Substituted triazole derivatives, preparation methods, pharmaceutical compositions and uses thereof

Abstract

The present invention discloses substituted triazole derivatives, preparation methods, pharmaceutical compositions and uses thereof, and specifically provides a compound represented by general formula (I), its cis-trans isomers, its enantiomers, its diastereomers, its racemates, its solvates, its hydrates or its pharmaceutically acceptable salts or its prodrugs, its preparation method, a pharmaceutical composition containing the compound and the compound as α5-GABA A Uses of receptor counter modulators.

Description

Technical Field

[0001] The present invention relates to α5-GABA A The invention relates to substituted triazole derivatives having receptor regulating function, their preparation, pharmaceutical compositions containing them and their use as medicines. Background Art

[0002] γ-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system of mammals. There are two types of GABA receptors in nature. One is GABA A receptors, which are members of the ligand-gated ion channel superfamily, and the other is GABA B GABA receptors are members of the G protein-coupled receptor superfamily. A The receptor subunits discovered include α1-6, β1-4, γ1-3, δ, ε, θ and ρ1-3. Among them, α subunit, β subunit and γ subunit form a complete functional GABA receptor. A The receptor is essential, and the alpha subunit is essential for benzodiazepines with GABA A Receptor binding is crucial.

[0003] GABA containing α5 A Receptor (α5-GABA A GABA receptors in the mammalian brain A The proportion of GABA receptors in the brain is less than 5%, and the expression level in the cerebral cortex is very low, but in the hippocampus of the brain, it is expressed at a very low level. A The proportion of α5-GABA receptors is greater than 20%, and other brain regions have almost no expression. A Many pharmaceutical companies, including Roche and Merck, have been working on the specific distribution and function of α5-GABA receptors in the hippocampus of the brain. A In the study of receptor ligands, a large number of compounds have been synthesized, especially those targeting the α5 subunit of GABA in the hippocampus of the brain. A The α5 subunit of GABA is a GABA receptor inverse agonist. Among them, α5IA and MRK-016 have shown good effects in treating cognitive diseases in animal disease models. A Receptor inverse agonists can be used to treat cognitive diseases, especially Alzheimer's disease. Patent application US20110224278 discloses GABA containing α5 subunit A Inverse agonists of the receptor can be used to treat multi-infarct dementia and stroke-related diseases.

[0004] Research in the past decade has shown (Zlokovic, BV et al. Nat Rev Neurosci. 12 (12), 723-738) that in many disease states, especially neurodegenerative diseases, Alzheimer's disease and stroke, the blood-brain barrier is damaged, and even substances that cannot enter the brain can play corresponding pharmacological effects. Therefore, GABA α5 subunit, which cannot cross the blood-brain barrier, can be inhibited. A Inverse agonists of the receptor may also be used to treat Alzheimer's disease and stroke.

[0005] In 2002, Zhang Xu's laboratory reported α5-GABA A The receptor is also mainly expressed in small neurons, and its expression is increased in the nerve axotomy model (Xiao HS et al., Proc Natl Acad Sci US A. 2002, 99 (12), 8360-8365). Patent application CN103239720 discloses α5-GABA A The receptor is expressed in the peripheral nervous system, and its expression is significantly increased in the partial nerve injury model, and α5-GABA A Inverse agonists of GABA receptors selectively bind to α5-GABA A Receptors play a role in inhibiting various types of pain. Data from animal experimental models show that the stronger the inverse agonist's inverse agonist effect, the better its pain-inhibiting effect.

[0006] Detect whether a compound is specific for GABA containing α5 subunit A A lot of research has been done on the inverse agonists or antagonists of receptors. For example, in international patent applications WO 1992022652 and WO1994013799, GABA A The combination of α5, β3 and γ2 of the receptor is used to detect whether a certain compound binds to the receptor; in the process of drug screening, the method described by Goeders et al. (Goeders, NE and Kuhar, MJ Life Sci. 1985, 37 (4), 345-355) is usually used. A There are many studies on whether the ligand bound by the receptor α5 subunit is an antagonist, agonist or inverse agonist. Please refer to the method described by Wafford et al. (Wafford, KA, Whiting, PJ and Kemp, JA Mol. Pharmacol. 1993, 43, 240-244).

[0007] There are many methods for screening whether a drug enters the blood-brain barrier. In the literature (Jones et al., Bioorg MedChem Lett. 2006, 16(4). 872-875), it is reported that the inhibition of the compound ( 3 H)RO-15-1788(α5-GABA A MRK016 can effectively inhibit the binding of specific inverse agonists of receptor markers in the brain. 3 H)RO-15-1788 binds to the central nervous system, while MRK016-M3 can hardly inhibit it significantly ( 3 H) Binding of RO-15-1788 in the central nervous system. It can also be tested by testing the drug in different tissues, such as testing the distribution ratio of the drug in the brain and plasma to determine whether the drug can effectively enter the blood-brain barrier.

[0008] Previous studies have found that using drugs or genetic methods to inhibit or reduce α5-GABA A Receptor-mediated inhibition of the salience effect can improve cognition and learning ability, but at the same time can lead to mild anxiety-like behavior. (Brickley, SG & Mody, I. Neuron. 2012, 73, 23-34; Harris, D. et al. J. Med. Chem. 2008, 51, 3788-3803; Savi MM et al. Brain Res. 2008, 1208, 150-159; Clément, Y. et al. Behav. Brain Res. 2012, 233, 474-482.). Studies have found that fear and anxiety traits are associated with a decrease in Gabra5 mRNA. (Heldt, SA & Ressler, KJ Eur. J. Neurosci. 2007, 26, 3631-3644; Tasan, RO et al. Neuroscience. 2011, 183, 71-80.). Paolo Botta et al. disclosed that α5-GABA A Receptors involved in the mechanisms of anxiety and fear. Specific knockout of α5-GABA in brain regions A Receptor expression can lead to fear and anxiety behaviors in animals. A Inverse agonists enter the brain and produce side effects of fear and anxiety, affecting their drugability. Summary of the invention

[0009] The present invention provides a substituted triazole derivative, a preparation method, a pharmaceutical composition and a use thereof. 5 -GABAA It has good pharmaceutical properties such as selective inverse agonist activity and bioavailability and less central nervous system exposure.

[0010] The present invention provides a compound as shown in formula I, its cis-trans isomers, its enantiomers, its diastereomers, its racemates, its solvates, its hydrates, its pharmaceutically acceptable salts or its prodrugs,

[0011]

[0012] in

[0013] Ring A is selected from a benzene ring or a 5-6 membered heteroaryl group;

[0014] R 1 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and / or 3-6 membered heterocycloalkyl are optionally substituted by 1-3 R';

[0015] R' is independently selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, cyclopropyl or methoxy;

[0016] k is 0, 1, 2, or 3;

[0017] T 1 and T 2 are independently selected from a carbon atom or a nitrogen atom;

[0018] R 2 Selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which may be optionally substituted by 1-3 R';

[0019] L is selected from -CH 2 -O-, -CH=CH- or -CH 2 -NH-;

[0020] Ring B is selected from a benzene ring or a 5-10 membered heteroaryl group;

[0021] R 3 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, each of which may be optionally substituted by 1-3 R';

[0022] m is 0, 1, 2 or 3;

[0023] Ring D is selected from 4-14 membered heterocycloalkyl;

[0024] The R 4 are independently selected from hydrogen, halogen, cyano, =O, -R 5 、-OR 6 、-COOR 6 、-C(O)R 5 、-NR 6 R 7 、-NR 6 COR 5 、-NR 6 SO 2 R 5 、-CH 2 -C(O)NR 6 R 7 、-C(O)NR 6 R 7 、-SO 2 R 6 or -SO 2 NR 6 R 7 ;

[0025] R 5 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R;

[0026] R 6 and R 7 are independently selected from hydrogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl (C 1-6 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-6 ) alkyl, each of which may be optionally substituted by 1 to 3 R;

[0027] When R4 Selected from -NR 6 R 7 、-C(O)NR 6 R 7 or -SO 2 NR 6 R 7 When R 6 and R 7 Together with the connected N atom, they can form a 4-7 membered heterocyclic ring, and the 4-7 membered heterocyclic ring can be optionally substituted by 1-3 R;

[0028] R is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R';

[0029] n is 0, 1, 2, 3, 4, 5 or 6.

[0030] In certain preferred embodiments of the present invention, certain groups in the compound of formula I, its cis-trans isomers, its enantiomers, its diastereomers, its racemates, its solvates, its hydrates, its pharmaceutically acceptable salts or its prodrugs are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention").

[0031] Ring A is selected from a benzene ring or a 5-6 membered heteroaryl group;

[0032] R 1 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and / or 3-6 membered heterocycloalkyl are optionally substituted by 1-3 R';

[0033] R' is independently selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, cyclopropyl or methoxy;

[0034] k is 0, 1, 2, or 3;

[0035] T 1 and / or T 2 are independently selected from a carbon atom or a nitrogen atom;

[0036] R 2 Selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, each of which may be optionally substituted by 1-3 R';

[0037] L is selected from -CH 2 -O-, -CH=CH- or -CH 2 -NH-;

[0038] Ring B is selected from a benzene ring or a 5-10 membered heteroaryl group;

[0039] R 3 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, each of which may be optionally substituted by 1-3 R';

[0040] m is 0, 1, 2 or 3;

[0041] Ring D is selected from 4-14 membered heterocycloalkyl;

[0042] Ring D may be formed by one or more independent R 4 Substitute, the R 4 are independently selected from hydrogen, halogen, cyano, =O, -R 5 、-OR 6 、-COOR 6 、-C(O)R 5 、-NR 6 R 7 、-NR 6 COR 5 、-NR 6 SO 2 R 5 、-C(O)NR 6 R 7 、-SO 2 R 6 or -SO 2 NR 6 R 7 ;

[0043] R 5 Selected from C 1-6 Alkyl, C3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R;

[0044] R 6 and / or R 7 are independently selected from hydrogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl (C 1-6 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-6 ) alkyl, each of which may be optionally substituted by 1 to 3 R;

[0045] When R 4 Selected from -NR 6 R 7 、-C(O)NR 6 R 7 or -SO 2 NR 6 R 7 When R 6 and R 7 Together with the connected N atom, they can form a 4-7 membered heterocyclic ring, and the 4-7 membered heterocyclic ring can be optionally substituted by 1-3 R;

[0046] R is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R';

[0047] n is 0, 1, 2, 3, 4, 5 or 6.

[0048] In one embodiment of the present invention, R 2 It is a 5-6 membered heteroaryl group.

[0049] In one embodiment of the present invention, R 4 are independently -CH 2 -C(O)NR 6 R7 .

[0050] In one embodiment of the present invention, R is independently COOH.

[0051] In one embodiment of the present invention, ring A and R 2 In the 5-6 membered heteroaryl group, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably pyridyl or isoxazolyl.

[0052] In one embodiment of the present invention, ring B, R 5 , R 6 and R 7 In the 5-10 membered heteroaryl group, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably pyridyl, pyridazinyl, pyrazinyl or pyridopyridazinyl.

[0053] In one embodiment of the present invention, R 1 , R', R 2 , R 3 , R 4 In R and R, the halogen is independently fluorine, chlorine, bromine or iodine; preferably fluorine or chlorine.

[0054] In one embodiment of the present invention, R 1 , R 3 , R 5 , R 6 , R 7 and R, the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0055] In one embodiment of the present invention, R 2 In the C 1-3 Alkyl is independently methyl, ethyl, n-propyl or isopropyl; preferably methyl.

[0056] In one embodiment of the present invention, R 1 , R 3 , R 6 , R 7 and R, the C 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; preferably methoxy.

[0057] In one embodiment of the present invention, R 2 In the C 1-3 Alkoxy is independently methoxy, ethoxy, n-propoxy or isopropoxy.

[0058] In one embodiment of the present invention, R 1 , R 2 , R 3 , R 6 , R 7 and R, the C 1-6 Alkylamino is independently -NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 3 )CH 2 CH 3 、-N(CH 2 CH 3 ) 2 、-NHCH 2 CH 2 CH 3 、-NHCH(CH 3 ) 2 or -NHCH 2 CH 2 CH 2 CH 3 ; preferably -NMe 2 .

[0059] In one embodiment of the present invention, R 1 , R 2 , R 3 , R 6 , R 7 and R, the C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; preferably cyclopropyl.

[0060] In one embodiment of the present invention, R 1 , R 2 , R 3 , R 6 , R 7 In R, the heteroatoms in the 3-6 membered heterocycloalkyl are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably oxetanyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, tetrahydropyranyl or piperidinyl.

[0061] In one embodiment of the present invention, in ring D, the 4-14 membered heterocycloalkyl group is a saturated or semi-saturated cyclic group having 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein the ring directly connected to ring B does not have aromaticity; preferably

[0062] In one embodiment of the present invention, in ring D, the 4-14 membered heterocycloalkyl group is a saturated cyclic group having 1, 2 or 3 heteroatoms selected from N, O and S, 1, 2, 3 or 4 heteroatoms, and a monocyclic, bicyclic or tricyclic ring.

[0063] In one embodiment of the present invention, when R 6 and R 7 When the connected N atoms can form a 4-7 membered heterocyclic ring, the 4-7 membered heterocyclic ring is a saturated cyclic group having 1, 2 or 3 heteroatoms selected from N, O and S, and a monocyclic or bicyclic ring; preferably

[0064] In one embodiment of the present invention, R 5 , R 6 and R 7 In the above, the 6-10 membered aryl groups are independently phenyl or naphthyl, preferably phenyl.

[0065] In one embodiment of the present invention, R 1 are independently hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 The cycloalkyl group is optionally substituted with 1-3 R's; preferably, R 1 are independently halogen, cyano, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl and / or C 1-3 The alkoxy group is optionally substituted with 1-3 R', each of which is independently hydrogen, halogen, hydroxy, cyano or methoxy; for example, each of which is independently hydrogen, halogen or hydroxy.

[0066] In one embodiment of the present invention, k is 0, 1 or 2; for example, k is 1.

[0067] In one embodiment of the present invention, R 2 Selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 3-6 cycloalkyl or 5-6 membered heteroaryl, each of which may be optionally substituted by 1-3 R'; for example, R 2 Selected from hydrogen, halogen, cyano, C 1-3 Alkyl or C 3-6 Cycloalkyl, which may each be optionally substituted by 1 to 3 R's.

[0068] In one embodiment of the present invention, when T 1 When it is a nitrogen atom, T2 is a carbon atom, for R 2 Selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 cycloalkyl or 5-6 membered heteroaryl, each of which may be optionally substituted by 1-3 R', wherein R' is as defined in any one of the present invention. 2 Selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C substituted by cyclopropyl or hydroxy 1-3 Alkyl, C 1-3 Alkyl-substituted 5-6 membered heteroaryl.

[0069] In one embodiment of the present invention, when T 1 When it is a nitrogen atom, T 2 is a carbon atom, R 2 Selected from H, F, Cl, CN, Me, CHF 2 CF 3 、-CH 2 OH, -CH 2 OCH 3 , Preferably, R 2 Selected from H, Cl, Me, CH 2 OH, CN, CHF 2 CF 3 ,

[0070] In one embodiment of the present invention, when T 1 When it is a carbon atom, T 2 is a nitrogen atom, for R 2 Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or 5-6 membered heteroaryl, each of which may be optionally substituted by 1-3 R', wherein R' is as defined in any one of the present invention. 2 Selected from Me or CHF 2 Most preferably, R 2 For me.

[0071] In one embodiment of the present invention, when T 1 When it is a nitrogen atom, T 2 is a carbon atom, for R 2 Selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, each of which may be optionally substituted by 1-3 R', wherein R' is as defined in any one of the present invention. 2 Selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C substituted by hydroxy 1-3 Alkyl or C 3-6 Cycloalkyl.

[0072] In one embodiment of the present invention, when T 1 When it is a carbon atom, T 2 is a nitrogen atom, for R 2 Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, each of which may be optionally substituted by 1-3 R', wherein R' is as defined in any one of the present invention. 2 Selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C substituted by hydroxy 1-3 Alkyl or C 3-6 More preferably, R 2 Selected from Me or CHF 2 Most preferably, R 2 For me.

[0073] In one embodiment of the present invention, R 3 are independently hydrogen, halogen, cyano, C 1-3 Alkyl or C 1-3 Alkoxy groups, which may each be optionally substituted by 1 to 3 R's.

[0074] In one embodiment of the present invention, m is 0 or 1, for example, m is 0.

[0075] In one embodiment of the present invention, R 4 are independently selected from hydrogen, halogen, cyano, =O, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl (C 1-3 )alkyl, -COOH, -CH 2 -C(O)NR 6 R 7 、-C(O)NR 6 R 7 、-SO 2 R 6or -SO 2 NR 6 R 7 ; said C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl may be optionally substituted by 1 to 3 R; when R 4 Selected from -C(O)NR 6 R 7 or -SO 2 NR 6 R 7 When R 6 and R 7 Together with the connected N atom, they can form a 4-7 membered heterocyclic ring, and the 4-7 membered heterocyclic ring can be optionally substituted by 1-3 R;

[0076] Preferably, R 4 are independently selected from the following substituents: hydrogen, cyano, =O, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl (C 1-3 )alkyl, -COOH, -C(O)NR 6 R 7 、-SO 2 R 6 or -SO 2 NR 6 R 7 , the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl may be optionally substituted by 1 to 3 R; when R 4 Selected from -C(O)NR 6 R 7 or -SO 2 NR 6 R 7 When R 6 and R 7Together with the attached N atom, they may form a 4-7 membered heterocyclic ring, and each of the 4-7 membered heterocyclic rings may be optionally substituted by 1-3 R.

[0077] In one embodiment of the present invention, R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 )alkyl, each of which may be optionally substituted by 1 to 3 R.

[0078] In one embodiment of the present invention, R is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1-3 R's; for example, R's are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1-3 R's.

[0079] In one embodiment of the present invention, n is 0, 1, 2, 3 or 4, for example, n is 1 or 2.

[0080] In one embodiment of the present invention, the structural unit For the structural unit (II)

[0081]

[0082] in

[0083] X 1 Selected from N or C;

[0084] for and, Selected from

[0085] X 2 is a carbon atom, -NR 4c -, -O-, or -S(O) w -, the carbon atom is represented by one or two independent R 4b Substitute, the R 4b are independently selected from hydrogen, -OR 6 、-NR 6 R 7 、-NR 6 COR 5 、-C(O)NR 6 R 7 or -SO 2 NR 6 R 7 ;

[0086] R 5 C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl, each of which may be optionally substituted by 1-3 R';

[0087] R 6 and R 7 are independently hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R;

[0088] When R 4b For-NR 6 R 7 、-C(O)NR 6 R 7 or -SO 2 NR 6 R 7 When R 6 and R 7 Together with the connected N atoms, a 4-7 membered heterocyclic ring may be formed, wherein the heterocyclic ring may optionally include 1 to 3 heteroatoms as ring atoms, and the heteroatoms may be independently selected from N, O, and S atoms, and the 4-7 membered heterocyclic ring may be optionally substituted by 1 to 3 R;

[0089] The R 4c are independently hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3) alkyl, each of which may be optionally substituted by 1 to 3 R;

[0090] R is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1-3 R';

[0091] R 4a are independently hydrogen, oxo, cyano, C 1-3 Alkyl, -COOR 6 、-CH 2 -C(O)NR 6 R 7 、-C(O)NR 6 R 7 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl; the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl may be optionally substituted by 1-3 R', wherein R' is as defined in any one of the present invention;

[0092] or two R attached to the same carbon atom 4a Together they form a 3-6 membered saturated heterocyclic ring, wherein the heterocyclic ring optionally includes 1 to 3 heteroatoms as ring atoms, and the heteroatoms may be independently selected from N, O and S atoms, and the 3-6 membered heterocyclic ring may each be optionally substituted by 1 to 3 R;

[0093] n is 0, 1, 2, 3 or 4;

[0094] p and q are each independently 0, 1 or 2, and p and q are not 2 at the same time;

[0095] w is 0, 1, or 2.

[0096] In one embodiment of the present invention, the structural unit Selected from structural unit (II)

[0097]

[0098] in

[0099] X 1 Selected from N or C;

[0100] for and, Selected from

[0101] X 2 Selected from carbon atoms, -NR 4c -, -O-, or -S(O) w -, the carbon atom is represented by one or two independent R 4b Substitute, the R 4b are independently selected from hydrogen, -OR 6 、-NR 6 R 7 、-NR 6 COR 5 、-NR 6 SO 2 R 5 、-C(O)NR 6 R 7 、-SO 2 R 5 or -SO 2 NR 6 R 7 ;

[0102] R 5 Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl, each of which may be optionally substituted by 1-3 R';

[0103] R 6 and / or R 7 are independently selected from hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R;

[0104] When R 4b Selected from -NR 6 R 7 、-C(O)NR 6 R 7 or -SO 2 NR 6 R 7 When R 6 and R 7 Together with the connected N atoms, a 4-7 membered heterocyclic ring may be formed, wherein the heterocyclic ring may optionally include 1 to 3 heteroatoms as ring atoms, and the heteroatoms may be independently selected from N, O, and S atoms, and the 4-7 membered heterocyclic ring may be optionally substituted by 1 to 3 R;

[0105] The R 4c are independently selected from hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R;

[0106] R is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1-3 R';

[0107] R 4a are independently selected from hydrogen, oxo, cyano, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl may be optionally substituted by 1-3 R', wherein R' is as defined in any one of the present invention;

[0108] n is selected from 0, 1, 2, 3 or 4;

[0109] p and q are each independently selected from 0, 1 or 2, and p and q are not 2 at the same time.

[0110] In one embodiment of the present invention, structural unit (II) for

[0111] In one embodiment of the present invention, structural unit (II) for

[0112] In one embodiment of the present invention, the structural unit For the structural unit (III)

[0113]

[0114] in,

[0115] X 1 N or C;

[0116] for and, for

[0117] X 2 For one or two independent R 4b Substituted carbon atom, -NR 4c -, -O-, or -S(O) w -, the R 4b For hydrogen, -OR 6 、-NR 6 R 7 、-NR 6 COR 5 、-NR 6 SO 2 R 5 、-C(O)NR 6 R 7 、-SO 2 R 5 or -SO 2 NR 6 R 7 ;

[0118] R 5 C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl, each of which may be optionally substituted by 1-3 R';

[0119] R 6 and R 7 Each is independently hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R;

[0120] When R 4b For-NR 6 R 7 、-C(O)NR 6 R 7 or -SO 2 NR 6 R 7 When R 6 and R 7Together with the connected N atoms, a 4-7 membered heterocyclic ring may be formed, wherein the heterocyclic ring may optionally include 1 to 3 heteroatoms as ring atoms, and the heteroatoms may be independently selected from N, O, and S atoms, and the 4-7 membered heterocyclic ring may be optionally substituted by 1 to 3 R;

[0121] The R 4c For hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R;

[0122] R is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1-3 R';

[0123] X 3 CR 4a or N;

[0124] R 4a are independently hydrogen, oxo, cyano, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl may be optionally substituted by 1-3 R', wherein R' is as defined in any one of the present invention;

[0125] u and v are independently 0, 1, 2, 3 or 4;

[0126] r, s, and t are each independently 0, 1, or 2.

[0127] w is 0, 1, or 2.

[0128] In one embodiment of the present invention, in the structural unit (III), R 4a are independently hydrogen, cyano, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, the C 1-3 Alkyl, C 3-6The cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl may be optionally substituted with 1-3 R', wherein R' is as defined in any one of the present invention.

[0129] In one embodiment of the present invention, structural unit (III) for Preferably, structural unit (III) for

[0130] In one embodiment of the present invention, structural unit (III) for

[0131] Preferably, structural unit (III) for

[0132] In one embodiment of the present invention, the structural unit For the structural unit (IV)

[0133]

[0134] in

[0135] R 4c For hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R;

[0136] R is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1-3 R';

[0137] R 4a are independently hydrogen, cyano, oxo, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl; the C 1-3Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl may be optionally substituted by 1-3 R', wherein R' is as defined in any one of the present invention;

[0138] n is selected from 0, 1, 2, 3 or 4;

[0139] In one embodiment of the present invention, the structural unit is the structural unit (V)

[0140]

[0141] in

[0142] X 2 For one or two independent R 4a Substituted carbon atom or -O-,

[0143] R 4a are independently hydrogen, cyano, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, or two R attached to the same carbon atom 4a together to form an oxo (C=O) group; the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl may be optionally substituted by 1-3 R', wherein R' is as defined in any one of the present invention;

[0144] u, v are each independently selected from 0, 1, 2, 3 or 4;

[0145] r is selected from 0 or 1.

[0146] In one embodiment of the present invention, the structural unit (V) for

[0147] In one embodiment of the present invention, the structural unit is the structural unit (VI)

[0148]

[0149] in

[0150] Ring E is a 5-6 membered saturated cycloalkyl, a benzene ring or a 5-6 membered heteroaryl;

[0151] R 4a are independently hydrogen, oxo, halogen, cyano, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl; the C 1-3 Alkyl, C3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl may be optionally substituted by 1-3 R', wherein R' is as defined in any one of the present invention;

[0152] R 4c For hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, preferably R 4c is hydrogen;

[0153] u and v are independently 0, 1, 2, 3 or 4;

[0154] In one embodiment of the present invention, the structural unit (VI) for

[0155] In one embodiment of the present invention, R 4a are independently H, =O, -F, -Cl, -Me, -i-Pr, -t-Bu, -CH 2 CH(CH 3 ) 2 , -COOH, -CN, -CH 2 CN、-CH 2 OH, -(CH 2 ) 2 OH, -CH 2 OCH 3 、-CONH 2 、-CONHCH 3 、-CON(CH 3 ) 2 、-CONHCH 2 CH 3 、-CH 2 CONHCH 2 CH 3 , Preferably, R 4a are independently H, =O, -F, -Me, -i-Pr, -t-Bu, -CH 2 CH(CH 3 ) 2 , -COOH, -CN, -CH 2 OH, -CONH 2 、-CONHCH 2 CH 3 、-CON(CH 3 ) 2 、-CH 2 CONHCH 2 CH 3 ,

[0156] In one embodiment of the present invention, R 4b are independently H, =O, -OCH 3 、-NMe 2 、-NHCOCH 3 、-NHSO 2 CH 3 、-SO 2 Me, -COOH, -CONH 2 、-CONHCH 3 、-CON(CH 3 ) 2 、-CONHCH 2 CH 3 、-SO 2 NHCH 3 , Preferably, R 4b Each is independently H, -OCH 3 、-NMe 2 、-NHCOCH 3 、-COOH、-CONHCH 2 CH 3 、-SO 2 NHCH 3 ,

[0157] In one embodiment of the present invention, R 4c H, -Me, -Et, -i-Pr, -CF, respectively. 3 , -CHF 2 、-CH 2 CF 3 、-CH 2 CF 2 H, -CH 2 CN、-(CH 2 ) 2 CN、-(CH 2 ) 3 CN、-(CH 2 ) 2 NH 2 、-(CH 2 ) 2 OH, -(CH 2 ) 2 OCH 3 、-(CH 2 ) 3 OCH 3、-COCH 3 、-COCH(CH 3 ) 2 、-SO 2 NHCH 3 、-SO 2 CH 3 ,

[0158] Preferably, R 4c are independently H, -Me, -CH 2 CF 3 、-CH 2 CN、-(CH 2 ) 3 CN、-(CH 2 ) 2 NH 2 、-(CH 2 ) 2 OH, -(CH 2 ) 2 OCH 3 、-(CH 2 ) 3 OCH 3 、-SO 2 CH 3 、-COCH 3 ,

[0159] In one embodiment of the present invention, R 1 are independently H, F, Cl, Me, CN, -CH 2 F, -CF 2 H.CF 3 、-OCF 2 H、-CH(CN) 2 、-CH 2 OH, -CH 2 OCH 3 or Preferably, R 1 F, Cl, Me, -CH 2 F, -CF 2 H.CF 3 、CN、-CH(CN) 2 、-CH 2 OH, -CH 2 OCH 3 or -OCF 2 H.

[0160] In one embodiment of the present invention, ring A is a benzene ring, a pyridine ring or a pyrimidine ring; preferably, ring A is a benzene ring or a pyridine ring.

[0161] In one embodiment of the present invention, the structural unit Selected from Preferably, the structural unit Selected from

[0162] In one embodiment of the present invention, the structural unit Selected from Preferably, the structural unit Selected from

[0163] In one embodiment of the present invention, L is -CH 2 -O-.

[0164] In one embodiment of the present invention, ring B is a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring or a pyridopyridazine ring; preferably, ring B is a pyridine ring, a pyridazine ring, a pyrazine ring or a pyridopyridazine ring; for example, ring B is a pyridine ring, a pyridazine ring or a pyridopyridazine ring.

[0165] In one embodiment of the present invention, R 3 Each independently is H, F, Cl, CN, Me or -OCH 3 More preferably, R 3 Each independently is H, CN, Me or -OCH 3 .

[0166] In one embodiment of the present invention, the structural unit for Preferably, the structural unit for

[0167] In one embodiment of the present invention, ring D is Preferably, ring D is

[0168] In one embodiment of the present invention, R 4 are independently H, F, Cl, =O, -Me, -COOH, -Et, -i-Pr, -t-Bu, -CH 2 CH(CH 3 )2 、 -CF 3 、 -CHF 2 、 -CH 2 CF 3 、 -CH 2 CF 2 、 -CN、 -CH 2 CN、 -(CH 2 ) 2 CN、 -(CH 2 ) 3 CN、 -CH 2 OH、 -(CH 2 ) 2 OH、 -CH 2 OCH 3 、 -OCH 3 、 -NMe 2 、 -NHCOCH 3 、 -NHSO 2 CH 3 、 -SO 2 Me、 -CONH 2 、 -CONHCH 3 、 -CON(CH 3 ) 2 、 -CONHCH 2 CH 3 、 -SO 2 NHCH 3 、 -COCH(CH 3 ) 2 、 -CONHCH 2 CH 3 、 -CH 2 CONHCH 2 CH 3 、 -(CH 2 ) 2 NH 2 、 -(CH 2 ) 2 OCH 3 、 -(CH 2 ) 3 OCH 3 、 -COCH 3 、 Preferably, R 4 is independently H, F, =O, -Me, -i-Pr, -t-Bu, -CH 2 CH(CH 3 ) 2 、 -OCH 3 、 -(CH 2 )2 OCH 3 、-(CH 2 ) 3 OCH 3 、-NMe 2 , -COOH, -CN, -CH 2 CN、-CH 2 OH, -CONH 2 、-CONHCH 3 、-CONHCH 2 CH 3 、-CON(CH 3 ) 2 、-CH 2 CONHCH 2 CH 3 、-NHCOCH 3 、-CH 2 CF 3 、-(CH 2 ) 2 NH 2 、-(CH 2 ) 2 OH, -SO 2 CH 3 、-SO 2 NHCH 3 、-(CH 2 ) 3 CN, -COCH 3 ,

[0169]

[0170] In one embodiment of the present invention, the structural unit is the following substituent:

[0171]

[0172]

[0173] Preferably, the structural unit Select from the following substituents:

[0174]

[0175]

[0176] In one embodiment of the present invention, the compound represented by formula I is a compound represented by formula IA:

[0177]

[0178] in, for

[0179] R 1 , R 2 , R 4a , R 4c , u, v, n and ring E are as defined in any one of the present invention.

[0180] In one embodiment of the present invention, In, R 4c For hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl (C 1-3 ) alkyl or 3-6 membered heterocycloalkyl;

[0181] R 4c In the C 1-3 The alkyl group is optionally substituted with 1-3 independently selected substituents: halogen, cyano, hydroxy, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 3-6 membered heterocycloalkyl substituted by 1-3 halogens;

[0182] R 4c wherein the 3-6 membered heterocycloalkyl is optionally substituted with 1-3 C 1-3 alkyl;

[0183] R 4c wherein the 5-10 membered heteroaryl is optionally substituted with 1-3 independently selected substituents: C 1-3 Alkyl or C 1-3 Haloalkyl;

[0184] R 4c wherein the 5-10 membered heteroaryl (C 1-3 ) alkyl is optionally substituted with 1-3 independently selected substituents: halogen, cyano or C 1-3 Alkoxy.

[0185] In one embodiment of the present invention, In, R 4c For hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0186] In one embodiment of the present invention, In, R 4c For hydrogen.

[0187] In one embodiment of the present invention, R 4c For hydrogen.

[0188] In one embodiment of the present invention, In, R 4a are independently hydrogen, oxo, C 1-3 Alkyl or COOH, n is 0, 1 or 2. Preferably, n is 0.

[0189] In one embodiment of the present invention, In, R 4a are independently hydrogen, oxo, C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl or 5-6 membered heteroaryl;

[0190] R 4a In the C 1-3 The alkyl group is optionally substituted with 1-3 C 1-3 alkyl;

[0191] R 4a wherein the 5-6 membered heteroaryl group is optionally substituted with 1-3 C 1-3 alkyl;

[0192] R 4a In the above, the phenyl group is optionally substituted with 1-3 halogens;

[0193] u is 0;

[0194] v is 0 or 1. Preferably, R 4a is hydrogen or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1-3 C 1-3 alkyl.

[0195] In one embodiment of the present invention, In, R 4a are independently hydrogen or halogen; u is 0, and v is 0 or 1. Preferably, u is 0, and v is 0.

[0196] In one embodiment of the present invention, the compound as shown in Formula I is selected from the following compounds:

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213] The present invention also provides a pharmaceutical composition, comprising a compound as shown in Formula I as described in any one of the above, its cis-trans isomers, its enantiomers, its diastereomers, its racemates, its solvates, its hydrates, its pharmaceutically acceptable salts or its prodrugs.

[0214] In some embodiments of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents or excipients.

[0215] In another aspect of the present invention, the present invention also proposes a compound as shown in formula I as described in any one of the above, its cis-trans isomers, its enantiomers, its diastereomers, its racemates, its solvates, its hydrates, its pharmaceutically acceptable salts or its prodrugs or the aforementioned pharmaceutical compositions in the preparation of α5-GABA A Use of receptor modulators.

[0216] In another aspect of the present invention, the present invention also provides a compound as described in any one of the above as shown in formula I, its cis-trans isomers, its enantiomers, its diastereomers, its racemates, its solvates, its hydrates, its pharmaceutically acceptable salts or its prodrugs or the aforementioned pharmaceutical compositions for the preparation of treatment or prevention of α5-GABA AUse in medicine for receptor-related diseases.

[0217] The present invention also provides a method for treating or preventing α5-GABA A A method for treating a receptor-related disease, comprising administering to a patient an effective dose of a compound as described in any one of the above as shown in Formula I, its cis-trans isomers, its enantiomers, its diastereomers, its racemates, its solvates, its hydrates, its pharmaceutically acceptable salts, or its prodrugs or pharmaceutical compositions.

[0218] The present invention also provides the use of the compound as shown in Formula I as described in any one of the above, its cis-trans isomers, its enantiomers, its diastereomers, its racemates, its solvates, its hydrates, its pharmaceutically acceptable salts or its prodrugs or pharmaceutical compositions in the preparation of drugs for treating or preventing the following diseases: pain, Alzheimer's disease, multi-infarct dementia and stroke.

[0219] The present invention also provides a method for treating or preventing pain, Alzheimer's disease, multi-infarct dementia and stroke, characterized in that an effective dose of a compound as shown in formula I as described in any one of the above, its cis-trans isomers, its enantiomers, its diastereomers, its racemates, its solvates, its hydrates, its pharmaceutically acceptable salts or its prodrugs or pharmaceutical compositions are administered to the patient.

[0220] In a preferred embodiment, the pain is neuropathic pain, inflammatory pain and cancer pain.

[0221] In a preferred embodiment, the pain is selected from the group consisting of headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, low back pain, lower limb pain, muscle and bone pain, vascular pain, gout, arthritis pain, visceral pain, pain caused by infectious diseases (such as AIDS and postherpetic neuralgia), polyostotic pain, sickle cell anemia, autoimmune disease, multiple sclerosis or inflammation-related pain, chronic pain caused by injury or surgery, nociceptive pain, diabetic peripheral neuropathy pain, trigeminal neuralgia, lumbar or cervical radiculopathy pain, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, cancer, chemical injury, toxins, nutritional deficiencies, and pain associated with degenerative osteoarthritis.

[0222] definition

[0223] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following definitions. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or active ingredient.

[0224] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0225] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention, prepared from a compound having a specific substituent discovered by the invention and a relatively nontoxic acid or base. When the compound of the invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium calcium, ammonium, organic amine or magnesium salts or similar salts. When the compound of the invention contains a relatively basic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc., and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and can be converted into any base or acid addition salt.

[0226] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0227] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0228] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0229] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability of a ring to rotate freely about double bonds or single bonds of ring carbon atoms.

[0230] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0231] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0232] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key

[0233] The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert to each other. If tautomers are possible (such as in solution), it is possible to reach a chemical equilibrium of tautomers. For example, proton tautomers (proton tautomers) (also known as prototropic tautomers) include interconversions carried out by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers (valencetautomers) include interconversions carried out by the reorganization of some bonding monads. Among them, a specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxy-3-ene-2-one.

[0234] The term "prodrug" generally refers to a compound of formula (I) that has been derivatized with a functional group, and its derivative can be easily converted into a compound of formula (I) in vivo. Generally, the selection and preparation of suitable prodrugs can be described in, for example, Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

[0235] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound, said isotopes having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that predominantly occurs in nature. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention. Isotopic variants may enhance certain therapeutic advantages, such as the substitution of heavy hydrogen for hydrogen to form deuterated drugs, the bond between deuterium and carbon being stronger than the bond between ordinary hydrogen and carbon, and the deuterated drugs having advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life compared to undeuterated drugs, or providing standard compounds that can be used as characterization of biological samples. Isotopically enriched compounds within the general formula (I) may be prepared without undue experimentation by conventional techniques well known to those skilled in the art, or by methods similar to those described in the routes and embodiments of the present invention, using appropriate isotopically enriched reagents and / or intermediates.

[0236] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0237] The naming convention used in the present invention is based on the IUPAC system nomenclature generated by ChemDraw software.Any open valence bonds occurring on carbon, oxygen, sulfur or nitrogen atoms in the structures given in the present invention indicate the presence of hydrogen atoms.

[0238] The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on the basis of chemical realization.

[0239] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0240] When the number of a linking group is 0, such as -(CRR) 0 -, indicating that the connecting group is a single bond.

[0241] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0242] When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The connecting group L is at this time You can connect the benzene ring and the cyclopentyl group in the same direction as reading from left to right to form It is also possible to connect phenyl and cyclopentyl groups in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0243] Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, "3-7 membered ring" refers to a "ring" having 3-7 atoms arranged around it.

[0244] Unless otherwise specified, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0245] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.

[0246] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of the alkyl group include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0247] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule through an oxygen atom. 1-6 Alkyl groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 Alkoxy, etc.; C 1-6Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0248] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule through an oxygen atom. 1-6 Alkyl groups include C 1-2 and C 2-3 Alkoxy, etc.; C 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0249] Unless otherwise specified, the term “C 1-6 "Alkylamino" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule via an amino group. 1-6 Alkyl groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 Alkylamino, etc.; C 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 3 )CH 2 CH 3 、-N(CH 2 CH 3 ) 2 、-NHCH 2 CH 2 CH 3 、-NHCH(CH 3 ) 2 、-NHCH 2 CH 2 CH 2 CH 3 wait.

[0250] Unless otherwise specified, the term “C 3-6"Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic system. 3-6 Cycloalkyl groups include C 3-5 , C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0251] Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated monocyclic radical consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) z , z is 1 or 2). In addition, for the "3-6 membered heterocycloalkyl", a heteroatom may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 4-6, 5-6, 4, 5 and 6 membered heterocycloalkyls, etc. Examples of 3-6 membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl (including tetrahydrofuran-2-yl), piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, etc.

[0252] Unless otherwise specified, the term "4-14 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated or semi-saturated cyclic group consisting of 4 to 14 ring atoms, 1, 2, 3, 4, 5 or 6 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) z , z is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems may be cyclic, spirocyclic and bridged ring systems; in addition, with respect to the "4-14 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl connects to the rest of the molecule. Part of the ring system of the bicyclic and tricyclic ring systems may be aromatic, and the ring connected to the rest of the molecule does not have aromaticity. Examples of 4-14 membered heterocycloalkyls include, but are not limited to, cyclopropyl, azetidinyl, oxetanyl, thiidine, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl,

[0253]

[0254] wait.

[0255] Unless otherwise specified, the terms "6-10 membered aromatic ring" and "6-10 membered aryl" can be used interchangeably, and the term "6-10 aryl" means a monovalent aromatic carbocyclic ring system containing 6-10 carbon atoms and having at least one aromatic ring or multiple condensed rings in which at least one ring is an aromatic ring. Examples of aryl are, but not limited to, phenyl, naphthyl, biphenyl or indanyl, etc.

[0256] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" are used interchangeably. The term "5-10 membered heteroaryl" refers to a cyclic group with a conjugated π electron system consisting of 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic ring or a fused bicyclic ring system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) z , z is 1 or 2). The 5-10 membered heteroaryl group may be attached to the rest of the molecule via a heteroatom or a carbon atom, including 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups, etc. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4- thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 2-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indazolyl (including 5-indazolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.), etc.

[0257] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention. The term "5-6 membered heteroaryl" refers to a cyclic group with a conjugated π electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) z , z is 1 or 2). The 5-6 membered heteroaryl may be attached to the rest of the molecule via a heteroatom or a carbon atom, and the 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl, etc. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), etc.

[0258] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-7 Including C 1 , C 2 , C 3 , C 4 , C 5 , C 6 and C 7 , also includes any range from n to n+m, such as C 1-7 Including C 1-3 , C 1-6 , C 3-6 , C 4-7 and C 5-7 Etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-7-membered ring includes 3-membered, 4-membered, 5-membered, 6-membered and 7-membered rings, and also includes any range from n to n+m, for example, 3-7-membered ring includes 3-6-membered ring, 4-7-membered ring, 5-7-membered ring and 6-7-membered ring, etc.

[0259] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-brosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.

[0260] The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0261] The term "treatment" as used herein refers to the administration of one or more pharmaceutical substances, in particular the compounds of formula (I) and / or pharmaceutically acceptable salts thereof, to an individual suffering from a disease or symptoms of the disease, in order to cure, alleviate, mitigate, alter, cure, improve, modify or affect the disease or symptoms of the disease. The term "prevention" as used herein refers to the administration of one or more pharmaceutical substances, in particular the compounds of formula (I) and / or pharmaceutically acceptable salts thereof, to an individual with a constitution susceptible to the disease, in order to prevent the individual from suffering from the disease. When referring to a chemical reaction, the terms "treating", "contacting" and "reacting" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction producing the indicated and / or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e., there may be one or more intermediates generated in the mixture, which ultimately lead to the formation of the indicated and / or desired product.

[0262] As used herein, "patient" is defined as any warm-blooded animal, such as but not limited to mice, guinea pigs, dogs, horses or humans, preferably the patient is a human.

[0263] The term "effective amount" used in the present invention refers to an amount that is generally sufficient to produce a beneficial effect on an individual. The effective amount of the compound of the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies or clinical trials) in combination with conventional influencing factors (e.g., mode of administration, pharmacokinetics of the compound, severity and course of the disease, individual medical history, individual health status, individual response to the drug, etc.).

[0264] As described above, the novel compounds of the present invention and their pharmaceutically acceptable salts and prodrugs have important pharmacological properties and are α5-GABA A Therefore, the compounds of the present invention can be used alone or in combination with other drugs to treat or prevent GABA receptors containing α5 subunits. A Receptor ligand-mediated diseases. These diseases include, but are not limited to, pain, Alzheimer's disease, multi-infarct dementia, and stroke.

[0265] Therefore, the present invention also relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable carrier and / or adjuvant.

[0266] Likewise, the present invention also includes the compounds as described above, for use in the preparation of drugs for treating or preventing α5-GABA A Drugs for diseases associated with the receptor, in particular for the treatment or prevention of the following diseases: pain, Alzheimer's disease, multi-infarct dementia and stroke.

[0267] Treatment or prevention of pain is preferred.

[0268] The treatment or prevention of neuropathic pain, inflammatory pain and cancer pain is particularly preferred.

[0269] As used in the present invention, "cancer pain" refers to the pain that occurs during the development of a malignant tumor. It is currently believed that there are three mechanisms for the occurrence of cancer pain, namely: pain directly caused by cancer development, pain caused by cancer chemotherapy drug treatment, and painful diseases concurrent with cancer patients.

[0270] As used herein, "neuropathic pain" is pain that is provoked or caused by primary damage and dysfunction of the nervous system.

[0271] As used in the present invention, "inflammatory pain" is pain caused by local acute inflammation or chronic inflammation irritating nerves.

[0272] As used herein, "acute pain" is defined as pain caused by noxious stimulation resulting from injury and / or disease of the skin, body structures, or internal organs, or pain caused by abnormal function of muscles or internal organs without actual tissue damage.

[0273] As used herein, "chronic pain" is defined as pain that persists beyond the normal course of an acute illness or reasonable time for healing of an injury, or is associated with a chronic pathological process that causes persistent pain, or pain that recurs at regular intervals for months or years. Pain is considered chronic if it persists after healing should have been achieved or beyond the normal course of treatment. The length of time required for pain to pass depends on the nature of the pain and the course of treatment associated with the pain. If the pain exceeds the normal course of treatment, the pain is chronic.

[0274] The drugs disclosed in the present invention can effectively treat chronic pain as defined above, and the drugs disclosed in the present invention can be used to treat pain sensitivity associated with other diseases, including hyperalgesia, abnormal pain, increased pain sensation and enhanced pain memory, and the invention will improve the treatment of their pain.

[0275] As used in the present invention, "headache" can be divided into primary headache and secondary headache, primary headache includes tension headache, migraine and cluster headache, and secondary headache is caused by other diseases. When the pain-sensitive tissues of the head and face are lesioned or stimulated, various headaches can be caused. These pain-sensitive tissues include those distributed in the scalp, face, mouth and throat, etc. Since they are mainly muscles or blood vessels of the head, they contain rich nerve fibers and are more sensitive to pain, so when these tissues are damaged, headaches can be caused.

[0276] As used herein, "facial pain" includes, but is not limited to, trigeminal neuralgia, atypical facial pain, facial nerve palsy, and hemifacial spasm.

[0277] As used in the present invention, "trigeminal neuralgia" is a unique chronic pain disease, also known as painful cramps, which refers to the occurrence of short-term, paroxysmal and recurrent electric shock-like severe pain in the distribution area of ​​the trigeminal nerve, or accompanied by spasms of the ipsilateral facial muscles. Trigeminal neuralgia is divided into two types: primary and secondary. Primary trigeminal neuralgia refers to clinically no neurological signs and no organic lesions found in examinations; secondary trigeminal neuralgia refers to clinically neurological signs and organic lesions found in examinations, such as tumors and inflammation.

[0278] As used in the present invention, "atypical facial pain" refers to pain caused by a variety of causes. It manifests as persistent burning pain, no intermittent, unrelated to special movements or triggering stimuli, and the pain is mostly bilateral. The pain often exceeds the distribution range of the trigeminal nerve and even involves the skin of the neck. The cause of the pain may be sinusitis, malignant tumors, jaw and skull base infections, etc., which stimulate or damage the trigeminal nerve.

[0279] As used in the present invention, "neck pain, back pain, shoulder pain" refers to pain caused by acute and chronic muscle strain, degenerative changes of bones and joints, and trauma. Common diseases that cause neck, shoulder and upper limb pain include cervical shoulder myofasciitis, nuchal ligamentitis, cervical spondylosis, scapulohumeral periarthritis, thoracic outlet syndrome, lateral epicondylitis, etc., or pain caused by autoimmune diseases is common in rheumatoid arthritis, ankylosing spondylitis, rheumatoid arthritis and other diseases. Other diseases that may cause neck pain, back pain, and shoulder pain include tumors of the neck and shoulders, neuritis, arteriovenous diseases, and various infections, as well as referred pain caused by lesions of chest and abdominal organs.

[0280] As used in the present invention, "chest, abdomen and back pain" refers to pain caused by diseases of the chest and abdominal viscera and chest and abdominal wall tissues.

[0281] As used in the present invention, "lower back and lower limb pain" refers to pain in the lower back, lumbar sacral, sacroiliac, hip, buttocks and lower limbs.

[0282] As used herein, "musculoskeletal pain" includes, but is not limited to, myofascial pain, trauma-induced pain, and chronic regional pain syndrome.

[0283] As used herein, "diabetic peripheral neuropathy pain" refers to pain caused by nerve damage associated with diabetes, where nerve damage in diabetes is caused at least in part by reduced blood flow and high blood sugar.

[0284] As used herein, "visceral pain" includes, but is not limited to, pain in irritable bowel syndrome (IBS), with or without chronic fatigue syndrome (CFS), inflammatory bowel disease (IBD), and interstitial cystitis.

[0285] As used herein, "vascular pain" is pain resulting from one or more of the following factors. First, improper perfusion of tissues. Causing temporary or continuous ischemia, such as occurs in limb muscles during exercise; second, delayed changes. For example, ulcers or gangrene in the skin or abdominal viscera; third, sudden or accelerated changes in the caliber of large vessels. For example, changes that occur in aneurysms; fourth, aortic rupture. The result is blood spillage, which stimulates nociceptive fibers in the peritoneal or pleural parietal layers; fifth, strong spasms caused by severe stimulation of the arterial endothelium due to intra-arterial injection; sixth, impairment of venous return, resulting in massive edema of rapidly expanding fascial compartments (Bonica et al., The Management of Pain, Vol. 1 (Second Edition), Philadelphia; Lea & Feboger, 1990).

[0286] As used in the present invention, "autonomic reflex pain" refers to pain caused by "reflex sympathetic atrophy". Reflex sympathetic atrophy refers to severe spontaneous pain and hypersensitivity to touch and pain after the body suffers acute or chronic injuries.

[0287] As used in the present invention, "postoperative pain" refers to a complex physiological response of the body to the disease itself and the tissue damage caused by surgery, which manifests as an unpleasant experience in psychology and behavior.

[0288] As used in the present invention, "arthritis pain" includes, but is not limited to, pain caused by diseases such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, gout, pseudogout, infectious arthritis, tendinitis, bursitis, bone lesions, and inflammation of joint soft tissues.

[0289] As used in the present invention, "postherpetic neuralgia" refers to the severe pain that persists under the skin in the original rash area for a long time after the rash of herpes zoster has healed.

[0290] As used herein, "nociceptive pain" is pain caused by tissue damaging processes that stimulate nociceptive afferents, or pain caused by prolonged excitation of nociceptors.

[0291] Technical and scientific terms used herein but not specifically defined have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs.

[0292] The solvent used in the present invention can be obtained commercially. The present invention uses the following abbreviations: Ac represents acetyl, ACN represents acetonitrile, B2pin2 represents bispinacol borate, CbzCl represents benzyl chloroformate, DAST represents diethylaminosulfur trifluoride, DCDMH represents dichlorohydantoin, DCM represents dichloromethane, DEAD represents diethyl azodicarboxylate, DIBAL-H represents diisobutylaluminum hydride, DIEA represents diisopropylethylamine, DMAP represents 4-dimethylaminopyridine, DMB represents 2,4-dimethoxybenzyl, DMF represents N,N-dimethylformamide, DMSO represents dimethyl sulfoxide, EDCI stands for 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, HATU stands for 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HOBt stands for 1-hydroxybenzotriazole, HPLC stands for high performance liquid chromatography, KHMDS stands for potassium bis(trimethylsilyl)amide, LAH stands for lithium aluminum tetrahydride, m-CPBA stands for meta-chloroperoxybenzoic acid, MsCl stands for methanesulfonyl chloride, MW stands for microwave heating, NCS stands for chlorosuccinimide, Pd(dppf)Cl 2 Represents 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, Pd 2 (dba)3 stands for tris dibenzylideneacetone dipalladium, PhNTf 2 stands for N-phenylbis(trifluoromethanesulfonimide), PMBCl stands for p-methoxybenzyl chloride, pyr. stands for pyridine, Ruphos stands for 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, Ruphos-Pd-G3 stands for methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II), SFC stands for supercritical fluid chromatography, TBAF stands for tetrabutylammonium fluoride, TBSCl stands for tert-butyldimethylsilyl chloride, t-BuXph os stands for 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, THF stands for tetrahydrofuran, TEA stands for triethylamine, TEAF stands for triethylamine trihydrofluoride, Tf stands for trifluoromethanesulfonyl, TFA stands for trifluoroacetic acid, TFAA stands for trifluoroacetic anhydride, TLC stands for thin layer chromatography, TMS stands for trimethylsilyl, Tol. stands for toluene, Ts stands for p-toluenesulfonyl, Xantphos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, LCMS stands for liquid chromatography-mass spectrometry, h stands for hour, and min stands for minute.

[0293] Preparation method

[0294] The present invention also relates to a method for producing the compound of the general formula (I) defined above. The compound synthesis method is shown in the figure:

[0295] Synthesis method (I):

[0296]

[0297] When T 1 is a nitrogen atom, T 2 For carbon atoms:

[0298] Usually, compound I-1 and compound I-3 are provided by commercial raw materials. Compound I-1 reacts with p-toluenesulfonyl hydrazide in an alcohol or ether solvent, such as ethanol, tetrahydrofuran, etc. to form hydrazone compound I-2. Aromatic amine I-3 acts as a nucleophilic agent to attack hydrazone compound I-2, and then undergoes intramolecular cyclization and aromatization to form triazole compound I-4. Reaction step b) is generally carried out in an alcohol or ether solvent, and the alcohol or ether solvent includes but is not limited to ethanol, isopropanol, tetrahydrofuran, etc. Compound I-4 can be subjected to reduction conditions to obtain compound I-5, and the reduction reaction includes but is not limited to the reaction using a reducing agent such as sodium borohydride, lithium borohydride, lithium aluminum hydride or DIBAL-H in an ether or alcohol solvent such as tetrahydrofuran, methanol, etc.

[0299] Synthesis method (II):

[0300]

[0301] Compound I-5 can also be prepared by synthesizing alkyne compound I-6 and azide compound I-7 through the Click reaction shown in step d), and the reaction is completed under the catalytic conditions of copper salts, and the copper salts include but are not limited to copper sulfate, cuprous iodide, copper acetate, etc. 2 Compound I-6 with an aromatic structure can be synthesized by Sonagashira coupling of the corresponding halogenated aromatic compound and ethyl propiolate; and compound I-7 can be synthesized by reacting the corresponding amino compound I-3 with a nitrite or nitrite ester, wherein the nitrite includes but is not limited to sodium nitrite, potassium nitrite, etc., and the nitrite ester includes but is not limited to tert-butyl nitrite and isoamyl nitrite, etc. For step d), different regional isomers may be produced in the reaction, and compound I-4 needs to be obtained by isomer separation.

[0302] Synthesis method (three):

[0303]

[0304] When T 1 is a carbon atom, T 2 When it is a nitrogen atom:

[0305] Compound I-11 can also be prepared by synthesizing alkynoic acid ester compound I-9 and azide compound I-8 through the Click reaction shown in step d), and the reaction is completed under the catalytic conditions of copper salts, and the copper salts include but are not limited to copper sulfate, cuprous iodide, copper acetate, etc. For alkynoic acid ester compound I-9, it can be synthesized by Sonagashira coupling of the corresponding halogenated aromatic compound and ethyl propiolate; for step d), different regional isomers may be produced in the reaction, and compound I-11 needs to be obtained by isomer separation.

[0306] Synthesis method (IV):

[0307]

[0308] In the synthesis method, compounds I-5 and I-11 are represented by the general formula compound I-12, and compound I-14 is synthesized by direct substitution or coupling reaction condition e) via compound I-12 and compound I-13, wherein the direct substitution reaction is a nucleophilic substitution reaction, and the corresponding reaction condition is an alkaline condition, such as using sodium hydride, cesium carbonate or potassium phosphate as a base in various solvents such as DMF, acetonitrile or tetrahydrofuran; the coupling reaction is a metal-catalyzed carbon-oxygen or carbon-nitrogen bond formation coupling reaction, including but not limited to palladium-catalyzed Buchwald reaction, copper-catalyzed Ullmann reaction, etc. When ring D is connected to ring B through a nitrogen atom, compound (I) can be generated by reacting compound I-14 with compound I-15 in step f), and step f) corresponds to alkaline direct nucleophilic substitution conditions, including but not limited to sodium hydride, cesium carbonate or potassium phosphate as a base in various solvents such as DMF, acetonitrile or tetrahydrofuran. Alternatively, step f) represents a metal-catalyzed coupling reaction, such as palladium-catalyzed Buchwald reaction, copper-catalyzed Ullmann reaction, etc. When ring D is connected to ring B via a carbon atom, compound (I) can be prepared by reacting compound I-14 with boronic acid compound I-16 or boronic ester compound I-17 in step g), and step g) corresponds to palladium-catalyzed Suzuki reaction, etc., and the palladium catalyst used includes but is not limited to Ruphos-Pd-G3, Pd(dppf)Cl 2 , Pd 2 (dba) 3 In the structural unit, Y 1 , Y 2 represents a leaving group, for example, triflate, p-toluenesulfonate, chlorine, bromine, iodine, and the like.

[0309] Synthesis method (V):

[0310]

[0311] In another technical solution provided by the present invention, the synthesis of compound (I) can be synthesized via direct substitution or coupling reaction step e) of compound I-12 and compound I-18. When ring D is connected to ring B via a nitrogen atom, compound I-18 can be generated by reacting compound I-13 with compound I-15 in step f); when ring D is connected to ring B via a carbon atom, compound I-18 can be generated by reacting compound I-13 with boronic acid compound I-16 or boronic ester compound I-17 in step g); the synthesis steps e), f), and g) are as described in the synthesis method (IV).

[0312] Synthesis method (VI):

[0313]

[0314] In another technical scheme provided by the present invention, compound I-19 and compound I-7 are subjected to step d) to obtain click reaction product I-20, and after the B ring is introduced in step e), compound I-21 is subjected to step h) to convert the trimethylsilyl group in the molecule into chlorine, and step h) corresponds to the conditions of using NCS, DCDMH, etc. as chlorine source and KF, TBAF, etc. as base. Compound I-22 is introduced into ring D by direct substitution or coupling reaction to obtain chlorotriazole compound I-23, and compound I-23 can be introduced into the molecule by metal-catalyzed coupling reaction. 2 Group, applicable to different R 2 Synthesis of the group compound: The synthesis steps d), e), f) and g) are as described in the synthesis method (iv).

[0315] The present invention also relates to compounds of general formula (I) as described above, which are prepared by the methods described above. If the preparation methods are not described in the examples, the compounds of general formula (I) and their intermediate products can be prepared by similar methods or according to the aforementioned methods. Raw materials known in the art can be obtained from commerce, or can be prepared by methods known in the art or by analogy to known methods.

[0316] It will be appreciated that the compounds of general formula (I) of this invention may be derivatized at functional groups to provide derivatives which are capable of reconversion into the parent compound in vivo.

[0317] Pharmaceutical composition

[0318] The present invention provides a method for treating a 5-GABA containing a therapeutically effective amount of α5-GABA. A Use of inverse agonist drug compounds. Although the α5-GABA used in the treatment of the present invention A The inverse agonist can be administered as a raw compound, but preferably the active ingredient, optionally in the form of a physiologically acceptable salt, is mixed with one or more additives, excipients, carriers, buffers, diluents and / or other conventional pharmaceutical adjuvants to form a pharmaceutical composition.

[0319] In a preferred embodiment, the present invention provides a 5-GABA-containing A Pharmaceutical composition of inverse agonist, wherein α5-GABA A The inverse agonist is mixed with one or more pharmaceutically acceptable carriers, and optionally with other therapeutic and / or prophylactic ingredients known or used in the art. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0320] The pharmaceutical compositions used in the present invention may be those suitable for oral, rectal, bronchial, nasal, pulmonary, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for inhalation or spray administration, including powder and liquid aerosol administration, or sustained-release system administration. Examples of suitable sustained-release systems include semi-permeable matrices of solid hydrophobic polymers containing the compounds of the present invention, wherein the matrix may be in the form of a shaped article, such as a film or microcapsule.

[0321] Therefore, the compounds used in the present invention can be prepared into pharmaceutical compositions and unit dosage forms thereof together with conventional additives or diluents. Such forms include solids (especially tablets, filled capsules, powders and pills), and liquids (especially aqueous or non-aqueous solutions, suspensions, emulsions, elixirs), and capsules filled with the above forms, all oral administration forms, suppositories for rectal administration, and sterile injectable solutions for parenteral administration. Such pharmaceutical compositions and unit dosage forms thereof may include conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and such unit dosage forms may contain any suitable effective amount of active ingredients corresponding to the desired daily application dosage range.

[0322] The compounds used in the present invention can be administered in various oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain the compounds of the present invention or their pharmaceutically acceptable salts as active ingredients.

[0323] To prepare the compounds used in the present invention into pharmaceutical compositions, pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, tablets, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances that also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrating agent, or encapsulating material.

[0324] In powders, the carrier is a finely divided solid, which is in admixture with the finely divided active ingredient.

[0325] In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0326] Powders and tablets preferably contain 5% or 10% to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, and the like. The term "formulation" includes the active compound formulated with an encapsulating material as a carrier, the encapsulating material providing a capsule in which the active ingredient, with or without a carrier, is surrounded by the carrier, thus being held together. Likewise, the formulation includes cachets and lozenges. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0327] To prepare suppositories, a low melting point wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed uniformly therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidified.

[0328] Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0329] Liquid preparations include solutions, suspensions and emulsions, for example, aqueous solutions or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as water-polyethylene glycol solutions.

[0330] Therefore, the compound used in the present invention can be formulated into a preparation for parenteral administration (e.g., injection, such as bolus injection or continuous infusion), and can be present in the form of a unit dose in an ampoule, a prefilled syringe, a small volume infusion bag or a multi-dose container together with an added preservative. The composition can take the form of a suspension, solution or emulsion of an oily or aqueous carrier, and can contain formulation ingredients such as suspending agents, stabilizers and / or dispersants. In addition, the active ingredient can be in the form of a powder, which can be obtained by aseptic separation of a sterilized solid or freeze-drying from a solution, for reconstitution with a suitable carrier such as sterile, pyrogen-free water before use.

[0331] Aqueous solutions suitable for oral administration can be prepared by dissolving the active component in water and adding the desired colorants, flavorings, stabilizers, and thickening agents.

[0332] Aqueous suspensions suitable for oral administration can be prepared by dispersing the finely divided active component in water with viscous material, such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0333] Also included are solid preparations designed to be converted into liquid preparations for oral administration shortly before use. Such liquid preparations include solutions, suspensions and emulsions. In addition to the active ingredient, such preparations may contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0334] For topical application to the epidermis, the compounds of the invention may be formulated into ointments, creams or lotions or transdermal patches. For example, ointments and creams may be formulated with aqueous or oily bases plus suitable thickeners and / or gelling agents. Lotions may be formulated with aqueous or oily bases and may also typically contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or coloring agents.

[0335] Compositions suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles containing the active ingredient in an inert basis such as gelatin and glycerin or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0336] Solutions or suspensions may be applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray.The composition may be in single-dose or multi-dose form.

[0337] Respiratory administration can also be achieved by aerosols, wherein the active ingredient is contained in a pressurized package together with a suitable propellant, and a suitable propellant includes fluorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gases. Aerosols can also suitably contain surfactants, such as lecithin. The dosage of the drug can be controlled by a metering valve.

[0338] In addition, the active ingredient can be in the form of a dry powder, such as a powder mixture of a compound and a suitable powder matrix such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). The powder carrier can easily form a gel in the nasal cavity. The powder composition can exist in the form of a unit dose, for example, in a capsule or cartridge (such as a gelatin capsule or cartridge), or in a blister package in which the powder can be administered through an inhaler.

[0339] In compositions for administration to the respiratory tract (including intranasal compositions), the compound will generally have a small particle size, for example, a particle size of the order of 5 microns or less. Such a particle size can be obtained by methods known in the art, for example, by micronization.

[0340] When desired, compositions adapted to give sustained release of the active ingredient may be employed.

[0341] The pharmaceutical preparation is preferably in unit dosage form. In this type of form, the preparation is subdivided into unit doses of appropriate amounts of the active ingredient. The unit dosage form may be a packaged preparation, wherein a sealed package contains a separate bulk preparation, such as packaged tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, troche or lozenge itself, or may be an appropriate amount of the above capsules, tablets, etc. in any packaged form.

[0342] Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions. Further details on formulation and administration techniques may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

[0343] The amount of active ingredient in a unit dose formulation can vary depending on the specific application and the potency of the active ingredient, and can be adjusted from 0.1 mg to about 1 g. For example, in medical use, the drug can be administered once to three times a day in capsules of 0.1 to about 400 mg, and the composition may also contain other compatible therapeutic agents if necessary. DETAILED DESCRIPTION

[0344] The present application is described in detail below by way of examples, but it is not intended that there is any adverse limitation to the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications to the specific embodiments of the present application will be made without departing from the spirit and scope of the present application.

[0345] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0346] Preparation of intermediates:

[0347] Synthesis of intermediate A8:

[0348] 3-Chloro-6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (A8)

[0349]

[0350] Step 1: Synthesis of ethyl 2,2-dichloro-3-oxobutanoate (A2)

[0351] A1 (20 g, 153.7 mmol) and ammonium chloride (4.11 g, 76.84 mmol) were dissolved in acetonitrile (300 mL), and dichlorohydantoin (45.42 g, 230.5 mmol) was added in batches. The mixture was stirred at room temperature for 18 hours under argon protection. The reaction was completed by TLC monitoring. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in petroleum ether (300 mL), washed with saturated brine (200 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product (30 g, colorless liquid).

[0352] Step 2: Synthesis of ethyl (3E)-2,2-dichloro-3-[(4-methylbenzenesulfonylamino)imino]butyrate (A3)

[0353] At room temperature, p-toluenesulfonyl hydrazide (13 g, 69.81 mmol) was dissolved in isopropanol (80 mL), A2 (14.59 g, 73.30 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to remove half of the solvent, and the residue was placed at 0°C for 2 hours. The filter cake was collected by filtration and dried under reduced pressure to obtain the title product (14 g, yellow solid).

[0354] Step 3: Synthesis of 4-(difluoromethyl)aniline hydrochloride (A5)

[0355] A4 (3.6 g, 20.79 mmol) was dissolved in ethyl acetate (70 mL), cooled to 0°C, wet palladium carbon (10%, 0.36 g) was added, hydrogen (hydrogen balloon) was replaced, and the reaction was stirred at 0°C for 18 hours. TLC monitored the completion of the reaction. The reaction solution was filtered at 0°C, and hydrochloric acid / ethyl acetate solution (4 mL, 4.0 M) was added dropwise to the filtrate under stirring. The mixed solution was stirred at 0°C for 30 minutes, filtered, the filter cake was collected, and dried under reduced pressure to obtain the title product (3.1 g, yellow solid).

[0356] Step 4: Synthesis of ethyl 1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylate (A6)

[0357] A5 (2.3 g, 16.07 mmol) and A3 (5.9 g, 16.07 mmol) were mixed in isopropanol (70 mL), cooled to 0°C, and triethylamine (0.36 g, 64.28 mmol) was added dropwise. The mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction was monitored by TLC to complete. The reaction solution was diluted with isopropanol (100 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:3) to obtain the title product (3.0 g, yellow solid).

[0358] MS (ESI) m / z [M+H]+ =282.1.

[0359] Step 5: Synthesis of 1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methanol (A7)

[0360] Under argon protection, A6 (3.0 g, 10.67 mmol) was dissolved in tetrahydrofuran (25 mL), cooled to 0 ° C, and diisobutylaluminum hydride (1.5 M toluene solution, 28.45 mL, 42.68 mmol) was added dropwise. The reaction solution was slowly warmed to room temperature and stirred for 3 hours. TLC monitored the completion of the reaction. The reaction solution was slowly poured into 1M hydrochloric acid (100 mL) at 0 ° C to quench, and the mixed solution was extracted with ethyl acetate (150 mL x 2), washed with water (200 mL) and saturated brine (100 mL), filtered, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title product (1.4 g, yellow solid).

[0361] MS (ESI) m / z [M+H] + =240.1.

[0362] Step 6: Synthesis of 3-chloro-6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (A8)

[0363] Under argon protection, A7 (1.4 g, 5.85 mmol) was dissolved in tetrahydrofuran (25 mL), cooled to 0°C, and sodium hydride (0.35 g, 8.77 mmol, 60%) was added. The reaction was stirred at 0°C for 0.5 hours, and 3,6-dichloropyridazine (1.31 g, 8.77 mmol) was added. The reaction solution was slowly warmed to room temperature and stirred for 1 hour. TLC monitored the completion of the reaction. The reaction solution was slowly poured into ice water (100 mL) at 0°C to quench, and the mixed solution was extracted with ethyl acetate (100 mL x 2), washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 2:1) to obtain the title product (1.8 g, yellow solid).

[0364] MS (ESI) m / z [M+H] + =352.1.

[0365] Synthesis of intermediate A9:

[0366] 3-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-6-iodopyridazine (A9)

[0367]

[0368] The experimental procedure was as described for the synthesis of intermediate A8, using A7 and 3-chloro-6-iodopyridazine as reactants to give the title product.

[0369] MS (ESI) m / z [M+H] + =443.8.

[0370] 1 H NMR (400MHz, CD 3 OD)δ7.91(d,J=9.2Hz,1H),7.79-7.74(m,4H),7.02-6.75(m,2H),5.59-5.64(m,2H),2.48-2.51(m,3H).

[0371] Synthesis of intermediate A10:

[0372] 5-Bromo-2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridine (A10)

[0373]

[0374] The experimental procedure was as described for the synthesis of intermediate A8, using A7 and 2-fluoro-5-bromopyridine as reactants to give the title product.

[0375] MS (ESI) m / z [M+H] + =395.2,397.2.

[0376] Synthesis of intermediate A11:

[0377] 2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-5-iodopyridine (A11)

[0378]

[0379] The experimental procedure was as described for the synthesis of intermediate A8, using A7 and 2-fluoro-5-iodopyridine as reactants to give the title product.

[0380] MS (ESI) m / z [M+H] + =443.0.

[0381] Synthesis of intermediate A12:

[0382] 6-Chloro-3-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine-4-carbonitrile (A12)

[0383]

[0384] The experimental procedure was as described for the synthesis of intermediate A8, using A7 and 3,6-dichloropyridazine-4-carbonitrile as reactants to give the title product.

[0385] MS (ESI) m / z [M+H] + =377.1.

[0386] Synthesis of intermediate B4:

[0387] 3-Chloro-6-((1-(5-chloropyridin-2-yl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (B4)

[0388]

[0389] Step 1: Synthesis of ethyl 1-(5-chloropyridin-2-yl)-4-methyl-1H-1,2,3-triazole-5-carboxylate (B2)

[0390] The experimental procedure was as described in step 4 of the synthesis of intermediate A8, using intermediate B1 and A3 as reactants to obtain the title product.

[0391] MS (ESI) m / z [M+H] + =267.1.

[0392] Step 2: Synthesis of (1-(5-chloropyridin-2-yl)-4-methyl-1H-1,2,3-triazol-5-yl)methanol (B3)

[0393] Under argon protection, compound B1 (200 mg, 0.75 mmol) was dissolved in tetrahydrofuran (20 mL), lithium borohydride (0.16 g, 7.50 mmol) was added, and the reaction was stirred at 30 ° C for 16 h. TLC monitored the completion of the reaction. The reaction solution was quenched by adding water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:2) to obtain the title product (0.12 g, white solid).

[0394] MS (ESI) m / z [M+H] + =225.1.

[0395] Step 3: Synthesis of 3-chloro-6-((1-(5-chloropyridin-2-yl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (B4)

[0396] The experimental procedure was as described for the synthesis of intermediate A8, using intermediate B3 and 3,6-dichloropyridazine as reactants to obtain the title product.

[0397] MS (ESI) m / z [M+H] + =337.0.

[0398] Synthesis of intermediate C4:

[0399] 3-Chloro-6-((1-(5-fluoropyridin-2-yl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (C4)

[0400]

[0401] The experimental procedure was as described for the synthesis of intermediate B4, starting from C1, to afford the title product.

[0402] MS (ESI) m / z [M+H] + =321.1

[0403] Synthesis of intermediate D4:

[0404] 3-Chloro-6-((1-(6-(difluoromethyl)pyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (D4)

[0405]

[0406] The synthesis method is as described for the synthesis of intermediate B4, starting from D1, to give the title product.

[0407] MS (ESI) m / z [M+H] + =353.1.

[0408] Synthesis of intermediate E4:

[0409] 3-Chloro-6-((1-(4-cyanophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (E4)

[0410]

[0411] The synthesis method is as described for the synthesis of intermediate B4, starting from E1, to give the title product.

[0412] MS (ESI) m / z [M+H] + =327.0.

[0413] Synthesis of intermediate F4:

[0414] 3-Chloro-6-((1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (F4)

[0415]

[0416] The synthesis method is as described for the synthesis of intermediate B4, starting from F1, to give the title product.

[0417] MS (ESI) m / z [M+H] + =319.8.

[0418] Synthesis of intermediate G5:

[0419] 3-((1-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-6-chloropyridazine (G5)

[0420]

[0421] Step 1: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)aniline (G2)

[0422] At room temperature, compound G1 (3.0 g, 24.4 mmol), tert-butyldimethylsilyl chloride (4.04 g, 26.8 mmol), DMAP (0.98 g, 8.04 mmol) and triethylamine (2.71 g, 26.8 mmol) were added to DMF (40.0 mL) in sequence and reacted at 20°C for 16 hours. The reaction solution was diluted with water (200 mL), extracted with dichloromethane (100 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (5.70 g, red liquid).

[0423] 1 H NMR (400 MHz, DMSO-d 6 )δ6.94(d,J=8.4Hz,2H),6.51(d,J=8.4Hz,2H),4.96(s,2H),4.49(s,2H),0.86(s,9H),0.03(s,6H).

[0424] Step 2: Synthesis of ethyl 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylate (G3)

[0425] The experimental procedure was as described in step 4 of the synthesis of intermediate A8, using intermediate A3 and G2 as reactants to obtain the title product.

[0426] 1 H NMR (400 MHz, CDCl 3 )δ7.52-7.43(m,2H),7.42-7.35(m,2H),4.83(s,2H),4.27(q,J=6.8Hz,2H),2.64(s,3H),1.24(t,J=7.2Hz,3H),0.97(s,9H),0.13(s,6H).

[0427] Step 3: Synthesis of (1-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methanol (G4)

[0428] The experimental procedure was as described in step 5 of the synthesis of intermediate A8, using intermediate G3 as the reactant to obtain the title product.

[0429] 1 H NMR (400 MHz, CDCl 3 )δ7.68-7.57(m,2H),7.53-7.46(m,2H),4.83(s,2H),4.70-4.65(m,2H),2.49-2.40(m,3H),0.97(s,9H),0.13(s,6H).

[0430] Step 4: Synthesis of 3-((1-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-6-chloropyridazine (G5)

[0431] The experimental procedure was as described in step 6 of the synthesis of intermediate A8, using intermediate G4 and 3,6-dichloropyridazine as reactants to obtain the title product.

[0432] MS (ESI) m / z [M+H] + =446.2.

[0433] 1 H NMR (400 MHz, CDCl 3 )δ7.55-7.45(m,4H),7.43(d,J=9.2Hz,1H),6.98(d,J=9.2Hz,1H),5.54(s,2H),4.81(s,2H),2.51(s,3H),0.96(s,9H),0.13(s,6H).

[0434] Synthesis of intermediate H5:

[0435] 3-Chloro-6-((4-cyclopropyl-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (H5)

[0436]

[0437] Step 1: Synthesis of 1-azido-4-(difluoromethyl)benzene (H2)

[0438] At 0°C, A5 (1.0 g, 5.59 mmol) was slowly added to a mixed solution of sulfuric acid (1 mL) and trifluoroacetic acid (5 mL), and then a sodium nitrite (501 mg, 7.26 mmol) aqueous solution (5 mL) was slowly added dropwise to the mixture, and the mixture was reacted at 0°C for 0.5 hours. At this temperature, a sodium azide (700 mg, 10.8 mmol) aqueous solution (2 mL) was slowly added dropwise to the mixture, and the mixture was heated to 16°C and reacted for 2 hours. TLC showed that the reaction was complete. The reaction solution was adjusted to pH = 9 with a 15% sodium hydroxide aqueous solution, stirred for 10 minutes, and then extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the title product (1.03 g, brown liquid).

[0439] Step 2: Synthesis of (4-cyclopropyl-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methanol (H4)

[0440] H3 (500 mg, 5.2 mmol) and H2 (2.64 g, 15.6 mmol) were added to toluene (15 mL) and stirred at 120 ° C for 12 hours under nitrogen protection. LCMS detected the product formation. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (chromatographic column: Phenomenex C18 150*40mm*5μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile; gradient: 25%-45% / 10min; flow rate: 60mL / min) to obtain the title product (270 mg, yellow solid).

[0441] MS (ESI) m / z [M+H] + =266.1.

[0442] 1 H NMR (400 MHz, DMSO-d 6)δ7.86-7.79(m,4H),7.16(t,J=55.6Hz,1H),5.59(t,J=5.2Hz,1H),4.82( d,J=5.6Hz,2H),2.10-2.00(m,1H),0.99-0.96(m,2H),0.92-0.91(m,2H).

[0443] Step 3: Synthesis of 3-chloro-6-((4-cyclopropyl-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (H5) The experimental procedure was as described for the synthesis of intermediate A8, using H4 and 3,6-dichloropyridazine as reactants to give the title product.

[0444] MS (ESI) m / z [M+H] + =378.0.

[0445] 1 H NMR (400 MHz, CDCl 3 )δ7.71-7.66(m,4H),7.44(d,J=9.2Hz,1H),6.99(d,J=9.2Hz,1H),6.72(t,J=56 .4Hz,1H),5.68(s,2H),2.07-2.03(m,1H),1.06-1.05(m,2H),1.04-1.03(m,2H).

[0446] Synthesis of intermediate J8:

[0447] 5-(((6-chloropyridazin-3-yl)oxy)methyl)-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (J8)

[0448]

[0449] Step 1: Synthesis of methyl 4-((tert-butyldimethylsilyl)oxy)but-2-ynoate (J2)

[0450] Dissolve J1 (5.0 g, 29.4 mmol) in anhydrous tetrahydrofuran (50 mL), cool to -78 ° C, slowly drop n-butyl lithium tetrahydrofuran solution (14.1 mL, 2.5 M, 35.3 mmol) under nitrogen, and stir for 30 minutes. Slowly add methyl chloroformate (3.18 g, 33.8 mmol) to the above reaction solution. Warm to room temperature and react for 12 hours. TLC shows that all the raw materials are consumed. The reaction solution is quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product is purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:3) to obtain the title product (4.36 g, yellow liquid).

[0451] 1 H NMR (400 MHz, CDCl 3 )δ4.43(s,2H),3.78(s,3H),0.91(s,9H),0.13(s,6H).

[0452] Step 2: Synthesis of methyl 5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazole-4-carboxylate (J3)

[0453] At room temperature, compound J2 (135 mg, 0.59 mmol) and compound H2 (100 mg, 0.59 mmol) were dissolved in anhydrous toluene (5.0 mL), and the reaction temperature was raised to 100 ° C and stirred for 12 hours. The reaction end point was monitored by TLC. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1 to 3: 1) to obtain the title product J3 (27 mg, light yellow solid) and the isomer compound K1 of J3 (27 mg, yellow oil).

[0454] Compound J3:

[0455] 1 H NMR (400MHz, CD 3 OD)δ7.86-7.81(m,2H),7.80-7.75(m,2H),6.89(t,J=56.0Hz,1H),5.08(s,2H),3.95(s,3H),0.76(s,9H),0.00(s,6H)

[0456] Compound K1:

[0457] 1 H NMR (400MHz, CD 3OD)δ7.75(d,J=8.0Hz,2H),7.65(d,J=8.8Hz,2H),6.91(t,J=56.0Hz,1H),5.05(s,2H),3.82(s,3H),0.93(s,9H),0.16(s,6H)

[0458] Step 3: Synthesis of methyl 1-(4-(difluoromethyl)phenyl)-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxylate (J4)

[0459] At room temperature, J3 (200 mg, 0.504 mmol) and TEAF (378 mg, 2.52 mmol) were added to anhydrous tetrahydrofuran (5 mL) in sequence, and the atmosphere was replaced with nitrogen three times. The mixture was reacted at 40 °C for 1 hour. TLC showed that all the starting materials were consumed. The reaction solution was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:3) to obtain the title product (105 mg, white solid).

[0460] 1 H NMR (400 MHz, CDCl 3 )δ7.80-7.75(m,2H),7.72-7.67(m,2H),6.77(t,J=56.4Hz,1H),4.87(d,J=7.6Hz,2H),4.08(s,3H),3.82(t,J=7.2Hz,1H)

[0461] Step 4: Synthesis of methyl 5-(((6-chloropyridazin-3-yl)oxy)methyl)-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazole-4-carboxylate (J5)

[0462] At room temperature, compound J4 (65 mg, 0.23 mmol), 3,6-dichloropyridazine (51 mg, 0.34 mmol) and cesium carbonate (225 mg, 0.69 mmol) were added to anhydrous DMF (4.0 mL) in sequence, replaced with nitrogen 3 times, and reacted for 14 hours. TLC showed that all the raw materials were consumed. The reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated brine (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (methanol: dichloromethane = 0:1 to 1:10) to obtain the title product (95 mg, yellow oil).

[0463] 1 H NMR (400MHz, CD 3OD)δ7.77(s,4H),7.63(d,J=9.2Hz,1H),7.08(d,J=9.2Hz,1H),6.89(t,J=55.6Hz,1H),5.92(s,2H),3.97(s,3H)

[0464] Step 5: Synthesis of 5-(((6-chloropyridazin-3-yl)oxy)methyl)-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (J6)

[0465] At room temperature, J5 (95.0 mg, 0.25 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL) and water (2 mL), and lithium hydroxide monohydrate (33 mg, 0.79 mmol) was added and reacted for 2 hours. TLC showed that all the starting materials were consumed. The reaction solution was adjusted to pH = 4 with 1.0 M dilute hydrochloric acid and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title product (95 mg, yellow solid).

[0466] 1 H NMR (400MHz, CD 3 OD)δ7.77(s,4H),7.63(d,J=9.2Hz,1H),7.09(d,J=9.2Hz,1H),6.89(t,J=55.6Hz,1H),5.92(s,2H)

[0467] Step 6: Synthesis of 5-(((6-chloropyridazin-3-yl)oxy)methyl)-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazole-4-carboxamide (J7)

[0468] At room temperature, J6 (95.0 mg, 0.25 mmol), HATU (142 mg, 0.37 mmol) and DIEA (96 mg, 0.75 mmol) were added to anhydrous DMF (2 mL) in sequence, replaced with nitrogen 3 times, and reacted for 1 hour. Ammonia water (21.0 mg, 30%, 0.37 mmol) was then added, and the reaction was continued at room temperature for 13 hours. LCMS showed that the reaction was complete. The reaction solution was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated citric acid aqueous solution (5 mL x 3), saturated sodium bicarbonate aqueous solution (5 mL x 3) and saturated brine (5 mL x 3) in sequence, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the title product (200 mg, yellow oil).

[0469] MS (ESI) m / z [M+H] + =380.1.

[0470] 1H NMR (400MHz, CD 3 OD)δ7.76(s,4H),7.62(d,J=9.2Hz,1H),7.10-7.05(m,1H),6.88(t,J=55.6Hz,1H),5.94(s,2H)

[0471] Step 7: Synthesis of 5-(((6-chloropyridazin-3-yl)oxy)methyl)-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (J8)

[0472] At room temperature, J7 (95.0 mg, 0.25 mmol), triethylamine (63 mg, 0.62 mmol) and trifluoroacetic anhydride (176 mg, 0.62 mmol) were added to anhydrous dichloromethane (2 mL) in sequence, replaced with nitrogen 3 times, and reacted for 15 hours. LCMS showed that the reaction was complete. The reaction solution was diluted with dichloromethane (50 mL) and washed with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (methanol: dichloromethane = 0:1 to 1:10) to obtain (40 mg, yellow oily liquid).

[0473] MS (ESI) m / z [M+H] + =362.8.

[0474] 1 H NMR (400MHz, CD 3 OD)δ7.84(s,4H),7.71(d,J=9.6Hz,1H),7.28(d,J=9.2Hz,1H),6.93(t,J=56.0Hz,1H),5.81(s,2H)

[0475] Synthesis of intermediate K3:

[0476] 3-(((4-(((tert-Butyldimethylsilyl)oxy)methyl)-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methoxy)-6-chloropyridazine (K3)

[0477]

[0478] Step 1: Synthesis of (4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methanol (K2)

[0479] Compound K1 (500 mg, 1.26 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL) at room temperature, cooled to 0 °C, and LiAlH4 (48.0mg, 1.26mmol), replace nitrogen 3 times. The reaction mixture was stirred at 0℃ for 10 minutes. TLC showed that the reaction was complete. Water (0.5mL), sodium hydroxide solution (15%, 0.5mL), and water (1.5mL) were added to the mixed solution in sequence. Ethyl acetate (100mL) was added to dilute. After the mixture was stirred at room temperature for 15 minutes, anhydrous sodium sulfate solid was added thereto and continued stirring for 15 minutes. The organic phase was filtered, filtered and concentrated under reduced pressure to obtain the title product (250mg, yellow solid).

[0480] 1 H NMR (400MHz, CD 3 OD)δ7.87(d,J=8.4Hz,2H),7.80(d,J=8.4Hz,2H),6.91(t,J=56.0Hz,1H),4.94(s,2H),4.72(s,2H),0.94(s,9H),0.18(s,6H)

[0481] Step 3: Synthesis of 3-(((4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methoxy)-6-chloropyridazine (K3)

[0482] Compound K2 (250 mg, 0.675 mmol) and 3,6-dichloropyridazine (143 mg, 1.012 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) at room temperature, cesium carbonate (441 mg, 1.35 mmol) was added, and nitrogen was replaced 3 times. The reaction mixture was stirred at 19 ° C for 12 hours. TLC showed that the reaction was complete. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title product (100 mg, yellow solid).

[0483] MS (ESI) m / z [M+H] + =482.0.

[0484] 1 H NMR (400MHz, CD 3 OD)δ7.79(s,4H),7.66(d,J=9.2Hz,1H),7.18(d,J=9.2Hz,1H),6.89(t,J=55.6Hz,1H),5.71(s,2H),5.02(s,2H),0.88(s,9H),0.12(s,6H).

[0485] Synthesis of intermediate L4:

[0486] 3-Chloro-6-((4-methyl-1-(p-tolyl)-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (L4)

[0487]

[0488] The synthesis method is as described in steps 4 to 6 in the synthesis of intermediate A8, starting from L1, to obtain the title product.

[0489] MS (ESI) m / z [M+H] + =301.1.

[0490] Synthesis of intermediate M4:

[0491] 3-Chloro-6-((1-(4-(difluoromethoxy)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (M4)

[0492]

[0493] The synthesis method is as described in steps 4 to 6 in the synthesis of intermediate A8, starting from M1, to give the title product.

[0494] MS (ESI) m / z [M+H] + =337.1.

[0495] Synthesis of intermediate N7:

[0496] 3-Chloro-6-((4-(4-(difluoromethyl)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (N7)

[0497]

[0498] Step 1: Synthesis of 1-(difluoromethyl)-4-ethynylbenzene (N2)

[0499] DAST (7.43 g, 46.1 mmol) was added dropwise to a solution of compound N1 (4 g, 30.74 mmol) in dichloromethane (50 mL) at 0°C. The reaction mixture was stirred at 16°C for 12 hours. The reaction endpoint was monitored by TLC. Saturated aqueous sodium bicarbonate solution (15 mL) was added to the reaction mixture to quench, and dichloromethane (50 mL x 3) was used for extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (4.5 g, yellow solid).

[0500] 1 H NMR (400 MHz, CDCl 3)δ7.59-7.56(m,2H),7.51-7.46(m,2H),6.65(t,J=56.0Hz,1H),3.20(s,3H)

[0501] Step 2: Synthesis of methyl 3-(4-(difluoromethyl)phenyl)propiolate (N3)

[0502] At -78°C, n-butyl lithium (5.8 mL, 14.5 mmol, 2.5 M) was slowly added dropwise to a tetrahydrofuran (20 mL) solution of compound N2 (1 g, 6.6 mmol), and the reaction mixture was stirred at -78°C for 0.5 hours. Methyl chloroformate (745 mg, 7.89 mmol) was slowly added dropwise, and stirring was continued at this temperature for 2 hours. TLC monitored the end point of the reaction. At -78°C, saturated aqueous ammonium chloride solution (20 mL) was slowly added dropwise to quench the reaction, and the reaction solution was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 95:5) to obtain the title product (500 mg, yellow solid).

[0503] 1 H NMR (400 MHz, CDCl 3 )δ7.68(d,J=8.4Hz,2H),7.54(d,J=8.4Hz,2H),6.67(t,J=56.0Hz,1H),3.87(s,3H).

[0504] Step 3: Synthesis of methyl 4-(4-(difluoromethyl)phenyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole-5-carboxylate (N4)

[0505] Under nitrogen protection, trimethylsilylazide (3.44 g, 26.6 mmol) was added to a solution of compound N3 (1.4 g, 6.66 mmol) in anhydrous toluene (30 mL), and the mixture was heated to 100 °C and stirred for 12 hours. LCMS monitored the formation of the product. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (chromatographic column: Xtimate C18 150*40mm*5μm; mobile phase: water (trifluoroacetic acid)-acetonitrile; gradient: 45%-75%; flow rate: 60 mL / min) to obtain the title product (660 mg, white solid).

[0506] MS (ESI) m / z [M+H] + =340.1.

[0507] 1 H NMR (400 MHz, DMSO-d6 )δ7.83(d,J=8.4Hz,2H),7.66(d,J=8.4Hz,2H),7.10(t,J=56.0Hz,1H),4.33(s,2H),3.83(s,3H),0.11(s,9H)

[0508] Step 4: Synthesis of (4-(4-(difluoromethyl)phenyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)methanol (N5)

[0509] At 0°C, lithium aluminum tetrahydride (106 mg, 2.8 mmol) was added in batches to a solution of compound N4 (660 mg, 1.87 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at 0°C for 1 hour. The reaction endpoint was monitored by TLC. Water (2 mL), aqueous sodium hydroxide solution (2 mL, 15%) and water (6 mL) were added to the reaction solution in sequence to quench. The mixture was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (550 mg, yellow solid).

[0510] 1 H NMR (400MHz, CD 3 OD)δ7.84(d,J=8.4Hz,2H),7.66(d,J=8.4Hz,2H),6.82(t,J=56.0Hz,1H),4.77(s,2H),3.99(s,2H),0.23(s,9H)

[0511] Step 5: Synthesis of (4-(4-(difluoromethyl)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol (N6)

[0512] Tetrabutylammonium fluoride (791 mg, 5.3 mmol) was added to a solution of compound N5 (550 mg, 1.77 mmol) in tetrahydrofuran (10 mL) and stirred at 22°C for 3 hours. The reaction endpoint was monitored by LCMS. The reaction solution was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the title product (340 mg, white solid).

[0513] MS (ESI) m / z [M+H] + =240.0.

[0514] 1 H NMR (400MHz, CD 3OD)δ7.84(d,J=8.4Hz,2H),7.66(d,J=8.4Hz,2H),6.83(t,J=56.0Hz,1H),4.81(s,2H),4.18(s,3H)

[0515] Step 6: Synthesis of 3-chloro-6-((4-(4-(difluoromethyl)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (N7)

[0516] Compound N6 (100 mg, 0.28 mmol) was dissolved in tetrahydrofuran (10 mL) at 0 °C. Sodium hydride (50 mg, 1.25 mmol, content: 60%) was added, the reaction mixture was stirred for half an hour, and 3,6-dichloropyridazine (187 mg, 1.25 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise. The reaction solution was heated to 19 °C and continued to stir for 2 hours. LCMS monitored the end point of the reaction. Water (2 mL) was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane: methanol = 10: 1) to obtain the title product (230 mg, yellow solid).

[0517] MS (ESI) m / z [M+H] + =353.0.

[0518] 1 H NMR (400MHz, CD 3 OD)δ7.88(d,J=8.0Hz,2H),7.70-7.64(m,3H),7.28(d,J=9.2Hz,1H),6.81(t,J=56.0Hz,1H),5.80(s,2H),4.28(s,3H)

[0519] Synthesis of intermediate P6:

[0520] 3-Chloro-6-((4-(4-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (P6)

[0521]

[0522] The synthesis method is as described in steps 2 to 6 in the synthesis of intermediate N7, starting from P1 to obtain the title product.

[0523] MS (ESI) m / z [M+H] + =320.1.

[0524] Synthesis of intermediate Q3:

[0525] 3-Chloro-6-((4-chloro-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (Q3)

[0526]

[0527] Step 1: Synthesis of (1-(4-(difluoromethyl)phenyl)-4-(trimethylsilyl)-1H-1,2,3-triazol-5-yl)methanol (Q1)

[0528] The experimental procedure was as described in step 2 of the synthesis of intermediate H5, using intermediate H2 and 3-(trimethylsilyl)prop-2-yn-1-ol as reactants to obtain the title product.

[0529] MS (ESI) m / z [M+H] + =298.1.

[0530] 1 H NMR (400 MHz, CDCl 3 )δ7.80-7.68(m,4H),6.73(t,J=56.0Hz,1H),4.73(d,J=4.4Hz,2H),2.10-2.04(m,1H),0.43(s,9H).

[0531] Step 2: Synthesis of 3-chloro-6-((1-(4-(difluoromethyl)phenyl)-4-(trimethylsilyl)-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (Q2)

[0532] The experimental procedure was as described in step 3 of the synthesis of intermediate H5, using intermediate Q1 and 3,6-dichloropyridazine as reactants to obtain the title product.

[0533] MS (ESI) m / z [M+H] + =410.1.

[0534] 1 H NMR (400 MHz, CDCl 3 )δ7.68-7.63(m,4H),7.44(d,J=9.2Hz,1H),6.97(d,J=9.2Hz,1H),6.71(t,J=56.0Hz,1H),5.55(s,2H),0.40(s,9H).

[0535] Step 3: Synthesis of 3-chloro-6-((4-chloro-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (Q3)

[0536] At room temperature, compound Q2 (40.0 mg, 0.098 mmol) was dissolved in acetonitrile (2.0 mL), potassium fluoride (34.8 mg, 0.58 mmol) and N-chlorosuccinimide (130 mg, 0.97 mmol) were added in sequence, and the reaction temperature was raised to 80 ° C and stirred for 16 hours. TLC monitored the reaction end point. The reaction solution was filtered, the filter cake was washed with acetonitrile (2.0 mL), the filtrate was combined, the solvent was removed under reduced pressure, and the residue was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 4:1) to obtain the title product (100 mg, white solid)

[0537] MS (ESI) m / z [M+H] + =372.0.

[0538] 1 H NMR (400 MHz, CDCl 3 )δ7.70(s,4H),7.44(d,J=9.2Hz,1H),6.99(d,J=9.2Hz,1H),6.72(t,J=56.0Hz,1H),5.58(s,2H).

[0539] Embodiment 1:

[0540] 3-(((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-6-(3-methoxypyrrolidin-1-yl)pyridazine (1)

[0541]

[0542] Under argon protection, A8 (30 mg, 0.085 mmol) and 3-methoxypyrrolidine (8.6 mg, 0.085 mmol) were dissolved in dioxane (3.0 mL), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (4 mg, 0.0085 mmol), cesium carbonate (28 mg, 0.085 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (7 mg, 0.0085 mmol) were added in sequence, and stirred at 100 ° C for 16 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with dichloromethane (50 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography

[0543] MS (ESI) m / z [M+H] + =417.2.

[0544] 1 H NMR (400 MHz, DMSO-d 6)δ7.79(s,4H),7.14(t,J=55.6Hz,1H),7.04-6.93(m,2H),5.43(s,2H),4.08-4.05(m,1 H),3.52-3.43(m,3H),3.38-3.35(m,1H),3.25(s,3H),2.40(s,3H),2.04-2.03(m,2H).

[0545] Embodiment 2:

[0546] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (2)

[0547]

[0548] The experimental operation was as described in Example 1, using A8 and 2-piperazinone as reactants to obtain the title product.

[0549] MS (ESI) m / z [M+H] + =416.2.

[0550] 1 H NMR (400 MHz, DMSO-d 6 )δ8.08(s,1H),7.78(s,4H),7.40(d,J=9.6Hz,1H),7.14(t,J=55.6Hz,1H),7.04(d,J=9.6H z,1H),5.45(s,2H),3.97(s,2H),3.66(t,J=5.2Hz,2H),3.27(t,J=5.2Hz,2H),2.39(s,3H).

[0551] Embodiment 3:

[0552] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1,4-diazepin-5-one (3)

[0553]

[0554] The experimental operation was as described in Example 1, using A8 and 1,4-diazepine-5-one hydrochloride as reactants to obtain the title product.

[0555] MS (ESI) m / z [M+H] + =430.2.

[0556] 1H NMR (400 MHz, DMSO-d 6 )δ7.79(s,4H),7.61(br s,1H),7.37(d,J=9.8Hz,1H),7.14(t,J=55.6Hz,1H),7.00(d,J=9.8Hz,1H),5.4 4(s,2H),3.73-3.69(m,4H),3.15-3.12(m,2H),2.46-2.42(m,2H),2.39(s,3H).

[0557] Embodiment 4:

[0558] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1,4-diazepin-2-one (4)

[0559]

[0560] The experimental operation was as described in Example 1, using A8 and 1,4-diazepine-2-one hydrochloride as reactants to obtain the title product.

[0561] MS (ESI) m / z [M+H] + =430.2.

[0562] 1 H NMR (400 MHz, DMSO-d 6 )δ7.78(s,4H),7.45(br s,1H),7.23(d,J=9.6Hz,1H),7.12(t,J=55.6Hz,1H),7.00(d,J=9.6Hz,1H),5.41(s,2 H),4.15(s,2H),3.87-3.85(m,2H),3.20-3.17(m,2H),2.38(s,3H),1.67-1.65(m,2H).

[0563] Embodiment 5:

[0564] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-2,6-dione (5)

[0565]

[0566] The experimental operation was as described in Example 1, using A8 and piperazine-2,6-dione as reactants to obtain the title product.

[0567] MS (ESI) m / z [M+H] +=430.1.

[0568] 1 H NMR (400 MHz, DMSO-d 6 )δ11.23(s,1H),7.77(s,4H),7.62(d,J=9.6Hz,1H),7.12(t,J=55.6Hz,1H),7.11(d,J=9.6Hz,1H),5.45(s,2H),4.32(s,4H),2.38(s,3H).

[0569] Embodiment 6:

[0570] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-6-methylpiperazin-2-one (6)

[0571]

[0572] The experimental operation was as described in Example 1, using A8 and compound 6-methylpiperazine-2-one as reactants to obtain the title product.

[0573] MS (ESI) m / z [M+H] + =430.1.

[0574] 1 H NMR (400MHz, CD 3 OD)δ7.76(s,4H),7.35(d,J=9.6Hz,1H),7.00(d,J=9.6Hz,1H),6.88(t,J=55.6Hz,1H),5.50(s,2H),4.28- 4.18(m,1H),4.04-3.93(m,2H),3.76-3.65(m,1H),3.28-3.20(m,1H),2.48(s,3H),1.26(d,J=6.4Hz,3H).

[0575] Embodiment 7:

[0576] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-6,6-dimethylpiperazin-2-one (7)

[0577]

[0578] The experimental operation was as described in Example 1, using A8 and 6,6-dimethylpiperazine-2-one as reactants to obtain the title product.

[0579] MS (ESI) m / z [M+H] + =443.9.

[0580] 1 H NMR (400MHz, CD 3 OD)δ7.77(s,4H),7.35(d,J=9.6Hz,1H),7.00(d,J=9.6Hz,1H),6.88(t,J=55 .6Hz,1H),5.50(s,2H),4.08(s,2H),3.58(s,2H),2.48(s,3H),1.32(s,6H).

[0581] Embodiment 8:

[0582] 7-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-4,7-diazaspiro[2.5]octan-5-one (8)

[0583]

[0584] The experimental procedure was as described in Example 1, using A8 and 4,7-diazaspiro[2.5]octan-5-one as reactants to obtain the title product.

[0585] MS (ESI) m / z [M+H] + =442.1.

[0586] 1 H NMR (400MHz, CD 3 OD)δ7.77(s,4H),7.31(d,J=9.6Hz,1H),6.72-7.06(m,2H),5.50(s,2H),4.22(s,2H),3.64(s,2H),2.48(s,3H),0.90-0.82(m,4H).

[0587] Embodiment 9:

[0588] (S)-8-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (9)

[0589]

[0590] The experimental procedure was as described in Example 1, using A8 and (S)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one as reactants to obtain the title product.

[0591] MS (ESI) m / z [M+H] + =472.2.

[0592] 1 H NMR (400 MHz, DMSO-d 6 )δ7.78(s,4H),7.43(d,J=9.4Hz,1H),7.13(t,J=55.6Hz,1H),7.03(d,J=9.4Hz,1H),5.46(s,2H),4.41-4.38(m, 1H),4.19-4.15(m,2H),4.05-4.02(m,3H),3.61-3.58(m,1H),2.80-2.77(m,2H),2.69-2.66(m,2H),2.39(s,3H).

[0593] Embodiment 10:

[0594] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-3,3-dimethylpiperazin-2-one (10)

[0595]

[0596] The experimental operation was as described in Example 1, using A8 and 3,3-dimethylpiperazine-2-one as reactants to obtain the title product.

[0597] MS (ESI) m / z [M+H] + =444.2.

[0598] 1 H NMR (400 MHz, DMSO-d 6 )δ7.80-7.78(m,5H),7.17(d,J=9.4Hz,1H),7.13(t,J=55.6Hz,1H),5.57(s, 2H),3.85(t,J=5.2Hz,2H),3.05(t,J=5.2Hz,2H),2.41(s,3H),1.30(s,6H).

[0599] Embodiment 11:

[0600] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-3-methylpiperazin-2-one (11)

[0601]

[0602] The experimental operation was as described in Example 1, using A8 and 3-methylpiperazine-2-one as reactants to obtain the title product.

[0603] MS (ESI) m / z [M+H] + =430.2.

[0604] 1 H NMR (400 MHz, DMSO-d 6 )δ7.99(s,1H),7.78(s,4H),7.35(d,J=9.4Hz,1H),7.13(t,J=55.6Hz,1H),7.00(d,J=9.4Hz,1H),5.4 4(s,2H),4.65-4.62(m,1H),4.12-4.09(m,1H),3.27-3.22(m,3H),2.39(s,3H),1.28(d,J=6.8Hz,3H).

[0605] Embodiment 12:

[0606] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N,N-dimethylpyrrolidin-3-amine (12)

[0607]

[0608] The experimental operation was as described in Example 1, using A8 and N,N-dimethylpyrrolidin-3-amine hydrochloride as reactants to obtain the title product.

[0609] MS (ESI) m / z [M+H] + =430.1.

[0610] 1 H NMR (400 MHz, DMSO-d 6 )δ7.79(s,4H),7.14(t,J=55.6Hz,1H),6.99(d,J=9.4Hz,1H),6.95(d,J=9.4Hz,1H),5.43(s,2H),3.66-3.62(m,1H),3.57-3.53( m,1H),3.33-3.31(m,1H),3.15-3.10(m,1H),2.82-2.80(m,1H),2.39(s,3H),2.21(s,6H),2.17-2.14(m,1H),1.84-1.74(m,1H).

[0611] Embodiment 13:

[0612] (S)-8-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)octahydropyrazino[2,1-c][1,4]oxazine (13)

[0613]

[0614] The experimental procedure was as described in Example 1, with A8 and (S)-octahydropyrazino[2,1-c][1,4]oxazine hydrochloride as reactants to give the title product.

[0615] MS (ESI) m / z [M+H] + =458.2.

[0616] 1 H NMR (400 MHz, DMSO-d 6 )δ7.78(s,4H),7.37(d,J=9.4Hz,1H),7.13(t,J=55.6Hz,1H),6.99(d,J=9.4Hz,1H),5.44(s,2H),4.06-3.92(m,2H),3.76-3.69(m, 2H),3.54-3.51(m,2H),3.16-3.11(m,1H),2.90-2.84(m,1H),2.79-2.76(m,1H),2.66-2.63(m,1H),2.39(s,3H),2.22-2.14(m,3H).

[0617] Embodiment 14:

[0618] (S)-2-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (14)

[0619]

[0620] The experimental procedure was as described in Example 1, using A8 and (S)-hexahydropyrrolo[1,2-a]pyrazine-4(1H)-one hydrochloride as reactants to obtain the title product.

[0621] MS (ESI) m / z [M+H] + =456.2.

[0622] 1 H NMR (400 MHz, DMSO-d 6)δ7.78(s,4H),7.37(d,J=9.4Hz,1H),7.13(t,J=55.6Hz,1H),7.00(d,J=9.4Hz,1H),5.44(s,2H),4.56-4.53(m,1H),4.36-4.31(m,1H),3.66 -3.62(m,2H),3.45-3.42(m,2H),2.81-2.76(m,1H),2.39(s,3H),2.08 -2.06(m,1H),1.92-1.90(m,1H),1.54-1.51(m,1H),1.50-1.46(m,1H).

[0623] Embodiment 15:

[0624] 3-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-6-(4-methylpiperazin-1-yl)pyridazine (15)

[0625]

[0626] The experimental operation was as described in Example 1, using A8 and 1-methylpiperazine as reactants to obtain the title product.

[0627] MS (ESI) m / z [M+H] + =416.2.

[0628] 1 H NMR (400 MHz, CDCl 3 )δ7.75-7.55(m,4H),7.08(d,J=9.4Hz,1H),6.86(d,J=9.4Hz,1H),6.62(t,J=55. 6Hz,1H),5.46(s,2H),3.64(br.s,4H),2.65(br.s,4H),2.49(s,3H),2.43(s,3H).

[0629] Embodiment 16:

[0630] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)morpholine (16)

[0631]

[0632] The experimental operation was as described in Example 1, using A8 and morpholine as reactants to obtain the title product.

[0633] MS (ESI) m / z [M+H] + =403.1.

[0634] 1 H NMR (400 MHz, CDCl 3 )δ7.72-7.65(m,4H),7.04(d,J=9.4Hz,1H),6.88(d,J=9.4Hz,1H),6.72(t,J= 55.6Hz,1H),5.47(s,2H),3.87-3.85(m,4H),3.53-3.50(m,4H),2.50(s,3H).

[0635] Embodiment 17:

[0636] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridin-3-yl)-1-methyl-1,4-diazepan-2-one (17)

[0637]

[0638] The experimental procedure was as described in Example 1, using A8 and 1-methyl-1,4-diazepan-2-one hydrochloride as reactants to give the title product.

[0639] MS (ESI) m / z [M+H] + =443.2.

[0640] 1 H NMR (400 MHz, DMSO-d 6 )δ7.79(s,4H),7.40(d,J=9.4Hz,1H),7.17(t,J=55.6Hz,1H),7.01(d,J=9.4Hz,1H),5.45( s,2H),3.74-3.68(m,4H),3.49-3.46(m,2H),2.85(s,3H),2.60-2.54(m,2H),2.39(s,3H).

[0641] Embodiment 18:

[0642] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)azetidin-2-one (18)

[0643]

[0644] Under argon protection, A8 (42.2 mg, 0.12 mmol) and 2-azetidinone (12.8 mg, 0.18 mmol) were dissolved in toluene (2 mL), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.94 mg, 0.012 mmol), cesium carbonate (78.20 mg, 0.24 mmol) and tris(dibenzylideneacetone)dipalladium (10.99 mg, 0.012 mmol) were added in sequence, and stirred at 100 ° C for 16 hours. TLC monitored the completion of the reaction. The reaction solution was diluted with dichloromethane (50 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 0: 1) to obtain the title product (25 mg, white solid).

[0645] MS (ESI) m / z [M+H] + =387.1.

[0646] 1 H NMR (400 MHz, DMSO-d 6 )δ7.84(d,J=9.4Hz,1H),7.79(s,4H),7.24(d,J=9.4Hz,1H),7.14(t,J=55.6H z,1H),5.55(s,2H),3.75(t,J=4.6Hz,2H),3.17(t,J=4.6Hz,2H),2.41(s,3H).

[0647] Embodiment 19:

[0648] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)imidazolidin-2-one (19)

[0649]

[0650] The experimental procedure was as described in Example 18, using A8 and 2-imidazolidinone as reactants to obtain the title product.

[0651] MS (ESI) m / z [M+H] + =402.1.

[0652] 1 H NMR (400 MHz, DMSO-d 6)δ8.41(d,J=9.2Hz,1H),7.77(s,4H),7.38(s,1H),7.13(d,J=9.2Hz,1H),7.11(t,J= 56.0Hz,1H),5.51(s,2H),3.98(t,J=8.4Hz,2H),3.41(t,J=8.4Hz,2H),2.39(s,3H).

[0653] Embodiment 20:

[0654] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)pyrrolidin-2-one (20)

[0655]

[0656] The experimental procedure was as described in Example 18, using A8 and pyrrolidin-2-one as reactants to obtain the title product.

[0657] MS (ESI) m / z [M+H] + =401.1.

[0658] 1 H NMR (400 MHz, DMSO-d 6 )δ8.46(d,J=9.6Hz,1H),7.77(s,4H),7.22(d,J=9.6Hz,1H),7.12(t,J=55.6Hz,1H),5. 55(s,2H),3.98(t,J=7.2Hz,2H),2.55(t,J=8.0Hz,2H),2.40(s,3H),2.10-1.99(m,2H).

[0659] Embodiment 21:

[0660] 4-(6-[(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy]pyridin-3-yl)piperazin-2-one (21)

[0661]

[0662] The experimental procedure was as described in Example 18, using A10 and 2-piperazinone as reactants to obtain the title product.

[0663] MS (ESI) m / z [M+H] + =415.2.

[0664] 1 H NMR (400 MHz, DMSO-d 6)δ8.02(s,1H),7.79(s,4H),7.71(d,J=2.6Hz,1H),7.46(dd,J=8.8,2.6Hz,1H),7.15(t,J= 55.6Hz,1H),6.70(d,J=8.8Hz,1H),5.33(s,2H),3.63(s,2H),3.28(br.s,4H),2.38(s,3H).

[0665] Embodiment 22:

[0666] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridin-3-yl)-1-methylpiperazin-2-one (22)

[0667]

[0668] The experimental procedure was as described in Example 18, using A10 and 1-methyl-2-piperazinone as reactants to obtain the title product.

[0669] MS (ESI) m / z [M+H] + =429.2.

[0670] 1 H NMR (400 MHz, CDCl 3 )δ7.75-7.65(m,5H),7.30-7.27(m,1H),6.85-6.58(m,2H),5.31(s,2H),3. 78(s,2H),3.48-3.46(m,2H),3.40-3.38(m,2H),3.04(s,3H),2.49(s,3H).

[0671] Embodiment 23:

[0672] 3-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)oxazolidin-2-one (23)

[0673]

[0674] The experimental procedure was as described in Example 18, using A8 and oxazolidin-2-one as reactants to obtain the title product.

[0675] MS (ESI) m / z [M+H] + =403.1.

[0676] 1 H NMR (400 MHz, CDCl 3)δ8.54(d,J=9.4Hz,1H),7.70-7.67(m,4H),7.06(d,J=9.4Hz,1H),6.70(t,J= 55.6Hz,1H),5.53(s,2H),4.59-4.56(m,2H),4.39-4.37(m,2H),2.51(s,3H).

[0677] Embodiment 24:

[0678] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-3-methylimidazolin-2-one (24)

[0679]

[0680] The experimental procedure was as described in Example 18, using A8 and 1-methylimidazolidin-2-one as reactants to obtain the title product.

[0681] MS (ESI) m / z [M+H] + =416.1.

[0682] 1 H NMR (400 MHz, CDCl 3 )δ8.63(d,J=9.4Hz,1H),7.68-7.66(m,4H),6.96(d,J=9.4Hz,1H),6.70(t,J=55. 6Hz,1H),5.48(s,2H),4.11(br.s,2H),3.54(br.s,2H),2.93(s,3H),2.49(s,3H).

[0683] Embodiment 25:

[0684] 3-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-5,5-dimethylimidazolidine-2,4-dione (25)

[0685]

[0686] Compound A9 (350 mg, 0.79 mmol), 5,5-dimethylimidazolidine-2,4-dione (350.0 mg, 0.79 mmol) and cuprous oxide (112 mg, 0.79 mmol) were added to anhydrous N,N-dimethylformamide (10.0 mL) in sequence, and nitrogen was replaced 3 times. Reacted at 180°C for 2.5 hours. LCMS showed that the product was generated. After the reaction solution was cooled to room temperature, ethyl acetate (150 mL) was added for dilution, the organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was separated and purified by high performance liquid chromatography (separation conditions: chromatographic column: Phenomenex C18 75*30 mm*3 μm; mobile phase: water (0.225% trifluoroacetic acid solution)-acetonitrile; gradient: B%: 30%-50%; flow rate: 30 mL / min) to obtain the title product (63.0 mg, white solid).

[0687] MS (ESI) m / z [M+H] + =444.2.

[0688] 1 H NMR (400 MHz, CD 3 OD)δ7.77(s,4H),7.71(d,J=9.2Hz,1H),7.31(d,J=9.2Hz,1H),6.88(t,J=56.0Hz,1H),5.70(s,2H),2.51(s,3H),1.53(s,6H).

[0689] Embodiment 26:

[0690] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-methylpiperazin-2-one (26)

[0691]

[0692] Under argon protection, Example 2 (40 mg, 0.096 mmol) was dissolved in N, N-dimethylformamide (4 mL), cooled to 0 ° C, sodium hydride (5.3 mg, 60%, 0.12 mmol) was added, stirred for 30 minutes, and iodomethane (16 mg, 0.11 mmol) was added dropwise. Stir at room temperature for 2 hours. TLC monitored the completion of the reaction. The reaction solution was poured into water (30 mL) for quenching and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 0: 1) and reverse phase C18 rapid preparative chromatography (acetonitrile: water = 0-40%) to obtain the title product (7 mg, white solid).

[0693] MS (ESI) m / z [M+H] + =430.2.

[0694] 1 H NMR (400 MHz, DMSO-d 6 )δ7.78(s,4H),7.43(d,J=9.6Hz,1H),7.14(t,J=55.6Hz,1H),7.04(d,J=9.6Hz,1H),5.45( s,2H),4.02(s,2H),3.74(t,J=5.4Hz,2H),3.39(t,J=5.4Hz,2H),2.87(s,3H),2.39(s,3H).

[0695] Embodiment 27:

[0696] (S)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-2-carboxylic acid (27)

[0697]

[0698] Step 1: Synthesis of (1-(tert-butyl)2-methyl(S)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-1,2-dicarboxylate (27-2)

[0699] The experimental operation was as described in Example 1, using A8 and 27-1 as reactants to obtain the title product.

[0700] MS (ESI) m / z [M+H] + =560.2.

[0701] Step 2: Synthesis of (S)-methyl 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-2-carboxylate (27-3)

[0702] 27-2 (130 mg, 0.23 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated under reduced pressure to obtain the title product 27-3 (130 mg, yellow oil), and the crude product was directly used in the next step without further purification.

[0703] MS (ESI) m / z [M+H] + =460.

[0704] Step 3: Synthesis of (S)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-2-carboxylic acid (27)

[0705] 27-3 (130 mg, 0.23 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL), sodium hydroxide (46 mg, 1.15 mmol) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed by LCMS monitoring, the pH of the reaction solution was adjusted to 3 with 1.0 M dilute hydrochloric acid, extracted with dichloromethane (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-35%) to obtain the title product (30 mg, white solid).

[0706] MS (ESI) m / z [M+H] + =446.2.

[0707] 1 H NMR (400 MHz, DMSO-d 6 )δ7.78(s,4H),7.44(d,J=9.6Hz,1H),7.14(t,J=55.6Hz,1H),7.05(d,J=9.6Hz,1H),5.46(s,2H),4.3 1-4.27(m,1H),3.99-3.96(m,1H),3.56(br.s,1H),3.20-3.14(m,3H),2.99-2.94(m,1H),2.39(s,3H).

[0708] Embodiment 28:

[0709] (R)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-2-carboxylic acid (28)

[0710]

[0711] The experimental operation was as described in Example 27, using A8 and (R)-1-tert-butyl 3-methylpiperazine-1,3-dicarboxylate as reactants, and the title product was obtained through coupling, deprotection and hydrolysis reaction steps.

[0712] MS (ESI) m / z [M+H] + =446.2.

[0713] 1 H NMR (400 MHz, DMSO-d 6 )δ7.78(s,4H),7.44(d,J=9.6Hz,1H),7.14(t,J=55.6Hz,1H),7.05(d,J=9.6Hz,1H),5.46(s,2H),4.2 8-4.25(m,1H),3.99-3.95(m,1H),3.56(br.s,1H),3.20-3.14(m,3H),2.99-2.93(m,1H),2.39(s,3H).

[0714] Embodiment 29:

[0715] (S)-1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-2-carboxylic acid (29)

[0716]

[0717] The experimental operation was as described in Example 27, using A8 and (S)-1-tert-butyl 3-methylpiperazine-1,3-dicarboxylate as reactants, and the title product was obtained through coupling, deprotection and hydrolysis reaction steps.

[0718] MS (ESI) m / z [M+H] + =446.2.

[0719] 1 H NMR (400 MHz, DMSO-d 6)δ7.77(s,4H),7.28(d,J=8.8Hz,1H),7.12(t,J=56.4Hz,1H),6.96(d,J=8.8Hz,1H),5.41(s,2H),4.66(s,1H) ,3.92-3.90(m,1H),3.52-3.49(m,1H),3.07-3.04(m,1H),2.92-2.89(m,1H),2.74-2.64(m,2H),2.37(s,3H).

[0720] Embodiment 30:

[0721] (S)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-methylpiperazine-2-carboxamide (30)

[0722]

[0723] Step 1: Synthesis of (S)-1-(tert-butyloxycarbonyl)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-2-carboxylic acid (30-1)

[0724] Dissolve 27-2 (200 mg, 0.36 mmol) in a mixed solution of tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL), add sodium hydroxide (14 mg, 0.36 mmol), and stir the mixture at room temperature for 3 h. After the reaction was completed by LCMS monitoring, adjust the pH of the reaction solution to 3 with 1.0 M dilute hydrochloric acid, extract with dichloromethane (10 mL x 3), dry the organic phase with anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain the title product (150 mg, yellow solid).

[0725] MS (ESI) m / z [M+H] + =546.2.

[0726] Step 2: (S)-tert-butyl 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-2-(methylcarbamoyl)piperazine-1-carboxylate (30-2)

[0727] 30-1 (50 mg, 0.092 mmol) and methylamine hydrochloride (7 mg, 0.10 mmol) were dissolved in N, N-dimethylformamide (3 mL), HATU (38 mg, 0.10 mmol) and N, N-diisopropylethylamine (36 mg, 0.28 mmol) were added, and the mixture was stirred at room temperature for 16 h. LCMS monitored the completion of the reaction. Saturated brine (20 mL) was added to the reaction solution, extracted with dichloromethane (5 mL x 3), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the title product (50 mg, yellow solid).

[0728] MS (ESI) m / z [M+H] + =559.3.

[0729] Step 3: (S)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-methylpiperazine-2-carboxamide (30)

[0730] 30-2 (50 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-35%) to obtain the title product (20 mg, white solid).

[0731] MS (ESI) m / z [M+H] + =459.2.

[0732] 1 H NMR (400 MHz, DMSO-d 6 )δ8.18(s,1H),7.86-7.85(m,1H),7.78(s,4H),7.35(d,J=9.6Hz,1H),7.13(t,J=55.6Hz,1H),6.99(d,J=9.6Hz,1H),5.44(s,2H), 3.97-3.95(m,1H),3.73-3.70(m,1H),3.29-3.27(m,1H),2.97-2.91(m,3H),2.73-2.71(m,1H),2.60(d,J=4.4Hz,3H),2.39(s,3H).

[0733] Embodiment 31:

[0734] (S)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N,N-dimethylpiperazine-2-carboxamide (31)

[0735]

[0736] The experimental operation is as described in steps 2 and 3 of Example 30, using intermediate 30-1 and dimethylamine hydrochloride as reactants, and undergoing condensation and deprotection reaction steps to obtain the title product.

[0737] MS (ESI) m / z [M+H] + =473.2.

[0738] 1 H NMR (400 MHz, DMSO-d 6 )δ9.14(br.s,1H),7.80(s,4H),7.54(d,J=9.6Hz,1H),7.14(t,J=55.6Hz,1H),7.13(d,J=9.6Hz,1H),5.46(s,2H),4.59-4 .56(m,2H),4.20-4.16(m,1H),3.33-3.32(m,1H),3.24(s,1H),3.15(s,3H),3.09-2.99(m,2H),2.91(s,3H),2.40(s,3H).

[0739] Embodiment 32:

[0740] (S)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-2-amide (32)

[0741]

[0742] The experimental operation is as described in steps 2 and 3 of Example 30, using intermediate 30-1 and ammonium chloride as reactants, and undergoing condensation and deprotection reaction steps to obtain the title product.

[0743] MS (ESI) m / z [M+H] + =445.2.

[0744] 1 H NMR (400 MHz, DMSO-d 6)δ7.78(s,4H),7.38-7.36(m,2H),7.18(br,1H),7.13(t,J=55.6Hz,1H),6.99(d,J=9.6Hz,1H),5.44(s,2H), 4.00-3.98(m,1H),3.75-3.72(m,1H),3.28-3.27(m,1H),3.00-2.90(m,3H),2.74-2.71(m,1H),2.39(s,3H).

[0745] Embodiment 33:

[0746] (S)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-2-carbonitrile (33)

[0747]

[0748] Step 1: Synthesis of (S)-tert-butyl 2-carbamoyl-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-1-carboxylate (33-1)

[0749] The experimental operation was as described in step 2 of Example 30, using intermediate 30-1 and ammonium chloride as reactants to obtain the title product (33-1).

[0750] Step 2: Synthesis of (S)-tert-butyl 2-cyano-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-1-carboxylate (33-2)

[0751] Dissolve 33-1 (100 mg, 0.18 mmol) in dichloromethane (8 mL), add triethylamine (73 mg, 0.72 mmol), and cool the mixture to 0 ° C. Slowly add trifluoroacetic anhydride (76 mg, 0.36 mmol), return the reaction solution to room temperature and stir for 1 hour. LCMS monitors the completion of the reaction. Adjust the pH of the reaction solution to 7.0 with saturated sodium bicarbonate aqueous solution, and extract with dichloromethane (10 mL x 2). The organic phase is dried over anhydrous sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0: 1 to 3: 1) to obtain the title product (45 mg, white solid).

[0752] MS (ESI) m / z [M+H] + =527.2.

[0753] Step 3: Synthesis of (S)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-2-carbonitrile (33)

[0754] 33-2 (45 mg, 0.085 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.8 mL, 10.73 mmol) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed by LCMS monitoring, the pH of the reaction solution was adjusted to 7.0 with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (10 mL x 2), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-35%) to obtain the title product (17 mg, light yellow solid).

[0755] MS (ESI) m / z [M+H] + =427.2.

[0756] 1 H NMR (400 MHz, DMSO-d 6 )δ7.77(s,4H),7.43(d,J=9.6Hz,1H),7.12(t,J=56.0Hz,1H),7.02(d,J=9.6Hz,1H),5.44(s,2H),4.23(s,1H) ,4.12-4.09(m,1H),3.88-3.86(m,1H),3.28-3.17(m,1H),3.10-3.06(m,1H),2.93-2.80(m,3H),2.38(s,3H).

[0757] Embodiment 34:

[0758] (S)-2-(4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-yl)-5-methyl-1,3,4-oxadiazole (34)

[0759]

[0760] Step 1: Synthesis of (S)-2-(2-acetylhydrazine-1-carbonyl)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol)-5-yl)methoxy)pyridazin-3-ylpiperazine-1-carboxylic acid tert-butyl ester (34-1)

[0761] The experimental procedure was as described in step 2 of Example 30, using intermediate 30-1 and acetic acid hydrazide as reactants to obtain the title product (34-1).

[0762] MS (ESI) m / z [M+H] + =602.3.

[0763] Step 2: Synthesis of (S)-tert-butyl 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)piperazine-1-carboxylate (34-2)

[0764] 34-1 (100 mg, 0.17 mmol) and N,N-diisopropylethylamine (220 mg, 1.70 mmol) were dissolved in dichloromethane (15 mL), p-toluenesulfonyl chloride (320 mg, 1.70 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction was completed by LCMS monitoring. Saturated brine (20 mL) was added to the reaction solution, and it was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (dichloromethane: methanol = 20: 1) to obtain the title product (90 mg, yellow solid).

[0765] MS (ESI) m / z [M+H] + =584.2.

[0766] Step 3: Synthesis of (S)-2-(4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-yl)-5-methyl-1,3,4-oxadiazole (34)

[0767] 34-2 (90 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-35%) to obtain the title product (31 mg, white solid).

[0768] MS (ESI) m / z [M+H] + =484.2.

[0769] 1 H NMR (400 MHz, DMSO-d 6)δ7.78(s,4H),7.41(d,J=9.6Hz,1H),7.14(t,J=56.0Hz,1H),7.01(d,J=9.6Hz,1H),5.45(s,2H),4.12-4.19(m,1H),4.09-4.06( m,1H),3.70-3.67(m,1H),3.34-3.31(m,1H),3.11-3.16(m,1H),2.99-2.96(m,1H),2.81-2.75(m,1H),2.47(s,3H),2.39(s,3H).

[0770] Embodiment 35:

[0771] (S)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)morpholine-2-carboxylic acid (35)

[0772]

[0773] Step 1: Synthesis of (S)-methyl 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)morpholine-2-carboxylate (35-1)

[0774] The experimental procedure was as described in Example 1, using A8 and (S)-morpholine-2-carboxylic acid methyl ester as reactants to obtain the title product.

[0775] MS (ESI) m / z [M+H] + =461.2.

[0776] Step 2: Synthesis of (S)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)morpholine-2-carboxylic acid (35)

[0777] 35-1 (50 mg, 0.11 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL), sodium hydroxide (46 mg, 1.15 mmol) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed by LCMS monitoring, the pH of the reaction solution was adjusted to 3 with 1.0 M dilute hydrochloric acid, extracted with dichloromethane (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-35%) to obtain the title product (18 mg, white solid).

[0778] MS (ESI) m / z [M+H] +=447.3.

[0779] 1 H NMR (400 MHz, DMSO-d 6 )δ7.79(s,4H),7.42(d,J=9.6Hz,1H),7.14(t,J=55.6Hz,1H),7.04(d,J=9.6Hz,1H),5.47(s, 2H),4.22-4.20(m,1H),4.02-3.91(m,2H),3.66-3.62(m,2H),3.25-3.10(m,2H),2.40(s,3H).

[0780] Embodiment 36:

[0781] (S)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-6-oxopiperazine-2-carboxylic acid (36)

[0782]

[0783] The experimental operation was as described in Example 35, using A8 and (S)-6-oxopiperazine-2-carboxylic acid methyl ester as reactants, and the title product was obtained through coupling and hydrolysis.

[0784] MS (ESI) m / z [M+H] + =460.1.

[0785] 1 H NMR (400 MHz, DMSO-d 6 )δ8.13(br.s,1H),7.78(s,4H),7.35(d,J=9.4Hz,1H),7.13(t,J=55.6Hz,1H),7.03(d,J=9. 4Hz,1H),5.44(s,2H),4.17-4.05(m,3H),3.84-3.80(m,1H),3.66-3.63(m,1H),2.39(s,3H).

[0786] Embodiment 37:

[0787] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)azetidine-3-carboxylic acid (37)

[0788]

[0789] The experimental operation was as described in Example 35, using A8 and azetidine-3-carboxylic acid methyl ester hydrochloride as reactants, and the title product was obtained through coupling and hydrolysis.

[0790] MS (ESI) m / z [M+H] + =417.1.

[0791] 1 H NMR (400 MHz, DMSO-d 6 )δ7.79(s,4H),7.15(t,J=55.6Hz,1H),7.01(s,1H),6.99(d,J=9.4Hz,1H),6.92(d,J=9.4H z,1H),5.44(s,2H),4.14-4.09(m,2H),4.05-3.96(m,2H),3.49-3.45(m,1H),2.39(s,3H).

[0792] Embodiment 38:

[0793] (S)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-methylmorpholine-2-carboxamide (38)

[0794]

[0795] Example 35 (60 mg, 0.13 mmol), methylamine hydrochloride (17.55 mg, 0.26 mmol) and HATU (152.95 mg, 0.26 mmol) were dissolved in dichloromethane (5 mL) at room temperature, triethylamine (37.02 mg, 0.39 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was completed by LCMS monitoring. Water (10 mL) was added to the reaction solution for dilution, and ethyl acetate was extracted (15 mL x 3). The liquids were separated, and the organic phase was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-40%) to obtain the title product (10 mg, white solid).

[0796] MS (ESI) m / z [M+H] + =460.2.

[0797] 1 H NMR (400 MHz, DMSO-d 6)δ7.86(br.s,1H),7.79(s,4H),7.43(d,J=9.6Hz,1H),7.15(t,J=55.6Hz,1H),7.03(d,J=9.6Hz,1H),5.47(s,2H),4.20-4.18(m,1H) ,4.02-3.99(m,2H),3.90-3.86(m,1H),3.69-3.64(m,1H),2.99-2.90(m,1H),2.83-2.74(m,1H),2.62(d,J=4.6Hz,3H),2.40(s,3H).

[0798] Embodiment 39:

[0799] 3-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-ethyl-3-azabicyclo[3.1.0]hexane-6-carboxamide (39)

[0800]

[0801] The experimental operation was as described in Example 35 and Example 38, using intermediate A8 and 3-azabicyclo[3.1.0]hexane-6-carboxylic acid methyl ester as reactants, and undergoing coupling, hydrolysis and condensation reaction steps to obtain the title product.

[0802] MS (ESI) m / z [M+H] + =470.3.

[0803] 1 H NMR (400 MHz, DMSO-d 6 )δ7.96(t,J=5.6Hz,1H),7.77(s,4H),7.12(t,J=55.6Hz,1H),7.01-6.95(m,2H),5.40(s,2H),3.67(d,J=10.4Hz,2 H),3.36(d,J=10.4Hz,2H),3.10-2.99(m,2H),2.37(s,3H),1.99-1.97(s,2H),1.42(s,1H),0.98(t,J=7.2Hz,3H).

[0804] Embodiment 40:

[0805] (R)-1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-azetidine-2-carboxamide (40)

[0806]

[0807] The experimental operation was as described in Example 35 and Example 38, using intermediate A8 and azetidine-2-carboxylic acid methyl ester as reactants, and undergoing coupling, hydrolysis and condensation reaction steps to obtain the title product.

[0808] MS (ESI) m / z [M+H] + =444.2.

[0809] 1 H NMR (400 MHz, DMSO-d 6 )δ8.04-8.03(m,1H),7.77(s,4H),7.13(t,J=55.6Hz,1H),7.00(d,J=9.4Hz,1H),6.83(d,J=9.4Hz,1H),5.42(s,2H),4.55-4 .49(m,1H),3.91-3.88(m,1H),3.86-3.80(m,1H),3.33-3.07(m,2H),2.38(s,3H),2.32-2.25(m,2H),1.00(t,J=7.2Hz,3H).

[0810] Embodiment 41:

[0811] (R)-1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-ethylpyrrolidine-2-carboxamide (41)

[0812]

[0813] The experimental operation was as described in Example 35 and Example 38, using intermediate A8 and (R)-proline methyl ester hydrochloride as reactants, and undergoing coupling, hydrolysis and condensation reaction steps to obtain the title product.

[0814] MS (ESI) m / z [M+H] + =444.2.

[0815] 1 H NMR (400 MHz, DMSO-d 6)δ7.82(br.s,1H),7.79(s,4H),7.15(t,J=55.6Hz,1H),6.99(d,J=9.4Hz,1H),6.89(d,J=9.4Hz,1H),5.43(s,2H),4.28-4.25(m,1H) ,3.68-3.62(m,1H),3.30-3.25(m,1H),3.05-3.01(m,2H),2.39(s,3H),1.94-1.89(m,2H),1.29-1.23(m,2H),0.95(t,J=7.0Hz,3H).

[0816] Embodiment 42:

[0817] (S)-1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-ethylpyrrolidine-2-carboxamide (42)

[0818]

[0819] The experimental operation was as described in Example 35 and Example 38, using intermediate A8 and (S)-proline methyl ester hydrochloride as reactants, and undergoing coupling, hydrolysis and condensation reaction steps to obtain the title product.

[0820] MS (ESI) m / z [M+H] + =444.2.

[0821] 1 H NMR (400 MHz, DMSO-d 6 )δ7.82(br.s,1H),7.79(s,4H),7.15(t,J=55.6Hz,1H),6.99(d,J=9.4Hz,1H),6.89(d,J=9.4Hz,1H),5.43(s,2H),4.28-4.25(m,1H) ,3.67-3.60(m,1H),3.30-3.25(m,1H),3.04-3.01(m,2H),2.39(s,3H),1.94-1.89(m,2H),1.29-1.23(m,2H),0.95(t,J=7.0Hz,3H).

[0822] Embodiment 43:

[0823] 1-(6-[(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy]pyridazin-3-yl)-N-ethylazetidine-3-carboxamide (43)

[0824]

[0825] The experimental procedure was as described in Example 38, using compound 37 and ethylamine hydrochloride as reactants to obtain the title product.

[0826] MS (ESI) m / z [M+H] + =444.2.

[0827] 1 H NMR (400 MHz, DMSO-d 6 )δ8.02(t,J=5.2Hz,1H),7.79(s,4H),7.22(t,J=55.6Hz,1H),7.00(d,J=9.4Hz,1H),6.91(d,J=9.4Hz,1H),5.44(s, 2H),4.08-4.03(m,2H),3.97-3.94(m,2H),3.44-3.34(m,1H),3.03-3.10(m,2H),2.40(s,3H),1.01(t,J=7.2Hz,3H).

[0828] Embodiment 44:

[0829] N-Cyclopropyl-1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)azetidine-3-carboxamide (44)

[0830]

[0831] The experimental procedure was as described in Example 38, using compound 37 and cyclopropylamine as reactants to obtain the title product.

[0832] MS (ESI) m / z [M+H] + =456.2.

[0833] 1 H NMR (400 MHz, DMSO-d 6 )δ8.08(br.s,1H),7.79(s,4H),7.22(t,J=55.6Hz,1H),6.99(d,J=9.4Hz,1H),6.91(d,J=9.4Hz,1H),5.43(s,2H),4.06- 4.02(m,2H),3.96-3.92(m,2H),3.43-3.37(m,1H),2.66-2.62(m,1H),2.39(s,3H),0.65-0.56(m,2H),0.43-0.40(m,2H).

[0834] Embodiment 45:

[0835] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-(oxetane-pyridin-3-yl)azetidine-3-carboxamide (45)

[0836]

[0837] The experimental procedure was as described in Example 38, using compound 37 and 3-oxetaneamine as reactants to obtain the title product.

[0838] MS (ESI) m / z [M+H] + =472.2.

[0839] 1 H NMR (400 MHz, DMSO-d 6 )δ8.77(d,J=8.0Hz,1H),7.78(s,4H),7.13(t,J=55.6Hz,1H),6.98(d,J=9.4Hz,1H),6.90(d,J=9.4Hz,1H),5.43(s,2H),4.8 1-4.77(m,1H),4.71-4.68(m,2H),4.44-4.40(m,2H),4.09-4.05(m,2H),3.98-3.94(m,2H),3.49-3.45(m,1H),2.38(s,3H).

[0840] Embodiment 46:

[0841] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-(1-methylpiperidin-4-yl)azetidine-3-carboxamide (46)

[0842]

[0843] The experimental procedure was as described in Example 38, using compound 37 and 1-methyl-4-aminopiperidine as reactants to obtain the title product.

[0844] MS (ESI) m / z [M+H] + =513.2.

[0845] 1 H NMR (400 MHz, DMSO-d 6)δ7.90(d,J=8.0Hz,1H),7.78(s,4H),7.13(t,J=55.6Hz,1H),6.98(d,J=9.4Hz,1H),6.89(d,J=9.4Hz,1H),5.42(s,2H),4.06-4.02(m,2H), 3.95-3.92(m,2H),3.45-3.32(m,2H),2.69-2.64(m,2H),2.38(s,3H), 2.12(s,3H),1.92-1.87(m,2H),1.70-1.65(m,2H),1.40-1.33(m,2H).

[0846] Embodiment 47:

[0847] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-phenylazetidine-3-carboxamide (47)

[0848]

[0849] The experimental procedure was as described in Example 38, using compound 37 and aniline as reactants to obtain the title product.

[0850] MS (ESI) m / z [M+H] + =492.2.

[0851] 1 H NMR (400 MHz, DMSO-d 6 )δ11.21(br.s,1H),7.79(s,4H),7.61(d,J=8.0Hz,1H),7.33-7.15(m,4H),7.0 7-7.01(m,2H),5.42(s,2H),4.35-4.28(m,4H),3.74-3.76(m,1H),2.41(s,3H).

[0852] Embodiment 48:

[0853] N-Benzyl-1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)azetidine-3-carboxamide (48)

[0854]

[0855] The experimental procedure was as described in Example 38, using compound 37 and benzylamine as reactants to obtain the title product.

[0856] MS (ESI) m / z [M+H] + =506.2.

[0857] 1 H NMR (400 MHz, DMSO-d 6 )δ8.52(br.s,1H),7.78(s,4H),7.33-7.13(m,6H),6.98(d,J=9.4Hz,1H),6.91(d,J=9.4Hz,1H),5. 43(s,2H),4.32-4.29(m,2H),4.11-4.07(m,2H),4.02-3.98(m,2H),3.55-3.53(m,1H),2.39(s,3H).

[0858] Embodiment 49:

[0859] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-(2-methoxyethyl)azetidine-3-carboxamide (49)

[0860]

[0861] The experimental procedure was as described in Example 38, using compound 37 and 2-methoxyethylamine as reactants to obtain the title product.

[0862] MS (ESI) m / z [M+H] + =474.2.

[0863] 1 H NMR (400 MHz, DMSO-d 6 )δ8.14(br.s,1H),7.78(s,4H),7.28-7.00(m,3H),5.42(s,2H),4.17-4.02( m,2H),4.05-4.02(m,2H),3.52-3.48(m,1H),3.26-3.23(m,7H),2.39(s,3H).

[0864] Embodiment 50:

[0865] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)azetidine-3-carboxamide (50)

[0866]

[0867] The experimental procedure was as described in Example 38, using compound 37 and 4-amino-tetrahydropyran as reactants to obtain the title product.

[0868] MS (ESI) m / z [M+H] + =500.2.

[0869] 1 H NMR (400 MHz, DMSO-d 6 )δ7.98(d,J=8.0Hz,1H),7.78(s,4H),7.13(t,J=55.6Hz,1H),6.98(d,J=9.4Hz,1H),6.89(d,J=9.4Hz,1H),5.42(s,2H),4.05(t ,J=5.2Hz,2H),3.95(t,J=5.2Hz,2H),3.46-3.42(m,1H),3.35-3.30(m,2H),2.38(s,3H),1.71-1.66(m,2H),1.40-1.33(m,2H).

[0870] Embodiment 51:

[0871] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-(tetrahydrofuran-3-yl)azetidine-3-carboxamide (51)

[0872]

[0873] The experimental procedure was as described in Example 38, using compound 37 and 3-aminotetrahydrofuran as reactants to obtain the title product.

[0874] MS (ESI) m / z [M+H] + =486.2.

[0875] 1 H NMR (400 MHz, DMSO-d 6 )δ8.23(br.s,1H),7.78(s,4H),7.13(t,J=55.6Hz,1H),6.98(d,J=9.4Hz,1H),6.90(d,J=9.4Hz,1H),5.44(s,2H),4.25-4.22(m,1H),4.08- 4.03(m,2H),3.97-3.94(m,2H),3.78-3.71(m,2H),3.68-3.64(m,1H), 3.47-3.44(m,2H),2.39(s,3H),2.21-2.05(m,1H),1.73-1.68(m,1H).

[0876] Embodiment 52:

[0877] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-(pyridin-4-yl)azetidine-3-carboxamide (52)

[0878]

[0879] The experimental procedure was as described in Example 38, using compound 37 and 4-aminopyridine as reactants to obtain the title product.

[0880] MS (ESI) m / z [M+H] + =493.2.

[0881] 1 H NMR (400 MHz, DMSO-d 6 )δ11.44(s,1H),8.42(d,J=7.6Hz,2H),7.57(d,J=7.6Hz,2H),7.14(t,J=55.6Hz,1H),7.01(d,J=9 .4Hz,1H),6.95(d,J=9.4Hz,1H),5.44(s,2H),4.18-4.14(m,2H),3.75-3.69(m,2H),2.39(s,3H).

[0882] Embodiment 53:

[0883] 2-(1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)azetidin-3-yl)-5-methyl-1,3,4-oxadiazole (53)

[0884]

[0885] Step 1: Synthesis of N'-acetyl-1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)azetidine-3-carbohydrazide (53-1)

[0886] The experimental procedure was as described in Example 38, using 37 and acetylhydrazine as reactants to obtain the title product.

[0887] Step 2: Synthesis of 2-(1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)azetidin-3-yl)-5-methyl-1,3,4-oxadiazole (53)

[0888] 53-1 (150 mg, 0.22 mmol) and N,N-diisopropylethylamine (220 mg, 1.70 mmol) were dissolved in dichloromethane (15 mL), p-toluenesulfonyl chloride (320 mg, 1.70 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction was completed by LCMS monitoring. Saturated brine (20 mL) was added to the reaction solution, and it was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (dichloromethane: methanol = 20: 1) to obtain the title product (63 mg, white solid).

[0889] MS (ESI) m / z [M+H] + =455.2.

[0890] 1 H NMR (400 MHz, DMSO-d 6 )δ7.79(s,4H),7.14(t,J=55.6Hz,1H),7.04-6.97(m,2H),5.45(s,2H),4.39- 4.35(m,2H),4.25-4.22(m,1H),4.17-4.13(m,2H),2.39(s,3H),2.47(s,3H).

[0891] Embodiment 54:

[0892] (S)-8-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)hexahydro-2H-pyrazino[1,2-a]pyrazin-1-(6H)-one (54)

[0893]

[0894] Step 1: Synthesis of (S)-1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-ylpiperazine-2-carboxylic acid methyl ester (54-1)

[0895] 27-3 (110 mg, 0.24 mmol) was dissolved in acetonitrile (15 mL), and potassium carbonate (66 mg, 0.48 mmol) and tert-butyl N-(2-bromoethyl)carbamate (81 mg, 0.36 mmol) were added in sequence. The mixture was stirred at 60 ° C for 16 h. After the reaction was completed by LCMS monitoring, saturated brine (15 mL) was added to the reaction solution, and it was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 1:1 to 1:0) to obtain the title product (80 mg, colorless oil).

[0896] MS (ESI) m / z [M+H] + =603.3.

[0897] Step 2: Synthesis of (S)-1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-2-carboxylic acid methyl ester (54-2)

[0898] 54-1 (78 mg, 0.13 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS, and the pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate aqueous solution. It was extracted with dichloromethane (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the title product (65 mg, yellow solid).

[0899] MS (ESI) m / z [M+H] + =503.2.

[0900] Step 3: Synthesis of (S)-8-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)hexahydro-2H-pyrazino[1,2-a]pyrazin-1-(6H)-one (54)

[0901] 54-2 (50 mg, 0.099 mmol) was dissolved in N,N-dimethylformamide (5 mL), and the reaction solution was stirred at 60 ° C for 16 hours. After the reaction was completed by LCMS monitoring, saturated brine (30 mL) was added to the reaction solution, and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-35%) to obtain the title product (12 mg, white solid).

[0902] MS (ESI) m / z [M+H] +=471.2.

[0903] 1 H NMR (400 MHz, DMSO-d 6 )δ7.79(s,5H),7.40(d,J=9.6Hz,1H),7.13(t,J=56.0Hz,1H),6.99(d,J=9.6Hz,1H),5.45(s,2H),4.45-4.43(m,1H),4.02 -3.99(m,1H),3.37-3.35(m,1H),3.09-3.05(m,1H),2.95-2.85(m,3H),2.65-2.61(m,2H),2.39(s,3H),2.33-2.25(m,2H).

[0904] Embodiment 55:

[0905] (R)-8-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)hexahydro-2H-pyrazino[1,2-a]pyrazin-1-(6H)-one (55)

[0906]

[0907] The experimental operation was as described in Example 54, using intermediate 28-3 as the reactant, and undergoing alkylation, deprotection and cyclization reaction steps to obtain the title product.

[0908] MS (ESI) m / z [M+H] + =471.2.

[0909] 1 H NMR (400 MHz, DMSO-d 6 )δ7.79(s,5H),7.40(d,J=9.6Hz,1H),7.13(t,J=56.0Hz,1H),6.99(d,J=9.6Hz,1H),5.45(s,2H),4.45-4.43(m,1H),4.02 -3.99(m,1H),3.37-3.35(m,1H),3.08-3.05(m,1H),2.93-2.85(m,3H),2.64-2.61(m,2H),2.39(s,3H),2.33-2.24(m,2H).

[0910] Embodiment 56:

[0911] (S)-8-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridin-3-yl)octahydro-1H-pyrazino[1,2-a]pyrazin-1-one (56)

[0912]

[0913] Step 1: Synthesis of (S)-1-tert-butyl 2-methyl 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridin-3-yl)piperazine-1,2-dicarboxylate (56-1)

[0914] The experimental operation was as described in Example 1, using intermediate A10 and 27-1 as reactants to obtain the title product.

[0915] MS (ESI) m / z [M+H] + =559.2.

[0916] Step 2: Synthesis of (S)-methyl 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridin-3-yl)piperazine-2-carboxylate (56-2)

[0917] The experimental procedure was as described in step 2 of Example 27, using intermediate 56-1 as the reactant to obtain the title product.

[0918] MS (ESI) m / z [M+H] + =459.2.

[0919] Step 3: Synthesis of (S)-methyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3)-triazol-5-yl)methoxy)pyridin-3-yl)piperazine-2-carboxylate (56-3)

[0920] The experimental procedure was as described in step 1 of Example 54, using intermediate 56-2 and tert-butyl (2-bromoethyl)carbamate as reactants to give the title product.

[0921] MS (ESI) m / z [M+H] + =602.2.

[0922] Step 4: Synthesis of (S)-methyl 1-(2-aminoethyl)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)yl)pyridin-3-yl)piperazine-2-carboxylate (56-4)

[0923] The experimental procedure was as described in step 2 of Example 54, using intermediate 56-3 as the reactant to obtain the title product.

[0924] MS (ESI) m / z [M+H] + =502.2.

[0925] Step 5: Synthesis of (S)-8-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridin-3-yl)octahydro-1H-pyrazino[1,2-a]pyrazin-1-one (56)

[0926] The experimental procedure was as described in step 3 of Example 54, using intermediate 56-4 as the reactant to obtain the title product.

[0927] MS (ESI) m / z [M+H] + =470.2.

[0928] 1 H NMR (400 MHz, DMSO-d 6 )δ7.78(s,4H),7.69(s,1H),7.43(d,J=9.4Hz,1H),7.14(t,J=55.6Hz,1H),6.98(d,J=9.4Hz,1H),5.32(s,2H),3.77-3.71(m,1H) ,3.38-3.35(m,1H),3.09-3.05(m,1H),2.95-2.91(m,2H),2.71-2.66(m,2H),2.43-2.39(m,2H),2.38(s,3H),2.35-2.31(m,2H).

[0929] Embodiment 57:

[0930] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-5,6-dihydropyridin-2(1H)-one (57)

[0931]

[0932] Step 1: Synthesis of 6-oxo-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (57-2)

[0933] Under argon protection, piperidine-2,4-dione (1g, 8.8mmol) and triethylamine (1.8g, 17.7mmol) were dissolved in tetrahydrofuran (30mL), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (3.8g, 10.6mmol) was added, and stirred at room temperature for 16 hours. TLC monitored the completion of the reaction. The reaction solution was diluted with water (50mL) and extracted with ethyl acetate (50mL x3). The organic phases were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the title product (1.8g, white solid).

[0934] MS (ESI) m / z [M+H] + =245.9.

[0935] Step 2: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-2-2(1H)-one (57-3)

[0936] Under argon protection, 6-oxo-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (500 mg, 2.04 mmol) and biboronic acid pinacol ester (620 mg, 2.45 mmol) were dissolved in dioxane (20 mL), and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (150 mg, 0.20 mmol) and potassium acetate (400 mg, 4.08 mmol) were added in sequence, and stirred at 70 ° C for 1.5 hours. TLC monitored the completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product 57-3 (500 mg). The crude product was used directly in the next step without further purification.

[0937] MS (ESI) m / z [M+H] + =224.0.

[0938] Step 3: Synthesis of 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-5,6-dihydropyridin-2(1H)-one (57)

[0939] Under argon protection, 3-chloro-6-(((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine (100 mg, 0.28 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-2-2(1H)-one (69 mg, 0.31 mmol) were dissolved in a mixed solvent of dioxane (4 mL) and water (4 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21 mg, 0.028 mmol) and sodium carbonate (74 mg, 0.70 mmol) were added in sequence, and stirred at 95°C for 16 hours. The reaction was monitored by TLC. The reaction solution was poured into water (20 mL) for quenching, and ethyl acetate (30 mL x 4% acetic acid) was added. 2) Extraction. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 0: 1) and reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-40%) to obtain the title product (20 mg, white solid).

[0940] MS (ESI) m / z [M+H] + =413.1.

[0941] 1 H NMR (400 MHz, DMSO-d 6 )δ8.16(d,J=9.4Hz,1H),7.79(s,4H),7.67(s,1H),7.25(d,J=9.4Hz,1H),7.13(t,J=55 .6Hz,1H),6.52(s,1H),5.65(s,2H),3.39-3.34(m,2H),2.88-2.85(m,2H),2.42(s,3H).

[0942] Embodiment 58:

[0943] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(tetrahydrofuran-3-yl)piperazin-2-one (58)

[0944]

[0945] Step 1: Synthesis of 3-oxo-4-(tetrahydrofuran-3-yl)piperazine-1-carboxylic acid benzyl ester (58-2)

[0946] Under argon protection, tetrahydrofuran-3-ol (1g, 11.35mmol) and pyridine (1.18g, 14.87mmol) were dissolved in dichloromethane (30mL), cooled to -10℃ in an ice bath, and trifluoromethanesulfonic anhydride (2.3mL) was added dropwise. Stir at -10℃ for 30 minutes, then slowly warm to room temperature and continue stirring for 3 hours to obtain 3-trifluoromethanesulfonate-tetrahydrofuran solution. Under argon protection, 3-oxopiperazine-1-carboxylic acid benzyl ester (200mg, 0.85mmol) was dissolved in a mixed solvent of tetrahydrofuran (13mL) and N,N-dimethylformamide (0.5mL), and the temperature was lowered to -60℃. Potassium bis(trimethylsilyl)amide (1.2 mL, 1.2 mmol) was added dropwise, and the temperature was raised to -10°C after stirring for 30 minutes. After stirring for 1 hour, the 3-trifluoromethanesulfonate-tetrahydrofuran solution (220 mg, 1.02 mmol) prepared above was added, and the reaction was stirred at 20°C for 16 hours. The reaction was monitored by TLC. The reaction solution was quenched by adding pure water (30 mL), diluted with ethyl acetate (50 mL), and separated. The aqueous phase was extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 2:3) to obtain the title product (120 mg, colorless oil).

[0947] MS (ESI) m / z [M+H] + =305.1.

[0948] Step 2: Synthesis of 1-(tetrahydrofuran-3-yl)piperazin-2-one (58-3)

[0949] 3-Oxo-4-(tetrahydrofuran-3-yl)piperazine-1-carboxylic acid benzyl ester (120 mg, 0.39 mmol) was dissolved in methanol (20 mL), and palladium / carbon (20 mg, 10%) was added to the reaction solution. After the reaction system was replaced with hydrogen three times, it was stirred at room temperature for 16 h under a hydrogen atmosphere. The reaction was monitored by TLC. The reaction solution was filtered, the catalyst was removed, and the title product 58-3 (60 mg, colorless oil) was obtained by concentration under reduced pressure.

[0950] MS (ESI) m / z [M+H] + =171.1.

[0951] Step 3: 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(tetrahydrofuran-3-yl)piperazin-2-one (58)

[0952] The experimental procedure was as described in Example 1, using A8 and intermediate 58-3 as reactants to obtain the title product.

[0953] MS (ESI) m / z [M+H] + =486.2.

[0954] 1 H NMR (400 MHz, DMSO-d 6 )δ7.78(s,4H),7.37(d,J=9.6Hz,1H),7.13(t,J=55.6Hz,1H),7.04(d,J=9.6Hz,1H),5.45(s,2H),5.12-5.08(m,1H),4.05(s,2H) ,3.91-3.89(m,1H),3.68-3.72(m,3H),3.67-3.53(m,2H),3.40-3.36(m,2H),2.39(s,3H),2.18-2.07(m,1H),1.87-1.83(m,1H).

[0955] Embodiment 59:

[0956] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(2-hydroxyethyl)piperazin-2-one (59)

[0957]

[0958] Step 1: Synthesis of tert-butyl 4-(2-((tert-butyldimethylsilyl)oxy)ethyl-3-oxopiperazine-1-carboxylate (59-2)

[0959] Under nitrogen protection, compound 59-1 (1.0 g, 4.99 mmol) was dissolved in N, N-dimethylformamide (20.0 mL), sodium hydride (399 mg, 9.99 mmol, 60%) was added in batches, stirred for half an hour, compound (2-bromoethoxy)-tert-butyldimethylsilane (2.99 g, 12.5 mmol) was added, and the stirring reaction was continued for 15 hours. The reaction solution was quenched with water (10 mL), concentrated under reduced pressure to remove the solvent, diluted with water (100 mL), extracted with dichloromethane (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1-1:1) to obtain the title product (1.43 g, colorless oily liquid).

[0960] 1 H NMR (400 MHz, CDCl 3)δ4.08(s,2H),3.81(t,J=5.2Hz,2H),3.68-3.58(m,2H),3.55-3.47(m,4H),1.48(s,9H),0.89(s,9H),0.05(s,6H).

[0961] Step 2: Synthesis of 1-(2-hydroxyethyl)piperazin-2-one (59-3)

[0962] At room temperature, compound 59-2 (630 mg, 1.68 mmol) was dissolved in dichloromethane (5 mL), and a solution of hydrogen chloride in ethyl acetate (5 mL, 4.0 M) was added, and the mixture was stirred for half an hour. The reaction solution was concentrated under reduced pressure to obtain the title product (250 mg, yellow solid), which was used directly in the next step without further purification.

[0963] 1 H NMR (400MHz, CD 3 OD)δ3.85(s,2H),3.79-3.73(m,4H),3.50-3.29(m,4H)

[0964] Step 3: Synthesis of 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(2-hydroxyethyl)piperazin-2-one (59)

[0965] The experimental operation was as described in Example 1, using A8 and intermediate 59-3 as reactants to obtain the title product.

[0966] MS (ESI) m / z [M+H] + =460.2.

[0967] 1 H NMR (400 MHz, CD 3 OD)δ7.77(s,4H),7.34(d,J=9.6Hz,1H),7.01(d,J=9.6Hz,1H),6.89(t,J=55.6Hz,1H),5.50(s,2H),4 .60(s,2H),3.83-3.78(m,2H),3.77-3.72(m,2H),3.67-3.62(m,2H),3.60-3.55(m,2H),2.47(s,3H).

[0968] Embodiment 60:

[0969] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(pyridin-2-ylmethyl)piperazin-2-one (60)

[0970]

[0971] The experimental operation is as described in step 1 of Example 59 and steps 2-3 of Example 58. The starting materials are benzyl 3-oxopiperazine-1-carboxylate and 2-(chloromethyl)pyridine. After alkylation, deprotection and coupling reaction steps, the title product is obtained.

[0972] MS (ESI) m / z [M+H] + =507.2.

[0973] 1 H NMR (400 MHz, DMSO-d 6 )δ8.51(d,J=8.0Hz,1H),7.78(s,4H),7.74(dd,J=7.6,8.0Hz,1H),7.43(d,J=9.4Hz,1H),7.28-7.24(m,2H),7.13(t,J=55.6Hz ,1H),7.05(d,J=9.4Hz,1H),5.46(s,2H),4.65(s,2H),4.14(s,2H),3.78(t,J=5.2Hz,2H),3.47(t,J=5.2Hz,2H),2.39(s,3H).

[0974] Example 61:

[0975] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(2-(pyrrolidin-1-yl)ethyl)piperazin-2-one (61)

[0976]

[0977] The experimental procedure was as described in Example 59. The starting materials were tert-butyl 3-oxopiperazine-1-carboxylate and 1-(2-chloroethyl)pyrrolidine. After alkylation, deprotection and coupling reaction steps, the title product was obtained.

[0978] MS (ESI) m / z [M+H] + =513.2.

[0979] 1 H NMR (400 MHz, CD 3OD)δ7.76(s,4H),7.34(d,J=9.6Hz,1H),7.01(d,J=9.6Hz,1H),6.90(t,J=55.6Hz,1H),5.50(s,2H),4.17(s,2H),3.83(t,J=5.2Hz,2 H),3.69(t,J=6.4Hz,2H),3.60-3.56(m,2H),2.99-2.91(m,2H),2.91-2.81(m,4H),2.47(s,2H),2.52-2.43(m,1H),1.95-1.85(m,4H)

[0980] Embodiment 62:

[0981] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(2,2,2-trifluoroethyl)piperazin-2-one (62)

[0982]

[0983] The experimental procedure was as described in Example 59. The starting materials were tert-butyl 3-oxopiperazine-1-carboxylate and 2,2,2-trifluoroethyl trifluoromethanesulfonate. After alkylation, deprotection and coupling reaction steps, the title product was obtained.

[0984] MS (ESI) m / z [M+H] + =498.1.

[0985] 1 H NMR (400MHz, CD 3 OD)δ7.76(s,4H),7.35(d,J=9.4Hz,1H),7.03(d,J=9.4Hz,1H),6.88(t,J=55.6Hz,1H),5.51 (s,2H),4.26(s,2H),4.24-4.19(m,4H),3.85-3.82(m,2H),3.70-3.67(m,2H),2.48(s,3H).

[0986] Embodiment 63:

[0987] 2-(4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)morpholin-2-yl)-N-ethylacetamide (63)

[0988]

[0989] Step 1: Synthesis of tert-butyl 2-(2-(ethylamino)-2-oxoethyl)morpholine-4-carboxylate (63-2)

[0990] At room temperature, compound 63-1 (250 mg, 1.01 mmol), ethylamine hydrochloride (98.0 mg, 1.22 mmol), HOBt (179 mg, 1.32 mmol), EDCI (254 mg, 1.32 mmol), diisopropylethylamine (395 mg, 3.05 mmol) were added to anhydrous dichloromethane (10.0 mL) in sequence, and nitrogen was replaced 3 times. The reaction mixture was stirred at room temperature for 12 hours. TLC showed that the reaction was complete. Dichloromethane (100 mL) was added to the reaction solution, and the organic phase was washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain (260 mg, yellow oil).

[0991] 1 H NMR (400MHz, CD 3 OD)δ3.92(d,J=12.8Hz,1H),3.83-3.80(m,3H),3.51-3.48(m1H),3.22-3.18(m,2H),2.39-2.27(m,2H),1.46(s,9H),1.11(t,J=7.2Hz,3H)

[0992] Step 2: Synthesis of N-ethyl-2-(morpholin-2-yl)acetamide (63-3)

[0993] At room temperature, compound 63-2 (260 mg, 0.955 mmol) was dissolved in anhydrous dichloromethane (4.0 mL), and hydrogen chloride / ethyl acetate (2 mL, 4.0 M) was added to the mixture, and nitrogen was replaced 3 times. The mixture was reacted at 16°C for 2 hours. TLC showed that the raw material was completely reacted. The reaction solution was concentrated under reduced pressure to obtain (160 mg, white solid, crude product).

[0994] 1 H NMR (400MHz, CD 3 OD)δ4.16-4.01(m,2H),3.84-3.81(m,1H),3.36(d,J=12.4Hz,1H),3.29-3. 08(m,4H),2.97(t,J=12.0Hz,1H),2.47-2.37(m,2H),1.12(t,J=7.2Hz,3H)

[0995] Step 3: Synthesis of 2-(4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)morpholin-2-yl)-N-ethylacetamide (63)

[0996] The experimental procedure was as described in Example 1, using A8 and intermediate 63-3 as reactants to obtain the title product.

[0997] MS (ESI) m / z [M+H] + =488.0.

[0998] 1 H NMR (400MHz, CD 3 OD)δ7.76(s,4H),7.34(d,J=9.6Hz,1H),7.04-6.73(m,2H),5.50(s,2H),4.04-3.92(m,3H),3.88(d,J=13.2Hz,1H),3.72-3 .70(m,1H),3.27-3.18(m,2H),2.99-2.97(m,1H),2.73-2.71(m,1H),2.47(s,3H),2.45-2.35(m,2H),1.13(t,J=7.2Hz,3H)

[0999] Embodiment 64:

[1000] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-methylpyrrolidine-3-sulfonamide (64)

[1001]

[1002] Step 1: Synthesis of tert-butyl 3-(N-methylsulfonylamino)pyrrolidine-1-carboxylate (64-2)

[1003] At room temperature, compound 64-1 (125 mg, 0.46 mmol) was dissolved in anhydrous dichloromethane (5.0 mL), and methylamine ethanol solution (247 mg, 2.32 mmol, 30%) was slowly added dropwise, and the reaction was stirred for 1 h. The reaction endpoint was monitored by TLC. The reaction solution was concentrated under reduced pressure to obtain the title product (150 mg, yellow oily liquid).

[1004] 1 H NMR (400MHz, CD 3OD)δ3.95-3.84(m,1H),3.72-3.64(m,2H),3.57-3.51(m,1H),3.45-3.36(m,1H),2.55(s,3H),2.34-2.24(m,2H),1.47(s,9H).

[1005] Step 2: Synthesis of N-methylpyrrolidine-3-sulfonamide (64-3)

[1006] The experimental procedure was as described in step 2 of Example 59, using 64-2 as the reactant to obtain the title product.

[1007] 1 H NMR (400MHz, CD 3 OD)δ4.15-4.06(m,1H),3.73-3.58(m,2H),3.54-3.36(m,2H),2.55(s,3H),2.50-2.41(m,2H)

[1008] Step 3: Synthesis of 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-methylpyrrolidine-3-sulfonamide (64)

[1009] The experimental operation was as described in Example 1, using A8 and intermediate 64-3 as reactants to obtain the title product.

[1010] MS (ESI) m / z [M+H] + =480.1.

[1011] 1 H NMR (400MHz, CD 3 OD)δ7.77(s,4H),7.09-7.05(m,1H),7.02-6.74(m,2H),5.48(s,2H),4.09-4.01(m,1H),3.86-3 .81(m,2H),3.71-3.67(m,1H),3.57-3.50(m,1H),2.76(s,3H),2.47(s,3H),2.46-2.43(m,2H).

[1012] Embodiment 65:

[1013] (R)-8-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)hexahydro-1H-pyrazino[1,2-a]pyrazine-1,4(6H)-dione (65)

[1014]

[1015] Step 1: Synthesis of (R)-1-((benzyloxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (65-2)

[1016] At room temperature, compound 65-1 (2.00 g, 8.70 mmol) was dissolved in dioxane (20.0 mL) and water (20.0 mL), and then solid sodium bicarbonate (1.46 g, 17.4 mmol) and benzyl chloroformate (1.78 g, 10.4 mmol) were added, and the reaction solution was stirred at 25°C for 16 hours. LCMS detected the formation of the product. The reaction solution was diluted with water (20.0 mL) and the pH was adjusted to about 3-4 with hydrochloric acid (1.0 M), and then extracted with ethyl acetate (20.0 mL x 3). The organic phases were combined and concentrated to dryness under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain (2.36 g, colorless oil).

[1017] MS (ESI) m / z [Mt-Bu+H] + =306.1.

[1018] 1 H NMR (400 MHz, CDCl 3 )δ7.35-7.31(m,5H),5.22-5.13(m,2H),4.83-4.58(m,2H),3.99-3.88(m,2H),3.32-3.08(m,2H),2.86-2.83(m,1H),1.43(s,9H).

[1019] Step 2: Synthesis of (R)-1-benzyl 4-tert-butyl 2-((2-methoxy-2-oxoethyl)carbamoyl)piperazine-1,4-dicarboxylate (65-3)

[1020] At room temperature, compound 65-2 (1.00 g, 2.70 mmol) was dissolved in anhydrous dichloromethane (25.0 mL), HOBt (556 mg, 4.1 mmol), EDCI (789 mg, 4.1 mmol), diisopropylethylamine (1.06 g, 8.2 mmol) and glycine methyl ester hydrochloride (0.4 g, 3.24 mmol) were added, and the reaction solution was stirred at 25 ° C for 3 hours. LCMS detected the formation of the product. The reaction solution was diluted with water (25.0 mL) and extracted with dichloromethane (25.0 mL x 3). The organic phases were combined and concentrated to dryness under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain (800 mg, colorless oil).

[1021] MS (ESI) m / z [Mt-Bu+H] + =380.1.

[1022] 1 H NMR (400 MHz, CDCl 3 )δ7.35-7.26(m,5H),6.73-6.58(m,1H),5.19-5.15(m,2H),4.72-4.49(m,2H),4.05-3.92( m,2H),3.91-3.90(m,2H),3.73(s,3H),3.25-3.12(m,2H),3.00-2.96(m,1H),1.44(s,9H).

[1023] Step 3: Synthesis of (R)-6,9-dioxohexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylic acid tert-butyl ester (65-4)

[1024] At room temperature, compound 65-3 (800 mg, 1.84 mmol) was dissolved in methanol (10.0 mL), 10% wet palladium / carbon (100 mg) was added, the reaction solution was replaced with hydrogen three times, and then reacted at 20°C for 16 hours under a hydrogen atmosphere (15 psi). LCMS detected the formation of the product. The reaction solution was filtered and the filter cake was washed with methanol (25.0 mL). The organic phases were combined and concentrated to dryness under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain (300 mg, white solid).

[1025] MS (ESI) m / z [M-Boc+H] + =214.1.

[1026] 1 H NMR (400 MHz, CDCl 3 )δ6.95(s,1H),4.56-4.53(m,2H),4.15-4.07(m,3H),3.96(dd,J=4.0,10.8Hz,1H),2.84-2.73(m,2H),2.70-2.67(m,1H),1.47(s,9H).

[1027] Step 4: Synthesis of (R)-hexahydro-1H-pyrazino[1,2-a]pyrazine-1,4-(6H)-dione (65-5)

[1028] At room temperature, compound 65-4 (300 mg, 1.11 mmol) was dissolved in dichloromethane (3.0 mL), and hydrochloric acid / ethyl acetate solution (1.5 mL, 4.0 M) was slowly added dropwise, and the reaction solution was stirred at 20°C for 3 hours. LCMS detected that the raw material had been consumed. The reaction solution was directly concentrated to obtain the hydrochloride of the title product (212 mg, white solid, crude product).

[1029] 1 H NMR (400 MHz, CDCl 3 )δ4.87-4.68(m,1H),4.45-4.41(m,1H),4.03-4.02(m,2H),3.79-3.75(m ,1H),3.49(d,J=11.6Hz,1H),3.25(t,J=12.4Hz,1H),3.10-3.01(m,2H).

[1030] Step 5: Synthesis of (R)-8-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)hexahydro-1H-pyrazino[1,2-a]pyrazine-1,4(6H)-dione (65)

[1031] The experimental procedure was as described in Example 1, using A8 and intermediate 65-5 as reactants to obtain the title product.

[1032] MS (ESI) m / z [M+H] + =485.1.

[1033] 1 H NMR (400 MHz, CD 3 OD)δ7.77(s,4H),7.43(d,J=9.4Hz,1H),7.03-6.75(m,2H),5.51(s,2H),4.59-4.54(m, 2H),4.23-4.19(m,2H),4.02(s,2H),3.08-3.02(m,1H),3.00-2.95(m,2H),2.48(s,3H).

[1034] Embodiment 66:

[1035] 3-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-5-(hydroxymethyl)oxazolidin-2-one (66)

[1036]

[1037] Step 1: Synthesis of 5-(((tert-butyldimethylsilyl)oxy)methyl)oxazolidin-2-one (66-2)

[1038] Under argon protection, 66-1 (300 mg, 2.56 mmol) and imidazole (348 mg, 5.12 mmol) were dissolved in N,N-dimethylformamide (10 mL), tert-butylchlorodimethylsilane (463 mg, 3.07 mmol) was added, and the reaction was stirred at 25 ° C for 2 hours. TLC monitoring of the reaction was complete. The reaction solution was quenched by adding water (50 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product (330 mg, yellow oil) was obtained.

[1039] MS (ESI) m / z [M+H] + =232.1.

[1040] Step 2: Synthesis of 5-(((tert-butyldimethylsilyl)oxy)methyl)-3-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)oxazolidin-2-one (66-3)

[1041] The experimental operation was as described in Example 18, using A8 and 66-2 as reactants in toluene to obtain the title product.

[1042] MS (ESI) m / z [M+H] + =547.2.

[1043] Step 3: Synthesis of 3-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-5-(hydroxymethyl)oxazolidin-2-one (66)

[1044] Under argon protection, 66-3 (60 mg, 0.11 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (3 mL, 1.5 M) was added, and the reaction was stirred at 25 ° C for 2 hours. TLC monitored the completion of the reaction. Water (30 mL) was added to the reaction solution, and ethyl acetate (50 mL x 2) was extracted. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 0: 1) and reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-40%) to obtain the title product (13 mg, white solid).

[1045] MS (ESI) m / z [M+H] +=433.1.

[1046] 1 H NMR (400 MHz, DMSO-d 6 )δ8.32(d,J=9.8Hz,1H),7.78(s,4H),7.26(d,J=9.8Hz,1H),7.13(t,J=55.6Hz,1H),5.55(s,2H),5.24-5.2 2(m,1H),4.76-4.74(m,1H),4.19(t,J=9.6Hz,1H),4.00-3.98(m,1H),3.70-3.68(m,1H),3.61-3.53(m,1H).

[1047] Embodiment 67:

[1048] 1-(2-Aminoethyl)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (67)

[1049]

[1050] Step 1: Synthesis of benzyl 4-(2-(((tert-butyloxycarbonyl)-1-2-azaalkyl)ethyl)-3-oxopiperazine-1-carboxylate (67-1)

[1051] Under argon protection, 58-1 (700 mg, 2.99 mmol) was dissolved in N,N-dimethylformamide (20 mL), sodium hydride (160 mg, 6.58 mmol, 60%) was added, the reaction was stirred at 25 ° C for 10 minutes, tert-butyl bromoethylcarbamate (740 mg, 3.29 mmol) was added, and the reaction was stirred at 25 ° C for 16 hours. TLC monitoring of the reaction was completed. The reaction solution was quenched by adding water (50 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-40%) to obtain the title product (200 mg, yellow oily liquid).

[1052] MS (ESI) m / z [M+H] + =378.2.

[1053] Step 2: Synthesis of tert-butyl (2-(2-oxopiperazin-1-yl)ethyl)carbamate (67-2)

[1054] Under argon protection, 67-1 (150 mg, 0.4 mmol) was dissolved in methanol (20 mL), palladium carbon (40 mg) was added, and hydrogen was replaced three times. The reaction was stirred at 25 ° C for 16 hours under hydrogen atmosphere. TLC monitored the completion of the reaction. The reaction solution was filtered, the filter cake was washed with methanol (10 mL x2), and the filtrate was concentrated under reduced pressure to obtain the title product (80 mg, yellow oily liquid).

[1055] MS (ESI) m / z [M+H] + =244.1.

[1056] Step 3: Synthesis of tert-butyl (2-(4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-2-oxopiperazin-1-yl)ethyl)carbamate (67-3)

[1057] The experimental operation was as described in Example 1, using intermediate A8 and intermediate 67-2 as reactants to obtain the title product.

[1058] MS (ESI) m / z [M+H] + =559.2.

[1059] Step 4: Synthesis of 1-(2-aminoethyl)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (67)

[1060] Under argon protection, 67-3 (40 mg, 0.072 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at 25 ° C for 2 hours. TLC monitoring of the reaction was complete. The reaction solution was quenched by adding saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-40%) to give the title product (2 mg, white solid).

[1061] MS (ESI) m / z [M+H] + =459.2.

[1062] 1 H NMR (400 MHz, DMSO-d 6)δ7.78(s,4H),7.40(d,J=9.6Hz,1H),7.13(t,J=55.6Hz,1H),7.04(d,J=9.6Hz,1H),5.44(s,2H),4.45(br.s ,2H),4.02(s,2H),3.73-3.71(m,2H),3.47-3.45(m,2H),3.30-3.27(m,2H),2.66-2.65(m,2H),2.38(s,3H).

[1063] Embodiment 68:

[1064] 2-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)hexahydro-1H-pyrazino[1,2-a]pyrazin-4-(6H)-one (68)

[1065]

[1066] Step 1: Synthesis of tert-butyl 4-(2-(((benzyloxy)carbonyl)amino)acetyl)-3-(hydroxymethyl)piperazine-1-carboxylate (68-2)

[1067] At room temperature, 68-1 (1000 mg, 4.62 mmol), HOBt (625 mg, 4.63 mol), EDCI (886 mg, 4.62 mmol), triethylamine (936 mg, 9.25 mmol) and N-benzyloxycarbonylglycine (645 mg, 3.08 mmol) were dissolved in dichloromethane (20 mL) in sequence and reacted at 20°C for 16 hours. LCMS showed that the product was generated. The reaction solution was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (methanol: dichloromethane = 1:20) to obtain the title product (800 mg, white solid).

[1068] (ESI)m / z[M+H] + =408.2.

[1069] 1 H NMR (400 MHz, CDCl 3 )δ7.36-7.30(m,5H),5.79(s,1H),5.11(s,2H),4.63-4.36(m,1H),4.14-3.99(m,4H),3.82-3.26(m,4H),2.96-2.86(m,2H),1.46(s,9H).

[1070] Step 2: Synthesis of tert-butyl 4-(2-(((benzyloxy)carbonyl)amino)acetyl)-3-formylpiperazine-1-carboxylate (68-3)

[1071] At -60 ° C, oxalyl chloride (206 mg, 1.62 mmol) was slowly added dropwise to a solution of dimethyl sulfoxide (230 mg, 2.94 mmol) in anhydrous dichloromethane (5.0 mL) and stirred for 5 minutes. A solution of compound 68-2 (600 mg, 1.47 mmol) in anhydrous dichloromethane (5.0 mL) was slowly added dropwise to the above solution and continued to stir for 15 minutes. Triethylamine (745 mg, 7.36 mmol) was added dropwise, and the reaction solution was slowly warmed to room temperature and stirred for 1 hour. TLC showed that the reaction was complete. Water (10.0 mL) was added to quench the reaction and extracted with dichloromethane (10 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (methanol: dichloromethane = 1:20) to obtain the title product (300 mg, colorless oil), which was directly used in the next step without further purification.

[1072] Step 3: Synthesis of tert-butyl 6-oxo-hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (68-4)

[1073] At room temperature, 68-3 (150 mg, 0.74 mol) was dissolved in methanol (5 mL), and then 10% wet palladium / carbon (30 mg) was added. The hydrogen was replaced three times, and the reaction solution was stirred at 20 ° C under a hydrogen atmosphere for 16 hours. TLC showed that the reaction was complete. The reaction solution was filtered and the filter cake was washed with methanol (10 mL). The filtrate was combined and concentrated under reduced pressure to obtain the title product (100 mg, colorless oil).

[1074] MS (ESI) m / z [M+H] + =256.2.

[1075] Step 4: Synthesis of tert-butyl 8-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-6-oxohexahydro-1H-pyrazino[1,2-a]pyrazine-2-(6H)-carboxylate (68-5)

[1076] The experimental procedure was as described in Example 1, using A8 and intermediate 68-4 as reactants to obtain the title product.

[1077] MS (ESI) m / z [M+H] + =571.2.

[1078] Step 5: Synthesis of 2-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)hexahydro-1H-pyrazino[1,2-a]pyrazin-4-(6H)-one (68)

[1079] At room temperature, 68-5 (137.0 mg, 0.24 mmol, 84%) was dissolved in anhydrous dichloromethane (4.0 mL), and hydrochloric acid / ethyl acetate solution (2 mL, 4.0 M) was added dropwise, and the reaction solution was stirred at 20°C for 2 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to remove the solvent, and the crude product was separated by high performance liquid chromatography (chromatographic column: Phenomenex C18 80*40mm*3um; mobile phase: water (0.05% ammonia water)-acetonitrile]; B%: 23%-53%, 8min; flow rate: 30ml / min) to obtain the title product (25.8 mg, light yellow solid).

[1080] MS (ESI) m / z [M+H] + =471.2.

[1081] 1 H NMR (400MHz, CD 3 OD)δ7.76(s,4H),7.39(d,J=9.4Hz,1H),7.01(d,J=9.4Hz,1H),6.89(t,J=55.6Hz,1H),5.50(s,2H),4.51-4.48(m,1H),4.39-4.35(m,1H),4.1 6-4.14(m,1H),4.01-3.96(m,1H),3.65-3.61(m,1H),3.27-3.24(m,1H) ,3.04-3.01(m,2H),2.69-2.65(m,2H),2.56-2.51(m,1H),2.47(s,3H).

[1082] Embodiment 69:

[1083] 2-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-8-methylhexahydro-1H-pyrazino[1,2-a]pyrazin-4(6H)-one (69)

[1084]

[1085] Example 68 (70.0 mg, 0.17 mmol, hydrochloride) was dissolved in anhydrous methanol (2.0 mL) at room temperature, and triethylamine (34.5 mg, 0.34 mol) was added. The reaction solution was stirred at 20°C for 30 minutes and then concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (2.0 ml), and 37% formaldehyde aqueous solution (138 mg, 1.7 mmol) and formic acid (78.3 mg, 1.7 mmol) were added in sequence. The reaction solution was replaced with nitrogen and stirred at 20°C for 1 hour. Sodium cyanoborohydride (32 mg, 0.51 mmol) was added and stirring was continued for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (10 mL), and extracted with dichloromethane (10 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was separated by high performance liquid chromatography (chromatographic column: Boston Green ODS150*30mm*5um; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile]; B%: 10%-40%, 7min; flow rate: 35ml / min) to give the title product (16.0mg, white solid).

[1086] MS (ESI) m / z [M+H] + =485.2.

[1087] 1 H NMR (400MHz, CD 3 OD)δ7.76(s,4H),7.39(d,J=9.4Hz,1H),7.01(d,J=9.4Hz,1H),6.89(t,J=55.6 Hz,1H),5.50(s,2H),4.55-4.52(m,1H),4.39-4.35(m,1H),4.23-4.20(m,1H),3 .99-3.95(m,1H),3.75-3.71(m,1H),3.32-3.29(m,1H),3.01-2.91(m,2H),2.8 3-2.80(m,1H),2.47(s,3H),2.36(s,3H),2.08-2.05(m,1H),2.00-1.95(m,1H).

[1088] Embodiment 70:

[1089] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridin-3-yl)piperazin-2-one (70)

[1090]

[1091] Step 1: Synthesis of tert-butyl 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridin-3-yl)-3-oxopiperazine-1-carboxylate (70-1)

[1092] Under argon protection, A10 (0.13 g, 0.33 mmol) and tert-butyl 3-oxapiperazine-1-carboxylate (66 mg, 0.33 mmol) were dissolved in toluene (1 mL), and N1, N2-dimethylethane-1, 2-diamine (29 mg, 0.033 mmol), potassium phosphate (140 mg, 0.66 mmol) and cuprous iodide (63 mg, 0.033 mmol) were added in sequence, and stirred at 110 ° C for 16 hours. TLC monitored the completion of the reaction. The reaction solution was diluted with dichloromethane (100 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 0: 1) to obtain the title product (85 mg, yellow solid).

[1093] MS (ESI) m / z [M+H] + =515.2.

[1094] Step 2: 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridin-3-yl)piperazin-2-one (70)

[1095] Under argon protection, 70-1 (82 mg, 0.16 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added dropwise, and the reaction was stirred at room temperature for 2 hours. The reaction was completed by LCMS monitoring. At 0°C, the reaction solution was poured into a saturated sodium bicarbonate solution (100 mL) and extracted with dichloromethane (80 mL x 2, containing 10% methanol). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-40%) to obtain the title product (33 mg, yellow solid).

[1096] MS (ESI) m / z [M+H] + =416.2.

[1097] 1 H NMR (400 MHz, DMSO-d 6)δ8.06(d,J=2.6Hz,1H),7.80(s,4H),7.68(dd,J=2.6,8.8Hz,1H),7.22(t,J=55.6Hz,1H),6.82(d,J=8.8Hz ,1H),5.41(s,2H),3.55(t,J=5.2Hz,2H),3.37(s,2H),2.99(t,J=5.2Hz,2H),2.76(br.s,1H),2.40(s,3H).

[1098] Embodiment 71:

[1099] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-one (71)

[1100]

[1101] Step 1: Synthesis of tert-butyl 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-3-oxopiperazine-1-carboxylate (71-1)

[1102] The experimental procedure was as described in Example 18, using A8 and tert-butyl 3-oxapiperazine-1-carboxylate as reactants to give the title product.

[1103] MS (ESI) m / z [M+H] + =516.2.

[1104] Step 2: Synthesis of 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-one (71)

[1105] Under argon protection, 71-1 (50 mg, 0.097 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at 25 ° C for 2 hours. TLC monitored the completion of the reaction. The reaction solution was quenched by adding saturated sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 0: 1) and reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-40%) to obtain the title product (13 mg, white solid).

[1106] MS (ESI) m / z [M+H] + =416.2.

[1107] 1 H NMR (400 MHz, DMSO-d 6 )δ7.91(d,J=9.4Hz,1H),7.78(s,4H),7.18(d,J=9.4Hz,1H),7.12(t,J=55.6Hz,1H), 5.56(s,2H),3.83(t,J=5.4Hz,2H),3.43(s,2H),3.01(t,J=5.4Hz,2H),2.40(s,3H).

[1108] Embodiment 72:

[1109] 4-(6-((1-(5-chloropyridin-2-yl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (72)

[1110]

[1111] The experimental operation was as described in Example 1, using intermediate B4 and 2-piperazinone as reactants to obtain the title product.

[1112] MS (ESI) m / z [M+H] + =401.2.

[1113] 1 H NMR (400 MHz, DMSO-d 6 )δ8.59(d,J=2.4Hz,1H),8.24(dd,J=8.8,2.4Hz,1H),8.07(s,1H),8.00(d,J=8.8Hz,1H),7.37(d,J=9.6Hz,1H ),6.98(d,J=9.6Hz,1H),5.79(s,2H),3.96(s,2H),3.65(t,J=5.2Hz,2H),3.27(t,J=5.2Hz,2H),2.38(s,3H).

[1114] Embodiment 73:

[1115] 4-(6-((1-(5-fluoropyridin-2-yl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (73)

[1116]

[1117] The experimental operation was as described in Example 1, using intermediate C4 and 2-piperazinone as reactants to obtain the title product.

[1118] MS (ESI) m / z [M+H]+ =385.2.

[1119] 1 H NMR (400 MHz, DMSO-d 6 )δ8.55(s,1H),8.10-7.97(m,3H),7.36(d,J=9.8Hz,1H),6.96(d,J=9.8Hz,1H) ,5.74(s,2H),3.95(s,2H),3.65-3.67(m,2H),3.28-3.24(m,2H),2.37(s,3H).

[1120] Embodiment 74:

[1121] 4-(6-((1-(6-(difluoromethyl)pyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (74)

[1122]

[1123] The experimental operation was as described in Example 1, using intermediate D4 and 2-piperazinone as reactants to obtain the title product.

[1124] MS (ESI) m / z [M+H] + =417.2.

[1125] 1 H NMR (400 MHz, DMSO-d 6 )δ8.97(s,1H),8.32(d,J=8.6Hz,1H),8.06(s,1H),7.94(d,J=8.2Hz,1H),7.38(d,J=9.6Hz,1H),7.06(t,J=54 .8Hz,1H),7.01(d,J=9.6Hz,1H),5.49(s,2H),3.96(s,2H),3.65-3.63(m,2H),3.27-3.25(m,2H),2.41(s,3H).

[1126] Embodiment 75:

[1127] 4-(6-((1-(4-cyanophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (75)

[1128]

[1129] The experimental operation was as described in Example 1, using intermediate E4 and 2-piperazinone as reactants to obtain the title product.

[1130] MS (ESI) m / z [M+H] + =391.2.

[1131] 1 H NMR (400 MHz, DMSO-d 6 )δ8.09-8.07(m,3H),7.86(d,J=8.4Hz,2H),7.40(d,J=9.6Hz,1H),7.01(d,J=9.6Hz, 1H),5.49(s,2H),3.97(s,2H),3.66(t,J=5.2Hz,2H),3.33-3.27(m,2H),2.39(s,3H).

[1132] Embodiment 76:

[1133] 4-(6-((1-(4-Fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (76)

[1134]

[1135] The experimental operation was as described in Example 1, using intermediate F4 and 2-piperazinone as reactants to obtain the title product.

[1136] MS (ESI) m / z [M+H] + =384.1.

[1137] 1 H NMR (400MHz, CD 3 OD)δ7.70-7.61(m,2H),7.38-7.28(m,3H),7.02(d,J=9.6Hz,1H),5.45( s,2H),4.13(s,2H),3.80-3.71(m,2H),3.51-3.42(m,2H),2.46(s,3H).

[1138] Embodiment 77:

[1139] (S)-8-(6-((1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)octahydro-1H-pyrazino[1,2-a]pyrazin-1-one (77)

[1140]

[1141] Step 1: Synthesis of (S)-1-tert-butyl 3-methyl 4-(2-(((benzyloxy)carbonyl)amino)ethyl)piperazine-1,3-dicarboxylate (77-2)

[1142] At room temperature, 77-1 (1.0 g, 4.09 mmol) and 77-1 (1.27 g, 4.91 mmol) were dissolved in anhydrous DMF (15.0 mL), potassium carbonate (678 mg, 4.91 mmol) was added, and the mixture was reacted at 100°C for 16 hours. TLC showed that the reaction was complete. The reaction solution was diluted with water (40 mL), extracted with dichloromethane (30 mL x 3), the organic phases were combined, washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (methanol: dichloromethane = 0:1 to 1:10) to obtain the title product (370 mg, yellow oil).

[1143] MS (ESI) m / z [M+H] + =422.5.

[1144] Step 2: Synthesis of (S)-tert-butyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylic acid tert-butyl ester (77-3)

[1145] At room temperature, 77-2 (370 mg, 0.87 mmol) was dissolved in methanol (6.0 mL), palladium / carbon (30 mg, 10%) was added, and the reaction was carried out for 16 hours under a hydrogen (15 psi) atmosphere. TLC showed that the reaction was complete. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the title product (210 mg, yellow oil).

[1146] Step 3: Synthesis of (S)-octahydro-1H-pyrazino[1,2-a]pyrazin-1-one (77-4)

[1147] At room temperature, 77-2 (60 mg, 0.24 mmol) was dissolved in anhydrous dichloromethane (4.0 mL), and hydrochloric acid / ethyl acetate solution (4.0 mL, 4.0 M) was slowly added dropwise, and the reaction was stirred for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the title product (50 mg, yellow solid, hydrochloride).

[1148] Step 4: Synthesis of (S)-8-(6-((1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)octahydro-1H-pyrazino[1,2-a]pyrazin-1-one (77)

[1149] The experimental operation was as described in Example 1, using intermediate F4 and 77-4 as reactants to obtain the title product.

[1150] MS (ESI) m / z [M+H] + =439.0.

[1151] 1 H NMR (400MHz, CD 3 OD)δ7.66-7.63(m,2H),7.39-7.33(m,3H),7.01(d,J=9.4Hz,1H),5.45(s,2H),4.49-4.45(m,1H),4.12-4.08(m,1H) ,3.52-3.50(m,1H),3.26-3.23(m,1H),3.05-3.00(m,3H),2.99-2.83(m,2H),2.62-2.59(m,1H),2.46-2.44(m,4H).

[1152] Embodiment 78:

[1153] 1-(4-(Difluoromethyl)phenyl)-5-(((6-(3-oxopiperazin-1-yl)pyridazin-3-yl)oxy)methyl)-1H-1,2,3-triazole-4-carbonitrile (78)

[1154]

[1155] The experimental operation was as described in Example 1, using intermediate J8 and 2-piperazinone as reactants to obtain the title product.

[1156] MS (ESI) m / z [M+H] + =427.2.

[1157] 1 H NMR (400MHz, CD 3 OD)δ7.84(s,4H),7.38(d,J=10.0Hz,1H),7.09(d,J=9.6Hz,1H),6.93(t,J= 55.6Hz,1H),5.70(s,2H),4.13(s,2H),3.77-3.74(m,2H),3.46-3.43(m,2H)

[1158] Embodiment 79:

[1159] 4-(6-((1-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (79)

[1160]

[1161] Step 1: Synthesis of 4-(6-((1-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (79-1)

[1162] The experimental operation was as described in Example 1, using intermediate G5 and 2-piperazinone as reactants to obtain the title product.

[1163] 1 H NMR (400MHz, CD 3 OD)δ7.49-7.64(m,4H),7.35(d,J=9.6Hz,1H),7.02(d,J=9.6Hz,1H),5.48(s,2H),5.45(s,2H), 4.12(s,2H),3.75(t,J=5.6Hz,2H),3.45(t,J=5.6Hz,2H),2.46(s,3H),0.95(s,9H),0.12(s,6H)

[1164] Step 2: Synthesis of 4-(6-((1-(4-(hydroxymethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (79)

[1165] At room temperature, 79-1 (60.0 mg, 0.118 mmol) and TEAF (98.5 mg, 0.60 mmol) were added to anhydrous acetonitrile (1.0 mL), nitrogen was replaced 3 times, and the mixture was reacted at 40°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (dichloromethane: methanol = 99: 1 to 10: 1) to obtain the title product (39 mg, white solid).

[1166] MS (ESI) m / z [M+H] + =396.5.

[1167] 1 H NMR (400 MHz, DMSO-d 6 )δ8.07(br.s,1H),7.61-7.47(m,4H),7.40(d,J=9.6Hz,1H),7.07(d,J=9.6Hz,1H),5.4 2-5.33(m,3H),4.57(d,J=5.2Hz,2H),3.69-3.64(m,2H),3.46-3.43(m,2H),2.38(s,3H)

[1168] Embodiment 80:

[1169] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-(hydroxymethyl)-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (80)

[1170]

[1171] The experimental operation was as described in Example 79, using intermediate K3 and 2-piperazinone as reactants, and after coupling and deprotection reaction steps, the title product was obtained.

[1172] MS (ESI) m / z [M+H] + =432.1.

[1173] 1 H NMR (400MHz, CD 3 OD)δ7.78(s,4H),7.34(d,J=9.6Hz,1H),7.04-6.74(m,2H),5.60(s,2H),4.60(s,2H),4.12(s,2H),3.77-3.73(m,2H),3.47-3.43(m,2H).

[1174] Embodiment 81 and Embodiment 82:

[1175] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-5-methylpyridazin-3-yl)piperazin-2-one (81)

[1176] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-4-methylpyridazin-3-yl)piperazin-2-one (82)

[1177]

[1178] Step 1: Synthesis of a mixture of 6-chloro-3-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-4-methylpyridazine (81-1) and 3-chloro-6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-4-methylpyridazine (82-1)

[1179] At 0°C, the intermediate A7 (200 mg, 0.84 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL), sodium hydride (30.2 mg, 1.26 mmol, 60%) was added, and the mixture was stirred at this temperature for 0.5 h. 3,6-dichloro-4-methylpyridazine (164 mg, 1.01 mmol) was added, and the mixture was heated to room temperature and stirred for 3 h. The reaction end point was monitored by TLC. Water (30 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:1) to obtain a mixture of the title products 81-1 and 82-1 (240 mg, yellow solid).

[1180] 81-1:MS(ESI)m / z[M+H] + =366.1.

[1181] 82-1:MS(ESI)m / z[M+H] + =366.1.

[1182] Step 2: Synthesis of 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-5-methylpyridazin-3-yl)piperazin-2-one (81) and 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-4-methylpyridazin-3-yl)piperazin-2-one (82)

[1183] The mixture of 81-1 and 82-1 in step 1 (370 mg, 1.01 mmol) and 2-piperazinone (121 mg, 1.21 mmol) were dissolved in dioxane (10.0 mL), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (47 mg, 0.1 mmol), cesium carbonate (658 mg, 2.0 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (84 mg, 0.1 mmol) were added in sequence, and the reaction was stirred at 100 ° C for 16 h. LCMS monitoring of the reaction was complete. The reaction solution was diluted with dichloromethane (50 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=15:1) to give the title products 81 (3 mg, white solid) and 82 (3 mg, white solid), respectively.

[1184] Compound 81:

[1185] MS (ESI) m / z [M+H] +=430.2.

[1186] 1 H NMR (400 MHz, DMSO-d 6 )δ8.02(br.s,1H),7.79(s,4H),7.25(s,1H),7.13(s,J=55.6Hz,1H),7.25(s,1H),5.5 1(s,2H),3.94(s,2H),3.62-3.58(m,2H),3.27-3.23(m,2H),2.40(s,3H),1.85(s,3H).

[1187] Compound 82:

[1188] MS (ESI) m / z [M+H] + =430.2.

[1189] 1 H NMR (400 MHz, DMSO-d 6 )δ7.87(br.s,1H),7.78(s,4H),7.13(s,J=55.6Hz,1H),6.99(s,1H),5.50(s,2H),3.69(s,2H),3.27-3.20(m,4H),2.40(s,3H),2.23(s,3H).

[1190] Embodiment 83:

[1191] 4-(6-((4-cyclopropyl-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methoxy)-pyridazin-3-yl)piperazin-2-one (83)

[1192]

[1193] The experimental operation was as described in Example 1, using intermediate H5 and 2-piperazinone as reactants to obtain the title product.

[1194] MS (ESI) m / z [M+H] + =442.1.

[1195] 1 H NMR (400 MHz, CDCl 3)δ7.70(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),7.02(d,J=9.4Hz,1H),6.94(d,J=9.4Hz,1H),6.57(t,J=55.6Hz,1H),6.15(br.s ,1H),5.54(s,2H),4.14(s,2H),3.94-3.91(m,2H),3.59-3.55(m,2H),2.04-2.00(m,1H),1.15-1.12(m,2H),1.04-1.01(m,2H).

[1196] Embodiment 84:

[1197] 7-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (84)

[1198]

[1199] The experimental procedure was as described in Example 1, using A8 and 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride as reactants to obtain the title product.

[1200] MS (ESI) m / z [M+H] + =439.9.

[1201] 1 H NMR (400MHz, CD 3 OD)δ8.48(s,1H),7.76(s,4H),7.51(d,J=9.6Hz,1H),7.05(d,J=9.6Hz,1H),6.88(t,J=55.6 Hz,1H),5.51(s,2H),4.93(s,2H),4.28(t,J=5.6Hz,2H),4.05(t,J=5.6Hz,2H),2.48(s,3H)

[1202] Embodiment 85:

[1203] 6-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-2-oxa-6-azaspiro[3.5]nonane (85)

[1204]

[1205] The experimental procedure was as described in Example 1, using A8 and 2-oxa-6-azaspiro[3.5]nonane as reactants to obtain the title product.

[1206] MS (ESI) m / z [M+H] + =443.2.

[1207] 1 H NMR (400 MHz, DMSO-d 6 )δ7.79(s,4H),7.47(d,J=9.4Hz,1H),7.14(t,J=55.6Hz,1H),7.98(d,J=9.4Hz,1H),5.46(s,2H),4.26( s,2H),3.64(s,2H),3.33-3.30(m,2H),2.40(s,3H),2.03(s,2H),1.83-1.80(m,2H),1.54-1.51(m,2H).

[1208] Embodiment 86:

[1209] 2-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-2,6-diazaspiro[3.4]octan-5-one (86)

[1210]

[1211] The experimental procedure was as described in Example 1, using A8 and 2,6-diazaspiro[3.4]octan-5-one hydrochloride as reactants to obtain the title product.

[1212] MS (ESI) m / z [M+H] + =442.2.

[1213] 1 H NMR (400MHz, CD 3 OD)δ7.77(s,4H),6.97(d,J=9.4Hz,1H),6.93(d,J=9.4Hz,1H),6.89(t,J=55.6Hz,1H),5.48(s,2H),4 .22(d,J=8.0Hz,2H),3,99(d,J=8.0Hz,2H),3.36(d,J=6.8Hz,2H),2.53(d,J=6.8Hz,2H),2.48(s,3H).

[1214] Embodiment 87:

[1215] 2-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-2,6-diazaspiro[3.4]octan-7-one (87)

[1216]

[1217] The experimental procedure was as described in Example 1, using A8 and 2,6-diazaspiro[3.4]octan-7-one p-toluenesulfonate as reactants to obtain the title product.

[1218] MS (ESI) m / z [M+H] + =442.2.

[1219] 1 H NMR (400MHz, CD 3 OD)δ7.76(s,4H),6.96(d,J=9.4Hz,1H),6.91(d,J=9.4Hz,1H),6.89(t,J=55 .6Hz,1H),5.49(s,2H),4.05(s,4H),3.66(s,2H),2.67(s,2H),2.47(s,3H).

[1220] Embodiment 88:

[1221] N-(1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)pyrrolidin-3-yl)acetamide (88)

[1222]

[1223] The experimental procedure was as described in Example 1, using A8 and N-(pyrrolidin-3-yl)acetamide as reactants to obtain the title product.

[1224] MS (ESI) m / z [M+H] + =444.2.

[1225] 1 H NMR (400 MHz, DMSO-d 6)δ8.13(d,J=6.4Hz,1H),7.79(s,4H),7.14(t,J=55.6Hz,1H),6.99-6.94(m,2H),5.42(s,2H),4.34-4.30(m,1H),3.5 8-3.56(m,1H),3.47-3.41(m,2H),3.23-3.21(m,1H),2.39(s,3H),2.16-2.11(m,1H),1.88-1.83(m,1H),1.80(s,3H).

[1226] Embodiment 89:

[1227] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-5-methylpiperazin-2-one (89)

[1228]

[1229] The experimental operation was as described in Example 1, using A8 and 5-methylpiperazine-2-one as reactants to obtain the title product.

[1230] MS (ESI) m / z [M+H] + =430.1.

[1231] 1 H NMR (400 MHz, DMSO-d 6 )δ8.06(br.s,1H),7.79(s,4H),7.32(d,J=9.6Hz,1H),7.13(t,J=55.6Hz,1H),7.01(d,J=9.6Hz,1H),5.45(s,2H),4.57(b r.s,1H),4.18-4.13(m,1H),3.66-3.62(m,1H),3.51-3.50(m,1H),3.11-3.07(m,1H),2.40(s,3H),1.00(d,J=3.2Hz,3H).

[1232] Embodiment 90:

[1233] 3-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-6-(5,6-dihydro-2H-pyran-3-yl)pyridazine (90)

[1234]

[1235] The experimental procedure was as described in step 3 of Example 57, using A8 and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as reactants to give the title product.

[1236] MS (ESI) m / z [M+H] + =400.2.

[1237] 1 H NMR (400 MHz, DMSO-d 6 )δ7.94(d,J=9.6Hz,1H),7.78(s,4H),7.17(d,J=9.6Hz,1H),7.13(t,J=55.6Hz,1H),6.76( br.s,1H),5.59(s,2H),4.56(s,2H),3.74(t,J=5.4Hz,2H),2.41(s,3H),2.30-2.28(m,2H).

[1238] Embodiment 91:

[1239] 2-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-8-(2,2,2-trifluoroethyl)octahydro-4H-pyrazino[1,2-a]pyrazin-4-one (91)

[1240]

[1241] At room temperature, Example 68 (50.0 mg, 0.11 mmol) was dissolved in anhydrous N,N-dimethylformamide (2.0 mL), and diisopropylethylamine (41.2 mg, 0.32 mol) and trifluoroethyl trifluoromethanesulfonate (37 mg, 0.16 mmol) were added in sequence, and the reaction solution was stirred for 16 h. The reaction endpoint was monitored by LCMS. Water (10 mL) was added to quench the reaction, and the reaction solution was extracted with dichloromethane (10 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex C18150*40 mm*5 μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile]; B%: 30%-60%; flow rate: 60 mL / min) to obtain the title product (16.8 mg, white solid).

[1242] MS (ESI) m / z [M+H] + =553.2.

[1243] 1 H NMR (400MHz, CD 3OD)δ7.76(s,4H),7.41(d,J=9.6Hz,1H),7.02(d,J=9.6Hz,1H),6.88(t,J=55.6H z,1H),5.50(s,2H),4.51-4.48(m,1H),4.38-4.34(m,1H),4.20-4.15(m,1H),4.0 0-3.96(m,1H),3.76-3.73(m,1H),3.43-3.20(m,1H),3.19-3.15(m,2H),3.11-2. 99(m,2H),2.87-2.84(m,1H),2.47(s,3H),2.45-2.41(m,1H),2.37-2.32(m,1H).

[1244] Embodiment 92:

[1245] 2-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-8-(pyrimidin-2-ylmethyl)octahydro-4H-pyrazino[1,2-a]pyrazin-4-one (92)

[1246]

[1247] The experimental procedure was as described in Example 91, using 68 and 2-(chloromethyl)pyrimidine as reactants to give the title product.

[1248] MS (ESI) m / z [M+H] + =563.2.

[1249] 1 H NMR (400MHz, CD 3 OD)δ8.80(d,J=4.8Hz,2H),7.76(s,4H),7.46-7.36(m,2H),6.99(d,J=9.6Hz,1H),6 .88(t,J=55.6Hz,1H),5.50(s,2H),4.52-4.49(m,1H),4.39-4.35(m,1H),4.19-4.17 (m,1H),3.99-3.95(m,1H),3.86(s,2H),3.81-3.77(m,1H),3.28-3.26(m,1H),3.10 -2.99(m,2H),2.91-2.89(m,1H),2.47(s,3H),2.27-2.24(m,1H),2.20-2.14(m,1H).

[1250] Embodiment 93:

[1251] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(pyrimidin-2-ylmethyl)piperazin-2-one (93)

[1252]

[1253] The experimental operation was as described in Example 59, using A8, tert-butyl 3-oxopiperazine-1-carboxylate and 2-(chloromethyl)pyrimidine as raw materials, and undergoing alkylation, deprotection and coupling reaction steps to obtain the title product.

[1254] MS (ESI) m / z [M+H] + =508.2.

[1255] 1 H NMR (400 MHz, DMSO-d 6 )δ8.75(d,J=4.8Hz,2H),7.79(s,4H),7.46-7.39(m,2H),7.14(t,J=55.6Hz,1H),7.06(d,J=9.6H z,1H),5.47(s,2H),4.77(s,2H),4.13(s,2H),3.83-3.80(m,2H),3.61-3.58(m,2H),2.41(s,3H).

[1256] Embodiment 94:

[1257] 4-(6-((1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(2,2,2-trifluoroethyl)piperazin-2-one (94)

[1258]

[1259] The experimental operation was as described in Example 1, using intermediate F4 and 62-2 as reactants to obtain the title product.

[1260] MS (ESI) m / z [M+H] + =466.2.

[1261] 1 H NMR (400MHz, CD 3 OD)δ7.67-7.63(m,2H),7.38-7.31(m,3H),7.03(d,J=9.6Hz,1H),5.46(s, 2H),4.25-4.19(m,4H),3.85-3.83(m,2H),3.71-3.68(m,2H),2.46(s,3H).

[1262] Embodiment 95:

[1263] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(2-morpholinoethyl)piperazin-2-one (95)

[1264]

[1265] The experimental operation was as described in step 1 of Example 59 and steps 2-3 of Example 58, using A8, tert-butyl 3-oxopiperazine-1-carboxylate and 4-(2-chloroethyl)morpholine as raw materials, and undergoing alkylation, deprotection and coupling reaction steps to obtain the title product.

[1266] MS (ESI) m / z [M+H] + =529.2.

[1267] 1 H NMR (400 MHz, DMSO-d 6 )δ7.78(s,4H),7.41(d,J=9.6Hz,1H),7.13(t,J=55.6Hz,1H),7.01(d,J=9.6Hz,1H) ,5.45(s,2H),4.02(s,2H),3.73-3.72(m,2H),3.49-3.45(m,8H),2.49-2.35(m,9H).

[1268] Embodiment 96:

[1269] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-((tetrahydrofuran-2-yl)methyl)piperazin-2-one (96)

[1270]

[1271] The experimental operation was as described in step 1 of Example 59 and steps 2-3 of Example 58, using A8, tert-butyl 3-oxopiperazine-1-carboxylate and 2-(bromomethyl)tetrahydrofuran as raw materials, and undergoing alkylation, deprotection and coupling reaction steps to obtain the title product.

[1272] MS (ESI) m / z [M+H] + =500.2.

[1273] 1 H NMR (400 MHz, DMSO-d 6)δ7.77(s,4H),7.39(d,J=9.6Hz,1H),7.12(t,J=55.6Hz,1H),7.03(d,J=9.6Hz,1H),5.45(s,2H),4.04(s,2H),3.99-3. 96(m,2H),3.73-3.70(m,2H),3.59-3.47(m,4H),3.30-3.26(m,1H),2.38(s,3H),1.90-1.74(m,3H),1.51-1.44(m,1H).

[1274] Embodiment 97:

[1275] 1-(Cyclopropylmethyl)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (97)

[1276]

[1277] The experimental operation was as described in step 1 of Example 59 and steps 2-3 of Example 58, using A8, 3-oxopiperazine-1-carboxylic acid benzyl ester and bromomethylcyclopropane as raw materials, and undergoing alkylation, deprotection and coupling reaction steps to obtain the title product.

[1278] MS (ESI) m / z [M+H] + =470.2

[1279] 1 H NMR (400 MHz, DMSO-d 6 )δ7.77(s,4H),7.41(d,J=9.6Hz,1H),7.12(t,J=55.6Hz,1H),7.04(d,J=9.6Hz,1H),5.45(s,2H),4.03(s,2H),3.74-3. 72(m,2H),3.51-3.49(m,2H),3.21-3.19(m,2H),2.38(s,3H),0.96-0.94(m,1H),0.43-0.41(m,2H),0.21-0.19(m,2H).

[1280] Embodiment 98:

[1281] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-((tetrahydrofuran-3-yl)methyl)piperazin-2-one (98)

[1282]

[1283] The experimental operation was as described in step 1 of Example 59 and steps 2-3 of Example 58, using A8, 3-oxopiperazine-1-carboxylic acid benzyl ester and 3-(bromomethyl)tetrahydrofuran as raw materials, and undergoing alkylation, deprotection and coupling reaction steps to obtain the title product.

[1284] MS (ESI) m / z [M+H] + =500.2

[1285] 1 H NMR (400 MHz, DMSO-d 6 )δ7.77(s,4H),7.40(d,J=9.6Hz,1H),7.13(t,J=55.6Hz,1H),7.03(d,J=9.6Hz,1H),5.45(s,2H),4.04(s,2H),3.73-3.71(m,3H) ,3.64-3.57(m,2H),3.44-3.42(m,2H),3.38-3.35(m,3H),2.54-2.52(m,1H),2.38(s,3H),1.88-1.85(m,1H),1.53-1.48(m,1H).

[1286] Embodiment 99:

[1287] 2-(4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-2-oxopiperazin-1-yl)acetonitrile (99)

[1288]

[1289] The experimental operation was as described in Example 59, using A8, tert-butyl 3-oxopiperazine-1-carboxylate and bromoacetonitrile as raw materials, and undergoing alkylation, deprotection and coupling reaction steps to obtain the title product.

[1290] MS (ESI) m / z [M+H] + =455.1

[1291] 1 H NMR (400 MHz, DMSO-d 6 )δ7.78(s,4H),7.45(d,J=9.6Hz,1H),7.13(t,J=55.6Hz,1H),7.06(d,J=9.6Hz,1H),5. 46(s,2H),4.47(s,2H),4.15(s,2H),3.83-3.81(m,2H),3.53-3.51(m,2H),2.39(s,3H).

[1292] Embodiment 100:

[1293] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(oxetan-3-ylmethyl)piperazin-2-one (100)

[1294]

[1295] The experimental operation was as described in step 1 of Example 59 and steps 2-3 of Example 58, using A8, 3-oxopiperazine-1-carboxylic acid benzyl ester and 3-(bromomethyl)oxetane as raw materials, and undergoing alkylation, deprotection and coupling reaction steps to obtain the title product.

[1296] MS (ESI) m / z [M+H] + =486.2

[1297] 1 H NMR (400 MHz, DMSO-d 6 )δ7.77(s,4H),7.39(d,J=9.6Hz,1H),7.13(t,J=55.6Hz,1H),7.03(d,J=9.6Hz,1H),5.45(s,2H),4.61-4.57( m,2H),4.33-4.31(m,2H),4.02(s,2H),3.70-3.65(m,4H),3.39-3.36(m,2H),3.24-3.19(m,1H),2.38(s,3H).

[1298] Embodiment 101:

[1299] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-(1-methyl-1H-pyrazol-3-yl)azetidine-3-carboxamide (101)

[1300]

[1301] The experimental procedure was as described in Example 38, using Example 37 and 1-methyl-1H-pyrazol-3-amine as reactants to obtain the title product.

[1302] MS (ESI) m / z [M+H] + =496.2.

[1303] 1 H NMR (400 MHz, DMSO-d 6)δ10.52(s,1H),7.78(s,4H),7.53(s,1H),7.13(t,J=55.6Hz,1H),6.99(d,J=9.4Hz,1H),6.92(d,J=9.4Hz,1H) ,6.45(s,1H),5.43(s,2H),4.13-4.09(m,2H),4.04-4.00(m,2H),3.72(s,3H),3.69-3.67(m,1H),2.39(s,3H).

[1304] Embodiment 102:

[1305] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-(1-methyl-1H-pyrazol-5-yl)azetidine-3-carboxamide (102)

[1306]

[1307] The experimental procedure was as described in Example 38, using Example 37 and 1-methyl-1H-pyrazol-5-amine as reactants to obtain the title product.

[1308] MS (ESI) m / z [M+H] + =496.2

[1309] 1 H NMR (400 MHz, DMSO-d 6 )δ10.07(s,1H),7.78(s,4H),7.31(s,1H),7.13(t,J=55.6Hz,1H),7.00(d,J=9.4Hz,1H),6.94(d,J=9.4Hz,1H) ,6.20(s,1H),5.43(s,2H),4.19-4.15(m,2H),4.09-4.05(m,2H),3.76-3.75(m,1H),3.65(s,3H),2.39(s,3H).

[1310] Embodiment 103:

[1311] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)azetidine-3-carboxamide (103)

[1312]

[1313] The experimental procedure was as described in Example 38, using Example 37 and 1-methyl-1H-pyrazol-4-amine as reactants to obtain the title product.

[1314] MS (ESI) m / z [M+H] + =496.2

[1315] 1 H NMR (400 MHz, DMSO-d 6 )δ10.07(s,1H),7.86(s,1H),7.78(s,4H),7.39(s,1H),7.13(t,J=55.6Hz,1H),6.99(d,J=9.6Hz,1H),6.92(d, J=9.6Hz,1H),5.43(s,2H),4.14-4.10(m,2H),4.04-4.01(m,2H),3.76(s,3H),3.63-3.60(m,1H),2.38(s,3H).

[1316] Embodiment 104:

[1317] (1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)azetidin-3-yl)(morpholino)methanone (104)

[1318]

[1319] The experimental procedure was as described in Example 38, using Example 37 and morpholine as reactants to obtain the title product.

[1320] MS (ESI) m / z [M+H] + =486.2

[1321] 1 H NMR (400 MHz, DMSO-d 6 )δ7.78(s,4H),7.13(t,J=55.6Hz,1H),6.98(d,J=9.6Hz,1H),6.92(d,J=9.6Hz,1H),5.42(s,2H),4.15-4.11(m, 2H),4.06-4.03(m,2H),3.87-3.79(m,1H),3.66-3.65(m,4H),3.46-3.45(m,2H),3.32-3.31(m,2H),2.38(s,3H).

[1322] Embodiment 105:

[1323] 9-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-6-oxa-2-thia-9-azaspiro[4.5]decane 2,2-dioxide (105)

[1324]

[1325] Step 1: Synthesis of 9-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-6-oxa-2-thia-9-azaspiro[4.5]decane (31-1)

[1326] The experimental procedure was as described in Example 1, using intermediate A8 and 6-oxa-2-thia-9-azaspiro[4.5]decane as reactants to obtain the title product.

[1327] MS (ESI) m / z [M+H] + =475.2.

[1328] Step 2: Synthesis of 9-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-6-oxa-2-thia-9-azaspiro[4.5]decane-2,2-dioxide (31)

[1329] At room temperature, 31-1 (150 mg, 0.31 mmol) was dissolved in methanol (10 mL), and sodium tungstate (168 mg, 0.62 mmol) and hydrogen peroxide (0.17 mL, 1.55 mmol, 30%) were added in sequence. The reaction was stirred for 1 hour. The reaction endpoint was monitored by LCMS. The reaction solution was poured into a saturated sodium thiosulfate solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-40%) to obtain the title product (85 mg, white solid).

[1330] MS (ESI) m / z [M+H] + =507.1.

[1331] 1 H NMR (400 MHz, DMSO-d 6)δ7.79(s,4H),7.43(d,J=9.4Hz,1H),7.14(t,J=55.6Hz,1H),7.06(d,J=9.4Hz,1H),5.46(s,2H),3.82-3. 76(m,3H),3.64-3.61(m,1H),3.49-3.45(m,1H),3.27-3.22(m,5H),2.38-2.29(m,4H),2.25-2.21(m,1H).

[1332] Embodiment 106:

[1333] 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-4-(methylsulfonyl)-1,4-diazaheptane (106)

[1334]

[1335] Step 1: Synthesis of tert-butyl 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1,4-azepane-1-carboxylate (106-1)

[1336] The experimental operation was as described in Example 1, using intermediate A8 and tert-butyl-1,4-diazepane-1-carboxylate as reactants to obtain the title product.

[1337] MS (ESI) m / z [M+H] + =516.2.

[1338] Step 2: Synthesis of 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1,4-diazepane (106-2)

[1339] The experimental procedure was as described in step 2 of Example 54, using intermediate 106-1 as the reactant to obtain the title product.

[1340] MS (ESI) m / z [M+H] + =416.2.

[1341] Step 3: Synthesis of 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-4-(methylsulfonyl)-1,4-diazaheptane (106)

[1342] At 0°C, compound 106-2 (200 mg, 0.48 mmol) was dissolved in dichloromethane (5 mL), triethylamine (145 mg, 1.44 mmol) and methanesulfonyl chloride (82 mg, 0.72 mmol) were added in sequence, and the mixture was heated to room temperature and stirred for 1 h. The reaction end point was monitored by LCMS. Water (10 mL) was added to quench the reaction, and the reaction solution was extracted with dichloromethane (15 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate: methanol = 10: 1) to obtain the title product (24 mg, white solid).

[1343] MS (ESI) m / z [M+H] + =494.2.

[1344] 1 H NMR (400 MHz, DMSO-d 6 )δ7.78(s,4H),7.25(d,J=9.6Hz,1H),7.13(t,J=55.6Hz,1H),6.97(d,J=9.6Hz,1H),5.43(s,2H),3.7 8(br.s,2H),3.69(br.s,2H),3.39(br.s,2H),3.19(br.s,2H),2.80(s,3H),2.39(s,2H),1.81(s,2H).

[1345] Embodiment 107:

[1346] (S)-8-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-2-methyloctahydro-1H-pyrazino[1,2-a]pyrazin-1-one (107)

[1347]

[1348] The experimental procedure was as described in Example 26, using compound 68 and iodomethane as reactants to obtain the title product.

[1349] MS (ESI) m / z [M+H] + =485.1.

[1350] 1 H NMR (400 MHz, DMSO-d 6)δ7.78(s,4H),7.38(d,J=9.6Hz,1H),7.13(t,J=55.6Hz,1H),6.98(d,J=9.6Hz,1H),5.45(s,2H),4.51-4.46(m,1H),4.01-3.98(m,1H),3. 48-3.41(m,1H),3.30-3.23(m,1H),3.18-3.12(m,1H),2.97-2.87(m, 3H),2.82(s,3H),2.67-2.56(m,2H),2.39(s,3H),2.27-2.20(m,1H).

[1351] Embodiment 108:

[1352] 1-Cyclopropyl-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (108)

[1353]

[1354] Step 1: Synthesis of 4-cyclopropyl-3-oxopiperazine-1-carboxylic acid benzyl ester (108-1)

[1355] Under air atmosphere, compound 58-1 (1 g, 4.27 mmol), cyclopropylboronic acid (0.73 g, 8.54 mmol), cesium carbonate (0.70 g, 2.13 mmol), pyridine (1.01 g, 12.81 mmol) and copper acetate (0.78 g, 4.27 mmol) were mixed in toluene (30 mL) and stirred at 110 ° C for 16 h. LCMS monitored the reaction end point. The reaction solution was filtered and the filter cake was washed with ethyl acetate (10 mL x 2). The filtrate was combined and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:0) to obtain the title product (500 mg, colorless oil).

[1356] MS (ESI) m / z [M+H] + =275.1.

[1357] Step 2: Synthesis of 1-cyclopropylpiperazin-2-one (108-2)

[1358] The experimental procedure was as described in step 2 of Example 58, using intermediate 108-1 as the reactant to obtain the title product.

[1359] MS (ESI) m / z [M+H] + =141.1.

[1360] Step 3: Synthesis of 1-cyclopropyl-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (108)

[1361] The experimental operation was as described in Example 1, using intermediate A8 and 108-2 as reactants to obtain the title product.

[1362] MS (ESI) m / z [M+H] + =456.1.

[1363] 1 H NMR (400 MHz, DMSO-d 6 )δ7.77(s,4H),7.37(d,J=9.6Hz,1H),7.12(t,J=55.6Hz,1H),7.00(d,J=9.6Hz,1H),5.44(s,2H),4. 00(s,2H),3.69-3.67(m,2H),3.34-3.32(m,2H),2.75-2.73(m,1H),2.38(s,3H),0.69-0.62(m,4H).

[1364] Embodiment 109:

[1365] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(2-(4,4-difluoropiperidin-1-yl)ethyl)piperazin-2-one (109)

[1366]

[1367] Step 1: Synthesis of tert-butyl 4-(2-hydroxyethyl)-3-oxopiperazine-1-carboxylate (109-1)

[1368] At room temperature, compound 59-2 (1.50 g, 4.18 mmol) and tetrabutylammonium fluoride (3.50 g, 20.9 mmol) were added to acetonitrile (20.0 mL) in sequence and reacted at 40°C for 15 h. TLC was used to monitor the end point of the reaction. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (100 mL), extracted with dichloromethane (50 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (dichloromethane: methanol = 99: 1 to 20: 1) to obtain the title product (998 mg, colorless oil).

[1369] 1 H NMR (400 MHz, CDCl 3)δ4.12(s,2H),3.83(t,J=5.2Hz,2H),3.67(t,J=5.2Hz,2H),3.59(t,J=5.2Hz,2H),3.47(t,J=5.2Hz,2H),1.48(s,9H).

[1370] Step 2: Synthesis of tert-butyl 3-oxo-4-(2-oxoethyl)piperazine-1-carboxylate (109-2)

[1371] At -65°C, oxalyl chloride (286 mg, 2.25 mmol) was dissolved in dichloromethane (10.0 mL), dimethyl sulfoxide (384 mg, 4.91 mmol) was added, and the mixture was stirred for 10 minutes. Compound 109-1 (500 mg, 2.05 mmol) was added dropwise to the mixture, and the reaction mixture was stirred at this temperature for 1 hour. Triethylamine (1.04 g, 2.05 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with water (10 mL), and most of the solvent was removed under reduced pressure. The residue was diluted with water (100 mL) and extracted with dichloromethane (50 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (dichloromethane: methanol = 99:1 to 30:1) to obtain the title product (290 mg, colorless oil).

[1372] 1 H NMR (400 MHz, CDCl 3 )δ9.62(s,1H),4.28(s,2H),4.16(s,2H),3.73(t,J=5.2Hz,2H),3.43-3.39(m,2H),1.9(s,9H).

[1373] Step 3: Synthesis of tert-butyl 4-(2-(4,4-difluoropiperidin-1-yl)ethyl)-3-oxopiperazine-1-carboxylate (109-3)

[1374] At room temperature, 4,4-difluoropiperidine (212 mg, 1.98 mmol) and triethylamine (200 mg, 1.98 mmol) were added to methanol (4.0 mL) in sequence, stirred for 0.5 h, compound 109-2 (240 mg, 1.98 mmol) and acetic acid (238 mg, 3.96 mmol) were added, the reaction was continued to stir for 2 h, sodium cyanoborohydride (249 mg, 3.96 mmol) was added, and the reaction was stirred for 3 h. TLC was used to monitor the end point of the reaction. The reaction solution was quenched with water (10 mL), concentrated under reduced pressure, the residue was diluted with water (100 mL), extracted with dichloromethane (50 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (dichloromethane: methanol = 50:1 to 20:1) to obtain the title product (180 mg, colorless oil).

[1375] MS (ESI) m / z [M+H] + =348.2.

[1376] Step 4: Synthesis of 1-(2-(4,4-difluoropiperidin-1-yl)ethyl)piperazin-2-one (109-4)

[1377] At room temperature, compound 109-3 (180 mg, 0.54 mmol) was dissolved in dichloromethane (4 mL), and a solution of hydrogen chloride in ethyl acetate (4 mL, 4.0 M) was added. The mixture was stirred at 24°C for 1 h. The reaction endpoint was monitored by TLC. The reaction solution was concentrated under reduced pressure to obtain the title product (150 mg, white solid).

[1378] Step 5: Synthesis of 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(2-(4,4-difluoropiperidin-1-yl)ethyl)piperazin-2-one (109)

[1379] The experimental operation was as described in Example 1, using intermediate A8 and 109-4 as reactants to obtain the title product.

[1380] MS (ESI) m / z [M+H] + =563.1

[1381] 1 H NMR (400MHz, CD 3OD)δ7.77(s,4H),7.35(d,J=9.6Hz,1H),7.01(d,J=9.6Hz,1H),6.88(t,J=55.6Hz,1H),5.50(s,2H),4 .16(s,2H),3.83-3.80(m,2H),3.62-3.57(m,4H),2.64-2.61(m,6H),2.47(s,3H),1.95-1.86(m,4H).

[1382] Embodiment 110:

[1383] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)piperazin-2-one (110)

[1384]

[1385] The experimental procedure was as described in steps 3 to 5 in the synthesis of Example 109, using intermediate 109-2, 3,3-difluoropyrrolidine and A8 as reactants to obtain the title product.

[1386] MS (ESI) m / z [M+Na] + =571.3

[1387] 1 H NMR (400MHz, CD 3 OD)δ7.76(s,4H),7.34(d,J=9.6Hz,1H),7.01(d,J=9.6Hz,1H),6.88(t,J=55.6Hz,1H),5.49(s,2H),4.15(s,2H),3.82-3.7 9(m,2H),3.62-3.57(m,4H),3.03(t,J=13.2Hz,2H),2.87-2.85(m,2H),2.77-2.75(m,2H),2.47(s,3H),2.27-2.20(m,2H).

[1388] Embodiment 111:

[1389] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(1-methyl-1H-pyrazol-4-yl)piperazin-2-one (111)

[1390]

[1391] Step 1: Synthesis of benzyl 4-(1-methyl-1H-pyrazol-4-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (111-1)

[1392] The experimental procedure was as described in Step 1 of Example 70, using benzyl 3-oxopiperazine-1-carboxylate and 4-iodo-1-methyl-1H-pyrazole as reactants to give the title product.

[1393] MS (ESI) m / z [M+H] + =315.1.

[1394] Step 2: Synthesis of 1-(1-methyl-1H-pyrazol-4-yl)piperazin-2-one (111-2)

[1395] The experimental procedure was as described in step 2 of Example 58, using intermediate 111-1 as the reactant to obtain the title product.

[1396] MS (ESI) m / z [M+H] + =181.1.

[1397] Step 3: Synthesis of 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(1-methyl-1H-pyrazol-4-yl)piperazin-2-one (111)

[1398] The experimental operation was as described in Example 1, using intermediate A8 and 111-2 as reactants to obtain the title product.

[1399] MS (ESI) m / z [M+H] + =496.1.

[1400] 1 H NMR (400 MHz, DMSO-d 6 )δ8.03(s,1H),7.78(s,4H),7.63(s,1H),7.48(d,J=9.6Hz,1H),7.12(t,J=55.6Hz,1H),7.06(d,J=9 .6Hz,1H),5.45(s,2H),4.21(s,2H),3.88-3.85(m,2H),3.80(s,3H),3.76-3.74(m,2H),2.39(s,3H).

[1401] Embodiment 112:

[1402] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(1-methyl-1H-pyrazol-3-yl)piperazin-2-one (112)

[1403]

[1404] The experimental operation was as described in Example 111, using 3-oxopiperazine-1-carboxylic acid benzyl ester, 3-iodo-1-methylpyrazole and A8 as raw materials, and undergoing coupling, deprotection and coupling reaction steps to obtain the title product.

[1405] MS (ESI) m / z [M+H] + =496.1.

[1406] 1 H NMR (400 MHz, DMSO-d 6 )δ7.77(s,4H),7.61(s,1H),7.43(d,J=9.6Hz,1H),7.12(t,J=55.6Hz,1H),7.05(d,J=9.6Hz,1H),6. 62(s,1H),5.45(s,2H),4.23(s,2H),3.94-3.92(m,2H),3.85-3.83(m,2H),3.76(s,3H),2.39(s,3H).

[1407] Embodiment 113:

[1408] 1-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (113)

[1409]

[1410] The experimental operation was as described in Example 111, using 3-oxopiperazine-1-carboxylic acid benzyl ester, 3-iodo-1-(difluoromethyl)pyrazole and A8 as raw materials, and coupling, deprotection and coupling reaction steps were performed to obtain the title product.

[1411] MS (ESI) m / z [M+H] + =532.1

[1412] 1 H NMR (400 MHz, DMSO-d 6)δ8.51(s,1H),8.09(s,1H),7.92-7.63(m,5H),7.49(d,J=9.6Hz,1H),7.12(t,J=55.6Hz,1H),7. 07(d,J=9.6Hz,1H),5.45(s,2H),4.27(s,2H),3.91-3.88(m,2H),3.84-3.82(m,2H),2.39(s,3H).

[1413] Embodiment 114:

[1414] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(pyridine-pyridin-4-yl)piperazin-2-one (114)

[1415]

[1416] Step 1: Synthesis of tert-butyl benzyl-3-oxo-4-(pyridin-4-yl)piperazine-1-carboxylate (114-1)

[1417] The experimental operation was as described in Example 18, using 3-oxopiperazine-1-carboxylic acid benzyl ester and 4-bromopyridine as reactants and toluene as solvent to obtain the title product.

[1418] MS (ESI) m / z [M+H] + =312.1.

[1419] Step 2: Synthesis of 1-(pyridin-4-yl)piperazin-2-one (114-2)

[1420] The experimental procedure was as described in step 2 of Example 58, using intermediate 114-1 as the reactant to obtain the title product.

[1421] MS (ESI) m / z [M+H] + =178.1.

[1422] Step 3: Synthesis of 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(pyridine-pyridin-4-yl)piperazin-2-one (114)

[1423] The experimental procedure was as described in Example 1, using intermediate A8 and intermediate 114-2 to obtain the title product.

[1424] MS (ESI) m / z [M+H] + =493.1.

[1425] 1H NMR (400 MHz, DMSO-d 6 )δ8.55(d,J=5.6Hz,2H),7.78(s,4H),7.52(d,J=5.6Hz,2H),7.44(d,J=9.6Hz,1H),7.13(t,J= 55.6Hz,1H),7.07(d,J=9.6Hz,1H),5.46(s,2H),4.29(s,2H),3.91-3.86(m,4H),2.39(s,3H).

[1426] Embodiment 115:

[1427] 2-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-ethyl-2-azabicyclo[2.1.1]hexane-1-carboxamide (115)

[1428]

[1429] The experimental operation was as described in Example 40, using intermediate A8 and 2-azabicyclo[2.1.1]hexane-1-carboxylic acid methyl ester as raw materials, and undergoing coupling, hydrolysis and condensation reaction steps to obtain the title product.

[1430] MS (ESI) m / z [M+H] + =470.1.

[1431] 1 H NMR (400 MHz, DMSO-d 6 )δ7.79(s,4H),7.53(t,J=5.6Hz,1H),7.15(t,J=55.6Hz,1H),7.06(d,J=9.4Hz,1H),7.01(d,J=9.4Hz,1H),5.44(s,2H),4. 44(s,2H),3.08-3.03(m,2H),2.79-2.77(m,1H),2.39(s,3H),2.04-2.02(m,2H),1.58-1.57(m,2H),0.96(t,J=7.2Hz,3H).

[1432] Embodiment 116:

[1433] (1R,4R)-5-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-2,5-diazabicyclo[2.2.1]heptan-3-one (116)

[1434]

[1435] Step 1: Synthesis of (1R,4R)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (116-2)

[1436] At 0°C, under nitrogen protection, compound 116-1 (244 mg, 1.0 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), KHMDS (1.2 mL, 1.0 M tetrahydrofuran solution) was added dropwise, and the reaction was stirred for 2 h at this temperature. The reaction endpoint was monitored by LCMS. Acetic acid (1.0 mL) was added dropwise to quench the reaction, and water (50 mL) and ethyl acetate (50 mL) were added to dilute to obtain a white mixed solution. Filter, separate the filtrate, separate the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the product (150 mg, white solid).

[1437] MS (ESI) m / z [M+H-56] + =157.1.

[1438] Step 2: Synthesis of (1R,4R)-tert-butyl 5-(4-methoxybenzyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (116-3)

[1439] At 0°C, under nitrogen protection, compound 116-2 (150 mg, 0.71 mmol) and PMBCl (133 mg, 0.85 mmol) were dissolved in N,N-dimethylformamide (5 mL), sodium hydride (57 mg, 0.14 mmol, 60%) was added, and the mixture was heated to room temperature and stirred for 1 h. The reaction endpoint was monitored by LCMS. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 4:1) to obtain the title product (160 mg, yellow oil).

[1440] MS (ESI) m / z [M+H] + =333.2.

[1441] Step 3: Synthesis of (1R,4R)-2-(4-methoxybenzyl)-2,5-diazabicyclo[2.2.1]heptan-3-one (116-4)

[1442] At room temperature, compound 116-3 (160 mg, 0.48 mmol) was dissolved in dichloromethane (5 mL), and a solution of hydrogen chloride in ethyl acetate (1.0 mL, 6.0 M) was added dropwise, and the reaction solution was stirred for 0.5 h. The reaction endpoint was monitored by LCMS. The reaction solution was poured into a saturated sodium bicarbonate solution (50 mL), extracted with dichloromethane (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (100 mg, yellow oil), which was directly used in the next step without further purification.

[1443] MS (ESI) m / z [M+H] + =233.1.

[1444] Step 4: Synthesis of (1R,4R)-5-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-2-(4-methoxybenzyl)-2,5-diazabicyclo[2.2.1]heptan-3-one (116-5)

[1445] The experimental operation was as described in Example 1, using intermediate A8 and 116-4 as reactants to obtain the title product.

[1446] MS (ESI) m / z [M+H] + =547.2.

[1447] Step 5: Synthesis of (1R,4R)-5-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-2,5-diazabicyclo[2.2.1]heptan-3-one (116)

[1448] At room temperature, compound 116-5 (110 mg, 0.018 mmol) was dissolved in trifluoroacetic acid (20 mL), and the reaction temperature was raised to 100 ° C and stirred for 48 h. LCMS monitored the reaction endpoint. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in saturated sodium bicarbonate (30 mL), extracted with dichloromethane (50 mL x 3, containing 10% isopropanol), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase C18 flash preparative chromatography (acetonitrile: water = 0-40%) to obtain the title product (5 mg, white solid).

[1449] MS (ESI) m / z [M+H] + =428.2.

[1450] 1 H NMR (400 MHz, DMSO-d 6)δ7.90-7.88(m,2H),7.83-7.79(m,4H),7.14(t,J=55.6Hz,1H),6.46(d,J=9.4Hz,1H),5.46(s,2H),4.3 7-4.32(m,1H),4.23-4.21(m,1H),3.88-3.84(m,1H),3.14-3.08(m,2H),2.63-2.58(m,1H),2.47(s,3H).

[1451] Embodiment 117:

[1452] (S)-8-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)hexahydro-1H-pyrazino[1,2-a]pyrazine-1,3-(2H)-dione (117)

[1453]

[1454] Step 1: Synthesis of (R)-1-(2-amino-2-oxoethyl)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5)-yl)methoxy)pyridazin-3-yl)piperazine-2-carboxylic acid methyl ester (117-1)

[1455] Under nitrogen protection, compound 28-3 (110 mg, 0.22 mmol), 2-bromoacetamide (37 mg, 0.27 mmol) and diisopropylethylamine (86 mg, 0.66 mol) were added to anhydrous N, N-dimethylformamide (4.0 mL) in sequence, and the reaction temperature was raised to 80 ° C and stirred for 14 h. LCMS monitored the reaction end point. The reaction solution was diluted with ethyl acetate (100 mL), washed with saturated brine (10.0 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (dichloromethane: methanol = 100: 1 to 20: 1) to obtain the title product (65 mg, yellow solid).

[1456] MS (ESI) m / z [M+H] + =517.0.

[1457] 1 H NMR (400MHz, CD 3OD)δ7.76(s,4H),7.33(d,J=6.0Hz,1H),7.04-6.73(m,2H),5.49(s,2H),4.20(dd,J=3.2,12.8Hz,1H),3.89-3.80(m,1H),3.70(t ,J=4.0Hz,1H),3.66(s,3H),3.57(dd,J=3.6,12.8Hz,1H),3.44-3.32(m,3H),3.22-3.14(m,1H),2.71-2.63(m,1H),2.47(s,3H).

[1458] Step 2: Synthesis of (S)-8-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)hexahydro-1H-pyrazino[1,2-a]pyrazine-1,3(2H)-dione (117)

[1459] At room temperature, compound 117-1 (65 mg, 0.13 mmol) and sodium hydroxide (5 mg, 0.13 mmol) were added to anhydrous ethanol (5.0 mL) in sequence and stirred for 1 h. The reaction endpoint was monitored by TLC. The reaction solution was quenched with saturated aqueous ammonium chloride solution (20.0 mL), extracted with ethyl acetate (20.0 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (dichloromethane: methanol = 100: 1 to 10: 1) to obtain the title product (33 mg, white solid).

[1460] MS (ESI) m / z [M+H] + =485.0

[1461] 1 H NMR (400MHz, CD 3 OD)δ7.77(s,4H),7.42(d,J=9.6Hz,1H),7.02(d,J=9.6Hz,1H),6.88(t,J=55.6Hz,1H),5.50(s,2H),4.38-4.35(m,1H),3.9 2-3.89(m,1H),3.63-3.59(m,1H),3.36-3.34(m,1H),3.25-3.20(m,3H),3.00-2.98(m,1H),2.52-2.51(m,1H),2.47(s,3H).

[1462] Embodiment 118:

[1463] (S)-7-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)tetrahydroimidazole[1,5-a]pyrazine-1,3(2H,5H)-dione (118)

[1464]

[1465] Step 1: Synthesis of (S)-methyl 2-carbamoyl-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (118-1)

[1466] At room temperature, compound 27-3 (130 mg, 0.28 mmol) and concentrated hydrochloric acid (1 mL) were dissolved in dioxane (2 mL), potassium isocyanate (46 mg, 0.57 mmol) in water (0.28 mL) was added, and the reaction was stirred for 16 h. The reaction endpoint was monitored by LCMS. The reaction solution was concentrated under reduced pressure to remove the solvent, water (30 mL) was added to the crude product, and it was extracted with dichloromethane (30.0 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product (134 mg, yellow solid).

[1467] MS (ESI) m / z [M+H] + =503.1.

[1468] Step 2: Synthesis of (S)-7-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)tetrahydroimidazole[1,5-a]pyrazine-1,3-(2H,5H)-dione (118)

[1469] At room temperature, compound 118-1 (84 mg, 0.16 mmol) was dissolved in ethanol (3.0 mL), sodium ethoxide (17 mg, 0.25 mmol) was added, and the mixture was stirred for 3 h. The reaction endpoint was monitored by TLC. The reaction solution was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (dichloromethane: methanol = 100: 1 to 10: 1) to obtain the title product (62 mg, off-white solid).

[1470] MS (ESI) m / z [M+H] + =471.0.

[1471] 1 H NMR (400 MHz, DMSO-d 6)δ10.97(br.s,1H),7.79(s,4H),7.53(d,J=9.6Hz,1H),7.06(d,J=9.6Hz,1H),7.14(t,J=55.6Hz,1H), 5.47(s,2H),4.51-4.47(m,1H),4.18-4.15(m,2H),3.85-3.83(m,1H),3.02-2.94(m,3H),2.40(s,3H).

[1472] Embodiment 119:

[1473] 6-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (119)

[1474]

[1475] Step 1: Synthesis of tert-butyl 1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-4-hydroxypiperidin-3-yl)carbamate (119-2)

[1476] The experimental operation was as described in Example 1, using intermediate A8 and 119-1 as reactants to obtain the title product.

[1477] MS (ESI) m / z [M+H] + =532.1.

[1478] 1 H NMR (400MHz, CD 3 OD)δ7.77(s,4H),7.38(d,J=9.6Hz,1H),7.04-6.74(m,2H),5.48(s,2H),4.10-4.03(m,2H),3.64-3.56(m,1H),3.45-3.35 (m,1H),3.08-2.96(m,1H),2.85(dd,J=9.6,13.2Hz,1H),2.47(s,3H),2.08-2.02(m,1H),1.66-1.53(m,1H),1.45(s,9H).

[1479] Step 2: Synthesis of 3-amino-1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazine-pyridin-3-yl)piperidin-4-ol (119-3)

[1480] The experimental procedure was as described in step 4 of Example 109, using intermediate 119-2 as the reactant to obtain the title product.

[1481] Step 3: Synthesis of 2-chloro-N-(1-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy))pyridazin-3-yl)-4-hydroxypiperidin-3-yl)acetamide (119-4)

[1482] Under nitrogen protection, compound 119-3 (35 mg, 0.075 mmol) and triethylamine (23 mg, 0.23 mml) were added to anhydrous dichloromethane (3.0 mL), and chloroacetyl chloride (13 mg, 0.11 mol) was slowly added dropwise, and the reaction was stirred at room temperature for 2 h. LCMS monitored the reaction end point. The reaction solution was diluted with dichloromethane (50.0 mL), and the organic phase was washed with saturated sodium bicarbonate aqueous solution (5.0 mL x 3) and saturated brine (5.0 mL x3) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product (100 mg, brown oil) was obtained.

[1483] MS (ESI) m / z [M+H] + =530.1.

[1484] Step 4: Synthesis of 6-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (119)

[1485] At 0°C, under nitrogen protection, compound 119-4 (38 mg, 0.075 mmol) was dissolved in anhydrous tetrahydrofuran (5.0 mL), sodium hydride (6 mg, 0.15 mmol, 60%) was added, and the mixture was stirred at room temperature for 1 h. The reaction end point was monitored by LCMS. The reaction solution was quenched with saturated aqueous ammonium chloride solution (10.0 mL), extracted with ethyl acetate (20.0 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol = 15: 1) to give the title product (3 mg, white solid).

[1486] MS (ESI) m / z [M+H] + =472.0.

[1487] 1 H NMR (400MHz, CD 3OD)δ7.77(s,4H),7.37(d,J=9.6Hz,1H),6.98(d,J=9.6Hz,1H),6.89(t,J=55.6Hz,1H),5.50(s,2H),4.44-4.40(m,1H),4.2 5-4.23(m,3H),3.55-3.52(m,1H),3.04-3.02(m,1H),2.78-2.72(m,1H),2.47(s,3H),2.05-2.02(m,1H),1.69-1.65(m,1H).

[1488] Embodiment 120:

[1489] (S)-2-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)octahydropyrazino[1,2-a][1,4]diazepin-10(2H)-one (120)

[1490]

[1491] Step 1: Synthesis of (S)-1-tert-butyl 3-methyl 4-(3-((tert-butoxycarbonyl)amino)propyl)piperazine-1,3-dicarboxylate (120-1)

[1492] At room temperature, intermediate 29-1 (900 mg, 3.68 mmol) and tert-butyl (3-bromopropyl)carbamate (1.31 g, 5.52 mmol) were dissolved in DMF (20 mL), potassium iodide (120 mg, 0.74 mmol) and potassium carbonate (1.02 g, 7.26 mmol) were added in sequence, and stirred at 60 ° C for 16 hours. LCMS showed that the product was generated. Ice water (30 mL) was added to the reaction, and ethyl acetate was extracted (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product (1.3 g, yellow solid).

[1493] MS (ESI) m / z [M+H] + =402.3.

[1494] Step 2: Synthesis of (S)-1-(3-aminopropyl)piperazine-2-carboxylic acid methyl ester (120-2)

[1495] The experimental procedure was as described in step 2 of Example 59, using intermediate 120-1 as the reactant to obtain the title product.

[1496] MS (ESI) m / z [M+H] + =202.3.

[1497] Step 3: Synthesis of (S)-octahydropyrazino[1,2-a][1,4]diazepin-10(2H)-one (120-3)

[1498] At room temperature, intermediate 120-2 (500 mg, 1.82 mmol) was dissolved in anhydrous methanol (15 mL), sodium methoxide (492 mg, 9.1 mmol) was added, and stirred at room temperature for 16 hours. LCMS showed that the product was generated. The reaction solution was concentrated under reduced pressure to obtain the crude title product (300 mg, white solid).

[1499] MS (ESI) m / z [M+H] + =170.1.

[1500] Step 4: Synthesis of (S)-2-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)octahydropyrazino[1,2-a][1,4]diazepin-10(2H)-one (120)

[1501] The experimental operation was as described in Example 1, using intermediate A8 and 120-3 as reactants to obtain the title product.

[1502] MS (ESI) m / z [M+H] + =485.2.

[1503] 1 H NMR (400 MHz, CDCl 3 )δ7.75(s,4H),7.37(d,J=9.6Hz,1H),6.93(d,J=9.6Hz,1H),6.85(t,J=56.0Hz,1H),5.46(s,2H),3.83-3.81(m,1H),3.75-3.73(m,1H),3.56 -3.45(m,3H),3.23-3.18(m,2H),3.00-2.97(m,2H),2.73-2.71(m,1H) ,2.47(s,3H),1.82-1.80(m,1H),1.73-1.71(m,1H),0.85-0.83(m,1H).

[1504] Embodiment 121:

[1505] 3-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-ethyl-3-azabicyclo[3.1.1]heptane-1-carboxamide (121)

[1506]

[1507] Step 1: Synthesis of tert-butyl 1-(ethylcarbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (121-2)

[1508] At room temperature, compound 121-1 (100 mg, 0.41 mmol), ethylamine (50 mg, 0.62 mmol), 1-hydroxybenzotriazole (84 mg, 0.62 mmol) and diisopropylethylamine (84 mg, 0.62 mmol) were dissolved in anhydrous dichloromethane (4.0 mL), EDCI (120 mg, 0.62 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction endpoint was monitored by TLC. The reaction solution was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (dichloromethane: methanol = 1:0 to 10:1) to obtain the title product (100 mg, yellow solid).

[1509] 1 H NMR (400 MHz, CDCl 3 )δ5.49-5.25(m,1H),3.56(d,J=6.8Hz,2H),3.49-3.40(m,2H),3.29-3.14(m,2H),2.42- 2.09(m,3H),1.62-1.58(m,1H),1.54-1.48(m,1H),1.44-1.38(m,9H),1.13-1.01(m,3H).

[1510] Step 2: Synthesis of N-ethyl-3-azabicyclo[3.1.1]heptane-1-carboxamide (121-3)

[1511] The experimental procedure was as described in step 4 of Example 109, using intermediate 121-2 as the reactant to obtain the title product.

[1512] Step 3: Synthesis of 3-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-N-ethyl-3-azabicyclo[3.1.1]heptane-1-carboxamide (121)

[1513] The experimental operation was as described in Example 1, using intermediate A8 and 121-3 as reactants to obtain the title product.

[1514] MS (ESI) m / z [M+H] + =484.0.

[1515] 1 H NMR (400 MHz, DMSO-d 6)δ7.80(s,4H),7.75(t,J=5.6Hz,1H),7.29-6.99(m,3H),5.46(s,2H),3.63-3.55(m,4H),3.14-3.07 (m,2H),2.51-2.49(m,1H),2.41(s,3H),2.27-2.24(m,2H),1.58-1.56(m,2H),1.03(t,J=7.2Hz,3H).

[1516] Embodiment 122:

[1517] (S)-3-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-2, trans-3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one (122)

[1518]

[1519] Step 1: Synthesis of (S)-4-(tert-butoxycarbonyl)-1-(2-nitrophenyl)piperazine-2-carboxylic acid (122-2)

[1520] Compound 122-1 (2 g, 8.69 mmol) and potassium carbonate (4.8 g, 34.7 mmol) were dissolved in tetrahydrofuran (30 mL), 1-fluoro-2-nitrobenzene (1.35 g, 9.55 mmol) was slowly added, and the temperature was raised to 60 ° C and stirred for 12 h. LCMS was used to monitor the reaction end point. The reaction solution was filtered to obtain a crude product. The crude product was dissolved in ethyl acetate (15 mL) and water (10 mL), the aqueous phase was separated, the pH of the aqueous phase was adjusted to 5.0 with dilute hydrochloric acid (1.0 M), and ethyl acetate (20 mL x 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product (1.1 g, yellow solid), which was directly used in the next step without further purification.

[1521] MS (ESI) m / z [M+Na] + =374.0.

[1522] 1 H NMR (400 MHz, CDCl 3)δ7.80-7.78(m,1H),7.49(t,J=7.2Hz,1H),7.31(d,J=8.4Hz,1H),7.11(t,J=7.6Hz,1H),4.46-4.30(m,1H),4.05 -3.90(m,2H),3.80-3.68(m,1H),3.45-3.40(m,1H),3.17(t,J=11.2Hz,1H),2.94(d,J=11.6Hz,1H),1.43(s,9H).

[1523] Step 2: Synthesis of (S)-1-tert-butyl 3-methyl 4-(2-nitrophenyl)piperazine-1,3-dicarboxylate (122-3)

[1524] Under nitrogen protection, compound 122-2 (400 mg, 1.14 mmol) was dissolved in methanol (10 mL), thionyl chloride (2.71 g, 22.8 mmol) was slowly added, and the temperature was raised to 70 ° C. and stirred for 2 h. The reaction end point was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 mL) and water (5 mL). The pH of the aqueous phase was adjusted to 8.0 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane (20 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure to obtain the title product (330 mg, yellow solid), which was directly used in the next step without further purification.

[1525] Step 3: Synthesis of (S)-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylic acid tert-butyl ester (122-4)

[1526] Under nitrogen protection, compound 122-3 (210 mg, 0.57 mmol) was dissolved in ethanol (10 mL), palladium / carbon (20 mg, 10% purity) was added, and the reaction solution was stirred for 3 h at 30 ° C under hydrogen (50 psi) atmosphere. LCMS monitored the reaction endpoint. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the title product (100 mg, yellow oil), which was directly used in the next step without further purification.

[1527] MS (ESI) m / z [M-Boc+H] + =204.1.

[1528] Step 4: Synthesis of (S)-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one (122-5)

[1529] The experimental procedure was as described in step 4 of Example 109, using intermediate 122-4 as the reactant to obtain the title product.

[1530] Step 5: Synthesis of (S)-3-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-2, trans-3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one (122)

[1531] The experimental operation was as described in Example 1, using intermediate A8 and 122-5 as reactants to obtain the title product.

[1532] MS (ESI) m / z [M+H] + =519.2.

[1533] 1 H NMR (400 MHz, CDCl 3 )δ7.73-7.67(m,5H),7.23-7.25(m,1H),7.07(t,J=8.0Hz,1H),6.94-6.57(m,5H),5.47(s,2H),4.63- 4.61(m,1H),4.53-4.50(m,1H),3.76-3.66(m,2H),3.27-3.19(m,2H),3.01-2.97(m,1H),2.50(s,3H).

[1534] Example 123 and Example 124:

[1535] cis-7-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-octahydro-2,7-naphthyridin-1(2H)-one (123)

[1536] trans-7-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-octahydro-2,7-naphthyridin-1(2H)-one (124)

[1537]

[1538] Step 1: Synthesis of 1-tert-butyl 3-ethyl 4-hydroxypiperidine-1,3-dicarboxylate (123-2)

[1539] At 0°C, compound 123-1 (5.0 g, 18.4 mmol) was dissolved in anhydrous ethanol (50.0 mL), sodium borohydride (421 mg, 11.0 mmol) was added, and the reaction mixture was stirred for 2 h. TLC was used to monitor the end point of the reaction. The reaction solution was concentrated under reduced pressure, and dichloromethane (100.0 mL) was added to dilute it. The organic phase was washed with 1.0 M sodium hydroxide aqueous solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 3:1) to obtain the title product (2.30 g, colorless oil).

[1540] MS (ESI) m / z [M+H] + =217.9.

[1541] 1 H NMR (400MHz, CD 3 OD)δ4.33(s,1H),4.21-4.07(m,2H),3.91(d,J=4.0Hz,1H),3.76-3.65(m,1H),3.48(br.s,1H),3.26- 3.20(m,1H),2.60-2.56(m,1H),1.94-1.76(m,1H),1.72-1.60(m,1H),1.45(s,9H),1.31-1.23(m,3H)

[1542] Step 2: Synthesis of 1-tert-butyl 3-ethyl 5,6-dihydropyridine-1,3(2H)-dicarboxylate (123-3)

[1543] At 0°C, under nitrogen protection, compound 123-2 (1.0 g, 3.66 mmol) and triphenylphosphine (2.39 g, 9.10 mmol) were added to anhydrous tetrahydrofuran (40.0 mL) in sequence, and DEAD (1.27 g, 7.32 mmol) was added. The mixture was heated to room temperature and stirred for 12 h. The reaction end point was monitored by LCMS. Ethyl acetate (100 mL) was added to the reaction solution, and the organic phase was separated and washed with saturated brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 5:1) to obtain the title product (830 mg, colorless oil).

[1544] MS (ESI) m / z [M+H] + =178.9.

[1545] 1 H NMR (400MHz, CD 3OD)δ7.11-7.05(m,1H),4.26-4.18(m,2H),4.09(d,J=2.0Hz,2H),3.49(s,2H),2.36-2.28(m,2H),1.48(s,9H),1.29(t,J=7.2Hz,3H)

[1546] Step 3: Synthesis of 1-tert-butyl 3-ethyl 4-(cyanomethyl)piperidine-1,3-dicarboxylic acid (123-4)

[1547] Under nitrogen protection at -78°C, trimethylsilylacetonitrile (107 mg, 0.840 mmol) was dissolved in anhydrous tetrahydrofuran (5.0 mL), and a tetrahydrofuran solution of n-butyl lithium (0.47 mL, 1.18 mmol, 2.5 M) was added. The mixture was stirred for 30 min, and compound 123-3 (200 mg, 0.784 mmol) was added. The mixture was stirred for 2 h at this temperature. The reaction end point was monitored by TLC. The reaction solution was naturally warmed to room temperature, and water (15.0 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (30.0 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (500 mg). The crude product was dissolved in acetonitrile (6.0 ml), cesium carbonate (767 mg, 2.35 mmol) was added, and the mixture was stirred at room temperature for 12 h. Ethyl acetate (100 mL) was added to the reaction solution, and the organic phase was washed with saturated brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-5:1) to give the title product (100 mg, colorless oil).

[1548] 1 H NMR (400MHz, CD 3 OD)δ4.25-4.12(m,2H),3.26-3.05(m,1H),3.00-2.73(m,2H),2.70-2.28(m,3H ),2.23-2.09(m,1H),1.92-1.86(m,1H),1.84-1.43(m,11H),1.33-1.24(m,3H)

[1549] Step 4: Synthesis of tert-butyl 8-oxooctahydro-2,7-naphthyridine-2(1H)-carboxylate (123-5)

[1550] At room temperature, compound 123-4 (310 mg, 1.04 mmol) was dissolved in ethanol (10.0 mL), and aqueous ammonia (1.0 mL) and Raney nickel (200 mg) were added to the mixture in sequence, and the mixture was stirred for 12 h under a hydrogen atmosphere. The reaction endpoint was monitored by LCMS. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product (120 mg, colorless oil).

[1551] MS (ESI) m / z [M+H] + =198.9.

[1552] 1 H NMR (400 MHz, DMSO-d 6 )δ7.44-7.36(m,1H),4.33(br.s,1H),3.53(br.s,1H),3.21-3.06(m,4H), 2.31-2.22(m,1H),2.06(d,J=3.6Hz,1H),1.79-1.51(m,4H),1.38(s,9H).

[1553] Step 5: Synthesis of octahydro-2,7-naphthyridin-1(2H)-one (123-6)

[1554] The experimental procedure was as described in step 4 of Example 109, using intermediate 123-5 as the reactant to obtain the title product.

[1555] Step 6: Synthesis of 7-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)octahydro-2,7-naphthyridin-1(2H)-one (123-7)

[1556] The experimental operation was as described in Example 1, using intermediate A8 and 123-6 as reactants to obtain the title product.

[1557] Step 7: Synthesis of cis-7-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-octahydro-2,7-naphthyridin-1(2H)-one (123) and trans-7-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-octahydro-2,7-naphthyridin-1(2H)-one (124)

[1558] The crude product 123-7 obtained in step 6 was separated and purified by HPLC (separation conditions: chromatographic column: Phenomenex C18 150*40mm*5μm; mobile phase: water (0.225% trifluoroacetic acid solution)-acetonitrile; gradient: B%: 5%-35% / 10min; flow rate: 60mL / min) to give the title compounds 123 (15mg, white solid) and 124 (19mg, white solid).

[1559] Analytical data of compound 123:

[1560] HPLC retention time 2.529min;

[1561] HPLC analysis conditions: chromatographic column: Ultimate C18 3*50mm 3μm; mobile phase: A: 1.5mL trifluoroacetic acid / 4L water, B: acetonitrile; gradient: B%: 10%-80% / 6min; flow rate: 1.2mL / min; column temperature: 50℃;

[1562] MS (ESI) m / z [M+H] + =470.2.

[1563] 1 H NMR (400MHz, CD 3 OD)δ7.76(s,4H),7.41(d,J=9.6Hz,1H),7.03-6.75(m,2H),5.47(s,2H),4.36-4.35(m,1H),4.16-4.12(m,1H),3.41-3.37(m,1H),3.27-3. 25(m,1H),3.20-3.16(m,1H),3.10-3.03(m,1H),2.59-2.58(m,1H),2 .47(s,3H),2.30-2.26(m,1H),1.95-1.92(m,2H),1.73-1.67(m,2H).

[1564] Analytical data of compound 124:

[1565] HPLC analysis retention time 2.672min;

[1566] HPLC analysis conditions: chromatographic column: Ultimate C18 3*50mm 3μm; mobile phase: A: 1.5mL trifluoroacetic acid / 4L water, B: acetonitrile; gradient: B%: 10%-80% / 6min; flow rate: 1.2mL / min; column temperature: 50℃;

[1567] MS (ESI) m / z [M+H] + =470.1.

[1568] 1 H NMR (400MHz, CD 3 OD)δ7.77(s,4H),7.37(d,J=9.6Hz,1H),7.02-6.74(m,2H),5.48(s,2H),4.57-4.55(m,1H),4.31-4.27(m,1H),3.37-3.33(m,2H) ,2.88-2.87(m,1H),2.76-2.70(m,1H),2.47(s,3H),2.13-2.12(m,1H),1.88-1.77(m,3H),1.65-1.55(m,1H),1.41-1.45(m,1H).

[1569] Embodiment 125:

[1570] N-ethyl-1-(6-((1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)azetidine-3-carboxamide (125)

[1571]

[1572] The experimental operation was as described in Examples 37 and 38, using F4 and azetidine-3-carboxylic acid methyl ester hydrochloride as raw materials, and undergoing coupling, hydrolysis and condensation reaction steps to obtain the title product.

[1573] MS (ESI) m / z [M+H] + =412.2.

[1574] 1 H NMR (400 MHz, DMSO-d 6 )δ7.99(br.s,1H),7.68-7.64(m,2H),7.48-7.44(m,2H),6.97(d,J=9.6Hz,1H),6.90(d,J=9.6Hz,1H),5.38(s,2H ),4.07-4.03(m,2H),3.96-3.93(m,2H),3.44-3.41(m,1H),3.12-3.05(m,2H),2.37(s,3H),1.00(t,J=7.2Hz,3H).

[1575] Embodiment 126:

[1576] (S)-8-(6-((1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)octahydropyrazino[2,1-c][1,4]oxazine (126)

[1577]

[1578] The experimental procedure was as described in Example 1, using F4 and (S)-octahydropyrazino[2,1-c][1,4]oxazine hydrochloride as reactants to obtain the title product.

[1579] MS (ESI) m / z [M+H] + =426.2.

[1580] 1 H NMR (400 MHz, DMSO-d 6 )δ7.68-7.64(m,2H),7.44-7.36(m,3H),6.99(d,J=9.6Hz,1H),5.40(s,2H),4.06-4.03(m,1H),3.95-3.92(m,1H),3.76-3.69(m,2H),3.55- 3.49(m,1H),3.17-3.12(m,1H),2.90-2.84(m,1H),2.80-2.77(m,1H), 2.67-2.64(m,1H),2.43-2.40(m,1H),2.37(s,3H),2.23-2.14(m,3H).

[1581] Embodiment 127:

[1582] 4-(6-((4-(4-(difluoromethyl)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (127)

[1583]

[1584] The experimental operation was as described in Example 1, using intermediate N7 and 2-piperazinone as reactants to obtain the title product.

[1585] MS (ESI) m / z [M+H] + =416.1.

[1586] 1 H NMR (400MHz, CD 3OD)δ7.87(d,J=8.0Hz,2H),7.65(d,J=8.0Hz,2H),7.38(d,J=9.6Hz,1H),7.11(d,J=9.6Hz,1H),6. 82(t,J=55.6Hz,1H),5.68(s,2H),4.27(s,3H),4.15(s,2H),3.79-3.75(m,2H),3.48-3.46(m,2H).

[1587] Embodiment 128:

[1588] 4-(6-((4-(4-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (128)

[1589]

[1590] The experimental operation was as described in Example 1, using intermediate P6 and 2-piperazinone as reactants to obtain the title product.

[1591] MS (ESI) m / z [M+H] + =384.1.

[1592] 1 H NMR (400 MHz, DMSO-d 6 )δ8.08(s,1H),7.79-7.76(m,2H),7.45(d,J=9.6Hz,1H),7.32(dd,J=8.8,9.2Hz,2H),7.15(d ,J=9.6Hz,1H),5.60(s,2H),4.16(s,3H),4.00(s,2H),3.70-3.67(m,2H),3.30-3.28(m,2H).

[1593] Embodiment 129:

[1594] (S)-8-(6-((4-methyl-1-(p-tolyl)-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)octahydro-1H-pyrazino[1,2-a]pyrazin-1-one (129)

[1595]

[1596] The experimental operation was as described in Example 1, using intermediate L4 and 77-4 as reactants to obtain the title product.

[1597] MS (ESI) m / z [M+H] + =435.2.

[1598] 1 H NMR (400 MHz, DMSO-d 6 )δ7.79(s,1H),7.46(d,J=7.9Hz,2H),7.40-7.35(m,3H),7.00(d,J=9.6Hz,1H),5.37(s,2H),4.47-4.39(m,1H),4.03-3.96 (m,1H),3.32-3.29(m,1H),3.09-3.04(m,1H),2.94-2.84(m,3H),2.65-2.61(m,2H),2.43-2.36(m,7H),2.28-2.22(m,1H).

[1599] Embodiment 130:

[1600] (S)-8-(6-((1-(4-(difluoromethoxy)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)octahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one (130)

[1601]

[1602] The experimental operation was as described in Example 1, using intermediate M4 and 77-4 as reactants to obtain the title product.

[1603] MS (ESI) m / z [M+H] + =487.2.

[1604] 1 H NMR (400 MHz, DMSO-d 6 )δ7.79(br.s,1H),7.69(d,J=8.4Hz,2H),7.54-7.17(m,5H),7.01(d,J=9.6Hz,1H),5.42(s,2H),4.49-4.41(m,1H),4.04-4.01(m,1 H),3.29-3.25(m,1H),3.09-3.07(m,1H),2.92-2.85(m,3H),2.67-2.59(m,2H),2.44-2.41(m,1H),2.39(s,3H),2.30-2.24(m,3H).

[1605] Embodiment 131:

[1606] 4-(6-((4-chloro-1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (131)

[1607]

[1608] The experimental operation was as described in Example 1, using intermediate Q3 and 2-piperazinone as reactants to obtain the title product.

[1609] MS (ESI) m / z [M+H] + =436.1.

[1610] 1 H NMR (400MHz, CD 3 OD)δ7.81-7.76(m,4H),7.35(d,J=9.6Hz,1H),7.01(d,J=9.6Hz,1H),6.89(t,J =55.6Hz,1H),5.52(s,2H),4.12(s,2H),3.77-3.74(m,2H),3.47-3.44(m,2H).

[1611] Embodiment 132:

[1612] 4-(6-((1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (132)

[1613]

[1614] Step 1: Synthesis of 4-(6-chloropyridazin-3-yl)piperazin-2-one (132-2)

[1615] At room temperature, compound 132-1 (1.96 g, 13.2 mmol) was dissolved in dimethyl sulfoxide (30.0 mL), and N, N-diisopropylethylamine (5.13 g, 39.7 mmol) and 2-piperazinone (1.40 g, 14.0 mmol) were added in sequence, and the reaction temperature was raised to 130 ° C and stirred for 16 h. The reaction end point was monitored by TLC. The reaction solution was filtered, and the filter cake was washed with methyl tert-butyl ether (20.0 mL), and the filter cake was collected and dried in vacuo to obtain the title product (1.70 g, brown solid).

[1616] MS (ESI) m / z [M+H] + =213.1.

[1617] 1 H NMR (400 MHz, CDCl 3 )δ7.40(d,J=9.6Hz,1H),7.15(d,J=9.6Hz,1H),4.16(s,2H),3.88(t,J=5.6Hz,2H),3.48(t,J=5.6Hz,2H).

[1618] Step 2: Synthesis of methyl 1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazole-5-carboxylate (132-3)

[1619] The experimental procedure was as described in step 2 of the synthesis of intermediate H5, using H2 and methyl propiolate as reactants to obtain the title product.

[1620] MS (ESI) m / z [M+H] + =254.1.

[1621] 1 H NMR (400 MHz, CDCl 3 )δ8.28(s,1H),7.71-7.69(m,2H),7.62-7.60(m,2H),6.75(t,J=56.0Hz,1H),3.87(s,3H).

[1622] Step 3: Synthesis of (1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methanol (132-4)

[1623] The experimental procedure was as described in step 1 of the synthesis of intermediate K3, using 132-3 as the reactant to obtain the title product.

[1624] MS (ESI) m / z [M+H] + =226.1.

[1625] Step 4: Synthesis of 4-(6-((1-(4-(difluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (132)

[1626] Under nitrogen protection, compound 132-4 (100.0 mg, 0.44 mmol) was dissolved in anhydrous toluene (3.0 mL), and cesium carbonate (434 mg, 1.33 mol), 132-2 (113.3 mg, 0.53 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (18.8 mg, 0.044 mmol) and palladium acetate (9.97 mg, 0.044 mmol) were added in sequence, and the reaction temperature was raised to 110°C and stirred for 16 hours. The reaction endpoint was monitored by TLC. The reaction solution was cooled to room temperature, diluted with water (10.0 mL), extracted with ethyl acetate (10.0 mL x 3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 150*40mm*5μm; mobile phase: water (0.225% trifluoroacetic acid solution)-acetonitrile]; B%: 12%-42%; flow rate: 60 mL / min) to give the title product (12.7 mg, white solid).

[1627] MS (ESI) m / z [M+H] + =402.1.

[1628] 1 H NMR (400MHz, CD 3 OD)δ8.04(s,1H),7.82-7.77(m,4H),7.36(d,J=9.6Hz,1H),7.04(d,J=9.6Hz,1H),6. 90(t,J=55.6Hz,1H),5.57(s,2H),4.13(s,2H),3.77-3.74(m,2H),3.47-3.44(m,2H).

[1629] Embodiment 133:

[1630] 3-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-6-(3-oxopiperazin-1-yl)pyridazine-4-carbonitrile (133)

[1631]

[1632] The experimental operation was as described in Example 1, using intermediate A12 and 2-piperazinone as reactants to obtain the title product.

[1633] MS (ESI) m / z [M+H] + =441.1.

[1634] 1 H NMR (400MHz, CD 3 OD)δ7.80(s,1H),7.79(s,4H),6.91(t,J=55.6Hz,1H),5.65(s,2H),4.16(s,2H),3.82-3.80(m,2H),3.47-3.45(m,2H),2.53(s,3H).

[1635] Example 134 and Example 135:

[1636] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-5-methoxypyridazin-3-yl)piperazin-2-one (134)

[1637] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-4-methoxypyridazin-3-yl)piperazin-2-one (135)

[1638]

[1639] Step 1: Synthesis of 6-chloro-3-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-4-methoxypyridazine (134-1) and 3-chloro-6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-4-methoxypyridazine (135-1)

[1640] At room temperature, intermediate A7 (300 mg, 1.25 mmol) and 3,6-dichloro-4-methoxypyridazine (268 mg, 1.5 mmol) were dissolved in N,N-dimethylformamide (8 mL), potassium carbonate (2.1 g, 15.0 mmol) was added, and the temperature was raised to 80 ° C and stirred for 1 h. TLC was used to monitor the reaction end point. The reaction solution was cooled to room temperature, filtered, and the filtrate was diluted with ethyl acetate (150 mL). The organic phase was washed with saturated brine (150 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:1) to obtain a mixture of the title products 134-1 and 135-1 (195 mg, white solid).

[1641] 134-1:MS(ESI)m / z[M+H] + =382.1.

[1642] 135-1:MS(ESI)m / z[M+H] + =382.1.

[1643] Step 2: Synthesis of 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-5-methoxypyridazin-3-yl)piperazin-2-one (134) and 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-4-methoxypyridazin-3-yl)piperazin-2-one (135)

[1644] The experimental procedures were as described in step 2 of the synthesis of Examples 81 and 82 to give the title products 134 and 135, respectively.

[1645] Compound 134:

[1646] MS (ESI) m / z [M+H] + =446.2.

[1647] 1 H NMR (400 MHz, DMSO-d 6)δ8.06(br.s,1H),7.78(s,4H),7.14(t,J=55.6Hz,1H),6.80(s,1H),5.45(s,2H ),3.99(s,2H),3.82(s,3H),3.70-3.68(m,2H),3.32-3.30(m,2H),2.39(s,3H).

[1648] Compound 135:

[1649] MS (ESI) m / z [M+H] + =446.2.

[1650] 1 H NMR (400 MHz, DMSO-d 6 )δ7.86(br.s,1H),7.79(s,4H),7.13(t,J=55.6Hz,1H),6.66(s,1H),5.47(s,2H ),3.85(s,3H),3.78(s,2H),3.48-3.46(m,2H),3.22-3.20(m,2H),2.40(s,3H).

[1651] Example 136 and Example 137:

[1652] 4-(8-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyrido[2,3-d]pyridazin-5-yl)piperazin-2-one (136)

[1653] 4-(5-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyrido[2,3-d]pyridazin-8-yl)piperazin-2-one (137)

[1654]

[1655] The experimental procedure was as described in Examples 81 and 82, using intermediate A7 and 5,8-dichloropyrido[2,3-d]pyridazine as starting materials, and after substitution and coupling reaction steps, the title products 136 and 137 were obtained, respectively.

[1656] Compound 136:

[1657] MS (ESI) m / z [M+H] + =467.3.

[1658] 1 H NMR (400 MHz, DMSO-d 6)δ9.18(dd,J=2.0,4.4Hz,1H),8.51(dd,J=1.6,8.4Hz,1H),7.98-7.94(m,2H),7.87(d,J=8.4Hz,2H),7.75(d,J=8. 4Hz,2H),7.10(t,J=55.6Hz,1H),5.68(s,2H),3.91(s,2H),3.54(t,J=5.2Hz,2H),3.39-3.36(m,2H),2.46(s,3H).

[1659] Compound 137:

[1660] MS (ESI) m / z [M+H] + =467.3.

[1661] 1 H NMR (400 MHz, DMSO-d 6 )δ9.18(dd,J=2.0,4.4Hz,1H),8.15(dd,J=1.6,8.4Hz,1H),7.99(s,1H),7.86-7.82(m,3H),7.75(d,J=8.4Hz, 2H),7.10(t,J=55.6Hz,1H),5.71(s,2H),4.26(s,2H),4.04(t,J=5.2Hz,2H),3.36-3.34(m,2H),2.46(s,3H).

[1662] Embodiment 138

[1663] 1-(2-(1H-pyrazol-1-yl)ethyl)-4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)piperazin-2-one (138)

[1664]

[1665] The experimental procedure was as described in step 1 of Example 59 and steps 2-3 of Example 58, using compounds 58-1 and 138-1 as starting materials to obtain the title product.

[1666] MS (ESI) m / z [M+H] + =510.3.

[1667] 1 H NMR (400 MHz, DMSO-d 6)δ7.78(s,4H),7.63(s,1H),7.40(s,1H),7.37(d,J=9.6Hz,1H),7.12(t,J=55.6Hz,1H),7.03(d,J=9.6Hz,1H),6.14(s,1H),5. 45(s,2H),4.26(t,J=5.8Hz,2H),4.02(s,2H),3.66(t,J=5.8Hz,2H),3.58(t,J=4.8Hz,2H),2.97(t,J=4.8Hz,2H),2.39(s,3H).

[1668] Embodiment 139

[1669] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(2-methoxyethyl)piperazin-2-one (139)

[1670]

[1671] The experimental operation was as described in step 1 of Example 59 and steps 2-3 of Example 58, using compound 58-1 and 2-bromoethyl methyl ether as starting materials to give the title product.

[1672] MS (ESI) m / z [M+H] + =474.2.

[1673] 1 H NMR (400 MHz, DMSO-d 6 )δ7.77(s,4H),7.39(d,J=9.6Hz,1H),7.12(t,J=56.0Hz,1H),7.03(d,J=9.6Hz,1H),5. 44(s,2H),4.03(s,2H),3.77-3.63(m,2H),3.54-3.41(m,6H),3.21(s,3H),2.38(s,3H).

[1674] Embodiment 140

[1675] 4-(6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-1-(3-methoxypropyl)piperazin-2-one (140)

[1676]

[1677] The experimental procedure was as described in step 1 of Example 59 and steps 2-3 of Example 58, using compound 58-1 and 3-bromopropyl methyl ether as starting materials to give the title product.

[1678] MS (ESI) m / z [M+H] + =488.2.

[1679] 1 H NMR (400 MHz, DMSO-d 6 )δ7.77(s,4H),7.39(d,J=9.6Hz,1H),7.12(d,J=55.6Hz,1H),7.02(t,J=9.6Hz,1H),5.44(s,2H) ,4.01(s,2H),3.77-3.6...

Claims

1. A compound as shown in formula I, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, in Ring A is selected from a benzene ring or a 5-6-membered heteroaryl group, wherein the heteroatoms in the 5-6-membered heteroaryl group are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; R1 is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkylamino group is optionally substituted with 1 to 3 R's; R's are independently selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, cyclopropyl or methoxy; k is 0, 1, 2, or 3; for R2 is selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which may be optionally substituted by 1-3 R'; L is selected from -CH2-O-; Ring B is selected from 5-10 membered heteroaryl; R3 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, each of which may be optionally substituted by 1 to 3 R'; m is 0, 1, 2 or 3; Ring D is selected from 4-14 membered heterocycloalkyl, wherein the 4-14 membered heterocycloalkyl is a monocyclic, bicyclic or tricyclic saturated or semi-saturated cyclic group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4, wherein, The ring directly connected to ring B is not aromatic; The R4 is independently selected from hydrogen, halogen, cyano, =O, -R5, -OR6, -COOR6, -C(O)R5, -NR6R7, -NR6COR5, -NR6SO2R5, -CH2-C(O)NR6R7, -C(O)NR6R7, -SO2R6 or -SO2NR6R7; R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R; R6 and R7 are independently selected from hydrogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl (C 1-6 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-6 ) alkyl, each of which may be optionally substituted by 1 to 3 R; When R4 is selected from -NR6R7, -C(O)NR6R7 or -SO2NR6R7, R6 and R7 together with the connected N atom may form a 4-7 membered heterocyclic ring, and the 4-7 membered heterocyclic ring may be optionally substituted by 1-3 R; R is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R'; n is 0, 1, 2, 3, 4, 5 or 6; In ring B, R5, R6 and R7, the heteroatoms in the 5-10 membered heteroaryl group are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; In R2, R6, R7 and R, the heteroatoms in the 3-6 membered heterocycloalkyl group are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3.

2. The compound of formula I as claimed in claim 1, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from a benzene ring or a 5-6 membered heteroaryl group; R1 is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkylamino group is optionally substituted with 1 to 3 R's; R' is independently selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, cyclopropyl or methoxy; k is 0, 1, 2, or 3; T1 and T2 are independently selected from carbon atoms or nitrogen atoms; R2 is selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, each of which may be optionally substituted by 1-3 R'; L is selected from -CH2-O-; Ring B is selected from 5-10 membered heteroaryl; R3 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, each of which may be optionally substituted by 1 to 3 R'; m is 0, 1, 2 or 3; Ring D is selected from 4-14 membered heterocycloalkyl; Ring D may be substituted by one or more independent R4, each of which is independently selected from hydrogen, halogen, cyano, =O, -R5, -OR6, -COOR6, -C(O)R5, -NR6R7, -NR6COR5, -NR6SO2R5, -C(O)NR6R7, -SO2R6 or -SO2NR6R7; R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R; R6 and / or R7 are independently selected from hydrogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl (C 1-6 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-6 ) alkyl, each of which may be optionally substituted by 1 to 3 R; When R4 is selected from -NR6R7, -C(O)NR6R7 or -SO2NR6R7, R6 and R7 together with the connected N atom may form a 4-7 membered heterocyclic ring, and the 4-7 membered heterocyclic ring may be optionally substituted by 1-3 R; R is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R'; n is 0, 1, 2, 3, 4, 5 or 6.

3. The compound of formula I as claimed in claim 1, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: It meets any of the following conditions: (1) R2 is a 5-6 membered heteroaryl group; (2) R4 are each independently -CH2-C(O)NR6R7; and (3) Each R is independently COOH.

4. The compound of formula I, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: It meets any of the following conditions: (1) In R1, R', R2, R3, R4 and R, the halogen is independently fluorine, chlorine, bromine or iodine; (2) Among R1, R3, R5, R6, R7 and R, the C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (3) In R2, the C 1-3 Alkyl is independently methyl, ethyl, n-propyl or isopropyl; (4) Among R1, R3, R6, R7 and R, the C 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (5) In R2, the C 1-3 Alkoxy is independently methoxy, ethoxy, n-propoxy or isopropoxy; (6) Among R1, R2, R3, R6, R7 and R, the C 1-6 Alkylamino is independently -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)2, -NHCH2CH2CH3, -NHCH(CH3)2 or -NHCH2CH2CH2CH3; (7) Among R2, R6, R7 and R, the C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (8) In ring D, the 4-14 membered heterocycloalkyl group is a monocyclic, bicyclic or tricyclic saturated cyclic group having 1, 2 or 3 heteroatoms selected from N, O and S, 1, 2, 3 or 4 heteroatoms; (9) When R6 and R7 together with the connected N atom can form a 4-7 membered heterocyclic ring, the 4-7 membered heterocyclic ring is a monocyclic or bicyclic saturated cyclic group with 1, 2 or 3 heteroatoms selected from N, O and S; and (10) In R5, R6 and R7, the 6-10 membered aryl group is independently phenyl or naphthyl.

5. The compound of formula I as claimed in claim 4, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: Among R1, R3, R6, R7 and R, the C 1-6 Alkoxy is independently methoxy.

6. The compound of formula I, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: It meets any of the following conditions: (1) In ring A and R2, the 5-6 membered heteroaryl group is pyridyl or isoxazolyl; (2) In ring B, R5, R6 and R7, the 5-10 membered heteroaryl group is pyridyl, pyridazinyl, pyrazinyl or pyridopyridazinyl; (3) In R1, R', R2, R3, R4 and R, the halogen is independently fluorine or chlorine; (4) In R2, the C 1-3 Alkyl is independently methyl; (5) Among R1, R2, R3, R6, R7 and R, the C 1-6 Alkylamino is independently -NMe2; (6) Among R2, R6, R7 and R, the C 3-6 Cycloalkyl is independently cyclopropyl; (7) In R2, R6, R7 and R, the 3-6 membered heterocycloalkyl group is oxetanyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, tetrahydropyranyl or piperidinyl; (8) In ring D, the 4-14 membered heterocycloalkyl group is (9) When R6 and R7 together with the connected N atom can form a 4-7 membered heterocyclic ring, the 4-7 membered heterocyclic ring is and (10) in R5, R6 and R7, the 6-10 membered aryl group is independently phenyl.

7. The compound of formula I, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: It meets any of the following conditions: (1) R1 is independently hydrogen, halogen, cyano, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally substituted with 1-3 R'; (2) k is 0, 1 or 2; (3) R2 is selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 3-6 Cycloalkyl or 5-6 membered heteroaryl, each of which may be optionally substituted by 1-3 R'; (4) When T1 is a nitrogen atom and T2 is a carbon atom, for R2 is selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 5-6 membered heteroaryl, each of which may be optionally substituted by 1-3 R'; (5) When T1 is a carbon atom and T2 is a nitrogen atom, for R2 is selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or 5-6 membered heteroaryl, each of which may be optionally substituted by 1-3 R'; (6) R3 are independently hydrogen, halogen, cyano, C 1-3 Alkyl or C 1-3 Alkoxy, each of which may be optionally substituted by 1 to 3 R'; (7) m is 0 or 1; (8) R4 are independently selected from hydrogen, halogen, cyano, =O, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl (C 1-3 )alkyl, -COOH, -CH2-C(O)NR6R7, -C(O)NR6R7, -SO2R6 or -SO2NR6R7; the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl may be optionally substituted by 1-3 R each; when R4 is selected from -C(O)NR6R7 or -SO2NR6R7, R6 and R7 together with the connected N atom may form a 4-7 membered heterocyclic ring, and the 4-7 membered heterocyclic ring may be optionally substituted by 1-3 R each; (9) R6 and R7 are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R; (10) R are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1-3 R'; (11) n is 0, 1, 2, 3 or 4; (12) Ring A is a benzene ring, a pyridine ring or a pyrimidine ring; (13) Ring B is a pyridine ring, a pyridazine ring, a pyrazine ring or a pyridopyridazine ring; and (14) R3 are independently H, F, Cl, CN, Me or -OCH3.

8. The compound of formula I, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: It meets any of the following conditions: (1) R1 is independently halogen, cyano, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl and / or C 1-3 The alkoxy group is optionally substituted by 1-3 R's, each of which is independently hydrogen, halogen, hydroxyl, cyano or methoxy; (2) k is 1; (3) R2 is selected from hydrogen, halogen, cyano, C 1-3 Alkyl or C 3-6 Cycloalkyl, each of which may be optionally substituted by 1 to 3 R'; (4) When T1 is a nitrogen atom and T2 is a carbon atom, for R2 is selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C substituted by cyclopropyl or hydroxy 1-3 Alkyl, 5-6 membered heteroaryl substituted by methyl; (5) When T1 is a carbon atom and T2 is a nitrogen atom, for R2 is selected from Me or CHF2; (6) m is 0; (7) R4 are independently selected from the following substituents: hydrogen, cyano, =O, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl (C 1-3 )alkyl, -COOH, -C(O)NR6R7, -SO2R6 or -SO2NR6R7, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl may be optionally substituted by 1-3 R each; when R4 is selected from -C(O)NR6R7 or -SO2NR6R7, R6 and R7 together with the connected N atom may form a 4-7 membered heterocyclic ring, and the 4-7 membered heterocyclic ring may be optionally substituted by 1-3 R each; (8) R are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1-3 R'; (9) n is 1 or 2; (10) Ring A is a benzene ring or a pyridine ring; (11) Ring B is a pyridine ring, a pyridazine ring, a pyrazine ring or a pyridopyridazine ring; and (12) R3 are each independently H, CN, Me or -OCH3.

9. The compound of formula I as claimed in claim 8, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: It meets any of the following conditions: (1) R1 is independently halogen, cyano, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally substituted by 1-3 R's, each of which is independently hydrogen, halogen or hydroxy; (2) When T1 is a carbon atom and T2 is a nitrogen atom, for R2 is Me; and (3) Ring B is a pyridine ring, a pyridazine ring or a pyridopyridazine ring.

10. The compound of formula I, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: It meets any of the following conditions: (1) When T1 is a nitrogen atom, T2 is a carbon atom, and R2 is selected from H, F, Cl, CN, Me, CHF2, CF3, -CH2OH, -CH2OCH3, and (2) R1 is independently H, F, Cl, Me, CN, -CH2F, -CF2H, CF3, -OCF2H, -CH(CN)2, -CH2OH or -CH2OCH3.

11. The compound of formula I as claimed in claim 10, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: It meets any of the following conditions: (1) When T1 is a nitrogen atom, T2 is a carbon atom, and R2 is selected from H, Cl, Me, CH2OH, CN, CHF2, CF3, and (2) R1 is independently F, Cl, Me, -CH2F, -CF2H, CF3, CN, -CH(CN)2, -CH2OH, -CH2OCH3 or -OCF2H.

12. The compound of formula I, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: It meets any of the following conditions: (1) Structural unit For the structural unit (II) in X1 is selected from N or C; for and, Selected from X2 is a carbon atom, -NR 4c -, -O-, or -S(O) w -, the carbon atom is represented by one or two independent R 4b Substitution, the R 4b Each is independently selected from hydrogen, -OR6, -NR6R7, -NR6COR5, -C(O)NR6R7 or -SO2NR6R7; R5 is C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl, each of which may be optionally substituted by 1-3 R'; R6 and R7 are independently hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R; When R 4b When it is -NR6R7, -C(O)NR6R7 or -SO2NR6R7, R6 and R7 together with the connected N atom can form a 4-7 membered heterocyclic ring, the heterocyclic ring can optionally include 1 to 3 heteroatoms as ring atoms, the heteroatoms can be independently selected from N, O, S atoms, and the 4-7 membered heterocyclic ring can be optionally substituted by 1-3 R; The R 4c are independently hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R; R is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1-3 R'; R 4a are independently hydrogen, oxo, cyano, C 1-3 Alkyl, -COOR6, -CH2-C(O)NR6R7, -C(O)NR6R7, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl; the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl may be optionally substituted by 1-3 R', wherein R' is as defined in claim 1; n is 0, 1, 2, 3 or 4; p and q are each independently 0, 1 or 2, and p and q are not 2 at the same time; w is 0, 1, or 2; (2) Structural unit For the structural unit (III) in, X1 is N or C; for and, for X2 is one or two independent R 4b Substituted carbon atom, -NR 4c -, -O-, or -S(O) w -, the R 4b is hydrogen, -OR6, -NR6R7, -NR6COR5, -NR6SO2R5, -C(O)NR6R7, -SO2R5 or -SO2NR6R7; R5 is C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl, each of which may be optionally substituted by 1-3 R'; R6 and R7 are each independently hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R; When R 4b When it is -NR6R7, -C(O)NR6R7 or -SO2NR6R7, R6 and R7 together with the connected N atom can form a 4-7 membered heterocyclic ring, the heterocyclic ring can optionally include 1 to 3 heteroatoms as ring atoms, the heteroatoms can be independently selected from N, O, S atoms, and the 4-7 membered heterocyclic ring can be optionally substituted by 1-3 R; The R 4c For hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R; R is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1-3 R'; X3 for CR 4a or N; R 4a are independently hydrogen, oxo, cyano, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl may be optionally substituted by 1-3 R', wherein R' is as defined in claim 1; u and v are independently 0, 1 or 2; r, s, and t are each independently 0, 1, or 2; w is 0, 1, or 2; (3) Structural unit For the structural unit (IV) in R 4c For hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, phenyl (C 1-3 )alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl (C 1-3 ) alkyl, each of which may be optionally substituted by 1 to 3 R; R is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1-3 R'; R 4a are independently hydrogen, cyano, oxo, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl; the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl may be optionally substituted by 1-3 R', wherein R' is as defined in claim 1; n is selected from 0, 1, 2, 3 or 4; (4) Structural unit is the structural unit (V) in X2 is one or two independent R 4a Substituted carbon atom or -O-, R 4a are independently hydrogen, cyano, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, or two R attached to the same carbon atom 4a together to form an oxo (C=O) group; the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl may be optionally substituted by 1-3 R', wherein R' is as defined in claim 1; u, v are each independently selected from 0, 1 or 2; r is selected from 0 or 1; and (5) Structural unit is the structural unit (VI) in Ring E is a 5-6 membered saturated cycloalkyl, a benzene ring or a 5-6 membered heteroaryl; R 4a are independently hydrogen, oxo, halogen, cyano, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl; the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl may be optionally substituted by 1-3 R', wherein R' is as defined in claim 1; R 4c For hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; u and v are independently 0, 1 or 2.

13. The compound of formula I as claimed in claim 12, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: In the structural unit (VI), R 4c For hydrogen.

14. The compound of formula I according to claim 12, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: It meets any of the following conditions: (1) Structural unit (II) for (2) Structural unit (III) for (3) Structural unit (V) for (4) Structural unit (VI) for (5) In structural unit (II), R 4a Each of the following is independently H, =O, -Me, -i-Pr, -t-Bu, -CH2CH(CH3)2, -COOH, -CN, -CH2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CH2CONHCH2CH3, (6) In the structural unit (III), R 4a are independently H, =O, -Me, -i-Pr, -t-Bu, -CH2CH(CH3)2, -CN, -CH2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, (7) In structural unit (IV), R 4a are independently H, =O, -Me, -i-Pr, -t-Bu, -CH2CH(CH3)2, -CN, -CH2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, (8) In the structural unit (V), R 4a are independently H, =O, -Me, -i-Pr, -t-Bu, -CH2CH(CH3)2, -CN, -CH2CN, -CH2OH, -(CH2)2OH, -CH2OCH3 (9) In structural unit (VI), R 4a are independently H, =O, -F, -Cl, -Me, -i-Pr, -t-Bu, -CH2CH(CH3)2, -CN, -CH2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, (10) In the structural unit (II), R 4b are independently H, -OCH3, -NMe2, -NHCOCH3, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -SO2NHCH3, (11) In the structural unit (III), R 4b are independently H, -OCH3, -NMe2, -NHCOCH3, -NHSO2CH3, -SO2Me, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -SO2NHCH3, (12) In the structural unit (II), R 4c are independently H, -Me, -Et, -i-Pr, -CF3, -CHF2, -CH2CF3, -CH2CF2H, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)2NH2, -(CH2)2OH, -(CH2)2OCH3, -(CH2)3OCH3, (13) In the structural unit (III), R 4c are independently H, -Me, -Et, -i-Pr, -CF3, -CHF2, -CH2CF3, -CH2CF2H, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)2NH2, -(CH2)2OH, -(CH2)2OCH3, -(CH2)3OCH3, (14) In structural unit (IV), R 4c are independently H, -Me, -Et, -i-Pr, -CF3, -CHF2, -CH2CF3, -CH2CF2H, -CH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)2NH2, -(CH2)2OH, -(CH2)2OCH3, -(CH2)3OCH3, (15) In the structural unit (VI), R 4c are independently H, -Me, -Et, -i-Pr, 15. The compound of formula I as claimed in claim 14, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: Structural unit (III) for 16. The compound of formula I according to claim 12, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: It meets any of the following conditions: (1) Structural unit (II) for (2) Structural unit (III) for (3) In structural unit (II), R 4a are independently H, =O, -Me, -i-Pr, -t-Bu, -CH2CH(CH3)2, -COOH, -CN, -CH2OH, -CONH2, -CONHCH2CH3, -CON(CH3)2, -CH2CONHCH2CH3, (4) In the structural unit (III), R 4a are independently H, =O, -Me, -i-Pr, -t-Bu, -CH2CH(CH3)2, -CN, -CH2OH, (5) In structural unit (IV), R 4a are independently H, =O, -Me, -i-Pr, -t-Bu, -CH2CH(CH3)2, -CN, -CH2OH, (6) In the structural unit (V), R 4a are independently H, =O, -Me, -i-Pr, -t-Bu, -CH2CH(CH3)2, -CN, -CH2OH, (7) In structural unit (VI), R 4a are independently H, =O, -F, -Me, -i-Pr, -t-Bu, -CH2CH(CH3)2, -CN, -CH2OH, (8) In structural unit (II), R 4b are independently H, -OCH3, -NMe2, -NHCOCH3, -CONHCH2CH3, -SO2NHCH3, (9) In the structural unit (III), R 4b are independently H, -OCH3, -NMe2, -NHCOCH3, -CONHCH2CH3, -SO2NHCH3, (10) In the structural unit (II), R 4c are independently H, -Me, -CH2CF3, -CH2CN, -(CH2)3CN, -(CH2)2NH2, -(CH2)2OH, -(CH2)2OCH3, -(CH2)3OCH3, (11) In the structural unit (III), R 4c are independently H, -Me, -CH2CF3, -CH2CN, -(CH2)3CN, -(CH2)2NH2, -(CH2)2OH, -(CH2)2OCH3, -(CH2)3OCH3, (12) In structural unit (IV), R 4c are independently H, -Me, -CH2CF3, -CH2CN, -(CH2)3CN, -(CH2)2NH2, -(CH2)2OH, -(CH2)2OCH3, -(CH2)3OCH3, (13) In the structural unit (VI), R 4c They are independently H, -Me, 17. The compound of formula I according to claim 16, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: Structural unit (III) for 18. The compound of formula I, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: It meets any of the following conditions: (1) Structural unit Selected from (2) Ring D is (3) R4 is independently H, F, Cl, =O, -Me, -COOH, -Et, -i-Pr, -t-Bu, -CH2CH(CH3)2, -CF3, -CHF2, -CH2CF3, -CH2CF2, -CN, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -OCH3, -NMe2, -NHCOCH3, -NHSO2CH3, -SO2Me, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -SO2NHCH3, -COCH(CH3)2, -CONHCH2CH3, -CH2CONHCH2CH3, -(CH2)2NH2, -(CH2)2OCH3, -(CH2)3OCH3, -COCH3, 19. The compound of formula I as claimed in claim 18, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: It meets any of the following conditions: (1) Structural unit Selected from (2) Ring D is (3) R4 is independently H, F, =O, -Me, -i-Pr, -t-Bu, -CH2CH(CH3)2, -OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -NMe2, -COOH, -CN, -CH2CN, -CH2OH, -CONH2, -CONHCH3, -CONHCH2CH3, -CON(CH3)2, -CH2CONHCH2CH3, -NHCOCH3, -CH2CF3, -(CH2)2NH2, -(CH2)2OH, -SO2CH3, -SO2NHCH3, -(CH2)3CN, -COCH3, 20. The compound of formula I, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: It meets any of the following conditions: (1) Structural unit Selected from (2) Structural unit for (3) Structural unit is the following substituent:

21. The compound of formula I according to claim 20, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: It meets any of the following conditions: (1) Structural unit Selected from (2) Structural unit Select from the following substituents:

22. The compound of formula I according to claim 12, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: The compound shown in Formula I is a compound shown in Formula IA: in, for R1, R2, R 4a , R 4c , u, v, n and ring E are as defined in claim 12.

23. The compound of formula I as claimed in claim 22, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: It meets any of the following conditions: (1) In, R 4c For hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl (C 1-3 ) alkyl or 3-6 membered heterocycloalkyl; R 4c In the C 1-3 The alkyl group is optionally substituted with 1-3 independently selected substituents: halogen, cyano, hydroxy, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 3-6 membered heterocycloalkyl substituted by 1-3 halogens; R 4c wherein the 3-6 membered heterocycloalkyl is optionally substituted with 1-3 C 1-3 alkyl; R 4c wherein the 5-10 membered heteroaryl is optionally substituted with 1-3 independently selected substituents: C 1-3 Alkyl or C 1-3 Haloalkyl; R 4c wherein the 5-10 membered heteroaryl (C 1-3 ) alkyl is optionally substituted with 1-3 independently selected substituents: halogen, cyano or C 1-3 Alkoxy; (2) In, R 4c For hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; (3) In, R 4c is hydrogen; (4) In, R 4a are independently hydrogen, oxo, C 1-3 Alkyl or COOH, n is 0, 1 or 2; (5) In, R 4a are independently hydrogen, oxo, C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl or 5-6 membered heteroaryl; R 4a In the C 1-3 The alkyl group is optionally substituted with 1-3 methyl groups; R 4a In the above formula (A), the 5-6 membered heteroaryl group is optionally substituted with 1-3 methyl groups; R 4a In the above, the phenyl group is optionally substituted with 1-3 halogens; u is 0; v is 0 or 1; and (6) In, R 4a are independently hydrogen or halogen; u is 0, and v is 0 or 1.

24. The compound of formula I as claimed in claim 23, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: It meets any of the following conditions: (1) In, n is 0; (2) Medium R 4a is hydrogen or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1 to 3 methyl groups; and (3) , u is 0 and v is 0.

25. The compound of formula I according to claim 1, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, characterized in that: The compound as shown in formula I is selected from the following compounds: 。 26. A pharmaceutical composition, characterized in that It comprises a compound as shown in formula I as described in any one of claims 1 to 25, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof.

27. The pharmaceutical composition according to claim 26, characterized in that The pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents or excipients.

28. A use of a compound of formula I as described in any one of claims 1 to 25, its enantiomer, its diastereomer, its racemate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in any one of claims 26 to 27, wherein the use is selected from (1) or (2): (1) Preparation of α5-GABA A Receptor modulators; (2) Preparation of treatment or prevention with α5-GABA A Drugs for receptor-related diseases.

29. The use of the compound of formula I, its enantiomer, its diastereomer, its racemate or its pharmaceutically acceptable salt or the pharmaceutical composition as claimed in claim 28, characterized in that: The medicine is used for preparing medicine for treating or preventing the following diseases: pain, Alzheimer's disease, multi-infarct dementia and stroke.

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