment, when R' is heteroaryl, the heteroaryl is, for example, pyrimidinyl, and as another example, In one embodiment, when R' is heterocyclyl, the heterocyclyl is, for example, tetrahydrofuranyl, oxetanyl, azetidinyl, morpholinyl, piperazinyl, and as another example, N.H. N.H. In one embodiment, when R' is Cl-6 alkylsulfuryl, the alkylsulfuryl Cl-6 is, for example, -SO2Me, -CH2CH2SO2Me, and as another example, -SO2Me. -29In one embodiment, when R4 or R5 is Cl-6 alkyl, the Cl-6 alkyl is, for example, Cl-3 alkyl, as another example, methyl, ethyl, n-propyl or isopropyl, and as another example , methyl, ethyl or n-propyl. In one embodiment, when R4 or R5 is halogen, the halogen is, for example, fluorine, chlorine, bromine or iodine, and as another example, fluorine. In one embodiment, when R4 and R5 are substituted with 1-5 substituents, the substituents are, for example, halogen, as another example, fluorine, chlorine, bromine or iodine, and as yet another example, fluorine. In one embodiment, when R4 or R5 are optionally substituted with 1-5 substituents, the number of substituents is, for example, 1, 2, 3, 4 or 5, and as another example, 1 or 2 or 3. In one embodiment, X is N or CH; R1 is selected from Cl-6 alkyl, Cl-6 alkyl substituted with halogen, Cl-6 alkyl substituted with C3-6 cycloalkyl; R3 is selected from Cl-6 alkyl, Cl-6 alkyl substituted with hydroxyl and Cl-6 alkyl substituted with Cl-6 alkoxy. R2 is phenyl or heteroaryl; R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, C3-6 cycloalkenyl, -NR4R5, -C(O )NR4R5, -COOH, -S02-alkyl Cl-6; R is selected from H, Cl-6 alkyl, Cl-6 alkenyl, 3-6 C cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with 1-3 R'. R' is selected from halogen, cyano, hydroxyl, C3-6 cycloalkyl, Cl-6 alkylamino, Cl-6 alkyl, alkoxy (Cl-6), Cl-3 alkyl substituted with cyano or halogen, Cl-6 alkylsulfuryl, heterocyclyl, heteroaryl; R4 or R5 is independently H or Cl-6 alkyl, and the Cl-6 alkyl may be substituted with 1-5 substituents, the substituents are independently selected from amino, halogen, halogen-substituted Cl-6 alkoxy, hydroxyl and Cl-alkoxy 6. In one embodiment, X is N or CH; R1 is selected from Cl-3 alkyl, Cl-3 alkyl substituted with fluorine or Cl-3 alkyl substituted with C3-6 cycloalkyl; R3 is selected from Cl-3 alkyl, Cl-3 alkyl substituted with hydroxyl or -30alkyl Cl-3 substituted with alkoxy Cl-3. R2 is phenyl or heteroaryl; R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, C3-6 cycloalkenyl, -NR4R5, -C(O )NR4R5, -COOH, -SO2-alkyl Cl-6; R is selected from H, Cl-6 alkyl, Cl-6 alkenyl, 3-6 C cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with 1-3 R'. R' is selected from halogene, cyano, hydroxyl, C3-6 cycloalkyl, C1-6 alkylamino, C1-6 alkyl, alkoxy (C1-6), cyano or halogen-substituted C1-3 alkyl, C1-6 alkylsulfuryl, heterocyclyl, heteroaryl; R4 or R5 is independently H or Cl-6 alkyl, and the Cl-6 alkyl may be substituted with 1-5 substituents, and the substituents are independently selected from amino, halogen, halogen-substituted Cl-6 alkoxy, hydroxyl and Cl alkoxy -6. In one embodiment, X is N or CH; R1 is selected from methyl, ethyl, cyclopropylmethyl, difluoromethyl; R3 is selected from methyl, hydroxymethyl, methoxymethyl; R2 is phenyl or heteroaryl; R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, C3-6 cycloalkenyl, -NR4R5, -C(O )NR4R5, -COOH, -S02-alkyl Cl-6; R is selected from H, Cl-6 alkyl, Cl-6 alkenyl, 3-6 C cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with 1-3 R'. R' is selected from halogen, cyano, hydroxyl, C3-6 cycloalkyl, Cl-6 alkylamino, Cl-6 alkyl, alkoxy (Cl-6), cyano or Cl-3 alkyl substituted with halogen, Cl-6 alkylsulfuryl, heterocyclyl, heteroaryl; R4 or R5 is independently H or Cl-6 alkyl, and the Cl-6 alkyl may be substituted with 1-5 substituents, the substituents are independently selected from amino, halogen, halogen-substituted Cl-6 alkoxy, hydroxyl and Cl-alkoxy 6. In one embodiment, X is N or CH; R1 is selected from Cl-6 alkyl, Cl-6 alkyl substituted with halogen, -31 Cl-6 alkyl substituted with C3-6 cycloalkyl; R3 is selected from Cl-6 alkyl, Cl-6 alkyl substituted with hydroxyl and Cl-6 alkyl substituted with Cl-6 alkoxy; R2 is selected from phenyl, triazolyl, pyridyl, triazolopyridyl, pyridinonyl, pyridazinyl, pyridazinonyl, pyrazinyl, pyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl, dihydropyrrolopyridyl, dihydropyrrolidinpyridyl, pyrazolopyridyl, imidazopyridyl, imidazopyridazinyl, pyridoxazinyl , 1,4-dioxinopyridyl, imidazopyridazinyl, heteronaphthyl, naphthyridinyl, naphthyridinonyl, dihydronaphthyridinonyl, quinolyl; R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, C3-6 cycloalkenyl, -NR4R5, -C(O )NR4R5, -COOH, -S02-alkyrl Cl-6; R is selected from C1-6 alkyl, C1-6 alkenyl, C3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with 1-3 R'; R' is selected from halogen, cyano, C3-6 cycloalkyl, Cl-6 alkylamino, Cl-6 alkyl, alkoxy (Cl-6), cyano or halogen-substituted Cl-3 alkyl, Cl-6 alkylsulfuryl, heterocyclyl, heteroaryl; R4 or R5 is independently selected from H, Cl-6 alkyl substituted with 1-5 halogens. In one embodiment, X is N or CH; R1 is selected from Cl-3 alkyl, Cl-3 alkyl substituted with fluorine or Cl-3 alkyl substituted with C3-6 cycloalkyl; R3 is selected from Cl-3 alkyl, Cl-3 alkyl substituted with hydroxyl and Cl-3 alkyl substituted with Cl-3 alkoxy. R2 is selected from phenyl, triazolyl, pyridyl, triazolopyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrazinyl, pyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl, dihydropyrrolopyridyl, dihydropyrrolidinpyridyl, pyrazolopyridyl, imidazopyridyl, imidazopyridazinyl, pyridoxazinyl, 1,4-dioxinopyridyl, imidazopyridazinyl, heteronaphthyl, naphthyridinyl, naphthyridinonyl, dihydronaphthyridinonyl, quinolyl; R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, C3-6 cycloalkenyl, -NR4R5, -C(O )NR4R5, -COOH, -S02-alkyl Cl-6; -32R is selected from C1-6 alkyl, C1-6 alkenyl, C3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with 1-3 R'; R' is selected from halogen, cyano, C3-6 cycloalkyl, Cl-6 alkylamino, Cl-6 alkyl, alkoxy (Cl-6), Cl-3 alkyl substituted with cyano or halogen, Cl-6 alkylsulfuryl, heterocyclyl, heteroaryl; R4 or R5 is independently selected from H, Cl-6 alkyl substituted with 1-5 halogens. In one embodiment, X is N or CH; R1 is selected from methyl, ethyl, cyclopropylmethyl, difluoromethyl; R3 is selected from methyl, hydroxymethyl, methoxymethyl. R2 is selected from phenyl, triazolyl, pyridyl, triazolopyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrazinyl, pyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl, dihydropyrrolopyridyl, dihydropyrrolidinpyridyl, pyrazolopyridyl, imidazopyridyl, imidazopyridazinyl, pyridoxazinyl, 1,4-dioxinopyridyl, imidazopyridazinyl, heteronaphthyl, naphthyridinyl, naphthyridinonyl, dihydronaphthyridinonyl, quinolyl; R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, C3-6 cycloalkenyl, -NR4R5, -C(O )NR4R5, -COOH, -S02-alkyrl Cl-6; R is selected from C1-6 alkyl, C1-6 alkenyl, C3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with 1-3 R'; R' is selected from halogen, cyano, C3-6 cycloalkyl, Cl-6 alkylamino, Cl-6 alkyl, alkoxy (Cl-6), Cl-3 alkyl substituted with cyano or halogen, Cl-6 alkylsulfuryl, heterocyclyl, heteroaryl; R4 or R5 is independently selected from H, Cl-6 alkyl substituted with 1-5 halogens. In one embodiment, X is N or CH; R1 is selected from Cl-3 alkyl, Cl-3 alkyl substituted with fluorine or Cl-3 alkyl substituted with C3-6 cycloalkyl; R3 is selected from Cl-3 alkyl, Cl-3 alkyl substituted with hydroxyl or Cl-3 alkyl substituted with Cl-3 alkoxy; R2 is selected from phenyl, triazolyl, pyridyl, triazolopyridyl, -33pyridonyl, pyridazinyl, pyridazinonyl, pyrazinyl, pyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl, dihydropyrrolopyridyl, dihydropyrrolidinpyridyl, pyrazolopyridyl, imidazopyridyl, imidazopyridazinyl, pyridoxazinyl, 1,4-dioxinopyridyl, imidazopyridazinyl, heterone phthyl, naphthyridinyl, naphthyridinonyl, dihydronaphthyridinonyl, quinolyl; R2 is optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, cyclohexenyl, -NR4R5, -C(O)NR4R5, -COOH, -S02-alkyl Cl-3; R is selected from Cl-3 alkyl, Cl-3 alkenyl, cyclopropyl, cyclobutyl, morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, spiro ring, aryl, pyrimidinyl, oxadiazolyl, and each of which is optionally substituted with 1-3 R'; R' is selected from halogen, cyano, cyclopropyl, Cl-3 alkylamino, Cl-3 alkyl, Cl-3 alkoxy, Cl-3 alkyl substituted with cyano or halogen, Cl-3 alkylsulfuryl, tetrahydrofuranyl, oxetanyl, azetidinyl, morpholinyl, piperazinyl , methylpiperazinyl, pyrimidinyl; R4 or R5 is selected from H, Cl-3 alkyl substituted with 1-3 fluorine. In one embodiment, X is N or CH; R1 is selected from methyl, ethyl, cyclopropylmethyl, difluoromethyl; R3 is selected from methyl, hydroxymethyl, methoxymethyl. R2 is selected from phenyl, triazolyl, pyridyl, triazolopyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrazinyl, pyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl, dihydropyrrolopyridyl, dihydropyrrolidinpyridyl, pyrazolopyridyl, imidazopyridyl, imidazopyridazinyl, pyridoxazinyl, 1,4-dioxanepyridyl, imidazopyridazinyl, heteronaphthyl, naphthyridinyl, naphthyridinonyl, dihydronaphthyridinonyl, quinolinyl; R2 is optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, cyclohexenyl, -NR4R5, -C(O)NR4R5, -COOH, -SO2-alkyl Cl-3; R is selected from Cl-3 alkyl, Cl-3 alkenyl, cyclopropyl, cyclobutyl, morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, spiro ring, aryl, pyrimidinyl, oxadiazolyl, and each of which is optionally substituted with 1-3 R'; R' is selected from halogen, cyano, cyclopropyl, Cl-3 alkylamino, alkyl -34Cl-3, Cl-3 alkoxy, Cl-3 alkyl substituted with cyano or halogen, algylsulfuryl Cl-3, tetrahydrofuranyl, oxetanyl, azetidinyl, morpholinyl, piperazinyl, methylpiperazinyl, pyrimidinyl; R4 or R5 is selected from H, Cl-3 alkyl substituted with 1-3 fluorine. In one embodiment, X is N or CH; R1 is selected from methyl, ethyl, cyclopropylmethyl, difluoromethyl; R3 is selected from methyl, hydroxymethyl, methoxymethyl. R2 is selected from phenyl and the following substituents: R2 is optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -0R, -C(O)R, -NHR, cyclohexenyl, -NR4R5, -C(O)NR4R5, -COOH, -S02-Cl-3 alkyl; R is selected from Cl-3 alkyl, Cl-3 alkenyl, cyclopropyl, cyclobutyl, morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, spiro ring, aryl, pyrimidinyl, -35oxadiazolyl, and each of which is optionally substituted with 1-3 R'; R' is selected from halogen, cyano, cyclopropyl, Cl-3 alkylamino, Cl-3 alkyl, Cl-3 alkoxy, Cl-3 alkyl substituted with cyano or halogen, Cl-3 alkylsulfuryl, tetrahydrofuranyl, oxetanyl, azetidinyl, morpholinyl, piperazinyl , methylpiperazinyl, pyrimidinyl; R4 or R5 is selected from H, Cl-3 alkyl substituted with 1-3 fluorine. In one embodiment, X is N or CH; R1 is selected from methyl, ethyl, cyclopropylmethyl, difluoromethyl; R3 is selected from methyl, hydroxymethyl, methoxymethyl. R2 is selected from phenyl, triazolyl, pyridyl, triazolopyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrazinyl, pyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl, dihydropyrrolopyridyl, dihydropyrrolidinpyridyl, pyrazolopyridyl, imidazopyridyl, imidazopyridazinyl, pyridoxazinyl, 1,4-dioxinopyridyl, imidazopyridazinyl, heteronaphthyl, naphthyridinyl, naphthyridinonyl, dihydronaphthyridinonyl, quinolyl; R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of -Me, -Et, -iPr, -CF3, -OCF3, -OCHF2, -Cl, -F, -CN, -OMe, -OEt, - NMe2, -CH2CF3, - (CH2)2CN, -(CH2)3CN, -CH2NHEt, -OCHF2, -OCH(CH3)2, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -SO2Me, -CH2CH2SO2Me , -COOH, In one embodiment, X is N or CH; R1 is selected from methyl, ethyl, cyclopropylmethyl, difluoromethyl; R3 is selected from methyl, hydroxymethyl, methoxymethyl; R2 is selected from phenyl and the following substituents: R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of -Me, -Et, -iPr, -CF3, -OCF3, -OCHF2, -Cl, -F, -CN, -OMe, -OEt, -NMe2, -CH2CF3, -(CH2)2CN, -(CH2)3CN, -CH2NHEt, -OCHF2, -OCH(CH3)2, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -SO2Me, -CH2CH2SO2Me, -COOH, In one embodiment, compound I is any of the following compounds: Realization Structure Realization Structure 1 z-o z^ J X o o 7 Z=z -y 91 z y-Z \ 44 / o '-z. \\ / z-o 2 0 4 4 92 < Ό 1 3 4 4 λ-γ 93 4 4 Λ λ-γ Ν' Α'-q·' 94 A N, / - N N । 5 or Xo >xY N 'Άρ 95 Λ? \^N N^\ N^ / N~N _ / N^\ F \X~oZZ\JH 0 6 VVn .X, -A °\ 96 X Y=N N=\ ΝγΝ'Ν N z° '— / 7 nfa nV κγ^νν N I 1 / ° 97 ,0^ / Np nX 8 4 p k-NY° n Ί I 98 f o n' 1 1 N -° Y Ya W\ / NH 9 \ O O k í Αγ 99 J^° ní 1 QN U- / . VCn^° 10 Ó k-N Ο^θ N 1 1 1 °\ 100 o A ''0V-NxA° 11 ó \=N Y F c N^ / N'N n~^ h Vf V^^Yf 101 x° / - N N=Z NYn'n , XC vlz> IVIA / a / ¿U¿¿ / UU / 4¿O 12 λο Vn 102 A M / N Y’N rw 13 λ? \=n nA N- N-N n-. 103 A n^ / n n\ i A 'N η VA -x A VA 14 N-n ___, j N'^íy- \ / OA^N N-0 •2 104 [o fU / V vA Va 'N=N\ ex 15 U A nA^ <z 105 x'p =n n="Z" nyn'n y aa^n 16 n-n j?’v 6 106 o-z x z. i o a a° ° \ 17 n-n c,i5 107 ^o zh c>„..... 'z \\ / Z-O 18 Q ή 108 V A O Z V / z-o 19 / o tpy R 109 y-Z \ ^O ¿H / A / o o^ A„ 'z \\ / Z-O MA / a / ¿U¿¿ / UU / 4¿0 20 n-n Cl 110 o-z AVZ-z V o o \ 21 ¡O Vn Sa Γ O'. ,-N ° O r 111 ) A 0 0^ A zzAv z-o 22 [ 0 ,Ν^ / ^Ν An. 1 N Ka < ^-o y-° 112 O-z V y—O O 8 - O \ 23 A Vn nA Ñ^ / N'N __ 0 113 o-z A k i ^o o 8' O. / / A / A / xo 24 oA o A O-z z'''. o a t ¿ J 114 N-AV0'AA 4 Voice 25 o \ ώ O-z Z^X 0 UPí ¿ j u / / Z-z 115 A Z~N n=A n^n. y N A-va / O Αζ\ / Νγ / o 26 z-z J \\ \ f OX^Z Z-Q o A° 116 I >—z P / \ O O \\ / z-o 27 n-n AÍ^ 117 z-z A A z A L? i r \ <° A Ζ-Ζ 0a%O MA / a / zuzz / uur^zo 28 rs z J 9 / iN'°\ o. x¿ / z í Z Z 118 Xo Vn N^\ n^n-n nX% / ° 29 •J V kv N \ 1 YX'q 1 119 NÍ 1 1 H VN. X .N. N O Y 'sp' 's Pn Xo' 30 Υχ\ T z O-Z 120 O o ÍL 31 Z-Q _0 o / 123 I z w / \ o o J jX'2 34 χγ, ν' 1 1 yn. X / n o^x nA nX_ 124 ΑΧ 1 / N N j 1 N^XX'O''' 35 Uf T / N \ ΐ 1] Ns Ί 1 N^xí^o^ 36 z-z J A x n. ,either. AJJ ¿í Y Ν^Χχ-χ MA / a / ¿u¿¿ / uur4¿o 37 ti o \ o— 127 zAAV 7 O o ti ) 38 Ν,,,^ν,,0·, U X f N O 1 Ό °\ 128 to V0' lp 1 ,N 1 ,N, .0. 0 Ai Y 'Μ'2''ΌΖ 39 o-z / \V i o o 129 Y° Y r° N^N-N __, / — Ñ=< \z= / X--V 'f ^o_ N-N 40 VA =í ' o N 130 w° zW / O o—' Άy z=Z 41 o o z 'z \\ / z-o 131 °x / X 7 / •ft,, Z / 'Z-O 42 ti o o ti.,,, Z \\ / z-O 132 NI 1 | y N O >1 nX i N O °Y 7| °\ 43 o-z λ z^ fí o o \ / < W1 135 0 ti «z\ A° Ζζ / λ^ \ MA / a / ¿U¿¿ / UU / 4¿0 46 OH N^=\ X>o^f 1 nV 0— 136 a / —N N= / γ% Ι^ύυι / O 1 47 Z~O 3 O o Έ O— 137 Ó \^N nX N^ / N~N n^. } νΛ 48 —o O o ο y-'V \ )=7 O-Z 138 \ Jl o—v z^\ tí 49 \^0 H / N ,N. \ 1'1 / n ι 1 139 0-V7 N^ N N-N / =^ o— 0 o— 50 lo VN ,—n / ° 140 N? T N-\ N-ti^N N=q y-0 N=\_ / \=< H / o— 51 rv0^ O O-Z Z^1_Q ¿ J % v Z-Z 141 .9 nVn'n O 52 n-n 142 \ V \ II o—ó >z ΙΓΑ 1 ” / 53 NH VoZ^L / 0 ó' 143 •i » ^o o— 'VjrV o-z IVIA / a / ¿U¿¿ / UU / 4¿0 54 γ F 144 z-o z / / λ ü o o, \ V O ex ti 55 N-N 145 z-O J .V z y^yy^ü o K 56 o o— y 146 V\ z i γ, ό Xí^y o ν' <x 57 N-V <0 í 147 Z-O z-zyXV Ó o J 0— 58 tí —o o h 148 Cz \ \ o \ 1Γ -z. o-z 59 —o o J 149 V0 L> λγζ'ζ o o 0' o—' / IVIA / a / ¿U¿¿ / UU / 4¿D 62? N-N 0 NU 5—0 )=\ X A \ II ^o-z 64 NX nA N< / N'n \_A~~cA~A. n-n z° 154 ζ'ζΆα A —o o^ 5 O ó 65 N-N Λ A Ό n χ V'fN h ;χ 155 F / rN na xx / T N-N / —<\ / >—0 X Vn nA Ñ^n-n __znYnX0 ΧΛθχΗ x 0 ΝχΥ <N / N \A / ^O-^X-N^ -° F 158 N-N X n=n 69 or Vn N^\ XX N^. H y xxa 159 o— IZ % o- J <χΧΑ MA / a / ¿u¿¿ / uur4¿o 70 n-n °b Ah Vnh 160 z. Á P z' V Z z 1 71 J R / ν' r ? y \ AH O ^¼ o z 161 %JyAz i o o A / ° / 72 vi I / N 0 A Sv / 0 N^N °\ 162 í%A <4 n,' A z\ / \ O N NO Y% x^ o Yy 73 0^ / y NT An-n Ν' I 1 N\AVY 75 7..,. / . 'A / V 0 165 N..=,rV..-0' νΙΑγ^ n. 16 l| N 'NO You Ao' óA 76 / \ z h n n \A\r A^OZ 77 IVIA / a / ¿U¿¿ / UU / 4¿O 79 Y ñ= / y-o n=<n A o / 169 NAV°X N 1 1 A YA 80 ,0^ Np nA ÑAn / AAq / 170 AyG0 -o 81 ú 0 / 171 AX^ N JL i! ,N ~N 0 i^i / ^6 l^o 82 rw:P\. 0 / 172 N 1 1 ηΓΛ^Ο°^ 83 0^ n'yi A-n nxT-lP-< 173 A-o A |An / ^ / °^Ay° 't ,Nk Χλ JL N N Ί 1 'nAA0 / 84 NpT nA ' ,N-N 174 Ν-γ / ν·0^ NÍ 1 1 f N 0 γΑ| I o [Αν n^AqAJ / Ά 85 NÍ T 1 Τ' N ' Y'o^^ N nX. NvY 0 \ 175 V° iT |AN ^° V ,0 A Y 1 86 n\ 1 I VN- <A / N 0 N y 'V^v 176 x^° A í^VNvV Ai Y 87 AY 177 Y'0 ' A A LzÁ Y'^N l^O V XN. ,O A and 1 IVIA / a / ¿U¿¿ / UU / 4¿D 88 \ ¿Η / o Y Z 'z \\ / Z-O 178 Vo ¡Y T .η γί Y^° N i I 89 Jo Vn nA ÑY'N ΖΎΜΗ Y V 0 / ° 179 3 Ώ ^O o— ,.ñ ογΥΥ 90 z y o y \\ / Z-O 180 z-^yJÍ ti 0 o 'tí o P 181 Y .0 <3 YY Ν'o Y V ,n .o. Λ A J uhN Y N N i 1 220 o o 182 O^\ ---Vo O o Z / 9, ΥΥ 221 Z'ZyJ° tí o o tí z y oz z 183 o o Y Y z 222 9. δ O o 184 δ O o Y? 223 you or or you 185 HO. V0' R [1 ,N Y íl Ί ? nY and N 224 \-or you. o o yR ογΥΥ 186 Q 0 0 .7 Y 225 °^JL ti. o o yR <γγΥ 187 P δ O o °Y<^z:- 226 z-zy^J ti o o 9 z ύ MA / a / ZUZZ / UU / 4Z0 188 Y mx 'Qz 227 qY z tí o o Λ °XVZ 189 ζ^Χ^ tí o o tí O^o 228 z'Y tf o o h z Λ z 190 \ o tí 7 O o X 229 O X-O r- X -N / X XUN nX Ύ N 191 \^-0 NQ Ti / n ^x AX~ \ ίΡΓϊ Y _n. JL-X. J o o Y 194 zX í 0 0 ti 0 z 233 X^° [YN ΧγΝ / x \ 1 nX n— V ,O. / ¼ / X / \z Xn -χ N Y OH Y-N. ,0. A Y ) F NZ 1 Y N 235 o o 197 \_ox XX U z,N tí YT T V ,N^ -P\ Y nX Y 236 n 0 0 1 198 0 y / ^xnY X vXO n 7 7 Y N ΝΎ / 8\οζ 237 z'zyY° tí o o tí z 1 199 z-W a 0 0 tí b >° 238 ζ'ζγΥ X 0 o tí δ MA / a / ¿U¿¿ / UU / 4¿0 200 y .Ν. / Ο. / Χ;α Ο Υ Ν N''YY'''q / 239 V. Y Y^ .n o^JL Yy < Ϊ Y N N'·.^ 201 F \ -Ο 0 r- 4-ϊ 0 .'ν A Α7 Υ .Ν^Υ Υο η Ν ί 1 N^YAq / 240 Y o o 7 z ^O 202 χ^ο ο Y / ν / χχο Α "Αχ rYx^ ν ν η \ , Ν. ' Ί I \ 204 Α Y ,Ν^οΥ^ Yy nY Y ^ N Y 206 Υ 0 0 J °2 / χ· 245 . .0. Λ Λ J L .F Ν 1 Υ Ν ι N*\A(f F 246 rz -z^-z.\) - 0 0 $ 208 A X 8 O o A Y / 2 247 z'zyA° 3 0 0 Jo ΓΛ-ζ\γζ °. / 209 ° / Ο=ω o o A χΎ 248 2'zAy Y 0 0 Ó . ΖΥ / ΖΎ^ \ P 210 y Ay Y o o « ω=ο / ú Y 249 \^0 YN yvy y-n-nyo^YY Ύ Y I Y— 211 ZYX Q o o Y r 250 o o Y °jYz IVIA / a / ¿U¿Z / UU / 4¿D 212 YN π\। / W o |Y Y 251 tt o o Y \ o 213 3 Y o o y yy 252 V o o Ο\ / 214 Y'N 1 N ^N'V°^N'N^ Ni I \_ Z 253 t / ΛΛ V XNYv° nY Ύ n 215 γ,ο LzN 1 N N 1 I N''YY^q'''' YΛ oz 254 9 & o o J °γΥζ 216 Y^o |KN \ f ?N n 7 y Y N \ 255 o O o § z / > 217 / YÍ d o o s z Y—yY Z V 256 z ω o o Y^ Y7 218 x o o Y 257 z Ó o o Y^ 'y'7 219 ó i: x 0 0 J oYV 258 & o o— ,ñ γΥ^ The present disclosure also provides a method of preparing the above-mentioned compound represented by formula I or II, and the method comprises: 1) Generally, compound 1 comes from commercial raw materials, for compound 1 with special structure, it can be obtained by substitution reaction of a corresponding alcohol with compound 8 through step 5a, generally reacting in ethers or the corresponding alcoholic solvents in the presence of an alkaline reagent, such as metallic sodium, sodium hydride, potassium tert-butanol, etc.; 2) Compound 3 can be prepared by step c, by directly heating the corresponding hydrazide and compound 1 in various ethers or alcoholic solvents under acid catalysis conditions, such as ptoluenesulfonic acid, etc., and at the same time, different regioisomers, which must be separated; Alternatively, for a substrate with low reactivity, the hydrazide can be reacted with compound 1 through step b under conditions similar to those of step c, and then compound 2 can be obtained by separation, and then compound 3 is also obtained by heating and cyclization in alcohols, acetic acid and other solvents in step d, and then separating the isomers; 3) compound 7 can be obtained from the corresponding ester compound 6 by the reduction of, for example, sodium borohydride and lithium hydride and - 53 aluminum in ethers, alcohols and other solvents through stage i; In addition, the ester compound 6, with a complex structure, can be obtained from the corresponding halogenated heteroaryl ester or phenolic hydroxyl substituted heteroaryl ester through step h, substitution, coupling and other reactions; Compound (I) can be directly generated by a substitution reaction of compound 3 and compound 7 in step f, corresponding to alkaline conditions, such as cesium carbonate, potassium phosphate, etc., reacting in various solvents such as DMF , acetonitrile, etc.; Alternatively, compound (I) can be obtained by converting compound 3 into the corresponding phenolic compound 4 by alkaline conditions, such as sodium hydroxide, potassium hydroxide, etc., in step e, and then replacing it with the corresponding compounds. commercially available halogenates through stage g under alkaline conditions, such as silver carbonate, cesium carbonate, etc. The present disclosure also relates to the compound of the general formula (I) or (II) as described above, which is prepared by the method as described above. If the preparation method is not described in the embodiments, then the compounds represented by the general formula (I) or (II) and intermediates thereof can be prepared according to a similar method or by the method described above. Raw materials known in the art may be commercially available, or may be prepared in known methods or a similar method based on methods known in the art. It is understandable that compounds of the general formula (I) or (II) of the present disclosure can be derivatized at the functional group to obtain derivatives that can be converted to the parent compound in vivo. If the preparation method is not described in the embodiments, then the compounds represented by the general formula (I) or (II) and intermediates thereof can be prepared according to a similar method or by the method described above. Raw materials known in the art may be commercially available, or may be prepared in known methods or a similar method based on methods known in the art. The present disclosure also provides a pharmaceutical composition, which -54 comprises the compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof, and a pharmaceutically acceptable excipient. The present disclosure also provides a use of the compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the salt pharmaceutically acceptable thereof or the prodrug thereof, or the pharmaceutical composition in the manufacture of a medicine. In one embodiment, the drug is used to treat, prevent or ameliorate a disease related to an α5-GABAA receptor. The disease related to the α5-GABAA receptor is, for example, one or more of cognitive diseases, Alzheimer's disease, dysmnesia, Down syndrome, amyotrophic lateral sclerosis (ALS), drug addiction, restless legs syndrome, cognitive deficiency, dementia multi-infarction, pain, stroke and attention deficit, as another example, pain. In one embodiment, the medication is used to treat, prevent or improve one or more of the following diseases: cognitive diseases, Alzheimer's disease, dysmnesia, Down syndrome, amyotrophic lateral sclerosis (ALS), drug addiction, restless legs syndrome, cognitive impairment, multi-infarct dementia, pain, stroke, and attention deficit, as another example, pain. In a preferred embodiment, the pain is one or more of neuropathic pain, inflammatory pain, and oncological pain. In a preferred embodiment, the pain is selected from: headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, waist pain, lower extremity pain, pain muscle and bone, vascular pain, gout, arthritic pain, visceral pain, pain caused by infectious diseases (for example, AIDS pain and postherpetic neuralgia), bone pain, pain associated with sickle cell anemia, pain associated with a disease autoimmune, pain associated with multiple sclerosis or pain associated with inflammation, chronic pain caused by injury or surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, girdle or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, pain associated with reflex sympathetic dystrophy, pain - 55 associated with nerve root avulsion, pain associated with cancer, pain associated with chemical injury, pain associated with a toxin, pain associated with nutritional deficiency, pain associated with infection by viruses or bacteria, and pain associated with osteoarthropathy degenerative. The present disclosure also provides a use of the above described compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof, or the pharmaceutical composition described above in the manufacture of a medicament for treating or preventing a disease related to a "5-GABAA" receptor. Herein, the α5-GABAA receptor-related disease is described in the present disclosure. The present disclosure also provides a use of the above described compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof, or the pharmaceutical composition described above in the manufacture of a medicament for treating or preventing a disease, wherein the disease is one or more of pain, Alzheimer's disease, multi-infarct dementia and accident cerebrovascular. Herein, pain is described in the present disclosure. The present disclosure also provides a method of treating or preventing a disease related to a 5-GABAA receptor, comprising administering to a patient an effective dose of the compound described above represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof, or the pharmaceutical composition described above. In one embodiment, in the composition, use and method of the present disclosure, the aforementioned compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof , the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof, may be in an effective dose. - 56 In one embodiment, in the composition, use and method of the present disclosure, the aforementioned compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof may be used in combination with other medications. The present disclosure also provides a use of the compound or composition described herein in the manufacture of a medicament for treating or preventing the following diseases: pain, Alzheimer's disease, multi-infarct dementia and stroke. The present disclosure also provides a method of treating or preventing a disease, comprising administering to a patient an effective dose of the aforementioned compound represented by formula I, the cistrans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof, or the pharmaceutical composition mentioned above, wherein the disease is one or more of pain, Alzheimer's disease, multi-infarct dementia and stroke. Herein, pain is described in the present disclosure. Unless otherwise specified, the following definitions are used to illustrate and define the meaning and scope of various terms used in the description of the present disclosure herein. The following definitions of general terms apply regardless of whether the terms appear alone or in combination. The nomenclature used in the present disclosure is based on the IUPAC systematic nomenclature generated using ChemDraw. The presence of any open valence bond on a carbon, oxygen, sulfur or nitrogen atom in the structures presented herein indicates the presence of a hydrogen atom. Some compounds of the present disclosure may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present disclosure. The substituted term, unless specifically defined otherwise, -57means that the specified group or moiety may have 1, 2, 3, 4, 5, or 6 substituents. Where any group bears multiple substituents and a variety of possible substituents are provided, the substituents are selected independently and need not be the same. The expression unsubstituted means that the specified group has no substituents. The expression optionally substituted with... means that the specified group is unsubstituted or is substituted with one or more substituents, selected independently of the group that consists of the group of possible substituents. When the number of substituents is indicated, the expression one or more means from one substituent to the highest possible substitution number, that is, the replacement of one hydrogen to the replacement of all hydrogens by the substituents. 1, 2, 3, 4 or 5 substituents are preferred, unless specifically defined otherwise. The term halogen refers to fluorine, chlorine, bromine and iodine. The term cycloalkyl refers to a monovalent saturated cyclic hydrocarbon group that includes bridged and spiro rings, preferably with 3-7 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, as well as those groups specifically exemplified below in This document. The term heterocycle or heterocyclyl refers to a cyclic hydrocarbon in which 1 to 4 carbon atoms have been replaced by heteroatoms independently selected from N, N(R), S, S(0), S(0) and O. The heterocycle can be saturated or unsaturated, but they are not aromatic. Heterocyclyl may also contain 1, 2, or 3 rings, including bridged ring and spiro ring structures. Some examples of suitable heterocyclyls include, but are not limited to: azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, 2oxopyrrolidinyl, pyrrolinyl, pyranyl, dioxolanyl, piperidinyl, 2oxopiperidinyl, pyrazolinyl, imidazolinyl, thiazolinyl, dithiocyclopentadienyl, oxathiocyclopentadienyl, dioxanyl, dio xenyl, dioxazolyl, oxatiozolyl , oxazolonyl, piperazinyl, morpholino, thiomorpholinyl, 3-oxomorpholinyl, ditianyl, tritianyl and oxazinyl. The term bridged ring compound refers to one or more atoms (i.e. - 58 i.e. C, O, N or S) that connect two non-adjacent carbon or nitrogen atoms. Some preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It should be noted that a bridge always converts a monocyclic ring into a triple ring. In bridged rings, ring substituents can also be on the bridge. The term spiro ring compound refers to a polycyclic compound in which two monocyclic rings share a carbon atom, and the shared carbon atom is called a spiro atom. The term aryl refers to a monovalent aromatic carbocyclic ring system, comprising 6 to 14, in particular 6 to 10, carbon atoms and having at least one aromatic ring or multiple fused rings in which at least one ring It is aromatic. Some examples of aryl are phenyl, naphthyl, biphenyl or indanyl, as well as those groups specifically illustrated by the examples below herein. A preferred aryl is phenyl. The aryl may also be substituted, for example, as defined below and in the claims. The term heteroaryl refers to a stable monocyclic, bicyclic or tricyclic ring containing up to i atoms in each ring, where at least one ring is an aromatic ring containing 1 to 4 heteroatoms selected from the group consisting of O, N and S. Heteroaryl, within the scope of this definition, includes, but is not limited to, acridinyl, carbazolyl, cinolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, IH, 3H-l-oxoisoindolyl, benzotriazolyl, furanyl, thienyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl, benzothiophenyl, benzofuranyl, benzodioxanyl, benzodioxaphenyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrahydroquinolyl , thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,4,5- tetrazinyl, tetrazolyl, xanthyl, phenazinyl, phenothiazinyl, phenoxazinyl, azepinyl, oxazepinyl and thiazinyl. A particular heteroaryl has a 5- or 6-membered ring, such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridomorpholinyl , IVIA / a / ¿UZZ / UU í - 59 pyridopiperidinyl, pyridopyrrolidinyl. Heteroaryl may also be substituted, as defined below and in the claims. Compounds of general formula (I) or (II) can form pharmaceutically acceptable acid addition salts. Some examples of such pharmaceutically acceptable salts are salts of compounds of formula (I) or (II) with physiologically compatible inorganic acids, such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid; or with organic acids, such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term pharmaceutically acceptable salt refers to said salts. Compounds of formula (I) or (II) comprising an acidic group, for example a COOH group, may further form salts with alkalis. Some examples of such salts are alkali metal salts, alkaline earth metal salts and ammonium salts, for example, Na-, K-, Ca- and trimethylammonium salt. The term pharmaceutically acceptable salt also refers to such salts. The term prodrug generally refers to the derivation of functional groups from the compound represented by the general formula (I) or (II), which is readily converted to the compound represented by the general formula (I) or (II) in vivo. The selection and preparation of suitable prodrugs can be found in, for example, Design of Prodrug, ed. H. Bundgaard, Elsevier, 1985. Illustrations of the racemates, the ambiscalemic and the scalemic or the compound in pure enantiomeric form used herein are from Maehr, J. Che. Ed. 1985, 62: 114-120. Unless otherwise specified, cuneiform links and point links are used to indicate the absolute configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include the E and Z geometric isomers. Likewise, all tautomeric forms are included within the scope of the present divulgation. The compound of the present disclosure may contain an unnatural ratio of atomic isotopes in one or more of the atoms constituting the compound, the isotopes having the same atomic number, but their atomic mass or mass number being different from those that predominantly exist in nature. For example, compounds may be labeled with radioisotopes, such as deuterium (2H), tritium IVIA / a / ZUZZ / UU / 4ZO - 60 (3Η), iodine-125 (1251) or C-14 (14C). All isotopic variations of the compound of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. Isotopic variants may enhance certain therapeutic advantages, such as deuterium enrichment may increase in vivo half-life or reduce dosing requirements, or provide compounds as standards for the characterization of biological samples. Isotope-enriched compounds within general formula (I) may be prepared by conventional techniques well known to those skilled in the art, or by methods similar to those described in the routes and embodiments herein, using reagents and / or intermediates. enriched with appropriate isotopes without the need to perform redundant experiments. As mentioned above, the new compound of the present disclosure and the pharmaceutically acceptable salts thereof and the prodrug have important pharmacological properties and are inverse agonists of the α5GABAA receptor. Therefore, the compound of the present disclosure can be used alone or in combination with other drugs to treat or prevent diseases mediated by GABAA receptor ligands containing "5" subunits. These diseases include, but are not limited to, pain, Alzheimer's disease, multi-infarct dementia, and stroke. Therefore, the present disclosure also relates to a pharmaceutical composition comprising the compound as defined above and a pharmaceutically acceptable carrier and / or adjuvant. Similarly, the present disclosure also provides the compound as described above for use in the manufacture of the medicament for treating or preventing diseases related to the "5GABAA" receptor, especially, for treating or preventing the following diseases: pain, Alzheimer's, multi-infarct dementia and stroke. It is preferred to treat or prevent pain. It is particularly preferable for treating or preventing neuropathic pain, inflammatory pain, and cancer pain. As used herein, cancer pain refers to pain that occurs during the development process of a malignant tumor. Currently, it is believed that there are three mechanisms of cancer pain, that is, pain caused directly by the development of cancer, pain caused after - 61 oncological treatment and concurrent painful diseases of cancer patients. As used herein, neuropathic pain refers to pain caused by primary damage and dysfunction of the nervous system. As used herein, inflammatory pain refers to pain caused by local acute inflammation or chronic inflammation that stimulates the nerves. As used herein, treatment also includes preventive administration, prevention or elimination of diseases after the onset of diseases. As used herein, patient is defined as any warm-blooded animal, including, but not limited to, mice, cavids, dogs, horses or humans. Preferably, the patient is a human being. As used herein, acute pain is defined as pain caused by injury to the skin, a body structure or internal organs and / or harmful stimulation of diseases, or pain caused by abnormal muscle function. or internal organs that does not produce real tissue damage. As used herein, chronic pain is defined as pain that lasts for a period that exceeds the usual course or healing time of acute illnesses, or that is associated with chronic disease processes that cause persistent pain, or that It reappears for several months or years with a certain interval. If the pain continues to exist after treatment that should cure the disease or exceeds the usual course, such pain can be considered chronic pain. The duration of the pain depends on the nature of the pain and the treatment process associated with the pain. If the pain exceeds the usual treatment process, then this pain is chronic. The medications disclosed by this disclosure can effectively treat chronic pain defined as above, and the medications disclosed by this disclosure can be used to treat hyperalgia accompanied with other diseases, including hyperalgesia, allodynia, improvement of algesia and pain memory. The present disclosure will improve the treatment of pain. As used herein, headache can be divided into primary headache and secondary headache. Primary headache includes tension headache, - 62 migraine and cluster headache, and secondary headache is caused by other diseases. Headache occurs when pain-sensitive tissue in the head and face is injured or stimulated. These pain-sensitive tissues are distributed in the scalp, face, oral cavity and throat, etc. Since they are mainly muscles and vessels in the head with abundant nerve fibers and sensitive to pain, headaches occur when these tissues are injured. As used herein, facial pain includes, but is not limited to, trigeminal neuralgia, atypical facial pain, facial paralysis and facial spasm. As used herein, trigeminal neuralgia is a unique chronic painful disease, also called tic douloureux, which represents transient, paroxysmal and repeated intense pain, similar to an electric shock, in the area of ​​the trigeminal nerve, or accompanied by an ipsilateral facial spasm. Trigeminal neuralgia can be divided into two classes: primary and secondary. Primary trigeminal neuralgia means that no neurological signs are found clinically and no organic disease is detected. Secondary trigeminal neuralgia means that neurological signs are clinically found and organic diseases such as tumor and inflammation are detected. As used herein, atypical facial pain refers to pain caused by various diseases, which appears as a burning and persistent pain, not intermittent and independent of a particular action or stimulus. The pain is usually bilateral and extends beyond the area of ​​the trigeminal nerve to even the cervical skin. The etiology may be stimulation by nasosinusitis, malignant tumor, infection of the jaw and skull base, or pain caused by injury to the trigeminal nerve. As used herein, neck pain, back pain, shoulder pain refer to pain caused by acute or chronic muscle strain and bone joint degeneration and injury. Common diseases causing pain in the neck, shoulders and upper extremities include cervicohumeral myofasciitis, neck desmitis, cervical spondylopathy, scapulohumeral periarthritis, upper thoracic outlet syndrome, external humeral epicondylitis, etc. Alternatively, these terms refer to the - 63 pain caused by autoimmune diseases, it is common in 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 disease, and various infections, as well as referred pain induced by injuries to thoracic and abdominal organs. As used herein, chest, abdominal and back pain refer to pain caused by diseases in the thoracic and abdominal organs, chest wall and abdominal tissues. As used herein, waist pain, lower extremity pain refer to low back, lumbosacral, sacroiliac, hip, buttock and lower limb pain. As used herein, muscle and bone pain includes, but is not limited to, myofascial pain, pain caused by trauma, and chronic regional pain syndrome. As used herein, diabetic peripheral neuropathy pain refers to pain caused by nerve injury complicated by diabetes, and nerve injury in diabetes is caused, at least partially, by reduced blood flow and hyperglycemia. . As used herein, visceral pain includes, but is not limited to, the pain of inflammatory bowel syndrome (ILS), with or without chronic fatigue syndrome (CFS), inflammatory bowel disease (ILD), and interstitial cystitis. As used herein, vascular pain refers to pain generated by one or more of the following factors. First, inadequate tissue perfusion, resulting in temporary or persistent ischemia, for example, ischemia in the muscles of the extremities during physical exercise. Secondly, delayed change, for example, ulcer or gangrene in the skin or abdominal organs. Third, the sudden and accelerated change in the diameter of the great vessels, for example, the change of arterial aneurysm. Fourth, rupture of the aorta, resulting in blood leakage and stimulation of nociceptive fibers in the parietal layers of the peritoneum or pleura. Fifth, strong cramp caused by intense stimulation of the arterial endothelium by an intra-arterial injection. Sixth, the damage to venous return, which gives rise to a large number of edemas of the compartment of the -64rapidly expanded fascia (Bonica et al., The Management of Pain, volume 1 (the 2aversion), Philadelphia; Leas and Feboger, 1990). As used herein, reflex autonomic nerve pain refers to pain caused by reflex sympathetic atrophy syndrome. In sympathetic atrophy syndrome, after the body suffers an acute or chronic injury, intense spontaneous pain occurs and the body is sensitive to the sense of touch and pain. As used herein, postoperative pain refers to a complex physiological response of the body to the disease itself and the tissue damage caused by the operation, showing an unpleasant psychological and behavioral experience. As used herein, arthritic pain includes, but is not limited to, pain caused by osteoarthritis, rheumatoid arthritis, ankylosing joint spondylitis, psoriatic arthropathy, gout, pseudogout, infectious arthritis, tendinitis, bursitis, bone damage and inflammation of soft joint tissues. As used herein, postherpetic neuralgia refers to long-lasting severe subcutaneous pain at the site of the rash after healing of the shingles rash. As used herein, nociceptive pain refers to pain caused by tissue injury caused by nociceptors, or pain caused by prolonged excitation of nociceptors. On the basis of not violating common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain preferred examples of the present disclosure. All reagents and raw materials used in the present disclosure are commercially available. The positive progress effect of the present disclosure is based on the triazolopyridazine derivative of the present disclosure having good inverse agonist activity, thermodynamic solubility, bioavailability and pharmacokinetic properties against "5-GABAA." Detailed description of the preferred embodiment Realization and preparation method Intermediate 1 - 65 3-(6-Chloro-7-methoxy-[1,2,4]triazolo[4,3-¿]pyridazin-3-yl)-5-inethylisoxazole 3,6-Dichloro-4-methoxy-pyridazine (9.9 g, 55.6 mmol) and 5-methyl-isoxazole-3-carboxylic acid hydrazide (7.8 g, 55.6 mmol) were added sequentially in 50 ml of n-butanol were heated and refluxed under argon protection for 4 hours. The solvent was evaporated to dryness, and a solid was suspended in dichloromethane. An insoluble substance was filtered off and the organic phase was concentrated. A residue was purified by column chromatography to obtain 500 mg of the title compound as a white solid in 3% yield. 1H-NMR (400 MHz, CDC13) δ = 7.35 (s, IH), 6.82 (s, IH), 4.07 (s, 3H). CLEM: m / z [M+H]+ = 266. Intermediate 2 (6-Morpholinopyridin-2-yl)methanol (6-fluoropyridin-2-yl)methanol (150 mg, 1.2 mmol) and morpholine (1 ml, 12 mmol) were mixed, and the reaction mixture was stirred in a sealed tube at 160 °C for 6 hours. The mixture was concentrated under reduced pressure and separated by thin layer chromatography to obtain 220 mg of the title compound in 94% yield as a pale yellow solid. LC-MS: m / z [M+H]+ = 195. Intermediate 3 (6-(Dimethylamino)pyridin-2-yl)methanol Yo (6-fluoropyridin-2-yl)methanol (150 mg, 1.2 mmol) and a tetrahydrofuran solution of dimethylamine (2 M, 3 ml, 6 mmol) were mixed, and the reaction mixture was -66 stirred in a sealed tube at 90 °C for 16 hours. The mixture was concentrated under reduced pressure to obtain 180 mg of a crude product of the title compound containing the starting material (6-fluoropyridyl-2-yl)methanol with pale yellow oil appearance. LC-MS: m / z [M+HJ+ = 153. Intermediate 4 7-Methoxy-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-¿]pyridazin-6-ol A 10% aqueous potassium hydroxide solution (5 ml) was added to a tetrahydrofuran solution (5 ml) of 3-(6-chloro-7-methoxy-[1,2,4]triazolo[4,3-b ]pyridazin3-yl)-5-methylisoxazole (380 mg, 1.43 mmol), and the mixture was stirred at room temperature for 3 days. The pH was adjusted to 2 with 1 N hydrochloric acid, and the precipitated solid was filtered and dried to obtain 310 mg of the title compound in 87.6% yield and pale yellow solid appearance. LC-MS: m / z [M+H]+ = 248. Intermediate 5 (5-(2-Methoxyethoxy)pyridin-2-yl)methanol Step 1) Preparation of methyl 5-(2-methoxyethoxy)picolinate Methyl 5-hydroxypicoünate (2.5 g, 16.3 mmol), l-bromo-2-methoxyethane (2.7 g, 19.6 mmol) and cesium carbonate (8.0 g, 24.0 mmol) were added sequentially. 5 mmol) in DMF (30 ml), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into ice water, extracted three times with dichloromethane. The organic phases were combined, washed three times with water and once with saturated brine. The organic phase was dried and concentrated to obtain 3.4 g of methyl 5-(2-methoxyethoxy)picolinate in a yield of 99%. LC-MS: m / z [M+H]+ = 212. Step 2) Preparation of (5-(2-methoxyethoxy)pyridin-2-yl)methanol Methyl 5-(2-methoxyethoxy) picolinate (3.4 g, 16.1 mmol) was dissolved in a mixed solvent of THF (80 mL) and MeOH (20 mL), and NaBH4 (1.2 g) was added. , 32.2 mmol) in portions, then the reaction mixture was stirred at temperature -67ambient for 16 hours. After quenching with ice water, the mixture was extracted three times with dichloromethane, and the organic phases were combined, washed once with water and once with saturated brine. The organic phase was dried and concentrated to obtain 2.31 g of crude product of the title compound. LC-MS: m / z [M+H] + = 184. Intermediate 6 4-((6-(Hydroxymethyl)pyridin-3-yl)oxy)butanenitrile / — CN / —\ / 0HO The experimental operation was the same as that of intermediate 5. In DMF (2 ml), methyl 5-hydroxypicolinate (150 mg, 1 mmol), 4-bromobutyronitrile (178 mg, 1.2 mmol) and potassium carbonate (207 mg) were added sequentially. , 1.5 mmol). 95 mg of the title compound was obtained by a two-step reaction in a yield of 49%. LC-MS: m / z [M+H]+ = 193. Intermediate 7 (5 - (3 -Metoxypropoxy )pyridin-2-yl)me tanol HO / =\ \\ / / °\ The experimental operation was the same as that of intermediate 5. In DMF (2 ml), methyl 5-hydroxypicolinate (150 mg, 1 mmol), 1-bromo-3-methoxypropane (184 mg, 1.2 mmol) and carbonate were added sequentially. of cesium (489 mg, 1.5 mmol). 100 mg of the title compound was obtained by a two-step reaction in a yield of 51%. LC-MS: m / z [M+H]+ = 198. Intermediate 8 Methyl 6-(((7-Methoxy-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6yl)oxy)methyl)nicotinate - 68 To 10 ml of acetonitrile, 6-chloro-7-methoxy-3-(5methyl-isoxazol-3-yl)-[1,2, 4]triazolo[4,3-¿>]pyridazine (240 mg) was added sequentially. , 0.9 mmol), methyl 6(hydroxymethyl)nicotinate (150 mg, 0.9 mmol) and cesium carbonate (585 mg, 1.8 mmol), then the mixture was heated to 50 °C and stirred for 2 hours. The solid cesium carbonate was filtered with diatomite and the organic phase was concentrated. The residue was purified by preparative TLC (dichloromethane / methanol = 20 / 1) to obtain 300 mg of the title compound as a white solid in 84% yield and white solid appearance. LC-MS: m / z [M+H]+ = 397. Intermediate 9 (4-(2-Methoxyethoxy)pyridin-2-yl)methanol The experimental operation referred to intermediate 5, starting from methyl 4hydroxypyridine-2-carboxylate (150 mg, 0.98 mmol) and l-bromo-2-methoxyethane (180 mg, 1.29 mmol), 47 mg of the compound were obtained of the title with a two-stage return of 26.5%. LC-MS: m / z [M+H]+ = 184. Intermediate 10 6-Chloro-7-ethoxy-3-(5-methyl-isoxazol-3-yl)-[1,2,4]triazolo[4,3-,b]pyridazine N-N ji [| i N-0 CL 3,6-Dichloro-4-ethoxypyridazine (2 g, 10.4 mmol, see Pharmaceutical Bulletin, 1958, vol. 6, p. 641 for synthesis), 5-methyl-isoxazole-3-hydrazide were added sequentially. carboxylic acid (1.47 g, 10.4 mmol) in 50 ml of n-butanol, and the synthesis procedure was the same as that of intermediate 1 to obtain 110 mg of the title compound as a white solid with a yield of 4%. LC-MS: m / z [M+H]+ = 280. Intermediate 11 N-Ethyl-6-hydroxymethyl-nicotinamide Methyl 6-hydroxymethyl-nicotinate (10 g, 60 mmol) was dissolved in 150 ml of a 35% ethanolic solution of ethylamine, the tube was sealed and the mixture was heated under reflux overnight. The solvent was evaporated to dryness to obtain 12 g of crude product of the title compound, LC-MS: m / z [M+HJ+ = 181. Intermediate 12 (5-Cyclohex-l-enyl-pyridin-2-yl)-methanol Dissolved were (5-bromo-pyridin-2-yl)-methanol (350 mg, 1.9 mmol), cycloethylene-l-boronic acid pinacol ester (350 mg, 1.9 mmol), [1, 1'bis(diphenylphosphino)ferrocene]palladium and the catalytic amount of cesium carbonate in 10 ml of dioxane, and the mixture was heated at 100 °C overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (dichloromethane / ethyl acetate = 1 / 2) to obtain 200 mg of the title compound as a yellow solid in 55% yield and a yellow liquid appearance. . LC-MS: m / z [M+H]+ = 190. Intermediate 13 3,6-Dichloro-4-cyclopropylniethoxy-pyridazine Cyclopropylmethanol (400 mg, 5.5 mmol) was dissolved in 20 ml of anhydrous tetrahydrofuran, cooled to 0 °C. Sodium hydride (250 mg, 5.5 mmol) was added and the mixture was stirred for 10 minutes and then 3,4,6trichloropyridazine (1 g, 5.5 mmol) was added and the mixture was raised to room temperature and stirred for 1 hour. A drop of water was added to inactivate the reaction. The mixture was concentrated and 20 ml of water was added to dissolve the solid, then the mixture was extracted twice with 20 ml of dichloromethane, -70 was dried (anhydrous sodium sulfate) and evaporated to obtain 1.2 g of the title compound as a white solid in 100% yield. LC-MS: m / z [M+H]+ = 219. Intermediate 14 6-Chloro-7-cyclqprqpilmethoxy-3-(5-methyl-isoxazol-3-yl)-[1,2,4]triazolo[4,3¿] pyridazine 3,6-Dichloro-4-cyclopropylethoxypyridazine (1.2 g, 5.4 mmol) and 5-methyl-isoxazole-3-carboxylic acid hydrazide (770 mg, 5.4 mmol) were added sequentially in 50 ml of n. -butanol, and the synthesis procedure was the same as that of intermediate 1 to obtain 100 mg of the title compound as a white solid with a yield of 10%. LC-MS: m / z [M+H]+ = 306. Intermediate 15 (5-Ethoxy-pyridin-2-yl)-methanol Methyl 5-ethoxy-pyridine-2-carboxylate (4 g, 10 mol) was dissolved in 100 ml of anhydrous tetrahydrofuran, stirred until completely dissolved and cooled to 0 °C. Lithium aluminum hydride (380 mg, 11 mmol) was added and the mixture was stirred for 15 minutes, and then 400 mg of lithium aluminum hydride was added and the mixture was stirred for 10 minutes. 0.8 ml of water, 1.5 ml of 15% sodium hydroxide solution, 2.5 ml of water were sequentially added and the mixture was filtered. The filtrate was dried (anhydrous sodium sulfate) and concentrated, and the residue was purified by column chromatography (dichloromethane / methanol = 30 / 1) to obtain 850 mg of the title compound as a yellow liquid with a 56% performance. LC-MS: m / z [M+H]+ = 154. Intermediate 16 Methyl 5-Difluoromethoxy-pyridine-2-carboxylate ocf2h Methyl 5-hydroxyl-pyridine-2-carboxylate (1 g, 6.54 mmol), sodium 2-chloro-2,2-difluoroacetate (2 g, 13.08 mmol) and potassium carbonate (1.1 g, 7.84 mmol) in 27 ml of (N,N-dimethylformamide / water = 8:1), under the protection of argon, the mixture was stirred at 100 °C for 2 hours, quenched and then extracted twice with 100 ml of ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, concentrated and subjected to column chromatography to obtain 800 mg of the title compound in 60% yield and appearing as a white solid. CLEM: m / z [M+H]+ = 204. Intermediate 17 Methyl 6-(2-Methoxy-ethoxy)-pyridazine-3-carboxylate Yo Methyl 6-oxo-l,6-dihydropyridazine-3-carboxylate (500 mg, 3.2 mmol), 2-bromoethyl methyl ether (541 mg, 3.9 mmol) and silver carbonate (1.0 mmol) were added sequentially. 78 g, 6.5 mmol) in 5 ml of toluene, and then the tube was sealed and the mixture was heated to 100 °C and stirred overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC (dichloromethane / methanol = 30 / 1) to obtain 90 mg of the title compound as a colorless oil in 13% yield. LC-MS: m / z [M+H]+ = 213. Intermediate 18 [6-(2-Methoxy-ethoxy)-pyridazin-3-yl]-methanol - 72 Methyl 6-(2-methoxy-ethoxy)-pyridazine-3-carboxylate (90 mg, 0.42 mol) was dissolved in 10 ml of anhydrous tetrahydrofuran, and sodium borohydride (32 mg, 0.84 mol) was added. mmol) and the mixture was stirred for 1 hour. 1 ml of methanol was added to quench, and the mixture was concentrated, and the residue was purified by preparative TLC (dichloromethane / methanol = 30 / 1) to obtain 40 mg of the title compound as a yellow oil with a yield of 52%. LC-MS: m / z [M+H] + = 185. Intermediate 19 Methyl 6-(3-Cyanopropoxy)pyridazine-3-carboxylate Methyl 6-oxo-1,6-dihydropyridazine-3-carboxylate (1 g, 6.4 mmol) and 4-bromobutyronitrile (1.5 g, 11.7 mmol) were dissolved in 50 ml of toluene, and added silver carbonate (3.6 g, 13.0 mmol), then the mixture was heated to 100 °C and stirred for 5 hours. The reaction solution was cooled, filtered, concentrated, and the residue was purified by preparative TLC (dichloromethane / methanol = 20 / 1) to obtain 100 mg of the target compound as an oil in 7% yield and a yellow oil appearance. LC-MS: m / z [M+H]+ = 222. Intermediate 20 4-((6-(Hydroxymethyl)pyridazin-3-yl)oxy)butanenitrile OH Methyl 6-(3-cyanopropoxy)-pyridazine-3-carboxylate (100 mg, 0.45 mol) was dissolved in 5 ml of anhydrous tetrahydrofuran, and sodium borohydride (34 mg, 0.90 mmol) was added and the mixture was stirred for 1 hour. 1 ml of methanol was added to inactivate and the organic phase was concentrated. The residue was purified by preparative TLC (dichloromethane / methanol = 20 / 1) to obtain 20 mg of the title compound as a yellow oil in 23% yield. LC-MS: m / z [M+H]+ = 194. Intermediate 21 - 73 3-Chloro-4-methoxy-6-(pyridin-2-methoxy)pyridazine and an isomer thereof Pyridine-2-methanol (13.7 g, 83.75 mmol) was added to tetrahydrofuran (250 ml), and then sodium hydride (5.1 g, 125.6 mmol, 60% in mineral oil) was added. and the reaction was carried out at room temperature for 30 minutes, and then cooled to 0 °C. 3,6-Dichloro-4-methoxypyridazine (15 g, 83.75 mmol) was added and the mixture was stirred at 40 °C for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, concentrated and subjected to column chromatography (dichloromethane / methanol = 50 / 1) to obtain a mixture of 3-chloro-4-methoxy-6- (pyridin-2-methoxy)pyridazine and a 6-chloro4-methoxy-3-(pyridin-2-methoxy)pyridazine isomer (11 g, 52%). The next step reaction was carried out directly without further purification. 1H-NMR (400 MHz, CDC13): δ 8.64-8.62 (m, 1H), 7.73-7.69 (m, 1H), 7.51-7.47 (m, 1H), 7.28-7.22 (m, 1H), 6.80 (s, 1H), 5.67 (s, 2H), 3.95 (s, 3H). Intermediate 22 N-(5-Methoxy-6-(2-pyridyl-methoxy)pyridazin-3-yl)-5-(methoxymethyl)isoxazole-3carbohydrazide A mixture of 3-chloro-4-methoxy-6-(pyridin-2-methoxy)pyridazine and 6chloro-4-methoxy-3-(pyridin-2-methoxy)pyridazine (600 mg, 23.84 mmol) was added. 5(methoxymethyl)isoxazole-3-carboxylhydrazide (605 mg, 35.76 mmol, see CN106854207A for synthesis) and p-toluenesulfonic acid monohydrate (453 mg, 23.84 mmol) to dioxane (100 ml), and the Reaction was carried out at 120 °C for 3 hours. The reaction solution was diluted with dichloromethane and methanol (10 / 1). A saturated aqueous sodium carbonate solution was added, and the mixture was extracted with dichloromethane and methanol (10 / 1), and the organic phases were combined, concentrated, and then subjected to column chromatography (dichloromethane / methanol = 10 / 1) to obtain N-(5-methoxy-6-(2-pyridyl-methoxy)pyridazin-3-yl)-5-74 (methoxymethyl)isoxazole-3-carbohydrazide (120 mg, 13%). LC-MS: m / z [M+H] + = 433. Intermediate 23 Methyl 6-(((tert-Butyldimethylsilyl)oxy)methyl)nicotinate \ N^\ O __ / / A__7 TBSO δ=δ O 6-(Hydroxymethyl)nicotinic acid (5.98 g, 38.8 mmol) was dissolved in dichloromethane (200 ml), then imidazole (2.9 g, 42.7 mmol) and tert-chloride were added respectively. butyldimethylsilyl (6.44 g, 42.7 mmol); After the addition was complete, the reaction was carried out at room temperature for 3 hours. The reaction solution was filtered, washed with dichloromethane, and the organic phase was washed with water (50 ml * 3 times), then washed with saturated ammonium chloride solution (50 ml) once, and then was washed with saturated brine (50 ml * once). The organic phase was dried and concentrated to obtain 2 g of the title compound in a yield of 18.9%. LC-MS: m / z [M+H]+ = 282. Intermediate 24 (6-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-3-yl)methanol Methyl 6-(('tert-butyldimethylsilyl)oxy)methyl)nicotinate (1.28 g, 4.5 mmol) was dissolved in tetrahydrofuran (20 ml), and sodium borohydride (684 mg, 22 mmol) was added. The reaction was then carried out at room temperature for 3 hours. The reaction solution was quenched, concentrated, and separated by a chromatographic column to obtain 325 mg of the title compound in a yield of 28.6%. LC-MS: m / z [M+H]+ = 254.2. Intermediate 25 2- (((tert-Butyldimethylsilyl)oxy)methyl)-5- (methoxymethyl)pyridine N—and O— __ / / A__ / TBSO (6-(((tere)-butyldimethylsilyloxy)methyl)pyridin-3-yl)methanol (270 mg, 1.06 mmol) was added to tetrahydrofuran (20 ml), under protection with argon, - 75 sodium hydride (51 mg, 1.28 mmol) and the mixture was stirred at 0° C for 10 minutes. Iodomethane (150 mg, 1.06 mmol) was added; After the addition was complete, the reaction was carried out at room temperature for 3 hours. The reaction solution was quenched with water, extracted with dichloromethane (20 ml * 3 times) and the organic phases were combined and then washed with saturated brine (15 ml * 1 time). The organic phase was dried and concentrated to obtain 300 mg of the title compound in 87% yield. LC-MS: m / z [M+H]+ = 268. Intermediate 26 (5-(Methoxymethyl)pyridin-2-yl)methanol 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(methoxymethyl)pyridine (300 mg, 1.12 mmol) was dissolved in tetrahydrofuran (10 ml), and then tetrabutylammonium fluoride (783 mg) was added. , 3.36 mmol), and the reaction was carried out at room temperature for 3 hours. The reaction solution was concentrated and separated by a chromatographic column to obtain 30 mg of the title compound with a yield of 17%. LC-MS: m / z [M+H]+ = 154. Intermediate 27 5-Cicloprppil-2-piconol 5-Bromo-2-piconol (1.0 g, 5.32 mmol), cyclopropylboronic acid (1.37 g, 15.96 mmol), tetracystriphenylphosphine palladium (612 mg, 0.53 mmol) and potassium carbonate were added. (2.2 g, 15.96 mmol) to dioxane (15 ml), and the mixture was stirred at 120 °C for 2 hours under nitrogen protection. The reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 50 / 1) to obtain the title compound (400 mg, 50%) as an oil. LC-MS: m / z [M+H]+ = 150. Intermediate 28 Methyl 1-(3-Cyanopropyl)-6-oxo-l,6-dihydropyridazine-3-carboxylate - 76 Aο Methyl 6-oxo-l,6-dihydropyridazine-3-carboxylate (1 g, 6.49 mmol), 4-bromobutyronitrile (960 mg, 6.49 mmol) and cesium carbonate (4.2 g, 13 mmol) in 50 ml of acetonitrile, and then the mixture was stirred at 50 °C for two hours. After inactivation, the mixture was filtered and concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 1 g of the title compound as a white solid in 69% yield. LC-MS: m / z [M+H]+ = 222. Intermediate 29 4-(3-(Hydroxymethyl)-6-oxppiridazin-l(6H)-yl)butanenitrile H.O. Xi VnA^cnO Methyl 1-(3-cyanopropyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (400 mg, 1.8 mol) was dissolved in 5 ml of anhydrous tetrahydrofuran, and sodium borohydride (102 mg) was added. , 2.7 mmol), then the mixture was stirred for 1 hour. 1 ml of methanol was added to quench, and the mixture was concentrated, and the residue was purified by preparative TLC (dichloromethane / methanol = 20 / 1) to obtain 90 mg of the title compound as a yellow oil with a yield of 26%. LC-MS: m / z [M+H]+ = 194. Intermediate 30 ((6-(Hydroxymethyl)pyridin-3-yl)methyl)tere-butylcarbamate (5-((ethylamino)methyl)pyridin-2-yl)methanol (800 mg crude product, 5 mmol), di-tere-butyl dicarbonate (1.5 mL, 6 mmol) and triethylamine (2 ml, 10 mmol) in 50 ml of dichloromethane, and the mixture was stirred at room temperature for two hours. 50 ml of water and 50 ml of - 77 an aqueous solution of ammonium chloride, and the mixture was extracted twice with 50 ml of dichloromethane, dried with sodium sulfate and concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 40 / 1) to obtain 120 mg of the title compound as a yellow liquid in a yield of 9%. LC-MS: m / z [M+H]+ = 267. Intermediate 31 (5- ((Ethylamino)methyl)pyridin-2-yl)methanol N-ethyl-6-(hydroxymethyl) nicotinamide (900 mg, 5 mmol) was dissolved in 20 ml of borane tetrahydrofuran solution, and the container was sealed, and then the mixture was heated at 70 °C until day following. 10 ml of 1 M hydrochloric acid was added to quench, and the solvent was concentrated to obtain 800 mg of crude product of the title compound as a yellow liquid in 100% yield. LC-MS: m / z [M+H]+ = 167. Intermediate 32 (5-(Methylsulfonyl)pyridin-2-yl)methanolHO\ PΆ °λ—C y— s— Methyl 5-(methylsulfonyl)picolinate (100 mg, 0.46 mmol) and tetrahydrofuran (20 mL) were added to a single-necked flask, then sodium borohydride (50 mg, 1.4 mmol) was added. and the external temperature was heated to 50 °C, and the reaction was carried out for 1 hour. 0.5 ml of water was added to quench excess sodium borohydride, then the mixture was concentrated, and the residue was purified by preparative TLC with dichloromethane / methanol = 20 / 1 as developing solvent to obtain 35 mg of the title compound in a yield of 40.2% and appearing as a yellow solid. LC-MS: m / z [M+H]+ = 188. Intermediate 33 3,6-Dichloro-4-(difluoromethoxy)pyridazine - 78 3,6-Dichloro-4-hydroxypyridazine (1.55 g, 9.5 mmol), potassium carbonate (1.54 g, 11.2 mmol) and sodium 2-chloro-2,2-difluoroacetate ( 2.88 g, 18.9 mmol) to N,N-dimethylformamide (40 ml) and water (5 ml), and the mixture was stirred in an oil bath at 100 °C for 3 hours. Water was added to the system, followed by extraction with ethyl acetate. The organic phase was washed with water, then washed with saturated brine, dried and concentrated. The resulting product was separated by column chromatography to obtain 0.83 g of the title compound in 40.8% yield as a pale yellow liquid. LC-MS: m / z [M+H]+ = 215. Intermediate 34 3-(6-Chloro-7-(difluorcmethoxy)-[1,2,4]triazolo[4,3-¿]pyridazin-3-yl)-5methylisoxazole 3,6-Dichloro-4-(difluoromethoxy)pyridazine (0.82 g, 3.8 mmol) and 5-methyllysoxazole-3-carboxyhydrazide (0.54 g, 3.8 mmol) were added to n-butanol (20 ml). , and the mixture was stirred in an oil bath at 120 °C for 3 hours under argon protection. The insolubles in the system were removed by filtration and the filtrate was concentrated and separated by column chromatography. The resulting product was further purified by preparative TLC to obtain 124 mg of the title compound in 10.7% yield as a yellow solid. CLEM: m / z [M+H] + = 302. Intermediate 35 Methyl 5-Cyclobutylpicolinate Under anhydrous and anaerobic conditions, magnesium powder (1.154 g, 48 mmol) was added to a three-neck flask and THE (2 ml) was added. At 40 °C, a lithium isopropylmagnesium chloride complex initiator solution was added. - 79 (dissolved in tetrahydrofuran, 1.3 M, 0.96 ml, 0.74 mmol). The starting material bromocyclobutane (5.0 g, 37 mmol) was dissolved in tetrahydrofuran (30 ml) and gradually added to the reaction solution. The reaction was carried out at 40 °C for 2 hours. Zinc chloride (5.54 g, 40.7 mmol) was added at 0 °C and the reaction was carried out at room temperature for 2 hours. The starting materials methyl 5-bromopicolinate (3.98 g, 18.5 mmol), cuprous iodide (351.5 g, 1.85 mmol) and [1,1'-bis(diphenylphosphino)ferrocene dichloride were added. ] palladium (1.35 g, 1.85 mmol) to the reaction solution. Then, under nitrogen protection, the reaction was carried out overnight at 80 °C. A saturated solution of ammonium chloride (100 ml) was added to the reaction solution, then the mixture was extracted with ethyl acetate three times, and the organic phases were collected, dried with anhydrous sodium sulfate, concentrated and were subjected to a preparative liquid phase to obtain the title compound as a yellow solid (1.04 g, 14.7%). 1HNMR (300 MHz, CDC13) : δ 8.56 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.69 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 4.00 (s, 3H), 3.66-3.62 (m, 1H), 2.46-2.39 (m, 2H), 2.22-2.10 (m, 3H), 1.96-1.92 (m, 1H). Intermediate 36 Methyl 6-(3-Methoxypropoxy)pyridazine-3-carboxylate Methyl 6-chloropyridazine-3-carboxylate (2 g, 11.63 mmol), 3-methoxypropanol (1.25 g, 14 mmol) and cesium carbonate (11.34 g, 34.89 mmol) were dissolved in 100 ml of acetonitrile, and the mixture was stirred overnight at room temperature under argon protection. The mixture was filtered and the filtrate was extracted twice with 100 ml of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain 0.5 g of the title compound as a colorless oil in 19% yield. LC-MS: m / z [M+H]+ = 227. Intermediate 37 (6-(3-Methoxypropoxy)pyridazin-3-yl)methanol -80ΗΟ Methyl 6-(3-methoxypropoxy)pyridazine-3-carboxylate (0.5 g, 2.21 mmol) was dissolved in 20 ml of tetrahydrofuran, and sodium borohydride (160 mg, 4.21 mmol) was added to it. The mixture was then stirred at room temperature for 1 hour. 1 ml of methanol was added to quench, and the mixture was concentrated and subjected to column chromatography to obtain 0.3 g of the title compound in 69% yield and colorless oil appearance. LC-MS: m / z [M+H]+ = 199. Intermediate 38 (5-Cyclobutylpyridin-2-yl)methanol Methyl 5-cyclobutylpicolinate (750 mg, 3.92 mmol) was dissolved in methanol (7 ml), and sodium borohydride (430 mg, 11.8 mmol) was added slowly at room temperature, and then the reaction was carried out at room temperature until the next day. The reaction solution was poured directly into water, extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, concentrated and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (550 mg, 85%) as a pale yellow oil. 1H-NMR (400 MHz, CDC13): δ= 8.39 (s, 1H), 7.55 (d, J= 6.4 Hz, 1H), 7.19 (d, J= 8 Hz, 1H) , 4.72 (s, 2H), 3.573.53 (m, 1H), 2.41-2.36 (m, 2H), 2.17-1.88 (m, 4H). Intermediate 39 Methyl 6-iodo-3-Methoxypicolinate Methyl 6-bromo-3-methoxypyridine-2-carboxylate (500 mg, 2.32 mmol) was dissolved in RN-dimethylformamide (5 ml), and copper iodide (1320 mg, 6.97 mmol) was added. and the reaction was carried out at 170 °C for 4 hours. The reaction solution is -81 was cooled and water (30 ml) was added, extracted with ethyl acetate (20 ml * 3 times), and the organic phases were combined, and then washed with saturated brine (15 ml * 1 time). The organic phase was dried and concentrated to obtain 400 mg of the title compound in 65% yield. LC-MS: m / z [M+HJ+ = 293.9. Intermediate 40 Methyl 3-Methoxy-6-(trifluoromethyl)pyridine-2-carboxylate A or ÍX Methyl 6-iodo-3-methoxypicolinate (106 mg, 0.55 mmol) was dissolved in N,Ndimethylformamide (20 mL), then copper iodide (106 mg, 0.55 mmol) and fluorosulfonyl diflucroacetate were added. of methyl (500 mg, 2.6 mmol) and the reaction was carried out at 90 °C for 1 hour. The reaction solution was cooled and water (30 ml) was added, extracted with ethyl acetate (20 ml * 3 times), and the organic phases were combined, and then washed with saturated brine (15 ml * 1 time) . The organic phase was dried, concentrated and separated by column chromatography to obtain 120 mg of the title compound in 92% yield. LC-MS: m / z [M+H]+ = 236. Intermediate 41 3-Methoxy-6-(trifluoromethyl)pyridin-2-methanol Fγ and OH Methyl 3-methoxy-6-(trifluoromethyl)pyridine-2-carboxylate (80 mg, 0.38 mmol) was dissolved in tetrahydrofuran (5 ml), and sodium borohydride (29 mg, 0.76 mmol) was added. The reaction was then carried out at room temperature for 3 hours. The reaction solution was quenched, concentrated, and separated by a chromatographic column to obtain 20 mg of the title compound in a yield of 25.3%. LC-MS: m / z [M+H]+ = 208. Intermediate 42 Pyrazolo[1,5-a]pyrimidin-5-ylmethanol -82ΗΟ\h Ν-ν Triethylamine (84 mg, 84 μΐ, 0.834 mmol) and isobutyl chloroformate (62 mg, 62 μΐ, 0.458 mmol) were added to a THF solution (15 ml) of pyrazolo[1,5-a]pyrimidin-5-acid. carboxylic acid (68 mg, 0.417 mmol), and the mixture was stirred completely at room temperature for 1 hour. Next, 1 ml of an aqueous solution of NaBH4 (31 mg, 0.834 mmol) was added dropwise. The mixture was stirred thoroughly and reacted at room temperature for 0.5 hour. LCMS showed that the reaction was complete. The mixture was concentrated and purified by preparative thin layer chromatography to obtain 33 mg of the title compound in 53% yield. LC-MS: m / z [M+H]+ = 210.1. Intermediate 43(E)-ethyl 4-Ethoxy-2-oxobut-3-enoate Ethyl vinyl ether (36 g, 263 mmol) was added dropwise to ethyl 2-chloro-2-oxoacetate (10 ml, 263 mmol) under argon protection and in an ice bath, and the process was continued for approx. 20 minutes. Ice bath protection was maintained for approximately 2 hours. The ice bath was then removed and the compound was slowly warmed to room temperature. After 15 hours of reaction, the reaction solution was fractionated and the product was collected to obtain 0.5 g of the title compound as a yellow oil. LC-MS: m / z [M+H]+ = 173.1. Intermediate 44 Ethyl pyrazolo[l,5-a]pyrimidine-7-carboxylate Ethyl (E)-4-ethoxy-2-oxobut-3-enoate (300 mg, 1.74 mmol) was dissolved in 10 ml of ethanol, and then 2-aminopyrazole (100 mg, 1.74 mmol) was added. mmol). The -83reaction solution was reacted at 90 °C for 16 hours. The reaction solution was concentrated and the residue was separated by a preparative plate to obtain 120 mg of the title compound. LC-MS: m / z [M+H]+ = 192.1. Intermediate 45 Pyrazolo[1,5-a]pyrimidin-7-ylmethanol Ethyl pyrazolo[l,5-a]pyrimidine-7-carboxylate (47.7 mg, 2.5 mmol) was dissolved in 5 ml of tetrahydrofuran and 5 ml of methanol, and then sodium borohydride (22, 5 mg, 7.5 mmol). The reaction solution was reacted at room temperature for 16 hours. The reaction solution was concentrated and the residue was separated by a preparative plate to obtain 27 mg of the title compound. LC-MS: m / z [M+H]+ = 150.1. Intermediate 46 Dimethyl 6-Methylpyridine-2,5-dicarboxylate EITHER EITHER 3,6-Dibromo-2-pyridine (7.5 g, 30 mmol) was added to methanol (100 ml), then triethylamine (9.1 g, 90 mmol) and [1,1 dichloride were added. '—bis(diphenylphosphino)ferrocene]palladium (1.1 g, 1.5 mmol), and the reaction was carried out overnight at 100 °C under an atmosphere of 5 MPa carbon monoxide. The reaction solution was concentrated and separated by column chromatography (petroleum ether / ethyl acetate = 10 / 1-2 / 1) to obtain the title compound as a pale solid (4.5 g , 72%). 1H-NMR (300 MHz, CDC13) δ 8.31 (d, J= 8.1 Hz, IH), 8.01 (d, J= 8.1 Hz, IH), 4.02 (s, 3H) , 3.95 (s, 3H), 4.80 (s, IH), 2.91 (s, 3H). LC-MS: m / z [M+H]+ = 210.1. Intermediate 47 Dimethyl 6-(Brcmomethyl)pyridine-2,5-dicarboxylate Dimethyl 6-methylpyridine-2,5-dicarboxylate (5.0 g, 23.9 mmol) was added to carbon tetrachloride (60 ml), and N-bromosuccinimide (4.25 g, 23.9 mmol) was added. ) and dibenzoyl peroxide (291 mg, 1.2 mmol), and the mixture was stirred at 80 °C overnight. The mixture was diluted with water, extracted with ethyl acetate; The organic phase was washed with sodium bicarbonate, washed with saturated brine, dried with anhydrous sodium sulfate and concentrated to obtain the title compound (5.6 g, 81%) as a yellow oil. LC-MS: m / z [M+H]+ = 288.0. Intermediate 48 2-(Hydroxymethyl)-6-(2-methoxyethyl)-6,7-dihydro-5H-pyrrolo[3,4-¿]pyridin-5-one Dimethyl 6-(bromomethyl)pyridine-2,5-dicarboxylate (1.0 g, 3.47 mmol) in acetonitrile (20 ml), 2-methoxyethylamine (260 mg, 3.47 mmol) and triethylamine (701 mg, 6.94 mmol), then the mixture was stirred at room temperature overnight. . The mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, dried and separated by column chromatography (dichloromethane:methanol = 100:1-50:1) to obtain 130 mg of the compound in the form of a white solid, which was added to methanol (1.5 ml). Sodium borohydride (30 mg, 0.78 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. A small amount of water was added to quench the reaction, then the mixture was concentrated and separated by column chromatography (dichloromethane:methanol = 100:1-20:1) to obtain the title compound (100 mg, a two-stage yield of 13%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.07 (d, J= 7.6 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 5.62 (t, J= 5.6 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H), 4.52 (s, 2H), 3.70 (t, J =5.6 Hz, 2H) , 3.57 (t, J = 5.6 Hz, 2H), 3.27 (s, 3H). LC-MS: m / z [M+HJ+ = 223.1. Intermediate 49 6-Ethyl-2-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[3,4-¿]pyridin-5-one Dimethyl 6-(bromomethyl)pyridine-2,5-dicarboxylate (5.6 g, 19.4 mmol) was dissolved in acetonitrile (60 ml), then ethylamine hydrochloride (1.90 g, 23 ml) was added. .28 mmol) and triethylamine (4.91 g, 48.6 mmol), and the mixture was stirred at 40 °C for 2 hours. The mixture was diluted with water, extracted with ethyl acetate and extracted with dichloromethane. The organic phases were combined and evaporated to dryness by rotary evaporation. The residue was mixed with silica gel and separated by column chromatography (dichloromethane:methanol = 100:1-25:1) to obtain the compound (1.0 g, 23%) as a yellow solid. pale, which was added to methanol (15 ml). Sodium borohydride (257 mg, 6.75 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and separated by column chromatography (dichloromethane:methanol = 100 / 1-25 / 1) to obtain the title compound (430 mg, two-step yield of 11%) as a solid of pale yellow color. 1H-NMR (400 MHz, DMSO-d6) δ 8.05 (d, J= 8.0 Hz, 1H), 7.57 (d, J= 8.0Hz, 1H), 5.62 (t, J = 6.0 Hz, 1H) , 4.66 (d, J= 6.0Hz, 2H) , 4.49 (s, 2H) , 3.56 (c, J = 7.2 Hz, 2H) , 1 .18 (t, J= 7.2 Hz, 3H) . LC-MS: m / z [M+H]+ = 193.1. Intermediate 50 Dimethyl 3-Cyanopyridin-l,6-dicarboxylate OR ON 2,6-Dichloronicotinonitrile (10.0 g, 57.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (4.23 g, 5.78 mmol), and triethylamine (17. 51 g, 173.4 mmol) in methanol (150 ml). The mixture was then reacted overnight under an atmosphere of 5 MPa carbon monoxide at 80 °C. The mixture was filtered, concentrated and separated by column chromatography (petroleum ether:ethyl acetate = 4:1-2:1) to obtain the title compound as a white solid (2.30 g, 18.1 %). 1H-NMR (400 MHz, CDC13) : δ 8.41(d, J= 8.0 Hz, 1H) , 8.34 (d, J = 8.0 Hz, 1H) , 4.10 (s, 3H) ), 4.07 (s, 3H). LC-MS: m / z [M+H]+ = 221. -86Intermediate 51 Methyl 7-Oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-carboxylate 9 O 3-cyanopyridin-l, dimethyl 6-dicarboxylate (2.3 g, 10.5 mmol) and Raney® niguel (1.24 g, 21.0 mmol) in methanol (300 ml) were added sequentially. The mixture was then reacted for 5 hours under 0.34 MPa (50 psi) hydrogen at 40 °C. The mixture was filtered under reduced pressure and concentrated to obtain 2.1 g of crude product of the title compound. LC-MS: m / z [M+H]+ = 193. Intermediate 52 6-Tero-Butyl-2-methyl-7-oxo-577-pyrrolo[3,4-b]pyridine-2,6(777)-dicarboxylate Methyl 7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2carboxylate (2.1 g, 11.0 mmol) and 4-dimethylaminepyridine (201 mg, 1.65 mmol) were added sequentially. mmol) in dichloromethane (20 ml). Then, the starting material di-tert-butyl dicarbonate (3.6 g, 16.5 mmol) was added dropwise, and the mixture was reacted at 50 °C for 30 minutes. The mixture was concentrated and separated by column chromatography (dichloromethane:methanol = 100 / 1) to obtain the title compound (1.7 g 53.0%) as a yellow solid. 1H NMR (400 MHz, CDC13) : δ 8.36 (d, J = 7.6 Hz, 1H), 8.03 (d, J= 8.0 Hz, 1H), 4.85 (s, 2H), 4.03 (s, 3H), 1.62 (s, 9H). LC-MS: m / z [M+H]+ = 293. Intermediate 53 Tere-butyl 7-Hydroxy-2-(hydroxymethyl)-5,7-dihydro-6.H-pyrrolo[3,4-¿]pyridine-6-carboxylate At 0 oC, the starting material 6-tert-butyl-2-methyl-7-oxo-5H-pyrrolo[3,4b]pyridine-2,6(7H)-dicarboxylate (930 mg, 3.2 mmol) was added to tetrahydrofuran (10 ml). Under nitrogen protection, the starting material diisobutyl aluminum hydride (dissolved in tetrahydrofuran, 9.6 ml, 9.6 mmol, 1 M) was added slowly, -87drop by drop, to the solution. The mixture was allowed to react overnight at room temperature. Water was added to the mixture to quench the reaction, concentrated and separated by column chromatography (dichloromethane / methanol = 30:1-20:1) to obtain the title compound as a brown solid (376 mg, 44.2%). 1H-NMR (400 MHz, CDC13): δ 7.63 (d, J= 7.6 Hz, 1H), 7.32 (dd, J= 8.0 Hz, 4.0 Hz, 1H), 4, 83 (s, 2H), 4.69-4.68 (m, 2H), 4.07-4.03 (m, 1H), 1.55 (s, 9H). LC-MS: m / z [M+H]+ = 267. Intermediate 54 Terebutyl 2-(Hydroxymethyl)-5,7-dihydro-6H-pyrrolo[3,4-¿]pyridine-6-carboxylate Tere-butyl 7-hydroxy-2-(hydroxymethyl)-5,7-dihydro-6Hpyrrolo[3,4-¿>]pyridine-6-carboxylate (376 mg, 1.4 mmol) and sodium cyanoborohydride (376 mg, 1.4 mmol) were added sequentially. 97.0 mg, 1.54 mmol) in acetic acid (4 ml). The mixture was reacted at room temperature for 1 hour. The acetic acid was evaporated to dryness by rotary evaporation at low temperature, and the residue was dissolved in dichloromethane / methanol = 10:1. The pH of the mixture was adjusted to approximately 9 with a saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane / methanol =10:1. The organic phase was collected, dried with anhydrous sodium sulfate, evaporated to dryness by rotary evaporation, and subjected to column chromatography (dichloromethane / methanol = 60:1-40:1) to obtain the title compound as of a yellow solid (200 mg, 57.1%) as a product. 1H-NMR (400 MHz, CDC13): δ 7.60-7.53 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 4.78-4.77 (m, 2H), 4.71-4.68 (m, 4E), 3.43-3.37 (m, 1H), 1.53 (s, 9H). LC-MS: m / z [M+H]+ = 251. Intermediate 55 (6,7-Dihydro-5H-pyrrolo[3,4-jb]pyridin-2-yl)methanol Tere-butyl 2-(hydroxymethyl)-5,7-dihydro-6H-pyrrolo[3,4b]pyridine-6-carboxylate (240 mg, 0.96 mmol) and trifluoroacetic acid (3 mL) in dichloromethane were added sequentially. (3 mi) . The mixture was reacted at room temperature for 30 minutes, and the solution was evaporated dryly by evaporation. -88rotary at low temperature, it was dissolved in methanol, an ion exchange resin was added and stirred for 3 hours until the pH of the solution was alkaline. The mixture was filtered and concentrated to obtain 200 mg of crude product of the title compound as a reddish-brown oil. 1H-NMR (400 MHz, CD3OD): δ 7.82 (d, J= 8.0 Hz, IH), 7.48 (d, J= 8.0 Hz, IH), 4.70 (s, 2H), 4.54 (s, 2H), 4.30 (s, 2H). LC-MS: m / z [M+H]+ = 151. Intermediate 56 (6-Methyl-6,7-dihydro-5H-pyrrolo[3,4-¿]pyridin-2-yl)methaneI > your N C N N C C N a (6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)methanol (150 mg, 1 mmol, crude product) was dissolved in dichloromethane (3 ml), and added dropwise to drop 1 drop of acetic acid, and then added an aqueous solution of formaldehyde (0.5 ml); The mixture was reacted at room temperature for 30 minutes, and then sodium triacetoxyborohydride (636 mg, 3 mmol) was added and the mixture was reacted at room temperature overnight. The reaction solution was concentrated, dissolved in methanol, concentrated and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain the title compound (80 mg, 30%) as an oil of Dun. 1H-NMR (400 MHz, CDC13 and CD3OD) δ 7.63 (d, J = 8.0 Hz, IH), 7.37 (d, J= 8.0 Hz, IH), 4.71 (s, 2H), 4.01-3.99 (m, 4H), 2.66 (s, 3H). Intermediate 57 (6-EtiI-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)methanol (6,7-dihydro-5H-pyrrolo[3,4-¿>]pyridin-2-yl)methanol (200 mg, 1.3 mmol), iodoethane (203 mg, 1.3 mmol) and triethylamine were added sequentially. (404 mg, 3.9 mmol) in acetonitrile (2 ml). The mixture was reacted overnight at 85 °C. The mixture was concentrated and separated by column chromatography (dichloromethane:methanol = 50:1-10:1) to obtain the title compound (120 mg, 70.2%) as a yellow solid. 1H-NMR (400 MHz, CD3OD) : δ 7.59 (d, J = 7.6 Hz, IH), 7.28 (d, J = 8.0 Hz, IH), 4.53 (s, 2H) ), 4.05-3.99 (m, 4H), 2.90-2.85 (m, 2H), 1.16-1.14 (m, 3H). LC-MS: m / z [M+H]+ = 179. Intermediate 58 Tere-butyl 2-(6-(Hydroxymethyl)pyridin-3-yl)-lphy-pyrrol-l-carboxylate In dioxane (25 ml), (5-bromopyridin-2-yl)methanol (2.5 g, 13.3 mmol), (1-(tert-butoxycarbonyl)-lH-pyrrol-2-yl)boronic acid ( 3.37 g, 15.96 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (974 mg, 1.33 mmol) and potassium carbonate (2.75 g, 39.9 mmol), and water (5 ml) was added, then the mixture was stirred at 100 °C for 4 hours under nitrogen protection. The mixture was concentrated and separated by column chromatography (petroleum ether / ethyl acetate = 50 / 1-10 / 1) to obtain the title compound as a yellow oil (3.5 g, 96 %). 1H-NMR (400 MHz, CDC13) δ 8.56-8.55 (m, 1H), 7.70-7.67 (m, 1H), 7.40-7.39 (m, 1H), 7 .26-7.24 (m, 1H), 6.27-6.24 (m, 2H), 4.79-4.78 (m, 2H), 3.67-3.64 (m, 1H) , 1.41 (s, 9H). LC-MS: m / z [M+H]+ = 275.0. Intermediate 59 Tere-butyl 2-(6-Hydroxymethylpyridin-3-yl)pyrrolidinecarboxylate boc N~\ ___ / / A___ / | SICKLE Terebutyl 2-(6-(hydroxymethyl)pyridin-3-yl)-IH-pyrrole-l-carboxylate (4.0 g, 3.65 mmol) was dissolved in methanol (20 ml), then added. palladium / carbon (10%, 4.0 g) and the mixture was reacted under an atmosphere of 0.34 MPa (50 psi) hydrogen at 50 °C. The mixture was filtered, concentrated and separated by column chromatography (dichloromethane:methanol = 100:1-20:1) to obtain the title compound (2.3 g, 57%) as a colored oil. pale yellow. 1H-NMR (400 MHz, CDC13) δ 8.41 (s, 1H), 7.51-7.48 (m, 1H), 7.207.18 (m, 1H), 4.95-4.81 (m , 1H), 4.75 (s, 2H), 3.64-3.49 (m, 2H), 2.40-2.31 (m, 1H), 1.93-1.90 (m, 2H) ), 1.85-1.77 (m, 1H), 1.45-1.21 (m, 9H). LC-MS: m / z [M+H]+ = 279.0. Intermediate 60 2-Bromo-6-((tert-butyldimethylsilyloxy)methyl)pyridine -90 (6-Bromopyridin-2-yl)methanol (9.96 g, 53.0 mmol) was added to dichloromethane (110 ml), then stirring was started and imidazole (10.82 g, 159 mmol) was added ) to the reaction solution. In an ice bath, detert-butyldimethylsilyl chloride (11.98 g, 79.5 mmol) was slowly added to the reaction solution, and the reaction solution was reacted at room temperature overnight under nitrogen protection. . The reaction solution was washed sequentially with a saturated ammonium chloride solution, a saturated sodium bicarbonate solution, and a saturated sodium chloride solution. The organic phase was concentrated and separated by column chromatography (petroleum ether:ethyl acetate = 50 / 1) to obtain the title compound (15.00 g, 94%) as a colorless oil. 1H-NMR (400 MHz, DMSO-d6) δ 7.78 (t, J= 8 Hz, 1H),7.52 (d, J= 8 Hz, 1H),7.45 (d, J= 8 Hz , 1H) , 4.73 (s, 2H) , 0.91 (s, 9H) , 0.09 (s, 6H) . Intermediate 61 Tere-butyl 3-Hydroxy-3-(6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)azetidine-1carboxylate 2-Bromo-6-((tert-butyldimethylsilyloxy)methyl)pyridine (5.0 g, 16.6 mmol) was dissolved in tetrahydrofuran (50 ml), then n-butyllithium (2.5 M, 7.3 ml, 18.3 mmol) at -78 °C; The mixture was stirred at -78 °C for 30 minutes, and tere-butyl 3-oxoazetidine-l-carboxylate (2.83 g, 16.6 mmol) was added and the mixture was stirred at -78 °C for 2 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography (PE:EA = 50:1-5 :1) to obtain the title compound (3.8 g, 58%) as a yellow oil. 1H-NMR (400 MHz, CDC13) δ 7.86-7.82 (m, 1H), 7.54-7.48 (m, 2H), 5.97 (s, 1H), 4.82 (s , 2H), 4.31-4.29 (m, 2H), 4.11-4.09 (m, 2H), 1.49 (s, 9H), 0.97 (s, 9H), 0, 13 (s, 6H). LC-MS: m / z [M+H]+ = 394.9. Intermediate 62 tert-butyl 3-Hydroxy-3-(6-(hydroxymethyl)pyridin-2-yl)azetidine-l-carboxylate Tere-butyl 3-hydroxy-3-(6-((tert-butyldimethylsiloxy)methyl)pyridin-2yl)azetidine-l-carboxylate (3.8 g, 9.6 mmol) was dissolved in tetrahydrofuran (30 ml), Then, tetrabutylammonium fluoride (1 M, 5.8 ml, 5.8 mmol) was added and the mixture was stirred at room temperature overnight. Ethyl acetate (150 ml) was added and the mixture was washed with saturated ammonium chloride solution (50 ml * 2), dried and concentrated to obtain the title compound (2.6 g, 96%). in the form of a yellow oil NMR-1H (400MHz, CDC13) δ 7.86-7.82 (m, 1H), 7.60-7.58 (m, 1H), 7.35-7.34 (m, 1H), 4.81 (s, 2H), 4.31-4.28 (m, 2H), 4.16-4.12 (m, 2H), 1.49 (s, 9H). LC-MS: m / z [M+H]+ = 281.0. Intermediate 63 tert-butyl 3-Hydroxy-3-(6-(acetoxymethyl)pyridin-2-yl)azetidine-l-carboxylate Tere-butyl 3-hydroxy-3-(6-(hydroxymethyl)pyridin-2-yl)azetidine-l-carboxylate (2.6 g, 9.3 mmol) was dissolved in dichloromethane (90 ml), then Triethylamine (1.88 g, 18.6 mmol) and acetic anhydride (949 mg, 9.3 mmol) were added at 0 °C. The reaction mixture was stirred at 0°C for 1 hour and then stirred at room temperature for 2 hours. Water (100 ml) was added and the mixture was extracted with dichloromethane, washed three times with saturated sodium chloride solution, dried and concentrated to obtain a crude product of the title compound (2.6 g, 87 %) in the form of a yellow oil. 1H-NMR (400MHz, CDC13) δ 7.77-7.73 (m, 1H), 7.53-7.52 (m, 1H), 7.26-7.24 (m, 1H), 5, 13 (s, 2H), 4.22-4.20 (m, 2H), 4, 02-3.99 (m, 2H), 2.01 (s, 3H), 1.39 (s, 9H) . LC-MS: m / z [M+H]+ = 322.9. Intermediate 64 Tere-butyl 3-Fluoro-3-(6-(acetoxymethyl)pyridin-2-yl)azetidine-l-carboxylate Tere-butyl 3-hydroxy-3-(6-(acetoxymethyl)pyridin-2-yl)azetidine-l-carboxylate (2.6 g, 8 mmol) was dissolved in dichloromethane (90 ml), then added diethylaminosulfur trifluoride (1.95 g, 12 rrmol) at 0 °C to react for 5 minutes. The reaction solution was poured into an aqueous solution (100 ml) containing sodium carbonate, extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography (PE:EA = 50:Ιό:!) to obtain the title compound (1.5 g, 57%) in the form of a yellow oil. 1H-NMR (400 MHz, CDC13) 07.77-7.75 (m, 1H), 7.45-7.43 (m, 1H), 7.31 7.29 (m, 1H), 5.25 (s, 2H), 4.54-4.46 (m, 2H), 4.32-4.24 (m, 2H), 2.19 (s, 3H), 1.49 (s, 9H). LC-MS: m / z [M+H-56]+ = 269.0. Intermediate 65 Tere-butyl 3-Fluoro-3-(6-(hydroxymethyl)pyridin-2-yl)azetidine-l-carboxylate Tere-butyl 3-fluoro-3-(6-(acetoxymethyl)pyridin-2-yl)azetidrn-l-carboxylate (1.5 g, 4.6 mmol) was dissolved in tetrahydrofuran (20 ml), and then Water (10 ml) and lithium hydroxide monohydrate (292 mg, 6.9 mmol) were added. The reaction solution was stirred at room temperature for 2 hours, poured into water, extracted with ethyl acetate, concentrated and separated by column chromatography (PE:EA = 20:1-5:1) to obtain the title compound (1.2 g, 92%) as a yellow solid. 1H-NMR (400 MHz, CDC13) δ 7.76-7.72 (m, 1H), 7.44-7.42 (m, 1H), 7.23-7.21 (m, 1H), 4 .79-4.78 (m, 2H), 4.524.45 (m, 2H), 4.35-4.27 (m, 2H), 3.68-3.69 (m, 1H), 1.48 (s, 9H). LC-MS: m / z [M+H]+ = 283.0. Intermediate 66 Tere-butyl 3-Fluoro-3-(6-(hydroxyineethyl)pyridin-3-yl)azetidine-l-carboxylate -93From (5-bromopyridin-2-yl)methanol (10.0 g, 53.4 mmol), the title compound (1.1 g, 63%) obtained by the same synthesis method as intermediate 65 , was a yellow oil, which turned into a yellow solid after standing for a while. 1H-NMR (400 MHz, CDC13) δ 8.69 (s, 1H), 7.797.77 (m, 1H), 7.36-7.34 (m, 1H), 4.80 (s, 2H), 4.45-4.41 (m, 2H), 4.29-4.22 (m, 2H), 3.64 (s, 1H), 1.49 (s, 9H) . Intermediate 67 4-L-methyl-lH-pyrazolo[4,3-b]pyridine oxide Or II 1-methyl-lH-pyrazolo[4,3-b]pyridine (1.03 g, 7.7 mmol) (referring to US20140343065A1) and m-chloroperoxybenzoic acid (1.47 g, 8.5 mmol) were added sequentially. , 85%) in dichloromethane (40 ml), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was adjusted to alkalinity with 4 M aqueous sodium hydroxide solution, extracted with dichloromethane, dried and concentrated to obtain 904 mg of the title compound in 75% yield. LC-MS: m / z [M+H]+ = 150. Intermediate 68 1-Methyl-lH-pyrazolo[4,3-b]pyridine-5-carbonitrile NC. / N. \ 1-Methyl-lH-pyrazolo[4,3-b]pyridine 4-oxide (870 mg, 5.8 mmol), trimethylsilyl cyanide (863 mg, 8.7 mmol) and triethylamine (1.17 mmol) were added sequentially. g, 11.6 mmol) in acetonitrile (30 ml), and the reaction mixture was stirred at 110 °C for 16 hours. The mixture was concentrated and separated by column chromatography to obtain 958 mg of the title compound in 100% yield. 1H-NMR (400 MHz, DMSO-d6) δ = 8.52 (s, 1H), 8.42 (d, J = 8.8 Hz, 1H), 7.98 (d, J= 8.8 Hz , 1H), 4.15 (s, 3H). LC-MS: m / z [M+H]+ = 159. Intermediate 69 (1-Methyl-lH-pyrazolo[4,3-b]pyridin-5-yl)methanol 1-methyl-1H-pyrazolo[4,S-bJpyridin-S-carbonitrile (200 mg, 1.26 mmol) and sodium hydroxide (202 mg, 5.04 mmol) were added sequentially in methanol (20 ml) and water ( 4 ml), and the reaction mixture was stirred at 100 °C for 16 hours. The mixture was concentrated, and the pH of the residue was adjusted to between 3 and 4 with 1 N hydrochloric acid. The precipitated solid was filtered and collected, dried to obtain 208 mg of 1-methyl-1H-pyrazolo[4, 3-b]pyridine-5-carboxylic. 1-methyl-lH-pyrazolo[4,3-b]pyridine-5-carboxylic acid and trimethylsilyldiazomethane (4.68 ml, 9.36 mmol, solution in 2 M n-hexane) in dichloromethane (4 ml) were added sequentially. ) and methanol (0.5 ml), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water, extracted with dichloromethane, dried and concentrated to obtain 260 mg of crude product of the title compound. The crude product and sodium borohydride (206 mg, 5.4 mmol) in tetrahydrofuran (6 mL) and methanol (1.5 mL) were added sequentially, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with water, extracted with ethyl acetate, dried and concentrated to obtain a crude product, and separated by thin layer chromatography to obtain 120 mg of the title compound. LC-MS: m / z [M+H]+ = 164. Intermediate 70 l-Methyl-3- (hydroxymethyl)pyridin~2 (1H) -one 3-(hydroxymethyl)pyridin-2(1H)-one (100 mg, 0.8 mmol), iodomethane (1.1 g, 8 mmol) and potassium carbonate (442 mg, 3.2 mmol) in methanol were added sequentially. (4 ml), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into water, extracted with dichloromethane, dried and concentrated, and separated by thin layer chromatography to obtain 93 mg of the title compound. Intermediate 71 1-(2-Methoxyethyl)-3-(hydroxymethyl)pyridin-2(1H)-one 3-(hydroxymethyl)pyridin-2(1H)-one (100 mg, 0.8 mmol), l-bromo-2-methoxyethane (667 mg, 4.8 mmol), and potassium carbonate (442 mg, 3 .2 mmol) in methanol (4 mi). The experimental operation was the same as that of intermediate 70, and the mixture was separated by thin layer chromatography to obtain 48 mg of the title compound. Intermediate 72 l-Ethyl-3-(hydroxymethyl)pyridin-2(1H)-one 3-(hydroxymethyl)pyridin-2(Ifi)-one (150 mg, 1.2 mmol), iodoethane (1.87 g, 12 mmol) and potassium carbonate (663 mg, 4.8 mmol) in methanol were added sequentially. (10 mi) . The experimental operation was the same as that of intermediate 70 to obtain 75 mg of the title compound. Intermediate 73 (5,6,7,8-Tetrahydro-l,6-naphthyridin-2-yl)methanol Trifluoroacetic acid (10 ml) was added to a dichloromethane solution (10 ml) of tere-butyl 2-(hydroxymethyl)-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate (1.1 g, 4.2 mmol), and the mixture was stirred for 16 hours. The mixture was concentrated to obtain 3 g of the title compound with a crude product yield of more than 99% and a pale yellow oil appearance. LC-MS: m / z [M+H]+ = 165. Intermediate 74 2-(((tert-Butyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-l,6-naphthyridine -96 (5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)methanol (2.9 g, 4.2 mmol, crude product) and diisopropylethylamine (11.2 g, 87 mmol) to tetrahydrofuran (80 ml), then a solution of tert-butyldimethylsilyl chloride (2.64 g, 17.4 mmol) in THE (20 ml) was added dropwise to the above solution, and the mixture was made react and stirred until the next day. The reaction solution was separated by column chromatography to obtain a mixture of the title compound and diisopropylethylamine (2.5 g, 40% purity) in 85% yield and yellow oil appearance. LC-MS: m / z [M+H]+ =279. Intermediate 75 (6-(2,2,2-Trifluoroethyl)-5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)methanol 2-(((tert-butyldimethylsilyl)oxy)methyl)-5,6,7,8tetrahydro-1,6-naphthyridine (500 mg, 40% purity, 0.72 mmol), 2,2-trifluoromethanesulfonate were added sequentially ,2-trifluoroethyl (335 mg, 1.44 mmol) and cesium carbonate (469 mg, 1.44 mmol) in acetonitrile (8 ml), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into water, extracted with ethyl acetate, dried and concentrated to obtain 140 mg of the title compound. The title compound and tetrabutylammonium fluoride trihydrate (246 mg, 0.78 mmol) in dichloromethane (5 mL) were added sequentially, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into water, extracted with dichloromethane, dried and concentrated to obtain a crude product, and separated by thin layer chromatography to obtain 54 mg of the title compound in a two-step yield of 30. 5 %. LC-MS: m / z [M+H]+ = 247. Intermediate 76 5- (2 -Methoxypropoxy)pyrazin-2-yl) methanol o—N=\ / — / γΛ / / ° H.O. Methyl 5-chloropyrazine-2-carboxylate (1 g, 5.8 mmol), ethylene glycol methyl ether (1 g, 11.6 mmol) and cesium carbonate (5.7 g, 17.4 mmol) were added sequentially in 50 ml of acetonitrile, then the mixture was heated to 50 °C and stirred overnight. The solid cesium carbonate was filtered with diatomite -97y the reaction solution was diluted with water, extracted with dichloromethane and the organic phase was concentrated. The residue was purified by a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to obtain 180 mg of 2-methoxyethyl 5-(2-methoxyethoxy)pyrazine-2-carboxylate as a liquid. yellow in color, which was dissolved in 20 ml of anhydrous tetrahydrofuran. Sodium borohydride (120 mg, 3.5 mmol) was added, and the mixture was heated to 70 °C and refluxed for 1 hour. 1 ml of methanol was added to quench, then the solid was filtered and the organic phase was concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 60 mg of the title compound as a colorless oil in a two-step yield of 6%. LC-MS: m / z [M+H]+ = 185. Intermediate 77 (5-(3-Methoxypropoxy)pyrazin-2-yl)methanol Methyl 5-chloropyrazine-2-carboxylate (1 g, 5.8 mmol), 3-methoxy-l-propanol (1 g, 11.6 mmol) and cesium carbonate (5.7 g, mmol) were added sequentially. in 50 ml of acetonitrile. The experimental operation was the same as that of intermediate 76 to obtain 120 mg of the title compound as a colorless oil with a two-step yield of 9%. LC-MS: m / z [M+H]+ = 199. Intermediate 78 1-2,5-Bis(methoxycarbonyl)pyridine oxide —O N=\ O— Dimethyl pyridine-2,5-dicarboxylate (4 g, 20 mmol) was dissolved in 200 mL of dichloromethane, then the mixture was cooled to 0 °C, and m-chloroperoxybenzoic acid (10.6 g, 61 mmol) in portions. The reaction solution was poured into aqueous sodium thiosulfate solution, extracted with dichloromethane and dried with sodium sulfate. The residue was purified by a silica gel column (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to obtain 3.5 g of the target compound as a yellow solid in a yield of -9881% and a yellow solid appearance. LC-MS: m / z [M+H]+ = 212. Intermediate 79 Dimethyl 6-Cyanopyridine-2,5-dicarboxylate CN —O N= / O— q / Vy Q 2,5-bis(methoxycarbonyl)pyridine 1-oxide (3.5 g, 15.8 mmol), TMSCN (3.1 g, 31.7 mmol), and triethylamine (2.4 g, 23.0 mmol) were added sequentially. 7 mmol) in 100 ml of acetonitrile, then the mixture was heated to 80 °C and stirred overnight. The reaction solution was concentrated. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to obtain 1.8 g of the target compound as a yellow solid in yield 52% and a yellow solid appearance. LC-MS: m / z [M+H]+ = 221. Intermediate 80 Methyl 5-Oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-carboxylate Dimethyl 6-cyanopyridine-2,5-dicarboxylate (1.8 g, 8.1 mol) was dissolved in 100 ml of methanol, then Raney® nickel was added and the mixture was stirred overnight. room temperature under a hydrogen atmosphere. The reaction solution was filtered and the filter cake was dried to obtain 1 g of the title compound as a gray solid in 64% yield. LC-MS: m / z [M+H]+ = 193. Intermediate 81 2-(Hydroxymethyl)-6,7-dihydro-5H-pyrrolo[3,4-¿]pyridin-5-one -99Methyl 5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-carboxylate (300 mg, 1.5 mol) was dissolved in 50 ml of anhydrous tetrahydrofuran, the mixture was cooled to -10 °C and DIBAL-H (1 N, 9 mL, 9 mmol) was added, and the mixture was stirred for 10 min, then warmed to room temperature and stirred for 1 hour. 1 ml of water was added thereto, and the reaction solution was concentrated, and the residue was purified by preparative TLC (dichloromethane / methanol = 50 / 1 to 20 / 1) to obtain 200 mg of the title compound as a gray solid with a yield of 78%. LC-MS: m / z [M+H]+ = 165. Intermediate 82 2-Methoxyethyl 1-(2-Methoxyethyl)-lH-pyrrolo[2,3-b]pyridine-6-carboxylate IH-pyrrolo[2,3-b]pyridine-6-carboxylate (200 mg, 1.23 mmol), 2-bromoethyl methyl ether (514 mg, 3.7 mmol), and potassium carbonate (852 mg, 6.2 mmol) in 50 ml of DMF, then the mixture was heated at 80 °C overnight. The reaction solution was diluted with water, extracted with ethyl acetate, dried and concentrated. The residue was purified by a silica gel column (dichloromethane / methanol = 50 / 1 to 20 / 1). 160 mg of the title compound were obtained in the form of liquid with a yield of 59% and a yellow oil appearance. LC-MS: m / z [M+HJ+ = 279. Intermediate 83 (1-(2-Methoxyethyl)-lH-pyrrolo[2,3-¿]pyridin-6-yl)methanol 2-Methoxyethyl 1-(2-methoxyethyl)-IH-pyrrolo[2,3-b]pyridine-6-carboxylate (320 mg, 1.2 mol) was dissolved in 10 ml of anhydrous tetrahydrofuran, then the mixture was cooled to 0 °C and lithium aluminum hydride (91 mg, 2.4 mmol) was added; The mixture was stirred for 10 minutes. Sequentially, they added - 100 0.1 ml of water, 0.1 ml of 15% sodium hydroxide solution and 0.3 ml of water. The solid was filtered and the organic phase was concentrated. The residue was purified by preparative TLC (dichloromethane / methanol = 50 / 1 to 20 / 1) to obtain 160 mg of the title compound as a yellow liquid in 65% yield and oil-like appearance. yellow color. LC-MS: m / z [M+H]+ = 207. Intermediate 84 (1-(3-Methoxypropyl)-lH-pyrrolo[2,3-b]pyridin-6-yl)methanol lH-pyrrolo[2,3-b]pyridine-6-carboxylate (200 mg, 1.23 mmol), l-bromo-3-methoxypropane (567 mg, 3.7 mmol), and potassium carbonate (852 mg) were added sequentially. , 6.2 mmol) in 50 ml of DMF, and the experimental operation was the same as the synthesis method of intermediate 83. A two-step reaction was carried out to obtain 170 mg of the title compound in the form of a liquid yellow in color with a yield of 65% and a yellow oil appearance. LC-MS: m / z [M+H]+ = 221. Intermediate 85 (1-Methyl-lH-pyrazolo[2,3-b]pyridin-6-yl)methanol IH-pyrrolo[2,3-b]pyridine-6-carboxylic acid (250 mg, 1.54 mmol), iodomethane (1.02 g, 7.7 mmol) and potassium carbonate (1.28 g, 9.2 mmol) in 10 ml of DMF, and the experimental operation was the same as the synthesis method of intermediate 83. A two-step reaction was carried out to obtain 150 mg of the title compound in the form of a liquid of yellow color with a yield of 67% and a yellow oil appearance. LC-MS: m / z [M+H]+ = 163. Intermediate 86 3-Fluoro-3-(6-(hydroxymethyl)pyridin-3-yl)piperidin-l-carboxylate tere- 101 - butyl From 5-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (4 g, 13.2 mmol) and tere-butyl 3-oxopiperidin-l-carboxylate (2.6 g, 13.2 mmol) 2 mmol), the experimental operation was the same as the synthesis method of intermediate 65 to obtain 130 mg of the title compound in the form of a yellow oil. LC-MS: m / z [M+H]+ = 311. Intermediate 87 Terebutyl 3-(6-(Acetoxymethyl)pyridin-3-yl)-3-hydroxypyrrolidin-l-carboxylate EITHER From 5-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (2 g, 6.6 mmol) and tere-butyl 3-oxopyrrolidin-l-carboxylate (1.2 g, 6.6 mmol) 6 mmol) as starting materials, the experimental operation was the same as the synthesis method of intermediate 63 to obtain 300 mg of the title compound in the form of a yellow liquid. LC-MS: m / z [M+H]+ = 337. Intermediate 88 Terebutyl 3-(6-(Hydroxymethyl)pyridin-3-yl))-2,5-dihydro-lg-pyrrol-l-carboxylate Tere-butyl 3-(6-(acetoxymethyl)pyridin-3-yl)-3-hydroxypyrrolidin-l-carboxylate (300 mg, 0.89 mmol) was dissolved in 50 ml of dichloromethane, then the mixture was cooled to 0 °C, and DAST (215 mg, 1.33 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was poured into 20 ml of aqueous sodium bicarbonate solution to inactivate it, extracted with dichloromethane, dried and concentrated to obtain 300 mg of 3-(6(acetoxymethyl)pyridin-3-yl)-2, Tere-butyl 5-dihydro-lH-pyrrole-l-carboxylate in the form of a yellow oil, dissolved in 5 ml of tetrahydrofuran. Lithium hydroxide monohydrate (60 mg, 1.4 mmol) was added, and the mixture was stirred at - 102 room temperature for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, dried and concentrated, and the residue was purified by a silica gel column (dichloromethane / methanol = 20 / 1) to obtain 250 mg of the compound. titer in the form of a yellow oil with a two-stage yield of 90%. LC-MS: m / z [M+H]+ = 277. Intermediate 89 Tere-butyl 3-(6-(Hydroxymethyl)pyridin-3-yl)pyrrolidine-l-carboxylate NBoc dissolved HOx= / Tere-butyl 3-(6-(hydroxymethyl)pyridin-3-yl)-2,5-dihydro-lH-pyrrole-l carboxylate (250 mg, 0.9 mmol) in 10 ml of methanol, then palladium-carbon catalyst (20 mg) was added and the mixture was stirred overnight at room temperature under a hydrogen atmosphere at normal pressure. The palladium carbon was filtered, and the reaction solution was concentrated to obtain 210 mg of the title compound as a yellow oil in a yield of 90%. LC-MS: m / z [M+H]+ = 279. Intermediate 90 l-Methyl-lg-pyrrolo[3,2-b]pyridine-5-carboxylate methyl Cesium carbonate (743 mg, 2.28 mmol) and methyl iodide (324 mg, 2.28 mmol) were added to a DMF solution (3 ml) of ΙΉ-pyrrolo[3,2-¿>]pyridin- methyl 5-carboxylate (200 mg, 1.14 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water (10 ml), extracted with ethyl acetate (4 ml x 4), dried with anhydrous sodium sulfate, filtered and concentrated to obtain 210 mg of the title compound in a yield of 97% and a pale yellow oil appearance. LC-MS: m / z [M+HJ+ = 191. Intermediate 91 (1-Methyl-lH-pyrazolo[3,2-b]pyridin-5-yl)methanol - 103 Methyl 1-methyl-lH-pyrrolo[3,2-b]pyridine-5-carboxylate (160 mg, 0.84 mmol) was added to a suspension in THF (10 ml) of LÍA1H4 (96 mg, 2 .53 mmol), and the mixture was stirred for 2 hours. 96 mg of water was added to quench, then the mixture was filtered and concentrated, then passed through a column to obtain 50 mg of the title compound in 37% yield and appearance of solid pale yellow in color. LC-MS: m / z [M+H]+ = 163. Intermediate 92 Dimethyl 3-Methylpyridine-2,6-dicarboxylate The compound 2,6-dichloro-3-methylpyridine (10.04 g, 62 mmol) was added to 180 ml of anhydrous methanol. Triethylamine (18.78 g, 186 mmol) and [1,1'bis(diphenylphosphino)ferrocene]palladium dichloride (4.54 g, 6.2 mmol) were added sequentially to the reaction solution. Carbon monoxide was pumped in at an internal pressure of 5.0 MPa, then the mixture was heated to 100 °C and reacted overnight. Water and dichloromethane were added to the reaction solution and the phases were separated. The organic phase was washed with saturated brine, concentrated and separated by silica gel column chromatography (petroleum ether:ethyl acetate from 8:1 to 2:1) to obtain the title compound (11.7 g, 90.7%) as a gray solid. CLEM: m / z [M+H]+ = 210. Intermediate 93 Dimethyl 3-(Brcmomethyl)pyridine-2,6-dicarboxylate O O Br At 0 °C, a starting material dimethyl 3-methylpyridine-2,6dicarboxylate (5.7 g, 27.3 mmol), a starting material N bromosuccinimide (4.86 g, 27.3 mmol) and benzoyl peroxide (339 mg, 1.4 mmol) in carbon tetrachloride (60 ml). The mixture was then heated to reflux and - 104 was reacted overnight at 85 oC. The mixture was dryly evaporated by rotary evaporation and subjected to column chromatography (petroleum ether / ethyl acetate = 20:1-10:1) to obtain a product as a white solid (6.14 mg, 78.1%). 1H-NMR (400 MHz, CDC13): δ 8.27-8.24 (m, 1H), 8.07-8.05 (m, 1H), 4.94 (s, 2H), 4.04- 4.02 (m, 6H). LC-MS: m / z [M+H]+ = 290. Intermediate 94 Methyl 6-Ethyl-7-oxo-6,7-dihydro-5g-pyrrolo[3,4-¿]pyridine-2-carboxylate A starting material dimethyl 3-(bromomethyl)pyridine-2,6dicarboxylate (4.44 g, 15.4 mmol), a starting material ethylamine hydrochloride (1.5 g, 18.5 mmol) and a starting material were sequentially added. Potassium carbonate (4.68 g, 34 mmol) in tetrahydrofuran (45 ml). The mixture was allowed to react overnight at room temperature. Water (100 ml) was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic phase was collected, dried with anhydrous sodium sulfate, evaporated to dryness by rotary evaporation and subjected to column chromatography (dichloromethane / methanol = 100:1-60:1) to obtain the title compound (1, 2 g, 35.4%) as a yellow solid. 1H NMR (400 MHz, CDC13): δ 8.30-8.28 (m, 1H), 7.99-7.97 (m, 1H), 4.49 (s, 2H), 4.03 (s, 3H), 3.80-3.75 (m, 2H), 1.32-1.29 (m, 3H). LC-MS: m / z [M+H]+=221. Intermediate 95 6-Ethyl-2-(hydroxymethyl)-5Hpyrrolo[3,4-b]pyridin-7(6H)-one At 0 °C, methyl 6-ethyl-7-oxo-6,7dihydro-5H-pyrrolo[3,4-b]pyridine-2-carboxylate (1.2 g, 5 ml) was added sequentially in methanol (15 ml). .5 mmol) and a sodium borohydride starting material (627 mg, 16.5 mmol). The mixture was allowed to react overnight at room temperature. The reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 60:1-50:1) to obtain the title compound (420 mg, 39.8%) as a yellow oil. like a product. 1H-NMR (400 MHz, CDC13): δ 7.82 (d, J = 8.0 Hz, 1H), 7.45 (d, J= 8.0 Hz, 1H), 4.90-4.89 (m, 2H), 4.41 (s, 2H), 3.77-3.75 - 105 (m, 2H), 1.33-1.29 (m, 3H). LC-MS: m / z [M+H]+ = 193. Intermediate 96 Terebutyl 6-(Hydroxymethyl)-5',6'-dihydro-[2,3'-bipyridin]-1'(2' Ή)-carboxylate (6-bromopyridin-2-yl)methanol (450 mg, 2.39 mmol), 3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6- were added terebutyl dihydropyridine-l(2H)-carboxylate (500 mg, 2.39 mmol), Pd(dppf)C12 (146 mg, 0.2 mmol) and potassium carbonate (990 mg, 7.17 mmol) in dioxane and water (8 ml / 2 ml), and the mixture was stirred at 100 °C for 5 hours under nitrogen protection. The reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a compound (500 mg, 72%). LC-MS: m / z [M+H]+ = 291. Intermediate 97 Tere-butyl 3-(6-(Hydroxymethyl)pyridin-2-yl)piperidine-l-carboxylate Tere-butyl 6-(hydroxymethyl)-5',6'-dihydro-[2,3'-bipyridin]-1'(2'H)-carboxylate (500 mg, 1.72 mmol) was dissolved in methanol ( 10 ml), then 10% palladium carbon (50 mg) was added and the mixture was stirred at room temperature for 4 hours under hydrogen protection. The reaction solution was filtered, concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (350 mg, 70%). LC-MS: m / z [M+H]+ = 293. Intermediate 98 (6-(Piperidin-3-yl)pyridin-2-yl)methanol Terebutyl 3-(6-hydroxymethylpyridin-2-yl)-1-piperidinecarboxylate (1.13 g, 3.86 mmol) was dissolved in dichloromethane (10 ml), then added. - 106 trifluoroacetic acid (6 ml) and the mixture was reacted overnight at room temperature. The reaction solution was directly evaporated to dryness by rotary evaporation, dissolved in methanol and a potassium carbonate solid was added, and the mixture was stirred for 30 minutes, filtered. Alkaline alumina was added to the filtrate and subjected to column chromatography (dichloromethane:methanol = 10:1) to obtain the title compound (500 mg, 67%) as a pale yellow oil. LC-MS: m / z [M+H)+ = 193. Intermediate 99 (6-(l-Ethylpiperidin-4-yl)pyridin-2-yl)methanol 6-(piperidin-3-yl)pyridin-2-yl)methanol (200 g, 1 mmol), iodoethane (468 mg, 3 mmol) and cesium carbonate (1.0 g, 3 mmol) were added sequentially in 10 ml of acetonitrile, then the mixture was stirred at room temperature overnight. The solid cesium carbonate was filtered with diatomite and the organic phase was concentrated. The residue was purified by preparative TLC (dichloromethane:methanol = 5 / 1) to obtain the title compound (80 mg, 35%) as a colorless oil. LC-MS: m / z [M+H]+ = 221. Intermediate 100 Imidazo[1,2-b]pyridazin-6-ylmethanol Methyl methylimidazo[1,2-b]pyridazine-6-carboxylate (200 mg, 1.13 mmol) was added to a mixed solution of tetrahydrofuran (5 ml) and methanol (2 ml). Under argon protection, sodium borohydride (85 mg, 2.26 mmol) was dissolved in tetrahydrofuran and added dropwise to the above solution in an ice bath, then the mixture was reacted at 0 °C for 2 hours, and the reaction solution was diluted with sodium carbonate solution (30 ml), extracted with ethyl acetate (20 ml * 3 times). The organic phases were combined and, - 107 were then washed with saturated brine (batches of 10 ml). The organic phase was concentrated to obtain 110 mg of the title compound in a yield of 64.9%. LC-MS: m / z [M+H]+ = 150. Intermediate 101 (5-((Tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)methanol N-, A-O Methyl 5-hydroxypicolinate (306 mg, 2 mmol), 2(bromomethyl)tetrahydrofuran (990 mg, 6 mmol), and potassium carbonate (1.38 g, 10 mmol) were added sequentially in 30 ml of acetonitrile, and the experimental operation was the same as that of intermediate 5 to obtain 40 mg of the title compound as a colorless oil with a yield of 22%. LC-MS: m / z [M+H]+ = 210. Intermediate 102 2-(Hydroxymethyl)-6-(3-methoxypropyl)-7,8-dihydro-l,6-naphthyridin-5(6H)-one (5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)methanol (1 g, 6.1 mmol), l-bromo-3-methoxypropane (1 g, 6.7 mmol) were added sequentially. ) and potassium carbonate (2.52 g, 18.3 mmol) in 30 ml of acetonitrile, and then the mixture was stirred at 70 °C overnight. The mixture was filtered under reduced pressure, and the mother liquor was evaporated to dryness to obtain 820 mg of a yellow oil, which was dissolved in 160 ml of a mixed solvent of THF and water (THF / H2O = 2.5 / 1), then sodium bicarbonate (2.85 g, 33.9 mmol) and iodine (6.46 g, 25.43 mmol) were added sequentially, and then the mixture was stirred until the next day. room temperature. The mixture was neutralized with sodium thiosulfate until the color faded, extracted with DCM, and subjected to column chromatography to obtain 400 mg of colorless oil in a two-step yield of 47%. LC-MS: m / z [M+H]+ = 251. Intermediate 103 6-Ethyl-2-(hydroxymethyl)-7,8-dihydro-l,6-naphthyridin-5(6H)-one - 108 (5, 6, 7,8-tetrahydro-l,6-naphthyridin-2-yl)methanol (400 mg, 2.44 mmol), iodoethane (380 mg, 2.44 mmol) and potassium carbonate were added sequentially (1.01 g, 7.32 mmol) in 20 ml of acetonitrile, and the experimental operation was the same as that of intermediate 102 to obtain 60 mg of the title compound as a colorless oil with a two-stage yield of 12.5%. LC-MS: m / z [M+H]+ = 207. Intermediate 104 (6-(2-Methoxyethyl)-5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)methanol ^o7 (5, 6, 7,8-tetrahydro-l,6-naphthyridin-2-yl)methanol (650 mg, 3.96 mmol), l-bromo-2-methoxyethane (650 mg, 4.76 mmol) were added sequentially. ) and potassium carbonate (1.64 g, 12 mmol) in 20 ml of acetonitrile, and the experimental operation was the same as that of intermediate 102 to obtain 85 mg of the title compound as a colorless oil in a yield of 10 %. LC-MS: m / z [M+H]+ = 237. Intermediate 105 Terebutyl 6-(Hydroxymethyl)-5',6'-dihydro-[3,4'-bipyridin]-1'(2'B)-carboxylate (5-bromopyridin-2-yl)methanol (1.88 g, 10 mmol), 4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5, Tere-butyl 6-dihydropyridin-l(2H)-carboxylate (4.5 g, 15 mmol), cesium carbonate (6.5 g, 20 mmol) and Pd(dppf)2C12 (0.8 g, 1 mmol ) in 80 ml of dioxane, and then the mixture was stirred at 100 °C overnight under argon protection. TLC (dichloromethane–methanol = 20:1) showed complete reaction of the starting materials. The mixture was filtered with diatomite under reduced pressure, concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 3 g of the title compound as a colorless oil. LC-MS: [M+H]+ = 291. Intermediate 106 Tere-butyl 4-(6-(Hydroxymethyl)pyridin-3-yl)piperidine-l-carboxylate - 109 - Tere-butyl 6-(hydroxymethyl)-5',6'-dihydro-[3,4'-bipyridin]-1'(2Ή)-carboxylate (3 g, 10.3 mmol) was dissolved in 50 ml of methanol, then palladium carbon (200 mg) was added and the mixture was hydrogenated and stirred overnight at normal temperature and pressure. The mixture was filtered and concentrated to obtain 2 g of the title compound as a yellow oil. LC-MS: [M+H]+ = 293. Intermediate 107 (2-Amino-6-chloropyridin-3-yl)benzyl carbamate OI nA AI Η2Ν^γ HN. Cbz 6-Chloropyridin-2,3-diamine (2.27 g, 15.8 mmol) was dissolved in 150 ml of 1,4dioxane. Benzyl chloroformate (2.70 g, 15.8 mmol) was added and the mixture was stirred overnight in the dark. The reaction solution was filtered and the solid was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution and saturated brine, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography (petroleum ether: acetate of ethyl = 5:1) to obtain 1.20 g of a pale yellow solid with a yield of 27%. LC-MS: m / z [M+H]+ = 278. Intermediate 108 6-Chloro-N3-methylpyridine-2,3-diamine Benzyl (2-amino-6-chloropyridin-3-yl)carbamate (1.20 g 4.60 mmol) was dissolved in tetrahydrofuran (60 ml). Lithium aluminum hydride (0.66 g, 17.5 mmol) was slowly added in three batches, and the mixture was heated at reflux for 15 minutes. The reaction was quenched with water. The solution was adjusted to neutrality with - 110 an acetic acid, extracted with ethyl acetate, dried, concentrated and separated by column chromatography (petroleum ether:ethyl acetate = 8 / 1) to obtain 375 mg of the title compound in a yield of 52%. LC-MS: m / z [M+H] + = 158. Intermediate 109 5-Chloro-l-methyl-lg-imidazo[4,5-¿]pyridine Cl N X ú I N t-N 6-Chloro-N3-methylpyridin-2,3-diamine (150 mg, 0.96 mmol) was dissolved in formic acid (7.5 ml), then the mixture was heated at reflux for 3 hours, and the solvent it was deleted. The residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate and saturated brine, and dried with anhydrous sodium sulfate. After concentration, 150 mg of product was obtained with a yield of 93%. 1H-NMR (400 MHz, DMSO-J6) 3.88 (s, 3H) 7.37 (d, J= 8.31 Hz, IH) 8.14 (d, J = 8.31 Hz, IH) 8 .49 (s, IH). LC-MS: m / z [M+H]+ = 168. Intermediate 110 l-Methyl-lH-imidazo[4,5-¿]methyl pyridine-5-carboxylate 5-chloro-l-methyl-lH-imidazo[4,5-b]pyridine (100 mg, 0.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene dichloride, ]palladium (43 mg, 0.059 mmol) and triethylamine (180 mg, 1.78 mmol), and the mixture was reacted under an atmosphere of 5 MPa carbon monoxide at 120 °C overnight. Additional [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (43 mg, 0.059 mmol) was added and the reaction of the mixture was continued overnight. The reaction solution was diluted with dichloromethane, concentrated and separated by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 60 mg of the title compound as an orange oil in a yield of 53%. LC-MS: m / z [M+H]+ = 192. - 111 Intermediate 111 (1-Methyl-lH-imidazo[4,5-¿>]pyridin-5-yl) methanolH0^T Y > \ 5-chloro-l-methyl-lfi-imidazo[4,5-b]pyridine (100 mg, 0.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene dichloride were dissolved in methanol (5 ml). ]palladium (43 mg, 0.059 mmol) and triethylamine (180 mg, 1.78 mmol), and the mixture was reacted under an atmosphere of 5 MPa carbon monoxide at 120 °C overnight. Additional [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (43 mg, 0.059 mmol) was added and the reaction of the mixture was continued under an atmosphere of 5 MPa carbon monoxide at 120 °C until day following. The reaction solution was diluted with dichloromethane, concentrated and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain an oily compound (60 mg, 53%), which was dissolved in tetrahydrofuran (3 ml). , and lithium aluminum hydride (48 mg, 1.256 mmol) was added at 0 °C to react at room temperature overnight. The reaction solution was diluted with a small amount of ethyl acetate, then quenched with a small amount of water; The mixture was directly mixed with silica gel and separated by column chromatography (dichloromethane / methanol = 30 / 1) to obtain the title compound as an orange oil (34 mg, 66% yield). 1H-NMR (400 MHz, CDC13): δ 8.07 (s, 1H), 7.74-7.72 (m, 1H), 7.22-7.20 (m, 1H), 4.89 ( s, 2H), 3.89 (s, 3H). LC-MS: m / z [M+HJ+ = 192. Intermediate 112 Tere-butyl 6-Bromo-2g-pyrido[3,2-¿][1,4]oxazin-4 (3H)-carboxylate In dichloromethane (30 ml), 6-bromo-3,4-dihydro-2H-pyrido[3,2b] [l,4]oxazine (1.86 g, 8.65 mmol), 4-dimethylaminopyridine (0. 21 g, 1.73 mmol), triethylamine (1.75 g, 17.3 mmol), and the mixture was cooled to 0 to 10 °C in an ice bath under nitrogen protection. BOC anhydride (2.83 g, 12.97 mmol) was added slowly to the reaction solution, then the mixture was stirred at room temperature for 15 minutes, heated to 40 °C and reacted. - 112 for 3 hours. The reaction solution was quenched by adding water, extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, and then concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 12 / 1) to obtain the title compound as a white solid (2.64 g, 97%). 1H-NMR (400 MHz, DMSO-d6) δ 7.26-7.21 (m, 2H), 4.24 (t, J = 4 Hz, 2H), 3.81 (t, J = 4 Hz, 2H), 1.48 (s, 9H). Intermediate 113 4-tert-Butyl-6-methyl-2.Hpyrido[3,2-jb][1,4]oxazin-4,6(3.H)-dicarboxylate Methyl tert-butyl-6-bromo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-carboxylate (2.32 g, 7.36 mmol) was added to anhydrous methanol ( 50 mi). Triethylamine (2.23 g, 22.08 mmol), 1,1'bisdiphenylphosphinoferrocene palladium dichloride (0.54 g, 0.74 mmol) were added sequentially. Carbon monoxide was pumped in and purged to an internal pressure of 6.0 MPa, and the mixture was heated to 120 °C to react overnight. Water and dichloromethane were added to the reaction solution and the phases were separated. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the title compound (0.81 g, 37%). ) in the form of a white solid. 1H-NMR (400 MHz, DMSO-Ó6) δ 7.74 (d, J = 8 Hz, 1H) , 7.38 (d, J= 8 Hz, 1H) , 4.33 (t, J = 4 Hz , 2H) , 3.85 (t, J = 4 Hz, 2H) , 3.83 (s, 1H) , 1.50 (s, 9H) . LC-MS: m / z [M+H]+ = 295 Intermediate 114 Tere-butyl 6-(Hydroxymethyl)-2-pyrido[3,2-b][1,4]oxazin-4(3H)-carboxylate Yo boc Methyl 4-tert-butyl-6-methyl-2H-pyrido[3,2-b] [1,4]oxazin-4,6(3H) dicarboxylate (590 mg, 2.0 mmol) was added to anhydrous tetrahydrofuran (8 ml), and the mixture was cooled to between 0 and 10 °C in an ice bath under protection with - 113 nitrogen. After stirring for 30 minutes, diisobutyl aluminum hydride (1.0 M in n-hexane) (5.0 mL) was slowly added to the reaction solution, and the mixture was reacted in an ice bath for 2 hours. The reaction solution was quenched by adding water, extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1). to obtain the title compound (210 mg, 39%) as an off-white solid. CLEM: m / z [M+H]+ = 267. Intermediate 115 2-(2,6-Dichloropyridin-3-yl)acetonitrile 3-(Bromomethyl)-2,6-dichloropyridine (500 mg, 2.08 mmol) was added to DMF (10 ml), then the mixture was cooled to 0 °C, and sodium cyanide solution was added. (508 mg, 2.08 mmol) in water (2 ml), and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the title compound (180 mg, 46%). 1H-NMR (400 MHz, CDC13) δ 7.85 (d, J = 8.0 Hz, IH) , 7.37 (d, J= 8.0 Hz, IH) , 3.84 (s, 2H) . Intermediate 116 Dimethyl 3-(Cyanomethyl)pyridine-2,6-dicarboxylate 2-(2,6-dichloropyridin-3-yl) acetonitrile (180 mg, 0.963 mmol), Pd(dppf)C12 (73 mg, 0.1 mmol) and triethylamine (292 mg, 2.89 mmol) were added to methanol (4 ml), and then the mixture was reacted overnight under an atmosphere of 5 MPa carbon monoxide at 100 °C. The reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the title compound (100 mg, 44%). 1H-NMR (400 MHz, CDC13) δ 8.34 (d, J= 8.0 Hz, IH), 8.19 (d, J = 8.0 Hz, IH), 4.34 (s, 2H) , 4.03 (s, 6H) . - 114Intermediate 117 Methyl 8-Oxo-5,6,7,8-tetrahydro-l,7-naphthyridine-2-carboxylate O O The starting material dimethyl 3-(cyanomethyl)pyridine-2,6dicarboxylate (100 mg, 0.43 mmol) and Raney® nickel (51 mg, 0.86 mmol) in methanol (300 ml) were added sequentially. The mixture was reacted at 40 °C under an atmosphere of 0.34 MPa (50 psi) hydrogen pressure for 5 hours. The mixture was filtered under reduced pressure and the filtrate was evaporated to dryness by rotary evaporation to obtain a crude product which was reacted directly in the next step. CLEM: m / z [M+H]+ = 207. Intermediate 118 (5,6,7,8-Tetrahydro-l,7-naphthyridin-2-yl)methanol Methyl 8-oxo-5,6,7,8-tetrahydro-l,7-naphthyridine-2-carboxylate (500 mg, 2.42 mmol) was added to tetrahydrofuran (10 ml), and the mixture was cooled to 0 °C. A tetrahydrofuran solution of lithium aluminum hydride (4.84 mL, 4.84 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was cooled to 0 °C and ethyl acetate was added dropwise, then water was added and the reaction solution was concentrated to obtain a crude product (1.0 g, 100%). Intermediate 119 Tere-butyl 2-(Hydroxymethyl)-5,6-dihydro-l,7-naphthyridine-7-(8H)-carboxylate (5, 6, 7,8-tetrahydro-l, 7-naphthyridin-2-yl)methanol (1.0 g, 6.1 mmol), di-tere-butyl dicarbonate (1.33 g, 6.1 mmol) were added. .1 mmol) and triethylamine (1.85 g, 18.3 mmol) to dichloromethane, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated and subjected to column chromatography to obtain a product (50 mg, 8%). LC-MS: m / z [M+H]+ = 265. Intermediate 120 (6-(1-(Oxetan-3-yl)-3-piperidinyl)pyridin-2-yl)methanol - 115 - (6-(piperidin-3-yl)pyridin-2-yl)methanol (100 mg, 0.52 mmol) was dissolved in dichloromethane (3 ml), and 1 drop of acetic acid was added dropwise. Next, oxetan-3-one (116 mg, 1.56 mmol) was added and the mixture was reacted at room temperature for 30 minutes, and then sodium triacetoxyborohydride (330 mg, 1.56 mmol) was added. ) and the mixture was reacted at room temperature until the next day. The reaction solution was directly filtered, concentrated, and the filtrate was subjected to thin layer chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (100 mg, 77%) as a colored oil. yellow. LC-MS: m / z [M+H]+ = 249. Intermediate 121 Methyl 6-(1-(tert-Butoxycarbonyl)-3-hydroxypyrrolidin-3-yl)picolinate 2,6-Dibromopyridine (7.0 g, 29.55 mmol) was added to tetrahydrofuran (70 ml) and the mixture was cooled to -78 °C, then n-butyllithium (13 ml) was added dropwise. , 32.5 mmol); The mixture was stirred at -78 °C for 30 minutes, and then tere-butyl 3-oxopyrrolidine-l-carboxylate (5.47 g, 32.5 mmol) was added and the mixture was heated naturally until room temperature and reacted for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated and subjected to column chromatography to obtain a product, 3-(6-bromopyridin-2-yl)-3hydroxypyrrolidin-l -tere-butyl carboxylate (3.0 g); Next, the product, Pd(dppf)C12 (637 mg, 0.87 mmol) and triethylamine (2.65 g, 26.22 mmol) were added to methanol (50 ml), and the mixture was reacted at 80 °C until the next day under an atmosphere of 1 MPa carbon monoxide. The reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (1.5 g, two-step yield of 16%). LC-MS: m / z [M+H]+ = 323. - 116 Intermediate 122 Tere-butyl 3-(6-(Hydroxymethyl)pyridin-2-yl)pyrrolidine-l-carboxylate H0.1Nn^Boc Methyl 6-(1-(tert-butoxycarbonyl)-3-hydroxypyrrolidin-3-yl)picolinate (860 mg, 2.67 mmol) and triethylamine (809 mg, 18.01 mmol) were dissolved in dichloromethane (10 ml). , then the mixture was cooled to 0 °C and methanesulfonyl chloride (397 mg, 3.47 mmol) was added, and then the mixture was reacted at room temperature overnight. The reaction solution was poured into water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 430 mg of a pale yellow solid. The pale yellow solid was dissolved in methanol (8 ml) and palladium / carbon (800 mg) was added, then the mixture was reacted overnight at 50 °C under a hydrogen atmosphere. The reaction solution was filtered to remove palladium / carbon. The filtrate was evaporated to dryness by rotary evaporation to obtain 440 mg of a crude product in the form of a gray a, and 200 mg of the crude product was taken and dissolved in tetrahydrofuran (2 ml). Diisobutyl aluminum hydride (1 M, 1.95 ml, 1.95 mmol) was added in an ethanolic ice bath, and the mixture was reacted for two hours at 0 °C. The reaction solution was poured into water, extracted with dichloromethane. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated and separated by column chromatography (dichloromethane / methanol = 50 / 1) to obtain 90 mg of a yellow oil with a multistage yield of 25%. LC-MS: m / z [M+H]+ = 279. Intermediate 123 (5-(3-Fluoro-l-methylazetidin-3-yl)pyridin-2-yl)methanol N— - 117 (5-(3-fluoroazanyl-3-yl)pyridin-2-yl)methanol (600 mg, 3.3 mmol) was dissolved in dichloromethane (6 ml). 1 drop of acetic acid and an aqueous solution of formaldehyde (1.5 ml) were added, and the mixture was reacted at room temperature for 30 minutes, then sodium triacetoxyborohydride (2 g, 9.9 ml) was added. mmol), and the mixture was allowed to react at room temperature until the next day. The reaction solution was evaporated to dryness by rotary evaporation and dissolved in methanol, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain 100 mg of the title compound as a yellow oil. with a yield of 13%. LC-MS: m / z [M+H]+ = 197. Intermediate 124 Tere-butyl 3-(6-Brcmqpyridin-2-yl)-3-hydroxypyrrolidin-l-carboxylate boc 2,6-Dibromopyridine (7.0 g, 29.55 mmol) was added to tetrahydrofuran (70 ml) and the mixture was cooled to -78 °C, then n-butyllithium (13 ml) was added dropwise. , 32.5 mmol) and the mixture was stirred at -78 °C for 30 minutes, and then 2 (5.47 g, 32.5 mmol) was added and the mixture was allowed to warm naturally to temperature environment and reacted for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 3.0 g of the compound. of the title with a yield of 30%. LC-MS: m / z [M+H-56]+ = 289. Intermediate 125 Methyl 6-(1-(tert-Butoxycarbonyl)-3-hydroxypyrrolidin-3-yl)picolinate - 118 Terebutyl 3-(6-bromopyridin-2-yl)-3-hydroxypyrrolidin-l-carboxylate (3.0 g, 8.74 mmol), Pd(dppf)C12 (637 mg, 0.87 mmol) were added. mmol) and triethylamine (2.65 g, 26.22 mmol) to methanol (50 ml), and the mixture was reacted at 80 °C under an atmosphere of 1 MPa carbon monoxide overnight. The reaction solution was concentrated and separated by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (1.5 g, 54%). LC-MS: m / z [M+H]+ = 323. Intermediate 126 tert-butyl 3-Fluoro-3-(6-(hydroxymethyl)pyridin-2-yl)pyrrolidine-l-carboxylate boc x Methyl 6-(1-(tert-butoxycarbonyl)-3-hydroxypyrrolidin-3-yl)picolinate (500 mg, 1.55 mmol) was added to dichloromethane (10 ml), and the mixture was cooled to 0°C. DAST (375 mg, 2.33 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, and the pH was adjusted to 8, then the mixture was extracted with dichloromethane. The organic phase was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 300 mg of a compound, which was added to tetrahydrofuran (5 ml), cooled to 0 °C . DIBAL-H (2.8 ml, 2.78 mmol) was added dropwise and the reaction was carried out for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated and separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the title compound ( 120 mg, a two-stage yield of 26.4%). LC-MS: m / z [M+H]+ = 297. Intermediate 127 (5-(3-Fluorazanil-3-yl)pyridin-2-yl)methanolN=\ E He / V-NH Tere-butyl 3-fluoro-3-(6-(hydroxymethyl)pyridin-3-yl)azetidine-l-carboxylate (500 mg, 1.77 mmol) was dissolved in dichloromethane (3 ml), and acid was added. - 119 trifluoroacetic acid (1 ml), then the mixture was reacted at room temperature for 1 hour. Additional trifluoroacetic acid (1 ml) was added to react at room temperature for 2 hours. The reaction solution was directly evaporated to dryness by rotary evaporation, then dissolved in methanol and a potassium carbonate solid was added, and the mixture was stirred for 30 minutes, filtered, evaporated to dryness by rotary evaporation, was subjected to alkaline alumina column chromatography (dichloromethane / methanol = 5 / 1) to obtain 200 mg of the title compound as a yellow oil in a yield of 62%. 1H-NMR (400 MHz, CDC13) δ 8.78 (s, 1H) , 7.90 (d, J= 9.6 Hz, 1H) , 7.327 (d, J= 8.4 Hz, 1H) , 4 .79 (s, 2H), 4.29-4.21 (m, 2H), 3.91-3.84 (m, 2H), 2.53-2.22 (m, 2H). Intermediate 128 (5-(3-Fluoro-l-(oxetan-3-yl)azetidin-3-yl)pyridin-2-yl)methanol (5-(3-fluoroazetidin-3-yl)pyridin-2-yl)methanol (150 mg, 0.81 mmol) was dissolved in dichloromethane (3 ml), and 1 drop of acetic acid was added dropwise. Next, oxetan-3-one (179.8 mg, 2.43 mmol) was added and the mixture was reacted at room temperature for 30 minutes, and then sodium triacetoxyborohydride (515 mg, 2.43 mmol) was added. 43 mmol) and the mixture was reacted at room temperature overnight. The reaction solution was poured into water, extracted with dichloromethane, dried with anhydrous sodium sulfate, concentrated, and separated by preparative column chromatography (dichloromethane / methanol = 20 / 1) to obtain 80 mg of the title compound. fit of a yellow solid in a yield of 30% Intermediate 129 5-Methyl-l,2,4-oxadiazol-3-carbohydrazide O and- Η N-O . LC-MS: m / z [M+H]+ = 239. Ethyl 5-methyl-1,2,4-oxadiazol-3-carboxylate (10 g, 64.1 mmol) was dissolved in ethanol (100 ml), and hydrazine hydrate (2.46 g) was added dropwise. , 76, 92 mmol, 99%) in an ice bath and at room temperature for 16 hours. The solution -120 reaction was filtered, and the filter cake was washed with ethanol, dried to obtain 7.2 g of the title compound with a yield of 78.5%. LC-MS: m / z [M+H]+ = 143. Intermediate 130 3-(6-Chloro-7-methoxy-[1,2,4]triazolo[4,3-.b]pyridazin-3-yl)-5-methyl-l,2,4oxadiazole 3,6-Dichloro-4-methoxypyridazine (1 g, 5.62 mmol) and 5-methyl-l,2,4oxadiazole-3-carbohydrazide (797 mg, 5.62 mmol) were dissolved in tert-butanol (20 ml ), then methanesulfonic acid (1.08 g, 11.24 mmol) was added, and the mixture was reacted at 85 °C for 16 hours under argon protection. The reaction solution was cooled, concentrated, and separated by column chromatography to obtain 36 mg of the title compound in a yield of 2.4%. LC-MS: m / z [M+H]+ =267. Intermediate 131 Methyl 1,6-Naphthyridine-2-carboxylate EITHER 4-Amino-3-pyridinecarbaldehyde (5.0 g, 41 mmol), sodium pyruvate (4.56 g, 41 mmol) and sodium hydroxide (0.62 g, 16 mmol) were dissolved in ethanol (300 ml); After the addition was complete, the mixture was heated to 70 °C and reacted for 5 hours. After the reaction was completed, the reaction solution was filtered, and the filter cake was rinsed with a small amount of ethanol and dried to obtain 7.83 g of a solid compound; The solid compound and concentrated sulfuric acid (9.0 ml) were dissolved in methanol (350 ml). Once the addition was complete, the mixture was heated to reflux and reacted for 3 hours. After the reaction was completed, most of the solvent was concentrated, then 150 ml of water was added to the residue and a saturated solution of sodium bicarbonate was added to adjust the pH value of the system to 8-9, at - 121 The mixture was then extracted with dichloromethane (400 ml * 2 times). The organic phases were combined and then washed with saturated brine (400 ml * 1 time). The organic phase was dried and concentrated to obtain 6.4 g of the title compound in a two-step yield of 83%. LC-MS: m / z [M+H]+ = 189.07. Intermediate 132 Methyl 5-Oxo-5,6-dihydro-l,6-naphthyridine-2-carboxylate Methyl 1,6-naphthyridine-2-carboxylate (5.1 g, 27 mmol) and mchloroperoxybenzoic acid (9.36 g, 54 mmol) were added to dichloromethane (75 mL), and the mixture was stirred at room temperature. for 2 hours. After the reaction was complete, saturated aqueous sodium carbonate solution (150 ml) was added and the mixture was stirred for 15 minutes, then allowed to stand for layer separation. The organic phase was separated, then an aqueous phase was extracted with dichloromethane (200 ml *3 times), and the organic phases were combined, then washed with saturated brine (300 ml *1 times). The organic phase was dried and evaporated to dryness by rotary evaporation to obtain a solid compound, which was dissolved in acetic anhydride (110 ml). After the addition was complete, the mixture was heated to 140 °C and stirred for 4 hours, then the system was cooled to 100 °C; Water (40 ml) was added and the reaction mixture was stirred for 0.5 hour, then the system was cooled to room temperature; Water (100 ml) was added to the reaction system, followed by extraction with ethyl acetate (250 ml * 3 times). The organic phases were combined and then washed with saturated brine (300 ml * 1 time). The organic phase was dried and concentrated to obtain 2.66 g of the title compound in a two-step yield of 48%. LC-MS: m / z [M+H]+ = 205.11. Intermediate 133 2-(Hydroxymethyl)-6-(2-methoxyethyl)-1,6-naphthyridin-5(6H)-one - 122 O Methyl 5-oxo-5,6-dihydro-l,6-naphthcridine-2-carboxylate (200 mg, 0.98 mmol) and l-bromo-2-methoxyethane (135 mg, 0.98 mmol) were dissolved in N,N-dimethylformamide (5 ml), and sodium hydride (58 mg, 1.47 mmol, 60%) was added, then the mixture was reacted at room temperature for 3 hours. The reaction solution was quenched with water, extracted with ethyl acetate (10 ml * 3 times), and the organic phases were combined and then washed with saturated brine (15 ml * 1 time). The organic phase was dried and concentrated to obtain a solid compound, which was dissolved in a mixed solution of tetrahydrofuran (5 ml) and methanol (5 ml), and sodium borohydride (87 mg, 2.29 mmol) was added. and the mixture was reacted at room temperature for 1 hour. Methanol was added to the reaction solution to inactivate it, and it was separated by column chromatography to obtain 82 mg of the title compound with a two-step yield of 36.2%. LC-MS: m / z [M+H]+ = 235. Intermediate 134 Methyl 5-(2-Bromoethoxy)picolinate Or Av Methyl 5-hydroxypicolinate (3 g, 19.5 mmol) and 1,2-dibromoethane (10.9 g, 58.5 mmol) were dissolved in N,W-dimethylformamide (50 ml), then added. cesium carbonate (6.3 g, 19.5 mmol) and the mixture was reacted overnight at 60 °C under argon protection. The reaction solution was cooled and water was added, extracted with ethyl acetate (20 ml * 3 times). The organic phases were combined and then washed with saturated brine (25 ml * 1 time). The organic phase was dried and concentrated to obtain 2.5 g of the title compound in a yield of 49.5%. LC-MS: m / z [M+H]+ = 259. Intermediate 135 (5-(2-(Azetidin-l-yl)ethoxy)pyridin-2-yl)methanol Methyl 5-(2-bromoethoxy)picolinate (100 mg, 0.39 mmol) was dissolved in tetrahydrofuran (10 ml), and sodium borohydride (30 mg, 0.78 mmol) was added, then the mixture was reacted at 50 °C for 5 hours. The reaction solution was quenched with methanol, evaporated to dryness by rotary evaporation, extracted with dichloromethane (10 ml * 3 times). The organic phases were combined and then washed with saturated brine (15 ml * 1 time). The organic phase was dried and concentrated to obtain 65 mg of a compound; The compound and azetidine (48 mg, 0.85 mmol) were dissolved in acetonitrile (10 ml) and then the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated to obtain 35 mg of the title compound with a two-step yield of 39%. LC-MS: m / z [M+H]+ = 209. Intermediate 136 Methyl 5-(Azetidin-3-yloxy)picoIinate trifluoroacetate Methyl 5-hydroxypicolinate (2 g, 13.0 mmol) and tere-butyl 3-iodoazetidine 1-carboxylate (7.4 g, 26.0 mmol) were dissolved in N,N-dimethylformamide (100 mL), then , cesium carbonate (8.4 g, 26 mmol) and cuprous iodide (2.5 g, 13 mmol) were added, respectively, and the mixture was reacted overnight at 100 °C under argon protection. The reaction solution was cooled and filtered with diatomite, washed with water and dichloromethane. The filtrate was extracted with dichloromethane (50 ml * 3 times) and the organic phases were combined, then washed with saturated brine (30 ml * 1 time). The organic phase was evaporated to dryness by rotary evaporation and separated by column chromatography to obtain 1.92 g of compound in a yield of 47.8%. 1 g of the compound was taken and dissolved in dichloromethane (20 ml), then trifluoroacetic acid (5 ml) was added and the mixture was reacted at room temperature for 3 hours. The reaction solution was evaporated to dryness by rotary evaporation and ethyl acetate was added, then evaporated - 124 to dryness by rotary evaporation, and toluene was added, then evaporated to dryness by rotary evaporation to obtain 1.04 g of the title compound in a yield of 100%. LC-MS: m / z [M+H] + = 209. Intermediate 137 (5-((l-Ethylazetidin-3-iI)oxy)pyridin-2-iI)methanol Methyl 5-(azetidin-3-yloxy)picolinate (1.04 g, 3.23 mmol) was dissolved in tetrahydrofuran (10 ml), and a tetrahydrofuran solution of acetaldehyde (6.26 ml, 6.26 ml) was added. 26 mmol), then sodium triacetoxyborohydride (2.05 g, 9.69 mmol) was added and the mixture was reacted at room temperature for 16 hours after the addition was complete. The reaction solution was concentrated and separated by column chromatography to obtain 283 mg of compound with a yield of 37.0%. The compound (113 mg, 0.55 mmol) was taken and dissolved in a mixed solution (4 ml) of tetrahydrofuran and methanol, then sodium borohydride (150 mg, 4 mmol) was added to react at room temperature for 6 hours. The reaction solution was quenched by adding ammonium chloride solution, extracted with ethyl acetate (10 ml * 3 times). The organic phases were combined, then washed with saturated saline (15 ml * 1 time). The organic phase was dried and concentrated to obtain 25 mg of the title compound in a yield of 21.8%. LC-MS: m / z [M+H]+ = 209. Intermediate 138 Imidazo[l ,2]pyridin-5-ylmethanol .OH Wn Imidazo[l,2]pyridine-5-carboxylate (100 mg, 0.62 mmol) was dissolved in tetrahydrofuran (5 ml), and lithium aluminum hydride (35 mg, 0.93 mmol) was added in a bath. of ice, then the mixture was reacted at room temperature for 2 hours under protection with argon, 15 ml of water and 15 ml of a 15% sodium hydroxide solution were added to the reaction solution to inactivate it, and The mixture was extracted with dichloromethane (20 ml * 3 times). The organic phases were combined and then washed with saturated brine (15 ml - 125 * 1 time). The organic phase was dried, concentrated and separated by column chromatography to obtain 45 mg of the title compound in a yield of 48.7%. LC-MS: m / z [M+H]+ = 149. Intermediate 139 (6-Methoxyquinolin-2-yl)methanol The starting material 6-methoxyquinoline-2-carboxylate (203 mg, 1 mmol) was added to anhydrous tetrahydrofuran (20 ml), then lithium aluminum hydride (60 mg, 1.5 mmol) was added and the mixture was stirred at room temperature for 1 hour. 3 drops of water were added to inactivate excess lithium aluminum hydride, and the mixture was filtered under reduced pressure. The filtrate was evaporated to dryness by rotary evaporation and purified by preparative plate to obtain 30 mg of the title compound as a colorless liquid in a yield of 15.8%. LC-MS: m / z [M+H]+ = 190. Intermediate 140 (1,6-Naphthyridin-2-yl)methanol Methyl 1,6-naphthyridine-2-carboxylate (200 mg, 1.06 mmol), methanol (4 ml), sodium borohydride (200 mg, 5.26 mmol) were dissolved in tetrahydrofuran (12 ml). After the addition was completed, the mixture was stirred at room temperature for 1.5 hours, and separated with a chromatographic column to obtain 62 mg of the title compound in a yield of 36.5%. LC-MS: m / z [M+H]+ = 161.10. Intermediate 141 (6-(Oxetan-3-yl)-5,6,7,8-tetrahydro-l,6-naphthalen-2-yl)methanol (5, 6, 7,8-tetrahydro-l,6-naphthalen-2-yl)methanol (400 mg, 2.44 mmol), oxetan-3-one (878.4 mg, 12.2 mmol) were added and sodium triacetoxyborohydride (2.58 g, 12.2 mmol) to 1,2-dichloroethane (40 ml), and the mixture was stirred for 15 hours. The mixture was added to a saturated sodium bicarbonate solution and stirred, extracted with - 126 dichloromethane (20 ml * 5), was concentrated and separated by preparative thin layer chromatography to obtain 140 mg of the title compound in a yield of 26.1% and a yellow solid appearance. LC-MS: m / z [M+H]+ = 221. Intermediate 142 2-(Hydroxymethyl)-6-(oxetan-3-yl)-7,8-dihydro-l,6-naphthyridin-5(6H)-one (6-(oxetan-3-yl)-5,6,7,8-tetrahydro-l,6-naphthalen2-yl)methanol (140 mg, 0.64 mmol), sodium bicarbonate (537.6 mg , 6.4 mmol) and iodine (1219.4 mg, 4.8 mmol) in 13 ml of a THF / H2O (2.5:1) solution, and the mixture was stirred at room temperature for 5 hours. A solution of Na2S2O3 was added dropwise until the reaction solution vanished, and the mixture was extracted with dichloromethane (10 ml * 5); The organic phases were combined, concentrated and separated by preparative thin layer chromatography to obtain 30 mg of the title compound in 20.0% yield and a colorless solid appearance. LC-MS: m / z [M+H]+ = 235. Intermediate 143 2-(Hydroxymethyl)-6-methyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one EITHER (5,6,7,8-tetrahydro-l,6-naphthalen-2-yl)methanol (400 mg, 1.68 mmol) and a 37 wt% formaldehyde solution (102.28 mg, 3) were added. .66 mmol) to methanol (10 ml). NaBH4 (369 mg, 9.76 mmol) was added portionwise in an ice-water bath, and the mixture was stirred for 1 hour. 5 ml of acetone was added and the mixture was stirred for 10 min, filtered with diatomite, concentrated and separated by preparative thin layer chromatography to obtain 230 mg of a yellow solid. 200 mg of the yellow solid, sodium bicarbonate (924 mg, 11 mmol) and iodine (2.1 g, 8.3 mmol) in 35 ml of a THF / H2O solution (2.5:1) were sequentially added. , and the mixture was stirred at room temperature for 5 hours. A solution of sodium thiosulfate was added drop by drop until the - 127 reaction solution was drained, and the mixture was extracted with dichloromethane (10 ml * 5); The organic phases were combined and concentrated to obtain 70 mg of the title compound in a two-step yield of 25% and a yellow solid appearance. LC-MS: m / z [M+H]+ = 193. Intermediate 144 2-(Hydroxymethyl)-6-(oxetan-3-yl)-1,6-naphthyridin-5(6H)-one Methyl 5-oxo-5,6-dihydro-l,6-naphthyridine-2-carboxylate (204 mg, 1.0 mmol), sodium hydride (60%) (80%) were dissolved in DMF (12.0 ml). mg, 2.0 mmol) and 3-iodooxetane (920 mg, 5.0 mmol). After the addition was complete, the mixture was heated to 50 °C and stirred for 3 hours. After the reaction was completed, water (50 ml) was added to the reaction system and then the mixture was extracted with ethyl acetate (50 ml * 2 times); The organic phases were combined and then washed with saturated brine (30 ml * 1 time). The organic phase was dried, concentrated and separated by column chromatography to obtain 18.0 mg of compound; The compound and sodium borohydride (80 mg, 2.35 mmol) were dissolved in a mixed solution of tetrahydrofuran and methanol (tetrahydrofuran:methanol =4:1) (10 ml). Once the addition was complete, the mixture was stirred and reacted at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was separated by column chromatography to obtain 10.0 mg of the title compound with a two-step yield of 4.3%. LC-MS: m / z [M+H]+ = 233.08. Intermediate 145 (5-Ethoxy-l,6-naphthalen-2-yl)methanol Methyl 5-oxo-5,6-dihydro-l,6-naphthyridine-2-carboxylate (200 mg, 1.0 mmol) was dissolved in phosphorus oxychloride (3.0 ml), and the temperature of the system was raised up to 80 °C, then the mixture was stirred and reacted for 4 hours. After the reaction was complete, the excess phosphorus oxychloride from the - 128 system was removed by distillation. Ethanol (20.0 ml) was then added to the residue and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, excess ethanol from the system was removed by distillation under reduced pressure. Water (20 ml) was added to the system, followed by extraction with ethyl acetate (40 ml * 2 times); The organic phases were combined and then washed with saturated brine (30 ml *1 time). The organic phase was dried and concentrated to obtain 200 mg of crude compound. 170 mg of the crude product and sodium borohydride (140 mg, 3.68 mmol) were dissolved in a mixed solution of tetrahydrofuran and methanol (tetrahydrofuran:methanol = 4:1) (10 ml). Once the addition was complete, the mixture was stirred and reacted at room temperature for 2.0 hours. After the reaction was completed, the reaction solution was concentrated and separated by column chromatography to obtain 147.0 mg of the title compound with a yield of 98.3%. LC-MS: m / z [M+H]+ = 205.11. Intermediate 146 Methyl 3,4-Dihydro-2g-pyrido[3,2-jb][l,4]oxazin-6-carboxylate Tere-butyl 6-bromo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-carboxylate (2.32 g, 7.36 mmol) was added to anhydrous methanol (50 ml ). Triethylamine (2.23 g, 22.08 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (0.54 g, 0.74 mmol) were added sequentially. Carbon monoxide was pumped in and purged to an internal pressure of 6.0 MPa, and the mixture was heated to 120 °C and reacted overnight. Water and dichloromethane were added to the reaction solution, and the phases were separated. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (0.87 g, 61%). ) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.26-7.24 (m, 2H),7.02 (d, J=8Hz, 1H), 4.17 (t, J = 4 Hz, 2H) ), 3.77 (s, 3H), 3, 42-3, 40 (m, 2H). LC-MS: m / z [M+H]+ = 195 Intermediate 147 Methyl 4-Methyl-3,4-dihydro-2g-pyrido[3,2-jb][l,4]oxazin-6-carboxylate - 129 - Methyl 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-carboxylate (194 mg, 1.0 mmol) was added to W,W-dimethylformamide (3 ml), and the agitation began. Cesium carbonate (488 mg, 1.5 mmol) and methyl iodide (142 mg, 1.0 mmol) were added sequentially to the reaction solution. under nitrogen protection, the reaction was heated to 40 °C and carried out overnight. The reaction solution was quenched by adding water, extracted with ethyl acetate; The organic phase was dried with anhydrous sodium sulfate, concentrated and separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the title compound as a yellow solid (42 mg , twenty %). LC-MS: m / z [M+H]+ = 209. Intermediate 148 4-Methyl-3,4-dihydro-2H-pyrido[3,2-jb] [l,4]oxazin-6~ylmethanol (nXY°h At 0 °C, methyl 4-methyl-3,4dihydro-2H-pyrido[3,2-b] [1,4]oxazin-6-carboxylate (71 mg, 0.2 ml) was added sequentially to tetrahydrofuran (2 ml). 34 mmol) and lithium aluminum hydride (38.8 mg, 1.02 mmol). The reaction was carried out for 2 h. Water was added to the reaction solution to quench the reaction, concentrated and separated by column chromatography (dichloromethane / methanol = 100:1-80:1) to obtain the title compound as a colored oil. yellow (53 mg, 86.9%) as a product. 1H-NMR (400 MHz, CDC13): δ 6.89 (d, J= 8.0 Hz, 1H), 6.39 (d, J= 7.6 Hz, 1H), 4.55 (s, 2H) ), 4,254.23 (m, 2H), 3.65-3.64 (m, 1H), 3.46-3.44 (m, 2H), 3.15 (s, 3H). LC-MS: m / z [M+H]+ = 181. Intermediate 149 (6-((3-Methylpyridin-3-yl)methoxy)pyridazin-3-yl)methanol - 130 Methyl 6-chloropyridazine-3-carboxylate (500 mg, 2.90 mmol) and (3-methylpyridin-3-yl)methanol (3 g, 29 mmol) were dissolved in acetonitrile (30 ml), and added cesium carbonate (1.9 g, 5.8 mmol), then the mixture was reacted at room temperature for 3 hours. 25 ml of water was added to the reaction solution and the mixture was extracted with ethyl acetate (20 ml * 3 times). The organic phases were combined, dried, concentrated and separated by column chromatography to obtain 250 mg of a colorless oil. The colorless oil was dissolved in a mixed solution of tetrahydrofuran (10 ml) and methanol (10 ml); Sodium borohydride (119 mg, 3.15 mmol) was added and the mixture was reacted at room temperature for 3 hours. The reaction solution was directly concentrated, separated, and purified by a chromatographic column to obtain the title compound (120 mg, two-step yield of 20%) as a colorless oil. LC-MS: m / z [M+H]+ = 211. Intermediate 150 Ethyl 6-(Brcmcmethyl)pyridazine-3-carboxylate Ethyl 6-methylpyridazine-3-carboxylate (460 mg, 2.8 mmol), NBS (605 mg, 3.4 mmol) and AIBN (49 mg, 0.3 mmol) in DME (6 ml) were added sequentially. and the mixture was heated to 80°C and stirred for 0.5 hours. The reaction mixture was poured into water, extracted three times with ethyl acetate and the combined organic phase was washed three times with water and washed once with saturated brine. The organic phase was dried and concentrated to obtain a crude product, and the crude product was separated by thin layer chromatography to obtain the title compound (400 mg, 58%) as a reddish-brown solid. . LC-MS: m / z [M+H]+ = 245 / 247. Intermediate 151 6-(methoxymethyl)pyridazine-3-carboxylic acid Ethyl 6-(bromomethyl)pyridazine-3-carboxylate (400 mg, 1.6 mmol) and a 1.8 M methanol solution of sodium methoxide (3.5 ml, 6.4 mmol) were dissolved in methanol (3 .5 ml), and the mixture was stirred at room temperature for 16 hours. The reaction solution was acidified to pH = 5 to 6 and dichloromethane was added -131 (35 ml) to dilute it, then the mixture was filtered through diatomite and the filtrate was concentrated to obtain the title compound (340 mg, crude product) as a pale yellow oil. LC-MS: m / z [M+HJ+ = 169. Intermediate 152 Methyl 6-(Methoxymethyl)pyridazine-3-carboxylate MeO2C^N, 6-(methoxymethyl)pyridazine-3-carboxylic acid (340 mg, crude product), oxalyl chloride (432 mg, 3.4 mmol) and a catalytic amount of DMF in dichloromethane (5 ml) were added sequentially, and the Reaction mixture was stirred at room temperature for 0.5 hour. Methanol (5 ml) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated sodium bicarbonate (40 ml), extracted three times with dichloromethane and the combined organic phase was washed once with saturated brine. The organic phase was dried and concentrated to obtain a crude product, and the crude product was separated by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (153 mg, a two-stage yield of 51%). LC-MS: m / z [M+H]+ = 183. Intermediate 153 (6-(Methoxymethyl)pyridazin-3-yl)methanol Methyl 6-(methoxymethyl)pyridazine-3-carboxylate (153 mg, 0.82 mmol) was dissolved in tetrahydrofuran (8 mL) and methanol (2 mL), then sodium borohydride (240 mg, 6.0 mL) was dissolved. 3 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction solution was filtered through diatomite, and the filtrate was concentrated and separated by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (95 mg, 75%) as of a pale yellow oil. LC-MS: m / z [M+H]+ = 155. Intermediate 154 (6-((Tetrahydro-2H-pyran-4-yl)oxy)pyridazin-3-yl)methanol - 132 .OH Methyl 6-chloropyridazine-3-carboxylate (500 mg, 2.90 mmol) and tetrahydro-2H-pyran-4-ol (1.48 g, 14.5 mmol) were dissolved in acetonitrile (50 ml), and Cesium carbonate (1.9 g, 5.8 mmol) was added, and the mixture was reacted at room temperature for 3 hours. 25 ml of water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate (30 ml * 3 times). The organic phases were combined, dried, concentrated and separated by column chromatography to obtain 180 mg of a colorless oil. The colorless oil was dissolved in a mixed solution of tetrahydrofuran (5 ml) and methanol (5 ml), and then sodium borohydride (86 mg, 2.27 mmol) was added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was directly concentrated, separated, and purified by a chromatographic column to obtain the title compound (134 mg, 84%) as a colorless oil. LC-MS: m / z [M+H]+ = 211. Intermediate 155 (6-(Oxetan-3-yloxy)pyridazin-3-yl)methanol N-N Methyl 6-chloropyridazine-3-carboxylate (2.9 g, 16.8 mmol), oxetan-3-ol (2.5 g, 33.7 mmol) and cesium carbonate (17.2 g, 52 mmol) were added. .8 mmol) in acetonitrile (80 ml), and the mixture was stirred at room temperature for 4 hours. Dichloromethane (200 ml) was added to the reaction solution, stirred for 0.5 h and then filtered. The filtrate was concentrated under reduced pressure to obtain 5.0 g of crude aster product. 3.5 g of the crude product of aster and sodium borohydride (1.9 g, 50.0 mmol) in methanol (20 mL) and tetrahydrofuran (80 mL) were added, then the mixture was stirred at room temperature. During 4 hours. The reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to obtain 3.5 g of a - 133 crude product of the title compound in the form of a yellow oil. LC-MS: m / z [M+H]+ = 183.1 Intermediate 156 (6-((Tetrahydrofuran-3-yl)oxy)pyridazin-3-yl)methanol Methyl 6-chloropyridazine-3-carboxylate (500 mg, 2.90 mmol) and tetrahydrofuran-3-ol (1.3 g, 14.5 mmol) were dissolved in acetonitrile (50 ml), and sodium carbonate was added. cesium (1.9 g, 5.8 mmol), then the mixture was reacted at room temperature for 3 hours. 25 ml of water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate (30 ml * 3 times). The organic phases were combined, dried, concentrated and separated by column chromatography to obtain 130 mg of compound as a colorless oil. The compound was dissolved in a mixed solution of tetrahydrofuran (10 ml) and methanol (5 ml), then sodium borohydride (50 mg, 1.28 mmol) was added and the mixture was reacted at room temperature for 3 hours. The reaction solution was directly concentrated, separated, and purified by a chromatographic column to obtain the title compound (83 mg, two-step yield of 15.6%) as a colorless oil. LC-MS: m / z [M+H]+ =197. Intermediate 157 6-Chloro-3-(3-methoxypropoxy)-4-methylpyridazine and 3-chloro-6-(3-methoxypropoxy)-4methylpyridazine N=N n=N and \ Y 3,6-Dichloro-4-methylpyridazrna (3 g, 18.4 mmol) and 3-methoxypropanyl-ol (1.82 g, 20.24 mmol) were dissolved in tetrahydrofuran (50 ml). 60% sodium hydride (736 mg, 18.4 mmol) was added at 0 °C, and then the mixture was reacted at room temperature for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated and separated by chromatography. - 134 in column (petroleum ether:ethyl acetate = 10:1) to obtain a mixture (2.4 g, 61%) of 6-chloro-3-(3-methoxypropoxy)-4-methylpyridazine and 3-chloro -6-(3methoxypropoxy)-4-methylpyridazine in the form of a yellow oil. 1H-NMR (400 MHz, CDC13) : δ 7.20 (s, 1H), 6.84 (s, 1H), 4.59-4.53 (m, 4H), 3.57-3.52 ( m, 4H), 3.35 (s, 6H), 2.34 (s, 3H), 2.22 (s, 3H), 2.12-2.06 (m, 4H) . Intermediate 158 Methyl 6-(3-Methoxypropoxy)-4-methylpyridazine-3-carboxylate and methyl 6-(3-methoxypropoxy)-5-methylpyridazine-3-carboxylate —O N=N —O N=N Ά\B\ A mixture of 6-chloro-3-(3-methoxypropoxy)-4-methylpyridazine and 3chloro-6-(3-methoxypropoxy)-4-methylpyridazine (2.4 g, 11.11 mmol), [1 ,1'-bis(diphenylphosphino)ferrocene]palladium (813 mg, 1.11 mmol) and triethylamine (3.36 g, 33.33 mmol) in methanol (24 ml), and the mixture was reacted overnight at 80 °C under an atmosphere of 5 MP carbon monoxide. The reaction solution was directly concentrated, and part of the residue was subjected to thin layer chromatography (petroleum ether:ethyl acetate = 3:1) twice and (petroleum ether:ethyl acetate = 2.5:1 ) twice to obtain methyl 6-(3methoxypropoxy)-4-methylpyridazine-3-carboxylate (140 mg) as a yellow oil. 1H-NMR (400 MHz, CDC13) : δ 6.81 (s, 1H), 4.68-4.65 (m, 2H), 4.00 (s, 3H), 3.56-3.53 ( m, 2H), 3.35 (s, 3H), 2.54 (s, 3H), 2.12-2.09 (m, 2H). Methyl 6-(3-Methoxypropoxy)-5-methylpyridazine-3-carboxylate (85 mg) as a yellow solid. 1H-NMR (400 MHz, CDC13) : δ 7.89 (s, 1H), 4.73-4.69 (m, 2H), 4.01 (s, 3H), 3.58-3.55 ( m, 2H), 3.36 (s, 3H), 2.27 (s, 3H), 2.15-2.12 (m, 2H). Intermediate 159 (6-(3-Methoxypropoxy)-4-methylpyridazin-3-yl)methanol HO N=N \ Methyl 6-(3-methoxypropoxy)-4-methylpyridazine-3-carboxylate (140 mg, 0.58 mmol) was dissolved in methanol (2 ml), then sodium borohydride (44.3 mg, 1.167 mmol) was added. mmol) at 0 °C, and the mixture was reacted at temperature - 135 atmosphere until the next day. The reaction solution was quenched by adding 0.5 ml water, concentrated, then dissolved in dichloromethane, concentrated and separated by column chromatography (dichloromethane-methanol = 50:1) to obtain the title compound ( 90 mg, 73% yield) as a yellow oil. LC-MS: m / z [M+HJ+ = 213. Intermediate 160 (6-(3-Methoxypropoxy)-5-methylpyridazin-3-yl)methanol The experimental operation was the same as the previous one, starting from the starting material methyl 6-(3-methoxypropoxy)-5-methylpyridazine-3-carboxylate (85 mg, 0.35 mmol) to obtain (6-(3-methoxypropoxy )-5-methylpyridazin-3-yl)methanol (56 mg, 75.6%) as a yellow solid. LC-MS: m / z [M+H]+ = 213. Intermediate 161 (5-(Oxetan-3-yloxy)pyrazin-2-yl)methanol Methyl 6-chloropyridazine-3-carboxylate (600 mg, 3.49 mmol) and oxetan-3-ol (774 mg, 10.46 mmol) were dissolved in acetonitrile (50 ml), and cesium carbonate ( 2.27 g, 6.98 mmol), then the mixture was reacted at room temperature for 3 hours. 25 ml of water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate (30 ml * 3 times). The organic phases were combined, dried, concentrated and separated by column chromatography to obtain 220 mg of compound as a colorless oil. The compound was dissolved in a mixed solution of tetrahydrofuran (10 ml) and methanol (5 ml), then sodium borohydride (108 mg, 2.86 mmol) was added and the mixture was reacted at room temperature for 3 hours. The reaction solution was directly concentrated, separated, and purified by a chromatographic column to obtain the title compound (85 mg, two-step yield of 14.7%) as a colorless oil. LC-MS: m / z [M+H]+ =183. Intermediate 162 - 136 (6- ((2-Methoxyethyl)amino)pyridazin-3-yl)inethanol OH φ HN. / EITHER Methyl 6-chloropyridazine-3-carboxylate (500 mg, 2.9 mmol) and 2-methoxyethylamine (2.15 g, 29 mmol) were dissolved in acetonitrile (20 ml), and cesium carbonate (1.9 g) was added. , 5.8 mmol), then the mixture was reacted overnight at room temperature. 20 ml of water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate (20 ml * 3 times). The organic phases were combined, dried, concentrated and separated by column chromatography to obtain 230 mg of crude product as a colorless oil. The compound was dissolved in a mixed solution of tetrahydrofuran (10 ml) and methanol (10 ml), then sodium borohydride (207 mg, 5.45 mmol) was added and the mixture was reacted at room temperature for 3 hours. The reaction solution was directly concentrated, separated, and purified by a chromatographic column to obtain the title compound (40 mg, 20%) as a colorless oil. LC-MS: m / z [M+H]+ = 184. Intermediate 163 (6- ((l-Methoxyprop-2-yl)oxy)pyridazin-3-yl)methanol Yo HO Y 'N < This compound was prepared in the same manner as intermediate 154 using l-methoxypropan-2-ol (607 mg, 6.7 mmol) to obtain a crude product of the title compound (80 mg, 46%) as a yellow oil. LC-MS: m / z [M+H]+ = 199. Intermediate 164 (6-((Tetrahydrofuran-3-yl)methoxy)pyridazin-3-yl)methanol - 137This compound was prepared in the same manner as intermediate 154 using 3-tetrahydrofuranmethanol (704 mg, 7.0 mmol) to obtain a crude product of the title compound (180 mg, 34%) as a colored oil. yellow. LC-MS: m / z [M+H]+ = 211. Intermediate 165 (6-((Tetrahydrofuran-2-yl)methoxy)pyridazin-3-yl)methanol HO N=N This compound was prepared in the same manner as intermediate 154 using tetrahydrofurfuryl alcohol (704 mg, 7.0 mmol) to obtain a crude product of the title compound (150 mg, 29%) as a yellow oil. LC-MS: m / z [M+H]+ = 211. Intermediate 166 (6-(2-(4-Methylpiperazin-l-yl)ethoxy)pyridazin-3-yl)methanol This compound was prepared in the same manner as intermediate 154 using 1-(2-hydroxyethyl)-4-methylpiperazine (1 g, 6.94 mmol) to obtain the title compound (34 mg, 2%) as a oil. LC-MS: m / z [M+H]+ = 253.16. Intermediate 167 (6-(2-Morpholinoethoxy)pyridazin-3-yl)methanol This compound was prepared in the same manner as intermediate 154 using N-(2-hydroxyethyl)morpholine (150 mg, 1.14 mmol) to obtain the title compound (34 mg, 12.2%) as an oil. . LC-MS: m / z [M+H]+ = 239.13. Intermediate 168 (6-((2-Methoxyethoxy)methyl)pyridazin-3-yl)methanol This compound was prepared in the same manner as intermediate 153 using ethyl 6-(bromomethyl)pyridazine-3-carboxylate (100 mg, 0.41 mmol) and ethylene glycol monomethyl ether (62 mg, 0.82 mmol) to obtain the title compound (10 mg, 71%) as a pale yellow oil. LC-MS: m / z [M+H]+ = 199. Intermediate 169 (6-(3-Ethoxypropoxy)pyridazin-3-yl)methanol - 138 - OH Methyl 6-chloropyridazine-3-carboxylate (500 mg, 2.9 mmol) and 3-ethoxypropan-l-ol (907 mg, 8.72 mmol) were dissolved in acetonitrile (20 ml), and cesium carbonate ( 1.9 g, 5.8 mmol), then the mixture was reacted overnight at room temperature. 15 ml of water was added to the reaction solution, and the reaction solution was extracted with dichloromethane (20 ml * 3 times). The organic phases were combined, dried, and concentrated to obtain 300 mg of a yellow oil. The yellow oil was dissolved in a mixed solution of tetrahydrofuran (10 ml) and methanol (5 ml), then sodium borohydride (98 mg, 2.60 mmol) was added and the mixture was reacted until day following room temperature. The reaction solution was directly concentrated, separated and purified by a chromatographic column to obtain 170 mg of the title compound as a colorless oil with a two-step yield of 27.7%. LC-MS: m / z [M+H]+ = 213. Intermediate 170 (6- (((tert-Butyldimethylsilyl)oxy)methyl)pyridin-3-yl)inethanol OTBS OH Methyl 6-(hydroxymethyl)nicotinate (2.0 g, 11.98 mmol) and TBSC1 (2.2 g, 14.37 mmol) were dissolved in dichloromethane (50 ml), and imidazole (2.44 ml) was added. g, 35.94 mmol) at 0 °C, then the mixture was reacted for 1 hour at room temperature. The reaction solution was poured into water, extracted with dichloromethane. The organic phase was dried with anhydrous sodium sulfate, concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a colorless liquid (3.5 g, crude product). The colorless liquid was dissolved in anhydrous tetrahydrofuran (50 ml) and lithium aluminum hydride (455 mg, 11.98 mmol) was added at 0 °C, then the mixture was reacted at room temperature for 10 minutes. . Sequentially, 0.5 ml of water, 0.5 ml of an aqueous hydroxide solution were added to the reaction solution. - 139 15% sodium and 1.5 ml of water. The mixture was stirred for 5 minutes, filtered under reduced pressure. A mother liquor was concentrated to obtain the title compound (3 g, crude product) as a light yellow oil, which was used directly in the next step. LC-MS: [M+H]+ = 254. Intermediate 171 (5-(Azetidin-l-ylmethyl)pyridin-2-yl)methanol (6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)methanol (0.5 g, 1.98 mmol) and triethylamine (1 g, 10 mmol) were dissolved in diethylamine (20 ml), and MsCl (338 mg, 2.96 mmol) was added dropwise to it at 0 °C, then the mixture was reacted at room temperature for 2 hours; then azetidine (339 mg, 5.94 mmol) was added and the mixture was reacted at room temperature for 2 hours. The reaction solution was poured into water, extracted with dichloromethane. The organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a compound (0.5 g, crude product) as a pale yellow oil. The compound was dissolved in dichloromethane (30 ml) and tetrabutylammonium fluoride (893 mg, 3.42 mmol) was added, and the mixture was reacted at 50 °C for 5 hours. The reaction solution was subjected to column chromatography to obtain the title compound (0.53 g, crude product) as a colorless oil. LC-MS: [M+H]+ = 179. Intermediate 172 (5-((3-Methylpyridin-3-yl)methoxy)pyridin-2-yl)methanol 5-fluoropyridin-2-carbaldehyde (500 mg, 4 mmol) and (3methylpyridin-3-yl)methanol (1.12 g, 12 mmol) were dissolved in )V,N-dimethylformamide (20 ml), and added cesium carbonate (2.6 g, 8 mmol), then the mixture was reacted at 100 °C for 2 hours. 25 ml of water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate (20 ml * 3 times). The organic phases were combined, dried, concentrated and separated by column chromatography to obtain a colorless oil. The colorless oil was dissolved in a mixed solution of tetrahydrofuran (10 ml) and methanol (10 ml), and then sodium borohydride (200 mg, 5.31 mmol) was added, and the - 140 mixture was reacted at room temperature for 3 hours. The reaction solution was directly concentrated, separated, and purified by a chromatographic column to obtain the title compound (120 mg, 54.2%) as a colorless oil. LC-MS: m / z [M+H]+ = 210. Intermediate 173 (6-((Tetrahydro-2H-pyran-4-yl)methoxy)pyridazin-3-yl)methanol Methyl 6-chloropyridazine-3-carboxylate (500 mg, 2.90 mmol) and (tetrahydro-2H-pyran-4-yl)methanol (1.01 g, 8.72 mmol) were dissolved in acetonitrile (20 ml). , and cesium carbonate (1.89 g, 5.8 mmol) was added, then the mixture was reacted at room temperature for 3 hours. 25 ml of water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate (30 ml * 3 times). The organic phases were combined, dried, concentrated and separated by column chromatography to obtain a yellow oil. The yellow oil was dissolved in a mixed solution of tetrahydrofuran (5 ml) and methanol (5 ml), then sodium borohydride (140 mg, 3.69 mmol) was added and the mixture was reacted at room temperature. environment for 16 hours. The reaction solution was directly concentrated, separated, and purified by a chromatographic column to obtain the title compound (97 mg, two-step yield of 19%) as a colorless oil. CLEM: m / z [M+H]+ = 225. Intermediate 174 (4-(Oxetan-3-yloxy)pyridin-2-yl)methanol Methyl 4-chloropicolinate (380 mg, 2.25 mmol) and oxetan-3-ol (170 mg, 2.25 mmol) were dissolved in acetonitrile (5 ml), and cesium carbonate (1.461 g, 4 .50 mmol), and the mixture was reacted at room temperature for 16 hours. The reaction solution was poured into water, extracted with dichloromethane. The organic phase was dried with anhydrous sodium sulfate, concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a compound in the form of a colorless liquid. The colorless liquid -141 dissolved in anhydrous tetrahydrofuran (20 ml) and lithium aluminum hydride (114 mg, 3.0 mmol) was added at 0 °C, then the mixture was reacted at room temperature for 10 minutes. Sequentially, 0.1 ml of water, 0.1 ml of 15% aqueous sodium hydroxide solution and 0.3 ml of water were added to the reaction solution. The mixture was stirred for 5 minutes, filtered under reduced pressure. A mother liquor was concentrated and purified by preparative thin layer chromatography to obtain the title compound (40 mg, 25%) as a pale yellow oil. LC-MS: m / z [M+H]+ = 182. Intermediate 175 (5-((Tetrahydrofuran-3-yl)methoxy)pyridin-2-yl)methanol ΛΟ HO N—λ / < I 5-fluoropyridine-2-carbaldehyde (380 mg, 3.1 mmol), 3-tetrahydrofuranmethanol (634 mg, 6.3 mmol), and cesium carbonate (4.0 g, 12.6 mmol) were added sequentially in 30 ml. of DMF, and the mixture was heated at 100 °C overnight. The mixture was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography (dichloromethane / methanol = 30 / 1). A yellow oil was obtained, which was dissolved in 5 ml of tetrahydrofuran. 1 ml of methanol and sodium borohydride (72 mg, 1.9 mmol) was added, and after stirring for 15 minutes, additional sodium borohydride (72 mg, 1.9 mmol) was added. 5 ml of methanol was added to quench, then the organic phase was concentrated and purified by column chromatography (dichloromethane / methanol = 15 / 1) to obtain the title compound (110 mg, 57% yield). in the form of a colorless oil. LC-MS: m / z [M+HJ+ = 210. Intermediate 176 (5-((Tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)methanol > your N C N N C C N a 5-fluoropyridin-2-carbaldehyde (330 mg, 2.6 mmol), tetrahydro-2H-pyran-4-ol (809 mg, 7.9 mmol), and cesium carbonate (1.7 g, 5.0 mmol) were added sequentially. 2 mmol) in DMF (15 ml), and the mixture was heated to 100 °C and stirred for 1.5 hours. The reaction mixture was poured into water, extracted three times with ethyl acetate and the combined organic phase was washed three times with water and washed once with saturated brine. The organic phase was dried and concentrated to obtain a crude compound, which was dissolved in tetrahydrofuran (4 ml) and methanol (1 ml). Borhydride was added - 142 sodium (86 mg, 2.3 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated and separated by preparative thin layer chromatography to obtain the title compound (133 mg, two-step yield of 24%) as a pale yellow oil. LC-MS: m / z [M+H]+ = 210. Intermediate 177 (5-(Oxetan-3-yloxy)pyridin-2-yl)methanol Methyl 6-fluoropyridine-3-carboxylate (300 mg, 1.94 mmol) and oxetan-3-ol (430 g, 5.8 mmol) were dissolved in acetonitrile (30 ml), and cesium carbonate ( 1.26 g, 3.88 mmol), then the mixture was reacted at room temperature for 5 hours. 25 ml of water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate (30 ml * 3 times). The organic phases were combined, dried, concentrated and separated by column chromatography to obtain a yellow oil. The yellow oil was dissolved in a mixed solution of tetrahydrofuran (5 ml) and methanol (5 ml), then sodium borohydride (43 mg, 1.15 mmol) was added and the mixture was reacted at 50° C for 16 hours. The reaction solution was directly concentrated, separated, and purified by a chromatographic column to obtain the title compound (61 mg, two-step yield of 17.5%) as a colorless oil. LC-MS: m / z [M+H]+ = 182. Intermediate 178 (2-Ethylimidazo[1,2-ib]pyridazin-6-yl)methanol Methyl 6-aminopyridazine-3-carboxylate (153 mg, 1.0 mmol), 1-bromobutan-2-one (222 mg, 1.2 mmol) in DMF (10 mL) were added, and the system was heated to 90° C and stirred for 4 hours. The reaction solution was cooled to room temperature, then dichloromethane (50 ml) and water (40 ml) were added for extraction. The organic phase was subjected to thin layer chromatography (dichloromethane / methanol = 20 / 1) to obtain a solid compound, and the solid compound was added to a mixed solution of tetrahydrofuran (10 ml) and methanol (2.5 ml). . Sodium borohydride (55.4 mg, 1.46 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and -143 separated by thin layer chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (50.0 mg, two-step yield of 28%). LC-MS: m / z [M+H]+ = 178.1. Intermediate 179 (5-((Tetrahydro-2H-pyran-4-yl)oxy)pyrazin-2-yl)methanol OH Methyl 6-chloropyridazine-3-carboxylate (400 mg, 2.33 mmol) and tetrahydro-2H-pyran-4-ol (711 mg, 6.98 mmol) were dissolved in acetonitrile (30 ml), and added cesium carbonate (1.5 g, 4.66 mmol), then the mixture was reacted at room temperature for 16 hours. 25 ml of water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate (30 ml * 3 times). The organic phases were combined, dried, concentrated and separated by a chromatographic column to obtain a yellow oil. The yellow oil was dissolved in a mixed solution of tetrahydrofuran (5 ml) and methanol (5 ml), then sodium borohydride (60 mg, 1.56 mmol) was added and the mixture was reacted at 50° C for 24 hours. The reaction solution was directly concentrated, separated, and purified by a chromatographic column to obtain the title compound (60 mg, two-step yield of 12.2%) as a white solid. LC-MS: m / z [M+H]+ = 211. Intermediate 180 (5-((Tetrahydrofuran-2-yl)methoxy)pyrazin-2-yl)methanol Methyl 5-chloropyrazine-2-carboxylate (600 mg, 3.5 mmol), tetrahydrosugar alcohol (711 mg, 7.0 mmol) and cesium carbonate (4.5 g, 13.9 mmol) were added sequentially in 20 ml of acetonitrile, and then the mixture was stirred at room temperature overnight. 30 ml of water was added to dissolve the cesium carbonate, and the organic solvent was removed. A large amount of solid precipitated, and the solid was filtered and dried to obtain the title compound (600 mg) as a yellow solid. 300 mg of the title compound were taken and dissolved in 5 ml of tetrahydrofuran. 1 ml of methanol and sodium borohydride (48 mg, 2.6 mmol) was added, and after stirring for 15 minutes, additional sodium borohydride (48 mg, 2.6 mmol) was added. You will - 144 added 5 ml of methanol to quench, then the organic phase was concentrated and purified by column chromatography (dichloromethane / methanol = 15 / 1) to obtain the title compound (180 mg, two-step yield 49%) in the form of a colorless oil. LC-MS: m / z [M+H]+ = 211. Intermediate 181 (6-((2-Oxaspiro[3.3]hept-6-yl)oxy)pyridazin-3-yl)methanol Methyl 6-chloropyridazine-3-carboxylate (300 mg, 1.74 mmol) and 2-oxaespiro[3.3]heptan-6-ol (200 mg, 1.74 mmol) were dissolved in acetonitrile (10 ml), and added cesium carbonate (1.13 g, 3.48 mmol), then the mixture was reacted overnight at room temperature. 20 ml of water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate (20 ml * 3 times). The organic phases were combined, dried, concentrated and separated by column chromatography to obtain a crude product in the form of a yellow oil. The crude product was dissolved in a mixed solution of tetrahydrofuran (10 ml) and methanol (10 ml), then sodium borohydride (96 mg, 2.52 mmol) was added and the mixture was reacted at room temperature for 2 hours. The reaction solution was directly concentrated, separated and purified by a chromatographic column to obtain the title compound (48 mg, two-step yield of 13%) as a white solid. LC-MS: m / z [M+H]+ = 223. Intermediate 182 3-Chloro-5-(oxetan-3-yloxy)pyridazine CL 3-oxethanol, CAS: 7748-36-9, (550 mg, 6.7 mmol) was dissolved in 20 ml of tetrahydrofuran, then the mixture was cooled to 0 °C. Sodium hydride (295 mg, 7 mmol) was added and the mixture was stirred for 15 minutes. 3,5-Dichloropyridazine, CAS: 1837-55-4, (1 g, 6.7 mmol) was added and the mixture was raised to room temperature and stirred for 1 hour. The reaction solution was quenched with water, extracted with ethyl acetate, dried and concentrated to - 145 obtain a crude product of the title compound (800 mg, 64%) in the form of a white solid. LC-MS: m / z [M+H]+ = 187. Intermediate 183 5-(Oxetan-3-yloxy)pyridazine-3-carbonitrile CN 3-Chloro-5-(oxetan-3-yloxy)pyridazine (700 mg, 3.8 mmol), zinc cyanide (308 mg, 2.6 mmol), Pd2 (dba) 3 (103 mg, 0 .11 mmol) and DPPF (125 g, 0.22 mmol) in 20 ml of DMF, and the mixture was heated at reflux overnight under argon protection. The reaction solution was concentrated and subjected to column chromatography (dichloromethane:methanol = 100:1) to obtain the title compound (1.5 g, 100%) as a black solid. LC-MS: m / z [M+H]+ = 178. Intermediate 184 Oxetan-3-yl 5-(Oxetan-3-yloxy)pyridazine-3-carboxylate 5-(oxetan-3-yloxy)pyridazine-3-carbonitrile (600 mg, 3.4 mmol) was dissolved in 5 ml of 3-oxethanol, and cesium carbonate (1 g, 10 mmol) was added, and then , the mixture was stirred at room temperature for 2 days. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was dried and concentrated. The residue was purified by preparative TLC (dichloromethane / methanol = 20 / 1) to obtain the title compound (150 mg, 22%) as a white solid. LC-MS: m / z [M+H]+ = 253. Intermediate 185 (5-(Oxetan-3-yloxy)pyridazin-3-yl)methanol OH Oxetan-3-yl 5-(oxetan-3-yloxy)pyridazine-3-carboxylate (150 mg, 0.7 mol) was dissolved in 5 ml of tetrahydrofuran. 1 ml of methanol was added and sodium borohydride (54 mg, 1.4 mmol) was added, then the mixture was stirred for 30 minutes. 10 ml of methanol were added to inactivate and the organic phase was concentrated -146 The residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to obtain the title compound (30 mg, 24%) as a yellow oil. LC-MS: m / z [M+H]+ = 183. Intermediate 186 6-Ethyl-2-(hydroxymethyl)-1,6-naphthyridin-5(6H)-one EITHER Methyl 5-oxo-5,6-dihydro-l,6-naphthyridine-2-carboxylate (150 mg, 0.735 mmol), sodium hydride (60%) (45 mg, 1.1 mmol) and iodoethane (1) were dissolved. .15 g, 7.35 mmol) in DMF (6.0 mi). Once the addition was complete, the mixture was stirred and reacted at room temperature for 3 hours. After the reaction was completed, water (20 ml) was added to the reaction system, and then the mixture was extracted with ethyl acetate (40 ml * 2 times); The organic phases were combined and then washed with saturated brine (30 ml * 1 time). The organic phase was dried, concentrated and dissolved with sodium borohydride (130 mg, 3.5 mmol) in a mixed solution of tetrahydrofuran and methanol (tetrahydrofuran:methanol =4:1) (10 ml). Once the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was separated by a chromatographic column to obtain 53 mg of a conventional para compound with a yield of 40.2%. LC-MS: m / z [M+H]+ = 205.12. Intermediate 187 EITHER From the starting materials methyl 5-oxo-5,6-dihydro-l,6-naphthyridine-2carboxylate (100 mg, 0.49 mmol) and 3-bromopropyl methyl ether (380 mg, 2.48 mmol) , the experimental operation was the same as that of intermediate 133 to obtain 40 mg of the title compound, LC-MS: m / z [M+H]+ = 249. Intermediate 188 (5-(2-Methoxyethoxy)pyridin-2-yl)methanol - 147 OH Methyl 5-hydroxypicolinate (1 g, 6.54 mmol) and 2-methoxyethanol (1 g, 13.16 mmol) were dissolved in dry tetrahydrofuran (30 ml), then triphenylphosphine (5.14 g, 19.62 mmol) and diisopropyl azodicarboxylate (3.96 g, 19.62 mmol) and the mixture was reacted at room temperature overnight. The reaction solution was mixed with silica gel, purified by chromatographic column. The filtrate was evaporated to dryness by rotary evaporation to obtain a solid compound, which was dissolved in tetrahydrofuran (20 ml), and then sodium borohydride (180 mg, 4.74 mmol) was added to react at room temperature for 16 hours. Methanol was added to the reaction solution to inactivate it, and it was separated by a chromatographic column to obtain 180 mg of the title compound in a two-step yield of 15%. LC-MS: m / z [M+H]+ = 184. Intermediate 187 2-(Hydroxymethyl)-6-(2-methoxyethyl)-7,8-dihydro-l,6-naphthyridin5(6H)-one (6-(2-methoxyethyl)-5,6,7,8-tetrahydro-l,6-naphthalen-2-yl)methanol (800 mg, 3.6 mmol) was dissolved in THF / H2O (2.5 / 1.35 mi). Sodium bicarbonate (3.027 g, 36 mmol) and iodine (6.685 g, 27 mmol) were added sequentially, followed by stirring at room temperature until the next day. TLC (dichloromethane–methanol = 20:1) showed complete reaction of the starting materials. The mixture was neutralized with sodium thiosulfate until the color faded, extracted with dichloromethane, and purified by column chromatography to obtain 85 mg of the title compound as a colorless oil in 10% yield. LC-MS: [M+H]+ = 237. Intermediate 188 [l,2,3]Triazolo[l,5-a]pyridine - 148 ν^ν Pyridine-2-carbaldehyde (2.0 g, 18.7 mmol) was added in methanol, then p-toluenesulfonyl hydrazide (3.48 g, 18.7 mmol) was added and the mixture was stirred at room temperature for 6 hours. The reaction solution was cooled to 0 °C, filtered, and the filter cake was washed with a small amount of methanol. The solid was dried to obtain a solid product, which was added to morpholine (30 ml), and the mixture was stirred and reacted at 100 °C for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow oil. (900 mg, two-stage yield of 40%). LC-MS: m / z [M+H]+ = 120. Intermediate 189 [l,2,3]Triazolo[l,5-a]pyridine-7-methanol Diisopropylamine (383 mg, 3.78 mmol) in tetrahydrofuran (5 ml) was added, the mixture was cooled to -78 °C, and n-butyllithium (1.2 ml, 3.02 ml) was added dropwise. mmol), and the mixture was reacted at 0 °C for 20 minutes, and then cooled to -78 °C. A tetrahydrofuran solution of [1,2,3]triazolo[1,5-a]pyridine (300 mg, 2.52 mmol) was added dropwise, and the mixture was stirred at -78 °C for 20 minutes. , and then DMF (0.5 ml) was added and the mixture was stirred for 20 minutes. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a product (230 mg, 62%). The product was added to methanol (5 ml), then sodium borohydride (119 mg, 3.13 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated and subjected to column chromatography (dichloromethane / methanol = 30 / 1) to obtain the title compound (120 mg, 52%). ). 1H-NMR (400 MHz, CDC13): 68.27 (s, IH), 7.92-7.89 (m, IH), 7.48-7.44 (m, IH), 7.21 7.19 (m, IH), 5.92-5.89 (m, IH), 5.06-5.05 (m, 2H). Intermediate 190 (3-MethiI-3H-imidazo[4,5-¿]pyridin-5-yl)methanol - 149 -ηο^Ύν / > The starting materials 5-chloro-3-methyl-3Himidazo[4,5-b]pyridine (200 mg, 1.2 mmol), [1,1'bis(diphenylphosphino)ferrocene]palladium chloride (88) were added sequentially. mg, 0.12 mmol) and triethylamine (364 mg, 3.6 mmol) in methanol (5 ml). The mixture was then reacted overnight under an atmosphere of 5 MPa carbon monoxide at 120 °C. The reaction solution was concentrated and separated by column chromatography to obtain a red solid (180 mg). The red solid and lithium aluminum hydride (107 mg, 2.82 mmol) in tetrahydrofuran (5 mL) were added sequentially at 0 °C. The mixture was reacted at room temperature for 12 hours. Water was added to the reaction solution to quench the reaction, concentrated, and separated by column chromatography to obtain a yellow solid (100 mg, 65.3%) as a product. 1H-NMR (400 MHz, CDC13) : δ 8.06-8.01 (m, 2H), 7.20 (d, J= 8.4 Hz, 1H), 4.89 (s, 2H), 3 .92 (s, 3H). LC-MS: m / z [M+H]+ = 164. Intermediate 191 (6-Cyclopropylpyridin-2-yl)methanol The compound (methyl 6-cyclopropylpicolinate) (1.81 g, 10.2 mmol) was dissolved in 20 ml of methanol, and the mixture was cooled to 0 to 5 °C in an ice bath under nitrogen protection. Sodium borohydride (1.15 g, 30.6 mmol) was slowly added to the reaction solution, and after addition, the mixture was stirred at room temperature for 5 hours. 1.0 ml water was added to the reaction solution, stirred for 1 hour, concentrated, and separated by column chromatography to obtain a colorless oil (1.10 g, 72%). 1H-NMR (400 MHz, DMSOd6): δ 7,631-7,593 (m, 1H), 7,203-7,184 (d, J= 7.6 Hz, 1H), 7,104-7,084 (d, J = 8 Hz, 1H), 5.284-5.256 (m, 1H), 4.464-4.450 (d, J= 5.6 Hz, 2H), 2.060-2.028 (m, 1H), 0.916-0.862 (m, 4H). LC-MS: m / z [M+H]+ = 150. Intermediate 192 Dimethyl 3-Cyanopyridin-l,6-dicarboxylate - 150 - Starting materials 2,6-dichloronicotinonitrile (17.0 g, 98.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (7.2 g, 9.87 mmol) and triethylamine ( 29.9 g, 296.1 mmol) were added sequentially in methanol (150 ml). The reaction was then carried out overnight under an atmosphere of 5 MPa carbon monoxide at 80 °C. The reaction was combined with N0036-78 for treatment. The reaction solution was filtered under reduced pressure, concentrated and separated by column chromatography (dichloromethane / methanol = 300:1) to obtain a white solid (2.16 g, 10.0%) as a product. . 1H-NMR (400 MHz, CDC13) : δ 8.39 (d, J = 8.0 Hz, IH), 8.33 (d, J= 8.0 Hz, IH), 4.10 (s, 3H) ), 4.07 (s, 3H). LC-MS: m / z [M+H]+ = 221. Intermediate 193 6-tert-Butyl-2-methyl-7-oxo-5H-pyrrolo[3,4-b]pyridine-2,6(7H)dicarboxylate The starting materials 3-cyanopyridin-l, dimethyl 6dicarboxylate (2.5 g, 11.4 mmol) and Raney® nickel (1.4 g, 22.8 mmol) in methanol (300 ml) were added sequentially. The reaction was then carried out under an atmosphere of 0.34 MPa (50 psi) hydrogen at 40 °C for 8 hours. The reaction solution was concentrated to obtain a gray solid, and the gray solid and 4-dimethylaminopyridine (124 mg, 1.02 mmol) in dichloromethane (10 mL) were added sequentially. Then, the starting material ditert-butyl dicarbonate (2.2 g, 10.2 mmol) was added and the reaction was carried out at 50 °C for 30 minutes. The reaction solution was concentrated and separated by column chromatography to obtain a reddish-brown solid (1.25 g, 63.0%) as a product. 1H-NMR (400 MHz, CDC13) : δ 8.36(d, J= 8.0 Hz, IH), 8.03 (d, J= 8.0 Hz, IH), 4.85 (s, 2H) ), 4.04 (s, 3H), 1.62 (s, 9H). LC-MS: m / z [M+H]+ = 293. Intermediate 194 Tere-butyl 7-Hydroxy-2-(hydroxymethyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)carboxylate At 0 oC, the starting material 6-tert-butyl-2-methyl-7-oxo-5H-pyrrolo[3,4b]pyridine-2,6(7H)-dicarboxylate (900 mg, 3.1 mmol) was added to tetrahydrofuran (10 ml). Then, under nitrogen protection, the starting material diisobutyl aluminum hydride (dissolved in tetrahydrofuran, 6.2 ml 6.2 mmol, 1 M) was added dropwise to the solution. After 2 hours of reaction, additional diisobutyl aluminum hydride starting material (6.2 ml, 6.2 mmol, 1 M) was added. The mixture was reacted at room temperature for 3 hours. Water (10 ml) was added dropwise to the reaction solution to quench excess diisobutyl aluminum hydride, and the mixture was filtered and concentrated, and separated by column chromatography to obtain the title compound (320 mg , 37.6%) in the form of a yellow solid. 1H-NMR (400 MHz, CDC13): δ 7.63 (d, J= 7.6 Hz, 1H), 7.31 (d, J= 8.0 Hz, 1H), 4.83 (s, 2H ), 4.68-4.61 (m, 2H), 3.70 (s, 1H), 1.59 (s, 9H). LC-MS: m / z [M+H]+ = 267. Intermediate 195 Tere-butyl 2-(Hydroxymethyl)-5H-pyrrolo[3,4-¿]pyridin-6(7H)-carboxylate The starting materials 7-hydroxy-2(hydroxymethyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate tere-butyl (320 mg, 1.2 mmol) and sodium cyanoborhydride were added sequentially. (83.2 mg, 1.32 mmol) in acetic acid (5 ml). The mixture was reacted at room temperature for 1 hour. The acetic acid was evaporated to dryness by rotary evaporation at low temperature, and the residue was dissolved in dichloromethane / methar.ol = 10:1. The pH of the mixture was adjusted to approximately 9 with saturated sodium carbonate solution, and the mixture was extracted with dichloromethane / methanol =10:1. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain the title compound (190 mg, 63.3%) as a yellow solid. 1H-NMR (400 MHz, CDC13) : δ 7.60-7.53 (m, 1H), 7.15 (d, J= 8.0 Hz, 1H), 4.78-4.77 (m, 2H), 4.71-4.67 (m, 4H), 1.50 (s, 9H). LC-MS: m / z [M+H]+ = 251. Intermediate 196 (6,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)methanol > your N C N N C C N a Tere-butyl 2-(hydroxymethyl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (300 mg, 1.2 mmol) was dissolved in dichloromethane (2 ml), and added trifluoroacetic acid (1 ml) and the mixture was reacted at room temperature for 1 hour. The reaction solution was directly concentrated, dissolved in methanol, ionic resin was added and stirred for 30 minutes, filtered and concentrated to obtain the title compound (180 mg, crude product) as a solid. Dun. LC-MS: m / z [M+H]+ = 151. Intermediate 197 (6-Methyl-6,7-dihydro-5H-pyrrolo[3,4-¿]pyridin-2-yl)methanol (6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)methanol (150 mg, 1 mmol, crude product) was dissolved in dichloromethane (3 ml), and added dropwise to drop 1 drop of acetic acid, and then an aqueous solution of formaldehyde (0.5 ml) was added and the mixture was reacted at room temperature for 30 minutes; Sodium triacetoxyborohydride (636 mg, 3 mmol) was added and the mixture was allowed to react at room temperature overnight. The reaction solution was concentrated, dissolved in methanol, concentrated and separated by column chromatography to obtain the title compound (80 mg, 30%) as a brown oil. 1H-NMR (400 MHz, CDC13 and CD3OD) δ 7.63 (d, J= 8.0 Hz, 1H), 7.37 (d, J= 8.0 Hz, 1H), 4.71 (s, 2H), 4.01-3.99 (m, 4H), 2.66 (s, 3H). Intermediate 198 (5-(2-Methoxyethoxy)-1,6-naphthyridin-2-yl)methanol Methyl 5-oxo-5,6-dihydro-l,6-naphthyridine-2-carboxylate (200 mg, 1.0 mmol) was dissolved in phosphorus oxychloride (3.0 ml), and the temperature of the system was raised up to 80 °C, and the mixture was stirred and reacted for 4 hours. After the reaction was complete, the system was cooled to room temperature. Ethylene glycol monomethyl ether (30.0 ml) was then added to the system and the mixture was stirred at room temperature for 0.5 hour. After that - 153 completion of the reaction, the pH of the reaction system was adjusted to 8-9 with a saturated sodium bicarbonate solution. Water (20 ml) was added to the reaction system, followed by extraction with ethyl acetate (40 ml * 2 times); The organic phases were combined and then washed with saturated brine (30 ml *1 time). The organic phase was dried, concentrated and dissolved with sodium borohydride (433 mg, 11.4 mmol) in a mixed solution of tetrahydrofuran and methanol (tetrahydrofuran:methanol =4:1) (20 ml). Once the addition was complete, the mixture was stirred and reacted at room temperature for 2.0 hours. After the reaction was completed, the reaction solution was separated by column chromatography to obtain the title compound (105.0 mg, 19.6%). LC-MS: m / z [M+H]+ = 235.10. Intermediate 199 Ethyl 2-(2-(Hydroxymethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)-2methylpropanoate Dissolved were (5, 6.7, 8-tetrahydro-l,6-naphthyridin-2-yl)methanol (1 g, 6.1 mmol), ethyl 2-bromoisobutyrate (CAS: 600-00-0, 2 g , 12 mmol) and potassium carbonate (2.5 g, 218 mmol) in 10 ml of acetonitrile, then the mixture was heated to 80 °C and stirred overnight. The solid was filtered, then the reaction solution was concentrated and purified by preparative plate (dichloromethane:methanol = 10:1) to obtain the title compound (1 g, 59%) as a colorless liquid. LC-MS: m / z [M+H]+ = 279. Intermediate 200 Ethyl 2-(2-(((tert-Butyldimethylsilyl)oxy)methyl)-7,8-dihydro-l,6naphthyridin-6(5H)-yl)-2-methylpropanoate Ethyl 2-(2-(hydroxymethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)-2methylpropanoate (1 g, 4 mmol) and imidazole (900 mg, 6 mmol) were dissolved. in 10 ml of dichloromethane, then the mixture was cooled to 0 °C. NBS (1 g, 15 mmol) was added and the mixture was stirred at room temperature for 2 hours. The solid was filtered, then the reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 30:1). - 154 to obtain the title compound (400 mg, 28%) as a yellow liquid. LC-MS: m / z [M+H]+ = 393. Intermediate 201 2- (2- (((tert-Butyldimethylsilyl)oxy)methyl)-7,8-dihydro-l,6naphthyridin-6(5fi)-yl)-2-methylpropan-l-ol TBSO Ethyl 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-7,8-dihydro-l,6naphthyridin-6(5H)-yl)-2-methylpropanoate (400 mg, 1 mmol) was dissolved in 10 ml of tetrahydrofuran, then the mixture was cooled to 0 °C, lithium aluminum hydride (80 mg, 2 mmol) was added and stirred at room temperature for 30 minutes. Sodium sulfate decahydrate was added to inactivate. The solid was filtered, and the reaction solution was concentrated and purified by preparative plate (dichloromethane:methanol = 10:1) to obtain the title compound (300 mg, 90%) as a colorless liquid. LC-MS: m / z [M+H]+ = 351. Intermediate 202 2-(((tert-Butyldimethylsilyl)oxy)methyl)-6-(l-methoxy-2methiIpropan-2-yl)-5,6,7,8-tetrahydro-l,6-naphthyridine TBSO 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-7, 8-dihydro-l, 6-naphthyridin-6 (5phy)-yl)-2-methylpropan-l-ol (300 mg, 0 .8 mmol) in 10 ml of tetrahydrofuran, then the mixture was cooled to 0 °C, lithium aluminum hydride (40 mg, 1 mmol) was added and stirred for 30 minutes. 0.5 ml of iodomethane was added and the mixture was stirred at room temperature for 2 hours. The solid was filtered, the reaction solution was concentrated and purified by preparative plate (dichloromethane-methanol = 10:1) to obtain the title compound (300 mg, 100%) as a colorless liquid. LC-MS: m / z [M+H]+ = 365. Intermediate 203 (6-(l-Methoxy-2-methylpropan-2-yl)-5,6,7,8-tetrahydro-l,6naphthyridin-2-yl)methanol - 155 (2-(((tert-butyldimethylsilyl)oxy)methyl)-6-(l-methoxy-2-methylpropan2-11)-5,6,7,8-tetrahydro-l,6-naphthyridine (300) was dissolved mg, 0.8 mmol) in 5 ml of tetrahydrofuran, then a 1 M tetrahydrofuran solution of tetrabutylaluminum fluoride (5 ml) was added and the mixture was stirred at room temperature overnight. reaction was concentrated and purified by preparative plate (dichloromethane:methanol = 10:1) to obtain the title compound (200 mg, 95%) as a colorless liquid. LC-MS: m / z [M+H ]+ = 251. Intermediate 204 (6-(5-Methylisoxazol-3-yl)-5,6,7,8-tetrahydro-l,6-naphthyridin-2yl)methanol 3-Bromo-5-methylisothiazole (CAS: 25741-97-3, 330 mg, 2 mmol) and methyl trifluoromethanesulfonate (1 ml) were heated to 80 °C, and the mixture was stirred for 1 hour, cooled, concentrated and dissolved in methanol, (5,6,7,8tetrahydro-1,6-naphthyridin-2-yl)methanol (330 mg, 2 mmol) was added, stirred at room temperature for 1 hour. Next, the reaction solution was concentrated, then DMF was added to dissolve and triphenylphosphine (500 mg, 2 mmol) was added, then the mixture was heated to 120 ° C overnight under protection with argon. Water was added thereto, and the mixture was extracted with dichloromethane, concentrated and purified by preparative plate (dichloromethane:methanol =10:1 and then ethyl acetate) to obtain the title compound (100 mg, 20 %) in the form of a yellow oil. LC-MS: m / z [M+H]+ = 246. Intermediate 205 3-(2-((((7-Methoxy-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3jb]pyridazin-6-yl]oxy)methyl) Tere-butyl -7,8-dihydro-l,6-naphthyridin-6(5H)-yl)azetidine-1carboxylate —^^NBoc - 156 3-(7-methoxy-6-(((5,6,7,8-tetrahydro-l,6-naphthopyridin-2yl)methoxy)-[1,2, 4] triazolo [4, 3] was dissolved -¿>] pyridazin-3-yl)-5-methylisoxazole (300 mg, 0.7 mmol) and 1-(tert-butoxycarbonyl)-3-azetidinone (CAS: 398489-26-4, 171 mg, 1 mmol) in 10 ml of methanol, then sodium cyanoborhydride (200 mg, 3 mmol) was added, and the mixture was stirred at room temperature until the next day. Water was added and the mixture was extracted with dichloromethane, separated , concentrated and purified by preparative plate (dichloromethane:methanol = 10:1) to obtain the title compound (300 mg, 78%) as a white solid. LC-MS: m / z [M +H]+ = 549. Intermediate 206 3-(6-((6-(azetidin-3-yl)-5,6,7,8-tetrahydro-l,6naphthyridin-2-yl)methoxy)-7-methoxy-[1,2) hydrochloride ,4]triazolo[4,3-¿]pyridazin-3-yl)-5methylisoxazole 3- (2- ((((7-methoxy-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4, 3b]pyridazin-6-yl]oxy)methyl) was dissolved Tere-butyl -7,8-dihydro-l,6-naphthyridin-6(5H)-yl)azetidine-1carboxylate (300 mg, 0.6 mmol) in 10 ml of dichloromethane, then 10 ml were added of a solution of hydrochloride in ethyl acetate and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, dissolved in methanol, neutralized by adding solid sodium bicarbonate until neutral, filtered and the organic phase was concentrated to obtain the title compound (300 mg, 100%) as a white solid. LC-MS: m / z [M+H]+ = 449. Intermediate 207 6-Chloroimidazo[1,2-jb]pyridazine-2-carboxamide Under nitrogen protection, methyl 6-chloroimidazo[1,2-b]pyridazine-2carboxylate (2.0 g, 9.45 mmol) was dispersed in acetonitrile (30 ml) at 40 °C, and ammonia water was added. (100 ml), and the reaction solution was stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to - 157room temperature, filtered and the solid was dried to obtain the title product (1.6 g, white solid) in 86% yield. LC-MS: m / z [M+H]+ = 197. Intermediate 208 Methyl 2-Carbamoylimidazo[l,2-jb]pyridazine-6-carboxylate In an autoclave, 6-chloroimidazo[1,2-b]pyridazine-2-carboxamide (937 mg, 4.8 mmol) was dispersed in methanol (30 ml). [1,1'bis(diphenylphosphino)ferrocene]palladium dichloride (936 mg, 1.15 mmol) and triethylamine (9 mL) were added and the reaction solution was reacted at 80 °C for 16 hours under an atmosphere of 3 MPa of carbon monoxide. After the reaction was completed, the temperature was reduced to room temperature and the reaction solution was filtered. The filtrate was concentrated and the residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title product (1 g, brown solid) in 99% yield. LC-MS: m / z [M+H]+ = 221. Intermediate 209 Methyl 2-Cyanoimidazo[1,2-b]pyridazine-6-carboxylate / A^CN—O N-N 1 \_ / / AN o7 Under nitrogen protection at room temperature, methyl 2-chloroimidazo[1,2-b]pyridazine-6-carboxylate (1 g, 4.55 mmol) was dissolved in tetrahydrofuran (20 ml), then triethylamine ( 920 mg, 9.10 mmol) and trifluoroacetic anhydride (3.81 g, 18.20 mmol). The reaction solution was stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title product (645 mg, white solid) with a 70% performance. LC-MS: m / z [M+H]+ = 203. Intermediate 210 6-(Hydroxymethyl)imidazo[l,2-.b]pyridazin-2-carbonitrile OH L / N. _ I Γ y—CN AAn - 158 Under nitrogen protection at 30 °C, 2-cyanoimidazo[1,2 was dissolved b]methyl pyridazine-6-carboxylate (550 mg, 2.72 mmol) in tetrahydrofuran (15 ml) Anhydrous calcium chloride (604 mg, 5.45 mmol) and sodium borohydride (206 mg, 5.45 mmol) were added. mmol), and the reaction solution was stirred for 2 hours. After the reaction was completed, the reaction solution was cooled and concentrated, and the residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title product (350 mg, colored solid white) with a yield of 73%. LC-MS: m / z [M+H]+ = 175. Intermediate 211 2-Bromo-1-(tetrahydro-2H-pyran-4-yl)ethan-l-one 1-(Tetrahydro-2h-pyran-4-yl)ethan-l-one was placed in anhydrous methanol (5 ml) and the mixture was cooled to 0 °C. Liquid bromine (0.4 ml) was added dropwise to the reaction solution at 0 °C, the mixture was kept at 0 °C for 45 minutes and then warmed to room temperature and reacted for 45 minutes. Then, concentrated sulfuric acid (2.7 ml) was added to the reaction solution, and the reaction was carried out at room temperature overnight. A saturated aqueous solution of sodium bisulfite (5 ml) was added to the reaction solution, then ethyl acetate (200 ml) was added. The ethyl acetate was washed three times with water and then dried with anhydrous sodium sulfate, and then evaporated to dryness by rotary evaporation to obtain the title compound (677 mg, 41.9%) as an oil. yellow. LC-MS: m / z [M+H]+ = 208. Intermediate 212 Methyl 2-(Tetrahydro-2H-pyran-4-yl)imidazo[1,2-¿]pyridazine-6carboxylate 2-Bromo-1-(tetrahydro-2H-pyran-4-yl)ethan-l-one (677 mg, 3.27 mmol) and methyl 6-aminopyridazine-3-carboxylate (500 mg, 3.27 mmol) were added. mmol) in ethylene glycol dimethyl ether (10 ml), and the mixture was reacted at 90 °C for 2 hours. The reaction solution was directly subjected to thin layer chromatography - 159 (anhydrous dichloromethane / methanol = 20 / 1) to obtain the title compound (430 mg, 50.4%) as a yellow solid. LC-MS: m / z [M+H]+ = 262. Intermediate 213 (2-(Tetrahydro-2B-pyran-4-yl)imidazo[l,2-b]pyridazin-6yl)methanol The experimental operation was the same as that of (2-(oxetan-3-yl)-2Hpyrazolo[4,3-b]pyridin-5-yl)methanol using starting material 2-(tetrahydro2H-pyrman-4-yl) Methyl imidazo[1,2-b]pyridazine-6-carboxylate (430 mg, 1.6 mmol) to obtain the title compound (200 mg, 52.1%) as a yellow solid. LC-MS: m / z [M+H]+ = 234. Intermediate 214 Methyl 2-(Bromomethyl)imidazo[l,2-b]pyridazine-6-carboxylate Methyl 6-aminopyridazine-3-carboxylate (300 mg, 2 mmol) and 1,2-dibromoacetone (440 mg, 2.2 mmol) in 1,2-dimethoxyethane (2 ml) were added and the mixture was reacted at 90 °C for 2 hours. The mixture was subjected to preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain the title compound (193 mg, 35.9%) as a yellow solid. LC-MS: m / z [M+H]+ = 270, 272. Intermediate 215 2-(methoxymethyl)imidazo[1,2-b]pyridazine-6-carboxylic acid Methyl 2-(bromomethyl)imidazo[1,2-b]pyridazine-6-carboxylate (190 mg, 0.72 mmol) was added to a mixed solution of tetrahydrofuran (2 ml) and methanol (1 ml), and to the reaction solution, potassium carbonate (200 mg, 1.45 mmol) was added and the mixture was reacted at 55 °C for 2 hours. The pH of the reaction solution is -160 adjusted to about 5 with glacial acetic acid, and the mixture was concentrated and purified by a reverse phase chromatographic column to obtain a crude product. Intermediate 216 Methyl 2-(Methoxymethyl)imidazo[l,2-jb]pyridazine-6-carboxylate 2-(methoxymethyl)imidazo[1,2-b]pyridazine-6-carboxylic acid (the crude product from the previous step) in methanol (5 ml) was added, and thionyl chloride (1 e) to the reaction solution, and the mixture was reacted at 60 °C for 1 hour. The mixture was subjected to preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain the title compound (87 mg, two-step yield of 54.9%) as a brownish-yellow solid. . LC-MS: m / z [M+H]+ = 222. Intermediate 217 (2-(Methoxymethyl)imidazo[l,2-b]pyridazin-6-yl)methanol Methyl 2-(methoxymethyl)imidazo[1,2-¿>]pyridazine-6-carboxylate (87 mg, 0.40 mmol) was added to a mixed solution of tetrahydrofuran (2 ml) and methanol (0.5 ml). . Sodium borohydride (45 mg, 1.2 mmol) was added to the reaction solution in two portions, and the mixture was stirred at room temperature for 1 hour. Methanol (20 ml) was added to the reaction solution to quench, and the mixture was concentrated and subjected to preparative thin layer chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (68 mg, 88%) in the form of a yellow solid. LC-MS: m / z [M+H]+ = 194. Intermediate 218 Methyl 3-Isopropyl-[1,2,4]triazolo[4,3-¿]pyridazine-6-carboxylate - 161 IV / \\ N-n Methyl 6-hydrazinopyridazine-3-carboxylate dihydrochloride (400 mg, 1.659 mmol), isobutyraldehyde (239 mg, 3.32 mmol), and potassium acetate (326 mg, 3.32 mmol) in anhydrous ethanol (3 mL) were added. , and the mixture was stirred at room temperature for 30 minutes. Copper bromide (407 mg, 1.83 mmol) was added to the reaction solution, and a salt of potassium peroxosulfate complex (1.123 g, 1.83 mmol) dissolved in water (2) was added to the reaction solution. e), and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered under reduced pressure, then the organic phase was concentrated and subjected to preparative thin layer chromatography (dichloromethane / methanol = 40 / 1) to obtain the title compound (280 mg, 76.7 %) in the form of a yellow solid. LC-MS: m / z [M+H]+ = 221. Intermediate 219 (3-Isopropyl-[1,2,4]triazolo[4,3-.b]pyridazin-6-yl)methanol .OH What \\ N—N Methyl 3-isopropyl-[1,2,4]triazolo[4,3-¿>]pyridazine-6-carboxylate (280 mg, 1,280 mmol) in tetrahydrofuran (2 ml) was added and the mixture was stirred at - 20 °C for 15 minutes. At -20 °C, lithium aluminum hydride (99 mg, 2.56 mmol) was added to the reaction solution in three portions, and the reaction was carried out at -20 °C for 30 minutes after completion. addition. Sodium sulfate decahydrate (5 g) was added to the reaction solution, and the reaction solution was filtered under reduced pressure. The organic phase was concentrated and subjected to preparative thin layer chromatography (dichloromethane / methanol = 25 / 1) to obtain the title compound (62 mg, 25.2%) as a brown oily liquid. LC-MS: m / z [M+H]+ = 193. Intermediate 220 Methyl 3-(Tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6carboxylate - 162 - Methyl 6-hydrazinopyridazine-3-carboxylate dihydrochloride (300 mg, 1.25 mmol), potassium acetate (366 mg, 3.74 mmol), and tetrahydropyran 4-carbaldehyde (284 mg, 2.49 mmol) in ethanol were added (2 e), and the mixture was stirred at room temperature for 30 minutes. Copper bromide (305 mg, 1.37 mmol) was added to the reaction solution, and a salt of potassium peroxosulfate complex (842 mg, 1.37 mmol) dissolved in water (1 .5 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered under reduced pressure, concentrated and subjected to preparative thin layer chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (184 mg, 56.4%) as a yellow liquid. LC-MS: m / z [M+H]+ =263. Intermediate 221 (3-(Tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[4,3-.b]pyridazin-6yl)methanol Methyl 3-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6carboxylate (168 mg, 0.641 mmol) was added to tetrahydrofuran (2 ml), and the mixture was stirred at -20 °C for 15 minutes. At −20 °C, lithium aluminum hydride (49 mg, 1.282 mmol) was added to the reaction solution in three portions, and the reaction was carried out at −20 °C for 30 minutes after the addition was completed. Sodium sulfate decahydrate (5 g) was added to the reaction solution, and the reaction solution was filtered under reduced pressure. The organic phase was concentrated and subjected to preparative thin layer chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (86 mg, 57.3%) as a brown oily liquid. LC-MS: m / z [M+H]+ = 235. Intermediate 222 Methyl 3-Methyl-[1,2,4]triazolo[4,3-jb]pyridazine-6-carboxylate - 163 ρ ν-ν Methyl 6-hydrazinopyridazine-3-carboxylate dihydrochloride (484 mg, 2 mmol) and potassium acetate (588 mg) were added to triethyl orthoformate (2 mL), and the mixture was reacted at 90 °C overnight. . The reaction solution was subjected to preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain the title compound (321 mg, 99.2%) as a yellow solid. LC-MS: m / z [M+H]+ = 193. Intermediate 223 (3-Methyl-[l,2,4]triazolo[4,3-.b]pyridazin-6-yl)inethanol,OH CL n-n Methyl 3-methyl-[1,2,4]triazolo[4,3-¿>]pyridazine-6-carboxylate (300 mg, 1.562 mmol) in tetrahydrofuran (4 ml) was added and the mixture was stirred at - 20 °C for 15 minutes. Lithium aluminum hydride (54 mg, 1.406 mmol) was added to the reaction solution in three portions at −20 °C and the mixture was stirred at −20 °C for 30 minutes. Sodium sulfate decahydrate (5 g) was added to the reaction solution, filtered under reduced pressure; The organic phase was concentrated and subjected to preparative plating (dichloromethane / methanol = 30 / 1) to obtain the title compound (88 mg, 34.3%) as a yellow solid. CLEM: m / z [M+H]+ = 165. Intermediate 224 (2-Chloropyrimidin-4-yl)methanol Methyl 2-chloropyrimidine-4-carboxylate (500 mg, 2.89 mmol) in tetrahydrofuran (4 ml) was added, and the mixture was stirred at -20°C for 15 minutes. At -20 °C, lithium aluminum hydride (99 mg, 2.6 mmol) was added to the reaction solution - 164 in three portions, and the reaction was carried out at -20 °C for 30 minutes after the addition was completed. Sodium sulfate decahydrate (10 g) was added to the reaction solution, and the mixture was filtered under reduced pressure. The organic phase was concentrated and subjected to preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain the title compound (168 mg, 40.3%) as a brownish-black solid. LC-MS: m / z [M+H]+ = 145, 147. Intermediate 225 (2-Hydrazinopyrimidin-4-yl)methanol HCL CX < .nh2N N2 h (2-chloropyrimidin-4-yl)methanol (168 mg, 1.16 mmol) and hydrazine hydrate (64 mg, 1.27 mmol) in anhydrous ethanol (2 ml) were added, and the mixture was reacted at 90 °C for 1.5 hours. The mixture was subjected to preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (141 mg, 86.9%) as a tan oily liquid. LC-MS: m / z [M+H]+ = 141. Intermediate 226 (3-(Tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[4,3-a]pyridazin-7yl)methanol (2-hydrazinopyrimidin-4-yl)methanol (141 mg, 1.0 mmol) and tetrahydropyran 4-carbaldehyde (228 mg, 2.0 mmol) in ethanol (2 ml) were added and the mixture was stirred at room temperature. environment for 1 hour. Copper bromide (246 mg, 1.1 mmol) was added to the reaction solution, and a salt of potassium peroxosulfate complex (681 mg, 1.1 mmol) dissolved in water (1 .5 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered under reduced pressure; The organic phase was concentrated and subjected to preparative thin layer chromatography (dichloromethane / methanol = 30 / 1) to obtain the title compound (101 mg, 43.1%) as a brown oily liquid. LC-MS: m / z [M+H]+ = 235. - 165 Intermediate 227 5-Brcmo-6-methoxy-l-methyl-lH-indazole (intermediate 227-A) —ObA Xa v___y i \^N 5-Bromo-6-methoxy-2-methyl-2g-indazole (intermediate 227-B) O bA, An v___Z i Under nitrogen protection at 0 °C, 5-bromo-6-methoxy-1H-indazole (2.27 g, 10 mmol) was dissolved in W,N-dimethylphermamide (100 ml), and sodium hydride was slowly added ( 0.48 g, 12 mmol, 60% dispersed in mineral oil). The reaction mixture was stirred at room temperature for 0.5 hour and then iodomethane (2.13 g, 15 mmol) was added. The mixture was continued to stir at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate (50 ml χ 3). The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain a small polar component 5bromo-e-methoxy-l-methyl-lH-indazole (1.5 g , a pale yellow solid) in a yield of 62.5%. LC-MS: m / z [M+HJ+ = 241; A large polar component 5-brcmo-6-methoxy-2-methyl-2H-indazole (800 mg, a pale yellow solid) was obtained in 33% yield. LC-MS: m / z [M+HJ+ = 241. Intermediate 228 6-methoxy-l-methyl-l.H-indazole-5-carboxylic acid —O hoocA v__ / i \^N Under nitrogen protection, 5-bromo-6-methoxy-l-methyl-lH-indazole (1.4 g, 5.8 mmol) was dissolved in 20 ml of tetrahydrofuran, and the solution was cooled to 78 °C under nitrogen protection. nitrogen. At this temperature, n-butyllithium (2.6 ml, 6.4 mmol, 2.5 M in n-hexane solution) was slowly added. After stirring at this temperature for 0.5 hours, carbon dioxide gas was introduced. - 166 After stirring the reaction solution at this temperature for 1 hour, the temperature was naturally raised to room temperature and stirring was continued for 12 hours. The pH was adjusted to 5-6 with 1 N hydrochloric acid. The reaction solution was extracted with dichloromethane (50 ml x 3). The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title product (700 mg, a yellow solid) in a yield of 59%. LC-MS: m / z [M+H]+ = 207. Intermediate 229 (6-Methoxy-l-methyl-lH-indazol-5-yl)methanol Under nitrogen protection, 6-methoxy-l-methyl-HI-indazole-5carboxylic acid (100 mg, 0.49 mmol) was dissolved in 5 ml of tetrahydrofuran, and the solution was cooled to 0 °C under nitrogen protection. At this temperature, lithium aluminum hydride (55 mg, 1.46 mmol) was slowly added. After stirring at this temperature for 2 hours. The reaction was quenched with water, and the mixture was filtered. The filtrate was extracted with dichloromethane (50 ml x 3). The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title product (70 mg, a white solid) in 75% yield. LC-MS: m / z [M+H]+ = 193. Intermediate 330 6-Methoxy-2-methyl-2H-indazole-5-carboxylic acid —O hooc^a Vn V___Z I Under nitrogen protection, 5-bromo-6-methoxy-2-methyl-2phy-indazole (300 mg, 1.24 mmol) was dissolved in 10 ml of tetrahydrofuran, and the solution was cooled to 78 °C under nitrogen protection. At this temperature, n-butyllithium (0.55 ml, 6.4 mmol, 2.5 M in n-hexane solution) was slowly added. After stirring at this temperature for 0.5 hours, carbon dioxide gas was introduced. After stirring the reaction solution at this temperature for 1 hour, the temperature was naturally raised to room temperature and stirring was continued for 12 hours. The pH was adjusted to 5-6 with 1 N hydrochloric acid. - 167reaction solution was extracted with dichloromethane (50 mi x 3). The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title product (250 mg, a yellow solid) in 97% yield. LC-MS: m / z [M+HJ+ = 207. Intermediate 231 (6-Methoxy-2-methyl-2H-indazoI-5-yl)methanol —O Under nitrogen protection, 6-methoxy-2-methyl-2H-indazole-5carboxylic acid (100 mg, 0.49 mmol) was dissolved in 5 ml of tetrahydrofuran, and the solution was cooled to 0 °C under nitrogen protection. At this temperature, lithium aluminum hydride (55 mg, 1.46 mmol) was slowly added. After stirring for 2 hours at this temperature, the reaction was quenched with water, and the mixture was filtered. The filtrate was extracted with dichloromethane (50 ml x 3). The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title product (60 mg, white solid) in 65% yield. LC-MS: m / z [M+H]+ = 193. Intermediate 232 Methyl 1-(2-Cyanppropyl)-IH-pyrazolo[4,3-b]pyridine-5-carboxylate Methyl IH-pyrazolo[4,3-b]pyridine-5-carboxylate (CAS: 103377223-4, 400 mg, 2.3 mmol), 2-iodo-2-methylpropionitrile (CAS: 19481-79-9) were dissolved , 800 mg, 4 mmol) and cesium carbonate (1.6 g, 5 mmol) in 10 ml of acetonitrile, then the mixture was heated to 70 °C and stirred overnight. The solid was filtered, then the reaction solution was concentrated and purified by preparative plate (dichloromethane:methanol = 20 / 1) to obtain the title compound (350 mg, 64%) as a colored solid. white. LC-MS: m / z [M+H]+ = 245. Intermediate 233 3- (5- (Hydroxymethyl) -lH-pyrazolo[4,3-jb]pyridin-l-yl)-2- 168 - methylpropionitrile Methyl 1-(2-cyanopropyl)-IH-pyrazolo[4,3-b]pyridine-5-carboxylate (200 mg, 0.9 mmol) was dissolved in 5 ml of tetrahydrofuran, then 5 ml were added. of methanol and sodium borohydride (100 mg, 3 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated and purified by preparative plate (dichloromethane:methanol = 10:1) to obtain the title compound (100 mg, 45%) as a white solid. CLEM: m / z [M+H]+ = 217. Intermediate 234 Methyl 2-Benzyl-2H-pyrazolo[4,3-Jb]pyridine-5-carboxylate (intermediate 234-A) O methyl l-Benzyl-lH-pyrazolo[4,3-¿]pyridine-5-carboxylate (intermediate 234-B) The experimental operation was the same as the synthesis method of intermediate 232. From the starting materials of methyl 2H-pyrrolo[4,3-b]pyridine-5-carboxylate (500 mg, 2.82 mmol), (bromomethyl)benzene (960 mg, 5.65 mmol), the title compound was obtained as a yellow solid; a large polar component methyl 2-benzyl-2H-pyrazolo[4,3-b]pyridine-5-carboxylate (170 mg, 22.5%), a small polar component 1-benzyl-lH-pyrazolo[4 Methyl ,3-b]pyridin5-carboxylate (300 mg, 39.8%). LC-MS: m / z [M+H]+ = 268. Intermediate 235 (1-Benzyl-lH-pyrazolo[4,3-¿]pyridin-5-yl)methanol - 169 - The experimental operation was the same as the synthesis method of intermediate 233. The title compound (300 mg, crude product) was obtained as a yellow oil from a starting material 1-benzyl-lHpyrazolo[ Methyl 4,3-b]pyridine-5-carboxylate (300 mg, 1.1 mmol). LC-MS: m / z [M+H]+ = 240. Intermediate 236 (2-Benzyl-2H-pyrazolo[4,3-jb]pyridin-5-yl)methanol The experimental operation was the same as the synthesis method of intermediate 233. The title compound (100 mg, 65.7%) was obtained as a yellow solid from a starting material 2-benzyl-2H -pyrazolo[4,ΟΙ?]methyl pyridine-5-carboxylate (170 mg, 0.64 mmol). LC-MS: m / z [M+H]+ = 240. Intermediate 237 Methyl 1-((5-Methylisoxazol-3-yl)methyl)-lH-pyrazolo[4,3-¿]pyridine-5-carboxylate (intermediate 237-A) Methyl 2-((5-Methylisoxazol-3-yl)methyl)-2H-pyrazolo[4,3-jb]pyridine-5-carboxylate (intermediate 237-B) - 170 Methyl IH-pyrazolo[4, 3-b]pyridine-5-carboxylate (300 mg, 1.65 mmol), cesium carbonate (1.6 g, 4.95 mmol) and 3-(chloromethyl) were added )-5-methyl isothiazole (217 mg, 1.65 mmol) in acetonitrile (10 ml), and the mixture was stirred at 85 °C overnight. The reaction solution was directly separated and purified by preparative plate (dichloromethane / methanol = 20 / 1) to obtain 2-((5methylisoxazol-3-yl)methyl)-2H-pyrazolo[4,3-b]pyridin -methyl 5-carboxylate (130 mg, 29%) and methyl 1-((5-methyllisoxazol-3-yl)methyl)-lH-pyrazolo[4,3-b]pyridine-5carboxylate (250 mg, 56% ). LC-MS: m / z [M+HJ+ = 273. Intermediate 238 (1-(((5-Methylisoxazol-3-yl)methyl)-lH-pyrazolo[4,3-¿]pyridin-5-yl)methanol Methyl 1-((5-methylisoxazol-3-yl)methyl)-Ifi-pyrazolo[4,3-b]pyridine-5carboxylate (230 mg, 0.84 mmol) and NaBH4 (300 mg, 8 mmol) were added. in THF / MeOH (6 / 3 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and purified by preparative plate (dichloromethane / methanol = 15:1) to obtain the title compound (160 mg, 78.4%) LC-MS: m / z [M+H]+ = 246. Intermediate 239 (2-(((5-Methylisoxazol-3-yl)methyl)-2H-pyrazolo[4,3-¿]pyridin-5-yl) methanol Methyl 2-((5-methylisoxazol-3-yl)methyl)-2H-pyrazolo[4,3-b]pyridine-5carboxylate (130 mg, 0.48 mmol) and NaBH4 (200 mg, 10 mmol) were added. in THF / MeOH (6 / 3 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and purified by preparative plate (dichloromethane / methanol = 15 / 1) to obtain the title compound (90 mg, 76.3%). LC-MS: m / z [M+H]+ = 246. Intermediate 240 - 171 Methyl 2-(Oxetan-3-yl)-2H-pyrazolo[4,3-b]pyridine-5-carboxylate (intermediate 240-A) EITHER Methyl 1-(Oxetan-3-yl)-lH-pyrazolo[4,3-b]pyridine-5-carboxylate (intermediate 240-B) either Methyl 2H-pyrazolo[4,3-b]pyridine-5-carboxylate (400 mg, 2.2 mmol), 3-iodooxetane (500 mg, 2.6 mmol) and cesium carbonate (2.20 mmol) were added. g, 6.6 mmol) in γΛΤ-dimethylformamide (20 ml), and then the mixture was stirred overnight at 60 °C. The reaction solution was directly purified by thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound as a white solid, with a large polar component of 2-( methyl oxetan-3-yl)-2H-pyrazolo[4,3-b]pyridine-5-carboxylate (100 mg, 19%), and a small polar component of 1-(oxetan-3-yl)-IH- Methyl pyrazolo[4,3-b]pyridin5-carboxylate, m / z [M+H]+ = 234. Intermediate 241 (2-(Oxetan-3-yl)-2g-pyrazolo[4,3-¿]pyridin-5-yl)methanol The experimental operation was the same as the synthesis method of intermediate 233. The title compound (20 mg, 28.5%) was obtained as a white oil from the starting material 2-(oxetan-3 Methyl -yl)-2H-pyrazolo[4,3b]pyridine-5-carboxylate (100 mg, 0.43 mmol). LC-MS: m / z [M+H]+ = 206. Intermediate 242 (1-(Oxetan-3-yl)-2H-pyrazolo[4,3-¿]pyridin-5-yl)methanol - 172 The experimental operation was the same as the synthesis method of intermediate 233. The title compound (100 mg, 75.8%) was obtained as a yellow solid from the starting material 1-(oxetan Methyl -3-yl)-IH-pyrazolo[4,3b]pyridine-5-carboxylate (150 mg, 0.64 mmol). LC-MS: m / z [M+HJ+ = 206. Intermediate 243 Methyl 1-(2-Cyanoethyl)-lH-pyrazolo[4,3-b]pyridine-5-carboxylate C.N. EITHER The experimental operation was the same as the synthesis method of intermediate 232. The title compound (570 mg, 87.7%) was obtained as a yellow solid from the starting materials of 2H-pyrazol[ methyl 4,3-b]pyridin5-carboxylate (500 mg, 2.82 mmol) and 3-bromopropanenitrile (680 mg, 5.65 mmol). LC-MS: m / z [M+H]+ = 231. Intermediate 244 3-(5-(Hydroxymethyl)-lH-pyrazolo[4,3-b]pyridin-l-yl)pionitrile C.N. The experimental operation was the same as the synthesis method of intermediate 233. The title compound (200 mg, 40%) was obtained as a yellow solid from the material 1-(2-cyanoethyl)-lH- Methyl pyrazolo[4,3-b]pyridine-5carboxylate (570 mg, 2.5 mmol). LC-MS: m / z [M+H]+ = 203. Intermediate 245 Methyl 2-Phenethyl-2H-pyrazolo[4,3-b]pyridine-5-carboxylate (intermediate 245-A) O Methyl l-Phenethyl-lH-pyrazolo[4,3-b]pyridine-5-carboxylate (intermediate 245-B) - 173 - EITHER The experimental operation was the same as the synthesis method of intermediate 232. From the starting materials methyl 2H-pyrazolo[4,3-b]pyridine-5-carboxylate (500 mg, 2.82 mmol) and ( 2-iodoethyl)benzene (1300 mg, 5.65 mmol), the title compound was obtained, a mixture of methyl 2-phenethyl-2H-pyrazolo[4,3-b]pyridine-5carboxylate / 1-phenethyl-lH Methyl-pyrazolo[4,3-b]pyridine-5-carboxylate (600 mg, 75.6%) as a yellow solid. LC-MS: m / z [M+H]+ = 282. Intermediate 246 (2-Phenethyl-2H-pyrazolo[4,3-¿]pyridin-5-yl)methanol (intermediate 246-A) (1-Phenethyl-lH-pyrazolo[4,3-b]pyridin-5-yl)methanol (intermediate 246-B) The experimental operation was the same as the synthesis method of intermediate 233. From the starting material, a mixture of methyl 2-phenethyl-2H-pyrazolo[4,3b]pyridine-5-carboxylate / 1-phenethyl-lH -methyl pyrazolo[4,3-b]pyridine-5carboxylate (600 mg, 2.14 mmol), the title compound was obtained, a mixture of (2-phenethyl-2H-pyrazolo[4,3-b]pyridin -5-yl)methanol / (1-phenethyl-lHpyrazolo[4,3-b]pyridin-5-yl)methanol (500 mg, 92.6%) as a yellow oil. LC-MS: LC-MS: m / z [M+H]+ = 254. Intermediate 247 Methyl 2-(Tetrahydrofuran-3-yl)-2H-pyrazolo[4,3-¿]pyridine-5-carboxylate (intermediate 247-A) - 174 O Methyl 1-(Tetrahydrofuran-3-iI)-lH-pyrazolo[4,3-¿]pyridine-5-carboxylate (intermediate 247-B) The experimental operation was the same as the synthesis method of intermediate 232. From the starting materials methyl 2B-pyrazolo[4,3-b]pyridine-5-carboxylate (500 mg, 2.82 mmol) and 3 -iodotetrahydrofuran (1100 mg, 5.65 mmol), the title compound was obtained as a yellow solid, and a large polar component 2-(tetrahydrofuran-3-yl)-2H-pyrazolo[4, methyl 3b]pyridine-5-carboxylate (230 mg, 33%) and a small polar component methyl 1(tetrahydrofuran-3-yl)-IH-pyrazolo[4,3-b]pyridine-5-carboxylate (330 mg , 47.3 %). LC-MS: m / z [M+H]+ = 248. Intermediate 248 (2-(Tetrahydrofuran-3-yl)-2H-pyrazolo[4,3-b]pyridin-5-yl)methanol The experimental operation was the same as the synthesis method of intermediate 233. The title compound (150 mg, 73.5%) was obtained as a yellow solid from the starting material 2-(tetrahydrofuran-3 Methyl -yl)-2Hpyrazolo[4,3-b]pyridine-5-carboxylate (230 mg, 1.1 mmol). LC-MS: m / z [M+H]+ = 220. Intermediate 249 (1-(Tetrahydrofuran-3-yl)-lH-pyrazolo[4,3-b]pyridin-5-yl)methanol H.O. The experimental operation was the same as the synthesis method of the intermediate - 175 - 233. The title compound (100 mg, 37.6%) was obtained as a yellow solid from the starting material l-(tetrahydrofuran-3-yl)-lHpyrazolo[4,3-b]pyridin -methyl 5-carboxylate (300 mg, 1.21 mmol). LC-MS: m / z [M+H]+ = 220. Intermediate 250 Methyl 2-(1-(tert-Butoxycarbonyl)azetidin-3-yl)-2H-pyrazolo[4,3-¿]pyridine-5carboxylate (intermediate 250-A) N-Boc EITHER Methyl 1-(1-(tert-Butoxycarbonyl)azetidin-3-yl)-lH-pyrazolo[4,3-b]pyridine-5carboxylate (intermediate 250-B) Boc / The experimental operation was the same as the synthesis method of intermediate 232. From the starting materials methyl iB-pyrazolofiR-bJpyridine-S-carboxylate (500 mq, 2.82 mmol) and 3-(toluenesulfonyloxy)azetidine- tere-butyl l-carboxylate (1600 mg, 5.65 mmol), the title compound was obtained as a colorless oil, and a large polar component 2-(1-(tert-butoxycarbonyl)azetidin-3-yl methyl )-2H-pyrazolo[4,3-b]pyridine-5-carboxylate (300 mg, 32%) and a small polar component l-(l-(tert-butoxycarbonyl)azetidine-311)-lH-pyrazolo[ Methyl 4,3-b]pyridine-5-carboxylate (400 mg, 42.6%). LC-MS: m / z [M+H]+ = 333. Intermediate 251 Tere-butyl 3-(5-(Hydroxymethyl)-2H-pyrazolo[4,3-b]pyridin-2-yl)azetidin-l-carboxylate N-Boc The experimental operation was the same as the synthesis method of the intermediate 233. The title compound (170 mg, 62.9%) was obtained as an oil - 176 colorless from the starting material methyl 2-(l-(tert-butoxycarbonyl)azetidin-3-yl)2H-pyrazolo[4,3-b]pyridine-5-carboxylate (300 mg, 0.9 mmol ). LC-MS: m / z [M+H]+ = 305. Intermediate 252 3-(5-((((7-Methoxy-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6yl]oxy)methyl)-2H tere-butyl -pyrazolo[4,3-b]pyridin-2-yl)azetidine-l-carboxylate N-Boc The experimental operation was the same as that of embodiment 226. The title compound (130 mg, 43.6%) was obtained as a yellow solid from the starting materials 3-(5-(hydroxymethyl tere-butyl )-2H-pyrazolo[4,3-b]pyridin2-yl)azetidine-l-carboxylate (170 mg, 0.56 mmol) and 3-(6-chloro-7methoxy-[1,2,4 ]triazolo[4,3-b]pyridazin-3-yl)-5-methyllysoxazole (150 mg, 0.56 mmol). LC-MS: m / z [M+H]+ = 534. Intermediate 253 3-(6-((2- (Azetidin-3-yl)-2H-pyrazolo[4,3-b]pyridin-5-yl)methoxy)-7-methoxy[1,2,4]triazolo[4, 3-b]pyridazin-3-yl)-5-methylisoxazole 3-(5-((((7-methoxy-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3b]pyridazin-6-yl]oxy)methyl) was placed Tere-butyl -2H-pyrazolo[4,3-¿>]pyridin-2-yl)azetidine-l-carboxylate (130 mg, 0.24 mmol) in ethyl acetate (5 ml), and hydrochloric acid was dripped / ethyl acetate (2 ml, 4 M) made internally into the reaction solution, and the reaction was carried out at room temperature for 4 hours. The reaction solution was adjusted to alkaline with the saturated aqueous sodium bicarbonate solution , and a solid precipitated. After filtration, the filter cake was washed with water three times to obtain the title compound (100 mg, 94.7%) as a yellow solid. LC-MS: m / z [M+H]+ = 434. Intermediate 254 3-(5-(Hydroxymethyl)-iH-pyrazolo[4,3-b]pyridin-2-yl)azetidin-l-carboxylate - 178 The experimental operation was the same as that of intermediate 253. The title compound (170 mg, 80.5%) was obtained as a yellow solid from the starting materials 3-(5-(( ((7-methoxy-3-(5-methylisoxazol-3-yl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)methyl)-IH-pyrazolo[4,3 -¿>]naphthalen-1yl) azetidine-l-carboxylate tere-butyl (260 mg, 0.49 mmol).LC-MS: m / z [M+H]+ = 434. Intermediate 257 Methyl 2-Isopropyl-2H-pyrazolo[4,3-¿]pyridine-5-carboxylate (intermediate 257A) / γχχ or methyl l-Isopropyl-lH-pyrazolo[4,3-b]pyridine-5-carboxylate ( intermediate 257B) EITHER The experimental operation was the same as the synthesis method of intermediate 232. From the starting materials methyl 2H-pyrazolo[4,3-Jb]pyridine-5-carboxylate (500 mg, 2.82 mmol) and 2 -iodopropane (960 mg, 5.65 mmol), the title compound was obtained in the form of a yellow liquid, and a large polar component 2-isopropyl-2H-pyrazolo[4,3-b]pyridin- methyl 5-carboxylate (260 mg, 42%) and a small polar component methyl 1-isopropyl-lH-pyrazolo[4,3-b]pyridine5-carboxylate (350 mg, 56.6%). LC-MS: m / z [M+H]+ = 220. Intermediate 258 (2-Isppropyl-2H-pyrazolo[4,3-¿]pyridin-5-yl)methanol The experimental operation was the same as the synthesis method of intermediate 233. The title compound (120 mg, 55%) was obtained as a yellow solid from the starting material 2-isopropyl-2H-pyrazolo[ Methyl 4,3-b]pyridine-5carboxylate (250 mg, 1.14 mmol). LC-MS: m / z [M+HJ+ = 192. Intermediate 259 - 179 - (1-Isqpropyl-lH-pyrazolo[4,3-b]pyridin-5-yl)methanol The experimental operation was the same as the synthesis method of intermediate 233. The title compound (220 mg, 72%) was obtained as a yellow oil from the starting material 1-isopropyl-1H-pyrazolo[ Methyl 4,3-b]pyridine-5carboxylate (350 mg, 1.6 mmol). LC-MS: m / z [M+H]+ = 192. Intermediate 260 l-Methyl-lH-pyrazolo[4,3-b]methyl pyridine-5-carboxylate (intermediate 260-A) EITHER Methyl 2-Methyl-2H-pyrazolo[4,3-b]pyridine-5-carboxylate (intermediate 260-B) AND NOT The experimental operation was the same as the synthesis method of intermediate 232. From the starting materials methyl 2H-pyrazolo[4,3-b]pyridine-5-carboxylate (500 mg, 2.82 mmol) and iodomethane (800 mg, 5.65 mmol), the title compound was obtained as a yellow solid, and a large polar component 2-methyl-2H-pyrazolo[4,3-t>]pyridin-5 was obtained. -methyl carboxylate (270 mg, 50%) and a small polar component methyl 1-methyl-lH-pyrazolo[4,3-b]pyridine-5carboxylate (200 mg, 37%). LC-MS: m / z [M+HJ+ = 192. Intermediate 261 (2-Methyl-2H-pyrazolo[4,3-b]pyridin-5-yl)methanol The experimental operation was the same as the synthesis method of intermediate 233. The title compound (200 mg, 117%) was obtained as a yellow oil from the starting material 2-methyl-2H-pyrazolo[ Methyl 4,3-b]pyridin5-carboxylate (200 mg, 1.05 mmol). LC-MS: m / z [M+H]+ = 164. - 180 Intermediate 262 Methyl 2-(Tetrahydro-2H-pyran-4-yl)-2H-pyrazolo[4,3-b]pyridine-5-carboxylate (intermediate 262-A) EITHER Methyl 1-(Tetrahydro-2H-pyran-4-yl)-lH-pyrazolo[4,3-¿]pyridine-5-carboxylate (intermediate 262-B) The experimental operation was the same as the synthesis method of the intermediate 232. From the starting materials methyl 2H-pyrazolo[4,3~b]pyridine-5-carboxylate (500 mg, 2.82 mmol) and tetrahydro-2H-pyran-4-yl-4-methylbenzenesulfonate ( 1400 mg, 5.65 mmol), the title compound was obtained as a yellow solid, and a large polar component 2-(tetrahydro-2H-pyran-4yl)-2H-pyrazolo[4, methyl 3-b]pyridine-5-carboxylate (220 mg, 29.8%) and a small polar component 1-(tetrahydro-2H-pyran-4-yl)-IH-pyrazolo[4,3-b]pyridine -methyl 5carboxylate (220 mg, 29.8 %). LC-MS: m / z [M+HJ+ = 262. Intermediate 263 (2-(Tetrahydro-2H-pyran-4-yl)-2H-pyrazolo[4,3-b]pyridin-5-yl)methanol ΗθΑζΧ'ΝΑ° The experimental operation was the same as the synthesis method of intermediate 233. The title compound (60 mg, 30.6%) was obtained as a white solid from the starting material 2-(tetrahydro-2H methyl -pyran-4-yl)-2Hpyrazolo[4,3-b]pyridine-5-carboxylate (220 mg, 0.84 mmol). LC-MS: m / z [M+H]+ = 234. Intermediate 264 (1-(Tetrahydro-2B-pyran-4-yl)-lH-pyrazolo[4,3-b]pyridin-5-yl)methanol - 181 - The experimental operation was the same as the synthesis method of intermediate 233. The title compound (100 mg, 51%) was obtained as a white solid from the starting material l-(tetrahydro-2H-pyran Methyl -4-yl)-lHpyrazolo[4,3-b]pyridine-5-carboxylate (220 mg, 0.84 mmol). LC-MS: m / z [M+H]+ = 234. Intermediate 265 Methyl 2-(2-Methoxyethyl)-2H-pyrazolo[4,3-b]pyridine-5-carboxylate (intermediate 265-A) EITHER Methyl 1-(2-Methoxyethyl)-lH-pyrazolo[4,3-¿>]pyridine-5-carboxylate (intermediate 265-B) EITHER The experimental operation was the same as the synthesis method of intermediate 232. From the starting materials methyl 2H-pyrazolo[4,3-Jb]pyridine-5-carboxylate (500 mg, 2.82 mmol) and l -bromo-2-methoxyethane (780 mg, 5.65 mmol), the title compound was obtained as a yellow solid, and a large polar component 2-(2-methoxyethyl)-2H-pyrazolo[ methyl 4,3-b]pyridine-5-carboxylate (290 mg, 43.7%) and a small polar component methyl 1-(2-methoxyethyl)-1Hpyrazolo[4,3-b]pyridine-5-carboxylate (340 mg, 51.2%) . LC-MS: m / z [M+H]+ = 236. Intermediate 266 (2-(2-Methoxyethyl)-2H-pyrazolo[4,3-.b]pyridin-5-yl)methanol - 182 - > your N C N N C C N a The experimental operation was the same as the synthesis method of intermediate 233. The title compound (100 mg, 39%) was obtained as a yellow oil from the starting material 2-(2-methoxyethyl)- Methyl 2H-pyrazolo[4,3b]pyridine-5-carboxylate (290 mg, 1.23 mmol). LC-MS: m / z [M+H]+ = 208. Intermediate 267 (1-(2-Methoxyethyl)-lH-pyrazolo[4,3-jb]pyridin-5-yl)methanol The experimental operation was the same as the synthesis method of intermediate 233. The title compound (200 mg, 66.7%) was obtained as a yellow oil from the starting material 1-(2-methoxyethyl Methyl )-pyrazolo[4,3¿>] pyridine-5-carboxylate (340 mg, 1.45 mmol). LC-MS: m / z [M+H]+ = 208. Intermediate 268 3-Methyl-l-(oxetan-3-yl)-LH-pyrazolo[4,3—Jb]pyridine (intermediate 268-A).N. 7 (Γ i 3-Methyl-2-(oxetan-3-yl)-2H-pyrazolo[4,3-¿]pyridine (intermediate 268-B) / I saw N^A n' Under nitrogen protection and at 80 °C, 3-methyl-lH-pyrazolo[4, 3b]pyridine (3.0 g, 22.5 mmol), 3-iodooxetane (4.97 g, 27.0 mmol) were dissolved. and cesium carbonate (8.81 g, 27.0 mmol) in 2V,A / -dimethylformamide (40 ml), and the reaction solution was stirred for 3 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by preparative liquid phase to obtain a small polar component 3-methyl-l-(oxetan-3-yl)-lH-pyrazolo[4,3 -b] - 183 pyridine (2.3 g, a white solid) in 54% yield, LC-MS: m / z [M+H]+ = 190; and to obtain a large polar component 3-methyl-2-(oxetan-3-yl)-2Hpyrazolo[4,3-b]pyridine (0.5 g, a white solid) in a yield of 11.7% . LC-MS: m / z [M+H]+ = 190. Intermediate 269 4-3-Methyl-l-(oxetan-3-yl)-IH-pyrazolo[4,3-b]pyridine oxide > your N C N N C C N σ 3-methyl-l-(oxetan-3-yl)-IH-pyrazolo[4,3-¿>]pyridine (1.6 g, 8.72 mmol) was dissolved in dichloromethane (20 ml), then mchloroperoxybenzoic acid (3.8 g, 21.8 mmol) was added and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title product (1.7 g, a yellow solid pale) with a yield of 99%. LC-MS: m / z [M+H]+ = 206. Intermediate 270 3-Methyl-l-(oxetan-3-yl)-lH-pyrazolo[4,3-b]pyridine-5-carbonitrile 3-Methyl-l-(oxetan-3-yl)-IH-pyrazolo[4,3-b]pyridine 4-oxide (1.7 g, 8.8 mmol) was dissolved in dichloromethane (25 ml). Trimethylsilyl cyanide (1.61 g, 16.4 mmol) and dimethylcarbamoyl chloride (1.77 g, 16.4 mmol) were added, and the reaction solution was stirred at 30 °C for 16 hours. The reaction solution was concentrated and the residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title product (1.2 g, white solid) in 69% yield. LC-MS: m / z [M+H]+ = 215. Intermediate 271 - 184 3-methyl-l-(oxetan-3-yl)-lH-pyrazolo[4,3-¿]pyridine-5-carboxylic acid 3-methyl-l-(oxetan-3-yl)-ly-pyrazolo[4,3-i>]pyridine-5-carbonitrile (500 mg, 2.3 mmol) was dissolved in ethanol (20 ml), then , a saturated aqueous solution of sodium hydroxide (934 mg, 23.4 mmol) was added and the reaction solution was stirred at 90 ° C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature; The pH of the reaction solution was adjusted to <7 with 1N hydrochloric acid, then the reaction solution was extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain the title product (437 mg , a white solid) with a yield of 54%. LC-MS: m / z [M+H]+ = 234. Intermediate 272 Methyl 3-Methyl-l-(oxetan-3-yl)-lH-pyrazolo[4,3—Jb]pyridine-5-carboxylate Under nitrogen, 3-methyl-l-(oxetan-3-yl)-IH-pyrazolo[4,3b]pyridine-5-carboxylic acid (280 mg, 1.2 mmol) was dissolved in methanol / toluene = 1 / 4 (7.5 ml), then (trimethylsilyl)diazomethane (466 mg, 4.1 mmol) was added and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain the title product (130 mg, a white solid) in a yield of 44%. LC-MS: m / z [M+H]+ = 248. Intermediate 273 (3-Methyl-l-(oxetan-3-yl)-lH-pyrazolo[4,3-¿]pyridin-5-yl)inethanol - 185 - Under nitrogen, methyl 3-methyl-l-(oxetan-3-yl)-lH-pyrazolo[4,3-b]pyridine5-carboxylate (130 mg, 0.52 nmol) was dissolved in tetrahydrofuran (5 ml). Anhydrous calcium chloride (117 mg, 1.04 mmol) and sodium borohydride (40 mg, 1.04 mmol) were added, and the reaction solution was stirred at 60 °C for 8 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by column chromatography to obtain the title product (90 mg, a white solid) in a yield of 78%. LC-MS: m / z [M+H]+ = 220. Intermediate 274 4-3-Methyl-2-(oxetan-3-yl)-2g-pyrazolo[4,3-jb]pyridine oxide 3-Methyl-2-(oxetan-3-yl)-2-pyrazolo[4,3-¿>]pyridine (0.5 g, 2.65 mmol) was dissolved in dichloromethane (10 ml), then mchloroperoxybenzoic acid (1.14 g, 6.6 mmol) was added and the reaction solution was stirred at 24 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title product (380 mg, a pale yellow solid). with a yield of 70%. LC-MS: m / z [M+H]+ = 206. Intermediate 275 3-Methyl-2-(oxetan-3-yl)-2H-pyrazolo[4,3-jb]pyridin-5-carbonitrile 3-Methyl-2-(oxetan-3-yl)-2H-pyrazolo[4,3-b]pyridine 4-oxide (330 mg, 1.61 mmol) was dissolved in dichloromethane (10 ml). Cyanide was added - 186 trimethylsilyl (320 mg, 3.2 mmol) and dimethylcarbamoyl chloride (346 mg, 3.2 mmol), and the reaction solution was stirred at 30 ° C for 16 hours. The reaction solution was concentrated and the residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title product (280 mg, white solid) in 80% yield. LC-MS: m / z [M+H]+ = 215. Intermediate 276 3-methyl-2-(oxetan-3-yl)-2H-pyrazolo[4,3-b]pyridine-5-carboxylic acid O HO^\_N_ / V° 3-Methyl-2-(oxetan-3-yl)-2H-pyrazolo[4,3-¿>]pyridine-5-carbonitrile (280 mg, 1.3 mmol) was dissolved in ethanol (20 ml), then , a saturated aqueous sodium hydroxide solution (523 mg, 13.1 mmol) was added and the reaction was stirred at 90 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the pH of the reaction solution was adjusted to <7 with 1 N hydrochloric acid; The reaction solution was extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain the title product (110 mg, a white solid) in a yield of 34%. LC-MS: m / z [M+H]+ = 234. Intermediate 277 Methyl 3-Methyl~2-(oxetan-3-yl)-2H-pyrazolo[4,3-b]pyridine-5-carboxylate Or __ / \x° Under nitrogen, 3-methyl-2-(oxetan-3-yl)-2H-pyrazolo[4,3b]pyridine-5-carboxylic acid (130 mg, 0.56 mmol) was dissolved in methanol / toluene = 1 / 4 (7.5 ml), then (trimethylsilyl)diazomethane (191 mg, 1.67 mmol) was added and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain the title product (110 mg, white solid) in 79% yield. LC-MS: m / z [M+H]+ = 248. Intermediate 278 - 187(3-Methyl-2- (oxetan-3-yl) -2g-pyrazolo[4,3-¿]pyridin-5-yl)inethanolHO'^YNX_ / VXnN Under nitrogen, methyl 3-methyl-2-(oxetan-3-yl)-2H-pyrazolo[4,3-b]pyridine5-carboxylate (110 mg, 0.44 mmol) was dissolved in tetrahydrofuran (5 ml). Anhydrous calcium chloride (99 mg, 0.88 mmol) and sodium borohydride (34 mg, 1.04 mmol) were added, and the reaction solution was stirred at 60 °C for 8 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by column chromatography to obtain the title product (30 mg, a white solid) in a yield of 34%. LC-MS: m / z [M+H]+ = 220. Intermediate 279 l-Ethyl-3-methyl-lH-pyrazolo[4,3-b]pyridine (intermediate 279-A) 3-methyl-1H-pyrazolo[4,3-b]pyridine (2.0 g, 15 mmol) was dissolved in N,Ndimethylformamide (20 ml), and sodium hydride (720 mg, 18 ml) was added to the reaction solution. .0 mmol, 60% dispersed in mineral oil) after cooling in an ice bath. The reaction solution was stirred for 30 minutes, then iodoethane (2.8 g, 18.0 mmol) was added and the reaction solution was stirred for 16 hours. The reaction solution was quenched by adding water, extracted with ethyl acetate, washed with saturated sodium chloride. The organic phase was dried, concentrated, and the residue was purified by preparative liquid phase to obtain a small polar component of a white solid l-ethyl-3-methyl-lH-pyrazolo[4,3¿]pyridine (1 .0 g, a yield of 43%). EM m / z (ESI): 162 [M+l]. A large polar component 2-ethyl-3-methyl-2H-pyrazolo[4,3-¿]pyridine (0.8 g, a white solid) was obtained in 34% yield. EM m / z (ESI): 162 [M+l]. - 188 Intermediate 280 4-L-ethyl-3-methyl-lH-pyrazolo[4,3-b]pyridine oxide l-ethyl-3-methyl-lH-pyrazolo[4,3-b]pyridine (1.0 g, 6.2 mmol) was dissolved in dichloromethane (20 ml), then m-chloroperoxybenzoic acid ( 2.14 g, 12.4 mmol) and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated and the residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title product (0.8 g, pale yellow solid) in 73% yield. . EM m / z (ESI): 178 [M+l]. Intermediate 281 l-Ethyl-3-methyl-lg-pyrazolo[4,3-b]pyridine-5-carbonitrile l-ethyl-3-methyl-lH-pyrazolo[4,3-b]pyridine 4-oxide (0.4 g, 2.26 mmol) was dissolved in dichloromethane (8 ml). Trimethylsilyl cyanide (0.45 g, 4.5 mmol) and dimethylcarbamoyl chloride (0.24 g, 2.26 mmol) were added, and the reaction solution was stirred at 30 °C for 16 hours. The reaction solution was concentrated and the residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title product (0.3 g, white solid) in 71% yield. MS m / z (ESI): 187 [M+I]. Intermediate 282 l-ethyl-3-methyl-lH-pyrazolo[4,3-b]pyridine-5-carboxylic acid l-ethyl-3-methyl-lH-pyrazolo[4,3-b]pyridin-5-carbonitrile (300 mg, - 189 1.61 mmol) in concentrated hydrochloric acid (5 ml), and the reaction solution was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, and the pH of the reaction solution was adjusted to between 6 and 7 with an aqueous sodium bicarbonate solution; The reaction solution was extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain the title product (200 mg, a white solid) in a yield of 61%. EM m / z (ESI): 206 [M+l]. Intermediate 283 methyl l-Ethyl-3-methyl-lg-pyrazolo[4,3-b]pyridine-5-carboxylate Under nitrogen, l-ethyl-3-methyl-lH-pyrazolo[4,3-b]pyridine-5carboxylic acid (200 mg, 0.97 mmol) was dissolved in methanol / toluene = 1 / 4 (7.5 ml). , then (trimethylsilyl)diazomethane (336 mg, 2.9 mmol) was added and ...

Claims

1. A compound represented by formula I, a cis-trans isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a solvate thereof, a hydrate thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof; OR R2 I wherein, Z is a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaromatic ring is optionally substituted with one or more R3s; R3 is independently halogen, cyano, Cl-6 alkyl, Cl-6 alkoxy (Cl6 alkyl), C3-6 cycloalkyl alkoxy (Cl-6), C3-6 cycloalkyl alkoxy (Cl-6) alkyl (Cl6), C3-7 heterocycloalkyl or C3-7 heterocycloalkyl alkyl (Cl-6), and R3 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, Cl-6 alkyl and Cl-6 alkylamino;R1 is H, Cl-6 alkyl, C3-6 cycloalkyl, C3-7 heterocycloalkyl, C3-6 cycloalkyl alkyl (Cl-6) or Cl-6 alkoxy alkyl (Cl-6), and R1 is optionally substituted with 1-4 substituents selected independently from the group consisting of halogen, cyano, hydroxyl, Cl-6 alkyl, Cl-6 alkoxy and Cl-6 alkylamino; R2 is heterocyclyl, phenyl or heteroaryl, and R2 is optionally substituted with 1-4 substituents selected independently from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, C3-6 cycloalkenyl, -NR4R5, -C(O)NR4R5, -COOH, -SO2-Cl-6 alkyl and -SO2NR6R7; R is independently H, Cl-6 alkyl, Cl-6 alkenyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, heterocyclyl, aryl or heteroaryl, and R is optionally substituted with 1-3 R';R' is independently halogen, cyano, hydroxyl, C3-6 cycloalkyl, Cl-6 alkylamino, Cl-6 alkyl, (Cl-6) alkoxy, Cl-3 alkyl substituted with cyano or halogen, Cl-6 alkylsulfuryl, heterocyclyl, heteroaryl, 5- to 10-281-membered heteroaryl substituted with 1-3 R'-l, -(C=O)NR8R9, C3-6 cycloalkyl substituted with 13 cyano, -(C=O)R'-2, C6-18 aryl, or 3- to 9-membered heterocyclyl substituted with 1-3 R'-3, -SO2R10; R'-l is independently Cl-6 alkyl; R8 and R9 are independently H or alkyl Cl-6, or R8 and R9 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, and the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; R'-2 is C3-6 cycloalkyl or alkyl Cl-6; R'-3 is independently alkyl Cl-6; RIO is alkyl Cl-6;R4 and R5 are independently H, Cl-6 alkyl, or C3-6 cycloalkyl, or R4 and R5 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl, the heteroatom being selected from one or more of N, S, and O, and the number of heteroatoms being 1, 2, or 3; each of R4 and R5 is optionally substituted with 1-5 substituents independently selected from: amino, halogen, hydroxyl, Cl-6 alkyl, and Cl-6 alkoxy; R6 and R7 are independently Cl-6 alkyl.

2. The compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof according to claim 1, wherein formula I is represented by formula II, wherein X is N or CH; preferably, formula II is represented by formula III: wherein Y is C or N; A is a 5- to 6-membered heterocyclic ring, a 5- to 6-membered heteroaromatic ring, or is absent, and the heteroatoms of the 5- to 6-membered heterocyclic ring and the 5- to 6-membered heteroaromatic ring are independently N, and the number of heteroatoms is 1 or 2; n is any integer from 0 to 4.

3. The compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof according to claim 1, wherein, R3 is Cl-6 alkyl or Cl-6 alkoxy alkyl (Cl-6) , and R3 is optionally substituted with 1-4 hydroxyl; R1 is Cl-6 alkyl or C3-6 cycloalkyl alkyl (Cl-6) , and R1 is optionally substituted with 1-4 halogens; R2 is phenyl or heteroaryl; and R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, C3-6 cycloalkenyl, -NR4R5, -C(O)NR4R5, -COOH, -SO2 Cl-6 alkyl and -SO2NR6R7; wherein, the -R is -Cl-6 alkyl, -Cl-6 alkenyl, -C3-6 cycloalkyl, heterocyclyl, -aryl or -heteroaryl; the -OR is -O-Cl-6 alkyl or -O-heterocyclyl;the -C(O)R is -C(0)-alkyl Cl-6, -C(0)-alkenyl Cl-6, -C(0)-cycloalkyl C3-6 or C(0)-aryl.; 4. The compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof according to any one of claims 1 to 3, wherein, R3 is Cl-6 alkyl or Cl-6 alkoxy alkyl (Cl-6), and R3 is optionally substituted with 1-4 hydroxyl; R1 is Cl-6 alkyl or C3-6 cycloalkyl alkyl (Cl-6), and R1 is optionally substituted with 1-4 halogens; R2 is either phenyl or heteroaryl, and the heteroaryl is either a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl, and the 9- to 10-membered bicyclic heteroaryl is a bicyclic heteroaryl of a 5- to 6-membered heteroaryl fused with a 5- to 6-membered heteroaryl;R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, C3-6 cycloalkenyl, -NR4R5, -SO2-Cl-6 alkyl, and -SO2NR6R7; the -R is -Cl-6 alkyl, -Cl-6 alkenyl, -C3-6 cycloalkyl, -heterocyclyl, -aryl, or -heteroaryl; the -OR is -O-Cl-6 alkyl or -heterocyclyl; the -C(O)R is -C(O)-Cl-6 alkyl, -C(O)Cl-6 alkenyl, -C(O)C3-6 cycloalkyl, or -C(O)-aryl.

5. The compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof according to any one of claims 1 to 3, wherein, R3 is Cl-6 alkyl; R1 is Cl-6 alkyl; R2 is a 9- to 10-membered bicyclic heteroaryl, and the 9- to 10-membered bicyclic heteroaryl is a bicyclic heteroaryl of a 5- to 6-membered heteroaryl fused with a 5- to 6-membered heteroaryl; R2 is optionally substituted with 1-4 substituents selected independently from the group consisting of halogen, cyano, oxo, -R, -OR, C3-6 cycloalkenyl, -NR4R5, -SO2-alkyl Cl-6 and -SO2NR6R7; the -R is -alkyl Cl-6, -alkenyl Cl-6, -cycloalkyl C3-6, -heterocyclyl, -aryl or -heteroaryl; the -OR is -O-alkyl Cl-6 or -heterocyclyl;-C(O)R is -C(O)-alkyl Cl-6, -C(O)alkenyl Cl-6, -C(O)-cycloalkyl C3-6 or -C(O)-aryl.; 6. The compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof according to any one of claims 1 to 3, wherein, R1 is Cl-6 alkyl; R3 is Cl-6 alkyl; R2 is heteroaryl; the heteroaryl is a 5- to 10-membered heteroaryl, wherein -284 the heteroatom is N and the number of heteroatoms is 1, 2, or 3; R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of cyano, -R, or -OR; R is independently Cl-6 alkyl or heterocyclyl, and R is optionally substituted with 1-3 R'; R' is independently halogen, hydroxyl, a 3- to 9-membered heterocyclyl substituted with 1-3 R'-3, a 5- to 10-membered heteroaryl substituted with R'-1 alkoxy (Cl-6).

7. The compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof according to claim 6, wherein, R1 is alkyl Cl-6; R3 is alkyl Cl-6; x and R2 are N; Y is C or N; A is a 5- to 6-membered heterocyclic ring, and the heteroatom of the 5- to 6-membered heterocyclic ring is N, and the number of heteroatoms is 1 or 2; R2 is optionally substituted with 1-4 substituents selected from the group consisting of alkyl Cl-6 or heterocyclyl; R' is independently hydroxyl or heteroaryl of 5 to 10 members substituted with 1-3 R'-l; When R2 is optionally substituted with 1-4 alkyl Cl-6 or heterocyclyl, the position of the substitution is on a heteroatom of ring A.

8. The compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof according to claim 1, wherein Z is a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaromatic ring is optionally substituted with one or more R3s; R3 is selected from halogen, cyano, alkyl Cl-6, alkoxy Cl-6 (alkyl Cl6), C3-6 cycloalkyl alkoxy (Cl-6), C3-6 cycloalkyl alkoxy (Cl-6) alkyl (Cl6), C3-7 heterocycloalkyl, C3-7 heterocycloalkyl alkyl (Cl-6), and each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, alkyl -285Cl-6 and alkylamino Cl-6;R1 is selected from H, Cl-6 alkyl, C3-6 cycloalkyl, C3-7 heterocycloalkyl, C3-6 cycloalkyl alkyl (Cl-6), Cl-6 alkoxy alkyl (Cl-6), and each of which is optionally substituted with 1-4 substituents selected independently from the group consisting of halogen, cyano, hydroxyl, Cl-6 alkyl, Cl-6 alkoxy, and Cl-6 alkylamino; R2 is heterocyclyl, phenyl, or heteroaryl; each of which is optionally substituted with 1-4 substituents selected independently from the group consisting of halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, C3-6 cycloalkenyl, -NR4R5, -C(O)NR4R5, -COOH, -SO2-Cl-6 alkyl; R is selected from H, Cl-6 alkyl, Cl-6 alkenyl, C3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, and each of which is optionally substituted with 1-3 R';R' is selected from halogen, cyano, hydroxyl, C3-6 cycloalkyl, alkylamino Cl-6, alkyl Cl-6, alkoxy (Cl-6), alkyl Cl-3 substituted with cyano or halogen, alkylsulfuryl Cl-6, heterocyclyl or heteroaryl; R4 or R5 is independently H or alkyl Cl-6, and the alkyl Cl-6 is optionally substituted with 1-5 substituents, the substituents being independently selected from amino, halogen, hydroxyl, alkyl Cl-6 or alkoxy Cl-6.

9. The compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof according to claim 1, wherein, R3 is independently Cl-6 alkyl or Cl-6 alkoxy alkyl (Cl-6); R3 is optionally substituted with 1-4 hydroxyl; and / or, Z is a 5-membered heteroaromatic ring containing 2 heteroatoms independently selected from oxygen and nitrogen; and / or, R1 is Cl-6 alkyl or C3-6 cycloalkyl alkyl (Cl-6), and R1 is optionally substituted with 1-4 halogens; and / or, R2 is phenyl or heteroaryl; The heteroaryl is a 5- to 10-membered heteroaryl; the heteroatoms of the 5- to 10-membered heteroaryl are nitrogen and / or oxygen, and the number of heteroatoms is 1-4, such as a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl;The 9- to 10-membered bicyclic heteroaryl is, for example, a bicyclic heteroaryl of a 5- to 6-membered IVIA / a / ¿UZZ / UU í 4 ¿O -286heteroaryl fused with a 5- to 6-membered heteroaryl, or, a bicyclic heteroaryl of a 5- to 6-membered heteroaryl fused with a 5- to 6-membered heterocyclyl; and / or, R2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, -R, -OR, -NHR, C3-6 cycloalkenyl, -NR4R5, -SO2-Cl-6 alkyl and -SO2NR6R7, preferably cyano, -R and -OR.

10. The compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof according to any one of claims 1 to 9, wherein, when Z is a 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, is a 5-membered heteroaromatic ring containing 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, e.g., isoxazole, such as NA > t N—O [ ,x~ b another example, , as yet another example, , end b thereof is connected to R3; and / or, when R3 is multiple, R3 is the same or different;and / or, the number of R3 is 1 or 2; and / or, when R3 is alkyl Cl-6, the alkyl Cl-6 is methyl, ethyl, n-propyl or isopropyl, for example, methyl; and / or, when R3 is alkoxy Cl-6 alkyl Cl-6, an alkyl end thereof is connected to Z; and / or, when R3 is alkoxy Cl-6 alkyl Cl-6, the alkoxy Cl-6 is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, and as another example, methoxy; and / or, when R3 is an alkoxy Cl-6 alkyl Cl-6, the alkyl Cl-6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl, for example, methyl, ethyl, n-propyl or isopropyl, and as another example, methyl; and / or, when R3 is substituted with 1-4 substituents, the number of - 287 substituents is 1, 2, 3 or 4, for example, 1 or 2;and / or, when R3 is alkyl Cl-6, the alkyl Cl-6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl, for example, methyl, ethyl, n-propyl, isopropyl, and as another example, methyl; and / or, when R1 is alkyl Cl-6, the alkyl Cl-6 is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl; and / or, when R1 is substituted with a halogen, the halogen is fluorine, chlorine, bromine or iodine, for example, fluorine; and / or, when R1 is substituted with 1-4 substituents, the number of substituents is 1, 2, 3 or 4, for example, 1 or 2; and / or, when R1 is C3-6 cycloalkyl alkyl (Cl-6), the Cl-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl, as another example, methyl; and / or, when R1 is C3-6 cycloalkyl alkyl (Cl-6), the C3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl or cyclobutyl;and / or, when R2 is heteroaryl, the heteroaryl is a 5- to 10-membered heteroaryl and the heteroatoms are nitrogen and / or oxygen, and the number of heteroatoms is 1-4; for example, a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl, as another example, a 5- to 6-membered monocyclic heteroaryl, a 9- to 10-membered bicyclic heteroaryl of a 5- to 6-membered heteroaryl condensed with a 5- to 6-membered heteroaryl, or, a 9- to 10-membered bicyclic heteroaryl of a 5- to 6-membered heteroaryl condensed with a 5- to 6-membered heterocyclyl;as another example, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolopyridyl, pyrrolopyridyl, pyridopyrrolonyl, naphthirdinyl, quinolyl, imidazopyridyl, dioxinopyridyl, pyridooxazinyl, pyrazolopyrimidinyl, pyridopyrazolyl, pyridopyrrolyl, pyridopyrazolyl, pyridonyl, pyridoimidazolyl, pyridotriazolyl, pyridonyl, pyridotriazolyl, pyridazinonyl, heteronaphthyl, naphthirdinonyl, imidazopyridazinyl, indolyl, diazanaphtyl, tetrahydronaphthirdinyl or naphthirdinyl, as another example, -288- and / or, the R2 is substituted with 1-4 substituents, the number of substituents is 5, 1, 2, 3 or 4, by for example, 1 or 2; and / or, when R2 is substituted with a halogen, the halogen is fluorine, chlorine, bromine or iodine, for example, fluorine or chlorine;and / or, when R2 is substituted with a C3-6 cycloalkenyl, the C3-6 cycloalkenyl is cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, for example, -289 and / or, when R2 is substituted with a -SO2-alkyl Cl-6, the Cl-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl, for example, methyl, ethyl, n-propyl or isopropyl, and as another example, methyl and ethyl; and / or, when the R is independently Cl-6 alkyl, the Cl-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl, for example, methyl, ethyl, n-propyl, isopropyl or tere-butyl; and / or, when the R is independently Cl-6 alkenyl, the Cl-6 alkenyl is ethenyl, and / or, when the R is independently C3-6 cycloalkyl, the C3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclobutyl or cyclopropyl;and / or, when the R is independently heterocyclyl, the heterocyclyl is a 3- to 10-membered heterocyclyl, wherein the heteroatoms are nitrogen and / or oxygen, and the number of heteroatoms is 1, 2, or 3, as another example, a 5- to 6-membered monoheterocyclyl or a 7- to 8-membered heterospirocyclyl, wherein the heteroatoms are independently nitrogen and / or oxygen, and the number of heteroatoms is 1 or 2, and as yet another example, morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, or 2-oxo-[3,3]heptyl, as yet another example, °, as an additional example, and / or, when the R is a C3-6 cycloalkenyl, the C3-6 cycloalkenyl is cyclohexenyl, cyclopropenyl, or cyclobutenyl, by for example, ; and / or, when the R is aryl, the aryl is C6-14 aryl, for example, phenyl, naphthyl, phenantrile or anthranyl, and as another example, phenyl;and / or, when R is heteroaryl, the heteroaryl is a 5- to 10-membered heteroaryl, wherein the heteroatom is nitrogen and / or oxygen, and the number of heteroatoms is 1, 2, or 3, for example, a 5-membered monocyclic heteroaryl, wherein the heteroatom is nitrogen and / or oxygen, and the number of heteroatoms is 2 or 3, as another example, pyrimidinyl, oxadiazolyl, or isoxazolyl, as another example; and / or, when R1 is independently halogen, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine; and / or, when R' is independently C3-6 cycloalkyl, the C3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, for example, cyclopropyl; and / or, when the R' is independently alkylamino Cl-6, the alkylamino Cl-6 is alkylamino Cl-3, for example, ethylamino, as another example, -NHEt;and / or, when R' is independently alkyl Cl-6, the alkyl Cl-6 is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, as another example, methyl, ethyl, n-propyl or isopropyl, as yet another example, methyl; and / or, when R' is independently alkoxy Cl-6, the alkoxy Cl-6 is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy, ethoxy, n-propoxy or isopropoxy, and as yet another example, methoxy; and / or, when the R' is independently alkyl Cl-3 substituted with cyano or halogen, the alkyl Cl-3 is methyl, ethyl, n-propyl or isopropyl, e.g., methyl;and / or, when R' is independently a heterocyclyl, the heterocyclyl is a 3- to 6-membered monocyclic heterocyclyl and the heteroatom is nitrogen and / or oxygen, and the number of heteroatoms is 1 or 2, for example, tetrahydrofuranyl, jA rp oxetanyl, azetidinyl, morpholinyl or piperazinyl, as another example, Λ , • NH . ! \ . / \ f OYI p ^-N nh sAh Ύ , — o 4— / , as yet another example, ;and / or, when R' is independently heteroaryl, the heteroaryl is a 5- to 10-membered heteroaryl, wherein the heteroatom is nitrogen and / or oxygen, and the number of heteroatoms is 1, 2, or 3, for example, a 5-membered monocyclic heteroaryl, wherein the heteroatom is nitrogen and / or oxygen, and the number of heteroatoms is 1, 2, or 3, as another example, pyrimidinyl, oxadiazolyl, or isoxazolyl, - 291 - as yet another example; and / or, when R' is independently a 5- to 10-membered heteroaryl substituted with 1-3 R'-l, the heteroaryl is a 5- to 6-membered heteroaryl and the heteroatoms are nitrogen and / or oxygen, and the number of heteroatoms is 1, 2, or 3, for example, oxadiazolyl or oxadiazolyl, for example, and / or, when the R'-l is independently alkyl Cl-6, the alkyl Cl-6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl, for example, methyl, ethyl, n-propyl or isopropyl, as another example, methyl;and / or, when the R' is independently a C3-6 cycloalkyl substituted with 1-3 cyano, the C3-6 cycloalkyl is a bridged 5-membered bicyclic cycloalkyl, for example, and / or, when the R' is independently a C6-14 aryl, the C6-14 aryl is phenyl, naphthyl, phenantrile or anthranyl, for example, phenyl; and / or, when the R' is independently a 3- to 6-membered heterocycle substituted with 1-3 R'-3, the 3- to 6-membered heterocycle is a 4- to 6-membered monoheterocycle, and the heteroatoms are nitrogen and / or oxygen, and the number of heteroatoms is 1 or 2, e.g., piperazinyl or oxethanyl, as another example, and / or, when the R'-3 is independently alkyl Cl-6, the alkyl Cl-6 is, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl, e.g., methyl, ethyl, n-propyl or isopropyl, as another example, methyl;and / or, when R8 and R9 are independently alkyl Cl-6, the alkyl Cl-6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl, for example, methyl, ethyl, n-propyl or isopropyl, as another example, methyl; and / or, when R8 and R9 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, the 5- or 6-membered heterocycle - 292 - and / or, when the RIO is alkyl Cl-6, the alkyl Cl-6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl, for example, methyl, ethyl, n-propyl or isopropyl, and as another example, methyl; and / or, when R4 and R5 are independently alkyl Cl-6, the alkyl Cl-6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl, as another example, methyl, ethyl or n-propyl;and / or, when R4 and R5 are independently C3-6 cycloalkyl, the C3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, for example, cyclohexyl; and / or, when R4 and R5 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl, the 5- or 6-membered heterocycloalkyl is Io; and / or, when R4 and R5 are independently substituted with 1-5 substituents, and the substituents are independently halogens, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine; and / or, when R4 and R5 are independently substituted with 1-5 substituents, the number of substituents is 1, 2, or 3; and / or, when R6 and R7 are independently alkyl Cl-6, the alkyl Cl-6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tere-butyl, for example, methyl, ethyl, n-propyl or isopropyl, as another example, methyl;and / or, when R2 is substituted with 1-4 substituents and the substituents are -R, the -R is -Cl-6 alkyl, -Cl-6 alkenyl, -C3-6 cycloalkyl, -heterocyclyl, aryl or -heteroaryl; and / or, when R2 is substituted with 1-4 substituents and the substituents are -OR, the -OR is -O-Cl-6 alkyl or -O-heterocyclyl; and / or, when R2 is substituted with 1-4 substituents and the substituents are -C(O)R, the -C(O)R is -C(O)-Cl-6 alkyl, -C(O)-Cl-6 alkenyl, -C(O)-C3-6 cycloalkyl or -C(O)-aryl.

11. The compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof according to claim 8, wherein, when R3 is alkyl Cl-6 alkoxy, the alkyl Cl-6 alkoxy is alkyl Cl-3 alkoxy, for example, Y; and / or, when R3 is hydroxyl-substituted Cl-6 alkyl, the R3 is; and / or, when R1 is C3-6 cycloalkyl (Cl-6) alkyl, the C3-6 cycloalkyl (Cl-6) alkyl is C3 cycloalkyl (Cl-3), for example, V; and / or, when R2 is substituted with 2, 3 or 4 substituents, the substituents are the same or different;and / or, when R2 is a 9- to 10-membered bicyclic heteroaryl of a 5- to 6-membered heteroaryl fused with a 5- to 6-membered heterocyclyl, the substitution position of the substituent is on the heteroatom of the 5- to 6-membered heterocyclyl; and / or, when R' is independently a 5- to 10-membered heteroaryl substituted with R'-l, the 5- to 10-membered heteroaryl substituted with R'-l is JV yo ; and / or, when R' is independently a 3- to 6-membered heterocyclyl substituted with 1-3 R'-3, the 3- to 6-membered heterocyclyl substituted with 1-3 R'Γ~\ 4-nn— 3 is o / ; 3 > your NCNNCCN ay / o, when R4 and R5 are independently substituted with 1-5 substituents, R4 and R5 are independently 3 or 01=2 .; 12. The compound represented by formula I, the cis-trans isomer of the same, the enantiomer of the same, the diastereomer of the same, the racemate of the same, the solvate of the same, the hydrate of the same, the pharmaceutically acceptable salt of the same or the propharmaceutical salt of the same. following compounds: Structure Realization Structure Realization - 294 - 1 FY n> / rn' X ' 'nAAo / 91 Ν; / χΟ\ ν' 1 I M. «A r not ΝΛ Y'N.. zz, y uA 0 NYA y-1 Y o<\ -9 O z^N / °x il YN 3 4 Υγ 93 yz NX^N / v AY ^oy y_N 4 4 YY y 'υΆοζ 94 \ 0 nA nn\ i Fax 5 ó X Yy 95 Y yN nA Ñ^zN~H F / X°_Y6N χ ¿γ °x 96 4 nY X'N n Υ^θ^ΥΥ^ΝΗ z° —1 7 9 Λ Nv nY Y^ ,n oYlX / Y y nY-Yq / / ° 97 NY nA yy- 8 / 4 p Y^A Ay 98 / ^ x NA x o N\A Ay^ / NH MA / a / u¿¿ / uur4¿o -295- 9 AAO or \ 99 °Y¿? Yz )--\ o OA only 10 zO ZJX & oo 'br° o— / / 100 L 9 nA^N NÍ 1 AN / N M.Yo^a^-n / 9 °A QYnY 11 Oz there> j \\ A ZZ 101 ÍAO An n=Z NYn'n , ¿ Y^ 12 Vn nY / 102 tí M / NN=A ÁÁ YN van / \ / NY 0 γ 'Ά Wí λ' / uncle. nA Α,ν-ν 103 Λ N^ / ^N Á 1 tí 'NHX -xr% (tíl^ 14 NN Jj VY \z oA^n No NV 104 °rz / K / '° Ca'z 15 NU. λ AN 0N 0^A / 1—5 ΓΑ 16 nn Y ?0 1 106 OZ AAH> tí oo 0 A° ° \ IVIA / a / ¿U¿ / UU / 4¿O -296- 17 NN A 107 / / —Z \ A0 ¿A / x^ o X,. o A 'z \\ / zo 19 nn á “ Y 109 Nyh / °\ ν' II M. YNO nA tí A υζΥ 0 20 NN tí Cl 110 ΧΛ tí 'y.......... 0 21 L ° ,nA*n' 1^N' ν N 1 SA / AN Ny / y / O\ NÍ 1 1 YnnAo nA tí.N. / \ X XXYo^ o 22 [ 0 n^Xn n 1 VN l N Αο^,ν 6 ¡i y-° 112 ν' II γΆο nA °χ 0 23 A V waan nA <XtAo / ° 7 113 O-Z y z <+ z i o O. / / «X / Ό 24 A NA N NN N^ γΑθΆΑ0 7° A 114 n\ i I XN'nAq tí tor IVIA / a / ¿U¿ / UU / 4¿O - 297 - 25 O^\ 3 Oz zÁ\ZO j P 1° Y \1\ zz^ 26 Υ° otí pz ζ^γΟ ¿ J x AY Z'Z 116 Oz Λ Y z 3 oo I 27 NN tí 117 nA ¿A 28 A <y nA Ñ^zN-N áy 118 Z-Z Y Y \ A P 'W o^Yz z-o 29 Z-O A A o —o zA^z 119 n'1 I H ΑΛχγ A^O'' 30 O / / Ao o— AR Λ / / z' o-z 120 N^Y^Y°\ n 1 1 7^ Ν O ^|< NH γ^ν / ^o 31 z-O z J λ —o zO 121 N^ / V°\ nz 1 1 A YA Yo 32 ‘f 1 1 o-z z- ,c aIa A A Y zz 122 Af^ ΥνΑαΆ Α^νΑ nAY-q / IVIA / a / ¿U¿¿ / UU / 4¿0 -298- 33 n-n o 123 tí o o \ / o xz I 34 Y o o X z 'z \\ / z-O 124 tí o o \ / v5 \ 35 V-n πΑ / Χχ ,N=\ hn-x / 0 125 tí o o \ / vAXj 36 Λ ? Λ N / nY \ nY'n λΝ~Ν O'V'Vo 0 126 H N T> A \ 11] Vi YN 37 tí O \ M o— 127 z-zyAo tí oo tí 38 VU i °\ 128 ϋ oo tí tí 39 Oz / A Zx -^\ / A z X oo V 129 ¥9 Νγ>Ν,\ N A r°°_ N^n O-— 40 p. 1 4 'y N 130 vi X y NO f bp.. 0 41 Y oop 'z \\ / ZO 131 Οχ / Υ 1 tí XV z. / Yo IVIA / a / ¿U¿ / UU / 4¿O -299- 42 oz XX z' ó oo'—5 O o wv 'z \\ / ZO 43 \ o .7 O o X '2 \\ / ZO 133 OZ XX z. -^X / ^X zioo 0' z^ 44 Oz XX ioo d' O \ 134 ,ζ Λ=Χ if h O fi ( 45 ζ-^ζί poo \ / vXX 135 ¡o N3⁄4^N NX TN YX / =0 NN X NN %X 4 NX The—. 136 Λ Xn N=Z n\\ n Y Χύγι / 0 W <o 1 47 <-o / I z'Xz^ 7 o o A o— 137 ,°-z zv\^o XX¿ J x % y 48 0^ X _¿ 1,-:-9n9- / ,0-- 138 N= / Y N Y 'N Vo-Y / n / 0 YYvY 49 \^0 II X X. \ Γ X V ,N„ .

0. Ζΐ / Ά X y / o ’'M'' Z ' qz 139 JV-» o^^ 1 IVIA / a / ¿U¿¿ / UU / 4¿O -300 - 50 Yo Vn z-n nX~N / ° 140 ¥ Y N-N / ^n Νχ Vo ,N \X o— 51 z-z X \\ \ í / W OX^Z Z-o o Γ z ^0X0 / 141 k· nVnn YX o 52 n-n χ XV V N-0 -O^N 142 A Xn Nk N\zN. y N τ °^í / ° ΧνΊ·χ o 53 J1 Y π Yv / 0 o' 143 3 e ^0 o— .. í! Wvz O-Z 54 ó ^X} 0^ F 144 k Cz o X ? \ / / Z o-z 55 N-N ΑΥΥ ο-χ 4 145 z-o z^ / / \ z - Y O o—. 56 0 o o— .k 146 Pxz N. V / 'z n-n / —ζ Yx; Y—0 N—<ζ XN o— 57 z / \ z' y-k Ό p —0 o 147 —o O o ..X \ / Γ z oz -301 - 58 zzrX 5 —O o 5 148 zO zv JJ xV z VAY' ó o \ \ o Y° 59 0 —oo A 149 vo YY NJJ | 1 60 Ü —oo Y o / 150 oz XX z •'Y / 'V zi 0 0 AY° όγ\ 61 ζ·ζγΧ X —oo X oo 151 / Vo Gz / \ oo Az^Y / ° 62 ? , NN 0 Ny V-0 0 Nv / cf3 152 0 0 ó oo— -A cYz 63 δ γΝ N^\ ^n~n / V / OH X^ / O \-7—% \ o 7° 153 ZO VAAX oo— \ 4 Y 7 Vn° 64 aj nA) V° Ϊ ¥ Yp η / N / AA Am'N^° X1 Y n^AA^q 1 65 oV γ Yz Vo A o / 155 λ° / / N n / v=v / , NN / —<\ / Vo na Vo Y o— 66 Ó γΝ5 —6 onY ÑYY Χγζζ o ZY 7 oo \ IVIA / a / ¿U¿ / UU / 4¿0 -302 - 67 Γ Y° 'Z 157 X. _ Vo π YX X^n Yxx X NI YN^YYO 1 68 XO nXX1 XX5 YX8^N^ / Υ NN vX X n=n 69 Y pN nX kx Y~°\ H γ ΧγΧ^δ 159 H kl,N^.N. Y^o YY b li ?N XsX Y ° k„-Y° 1 NI Y 1 70 nn χχ 0. An mf Ynh 160 YP zz tí 1 71 ? AAF\ / \ ¿ ,N“N, AA\ nh N< Y0 WV 0 / 161 V1+ ,Υγ Y / NO qq |1 rX Nk- X h NNOZ ° °\ 72 ,NYV°'- NgN..X / NO X Sx YO N^N °\ 162 νλ X y NO >9 |1 rY N s JL Η > 'Ν^Ό^γ^θ / o X / 73 ,0^ / γ nX Xn'n λνΧν ΥγΥ / ΥΥ 0QΧ- 16 XnyoXnn X- NI 1 Nz'Voz 74 4 X' Xny° 0 ji ΪΥΥ9 164 XX YXX Χ-νυοΧΝν XN' x 1 nXXoz MA / a / ¿u¿o / uur4¿o -35 o ζ - \ zo 165 Ay Ó ooy υ 76 zO < JA z Y oo A <. 166 νΑγύ iA n - A o / - l| XN 'NO Ao 77 1 oh II / / 167 yA O oo \ / o zA 78 Y IT N'N ,Ν^γτ Ñ=YY 0 / 168 ) oo Yo 2 A Λ / / oz 79 Npf Y NY _ / \Y Ñ= / ooj H Vo N=\0,NA nA nY ÑvN'N NYZ / -o 170 k° Y oo 'z \\ / ZO 81 RyAA / 171 nA Y jno Yr YA N'nA / Xt / X| Yó y¿ 82 Af km 0 / 172 Y o Y oo Y-,... 'z \\ / zo -304- 83 ANA i NN W 173 X . / =3 / Vr-YX Ns 1 1 nvRq / 84 OR y nA m ,N~N RR o'y°4.V vi YXNO Xj] 1° ÍRn nVrVJ / ^d 85 RR / rA NÍ I 1 XNON nR ΝΗη 0 \ I 175 Ά-° ιΓ XA Iy ju R .R _O RN n R^ nx YV Ί 1 ^°ν^η wr. XN 0 RNX ^0—0- 176 R^° AV ,N .O. Xj .nX yy AN n^RA^q^ 87 I Rn N=\ 177 v χΥΌο R ,N. .0 N 1 Y n^A'O 1 88 oz AA z' z ϋ 7-0 O / =< z M Cr 178 A^0 ΓΑ y jíX0^0 1n.ny N 1 1 n^RAtr 89 AR nA / X Ñ^ / N'N / NYnH “Yo VY9°AAy n^vA0 1 90 NRV0'' ν' 1 I M. AXNO nA 'RRx v uO 180 Y° I? 220 Z'zyXfo yoo Y 182 Y ί-γΎ / -Ν-γο^Α> 221 \-ot;n na cn \ íl Λ V ,N .0 tí ooy 222 zy'í 2 ¢. O 0 k A 185 HO θ 1 Ü / Y 1 f Ί ? Y xN^ X AJ NU YN 224 z-zyAÍ tí enter Y 225 A house .,1 ο0 v-N18*Ω .o. j< Y\ ym NI YN \ N-'^ 226 ζ'ζγΥγ tí 0 0 iz 188 Z^ ZT 1° oo A pA- 227 z'zyk^° tí oo Y z Vo 189 Y oo tí ok 228 CN X^Y° oo N^ YYz 229 z-pyk oohz Y 191 \,0 N-° II ,N tí-A ' \ YYY V .Ν.,Ο U. J N7 ? 9 3 O o ,,w 193 o / A ooo ojAz 232 v°.9th ( / / tírN 9 ,no X YVN nY Y n N -·2''ό / 194 z Ü 3 O o Y °AZ 233 z-zyV AO o Y ζ z 1 195 z'VV & oo tí tí oz 234 zvΥ-\ 356 Y zγ 3 tí oo 9 ^z^ 197 \Α ΖΥ Ü / VA ΓΎ 7 V _hk .o γΑ J n Ί 1 236 z-zyYo oo 198 0 A irYAY Χύαλ> m+i9 Y z10 237 z'Y. zN Y^ \ Y aaA aYV γ-Ν A n N 1 I N'vYq / 238 Ύ^θ La \ 1 N—( 0 V .n. xa Ya Y^ / \__ / N 1 i 200 zzY f> oo 239 --ΖνΧ 20 A ZO oo Z-kc z'zvY° <tí o o tí z o 202 0 °Y 3 O o Y yA 241 O— 09 s tíYN xvn A r . / o Y XrN n z 7 A N IVIA / a / ¿U¿¿ / UU / 4¿O -307- 203 \^o o Y Ν / Ύ Γ Ύ Ν N X ,ν^οΧ X> . N i 1 N^xX'o' 242 oA z tí 0 0 Y οχν 204 XV tí oo tí X 243 z'XX tí oo M z Λ 205 \ oz— — b' Ο=ω OO Ά χΥ^Oγ 2420 oo XΧ6 Y °XZ N''-tí'oz 245 z'zYx d O o Y 207 xd HU 0 0 í >0 / —z _ / T 246 Xo z^z^XX^ Y oo .Y 1XZ 208 ζχΧ Y ooyx 247 rY zνω3 / ο2 y=Ο0 y OO 4t px 248 ζ-ζΧχ tí oo ' b 210 y Ο=ω 0 0 .,3 χν 249 Vo' Y XN\ XvY-Nx Νχ 1 1 X_ 211 zo tí oo ,3 °lX0 1.p 250212 XX [!> χ^N \ । / )—( o V ,ΧΧ.Υα ,nx \_ / XYN 251 Y oo MA / a / ¿u¿¿ / uur4¿o -308 - 214 Ύ-° UN AVN or NN \ n; i I \_____ / 253 1 & oo aa 215 ü 0 0 3 254 V ti oo .5 γΥζ 216 Y°' AN Vvn A yn \ 255 Ao A a A .n^oA AnA° AYN 217 Ao \a T ZN A Λ A > ΑΝ'ΝγΟχΖΝ AN 1 1 'nAAq / 256 z-aY° O oo 4 zo Z 218 ' oo 3 °\J z 257 z ti oo 3^ 219 ti OO \ z 1 258 oo— Y^.

13. The compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof as defined in any one of claims 1 to 12, wherein it comprises the following steps: -309 - iviA / a / zuzz / uuz+zo wherein, X is a halogen, and the definitions of Z, R1, and R2 are described in any one of claims 1 to 12.

14. A pharmaceutical composition, comprising the compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof as defined in any one of claims 1 to 12, and a pharmaceutically acceptable carrier.

15. Use of the compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof as defined in any one of claims 1 to 12, or the pharmaceutical composition thereof as defined in claim 14, in the manufacture of a medicament.

16. The use as defined in claim 15, wherein the drug is used to treat, prevent, or improve a disease related to a 5-GABAA receptor; the 5-GABAA receptor-related disease being, for example, one or more of cognitive diseases, Alzheimer's disease, dysmnesia, Down syndrome, amyotrophic lateral sclerosis, drug addiction, restless legs syndrome, cognitive impairment, multi-infarct dementia, pain, stroke, and attention deficit, as another example, pain.

17. Use of the compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof as defined in any one of claims 1 to 12, or the pharmaceutical composition as defined in claim 14, in the manufacture of a medicament for treating or preventing an α5-GABAA receptor-related disease.

18. Use of the compound represented by formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof as defined in any one of claims 1 to 12, or the pharmaceutical composition as defined in claim 14, in the manufacture of a medicament for treating or preventing a disease, wherein the disease is one or more of pain, Alzheimer's disease, multi-infarct dementia, and stroke.

19. A method for treating or preventing a disease related to a 5-GABAA receptor, comprising administering to a patient an effective dose of the compound represented by Formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof as defined in any one of claims 1 to 14, or the pharmaceutical composition as defined in claim 12.

20. A method for treating or preventing a disease, comprising administering to a patient an effective dose of the compound represented by Formula I, the cis-trans isomer thereof, the enantiomer thereof, the diastereomer thereof, the racemate thereof, the solvate thereof, the hydrate thereof, the pharmaceutically acceptable salt thereof, or the prodrug thereof as defined in any one of claims 1 to 12, or the pharmaceutical composition as defined in claim 14, wherein the disease is one or more of pain, Alzheimer's disease, multi-infarct dementia, and stroke.