Imidazole fused ring compound, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are an imidazole fused ring compound, and a preparation method therefor and the use thereof. The imidazole fused ring compound of the present invention is a compound as represented by 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. The compound of the present invention exhibits a strong inverse agonistic activity against α5-GABAA. Furthermore, the compound of the present invention exhibits high bioavailability and has good prospects in becoming medicine.

Description

Imidazole-based fused-ring compounds, their preparation methods 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 an imidazole-based fused-ring compound, its preparation method, and its applications. 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... A Inverse agonists of the receptor can be used to treat cognitive disorders, particularly Alzheimer's disease. Patent application US20110224278 discloses GABA containing the α5 subunit. AReverse 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 Receptor inverse agonists 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 subunitA 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 made of 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. This invention provides a class of fused-ring compounds, their preparation method, and applications. Compared to previously reported compounds, these compounds exhibit improved inverse agonist activity against α5-GABA. A The receptor has a stronger reverse agonist effect. By modulating the physicochemical properties of the compound, and depending on whether the compound can cross the blood-brain barrier, the compound disclosed in this invention can be used to treat cognitive or pain-related diseases. Summary of the Invention

[0010] This invention provides an imidazole-based fused-ring compound, its preparation method, and its application. The compound of this invention is effective against α5-GABA. A It has strong reverse agonist activity, and furthermore, the compounds of the present invention have good bioavailability and few side effects on the central nervous system.

[0011] This invention provides an imidazole fused-ring compound, which is a compound as shown in Formula I, its cis-trans isomer, its enantiomer, its diastereomer, its racemic mixture, its solvate, its hydrate, or a pharmaceutically acceptable salt thereof.

[0012] Where Z1 is CH or N;

[0013] Z2 is CR 4aOr N;

[0014] Z3 is CR 4b Or N;

[0015] Ring A is a 6-10 aryl, a 5-10 heteroaryl, or a 5-10 heterocyclic alkenyl;

[0016] m is 1, 2, 3, 4 or 5;

[0017] Each R1 group can be independently hydrogen, halogen, cyano, hydroxyl, carboxyl, amino, or C. 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C) 1-6 2. Alkane Or -C(O)NR6R7, or two R1 atoms attached to the same carbon atom together with C to form -C(=O)-; the C 1-6 Alkyl, the C 1-6 Alkoxy, -NH-C 1- 6-Alkane and -NH-(C 1-6 Alkane)2 can be optionally surrounded by one or more R RA replace:

[0018] Each R RA It can be independently a halogen, hydroxyl, or carboxyl group;

[0019] n is 1, 2, 3, 4 or 5;

[0020] Ring B is C 3-14 Cycloalkyl, 3-14-membered heterocycloalkyl, 3-14-membered heterocycloalkenyl, 6-10-membered aryl or 5-10-membered heteroaryl;

[0021] Each R5 group is independently hydrogen, carboxyl, oxo (=O), cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 3-6 Cycloalkyl, 3-14-membered heterocycloalkyl, -O-3-14-membered heterocycloalkyl, C(O)NR8R 9、 -NR 10 R 11、 The C 1-6 Alkyl, the C 1-6 Alkoxy, C 2-6 alkenyl, C 3-6 Cycloalkyl, 3-14-membered heterocycloalkyl and -O-3-14-membered heterocycloalkyl can be independently and optionally surrounded by one or more R RB replace:

[0022] Each R RBIndependently halogen, hydroxyl, carboxyl, amino, -OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkylene-OC 1-6 Alkyl, -OC 2-6 alkenyl, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl) 2, -3-14 membered heterocyclic alkyl, -C 1-6 Alkylene-3-14-membered heterocyclic alkyl, -O-3-14-membered heterocyclic alkyl, -OC 1-6 Alkylene-3-14-membered heterocyclic alkyl, C 3-6 cycloalkyl, -C 1-6 Alkylene-C 3-6 cycloalkyl or -OC 1-6 Alkylene-OC 1-6 Alkylene-C3-6 cycloalkyl, wherein -OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkylene-OC 1-6 Alkyl, -OC 2-6 alkenyl, -NH (C1-6 alkyl), -N (C 1-6 Alkyl) 2, -3-14 membered heterocyclic alkyl, -C 1-6 Alkylene-3-14-membered heterocyclic alkyl, -O-3-14-membered heterocyclic alkyl, -OC 1-6 Alkylene-3-14-membered heterocyclic alkyl, C 3-6 cycloalkyl, -C 1-6 Alkylene-C 3-6 cycloalkyl and -OC 1-6 Alkylene-OC 1-6 Alkylene-C 3-6 The cycloalkyl group may optionally be surrounded by one or more R... RB- 1 replace:

[0023] Each R RB-1 Independently hydroxyl, halogen, C 1-6 Alkyl or -OC 1-6 alkyl;

[0024] R6, R7, R8, R9, R 10 R 11 R 12 R 13 or R 14Independently hydrogen, C 1-6 Alkyl, -OC 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl,

[0025] Alternatively, R6 and R7 together with the N linked to them form 3-14 membered heterocyclic alkyl groups.

[0026] Alternatively, R8 and R9 together with the N linked to them can form 3-14 membered heterocyclic alkyl groups.

[0027] Or, R 10 and R 11 Together with the N linked to it, they form 3-14 membered heterocyclic alkyl groups;

[0028] The C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-6 The cycloalkyl group, the 3-14 membered heterocycloalkyl group, the 6-10 membered aryl group, and the 5-10 membered heteroaryl group may be independently and optionally surrounded by one or more R groups. RC replace;

[0029] Each R RC Independently hydroxyl, halogen, -CN, oxo group, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(=O)-OC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1- 6-alkyl)2、-S(=O)2-C 1-6 Alkyl, -3-14 membered heterocyclic alkyl or -C(=O)NR a R b ;

[0030] R a and R b Independent of H and C 1-6 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic alkyl;

[0031] R2 is -(CH2) Y -R 2a C 3-10 cycloalkyl or phenyl, the C 3-10 The cycloalkyl and phenyl groups are independently, optionally, associated with one or more R groups. RD replace;

[0032] Y is 1, 2, 3, 4, 5, or 6, -(CH2) Y -One or both of -CH2- are optionally selected from -CR 2b R2c -、-C(=O)NH- and -C(=O)NC 1-6 Alkyl-, C 3-6 Cycloalkylene and one or more R RD Replacement C 3-6 One or two substitutions of cycloalkyl groups;

[0033] R 2b and R 2c Independent of H, halogen, C 1-6 Alkyl or with one or more R RD Replacement C 1-6 Alkyl, or R 2b and R 2c Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl;

[0034] R 2a Hydroxyl, carboxyl, CN, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, -3-6 membered heterocyclic alkyl, or with one or more R RD Substituted 3-6-membered heterocyclic alkyl groups;

[0035] Each R RD Independently halogen, cyano, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-S(=O)2-C 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl group or -C(=O)OC 1-6 alkyl;

[0036] R3 is hydrogen, C 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 alkyl;

[0037] R 4a It is hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 3-6 Cycloalkyl or 3-14 membered heterocycloalkyl, wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-6The cycloalkyl group and the 3-14 membered heterocycloalkyl group may be independently and optionally bound by one or more R groups. RE replace;

[0038] Each R RE Independently halogen, hydroxyl, C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 Alkoxy, -OC 1-3 Alkyl-OC 1-3 Alkyl or oxo;

[0039] R 4b For hydrogen, halogen, C 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 alkyl;

[0040] The compound shown in Formula I satisfies conditions 1 and / or 2:

[0041] Condition 1: At least one R1 is -NH-C 1-6 Alkane, -N(C) 1-6 2. Alkane Or -C(O)NR6R7; the -NH-C 1-6 Alkane and -NH-(C 1-6 Alkane)2 can be optionally surrounded by one or more R RA Replace; when R1 is independent as - At least one R5 is C(O)NR8R 9、 -NR 10 R 11 ,

[0042] Condition 2: R2 is -(CH2) Y -R 2a C 3-10 cycloalkyl or phenyl, the C 3-10 The cycloalkyl and phenyl groups are independently, optionally, associated with one or more R groups. RD replace;

[0043] When R2 is -(CH2) Y -R 2a Time; R 2a Hydroxyl, carboxyl, CN, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-S(=O)2-C 1-6 Alkyl, -3-6 membered heterocyclic alkyl, or with one or more R RD Substituted 3-6-membered heterocyclic alkyl groups;

[0044] The heteroatoms in the above-mentioned heteroaryl, heterocyclic alkyl and heterocyclic alkenyl groups are independently selected from 1, 2 or 3 of N, S and O, and the number is 1, 2, 3 or 4.

[0045] In this invention, the definition of the fused ring compound as shown in Formula I can be as follows, and the definitions of any undefined groups can be the same as those defined in any embodiment of this invention.

[0046] In some schemes, the 6-10 aryl group in ring A is phenyl or naphthyl, for example, phenyl.

[0047] In some embodiments, in ring A, the 5-10 membered heteroaryl group is a 5-6 membered monocyclic heteroaryl group, a benzo5-6 membered monocyclic heteroaryl group, a 5-6 membered monocyclic heteroaryl-5-6 membered monocyclic alkyl group, or a 5-6 membered monocyclic heteroaryl-5-6 membered monocyclic heterocyclic group. The heteroatom is selected from N and O and can be pyridinyl, pyrimidinyl, pyridazinyl, benzo[] azole group, benzopyrazole group, pyridopiperidinyl group, pyridomorpholinyl group, pyrido Azolyl, pyridopyrazolyl, pyridoimidazolyl, pyridopyridyl, imidazopyridazinyl, or quinolinyl, such as pyridyl, pyridazinyl, benzo[] azole, pyridopiperidinyl, pyridomorpholinyl, pyrido azole or pyridyl Azolium group.

[0048] In some schemes, in ring A, the 5-10 membered heterocyclic alkenyl group is a 5-6 membered monocyclic heterocyclic alkenyl group containing one or two double bonds, the heteroatom is N, the number is one or two, and it can be 2H-pyridyl.

[0049] In some schemes, each R1, R 4a R 4b R 2b R 2c R 4a R 4b Each R5, each R RA Each R RB Each R RB-1 Each R RC Each R RD and each R RE In this context, the halogen is F, Cl, or Br.

[0050] In some schemes, each R1, R 2b R 2c R3, R 4a R 4b R5, R6, R7, R8, R9, R 10 R 11Each R RC R a R b Each R RE In, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0051] In some schemes, R1, R3, and R... 2b R 2c R 4a R 4b R5, R6, R7, R8, R9, R 10 R 11 Each R RC R RD and each R RE In, the C 1-6 The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0052] In some schemes, in each R1, the -NH-C 1-6 C in alkane 1-6 Alkyl groups and the -N(C) 1-6 C in alkyl)2 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0053] In some schemes, in ring B, the C 3-14 Cycloalkyl group is C 3-6 Monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopenthexyl or cyclohexyl.

[0054] In some embodiments, in ring B, the 3-14 membered heterocyclic alkyl group is a 3-6 membered monocyclic heterocyclic alkyl group or a 9-10 membered bicyclic heterocyclic alkyl group, and the heteroatom is selected from N and O, and the number is 1, 2 or 3, and can be oxetane, imidazoalkyl, morpholinyl, piperazine, or octahydropyrazino[2,1-c][1,4]. Azine group.

[0055] In some schemes, in ring B, the 3-14 membered heterocyclic alkenyl group is a 5-6 membered monocyclic heterocyclic alkenyl group containing one or two double bonds, the heteroatom being selected from N and O, the number being one or two, and it can be 1,2-dihydropyrimidinyl or 2,3-dihydropyridinyl.

[0056] In some schemes, the 6-10 aryl group in ring B is phenyl or naphthyl.

[0057] In some embodiments, the 5-10 membered heteroaryl group in ring B is a 5-6 membered monocyclic heteroaryl, a 5-6 membered monocyclic heteroaryl-5-6 membered monocyclic heteroaryl, or a 5-6 membered monocyclic heteroaryl-5-6 membered monocyclic heteroaryl, wherein the heteroatom is selected from N and O, and may be pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazolyl, or pyridinyl-1,2,4-triazol ... Azinyl or 1,2,4-triazolylpyrrolidinyl.

[0058] In some schemes, each R 4a R5, R6, R7, R8, R9, R 10 R 11 R a and R b In, the C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0059] In some schemes, in each R5, the 3-14 membered heterocyclic alkyl group and the -O-3-14 membered heterocyclic alkyl group are 3-6 membered monocyclic heterocyclic alkyl groups, and the heteroatoms are selected from N and O, and the number is 1 or 2, which can be oxocyclic butyl or oxocyclic pentyl.

[0060] In some schemes, in each R5, the C 2-6 The alkenyl group is C 2-4 Alkenyl, which can be vinyl.

[0061] In some schemes, each R RB In, the -NH(C) 1-6 C in alkyl) 1-6 Alkyl group, the -NH(C) 1-6 C in alkyl)2 1-6 Alkyl, -OC 1-6 C in alkyl 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 C in alkyl 1-6 Alkyl and -OC 1-6 Alkylene-OC 1-6 Alkylene-OC 1-6 C in alkyl 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0062] In some schemes, each R RB In the context, the -OC 1-6 Alkylene-OC 1-6 C in alkyl 1-6 Alkylene, -OC 1-6 Alkylene-OC 1-6 Alkylene-OC1-6 C in alkyl 1-6 Alkylene, -C(O)-C 1-6 C in alkylene 3-14 membered heterocyclic alkyl groups 1-6 Alkylene, -OC 1-6 C in alkylene-3-14-membered heterocyclic alkyl 1-6 Alkylene and -OC 1-6 Alkylene-OC 1-6 Alkylene-C 3-6 C in cycloalkyl 1-6 The alkylene group is independently methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, or tert-butylene.

[0063] In some schemes, each R RB In the context, the 3-14 membered heterocyclic alkyl group, -C 1-6 3-14-membered heterocyclic alkyl groups in alkylene-3-14-membered heterocyclic alkyl groups, 3-14-membered heterocyclic alkyl groups in -O-3-14-membered heterocyclic alkyl groups, and -OC 1-6 The 3-14-membered heterocyclic alkyl group in the alkylene-3-14-membered heterocyclic alkyl group is independently a 4-6-membered monocyclic heterocyclic alkyl group or a 7-10-membered bridged heterocyclic alkyl group. The heteroatoms are selected from N and O, and the number is 1 or 2. They can be oxobutane, dioxopranyl, pyrrolidinyl, piperazine, morpholinyl or 2-oxabicyclo[2.2.1]heptyl.

[0064] In some schemes, each R RB In, the C 3-6 cycloalkyl, the -C 1-6 Alkylene-C 3-6 C in cycloalkyl 3-6 cycloalkyl groups and the -OC 1-6 Alkylene-OC 1-6 Alkylene-C 3-6 C in cycloalkyl 3-6 C in cycloalkyl 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclobutyl.

[0065] In some schemes, each R RB-1 In the context, the -OC 1-6 C in alkyl 1-6 C in alkyl 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0066] In some schemes, R6, R7, R8, R9, and R... 10 R 11 R RB-1 R RD RRE R RE-1 R a and R b In this context, the 3-14 membered heterocyclic alkyl group is a 4-6 membered monocyclic heterocyclic alkyl group or a 7-10 membered bridged heterocyclic alkyl group, and the heteroatom is selected from N and O, and the number is 1 or 2, which can be oxocyclic butyl, azacyclic butyl, pyrrolidinyl, piperazine, morpholinyl or 2-oxabicyclo[2.2.1]heptyl.

[0067] In some schemes, each R RE R6, R7, R8, R9, R 10 R 11 and R 4a In this context, the 6-10 aryl group is phenyl or naphthyl.

[0068] In some schemes, each R RE R6, R7, R8, R9, R 10 R 11 and R 4a In this context, the 5-10 membered heteroaryl group is a 5-6 membered monocyclic heteroaryl group, and the heteroatom is selected from N and O, and may be 1H-pyrazolyl, iso-pyrazolyl, etc. Azolylpyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl.

[0069] In some schemes, each R RC In the context, -C(=O)O(C) 1-6 C in alkyl) 1-6 Alkyl group, the -NH-C 1-6 C in alkyl 1-6 C in alkyl 1-6 Alkyl, the -N(C) 1-6 C in alkyl)2 1-6 Alkyl groups and the -S(=O)2-C 1-6 C in alkyl 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0070] In some schemes, in R2, the C 3-10 Cycloalkyl group is C 3-6 Monocyclic cycloalkyl or C 4-6 Bicyclic bridged cycloalkyl, which may be cyclopropyl, cyclobutyl or bicyclic [1.1.1]pentyl.

[0071] In some schemes, in R2, when -(CH2) Y -One or both of -CH2- are optionally selected from -CR 2b R 2c -、-C(=O)NH- and -C(=O)NC 1-6 Alkyl-, C3-6 Cycloalkylene and one or more R RD Replacement C 3-6 When one or both of the cyclohexene alkyl groups are replaced, the C 3-6 Cycloalkylene and the one or more R RD Replacement C 3-6 C in cycloalkylene 3-6 The cycloalkyl group is independently cyclobutylene or bicyclo[1.1.1]pentylene.

[0072] In some schemes, R 2b and R 2c In, the C 1-6 Alkyl groups and the one or more R RD Replacement C 1-6 C in alkyl 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0073] In some schemes, R 2a In the context, the -OC 1-6 C in alkyl 1-6 Alkyl group, the -NH-C 1-6 C in alkyl 1-6 Alkyl, the -N(C) 1-6 C in alkyl)2 1-6 Alkyl groups and the -S(=O)2-C 1-6 C in alkyl 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0074] In some schemes, R 2a In this context, the -3-6 membered heterocyclic alkyl group and the group containing one or more R RD The substituted -3-6-membered heterocyclic alkyl group is independently a -5-6-membered monocyclic heterocyclic alkyl group, which can be a pyrrolidinyl group.

[0075] In some schemes, each R RD In, the C 1-6 Alkyl group, the -NH-C 1-6 C in alkyl 1-6 Alkyl, the -N(C) 1-6 C in alkyl)2 1-6 Alkyl group, the -S(=O)2-C 1-6 C in alkyl 1-6 Alkyl groups and the -C(=O)OC 1-6 C in alkyl 1-6The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0076] In some schemes, R 3 In the context, the C substituted with one or more halogens 1-6 C in alkyl 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0077] In some schemes, R 3 In the context, the C substituted with one or more halogens 1-6 Difluoromethyl in alkyl groups.

[0078] In some schemes, R 4a In, the C 3-6 The cycloalkyl group is cyclopropane, cyclobutane, cyclopentane, or cyclobutane.

[0079] In some schemes, R 4a In this context, the 3-14 membered heterocyclic alkyl group is a 3-6 membered monocyclic heterocyclic alkyl group or a 9-10 membered bicyclic heterocyclic alkyl group.

[0080] In some schemes, for Y 1a Y 2a Y 3a Y 4a Y 5a Y 6a Y 7a and Y 8a Independently N or CR1, and Y 1a Y 2a Y 3a and Y 4a Not simultaneously N, Y 5a Y 6a Y 7a and Y 8a Not simultaneously N; ring c 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 is 1, 2 or 3;

[0081] Preferred

[0082] In some schemes, for n is 1 or 0, Y 1b Y 2b Y 3bY 4b Y 5b Y 6b Y 7b and Y 8b Independently N or CR5, and Y 1b Y 2b Y 3b and Y 4b Not simultaneously N, Y 5b Y 6b Y 7b and Y 8b The ring C is not N; it 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.

[0083] Preferred

[0084] In some schemes, R6, R7, R8, R9, R 10 R 11、 R 12 R 13 or R 14 Independently hydrogen, C 1-6 Alkyl, -OC 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl,

[0085] Alternatively, R6 and R7 together with the N linked to them form 3-14 membered heterocyclic alkyl groups.

[0086] Alternatively, R8 and R9 together with the N linked to them can form 3-14 membered heterocyclic alkyl groups.

[0087] Or, R 10 and R 11 Together with the N linked to it, they form 3-14 membered heterocyclic alkyl groups;

[0088] The C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-6 The cycloalkyl group, the 3-14 membered heterocycloalkyl group, the 6-10 membered aryl group, and the 5-10 membered heteroaryl group may be independently and optionally surrounded by one or more R groups. RC Replace; each R RC Independently hydroxyl, halogen or C 1-6 alkyl;

[0089] Preferably, R6, R7, R8, R9, R 10 R11、 R 12 R 13 or R 14 Independently H, CH3, -OCH3,

[0090] In some schemes, each R5 group is independently selected from hydrogen, carboxyl, oxo (=O), amino, -CH3, -OCH3、

[0091] In some schemes, each R1 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.

[0092] Or two R1 atoms attached to the same carbon atom can form an oxo (C=O) group.

[0093] In some schemes, Structural unit is

[0094] In some schemes, R 2b and R 2c Independent of H, halogen, C 1-6 Alkyl groups or C groups substituted with one or more halogens 1-6 Alkyl, or R 2b and R 2c Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl;

[0095] Preferred, R 2b and R 2c It can be represented independently as H, F, -CH3, -CF3, -CHF2, -CH2CF3, or -CH2CF2H.

[0096] In some schemes, -CR 2b R 2c- is -C(CH3)2-, -C(CF3)2-, Or -C(F)2-, * indicates that a spiro loop is formed with carbon at this position.

[0097] In some schemes, -(CH2) Y -R 2a -(CH2) Y - where Y is 1, 2, 3, 4, 5, or 6, -(CH2) Y -Any one CH2-is arbitrarily selected from -CR 2b R 2c -、C 3-6 Cycloalkylene and one or more R RD Replacement C 3-6 A substitution in a cycloalkylene group, or -(CH2). Y -Any two CH2-are randomly selected from -CR 2b R 2c -、-C(=O)NH- and -C(=O)NC 1-6 Alkyl-, C 3-6 Cycloalkylene and one or more R RD Replacement C 3-6 One or two substitutions of cycloalkyl groups;

[0098] -(CH2) Y -R 2a -(CH2) Y -Preferred *End and R 2a connect.

[0099] In some schemes, -(CH2) Y -R 2a for

[0100] In some schemes, R2 is

[0101] In some schemes, R 4a It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 3-6 Cycloalkyl or 3-14 membered heterocycloalkyl, wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-6Cycloalkyl groups, the 3-14 membered heterocycloalkyl groups, can be independently and optionally bound by one or more R groups. RE replace;

[0102] Preferred, R 4a For H, -CN, F, Cl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, Morpholinyl or

[0103] In some schemes, R 4b It is hydrogen or C 1-6 alkyl;

[0104] Preferred, R 4b It can be H or -CH3.

[0105] In some schemes, for

[0106] Preferred, for

[0107] In some schemes, R3 is hydrogen, C 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 alkyl

[0108] Preferably, R3 is H or difluoromethyl.

[0109] In some schemes, Equation I is any one of the general formulas I-AI to IA-AIV:

[0110] In some schemes, Equation I is any one of the general formulas IA-BI to IA-BIV:

[0111] Preferably, in formula I-BIV, -(CH2) Y -OH is

[0112] In some embodiments, the fused-ring compound is any of the following compounds:

[0113] Its cis-trans isomers, its enantiomers, its diastereomers, its racemic mixtures, its solvates, its hydrates, or its pharmaceutically acceptable salts.

[0114] Pharmaceutical Composition

[0115] This invention relates to a pharmaceutical composition comprising (effective amount) an imidazole fused-ring compound as described herein.

[0116] Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0117] Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] In the powder, the carrier is a finely divided solid, which is mixed with finely divided active ingredients.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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 a suspension, solution, or emulsion with an oily or aqueous carrier, 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 a solution, for reconstitution with a suitable carrier, such as sterile, pyrogen-free water, immediately before use.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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; pastils 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] When necessary, compositions suitable for sustained release of active ingredients can be applied.

[0141] 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.

[0142] Preferred compositions include tablets or capsules for oral administration and liquids and continuous infusions for intravenous administration.

[0143] 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.

[0144] This invention also provides a method for preparing α5-GABA using fused-ring compounds or pharmaceutical compositions as described herein. A Application of receptor modulators.

[0145] This invention also provides a fused-ring compound or pharmaceutical composition as described herein for the preparation of a treatment or preventative treatment of α5-GABA. A Use in drugs for receptor-related diseases.

[0146] The relationship with α5-GABA A The receptor-related diseases are preferably one or more of pain, Alzheimer's disease, multi-infarct dementia, and stroke.

[0147] The pain is preferably neuropathic pain, inflammatory pain, and cancer pain. More preferably, the pain is selected from one or more of the following: 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.

[0148] Treatment

[0149] This invention provides a method for preparing α5-GABA. A receptor modulators or those with α5-GABA A Treatment of receptor modulator-related diseases (such as pain, Alzheimer's disease, multi-infarct dementia, and stroke as described above) includes administering to a patient an effective dose of a fused-ring compound or a combination as described herein.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] The "-" at the end of a group indicates that the group is connected to the rest of the molecule through that site. For example, -OC 1-6 Alkyl-3-6-membered heterocyclic alkyl refers to a alkyl group that is attached to the rest of the molecule via an oxygen atom.

[0154] 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.

[0155] 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.

[0156] The compounds of this invention may 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.

[0157] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0158] 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.

[0159] 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.

[0160] Unless otherwise stated, "(D)" or "(+)" indicates right-handed rotation, "(L)" or "(-)" indicates left-handed rotation, and "(DL)" or "(±)" indicates racemic rotation.

[0161] 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

[0162] 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.

[0163] The term "prodrug" usually refers to a compound of general formula (I) that has been functionalized, and whose derivatives can be readily converted into compounds of general formula (I) in vivo.

[0164] 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.

[0165] "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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] Unless otherwise specified, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0174] Unless otherwise specified, the term "alkyl" is used to denote a saturated hydrocarbon group in a straight-chain or branched composition. The C 1-6 Alkyl groups include C1-5 C 1-4 C 1-3 C 1- 2. C 2-6 C 2-4 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.

[0175] The term "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.

[0176] The term "cycloalkyl" refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms; it 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.

[0177] The term "heterocyclic alkyl" itself, or in combination with other terms, refers to a saturated monocyclic, bicyclic, or tricyclic group composed of 3 to 14 ring atoms, wherein the 1st, 2nd, 3rd, and 4th ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. Furthermore, with respect to "heterocyclic alkyl," heteroatoms can occupy the bonding positions between the heterocyclic alkyl group and the rest of the molecule. The 3-14 membered heterocyclic alkyl groups include 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered heterocyclic alkyl groups, which can be monocyclic or fused-ring. The heterocyclic alkyl group is bonded to the rest of the molecule via carbon atoms or heteroatoms. Examples of monocyclic heterocyclic alkyl groups include, but are not limited to, azaheterobutyl, oxacyclobutyl, thioheterobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiophenyl, tetrahydrofuranyl (including tetrahydrofuran-2-yl), piperidinyl, tetrahydropyranyl, tetrahydrothiophenyl, piperazine, morpholinyl, thiomorpholinyl, etc. Examples of bicyclic heterocyclic alkyl groups include, but are not limited to, […].

[0178] 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.

[0179] The terms "6-10-membered aromatic ring" and "6-10-membered aryl" are used interchangeably. The term "6-10-aryl" refers to a monovalent aromatic carbocyclic 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.

[0180] In this invention, the terms "5-10-membered heteroaryl ring" and "5-10-membered heteroaryl" are used interchangeably. The term "5-10-membered heteroaryl" refers to a cyclic group with a conjugated π-electron system composed of 5 to 10 ring atoms, where 1, 2, 3, or 4 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 5-10-membered heteroaryl group can be attached to the rest of the molecule via heteroatoms or carbon atoms, and the heteroaryl group includes 5-10-membered, 5-8-membered, 5-7-membered, 5-6-membered, 5-membered, and 6-membered heteroaryl groups, etc. Examples of the 5-10 membered heteroaryl groups 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 imidazoleyl (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), 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] In this invention, "multiple" can refer to 2, 3, 4, 5 or 6.

[0187] 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.

[0188] 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.).

[0189] 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.

[0190] 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.

[0191] As used in this article, "neuropathic pain" refers to pain caused or triggered by primary damage and dysfunction of the nervous system.

[0192] As used in this article, "inflammatory pain" refers to pain caused by local acute or chronic inflammation stimulating nerves.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] As used in this article, “facial pain” includes, but is not limited to, trigeminal neuralgia, atypical facial pain, facial nerve palsy, and hemifacial spasm.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] As used in this article, “musculoskeletal pain” includes, but is not limited to, myofascial pain, trauma-induced pain, and chronic regional pain syndromes.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] Therefore, the present invention also relates to pharmaceutical compositions comprising compounds as defined above and pharmaceutically acceptable carriers and / or excipients.

[0214] 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.

[0215] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0216] The reagents and raw materials used in this invention are all commercially available.

[0217] The positive and progressive effects of this invention are as follows: the fused-ring compound of this invention has good α5-GABA content. AReceptor inverse agonist activity; furthermore, the fused-ring compounds of the present invention are well absorbed and have a low brain penetration ratio (B / P < 5%). Detailed Implementation

[0218] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0219] Preparation method

[0220] The solvents used in this invention are commercially available. The following abbreviations are used in this invention: ACN represents acetonitrile, Ac2O represents acetic anhydride, Boc2O represents di-tert-butyl dicarbonate, Bpin represents phenazine borate, BINAP represents 2,2-bis-(diphenylphosphino)-1,1-naphthyl, BrettPhos-Pd-G3 represents methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II), Cu(OAc)2 represents copper acetate, and DAST represents diethylaminotriethylamine. Sulfur fluoride, 2,2'-Dipyridine represents 2,2'-bispyridine, DCE represents 1,2-dichloroethane, DCM represents dichloromethane, DIBAL-H represents diisobutylaluminum hydride, DIEA represents diisopropylethylamine, Dioxane represents dioxane, DMA represents N,N-dimethylacetamide, DMAP represents 4-dimethylaminopyridine, DMF represents N,N-dimethylformamide, DMSO represents dimethyl sulfoxide, EA represents ethyl acetate, EDCI represents 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt, EtOH represents ethanol, EtNH2 represents ethylamine, HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, HOAc represents acetic acid, HPLC represents high performance liquid chromatography, LAH represents lithium aluminum hydride, LiHMDS represents lithium hexamethyldisilamide, m-CPBA represents m-chloroperoxybenzoic acid, MeI represents iodomethane, MeMgBr represents methyl magnesium bromide, MeOH represents methanol, NaBH(OAc)3 represents sodium triacetoxyborohydride, NBS represents N-bromosuccinimide NCS represents N-chlorosuccinimide, NMP represents 1-methyl-2-pyrrolidone, PE represents petroleum ether, Pd(dppf)Cl2 represents 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, Pd2(dba)3 represents tris(dibenzylacetone)palladium, Pd(PPh3)4 represents tetra(triphenylphosphine)palladium, PhI(OAc)2 represents iodophenyldiacetic acid, PMBCl represents p-methoxybenzyl chloride, PMBNH2 represents p-methoxybenzylamine, p-TsCl represents p-toluenesulfonyl chloride, p-TsOH represents p-toluenesulfonic acid, and pyr.Ruphos represents pyridine, Ruphos represents 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, Ruphos-Pd-G4 represents (methanesulfonic acid (2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II), TBAN represents tetrabutylammonium nitrate, t-BuOH represents tert-butanol, and t-BuXPhos represents 2-di-tert-butylphosphine-2',4'- 6'-Triisopropylbiphenyl, TEA represents triethylamine, TFA represents trifluoroacetic acid, THF represents tetrahydrofuran, TLC represents thin-layer chromatography, Tol. represents toluene, Ts represents p-toluenesulfonyl, XantPhos represents 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, XPhos represents 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, LCMS represents liquid chromatography-mass spectrometry, h represents hours, and min represents minutes.

[0221] Synthesis of intermediates:

[0222] Synthesis of intermediate A1:

[0223] Step 1: 6-Chloro-N-(cyclopropylmethyl)-3-nitropyridine-2-amine (A1-2)

[0224] A1-1 (2 g, 10.36 mmol) and cyclopropylmethylamine (1.47 g, 20.72 mmol) were dissolved in ACN (40 mL), and potassium carbonate (4.30 g, 31.08 mmol) was added. The mixture was reacted at 40 °C for 16 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (PE:EA = 1:0 to 5:1) to give the title product (2.1 g, yellow solid).

[0225] MS(ESI)m / z[M+H] + =228.

[0226] Step 2: 5-Chloro-3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridine (A1)

[0227] Al-2 (2.1 g, 5.93 mmol) was dissolved in a mixed solution of methanol (25 mL) and water (8 mL). Iron powder (1.66 g, 29.65 mmol), ammonium chloride (1.57 g, 29.65 mmol), and paraformaldehyde (1.78 g, 59.3 mmol) were added sequentially, and the reaction was carried out at 80 °C for 16 h. The reaction solution was filtered, and the residue was purified by rapid silica gel column chromatography (DCM:MeOH = 1:0 to 10:1) to give the title product (1.1 g, yellow solid).

[0228] MS(ESI)m / z[M+H] + =208.

[0229] Referring to the synthesis method of intermediate A1, the following intermediate was obtained:

[0230] Synthesis of intermediate A13:

[0231] Step 1: 4-Bromo-3-fluoro-2-methyl-6-nitroaniline (A13-2)

[0232] A13-1 (3 g, 17.63 mmol) and NBS (3.45 g, 19.39 mmol) were mixed in ACN (30 mL) and stirred at 90 °C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with saturated brine (60 mL) and extracted with dichloromethane (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude title product (4 g, yellow solid).

[0233] MS(ESI)m / z[M+H] + =249 & 251.

[0234] Step 2: 6-Bromo-5-fluoro-4-methyl-1H-benzo[d]imidazole (A13-3)

[0235] A13-2 (4 g, 16.06 mmol) was dissolved in a mixed solvent of methanol (80 mL) and water (20 mL). Iron powder (8.97 g, 160.6 mmol), ammonium chloride (8.59 g, 160.6 mmol), and paraformaldehyde (14.6 g, 80.3 mmol) were added, and the mixture was stirred overnight at 70 °C. LC-MS showed the reaction was complete. The reaction solution was diluted with saturated brine (100 mL), filtered, and the filtrate was extracted with dichloromethane (150 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under pressure. The residue was purified by rapid silica gel column chromatography (DCM:MeOH = 20:1) to give the title product (3.1 g, yellow solid).

[0236] MS(ESI)m / z[M+H] + =229 & 231.

[0237] Step 3: 6-Bromo-1-(cyclopropylmethyl)-5-fluoro-4-methyl-1H-benzo[d]imidazole (A13)

[0238] A13-3 (500 mg, 2.18 mmol), bromomethylcyclopropane (323.73 mg, 2.40 mmol), and potassium carbonate (0.30 g, 2.18 mmol) were dissolved in DMF (6 mL) and stirred overnight at 30 °C. LC-MS showed product formation. The reaction mixture was diluted with saturated brine (30 mL), extracted with dichloromethane (50 mL x 2), 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 (DCM:MeOH = 20:1) to give the title product (500 mg, yellow oil).

[0239] MS(ESI)m / z[M+H] + =283 & 285.

[0240] The following intermediate was obtained by referring to the synthesis method of intermediate A13:

[0241] Synthesis of intermediate A16:

[0242] Step 1: 6-Chloro-5-(trifluoromethyl)pyridin-2-ol (A16-2)

[0243] A16-1 (25 g, 115.75 mmol) and potassium hydroxide (32.47 g, 578.75 mmol) were dissolved in a mixed solvent of tert-butanol (75 mL) and water (75 mL), and stirred overnight at 110 °C. LC-MS showed product formation. The reaction mixture was cooled to 0 °C, diluted with saturated brine (100 mL), and the pH of the mixture was adjusted to approximately 5 with concentrated hydrochloric acid. Extraction was performed with dichloromethane (200 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude title product (20 g, white solid).

[0244] MS(ESI)m / z[M+H] + =198.

[0245] Step 2: 6-Chloro-3-nitro-5-(trifluoromethyl)pyridin-2-ol (A16-3)

[0246] A16-2 (20 g, 91.06 mmol) was mixed into concentrated sulfuric acid (100 mL), heated to 80 °C, and concentrated nitric acid (16.69 g, 172.12 mmol) was slowly added dropwise while maintaining the temperature at approximately 80 °C–90 °C. The reaction mixture was stirred at 80 °C for 1 h. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (200 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (16 g, yellow solid).

[0247] MS(ESI)m / z[M+H] + =243.

[0248] Step 3: 2,6-Dichloro-3-nitro-5-(trifluoromethyl)pyridine (A16-4)

[0249] A16-3 (16 g, 62.23 mmol) and quinoline (16.65 g, 120.46 mmol) were dissolved in phosphorus oxychloride (50 mL) and stirred at 105 °C for 2 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with water (100 mL). The pH was adjusted to approximately 8 with saturated sodium bicarbonate solution, and the solution was extracted with dichloromethane (200 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product (10 g, yellow solid).

[0250] Step 4: 1-((6-chloro-3-nitro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-methylprop-2-ol (A16-5)

[0251] A16-4 (5.3 g, 20.31 mmol) and 1-amino-2-methyl-2-propanol (1.81 g, 20.31 mmol) were dissolved in ACN (60 mL), and potassium carbonate (8.42 g, 60.93 mmol) was added. The reaction mixture was stirred at 20 °C for 1 h. LC-MS showed product formation. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (PE:EA = 2:1) to give the title product (5.3 g, yellow solid).

[0252] MS(ESI)m / z[M+H] + =314.

[0253] Step 5: 1-((3-amino-6-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)-2-methylprop-2-ol (A16-6)

[0254] A16-5 (4 g, 12.75 mmol) was added to a mixed solution of methanol (60 mL) and water (20 mL), followed by the addition of iron powder (3.56 g, 63.75 mmol) and ammonium chloride (3.41 g, 63.75 mmol). The reaction mixture was stirred at 50 °C for 3 h. The reaction was monitored by LCMS to indicate completion. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (2.5 g, black solid).

[0255] MS(ESI)m / z[M+H] + =284.

[0256] Step 6: 1-(5-chloro-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (A16-7)

[0257] A16-6 (2.5 g, 8.81 mmol) and p-toluenesulfonic acid monohydrate (0.15 g, 0.88 mmol) were added to trimethyl orthoformate (30 mL), and the reaction mixture was stirred at 50 °C for 16 h. The reaction was monitored by LCMS to indicate completion. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the product (2 g, yellow solid).

[0258] MS(ESI)m / z[M+H] + =294.

[0259] Step 7: 1-(5-((4-methoxybenzyl)amino)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (A16-8)

[0260] A16-7 (800 mg, 2.72 mmol), PMB-NH2 (373.1 mg, 2.72 mmol), Pd2(dba)3 (156.4 mg, 0.27 mmol), XantPhos (129.67 mg, 0.27 mmol), and cesium carbonate (1.77 g, 5.44 mmol) were added sequentially to 1,4-Dioxane (20 mL), purged with argon, and stirred at 100 °C for 2 h. The reaction was monitored by LCMS to indicate completion. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to obtain the product (600 mg, yellow solid).

[0261] MS(ESI)m / z[M+H] + =395.

[0262] Step 8: 1-(5-amino-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (A16)

[0263] A16-8 (600 mg, 1.52 mmol) and anisole (821.86 mg, 7.6 mmol) were added to DCM (5 mL), and TFA (5 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 h. LC-MS showed product formation. The reaction mixture was quenched in ice water (20 mL), and the pH was adjusted to approximately 8 with sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the title product (300 mg, yellow solid).

[0264] MS(ESI)m / z[M+H] + =275.

[0265] The following examples were obtained by referring to the synthesis method of intermediate A16:

[0266] Synthesis of intermediate A19:

[0267] Step 1: 6-Chloro-3-nitro-5-(trifluoromethyl)pyridine-2-amine (A19-1)

[0268] A16-4 (300 mg, 1.15 mmol) was dissolved in THF (5 mL), and ammonia (2.5 mL, 17.77 mmol, 28–30% aqueous solution) was added at 0 °C. The mixture was slowly heated to room temperature and stirred for 30 min. TLC showed product formation. The reaction solution was diluted with saturated saline (20 mL) and extracted with dichloromethane (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product (230 mg, white solid).

[0269] MS(ESI)m / z[M+H] + =242.

[0270] Step 2: 6-Chloro-5-(trifluoromethyl)pyridine-2,3-diamine (A19-2)

[0271] A19-1 (200 mg, 0.83 mmol) was dissolved in methanol (5 mL), and platinum dioxide (18.85 mg, 0.083 mmol) was added to displace hydrogen gas. The reaction was carried out under a hydrogen atmosphere (hydrogen balloon) at room temperature with stirring for 2 h. LC-MS showed product formation. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title product (150 mg, brown solid).

[0272] MS(ESI)m / z[M+H] + =212.

[0273] Step 3: 5-Chloro-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine (A19-3)

[0274] The title product was obtained by referring to step 6 of the synthesis of intermediate A16.

[0275] MS(ESI)m / z[M+H] + =222.

[0276] Step 4: 2-[(5-chloro-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-1.1,1,3,3,3-hexafluoropropane-2-ol (A19)

[0277] A19-3 (50 mg, 0.23 mmol) and 2,2-bis(trifluoromethyl)ethylene oxide (53 mg, 0.30 mmol) were dissolved in DMF (1 mL) and stirred overnight at 80 °C. LC-MS showed product formation. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (60 mg, yellow solid).

[0278] MS(ESI)m / z[M+H] + =402.

[0279] Synthesis of intermediate A20:

[0280] Step 1: 2,6-Dichloro-3-(difluoromethyl)pyridine (A20-2)

[0281] A20-1 (10 g, 56.82 mmol) was dissolved in DCM (100 mL), cooled to 0 °C, and DAST (27.48 g, 170.46 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h. LC-MS showed product formation. The reaction mixture was quenched with water (100 mL), extracted with dichloromethane (150 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title product (10 g, crude).

[0282] MS(ESI)m / z[M+H] + =198.

[0283] Step 2: 2,6-Dichloro-3-(difluoromethyl)-5-nitropyridine (A20)

[0284] A20-2 (9 g, 45.45 mmol) was mixed into concentrated sulfuric acid (50 mL), cooled to 0 °C, and then fuming nitric acid (90 mL) was slowly added dropwise. The reaction mixture was stirred at 100 °C for 4 h. Product formation was monitored by LCMS. The reaction mixture was quenched in ice water (200 mL), extracted with dichloromethane (200 mL x 2), 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 (PE:EA = 1:0–5:1) to give the title product (8 g, yellow oil).

[0285] Synthesis of intermediate A21:

[0286] Step 1: 3,5-Dichloro-6-(trifluoromethyl)pyridine-2-amine (A21-2)

[0287] In an argon-filled three-necked flask, A21-1 (25 g, 154.22 mmol) and NCS (41.19 g, 308.44 mmol) were dissolved in DMF (100 mL) and stirred at 60 °C for 3 hours. LC-MS showed the reaction was complete. The reaction mixture was poured into 500 mL of water and extracted with EA (200 mL x 2). The organic phases were combined, 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 (DCM:MeOH = 10:1) to give the title product (25 g, white solid).

[0288] MS(ESI)m / z[M+H] + =231.

[0289] Step 2: N-(3,5-dichloro-6-(trifluoromethyl)pyridin-2-yl)-1,1-dimethyl-14-thioaniline (A21-3)

[0290] In an argon-filled three-necked flask, A21-2 (19 g, 82.25 mmol) and dimethyl sulfide (5.62 g, 90.48 mmol) were dissolved in DCM (200 mL). The mixture was cooled to -20 °C, and NCS (12.08 g, 90.48 mmol) was added. After stirring for 2 hours, sodium methoxide (22.2 g, 411.25 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. LC-MS showed that the reaction was complete. The reaction mixture was poured into 500 mL of water and extracted with DCM (300 mL x 2). The organic phases were combined, 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 (DCM:MeOH = 10:1) to give the title product (20 g, white solid).

[0291] MS(ESI)m / z[M+H] + =291.

[0292] Step 3: 3,5-Dichloro-2-nitroso-6-(trifluoromethyl)pyridine (A21-4)

[0293] In an argon-filled three-necked flask, A21-3 (10 g, 34.35 mmol) was dissolved in methanol (100 mL), and m-CPBA (11.86 g, 68.7 mmol) was added in portions. The mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was complete. The reaction mixture was poured into 100 mL of water and extracted with EA (100 mL x 2). The organic phases were combined, 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 (DCM:MeOH = 10:1) to give the title product (5.5 g, pale green solid).

[0294] MS(ESI)m / z[M+H] + =245.

[0295] Step 4: 3,5-Dichloro-2-nitro-6-(trifluoromethyl)pyridine (A21)

[0296] In an argon-filled three-necked flask, A21-4 (3 g, 12.25 mmol) was dissolved in a mixed solvent of acetic acid (30 mL) and nitric acid (7.5 mL), and hydrogen peroxide (22 mL, 30%) was slowly added. The mixture was stirred at 80 °C for 3 hours. TLC analysis of the reaction solution showed that the reaction was complete. The reaction solution was poured into 100 mL of water and extracted with EA (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title product (3.1 g, crude product).

[0297] MS(ESI)m / z[M+H] + =261.

[0298] Following the method in step 4 of the synthesis of intermediate A16, the following intermediate was obtained:

[0299] Synthesis of intermediate A37:

[0300] Step 1: 1-((6-chloro-5-iodo-3-nitropyridin-2-yl)amino)-2-methylprop-2-ol (A37-2)

[0301] A37-1 (2.5 g, 10.18 mmol) and silver sulfate (3.17 g, 10.18 mmol) were added to ethanol (30 mL), followed by elemental iodine (2.58 g, 10.18 mmol). The reaction mixture was stirred at 20 °C for 1 hour. LC-MS showed product formation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (PE:EA = 2:1) to give the title product (3.5 g, yellow solid).

[0302] MS(ESI)m / z[M+H] + =372.

[0303] Step 2: 1-((6-chloro-5-cyclopropyl-3-nitropyridin-2-yl)amino)-2-methylprop-2-ol (A37)

[0304] A37-2 (1 g, 2.69 mmol), cyclopropylboronic acid (0.23 g, 2.69 mmol), sodium carbonate (0.57 g, 5.38 mmol), and tetrakis(triphenylphosphine)palladium (0.31 g, 0.27 mmol) were added sequentially to a mixture of 1,4-Dioxane (15 mL) and water (5 mL), purged with argon, and stirred at 100 °C for 24 h. Product formation was monitored by LC-MS. The reaction mixture was cooled to room temperature, quenched with water (20 mL), extracted with dichloromethane (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (200 mg, yellow solid).

[0305] MS(ESI)m / z[M+H] + =286.

[0306] Synthesis of intermediate A38:

[0307] Step 1: 2-Chloro-6-((2-hydroxy-2-methylpropyl)amino)-5-nitronitrile (A38)

[0308] A37-2 (3 g, 8.07 mmol) was dissolved in DMA (10 mL), and cuprous cyanide (0.72 g, 8.07 mmol) was added. The reaction mixture was stirred at 100 °C for 24 h. Product formation was monitored by LCMS. The reaction mixture was cooled to room temperature, quenched with water (50 mL), and 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, and the residue was purified by rapid silica gel column chromatography (PE:EA = 2:1) to give the product (1 g, yellow solid).

[0309] MS(ESI)m / z[M+H]+ =271.

[0310] Synthesis of intermediate A39:

[0311] Step 1: 6-Amino-1'-methyl-[3,4'-bipyridine]-2'(1'H)-one (A39)

[0312] A39-1 (2.0 g, 14.50 mmol) and 4-chloro-1-methyl-2-pyridone (2.29 g, 15.95 mmol) were dissolved in a mixed solvent of 1,4-Dioxane (30 mL) and water (6 mL). Pd(dppf)Cl2 (1.06 g, 1.45 mmol) and sodium carbonate (3.07 g, 29 mmol) were added, and the mixture was stirred overnight at 100 °C. LC-MS showed 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 (DCM:MeOH = 20:1) to give the title product (1.1 g, yellow solid).

[0313] MS(ESI)m / z[M+H] + =202.

[0314] Synthesis of intermediate A40:

[0315] Step 1: 3-((2-(benzyloxy)ethoxy)methyl)oxecyclobutane (A40-1)

[0316] A40-1 (3 g, 13.95 mmol) and oxetane-3-methanol (1.84 g, 20.92 mmol) were dissolved in DMF (30 mL). Sodium hydride (1.12 g, 27.9 mmol, purity: 60%) was added under ice bath conditions, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC until completion. The reaction solution was quenched with water (40 mL), extracted with ethyl acetate (40 mL x 3), and the organic phases were combined. The mixture 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 (petroleum ether:ethyl acetate = 2:1) to give the title product (1.9 g colorless oil).

[0317] MS(ESI)m / z[M+H] + =223.

[0318] Step 2: 2-(oxetane-3-ylmethoxy)ethane-1-ol (A40)

[0319] A40-2 (3.3 g, 14.85 mmol) was dissolved in methanol (2 mL), and wet palladium / carbon (158.03 mg, 1.49 mmol, purity: 10%) was added. The mixture was purged three times with hydrogen balloons and stirred at room temperature for 16 hours. The reaction was monitored by TLC until completion. The reaction solution was filtered through a diatomaceous earth filter, and the filter cake was washed with dichloromethane (20 mL x 3). The filtrate was collected and concentrated under reduced pressure to obtain the title product (1.52 g crude product), which was used directly in the next step.

[0320] Synthesis of intermediate A41:

[0321] Under argon protection, tert-butyl (2-hydroxyethyl) (methyl)carbamate (1.75 g, 9.99 mmol) was dissolved in DMF (20 mL). Sodium hydride (0.36 g, 14.98 mmol, purity: 60%) was added at 0 °C and stirred for 30 min. Then, 5-bromo-2-fluoropyridine (1.76 g, 9.99 mmol) was added, and the reaction was stirred at 0 °C for 2 h. The reaction was monitored by LC-MS until complete. The reaction solution was quenched with water (10 mL), and the aqueous phase was extracted with EA (20 mL x 3). The combined organic phases were washed with saturated brine (20 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 (1.8 g, yellow solid).

[0322] MS(ESI)m / z[M+H] + =331&333.

[0323] Synthesis of intermediate A42:

[0324] Step 1: 2-(5-bromopyrimidin-2-yl)prop-2-ol (A41)

[0325] Under ice-water bath conditions, A42-1 (2.4 g, 11.06 mmol) was dissolved in THF (30 mL), and methyl magnesium bromide (5.28 g, 44.24 mmol, 3 M tetrahydrofuran solution) was slowly added dropwise. The reaction was continued at low temperature for 2 hours. TLC showed that the reaction was complete. The reaction solution was quenched in ammonium chloride solution (20 mL), extracted with EA (30 mL × 3), the organic phases were combined, 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 = 1:1) to give the product (0.8 g, yellow solid).

[0326] MS(ESI)m / z[M+H] + =217 & 219.

[0327] Synthesis of intermediate A43:

[0328] Step 1: 4-Bromo-1-cyclopropylpyridine-2(1H)-one (A43)

[0329] Under air conditions, A43-1 (1.74 g, 10 mmol) and cyclopropylboronic acid (0.86 g, 10 mmol) were dissolved in DCE (50 mL), followed by the sequential addition of 2,2'-bispyridine (1.56 g, 10 mmol), copper acetate (1.82 g, 10 mmol), and sodium carbonate (2.12 g, 20 mmol). The reaction was stirred at 70 °C for 1 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with water (30 mL) and extracted with DCM (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 (1.8 g, crude).

[0330] MS(ESI)m / z[M+H] + =214 & 216.

[0331] Synthesis of intermediate A44:

[0332] Step 1: 4-Chloro-1-(2-methoxyethyl)pyridin-2(1H)-one (A44)

[0333] A44-1 (500 mg, 3.86 mmol) and 1-bromo-2-methoxyethane (536.50 mg, 3.86 mmol) were dissolved in ACN (25 mL), and potassium carbonate (1.1 g, 7.72 mmol) was added. The mixture was stirred overnight at 80 °C. LC-MS showed that the reaction was complete. The reaction solution was diluted with saturated brine (50 mL) and extracted with EA (50 mL x 2). The organic phases were combined, 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 (PE:EA = 3:1) to give the title product (300 mg, brown solid).

[0334] MS(ESI)m / z[M+H] + =188.

[0335] Synthesis of intermediate A45:

[0336] 3,6-Dibromopyridazine (2 g, 8.41 mmol), (2-chloropyrimidin-5-yl)boronic acid (1.33 g, 8.41 mmol), Pd(dppf)Cl2 (0.62 g, 0.84 mmol), and sodium carbonate (1.78 g, 16.82 mmol) were added sequentially to a mixed solution of 1,4-Dioxane (30 mL) and water (10 mL). The mixture was purged with argon and stirred at 100 °C for 24 h. Product formation was monitored by LCMS. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (50 mL x 2). The organic phases were combined, 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 (PE:EA = 1:0–3:1) to give the product (1.2 g, yellow solid).

[0337] MS(ESI)m / z[M+H] + =271 & 273.

[0338] Synthesis of intermediate A46:

[0339] Step 1: 4-(2-[(5-bromopyrimidin-2-yl)oxy]ethyl)morpholine (A46-1)

[0340] 5-Bromo-2-chloropyridine (1 g, 5.17 mmol) was dissolved in DMF (10 mL). Sodium hydride (0.31 g, 7.75 mmol, purity: 60%) was added under argon protection in an ice-water bath. The mixture was stirred at 0 °C for 30 min, followed by the addition of 2-morpholine-4-ethanol (0.88 g, 6.72 mmol). The reaction mixture was stirred for 1 hour. LC-MS showed the reaction was complete. Ethyl acetate (80 mL) was slowly added to the reaction mixture, which was washed with saturated brine (3 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title product (900 mg, yellow solid).

[0341] MS(ESI)m / z[M+H] + =288 & 290.

[0342] Step 2: 5-(6-chloropyridin-3-yl)-2-(2-(2-methoxyethoxy)ethoxy]pyrimidine (A46)

[0343] (6-chloropyridin-3-yl)boronic acid (300 mg, 1.91 mmol) was dissolved in 1,4-Dioxane (1 mL) and water (0.25 mL). Under argon protection, A46-1 (342.24 mg, 1.23 mmol), Pd(dppf)Cl2 (1.98 mg, 0.0027 mmol), and sodium carbonate (404.8 mg, 3.82 mmol) were added, and the reaction was stirred at 80 °C for 0.5 h. 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 (DCM:MeOH = 12:1) to give the title product (210 mg, yellow solid).

[0344] MS(ESI)m / z[M+H] + =321.

[0345] The following intermediate was obtained by referring to the synthesis method of the intermediate or A40:

[0346] The following intermediate was obtained by referring to the synthesis method of the intermediate or A46:

[0347] The following intermediate was obtained by referring to the synthesis method of intermediate A39:

[0348] Synthesis of intermediate A78:

[0349] Step 1: 5-(6-chloropyridin-3-yl)pyrimidin-2(1H)-one (A78-1)

[0350] A50 (1.8 g, 8.12 mmol) was added to hydrogen chloride (4 M EA solution, 20 mL) and stirred at 100 °C for 2 h. LC-MS showed product formation. The reaction mixture was quenched in ice water (20 mL), and the pH of the mixture was adjusted to approximately 8 with sodium bicarbonate solution. Extraction was performed with dichloromethane (3 x 30 mL). The organic phases were combined, 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 (DCM:MeOH = 10:1) to give the title product (400 mg, crude).

[0351] MS(ESI)m / z[M+H] + =208.

[0352] Step 2: 5-(6-chloropyridin-3-yl)-1-methylpyrimidin-2(1H)-one (A78)

[0353] A78-1 (400 mg, 1.93 mmol) was dissolved in DMF (20 mL), cooled to 0 °C, and then sodium hydride (93 mg, 3.86 mmol, purity: 60%) and methyl iodide (550 mg, 3.86 mmol) were added. The mixture was stirred at room temperature for 2 h, and LC-MS showed product formation. The reaction solution was quenched in ice water (20 mL), extracted with dichloromethane (3 x 30 mL), 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 (PE:EA = 2:1) to give the product (100 mg, yellow solid).

[0354] MS(ESI)m / z[M+H] + =222.

[0355] Synthesis of intermediate A79:

[0356] Step 1: 3-Cyclopropyl-7-iodo-[1,2,4]triazolo[4,3-a]pyridine (A79)

[0357] In an argon-filled three-necked flask, A79-1 (900 mg, 3.83 mmol) and cyclopropylformaldehyde (268.44 mg, 3.83 mmol) were dissolved in ethanol (10 mL) and stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature, and DCM (25 mL) and iodobenzene acetate (1.48 g, 4.60 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. LC-MS showed the reaction was complete. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (80 mL x 2). 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 (DCM:MeOH = 10:1) to give the title product (500 mg, yellow solid).

[0358] MS(ESI)m / z[M+H] + =286.

[0359] Synthesis of intermediate A80:

[0360] A43-1 (1.0 g, 5.75 mmol) and (2-methoxypyrimidin-5-yl)boronic acid (1.77 g, 11.5 mmol) were dissolved in DCE (30 mL), and copper acetate (0.22 g, 1.15 mmol), pyridine (0.91 g, 11.5 mmol), and 4A molecular sieve (1.0 g) were added. The mixture was stirred overnight at room temperature. LC-MS showed product formation. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL x 2). 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 (DCM:MeOH = 20:1) to give the title product (400 mg, yellow solid).

[0361] MS(ESI)m / z[M+H] + =282.

[0362] Synthesis of intermediates A81 & A82:

[0363] Step 1: 3-Hydroxy-3-methylbutyl-4-methylbenzenesulfonate (A81-2)

[0364] A81-1 (1.0 g, 9.60 mmol) was dissolved in DCM (20 mL), followed by the addition of p-methylsulfonyl chloride (2.20 g, 11.52 mmol) and pyridine (1.52 g, 19.2 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC until completion. The reaction solution was quenched with water (20 mL), and the mixture was separated. The aqueous phase was extracted with DCM (30 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 rapid silica gel column chromatography (ethyl acetate: petroleum ether = 1:5) to give the title product (1.1 g, colorless oil).

[0365] MS(ESI)m / z[M+H] + =259.

[0366] Step 2: 4-(5-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-2-methylbut-2-ol (A81) and 4-(5-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylbut-2-ol (A82)

[0367] A81-3 (300 mg, 1.51 mmol) was dissolved in ACN (5 mL), followed by the addition of A81-2 (468 mg, 1.81 mmol) and potassium carbonate (417 mg, 3.02 mmol). The mixture was stirred at 50 °C for 3 hours. The reaction was monitored by LCMS until completion. The reaction mixture was quenched with water (20 mL), separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give the title products A81 (150 mg, yellow solid) and A82 (150 mg, yellow solid).

[0368] MS(ESI)m / z[M+H] + =284 & 286.

[0369] The following intermediate was obtained by referring to the synthesis method of intermediate A81:

[0370] Synthesis of intermediate A85:

[0371] Step 1: 6-Chlorpyridazine-3-carbazide (A85-2)

[0372] A85-1 (1 g, 5.79 mmol) was added to ethanol (10 mL), the mixture was cooled to 0 °C, and hydrazine hydrate (2.90 g, 57.9 mmol) was added. The reaction mixture was stirred at 0 °C for 2 hours to obtain a white suspension. LCMS 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).

[0373] MS(ESI)m / z[M+H] + =173.

[0374] Step 2: 3-(6-chloropyridazin-3-yl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4] Azine (A85)

[0375] Add A85-2 (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).

[0376] MS(ESI)m / z[M+H] + =238.

[0377] Following the synthesis method of intermediate A85, the following intermediate was obtained:

[0378] Synthesis of intermediate A88:

[0379] Step 1: Synthesis of 6-chloropyridazine-3-carboxaldehyde (A88-2)

[0380] A88-1 (1 g, 5.36 mmol) was dissolved in tetrahydrofuran (15 mL), cooled to 0 °C, and diisobutylaluminum hydride (1.52 g, 10.7 mmol, 1 M toluene solution) was slowly added dropwise. The reaction temperature was gradually raised to room temperature, and the mixture was stirred for 2 hours. The reaction solution 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 product).

[0381] MS(ESI)m / z[M+H] + =143.

[0382] Step 2: Synthesis of 6-chloropyridazine-3-carboxaldehyde oxime (A88-3)

[0383] A88-2 (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).

[0384] MS(ESI)m / z[M+H] + =158.

[0385] Step 3: 3-(6-Chlorpyridazine-3-yl)iso Synthesis of ethyl 5-oxazolium carboxylate (A88)

[0386] A88-3 (400 mg, 2.54 mmol) and ethyl propargyl acid (748 mg, 7.62 mmol) were added to tetrahydrofuran (5 mL), cooled to 0 °C, and sodium hypochlorite solution (3.03 mL, 14% available chlorine) was slowly added dropwise. 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).

[0387] MS(ESI)m / z[M+H] + =254.

[0388] Synthesis of intermediate A89:

[0389] In an argon-filled three-necked flask, A89-1 (1 g, 5.93 mmol) and 3-oxetane (4.27 g, 59.3 mmol) were dissolved in DCE (20 mL), and sodium triacetoxyborohydride (12.57 g, 59.3 mmol) was added. The mixture was stirred at room temperature for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was poured into 100 mL of water and extracted with EA (50 mL x 2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1), and the eluent was collected and concentrated to give the title product (700 mg, yellow solid).

[0390] MS(ESI)m / z[M+H] + =225.

[0391] Synthesis of intermediate A90:

[0392] Step 1: 4-(6-bromopyridazin-3-yl)-1-methylpiperazin-2-one (A90)

[0393] In a screw-top vial, 3,6-dibromopyridazine (3 g, 12.61 mmol) and 1-methylpiperazin-2-one (1.73 g, 15.13 mmol) were dissolved in DMF (30 mL), and cesium carbonate (8.22 g, 25.22 mmol) was added. The vial was sealed and stirred at 70 °C for 3 hours. TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was diluted with EA (100 mL) and water (100 mL), and extracted with EA (100 mL x 2). The organic phases were combined, 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 (DCM:MeOH = 10:1) to give the title product (500 mg, brown solid).

[0394] MS(ESI)m / z[M+H] + =271 & 273.

[0395] Following the synthesis method of intermediate A90, the following intermediate was obtained:

[0396] Synthesis of intermediate A94:

[0397] Step 1: 5-Chloro-3-(ethoxymethyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine (A94)

[0398] A19-3 (200 mg, 0.90 mmol) was added to THF (5 mL), and the mixture was cooled to 0 °C. Sodium hydride (43.2 mg, 1.8 mmol) and bromoethyl ether (85.09 mg, 0.90 mmol) were then added. The reaction mixture was stirred at 0 °C for 1 h. LC-MS monitoring showed product formation. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (30 mL x 2). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (PE:EA = 2:1) to give the title product (80 mg, yellow solid).

[0399] MS(ESI)m / z[M+H] + =280.

[0400] The following intermediate was obtained by referring to the synthesis method of intermediate A39:

[0401] Referring to the synthesis method of intermediate A16-7, the following intermediate was obtained:

[0402] Synthesis of intermediate A101:

[0403] Step 1: N-(3-chloro-4-(trifluoromethoxy)phenyl)acetamide (A101-2)

[0404] In an argon-filled three-necked flask, A101-1 (25 g, 118.16 mmol) was dissolved in DCM (200 mL), followed by the addition of acetic anhydride (14.48 g, 141.79 mmol) and TEA (23.91 g, 236.32 mmol). The mixture 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 (DCM:MeOH = 10:1) to give the title product (29 g, white solid).

[0405] MS(ESI)m / z[M+H] +=254.

[0406] Step 2: N-(5-chloro-2-nitro-4-(trifluoromethoxy)phenyl)acetamide (A101-3)

[0407] In a three-necked flask filled with argon gas, A101-2 (10 g, 39.43 mmol) was dissolved in a mixed solvent of concentrated sulfuric acid (1.93 g, 19.71 mmol) and acetic acid (8 mL). Acetic anhydride (15 mL) was added, the mixture was cooled to 0 °C, and concentrated nitric acid (2.98 g, 47.32 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction solution was poured into water (50 mL), and a large amount of solid was formed. The solid was filtered to obtain the crude product (12 g, yellow solid).

[0408] MS(ESI)m / z[M+H] + =299.

[0409] Step 3: 6-Chloro-5-(trifluoromethoxy)-1H-benzo[d]imidazole (A101-4)

[0410] In a three-necked flask filled with argon gas, A101-3 (14 g, 46.89 mmol) was dissolved in a mixed solvent of methanol (40 mL) and water (10 mL), and sodium hydroxide (2.25 g, 56.27 mmol) was added. The mixture was stirred at room temperature for 3 hours. LC-MS showed that the reaction was complete. 100 mL of water was added to the reaction solution, resulting in the formation of a large amount of solid. The solid was filtered to obtain the crude product (5 g, yellow solid).

[0411] MS(ESI)m / z[M+H] + =257.

[0412] Step 4: 5-Chloro-2-nitro-4-(trifluoromethoxy)aniline (A101-5)

[0413] In an argon-filled three-necked flask, A101-4 (4.2 g, 11.26 mmol) was dissolved in a mixture of methanol (90 mL) and water (30 mL). Iron powder (6.29 g, 112.6 mmol), ammonium chloride (6.02 g, 112.6 mmol), and paraformaldehyde (20.51 g, 112.6 mmol) were added sequentially, and the mixture was stirred at 80 °C for 3 hours. TLC showed 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 (DCM:MeOH = 10:1) to give the title product (1.2 g, white solid).

[0414] MS(ESI)m / z[M+H] + =237.

[0415] Step 5: 1-(6-chloro-5-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)-2-methylprop-2-ol (A101)

[0416] In an argon-filled three-necked flask, A101-5 (0.9 g, 3.20 mmol) was dissolved in DMSO (20 mL), followed by the addition of 1-bromo-2-methyl-2-propanol (0.73 g, 4.80 mmol) and cesium carbonate (2.61 g, 8 mmol). The mixture was stirred overnight at 60 °C. TLC showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was poured into 100 mL of water and extracted with EA (100 mL x 2). 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, and the residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (0.9 g, white solid).

[0417] MS(ESI)m / z[M+H] + =309.

[0418] Synthesis of intermediate A102:

[0419] Step 1: 6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridazin-3-amine (A102)

[0420] A86 (200 mg, 0.75 mmol) and ammonia (0.92 mL, 7.5 mmol, 28% aqueous solution) were dissolved in DMSO (10 mL), and the reaction was stirred at 120 °C for 1 h. LCMS showed that the reaction was complete. Water (30 mL) was added to the reaction solution, and the product precipitated. The reaction solution was filtered to give the title product (0.1 g, yellow solid).

[0421] MS(ESI)m / z[M+H] + =203.

[0422] Intermediate A103 was obtained by referring to the synthesis method of intermediate A102:

[0423] Synthesis of intermediate A104:

[0424] Step 1: 5-Chloro-3-(2-hydroxy-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-6-ol (A104-2)

[0425] In a screw-top vial, A104-1 (1 g, 3.28 mmol), potassium hydroxide (0.92 g, 16.4 mmol), Pd2(dba)3 (0.30 g, 0.33 mmol), and tBuXPhos (0.14 g, 0.33 mmol) were added to 1,4-Dioxane (20 mL) and water (5 mL). The vial was purged with argon, sealed, and stirred at 100 °C for 3 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to approximately 7 with 6N dilute hydrochloric acid. The reaction solution was then concentrated. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1), and the eluent was collected and concentrated to obtain the title product (1 g, crude product).

[0426] MS(ESI)m / z[M+H] + =242.

[0427] Step 2: 1-(5-chloro-6-(difluoromethoxy)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (A104)

[0428] In an argon-filled three-necked flask, A104-2 (400 mg, 1.66 mmol), sodium 2-chloro-2,2-difluoroacetate (380 mg, 2.49 mmol), and cesium carbonate (81 mg, 2.49 mmol) were added to DMF (10 mL), and the mixture was stirred at 80 °C for 3 hours. The reaction mixture was poured into 50 mL of water and extracted with EA (50 mL x 2). The organic phase was 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), and the eluent was collected and concentrated to give the title product (150 mg, yellow solid).

[0429] MS(ESI)m / z[M+H] + =292.

[0430] Synthesis of intermediate A105:

[0431] A104-1 (500 mg, 1.64 mmol), morpholine (142.88 mg, 1.64 mmol), Pd2(dba)3 (94.3 mg, 0.16 mmol), XPhos (78.18 mg, 0.16 mmol), and cesium carbonate (1068 mg, 3.28 mmol) were added sequentially to 1,4-Dioxane (10 mL), purged with argon, and stirred at 100 °C for 16 h. The reaction was monitored by LCMS to indicate completion. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 10:1). The eluent was collected and concentrated to give the title product (200 mg, yellow solid).

[0432] MS(ESI)m / z[M+H] + =311.

[0433] Synthesis of the Implementation Examples

[0434] Example 1: 6-((3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)-N-ethylnicotinamide (1)

[0435] Step 1: 6-((3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)nicotinic acid methyl ester (1-1)

[0436] A1 (500 mg, 2.41 mmol) and methyl 2-chloronicotinic acid (550.02 mg, 3.62 mmol) were dissolved in 1,4-Dioxane (15 mL), and Pd2(dba)3 (0.22 g, 0.24 mmol), XantPhos (0.14 g, 0.24 mmol), and cesium carbonate (1570.45 mg, 4.82 mmol) were added. The mixture was stirred at 130 °C for 5 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with saturated brine (30 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude title product (700 mg, yellow solid).

[0437] MS(ESI)m / z[M+H] + =324.

[0438] Step 2: 6-(((3-(propane)-3H-imidazol[4,5-b]pyridine-5-)ammonium)(1-2)

[0439] Dissolve 1-2 (700 mg, 2.07 mmol) in a mixed solvent of methanol (10 mL), water (10 mL), and THF (10 mL), then add sodium hydroxide (828.00 mg, 20.7 mmol) and stir overnight at room temperature. LCMS showed that the reaction was complete. Adjust the pH of the solution to approximately 4 by adding 3N hydrochloric acid solution. Collect the precipitated solid by filtration, and dry the filter cake under reduced pressure to obtain the title product (500 mg, yellow solid).

[0440] MS(ESI)m / z[M+H] + =310.

[0441] Step 3: 6-((3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)-N-ethylnicotinamide (1)

[0442] Dissolve 1-2 (100 mg, 0.32 mmol), ethylamine hydrochloride (52.19 mg, 0.64 mmol), and HATU (0.15 g, 0.38 mmol) in DMF (5 mL), add DIEA (0.083 g, 0.64 mmol), and stir overnight at room temperature. LCMS showed the reaction was complete. The reaction solution was diluted with saturated saline (10 mL) and extracted with EA (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase C18 column chromatography (ACN / H2O = 0–30%) to give the title product (29.6 mg, white solid).

[0443] 1H NMR (400MHz, DMSO-d6) δ8.72(d,J=2.4,1H),8.40(t,J=5.6Hz,1H),8.28(s,1H),8.22-8.09(m,2H),7.98(d,J=8.8Hz,1H),7.42(d,J= 8.8Hz,1H),4.11(d,J=7.2Hz,2H),3.34-3.23(m,2H),1.44-1.31(m,1H),1.13(t,J=7.2Hz,2H),0.61-0.52(m,2H),0.52-0.43(m,2H).

[0444] MS(ESI)m / z[M+H] + =337.

[0445] Referring to the method described in Example 1, the following example is obtained:

[0446] Example 32: 4-(6-[(3-(bicyclo[1.1.1]pent-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)amino]pyridazin-3-yl)piperazin-2-one (32)

[0447] Step 1: N2-(bicyclo[1.1.1]pentan-1-yl)-N6-(6-chloropyridazin-3-yl)-3-nitropyridine-2,6-diamine (32-2)

[0448] 32-1 (350 mg, 1.59 mmol) and 2-amino-6-chloropyridazine (362.88 mg, 2.39 mmol) were dissolved in 1,4-Dioxane (15 mL), and Pd2(dba)3 (381.86 mg, 0.42 mmol), XantPhos (241.28 mg, 0.42 mmol), and cesium carbonate (2717.34 mg, 8.34 mmol) were added. The mixture was stirred overnight at 100 °C. 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 (PE:EA = 2:1) to give the title product (600 mg, yellow solid).

[0449] MS(ESI)m / z[M+H] + =333.

[0450] Step 2: 3-(bicyclo[1.1.1]pentan-1-yl)-N-(6-chloropyridazin-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine (32-3)

[0451] 32-2 (300 mg, 0.90 mmol), iron powder (502.65 mg, 8.97 mmol), ammonium chloride (481.41 mg, 8.97 mmol), and paraformaldehyde (819.76 mg, 4.49 mmol) were mixed in a mixture of methanol (15 mL) and water (5 mL) and stirred overnight at 70 °C. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature and filtered. The filtrate was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude title product (230 mg, brown solid).

[0452] MS(ESI)m / z[M+H] + =313.

[0453] Step 3: 4-(6-((3-(bicyclo[1.1.1]pent-1-yl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)pyridazin-3-yl)piperazin-2-one (32)

[0454] 32-3 (100 mg, 0.32 mmol) and 2-piperazinone (64.08 mg, 0.64 mmol) were dissolved in NMP (2 mL), and p-toluenesulfonic acid monohydrate (30.44 mg, 0.16 mmol) was added. The mixture was stirred at 180 °C for 2 h under microwave conditions. LCMS showed that the reaction was complete. The reaction solution was purified by reverse-phase C18 column chromatography (ACN / H2O = 0–35%) to give the title product (7.6 mg, white solid).

[0455] 1 H NMR (400MHz, DMSO-d6) δ9.89(s,1H),8.34(d,J=9.8Hz,1H),8.12-8.07(m,2H),7.91(d,J=8.8Hz,1H),7.48(d,J= 9.8Hz,1H),7.16(d,J=8.8Hz,1H),4.03(s,2H),3.75-3.71(m,2H),3.36-3.29(m,2H),2.73(s,1H),2.44(s,6H).

[0456] MS(ESI)m / z[M+H] + =377.

[0457] The following examples were obtained by referring to the synthesis method of Example 32:

[0458] Example 35: 1-(6-((3-(2-methoxy-2-methylpropyl)-6-methyl-3H-imidazo[4,5-b]pyridin-5-yl)amino)pyridazin-3-yl)imidazolidin-2-one (35)

[0459] Steps 1-2: N-(6-chloropyridazin-3-yl)-3-(2-methoxy-2-methylpropyl)-6-methyl-3H-imidazo[4,5-b]pyridine-5-amine (35-3)

[0460] The title product was obtained by referring to steps 1-2 of the synthesis in Example 32.

[0461] MS(ESI)m / z[M+H] + =347.

[0462] Step 3: (6-Chlorpyridazin-3-yl)(3-(2-methoxy-2-methylpropyl)-6-methyl-3H-imidazo[4,5-b]pyridin-5-yl)tert-butyl carbamate (35-4)

[0463] 35-3 (300 mg, 0.87 mmol) and di-tert-butyl dicarbonate (227.85 mg, 1.04 mmol) were dissolved in DCE (1 mL), and DMAP (53.14 mg, 0.43 mmol) was added. The mixture was stirred at room temperature for 4 h. LCMS 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 (PE:EA = 1:1) to give the title product (270 mg, yellow solid).

[0464] MS(ESI)m / z[M+H] + =447.

[0465] Step 4: (3-(2-methoxy-2-methylpropyl)-6-methyl-3H-imidazo[4,5-b]pyridin-5-yl)(6-(2-oxoimidazolidin-1-yl)pyridazin-3-yl)tert-butyl carbamate (35-5)

[0466] The title product is obtained by referring to the method described in step 1 of Example 1.

[0467] MS(ESI)m / z[M+H] + =497.

[0468] Step 5: 1-(6-((3-(2-methoxy-2-methylpropyl)-6-methyl-3H-imidazo[4,5-b]pyridin-5-yl)amino)pyridazin-3-yl)imidazolidin-2-one (35)

[0469] 35-5 (70 mg, 0.14 mmol) was dissolved in DCM (2 mL), and hydrogen chloride (5 mL, 4 M EA solution) was added. The mixture was stirred at room temperature for 13 h. LC-MS showed product formation. The reaction solution was concentrated under reduced pressure, and the residue was adjusted to pH 9 with saturated sodium bicarbonate solution and extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase C18 column chromatography (ACN / MeOH = 0–35%) to give the title product (20 mg, white solid).

[0470] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.40(d,J=9.8Hz,1H),8.18(d,J=9.8Hz,1H),8.01(s,1H),7.86(s,1H) ,7.33(s,1H),4.16(s,2H),4.08(t,J=7.6Hz,2H),3.51-3.46(m,2H),3.18(s,3H),2.41(s,3H),1.09(s,6H).

[0471] MS(ESI)m / z[M+H] + =397.

[0472] Example 36: 6-((3-(2-hydroxy-2-methylpropyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)-1'-methyl-[3,4'-bipyridine]-2'(1'H)-one (36)

[0473] Step 1: 6-((6-((2-hydroxy-2-methylpropyl)amino)-5-nitro-3-(trifluoromethyl)pyridin-2-yl)amino)-1'-methyl-[3,4'-bipyridine]-2'(1'H)-one (36-1)

[0474] The title product is obtained by referring to the method described in step 1 of Example 32.

[0475] Step 2: 6-((3-(2-hydroxy-2-methylpropyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)-1'-methyl-[3,4'-bipyridine]-2'(1'H)-one (36)

[0476] In a screw-top vial, 36-1 (500 mg, 1.05 mmol), iron powder (586.43 mg, 10.5 mmol), ammonium chloride (561.64 mg, 10.5 mmol), and paraformaldehyde (1912.78 mg, 10.5 mmol) were dissolved in a mixture of methanol (15 mL) and water (5 mL). The vial was sealed and stirred overnight at 80 °C. LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (56 mg, white solid).

[0477] 1H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.51(s,1H),8.41(s,2H),8.14(d,J=8.8Hz,1H),7.91(d,J=8.8Hz,1H),7 .78(d,J=6.8Hz,1H),6.75(s,1H),6.65(d,J=6.8Hz,1H),4.93(s,1H),4.19(s,2H),3.46(s,3H),1.15(s,6H).

[0478] MS(ESI)m / z[M+H] + =459.

[0479] The following examples were obtained by referring to the synthesis method of Example 36:

[0480] Example 44: 6-((6-fluoro-3-(2-hydroxy-2-methylpropyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)-1'-methyl-[3,4'-bipyridine]-2'(1'H)-one (44)

[0481] Step 1: 6-((3-fluoro-6-((2-hydroxy-2-methylpropyl)amino)-5-nitropyridin-2-yl)amino)-1'-methyl-[3,4'-bipyridine]-2'(1'H)-one (44-2)

[0482] The title product was obtained by referring to the method described in step 1 of the synthesis in Example 32.

[0483] MS(ESI)m / z[M+H] + =429.

[0484] Step 2: 6-((5-amino-3-fluoro-6-((2-hydroxy-2-methylpropyl)amino)pyridin-2-yl)amino)-1'-methyl-[3,4'-bipyridine]-2'(1'H)-one (44-3)

[0485] 44-2 (400 mg, 0.93 mmol), iron powder (259.70 mg, 4.65 mmol), and ammonium chloride (248.73 mg, 4.65 mmol) were added sequentially to a mixed solution of methanol (30 mL) and water (10 mL), and stirred at 80 °C for 16 h. The reaction was monitored by LCMS to indicate completion. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (300 mg, yellow solid).

[0486] MS(ESI)m / z[M+H] + =399.

[0487] Step 3: 6-((6-fluoro-3-(2-hydroxy-2-methylpropyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)-1'-methyl-[3,4'-bipyridine]-2'(1'H)-one (44)

[0488] 44-3 (140 mg, 0.35 mmol) was dissolved in a mixed solvent of trimethyl orthoformate (3 mL) and DMF (3 mL), and p-toluenesulfonic acid monohydrate (60.27 mg, 0.35 mmol) was added. The reaction mixture was stirred at 90 °C for 2 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (8 mg, white solid).

[0489] 1H NMR (400MHz, DMSO-d6) δ9.40 (s, 1H), 8.63 (s, 1H), 8.21 (s, 1H), 8.12 (d, J = 8.8Hz, 1H), 8.09-8.01 (m, 2H), 7. 76(d,J=7.0Hz,1H),6.74(s,1H),6.66(d,J=7.0Hz,1H),4.91(s,1H),4.15(s,2H),3.44(s,3H),1.13(s,6H).

[0490] MS(ESI)m / z[M+H] + =409.

[0491] The following examples were obtained by referring to the synthesis method of Example 44:

[0492] Example 61: (3-(6-((3-cyclopropyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)pyridazin-3-yl)iso Azol-5-yl)(morpholino)methyl ketone (61)

[0493] Step 1: 3-(6-((6-(cyclopropylamino)-5-nitro-3-methylpyridin-2-yl)amino)pyridazine-3-yl)iso Ethyl 5-oxo-azole (61-2)

[0494] The title product is obtained by referring to the method described in step 1 of Example 32.

[0495] MS(ESI)m / z[M+H] + =426.

[0496] Steps 2-3: 3-(6-((3-cyclopropyl-6-methyl-3H-imidazo[4,5-b]pyridin-5-yl)amino)pyridazin-3-yl)iso Ethyl 5-oxo-azolium carboxylate (61-4)

[0497] The title product was obtained by referring to steps 2-3 of the synthesis in Example 44.

[0498] MS(ESI)m / z[M+H] + =406.

[0499] Steps 4-5: (3-(6-((3-cyclopropyl-6-methyl-3H-imidazo[4,5-b]pyridin-5-yl)amino)pyridazin-3-yl)iso Azol-5-yl)(morpholino)methyl ketone (61)

[0500] The title product is obtained by referring to the method described in steps 3-4 of Example 1.

[0501] MS(ESI)m / z[M+H] + =447.

[0502] Example 62: 1-(5-((5-(2-methoxypyrimidin-5-yl)pyridin-2-yl)amino)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (62)

[0503] In a screw-top vial, A16 (50 mg, 0.18 mmol) and A50 (39.90 mg, 0.18 mmol) were dissolved in 1,4-Dioxane (2 mL). Pd2(dba)3 (16.48 mg, 0.018 mmol), XantPhos (10.42 mg, 0.018 mmol), and cesium carbonate (146.62 mg, 0.45 mmol) were added sequentially. The vial was purged with argon, sealed, and stirred overnight at 100 °C. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (3 mg, white solid).

[0504] 1 H NMR(400MHz,DMSO-d6)δ8.97(s,2H),8.60(s,1H),8.49(s,1H),8.39(s,1H),8.24(s,1H),8.1 4(d,J=8.8Hz,0H),8.02(d,J=8.8Hz,1H),4.92(s,1H),4.18(s,2H),3.97(s,3H),1.14(s,6H).

[0505] MS(ESI)m / z[M+H] + =460.

[0506] The following examples were obtained by referring to the synthesis method of Example 62:

[0507] Example 72: 6-((3-(ethoxymethyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)-1'-methyl-[3,4'-bipyridine]-2'(1'H)-one (72)

[0508] A94 (80 mg, 0.29 mmol) and A39 (88 mg, 0.44 mmol) were dissolved in 1,4-Dioxane (10 mL), and Pd2(dba)3 (16.67 mg, 0.029 mmol), XPhos (138.25 mg, 0.29 mmol), and cesium carbonate (188.98 mg, 0.58 mmol) were added sequentially. The mixture was purged with argon and stirred at 100 °C for 2 h. The reaction was monitored by LCMS to indicate completion. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography to obtain the crude product. The crude product was further purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to obtain the title product (2 mg, white solid).

[0509] 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.62(s,1H),8.54(s,1H),8.44(s,1H),8.13(d,J=8.8Hz,1H),7.94(d,J=8.8Hz,1H),7.7 7(d,J=7.0Hz,1H),6.74(s,1H),6.64(d,J=7.0Hz,1H),5.65(s,2H),3.57(q,J=6.8Hz,2H),3.45(s,3H),1.10(t,J=6.8Hz,3H).

[0510] MS(ESI)m / z[M+H] + =445.

[0511] The following examples were obtained by referring to the synthesis method of Example 72:

[0512] Example 83: 6-((5-fluoro-1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzo[d]imidazol-6-yl)amino)-1'-methyl-[3,4'-bipyridine]-2'(1'H)-one (83)

[0513] The title product was obtained by synthesizing the product according to the method described in Example 62.

[0514] 1H NMR (400MHz, DMSO-d6) δ8.89(s,1H),8.49(s,1H),8.06(s,1H),7.88(d,J=8.8Hz,2H),7.71(d,J=7.6Hz,1H),6.86(d ,J=8.8Hz,1H),6.64(s,1H),6.60(d,J=7.6Hz,1H),4.77(s,1H),4.08(s,2H),3.42(s,3H),2.47(s,3H),1.10(s,6H).

[0515] MS(ESI)m / z[M+H] + =422.

[0516] The following examples were obtained by referring to the synthesis methods of Examples 62 and 83:

[0517] Example 92: 1-(5-((5-(2-(2-methoxyethoxy)ethoxypyrimidin-5-yl)pyridin-2-yl)amino)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (92)

[0518] A16 (50 mg, 0.18 mmol) was dissolved in 1,4-Dioxane (5 mL). Under argon protection, A53 (72.48 mg, 0.23 mmol), cesium carbonate (117.30 mg, 0.36 mmol), RuPhos-Pd-G4 (15.31 mg, 0.018 mmol), and RuPhos (8.40 mg, 0.018 mmol) were added. The reaction was stirred at 100 °C for 2 hours. LC-MS showed 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 (DCM:MeOH = 12:1) to give a crude product. The crude product was further purified by reversed-phase C18 column chromatography (ACN / H2O = 0–20%) to give the title product (47 mg, white solid).

[0519] 1H NMR (400MHz, DMSO-d6) δ8.97(s,2H),8.60(d,J=2.4Hz,1H),8.49(s,1H),8.39(s,1H),8.24(s,1H),8.14(dd,J=8.8,2.4Hz,1H),8.01(d,J=8 .8Hz,1H),4.92(s,1H),4.50-4.43(m,2H),4.17(s,2H),3.81-3.74(m ,2H),3.63-3.56(m,2H),3.50-3.43(m,2H),3.25(s,3H),1.14(s,6H).

[0520] MS(ESI)m / z[M+H] + =548.

[0521] The following examples were obtained by referring to the synthesis method of Example 92:

[0522] Example 125: 2-Methyl-1-(5-[(5-(2-(methylamino)ethoxy)pyrimidin-5-yl)pyridin-2-yl)amino]-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)prop-2-ol (125)

[0523] Step 1: N-(2-[(5-(6-[(3-(2-hydroxy-2-methylpropyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino]pyridin-3-yl)pyrimidin-2-yl)oxy]ethyl)-N-methylcarbamate tert-butyl ester (125-1)

[0524] The title product was obtained by referring to the method described in Example 92.

[0525] MS(ESI)m / z[M+H] + =603.

[0526] Step 2: 2-Methyl-1-(5-[(5-(2-(methylamino)ethoxy)pyrimidin-5-yl)pyridin-2-yl)amino]-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)prop-2-ol (125)

[0527] 125-1 (50 mg, 0.083 mmol) was dissolved in DCM (1 mL), and TFA (1 mL) was added. The reaction was stirred at room temperature for two hours. The reaction was monitored for completeness by LCMS. NaOH solution was slowly added to the reaction solution to adjust the pH to about 8. The mixture was extracted with DCM (3 x 20 mL), the organic phases were combined, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase C18 column chromatography (ACN / H2O = 0–20%) to give the title product (27 mg, white solid).

[0528] 1 H NMR (400MHz, DMSO-d6) δ9.00(s,2H),8.61(s,1H),8.49(s,1H),8.40(s,1H),8.27(s,1H),8.15(dd,J=8.8,2.4Hz,1H ),8.00(d,J=8.8Hz,1H),4.93(s,1H),4.57-4.51(m,2H),4.17(s,2H),3.25-3.20(m,2H),2.54(s,3H),1.14(s,6H).

[0529] MS(ESI)m / z[M+H] + =503.

[0530] Example 126: 1-(2-((5-(2-methoxypyrimidin-5-yl)pyridin-2-yl)amino)-9H-purine-9-yl)-2-methylprop-2-ol (126)

[0531] In a screw-top vial, A112 (80 mg, 0.35 mmol) and A95 (70.77 mg, 0.35 mmol) were dissolved in 1,4-Dioxane (3 mL). Pd2(dba)3 (32.05 mg, 0.035 mmol), BINAP (21.79 mg, 0.035 mmol), and cesium carbonate (285.09 mg, 0.88 mmol) were added sequentially. The vial was purged with argon, sealed, and stirred overnight at 100 °C. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (7 mg, white solid).

[0532] 1H NMR (400MHz, DMSO-d6) δ9.96(s,1H),8.99(s,2H),8.92(s,1H),8.66(d,J=2.4Hz,1H),8.53(d,J=8.8H z,1H),8.22(s,1H),8.17(dd,J=8.8,2.4Hz,1H),4.94(s,1H),4.14(s,2H),3.97(s,3H),1.16(s,6H).

[0533] MS(ESI)m / z[M+H] + =393.

[0534] The following examples were obtained by referring to the synthesis method of Example 126:

[0535] Example 128: 5-(6-((3-(2-hydroxy-2-methylpropyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)pyridin-3-yl)pyrimidin-2(1H)-one (128)

[0536] 0.14 g (0.30 mmol) of 62 was dissolved in 15 mL of DCM, and boron tribromide (0.38 g, 1.5 mmol) was added at -20 °C. The reaction was stirred at room temperature for 2 h. The reaction was monitored by LCMS until complete. The reaction solution was quenched with 30 mL of methanol and concentrated under reduced pressure. The residue was purified by reversed-phase C18 column chromatography (acetonitrile:water = 0–15%) to give the title product (14 mg, white solid).

[0537] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,2H),8.50(s,1H),8.47(s,1H),8.11(s,1H),8.03(s,2H),4.93(s,1H),4.17(s,2H),1.14(s,6H).

[0538] MS(ESI)m / z[M+H] + =446.

[0539] Example 129: 1-(5-[(6-(2-aminopyrimidin-5-yl)pyridazin-3-yl)amino]-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (129)

[0540] Step 1: 1-(5-((6-chloropyridazin-3-yl)amino)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (127-1)

[0541] The title product is obtained by referring to the method described in step 1 of Example 32.

[0542] MS(ESI)m / z[M+H] + =387.

[0543] Step 2: 1-(5-[(6-(2-aminopyrimidin-5-yl)pyridazin-3-yl)amino]-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (129)

[0544] 129-1 (70 mg, 0.18 mmol) and 2-aminopyrimidine-5-boronic acid (25.01 mg, 0.18 mmol) were dissolved in a mixed solvent of 1,4-Dioxane (6 mL) and water (2 mL). Pd(dppf)Cl2 (13.17 mg, 0.018 mmol) and sodium carbonate (38.16 mg, 0.36 mmol) were added sequentially, followed by argon purging and stirring at 100 °C for 24 h. Product formation was monitored by LCMS. The reaction mixture was quenched with water (20 mL), extracted with dichloromethane (20 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the title product (10 mg, white solid).

[0545] 1 H NMR(400MHz,DMSO-d6)δ8.92(s,2H),8.80(s,1H),8.52(s,1H),8.40(s,1H),8.09(d,J= 9.2Hz,1H),8.03(d,J=9.2Hz,1H),7.03(s,2H),4.90(s,1H),4.13(s,2H),1.11(s,6H).

[0546] MS(ESI)m / z[M+H] + =446.

[0547] Example 130: 3-(5-[(5-(2-(2-methoxyethoxy)pyrimidin-5-yl)pyridin-2-yl)amino]-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,2-dimethylprop-1-ol (130)

[0548] A98 (100 mg, 0.30 mmol) was dissolved in 1,4-Dioxane (10 mL). Under argon protection, A77 (96.05 mg, 0.39 mmol), cesium carbonate (195.49 mg, 0.60 mmol), RuPhos-Pd-G4 (25.51 mg, 0.030 mmol), and RuPhos (14.00 mg, 0.030 mmol) were added. The reaction was stirred overnight at 100 °C. The reaction was monitored for completeness by LC-MS. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (DCM:MeOH = 12:1) to obtain the crude product. The crude product was further purified by reversed-phase C18 column chromatography (ACN / H2O = 0–15%) to give the title product (21 mg, white solid).

[0549] 1 H NMR (400MHz, DMSO-d6) δ8.94(s,2H),8.58(d,J=2.4Hz,1H),8.45(s,1H),8.38(s,1H),8.20(s,1H),8.12(dd,J=8.8,2.5Hz,1H),8.06(d, J=8.7Hz,1H),4.90(t,J=5.2Hz,1H),4.48-4.41(m,2H),4.11(s,2H),3.71-3.64(m,2H),3.32(s,3H),3.17(d,J=5.2Hz,2H),0.85(s,6H).

[0550] MS(ESI)m / z[M+H] + =518.

[0551] Example 131: 1-(6-((6-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]) (131)pyridazin-3-yl)amino)-5-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)-2-methylprop-2-ol

[0552] In a screw-top vial, A101 (200 mg, 0.57 mmol) was dissolved in 1,4-Dioxane (15 mL), followed by the addition of A103 (124.39 mg, 0.57 mmol), BrettPhos-Pd-G3 (48.70 mg, 0.057 mmol), and cesium carbonate (464.29 mg, 1.42 mmol). The vial was purged with argon, sealed, and stirred overnight at 100 °C. TLC showed the reaction was complete. The reaction solution was concentrated, and the residue was purified by rapid silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (30 mg, white solid).

[0553] 1 H NMR (400MHz, DMSO-d6) δ9.30(s,1H),8.21(s,1H),8.05(d,J=9.6Hz,1H),8.01(s,1H),7.70(s,1H),7.21(d,J= 9.6Hz,1H),4.94(s,2H),4.77(s,1H),4.41(t,J=5.2Hz,2H),4.13(s,2H),3.99(t,J=5.2Hz,2H),1.08(s,6H).

[0554] MS(ESI)m / z[M+H] + =491.

[0555] Referring to the synthesis method of Example 131, the following examples were obtained:

[0556] Example 133: 2-Methyl-1-(6-((6'-(2-(methylamino)ethoxy)-[3,3'-bipyridine]-6-yl)amino)-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)prop-2-ol (133)

[0557] The title product is obtained by referring to the methods described in steps 1-2 of Example 61 and step 2 of Example 125.

[0558] 1H NMR (400MHz, DMSO-d6) δ8.37(s,2H),8.27(s,2H),8.00(s,1H),7.95(d,J=8.8Hz,1H),7.87(s,1H),7.79-7.71(m,1H),6.88(d,J= 8.8Hz,1H),6.65(d,J=8.8Hz,1H),4.76(s,1H),4.46(t,J=5.2Hz,2H),4.15(s,2H),3.30-3.32(m,2H),2.56(s,3H),1.05(s,6H).

[0559] MS(ESI)m / z[M+H] + =501.

[0560] Example 134: 4-(6-((1-(3-hydroxy-2,2-dimethylpropyl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)amino)pyridin-3-yl)benzoic acid (134)

[0561] The title product was obtained by referring to the synthesis method of Example 130 and the method described in step 2 of Example 1.

[0562] 1H NMR (400MHz, DMSO-d6) δ8.49(s,1H),8.36(d,J=2.4Hz,1H),8.28(s,1H),8.00(s,1H),7.94(d,J=8.2Hz,2H),7.89(s,1H),7.86(dd,J= 8.8, 2.4Hz, 1H), 7.70 (d, J = 8.8Hz, 2H), 6.69 (d, J = 8.8Hz, 1H), 4.90 (t, J = 5.2Hz, 1H), 4.10 (s, 2H), 3.08 (d, J = 5.0Hz, 2H), 0.81 (s, 6H).

[0563] MS(ESI)m / z[M+H] + =485.

[0564] Example 135: 1-(5-((5-(2-aminopyrimidin-5-yl)pyridin-2-yl)amino)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (135)

[0565] Step 1: (5-(6-(((2-hydroxy-2-methylpropyl)amino)-5-nitro-3-(trifluoromethyl)pyridin-2-yl)amino)pyridin-3-yl)pyrimidin-2-yl)amino-tert-butyl dicarboxylate (135-1)

[0566] The title product was obtained by synthesizing the method described in Example 130.

[0567] MS(ESI)m / z[M+H] + =665.

[0568] Steps 2-3: Synthesis of 135-3

[0569] The title product was obtained by referring to steps 2-3 of the synthesis in Example 44.

[0570] MS(ESI)m / z[M+H] + =645.

[0571] Step 4: 1-(5-((5-(2-aminopyrimidin-5-yl)pyridin-2-yl)amino)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (135)

[0572] The title product was obtained by referring to the method described in step 2 of the synthesis in Example 125.

[0573] 1 H NMR (400MHz, DMSO-d6) δ8.60(s,2H),8.52-5.47(m,2H),8.36(s,1H),8.10-8.04(m,3H),6.81(s,2H),4.94(s,1H),4.17(s,2H),1.14(s,6H).

[0574] MS(ESI)m / z[M+H] + =445.

[0575] Example 136: 6'-((1-(bicyclo[1.1.1]pentan-1-yl)-5-(trifluoromethyl)-1H-benzi[d]imidazol-6-yl)amino)-[3,3'-bipyridine]-6-carboxylic acid (136)

[0576] The title product is obtained by referring to the methods described in step 2 of Example 131 and Example 1.

[0577] 1 H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.59(s,2H),8.44-8.34(m,2H),8.17-8.11(m,2 H),8.07-7.98(m,2H),7.90(s,1H),6.81(d,J=8.8Hz,1H),2.68(s,1H),2.41(s,6H).

[0578] MS(ESI)m / z[M+H] + =466.

[0579] Example 137: 2-((6'-((1-(bicyclo[1.1.1]pent-1-yl)-5-(trifluoromethyl)-1H-benzi[d]imidazol-6-yl)amino)-[3,3'-bipyridine]-6-yl)oxy)-2-methylpropionic acid (137)

[0580] The title product is obtained by referring to the methods described in step 2 of Example 131 and Example 1.

[0581] 1 H NMR (400MHz, DMSO-d6) δ8.43-8.38(m,2H),8.34-8.29(m,2H),8.07(s,1H),7.97-7.92(m,2H),7.83( d,J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),6.81(d,J=8.8Hz,1H),2.72(s,1H),2.45(s,6H),1.61(s,6H).

[0582] MS(ESI)m / z[M+H] + =524.

[0583] Example 138: 1,1,1,3,3-Hexafluoro-2-((5-(5-(2-(methylamino)ethoxy)pyrimidin-5-yl)pyridin-2-yl)amino)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)prop-2-ol (138)

[0584] The title product was obtained by referring to the method described in step 2 of the synthesis in Examples 130 and 125.

[0585] 1 H NMR(400MHz,DMSO-d6)δ9.00(s,2H),8.65(s,1H),8.55(s,1H),8.48(s,1H),8.31(s,1H ),8.13(s,2H),4.92(s,2H),4.47(t,J=5.6Hz,2H),3.02(t,J=5.6Hz,2H),2.44(s,3H).

[0586] MS(ESI)m / z[M+H] + =611.

[0587] Example 139: 1-(5-((5-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)pyridin-2-yl)amino)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (139)

[0588] The title product was obtained by referring to the method described in Example 72.

[0589] 1H NMR (400MHz, DMSO-d6) δ9.20 (s, 2H), 8.72 (d, J = 2.4Hz, 1H), 8.55 (s, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 8.26 (dd ,J=8.8,2.4Hz,1H),8.04(d,J=8.8Hz,1H),5.17(s,1H),4.98(s,1H),4.24(s,2H),1.59(s,6H),1.19(s,6H).

[0590] MS(ESI)m / z[M+H] + =488.

[0591] Referring to the method described in Example 1, the following example is obtained:

[0592] Referring to the method described in Example 72, the following examples are obtained:

[0593] Referring to the methods described in step 2 of Example 72 and Example 1, the following examples are obtained:

[0594] Referring to the methods described in steps 2-3 of Example 72 and Example 1, the following examples are obtained:

[0595] Example 173: 2-Methyl-1-(5-(5-(2-(2-(((1-methylazacyclobutan-3-yl)oxy)ethoxy)pyrimidin-5-yl)pyridin-2-yl)amino)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)prop-2-ol (173)

[0596] Steps 1-2: 1-(5-((5-(2-(2-(azacyclobutane-3-yloxy)ethoxy)pyrimidin-5-yl)pyridin-2-yl)amino)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (173-3)

[0597] The title product is obtained by referring to the method described in Example 72 and the method described in step 2 of Example 125.

[0598] Step 3: 2-Methyl-1-(5-(5-(2-(2-(((1-methylazacyclobutan-3-yl)oxy)ethoxy)pyrimidin-5-yl)pyridin-2-yl)amino)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)prop-2-ol (173)

[0599] Under argon protection, 173-2 (84 mg, 0.15 mmol), ethanol (13.0 mg, 0.15 mmol), sodium triacetoxyborohydride (127 mg, 0.60 mmol), and acetic acid (9.01 mg, 0.15 mmol) were sequentially added to DCE (6 mL), and the mixture was stirred at room temperature for 12 hours. LC-MS showed product formation. The pH of the reaction solution was adjusted to 7–8 by adding saturated sodium bicarbonate aqueous solution, and the mixture was extracted with DCM (20 mL × 3). The organic phases were combined, 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 (DCM:MeOH = 5:1) to give the title product (45 mg, yield: 52.23%).

[0600] 1 H NMR (400MHz, DMSO-d6) δ8.98(s,2H),8.61(s,1H),8.48(s,1H),8.42(s,1H),8.25(s,1H),8.16(d,J=8.8Hz,1H),8.04(d,J=8.8Hz,1 H),5.04(s,1H),4.53-4.43(m,2H),4.38-4.27(m,1H),4.20(s,2H),4.09-4.00(m,2H),3.81-3.76(m,2H),2.63(s,3H),1.15(s,6H).

[0601] MS(ESI)m / z[M+H] + =559

[0602] Referring to the method described in Example 92, the following examples are obtained:

[0603] Example 178: (3-(6-(3-(2-hydroxy-2-methylpropyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)pyridin-3-yl)iso Azol-5-yl)(morpholino)methyl ketone (178)

[0604] The title product was obtained by referring to the methods described in steps 2-3 of Example 92 and Example 1.

[0605] 1 H NMR (400MHz, DMSO-d6) δ8.77(d,J=2.0Hz,1H),8.59(s,1H),8.53(s,1H),8.44(s,1H),8.26(dd,J=8.8 ,2.2Hz,1H),7.90(d,J=8.8Hz,1H),7.59(s,1H),4.93(s,1H),4.20(s,2H),3.68(s,8H),1.15(s,6H).

[0606] MS(ESI)m / z[M+H] + =532

[0607] Referring to the method described in Example 130, the following examples are obtained:

[0608] Referring to the method described in step 2 of Examples 130 and 125, the following examples are obtained:

[0609] Referring to the methods described in step 2 of Example 130 and Example 1, the following examples are obtained:

[0610] Example 200: 1'-(2-hydroxy-2-methylpropyl)-6-((3-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)-[3,4'-bipyridine]-2'(1'H)-one (200)

[0611] Step 1: 3-(5-((1'-(2-hydroxy-2-methylpropyl)-2'-oxo-1',2'-dihydro-[3,4'-bipyridin]-6-yl)amino)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (200-2)

[0612] The title product was obtained by referring to the method described in Example 130.

[0613] Step 2: 1'-(2-hydroxy-2-methylpropyl)-6-((3-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)-[3,4'-bipyridine]-2'(1'H)-one (200)

[0614] 200-2 (20 mg, 0.058 mmol) was dissolved in THF (3 mL), cooled to 0 °C, and lithium aluminum hydride (5.01 mg, 0.13 mmol) was slowly added. The reaction was stirred at 0 °C for 12 hours. LC-MS showed product formation. The reaction mixture was quenched with ice water (10 mL) and extracted with DCM (20 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 reversed-phase C18 column chromatography (acetonitrile:H2O = 0–35:65) to give the title product (14 mg, yield: 28.98%).

[0615] 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.53-8.48(m,2H),8.32(s,1H),8.23(dd,J=8.8,2.4Hz,1H),8.05(d,J=8.8Hz,1H),7.72(d,J=7.2Hz,1H),6. 80(d,J=1.6Hz,1H),6.69(dd,J=7.2,1.6Hz,1H),4.90(s,1H),4.79(t,J= 5.4Hz,1H),3.95(s,2H),3.64(d,J=5.4Hz,3H),2.34(s,6H),1.12(s,6H).

[0616] MS(ESI)m / z[M+H] + =541

[0617] Referring to the method described in step 2 of Examples 130 and 200, the following examples are obtained:

[0618] Example 203: 6-((3-(2-hydroxy-2-methylpropyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)-1'-(2-(2-methoxyethoxy)ethyl)-[3,4'-bipyridine]-2'(1'H)-one (203)

[0619] The title product was obtained by referring to the method described in Example 72.

[0620] 1 H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.51(s,1H),8.47-8.37(m,2H),8.15(dd, J=8.8,2.0Hz,2H),7.93(d,J=8.8Hz,1H),7.71(d,J=7.2Hz,1H),6.75(s,1H),6 .65(d,J=7.2Hz,1H),5.00(s,1H),4.20(s,2H),4.08(t,J=5.2Hz,2H),3.69(t, J=5.2Hz,2H),3.57-3.54(m,2H),3.46-3.44(m,2H),3.23(s,3H),1.15(s,6H).

[0621] MS(ESI)m / z[M+H] + =547.

[0622] Referring to the methods described in Examples 130 and 203, the following examples are obtained:

[0623] Referring to the method described in Example 131, the following example is obtained:

[0624] Referring to the method described in Example 72, the following example is obtained:

[0625] Referring to the method described in Example 130, the following example is obtained:

[0626] Example 305: N-hydroxy-5-(6-((3-(2-hydroxy-2-methylpropyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)pyridin-3-yl)pyrimidine-2-formamidin (305)

[0627] 305-1 (50 mg, 0.11 mmol), hydroxylamine hydrochloride (11.47 mg, 0.17 mmol), and triethylamine (22.26 mg, 0.22 mmol) were mixed in ethanol (5 mL) and stirred overnight at 85 °C. LC-MS showed product formation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 8:1) to obtain the crude product. The crude product was further purified by reversed-phase C18 column chromatography (acetonitrile:water = 0–35%), and lyophilized to obtain the title product (6 mg).

[0628] 1 H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.23(s,2H),8.74(s,1H),8.52(s,1H),8.43(s,2H),8.2 8(d,J=8.8Hz,1H),7.98(d,J=8.8Hz,1H),5.93(s,2H),4.96(s,1H),4.20(s,2H),1.16(s,6H).

[0629] MS(ESI)m / z[M+H] + =488.

[0630] Example 306: 1-(5-((difluoromethyl)(5-(2-(2-(2-(2-hydroxyethoxy)ethoxy)pyrimidin-5-yl)pyridin-2-yl)amino)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylprop-2-ol (306)

[0631] 306-1 (150 mg, 0.28 mmol) and potassium carbonate (77.40 mg, 0.56 mmol) were mixed in DMF (2 mL), and sodium 2-chloro-2,2-difluoroacetate (128.0 mg, 0.84 mmol) was added. The reaction mixture was stirred at 80 °C for 1 hour. LC-MS 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 obtain the crude product. The crude product was further purified by reversed-phase C18 column chromatography (acetonitrile:water = 40:60), and lyophilized to obtain the title product (19 mg).

[0632] 1H NMR (400MHz, DMSO-d6) δ8.92(s,2H),8.38(s,1H),8.34(s,1H),8.25(d,J=2.2Hz,1H),8.03(t,J=60.2Hz,1H),7.81(dd,J=10.0,2.2Hz,1H),7.50 (d,J=10.0Hz,1H),4.92(s,1H),4.66(t,J=5.2Hz,1H),4.48(t,J=4.8Hz, 2H), 4.15 (s, 2H), 3.79 (t, J = 4.8Hz, 2H), 3.55-3.50 (m, 4H), 1.14 (s, 6H).

[0633] MS(ESI)m / z[M+H] + =584.

[0634] Biological experimental methods:

[0635] 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.

[0636] Effect Example

[0637] I. The compounds of this invention react with different isoforms of GABA A Receptor affinity activity

[0638] 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.

[0639] 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 min at 4 °C. The supernatant was collected, and the above steps were repeated. The supernatant was centrifuged at 4 °C (33800 g; Thermo, rotor: A27-8 x 50) for 60 min, 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.

[0640] 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 -6Within 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 A The 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 Ki of the sample to evaluate the sample's affinity for GABA. A The binding capacity of each receptor subtype.

[0641] 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.

[0642] Table 1. The effects of compounds on α5-GABA A Receptor affinity activity

[0643] As can be seen from Table 1, the compound described in this invention will 3 H-flunitrazepam is derived from human α5-GABA. A The Ki value of the receptor replacement is 100 nM or less, indicating that the compound of the present invention is 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. AThe Ki replaced by the receptor is less than 10 nM, or even less than 1 nM, indicating that the α5-GABAA subunit of the compound of the present invention has a strong affinity.

[0644] II. The effect of the compounds of this invention on α5-GABA A Reverse agonistic activity of receptors

[0645] 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:

[0646] 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. A The 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.

[0647] 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. 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. TMAfter the cells have adhered to the culture vessel, experiments can be performed. The cell culture time for electrophysiological purposes should not exceed 48 hours.

[0648] Drug concentration settings: The final concentration of 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 referred to the method reported in 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 triethylamine (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.

[0649] 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).

[0650] The results of the compound screening:

[0651] Table 2: Effects of compounds on α5-GABA A Reverse agonistic activity of receptors

[0652] 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 described in this patent 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.

[0653] III. Rat Pharmacokinetic Experiment

[0654] The absorption of the compound in rats was evaluated by measuring the maximum plasma concentration (Cmax) in rat pharmacokinetic studies. Male SD rats were administered the dissolved compound orally (po) via gavage after fasting overnight. Blood samples (approximately 100 μL each) were collected via venous puncture at 0.25, 0.5, 1, 2, 4, and 7 hours post-administration. Simultaneously, whole brain tissue samples were collected and homogenized with three times the volume of PBS for analysis. Plasma and brain tissue drug concentrations were determined using LM-MS / MS, and the brain absorption ratio (B / P) was calculated based on the compound's AUC. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0. The administration solvent was a 5% CMC-Na aqueous solution.

[0655] Table 3: Maximum plasma concentration (Cmax) and brain penetration ratio (B / P) of compounds in rats.

[0656] As shown in Table 3, in the rat pharmacokinetic experiment, compared with Example 141 in WO2015115673... The compound of this invention exhibits a high maximum plasma concentration (Cmax) at the stated dosage, indicating good absorption; simultaneously, the low brain penetration ratio (B / P < 5%) suggests that the compound binds to α5-GABA in the peripheral nervous system. A These receptors, while inhibiting various types of pain, do not easily cross the blood-brain barrier in the body, resulting in fewer side effects on the central nervous system.

Claims

An imidazole fused ring compound characterized in that, which is a compound as shown in 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; Z1is CH or N; Z2is CR 4a or N; Z3is CR 4b or N; ring A is a 6-10 membered aryl, a 5-10 membered heteroaryl or a 5-10 membered heterocycloalkenyl; m is 1, 2, 3, 4 or 5; each R1is independently hydrogen, halogen, cyano, hydroxy, carboxy, amino, C 1-6 alkyl, C 1-6 alkoxy, -NH-C 1-6 alkyl, -N(C 1-6 alk)2、 or -C(O)NR6R7, or two R1bound to the same carbon atom form together with C a -C(=O)-; said C 1-6 alkyl, said C 1-6 alkoxy, -NH-C 1- 6alkyl and -NH-(C 1-6 alkyl)2may optionally be substituted by 1 or more R RA substituents: Each R RA It can be independently a halogen, hydroxyl, or carboxyl group; n is 1, 2, 3, 4 or 5; Ring B is C 3-14 cycloalkyl, 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl; each R5is independently hydrogen, carboxyl, oxo, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-14 membered heterocycloalkyl, -O-3-14 membered heterocycloalkyl, C(O)NR8R 9、 -NR 10 R 11 , said C 1-6 alkyl, said C 1-6 alkoxy, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-14 membered heterocycloalkyl, and -O-3-14 membered heterocycloalkyl can be independently optionally substituted with 1 or more R RB substituents: each R RB is independently halogen, hydroxyl, carboxyl, amino, -O-C 1-6 alkyl, -O-C 1-6 alkylene-O-C 1-6 alkyl, -O-C 1-6 alkylene-O-C 1-6 alkylene-O-C 1-6 alkyl, -O-C 2-6 alkenyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -3-14 membered heterocycloalkyl, -C 1-6 alkylene-3-14 membered heterocycloalkyl, -O-3-14 membered heterocycloalkyl, -O-C 1-6 alkylene-3-14 membered heterocycloalkyl, C 3-6 cycloalkyl, -C 1-6 alkylene-C 3-6 cycloalkyl or -O-C 1-6 alkylene-O-C 1-6 alkylene-C 3- 6cycloalkyl, the -O-C 1-6 alkyl, -O-C 1-6 alkylene-O-C 1-6 alkyl, -O-C 1-6 alkylene-O-C 1-6 alkylene-O-C 1-6 alkyl, -O-C 2-6 alkenyl, -NH(C 1- 6alkyl), -N(C 1-6 alkyl)2, -3-14 membered heterocycloalkyl, -C 1-6 alkylene-3-14 membered heterocycloalkyl, -O-3-14 membered heterocycloalkyl, -O-C 1-6 alkylene-3-14 membered heterocycloalkyl, C 3-6 cycloalkyl, -C 1-6 alkylene-C 3-6 cycloalkyl and -O-C 1-6 alkylene-O-C 1-6 alkylene-C 3-6 cycloalkyl can be optionally substituted with 1 or more R RB- 1 substituents: each R is independently hydroxyl, halogen, C RB-1 independently hydroxyl, halogen, C 1-6 alkyl or -O-C 1-6 alkyl; R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 or R 14 are independently hydrogen, C 1-6 1-6 alkyl, -C 1-6 1-6 alkoxy, C 3-6 3-14 cycloalkyl, 3-14 heterocycloalkyl, 6-10 aryl, or 5-10 heteroaryl, or R6and R7together with the N to which they are attached form a 3-14 membered heterocycloalkyl, or R8and R9together with the N to which they are attached form a 3-14 membered heterocycloalkyl, or R 10 and R 11 with the N to which it is attached form a 3-14 membered heterocycloalkyl; said C 1-6 alkyl, said C 1-6 alkoxy, said C 3-6 cycloalkyl, said 3-14 membered heterocycloalkyl, said 6-10 membered aryl, and said 5-10 membered heteroaryl are each independently optionally substituted with 1 or more R RC substituents; Each R RC Independently hydroxyl, halogen, -CN, oxo group, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(=O)-OC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1- 6-alkyl)2、-S(=O)2-C 1-6 Alkyl, -3-14 membered heterocyclic alkyl or -C(=O)NR a R b ; R a and R b are independently H, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; R2is -(CH2) Y -R 2a , C 3-10 cycloalkyl or phenyl, said C 3-10 cycloalkyl and phenyl are independently optionally substituted with 1 or more R RD substituents; Y is 1, 2, 3, 4, 5 or 6, -(CH2) Y - each of one or two -CH2- is optionally replaced by one or more R 2b R 2c -, -C(=O)NH- and -C(=O)NC 1-6 alkyl-, C 3-6 cycloalkylene and one or more R RD substituted C 3-6 cycloalkylene is replaced by one or two of alkyl-, C R 2b and R 2c are independently H, halogen, C 1-6 alkyl or C RD alkyl substituted by one or more R 1-6 alkyl, or R 2b and R 2c together with the carbon they are attached to form a C 3-6 cycloalkyl group; R 2a is hydroxyl, carboxyl, CN, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, -S(=O)2-C 1-6 alkyl, C 3-6 cycloalkyl, -3-6 membered heterocycloalkyl or -3-6 membered heterocycloalkyl substituted by one or more R RD substituted -3-6 membered heterocycloalkyl; Each R RD Independently halogen, cyano, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -S(=O)2-C 1-6 Alkyl, C 1-6 Alkyl, -OC 1-6 Alkyl group or -C(=O)OC 1-6 alkyl; R3is hydrogen, C 1-6 alkyl or C 1-6 alkyl; R 4a is hydrogen, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, C 3-6 cycloalkyl or 3-14 membered heterocycloalkyl, said C 1-6 alkyl, said C 1-6 alkoxy, said C 3-6 cycloalkyl and said 3-14 membered heterocycloalkyl can be independently optionally substituted with 1 or more R RE substituents; Each R RE Independently halogen, hydroxyl, C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 Alkoxy, -OC 1-3 Alkyl-OC 1-3 Alkyl or oxo; R 4b is hydrogen, halogen, C 1-6 alkyl or C 1-6 alkyl substituted by one or more halogen; the compound of formula I satisfies condition 1 and / or 2: Condition 1 : at least one R1is -NH-C 1-6 alkyl, -N(C 1-6 alkyl, -N(C or -C(O)NR6R7; said -NH-C 1-6 alkyl and -NH-(C 1-6 alkyl)2may be optionally substituted with 1 or more R RA substituents; when R1is independently at least one R5is C(O)NR8R9, -NR 10 R 11 、 Condition 2: R2is -(CH2) Y -R 2a , C 3-10 cycloalkyl or phenyl, said C 3-10 cycloalkyl and phenyl are independently optionally substituted with 1 or more R RD substituents; when R2is -(CH2) Y -R 2a ; R 2a is hydroxyl, carboxyl, CN, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, -S(=O)2-C 1-6 alkyl, -3-6 membered heterocycloalkyl or -3-6 membered heterocycloalkyl substituted with one or more R RD ; the heteroatom in the heteroaryl, the heterocycloalkyl and the heterocycloalkenyl is independently 1, 2 or 3 of N, S and O, and the number is 1, 2, 3 or 4. The imidazole fused ring compound according to claim 1, wherein satisfies one or more of the following conditions: (1) in ring A, the 6-10 membered aryl is phenyl or naphthyl; (2) in ring A, the 5-10 membered heteroaryl is a 5-6 membered monocyclic heteroaryl, benzo 5-6 membered monocyclic heteroaryl, 5-6 membered monocyclic heteroaryl and 5-6 membered monocyclic alkyl, or 5-6 membered monocyclic heteroaryl and 5-6 membered monocyclic heterocyclyl, the heteroatoms are selected from N and O, which can be pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzo azole group, benzopyrazole group, pyridopiperidinyl group, pyridomorpholinyl group, pyrido Azolyl, pyridopyrazolyl, pyridoimidazolyl, pyridopyridyl, imidazopyridazinyl, or quinolinyl, such as pyridyl, pyridazinyl, benzo[] azolyl, pyridinopiperidinyl, pyridinomorpholinyl, pyridino azolyl or pyridino oxazolyl; (3) in ring A, the 5-10 membered heterocycloalkenyl is a 5-6 membered monocyclic heterocycloalkenyl containing 1 or 2 double bonds, the heteroatom is N, and the number is 1 or 2, which can be 2H-pyridyl; (4) each R1, R 4a , R 4b , R 2b , R 2c , R 4a , R 4b , each R5, each R RA , each R RB , each R RB-1 , each R RC , each R RD , and each R RE , is F, Cl or Br; (5) each of R1, R 2b , R 2c , R3, R 4a , R 4b , each of R5, R6, R7, R8, R9, R 10 , R 11 , each of R RC , R a , R b , each of R RE , the C 1-6 alkyl group is a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, or a t-butyl group; (6) each of R1, R3, R 2b , R 2c , R 4a , R 4b , each of R5, R6, R7, R8, R 10 , R 11 , each of R RC , R RD and each of R RE , the C 1-6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (7) in each R1, the -NH-C 1-6 alkyl and the -N(C 1-6 alkyl)2 1-6 alkyl and the -N(C 1-6 alkyl)2 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl; (8) in ring B, said C 3-14 Cycloalkyl is a C 3-6 Monocycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; (9) in ring B, the 3-14 membered heterocycloalkyl is a 3-6 membered monocyclic heterocycloalkyl or a 9-10 membered bicyclic heterocycloalkyl, the heteroatoms are selected from N and O, the number is 1, 2 or 3, which can be oxetanyl, imidazolidinyl, morpholinyl, piperazinyl or octahydropyrazino[2,1-c][1,4]oxazinyl oxazinyl; (10) in ring B, the 3-14 membered heterocycloalkenyl is a 5-6 membered monocyclic heterocycloalkenyl containing 1 or 2 double bonds, the heteroatom is selected from N and O, and the number is 1 or 2, which can be 1,2-dihydropyrimidinyl or 2,3-dihydropyridyl; (21) in ring B, the 6-10 membered aryl is phenyl or naphthyl; (22) in ring B, the 5-10 membered heteroaryl is a 5-6 membered monocyclic heteroaryl, a 5-6 membered monocyclic heteroaryl and a 5-6 membered monocyclic heteroaryl, or a 5-6 membered monocyclic heteroaryl and a 5-6 membered monocyclic heteroaryl, the heteroatoms are selected from N and O, which can be pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazolyl, and oxazinyl or 1,2,4-triazolylpyrrolidinyl; (23) each R 4a , R5, R6, R7, R8, R9, R 10 , R 11 , R a and R b , the C 3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (24) in each R5, the 3-14 membered heterocycloalkyl in the 3-14 membered heterocycloalkyl and the -O-3-14 membered heterocycloalkyl is a 3-6 membered monocyclic heterocycloalkyl, the heteroatom is selected from N and O, and the number is 1 or 2, which can be oxetanyl or oxolanyl; (25) In each R5, the C 2-6 The alkenyl group is C 2-4 Alkenyl, which can be vinyl; (26) each R RB -NH(C 1-6 alkyl) in said -NH(C 1-6 alkyl), C 1-6 alkyl in said -NH(C 1-6 alkyl), C 1-6 alkyl in said -O-C 1-6 alkyl, C 1-6 alkylene-O-C 1-6 alkyl, C 1-6 alkyl and C 1-6 alkylene-O-C 1-6 alkylene-O-C 1-6 alkyl, C 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl; (27) each R RB in particular, said -O-C 1-6 alkylene-O-C 1-6 C in alkyl 1-6 alkylene, -O-C 1-6 alkylene-O-C 1-6 alkylene-O-C 1-6 C in alkyl 1- 6alkylene, -C(O)-C 1-6 C in alkylene 3-14 membered heterocycloalkyl 1-6 alkylene, -O-C 1-6 C in alkylene 3-14 membered heterocycloalkyl 1-6 alkylene and -O-C 1- 6alkylene-O-C 1-6 alkylene-C 3-6 C in cycloalkyl 1-6 alkylene is independently methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, or t-butylene; (28) Each R RB In the context, the 3-14 membered heterocyclic alkyl group, -C 1-6 3-14-membered heterocyclic alkyl groups in alkylene-3-14-membered heterocyclic alkyl groups, 3-14-membered heterocyclic alkyl groups in -O-3-14-membered heterocyclic alkyl groups, and -OC 1-6 The 3-14-membered heterocyclic alkyl group in the alkylene-3-14-membered heterocyclic alkyl group is independently a 4-6-membered monocyclic heterocyclic alkyl group or a 7-10-membered bridged heterocyclic alkyl group, and the heteroatom is selected from N and O, and the number is 1 or 2, which can be oxobutyl, dioxopranyl, pyrrolidinyl, piperazine, morpholinyl or 2-oxabicyclo[2.2.1]heptyl; (29) each R RB In particular, the C 3-6 cycloalkyl, the -C 1-6 alkylene-C 3-6 C in cycloalkyl 3-6 cycloalkyl and the -O-C 1-6 alkylene-O-C 1-6 alkylene-C 3-6 C in cycloalkyl 3-6 C in cycloalkyl 3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclobutyl; (30) each R RB-1 -O-C 1-6 C in the alkyl group 1-6 C in the alkyl group 1-6 The alkyl groups are independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl. (31) each of R6, R7, R8, R9, R 10 , R 11 , R RB-1 , R RD , R RE , R RE-1 , R a and R b , the 3-14 membered heterocycloalkyl is a 4-6 membered monocyclic heterocycloalkyl or a 7-10 membered bridged heterocycloalkyl, the heteroatoms are selected from N and O, the number is 1 or 2, and can be an oxetanyl group, an azetidinyl group, a pyrrolidinyl group, a piperazinyl group, a morpholinyl group, or a 2-oxabicyclo[2.2.1]heptanyl group; (32) each R RE , R6, R7, R8, R 10 , R 11 and R 4a , the 6-10 membered aryl group is phenyl or naphthyl; (33) each R RE , R6, R7, R8, R 10 , R 11 , and R 4a , the 5-10 membered heteroaryl is a 5-6 membered monocyclic heteroaryl, the heteroatom is selected from N and O, and can be 1H-pyrazolyl, isothiazolyl, isoxazolyl, or oxazolyl. oxazolylpyridyl, pyrimidinyl, pyridazinyl or pyrazinyl; (34) each R RC -C(=O)O(C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1- alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl; (35) In R2, the C 3-10 Cycloalkyl is C 3-6 Monocyclic cycloalkyl or C 4-6 Bicyclic bridged cycloalkyl, which can be cyclopropyl, cyclobutyl or bicyclo[1.1.1]pentyl; (36) In R2, when - (CH2) Y - one or two -CH2- are optionally replaced by one or two groups independently selected from -CR 2b R 2c -, -C(=O)NH- and -C(=O)NC 1-6 alkyl-, C 3-6 cycloalkylene and C RD alkyl- substituted by one or more R 3-6 cycloalkylene and C 3-6 alkyl- substituted by one or more R RD cycloalkylene and C 3-6 alkyl- substituted by one or more R 3-6 cycloalkylene is independently cyclobutylene or bicyclo[l. l. l]pentanylene; (37)R 2b and R 2c In, the C 1-6 Alkyl groups and the one or more R RD Replacement C 1-6 C in alkyl 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (38) R 2a in said -O-C 1-6 in said -O-C 1-6 in said -NH-C 1-6 in said -NH-C 1-6 in said -N(C 1-6 in said -N(C 1-6 in said -S(=O)2-C 1-6 in said -S(=O)2-C 1-6 in said -S(=O)2-C (39)R 2a In some embodiments, the -3-6 membered heterocycloalkyl of the -3-6 membered heterocycloalkyl group and the -3-6 membered heterocycloalkyl of the -3-6 membered heterocycloalkyl group substituted by one or more R RD In some embodiments, the -3-6 membered heterocycloalkyl of the -3-6 membered heterocycloalkyl group and the -3-6 membered heterocycloalkyl of the -3-6 membered heterocycloalkyl group substituted by one or more R (40) each R RD C, wherein the C 1-6 alkyl, the -NH-C 1-6 alkyl, the -NH-C 1-6 alkyl, the -N(C 1-6 alkyl), the -S(=O)2-C 1-6 alkyl, the -S(=O)2-C 1-6 alkyl, the -S(=O)2-C 1-6 alkyl, the -S(=O)2-C 1-6 alkyl, the -S(=O)2-C 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl; (41) R 3 C1-C6alkyl substituted with 1 or more halogens 1-6 C1-C6alkyl independently is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl 1-6 C1-C6alkyl independently is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl (42) R 4a In particular, the C 3-6 Cycloalkyl is cyclopropane, cyclobutane, cyclopentane or cyclobutane. (43) R 4a In some embodiments, the 3-14 membered heterocycloalkyl is a 3-6 membered monocyclic heterocycloalkyl or a 9-10 membered bicyclic heterocycloalkyl. The imidazole fused ring compound according to claim 1, wherein satisfies one or more of the following conditions: (1) For Y 1a , Y 2a , Y 3a , Y 4a , Y 5a , Y 6a , Y 7a and Y 8a are independently N or CR1, and Y 1a , Y 2a , Y 3a and Y 4a are not simultaneously N, Y 5a , Y 6a , Y 7a and Y 8a are not simultaneously N; ring c 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 being one or more of N, O and S, the number being 1, 2 or 3; (2) For n is 1 or 0, Y 1b , Y 2b , Y 3b , Y 4b , Y 5b , Y 6b , Y 7b and Y 8b are independently N or CR5, and Y 1b , Y 2b , Y 3b and Y 4b are not simultaneously N, Y 5b , Y 6b , Y 7b and Y 8b are not simultaneously N; ring C is a 5-6 membered monocyclic heterocycle or a 5-6 membered monocyclic heteroaromatic ring, 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, the number being 1, 2 or 3; Preferably (3) R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 or R 14 are independently hydrogen, C 1-6 alkyl, -O-C 1-6 alkyl, C 3-6 cycloalkyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, or R6and R7together with the N to which they are attached form a 3-14 membered heterocycloalkyl, or R8and R9together with the N to which they are attached form a 3-14 membered heterocycloalkyl, or R 10 and R 11 with the N to which it is attached form a 3-14 membered heterocycloalkyl; said C 1-6 alkyl, said C 1-6 alkoxy, said C 3-6 cycloalkyl, said 3-14 membered heterocycloalkyl, said 6-10 membered aryl, and said 5-10 membered heteroaryl are each independently optionally substituted with 1 or more R RC each R RC is independently hydroxyl, halogen, or C 1-6 alkyl; R6, R7, R8, R9, R 10 R6, R7, R8, R9, R 11、 R6, R7, R8, R9, R 12 R6, R7, R8, R9, R 13 R6, R7, R8, R9, R 14 R6, R7, R8, R9, R (4) R 2b and R 2c are independently H, halogen, C 1-6 alkyl or C 1-6 alkyl substituted by one or more halogen; or R 2b and R 2c form together with the carbon they are attached to a C 3-6 cycloalkyl; Preferably, R 2b and R 2c are independently H, F, -CH3, -CF3, -CHF2, -CH2CF3, or -CH2CF2H; (5) R 4a is hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, C 3-6 cycloalkyl or 3-14 membered heterocycloalkyl, said C 1-6 alkyl, said C 1-6 alkoxy, said C 3-6 cycloalkyl, said 3-14 membered heterocycloalkyl, can be independently optionally substituted with 1 or more R RE substituents; Preferably, R 4a is H, -CN, F, Cl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, morpholino or (6) R 4b is hydrogen or C 1-6 alkyl; Preferably, R 4b is H or -CH3; (7) R3is hydrogen, C 1-6 alkyl or C 1-6 alkyl. The imidazole fused ring compound according to claim 3, characterized by satisfies one or more of the following conditions: (1) each R5is independently hydrogen, carboxyl, oxo (=0), amino, -CH3, -OCH3, (2)-(CH2) Y -R 2a -(CH2) Y - where Y is 1, 2, 3, 4, 5, or 6, -(CH2) Y -Any one CH2-is arbitrarily selected from -CR 2b R 2c -、C 3-6 Cycloalkylene and one or more R RD Replacement C 3-6 A substitution in a cycloalkylene group, or -(CH2). Y -Any two CH2-are randomly selected from -CR 2b R 2c -、-C(=O)NH- and -C(=O)NC 1-6 Alkyl-, C 3-6 Cycloalkylene and one or more R RD Replacement C 3-6 One or two substitutions of cycloalkyl groups; -(CH2) Y -R 2a -(CH2) Y - preferably is * end with R 2a Connection. The imidazole fused ring compound according to any one of claims 1 to 4, wherein satisfies one or more of the following conditions: (1) For (2) each R1is 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 R1s connected to the same carbon atom together form an oxo group; (2) R2 is (5) R3is H or difluoromethyl; (8) For (9) R 4a H, -CN, F, Cl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, morpholino or (10) R 4b is H or -CH3. The imidazole fused ring compound according to any one of claims 1 to 4, wherein satisfies one or more of the following conditions: (1) The structural unit is The imidazole fused ring compound according to claim 1, wherein satisfies one or more of the following conditions: Formula I refers to any one of the general formulas I-AI to IA-AIV, and general formulas IA-BI to IA-BIV: The imidazole fused ring compound according to claim 1, wherein The imidazole fused ring compound is any one of the following compounds: a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the imidazole fused ring compound according to any one of claims 1-8. The use of a fused ring compound as described in any one of claims 1 to 8 or a pharmaceutical composition as described in claim 9 for the manufacture of a medicament for the treatment or prevention of a disease associated with the alpha5-GABA A receptor. A receptor. The use as claimed in claim 10, characterized in that The α5-GABA A The disease associated with the α5-GABA A receptor is one or more of pain, Alzheimer's disease, multi-infarct dementia, and stroke. The use as claimed in claim 11, characterized in that the pain is one or more of neuropathic pain, inflammatory pain and cancer pain; the pain is one or more of neuropathic pain, inflammatory pain and cancer pain; Preferably, the pain is one or more of headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, lower extremity pain, musculoskeletal pain, vascular pain, gout, arthritic pain, visceral pain, pain associated with infectious disease, bony pain, pain associated with sickle cell anemia, autoimmune disease, multiple sclerosis or inflammation, chronic pain associated with injury or surgery, nociceptive pain, painful diabetic neuropathy, trigeminal neuralgia, pain associated with lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex sympathetic dystrophy, reflex sympathetic dystrophy, nerve root avulsion, cancer, chemical injury, toxin, nutritional deficiency, viral or bacterial infection, and degenerative joint and bone disease.

Images