CN107344936A

CN107344936A - Triazole pyridazine analog derivative, its preparation method, pharmaceutical composition and purposes

Info

Publication number: CN107344936A
Application number: CN201610298009.4A
Authority: CN
Inventors: 李帅; 孙勇; 李扬
Original assignee: Rudong Sai Murrow 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: 2017-11-14
Anticipated expiration: 2036-05-06
Also published as: WO2017190707A1; CN107344936B

Abstract

The present invention is triazole pyridazine analog derivative, its preparation method, pharmaceutical composition and purposes, a kind of compound shown in logical formula (I), its cis-trans-isomer, enantiomter, diastereoisomer, racemic modification, solvate, hydrate or its pharmaceutically acceptable salt and ester are provided, its preparation method, contain the compound pharmaceutical composition and the compound as the GABA of α 5_AThe purposes of receptor modulators, wherein Z, A and Y are defined as in the description.

Description

Triazole pyridazine analog derivative, its preparation method, pharmaceutical composition and purposes

Technical field:

The present invention relates to α 5-GABA_AAcceptor have regulatory function triazole pyridazine analog derivative, they preparation, contain There are their pharmaceutical composition and their applications as medicine.

Background technology:

γ-aminobutyric acid (GABA) is inhibitory neurotransmitter important in mammalian central nervous system, there is two classes GABA acceptors are present in nature, and one kind is GABA_AAcceptor, the receptoroid for ligand-gated ion channel superfamily into Member, another kind of is GABA_BAcceptor, the receptoroid are for the member of g protein coupled receptor superfamily.GABA in mammal_ABy What body subunit was found has the subunits such as α 1-6, β 1-4, γ 1-3, δ, ε, θ and ρ 1-2, and wherein α subunits, β subunits and γ subunits are to shape Into a complete functional form GABA_AAcceptor is essential, and α subunits are to benzene phenodiazine and GABA_AThe combination of acceptor is to pass Important.

GABA containing α 5_AAcceptor (α 5-GABA_AAcceptor) in the GABA of mammalian brain_AShared ratio is less than in acceptor 5%, expression is very low in cerebral cortex, but the GABA in cerebral hippocampus tissue_AProportion is more than in acceptor 20%, other brain regions are hardly expressed.In view of α 5-GABA_AThe distribution of specific in cerebral hippocampus tissue of acceptor and Functional study, many drugmakers including Roche engage in α 5-GABA_AThe research of receptors ligand, have successively substantial amounts of Compound synthesis comes out, especially for the GABA containing Alpha 5 subunit of cerebral hippocampus tissue_AThe inverse agonist of acceptor, wherein α 5IA and MRK-016 shows the effect of good treatment cognition class disease in animal disease model and human trial, particularly Treat Alzheimer's.Generally believe the GABA of Alpha 5 subunit_AThe inverse agonist of acceptor can be used for treating cognition class disease Disease, particularly treat Alzheimer's.The A1 of patent application US 2,011 0224278 disclose the GABA containing Alpha 5 subunit_AAcceptor Inverse agonist can be used for treatment multi-infarct dementia and apoplexy relevant disease.

The research of last decade has shown that (Zlokovic et al.Nat Rev Neurosci.；12(12):723-738) permitted Under more morbid states, especially nerve degenerative diseases, Alzheimer's and apoplexy etc., blood-brain barrier is destroyed, even if Those materials that cannot be introduced into brain originally can also play corresponding pharmacological action, therefore originally can not be across blood-brain barrier The GABA of Alpha 5 subunit_AThe inverse agonist of acceptor can also be used for treating Alzheimer's and apoplexy.

2002 rising sun laboratory report α 5-GABA_AAcceptor is also mainly expressed in small neuron, and in neural cutting mould Expression rise (Xiao HS et al., Identification of gene expression profile of in type dorsal root ganglion in the rat peripheral axotomy model of neuropathic Pain. " Proc Natl Acad Sci U S A.2002 on June 11, in；99 (12), patent application CN103239720A disclose α 5-GABA_AAcceptor is expressed in peripheral neverous system, and expression raises clearly in neural part damage model, and α 5- GABA_AThe inverse agonist of acceptor is by being optionally incorporated into the α 5-GABA of peripheral neverous system_AAcceptor, play and suppress all kinds of The effect of pain, animal experimental model data show that the reverse excitement effect of inverse agonist is stronger, the effect of its inhibition of pain Better.

Detect whether a compound is to be directed to the GABA comprising Alpha 5 subunit_AThe inverse agonist or antagonist of acceptor, The research work of this respect has been done a lot, such as in International Application WO 92/22652 and WO 94/13799, is used GABA_Aα 5, the β 3 and γ 2 of acceptor are combined to detect whether some compound is combined with this receptor；Carrying out drug screening During, generally with (Goeders N E and Kuhar M J (1985) Benzodiazepine such as Goeders binding in vivo with[.sup.3H]Ro 15-1788.Life Sci 37:Method described in 345-355).Detection one Individual energy and GABA_AThe part that acceptor Alpha 5 subunit combines is antagonist, activator or inverse agonist, research in this regard Also it is a lot, it is referred to (Wafford K A, Whiting the P J and Kemp J A (1993) such as Wafford Differences in affinity and efficacy of benzodiazepine receptor ligands on recombinant GABA.sub.A receptor subtypes.Mol.Pharmacol 43:Method described in 240-244).

Screen medicine whether enter blood-brain barrier method than wide, document (Jones et al., Pharmacokinetics and metabolism studies on(3-tert-butyl-7-(5-methylisoxazol- 3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d][1,2,4] triazine,a functionally selective GABA_A α5inverse agonist for cognitive dysfunction.Bioorg Med Chem Lett.2006Feb 15；16(4):Report can be with detection compound in 872-5) Suppress (³H)R0-15-1788(α5GABA_AThe specific inverse agonist of receptor marker) combination in the brain, MRK016 can be with Effectively suppress (³H) R0-15-1788 maincenter combination, and MRK016-M3 can hardly significantly suppress (³H)R0-15- 1788 maincenter combination.Can also be detected by detecting medicine in the method for different tissues, for example, detection medicine in brain and Distribution proportion in blood plasma determines whether medicine can be efficiently entering blood-brain barrier.

Conventional research finds to suppress or reduce α 5GABA using medicine or genetic method_APress down outside receptor-mediated protrusion Effect processed can improve cognition and learning ability, but can cause mild anxiety sample behavior simultaneously.(Brickley,S.G.&Mody, I.Extrasynaptic GABAA receptors:their function in the CNS and implications for disease.Neuron 73,23–34(2012).；Harris,D.et al.Selective influence on contextual memory:physiochemical properties associated with selectivity of benzodiazepine ligands at GABAA receptors containing the alpha5 subunit.J.Med.Chem.51,3788–3803(2008).；Savic′,M.M.et al.PWZ-029,a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5subunits,improves passive,but not active,avoidance learning in rats.Brain Res.1208,150–159(2008)；Clément,Y.et al.Gabra5-gene haplotype block associated with behavioral properties of the full agonist benzodiazepine chlordiazepoxide.Behav.Brain Res.233,474–482(2012)).Research find frightened and anxiety speciality and Gaba5mRNA reduction is related.(Heldt,S.A.&Ressler,K.J.Training-induced changes in the expression of GABA_A associated genes in the amygdala after the acquisition and extinction of Pavlovian fear.Eur.J.Neurosci.26,3631–3644(2007).；Tasan, R.O.et al.Altered GABA transmission in a mouse model of increased trait anxiety.Neuroscience 183,71–80(2011).).Paolo Botta etc. disclose α 5GABA_AAcceptor participates in anxiety With the mechanism of fear.In the specific knockout α 5GABA in brain area domain_AExpression of receptor can cause animal to produce frightened and anxiety behavior. Thus, the α 5GABA of passing disclosure_AInverse agonist, which enters brain, can produce frightened and anxiety side effect, it is impossible to directly should For field of medicaments, it is necessary to which it is transformed.

The content of the invention

It is an object of the present invention to provide the compound shown in logical formula (I) and (II), its cis-trans-isomer, mapping are different Structure body, diastereoisomer, racemic modification, solvate, hydrate or its pharmaceutically acceptable salt and ester.

It is another object of the present invention to provide the preparation method of compound shown in logical formula (I) and (II).

It is another object of the present invention to provide compound shown in logical formula (I) and (II) as α 5-GABA_ARegulation The purposes of agent, so as to prepare for preventing, treating or improving and α 5-GABA_AApplication in the medicine of receptor related disease, The disease for example cognitive illnesses, Alzheimer's, memory disorders, Down syndrome, ALS (ALS), Drug habit, restless leg syndrome, cognition deficiency, multi-infarct dementia, pain, apoplexy and attention deficit, or preparing Purposes in pain of alleviation medicine.

It is another object of the present invention to provide a kind of pharmaceutical composition, and it includes one or more dose therapeutically effectives Logical formula (I) and (II) shown in compound or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier and/or Adjuvant.

Prevent, treat or improve and disease receptor related α 5-GABAA it is another object of the present invention to provide a kind of Method, including give compound shown in logical formula (I) of the present invention and (II) or its pharmaceutically acceptable salt or this The described composition of invention.

In the first aspect of the present invention, there is provided the compound shown in Formulas I, its cis-trans-isomer, enantiomter, diastereomeric Isomers, racemic modification, solvate, hydrate or its pharmaceutically acceptable salt and ester,

Wherein

Z represents to contain 1,2 or 3 heteroatomic 5 yuan of hetero-aromatic ring for being independently selected from oxygen, nitrogen and sulphur, 5 yuan of hetero-aromatic ring quilts One or more optionally substitutes selected from following substituent：Hydroxyl, halogen ,-R1 ,-OR1 ,-OC (O) R1 ,-NR2R3, CN, cyano group (C1-6) alkyl-or R2；

R1 represents C1-6 alkyl, C2-6 alkenyls, C2-6 alkynyls, C3-6 cycloalkyl, C3-6 cycloalkyl (C1-6) alkyl, cyanogen The C1-6 alkyl of base (C1-6) alkyl, hydroxyl or amino substitution, and R1 is optionally one, two or three fluoro；

R2 or R3 independently is hydrogen, C1-6 alkyl, C2-6 alkenyls, C2-6 alkynyls, C3-6 cycloalkyl or CF3, or R2 and R3 forms the miscellaneous cycloaliphatic ring of 4-7 members together with the nitrogen-atoms that they are connected jointly, and the miscellaneous cycloaliphatic ring contains the nitrogen-atoms and one Optionally optionally optionally substituted by one or more R1 groups from O, N and S other hetero atoms, the miscellaneous cycloaliphatic ring；

Preferably Z is represented containing 1,2 or 3 heteroatomic 5 yuan of hetero-aromatic ring for being independently selected from oxygen, nitrogen and sulphur, wherein at most It is oxygen or sulphur to have 1 hetero atom, and when 1 hetero atom is nitrogen-atoms, at least there is also 1 oxygen or sulphur atom, described 5 yuan Hetero-aromatic ring is optionally substituted by one or more selected from following substituent：C1-C4 alkyl, hydroxyl, halogen, hydroxyl or amino substitution C1-C4 alkyl, C2-C4 alkenyls, C2-C4 alkynyls and C1-C4 alkoxies；

More preferably Z is represented containing 2 heteroatomic 5 yuan of hetero-aromatic rings for being independently selected from oxygen, nitrogen and sulphur, and a miscellaneous original Son is oxygen or sulphur, and another atom is nitrogen；5 yuan of hetero-aromatic rings are optionally substituted by one or more selected from following substituent： C1-6 alkyl and hydroxyl C1-6 alkyl；

Most preferably Z represents oxa- ribavirin, furyl, thienyl Huo isoxazolyls, the isoxazolyl by one or It is multiple optionally to substitute selected from following substituent：H, C1-6 alkyl and hydroxyl C1-6 alkyl；

A is-NR2-；Or A be containing 1,2,3 or 4 heteroatomic 5 yuan of heteroarylidene for being independently selected from oxygen, nitrogen and sulphur and It is oxygen or sulphur to be up to 1 in hetero atom；Or be 6 yuan of heteroarylidenes containing 1,2 or 3 nitrogen-atoms, or it is described 5 or 6 yuan it is miscellaneous Arlydene is also optionally condensed on phenyl ring or pyridine ring, and 5 or 6 yuan of heteroarylidenes are optionally taken by Rx and/or Ry and/or Rz Generation, wherein Rx be halogen ,-R1 ,-OR1 ,-OC (O) R1 ,-C (O) OR1 ,-NR2R3 ,-NR2C (O) R3 ,-OH ,-CN, Ry are halogen Element ,-R1 ,-OR1 ,-OC (O) R1 ,-NR2R3 ,-NR2C (O) R3 or CN, Rz are-R1 ,-OR1 or-OC (O) R1, on condition that working as A For pyridine derivate when, the pyridine ring is optionally N- oxide forms；Or A is to be independently selected from following group by 1,2 or 3 to appoint Choose the phenylene in generation：Halogen, cyano group, C1-6 alkyl, C2-6 alkenyls, C2-6 alkynyls and C3-6 cycloalkyl；

Preferably A is expressed as containing 1,2 or 3 heteroatomic 5 yuan of heteroarylidene for being independently selected from oxygen, nitrogen and sulphur and miscellaneous original It is oxygen or sulphur to be up to 1 in son, or 6 yuan of heteroarylidenes or phenylene containing 1,2 or 3 nitrogen-atoms；Described 5 yuan miscellaneous sub- virtues Base, 6 yuan of heteroarylidenes and phenylene are optionally independently selected from following substituent and substituted：Halogen, cyano group and C1-6 alkyl；

More preferably A represents phenylene, sub- pyridine radicals, Ya isoxazolyls；Optionally it is independently selected from by 1,2 or 3 following Substituent substitution：Halogen, cyano group and C1-6 alkyl；

Y is-NY1Y2 or-NH-NY3Y4；

Y1 is selected from：H；C1-6 alkyl；The C1-6 alkyl substituted by 1-5 substituent, the substituent independently selected from：Ammonia Base, halogen, halo-C1-6 alkoxies, hydroxyl, C1-6 alkoxies, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, Nitro and C1-6 alkyl-S (O)₂-；

Preferably Y1 is expressed as H, and C1-6 alkyl or the C1-6 alkyl substituted by 1-5 substituent, the substituent are independent Ground is selected from：Amino, hydroxyl, C1-6 alkoxies, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S (O)₂-；

More preferably Y1 is expressed as H or C1-6 alkyl；

Most preferred Y1 is expressed as H or methyl；

Y2 is selected from：H；C1-6 alkyl；The C1-6 alkyl substituted by 1-5 substituent, the substituent independently selected from：Ammonia Base, halogen, halo-C1-6 alkoxies, hydroxyl, C1-6 alkoxies, cycloalkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkane Base, H) N-, nitro and C1-6 alkyl-S (O)₂-；

Heteroaryl, or the heteroaryl substituted by 1-4 substituent, the substituent of the heteroaryl independently selected from：Acetyl Amido, acetyl group, acetyl-amino, acylamino-, amino, carboxyl, cyano group, halogen, halo-C1-6 alkoxies, halo-C1-6 alkane Base, hydroxyl, hydroxyl-C1-6 alkyl, C1-6 alkoxies, C1-6 alkoxy -C 1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 Alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O)₂-；

Cycloalkyl, or the cycloalkyl substituted by 1-4 substituent, described substituent independently selected from：Acetamido, second Acyl group, acetyl-amino, acylamino-, amino, carboxyl, cyano group, halogen, halo-C1-6 alkoxies, halo-C1-6 alkyl, hydroxyl Base, hydroxyl-C1-6 alkyl, C1-6 alkoxies, C1-6 alkoxy -C 1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O)₂-；

Heterocyclic radical, or the Heterocyclylalkyl substituted by 1-4 substituent, the substituent independently selected from：Acetamido, second Acyl group, acetyl-amino, acylamino-, amino, carboxyl, cyano group, halogen, halo-C1-6 alkoxies, halo-C1-6 alkyl, hydroxyl Base, hydroxyl-C1-6 alkyl, C1-6 alkoxies, C1-6 alkoxy -C 1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O)₂-；

Preferably Y2 is selected from C1-6 alkyl；The C1-6 alkyl substituted by 1-5 substituent, the substituent individually select From：Amino, halogen, hydroxyl, methyl, C1-6 alkoxies, cycloalkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- With C1-6 alkyl-S (O)₂-；

Contain the 1-3 heteroatomic C5-C6 heteroaryls for being selected from N, O or S；By C1-6 it is alkyl-substituted contain 1-3 choosing From N, O or S heteroatomic C5-C6 heteroaryls；

C3-6 cycloalkyl；The C3-6 cycloalkyl substituted by 1-4 substituent, the substituent are individually selected from：Amino, hydroxyl Base, hydroxyl-C1-6 alkyl, C1-6 alkoxies, C1-6 alkoxy -C 1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S (O)₂-；

Contain the 1-3 heteroatomic C4-C6 heterocyclic radicals for being selected from N, O or S；Substituted by 1-4 substituent individual containing 1-3 Heteroatomic C4-C6 heterocyclic radicals selected from N, O or S, the substituent are individually selected from：Methyl, amino, hydroxyl, hydroxyl-C1-6 Alkyl, C1-6 alkoxies, C1-6 alkoxy -C 1-6 alkyl, C1-6 alkyl and C1-6 alkyl-S (O)₂-；

More preferably Y2 is selected from C1-6 alkyl；The C1-6 alkyl substituted by 1-5 substituent, the substituent individually select From：Hydroxyl, halogen, C1-6 alkoxies, cycloalkyl and methyl；

C4-6 cycloalkyl；The C3-6 cycloalkyl substituted by 1-4 substituent, the substituent are hydroxyls；

Contain the 1-3 heteroatomic C4-C6 Heterocyclylalkyls for being selected from N, O or S；Contain 1-3 by what 1-4 substituent substituted The individual heteroatomic C4-C6 Heterocyclylalkyls selected from N, O or S, the substituent is methyl；

Preferred Y2 is selected from hydroxyl normal propyl alcohol base, hydroxycyclopent base, cyclopropyl, methylpyrazole base, isopropyl, trifluoro second Base, methoxy ethyl, THP trtrahydropyranyl, methyl, tetrahydrofuran base, cyclobutyl, amino, Cvclopropvlmethvl, hydroxyl dimethyl second Base, methylol-butyl and ethyl；

Most preferred Y2 is selected from 1- hydroxyl normal propyl alcohol -2- bases, 2- hydroxycyclopent bases, cyclopropyl, 1- methyl isophthalic acid H- pyrazoles -4- Base, isopropyl, 2,2,2- trifluoroethyls, 2- methoxy ethyls, tetrahydrochysene -2H- pyrans -4- bases, methyl, tetrahydrofuran -3- bases, ring Butyl, amino, Cvclopropvlmethvl, 2- hydroxyl -1,1- dimethyl-ethyIs, 1- methylol-butyls and ethyl；

Or Y1, Y2 form 4-6 circle heterocycles bases together with the N atoms that they are connected；Or Y1, Y2 are connected with them N atoms form cycloalkyl together；

Preferably or Y1, Y2 form 4-6 circle heterocycles bases together with the N atoms that they are connected, the heterocyclic radical except Can be its oxidation also containing zero, one or more hetero atoms for being selected from O and S, and the S atom outside containing nitrogen-atoms Thing form；Or Y1, Y2 form cycloalkyl together with the N atoms that they are connected；

Preferred or Y1 and Y2 forms dioxide thio-morpholinyl, morpholine together with the nitrogen-atoms that they are connected Base, azelidinyl, pyrrolidinyl or piperidyl；

Most preferably or Y1 and Y2 forms 1,1- Dioxo-thiomorpholins -4- together with the nitrogen-atoms that they are connected Base, morpholine -4- bases, azetidine -1- bases, pyrrolidin-1-yl or piperidin-1-yl；

Y3, Y4 are selected from independently of each other：Hydrogen, C1-C6 alkyl, SO₂- C1-C6 alkyl, cycloalkyl or Y3 and Y4 and their institutes The nitrogen-atoms of connection forms heterocyclic radical together；

Preferably Y3, Y4 are selected from independently of each other：Hydrogen, C1-C6 alkyl, SO₂- C1-C6 alkyl, cycloalkyl and heterocyclic radical, appoint The substituent that choosing is independently selected from following groups by 1-4 substitutes：Halogen, cyano group, hydroxyl, C1-C6 alkyl and C1-C6 alkoxies,

Or wherein Y3, Y4 form heterocyclic radical together with the nitrogen-atoms that they are connected, the heterocyclic radical is optionally only by 1-4 The vertical substituent selected from following groups substitutes：Halogen, cyano group, hydroxyl, oxo, C1-C6 alkyl and C1-C6 alkoxies.

Preferred Y3 and Y4 is selected from independently of each other：Hydrogen, or heterocyclic radical is formed together with the nitrogen-atoms that they are connected, Selected from morpholinyl, pyrrolidinyl, piperidyl and dioxothiomorpholinyl.

Most preferred Y3 and Y4 is selected from independently of each other：Hydrogen, or heterocyclic radical is formed together with the nitrogen-atoms that they are connected, Selected from morpholine -4- bases, pyrrolidin-1-yl, piperidin-1-yl and 1,1- Dioxo-thiomorpholin -4- bases.

The present invention also provides the compound with below general formula II:

Wherein

R4 is the C1-C4 alkyl that C1-C4 alkyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H, and C1-6 alkyl or the C1-6 alkyl substituted by 1-5 substituent, the substituent are individually selected from：Ammonia Base, hydroxyl, C1-6 alkoxies, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S (O)₂-；

Y2 is selected from C1-6 alkyl；The C1-6 alkyl substituted by 1-5 substituent, the substituent are individually selected from：Amino, Halogen, hydroxyl, methyl, C1-6 alkoxies, cycloalkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkane Base-S (O)₂-；

Or Y1, Y2 form 4-6 circle heterocycles bases together with the N atoms that they are connected；

Or Y1, Y2 form cycloalkyl together with the N atoms that they are connected；

Y3, Y4 are selected from independently of each other：Hydrogen, C1-C6 alkyl, SO₂- C1-C6 alkyl, or Y3 and Y4 are connected with them Nitrogen-atoms forms heterocyclic radical together；

In a preferred embodiment, in compounds of formula II,

R4 is the methyl that methyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Or Y1, Y2 form cycloalkyl together with the N atoms that they are connected；

Y3, Y4 are selected from independently of each other：Hydrogen, C1-C6 alkyl and SO₂- C1-C6 alkyl, or Y3 and Y4 are connected with them Nitrogen-atoms form heterocyclic radical together.

In a preferred embodiment, in compounds of formula II,

R4 is the C1-C4 alkyl that C1-C4 alkyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H or C1-6 alkyl；

Y2 is selected from C1-6 alkyl；The C1-6 alkyl substituted by 1-5 substituent, the substituent are individually selected from：Hydroxyl, Halogen, C1-6 alkoxies, cycloalkyl and methyl；

Or Y1, Y2 form 4-6 circle heterocycles bases together with the N atoms that they are connected, the heterocyclic radical is except containing nitrogen Outside atom, also containing zero, one or more hetero atoms for being selected from O and S, and the S atom can be its oxide form；

Or Y1, Y2 form cycloalkyl together with the N atoms that they are connected；

Y3 and Y4 are selected from independently of each other：Hydrogen, or Y3 and Y4 form heterocyclic radical together with the nitrogen-atoms that they are connected.

In a preferred embodiment, in compounds of formula II,

R4 is the methyl that methyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H or C1-6 alkyl；

Or Y1, Y2 form cycloalkyl together with the N atoms that they are connected；

In a preferred embodiment, in compounds of formula II,

R4 is the C1-C4 alkyl that C1-C4 alkyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H or methyl；

Or Y1, Y2 form cycloalkyl together with the N atoms that they are connected；

In a preferred embodiment, in compounds of formula II,

R4 is the methyl that methyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H or methyl；

Or Y1, Y2 form cycloalkyl together with the N atoms that they are connected；

In a preferred embodiment, in compounds of formula II,

R4 is the C1-C4 alkyl that C1-C4 alkyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H or methyl；

Or Y1, Y2 form cycloalkyl together with the N atoms that they are connected；

In a preferred embodiment, in compounds of formula II,

R4 is the methyl that methyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H or methyl；

Or Y1, Y2 form cycloalkyl together with the N atoms that they are connected；

In a preferred embodiment, in compounds of formula II,

R4 is the C1-C4 alkyl that C1-C4 alkyl or hydroxyl substitute；

Y is-NY1Y2 or-NH-NY3Y4；

Y1 is H or C1-6 alkyl；

Y2 is selected from hydroxyl normal propyl alcohol base, hydroxycyclopent base, cyclopropyl, methylpyrazole base, isopropyl, trifluoroethyl, methoxy Base ethyl, THP trtrahydropyranyl, methyl, tetrahydrofuran base, cyclobutyl, amino, Cvclopropvlmethvl, hydroxyl dimethyl ethyl, hydroxyl first Base butyl and ethyl；

Or Y1 and Y2 forms dioxide thio-morpholinyl, morpholinyl, azepine together with the nitrogen-atoms that they are connected Cyclobutyl, pyrrolidinyl or piperidyl；

Y3 and Y4 are selected from independently of each other：Hydrogen, or heterocyclic radical is formed together with the nitrogen-atoms that they are connected, selected from morpholine Base, pyrrolidinyl, piperidyl and dioxothiomorpholinyl.

In a preferred embodiment, in compounds of formula II,

R4 is the methyl that methyl or hydroxyl substitute；

Y is-NY1Y2 or-NH-NY3Y4；

Y1 is H or C1-6 alkyl；

In a preferred embodiment, in compounds of formula II,

R4 is the C1-C4 alkyl that C1-C4 alkyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H or C1-6 alkyl；

Y2 is selected from 1- hydroxyl normal propyl alcohol -2- bases, 2- hydroxycyclopent bases, cyclopropyl, 1- methyl isophthalic acid H- pyrazoles -4- bases, isopropyl Base, 2,2,2- trifluoroethyls, 2- methoxy ethyls, tetrahydrochysene -2H- pyrans -4- bases, methyl, tetrahydrofuran -3- bases, cyclobutyl, ammonia Base, Cvclopropvlmethvl, 2- hydroxyl -1,1- dimethyl-ethyIs, 1- methylol-butyls and ethyl；

Or Y1 and Y2 forms 1,1- Dioxo-thiomorpholin -4- bases together with the nitrogen-atoms that they are connected, morpholine - 4- bases, azetidine -1- bases, pyrrolidin-1-yl or piperidin-1-yl；

Y3 and Y4 are selected from independently of each other：Hydrogen, or heterocyclic radical is formed together with the nitrogen-atoms that they are connected, selected from Quinoline -4- bases, pyrrolidin-1-yl, piperidin-1-yl and 1,1- Dioxo-thiomorpholin -4- bases.

In a preferred embodiment, in compounds of formula II,

R4 is the methyl that methyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H or C1-6 alkyl；

In a preferred embodiment, in compounds of formula II,

R4 is the C1-C4 alkyl that C1-C4 alkyl or hydroxyl substitute；

Y is-NY1Y2 or-NH-NY3Y4；

Y1 is H or methyl；

In a preferred embodiment, in compounds of formula II,

R4 is the methyl that methyl or hydroxyl substitute；

Y is-NY1Y2 or-NH-NY3Y4；

Y1 is H or methyl；

In a preferred embodiment, in compounds of formula II,

R4 is the C1-C4 alkyl that C1-C4 alkyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H or methyl；

In a preferred embodiment, in compounds of formula II,

R4 is the methyl that methyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H or methyl；

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

The present invention also provides a kind of composition, and it includes compound as described above or its pharmaceutically acceptable Salt.

The present invention also provides the purposes of compound as described above or composition in medicine is prepared.

The present invention also provides a kind of method for treating or preventing disease, including applies the as described above of effective dose to patient Compound or composition.

The present invention also provides compound as described herein or composition and is preparing treatment or prevention and α 5-GABA_AAcceptor has Purposes in the medicine of the disease of pass.

The present invention also provides a kind of treat or prevent and α 5-GABA_AThe method of receptor related disease, it is characterised in that to Patient applies the compound as described above or composition of effective dose.

The present invention also provides compound as described herein or composition in the medicine for treating or preventing following disease is prepared Purposes：Pain, Alzheimer's, multi-infarct dementia and apoplexy.

In a preferred embodiment, described pain is neurogenic pain, inflammatory pain and carcinomas pain.

In a preferred embodiment, described pain is selected from：Headache, face pain, cervicodynia, shoulder pain, backache, pectoralgia, Stomachache, back pain, pain in the back, melosalgia, muscle and skeleton pain, vascular pain, gout, arthritis ache, visceral pain, infection Pain caused by property disease (such as AIDS and PHN), more bone pains, sickle cell anemia, LADA disease Chronic ache caused by the pain of disease, multiple sclerosis or inflammation-related, damage or operation, nociceptive pain, painful Diabetes, trigeminal neuralgia, waist or cervical radiculopathies pain, glossopharyngeal neuralgia, autonomic reflex pain, reflectivity Sympathetic dystrophy, nerve root avulsion, cancer, chemical damage, toxin, nutritional deficiency, virus or bacterium infection, degeneration The relevant pain of osteoarthropathy.

The present invention also provides a kind of side for treating or preventing pain, Alzheimer's, multi-infarct dementia and apoplexy Method, it is characterised in that the compound as described herein or composition of effective dose are applied to patient.

The invention further relates to the method for producing formula (I) compound defined above, this method includes：

A) formula (IV) compound is made

WithReaction obtains formula (1-3) compound, and wherein G and W are selected from Cl, Br, I, OH, OTs, OTf and OMs, R5 are alkyl, methyl, ethyl, the tert-butyl group and benzyl；Wherein Z, Y, A be as hereinbefore defined；

Then formula (1-3) compound is made

With Y reactions, wherein Z, Y, A as hereinbefore defined；Or

B) formula (1-4) compound is made：

With Y reactions, wherein Z, Y, A as hereinbefore defined；

C) it is formula (1-4) compound by the compound saponification of formula (1-3), is then reacted with Y, wherein, wherein Z, Y, A be as above Text is defined；Or

D) formulaCompound and formulaThe reaction of compound.

In the compound of formula I and II in the present invention, Z represents to be independently selected from oxygen, nitrogen and sulphur containing 1,2 or 3 Heteroatomic 5 yuan of hetero-aromatic rings, 5 yuan of hetero-aromatic rings are optionally substituted by one or more selected from following substituent：Hydroxyl, halogen Element ,-R1 ,-OR1 ,-OC (O) R1 ,-NR2R3, CN, cyano group (C1-6) alkyl-or R2；Wherein R1 represents C1-6 alkyl, C2-6 chains Alkenyl, C2-6 alkynyls, C3-6 cycloalkyl, C3-6 cycloalkyl (C1-6) alkyl, cyano group (C1-6) alkyl, hydroxyl or amino substitution C1-6 alkyl, and R1 is optionally one, two or three fluoro；R2 or R3 independently is hydrogen, C1-6 alkyl, C2-6 alkenyls, C2-6 Alkynyl, C3-6 cycloalkyl or CF3, or R2 and R3 form the miscellaneous cycloaliphatic ring of 4-7 members, the fat together with the nitrogen-atoms that they are connected jointly Fat ring contains the nitrogen-atoms and one optionally from O, N and S other hetero atoms, and the ring is optionally by one or more R1 groups Optionally substitution；Preferably, Z is represented containing 1,2 or 3 heteroatomic 5 yuan of hetero-aromatic ring for being independently selected from oxygen, nitrogen and sulphur, wherein most To have 1 hetero atom be oxygen or sulphur more, and when 1 hetero atom is nitrogen-atoms, at least there is also 1 oxygen or sulphur atom, described 5 First hetero-aromatic ring is optionally substituted by one or more selected from following substituent：C1-C4 alkyl, hydroxyl, halogen, hydroxyl or amino take C1-C4 alkyl, C2-C4 alkenyls, C2-C4 alkynyls, the C1-C4 alkoxies in generation；More preferably Z is represented containing 1 or 2 independent choosing From heteroatomic 5 yuan of hetero-aromatic rings of oxygen, nitrogen and sulphur, and be up to 1 hetero atom is oxygen or sulphur, and when 1 hetero atom is During nitrogen-atoms, there is also 1 oxygen atom or 1 sulphur atom；Preferably Z represents to contain 2 miscellaneous originals for being independently selected from oxygen, nitrogen and sulphur 5 yuan of hetero-aromatic rings of son, and a hetero atom is oxygen or sulphur, and another atom is nitrogen；5 yuan of hetero-aromatic rings are one or more Optionally substitute selected from following substituent：C1-6 alkyl or hydroxyl C1-6 alkyl；Preferably Z represent oxa- ribavirin, furyl, Thienyl Huo isoxazolyls, the oxa- ribavirin, furyl, thienyl Huo isoxazolyls are by one or more selected from following Substituent optionally substitutes：C1-6 alkyl or hydroxyl C1-6 alkyl；It is highly preferred that Z represents oxa- ribavirin, furyl, thienyl Huo isoxazolyls, the oxa- ribavirin, furyl, thienyl Huo isoxazolyls are selected from following substituent by one or more Optionally substitution：Methyl and hydroxymethyl.

In the compound of formula I and II in the present invention, A is-NR2-；Or A is to be independently selected from containing 1,2,3 or 4 It is oxygen or sulphur that 1 is up in the heteroatomic 5 yuan of heteroarylidenes and hetero atom of oxygen, nitrogen and sulphur, or to contain 1,2 or 3 nitrogen 6 yuan of heteroarylidenes of atom, or 5 or 6 yuan of heteroarylidenes are also optionally condensed on phenyl ring or pyridine ring, described 5 or 6 yuan Heteroarylidene is optionally substituted by Rx and/or Ry and/or Rz, wherein Rx be halogen ,-R1 ,-OR1 ,-OC (O) R1 ,-C (O) OR1 ,- NR2R3 ,-NR2C (O) R3 ,-OH ,-CN, Ry are halogen ,-R1 ,-OR1 ,-OC (O) R1 ,-NR2R3 ,-NR2C (O) R3 or CN, Rz For-R1 ,-OR1 or-OC (O) R1, on condition that when A is pyridine derivate, the pyridine ring is optionally N- oxide forms；Or A is The phenylene for being independently selected from following group by 1,2 or 3 and optionally being substituted：Halogen, cyano group, C1-6 alkyl, C2-6 alkenyls, C2-6 alkynyls and C3-6 cycloalkyl；Preferably A represents miscellaneous containing 1,2 or 3 be independently selected from oxygen, nitrogen and sulphur heteroatomic 5 yuan It is oxygen or sulphur to be up to 1 in arlydene and hetero atom, or 6 yuan of heteroarylidenes or phenylene containing 1,2 or 3 nitrogen-atoms； 5 yuan of heteroarylidenes, 6 yuan of heteroarylidenes and phenylene are optionally substituted selected from following substituent：Halogen, cyano group and C1-6 alkyl；More preferably A represents phenylene, sub- pyridine radicals, Ya isoxazolyls；Optionally it is independently selected from by 1,2 or 3 following Substituent substitution：Halogen, cyano group and C1-6 alkyl；

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

More preferably Y1 is expressed as H or C1-6 alkyl；

Most preferred Y1 is expressed as H or methyl；

Embodiment

It is outer unless specified otherwise, following definition be used to illustrate and define be used to describing herein using during the present invention it is various The meaning and scope of term.

Either individually occur or combination occurs, the following definition of general terms is applicable.

Naming rule used herein is to be based on AutoNomTM 2000, for producing IUPAC systematic naming methods The system of Beilstein Institute computerization.The chemical constitution provided herein is to use ChemDraw versions 12 Obtain.Any open valency key table for occurring on carbon, oxygen, sulphur or nitrogen-atoms in the structure provided herein is bright to have hydrogen original Son.

Unless otherwise indicated, term " substituted " refers to that the group specified or part can have 1,2,3,4,5 or 6 and take Dai Ji.When that can have multiple substituents on group and give a variety of possible substituents, the substituent independently selects Select, it is not necessary to be identical.

Do not have substituent on the group that term " unsubstituted " refers to specify.

The group that term " optionally substituting " refers to specify is unsubstituted or be independently selected from by one or more can What the substituent of the substituent of energy was substituted.

When indicating the number of substituent, term " one or more " refers to a substitution to most possible numbers of substitution Mesh, that is, a hydrogen to all hydrogen is substituted to be substituted with a substituent.It is outer unless specified otherwise, preferably 1,2,3,4 or 5 substituent.

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

Term " low alkyl group " used herein refers to the straight or branched alkyl containing 1-6 carbon atom, can be with this C1-6 alkyl described in text exchanges, C1-6 alkyl example such as methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl Those groups of base, sec-butyl or the tert-butyl group and hereinafter special example.Particularly preferred " low alkyl group " is for methyl and just Butyl.

Term " lower alkoxy " refers to group-O-R, and wherein R is low alkyl group as defined above.

Term " cycloalkyl " refers to the cyclic hydrocarbon group of monovalent saturation, preferably individual with 3-7 ring carbon atom, more preferably 3-6 The cyclic hydrocarbon group of the monovalent saturation of carbon atom, such as cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, and hereinafter especially show Those groups of example.

Term " heterocyclic radical " refers to have heteroatomic saturation or part is undersaturated monocyclic or polycyclic moiety, preferably comprises The undersaturated monocyclic ring of monovalent 3-7 members saturation or part of 1,2 or 3 ring hetero atom selected from N, O or S.Preferably comprise 1 Individual or 2 ring hetero atoms.Preferably comprise the 4-6 circle heterocycles bases of 1 or 2 ring hetero atom selected from N, O or S.S can be optionally by two Individual oxo group substitution.The example of heterocyclic radical is pyrrolidinyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro-thienyl, tetrahydrochysene pyrrole Piperidinyl, nafoxidine base, azetidinyl, thiazolidinyl, oxazolidinyl, piperidyl, morpholinyl, thio-morpholinyl, 1,1- bis- Oxo-thiomorpholin -4- bases, piperazinyl, nitrogen heterocyclic heptyl, Diazesuberane base, oxaza heptane base or dihydro-azoles Those groups of base and hereinafter special example.Preferable heterocyclic radical is morpholine -4- bases, piperidin-1-yl, pyrrolidines -1- Base, thiomorpholine -4- bases and 1,1- Dioxo-thiomorpholin -4- bases, particularly preferred heterocyclic radical are morpholine -4- bases, pyrroles Alkane -1- bases and 1,1- Dioxo-thiomorpholin -4- bases.

Term " aryl " refers to containing 6-14, preferably 6-10 carbon atoms and there is at least one aromatic ring or wherein at least one Individual ring is the monovalent aromatic carbocyclic ring system of more fused rings of aromatic ring.The example of aryl is phenyl, naphthyl, xenyl or indanyl, And hereinafter those groups of special example.Preferable aryl is phenyl, and aryl can also be substituted, and following article and right will Defined in asking.

Term " heteroaryl " be containing heteroatomic aromatic group, preferably comprise 1,2 or 3 selected from nitrogen, oxygen and/or The aromatics 5-6 unit monocycles or 9-10 membered bicyclics of the atom of sulphur, such as furyl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, thiophene Fen base, isoxazolyl, oxazolyls, di azoly, imidazole radicals, pyrrole radicals, pyrazolyl, triazolyl, tetrazole radical, thiazolyl, isothiazolyl, Thiadiazolyl group, benzimidazolyl, indyl, indazolyl, benzothiazolyl, benzisothia oxazolyl, benzoxazolyl group, benzo isoxazole Base, quinolyl or isoquinolyl, and hereinafter those groups of special example.Heteroaryl can also be substitution, following article Defined in claim.Preferable heteroaryl is the fluoro- pyridine -2- bases of 5-.

Term " low alkyl group being optionally substituted by halogen " refers to by the single or multiple substituted low alkyl group of halogen.It is optionally substituted by halogen The example of low alkyl group is such as CFH₂、CF₂H、CF₃、CF₃CH₂、CF₃(CH₂)₂、(CF₃)₂CH or CF₂H-CF₂, and hereinafter Those groups of special example.

Term " low alkyl group being optionally substituted by a hydroxyl group " refers to what the hydrogen atom in wherein at least one alkyl was optionally substituted by a hydroxyl group Low alkyl group as defined above.The example for the low alkyl group being optionally substituted by a hydroxyl group include but is not limited to by one or more hydroxyls, Particularly one, two or three hydroxyl, methyl, ethyl, propyl group, isopropyl, the isobutyl of preferably one or two hydroxyl substitution Base, sec-butyl, tert-butyl, amyl group or n-hexyl.

Formula (I) and the compound of (II) can form pharmaceutically acceptable acid-addition salts.It is such pharmaceutically acceptable The example of salt is formula (I) and (II) compound and physiologically compatible inorganic acid or the salt of organic acid formation, exemplified by inorganic acid Such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid；Organic acid is such as Loprazolam, p- toluenesulfonic acids, acetic acid, lactic acid, trifluoroacetic acid, Citric acid, fumaric acid, maleic acid, tartaric acid, butanedioic acid or salicylic acid.Term " pharmaceutically acceptable salt " refers to such salt. Formula (I) compound containing acidic-group such as COOH can also be with alkali forming salt.The example of such salt is alkali metal, alkaline earth gold Category and ammonium salt, such as Na-, K-, Ca- and leptodactyline.Term " pharmaceutically acceptable salt " also refers to such salt.

Term " pharmaceutically acceptable ester " includes the derivative of formula (I) and (II) compound, and wherein carboxyl is converted into Ester.Low alkyl group, the low alkyl group being optionally substituted by a hydroxyl group, the low alkyl group substituted by lower alkoxy, Amino-lower alkyl, list- Or two lower alkyl-amino-lower alkyl, morpholino-low alkyl group, pyrrolidino-low alkyl group, piperidino-rudimentary Alkyl, Piperazino-low alkyl group, lower alkyl-piperazin subbase-low alkyl group and aryl-lower-alkyl ester are appropriate esters Example.It is preferred that methyl, ethyl, propyl group, butyl and benzyl ester.Term " pharmaceutically acceptable ester " also includes formula (I) chemical combination The derivative of thing, wherein hydroxyl are converted into corresponding ester by inorganic or organic acid, inorganic or organic acid is such as nitric acid, sulfuric acid, Phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, butanedioic acid, tartaric acid, methanesulfonic acid, p- toluenesulfonic acids etc., these acid are to organism It is nontoxic.

Preparation method

A) formula (IV) compound is made

WithReaction, wherein G and W are optional Cl, Br, I, OH, OTs, OTf and OMs etc.；R5 It is alkyl, methyl, ethyl, the tert-butyl group and benzyl, then

Make formula (1-3) compound

With Y reaction or

B) formula (1-4) compound is made：

Reacted with Y；Or

C) it is formula (1-4) compound by the compound saponification of formula (1-3), is then reacted with Y；Or

D) formulaCompound and formulaThe reaction of compound,

Wherein Z, Y, A be as hereinbefore defined.

Make formulaWithReaction, wherein G and W are Cl, Br, I, OH, OTs, OTf and OMs etc. optional Substituent.Reaction can it is described in instances under conditions of or carry out under the conditions of well known by persons skilled in the art.Example Such as, the reaction can under LDA, NaH, potassium tert-butoxide or sodium etc., in appropriate solvent (such as dioxane), at room temperature Carried out under (such as 20 DEG C).It is either raw using Mitsunobu conditions (PPh3, DEAD), phase transfer catalyst (TBAB, crown ether) etc. Into the working condition of ether.

FormulaThe reaction that compound reacts to obtain formula (I) compound with Y can be described in instances Under conditions of or carry out under the conditions of well known by persons skilled in the art.For example, the reaction can exist in trimethyl aluminium Under, carry out in appropriate solvent (such as dioxane), at elevated temperature (such as 85-95 DEG C).

FormulaThe reaction that compound and Y react to obtain formula (I) compound can institute in instances Carried out under conditions of stating or under the conditions of well known by persons skilled in the art.For example, the reaction can H ü nigs alkali (N, N- diisopropyl ethyl amines) and O- (BTA -1- bases)-N, N, N ', in the presence of N '-tetramethylurea tetrafluoroborate, suitable When solvent (such as dimethylformamide) in, carry out at room temperature.Or the reaction can exist in 1,1 '-carbonyl dimidazoles Under, carry out in appropriate solvent (such as dimethylformamide), at elevated temperature (such as 80 DEG C).In addition, the reaction may be used also With in 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride, N1- hydroxybenzotriazoles and H ü nigs alkali (N, N- Diisopropyl ethyl amine) in the presence of, in appropriate solvent (such as dichloromethane), carry out at room temperature.

FormulaCompound saponification can be described in instances for the reaction of formula (1-4) compound Under conditions of or carry out under the conditions of well known by persons skilled in the art.For example, the reaction can exist in sodium hydroxide Under, in appropriate solvent (such as water), carry out at room temperature.Or the reaction can deposit in sodium hydroxide or lithium hydroxide Under, in appropriate solvent (such as tetrahydrofuran or water), carry out at room temperature.Either it is other it is described under conditions of or Carried out under the conditions of well known by persons skilled in the art, for example benzyl class, the acid condition hydrolysis tert-butyl group etc. bar is taken off in hydrogenation Part.

FormulaCompound and formulaThe reaction that the reaction of compound obtains formula (I) compound can be Carried out under conditions of described in example or under the conditions of well known by persons skilled in the art.For example, for example, the reaction can be with Under LDA, NaH, potassium tert-butoxide or sodium etc., in appropriate solvent (such as dioxane, THF and DMF), at room temperature (such as 20 DEG C) under carry out.It is either raw using Mitsunobu conditions (PPh3, DEAD), phase transfer catalyst (TBAB, crown ether etc.) etc. Into the working condition of ether.Enter in appropriate solvent (such as dioxane, THF and DMF), at elevated temperature (such as 80 DEG C) OK, product is generated under corresponding alkali or catalysts conditions.

The invention further relates to formula as described above (II) compound, prepared by method as described above.

Formula (II) compound and its pharmaceutically acceptable salt of the present invention can be prepared by following method.

If the not its preparation method described in embodiment, then formula (II) compound and its midbody product can roots Prepared according to similar method or according to preceding method.Raw material known in the art can derive from business, or can be according to this It is prepared by method known to field or the similar approach of known method.

It is appreciated that the logical formula (II) compound of the present invention can derive in functional group, so as to which obtain can be in vivo It is then converted to the derivative of parent compound.

As described above, novel compound of present invention and its pharmaceutically acceptable salt and ester have important pharmacology Matter, it is α 5GABA_AReceptor inverse agonists.Therefore, the compounds of this invention can be used alone or is applied in combination with other drugs, For treating or preventing by the GABA containing the subunits of α 5_AThe disease of receptors ligand mediation.These diseases include but is not limited to ache Bitterly, Alzheimer's, multi-infarct dementia and apoplexy.

Therefore, the invention further relates to Pharmaceutical composition, the Pharmaceutical composition to include compound as defined above and medicine Acceptable carrier and/or adjuvant on.

Equally, present invention additionally comprises compound as described above, treated or prevented and α 5GABA as preparing_AIt is receptor related Disease medicine, especially treat or prevent following disease：Pain, Alzheimer's, multi-infarct dementia and apoplexy.

Preferred therapeutic or pre- pain.Particularly preferably treat or prevent neuropathic pain, inflammatory pain and carcinomas pain.

As used herein, " carcinomas pain " refers to the pain that malignant tumour occurs in its evolution, and mesh occurs for carcinomas pain Before think there are three kinds of mechanism, i.e.,：Pain and cancer patient are concurrent caused by after pain that cancer development directly contributes, treatment of cancer Painful diseases.

As used herein, " neuropathic pain " is to be excited or being drawn by nervous system primary lesion and dysfunction The pain risen.

As used herein, " inflammatory pain " is the pain caused by topical acute inflammation or chronic inflammation stimulation nerve.

As used herein, " treatment " also includes preventive administration, alleviates after illness foundation or eliminates the disease Disease.

As used herein, " patient " is defined as any warm-blooded animal, such as is not limited to mouse, cavy, dog, horse or people, institute It is preferably people to state patient.

As used herein, " Acute Pain " is defined as pathogenetic by the damage of skin, body structure or internal organ and/or disease Pain caused by destructive stimulus, or the pain as caused by not producing the muscle of actual tissue infringement or the abnormal function of internal organ Bitterly.

As used herein, " chronic ache " is defined as persistently exceeding the common course of disease of acute illness or damages the reasonable of healing Time, or relevant with causing the chronic pathology process of constant pain, or pain recur several months or several years at certain intervals, if It should reach after healing or more than still suffering from pain after common therapeutic process, then it is assumed that be chronic ache.Needed in pain Elapsed time length is wanted to depend on the property of pain and the therapeutic process relevant with pain, if pain exceedes common treatment Process, then pain is chronic.Chronic ache includes but is not limited to headache, facial pain, cervicodynia, shoulder pain, pectoralgia, stomachache, back Bitterly, pain in the back, melosalgia, flesh and skeleton pain, the pain relevant with somatoform disorders, splanchnodynia, painful diabetic Nerve disease, vascular pain, gout, Arthritic pain, cancer pain, autonomic reflex pain, infectious diseases are (such as AIDS and herpes zoster) caused by ache caused by pain, active chronic inflammation caused by pain, autoimmune disease (rheumatism) Bitterly, postoperative pain and burnt degree pain.

The medicine that the present invention discloses can effectively treat chronic ache as defined above, and the medicine that the present invention discloses can It is quick with the pain of other illnesss for treating, including hyperalgia, allodynia, pain sensation enhancing and pain memory-enhancing effect, should Invention will improve treatment to its pain.

As used herein, " headache " can be divided into primary headaches and secondary headache, and primary headaches include tonicity head Bitterly, antimigraine and cluster headache, and secondary headache is due to caused by other diseases.The pain sensitive organization of Head And Face occurs Lesion or when being upset, can cause various headaches, these pain sensitive organizations include being distributed in scalp, face, oral cavity and throat Deng, it is more sensitive to pain containing abundant nerve fibre because they are mainly the muscle or blood vessel on head, so working as this A little tissues can cause headache when coming to harm.

As used herein, " face pain " includes but is not limited to trigeminal neuralgia, atypia prosopodynia, facioplegia and facial muscle Spasm.

As used herein, " trigeminal neuralgia " is a kind of unique chronic paining diseases, also known as trismus dolorificus, is referred to There is of short duration, paroxysmal and recurrent exerbation electric shock sample severity pain in trigeminal neuralgia distributed areas, or with ipsilateral Muscle spasmus.Trigeminal neuralgia is divided into primary and Secondary cases two types, and primary trigeminal neuralgia refers to not find clinically Nervous system signs, inspection do not find organic disease；Secondary trigeminal neuralgia refers to clinically there are nervous system signs, Check that discovery has organic disease, such as tumour and inflammation.

As used herein, " atypia prosopodynia " refers to the pain as caused by Different types of etiopathogenises.Show as continuation and burn sample pain Bitterly, Non-intermittent, with special action or triggering stimulation it is unrelated, pain is mostly bilateral, pain usually beyond trifacial point Cloth scope even involves skin of neck.The cause of disease can be stimulated by reasons such as nasosinusitis, malignant tumour, jaw and basis cranii infection or damage three Fork is neural and causes pain.

As used herein, " cervicodynia, backache, shoulder pain " refer to due to acute and chronic muscular strain and Bones and joints retrogression and Pain caused by wound etc..Cause neck, shoulder and upper extremity pain common disease have neck and shoulder fasciitis, poll-evil, cervical spondylopathy, Scapulohumeral periarthritis, Thoracic outlet syndrome, external humeral epicondylitis etc., or pain is common in rheumatoid as caused by autoimmune disease The diseases such as property arthritis, ankylosing spondylitis and rheumatic arthritis, other may cause cervicodynia, backache, shoulder pain disease also There are neck, the tumour of shoulder, neuritis, referred pain etc. caused by arteriovenous disorders and various infection and chest, abdominal viscera lesion.

As used herein, " chest, abdomen and back pain " refer to due to thorax abdomen internal organ, chest abdominal wall tissue disease caused by pain Bitterly, including but not limited to intercostal neuralgia, intercostal chondritis, angina pectoris, stomachache (acute abdominal viscera pain) and the small of the back flesh muscle Hyaline membrane disease.

As used herein, " waist, melosalgia " refers to lower waist, waist sacrum, sacrum ilium, hip, stern and melosalgia.Waist and melosalgia are often Be not independent disease, but the common characteristic of a variety of diseases, diverse clinical manifestations, the cause of disease is sufficiently complex, with degeneration and Damage to be more, including but not limited to protrusion of lumber intervertebral disc, acute lumbar muscle sprain, sciatica, osteoporosis, third lumbar vertebra are horizontal The pain that prominent syndrome, piriformis syndrome, knee joint osseous arthritis, tail pain and talagia etc. are related to.

As used herein, the pain and chronic that " flesh and skeleton pain " includes but is not limited to myofacial pain, wound triggers Regional pain syndrome.

As used herein, " painful diabetic " refers to pain caused by diabetes complicated neurotrosis, diabetes In neurotrosis at least partly be due to caused by Oligemia and hyperglycaemia.Neuropathy does not occur for some diabetics Become, and the disease just occurs early stage for other patients, diabetic neuropathy pain, which can be divided into, is related to one or more focus portion The mononeuropathy and systemic polyneuropathy of position, the polyneuropathy can be spread and symmetrically, generally relate generally to feel Mode (Merrit ' s Textbook of Neurology, the 9th edition, LPRowland LP are edited).Diabetic neuropathy Performance can include vegetative nerve functional disturbance, cause the insufficiency of accommodation including heart, smooth muscle and body of gland, cause low blood Pressure, diarrhoea, constipation and impotence.Diabetic neuropathy often phase in, in early days in nerve endings area, autonomic neuropathies or The when generation of esthesioneurosis occurs to enclose in face and eye circumference in foot, cranial nerve disease, intermittent pain and tingle occurs, In the subsequent stage, the stronger and frequent generation of pain, finally, when a certain region analgesia, painless nerve is occured as Disease, due to instruction of no pain as damage, considerably increase the risk that severe tissue damage occurs.

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

As used herein, " vascular pain " is the pain as caused by one or more of factor.First, the perfusion of tissue It is improper.Cause temporary transient or continuous ischaemic, the ischaemic in limb muscle such as occurs during movement；Second, late The change of hair property.Such as ulcer or gangrene in skin or abdominal viscera；3rd, the unexpected or acceleration change of big external caliber. Such as the change that aneurysm occurs；4th, aortoclasia.Result is blood from overflowing, stimulates the wound in peritonaeum or pleura parietalis Evil experiences fiber；5th, the strong spasm caused by intra-arterial injection seriously stimulates arterial endothelium；6th, venous return Infringement, result be rapid expansion manadesma compartment a large amount of oedema (Bonica etc., The Management of Pain, first Roll up (second edition), Philadelphia；Lea＆Feboger, 1990).Example includes but is not limited to arteriosclerosis, occlusion Property thromboangiitis, acute arterial closure, embolism, congenital arteriovenous aneurysm, vasospasm disease, Rayaud disease, Shou Zufa Dark purple, Acute Venous closure, thrombophlebitis, varication and lymphedema.

As used herein, " autonomic reflex pain " refers to ache caused by " sympathetic reflex atrophy sign " Bitterly.Sympathetic reflex atrophy sign refers to that body by after acute and chronic injury, has violent idiopathic pain, to tactile and the pain sensation Allergy, it can then may occur in which the symptoms such as dystrophia and the atrophy of skin and muscle skeleton with edema and blood obstacle.

As used herein, " postoperative pain " refer to body to disease in itself with operation caused by tissue damage one kind it is complicated Physiological reaction, it show as psychology and behavior on a kind of sour experience.

As used herein, " Arthritic pain " includes but is not limited to osteoarthritis, rheumatoid arthritis, arthrocleisis Property spondylitis, arthropathia psoriatica, gout, pseudogout, infectious arthritis, tendonitis, bursal synovitis, Bone destruction and joint are soft Pain caused by the diseases such as tissue inflammation.

As used herein, after " neuralgia after herpes zoster " refers to the fash healing of herpes zoster, in original fash area Subcutaneous long-standing severe pain.

As used herein, " nociceptive pain " is that the histologic lesion's process being passed to by stimulation nociceptor causes Pain, or as nociceptor extend excitement caused by pain.Ache caused by the excitement extended by nociceptor Pain can be due to the lasting destructive stimulus of nociceptor or it is sensitized or both causes jointly, or they can be by these Factor causes, and is extended by its persistence, various reflex mechanisms and other factors.

Pharmaceutical composition

The present invention provides the α 5-GABA containing therapeutically effective amount_AThe purposes of the medicine compound of inverse agonist.Although for this Invent the α 5-GABA for the treatment of_AInverse agonist can be administered in the form of starting compound, but preferably by active component, optionally In the form of physiologically acceptable salt, with one or more additives, excipient, carrier, buffer, diluent and/or its Its conventional excipient substance is mixed together into pharmaceutical composition.

In preferred embodiments, the present invention provides 5-GABA containing α_AThe pharmaceutical composition of inverse agonist, wherein α 5- GABA_AInverse agonist and one or more pharmaceutically acceptable carriers and optionally with it is other known in the art or make Curative and/or preventative component mixing.The carrier must be " acceptable ", i.e., with other compositions in preparation It is compatible and its recipient will not be harmful to.

Pharmaceutical composition for the present invention can be that those are suitable for oral, rectum, bronchus, nasal cavity, lung, part (including in cheek and sublingual), percutaneous, vagina or parenteral (including skin, subcutaneous, intramuscular, intraperitoneal, intravenous, intra-arterial, Intracerebral, intraocular injection or infusion) administration composition, or those to be in the form of being suitable for sucking or spray and be administered, including powder With the pharmaceutical composition of Liquid Aerosol administration or slow-released system administration.The example of suitable slow-released system is included containing the present invention The semi-permeable matrix of the solid hydrophobic polymers of compound, its mesostroma can be shaped article forms, such as film or micro- Capsule.

Therefore can will for the present invention compound with routine additive or diluent together be made pharmaceutical composition and The form of its unit dose.Such form includes solid (the especially shape of tablet, filling capsule, powder and pill Formula) and it is liquid (the especially aqueous solution or non-aqueous solution, suspension, emulsion, elixir) and the capsule of the above-mentioned form of filling, all The solution of the sterile injectable of the form of oral administration, the suppository of rectally and parenteral.Such medicine group Compound and its unit dosage form may include the conventional ingredient of conventional ratio, with or without other reactive compound or composition, This kind of unit dosage form can contain the active component of any suitable effective dose suitable with required daily application dose scope.

Compound for the present invention can be administered with various oral and parenteral formulations.The technology in field is said to this Following formulations can contain the compound of the invention or its pharmaceutically acceptable salt as active component for personnel.

For the compound for the present invention is made into pharmaceutical composition, pharmaceutically acceptable carrier can be solid or Liquid.The preparation of solid form includes powder, tablet, nine doses, capsule, cachet, suppository and dispersible granule.Gu Body carrier can be that one or more also play diluent, flavor enhancement, solubilizer, lubricant, suspending agent, adhesive, preservative, piece The material of agent disintegrant or encapsulated material effects.

In powder, carrier is the solid of subdivision, and it is mixed with the active component segmented.

In tablet, active component is mixed and is compressed into required in the proper ratio with the carrier with necessary bond properties Shapes and sizes.

Powder and tablet preferably contain 5% or 10% to about 70% reactive compound.Suitable carrier is magnesium carbonate, firmly Fatty acid magnesium, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, The wax of low melting point, cocoa butter etc..Terms " formulation " is included containing the reactive compound with the encapsulated material preparation as carrier, capsule Change material and capsule is provided, wherein the active component with or without carrier is surrounded by a carrier, so together with it.Similarly, Preparation includes cachet and lozenge (lozenges).Tablet, powder, capsule, pill, cachet and lozenge may be used as being suitable for The solid form of oral administration.

To prepare suppository, the wax of low melting point, such as the mud compound of fatty glyceride or cocoa butter are melted first, Ran Houtong Stirring is crossed to be evenly dispersed therein active component.Then the homogeneous mixture of the fusing is poured into appropriately sized mould, It is allowed to cool and thus solidifies.

The composition for being suitable for vagina administration can be with pessary, tampon, cream, gel, paste, foam or spraying The form of agent is present, and composition also contains suitable carrier known in the art in addition to containing active component.

Liquid preparation includes solution, suspension and emulsion, for example, the aqueous solution or water-propylene glycol solution.For example, parenteral Injecting fluid preparation can be configured to the solution of water-polyethylene glycol.

Thus be accordingly used in the compound of the present invention can be configured to be used for parenteral (such as to inject, such as bolus injection or company Continuous infusion) preparation, and can be with being present in ampoule, pre-filled injection together with the preservative of addition in the form of unit dose Device, small size infusion bag in or multi-dose container in.Said composition can take the suspension of oiliness or aqueous carrier, solution or The form of emulsion, and formulation ingredients can be contained, such as suspending agent, stabilizer and/or dispersant.In addition, active component can be powder Form, can be obtained by the solid sterile separation that sterilizes or by solution is lyophilized, for before use with suitable carrier it is for example sterile, Pyrogen-free water is rebuild.

The aqueous solution for being suitable for being administered orally can pass through the colouring agent needed for active component is dissolved in the water and added, tune It is prepared by taste agent, stabilizer and thickener.

The water slurry for being suitable for being administered orally can be such as natural by the way that the active component of subdivision is scattered in containing stickum Or the natural gum of synthesis, resin, methylcellulose, sodium carboxymethylcellulose or other well known suspending agent water in and prepare.

Also include to be converted into the solid pharmaceutical preparation designed for the liquid formulation of oral administration soon before use.It is this kind of Liquid preparation includes solution, suspension and emulsion.In addition to the active ingredient (s), this kind of preparation can contain colouring agent, flavor enhancement, stably Agent, buffer, artificial and natural sweetener, dispersant thickener, solubilizer etc..

In order to locally apply to epidermis, the compound of the present invention can be configured to ointment, cream or lotion or transdermal Patch.For example, ointment and cream can be prepared with the additional suitable thickener of water-based or oleaginous base and/or gelling agent and Into.Lotion can be formulated with water-based or oleaginous base, and generally also containing one or more emulsifying agents, stabilizer, dispersant, outstanding Floating agent, thickener or colouring agent.

Being suitable for the composition of oral cavity local medication, to be included in flavoured base be usually sucrose and acacin or western yellow alpine yarrow Lozenge (lozenges) in glue containing active component；Contain in inert matrix such as gelatin and glycerine or sucrose and acacin The lozenge (pastiIles) of active component；And the mouth-wash containing active component in suitable liquid-carrier.

Solution or suspension for example can be applied directly to nasal cavity with conventional method with dropper, suction pipe or sprayer.The group Compound can be the form of single dose or multiple dose.

Respiratory tract administration can also realize that wherein active component is mounted in pressurization together with suitable propellant by aerosol Packaging in, suitable propellant includes CFC (CFC) such as dicholorodifluoromethane, Arcton 11 or dichloro-tetrafluoro second Alkane, carbon dioxide or other suitable gases.Aerosol can also suitably contain surfactant, such as lecithin.The dosage of medicine Can the control of throughput valve.

Other active component can be the form of dry powder, such as compound and suitable powder base such as lactose, starch, starch The mixture of powders of derivative such as hydroxypropyl methyl cellulose and polyvinylpyrrolidone (PVP).Dust carrier can easily exist Gel is formed in nasal cavity.Powder composition can exist in the form of unit dose, such as be present in capsule or cartridge case (such as gelatin Glue fur coat or cartridge case) in, or be present in the blister package that powder can be administered through inhalator.

In for the composition of respiratory tract administration (including intranasal composition), usual compound has small grain Degree, for example, 5 microns or the more granularity of decimal magnitude.Such granularity can use methods known in the art, such as by micro- Efflorescence obtains.

When needing, the composition for being suitable to active component sustained release can be applied.

Pharmaceutical preparation is preferably unit dosage form.In this kind of form, preparation is subdivided into the list of appropriate amount active component Position dosage.Unit dosage form can be the preparation of encapsulation, wherein the piece of the big volume preparation containing separation in packing, such as encapsulation Agent, capsule and the powder being fitted into bottle or ampoule.In addition, unit dosage form can be capsule, tablet, flat fur coat agent or lozenge (lozenge) in itself, or can be the appropriate above-mentioned capsule of any packing forms, tablet etc..

Tablet for oral administration or capsule and liquid for intravenously administrable and continuous transfusion are preferable group Compound.

Can be in Remington's Pharmaceutical on the more detailed information of preparation and medicine-feeding technology Seen on Sciences (Remington pharmaceutical science) (Maack Publishing Co., Easton, PA) newest version.

The amount of active constituent can change according to the effect of specific application and active constituent in unit dose formulations, adjustable Section is from 0.01mg to about 0.1g.For example, in medical usage, the medicine can be with 0.01 to about 100mg capsule daily administration three Secondary, said composition can also contain other compatible therapeutic agents if necessary.

Treatment method

In therapeutical uses, the compound for the present invention is with the daily 0.001mg/kg of initial dose to 10mg/kg body weight. But these dosage can change according to the needs of patient, the seriousness of condition being treated and the compound that uses, typically For, start, to treat less than the smaller dose of the compound optimal dose, hereafter, to increase this dosage in a small amount and reach best effective Fruit, for the sake of convenient, total daily dose can be sub-divided into divided doses in one day if desired.

The pharmaceutical composition of the present invention can also treat pain, Alzheimer's, multi-infarct dementia with other simultaneously With the Drug combination of apoplexy, including but not limited to morphine, Gabapentin etc..Therefore, it is used to control the invention provides one kind The medicine of the medicine of pain, Alzheimer's, multi-infarct dementia and apoplexy is treated, the medicine is not only effective, and does not have Obvious side effect, it is a further object to provide one kind for especial patient colony, such as old man, with liver or kidney function Energy decline or the patient of cardiovascular disease, there is the medicine of tight security.

Embodiment

Synthetic route 1：

In A-1 (CAS：NaOH aqueous solvents 90607-22-0) are added in the tetrahydrofuran solution of (3.0g, 17.5mmol), often Temperature stirring 1 hour, TLC analytical reactions are finished, and reactant mixture is concentrated under reduced pressure, and add water dilution, and pH=2-3, second are adjusted with hydrochloric acid Acetoacetic ester extracts (25mLX6), and organic layer merges, and anhydrous sodium sulfate drying, evaporated under reduced pressure obtains 2.1 grams of yellow solid crude products, without Cross purifying and be directly entered and react in next step.Under 0 degree, previous step carboxylic acid compound (1.43g, 10mmol) and imidazoles (3.4g, TBSCl (2.25g, 120mmol) is added in DCM (50mL) solution 50mmol), natural temperature reaction is stayed overnight.TLC shows raw material Disappear, reaction solution is concentrated under reduced pressure, and residue is dissolved in ethyl acetate, and washing, anhydrous sodium sulfate drying, evaporated under reduced pressure obtains 2.2 grams of Huangs Color solid A-2.

Zero degree is cooled in ice bath, argon gas protection is lower to add BOP-Cl (2.79g, 11mmol), and stirring adds after 20 minutes A-2 (1.8g, 9mmol), then add A-3 (bibliography：US6630471) natural temperature reaction is stayed overnight.TLC displays have been reacted Finish, reaction solution is concentrated under reduced pressure, and residue is dissolved in ethyl acetate, and washing, anhydrous sodium sulfate drying, evaporated under reduced pressure obtains 3.56 grams of yellow Solid A-4, yield 90%.

The mixture of A-4 (10.5g, 23.8mmol) and diphenyl ether is heated to 150 degree and reacted 1 hour, TLC (PE:EA=2: 1) display reaction finishes, and crosses silicagel column and purifies to obtain 0.95 gram of yellow solid A-5, yield 10%.

Under zero degree, NaH (252mg, 6.3mmol) is added into A-5 (700mg, 4.2mmol) THF (50mL) solution. After argon gas protection stirring 15min, A-6 (CAS:56026-36-9) (900mg, 2.1mmol) is added in reaction solution above, room Temperature stirring 1.5h, TLC (PE:EA=2:1) it is anti-in next step not carry out purifying directly progress for monitoring reaction raw materials disappearance crude products Should.Aq.NaOH (0.84g in 10mL water) is forwardly added in reaction solution, after reacting 4h, TLC (PE:EtOAc=5:1, Rf=0.01 raw material disappearance) is monitored.Residue watery hydrochloric acid adjusts pH 2-3 after reactant mixture is concentrated under reduced pressure, and separates out solid filtering 0.6g yellow solids A-7 is obtained after drying.

Embodiment 1

6- ((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazines - 6- yls) epoxide) methyl)-N- morpholinoes niacinamide (01)

The addition HOBt (32mg, 0.24mmol) in 25mL single port bottles, EDCI (46mg, 0.24mmol), A-7 (50mg, 0.12mmol) and DMF (2mL), stirring and dissolving, argon gas protect lower addition N- amino-morpholines (CAS:4319-49-7) and DIPEA, Stirring at normal temperature is stayed overnight, and TLC shows that reaction finishes, and adds 25 milliliters of dchloromethanes, is washed three times, anhydrous sodium sulfate drying, Evaporated under reduced pressure, prepare silica gel plate and purify to obtain 16 milligrams of yellow solids, yield 29%.

¹H NMR(DMSO,400MHz,ppm):δ 9.71 (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]⁺。

Embodiment 2

(R)-N- (1- hydroxyl normal propyl alcohol -2- bases) 6- ((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases) - [1,2,4] triazol [4,3-b] pyridazine -6- bases) epoxide) methyl) niacinamide (02)

Experimental implementation is as described in Example 1：Intermediate A -7 and (R) -2- amino normal propyl alcohols (CAS：2799-16-8) it is condensed Reaction obtains target compound 68mg, yield 40%, and outward appearance is faint yellow solid.

¹H NMR(DMSO,400MHz,ppm):δ 9.04 (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 C₂₃H₂₇N₇O₅ 482[M+1]⁺。

Embodiment 3

N- ((1S, 2S) -2- hydroxycyclopents base) -6- ((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases) - [1,2,4] triazol [4,3-b] pyridazine -6- bases) epoxide) methyl) niacinamide (03)

Experimental implementation is as described in Example 1：Intermediate A -7 and trans-(1S, 2S) -2- amino-cyclopentanol hydrochlorides (CAS：68327-04-8) condensation reaction obtains compound 68mg, yield 40%, and outward appearance is white solid.

¹H NMR(DMSO,400MHz,ppm):δ 9.02 (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]⁺。

Embodiment 4

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazines - 6- yls) epoxide) methyl)-N- cyclopropyl niacinamide (04)

Experimental implementation is as described in Example 1：Intermediate A -7 and cyclopropylamine (CAS：765-30-0) condensation reaction obtains 16 milligrams Yellow solid, yield 29%.

¹H NMR(DMSO,400MHz,ppm):δ 8.98 (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]⁺。

Embodiment 5

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazines - 6- yls) epoxide) methyl)-N- (1- methyl isophthalic acid H- pyrazoles -4- bases) niacinamide (05)

Experimental implementation is as described in Example 1：Intermediate A -7 and 1- methyl isophthalic acid H- pyrazoles -4- amine (CAS：69843-13-6) Condensation reaction obtains 12 milligrams of yellow solids, yield 22%.

¹H NMR(DMSO,400MHz,ppm):δ 10.63 (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]⁺。

Embodiment 6

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine 6- yls) epoxide) methyl)-N- isopropyinicotinamides (06)

Experimental implementation is as described in Example 1：Intermediate A -7 and isopropylamine (CAS：75-31-0) condensation reaction obtains 10 milligrams Yellow solid, yield 18%.

¹H NMR(DMSO,400MHz,ppm):δ 9.01 (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]⁺。

Embodiment 7

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridines - 6- yls) epoxide) methyl)-N- (2- hydroxyethyls) niacinamide (07)

Experimental implementation is as described in Example 1：Intermediate A -7 and monoethanolamine (CAS：141-43-5) condensation reaction obtains 10 milligrams Yellow solid, yield 18%.

¹H NMR(DMSO,400MHz,ppm):δ 9.04 (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]⁺。

Embodiment 8

(6- (((rattle away by 7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] Piperazine -6- bases) epoxide) methyl) pyridin-3-yl) (1,1- dioxide thiomorpholine generations) ketone (08)

Experimental implementation is as described in Example 1：Intermediate A -7 and thiomorpholine 1,1- dioxide. HCls (CAS: 59801-62-6) condensation reaction obtains 12 milligrams of yellow solids, yield 22%.

¹H NMR(DMSO,400MHz,ppm):δ 8.76 (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]⁺。

Embodiment 9

(6- (((rattle away by 7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] Piperazine -6- bases) epoxide) methyl) pyridin-3-yl) (morpholino) ketone (09)

Experimental implementation is as described in Example 1：Intermediate A -7 and morpholine (CAS:110-91-8) condensation reaction obtains 14 milligrams of Huangs Color solid, yield 25%.

¹H NMR(DMSO,400MHz,ppm):δ 8.67 (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]⁺。

Embodiment 10

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazines - 6- yls) epoxide) methyl)-N- (2,2,2- trifluoroethyls) niacinamide (10)

Experimental implementation is as described in Example 1：Intermediate A -7 and 2,2,2- trifluoroethylamine hydrochlorides (CAS:373-88-6) contract 11 milligrams of yellow solids, yield 20% are reacted to obtain in conjunction.

¹H NMR(CDCl3,400MHz,ppm):δ 9.05 (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]⁺。

Embodiment 11

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazines - 6- yls) oxygen) methyl)-N- (2- methox-etlayls) niacinamide (11)

Experimental implementation is as described in Example 1：Intermediate A -7 and 2- methoxyethyl amines (CAS:109-85-3) condensation reaction obtains 11 milligrams of yellow solids, yield 20%.

¹H NMR(DMSO,400MHz,ppm):δ 9.03 (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 C₂₃H₂₇N₇O₅ 482[M+1]⁺。

Embodiment 12

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazines - 6- yls) epoxide) methyl)-N- (tetrahydrochysene -2H- pyrans -4- bases) niacinamide (12)

Experimental implementation is as described in Example 1：Intermediate A -7 and 4- amino tetrahydro pyran hydrochloric acid (CAS:33024-60-1) contract 21 milligrams of yellow solids, yield 38% are reacted to obtain in conjunction.

¹H NMR(DMSO,400MHz,ppm):δ 9.02 (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]⁺。

Embodiment 13

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazines - 6- yls) epoxide) methyl)-N, N- dimethyl nicotinamides (13)

Experimental implementation is as described in Example 1：Intermediate A -7 and dimethylamine hydrochloride (CAS:506-59-2) condensation reaction obtains 15 Milligram yellow solid, yield 27%.

¹H NMR(DMSO,400MHz,ppm):δ 8.66 (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]⁺。

Embodiment 14

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazines - 6- yls) epoxide) methyl)-N- (tetrahydrofuran -3- bases) niacinamide (14)

Intermediate A -7 and 3- amido tetrahydrofuran hydrochlorides (CAS:204512-94-7) condensation reaction obtains 14 milligrams of yellow Solid, yield 25%.

¹H NMR(DMSO,400MHz,ppm):δ 9.03 (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]⁺。

Embodiment 15

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazines - 6- yls) epoxide) methyl)-N- cyclobutyl niacinamide (15)

Experimental implementation is as described in Example 1：Intermediate A -7 and cyclobutyl amine (CAS:2516-34-9) condensation reaction obtains 13 Milligram yellow solid, yield 24%.

¹H NMR(DMSO,400MHz,ppm):δ 9.01 (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]⁺。

Embodiment 16

Azetidine -1- bases (6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] three Azoles simultaneously [4,3-b] pyridazine -6- bases) epoxide) methyl) pyridin-3-yl) ketone (16)

Experimental implementation is as described in Example 1：Intermediate A -7 and heterocyclic butane (CAS:503-29-7) condensation reaction obtains 14 Milligram yellow solid, yield 25%.

¹H NMR(DMSO,400MHz,ppm):δ 8.83 (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]⁺。

Embodiment 17

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazines - 6- yls) epoxide) methyl) nicotinic acid hydrazide (17)

Experimental implementation is as described in Example 1：Intermediate A -7 and tert-butyl carbazate (CAS:870-46-2) condensation reaction After take off Boc and obtain 10 milligrams of yellow solids, yield 18%.

¹H NMR(DMSO,400MHz,ppm):δ 9.97 (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]⁺。

Embodiment 18

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazines - 6- yls) oxygen) methyl)-N- (pyrrolidin-1-yl) niacinamide (18)

Experimental implementation is as described in Example 1：Intermediate A -7 and N- amino-pyrrolidines (CAS:16596-41-1) condensation reaction Obtain 2 milligrams of yellow solids, yield 4%.

¹H NMR(DMSO,400MHz,ppm):δ 8.76 (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]⁺。

Embodiment 19

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazines - 6- yls) epoxide) methyl)-N- (piperidin-1-yl) niacinamide (19)

Experimental implementation is as described in Example 1：Intermediate A -7 and N- amido piperidine hydrochlorates (CAS:63234-70-8) it is condensed React to obtain 10 milligrams of yellow solids, yield 18%.

¹H NMR(DMSO,400MHz,ppm):δ 9.59 (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]⁺。

Embodiment 21

(6- (((rattle away by 7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] Piperazine -6- bases) epoxide) methyl) pyridin-3-yl) (pyrrolidin-1-yl) ketone (21)

Experimental implementation is as described in Example 1：Intermediate A -7 and nafoxidine (CAS:123-75-1) condensation reaction obtains 14 millis Gram yellow solid, yield 25%.

¹H NMR(DMSO,400MHz,ppm):δ 8.76 (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]⁺。

Embodiment 22

6- (((7- (tert-butyl group) -3- (5- (hydroxymethyl) isoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazines - 6- yls) epoxide) methyl)-N-ethylnicotinamide (22)

Experimental implementation is as described in Example 1：Intermediate A -7 and ethylamine hydrochloride (CAS:557-66-4) condensation reaction obtains 20 Milligram yellow solid, yield 35%.

¹H NMR(DMSO,400MHz,ppm):δ 9.02 (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]⁺。

Synthetic route 2

Experimentation:

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-nicotinic acid (B3)

By B2 6- methylol methyl nicotinates (CAS:56026-36-9) (2.35g, 14.1mmol) is dissolved in 280 milliliters In anhydrous THF, argon gas protection, ice bath is cooled to 0 DEG C, adds sodium tert-butoxide (1.81g, 18.8mmol) and stirs 15 minutes, then adds Enter B1 (2.74g, 9.4mmol) (preparing synthesized reference patent US6297235B1), finish and continue ice bath one and a half hours, TLC (PE:EA=1:1) reaction is complete, it is not necessary to handles, directly casts single step reaction.Upper step reaction solution is added into NaOH solution (1.13g in 10mL water), reactant mixture is stirred at room temperature 16 hours, TLC (DCM:MeOH=20:1, Rf=0.2) Show that raw material reaction is complete, reactant mixture, which is depressurized, to be evaporated, and residue adds appropriate water to dissolve, and pH value is being adjusted to 2 with concentrated hydrochloric acid ~3, there is solid precipitation, filter, washing, dry yellow solid 1.6g, yield 41.7%.

Embodiment 23

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N- morpholines -4- bases-niacinamide (23)

Experimental implementation is as described in Example 1：Intermediate B 3 and N- amino-morpholines (CAS:4319-49-7) used after condensation reaction Prepare silica gel plate and purify to obtain 16.8 milligrams of off-white powders, yield 7%.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]⁺。

Embodiment 24

(R)-N- (1- hydroxyl normal propyl alcohol -2- bases) 6- ((7- (tert-butyl group) -3- (5- methylisoxazole -3- bases)-[1,2,4] Triazol [4,3-b] pyridazine -6- bases) epoxide) niacinamide (24)

Experimental implementation is as described in Example 1：Intermediate B 3 and (R) -2- amino normal propyl alcohols (CAS：2799-16-8) condensation is anti- 15.4 milligrams of off-white powders, yield 13.5% should be obtained.

¹H NMR(DMSO,400MHz,ppm):δ 9.03 (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]⁺。

Embodiment 25

N- ((1S, 2S) -2- hydroxycyclopents base) -6- ((7- (tert-butyl group) -3- (5- methylisoxazole -3- bases)-[1,2,4] Triazol [4,3-b] pyridazine -6- bases) epoxide) niacinamide (25)

Experimental implementation is as described in Example 1：Intermediate B 3 and trans-(1S, 2S) -2- amino-cyclopentanol hydrochlorides (CAS： 68327-04-8) condensation reaction obtains 52mg white solids, yield 43.3%.

¹H NMR(DMSO,400MHz,ppm):δ 9.02 (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]⁺。

Embodiment 26

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N- cyclopropyl niacinamide (26)

Experimental implementation is as described in Example 1：Intermediate B 3 and cyclopropylamine (CAS：765-30-0) condensation reaction obtains 26mg (23.8%).

¹H NMR(DMSO,400MHz,ppm):δ 8.99 (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]⁺。

Embodiment 27

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N- isopropyinicotinamides (27)

Experimental implementation is as described in Example 1：Intermediate B 3 and isopropylamine (CAS：75-31-0) it is solid to obtain white for condensation reaction Body 29.8mg (27.1%).

¹H NMR(DMSO,400MHz,ppm):δ 9.02 (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]⁺。

Embodiment 29

(6- (((7- (tert-butyl group) -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridine -6- bases) Epoxide) methyl) pyridazine -3- bases) (1,1- dioxide thiomorpholine generations) ketone (29)

Experimental implementation is as described in Example 1：Intermediate B 3 and thiomorpholine 1,1- dioxide. HCls (CAS:59801- 62-6) condensation reaction obtains 20mg solids (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]⁺。

Embodiment 30

{ 6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- base epoxides Methyl]-pyridin-3-yl }-morpholine -4- bases-ketone (30)

Experimental implementation is as described in Example 1：Intermediate B 3 and morpholine (CAS:110-91-8) it is solid to obtain white for condensation reaction Body 66mg (56.6%).

¹H NMR(DMSO,400MHz,ppm):δ 8.68 (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]⁺。

Embodiment 31

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N- Cvclopropvlmethvls niacinamide (31)

Experimental implementation is as described in Example 1：Intermediate B 3 and cyclopropylmethylamine (CAS:2516-47-4) condensation reaction obtains Obtain white solid 51mg (45.2%).

¹H NMR(DMSO,400MHz,ppm):δ 9.04 (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]⁺。

Embodiment 32

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N- (2,2,2- trifluoro ethyls)-niacinamide (32)

Experimental implementation is as described in Example 1：Intermediate B 3 and 2,2,2- trifluoroethylamine hydrochlorides (CAS:373-88-6) contract Close reaction and obtain white solid 48mg (40.1%).

¹H NMR(DMSO,400MHz,ppm):δ 9.34 (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]⁺。

Embodiment 33

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N- (2- methox-etlayls)-niacinamide (33)

Experimental implementation is as described in Example 1：Intermediate B 3 and 2- methoxyethyl amines (CAS:109-85-3) condensation reaction obtains To off-white powder 13mg (11.4%).

¹H NMR(DMSO,400MHz,ppm):δ 9.04 (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 ]⁺。

Embodiment 35

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N- (2- hydroxyl -1,1- dimethyl-ethyIs)-niacinamide (35)

Experimental implementation is as described in Example 1：Intermediate B 3 and 2-amino-2-methyl-1-propanol (CAS:124-68-5) contract Close reaction and obtain white solid 48mg (41%).

¹H NMR(DMSO,400MHz,ppm):δ 9.05 (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]⁺。

Embodiment 36

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N- (1- methylols-butyl)-niacinamide (36)

Experimental implementation is as described in Example 1：Intermediate B 3 and 2- amino fourth propyl alcohol (CAS:96-20-8) condensation reaction obtains Off-white powder 48.8mg (41.7%).

¹H NMR(DMSO,400MHz,ppm):δ 9.04 (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]⁺。

Embodiment 37

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N- (ttetrahydro-pyran -4- bases)-niacinamide (37)

Experimental implementation is as described in Example 1：Intermediate B 3 and 4- amino tetrahydro pyran hydrochloric acid (CAS:33024-60-1) contract Close reaction and obtain off-white powder 56mg (46.7%).

¹H NMR(DMSO,400MHz,ppm):δ 9.03 (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]⁺。

Embodiment 38

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N, N- dimethyl nicotinamides (38)

Experimental implementation is as described in Example 1：Intermediate B 3 and dimethylamine hydrochloride (CAS:506-59-2) condensation reaction obtains Off-white powder 18mg (16.9%).

¹H NMR(DMSO,400MHz,ppm):δ 8.67 (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]⁺。

Embodiment 39

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N- (tetrahydrofuran -3- bases)-niacinamide (39)

Experimental implementation is as described in Example 1：Intermediate B 3 and 3- amido tetrahydrofuran hydrochlorides (CAS:204512-94-7) Condensation reaction obtains white solid 61mg (52.3%).

¹H NMR(DMSO,400MHz,ppm):δ 9.03 (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]⁺。

Embodiment 40

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N- cyclobutyl niacinamide (40)

Experimental implementation is as described in Example 1：Intermediate B 3 and cyclobutyl amine (CAS:2516-34-9) condensation reaction obtains class White solid 33.8mg (30%).

¹H NMR(DMSO,400MHz,ppm):δ 9.02 (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]⁺。

Embodiment 41

Azetidine -1- bases-{ 6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3- B] pyridazine -6- base epoxides methyl]-pyridin-3-yl }-ketone (41)

Experimental implementation is as described in Example 1：Intermediate B 3 and heterocyclic butane (CAS:503-29-7) condensation reaction obtains White solid 27mg (24.7%).

¹H NMR(DMSO,400MHz,ppm):δ 8.84 (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 C₂₃H₂₅N₇O₃ 448[M+1]⁺。

Embodiment 42

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N- ethyls-niacinamide (42)

Experimental implementation is as described in Example 1：Intermediate B 3 and ethylamine hydrochloride (CAS:557-66-4) condensation reaction obtains Off-white powder 21.6mg (20.3%).

¹H NMR(DMSO,400MHz,ppm):δ 9.02 (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 C₂₂H₂₅N₇O₃ 436[M+1]⁺。

Embodiment 43

6- [the 7- tert-butyl groups -3- (5- methylisoxazole -3- bases)-[1,2,4] triazol [4,3-b] pyridazine -6- Ji Yangjijia Base]-N- piperidin-1-yls-niacinamide (43)

Experimental implementation is as described in Example 1：Intermediate B 3 and N- amido piperidine hydrochlorates (CAS:63234-70-8) it is condensed Reaction obtains white solid 37mg (15.4%).

¹H NMR(DMSO,400MHz,ppm):δ 9.59 (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]⁺。

Biological experimental method：

Recent study result shows, GABA_AReceptor-mediated at least two kinds of suppression modes, catatonic type suppress (tonic Inhibition) and when facies pattern suppress (phasic inhibition).When GABA is with mM level concentration increase, GABA_ABy The rapid desensibilization of body, facies pattern suppresses during formation.When GABA is with hundreds of nanomoles to tens micromolar concentration activation GABA_AAcceptor When, the extrasynaptic GABA of high-affinity_AReceptor-mediated catatonic type suppression, adjust nerve excitability and signal transmission. (Farrant M et al.(2005)Variations on an inhibitory theme:phasic and tonic activation of GABA(A)receptors.Nat Rev Neurosci 6:215–229Y).Yeung JY et al are draped over one's shoulders The GABA of dew low concentration is more easy to activate α 5-GABA_AAcceptor (Yeung JY et al (2003) .Tonically activated GABA_A receptors in hippocampal neurons are high-affinity,low-conductance sensors for extracellular GABA.Mol Pharmacol；63:2–8).K.Y.LEE etc. is reported in culture 24 Low concentration GABA activation is detected on DRGs (Dorsal root ganglia, DRG) cell of the separation of hour The GABA of sustained_AElectric current, the GABA of the sustained of 20 μM of GABA activation_AElectric current is of about 100pA/pF.(Lee KY et al.Upregulation of high-affinity GABA(A)receptors in cultured rat dorsal root ganglion neurons.Neuroscience 208(2012)133–142)。

MRK016 is representative α 5-GABA_AAcceptor is completely reversed activator (full inverse agonist).Existing literature (CN103239720A) shows MRK016 α 5-GABA_AReceptor inverse excitement efficiency is higher than α 5IA.

Cell-based screening

The present inventor detects the reverse excitement efficiency of test substance by the method for electro physiology.Specific method is as follows:

1) by GABA_AThe different subunit expressions of acceptor are in cell line, predominantly in human embryonic kidney cell line (HEK293).Will The cell culture is in culture medium, the cell model using this kind of cell as the medicine for screening inhibition of pain.α subunits, β Subunit and γ subunits are to forming a complete functional form GABA_AAcceptor is essential.In this embodiment, the present inventor Establish following cell model：(a) with Alpha 5 subunit (protein sequence is shown in GenBank accession number NP_001158509), the subunit (eggs of β 3 Bai Xulie is shown in GenBank accession number NP_068712) and the subunits of γ 2 (protein sequence is shown in GenBank accession number：NP_944494 it is) same When expression in HEK293 cell lines, form 5-GABA containing α_AThe acceptor with complete function.

2) cell is the γ 3-GABA of 5 β of express alpha 2 of green fluorescent protein (GFP) mark_A293 cells of acceptor surely turn strain. 293 cell culture treat that cell grows to 80%-90% and passed on 10cm culture dishes.During passage, culture medium is first siphoned away, so Afterwards by 3mL DMEM culture mediums (Gibco^TM) add in culture dish, by culture dish slight wobble, then suck DMEM.Add 3mL pancreases Enzyme (Trypsin-EDTA 0.05%, Gibco^TM), digested 3 minutes at 37 DEG C.Then 3mL complete mediums (DMEM+ is added 10%horse serum (Gibco^TM)) dispel the cell of culture dish bottom surface, it is transferred to 15mL centrifuge tubes 200g is centrifuged 3 minutes.Supernatant is abandoned, 4mL complete mediums is added, gently blows and beats, cell is resuspended standby.Such as carry out cell Passage, cell suspension is pressed 1:5 or 1:10 dilution proportion.Electro physiology cell is such as prepared, by cell suspension according to 1:12 After dilution proportion, add and be placed with advance with 24 porose discs of the Poly-D-Lysine slides treatedIn, treat thin Tested after born of the same parents are adherent.Electro physiology is no more than 24 hours with the cell culture time.

3) drug concentration is set：The medicine final concentration that drug screening uses is 100nM, and GABA concentration ranges are 0.05~ 0.1μM.Medicine final concentration of 1nM, 10nM, 50nM, 100nM and the 1000nM that dosage-reverse excitement efficiency (%) experiment uses. Electrophysiologic testing uses whole-cell patch-clamp recording technique, and this method can refer to document (I.Lecker, Y.Yin, D.S.Wang and B.A.Orser,(2013)Potentiation of GABA_A receptor activity by volatile anaesthetics is reduced byα5-GABA_A receptor-preferring inverse agonists, British Journal of Anaesthesia 110(S1):I73-i81) report method.Electro physiology extracellular fluid into Divide as follows：150mM NaCl, 5mM KCl, 2.5mM CaCl₂, 1mM MgCl₂, 10mM HEPES and 10mM glucose (use NaOH adjusts pH to 7.4, and osmotic pressure is 320-330mOsm).Formula of liquid is as follows in electro physiology electrode：140mM CsCl, 10mM HEPES, 11mM EGTA, 2mM MgCl₂,1mM CaCl₂, 4mM MgATP, 2mM TEA, (adjust pH to 7.4, infiltration with CsOH Press as 285-295mOsm).Signal acquisition uses the amplifiers of EPC 10 and PatchMaster softwares (HEKA).Recording electrode makes With borosilicate (borosilicate) glass-pulling, electrode resistance is 5~6M Ω.Extracellular administration uses OCTAFLOW II^TMSystem System.During record, choose that GFP is positive and the cell of single independent growths.In recording process, cell membrane potential is clamped at -60mV. During experiment, first in the extracellular extracellular fluid for applying about 20 seconds.After baseline stability, extracellular fluid is switched into GABA.At this point it is possible to Detect electric current caused by GABA.About 20~40 seconds, after electric current is stable, extracellular fluid is switched into corresponding drug solution, Detect the effect of medicine.Finally, solution is switched into extracellular fluid, treats that baseline is returned to horizontal end experiment before administration.Only The data that baseline can reply can just do subsequent analysis.GABA is diluted in extracellular fluid according to 0.05~0.1 μM of final concentration In.Then, by medicine according to required concentration dilution into the extracellular fluid containing GABA.

4) analysis of experimental result uses PatchMaster softwares.During analysis, GABA electric currents before dosing are measured respectively (Ipre) GABA electric currents (Ipost) and after dosing, effect of drugs is calculated by below equation：Reverse excitement efficiency (%)= (Ipost–Ipre)*100/Ipre.N is test number (TN).

5) the selection result of compound:

MRK016 reverse excitement efficiency is -7.75% (N=6).

By result above it can be found that the compound biology effect of the present invention is substantially better than conventional α 5-GABA_AAcceptor Inverse agonist, and because the compound of the present invention is not easily accessible brain, conventional α 5-GABA will not be produced_AReceptor inverse excitement Issuable frightened and anxiety the side effect of agent.

Claims

1. the compound shown in a kind of Formulas I, its cis-trans-isomer, enantiomter, diastereoisomer, racemic modification, solvent Compound, hydrate or its pharmaceutically acceptable salt and ester,

Wherein

Z represents that containing 1,2 or 3 heteroatomic 5 yuan of hetero-aromatic ring for being independently selected from oxygen, nitrogen and sulphur 5 yuan of hetero-aromatic rings are by one Or multiple optionally substitute selected from following substituent：Hydroxyl, halogen ,-R1 ,-OR1 ,-OC (O) R1 ,-NR2R3, CN, cyano group (C1- 6) alkyl-and R2；

R1 represents C1-6 alkyl, C2-6 alkenyls, C2-6 alkynyls, C3-6 cycloalkyl, C3-6 cycloalkyl (C1-6) alkyl, cyano group (C1-6) the C1-6 alkyl of alkyl, hydroxyl or amino substitution, and R1 is optionally one, two or three fluoro；

R2 or R3 independently is hydrogen, C1-6 alkyl, C2-6 alkenyls, C2-6 alkynyls, C3-6 cycloalkyl or CF3, or R2 and R3 with The nitrogen-atoms that they are connected jointly forms the miscellaneous cycloaliphatic ring of 4-7 members together, and the miscellaneous cycloaliphatic ring contains the nitrogen-atoms and one optional From O, N and S other hetero atoms, the miscellaneous cycloaliphatic ring is optionally optionally substituted by one or more R1 groups；

Preferably Z is represented containing 1,2 or 3 heteroatomic 5 yuan of hetero-aromatic ring for being independently selected from oxygen, nitrogen and sulphur, wherein be up to 1 Hetero atom is oxygen or sulphur, and when 1 hetero atom is nitrogen-atoms, at least there is also 1 oxygen or sulphur atom, 5 yuan of heteroaryls Ring is optionally substituted by one or more selected from following substituent：C1-C4 alkyl, what hydroxyl, halogen, hydroxyl or amino substituted C1-C4 alkyl, C2-C4 alkenyls, C2-C4 alkynyls and C1-C4 alkoxies；

More preferably Z is represented containing 2 heteroatomic 5 yuan of hetero-aromatic rings for being independently selected from oxygen, nitrogen and sulphur, and a hetero atom is Oxygen or sulphur, another atom are nitrogen, and 5 yuan of hetero-aromatic rings are optionally substituted by one or more selected from following substituent：C1-6 Alkyl and hydroxyl C1-6 alkyl；

Most preferably Z expression oxa-s ribavirin, furyl, thienyl Huo isoxazolyls, the isoxazolyl are one or more Optionally substitute selected from following substituent：H, C1-6 alkyl or hydroxyl C1-6 alkyl；

A is-NR2-；Or A is to contain 1,2,3 or 4 heteroatomic 5 yuan of heteroarylidene for being independently selected from oxygen, nitrogen and sulphur and miscellaneous original It is oxygen or sulphur to be up to 1 in son；Or be 6 yuan of heteroarylidenes containing 1,2 or 3 nitrogen-atoms, or 5 or 6 yuan of miscellaneous sub- virtues Base is also optionally condensed on phenyl ring or pyridine ring, and 5 or 6 yuan of heteroarylidenes are 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 be halogen ,- R1 ,-OR1 ,-OC (O) R1 ,-NR2R3 ,-NR2C (O) R3 or CN, Rz are-R1 ,-OR1 or-OC (O) R1, on condition that when A is pyrrole During piperidine derivatives, the pyridine ring is optionally N- oxide forms；Or A optionally takes to be independently selected from following group by 1,2 or 3 The phenylene in generation：Halogen, cyano group, C1-6 alkyl, C2-6 alkenyls, C2-6 alkynyls and C3-6 cycloalkyl；

Preferably A is expressed as containing in 1,2 or 3 heteroatomic 5 yuan of heteroarylidene for being independently selected from oxygen, nitrogen and sulphur and hetero atom Be up to 1 is oxygen or sulphur, or 6 yuan of heteroarylidenes or phenylene containing 1,2 or 3 nitrogen-atoms, 5 yuan of heteroarylidenes, 6 First heteroarylidene and phenylene are optionally independently selected from following substituent and substituted：Halogen, cyano group and C1-6 alkyl；

More preferably A represents phenylene, sub- pyridine radicals, Ya isoxazolyls, is optionally independently selected from following take by 1,2 or 3 Substitute for base：Halogen, cyano group and C1-6 alkyl；

Y is-NY1Y2 or-NH-NY3Y4；

Y1 is selected from：H；C1-6 alkyl；The C1-6 alkyl substituted by 1-5 substituent, the substituent independently selected from：Amino, Halogen, halo-C1-6 alkoxies, hydroxyl, C1-6 alkoxies, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitre Base and C1-6 alkyl-S (O)₂-；

Y2 is selected from：H；C1-6 alkyl；The C1-6 alkyl substituted by 1-5 substituent, the substituent independently selected from：Amino, Halogen, halo-C1-6 alkoxies, hydroxyl, C1-6 alkoxies, cycloalkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O)₂-；

Heteroaryl, or the heteroaryl substituted by 1-4 substituent, the substituent of the heteroaryl independently selected from：Acetamido, Acetyl group, acetyl-amino, acylamino-, amino, carboxyl, cyano group, halogen, halo-C1-6 alkoxies, halo-C1-6 alkyl, hydroxyl Base, hydroxyl-C1-6 alkyl, C1-6 alkoxies, C1-6 alkoxy -C 1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O)₂-；

Cycloalkyl, or the cycloalkyl substituted by 1-4 substituent, described substituent independently selected from：Acetamido, acetyl Base, acetyl-amino, acylamino-, amino, carboxyl, cyano group, halogen, halo-C1-6 alkoxies, halo-C1-6 alkyl, hydroxyl, Hydroxyl-C1-6 alkyl, C1-6 alkoxies, C1-6 alkoxy -C 1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O)₂-；

Heterocyclic radical, or the Heterocyclylalkyl substituted by 1-4 substituent, the substituent independently selected from：Acetamido, acetyl Base, acetyl-amino, acylamino-, amino, carboxyl, cyano group, halogen, halo-C1-6 alkoxies, halo-C1-6 alkyl, hydroxyl, Hydroxyl-C1-6 alkyl, C1-6 alkoxies, C1-6 alkoxy -C 1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O)₂-；

Or Y1, Y2 form cycloalkyl together with the N atoms that they are connected；

Y3, Y4 are selected from independently of each other：Hydrogen, C1-C6 alkyl, SO₂- C1-C6 alkyl, cycloalkyl and heterocyclic radical, optionally by 1-4 solely The vertical substituent selected from following groups substitutes：Halogen, cyano group, hydroxyl, C1-C6 alkyl and C1-C6 alkoxies,

Or wherein Y3, Y4 form heterocyclic radical together with the nitrogen-atoms that they are connected, the heterocyclic radical is optionally by 1-4 independent choosing Substitute from the substituent of following groups：Halogen, cyano group, hydroxyl, oxo, C1-C6 alkyl and C1-C6 alkoxies.

2. compound as claimed in claim 1, it has below general formula II:

Wherein

R4 is the C1-C4 alkyl that C1-C4 alkyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H, and C1-6 alkyl or the C1-6 alkyl substituted by 1-5 substituent, the substituent are individually selected from：Amino, hydroxyl Base, C1-6 alkoxies, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S (O)₂-；

Y2 is selected from C1-6 alkyl；The C1-6 alkyl substituted by 1-5 substituent, the substituent are individually selected from：Amino, halogen Element, hydroxyl, methyl, C1-6 alkoxies, cycloalkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkane Base-S (O)₂-；

Contain the 1-3 heteroatomic C5-C6 heteroaryls for being selected from N, O or S；N, O are selected from containing 1-3 by C1-6 is alkyl-substituted Or S heteroatomic C5-C6 heteroaryls；

C3-6 cycloalkyl；The C3-6 cycloalkyl substituted by 1-4 substituent, the substituent are individually selected from：Amino, hydroxyl, Hydroxyl-C1-6 alkyl, C1-6 alkoxies, C1-6 alkoxy -C 1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S (O)₂-；

Contain the 1-3 heteroatomic C4-C6 heterocyclic radicals for being selected from N, O or S；It is selected from by what 1-4 substituent substituted containing 1-3 N, O or S heteroatomic C4-C6 heterocyclic radicals, the substituent are individually selected from：Methyl, amino, hydroxyl, hydroxyl-C1-6 alkane Base, C1-6 alkoxies, C1-6 alkoxy -C 1-6 alkyl, C1-6 alkyl and C1-6 alkyl-S (O)₂-；

Or Y1, Y2 form cycloalkyl together with the N atoms that they are connected；

Y3, Y4 are selected from independently of each other：Hydrogen, C1-C6 alkyl and SO₂- C1-C6 alkyl, or Y3 and Y4 and their nitrogen for being connected it is former Son forms heterocyclic radical together.

3. compound as claimed in claim 2, it is characterised in that R4 is the methyl that methyl or hydroxyl substitute.

4. compound as claimed in claim 2, it has below general formula II:

Wherein

R4 is the C1-C4 alkyl that C1-C4 alkyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H or C1-6 alkyl；

Y2 is selected from C1-6 alkyl；The C1-6 alkyl substituted by 1-5 substituent, the substituent are individually selected from：Hydroxyl, halogen Element, C1-6 alkoxies, cycloalkyl and methyl；

Contain the 1-3 heteroatomic C4-C6 Heterocyclylalkyls for being selected from N, O or S；Selected by what 1-4 substituent substituted containing 1-3 From N, O or S heteroatomic C4-C6 Heterocyclylalkyls, the substituent is methyl；

Or Y1, Y2 form 4-6 circle heterocycles bases together with the N atoms that they are connected, the heterocyclic radical is except containing nitrogen-atoms Outside, also containing zero, one or more hetero atoms for being selected from O and S, and the S atom can be its oxide form；

Or Y1, Y2 form cycloalkyl together with the N atoms that they are connected；

5. compound as claimed in claim 4, it is characterised in that R4 is the methyl that methyl or hydroxyl substitute.

6. the compound as any one of claim 2 to 5, it is characterised in that Y1 is H or methyl.

7. compound as claimed in claim 2, it has below general formula II:

R4 is the C1-C4 alkyl that C1-C4 alkyl or hydroxyl substitute；

Y is-NY1Y2 or-NH-NY3Y4；

Y1 is H or C1-6 alkyl；

Y2 is selected from hydroxyl normal propyl alcohol base, hydroxycyclopent base, cyclopropyl, methylpyrazole base, isopropyl, trifluoroethyl, methoxyl group second Base, THP trtrahydropyranyl, methyl, tetrahydrofuran base, cyclobutyl, amino, Cvclopropvlmethvl, hydroxyl dimethyl ethyl, methylol fourth Base and ethyl；

Or Y1 and Y2 forms dioxide thio-morpholinyl, morpholinyl, azetidin together with the nitrogen-atoms that they are connected Base, pyrrolidinyl or piperidyl；

Y3 and Y4 are selected from independently of each other：Hydrogen, or heterocyclic radical is formed together with the nitrogen-atoms that they are connected, selected from morpholinyl, Pyrrolidinyl, piperidyl and dioxothiomorpholinyl.

8. compound as claimed in claim 7, it is characterised in that R4 is the methyl that methyl or hydroxyl substitute.

9. compound as claimed in claim 2, it has below general formula II:

R4 is the C1-C4 alkyl that C1-C4 alkyl or hydroxyl substitute；

Y is NY1Y2 or NH-NY3Y4；

Y1 is H or C1-6 alkyl；

Y2 is selected from 1- hydroxyl normal propyl alcohol -2- bases, 2- hydroxycyclopent bases, cyclopropyl, 1- methyl isophthalic acid H- pyrazoles -4- bases, isopropyl, and 2, 2,2- trifluoroethyls, 2- methoxy ethyls, tetrahydrochysene -2H- pyrans -4- bases, methyl, tetrahydrofuran -3- bases, cyclobutyl, amino, ring Hydroxypropyl methyl, 2- hydroxyl -1,1- dimethyl-ethyIs, 1- methylol-butyls and ethyl；

Or Y1 and Y2 forms 1,1- Dioxo-thiomorpholin -4- bases together with the nitrogen-atoms that they are connected, morpholine -4- bases, Azetidine -1- bases, pyrrolidin-1-yl or piperidin-1-yl；

Y3 and Y4 are selected from independently of each other：Hydrogen, or heterocyclic radical is formed together with the nitrogen-atoms that they are connected, selected from morpholine -4- Base, pyrrolidin-1-yl, piperidin-1-yl and 1,1- Dioxo-thiomorpholin -4- bases.

10. compound as claimed in claim 9, it is characterised in that R4 is the methyl that methyl or hydroxyl substitute.

11. the compound as any one of claim 7 to 10, it is characterised in that Y1 is H or methyl.

12. the compound any one of claim 1-11, its independently selected from:

13. the compound any one of claim 1-11, its independently selected from:

14. a kind of composition, it, which includes compound as any one of claim 1-13 or its, can pharmaceutically receive Salt.

15. the composition as described in compound or claim 14 any one of claim 1-13 is in medicine is prepared Purposes.

A kind of 16. method for treating or preventing disease, it is characterised in that to patient using effective dose such as claim 1-13 Any one of compound or claim 14 described in composition.

17. the compound or composition as claimed in claim 14 as any one of claim 1-13 are preparing treatment Or prevention and α 5-GABA_APurposes in the medicine of receptor related disease.

18. one kind treats or prevents and α 5-GABA_AThe method of receptor related disease, it is characterised in that apply effective agent to patient The compound as any one of claim 1-13 of amount or composition as claimed in claim 14.

19. compound as any one of claim 1-13 or as the composition that claim 14 is stated prepare treatment or Prevent the purposes in the medicine of following disease：Pain, Alzheimer's, multi-infarct dementia and apoplexy.

A kind of 20. method for treating or preventing pain, Alzheimer's, multi-infarct dementia and apoplexy, it is characterised in that To patient apply effective dose compound as any one of claim 1-13 or as claimed in claim 14 group Compound.

21. purposes as claimed in claim 19, it is characterised in that described pain is neurogenic pain, inflammatory pain And carcinomas pain.

22. method as claimed in claim 20, it is characterised in that described pain is neurogenic pain, inflammatory pain And carcinomas pain.

23. purposes as claimed in claim 19, it is characterised in that described pain is selected from：Headache, face pain, cervicodynia, shoulder Bitterly, backache, pectoralgia, stomachache, back pain, pain in the back, melosalgia, muscle and skeleton pain, vascular pain, gout, arthritis ache, Visceral pain, pain caused by infectious diseases (such as AIDS and PHN), more bone pains, Sickle Cell are poor Chronic ache caused by blood, autoimmune disease, the pain of multiple sclerosis or inflammation-related, damage or operation, injury sense It is anti-by property pain, painful diabetic, trigeminal neuralgia, waist or cervical radiculopathies pain, glossopharyngeal neuralgia, autonomic nerve Penetrating property pain, sympathetic reflex dystrophy, nerve root avulsion, cancer, chemical damage, toxin, nutritional deficiency, virus or The relevant pain of bacterium infection, degenerative osteoarthropathy.

24. method as claimed in claim 20, it is characterised in that described pain is selected from：Headache, face pain, cervicodynia, shoulder Bitterly, backache, pectoralgia, stomachache, back pain, pain in the back, melosalgia, muscle and skeleton pain, vascular pain, gout, arthritis ache, Visceral pain, pain caused by infectious diseases (such as AIDS and PHN), more bone pains, Sickle Cell are poor Chronic ache caused by blood, autoimmune disease, the pain of multiple sclerosis or inflammation-related, damage or operation, injury sense It is anti-by property pain, painful diabetic, trigeminal neuralgia, waist or cervical radiculopathies pain, glossopharyngeal neuralgia, autonomic nerve Penetrating property pain, sympathetic reflex dystrophy, nerve root avulsion, cancer, chemical damage, toxin, nutritional deficiency, virus or The relevant pain of bacterium infection, degenerative osteoarthropathy.

25. the preparation method of the compound as any one of claim 1-13, this method is selected from any of following：

A) formula (IV) compound is made

WithReaction obtains formula (1-3) compound, and wherein G and W are selected from Cl, Br, I, OH, OTs, OTf And OMs, R5 are alkyl, methyl, ethyl, the tert-butyl group and benzyl, wherein Z, Y, A is as defined in claim 1；

Then formula (1-3) compound is made

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

B) formula (1-4) compound is made：

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

C) it is formula (1-4) compound by the compound saponification of formula (1-3), is then reacted with Y, wherein, wherein Z, Y, A such as right will Ask defined in 1；Or

D) formulaCompound and formulaThe reaction of compound.