WO2017190707A1

WO2017190707A1 - Triazolopyridazine derivative, preparation method, pharmaceutical composition and use thereof

Info

Publication number: WO2017190707A1
Application number: PCT/CN2017/083405
Authority: WO
Inventors: 李帅; 孙勇
Original assignee: 如东赛默罗生物科技有限公司
Priority date: 2016-05-06
Filing date: 2017-05-08
Publication date: 2017-11-09
Also published as: CN107344936A; CN107344936B

Abstract

Disclosed are a compound as shown in formula (I), cis-and trans-isomers, an enantiomer, diastereoisomer, racemate, solvate and hydrate thereof, or a pharmaceutically acceptable salt and ester, a preparation method thereof, a pharmaceutical composition containing the compound and the use of the compound as an α5-GABA_A receptor modulator, wherein Z, A and Y are as defined in the description.

Description

Triazolium derivative, preparation method thereof, pharmaceutical composition and use thereof

Technical field:

The present invention relates to triazolium derivatives having a regulatory function to α5-GABA _A receptors, their preparation, pharmaceutical compositions containing them and their use as medicaments.

Background technique:

γ- aminobutyric acid (GABA) in the mammalian central nervous system is the major inhibitory neurotransmitter, there are two types of GABA receptors are present in nature, is a class of GABA _A receptor, such receptors are ligand-gated Members of the ion-control channel superfamily, the other is the GABA _B receptor, which is a member of the G-protein coupled receptor superfamily. The GABA _A receptor subunits in mammals are found to have subunits such as α1-6, β1-4, γ1-3, δ, ε, θ and ρ1-2, of which α subunit, β subunit and γ sub The base pair is essential for the formation of a complete functional GABA _A receptor, and the alpha subunit is critical for the binding of benzodiazepine to the GABA _A receptor.

The α5-containing GABA _A receptor (α5-GABA _A receptor) accounts for less than 5% of the GABA _A receptor in the mammalian brain, and has a very low expression level in the cerebral cortex, but GABA in the hippocampus of the brain. _The proportion of _A receptors is greater than 20%, and other brain regions are hardly expressed. Considering the specific distribution and function of α5-GABA _A receptors in the hippocampus of the brain, many pharmaceutical companies including Roche have been engaged in the study of α5-GABA _A receptor ligands, and a large number of compounds have been synthesized. especially for hippocampal tissue α5 containing subunits of GABA _a receptor inverse agonist, wherein α5IA MRK-016, and show the effect of a good treatment of cognitive diseases in animal disease models and human trials, in particular Treating Alzheimer's disease. Inverse agonists of the GABA _A receptor of the α5 subunit are generally considered to be useful in the treatment of cognitive diseases, particularly in the treatment of Alzheimer's disease. Patent application US 2011 0224278 A1 discloses that inverse agonists of the GABA _A receptor containing the α5 subunit can be used to treat multi-infarct dementia and stroke-related diseases.

A decade of research has proven (Zlokovic et al. Nat Rev Neurosci.; 12(12): 723–738) in many disease states, especially neurodegenerative diseases, Alzheimer's disease and stroke, etc. The barrier is destroyed, even if the substances that could not enter the brain can exert the corresponding pharmacological effects, so the inverse agonist of the GABA _A receptor, which could not cross the α5 subunit of the blood-brain barrier, can also be used to treat Alzheimer. Disease and stroke.

In 2002 Zhang Xu lab reports α5-GABA _A receptor is mainly expressed in small neurons, and cut off the elevated expression (Xiao HS et al model in the nerve., Identification of gene expression profile of dorsal root ganglion in the rat peripheral "Axotomy model of neuropathic pain." Proc Natl Acad Sci US A. June 11, 2002; 99(12), patent application CN103239720A discloses that the α5-GABA _A receptor is expressed in the peripheral nervous system and is expressed in the neural partial injury model. high very obvious, and α5-GABA _a receptor inverse agonists by selective binding to a receptor α5-GABA _a peripheral nervous system, the effect of suppressing action of various types of pain, animal model data, inverse agonist The stronger the reverse agonistic effect of the agent, the better its effect of suppressing pain.

To test whether a compound is an inverse agonist or antagonist against a GABA _A receptor comprising an α5 subunit, research work has been done in this regard, for example, in the international patent applications WO 92/22652 and WO 94/13799, with α5 GABA _a receptors, γ2 beta] 3, and a combination to detect whether a compound binds to this receptor; in the drug screening procedure is performed, and the like usually Goeders (Goeders NE and Kuhar MJ (1985 ) Benzodiazepine binding in vivo The method described with with [.sup. 3H] Ro 15-1788. Life Sci 37:345-355). To detect whether a ligand that binds to the GABA _A receptor α5 subunit is an antagonist, agonist or inverse agonist, there are many studies in this area. See Wafford et al. (Wafford KA, Whiting PJ and Kemp JA ( 1993) Differences in affinity and efficacy of benzodiazepine receptor ligands on recombinant GABA.sub.A receptor subtypes. Mol. Pharmacol 43:240-244).

Screening for drugs entering the blood-brain barrier is widely available in the literature (Jones et al., Pharmacokinetics and metabolism studies on(3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl) -1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine,a functionally selective GABA _A α5 inverse agonist for cognitive dysfunction.Bioorg Med Chem Lett.2006Feb 15; 16 (4): 872-5) reported compounds to inhibit can be detected ^{(3 H) R0-15-1788 (α5 GABA} a receptor inverse agonist labeled specific) binding in the brain, MRK016 effective Inhibition of ( ³ H)R0-15-1788 in the central binding, while MRK016-M3 can hardly significantly inhibit ( ³ H)R0-15-1788 in the central binding. It can also be detected by different methods in drugs. Detection, for example, detecting the distribution of drugs in the brain and plasma to determine whether the drug can effectively enter the blood-brain barrier.

Previous studies have found that the use of drugs or genetic methods to inhibit or reduce the α5 GABA _A receptor-mediated extra-exhibition inhibition can improve cognitive and learning ability, but at the same time lead to mild anxiety-like behavior. (Brickley, SG & Mody, I. Extrasynaptic GABAA receptors: their function in the CNS and implications for disease. Neuron 73, 23–34 (2012).; Harris, D. et al. Selective influence on contextual memory: physiochemical properties associated with Selective benzodiazepine ligands at GABAA receptors containing the alpha5 subunit.J.Med.Chem.51,3788–3803 (2008).;Savic',MMet al.PWZ-029,a compound with moderate inverse agonist functional selectivity at GABAA receptors containing 55 subunits,improves passive,but not active,avoidance learning in rats.Brain Res.1208,150–159(2008);Clément,Y.et al.Gabra5-gene haplotype block associated with behavioral properties of the full agonist benzodiazepine chlordiazepoxide. Behav. Brain Res. 233, 474–482 (2012)). The study found that fear and anxiety traits are associated with a decrease in Gabra5 mRNA. (Heldt, SA & Ressler, KJ Training-induced changes in the expression of GABA _A associated genes in the amygdala after the acquisition and extinction of Pavlovian fear. Eur. J. Neurosci. 26, 3631–3644 (2007).; Tasan, RO et al .Altered GABA transmi ssion in a mouse model of increased trait anxiety. Neuroscience 183, 71–80 (2011).). Paolo Botta et al. disclosed the mechanism by which the α5 GABA _A receptor is involved in anxiety and fear. Specific knockout of α5 GABA _A receptor expression in the brain region results in fear and anxiety behavior in animals. Thus, the previously disclosed α5 GABA _A inverse agonist enters the brain and produces side effects of fear and anxiety, which cannot be directly applied to the medical field and must be modified.

Summary of the invention

It is an object of the present invention to provide compounds of the formulae (I) and (II), cis-trans isomers, enantiomers, diastereomers, racemates, solvates thereof, Hydrates, or pharmaceutically acceptable salts and esters thereof.

Another object of the present invention is to provide a process for the preparation of the compounds of the formulae (I) and (II).

Another object of the present invention is to provide the use of the compounds of the formulae (I) and (II) as modulators of α5-GABA _A receptors for the preparation, prevention, treatment or amelioration of α5-GABA _A receptors. Use of drugs for diseases such as cognitive diseases, Alzheimer's disease, memory disorders, Down's syndrome, amyotrophic lateral sclerosis (ALS), drug addiction, restless leg syndrome , cognitive deficits, multi-infarct dementia, pain, stroke and attention deficits, or use in the preparation of pain-relieving drugs.

Another object of the present invention is to provide a pharmaceutical composition comprising one or more effective therapeutic doses of a compound of the formula (I) and (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt Accepted carrier and/or adjuvant.

Another object of the present invention is to provide a method for preventing, treating or ameliorating a disease associated with an α5-GABA _A receptor comprising administering a compound of the formula (I) and (II) according to the present invention or a pharmaceutical thereof Acceptable salts or compositions of the invention.

In a first aspect of the invention, there is provided a compound of formula I, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate, a hydrate, or Pharmaceutically acceptable salts and esters,

among them

Z represents a 5-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, said 5-membered heteroaryl ring being optionally substituted by one or more substituents selected from the group consisting of: , halogen, -R1, -OR1, -OC(O)R1, -NR2R3, CN, cyano(C1-6)alkyl- or R2;

R1 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkyl (C1-6) alkyl, cyano (C1-6) alkane a C1-6 alkyl group substituted with a hydroxy group or an amino group, and R1 is optionally mono-, di- or trifluoro;

R2 or R3 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl or CF3, or R2 and R3 together with the nitrogen atom to which they are attached form 4 a -7 membered heteroalicyclic ring containing the nitrogen atom and one additional heteroatom selected from O, N and S, optionally substituted by one or more R1 groups;

Preferably Z represents a 5-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein at most one heteroatom is oxygen or sulfur, and when one heteroatom is a nitrogen atom At least one oxygen or sulfur atom is also present, and the 5-membered heteroaryl ring is optionally substituted with one or more substituents selected from the group consisting of C1-C4 alkyl, hydroxy, halogen, hydroxy or amino substituted C1. -C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C1-C4 alkoxy;

More preferably Z represents a 5-membered heteroaryl ring containing 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, and one heteroatom is oxygen or sulfur and the other atom is nitrogen; the 5-membered heteroaryl ring is one Or a plurality of substituents selected from the group consisting of C1-6 alkyl and hydroxy C1-6 alkyl;

Most preferably Z represents oxadiazolyl, furyl, thienyl or isoxazolyl, which is optionally substituted by one or more substituents selected from H, C1-6 alkyl And a hydroxy C1-6 alkyl group;

A is -NR2-; or A is a 5-membered heteroarylene containing 1, 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur and at most one of the heteroatoms is oxygen or sulfur; Is a 6-membered heteroarylene containing 1, 2 or 3 nitrogen atoms, or the 5 or 6-membered heteroarylene is optionally fused to a benzene or pyridine ring, said 5 or 6-membered The arylene group is optionally substituted by Rx and/or Ry and/or Rz, wherein Rx is halogen, -R1, -OR1, -OC(O)R1, -C(O)OR1, -NR2R3, -NR2C(O) R3, -OH, -CN, Ry is halogen, -R1, -OR1, -OC(O)R1, -NR2R3, -NR2C(O)R3, or CN, and Rz is -R1, -OR1 or -OC(O R1, provided that when A is a pyridine derivative, the pyridine ring is optionally in the form of an N-oxide; or A is a phenylene group optionally substituted by 1, 2 or 3 groups independently selected from: Halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C3-6 cycloalkyl;

Preferably A is represented by a 5-membered heteroarylene containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur and wherein at most one of the heteroatoms is oxygen or sulfur, or contains 1, 2 or 3 a 6-membered heteroarylene or phenylene group of a nitrogen atom; the 5-membered heteroarylene group, 6-membered heteroarylene group and phenylene group are optionally substituted with a substituent independently selected from the group consisting of halogen and cyanogen And a C1-6 alkyl group;

More preferably A represents a phenylene, pyridylene, or isoxazolyl group; optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano and C1-6 alkyl;

Y is -NY1Y2 or -NH-NY3Y4;

Y1 is selected from the group consisting of: H; C1-6 alkyl; C1-6 alkyl substituted by 1 to 5 substituents independently selected from the group consisting of amino, halogen, halo-C1-6 alkoxy, Hydroxy, C1-6 alkoxy, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S(O) ₂ -;

Preferably, Y1 is represented by H, C1-6 alkyl or C1-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of amino, hydroxy, C1-6 alkoxy, (C1) -6 alkyl, C 1-6 alkyl) N-, (C 1-6 alkyl, H) N- and C 1-6 alkyl-S(O) ₂ -;

More preferably, Y1 is represented by H or C1-6 alkyl;

Most preferably Y1 is represented by H or methyl;

Y2 is selected from the group consisting of: H; C1-6 alkyl; C1-6 alkyl substituted by 1 to 5 substituents independently selected from the group consisting of amino, halogen, halo-C1-6 alkoxy, Hydroxy, C1-6 alkoxy, cycloalkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl- S(O) ₂ -;

a heteroaryl group, or a heteroaryl group substituted by 1 to 4 substituents, the substituent of which is independently selected from the group consisting of: acetamido, acetyl, acetylamino, amido, amino, carboxyl, cyanide Base, halogen, halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 Alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S(O) ₂ -;

a cycloalkyl group, or a cycloalkyl group substituted by 1 to 4 substituents, the substituents being independently selected from the group consisting of: acetamido, acetyl, acetylamino, amido, amino, carboxyl, cyano, halogen , halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S(O) ₂ -;

a heterocyclic group, or a heterocycloalkyl group substituted by 1 to 4 substituents independently selected from the group consisting of acetamido, acetyl, acetylamino, amido, amino, carboxyl, cyano, halogen , halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S(O) ₂ -;

Preferably Y2 is selected from C1-6 alkyl; C1-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of amino, halogen, hydroxy, methyl, C1-6 alkoxy , cycloalkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S(O) ₂ -;

a C5-C6 heteroaryl group containing 1-3 hetero atoms selected from N, O or S; a C1-alkyl substituted a C5-C6 heteroaryl having 1-3 heteroatoms selected from N, O or S;

C3-6 cycloalkyl; C3-6 cycloalkyl substituted by 1-4 substituents, which are individually selected from the group consisting of: amino, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy , C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1- 6 alkyl-S(O) ₂ -;

a C4-C6 heterocyclic group containing 1-3 hetero atoms selected from N, O or S; C4-containing 1-4 hetero atoms selected from N, O or S substituted by 1 to 4 substituents a C6 heterocyclic group, which is independently selected from the group consisting of methyl, amino, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1 -6 alkyl and C 1-6 alkyl-S(O) ₂ -;

More preferably, Y2 is selected from a C1-6 alkyl group; a C1-6 alkyl group substituted with 1 to 5 substituents, which are individually selected from the group consisting of: a hydroxyl group, a halogen, a C1-6 alkoxy group, a cycloalkyl group And methyl;

a C5-C6 heteroaryl group containing 1-3 heteroatoms selected from N, O or S; a C5-C6 substituted with a C1-6 alkyl group containing 1-3 heteroatoms selected from N, O or S Heteroaryl

a C4-6 cycloalkyl group; a C3-6 cycloalkyl group substituted with 1 to 4 substituents, the substituent being a hydroxyl group;

a C4-C6 heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S; C4 having 1 to 3 hetero atoms selected from N, O or S substituted by 1 to 4 substituents a -C6 heterocycloalkyl group, said substituent being a methyl group;

More preferably Y2 is selected from the group consisting of hydroxy-n-propanol, hydroxycyclopentyl, cyclopropyl, methylpyrazolyl, isopropyl, trifluoroethyl, methoxyethyl, tetrahydropyranyl, methyl , tetrahydrofuranyl, cyclobutyl, amino, cyclopropylmethyl, hydroxydimethylethyl, hydroxymethylpropyl, hydroxyethyl, hydroxymethylbutyl and ethyl;

The most preferred Y2 is selected from the group consisting of 1-hydroxy-n-propanol-2-yl, 2-hydroxycyclopentyl, cyclopropyl, 1-methyl-1H-pyrazol-4-yl, isopropyl, 2,2, 2-Trifluoroethyl, 2-methoxyethyl, tetrahydro-2H-pyran-4-yl, methyl, tetrahydrofuran-3-yl, cyclobutyl, amino, cyclopropylmethyl, 2- Hydroxy-1,1-dimethyl-ethyl, 1-hydroxymethylpropyl, 2-hydroxyethyl, 1-hydroxymethylbutyl and ethyl;

Or Y1, Y2 together with the N atom to which they are attached form a 4-6 membered heterocyclic group;

Preferably, either Y1, Y2 together with the N atom to which they are attached form a 4-6 membered heterocyclic group containing, in addition to a nitrogen atom, zero, one or more impurities selected from O and S An atom, and the S atom may be in the form of its oxide;

More preferably, or Y1 and Y2 together with the nitrogen atom to which they are attached form a dioxide thiomorpholinyl, morpholinyl, azetidinyl, pyrrolidinyl or piperidinyl;

Most preferably either Y1 and Y2 together with the nitrogen atom to which they are attached form a 1,1-dioxo- Thiomorpholin-4-yl, morpholin-4-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl;

Y3, Y4 each independently selected from: hydrogen, C1-C6 alkyl, SO ₂ -C1-C6 alkyl, cycloalkyl, or Y3 and Y4 nitrogen atom to which they are attached form a heterocyclyl;

Preferably, Y3, Y4 each independently selected from: hydrogen, C1-C6 alkyl, SO ₂ -C1-C6 alkyl, cycloalkyl and heterocyclyl optionally substituted with 1-4 groups independently selected from the group of Base substitution: halogen, cyano, hydroxy, C1-C6 alkyl and C1-C6 alkoxy,

Or wherein Y3, Y4 together with the nitrogen atom to which they are attached form a heterocyclic group which is optionally substituted with from 1 to 4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C6 alkyl and C1-C6 alkoxy.

More preferably, Y3 and Y4 are independently selected from hydrogen: or together with the nitrogen atom to which they are attached to form a heterocyclic group selected from the group consisting of morpholinyl, pyrrolidinyl, piperidinyl and dioxothiomorpholinyl.

Most preferably Y3 and Y4 are independently selected from the group consisting of: hydrogen or, together with the nitrogen atom to which they are attached, form a heterocyclic group selected from the group consisting of morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl and 1,1-dioxo-thiomorpholin-4-yl.

The invention also provides a compound having the following general formula II:

among them

R4 is a C1-C4 alkyl group or a hydroxy-substituted C1-C4 alkyl group;

Y is NY1Y2 or NH-NY3Y4;

Y1 is H, C1-6 alkyl or C1-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of amino, hydroxy, C1-6 alkoxy, (C1-6 alkane) Base, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S(O) ₂ -;

Y2 is selected from C1-6 alkyl; C1-6 alkyl substituted by 1-5 substituents, which are individually selected from the group consisting of: amino, halogen, hydroxy, methyl, C1-6 alkoxy, ring Alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S(O) ₂ -;

a C4-C6 heterocyclic group containing 1-3 hetero atoms selected from N, O or S; C4-containing 1-4 hetero atoms selected from N, O or S substituted by 1 to 4 substituents a C6 heterocyclic group, which is independently selected from the group consisting of methyl, amino, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1 -6 alkyl group and C1-6 alkyl group -S (O) ₂ -;

Y3, Y4 each independently selected from: hydrogen, C1-C6 alkyl, SO ₂ -C1-C6 alkyl, or Y3 and Y4 together with the nitrogen atom to which they are attached a heterocyclic group;

In a preferred embodiment, among the compounds of formula II,

R4 is a methyl group substituted by a methyl group or a hydroxy group;

Y is NY1Y2 or NH-NY3Y4;

Y3, Y4 are independently selected from the group consisting of hydrogen, C1-C6 alkyl and SO2-C1-C6 alkyl, or Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group.

In a preferred embodiment, among the compounds of formula II,

R4 is a C1-C4 alkyl group or a hydroxy-substituted C1-C4 alkyl group;

Y is NY1Y2 or NH-NY3Y4;

Y1 is H or C1-6 alkyl;

Y2 is selected from C1-6 alkyl; C1-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of: hydroxy, halogen, C1-6 alkoxy, cycloalkyl and methyl ;

Or Y1, Y2 together with the N atom to which they are attached form a 4-6 membered heterocyclic group containing, in addition to a nitrogen atom, zero, one or more heteroatoms selected from O and S, And the S atom may be in the form of its oxide;

Y3 and Y4 are independently selected from each other: hydrogen, or Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group.

In a preferred embodiment, among the compounds of formula II,

R4 is a methyl group substituted by a methyl group or a hydroxy group;

Y is NY1Y2 or NH-NY3Y4;

Y1 is H or C1-6 alkyl;

In a preferred embodiment, among the compounds of formula II,

R4 is a C1-C4 alkyl group or a hydroxy-substituted C1-C4 alkyl group;

Y is NY1Y2 or NH-NY3Y4;

Y1 is H or methyl.

In a preferred embodiment, among the compounds of formula II,

R4 is a methyl group substituted by a methyl group or a hydroxy group.

Y is NY1Y2 or NH-NY3Y4;

Y1 is H or methyl;

C3-6 cycloalkyl; C3-6 cycloalkyl substituted by 1-4 substituents, which are individually selected from the group consisting of: amino, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy , C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1- 6 alkyl -S (O) ₂ -;

Y3, Y4 each independently selected from: hydrogen, C1-C6 alkyl, and SO ₂ -C1-C6 alkyl, or Y3 and Y4 together form a heterocyclic group with the nitrogen atom to which they are attached.

In a preferred embodiment, among the compounds of formula II,

R4 is a C1-C4 alkyl group or a hydroxy-substituted C1-C4 alkyl group;

Y is NY1Y2 or NH-NY3Y4;

Y1 is H or methyl;

In a preferred embodiment, among the compounds of formula II,

R4 is a methyl group substituted by a methyl group or a hydroxy group;

Y is NY1Y2 or NH-NY3Y4;

Y1 is H or methyl;

In a preferred embodiment, among the compounds of formula II,

R4 is a C1-C4 alkyl group or a hydroxy-substituted C1-C4 alkyl group;

Y is -NY1Y2 or -NH-NY3Y4;

Y1 is H or C1-6 alkyl;

Y2 is selected from the group consisting of hydroxy-n-propanol, hydroxycyclopentyl, cyclopropyl, methylpyrazolyl, isopropyl, trifluoroethyl, methoxyethyl, tetrahydropyranyl, methyl, tetrahydrofuranyl , cyclobutyl, amino, cyclopropylmethyl, hydroxydimethylethyl, hydroxymethylpropyl, hydroxyethyl, hydroxymethylbutyl and ethyl;

Or Y1 and Y2 together with the nitrogen atom to which they are attached form a dioxide thiomorpholinyl, morpholinyl, azetidinyl, pyrrolidinyl or piperidinyl;

Y3 and Y4 are independently selected from each other: hydrogen, or together with the nitrogen atom to which they are attached, form a heterocyclic group selected from the group consisting of morpholinyl, pyrrolidinyl, piperidinyl and dioxothiomorpholinyl.

In a preferred embodiment, among the compounds of formula II,

R4 is a methyl group substituted by a methyl group or a hydroxy group;

Y is -NY1Y2 or -NH-NY3Y4;

Y1 is H or C1-6 alkyl;

In a preferred embodiment, among the compounds of formula II,

R4 is a C1-C4 alkyl group or a hydroxy-substituted C1-C4 alkyl group;

Y is NY1Y2 or NH-NY3Y4;

Y1 is H or C1-6 alkyl;

Y2 is selected from the group consisting of 1-hydroxy-n-propanol-2-yl, 2-hydroxycyclopentyl, cyclopropyl, 1-methyl-1H-pyrazol-4-yl, isopropyl, 2,2,2-tri Fluoroethyl, 2-methoxyethyl, tetrahydro-2H-pyran-4-yl, methyl, tetrahydrofuran-3-yl, cyclobutyl, amino, cyclopropylmethyl, 2-hydroxy-1 , 1-dimethyl-ethyl, 1-hydroxymethylpropyl, 2-hydroxyethyl, 1-hydroxymethylbutyl and ethyl;

Or Y1 and Y2 together with the nitrogen atom to which they are attached form 1,1-dioxo-thiomorpholin-4-yl, morpholin-4-yl, azetidin-1-yl, pyrrolidine- 1-yl or piperidin-1-yl;

Y3 and Y4 are independently selected from each other: hydrogen or together with the nitrogen atom to which they are attached to form a heterocyclic group selected from the group consisting of morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl and 1,1 - dioxo-thiomorpholin-4-yl.

In a preferred embodiment, among the compounds of formula II,

R4 is a methyl group substituted by a methyl group or a hydroxy group;

Y is NY1Y2 or NH-NY3Y4;

Y1 is H or C1-6 alkyl;

In a preferred embodiment, among the compounds of formula II,

R4 is a C1-C4 alkyl group or a hydroxy-substituted C1-C4 alkyl group;

Y is -NY1Y2 or -NH-NY3Y4;

Y1 is H or methyl;

Y2 is selected from the group consisting of hydroxy-n-propanol, hydroxycyclopentyl, cyclopropyl, methylpyrazolyl, isopropyl, Trifluoroethyl, methoxyethyl, tetrahydropyranyl, methyl, tetrahydrofuranyl, cyclobutyl, amino, cyclopropylmethyl, hydroxydimethylethyl, hydroxymethylpropyl, hydroxyethyl Base, hydroxymethylbutyl and ethyl;

In a preferred embodiment, among the compounds of formula II,

R4 is a methyl group substituted by a methyl group or a hydroxy group;

Y is -NY1Y2 or -NH-NY3Y4;

Y1 is H or methyl;

In a preferred embodiment, among the compounds of formula II,

R4 is a C1-C4 alkyl group or a hydroxy-substituted C1-C4 alkyl group;

Y is -NY1Y2 or -NH-NY3Y4;

Y1 is H or methyl;

In a preferred embodiment, among the compounds of formula II,

R4 is a methyl group substituted by a methyl group or a hydroxy group;

Y is -NY1Y2 or -NH-NY3Y4;

Y1 is H or methyl;

In a preferred embodiment, the compound of formula II is selected from the group consisting of:

In a more preferred embodiment, the compound of formula II is selected from the group consisting of:

The invention also provides a composition comprising a compound as described above or a pharmaceutically acceptable salt thereof.

The invention also provides the use of a compound or composition as described above for the preparation of a medicament.

The invention also provides a method of treating or preventing a disease comprising administering to a patient an effective amount of a compound or composition as described above.

The invention also provides the use of a compound or composition described herein for the manufacture of a medicament for the treatment or prevention of a disease associated with the α5-GABA _A receptor.

The invention also provides a method of treating or preventing a disease associated with an α5-GABA _A receptor, characterized by administering to a patient an effective amount of a compound or composition as described above.

The invention also provides the use of a compound or composition described herein in the manufacture of a medicament for the treatment or prevention of pain, Alzheimer's disease, multi-infarct dementia and stroke.

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

In a preferred embodiment, the pain is selected from the group consisting of: headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, back pain, lower limb pain, musculoskeletal pain, vascular pain, gout , arthritis pain, visceral pain, pain caused by infectious diseases (such as AIDS and post-herpetic neuralgia), bone pain, sickle cell anemia, autoimmune disease, multiple sclerosis or inflammation-related pain, injury or Chronic pain caused by 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 osteoarthrosis.

The invention also provides a method of treating or preventing pain, Alzheimer's disease, multi-infarct dementia and stroke, characterized by administering to a patient an effective amount of a compound or combination as described herein. Things.

The invention further relates to a process for the production of a compound of formula (I) as defined above, which process comprises:

a) making a compound of formula (IV)

versus

The reaction gives a compound of the formula (1-3) wherein G and W are selected from the group consisting of Cl, Br, I, OH, OTs, OTf and OMs, and R5 is an alkyl group and a benzyl group, preferably a methyl group, an ethyl group, a t-butyl group; Z, Y, A are as defined above;

Then make the compound of formula (1-3)

Reacting with Y, wherein Z, Y, A are as defined above; or

b) Compounds of formula (1-4):

Reacting with Y, wherein Z, Y, A are as defined above;

c) saponifying a compound of formula (1-3) to a compound of formula (1-4), followed by reaction with Y, wherein Z, Y, A are as defined above;

d)

Compound and formula

The reaction of the compound.

In the compounds of the formulae I and II in the present invention, Z represents a 5-membered heteroaryl ring containing 1, 2 or 3 hetero atoms independently selected from the group consisting of oxygen, nitrogen and sulfur, and the 5-membered heteroaryl ring is a Or a plurality of substituents selected from the group consisting of: hydroxy, halogen, -R1, -OR1, -OC(O)R1, -NR2R3, CN, cyano(C1-6)alkyl- or R2; wherein R1 Represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkyl (C1-6) alkyl, cyano (C1-6) alkyl a hydroxy or amino substituted C1-6 alkyl group, and R1 is optionally mono-, di- or trifluoro; R2 or R3 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 Alkynyl, C3-6 cycloalkyl or CF3, or R2 and R3 together with the nitrogen atom to which they are attached form a 4-7 membered heteroaliphatic ring containing the nitrogen atom and one optionally selected from O, N and Other heteroatoms of S, said ring optionally being optionally substituted by one or more R1 groups; preferably Z represents a 5-membered impurity containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur An aromatic ring in which at most one hetero atom is oxygen or sulfur, and when one hetero atom is a nitrogen atom, at least one oxygen or sulfur is also present The 5-membered heteroaryl ring is optionally substituted with one or more substituents selected from the group consisting of C1-C4 alkyl, hydroxy, halogen, a hydroxy or amino substituted C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 alkoxy group; more preferably Z represents 1 or 2 independently selected from the group consisting of oxygen, nitrogen and sulfur. a 5-membered heteroaryl ring of a hetero atom, and at most one hetero atom is oxygen or sulfur, and when one hetero atom is a nitrogen atom, one oxygen atom or one sulfur atom is also present; preferably Z represents 2 a 5-membered heteroaryl ring independently selected from heteroatoms of oxygen, nitrogen and sulfur, and one hetero atom is oxygen or sulfur and the other atom is nitrogen; the 5-membered heteroaryl ring is one or more selected from the group consisting of The substituent is optionally substituted: C1-6 alkyl or hydroxy C1-6 alkyl; preferably Z represents oxadiazole, furyl, thienyl or isoxazolyl, said oxadiazole, furanyl The thienyl or isoxazolyl group is optionally substituted by one or more substituents selected from C1-6 alkyl or hydroxy C1-6 alkyl; more preferably, Z represents oxadiazole, furanyl Or a thienyl or isoxazolyl group, the oxadiazole, furyl, thienyl or isoxazolyl is optionally substituted by one or more substituents selected from the group consisting of methyl and hydroxymethyl.

In the compounds of the formulae I and II in the present invention, A is -NR2-; or A is a 5-membered heteroarylene containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. And at most one of the heteroatoms is oxygen or sulfur, or a 6-membered heteroarylene containing 1, 2 or 3 nitrogen atoms, or the 5 or 6-membered heteroarylene is optionally fused to On the phenyl or pyridine ring, the 5 or 6 membered heteroarylene is optionally substituted by Rx and/or Ry and/or Rz, wherein Rx is halo, -R1, -OR1, -OC(O)R1, - C(O)OR1, -NR2R3, -NR2C(O)R3, -OH, -CN, Ry is halogen, -R1, -OR1, -OC(O)R1, -NR2R3, -NR2C(O)R3, or CN, Rz is -R1, -OR1 or -OC(O)R1, provided that when A is a pyridine derivative, the pyridine ring is optionally in the form of an N-oxide; or A is 1, 2 or 3 independently An optionally substituted phenylene group selected from the group consisting of halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C3-6 cycloalkyl; preferably A represents 1, 2 or 3 5-membered heteroarylenes independently selected from heteroatoms of oxygen, nitrogen and sulfur and up to 1 of which are oxygen or sulfur, or 6 yuan containing 1, 2 or 3 nitrogen atoms a heteroarylene or phenylene group; The 5-membered heteroarylene, 6-membered heteroarylene and phenylene are optionally substituted with a substituent selected from the group consisting of halogen, cyano and C1-6 alkyl; more preferably A represents phenylene, a pyridylene group, an isoxazolyl group; optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano and C1-6 alkyl;

In the compounds of the formula I and II in the present invention, Y is -NY1Y2 or -NH-NY3Y4;

More preferably, Y1 is represented by H or C1-6 alkyl;

Most preferably Y1 is represented by H or methyl;

Most preferably, or Y1 and Y2 together with the nitrogen atom to which they are attached form 1,1-dioxo-thiomorpholin-4-yl, morpholin-4-yl, azetidin-1-yl, Pyrrolidin-1-yl or piperidin-1-yl;

detailed description

Unless otherwise indicated, the following definitions are used to illustrate and define the meaning and scope of the various terms used herein to describe the invention.

The following definitions of general terms apply whether they occur individually or in combination.

The naming convention used in this application is based on AutoNomTM 2000, a Beilstein Institute computerized system for generating IUPAC system naming. The chemical structure given herein was obtained using ChemDraw version 12. Any open valence bond present on a carbon, oxygen, sulfur or nitrogen atom in the structure given herein indicates the presence of a hydrogen atom.

Unless otherwise indicated, the term "substituted" means that the specified group or moiety may have 1, 2, 3, 4, 5 or 6 substituents. When a group may have a plurality of substituents and a plurality of possible substituents are given, the substituents are independently selected and are not necessarily the same.

The term "unsubstituted" means that the specified group does not have a substituent.

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

When the number of substituents is indicated, the term "one or more" refers to the most likely number of substitutions to substitutions, i.e., substitution of one hydrogen to all hydrogens is replaced by a substituent. Unless otherwise specified, 1, 2, 3, 4 or 5 substituents are preferred.

The term "halogen" means fluoro, chloro, bromo and iodo, preferably fluoro.

The term "lower alkyl" as used herein, refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, which may be interchanged with a C1-6 alkyl group as described herein, and an example of a C1-6 alkyl group. For example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl groups and those groups specifically exemplified below. Particularly preferred "lower alkyl" are methyl and n-butyl.

The term "lower alkoxy" refers to the group -O-R, wherein R is lower alkyl as defined above.

The term "cycloalkyl" refers to a monovalent saturated cyclic hydrocarbon group, preferably a monovalent saturated cyclic hydrocarbon group having from 3 to 7 ring carbon atoms, more preferably from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl, as well as those groups specifically exemplified below.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic group having a hetero atom, preferably containing one, two or three ring heteroatoms selected from N, O or S. -7-membered saturated or partially unsaturated monocyclic ring. It preferably contains one or two ring heteroatoms. A 4-6 membered heterocyclic group containing one or two ring hetero atoms selected from N, O or S is preferred. S can be optionally substituted with two oxo groups. Examples of heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidin Pyridyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, piperazinyl, azepanyl, diazepanyl, oxygen Azepanyl or dihydro-oxazolyl, and those groups specifically exemplified below. Preferred heterocyclic groups are morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4-yl and 1,1-dioxo-thiomorpholine-4 Particularly preferred heterocyclic groups are morpholin-4-yl, pyrrolidin-1-yl and 1,1-dioxo-thiomorpholin-4-yl.

The term "aryl" refers to a monovalent aromatic carbocyclic ring system containing 6-14, preferably 6-10, carbon atoms and having at least one aromatic ring or a polyfused ring wherein at least one ring is an aromatic ring. Examples of aryl groups are phenyl, naphthyl, biphenyl or indanyl, as well as those groups specifically exemplified below. Preferred aryl groups are phenyl groups, and aryl groups can also be substituted, as defined below and in the claims.

The term "heteroaryl" is an aromatic radical containing a hetero atom, preferably an aromatic 5-6 membered monocyclic ring or 9-10 member containing one, two or three atoms selected from nitrogen, oxygen and/or sulfur. Bicyclic rings such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetra Azyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, fluorenyl, oxazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, Quinolinyl or isoquinolyl, as well as those groups specifically exemplified below. Heteroaryl groups can also be substituted, as defined below and in the claims. A preferred heteroaryl group is 5-fluoro-pyridin-2-yl.

The term "lower alkyl substituted by halogen" means a lower alkyl group which is mono- or polysubstituted by halogen. Examples of lower alkyl substituted by halogen are, for example, CFH ₂ , CF ₂ H, CF ₃ , CF ₃ CH ₂ , CF ₃ (CH ₂ ) ₂ , (CF ₃ ) ₂ CH or CF ₂ H-CF ₂ , and Those groups specifically exemplified herein.

The term "lower alkyl substituted by hydroxy" means a lower alkyl group as defined above wherein a hydrogen atom in at least one alkyl group is substituted by a hydroxy group. Examples of lower alkyl substituted by hydroxy include, but are not limited to, methyl, ethyl, propyl, isopropyl substituted by one or more hydroxyl groups, particularly one, two or three hydroxyl groups, preferably one or two hydroxyl groups. Base, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl.

The compounds of formula (I) and (II) can form pharmaceutically acceptable acid addition salts. Examples of such pharmaceutically acceptable salts are those formed by the compounds of formula (I) and (II) with a physiologically compatible inorganic or organic acid such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid; organic acids For example, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term "pharmaceutically acceptable salt" refers to such salts. The compound of formula (I) containing an acidic group such as COOH can also form a salt with a base. Examples of such salts are alkali metal, alkaline earth metal and ammonium salts, such as Na-, K-, Ca- and trimethylammonium salts. The term "pharmaceutically acceptable salt" also refers to such salts.

The term "pharmaceutically acceptable ester" includes derivatives of the compounds of formula (I) and (II) wherein the carboxyl group is converted to an ester. Lower alkyl, lower alkyl substituted by hydroxy, lower alkyl substituted by lower alkoxy, amino-lower alkyl, mono- or di-lower alkyl-amino-lower alkyl, morpholino-lower alkyl , pyrrolidino-lower alkyl, piperidino-lower alkyl, piperazino-lower alkyl, lower alkyl-piperazino-lower alkyl and aryl-lower-alkyl ester are An example of a suitable ester. Preference is given to methyl, ethyl, propyl, butyl and benzyl esters. The term "pharmaceutically acceptable ester" also includes derivatives of the compounds of formula (I) wherein the hydroxy group is converted to the corresponding ester by an inorganic or organic acid such as nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, Maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, etc., these acids are non-toxic to organisms.

Preparation

a) making a compound of formula (IV)

versus

a reaction wherein G and W are optionally Cl, Br, I, OH, OTs, OTf and OMs, etc.; R5 is alkyl and benzyl, preferably methyl, ethyl, tert-butyl, and then

Compound of formula (1-3)

React with Y or

b) Compounds of formula (1-4):

Reacts with Y; or

c) saponifying a compound of formula (1-3) to a compound of formula (1-4), followed by reaction with Y;

d)

Compound and formula

Compound reaction,

Wherein Z, Y, and A are as defined above.

Make

versus

The reaction wherein G and W are optional substituents such as Cl, Br, I, OH, OTs, OTf and OMs. The reaction can be carried out under the conditions described in the examples or under conditions known to those skilled in the art. For example, the reaction can be carried out under LDA, NaH, potassium or sodium t-butoxide, in a suitable solvent such as dioxane at room temperature (e.g., 20 ° C). Alternatively, it is a production condition for producing an ether using Mitsunobu conditions (PPh3, DEAD), a phase transfer catalyst (TBAB, crown ether), or the like.

formula

The reaction of the compound with Y to give a compound of formula (I) can be carried out under the conditions described in the examples or under conditions known to those skilled in the art. For example, the reaction can be carried out in the presence of trimethylaluminum in a suitable solvent such as dioxane at elevated temperatures (e.g., 85-95 ° C).

formula

The reaction of the compound with Y to give a compound of formula (I) can be carried out under the conditions described in the examples or under conditions known to those skilled in the art. For example, the reaction can be carried out in Hünigs base (N,N-diisopropylethylamine) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea The reaction is carried out in the presence of tetrafluoroborate in a suitable solvent such as dimethylformamide at room temperature. Alternatively, the reaction can be carried out in the presence of 1,1'-carbonyldiimidazole in a suitable solvent such as dimethylformamide at elevated temperature (e.g., 80 ° C). In addition, the reaction can also be carried out in 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N1-hydroxybenzotriazole and Hünigs base (N,N-diisopropyl) The reaction is carried out in the presence of a base ethylamine in a suitable solvent such as dichloromethane at room temperature.

formula

The saponification of the compound to the compound of formula (1-4) can be carried out under the conditions described in the examples or under conditions known to those skilled in the art. For example, the reaction can be carried out in the presence of sodium hydroxide in a suitable solvent such as water at room temperature. Alternatively, the reaction can be carried out in the presence of sodium hydroxide or lithium hydroxide in a suitable solvent such as tetrahydrofuran or water at room temperature. Alternatively, it may be carried out under other conditions as described or under conditions known to those skilled in the art, such as hydrogenation of the benzyl group, hydrolysis of the t-butyl group under acidic conditions and the like.

formula Compound and formula

The reaction of the compound to give the compound of formula (I) can be carried out under the conditions described in the examples or under conditions known to those skilled in the art. For example, the reaction can be carried out under LDA, NaH, potassium or sodium t-butoxide, in a suitable solvent (such as dioxane, THF, DMF, etc.) at room temperature (eg, 20 ° C). . Alternatively, it is a production condition for producing an ether using Mitsunobu conditions (PPh3, DEAD), a phase transfer catalyst (TBAB, crown ether, etc.). The product is formed under appropriate base or catalyst conditions in a suitable solvent such as dioxane, THF and DMF, at elevated temperature (e.g., 80 ° C).

The invention further relates to compounds of formula (II) as described above, which are prepared by the methods described above.

The compound of the formula (II) of the present invention and a pharmaceutically acceptable salt thereof can be produced by the following methods.

If the preparation process is not described in the examples, the compound of the formula (II) and its intermediate product can be produced according to a similar method or according to the aforementioned method. Starting materials known in the art may be obtained commercially or may be prepared according to methods known in the art or analogous methods known in the art.

It will be appreciated that the compounds of formula (II) of the present invention can be derivatized on functional groups to provide derivatives which are capable of reconversion into the parent compound in vivo.

As described above, the novel compounds of the present invention and pharmaceutically acceptable salts and esters thereof have important pharmacological properties and are α5 GABA _A receptor inverse agonists. Thus, the compounds of the invention may be used alone or in combination with other drugs for the treatment or prevention of diseases mediated by GABA _A receptor ligands containing the alpha 5 subunit. These diseases include, but are not limited to, pain, Alzheimer's disease, multiple infarct dementia, and stroke.

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

Also, the present invention includes the compounds as described above for use in the preparation of a medicament for the treatment or prevention of a disease associated with the α5 GABA _A receptor, in particular for the treatment or prevention of the following diseases: pain, Alzheimer's disease, multi-infarctability Dementia and stroke.

It is preferred to treat or prevent pain. It is particularly preferred to treat or prevent neuropathic pain, inflammatory pain, and cancer pain.

As used herein, "cancerous pain" refers to the pain that occurs during the development of a malignant tumor. The occurrence of cancer pain is currently believed to have three mechanisms: pain directly caused by cancer development, pain caused by cancer treatment, and cancer patients. Complicated with painful diseases.

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

As used herein, "inflammatory pain" is pain caused by local acute inflammation or chronic inflammation stimulating nerves.

As used herein, "treatment" also includes prophylactic administration to alleviate or eliminate the condition once the condition is established.

As used herein, "patient" is defined as any warm-blooded animal, such as, but not limited to, a mouse, a guinea pig, a dog, a horse, or a human, preferably a human.

As used herein, "acute pain" is defined as pain caused by damage to the skin, body structure or internal organs and/or harmful irritation of the disease, or pain caused by abnormal function of the muscle or viscera that does not cause actual tissue damage. .

As used herein, "chronic pain" is defined as a reasonable period of time beyond the usual course of the acute disease or the healing of the injury, or associated with a chronic pathological process that causes persistent pain, or pain that recurs at intervals of months or years, if It is considered to be chronic pain after pain has been reached or after the usual treatment process. The length of time required for pain depends on the nature of the pain Quality and pain-related treatment processes, 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, back pain, lower limb pain, musculoskeletal pain, pain associated with somatic-like mental disorders, visceral pain, painful diabetes Sexual neuropathy, vascular pain, gout, arthritic pain, cancer pain, autonomic reflex pain, pain caused by infectious diseases (such as AIDS and herpes zoster), pain caused by autoimmune diseases (rheum), acute and chronic Pain caused by inflammation, post-operative pain, and pain after burns.

The medicament disclosed in the present invention can effectively treat chronic pain as defined above, and the medicament disclosed in the present invention can be used for treating pain sensitivity accompanying other disorders, including hyperalgesia, allodynia, pain enhancement and pain memory enhancement, and the invention will improve Treatment of its pain.

As used herein, "headache" can be divided into primary headaches and secondary headaches. Primary headaches include tension headaches, migraine headaches, and cluster headaches, while secondary headaches are caused by other diseases. Pain-sensitive tissue of the head and face can cause various headaches when it is damaged or stimulated. These pain-sensitive tissues include the scalp, face, mouth and throat. Because they are mainly the muscles or blood vessels of the head, they are rich in nerves. Fiber, which is sensitive to pain, can cause headaches when these tissues are damaged.

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

As used herein, "trigeminal neuralgia" is a unique chronic painful condition, also known as painful convulsion, which refers to the appearance of transient, paroxysmal and recurrent electric shock-like severe pain in the area of the trigeminal nerve. Or accompanied by the same side tendon. Trigeminal neuralgia is divided into two types: primary and secondary. Primary trigeminal neuralgia refers to no clinical signs of the nervous system. No organic lesions are found. Secondary trigeminal neuralgia refers to clinical There are signs of the nervous system, and organic diseases such as tumors and inflammation are found.

As used herein, "atypical facial pain" refers to pain caused by a variety of causes. It is characterized by persistent burning pain, no intermittentness, and no special action or triggering stimulation. The pain is mostly bilateral, and the pain often exceeds the distribution of the trigeminal nerve and even the skin of the neck. The cause can be caused by sinusitis, malignant tumor, jaw and skull base infection or other causes of stimulation or damage to the trigeminal nerve.

As used herein, "neck pain, back pain, shoulder pain" refers to pain caused by acute and chronic muscle strain and degenerative changes and trauma of bones and joints. Common diseases that cause pain in the neck, shoulders and upper extremities are neck and shoulders Myofasciitis, ligament inflammation, cervical spondylosis, frozen shoulder, thoracic outlet syndrome, external humeral epicondylitis, or pain caused by autoimmune diseases are common in rheumatoid arthritis, ankylosing spondylitis, and Rheumatoid arthritis and other diseases, other diseases that may cause neck pain, back pain, shoulder pain, neck and shoulder tumors, neuritis, arteriovenous diseases and various infections, as well as pains involved in chest and abdominal organ diseases Wait.

As used herein, "chest, abdomen and back pain" refers to pain caused by diseases of the visceral and thoracic and abdominal tissues of the chest and abdomen, including but not limited to intercostal neuralgia, intercostal chondritis, angina pectoris, abdominal pain (acute abdominal visceral pain). And lumbar back myofascial syndrome.

As used herein, "waist, lower limb pain" refers to lower back, lumbosacral, sacral, hip, hip, and lower extremity pain. Waist and lower extremity pain is often not an independent disease, but a common feature of a variety of diseases, clinical manifestations are diverse, the cause is very complex, with degenerative and injury, including but not limited to lumbar disc herniation, acute lumbar sprain, sciatica Osteoporosis, third lumbar transverse process syndrome, piriformis syndrome, knee osteoarthritis, tail pain and heel pain.

As used herein, "muscle and bone pain" includes, but is not limited to, myofascial pain, wound-induced pain, and chronic regional pain syndrome.

As used herein, "painful diabetes" refers to pain caused by a neurological injury associated with diabetes, which is at least in part due to reduced blood flow and hyperglycemia. Some diabetic patients do not develop neuropathy, and other patients develop the disease early. Diabetic neuropathic pain can be divided into single neuropathy and systemic polyneuropathy involving one or more lesion sites, which may be diffusion and symmetry. Often, it mainly involves the way of feeling (Merrit's Textbook of Neurology, 9th edition, edited by LPRowland LP). The manifestations of diabetic neuropathy can include autonomic dysfunction, leading to dysregulation including the heart, smooth muscles, and glands, causing hypotension, diarrhea, constipation, and sexual incompetence. Diabetic neuropathy often develops in stages, early in the nerve ending area, autonomic or sensory neuropathy occurs in the foot, cranial neuropathy occurs around the face and around the eyes, intermittent pain and tingling, in the subsequent stages, Pain is stronger and more frequent. Finally, when pain loss occurs in a certain area, it occurs as a painless neuropathy. Since there is no pain as an indication of injury, the risk of serious tissue damage is greatly increased.

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

As used herein, "vascular pain" is pain that results from one or more of the following factors. the first, Improper perfusion of the tissue. Causes temporary or continuous ischemia, such as ischemia in the limb muscles during exercise; second, delayed onset. For example, ulcers or gangrene in the skin or abdominal viscera; third, sudden or accelerated changes in the caliber of large vessels. For example, changes in aneurysm; fourth, aortic rupture. The result is blood spillage, stimulation of nociceptive fibers in the peritoneal or pleural wall; fifth, due to intra-arterial injection of severe stimulation of the arterial endothelium; and sixth, venous return damage, the result is rapid expansion of the fascial septum A large amount of edema in the chamber (Bonica et al, The Management of Pain, Vol. I (Second Edition), Philadelphia; Lea & Feboger, 1990). Examples include, but are not limited to, occlusive arteriosclerosis, occlusive thromboangiitis, acute arterial occlusion, embolism, congenital arteriovenous vascular disease, vasospasm disease, Rayaud disease, hand and foot cyanosis, acute venous closure, thrombophlebitis, varicose veins And lymphedema.

As used herein, "autonomic reflex pain" refers to pain caused by "reflex sympathetic atrophy." Reflex sympathetic atrophy sign refers to the body's acute and chronic pain, severe spontaneous pain, allergies to touch and pain, may be accompanied by edema and blood disorder, followed by skin and musculoskeletal nutrition disorders and atrophy.

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

As used herein, "arthritic pain" includes, but is not limited to, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriasis joint disease, gout, pseudogout, infectious arthritis, tendonitis, bursa Pain caused by diseases such as inflammation, bone damage and joint soft tissue inflammation.

As used herein, "herbalgia after herpes zoster" refers to the severe pain that persists under the skin of the original rash area after healing of the rash of herpes zoster.

As used herein, "nociceptive pain" is pain caused by a process of tissue damage induced by stimulation of nociceptors, or by excitability prolonged by nociceptors. The pain caused by the excitability of the nociceptors may be caused by the persistent noxious stimuli of the nociceptors or their sensitization or both, or they may be caused by these factors, and by their persistence, various reflex mechanisms and other factors And extended.

Pharmaceutical composition

The invention provides the use of a pharmaceutical composition comprising a therapeutically effective amount of an α5-GABA _A inverse agonist. While the α5-GABA _A inverse agonist for use in the treatment of the present invention may be administered as a starting compound, it is preferred to have the active ingredient, optionally in the form of a physiologically acceptable salt, with one or more additives, Excipients, carriers, buffers, diluents and/or other conventional pharmaceutical excipients are combined together to form a pharmaceutical composition.

In a preferred embodiment, the invention provides a pharmaceutical composition comprising an α5-GABA _A inverse agonist, wherein the α5-GABA _A inverse agonist is combined with one or more pharmaceutically acceptable carriers, and optionally Mix with other therapeutic and/or prophylactic components known or used in the art. The carrier must be "acceptable", i.e., compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical compositions for use in the present invention may be those suitable for oral, rectal, bronchial, nasal, pulmonary, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including skin, subcutaneous, intramuscular, Compositions for intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion, or those in a form suitable for inhalation or spray administration, including powders and liquid aerosols, or A pharmaceutical composition for sustained release system administration. Examples of suitable sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compounds of the invention, wherein the matrices can be in the form of shaped articles, such as films or microcapsules.

The compound for use in the present invention can thus be formulated into a pharmaceutical composition and unit dosage form thereof together with conventional additives, or diluents. Forms such as these include solids (especially in the form of tablets, filled capsules, powders and pills), and liquids (especially aqueous or non-aqueous solutions, suspensions, emulsions, elixirs), and capsules filled with the above forms, all orally Forms for administration, suppositories for rectal administration, and sterile injectable solutions for parenteral administration. Such pharmaceutical compositions and unit dosage forms thereof may include conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and such unit dosage forms may contain any suitable, effective, equivalent Amount of active ingredient.

The compounds used in the present invention can be administered in a variety of oral and parenteral dosage forms. The dosage form described below may contain, as an active ingredient, a compound of the invention or a pharmaceutically acceptable salt thereof, to those skilled in the art.

For the pharmaceutical composition to be used in the present invention, the pharmaceutically acceptable carrier can be either solid or liquid. Solid form preparations include powders, tablets, nine doses, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances which may also act as a diluent, a flavoring agent, a solubilizer, a lubricant, a suspension, a binder, a preservative, a tablet disintegrating agent, or a encapsulated material.

In powders, the carrier is a finely divided solid which is admixed with the finely divided active ingredient.

In the tablet, the active ingredient is mixed with a carrier having the necessary adhesive properties in an appropriate ratio and compressed into a desired shape and size.

The powders and tablets preferably contain from 5% or 10% to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax , cocoa butter, etc. The term "formulation" includes active compounds formulated with a encapsulating material as a carrier, the encapsulating material providing a capsule in which the active ingredient with or without the carrier is surrounded by the carrier so as to be bound thereto. Likewise, the formulations include cachets and lozenges. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.

To prepare a suppository, a low melting wax such as a fatty acid glyceride or a cocoa butter mash is first melted, and then the active ingredient is uniformly dispersed therein by stirring. The molten homogeneous mixture is then poured into a suitably sized mold which is allowed to cool and thereby solidify.

Compositions suitable for vaginal administration may be presented in the form of pessaries, tampons, creams, gels, pastes, foams or sprays. In addition to the active ingredient, compositions comprise suitable carriers known in the art. .

Liquid preparations include solutions, suspensions and emulsions, for example, aqueous solutions or water-propylene glycol solutions. For example, a parenteral injection liquid preparation can be formulated as a solution of water-polyethylene glycol.

Thus, the compounds for use in the present invention may be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion), and may be presented in unit dosage form in ampules, together with the added preservatives. Filled syringes, small volume infusion bags or multi-dose containers. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain such ingredients such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in the form of a powder, which may be obtained in the form of a sterile solid or a lyophilized solution for reconstitution with a suitable vehicle such as sterile, pyrogen-free water.

Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding the desired coloring, flavoring, stabilizing and thickening agents.

Aqueous suspensions suitable for oral administration can be prepared by dispersing the finely divided active ingredient in a viscous material such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other known suspensions Prepared in water.

Also included are solid formulations designed to be converted to liquid formulations for oral administration shortly before use. Such liquid preparations include solutions, suspensions and emulsions. Such preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersant thickeners, solubilizing agents, and the like.

For topical application to the epidermis, the compounds of the invention may be formulated as ointments, creams or lotions or as a transdermal patch. For example, ointments and creams may be formulated with aqueous or oily bases in admixture with suitable thickening agents and/or gels. Lotions may be formulated with aqueous or oily bases and usually contain one or more emulsifying, stabilizing, dispersing, suspending, thickening or coloring agents.

Compositions suitable for topical oral administration include lozenges containing the active ingredient in a flavoring base, typically sucrose and acacia or tragacanth; in inert matrices such as gelatin and glycerin or sucrose and acacia An active ingredient-containing tablet (pastiIles); and a mouthwash containing the active ingredient in a suitable liquid carrier.

The solution or suspension can be applied directly to the nasal cavity by conventional means such as with a dropper, pipette or spray. The composition may be in the form of a single dose or multiple doses.

Respiratory administration can also be achieved by aerosols in which the active ingredient is packaged in a pressurized package together with a suitable propellant, including a chlorofluorocarbon (CFC) such as dichlorodifluoromethane or trichlorofluoride. Methane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Aerosols may also suitably contain a surfactant such as lecithin. The dose of the drug can be controlled by a metering valve.

Further the active ingredient may be in the form of a dry powder, for example a powder mix of the compound with a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). The powder carrier conveniently forms a gel in the nasal cavity. The powder composition may be presented in unit dosage form, for example, in a capsule or cartridge (such as a gelatin capsule or cartridge), or in a blister pack in which the powder can be administered via an inhaler.

In compositions for respiratory administration, including intranasal compositions, typically the compound has a small particle size, such as a particle size on the order of 5 microns or less. Such particle size can be obtained by methods known in the art, such as by micronization.

A composition suitable for sustained release of the active ingredient can be applied as needed.

The pharmaceutical preparation is preferably in unit dosage form. In such forms, the preparation is subdivided into unit doses of the appropriate amount of active ingredient. The unit dosage form can be a packaged preparation wherein the sealed package contains discrete quantities of the preparation, such as encapsulated tablets, capsules, and powders in vials or ampoules. In addition, the unit The dosage form may be a capsule, a tablet, a sputum or lozenge itself, or may be an appropriate amount of the above capsules, tablets or the like in any package.

Tablets or capsules for oral administration and liquids for intravenous administration as well as continuous infusion are preferred compositions.

More detailed information on formulation and administration techniques can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

The amount of active ingredient in a unit dosage formulation can vary depending on the particular application and the effectiveness of the active ingredient, and can be adjusted from 0.01 mg to about 0.1 g. For example, in medical use, the drug may be administered three times a day in capsules of from 0.01 to about 100 mg, and if desired, the composition may also contain other compatible therapeutic agents.

treatment method

For therapeutic use, the compounds used in the present invention are administered at a starting dose of from 0.001 mg/kg to 10 mg/kg body weight per day. However, these dosages may vary depending on the needs of the patient, the severity of the condition being treated, and the compound to be employed. In general, treatment with a smaller dose that is less than the optimal dose of the compound is initially initiated, after which a small increase in dose is achieved. Good results, for convenience, the total daily dose can be subdivided into divided doses within one day if needed.

The pharmaceutical compositions of the present invention may also be used in combination with other drugs for the treatment of pain, Alzheimer's disease, multi-infarct dementia and stroke, including but not limited to morphine, gabapentin and the like. Accordingly, the present invention provides a medicament for treating a pain, Alzheimer's disease, multi-infarct dementia and stroke, which is not only effective but has no obvious side effects, and another object of the present invention is to provide A highly safe drug for a particular patient population, such as the elderly, patients with liver or kidney failure, or cardiovascular disease.

Example

Synthetic route 1:

Add a NaOH water solvent to a solution of A-1 (CAS: 90607-22-0) (3.0 g, 17.5 mmol) in tetrahydrofuran, and stir at room temperature for 1 hour. After completion of TLC analysis, the reaction mixture was concentrated under reduced pressure and diluted with water. Hydrochloric acid was adjusted to pH 2-3, ethyl acetate was extracted (25 mL EtOAc), and the organic layer was combined, dried over anhydrous sodium sulfate, and evaporated to dryness. TBSCl (2.25 g, 120 mmol) was added to a solution of the carboxylic compound (1.43 g, 10 mmol The residue was evaporated to dryness.

After cooling to zero temperature in an ice bath, BOP-Cl (2.79 g, 11 mmol) was added under argon atmosphere. After stirring for 20 minutes, A-2 (1.8 g, 9 mmol) was added, and then A-3 (reference: US6630471) was added to heat naturally. The reaction was overnight. TLC showed the reaction was completed, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated.

A mixture of A-4 (10.5 g, 23.8 mmol) and diphenyl ether was heated to 150 °C for 1 hour. TLC (PE: EA = 2:1) showed that the reaction was completed and purified by silica gel column to yield The yield is 10%.

NaH (252 mg, 6.3 mmol) was added to a solution of EtOAc (50 mL). After stirring for 15 min with argon gas, A-6 (CAS: 56026-36-9) (900 mg, 2.1 mmol) was added to the previous reaction mixture, stirred at room temperature for 1.5 h, and monitored by TLC (PE: EA = 2:1). The starting material disappeared. The crude product was directly subjected to the next reaction without purification. Aq. NaOH (0.84 g in 10 mL water) was added to the previous reaction mixture, and after 4 h of reaction, the disappearance of the starting material was monitored by TLC (PE: EtOAc = 5:1, Rf = 0.01). The reaction mixture was concentrated under reduced pressure, and the residue was adjusted to pH 2-3 with dilute hydrochloric acid.

Example 1

6-((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine -6-yl)oxy)methyl)-N-morpholinoicotinamide (01)

Add HOBt (32 mg, 0.24 mmol), EDCI (46 mg, 0.24 mmol), A-7 (50 mg, 0.12 mmol) and DMF (2 mL) in a 25 mL vial, stir and dissolve, and add N-aminomorpholine under argon protection. (CAS: 4319-49-7) and DIPEA, stirring at room temperature overnight, TLC showed the reaction was completed, diluted with 25 ml of dichloromethane, washed three times with water, dried over anhydrous sodium sulfate and evaporated to dryness. Yellow solid, yield 29%.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.71 (s, 1H), 8.96 (d, J = 2.0 Hz, 1H), 8.20-8.18 (m, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 5.85 (t, J = 6.4 Hz, 1H), 5.67 (s, 2H), 4.72 (d, J = 6.4 Hz, 2H), 3.66 (t, J = 4.4 Hz, 4H), 2.88 (t, J = 4.6 Hz, 4H), 1.43 (s, 9H); LC-MS: m/z (ESI+) for C ₂₄ H ₂₈ N ₈ O ₅ 509 [M+1] ⁺ .

Example 2

(R)-N-(1-hydroxy-n-propan-2-yl)6-((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[ 1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)methyl)nicotinamide (02)

The experimental procedure was as described in Example 1: Intermediate A-7 and (R)-2-amino-n-propanol (CAS: 2799-16-8) were condensed to give the title compound 68 mg, yield 40%. solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.04 (d, 1H, J = 2.0), 8.40 (d, J = 8.0 Hz, 1H), 8.31-8.28 (m, 1H), 8.16 (s, 1H) ), 7.72 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 5.91 (t, J = 6.0 Hz, 1H), 5.66 (s, 2H), 4.80 (d, J = 6.4 Hz, 2H) ), 4.70 (d, J = 6.0 Hz, 2H), 4.06-3.95 (m, 1H), 3.48-3.42 (m, 1H), 3.38-3.33 (m, 1H) 1.42 (s, 9H), 1.11 (d) , J = 6.4, 3H); LC-MS: m/z (ESII+) for C ₂₃ H ₂₇ N ₇ O ₅ 482 [M+1] ⁺ .

Example 3

N-((1S,2S)-2-hydroxycyclopentyl)-6-((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)methyl)nicotinamide (03)

The experimental procedure was as described in Example 1: Intermediate A-7 and trans-(1S,2S)-2-amino-cyclopentanol hydrochloride (CAS: 68327-04-8) were condensed to give compound 68 mg. The rate is 40% and the appearance is white solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.02 (d, 1H, J = 2.0), 8.40 (d, J = 8.0 Hz, 1H), 8.28-8.258 (m, 1H), 8.16 (s, 1H) ), 7.72 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 5.91 (t, J = 6.0 Hz, 1H), 5.67 (s, 2H), 4.81 (d, J = 6.4 Hz, 2H) ), 4.71 (d, J = 6.0 Hz, 2H), 4.10-3.90 (m, 1H), 2.05-1.95 (m, 1H), 1.87-1.80 (m, 1H), 1.70-1.60 (m, 2H), 1.50-1.40 (m, 2H) 1.42 (s, 9H); LC-MS: m/z (ESI+) for C ₂₅ H ₂₉ N ₇ O ₅ 508 [M+1] ⁺ .

Example 4

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]indole Pyrida-6-yl)oxy)methyl)-N-cyclopropylnicotinamide (04)

The experimental procedure was as described in Example 1: Intermediate A-7 and cyclopropylamine (CAS: 765-30-0) were condensed to give 16 mg of a yellow solid, yield 29%.

¹ H NMR (DMSO, 400 MHz, ppm): δ 8.98 (d, J = 1.6 Hz, 1H), 8.64 (d, J = 4.0 Hz, 1H), 8.23 - 8.17 (m, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.10 (s, 1H), 5.84 (t, J = 6.4 Hz, 1H), 5.67 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 2.85 (m, 1H), 1.43 (s, 9H), 0.72-0.70 (m, 2H), 0.58-0.56 (m, 2H); LC-MS: m/z (ESI+) for C ₂₃ H ₂₅ N ₇ O ₄ 464 [M +1] ⁺ .

Example 5

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]indole Pyrida-6-yl)oxy)methyl)-N-(1-methyl-1H-pyrazol-4-yl)nicotinamide (05)

The experimental procedure was as described in Example 1: Intermediate A-7 and 1-methyl-1H-pyrazol-4-amine (CAS: 69843-13-6) were condensed to give 12 mg of a yellow solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 10.63 (s, 1H), 9.11 (d, J = 1.6 Hz, 1H), 8.35-8.3 (dd, J = 2.4 Hz, J = 8.0 Hz, 1H) , 8.18 (s, 1H), 8.03 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.11 (s, 1H), 5.85 (t, J = 6.2 Hz, 1H), 5.70 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 3.83 (s, 3H), 1.45 (s, 9H); LC-MS: m/z (ESI+) for C ₂₄ H ₂₅ N ₉ O ₄ 504[M+1] ⁺ .

Example 6

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]indole Pyrazine 6-yl)oxy)methyl)-N-isopropylnicotinamide (06)

The experimental procedure was as described in Example 1: Intermediate A-7 and isopropylamine (CAS: 75-31-0) were condensed to give 10 mg of a yellow solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.01 (d, J = 1.6 Hz, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.25-8.18 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 5.85 (t, J = 6.2 Hz, 1H), 5.67 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 4.12-4.07 ( m, 1H), 1.43 (s, 9H), 1.16 (d, J = 6.8 Hz, 6H); LC-MS: m/z (ESI+) for C ₂₃ H ₂₇ N ₇ O ₄ 466 [M+1] ⁺ .

Example 7

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridine -6-yl)oxy)methyl)-N-(2-hydroxyethyl)nicotinamide (07)

The experimental procedure was as described in Example 1: Intermediate A-7 and ethanolamine (CAS: 141-43-5) were condensed to give 10 mg of a yellow solid in a yield of 18%.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.04 (d, J = 2.0 Hz, 1H), 8.68 (s, 1H), 8.28-8.25 (m, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 5.85 (t, J = 6.0 Hz, 1H), 5.68 (s, 2H), 4.77-4.72 (m, 3H), 3.37 (s, 2H), 1.44 (s, 9H); LC-MS: m / z (ESI +) for C 22 H 25 N 7 O 5 468 [m + 1] +.

Example 8

(6-((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b] Pyridazin-6-yl)oxy)methyl)pyridin-3-yl)(1,1-dioxidethiomorpholino)methanone (08)

The experimental procedure was as described in Example 1: Intermediate A-7 and thiomorpholine 1,1-dioxide hydrochloride (CAS: 59801-62-6) were condensed to give 12 mg of a yellow solid, yield 22%. .

¹ H NMR (DMSO, 400 MHz, ppm): δ 8.76 (d, J = 1.6 Hz, 1H), 8.20 (s, 1H), 8.1 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H) , 7.08 (s, 1H), 5.84 (t, J = 6.0 Hz, 1H), 5.68 (s, 2H), 4.73 (d, J = 6.0 Hz, 2H), 4.03 (s, 2H), 3.70 (s, 2H), 3.28 (s, 4H), 1.45 (s, 9H); LC-MS: m/z (ESI+) for C ₂₄ H ₂₇ N ₇ O ₆ S 542 [M+1] ⁺ .

Example 9

(6-((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b] Pyridazine-6-yl)oxy)methyl)pyridin-3-yl)(morpholino)methanone (09)

The experimental procedure was as described in Example 1: Intermediate A-7 and morpholine (CAS: 110-91-8) were condensed to give 14 mg of a yellow solid.

^{1 H NMR (DMSO, 400MHz,} ppm): δ8.67 (d, J = 1.6Hz, 1H), 8.18 (s, 1H), 7.95-7.92 (dd, J = 2.0Hz, J = 8.0Hz, 1H) , 7.68 (d, J = 7.6 Hz, 1H), 7.07 (s, 1H), 5.84 (t, J = 6.0 Hz, 1H), 5.67 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H) , 3.63-3.55 (m, 6H), 3.40 (s, 2H), 1.45 (s, 9H); LC-MS: m/z (ESI+) for C ₂₄ H ₂₇ N ₇ O ₅ 494 [M+1] ⁺ .

Example 10

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]indole Pyrazin-6-yl)oxy)methyl)-N-(2,2,2-trifluoroethyl)nicotinamide (10)

The experimental procedure was as described in Example 1: Intermediate A-7 and 2,2,2-trifluoroethylamine hydrochloride (CAS: 373-88-6).

^{1 H NMR (CDCl3,400MHz, ppm)} : δ9.05 (d, J = 2.0Hz, 1H), 8.23-8.20 (dd, J = 1.6Hz, J = 8.0Hz, 1H), 7.95 (s, 1H) , 7.72 (t, J = 6.2 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 5.71 (s, 2H), 4.84 (s, 2H), 4.12 (m, 2H), 1.52 (s, 9H); LC-MS: m/z (ESI+) for C ₂₂ H ₂₂ F ₃ N ₇ O ₄ 506 [M+1] ⁺ .

Example 11

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]indole Pyrazin-6-yl)oxy)methyl)-N-(2-methoxy-ethyl)nicotinamide (11)

The experimental procedure was as described in Example 1: Intermediate A-7 and 2-methoxyethylamine (CAS: 109-85-3) were condensed to give 11 mg of a yellow solid.

^{1 H NMR (DMSO, 400MHz,} ppm): δ9.03 (d, J = 1.6Hz, 1H), 8.76 (s, 1H), 8.27-8.18 (m, 2H), 7.74 (d, J = 8.0Hz, 1H), 7.12 (s, 1H), 5.85 (t, J = 6.0 Hz, 1H), 5.68 (s, 2H), 4.73 (d, J = 6.0 Hz, 2H), 3.47-3.44 (m, 4H), 3.27 (s, 3H), 1.44 (s, 9H); LC-MS: m/z (ESI+) for C ₂₃ H ₂₇ N ₇ O ₅ 482 [M+1] ⁺ .

Example 12

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]indole Pyrazin-6-yl)oxy)methyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (12)

The experimental procedure was as described in Example 1: Intermediate A-7 and 4-aminotetrahydropyran hydrochloride (CAS: 33024-60-1) were condensed to give 21 mg of a yellow solid, yield 38%.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.02 (d, J = 1.6 Hz, 1H), 8.53 (d, J = 7.6 Hz, 1H), 8.26-8.18 (m, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 5.85 (t, J = 6.0 Hz, 1H), 5.68 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.05 - 3.95 ( m,1H), 3.89-3.85 (m, 2H), 3.41-3.35 (m, 2H), 1.79-1.75 (dd, J = 2.4 Hz, J = 12.4 Hz, 2H), 1.61-1.51 (m, 2H) , 1.43 (s, 9H); LC-MS: m/z (ESI+) for C ₂₅ H ₂₉ N ₇ O ₅ 508 [M+1] ⁺ .

Example 13

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]indole Pyrida-6-yl)oxy)methyl)-N,N-dimethylnicotinamide (13)

The experimental procedure was as described in Example 1: Intermediate A-7 and dimethylamine hydrochloride (CAS: 506-59-2) were condensed to give 15 mg of a yellow solid, yield 27%.

¹ H NMR (DMSO, 400 MHz, ppm): δ 8.66 (d, J = 1.2 Hz, 1H), 8.18 (s, 1H), 7.94 - 7.92 (dd, J = 3.2 Hz, J = 8.0 Hz, 1H) , 7.67 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 5.84 (t, J = 6.2 Hz, 1H), 5.67 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H) , 3.00 (s, 3H), 2.90 (s, 3H), 1.44 (s, 9H); LC-MS: m/z (ESI+) for C ₂₂ H ₂₅ N ₇ O ₄ 452 [M+1] ⁺ .

Example 14

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]indole Pyrazin-6-yl)oxy)methyl)-N-(tetrahydrofuran-3-yl)nicotinamide (14)

The condensation of intermediate A-7 with 3-aminotetrahydrofuran hydrochloride (CAS: 204512-94-7) gave 14 mg of a yellow solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.03 (d, J = 1.6 Hz, 1H), 8.75 (d, J = 6.4 Hz, 1H), 8.27-8.18 (m, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 5.84 (t, J = 6.0 Hz, 1H), 5.68 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 4.46 (m, 1H), 3.87-3.82 (m, 2H), 3.74-3.70 (m, 1H), 3.61-3.58 (dd, J = 4 Hz, J = 9.2 Hz, 1H), 2.18-2.13 (m, 1H), 1.95- 1.87 (m, 1H), 1.43 (s, 9H); LC-MS: m/z (ESI+) for C ₂₄ H ₂₇ N ₇ O ₅ 494 [M+1] ⁺ .

Example 15

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]indole Pyrazin-6-yl)oxy)methyl)-N-cyclobutylnicotinamide (15)

The experimental procedure was as described in Example 1: Intermediate A-7 and cyclobutylamine (CAS: 2516-34-9) were condensed to give 13 mg of a yellow solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.01 (d, J = 1.6 Hz, 1H), 8.81 (d, J = 7.6 Hz, 1H), 8.25-8.18 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 5.85 (t, J = 6.0 Hz, 1H), 5.67 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 4.41 (m, 1H), 2.22 (m, 2H), 2.10-2.03 (m, 2H), 1.71-1.65 (m, 2H), 1.43 (s, 9H); LC-MS: m/z (ESI+) for C ₂₄ H ₂₇ N ₇ O ₄ 478 [M+1] ⁺ .

Example 16

Azetidin-1-yl (6-((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]3 Zoxa[4,3-b]pyridazin-6-yl)oxy)methyl)pyridin-3-yl)methanone (16)

The experimental procedure was as described in Example 1: Intermediate A-7 and azacyclobutane (CAS: 503-29-7) were condensed to give 14 mg of a yellow solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 8.83 (d, J = 1.2 Hz, 1H), 8.18 (s, 1H), 8.08 (dd, J = 2.0 Hz, J = 8.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.07 (s, 1H), 5.85 (t, J = 6.0 Hz, 1H), 5.68 (s, 2H), 4.71 (d, J = 6.0 Hz, 2H), 4.32 (t, J = 7.8 Hz, 2H), 4.06 (t, J = 7.8 Hz, 2H), 2.26 (m, 2H), 1.44 (s, 9H); LC-MS: m/z (ESI+) for C ₂₃ H ₂₅ N ₇ O ₄ 464 [M+1] ⁺ .

Example 17

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]indole Pyrida-6-yl)oxy)methyl)nicotinylhydrazide (17)

The experimental procedure was as described in Example 1: Intermediate A-7 and tert-butyl carbazate (CAS: 870-46-2) were subjected to a condensation reaction to remove Boc to give 10 mg of a yellow solid in a yield of 18%.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.97 (s, 1H), 9.00 (d, J = 2.0 Hz, 1H), 8.24 - 8.18 (m, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.10 (s, 1H), 5.85 (t, J = 6.0 Hz, 1H), 5.68 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 4.57 (s, 2H), 1.44 ( s, 9H); LC-MS : m / z (ESI +) for C 20 H 22 N 8 O 4 439 [m + 1] +.

Example 18

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]indole Pyrazin-6-yl)oxy)methyl)-N-(pyrrolidin-1-yl)nicotinamide (18)

The experimental procedure was as described in Example 1: Intermediate A-7 and N-aminopyrrolidine (CAS: 16596-41-1) were condensed to give 2 mg of a yellow solid, yield 4%.

¹ H NMR (DMSO, 400 MHz, ppm): δ 8.76 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 8.02 (dd, J = 2.0 Hz, J = 8.0 Hz, 1H) 7.68 ( d, J = 8.0 Hz, 1H), 7.10 (s, 1H), 5.85 (t, J = 6.2 Hz, 1H), 5.68 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 2.90- 2.94 (m, 4H), 1.88-1.82 (m, 4H), 1.45 (s, 9H); LC-MS: m/z (ESI+) for C ₂₄ H ₂₈ N ₈ O ₄ 493 [M+1] ⁺ .

Example 19

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]indole Pyrazin-6-yl)oxy)methyl)-N-(piperidin-1-yl)nicotinamide (19)

The experimental procedure was as described in Example 1: Intermediate A-7 and N-aminopiperidine hydrochloride (CAS: 63234-70-8) were condensed to give 10 mg of a yellow solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.59 (s, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.20-8.18 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 5.86 (t, J = 6.0 Hz, 1H), 5.67 (s, 2H), 4.73 (d, J = 6.0 Hz, 2H), 2.82 (t, J = 5.2 Hz, 4H), 1.60 (s, 4H), 1.44-1.24 (m, 11H); LC-MS: m/z (ESI+) for C ₂₅ H ₃₀ N ₈ O ₄ 507 [M+1] ⁺ .

Example 21

(6-((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b] Pyridazin-6-yl)oxy)methyl)pyridin-3-yl)(pyrrolidin-1-yl)methanone (21)

The experimental procedure was as described in Example 1: Intermediate A-7 and tetrahydropyrrole (CAS: 123-75-1) were condensed to give 14 mg of a yellow solid in a yield of 25%.

¹ H NMR (DMSO, 400 MHz, ppm): δ 8.76 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 8.02 (dd, J = 2.0 Hz, J = 8.0 Hz, 1H) 7.68 ( d, J = 8.0 Hz, 1H), 7.10 (s, 1H), 5.85 (t, J = 6.2 Hz, 1H), 5.68 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 3.48 ( t,2H), 3.39 (t, 2H), 1.88-1.82 (m, 4H), 1.45 (s, 9H); LC-MS: m/z (ESI+) for C ₂₄ H ₂₇ N ₇ O ₄ 478 [M +1] ⁺ .

Example 22

6-(((7-(tert-butyl)-3-(5-(hydroxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[4,3-b]indole Pyrida-6-yl)oxy)methyl)-N-ethylnicotinamide (22)

The experimental procedure was as described in Example 1: Intermediate A-7 and ethylamine hydrochloride (CAS: 557-66-4) were condensed to give 20 mg of a yellow solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.02 (d, J = 2.0 Hz, 1H), 8.69 (d, J = 6.4 Hz, 1H), 8.25 (m, 1H), 8.17 (s, 1H) , 7.74 (d, J = 2.4 Hz, 1H), 7.12 (s, 1H), 5.85 (t, J = 6.2 Hz, 1H), 5.68 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H) , 3.31 (t, 2H), 1.45 (s, 9H), 1.13 (t, J = 2.8 Hz, 3H); LC-MS: m/z (ESI+) for C ₂₂ H ₂₅ N ₇ O ₄ 452 [M+ 1] ⁺ .

Synthetic route 2

experiment procedure:

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-nicotinic acid (B3)

Methyl B2 6-hydroxymethylnicotinate (CAS: 56026-36-9) (2.35 g, 14.1 mmol) was dissolved in 280 ml of anhydrous THF, argon-protected, cooled to 0 ° C in ice bath, Sodium butoxide (1.81 g, 18.8 mmol) was stirred for 15 minutes, then B1 (2.74 g, 9.4 mmol) was added (preparation of synthetic reference US6297235 B1), and the ice bath was continued for one and a half hours, TLC (PE: EA=1: 1) The reaction is complete, no treatment is required, and the next reaction is directly administered. The reaction solution was added to a NaOH solution (1.13 g in 10 mL water), and the reaction mixture was stirred at room temperature for 16 hours. TLC (DCM:MeOH = 20:1, Rf=0.2) The residue was dissolved in an appropriate amount of water, adjusted to pH 2-3 with concentrated hydrochloric acid, and solid precipitated, filtered, washed with water, and dried to give a yellow solid, 1.6 g, yield 41.7%.

Example 23

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-N-morpholin-4-yl-nicotinamide (23)

The experimental procedure was as described in Example 1: Intermediate B3 and N-aminomorpholine (CAS: 4319-49-7) were subjected to a condensation reaction and purified by silica gel chromatography to give 16.8 mg of a white solid. ¹ H NMR (DMSO, 400 MHz, ppm): δ 9.72 (s, 1H), 8.96 (d, J = 0.8 Hz, 1H), 8.20-8.16 (m, 2H), 7.74 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 5.67 (s, 2H), 3.66 (t, J = 4.4 Hz, 4H), 2.88 (t, J = 4.4 Hz, 4H), 2.56 (s, 3H), 1.43 ( s, 9H); LC-MS: m/z (ESI+) for C ₂₄ H ₂₈ N ₈ O ₄ 493 [M+1] ⁺ .

Example 24

(R)-N-(1-hydroxy-n-propan-2-yl)6-((7-(tert-butyl)-3-(5-methylisoxazol-3-yl)-[1,2 ,4]triazolo[4,3-b]pyridazin-6-yl)oxy)nicotinamide (24)

The experimental procedure was as described in Example 1: Intermediate B3 and (R)-2-amino-n-propanol (CAS: 2799-16-8) were condensed to give 15.4 mg of a white solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.03 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.27 to 8.24 (m, 1H), 8.16 (s, 1H), 7.73 ( d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 5.67 (s, 2H), 4.74 (t, J = 6.0 Hz, 1H), 4.05 to 3.98 (m, 1H), 3.47 to 3.42 (m) , 2H), 2.56 (s, 3H), 1.43 (s, 9H), 1.13 (d, J = 6.8Hz, 3H); LC-MS: m / z (ESI +) for C 23 H 27 N 7 O 4 466 [M+1] ⁺ .

Example 25

N-((1S,2S)-2-hydroxycyclopentyl)-6-((7-(tert-butyl)-3-(5-methylisoxazol-3-yl)-[1,2, 4] Triazolo[4,3-b]pyridazin-6-yl)oxy)nicotinamide (25)

The experimental procedure was as described in Example 1: Intermediate B3 and trans-(1S,2S)-2-amino-cyclopentanol hydrochloride (CAS: 68327-04-8) condensation reaction gave 52 mg of white solid. 43.3%.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.02 (s, 1H), 8.45 (d, J = 7.2 Hz, 1H), 8.26 - 8.16 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 5.67 (s, 2H), 4.80 (d, J = 4.0 Hz, 1H), 4.04 to 3.94 (m, 2H), 2.56 (s, 3H), 2.03 to 1.95 (m) , 1H), 2.03 to 1.95 (m, 1H), 1.89 to 1.80 (m, 1H), 1.69 to 1.61 (m, 1H), 1.51 to 1.43 (m, 2H), 1.43 (s, 9H); LC-MS : m/z (ESI+) for C ₂₅ H ₂₉ N ₇ O ₄ 492 [M+1] ⁺ .

Example 26

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-N-cyclopropylnicotinamide (26)

The experimental procedure was as described in Example 1: Intermediate B3 and cyclopropylamine (CAS: 765-30-0) were condensed to give 26 mg (23.8%).

¹ H NMR (DMSO, 400 MHz, ppm): δ 8.99 (d, J = 1.6 Hz, 1H), 8.66 (d, J = 4.0 Hz, 1H), 8.28 to 8.16 (m, 2H), 7.72 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 5.67 (s, 2H), 2.88 to 2.81 (m, 1H), 2.56 (s, 3H), 1.43 (s, 9H), 0.73 to 0.68 (m) , 2H), 0.59 ~ 0.54 ( m, 2H); LC-MS: m / z (ESI +) for C 23 H 25 N 7 O 3 448 [m + 1] +.

Example 27

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-N-isopropylnicotinamide (27)

The experimental procedure was as described in Example 1 : condensation of intermediate B3 with isopropylamine (CAS: 75-31-0) afforded 29.8 mg (27.1%) as a white solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.02 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.26 to 8.23 (m, 1H), 8.16 (s, 1H), 7.73 ( d, J=8.0 Hz, 1H), 6.93 (s, 1H), 5.67 (s, 2H), 4.14 to 4.05 (m, 1H), 2.56 (s, 3H), 1.43 (s, 9H), 1.17 (d , J = 6.8 Hz, 6H); LC-MS: m/z (ESI+) for C ₂₃ H ₂₇ N ₇ O ₃ 450 [M+1] ⁺ .

Example 29

(6-((7-(tert-butyl)-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridine-6 -yl)oxy)methyl)pyridazin-3-yl)(1,1-dioxidethiomorpholino)methanone (29)

The experimental procedure was as described in Example 1: Intermediate B3 and thiomorpholine 1,1-dioxide hydrochloride (CAS: 59801-62-6) were condensed to give 20 mg of solid (15.6%).

¹ H NMR (DMSO, 400 MHz, ppm): δ 8.76 (s, 1H), 8.18 (s, 1H), 8.03 - 8.00 (m, 1H), 7.72 (d, J = 8.4 Hz, 1H), 6.91 ( s, 1H), 5.66 (s, 2H), 4.16 to 3.92 (m, 2H), 3.79 to 3.59 (m, 2H), 3.32 to 3.22 (m, 4H), 2.56 (s, 3H), 1.44 (s, 9H) .LC-MS: m / z (ESI +) for C 24 H 27 N 7 O 5 S 526 [m + 1] +.

Example 30

{6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6-yloxy Methyl]-pyridin-3-yl}-morpholin-4-yl-methanone (30)

The experimental procedure was as described in Example 1 : condensation of intermediate B3 with morpholine (CAS: 110-91-8) afforded 66 mg (56.6%) as a white solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 8.68 (d, J = 2.0 Hz, 1H), 8.16 (s, 1H), 7.94 - 7.92 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 6.88 (s, 1H), 5.67 (s, 2H), 3.71 to 3.47 (m, 6H), 3.33 to 3.27 (m, 2H), .56 (s, 3H), 1.44 (s, 9H); LC-MS: m / z ( ESI +) for C 24 H 27 N 7 O 4 478 [m + 1] +.

Example 31

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-N-cyclopropylmethylnicotinamide (31)

The experimental procedure was carried out as described in Example 1 : Intermediate B3 and cyclopropylmethylamine (CAS: 2516-47-4) were condensed to give 51 mg (45.2%) as a white solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.04 (d, J = 2.0 Hz, 1H), 8.80 (t, J = 5.6 Hz, 1H), 8.28 to 8.16 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 5.68 (s, 2H), 3.15 (t, J = 6.4 Hz, 2H), 2.56 (s, 3H), 1.43 (s, 9H), 1.05 - 0.96 (m, 1H), 0.45 ~ 0.42 (m, 2H), 0.25 ~ 0.20 (m, 2H).

LC-MS: m / z ( ESI +) for C 24 H 27 N 7 O 3 462 [M + 1] +.

Example 32

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-N-(2,2,2-trifluoro-ethyl)-nicotinamide (32)

The experimental procedure was carried out as described in Example 1 : Intermediate B3 and 2,2,2-trifluoroethylamine hydrochloride (CAS: 373-88-6) condensed to give a white solid, 48 mg (40.1%).

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.34 (t, J = 6.0 Hz, 1H), 9.08 (d, J = 2.0 Hz, 1H), 8.32 to 8.16 (m, 2H), 7.76 (d, J=8.0 Hz, 1H), 6.89 (s, 1H), 5.69 (s, 2H), 4.18 to 4.08 (m, 2H), 2.55 (s, 3H), 1.43 (s, 9H).

LC-MS: m/z (ESI+) for C ₂₂ H ₂₂ F ₃ N ₇ O ₃ 490 [M+1] ⁺ .

Example 33

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-N-(2-methoxy-ethyl)-nicotinamide (33)

The experimental procedure was carried out as described in Example 1: Intermediate B3 and 2-methoxyethylamine (CAS: 109-85-3) were condensed to give 13 mg (11.4%) as a white solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.04 (d, J = 1.6 Hz, 1H), 8.77 (t, J = 4.8 Hz, 1H), 8.27 to 8.24 (m, 1H), 8.16 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 5.67 (s, 2H), 3.50 to 3.40 (m, 4H), 3.26 (s, 3H), 2.56 (s, 3H) ), 1.43 (s, 9H); LC-MS: m/z (ESI+) for C ₂₃ H ₂₇ N ₇ O ₄ 466 [M+1] ⁺ .

Example 35

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide (35)

The experimental procedure was carried out as described in Example 1: Intermediate B3 and 2-amino-2-methyl-1-propanol (CAS: 124-68-5) were obtained as a white solid (yield: 48%).

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.05 (d, J = 2.0 Hz, 1H), 8.52 (t, J = 6.0 Hz, 1H), 8.29 - 8.26 (m, 1H), 8.16 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 5.68 (s, 2H), 4.54 (s, 1H), 3.26 (d, J = 5.6 Hz, 2H), 2.56 ( s, 3H), 1.43 (s, 9H), 1.10 (s, 6H); LC-MS: m/z (ESI+) for C ₂₄ H ₂₉ N ₇ O ₄ 480 [M+1] ⁺ .

Example 36

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-N-(1-hydroxymethyl-butyl)-nicotinamide (36)

The experimental procedure was as described in Example 1: Intermediate B3 and 2-aminobutanol (CAS: 96-20-8) were condensed to give 48.8 mg (41.7%) as a white solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.04 (d, J = 1.2 Hz, 1H), 8.27 (d, J = 8.4 Hz, 2H), 8.16 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 5.67 (s, 2H), 4.70 (t, J = 6.0 Hz, 1H), 3.90 to 3.80 (m, 1H), 3.49 to 3.35 (m, 2H), 2.56 (s, 3H), 2.04 to 1.92 (m, 1H), 1.70 to 1.60 (m, 1H), 1.42 (s, 9H), 0.86 (t, J = 7.2 Hz, 3H); LC-MS: m/ z(ESI+) for C ₂₄ H ₂₉ N ₇ O ₄ 480 [M+1] ⁺ .

Example 37

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-N-(tetrahydro-pyran-4-yl)-nicotinamide (37)

The experimental procedure was as described in Example 1: Intermediate B3 and 4-aminotetrahydropyran hydrochloride (CAS: 33024-60-1) were condensed to give an off-white solid, 56 mg (46.7%).

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.03 (d, J = 1.2 Hz, 1H), 8.55 (d, J = 7.6 Hz, 1H), 8.27-8.16 (m, 2H), 7.74 (d, J=8.0Hz, 1H), 6.92(s,1H), 5.67(s,2H), 4.05-3.82(m,3H),3.43-3.35(m,2H),2.56(s,3H),1.80-1.72 (m, 2H), 1.62-1.50 (m, 2H), 1.42 (s, 9H); LC-MS: m/z (ESI+) for C ₂₅ H ₂₉ N ₇ O ₄ 492 [M+1] ⁺ .

Example 38

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-N,N-dimethylnicotinamide (38)

The experimental procedure was as described in Example 1: Intermediate B3 and dimethylamine hydrochloride (CAS: 506-59-2) were condensed to give 18 mg (16.9%) as a white solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 8.67 (d, J = 1.2 Hz, 1H), 8.17 (s, 1H), 7.96-7.90 (m, 1H), 7.67 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 5.66 (s, 2H), 2.99 (s, 3H), 2.90 (s, 3H), 2.56 (s, 3H), 1.42 (s, 9H); LC-MS: m /z(ESI+) for C ₂₂ H ₂₅ N ₇ O ₃ 436[M+1] ⁺ .

Example 39

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-N-(tetrahydrofuran-3-yl)-nicotinamide (39)

The experimental procedure was as described in Example 1 : Intermediate B3 and 3-aminotetrahydrofuran hydrochloride (CAS: 204512-94-7) were obtained as a white solid (yield: 52.3%).

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.03 (d, J = 1.2 Hz, 1H), 8.77 (d, J = 6.8 Hz, 1H), 8.28-8.24 (m, 1H), 8.16 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 6.93 (s, 1H), 5.67 (s, 2H), 4.50-4.42 (m, 1H), 3.88-3.80 (m, 2H), 3.75-3.66 (m, 1H), 3.62-3.55 (m, 1H), 2.56 (s, 3H), 2.21-2.10 (m, 1H), 1.95-1.86 (m, 1H), 1.42 (s, 9H); LC-MS : m/z (ESI+) for C ₂₄ H ₂₇ N ₇ O ₄ 478 [M+1] ⁺ .

Example 40

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6-yl Oxymethyl]-N-cyclobutylnicotinamide (40)

The experimental procedure was as described in Example 1: Intermediate B3 and cyclobutylamine (CAS: 2516-34-9) were condensed to give 33.8 mg (30%) as white solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.02 (d, J = 1.2 Hz, 1H), 8.84 (d, J = 8.0 Hz, 1H), 8.27-8.22 (m, 1H), 8.16 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 6.93 (s, 1H), 5.67 (s, 2H), 4.47-4.35 (m, 1H), 2.56 (s, 3H), 2.26-2.17 (m , 2H), 2.12-1.98 (m, 2H), 1.74-1.61 (m, 2H), 1.42 (s, 9H); LC-MS: m/z (ESI+) for C ₂₄ H ₂₇ N ₇ O ₃ 462 [M +1] ⁺ .

Example 41

Azetidin-1-yl-{6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3 -b]pyridazine-6-yloxymethyl]-pyridin-3-yl}-methanone (41)

The experimental procedure was carried out as described in Example 1 : Intermediate B3 and a mixture of <RTI ID=0.0></RTI> </RTI> <RTIgt;

¹ H NMR (DMSO, 400 MHz, ppm): δ 8.84 (d, J = 2.0 Hz, 1H), 8.16 (s, 1H), 8.10-8.06 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 6.88 (s, 1H), 5.67 (s, 2H), 4.32 (t, J = 7.6 Hz, 2H), 4.06 (t, J = 7.6 Hz, 2H), 2.56 (s, 3H), 2.31 2.20 (m, 2H), 1.42 (s, 9H); LC-MS: m/z (ESI+) for C ₂₃ H ₂₅ N ₇ O ₃ 448 [M+1] ⁺ .

Example 42

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-N-ethyl-nicotinamide (42)

The experimental procedure was as described in Example 1 : condensation of intermediate B3 with ethylamine hydrochloride (CAS: 557-66-4) afforded 21.6 mg (20.3%) as a white solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.02 (d, J = 1.2 Hz, 1H), 8.68 (t, J = 5.6 Hz, 1H), 8.26 - 8.22 (m, 1H), 8.16 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 5.67 (s, 2H), 3.35 to 3.25 (m, 2H), 2.56 (s, 3H), 1.43 (s, 9H) ), 1.12 (t, J = 7.2 Hz, 3H); LC-MS: m/z (ESI+) for C ₂₂ H ₂₅ N ₇ O ₃ 436 [M+1] ⁺ .

Example 43

6-[7-tert-butyl-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yloxy Methyl]-N-piperidin-1-yl-nicotinamide (43)

The experimental procedure was carried out as described in Example 1 : Intermediate B3 and N-aminopiperidine hydrochloride (CAS: 63234-70-8) condensed to give 37 mg (15.4%) as a white solid.

¹ H NMR (DMSO, 400 MHz, ppm): δ 9.59 (s, 1H), 8.95 (d, J = 1.6 Hz, 1H), 8.20-8.15 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 5.66 (s, 2H), 2.81 (t, J = 5.2 Hz, 4H), 2.56 (s, 3H), 1.63-1.55 (m, 4H), 1.42 (s, 9H) 1.40-1.31 (m, 2H); LC-MS: m/z (ESI+) for C ₂₅ H ₃₀ N ₈ O ₃ 491 [M+1] ⁺ .

Biological experiment method:

Recent studies have shown that GABA _A receptors mediate at least two modes of inhibition, tonic inhibition and phasic inhibition. When GABA is increased in millimolar concentrations, the GABA _A receptor is rapidly desensitized to form phase-type inhibition. When GABA activates the GABA _A receptor at concentrations ranging from a few hundred nanomolar to tens of micromolar, the high affinity synaptic GABA _A receptor mediates tone-type inhibition, regulating neural excitability and signaling. (Farrant M et al. (2005) Variations on an inhibitory theme: phasic and tonic activation of GABA (A) receptors. Nat Rev Neurosci 6: 215-229Y). Yeung JY et al disclosed that low concentrations of GABA are more likely to activate α5-GABA _A receptors (Yeung JY et al (2003). Tonically activated GABA _A receptors in hippocampal neurons are high-affinity, low-conductance sensors for extracellular GABA. Mol Pharmacol; 63:2–8). KYLEE other reported the (Dorsal root ganglia, DRG) on the cell detected to a low concentration of GABA-activated continuous type GABA _A current for type GABA _A current of 20 uM GABA activation of the culturing isolated 24 hours dorsal root ganglia from about 100pA/pF. (Lee KY et al. Upregulation of high-affinity GABA (A) receptors in cultured rat dorsal root ganglion neurons. Neuroscience 208 (2012) 133-142).

MRK016 is a representative full inverse agonist of the α5-GABA _A receptor. The existing literature (CN103239720A) indicates that the α5-GABA _A receptor reverse agonistic efficiency of MRK016 is higher than that of α5IA.

Cell level screening

The inventors detected the reverse activation efficiency of the substance to be tested by an electrophysiological method. The specific method is as follows:

1) The different subunits of GABA _A receptor expressed in a cell line, mainly human embryonic kidney cell line (HEK293). The cells were cultured in a medium, and the cells were used as a cell model for screening drugs for suppressing pain. The alpha subunit, beta subunit and gamma subunit are essential for the formation of a complete functional GABA _A receptor. In this example, the inventors established the following cell models: (a) using the α5 subunit (see GenBank accession number NP_001158509 for the protein sequence), the β3 subunit (see GenBank accession number NP_068712 for the protein sequence), and the γ2 subunit (protein) The sequence is shown in GenBank accession number: NP_944494) and simultaneously expressed in the HEK293 cell line to constitute a fully functional receptor containing α5-GABA _A.

2) The cells are green fluorescent protein (GFP)-labeled 293 cell stably transformed strains expressing α5β2γ3-GABA _A receptor. 293 cells were cultured on 10 cm culture dishes, and cells were passaged to 80%-90% for passage. When passaged, the first medium is aspirated, then 3mL DMEM medium (Gibco ^TM) added to the culture dish, the dish slightly shaken, and then aspirated DMEM. Was added 3mL trypsin (Trypsin-EDTA 0.05%, Gibco TM), digested at 37 ℃ 3 minutes. Then add 3 mL of complete medium (DMEM + 10% horse serum (Gibco ^TM )) to blow the cells on the bottom of the dish and transfer to a 15 mL centrifuge tube.

Centrifuge at 200g for 3 minutes. Discard the supernatant, add 4 mL of complete medium, gently pipette, and resuspend the cells for later use. For cell passage, the cell suspension is diluted 1:5 or 1:10. For the preparation of cells for electrophysiology, the cell suspension is diluted in a ratio of 1:12, and a 24-well plate placed with a slide previously treated with Poly-D-Lysine is added.

In the experiment, the cells were tested after adhering to the cells. The cell culture time for electrophysiology is not more than 24 hours.

3) Drug concentration setting: The final concentration of the drug used for drug screening is 100 nM, and the concentration of GABA is 0.05-0.1 μM. The dose-reverse activation efficiency (%) test used a final concentration of 1 nM, 10 nM, 50 nM, 100 nM and 1000 nM. The electrophysiological test uses a whole-cell patch clamp technique, which can be referred to the literature (I. Lecker, Y. Yin, DS Wang and BA Orser, (2013) Potentiation of GABA _A receptor activity by volatile anaesthetics is reduced by α5-GABA _A receptor-preferring inverse The methods reported by agonists, British Journal of Anaesthesia 110 (S1): i73–i81). The electrophysiological extracellular fluid components were as follows: 150 mM NaCl, 5 mM KCl, 2.5 mM CaCl ₂ , 1 mM MgCl ₂ , 10 mM HEPES and 10 mM glucose (pH adjusted to 7.4 with NaOH, osmotic pressure 320-330 mOsm). Electrophysiological with pipette solution having the following formulation: 140mM CsCl, 10mM HEPES, 11mM EGTA, 2mM MgCl 2, 1mM CaCl 2, 4mM MgATP, 2mM TEA, ( pH adjusted to 7.4 with CsOH, osmolality of 285-295mOsm). Signal acquisition uses the EPC 10 amplifier and the PatchMaster software (HEKA). The recording electrode was drawn using borosilicate glass and the electrode resistance was 5 to 6 MΩ. Extracellular administration employed OCTAFLOW II ^TM system. At the time of recording, GFP-positive and single independently growing cells were selected. During recording, the cell membrane potential was clamped at -60 mV. At the time of the test, an extracellular fluid was applied extracellularly for about 20 seconds. After the baseline is stabilized, the extracellular fluid is switched to GABA. At this time, the current caused by GABA can be detected. After about 20 to 40 seconds, after the current is stabilized, the extracellular fluid is switched to the corresponding drug solution to detect the effect of the drug. Finally, the solution was switched to the extracellular fluid and the test was terminated until the baseline returned to the pre-dose level. Only the data that the baseline can reply to will be analyzed later. GABA was diluted in the extracellular fluid at a final concentration of 0.05 to 0.1 μM. The drug is then diluted to the extracellular fluid containing GABA at the desired concentration.

4) Analysis of experimental results using PatchMaster software. At the time of analysis, the GABA current (Ipre) before dosing and the GABA current (Ipost) after dosing were measured, and the drug effect was calculated by the following formula: reverse activation efficiency (%) = (Ipost - Ipre) * 100 / Ipre. N is the number of trials.

5) Screening results of compounds:

The reverse activation efficiency of MRK016 was -7.75% (N=6).

From the above results, it was found that the biological effects of the compound of the present invention are remarkably superior to those of the conventional α5-GABA _A receptor inverse agonist, and since the compound of the present invention does not easily enter the brain, the conventional α5-GABA _A receptor is not produced. Side effects of fear and anxiety that may be produced by agonists.

Claims

a compound of formula I, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof ester,

among them

Z represents a 5-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, said 5-membered heteroaryl ring being optionally substituted by one or more substituents selected from the group consisting of: , halogen, -R1, -OR1, -OC(O)R1, -NR2R3, CN, cyano(C1-6)alkyl- and R2;

R1 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkyl (C1-6) alkyl, cyano (C1-6) alkane a C1-6 alkyl group substituted with a hydroxy group or an amino group, and R1 is optionally mono-, di- or trifluoro;

R2 or R3 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl or CF3, or R2 and R3 together with the nitrogen atom to which they are attached form 4 a -7 membered heteroalicyclic ring containing the nitrogen atom and one additional heteroatom selected from O, N and S, optionally substituted by one or more R1 groups;

Preferably Z represents a 5-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein at most one heteroatom is oxygen or sulfur, and when one heteroatom is a nitrogen atom At least one oxygen or sulfur atom is also present, and the 5-membered heteroaryl ring is optionally substituted with one or more substituents selected from the group consisting of C1-C4 alkyl, hydroxy, halogen, hydroxy or amino substituted C1. -C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C1-C4 alkoxy;

More preferably Z represents a 5-membered heteroaryl ring containing 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, and one hetero atom is oxygen or sulfur, the other atom is nitrogen, and the 5-membered heteroaryl ring is one Or a plurality of substituents selected from the group consisting of C1-6 alkyl and hydroxy C1-6 alkyl;

Most preferably Z represents oxadiazolyl, furyl, thienyl or isoxazolyl, which is optionally substituted by one or more substituents selected from H, C1-6 alkyl Or a hydroxy C1-6 alkyl group;

A is -NR2-; or A is a 5-membered heteroarylene containing 1, 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur and at most one of the heteroatoms is oxygen or sulfur; Is a 6-membered heteroarylene containing 1, 2 or 3 nitrogen atoms, or the 5 or 6-membered heteroarylene is optionally fused to a benzene or pyridine ring, said 5 or 6-membered The arylene group is optionally substituted by Rx and/or Ry and/or Rz, wherein Rx is halogen, -R1, -OR1, -OC(O)R1, -C(O)OR1, -NR2R3, -NR2C(O) R3, -OH, -CN, Ry is halogen, -R1, -OR1, -OC(O)R1, -NR2R3, -NR2C(O)R3, or CN, and Rz is -R1, -OR1 or -OC(O R1, provided that when A is a pyridine derivative, the pyridine ring is optionally in the form of an N-oxide; or A is a phenylene group optionally substituted by 1, 2 or 3 groups independently selected from: Halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C3-6 cycloalkyl;

Preferably A is represented by a 5-membered heteroarylene containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur and wherein at most one of the heteroatoms is oxygen or sulfur, or contains 1, 2 or 3 a 6-membered heteroarylene or phenylene group of a nitrogen atom, the 5-membered heteroarylene group, 6-membered heteroarylene group and phenylene group being optionally substituted by a substituent independently selected from the group consisting of halogen and cyanogen And a C1-6 alkyl group;

More preferably A represents a phenylene group, a pyridylene group, an isoxazolyl group, optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano and C1-6 alkyl;

Y is -NY1Y2 or -NH-NY3Y4;

Y1 is selected from the group consisting of: H; C1-6 alkyl; C1-6 alkyl substituted by 1 to 5 substituents independently selected from the group consisting of amino, halogen, halo-C1-6 alkoxy, Hydroxy, C1-6 alkoxy, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S(O) 2 -;

Y2 is selected from the group consisting of: H; C1-6 alkyl; C1-6 alkyl substituted by 1 to 5 substituents independently selected from the group consisting of amino, halogen, halo-C1-6 alkoxy, Hydroxy, C1-6 alkoxy, cycloalkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl- S(O) 2 -;

a heteroaryl group, or a heteroaryl group substituted by 1 to 4 substituents, the substituent of which is independently selected from the group consisting of: acetamido, acetyl, acetylamino, amido, amino, carboxyl, cyanide Base, halogen, halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 Alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S(O) 2 -;

a cycloalkyl group, or a cycloalkyl group substituted by 1 to 4 substituents, the substituents being independently selected from the group consisting of: acetamido, acetyl, acetylamino, amido, amino, carboxyl, cyano, halogen , halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S(O) 2 -;

a heterocyclic group, or a heterocycloalkyl group substituted by 1 to 4 substituents independently selected from the group consisting of acetamido, acetyl, acetylamino, amido, amino, carboxyl, cyano, halogen , halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S(O) 2 -;

Or Y1, Y2 together with the N atom to which they are attached form a 4-6 membered heterocyclic group;

Y3, Y4 each independently selected from: hydrogen, C1-C6 alkyl, SO 2 -C1-C6 alkyl, cycloalkyl and heterocyclyl optionally substituted with 1-4 groups independently selected from the group of substituents Halogen, cyano, hydroxy, C1-C6 alkyl and C1-C6 alkoxy,

Or wherein Y3, Y4 together with the nitrogen atom to which they are attached form a heterocyclic group which is optionally substituted with from 1 to 4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C6 alkyl and C1-C6 alkoxy.
The compound of claim 1 having the following formula II:

among them

R4 is a C1-C4 alkyl group or a hydroxy-substituted C1-C4 alkyl group;

Y is NY1Y2 or NH-NY3Y4;

Y1 is H, C1-6 alkyl or C1-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of amino, hydroxy, C1-6 alkoxy, (C1-6 alkane) Base, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S(O) 2 -;

Y2 is selected from C1-6 alkyl; C1-6 alkyl substituted by 1-5 substituents, which are individually selected from the group consisting of: amino, halogen, hydroxy, methyl, C1-6 alkoxy, ring Alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S(O) 2 -;

a C5-C6 heteroaryl group containing 1-3 heteroatoms selected from N, O or S; a C5-C6 substituted with a C1-6 alkyl group containing 1-3 heteroatoms selected from N, O or S Heteroaryl

C3-6 cycloalkyl; C3-6 cycloalkyl substituted by 1-4 substituents, which are individually selected from the group consisting of: amino, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy , C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1- 6 alkyl-S(O) 2 -;

a C4-C6 heterocyclic group containing 1-3 hetero atoms selected from N, O or S; C4-containing 1-4 hetero atoms selected from N, O or S substituted by 1 to 4 substituents a C6 heterocyclic group, which is independently selected from the group consisting of methyl, amino, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1 -6 alkyl and C 1-6 alkyl-S(O) 2 -;

Or Y1, Y2 together with the N atom to which they are attached form a 4-6 membered heterocyclic group;

Y3, Y4 each independently selected from: hydrogen, C1-C6 alkyl, and SO 2 -C1-C6 alkyl, or Y3 and Y4 together form a heterocyclic group with the nitrogen atom to which they are attached.
The compound of claim 2 wherein R4 is methyl or hydroxy substituted methyl.
The compound of claim 2 having the following formula II:

among them

R4 is a C1-C4 alkyl group or a hydroxy-substituted C1-C4 alkyl group;

Y is NY1Y2 or NH-NY3Y4;

Y1 is H or C1-6 alkyl;

Y2 is selected from C1-6 alkyl; C1-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of: hydroxy, halogen, C1-6 alkoxy, cycloalkyl and methyl ;

a C5-C6 heteroaryl group containing 1-3 heteroatoms selected from N, O or S; a C5-C6 substituted with a C1-6 alkyl group containing 1-3 heteroatoms selected from N, O or S Heteroaryl

a C4-6 cycloalkyl group; a C3-6 cycloalkyl group substituted with 1 to 4 substituents, the substituent being a hydroxyl group;

a C4-C6 heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S; C4 having 1 to 3 hetero atoms selected from N, O or S substituted by 1 to 4 substituents a -C6 heterocycloalkyl group, said substituent being a methyl group;

Or Y1, Y2 together with the N atom to which they are attached form a 4-6 membered heterocyclic group containing, in addition to a nitrogen atom, zero, one or more heteroatoms selected from O and S, And the S atom may be in the form of its oxide;

Y3 and Y4 are independently selected from each other: hydrogen, or Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group.
The compound according to claim 4, wherein R4 is a methyl group or a hydroxy-substituted methyl group.
The compound according to any one of claims 2 to 5, wherein Y1 is H or methyl.
The compound of claim 2 having the following formula II:

R4 is a C1-C4 alkyl group or a hydroxy-substituted C1-C4 alkyl group;

Y is -NY1Y2 or -NH-NY3Y4;

Y1 is H or C1-6 alkyl;

Y2 is selected from the group consisting of hydroxy-n-propanol, hydroxycyclopentyl, cyclopropyl, methylpyrazolyl, isopropyl, trifluoroethyl, methoxyethyl, tetrahydropyranyl, methyl, tetrahydrofuranyl , cyclobutyl, amino, cyclopropylmethyl, hydroxydimethylethyl, hydroxymethylpropyl, hydroxyethyl, hydroxymethylbutyl and ethyl;

Or Y1 and Y2 together with the nitrogen atom to which they are attached form a dioxide thiomorpholinyl, morpholinyl, azetidinyl, pyrrolidinyl or piperidinyl;

Y3 and Y4 are independently selected from each other: hydrogen, or together with the nitrogen atom to which they are attached, form a heterocyclic group selected from the group consisting of morpholinyl, pyrrolidinyl, piperidinyl and dioxothiomorpholinyl.
The compound according to claim 7, wherein R4 is a methyl group or a hydroxy-substituted methyl group.
The compound of claim 2 having the following formula II:

R4 is a C1-C4 alkyl group or a hydroxy-substituted C1-C4 alkyl group;

Y is NY1Y2 or NH-NY3Y4;

Y1 is H or C1-6 alkyl;

Y2 is selected from the group consisting of 1-hydroxy-n-propanol-2-yl, 2-hydroxycyclopentyl, cyclopropyl, 1-methyl-1H-pyrazol-4-yl, isopropyl, 2,2,2-tri Fluoroethyl, 2-methoxyethyl, tetrahydro-2H-pyran-4-yl, methyl, tetrahydrofuran-3-yl, cyclobutyl, amino, cyclopropylmethyl, 2-hydroxy-1 , 1-dimethyl-ethyl, 1-hydroxymethylpropyl, 2-hydroxyethyl, 1-hydroxymethylbutyl and ethyl;

Or Y1 and Y2 together with the nitrogen atom to which they are attached form 1,1-dioxo-thiomorpholin-4-yl, morpholin-4-yl, azetidin-1-yl, pyrrolidine- 1-yl or piperidin-1-yl;

Y3 and Y4 are independently selected from each other: hydrogen or together with the nitrogen atom to which they are attached to form a heterocyclic group selected from the group consisting of morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl and 1,1 - dioxo-thiomorpholin-4-yl.
The compound according to claim 9, wherein R4 is a methyl group or a hydroxy-substituted methyl group.
The compound according to any one of claims 7 to 10, wherein Y1 is H or methyl.
A compound according to any one of claims 1 to 11 which is independently selected from the group consisting of:
A compound according to any one of claims 1 to 11 which is independently selected from the group consisting of:
A composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.
Use of a compound according to any one of claims 1 to 13 or a composition according to claim 14 for the preparation of a medicament.
A method of treating or preventing a disease, characterized by administering an effective amount of the compound according to any one of claims 1 to 13 or the composition of claim 14 to a patient.
Use of a compound according to any one of claims 1 to 13 or a composition according to claim 14 for the manufacture of a medicament for the treatment or prevention of a disease associated with the α5-GABA A receptor.
A method of treating or preventing a disease associated with an α5-GABA A receptor, characterized by administering to a patient an effective amount of a compound according to any one of claims 1 to 13 or a combination according to claim 14. Things.
Use of a compound according to any one of claims 1 to 13 or a composition according to claim 14 for the preparation of a medicament for the treatment or prevention of pain, Alzheimer's disease, multi-infarct dementia and Stroke.
A method of treating or preventing pain, Alzheimer's disease, multi-infarct dementia and stroke, characterized by administering to a patient an effective amount of a compound according to any one of claims 1 to 13 or as claimed 14 The composition described.
The use according to claim 19, wherein the pain is neuropathic pain, inflammatory pain and cancer pain.
The method of claim 20 wherein said pain is neuropathic pain, inflammatory pain, and cancer pain.
The use according to claim 19, wherein the pain is selected from the group consisting of headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, back pain, lower limb pain, muscle and Bone pain, vascular pain, gout, arthritis pain, visceral pain, pain from infectious diseases (such as AIDS and post-herpetic neuralgia), bone pain, sickle cell anemia, autoimmune disease, multiple sclerosis or Inflammation-related pain, 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, pain associated with degenerative osteoarthrosis.
The method of claim 20 wherein said pain is selected from the group consisting of: headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, back pain, lower limb pain, musculoskeletal pain , vascular pain, gout, arthritis pain, visceral pain, pain caused by infectious diseases (such as AIDS and post-herpetic neuralgia), bone pain, sickle cell anemia, autoimmune disease, multiple sclerosis or inflammation Pain, 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, pain associated with degenerative osteoarthrosis.
A process for the preparation of a compound according to any one of claims 1 to 13 which is selected from any one of the following:

a) making a compound of formula (IV)

versus
The reaction gives a compound of the formula (1-3) wherein G and W are selected from the group consisting of Cl, Br, I, OH, OTs, OTf and OMs, and R5 is an alkyl group and a benzyl group, preferably a methyl group, an ethyl group, a t-butyl group, wherein Z, Y, A are as defined in claim 1;

Then make the compound of formula (1-3)

Reacting with Y, wherein Z, Y, A are as defined in claim 1; or

b) Compounds of formula (1-4):

Reacting with Y, wherein Z, Y, A are as defined in claim 1;

c) saponifying a compound of formula (1-3) to a compound of formula (1-4), followed by reaction with Y,

Wherein Z, Y, A are as defined in claim 1; or

d)
Compound and formula
The reaction of the compound.