CN107344936B

CN107344936B - Triazolopyridazine derivative, preparation method, pharmaceutical composition and application thereof

Info

Publication number: CN107344936B
Application number: CN201610298009.4A
Authority: CN
Inventors: 李帅; 孙勇; 李扬
Original assignee: Rudong Simr Biotech Co ltd; Shanghai Semerode Biotechnology Co ltd; Shanghai Simr Biotechnology Co ltd
Current assignee: Rudong Simr Biotech Co ltd; Shanghai Semerode Biotechnology Co ltd; Shanghai Simr Biotechnology Co ltd
Priority date: 2016-05-06
Filing date: 2016-05-06
Publication date: 2022-06-03
Anticipated expiration: 2036-05-06
Also published as: WO2017190707A1; CN107344936A

Abstract

The invention provides a triazolopyridazine derivative, a preparation method, a pharmaceutical composition and application thereof, and provides a compound shown in a general formula (I), a cis-trans isomer, an enantiomer, a diastereoisomer, a racemate, a solvate, a hydrate thereof or pharmaceutically acceptable salts and esters thereof, a preparation method, a pharmaceutical composition containing the compound and an application of the compound as alpha 5-GABA_AUse of a receptor modulator, wherein Z, A and Y are as defined in the specification.

Description

Triazolopyridazine derivative, preparation method, pharmaceutical composition and application thereof

The technical field is as follows:

the present invention relates to para-alpha 5-GABA_ATriazolopyridazine derivatives whose receptors have a modulatory effect, their preparation, pharmaceutical compositions containing them and their use as medicaments.

Background art:

gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system of mammals, and two types of GABA receptors exist in the nature, namely GABA_AReceptors which are members of the ligand-gated ion channel superfamily, the other class being GABA_BReceptors, which are members of the superfamily of G protein-coupled receptors. GABA in mammals_AThe receptor subunits were found to be alpha 1-6, beta 1-4, gamma 1-3, delta, epsilon, theta, and rho 1-2 subunits, among which the alpha, beta, and gamma subunit pairs form an integral functional GABA_AThe receptor is essential, and the alpha subunit is p-benzodiazepine and GABA_AReceptor binding is crucial.

GABA containing alpha5_AReceptor (alpha 5-GABA_AReceptor) in mammalian brain_AThe receptor accounts for less than 5%, and the expression level in cerebral cortex is very low, but GABA in cerebral hippocampal tissue_AThe proportion of receptors is greater than 20%, and other brain regions are hardly expressed. Taking into account alpha 5-GABA_AStudy of receptor specific distribution and function in hippocampal tissues of brain, many pharmaceutical companies, including Roche, are engaged in alpha 5-GABA_AResearch on receptor ligands, and a large number of compounds are synthesized successively, especially GABA containing alpha 5subunit of brain hippocampus_AInverse agonists of the receptor, of which α 5IA and MRK-016 show good therapeutic effects in the treatment of cognitive diseases, in particular alzheimer's disease, in animal disease models and in human trials. GABA of the α 5subunit is widely believed_AInverse agonists of the receptor may be used for the treatment of cognitive disorders, in particular for the treatment of Alzheimer's disease. Patent application US 20110224278A 1 discloses GABA containing alpha 5subunit_AInverse agonists of the receptor are useful in the treatment of multi-infarct dementia and stroke-related diseases.

A recent decade of research has demonstrated that (ZLokovic et al Nat Rev neurosci.; 12(12): 723-738) in many disease states, especially neurodegenerative diseases, Alzheimer's disease and stroke, the blood-brain barrier is disrupted, and even those substances that would otherwise not enter the brain can exert their pharmacological effects, and thus GABA, which would otherwise not cross the α 5subunit of the blood-brain barrier, is unable to cross the blood-brain barrier_AInverse agonists of the receptor are also useful in the treatment of alzheimer's disease and stroke.

Asahi laboratory in 2002 reports alpha 5-GABA_AReceptors are also predominantly expressed in small neurons and increased in the neurostimulation model (Xiao HS et al, Identification of gene expression profile of multiple root growth in the rat periphytol axotomy model of neuropathic pain, Proc Natl Acad Sci U S A.2002, 11 th.2002; 99(12), patent application CN103239720A discloses alpha 5-GABA_AThe receptor is expressed in the peripheral nervous system, the expression is obviously increased in a nerve part damage model, and the alpha 5-GABA_AInverse agonists of receptors through selective binding to alpha 5-GABA in the peripheral nervous system_AThe receptor plays a role in inhibiting various pains, and animal experimental model data show that the stronger the inverse exciting effect of the inverse exciting agent is, the better the pain inhibiting effect is.

Detecting whether a compound is directed against GABA comprising an alpha 5subunit_AInverse agonists or antagonists of the receptor, for which much research has been carried out, for example in International applications WO 92/22652 and WO 94/13799, using GABA_AThe combination of α 5, β 3 and γ 2 of the receptor to detect whether a compound binds to the receptor; in the course of performing drug screening, Goeders et al (Goeders N E and Kuhar M J (1985) Benzodiazepine binding in vivo with. sup.3H) are commonly used]Ro 15-1788 Life Sci 37: 345-355). Detection of an energy and GABA_AThe ligand to which the alpha 5subunit of the receptor binds is an antagonist, agonist or inverse agonist, and many studies have been made in this regard, as described by Wafford et al (Wafford K A, stirring P J and Kemp J A (1993) Differences in affinity and efficiency of benzene derivatives receptors on receptors GABA. sub. A receptors subunit. mol. Pharmacol 43: 240-charge 244).

The methods for screening whether a drug enters the blood brain barrier are relatively extensive and are described in the literature (Jones et al, pharmaceuticals and metabolic students on (3-tert-butyl-7- (5-methylisoxazol-3-yl) -2- (1-methyl-1H-1,2, 4-triazo-5-ylmethoxy) pyrazolo [1,5-d ]][1,2,4]triazine,a functionally selective GABA_A α5inverse agonist for cognitive dysfunction.Bioorg Med Chem Lett.2006Feb 15；Report in 16(4) 872-5) that inhibition by a compound can be detected³H)R0-15-1788(α5GABA_AReceptor-labeled specific inverse agonist) binding in brain, MRK016 can effectively inhibit (³H) The central binding of R0-15-1788, while MRK016-M3 hardly inhibited (³H) R0-15-1788 is centrally combined. It can also be determined whether the drug can effectively enter the blood brain barrier by detecting the drug in different tissues, for example, by detecting the distribution ratio of the drug in the brain and the blood plasma.

Previous studies have found that α 5GABA is inhibited or reduced using drugs or genetic methods_AReceptor-mediated extrasynaptic inhibition may improve cognition and learning, but at the same time lead to mild anxiety-like behavior. (Brickley, S.G.&(2012), the pair of computers, and the pair of computers, wherein each computer is a module, i.e. an external synthetic GABAA receptors, the pair of computers, and the pair of computers; (ii) Harris, D.et al.Selective infection on conditional memory physical properties of physical properties associated with selection of benzodiazepine ligands at GABAA receptors associating the alpha5 subnitrile.J.Med.chem.51, 3788-3803 (2008); savic', m.m.et al.pwz-029, a compound with modulated input gain feedback regulation α 5 subbunits, improved passive, but active, available learning in rate brain Res.1208, 150-159 (2008); cl element, Y.et al.Garba5-gene amplified block associated with a molecular property of the full agglomerated nitrile chloride. Behav.brain Res.233, 474-482 (2012)). Fear and anxiety traits were found to be associated with a decrease in Gaba5 mRNA. (Heldt, S.A.&Ressler,K.J.Training-induced changes in the expression of GABA_Aassociated genes in the amygdala after the acquisition and inactivation of Pavlovian fear.eur.J.Neurosci.26, 3631-3644 (2007); tasan, r.o.et al.alternate GABA transmission in a motor model of established train identity 183, 71-80 (2011). Paolo Botta et al disclose α 5GABA_AThe receptors are involved in the mechanisms of anxiety and fear. Knock-out of alpha 5GABA specific in brain regions_AReceptor expression can lead to fear in animalsAnd anxiety behavior. Thus, alpha 5GABA disclosed in the past_AInverse agonists entering the brain produce fear and anxiety side effects that cannot be applied directly in the medical field and must be modified.

Disclosure of Invention

An object of the present invention is to provide compounds represented by the general formulae (I) and (II), their cis-trans isomers, enantiomers, diastereomers, racemates, solvates, hydrates, or pharmaceutically acceptable salts and esters thereof.

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

Another object of the present invention is to provide compounds of the general formulae (I) and (II) as α 5-GABA_AUse of a receptor modulator for the preparation of a medicament for the prevention, treatment or amelioration of α 5-GABA_AUse in medicine for a disorder related to a receptor, such as cognitive disorders, 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 deficit, or in the manufacture of a medicament for relieving pain.

Another object of the present invention is to provide a pharmaceutical composition comprising one or more therapeutically effective amounts of the compounds of formulae (I) and (II) or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers and/or adjuvants.

It is another object of the present invention to provide a method for preventing, treating or ameliorating diseases related to α 5-GABAA receptor, which comprises administering the compounds represented by the general formulae (I) and (II) or pharmaceutically acceptable salts thereof or the composition of the present invention.

In a first aspect of the invention, there is provided a compound of formula I, its cis-trans isomers, enantiomers, diastereomers, racemates, solvates, hydrates, or pharmaceutically acceptable salts and esters thereof,

wherein

Z represents a 5-membered heteroaromatic ring containing 1,2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, said 5-membered heteroaromatic ring being optionally substituted with one or more substituents selected from: hydroxy, 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) alkyl, hydroxy-or amino-substituted C1-6 alkyl, and R1 is optionally mono-, di-or tri-fluorinated;

r2 or R3 are 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 both attached form a 4-7 membered heteroaliphatic ring containing said nitrogen atom and one other heteroatom optionally selected from O, N and S, said heteroaliphatic ring being optionally substituted with one or more R1 groups;

preferably Z represents a5 membered heteroaromatic ring containing 1,2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, of which up to 1 heteroatom is oxygen or sulphur and at least 1 oxygen or sulphur atom is also present when 1 heteroatom is a nitrogen atom, said 5 membered heteroaromatic ring being optionally substituted by one or more substituents selected from: 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 heteroaromatic ring containing 2 heteroatoms independently selected from oxygen, nitrogen and sulphur, and one heteroatom is oxygen or sulphur and the other atom is nitrogen; the 5-membered heteroaromatic ring is optionally substituted with one or more substituents selected from the group consisting of: c1-6 alkyl and hydroxy C1-6 alkyl;

most preferably Z represents oxa-diazolyl, furyl, thienyl or isoxazolyl, said isoxazolyl being optionally substituted by one or more substituents selected from: h, C1-6 alkyl and hydroxy C1-6 alkyl;

a is-NR 2-; or A is a 5-membered heteroarylene group containing 1,2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur and up to 1 of the heteroatoms is oxygen or sulfur; OR is a 6-membered heteroarylene group containing 1,2 OR 3 nitrogen atoms, OR the 5-OR 6-membered heteroarylene group is further optionally fused to a benzene OR pyridine ring, the 5-OR 6-membered heteroarylene group being 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, Rz is-R1, -OR1 OR-OC (O) R1, with the proviso that when A is a pyridine derivative, the pyridine ring is optionally in the form of an N-oxide; or a is phenylene optionally substituted with 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 represents a 5-membered heteroarylene group containing 1,2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur and up to 1 of the heteroatoms being oxygen or sulfur, or a 6-membered heteroarylene group or phenylene group containing 1,2 or 3 nitrogen atoms; the 5-membered heteroarylene group, the 6-membered heteroarylene group, and the phenylene group are optionally substituted with a substituent independently selected from the group consisting of: halogen, cyano and C1-6 alkyl;

more preferably a represents phenylene, pyridylene, isoxazolylene; optionally substituted with 1,2 or 3 substituents independently selected from: halogen, cyano and C1-6 alkyl;

y is-NY 1Y2 or-NH-NY 3Y 4;

y1 is selected from: h; c1-6 alkyl; c1-6 alkyl substituted with 1-5 substituents independently selected from the group consisting of: amino, halogen, halo-C1-6 alkoxy, hydroxy, C1-6 alkoxy, (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 with 1-5 substituents independently selected from: amino, hydroxy, C1-6 alkoxy, (C1-6 alkyl ) N-, (C1-6 alkyl, H) N-and C1-6 alkyl-S (O)₂-；

More preferably Y1 represents H or C1-6 alkyl;

most preferably Y1 represents H or methyl;

y2 is selected from: h; c1-6 alkyl; c1-6 alkyl substituted with 1-5 substituents independently selected from the group consisting of: amino, halogen, halo-C1-6 alkoxy, hydroxy, C1-6 alkoxy, cycloalkyl, (C1-6 alkyl ) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O)₂-；

Heteroaryl, or heteroaryl substituted with 1-4 substituents independently selected from: acetamido, acetyl, acetylamino, acylamino, amino, carboxy, cyano, halogen, halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl ) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O)₂-；

Cycloalkyl, or cycloalkyl substituted with 1 to 4 substituents independently selected from: acetamido, acetyl, acetylamino, acylamino, amino, carboxy, cyano, halogen, halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl ) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O)₂-；

Heterocyclyl, or heterocycloalkyl substituted with 1-4 substituents independently selected from: acetamido, acetyl, acetylamino, acylamino, amino, carboxy, cyano, halogen, halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-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 with 1-5 substituents independently selected from the group consisting of: amino, halogen, hydroxy, methyl, C1-6 alkoxy, cycloalkyl, (C1-6 alkyl ) N-, (C1-6 alkyl, H) N-, and C1-6 alkyl-S (O)₂-；

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

c3-6 cycloalkyl; c3-6 cycloalkyl substituted with 1-4 substituents independently selected from the group consisting of: amino, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl ) N-, (C1-6 alkyl, H) N-and C1-6 alkyl-S (O)₂-；

C4-C6 heterocyclyl containing 1-3 heteroatoms selected from N, O or S; C4-C6 heterocyclyl containing 1-3 heteroatoms selected from N, O or S, substituted with 1-4 substituents independently selected from: methyl, amino, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl and C1-6 alkyl-S (O)₂-；

More preferably Y2 is selected from C1-6 alkyl; c1-6 alkyl substituted with 1-5 substituents independently selected from the group consisting of: hydroxy, halogen, C1-6 alkoxy, cycloalkyl and methyl;

c4-6 cycloalkyl; c3-6 cycloalkyl substituted with 1-4 substituents which are hydroxy;

C4-C6 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S; C4-C6 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, substituted with 1-4 substituents which are methyl;

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

most preferably 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-hydroxymethylbutyl and ethyl;

or Y1, Y2 together with the N atom to which they are attached form a 4-6 membered heterocyclyl; or Y1, Y2 together with the N atom to which they are attached form cycloalkyl;

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

more preferably either Y1 and Y2 together with the nitrogen atom to which they are attached form a dioxidothiomorpholinyl, morpholinyl, azetidinyl, pyrrolidinyl or piperidinyl group;

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

y3, Y4 are independently selected from: hydrogen, C1-C6 alkyl, SO₂-C1-C6 alkyl, cycloalkyl or Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group;

preferably Y3, Y4 are independently selected from: hydrogen, C1-C6 alkyl, SO₂-C1-C6 alkyl, cycloalkyl and heterocyclyl, optionally substituted with 1-4 substituents independently selected from the group consisting of: 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 heterocyclic group is optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, and C1-C6 alkoxy.

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

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

The present invention also provides compounds having the following general formula II:

wherein

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

y is NY1Y2 or NH-NY3Y 4;

y1 is H, C1-6 alkyl or C1-6 alkyl substituted with 1-5 substituents independently selected from: amino, hydroxy, C1-6 alkoxy, (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 with 1-5 substituents independently selected from the group consisting of: amino, halogen, hydroxy, methyl, C1-6 alkoxy, cycloalkyl, (C1-6 alkyl ) N-, (C1-6 alkyl, H) N-, 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 heterocyclyl;

or Y1, Y2 together with the N atom to which they are attached form cycloalkyl;

y3, Y4 are independent of each otherIs selected from: hydrogen, C1-C6 alkyl, 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, in the compound of formula II,

r4 is methyl or hydroxy-substituted methyl;

y is NY1Y2 or NH-NY3Y 4;

or Y1, Y2 together with the N atom to which they are attached form cycloalkyl;

y3, Y4 are independently selected from: hydrogen, C1-C6 alkyl and SO₂-C1-C6 alkyl, or Y3 and Y4 with themThe attached nitrogen atoms together form a heterocyclic group.

In a preferred embodiment, in the compound of formula II,

r4 is C1-C4 alkyl or hydroxy-substituted C1-C4 alkyl;

y is NY1Y2 or NH-NY3Y 4;

y1 is H or C1-6 alkyl;

y2 is selected from C1-6 alkyl; c1-6 alkyl substituted with 1-5 substituents independently selected from the group consisting of: hydroxy, halogen, C1-6 alkoxy, cycloalkyl and methyl;

c4-6 cycloalkyl; c3-6 cycloalkyl substituted with 1 to 4 substituents which are hydroxy;

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

or Y1, Y2 together with the N atom to which they are attached form cycloalkyl;

y3 and Y4 are independently selected from: hydrogen, or Y3 and Y4 form together with the nitrogen atom to which they are attached a heterocyclic group.

In a preferred embodiment, in the compound of formula II,

r4 is methyl or hydroxy-substituted methyl;

y is NY1Y2 or NH-NY3Y 4;

y1 is H or C1-6 alkyl;

or Y1, Y2 together with the N atom to which they are attached form cycloalkyl;

y3 and Y4 are independently selected from: hydrogen, or Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group.

In a preferred embodiment, in the compound of formula II,

r4 is C1-C4 alkyl or hydroxy-substituted C1-C4 alkyl;

y is NY1Y2 or NH-NY3Y 4;

y1 is H or methyl;

Contains 1-3C 4-C6 heterocyclyl with heteroatoms selected from N, O or S; C4-C6 heterocyclyl containing 1-3 heteroatoms selected from N, O or S, substituted with 1-4 substituents independently selected from: methyl, amino, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl and C1-6 alkyl-S (O)₂-；

or Y1, Y2 together with the N atom to which they are attached form cycloalkyl;

y3, Y4 are independently selected from: hydrogen, C1-C6 alkyl, 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, in the compound of formula II,

r4 is methyl or hydroxy-substituted methyl;

y is NY1Y2 or NH-NY3Y 4;

y1 is H or methyl;

C4-C6 heterocyclyl containing 1-3 heteroatoms selected from N, O or S; C4-C6 heterocyclyl containing 1-3 heteroatoms selected from N, O or S, substituted with 1-4 substituents independently selected from: methyl, amino, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl andc1-6 alkyl-S (O)₂-；

or Y1, Y2 together with the N atom to which they are attached form cycloalkyl;

y3, Y4 are independently selected from: 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, in the compound of formula II,

r4 is C1-C4 alkyl or hydroxy-substituted C1-C4 alkyl;

y is NY1Y2 or NH-NY3Y 4;

y1 is H or methyl;

or Y1, Y2 together with the N atom to which they are attached form cycloalkyl;

In a preferred embodiment, in the compound of formula II,

r4 is methyl or hydroxy-substituted methyl;

y is NY1Y2 or NH-NY3Y 4;

y1 is H or methyl;

or Y1, Y2 together with the N atom to which they are attached form cycloalkyl;

In a preferred embodiment, in the compound of formula II,

r4 is C1-C4 alkyl or hydroxy-substituted C1-C4 alkyl;

y is-NY 1Y2 or-NH-NY 3Y 4;

y1 is H or C1-6 alkyl;

y2 is selected from hydroxy n-propanolyl, hydroxycyclopentyl, cyclopropyl, methylpyrazolyl, isopropyl, trifluoroethyl, methoxyethyl, tetrahydropyranyl, methyl, tetrahydrofuranyl, cyclobutyl, amino, cyclopropylmethyl, hydroxydimethylethyl, hydroxymethylbutyl and ethyl;

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

y3 and Y4 are independently selected from: hydrogen, or together with the nitrogen atom to which they are attached form a heterocyclyl selected from morpholinyl, pyrrolidinyl, piperidinyl and dioxothiomorpholinyl.

In a preferred embodiment, in the compound of formula II,

r4 is methyl or hydroxy-substituted methyl;

y is-NY 1Y2 or-NH-NY 3Y 4;

y1 is H or C1-6 alkyl;

In a preferred embodiment, in the compound of formula II,

r4 is C1-C4 alkyl or hydroxy-substituted C1-C4 alkyl;

y is NY1Y2 or NH-NY3Y 4;

y1 is H or C1-6 alkyl;

y2 is selected from 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-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, pyrrolidin-1-yl or piperidin-1-yl;

y3 and Y4 are independently selected from: hydrogen, or together with the nitrogen atom to which they are attached form a heterocyclyl group selected from morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl and 1, 1-dioxo-thiomorpholin-4-yl.

In a preferred embodiment, in the compound of formula II,

r4 is methyl or hydroxy-substituted methyl;

y is NY1Y2 or NH-NY3Y 4;

y1 is H or C1-6 alkyl;

y3 and Y4 are independently selected from: hydrogen, or together with the nitrogen atom to which they are attached form a heterocyclic group selected from morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl and 1, 1-dioxo-thiomorpholin-4-yl.

In a preferred embodiment, in the compound of formula II,

r4 is C1-C4 alkyl or hydroxy-substituted C1-C4 alkyl;

y is-NY 1Y2 or-NH-NY 3Y 4;

y1 is H or methyl;

y2 is selected from the group consisting of hydroxy n-propanolyl, hydroxycyclopentyl, cyclopropyl, methylpyrazolyl, isopropyl, trifluoroethyl, methoxyethyl, tetrahydropyranyl, methyl, tetrahydrofuranyl, cyclobutyl, amino, cyclopropylmethyl, hydroxydimethylethyl, hydroxymethylbutyl, and ethyl;

In a preferred embodiment, in the compound of formula II,

r4 is methyl or hydroxy-substituted methyl;

y is-NY 1Y2 or-NH-NY 3Y 4;

y1 is H or methyl;

In a preferred embodiment, in the compound of formula II,

r4 is C1-C4 alkyl or hydroxy-substituted C1-C4 alkyl;

y is NY1Y2 or NH-NY3Y 4;

y1 is H or methyl;

In a preferred embodiment, in the compound of formula II,

r4 is methyl or hydroxy-substituted methyl;

y is NY1Y2 or NH-NY3Y 4;

y1 is H or methyl;

In a preferred embodiment, the compound of formula II is selected from the following compounds:

in a more preferred embodiment, the compound of formula II is selected from the following compounds:

the present 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 in the manufacture 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 as described herein for the preparation of a medicament for the treatment or prevention of inflammation associated with alpha 5-GABA_AThe use in the preparation of a medicament for treating a receptor-related disease.

The invention also provides a method for treating or preventing alpha 5-GABA_AA method of treating a subject associated with a disorder characterized by administering to the subject an effective amount of a compound or composition as described above.

The present invention also provides the use of a compound or composition as 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, low limb pain, musculoskeletal pain, vascular pain, gout, arthritic pain, visceral pain, pain caused by infectious diseases (such as AIDS and postherpetic neuralgia), bony pain, sickle cell anemia, autoimmune diseases, multiple sclerosis or inflammation-related pain, chronic pain caused by injury or surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, pain in lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic neuropathic pain, reflex sympathetic dystrophy, nerve avulsion, cancer, chemical injury, toxins, nutritional deficiencies, viral or bacterial infections, degenerative osteoarthropathy-related pain.

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 dose of a compound or composition as described herein.

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

a) reacting a compound of formula (IV)

And

reacting to obtain a compound of formula (1-3) wherein G and W are selected from Cl, Br, I, OH, OTs, OTf and OMs, and R5 is alkyl, methyl, ethyl, t-butyl and benzyl; wherein Z, Y, A is as defined above;

then reacting the compound of formula (1-3)

With Y, wherein Z, Y, A is as defined above; or

b) Reacting a compound of formula (1-4):

with Y, wherein Z, Y, A is as defined above;

c) saponifying a compound of formula (1-3) to a compound of formula (1-4) and subsequently reacting with Y, wherein Z, Y, A is as defined above; or

d) Formula (II)

Compounds and formulae

Reaction of the compounds.

In the compounds of formulae I and II in the present invention, Z represents a 5-membered heteroaromatic ring containing 1,2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, said 5-membered heteroaromatic ring being optionally substituted with one or more substituents selected from: 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, hydroxy-or amino-substituted C1-6 alkyl, and R1 is optionally mono-, di-or tri-fluorinated; r2 or R3 are 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 both attached form a 4-7 membered heteroaliphatic ring containing said nitrogen atom and one other heteroatom optionally selected from O, N and S, said ring being optionally substituted by one or more R1 groups; preferably, Z represents a 5-membered heteroaromatic ring containing 1,2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, of which up to 1 heteroatom is oxygen or sulphur, and when 1 heteroatom is a nitrogen atom, at least 1 oxygen or sulphur atom is also present, the 5-membered heteroaromatic ring being optionally substituted with one or more substituents selected from: C1-C4 alkyl, hydroxy, halogen, hydroxy or amino substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy; more preferably Z represents a5 membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulphur, and up to 1 heteroatom is oxygen or sulphur, and when 1 heteroatom is a nitrogen atom, 1 oxygen atom or1 sulphur atom is also present; preferably Z represents a 5-membered heteroaromatic ring containing 2 heteroatoms independently selected from oxygen, nitrogen and sulphur, and one heteroatom is oxygen or sulphur and the other atom is nitrogen; the 5-membered heteroaromatic ring is optionally substituted with one or more substituents selected from the group consisting of: c1-6 alkyl or hydroxy C1-6 alkyl; preferably Z represents an oxa-diazolyl, furyl, thienyl or isoxazolyl group, optionally substituted by one or more substituents selected from: c1-6 alkyl or hydroxy C1-6 alkyl; more preferably, Z represents an oxa-diazolyl, furyl, thienyl or isoxazolyl group, optionally substituted by one or more substituents selected from: methyl and hydroxymethyl.

In the compounds of the general formulae I and II according to the invention, A is-NR 2-; OR A is a 5-membered heteroarylene group containing 1,2, 3 OR 4 heteroatoms independently selected from oxygen, nitrogen and sulfur and up to 1 of the heteroatoms being oxygen OR sulfur, OR is a 6-membered heteroarylene group containing 1,2 OR 3 nitrogen atoms, OR said 5-OR 6-membered heteroarylene group is further optionally fused to a benzene OR pyridine ring, said 5-OR 6-membered heteroarylene group being 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, Rz is-R1, -OR1 OR-OC 1, with the proviso that when A is a pyridine derivative, the pyridine ring is optionally in the form of an N-oxide; or a is phenylene optionally substituted with 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 represents a 5-membered heteroarylene group containing 1,2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur and up to 1 of the heteroatoms being oxygen or sulfur, or a 6-membered heteroarylene group or phenylene group containing 1,2 or 3 nitrogen atoms; the 5-membered heteroarylene group, the 6-membered heteroarylene group and the phenylene group are optionally substituted with a substituent selected from the group consisting of: halogen, cyano and C1-6 alkyl; more preferably a represents phenylene, pyridylene, isoxazolylene; optionally substituted with 1,2 or 3 substituents independently selected from: halogen, cyano and C1-6 alkyl;

in the compounds of the general formulae I and II of the present invention, Y is-NY 1Y2 or-NH-NY 3Y 4;

More preferably Y1 represents H or C1-6 alkyl;

most preferably Y1 represents H or methyl;

Heteroaryl, or heteroaryl substituted with 1-4 substituents independently selected from: acetamido, acetyl, acetylamino, acylamino, amino, carboxyl, cyano, halogen, halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl ) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O)₂-；

Heterocyclyl, or heterocycloalkyl substituted with 1-4 substituents independently selected from: acetamido, acetyl, acetylamino, acylamino, amino, carboxyl, cyano, halogen, halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl ) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O)₂-；

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

Detailed Description

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

The following definitions of the general terms apply, whether appearing individually or in combination.

The naming convention used in this application is based on AutoNomTM 2000, a Beilstein Institute computerized system used to generate IUPAC system nomenclature. The chemical structures presented herein were obtained using ChemDraw version 12. Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures given herein indicates the presence of a hydrogen atom.

The term "substituted" means that the specified group or moiety may have 1,2, 3,4, 5, or 6 substituents, unless otherwise specified. When there are multiple substituents on a group and a variety of possible substituents are given, the substituents are independently selected and need not be the same.

The term "unsubstituted" means that the indicated group has no substituents.

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

When referring to the number of substituents, the term "one or more" refers to one substitution up to the maximum possible number of substitutions, i.e., one hydrogen is substituted up to all hydrogens are substituted with substituents. Preference is given to 1,2, 3,4 or 5 substituents, unless otherwise indicated.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine.

The term "lower alkyl" as used herein means a straight or branched chain alkyl group having 1 to 6 carbon atoms, which may be interchanged with the C1-6 alkyl group described herein, and examples of the C1-6 alkyl group include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl groups and those specifically exemplified hereinafter. Particularly preferred "lower alkyl" groups 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 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 specifically exemplified hereinafter.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic group having heteroatoms, preferably a monovalent 3-7 membered saturated or partially unsaturated monocyclic ring containing 1,2 or 3 ring heteroatoms selected from N, O or S. Preferably containing 1 or 2 ring heteroatoms. Preferred are 4-6 membered heterocyclyl groups containing 1 or 2 ring heteroatoms selected from N, O or S. S may be optionally substituted with two oxo groups. Examples of heterocyclyl groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-dioxo-thiomorpholin-4-yl, piperazinyl, azepanyl, diazepanyl, oxazepanyl or dihydro-oxazolyl, and those specifically exemplified below. Preferred heterocyclyl groups are morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4-yl and 1, 1-dioxo-thiomorpholin-4-yl, and particularly preferred heterocyclyl 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 from 6 to 14, preferably from 6 to 10, carbon atoms and having at least one aromatic ring or multiple fused rings in which at least one ring is aromatic. Examples of aryl groups are phenyl, naphthyl, biphenyl or indanyl, as well as those specifically exemplified below. A preferred aryl group is phenyl, which may also be substituted, as defined below and in the claims.

The term "heteroaryl" is an aromatic group containing a heteroatom, preferably an aromatic 5-6 membered monocyclic or 9-10 membered bicyclic ring containing 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulfur, for example furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl or isoquinolinyl, and those specifically exemplified below. Heteroaryl groups may also be substituted, as defined below and in the claims. Preferred heteroaryl groups are 5-fluoro-pyridin-2-yl.

The term "lower alkyl substituted by halogen" refers to lower alkyl mono-or poly-substituted by halogen. Examples of lower alkyl substituted by halogen are e.g. CFH₂、CF₂H、CF₃、CF₃CH₂、CF₃(CH₂)₂、(CF₃)₂CH or CF₂H-CF₂And those specifically exemplified below.

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

The compounds of formula (I) and (II) may form pharmaceutically acceptable acid addition salts. Examples of such pharmaceutically acceptable salts are salts of the compounds of formulae (I) and (II) with physiologically compatible inorganic or organic acids, such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid; organic acids are, for example, methane sulfonic acid, p-toluene sulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term "pharmaceutically acceptable salts" refers to such salts. The compounds of formula (I) containing an acidic group such as COOH may also form salts with bases. 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 salts" 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 examples of suitable esters. Methyl, ethyl, propyl, butyl and benzyl esters are preferred. The term "pharmaceutically acceptable esters" also includes derivatives of the compounds of formula (I) wherein the hydroxyl groups are converted to the corresponding esters by inorganic or organic acids, 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 and the like, which are non-toxic to organisms.

Preparation method

a) reacting a compound of formula (IV)

And

reaction, wherein G and W are optionally Cl, Br, I, OH, OTs, OTf, OMs, etc.; r5 is alkyl, methyl, ethyl, tert-butyl and benzyl, then

Reacting a compound of formula (1-3)

With Y or

b) Reacting a compound of formula (1-4):

reacting with Y; or

c) Saponifying the compound of formula (1-3) into a compound of formula (1-4), followed by reaction with Y; or

d) Formula (II)

Compounds and formulae

The reaction of the compound(s) is carried out,

wherein Z, Y, A is as defined above.

Make formula

And

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

Formula (II)

The reaction of the compounds with Y to give the compounds of the formula (I) can be carried out under the conditions described in the examples or under conditions known to the person skilled in the art. For example, the reaction may be carried out in the presence of trimethylaluminum in a suitable solvent (e.g., dioxane) at elevated temperature (e.g., 85-95 ℃).

Formula (II)

The reaction of the compounds with Y to give the compounds of the formula (I) can be carried out under the conditions described in the examples or under conditions known to the person skilled in the art. For example, the reaction can be carried out in the presence of Hunigs base (N, N-diisopropylethylamine) and O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate in a suitable solvent (e.g., dimethylformamide) at room temperature. Alternatively, the reaction may be carried out in the presence of 1, 1' -carbonyldiimidazole in a suitable solvent such as dimethylformamide at elevated temperature such as 80 ℃. Furthermore, the reaction can also be carried out in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N1-hydroxybenzotriazole and Hunigs base (N, N-diisopropylethylamine) in a suitable solvent, such as dichloromethane, at room temperature.

Formula (II)

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

Formula (II)

Compounds and formulae

Reaction of the Compounds to give the Compounds of formula (I) the reaction may be under the conditions described in the examples or within the skill in the artUnder conditions known to the person. For example, the reaction can be carried out in LDA, NaH, potassium or sodium t-butoxide, etc., in a suitable solvent (e.g., dioxane, THF, DMF, etc.) at room temperature (e.g., 20 ℃ C.). Or production conditions for producing an ether using Mitsunobu conditions (PPh3, DEAD), a phase transfer catalyst (TBAB, crown ether, etc.), etc. In a suitable solvent (e.g., dioxane, THF, DMF, etc.) at elevated temperature (e.g., 80 deg.C) to form the product under the corresponding base or catalyst conditions.

The invention also relates to compounds of formula (II) as described above, prepared by a process as described above.

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

If their preparation is not described in the examples, the compounds of formula (II) and their intermediate products can be prepared according to analogous methods or according to the methods described previously. Starting materials known in the art can be obtained commercially or can be prepared according to methods known in the art or analogous methods to known methods.

It will be appreciated that the compounds of formula (II) of the present invention may be derivatised at functional groups to give derivatives which can be reconverted to the parent compound in vivo.

As mentioned above, the novel compounds of the present invention, and the pharmaceutically acceptable salts and esters thereof, have important pharmacological properties, being α 5GABA_AA receptor inverse agonist. Thus, the compounds of the present invention can be used alone or in combination with other drugs for the treatment or prevention of diseases caused by GABA containing alpha 5subunit_AReceptor ligandsA body-mediated disease. These diseases include, but are not limited to, pain, Alzheimer's disease, multi-infarct dementia, and stroke.

The invention therefore also relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.

Also encompassed by the present invention are compounds as described above for use in the preparation of a medicament for the treatment or prevention of a disease associated with α 5GABA_AA medicament for the treatment or prevention of a receptor-related disease, in particular: pain, alzheimer's disease, multi-infarct dementia and stroke.

Preferably, pain is treated or prevented. Particularly preferred is the treatment or prevention of neuropathic, inflammatory and cancerous pain.

As used herein, "cancer pain" refers to the pain that occurs during the development of a malignant tumor, which is currently thought to occur by three mechanisms, namely: pain directly from cancer development, pain following cancer treatment, and painful disease associated with cancer patients.

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

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

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

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

As used herein, "acute pain" is defined as pain caused by harmful stimuli occurring from injury and/or disease of the skin, body structure or internal organs, or pain caused by abnormal function of muscles or internal organs that do not produce actual tissue damage.

As used herein, "chronic pain" is defined as lasting beyond the usual course of an acute disease or a reasonable time for the injury to heal, or associated with a chronic pathological process that causes persistent pain, or pain that recurs at intervals of months or years, and is considered chronic if it is present after healing should have been achieved or beyond the usual course of treatment. The length of time that pain needs to elapse depends on the nature of the pain and the course of treatment associated with the pain, and 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, lumbago, lower limb pain, musculoskeletal pain, pain associated with somatoform mental disorder, visceral pain, painful diabetic neuropathy, vascular pain, gout, arthritic pain, cancer pain, autonomic neuroreflex pain, pain caused by infectious diseases such as aids and shingles, pain caused by autoimmune diseases (rheumatism), pain caused by acute and chronic inflammation, post-operative pain, and post-burn pain.

The medicament disclosed by the invention is effective in treating chronic pain as defined above, and the medicament disclosed by the invention can be used for treating hyperalgesia accompanied with other symptoms, including hyperalgesia, allodynia, hyperalgesia and pain memory enhancement, and the invention improves the treatment of the pain.

As used herein, "headache" can be divided into primary headaches including tension headaches, migraine headaches, and cluster headaches, and secondary headaches due to other diseases. When affected or stimulated, pain sensitive tissues of the head and face, including those distributed on the scalp, face, mouth and throat, etc., are affected and damaged, because they are mainly muscles or blood vessels of the head, contain abundant nerve fibers and are sensitive to pain, they can cause various headaches.

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

As used herein, "trigeminal neuralgia" is a unique chronic painful condition, also known as painful convulsions, which refers to transient, paroxysmal and recurrent electrical shock-like severe pain in the trigeminal nerve distribution, or with ipsilateral muscle spasm. The trigeminal neuralgia is divided into primary trigeminal neuralgia and secondary trigeminal neuralgia, wherein the primary trigeminal neuralgia is clinically without nervous system signs and organic lesions; the secondary trigeminal neuralgia is characterized in that the nervous system signs exist clinically, and organic lesions such as tumors and inflammations are detected and discovered.

As used herein, "atypical facial pain" refers to pain caused by a variety of etiologies. It is manifested as persistent burning-like pain, no intermittency, no association with specific actions or triggering stimuli, mostly bilateral, pain often outside the trigeminal range and even affecting the neck skin. The causes of the disease can be nasosinusitis, malignant tumor, infection of jaw and skull base and the like, which stimulate or injure trigeminal nerve to cause pain.

As used herein, "neck pain, back pain, shoulder pain" refers to pain due to acute and chronic muscle strain, degeneration of bone joints, trauma, and the like. Common diseases causing pains on the neck, the shoulder and the upper limb comprise neck-shoulder myofascitis, neck-ligament inflammation, cervical spondylosis, scapulohumeral periarthritis, thoracic outlet syndrome, external humeral epicondylitis and the like, or the pains caused by autoimmune diseases are common in diseases such as rheumatoid arthritis, ankylosing spondylitis, rheumatoid arthritis and the like, and other diseases possibly causing neck pain, back pain and shoulder pain comprise tumors of the neck and the shoulder, neuritis, arteriovenous diseases, various infections, involvement pain caused by pathological changes of thoracic organs and abdominal organs and the like.

As used herein, "chest, abdominal and back pain" refers to pain due to disease of the thoracoabdominal viscera, thoracoabdominal wall tissues, including but not limited to intercostal neuralgia, intercostal chondritis, angina, abdominal pain (acute abdominal visceral pain) and psoas myofascial syndrome.

As used herein, "low back, low limb pain" refers to low back, lumbosacral, sacroiliac, hip, and low limb pain. The pain of the waist and the lower limbs is not independent diseases but has the common characteristics of various diseases, has various clinical manifestations and very complex causes, and has many degenerative and injurious symptoms, including but not limited to pain related to lumbar disc herniation, acute lumbar sprain, sciatica, osteoporosis, third lumbar transverse process syndrome, piriformis syndrome, knee osteoarthritis, tail pain, heel pain and the like.

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

As used herein, "painful diabetes" refers to pain that results from nerve damage that is concomitant to diabetes, in which nerve damage is caused, at least in part, by reduced blood flow and hyperglycemia. Some diabetic patients do not develop neuropathy, while others develop the disease early, and diabetic neuropathy can be classified into mononeuropathies and generalized polyneuropathy involving one or more focal sites, which can be diffuse and symmetric, usually involving mainly sensory modalities (Merrit's Textbook of Neurology, 9 th edition, edited by LPRowland LP). Manifestations of diabetic neuropathy may include autonomic nerve dysfunction leading to dysregulation including heart, smooth muscle and glands, resulting in hypotension, diarrhea, constipation and impotence. Diabetic neuropathy often develops in stages, occurring early in the nerve ending region, in the foot when autonomic or sensory neuropathy occurs, in cranial neuropathy occurs around the face and eyes, with intermittent pain and tingling, and in later stages, pain is more intense and frequent, and finally, when pain is lost in an area, painless neuropathy occurs, with the absence of pain as an indicator of injury, greatly increasing the risk of severe tissue damage.

As used herein, "visceral pain" includes, but is not limited to, pain associated with Irritable Bowel Syndrome (IBS), with or without Chronic Fatigue Syndrome (CFS), Inflammatory Bowel Disease (IBD), and interstitial cystitis.

As used herein, "vascular pain" is pain that results from one or more of the following factors. First, the perfusion of the tissue is not proper. Causing transient or continuous ischemia, such as occurs in limb muscles during exercise; second, late changes. Ulcers or gangrene, for example, in the skin or abdominal viscera; third, sudden or accelerated changes in the calibre of large vessels. Changes such as those occurring in aneurysms; fourth, the aorta ruptures. The result is blood extravasation, stimulation of nociceptive fibers in the peritoneum or parietal pleura; fifth, strong spasm due to severe stimulation of arterial endothelium by intra-arterial injection; sixth, damage from venous return results in massive edema that rapidly dilates The fascial compartment (Bonica et al, The Management of Pain, first roll (second edition), Philadelphia; Lea & Feboger, 1990). Examples include, but are not limited to, arteriosclerosis obliterans, thromboangiitis obliterans, acute arterial closure, embolism, congenital arteriovenous tumors, vasospastic diseases, Rayaud's disease, cyanosis of hands and feet, acute venous closure, thrombophlebitis, varicose veins and lymphedema.

As used herein, "autonomic reflex pain" refers to pain caused by the "reflex sympathetic atrophy signature". Reflex sympathetic atrophy is characterized by severe spontaneous pain after acute and chronic injury, and can be accompanied by edema and blood circulation disorder, and symptoms such as skin and musculoskeletal dystrophy and atrophy.

As used herein, "post-operative pain" refers to a complex physiological response of the body to the disease itself and to the tissue damage resulting from surgery, which is manifested as an unpleasant experience in mind and behavior.

As used herein, "arthritic pain" includes, but is not limited to, pain resulting from diseases such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthropathy, gout, pseudogout, infectious arthritis, tendonitis, bursitis, bone damage, and joint soft tissue inflammation.

As used herein, "postherpetic neuralgia" refers to the intense pain that persists long beneath the skin in the original rash area after the healing of the rash of herpes zoster.

As used herein, "nociceptive pain" is pain caused by a process of tissue damage that stimulates the afferent passage of nociceptors, or pain caused by prolonged excitation of nociceptors. Pain caused by prolonged excitation of nociceptors may be due to persistent noxious stimulation of nociceptors or their sensitization or both, or they may be caused by these factors and prolonged by their persistence, various reflex mechanisms and other factors.

Pharmaceutical composition

The present invention provides compositions comprising a therapeutically effective amount of alpha 5-GABA_AUse of a pharmaceutical compound of an inverse agonist. Alpha 5-GABA despite use in the treatment of the present invention_AThe inverse agonist may be administered as the starting compound, but preferably the active ingredient, optionally in the form of a physiologically acceptable salt, is mixed with one or more additives, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical excipients to form a pharmaceutical composition.

In a preferred embodiment, the present invention provides compositions comprising α 5-GABA_APharmaceutical compositions of inverse agonists, wherein alpha 5-GABA_AThe inverse agonist is mixed with one or more pharmaceutically acceptable carriers, and optionally with other therapeutic and/or prophylactic components known or used in the art. The carrier must be "acceptable" in the sense of being 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 dermal, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or spray, including powder and liquid aerosol administration, or sustained release systems. Examples of suitable sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in the form of shaped articles, e.g., films, or microcapsules.

The compounds for use in the present invention may thus be formulated together with conventional additives, or diluents, into pharmaceutical compositions and unit dosage forms thereof. 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 forms for oral administration, suppositories for rectal administration, and sterile injectable solutions for parenteral administration. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the desired daily dosage range to be employed.

The compounds for use in the present invention may be administered in a variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain, as the active ingredient, a compound of the present invention or a pharmaceutically acceptable salt thereof.

For formulating the compounds for use in the present invention into pharmaceutical compositions, the pharmaceutically acceptable carrier may be either solid or liquid. Solid form preparations include powders, tablets, nine doses, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that also function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

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

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

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, a low melting wax, cocoa butter, and the like. The term "formulation" includes a composition comprising an active compound formulated with an encapsulating material as a carrier, the encapsulating material providing a capsule in which the active ingredient, with or without a carrier, is surrounded by a carrier and thus held together. Similarly, formulations include cachets and lozenges (lozenes). Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a puree of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is then dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, allowed to cool and thereby solidify.

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

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

The compounds for use in the present invention may thus be formulated for parenteral administration (e.g. by injection, such as bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion bags or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use, by sterile isolation from a sterile solid or by lyophilization from solution.

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 water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

Also included are solid formulations designed to be converted, shortly before use, to liquid formulations for oral administration. Such liquid formulations include solutions, suspensions and emulsions. Such formulations may contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickening agents, 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 an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

Compositions suitable for topical administration in the oral cavity include lozenges (lozenes) containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; lozenges (pastilles) containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The solution or suspension can be applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or nebulizer. The composition may be in single or multiple dose form.

Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is packaged in a pressurised pack together with a suitable propellant, including a chlorofluorocarbon (CFC) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may also suitably contain a surfactant, such as lecithin. The dosage of the drug can be controlled by a metering valve.

Alternatively 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 derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). The powder carrier can conveniently form a gel in the nasal cavity. The powder compositions may be presented in unit dose form, for example in capsules or cartridges (e.g. of gelatine, e.g. cuffed or cartridges), or in blister packs in which the powder may be administered by means of an inhaler.

In compositions for administration to the respiratory tract, including intranasal compositions, it is common for the compound to have a small particle size, for example on the order of 5 microns or less. Such particle sizes may be obtained by methods known in the art, for example by micronization.

If desired, compositions suitable for sustained release of the active ingredient may be employed.

The pharmaceutical preparation is preferably in unit dosage form. In such forms, the formulations are subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, wherein the sealed package contains discrete quantities of the preparation, e.g., packaged tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, troche or lozenge (lozenge) per se, or may be any suitable number of such capsules, tablets and the like in any packaged form.

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 on the latest version of Remington's Pharmaceutical Sciences (Maack Publishing co., Easton, PA).

The amount of active ingredient in a unit dose formulation can vary depending on the particular application and the potency of the active ingredient, and can be adjusted from 0.01mg to about 0.1 g. For example, in pharmaceutical applications, the drug may be administered three times daily in a capsule of 0.01 to about 100mg, and the composition may also contain other compatible therapeutic agents as necessary.

Method of treatment

In therapeutic use, the compounds for use in the present invention are administered in an initial dose of 0.001mg/kg to 10mg/kg body weight per day. However, these dosages may vary depending on the patient's needs, the severity of the condition being treated and the compound being used, and generally, treatment will be initiated with smaller dosages less than the optimum dose of the compound, after which the dose is increased by small amounts to achieve optimum results, conveniently the total daily dosage may be subdivided into daily divided administrations if desired.

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 drug for treating pain, alzheimer's disease, multi-infarct dementia and stroke, which is not only effective but also has no significant side effects, and another object of the present invention is to provide a drug having high safety for a special patient group such as the elderly, patients suffering from liver or renal function deterioration, or cardiovascular diseases.

Examples

Scheme 1:

adding NaOH aqueous solvent into a tetrahydrofuran solution of A-1 (CAS: 90607-22-0) (3.0g,17.5mmol), stirring at normal temperature for 1 hour, TLC analysis is performed to complete the reaction, the reaction mixture is concentrated under reduced pressure, water is added for dilution, hydrochloric acid is used for adjusting the pH value to 2-3, ethyl acetate is used for extraction (25mLX6), organic layers are combined, anhydrous sodium sulfate is dried, reduced pressure evaporation is performed to obtain 2.1 g of yellow solid crude product, and the crude product directly enters the next reaction without purification. TBSCl (2.25g,120mmol) was added to a solution of the carboxylic acid compound (1.43g,10mmol) and imidazole (3.4g,50mmol) in the previous step in DCM (50mL) at 0 deg.C, and the reaction was allowed to warm up naturally overnight. TLC showed disappearance of the starting material, the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to give 2.2 g of a yellow solid A-2.

After cooling to zero degree in an ice bath, BOP-Cl (2.79g,11mmol) was added under an argon atmosphere, and after stirring for 20 minutes, A-2(1.8g,9mmol) was added, followed by A-3 (reference: US6630471) and allowed to react overnight at a natural temperature. TLC showed the reaction was complete, the reaction was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 3.56 g of yellow solid A-4 in 90% yield.

A mixture of a-4(10.5g,23.8mmol) and diphenyl ether was heated to 150 ℃ for 1 hour, TLC (PE: EA ═ 2:1) showed complete reaction, and purified on silica gel column to give a yellow solid, 0.95 g, a-5, in 10% yield.

To a solution of A-5(700mg,4.2mmol) in THF (50mL) at zero degrees was added NaH (252mg,6.3 mmol). After stirring under argon for 15min, a-6(CAS:56026-36-9) (900mg,2.1mmol) was added to the previous reaction mixture, stirred at room temperature for 1.5h, TLC (PE: EA ═ 2:1) monitored the disappearance of the starting material and the crude product was directly subjected to the next reaction without purification. To the previous reaction was added aq. naoh (0.84g in 10mL water) and after 4h of reaction, TLC (PE: EtOAc ═ 5:1, Rf ═ 0.01) monitored the disappearance of starting material. After the reaction mixture was concentrated under reduced pressure, the residue was adjusted to pH 2 to 3 with dilute hydrochloric acid, and the precipitated solid was filtered and dried to obtain 0.6g of a yellow solid A-7.

Example 1

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

HOBt (32mg,0.24mmol), EDCI (46mg,0.24mmol), A-7(50mg,0.12mmol) and DMF (2mL) are added into a 25mL single-mouth bottle, stirred for dissolution, N-aminomorpholine (CAS:4319-49-7) and DIPEA are added under the protection of argon, stirred at normal temperature overnight, TLC shows that the reaction is finished, 25mL of dichloromethane is added for dilution, washed for three times with water, dried by anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and a silica gel plate is prepared and purified to obtain 16 mg of yellow solid with the yield of 29%.

¹H NMR(DMSO,400MHz,ppm):δ9.71(s,1H),8.96(d,J＝2.0Hz,1H),8.20-8.18(m,2H),7.74(d,J＝8.0Hz,1H),7.11(s,1H),5.85(t,J＝6.4Hz,1H),5.67(s,2H),4.72(d,J＝6.4Hz,2H),3.66(t,J＝4.4Hz,4H),2.88(t,J＝4.6Hz,4H),1.43(s,9H)；LC-MS:m/z(ESI+)for C₂₄H₂₈N₈O₅ 509[M+1]⁺。

Example 2

(R) -N- (1-hydroxy-N-propanol-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: the intermediate A-7 and (R) -2-amino-n-propanol (CAS: 2799-16-8) were condensed to give the title compound in 68mg, 40% yield, as a pale yellow solid.

¹H NMR(DMSO,400MHz,ppm):δ9.04(d,1H,J＝2.0),8.40(d,J＝8.0Hz,1H),8.31-8.28(m,1H),8.16(s,1H),7.72(d,J＝8.4Hz,1H),7.12(s,1H),5.91(t,J＝6.0Hz,1H),5.66(s,2H),4.80(d,J＝6.4Hz,2H),4.70(d,J＝6.0Hz,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 C₂₃H₂₇N₇O₅482[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: condensation of intermediate A-7 with trans- (1S,2S) -2-amino-cyclopentanol hydrochloride (CAS: 68327-04-8) gave 68mg of compound in 40% yield as a white solid.

¹H NMR(DMSO,400MHz,ppm):δ9.02(d,1H,J＝2.0),8.40(d,J＝8.0Hz,1H),8.28-8.258(m,1H),8.16(s,1H),7.72(d,J＝8.4Hz,1H),7.12(s,1H),5.91(t,J＝6.0Hz,1H),5.67(s,2H),4.81(d,J＝6.4Hz,2H),4.71(d,J＝6.0Hz,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 C₂₅H₂₉N₇O₅ 508[M+1]⁺。

Example 4

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

The experimental procedure was as described in example 1: condensation reaction of intermediate A-7 with cyclopropylamine (CAS: 765-30-0) gave 16 mg of yellow solid in 29% yield.

¹H NMR(DMSO,400MHz,ppm):δ8.98(d,J＝1.6Hz,1H),8.64(d,J＝4.0Hz,1H),8.23-8.17(m,2H),7.72(d,J＝8.4Hz,1H),7.10(s,1H),5.84(t,J＝6.4Hz,1H),5.67(s,2H),4.72(d,J＝6.0Hz,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 C₂₃H₂₅N₇O₄ 464[M+1]⁺。

Example 5

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

The experimental procedure was as described in example 1: condensation of intermediate A-7 with 1-methyl-1H-pyrazol-4-amine (CAS: 69843-13-6) gave 12 mg of a yellow solid in 22% yield.

¹H NMR(DMSO,400MHz,ppm):δ10.63(s,1H),9.11(d,J＝1.6Hz,1H),8.35-8.3(dd,J＝2.4Hz,J＝8.0Hz,1H),8.18(s,1H),8.03(s,1H),7.79(d,J＝8.4Hz,1H),7.56(s,1H),7.11(s,1H),5.85(t,J＝6.2Hz,1H),5.70(s,2H),4.72(d,J＝6.0Hz,2H),3.83(s,3H),1.45(s,9H)；LC-MS:m/z(ESI+)for C₂₄H₂₅N₉O₄ 504[M+1]⁺。

Example 6

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

The experimental procedure was as described in example 1: condensation of intermediate A-7 with isopropylamine (CAS: 75-31-0) gave 10mg of a yellow solid in 18% yield.

¹H NMR(DMSO,400MHz,ppm):δ9.01(d,J＝1.6Hz,1H),8.44(d,J＝7.6Hz,1H),8.25-8.18(m,2H),7.73(d,J＝8.0Hz,1H),7.12(s,1H),5.85(t,J＝6.2Hz,1H),5.67(s,2H),4.72(d,J＝6.0Hz,2H),4.12-4.07(m,1H),1.43(s,9H),1.16(d,J＝6.8Hz,6H)；LC-MS:m/z(ESI+)for C₂₃H₂₇N₇O₄ 466[M+1]⁺。

Example 7

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

The experimental procedure was as described in example 1: condensation of intermediate A-7 with ethanolamine (CAS: 141-43-5) gave 10mg of a yellow solid in 18% yield.

¹H NMR(DMSO,400MHz,ppm):δ9.04(d,J＝2.0Hz,1H),8.68(s,1H),8.28-8.25(m,2H),7.74(d,J＝8.0Hz,1H),7.12(s,1H),5.85(t,J＝6.0Hz,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 C₂₂H₂₅N₇O₅ 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-dioxide thiomorpholino) methanone (08)

The experimental procedure was as described in example 1: condensation of intermediate A-7 with thiomorpholine 1, 1-dioxide hydrochloride (CAS:59801-62-6) gave 12 mg of a yellow solid in 22% yield.

¹H NMR(DMSO,400MHz,ppm):δ8.76(d,J＝1.6Hz,1H),8.20(s,1H),8.01(m,1H),7.72(d,J＝8.0Hz,1H),7.08(s,1H),5.84(t,J＝6.0Hz,1H),5.68(s,2H),4.73(d,J＝6.0Hz,2H),4.03(s,2H),3.70(s,2H),3.28(s,4H),1.45(s,9H)；LC-MS:m/z(ESI+)for C₂₄H₂₇N₇O₆S 542[M+1]⁺。

Example 9

(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) (morpholino) methanone (09)

The experimental procedure was as described in example 1: condensation of intermediate A-7 with morpholine (CAS:110-91-8) gave 14 mg of a yellow solid in 25% yield.

¹H 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＝7.6Hz,1H),7.07(s,1H),5.84(t,J＝6.0Hz,1H),5.67(s,2H),4.72(d,J＝6.0Hz,2H),3.63-3.55(m,6H),3.40(s,2H),1.45(s,9H)；LC-MS:m/z(ESI+)for C₂₄H₂₇N₇O₅ 494[M+1]⁺。

Example 10

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

The experimental procedure was as described in example 1: condensation of intermediate A-7 with 2,2, 2-trifluoroethylamine hydrochloride (CAS:373-88-6) gave 11 mg of a yellow solid in 20% yield.

¹H 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＝6.2Hz,1H),7.61(d,J＝8.0Hz,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 C₂₂H₂₂F₃N₇O₄ 506[M+1]⁺。

Example 11

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

The experimental procedure was as described in example 1: condensation of intermediate A-7 with 2-methoxyethylamine (CAS:109-85-3) gave 11 mg of a yellow solid in 20% yield.

¹H 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＝6.0Hz,1H),5.68(s,2H),4.73(d,J＝6.0Hz,2H),3.47-3.44(m,4H),3.27(s,3H),1.44(s,9H)；LC-MS:m/z(ESI+)for C₂₃H₂₇N₇O₅482[M+1]⁺。

Example 12

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

The experimental procedure was as described in example 1: condensation of intermediate A-7 with 4-aminotetrahydropyran hydrochloride (CAS:33024-60-1) gave 21 mg of a yellow solid in 38% yield.

¹H NMR(DMSO,400MHz,ppm):δ9.02(d,J＝1.6Hz,1H),8.53(d,J＝7.6Hz,1H),8.26-8.18(m,2H),7.74(d,J＝8.4Hz,1H),7.11(s,1H),5.85(t,J＝6.0Hz,1H),5.68(s,2H),4.72(d,J＝5.6Hz,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＝2.4Hz,J＝12.4Hz,2H),1.61-1.51(m,2H),1.43(s,9H)；LC-MS:m/z(ESI+)for C₂₅H₂₉N₇O₅ 508[M+1]⁺。

Example 13

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

The experimental procedure was as described in example 1: condensation of intermediate A-7 with dimethylamine hydrochloride (CAS:506-59-2) gave 15 mg of a yellow solid in 27% yield.

¹H NMR(DMSO,400MHz,ppm):δ8.66(d,J＝1.2Hz,1H),8.18(s,1H),7.94-7.92(dd,J＝3.2Hz,J＝8.0Hz,1H),7.67(d,J＝8.0Hz,1H),7.08(s,1H),5.84(t,J＝6.2Hz,1H),5.67(s,2H),4.72(d,J＝6.0Hz,2H),3.00(s,3H),2.90(s,3H),1.44(s,9H)；LC-MS:m/z(ESI+)for C₂₂H₂₅N₇O₄ 452[M+1]⁺。

Example 14

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

Condensation of intermediate A-7 with 3-aminotetrahydrofuran hydrochloride (CAS:204512-94-7) gave 14 mg of a yellow solid in 25% yield.

¹H NMR(DMSO,400MHz,ppm):δ9.03(d,J＝1.6Hz,1H),8.75(d,J＝6.4Hz,1H),8.27-8.18(m,2H),7.74(d,J＝8.0Hz,1H),7.11(s,1H),5.84(t,J＝6.0Hz,1H),5.68(s,2H),4.72(d,J＝6.0Hz,2H),4.46(m,1H),3.87-3.82(m,2H),3.74-3.70(m,1H),3.61-3.58(dd,J＝4Hz,J＝9.2Hz,1H),2.18-2.13(m,1H),1.95-1.87(m,1H),1.43(s,9H)；LC-MS:m/z(ESI+)for C₂₄H₂₇N₇O₅ 494[M+1]⁺。

Example 15

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

The experimental procedure was as described in example 1: condensation of intermediate A-7 with cyclobutyl amine (CAS:2516-34-9) gave 13mg of yellow solid in 24% yield.

¹H NMR(DMSO,400MHz,ppm):δ9.01(d,J＝1.6Hz,1H),8.81(d,J＝7.6Hz,1H),8.25-8.18(m,2H),7.73(d,J＝8.4Hz,1H),7.11(s,1H),5.85(t,J＝6.0Hz,1H),5.67(s,2H),4.72(d,J＝6.0Hz,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 C₂₄H₂₇N₇O₄ 478[M+1]⁺。

Example 16

Azetidin-1-yl (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) methanone (16)

The experimental procedure was as described in example 1: condensation of intermediate A-7 with azetidine (CAS:503-29-7) gave 14 mg of a yellow solid in 25% yield.

¹H NMR(DMSO,400MHz,ppm):δ8.83(d,J＝1.2Hz,1H),8.18(s,1H),8.08(dd,J＝2.0Hz,J＝8.2Hz,1H),7.69(d,J＝8.4Hz,1H),7.07(s,1H),5.85(t,J＝6.0Hz,1H),5.68(s,2H),4.71(d,J＝6.0Hz,2H),4.32(t,J＝7.8Hz,2H),4.06(t,J＝7.8Hz,2H),2.26(m,2H),1.44(s,9H)；LC-MS:m/z(ESI+)for C₂₃H₂₅N₇O₄ 464[M+1]⁺。

Example 17

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

The experimental procedure was as described in example 1: condensation of intermediate A-7 with tert-butyl carbazate (CAS:870-46-2) followed by removal of Boc gave 10mg of a yellow solid in 18% yield.

¹H NMR(DMSO,400MHz,ppm):δ9.97(s,1H),9.00(d,J＝2.0Hz,1H),8.24-8.18(m,2H),7.72(d,J＝8.4Hz,1H),7.10(s,1H),5.85(t,J＝6.0Hz,1H),5.68(s,2H),4.72(d,J＝6.0Hz,2H),4.57(s,2H),1.44(s,9H)；LC-MS:m/z(ESI+)for C₂₀H₂₂N₈O₄ 439[M+1]⁺。

Example 18

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

The experimental procedure was as described in example 1: condensation of intermediate A-7 with N-aminopyrrolidine (CAS:16596-41-1) gave 2mg of a yellow solid in 4% yield.

¹H NMR(DMSO,400MHz,ppm):δ8.76(d,J＝2.0Hz,1H),8.19(s,1H),8.02(dd,J＝2.0Hz,J＝8.0Hz,1H)7.68(d,J＝8.0Hz,1H),7.10(s,1H),5.85(t,J＝6.2Hz,1H),5.68(s,2H),4.72(d,J＝6.0Hz,2H),2.90-2.94(m,4H),1.88-1.82(m,4H),1.45(s,9H)；LC-MS:m/z(ESI+)for C₂₄H₂₈N₈O₄ 493[M+1]⁺。

Example 19

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

The experimental procedure was as described in example 1: condensation of intermediate A-7 with N-aminopiperidine hydrochloride (CAS:63234-70-8) gave 10mg of a yellow solid in 18% yield.

¹H NMR(DMSO,400MHz,ppm):δ9.59(s,1H),8.95(d,J＝2.0Hz,1H),8.20-8.18(m,2H),7.73(d,J＝8.0Hz,1H),7.12(s,1H),5.86(t,J＝6.0Hz,1H),5.67(s,2H),4.73(d,J＝6.0Hz,2H),2.82(t,J＝5.2Hz,4H),1.60(s,4H),1.44-1.24(m,11H)；LC-MS:m/z(ESI+)for C₂₅H₃₀N₈O₄ 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: condensation of intermediate A-7 with tetrahydropyrrole (CAS:123-75-1) gave 14 mg of a yellow solid in 25% yield.

¹H NMR(DMSO,400MHz,ppm):δ8.76(d,J＝2.0Hz,1H),8.19(s,1H),8.02(dd,J＝2.0Hz,J＝8.0Hz,1H)7.68(d,J＝8.0Hz,1H),7.10(s,1H),5.85(t,J＝6.2Hz,1H),5.68(s,2H),4.72(d,J＝6.0Hz,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 C₂₄H₂₇N₇O₄ 478[M+1]⁺。

Example 22

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

The experimental procedure was as described in example 1: condensation of intermediate A-7 with ethylamine hydrochloride (CAS:557-66-4) gave 20mg of a yellow solid in 35% yield.

¹H NMR(DMSO,400MHz,ppm):δ9.02(d,J＝2.0Hz,1H),8.69(d,J＝6.4Hz,1H),8.25(m,1H),8.17(s,1H),7.74(d,J＝2.4Hz,1H),7.12(s,1H),5.85(t,J＝6.2Hz,1H),5.68(s,2H),4.72(d,J＝6.0Hz,2H),3.31(t,2H),1.45(s,9H),1.13(t,J＝2.8Hz,3H)；LC-MS:m/z(ESI+)for C₂₂H₂₅N₇O₄ 452[M+1]⁺。

Synthesis scheme 2

The experimental process comprises the following steps:

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

B26-hydroxymethyl methyl nicotinate (CAS:56026-36-9) (2.35g,14.1mmol) is dissolved in 280 ml of anhydrous THF, argon is used for protection, the temperature of an ice bath is reduced to 0 ℃, sodium tert-butoxide (1.81g,18.8mmol) is added for stirring for 15 minutes, B1(2.74g,9.4mmol) is added (preparation synthesis patent US6297235B1), the ice bath is continued for one half hour after the addition is finished, TLC (PE: EA is 1:1) is completely reacted without treatment, and the next reaction is directly carried out. The reaction mixture was stirred at room temperature for 16 hours with NaOH solution (1.13g in 10mL water) added, TLC (DCM: MeOH: 20:1, Rf: 0.2) showed complete reaction of the starting material, the reaction mixture was evaporated to dryness under reduced pressure, the residue was dissolved in water, the pH was adjusted to 2-3 with concentrated hydrochloric acid, a solid precipitated, filtered, washed with water and dried to give 1.6g yellow solid with 41.7% yield.

Example 23

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

The experimental procedure was as described in example 1: condensation of intermediate B3 with N-aminomorpholine (CAS:4319-49-7) followed by purification on preparative silica gel plates afforded 16.8 mg of an off-white solid in 7% yield.¹H NMR(DMSO,400MHz,ppm):δ9.72(s,1H),8.96(d,J＝0.8Hz,1H),8.20-8.16(m,2H),7.74(d,J＝8.0Hz,1H),6.93(s,1H),5.67(s,2H),3.66(t,J＝4.4Hz,4H),2.88(t,J＝4.4Hz,4H),2.56(s,3H),1.43(s,9H)；LC-MS:m/z(ESI+)for C₂₄H₂₈N₈O₄ 493[M+1]⁺。

Example 24

(R) -N- (1-hydroxy-N-propanol-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: condensation of intermediate B3 with (R) -2-amino-n-propanol (CAS: 2799-16-8) gave 15.4 mg of an off-white solid in 13.5% yield.

¹H NMR(DMSO,400MHz,ppm):δ9.03(s,1H),8.36(d,J＝8.0Hz,1H),8.27～8.24(m,1H),8.16(s,1H),7.73(d,J＝8.0Hz,1H),6.94(s,1H),5.67(s,2H),4.74(t,J＝6.0Hz,1H),4.05～3.98(m,1H),3.47～3.42(m,2H),2.56(s,3H),1.43(s,9H),1.13(d,J＝6.8Hz,3H)；LC-MS:m/z(ESI+)for C₂₃H₂₇N₇O₄ 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: condensation of intermediate B3 with trans- (1S,2S) -2-amino-cyclopentanol hydrochloride (CAS: 68327-04-8) gave 52mg of a white solid in 43.3% yield.

¹H NMR(DMSO,400MHz,ppm):δ9.02(s,1H),8.45(d,J＝7.2Hz,1H),8.26～8.16(m,2H),7.73(d,J＝8.0Hz,1H),6.94(s,1H),5.67(s,2H),4.80(d,J＝4.0Hz,1H),4.04～3.94(m,2H),2.56(s,3H),2.03～1.95(m,1H),2.03～1.95(m,1H),1.89～1.80(m,1H),1.69～1.61(m,1H),1.51～1.43(m,2H),1.43(s,9H)；LC-MS:m/z(ESI+)for C₂₅H₂₉N₇O₄ 492[M+1]⁺。

Example 26

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

The experimental procedure was as described in example 1: condensation of intermediate B3 with cyclopropylamine (CAS: 765-30-0) gave 26mg (23.8%).

¹H NMR(DMSO,400MHz,ppm):δ8.99(d,J＝1.6Hz,1H),8.66(d,J＝4.0Hz,1H),8.28～8.16(m,2H),7.72(d,J＝8.0Hz,1H),6.92(s,1H),5.67(s,2H),2.88～2.81(m,1H),2.56(s,3H),1.43(s,9H),0.73～0.68(m,2H),0.59～0.54(m,2H)；LC-MS:m/z(ESI+)for C₂₃H₂₅N₇O₃ 448[M+1]⁺。

Example 27

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

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

¹H NMR(DMSO,400MHz,ppm):δ9.02(s,1H),8.46(d,J＝8.0Hz,1H),8.26～8.23(m,1H),8.16(s,1H),7.73(d,J＝8.0Hz,1H),6.93(s,1H),5.67(s,2H),4.14～4.05(m,1H),2.56(s,3H),1.43(s,9H),1.17(d,J＝6.8Hz,6H)；LC-MS:m/z(ESI+)for C₂₃H₂₇N₇O₃ 450[M+1]⁺。

Example 29

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

The experimental procedure was as described in example 1: condensation of intermediate B3 with thiomorpholine 1, 1-dioxide hydrochloride (CAS:59801-62-6) gave 20mg of a solid (15.6%).

¹H NMR(DMSO,400MHz,ppm):δ8.76(s,1H),8.18(s,1H),8.03-8.00(m,1H),7.72(d,J＝8.4Hz,1H),6.91(s,1H),5.66(s,2H),4.16～3.92(m,2H),3.79～3.59(m,2H),3.32～3.22(m,4H),2.56(s,3H),1.44(s,9H).LC-MS:m/z(ESI+)for C₂₄H₂₇N₇O₅S 526[M+1]⁺。

Example 30

{6- [ 7-tert-butyl-3- (5-methylisoxazol-3-yl) - [1,2,4] triazolo [4,3-b ] pyridazin-6-yloxymethyl ] -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) gave 66mg (56.6%) of a white solid.

¹H NMR(DMSO,400MHz,ppm):δ8.68(d,J＝2.0Hz,1H),8.16(s,1H),7.94-7.92(m,1H),7.68(d,J＝8.0Hz,1H),6.88(s,1H),5.67(s,2H),3.71～3.47(m,6H),3.33～3.27(m,2H),.56(s,3H),1.44(s,9H)；LC-MS:m/z(ESI+)for C₂₄H₂₇N₇O₄ 478[M+1]⁺。

Example 31

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

The experimental procedure was as described in example 1: condensation reaction of intermediate B3 with cyclopropylmethylamine (CAS:2516-47-4) gave 51mg (45.2%) of a white solid.

¹H NMR(DMSO,400MHz,ppm):δ9.04(d,J＝2.0Hz,1H),8.80(t,J＝5.6Hz,1H),8.28～8.16(m,2H),7.73(d,J＝8.0Hz,1H),6.92(s,1H),5.68(s,2H),3.15(t,J＝6.4Hz,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 C₂₄H₂₇N₇O₃ 462[M+1]⁺。

Example 32

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

The experimental procedure was as described in example 1: condensation of intermediate B3 with 2,2, 2-trifluoroethylamine hydrochloride (CAS:373-88-6) gave 48mg (40.1%) of a white solid.

¹H NMR(DMSO,400MHz,ppm):δ9.34(t,J＝6.0Hz,1H),9.08(d,J＝2.0Hz,1H),8.32～8.16(m,2H),7.76(d,J＝8.0Hz,1H),6.89(s,1H),5.69(s,2H),4.18～4.08(m,2H),2.55(s,3H),1.43(s,9H).

LC-MS:m/z(ESI+)for C₂₂H₂₂F₃N₇O₃ 490[M+1]⁺。

Example 33

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

The experimental procedure was as described in example 1: condensation of intermediate B3 with 2-methoxyethylamine (CAS:109-85-3) gave 13mg (11.4%) of an off-white solid.

¹H NMR(DMSO,400MHz,ppm):δ9.04(d,J＝1.6Hz,1H),8.77(t,J＝4.8Hz,1H),8.27～8.24(m,1H),8.16(s,1H),7.72(d,J＝8.0Hz,1H),6.90(s,1H),5.67(s,2H),3.50～3.40(m,4H),3.26(s,3H),2.56(s,3H),1.43(s,9H)；LC-MS:m/z(ESI+)for C₂₃H₂₇N₇O₄ 466[M+1]⁺。

Example 35

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

The experimental procedure was as described in example 1: condensation of intermediate B3 with 2-amino-2-methyl-1-propanol (CAS:124-68-5) gave 48mg (41%) of a white solid.

¹H NMR(DMSO,400MHz,ppm):δ9.05(d,J＝2.0Hz,1H),8.52(t,J＝6.0Hz,1H),8.29～8.26(m,1H),8.16(s,1H),7.73(d,J＝8.0Hz,1H),6.92(s,1H),5.68(s,2H),4.54(s,1H),3.26(d,J＝5.6Hz,2H),2.56(s,3H),1.43(s,9H),1.10(s,6H)；LC-MS:m/z(ESI+)for C₂₄H₂₉N₇O₄ 480[M+1]⁺。

Example 36

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

The experimental procedure was as described in example 1: condensation of intermediate B3 with 2-aminobutapropanol (CAS:96-20-8) gave 48.8mg (41.7%) of an off-white solid.

¹H NMR(DMSO,400MHz,ppm):δ9.04(d,J＝1.2Hz,1H),8.27(d,J＝8.4Hz,2H),8.16(s,1H),7.74(d,J＝8.0Hz,1H),6.93(s,1H),5.67(s,2H),4.70(t,J＝6.0Hz,1H),3.90～3.80(m,1H),3.49～3.35(m,2H),2.56(s,3H),2.04～1.92(m,1H),1.70～1.60(m,1H),1.42(s,9H),0.86(t,J＝7.2Hz,3H)；LC-MS:m/z(ESI+)for C₂₄H₂₉N₇O₄ 480[M+1]⁺。

Example 37

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

The experimental procedure was as described in example 1: condensation of intermediate B3 with 4-aminotetrahydropyranyl hydrochloride (CAS:33024-60-1) gave 56mg (46.7%) of an off-white solid.

¹H NMR(DMSO,400MHz,ppm):δ9.03(d,J＝1.2Hz,1H),8.55(d,J＝7.6Hz,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 C₂₅H₂₉N₇O₄ 492[M+1]⁺。

Example 38

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

The experimental procedure was as described in example 1: condensation of intermediate B3 with dimethylamine hydrochloride (CAS:506-59-2) gave 18mg (16.9%) of an off-white solid.

¹H NMR(DMSO,400MHz,ppm):δ8.67(d,J＝1.2Hz,1H),8.17(s,1H),7.96-7.90(m,1H),7.67(d,J＝8.0Hz,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 C₂₂H₂₅N₇O₃ 436[M+1]⁺。

Example 39

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

The experimental procedure was as described in example 1: condensation of intermediate B3 with 3-aminotetrahydrofuran hydrochloride (CAS:204512-94-7) gave 61mg (52.3%) of a white solid.

¹H NMR(DMSO,400MHz,ppm):δ9.03(d,J＝1.2Hz,1H),8.77(d,J＝6.8Hz,1H),8.28-8.24(m,1H),8.16(s,1H),7.74(d,J＝8.4Hz,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 C₂₄H₂₇N₇O₄ 478[M+1]⁺。

Example 40

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

The experimental procedure was as described in example 1: condensation of intermediate B3 with cyclobutyl amine (CAS:2516-34-9) gave 33.8mg (30%) of an off-white solid.

¹H NMR(DMSO,400MHz,ppm):δ9.02(d,J＝1.2Hz,1H),8.84(d,J＝8.0Hz,1H),8.27-8.22(m,1H),8.16(s,1H),7.73(d,J＝8.4Hz,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 C₂₄H₂₇N₇O₃ 462[M+1]⁺。

EXAMPLE 41

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

The experimental procedure was as described in example 1: condensation of intermediate B3 with azetidine (CAS:503-29-7) gave 27mg (24.7%) of a white solid.

¹H NMR(DMSO,400MHz,ppm):δ8.84(d,J＝2.0Hz,1H),8.16(s,1H),8.10-8.06(m,1H),7.68(d,J＝8.0Hz,1H),6.88(s,1H),5.67(s,2H),4.32(t,J＝7.6Hz,2H),4.06(t,J＝7.6Hz,2H),2.56(s,3H),2.31-2.20(m,2H),1.42(s,9H)；LC-MS:m/z(ESI+)for C₂₃H₂₅N₇O₃448[M+1]⁺。

Example 42

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

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

¹H NMR(DMSO,400MHz,ppm):δ9.02(d,J＝1.2Hz,1H),8.68(t,J＝5.6Hz,1H),8.26～8.22(m,1H),8.16(s,1H),7.72(d,J＝8.0Hz,1H),6.91(s,1H),5.67(s,2H),3.35～3.25(m,2H),2.56(s,3H),1.43(s,9H),1.12(t,J＝7.2Hz,3H)；LC-MS:m/z(ESI+)for C₂₂H₂₅N₇O₃436[M+1]⁺。

Example 43

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

The experimental procedure was as described in example 1: condensation of intermediate B3 with N-aminopiperidine hydrochloride (CAS:63234-70-8) gave 37mg (15.4%) of a white solid.

¹H NMR(DMSO,400MHz,ppm):δ9.59(s,1H),8.95(d,J＝1.6Hz,1H),8.20-8.15(m,2H),7.72(d,J＝8.0Hz,1H),6.92(s,1H),5.66(s,2H),2.81(t,J＝5.2Hz,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 C₂₅H₃₀N₈O₃ 491[M+1]⁺。

The biological experimental method comprises the following steps:

recent research results show that GABA_AThe receptor mediates at least 2 modes of inhibition, tonic inhibition (tonic inhibition) and phasic inhibition (phasic inhibition). GABA as it increases in millimolar concentrations_AThe receptor is rapidly desensitized to form a phase-type inhibition. GABA is activated when GABA is in a concentration of several hundred nanomoles to several tens of micromoles_AHigh affinity extrasynaptic GABA at receptor_AReceptors mediate tonic-type inhibition, modulation of neuronal excitability and signaling. (Farrant M et al (2005) Variations on an inhibition of the phase and sonic activation of GABA (A) receptors. Nat Rev Neurosci 6: 215. 229Y). Yeung JY et al discloses that low concentrations of GABA more readily activate alpha 5-GABA_AReceptor (Yeung JY et al (2003) Tonically activated GABA_Areceptors in hippoparam neurones are high-affinity, low-conductivity sensors for extracellular GABA. mol Pharmacol; 63:2-8). Lee et al report that low concentrations of GABA-activated persisting GABA were detected on isolated Dorsal Root Ganglion (DRG) cells cultured for 24 hours_ACurrent, 20 μ M sustained GABA activation_AThe current reached about 100 pA/pF. (Lee KY et al. alignment of high-affinity GABA (A) receptors in culture of multiple roots in growth nerves. neuroscience 208(2012) 133-.

MRK016 is representative of alpha 5-GABA_AFull inverse agonists of the receptor (full inverse agonists). The prior art (CN103239720A) shows that MRK016 has alpha 5-GABA_AThe receptor inverse agonistic efficiency is higher than α 5 IA.

Cell level screening

The inventor detects the inverse excitation efficiency of a substance to be detected by an electrophysiological method. The specific method is as follows:

1) will GABA_ADifferent subunits of the receptor are expressed in cell lines, mainly in the human embryonic kidney cell line (HEK 293). The cells are cultured in a medium, and the cells are used as a cell model for screening a drug for suppressing pain. The alpha subunit, beta subunit and gamma subunit form a complete functional GABA_AReceptors are essential. In this embodiment, the present inventors have establishedThe following cell models: (a) alpha 5subunit (protein sequence shown in GenBank accession number NP-001158509), beta 3 subunit (protein sequence shown in GenBank accession number NP-068712) and gamma 2 subunit (protein sequence shown in GenBank accession number NP-944494) are simultaneously expressed in HEK293 cell line to form the recombinant human immunodeficiency virus (HEK) containing alpha 5-GABA_AHave a fully functional receptor.

2) The cells are marked by Green Fluorescent Protein (GFP) and express alpha5 beta 2 gamma 3-GABA_ARecipient 293 cells were stably transformed. 293 cells were cultured on 10cm dishes and passaged until 80% -90% of the cells grew. At passage, the medium was aspirated, then 3mL of DMEM medium (Gibco)^TM) Add to the dish, shake the dish gently, and aspirate DMEM. 3mL of pancreatin (Trypsin-EDTA 0.05%, Gibco) was added^TM) Digestion was carried out at 37 ℃ for 3 minutes. Then 3mL of complete medium (DMEM + 10% horse serum (Gibco) was added^TM) Blow out the cells from the bottom of the dish and transfer them to a 15mL centrifuge tube

Centrifuge at 200g for 3 minutes. Discard the supernatant, add 4mL complete medium, gently blow and resuspend the cells for use. If cell passage is performed, the cell suspension is diluted at a ratio of 1:5 or 1: 10. For example, in the preparation of cells for electrophysiological use, the cell suspension was diluted at a ratio of 1:12, and then added to a 24-well plate on which a slide glass previously treated with Poly-D-Lysine was placed

In (1), the test is carried out after the cells adhere to the wall. The cell culture time for electrophysiology does not exceed 24 hours.

3) Setting the concentration of the medicine: the final concentration of the drugs used in drug screening is 100nM, and the GABA concentration range is 0.05-0.1 μ M. Dose-inverse agonist efficiency (%) assay uses drugs at final concentrations of 1nM, 10nM, 50nM, 100nM and 1000 nM. Electrophysiological experiments using the whole-cell patch clamp technique can be referred to in the literature (I.Lecker, Y.yin, D.S.Wang and B.A.Orser, (2013) location of GABA_A receptor activity by volatile anaesthetics is reduced byα5-GABA_A receptor-preferring inverse agonists,British Journal of Anaesthesia 110(S1): i 73-i 81). The extracellular fluid for electrophysiology comprises the following components: 150mM NaCl, 5mM KCl, 2.5mM CaCl₂，1mM MgCl₂10mM HEPES and 10mM glucose (pH adjusted to 7.4 with NaOH, osmotic pressure 320-330 mOsm). The formula of the electrophysiological electrode internal liquid is as follows: 140mM CsCl, 10mM HEPES,11mM EGTA, 2mM MgCl₂,1mM CaCl₂4mM MgATP, 2mM TEA, (pH adjusted to 7.4 with CsOH, osmolality 285-295 mOsm). Signal acquisition used EPC 10 amplifier and PatchMaster software (HEKA). The recording electrode is formed by drawing borosilicate glass (borosilicate) and has an electrode resistance of 5-6M omega. The extracellular administration adopts OCTAFLOW II^TMProvided is a system. Upon recording, GFP positive and single independently growing cells were selected. During the recording, the cell membrane potential was clamped at-60 mV. For the test, extracellular fluid was applied extracellularly for about 20 seconds. After the baseline stabilized, the extracellular fluid was switched to GABA. At this time, the current caused by GABA can be detected. And (4) switching the extracellular fluid to a corresponding medicine solution after the current is stabilized for about 20-40 seconds, and detecting the effect of the medicine. Finally, the solution was switched to extracellular fluid and the test was terminated when the baseline returned to the pre-dose level. Only data that the baseline can reply will be subsequently analyzed. GABA was diluted in extracellular fluid at a final concentration of 0.05-0.1. mu.M. The drug is then diluted to the desired concentration in the extracellular fluid containing GABA.

4) The results of the experiment were analyzed using PatchMaster software. During analysis, GABA current before dosing (Ipre) and GABA current after dosing (Ipost) are respectively measured, and the drug effect is calculated by the following formula: inverse agonism efficiency (%) - (Ipost-Ipre) × 100/Ipre. And N is the test times.

5) Screening results for compounds:

MRK016 inverse agonism efficiency is-7.75% (N ═ 6).

From the above results, it was found that the biological effect of the compound of the present invention is significantly superior to that of the conventional α 5-GABA_AReceptor inverse agonists, and since the compounds of the invention do not readily enter the brain, they do not produce the conventional alpha 5-GABA_AFear and anxiety side effects may arise with receptor inverse agonists.

Claims

1. A compound of formula II, an enantiomer or a pharmaceutically acceptable salt thereof:

r4 is C1-C4 alkyl or hydroxy-substituted C1-C4 alkyl;

y is-NY 1Y2 or-NH-NY 3Y 4;

y1 is H or C1-6 alkyl;

y2 is selected from the group consisting of hydroxy n-propyl, hydroxycyclopentyl, cyclopropyl, methyl pyrazolyl, isopropyl, trifluoroethyl, methoxyethyl, tetrahydropyranyl, methyl, tetrahydrofuranyl, cyclobutyl, cyclopropylmethyl, hydroxydimethylethyl, hydroxymethylbutyl and ethyl;

2. The compound of claim 1, wherein R4 is C1-C4 alkyl or hydroxy-substituted C1-C4 alkyl;

y is NY1Y2 or NH-NY3Y 4;

y1 is H or C1-6 alkyl;

y2 is selected from the group consisting of 1-hydroxy-n-prop-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, cyclopropylmethyl, 2-hydroxy-1, 1-dimethyl-ethyl, 1-hydroxymethylbutyl and ethyl;

3. A compound of claim 2, wherein R4 is methyl or hydroxy-substituted methyl.

4. A compound according to any one of claims 1 to 3 wherein Y1 is H or methyl.

5. A compound independently selected from:

6. the compound of any one of claims 1-3, independently selected from:

7. a composition comprising a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof.

8. Use of a compound according to any one of claims 1 to 6 or a composition according to claim 7 for the preparation of a medicament for the treatment or prophylaxis of conditions associated with α 5-GABA_AThe use in the preparation of a medicament for treating a receptor-related disease.

9. Use of a compound according to any one of claims 1 to 6 or a composition according to claim 7 for the manufacture of a medicament for the treatment or prevention of: pain, alzheimer's disease, multi-infarct dementia and stroke.

10. The use according to claim 9, wherein the pain is neuropathic pain, inflammatory pain and cancer pain.

11. The use according to claim 9, wherein the pain is selected from the group consisting of: headache, facial pain, neck pain, shoulder pain, chest pain, abdominal pain, back pain, lower limb pain, muscle pain, skeletal pain, vascular pain, gout, arthritis pain, visceral pain, pain resulting from infectious diseases, sickle cell anemia, pain associated with autoimmune diseases, chronic pain caused by injury or surgery, nociceptive pain, painful diabetes, pain in lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic neuro-reflex pain, reflex sympathetic dystrophy, nerve root avulsion, cancer, chemical injury, toxins or nutritional deficiencies.

12. The use according to claim 9, wherein the pain is selected from the group consisting of: bony pain, pain associated with multiple sclerosis, pain associated with inflammation, trigeminal neuralgia, pain associated with viral or bacterial infections.

13. The use according to claim 9, wherein the pain is selected from the group consisting of: AIDS and postherpetic neuralgia, back pain, lumbago, pain associated with degenerative osteoarthropathy.

14. A process for the preparation of a compound as claimed in any one of claims 1 to 6, selected from any one of the following:

a) reacting a compound of formula (IV)

And

reacting to obtain a compound of formula (1-3) wherein G and W are selected from Cl, Br, I, OH, OTs, OTf and OMs, R5 is alkyl and benzyl, wherein Z, Y, A is as defined in claims 1-6;

then reacting the compound of formula (1-3)

With Y, wherein Z, Y, A is as defined in claims 1-6; or

b) Reacting a compound of formula (1-4):

with Y, wherein Z, Y, A is as defined in claims 1 to 6;

c) saponifying a compound of formula (1-3) to a compound of formula (1-4) and subsequently reacting with Y, wherein Z, Y, A is as defined in claims 1-6; or

d) Formula (II)

Compounds and formulae

Reaction of the compounds.

15. The method of claim 14, wherein R5 is methyl, ethyl, t-butyl.