Fused ring compound, and intermediate thereof and use thereof

Abstract

Provided in the present invention are a fused ring compound, and an intermediate thereof and the use thereof. Specifically, the present invention relates to a compound as shown in general formula (I), a cis-trans isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. The compound of the present invention has a good modulatory effect on an α5-GABAA receptor, and has good pharmaceutical application prospects.

Description

Fused cyclic compounds, their intermediates and applications

[0001] This application claims priority to Chinese patent application CN2024110588812, filed on August 2, 2024. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to a fused cyclic compound, its intermediates, and their applications, specifically to a compound for α5-GABA. A Fused cyclic compounds with receptor-regulating functions, their preparation, pharmaceutical compositions containing them, and its Their application as medicines. Background Technology

[0003] γ-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the mammalian central nervous system. Two types of GABA receptors exist in nature: one is GABAB... A Receptors, which are members of the ligand-gated ion channel superfamily, and another type is GABA. B Receptors, these receptors are members of the G protein-coupled receptor superfamily. GABA in mammals. A The receptor subunits discovered include α1-6, β1-4, γ1-3, δ, ε, θ, and ρ1-3, among which the α, β, and γ subunits form a complete functional GABA. A The acceptor is essential, while the α-subunit terephthalamide... with GABA A Receptor binding is crucial.

[0004] GABA containing α5 A receptor (α5-GABA) A GABA receptors in the mammalian brain A It accounts for less than 5% of the receptors and has very low expression levels in the cerebral cortex, but it is present in the hippocampus of the brain. A It accounts for more than 20% of the receptors, but is hardly expressed in other brain regions. Considering α5-GABA... A Studies on the specific distribution and function of α5-GABA receptors in the hippocampus of the brain are being conducted by many pharmaceutical companies, including Roche and Merck. A Research on receptor ligands has led to the synthesis of numerous compounds, particularly GABA containing the α5 subunit targeting the hippocampus of the brain. A GABA receptor inverse agonists, among which α5IA and MRK-016 have shown promising therapeutic effects on cognitive disorders in animal disease models. It is generally believed that the α5 subunit of GABA... AInverse agonists of the receptor can be used to treat cognitive disorders, particularly Alzheimer's disease. Patent application US20110224278 discloses GABA containing the α5 subunit. A Reverse agonists of the receptor can be used to treat multi-infarct dementia and stroke-related diseases.

[0005] GABA as the α5 subunit A When receptor-inverse agonists are used to treat related diseases such as Alzheimer's disease, multi-infarct dementia, and stroke, the compounds need to cross the blood-brain barrier and enter the brain to exert their effects. The literature (Jones et al., Bioorg Med Chem Lett. 2006, 16(4). 872-875) reports the ability to detect the inhibition of ( ) receptors. 3 The binding of H)RO-15-1788 (a specific inverse agonist of the α5-GABAA receptor) in the brain can be effectively inhibited by MRK016. 3 H)RO-15-1788 binds in the central nervous system, while MRK016-M3 has almost no significant inhibitory effect. 3 H)RO-15-1788 binds in the central nervous system. MRK016-M3 is thought to be unable to bind to GABA in the α5 subunit of the brain. A The receptors exert a reverse agonistic function.

[0006] In 2002, Zhang Xu's laboratory reported α5-GABA. A The receptor is also mainly expressed in small neurons, and its expression is elevated in the neural transection 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 elevated in a partial nerve injury model, and α5-GABA... A Reverse agonists of the receptor selectively bind to α5-GABA in the peripheral nervous system. A Receptors play a role in inhibiting various types of pain. Animal experimental model data show that the stronger the reverse agonist effect, the better its pain-inhibiting effect.

[0007] For different disease types, it is necessary to target the corresponding α5 subunit of GABA. A The selection is based on whether the inverse agonist of the receptor has blood-brain barrier permeability; α5-GABA binds to the peripheral nervous system. A Inverse agonists of receptors can inhibit various types of pain while avoiding central nervous system side effects; while α5-GABA, which binds to the central nervous system...A Inverse agonists of receptors are used to treat cognitive disorders.

[0008] GABA-mediated targeting of the α5 subunit A The structure of the compound of the receptor inverse agonist is modified to adjust the physicochemical properties of the compound (such as log D, PSA, etc.) so that the efflux transporter located at the blood-brain barrier (such as the Pgp transporter) can exert the effect of the compound. By controlling its efflux ratio, the compound can be obtained with properties such as good blood-brain barrier permeability or inability to cross the blood-brain barrier, and can play a role in different types of diseases.

[0009] Currently, GABA for the α5 subunit A Numerous reports have been published on receptor inverse agonists. The Merck series, represented by α5IA and MRK-016, exhibits low nM-level binding activity (Ki value) and high inverse agonist activity (Maramai et al., J. Med. Chem. 2020, 63, 3425-3446). The Roche series, represented by RO4938581 and RG1662, possesses high affinity selectivity and functional selectivity. Additionally, the ONO series, represented by ONO-8590580, also exhibits low nM-level binding activity (Ki value), high inverse agonist activity, and functional selectivity. Because the inverse agonist effect is correlated with animal efficacy, improving the inverse agonist effect of a compound will have a positive effect on its efficacy. Summary of the Invention

[0010] This invention provides a fused cyclic compound, its preparation method, pharmaceutical composition, and uses, which are completely different from existing technologies. This type of compound is effective against α5-GABA. A They exhibit excellent reverse agonistic activity, and some fused ring compounds, in particular, possess pharmaceutical properties such as good solubility or high bioavailability.

[0011] In a first aspect, the present invention provides a fused ring compound, which is a compound of formula (I), its cis-trans isomer, its enantiomer, its diastereomer, its racemic mixture, its solvate, its hydrate or a pharmaceutically acceptable salt thereof.

[0012] Among them, Z1, Z2 and Z3 are independently C or N, and only one of Z1, Z2 and Z3 is N, while the rest are C;

[0013] Z4 is CH or N;

[0014] R1 represents H and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, phenyl, 5-6 membered heteroaryl, phenyl C 1-3 Alkyl or 5-6-membered heteroaryl C 1-3 Alkyl, the C 1-6 One C atom of the alkyl group is optionally replaced by an O atom; the C 3-6 One C atom on the ring of the cycloalkyl group may optionally be replaced by an O atom, an N atom, or an S atom; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 Alkyl, phenyl, 5-6 membered heteroaryl, phenyl C 1-3 Alkyl and 5-6-membered heteroaryl C 1-3 Alkyl groups may be optionally substituted with 1-3 R's;

[0015] R2 is hydrogen, halogen, or C. 1-6 Alkyl, hydroxyl or C 1-6 Alkoxy; the C 1-6 Alkyl and C 1-6 The alkoxy group may be optionally substituted by 1-3 R's;

[0016] R3 can be hydrogen, halogen, amino, hydroxyl, or -NH-C. 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl or C 3-6 cycloalkyl; the C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 The cycloalkyl group may be optionally substituted with 1-3 R's;

[0017] X1 is O, S, NR9, -S(=O)2-, or CR 10 R 11 ;

[0018] R9 is hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally substituted with 1-3 R's;

[0019] R 10 and R 11 Each can be independently identified as hydrogen, halogen, hydroxyl, or C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6cycloalkyl, or R 10 and R 11 Together with C, they form -C(=O)-; the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 The cycloalkyl group may be optionally substituted with 1-3 R's;

[0020] R4, R5, R6, and R7 are independently selected from hydrogen, halogen, and C, respectively. 1-6 Alkyl or C 3-6 cycloalkyl; the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally substituted with 1-3 R', or R5 and R6 together form an oxo group (forming a C=O group with the linkage), or R6 and R7 together form an oxo (C=O) group;

[0021] n is 0 or 1 (when n is 0, it means that X1 is directly connected to the carbon atoms of R6 and R7 through a single bond);

[0022] Ring A is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 5-6 membered heterocyclic alkene, or a fused ring formed by ring A1 and ring A2, wherein the 6-10 membered aromatic ring, the 5-10 membered heteroaromatic ring, the 5-6 membered heterocyclic alkene, and the fused ring are independently and optionally converted by halogen, oxy, or C. 1-3 Alkyl substitution; ring A1 is a benzene ring or a 5-6 membered heteroaromatic ring, and ring A2 is a 5-7 membered monocyclic heterocycle;

[0023] Each R8 group 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, 4-14 membered heterocycloalkyl, 4-14 membered heterocycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or -C(O)NR 12 R 14 Or, two R8 atoms attached to the same carbon atom can form an oxo (C=O) group;

[0024] The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-14-membered heterocycloalkyl, 4-14-membered heterocycloalkenyl and 5-10-membered heteroaryl are each optionally surrounded by 1-3 groups selected from hydrogen, halogen, carboxyl, hydroxyl, C 1-3 Alkyl, hydroxyl substituted C 1-3 Alkyl groups, halogenated C 1-3 C substituted with alkyl or carboxylic acids 1-3 Alkyl, -C 1-3 Alkyl-NR12 R 14 C 1-3 Alkoxy, -C 1-3 Alkoxy-OC 1-3 Alkyl, -C 1-3 Alkoxy-OC 1-3 Alkyl-OC 1-3 Alkyl, C 3-6 Cycloalkyl groups, C substituted with 1-3 R's 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted with 1-3 R', 5-6 membered heteroaryl, 5-6 membered heteroaryl substituted with 1-3 R', C 1-6 Alkoxy, oxo, -NR 12 R 14 -C(O)-OC 1-3 Alkyl-OC 1-3 Alkyl-OC 1-3 Alkyl, -C(O)NR 12 R 14 -NR 12 C(O)C 1-3 Alkyl and -NR 12 C(O)C 1-3 Alkyl-OC 1-3 Alkyl groups are substituted;

[0025] Each R 12 and each R 14 Selected independently from hydrogen and C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl, or R 12 and R 14 Together with the adjacent N atom, they can optionally form a 4-7 membered heterocyclic group; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, and 5-10-membered heteroaryl groups are each optionally substituted with 1-3 R's;

[0026] Each R' can be independently represented as hydrogen, hydroxyl, halogen, -CN, oxo group, -C(=O)OH, C 1-3 Alkyl, -NH-C 1-3 Alkyl, -NH-(C 1-3 Alkyl)2, -S(=O)2-C 1-3 Alkyl, -C(=O)NR a R b -C(=O)-OC 1-3 Alkyl or C 1-3 Alkoxy;

[0027] m is 1, 2, 3, 4 or 5;

[0028] The heteroatoms in the aforementioned heteroaromatic rings, heteroaryl groups, heterocyclic alkenes, heterocycles, and heterocyclic alkyl groups are independently one or more of N, O, and S, and the number is 1, 2, 3, or 4.

[0029] In some embodiments, the compounds of the present invention as shown in Formula I:

[0030] Z1, Z2, and Z3 are each independently C or N, and there is exactly one N among Z1, Z2, and Z3, while the rest are C;

[0031] Z4 is CH or N;

[0032] R1 represents H and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 Alkyl or 5-6-membered heteroaryl C 1-3 Alkyl, the C 1-6 One C atom of the alkyl group is optionally replaced by an O atom; the C 3-6 One C atom on the ring of the cycloalkyl group may optionally be replaced by an O atom or an S atom; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 Alkyl or 5-6-membered heteroaryl C 1-3 Alkyl groups may be optionally substituted with 1-3 R's; each R' may be independently hydrogen, hydroxyl, halogen, or C. 1-3 alkyl;

[0033] R2 is hydrogen, halogen, or C. 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy; the C 1-6 Alkyl groups may be optionally substituted with 1-3 R's;

[0034] R3 can be hydrogen, halogen, amino, hydroxyl, or C. 1-6 Alkyl, C 2-6 alkenyl, or C 3-6 cycloalkyl; the C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 The cycloalkyl group may be optionally substituted with 1-3 R's;

[0035] X1 is O, S, NR9, or CR. 10 R 11 ;

[0036] R9 is hydrogen, C 1-6Alkyl or C 3-6 cycloalkyl; the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally substituted with 1-3 R's;

[0037] R 10 R 11 Each can be independently identified as hydrogen, halogen, hydroxyl, or C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally substituted with 1-3 R's.

[0038] R4, R5, R6, and R7 are independently hydrogen, halogen, and carbon, respectively. 1-6 Alkyl or C 3-6 cycloalkyl; the C 1-6 Alkyl, C 3-6 The cycloalkyl group may be optionally substituted with 1-3 R's; or R6 and R7 together may form an oxo (C=O) group;

[0039] n is 0 or 1. When n is 0, it means that X1 is directly connected to the carbon atoms of R6 and R7 through a single bond.

[0040] Ring A is a 6-10 aryl group, a 5-10 heteroaryl group, or a fused ring formed by ring A1 and ring A2. Ring A1 is a benzene ring or a 5-6 heteroaryl ring, and ring A2 is a 5-7 monocyclic heterocycle. The 5-6 heteroaryl ring includes one, two, or three heteroatoms of N, O, or S as ring atoms. The 5-7 monocyclic heterocycle includes one, two, or three heteroatoms of N, O, or S as ring atoms. The 6-10 aryl group, 5-10 heteroaryl group, or fused ring is optionally converted by halogen, oxidative oxidation, or carbon oxidation. 1-3 Alkyl substitution;

[0041] R8 can be independently represented by hydrogen, halogen, cyano, hydroxyl, amino, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino; C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl or -C(O)NR 12 R 14 ; or two R8 atoms attached to the same carbon atom together form an oxo (C=O) group; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-14-membered heterocycloalkyl and 5-10-membered heteroaryl groups are each optionally surrounded by 1-3 hydrogen, halogen, carboxyl, hydroxyl, C 1-3 Alkyl, hydroxyl substituted C1-3 Alkyl, 3-6 membered heterocyclic alkyl, C 1-6 Alkoxy, oxo, -C(O)NR 12 R 14 and -NR 12 R 14 C(O)C 1-3 Alkyl groups are substituted;

[0042] R 12 and R 14 They are hydrogen and C, respectively. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl or 5-10-membered heteroaryl groups are each optionally substituted with 1-3 R's;

[0043] Or R 12 and R 14 Together with the connected N atom, they can be optionally formed into a 4-7 membered heterocycle, wherein the 4-7 membered heterocycle includes 1, 2 or 3 heteroatoms of N, O or S as ring atoms, and each of the 4-7 membered heterocycles is optionally replaced by 1-3 R' atoms;

[0044] m can be 1, 2, 3, 4, or 5.

[0045] In some schemes, R1, R2, R 3、 R4, R5, R6, R7, R8, R9, R 10 and R 11 In the context, C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0046] In some schemes, in R1, when the C 1-6 When one C atom of an alkyl group is replaced by an O atom, the C... 1-6 alkyl

[0047] In some schemes, in R1, the C mentioned 3-6 cycloalkyl and the C 3-6 cycloalkyl C 1-3 C in alkyl 3-6 The cycloalkyl group is independently C 3-6 Monocyclic cycloalkyl or C 5-6 The cycloalkyl group of the bicyclic bridged ring can be cyclopropyl, cyclobutyl, cyclopentane or cyclohexyl or bicyclic [1.1.1]pentane.

[0048] In some schemes, in R1, when the C3-6 When a C atom on the ring of a cycloalkyl group is replaced by an O atom, a N atom, or a S atom, the C... 3-6 Cycloalkyl group is C 3-6 In a monocyclic cycloalkyl group, one C atom is replaced by an O atom, which can be oxobutyl or tetrahydrofuranyl.

[0049] In some schemes, in R1, the 5-6 membered heteroaryl group and the -C group... 1-3 The 5-6-membered heteroaryl group in the alkyl-5-6-membered heteroaryl group is independently a 5-6-membered monocyclic heteroaryl group, with heteroatoms being N and / or O, and the number being 1, 2, 3, or 4, which can be pyridyl, 1H-pyrazolyl, or isoaryl. Azolium group.

[0050] In some schemes, in R1, C 3-6 cycloalkyl C 1-3 Alkyl group is -C 1-3 Alkyl-C 3-6 Cycloalkyl.

[0051] In some schemes, in R1, phenyl C 1-3 Alkyl group is -C 1-3 Alkyl-phenyl.

[0052] In some schemes, in R1, there are 5-6 member heteroaryl C 1-3 Alkyl group is -C 1-3 Alkyl-5-6-membered heteroaryl.

[0053] In some schemes, R2, R3, R4, R5, R6, R7, R8, R 10 R 11 In each of R', the halogen is F, Cl or Br.

[0054] In some schemes, R2, R8, R 10 and R 11 In the context, C 1-6 The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0055] In some schemes, R4 and R5 together with their connected C form C 3-6 In the case of cycloalkanes, the C 3-6 The cycloalkane is cyclopropane.

[0056] In some schemes, the 5-10 membered heteroaromatic ring in ring A is a 5-6 membered monocyclic heteroaromatic ring or a 9-10 membered bicyclic heteroaromatic ring, and the heteroatom is one, two or three of N, O and S, which can be a pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, imidazo[1,2-b]pyridazine ring, pyridine-imidazolium ring or quinoline ring.

[0057] In some schemes, the 5-6 membered heterocyclic alkene in ring A can be a 5-6 membered heterocyclic alkene containing one or two double bonds, and the heteroatoms are one, two or three of N, O and S, in number one or two, and can be a dihydropyridine ring.

[0058] In some schemes, the 5-6 membered heteroaromatic ring in ring A1 is a 5-6 membered monocyclic heteroaromatic ring, and the heteroatom is one, two or three of N, O and S, and the number is one or two, which can be a pyridine ring, 1H-pyrazole ring, thiazole ring, pyrimidine ring, pyrazine ring or pyridazine ring.

[0059] In some embodiments, the 5-7 membered monocyclic heterocycle in ring A2 can be a 5-6 membered monocyclic heterocycle, with one, two, or three heteroatoms selected from N, O, and S, and one or two heteroatoms in total. These heteroatoms can be piperidinyl, morpholino, piperazine, pyrrolidinyl, or... Azolyl alkyl group.

[0060] In some schemes, the fused ring formed by ring A1 and ring A2 in ring A is a 5-6 membered heteroaromatic ring and a 5-6 membered heterocyclic ring, which can be a pyridine ring and a piperidine ring, a pyridine ring and a morpholine ring, or a 1H-pyrazole ring and a piperidine ring.

[0061] In some schemes, in each R8, the 4-14 membered heterocyclic alkyl group is a 4-6 membered monocyclic heterocyclic alkyl group or an 8-10 membered bicyclic heterocyclic alkyl group, the heteroatom is N and / or O, and the number is 1, 2, 3 or 4, which can be nitrogen-heterocyclic butyl alkyl, oxocyclic butyl alkyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl.

[0062] In some schemes, in each R8, the 4-14 membered heterocyclic alkenyl group is a 4-6 membered monocyclic heterocyclic alkenyl group, an 8-10 membered bicyclic heterocyclic alkenyl group, or a 12-14 membered 3, 4, or 5-cyclic heterocyclic alkenyl group, containing 1 or 2 double bonds, with heteroatoms being N and / or O, and the number being 1, 2, 3, or 4, which can be 1,2-dihydropyridinyl, 1,6-dihydropyrimidinyl, or 1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazinyl or

[0063] In some schemes, the 6-10 aryl group in each R8 is a phenyl group.

[0064] In some schemes, in each R8, the 5-10 membered heteroaryl group is a 5-6 membered monocyclic heteroaryl group or an 8-10 membered bicyclic heteroaryl group, and the heteroatom is 1, 2, or 3 of N, O, and S, and the number is 1, 2, 3, or 4, and it can be imidazole, pyrazol, triazolyl, tetrazolyl, furanyl, iso... azole group, 1,3,4- Diazole, pyridyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole, 5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazolidinyl or 5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]thiazine.

[0065] In some schemes, C 1-6 The alkylamino group is -NH-C 1-6 Alkylamino.

[0066] In some schemes, R 12 and R 14 In the context, C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0067] In some schemes, R 12 and R 14 In the context, C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0068] In some schemes, R 12 and R 14 In this context, the 3-6 membered heterocyclic alkyl group is a 3-6 membered monocyclic heterocyclic alkyl group, with heteroatoms being N and / or O, and the number being 1 or 2, which can be oxoheterobutyl alkyl or nitrogen-heterobutyl alkyl.

[0069] In some schemes, R 12 and R 14 In this context, the 5-10 member heteroaryl group refers to a 5-6 member monocyclic heteroaryl group.

[0070] In some schemes, R1 is H and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl-, phenyl or 5-6-membered heteroaryl, phenyl C 1-3 Alkyl- or 5-6-membered heteroaryl C 1-3 Alkyl-, the C 1-6 One C atom of the alkyl group is optionally replaced by an O atom; the C 3-6 One C atom on the ring of the cycloalkyl group may optionally be replaced by an O atom, an N atom, or an S atom; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 Alkyl and 5-6-membered heteroaryl C1-3 Alkyl groups may be optionally substituted with 1-3 R' groups; R' is a hydroxyl group, halogen, -CN, oxo group, C 1-3 Alkyl, -NH-C 1-3 Alkyl, -NH-(C 1-3 Alkyl)2, -S(=O)2-C 1-3 Alkyl, -C(=O)NR a R b -C(=O)-OC 1-3 Alkyl or C 1-3 Alkoxy;

[0071] R a and R b H and C, respectively 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups.

[0072] Preferably, R1 is H. -CH3、

[0073] More preferably, R1 is

[0074] In some schemes, R2 is hydrogen.

[0075] In some schemes, R3 is hydrogen, halogen, amino, hydroxyl, or C. 1-6 Alkyl or C 3-6 cycloalkyl; the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally substituted by 1-3 R'; each R' is independently a hydroxyl group, a halogen, or -CN;

[0076] Preferably, R3 is H, F, Cl, NH2, Me, Et, i-Pr, CF3, CHF2 or

[0077] More preferably, R3 is H, Cl, NH2 or Me.

[0078] In some schemes, R 10 and R 11 Each can be independently identified as hydrogen, halogen, hydroxyl, or C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl, or R 10 and R 11 Together with C, they form -C(=O)-; the C 1-6 Alkyl and C 3-6The cycloalkyl group may be optionally substituted by 1-3 R'; each R' is independently a hydroxyl group, a halogen, or -CN;

[0079] Preferably, R 10 and R 11 Selected independently from H, F, Cl, Me, Et, i-Pr, CF3, CF3, CHF2, -CH2CF3, -CH2CHF2, -OCH3 or

[0080] In some schemes, X1 is O, S, -S(=O)2-, or CR 10 R 11 .

[0081] Preferably, X1 is -O-, -S-, -S(=O)2-, -CH(CH3)-, -C(CH3)2- or -CH(OCH3)-.

[0082] In some schemes, R4, R5, R6, and R7 are independently selected from hydrogen, halogens, and C, respectively. 1-6 Alkyl or C 3-6 Cycloalkyl groups, or R4 and R5 together with the C atoms attached to them, form C3 groups. 3-6 A ring or -C (=O)-, or R6 and R7 together with the C connected to them form C. 3-6 Ring or -C(=O)-; the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally replaced by 1-3 halogens;

[0083] Preferably, R4, R5, R6, and R7 are independently H, F, Cl, Me, Et, i-Pr, CF3, CHF2, -CH2CF3, -CH2CHF2, respectively.

[0084] In some schemes, R9 represents hydrogen and C. 1-6 Alkyl or C 3-6 cycloalkyl; the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally replaced by 1-3 halogens;

[0085] Preferably, R9 is H, Me, Et, i-Pr, CF3, CHF2, -CH2CF3, -CH2CHF2 or

[0086] More preferably, R9 is Me, i-Pr, or

[0087] In some schemes, m is 1, 2, or 3.

[0088] In some schemes, each R8 group is independently H, -Cl, oxo group, -OCH3, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CHF2, -CH2CF3, -CH2CF2H, -(CH2)2OCH3, -(CH2)3OCH3, -CN, -CH2CN, -(CH2)2CN, -(CH2)3CN, -NH2COCH3, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CONHCH(CH3)2.

[0089] In some schemes, for Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Independently N or CR8, and Y 1 Y 2 Y 3 and Y 4 If not both of them are N (for example, two of them are N), Y 5 Y 6 Y 7 and Y 8 Not all of them are N (for example, two of them are N);

[0090] Ring B is a 5-6 membered monocyclic heterocycle or a 5-6 membered monocyclic heteroaromatic ring. The heteroatoms in the 5-6 membered monocyclic heterocycle and the 5-6 membered monocyclic heteroaromatic ring are one or more of N, O and S, and the number is 1, 2 or 3.

[0091] Ring B is preferably a morpholine ring, a piperidine ring, or an imidazole ring.

[0092] Preferred

[0093] In some schemes, for

[0094] In some schemes, for

[0095] Preferred This indicates that a fused ring is formed with the parent body at this location.

[0096] In some schemes, for

[0097] Preferred, It can be any of the following structures:

[0098] In some schemes, equation (II) is any one of equations (II) to (VII):

[0099] The definitions of R1, R2, R3, R4, R5, R6, R7, R8, A, X1, m, and n are as described above.

[0100] Preferably, in formulas (I) to (VII), R4, R5, R6, and R7 are independently hydrogen, halogen, and C, respectively. 1-6 Alkyl or C 3-6 cycloalkyl; the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally substituted with 1-3 halogens, preferably hydrogen or C. 1-6 alkyl.

[0101] Preferably, in equations (I) to (VII), R 10 and R 11 They are independently hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 alkoxy, or R 10 and R 11 Together with C, they form -C(=O)-, where C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally replaced by 1-3 halogens;

[0102] More preferably, R4, R5, R6, R7, R 10 and R 11 They can be independently identified as H, F, Me, Et, i-Pr, CF3, CHF2, -CH2CF3, -CH2CHF2, or Preferably, R4, R5, R6, and R7 are each independently selected from H or Me; more preferably, R 10 and R 11 Each can be independently selected from H, F, or Me.

[0103] Preferably, in formulas (I) to (VII), ring A is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyridinyl, pyridinium-imidazolyl, pyridopyridinyl, imidazopyridazinyl, or quinolinyl, and ring A1 is selected from benzene ring, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyridazinyl; preferably, ring A is selected from pyridazinyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazopyridazinyl, or pyridinium-imidazolyl, ring A1 is selected from benzene ring or pyridinyl, and ring A2 is selected from morpholine ring, piperidinyl, piperazinyl, pyrrolidinyl, or... Azolyl alkyl group.

[0104] Preferably, in formulas (I) to (VII), R8 is independently selected from H, -F, -Cl, -OH, -Me, -Et, -i-Pr, -CF3, -CHF2, -CH2CF3, -CH2CF2H, -OMe, -(CH2)2OCH3, -(CH2)3OCH3, -CN, -CH2CN, -(CH2)2CN, -(CH2)3CN, -NH2COCH3, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CONHCH(CH3)2, Alternatively, two R8 atoms attached to the same carbon atom may form an oxo (C=O) group; preferably, the R8 atoms are independently selected from H, Cl, -OH, -Me, -OMe, -CONHCH2CH3, -CONHCH(CH3)2, etc. Or two R8 atoms attached to the same carbon atom can form an oxo (C=O) group.

[0105] Preferably, in equations (I) to (VII), Structural units are selected from

[0106] Preferred Structural units are selected from

[0107] In some embodiments, the compound of formula (I) in this invention is of formula (I-1):

[0108] In equation (I-1),

[0109] Z1, Z2, and Z3 are each independently selected from C or N, and only one of Z1, Z2, and Z3 is selected from N, while the rest are C; preferably, when Z1 is C, Z2 is N, or when Z2 is C, Z1 is N; preferably, Z3 is C; Z4 is CH or N; preferably, Z4 is N;

[0110] R1 represents H and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 Alkyl or 5-6-membered heteroaryl C 1-3 Alkyl, the C 1-6 One C atom of the alkyl group is optionally replaced by an O atom; the C 3-6 One C atom on the ring of the cycloalkyl group may optionally be replaced by an O or S atom; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 Alkyl or 5-6-membered heteroaryl C 1-3 Alkyl groups may be optionally substituted with 1-3 R's;

[0111] Preferably, R1 is selected from H, More preferably, R1 is selected from

[0112] R' can be independently hydrogen, hydroxyl, halogen, or C. 1-3 Alkyl group; preferably, R' is hydrogen;

[0113] R3 can be hydrogen, halogen, amino, or C. 1-6 Alkyl or C 3-6 cycloalkyl; the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 1-3 R's; preferably, R3 is selected from H, F, Cl, NH2, Me, Et, i-Pr, CF3 or CHF2; more preferably, R3 is selected from H, Cl, NH2 or Me;

[0114] X1 is O or CR 10 R 11 ;

[0115] R 10 R 11 Each element is independently selected from hydrogen, halogen, or C. 1-6 Alkyl; the C 1-6Alkyl groups may optionally be substituted with 1-3 R's; preferably, R's are substituted with 1-3 R's. 10 R 11 Each is independently selected from hydrogen or C 1-3 alkyl;

[0116] R4, R5, R6, and R7 are each independently selected from hydrogen or C. 1-6 Alkyl; the C 1-6 The alkyl group may optionally be substituted with 1-3 R's; preferably, R4, R5, R6, and R7 are each independently selected from hydrogen or C. 1-3 Alkyl group, more preferably, R4, R5, R6, and R7 are each independently hydrogen or methyl;

[0117] n is 0 or 1. When n is 0, it means that X1 is directly connected to the carbon atoms of R6 and R7 through a single bond.

[0118] Ring A is a phenyl, a 5-10 membered heteroaryl group, or a fused ring formed by ring A1 and ring A2, wherein ring A1 is a benzene ring or a 5-6 membered heteroaryl ring, and ring A2 is a 5-7 membered monocyclic heterocycle. The 5-6 membered heteroaryl ring or the 5-7 membered monocyclic heterocycle includes 1, 2, or 3 heteroatoms selected from N, O, or S as ring atoms. The phenyl, 5-10 membered heteroaryl group, or fused ring is optionally converted by halogen, oxo, or C. 1-3 Alkyl substitution; preferably, ring A is selected from pyridazinyl, pyridinyl, pyrazinyl, pyrimidinyl, imidazopyridazinyl, pyridinimidazoleyl or preferably, ring A1 is a benzene ring or pyridinyl, and ring A2 is a morpholine ring or piperidinyl;

[0119] R8 can be independently represented by hydrogen, halogen, cyano, hydroxyl, amino, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)NR 12 R 14 Or two R8 atoms attached to the same carbon atom may together form an oxo (C=O) group; the C 1-6 Alkyl, C 1- 6-alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-14-membered heterocycloalkyl and 5-10-membered heteroaryl groups are each optionally surrounded by 1-3 groups selected from hydrogen, halogen, carboxyl, hydroxyl, C 1-3 Alkyl, hydroxyl substituted C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, C 1-6 Alkoxy, oxo, -C(O)NR 12 R 14 and -NR 12 R 14 C(O)C 1-3Alkyl groups are substituted;

[0120] R 12 and R 14 They are hydrogen and C, respectively. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl or 5-10-membered heteroaryl groups are each optionally substituted with 1-3 R's;

[0121] Or R 12 and R 14 Together with the connected N atom, they can be optionally formed into a 4-7 membered heterocycle, wherein the 4-7 membered heterocycle includes 1, 2 or 3 heteroatoms selected from N, O or S as ring atoms, and each of the 4-7 membered heterocycles is optionally replaced by 1-3 R' atoms;

[0122] Preferably, R8 is independently selected from H, -F, -Cl, -OH, -Me, -Et, -i-Pr, -OMe, -CN, -NH2COCH3, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CONHCH(CH3)2, Alternatively, two R8 atoms attached to the same carbon atom may form an oxo (C=O) group; preferably, the R8 atoms are independently selected from H, Cl, -OH, -Me, -OMe, -CONHCH2CH3, -CONHCH(CH3)2, etc. Or two R8 atoms attached to the same carbon atom can form an oxo (C=O) group;

[0123] m is 1, 2 or 3; preferably, m is 1 or 2.

[0124] Preferably, the compound of the present invention has formula (I-1), wherein

[0125] When Z1 is C, Z2 is N, or when Z2 is C, Z1 is N;

[0126] Z3 is C;

[0127] Z4 is N;

[0128] R1 represents H and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, phenyl or 5-6 membered heteroaryl, phenyl C1-3 Alkyl or 5-6-membered heteroaryl C 1-3 Alkyl, the C 1-6 One C atom of the alkyl group is optionally replaced by an O atom; the C 3-6 One C atom on the ring of the cycloalkyl group may optionally be replaced by an O or S atom; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 Alkyl or 5-6-membered heteroaryl C 1-3 The alkyl group may optionally be substituted with 1-3 R'; preferably, R1 is... More preferably, R1 is selected from

[0129] R' can be independently hydrogen, hydroxyl, halogen, or C. 1-3 Alkyl group; preferably, R' is hydrogen;

[0130] R3 is hydrogen, halogen, amino, or C. 1-6 Alkyl; more preferably, R3 is selected from H, Cl, NH2 or Me;

[0131] X1 is O or CR 10 R 11 ;

[0132] R 10 and R 11 Each can be independently hydrogen, halogen, or C. 1-6 Alkyl; preferably, R 10 R 11 It can be hydrogen or methyl;

[0133] R4, R5, R6, and R7 are each independently hydrogen or carbon. 1-6 Alkyl group; preferably, R4, R5, R6, and R7 are each independently methyl.

[0134] R8 can be independently represented by hydrogen, halogen, cyano, hydroxyl, amino, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino; C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl or -C(O)NR 12 R 14 ; or two R8 atoms attached to the same carbon atom together form an oxo (C=O) group; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6Cycloalkyl, 4-14-membered heterocycloalkyl and 5-10-membered heteroaryl groups are each optionally surrounded by 1-3 groups selected from hydrogen, halogen, carboxyl, hydroxyl, C 1-3 Alkyl, hydroxyl substituted C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, C 1-6 Alkoxy, oxo, -C(O)NR 12 R 14 and -NR 12 R 14 C(O)C 1-3 Alkyl groups are substituted;

[0135] R 12 and R 14 They are hydrogen and C, respectively. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl or 5-10-membered heteroaryl groups are each optionally substituted with 1-3 R's;

[0136] Or R 12 and R 14 Together with the connected N atom, they can be optionally formed into a 4-7 membered heterocycle, wherein the 4-7 membered heterocycle includes 1, 2 or 3 heteroatoms selected from N, O or S as ring atoms, and each of the 4-7 membered heterocycles is optionally replaced by 1-3 R' atoms;

[0137] Or preferably, R8 is independently H, -F, -Cl, -OH, -Me, -Et, -i-Pr, -OMe, -CN, -NH2COCH3, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CONHCH(CH3)2, Or two R8 atoms attached to the same carbon atom can form an oxo (C=O) group.

[0138] In some embodiments, formula (I) of the present invention is formula (II-A), (III-A), (IV-A), or (VA):

[0139] R1 is C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 Alkyl or 5-6-membered heteroaryl C 1-3 Alkyl, the C 1-6One C atom of the alkyl group is optionally replaced by an O atom to form an alcohol or ether; the C 3-6 One C atom on the ring of the cycloalkyl group may optionally be replaced by an O atom; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 Alkyl or 5-6-membered heteroaryl C 1-3 Alkyl groups may be optionally substituted with 1-3 R's;

[0140] Preferably, R1 is More preferably, R1 is

[0141] R' can be independently hydrogen, hydroxyl, halogen, or C. 1-3 alkyl;

[0142] R3 is hydrogen, halogen, amino, or C. 1-6 Alkyl; more preferably, R3 is H, Cl, NH2 or Me;

[0143] X1 is O or CR 10 R 11 ;

[0144] R 10 and R 11 Each can be independently hydrogen or C 1-6 Alkyl; preferably, R 10 R 11 It is H or methyl;

[0145] R4, R5, R6, and R7 are each independently hydrogen or carbon. 1-6 Alkyl group, preferably, R4, R5, R6, and R7 are each independently selected from hydrogen or methyl;

[0146] Ring A is pyridinyl, pyridinyl, pyridinyl, pyridinoimidazole, or imidazopyridinyl; ring A1 is a benzene ring or pyridinyl; and ring A2 is a morpholine ring or piperidinyl.

[0147] R8 can be independently represented as H, -F, -Cl, -OH, -Me, -Et, -i-Pr, -OMe, -CN, -NH2COCH3, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, or -CONHCH(CH3)2. Or two R8 atoms attached to the same carbon atom can form an oxo (C=O) group;

[0148] n is 0 or 1. When n is 0, it means that X1 is directly connected to the carbon atoms of R6 and R7 through a single bond.

[0149] m is 1 or 2.

[0150] Preferably, in formulas (I-1), (II-A), (III-A), and (VA), Structural units are selected from

[0151] Preferably, the compound of the present invention is any one of the following compounds:

[0152] Its cis-trans isomers, its enantiomers, its diastereomers, its racemic mixtures, its solvates, its hydrates, its pharmaceutically acceptable salts, or its prodrugs.

[0153] In a second aspect, the present invention relates to a pharmaceutical composition comprising (effective amount) a fused-ring compound as described herein.

[0154] Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0155] In a third aspect, the present invention provides fused-ring compounds or pharmaceutical compositions as described herein for the preparation of α5-GABA. A Application of receptor modulators.

[0156] In a fourth aspect, the present invention provides fused-ring compounds or pharmaceutical compositions as described herein for the preparation of treatments or preventative measures against α5-GABA. A Use in drugs for receptor-related diseases.

[0157] In a fifth aspect, the present invention provides a treatment or prevention of α5-GABA A Methods for treating receptor-related diseases include administering to a patient an effective dose of a fused-ring compound or a pharmaceutical composition as described herein.

[0158] In a sixth aspect, the invention provides the use of the fused-ring compounds or pharmaceutical compositions described herein in the preparation of medicaments for the treatment or prevention of pain, Alzheimer's disease, multi-infarct dementia, and stroke.

[0159] In a seventh aspect, the present invention provides a method for treating or preventing pain, Alzheimer's disease, multi-infarct dementia, and stroke, comprising administering to a patient an effective dose of a fused-ring compound as described herein or a composition as described herein.

[0160] Preferably, the pain is neuropathic pain, inflammatory pain, and cancer pain. More preferably, the pain is selected from: headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, lower 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), polyostosis, sickle cell anemia, autoimmune diseases, pain associated with multiple sclerosis or inflammation, chronic pain caused by injury or surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, cancer, chemical damage, toxins, nutritional deficiencies, viral or bacterial infections, and pain associated with degenerative osteoarthritis.

[0161] In an eighth aspect, the present invention provides a compound of formula A:

[0162] The definitions of R1, R2, R3, R4, R5, R6, R7, R6, Z1, Z2, Z3, Z4 and n are the same as those described above.

[0163] Preferably, the compound of formula A is

[0164] In structural fragments This refers to the structural segment being connected to the rest of the molecule through this site. For example, Both refer to cyclohexyl.

[0165] In structural fragments It also refers to the structural segment forming a fused ring with the ring it is connected to through the bond. For example, the structure... Excerpt This refers to the formation of a fused ring with the parent structure at this location.

[0166] The "-" at the end of a group indicates that the group is attached to the rest of the molecule through that site. For example, -C 1-3-Phenyl refers to C 1-3 It is connected to the rest of the molecule.

[0167] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following definitions. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears in this document, it is intended to refer to the corresponding product or active ingredient.

[0168] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0169] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds 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 compounds of this invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Pharmaceutically acceptable examples of 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, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; salts of amino acids (such as arginine); and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0170] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0171] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0172] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0173] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0174] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being a non-mirror image of each other.

[0175] Unless otherwise stated, "(D)" or "(+)" indicates right-handed rotation, "(L)" or "(-)" indicates left-handed rotation, and "(DL)" or "(±)" indicates racemic rotation.

[0176] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key and straight dashed key

[0177] The compounds of this invention can exist in specific forms. Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting. If tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomer may be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers, pentane-2,4-dione and 4-hydroxy-3-en-2-one.

[0178] The compounds of the present invention may have one or more atoms constituting the compound that are naturally abundant atoms or atomic isotopes in non-natural proportions, the isotopes having the same number of atoms but having an atomic mass or mass number different from that of atoms that are predominantly found 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 this invention, regardless of radioactivity, are included within the scope of this invention. Isotopic variants may enhance certain therapeutic advantages, such as the use of deuterium to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared to undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. Alternatively, they may provide standard compounds that can be used for characterization of biological samples. Isotope-enriched compounds of general formula (I) can be prepared without extensive experimentation using conventional techniques well known to those skilled in the art, or by methods similar to those described in the routes and embodiments of this invention, using appropriate isotope-enriched reagents and / or intermediates.

[0179] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.

[0180] The naming conventions used in this invention are based on the IUPAC system. Any open valence bonds appearing on carbon, oxygen, sulfur, or nitrogen atoms in the structures given in this invention indicate the presence of hydrogen atoms.

[0181] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on a chemically feasible basis.

[0182] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0183] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0184] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that its structure is actually AZ.

[0185] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linking group L is at this time The benzene ring and cyclopentyl group can be connected in the same direction as the reading order from left to right to form the structure. Alternatively, the phenyl and cyclopentyl groups can be connected in the reverse order of reading from left to right to form the phenyl group. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0186] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a “3-7 elemental ring” refers to a “ring” with 3 to 7 atoms arranged around it.

[0187] Unless otherwise specified, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0188] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C2-4 C6 and C5 alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., 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, sec-butyl and tert-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0189] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0190] Unless otherwise specified, the term "C" 2-6 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 6 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. 2-6 Alkenes include C 2-4 C 2-3 C4, C3, C2 alkenyl groups, etc.; they can be monovalent, divalent, or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, and pentadienyl.

[0191] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to other parts of a molecule by an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc.; C 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy and tert-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

[0192] Unless otherwise specified, the term "C" 1-6"Alkylamino" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to other parts of a molecule via an amino group. The C 1-6 Alkylamino groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, C3, and C2 alkylamino groups, etc.; C 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)2, -NHCH2CH2CH3, -NHCH(CH3)2, -NHCH2CH2CH2CH3, etc.

[0193] Unless otherwise specified, the term "cycloalkyl" refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms, which can be monocyclic or bicyclic. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a bridged ring or spiro ring in monocyclic and bicyclic systems. 3-6 Cycloalkyl groups include C 3-5 C 4-5 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups include, but are not limited to: wait.

[0194] Unless otherwise specified, the term "4-14 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated monocyclic, bicyclic, tricyclic, tetracyclic, or pentacyclic group consisting of 4 to 14 ring atoms, wherein the 1st, 2nd, 3rd, 4th, 5th, and 6th ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). z (z is 1 or 2). Furthermore, regarding the "4-14 membered heterocyclic alkyl group," the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 4-14 membered heterocyclic alkyl group includes 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered heterocyclic alkyl groups, etc., and the heterocyclic alkyl group can be monocyclic or fused-ring. The heterocyclic alkyl group is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocyclic alkyl groups include, but are not limited to: wait

[0195] Unless otherwise specified, the term "3-6 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated monocyclic group consisting of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). z (where z is 1 or 2). Furthermore, regarding the "3-6 membered heterocyclic alkyl group," the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 3-6 membered heterocyclic alkyl group includes 4-6, 5-6, 4, 5, and 6 membered heterocyclic alkyl groups, etc., and can be monocyclic or fused-ring. Examples of 3-6 membered heterocyclic alkyl groups include, but are not limited to, nitrogen-containing heterocyclic butyl, oxocyclic butyl, thiocyclic butyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiophenyl, tetrahydrofuranyl (including tetrahydrofuran-2-yl), piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazine, morpholinyl, thiomorpholinyl, etc.

[0196] The term "heterocyclic alkenyl" refers to a cyclic, unsaturated hydrocarbon group having a specified number of ring atoms (e.g., 5 to 10), a specified number of heteroatoms (e.g., 1, 2, 3, or 3), and a specified heteroatom type (one or more of N, O, and S), having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 2 A double bond, which can be monocyclic, bicyclic, tricyclic, or tetracyclic. (Monocyclic) heterocyclic alkenyl groups are attached to the rest of the molecule via carbon atoms or heteroatoms. (Monocyclic) heterocyclic alkenyl groups include, but are not limited to: wait.

[0197] Unless otherwise specified, the terms "6-10-membered aromatic ring" and "6-10-membered aryl" are used interchangeably, and the term "6-10-aryl" refers to a monovalent aromatic carbon ring system containing 6-10 carbon atoms and having at least one aromatic ring or at least one of the rings being aromatic rings. Examples of aryl groups are, but are not limited to, phenyl, naphthyl, biphenyl, or indenyl.

[0198] Unless otherwise specified, the terms "5-10-membered heteroaryl ring" and "5-10-membered heteroaryl" are used interchangeably in this invention. The term "5-10-membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. It can be a monocyclic or fused bicyclic system, wherein at least one ring in the system is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). z(where z is 1 or 2). A 5-10 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or carbon atom. These 5-10 membered heteroaryl groups include 5-8, 5-7, 5-6, 5, and 6 membered heteroaryl groups. Examples of these 5-10 membered heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), and imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl). azole groups (including 2-) azole group, 4- azole and 5- (e.g., azole group), triazole group (1H-1,2,3-triazole group, 2H-1,2,3-triazole group, 1H-1,2,4-triazole group and 4H-1,2,4-triazole group), tetrazolium group, isotriazole group, etc. Azolium (including 3-isopropyl) azole group, 4-iso azole and 5-iso (e.g., azole group), thiazolyl group (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl group), furanyl group (including 2-furanyl and 3-furanyl group), thienyl group (including 2-thienyl and 3-thienyl group), pyridyl group (including 2-pyridyl, 3-pyridyl, and 4-pyridyl group), pyrazinyl group, pyrimidinyl group (including 2-pyrimidinyl and 4-pyrimidinyl group), benzothiazolyl group (including 2-benzothiazolyl group), purine group, benzimidazolyl group (including 2-benzimidazolyl group), benzo[…] Azolyl, indazole (including 5-indazole, etc.), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl, etc.), quinoxalyl (including 2-quinoxalyl and 5-quinoxalyl, etc.), or quinolinyl (including 3-quinolinyl and 6-quinolinyl, etc.) etc.

[0199] Unless otherwise specified, the terms "5-6 membered heteroaryl" and "5-6 membered heteroaryl" are used interchangeably in this invention. The term "5-6 membered heteroaryl" refers to a cyclic group consisting of 5 to 6 ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). z(where z is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or carbon atom, and includes 5-membered and 6-membered heteroaryl groups, etc. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), and imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.). azole groups (including 2-) azole group, 4- azole and 5- (e.g., azole group), triazole group (1H-1,2,3-triazole group, 2H-1,2,3-triazole group, 1H-1,2,4-triazole group and 4H-1,2,4-triazole group), tetrazolium group, isotriazole group, etc. Azolium (including 3-isopropyl) azole group, 4-iso azole and 5-iso (e.g., azole group), thiazolyl group (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl group), furanyl group (including 2-furanyl and 3-furanyl group), thienyl group (including 2-thienyl and 3-thienyl group), pyridyl group (including 2-pyridyl, 3-pyridyl and 4-pyridyl group), pyrazinyl group, pyrimidinyl group (including 2-pyrimidinyl and 4-pyrimidinyl group), etc.

[0200] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-7 This includes C1, C2, C3, C4, C5, C6, and C7, as well as 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 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-7-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, and 7-membered rings, and also include any range from n to n+m. For example, 3-7-membered rings include 3-6-membered rings, 4-7-membered rings, 5-7-membered rings, and 6-7-membered rings, etc.

[0201] 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 (such as a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonates; chlorine, bromine, and iodine; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-bromobenzenesulfonates, p-toluenesulfonates, etc.; acyloxy groups, such as acetoxy groups, trifluoroacetoxy groups, etc.

[0202] 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 nitrogen position of an amino group. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenemethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanolyl groups (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), etc.

[0203] As used in this invention, the term "treatment" refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) and / or pharmaceutically acceptable salts thereof, to an individual suffering from or exhibiting symptoms of a disease, to cure, alleviate, reduce, alter, treat, improve, enhance, or influence the disease or its symptoms. The term "prevention" as used in this invention refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) and / or pharmaceutically acceptable salts thereof, to an individual with a predisposition to the disease, to prevent the individual from contracting the disease. When chemical reactions are involved, the terms "treatment," "contact," and "reaction" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and / or desired products. It should be understood that the reaction producing the indicated and / or desired products may not necessarily originate directly from the initial combination of the two reagents added; that is, one or more intermediates may be present in the mixture, which ultimately lead to the formation of the indicated and / or desired products.

[0204] As used in this invention, "patient" is defined as any warm-blooded animal, such as, but not limited to, mice, guinea pigs, dogs, horses, or humans, with the patient preferably being a human.

[0205] The term "effective amount" as used in this invention refers to an amount that is generally sufficient to produce a beneficial effect on an individual. The effective amount of the compounds of this invention can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., route of administration, pharmacokinetics of the compound, severity and course of disease, individual medical history, individual health status, individual response to the drug, etc.).

[0206] As described above, the novel compounds of the present invention, as well as their pharmaceutically acceptable salts and prodrugs, possess important pharmacological properties, being α5-GABA. A Receptor inverse agonists. Therefore, the compounds of this invention can be used alone or in combination with other drugs for the treatment or prevention of GABA-mediated agonism containing the α5 subunit. A Receptor-ligand mediated diseases. These diseases include, but are not limited to, pain, Alzheimer's disease, multi-infarct dementia, and stroke.

[0207] Therefore, the present invention also relates to pharmaceutical compositions comprising compounds as defined above and pharmaceutically acceptable carriers and / or excipients.

[0208] Similarly, the present invention also includes compounds as described above, used in the preparation of treatments or preventative agents related to α5-GABA. A Medications for receptor-related diseases, especially for the treatment or prevention of the following conditions: pain, Alzheimer's disease, multi-infarct dementia, and stroke.

[0209] The undefined techniques and scientific terms used in this invention have the meanings commonly understood by those skilled in the art to which this invention pertains.

[0210] As used in this article, "cancer pain" refers to the pain that occurs during the development of malignant tumors. There are currently three mechanisms for the occurrence of cancer pain: pain directly caused by cancer development, pain caused after cancer treatment, and pain-related diseases in cancer patients.

[0211] As used in this article, "neuropathic pain" refers to pain caused or triggered by primary damage and dysfunction of the nervous system.

[0212] As used in this article, "inflammatory pain" refers to pain caused by local acute or chronic inflammation stimulating nerves.

[0213] As used in this article, “acute pain” is defined as pain caused by harmful stimuli resulting from damage and / or disease of the skin, body structure or internal organs, or pain caused by abnormal function of muscles or internal organs that does not produce actual tissue damage.

[0214] As used in this article, “chronic pain” is defined as pain that persists beyond the usual course of an acute illness or a 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 over months or years. Pain is considered chronic if it persists after a period that should have been cured or after the usual course of treatment. The length of time pain needs to endure depends on the nature of the pain and the course of treatment associated with it; if the pain exceeds the usual course of treatment, the pain is chronic. Chronic pain includes, but is not limited to, headache, facial pain, neck pain, shoulder pain, chest pain, abdominal pain, back pain, lower back pain, lower extremity pain, musculoskeletal pain, pain associated with somatic illness-like mental disorders, visceral pain, painful diabetic neuropathy, vascular pain, gout, arthritic pain, cancer pain, autonomic reflex pain, pain caused by infectious diseases (such as HIV and shingles), pain caused by autoimmune diseases (rheumatism), pain caused by acute or chronic inflammation, postoperative pain, and post-burn pain.

[0215] The drug disclosed in this invention can effectively treat chronic pain as defined above, and the drug disclosed in this invention can be used to treat pain hypersensitivity associated with other conditions, including hyperalgesia, atypical pain, hyperalgesia, and enhanced pain memory. This invention will improve the treatment of such pain.

[0216] As used in this article, "headache" can be divided into primary headache and secondary headache. Primary headache includes tension headache, migraine, and cluster headache, while secondary headache is caused by other diseases. Various types of headaches can be caused by lesions or stimulation of pain-sensitive tissues in the head and face. These pain-sensitive tissues include those distributed in the scalp, face, mouth, and throat. Because they are mainly muscles or blood vessels in the head and contain abundant nerve fibers, they are relatively sensitive to pain. Therefore, damage to these tissues can cause headaches.

[0217] As used in this article, “facial pain” includes, but is not limited to, trigeminal neuralgia, atypical facial pain, facial nerve palsy, and hemifacial spasm.

[0218] As used in this article, "trigeminal neuralgia" is a unique chronic pain disorder, also known as painful tic, which refers to brief, paroxysmal, and recurrent episodes of severe, electric shock-like pain in the distribution area of ​​the trigeminal nerve, sometimes accompanied by ipsilateral facial muscle spasms. Trigeminal neuralgia is divided into two types: primary and secondary. Primary trigeminal neuralgia is characterized by the absence of clinical neurological signs and the absence of organic lesions on examination. Secondary trigeminal neuralgia is characterized by the presence of clinical neurological signs and the discovery of organic lesions on examination, such as tumors and inflammation.

[0219] As used in this article, "atypical facial pain" refers to pain caused by a variety of etiologies. It manifests as persistent, burning pain, without intermittent episodes, unrelated to specific movements or triggering stimuli. The pain is often bilateral, frequently extending beyond the distribution area of ​​the trigeminal nerve and even affecting the skin of the neck. Causes can include sinusitis, malignant tumors, and infections of the jaw and skull base, which can irritate or damage the trigeminal nerve and cause pain.

[0220] As used in this article, "neck pain, back pain, and shoulder pain" refers to pain caused by acute and chronic muscle strain, degenerative changes in bones and joints, and trauma. Common diseases that cause neck, shoulder, and upper limb pain include cervical and shoulder myofascitis, nuchal ligamentitis, cervical spondylosis, frozen shoulder, thoracic outlet syndrome, and lateral epicondylitis of the humerus. Pain caused by autoimmune diseases is commonly seen in rheumatoid arthritis, ankylosing spondylitis, and rheumatoid arthritis. Other diseases that may cause neck, back, and shoulder pain include tumors of the neck and shoulder, neuritis, arteriovenous diseases, various infections, and referred pain caused by lesions of the thoracic and abdominal organs.

[0221] As used in this article, “chest, abdominal and back pain” refers to pain caused by diseases of the viscera of the chest and abdomen and the tissues of the chest and abdominal wall, including but not limited to intercostal neuralgia, intercostal chondritis, angina pectoris, abdominal pain (acute abdominal visceral pain) and myofascial syndrome of the lumbar and back.

[0222] As used in this article, "lower back and lower limb pain" refers to pain in the lower back, lumbosacral region, sacroiliac region, hip, buttocks, and lower limbs. Lower back and lower limb pain is often not an independent disease, but rather a common feature of multiple diseases. It presents with diverse clinical manifestations and has very complex causes, mostly degenerative and injury-related, including but not limited to pain related to lumbar disc herniation, acute lumbar sprain, sciatica, osteoporosis, third lumbar transverse process syndrome, piriformis syndrome, knee osteoarthritis, coccyx syndrome, and heel pain.

[0223] As used in this article, “musculoskeletal pain” includes, but is not limited to, myofascial pain, trauma-induced pain, and chronic regional pain syndromes.

[0224] As used in this article, "painful diabetes" refers to pain caused by nerve damage resulting from diabetes mellitus. Nerve damage in diabetes is at least partly due to reduced blood flow and hyperglycemia. Some diabetic patients do not develop neuropathy, while others develop it early in the course of the disease. Diabetic neuropathy can be classified into mononeuropathy involving one or more lesions and generalized polyneuropathy. Polyneuropathy can be diffuse and symmetrical, typically primarily affecting sensory modes. Manifestations of diabetic neuropathy can include autonomic dysfunction, leading to regulatory disturbances in organs including the heart, smooth muscle, and glands, causing hypotension, diarrhea, constipation, and impotence. Diabetic neuropathy often develops in stages. In the early stages, in peripheral nerve areas, autonomic or sensory neuropathy occurs in the feet, while cranial neuropathy occurs in the face and around the eyes, presenting as intermittent pain and tingling. In subsequent stages, the pain becomes more intense and frequent. Finally, when pain sensation is lost in a certain area, analgesia occurs. Because there is no pain as an indicator of damage, the risk of serious tissue damage is greatly increased.

[0225] As used in this article, “visceral pain” includes, but is not limited to, pain associated with irritable bowel syndrome (IBS), with or without chronic fatigue syndrome (CFS), inflammatory bowel disease (IBD), and interstitial cystitis.

[0226] As used in this article, “vascular pain” is pain caused by one or more of the following factors: First, improper tissue perfusion, causing temporary or continuous local ischemia, such as local ischemia in limb muscles during exercise; Second, delayed changes, such as ulceration or gangrene in the skin or abdominal viscera; Third, sudden or accelerated changes in the diameter of large blood vessels, such as changes in the formation of aneurysms; Fourth, aortic rupture, resulting in blood spillage that irritates nociceptive fibers in the parietal peritoneum or pleura; Fifth, severe spasm caused by severe intra-arterial injection that severely irritates the arterial endothelium; Sixth, impairment of venous return, resulting in massive edema that rapidly expands the fascial compartments. Examples include, but are not limited to, occlusive arteriosclerosis, thromboangiitis obliterans, acute arterial closure, embolism, congenital arteriovenous aneurysm, vasospastic disorders, Rayau's disease, cyanosis of the hands and feet, acute venous closure, thrombophlebitis, varicose veins, and lymphedema.

[0227] As used in this article, "autonomic reflex pain" refers to pain caused by "reflex sympathetic atrophy." Reflex sympathetic atrophy refers to severe spontaneous pain, hypersensitivity to touch and pain, and may be accompanied by edema and impaired blood circulation after acute or chronic injury to the body. Subsequently, symptoms such as nutritional disorders and atrophy of the skin, muscles, and bones may appear.

[0228] As used in this article, "postoperative pain" refers to a complex physiological response of the body to the disease itself and the tissue damage caused by the surgery. It manifests as an unpleasant psychological and behavioral experience.

[0229] As used in this article, "articular 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 damage, and inflammation of joint soft tissues.

[0230] As used in this article, "postherpetic neuralgia" refers to the severe pain that persists under the skin in the original rash area after the shingles rash has healed.

[0231] As used in this article, "nociceptive pain" is pain caused by the tissue damage process transmitted through stimulation of nociceptors, or pain caused by prolonged excitation of nociceptors. Pain caused by prolonged excitation of nociceptors can be caused by persistent noxious stimulation of nociceptors or their sensitization or both, or they can be caused by these factors and prolonged by their persistence, various reflex mechanisms and other factors.

[0232] As described above, the novel compounds of the present invention, as well as their pharmaceutically acceptable salts and prodrugs, possess important pharmacological properties, being α5-GABA. A Receptor inverse agonists. Therefore, the compounds of this invention can be used alone or in combination with other drugs for the treatment or prevention of GABA-mediated agonism containing the α5 subunit. A Receptor-ligand mediated diseases. These diseases include, but are not limited to, pain, Alzheimer's disease, multi-infarct dementia, and stroke.

[0233] Therefore, the present invention also relates to pharmaceutical compositions comprising compounds as defined above and pharmaceutically acceptable carriers and / or excipients.

[0234] Similarly, the present invention also includes compounds as described above, used in the preparation of treatments or preventative agents related to α5-GABA. A Medications for receptor-related diseases, especially for the treatment or prevention of the following conditions: pain, Alzheimer's disease, multi-infarct dementia, and stroke.

[0235] The undefined techniques and scientific terms used in this invention have the meanings commonly understood by those skilled in the art to which this invention pertains.

[0236] Pharmaceutical Composition

[0237] This invention provides a therapeutically effective amount of α5-GABA. A Use of pharmaceutical compounds containing inverse agonists. Although α5-GABA is used in the treatment of this invention...A Reverse agonists may be administered in the form of a raw material 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 excipients to form a pharmaceutical composition.

[0238] In a preferred embodiment, the present invention provides α5-GABA-containing... A Pharmaceutical compositions of inverse agonists, wherein α5-GABA A The reverse agonist is mixed with one or more pharmaceutically acceptable carriers, and optionally with other therapeutic and / or prophylactic components known or used in the art. The carrier must be "acceptable," meaning it is compatible with other components in the formulation and will not be harmful to the recipient.

[0239] Pharmaceutical compositions used in this invention can be those suitable for oral, rectal, bronchial, nasal, pulmonary, local (including buccal and sublingual), transdermal, vaginal, or parenteral (including skin, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, and intraocular injection or infusion) administration, or those in forms suitable for inhalation or spray administration, including powder and liquid aerosol administration, or sustained-release systems administration. Examples of suitable sustained-release systems include semi-permeable matrices of solid hydrophobic polymers containing compounds of this invention, wherein the matrix can be in the form of shaped articles, such as membranes or microcapsules.

[0240] Therefore, the compounds used in this invention can be formulated into pharmaceutical compositions and their unit dose forms together with conventional additives or diluents. Such forms include solids (especially tablets, filled capsules, powders, and pills), liquids (especially aqueous or non-aqueous solutions, suspensions, emulsions, elixirs), and capsules filled with the above forms, all oral administration forms, rectal suppositories, and sterile injectable solutions for parenteral administration. Such pharmaceutical compositions and their unit dose forms may include conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and such unit dose forms may contain any suitable effective amount of active ingredient equivalent to the desired daily application dose range.

[0241] The compounds used in this invention can be administered in various oral and parenteral dosage forms. To those skilled in the art, the following dosage forms may contain the compounds of this invention as active ingredients or pharmaceutically acceptable salts thereof.

[0242] For the formulation of the compounds used in this invention into pharmaceutical compositions, a pharmaceutically acceptable carrier may be a solid or a liquid. Solid forms of formulations include powders, tablets, tablets, capsules, suppositories, and dispersible granules. The solid carrier may be one or more substances that also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrant, or encapsulating material.

[0243] In the powder, the carrier is a finely divided solid, which is mixed with finely divided active ingredients.

[0244] In tablets, the active ingredient is mixed with a carrier that has the necessary adhesive properties in an appropriate ratio and compressed into the desired shape and size.

[0245] Powders and tablets preferably contain 5% or 10% to about 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point waxes, cocoa butter, etc. The term "formulation" includes active compounds 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 and thus bound to the carrier. Similarly, formulations include capsules and lozenges. Tablets, powders, capsules, pills, capsules, and lozenges can be used as solid forms suitable for oral administration.

[0246] To prepare the suppositories, a low-melting-point wax, such as a fatty acid glyceride or cocoa butter mixture, is first melted, and then the active ingredient is uniformly dispersed in it by stirring. The molten, homogeneous mixture is then poured into a mold of appropriate size and allowed to cool and solidify.

[0247] Compositions suitable for vaginal administration may be in the form of vaginal suppositories, tampons, creams, gels, pastes, foams or sprays, and in addition to containing the active ingredient, the composition may also contain a suitable carrier known in the art.

[0248] Liquid formulations include solutions, suspensions, and emulsions, such as aqueous solutions or water-propylene glycol solutions. For example, parenteral liquid formulations can be formulated as water-polyethylene glycol solutions.

[0249] Therefore, the compounds used in this invention can be formulated into preparations for parenteral administration (e.g., injection, such as rapid concentration or continuous infusion), and can be present in unit doses in ampoules, pre-filled syringes, small-volume infusion bags, or multi-dose containers together with added preservatives. The composition can be in the form of suspensions, solutions, or emulsions with oily or aqueous carriers, and may contain formulation components such as suspending agents, stabilizers, and / or dispersants. Additionally, the active ingredient can be in powder form, obtained by aseptic separation of sterile solids or by lyophilization of solutions, for reconstitution with a suitable carrier, such as sterile, pyrogen-free water, immediately before use.

[0250] Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding the desired colorants, flavorings, stabilizers and thickeners.

[0251] Aqueous suspensions suitable for oral administration can be prepared by dispersing finely divided active ingredients in water containing a viscous substance, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other known suspending agents.

[0252] This also includes solid dosage forms designed to be converted into liquid formulations for oral administration shortly before market launch. These liquid formulations include solutions, suspensions, and emulsions. In addition to the active ingredient, these formulations may contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0253] For topical application to the epidermis, the compounds of the present invention can be formulated as ointments, creams, lotions, or transdermal patches. For example, ointments and creams can be formulated with an aqueous or oil-based base plus a suitable thickener and / or gelling agent. Lotions can be formulated with an aqueous or oil-based base and typically also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants.

[0254] Compositions suitable for topical oral administration include lozenges containing the active ingredient in a flavoring matrix typically composed of sucrose and acacia gum or tragacanth gum; pastilis containing the active ingredient in an inert matrix such as gelatin and glycerin or sucrose and acacia gum; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0255] The solution or suspension can be applied directly to the nasal cavity using conventional methods such as a dropper, pipette, or nebulizer. The composition can be in single-dose or multi-dose form.

[0256] Inhalational administration can also be achieved via aerosols, in which the active ingredient is packaged with a suitable propellant in a pressurized container. Suitable propellants include chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. Aerosols may also contain surfactants, such as lecithin, as appropriate. The dosage of the drug can be controlled via a dispensing valve.

[0257] Alternatively, the active ingredient can be in the form of a dry powder, such as a mixture of the compound with a suitable powder matrix such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose, and polyvinylpyrrolidone (PVP). The powder carrier can conveniently form a gel in the nasal cavity. The powder composition can be present in unit dose form, for example, in capsules or cartridges (such as gelatin sheets or cartridges), or in blister packs in which the powder can be administered via an inhaler.

[0258] In compositions intended for respiratory administration (including intranasal compositions), the compounds typically have small particle sizes, such as 5 micrometers or smaller. Such particle sizes can be obtained using methods known in the art, such as micronization.

[0259] When necessary, compositions suitable for sustained release of active ingredients can be applied.

[0260] Pharmaceutical formulations are preferably in unit dose form. In this type of form, the formulation is subdivided into unit doses of appropriate amounts of the active ingredient. Unit dose form can be a packaged formulation containing a separate, large quantity of the formulation in a sealed package, such as packaged tablets, capsules, and powders contained in vials or ampoules. Alternatively, unit dose form can be the capsule, tablet, lozenge, or tablet itself, or an appropriate amount of the aforementioned capsules, tablets, etc., in any packaging form.

[0261] Preferred compositions include tablets or capsules for oral administration and liquids and continuous infusions for intravenous administration.

[0262] 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 0.01 mg to about 0.5 g. For example, in pharmaceutical use, the drug can be administered three times daily in capsules of 0.01 to 100 mg, and the composition may also contain other compatible therapeutic agents if necessary.

[0263] Treatment

[0264] In therapeutic use, the compounds of the present invention are used at an initial dose of 0.001 mg / kg to 10 mg / kg body weight per day. However, these doses may vary depending on the patient's needs, the severity of the condition being treated, and the compound used. Generally, treatment is started with a smaller dose than the optimal dose of the compound, and then the dose is gradually increased to achieve the best effect. For convenience, the total daily dose may be further subdivided into multiple doses throughout the day if necessary.

[0265] The pharmaceutical composition of the present invention can also be used in combination with other drugs for treating pain, Alzheimer's disease, multi-infarct dementia, and stroke, including but not limited to morphine and gabapentin. Therefore, the present invention provides a drug for treating pain, Alzheimer's disease, multi-infarct dementia, and stroke that is not only effective but also has no significant side effects. Another object of the present invention is to provide a drug with high safety for specific patient groups, such as the elderly, patients with liver or kidney dysfunction, or patients with cardiovascular disease. Detailed Implementation

[0266] Preparation method

[0267] The solvents used in this invention are commercially available. The following abbreviations are used in this invention: ACN represents acetonitrile, Bpin represents phenazine borate, BINAP represents 2,2-bis-(diphenylphosphino)-1,1-naphthyl, DCC represents N,N'-dicyclohexylcarbodiimide, DCE represents 1,2-dichloroethane, DCM represents dichloromethane, DDQ represents 2,3-dichloro-5,6-dicyanobenzoquinone, DHP represents 3,4-dihydropyran, DIBAL-H represents diisobutylaluminum hydride, DIEA represents... Table 2 shows that isopropyl ethylamine, 1,4-Dioxane represents 1,4-dioxane, DMB-NH2 represents 4-methoxybenzylamine, DMF represents N,N-dimethylformamide, DMP represents Dysmart reagent, DMSO represents dimethyl sulfoxide, EA represents ethyl acetate, EDCI represents 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea. Hexafluorophosphate, HOBt represents 1-hydroxybenzotriazole, HPLC represents high performance liquid chromatography, LiHMDS represents lithium hexamethyldisilamide, m-CPBA represents m-chloroperoxybenzoic acid, MOM-Br represents bromomethyl methyl ether, MsCl represents methanesulfonyl chloride, NMP represents 1-methyl-2-pyrrolidone, PE represents petroleum ether, PCC represents pyridinium chlorochromate, Pd(dppf)Cl2 represents 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride. Tris(dibenzylacetone)dipalladium represents tris(dibenzylacetone)dipalladium, Pd(dtpf)Cl2 represents dichloro[1,1'-bis(o-tert-butylphosphine)ferrocenepalladium(II), Pd(OAc)2 represents palladium acetate, PG represents protecting group, PMBCl represents p-methoxybenzyl chloride, PMBNH2 represents p-methoxybenzylamine, p-TsOH represents p-toluenesulfonic acid, PyBOP represents 1H-benzotriazol-1-yloxytripyrryl hexafluorophosphate, and pyr.Ruphos represents pyridine, Ruphos represents 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl, Ruphos-Pd-G3 represents (2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II), Ruphos-Pd-G4 represents (2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II), SEM-Cl represents 2-(trimethylsilyl)ethoxymethyl chloride, and T3P represents tripropylphosphophosphate. Cyclic anhydride, TBAN represents tetrabutylammonium nitrate, TCFH represents N,N,N',N'-tetramethylchlorourea hexafluorophosphate, TEA represents triethylamine, TEAF represents triethylamine trifluoride, TFA represents trifluoroacetic acid, TFAA represents trifluoroacetic anhydride, THF represents tetrahydrofuran, TLC represents thin-layer chromatography, TMEDA represents tetramethylethylenediamine, TMS represents trimethylsilyl, Tol. represents toluene, Ts represents p-toluenesulfonyl, XantPhos represents 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene, LCMS represents liquid chromatography-mass spectrometry, h represents hours, and min represents minutes.

[0268] Preparation method

[0269] This invention also relates to a method for producing compounds of general formula (I) as defined above, the method of which is shown in the figure:

[0270] Synthesis Method (I):

[0271] Route 1:

[0272] When Z1 is an N atom, Z2 and Z3 are C atoms, and Z4 is CH, the synthesis of the parent nucleus II-8 can be carried out by, but is not limited to, the synthesis method described in route 1.

[0273] In this synthetic method, compound II-3 is synthesized from compounds II-1 and II-2 via nucleophilic substitution or acylation reaction condition IIa). Y2 represents a leaving group (e.g., trifluoromethanesulfonate, p-toluenesulfonate, chlorine, bromine, iodine, etc.) or a hydroxyl group. When Y2 represents a leaving group, reaction condition IIa) corresponds to a nucleophilic substitution reaction, and the corresponding reaction condition is basic, such as reacting with TEA, DIEA, sodium hydride, cesium carbonate, or potassium phosphate as a base in various solvents such as DCM, DMF, acetonitrile, or tetrahydrofuran. When Y2 represents a hydroxyl group, reaction condition IIa) corresponds to an amide condensation reaction, and the corresponding reaction condition is amide condensation, including but not limited to reactions with condensing agents such as EDCI, CDI, HATU, and T3P in various solvents such as DCM, THF, and DMF. Y1 represents a halogen (e.g., fluorine, chlorine, bromine, iodine, etc.).

[0274] Compound II-4 is synthesized from compound II-3 via Friedel-Crafts alkylation reaction IIb). Here, Y3 represents a halogen (chlorine, bromine, or iodine) or a hydroxyl group. The Friedel-Crafts alkylation reaction IIb) is catalyzed by a Lewis acid or a protic acid in various solvents such as DCM, DCE, or nitrobenzene. The Lewis acid includes, but is not limited to, aluminum chloride, ferric chloride, and tin chloride, while the protic acid includes, but is not limited to, sulfuric acid, polyphosphoric acid, and trifluorosulfonic acid.

[0275] Compound II-4 is synthesized from cyclic compound II-5 via nitration reaction IIc), wherein the nitration reaction conditions include, but are not limited to, reactions in various solvents such as sulfuric acid, TFA, and DCE, using nitric acid, nitrates, or tetrabutylammonium nitrate as nitrating agents. Compound II-6 is synthesized from compound II-5 and an alkylamine via direct substitution or coupling reaction conditions IId). Step IId) corresponds to basic direct nucleophilic substitution conditions, including but not limited to reactions in various solvents such as DMF, acetonitrile, or tetrahydrofuran, using DIEA, sodium hydride, cesium carbonate, or potassium phosphate as bases. Alternatively, step IId) represents a metal-catalyzed coupling reaction, such as the palladium-catalyzed Buchwald reaction or the copper-catalyzed Ullmann reaction.

[0276] Tricyclic compound II-7 is synthesized from compound II-6 via a nitro reduction cyclization reaction under conditions IIe). These nitro reduction reaction conditions include, but are not limited to, reactions involving iron powder / ammonium chloride, iron powder / acetic acid, zinc powder / acetic acid, zinc powder / ammonium chloride, stannous chloride, sodium hydrosulfite, and catalytic hydrogenation. The addition of paraformaldehyde promotes the synthesis of the imidazole ring, significantly improving the efficiency of the one-step nitro reduction-imidazole ring synthesis and achieving a high yield of tricyclic compound II-7. Under preferred conditions, with the promotion of paraformaldehyde, the yield of this one-step nitro reduction-imidazole ring synthesis reaction is greater than 80%.

[0277] Compound II-7 is reduced to compound II-8 via an amide reduction reaction (IIf). The conditions for the reduction reaction (IIf) include, but are not limited to, the use of lithium aluminum hydride, borane, lithium borohydride, sodium borohydride, red aluminum, etc., as reducing agents, and the reaction in various solvents such as DCM, THF, toluene, etc.

[0278] Synthesis Method (II):

[0279] Route 2:

[0280] In the compound of general formula (I) of this invention, when Z1 and Z4 are N atoms and Z2 and Z3 are C atoms, the synthesis of the parent core III-5 can be carried out by, but is not limited to, the synthetic method described in route 2. PG2 represents an alkyl protecting group, preferably a benzyl protecting group, such as 4-methoxybenzyl, 2,4-dimethoxybenzyl, etc.

[0281] Compound III-1 is synthesized by steps IIc), IId) and IIe) as described in synthesis method (I) to obtain tricyclic compound III-4. After the removal of protecting group PG2 from III-4, the synthesis of the parent core III-5 is completed. The removal conditions of protecting group PG2 (IIIa) include, but are not limited to, under acidic conditions such as TFA, sulfonic acid, hydrochloric acid, hydrobromic acid, etc., with the addition of proton scavengers such as anisole, anisole sulfide, triethylsilane or triisopropylsilane, direct heating or reaction in various solvents such as toluene, NMP, etc.

[0282] The synthesis of the cyclic intermediate III-1 can be carried out, depending on its specific structure, by, but not limited to, the synthesis method described in route 3 below.

[0283] Route 3:

[0284] In the cyclic intermediate III-1 structure, when n = 0 and X1 is CHR 10 The structure is represented by III-8. Its synthesis can be achieved, but is not limited to, the method described in route 3(1), where compound III-7 is synthesized from compound III-6 via reduction reaction condition IIIb), which includes, but is not limited to, reactions using sodium cyanoborohydride, catalytic hydrogenation, or borane as reducing agents in various solvents such as acetic acid, THF, and acetonitrile. Introducing a protecting group PG2 into the amino group of compound III-7 yields compound III-8. The corresponding reaction condition IIIc) is a nucleophilic substitution reaction under basic conditions, for example, using TEA, DIEA, sodium hydride, cesium carbonate, or potassium phosphate as bases in various solvents such as DCM, DMF, acetonitrile, or tetrahydrofuran.

[0285] In the cyclic intermediate III-1, when n = 1 and X1 is O, S, or NR9, the structure is represented by III-13. Its synthesis can be achieved, but is not limited to, the method described in route 3, 2). In this method, compound III-9 and β-substituted acetate III-10 are reacted via direct substitution reaction under condition IIIc) to synthesize compound III-11; compound III-12 is obtained from compound III-11 via nitro reduction-in-situ cyclization reaction IIId). The nitro reduction cyclization reaction conditions include, but are not limited to, iron powder / ammonium chloride, iron powder / acetic acid, zinc powder / acetic acid, zinc powder / ammonium chloride, stannous chloride, sodium hydrosulfite, catalytic hydrogenation, etc. The amide in compound III-12 is reduced, and a protecting group is introduced onto the N atom to obtain compound III-13. In the structural unit, W1 represents a heteroatom substituent with active hydrogen, such as amino, hydroxyl, or thiol.

[0286] In the cyclic intermediate III-1 structure, when n=1 and X1 is CR 10 R 11 The structure is represented by III-17. Its synthesis can be achieved using, but is not limited to, the methods described in routes 3) and 4). In synthesis method 3), compound III-16 can be obtained from compound III-14 and dihalogenated compound III-15 through two nucleophilic substitution reactions. The ring-closing reaction conditions (IIIe) include, but are not limited to, reactions using alkyl lithium reagents, amino lithium reagents, etc., as bases in various aprotic solvents such as THF, toluene, etc. Replacing the protecting group of compound III-16 yields compound III-17. PG1 represents acyl protecting agents such as tert-butoxycarbonyl, trifluoroacetyl, etc.; Y4 and Y5 represent leaving groups (e.g., trifluoromethanesulfonate, p-toluenesulfonate, chlorine, bromine, iodine, etc.); PG2 represents an alkyl amino protecting group, preferably a benzyl protecting group, such as 4-methoxybenzyl, 2,4-dimethoxybenzyl, etc.

[0287] In synthetic method 4), compound III-18 and alkenyl compound III-19 undergo a nucleophilic substitution reaction IIIc) to obtain compound III-20. Compound III-16 can be synthesized from compound III-20 under reducing Heck reaction conditions IIIg). These reducing Heck reaction conditions IIIg include, but are not limited to, reactions using palladium acetate, tetra-triphenylphosphine palladium, etc., as metal catalysts, TEA, sodium carbonate, potassium carbonate, etc., as bases, and formic acid, ammonium formate, sodium formate, etc., as reducing agents, in various solvents such as THF, toluene, dioxane, etc. The reducing Heck reaction can be carried out with or without a ligand, including but not limited to triphenylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene, Ruphos, etc. Replacing the protecting group in compound III-16 yields compound III-17.

[0288] Synthesis Method (III):

[0289] Route 4:

[0290] In the compound of general formula (I) of this invention, when Z1 and Z3 are C atoms, Z2 and Z4 are N atoms, and X1 is an O atom, the synthesis of the parent core V-12 can be carried out by, but is not limited to, the synthetic method described in route 4. PG3 represents methoxymethyl, benzyl, silane (such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.) protecting groups, etc.

[0291] In this synthetic method, compound V-3 is synthesized from compounds V-1 and V-2 via a pyrimidine ring closure reaction (Va) under basic conditions. The ring-closure reaction conditions include, but are not limited to, reactions using sodium alkoxide or potassium carbonate as bases in various solvents such as ethanol, DMF, and THF. Compound V-3 is then reprotected to obtain compound V-4. The introduction of the R1 group in the parent nucleus is accomplished by the reduction of the alcohol generated from the reaction of aldehyde V-6 with a (Ve) Grignard reagent or lithium reagent. This can be achieved using, but is not limited to, steps (Vc), (Vd), (Ve), and (Vf). Specifically, compound V-5 is synthesized from compound V-4 via a reduction reaction (Vc), where PG3 represents methoxymethyl, benzyl, or silane (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.) protecting groups. The reduction conditions include, but are not limited to, reactions using lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride, sodium borohydride, or red aluminum as reducing agents in various solvents such as DCM, THF, and toluene. Compound V-6 was synthesized from compound V-5 via an oxidation reaction under conditions Vd), which included, but was not limited to, Desmond-Martin reagent, PCC, manganese dioxide, and Swern oxidation. Compound V-7 was synthesized from compound V-6 via an addition reaction Ve), wherein R... 1a Indicate C 1-5 Alkyl or C 3-6 cycloalkyl, the C 3-6 One C atom on the ring of the cycloalkyl group may optionally be replaced by an O atom; the C 1-6 Alkyl or C 3-6The cycloalkyl group is optionally substituted with 1-3 R's, as described above; the addition reaction conditions represent reactions using alkyl Grignard reagents or alkyl lithium reagents as reactants in various solvents such as THF and toluene. Compound V-7 is dehydroxylated to give compound V-8, and the dehydroxylation reaction conditions include, but are not limited to, reactions using triethylsilane, sodium borohydride, or Barton's reagent as reducing agents in various solvents such as TFA and THF. After introducing the R1 group, compound V-8 is deprotected and then undergoes nucleophilic substitution under condition IIIc) to give compound V-10. Compound V-10 is deprotected, and intramolecular cyclization completes the synthesis of compound V-12, where the cyclization reaction conditions Vi) include, but are not limited to, reactions using triethylamine, sodium hydride, cesium carbonate, or potassium phosphate as bases in various solvents such as dioxane, DMF, acetonitrile, or tetrahydrofuran.

[0292] Synthesis Method (IV):

[0293] Route 5:

[0294] The compound of general formula (I) described in this invention, wherein Z1 and Z3 are C atoms, Z2 and Z4 are N atoms, and X1 is C atom, is a compound of general formula (I). 10 R 11 At that time, the synthesis of the parent core V-20 can be carried out using, but is not limited to, the synthesis method described in route 5.

[0295] In this synthetic method, compound V-15 is synthesized from compounds V-13 and V-14 under pyrimidine synthesis reaction conditions Va). Compound V-16 is synthesized from compound V-15 under chlorination reaction conditions Vj), wherein the halogenation reaction conditions include, but are not limited to, reactions using phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, etc., as chlorinating agents, either by direct heating or in various solvents such as acetonitrile, DCM, etc. Compound V-17 is synthesized from compound V-16 under reduction reaction conditions Vk), wherein the reduction reaction conditions include, but are not limited to, reactions using iron powder / ammonium chloride, zinc-copper coupling reagents as reducing agents, in various solvents such as ethanol, THF, etc.; or by introducing an R3 substituent under coupling reaction conditions Vk), wherein the coupling reaction conditions include, but are not limited to, iron-catalyzed Kumada reaction, palladium-catalyzed Suzuki coupling reaction, etc. Compound V-18 is synthesized from compound V-17 via Friedel-Crafts acylation reaction Vm), followed by carbonyl removal under reduction reaction conditions Vf), wherein in compound V-17b, R... 1a Indicate C 1-5 Alkyl or C 3-6 cycloalkyl, the C 3-6 One C atom on the ring of the cycloalkyl group may optionally be replaced by an O atom; the C 1-6 Alkyl or C 3-6The cycloalkyl group is optionally substituted with 1-3 R's, as described above. The Friedel-Crafts acylation reaction (Vm) is achieved under Lewis acid or protic acid catalysis in various solvents such as DCM, DCE, or nitrobenzene. The Lewis acid includes, but is not limited to, aluminum chloride, ferric chloride, and tin chloride, while the protic acid includes, but is not limited to, sulfuric acid, polyphosphoric acid, trifluorosulfonic acid, and Eaton's reagent. Alternatively, compound V-18 is synthesized from compound V-17 via Vilsmier-Haak formylation (Vn), Grignard reagent addition (Ve), and dehydroxylation (Vf). Compound V-19 is synthesized from compound V-18 with a protecting amino compound PG2NH2 via a ring-closure reaction (Vo). The ring-closure reaction conditions include, but are not limited to, reactions using TEA, potassium carbonate, sodium hydride, and sodium hydroxide as bases in various solvents such as DMF, THF, and DCM. Deprotection of compound V-19 yields compound V-20.

[0296] Synthesis Method (5):

[0297] Route 6:

[0298] When Z1 and Z2 are C atoms, Z3 and Z4 are N atoms, and X1 is O, S, or NR9, the synthesis of the parent core V-20 can be carried out by, but is not limited to, the synthesis method described in route 6.

[0299] In this synthetic method, compound VII-3 is synthesized via direct substitution reaction (condition IIIc) of compounds VII-1 and VII-2, with in-situ cyclization of the intermediate. Reduction of the amide group in VII-3 followed by the introduction of protecting group PG2 yields compound VII-4. Compound VII-5 is synthesized via direct substitution reaction or coupling reaction (condition VIIb) of compound VII-4 and acyl-protected ammonia, where PG1 and PG2 are as defined above. Compound VII-7 is synthesized via direct substitution reaction (condition VIIc) of compounds VII-5 and VII-6, wherein the direct substitution reaction conditions include, but are not limited to, reactions using lithium tert-butoxide, sodium hydride, cesium carbonate, or potassium phosphate as bases in various solvents such as DMF, acetonitrile, and tetrahydrofuran. Compound VII-8 is synthesized via dehydration cyclization reaction (condition VIId) of compound VII-7, wherein the dehydration reaction conditions include, but are limited to, reactions using TFAA / Pyr., Burgess reagent, etc., as dehydrating agents in various solvents such as acetonitrile and DCM. Deprotection of compound VII-8 yields compound VII-9.

[0300] Synthesis Method (VI):

[0301] Route 7:

[0302] The final synthesis of the compound of general formula (I) described in this invention can be carried out by, but is not limited to, the synthetic method described in route 6. The parent compounds II-8, III-5, V-12, V-20, and VII-9 described in synthetic methods (I) to (V) are represented by general formula I-1.

[0303] In this synthetic method, compound I can be synthesized from compound I-1 and compound I-2 via direct substitution or coupling reaction under condition Ia). Alternatively, I-4 can be synthesized from compound I-1 and compound I-3 via direct substitution or coupling reaction under condition Ia), and then I-4 can be further synthesized by introducing substituent R8 under condition Ia) or Ib), thus completing the synthesis of compound I. Step Ia) corresponds to direct nucleophilic substitution conditions, including but not limited to reactions using sodium hydride, cesium carbonate, or potassium phosphate as bases, or using p-toluenesulfonic acid, hydrochloric acid, etc., as acid catalysts in various solvents such as NMP, DMF, acetonitrile, or tetrahydrofuran. Alternatively, step Ia) represents a metal-catalyzed coupling reaction, such as the palladium-catalyzed Buchwald reaction or the copper-catalyzed Ullmann reaction. Step Ib) corresponds to the palladium-catalyzed Suzuki reaction, etc., and the palladium catalysts used include, but are not limited to, Ruphos-Pd-G3, Pd(dppf)Cl2, Pd2(dba)3, etc.

[0304] Synthesis of intermediates:

[0305] Synthesis of intermediate M1:

[0306] Step 1: Synthesis of 7-chloro-1-(4-methoxybenzyl)-1,2,3,4-tetrahydro-1,8-naphthidine (M1-2)

[0307] M1-1 (3.2 g, 18.98 mmol) and PMB-Cl (3.57 g, 22.78 mmol) were dissolved in DMF (25 mL), and potassium carbonate (5.25 g, 37.96 mmol) and potassium iodide (0.32 g, 1.90 mmol) were added. The reaction mixture was stirred at 65 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with saturated brine (30 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give the title product (4.5 g, white solid).

[0308] MS(ESI)m / z[M+H] + =289.1.

[0309] Step 2: Synthesis of 7-chloro-1-(4-methoxybenzyl)-6-nitro-1,2,3,4-tetrahydro-1,8-naphthidine (M1-3)

[0310] M1-2 (3.5 g, 12.12 mmol) and tetrabutylammonium nitrate (3.69 g, 12.12 mmol) were dissolved in dichloromethane (60 mL), cooled to 0 °C, and trifluoroacetic acid (1.66 g, 14.54 mmol) and trifluoroacetic anhydride (3.05 g, 14.54 mmol) were added dropwise. The reaction was stirred at 0 °C for 15 min. LC-MS showed that the reaction was complete. The reaction was quenched with ice water (30 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:10) to give the title product (3.2 g, yellow solid).

[0311] MS(ESI)m / z[M+H] + =334.1.

[0312] Step 3: Synthesis of N-(cyclopropylmethyl)-8-(4-methoxybenzyl)-3-nitro-5,6,7,8-tetrahydro-1,8-naphthidine-2-amine (M1-4)

[0313] M1-3 (3.2 g, 9.59 mmol) and cyclopropylmethylamine (1.02 g, 14.38 mmol) were dissolved in acetonitrile (60 mL), and potassium carbonate (3.7 g, 26.81 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 2:1) to give the title product (3.0 g, yellow solid).

[0314] MS(ESI)m / z[M+H] + =369.2.

[0315] Step 4: Synthesis of 3-(cyclopropylmethyl)-5-(4-methoxybenzyl)-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (M1-5)

[0316] M1-4 (2 g, 5.43 mmol), iron powder (1.5 g, 27.2 mmol), ammonium chloride (1.4 g, 27.2 mmol), and paraformaldehyde (1.63 g, 54.3 mmol) were added to a mixed solution of methanol (30 mL) and water (10 mL), and reacted at 80 °C for 16 hours. The reaction solution was filtered while hot, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 1:4) to give the title product (1.5 g, yellow solid).

[0317] MS(ESI)m / z[M+H] + =349.2.

[0318] Step 5: Synthesis of 3-(cyclopropylmethyl)-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (M1)

[0319] M1-5 (1.5 g, 4.30 mmol) was dissolved in dichloromethane (10 mL), anisole (0.93 g, 8.6 mmol) was added, and trifluoroacetic acid (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, and the pH was adjusted to approximately 8 with sodium bicarbonate. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane / methanol = 10:1) to give the title product (800 mg, yellow solid).

[0320] MS(ESI)m / z[M+H] + =229.1.

[0321] Synthesis of intermediate M4-4:

[0322] Step 1: Synthesis of ethyl 2-((6-bromo-2-nitropyridin-3-yl)oxy)-2-methylpropionate (M4-2)

[0323] M4-1 (15 g, 68.50 mmol), ethyl 2-bromoisobutyrate (20 g, 103 mmol), and potassium carbonate (28.4 g, 205 mmol) were added to DMF (10 mL) and stirred overnight at 50 °C. Product formation was detected by LC-MS. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (400 mL), 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 (petroleum ether:ethyl acetate = 5:1) to give the title product (20.5 g, pale yellow solid).

[0324] MS(ESI)m / z[M+H] + =333.0,335.0

[0325] Step 2: 6-Bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4] Synthesis of azinon-3(4H)-one (M4-3)

[0326] M4-2 (20 g, 60.03 mmol) and iron powder (3.35 g, 60.03 mmol) were added to acetic acid (150 mL), and the mixture was heated and stirred at 90 °C for 2 hours. The product formation was detected by LCMS. The reaction solution was filtered, and the filtrate was concentrated to obtain the title product (14 g, gray solid, crude product).

[0327] MS(ESI)m / z[M+H] + =256.9,258.9.

[0328] Step 3: 6-Bromo-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4] Synthesis of aziridines (M4-4)

[0329] M4-3 (14 g, 54.5 mmol) and borane (dimethyl sulfide complex) (41.4 g, 545 mmol) were added to tetrahydrofuran (50 mL) and heated under reflux overnight. Product formation was detected by LC-MS. The reaction was quenched with methanol (50 mL), diluted with water (300 mL), and extracted with ethyl acetate (300 mL x 2). The combined organic phases were washed with saturated brine (500 mL), 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 (dichloromethane:methanol = 100:1) to give the title product (6.8 g, yellow solid).

[0330] MS(ESI)m / z[M+H] + =243.0,245.0.

[0331] Synthesis of intermediate M5-7:

[0332] Step 1: Synthesis of 3-methylbut-3-en-1-ylmethanesulfonate (M5-2)

[0333] M5-1 (10 g, 116 mmol) was dissolved in dichloromethane (100 mL), and methanesulfonyl chloride (15.96 g, 139 mmol) and triethylamine (17.6 g, 174 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title product (18 g, yellow oil, crude product).

[0334] Step 2: Synthesis of (6-chloro-3-iodopyridin-2-yl)carbamate tert-butyl ester (M5-4)

[0335] M5-3 (9 g, 35.4 mmol) was dissolved in tetrahydrofuran (90 mL), and LiHMDS (8.88 g, 53.1 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 1 h, followed by the addition of di-tert-butyl dicarbonate (9.26 g, 42.4 mmol). The reaction mixture was stirred at room temperature for 16 h. LC-MS showed product formation. The reaction mixture was quenched in ice water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:5) to give the title product (12 g, yellow oil).

[0336] MS(ESI)m / z[M+H] + =354.8.

[0337] Step 3: Synthesis of (6-chloro-3-iodopyridin-2-yl)(3-methylbut-3-en-1-yl)tert-butyl carbamate (M5-5)

[0338] M5-4 (15 g, 42.3 mmol) was dissolved in DMF (150 mL), cooled to 0 °C, and sodium hydride (2.54 g, 63.45 mmol, purity: 60%) was added. The mixture was stirred at 0 °C for 1 hour. M5-2 (8.33 g, 50.76 mmol) was then added to the above solution, and the reaction mixture was slowly heated to 80 °C and stirred for 16 hours. LC-MS showed product formation. The reaction mixture was cooled to room temperature and slowly poured into ice water (500 mL). Extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1–1:4) to give the title product (8.3 g, yellow oil).

[0339] MS(ESI)m / z[Mt-Bu+H] +=366.1.

[0340] Step 4: Synthesis of 7-chloro-4,4-dimethyl-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester (M5-6)

[0341] M5-5 (200 mg, 0.47 mmol) was dissolved in DMF (4 mL), and Pd(OAc)₂ (10.6 mg, 0.047 mmol), sodium acetate (96.4 mg, 1.17 mmol), sodium formate (38.4 mg, 0.56 mmol), and triethylamine (93.45 mg, 0.56 mmol) were added. The reaction mixture was stirred at 95 °C for 4 hours. LC-MS showed product formation. The reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (100 mL), 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 (ethyl acetate: petroleum ether = 0:1 to 1:5) to give the title product (70 mg, yellow oil).

[0342] MS(ESI)m / z[Mt-Bu+H] + =297.1.

[0343] Step 5: Synthesis of 7-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-1,8-naphthidine (M5-7)

[0344] M5-6 (3.5 g, 11.79 mmol) was added to hydrochloric acid gas (ethyl acetate solution) (40 mL) at room temperature and stirred for 4 hours. LC-MS showed product formation. The reaction mixture was slowly poured into a saturated sodium bicarbonate solution (80 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title product (2.3 g, yellow solid).

[0345] MS(ESI)m / z[M+H] + =197.1.

[0346] Synthesis of intermediate M6-3:

[0347] Step 1: Synthesis of tert-butyl 5,7-dichloro-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid (M6-2)

[0348] Under argon protection at -20°C, tetramethylethylenediamine (13.91 g, 119.7 mmol) was dissolved in tetrahydrofuran (200 mL), and n-butyllithium (12.78 g, 199.5 mmol) was added. The reaction mixture was stirred for 30 min. At -40°C, M6-1 (21 g, 79.8 mmol) was added, and stirring continued for 1 h. Then, cuprous iodide (22.80 g, 119.7 mmol) and 1-chloro-3-iodopropane (24.5 g, 119.7 mmol) were added. The reaction mixture was slowly heated to 60°C and stirred for 24 h. The reaction was monitored for completeness by LC-MS. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (500 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 (dichloromethane:methanol = 10:1) to give the title product (8 g, yellow solid).

[0349] MS(ESI)m / z[M+H] + =303.0.

[0350] Step 2: Synthesis of 5,7-dichloro-1,2,3,4-tetrahydro-1,8-naphthyridine (M6-3)

[0351] At room temperature, M6-2 (2.0 g, 6.60 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (1.13 g, 9.90 mmol) was added dropwise, followed by stirring for 2 h. The reaction was monitored by LCMS until complete. The reaction solution was quenched in saturated sodium bicarbonate solution (30 mL), diluted with water (20 mL), and extracted with dichloromethane (60 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (1.1 g, yellow solid).

[0352] MS(ESI)m / z[M+H] + =203.1.

[0353] Synthesis of intermediate M7-5:

[0354] Step 1: Synthesis of 6-chloro-2-((2-methylallyl)amino)nicotinonitrile (M7-2)

[0355] Under an argon atmosphere, 12.9 g (182 mmol) of 2-methylprop-2-en-1-amine, 50.3 g (364 mmol) of potassium carbonate, and 20 g (116 mmol) of M7-1 were mixed in 200 mL of o-xylene, and the reaction was stirred at 70 °C for 5 hours. TLC showed that the reaction was complete. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (100 mL x 2) and dried under reduced pressure. The crude product was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1–1:8) to give the title product (7.3 g, white solid).

[0356] Step 2: Synthesis of 7-chloro-3,3-dimethyl-2,3-dihydro-1,8-naphthidium-4(1H)-one (M7-3)

[0357] Under open conditions, benzylsilane (9.85 g, 91.0 mmol) was dissolved in isopropanol (100 mL), and M7-2 (6.3 g, 30.4 mmol) and iron triacetylacetone (2.14 g, 6.07 mmol) were added. The reaction mixture was stirred at 50 °C for 1 hour. 4 mL of 2M hydrochloric acid solution was added to the reaction mixture, and the mixture was stirred at 75 °C for 1 hour. LC-MS showed product formation. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give the title product (6.4 g, white solid, crude).

[0358] MS(ESI)m / z[M+H]+=211.1.

[0359] Step 3: Synthesis of 7-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-1,8-naphthidine-4-ol (M7-4)

[0360] At room temperature, M7-3 (5.5 g, 26.1 mmol) was dissolved in methanol (50 mL), and sodium borohydride (9.88 g, 261 mmol) was added in portions. After completion, the mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction was quenched with 100 mL of water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give the title product (3.4 g, white solid).

[0361] MS(ESI)m / z[M+H]+=213.1.

[0362] Step 4: Synthesis of 7-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-1,8-naphthidine (M7-5)

[0363] At 0 °C, triethylsilane (5.41 g, 46.6 mmol) was added to trifluoroacetic acid (50 mL), and after stirring for 30 minutes, M7-4 (3.3 g, 15.5 mmol) was added (in 20 mL of dichloromethane solution). The reaction was carried out at 50 °C with stirring for 16 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution (50 mL), and the organic phase was washed with saturated brine (200 mL). The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (3.3 g, white solid, crude product).

[0364] MS(ESI)m / z[M+H]+=197.1.

[0365] Synthesis of intermediate M47-4:

[0366] Step 1: Synthesis of ethyl 2-((2-amino-6-chloropyridin-3-yl)thio)ethyl acetate (M47-2)

[0367] M47-1 (5 g, 24.1 mmol) was dissolved in 1,4-dioxane (50 mL), and ethyl mercaptoacetate (5.79 g, 48.2 mmol), Pd2(dba)3 (2.21 g, 2.41 mmol), XantPhos (1.39 g, 2.41 mmol), and N,N-diisopropylethylamine (6.23 g, 48.2 mmol) were added. The reaction was purged with argon and stirred overnight at 80 °C. LC-MS showed that the reaction was complete. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 12:1) to give the title product (3.5 g, yellow oil).

[0368] MS(ESI)m / z[M+H] + =247.0.

[0369] Step 2: Synthesis of 6-chloro-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one (M47-3)

[0370] M47-2 (2 g, 8.11 mmol) was dissolved in ethanol (20 mL), and cesium carbonate (5.28 g, 16.2 mmol) was added. The reaction was stirred at 80 °C for 5–10 min. LC-MS showed that the reaction was complete. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 12:1) to give the title product (1.3 g, white solid).

[0371] MS(ESI)m / z[M+H] + =201.0.

[0372] Step 3: Synthesis of 6-chloro-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine (M47-4)

[0373] M47-3 (250 mg, 0.78 mmol) was dissolved in tetrahydrofuran (5 mL), and borane (tetrahydrofuran complex) (2.34 mL, 2.34 mmol) was added. The reaction was stirred at 70 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 12:1) to give the title product (160 mg, yellow oil).

[0374] MS(ESI)m / z[M+H] + =187.0.

[0375] Synthesis of intermediate M49-2:

[0376] Step 1: 6-Bromo-3-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4] Synthesis of aziridine (M49-2)

[0377] Compound M49-1 (1.60 g, 7 mmol) was dissolved in tetrahydrofuran (20 mL), and methylmagnesium bromide (2.50 g, 21.0 mmol) was added at 0 °C. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid. The solid was dissolved in dichloromethane (20 mL), and acetic acid (42 mg, 0.70 mmol) and sodium triacetoxyborohydride (2.22 g, 10.5 mmol) were added. The mixture was stirred at room temperature for 2 hours, and LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (0.8 g, yellow solid).

[0378] MS(ESI)m / z[M+H] + =229.0,231.0.

[0379] Synthesis of intermediate M50-5:

[0380] Steps 1-3: Synthesis of 7-chloro-4-methylene-1,2,3,4-tetrahydro-1,8-naphthidine (M50-3)

[0381] The synthesis method is as described in steps 3 to 5 of the synthesis of intermediate M5-7, to obtain the title product (crude product).

[0382] MS(ESI)m / z[M+H]+=181.1.

[0383] Step 4: Synthesis of 7-chloro-1-(4-methoxybenzyl)-4-methylene-1,2,3,4-tetrahydro-1,8-naphthidine (M50-4)

[0384] The synthesis was performed as described in step 1 of the synthesis of intermediate M1, yielding the title product (yield: 33.0%).

[0385] MS(ESI)m / z[M+H]+=301.1.

[0386] Step 5: Synthesis of 7-chloro-1-(4-methoxybenzyl)-4-methyl-1,2,3,4-tetrahydro-1,8-naphthidine (M50-5)

[0387] At room temperature, M50-4 (350 mg, 1.16 mmol), platinum dioxide (26.3 mg, 0.12 mmol), and methanol (0.5 mL) were added to ethyl acetate (5 mL), and the mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:7) to give the title product (270 mg, yellow solid).

[0388] MS(ESI)m / z[M+H]+=303.1.

[0389] Following the synthesis method of intermediate M1, the following intermediate was obtained:

[0390] Synthesis of intermediate M51:

[0391] Step 1: Synthesis of 5-(4-methoxybenzyl)-2-methyl-3-((tetrahydrofuran-3-yl)methyl)-5,6,7-8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (M51-2)

[0392] Compound M51-1 (1.1 g, 2.76 mmol) was dissolved in ethanol (15 mL) and water (5 mL), followed by the addition of iron powder (0.77 g, 13.80 mmol) and ammonium chloride (0.74 g, 13.80 mmol). The reaction was stirred at 80 °C for 2 h. The reaction was monitored by LCMS until complete. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to the title product (0.66 g, yellow solid).

[0393] MS(ESI)m / z[M+H] + =393.2.

[0394] Step 2: Synthesis of 2-methyl-3-((tetrahydrofuran-3-yl)methyl)-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (M51)

[0395] Following the method described in step 5 of the synthesis of intermediate M1, the title product was obtained (yield: 83.0%).

[0396] MS(ESI)m / z[M+H] + =273.0.

[0397] Synthesis of intermediate M52:

[0398] Step 1: Synthesis of 9-chloro-3-(cyclopropylmethyl)-5-(4-methoxybenzyl)-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (M52-1)

[0399] The synthesis method is as described in step 1 of the synthesis of intermediate M1, to obtain the title product (crude product).

[0400] Step 2: Synthesis of 3-(cyclopropylmethyl)-5-(4-methoxybenzyl)-9-methyl-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (M52-2)

[0401] Under argon protection, compound M52-1 (10 mg, 0.026 mmol) and methylboric acid (1.56 mg, 0.026 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL). Pd(dtpf)Cl2 (1.69 mg, 0.0026 mmol) and potassium carbonate (0.0072 g, 0.052 mmol) were added sequentially, and the reaction was stirred at 100 °C for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered, and the filtrate was evaporated to dryness. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1–1:3) to give the title product (5 mg, crude).

[0402] MS(ESI)m / z[M+H] + =363.2.

[0403] Step 3: Synthesis of 3-(cyclopropylmethyl)-9-methyl-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (M52)

[0404] The synthesis method is as described in step 5 of the synthesis of intermediate M1, yielding the title product (yield: 97.4%).

[0405] MS(ESI)m / z[M+H] + =242.2.

[0406] Synthesis of intermediate M53:

[0407] Step 1: Synthesis of tert-butyl 7-chloro-4-oxo-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid (M53-2)

[0408] M53-1 (25 g, 93.0 mmol) and sodium dihydrogen phosphate (27.90 g, 232.57 mmol) were dissolved in tert-butanol (100 mL) and water (100 mL). Potassium permanganate (73.5 g, 465 mmol) was slowly added, and the reaction was stirred at 50 °C for 1 hour. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (19 g, yellow solid).

[0409] MS(ESI)m / z[M+H] + =283.1.

[0410] Step 2: Synthesis of tert-butyl 7-(cyclopropylamino)-4-oxo-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid (M53-3)

[0411] Compound M53-2 (5 g, 17.69 mmol), cyclopropylamine (1.01 g, 17.7 mmol), and DIEA (4.57 g, 35.4 mmol) were dissolved in DMSO (20 mL), and the reaction was stirred at 80 °C for 24 h. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 3, containing 10% methanol). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (3.5 g, yellow solid).

[0412] MS(ESI)m / z[M+H] + =304.1.

[0413] Step 3: Synthesis of tert-butyl 6-bromo-7-(cyclopropylamino)-4-oxo-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid (M53-4)

[0414] Compound M53-3 (3 g, 9.89 mmol) was dissolved in acetonitrile (20 mL), and NBS (1.76 g, 9.89 mmol) was added at 0 °C. The reaction was stirred at 0 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 3, containing 10% methanol). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give the title product (3.0 g, yellow solid).

[0415] MS(ESI)m / z[M+H] + =382.1.

[0416] Step 4: Synthesis of tert-butyl 6-amino-7-(cyclopropylamino)-4-oxo-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid (M53-5)

[0417] M53-4 (900 mg, 2.35 mmol), ammonia (2.5 mL, 30%), copper acetylacetonate (123 mg, 0.47 mmol), acetylacetone (118 mg, 1.18 mmol), and cesium carbonate (1.15 g, 3.53 mmol) were sequentially added to 1-methyl-2-pyrrolidone (5 mL), sealed, and stirred overnight at 110 °C. LC-MS showed product formation. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-25%) to give the title product (200 mg, brown solid).

[0418] MS(ESI)m / z[M+H] + =319.2.

[0419] Step 5: Synthesis of 3-cyclopropyl-8-oxo-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyl-5-carboxylic acid tert-butyl ester (M53-6)

[0420] M53-5 (200 mg, 0.63 mmol) was added to trimethyl orthoformate (4 mL) and water (0.5 mL), sealed, and stirred at 100 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (180 mg, yellow solid).

[0421] MS(ESI)m / z[M+H] + =329.1.

[0422] Step 6: Synthesis of 3-cyclopropyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,8]naphthidium-8-one (M53)

[0423] Following the method described in step 2 of the synthesis of intermediate M6-3, the title product was obtained (yield: 85.5%).

[0424] MS(ESI)m / z[M+H] + =229.1.

[0425] Synthesis of intermediate M54:

[0426] Step 1: Synthesis of 3-cyclopropyl-8-hydroxy-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyl-5-carboxylic acid tert-butyl ester (M54-1)

[0427] M53-6 (0.12 g, 0.37 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (1 mL). Sodium borohydride (14 mg, 0.37 mmol) was added at -5 °C, and the reaction was stirred at 0 °C for 1 hour. LC-MS showed that the reaction was complete. The reaction solution was quenched in saturated sodium bicarbonate solution (10 mL), extracted with dichloromethane (30 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (0.05 g, yellow solid).

[0428] MS(ESI)m / z[M+H]+ =331.1.

[0429] Step 2: Synthesis of 3-cyclopropyl-8-methoxy-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyl-5-carboxylic acid tert-butyl ester (M54-2)

[0430] Under argon atmosphere, M54-1 (0.13 g, 0.39 mmol) was dissolved in DMF (5 mL). Sodium hydride (9.4 mg, 0.39 mmol, purity: 60%) was added at 0 °C, and the mixture was stirred for 30 minutes. Iodomethane (55 mg, 0.39 mmol) was then added, and the reaction temperature was slowly raised to room temperature, followed by stirring for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was quenched with water (10 mL) and extracted with dichloromethane (containing 10% methanol, 30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the product (100 mg, yellow solid).

[0431] MS(ESI)m / z[M+H] + =345.1.

[0432] Step 3: Synthesis of 3-cyclopropyl-8-methoxy-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (M54-3)

[0433] Following the method described in step 2 of the synthesis of intermediate M6-3, the title product (yield: 50%) was obtained.

[0434] MS(ESI)m / z[M+H] + =245.1.

[0435] Synthesis of intermediate M55:

[0436] Step 1: Synthesis of 3-chloro-N-(3-fluorophenyl)propionamide (M55-2)

[0437] M55-1 (20 g, 180 mmol) was dissolved in dichloromethane (200 mL), and 3-chloropropionyl chloride (27.4 g, 216 mmol) and pyridine (35.6 g, 450 mmol) were added under an argon atmosphere. The mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the title product (28.8 g, yellow solid).

[0438] Step 2: Synthesis of 7-fluoro-3,4-dihydroquinoline-2(1H)-one (M55-3)

[0439] M55-2 (23.8 g, 118 mmol) and aluminum chloride (55.1 g, 413 mmol) were mixed together and stirred at 130 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was slowly added to ice water (300 mL) and filtered. The filter cake was washed successively with water (100 mL) and diethyl ether (100 mL), and then dried under vacuum to give the title product (25 g, yellow solid).

[0440] Step 3: Synthesis of 7-fluoro-6-nitro-3,4-dihydroquinoline-2(1H)-one (M55-4)

[0441] M55-3 (20 g, 121 mmol) was dissolved in concentrated sulfuric acid (120 mL), and concentrated nitric acid (7.63 g, 121 mmol) was slowly added dropwise at 0 °C. The reaction was stirred at 0 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was slowly added to an ice-water bath (200 mL), filtered, and the filter cake was collected. The filter cake was washed with diethyl ether (100 mL) and water (100 mL), and dried under vacuum to give the title product (18 g, yellow solid).

[0442] Steps 4-5: Synthesis of 3-(cyclopropylmethyl)-3,5,7,8-tetrahydro-6H-imidazo[4,5-g]quinoline-6-one (M55-6)

[0443] The synthesis method is as described in steps 3-4 of the synthesis of intermediate M1, yielding the title product (yield: 24.4%).

[0444] MS(ESI)m / z[M+H] + =242.1.

[0445] Step 6: Synthesis of 3-(cyclopropylmethyl)-5,6,7,8-tetrahydro-3H-imidazo[4,5-g]quinoline (M55)

[0446] The synthesis method is as described in step 3 of the synthesis of intermediate M4-4, yielding the title product (yield: 31.3%).

[0447] MS(ESI)m / z[M+H] + =228.1.

[0448] Synthesis of intermediate M56:

[0449] Step 1: Synthesis of (Z / E)-2,3-dimethoxymethyl acrylate (M56-2)

[0450] Ethyl 2-methoxyethyl (30 g, 288 mmol) and methyl formate (20.77 g, 346 mmol) were dissolved in tetrahydrofuran (350 mL). NaH (16.14 g, 403 mmol, purity: 60%) was slowly added at 0 °C. The reaction mixture was heated to room temperature and stirred for 12 hours. The reaction mixture was filtered, and the filter cake was collected and dried under reduced pressure to give the title product (40 g, pale yellow solid).

[0451] Step 2: Synthesis of ethyl 6-methoxy-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (M56-4)

[0452] M56-3 (30 g, 193 mmol) was dissolved in DMF (450 mL), and M56-2 (33.9 g, 232 mmol) and cesium carbonate (113 g, 348 mmol) were added. The reaction was stirred at 110 °C for 12 hours. The reaction mixture was diluted with water (1.0 L), and then hydrochloric acid (5 M, 60 mL) was slowly added dropwise, resulting in the precipitation of a solid. The filter cake was collected and washed with methanol (60 mL). The solid was collected and dried under reduced pressure to give the title product (45 g, yellow solid).

[0453] MS(ESI)m / z[M+H] + =238.1.

[0454] Step 3: Synthesis of ethyl 5-chloro-6-methoxypyrazolo[1,5-a]pyrimidine-3-carboxylate (M56-5)

[0455] M56-4 (14 g, 59.02 mmol) was dissolved in phosphorus oxychloride (100 mL) and stirred at 110 °C for 7 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure until a solid precipitated. Water (1.00 L) was added to the residue and the mixture was filtered. The filter cake was dissolved in dichloromethane (2.00 L) and washed with water (2.00 L). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title product (12 g, gray solid).

[0456] MS(ESI)m / z[M+H] + =256.1.

[0457] Step 4: Synthesis of ethyl 5-chloro-6-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (M56-6)

[0458] Aluminum chloride (26.1 g, 196 mmol) was added to DCE (150 mL), and the mixture was stirred at 20 °C for 10 minutes. M56-5 (10 g, 39.1 mmol) was added in portions. The mixture was stirred at 20 °C for 24 hours. The reaction was quenched at 0 °C with hydrochloric acid (5 M, 500 mL), diluted with water (500 mL), and extracted with ethyl acetate (500 mL x 3). The combined organic phases were washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title product (7 g, gray solid).

[0459] MS(ESI)m / z[M+H] + =242.0.

[0460] Step 5: Synthesis of ethyl 5-chloro-6-(methoxymethoxy)pyrazolo[1,5-a]pyrimidine-3-carboxylate (M56-7)

[0461] M56-6 (1.0 g, 4.14 mmol) and bromomethyl methyl ether (1.0 g, 8.28 mmol) were dissolved in tetrahydrofuran (20 mL), and DIEA (1.6 g, 12.42 mmol) was added. The reaction was carried out at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:5) to give the title product (400 mg, yellow solid).

[0462] MS(ESI)m / z[M+H] + =286.0.

[0463] Step 6: Synthesis of (5-chloro-6-(methoxymethoxy)pyrazolo[1,5-a]pyrimidin-3-yl)methanol (M56-8)

[0464] M56-7 (3.0 g, 10.50 mmol) was mixed into tetrahydrofuran (100 mL), cooled to -78 °C, and DIBAL-H (3.73 g, 26.3 mmol) was added. The reaction was stirred at -78 °C for 30 min. LC-MS showed that the reaction was complete. The reaction was quenched with ice water (30 mL), extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title product (1.0 g, yellow solid).

[0465] MS(ESI)m / z[M+H] + =244.1.

[0466] Step 7: Synthesis of 5-chloro-6-(methoxymethoxy)pyrazolo[1,5-a]pyrimidine-3-carboxaldehyde (M56-9)

[0467] M56-8 (1.0 g, 2.46 mmol) was dissolved in dichloromethane (50 mL), cooled to 0 °C, and DMP (2.1 g, 4.92 mmol) was added. The reaction mixture was heated to room temperature and stirred for 2 hours. LC-MS showed that the reaction was complete. The reaction was quenched with ice water (30 mL), extracted with dichloromethane (50 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 = 0:1 to 1:2) to give the title product (730 mg, yellow solid).

[0468] MS(ESI)m / z[M+H] + =242.0.

[0469] Step 8: Synthesis of (5-chloro-6-(methoxymethoxy)pyrazolo[1,5-a]pyrimidin-3-yl)(cyclopropyl)methanol (M56-10)

[0470] M56-9 (450 mg, 1.86 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to -78 °C, and cyclopropylmagnesium bromide (2.66 mL, 0.7 M THF solution, 1.86 mmol) was added. The reaction was stirred at -78 °C for 1 hour. LC-MS showed that the reaction was complete. The reaction was quenched with ice water (30 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. 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 give the title product (300 mg, yellow solid).

[0471] MS(ESI)m / z[M+H] + =284.0.

[0472] Step 9: Synthesis of 5-chloro-3-(cyclopropylmethyl)-6-(methoxymethoxy)pyrazolo[1,5-a]pyrimidine (M56-11)

[0473] M56-10 (600 mg, 0.63 mmol) was dissolved in dichloromethane (15 mL), and triethylsilane (220 mg, 1.89 mmol) and trifluoroacetic acid (216 mg, 1.89 mmol) were added. The reaction was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction was quenched with ice water (30 mL), the pH was adjusted to approximately 9 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was examined for concentration. The residue was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 4:1) to give the title product (150 mg, yellow solid).

[0474] MS(ESI)m / z[M+H] + =268.1.

[0475] Step 10: Synthesis of 5-chloro-3-(cyclopropylmethyl)pyrazolo[1,5-a]pyrimidin-6-ol (M56-12)

[0476] M56-11 (150 mg, 0.56 mmol) was dissolved in tetrahydrofuran (10 mL), and dilute hydrochloric acid (3 M, 5 mL) was added. The mixture was stirred at 50 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction was quenched with ice water (30 mL), extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (53 mg, yellow solid).

[0477] MS(ESI)m / z[M+H] + =224.1.

[0478] Step 11: Synthesis of tert-butyl (2-((5-chloro-3-(cyclopropylmethyl)pyrazolo[1,5-a]pyrimidin-6-yl)oxy)ethyl)carbamate (M56-13)

[0479] M56-12 (80 mg, 0.36 mmol), 1,2,3-oxathiazolidin-3-carboxylic acid tert-butyl ester 2,2-dioxide (161 mg, 0.72 mmol), and potassium carbonate (199 mg, 1.44 mmol) were mixed in a mixed solvent of ethyl acetate (10 mL) and DMF (1 mL) and stirred at room temperature for 16 hours. LC-MS showed product formation. The reaction solution was concentrated under reduced pressure to give the title product (120 mg, yellow solid).

[0480] MS(ESI)m / z[M+H] + =367.1.

[0481] Step 12: Synthesis of 2-((5-chloro-3-(cyclopropylmethyl)pyrazolo[1,5-a]pyrimidin-6-yl)oxy)ethyl-1-amine (M56-14)

[0482] M56-13 (80 mg, 0.22 mmol) was dissolved in ethyl acetate (6 mL), and HCl (gas) (4 M ethyl acetate solution, 4 mL) was added. The reaction was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give the title product (50 mg, yellow solid).

[0483] MS(ESI)m / z[M+H] + =267.1.

[0484] Step 13: 6-(cyclopropylmethyl)-3,4-dihydro-2H-pyrazolo[1',5':1,2]pyrimidine[5,4-b][1,4] Synthesis of aziridine (M56)

[0485] M56-14 (80 mg, 0.30 mmol) and DIEA (0.39 g, 3.0 mmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL), and the reaction was stirred at 60 °C for 5 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give the title product (55 mg, yellow solid).

[0486] MS(ESI)m / z[M+H] + =231.1.

[0487] Synthesis of intermediate M57:

[0488] Step 1: Synthesis of diethyl 2-(3-((tert-butyldimethylsilyl)oxy)propyl)malonate (M57-2)

[0489] M57-1 (50 g, 312 mmol) was dissolved in ethanol (150 mL), and sodium ethoxide (159 g, 468 mmol) was added. The reaction mixture was stirred at 90 °C for 1 hour. The reaction mixture was cooled to room temperature, and (3-bromopropoxy)(tert-butyl)dimethylsilane (87 g, 343 mmol) was added. The reaction mixture was stirred at 95 °C overnight. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove ethanol, diluted with water (300 mL), and extracted with dichloromethane (300 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title product (103 g, yellow oil, crude product).

[0490] Step 2: Synthesis of 6-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (M57-3)

[0491] 5-Aminopyrazole (24 g, 289 mmol) and M57-2 (103 g, 309 mmol) were dissolved in ethanol (500 mL), and sodium ethoxide (197 g, 578 mmol) was added. The reaction was carried out overnight at 90 °C. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature, quenched with saturated brine (100 mL), and the pH of the solution was adjusted to approximately 5 with 5 M HCl solution. The filter cake was collected by filtration. The filter cake was diluted with water (100 mL) and 5 M HCl solution (5 mL), stirred for 10 hours, and then filtered. The filter cake was dried under reduced pressure to give the title product (55 g, yellow solid).

[0492] Step 3: Synthesis of 5,7-dichloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine (M57-4)

[0493] M57-3 (15 g, 71.7 mmol) was mixed into phosphorus oxychloride (30 mL), and triethylamine (2.92 g, 28.9 mmol) was added. The reaction was stirred overnight at 100 °C. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was poured into ice water (200 mL) and extracted with dichloromethane (200 mL x 3). The combined organic phases were washed with saturated sodium bicarbonate solution (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:4) to give the title product (5.0 g, white solid).

[0494] MS(ESI)m / z[M+H] + =264.0,266.0.

[0495] Step 4: Synthesis of 5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine (M57-5)

[0496] M57-4 (5.2 g, 19.7 mmol) was dissolved in a mixture of methanol (50 mL) and water (30 mL), and zinc powder (1.29 g, 19.7 mmol) and ammonium chloride (10.5 g, 197 mmol) were added. The reaction was stirred overnight at 50 °C. LC-MS showed that the reaction was complete. The reaction mixture was quenched with water (100 mL) and extracted with dichloromethane (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:5) to give the title product (3.0 g, yellow solid).

[0497] MS(ESI)m / z[M+H] + =230.0.

[0498] Step 5: Synthesis of 5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine-3-carboxaldehyde (M57-6)

[0499] M57-5 (1.5 g, 6.52 mmol) was dissolved in DMF (20 mL), and phosphorus oxychloride (2.5 g, 16.3 mmol) was added. The reaction was stirred overnight at 30 °C. LC-MS showed product formation. The reaction was quenched with saturated sodium bicarbonate solution, and the pH of the solution was adjusted to approximately 8. The mixture was extracted with dichloromethane (100 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1–1:3) to give the title product (1.45 g, yellow solid).

[0500] MS(ESI)m / z[M+H] + =258.3.

[0501] Steps 6-7: Synthesis of 5-chloro-6-(3-chloropropyl)-3-(cyclopropylmethyl)pyrazolo[1,5-a]pyrimidine (M57-8)

[0502] The synthesis method is as described in steps 8-9 of the synthesis of intermediate M56, yielding the title product (yield: 49.7%).

[0503] MS(ESI)m / z[M+H] + =284.1.

[0504] Step 8: Synthesis of 3-(cyclopropylmethyl)-5-(2,4-dimethoxybenzyl)-5,6,7,8-tetrahydropyrazolo[1,5-a]pyridolo[2,3-d]pyrimidine (M57-9)

[0505] M57-8 (890 mg, 2.82 mmol), 2,4-dimethoxybenzylamine (943 mg, 5.64 mmol), and potassium carbonate (780 mg, 5.64 mmol) were mixed in DMF (15 mL) and stirred at 110 °C for 1 hour. LC-MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution, and the pH of the solution was adjusted to approximately 8. The mixture was extracted with dichloromethane (100 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 rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1–1:3) to give the title product (400 mg, yellow solid).

[0506] MS(ESI)m / z[M+H] + =379.2.

[0507] Step 9: Synthesis of 3-(cyclopropylmethyl)-5,6,7,8-tetrahydropyrazolo[1,5-a]pyridolo[2,3-d]pyrimidine (M57)

[0508] The synthesis method is as described in step 5 of the synthesis of intermediate M1, yielding the title product (yield: 90.9%).

[0509] MS(ESI)m / z[M+H] + =229.1.

[0510] Synthesis of intermediate M58:

[0511] Step 1: Synthesis of 3-bromo-5,7-dichloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine (M58-1)

[0512] M57-4 (3.0 g, 11.3 mmol) was added to dichloromethane (50 mL), and NBS (2.02 g, 11.3 mmol) was added at 0 °C. The reaction was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:5) to give the title product (4.5 g, yellow solid).

[0513] MS(ESI)m / z[M+H] + =341.9,343.9.

[0514] Step 2: Synthesis of 3-bromo-5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine (M58-2)

[0515] The synthesis method is as described in step 4 of the synthesis of intermediate M57, yielding the title product (yield: 81.5%).

[0516] MS(ESI)m / z[M+H] + =308.0,310.0.

[0517] Step 3: Synthesis of 3-bromo-5-(2,4-dimethoxybenzyl)-5,6,7,8-tetrahydropyrazolo[1,5-a]pyridolo[2,3-d]pyrimidine (M58-3)

[0518] The synthesis method is as described in step 8 of the synthesis of intermediate M57, yielding the title product (yield: 9.30%).

[0519] MS(ESI)m / z[M+H] + =403.1.

[0520] Step 4: Synthesis of 5-(2,4-dimethoxybenzyl)-3-phenyl-5,6,7,8-tetrahydropyrazolo[1,5-a]pyridolo[2,3-d]pyrimidine (M58-4)

[0521] M58-3 (1.8 g, 4.46 mmol) and phenylboronic acid (1.09 g, 8.92 mmol) were added to a mixed solvent of 1,4-dioxane (30 mL) and water (6 mL), followed by the addition of bis(diphenylphosphine)ferrocene palladium dichloromethane adduct (364 mg, 0.45 mmol) and potassium phosphate (1.89 g, 8.92 mmol). The reaction was stirred overnight at 100 °C. LC-MS showed product formation. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1–1:3) to give the title product (1.5 g, yellow solid).

[0522] MS(ESI)m / z[M+H] + =401.2.

[0523] Step 5: Synthesis of 3-phenyl-5,6,7,8-tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine (M58)

[0524] The synthesis method is as described in step 5 of the synthesis of intermediate M1, yielding the title product (yield: 64.0%).

[0525] MS(ESI)m / z[M+H] + =251.1.

[0526] The following intermediate was obtained by referring to the synthesis method of intermediate M58.

[0527] Synthesis of intermediate M61:

[0528] Step 1: Synthesis of 5-chloro-6-(3-chloropropyl)-7-methylpyrazolo[1,5-a]pyrimidine (M61-1)

[0529] M57-4 (5 g, 18.90 mmol) and ferric triacetylacetone (2 g, 5.67 mmol) were dissolved in tetrahydrofuran (50 mL), cooled to -78 °C, and methylmagnesium bromide (37.8 mL, 37.8 mmol, 1.0 M tetrahydrofuran solution) was added dropwise. The reaction mixture was slowly heated to room temperature and stirred overnight. LC-MS showed product formation. The reaction mixture was quenched with ice water (50 mL), filtered, and the filtrate was extracted with dichloromethane (50 mL x 2). The combined organic phases were 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 = 0:1 to 1:4) to give the title product (3 g, white solid).

[0530] MS(ESI)m / z[M+H] + =244.0.

[0531] Step 2: Synthesis of (5-chloro-6-(3-chloropropyl)-7-methylpyrazolo[1,5-a]pyrimidin-3-yl)(cyclopropyl) methyl ketone (M61-2)

[0532] M61-1 (1.0 g, 4.10 mmol) and aluminum chloride (1.6 g, 10.29 mmol) were dissolved in dichloromethane (20 mL), and cyclopropylformyl chloride (860 mg, 8.24 mmol) was added. The mixture was stirred overnight at room temperature. LC-MS showed product formation. The reaction mixture was quenched with ice water (20 mL), filtered, and the filtrate was extracted with dichloromethane (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. 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 give the title product (1 g, white solid).

[0533] MS(ESI)m / z[M+H] + =312.1.

[0534] Step 3: Synthesis of cyclopropyl (5-(3,4-dimethylbenzyl)-9-methyl-5,6,7,8-tetrahydropyrazolo[1,5-a]pyridolo[2,3-d]pyrimidin-3-yl) methyl ketone (M61-3)

[0535] The synthesis method is as described in step 8 of the synthesis of intermediate M57, yielding the title product (yield: 41.0%).

[0536] MS(ESI)m / z[M+H] + =407.2.

[0537] Step 4: Synthesis of 3-(cyclopropylmethyl)-5-(3,4-dimethylbenzyl)-9-methyl-5,6,7,8-tetrahydropyrazolo[1,5-a]pyridolo[2,3-d]pyrimidine (M61-4)

[0538] M61-3 (400 mg, 0.98 mmol) was dissolved in tetrahydrofuran (15 mL), cooled to 0 °C, and sodium borohydride (74.2 mg, 1.96 mmol) was added. The reaction mixture was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction mixture was quenched with ice water (20 mL), filtered, and the filtrate was extracted with dichloromethane (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. 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 give the title product (50 mg, yellow solid).

[0539] MS(ESI)m / z[M+H] + =393.2.

[0540] Step 5: Synthesis of 3-(cyclopropylmethyl)-9-methyl-5,6,7,8-tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine (M61)

[0541] The synthesis method is as described in step 5 of the synthesis of intermediate M1, yielding the title product (yield: 95.3%).

[0542] MS(ESI)m / z[M+H] + =243.2.

[0543] Synthesis of intermediate M62:

[0544] Step 1: Synthesis of 3,6-dichloro-4-(3-chloropropyl)pyridazine (M62-2)

[0545] Dichlorotetraazine (10 g, 66.3 mmol) was dissolved in toluene (100 mL), and 5-chloro-pentan-1-yne (13.6 g, 133 mmol) was added under an argon atmosphere. The reaction was stirred overnight at 100 °C. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give the title product (13 g, black solid, crude product).

[0546] MS(ESI)m / z[M+H]+=224.9.

[0547] Step 2: Synthesis of tert-butyl (6-chloro-5-(3-chloropropyl)pyridazin-3-yl)carbamate (M62-3)

[0548] M62-2 (5 g, 22.2 mmol) was dissolved in toluene (80 mL). Tert-butyl carbamate (3.12 g, 26.6 mmol), Pd2(dba)3 (2.03 g, 2.22 mmol), XantPhos (1.28 g, 2.22 mmol), and cesium carbonate (14.5 g, 44.3 mmol) were added under an argon atmosphere. The reaction mixture was stirred overnight at 100 °C. LC-MS showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1–1:7) to give the title product (700 mg, brown solid).

[0549] MS(ESI)m / z[M+H]+=306.1.

[0550] Step 3: Synthesis of 6-chloro-5-(3-chloropropyl)pyridazine-3-amine (M62-4)

[0551] The synthesis method is as described in step 2 of the synthesis of intermediate M62-3, yielding the title product (yield: 86.7%).

[0552] MS(ESI)m / z[M+H]+=206.1.

[0553] Step 4: Synthesis of 6-chloro-7-(3-chloropropyl)imidazo[1,2-b]pyridazine (intermediate M62-5)

[0554] M62-4 (350 mg, 1.70 mmol) was dissolved in ethanol (6 mL), and chloroacetaldehyde (400 mg, 5.1 mmol) was added under an argon atmosphere. The reaction was stirred at 80 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (methanol:dichloromethane = 1:9) to give the title product (200 mg, yellow solid).

[0555] MS(ESI)m / z[M+H]+=230.0.

[0556] Step 5: Synthesis of 6-(4-methoxybenzyl)-6,7,8,9-tetrahydroimidazo[1,2-b]pyrido[3,2-e]pyridazine (intermediate M62-6)

[0557] M62-5 (200 mg, 0.87 mmol) was dissolved in DMF (6 mL). 4-Methoxybenzylamine (597 mg, 4.35 mmol) and triethylamine (264 mg, 2.61 mmol) were added under an argon atmosphere, and the reaction was stirred at 140 °C for 2 hours. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine (3 x 20 mL), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (methanol:dichloromethane = 0:1–1:12) to give the title product (80 mg, yellow solid).

[0558] MS(ESI)m / z[M+H]+=295.1.

[0559] Step 6: Synthesis of 3-iodo-6-(4-methoxybenzyl)-6,7,8,9-tetrahydroimidazo[1,2-b]pyrido[3,2-e]pyridazine (intermediate M62-7)

[0560] M62-6 (80 mg, 0.27 mmol) was dissolved in dichloromethane (2 mL), and NIS (121 mg, 0.54 mmol) was added under an argon atmosphere. The reaction was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:1) to give the title product (60 mg, yellow solid).

[0561] MS(ESI)m / z[M+H]+=421.0.

[0562] Step 7: Synthesis of 3-cyclopropyl-6-(4-methoxybenzyl)-6,7,8,9-tetrahydroimidazo[1,2-b]pyrido[3,2-e]pyridazine (intermediate M62-8)

[0563] M62-7 (70 mg, 0.17 mmol) was dissolved in 1,4-Dioxane (2 mL). Cyclopropylboronic acid (17.52 mg, 0.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11.08 mg, 0.017 mmol), and potassium carbonate (R3, 46.99 mg, 0.34 mmol) were added under argon protection. The reaction mixture was stirred at 90 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title product (50 mg, yellow oil).

[0564] MS(ESI)m / z[M+H]+=335.1.

[0565] Step 8: Synthesis of 3-cyclopropyl-6,7,8,9-tetrahydroimidazo[1,2-b]pyrido[3,2-e]pyridazine (intermediate M62)

[0566] The synthesis method is as described in step 5 of the synthesis of intermediate M1, yielding the title product (yield: 78.0%).

[0567] MS(ESI)m / z[M+H]+=215.2

[0568] Synthesis of intermediate M63:

[0569] 3-Phenylacetazolo[1,2-b]pyrido[3,2-e]pyridazine (M63)

[0570] MS(ESI)m / z[M+H]+=251.

[0571] Synthesis of intermediate M64:

[0572] Step 1: Synthesis of tert-butyl 6-chloro-3,4-dihydro-1,7-naphthyridine-1(2H)-carboxylic acid (M64-2)

[0573] M64-1 (23 g, 101 mmol) was dissolved in tetrahydrofuran (500 mL), cooled to -40 °C, and n-butyllithium (100 mL, 250 mmol) was added dropwise under an argon atmosphere. After stirring for 30 minutes, 1-chloro-3-iodopropane (24.7 g, 121 mmol) was added at -40 °C, and the mixture was stirred for 2 hours. The temperature was then raised to 70 °C, and stirring was continued for 24 hours. TLC showed that the reaction was complete. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (200 mL x 3), and the combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give the title product (19 g, yellow solid).

[0574] Step 2: Synthesis of tert-butyl 6-(benzylamino)-3,4-dihydro-1,7-naphthylpyridine-1(2H)-carboxylic acid (M64-3)

[0575] Under an argon atmosphere, M64-2 (6.3 g, 23.44 mmol) and benzylamine (5.02 g, 46.9 mmol) were dissolved in 1,4-dioxane (50 mL), followed by the addition of Pd2(dba)3 (2.15 g, 2.34 mmol), BINAP (1.46 g, 2.34 mmol), and sodium tert-butoxide (4.51 g, 46.9 mmol). The reaction was stirred at 100 °C for 2 hours. TLC showed that the reaction was complete. The reaction solution was diluted with water (50 mL) and extracted with dichloromethane (80 mL x 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give the title product (2.1 g, yellow solid).

[0576] MS(ESI)m / z[M+H] + =340.2.

[0577] Step 3: Synthesis of 6-amino-3,4-dihydro-1,7-naphthyridine-1(2H)-carboxylic acid tert-butyl ester (M64-4)

[0578] M64-3 (2.6 g, 7.66 mmol) was dissolved in 1,4-dioxane (50 mL), cooled to 0 °C, and 2,3-dichloro-5,6-dicyanobenzoquinone (1.39 g, 6.13 mmol) was slowly added dropwise. The reaction was stirred at 0 °C for 5 minutes. LC-MS product was formed. The reaction solution was quenched with vitamin C aqueous solution, and the pH was adjusted to approximately 9 with saturated sodium carbonate solution, followed by extraction with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give the title product (0.34 g, yellow solid).

[0579] MS(ESI)m / z[M+H] + =250.2.

[0580] Step 4: Synthesis of 8,9-dihydroimidazo[2,1-g][1,7]naphthylpyridine-6(7H)-carboxylic acid tert-butyl ester (M64-5)

[0581] The synthesis method is as described in step 4 of the synthesis of intermediate M62, yielding the title product (yield: 86.1%).

[0582] MS(ESI)m / z[M+H] + =274.1.

[0583] Step 5: Synthesis of 3-bromo-8,9-dihydroimidazo[2,1-g][1,7]naphthyl-6(7H)-carboxylic acid tert-butyl ester (M64-6)

[0584] M64-5 (600 mg, 2.20 mmol) was dissolved in tetrahydrofuran (20 mL), and NBS (0.31 g, 1.76 mmol) was added at -40 °C. The reaction was stirred at -40 °C for 2 minutes. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (30 mL), extracted with dichloromethane (50 mL x 2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (710 mg, yellow solid).

[0585] MS(ESI)m / z[M+H] + =352.0,354.0.

[0586] Step 6: Synthesis of 3-phenyl-8,9-dihydroimidazo[2,1-g][1,7]naphthylpyridine-6(7H)-carboxylic acid tert-butyl ester (M64-7)

[0587] The synthesis method is as described in step 2 of the synthesis of intermediate M52, yielding the title product (yield: 31.2%).

[0588] MS(ESI)m / z[M+H] + =350.1.

[0589] Step 7: Synthesis of 3-phenyl-6,7,8,9-tetrahydroimidazo[2,1-g][1,7]naphthylpyridine (M64)

[0590] The synthesis method is as described in step 2 of the synthesis of intermediate M6-3, yielding the title product (yield: 65.2%).

[0591] MS(ESI)m / z[M+H] + =250.1.

[0592] Synthesis of intermediate M65:

[0593] Step 1: Synthesis of 4-(oxetane-3-yl)-3-oxoperazine-1-carboxylic acid benzyl ester (M65-2)

[0594] Under an argon atmosphere, M65-1 (2 g, 8.54 mmol) was dissolved in DMF (20 mL), cooled to 0 °C, and sodium hydride (0.27 g, 11.10 mmol, purity: 60%) was added. The mixture was stirred at 0 °C for 30 minutes, followed by the addition of 3-iodooxetine (2.36 g, 12.8 mmol). The mixture was then heated to room temperature and stirred for 2 hours. LC-MS showed product formation. The reaction mixture was quenched in ice water (30 mL) and extracted with dichloromethane (containing 10% methanol, 30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (methanol:dichloromethane = 1:10) to give the title product (500 mg, yellow oil).

[0595] MS(ESI)m / z[M+H]+=191.1.

[0596] Step 2: Synthesis of 1-(oxetane-3-yl)piperazin-2-one (M65)

[0597] M65-2 (500 mg, 1.72 mmol) was dissolved in methanol (20 mL), and wet palladium / carbon (183 mg, 0.17 mmol) was added. The reaction was purged with hydrogen and stirred at room temperature for 3 hours under a hydrogen atmosphere (hydrogen balloon, 15 psi). LC-MS showed product formation. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title product (160 mg, yellow oil).

[0598] MS(ESI)m / z[M+H]+=157.2.

[0599] Following the synthesis method of intermediate M65, the following intermediate was obtained:

[0600] Synthesis of intermediate M72:

[0601] Step 1: Synthesis of 4-(6-chloropyridazin-3-yl)pyridin-2(1H)-one (M72-1)

[0602] The synthesis method is as described in step 7 of intermediate M62, yielding the title product (yield: 14.4%).

[0603] MS(ESI)m / z[M+H]+=208.1.

[0604] Step 2: Synthesis of 4-(6-chloropyridazin-3-yl)-1-(oxetane-3-yl)pyridin-2(1H)-one (M72)

[0605] The synthesis method is as described in step 3 of the synthesis of intermediate M1, yielding the title product (yield: 29.5%).

[0606] MS(ESI)m / z[M+H]+=264.0.

[0607] Synthesis of intermediate M73:

[0608] Step 1: Synthesis of methyl 4-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (M73-2)

[0609] Following the method described in step 3 of the synthesis of intermediate M1, the title product was obtained (yield: 21.6%).

[0610] MS(ESI)m / z[M+H] + =375.0.

[0611] Step 2: Synthesis of 8-bromo-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (M73-3)

[0612] M73-2 (680 mg, 1.81 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then quenched in ice water (20 mL), and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The mixture was stirred for another 10 minutes. The mixture was extracted with dichloromethane (30 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (220 mg, yellow solid).

[0613] MS(ESI)m / z[M+H] + =243.0.

[0614] Step 3: Synthesis of 8-(6-chloropyridin-3-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (M73-5)

[0615] Following the method described in step 7 of the synthesis of intermediate M62, the title product (crude product) was obtained.

[0616] MS(ESI)m / z[M+H] + =276.0.

[0617] Step 4: Synthesis of 8-(6-chloropyridin-3-yl)-2-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (M73)

[0618] Following the method described in step 3 of the synthesis of intermediate M5-7, the title product was obtained (yield: 95.2%).

[0619] MS(ESI)m / z[M+H] + =290.1.

[0620] Using M73-4 and its corresponding halogenated derivatives as starting materials, the following intermediate was obtained by referring to step 3 of the synthesis of intermediate M73:

[0621] Synthesis of intermediate M76:

[0622] Step 1: Synthesis of 4-chloro-6-(6-chloropyridin-3-yl)-2-methylpyrimidine (M76-2)

[0623] Following the method described in step 7 of the synthesis of intermediate M62, the title product was obtained (yield: 69.9%).

[0624] MS(ESI)m / z[M+H] + =240.0.

[0625] Step 2: Synthesis of 6-(6-chloropyridin-3-yl)-2-methylpyrimidin-4(3H)-one (M76-3)

[0626] M76-2 (1.0 g, 4.17 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2.5 mL), and sodium hydroxide (830 mg, 20.9 mmol) was added to give a red mixture. The reaction was stirred overnight at 80 °C. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and the pH was adjusted to approximately 6 by slow addition of dilute hydrochloric acid. The solution was then extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0 -20%) to give the title product (420 mg, white solid).

[0627] MS(ESI)m / z[M+H] + =222.0.

[0628] Step 3: Synthesis of 6-(6-chloropyridin-3-yl)-2,3-dimethylpyrimidin-4(3H)-one (M76)

[0629] Following the method described in step 3 of the synthesis of intermediate M5-7, the title product was obtained (yield: 37.6%).

[0630] MS(ESI)m / z[M+H] +=236.0.

[0631] Synthesis of intermediate M77:

[0632] Step 1: Synthesis of ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)propionate (M77-2)

[0633] Following the method described in step 3 of the synthesis of intermediate M1, the title product was obtained (yield: 53.5%).

[0634] MS(ESI)m / z[M+H] + =182.1.

[0635] Step 2: Synthesis of ethyl 2-(4-(6-chloropyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropionate (M77-3)

[0636] Following the method described in step 7 of the synthesis of intermediate M62, the title product was obtained (yield: 45.0%).

[0637] MS(ESI)m / z[M+H] + =294.1.

[0638] Synthesis of intermediate M78:

[0639] Step 1: Synthesis of 6-chloropyridazine-3-carbonylhydrazide (M78-2)

[0640] M78-1 (1 g, 5.79 mmol) was added to ethanol (10 mL), and the mixture was cooled to 0 °C in an ice bath. Hydrazine hydrate (2.90 g, 57.9 mmol) was then added, and the reaction was stirred at 0 °C for 2 hours to obtain a white suspension. LC-MS showed product formation. The reaction mixture was filtered, and the filter cake was dried under reduced pressure to give the title product (700 mg, white solid).

[0641] MS(ESI)m / z[M+H] + =173.0.

[0642] Step 2: 3-(6-chloropyridazin-3-yl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4] Synthesis of aziridine (M78)

[0643] Add M78-2 (0.5 g, 2.9 mmol) to ethanol (10 mL), then add 5-methoxy-3,6-dihydro-2H- Azine (3.3 g, 29 mmol) was reacted with the solution at 80 °C for 2 h with stirring. LC-MS showed product formation. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (500 mg, yellow solid).

[0644] MS(ESI)m / z[M+H] + =238.0.

[0645] The following intermediate was obtained by referring to the synthesis method of intermediate M78:

[0646] Synthesis of intermediate M83:

[0647] Step 1: Synthesis of 6-chloropyridazine-3-carboxaldehyde (M83-2)

[0648] M83-1 (1 g, 5.36 mmol) was dissolved in tetrahydrofuran (15 mL), and the mixture was cooled to 0 °C in an ice bath. Diisobutylaluminum hydride (1.52 g, 10.7 mmol, 1 M toluene solution) was slowly added dropwise, and the reaction temperature was gradually raised to room temperature with stirring for 2 hours. The reaction mixture was quenched dropwise in ice water (20 mL), filtered, and the filtrate was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title product (700 mg, crude).

[0649] MS(ESI)m / z[M+H] + =143.0.

[0650] Step 2: Synthesis of 6-chloropyridazine-3-carboxaldehyde oxime (M83-3)

[0651] M83-2 (650 mg, 4.56 mmol), sodium carbonate (483 mg, 4.56 mmol), and hydroxylamine hydrochloride (301 mg, 9.12 mmol) were added to methanol (10 mL) and water (10 mL), and the reaction was stirred overnight at room temperature. LC-MS showed product formation. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give the title product (500 mg, yellow solid).

[0652] MS(ESI)m / z[M+H] + =158.0.

[0653] Step 3: 3-(6-Chlorpyridazine-3-yl)iso Synthesis of ethyl 5-carboxylate (M83)

[0654] M83-3 (400 mg, 2.54 mmol) and ethyl propynate (748 mg, 7.62 mmol) were added to tetrahydrofuran (5 mL), and the mixture was cooled to 0 °C in an ice bath. Sodium hypochlorite solution (3.03 mL, 14% available chlorine) was slowly added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL), extracted with dichloromethane (20 mL x 3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give the title product (300 mg, yellow solid).

[0655] MS(ESI)m / z[M+H] + =254.0.

[0656] Synthesis of intermediate M84:

[0657] Step 1: Synthesis of 4-bromo-2-(methoxycarbonyl)pyridine-1-oxide (M84-2)

[0658] M84-1 (20 g, 92.6 mmol) was added to dichloromethane (150 mL), and the mixture was cooled to 0 °C in an ice bath. m-chloroperoxybenzoic acid (11.9 g, 68.8 mmol) was added in portions, and the reaction mixture was stirred at 45 °C for 16 hours. LC-MS showed product formation. The reaction mixture was poured into water (150 mL), and the reaction was quenched by slowly adding an aqueous sodium thiosulfate solution. The pH was adjusted to approximately 8 by adding saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (200 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (16 g, yellow solid).

[0659] MS(ESI)m / z[M+H] + =231.9.

[0660] Step 2: Synthesis of methyl 4-bromo-6-oxo-1,6-dihydropyridine-2-carboxylic acid (M84-3)

[0661] M84-2 (16 g, 69.0 mmol) and triethylamine (21 g, 207 mmol) were added to tetrahydrofuran (60 mL), cooled to 0 °C, and trifluoroacetic anhydride (4.63 g, 221 mmol) was added dropwise. The reaction mixture was slowly heated to room temperature and stirred for 4 hours. LC-MS showed product formation. The reaction mixture was quenched with water (100 mL) and extracted with dichloromethane (150 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 20:1) to give the title product (5 g, yellow solid).

[0662] MS(ESI)m / z[M+H] + =231.9.

[0663] Step 3: Synthesis of methyl 6-chloro-6'-oxo-1',6'-dihydro-[3,4'-bipyridine]-2'-carboxylic acid (M84)

[0664] Following the method described in step 7 of intermediate M62, the title product was obtained (yield: 26.3%).

[0665] MS(ESI)m / z[M+H] + =265.0.

[0666] Synthesis of intermediates M85 and M86:

[0667] The title product was obtained by referring to the method described in step 1 of the synthesis of intermediate M1.

[0668] M85:MS(ESI)m / z[M+H] + =279.0.

[0669] M86:MS(ESI)m / z[M+H] + =279.0.

[0670] Synthesis of intermediate M87:

[0671] Step 1: Hexahydro-3H-imidazo[5,1-c][1,4] Synthesis of 3-azine-one (M87)

[0672] M87-1 (200 mg, 1.72 mmol) was dissolved in dichloromethane (10 mL), and carbonyl diimidazole (697 mg, 4.3 mmol) and triethylamine (870 mg, 8.6 mmol) were added. The mixture was stirred at room temperature for 5 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (80 mg, white solid).

[0673] MS(ESI)m / z[M+H] + =143.1.

[0674] Synthesis of intermediate M88:

[0675] Step 1: Synthesis of 2-(2-ethoxy-2-oxoethyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (M88-2)

[0676] M88-1 (10 g, 53.70 mmol), di-tert-butyl dicarbonate (14.06 g, 64.44 mmol), and triethylamine (16.30 g, 161.1 mmol) were added to dichloromethane (100 mL) and stirred at room temperature for 3 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (11 g, white solid).

[0677] MS(ESI)m / z[M+H] + =287.1.

[0678] Step 2: Synthesis of 2-(2-ethoxy-2-oxoethyl)-4-isopropyl-3-oxoperpiperazine-1-carboxylic acid tert-butyl ester (M88-3)

[0679] M88-2 (5 g, 17.46 mmol), 2-iodopropane (29.68 g, 174.60 mmol), and cesium carbonate (17.07 g, 52.38 mmol) were added to dimethyl sulfoxide (30 mL) and stirred at 60 °C for 3 hours. The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (2 g, colorless oil).

[0680] MS(ESI)m / z[M+H] + =329.2.

[0681] Step 3: Synthesis of 2-(1-(tert-butyloxycarbonyl)-4-isopropyl-3-oxoperazin-2-yl)acetic acid (M88-4)

[0682] In a three-necked flask filled with argon gas, M88-3 (2 g, 6.09 mmol) sodium hydroxide (0.61 g, 15.22 mmol) was added to a mixed solvent of water (10 mL), methanol (10 mL), and tetrahydrofuran (10 mL), and stirred at room temperature for 3 h. LC-MS showed that the reaction was complete. The pH of the reaction solution was adjusted to approximately 7 with dilute hydrochloric acid, and the reaction solution was lyophilized to obtain the title product (2.1 g, crude product).

[0683] MS(ESI)m / z[M+H] + =301.2.

[0684] Step 4: Synthesis of 2-(2-amino-2-oxoethyl)-4-isopropyl-3-oxoperpiperazine-1-carboxylic acid tert-butyl ester (M88-5)

[0685] At room temperature, M88-4 (1.9 g, 6.33 mmol) and ammonium chloride (0.68 g, 12.66 mmol) were added to DMF (20 mL), followed by diisopropylethylamine (2.45 g, 18.99 mmol) and HATU (3.61 g, 9.50 mmol). The mixture was stirred at room temperature for 3 h. LC-MS showed that the reaction was complete. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine, 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 (dichloromethane:methanol = 10:1) to give the title product (1.2 g, colorless oil).

[0686] MS(ESI)m / z[M+H] + =300.2.

[0687] Step 5: Synthesis of 2-(aminomethyl)-4-isopropyl-3-oxoperpiperazine-1-carboxylic acid tert-butyl ester (M88-6)

[0688] In an argon-filled three-necked flask, M88-5 (650 mg, 2.17 mmol) was dissolved in a mixed solvent of water (2 mL), ethyl acetate (4 mL), and acetonitrile (4 mL). Iodophenylacetic acid (839 mg, 2.60 mmol) was added, and the mixture was stirred at room temperature for 5 hours. LC-MS showed that the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL x 3, containing 10% isopropanol). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (150 mg, colorless oil).

[0689] MS(ESI)m / z[M+H] + =272.2.

[0690] Step 6: Synthesis of 3-(aminomethyl)-1-isopropylpiperazin-2-one (M88-7)

[0691] Following the method described in step 5 of the synthesis of intermediate M5-7, the title product (crude product) was obtained.

[0692] MS(ESI)m / z[M+H] + =172.1.

[0693] Step 7: Synthesis of 7-isopropyltetrahydroimidazo[1,5-a]pyrazine-3,8(2H,5H)-dione (M88)

[0694] Following the synthetic method of intermediate M87, the title product was obtained (yield: 34.7%).

[0695] MS(ESI)m / z[M+H] + =198.1.

[0696] Synthesis of intermediate M89:

[0697] Step 1: Synthesis of 6-oxo-1,2,3,6-tetrahydropyridine-4-yltrifluoromethanesulfonate (M89-2)

[0698] Under an argon atmosphere, piperidine-2,4-dione (1 g, 8.8 mmol) and triethylamine (1.8 g, 17.7 mmol) were dissolved in tetrahydrofuran (30 mL), and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (3.8 g, 10.6 mmol) was added. The mixture was stirred at room temperature for 16 hours. TLC showed that the reaction was complete. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give the title product (1.8 g, white solid).

[0699] MS(ESI)m / z[M+H]+=245.9.

[0700] Step 2: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-5,6-dihydropyridin-2-2(1H)-one (M89)

[0701] Under an argon atmosphere, 6-oxo-1,2,3,6-tetrahydropyridine-4-yltrifluoromethanesulfonate (500 mg, 2.04 mmol) and linalool diboronate (620 mg, 2.45 mmol) were dissolved in 1,4-dioxane (20 mL), followed by the sequential addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (150 mg, 0.20 mmol) and potassium acetate (400 mg, 4.08 mmol). The mixture was stirred at 70 °C for 1.5 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give the title product (500 mg, black oil, crude product).

[0702] MS(ESI)m / z[M+H]+=224.0.

[0703] Synthesis of intermediate M90:

[0704] Step 1: 7-Bromo-4-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrido[3,2-b][1,4] Synthesis of azinon-3(4H)-one (M90)

[0705] The synthesis method is as described in step 3 of the synthesis of intermediate M5-7, yielding the title product (yield: 94.1%).

[0706] MS(ESI)m / z[M+H] + =359.0,361.0.

[0707] Synthesis of intermediate M91:

[0708] Step 1: Synthesis of 6-bromo-1-methyl-3,4-dihydro-1,8-naphthidium-2(1H)-one (M91)

[0709] The synthesis method is as described in step 3 of the synthesis of intermediate M5-7, yielding the title product (yield: 56.6%).

[0710] MS(ESI)m / z[M+H] + =241.0,243.0.

[0711] Synthesis of intermediate M92:

[0712] Step 1: Synthesis of 9-chloro-3-(cyclopropylmethyl)-3,6,7,8-tetrahydro-5H-imidazolium[4,5-b][1,8]naphthyl-5-carboxylic acid tert-butyl ester (M92-1)

[0713] M6 (262.7 mg, 1.0 mmol) was dissolved in 1,2-dichloroethane (5 mL), followed by the addition of di-tert-butyl dicarbonate (0.22 g, 1 mmol) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmol). The reaction was stirred at 80 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give the title product (180 mg, yellow solid).

[0714] MS(ESI)m / z[M+H] + =363.0.

[0715] Step 2: Synthesis of 3-(cyclopropylmethyl)-9-(2,4-dimethoxybenzyl)amino)-3,6,7,8-tetrahydro-5H-imidazolium[4,5-b][1,8]naphthyl-5-carboxylic acid tert-butyl ester (M92-2)

[0716] Under an argon atmosphere, M92-1 (200 mg, 0.55 mmol) and (2,4-dimethoxyphenyl)methylamine (200 mg, 1.20 mmol) were dissolved in 1,4-dioxane (15 mL), followed by the sequential addition of t-BuBrettPhos-Pd-G3 (0.47 g, 0.55 mmol) and sodium tert-butoxide (0.053 g, 0.55 mmol). The reaction was stirred at 100 °C for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (300 mg, yellow solid).

[0717] MS(ESI)m / z[M+H] + =494.2.

[0718] Step 3: Synthesis of 3-(cyclopropylmethyl)-5,6,7,8-tetrahydro-3H-imidazolium[4,5-b][1,8]naphthyl-9-amine (M92)

[0719] The synthesis method is as described in step 2 of the synthesis of intermediate M6-3, yielding the title product (yield: 72.4%).

[0720] Synthesis of intermediate M93:

[0721] Step 1: Synthesis of N'-acetyl-6-chloronicotinamide (M93-2)

[0722] M93-1 (950 mg, 6.03 mmol) was dissolved in DCM (10 mL), and acetylhydrazine (1.34 g, 18.1 mmol), HATU (3.44 g, 9.04 mmol), and DIEA (3.11 g, 24.1 mmol) were added sequentially. The reaction mixture was reacted at room temperature for 16 h. The reaction was quenched with water (10 mL), diluted with dichloromethane (20 mL), and separated. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (110 mg, white solid).

[0723] MS(ESI)m / z[M+H]+=214.1.

[0724] Step 2: 2-(6-chloropyridin-3-yl)-5-methyl-1,3,4- Synthesis of diazole (M93)

[0725] M93-2 (150 mg, 0.48 mmol) and p-toluenesulfonyl chloride (0.11 g, 0.58 mmol) were dissolved in dichloromethane (10 mL), and triethylamine (0.097 g, 0.96 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed product formation. The reaction mixture was quenched in ice water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic phases were concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (60 mg, white solid).

[0726] MS(ESI)m / z[M+H]+=196.0.

[0727] Synthesis of intermediate M94:

[0728] Step 1: Synthesis of methyl 1-(4-(3-((tetrahydrofuran-3-yl)methyl)-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)phenyl)-1H-imidazo-4-carboxylate (M94):

[0729] 1,4-Dibromobenzene (3.0 g, 12.7 mmol), imidazole-4-carboxylic acid methyl ester (1.60 g, 12.7 mmol), ferric acetylacetone (0.90 g, 2.54 mmol), copper acetate (0.46 g, 2.54 mmol), and potassium carbonate (3.52 g, 25.4 mmol) were sequentially added to N,N-dimethylformamide (60 mL). The reaction mixture was purged with argon and stirred at 120 °C for 24 hours. LC-MS showed product formation. The reaction mixture was cooled to room temperature, quenched with 50 mL of water, filtered, and the filtrate was extracted with dichloromethane (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give the title product (300 mg, yellow solid).

[0730] MS(ESI)m / z[M+H] + =281.0,283.0.

[0731] Synthesis of intermediate M95-4:

[0732] Step 1: 7-Chloro-1-(4-methoxybenzyl)-1,8-naphthidium-2(1H)-one (M95-2)

[0733] In an argon-filled three-necked flask, M95-1 (3.5 g, 19.38 mmol) 1-(chloromethyl)-4-methoxybenzene (3.04 g, 19.38 mmol) was dissolved in DMF (50 mL), and sodium hydride (1.16 g, 48.45 mmol) was added. The mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was poured into 200 mL of water and extracted with EA (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (5.2 g, yellow solid).

[0734] MS(ESI)m / z[M+H]+=301.1.

[0735] Step 2: 5-Chloro-3-(4-methoxybenzyl)-1,1a,3,7b-tetrahydro-2H-cyclopropane[c][1,8]naphthidin-2-one (M95-3)

[0736] In an argon-filled three-necked flask, trimethyl sulfoxide (5.49 g, 24.93 mmol) was dissolved in THF (30 mL). Butyllithium (10 mL, 25.0 mmol, 2.5 M n-hexane solution) was added dropwise, and the mixture was stirred for 1 hour. Then, M95-2 (2.5 g, 8.31 mmol) in THF (20 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 200 mL of water and extracted with EA (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (4.6 g, white solid).

[0737] MS(ESI)m / z[M+H]+=314.1.

[0738] Step 3: 5-Chloro-3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropane[c][1,8]naphthidine (M95-4)

[0739] The title product was obtained by referring to step 4 of the synthesis of M47-4.

[0740] MS(ESI)m / z[M+H]+=301.1.

[0741] Synthesis of intermediate M96-5:

[0742] Step 1: 1-((2-((tert-butoxycarbonyl)amino)-6-chloropyridin-3-yl)(hydroxy)methyl)cyclopropane-1-carboxylic acid methyl ester (M96-2)

[0743] In an argon-filled three-necked flask, M96-1 (7 g, 30.61 mmol) and TMEDA (7.47 g, 64.28 mmol) were added to THF (100 mL). Butyllithium (4.12 g, 64.28 mmol) was added dropwise at -78 °C, and the mixture was stirred at -20 °C for 2 hours. The temperature was then lowered to -78 °C, and methyl 1-formylcyclopropane-1-carboxylate (5.10 g, 39.79 mmol) was added dropwise. The mixture was stirred at 0 °C for 30 minutes. LC-MS showed the reaction was complete. The reaction mixture was poured into 200 mL of water and extracted with EA (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (4.0 g, pale yellow solid).

[0744] MS(ESI)m / z[M+H]+=357.1.

[0745] Step 2: Methyl 1-((2-amino-6-chloropyridin-3-yl)(hydroxy)methyl)cyclopropane-1-carboxylate (M96-3)

[0746] Add M96-2 (4 g, 11.21 mmol) to a three-necked flask filled with argon gas, then add hydrogen chloride (40.87 g, 1121 mmol, 4 M dioxane solution) (30 mL) dropwise. Stir at room temperature for 3 hours. Concentrate the reaction solution to obtain 4.8 g of the title product. The crude product is used directly in the next step.

[0747] MS(ESI)m / z[M+H]+=257.1.

[0748] Step 3: 7'-Chloro-4'-hydroxy-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-[1,8]naphthidine]-2'-one (M96-4)

[0749] M96-3 (4 g, 15.58 mmol) and cesium carbonate (10.15 g, 31.16 mmol) were mixed in 30 mL of DMSO in an argon-filled three-necked flask and stirred at 70 °C for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was filtered, poured into 200 mL of water, and extracted with EA (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (2.4 g, yellow solid).

[0750] MS(ESI)m / z[M+H]+=225.0.

[0751] Step 4: 7'-chloro-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-[1,8]naphthidine] (M96-5)

[0752] The title product was obtained by referring to step 4 of the synthesis of M47-4.

[0753] MS(ESI)m / z[M+H]+=195.1.

[0754] The following intermediates were obtained by referring to the synthesis method of intermediate M1:

[0755] Synthesis of the Implementation Examples

[0756] Example 1: 4-(6-(3-(cyclopropylmethyl)-6,7-dihydroimidazo[4,5-b]pyrrolo[3,2-e]pyridin-5(3H)-yl)pyridazin-3-yl)piperazin-2-one (1)

[0757] Step 1: Synthesis of 5-(6-chloropyridazin-3-yl)-3-(cyclopropylmethyl)-3,5,6,7-tetrahydroimidazo[4,5-b]pyrrolo[3,2-e]pyridine (1-1)

[0758] 3,6-Dichloropyridazine (160 mg, 1.07 mmol) and M2 (121 mg, 0.57 mmol) were dissolved in 1,4-Dioxane (10 mL), and RuPhos-Pd-G3 (89.49 mg, 0.11 mmol), RuPhos (49.9 mg, 0.11 mmol), and cesium carbonate (697 mg, 2.14 mmol) were added. The reaction was stirred at 100 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 0:1) to give the title product (170 mg, yellow solid).

[0759] MS(ESI)m / z[M+H] + =327.1.

[0760] Step 2: Synthesis of 4-(6-(3-(cyclopropylmethyl)-6,7-dihydroimidazo[4,5-b]pyrrolo[3,2-e]pyridin-5(3H)-yl)pyridazin-3-yl)piperazin-2-one (1)

[0761] 1-1 (50 mg, 0.15 mmol) and 2-piperazinone (18.02 mg, 0.18 mmol) were dissolved in 1,4-Dioxane (15 mL), followed by the addition of RuPhos-Pd-G3 (12.55 mg, 0.015 mmol), RuPhos (7.00 mg, 0.015 mmol), and cesium carbonate (97.75 mg, 0.30 mmol). The reaction was stirred at 100 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase C18 preparative chromatography (acetonitrile / water = 0-35%) to give the title product (13 mg, yellow solid).

[0762] MS(ESI)m / z[M+H] + =391.2.

[0763] 1 H NMR (400MHz, DMSO-d6) δ8.91(d,J=9.6Hz,1H),8.12(s,1H),8.07(s,1H),7.79(s,1H),7.48(d,J=9.6Hz,1H),4.29(t,J=8.0Hz,2H),4. 06-4.02(m,4H),3.74-3.71(m,2H),3.32-3.28(m,2H),3.20(t,J=8.0Hz,2H),1.34-1.30(m,1H),0.55-0.50(m,2H),0.48-0.42(m,2H).

[0764] Referring to the synthesis method described in step 1 of Example 1, the following examples are obtained:

[0765] Example 85: 1-(6-(3-(cyclopropylmethyl)-6,7-dihydroimidazo[4,5-b]pyrrolo[3,2-e]pyridin-5(3H)-yl)pyridin-3-yl)-N-ethylaza-3-carboxamide (85)

[0766] Step 1: Synthesis of methyl 1-(5-bromopyridin-2-yl)azacyclobutane-3-carboxylic acid (85-2)

[0767] 85-1 (200 mg, 1.14 mmol), methyl aziridine-3-carboxylate (172.8 mg, 1.14 mmol, hydrochloride), and cesium carbonate (557.15 mg, 1.71 mmol) were mixed in DMF (10 mL) and stirred at 70 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with saturated brine (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 10:1) to give the title product (200 mg, yellow oil).

[0768] MS(ESI)m / z[M+H] + =271.0,273.0.

[0769] Step 2: Synthesis of methyl 1-(5-(3-(cyclopropylmethyl)-6,7-dihydroimidazo[4,5-b]pyrrolo[3,2-e]pyridin-5(3H)-yl)pyridin-2-yl)azacyclobutane-3-carboxylic acid (85-3)

[0770] 85-2 (55 mg, 0.20 mmol) and M2 (42.85 mg, 0.20 mmol) were dissolved in 1,4-dioxane (5 mL), followed by the addition of RuPhos-Pd-G3 (16.7 mg, 0.020 mmol), RuPhos (9.33 mg, 0.020 mmol), and cesium carbonate (130 mg, 0.40 mmol). The reaction was purged with argon and stirred at 100 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to give the title product (80 mg, brown solid).

[0771] MS(ESI)m / z[M+H] + =405.2.

[0772] Step 3: Synthesis of 1-(5-(3-(cyclopropylmethyl)-6,7-dihydroimidazo[4,5-b]pyrrolo[3,2-e]pyridin-5(3H)-yl)pyridin-2-yl)azacyclobutane-3-carboxylic acid (85-4)

[0773] Dissolve 85-3 (85 mg, 0.21 mmol) in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL), then add sodium hydroxide (84 mg, 2.1 mmol) and stir at 30 °C for 3 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to remove the solvent, and the pH was adjusted to approximately 3 with 1 M HCl solution. Then, back-extracted with dichloromethane (10 mL x 3). The aqueous phase was concentrated under reduced pressure to give the title product (70 mg, yellow solid, crude product).

[0774] MS(ESI)m / z[M+H] + =391.2.

[0775] Step 4: Synthesis of 1-(6-(3-(cyclopropylmethyl)-6,7-dihydroimidazo[4,5-b]pyrrolo[3,2-e]pyridin-5(3H)-yl)pyridin-2-yl)-N-ethylazacyclobutane-3-carboxamide (85)

[0776] 85-4 (30 mg, 0.077 mmol) and ethylamine hydrochloride (9.42 mg, 0.12 mmol) were dissolved in DMF (5 mL), and DIEA (19.9 mg, 0.15 mmol) and HATU (35.1 mg, 0.092 mmol) were added. The reaction was stirred at room temperature for 3 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-40%) to give the title product (23 mg, white solid).

[0777] MS(ESI)m / z[M+H] + =418.2.

[0778] 1 H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.32(s,2H),8.01(s,2H),7.65(s,1H) ,6.48(d,J=8.4Hz,1H),4.04-3.97(m,3H),3.89(t,J=8.0Hz,2H),3.50-3.4 6(m,2H),3.31-3.22(m,2H),3.16(t,J=8.0Hz,2H),3.10-3.05(m,2H),1.32 -1.28(m,1H),1.02(t,J=7.2Hz,3H),0.53-0.48(m,2H),0.45-0.41(m,2H).

[0779] Example 86: 1-(6-(3-phenyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridin-3-yl)-1H-imidazo-4-carboxylic acid (86)

[0780] The title product is obtained by referring to the method described in steps 1-3 of Example 85.

[0781] MS(ESI)m / z[M+H] + =438.0

[0782] 1 H NMR(400MHz,CD3OD)δ7.17(s,1H),6.88-6.84(m,3H),6.47-6.41(m,3H),6.30-6.21 (m,3H),5.99-5.90(m,2H),3.77-3.58(m,2H),3.02-2.86(m,2H),2.59-2.51(m,2H).

[0783] The following examples were obtained by referring to the synthesis method described in Example 85.

[0784] Referring to the synthesis method described in steps 2-4 of Example 85, the following examples were obtained:

[0785] Referring to the synthesis method described in steps 2-3 of Example 85, the following examples were obtained:

[0786] Referring to the synthesis method described in steps 1-2 of Example 85, the following examples were obtained:

[0787] Example 198: 6-(3-(cyclopropylmethyl)-6,7-dihydroimidazo[4,5-b]pyrrolo[3,2-e]pyridin-5(3H)-yl)-N-ethyl-3H-imidazo[4,5-b]pyridin-2-carboxamide (198)

[0788] Step 1: Synthesis of 6-bromo-3H-imidazo[4,5-b]pyridine-2-carboxylic acid (198-2)

[0789] 198-1 (4.1 g, 17.98 mmol) and sodium carbonate (2.10 g, 19.8 mmol) were added to water (100 mL) and heated to 100 °C to dissolve. While still hot, the solution was added to an aqueous solution of KMnO4 (4.83 g, 30.6 mmol) at 100 °C (100 mL). The reaction was stirred at 100 °C for 4 hours. The reaction solution was filtered, and the pH of the filtrate was adjusted to approximately 3 with 3 M HCl solution. The filtrate was then filtered again, and the filter cake was washed with water (10 mL x 3) and dried under reduced pressure to obtain the title product (3.1 g, yellow solid).

[0790] MS(ESI)m / z[M+H] + =241.9,243.9.

[0791] Step 2: Synthesis of 6-bromo-N-ethyl-3H-imidazo[4,5-b]pyridine-2-carboxamide (198-3)

[0792] 198-2 (1.4 g, 5.78 mmol), ethylamine hydrochloride (530 mg, 11.6 mmol), HOBt (1.77 g, 11.6 mmol), and EDCI (1.79 g, 11.6 mmol) were added to dichloromethane (10 mL), cooled to 0 °C, and DIEA (3.74 g, 28.9 mmol) was added. The reaction mixture was stirred at 0 °C for 2 hours. LC-MS showed product formation. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were 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 (ethyl acetate: petroleum ether = 0:1 to 1:0) to give the title product (160 mg, yellow oil).

[0793] MS(ESI)m / z[M+H] + =269.0,271.0.

[0794] Step 3: Synthesis of 6-bromo-N-ethyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine-2-carboxamide (198-4)

[0795] 198-3 (160 mg, 0.59 mmol) was added to tetrahydrofuran (5 mL), the mixture was cooled to 0 °C, and TEA (210 mg, 2.05 mmol) and SEM-Cl (148 mg, 0.89 mmol) were added. The reaction mixture was stirred at 0 °C for 2 hours under an argon atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were 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 (ethyl acetate: petroleum ether = 0:1 to 1:3) to give the title product (20 mg, yellow oil).

[0796] MS(ESI)m / z[M+H] + =399.1,401.1.

[0797] Step 4: Synthesis of 6-(3-(cyclopropylmethyl)-6,7-dihydroimidazo[4,5-b]pyrrolo[3,2-e]pyridin-5(3H)-yl)-N-ethyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-carboxamide (198-5)

[0798] The synthesis method was as described in step 1 of Example 1, yielding the title product (yield: 75.1%).

[0799] MS(ESI)m / z[M+H] + =533.3.

[0800] Step 5: Synthesis of 6-(3-(cyclopropylmethyl)-6,7-dihydroimidazo[4,5-b]pyrrolo[3,2-e]pyridin-5(3H)-yl)-N-ethyl-3H-imidazo[4,5-b]pyridin-2-carboxamide (198)

[0801] 198-5 (20 mg, 0.038 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred under an argon atmosphere for 2 hours. The pH of the reaction solution was adjusted to approximately 8 with sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the title product (4.7 mg, yellow solid).

[0802] MS(ESI)m / z[M+H] + =403.2..

[0803] 1H NMR(400MHz,DMSO-d6)δ13.33(br,1H),9.05(s,1H),8.92(s,1H),8.81(s,1H),8.13(s,1H),7.78(s,1H) ,4.22(t,J=8.0Hz,2H),4.11(d,J=6.8Hz,2H),3.30-3.25(m,4H),1.19-1.13(m,4H),0.54-0.48(m,4H).

[0804] Referring to the synthesis method described in steps 4-5 of Example 198, the following examples were obtained:

[0805] Example 205: 4-(6-(3-(cyclopropylmethyl)-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridazin-3-yl)piperazin-2-one (205)

[0806] Step 1: Synthesis of 4-(6-(3-(cyclopropylmethyl)-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridazin-3-yl)piperazin-2-one (205)

[0807] 3 (30 mg, 0.088 mmol) was dissolved in 1-methyl-2-pyrrolidone (2 mL), and 2-piperazinone (17.6 mg, 0.18 mmol) and p-toluenesulfonic acid (15.2 mg, 0.088 mmol) were added. The reaction mixture was stirred at 200 °C for 2 hours under microwave conditions. The reaction solution was purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-40%) to give the title product (9 mg, white solid).

[0808] MS(ESI)m / z[M+H] + =405.2.

[0809] 1 H NMR (400MHz, CD3OD) δ8.25(s,1H),7.90(d,J=9.6Hz,1H),7.80(s,1H),7.31(d,J=9.6Hz,1H),4.24(s,2H),4.07-4.03(m,2H),3.96(d,J=6.8H z,2H),3.90-3.85(m,2H),3.54-3.50(m,2H),3.04-3.00(m,2H),2.15- 2.12(m,2H),0.93-0.88(m,1H),0.60-0.56(m,2H),0.40-0.36(m,2H).

[0810] The following examples were obtained by referring to the synthesis methods described in Examples 1 and 205.

[0811] Example 259: 4-(5-(3-(cyclopropylmethyl)-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthid-5-yl)pyridin-2-yl)piperazin-2-one (259)

[0812] Step 1: Synthesis of 5-(6-chloropyridin-3-yl)-3-(cyclopropylmethyl)-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (259-1)

[0813] M1 (100 mg, 0.44 mmol) and 5-bromo-2-chloropyridine (0.17 g, 0.88 mmol) were mixed in toluene (1 mL), followed by the addition of Pd2(dba)3 (40 mg, 0.044 mmol), BINAP (27 mg, 0.044 mmol), and potassium tert-butoxide (49 mg, 0.44 mmol). The reaction mixture was stirred at 75 °C for 15 min, then heated to 100 °C and stirred for 50 min under microwave conditions. LCMS showed product formation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) to give the title product (50 mg, yellow solid).

[0814] MS(ESI)m / z[M+H] + =340.1.

[0815] Step 2: Synthesis of 4-(5-(3-(cyclopropylmethyl)-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridin-2-yl)piperazin-2-one (259)

[0816] The synthesis method is as described in Example 205, yielding the title product (yield: 2.31%).

[0817] MS(ESI)m / z[M+H] + =404.2

[0818] 1H NMR (400MHz, DMSO-d6) δ8.16(d,J=2.4Hz,1H),8.07(s,1H),7.96(s,1H),7.61(dd,J=9.0,2.4Hz,1H),7.58(s,1H),6.84(d,J=9.0Hz,1H),3.98( s,2H),3.75-3.66(m,6H),3.27-3.24(m,2H),2.92(t,J=6.0Hz,2H),2.0 7-1.90(m,2H),1.17-1.03(m,1H),0.46-0.34(m,2H),0.32-0.19(m,2H).

[0819] Example 260: 4-(6-(6-(cyclopropylmethyl)-2,3-dihydro-4H-pyrazolo[1',5':1,2]pyrimidine[5,4-b][1,4] (260) pyridazin-3-ylpiperazin-2-one

[0820] Step 1: Synthesis of 3-(cyclopropylmethyl)-5-(6-fluridazin-3-yl)-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (260-1)

[0821] M56 (40 mg, 0.17 mmol) was dissolved in DMF (2.5 mL), and sodium hydride (10.2 mg, 0.26 mmol) was added at 0 °C. The mixture was stirred for 30 minutes, and then 3,6-difluoropyridazine (29.6 mg, 0.26 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title product (40 mg, yellow solid).

[0822] MS(ESI)m / z[M+H] + =327.1.

[0823] Step 2: 4-(6-(6-(cyclopropylmethyl)-2,3-dihydro-4H-pyrazolo[1',5':1,2]pyrimidine[5,4-b][1,4] Synthesis of azinon-4-ylpyridazin-3-ylpiperazin-2-one (260)

[0824] The synthesis method is as described in Example 205, using 260-1 and 2-piperazinone as reactants and isopropanol as solvent to give the title product (yield: 59.5%).

[0825] MS(ESI)m / z[M+H] + =407.2.

[0826] 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.25(d,J=9.6Hz,1H),8.21(s,1H),7.76(s,1H),7.58(d,J=9.6Hz,1H),4.43-4.27(m,2H),4.18-4.13(m ,2H),4.12(s,2H),3.86-3.68(m,2H),3.34(t,J=6.4Hz,2H),2.41(d,J =6.8Hz,2H),1.05-0.82(m,1H),0.52-0.28(m,2H),0.18-0.02(m,2H).

[0827] Referring to the synthesis method described in Example 60, the following examples were obtained:

[0828] Example 262: 3-(cyclopropylmethyl)-5-(5-(1-methyl-1H-imidazol-4-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-3H-imidazol[4,5-b][1,8]naphthidine (262)

[0829] Step 1: Synthesis of 2-chloro-5-(1-methyl-1H-imidazol-4-yl)pyridine (262-1)

[0830] M73-4 (1 g, 6.35 mmol) was dissolved in 1,4-dioxane (1 mL) and water (1 mL), followed by the addition of 1-methyl-4-bromoimidazole (920 mg, 5.71 mmol), Pd(dtbpf)Cl2 (0.41 g, 0.64 mmol), and potassium phosphate (3.4 g, 15.9 mmol). The reaction mixture was stirred at 100 °C for 2 hours. LC-MS showed product formation. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (100% ethyl acetate) to give the title product (300 mg, yellow oil).

[0831] MS(ESI)m / z[M+H] + =194.1.

[0832] Step 2: Synthesis of 3-(cyclopropylmethyl)-5-(5-(1-methyl-1H-imidazol-4-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-3H-imidazol[4,5-b][1,8]naphthidine (262)

[0833] The synthesis method was as described in step 1 of Example 1, yielding the title product (yield: 23.6%).

[0834] MS(ESI)m / z[M+H] + =386.2.

[0835] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.17(s,1H),7.91(dd,J=8.8,2.0Hz,1H),7.82(d,J=8.8Hz,1H),7.77(s,1H),7.65(s,1H),7.62(s,1H),4.04- 3.97(m,2H),3.92(d,J=7.2Hz,2H),3.69(s,3H),2.90(t,J=6.2Hz,2H),2. 02-1.93(m,2H),1.32-1.24(m,1H),0.53-0.46(m,2H),0.40-0.32(m,2H).

[0836] Referring to the synthesis method described in Example 262, the following examples were obtained:

[0837] Example 269: 4-(6-(3-(cyclopropylmethyl)-7,8-dihydropyrazole[1,5-a]pyridyl[2,3-d]pyrimidin-5(6H)-yl)pyridazin-3-yl)pyridin-2(1H)-one (269)

[0838] Step 1: Synthesis of 5-(6-chloropyridin-3-yl)-3-(cyclopropylmethyl)-5,6,7,8-tetrahydropyrazole[1,5-a]pyridine[2,3-d]pyrimidine (269-1)

[0839] The synthesis method was as described in step 1 of Example 1, yielding the title product (yield: 47.3%).

[0840] MS(ESI)m / z[M+H] + =341.1.

[0841] Step 2: Synthesis of 4-(6-(3-(cyclopropylmethyl)-7,8-dihydropyrazole[1,5-a]pyridyl[2,3-d]pyrimidin-5(6H)-yl)pyridazin-3-yl)pyridin-2(1H)-one (269)

[0842] Dissolve 269-1 (25 mg, 0.073 mmol) and M72-1 (32.3 mg, 0.15 mmol) in a mixed solvent of 1,4-dioxane (2.5 mL) and water (0.5 mL), and then add Pd(dppf)Cl sequentially. 2( 5.34 mg (0.0073 mmol) and sodium carbonate (15.47 mg, 0.15 mmol) were stirred overnight at 100 °C. LC-MS showed product formation. The reaction was quenched with saturated brine (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-35%) to give the title product (2.4 mg, yellow solid).

[0843] MS(ESI)m / z[M+H] + =400.1.

[0844] 1 H NMR(400MHz,DMSO-d6)δ11.76(br.s,1H),8.74(s,1H),8.41(d,J=9.6Hz,1H) ,8.25(d,J=9.6Hz,1H),7.86(s,1H),7.54(d,J=8.4Hz,1H),7.07(s,1H),7.0 0(d,J=8.4Hz,1H),4.26-4.17(m,2H),3.24-3.15(m,2H),2.92-2.84(m,2H), 2.11-2.02(m,2H),1.01-0.90(m,1H),0.46-0.36(m,2H),0.16-0.07(m,2H).

[0845] Referring to the synthesis method described in Example 269, the following examples were obtained:

[0846] Example 285: 1-(6-(3-(cyclopropylmethyl)-7,8-dihydropyrazole[1,5-a]pyridin[2,3-d]pyrimidin-5(6H)-yl)pyridazin-3-yl)imidazolin-2-one (285)

[0847] 269-1 (100 mg, 0.29 mmol) and 2-imidazolidineone (37 mg, 0.44 mmol) were dissolved in toluene (5 mL), and Pd2(dba)3 (47.62 mg, 0.052 mmol), XantPhos (18 mg, 0.029 mmol), and cesium carbonate (189 mg, 0.58 mmol) were added sequentially. The reaction was stirred at 100 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with saturated brine (20 mL), separated, and the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give the title product (50 mg, yellow solid).

[0848] MS(ESI)m / z[M+H] + =391.2.

[0849] 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.42(d,J=9.8Hz,1H),8.05(d,J=9.8Hz,1H),7.77(s,1H),7.46(s,1H),4.16-4.00(m,4H),3.48(t, J=8.0Hz,2H),2.86(t,J=5.6Hz,2H),2.37(d,J=6.6Hz,2H),2.10-1.97(m,2H),0.97-0.85(m,1H),0.42-0.30(m,2H),0.14-0.03(m,2H).

[0850] The following examples were obtained by referring to the synthesis method of Example 285.

[0851] Example 296: 3-(cyclopropylmethyl)-5-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydro-3H-imidazolium[4,5-g]quinoline (296)

[0852] M55 (100 mg, 0.44 mmol) was dissolved in 1,4-dioxane (3 mL). Under an argon atmosphere, 2-chloro-4-methoxypyrimidine (95.41 mg, 0.66 mmol), Pd2(dba)3 (40.29 mg, 0.044 mmol), BINAP (27.40 mg, 0.044 mmol), and sodium tert-butoxide (84.57 mg, 0.88 mmol) were added sequentially. The reaction was stirred overnight at 100 °C. LC-MS showed the reaction was complete. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (ethyl acetate: methanol = 19:1) to obtain the crude product. The crude product was further purified by preparative thin-layer chromatography (ethyl acetate: methanol = 19:1) to obtain the title product (9 mg, yellow solid).

[0853] MS(ESI)m / z[M+H]+=336.2.

[0854] 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=5.6Hz,1H),8.16(s,1H),7.98(s,1H),7.41(s,1H),6.27(d,J=5.6Hz,1H),4.01(d,J=7.0Hz,2H),3 .79(s,3H),3.96(t,J=6.4Hz,2H),2.79(t,J=6.4Hz,2H),1.98-1.89(m,2H),1.30-1.24(m,1H),0.54-0.48(m,2H),0.42-0.36(m,2H).

[0855] Example 297: 4-(6-(3-(cyclopropylmethyl)-9-methyl-3,6,7,8-tetrahydro-5H-imidazol[4,5-b][1,8]naphthidin-5-yl)pyridazin-3-yl)piperazin-2-one (297)

[0856] Under an argon atmosphere, 208 (40 mg, 0.091 mmol) and methylboric acid (20 mg, 0.33 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (0.2 mL), and Pd(dtbpf)Cl was added sequentially. 2(5.9 mg (0.091 mmol) and potassium carbonate (13 mg, 0.091 mmol) were added, and the reaction was carried out at 100 °C with stirring for 1 hour. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (20 mL), separated, and the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-60%) to give the title product (10 mg, white solid).

[0857] MS(ESI)m / z[M+H] + =419.2.

[0858] 1 H NMR(400MHz,DMSO-d6)δ8.10(br.s,1H),8.07(s,1H),7.77(d,J=9.8Hz,1H) ,7.27(d,J=9.8Hz,1H),4.05(s,2H),4.00-3.90(m,2H),3.84(d,J=6.8Hz,2H ),3.79-3.69(m,2H),3.31-3.27(m,2H),2.84(t,J=6.4Hz,2H),2.46(s,3H), 2.06-1.98(m,2H),1.25-1.19(m,1H),0.50-0.43(m,2H),0.34-0.28(m,2H).

[0859] Example 298: 5-(3-(cyclopropylmethyl)-7,8-dihydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-5(6H)-yl)pyridazin-3(2H)-one (298)

[0860] Step 1: Synthesis of 5-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (298-2)

[0861] At room temperature, 298-1 (100 mg, 0.77 mmol) and 3,4-dihydropyran (129 mg, 1.54 mmol) were dissolved in tetrahydrofuran (10 mL), and p-toluenesulfonic acid monohydrate (14.6 mg, 0.077 mmol) was added. The reaction mixture was stirred overnight at 75 °C. LC-MS showed that the reaction was complete. The reaction was quenched with saturated brine (20 mL) and extracted with dichloromethane (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give the title product (50 mg, white solid).

[0862] MS(ESI)m / z[M+H]+=215.1.

[0863] Step 2: Synthesis of 5-(3-(cyclopropylmethyl)-7,8-dihydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-5(6H)-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (298-3)

[0864] The synthesis method was as described in step 1 of Example 1, yielding the title product (yield: 56.2%).

[0865] MS(ESI)m / z[M+H]+=407.2.

[0866] Step 3: Synthesis of 5-(3-(cyclopropylmethyl)-7,8-dihydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-5(6H)-yl)pyridazin-3(2H)-one (298)

[0867] At room temperature, 298-3 (130 mg, 0.32 mmol) was dissolved in tetrahydrofuran (5 mL), and 2M hydrochloric acid solution (1 mL, 2.0 mmol) was added. The mixture was stirred overnight at 65 °C. LC-MS showed that the reaction was complete. The pH of the reaction mixture was adjusted to approximately 8 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-35%) to give the title product (35.3 mg, white solid).

[0868] MS(ESI)m / z[M+H]+=323.1.

[0869] 1 H NMR (400MHz, DMSO-d6) δ12.55(br.s,1H),8.67(s,1H),8.25(s,1H),7.83(s,1H),6.57(s,1H),3.76(t,J=5.8Hz,2H),2. 78(t,J=6.0Hz,2H),2.43(d,J=6.8Hz,2H),2.05-1.95(m,2H),1.00-0.89(m,1H),0.42-0.34(m,2H),0.15-0.08(m,2H).

[0870] The following examples were obtained by referring to the synthesis method described in Example 298:

[0871] Example 303: 2-(3-(4-fluorophenyl)-6,7-dihydroimidazo[4',5':5,6]pyrido[3,2-b][1,4] Azine-5(3H)-yl)-N-methylpyridin-4-amine (303)

[0872] Step 1: Synthesis of N-(2-chloropyridin-4-yl)-N-methylacetamide (303-2)

[0873] At room temperature, 0.85 g (5 mmol) of 303-1 and cesium carbonate (3.26 g, 10 mmol) were dissolved in 10 mL of DMF, and 0.71 g (4.98 mmol) of iodomethane were added. The reaction was stirred at 100 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was filtered, the filtrate was diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (473 mg, yellow solid).

[0874] MS(ESI)m / z[M+H]+=185.1.

[0875] Step 2: N-(2-(3-(4-fluorophenyl)-6,7-dihydroimidazo[4',5':5,6]pyrido[3,2-b][1,4]) Synthesis of azinon-5(3H)-yl)pyridin-4-yl)-N-methylacetamide (303-3)

[0876] The synthesis method was as described in step 1 of Example 1, yielding the title product (yield: 78.5%).

[0877] MS(ESI)m / z[M+H]+=419.0.

[0878] Step 3: 2-(3-(4-fluorophenyl)-6,7-dihydroimidazo[4',5':5,6]pyrido[3,2-b][1,4] Synthesis of azinon-5(3H)-yl)-N-methylpyridin-4-amine (303)

[0879] At room temperature, 303-3 (0.42.0 mg, 0.1 mmol) was dissolved in methanol (5 mL), and 3M hydrochloric acid solution (0.5 mL, 1.50 mmol) was slowly added. The reaction was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (30 mL), and the aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-35%) to give the title product (23 mg, yellow solid).

[0880] MS(ESI)m / z[M+H]+=377.1.

[0881] 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),8.00-7.90(m,2H),7.84(d,J=5.8Hz,1H),7.60(s,1H),7.34(t,J=8.4H z,2H),7.12(s,1H),6.36(s,1H),6.24(d,J=5.8Hz,1H),4.33-4.25(m,2H),4.16-4.07(m,2H),3.34(s,3H).

[0882] Example 304: 5-(6-(3-phenyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridin-3-yl)iso Azoxyl-3-ol (304)

[0883] Step 1: Synthesis of ethyl 3-(6-chloropyridin-3-yl)propionate (304-2)

[0884] 304-1 (5 g, 20.88 mmol) and ethyl propargyl acid (6.14 g, 62.6 mmol) were dissolved in DMF (50 mL), and cuprous oxide (2.99 g, 20.9 mmol) was added. The reaction mixture was stirred overnight at 100 °C. LC-MS showed product formation. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title product (4 g, yellow solid).

[0885] MS(ESI)m / z[M+H]+=210.1.

[0886] Step 2: 5-(6-chloropyridin-3-yl)iso Synthesis of 3-azole alcohol (304-3)

[0887] 304-2 (4 g, 20.5 mmol) and hydroxylamine hydrochloride (4.26 g, 61.4 mmol) were dissolved in a mixed solvent of ethanol (30 mL) and tetrahydrofuran (8 mL). The mixture was cooled to 5 °C, and sodium hydroxide (4.09 g, 102.3 mmol, 20 mL aqueous solution) was added dropwise. The reaction mixture was stirred at 60 °C for 3 hours. The temperature of the reaction solution was adjusted to 5 °C, and the pH of the reaction solution was adjusted to approximately 5 by adding hydrochloric acid aqueous solution. The precipitated white solid was filtered, and the filter cake was dried under reduced pressure to obtain the title product (2 g, white solid).

[0888] MS(ESI)m / z[M+H]+=197.1.

[0889] Step 3: 5-(6-chloropyridin-3-yl)-3-(methoxymethoxy)iso Synthesis of azole (304-4)

[0890] 304-3 (2.0 g, 10.17 mmol) and triethylamine (3.09 g, 30.5 mmol) were added to tetrahydrofuran (20 mL), cooled to 0 °C, and bromomethyl methyl ether (1.91 g, 15.2 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. LC-MS showed product formation. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title product (500 mg, white solid).

[0891] Step 4: 3-(methoxymethoxy)-5-(6-(3-phenyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridin-3-yl)iso Synthesis of azole (304-5)

[0892] M11 (200 mg, 0.80 mmol), 304-4 (0.19 g, 0.80 mmol), cesium carbonate (782 mg, 2.40 mmol), RuPhos (37.3 mg, 0.080 mmol), and RuPhos-Pd-G4 (68.0 mg, 0.080 mmol) were added to 1,4-Dioxane (10 mL), and the mixture was purged with argon and reacted at 100 °C for 16 h. LC-MS showed product formation. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 10:1) to give the title product (200 mg, yellow solid).

[0893] MS(ESI)m / z[M+H]+=455.1.

[0894] Step 5: 5-(6-(3-phenyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridin-3-yl)iso Synthesis of 3-azole alcohol (304)

[0895] 304-5 (100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (1 mL), and 3M hydrochloric acid solution (0.3 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. LC-MS showed product formation. The reaction mixture was poured into a saturated sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-35%) to give the title product (3 mg, yellow solid).

[0896] MS(ESI)m / z[M+H]+=411.1.

[0897] 1 H NMR (400MHz, DMSO-d6) δ8.63 (s, 1H), 8.56 (s, 1H), 7.99-7.79 (m, 5H), 7.52 (t, J = 7.0Hz, 2H), 7.37(t,J=7.6Hz,1H),5.85(s,1H),4.09-4.00(m,2H),3.00-2.93(m,2H),2.08-1.97(m,2H).

[0898] The following examples were obtained by referring to the synthesis method described in Example 304:

[0899] Example 310: 5-(hydroxymethyl)-3-(6-(3-((tetrahydrofuran-3-yl)methyl)-6,7-dihydroimidazo[4',5':5,6]pyrido[3,2-b][1,4] (azine-5(3H)-yl)pyridazine-3-yl) 2-Zolpidem-2-one (310)

[0900] Step 1: 5-(((tert-butyldimethylsilyl)oxy)methyl) Synthesis of zosidine-2-one (310-2)

[0901] Under an argon atmosphere, 310-1 (300 mg, 2.56 mmol) and imidazole (348 mg, 5.12 mmol) were dissolved in DMF (10 mL), and tert-butyldimethylchlorosilane (463 mg, 3.07 mmol) was added. The reaction was stirred at 25 °C for 2 hours. TLC showed that the reaction was complete. The reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title product (330 mg, white solid, crude).

[0902] MS(ESI)m / z[M+H] + =232.1.

[0903] Step 2: 5-(((tert-butyldimethylsilyl)oxy)methyl)-3-(6-(3-((tetrahydrofuran-3-yl))methyl)-6,7-dihydroimidazo[4',5':5,6]pyrido[3,2-b][1,4] (azine-5(3H)-yl)pyridazine-3-yl) Synthesis of zosidine-2-one (310-3)

[0904] The synthesis method is as described in Example 285, yielding the title product (crude product).

[0905] MS(ESI)m / z[M+H] + =568.1.

[0906] Step 3: 5-(hydroxymethyl)-3-(6-(3-((tetrahydrofuran-3-yl)methyl)-6,7-dihydroimidazo[4',5':5,6]pyrido[3,2-b][1,4] (azine-5(3H)-yl)pyridazine-3-yl) Synthesis of azole-2-one (310)

[0907] 310-3 (105 mg, 0.18 mmol) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (0.24 g, 0.90 mmol) was added. The reaction was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-35%) to give the title product (13 mg, white solid).

[0908] MS(ESI)m / z[M+H] + =454.1.

[0909] 1 H NMR (400MHz, DMSO-d6) δ8.48(d,J=9.8Hz,1H),8.33(d,J=9.8Hz,1H),8.23(s, 1H),7.59(s,1H),5.27(t,J=5.2Hz,1H),4.84-4.77(m,1H),4.40-4.35(m,2H), 4.29(t,J=9.8Hz,1H),4.26-4.21(m,2H),4.14-4.04(m,3H),3.80-3.70(m,2H ),3.67-3.57(m,3H),3.48-3.44(m,1H),1.93-1.82(m,1H),1.64-1.57(m,2H).

[0910] Referring to the synthesis method described in Example 310, the following examples were obtained:

[0911] Example 315: 5-(5-(1H-tetrazol-1-yl)pyridin-2-yl)-3-cyclopropyl-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (315)

[0912] Step 1: Synthesis of 3-cyclopropyl-5-(5-nitropyridin-2-yl)-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (315-1)

[0913] The synthesis method was as described in step 1 of Example 1, yielding the title product (yield: 56.6%).

[0914] MS(ESI)m / z[M+H]+=337.1.

[0915] Step 2: Synthesis of 6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridine-3-amine (315-2)

[0916] At room temperature, 315-1 (100 mg, 0.30 mmol) and iron powder (167.5 mg, 3.0 mmol) were mixed in ethanol (30 mL) and water (10 mL), and ammonium chloride (160 mg, 3.0 mmol) was added. The reaction was stirred at 80 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the title product (50 mg, yellow solid, crude product).

[0917] MS(ESI)m / z[M+H]+=307.1.

[0918] Step 3: Synthesis of 5-(5-(1H-tetrazol-1-yl)pyridin-2-yl)-3-cyclopropyl-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (315)

[0919] Dissolve 315-2 (50 mg, 0.16 mmol) and sodium acetate (13.1 mg, 0.16 mmol) in acetic acid (5 mL), add trimethyl orthoformate (45.8 mg, 0.43 mmol), and stir at room temperature for 30 minutes. Add azidotrimethylsilane (38.7 mg, 0.34 mmol), raise the temperature to 70 °C, and stir overnight. LC-MS showed the reaction was complete. Pour the reaction mixture into 20 mL of ice water, adjust the pH to approximately 12 with 2 M NaOH aqueous solution, and extract with ethyl acetate (50 mL x 2). Wash the combined organic phases with saturated brine (50 mL), dry to anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure. Purify the residue by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the title product (21 mg, white solid).

[0920] MS(ESI)m / z[M+H]+=360.2.

[0921] 1H NMR (400MHz, DMSO-d6) δ10.06(s,1H),8.82(s,1H),8.29(d,J=8.4Hz,1H),8.12(d,J=8.4Hz,1H),7.96(s,1H) ,7.84(s,1H),4.12-4.07(m,2H),3.44-3.40(m,1H),2.95-2.89(m,2H),2.03-1.98(m,2H),1.11-1.09(m,4H).

[0922] Example 316: 5-(5-(2H-tetrazol-5-yl)pyridin-2-yl)-3-cyclopropyl-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (316)

[0923] Step 1: Synthesis of 6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthid-5-yl)nicotinonitrile (316-1)

[0924] The synthesis method was as described in step 1 of Example 1, yielding the title product (yield: 61.3%).

[0925] MS(ESI)m / z[M+H]+=317.1.

[0926] Step 2: Synthesis of 6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthid-5-yl)nicotinamide hydrazide (316-2)

[0927] 316-1 (210 mg, 0.66 mmol) and hydrazine hydrate (330 mg, 6.60 mmol, purity: 98%) were dissolved in methanol (5 mL), and sodium methoxide (356 mg, 6.60 mmol) was added. The tube was sealed and stirred overnight at 70 °C. LC-MS product was formed. The reaction solution was used directly in the next step without post-treatment.

[0928] MS(ESI)m / z[M+H]+=349.2.

[0929] Step 3: Synthesis of 5-(5-(2H-tetrazol-5-yl)pyridin-2-yl)-3-cyclopropyl-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (316)

[0930] 316-2 (100 mg, crude methanol solution) was dissolved in acetic acid (2 mL) and water (2 mL), and sodium nitrite solution (100 mg, 1.45 mmol, 0.5 mL aqueous solution) was added dropwise. The mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was poured into 20 mL of saturated sodium carbonate solution and back-extracted with ethyl acetate (30 mL x 2). The aqueous phase was retained, and the pH was adjusted to approximately 5 with 6 M hydrochloric acid solution, followed by extraction with dichloromethane (containing 10% methanol, 50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the title product (9 mg, white solid).

[0931] MS(ESI)m / z[M+H]+=360.1.

[0932] 1 H NMR (400MHz, DMSO-d6) δ8.95 (s, 1H), 8.22-8.11 (m, 3H), 7.83 (s, 1H), 4.10 (t, J = 6.0Hz ,2H),3.46-3.40(m,1H),2.91(t,J=6.0Hz,2H),2.05-1.93(m,2H),1.15-0.96(m,4H).

[0933] Example 317: 5-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridazin-3-yl)-N-(oxetane-3-yl)nicotinamide (317)

[0934] Using 317-1 (synthesis method as described in Example 269) as raw material, the title product (yield: 32.4%) was obtained by referring to steps 3-4 of Example 85.

[0935] MS(ESI)m / z[M+H]+=469.1.

[0936] 1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),9.46(s,1H),9.12(s,1H),8.99(s,1H),8. 47(d,J=9.6Hz,1H),8.26(d,J=9.6Hz,1H),8.19(s,1H),7.86(s,1H),5.15-5.0 0(m,1H),4.82(t,J=6.4Hz,2H),4.67(t,J=6.4Hz,2H),4.23(t,J=5.6Hz,2H),3 .44-3.39(m,1H),2.95(t,J=5.6Hz,2H),2.13-2.01(m,2H),1.13-0.97(m,4H).

[0937] Referring to the synthesis method described in Example 317, the following examples were obtained:

[0938] Referring to the synthesis method described in step 1 of Example 317, the following example was obtained.

[0939] Example 326: 7-(3-(cyclopropylmethyl)-7,8-dihydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-5(6H)-yl)-4-methyl-2H-pyrido[3,2-b][1,4] Azine-3(4H)-one (326)

[0940] M57 (60 mg, 0.26 mmol) and 326-1 (94.79 mg, 0.39 mmol) were dissolved in 1,4-dioxane (3 mL), followed by the addition of (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (7.40 mg, 0.052 mmol), cesium carbonate (169 mg, 0.52 mmol), and cuprous iodide (9.90 mg, 0.052 mmol). The reaction mixture was stirred at 120 °C for 16 hours in a sealed tube. LC-MS showed that the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the crude product. The crude product was further purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-40%) to obtain the title product (27 mg, white solid).

[0941] MS(ESI)m / z[M+H] + =391.2.

[0942] 1H NMR (400MHz, DMSO-d6) δ8.49(s,1H),8.15(d,J=2.2Hz,1H),7.69(s,1H),7.57(d,J=2.2Hz,1H),4.78(s,2H),3.90–3.64(m,2H),3.3 6(s,3H),2.83(t,J=6.0Hz,2H),2.28(d,J=6.8Hz,2H),2.06–1.97(m,2H),0.90–0.81(m,1H),0.35–0.30(m,2H),0.09–0.03(m,2H).

[0943] Referring to the synthesis method described in Example 326, the following examples were obtained:

[0944] Example 330: 6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyridin-5-yl)pyridin-3-yl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4] Azine (330)

[0945] Step 1: Synthesis of methyl 6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyridin-5-yl)nicotinic acid (330-1)

[0946] The synthesis method is as described in step 1 of Example 1, and the title product (crude product) is obtained.

[0947] Step 2: Synthesis of 6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyridin-5-yl)nicotinamide (330-2)

[0948] 330-1 (150 mg, 0.43 mmol) was dissolved in methanol (5 mL), followed by the addition of sodium methoxide (232 mg, 4.3 mmol) and hydrazine hydrate (215 mg, 4.3 mmol). The tube was sealed and stirred overnight at 60 °C. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (120 mg, yellow solid).

[0949] MS(ESI)m / z[M+H]+=350.1.

[0950] Step 3: 3-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyridin-5-yl)pyridin-3-yl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4] Synthesis of aziridine (330)

[0951] 330-2 (80 mg, 0.23 mmol) and 5-methoxy-3,6-dihydro-2H- The aziridine (26.5 mg, 0.23 mmol) was dissolved in ethanol (5 mL), sealed in a tube, and stirred overnight at 90 °C. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (15 mg, white solid).

[0952] MS(ESI)m / z[M+H]+=415.1.

[0953] 1 H NMR (400MHz, DMSO-d6) δ8.72(s,1H),8.23-8.16(m,2H),8.02(d,J=9.0Hz,1H),7.83(s,1H),4.97(s,2H),4.26(t,J=5.0Hz,2H),4.13- 4.08(m,2H),4.02(t,J=5.0Hz,2H),3.46-3.41(m,1H),2.91(t,J=6.0Hz,2H),2.05-1.95(m,2H),1.13-1.06(m,2H),1.06-0.98(m,2H).

[0954] Example 331: 3-Cyclopropyl-5-(5-(7-(oxacyclobutane-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)-56,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthylpyridine (331)

[0955] Steps 1-2: Synthesis of 3-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridin-3-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-tert-butyl carboxylate (331-3)

[0956] The synthesis method was as described in steps 1-2 of Example 262, yielding the title product (yield: 52.2%).

[0957] MS(ESI)m / z[M+H]+=514.3.

[0958] Step 3: Synthesis of 3-cyclopropyl-5-(5-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthylpyridine (331-4)

[0959] A solution of 1,4-dioxane (10 mL, 4 M) of hydrogen chloride was added to a round-bottom flask containing 331-3 (100 mg, 0.19 mmol), and the mixture was stirred at room temperature for 3 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give the title product (80 mg, white solid, crude product).

[0960] Step 4: Synthesis of 3-cyclopropyl-5-(5-(7-(oxecyclobutane-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)-56,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthylpyridine (331)

[0961] 331-4 (50 mg, 0.12 mmol) and 3-oxetane (43.2 mg, 0.60 mmol) were dissolved in 1,2-dichloroethane (3 mL), and sodium triacetoxyborohydride (127 mg, 0.60 mmol) was added. The tube was sealed and stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (methanol:dichloromethane = 1:10) to give the title product (7 mg, white solid).

[0962] MS(ESI)m / z[M+H]+=470.2.

[0963] 1 H NMR(400MHz, DMSO-d6)δ8.71(s,1H),8.22-8.16(m,2H),8.02(d,J=9.0Hz,1H),7.83(s,1H),4.69-4.60(m,2H),4.59-4.48(m,2H),4.27-4.17 (m,2H),4.14-4.03(m,2H),3.83-3.71(m,3H),3.46-3.38(m,1H),2.96 -2.88(m,2H),2.83-2.77(m,2H),2.06-1.93(m,2H),1.14-0.96(m,4H).

[0964] Example 332: 2-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridin-3-yl)-4,5-dihydropyrazolo[1,5-a]pyrazin-6(7H)-one (332)

[0965] Step 1: Synthesis of ethyl 2-(3-bromo-5-methyl-1H-pyrazole-1-yl)acetate (332-2)

[0966] The synthesis method is as described in step 3 of the synthesis of intermediate M1, yielding the title product (yield: 70.4%).

[0967] Step 2: Synthesis of ethyl 2-(3-bromo-5-(bromomethyl)-1H-pyrazol-1-yl)acetate (332-3)

[0968] Compound 332-2 (6.2 g, 25.1 mmol) was dissolved in tetrahydrofuran (60 mL), and azobisisobutyronitrile (0.41 g, 2.51 mmol) was added. The mixture was stirred at room temperature for 5 minutes, followed by the addition of NBS (4.69 g, 26.3 mmol). The reaction was stirred at 80 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to give the title product (3.4 g, pale yellow oil).

[0969] MS(ESI)m / z[M+H] + =326.9.

[0970] Step 3: Synthesis of 2-bromo-5-(2,4-dimethoxybenzyl)-4,5-dihydropyrazole[1,5-a]pyrazine-6(7H)-one (332-4)

[0971] Compound 332-3 (5.6 g, 17.2 mmol) and 2,4-dimethoxybenzylamine (28.7 g, 172 mmol) were dissolved in tetrahydrofuran (50 mL) under an argon atmosphere and stirred at 70 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filter cake was washed with tetrahydrofuran (5 mL x 3) and dried under reduced pressure. The crude product was slurried with water (100 mL), filtered, and the title product (3.5 g, white solid) was obtained.

[0972] MS(ESI)m / z[M+H] + =366.0,368.0.

[0973] Steps 4-5: Synthesis of 2-(6-(3-(cyclopropylmethyl)-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridin-3-yl)-5-(2,4-dimethoxybenzyl)-4,5-dihydropyrazol[1,5-a]pyrazin-6(7H)-one (332-6)

[0974] The synthesis method is as described in steps 1-2 of Example 262, yielding the title product (yield: 31.6%).

[0975] MS(ESI)m / z[M+H] + =577.3.

[0976] Step 6: Synthesis of 2-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridin-3-yl)-4,5-dihydropyrazolo[1,5-a]pyrazin-6(7H)-one (332)

[0977] The synthesis method is as described in step 5 of the synthesis of intermediate M1, yielding the title product (yield: 9.26%).

[0978] MS(ESI)m / z[M+H] + =427.1.

[0979] 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),8.50(s,1H),8.13(s,1H),8.05(d,J=8.4Hz,1H),8.00(d,J=8.4Hz,1H),7.78(s,1H),6.67(s,1H),4. 75(s,2H),4.53(s,2H),4.08-4.03(m,2H),3.43-3.38(m,1H),2.94-2 .87(m,2H),2.04-1.94(m,2H),1.12-1.05(m,2H),1.02-0.98(m,2H).

[0980] Example 333: 1-(4-cyano-6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridin-3-yl)-N-(oxetane-3-yl)-1H-imidazo-4-carboxamide (333)

[0981] Step 1: Synthesis of 2-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthid-5-yl)-5-fluoroisonicotinic acid (333-1)

[0982] Referring to the method described in step 1 of Example 1, the title product was obtained (yield: 64.1%).

[0983] MS(ESI)m / z[M+H]+=335.1.

[0984] Step 2: Synthesis of methyl 1-(4-cyano-6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridin-3-yl)-1H-imidazo-4-carboxylate (333-2)

[0985] Following the method described in step 3 of the synthesis of intermediate M1, the title product was obtained (yield: 75.9%).

[0986] MS(ESI)m / z[M+H]+=441.2.

[0987] Steps 3-4: Synthesis of 2-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthid-5-yl)-5-(4-(oxacyclobutane-3-ylcarbamoyl)-1H-imidazo-1-yl)isonicotinamide (333-4)

[0988] Using 333-2 as the starting material, the title product (yield: 59.3%) was obtained by referring to the methods described in steps 3-4 of Example 85.

[0989] MS(ESI)m / z[M+H]+=500.2.

[0990] Step 5: 1-(4-cyano-6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridin-3-yl)-N-(oxetane-3-yl)-1H-imidazo-4-carboxamide (333)

[0991] 333-4 (90 mg, 0.18 mmol) and triethylamine (36.43 mg, 0.36 mmol) were dissolved in dichloromethane (5 mL), and the solution was cooled to 0 °C in an ice bath. Trifluoroacetic anhydride (151.22 mg, 0.72 mmol) was added dropwise. The reaction mixture was slowly heated to room temperature and stirred overnight. LC-MS showed product formation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-35%) to give the title product (19 mg, yellow solid).

[0992] MS(ESI)m / z[M+H]+=482.2.

[0993] 1H NMR (400MHz, DMSO-d6) δ8.91(s,1H),8.86(d,J=2.4Hz,1H),8.71(d,J=2.4Hz,1H),8.28-8.21(m,2H),8.19(s,1H),7.90(s,1H),5. 03-5.00(s,1H),4.80-4.61(m,4H),4.19-4.05(m,2H),3.45-3.40(m,1H),3.00-2.90(m,2H),2.11-1.99(m,2H),1.19-1.06(m,4H).

[0994] Referring to the synthesis method described in Example 333, the following examples were obtained:

[0995] Example 335: 3-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridazin-3-yl)-5-((iso (azol-3-ylamino)methyl) 2-Zolpidem-2-one (335)

[0996] Steps 1-2: 3-(6-Chlorpyridazine-3-yl)-5-(Hydroxymethyl) Synthesis of azole-2-one (335-2)

[0997] Referring to the method described in steps 2-3 of Example 310, the title product (yield: 80.0%) was obtained.

[0998] MS(ESI)m / z[M+H] + =230.0.

[0999] Step 3: (3-(6-chloropyridazine-3-yl)-2-oxo Synthesis of 5-yl(azolomide)methylmethanesulfonate (335-3)

[1000] 335-2 (0.7 g, 3.05 mmol) was dissolved in dichloromethane (15 mL), cooled to 0 °C in an ice bath, and methanesulfonyl chloride (0.42 g, 3.66 mmol) and triethylamine (0.62 g, 6.1 mmol) were added under argon protection. The reaction was stirred at 0 °C for 1 hour. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (677 mg, yellow solid).

[1001] MS(ESI)m / z[M+H] + =308.0.

[1002] Step 4: (3-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridazin-3-yl)-2-oxo Synthesis of (335-4) azoline-5-yl)methylmethanesulfonate

[1003] Referring to the method described in step 2 of Example 85, the title product was obtained (yield: 42.9%).

[1004] MS(ESI)m / z[M+H] + =486.2.

[1005] Step 5: (3-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridazin-3-yl)-2-oxo (5-yl)azolidinyl)methyl)iso ... 5- Synthesis of tert-butyl 3-(zol-3-yl)carbamate (335-5)

[1006] Under argon protection, the different Tert-butyl 3-azolo-3-ylcarbamate (41 mg, 0.22 mmol) was dissolved in DMF (3 mL). Sodium hydride (6.3 mg, 0.26 mmol) was added at 0 °C, and the mixture was stirred for 30 minutes. Then, 335-4 (107 mg, 0.22 mmol) was added, and the reaction was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (30 mL x 3, containing 10% methanol). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product (40 mg, yellow solid).

[1007] MS(ESI)m / z[M+H] + =574.2.

[1008] Step 6: 3-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthid-5-yl)pyridazin-3-yl)-5-((iso (azol-3-ylamino)methyl) 2-Zolpidem-2-one (335)

[1009] Starting with 335-5, and following the method described in step 2 of the synthesis of intermediate M6-3, the title product was obtained (yield: 48.5%).

[1010] MS(ESI)m / z[M+H] + =474.2.

[1011] 1H NMR (400MHz, DMSO-d6) δ8.40(s,1H),8.28(d,J=9.8Hz,1H),8.23(d,J=9.8H z,1H),8.13(s,1H),7.80(s,1H),6.60(t,J=6.0Hz,1H),6.02(s,1H),5.01- 4.92(m,1H),4.40-4.31(m,1H),4.11-4.03(m,3H),3.54-3.50(m,3H),2.93 (t,J=6.4Hz,2H),2.09-1.98(m,2H),1.10-1.04(m,2H),0.99-0.90(m,2H).

[1012] Example 336: 2-((6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridazin-3-yl)oxy)-N-ethylacetamide (336)

[1013] Steps 1-2: The synthesis of 2-((6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridazin-3-yl)oxy)ethyl acetate (336-3) was performed according to the method described in steps 1-2 of Example 85, yielding the title product (yield: 27.5%).

[1014] MS(ESI)m / z[M+H] + =395.1.

[1015] Step 3: Synthesis of 2-((6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridazin-3-yl)oxy)-N-ethylacetamide (336)

[1016] 336-3 (80 mg, 0.20 mmol) and ethylamine hydrochloride (64.8 mg, 0.8 mmol) were added to methanol (2 mL), followed by triethylamine (101 mg, 1 mmol). The reaction mixture was stirred at 70 °C for 1 hour. LCMS showed product formation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-35%) to give the title product (50 mg, white solid).

[1017] MS(ESI)m / z[M+H] + =394.1.

[1018] 1 H NMR (400MHz, DMSO-d6) δ8.15(d,J=9.6Hz,1H),8.11(t,J=5.2Hz,1H),8.09(s,1H),7.76(s,1H),7.16(d,J=9.6Hz,1H),4.81(s,2H),4.02 (t,J=6.0Hz,2H),3.51-3.47(m,1H),3.19-3.09(m,2H),2.91(t,J=6.2Hz,2H),2.07-1.96(m,2H),1.07-1.00(m,5H),1.00-0.92(m,2H).

[1019] Example 337: N-(5-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridin-3-yl)pyridin-3-yl)-2-methoxyacetamide (337)

[1020] Step 1: N-(5-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridin-3-yl)pyridin-3-yl)-2-methoxyacetamide (337)

[1021] 337-1 (40 mg, 0.10 mmol) (synthesized as described in Example 269) and triethylamine (20.2 mg, 0.20 mmol) were dissolved in dichloromethane (1 mL), purging the mixture with argon. 2-Methoxyacetyl chloride (13.0 mg, 0.12 mmol) was added under ice bath conditions. The reaction mixture was slowly brought to room temperature and stirred for 2 hours. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-20%) to give the title product (7 mg, yellow solid).

[1022] MS(ESI)m / z[M+H] + =457.2.

[1023] 1H NMR (400MHz, DMSO-d6) δ10.20(s,1H),8.98(d,J=2.4Hz,1H),8.92(d,J=2.4Hz,1H),8.86(s,1H),8.41(d,J=9.8Hz,1H),8.17(s,1H),8.07(d ,J=9.8Hz,1H),7.84(s,1H),4.24-4.17(m,2H),4.08(s,2H),3.44-3.4 0(m,4H),2.95(t,J=6.8Hz,2H),2.10-2.01(m,2H),1.09-0.96(m,4H).

[1024] Example 338: (3S, 11aR)-7-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyridin-5-yl)pyridin-3-yl)-3,4-dihydro-1H,9H,11H-3,11a-methylpyrido[6',1':2,3]imidazo[5,1-c][1,4] Azine-9-one (338)

[1025] Step 1: Synthesis of 5-(5-chloropyridin-2-yl)-3-cyclopropyl-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthylpyridine (338-1)

[1026] The synthesis method is as described in step 1 of Example 1, and the title product is obtained.

[1027] Step 2: Synthesis of (6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthylpyridin-5-yl)pyridin-3-yl)boronic acid (338-2)

[1028] In a reaction vial, 338-1 (100 mg, 0.31 mmol), bis(dba)3 (237 mg, 0.93 mmol), Pd2(dba)3 (28.4 mg, 0.031 mmol), XPhos (29.6 mg, 0.062 mmol), and potassium acetate (91.3 mg, 0.93 mmol) were added to 1,4-dioxane (4 mL). The reaction was purged with argon, sealed, and stirred overnight at 100 °C. LC-MS showed product formation. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 5:1) to give the title product (30 mg, yellow solid).

[1029] MS(ESI)m / z[M+H] + =336.1.

[1030] Step 3: (3S, 11aR)-7-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyridin-5-yl)pyridin-3-yl)-3,4-dihydro-1H,9H,11H-3,11a-methylpyrido[6',1':2,3]imidazo[5,1-c][1,4] Azine-9-one (338)

[1031] Using 338-2 and 338-3 (synthesis method reference: CN112778331) as starting materials, the title product (yield: 15.8%) was obtained by referring to the method described in step 2 of Example 269.

[1032] MS(ESI)m / z[M+H] + =495.2.

[1033] 1 H NMR(400MHz, DMSO-d6)δ9.01(s,1H),8.27-8.15(m,2H),8.00(d,J=9.2Hz,1H),7.85(s,1H),6.47(s,1H),4.82-4.70(m,2H),4.38(d,J=12.6Hz,1 H),4.13-4.06(m,2H),4.03(d,J=12.6Hz,1H),3.97-3.86(m,2H),3.47-3 .43(m,2H),2.91(t,J=6.2Hz,2H),2.04-1.84(m,4H),1.17-0.94(m,4H).

[1034] Example 339: 6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyridin-5-yl)-6-(3-methoxyazacyclobutane-1-carbonyl)-[3,4'-bipyridine]-2'(1'H)-one (339)

[1035] Step 1: Synthesis of methyl 6-chloro-1'-(4-methoxybenzyl)-6'-oxo-1',6'-dihydro-[3,4'-bipyridine]-2'-carboxylic acid (339-1)

[1036] Following the method described in step 1 of the synthesis of intermediate M1, the title product was obtained (yield: 21.5%).

[1037] MS(ESI)m / z[M+H] + =385.1.

[1038] Steps 2–4: Synthesis of 6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyridin-5-yl)-6-(3-methoxyazacyclobutane-1-carbonyl)-1-(4-methoxybenzyl)-[3,4'-bipyridine]-2'(1'H)-one (339-4)

[1039] Using 339-1 and M3 as starting materials, and referring to the methods described in steps 2 to 4 of Example 85, the title product was obtained (yield: 23.7%).

[1040] MS(ESI)m / z[M+H] + =618.3.

[1041] Step 5: Synthesis of 6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyridin-5-yl)-6-(3-methoxyazacyclobutane-1-carbonyl)-[3,4'-bipyridine]-2'(1'H)-one (339)

[1042] Starting with 339-4, and following the method described in step 5 of the synthesis of intermediate M1, the title product was obtained (yield: 23.7%).

[1043] MS(ESI)m / z[M+H] + =498.2.

[1044] 1 H NMR(400MHz,DMSO-d6)δ10.9(br.s,1H),8.76(s,1H),8.20-8.12(m,2H),8.05(d d,J=9.2&2.8Hz,1H),7.81(s,1H),7.00(s,1H),4.76-4.62(m,1H),4.43-4.33(m ,1H),4.30-4.21(m,2H),4.09(t,J=6.0Hz,2H),3.89-3.81(m,1H),3.43-3.41(m ,1H),3.24(s,3H),2.90(t,J=6.2Hz,2H),2.05-1.95(m,2H),1.10-1.02(m,4H).

[1045] Example 340: 6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyridin-5-yl)-1'-methyl-6'-oxo-1',6'-dihydro-[3,4'-bipyridine]-2'-nitrile (340)

[1046] Referring to the method described in step 5 of Example 333, the title product was obtained (yield: 7.30%).

[1047] MS(ESI)m / z[M+H] + =424.1.

[1048] 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.22-8.15(m,2H),8.11(d,J=9.2Hz,1H),7.84(s,1H),7.68(s,1H),7.19(s, 1H),4.14-4.06(m,2H),3.58(s,3H),3.45-3.42(m,1H),2.96-2.87(m,2H),2.06-1.95(m,2H),1.14-1.03(m,4H).

[1049] Example 341: 8-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyridin-5-yl)pyridazin-3-yl)hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one (341)

[1050] Step 1: Synthesis of methyl 4-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridazin-3-yl)piperazine-2-carboxylate (341-2)

[1051] Using 341-1 (synthesis method as described in Example 1) as the starting material, and referring to step 2 of the synthesis of intermediate M6-3, the title product (yield: 41.0%) was obtained.

[1052] MS(ESI)m / z[M+H] + =435.2.

[1053] Step 2: Synthesis of methyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridazin-3-yl)piperazine-2-carboxylate (341-4)

[1054] Using 341-2 and 341-3 as starting materials, the title product was obtained (yield: 98.1%) by referring to step 3 of the synthesis of intermediate M1.

[1055] MS(ESI)m / z[M+H] + =578.3.

[1056] Step 3; Synthesis of 8-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthyridin-5-yl)pyridazin-3-yl)hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one (341)

[1057] Starting with 341-4, the title product (yield: 7.83%) was obtained by referring to step 2 of the synthesis of intermediate M73.

[1058] MS(ESI)m / z[M+H] + =446.2.

[1059] 1 H NMR(400MHz, DMSO-d6)δ8.07(s,1H),8.00(d,J=9.6Hz,1H),7.83(s,1H),7.73( s,1H),7.31(d,J=9.6Hz,1H),4.63-4.50(m,1H),4.23-4.12(m,1H),4.08-3.97( m,2H),3.44-3.41(m,1H),3.17-3.06(m,1H),3.02-2.89(m,6H),2.73-2.68(m,2 H),2.47-2.39(m,1H),2.36-2.24(m,1H),2.11-1.93(m,2H),1.09-0.92(m,4H).

[1060] Example 342: 3-(4-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridazin-3-yl)piperazin-1-yl)thiophene ethane 1,1-dioxide (342)

[1061] Step 1: Synthesis of 3-cyclopropyl-5-(6-(4-(thiocyclobutane-3-yl)piperazin-1-yl)pyridazin-3-yl)-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,8]naphthidine (342-2)

[1062] 342-1 (180 mg, 0.48 mmol) (synthesized according to the method described in Example 1), thiocyclobutane-3-one (126.9 mg, 1.44 mmol), and acetic acid (28.82 mg, 0.48 mmol) were mixed in 1,2-dichloroethane (5 mL), and sodium triacetoxyborohydride (508.7 mg, 2.4 mmol) was added. The reaction mixture was stirred overnight at 20 °C. LCMS showed product formation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 20:1) to give the title product (150 mg, yellow solid).

[1063] MS(ESI)m / z[M+H] + =449.1.

[1064] Step 2: Synthesis of 3-(4-(6-(3-cyclopropyl-3,6,7,8-tetrahydro-5H-imidazo[4,5-b][1,8]naphthidin-5-yl)pyridazin-3-yl)piperazin-1-yl)thiocyclobutane-1,1-dioxide (342)

[1065] 342-2 (50 mg, 0.11 mmol) was added to dichloromethane (5 mL), followed by m-chloroperoxybenzoic acid (37.97 mg, 0.22 mmol). The reaction mixture was stirred at 20 °C for 4 hours. LCMS showed product formation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 5:1) to give the product (3 mg, yellow solid).

[1066] MS(ESI)m / z[M+H] + =481.1.

[1067] 1 H NMR (400MHz, DMSO-d6) δ8.06 (s, 1H), 8.00 (d, J = 9.8Hz, 1H), 7.73 (s, 1H), 7.38 (d,J=9.8Hz,1H),4.81-4.71(m,1H),4.20-4.12(m,2H),4.11-4.05(m,2H),4.0 1(t,J=6.0Hz,2H),3.64-3.52(m,2H),3.41-3.37(m,1H),3.28-3.19(m,4H),3 .17-3.09(m,2H),2.91(t,J=6.2Hz,2H),2.05-1.96(m,2H),1.05-0.93(m,4H).

[1068] Example 343: 3-Cyclopropyl-5-(6-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]) [3,4-(pyridazin-3-yl)-3,5,6,7-tetrahydroimidazo[4',5':5,6]pyrido[3,2-b][1,4]thiazine-8,8-dioxide(343)]

[1069] 53 (160 mg, 0.45 mmol) was dissolved in dichloromethane (1 mL), and m-chloroperoxybenzoic acid (23.81 mg, 0.14 mmol) was added under ice bath conditions. The reaction was stirred at room temperature for one hour. LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 12:1) to give the crude product. The crude product was further purified by reversed-phase C18 rapid preparative chromatography (acetonitrile:water = 0-25%), and the eluent was collected to give the title product (2 mg, white solid).

[1070] MS(ESI)m / z[M+H] + =466.1.

[1071] 1 H NMR (400MHz, DMSO-d6) δ8.52-8.47(m,1H),8.35(d,J=9.6Hz,1H),8.29(d,J=9.6Hz,1H),5.03(s,2H),4.79- 4.72(m,2H),4.60-4.52(m,2H),4.10-4.04(m,2H),3.95-3.89(m,2H),1.13-1.07(m,2H),1.01-0.95(m,2H).

[1072] Referring to the synthesis method described in Example 343, the following examples were obtained:

[1073] Example 346: 7-(3-(cyclopropylmethyl)-6,7-dihydroimidazo[4',5':5,6]pyrido[3,2-b][1,4]) Azine-5(3H)-yl)-2H-benzo[b][1,4] Synthesis of azinon-3(4H)-one (346)

[1074] Step 1: Synthesis of 2-(2-nitrophenoxy)ethyl acetate (346-2)

[1075] The synthesis method is as described in step 3 of the synthesis of intermediate M1, yielding the title product (yield: 57.3%).

[1076] MS(ESI)m / z[M+H]+ =226.1.

[1077] Step 2: 2-(5-(3-(cyclopropylmethyl)-6,7-dihydroimidazo[4',5':5,6]pyrido[3,2-b][1,4]) Synthesis of azinon-5(3H)-yl)-2-nitrophenoxy)ethyl acetate (346-3)

[1078] The synthesis method is as described in step 1 of Example 1, yielding the title product (yield: 10.0%).

[1079] MS(ESI)m / z[M+H] + =454.2.

[1080] Step 3: 7-(3-(cyclopropylmethyl)-6,7-dihydroimidazo[4',5':5,6]pyrido[3,2-b][1,4] Azine-5(3H)-yl)-2H-benzo[b][1,4] Synthesis of azinon-3(4H)-one (346)

[1081] The synthesis method is as described in step 2 of the synthesis of intermediate M4-4, yielding the title product (yield: 17.9%).

[1082] MS(ESI)m / z[M+H] + =378.1.

[1083] 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),8.05(s,1H),7.39(s,1H),7.10(d,J=2.2Hz,1H),7.06(dd,J=8.4,2.2Hz,1H),6.88(d ,J=8.4Hz,1H),4.55(s,2H),4.28-4.24(m,2H),3.85-3.80(m,4H),1.25-1.18(m,1H),0.48-0.41(m,2H),0.34-0.28(m,2H).

[1084] Referring to the synthesis method described in Example 343, the following examples were obtained:

[1085] Referring to the method described in step 1 of Example 1, the following example is obtained:

[1086] Referring to the methods described in steps 1-2 of Example 85, the following example is obtained:

[1087] Referring to the synthesis method described in step 1 of Example 1, the following examples are obtained:

[1088] Referring to the synthesis method described in steps 2-4 of Example 85, the following examples were obtained:

[1089] Biological experimental methods:

[1090] Recent research results indicate that GABA A Receptors mediate at least two modes of inhibition: phasic inhibition and tonic inhibition. GABA within the synapse... A The receptor, due to the action potential, synchronously releases GABA-containing vesicles from the synapse, resulting in a rapid increase in millimolecular-level GABA concentration in the synaptic cleft, thereby triggering postsynaptic GABA production. A Synchronous activation and rapid desensitization of receptors lead to phase-type inhibition. Meanwhile, GABA, located outside the synapse... A The receptor is typically present in a persistent low concentration of GABA, ranging from tens of nanomoles to several millimoles. A In the environment, GABA with high affinity for GABA A Receptors are continuously and asynchronously activated, resulting in tonic inhibition. Both phasic inhibition and tonic inhibition jointly regulate neural excitability and signal transmission. Yeung JY et al. disclosed that low concentrations of GABA more readily activate α5-GABA. A Receptor. KYLee reported detecting low concentrations of GABA-activated, sustained high-affinity GABA in isolated DRG cells cultured for 24 hours. A Current. In 2013, I. Lecker et al. disclosed α5-GABA. A The receptor inverse agonist L-655,708 dose-dependently inhibited the current induced by low concentrations of GABA (5, 50, and 500 nM). When the GABA concentration was increased to 1 μM, the highest concentration of L-655,708 could only inhibit the current by 15%. When the GABA concentration continued to increase, L-655,708 had no inhibitory effect on the GABA-induced current.

[1091] Effect Example

[1092] I. The compounds of this invention react with different isoforms of GABA A Receptor affinity activity

[1093] Through competition 3 The binding of H-flunitrazepam to HEK293 cells stably expressing human α1β3γ2, α2β3γ2, α3β3γ2, and α5β3γ2 receptors was used to determine the compound's effect on GABA. A Affinity of each receptor subtype.

[1094] Cells were suspended in 50 mM Tris-HCl buffer (pH 7.4) and homogenized on ice for 20 seconds, 10 times, followed by centrifugation at 1000 g for 10 minutes at 4 °C. The supernatant was collected, and the above steps were repeated. The supernatant was centrifuged at 4 °C (33800 g; Thermo, rotor: A27-8x50) for 60 minutes, and the precipitate was resuspended in Tris buffer (50 mM Tris-HCl, 10 mM MgCl2, 0.5 mM EDTA, 10% glycerol). Protein was determined (BCA method, Pierce), and 1 mL aliquots were prepared and stored at -80 °C.

[1095] The radioligand competition binding assay was performed in a 200 μL system (96-well plate) containing 100 μL of cell membrane. 3 The concentration of H-flunitrazepam was 1 nM, and the concentration of the analyte was 1 x 10⁻⁶. -5 -10 -6 Within the M range. Flumazenil was used as a control. 1 μL of 2 mM flumazenil (final concentration 10 μM) was added to the low control well (LC), and 1 μL of DMSO was added to the high control well (HC). The final concentration of the target membrane protein was 5 μg / well. All sample stock solutions for the test compounds were 10 mM. The working concentration of the samples was achieved by diluting all samples to 0.2 mM with DMSO, followed by a 4-fold serial dilution, for a total of 8 concentration gradients. The 96-well plate was sealed with sealing film and incubated on a shaker at room temperature for 1 hour. Simultaneously, the GF / C filter plate was soaked in soaking buffer (0.3% PEI, stored at 4°C) for at least 0.5 hours. After binding incubation, cells were collected onto the GF / C filter plate using a cell collector and washed 4 times with wash buffer (50 mM Tris-HCl, pH 7.4, stored at 4°C). After drying in a 50℃ oven for 1 hour, the bottom of the dried GF / C filter plate was sealed. Residual radioactivity of the filter membrane was detected using liquid scintillation counting. 50 μL of scintillation liquid was added to each well, and the plate was sealed. Readings were performed using a Microbeta 2. The test sample pair was calculated. 3 H-flunitrazepam and GABA AThe inhibitory activity against receptor membrane protein binding was determined by calculating the IC50 of each test sample using dose-response curve fitting (GraphPad Prism 5 software). 50 and through IC 50 Calculate the K of the sample i To evaluate the sample's relationship with GABA A The binding capacity of each receptor subtype.

[1096] The above measurements were used to express human GABA. A Representative results obtained by the HEK293 cell binding affinity assay for the receptor are shown in the table below.

[1097] Table 1 shows the effects of compounds on α5-GABA. A Receptor affinity activity

[1098] As can be seen from Table 1, the compound described in this invention will 3 H-flunitrazepam is derived from human α5-GABA. A K replaced by the receptor i Values ​​of 100 nM and below indicate that the compounds of this invention are effective against α5-GABA. A The receptor has good affinity. In a preferred embodiment, the compound will... 3 H-flunitrazepam is derived from human α5-GABA. A K replaced by the receptor i <10 nM indicates that the compound α5-GABA of the present invention A The subunit has a strong affinity.

[1099] II. The effect of the compounds of this invention on α5-GABA A Reverse agonistic activity of receptors

[1100] The inventors used an electrophysiological method to detect the effect of the test drug on α5-GABA. A The reverse activation efficiency of the receptor. The specific method is as follows:

[1101] Will GABA A Different subunits of the receptor were simultaneously expressed in the HEK293 cell line to construct a fully functional GABAergic receptor. A The receptor, consisting of the α, β, and γ subunits, forms a complete functional GABAergic receptor. AThe receptor is essential. In this embodiment, the present invention established the following cell model: the α5 subunit (protein sequence see GenBank accession number: NM_000810.3), β3 subunit (protein sequence see GenBank accession number: NM_000814.5), and γ2 subunit (protein sequence see GenBank accession number: NM_000816.3) were simultaneously expressed in the HEK293 cell line, and a single-clonal stable cell line was screened. This cell line expresses α5-GABA with full function. A Receptors.

[1102] Expressing α5-GABA A The recipient's HEK293 cell monoclonal stable transgenic line was cultured on 10cm culture dishes and passaged when the cells reached 80%-90% confluence. During passage, the culture medium was first aspirated, and then 3mL of DPBS (Gibberellin) was added. TM Add the contents to a culture dish, gently shake the dish, and then aspirate the DPBS. Add 1 mL of TrypLE Express trypsin and Gibco. TM Digest at 37°C for 1-2 minutes. Then add 3 mL of complete culture medium (DMEM + 10% FBS (Gibco)). TM Disperse the cells from the bottom of the culture dish and transfer them to a 15mL centrifuge tube (Corning). Centrifuge at 200g for 3 minutes. Discard the supernatant, add 4mL of complete culture medium, and gently pipette to resuspend the cells. For cell passage, dilute the cell suspension at a ratio of 1:5 or 1:10. For preparing cells for electrophysiological assays, dilute the cell suspension at a ratio of 1:12 and add it to a 24-well dish (Corning) containing a slide pre-treated with Poly-D-Lysine. TM After the cells have adhered to the culture vessel, experiments can be performed. The cell culture time for electrophysiological purposes should not exceed 48 hours.

[1103] Drug concentration settings: The final concentration of all drugs used for drug screening was 100 nM, and the GABA concentration was 0.05 μM. Electrophysiological experiments were performed using the whole-cell patch-clamp technique, which can be referenced from the literature (I. Lecker, Y. Yin, D.S. Wang and BA Orser, British Journal of Anaesthesia, 2013, 110(S1), i73-i81). The extracellular fluid composition for electrophysiology was as follows: 150 mM NaCl, 5 mM KCl, 2.5 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 10 mM glucose (pH 7.4); the electrode internal fluid composition was as follows: 140 mM CsCl, 11 mM EGTA, 10 mM HEPES, 2 mM CaCl2, 1 mM MgCl2, 4 mM MgATP, and 2 mM TEA (pH 7.3). Signal acquisition was performed using an EPC 10 amplifier and PatchMaster software (HEKA) or an Axon 700B amplifier and Clampex software (AXON). Recording electrodes were made of borosilicate glass with an electrode resistance of 4–6 MΩ. Extracellular drug delivery was performed using ALA-VC-8PG. TM System. During recording, a single, independently growing cell was selected. The cell membrane potential was clamped at -60 mV during recording. In the experiment, extracellular fluid was first applied for approximately 20 seconds. After the baseline stabilized, the extracellular fluid was switched to GABA. At this point, a current induced by GABA could be detected. After approximately 20–40 seconds, once the current stabilized, the extracellular fluid was switched to the appropriate drug solution to detect the drug's effect. Finally, the solution was switched back to extracellular fluid, and the experiment was terminated once the baseline returned to the pre-drug level. Only data with a baseline less than -120 pA and recoverable after drug administration were used for subsequent analysis. GABA was diluted in the extracellular fluid to a final concentration of 0.05 μM. Then, the drug was diluted in the GABA-containing extracellular fluid to the desired concentration.

[1104] The experimental results were analyzed using PatchMaster software. During the analysis, the leakage current (Ileakage) was measured. leak ), GABA current before drug administration (I) pre ) and GABA current (I) after drug administration post The drug effect is calculated using the following formula: Reverse agonist efficiency (%) = 100 - 100 * (I post -I leak ) / (I pre -I leak ).

[1105] The results of the compound screening:

[1106] Table 2: Effects of compounds on α5-GABA A Reverse agonistic activity of receptors

[1107] As can be seen from Table 2, the compounds described in this invention have strong α5-GABA content. A Reverse agonistic activity of the receptor; in a preferred embodiment, the compound of the present invention is agonistic to α5-GABA. A The receptor's reverse agonistic efficiency is below -60%, even below -80%; compared to the compound reported in patent WO2015115673, the compound of this invention exhibits stronger α5-GABA. A Reverse agonistic activity of the receptor. Furthermore, compared to previously reported compounds, such as α5IA, MRK-016, or RG1662, which are in clinical trials, the compounds of this invention exhibit reactivity against α5-GABA. A It also has a significant advantage in terms of the reverse agonistic activity of the receptor.

Claims

1. A condensed ring compound, characterized by, The fused ring compound is a compound as shown in formula (I), a cis-trans isomer thereof, an enantiomer thereof, a diastereoisomer thereof, a racemate thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. Z1, Z2and Z3are independently C or N, and only one of Z1, Z2and Z3is N, and the others are C; Z4is CH or N; R1is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, phenyl, 5-6 membered heteroaryl, phenyl C 1-3 alkyl or 5-6 membered heteroaryl C 1-3 alkyl, said C 1-6 one C atom of the alkyl group is optionally replaced with an O atom; said C 3-6 one C atom of the ring of the cycloalkyl group is optionally replaced with an O atom, an N atom or an S atom; said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, phenyl, 5-6 membered heteroaryl, phenyl C 1-3 alkyl and 5-6 membered heteroaryl C 1-3 alkyl is optionally substituted with 1-3 R'; R2is hydrogen, halogen, C 1-6 alkyl, hydroxy or C 1-6 alkoxy; said C 1-6 alkyl and C 1-6 alkoxy is optionally substituted with 1-3 R'; R3is hydrogen, halogen, amino, hydroxyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, or C 3-6 cycloalkyl; said C 1-6 alkyl, C 2-6 alkenyl, and C 3-6 cycloalkyl is optionally substituted with 1-3 R'; X1is O, S, NR9, S(=O)2-, or CR 10 R 11 ; R9is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; said C 1-6 alkyl and C 3-6 cycloalkyl is optionally substituted with 1-3 R' R 10 and R 11 are each independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, or R 10 and R 11 together with C to which they are attached form a C 3-6 cycloalkyl or -C(=O)-; said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and C 3-6 cycloalkyl is optionally substituted with 1-3 R'; R4, R5, R6and R7are each independently selected from hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl; said C 1-6 alkyl and C 3-6 cycloalkyl is optionally substituted with 1-3 R', or R4and R5together with the C to which they are attached form a C 3-6 ring or -C(=O)-, or R6and R7together with the C to which they are attached form a C 3-6 cycloalkyl or -C(=O)-; n is 0 or 1; Ring A is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 5-6 membered heterocycloalkene, or a fused ring formed by ring A1and ring A2, which 6-10 membered aromatic ring, 5-10 membered heteroaromatic ring, 5-6 membered heterocycloalkene, and fused ring are each independently optionally substituted with halo, oxo, or C 1-3 alkyl; ring A1is a phenyl ring or a 5-6 membered heteroaromatic ring, and ring A2is a 5-7 membered monocyclic heterocyclic ring; each R8is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, 4-14 membered heterocycloalkyl, 4-14 membered heterocycloalkenyl, 6-10 membered aryl, -NR 12 R 14 , 5-10 membered heteroaryl, or -C(O)NR 12 R 14 , or two R8on the same carbon atom together form an oxo group; said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, 4-14 membered heterocycloalkyl, 4-14 membered heterocycloalkenyl, and 5-10 membered heteroaryl are each optionally substituted with 1-3 groups selected from hydrogen, halogen, carboxyl, hydroxyl, C 1-3 alkyl, hydroxyl-substituted C 1-3 alkyl, halogen-substituted C 1-3 alkyl, carboxylic acid-substituted C 1- alkyl, -C 1-3 alkyl-N R 12 R 14 , C 1-3 alkoxy, -C 1-3 alkoxy-O-C 1-3 alkyl, -C 1-3 alkoxy-O-C 1-3 alkyl-O-C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted with 1-3 R’, 5-6 membered heteroaryl, 5-6 membered heteroaryl substituted with 1-3 R’, C 1-6 alkoxy, oxo, -N R 12 R 14 , -C(O)-O-C 1-3 alkyl-O-C 1-3 alkyl-O-C 1-3 alkyl, -C(O)NR 12 R 14 , -NR 12 C(O)C 1- alkyl and -NR 12 C(O)C 1-3 alkyl-O-C 1-3 alkyl each R 12 and each R 14 is independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or 5-10 membered heteroaryl, or R 12 and R 14 together with the attached N atom optionally form a 4-7 membered heterocyclyl; said C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl are each optionally substituted with 1-3 R'; each R' is independently hydrogen, hydroxyl, halogen, -CN, oxo, -C(=O)OH, C 1-3 alkyl, -NH-C 1-3 alkyl, -N-(C 1-3 alkyl)2, -S(=O)2-C 1-3 alkyl, -C(=O)NR a R b , -C(=O)-O C 1-3 alkyl or C 1-3 alkoxy; R a and R b are each independently H, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; m is 1, 2, 3, 4 or 5; the heteroatom in the heteroaromatic ring, the heteroaryl group, the heterocycloalkenyl group, the heterocycle and the heterocycloalkyl group is independently one or more of N, O and S, and the number thereof is 1, 2, 3 or 4.

2. The fused ring compound according to claim 1, wherein The formula (I) is any one of the formulas (II) to (VII):

3. The fused ring compound according to claim 1 or 2, wherein which satisfies one or more of the following conditions: (1) R1, R2, R 3、 R4, R5, R6, R7, R8, R9, R 10 and R 11 Among them, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, (2) R1is C 3-6 alkyl and said C 3-6 alkyl C 1-3 alkyl C 3-6 alkyl C 3-6 monocyclic cycloalkyl or C 5-6 bicyclic bridged ring cycloalkyl, which can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[l. l. l]pentyl; (3) R1in the above formula, when the C 3-6 when one C atom in the ring of the cycloalkyl group is replaced by an O atom, N atom or S atom, the C 3-6 when one C atom in the ring of the cycloalkyl group is replaced by an O atom, N atom or S atom, the C (4) In R1, the 5-6 membered heteroaryl group and the -C 1-3 The 5-6-membered heteroaryl group in the alkyl-5-6-membered heteroaryl group is independently a 5-6-membered monocyclic heteroaryl group, with heteroatoms being N and / or O, and the number being 1, 2, 3, or 4, which can be pyridyl, 1H-pyrazolyl, or isoaryl. oxazolyl; (5) R2, R3, R4, R5, R6, R7, R8, R 10 , R 11 and each R' is H, F, Cl, Br, or CH3; (6) R2, R8, R 10 and R 11 Among them, the C 1-6 Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (7) when R4and R5together with the C to which they are attached form a C 3-6 cycloalkane, said C 3-6 cycloalkane is cyclopropane; - (8) in ring A, the 5-10 membered heteroaromatic ring is a 5-6 membered monocyclic heteroaromatic ring or a 9-10 membered bicyclic heteroaromatic ring, and the heteroatom is one, two or three of N, O and S, which can be a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, an imidazo[1,2-b]pyridazine ring, a pyridine ring and an imidazole ring, or a quinoline ring; (9) in ring A1, the 5-6 membered heteroaromatic ring is a 5-6 membered monocyclic heteroaromatic ring, and the heteroatom is one, two or three of N, O and S, and the number thereof is one or two, which can be a pyridine ring, a 1H-pyrazole ring, a thiazole ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring; (10) In ring A2, the 5-7 membered monocyclic heterocycle can be a 5-6 membered monocyclic heterocycle, the heteroatoms being 1, 2, or 3 in number selected from N, O, and S, and the number of heteroatoms being 1 or 2, which can be piperidinyl or morpholinyl, piperazinyl, pyrrolidinyl, or oxazolidinyl; (11) in ring A, the fused ring formed by ring A1and ring A2is a 5-6 membered heteroaromatic ring and a 5-6 membered heterocycle, which can be a pyridine ring and a piperidine ring, a pyridine ring and a morpholine ring, or a 1H-pyrazole ring and a piperidine ring; (12) in each R8, the 4-14 membered heterocycloalkyl group is a 4-6 membered monocyclic heterocycloalkyl group or an 8-10 membered bicyclic heterocycloalkyl group, and the heteroatom is N and / or O, and the number thereof is 1, 2, 3 or 4, which can be an azetidinyl group, an oxetanyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group or a 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl group; (13) each R8, the 4-14 membered heterocycloalkenyl is a 4-6 membered monocyclic heterocycloalkenyl, an 8-10 membered bicyclic heterocycloalkenyl, or a 12-14 membered 3, 4, or 5 ring heterocycloalkenyl, containing 1 or 2 double bonds, with heteroatoms being N and / or O, in a number of 1, 2, 3, or 4, which can be 1,2-dihydropyridinyl, 1,6-dihydropyrimidinyl, or 1,3,4,6-tetrahydro-2H-pyrido[l,2-a]pyrazinyl, or (14) in each R8, the 6-10 membered aryl group is a phenyl group; and, (15) in each R8, the 5-10 membered heteroaryl is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl, the heteroatoms are 1, 2 or 3 of N, O and S, the number is 1, 2, 3 or 4, and it can be imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, isothiazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazinyl, tetrazinyl, or the like, and oxazolyl, 1,3,4- oxadiazole, pyridyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole, 5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepinyl or 5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]thiazine.

4. The fused ring compound according to claim 1 or 2, wherein which satisfies one or more of the following conditions: (1) R1is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl-, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 alkyl- or 5-6 membered heteroaryl C 1-3 alkyl-, said C 1-6 one C atom of said alkyl is optionally replaced with an O atom; said C 3-6 one C atom of the ring of said cycloalkyl is optionally replaced with an O atom, N atom or S atom; said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl-, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 alkyl and 5-6 membered heteroaryl C 1-3 alkyl is optionally substituted with 1-3 R'; R' is hydroxy, halogen, -CN, oxo, C 1-3 alkyl, -NH-C 1-3 alkyl, -NH-(C 1-3 alkyl)2, -S(=O)2-C 1-3 alkyl, -C(=O)NR a R b , -C(=O)-O C 1-3 alkyl or C 1-3 alkoxy; R a and R b are each independently H, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; (2) R2is hydrogen; (3) R3is hydrogen, halogen, amino, hydroxyl, C 1-6 alkyl or C 3-6 cycloalkyl; said C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted with 1-3 R'; each R' is independently hydroxyl, halogen or -CN; (4) R 10 and R 11 are each independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, or R 10 and R 11 together with the carbon to which they are attached form -C(=O)-; said C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted with 1-3 R'; each R' is independently hydroxyl, halogen or -CN; (5) R4, R5, R6and R7are each independently selected from hydrogen, halo, C 1-6 alkyl or C 3-6 cycloalkyl, or R4and R5together with the C to which they are attached form a C 3-6 ring or -C(=O)-, or R6and R7together with the C to which they are attached form a C 3-6 ring or -C(=O)-; said C 1-6 alkyl and C 3-6 cycloalkyl optionally substituted with 1-3 halo; (6) R9is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; said C 1-6 alkyl and C 3-6 cycloalkyl is optionally substituted with 1-3 halogen; (7) m is 1, 2 or 3; (9) For Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are independently N or CR8, and Y 1 , Y 2 , Y 3 and Y 4 are not simultaneously N, Y 5 , Y 6 , Y 7 and Y 8 are not simultaneously N; ring B is a 5-6 membered monocyclic heterocycle or a 5-6 membered monocyclic heteroaromatic ring, and the heteroatom in the 5-6 membered monocyclic heterocycle and the 5-6 membered monocyclic heteroaromatic ring is one or more of N, O and S, and the number thereof is 1, 2 or 3; and, (10) For 5. The fused ring compound according to claim 1 or 2, wherein which satisfies one or more of the following conditions: (1) R1is H, (2) R3is H, F, Cl, NH2, Me, Et, i-Pr, CF3, CHF2, or (3) X1is -O-, -S-, -S(=O)2-, -CH(CH3)-, -C(CH3)2- or -CH(OCH3)-; (4) R4, R5, R6and R7are each independently H, F, CI, Me, Et, i-Pr, CF3, CHF2, -CH2CF3, -CH2CHF2, (5) R9is H, Me, Et, i-Pr, CF3, CHF2, -CH2CF3, -CH2CHF2, or More preferably, R9is Me, i-Pr or (6) each R8is independently H, -CI, oxo, -OCH3, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CHF2, -CH2CF3, -CH2CF2H, -(CH2)20CH3, -(CH2)30CH3, -CN, -CH2CN, -(CH2)2CN, -(CH2)3CN, -NH2COCH3, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CONHCH(CH3)2, (7) Preferably and, (8) For 6. The fused ring compound according to claim 1 or 2, wherein which satisfies one or more of the following conditions: (1) R4, R5, R6and R7are each independently hydrogen or C 1-6 alkyl, or; preferably hydrogen, -CH3or cyclopropane; (2) R 10 and R 11 are each independently hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy; preferably hydrogen, F or -CH3; (3) ring A is selected from phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazyl, pyridopyrimidyl, pyridopyridazyl, imidazopyridazyl, or quinolyl, ring A1is selected from phenyl, pyrazolyl, thiazolyl, pyridyl, pyrimidyl, pyrazyl, or pyridazyl; preferably, ring A is selected from pyridazyl, pyridyl, pyrimidyl, pyrazyl, imidazopyridazyl, or pyridopyrimidyl, ring A1is selected from phenyl or pyridyl, ring A2is selected from morpholino, piperidyl, piperazinyl, pyrrolidinyl, or oxazolidinyl; and, (4) R8is independently selected from the group consisting of H, -F, -Cl, -OH, -Me, -Et, -i-Pr, -CF3, -CHF2, -CH2CF3, -CH2CF2H, -OMe, -(CH2)2OCH3, -(CH2)3OCH3, -CN, -CH2CN, -(CH2)2CN, -(CH2)3CN, -NH2COCH3, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CONHCH(CH3)2, or two R8s attached to the same carbon atom together form an oxo (C=O) group.

7. The fused ring compound according to claim 1, wherein the formula (I) is formula (I-1): Z1, Z2and Z3are independently selected from C or N, and only one of Z1, Z2and Z3is N, and the rest are C; R1is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 alkyl or 5-6 membered heteroaryl C 1-3 alkyl, said C 1-6 one C atom of the alkyl group is optionally replaced with an O atom; said C 3-6 one C atom of the ring of the cycloalkyl group is optionally replaced with an O atom or an S atom; said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 alkyl or 5-6 membered heteroaryl C 1-3 alkyl is optionally substituted with 1-3 R'; R' is independently hydrogen, hydroxyl, halogen or C 1-3 alkyl; R3is hydrogen, halogen, amino, C 1-6 alkyl or C 3-6 cycloalkyl; said C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with 1-3 R'; X1is O or CR 10 R 11 ; R 10 , R 11 are each independently selected from hydrogen, halogen, or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with 1-3 R'; R4, R5, R6, R7are each independently selected from hydrogen or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with 1-3 R'; n is 0 or 1; R1is hydrogen, halogen, -ORa, -N(Ra)2, -CN, -C(O)Ra, -C(O)N(Ra)2, -NRaC(O)Ra, -NRaC(O)ORa, -NRaC(O)N(Ra)2, -NRaS(O)tRa(where t is 1 or 2), -OC(O)Ra, -OC(O)N(Ra)2, -SRa, -S(O)tRa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -P(O)Ra2, -P(O)(ORa)2, -P(O)(N(Ra)2)2, -NO2, -Si(Ra)3, -CHO, -Mo, -C(=NRa)Ra, -C(=NORa)Ra, or -L1-R6; 1-3 alkyl; and each Rais independently hydrogen or C1-6alkyl. R8is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)NR 12 R 14 or two R8on the same carbon atom together form an oxo (C=O) group; said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, 4-14 membered heterocycloalkyl and 5-10 membered heteroaryl are each optionally substituted with 1-3 groups selected from hydrogen, halogen, carboxyl, hydroxyl, C 1-3 alkyl, hydroxyl substituted C 1-3 alkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, oxo, -C(O)NR 12 R 14 and -NR 12 R 14 C(O)C 1-3 alkyl; R 12 and R 14 They are hydrogen and C, respectively. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl or 5-10-membered heteroaryl groups are each optionally substituted with 1-3 R's; or R 12 and R 14 together with the attached N atom optionally form a 4-7 membered heterocyclic ring, which includes 1, 2 or 3 heteroatoms selected from N, O or S as ring atoms, each of which is optionally substituted with 1-3 R'; m is 1, 2 or 3.

8. The fused ring compound according to any one of claims 1 to 2 and 7, wherein The formula (I) is formula (II-A), (III-A), (IV-A) or (V-A): wherein R1is C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 alkyl or 5-6 membered heteroaryl C 1- 3 alkyl, said C 1-6 one C atom of the alkyl group is optionally replaced by an O atom to an alcohol or ether; said C 3-6 one C atom of the ring of the cycloalkyl group is optionally replaced by an O atom; said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 alkyl or 5-6 membered heteroaryl C 1-3 alkyl is optionally substituted by 1-3 R'; R' is independently hydrogen, hydroxyl, halogen or C 1-3 alkyl; R3is hydrogen, halogen, amino or C 1-6 alkyl; X1is O or CR 10 R 11 ; R 10 and R 11 are each independently hydrogen or C 1-6 alkyl; R4, R5, R6and R7are each independently hydrogen or C 1-6 alkyl; ring A is pyridyl, pyrazinyl, pyridimidazolyl or imidazopyridazinyl, ring A1is phenyl or pyridyl, and ring A2is morpholino or piperidyl; R8is independently H, -F, -Cl, -OH, -Me, -Et, -i-Pr, -OMe, -CN, -NH2COCH3, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CONHCH(CH3)2, or two R8s attached to the same carbon atom together form an oxo (C=O) group; n is 0 or 1; m is 1 or 2.

9. The fused ring compound according to any one of claims 1 to 2 and 7 to 8, wherein which satisfies one or more of the following conditions: (1) For and, (2) For either of the following structures:

10. The fused ring compound according to claim 1, wherein in the compound of formula I: Z1, Z2and Z3are independently C or N, and only one of Z1, Z2and Z3is N, and the rest are C; Z4is CH or N; R1is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 alkyl or 5-6 membered heteroaryl C 1-3 alkyl, said C 1-6 one C atom of said alkyl is optionally replaced with an O atom; said C 3-6 one C atom of the ring of said cycloalkyl is optionally replaced with an O atom, or an S atom; said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, phenyl or 5-6 membered heteroaryl, phenyl C 1-3 alkyl or 5-6 membered heteroaryl C 1- 3 alkyl is optionally substituted with 1-3 R'; each R' is independently hydrogen, hydroxyl, halogen or C 1-3 alkyl; R2is hydrogen, halogen, C 1-6 alkyl, hydroxy, C 1-6 alkoxy; said C 1-6 alkyl is optionally substituted with 1-3 R'; R3is hydrogen, halogen, amino, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, or C 3-6 cycloalkyl; said C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl is optionally substituted with 1-3 R'; X1is O, S, NR9or CR 10 R 11 ; R9is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; said C 1-6 alkyl and C 3-6 cycloalkyl is optionally substituted with 1-3 R'; R 10 , R 11 are each independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; said C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted with 1-3 R'; R4, R5, R6, R7are each independently hydrogen, halogen, C 1-6 alkyl or C 3-6 cycloalkyl; said C 1-6 alkyl, C 3-6 cycloalkyl is optionally substituted with 1-3 R'; or R6, R7together form an oxo (C=O) group; n is 0 or 1; Ring A is a 6-10 membered aryl, 5-10 membered heteroaryl, or a fused ring formed by ring A1and ring A2, said ring A1is a phenyl ring or a 5-6 membered heteroaromatic ring including 1, 2, or 3 heteroatoms as ring atoms which are N, O, or S, ring A2is a 5-7 membered monocyclic heterocyclic ring including 1, 2, or 3 heteroatoms as ring atoms which are N, O, or S, said 6-10 membered aryl, 5-10 membered heteroaryl, or fused ring is optionally substituted with halogen, oxo, or C1-6alkyl; 1-3 alkyl substituted; R8is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino; C 3-6 cycloalkyl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl, or -C(O)NR 12 R 14 ; or two R8on the same carbon atom together form an oxo (C=O) group; said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, 4-14 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted with 1-3 groups that are hydrogen, halogen, carboxyl, hydroxyl, C 1-3 alkyl, hydroxyl substituted C 1-3 alkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, oxo, -C(O)NR 12 R 14 and -NR 12 R 14 C(O)C 1-3 alkyl; R 12 and R 14 They are hydrogen and C, respectively. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl or 5-10-membered heteroaryl groups are each optionally substituted with 1-3 R's; or R 12 and R 14 together with the attached N atom optionally form a 4-7 membered heterocyclic ring comprising 1, 2 or 3 heteroatoms which are N, O or S as ring atoms, each of said 4-7 membered heterocyclic ring being optionally substituted with 1-3 R'; m is 1, 2, 3, 4 or 5.

11. The fused ring compound according to claim 1, wherein The condensed ring compound is any one of the following compounds: its enantiomer, its diastereomer, its racemate, its solvate, its hydrate, its pharmaceutically acceptable salt or its prodrug.

12. A pharmaceutical composition, characterized by, which comprises the fused ring compound of any one of claims 1-11.

13. Use of a fused ring compound of any one of claims 1-11 or a pharmaceutical composition of claim 12 in the manufacture of a medicament for modulating an alpha 5-GABA A receptor or treating or preventing a disease associated with an alpha 5-GABA A receptor.

1. A fused ring compound of Formula (I): ###0001### (I) wherein: R1 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, halo heteroaryl, halo heteroalicyclic, halo 14. Use according to claim 13, wherein the compound is ###0002### The α5-GABA A The disease associated with the α5-GABA receptor is one or more of pain, Alzheimer's disease, multi-infarct dementia, and stroke. Preferably, the pain is neuropathic pain, inflammatory pain and cancer pain; More preferably, the pain is one or more of headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, lower extremity pain, muscle and bone pain, vascular pain, gout, arthritic pain, visceral pain, pain caused by infectious diseases, multiple bone pain, pain associated with sickle cell anemia, autoimmune diseases, multiple sclerosis or inflammation, chronic pain caused by injury or surgery, nociceptive pain, painful diabetic neuropathy, trigeminal neuralgia, lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, cancer, chemical injury, toxin, nutritional deficiency, viral or bacterial infection and degenerative joint disease.

15. A compound of formula A: ###0001### A R1, R2, R3, R4, R5, R6, R7, R6, Z1, Z2, Z3, Z4and n are as defined in any one of claims 1-11; R1, R2, R3, R4, R5, R6, R7, R6, Z1, Z2, Z3, Z4and n are as defined in any one of claims 1-11; Preferably, the compound of formula A is

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